CA1064478A - 7-methoxycephalosporin derivatives - Google Patents
7-methoxycephalosporin derivativesInfo
- Publication number
- CA1064478A CA1064478A CA233,102A CA233102A CA1064478A CA 1064478 A CA1064478 A CA 1064478A CA 233102 A CA233102 A CA 233102A CA 1064478 A CA1064478 A CA 1064478A
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- beta
- methoxy
- alpha
- methyl
- sodium salt
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cephalosporin Compounds (AREA)
Abstract
Abstract of the disclosure A compound of the formula:
Description
~--`
1~64478 This invention relates to novel cephalosporin compounds having novel acyl groups at the 7-position and preparations thereof More particularly, this invention relates to 7-methoxycephalospori~ compounds which have the formula:
NH2 ~S ~ R2 O,CM3 N CH2CO~H j ~S~
N ~ ~3 (I) COOE
wherein ~2 stands for hydrogen or a halogen; ~3 stands for methyl, acetoxymethyl, carbamoyloxymethyl, an alkoxy-methyl, an alkylthiomethyl, 2-carboxy-1-ethenyl or a hetero-cyclic thiomethyl group, or a pharmaceutically acceptable salt thereof and also relates to processes for producing the same.
Hereto~ore, studies on synthestic cephalosporin compounds have been directed to the conversion of 7-amino-cephalospora~ic acid to various acyl derivatives at the 7-position or to derivatives at the 3-acetoxy group in order to synthesize compounds having either a broad antibacterial spectrum or a specific antibacterial spectrum. However, these known cephalosporin derivatives are not yet satis-factory in antimicrobial activities against a wide variety of microorganisms. Hence, a compound has been sought after which has a broad antimicrobial spectrum and is effective even at a lower concentration After a research we discovered that 7-methoxycephalos-porin compounds of the above general formula (I) are not only highly active against a broad spectrum of Gram-positive -:, . , : .
and Gram-negative bacteria but also eminently active against antibiotic resistant strains and even those species of micro-organisms against which the conventional cephalosporin compounds are inactive. The invention is based on the above finding.
Referring, now, to the above formula (I), ~2 means hydrogen or a halogen such as chlorine and bromine, R3 stands for methyl, acetoxymethyl, carbamoyloxymethyl, an alkoxy-methyl such as methoxymethyl, an alkylthiomethyl such as methylthiomethyl, 2-carboxy-1-ethenyl, or a heterocyclic-thiomethyl group. ~he heterocyclic group contains not less than one nitrogen which may be in the oxide form or, in addition to nitrogen or nitrogens, such others as oxygen or/and sulfur. ~he nitrogen-containing heterocyclic group desirably has one to four hetero atoms in its heterocyclic ring and the ring may be 5 or 6 membered one As such heterocyclic group are exemplified pyridyl, N-oxido-pyridyl, pyrimidyl, pyridazinyl, ~-oxido-pyridazinyl, pyrazolyl, diazolyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, lH-tetrazolyl, 2H-tetra-zolyl and so on. And these heterocyclic groups may have such common substituents as lower alkyl groups, e.g. methyl, ethyl, trifluoromethyl, propyl,isopropyl, butyl, and ., -~ isobutyl, lower alkoxy groups, e.g. methoxy, ethoxy, propoxy, isopropoxy, and butoxy, halogens, e.g. chlorine, and bromine, and so on.
1~64478 This invention relates to novel cephalosporin compounds having novel acyl groups at the 7-position and preparations thereof More particularly, this invention relates to 7-methoxycephalospori~ compounds which have the formula:
NH2 ~S ~ R2 O,CM3 N CH2CO~H j ~S~
N ~ ~3 (I) COOE
wherein ~2 stands for hydrogen or a halogen; ~3 stands for methyl, acetoxymethyl, carbamoyloxymethyl, an alkoxy-methyl, an alkylthiomethyl, 2-carboxy-1-ethenyl or a hetero-cyclic thiomethyl group, or a pharmaceutically acceptable salt thereof and also relates to processes for producing the same.
Hereto~ore, studies on synthestic cephalosporin compounds have been directed to the conversion of 7-amino-cephalospora~ic acid to various acyl derivatives at the 7-position or to derivatives at the 3-acetoxy group in order to synthesize compounds having either a broad antibacterial spectrum or a specific antibacterial spectrum. However, these known cephalosporin derivatives are not yet satis-factory in antimicrobial activities against a wide variety of microorganisms. Hence, a compound has been sought after which has a broad antimicrobial spectrum and is effective even at a lower concentration After a research we discovered that 7-methoxycephalos-porin compounds of the above general formula (I) are not only highly active against a broad spectrum of Gram-positive -:, . , : .
and Gram-negative bacteria but also eminently active against antibiotic resistant strains and even those species of micro-organisms against which the conventional cephalosporin compounds are inactive. The invention is based on the above finding.
Referring, now, to the above formula (I), ~2 means hydrogen or a halogen such as chlorine and bromine, R3 stands for methyl, acetoxymethyl, carbamoyloxymethyl, an alkoxy-methyl such as methoxymethyl, an alkylthiomethyl such as methylthiomethyl, 2-carboxy-1-ethenyl, or a heterocyclic-thiomethyl group. ~he heterocyclic group contains not less than one nitrogen which may be in the oxide form or, in addition to nitrogen or nitrogens, such others as oxygen or/and sulfur. ~he nitrogen-containing heterocyclic group desirably has one to four hetero atoms in its heterocyclic ring and the ring may be 5 or 6 membered one As such heterocyclic group are exemplified pyridyl, N-oxido-pyridyl, pyrimidyl, pyridazinyl, ~-oxido-pyridazinyl, pyrazolyl, diazolyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, lH-tetrazolyl, 2H-tetra-zolyl and so on. And these heterocyclic groups may have such common substituents as lower alkyl groups, e.g. methyl, ethyl, trifluoromethyl, propyl,isopropyl, butyl, and ., -~ isobutyl, lower alkoxy groups, e.g. methoxy, ethoxy, propoxy, isopropoxy, and butoxy, halogens, e.g. chlorine, and bromine, and so on.
- 2 -., .. : : . ::: .
:' . , ~ . ~ :' ' ' ', .
-The 7-methoxycephalosporin compounds (I) may be used with the 4-carboxyl function being left free or, if desired, may be put to use as salts, for example the salts of non-toxic cations, e.g sodium, potassium etc ; basic amino acids~ e.g. arginine, ornithine, lysine, and histidine,;
polyhydroxyalkylamine; e g N-methylglucamine, diethanol-amine, triethanolamine, tris-hydroxymethylaminomethane and so on '~he aforesaid compounds may each be used also with its 4-carboxyl group transformed into an ester, for example as a biologically active ester derivative which, for instance, is conducive to an increased blood level and a prolonged action As the ester residues beneficial to this goal, there may be mentioned a-alkoxy-a-substituted methyl groups, e g alkoxylmethyl groups, a-alkoxyethyl ~roups such as methoxymethyl, ethoxymethyl, isopropoxymethyl, a-methoxyethyl, a-ethoxyethyl, etc ; alkylthiomethyl groups such as methylthiomethyl, ethylthiomethyl,isopropylthio-methyl, etc ; acyloxymethyl groups or a-acyloxy-a-substi-tuted methyl groups such as pivaloyloxymethyl, a-acetoxy-butyl, etc ~ he contemplated compound of this in~ention may take two tautomeric forms as shown below by way of formulas but, in this specification, the compound is shown in the thiazole form, i.e. formula (I), NH2 ~ S ~ R2 O,CH3 ~, ~ OCH3 N CH2CONH ~ ~ ~3 = HN CH2CO~H ~ ~ 3 (I) COOH (I COOH
,','.
. ~ .
:' . , ~ . ~ :' ' ' ', .
-The 7-methoxycephalosporin compounds (I) may be used with the 4-carboxyl function being left free or, if desired, may be put to use as salts, for example the salts of non-toxic cations, e.g sodium, potassium etc ; basic amino acids~ e.g. arginine, ornithine, lysine, and histidine,;
polyhydroxyalkylamine; e g N-methylglucamine, diethanol-amine, triethanolamine, tris-hydroxymethylaminomethane and so on '~he aforesaid compounds may each be used also with its 4-carboxyl group transformed into an ester, for example as a biologically active ester derivative which, for instance, is conducive to an increased blood level and a prolonged action As the ester residues beneficial to this goal, there may be mentioned a-alkoxy-a-substituted methyl groups, e g alkoxylmethyl groups, a-alkoxyethyl ~roups such as methoxymethyl, ethoxymethyl, isopropoxymethyl, a-methoxyethyl, a-ethoxyethyl, etc ; alkylthiomethyl groups such as methylthiomethyl, ethylthiomethyl,isopropylthio-methyl, etc ; acyloxymethyl groups or a-acyloxy-a-substi-tuted methyl groups such as pivaloyloxymethyl, a-acetoxy-butyl, etc ~ he contemplated compound of this in~ention may take two tautomeric forms as shown below by way of formulas but, in this specification, the compound is shown in the thiazole form, i.e. formula (I), NH2 ~ S ~ R2 O,CH3 ~, ~ OCH3 N CH2CONH ~ ~ ~3 = HN CH2CO~H ~ ~ 3 (I) COOH (I COOH
,','.
. ~ .
- 3 -- .
~ . : '.: ' ' ' ' . ' .' ' :
, ~064478 The 7-methoxycephalosporin compounds (I) of this invention each have a broad antimicrobial spectrum, i.e.
activity against Gram-negative and Gram-positive bacteria, and particularly display greater activity than the known cephalosporins against antibiotic resistant strains of such Gram-negative bacteria as ~scherichia coli, Serratia marcesens, Proteus vulgaris, Pseudomonas aeruginosa and so on. ~here-fore, these compounds are of use in the treatment of infec-tions with the aforementioned bacteria in man and animals, giving excellent therapeutic effects, Like the known cephalos-porin dru~s, the contemplated compounds (I) of this invention may each be administered to patients in such dosage forms as in~ections, capsules, tablets, granules, etc. and, if necessary, together with a physiologically acceptable vehicle or excipient, as solutions, suspensions, solid preparations and so on.
;- Specifically, sodium 7~-methoxy-7~-(2-aminothiazol-4-ylacetamido)-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate, for instance, is administered intra-muscularly at a daily dose level of about 5 to 20 milli-grams per kilogram body weight in three to five divided doses daily and this therapy is particularly effective in the treatment of respiratory and urinary tract infections.
~ he 7-methoxycephalosporin compounds (I) can be pre-pared by means of a method known for the production of analogous compounds thereof. For example, by reacting a 7-methoxycephalosporin compound of the formula:
.
.- . - .
' ::, ., ~ . : . , ~
.
: . . . . . . . .
2 ,~ (]I) . COOH
wherein the symbol has the meaning defined hereinbefore, with a reactive derivative of an aminothiazolylacetic acid derivative of the formula:
~1 ~ S ~2 N ~ CH2COOH (IIIj wherein Rl stands for a protected amino grouP; R2 has the meaning defined hereinbefore, followed, if necessary, by removal of the protective group. ~he starting compound (II) for this reaction is put to use with its 4-carboxyl group being in the form of an alkali metal or organic amine salt, e g. the sodium, potassium, triethylamine or other salt, or in the fo~m of an ester which may be converted to a free carboxyl group under mild conditions, e g. by the action of a¢id or alkali or by reduction. The ester may be exemplified by, for example, ~-methylsulfonylethyl, trimethyl-silyl, dimethylsilenyl, benzhydryl, ~ -trichloroethyl, phenacyl, p-methoxybenzyl, p-nitrobenzyl or methoxymethyl.
xl in the mating material (III) means an amino group protected by an easily-removable amino-protective group which is used in general peptide chemistry, e.g. t-butoxy-. ~:;... . .
carbonyl, p-nitrobenzyloxycarbonyl~ -trichloroethoxy-.:
; carbonyl, benzyloxycarbonyl, isobornyloxycarbonyl, etc. or b~ proton The halogen atom, R2, is normally chlorine or bromine, for instance. The reactive derivative of starting compound (III) may for example be the acid halide, acid - 5 ~
,,: ' . ' ' ~
.
' . ..
-anhydride, mixed acid anhydride, active amide or active ester, Normally this reaction can be conducted smoothly and with advantage in a solvent. ~he solvent is one which does not interfere with the reaction, e.g. acetone, tetra-hydrofuran, dioxane, acetonitrile, chloroform, dichloro-methane, dichloroethylene, pyridine, dimethylaniline, dimethylformamide, dimethylacetamide, dimethylsulfoxide or a mixture of such solvents. While there is no special limitation on the reaction temperature, the reaction is normally carried out under cooling or at room temperature.
If necessary, the protective group is removed from the resultant 7-methoxycephalosporin derivative to produce a 7-methoxycephalosporin derivative of general formula (I).
As to the removal of protective groups, t-butoxycarbonyl is removed by acid; ~ -trichloroethoxycarbonyl by reduction using zinc and acid; p-nitrobenzyloxycarbonyl by catalytic reduction; for instance. As to the removal of the ester residue from the 4-carboxyl group, benzhydryl, p~methoxy-benzyl, etc. are removed by acid; ~-methylsulfonylethyl by alkalii trimethylsilyl, dimethylsilenyl, etc. by water alone; ~ trichloroethyl by reduction using zinc and acid; p-nitrobenzyl, etc. by reduction; for instance. The removal of these protective groups may be carried out simul-taneously or, alternatively, one after another, which protec-tive group should be first removed being determined in con-sideration of the types of protective groups, the subsequent reaction and other factors.
The 7-methoxycephalosporin compounds (I) wherein R2 .
. - . . -' .
stands for hydrogen can be also prepared by reacting a compound of the for~ula:
OCH
hal CH2COCH2CONH ~ ` (IV) COOH
wherein hal stands for a halogen and R3 has the meanings defined hereinbefore, with thiourea. The starting material compound (IV) can be obtained by the reaction of a 7-aminocephalosporin compound (II) with the 4-halogeno-3-oxo-butyryl halide which is obtainable bythe reaction of dike-tene with a halogen such as chlorine or bromine (~ournal of the Chemical ~ociety 97, 1987(1910)~.
The 7-methoxycephalosporin compounds of formula (V) can be produced by reacting the above compound (IV) with ~hiourea. This reaction proceeds smoothly in a solvent, e.g.
any of the common solvents which do not interfere with the contemplated reaction, e g. water, methanol, ethanol, acetone, dioxane, acetonitrile, chloroform, ethylene chloride, tetra-,!, .
hydrofuran, eth~l acetate, dimethylformamide, dimethyl-acetamide or the like or a mixture of such solvents. While the addition of an acid acceptor is not essential, there are cases in which the reaction proceeds more smoothly in the presence of an acid acceptor, provided that the addition of the particular acceptor does not modify the cephalosporin ,, ~
nucleus. As the acceptor for this purpose, there may be mentioned inorganic and organic bases such as alkali metal hydroxides, alkali metal hydrogen carbonates, triethylamine, pyridine, N,N-dimethylaniline and 50 on. ~he starting ' ~064478 compound (IV) is subaected to the reaction in the form of free acid, an alkali metal salt, e g. sodium or potassium salt, or an ester such as those mentioned hereinbefore in - connection with the 4-carboxyl group ~ormally the reaction proceeds adequately at room temperature, although it may be ;: conducted under heating or cooling as required The compounds (I) may be prepared by reacting a 7-methoxycephalosporin compound of the formula:
R4 y ~ R2 , 3 N CH2CONH~ f ~
N ~ CH2X ~VI) COO~
wherein X stands for an acetoxy or carbamoyloxy group; R4 stands for an amino group which may be protected; the other symbols have the meanings defined hereinbefore with a mercapto compound, followed, if necessary, by removal of the protec-tive group The compounds (VI) is normally used in the form . of the sodium, potassium or other salt at the 4-carbox~l function The mercapto compound means, for example, any of : such alkylmercaptans as methylmercaptan, ethylmercaptan, butylmercaptan, etc or a heterocyclic compound containing ; a mercapto group. The term, heterocyclic compound, as used herein means a 5-membered or 6-membered cyclic compound containing, in addition to carbon, one or several hetero-atoms such as ~, O or/and S, and when ~ is involved, the ~-oxides are also included. Thus, for example, imidazole, methylimidazole, pyrazole, triazole, methyltriazole, tetra-zole, methyltetrazole, oxazole, isoxazole, thiazole, .:
. . .
