JPS61109791A - 6-(substituted)methylene penicillanic acid and 6-(substituted)hydroxymethylpenicillanic acid and derivatives thereof - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel 6-(substituted) medeleninisilane acids,
and novel 6-(substituted) and α-dimethylinisilane acids, certain esters and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them, processes for their preparation, and beta-lactamase inhibitors. This article relates to its use as a chemical and intermediates therefor.

One of the most well-known and widely used classes of antibacterial agents are those known as beta-lactam antibiotics. These compounds are characterized by having a core consisting of a fused 2-azetidinone (beta-lactam) ring, either thiazolidine or dihydro-1,3-thiazine. When the core contains a thiazolidine ring, the compound is usually referred to collectively as a penicillin, while when the core contains a dihydrothiazine ring, the compound is referred to as a se7allosporin. Typical examples of the four nigilins commonly used in clinical practice are: penzylinicillin (-e2'isu: yQ), phenoxymethyl (nidyline (4nidyline y), ampicillin, and carbenicillin): common Typical examples of cephalosporins are cephalosporin, cephalex, and cefazolin.

However, despite the widespread use and wide acceptance of beta-lactam antibiotics as useful chemotherapeutic agents, they suffer from the major drawback that certain compounds within them are not active against certain microorganisms. have. In many cases, this resistance of a particular microorganism to a given beta-lactam antibiotic is believed to occur because the microorganism produces a beta-lactamase. This latter substance is an enzyme that cleaves the beta-lactam ring of penicillins and cephalosporins to yield a product without antimicrobial activity. However, some substances have the ability to inhibit beta-lactamases, and when beta-lactamase inhibitors are used in combination with penicillins or cephalosporins, this may inhibit certain microorganisms. The antimicrobial effectiveness of phosphorus can be increased or enhanced. Enhanced antimicrobial activity is considered when the antimicrobial activity of a combination of a beta-lactamase inhibitor and a beta-lactam antibiotic is significantly greater than the sum of the antimicrobial activities of the individual components.

As described above, according to the present invention, novel compounds are obtained which are 6-(substituted)methylenepenicillane, its 1-oxides, 1-1-dioxides, and its esters that can be easily hydrolyzed in vivo. It will be done. These novel penicillanic acids and their easily hydrolyzable esters in vivo are potent inhibitors of microbial beta-lactamases. Thus, methods are also provided for enhancing the effectiveness of beta-lactam antibiotics using these new acids, their salts and certain easily hydrolyzed esters thereof.

6-(substituted) also has a carboxy protecting group
Methylenepenicillanic acid, its l-oxides and 1.
1-dioxides are also obtained, and these compounds are useful as chemical intermediates.

Moreover, 6-(substituted)hydroxymethylpenicillanic acid, its 1-oxide, 1,1-
Dioxide and its salts and esters are obtained.

European Patent Application No. 50,805 describes compounds of the formula that are useful as beta-lactamase inhibitors. In the formula, is O, It or 2, and R1 is C
N or a certain carbonyl moiety; R1 is hydrogen, a lower alkyl group, or a halogen, and R1 is hydrogen or a readily hydrolyzable group. This same document also describes its use in the preparation of compounds of formula 2 by reaction with phosphorane of formula RIRtC-PCCJw)s.
6-oxbenisilanic acid esters, the corresponding sulfoxides and sulfones are described.

United Kingdom Patent Application No. GB2.053.22OA states:
Among them, 3 in the formula is 2, R1 and R1 are independently hydrogen, an optionally substituted alkyl group, an aryl group, an optionally substituted cycloalkyl group, an aralkyl group, or an optionally substituted amino R3 together with the carbon atom representing the group or to which they are attached
and R1 forms a 3- to 7-membered carbocyclic or heterocyclic ring. Specific 6-methylene-1 of the above formula (g),
1-dioquino-penicillanic acid and esters are described.

U.S. Pat. No. 287,181 discloses that the 6-substituent is R1 4-CH, inter alia R1 is Hl or an alkanoyl group and R4 is H, (("s-(1'4)alkyl) A specific 6 group that is a group, phenyl group, benzyl group or pyridyl group
-Substituted inisyl/acid 1,1-dioxides and their esters have been described and are useful as beta-lactamase inhibitors.

The present invention provides a novel 6-(substituted)methylene dilanic acid ester of the formula [
where n is 0% it or 2: R1 is Ra or Rb (where 86 is %7' based on tetrahydropirani)
Hb is the residue of a carboxy-protecting group selected from the group consisting of: R4 and R1 is each hydrogen or CHa, R6 is a (C1-C*) alkyl group, and R14 is (where Xt is a 3-substituent of a known cephalosporin beta-lactam antibiotic; R'' is a 6- or 7-substituent, respectively, of a known penicillin or 7770 sporin beta-lactam antibiotic), and particularly preferred R'' is a 2-y enylacetamide group,
2-phenoxyquacetamide group, D-2-amino-2-phenylacetamide group, D-2-amino-2-(4-hydroxyphenyl)acetamide group, 2-carboxy-2-
Phenylacetamide group, 2-carboxy-2-(2-thenyl)acetamide group, 2-carboxy-2-(3-thenyl)acetamide group, D-2-(4-nibble-2,3
-dioxopiperazino-carbonylamino)-2-phenylacetamide group, D-2-(4-ethyl-2,3-dioxopiperazino-carbonylamino)-2-(4-hydroxydiphenyl)acetamide group or 2 + 2-
') Methyl-4-phenyl-5-imidazolidinone-1
-yl group. is the penicillin residue described above): one of r and R1 is hydrogen, the other is CjlCM,
OH, vinyl group, (C*-C4) alkylthio group, (C
+C4) Alkylsulfonyl group, furyl group, chenyl group, N-methylpyrrolyl group, N-acetyl, milk is 2 or 3, p is 0 or 1, C is 0.1
1 or 2, 21 is S10 or NAl1,
R7 is hydrogen, Cc+-C4) alkyl group, (cs-C4
) alkoxy group, allyloxy group, hydroxyl group, carboxyl is, (C-containing -C1) alkoxycarbonyl group, Cc*-c,) alkylcarbonyl group, phenyl group, hensyl group, naphthyl group, pyridyl group, NR"R"
, C0NR"R・, NHCOE", AlOx, CI
, Bde, CFs 1tJiSR'T'a'); R1 and Ro are each hydrogen, (C1-C4) alkyl group, phenyl group, or benzyl group; RI is ((+-Q) alkyl group, CFx" t or 7 enyl group; R'' is hydrogen, C11s CJ@ or CHsCO;
R'' and 81? are each H-(Cs-C4) alkyl group, (Cm (1''4) hydroxyalkyl group, or together with the nitrogen atom to which they are bonded, R''k and R1 ? forms a 5- to 7-membered heterocyclic group (particularly preferred such heterocyclic groups are pyrrolidino group, pyrrolidino group, morpholino group, thiomorpholino group,
or 4-methylpiperazino group)], or 8
2′! or BS is a group containing a basic nitrogen atom; Provides a pharmaceutically acceptable cationic salt.

