CA1244823A - Thiazole derivatives - Google Patents
Thiazole derivativesInfo
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- CA1244823A CA1244823A CA000444818A CA444818A CA1244823A CA 1244823 A CA1244823 A CA 1244823A CA 000444818 A CA000444818 A CA 000444818A CA 444818 A CA444818 A CA 444818A CA 1244823 A CA1244823 A CA 1244823A
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Abstract
Abstract A novel aminothiazoleacetic acid derivative which is an advantageous synthetic intermediate for .beta.-lactam antibiotics, and its production method and use. Starting with diketene, the production method comprises the following sequence of steps.
halogenation Diketene ? 4-haloacetoacetyl halide (In the above formulas, R is lower alkyl or phenyl; R1 and R2 each are hydrogen or lower alkyl; X and X' each are halogen;
W is S or SO2; and W' is OH or
halogenation Diketene ? 4-haloacetoacetyl halide (In the above formulas, R is lower alkyl or phenyl; R1 and R2 each are hydrogen or lower alkyl; X and X' each are halogen;
W is S or SO2; and W' is OH or
Description
B~3 Thiazole Derivatives This invention relates to novel aminothiazoleacetic acid derivatives which are useful as synthetic intermediates for ~-lactam antibiotics, a prccess for preparing the same, and a use thereof.
As synthetic intermediates useful for the production of ~-lactam antibiotics having high antimicrobial activities, such as penicillins, cephalosporins, etc., there are known
As synthetic intermediates useful for the production of ~-lactam antibiotics having high antimicrobial activities, such as penicillins, cephalosporins, etc., there are known
2-(2-aminothiazol-4-yl)-(Z)-2-(carboxyalkyloxyimino)-acetic acid derivatives. For example, some of them have been used as the 7-side chain groups of ceftazidime, etc.
which are known as the so-called third generation anti-biotics, while other have been considered to be promising side chain moieties of azetidinones which are candidates of the fourth generation antibiotics. It is therefore expected thàt such and other 2-(2-aminothiazol-4-yl)-(Z)-2-(carboxyalkyloxyimino)-acetic acid derivatives will be utilized more often than they are today.
So far, many different processes have been proposed for the production of such 2-(2-aminothiazol-4-yl)-(Z)-2Q 2-(carboxyalkyloxyimino)-acetic acid d~rivatives, and among these known processes, the commercially advantageous processes may be classified into the following two major categories. One of the categories includes the method starting with an acetoacetic acid alkyl ester, which comprises oximating the ester with an alkali nitrite to an oxyiminoacetic~acid ester, etherlfying the oxime and, then, `
halogenating, and finally cyclizing the halogenation product with thiourea. The other category includes the method starting with 4-chloroacetoacetyl chloride, which comprises reacting the chloride with ethanol, butanol or the like to give a 4-chloroacetoacetic acid ester, oximat-ing the ester with an alkali nitrite, cyclizing the oxime with thiourea to give a 2-(2-amino~hiazol-4-yl)-(Z)-2-hydroxyiminoacetic acid ester, and finally etherifying the ester.
The 2-(2-aminothiazol-4-yl)-(Z)-2-(carboxyalkyloxy-imino)-acetic acid derivatives thus obtained are utilized, each in the form of acid halide, acid anhydride or active amide, as acylating agents in the synthesis of ~-lactam antibiotics. In this acylation reaction, it is necessary to use a 2-(2-aminothiazol-4-yl)-(Z)-2-(carboxyalkyloxy-imino)-acetic acid derivative whose amino group has been protected so as to prevent occurrence of side reactions, with the result that in the synthetic processes heretofore used, 2-(2-aminothiazol-4-yl)-(Z)-2-(carboxyalkyloxyimino)-acetic acid derivatives whose amino groups have beenprotected are mainly synthesized. Moreover, because the carboxy group in the carboxyalkyloxyimino moiety and the carboxy group in the acetic acid moiety of such 2-~2-aminothiazol-4-yl)-(Z)-2-(carboxyalkyloxyimino)-acetic acid derivatives are more or less alike in chemical property, the carboxy group in the carboxyalkyloxyimino moiety must be protected to prevent side reactions before the derivatives are converted to reactive derivatives such as acid halides, acid anhydrides, active amides, etc.
As protective groups for the carboxy group in the carboxv-alkyloxyimino moiety, those groups which can be eliminated by catalytic reduction, such as p-nitrobenzyl, have been commonly employed but these groups are commercially disadvantageous in that it is difficult to remove them following the acylation reaction mentioned above. There has also been employed a tert-butyl group which is thought to be removable by acid hydrolysis but in the aforementioned second method for producing 2-(2-aminothiazol-4-yl)~(Z)-2-(carboxyalkyloxyimino)-acetic acid derivatives wherein the earboxy group in the acetic acid moiety has been mostly esterified by an alkyl group, the tert-butyl group is also eliminated during the de-esterification reaction prior to said conversion to reactive derivatives. Thus, there has not been established an industrially profitable method for producing an 2-(2-aminothiazol-4-yl) (Z)-2-(earboxyalkyloxyimino)-aeetic aeid derivative whose amino group and carboxy group in the acetic acid moiety have not been protected but whose earboxy group in the earboxy-alkyloxyimino moiety only has been proteeted.
The present inventors found that in utilizing an 2-(2-aminothiazol-4-yl)-~Z)-2-(earboxyalkyloxyimino)-aeetie aeid derivative as an aeylating agent for the synthetie produetion of ~-laetam antibioties, the steps of proteeting the amino group prior to the aeylation reaetion to prevent side reaetions and removing the protective group for the amino group after the acylation reaction can be omitted if the 2-(2-aminothiazol-4-yl)-(Z)-2-(earboxyalkyloxyimino)_ aeetie aeid derivative is used in the form of an aetive thioester, and eonducted a study to develop a eommereially advantageous proeess ior produeing an 2-(2-aminothiazol-4-yl)-(Z)-2-(earboxyalkyloxyimino)-aeetie aeid derivative of whieh the amino group and the earboxy group in the aeetie aeid moiety are unproteeted and the earboxy group in the earboxyalkyloxyimino moiety is proteeted. It was, found, surprisingly, that among the various eonceivable eombinations of reaction steps, the following process provides a novel aminothiazoleacetie acid derivative of the formula ~ . ..
:
8~3 2 ~ ~
- N C-COW' (I) OCCOOC(CH3)3 wherein Rl and R2 each are a hydrogen atom or a lower alkyl group, and W' is h~droxyl or 2-benzothiazolylthio, or a salt thereof in good yield. Thus, this process comprises reacting diketene with a halogen and then with a ~-lower alkyl- or phenyl-thio- or sulfonyl-ethanol, oximating the reaction product withnitrous acid or a salt thereof, reacting it further with thiourea or a salt thereof, etherifying the oxime, if necessary oxidizing the same, and finally eliminatiny the protective group for the carboxy group in the acetic acid moiety. ~his process permits easy and selective removal of the protective group from said carboxy group in acetic acid moiety. It was further found that the compound tI) wherein W' is O~
thus obtained can be reacted with 2,2-dithiobis-benzo-thiazole to produce an active thioester, i.e. the compound (I) wherein W' is 2-benzothiazolylthio, which is an advantageous synthetic intermediate for ~~lactam antibiotics.
The present invention is based on the above findings.
Thus, this invention relates to an aminothiazole-acetic acid derivative (I), a use of the derivati~e (I) as an intermediate for the synthetic production of ~-lactam antibiotics, and a process for preparing the derivative (I) characterized by:
reacting diketene with halogen;
reacting the resulting 4~haloacetoacetyl halide with an alcohol of formula (II):
R-W-C2H4OH (II) wherein R is lower alkyl or phenyl; and W is S or SO2;
reacting the resulting compound of formula (III):
CH2Coc 2CO 2 4 (III) whereln X is~a halogen atom; and R and W are as defined 1~4~823 above with nitrous acid or a salt thereof;
reacting the resulting compound of formula (IV):
XcH2colclcooc2H4-~-R ~IV) NOH
wherein the symb'ols are as defined above, with thiourea or a salt thereof;
reacting the resulting compound of formula (V):
N~ ~_C-COOC H -W-R (V) OH
wherein the symbols are as defined above or a salt thereof, with a compound of formula (VI):
X'-C-COOC(CH3)3 (VI) wherein X' is a halogen atom; and other symbols are as defined above, to produce a compound of formula (V') N ~ C-COOC2H4-W-R (V') N\ ll O-CI-COOC(CH3)3 wherein the symbols are as defined above, or a salt 5 thereof;
o~idizing further the reaction product (V') or a salt thereof when W is S; and (i) hydrolyæing the resulting compound of formula (VII):
Nl ~ C-COOC2H4SO2R (VII) o-c-coac (CH3)3 wherein the sybmols are as deined above, or a salt thereof, in the presence of a base, to obtain the derivative (I) wherein W' lS OH or (ii) hydrolyzing the compound (VII) .
or a salt thereof in the presence of a base, and reacting the obtained derivative (I) wherein W' is OH with 2,2-dithiobis-benzothiazole to obtain the derivative (I) wherein W' is 2-benzothiazolylthio.
Referring to the above formulas, Rl and R2 are the same or different and each represents hydrogen or lower alkyl. The lower alkyl group Rl or R2 may be a group containing l to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc. Preferred are the cases in which both Rl and R2 are hydrogen or methyl, or one of Rl and R2 is hydrogen and the other methyl. R is lower alkyl or phenyl. The lower alkyl R may for example be a Cl 4 lower alkyl as mentioned for Rl and R2. Preferred examples of R are methyl and ethyl. The halogen X, X' may for example be chlorine, bromine, iodine or fluorine. X and X' may be the same halogen or different halogens. Frequently used examples of X and X' are chlorine and bromine. W stands for S or SO2 W' is OH or -S ~/S ~
In the method accoxding to this invention, diketene is reacted with a halogen in the first place to give a 4-haloacetoacetyl halide. In this step, diketene may be reacted with an equimolar or slig~htly less than equimolar amount of a halogen under cooling. This reaction may be conducted in a solvent. As the solvent, a halogenated hydrocarbon such as methylene chloride, chloroform, etc., an ester such as ethyl acetate, etc., or an ether such as ether, dioxane, etc., for instance, may be employed.
The reaction may be conducted under cooling, i.e. from -70C to 10C. The reaction time may be very short and generally the reaction may go to completion substantially upon completion of addition of the halogen. It may be, therefore! sufficient to stir the reaction system for about 30 minutes after addition of the halogen. The resulting 4-haloacetoacetyl halide can be separated and purified by the conventional procedure, e.g. concentration, ... .
i323 solvent extraction, pH adjustment, crystallization, chromatography, etc., but it is advantageous to submit the reaction mixture as such to the next reaction step.
The 4-haloacetoacetyl halide is then reacted with alcohol (II) to give compound ~III).
In this step, the 4-haloacetoacetyl halide is preferably reacted with an equivalent or slightly less than equivalent amount of alcohol (II). This reaction may be conducted in a solvent. The solvent may be any solvent that does not interfere with the reaction, and may be preferably a halogenated hydrocarbon such as methylene chloride, chloroform, carbon tetrachloride, etc. or an ether such as tetrahydrofuran, dioxane, diethyl ether, etc., for instance. Further, this reaction is preferably carried out in the presence of a base. As such a base, there may, for example, be employed aromatic amines such as pyridine, picoline, N,N-dimethylaniline, etc. and aliphatic tertiary amines such as trimethylamine, triethylamine, etc. The amount of the base is about 1-3 moles per mole of alcohol (II). Generally, the reaction may be conducted under cooling or at room temperature (at -20 to 40C). The reaction generall~ goes to completion in tens of minutes to a few hours. The resulting 4-haloacetoacetic acid ester (III) can be purified by the conventional purification procedure such as distillation, phasic transfer, recrystal-lization, etc. but since this reaction proceeds in high yield, the reaction mixture may be submitted to the next reaction step without prior purification.
The 4-haloacetoacetic acid ester (III) is then reacted with nitrous acid or a salt thereof to give the oxime.
The reaction is generally carried out using compound (III~ and nitrous acid in an approximately equimolar ratio, although nitrous acid may be used in slight excess. While nitrous acid may be used as it is, it can be used as a salt with an~alkali metal su-h as sodium or potassium, for instance The reaction may proceed in a solvent~ The reaction temperature may be under cooling or at room temperature (at -50 to 50C, preferably -10 to 40C). The solvent used for this reaction may for example be an ether, e.g. tetrahydrofuran, dioxane, diethyl ether, etc., a fatty acid such as glacial acetic acid, or a mixture thereof. The amount of water which may be added to such solvent is virtually op~ional. As an alternative, an aqueous solution of nitrite (e.g. sodium nitrite) may be added to consequently introduce water into the reaction system. The reaction time depends on the amounts of starting compounds, the solvent, etc. The reaction may go to completion in a very short time (20 minutes to 3 hours). The product oxime (IV) can be purified by the known procedure such as distillation, solvent extraction, concentration, recrystallization<, etc., but it is generally unnecessary to purify it but the reaction mixture as such may be used as the reactant for the next step.
The compound (V) or a salt thereof can be produced by reacting this oxime compound (IV) with thiourea or a salt thereof.
Generally, each mole of compound (IV) is reacted with one mole or a slight excess of thiourea or a salt thereof, although thiourea may be used in larger excess unless the reaction is not thereby adversely affected. As a salt of thiourea, there may, for example, be a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc. This reaction is generally conducted in a solvent. The solvent is preferably a mixture of water with a water-miscible solvent such as an alcohol, eOg. methanol, ethanol, etc~, a ketone, e.g. acetone, diethyl ketone, etc., an ether e.g~ tetrahydrofuran, dioxane, diethyl ether, etc., an acid amide, e.g. N,N-dimethylformamide, N,N-dimethyl-acetamide, etc., or an organic amine, e.g. N-methyl-piperidone, etc. Furthermore, the syn~isomer (V) is selectively produced when the reaction is conducted in the presence of a basic reagent. The basic reagent used for this reaction may be an alkali metal or alkaline earth metal salt of a lower aliphatic carbo~ylic acid, or an inorganic or organic base having a pKa value of 9,5 or more, preferably a pKa value of 9.8 to 12Ø Examples of the lower aliphatic carboxylic acid salt include salts of lower aliphatic carboxylic acids containing 1 to 6 carbon atoms, e.g. sodium acetate, potassium acetate, calcium acetate, barium acetate, sodium formate, sodium propionate, potassium hexanoate, etc. The inorganic base may for example be a carbonic acid al~ali metal salt such as sodium carbonate, potassium carbonate, etc. While, the organic base is exemplified by tri-lower (Cl 4)alkyl-substituted amines such as trimethylamine, triethylamine,tributylamine, etc. and N-lower (Cl 2)alkyl-substituted 5- to 6-membered cyclic amines such as N-methylpyrrolidine, N-ethylpyrrolidine, N-methylpiperazine, N-ethylpiperazine, etc. When any of said N,N-dimethylformamide, N,N~dimethyl-acetamide and N-methylpyrrolidone is used as the solvent, the above-mentioned base may not necessarily be added.
While the addition level of such base depends on the kinds of starting material and solvent, it may range from O.S to 1.5 moles pex mole of compound (IV). The reaction is generally conducted at 0 to 40C, although the reaction system may be cooled or warmed to control the reaction rate. The reaction may to completion in 10 minutes to 4 hours. The resulting compound of formula (V) can be separated and purified by the conventional procedure such as distillation, pH adjustment, crystallization, recrystal-lization, etc. When the a -isomer i5 included as an impurity, it-can be separated by the conventional procedure such as fractional crystallization, chromatography, etc.
Since compound (V) has basic amino group in 2-position of the thiazole ring, it may be converted to the salt with an organic acid such as acetic acid, tartaric acid, ~4~23 methanesulfonic acid, etc., an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc~ or an acidic amino acid such as arginine, aspartic acid, glutamic acid, etc. by the con-ventional procedure and isolated as such salt.
The compound (V) or a salt thereof is then reacted with compound (VI) and, if W is S, the reaction product is further oxidized to a compound of formula (VII) or a salt thereof.
The compound (V) may be one having a free amino group or one in which the amino group has formed a salt with one of the acids as mentioned above. Theoretically, one molar equivalent of compound (VI) may be reacted with one equivalent of compound (V) or a salt thereof. Usually, however, 1.5 to 2.0 equivalents of compound (VI) may be used per mole of compound (V) or a salt thereof. This reaction is conducted in a solvent.
The solvnet is preferably a ketone such as acetone, methyl ethyl ketone, etc. or a nitrile such as acetonitrile, propionitrile, etc.
~ base may be added to the reaction system for the purpose of conducting the reaction advantageously. The base may be any base that will promote the reaction and is preferably an alkali carbonate such as potassium carbonate, sodium carbonate, sodium hydrogen carbonate, etc. The amount of such base may be 1.5 to 10 molar equivalents, preferably 1.5 to 5 equivalents, based on starting compound (V). For a smooth conduct of the reac-tion, it is preferable to add water to the reaction system, and particularly to the solvent, and the addition level of water may be 0.1 to 2% by volume, preferably 0.5 to 1.5% by volume, relative to the solvent. The reaction temperature may be 10 to 60C and preferably 20 to 50C.
Under these conditions the reaction proceeds quantitatively and the starting materials disappear in 0.5 to 3 hours.
rrhus, the reaction may be completed at this time point.
After completion of the reaction, the desired ~y~-isomer (V') can be separated and purified by the conventional procedure such as extraction, pH adjustment, chromatography, etc.
When W of compound (V) is S, the resulting compound of the formula [i.e. the formula (V') wherein W is S]:
N ~ C-COOC2H4SR (VII') N\ ll O-C-COOC(CH3)3 wherein the symbols are as defined hereinbefore, is further oxidized to compound (VII). This oxidation of sulfide to sulfone is conducted using an oxidizing agent such as hydrogen peroxide, ozone or a peracid (e.g. sodium meta-periodate, perbenzoic acid, etc.). Among others, hydrogen peroxide, etc. is employed. The reaction may be readily accelerated by adding a catalyst to such oxidizing agent.
For example, when hydrogen peroxide is used as the oxidizing agent, the addition of a catalytic amount of ammonium molybdate, sodium tungustate or the like accelerates the reaction. The amount of oxidizing agent may ~e 2 to 15 molar equivalents, pre~erably 2 to 7 equivalents, relative to the sulfide. This reaction may be conducted at 0 to 40C, and preferably at room tempera-ture. The reaction may go to completion in 2 to 7 hours.
This reaction is conducted in a solvent. As the solvent, there may be employed a hydrophilic solvent such as acetone, acetonitrile, glacial acetic acid, etc~, for instance,and these solvents may be used in admixture with water.
The resulting sulfone (VII) can be separated and purified by the conventional procedure such as extraction, crystallization,~chromatography, etc. However, since ~2~23 this reaction is substantially not accompanied by side reactions, the reaction mixture may be directly submitted to the next reaction step, i.e. hydrolysis under alkaline conditions, on completion of the oxidation reaction.
The compounds (V'), (VII') and (VII), as well as compound (V), have an amino group in 2-position of the thiazole ring and, therefore, can be converted to a salt such as those mentioned for compound (V) before isolation.
However, the reaction mixture as such i~s preferably submitted to^the next hydrolysis step without separation of compound (VII) or a salt thereof.
The compound (VII) or a salt thereof prepared as above is then hydrolyzed in the presence of a base to give the desired compound (I) wherein W' is OH or a salt thereof.
While it is more convenient to use the reaction mixture from the synthesis of (VII) than to employ the isolated compound (VII), the latter may of course be employed either as a free compound or in the form of salt referred to above. Hydrolysis of compound (VII) or a salt thereof may be conducted by permitting a base to act on (VII) or a salt thereof. The hydrolysis may be conducted a hydro-philic solvent. Water may be added to accelerate the reaction. When a base was employed in the synthesis of (VII), the addition of water alone to the reaction mixture causes hydrolysis to take place in succession to the formation of (VII). The hydrophilic solvent may for example be an alcohol, e.g. methanol; ethanol, etc.; a ketone, e.g. acetone, etc.; or a nitrile, e.g. acetonitrile.
The amount of the solvent may be 2 to 50 volumes, preferably 5 - 10 volumes, relative to the compound (VII). The amount of water to be mixed with such solvent may be 0.5 to 10 volumes, relative to the solvent. The hydrolysis temperature is preferably 5 to 50C. The base may be any one showing pH ranging from about 9 to 12, and may for example be an alkali carbonate such as potassium hydrogen carbonate, potassium carbonate, etc. or an organic amine ~2~3Z3 such as triethylamine, isopropylamine, etc. The amount of the base is preferably one molar equivalent to about ~ equivalents, relative to the compound (VII) or a salt thereof and the hydrolysis generally may go to completion in 30 minutes to 2 hours. The resulting com-pound (I) wherein W' is OH can be separated and purified by the conventional procedure mentioned hereinbefore.
However, the reaction mixture as such may be submitted to the next step without separation of the compound (I) wherein W' is OH. The product compound (I) wherein W' is OH can be converted to an acid salt at the 2-amino group of the thiazole ring just as mentioned for compounds (V) and (VII), and because it has a carboxy group, can also be converted to the salt of an alkali metal such as sodium, potassium, etc. or an alkaline earth metal such~às ~alcium, magnesium, etc. by the conventional procedure.
The product compound (I) wherein W' is OH thus ` obtained can be easily converted to an active thioester at the carboxy group thereof, i.e. the compound (I) wherein W' is -S ~ ~ and can be used as an advantageous acylating agent in the synthesis of ~-lactam antibiotics.
In this application, the steps of protecting the amino group prior to the acylation reaction to prevent side reactions and removing the protective group for the amino group after the acylation reaction, which are necessary in the conventional method for producing the ~-lactam antibiotics, can be omitted~ N
` The compound (I) wherein W' is ~S~~s ~ is produced by reacting the compound (I) wherein W' is O~
with 2,2-dithiobis-benzothiazole. 2,2-Dithiobis-benzo-thiazole may be used in an amount of 1 to 4 moles per mole of (I) wherein W' is OH. The reaction may be conducted in an inactive organic solvent having no hydroxy group in its molecule. A phosphine or phosphite may be added to the reaction system to accelerate the reaction.
As such a phosphine, use may be made of aryl phosphines such as triphenyl phosphine, and as such a phosphite~ use may be made of tri-lower alkyl phosphites such a.s trimethyl phosphite or triethyl phosphite. The phosphine or phosphite is preferably used in an amount of 1 to 2 moles per 1 mole of (I) wherein W' is OH~ The inactive organic solvent in this reaction includes halogenated hydrocarbons such as dichloromethane, chloroform, etc., nitriles such as acetonitrile, propionitrile, etc., esters such as ethyl acetate, isopropyl acetate, etc. Among them, nitriles such as acetonitrile, for instance~ are especially preferable. The amount of the solvent may be 10 -50 times (weight) of that of the compound (I) wherein W' is OH. In order to dissolve ~I) wherein W' is OH, a base may be added to the solvent. For example, an organic base such as pyridine, N-methylmorpholine, triethylamine, etc. may be used as the base. The amount of the base may be 1- 2.5 moles per 1 mole of (I) wherein W' is OH. The reaction temperature is normally -30C -50C, preferably -20C - 25C, more preferably -5C -5C. The reaction time is usually about 1 -20 hours. Generally, thus obtained compound (I) wherein W' is 2-benzothiazolylthio(-S <N ~ ) f~rms precipitation and so may be isolated by filtration. If necessary, before the filtration, putting the obtained reaction mixture into water, extracting the aqueous-solution with such an organic solvent as mentioned above and then adding n-hexane, etc. to the extract in this order may be conducted to get the compound (I) wherein W' is 2-benzothiazolylthio as precipitates. Thus, e.g. 2-(2-amino~
thiazol-4-yl)-(Z)-2-(t-butoxycarbonylmethoxyimino)-acetic acid or 2-(2-aminothiazol-4-yl)-(Z)-2-(1-t-butoxycarbonyl-l-methylethoxyimino) acetic acid may be converted to a 2-benzothiazolethio ester, then the latter may be reacted with 7-amino-3-pyridinomethyl-3-cephem-4-carboxylate, and finally the protective group for the carboxy group may be eliminated in the conventionlal manner to give 7-[2-(2-aminothiazol-4-yl)-(Z)-2-(carboxymethoxyimino)acetamido]
which are known as the so-called third generation anti-biotics, while other have been considered to be promising side chain moieties of azetidinones which are candidates of the fourth generation antibiotics. It is therefore expected thàt such and other 2-(2-aminothiazol-4-yl)-(Z)-2-(carboxyalkyloxyimino)-acetic acid derivatives will be utilized more often than they are today.
So far, many different processes have been proposed for the production of such 2-(2-aminothiazol-4-yl)-(Z)-2Q 2-(carboxyalkyloxyimino)-acetic acid d~rivatives, and among these known processes, the commercially advantageous processes may be classified into the following two major categories. One of the categories includes the method starting with an acetoacetic acid alkyl ester, which comprises oximating the ester with an alkali nitrite to an oxyiminoacetic~acid ester, etherlfying the oxime and, then, `
halogenating, and finally cyclizing the halogenation product with thiourea. The other category includes the method starting with 4-chloroacetoacetyl chloride, which comprises reacting the chloride with ethanol, butanol or the like to give a 4-chloroacetoacetic acid ester, oximat-ing the ester with an alkali nitrite, cyclizing the oxime with thiourea to give a 2-(2-amino~hiazol-4-yl)-(Z)-2-hydroxyiminoacetic acid ester, and finally etherifying the ester.
The 2-(2-aminothiazol-4-yl)-(Z)-2-(carboxyalkyloxy-imino)-acetic acid derivatives thus obtained are utilized, each in the form of acid halide, acid anhydride or active amide, as acylating agents in the synthesis of ~-lactam antibiotics. In this acylation reaction, it is necessary to use a 2-(2-aminothiazol-4-yl)-(Z)-2-(carboxyalkyloxy-imino)-acetic acid derivative whose amino group has been protected so as to prevent occurrence of side reactions, with the result that in the synthetic processes heretofore used, 2-(2-aminothiazol-4-yl)-(Z)-2-(carboxyalkyloxyimino)-acetic acid derivatives whose amino groups have beenprotected are mainly synthesized. Moreover, because the carboxy group in the carboxyalkyloxyimino moiety and the carboxy group in the acetic acid moiety of such 2-~2-aminothiazol-4-yl)-(Z)-2-(carboxyalkyloxyimino)-acetic acid derivatives are more or less alike in chemical property, the carboxy group in the carboxyalkyloxyimino moiety must be protected to prevent side reactions before the derivatives are converted to reactive derivatives such as acid halides, acid anhydrides, active amides, etc.
As protective groups for the carboxy group in the carboxv-alkyloxyimino moiety, those groups which can be eliminated by catalytic reduction, such as p-nitrobenzyl, have been commonly employed but these groups are commercially disadvantageous in that it is difficult to remove them following the acylation reaction mentioned above. There has also been employed a tert-butyl group which is thought to be removable by acid hydrolysis but in the aforementioned second method for producing 2-(2-aminothiazol-4-yl)~(Z)-2-(carboxyalkyloxyimino)-acetic acid derivatives wherein the earboxy group in the acetic acid moiety has been mostly esterified by an alkyl group, the tert-butyl group is also eliminated during the de-esterification reaction prior to said conversion to reactive derivatives. Thus, there has not been established an industrially profitable method for producing an 2-(2-aminothiazol-4-yl) (Z)-2-(earboxyalkyloxyimino)-aeetic aeid derivative whose amino group and carboxy group in the acetic acid moiety have not been protected but whose earboxy group in the earboxy-alkyloxyimino moiety only has been proteeted.
The present inventors found that in utilizing an 2-(2-aminothiazol-4-yl)-~Z)-2-(earboxyalkyloxyimino)-aeetie aeid derivative as an aeylating agent for the synthetie produetion of ~-laetam antibioties, the steps of proteeting the amino group prior to the aeylation reaetion to prevent side reaetions and removing the protective group for the amino group after the acylation reaction can be omitted if the 2-(2-aminothiazol-4-yl)-(Z)-2-(earboxyalkyloxyimino)_ aeetie aeid derivative is used in the form of an aetive thioester, and eonducted a study to develop a eommereially advantageous proeess ior produeing an 2-(2-aminothiazol-4-yl)-(Z)-2-(earboxyalkyloxyimino)-aeetie aeid derivative of whieh the amino group and the earboxy group in the aeetie aeid moiety are unproteeted and the earboxy group in the earboxyalkyloxyimino moiety is proteeted. It was, found, surprisingly, that among the various eonceivable eombinations of reaction steps, the following process provides a novel aminothiazoleacetie acid derivative of the formula ~ . ..