.
..
isothiazole, oxadiazole, thiadiazole, methylthiadiazole, pyridine-N-oxide, pyridazine-N-oxide, etc. fall within this category. Such a mercapto compound, though it may be used in its free form, is employed with advantage as an alkali metal salt, e.g sodium or potassium salt. This reaction is preferably conducted in a solvent. For this purpose, use is made, for example, of water, heavy water or an organic solvent which is easily miscible with water and does not react with the material compounds, e.g. dimethyl-formamide, dimethylacetamide, dioxane, acetone, alcohol, acetonitrile, dimethylsulfoxide, tetrahydrofuran or the like. ~he reaction temperature and time depend upon the ;
particular materials and solvent employed, among other factors but, generally,may be selected from the range of 0C
to 100C and the range of a few hours to several days, res-pectively. ~he reaction is preferably carried out in the ~i~ neighborhood of neutrality, i.e. at pH 2 to 8 and, for -.; . ~.
still better results, at pH 5 to 8. This reaction may at times be caused to proceed more smoothly by adding a quaternary ammonium salt having surface activity, e.g.
~rimethylbenzylammonium bromide, triethylbenzylammonium bromide, triethylbenzylammonium hydroxide or the like, to the reaction system. More satisfactory results may be achieved by conducting the reaction in an inert gaseous atmosphere, e.g. nitrogen gas, so as to prevent atmospheric oxidation of the mercapto compound.
~he 7-methoxycephalosporin compounds (I) may be , .
prepared also by reacting a 7-methoxycephalosporin compound .:~
~ _ 9 _ ....
, .
.
, ,j.......... . . . . .
: 106447~3 of the formula:
OCH
; ~/CH(cH2)3coNH ~ R3 (VIII) CCH2CC~3 COOH
,; .
; wherein the symbol has the meaning defined hereinbefore, with a reactive derivative of an aminothiazolylacetic acid derivative of the formula (III) in the presence of a silylat-~- ing agent and, then, subjecting the reaction product to a reaction leading to removal of the protected aminoadipoyl :
group. The 4-carboxyl group of starting material compound .
(VIII) may be free or have been esterified as in the afore-mentioned case of compound (II) insofar as the particular ester is not detrimental to the contemplated reaction.
This reaction comprises reacting a compound (VIII) with a ~ reactive derivative of a compound (III) in a suitable -i~ solvent~and in the presence of a silylating agent such as a tri-substituted silyl derivative of a electro-negatively substituted amide. The reaction can be smoothly conducted at a temperature of -20C to 50C, normally in the range of 15C to 45C. ~he solvent may for example be chloroform, . . ~
~ dichloromethane, acetonitrile or dioxane.
.~, .
P ~he aforementioned negatively substituted tri-substi-tuted silyl derivative is a compound *hich is synthesized by reacting a electro negatively substituted amide or imide with a tri-substituted silyl halide. As said amide or ` imide, there may be mentioned succinimide, phthalimide, cyanoacetamide, trifluoroacetamide, trichloroacetamide and , .~ .
, .
... .
.
, . . . ' ' , ': . ';;. , . ' .. ' ' ' ''. .. ;,, : . . ' `\
so on, Particularly useful for the contemplated reaction are N-trimethylsilyltrifluoroacetamide and N-trimethylsllyl- ' phthalimide. ~he resultant reaction product, as it OCCUr5 in the reaction mixture or after a suitable treatment such as concentration or isolation, is subaected to a reaction leading to removal of the protected aminoadipoyl group.
~his reaction is normally conducted under conditions similar ' ... .
to those used for removal of ~ -trichloroethoxycarbonyl.
' Thus, for example, it comprises the reaction with zinc and ;' aqueous acetic acid or aqueous formic acid, The reaction can normally be accomplished satisfactorily at room tempera-' ture, the range of 10 to 40C being useful.
~he 7--methoxyoephalosporin compounds (I) as obtained ` by the processes thus far described in detail can be purified by E~ se conventional procedures, e g. column chromatography, extraction, precipitation, recrystallization and so on.
The am~Noth~azolylaGe*ic acid derivatives (III) can ';Y be prepared by, for example, reacting a chloroformic acid 2- -~ halogénoethyl ester with thiocyanate to obtain a 2-halogeno-:, .
~ ethoxycarbonyl isothiocyanate, reacting thus obtained compound .-with ammonia to obtain an ~-(2-halogenoethoxycarbonyl)thiourea, - reacting the compo.und with an ~-halogenoacetoacetic acid alkyl .. .. .
'~ ester~to gïve a 2-(2'-halogenoethoxycarbonylamino)thiazol-4-~ ~lacetic acid alkyl ester and hydrolyzing the alkyl ester ~( . .
to obtain a 2-(2'-halogenoethoxycarbonylamino)th~zol=4-ylacetic acid. Alternatively, the 2-(2'-halogenoethoxy-carbonylamino)th'iazol-4-ylacet d acid may be prepared by '~ reacting an 2-aminothiazol-4-ylacetic acid alkyl ester with . : , .
.
:.k.~, ' -- 11 --' ~ '' ' ' '' " ''' ' ' .
~o644q8 a chloroformic acid 2-halogenoethyl ester and hydrolyzing thus obtained 2-(2'-halogenoethoxycarbonylamino)th~azol-; 4-ylacetic acid alkyl ester.
Ifhe following description pertains, in the first place, to the process comprising reacting an ~-(2-halogeno-ethoxycarbonyl)thiourea with aff~-haloacetoacetic acid alkyl ester One of the reactants, an ~-(2-halogenoethoxy-carbonyl)thiourea, is prepared by reacting a chloroformic acid 2-halogenoethyl ester with thiocyanate and adding ~ ammonia to the resultant 2-halogenoethoxycarbonyl isothio-- cyanate. This compound is a novel compound which has never been described in the literature. The halogen, substituting the 2-position of the ethyl group of said chloroformic acid ethyl ester, may for example be chlorine, bromine or/and fluorine, and one to three such halogen atoms may be present as substituents. Thus, trichloro-, dibromo and other com-pounds are commonly employed. Thiocyanic acid, for the ~ purposes of this reaction, may be used in its free form, ."..
although normally it is more conveniently reacted as one of the salts of alkali metals, e,g~ sodium, potassium, etc., ,. .
the salts of heavy metals, e.g. copper, lead, etc., the ammonium salt and so on. This reaction proceeds smoothly in a solvent. The solvent to be normally employed is pre-ferably a nonprotonating solvent, such as, acetone, ~ethyl ethyl ketone, tetrahydrofuran, dioxane, acetonitrile, ether, ~ benzene or toluene. Advantageously the reaction is conducted ,~ at a low temperature so as to avoid undesirable side reac-tions. Normally the reaction can be conducted smoothly , : ' ~'..' , -::
within the range of 5C to -20C.
The 2-halogenoethoxycarbonyl isothiocyanate thus ,;, .
obtained is so reactive that it is normally not isolated but the reaction mixture as such is subjected to the next treatment, i.e. reaction with ammonia, to produce an ~-(2-halogenoethoxycarbonyl)thiourea. This ammonia-addition reaction may be carried out by introducing ammonia into the reaction mixture obtained in the aforementioned production stage for 2-halogenoethoxycarbonyl isothiocyanate, but normally the metal halide or ammonium halide by-produced from a chloroformic acid 2-halogenoethyl ester and a thiocyanate salt is first separated by filtration and, then, ammonia is introduced into the filtrate. The ammonia may be added in gaseous state, or a solution of ammonia in a suitable :. .
solvent, e.g. methanol or ethanol, may be introduced. The reaction is preferably carried out at a low temperature, normally within the range of 5C to -10C
The reaction of an ~-haloacetoacetic acid compound with an N-(2-trichloroethoxycarbonyl)thiourea to produce a 2-(2'-trichloroethoxycarbonylamino)thiazol-4-ylacetic acid is normally conducted with advantage in a solvent and in the presence of a base. ~he solvent just mentioned may be any solvent that is able to dissolve the two starting materials and, at the same time, will not interfere with the contemplated reaction. Thus, use may be made of alcohols such as methanol, ethanol, propanol, etc.; ketones such as acetone, me~hYl ethyl ketone, etc.; ethers, such as ether, tetrahydrofuran, dioxane, etc. and their mixtures, to name , '~
' .
.
., , ~ ~ :
but a few. ~hls reaction proceeds smoothly in the presence of a base. As the base, there may be mentioned organic tertiary bases such as pyridine, picoline, quinoline, isoquinoline, triethylamine, tributylamine, ~-methyl-piperidine, N-methylmorpholine, N,N-dimethylaniline, N,~-diethylaniline and so on, The reaction proceeds at room temperature but, there are cases where the reaction is hastened by heating. The heating temperature in the neighbor-hood of the boiling point of the solvent employed is normally advantageous, As to the mating starting material, i~e. an ~-haloacetoacetic acid alkyl ester, there may be employed methyl ~-chloroacetoacetate, ethyl ~-chloroacetoacetate, .~ ,~. .
methyl ~-bromoacetoacetate, ethyl ~rbromoacetoacetate and other ; ~ -halogenoacetoacetic acid alkyl esters.
The following description pertains to the process which comprises reacting an 2-aminothiazol-4-ylacetic acid alkyl ester with 2-trichloroethyl chloroformate to produce a 2-(2'-halogenoethoxycarbonylamino)thiazol-4-ylacetic acid alkyl ester. This reaction is normally conducted smoothly in a solvent and in the presence of a base. The solvent may be any solvent that will not interfere with . ~ .
the contemplated reaction. Normally,use is made of a non-protonating organic solvent such as, chloroform, dichloro-; .:
methane, dichloroethylene, carbon tetrachloride, chloro-benzene, ether, tetrahydrofuran, dioxane, acetone or methyl ,, ~ ethyl ketone, or a mixture of such solvents. The base may !~
~ be any base that is able to accept or combine with the ~ .
~ hydrogen halide by-produced in the course of the reaction ~, .
.
~ - 14 -:` ~
:
~ ~064478 i. ~, . .
and that does not interfere with the reaction, ~hus, normally, organic tertiary bases such as pyridine, picoline, quinoline, isoquinoline, triethylamine, tributylamine, N-methylpiperidine, ~-methylmorpholine, N,N-dimethylaniline or ~,N-diethylaniline, may be employed. While the reaction proceeds smoothly at room temperature, the reaction system .
- ~ may be cooled or heated as occation requires.
The 2-(2'-halo~enoethoxycarbonylamino)thiazol-4-ylacetic acid ester thus obtained is partially hydrolyzed to a 2-(2'-halogenoethoxycarbonylamino)thiazol-4-ylacetic acld~ This hydrolysis reaction is carried out in a solvent and in the presence of a base. The solvent is preferably one that is able to dissolve both the starting material ester and the base. Thus, normally, a mixture of water and an organic solvent miscible with water, such as methanol, ethanol, acetone or tbe like, is employed. As the base, use is~normally;made of an inorganic strong base such as, sodium:hydroxide, potassium hydroxide or barium hydroxide.
his reaction is~conducted with advantage at a temperature `near ro~om~temperature~so as to~avoid occurence of undesirable side reactions.~
,.Z~
he;present inv~ention is illustrated in further detail ~s~ below with reference~to examples, but it is to be under-stood that the examples are solely for the purpose of ;illustratlon and not to be construed as limitations of the ,. . ~
invention, and that many variations may be resorted to wlthout departlng from the spirlt and scope of the inven-p~ tion. In this specification, "g.", "mg.", "m~", "cm.", ; ~ - 15 -- :. . -~.. - . .. , ~ . . . .. -.. . . . . .
~ . : . , ~ . . . :
:~.. : , - . ... .
' : . ' ' . ' , ! , . . . .
-"ppm", and "Mc" are abbreviations of "gram", "milligram", "millili~er"9 "cen~im~ter"9 "part pe~ million"9 and "megacycle", repsectively. Resins named "Amberlite"
are products manufactured by Rohm & Haas Co, in U.S.A.
All the temperatures are uncorrected and the percentages are all on the weight basis except specifically defined.
~I) Preparation of 2-(2',2',2'-trichloroethoxycarbonyl-amino)thiazol-4-ylacetic acid (1) In 250 ml of acetone was dissolved 25.2 g. of potassium thiocyanate and while the solution was cooled at -20C, 50 g.
of 2,2,2-trichloroethyl chloroformate was added dropwise.
;~ 1; `
After the dropwise addition had been completed, the mixture was stirred at that temperature for 30 minutes. ~he preci-pitated potassium chloride was filtered off. ~o the filt-rate was added 26 g. of 17 % methanolic ammonia at -10C.
he mixture was stirred for 45 minutes, after which the .,1.~, ;: . : -solvent was distilled off. ~he syrupy residue was recrystal-lized from aqueous methanol to obtain 21.8 g. of N-(2,2,2-trichloroethoxycarbonyl)thiourea as colorless prisms melting at 189-190-C.
Elemental analysis, for C4H5C~3N202S:
Calculated C, 19.10; H, 2.00; N, 11.14 Found C, 19.22; H, 1.96; N, 11.50 (2) In 3 m~ of ethanol was dissolved 500 mg. N-(2,2,2-trichloroethoxycarbonyl)thiourea, 416 mg. ethylo~-bromo-. : .
acetoacetate and 363 mg. N,~-dimethylaniline and the solu-tion was stirred at room temperature for 24 hours. After the solvent was distilled off under reduced pressure, the ', .. . . . ... . . .
.. .. . .: , .
;
: 1064478 residue was dissolved in chloroform and washed once with 10 % hydrochloric acid and, then, three times with a saturated aqueous solution of sodium chloride. After drying over magnesium sulfate, the chloroform layer was concentrated and the oily residue was passed through a column of silica gel a~d eluted with a 1:1 mixture of benzene and chloroform The above isolation-purification procedure provided 540 mg.
of ethyl 2-(2',2',2'-trichloroethoxycarbonylamino)thiazol-
~ . : '.: ' ' ' ' . ' .' ' :
, ~064478 The 7-methoxycephalosporin compounds (I) of this invention each have a broad antimicrobial spectrum, i.e.
activity against Gram-negative and Gram-positive bacteria, and particularly display greater activity than the known cephalosporins against antibiotic resistant strains of such Gram-negative bacteria as ~scherichia coli, Serratia marcesens, Proteus vulgaris, Pseudomonas aeruginosa and so on. ~here-fore, these compounds are of use in the treatment of infec-tions with the aforementioned bacteria in man and animals, giving excellent therapeutic effects, Like the known cephalos-porin dru~s, the contemplated compounds (I) of this invention may each be administered to patients in such dosage forms as in~ections, capsules, tablets, granules, etc. and, if necessary, together with a physiologically acceptable vehicle or excipient, as solutions, suspensions, solid preparations and so on.
;- Specifically, sodium 7~-methoxy-7~-(2-aminothiazol-4-ylacetamido)-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate, for instance, is administered intra-muscularly at a daily dose level of about 5 to 20 milli-grams per kilogram body weight in three to five divided doses daily and this therapy is particularly effective in the treatment of respiratory and urinary tract infections.
~ he 7-methoxycephalosporin compounds (I) can be pre-pared by means of a method known for the production of analogous compounds thereof. For example, by reacting a 7-methoxycephalosporin compound of the formula:
.
.- . - .
' ::, ., ~ . : . , ~
.
: . . . . . . . .
2 ,~ (]I) . COOH
wherein the symbol has the meaning defined hereinbefore, with a reactive derivative of an aminothiazolylacetic acid derivative of the formula:
~1 ~ S ~2 N ~ CH2COOH (IIIj wherein Rl stands for a protected amino grouP; R2 has the meaning defined hereinbefore, followed, if necessary, by removal of the protective group. ~he starting compound (II) for this reaction is put to use with its 4-carboxyl group being in the form of an alkali metal or organic amine salt, e g. the sodium, potassium, triethylamine or other salt, or in the fo~m of an ester which may be converted to a free carboxyl group under mild conditions, e g. by the action of a¢id or alkali or by reduction. The ester may be exemplified by, for example, ~-methylsulfonylethyl, trimethyl-silyl, dimethylsilenyl, benzhydryl, ~ -trichloroethyl, phenacyl, p-methoxybenzyl, p-nitrobenzyl or methoxymethyl.
xl in the mating material (III) means an amino group protected by an easily-removable amino-protective group which is used in general peptide chemistry, e.g. t-butoxy-. ~:;... . .
carbonyl, p-nitrobenzyloxycarbonyl~ -trichloroethoxy-.:
; carbonyl, benzyloxycarbonyl, isobornyloxycarbonyl, etc. or b~ proton The halogen atom, R2, is normally chlorine or bromine, for instance. The reactive derivative of starting compound (III) may for example be the acid halide, acid - 5 ~
,,: ' . ' ' ~
.