The above compounds in which R1 is R1 are useful as intermediates for the preparation of compounds in which R1 is Rh. This latter compound is an active potassium lactamase inhibitor of the present invention.

The invention further provides ranic acid, its 1-oxides, 1,1-dioxides and esters: or its pharmaceutically acceptable acid addition salts or carboxylic acid salts. In the formula, Ru and R1 are represented by the formula (
As defined above for the compound of I), %XA is H"l or Bde, % Sulfonyl group, furyl group, chenyl group, N-methylpyrrolyl group, N-acetylpyrrolyl group, R'CJh, CH
CR'>NR"R", Crystal 3 When a is 0, R1 is a group other than Ht or CH; R■ is a Hl (Ct-Cm) alkanoyl group, (C
m-Cm) alkoxycarbonyl group, pyrazinecarbonyl group, benzoyl group, CF, Co'! or C0NR
"R@; and the door, 2% t%R', R-R"
, R11, R1'', R'' and Xl are as defined above.

All compounds of formula 1) are useful as chemical intermediates for the production of mono(substituted) methylene-1,1-dioquinoisilane esters of the corresponding formula (υ).However, in addition, if Rt is hydrogen or a residue of an ester group, Rh, which is readily hydrolyzable in vivo as defined above, the compound of formula (II) is particularly useful in conjunction with beta-lactam antibiotics because of its beta-lactamase inhibitory activity. It is useful when

Particularly preferable compounds of formula (1) include 3 in which 3 is Ol or 2
This is a compound in which one of R'' and Hs is hydrogen and the other is a furyl group, a chenyl group, a C&OH1 phenyl group, a methylsulfonyl group, or an N-methylpyrrolyl group.

Particularly preferred compounds of the formula (V) are those in which n is 0 or 2, one of R1'' and R1 is H, and the other is a vinyl group, 2-furyl group, 2-chenyl group, N-methylpyrrole-2- yl group, N-acetylpyrrol-2-yl group, 3
-Hydroxy-2-1: 'lysyl group, 4-methoxy-2
-pyridyl group, and R1″ is Hl or CHs
It is a compound that is CO. Particularly preferred groups as the carpogysi protecting group R6 are a 1-lyl group, a benzyl group, a t-butyl group, and a 2,2,2-trichloroethyl group,
Because they are relatively easy to selectively produce and remove,
Particularly preferred is an allyl group.

Particularly preferred as a residue of an ester group that can be easily hydrolyzed in vivo, ie Rh as defined above, are, especially in the formula R4 and Rg are hydrogen and R
Preferably, @ is as defined above.

In addition to providing methods for making compounds of formulas (1) and (II), the present invention further provides methods for treating bacterial infections in mammalian patients, including humans. This method administers an antimicrobially effective amount of the formula (
I) wherein RI is Rh as defined above.

Also provided is a pharmaceutical composition for treating bacterial infections in mammals, including humans, comprising an antimicrobially effective amount of a compound of formula (I), wherein R1 is Bb. ing.

Formula (I) and 1 where Rt is Rh as defined above
) are useful as inhibitors of the Peter lactase enzyme. By this mechanism, these compounds are resistant or partially resistant to beta-lactam antibiotics, especially due to the production of enzymes (beta-lactamases) that would otherwise degrade or partially degrade beta-lactam antibiotics. Enhances the activity of beta-lactam antibiotics (4nidylins and cephalosporins) against microorganisms. In this way, the spectrum of activity of beta-lactam antibiotics is increased.

Furthermore, the present invention provides a method for treating M. fungi infections in mammalian patients, including humans, which method comprises administering to the mammal in need of such treatment an antimicrobially effective amount of penicillin. or by administering a cephalosporin (especially those listed below) and a beta-lactamase inhibiting amount of a compound of formula (1) or (It).

Although the present compounds are effective in enhancing the activity of beta-Lacum antibiotics in general, their preferred use is with inicillins or cephalosporins with established clinical efficacy, namely amoxicillin, ampicillin, ampicillin, ampicillin, azthreonam, bacampicillin, carbenicillin. , carbenicillin indanyl, carbenicillin phenyl, cefaclor, cefadroxil, cephalolam, cefamandole, cefamandole naphate, cefavalor, cefatridine, cefazolin, cefbuperazone, cefonide 7d, cefmetuxime, cefodijime, cefo(razon, cefoni 7, cephalosin, Cefoteium, cefaquiqun, 77 viramide, heptafupirome, cesarodin, ceftazidime, cephalocin, ce7 triaxone, cephalocin, cephaleptatril, cephalexicun, cephaloglycine, cephaloridine, cephalocin, cephapirin, cefrazine, cyclacillin, evicillin, frazlocillin, hetacillin, Renampicillin, repoprobiltaline, mecillinum, mezrocline 4, nigilline G1, penicillin Y1, pheneticillin, biilafurin, pirpenicillin, pivampicillin, cyclacillin, sulpicillin, sancillin,
found when they are combined with talampicillin and ticarcillin (including their pharmaceutically acceptable salts). The names used for these beta-lactams are generally US A//.

i.e. Utsttgd 3tatas
AdaptedNames ).