:
8~3 2 ~ ~
- N C-COW' (I) OCCOOC(CH3)3 wherein Rl and R2 each are a hydrogen atom or a lower alkyl group, and W' is h~droxyl or 2-benzothiazolylthio, or a salt thereof in good yield. Thus, this process comprises reacting diketene with a halogen and then with a ~-lower alkyl- or phenyl-thio- or sulfonyl-ethanol, oximating the reaction product withnitrous acid or a salt thereof, reacting it further with thiourea or a salt thereof, etherifying the oxime, if necessary oxidizing the same, and finally eliminatiny the protective group for the carboxy group in the acetic acid moiety. ~his process permits easy and selective removal of the protective group from said carboxy group in acetic acid moiety. It was further found that the compound tI) wherein W' is O~
thus obtained can be reacted with 2,2-dithiobis-benzo-thiazole to produce an active thioester, i.e. the compound (I) wherein W' is 2-benzothiazolylthio, which is an advantageous synthetic intermediate for ~~lactam antibiotics.
The present invention is based on the above findings.
Thus, this invention relates to an aminothiazole-acetic acid derivative (I), a use of the derivati~e (I) as an intermediate for the synthetic production of ~-lactam antibiotics, and a process for preparing the derivative (I) characterized by:
reacting diketene with halogen;
reacting the resulting 4~haloacetoacetyl halide with an alcohol of formula (II):
R-W-C2H4OH (II) wherein R is lower alkyl or phenyl; and W is S or SO2;
reacting the resulting compound of formula (III):
CH2Coc 2CO 2 4 (III) whereln X is~a halogen atom; and R and W are as defined 1~4~823 above with nitrous acid or a salt thereof;
reacting the resulting compound of formula (IV):
XcH2colclcooc2H4-~-R ~IV) NOH
wherein the symb'ols are as defined above, with thiourea or a salt thereof;
reacting the resulting compound of formula (V):
N~ ~_C-COOC H -W-R (V) OH
wherein the symbols are as defined above or a salt thereof, with a compound of formula (VI):
X'-C-COOC(CH3)3 (VI) wherein X' is a halogen atom; and other symbols are as defined above, to produce a compound of formula (V') N ~ C-COOC2H4-W-R (V') N\ ll O-CI-COOC(CH3)3 wherein the symbols are as defined above, or a salt 5 thereof;
o~idizing further the reaction product (V') or a salt thereof when W is S; and (i) hydrolyæing the resulting compound of formula (VII):
Nl ~ C-COOC2H4SO2R (VII) o-c-coac (CH3)3 wherein the sybmols are as deined above, or a salt thereof, in the presence of a base, to obtain the derivative (I) wherein W' lS OH or (ii) hydrolyzing the compound (VII) .
or a salt thereof in the presence of a base, and reacting the obtained derivative (I) wherein W' is OH with 2,2-dithiobis-benzothiazole to obtain the derivative (I) wherein W' is 2-benzothiazolylthio.
Referring to the above formulas, Rl and R2 are the same or different and each represents hydrogen or lower alkyl. The lower alkyl group Rl or R2 may be a group containing l to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc. Preferred are the cases in which both Rl and R2 are hydrogen or methyl, or one of Rl and R2 is hydrogen and the other methyl. R is lower alkyl or phenyl. The lower alkyl R may for example be a Cl 4 lower alkyl as mentioned for Rl and R2. Preferred examples of R are methyl and ethyl. The halogen X, X' may for example be chlorine, bromine, iodine or fluorine. X and X' may be the same halogen or different halogens. Frequently used examples of X and X' are chlorine and bromine. W stands for S or SO2 W' is OH or -S ~/S ~
In the method accoxding to this invention, diketene is reacted with a halogen in the first place to give a 4-haloacetoacetyl halide. In this step, diketene may be reacted with an equimolar or slig~htly less than equimolar amount of a halogen under cooling. This reaction may be conducted in a solvent. As the solvent, a halogenated hydrocarbon such as methylene chloride, chloroform, etc., an ester such as ethyl acetate, etc., or an ether such as ether, dioxane, etc., for instance, may be employed.
The reaction may be conducted under cooling, i.e. from -70C to 10C. The reaction time may be very short and generally the reaction may go to completion substantially upon completion of addition of the halogen. It may be, therefore! sufficient to stir the reaction system for about 30 minutes after addition of the halogen. The resulting 4-haloacetoacetyl halide can be separated and purified by the conventional procedure, e.g. concentration, ... .
i323 solvent extraction, pH adjustment, crystallization, chromatography, etc., but it is advantageous to submit the reaction mixture as such to the next reaction step.
The 4-haloacetoacetyl halide is then reacted with alcohol (II) to give compound ~III).
In this step, the 4-haloacetoacetyl halide is preferably reacted with an equivalent or slightly less than equivalent amount of alcohol (II). This reaction may be conducted in a solvent. The solvent may be any solvent that does not interfere with the reaction, and may be preferably a halogenated hydrocarbon such as methylene chloride, chloroform, carbon tetrachloride, etc. or an ether such as tetrahydrofuran, dioxane, diethyl ether, etc., for instance. Further, this reaction is preferably carried out in the presence of a base. As such a base, there may, for example, be employed aromatic amines such as pyridine, picoline, N,N-dimethylaniline, etc. and aliphatic tertiary amines such as trimethylamine, triethylamine, etc. The amount of the base is about 1-3 moles per mole of alcohol (II). Generally, the reaction may be conducted under cooling or at room temperature (at -20 to 40C). The reaction generall~ goes to completion in tens of minutes to a few hours. The resulting 4-haloacetoacetic acid ester (III) can be purified by the conventional purification procedure such as distillation, phasic transfer, recrystal-lization, etc. but since this reaction proceeds in high yield, the reaction mixture may be submitted to the next reaction step without prior purification.
The 4-haloacetoacetic acid ester (III) is then reacted with nitrous acid or a salt thereof to give the oxime.
The reaction is generally carried out using compound (III~ and nitrous acid in an approximately equimolar ratio, although nitrous acid may be used in slight excess. While nitrous acid may be used as it is, it can be used as a salt with an~alkali metal su-h as sodium or potassium, for instance The reaction may proceed in a solvent~ The reaction temperature may be under cooling or at room temperature (at -50 to 50C, preferably -10 to 40C). The solvent used for this reaction may for example be an ether, e.g. tetrahydrofuran, dioxane, diethyl ether, etc., a fatty acid such as glacial acetic acid, or a mixture thereof. The amount of water which may be added to such solvent is virtually op~ional. As an alternative, an aqueous solution of nitrite (e.g. sodium nitrite) may be added to consequently introduce water into the reaction system. The reaction time depends on the amounts of starting compounds, the solvent, etc. The reaction may go to completion in a very short time (20 minutes to 3 hours). The product oxime (IV) can be purified by the known procedure such as distillation, solvent extraction, concentration, recrystallization<, etc., but it is generally unnecessary to purify it but the reaction mixture as such may be used as the reactant for the next step.
The compound (V) or a salt thereof can be produced by reacting this oxime compound (IV) with thiourea or a salt thereof.
Generally, each mole of compound (IV) is reacted with one mole or a slight excess of thiourea or a salt thereof, although thiourea may be used in larger excess unless the reaction is not thereby adversely affected. As a salt of thiourea, there may, for example, be a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc. This reaction is generally conducted in a solvent. The solvent is preferably a mixture of water with a water-miscible solvent such as an alcohol, eOg. methanol, ethanol, etc~, a ketone, e.g. acetone, diethyl ketone, etc., an ether e.g~ tetrahydrofuran, dioxane, diethyl ether, etc., an acid amide, e.g. N,N-dimethylformamide, N,N-dimethyl-acetamide, etc., or an organic amine, e.g. N-methyl-piperidone, etc. Furthermore, the syn~isomer (V) is selectively produced when the reaction is conducted in the presence of a basic reagent. The basic reagent used for this reaction may be an alkali metal or alkaline earth metal salt of a lower aliphatic carbo~ylic acid, or an inorganic or organic base having a pKa value of 9,5 or more, preferably a pKa value of 9.8 to 12Ø Examples of the lower aliphatic carboxylic acid salt include salts of lower aliphatic carboxylic acids containing 1 to 6 carbon atoms, e.g. sodium acetate, potassium acetate, calcium acetate, barium acetate, sodium formate, sodium propionate, potassium hexanoate, etc. The inorganic base may for example be a carbonic acid al~ali metal salt such as sodium carbonate, potassium carbonate, etc. While, the organic base is exemplified by tri-lower (Cl 4)alkyl-substituted amines such as trimethylamine, triethylamine,tributylamine, etc. and N-lower (Cl 2)alkyl-substituted 5- to 6-membered cyclic amines such as N-methylpyrrolidine, N-ethylpyrrolidine, N-methylpiperazine, N-ethylpiperazine, etc. When any of said N,N-dimethylformamide, N,N~dimethyl-acetamide and N-methylpyrrolidone is used as the solvent, the above-mentioned base may not necessarily be added.
While the addition level of such base depends on the kinds of starting material and solvent, it may range from O.S to 1.5 moles pex mole of compound (IV). The reaction is generally conducted at 0 to 40C, although the reaction system may be cooled or warmed to control the reaction rate. The reaction may to completion in 10 minutes to 4 hours. The resulting compound of formula (V) can be separated and purified by the conventional procedure such as distillation, pH adjustment, crystallization, recrystal-lization, etc. When the a -isomer i5 included as an impurity, it-can be separated by the conventional procedure such as fractional crystallization, chromatography, etc.
Since compound (V) has basic amino group in 2-position of the thiazole ring, it may be converted to the salt with an organic acid such as acetic acid, tartaric acid, ~4~23 methanesulfonic acid, etc., an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc~ or an acidic amino acid such as arginine, aspartic acid, glutamic acid, etc. by the con-ventional procedure and isolated as such salt.
The compound (V) or a salt thereof is then reacted with compound (VI) and, if W is S, the reaction product is further oxidized to a compound of formula (VII) or a salt thereof.
The compound (V) may be one having a free amino group or one in which the amino group has formed a salt with one of the acids as mentioned above. Theoretically, one molar equivalent of compound (VI) may be reacted with one equivalent of compound (V) or a salt thereof. Usually, however, 1.5 to 2.0 equivalents of compound (VI) may be used per mole of compound (V) or a salt thereof. This reaction is conducted in a solvent.
The solvnet is preferably a ketone such as acetone, methyl ethyl ketone, etc. or a nitrile such as acetonitrile, propionitrile, etc.
~ base may be added to the reaction system for the purpose of conducting the reaction advantageously. The base may be any base that will promote the reaction and is preferably an alkali carbonate such as potassium carbonate, sodium carbonate, sodium hydrogen carbonate, etc. The amount of such base may be 1.5 to 10 molar equivalents, preferably 1.5 to 5 equivalents, based on starting compound (V). For a smooth conduct of the reac-tion, it is preferable to add water to the reaction system, and particularly to the solvent, and the addition level of water may be 0.1 to 2% by volume, preferably 0.5 to 1.5% by volume, relative to the solvent. The reaction temperature may be 10 to 60C and preferably 20 to 50C.
Under these conditions the reaction proceeds quantitatively and the starting materials disappear in 0.5 to 3 hours.
rrhus, the reaction may be completed at this time point.
After completion of the reaction, the desired ~y~-isomer (V') can be separated and purified by the conventional procedure such as extraction, pH adjustment, chromatography, etc.
When W of compound (V) is S, the resulting compound of the formula [i.e. the formula (V') wherein W is S]:
N ~ C-COOC2H4SR (VII') N\ ll O-C-COOC(CH3)3 wherein the symbols are as defined hereinbefore, is further oxidized to compound (VII). This oxidation of sulfide to sulfone is conducted using an oxidizing agent such as hydrogen peroxide, ozone or a peracid (e.g. sodium meta-periodate, perbenzoic acid, etc.). Among others, hydrogen peroxide, etc. is employed. The reaction may be readily accelerated by adding a catalyst to such oxidizing agent.
For example, when hydrogen peroxide is used as the oxidizing agent, the addition of a catalytic amount of ammonium molybdate, sodium tungustate or the like accelerates the reaction. The amount of oxidizing agent may ~e 2 to 15 molar equivalents, pre~erably 2 to 7 equivalents, relative to the sulfide. This reaction may be conducted at 0 to 40C, and preferably at room tempera-ture. The reaction may go to completion in 2 to 7 hours.
This reaction is conducted in a solvent. As the solvent, there may be employed a hydrophilic solvent such as acetone, acetonitrile, glacial acetic acid, etc~, for instance,and these solvents may be used in admixture with water.
The resulting sulfone (VII) can be separated and purified by the conventional procedure such as extraction, crystallization,~chromatography, etc. However, since ~2~23 this reaction is substantially not accompanied by side reactions, the reaction mixture may be directly submitted to the next reaction step, i.e. hydrolysis under alkaline conditions, on completion of the oxidation reaction.
The compounds (V'), (VII') and (VII), as well as compound (V), have an amino group in 2-position of the thiazole ring and, therefore, can be converted to a salt such as those mentioned for compound (V) before isolation.
However, the reaction mixture as such i~s preferably submitted to^the next hydrolysis step without separation of compound (VII) or a salt thereof.
The compound (VII) or a salt thereof prepared as above is then hydrolyzed in the presence of a base to give the desired compound (I) wherein W' is OH or a salt thereof.
While it is more convenient to use the reaction mixture from the synthesis of (VII) than to employ the isolated compound (VII), the latter may of course be employed either as a free compound or in the form of salt referred to above. Hydrolysis of compound (VII) or a salt thereof may be conducted by permitting a base to act on (VII) or a salt thereof. The hydrolysis may be conducted a hydro-philic solvent. Water may be added to accelerate the reaction. When a base was employed in the synthesis of (VII), the addition of water alone to the reaction mixture causes hydrolysis to take place in succession to the formation of (VII). The hydrophilic solvent may for example be an alcohol, e.g. methanol; ethanol, etc.; a ketone, e.g. acetone, etc.; or a nitrile, e.g. acetonitrile.
The amount of the solvent may be 2 to 50 volumes, preferably 5 - 10 volumes, relative to the compound (VII). The amount of water to be mixed with such solvent may be 0.5 to 10 volumes, relative to the solvent. The hydrolysis temperature is preferably 5 to 50C. The base may be any one showing pH ranging from about 9 to 12, and may for example be an alkali carbonate such as potassium hydrogen carbonate, potassium carbonate, etc. or an organic amine ~2~3Z3 such as triethylamine, isopropylamine, etc. The amount of the base is preferably one molar equivalent to about ~ equivalents, relative to the compound (VII) or a salt thereof and the hydrolysis generally may go to completion in 30 minutes to 2 hours. The resulting com-pound (I) wherein W' is OH can be separated and purified by the conventional procedure mentioned hereinbefore.
However, the reaction mixture as such may be submitted to the next step without separation of the compound (I) wherein W' is OH. The product compound (I) wherein W' is OH can be converted to an acid salt at the 2-amino group of the thiazole ring just as mentioned for compounds (V) and (VII), and because it has a carboxy group, can also be converted to the salt of an alkali metal such as sodium, potassium, etc. or an alkaline earth metal such~às ~alcium, magnesium, etc. by the conventional procedure.
The product compound (I) wherein W' is OH thus ` obtained can be easily converted to an active thioester at the carboxy group thereof, i.e. the compound (I) wherein W' is -S ~ ~ and can be used as an advantageous acylating agent in the synthesis of ~-lactam antibiotics.
In this application, the steps of protecting the amino group prior to the acylation reaction to prevent side reactions and removing the protective group for the amino group after the acylation reaction, which are necessary in the conventional method for producing the ~-lactam antibiotics, can be omitted~ N
` The compound (I) wherein W' is ~S~~s ~ is produced by reacting the compound (I) wherein W' is O~
with 2,2-dithiobis-benzothiazole. 2,2-Dithiobis-benzo-thiazole may be used in an amount of 1 to 4 moles per mole of (I) wherein W' is OH. The reaction may be conducted in an inactive organic solvent having no hydroxy group in its molecule. A phosphine or phosphite may be added to the reaction system to accelerate the reaction.
As such a phosphine, use may be made of aryl phosphines such as triphenyl phosphine, and as such a phosphite~ use may be made of tri-lower alkyl phosphites such a.s trimethyl phosphite or triethyl phosphite. The phosphine or phosphite is preferably used in an amount of 1 to 2 moles per 1 mole of (I) wherein W' is OH~ The inactive organic solvent in this reaction includes halogenated hydrocarbons such as dichloromethane, chloroform, etc., nitriles such as acetonitrile, propionitrile, etc., esters such as ethyl acetate, isopropyl acetate, etc. Among them, nitriles such as acetonitrile, for instance~ are especially preferable. The amount of the solvent may be 10 -50 times (weight) of that of the compound (I) wherein W' is OH. In order to dissolve ~I) wherein W' is OH, a base may be added to the solvent. For example, an organic base such as pyridine, N-methylmorpholine, triethylamine, etc. may be used as the base. The amount of the base may be 1- 2.5 moles per 1 mole of (I) wherein W' is OH. The reaction temperature is normally -30C -50C, preferably -20C - 25C, more preferably -5C -5C. The reaction time is usually about 1 -20 hours. Generally, thus obtained compound (I) wherein W' is 2-benzothiazolylthio(-S <N ~ ) f~rms precipitation and so may be isolated by filtration. If necessary, before the filtration, putting the obtained reaction mixture into water, extracting the aqueous-solution with such an organic solvent as mentioned above and then adding n-hexane, etc. to the extract in this order may be conducted to get the compound (I) wherein W' is 2-benzothiazolylthio as precipitates. Thus, e.g. 2-(2-amino~
thiazol-4-yl)-(Z)-2-(t-butoxycarbonylmethoxyimino)-acetic acid or 2-(2-aminothiazol-4-yl)-(Z)-2-(1-t-butoxycarbonyl-l-methylethoxyimino) acetic acid may be converted to a 2-benzothiazolethio ester, then the latter may be reacted with 7-amino-3-pyridinomethyl-3-cephem-4-carboxylate, and finally the protective group for the carboxy group may be eliminated in the conventionlal manner to give 7-[2-(2-aminothiazol-4-yl)-(Z)-2-(carboxymethoxyimino)acetamido]
3-pyridinomethyl-3-cephem-4-carboxylate or ceftazidime (U.S.P. 4,258,041).
In practicing the above method, 7-amino-3-pyridino-methyl-3-cephem-4-carboxylate is reacted with the 2-benzothiazolethio ester in a proportion of 1 mole of the former to at least 1 mole, preferably 1-4 moles of the latter. The reaction may be carried out in a solvent.
The solvent includes water, acetone, dioxane, acetonitrile, methylene chloride, chloroform, dichloroethane, tetra-hydrofuran, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, pyridine and other common organic solvents inert to the reaction. Hydrophilic solvents may be used in admixture with water. The reaction may also be conducted in thepresence of such a base as an alkali metal carbonate, a trialkylamine (e.g. trimethylamine, triethylamine, tributylamine~,N-methylmorpholine, N-methylpiperidine , N,N-dialkylaniline, N,~-dialkylbenzyl-amine, pyridine, picoline, lutidine, 1,5-diazabicyclo(4,3,0)-non-5-ene, 1,4-diazabicyclo(2,2,2)octane or 1,8-diazabi-cyclo(5,4,~)undecene-7. When the base is a li~uid, it may also serve as the solvent. A
preferable solvent is a halogenated alkane such as methylene chloride, etc., and as a base, for example, an trialkyl-amine such as trimethylamine, etc. is advantageously used.
The reaction temperature is not critical but, generally, the reaction is carried out in many cases with cooling or at room temperature. The reaction is complete in several minutes to a few scores of hours. The reaction temperature and time are 0 -40C and a few minutes to several hours, respectiveIy, to gain a good result. The protective group for the carbo~yl group of thus obtained compound may be removed in the conventional manner, e.g.
acid or base catalysed hydrolysis~ The reaction product can be recovered and purified by per se known methods, such as concentra~ion, pH adjustment, phase transfer, solvent extraction, crystallization, recrystallization, fractional distillation and chromatography.
And, in the same manner as mentioned above, the 2-benzothiazolethio ester of 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonylmethoxyimino)-acetic acid may be reacted with 7-amino-3-methylthiomethyl or [(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl]-3-cephem-4-carboxylic acid, and then the protective group of the carboxyl group in the t-butoxycarbonylmethoxyimino moiety may be removed to produce disodium 7~-[2-(2-aminothiazo]-4-yl)-(Z)-2-(carboxymethoxyimino)acetamido]-3-methylthiomethyl-3-cephem-4-carboxylate [Compound (A)], or disodium 7~-[2-(2-aminothiazol-4-yl)-(Z)-2-(carboxymethoxyimino)acetamido-3-[(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl]-3-cephem-4-carboxylate [Compound (B)]. Thus obtained compounds (A) and (B) show excellent activity against a broad spectrum of bacteria inclusive of gram-negative bacteria, such as Escherichia coli, Serratia marcescens, Proteus . _ . ~ .
rettgeri, Enterobacter cloacae and Citrobacter freundii, and are resistant to ~-lactamase. The Compounds (A) and (B) may be used, for example as a disinfectant for removing the aforesaid microorganisms from surgical instru-ments or as an anti-infective agent. When -the Compounds (~) and (B) areemployed as an antiinfective agent, for example for the treatment of intraperitoneal infections, respiratory organ infections, urinary tract infections and other infectious deseases caused by the aforementioned microorganisms, it may be safely administered to mammals including humans; mice and rats at a daily dose level of 0.5 to 80 mg per kilogram body weight, preferably 1 to 20 mg on the same basis, in 3 to 4 installments daily. The compounds (A) and (B) may be administered orally or parenterally in varied dosage forms .such as injections, capsules, powders, granules and tablets which may be manufactured by estabIished or known arts. Where the compound (A) or (B) is used as an injection, the carrier ~Z~8Z3 may for example be distilled water or physiological saline.
In the case the compound (A) or (s) is used as a capsule, powder, granules or tablet, the compound (A) or (B) is employed, for example in admixture with pharmacologically acceptable, per se known excipients (e.g. starch, lactose, sucrose, calcium carbonate, calcium phosphate), binders (starch, gum arabic, carboxymethyl-cellulose, hydroxy-propylcellulose, crystalline cellulose, etc.), lubricants (e.g. magnesium stearate, talc, etc.), and disintegrating agents (e.g. carboxymethyl calcium, talc, etc.).
The following working and reference examples are further illustrative of this inventionO In these examples, NMR
spectra were determined with a Varian T60 spectrometer (60 MHz)[manufactured by Varian Analytical Instrument Division in U.S.A.] using tetramethylsilane as a reference and the ~ values are expressed in ppm. In the spectra, s represents a singlet, d a doublet, t a triplet, q a ~uartet, m a multiplet, J a coupling constant, DMSO dimethyl sulfoxide, br. broard, and arom. aromatic.
- lg -Example 1 In 260 ml of methylene chloride was dissolved 87.9 g (1.407 moles) of diketene. ~he solution was cooled to -35C and 74.2 g (1.045 moles) of chlorine gas was bubbled into the solution at -35 to -30C for about 2 hours to prepare a methylene chloride solution of 4-chloroacetoacetyl chloride. Separately, 100 g (0.805 mole) of methylsulfonylethanol was dissolved in 130 ml of methylene chloride followed by addition of 63.7 g of pyridine. To this solution was added the above methylene chloride solution of 4-chloroaceto-acetyl chloride at -5 to 0C dropwise over.a period of about 1.5 hours. The mixture was then stirred for 30 minutes and poured in water, and 800 ml of methylene chloride was added to extract the reaction product~ The water layer was further extracted with methylene chloride and the organic layers were com-bined and washed with water. The organic solution was concentrated to dryness and the concentrate was dissolved in 50 ml of methylene chloride and crystal-lized by addition of 200 ml of isopropyl ether togive 156.3 g (yield: 80% based on m~thylsulfonylethanol) of methyIsulfonylethyl 4-chloroacetoacetate as white crystals.
NMR (60MHz, CDCI 3 ) ~i: 3. 00 ~3H. s, S 0 2 C H 3 ), 3 . 3 8 ( 2 H, t, J = 7 H z, - C H
~ S 0 2 - ~ . 3 . 7 2 ( 2 H . s, C O C H 2 C O ) 4 .
2 5 ( 2H. s, Cl CH2 CO) . 4. 60 ( 2H. t, J=7HZ . COCH2 CH2 ) K B r I R v ctn~l : 3 4 3 O. 1 7 4 5 . 1 7 3 0 ~ a x I, . ..
Example 2 In 315 ml of glacial acetic acid was suspended 156.3 g (0.644 mole) of methylsulfonyle-thyl 4-chloro acetoacetate as obtained in Example 1. The suspension was cooled to 50c or below and a solution of 44.4 g (0.644 mole) of sodium nitrite in 140 ml of water was added at 0-5 C over a period of about 2 hours. The mixture was stirred for 30 minutes, poured in ice~water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was then distilled off to give 148.7 g of methylsulfonylethyl 4-chloro-2-hydroxyimino-acetoacetate as an oil.
NMR ( 6;~0MHz~, DMSO- d6 ) ~: 1 . 90 (3H.
: s . S: 0 2 :C H 3 ) , 3 . 5 2 ( 2 H . t . J = 7 H Z
C ~S O 2 - ~ . 4 . 5: 8 ~ 2 H . t . J = 7 H Z . C H
: 2 C H 2 S 0 2 ) . 4 . 8 7 ( 2 H . s . C I C H 2 -' ) ` I R ( N eat ~) cm~l: 3 2 5 0 . 1 7 5 0 . 1 7 1 0 . 1 6 3 5 i :
: :
:
~2~8;~3 Example 3 In a mixture of 594 ml of ethanol and 60 ml of water was dissolved 148.7 g (0.613 mole) of oily methylsulfonylethyl 4-chloro-2-hydroxyiminoacetoacetate as obtained in Example 2, and 50.0 g (0.656 mole) of thiourea and 74.4 g (0.547 mole) of sodium acetate were directly added. The mixture was stirred at 25-30C
f~r about 30 minutes and 300 ml of ethanol was added.
The mi~ture was cooled to 0C or below, and the crystalline precipitate waS collected by filtration to give 104.3 g of methylsulfonylethyl 2-(2-aminothiazol-4-yl~-(Z)-2-hydroxy-iminoacetate as white crystals. (Yield: 55.2~ based ~n methyl-sulfonylethyl 4-chloroacetoacetate) Element~l analysis Calcd. for C 8 H 1l N 3 0 5 S 2 = 2 9 3 . 3 1 C3 2. 76Yo, H3. 78%. N1 4. 33%
Found: C 3 2 2 2 %. H 3 . 7 2 %, N 1 3 . 9 5 %
INMR (60MHz, Dl~lS0-- d6 ) ~: 3. 00 (3H.
S , SO 2 CH3 ) . 3. 58 (2H. t . J=7HZ . --CH2S02 ) . 4. 62 (2H. t . J=7HZ . COC
H 2 C H 2 ) . 6 . 9 0 ( 1 H . s, thiazole 5 - H ) .
7 . 1 0 ( 2 H. s . N H 2--) KBr I R ~ c7n~l: 3 4 5 0, 3 3 0 0. 1 7 2 0. 1 6 1 0.
a x 1 535. 1 408. 1 290 .. . .
Example 4 In 200 ml of acetone was suspended 10 g (0.0341 rnole) of methylsulfonylethyl 2-(2~aminothiazol-4-yl)-(Z)-2-hydroxy-iminoacetate as obtained in Example 3. After a serial addition of 9.98 g (0.0512 mole) of t-butyl bromoacetate, O.6 ml of water and 18.85 g of anhydrous potassium carbonate, the mixture was stirred at 40C for 2 hours followed by addition of 200 ml of water. The mixture was stirred at 30-35C for about an hour, whereby the methylsulfonylethyl group was hydrolytically eliminated.