' . ..
-anhydride, mixed acid anhydride, active amide or active ester, Normally this reaction can be conducted smoothly and with advantage in a solvent. ~he solvent is one which does not interfere with the reaction, e.g. acetone, tetra-hydrofuran, dioxane, acetonitrile, chloroform, dichloro-methane, dichloroethylene, pyridine, dimethylaniline, dimethylformamide, dimethylacetamide, dimethylsulfoxide or a mixture of such solvents. While there is no special limitation on the reaction temperature, the reaction is normally carried out under cooling or at room temperature.
If necessary, the protective group is removed from the resultant 7-methoxycephalosporin derivative to produce a 7-methoxycephalosporin derivative of general formula (I).
As to the removal of protective groups, t-butoxycarbonyl is removed by acid; ~ -trichloroethoxycarbonyl by reduction using zinc and acid; p-nitrobenzyloxycarbonyl by catalytic reduction; for instance. As to the removal of the ester residue from the 4-carboxyl group, benzhydryl, p~methoxy-benzyl, etc. are removed by acid; ~-methylsulfonylethyl by alkalii trimethylsilyl, dimethylsilenyl, etc. by water alone; ~ trichloroethyl by reduction using zinc and acid; p-nitrobenzyl, etc. by reduction; for instance. The removal of these protective groups may be carried out simul-taneously or, alternatively, one after another, which protec-tive group should be first removed being determined in con-sideration of the types of protective groups, the subsequent reaction and other factors.
The 7-methoxycephalosporin compounds (I) wherein R2 .
. - . . -' .
stands for hydrogen can be also prepared by reacting a compound of the for~ula:
OCH
hal CH2COCH2CONH ~ ` (IV) COOH
wherein hal stands for a halogen and R3 has the meanings defined hereinbefore, with thiourea. The starting material compound (IV) can be obtained by the reaction of a 7-aminocephalosporin compound (II) with the 4-halogeno-3-oxo-butyryl halide which is obtainable bythe reaction of dike-tene with a halogen such as chlorine or bromine (~ournal of the Chemical ~ociety 97, 1987(1910)~.
The 7-methoxycephalosporin compounds of formula (V) can be produced by reacting the above compound (IV) with ~hiourea. This reaction proceeds smoothly in a solvent, e.g.
any of the common solvents which do not interfere with the contemplated reaction, e g. water, methanol, ethanol, acetone, dioxane, acetonitrile, chloroform, ethylene chloride, tetra-,!, .
hydrofuran, eth~l acetate, dimethylformamide, dimethyl-acetamide or the like or a mixture of such solvents. While the addition of an acid acceptor is not essential, there are cases in which the reaction proceeds more smoothly in the presence of an acid acceptor, provided that the addition of the particular acceptor does not modify the cephalosporin ,, ~
nucleus. As the acceptor for this purpose, there may be mentioned inorganic and organic bases such as alkali metal hydroxides, alkali metal hydrogen carbonates, triethylamine, pyridine, N,N-dimethylaniline and 50 on. ~he starting ' ~064478 compound (IV) is subaected to the reaction in the form of free acid, an alkali metal salt, e g. sodium or potassium salt, or an ester such as those mentioned hereinbefore in - connection with the 4-carboxyl group ~ormally the reaction proceeds adequately at room temperature, although it may be ;: conducted under heating or cooling as required The compounds (I) may be prepared by reacting a 7-methoxycephalosporin compound of the formula:
R4 y ~ R2 , 3 N CH2CONH~ f ~
N ~ CH2X ~VI) COO~
wherein X stands for an acetoxy or carbamoyloxy group; R4 stands for an amino group which may be protected; the other symbols have the meanings defined hereinbefore with a mercapto compound, followed, if necessary, by removal of the protec-tive group The compounds (VI) is normally used in the form . of the sodium, potassium or other salt at the 4-carbox~l function The mercapto compound means, for example, any of : such alkylmercaptans as methylmercaptan, ethylmercaptan, butylmercaptan, etc or a heterocyclic compound containing ; a mercapto group. The term, heterocyclic compound, as used herein means a 5-membered or 6-membered cyclic compound containing, in addition to carbon, one or several hetero-atoms such as ~, O or/and S, and when ~ is involved, the ~-oxides are also included. Thus, for example, imidazole, methylimidazole, pyrazole, triazole, methyltriazole, tetra-zole, methyltetrazole, oxazole, isoxazole, thiazole, .:
. . .
.
..
isothiazole, oxadiazole, thiadiazole, methylthiadiazole, pyridine-N-oxide, pyridazine-N-oxide, etc. fall within this category. Such a mercapto compound, though it may be used in its free form, is employed with advantage as an alkali metal salt, e.g sodium or potassium salt. This reaction is preferably conducted in a solvent. For this purpose, use is made, for example, of water, heavy water or an organic solvent which is easily miscible with water and does not react with the material compounds, e.g. dimethyl-formamide, dimethylacetamide, dioxane, acetone, alcohol, acetonitrile, dimethylsulfoxide, tetrahydrofuran or the like. ~he reaction temperature and time depend upon the ;
particular materials and solvent employed, among other factors but, generally,may be selected from the range of 0C
to 100C and the range of a few hours to several days, res-pectively. ~he reaction is preferably carried out in the ~i~ neighborhood of neutrality, i.e. at pH 2 to 8 and, for -.; . ~.
still better results, at pH 5 to 8. This reaction may at times be caused to proceed more smoothly by adding a quaternary ammonium salt having surface activity, e.g.
~rimethylbenzylammonium bromide, triethylbenzylammonium bromide, triethylbenzylammonium hydroxide or the like, to the reaction system. More satisfactory results may be achieved by conducting the reaction in an inert gaseous atmosphere, e.g. nitrogen gas, so as to prevent atmospheric oxidation of the mercapto compound.
~he 7-methoxycephalosporin compounds (I) may be , .
prepared also by reacting a 7-methoxycephalosporin compound .:~
~ _ 9 _ ....
, .
.
, ,j.......... . . . . .
: 106447~3 of the formula:
OCH
; ~/CH(cH2)3coNH ~ R3 (VIII) CCH2CC~3 COOH
,; .
; wherein the symbol has the meaning defined hereinbefore, with a reactive derivative of an aminothiazolylacetic acid derivative of the formula (III) in the presence of a silylat-~- ing agent and, then, subjecting the reaction product to a reaction leading to removal of the protected aminoadipoyl :
group. The 4-carboxyl group of starting material compound .
(VIII) may be free or have been esterified as in the afore-mentioned case of compound (II) insofar as the particular ester is not detrimental to the contemplated reaction.
This reaction comprises reacting a compound (VIII) with a ~ reactive derivative of a compound (III) in a suitable -i~ solvent~and in the presence of a silylating agent such as a tri-substituted silyl derivative of a electro-negatively substituted amide. The reaction can be smoothly conducted at a temperature of -20C to 50C, normally in the range of 15C to 45C. ~he solvent may for example be chloroform, . . ~
~ dichloromethane, acetonitrile or dioxane.
.~, .
P ~he aforementioned negatively substituted tri-substi-tuted silyl derivative is a compound *hich is synthesized by reacting a electro negatively substituted amide or imide with a tri-substituted silyl halide. As said amide or ` imide, there may be mentioned succinimide, phthalimide, cyanoacetamide, trifluoroacetamide, trichloroacetamide and , .~ .
, .
... .
.
, . . . ' ' , ': . ';;. , . ' .. ' ' ' ''. .. ;,, : . . ' `\
so on, Particularly useful for the contemplated reaction are N-trimethylsilyltrifluoroacetamide and N-trimethylsllyl- ' phthalimide. ~he resultant reaction product, as it OCCUr5 in the reaction mixture or after a suitable treatment such as concentration or isolation, is subaected to a reaction leading to removal of the protected aminoadipoyl group.
~his reaction is normally conducted under conditions similar ' ... .
to those used for removal of ~ -trichloroethoxycarbonyl.
' Thus, for example, it comprises the reaction with zinc and ;' aqueous acetic acid or aqueous formic acid, The reaction can normally be accomplished satisfactorily at room tempera-' ture, the range of 10 to 40C being useful.
~he 7--methoxyoephalosporin compounds (I) as obtained ` by the processes thus far described in detail can be purified by E~ se conventional procedures, e g. column chromatography, extraction, precipitation, recrystallization and so on.
The am~Noth~azolylaGe*ic acid derivatives (III) can ';Y be prepared by, for example, reacting a chloroformic acid 2- -~ halogénoethyl ester with thiocyanate to obtain a 2-halogeno-:, .
~ ethoxycarbonyl isothiocyanate, reacting thus obtained compound .-with ammonia to obtain an ~-(2-halogenoethoxycarbonyl)thiourea, - reacting the compo.und with an ~-halogenoacetoacetic acid alkyl .. .. .
'~ ester~to gïve a 2-(2'-halogenoethoxycarbonylamino)thiazol-4-~ ~lacetic acid alkyl ester and hydrolyzing the alkyl ester ~( . .
to obtain a 2-(2'-halogenoethoxycarbonylamino)th~zol=4-ylacetic acid. Alternatively, the 2-(2'-halogenoethoxy-carbonylamino)th'iazol-4-ylacet d acid may be prepared by '~ reacting an 2-aminothiazol-4-ylacetic acid alkyl ester with . : , .
.
:.k.~, ' -- 11 --' ~ '' ' ' '' " ''' ' ' .
~o644q8 a chloroformic acid 2-halogenoethyl ester and hydrolyzing thus obtained 2-(2'-halogenoethoxycarbonylamino)th~azol-; 4-ylacetic acid alkyl ester.
Ifhe following description pertains, in the first place, to the process comprising reacting an ~-(2-halogeno-ethoxycarbonyl)thiourea with aff~-haloacetoacetic acid alkyl ester One of the reactants, an ~-(2-halogenoethoxy-carbonyl)thiourea, is prepared by reacting a chloroformic acid 2-halogenoethyl ester with thiocyanate and adding ~ ammonia to the resultant 2-halogenoethoxycarbonyl isothio-- cyanate. This compound is a novel compound which has never been described in the literature. The halogen, substituting the 2-position of the ethyl group of said chloroformic acid ethyl ester, may for example be chlorine, bromine or/and fluorine, and one to three such halogen atoms may be present as substituents. Thus, trichloro-, dibromo and other com-pounds are commonly employed. Thiocyanic acid, for the ~ purposes of this reaction, may be used in its free form, ."..
although normally it is more conveniently reacted as one of the salts of alkali metals, e,g~ sodium, potassium, etc., ,. .
the salts of heavy metals, e.g. copper, lead, etc., the ammonium salt and so on. This reaction proceeds smoothly in a solvent. The solvent to be normally employed is pre-ferably a nonprotonating solvent, such as, acetone, ~ethyl ethyl ketone, tetrahydrofuran, dioxane, acetonitrile, ether, ~ benzene or toluene. Advantageously the reaction is conducted ,~ at a low temperature so as to avoid undesirable side reac-tions. Normally the reaction can be conducted smoothly , : ' ~'..' , -::
within the range of 5C to -20C.
The 2-halogenoethoxycarbonyl isothiocyanate thus ,;, .
obtained is so reactive that it is normally not isolated but the reaction mixture as such is subjected to the next treatment, i.e. reaction with ammonia, to produce an ~-(2-halogenoethoxycarbonyl)thiourea. This ammonia-addition reaction may be carried out by introducing ammonia into the reaction mixture obtained in the aforementioned production stage for 2-halogenoethoxycarbonyl isothiocyanate, but normally the metal halide or ammonium halide by-produced from a chloroformic acid 2-halogenoethyl ester and a thiocyanate salt is first separated by filtration and, then, ammonia is introduced into the filtrate. The ammonia may be added in gaseous state, or a solution of ammonia in a suitable :. .
solvent, e.g. methanol or ethanol, may be introduced. The reaction is preferably carried out at a low temperature, normally within the range of 5C to -10C
The reaction of an ~-haloacetoacetic acid compound with an N-(2-trichloroethoxycarbonyl)thiourea to produce a 2-(2'-trichloroethoxycarbonylamino)thiazol-4-ylacetic acid is normally conducted with advantage in a solvent and in the presence of a base. ~he solvent just mentioned may be any solvent that is able to dissolve the two starting materials and, at the same time, will not interfere with the contemplated reaction. Thus, use may be made of alcohols such as methanol, ethanol, propanol, etc.; ketones such as acetone, me~hYl ethyl ketone, etc.; ethers, such as ether, tetrahydrofuran, dioxane, etc. and their mixtures, to name , '~
' .
.
., , ~ ~ :
but a few. ~hls reaction proceeds smoothly in the presence of a base. As the base, there may be mentioned organic tertiary bases such as pyridine, picoline, quinoline, isoquinoline, triethylamine, tributylamine, ~-methyl-piperidine, N-methylmorpholine, N,N-dimethylaniline, N,~-diethylaniline and so on, The reaction proceeds at room temperature but, there are cases where the reaction is hastened by heating. The heating temperature in the neighbor-hood of the boiling point of the solvent employed is normally advantageous, As to the mating starting material, i~e. an ~-haloacetoacetic acid alkyl ester, there may be employed methyl ~-chloroacetoacetate, ethyl ~-chloroacetoacetate, .~ ,~. .
methyl ~-bromoacetoacetate, ethyl ~rbromoacetoacetate and other ; ~ -halogenoacetoacetic acid alkyl esters.
The following description pertains to the process which comprises reacting an 2-aminothiazol-4-ylacetic acid alkyl ester with 2-trichloroethyl chloroformate to produce a 2-(2'-halogenoethoxycarbonylamino)thiazol-4-ylacetic acid alkyl ester. This reaction is normally conducted smoothly in a solvent and in the presence of a base. The solvent may be any solvent that will not interfere with . ~ .
the contemplated reaction. Normally,use is made of a non-protonating organic solvent such as, chloroform, dichloro-; .:
methane, dichloroethylene, carbon tetrachloride, chloro-benzene, ether, tetrahydrofuran, dioxane, acetone or methyl ,, ~ ethyl ketone, or a mixture of such solvents. The base may !~
~ be any base that is able to accept or combine with the ~ .
~ hydrogen halide by-produced in the course of the reaction ~, .
.
~ - 14 -:` ~
:
~ ~064478 i. ~, . .
and that does not interfere with the reaction, ~hus, normally, organic tertiary bases such as pyridine, picoline, quinoline, isoquinoline, triethylamine, tributylamine, N-methylpiperidine, ~-methylmorpholine, N,N-dimethylaniline or ~,N-diethylaniline, may be employed. While the reaction proceeds smoothly at room temperature, the reaction system .
- ~ may be cooled or heated as occation requires.
The 2-(2'-halo~enoethoxycarbonylamino)thiazol-4-ylacetic acid ester thus obtained is partially hydrolyzed to a 2-(2'-halogenoethoxycarbonylamino)thiazol-4-ylacetic acld~ This hydrolysis reaction is carried out in a solvent and in the presence of a base. The solvent is preferably one that is able to dissolve both the starting material ester and the base. Thus, normally, a mixture of water and an organic solvent miscible with water, such as methanol, ethanol, acetone or tbe like, is employed. As the base, use is~normally;made of an inorganic strong base such as, sodium:hydroxide, potassium hydroxide or barium hydroxide.
his reaction is~conducted with advantage at a temperature `near ro~om~temperature~so as to~avoid occurence of undesirable side reactions.~
,.Z~
he;present inv~ention is illustrated in further detail ~s~ below with reference~to examples, but it is to be under-stood that the examples are solely for the purpose of ;illustratlon and not to be construed as limitations of the ,. . ~
invention, and that many variations may be resorted to wlthout departlng from the spirlt and scope of the inven-p~ tion. In this specification, "g.", "mg.", "m~", "cm.", ; ~ - 15 -- :. . -~.. - . .. , ~ . . . .. -.. . . . . .