Furthermore, the beta-lactamase inhibitor of the present invention and 7-(2
-(2-amino-4-thiazolyl)-2-(methoxyiminoacetamide)-3-(5,6-dihydro-a-4-pyrinzonium)methyl-3-cephem-4-carboxylate (HR-810) ;7-(2-(2-amino-4-
Thiazolyl)-2-methoxyiminoacetamide)-3-
(#-Methylhyrolysinicum) Methyl-3-cephem-
4-carboxyle) (3M1'-28,142) and 7-CD-C2-C4-carboxy-5-imidazolecarboxamide))-2-phenylacetamide)-3
-(4-(2-sulfonateethyl)pyridinicum)-
Also included are combinations with 3-cephem-4-carboxylic acid.

Although the compounds of the invention can be administered separately from the beta-lactam antibiotic, combined dosage forms are preferred. Whether for oral or parenteral use, the pharmaceutical composition may contain the formula (1
) or (1) a beta-lactamase inhibitor and a beta-lactam antibiotic (together in an amount sufficient to effect the treatment of a bacterial infection in a mammal in a single dose or more commonly in multiple doses).

Compounds of the invention of formulas (1) and ([l) in which one of the groups R'', R'S R'' or R'' contains a basic nitrogen atom gold may not form acid addition salts. I can do it.

Salts with such pharmaceutically acceptable acids are included in the invention. Examples of such acids are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, malic acid, tartaric acid, maleic acid, fumaric acid, gluconic acid, saccharic acid, benzenesulfonic acid, j-)luenesulfonic acid, p-chlorobenzenesulfonic acid and 2-naphthalenesulfonic acid.

Additionally, compounds of formula (1) and C11) where R1 is hydrogen form cationic salts, and salts with such pharmaceutically acceptable cations are included in the invention.

Examples of such cations are sodium, potassium, ammonium, calcium, magnesium, zinc; and amines such as jetanolamine, choline, ethylenediamine, ethanolamine, N-methylglucamine and procaine. is a substituted ammonium salt.

The present invention relates to derivatives of penicillanic acid represented by the following structural formula: In the derivatives of penicillanic acid, the dashed bond of the substituent to the bicyclic wave (
) indicates that this substituent is below the plane of this nucleus. Such substituents are said to be in the alpha configuration. Conversely, a broad loose bond (-) of a substituent to a bicyclic wave indicates that this substituent is above the plane of this nucleus.

This latter configuration is called the beta configuration. As used herein, a solid bond (-) of a substituent to a bicyclic wave indicates that the substituent may be in either the alpha or beta configuration.

Compounds of the invention are made, for example, by one or more of the following general methods.

1 method 4 GV) (V) (■) R-R
” (■) fl-R' (■) R1-R
The required Witzteig (W<ttsg) salt of 6〈-(Vl) R''-Hbφ■Cm & is a known compound or can be obtained commercially by conventional synthetic methods, e.g. as shown below. It is easily manufactured from precursors that can be used.

The primary alcohol (of general formula R"CHxOHI!') is typically a solvent that is inert to the reaction at or near room temperature.
For example, this alcohol is converted to the corresponding chloromethyl compound by reacting with an equimolar amount of thionyl chloride in the presence of chloroform or methylene chloride.

The product is isolated, for example, by neutralization and extraction of the reaction mixture.

Next, this chloromethyl compound, RjCH,CI,
It is converted into the desired Wit t iσ salt, for example by reaction with equimolar amounts of triphenylphosphine. Typically, this step is carried out in a solvent such as toluene at elevated temperature, preferably at reflux temperature.

The desired product forms a precipitate, which is collected by filtration.

6-Alphahydroquicubenyl heptalanic acid is a known compound, for example, Hauser et al., HgLv, C
him, Acta, 50, 1327 (1967)
Please refer to This acid can be converted into a carboxyl-protected derivative of formula (IV). The identity of the carboxy protecting group is not critical. As the carboxy protecting group R6 is required: (1) the oxidation conditions used to form the 6-oxininisilane ester (V) and subsequent 6-
(Substituted) Must be stable to reaction with Witstei ζ reagent to form methylene 4-nidylanic acid ester; (it) Beta-lactam and 6-(Substituted)
1 using conditions in which both methylene groups remain virtually intact.
S QiD must be able to be selectively removed from a compound of formula (■, R''-, P) to form a sulfone of formula (■) or a corresponding sulfoxide (Vl, R'-) Typical carboxy protecting groups as per the above requirements are: tetrahydropyranyl, beazyl, benzhydryl, 2,2,2-) lychloroethyl group, allyl group, t-butyl group, and phenacyl group.
, 850 and 3,197,466: British Patent No. 1.041,985;
Journal of the American Chemical Industry
mgriaan Chemical 5ociety
λ 8B, 852 (1966);
(Journal of Organic Chemistry with Chaxvatta)
anic Chgtniatn included 36°1259(
1971); Sheehan et al., Journal of Organic Chemistry
al of Organic Chemistry
, 2 9 +2006 (1964); and Academic Press.
, Inc., χ1972.

In ``Cephalosporins and Penicillins, Chemistry and Biology'', edited by H.E. Flynn.
nand pencilltns, chgrniat
Please refer to RY and Biology. Particularly preferred such groups are allyl, benzyl and 2,2,2-trichloroethyl, with allyl being particularly preferred due to its ease of preparation and selective removal.

The oxidation of the carboxy-protected 6-alphahydrogydisilane ester (CrV) to the corresponding 6-oxilayi disilane (X) is typically carried out in a solvent inert to the reaction (e.g. chloroform). or methylene chloride)
The procedure is carried out using approximately equimolar amounts of trifluoroacetic anhydride and a heptal excess of dimethyl sulfoxide in the presence of . This reaction is preferably carried out at a temperature of about -80° to -70 Tt. The reaction mixture is neutralized, for example, by the addition of a tertiary amine, such as triethylamine, and then the mixture is separated, for example, by partitioning between water and a water-immiscible solvent and evaporating the organic layer. Let go.

make them respond. This reaction can be carried out using organic solvents that are inert to the reaction, e.g.
Hydrocarbons such as uf, -ethane, hexano, benzene, toluene or xylene; methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, lI2-
Preference is given to working in the presence of halogenated hydrocarbons such as dibromoethane or chlorobenzene; ethers such as tetrahydrofuran, dioxane, diethyl ether, 1,2-dimethoxyethane or t-butyl methyl ether. This reaction ranges from about -100@ to +5
0'C'! The preferred temperature is within the range of about -78° to 25°C, although it can be carried out at temperatures ranging from about -78° to 25°C.