Then, ethyl acetate was added to the hydrolysis reaction mixture. The organic layer was extracted with water and the aqueous layers were combined and adjusted to pH 2 with 2 N HCl. The resulting white crystalline precipitate was collected by filtration and dried to give 9.0 g of 2-~2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonylmethoxyLmino)acetic acid. (Yiled, 87.6%) Elemental analysis I Calcd. for C 1I H ~ N 3 0 s S 0. 5 H 2 0 :
20 1 C 4 2. 5 8 %? H 5 . 2 0 %. N 1 3 . 5 4 %.
S1 O. 33%
~ound: C 4 2 .. 6 2 %. H 5 . 2 3 %. N 1 3 7 4 %.
S1 0.: 8 7%
NMR (60MHZ . DMSO- d6 ) ~: 1. 42 (9H.
I s . C (CH3 ) 3 ) . 4. 55 ~2H, s . OCH2 CO) 6 . 8 2 ( 1 H. s, thiazole - H ) . 7 . 2 0 ( 2 H.
br., NH2 t K B r I R ~ : 3 3 5 O, 1 7 4 5. 1 6 4 0 . . m a x ~2~8Z3 O Isolation of the synthesi~ intermediate, i.e. methyl-sulfonylethyl 2-(2-ami~othiazol-4-yl)-(Z)-2-(t-butoxy-carbonylmethoxyimino)acetate,and its physical properties The above-reaction mixture was poured in aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and concentrated to dryness and the concentrate was crystallized from ethyl acetate-isopropyl ether (1:5) to give the desired product.
I N M R ( 6 0 M H z, D M S O - d 6 ~ ~: 1 . 4 2 ( 9 H , s, C (CH3 ) 3 ), 2. 99 (3H. s, CH3 SO2 ) .
3. 58 ( 2~. t . J=7Hz . -CH2 SO 2 ) .
In practicing the above method, 7-amino-3-pyridino-methyl-3-cephem-4-carboxylate is reacted with the 2-benzothiazolethio ester in a proportion of 1 mole of the former to at least 1 mole, preferably 1-4 moles of the latter. The reaction may be carried out in a solvent.
The solvent includes water, acetone, dioxane, acetonitrile, methylene chloride, chloroform, dichloroethane, tetra-hydrofuran, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, pyridine and other common organic solvents inert to the reaction. Hydrophilic solvents may be used in admixture with water. The reaction may also be conducted in thepresence of such a base as an alkali metal carbonate, a trialkylamine (e.g. trimethylamine, triethylamine, tributylamine~,N-methylmorpholine, N-methylpiperidine , N,N-dialkylaniline, N,~-dialkylbenzyl-amine, pyridine, picoline, lutidine, 1,5-diazabicyclo(4,3,0)-non-5-ene, 1,4-diazabicyclo(2,2,2)octane or 1,8-diazabi-cyclo(5,4,~)undecene-7. When the base is a li~uid, it may also serve as the solvent. A
preferable solvent is a halogenated alkane such as methylene chloride, etc., and as a base, for example, an trialkyl-amine such as trimethylamine, etc. is advantageously used.
The reaction temperature is not critical but, generally, the reaction is carried out in many cases with cooling or at room temperature. The reaction is complete in several minutes to a few scores of hours. The reaction temperature and time are 0 -40C and a few minutes to several hours, respectiveIy, to gain a good result. The protective group for the carbo~yl group of thus obtained compound may be removed in the conventional manner, e.g.
acid or base catalysed hydrolysis~ The reaction product can be recovered and purified by per se known methods, such as concentra~ion, pH adjustment, phase transfer, solvent extraction, crystallization, recrystallization, fractional distillation and chromatography.
And, in the same manner as mentioned above, the 2-benzothiazolethio ester of 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonylmethoxyimino)-acetic acid may be reacted with 7-amino-3-methylthiomethyl or [(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl]-3-cephem-4-carboxylic acid, and then the protective group of the carboxyl group in the t-butoxycarbonylmethoxyimino moiety may be removed to produce disodium 7~-[2-(2-aminothiazo]-4-yl)-(Z)-2-(carboxymethoxyimino)acetamido]-3-methylthiomethyl-3-cephem-4-carboxylate [Compound (A)], or disodium 7~-[2-(2-aminothiazol-4-yl)-(Z)-2-(carboxymethoxyimino)acetamido-3-[(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl]-3-cephem-4-carboxylate [Compound (B)]. Thus obtained compounds (A) and (B) show excellent activity against a broad spectrum of bacteria inclusive of gram-negative bacteria, such as Escherichia coli, Serratia marcescens, Proteus . _ . ~ .
rettgeri, Enterobacter cloacae and Citrobacter freundii, and are resistant to ~-lactamase. The Compounds (A) and (B) may be used, for example as a disinfectant for removing the aforesaid microorganisms from surgical instru-ments or as an anti-infective agent. When -the Compounds (~) and (B) areemployed as an antiinfective agent, for example for the treatment of intraperitoneal infections, respiratory organ infections, urinary tract infections and other infectious deseases caused by the aforementioned microorganisms, it may be safely administered to mammals including humans; mice and rats at a daily dose level of 0.5 to 80 mg per kilogram body weight, preferably 1 to 20 mg on the same basis, in 3 to 4 installments daily. The compounds (A) and (B) may be administered orally or parenterally in varied dosage forms .such as injections, capsules, powders, granules and tablets which may be manufactured by estabIished or known arts. Where the compound (A) or (B) is used as an injection, the carrier ~Z~8Z3 may for example be distilled water or physiological saline.
In the case the compound (A) or (s) is used as a capsule, powder, granules or tablet, the compound (A) or (B) is employed, for example in admixture with pharmacologically acceptable, per se known excipients (e.g. starch, lactose, sucrose, calcium carbonate, calcium phosphate), binders (starch, gum arabic, carboxymethyl-cellulose, hydroxy-propylcellulose, crystalline cellulose, etc.), lubricants (e.g. magnesium stearate, talc, etc.), and disintegrating agents (e.g. carboxymethyl calcium, talc, etc.).
The following working and reference examples are further illustrative of this inventionO In these examples, NMR
spectra were determined with a Varian T60 spectrometer (60 MHz)[manufactured by Varian Analytical Instrument Division in U.S.A.] using tetramethylsilane as a reference and the ~ values are expressed in ppm. In the spectra, s represents a singlet, d a doublet, t a triplet, q a ~uartet, m a multiplet, J a coupling constant, DMSO dimethyl sulfoxide, br. broard, and arom. aromatic.
- lg -Example 1 In 260 ml of methylene chloride was dissolved 87.9 g (1.407 moles) of diketene. ~he solution was cooled to -35C and 74.2 g (1.045 moles) of chlorine gas was bubbled into the solution at -35 to -30C for about 2 hours to prepare a methylene chloride solution of 4-chloroacetoacetyl chloride. Separately, 100 g (0.805 mole) of methylsulfonylethanol was dissolved in 130 ml of methylene chloride followed by addition of 63.7 g of pyridine. To this solution was added the above methylene chloride solution of 4-chloroaceto-acetyl chloride at -5 to 0C dropwise over.a period of about 1.5 hours. The mixture was then stirred for 30 minutes and poured in water, and 800 ml of methylene chloride was added to extract the reaction product~ The water layer was further extracted with methylene chloride and the organic layers were com-bined and washed with water. The organic solution was concentrated to dryness and the concentrate was dissolved in 50 ml of methylene chloride and crystal-lized by addition of 200 ml of isopropyl ether togive 156.3 g (yield: 80% based on m~thylsulfonylethanol) of methyIsulfonylethyl 4-chloroacetoacetate as white crystals.
NMR (60MHz, CDCI 3 ) ~i: 3. 00 ~3H. s, S 0 2 C H 3 ), 3 . 3 8 ( 2 H, t, J = 7 H z, - C H
~ S 0 2 - ~ . 3 . 7 2 ( 2 H . s, C O C H 2 C O ) 4 .
2 5 ( 2H. s, Cl CH2 CO) . 4. 60 ( 2H. t, J=7HZ . COCH2 CH2 ) K B r I R v ctn~l : 3 4 3 O. 1 7 4 5 . 1 7 3 0 ~ a x I, . ..
Example 2 In 315 ml of glacial acetic acid was suspended 156.3 g (0.644 mole) of methylsulfonyle-thyl 4-chloro acetoacetate as obtained in Example 1. The suspension was cooled to 50c or below and a solution of 44.4 g (0.644 mole) of sodium nitrite in 140 ml of water was added at 0-5 C over a period of about 2 hours. The mixture was stirred for 30 minutes, poured in ice~water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was then distilled off to give 148.7 g of methylsulfonylethyl 4-chloro-2-hydroxyimino-acetoacetate as an oil.
NMR ( 6;~0MHz~, DMSO- d6 ) ~: 1 . 90 (3H.
: s . S: 0 2 :C H 3 ) , 3 . 5 2 ( 2 H . t . J = 7 H Z
C ~S O 2 - ~ . 4 . 5: 8 ~ 2 H . t . J = 7 H Z . C H
: 2 C H 2 S 0 2 ) . 4 . 8 7 ( 2 H . s . C I C H 2 -' ) ` I R ( N eat ~) cm~l: 3 2 5 0 . 1 7 5 0 . 1 7 1 0 . 1 6 3 5 i :
: :
:
~2~8;~3 Example 3 In a mixture of 594 ml of ethanol and 60 ml of water was dissolved 148.7 g (0.613 mole) of oily methylsulfonylethyl 4-chloro-2-hydroxyiminoacetoacetate as obtained in Example 2, and 50.0 g (0.656 mole) of thiourea and 74.4 g (0.547 mole) of sodium acetate were directly added. The mixture was stirred at 25-30C
f~r about 30 minutes and 300 ml of ethanol was added.
The mi~ture was cooled to 0C or below, and the crystalline precipitate waS collected by filtration to give 104.3 g of methylsulfonylethyl 2-(2-aminothiazol-4-yl~-(Z)-2-hydroxy-iminoacetate as white crystals. (Yield: 55.2~ based ~n methyl-sulfonylethyl 4-chloroacetoacetate) Element~l analysis Calcd. for C 8 H 1l N 3 0 5 S 2 = 2 9 3 . 3 1 C3 2. 76Yo, H3. 78%. N1 4. 33%
Found: C 3 2 2 2 %. H 3 . 7 2 %, N 1 3 . 9 5 %
INMR (60MHz, Dl~lS0-- d6 ) ~: 3. 00 (3H.
S , SO 2 CH3 ) . 3. 58 (2H. t . J=7HZ . --CH2S02 ) . 4. 62 (2H. t . J=7HZ . COC
H 2 C H 2 ) . 6 . 9 0 ( 1 H . s, thiazole 5 - H ) .
7 . 1 0 ( 2 H. s . N H 2--) KBr I R ~ c7n~l: 3 4 5 0, 3 3 0 0. 1 7 2 0. 1 6 1 0.
a x 1 535. 1 408. 1 290 .. . .
Example 4 In 200 ml of acetone was suspended 10 g (0.0341 rnole) of methylsulfonylethyl 2-(2~aminothiazol-4-yl)-(Z)-2-hydroxy-iminoacetate as obtained in Example 3. After a serial addition of 9.98 g (0.0512 mole) of t-butyl bromoacetate, O.6 ml of water and 18.85 g of anhydrous potassium carbonate, the mixture was stirred at 40C for 2 hours followed by addition of 200 ml of water. The mixture was stirred at 30-35C for about an hour, whereby the methylsulfonylethyl group was hydrolytically eliminated.
Then, ethyl acetate was added to the hydrolysis reaction mixture. The organic layer was extracted with water and the aqueous layers were combined and adjusted to pH 2 with 2 N HCl. The resulting white crystalline precipitate was collected by filtration and dried to give 9.0 g of 2-~2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonylmethoxyLmino)acetic acid. (Yiled, 87.6%) Elemental analysis I Calcd. for C 1I H ~ N 3 0 s S 0. 5 H 2 0 :
20 1 C 4 2. 5 8 %? H 5 . 2 0 %. N 1 3 . 5 4 %.
S1 O. 33%
~ound: C 4 2 .. 6 2 %. H 5 . 2 3 %. N 1 3 7 4 %.
S1 0.: 8 7%
NMR (60MHZ . DMSO- d6 ) ~: 1. 42 (9H.
I s . C (CH3 ) 3 ) . 4. 55 ~2H, s . OCH2 CO) 6 . 8 2 ( 1 H. s, thiazole - H ) . 7 . 2 0 ( 2 H.
br., NH2 t K B r I R ~ : 3 3 5 O, 1 7 4 5. 1 6 4 0 . . m a x ~2~8Z3 O Isolation of the synthesi~ intermediate, i.e. methyl-sulfonylethyl 2-(2-ami~othiazol-4-yl)-(Z)-2-(t-butoxy-carbonylmethoxyimino)acetate,and its physical properties The above-reaction mixture was poured in aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and concentrated to dryness and the concentrate was crystallized from ethyl acetate-isopropyl ether (1:5) to give the desired product.
I N M R ( 6 0 M H z, D M S O - d 6 ~ ~: 1 . 4 2 ( 9 H , s, C (CH3 ) 3 ), 2. 99 (3H. s, CH3 SO2 ) .
3. 58 ( 2~. t . J=7Hz . -CH2 SO 2 ) .
4. 59 ( 2H. s, OCH2 COO), 4. 6 1 ( 2H. t, J= 7Hz . -OC~_CH2 S02 ), 6. 9 8 ( 1 H. s, ¦ thiazole'- H ) . 7 . 2 6 ( 2 H, s . N H 2 - ) K B r I R 1~ c~~l : 3 4 1 O. 1 7 5 O. 1 7 1 5. 1 5 2 3.
m a x , 1 ~ 4 0 Example 5 In 120 ml of acetone was suspended 6 g (0.0205 mole) of methylsulfonylethyl 2-(2-aminothiazol 4-yl)-(Z)-2-hydroxyimlnoacetate as obtained in Example 3, followed by a serial addi:tion of 4.6 g (0.0307 mole) of t-butyl chloroacetate, 0.36 ml of water, lZ~323 -~3-11.31 g of anhydrous potassium carbonate and 6.13 g of sodium iodide. The mixture was stirred at 40C for 4.5 hours. To thisreaction mixture was added 120 ml o~
water~ and the mixture was stirred at 30-35C for an hour.
S Ethyl acetate was then added as an extxaction solvent.
The organic layer was separated and extracted with water. The aqueous layers were combined and adjusted to pH 2 with 2 N HCl. The resulting white precipitate was collected by fil~ration and dried to give 4.63 g (yield, 75~) of 2-(2 aminothiazol-4-yl) ~Z)-2-( t-butoxycarbonylmethoxyimino)acetic acid as white crystals.
Exampl~e 6 (1~ In 2.52 liters of methylene chloride was dissolved 840 g of diketene, The solution was cooled to -30C or below and 708 g of chlorine gas was bubbled into the solution at -35 to~-30C for about 2 hours.
The solution was stirred for 30 minutes and a solution of 953 g of methylsulfony}ethanol and 608 g of pyridine in 1.2 liters of ethylene chloride was added at -20C
or below over a period - of within 30 minutes. The tem-, perature was increased gradually and the reaction was allowed to proceed at -5C for about an hour. After completlon of the reaction, 8 liters of methylene chloride was added and the mixture was poured into , -_24-7 liters of water. After phase separation, the aqueous layer was extracted with methylene chloride. The or~anic layers were combined, washed with water and concentrated to dryness under reduced pressure to give colorless crystals.
(2~ The above-obtained crystals were suspended in a mixture of 1.875 liters of ethyl acetate and 3.75 liters of glacial acetic acid. The suspension was cooled to 5C or below and a solution of 530 g of sodium nitrite in 1.665 liters of water was added dropwise at 0-5C over a period of about 2 hours. After completion of addition~ the reaction was allowed to proceed for 30 minutes, as the end of which time the reaction mixture was àdded to lO liters of ice water to extract.
The aqueous layer was separated and further extracted with 5 liters of ethyl acetate. The organic layers were combined~ washed with water and concentrated to dryness under reduced pressure to give an oil.
~3~ The above-obtained oil was dissolved in a 2Q mixture of 8.34 liters of ethanol and 0.43 liter of water, and 530 g of thiourea and 1045 g of sodium acetate were directly added. The reactlon was allowed to proceed at room temperature for an houF. The reaction mixture , was concentrated under reduced pressure and 8 liter of ethanol was added to the residue. The mixture was then cooled to 5C or below and the crystalline precipitate was collec~ed by filtration and dried in vacuo at 40C to give 1250 g of methylsulfonylethyl 2-(2-aminothiazol-4-yl~-~Z)-2-hydroxyiminoacetate. (Yield:
55.5% based on methylsulfonylethanol) N M R (60MHz . DMS0- d6 ) ~: 3. 02 (3H.
s, S02 CH3 ) . 3. 58 (2H. t . J=7Hz, C
H2S02 ) . 4. 60 (2H. t . J=7HZ . OC112 C H 2 ), ~ . 9 0 ( 1 H, s, thia~ole 5--H ), 7 .
1 6 (2H. s . NH2--~ -i R ~KBr ) cm~l: 3450. 3300, 1 720.
1 61 0. 1 535, 1 4 1 0 Ex`ample 7 In 200 ml of acetonitrile was suspended 10 g of methylsulfonylethyl 2-(2-aminothiazol-4-yl) (Z)-2-hydroxy-iminoacetate as obtained in Example 3, and 7.7 g of t-butyl chloroacetate was added~ Then, after a serial addition of 1.2 ml of water~ 18.85 g of anhydrous potassium carbonate powder and S.6 g of sodium iodide, the reactlon was allowed~ to proceed at room temperature.
After completlon~of the reaction, the precipitate was filtered off. To the filtrate was added 300 ml of water~ and a 40~ solutLon of potassium carbonate was added, lZ~L~8Z~
dropwise for hydrolysis while maintaininy pH at 10-lO.S.
The reaction mixture was then adjusted to pH 2 with 2 N hydrochloric acid, whereupon a white precipitate separated out. After cooling to 5C or ~elow, the crystalline precipitate was collected by filtration and dried to give 7.09 g of 2-(2-aminothiazol-4-yl)-(Z)-2-~t-butoxycarbonylmethoxyimino)acetic acid as white crystals.
NMR (60MHZ . DMSO- d6 ) ~: 1. 40 (9H.
s, C ~CH3 ) 3 ) . 4. 53 (2H. s, OCH2 CO) 6 8 0 ( 1 H, s, thiazole 5--H ) . 7. 2 0 ( 2 H. br.
~ KE3r I R Y cm~l : 3 3 5 O. 1 7 4 5 . 1 6 4 0 ~ a x Example 8 (1) In 100 ml of acetone was suspended 5 g (0.017 2Q mole) of methylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-hydroxyiminoacetate and 5.33 g (0.0255 mole) of t-butyl 2-bromopropionate was added. After a serial addition of 0.3 ml of water~ and 9.4 g of anhydrous potassium carbonate, the mixture was stirred at 40C for about 2.5 hours. After completion Oe the reaction, the insoLuble matter w~s fi1teFsd off~ To the filtrate was added 100 ml of water and the mixture was exkracted with 150 ml of ethyl acetate. The organic layer was washed with 50 ml of saturated aqueous sodium chloride soluti~n and dried over anhydrous sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated to dryness under reduced pressure. The concent~ate was crystallizel from-ethyl acetate-isopropyl ether (1:5, v/v). After cooling to 0C or below, the crystalline precipitate was collected by filtration and dried under reduced pressure to give 5.4 g (yield, 75.4%) of methylsulfonyl-ethyl 2-.(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl-l-methylmethoxyimino)acetate as white crystals.
Elemental analysis Calcd. ~or C ~ H ~ N 3 0 7.S 2 = 4 2 1 . 4 ~
C4 2. 75%. H5. 50%, N9. 9 7%
, Found: C4 2. 98%. H5. 3 1 %, N9. 7 1 %
NMR ( 60MHz . DMS0- d6 ) ~: 1 . 3 1~1 . 4 4 ( 1 2H, m . CH~ -CH & C (CH3 ) 3 ) . 3. 0 2 t3H. s . S02 CH3 ) . 3. 49 (2H. t, J=
7Hz, C~2 SO2 ), 4. 5 0~4. 7 5 (3Hg m .
C 0 0 C H 2 ~ C H--C H 3 ), 6 . 9 6 ( 1 H . s, thia-` zole 5--H ) . 7. 2 5 ( 2 H, s, N H 2 ) IR vmax cm : 3400-2995, 1750, 1720, 1630, 1550 (2) In a mixture of 12 ml of acetone and 6 ml of water was dissolved 0.3 g (0.71 millimole) of methyl-:
~ Z 3 sulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-t-bu-toxycarbonyl-l-methylmethoxyimino)acetate as obtained in (1). The solution was warmed to 30-32C and a 40% aqueous solution of potassium carbonate was added dropwise while maintaining the pH at 10-10.5. The reaction mixture was ad]usted to pH
about 6 with lN HCl and the solvent was distilled off under reduced pressure. Then, pH was further adjusted to 2 with lN HCl, whereupon a white crystalline precipitate separ~ted out. A~ter cooling, the precipitate was collected by filtration and dried to give 0.18 g (yield, 80.3%) of 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl-l-methylmethoxyimino)acetic acid as white crystals.
,~. N M R ( 6 0 M H z , D M S 0 - d6 ) ~ : 1 . 3 0 ~
1 ~ 4 a ~ 1 2 H. m , C H 3 - C H & C ( C ~l~L~ _L) .
i 4. 5 5 ( 1 H. q . J = 8 H Z , - C H C H 3 ) .
6. 8 2 ( 1 H. s , thiazole - 5 - H ) K B r I R . ~ 3 3 5 0~ 1 7 2 5. 1 6 5 0.
j m a x ~ -i - 1 6 0 5. 1 4 5 5 Elemental analysis calcd- for C12H17N35S H2 C, 43023%; H, 5.74%; N, 12.61%
Found: C, 43.07~; H, 5.65%; N, 12.36%
.
Example 9 (1) In 150 ml of methylene chloride was dissolved 39.5 g (0.470 mole) of diketene. The solution was cooled to -30C or below and 33.4 g (0.47 mole) of chlorine gas was bubbled into the solution at 35 to -30C for about 1.5 hours. The solution was stirred for 30 minutes and a solution of 50 g (0.362 mole) of ethylsulfonylethanol and 28.7 g (0.362 mole) of pyridine in 75 ml of methylene chloride was added dropwise at - -20C or below over a period of 30 minutes. The temperature was increased and the reaction was allowed to proceed at -5C for about 30 minutes. The reaction mixture was poured into wa~er and 400 ml of methylene chloride was added as an extraction solvent.
The aqueous layer was further extracted with methylene chloride and the organic layers were combined, washed with water and concentrated to dryness to give 87.0 g of ethylsulfonylethyl 4-chloroacetoacetate. (Yield, 93.6% based on lethylsulfonylethanol) INMR (60MHZ . C~CI 3 ) a: 1. 40 (3H. t J 8HZ . CH2 CH~ ) . 3. O5 (2H n . J=8 HZ j S-O~ C~ CH3 ) . 3; 32 (2H. t . J=8 HZ . CH2 CH~SO2 ) . 3 71 (2H. S . CI C
~ H2 CO--) . 4~ 30 (2H. S . COCH2 CO) 4.
6 O ( 2 H t J = 8 H Z . C O O C H ~ C H 2 S ) . ~ . . . .. . ..
IR vmax cm : 1740, 1730 (2) In a mixture of 190 ml of glacial acetic acid and 75 ml of ethyl acetate w~s suspended 87 g (0.339 mole) of ethylsulfonylethyl 4-chloroacetoacetate as obtained in (1). The suspension was cooled to 10C or belowanda solution of 23.4 g of sodium nitrite in 100 ml of water was added at 0-5C over a period of about an hour. The mixture was stirred for about an hour, added to ice water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure to give 84.8 g of ethylsulfonylethyl 4-chloro-2-hydroxyimino-acetoacetate as white crystals. (Yieldj 87.6%) NMR (60MHz . DMSO- d6 ) ~: 1. 20 (3H.
t . J=8HZ, CHz CH3 ), 3. 1 0 ( 2H> q . J
-`8Wz > SO2 CH_2 CH3 ), 3. 5 2 ( 2H. t, J
=8HZ: . CH2 SO2 CH2 ), 4. 60 ( 2H. t, J
1 =8HZ . COOCH2 CH2 ) . 4. 90 (2H. s . C
I C H ~ C O ) : ,. ' ' ' KBr ~ ~
Il I R ` v cm~l : 345C). 1 745. 1 71 O.
1l m a x `
~`` ` ~ :
(3) In a mixture of 384 ml of ethanol and 38.4 ml of water was dissolved 83.8 y (0.293 mole) of crude ethylsulfonylethyl 4-chloro-2-hydroxyiminoaceto~cetate as obtained in (2) and 22.3 g of thiourea and 39.9 g of sodium acetate were added directly to the solution.
The mixture was stirred at 25-30C for about an hour and the ethanol was distilled off under reduced pressure, followed by addition l liter of water. The mixture was cooledto 5Cor~below and the resulting crystalline precipitate was collected by filtration to give 45.l g of ethylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-hydroxyiminoacetate as white crystals. (Yield, 50.0~) Elemental analysis Calcd. ~or (, 9 H ~ N 3 0 5 S 2 = 3 7 3 4 C35. 1 7%. H4. 26%. N1 3. 67%.
S 2 0. 8 6%
Found: C 3 5 . 2 4 % . H 4 . 2 3 % . N 1 3 5 2 % .
S20. 68%: -NMR (60MHz . DMS0- d6 ) ~: 1. 1 9 (3H.
It 7 J=8Hz . -CH2 CH3 )-. 3. 1 2 (2H. q .
= 8 H Z, S .0 2 C H 2 C H 3 ) . 3 . 5 2 ( 2 H . t .
J=8Hz . -CHz CH2S), 4. 53 (2H. t . J
= 8 Hz . C 0 0 C H z ) . 6 . 9 0 ( 1 H, s, thia~ole
m a x , 1 ~ 4 0 Example 5 In 120 ml of acetone was suspended 6 g (0.0205 mole) of methylsulfonylethyl 2-(2-aminothiazol 4-yl)-(Z)-2-hydroxyimlnoacetate as obtained in Example 3, followed by a serial addi:tion of 4.6 g (0.0307 mole) of t-butyl chloroacetate, 0.36 ml of water, lZ~323 -~3-11.31 g of anhydrous potassium carbonate and 6.13 g of sodium iodide. The mixture was stirred at 40C for 4.5 hours. To thisreaction mixture was added 120 ml o~
water~ and the mixture was stirred at 30-35C for an hour.
S Ethyl acetate was then added as an extxaction solvent.
The organic layer was separated and extracted with water. The aqueous layers were combined and adjusted to pH 2 with 2 N HCl. The resulting white precipitate was collected by fil~ration and dried to give 4.63 g (yield, 75~) of 2-(2 aminothiazol-4-yl) ~Z)-2-( t-butoxycarbonylmethoxyimino)acetic acid as white crystals.
Exampl~e 6 (1~ In 2.52 liters of methylene chloride was dissolved 840 g of diketene, The solution was cooled to -30C or below and 708 g of chlorine gas was bubbled into the solution at -35 to~-30C for about 2 hours.
The solution was stirred for 30 minutes and a solution of 953 g of methylsulfony}ethanol and 608 g of pyridine in 1.2 liters of ethylene chloride was added at -20C
or below over a period - of within 30 minutes. The tem-, perature was increased gradually and the reaction was allowed to proceed at -5C for about an hour. After completlon of the reaction, 8 liters of methylene chloride was added and the mixture was poured into , -_24-7 liters of water. After phase separation, the aqueous layer was extracted with methylene chloride. The or~anic layers were combined, washed with water and concentrated to dryness under reduced pressure to give colorless crystals.
(2~ The above-obtained crystals were suspended in a mixture of 1.875 liters of ethyl acetate and 3.75 liters of glacial acetic acid. The suspension was cooled to 5C or below and a solution of 530 g of sodium nitrite in 1.665 liters of water was added dropwise at 0-5C over a period of about 2 hours. After completion of addition~ the reaction was allowed to proceed for 30 minutes, as the end of which time the reaction mixture was àdded to lO liters of ice water to extract.