~ . : . , ~ . . . :
:~.. : , - . ... .
' : . ' ' . ' , ! , . . . .
-"ppm", and "Mc" are abbreviations of "gram", "milligram", "millili~er"9 "cen~im~ter"9 "part pe~ million"9 and "megacycle", repsectively. Resins named "Amberlite"
are products manufactured by Rohm & Haas Co, in U.S.A.
All the temperatures are uncorrected and the percentages are all on the weight basis except specifically defined.
~I) Preparation of 2-(2',2',2'-trichloroethoxycarbonyl-amino)thiazol-4-ylacetic acid (1) In 250 ml of acetone was dissolved 25.2 g. of potassium thiocyanate and while the solution was cooled at -20C, 50 g.
of 2,2,2-trichloroethyl chloroformate was added dropwise.
;~ 1; `
After the dropwise addition had been completed, the mixture was stirred at that temperature for 30 minutes. ~he preci-pitated potassium chloride was filtered off. ~o the filt-rate was added 26 g. of 17 % methanolic ammonia at -10C.
he mixture was stirred for 45 minutes, after which the .,1.~, ;: . : -solvent was distilled off. ~he syrupy residue was recrystal-lized from aqueous methanol to obtain 21.8 g. of N-(2,2,2-trichloroethoxycarbonyl)thiourea as colorless prisms melting at 189-190-C.
Elemental analysis, for C4H5C~3N202S:
Calculated C, 19.10; H, 2.00; N, 11.14 Found C, 19.22; H, 1.96; N, 11.50 (2) In 3 m~ of ethanol was dissolved 500 mg. N-(2,2,2-trichloroethoxycarbonyl)thiourea, 416 mg. ethylo~-bromo-. : .
acetoacetate and 363 mg. N,~-dimethylaniline and the solu-tion was stirred at room temperature for 24 hours. After the solvent was distilled off under reduced pressure, the ', .. . . . ... . . .
.. .. . .: , .
;
: 1064478 residue was dissolved in chloroform and washed once with 10 % hydrochloric acid and, then, three times with a saturated aqueous solution of sodium chloride. After drying over magnesium sulfate, the chloroform layer was concentrated and the oily residue was passed through a column of silica gel a~d eluted with a 1:1 mixture of benzene and chloroform The above isolation-purification procedure provided 540 mg.
of ethyl 2-(2',2',2'-trichloroethoxycarbonylamino)thiazol-
4-ylacetate, melting point: 91-92C
Elemental analysis, for CloHllC~3~204S:
Calculated C, 33,21; H, 3.07; N,7.75 ~ound C, 33.38; H, 2.85; ~,7.73 (3) In 3 ml of acetone were dissolved 500 mg. N-(2,2,2-trichloroethoxycarbonyl)thiourea, 328 mg. ethyl ~-chloro-acetoacetate and 237 mg. pyridine and the solution was stirred at room temperature for 24 hours. ~hereafter, the treatment similar to Example 2 gave 502 mg. of ethyl 2-(2', 2',2'-trichloroethoxycarbonylamino)thiazol-4-ylacetate.
~his product was identified with the compound prepared according to the procedure described above (2).
(4) In 100 ml of dichloromethane were dissolved 18.6 g, : . ~
ethyl 2-aminothiazol-4-ylacetate and 11.1 g. triethylamine and, while the solution was cooled with ice, 23.3 g. of 2,2,2-trichloroethylchloroformate was added dropwise.
A~ter the dropwise addition had been completed, the mixture , ;~ was stirred for 1 hour, at the end of which time 50 m~ of ~: .
- water was added to the reaction mixture.
The organic layer was taken, washed twice with 10 :
''`'''~:
.,,, .. ,, , . .. , , . , - .: : . : ~ :
:
1064478 : ~
-, . :
hydrochloric acid and once with water, then washed once with 10 Yo aqueous sodium hydrogen carbonate solution and twice wlth saturated aqueous sodium chloride solution.
Then, after drying over magnesium sulfate, the magnesium . ' ' sulfate was filtered off and the dichloromethane was removed by distillation. To the resultant oily residue was added - ' 80 me of ethanoi and the.precipitate was filtered off ;(un~reacted~ethyl 2-aminothiazol-4-ylacetate: 9.7 g.). The :~
filtrate:wa~s ¢oncentrated and passed through a column of :-'"
8i11ca~gel~and eluted with a 1:1 mixture of chloroform and benzene~ he above isolation-purification procedure provided ; .~:
12.~2~g ~ of ethyl 2-(2'j2',2'-trichloroethoxycarbonylamino)~
thiaz.ol-4-ylacet.ate. This pr.~oduct.:was identified with the ~ ' compound prepared according to (2) above.
1: . J~
Elemental analysis, for CloHllC~3~204S:
Calculated C, 33,21; H, 3.07; N,7.75 ~ound C, 33.38; H, 2.85; ~,7.73 (3) In 3 ml of acetone were dissolved 500 mg. N-(2,2,2-trichloroethoxycarbonyl)thiourea, 328 mg. ethyl ~-chloro-acetoacetate and 237 mg. pyridine and the solution was stirred at room temperature for 24 hours. ~hereafter, the treatment similar to Example 2 gave 502 mg. of ethyl 2-(2', 2',2'-trichloroethoxycarbonylamino)thiazol-4-ylacetate.
~his product was identified with the compound prepared according to the procedure described above (2).
(4) In 100 ml of dichloromethane were dissolved 18.6 g, : . ~
ethyl 2-aminothiazol-4-ylacetate and 11.1 g. triethylamine and, while the solution was cooled with ice, 23.3 g. of 2,2,2-trichloroethylchloroformate was added dropwise.
A~ter the dropwise addition had been completed, the mixture , ;~ was stirred for 1 hour, at the end of which time 50 m~ of ~: .
- water was added to the reaction mixture.
The organic layer was taken, washed twice with 10 :
''`'''~:
.,,, .. ,, , . .. , , . , - .: : . : ~ :
:
1064478 : ~
-, . :
hydrochloric acid and once with water, then washed once with 10 Yo aqueous sodium hydrogen carbonate solution and twice wlth saturated aqueous sodium chloride solution.
Then, after drying over magnesium sulfate, the magnesium . ' ' sulfate was filtered off and the dichloromethane was removed by distillation. To the resultant oily residue was added - ' 80 me of ethanoi and the.precipitate was filtered off ;(un~reacted~ethyl 2-aminothiazol-4-ylacetate: 9.7 g.). The :~
filtrate:wa~s ¢oncentrated and passed through a column of :-'"
8i11ca~gel~and eluted with a 1:1 mixture of chloroform and benzene~ he above isolation-purification procedure provided ; .~:
12.~2~g ~ of ethyl 2-(2'j2',2'-trichloroethoxycarbonylamino)~
thiaz.ol-4-ylacet.ate. This pr.~oduct.:was identified with the ~ ' compound prepared according to (2) above.
1: . J~
5)~ ~In a mixture of 50 me water and 50 m~ methanol were . .
d~'~8solved~5.9~~g~. of~ethyl~2-(2'',2~'',2''-trichloroethoxycarbonyI-n~m ~i);t.hiaz.ol.-4:~ylacetate.~and~ 3.~g .of= sodi~m hydroxide ''"
andj~the:~solution~was:~stlrred:at room temperature for 4 hours.
A~:ma3'or;portion:of~the mlethanol~wa~distilled.off under .
e ~ ed pre~s~u're~an~t~e~'resid~e~was~wàshed wIth 20 me ethyl ac~etate,~made~acidio~:wlth lO y:~hydrochlorlc acid and extracted twice~with~5o~me port:ions of ether The ether extract was s:h~cd~with w.'ater,~dried-~and concentr'àted. The procedure pPoVided 3~ g :~of 2-(2~',2'-,~2'-trichloroethoxycarbonylamino)-thiazol-4-ylacetic acid,~:~melting:;~polnt: 164-164~5C.
Elemental~analysls, for c8H7ce3 ~ 04S: .
CalGulat:ed C, 28.81; H:, 2.12;.N, 8.40 Found C,. 28..92;. H, 2 20; N, 8.44 , .. , ~ ., .
r, ~. : i (II) Preparation of 2~ -trichloroethoxycarbonylamino)-5-chlorothiazol-4-ylacetyl chloride hydrochlorlde (1) ~o a suspension of 5 g. of 2-(~ -trichloroethoxy-carbonylamino)thiazol-4-ylacetic acid in 75 m~ of chloro-form, was added dropwise 14 9 m~ of a 10 /0 (weight per - volume) chlorine solution in dichloromethane. In 5 minutes after the completion of the addition, the mixture became a - complete solution and was stirred for further 15 minutes, followed by extracting three times with 50 m~ each of a 5 %
aqueous solution of sodium hy-drogencarbonate. ~he extracts , :' ~-~ were combined and acidified with diluted hydrochloric acid to precipitate 2~ trichloroethoxycarbonylamino)-5-chlorothiazol-4-ylacetic acid. ~he precipitates were i collected by filtration and recrystallized from chloroform-~,.
;~ ether to give 3.5 g. of pure compound as colorless crystals melting at 112.0C
Elemental analysis, for C8H604H2C~4S
Calculated C, 26 10; H, 1.64; ~,7 61 Found C, 25.96; H, 1.80; ~,7.25 (2? To a suspension of 4~2 g. of 2~ -trichloro-ethoxycarbonylamino)-5-chlorothiazol-4-ylacetic acid in 10 m~ of dichloromethane, was added 2 38 g of phosphorus pentachloride and the mixture was stirred for 30 minutes at room temperature to precipitate 2-(~ -trichloro-:
~ ~ ethoxycarbonylamino)-5-chlorothiazol-4-ylacetyl chloride ., ., ~
hydrochloride The precipitates were collected by filtra-tion and washed with a small amount of dichloromethane.
Yield 3.38 g. colorless powder. Melting point: 99.8C.
-- l 9 : ';
.~ . ., .. . , . . .. .. , .. ~ . . . .. - - ... - .. . . - .- . .
. . . . . .... .. . .. . ., . . , . . . , . . . . . .
~ , . . .. ~. .
, Elemental analysis; for C8H503N2C~5S~HC~
Calculated C, 22.72; H, 1.43; H, 6,62 Found C, 23.L~4; H, 1.63; N, 6.77 (III) Preparation of 7-methoxycephalosporin derivatives ;
Example 1 (1) In 20 m~e of dichloromethane was suspended 6.67 g. of -; 2-(B,~ trichloroethoxycarbonylamino)thiazol~-ylacetic acid and, while the suspension was stirred under cooling with ice, 4.15 g. of finely crushed phosphorus pentachloride ~` ' was added, whereupon the suspended acid was completely dissolved. ~hen, after an elapse of about 5 minutes, fresh crystalline substance separated. ~he mixture was stirred at room temperature for 1 hour, after which time the preci-pitates were collected by filtration and rinsed with petro-leum ether ~he procedure provided 6,59 g. (yield 84,8 %) of 2-(,B,,13,~-trichloroethoxycarbonylamino~thiazol-4-ylacetyl chloride.hydrochloride~ melting point: 109 7C (decomposition) Elemental analysis, for C8H603N2C~4$-HC~
Calculated C, 24.73; H, 1.81; N, 7.21 Found C, 24.40; H, 1.63; N, 6.94 (2) In 10 m~ of dichloromethane was dissolved 1.638 g.
of benzhydryl 7a-methoxy-7~-aminocephalosporanate and, while the solution was cooled with ice, 1.5 m~ of pyridine and, immediately thereafter, 2.70 g. of 2-(,B,B,~-trichloro-ethoxycarbonylamino)thiazol-4-ylacetylchloride.hYdrochloride were added. The mixture was stirred for 15 minutes. It was further stirred at room temperature for 20 minutes, after which it was poured in ice-water and extracted with ` - 20 -, .
.. : . .: ., . :
.
, . . .
.
`~"
ethyl acetate. The ethyl acetate layer was washed with 0.5~ hydrochloric acid, water, a 5 /0 aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride ... .
solution in the order mentioned, followed by drying over magnesium sulfate. ~hereafter, the ethyl acetate was dis-tilled off to obtain an oily residue. ~he oil was purified by chromatography on silica gel. The above procedure provided 1.096 g.(yield 39.9 %) of benzhydryl 7a-methoxy-7~-(2-(~ -trichloroethoxycarbonylamino)thiazol-4-ylacet-amido)cephalosporanate.
~ he infrared absorption spectrum (KBr)of this product shows an absorption of ~-lactam at 1770 cm l. The nuclear magnetic resonance spectrum (60 Mc, in deuteriochloroform) ., - ~ of the product shows a singlet assignable to the ~-acetyl group at 1.98 ppm, a singlet due to 2-methylene protons at . .
.33 ppm, a singlet due to 7a-methoxy at 3.34 ppm, a singlet ~; assignable to the methylene protons of the thiazolylacetic ...,~
acid moiety at 3.74 ppm, a singlet due to the methylene protons of trichloroethoxycarbonyl at 4,84 ppm, a quartet due to 3-methylene protons at 4.90 ppm, a singlet of the :
d~'~8solved~5.9~~g~. of~ethyl~2-(2'',2~'',2''-trichloroethoxycarbonyI-n~m ~i);t.hiaz.ol.-4:~ylacetate.~and~ 3.~g .of= sodi~m hydroxide ''"
andj~the:~solution~was:~stlrred:at room temperature for 4 hours.
A~:ma3'or;portion:of~the mlethanol~wa~distilled.off under .
e ~ ed pre~s~u're~an~t~e~'resid~e~was~wàshed wIth 20 me ethyl ac~etate,~made~acidio~:wlth lO y:~hydrochlorlc acid and extracted twice~with~5o~me port:ions of ether The ether extract was s:h~cd~with w.'ater,~dried-~and concentr'àted. The procedure pPoVided 3~ g :~of 2-(2~',2'-,~2'-trichloroethoxycarbonylamino)-thiazol-4-ylacetic acid,~:~melting:;~polnt: 164-164~5C.
Elemental~analysls, for c8H7ce3 ~ 04S: .
CalGulat:ed C, 28.81; H:, 2.12;.N, 8.40 Found C,. 28..92;. H, 2 20; N, 8.44 , .. , ~ ., .
r, ~. : i (II) Preparation of 2~ -trichloroethoxycarbonylamino)-5-chlorothiazol-4-ylacetyl chloride hydrochlorlde (1) ~o a suspension of 5 g. of 2-(~ -trichloroethoxy-carbonylamino)thiazol-4-ylacetic acid in 75 m~ of chloro-form, was added dropwise 14 9 m~ of a 10 /0 (weight per - volume) chlorine solution in dichloromethane. In 5 minutes after the completion of the addition, the mixture became a - complete solution and was stirred for further 15 minutes, followed by extracting three times with 50 m~ each of a 5 %
aqueous solution of sodium hy-drogencarbonate. ~he extracts , :' ~-~ were combined and acidified with diluted hydrochloric acid to precipitate 2~ trichloroethoxycarbonylamino)-5-chlorothiazol-4-ylacetic acid. ~he precipitates were i collected by filtration and recrystallized from chloroform-~,.
;~ ether to give 3.5 g. of pure compound as colorless crystals melting at 112.0C
Elemental analysis, for C8H604H2C~4S
Calculated C, 26 10; H, 1.64; ~,7 61 Found C, 25.96; H, 1.80; ~,7.25 (2? To a suspension of 4~2 g. of 2~ -trichloro-ethoxycarbonylamino)-5-chlorothiazol-4-ylacetic acid in 10 m~ of dichloromethane, was added 2 38 g of phosphorus pentachloride and the mixture was stirred for 30 minutes at room temperature to precipitate 2-(~ -trichloro-:
~ ~ ethoxycarbonylamino)-5-chlorothiazol-4-ylacetyl chloride ., ., ~
hydrochloride The precipitates were collected by filtra-tion and washed with a small amount of dichloromethane.
Yield 3.38 g. colorless powder. Melting point: 99.8C.