The product of the desired formula (■, RI-m) can be isolated by known techniques, e.g. by quenching the reaction by adding an aqueous ammonium chloride solution, extracting with a water-immiscible solvent and evaporating the solvent. The product thus obtained is purified, if desired, by conventional methods known to those skilled in the art, such as column chromatography over silica gel.

Formula (
■, R' = one ester is then converted to the corresponding ester or ester of the formula (■ B'-Hb), where Rh is hydrogen or an ester-forming residue that is easily hydrolyzed in vivo. be able to. Typically, the carboxy protecting group is removed from the intermediate compound of formula (vl, R'-R') to form the corresponding carboxylic acid. The particular method chosen for removal of this carboxy protecting group will depend on the nature of the ester residue R6, but suitable methods will be readily apparent to those skilled in the art.

As mentioned above, a particularly preferred carboxy protecting group t is a ryoryl group. Although this group can be successfully removed by mild acid or alkaline hydrolysis methods, a particularly preferred method for its removal uses soluble palladium (a complex of tetrakis(l-phenylphosphine)palladium Co) as a catalyst. , firstly Jeffrey CJgffre.
v) and J, 031. by McCornbig. Chgm.

47.587-590 (1982). In a typical method, the allyl ester in a reaction-inert solvent (e.g. ethylene dichloride, chloroform, ethyl acetate) and a catalytic amount of tetrakis(triphenylphosphine)palladium(O) (e.g. the allyl ester t-group) (approximately 1 to 5 mole percent)
, and approximately equal weights of triphenylphosphine are combined under a nitrogen atmosphere. To this is added an equimolar amount of the sodium or potassium salt of the 2-ethylhex/acid relative to the starting allyl ester, and the resulting mixture is mixed with the desired salt, e.g. A certain expression (
Stir at ambient temperature until precipitation of the vT) salt is complete. Typically, this reaction is substantially complete in about 2 to 20 hours. This salt is then collected, for example by filtration.

When the sulfoxides or sulfones of the invention, such as those of formula (I) in which R is 1 or 2, are nitrogenous, any of the wide variety of oxidizing agents known in the art for the oxidation of sulfoxides to sulfones can be used. The formula (
oxidize the sulfide of Vl). However, particularly useful reagents are metal permanganate/acid salts, such as alkali metal permanganates and alkaline earth metal permanganates, and organic yloxy acids, such as organic peroxycarboxylic acids. Good individual reagents are sodium permanganate, potassium permanganate, 3-chloroperbenzoic acid and peracetic acid.

A particularly preferred group of oxidizing agents are organicyloxy acids, and a preferred organic peroxy acid is 3-alperbenzoic acid.

When the desired oxidation product is a sulfoxide of formula (1) where
? & is 0) and an oxidizing agent.

The desired product is a sulfone (e.g. formula (1)
), the sulfide is contacted with two or more molar equivalents of an oxidizing agent. Alternatively, of course, the sulfoxide can serve as starting material for the preparation of the corresponding sulfone, using at least approximately equimolar amounts of oxidizing agent.

For example, the formula (■) where R6 is as defined above.

When a compound of formula (RlwRa) is oxidized with an organicyloxy acid (e.g. peroxycarboxylic acid) to give the corresponding compound of formula (■), this reaction is usually carried out in an organic solvent inert to the reaction. Formula (vl.

R"-A') with about 2 to about 4 molar equivalents of an oxidizing agent. Typical solvents are chlorinated hydrocarbons such as dichloromethane, chloroform and 1°2-dichloroethane; and ethers such as diethyl ether, tetrahydrofura/, and 1,2-dimethoxyethane; this reaction is normally carried out at a temperature of about -20°C to about 50°C, preferably about 25°C. ℃, reaction times from about 2 to about 16 hours are typical.The product is isolated by removing the solvent, usually by vacuum evaporation.The product can be purified by conventional methods well known in the art. can.

In the above-mentioned oxidation method, it is preferable to use a starting material whose carboxy group is protected with the above-mentioned carboxy protecting group, paper. Removal of the carboxy protecting group from the product sulfokide or sulfone is carried out in a conventional manner for the particular protecting group being used, e.g.
, H1=NOL>, as described above.

Compounds of the invention, e.g. of formula (I) or (I), in which RI is an ester-forming residue that is easily hydrolysable in vivo, can be prepared by common esterification techniques from the corresponding compounds in which RI is hydrogen. Can be produced directly from compounds. The particular method chosen will depend on the exact structure of the ester-forming residue, but a suitable method will be readily selected by one skilled in the art. RI is selected from a 3-phthalidyl group, a 4-crotonolactonyl group, a gamma-butyrolactone-4-yl group and a group of the formula In these cases, these include suitable compounds of the invention in which R1 is hydrogen, such as halides of the formula RbQ, which include 3-7meridyl halides, 4-crotonolactonyl halides, gamma-butyrolactone halides. 4-yl or formula% (wherein Q is a silogen and SR'%R'' and R6
is a compound as defined above)]. The terms "halide" and "--logen" refer to chlorine,
Denotes derivatives of bromine and iodine. This reaction is typically performed for example in formula (1) where RI is hydrogen or (I
f) Compounds of compound in an appropriately polar organic solvent 1, e.g.
-dimethylformamide, and then adding about 1 molar equivalent of excess halide (RbQ).