The aqueous layer was separated and further extracted with 5 liters of ethyl acetate. The organic layers were combined~ washed with water and concentrated to dryness under reduced pressure to give an oil.
~3~ The above-obtained oil was dissolved in a 2Q mixture of 8.34 liters of ethanol and 0.43 liter of water, and 530 g of thiourea and 1045 g of sodium acetate were directly added. The reactlon was allowed to proceed at room temperature for an houF. The reaction mixture , was concentrated under reduced pressure and 8 liter of ethanol was added to the residue. The mixture was then cooled to 5C or below and the crystalline precipitate was collec~ed by filtration and dried in vacuo at 40C to give 1250 g of methylsulfonylethyl 2-(2-aminothiazol-4-yl~-~Z)-2-hydroxyiminoacetate. (Yield:
55.5% based on methylsulfonylethanol) N M R (60MHz . DMS0- d6 ) ~: 3. 02 (3H.
s, S02 CH3 ) . 3. 58 (2H. t . J=7Hz, C
H2S02 ) . 4. 60 (2H. t . J=7HZ . OC112 C H 2 ), ~ . 9 0 ( 1 H, s, thia~ole 5--H ), 7 .
1 6 (2H. s . NH2--~ -i R ~KBr ) cm~l: 3450. 3300, 1 720.
1 61 0. 1 535, 1 4 1 0 Ex`ample 7 In 200 ml of acetonitrile was suspended 10 g of methylsulfonylethyl 2-(2-aminothiazol-4-yl) (Z)-2-hydroxy-iminoacetate as obtained in Example 3, and 7.7 g of t-butyl chloroacetate was added~ Then, after a serial addition of 1.2 ml of water~ 18.85 g of anhydrous potassium carbonate powder and S.6 g of sodium iodide, the reactlon was allowed~ to proceed at room temperature.
After completlon~of the reaction, the precipitate was filtered off. To the filtrate was added 300 ml of water~ and a 40~ solutLon of potassium carbonate was added, lZ~L~8Z~
dropwise for hydrolysis while maintaininy pH at 10-lO.S.
The reaction mixture was then adjusted to pH 2 with 2 N hydrochloric acid, whereupon a white precipitate separated out. After cooling to 5C or ~elow, the crystalline precipitate was collected by filtration and dried to give 7.09 g of 2-(2-aminothiazol-4-yl)-(Z)-2-~t-butoxycarbonylmethoxyimino)acetic acid as white crystals.
NMR (60MHZ . DMSO- d6 ) ~: 1. 40 (9H.
s, C ~CH3 ) 3 ) . 4. 53 (2H. s, OCH2 CO) 6 8 0 ( 1 H, s, thiazole 5--H ) . 7. 2 0 ( 2 H. br.
~ KE3r I R Y cm~l : 3 3 5 O. 1 7 4 5 . 1 6 4 0 ~ a x Example 8 (1) In 100 ml of acetone was suspended 5 g (0.017 2Q mole) of methylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-hydroxyiminoacetate and 5.33 g (0.0255 mole) of t-butyl 2-bromopropionate was added. After a serial addition of 0.3 ml of water~ and 9.4 g of anhydrous potassium carbonate, the mixture was stirred at 40C for about 2.5 hours. After completion Oe the reaction, the insoLuble matter w~s fi1teFsd off~ To the filtrate was added 100 ml of water and the mixture was exkracted with 150 ml of ethyl acetate. The organic layer was washed with 50 ml of saturated aqueous sodium chloride soluti~n and dried over anhydrous sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated to dryness under reduced pressure. The concent~ate was crystallizel from-ethyl acetate-isopropyl ether (1:5, v/v). After cooling to 0C or below, the crystalline precipitate was collected by filtration and dried under reduced pressure to give 5.4 g (yield, 75.4%) of methylsulfonyl-ethyl 2-.(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl-l-methylmethoxyimino)acetate as white crystals.
Elemental analysis Calcd. ~or C ~ H ~ N 3 0 7.S 2 = 4 2 1 . 4 ~
C4 2. 75%. H5. 50%, N9. 9 7%
, Found: C4 2. 98%. H5. 3 1 %, N9. 7 1 %
NMR ( 60MHz . DMS0- d6 ) ~: 1 . 3 1~1 . 4 4 ( 1 2H, m . CH~ -CH & C (CH3 ) 3 ) . 3. 0 2 t3H. s . S02 CH3 ) . 3. 49 (2H. t, J=
7Hz, C~2 SO2 ), 4. 5 0~4. 7 5 (3Hg m .
C 0 0 C H 2 ~ C H--C H 3 ), 6 . 9 6 ( 1 H . s, thia-` zole 5--H ) . 7. 2 5 ( 2 H, s, N H 2 ) IR vmax cm : 3400-2995, 1750, 1720, 1630, 1550 (2) In a mixture of 12 ml of acetone and 6 ml of water was dissolved 0.3 g (0.71 millimole) of methyl-:
~ Z 3 sulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-t-bu-toxycarbonyl-l-methylmethoxyimino)acetate as obtained in (1). The solution was warmed to 30-32C and a 40% aqueous solution of potassium carbonate was added dropwise while maintaining the pH at 10-10.5. The reaction mixture was ad]usted to pH
about 6 with lN HCl and the solvent was distilled off under reduced pressure. Then, pH was further adjusted to 2 with lN HCl, whereupon a white crystalline precipitate separ~ted out. A~ter cooling, the precipitate was collected by filtration and dried to give 0.18 g (yield, 80.3%) of 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl-l-methylmethoxyimino)acetic acid as white crystals.
,~. N M R ( 6 0 M H z , D M S 0 - d6 ) ~ : 1 . 3 0 ~
1 ~ 4 a ~ 1 2 H. m , C H 3 - C H & C ( C ~l~L~ _L) .
i 4. 5 5 ( 1 H. q . J = 8 H Z , - C H C H 3 ) .
6. 8 2 ( 1 H. s , thiazole - 5 - H ) K B r I R . ~ 3 3 5 0~ 1 7 2 5. 1 6 5 0.
j m a x ~ -i - 1 6 0 5. 1 4 5 5 Elemental analysis calcd- for C12H17N35S H2 C, 43023%; H, 5.74%; N, 12.61%
Found: C, 43.07~; H, 5.65%; N, 12.36%
.
Example 9 (1) In 150 ml of methylene chloride was dissolved 39.5 g (0.470 mole) of diketene. The solution was cooled to -30C or below and 33.4 g (0.47 mole) of chlorine gas was bubbled into the solution at 35 to -30C for about 1.5 hours. The solution was stirred for 30 minutes and a solution of 50 g (0.362 mole) of ethylsulfonylethanol and 28.7 g (0.362 mole) of pyridine in 75 ml of methylene chloride was added dropwise at - -20C or below over a period of 30 minutes. The temperature was increased and the reaction was allowed to proceed at -5C for about 30 minutes. The reaction mixture was poured into wa~er and 400 ml of methylene chloride was added as an extraction solvent.
The aqueous layer was further extracted with methylene chloride and the organic layers were combined, washed with water and concentrated to dryness to give 87.0 g of ethylsulfonylethyl 4-chloroacetoacetate. (Yield, 93.6% based on lethylsulfonylethanol) INMR (60MHZ . C~CI 3 ) a: 1. 40 (3H. t J 8HZ . CH2 CH~ ) . 3. O5 (2H n . J=8 HZ j S-O~ C~ CH3 ) . 3; 32 (2H. t . J=8 HZ . CH2 CH~SO2 ) . 3 71 (2H. S . CI C
~ H2 CO--) . 4~ 30 (2H. S . COCH2 CO) 4.
6 O ( 2 H t J = 8 H Z . C O O C H ~ C H 2 S ) . ~ . . . .. . ..
IR vmax cm : 1740, 1730 (2) In a mixture of 190 ml of glacial acetic acid and 75 ml of ethyl acetate w~s suspended 87 g (0.339 mole) of ethylsulfonylethyl 4-chloroacetoacetate as obtained in (1). The suspension was cooled to 10C or belowanda solution of 23.4 g of sodium nitrite in 100 ml of water was added at 0-5C over a period of about an hour. The mixture was stirred for about an hour, added to ice water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure to give 84.8 g of ethylsulfonylethyl 4-chloro-2-hydroxyimino-acetoacetate as white crystals. (Yieldj 87.6%) NMR (60MHz . DMSO- d6 ) ~: 1. 20 (3H.
t . J=8HZ, CHz CH3 ), 3. 1 0 ( 2H> q . J
-`8Wz > SO2 CH_2 CH3 ), 3. 5 2 ( 2H. t, J
=8HZ: . CH2 SO2 CH2 ), 4. 60 ( 2H. t, J
1 =8HZ . COOCH2 CH2 ) . 4. 90 (2H. s . C
I C H ~ C O ) : ,. ' ' ' KBr ~ ~
Il I R ` v cm~l : 345C). 1 745. 1 71 O.
1l m a x `
~`` ` ~ :
(3) In a mixture of 384 ml of ethanol and 38.4 ml of water was dissolved 83.8 y (0.293 mole) of crude ethylsulfonylethyl 4-chloro-2-hydroxyiminoaceto~cetate as obtained in (2) and 22.3 g of thiourea and 39.9 g of sodium acetate were added directly to the solution.
The mixture was stirred at 25-30C for about an hour and the ethanol was distilled off under reduced pressure, followed by addition l liter of water. The mixture was cooledto 5Cor~below and the resulting crystalline precipitate was collected by filtration to give 45.l g of ethylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-hydroxyiminoacetate as white crystals. (Yield, 50.0~) Elemental analysis Calcd. ~or (, 9 H ~ N 3 0 5 S 2 = 3 7 3 4 C35. 1 7%. H4. 26%. N1 3. 67%.
S 2 0. 8 6%
Found: C 3 5 . 2 4 % . H 4 . 2 3 % . N 1 3 5 2 % .
S20. 68%: -NMR (60MHz . DMS0- d6 ) ~: 1. 1 9 (3H.
It 7 J=8Hz . -CH2 CH3 )-. 3. 1 2 (2H. q .
= 8 H Z, S .0 2 C H 2 C H 3 ) . 3 . 5 2 ( 2 H . t .
J=8Hz . -CHz CH2S), 4. 53 (2H. t . J
= 8 Hz . C 0 0 C H z ) . 6 . 9 0 ( 1 H, s, thia~ole
- 5 - H ~ . 7 . 1 5 ( 2 H . s, N H 2 - ) .
K B r ~
I R ~7 C~ 3 4 00~3 1 00. 1 7 3 0.
.
~ax 1 61 S . 1 5 3 5 :
Example 10 (1) In 180 ml of acetone was suspended 6 y (0.019 mole) of ethylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-hydroxyiminoacetate as obtained in Example 9 followed by a serial addition of 5.7 g (0.0292 mole) of t-butyl bromoacetate, 0.9 ml of water and 10.8 g of anhydrous potassium carbonate. The mixture was stirred at 40C for 2 hoursand the insoluble matter was filtered off. To the filtrate was added 200 ml of water and 200 ml of ethyl acetate was added to extract the reaction product. The aqueous layer was further extracted with ethyl acetate. The organic layers were combined, washed with water and concentrated to dryness under reduced pressure to give
K B r ~
I R ~7 C~ 3 4 00~3 1 00. 1 7 3 0.
.
~ax 1 61 S . 1 5 3 5 :
Example 10 (1) In 180 ml of acetone was suspended 6 y (0.019 mole) of ethylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-hydroxyiminoacetate as obtained in Example 9 followed by a serial addition of 5.7 g (0.0292 mole) of t-butyl bromoacetate, 0.9 ml of water and 10.8 g of anhydrous potassium carbonate. The mixture was stirred at 40C for 2 hoursand the insoluble matter was filtered off. To the filtrate was added 200 ml of water and 200 ml of ethyl acetate was added to extract the reaction product. The aqueous layer was further extracted with ethyl acetate. The organic layers were combined, washed with water and concentrated to dryness under reduced pressure to give
6.0 g of ethylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonylmethoxyimino)acetate as white crystals. (Yield~ 73.0~) ~ NMR (60MHz . DMSO- d6 ) ~: 1. 20 (3H.
1I t, J=8HZ, CH2 CH3 ) . 1 . 44 (9H. s, C
(CH3 ) 3 ) . 3. 1 2 (2H. q . J=8Hz, SCH
C H 3 ~ . 3 . 5 5 ( 2 H . t . J = 7 H z . C H 2 S ) .
4. 5 2~4. ~0 (4H. m . COOCH2 CO& COO
G H 2 C H 2 ) . 7 . O O ( 1 H, s, thiazole --5--H ) 1 , 7 . 2 8 ( 2 H . s, ~N H 2 - ) ~ ;:
. ~:
_33_ ~2~ 3 IR vrnax cm : 3400-2950, 1750, 1740, 1715, 1630 1615, 1550 (2) In 100 ml of acetone-water (1:1, vjv) was dissolved 5.0 g (0.0119 mole) of ethylsulfonylethyl 2-(2-aminothiazol-4-yl)-(z)~2-(t-butoxycarbonylmethoxy-imino)acetate as obtained in (1) and a 40% aqueous solution of potassium carbonate was added dropwise at 30-35C while maintaining the pH at 10-10.5. After completion of the reaction, the solvent was distilled off and pH was adjusted to 2 with lN-HCl, whereupon white crystals separated out.
After cooling, the crystals were collected by filtration to give 2.~ g of 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonylmethoxyimino)acetic acid. (Yield, 15 78.1%) The NMR and IR spectra of this product were in good agreement with those of an authentic sample.
Example 11 (1) In 100 ml of methylene chloride was dissolved 20 20.5 g (0.244 mole) of diketene,and 17.3 g (0.244 mole) of chlorine gas was bubbled into the solution with cooling ~t -30C; o~ belo~. A solution of 35 g (0.188 mole)of phenyl-sulfonylethanol and 14.9 g (0.188 mole) of pyridine in 75 ml ofrnethylene chlorlde was added dropwise to ~the above solution with cool-ingiat -25C or beI~ over a period of 30 minutes. The _34~ 8 2 3 mixture was stirred at 0C for about an hour and poured into ice water for separation. The aqueous layer was further extracted with 140 ml of methylene chloride .
The organic layers were combined, washed with water 5 and concentrated to dryness to give 54.9 g (yield, 95.8%) of phenylsulfonylethyl 4-chloroacetoacetate as an oil.
jNMR (60MHZ . DMS0- d~ 3. 49 (4H.
m, C H 2 S 0 2 & 0 C H 2 C 0 ) .4 . 2 0 ( 2 H, s, C l C.H 2 C 0 ) . 4 . 4 9 ~ 2 H . t . J = 8 H z . C 0 o I V C H 2 C H z ) ~. .
!Neat I R v c7n-l : 1 7 5 5 . 1 7 3 ~ . 1 4 5 O.
~ a x 1 400 (2) In a mixture of 119 ml of acetic acid and 47 ml of ethyl acetate was dissolved 54.3 g (0.178 mole) of oily phenylsulfonylethyl 4-chloroacetoacetate as obtained in (1). The solution was cooled to 5C or below and a solution of 12.3 g (0.178 moL~) of sodium-nitrite;in 63 ml of water was added dropwise to the above solution over a period of about an hour. The mixture was stirred for an hour, poured into 300 ml of ice water and ex-tracted with 500 ml of ethyl acetate. The aqueous layer was further extrac~ted with 100 ml of ethyl acetate. The organic layers were ccmbined, wash^d with 100 ml of 5% aqueous ~2~Z3 sodium hydrogen carbonate and concentrated to dryness -under reduced pressure to give 62.5 g (Yield, 105.2~) of phen~l-sulfonylethyl 4-chloro-2-hydroxyiminoacetoacetate as an oil. This oil contained a little amount of acetic acid as impurity.
NMR (60MH z . CDCI 3 ) ~ : 3. 5 7 ( 2 H. t , J`= 8 H z, - C H 2 S O 2 ) . 4 . 5 0 ( 2 H . s . C I
C H 2 C O ~ . 4 . 6 2 ( 2 H . t, J = 8 H z . C O O C
H 2 C H 2 ) . 7 . 5 5 ~ 8 . O O ( 5 H . m, ~rom.) N ea t ~ I R v cm~l : 3 3 0 0 . 1 7 5 O, 1 7 1 0.
I -~ m a x ~ 1 6 3 0 . 1 5 g 0. 1 4 5 0 (3) In a mixture of 273 ml of ethanol and 27.3 ml of water was dissolved 62.5 g (0.187 mole, unadjusted-for purity) of crude phenylsulfonylethyl 4-chloro-2-hydroxyiminoacetoacetate as obtained in (2),and 14.1 g (0.185 mole) of thiourea and 25.1 g (0.184 mole) of sodium acetate were added directly to the solution.
The mixture was stirred at 25-30C for about 5 hours and 1 liter of water was added. The mixture was cooled to 5C or below and the resulting crystalline precipitate was collected by filtration to give 28.4 g of phenyl-sulfonylethyl 2-(2-aminothiazol-4-yl~(Z)-2-hydroxyimino-, acetate as white crystals. (Yield: 44.9% based on phenyl-sulfonylethyl 4-chloroacetoacetate~
Elemental analysls Calcd. for C 13 H 13 N 3 0 s S 2 = 3 5 5- 3 3 C43. 94%, H3. 69%. N1 1. 82%.
S 1 8. 04%
ound: C 4 3 . 9 0 %. H 3 . 7 3 % . N 1 1 4 O % -S1 7. 37%
NMR (60MHz . DMSO- d6 ) a: 3. 77 (2H, , t, J =8 H2 . -CH 2 S ) , 4. 4 8 ( 2 H. t, J=.
8Hz . COCH2 CH2 ) . 6. 8 O ( 1 H. s, thia-zole--5--H) . 7. 2 O ( 2H, s, NH 2 --) . 7. 5 0 ~ 8 . 0 0 ( 5 H . m, arom.
- K13r R v c~ 3 4 0 0 ~ 3 1 0 0. 1 7 25.
: m a x -I . 1 6 1 5. 1 5 3 5 Example 12 (1) In 100 ml of acetone was suspended 5 g tO.0141 mole) of phenylsulfonylethyl 2-(2-aminothiazol~
4-yl)-(Z)-2-hydroxyiminoacetate as obtained in Example 11.
After a serial addition of 4.0 g (0.0205 mole) of t-butyl bromoacetate, 0.3 ml of water and 7.7 g of anhydrous potassium carbonate, the mixture was stirred at 40C for 1.5 hours. After completion of the reaction, the insoluble matter was~filtered oFf and 100 ml of :
water and 100 ml of ethyl acetate were added to extract the reaction product. The aqueous layer was further extracted with ethyl acetate and the organic layers were combined, washed twice with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and ethyl acetate-isopropyl ether (1:5, v/v) was added to the residue, whereupon white crystals separated out.
After cooling, the crystals were collected by filtration to gi~e 4.1 g (yield, 62~) of phenylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonylmethoxyimino)-acetate.
NMR ~60MHz, DMS0- d6 ) ~: 1. 40 (9H.
s, C ~ C H 3 ) 3 ~, 3 . 7 6 ( 2 H . t, J = 8 H z .
I C H ~ S 0 2 ) . 4 . 4 0~ 4; 6 0 ( 4 H, m, G 0 0 C H 2 C H 2 & O C H 2 C 0 0 ) . 6 . 8 6 ( 1 H .
S, thiazole --5--H ) . 7 . 2 5 ( 2 H . ~ . N H 2 )
1I t, J=8HZ, CH2 CH3 ) . 1 . 44 (9H. s, C
(CH3 ) 3 ) . 3. 1 2 (2H. q . J=8Hz, SCH
C H 3 ~ . 3 . 5 5 ( 2 H . t . J = 7 H z . C H 2 S ) .
4. 5 2~4. ~0 (4H. m . COOCH2 CO& COO
G H 2 C H 2 ) . 7 . O O ( 1 H, s, thiazole --5--H ) 1 , 7 . 2 8 ( 2 H . s, ~N H 2 - ) ~ ;:
. ~:
_33_ ~2~ 3 IR vrnax cm : 3400-2950, 1750, 1740, 1715, 1630 1615, 1550 (2) In 100 ml of acetone-water (1:1, vjv) was dissolved 5.0 g (0.0119 mole) of ethylsulfonylethyl 2-(2-aminothiazol-4-yl)-(z)~2-(t-butoxycarbonylmethoxy-imino)acetate as obtained in (1) and a 40% aqueous solution of potassium carbonate was added dropwise at 30-35C while maintaining the pH at 10-10.5. After completion of the reaction, the solvent was distilled off and pH was adjusted to 2 with lN-HCl, whereupon white crystals separated out.
After cooling, the crystals were collected by filtration to give 2.~ g of 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonylmethoxyimino)acetic acid. (Yield, 15 78.1%) The NMR and IR spectra of this product were in good agreement with those of an authentic sample.
Example 11 (1) In 100 ml of methylene chloride was dissolved 20 20.5 g (0.244 mole) of diketene,and 17.3 g (0.244 mole) of chlorine gas was bubbled into the solution with cooling ~t -30C; o~ belo~. A solution of 35 g (0.188 mole)of phenyl-sulfonylethanol and 14.9 g (0.188 mole) of pyridine in 75 ml ofrnethylene chlorlde was added dropwise to ~the above solution with cool-ingiat -25C or beI~ over a period of 30 minutes. The _34~ 8 2 3 mixture was stirred at 0C for about an hour and poured into ice water for separation. The aqueous layer was further extracted with 140 ml of methylene chloride .
The organic layers were combined, washed with water 5 and concentrated to dryness to give 54.9 g (yield, 95.8%) of phenylsulfonylethyl 4-chloroacetoacetate as an oil.
jNMR (60MHZ . DMS0- d~ 3. 49 (4H.
m, C H 2 S 0 2 & 0 C H 2 C 0 ) .4 . 2 0 ( 2 H, s, C l C.H 2 C 0 ) . 4 . 4 9 ~ 2 H . t . J = 8 H z . C 0 o I V C H 2 C H z ) ~. .
!Neat I R v c7n-l : 1 7 5 5 . 1 7 3 ~ . 1 4 5 O.
~ a x 1 400 (2) In a mixture of 119 ml of acetic acid and 47 ml of ethyl acetate was dissolved 54.3 g (0.178 mole) of oily phenylsulfonylethyl 4-chloroacetoacetate as obtained in (1). The solution was cooled to 5C or below and a solution of 12.3 g (0.178 moL~) of sodium-nitrite;in 63 ml of water was added dropwise to the above solution over a period of about an hour. The mixture was stirred for an hour, poured into 300 ml of ice water and ex-tracted with 500 ml of ethyl acetate. The aqueous layer was further extrac~ted with 100 ml of ethyl acetate. The organic layers were ccmbined, wash^d with 100 ml of 5% aqueous ~2~Z3 sodium hydrogen carbonate and concentrated to dryness -under reduced pressure to give 62.5 g (Yield, 105.2~) of phen~l-sulfonylethyl 4-chloro-2-hydroxyiminoacetoacetate as an oil. This oil contained a little amount of acetic acid as impurity.
NMR (60MH z . CDCI 3 ) ~ : 3. 5 7 ( 2 H. t , J`= 8 H z, - C H 2 S O 2 ) . 4 . 5 0 ( 2 H . s . C I
C H 2 C O ~ . 4 . 6 2 ( 2 H . t, J = 8 H z . C O O C
H 2 C H 2 ) . 7 . 5 5 ~ 8 . O O ( 5 H . m, ~rom.) N ea t ~ I R v cm~l : 3 3 0 0 . 1 7 5 O, 1 7 1 0.
I -~ m a x ~ 1 6 3 0 . 1 5 g 0. 1 4 5 0 (3) In a mixture of 273 ml of ethanol and 27.3 ml of water was dissolved 62.5 g (0.187 mole, unadjusted-for purity) of crude phenylsulfonylethyl 4-chloro-2-hydroxyiminoacetoacetate as obtained in (2),and 14.1 g (0.185 mole) of thiourea and 25.1 g (0.184 mole) of sodium acetate were added directly to the solution.
The mixture was stirred at 25-30C for about 5 hours and 1 liter of water was added. The mixture was cooled to 5C or below and the resulting crystalline precipitate was collected by filtration to give 28.4 g of phenyl-sulfonylethyl 2-(2-aminothiazol-4-yl~(Z)-2-hydroxyimino-, acetate as white crystals. (Yield: 44.9% based on phenyl-sulfonylethyl 4-chloroacetoacetate~
Elemental analysls Calcd. for C 13 H 13 N 3 0 s S 2 = 3 5 5- 3 3 C43. 94%, H3. 69%. N1 1. 82%.
S 1 8. 04%
ound: C 4 3 . 9 0 %. H 3 . 7 3 % . N 1 1 4 O % -S1 7. 37%
NMR (60MHz . DMSO- d6 ) a: 3. 77 (2H, , t, J =8 H2 . -CH 2 S ) , 4. 4 8 ( 2 H. t, J=.
8Hz . COCH2 CH2 ) . 6. 8 O ( 1 H. s, thia-zole--5--H) . 7. 2 O ( 2H, s, NH 2 --) . 7. 5 0 ~ 8 . 0 0 ( 5 H . m, arom.
- K13r R v c~ 3 4 0 0 ~ 3 1 0 0. 1 7 25.
: m a x -I . 1 6 1 5. 1 5 3 5 Example 12 (1) In 100 ml of acetone was suspended 5 g tO.0141 mole) of phenylsulfonylethyl 2-(2-aminothiazol~
4-yl)-(Z)-2-hydroxyiminoacetate as obtained in Example 11.
After a serial addition of 4.0 g (0.0205 mole) of t-butyl bromoacetate, 0.3 ml of water and 7.7 g of anhydrous potassium carbonate, the mixture was stirred at 40C for 1.5 hours. After completion of the reaction, the insoluble matter was~filtered oFf and 100 ml of :
water and 100 ml of ethyl acetate were added to extract the reaction product. The aqueous layer was further extracted with ethyl acetate and the organic layers were combined, washed twice with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and ethyl acetate-isopropyl ether (1:5, v/v) was added to the residue, whereupon white crystals separated out.
After cooling, the crystals were collected by filtration to gi~e 4.1 g (yield, 62~) of phenylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonylmethoxyimino)-acetate.
NMR ~60MHz, DMS0- d6 ) ~: 1. 40 (9H.
s, C ~ C H 3 ) 3 ~, 3 . 7 6 ( 2 H . t, J = 8 H z .
I C H ~ S 0 2 ) . 4 . 4 0~ 4; 6 0 ( 4 H, m, G 0 0 C H 2 C H 2 & O C H 2 C 0 0 ) . 6 . 8 6 ( 1 H .
S, thiazole --5--H ) . 7 . 2 5 ( 2 H . ~ . N H 2 )
7 . 5 0~ 8 . ~0 0 ( ~ H, m, arom.
~K B r I R v cm~~: 3 4 0 0~ 2 9 0 0 . 1 7 5 0 .
m a x 1 7 1 0. i 6 2 0. 1 5 5 0 (2) In 20 ml of acetone-water (1:1, v/v) was dissolved 1 g (0. 00213 mole) of phenylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z1 -2- (t-butoxycarbonylmethoxy-, imino)acetate as obtained in (l), and a 40% aqueous solution of potassium carbonate was added dropwise to the solution while maintainLng the pH at 10-10.5. After completion of the reaction, the mixture was adjusted to pH 6 with l N HCl and the acetone was distilled off. Then, pH
was adjusted to 2 with 1 N HCl, whereupon white crystals separated out. After cooling, the crystals were collected by filtration to give 0.42 g (yield, 65.4%) of 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl-methoxyimino)acetic acid, I NMR ( 60MHz . DMS0- d6 ) ~: 1 . 4 2 (9H.
s . C (CH3 ) 3~ . 56 (2H. s . 0C~_C0) 6 . 8 5 ( 1 H . s, thiazole -- 5 --tl ~ . 7 . 2 5 . ( 2 H. br, N H 2 - ) . .
.. ' ~ ; ' 'i ' ' :. . ' K 8 r I R ~ 3 5 5 0~ 2 9 0 0 . 1 7 4 5 .
m a x 1 6 4 5 . 1 6`1 0. 1 5 8 0 Example 13 Using 2 g (0.00563 mole) of phenylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-hydroxyiminoacetate as obtained in Example ll and 1.17 g (0.00559 mole) of t-butyl 2-bromopropionate and following the reaction - procedure of Example 12, there was obtained 1.63g (yièla, 60.0 of phenylsulfonyletbyl 2- (2-aminothiazol-4-yl)-(Z)-2-,. ~
. . ~
:
L8;23 (t-butoxycarbonyl-l-methylmethoxyimino)acetate.