-- l 9 : ';
.~ . ., .. . , . . .. .. , .. ~ . . . .. - - ... - .. . . - .- . .
. . . . . .... .. . .. . ., . . , . . . , . . . . . .
~ , . . .. ~. .
, Elemental analysis; for C8H503N2C~5S~HC~
Calculated C, 22.72; H, 1.43; H, 6,62 Found C, 23.L~4; H, 1.63; N, 6.77 (III) Preparation of 7-methoxycephalosporin derivatives ;
Example 1 (1) In 20 m~e of dichloromethane was suspended 6.67 g. of -; 2-(B,~ trichloroethoxycarbonylamino)thiazol~-ylacetic acid and, while the suspension was stirred under cooling with ice, 4.15 g. of finely crushed phosphorus pentachloride ~` ' was added, whereupon the suspended acid was completely dissolved. ~hen, after an elapse of about 5 minutes, fresh crystalline substance separated. ~he mixture was stirred at room temperature for 1 hour, after which time the preci-pitates were collected by filtration and rinsed with petro-leum ether ~he procedure provided 6,59 g. (yield 84,8 %) of 2-(,B,,13,~-trichloroethoxycarbonylamino~thiazol-4-ylacetyl chloride.hydrochloride~ melting point: 109 7C (decomposition) Elemental analysis, for C8H603N2C~4$-HC~
Calculated C, 24.73; H, 1.81; N, 7.21 Found C, 24.40; H, 1.63; N, 6.94 (2) In 10 m~ of dichloromethane was dissolved 1.638 g.
of benzhydryl 7a-methoxy-7~-aminocephalosporanate and, while the solution was cooled with ice, 1.5 m~ of pyridine and, immediately thereafter, 2.70 g. of 2-(,B,B,~-trichloro-ethoxycarbonylamino)thiazol-4-ylacetylchloride.hYdrochloride were added. The mixture was stirred for 15 minutes. It was further stirred at room temperature for 20 minutes, after which it was poured in ice-water and extracted with ` - 20 -, .
.. : . .: ., . :
.
, . . .
.
`~"
ethyl acetate. The ethyl acetate layer was washed with 0.5~ hydrochloric acid, water, a 5 /0 aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride ... .
solution in the order mentioned, followed by drying over magnesium sulfate. ~hereafter, the ethyl acetate was dis-tilled off to obtain an oily residue. ~he oil was purified by chromatography on silica gel. The above procedure provided 1.096 g.(yield 39.9 %) of benzhydryl 7a-methoxy-7~-(2-(~ -trichloroethoxycarbonylamino)thiazol-4-ylacet-amido)cephalosporanate.
~ he infrared absorption spectrum (KBr)of this product shows an absorption of ~-lactam at 1770 cm l. The nuclear magnetic resonance spectrum (60 Mc, in deuteriochloroform) ., - ~ of the product shows a singlet assignable to the ~-acetyl group at 1.98 ppm, a singlet due to 2-methylene protons at . .
.33 ppm, a singlet due to 7a-methoxy at 3.34 ppm, a singlet ~; assignable to the methylene protons of the thiazolylacetic ...,~
acid moiety at 3.74 ppm, a singlet due to the methylene protons of trichloroethoxycarbonyl at 4,84 ppm, a quartet due to 3-methylene protons at 4.90 ppm, a singlet of the :
6-hydrogen at 5.05 ppm, a singlet assignable to the 5-` ~; hydrogen of the thiazole ring at 6.57 ppm, a singlet assignable to the methine protons of benzhydryl at 6.85 ppm, and a singlet due to the phenyl protons of benzhydryl at 7.30 ppm.
.. .
; (3) In 25 m~. of 9~/0 formic acid was dissolved 990 mg.
of benzhydryl 7~-methoxy-7~2~ -trichloroethoxycarbonyl--~ amino3thiazol-4-ylacetamido~cephalosporanate and, after the '':
., , . : . ,, ~ , ., . . .: : . .
-addition of 860 mg zinc dust under cooling with ice, the mixture was stirred for 1 hour. The reaction mixture was poured in a saturated aqueous solution of sodium chloride and extracted with ethyl acetate. The ethyl acetate layer was washed with water, a 5 /c aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution in the order mentioned, followed by drying over magnesium sulfate. ~hereafter? the ethyl acetate was distilled off ., .
- to obtain 472 mg. (yield 61.5 %) of benzhydryl 7-methoxy-
.. .
; (3) In 25 m~. of 9~/0 formic acid was dissolved 990 mg.
of benzhydryl 7~-methoxy-7~2~ -trichloroethoxycarbonyl--~ amino3thiazol-4-ylacetamido~cephalosporanate and, after the '':
., , . : . ,, ~ , ., . . .: : . .
-addition of 860 mg zinc dust under cooling with ice, the mixture was stirred for 1 hour. The reaction mixture was poured in a saturated aqueous solution of sodium chloride and extracted with ethyl acetate. The ethyl acetate layer was washed with water, a 5 /c aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution in the order mentioned, followed by drying over magnesium sulfate. ~hereafter? the ethyl acetate was distilled off ., .
- to obtain 472 mg. (yield 61.5 %) of benzhydryl 7-methoxy-
7~-(2-aminothiazol-4-ylacetamido)cephalosporanate. The infrared absorption spectrum of this product shows an absorption of ~-lactam at 1770 cm 1.
; . .
,~ The nuclear magnetic resonance spectrum (60 Mc, in . . ~
~ deuteriochloroform) of this ester shows a singlet assignable ,. . .
to the 3-acetyl group at 2.00 ppm, a quartet due to 2-methyl-t ~ ene protons at 3.36 ppm, a singlet due to 7-methoxy at 3.45 ~- ppm, a singlet assignable to the methylene protons of thia-zolyl acetic acid at 3.56 ppm, a quartet assignable to 2-,., ~
methylene protons at 4.90 ppm, a singlet due to 6-hydrogen at 5.08 ppm, a singlet assignable to the 5-hydrogen of the thiazole ring at 6.28 ppm, a singlet due to the methine protons of benzhydryl at 6.93 ppm and a singlet due to the phenyl nuclear protons of benzhydryl at 7.30 ppm.
(4) Under cooling with ice and stirring, 335 mg. of benz-hydryl 7~-methoxy-7~-(2-aminothiazol ~I-ylacetamido)cephalos-poranate was added to a mixture of 1.5 ml trifluoroacetic acid and 1.5 m~ anisole and the mixture was stirred for 30 minutes. The reaction mixture was poured in 50 m~ anhydrous ,, .
.~ .
.
~i . . . .. .
: 1064478 ' ether and the resultant white precipitat~s llere collected- ~ and rinsed with ether. The proced~re provided crude 7a-- methoxy-7~-(2-aminothiazol-4-ylacetamido)cephalosporanic -`, acid trifluoroacetate (185 mg.). This product was dissolved in a 5 % aqueous solution of sodivm hydrogen carbonate and the solution was run onto a column of Amberlite XAD~2(trade name) and eluted wi-th water. ~his purifica-tion procedure provided 131 mg. (50.8 %) of sodium 7a-methoxy-7~-(2-; aminothiazol-4-ylacetamido)-cephalosporanate.trihydrate.
';; , ~lemental analysiS 9 for C16H1707N4S2Na 3H20 , .
Calculated ~, 37,o6~9 H9 4.47%; N9 10~80~o ~'ound Cs 37.36c,~9 ~, 4,14%9 N9 10.50%
,' ~he nuclear resonance spectrum (100 Mc9 in D20) of ~' this product showed a singlet due to 3-acetyl at 2.26 ppm9 quartet ~ssignable to 2-methylene protons at ~.52 ppm9 a ~ singlet assignable to 7-methoYy at ,3.70 ppm9 a singlet - , assignable to the methylene protons o~ thiazolylacetic acid ,; , function at 3.80 ppm9 a quartet due to 3-methylene pro-tons at 4.95 ppm, a singlet due to 6-hydrogen at 5.32 ppm and a ~' singl0t assignable to the 5-hydrogen of the thiazole ring -' at 6.70 ppm.
~ (5) ~he ~ollowing compounds were prepared by a similar ,~, manner as above Example; 7~-methoxy-7~-(2-aminothiazol-4-.
," ylacetamido)-3-methoxymethyl-3-cephem-4-carboxylic acid9 7~methoxy-7~-(2-aminothiazol-4-ylacetamido)-3-(2-carbogyl-''~ ethenyl)-3-cephem-4-carboXYlic acid9 7~-metho~y 7~-(2-~' aminothiazol-4-ylacetamido)-3-methylthiomethyl-3-cephem-4-: ca~boxylic acid.
xamPle ?
(1) In 4 m~ of water containing 208 mg. of sodium hydrogen . .
... .
. ' , .
` 1064478 carbonate, there were dissolved 431 mg. of 7~-methoxy-7~-(2-aminothiazol-4-ylacetamido)cephalosporanic acid-trifluo-roacetate, 108 mg. of 1-methyl-lH-tetrazole-5-thiol and 24.6 mg. of triethylbenzylammonium bromide, and the reaction mixture was stirred at 60C for 6 hours in an atomosphere of nitrogen gas. After cooling, the reaction mixture was passed through a column of Amberlite XAD-2(trade name) and eluted with water ~he above purification procedure provided 158 mg. (36.8 %) of sodium 7-methoxy-7~-(2-aminothiazol-4 ylacetamido)-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-~ ,;
~ ~ cephem-4-carboxylate.
!,.' Elemental analysis, for C16H1705N8SNa.H20 ~ Calculated C, 35.68; H, 3.55; N, 20.86 ;"
~ound C, 35.56; H, 3.36; N, 19.83 The infrared absorption spectrum (KBr) of this product showed an absorption of ~-lactam at 1750 cm 1. The nuclear :;i ~, ,,b~ magnetic resonance spectrum (100 Mc, in D20) of the same . ~
product showed a quartet assignable to 2-methylene protons at 3.60 ppm, a singlet due to 7-methoxy at 3.65 ppm, a singlet due to the methylene protons of thiazolylacetic acid function at 3.77 ppm, a singlet assignable to tetrazole-methyl protons at 4.17 ppm, a quartet assignable to 3-methyl-ene protons at 4.30 ppm, a singlet assignab~e to 6-hydrogen at 5 24 ppm and a singlet due to the 5-hydrogen of the thiazole ring at 6.67 ppm.
(2) The same procedure as (l)in the absence of triethyl-benzylammonium bromide also gave sodium 7-methoxy-7~-(2-aminothiazol-4-ylacetamido)-3-(1-methyl-lH-tetrazol-5-.
.,, , , :
.. : . . , ylthiomethyl)-3-cephem-4-carboxylate salt. This product was identical with the compound obtained in (1).
.:
Example In 20 m~ of dichloromethane was dissolved 2 62 g. of benzhydryl 7~-methoxy-7~-amino-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate and,under cooling -with ice, 3 0 m~ of pyridine and, then, 3,88 g ol 2~(~
trichloroethoxycarbonylamino)thiazol-4-ylacetyl chloride-hydrochloride were added ~he mixture was stirred for 15 minutes and, then, at room temperature for 20 minutes ~hereafter, the reaction mixture was poured in ice-water ., and extracted with ethyl acetate. The ethyl acetate layer was washed with 0 5N hydrochloric acid, water and a saturated aqueous sodium chloride solution in the order mentioned, followed by drying over magnesium sulfate. The ethyl acetate was distilled off to obtain an oily residue. ~his oil was purified by chromatography on silica gel. ~he procedure provided 1.82 g. (43 %) of benzhydryl 7a-methoxy-7~-~2-trichloroethoxycarbonylamino)-thiazol-4-ylacetamido)-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxy-late. A 1.50 g portion of this ester was dissolved in 40 m~ of 90 /0 formic acid and, under cooling with ice and stirring, 1.30 g of zinc dust was added The reaction mixture was thus stirred for 1 hour. The reaction product was poured in a saturated aqueous solution of sodium chloride and extracted with ethyl acetate. ~'he ethyl acetate layer was washed with water and a saturated aqueous sodium chloride solution, followed by drying over magnesium ' l - 25 -.:
: - . . . . . . .
`' ~ ` ' ' ` ' ' ` `' '" " ~ " " " " ' ` ' ' `` `' ' : ~ ' ' ' ` ' ` : ''' , ~ `
~ 1064478 sulfate, The ethyl acetate was distilled off to obtain 753 mg. (63,4 %) of crude benzhydryl 7a-methoxy-7~-(2-aminothia-zol-4-ylacetamido)-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-' 3-cephem-4-carboxylate.
A 700 mg. portion of this product was added to a mixture of 3.0 ml trifluoroacetic acid and 3.0 m~ anisole and, under cooling with ice and stirring, the reaction was carried out under cooling with ice and stirring. ~he reac--~ tion mixture was poured in 100 m~ of anhydrous ether and ~ the resultant precipitates were collected by suction and ,~; rinsed with ether. ~he procedure provided 373 mg. of 7~- :
methoxy-7~-(2-aminothiazol-4-ylacetamido)-3-(1-methyl-lH-~, . . .
tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid-trifluo-roacetate, Thls product was dlssolved ln a 5 % aqueous solution of sodium hydrogen carbonate and passed through a column of Amberlite XAD-2 (trade name), followed by elution with water~ ~he above purification procedure provided 303 mg, of sodium 7a-methoxy-7~-(2-aminothiazol-4-ylacetamido)-. , .,:
3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxy-late.
This product was completely identical with the product ~-; obtained in Example 2.
Example 4 In 2 m~ of water containing 95 mg. of sodium hydrogen carbonate were dissolved 200 mg, of 7a-methoxy-7~-(2-amino-thiazol-4-ylacetamido)cephalosporanic acid-trifluoroacetate and 59 mg. of 6-methylpyridazine-3-thiol l-oxide, followed - by the addition of 11 mg. triethylbenzylammonium bromide.
,,, ~ - 26 -;1,.
,:
.. .
, . ., :
. . ~
. .
, . -- :
.
' The mixture was stirred in an atmosphere of nitrogen gas at 60C for 6 hours. After cooling, the reaction mixture was passed through a column of Amberlite XAD-2(trade name), followed by elution with water. The above purification procedure provided 62 mg. (yield 31.6 %) of 7a-methoxy-7~-(2-aminothiazol-4-ylacetamido)-3-(6-methylpyridazin-~-ylthiomethyl)-3-cephem-4-carboxylic acid l-oxide sodium salt.
~lemental analysis, for C19H1906~6S3Na 4.5H20 Calculated C, 36.36; H, 4.58; ~, 13.39 ~ound C, 36.12; H, 3.96; N, 12.64 ~he infrared absorption spectrum (KBr) of this product ~;
showed an absorption of ~-lactam at 1760 cm 1. The nuclear magnetic resonance spectrum (100 Mc, in D20) showed a singlet assignable to the methyl protons on the pyridazine ring at 2.61 ppm, a quartet due to 2-methylene protons, a singlet due to 7-methoxy-protons at 3.65 ppm, a singlet of the methylene protons of the thiazolylacetic acid function at 3.77 ppm, a singlet due to 6-hydrogen at 5.24 ppm, a singlet assignable to the 5-hydrogen of the thiazole ring at 6.67 ppm and a doublet assignable to pyridazine ring protons at 7.51 and 7 88 ppm, respectively.
Example 5 In 10 m~ of water containing 184 mg. of sodium hydrogen carbonate were dissolved 556 mg. of 7a-methoxy-7~-(2-amino-. . .
; thiazol-4-ylacetamido)cephalosporanic acid-trifluoroacetate, 185 mg. of 2-methyl-1,3,4-thiadiazole-5-thiol sodium salt and 30 mg of triethylbenzylammonium chloride and the solu-tion was stirred in nitrogen streams at 58C for 6 hours.
. .
~ - 27 -''~
. ' .
~ ;~ . , . . . . .. . -.. . : . ... . ,, . . :, . . : , . - .,- , ~ 1064478 After cooling, the reaction mixture was passed through a column .
of Amberlite XAD-2 (trade name), elution being carried out with water. Upon this purification treatment, there was obtained 121 mg. (yield 22.5%) of sodium 7~-methoxy-7~-(2-aminothiazol-4-ylacet-amido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4--.~
~ carboxylate.
.~........................................................................... .