When the reaction has proceeded to virtual completion, the product is isolated by standard techniques. It is often sufficient to simply dilute the reaction medium with excess water, then extract the product into a water-immiscible organic solvent and recover it by evaporation of the solvent. Commonly used starting material salts include alkali metal salts such as sodium and potassium salts, tertiary amine salts such as triethylamine, N-ethylpiperidine, N,N-dimethylaniline and N-methylmorpholine salts, tetramethylalcohol salts, quaternary ammonium salts, such as monicum and tetrabutylammonium salts. The reaction is carried out at a temperature in the range of about 0 to 100'C1, usually about 25°C. The length of time required for completion will vary depending on various factors, such as the concentration of each reactant and the reactivity of the reagents. Therefore, when considering halogenated compounds, iodide reacts faster than bromide;
This bromide also reacts faster than chloride. In fact, when using chlorinated adducts it is sometimes advantageous to add up to 17 tons of alkali metal iodide.

This method has the effect of speeding up the reaction. Reaction times of about 1 to about 24 hours are commonly used, taking into account the various factors discussed above.

The formula (
When using method B outlined above to prepare a compound of the invention of It) or a compound of formula (■),
The required 6-alphabromo-1,1-dioquine benicillane starting material (IK) is prepared at a temperature of -80 to 25°C, typically -78°C, in a tenoetheric solvent, preferably tetrahydrofuran or ethyl. It is converted to a Grignard reagent by reaction with an equimolar amount of a low molecular weight Grignard reagent such as methylmagnesium bromide, ethylmagnesium chloride or n-butylmagnesium iodide in ether. After stirring for several minutes, add an equimolar amount of the appropriate RI! Add the HII C=Q aldehyde and continue stirring until the reaction is virtually complete (usually between about 10 minutes and about 4 Wf at the same temperature). Next, the desired formula (1) (
The ester of a-2) is isolated by standard methods. For example, the reaction is quenched with an ammonium chloride water bath and the product is extracted with a water-immiscible solvent. The product thus formed, (I[), is further purified, for example by silica gel chromatography.

Next, the secondary alcohol of formula (1) (n-2, compound can be obtained. Although various methods known in the art for dehydrating secondary alcohols to olefins can be used to carry out this step, the preferred method involves dehydrating at least equimolar amounts of anhydrous Conversion of alcohol to acetate ester by reaction with acetic acid and pyridine followed by conversion of 1 to 10 at room temperature.
Considerable amount of sv-fin formation by time agitation is used. The reaction is usually quenched with water and the desired product (I), nam 2 , isolated by extraction methods and purified if necessary.

The product of formula α8 or (■) obtained as above is
RI is a carboxy protecting group, as defined above, or the residue of an ester group, Hb, which is easily hydrolyzable in vivo, as defined above.

is an ester. These esters in which R is 86 can be converted to the corresponding carboneRCR by the method described above.
h is hydrogen). Of course, when necessary, the carboxylic acids of formulas (1) and (■) can be converted into corresponding compounds in which R1 is the residue of an ester group that can be easily hydrolyzed in vivo, also by the method described above. can be changed to

Typically, the starting material 6-AlphaArp"A-1
sl-dioquine heptalanic acid varnish fMX) is 6,6-
It is prepared from dipromu-1,1-dioquininini-7lanic acid by treatment with sodium bicarbonate and sodium bisulfite, followed by acidification. The 6-alphabromo-1,1-dioquinoiniclanic acid thus obtained is then converted into an ester of formula (黄).

Formula (1) of the starting material used in Method C outlined above
The esters of are known compounds (e.g. U.S. Pat. No. 4,
234,579). In a typical procedure carried out by this method, a solvent inert to the reaction;
starting material ester in toluene, xylene, (butane, tetrahydrofuran, ethyl ether or various mixtures thereof), at low temperature, equimolar amounts of alkyllithium reagent 5, such as loopyllithium, t-butyllithium or methyllithium, This is immediately contacted with an equimolar amount of the aldehyde, E"R"Co (where R"R" is as defined above), and the mixture is -1
00 to -50°C, preferably -78°C, about 1-4
The reaction is then stopped by stirring for an hour, the bromohydrin intermediate of formula (II) is partitioned between e.g.
It is isolated by purification by column chromatography on ade(bar) (magnesium silicate).

Alternatively, the dibrome ester of the starting material 2) above is reacted with an equimolar amount of a low molecular weight Grignard reagent of formula CM) using the same reagents and conditions described above for Method B. of bromohydrin is obtained.

This bromohydrin (XI) is acylated, and R in the formula
Corresponding compounds (XI) can be obtained in which I- is a group other than hydrogen as defined above. Typically, this acylation is carried out at room temperature or below in the presence of a reaction-inert organic solvent, preferably methylene chloride, tetrahydrofuran or ethyl acetate. or by reacting the corresponding acid anhydride, intermediate bromohydrine of 2011) and a tertiary amine such as pyridine, N-methylmorpholine or the like.
The desired diester of formula (X11) is then isolated by well known methods such as extraction and evaporation of the solvent, and if necessary purified, for example by column chromatography.

Next, the bromine atom is removed from the bromohydroline ester intermediate (XI) or the bromodiester (XI) under t-hydrogenolysis conditions. This reaction can be carried out using a variety of known reducing agents and conditions (e.g. bromohydrin).

This is done either by treatment with hydrogen in the presence of a noble metal catalyst or by reduction with certain organotin hydrides).

Preferred organotin hydride reducing agents include dialkyltin dihydrides, trialkyltin dihydrides having from 1 to 6 carbon atoms in each alkyl group, and those in which the aryl group is phenyl or nitro-based. or a phenyl group substituted with an alkyl group or an alkoxy group having 1 to 3 carbon atoms. Particularly preferred are triphenyltin hydride and trilouptyltin hydride, the latter being particularly preferred for reasons of economy and efficiency.

The above reactions using tin hydrides are usually carried out in the presence of a solvent inert to the reaction. Solvents suitable for use with organotin hydride reducing agents are virtually
or (XI) which dissolves the starting compound but does not itself react with the hydride reducing agent. Examples of such solvents are aromatic hydrocarbons such as bene, toluene, gysylene, chlorobenzene and naphthalene; and ethers such as ethyl ether, isopropyl ether, tetrahydrofuran, dioxa/and 1,2-dimethoxyethane: It is. Particularly preferred solvents for reasons of economy and efficiency are benzene and toluene.