NMR ( 6 OMHz . DMSO-- d6 ) ~: 1 . 3 8~
1 . 4 2 ~ 1 2H. ~, C ~CH3 ) 3 & CH-C~) .
3 . 7 3 ( 2 H . t . J--7 H Z, C H 2 S O 2 ) .
! 4 . 4 5 ~ 4 . 6 0 ( 3 H . m, C O O C H 2 & C H C H 3 ) ¦ 6 . 9 0 ( 1 H, s, thiazole - 5 - H ) . 7 . 2 0 (2H. s, NH2 ) . 7. 48~8. OO (5H. m, aro~.
::
o 1: K B r I R ~ 3400~2950. 1 745.
ax ~ 1 7 3 0. 1 6 3 O. 1 5 9 5 . 1 5 ~
The above-obtained phenylslllfonylethyl 2-(2-15 aminothiazol-4-yl)-(z)-2-(t-butoxycarbonyl-l-methylmeth imino)acetate (1.2 g, 0.00248 mole) was hydrolyzed to give 0.52 ~ (~ield,, 66.5%) of 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl-l~methylmethoxyimino)acetic acid.
The NMR and IR of this product was in good agreement with those of the product obtained in Example 8.
Example 14 Using 5 g (0.0141 mole~ of phenylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-hydroxyiminoacetate as obtained in Example 11 and 4.7 g (0.0211 mole) of t-butyl 2-bromoisobutyrate and following the reaction procedure of Example 12, there was obtained`4.lg-(yie,ld,~58.4%) oiE phenylsulfonylethyl 2-(2-aminothiazol-4-yl~-~(Z)-2-(t-butoxycarbonyl-1,1-: dimethylmethoxyimino)acetate.
NMR ( 60MHz . DMS0- d6 ) ~: 1 . 40 ( 1 5H.
s, C ~CH3 ) ~ &C (CH3 ) 2 ) .
3 ~ 7 2 ( 2 H . t, J = 8 H z . C H 2 S O 2 ) .
4. 60 (2H. t, J=8Hz . COOCH2 ) .
6 . - 9 0 ( 1 H . s ~ thiazole --5--H ), 7 2 7 ~2H. s . NH2 ), 7. 49~7. 98 (5H~ m, arom. ) I`" ~
I K B r : .
I R IJ cm-l : 3 4 0 0 ~ 3 0 0 0, 1 7 5 0, ` - ~ a x 1 71 5. 1 635. 1 595. 1 ~4 Then, the above ester compound was hydrolyzed to give 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl-l,l-dimethylmethoxyimino)acetic acid. (Yield, 72.0~) Elemental analysis .
I Calcd.~o~ ~ H 19 N 3 0 5 S 0. 7 H 2 0 = 3 4 1 . 9 8 1 C 4 5 . 6 7 %, H 6 . 0 1 %. N 1 2 . 2 9 ~
¦ Found: C 4 5. 9 9 ,~, H 6. 3 2%. N 1 2 3 2%
!NMR ~60MHz, DMS0- d6 ) 8 :-1. 41 ~1 5H.
s, C (CH i ) 2 &C ( CH~ ) ~ ) . 6. 79 (s . 1 H, thiazole - 5 H ): . 7 . 2 0 ( 2 H, br~ - N H 2_) ~ : :
K B r I R lJ c~ 3 4 0 0~ 2 9 0 0 . 1 7 2 0 .
`: m a x : ~ 1 6 4 5, 1 6 0 0 .
~4~ 3 E~ample 15 (l) In 1.26 liters of methylene chloride was dissolved 420 g (5.0 molesj of diketene. Ihe solution was o~oled at -30 to -35C and 354 g (4.99 moles) of chlorine gas was bubbled into the solution for about an hour to prepare a 4-chloroacetoacetyl chloride solution.
244 ml of this solution (4-chloroacetoacetyl chloride:
109.2 g, 0.705 mole) was cooled to -30 to -40C
and a solution of 50 g (0.543 mole) of methylthioethanol and 43 g (0.543 mole) of pyridine in 85 ml of methylene chloride was added dropwise at -20 to -30C over a period of about 30 minutes. After completion of addition, the reaction was allowed to proceed at -5C
for 30 minutes. To the reaction mixture were added 500 ml of methylene chloride and l liter of water to extract the reaction product. The aqueous layer was further extracted with 500 ml of methylene chloride. The organic layers were combined, washed with 500 ml of water and concentrated to dryness under reduced pressure to give 114 y of methylthioethyl 4-chloroacetoacetate as an oil.
NMR ~60MHz . DMSO-- d6 ) ~: 2. i O (3H.
s, S--CH 3 ) . 2. 7 1 ( 2H. t, J-8Hz . CH
2 S--(~H3 3 ~ 3. 7 2 ~ 2H, s, COC~CO~ 4.
25 ~2~H. t . J=8HZ . COOGH 2 CH2 ) . 4.
60 (2H. s . Ci CH 2 CO ) - ~
,,.
~ : :
~K B r I R v cm~~: 3 4 0 0~ 2 9 0 0 . 1 7 5 0 .
m a x 1 7 1 0. i 6 2 0. 1 5 5 0 (2) In 20 ml of acetone-water (1:1, v/v) was dissolved 1 g (0. 00213 mole) of phenylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z1 -2- (t-butoxycarbonylmethoxy-, imino)acetate as obtained in (l), and a 40% aqueous solution of potassium carbonate was added dropwise to the solution while maintainLng the pH at 10-10.5. After completion of the reaction, the mixture was adjusted to pH 6 with l N HCl and the acetone was distilled off. Then, pH
was adjusted to 2 with 1 N HCl, whereupon white crystals separated out. After cooling, the crystals were collected by filtration to give 0.42 g (yield, 65.4%) of 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl-methoxyimino)acetic acid, I NMR ( 60MHz . DMS0- d6 ) ~: 1 . 4 2 (9H.
s . C (CH3 ) 3~ . 56 (2H. s . 0C~_C0) 6 . 8 5 ( 1 H . s, thiazole -- 5 --tl ~ . 7 . 2 5 . ( 2 H. br, N H 2 - ) . .
.. ' ~ ; ' 'i ' ' :. . ' K 8 r I R ~ 3 5 5 0~ 2 9 0 0 . 1 7 4 5 .
m a x 1 6 4 5 . 1 6`1 0. 1 5 8 0 Example 13 Using 2 g (0.00563 mole) of phenylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-hydroxyiminoacetate as obtained in Example ll and 1.17 g (0.00559 mole) of t-butyl 2-bromopropionate and following the reaction - procedure of Example 12, there was obtained 1.63g (yièla, 60.0 of phenylsulfonyletbyl 2- (2-aminothiazol-4-yl)-(Z)-2-,. ~
. . ~
:
L8;23 (t-butoxycarbonyl-l-methylmethoxyimino)acetate.
NMR ( 6 OMHz . DMSO-- d6 ) ~: 1 . 3 8~
1 . 4 2 ~ 1 2H. ~, C ~CH3 ) 3 & CH-C~) .
3 . 7 3 ( 2 H . t . J--7 H Z, C H 2 S O 2 ) .
! 4 . 4 5 ~ 4 . 6 0 ( 3 H . m, C O O C H 2 & C H C H 3 ) ¦ 6 . 9 0 ( 1 H, s, thiazole - 5 - H ) . 7 . 2 0 (2H. s, NH2 ) . 7. 48~8. OO (5H. m, aro~.
::
o 1: K B r I R ~ 3400~2950. 1 745.
ax ~ 1 7 3 0. 1 6 3 O. 1 5 9 5 . 1 5 ~
The above-obtained phenylslllfonylethyl 2-(2-15 aminothiazol-4-yl)-(z)-2-(t-butoxycarbonyl-l-methylmeth imino)acetate (1.2 g, 0.00248 mole) was hydrolyzed to give 0.52 ~ (~ield,, 66.5%) of 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl-l~methylmethoxyimino)acetic acid.
The NMR and IR of this product was in good agreement with those of the product obtained in Example 8.
Example 14 Using 5 g (0.0141 mole~ of phenylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-hydroxyiminoacetate as obtained in Example 11 and 4.7 g (0.0211 mole) of t-butyl 2-bromoisobutyrate and following the reaction procedure of Example 12, there was obtained`4.lg-(yie,ld,~58.4%) oiE phenylsulfonylethyl 2-(2-aminothiazol-4-yl~-~(Z)-2-(t-butoxycarbonyl-1,1-: dimethylmethoxyimino)acetate.
NMR ( 60MHz . DMS0- d6 ) ~: 1 . 40 ( 1 5H.
s, C ~CH3 ) ~ &C (CH3 ) 2 ) .
3 ~ 7 2 ( 2 H . t, J = 8 H z . C H 2 S O 2 ) .
4. 60 (2H. t, J=8Hz . COOCH2 ) .
6 . - 9 0 ( 1 H . s ~ thiazole --5--H ), 7 2 7 ~2H. s . NH2 ), 7. 49~7. 98 (5H~ m, arom. ) I`" ~
I K B r : .
I R IJ cm-l : 3 4 0 0 ~ 3 0 0 0, 1 7 5 0, ` - ~ a x 1 71 5. 1 635. 1 595. 1 ~4 Then, the above ester compound was hydrolyzed to give 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl-l,l-dimethylmethoxyimino)acetic acid. (Yield, 72.0~) Elemental analysis .
I Calcd.~o~ ~ H 19 N 3 0 5 S 0. 7 H 2 0 = 3 4 1 . 9 8 1 C 4 5 . 6 7 %, H 6 . 0 1 %. N 1 2 . 2 9 ~
¦ Found: C 4 5. 9 9 ,~, H 6. 3 2%. N 1 2 3 2%
!NMR ~60MHz, DMS0- d6 ) 8 :-1. 41 ~1 5H.
s, C (CH i ) 2 &C ( CH~ ) ~ ) . 6. 79 (s . 1 H, thiazole - 5 H ): . 7 . 2 0 ( 2 H, br~ - N H 2_) ~ : :
K B r I R lJ c~ 3 4 0 0~ 2 9 0 0 . 1 7 2 0 .
`: m a x : ~ 1 6 4 5, 1 6 0 0 .
~4~ 3 E~ample 15 (l) In 1.26 liters of methylene chloride was dissolved 420 g (5.0 molesj of diketene. Ihe solution was o~oled at -30 to -35C and 354 g (4.99 moles) of chlorine gas was bubbled into the solution for about an hour to prepare a 4-chloroacetoacetyl chloride solution.
244 ml of this solution (4-chloroacetoacetyl chloride:
109.2 g, 0.705 mole) was cooled to -30 to -40C
and a solution of 50 g (0.543 mole) of methylthioethanol and 43 g (0.543 mole) of pyridine in 85 ml of methylene chloride was added dropwise at -20 to -30C over a period of about 30 minutes. After completion of addition, the reaction was allowed to proceed at -5C
for 30 minutes. To the reaction mixture were added 500 ml of methylene chloride and l liter of water to extract the reaction product. The aqueous layer was further extracted with 500 ml of methylene chloride. The organic layers were combined, washed with 500 ml of water and concentrated to dryness under reduced pressure to give 114 y of methylthioethyl 4-chloroacetoacetate as an oil.
NMR ~60MHz . DMSO-- d6 ) ~: 2. i O (3H.
s, S--CH 3 ) . 2. 7 1 ( 2H. t, J-8Hz . CH
2 S--(~H3 3 ~ 3. 7 2 ~ 2H, s, COC~CO~ 4.
25 ~2~H. t . J=8HZ . COOGH 2 CH2 ) . 4.
60 (2H. s . Ci CH 2 CO ) - ~
,,.
~ : :
8;23 IR vmaxa cm : 1750-1730, 1670 (2) In a mixture of 115 ml of ethyl acetate and 230 ml of glacial acetic acid was dissolved 114 g (0.541 mole) of crude methylthioethyl 4-chloroaceto-acetate as obtained in (1). The solution was cooled to 5Cor below and a solution of 37.5 g (0.543 mole) of sodium nitrite.in 118 ml of water was added dropwise to the solution atl 5c or below over a period of about 2 hours.
The reaction mixture was poured into 1 liter of ice water to extract the reaction product. The aqueous layer was further extracted with 1 liter of ethyl acetateO The organic layers were combined, washed with 400 ml of 5% aqueous sodium hydrogen carbonate and concentrated under reduced pressure to give 130 g of methylthioethyl 4-chloro-2-hydroxyiminoacetoacetate as an oil.
NMR (60MHz . DMS0- d6 ~ ~: 2. 1 ~ (3H.
. s . S--CH 3 ) . 2. 75 (211. t . J=8Hz CH
2 CH2 S) . 4. 40 ~2H. t, J=8Hz . COOC:
`~2_CH2 ) . 4. 89 (2H. s . Cl CH~C0) ~ Neat:
I R ~ c7n~l: 3 1 5 0~3 0 0 0. 1 7 4 5 . 1 7 1 5 : - m a x (3) In a mixture of 520 ml of ethanol and 28 ml of water was dissolved 130 g (0.542 mole) of methylthio-ethyl 4-chloro-2-hydroxyiminoacetoacetate as obtained in (2), and 41.3 g (0.543 mole) of thiourea and 73.9 g (0.543 mole) of sodium acetate were added. The reaction was allowed to proceed at room temperature for 60 minutes.
The solvent was then distilled off under reduced pressure, followed by addition of 300 ml of water.
The mixture was cooled and the crystalline precipitate was collected by filtration and dried under reduced pressure to give 72.6 g (yield: 51.2% based on methylthioethanol) of methylthioethyl 2-(2-aminothiazol-4-yl)-(z)-2-hydroxyiminoacetate as white crystals.
Elemental analysis Calcd. for C 8 ~ 1I N 3 0 3 S 2 = 2 6 1 . 3 1 C36. 77%. H4. 24%. N1 6. 08%
Found: ~ 3 6 . 7 1 % . H 4 . 2 3 % . N 1 5 . 9 4 %
NMR (60MHz . DMS0-- d6 ) 8 ::2. 1 1 (3H.
s, S-CH3 ) . 2. 77 (2H, t . J;=8HZ, C 2 S ~ . 4 . 3 8 ~ 2 H . t , J = 8 H z .
C H 2 C H 2 S ) , 6 . 8 4 ( 1 H . s, thia~ole-5 - H ) . 7 . 1 5 ( 2 H ,~ s . N ~ 2 ) ~ ~ K~B r ~
I R v~ cm-l: 3 4 0 0~3 1 5 0, 1 7 2 0.
m a: x ~
1 61 0. 1 5 3 5 1;~4~2,3 ~ -44-Example 16 (1) In 100 ml of acetone was suspended 5 g (0.0191 mole) of methylthioethyl 2-(2-aminothiazol-4-yl)-(Z)-2-hydroxyiminoacetate as obtained in Example 15, S and 4.32 g (0.029 mole) of t-butyl chloroacetate, 0.3 ml of water, 10.56 g (0.076 mole) of anhydrous potassium carbonate and 3.15 g (0.021 mole) of sodium iodide were added in that order. The reaction was allowed to proceed at 40C for about 6 hours. The reaction mixture was poured into 300 ml of water and extracted with 500 ml of ethyl acetate. The organic layer was washed with water, dehydrated with anhydrous sodium sulfate and concentrated to dryness under reduced pressure. Ether was added to the residue to give 6.56 g ~yièld, 91.5%) of methylthioethyl 2 (2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonylmethoxyimino)acetate as white crystals.
Elemental anlaysis I Calcd. for C t4 H 2~ N~3 0 3 S 2 = 3 7 5. 4 6 ` C 4 4 . 7 9 %. H 5 . 6 4 %. N 1 1 . 1 9 ~q Found:- C ~ 5 . 0 7 % . H 5 . 7 8 % . N 1 1 . 0 5 %
NMR (60MHz . D~ISO-- d6 ) ~: 1. -42 (9H.
l s, C H ~ x 3 ) . 2 . 1 0 ( 3 H . S, S C ~
¦ 2. 7 8 ( 2 H, t, J = 8 H z, C~S C H 3 ) .-4 . 4 0 ~ 2 H. t, J =:8 Hz, COOC~2 CH 2 S ) , 4. 57 (2:H. s, OGH~CO), 6. 02 (1H. s, thiazole ~ --5--~ H~, 7 . 2 5~ ( 2 H, s, N H 2--) ;
~ .
IR vmax cm : 3400-2900, 1740, 1710, 1625, 1550 (2) In a mixture of 47 ml of acetone and 9.4 ml of water was dissolved 6.0 g (0.0160 mole) of methyl-thioethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxy-carbonylmethoxyimino)acetate as obtained in (1), andO.05 g of ammonium molybdate was added. Further, 10.9 ml (0.112 mole) of 35% aqueous hydrogen peroxide was added at 25-30C and the reaction was allowed to proceed for 6 hours. The reaction mixture was poured into 500 ml of water and extracted with 500 ml of ethyl acetate. The organic layer was washed with 500 ml of 5% sodium sulfite and 500 ml of water and concentrated to dryness. To the residue was added about 50 ml of ether, whereby white crystals separated out. After cooling, the crystals were collected by filtration to give 6.1 g (Yleld, 93.6 %) of methylsulfonylethyl 2-(2-amino-thlazol-4-yl)-(Z)-2-(t-butoxycarbonylmethoxyimino)-acetate.
Elemental analysis Calcd. for C ~ H 21 N 3 0 7 S 2 O- 5 H 2 O
~- = 4 1 6. 4~7; ~ ~ ~
40. 38%. H5. 32%. N1 :). O9%
Found: C 4 0 . 1 1 %. H 5 . 1 5 %. N 9 . 8 9 %
NMR ( 6 OMHZ . DMS0~-- d6 ) a: 1 . 4 2 ( 9 H.
~s .~ CH3 x3), 3. 00 (3H, s, SCH~ ) .
::
- ~6 -3. 57 (2H, t . J=8Hz . C ~ Sc H 3 ) . 4.
¦ 55~4. 62 (4H, m, COOC~CHz& OCH 2 j C O O ), 7 . O O ( 1 H . s, thiazole - 5 - H ), 7 .
- 28 (2H. s . NH2-) K B r I R v cm-t : 3 4 0 0 ~ 2 9 9 5 . 1 7 5 0 .
m a x 1 7 2 Q. 1 6 2 8 . 1 5 4 5 (3) In a mixture of 200 ml of acetone and 200 ml of water was dissolved 4 g (0.00982 mole) of methyl-sulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxy-carbonylmethoxyimino)ac~tate as obtained in (2), and a 40~
aqùeous solution of potassium carbonate was added dropwise to the solution at 30-35C while maintaining pH at about 10.5. The reaction mixture was washed with 500 ml of ethyl acetate.
The aqueous layer was adjusted to pH about 2 with 2 N
HCl, whereby~crystals separated out. After cooling the crystalline precipitate was collected by filtration to gi~e 2.5 ~ (yield~84.5~) of 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonylme~hoxyimino)acetic acid as white crystals.
ElementaI analysis ~ . .. . .. . . .
Calcd. forC 1I H ~ N 3 O 5 S 0. 5 H 2 0 = 3 1 0. 3 2 . ~ C 4:2. 58 oi. H5. 20%. N1 3. 54%
Found: C 4 2 . 9 5 %. H 5 . 1 2 %. N 1 3 . 3 8 %
N M R ( 6 O M H z . D M S O - d 6 ) ~ 1 . 4 4 ( 9 H .
¦~: s . CH3 x3 j, 4. 5 7 ( 2H. s . OC712 CO) .
6 . 8 5 ( 1 H~. s, ~ thiazole --5--H ) 7 2 5 ~ :( 2 H. br N H 2 ) l ~ 32~
IR vKBx cm : 3350-3000~ 1740, 1640, 1600, 1580 Example 17 (1) In 100 ml of acetone was suspended 5 g (0.0191 mole) of methylthioethyl 2-(2-aminothiazol-4-yl)-(Z)-2-hydroxyiminoacetate as obtained in ~xample 15, and 6.4 g (0.0287 mole) of t-butyl 2-bromoisobutyrate, 0.3 ml of water and 10.56 g (0.076 mole) of anhydrous potassium carbonate were added in that order~ The reaction was allowed toproceed at 40C for 20 hours.
The reaction mixture was poured into 100 ml of water and extracted with 100 ml of ethyl acetate. The organic layer was washed with water and dried over anhyrous sodium sul-fate and concentrated to dryness. To the residue was added 50 ml of ether and the mixture was cooled.
The precipitate was collected by filtration to give 6.17 g (yield, 80~ b~) of methylthioethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl-1,1-dimethylmethoxyimino)-acetate as white crystals.
Elemental analysis l Calcd. for C 16 H ~ N 3 0 5 S 2 - 4 0 3 . 5 1 i ~ ` C4 7. 6~3%. H6. 24%. N1 O. 41%
Found C 4 7 :. 3 7 %, H 6: . 2 3 % . N 1 O . 3 4 %
Nl~tlR ( 6 0M:H z, DMSQ-d 6 ) ~ : 1 . 4 a ( 1 5 H.
~ s .: C :( CH 3 ) ~ & C ( CH 3 ) 2 ) . 2 . 1: 2 ~ 3 H . S, --S C H .~ ~ . 2 . 7 8 ( 2 H . t, J 2 8 H2, . ~ , ~ . - . . . . ,, - , ., C H_2 S C H 3 ) . 4 . 4 1 ~ 2 H . t . J = 8 H ~ ~ - C
~C H 2 S ) . 6 . 8 8 ( 1 H . s, thia~ole~ - 5 7~ 26 (2H.~S .~NH: 2 - ) ~
:
max cm : 3400_3000, 1735, 1730, 1630, 1550 (2) In a mixture of 25 ml of acetone and 5 ml of water was dissolved 2.5 g (0.0062 mole) of methyl-thioethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxy-carbonyl-l,l-dimethylmethoxyimino)acetate as obtained in (1) ~ and 0.029 g of ammonium molybdate was added, Then, at 30C, 1.94 ml of 35% aqueous hydrogen peroxide was added dropwise to the mixture.- The resulting mixture was stirred at the same temperature for 7.5 hours, poured into 200 ml of water and extracted with 200 ml of ethyl acetate. The organic layer was washed with 400 ml of 5% sodium sulfite and 200 ml of water and the solvent was distilled off under reduced pressure.
To the residue was added 100 ml of ether, whereupon white crystals separated out. After cooling~ the crystals were collected by filtration to give 2.4 g (yield, 88.9%) of methylsulfonylethyl 2-(2-aminothiazol-4-yl)-tZ)-2-(t-butoxycarbonyl-1,1-dimethylmethoxyimino)acetate.
Elemental analysis ~ Calcd. for C 16 H ~ N 3 0 7 S 2 = 4 3 ~. 5 C44. 1 3%, H5. 79%. N9. 65%
Found: C 4 4 . 1 5 % . H 5 . 3 3 % . N 9 . 6 0 %
NMR ( 60MHz, DMS0--d 6 ) 8: 1 . 40 ( 1 5H.
s, CH 3 X 5), 3. o4 (3H. s, SCH 3 3 . 5 8 ( 2 H . t, J = 8 H z . C~S C H 3 ) .
4 . 6 2 ( 2 H . t, J = 8 H z . C H 2 C H 2 S C H 3 j >
6~. 9 2 ( 1 H . s, ~thiazole --5--H ), 7 ~ ~3 (~2H. b r. NH 2 - ) ~2~ 3 IR vma cm : 3350-3000, 1750, 1725, 1645, 1550 (3) In a mixture of 45 ml of acetone and 45 ml of water was dissolved 2.2 g (0.00505 mole) of methyl-sulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl-l,l-dimethylmethoxyimino)acetate as obtained in (2), and a 40% aqueous solution of potassium carbonate was added dro~wise to the solution at 30-35C while maintaining the pH at 10-10.5. The mixture was stirred for about an hour and washed with 100 ml of ethyl acetate. The aqueous layer was adjusted to pH about 2 with 2 N HCl and then cooled. The white crystals were collected b~ filtration to give 1.29 g (yield, 77.6%) of 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl~ dimethy~methoxyimino)acetic acid.
Elemental analysis Calcd.~for C ~ H ~ N 3 0 5 S O . 7 7 H 2 0 = 3 4 3. 2 3 . C 4 5 . 4 9 % . H 6 . 0 2 % . N l 2 . 2 4 %.
. S 9 3 4 %
Found: C4 5. 4 9%. H 6. 2 2/~, N 1 2. 1 7%.
~ S9. 24%: : ~
NMR (60MHZ. D:MS0-d 6 ) ~i 1. 40 (1 5H.
s, (CH3 ) 3 & C (:CH_3 ) z ), 6. 79 ( 1 H, S, ........
thiazole - 5 - H ) . 7 . 2 0 ( 2 H, br, N H 2 - ) ~ ~
K B r R v cm-l : 3 5 5 0 ~ 2 8 0 0 . 1 7 2 0, 1 6 5 0 .
. m a x . : 1 63~0. 1 61 0. 1 580. 1 560 .
Example 18 Using 146 g (0.942 mole) of 4-chloroacetoacetyl chloride (synthesi2ed from diketene and chlorine) and lOO g (0.942 mole) of ethylthioethanol and following the procedure of Example 15, there was obtained 138.8 g of ethylthioethyl 2-(2-aminothiazol-4-yl)-(Z)-2-hydroxy-iminoacetate via ethylthioethyl 4-chloroacetoacetate and ethylthioethyl 4-chloro-2-hydroxyiminoacetate.
(Yield, 53.5% basèd on ethyltllioethanol) Elemental analysis Calcd. for C 9 H ~ N ~ 0 3 S 2 = 2 7 5. 3 4 C39. 26%, H4. 76%. N1 5. 26%.
S23. 29%
Fo~ d: C 3 9 . 4 3 %. H 4 . 8 1 %, N 1 5 . O 1 %.
S 2 3. 0 7%
NMR (60MHz. DMSO--d6 ) ~i: 1. 28 (3H.
t . ~ = 8 H z . C H 2 C H 3 .) . 2 . 5 5 ( 2 H . q .
J = 8 H z . CH 2 S CH 2 ) . 2 . 8 0 t 2 H. t .
J 2 8 H z . C H 2_C H 2 S ) . 4 . 3 8 ( 2 H . t , J=8Hz. COOC~CH2 ) . 6. 86 (1 H. s, thiazole ~ 5--H ) . 7 . 1 8 ( 2 H, s . N H z --; KBr I R s~ c7n~1: 3 4 0 0 ~ 3 1 0 0 . 1 7 3 0 . 1 6 2 0 .
~` m a x ~ 5 3 b -~
Physical characteristics of the intermediates O Ethylthioethyl 4-chloroacetoacetate ¦ N M R ( 6 0 M H z, C D C 1 3 ) ~i : 1 . 2 5 ( 3 H, t, J = 8 H z . C H z C H 3 ) , 2 ~ 5 5 ( 2 H, q, J=8Hz, SCHz CH3i ), 2. 77 (2H, t, J = 8 H z , C H 2 C ~ S ) . 3 . 6 ~ ( 2 H , s ~
COOCH2 CO) . 4. 30 (4H, m, COOCH2 &
C I C H 2 C O ), - - !
., , - . .
o N ea ~ -I R iJ - cm-l . 1 7 5 0 . 1 7 3 0, 1 6 7 0, ~ a x O Ethylthioethyl 4-chloro-2-hydroxyiminoacetate I N M R ( 6 0 ~ H 7, C ~ C 1 3 ) ~ : 1 . 2 7 ( 3 H , t , ~ J=8Hz, CH2 CH3 ), 2. 60 (2H, q, J=8Hz, CH2 SCH2 CH3 ), 2. 8 2 ( 2H. t, J = 8 H z, C H 2 S G H 2 ), 4 . 4 5 ( 2 H . t, J=8Hz, COOCH2 ~, 4. 62 (2H, s, C l C ~ 2 ) , N eat I Rv cm i: 3350~2900, 1 740, 1 71 O.
m a x 1 6 2 0 - :
Example 19 (1~ In 300 ml of acetone was suspended 15 g (0.0545 mole) of ethylthioethyl 2~(2-amlnothiazol-4-yl)-~)-2-i.
hy ~ L~x~cetate as obtained in Example 18, and 12.3 g (0.0187 mole) ' .