Example 6 ; In 20 mQ of dichloromethane was dissolved 953 mg. of .
'; benzhydryl 7~-methoxy-7~-(D-5-trichloroethoxycarbonylamino-5-benzhydryloxycarbonylvalerylamino)cephalosporanate, followed by the addition of 740.8 mg. of N-trimethylsilyltrifluoroacetamide and 1555.4 mg. of 2-(~ -trichloroethoxycarbonylamino)thiazol-~;~ 4-ylacetylchloride-hydrochloride. The mixture was heated at 41C
with stirring for 24 hours. After cooling, the reaction mixture was filtered to remove the insoluble matters and the filtrate , ~ was concentrated under reduced pressure. The residue, which was ; crude benzhydryl 7~-methoxy-7~-[(D-5-trichloroethoxycarbonylamino-... ..
! 5-benzhydryloxycarbonylvaleryl~-(2-~ -trichloroethoxycarbonyl-aminothiazol-4-ylacetyl)amino]-cephalosporanate, was dissolved in 10 mQ of 90% formic acid. After the addition of 4 g. of zinc dust, the solution was stirred at room temperature for 5 hours ` and, then, filtered. To the filtrate was added 5 mQ of a saturated ` ~ sodium chloride solution followed by extraction with ethyl acetate.
.~ .. . .
.;~ .
The ethyl acetate layer was washed with water and dried over magnesium sulfate. The ethyl acetate was then distilled off and the oily residue was purified by chromatography on silica gel.
..
; ; - 28 -.
.
- :
,; ~.
.
- .
-:
`` 1064478 The procedure provided 197 mg. (32,4%) of benzhydryl 7 methoxy-7~-(2-aminothiazol~4-ylacetamido)cephalosporanate.
This product was identical with the product obtained in Example 1 (3).
~ Example 7 ; In 20 mQ of acetonitrile was dissolved benzhydryl 7-methoxy-7~-(D-S-trichloroethoxycarbonylamino-5-benzhydryl-oxycarbonylvalerylamino)-3-carbamoyloxymethyl-3-cephem-4-carboxylate, followed by the addition of 876.3 mg. of N-tri-., methylsilylphthalimide and 1555.4 mg. of 2-(~ -trichloro-ethoxycarbonylamino)thiazol-4-ylacetyl chloride-hydrochloride.
The mixture was stirred under heating at 41C for 24 hours.
After the reaction mixture was cooled, the insoluble matters were filtered off and the filtrate was concentrated under re-duced pressure. The resultant residue, i.e. crude benzhydryl 7-methoxy-7~-[(D-trichloroethoxycarbonylamino-5-benzhydryl-oxycarbonylvaleryl)-(2-trichloroethoxycarbonylaminothiazol-4-;i ylacetyl)amino]-3-carbamoyloxymethyl-3-cephem-4-carboxylate, was dissolved in 10 mQ of 90% acetic acid. After the addition of 4 g. zinc dust, the solution was stirred at room temperature ; ~ for 8 hours. It was then filtered and 10 mQ of saturated -' ~ aqueous sodi D chloride solution was added to the filtrate.
The mixture was extracted with ethyl acetate, washed with water and dried. The oily product from the ethyl acetate layer was then -, purified by chromatography on silica gel. The procedure pro-. j , ~- vided 120 mg. of benzhydryl 7~-methoxy-7~-(2-aminothiazol-4-ylacetamido)-3-carbamoyloxymethyl-3-cephem-4-carboxy-.;
. .. . .. . ... ..... . . .. ... .. ...... . . . . . .. . . .. .
;- 1064478 `
late. Under cooling with ice, the above product was added to a mixture of 0 75 m~ trifluoroacetic acid and 0.75 m~
anisole and the mixture was stirred for 30 minutes, followed by the addition of 50 m~ anhydrous ether. ~he resultant precipitate was collected by suction, rinsed with ether and dissolved in a 5 % aqueous solution of sodium hydrogen carbonate. ~he solution was passed through a column of Amberlite XAD-2(trade name), elution being carried out with water. Upon this purification, there was obtained sodium 7a-methoxy-7~-(2-aminothiazol-4-ylacetamido)-3-carbamoyloxymethyl-3-cephem-4-carboxylate.
:
Exam~le 8 In 30 m~ of chloroform was dissolved 2.05 g. of benz-hydryl 7a-methoxy-7~-amino-3-desacetoxycephalosporanate and, ~; under cooling with ice 3.0 m~ of pyridine and, then, 3.88 g.
of 2-(~ -trichloroethoxycarbonylamino)thiazol-4-ylacetyl .,., ~
chloride-hydrochloride were added. ~he mixture was stirred for 15 minutes. Then, at room temperature, the mixture was , . ..
further stirred for 20 minutes. ~hen, it was poured in 20 m~ of ice-water and extracted with ethyl acetate. The ethyl acetate layer was washed with 0.5~ hydrochloride, water and saturated aqueous sodium chloride solution, followed by drying over magnesium sulfate. The ethyl acetate was distilled ofX to obtain an oily residue, which was purified by chromatography on silica gel. ~he procedure provided benzhydryl 7~-methoxy-7~-~2-(~ -trichloroethoxycarbonyl-amino)thiazol-4-ylacetamido)-3-desacetoxycephalosporanate.
~his ester was dissolved in 40 ml of 90 % formic acid and, '"
~, ., ' ' . .: .
, ,. . -.
.. ~ .
. ~
:
under cooling with ice and stirring, 1,30 g, of zinc dust was added and the reaction was allowed to proceed for 1 hour, ~he reaction mixture was poured in 30 m~ of a satu-rated aqueous sodium chloride solution and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate, The ethyl acetate was then distilled off to obtain crude benzhydryl 7a-methoxy-7~-(2-aminothiazol-4-ylacetamido)-~-desacetoxycephalosporate, Under cooling with ice, this crude product was added to a mixture of 3,0 m~, trifluoroacetic acid and 3,0 m~ anisole and the mixture was stirred for 30 minutes. To the reaction mixture was added 100 m~ of anhydrous ether and the precipitates were collected by suction. ~he procedure provided crude 7a-methoxy-7~-(2-aminothiazol-4-ylacetamido)-3-desacetoxy-,~
cephalosporanic acid-trifluoroacetate. This product was dissolved in a 3 % aqueous solution of sodium hydrogen carbonate and passed through a column of Amberlite XAD-2 (trade name), elution being carried out with water. The procedure provided 256 mg. of sodium 7a-methoxy-7~-(2-aminothiazol-4-ylacetamido)-3-desacetoxycephalosporanate.
, , , - ' ' .' xamPle 9 To 50 m~ of dichloromethane was added 4.68 g. of ~'~ benzhydryl 7a-methoxy-7~-aminocephalosporanate and, while the mixture was cooled at -40C, 2.4 g. of N,~-dimethyl-aniline was added. Under vigorous stirring, 2.91 g. of 4-bromo-3-oxobutyryl bromide was added dropwise over a period of about 10 minutes, during which time the temperature of ,'' .
~" .
.,, , . . , ;, . , , . . , . . : . , ~ . , .: ~ ,, ,, -. . .. .
`: 1064478 the reaction mixture rose from -40C to -15C. Thereafter, stirring was continued at -15C to -10C for 30 minutes, ~he reaction mixture was washed with water, dilute hydrochlo-ric acid, water and saturated aqueous sodium chloride solu-tion, followed by drying. ~he solvent was then distilled off to obtain an oily residue. This product, i.e. crude benzhydryl 7-methoxy-7~-(4-bromo-3-oxobutyrylamido)-cephalosporanate, was dissolved in 50 m~ of methanol and, following the addition of 0.91 g. thiourea, the reaction was conducted at room temperature with stirring for 2 hours ~he methanol was distilled off under reduced pressure and the residue was washed with ethyl acetate and dissolved by i .
the addition of 30 m~ water. ~hen, a 5 % aqueous solution of sodium hydrogen carbonate was added and the substance that separated out was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated sodium chlo-ride solution and dried. The ethyl acetate was then distilled .
off to obtain 2.43 g. of an oily residue. This product was identical with the benzhydryl 7a-methoxy-7~-(2-aminothiazol-4-ylacetamido)-cephalosporanate obtained in Example 1 (3).
Example _10 o 30 m~ of dime~hylacetamide was added 5.24 g. of benzhydryl 7a-methoxy-7~-amino-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate and, under cooling at -40C, 2.91 g. of 4-bromo-3-oxobutyryl bromide was added over a period of about 10 minutes. During this period, the tempe-rature of the reaction mixture rose from -40C to -15C.
The mixture was further stirred between -15C to -10C for '` ' - - . . : .
. ., : , .
. . , . : . : .--. .
an additional hour, after which it was poured in 100 m~
of ice-water. The mixture was adjusted to pH 8 0-8.5 with sodium hydrogen carbonate and extracted with ethyl acetate.
~he ethyl acetate layer was washed with water, dilute hydrochloric acid and a saturated aqueous sodium chloride solution in the order mentioned, followed by drying. ~he ethyl acetate was then distilled off under reduced pressure to obtain an oily residue This product, i e benzhydryl 7-methoxy-7~-(4-bromo-3-oxobutyrylamido)-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem ~I-carboxylate, was dissolved in 50 m~ of methanol and, following the addition of 0.91 g. thiourea, the mixture was stirred at room temperature for 2 hours. ~he methanol was distilled off under reduced pressure and the residue was washed with ethyl acetate and dissolved in 30 m~ of water. Following the addition of a 5 /0 aqueous solution of sodium hydrogen carbonate, the substance that had separated was extracted with ethyl acetate. ~he ethyl acetate layer was washed with water and saturated aqueous sodium chloride solution, followed by drying. The ethyl acetate was distilled off under reduced pressure to obtain crude benzhydryl 7a-methoxy-7~-(2-aminothiazol-4-ylacetamido)-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carbonate. Under cooling with ice and stirring, this product was added to a mixture of 35 m~ trifluoroacetic acid and 35 m~ anisole and the reaction was allowed to proceed for 30 minutes Then, follow-ing the addition of 700 m~ anhydrous ether, the precipitate was collected by suction and rinsed with ether. The proce-dure provided crude 7a-methoxy-7~-(2-aminothiazol-4-ylacet-.
~ - 33 -.
. . .
- . .
. ~ , . . . . . .
.
amido)-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid-trifluOroacetate~ This product was dissolved in a 3 % aqueous solution of sodi~m hydrogen carbonate and the solution was passed through a column of Amberlite XAD-2 (trade mark), elution being carried out with water. ~he procedure provided 1.25 g. of sodium 7a-methoxy-7~-(2-amino-thiazol-4-ylacetamido)-3-(1-methyl-lH-tetrazol-5-ylthio-methyl)-~-cephem-4-carboxylate. This product was identical with the product obtained in Example 2 (1).
Example 11 (1) ~o a solution of 1.638 g. of 7-methoxy-7~-amino-cephalosporanic acid benzhydrylester dissolved in 10 m~ of dichloromethane, was added under ice-cooling 1.5 m~ of pyridine and then 2.22 g. of 2-(~ -trichloroethoxy-carbonylamino)-5-chlorothiazol-4-ylacetyl chloride~hydroch loride and the mixture was stirred for 30 minutes at room temperature, followed by pouri~g into ice-water. ~he mixture was extracted with ethyl acetate. ~he ethyl acetate layer was washed with 0.5N-hydrochloric acid, a 5 % aqueous solu-tion of sodium hydrrogencarbonate and saturated aqueous solution of sodium chloride, in this order and dried with magnesium sulfate, followed by removal of ethyl acetate to give oily residue. ~he oily residue was purified by chro-matography on silica gel to obtain 7a-methoxy-7~-~2-(~
trichloroethoxycarbonylamino)-5-chlorothiazol-4-ylacetamido)-cephalosporanic acid benzhydrylester. ~he nuclear magnetic resonance spectrum (60 Mc, in CDC~3) showed a singlet assignable to 3-acetyl protons at 2.00 ppm, a singlet due '"'~
,~. , ... .
., : ~ , .
~, ',. ' , :
to methoxy protons at 3.42 ppm and a singlet due to trichlo-roethyl protons at 4 86 ppm.
(2) To a solution of 1000 mg o~ the product obtained in above (1) dissolved in 25 me of 90 /0 formic acid, was added 860 mg. of zinc powder under ice-cooling and stirring, followed by keeping the mixture under same conditions for 1 hour. ~he reaction mixture was poured into a saturated aqueous solution of sodium chloride and the mixture was extracted with ethyl acetate, The ethyl acetate layer was washed with water and dried with magnesium sulfate and then subjected to the distillation of ethyl acetate to give 7a-methoxy-7~-(2-amino-5-chlorothiazol-4-ylacetamido)cephalos-poranic acid benzhydrylester. ~he nuclear magnetic resonance spectrum (60 Mc, in CDC~3) showed a singlet due to acetyl protons at 2.02 ppm, a singlet due to methoxy protons at 3.48 ppm, and a singlet due to 6-hydrogen at 5.18 ppm.
(3) To a mixture of 1.5 me of trifluoroacetic acid and 1.5 me of anisole was added 350 mg. of 7a-methoxy-7~-(2-amino-5-chlorothiazol-4-ylacetamido)cephalosporanic acid benzhydrylester, and the resultant mixture was stirred for 20 minutes. The reaction mixture was poured into 50 me of dry ether to give white precipitates which were collected by filtration-and washed with ether to give crude trifluo-roacetic acid salt of 7a-methoxy-7~-(2-amino-5-chlorothiazol-4-ylacetamido)cephalosporanic acid~ ~he crude salt was dissolved in 5 me of a 5 % aqueous solution of sodium hydrogencarbonate and the resultant solution was passed through a column of Amberlite XAD-2 (trade name), followed ` - 35 -:
- ' by elution with water to obtain sodium 7~-methoxy-7~-(2-amino-5-chlorothiazol-4-ylacetamido)cephalosporanate as colorless powder. ~he nuclear magnetic resonance spectrum (100 Mc, in D20) showed a singlet due to acetyl protons at 2.25 ppm, a singlet due to methylene protons of thiazolyl-acetyl group at 3.70 ppm, and a singlet due to 6-hydrogen at 5.29 ppm.
~ ' .
;
'~
.
: '' . ~ .
.
'.,-~: ': -~'''' ~ , . ~, ' ~
~... .
:
"'"' . ,, ~
. ~
`'';'' '~" ."
, . . .
; . .
,~ The nuclear magnetic resonance spectrum (60 Mc, in . . ~
~ deuteriochloroform) of this ester shows a singlet assignable ,. . .
to the 3-acetyl group at 2.00 ppm, a quartet due to 2-methyl-t ~ ene protons at 3.36 ppm, a singlet due to 7-methoxy at 3.45 ~- ppm, a singlet assignable to the methylene protons of thia-zolyl acetic acid at 3.56 ppm, a quartet assignable to 2-,., ~
methylene protons at 4.90 ppm, a singlet due to 6-hydrogen at 5.08 ppm, a singlet assignable to the 5-hydrogen of the thiazole ring at 6.28 ppm, a singlet due to the methine protons of benzhydryl at 6.93 ppm and a singlet due to the phenyl nuclear protons of benzhydryl at 7.30 ppm.
(4) Under cooling with ice and stirring, 335 mg. of benz-hydryl 7~-methoxy-7~-(2-aminothiazol ~I-ylacetamido)cephalos-poranate was added to a mixture of 1.5 ml trifluoroacetic acid and 1.5 m~ anisole and the mixture was stirred for 30 minutes. The reaction mixture was poured in 50 m~ anhydrous ,, .
.~ .
.
~i . . . .. .
: 1064478 ' ether and the resultant white precipitat~s llere collected- ~ and rinsed with ether. The proced~re provided crude 7a-- methoxy-7~-(2-aminothiazol-4-ylacetamido)cephalosporanic -`, acid trifluoroacetate (185 mg.). This product was dissolved in a 5 % aqueous solution of sodivm hydrogen carbonate and the solution was run onto a column of Amberlite XAD~2(trade name) and eluted wi-th water. ~his purifica-tion procedure provided 131 mg. (50.8 %) of sodium 7a-methoxy-7~-(2-; aminothiazol-4-ylacetamido)-cephalosporanate.trihydrate.
';; , ~lemental analysiS 9 for C16H1707N4S2Na 3H20 , .