When carrying out a complete hydrogenolysis using an organotin hydride reducing agent, equimolar amounts of bromohydrin (II) or bromodiester (XI) and hydride are theoretically required. In practice, an excess of hydride, for example a 5-50% molar excess, is often used to drive complete reaction.

Hydrogenolysis with organotin hydrides proceeds almost completely under the preferred conditions described above without the use of catalysts. However, this reaction can be accelerated by a free radical source such as ultraviolet S or a catalytic amount of a peroxide such as azobisisobutyronitrile or benzoyl peroxide. Catalytic amounts of azobisin butyronitrile are the preferred source of free radicals for this reaction.

Typically, the compound of formula 01) or (X11) is dissolved in a reaction-inert solvent, the solution is kept under an inert atmosphere, such as a nitrogen or argon atmosphere, and an appropriate amount of organotin hydrogen is added. The compound, optionally a free radical source (eg, azobisin butyronitrile), and gold are added and the resulting mixture is stirred at a temperature within a suitable range from about 0° C. to the boiling point of the solvent.

The reaction is usually complete in a few minutes to about a few hours (eg, from 5 minutes at the boiling point of benzene to about 20 hours at 0° C.). The product of formula CM, X5-H) is then isolated by methods known to those skilled in the art, e.g.
Isolate by evaporation of the solvent and chromatography of the residue on silica gel.

Compounds of formula Cm, xs-1 formed by organotin hydride debromination as described above contain primarily (, te 6-beta isomer (sunawachi 6-RI!RIsC(OR饅) substituents was found to be in beta placement).

When the hydrocracking step is carried out with hydrogen in the presence of a noble metal catalyst, a convenient way to carry out this conversion is to carry out hydrogen or hydrogen, such as nitrogen or arbol, in the presence of a noble metal hydrocracking catalyst. Stirring or shaking a solution of a compound of formula (XI) or (Xll) under an atmosphere of hydrogen mixed with an inert diluent. A suitable solvent for this hydrogenolysis reaction is a solvent which substantially dissolves the starting compound of formula (XI) or (XI), but which does not itself undergo hydrogenation or hydrogenolysis. Examples of such solvents are diethyl ether, tetrahydrofuran, dioxane and
．． Ethers such as 2-dimethoxyethane; low molecular weight esters such as ethyl acetate and butyl acetate a:N,
tertiary amides such as N-dimethylformamide, NlN-dimethylacetamide and N-methylpyrrolidone; water; and various mixtures thereof. moreover,
This reaction mixture is about 4 to 9'! It is often desirable to buffer to operate at a pH in the range of about 6 to 8, preferably about 6 to 8. Borate, bicarbonate and phosphate buffers are commonly used. Introduction of hydrogen gas into the reaction medium is usually accomplished by carrying out the reaction in a sealed vessel containing the compound of formula (XI) or (XI), a solvent, a catalyst, and hydrogen. The pressure within the reaction vessel can vary from about 1 to about 100 am" to 97 am". When the atmosphere within the reaction vessel is substantially pure hydrogen, the preferred pressure range is from about 2 to about 5 kg/tx," It is. Hydrogenolysis is generally carried out at temperatures of from about 0.1°C to about 60°C, preferably from about 25°C to about 50°C. Using preferred temperatures and pressures, hydrogenolysis generally occurs over several hours, such as from about 2 hours to about 20 hours.

Preferred noble metal catalysts used in this hydrogenolysis reaction are agents of the type known in the art for this type of conversion, such as nickel, palladium, platinum and rhodium, with palladium being particularly preferred. is usually expressed as the formula (X
It is present in an amount of from about α01 to about 25 weight percent, preferably from about 0.1 to about 10 weight percent, based on the compound of I). It is often convenient to disperse the catalyst on an inert support; a particularly convenient catalyst is palladium dispersed on an inert support such as carbon.

When this hydrogenolysis is substantially complete, the desired product of formula ([= The product, if any, is prepared by well known methods such as crystallization or chromatography.

When the starting compound of formula (XI) or (Xll) is a benzyl ester (RI=wR''-benzyl group),
The water solution using the above catalyst is 1, which also causes cleavage of the benzyl group and the product is of formula (If) where X and Rt are each hydrogen.

6-([transformed)human mixymethylpenicillanic acid or ester of formula (Xi[) or (11, fon-J7) in which 1 is 0] can be prepared by any of the known methods for converting sulfides into sulfoxides and sulfones. , for example, by oxidizing with the above-mentioned 4-al-alperbenzoic acid to obtain the formula (X11'')
Alternatively, corresponding sulfoxides or sulfones can be obtained in which (m, x, -i) are each L4 or 2. However, the formula (XD, (XI)
or (c) A preferred method for obtaining the sulfone is
In Method C above, a suitable 6,6-dipromo-1,1-dioquino(niclanic acid ester (X)), which is 2, is used as the starting material.

RI! and R'' are as defined above.
Starting material aldehydes for RR1mCQ can be obtained commercially or by methods well known in the art, such as 1, eg, potassium dichromate, chromium a! 2. Oxidation of the corresponding primary alcohol prepared above as a Witzteig reagent precursor using an oxidizing agent such as /pyridine, catalytic oxidation in the presence of a noble metal, manganese dioxide, 2. The corresponding methyl-substituted aromatic hydrocarbon. and, for example, with selenium dioxide, 3. the equivalent sulfur C at low temperature in the presence of an ethereal solvent.
Metal hydride reduction of l-C4 alkoxycarbonyl compounds, suitable metal hydrides include libram aluminum hydride and diynbutyl aluminum hydride (DIBAL-
H), 4. By the reaction of the appropriate aromatic hydrocarbon precursor with loop tillithium and dimethylformamide, the trap is
Containers are manufactured from available starting materials.