.
.A~Z3 of t-butyl chloroacetate, 0.9 ml of water, 30.1 g (0.~18 mole) of anhydrous potassium carbonate and 8.98 g (0.0599 mole) of sodium iodide were added to the suspension. The reaction was allowed to proceed at room temperature for lO hours. The precipitate was filtered off and 450 ml of ethyl acetate and 450 ml of water were added or effecting extrac-tion. The aqueous layer was further extracted with lO0 ml of ethyl acetate. The organic layers were combined, washed twice with 5% aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and 600 ml of acetone was added to the residue for dissolution, followed by addtion of 1.5 liters of water. The mixture was cooled to 5C or below and the resulting crystalline precipitate was collected by filtration to give 19.1 g (yiela, 90.0%) of ethylthio-ethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl--methoxyimino)acetate.
Elemental analysis Ca1cd- for Cl5H23N3O5S2 C, 46.26%; H, 5.95%, N, 10.79~; S, 16.46 Found: C, 46.56%; H, 6.00%; N, 10.52%; S, 15.88 :
1%L~823 NMR t 60MH Z, DMSO--d 6 ) t~i 1 . 1 8 (3 H.
t , J = 8 H Z , C H 2 C H 3 ) , 1 . 4 4 ( 9 H , S
C (CH3 ) 3 ), 2. 55 (2H. q, J=8HZ, SCH2 CH3 ), 2. 80 (2H. t, J=8Hz.
j CH2 SCH2 ), 4. 3 8 ~ 2H, t, J=8HZ, C O O C H 2 C H 2 ), 4 . 5 6 ( 2 H . s, O C H 2 C O ) 6 . 9 0 ~ 1 H, s, thiazole --5--H ), 7 . 2 2 ( 2 H . S, N H 2--~
. -o K B r I R v - cm~l: 3 4 5 0~2 9 00. 1 7 60. 1 7 5 0.
m a x 1 6 2 0 . 1 5 5 5 .
.
(2) In a mixture of 200 ml of ace-tone and 40 ml of water was dissolved 19.1 g (0.0~90 mole) of ethyl-thioethyl 2-(2-aminothlazol-4-yl)-(Z)-2-(t-butoxy-carbonylmethoxyimino)acetate as obtained in (1). To the solution was added 0.23 g of ammonium molybdate and 8.3 g (0.073 mole) of 30~ aque~us hydrogen peroxide was added dropwise with cooling at 30C or below. The mixture was stirred for an hour to give an intermediate.
Further, 4.73 g (0.417 mole) of 30% aqueous hydrogen peroxide was added dropwise. The mixture was stirred at room temperature overnight and adjusted to pH about 7 with a 40~ potassium carbonate solution, and 200 ml of ethyl acetate and 160 ml of water were added for extraction. The aqueous layer was further extracted with 100 ml of ethyl acetate. The organic layers were combined and 5~ aqueous sodium sulfite was added with cooling, followed by sha~ing. The organic solution was then washed with 5~ aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and 100 ml of ethyl acetate~isopropyl ether (1:5, v/v) was added to the residue. The mixture was cooled to 5C or below and the resulting crystalline precipitate was collected by filtration to give 20.0 g (yield, 96.8~) of ethylsulfonylethyl 2~(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonylmethoxy-imino)acetate.
Elemental analysis ¦ Calcd. for C ~ H ~ N 3 O 7 S 2 = 4 2 1 . 4 8 ~ C 4 2. 75%. H5. 50~. Ng. 97%.
S1 5. 2 1 %
Found: C 4 2 . 9 6 /0 . ~1 5 .8 6 % . N 9 . 8 5 %, S 1 4 . 6 0 %
N M R ( 6 0 M H z . D M S O - d 6 ) ~ 1 . 2 0 ( 3 11.
o t, J=8Hz. CH2 CH3 ) . 1. 45 (9H. s, C (CH3 ) 3 ) . 3. 1 4 (2H, q . J=8Hz.
SCH2 CH3 ) . 3. 55 (2H. t, J=8Hz.
C H 2 S C H 2 ) . 4 . 6 0 ( 4 H . m . C O O C H 2 &
O C H 2 C O ) , 7 . O O ( 1 H . s, thiazole - 5 - H ) 7 . 2 8 ( 2 H. S . N H 2--) . . , ' .
K B r I R ~cm~l : 3 4 0 0 ~ 3 0 0 0 . 1 7 5 5 .1 7 4 O .
~ a x --- 1 7 1 5 . 1 6 3 0. 1 6 1 0. 1 545 The filtrate obtained in the above procedure (2) was poured~into water and extracted with ethyl acetate.
The extract was concentrated to dryness and the residue 25 was crystalli~ed from ethyl acetate-isopropyl ether ~l:l, v/v) to give ethylsulfinylethyl 2-(2-amino-thlazo1-4-yl)-(Z)-2-~t-butoxycarbonylmethoxyimino)acetate.
. ~ ~
Elemental analysis Calcd. for C 15 H ~ N 3 0 6 S 2 = 4 0 5 . 4 8 C44. 43/0, H5. 7 2%, N 1 O. 3 6%.
S1 5. 8 1 %
1 ~ound: C 4 4 . 5 0 % . H 5 . 6 8 %. N 1 0 . 1 7 %.
S 1 5 . 5 2 %
NMR (60MH~. DMSO--d6 ) 8; 1. 1 8 (3H.
t, J=8Hz. CH2 CH3 ) . 1 . 42 ~9H. s, C ( CH 3 ) 3 ) . 2. 70~3. 20. (4H. m.
C H 2 S 0 C H z & C H 2 S O C H 2 ) , 4.. 6 0 ( 4 H .
m, OCHz CO ~COOCH2 CH2 ) . 7. 00 (1 H.
S , thiazole . - 5 - H ) . 7 . 3 0 ( 2 H . s . N H 2 -.. . ... . ..
, :-. ., - -. ,:. . -K B r - - -I R u ctn~l: 3 3 5 0~ 2 g 5 0 . 1 7 4 5 . 1 7 2 0 .
a x -1 6 2 0. 1 5 5 0 (3) :In 600 ml of acetone-water (l:l, v/v) was dissolved 20 g (0.0475 mole) of ethylsulfonylethyl 2-~2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonylmethoxy-imino)acetate as obtained in (2), and a 40~ aqueous solution of ~otassium carbonate was added.with warming at 30-35C:while maintaining the pH at lO-lO.5. The mixture .
was stirred for about:an hour and ad~usted to pH about 6 with 2 N HCl and 300 ml of ethyl acetate-was added, .: :
followed by snaking.~q'he organic layer was extracted with 30 ml of 5% aqueous sodium chlrodle.
~ ' ~2~ 3 The a~ueous layers were co~bined, adjusted to pH 2 with 2 N HC1 and coole~. The resulting crystalline precipitate was collected by filtration to give 12.5 g (yield, 87.3%) of 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxy-carbonylmethoxyimino)acetate as white crystals. The NMR and IR of this product were in good agreement with those obtained in (3) of Example 16.
Example 20 (1) Using 6 g (0.0218,mole) of ethylthioethyl 2-~2-amino ~ azol-4-yl)-(Z)-2-hydroxy~noace~te as obtained in Example 18 and 6.83 g (0.0327 mole) of t-butyl 2-bromopropionate and following the procedure (1) of Example 19, there was obtained 7.04 g (yield, 80.0%) of ethylthioethyl 2-(2-amino-thiazol-4-yl)-(Z)-2-(t-butoxycarbonyl-1-methylmethoxy-imino)acetate.
Elemental analysis Calcd- fox C16H25N3O5S2 ' C, 47.63%; H, 6.24%; N, 10.40~; S, 15.80%
Found: Cj 47.62%; Hj 6.15~; N, 10.39%; S, 15.50%
' N M R ( 6 0 M H z . D M S O - d 6 ) ~ : 1 . 0 5 ~-1 . 4 O ( 1 5 H . m . C H 2 C H 3'&C H - C H ~ & C ( C H ~ ) `3 ) , 2 . 5 5 ( 2 tJ, q . J = 8 H z, S C t~ ? C H 3 ) .
: 2. 80 ( 2H. t, J=8Hz, -CH2 SCH2 CH~ ) :. 4. 39 (2H, t, J=8Hz. COOCH2 ) . 4.
4 8 ~ 1 H ~ q, J= 8 H z . C H C H 3 ~ . 6 . 9 0 ( 1 .
H. s . thiazole - 5 - H ) . 7 . 2 5 ( 2 H. s . N H
2 - ) '' ' ~ - , ' , , ,. ~
~Z,~a~823 IR KBr cm : 3400-2900, 1730, 1620, 1540 (2) In 60 ml of acetone-water (5:1, v/v) was dissolved 5 g (0~0124 mole) of ethylthioethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl-1-methylmethoxy-imino)acetate as obtained in (1) followed by oxidation in thesame manner as (2) of Example 19 to give 4.8 g (yield, 88.8%) of ethylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl-l-methylmethoxyimino)acetate as white crystals. The acetate was then hydrolyzed in the same manner as (3~ of Example 19 to give 2.8 g (yield, 80.6%) of 2-(2-aminothiazol-~-yl)-(Z)-2-(t-butoxycarbonyl-1-methylmethoxyimino)acetic acid.
. Elemental analysis Calod. for C ~ H l7 N 3 0 s S 0. 2 H 2 0 = 3 1 8 .q4 . C4 5. 1 9%. H 5. 50%. N 1 3. 1 7%, S10. 05%
¦ Found: C45. 40%. H5. 95%. N1 3. Oi7%.
S 1 0. 3 5%
N M R ( 6 0 M H Z , [) 1\/l S 0 - d 6 ) ~ 1 . 3 5 ( 3 H .
d, J = 8 H Z . C H - C ~ ), 1, 4 4 ( 9 H . s . C
(CH3 ) 3 ) . 4. 58 ( 1 H. q. J=8HZ. CH-C H 3 ) . 6 . 8 3 ( 1 H, s, thiazole - 5 - H ) 7 .
2 5 ( 2 H . b r~ N H 2 - ) .
IR~vmax-cm : 3350-2900, 1725, 1650, 1610, 1590 .
8~3 Example 21 (1) Using 6 g (0.0218 mole) of ethylthioethyl 2-(2-aminothiazol-4-yl)-(Z)-2-hydroxyiminoacetate as obtained in Example 18 and 7.29 g (0.0327 mole) of t-butyl 2-bromoisobutyrate and following the procedure of (1)of Examplel9, there was obtained 7.7 g (yield, 84.6%) of ethylthioethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxy-carbonyl-l,l-dimethylmethoxyimino)acetate.
Elemental analysis ... . .... . . .
¦ Calcd. for C V H 27 N 3 0 5 S 2 = 4 1 7 . 5 4 C48. gO~O, H6. 52%. N10. 06~.
S 1 5. 3 6% -Found: C 4 8 . 9 6 %. H 6 . 4 5 % . N 1 0 . 2 9 % .
S1 5. 33%
, N M R ( 6 O M H z, D M S O - d 6 ) /~3 1 . 1 8 ( 3 H .
t, J=8Hz. CH2 CH3 3 . 1 . 40 ~ 1 5H. s, C (CH3 ) 3 & C (CHi ) 2 ) . 2. 55 (2H. q.
- J=8Hz, SCH2 CH3 ) . 2. 79 (2H, t, J=
8 H Z, --C H:2 S ) . 4 . 3 8 ( 2 H, t, J = 8 Hz .
- C O O C H 2 - ) . 6 . 8 5 ( 1 H, s, thiazole - 5 -H) . 7. 25 (2H, s, NH2--) KBr I R 2~ 3 4 0 0 ~ 3 0 0 0, 1 7 4 (:) . 1 7 3 0, 1 m a x :. -¦ ~ 1 6 3 5. 1 5 5 0 :~2~ 3 (2) Ethylthioethyl 2-(2-aminothiazol~4-yl)-(Z)-2-(t-butoxycarbonyl-1,1-dimethylmethoxyimino)acetate (2 g, 0.0048 mole) as obtained in (1) was oxidized and hydrolyzed in the same manner as (2) and (3) of Example 19 to give 1.1 g (yield, 69.6~) of 2-(2-aminothiazol-40yl)-(Z)-2-(t-butoxycarbonyl-1,1-dimethylmethoxyiminO)acetic acid.
NMR ~60MHz, DMS0-d6 ) 8: 1. 42 (1 5tf s ~ C (CH 3 ) 3 & C ~ ) , 6. 78 1 H. s, thiazole - 5 - H ) . 7 . 2 0 ( 2 H . b r.
N H 2 ~ ) K E~ r I R 2~ 3 4 0 0~ 2 9 0 0 . -1 7 2 0 . 1 6 4 5 .
1 m a x I - 1 6 0 0. 1 ~ 9 0 Example 22 In 100 ml of methylene chloride was dissolved 35.4 g (0.421 mole) of diketene. The solution was cooled to -30 to-35C and 29.5 g (0.415 mole) of chlorine was bubbled into the solution for about an hour to prepare 4-chloroacetoacetyl chloride. The solution was cooled to 40C or below and a solution of 50 g (0.324 mole) of phenylthloethanol~and 2S.6 g (0.324 mole) of pyridine in 52 ml of methylene chloride was added dropwise to the solution at -20C or below over a period of about an hour. After completion of addition, ~ , :
-61- ~2~
the reaction was allowed to proceed at -5C for about an hour. To the reaction mixture were added 400 ml of methylene chloride and 700 ml of water to extract the reaction product. The aqueous layer was further extracted with 200 ml of methylene chloride. The organic layers were combined, washed with water and concentrated to dryness under reduced pressure to give 88.5 g of phenylthioethyl 4-chloroacetoacetate as an oil.
The above oil (88.5 g) was dissolved in a mixture of 90 ml of ethyl acetate and 180 ml of glacial acetic acid. The solution was cooled to 5C or below and a solution of 28.5 g of sodium nitrite in 80 ml of water was added dropwise to the sorutlon at 5C or below over a period of about 2 hours. The mixture was poured into 800 ml of water to for extraction. The aqueous layer was further extracted with 1 liter of ethyl acetate. The organic layers were combined, washed with 500 ml of 5% aqueous sodium hydrogen carbonate and concentrated under reduced pressure to give 89 g of phenylthioeth~l 4-chloro-2-hydroxyiminoacetate as an oil.
The above oil (89 g) was dissolved in a mixture of 400 ml of ethanol and 40 ml of water, and 23 g of thiourea and 41.2 g of sodium acetate were added.
The mixture was stirred at room temperature for 3 hours.
After completion of the reaction, 400 ml of water was added and the mixture was cooled to 5C or below. The resulting crystalline precipitate was collected by filtration to give 40.1 g of phenylthioethyl 2-(2-aminothiazol-4-yl)-(z)-2-hydroxyiminoacetate. Yield:
38.3% based on phenylthioethanol.
... .. . . ..
NMR (60M117. DMS(::--d 6 ) l~i: 3. 4û (~H.
t, J=8Hz, CH2 SC fi Hs ), 4. 40 (2H, t, 0 J = 8 HZ,--C H 2 C H 2 S ) . 6 . g O ( 1 H . s, thia-zole - ~ - H ~ . 7 . 2 0~ 7 . 5 O ( 7 H . m, arom.
and N H 2 - ) -.
K B r ~ ~
1 I R u cm-l : 3 4 0 0~ 2 9 0 0 . 1 7 3 0, 1 6 2 0 .
m a x ~ 1 6 0 0, 1 5 9 0. 1 5 4 5 Example 23 (1) In 100 ml of acetone was suspended 5 g 20 (0.0155 mole) of phenylthioethyl 2-(2-aminothiazol-4-yl)-(z?-2-hydroxyiminoacetate as obtained in Example 22, and 0~3 ml of water, 4.5 g (0.023 mole) of t-butyl bromoacetate and 8.5 g of anhydrous potassium carbonate - were added in that order. The reaction was allowed to 25 proceed at 40C for~6 hours. After completion of the reaction, the insoluble matter was filtered off and : ~:
.
-63~ 8Z3 200 ml of ethyl acetate and 200 ml of water were added for effecting extraction. The organic layer was washed with 200 ml of 5~ aqueous sodium chloride and dehydrated by addition of anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and 100 ml of ethyl acetate-isopropyl ether (1:5, v/v) was added to the residue. After cooling, the crystalline precipitate was collected by filtration to give 5.8 g (yield, 85.5%) of phenylthioethyl 2 (2-aminothiazol-4-yl)-(z)-2-(t-butoxycarbonylmethoxy-imino)acetate as white crystals.
Elemental analysis , _ . . .
Calcd. :Eor C 19 H 23 N 3 0 5 S 2 = 4 3 7 . 5 3 - - C 5 2 . 1 1 % . H 5 . 2 5 /0 . N 9 . 6 0 %.
, Found:` C 5 2 . O ~ %. H 5 . 2 9 %. N 9 . 1 1 %, NMR (60MHz. DMSO-d6 ) 8: 1. 45 (9H.
! s, C ( C H ~ ) . 3 . 3 0 ( 2 H . t, J = 8 H z . C H
2 SC~ H 5 ), 4. 40 ( 2H, t, J=8Hz. COOCH
2 ) . 4. 60 ~2H. s, OCH2 CO), . . . . . .. . ..
6 . 3 5 ~ 1 H. s, thiazole~ - 5 - H ) . 7. 2 O~
7 . 5 0 ( 7 H, m, arom. and ~ `, N H 2 - ) K B r I R lJ ~ cm~l: 3 4 5 0 ~ 2 9 5 0~. 1 7 4 0 . 1 6 2 0 .
: `m a x . . ~ ~ 1 5 9 0, 1 5 4 5 -64- 12~8Z3 (2) In a mixture of 50 ml of acetone and 10 ml of water was dissolved 5.0 g (0.0114 mole) of phenyl-thioethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxy-carbonylmethoxyimino)acetate as obtained in (1). To the solution was added 0.05 g of ammonium molybdate and, at 25-30C, 13 ml (0.115 mole) of 30% hydrogen peroxide was added. The reaction was allowed to proceed for 4 hours. The reaction mixture was poured into 500 ml of water and extracted with 500 ml of ~
ethyl acetate. The organic layer was washed with 500 ml of 5% sodium sulfite and 500 ml of water in that order and concentxated to dryness. The residue was dissolved in a mixture of 200 ml of acetone and 50 ml of water, and a 40% potassium carbonate solution was added dropwise at 30-35C at pH 10-11 for hydrolysis. The mixture was stirred for about 2 hours and 100 ml of water was added, followed by additlon of 500 ml of ethyl acetate for extraction purification. The aqueous layer was adjusted to pH about 2 with 2 N HCl, whereupon crystals separated out. The mixture was cooled to 5C
or below and the crystalline precipitate was collected by filtration to give 2.57 g ~yield, 74.8%) of 2-(2-amino-thiazol-4-yl)-(Z)-2-(t-butoxycarbonylmethoxyimino)acetic acid as white crystals.
, !
~LZ~32~
The NMR and IR spectra of this product were identical with those of the compound obtained in Example 16.
Example 24 (1) Using 5 g (0.0156 mole) of phenylthioethyl 2-(2-aminothiazol-4-yl) (Z)-2-hydroxyiminoacekate as obtained in Example 22 and 4.9 g (0.0234 mole) of t-butyl 2-bromopropionate and following the procedure (1) of Example 23, there was obtained 5.8 g (yield, 82.3%) of phen~lthioethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl-l-methylmethoxyimino)acetate as white crystals.
Elemental analysis Calcd- for C20H25N3O5S2 C, 53.15%; H,.5.53%; N, 9.30%
Found: C, 53~30%; H, 5.50%; N, 9.07%
I NMR ( 60MHz, DMS0-d 6 ) ~ 1 . 35 (3H.
d, J = 8 H z . C H C H 3~) . 1 . 4 1 ( 9 H . s, C ~ C H 3 ) ~ ), 3 . 2 8 ( 2 H . t, J = 8 H z .
C H ~S ) .: 4 . 4 0 ( 2 H . t , -J = 8 H z .
¦ CH2 CH 2 S) . 4. 6:0 ( 1 H. q. J=8Hz.
C H ~ C H 3 ~ . 6 . 9 0 ( 1 H . s, thia~ole - 5 - H ) 7 . 2 0 ~ 7 ~ 5 0 ( 7 H, m, arom. and N H 2 - ) K B r ` ` -I R v cm-l: 3 4 0 0 ~ 2 9 5 0 . 1 7 4 0 . 1 7 2 5 .
a x - . 1 6 3 0 . 1 5 9 5 . 1 5 5 0 - , ~
~2~L8Z3 _66-(2) In the same manner as (2) of Example 23, 4.0 g (0.0089 mole) of phenylthioethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl-1-methylmethoxyimino)acetate as obtained in (1) was oxidized with aqueous hydrogen peroxide and then hydrolyzed in an alkaline condition adjusted with potassium carbonate. Adjustment of the pH to about 2 gave 2~0 g (yield, 71.3~) of 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl-1-me~hylmethoxyimino)acetic acid as white crystals.
The NMR and IR data confirmed that this product was identical with the compound obtained in Example 20.
Example 25 (1) Using 5 g (0.0156 mole) of phenylthioethyl 2-(2-aminothiazol-4-yl)-(Z)-2-hydroxyiminoacetate as obtained in Example 22 and 5.2 g (0.0233 mole) of t-butyl 2-bromoisobutyrate and following the procedure (1) of Example 23, there was obtained 6.0 g (yield, 82.6%) of phenylthioethyl 2-(2-aminothiazole-4-yl)-(Z)-2-(t-butoxycarbonyl-l,l-dimethylmethoxyimino) acetate as white crystals Elemental analysis CalCd- for C21H27N3O5S2 .: - -- - - - . .
C54. 1 3%, H5. 80%. N9. 02%
Found: C 5 4 . 4 7 %, H 5 . 6 4 % . N 8 . 7 8 %
NMR ~ 60MHz. DMS0--d 6 ) 8 1 . 4 0 ~ 1 5H.
s . C ( C H 3 ) 3 & C ( C H~ ) . 3 . 3 0 ~ 2 H, t, J=8Hz. CH~S-) . 4. 40 (2H. t, J=
:81iz, COC~CH2 ) . 6. 90 ( 1 H. s, thia-zole _- 5~ - H ) . 7 . 2 0 ~ 7 . 5 0 ( 7 H, m, arom.
and N H 2 ~ ) . .
.
-67- 1 ~ 4 48 2 3 IR Vma cm : 3400-2950, 1740, 1710, 1630, 1590, (2) In the same manner as (2) of Example 23, 5.0 g (0.0107 mole) of phenylthioethyl 2-(2~amino-S thiazol-4-yl)-(Z)-2-(t-butoxycarbonyl-1,1-dimethyl-methoxyimino)acetate as obtained in (1) was oxidized with a~ueous hydrogen peroxide and then hydrolyzed. Adjustment of the p~I to about2 gave 2.0 g (yield, 56.7~) of 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl~ dimethyl-methoxyimino~acetic acid as white crystals.
The NMR and IR data confirmed that this productwas identical with the compound obtalned in Example 21.
Example 26 In 140 ml of acetonitrile was suspended 5.42 g of 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxy-carbonylmethoxyimino)acetic acid as obtained in Example 4 followed by a serial addition of 2.96 ml of N-methylmorpholine and 7.2 g of 2,2-dithiobis-benzothiazole. The suspension was cooled to 0C
and a solution of 5.38 ml of triethyl phosphite in 35 ml of acetonitrile was added to the suspension over a period of 4.5 hours. The mixture was stirred for 30 minutes and cooled to -10C or below. The resultlng preclpitate was colleoted by filtrationJ
-6~ 823 washed with 20 ml of cold acetonitrile and dxied in vacuo at room temperature to give 6.2 g (yield, 76.5~) of s-~2-benzothiazolyl) 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonylmethoxyimino)thioacetate as light-yellow crystals.
N M R ( 6 0 ~1 H z . U M S O - d 6 ) 8: 1 . 4 7 ( 9 H .
s, C (CH3 ) 3 ), 4. 71 (2H. s, OCH2 CO) 7 . 0 5 ( 1 H, s, thia~ole 5 ~ H ) . 7 . 3 9 ( 2 H .
s, NH2 ) . 7. 45~7. 62 (2H. m~ arorn), 1 8. 00~8. 28 (2H, m, arom) I R ( K B r ) cm-l: 3 4 2 5 . 3 1 5 0 . 1 7 4 0 .
1 71 O. 1 620. 1 540 Reference Exam_le 1 (1) In 40 ml of tetrahydrofuran-water (4:1j was suspended 1.5 g of 7-amino-3-methylthiomethylcephem-4-carboxylic acid, and 1.6 ml of triethylamine was added at room temperature. Thenj 2.86 g of thioester obtained in Example 26 was added to the suspension and the reaction was allowed to proceed at room temperature for 2 hours. After completion of the reaciton, the solvent was distilled off and 50 ml of water was added to the residue. The mixture was washed with ethyl acetate and the washings were adjusted to pH about 2.5 with hydrochloric acid and - 69 ~ 3Z3 extracted with 50 ml of ethyl acetate. l~he extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. With ice-cooling, 20 ml of trifluoroacetic acid was added and the reaction was allowed to proceed for 2.5 hours. A~ter completion of the reaction, the trifl~oroacetic acid was distilled off under reduced pressure and water and 10% aqueous sodium hydrogen carbonate were added to the residue q for dissolution. This solution was chromatographed on 200 ml of Amberlite~XAD-II (manufactured by Rohm & Haas Co., V.S.A.), elution being carried~out with water. The active fractions were combined and lyophilized to give 1.8 ~ of disodium 7~-[2-(2-aminothiazol-4-yl)-(Z)-2-(carboxymet~oxyimino)acetamido]-~ 3-methylthiomethyl-3-cephem-4-carboxylate as a white powder.
Elemental analysis Càicd. for C 16 ~ 15 N 5 0 7 S 3 N a 2 5 H 2 0 . C.30. 90%. H4. 05%. N1 1. 31%
Found: C 3 0 . 9 5 %. H 3 . 8 6 %. N 1 1 . 2 6 Y0 ~ NMR (60MHz. D 2 0 ) ~ : 2. 0 0 (3H. s, S C H 3 ) . 3 . 1 0 ~ 3 . 9 5 ( 4 H . m,mephoYltinona2 and ~ S C H 3 ) . 4. 5 6 ( 2H, s,=N0CH 2 ) 5 2 1 ( 1 H d J = 5 H Z protoin at ! 5 7 5 ( 1 H d J 5 H z protoin at ) 7 0 3 ( 1 H. s, thiazOle 5--H ) 2s I R ( K B r ) c~ 3 4 0 0 . 1 7 6 0 . 1 6 1 0. 1535 ~Z~3Z3 (3) Using 7-amino-3-[(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl]-3-cephem-4-carboxylic acid and thiG-ester obtained in Example 26, in the same manner as the above reaction procedure (1), disodium 7~-[2-(2-aminothiazol-4-yl)-(Z)-2-(carboxymethoxyimina)acetamido-3-[(5-methyl-1,3,4-thiadiazol-2-yl)thio~ethyl~-3-cephem-4-carboxylate was obtained.
Elemental analysis ¦ Calcd.
`C31 . 44%. H3. 3 7%. Nl 4. 26%
0 Found: C 3 1 . ~ 0 % . H 3 . 3 7 %, N 1 3 . 4 8 %
NMR ~ 60MHz. D2 0) ~: 2. 80 (3H, S, C H 3 ~ , 3 . 6 5 ~ 2 H, q . position 2 ) , 4 . 1 5 ( 2 H . s . N 0 C H 2 C 0 ) . - 5 . 2 5 ( 1 H . d, proton at ~ F ~ e ~ ~ proton at position 6 J ~ ~ ~ ~ I H. d . position 7 157 . 0 0 ( 1 H, s, thiazole 5 _ H ) .