Calculated ~, 37,o6~9 H9 4.47%; N9 10~80~o ~'ound Cs 37.36c,~9 ~, 4,14%9 N9 10.50%
,' ~he nuclear resonance spectrum (100 Mc9 in D20) of ~' this product showed a singlet due to 3-acetyl at 2.26 ppm9 quartet ~ssignable to 2-methylene protons at ~.52 ppm9 a ~ singlet assignable to 7-methoYy at ,3.70 ppm9 a singlet - , assignable to the methylene protons o~ thiazolylacetic acid ,; , function at 3.80 ppm9 a quartet due to 3-methylene pro-tons at 4.95 ppm, a singlet due to 6-hydrogen at 5.32 ppm and a ~' singl0t assignable to the 5-hydrogen of the thiazole ring -' at 6.70 ppm.
~ (5) ~he ~ollowing compounds were prepared by a similar ,~, manner as above Example; 7~-methoxy-7~-(2-aminothiazol-4-.
," ylacetamido)-3-methoxymethyl-3-cephem-4-carboxylic acid9 7~methoxy-7~-(2-aminothiazol-4-ylacetamido)-3-(2-carbogyl-''~ ethenyl)-3-cephem-4-carboXYlic acid9 7~-metho~y 7~-(2-~' aminothiazol-4-ylacetamido)-3-methylthiomethyl-3-cephem-4-: ca~boxylic acid.
xamPle ?
(1) In 4 m~ of water containing 208 mg. of sodium hydrogen . .
... .
. ' , .
` 1064478 carbonate, there were dissolved 431 mg. of 7~-methoxy-7~-(2-aminothiazol-4-ylacetamido)cephalosporanic acid-trifluo-roacetate, 108 mg. of 1-methyl-lH-tetrazole-5-thiol and 24.6 mg. of triethylbenzylammonium bromide, and the reaction mixture was stirred at 60C for 6 hours in an atomosphere of nitrogen gas. After cooling, the reaction mixture was passed through a column of Amberlite XAD-2(trade name) and eluted with water ~he above purification procedure provided 158 mg. (36.8 %) of sodium 7-methoxy-7~-(2-aminothiazol-4 ylacetamido)-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-~ ,;
~ ~ cephem-4-carboxylate.
!,.' Elemental analysis, for C16H1705N8SNa.H20 ~ Calculated C, 35.68; H, 3.55; N, 20.86 ;"
~ound C, 35.56; H, 3.36; N, 19.83 The infrared absorption spectrum (KBr) of this product showed an absorption of ~-lactam at 1750 cm 1. The nuclear :;i ~, ,,b~ magnetic resonance spectrum (100 Mc, in D20) of the same . ~
product showed a quartet assignable to 2-methylene protons at 3.60 ppm, a singlet due to 7-methoxy at 3.65 ppm, a singlet due to the methylene protons of thiazolylacetic acid function at 3.77 ppm, a singlet assignable to tetrazole-methyl protons at 4.17 ppm, a quartet assignable to 3-methyl-ene protons at 4.30 ppm, a singlet assignab~e to 6-hydrogen at 5 24 ppm and a singlet due to the 5-hydrogen of the thiazole ring at 6.67 ppm.
(2) The same procedure as (l)in the absence of triethyl-benzylammonium bromide also gave sodium 7-methoxy-7~-(2-aminothiazol-4-ylacetamido)-3-(1-methyl-lH-tetrazol-5-.
.,, , , :
.. : . . , ylthiomethyl)-3-cephem-4-carboxylate salt. This product was identical with the compound obtained in (1).
.:
Example In 20 m~ of dichloromethane was dissolved 2 62 g. of benzhydryl 7~-methoxy-7~-amino-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate and,under cooling -with ice, 3 0 m~ of pyridine and, then, 3,88 g ol 2~(~
trichloroethoxycarbonylamino)thiazol-4-ylacetyl chloride-hydrochloride were added ~he mixture was stirred for 15 minutes and, then, at room temperature for 20 minutes ~hereafter, the reaction mixture was poured in ice-water ., and extracted with ethyl acetate. The ethyl acetate layer was washed with 0 5N hydrochloric acid, water and a saturated aqueous sodium chloride solution in the order mentioned, followed by drying over magnesium sulfate. The ethyl acetate was distilled off to obtain an oily residue. ~his oil was purified by chromatography on silica gel. ~he procedure provided 1.82 g. (43 %) of benzhydryl 7a-methoxy-7~-~2-trichloroethoxycarbonylamino)-thiazol-4-ylacetamido)-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxy-late. A 1.50 g portion of this ester was dissolved in 40 m~ of 90 /0 formic acid and, under cooling with ice and stirring, 1.30 g of zinc dust was added The reaction mixture was thus stirred for 1 hour. The reaction product was poured in a saturated aqueous solution of sodium chloride and extracted with ethyl acetate. ~'he ethyl acetate layer was washed with water and a saturated aqueous sodium chloride solution, followed by drying over magnesium ' l - 25 -.:
: - . . . . . . .
`' ~ ` ' ' ` ' ' ` `' '" " ~ " " " " ' ` ' ' `` `' ' : ~ ' ' ' ` ' ` : ''' , ~ `
~ 1064478 sulfate, The ethyl acetate was distilled off to obtain 753 mg. (63,4 %) of crude benzhydryl 7a-methoxy-7~-(2-aminothia-zol-4-ylacetamido)-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-' 3-cephem-4-carboxylate.
A 700 mg. portion of this product was added to a mixture of 3.0 ml trifluoroacetic acid and 3.0 m~ anisole and, under cooling with ice and stirring, the reaction was carried out under cooling with ice and stirring. ~he reac--~ tion mixture was poured in 100 m~ of anhydrous ether and ~ the resultant precipitates were collected by suction and ,~; rinsed with ether. ~he procedure provided 373 mg. of 7~- :
methoxy-7~-(2-aminothiazol-4-ylacetamido)-3-(1-methyl-lH-~, . . .
tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid-trifluo-roacetate, Thls product was dlssolved ln a 5 % aqueous solution of sodium hydrogen carbonate and passed through a column of Amberlite XAD-2 (trade name), followed by elution with water~ ~he above purification procedure provided 303 mg, of sodium 7a-methoxy-7~-(2-aminothiazol-4-ylacetamido)-. , .,:
3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxy-late.
This product was completely identical with the product ~-; obtained in Example 2.
Example 4 In 2 m~ of water containing 95 mg. of sodium hydrogen carbonate were dissolved 200 mg, of 7a-methoxy-7~-(2-amino-thiazol-4-ylacetamido)cephalosporanic acid-trifluoroacetate and 59 mg. of 6-methylpyridazine-3-thiol l-oxide, followed - by the addition of 11 mg. triethylbenzylammonium bromide.
,,, ~ - 26 -;1,.
,:
.. .
, . ., :
. . ~
. .
, . -- :
.
' The mixture was stirred in an atmosphere of nitrogen gas at 60C for 6 hours. After cooling, the reaction mixture was passed through a column of Amberlite XAD-2(trade name), followed by elution with water. The above purification procedure provided 62 mg. (yield 31.6 %) of 7a-methoxy-7~-(2-aminothiazol-4-ylacetamido)-3-(6-methylpyridazin-~-ylthiomethyl)-3-cephem-4-carboxylic acid l-oxide sodium salt.
~lemental analysis, for C19H1906~6S3Na 4.5H20 Calculated C, 36.36; H, 4.58; ~, 13.39 ~ound C, 36.12; H, 3.96; N, 12.64 ~he infrared absorption spectrum (KBr) of this product ~;
showed an absorption of ~-lactam at 1760 cm 1. The nuclear magnetic resonance spectrum (100 Mc, in D20) showed a singlet assignable to the methyl protons on the pyridazine ring at 2.61 ppm, a quartet due to 2-methylene protons, a singlet due to 7-methoxy-protons at 3.65 ppm, a singlet of the methylene protons of the thiazolylacetic acid function at 3.77 ppm, a singlet due to 6-hydrogen at 5.24 ppm, a singlet assignable to the 5-hydrogen of the thiazole ring at 6.67 ppm and a doublet assignable to pyridazine ring protons at 7.51 and 7 88 ppm, respectively.
Example 5 In 10 m~ of water containing 184 mg. of sodium hydrogen carbonate were dissolved 556 mg. of 7a-methoxy-7~-(2-amino-. . .
; thiazol-4-ylacetamido)cephalosporanic acid-trifluoroacetate, 185 mg. of 2-methyl-1,3,4-thiadiazole-5-thiol sodium salt and 30 mg of triethylbenzylammonium chloride and the solu-tion was stirred in nitrogen streams at 58C for 6 hours.
. .
~ - 27 -''~
. ' .
~ ;~ . , . . . . .. . -.. . : . ... . ,, . . :, . . : , . - .,- , ~ 1064478 After cooling, the reaction mixture was passed through a column .
of Amberlite XAD-2 (trade name), elution being carried out with water. Upon this purification treatment, there was obtained 121 mg. (yield 22.5%) of sodium 7~-methoxy-7~-(2-aminothiazol-4-ylacet-amido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4--.~
~ carboxylate.
.~........................................................................... .
Example 6 ; In 20 mQ of dichloromethane was dissolved 953 mg. of .
'; benzhydryl 7~-methoxy-7~-(D-5-trichloroethoxycarbonylamino-5-benzhydryloxycarbonylvalerylamino)cephalosporanate, followed by the addition of 740.8 mg. of N-trimethylsilyltrifluoroacetamide and 1555.4 mg. of 2-(~ -trichloroethoxycarbonylamino)thiazol-~;~ 4-ylacetylchloride-hydrochloride. The mixture was heated at 41C
with stirring for 24 hours. After cooling, the reaction mixture was filtered to remove the insoluble matters and the filtrate , ~ was concentrated under reduced pressure. The residue, which was ; crude benzhydryl 7~-methoxy-7~-[(D-5-trichloroethoxycarbonylamino-... ..
! 5-benzhydryloxycarbonylvaleryl~-(2-~ -trichloroethoxycarbonyl-aminothiazol-4-ylacetyl)amino]-cephalosporanate, was dissolved in 10 mQ of 90% formic acid. After the addition of 4 g. of zinc dust, the solution was stirred at room temperature for 5 hours ` and, then, filtered. To the filtrate was added 5 mQ of a saturated ` ~ sodium chloride solution followed by extraction with ethyl acetate.
.~ .. . .
.;~ .
The ethyl acetate layer was washed with water and dried over magnesium sulfate. The ethyl acetate was then distilled off and the oily residue was purified by chromatography on silica gel.
..
; ; - 28 -.
.
- :
,; ~.
.
- .
-:
`` 1064478 The procedure provided 197 mg. (32,4%) of benzhydryl 7 methoxy-7~-(2-aminothiazol~4-ylacetamido)cephalosporanate.
This product was identical with the product obtained in Example 1 (3).
~ Example 7 ; In 20 mQ of acetonitrile was dissolved benzhydryl 7-methoxy-7~-(D-S-trichloroethoxycarbonylamino-5-benzhydryl-oxycarbonylvalerylamino)-3-carbamoyloxymethyl-3-cephem-4-carboxylate, followed by the addition of 876.3 mg. of N-tri-., methylsilylphthalimide and 1555.4 mg. of 2-(~ -trichloro-ethoxycarbonylamino)thiazol-4-ylacetyl chloride-hydrochloride.
The mixture was stirred under heating at 41C for 24 hours.
After the reaction mixture was cooled, the insoluble matters were filtered off and the filtrate was concentrated under re-duced pressure. The resultant residue, i.e. crude benzhydryl 7-methoxy-7~-[(D-trichloroethoxycarbonylamino-5-benzhydryl-oxycarbonylvaleryl)-(2-trichloroethoxycarbonylaminothiazol-4-;i ylacetyl)amino]-3-carbamoyloxymethyl-3-cephem-4-carboxylate, was dissolved in 10 mQ of 90% acetic acid. After the addition of 4 g. zinc dust, the solution was stirred at room temperature ; ~ for 8 hours. It was then filtered and 10 mQ of saturated -' ~ aqueous sodi D chloride solution was added to the filtrate.
The mixture was extracted with ethyl acetate, washed with water and dried. The oily product from the ethyl acetate layer was then -, purified by chromatography on silica gel. The procedure pro-. j , ~- vided 120 mg. of benzhydryl 7~-methoxy-7~-(2-aminothiazol-4-ylacetamido)-3-carbamoyloxymethyl-3-cephem-4-carboxy-.;
. .. . .. . ... ..... . . .. ... .. ...... . . . . . .. . . .. .
;- 1064478 `
late. Under cooling with ice, the above product was added to a mixture of 0 75 m~ trifluoroacetic acid and 0.75 m~
anisole and the mixture was stirred for 30 minutes, followed by the addition of 50 m~ anhydrous ether. ~he resultant precipitate was collected by suction, rinsed with ether and dissolved in a 5 % aqueous solution of sodium hydrogen carbonate. ~he solution was passed through a column of Amberlite XAD-2(trade name), elution being carried out with water. Upon this purification, there was obtained sodium 7a-methoxy-7~-(2-aminothiazol-4-ylacetamido)-3-carbamoyloxymethyl-3-cephem-4-carboxylate.
:
Exam~le 8 In 30 m~ of chloroform was dissolved 2.05 g. of benz-hydryl 7a-methoxy-7~-amino-3-desacetoxycephalosporanate and, ~; under cooling with ice 3.0 m~ of pyridine and, then, 3.88 g.
of 2-(~ -trichloroethoxycarbonylamino)thiazol-4-ylacetyl .,., ~
chloride-hydrochloride were added. ~he mixture was stirred for 15 minutes. Then, at room temperature, the mixture was , . ..
further stirred for 20 minutes. ~hen, it was poured in 20 m~ of ice-water and extracted with ethyl acetate. The ethyl acetate layer was washed with 0.5~ hydrochloride, water and saturated aqueous sodium chloride solution, followed by drying over magnesium sulfate. The ethyl acetate was distilled ofX to obtain an oily residue, which was purified by chromatography on silica gel. ~he procedure provided benzhydryl 7~-methoxy-7~-~2-(~ -trichloroethoxycarbonyl-amino)thiazol-4-ylacetamido)-3-desacetoxycephalosporanate.
~his ester was dissolved in 40 ml of 90 % formic acid and, '"
~, ., ' ' . .: .
, ,. . -.
.. ~ .
. ~
:
under cooling with ice and stirring, 1,30 g, of zinc dust was added and the reaction was allowed to proceed for 1 hour, ~he reaction mixture was poured in 30 m~ of a satu-rated aqueous sodium chloride solution and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate, The ethyl acetate was then distilled off to obtain crude benzhydryl 7a-methoxy-7~-(2-aminothiazol-4-ylacetamido)-~-desacetoxycephalosporate, Under cooling with ice, this crude product was added to a mixture of 3,0 m~, trifluoroacetic acid and 3,0 m~ anisole and the mixture was stirred for 30 minutes. To the reaction mixture was added 100 m~ of anhydrous ether and the precipitates were collected by suction. ~he procedure provided crude 7a-methoxy-7~-(2-aminothiazol-4-ylacetamido)-3-desacetoxy-,~
cephalosporanic acid-trifluoroacetate. This product was dissolved in a 3 % aqueous solution of sodium hydrogen carbonate and passed through a column of Amberlite XAD-2 (trade name), elution being carried out with water. The procedure provided 256 mg. of sodium 7a-methoxy-7~-(2-aminothiazol-4-ylacetamido)-3-desacetoxycephalosporanate.
, , , - ' ' .' xamPle 9 To 50 m~ of dichloromethane was added 4.68 g. of ~'~ benzhydryl 7a-methoxy-7~-aminocephalosporanate and, while the mixture was cooled at -40C, 2.4 g. of N,~-dimethyl-aniline was added. Under vigorous stirring, 2.91 g. of 4-bromo-3-oxobutyryl bromide was added dropwise over a period of about 10 minutes, during which time the temperature of ,'' .
~" .
.,, , . . , ;, . , , . . , . . : . , ~ . , .: ~ ,, ,, -. . .. .