As indicated above, formula (I) in which R1 is H or (
The compounds of V and their salts exhibit synergistic activity in in vitro antibacterial tests when combined with beta-lactam antibiotics. Such activity suggests that rlLag against various microorganisms
/d by measuring the minimum inhibitory concentration CMIC's). The method to follow is the International Collaborative Research on Antibiotic Sensitivity Testing.
nal Coltab Orativg 5txdy
onrib tibiotic 5avssitivit
y Tasting) [Eritzkun y (Er1ccson) and Schetsx (5ha
rris), Acta Pathology8atM
[1971] using brain heart infusion (BHI) agar and an inoculum repeater. - Night growth tubes were grown 100x for use as a standard inoculum (20.000-IO, OOO cells of approximately 0.002 ad are placed on the agar surface; 20114 EHI agar/dish, dilute to 2 of the test compound
A 12-fold dilution is used, with an initial concentration of test drug of 200 cg7'd. Ignore single colonies when reading the plates after 18 hours at 37°C. Test MiM susceptibility (MIC
) is taken as the lowest concentration of the test compound or combination of compounds that can completely inhibit growth as determined by oral administration.

Compounds of formulas (1) and (II) (R' is H), and salts thereof, in combination with known beta-lactam antibiotics, can be used for topical application as disinfectants, as well as for water treatment, e.g. It is useful as an industrial fungicide in silt control, paste preservation, and wood preservation. When these compounds are employed in such applications, it is often convenient to mix the active ingredient with a non-toxic carrier such as a vegetable or mineral oil or an emollient cream.

Similarly, they can be dissolved or dispersed in liquid diluents or solvents such as water, alcohols, glycols or mixtures thereof. In most cases, a concentration of active ingredient of from about 0.1 percent to about 10 percent by weight, based on the total composition, is reasonable.

Compounds of formula (I) and values in which % E' is Rh as indicated above have further particular value as potent inhibitors of microbial beta-lactamases. By this mechanism, they increase the antibacterial efficacy of beta-lactam antibiotics (4nidylines and cefamisporins) against many microorganisms (microorganisms that produce beta-lactamases).

The ability of the compounds of formula (1) or ([) above to increase the efficacy of beta-lactam antibiotics is due to the ability of the compounds of formula (1) or ([) to increase the efficacy of beta-lactam antibiotics.
and only compounds of formula (1) or (II) whose R-richness is hydrogen, can be evaluated against experiments that measure the MICfK of MI obtained for the combination with the compound (1) or (I) (wherein 81 is hydrogen)
Compare with C value. When the antimicrobial efficacy of the combination is significantly greater than would be assumed from the efficacy of the individual compounds, this is considered to constitute enhanced activity. The MIC of the combination was published by the American Society for Microbiology.
), 1974 Lanattg, SpasEding and Toruant (
Trsa%t) Woven [Manual Op Clinical Microbiology Ck1ansatof CLin1
It is determined using the method described by Barg and Sabath in cG (Microbiology) J 2nd edition.

Compounds of formulas (1) and (It) in which R1 is hydrogen or the residue of an ester group that is easily hydrolyzed in vivo,
Enhances the antibacterial efficacy of beta-lactam antibiotics in vivo. That is, they reduce the amount of antibiotic needed to protect mice against an otherwise lethal inoculum of certain beta-lactamase-producing bacteria. Measurements of such activity involve acute experimental infection of mice by intraperitoneal inoculation of a standardized culture of test bacteria suspended in 5% pig stomach mucus. I vomited. Severity of infection is standardized such that the mouse receives a lethal dose of bacteria (lethal dose is the minimum amount of bacteria required to consistently kill 100% of infected, untreated control mice). inoculum). Test compounds in combination with antibiotics are administered orally or by intraperitoneal injection to several groups of infected mice at various dose levels.

At the end of this test, the activity of the mixture is evaluated by counting the number of survivors among treated animals at a given dose. Activity is expressed as the percentage of animals surviving at a given dose, or PD, (50
% of the dose that protects against infection).

Because of the ability of compounds of formulas (!) and (V above to enhance the efficacy of beta-lactam antibiotics against beta-lactamase-producing Mycobacterium mitosis, they are recommended as beta-lactam antibiotics for the treatment of bacterial infections in mammals, especially humans. In the treatment of bacterial infections, compounds of formula (I) or l can be mixed with beta-lactam antibiotics, or Rh is CHCR').
a beta-lactam antibiotic has the formula (
I) or (If) is chemically linked to the compound, whereby the two agents are administered simultaneously. Alternatively, the compound of formula (1) or (1) may be administered as a separate agent during treatment with beta-lactam antibiotics, in some cases during treatment with beta-lactam antibiotics. It may be advantageous to pre-administer a compound of formula or (1) to the patient before commencing treatment.

Formula (1) or C where R1 is Rh as defined above
) is used to enhance the efficacy of a beta-lactam antibiotic, a mixture of the above compound and a beta-lactam antibiotic, or Rh is CHCIP)
OCOR", the compounds of the present invention are administered alone, preferably in combination with standard pharmaceutical carriers or diluents. A pharmaceutically acceptable carrier, a beta-lactam antibiotic and/or a compound of the formula Pharmaceutical compositions comprising the above compounds of 1) will normally contain from about 5 to about 80 percent by weight of a pharmaceutically acceptable carrier.

When a compound of the above formula (Xia) or (Feng) is used in combination with another beta-lactam antibiotic, the above compound may be administered orally or parenterally, i.e. intramuscularly,
It can be administered subcutaneously or intraperitoneally. Ultimately, the prescribing physician will decide the dosage to be used in a human patient, but the formula (!) or (I
The daily dose ratio of compound D to beta-lactam antibiotic will normally range from about 1:3 to 3:1 by weight. Additionally, when using a compound of formula (1) or (1) in combination with a beta-lactam antibiotic, the daily oral dose of each component is typically about 10 mg/kg body weight.
and about 200 ml, and the daily parenteral dose of each ingredient is usually about 10 to about 4 per gram or body weight.
These daily doses will normally be divided and, in some cases, the prescribing physician will determine that doses outside such limits are necessary.

As those skilled in the art will appreciate, some beta-lactam compounds are effective when administered orally or parenterally, while others are effective when administered by the parenteral route. Formula (1)'t or (I
When a compound of I) must be used simultaneously (i.e., in admixture) with a beta-lactam antibiotic that is effective only when administered parenterally, a combination formulation suitable for parenteral use is required. a compound of formula (I) or (1) at the same time (i.e., in admixture) with an orally or parenterally effective beta-lactam antibiotic.
When used, combinations can be prepared that are suitable for either oral or parenteral administration. Furthermore, it is possible to administer a formulation of an active compound of formula (1) or [) orally while simultaneously administering another beta-lactam antibiotic parenterally;
It is also possible to administer a formulation of a compound of formula (1) or (1) above parenterally while simultaneously administering another beta-lactam antibiotic orally.