_71_ ~2~Z~
Reference Example 2 (1) In 140 ml of dry acetonitrile is suspended 5.42 g (18 mmol) of (Z)-2-(2-amino-4-thiazolyl)-2-(t-butoxy-carbonylmethoxyimino)acetic acid, 2.96 ml (27 mmol) of N-methyl morpholine and then 7.2 g (21.6 mmol) of bis-benzothiazol-2-yl disulfide are added, and the mixture is cooled to 0C. A solution of 5.38 ml (31.4 mmol) of triethyl phosphite in 35 ml of dry acetonitrile is added dropwise over 4.5 hours and ~he mixture is stirred at the same temperature for 30 minutes and then cooled to -10C.
The resulting crystalline precipitate is collected by filtration, washed with a small amount of acetonitrile and dried under reduced pressure to give 5.1 g of (Z)-2-t2-amino-4-thiazolyl)-2-(t-butoxycarbonylmethoxyimino)acetic 15 acid 2-benzothiazolylthiol ester.
IRv (KBr~ cm 1 3400, 3120, 1738, 1710, 1620, 15~0, 1450, 1415, 1370.
NMR (d6-DMSO) ~: 1.50(9H, s, CH3 x3), 4.78(2H, s, NOCH2COO), 7.10(1H, s, thiazole-SH), 7~4-7.65(2H, m, aromatic protons), 8.0-8.3(2H, m, aromatic protons).
(2) A flask of 1.0 Q capacity is charged with 0.06 kg (0.2508 mole) of (3S,4S)-3-amino-4-carbamoyloxymethyl-2-azetidinone-l-sulfonic acid and 0.9 Q of methylene chloride tomake a suspension, 0.070 Q (0.2508 x 2 mol) of triethylamine and then 0.124 kg;(0.2508 x 1.1 mol) of (Z)-2-(2-amino-4-thiazolyI-2-t-butoxycarbonylmethoxyimino)~
acetic acid 2-benzothiazolylthio ester obtained in (1) are added to the suspension under stirring at 10-20C, and the mixture is stirred at 25-27C for 4 hours. ~he insoluble matter is filtered off and the filtrate is further stirred for about an hour and extracted with 0.9 Q
of water. The a~-~eous layer is washed with 0.19 Q of methylene chloride, 0.38 Q of ethyl acetate and 0.19 Q of methylene chloride in that order. After degassing, 0.45 Q
of concentrated hydrochloric acid is added and the mixture ~4a~8z3 is stirred at 25C for about 2 hours. To the resulting slurry is added 0.9 Q of water and the mixture is stirred at about 25C for about 2 hours and then allowed to stand at O ~2C overnight. The resulting precipitates are collected by filtration and washed with about 0.6 Q of cold water to give about 0.27 kg of (3S,4S)-3-[2-(2-amino-4-thiazolyl)-(Z)-2-(carboxymethoxyimino)acetamido]-4-carbamoyloxymethyl-2-acetidinone-1-sulfonic acid as wet crystals.
[~]D6 45o (c=l, DMSO) IRv mBaXCm 1 1760, 1715, 1670, 1640 NMR(d6-DMSO) ~: 3.9-4.4(3H, C4-H, C4-CH2), 4.66(2H, s, NO-CH2), 5.28(1H, d.d, J=4.5, lOHz, C3-H), 6.92(1H, s, proton at position 5 of the thiazole nuclear), 9.33(lH, d, J=lOHz, c3-NH) Antimicrobial potency (MIC) against K. pneumoniae TN 1711:
0 1 mcg/ml
The reaction mixture was poured into 1 liter of ice water to extract the reaction product. The aqueous layer was further extracted with 1 liter of ethyl acetateO The organic layers were combined, washed with 400 ml of 5% aqueous sodium hydrogen carbonate and concentrated under reduced pressure to give 130 g of methylthioethyl 4-chloro-2-hydroxyiminoacetoacetate as an oil.
NMR (60MHz . DMS0- d6 ~ ~: 2. 1 ~ (3H.
. s . S--CH 3 ) . 2. 75 (211. t . J=8Hz CH
2 CH2 S) . 4. 40 ~2H. t, J=8Hz . COOC:
`~2_CH2 ) . 4. 89 (2H. s . Cl CH~C0) ~ Neat:
I R ~ c7n~l: 3 1 5 0~3 0 0 0. 1 7 4 5 . 1 7 1 5 : - m a x (3) In a mixture of 520 ml of ethanol and 28 ml of water was dissolved 130 g (0.542 mole) of methylthio-ethyl 4-chloro-2-hydroxyiminoacetoacetate as obtained in (2), and 41.3 g (0.543 mole) of thiourea and 73.9 g (0.543 mole) of sodium acetate were added. The reaction was allowed to proceed at room temperature for 60 minutes.
The solvent was then distilled off under reduced pressure, followed by addition of 300 ml of water.
The mixture was cooled and the crystalline precipitate was collected by filtration and dried under reduced pressure to give 72.6 g (yield: 51.2% based on methylthioethanol) of methylthioethyl 2-(2-aminothiazol-4-yl)-(z)-2-hydroxyiminoacetate as white crystals.
Elemental analysis Calcd. for C 8 ~ 1I N 3 0 3 S 2 = 2 6 1 . 3 1 C36. 77%. H4. 24%. N1 6. 08%
Found: ~ 3 6 . 7 1 % . H 4 . 2 3 % . N 1 5 . 9 4 %
NMR (60MHz . DMS0-- d6 ) 8 ::2. 1 1 (3H.
s, S-CH3 ) . 2. 77 (2H, t . J;=8HZ, C 2 S ~ . 4 . 3 8 ~ 2 H . t , J = 8 H z .
C H 2 C H 2 S ) , 6 . 8 4 ( 1 H . s, thia~ole-5 - H ) . 7 . 1 5 ( 2 H ,~ s . N ~ 2 ) ~ ~ K~B r ~
I R v~ cm-l: 3 4 0 0~3 1 5 0, 1 7 2 0.
m a: x ~
1 61 0. 1 5 3 5 1;~4~2,3 ~ -44-Example 16 (1) In 100 ml of acetone was suspended 5 g (0.0191 mole) of methylthioethyl 2-(2-aminothiazol-4-yl)-(Z)-2-hydroxyiminoacetate as obtained in Example 15, S and 4.32 g (0.029 mole) of t-butyl chloroacetate, 0.3 ml of water, 10.56 g (0.076 mole) of anhydrous potassium carbonate and 3.15 g (0.021 mole) of sodium iodide were added in that order. The reaction was allowed to proceed at 40C for about 6 hours. The reaction mixture was poured into 300 ml of water and extracted with 500 ml of ethyl acetate. The organic layer was washed with water, dehydrated with anhydrous sodium sulfate and concentrated to dryness under reduced pressure. Ether was added to the residue to give 6.56 g ~yièld, 91.5%) of methylthioethyl 2 (2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonylmethoxyimino)acetate as white crystals.
Elemental anlaysis I Calcd. for C t4 H 2~ N~3 0 3 S 2 = 3 7 5. 4 6 ` C 4 4 . 7 9 %. H 5 . 6 4 %. N 1 1 . 1 9 ~q Found:- C ~ 5 . 0 7 % . H 5 . 7 8 % . N 1 1 . 0 5 %
NMR (60MHz . D~ISO-- d6 ) ~: 1. -42 (9H.
l s, C H ~ x 3 ) . 2 . 1 0 ( 3 H . S, S C ~
¦ 2. 7 8 ( 2 H, t, J = 8 H z, C~S C H 3 ) .-4 . 4 0 ~ 2 H. t, J =:8 Hz, COOC~2 CH 2 S ) , 4. 57 (2:H. s, OGH~CO), 6. 02 (1H. s, thiazole ~ --5--~ H~, 7 . 2 5~ ( 2 H, s, N H 2--) ;
~ .
IR vmax cm : 3400-2900, 1740, 1710, 1625, 1550 (2) In a mixture of 47 ml of acetone and 9.4 ml of water was dissolved 6.0 g (0.0160 mole) of methyl-thioethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxy-carbonylmethoxyimino)acetate as obtained in (1), andO.05 g of ammonium molybdate was added. Further, 10.9 ml (0.112 mole) of 35% aqueous hydrogen peroxide was added at 25-30C and the reaction was allowed to proceed for 6 hours. The reaction mixture was poured into 500 ml of water and extracted with 500 ml of ethyl acetate. The organic layer was washed with 500 ml of 5% sodium sulfite and 500 ml of water and concentrated to dryness. To the residue was added about 50 ml of ether, whereby white crystals separated out. After cooling, the crystals were collected by filtration to give 6.1 g (Yleld, 93.6 %) of methylsulfonylethyl 2-(2-amino-thlazol-4-yl)-(Z)-2-(t-butoxycarbonylmethoxyimino)-acetate.
Elemental analysis Calcd. for C ~ H 21 N 3 0 7 S 2 O- 5 H 2 O
~- = 4 1 6. 4~7; ~ ~ ~
40. 38%. H5. 32%. N1 :). O9%
Found: C 4 0 . 1 1 %. H 5 . 1 5 %. N 9 . 8 9 %
NMR ( 6 OMHZ . DMS0~-- d6 ) a: 1 . 4 2 ( 9 H.
~s .~ CH3 x3), 3. 00 (3H, s, SCH~ ) .
::
- ~6 -3. 57 (2H, t . J=8Hz . C ~ Sc H 3 ) . 4.
¦ 55~4. 62 (4H, m, COOC~CHz& OCH 2 j C O O ), 7 . O O ( 1 H . s, thiazole - 5 - H ), 7 .
- 28 (2H. s . NH2-) K B r I R v cm-t : 3 4 0 0 ~ 2 9 9 5 . 1 7 5 0 .
m a x 1 7 2 Q. 1 6 2 8 . 1 5 4 5 (3) In a mixture of 200 ml of acetone and 200 ml of water was dissolved 4 g (0.00982 mole) of methyl-sulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxy-carbonylmethoxyimino)ac~tate as obtained in (2), and a 40~
aqùeous solution of potassium carbonate was added dropwise to the solution at 30-35C while maintaining pH at about 10.5. The reaction mixture was washed with 500 ml of ethyl acetate.
The aqueous layer was adjusted to pH about 2 with 2 N
HCl, whereby~crystals separated out. After cooling the crystalline precipitate was collected by filtration to gi~e 2.5 ~ (yield~84.5~) of 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonylme~hoxyimino)acetic acid as white crystals.
ElementaI analysis ~ . .. . .. . . .
Calcd. forC 1I H ~ N 3 O 5 S 0. 5 H 2 0 = 3 1 0. 3 2 . ~ C 4:2. 58 oi. H5. 20%. N1 3. 54%
Found: C 4 2 . 9 5 %. H 5 . 1 2 %. N 1 3 . 3 8 %
N M R ( 6 O M H z . D M S O - d 6 ) ~ 1 . 4 4 ( 9 H .
¦~: s . CH3 x3 j, 4. 5 7 ( 2H. s . OC712 CO) .
6 . 8 5 ( 1 H~. s, ~ thiazole --5--H ) 7 2 5 ~ :( 2 H. br N H 2 ) l ~ 32~
IR vKBx cm : 3350-3000~ 1740, 1640, 1600, 1580 Example 17 (1) In 100 ml of acetone was suspended 5 g (0.0191 mole) of methylthioethyl 2-(2-aminothiazol-4-yl)-(Z)-2-hydroxyiminoacetate as obtained in ~xample 15, and 6.4 g (0.0287 mole) of t-butyl 2-bromoisobutyrate, 0.3 ml of water and 10.56 g (0.076 mole) of anhydrous potassium carbonate were added in that order~ The reaction was allowed toproceed at 40C for 20 hours.
The reaction mixture was poured into 100 ml of water and extracted with 100 ml of ethyl acetate. The organic layer was washed with water and dried over anhyrous sodium sul-fate and concentrated to dryness. To the residue was added 50 ml of ether and the mixture was cooled.
The precipitate was collected by filtration to give 6.17 g (yield, 80~ b~) of methylthioethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl-1,1-dimethylmethoxyimino)-acetate as white crystals.
Elemental analysis l Calcd. for C 16 H ~ N 3 0 5 S 2 - 4 0 3 . 5 1 i ~ ` C4 7. 6~3%. H6. 24%. N1 O. 41%
Found C 4 7 :. 3 7 %, H 6: . 2 3 % . N 1 O . 3 4 %
Nl~tlR ( 6 0M:H z, DMSQ-d 6 ) ~ : 1 . 4 a ( 1 5 H.
~ s .: C :( CH 3 ) ~ & C ( CH 3 ) 2 ) . 2 . 1: 2 ~ 3 H . S, --S C H .~ ~ . 2 . 7 8 ( 2 H . t, J 2 8 H2, . ~ , ~ . - . . . . ,, - , ., C H_2 S C H 3 ) . 4 . 4 1 ~ 2 H . t . J = 8 H ~ ~ - C
~C H 2 S ) . 6 . 8 8 ( 1 H . s, thia~ole~ - 5 7~ 26 (2H.~S .~NH: 2 - ) ~
:
max cm : 3400_3000, 1735, 1730, 1630, 1550 (2) In a mixture of 25 ml of acetone and 5 ml of water was dissolved 2.5 g (0.0062 mole) of methyl-thioethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxy-carbonyl-l,l-dimethylmethoxyimino)acetate as obtained in (1) ~ and 0.029 g of ammonium molybdate was added, Then, at 30C, 1.94 ml of 35% aqueous hydrogen peroxide was added dropwise to the mixture.- The resulting mixture was stirred at the same temperature for 7.5 hours, poured into 200 ml of water and extracted with 200 ml of ethyl acetate. The organic layer was washed with 400 ml of 5% sodium sulfite and 200 ml of water and the solvent was distilled off under reduced pressure.
To the residue was added 100 ml of ether, whereupon white crystals separated out. After cooling~ the crystals were collected by filtration to give 2.4 g (yield, 88.9%) of methylsulfonylethyl 2-(2-aminothiazol-4-yl)-tZ)-2-(t-butoxycarbonyl-1,1-dimethylmethoxyimino)acetate.
Elemental analysis ~ Calcd. for C 16 H ~ N 3 0 7 S 2 = 4 3 ~. 5 C44. 1 3%, H5. 79%. N9. 65%
Found: C 4 4 . 1 5 % . H 5 . 3 3 % . N 9 . 6 0 %
NMR ( 60MHz, DMS0--d 6 ) 8: 1 . 40 ( 1 5H.
s, CH 3 X 5), 3. o4 (3H. s, SCH 3 3 . 5 8 ( 2 H . t, J = 8 H z . C~S C H 3 ) .
4 . 6 2 ( 2 H . t, J = 8 H z . C H 2 C H 2 S C H 3 j >
6~. 9 2 ( 1 H . s, ~thiazole --5--H ), 7 ~ ~3 (~2H. b r. NH 2 - ) ~2~ 3 IR vma cm : 3350-3000, 1750, 1725, 1645, 1550 (3) In a mixture of 45 ml of acetone and 45 ml of water was dissolved 2.2 g (0.00505 mole) of methyl-sulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl-l,l-dimethylmethoxyimino)acetate as obtained in (2), and a 40% aqueous solution of potassium carbonate was added dro~wise to the solution at 30-35C while maintaining the pH at 10-10.5. The mixture was stirred for about an hour and washed with 100 ml of ethyl acetate. The aqueous layer was adjusted to pH about 2 with 2 N HCl and then cooled. The white crystals were collected b~ filtration to give 1.29 g (yield, 77.6%) of 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl~ dimethy~methoxyimino)acetic acid.
Elemental analysis Calcd.~for C ~ H ~ N 3 0 5 S O . 7 7 H 2 0 = 3 4 3. 2 3 . C 4 5 . 4 9 % . H 6 . 0 2 % . N l 2 . 2 4 %.
. S 9 3 4 %
Found: C4 5. 4 9%. H 6. 2 2/~, N 1 2. 1 7%.
~ S9. 24%: : ~
NMR (60MHZ. D:MS0-d 6 ) ~i 1. 40 (1 5H.
s, (CH3 ) 3 & C (:CH_3 ) z ), 6. 79 ( 1 H, S, ........
thiazole - 5 - H ) . 7 . 2 0 ( 2 H, br, N H 2 - ) ~ ~
K B r R v cm-l : 3 5 5 0 ~ 2 8 0 0 . 1 7 2 0, 1 6 5 0 .
. m a x . : 1 63~0. 1 61 0. 1 580. 1 560 .
Example 18 Using 146 g (0.942 mole) of 4-chloroacetoacetyl chloride (synthesi2ed from diketene and chlorine) and lOO g (0.942 mole) of ethylthioethanol and following the procedure of Example 15, there was obtained 138.8 g of ethylthioethyl 2-(2-aminothiazol-4-yl)-(Z)-2-hydroxy-iminoacetate via ethylthioethyl 4-chloroacetoacetate and ethylthioethyl 4-chloro-2-hydroxyiminoacetate.
(Yield, 53.5% basèd on ethyltllioethanol) Elemental analysis Calcd. for C 9 H ~ N ~ 0 3 S 2 = 2 7 5. 3 4 C39. 26%, H4. 76%. N1 5. 26%.
S23. 29%
Fo~ d: C 3 9 . 4 3 %. H 4 . 8 1 %, N 1 5 . O 1 %.
S 2 3. 0 7%
NMR (60MHz. DMSO--d6 ) ~i: 1. 28 (3H.
t . ~ = 8 H z . C H 2 C H 3 .) . 2 . 5 5 ( 2 H . q .
J = 8 H z . CH 2 S CH 2 ) . 2 . 8 0 t 2 H. t .
J 2 8 H z . C H 2_C H 2 S ) . 4 . 3 8 ( 2 H . t , J=8Hz. COOC~CH2 ) . 6. 86 (1 H. s, thiazole ~ 5--H ) . 7 . 1 8 ( 2 H, s . N H z --; KBr I R s~ c7n~1: 3 4 0 0 ~ 3 1 0 0 . 1 7 3 0 . 1 6 2 0 .
~` m a x ~ 5 3 b -~
Physical characteristics of the intermediates O Ethylthioethyl 4-chloroacetoacetate ¦ N M R ( 6 0 M H z, C D C 1 3 ) ~i : 1 . 2 5 ( 3 H, t, J = 8 H z . C H z C H 3 ) , 2 ~ 5 5 ( 2 H, q, J=8Hz, SCHz CH3i ), 2. 77 (2H, t, J = 8 H z , C H 2 C ~ S ) . 3 . 6 ~ ( 2 H , s ~
COOCH2 CO) . 4. 30 (4H, m, COOCH2 &
C I C H 2 C O ), - - !
., , - . .
o N ea ~ -I R iJ - cm-l . 1 7 5 0 . 1 7 3 0, 1 6 7 0, ~ a x O Ethylthioethyl 4-chloro-2-hydroxyiminoacetate I N M R ( 6 0 ~ H 7, C ~ C 1 3 ) ~ : 1 . 2 7 ( 3 H , t , ~ J=8Hz, CH2 CH3 ), 2. 60 (2H, q, J=8Hz, CH2 SCH2 CH3 ), 2. 8 2 ( 2H. t, J = 8 H z, C H 2 S G H 2 ), 4 . 4 5 ( 2 H . t, J=8Hz, COOCH2 ~, 4. 62 (2H, s, C l C ~ 2 ) , N eat I Rv cm i: 3350~2900, 1 740, 1 71 O.
m a x 1 6 2 0 - :
Example 19 (1~ In 300 ml of acetone was suspended 15 g (0.0545 mole) of ethylthioethyl 2~(2-amlnothiazol-4-yl)-~)-2-i.
hy ~ L~x~cetate as obtained in Example 18, and 12.3 g (0.0187 mole) ' .
.
.A~Z3 of t-butyl chloroacetate, 0.9 ml of water, 30.1 g (0.~18 mole) of anhydrous potassium carbonate and 8.98 g (0.0599 mole) of sodium iodide were added to the suspension. The reaction was allowed to proceed at room temperature for lO hours. The precipitate was filtered off and 450 ml of ethyl acetate and 450 ml of water were added or effecting extrac-tion. The aqueous layer was further extracted with lO0 ml of ethyl acetate. The organic layers were combined, washed twice with 5% aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and 600 ml of acetone was added to the residue for dissolution, followed by addtion of 1.5 liters of water. The mixture was cooled to 5C or below and the resulting crystalline precipitate was collected by filtration to give 19.1 g (yiela, 90.0%) of ethylthio-ethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl--methoxyimino)acetate.
Elemental analysis Ca1cd- for Cl5H23N3O5S2 C, 46.26%; H, 5.95%, N, 10.79~; S, 16.46 Found: C, 46.56%; H, 6.00%; N, 10.52%; S, 15.88 :
1%L~823 NMR t 60MH Z, DMSO--d 6 ) t~i 1 . 1 8 (3 H.
t , J = 8 H Z , C H 2 C H 3 ) , 1 . 4 4 ( 9 H , S
C (CH3 ) 3 ), 2. 55 (2H. q, J=8HZ, SCH2 CH3 ), 2. 80 (2H. t, J=8Hz.
j CH2 SCH2 ), 4. 3 8 ~ 2H, t, J=8HZ, C O O C H 2 C H 2 ), 4 . 5 6 ( 2 H . s, O C H 2 C O ) 6 . 9 0 ~ 1 H, s, thiazole --5--H ), 7 . 2 2 ( 2 H . S, N H 2--~
. -o K B r I R v - cm~l: 3 4 5 0~2 9 00. 1 7 60. 1 7 5 0.
m a x 1 6 2 0 . 1 5 5 5 .
.
(2) In a mixture of 200 ml of ace-tone and 40 ml of water was dissolved 19.1 g (0.0~90 mole) of ethyl-thioethyl 2-(2-aminothlazol-4-yl)-(Z)-2-(t-butoxy-carbonylmethoxyimino)acetate as obtained in (1). To the solution was added 0.23 g of ammonium molybdate and 8.3 g (0.073 mole) of 30~ aque~us hydrogen peroxide was added dropwise with cooling at 30C or below. The mixture was stirred for an hour to give an intermediate.
Further, 4.73 g (0.417 mole) of 30% aqueous hydrogen peroxide was added dropwise. The mixture was stirred at room temperature overnight and adjusted to pH about 7 with a 40~ potassium carbonate solution, and 200 ml of ethyl acetate and 160 ml of water were added for extraction. The aqueous layer was further extracted with 100 ml of ethyl acetate. The organic layers were combined and 5~ aqueous sodium sulfite was added with cooling, followed by sha~ing. The organic solution was then washed with 5~ aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and 100 ml of ethyl acetate~isopropyl ether (1:5, v/v) was added to the residue. The mixture was cooled to 5C or below and the resulting crystalline precipitate was collected by filtration to give 20.0 g (yield, 96.8~) of ethylsulfonylethyl 2~(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonylmethoxy-imino)acetate.
Elemental analysis ¦ Calcd. for C ~ H ~ N 3 O 7 S 2 = 4 2 1 . 4 8 ~ C 4 2. 75%. H5. 50~. Ng. 97%.
S1 5. 2 1 %
Found: C 4 2 . 9 6 /0 . ~1 5 .8 6 % . N 9 . 8 5 %, S 1 4 . 6 0 %
N M R ( 6 0 M H z . D M S O - d 6 ) ~ 1 . 2 0 ( 3 11.
o t, J=8Hz. CH2 CH3 ) . 1. 45 (9H. s, C (CH3 ) 3 ) . 3. 1 4 (2H, q . J=8Hz.
SCH2 CH3 ) . 3. 55 (2H. t, J=8Hz.
C H 2 S C H 2 ) . 4 . 6 0 ( 4 H . m . C O O C H 2 &
O C H 2 C O ) , 7 . O O ( 1 H . s, thiazole - 5 - H ) 7 . 2 8 ( 2 H. S . N H 2--) . . , ' .
K B r I R ~cm~l : 3 4 0 0 ~ 3 0 0 0 . 1 7 5 5 .1 7 4 O .
~ a x --- 1 7 1 5 . 1 6 3 0. 1 6 1 0. 1 545 The filtrate obtained in the above procedure (2) was poured~into water and extracted with ethyl acetate.
The extract was concentrated to dryness and the residue 25 was crystalli~ed from ethyl acetate-isopropyl ether ~l:l, v/v) to give ethylsulfinylethyl 2-(2-amino-thlazo1-4-yl)-(Z)-2-~t-butoxycarbonylmethoxyimino)acetate.
. ~ ~
Elemental analysis Calcd. for C 15 H ~ N 3 0 6 S 2 = 4 0 5 . 4 8 C44. 43/0, H5. 7 2%, N 1 O. 3 6%.
S1 5. 8 1 %
1 ~ound: C 4 4 . 5 0 % . H 5 . 6 8 %. N 1 0 . 1 7 %.
S 1 5 . 5 2 %
NMR (60MH~. DMSO--d6 ) 8; 1. 1 8 (3H.
t, J=8Hz. CH2 CH3 ) . 1 . 42 ~9H. s, C ( CH 3 ) 3 ) . 2. 70~3. 20. (4H. m.
C H 2 S 0 C H z & C H 2 S O C H 2 ) , 4.. 6 0 ( 4 H .
m, OCHz CO ~COOCH2 CH2 ) . 7. 00 (1 H.
S , thiazole . - 5 - H ) . 7 . 3 0 ( 2 H . s . N H 2 -.. . ... . ..
, :-. ., - -. ,:. . -K B r - - -I R u ctn~l: 3 3 5 0~ 2 g 5 0 . 1 7 4 5 . 1 7 2 0 .
a x -1 6 2 0. 1 5 5 0 (3) :In 600 ml of acetone-water (l:l, v/v) was dissolved 20 g (0.0475 mole) of ethylsulfonylethyl 2-~2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonylmethoxy-imino)acetate as obtained in (2), and a 40~ aqueous solution of ~otassium carbonate was added.with warming at 30-35C:while maintaining the pH at lO-lO.5. The mixture .
was stirred for about:an hour and ad~usted to pH about 6 with 2 N HCl and 300 ml of ethyl acetate-was added, .: :
followed by snaking.~q'he organic layer was extracted with 30 ml of 5% aqueous sodium chlrodle.
~ ' ~2~ 3 The a~ueous layers were co~bined, adjusted to pH 2 with 2 N HC1 and coole~. The resulting crystalline precipitate was collected by filtration to give 12.5 g (yield, 87.3%) of 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxy-carbonylmethoxyimino)acetate as white crystals. The NMR and IR of this product were in good agreement with those obtained in (3) of Example 16.
Example 20 (1) Using 6 g (0.0218,mole) of ethylthioethyl 2-~2-amino ~ azol-4-yl)-(Z)-2-hydroxy~noace~te as obtained in Example 18 and 6.83 g (0.0327 mole) of t-butyl 2-bromopropionate and following the procedure (1) of Example 19, there was obtained 7.04 g (yield, 80.0%) of ethylthioethyl 2-(2-amino-thiazol-4-yl)-(Z)-2-(t-butoxycarbonyl-1-methylmethoxy-imino)acetate.
Elemental analysis Calcd- fox C16H25N3O5S2 ' C, 47.63%; H, 6.24%; N, 10.40~; S, 15.80%
Found: Cj 47.62%; Hj 6.15~; N, 10.39%; S, 15.50%
' N M R ( 6 0 M H z . D M S O - d 6 ) ~ : 1 . 0 5 ~-1 . 4 O ( 1 5 H . m . C H 2 C H 3'&C H - C H ~ & C ( C H ~ ) `3 ) , 2 . 5 5 ( 2 tJ, q . J = 8 H z, S C t~ ? C H 3 ) .
: 2. 80 ( 2H. t, J=8Hz, -CH2 SCH2 CH~ ) :. 4. 39 (2H, t, J=8Hz. COOCH2 ) . 4.
4 8 ~ 1 H ~ q, J= 8 H z . C H C H 3 ~ . 6 . 9 0 ( 1 .
H. s . thiazole - 5 - H ) . 7 . 2 5 ( 2 H. s . N H
2 - ) '' ' ~ - , ' , , ,. ~
~Z,~a~823 IR KBr cm : 3400-2900, 1730, 1620, 1540 (2) In 60 ml of acetone-water (5:1, v/v) was dissolved 5 g (0~0124 mole) of ethylthioethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl-1-methylmethoxy-imino)acetate as obtained in (1) followed by oxidation in thesame manner as (2) of Example 19 to give 4.8 g (yield, 88.8%) of ethylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl-l-methylmethoxyimino)acetate as white crystals. The acetate was then hydrolyzed in the same manner as (3~ of Example 19 to give 2.8 g (yield, 80.6%) of 2-(2-aminothiazol-~-yl)-(Z)-2-(t-butoxycarbonyl-1-methylmethoxyimino)acetic acid.