`: 1064478 the reaction mixture rose from -40C to -15C. Thereafter, stirring was continued at -15C to -10C for 30 minutes, ~he reaction mixture was washed with water, dilute hydrochlo-ric acid, water and saturated aqueous sodium chloride solu-tion, followed by drying. ~he solvent was then distilled off to obtain an oily residue. This product, i.e. crude benzhydryl 7-methoxy-7~-(4-bromo-3-oxobutyrylamido)-cephalosporanate, was dissolved in 50 m~ of methanol and, following the addition of 0.91 g. thiourea, the reaction was conducted at room temperature with stirring for 2 hours ~he methanol was distilled off under reduced pressure and the residue was washed with ethyl acetate and dissolved by i .
the addition of 30 m~ water. ~hen, a 5 % aqueous solution of sodium hydrogen carbonate was added and the substance that separated out was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated sodium chlo-ride solution and dried. The ethyl acetate was then distilled .
off to obtain 2.43 g. of an oily residue. This product was identical with the benzhydryl 7a-methoxy-7~-(2-aminothiazol-4-ylacetamido)-cephalosporanate obtained in Example 1 (3).
Example _10 o 30 m~ of dime~hylacetamide was added 5.24 g. of benzhydryl 7a-methoxy-7~-amino-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate and, under cooling at -40C, 2.91 g. of 4-bromo-3-oxobutyryl bromide was added over a period of about 10 minutes. During this period, the tempe-rature of the reaction mixture rose from -40C to -15C.
The mixture was further stirred between -15C to -10C for '` ' - - . . : .
. ., : , .
. . , . : . : .--. .
an additional hour, after which it was poured in 100 m~
of ice-water. The mixture was adjusted to pH 8 0-8.5 with sodium hydrogen carbonate and extracted with ethyl acetate.
~he ethyl acetate layer was washed with water, dilute hydrochloric acid and a saturated aqueous sodium chloride solution in the order mentioned, followed by drying. ~he ethyl acetate was then distilled off under reduced pressure to obtain an oily residue This product, i e benzhydryl 7-methoxy-7~-(4-bromo-3-oxobutyrylamido)-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem ~I-carboxylate, was dissolved in 50 m~ of methanol and, following the addition of 0.91 g. thiourea, the mixture was stirred at room temperature for 2 hours. ~he methanol was distilled off under reduced pressure and the residue was washed with ethyl acetate and dissolved in 30 m~ of water. Following the addition of a 5 /0 aqueous solution of sodium hydrogen carbonate, the substance that had separated was extracted with ethyl acetate. ~he ethyl acetate layer was washed with water and saturated aqueous sodium chloride solution, followed by drying. The ethyl acetate was distilled off under reduced pressure to obtain crude benzhydryl 7a-methoxy-7~-(2-aminothiazol-4-ylacetamido)-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carbonate. Under cooling with ice and stirring, this product was added to a mixture of 35 m~ trifluoroacetic acid and 35 m~ anisole and the reaction was allowed to proceed for 30 minutes Then, follow-ing the addition of 700 m~ anhydrous ether, the precipitate was collected by suction and rinsed with ether. The proce-dure provided crude 7a-methoxy-7~-(2-aminothiazol-4-ylacet-.
~ - 33 -.
. . .
- . .
. ~ , . . . . . .
.
amido)-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid-trifluOroacetate~ This product was dissolved in a 3 % aqueous solution of sodi~m hydrogen carbonate and the solution was passed through a column of Amberlite XAD-2 (trade mark), elution being carried out with water. ~he procedure provided 1.25 g. of sodium 7a-methoxy-7~-(2-amino-thiazol-4-ylacetamido)-3-(1-methyl-lH-tetrazol-5-ylthio-methyl)-~-cephem-4-carboxylate. This product was identical with the product obtained in Example 2 (1).
Example 11 (1) ~o a solution of 1.638 g. of 7-methoxy-7~-amino-cephalosporanic acid benzhydrylester dissolved in 10 m~ of dichloromethane, was added under ice-cooling 1.5 m~ of pyridine and then 2.22 g. of 2-(~ -trichloroethoxy-carbonylamino)-5-chlorothiazol-4-ylacetyl chloride~hydroch loride and the mixture was stirred for 30 minutes at room temperature, followed by pouri~g into ice-water. ~he mixture was extracted with ethyl acetate. ~he ethyl acetate layer was washed with 0.5N-hydrochloric acid, a 5 % aqueous solu-tion of sodium hydrrogencarbonate and saturated aqueous solution of sodium chloride, in this order and dried with magnesium sulfate, followed by removal of ethyl acetate to give oily residue. ~he oily residue was purified by chro-matography on silica gel to obtain 7a-methoxy-7~-~2-(~
trichloroethoxycarbonylamino)-5-chlorothiazol-4-ylacetamido)-cephalosporanic acid benzhydrylester. ~he nuclear magnetic resonance spectrum (60 Mc, in CDC~3) showed a singlet assignable to 3-acetyl protons at 2.00 ppm, a singlet due '"'~
,~. , ... .
., : ~ , .
~, ',. ' , :
to methoxy protons at 3.42 ppm and a singlet due to trichlo-roethyl protons at 4 86 ppm.
(2) To a solution of 1000 mg o~ the product obtained in above (1) dissolved in 25 me of 90 /0 formic acid, was added 860 mg. of zinc powder under ice-cooling and stirring, followed by keeping the mixture under same conditions for 1 hour. ~he reaction mixture was poured into a saturated aqueous solution of sodium chloride and the mixture was extracted with ethyl acetate, The ethyl acetate layer was washed with water and dried with magnesium sulfate and then subjected to the distillation of ethyl acetate to give 7a-methoxy-7~-(2-amino-5-chlorothiazol-4-ylacetamido)cephalos-poranic acid benzhydrylester. ~he nuclear magnetic resonance spectrum (60 Mc, in CDC~3) showed a singlet due to acetyl protons at 2.02 ppm, a singlet due to methoxy protons at 3.48 ppm, and a singlet due to 6-hydrogen at 5.18 ppm.
(3) To a mixture of 1.5 me of trifluoroacetic acid and 1.5 me of anisole was added 350 mg. of 7a-methoxy-7~-(2-amino-5-chlorothiazol-4-ylacetamido)cephalosporanic acid benzhydrylester, and the resultant mixture was stirred for 20 minutes. The reaction mixture was poured into 50 me of dry ether to give white precipitates which were collected by filtration-and washed with ether to give crude trifluo-roacetic acid salt of 7a-methoxy-7~-(2-amino-5-chlorothiazol-4-ylacetamido)cephalosporanic acid~ ~he crude salt was dissolved in 5 me of a 5 % aqueous solution of sodium hydrogencarbonate and the resultant solution was passed through a column of Amberlite XAD-2 (trade name), followed ` - 35 -:
- ' by elution with water to obtain sodium 7~-methoxy-7~-(2-amino-5-chlorothiazol-4-ylacetamido)cephalosporanate as colorless powder. ~he nuclear magnetic resonance spectrum (100 Mc, in D20) showed a singlet due to acetyl protons at 2.25 ppm, a singlet due to methylene protons of thiazolyl-acetyl group at 3.70 ppm, and a singlet due to 6-hydrogen at 5.29 ppm.
~ ' .
;
'~
.
: '' . ~ .
.
'.,-~: ': -~'''' ~ , . ~, ' ~
~... .
:
"'"' . ,, ~
. ~
`'';'' '~" ."
, . . .
Claims (18)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound of the formula:
(I) wherein R2 is hydrogen or a halogen and R3 stands for methyl, acetoxymethyl, carbamoyloxymethyl, an alkoxymethyl, an alkylthiomethyl, 2-carboxy-1-ethenyl, or a heterocyclic thiomethyl, or a pharmaceutically acceptable salt thereof, which comprises (1) reacting a 7-methoxycephalosporin derivative of the formula:
wherein R3 is as defined above, with an aminothiazolylacetic acid derivative of the formula wherein R1 is a protected amino group and R2 is as defined above, followed, if necessary, by removal of the protective group; or (2) reacting a compound of the formula:
wherein Hal stands for a halogen and R3 is as defined above, with thiourea;
or (3) reacting a 7-methoxycephalosporin derivative of the formula:
wherein R4 stands for an amino group which may optionally be protected; X
stands for an acetoxy or carbamoyloxy group and R2 is as defined above, with a mercapto compound of the formula wherein R1 is alkyl or heterocyclyl, followed, if necessary, by removal of the protective group; or (4) reacting a 7-methoxycephalosporin compound of the formula:
wherein R3 is as defined above, with a reactive derivative of an amino-thiazolylacetic acid derivative of the formula:
wherein the symbols are as defined above, in the presence of a silylating agent, and then splitting off the protected aminoadipoyl group;
and where required converting any compound of formula (I) so formed into a pharmaceutically acceptable salt thereof.
(I) wherein R2 is hydrogen or a halogen and R3 stands for methyl, acetoxymethyl, carbamoyloxymethyl, an alkoxymethyl, an alkylthiomethyl, 2-carboxy-1-ethenyl, or a heterocyclic thiomethyl, or a pharmaceutically acceptable salt thereof, which comprises (1) reacting a 7-methoxycephalosporin derivative of the formula:
wherein R3 is as defined above, with an aminothiazolylacetic acid derivative of the formula wherein R1 is a protected amino group and R2 is as defined above, followed, if necessary, by removal of the protective group; or (2) reacting a compound of the formula:
wherein Hal stands for a halogen and R3 is as defined above, with thiourea;
or (3) reacting a 7-methoxycephalosporin derivative of the formula:
wherein R4 stands for an amino group which may optionally be protected; X
stands for an acetoxy or carbamoyloxy group and R2 is as defined above, with a mercapto compound of the formula wherein R1 is alkyl or heterocyclyl, followed, if necessary, by removal of the protective group; or (4) reacting a 7-methoxycephalosporin compound of the formula:
wherein R3 is as defined above, with a reactive derivative of an amino-thiazolylacetic acid derivative of the formula:
wherein the symbols are as defined above, in the presence of a silylating agent, and then splitting off the protected aminoadipoyl group;
and where required converting any compound of formula (I) so formed into a pharmaceutically acceptable salt thereof.
2. A process as claimed in claim 1, wherein R2 represents hydrogen.
3. A process as claimed in claim 2, wherein R3 represents acetoxy-methyl.
4. A process as claimed in claim 2, wherein R3 represents carbamoyl-oxymethyl.
5. A process as claimed in claim 2, wherein R3 represents a hetero-cyclic thiomethyl.
6. A process as claimed in claim 5, wherein the heterocyclic group consists of a 5 or 6 membered ring containing 1 to 4 hetero atoms selected from the group consisting of nitrogen, sulfur and oxygen.
7. A process as claimed in claim 5, wherein the heterocyclic group has a substituent selected from the group consisting of lower alkyl, lower alkoxy, and halogens.
8. A process as claimed in claim 7, wherein R3 is 2-methyl-1,3,4-thiadiazol-5-ylthiomethyl.
9. A process as claimed in claim 7, wherein R3 is 1-methyl-1H-tetra-zol-5-ylthiomethyl.
10. A process for the preparation of 7.alpha.-methoxy-7.beta.-(2-aminothiazol-4-ylacetamido)cephalosporanic acid sodium salt which comprises reacting the 7.alpha.-methoxy-7.beta.-aminocephalosporanic acid benzhydryl ester with 2-(.beta.,.beta.,.beta.-trichloro-ethoxycarbonylamino)thiazol-4-ylacetyl chloride, then removing the N-protective .beta.,.beta.,.beta.-trichloroethoxycarbonyl group by reduction, and converting the resulting benzhydryl ester into the sodium salt.
11. A process for the preparation of 7.alpha.-methoxy-7.beta.-(2-aminothiazol-4-ylacetamido)cephalosporanic acid sodium salt which comprises reacting 7.alpha.-meth-oxy-7.beta.-(D-5-trichloroethoxycarbonylamino-5-benzhydryloxycarbonylvalerylamino) -cephalosporanic acid benzhydryl ester with 2-(.beta.,.beta.,.beta.-trichloroethoxycarbonyl-amino)thiazol-4-ylacetyl chloride, then removing the N-protective D-5-trichloro-ethoxycarbonylamino-5-benzhydryloxycarbonylvaleryl and .beta.,.beta.,.beta.-trichloroethoxy-carbonyl groups by reduction, and converting the resulting benzhydryl ester into the sodium salt.
12. A process for the preparation of 7.alpha.-methoxy-7.beta.-(2-aminothiazol-4-ylacetamido(cephalosporanic acid sodium salt which comprises reacting 7.alpha.-meth-oxy-7.beta.-(4-bromo-3-oxobutyrylamino)-cephalosporanic acid benzhydryl ester with thiourea, and converting the resulting benzhydryl ester into the sodium salt.
13. A process for the preparation of 7.alpha.-methoxy-7.beta.-(2-aminothiazol-4-ylacetamido)-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid sodium salt which comprises reacting 7.alpha.-methoxy-7.beta.-(D-5-trichloroethoxycarbonylamino-5-benz-hydryloxycarbonylvalerylamino)-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid benzhydryl ester with 2-(.beta.,.beta.,.beta.-trichloroethoxycarbonylamino)-thiazol-4-yl-acetyl chloride, then removing the N-protective D-5-trichloroethoxycarbonyl-amino-5-benzhydryloxycarbonylvaleryl and .beta.,.beta.,.beta.-trichloroethoxycarbonyl groups by reduction, and converting the resulting benzhydryl ester into the sodium salt.
14. A process for the preparation of 7.alpha.-methoxy-7.beta.-(2-aminothiazol-4-ylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid sodium salt which comprises reacting 7.alpha.-methoxy-7.beta.-(2-aminothiazol-4-yl-acetamido)cephalosporanic acid with 2-methyl-1,3,4-thiadiazole-5-thiol sodium salt.
15. A process for the preparation of 7.alpha.-methoxy-7.beta.-(2-aminothiazol-4-ylacetamido)-3-(1-methyl-1H-tetrazol-5-yl-thiomethyl)-3-cephem-4-carboxylic acid sodium salt which comprises reacting 7.alpha.-methoxy-7.beta.-(2-aminothiazol-4-yl-acetamido)cephalosporanic acid with 1-methyl-1H-tetrazole-5-thiol in the pre-sence of sodium carbonate.
16. A process for the preparation of 7.alpha.-methoxy-7.beta.-(2-aminothiazol-4-ylacetamido)-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid sodium salt which comprises reacting 7.alpha.-methoxy-7.beta.-amino-3-(1-methyl-1H-tetra-zol-5-ylthiomethyl)-3-cephem-4-carboxylic acid benzhydryl ester with 2-(.beta.,.beta.,.beta.-trichloroethoxycarbonylamino)thiazol-4-ylacetyl chloride, then removing the N-protective .beta.,.beta.,.beta.-trichloroethoxycarbonyl group by reduction, and converting the resulting benzhydryl ester into the sodium salt.
17. A process for the preparation of 7.alpha.-methoxy-7.beta.-(2-aminothiazol-4-ylacetamido)-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid sodium salt which comprises reacting 7.alpha.-methoxy-7.beta.-(4-bromo-3-oxybutyryl-amino)-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid benz-hydryl ester with thiourea, and converting the resulting benzhydryl ester into the sodium salt.
18. Compounds of formula (I) defined in claim 1, and their pharma-ceutically acceptable salts, when prepared by the process of claim 1 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP49125130A JPS596879B2 (en) | 1974-10-29 | 1974-10-29 | 7- Methoxycephalosporin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1064478A true CA1064478A (en) | 1979-10-16 |
Family
ID=14902583
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA233,102A Expired CA1064478A (en) | 1974-10-29 | 1975-08-08 | 7-methoxycephalosporin derivatives |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JPS596879B2 (en) |
| CA (1) | CA1064478A (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4165429A (en) * | 1976-06-28 | 1979-08-21 | Yamanouchi Pharmaceutical Co., Ltd. | 7α-METHOXY-CEPHALOSPORANIC ACID DERIVATIVES |
| JPS6244474U (en) * | 1985-09-04 | 1987-03-17 |
-
1974
- 1974-10-29 JP JP49125130A patent/JPS596879B2/en not_active Expired
-
1975
- 1975-08-08 CA CA233,102A patent/CA1064478A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| JPS596879B2 (en) | 1984-02-15 |
| JPS5152195A (en) | 1976-05-08 |
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