. Elemental analysis Calod. for C ~ H l7 N 3 0 s S 0. 2 H 2 0 = 3 1 8 .q4 . C4 5. 1 9%. H 5. 50%. N 1 3. 1 7%, S10. 05%
¦ Found: C45. 40%. H5. 95%. N1 3. Oi7%.
S 1 0. 3 5%
N M R ( 6 0 M H Z , [) 1\/l S 0 - d 6 ) ~ 1 . 3 5 ( 3 H .
d, J = 8 H Z . C H - C ~ ), 1, 4 4 ( 9 H . s . C
(CH3 ) 3 ) . 4. 58 ( 1 H. q. J=8HZ. CH-C H 3 ) . 6 . 8 3 ( 1 H, s, thiazole - 5 - H ) 7 .
2 5 ( 2 H . b r~ N H 2 - ) .
IR~vmax-cm : 3350-2900, 1725, 1650, 1610, 1590 .
8~3 Example 21 (1) Using 6 g (0.0218 mole) of ethylthioethyl 2-(2-aminothiazol-4-yl)-(Z)-2-hydroxyiminoacetate as obtained in Example 18 and 7.29 g (0.0327 mole) of t-butyl 2-bromoisobutyrate and following the procedure of (1)of Examplel9, there was obtained 7.7 g (yield, 84.6%) of ethylthioethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxy-carbonyl-l,l-dimethylmethoxyimino)acetate.
Elemental analysis ... . .... . . .
¦ Calcd. for C V H 27 N 3 0 5 S 2 = 4 1 7 . 5 4 C48. gO~O, H6. 52%. N10. 06~.
S 1 5. 3 6% -Found: C 4 8 . 9 6 %. H 6 . 4 5 % . N 1 0 . 2 9 % .
S1 5. 33%
, N M R ( 6 O M H z, D M S O - d 6 ) /~3 1 . 1 8 ( 3 H .
t, J=8Hz. CH2 CH3 3 . 1 . 40 ~ 1 5H. s, C (CH3 ) 3 & C (CHi ) 2 ) . 2. 55 (2H. q.
- J=8Hz, SCH2 CH3 ) . 2. 79 (2H, t, J=
8 H Z, --C H:2 S ) . 4 . 3 8 ( 2 H, t, J = 8 Hz .
- C O O C H 2 - ) . 6 . 8 5 ( 1 H, s, thiazole - 5 -H) . 7. 25 (2H, s, NH2--) KBr I R 2~ 3 4 0 0 ~ 3 0 0 0, 1 7 4 (:) . 1 7 3 0, 1 m a x :. -¦ ~ 1 6 3 5. 1 5 5 0 :~2~ 3 (2) Ethylthioethyl 2-(2-aminothiazol~4-yl)-(Z)-2-(t-butoxycarbonyl-1,1-dimethylmethoxyimino)acetate (2 g, 0.0048 mole) as obtained in (1) was oxidized and hydrolyzed in the same manner as (2) and (3) of Example 19 to give 1.1 g (yield, 69.6~) of 2-(2-aminothiazol-40yl)-(Z)-2-(t-butoxycarbonyl-1,1-dimethylmethoxyiminO)acetic acid.
NMR ~60MHz, DMS0-d6 ) 8: 1. 42 (1 5tf s ~ C (CH 3 ) 3 & C ~ ) , 6. 78 1 H. s, thiazole - 5 - H ) . 7 . 2 0 ( 2 H . b r.
N H 2 ~ ) K E~ r I R 2~ 3 4 0 0~ 2 9 0 0 . -1 7 2 0 . 1 6 4 5 .
1 m a x I - 1 6 0 0. 1 ~ 9 0 Example 22 In 100 ml of methylene chloride was dissolved 35.4 g (0.421 mole) of diketene. The solution was cooled to -30 to-35C and 29.5 g (0.415 mole) of chlorine was bubbled into the solution for about an hour to prepare 4-chloroacetoacetyl chloride. The solution was cooled to 40C or below and a solution of 50 g (0.324 mole) of phenylthloethanol~and 2S.6 g (0.324 mole) of pyridine in 52 ml of methylene chloride was added dropwise to the solution at -20C or below over a period of about an hour. After completion of addition, ~ , :
-61- ~2~
the reaction was allowed to proceed at -5C for about an hour. To the reaction mixture were added 400 ml of methylene chloride and 700 ml of water to extract the reaction product. The aqueous layer was further extracted with 200 ml of methylene chloride. The organic layers were combined, washed with water and concentrated to dryness under reduced pressure to give 88.5 g of phenylthioethyl 4-chloroacetoacetate as an oil.
The above oil (88.5 g) was dissolved in a mixture of 90 ml of ethyl acetate and 180 ml of glacial acetic acid. The solution was cooled to 5C or below and a solution of 28.5 g of sodium nitrite in 80 ml of water was added dropwise to the sorutlon at 5C or below over a period of about 2 hours. The mixture was poured into 800 ml of water to for extraction. The aqueous layer was further extracted with 1 liter of ethyl acetate. The organic layers were combined, washed with 500 ml of 5% aqueous sodium hydrogen carbonate and concentrated under reduced pressure to give 89 g of phenylthioeth~l 4-chloro-2-hydroxyiminoacetate as an oil.
The above oil (89 g) was dissolved in a mixture of 400 ml of ethanol and 40 ml of water, and 23 g of thiourea and 41.2 g of sodium acetate were added.
The mixture was stirred at room temperature for 3 hours.
After completion of the reaction, 400 ml of water was added and the mixture was cooled to 5C or below. The resulting crystalline precipitate was collected by filtration to give 40.1 g of phenylthioethyl 2-(2-aminothiazol-4-yl)-(z)-2-hydroxyiminoacetate. Yield:
38.3% based on phenylthioethanol.
... .. . . ..
NMR (60M117. DMS(::--d 6 ) l~i: 3. 4û (~H.
t, J=8Hz, CH2 SC fi Hs ), 4. 40 (2H, t, 0 J = 8 HZ,--C H 2 C H 2 S ) . 6 . g O ( 1 H . s, thia-zole - ~ - H ~ . 7 . 2 0~ 7 . 5 O ( 7 H . m, arom.
and N H 2 - ) -.
K B r ~ ~
1 I R u cm-l : 3 4 0 0~ 2 9 0 0 . 1 7 3 0, 1 6 2 0 .
m a x ~ 1 6 0 0, 1 5 9 0. 1 5 4 5 Example 23 (1) In 100 ml of acetone was suspended 5 g 20 (0.0155 mole) of phenylthioethyl 2-(2-aminothiazol-4-yl)-(z?-2-hydroxyiminoacetate as obtained in Example 22, and 0~3 ml of water, 4.5 g (0.023 mole) of t-butyl bromoacetate and 8.5 g of anhydrous potassium carbonate - were added in that order. The reaction was allowed to 25 proceed at 40C for~6 hours. After completion of the reaction, the insoluble matter was filtered off and : ~:
.
-63~ 8Z3 200 ml of ethyl acetate and 200 ml of water were added for effecting extraction. The organic layer was washed with 200 ml of 5~ aqueous sodium chloride and dehydrated by addition of anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and 100 ml of ethyl acetate-isopropyl ether (1:5, v/v) was added to the residue. After cooling, the crystalline precipitate was collected by filtration to give 5.8 g (yield, 85.5%) of phenylthioethyl 2 (2-aminothiazol-4-yl)-(z)-2-(t-butoxycarbonylmethoxy-imino)acetate as white crystals.
Elemental analysis , _ . . .
Calcd. :Eor C 19 H 23 N 3 0 5 S 2 = 4 3 7 . 5 3 - - C 5 2 . 1 1 % . H 5 . 2 5 /0 . N 9 . 6 0 %.
, Found:` C 5 2 . O ~ %. H 5 . 2 9 %. N 9 . 1 1 %, NMR (60MHz. DMSO-d6 ) 8: 1. 45 (9H.
! s, C ( C H ~ ) . 3 . 3 0 ( 2 H . t, J = 8 H z . C H
2 SC~ H 5 ), 4. 40 ( 2H, t, J=8Hz. COOCH
2 ) . 4. 60 ~2H. s, OCH2 CO), . . . . . .. . ..
6 . 3 5 ~ 1 H. s, thiazole~ - 5 - H ) . 7. 2 O~
7 . 5 0 ( 7 H, m, arom. and ~ `, N H 2 - ) K B r I R lJ ~ cm~l: 3 4 5 0 ~ 2 9 5 0~. 1 7 4 0 . 1 6 2 0 .
: `m a x . . ~ ~ 1 5 9 0, 1 5 4 5 -64- 12~8Z3 (2) In a mixture of 50 ml of acetone and 10 ml of water was dissolved 5.0 g (0.0114 mole) of phenyl-thioethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxy-carbonylmethoxyimino)acetate as obtained in (1). To the solution was added 0.05 g of ammonium molybdate and, at 25-30C, 13 ml (0.115 mole) of 30% hydrogen peroxide was added. The reaction was allowed to proceed for 4 hours. The reaction mixture was poured into 500 ml of water and extracted with 500 ml of ~
ethyl acetate. The organic layer was washed with 500 ml of 5% sodium sulfite and 500 ml of water in that order and concentxated to dryness. The residue was dissolved in a mixture of 200 ml of acetone and 50 ml of water, and a 40% potassium carbonate solution was added dropwise at 30-35C at pH 10-11 for hydrolysis. The mixture was stirred for about 2 hours and 100 ml of water was added, followed by additlon of 500 ml of ethyl acetate for extraction purification. The aqueous layer was adjusted to pH about 2 with 2 N HCl, whereupon crystals separated out. The mixture was cooled to 5C
or below and the crystalline precipitate was collected by filtration to give 2.57 g ~yield, 74.8%) of 2-(2-amino-thiazol-4-yl)-(Z)-2-(t-butoxycarbonylmethoxyimino)acetic acid as white crystals.
, !
~LZ~32~
The NMR and IR spectra of this product were identical with those of the compound obtained in Example 16.
Example 24 (1) Using 5 g (0.0156 mole) of phenylthioethyl 2-(2-aminothiazol-4-yl) (Z)-2-hydroxyiminoacekate as obtained in Example 22 and 4.9 g (0.0234 mole) of t-butyl 2-bromopropionate and following the procedure (1) of Example 23, there was obtained 5.8 g (yield, 82.3%) of phen~lthioethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl-l-methylmethoxyimino)acetate as white crystals.
Elemental analysis Calcd- for C20H25N3O5S2 C, 53.15%; H,.5.53%; N, 9.30%
Found: C, 53~30%; H, 5.50%; N, 9.07%
I NMR ( 60MHz, DMS0-d 6 ) ~ 1 . 35 (3H.
d, J = 8 H z . C H C H 3~) . 1 . 4 1 ( 9 H . s, C ~ C H 3 ) ~ ), 3 . 2 8 ( 2 H . t, J = 8 H z .
C H ~S ) .: 4 . 4 0 ( 2 H . t , -J = 8 H z .
¦ CH2 CH 2 S) . 4. 6:0 ( 1 H. q. J=8Hz.
C H ~ C H 3 ~ . 6 . 9 0 ( 1 H . s, thia~ole - 5 - H ) 7 . 2 0 ~ 7 ~ 5 0 ( 7 H, m, arom. and N H 2 - ) K B r ` ` -I R v cm-l: 3 4 0 0 ~ 2 9 5 0 . 1 7 4 0 . 1 7 2 5 .
a x - . 1 6 3 0 . 1 5 9 5 . 1 5 5 0 - , ~
~2~L8Z3 _66-(2) In the same manner as (2) of Example 23, 4.0 g (0.0089 mole) of phenylthioethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl-1-methylmethoxyimino)acetate as obtained in (1) was oxidized with aqueous hydrogen peroxide and then hydrolyzed in an alkaline condition adjusted with potassium carbonate. Adjustment of the pH to about 2 gave 2~0 g (yield, 71.3~) of 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl-1-me~hylmethoxyimino)acetic acid as white crystals.
The NMR and IR data confirmed that this product was identical with the compound obtained in Example 20.
Example 25 (1) Using 5 g (0.0156 mole) of phenylthioethyl 2-(2-aminothiazol-4-yl)-(Z)-2-hydroxyiminoacetate as obtained in Example 22 and 5.2 g (0.0233 mole) of t-butyl 2-bromoisobutyrate and following the procedure (1) of Example 23, there was obtained 6.0 g (yield, 82.6%) of phenylthioethyl 2-(2-aminothiazole-4-yl)-(Z)-2-(t-butoxycarbonyl-l,l-dimethylmethoxyimino) acetate as white crystals Elemental analysis CalCd- for C21H27N3O5S2 .: - -- - - - . .
C54. 1 3%, H5. 80%. N9. 02%
Found: C 5 4 . 4 7 %, H 5 . 6 4 % . N 8 . 7 8 %
NMR ~ 60MHz. DMS0--d 6 ) 8 1 . 4 0 ~ 1 5H.
s . C ( C H 3 ) 3 & C ( C H~ ) . 3 . 3 0 ~ 2 H, t, J=8Hz. CH~S-) . 4. 40 (2H. t, J=
:81iz, COC~CH2 ) . 6. 90 ( 1 H. s, thia-zole _- 5~ - H ) . 7 . 2 0 ~ 7 . 5 0 ( 7 H, m, arom.
and N H 2 ~ ) . .
.
-67- 1 ~ 4 48 2 3 IR Vma cm : 3400-2950, 1740, 1710, 1630, 1590, (2) In the same manner as (2) of Example 23, 5.0 g (0.0107 mole) of phenylthioethyl 2-(2~amino-S thiazol-4-yl)-(Z)-2-(t-butoxycarbonyl-1,1-dimethyl-methoxyimino)acetate as obtained in (1) was oxidized with a~ueous hydrogen peroxide and then hydrolyzed. Adjustment of the p~I to about2 gave 2.0 g (yield, 56.7~) of 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl~ dimethyl-methoxyimino~acetic acid as white crystals.
The NMR and IR data confirmed that this productwas identical with the compound obtalned in Example 21.
Example 26 In 140 ml of acetonitrile was suspended 5.42 g of 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxy-carbonylmethoxyimino)acetic acid as obtained in Example 4 followed by a serial addition of 2.96 ml of N-methylmorpholine and 7.2 g of 2,2-dithiobis-benzothiazole. The suspension was cooled to 0C
and a solution of 5.38 ml of triethyl phosphite in 35 ml of acetonitrile was added to the suspension over a period of 4.5 hours. The mixture was stirred for 30 minutes and cooled to -10C or below. The resultlng preclpitate was colleoted by filtrationJ
-6~ 823 washed with 20 ml of cold acetonitrile and dxied in vacuo at room temperature to give 6.2 g (yield, 76.5~) of s-~2-benzothiazolyl) 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonylmethoxyimino)thioacetate as light-yellow crystals.
N M R ( 6 0 ~1 H z . U M S O - d 6 ) 8: 1 . 4 7 ( 9 H .
s, C (CH3 ) 3 ), 4. 71 (2H. s, OCH2 CO) 7 . 0 5 ( 1 H, s, thia~ole 5 ~ H ) . 7 . 3 9 ( 2 H .
s, NH2 ) . 7. 45~7. 62 (2H. m~ arorn), 1 8. 00~8. 28 (2H, m, arom) I R ( K B r ) cm-l: 3 4 2 5 . 3 1 5 0 . 1 7 4 0 .
1 71 O. 1 620. 1 540 Reference Exam_le 1 (1) In 40 ml of tetrahydrofuran-water (4:1j was suspended 1.5 g of 7-amino-3-methylthiomethylcephem-4-carboxylic acid, and 1.6 ml of triethylamine was added at room temperature. Thenj 2.86 g of thioester obtained in Example 26 was added to the suspension and the reaction was allowed to proceed at room temperature for 2 hours. After completion of the reaciton, the solvent was distilled off and 50 ml of water was added to the residue. The mixture was washed with ethyl acetate and the washings were adjusted to pH about 2.5 with hydrochloric acid and - 69 ~ 3Z3 extracted with 50 ml of ethyl acetate. l~he extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. With ice-cooling, 20 ml of trifluoroacetic acid was added and the reaction was allowed to proceed for 2.5 hours. A~ter completion of the reaction, the trifl~oroacetic acid was distilled off under reduced pressure and water and 10% aqueous sodium hydrogen carbonate were added to the residue q for dissolution. This solution was chromatographed on 200 ml of Amberlite~XAD-II (manufactured by Rohm & Haas Co., V.S.A.), elution being carried~out with water. The active fractions were combined and lyophilized to give 1.8 ~ of disodium 7~-[2-(2-aminothiazol-4-yl)-(Z)-2-(carboxymet~oxyimino)acetamido]-~ 3-methylthiomethyl-3-cephem-4-carboxylate as a white powder.
Elemental analysis Càicd. for C 16 ~ 15 N 5 0 7 S 3 N a 2 5 H 2 0 . C.30. 90%. H4. 05%. N1 1. 31%
Found: C 3 0 . 9 5 %. H 3 . 8 6 %. N 1 1 . 2 6 Y0 ~ NMR (60MHz. D 2 0 ) ~ : 2. 0 0 (3H. s, S C H 3 ) . 3 . 1 0 ~ 3 . 9 5 ( 4 H . m,mephoYltinona2 and ~ S C H 3 ) . 4. 5 6 ( 2H, s,=N0CH 2 ) 5 2 1 ( 1 H d J = 5 H Z protoin at ! 5 7 5 ( 1 H d J 5 H z protoin at ) 7 0 3 ( 1 H. s, thiazOle 5--H ) 2s I R ( K B r ) c~ 3 4 0 0 . 1 7 6 0 . 1 6 1 0. 1535 ~Z~3Z3 (3) Using 7-amino-3-[(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl]-3-cephem-4-carboxylic acid and thiG-ester obtained in Example 26, in the same manner as the above reaction procedure (1), disodium 7~-[2-(2-aminothiazol-4-yl)-(Z)-2-(carboxymethoxyimina)acetamido-3-[(5-methyl-1,3,4-thiadiazol-2-yl)thio~ethyl~-3-cephem-4-carboxylate was obtained.
Elemental analysis ¦ Calcd.
`C31 . 44%. H3. 3 7%. Nl 4. 26%
0 Found: C 3 1 . ~ 0 % . H 3 . 3 7 %, N 1 3 . 4 8 %
NMR ~ 60MHz. D2 0) ~: 2. 80 (3H, S, C H 3 ~ , 3 . 6 5 ~ 2 H, q . position 2 ) , 4 . 1 5 ( 2 H . s . N 0 C H 2 C 0 ) . - 5 . 2 5 ( 1 H . d, proton at ~ F ~ e ~ ~ proton at position 6 J ~ ~ ~ ~ I H. d . position 7 157 . 0 0 ( 1 H, s, thiazole 5 _ H ) .
_71_ ~2~Z~
Reference Example 2 (1) In 140 ml of dry acetonitrile is suspended 5.42 g (18 mmol) of (Z)-2-(2-amino-4-thiazolyl)-2-(t-butoxy-carbonylmethoxyimino)acetic acid, 2.96 ml (27 mmol) of N-methyl morpholine and then 7.2 g (21.6 mmol) of bis-benzothiazol-2-yl disulfide are added, and the mixture is cooled to 0C. A solution of 5.38 ml (31.4 mmol) of triethyl phosphite in 35 ml of dry acetonitrile is added dropwise over 4.5 hours and ~he mixture is stirred at the same temperature for 30 minutes and then cooled to -10C.
The resulting crystalline precipitate is collected by filtration, washed with a small amount of acetonitrile and dried under reduced pressure to give 5.1 g of (Z)-2-t2-amino-4-thiazolyl)-2-(t-butoxycarbonylmethoxyimino)acetic 15 acid 2-benzothiazolylthiol ester.
IRv (KBr~ cm 1 3400, 3120, 1738, 1710, 1620, 15~0, 1450, 1415, 1370.
NMR (d6-DMSO) ~: 1.50(9H, s, CH3 x3), 4.78(2H, s, NOCH2COO), 7.10(1H, s, thiazole-SH), 7~4-7.65(2H, m, aromatic protons), 8.0-8.3(2H, m, aromatic protons).
(2) A flask of 1.0 Q capacity is charged with 0.06 kg (0.2508 mole) of (3S,4S)-3-amino-4-carbamoyloxymethyl-2-azetidinone-l-sulfonic acid and 0.9 Q of methylene chloride tomake a suspension, 0.070 Q (0.2508 x 2 mol) of triethylamine and then 0.124 kg;(0.2508 x 1.1 mol) of (Z)-2-(2-amino-4-thiazolyI-2-t-butoxycarbonylmethoxyimino)~
acetic acid 2-benzothiazolylthio ester obtained in (1) are added to the suspension under stirring at 10-20C, and the mixture is stirred at 25-27C for 4 hours. ~he insoluble matter is filtered off and the filtrate is further stirred for about an hour and extracted with 0.9 Q
of water. The a~-~eous layer is washed with 0.19 Q of methylene chloride, 0.38 Q of ethyl acetate and 0.19 Q of methylene chloride in that order. After degassing, 0.45 Q
of concentrated hydrochloric acid is added and the mixture ~4a~8z3 is stirred at 25C for about 2 hours. To the resulting slurry is added 0.9 Q of water and the mixture is stirred at about 25C for about 2 hours and then allowed to stand at O ~2C overnight. The resulting precipitates are collected by filtration and washed with about 0.6 Q of cold water to give about 0.27 kg of (3S,4S)-3-[2-(2-amino-4-thiazolyl)-(Z)-2-(carboxymethoxyimino)acetamido]-4-carbamoyloxymethyl-2-acetidinone-1-sulfonic acid as wet crystals.
[~]D6 45o (c=l, DMSO) IRv mBaXCm 1 1760, 1715, 1670, 1640 NMR(d6-DMSO) ~: 3.9-4.4(3H, C4-H, C4-CH2), 4.66(2H, s, NO-CH2), 5.28(1H, d.d, J=4.5, lOHz, C3-H), 6.92(1H, s, proton at position 5 of the thiazole nuclear), 9.33(lH, d, J=lOHz, c3-NH) Antimicrobial potency (MIC) against K. pneumoniae TN 1711:
0 1 mcg/ml
Claims (16)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process of producing an aminothiazoleacetic acid derivative of the formula (I) wherein R1 and R2 each is hydrogen or lower alkyl; and W' is hydroxyl or 2-benzothiazolylthio, or a salt thereof, characterized by reacting diketene with a halogen, reacting the resulting 4-haloacetoacetyl halide with an alcohol of the formula R-W-C2H4OH (II) wherein R is lower alkyl or phenyl; and W is S or SO2, reacting the resulting compound of the formula XCH2COCH2COOC2H4-W-R (III) wherein X is halogen; and R and W are as defined above, with nitrous acid, or a salt thereof, reacting the resulting compound of the formula::
(IV) wherein the symbols are as defined above with thiourea or a salt thereof reacting the resulting compound of the formula (V) wherein the symbols are as defined above, or a salt thereof, with a compound of the formula (VI) wherein X' is halogen; and R1 and R2 are as defined above, oxidizing the reaction product when W is S, and (i) hydrolyzing the compound thus obtained of the formula (VII) wherein the symbols are as defined above, or a salt thereof, in the presence of a base, or (ii) hydrolyzing the compound (VII) or a salt thereof in the presence of a base, and reacting the resulting product with 2,2-dithiobis-benzo-thiazole.
(IV) wherein the symbols are as defined above with thiourea or a salt thereof reacting the resulting compound of the formula (V) wherein the symbols are as defined above, or a salt thereof, with a compound of the formula (VI) wherein X' is halogen; and R1 and R2 are as defined above, oxidizing the reaction product when W is S, and (i) hydrolyzing the compound thus obtained of the formula (VII) wherein the symbols are as defined above, or a salt thereof, in the presence of a base, or (ii) hydrolyzing the compound (VII) or a salt thereof in the presence of a base, and reacting the resulting product with 2,2-dithiobis-benzo-thiazole.
2. A process according to Claim 1, wherein R1 and R2 both are hydrogen.
3. A process according to Claim 1, wherein R is lower alkyl,
4. A process according to Claim 1, wherein W is S.
5. A process according to Claim 1, wherein W' is hydroxyl.
6. A process according to Claim 1, wherein W' is 2-benzothiazolylthio.
7. A process for producing an aminothiazoleacetic acid derivative of the formula (I) wherein R1 and R2 are each independently hydrogen or lower alkyl; and W' is hydroxy or 2-benzothiazolylthio, or a salt thereof, which process comprises:
(i) when a compound of formula (I) wherein W' is OH is required, hydrolyzing a compound of the formula (VII) wherein R1 and R2 are as defined above, and R is lower alkyl or phenyl, or a salt thereof in the presence of a base , and (ii) when a compound of formula (I) wherein W' is 2-benzothia-zolylthio is required, reacting the compound prepared in step (i) above or a salt thereof with 2,2-dithiobis-benzothiazole, and (iii) if desired, converting a compound of the step (i) or (ii) to a salt thereof.
(i) when a compound of formula (I) wherein W' is OH is required, hydrolyzing a compound of the formula (VII) wherein R1 and R2 are as defined above, and R is lower alkyl or phenyl, or a salt thereof in the presence of a base , and (ii) when a compound of formula (I) wherein W' is 2-benzothia-zolylthio is required, reacting the compound prepared in step (i) above or a salt thereof with 2,2-dithiobis-benzothiazole, and (iii) if desired, converting a compound of the step (i) or (ii) to a salt thereof.
8. An aminothiazoleacetic acid derivative of the formula (I) (wherein R1 and R2 are each independently hydrogen or lower alkyl; and W' is hydroxy or 2-benzothiazolylthio, or a salt thereof).
9. A process according to claim 7, wherein process steps (i) and, if desired, (iii) are carried out whereby a compound of formula (I) wherein W' is hydroxy or a salt thereof is obtained.
10. A process according to claim 7, wherein process steps (i), (ii) and, if desired (iii) are carried out whereby a compound of formula (I) wherein W' is .alpha.-benzothiazolylthio is obtained.
11. A process according to claim 7, 9 or 10, wherein in formula (VII), both R1 and R2 are hydrogen or methyl, or one of R1 and R2 is hydrogen and the other is methyl.
12. A method of acylating the amino group of 7-amino-3-pyridinomethyl-3-cepham-4-carboxylate, 7-amino-3-methylthiomethyl-3-cephem-4-carboxylic acid, 7-amino-3-[(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl]-3-cephem-4-carboxylic acid or (3S,4S)-3-amino-4-carbamoyloxymethyl-2-azetidinone-1-sulfonic acid, which method comprises reacting a compound of formula (I) of claim 8 wherein R1 and R2 are each independently hydrogen or lower alkyl and W' is 2-benzothiazolylthio; with 7-amino-3-pyridinomethyl-3-cephem-4-carboxylate, 7-amino-3-methylthiomethyl-3-cephem-4-carboxylic acid, 7-amino-3-[(5-methyl-1,3,4-thiadiazol-2-yl)thio-methyl]-3-cephem-4-carboxylic acid or (3S, 4S)-3-amino-4-carbamoyloxymethyl-2-azetidinone-1-sulfonic acid, and, if desired, removing the carboxyl-protecting group in the alkoxy imino moiety.
13. A derivative according to claim 8, wherein R1 and R2 both are hydrogen.
14. A derivative according to claim 8, wherein R is lower alkyl.
15. A derivative according to claim 8, 13 or 14, wherein W' is hydroxyl.
16. A derivative according to claim 8, 13 or 14, wherein W' is 2-benzothiazolylthio.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP83/00003 | 1983-01-07 | ||
| PCT/JP1983/000038 WO1983002769A1 (en) | 1982-02-12 | 1983-02-07 | Water treatment apparatus |
| PCT/JP1983/000135 WO1984004305A1 (en) | 1983-05-02 | 1983-05-02 | Process for preparing aminothiazoleacetic acid derivatives |
| JP83/00135 | 1983-05-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1244823A true CA1244823A (en) | 1988-11-15 |
Family
ID=26424028
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000444818A Expired CA1244823A (en) | 1983-01-07 | 1984-01-06 | Thiazole derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1244823A (en) |
-
1984
- 1984-01-06 CA CA000444818A patent/CA1244823A/en not_active Expired
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