The present invention will be specifically explained using the following practical examples. However, it should be understood that the invention is not limited to the specific details of these embodiments. Proton and C18 nuclear magnetic resonance spectra, cheterochloroform (CDCIs), dez-f9ium oxide (AO), -e
60.90.250 or 300 MHz for solutions in rhodeetheracetone (CDscocm) or verbuniterodimethylsulfoxide CDMSO-d.
``r! Measurement: Peak positions are expressed in parts per million (ppn%) downfield from tetramethylsilane.

The following abbreviations are conveniently used:8. Single line: d, double @
; dd, double S[; t, triple 1Ill:
q, four-fold tightness: Ko, multi-fold tightness: b1 wide.

Example L 851i (
0,39 mol] of 6-fur7-hydroxypenicillanic acid, 34 mg (0,39 mol) of allyl bromide, 54 sg (0-39 mol) of triethylamine and 2! After treatment with i. sodium bicarbonate, the mixture was stirred at room temperature for 15 h. The reaction was quenched with water and after extraction with ethyl ether, the ether layer was washed with saturated aqueous bicarbonate solution and water, dried ( MgSO4) and concentrated under reduced pressure to obtain 431 crude product.

The crude product was purified by silica gel column chromatography and eluted with a mixed solvent of Cl+2 form-ethyl acetate (9:1) to obtain the allyl ester of 22.75Ii (23X).

Otori HNMR (CJ) CIs) (δ): 1.42
(a, 3ff), 1.60Ca, 3K), 4.45 (#
, 1Jr), 4.5-5.0 (regret, 3H), 5.2-6
．． 2C%, 4H)*Ha%aml at
Gl, Eels Chith, Acta, *50
1327 (1967).

B, 6-alphahydroxypenicicone 977 (0,041 mol) of pipatetrayloxymethyl ester, 40-dimethylformamide, 7.
A mixture of 4 mg (0,041 moles) of diisopropylethylamine, 6 sd (0,0414 l) of lolomethyl chloride on pivaline, and 6.15.9 (0,041 l) of sodium iodide is stirred at room temperature for 15 hours. .

Water was added, the mixture was extracted with ethyl ether, and the extract was dried and concentrated to obtain the crude ester form of 9y.

This substance was purified using a silica gel column and eluted with a mixed solvent of chloroform-ethyl acetate (9:1).

The eluted portions of the product were combined to yield 4.384.9 (32N).

C, benzyl ester 20jl (0,092 mol) of 6-alpha-hydroxypenecin, 12.9 Hg (0,092 mol) of triethylamine, 1.105 # (0,013 mol)
.

of sodium bicarbonate and 200 sd of dimethylformamide (DMF) was added 12.0 Hwj (0,
Add 10 i&l) of benzyl bromide. After stirring the mixture at room temperature for 20 hours, partition extraction was carried out with ethyl ether and water.
The aqueous layer was adjusted to pH 2.0 with 6N aqueous hydrochloric acid. The two layers are separated and the aqueous layer is extracted with double ether. The ether layers are combined, washed with an aqueous sodium bicarbonate solution and water, dried, and the solvent is distilled off.

The residue was recrystallized using a form-hexane mixed solvent by hot chromatography.
Colorless crystals of 91p (F, 165-167°C) are obtained.

15 # (0,078 mol) of -(5-methyl-
2-oxo-1,3-dioxol-4-yl)methyl and 225-l) 18.7. p(0,07
8 mol) of hydroxypenicillanic acid at room temperature.
After stirring for a period of time, it is poured into water and treated as described above to obtain the desired ester.

Example 2 A mixture of 2.84 mg (0.04 mol) dimethyl sulfoxide, 3.67 mg (0.026-T-nyl) trifluoroacetic anhydride and 50 mg methylene chloride was
Stir for 10 minutes at 8°C. After addition of a solution of allyl 6-alphahydroxypenicillanate (5.1410.02 mol) in 10-methylene chloride at -78 DEG C., the reaction mixture is stirred for 40 minutes. Triethylamine (7,24m,
0.052 mol) at −78° C., the mixture is gently allowed to warm to room temperature, and water is added to stop the reaction.

After extraction with methylene chloride, the organic layer was washed with water three times, and after drying, the solvent was distilled off under reduced pressure to obtain the mentioned compound 5 as a yellow oil.
．． 1. P(100X)-V- is obtained.

“H-NMRCCDCIs) Pj”l(δ): L60
(g, 6ff), 4.75 (palace, 2H), 4.82 (
#, 1ff), s, 17ct, aha, 3ff), &8
2(a,1ff) 0.3611C (5.06 mmol) dimethyl sulfoxide, 0.47 m (3.29 mmol) anhydrous trifluoro vinegar, 839 mg (2.53 mmol) 6-alpha-hydroxypenicillane. After stirring a mixture of baloyloxymethyl and 5d methylene chloride at -78°C for 30 minutes,
Add triethylamine (J4). Part A above
The product was treated as described in 788j9 (95N
) to obtain the desired ketone bodies.

'H-NMR<CDC1m)jjm(J): 1.3(
J, 9H), 1.55 (g, 6ff), 4-85 (s,
If), 5.8 (chicken.

3H).

Examples & 2-picolyl-triphenylphosphonium chloride and (Fo, 265J
A mixture of a solution of 9 (6.8 mmol) of sodium amide in 6 m of anhydrous tetrahydrofuran (THF) was prepared at room temperature for 30 m
Stir for a minute. The resulting brown suspension is
Cool to ℃. Another 1.851 (7,0 mmol)
A solution of anhydrous THIP 4- of 6-okinobenshikune-hui allyl is added in one portion and the mixture is stirred at -78°C for 3 minutes. After quenching the reaction by adding a saturated aqueous ammonium chloride solution and extracting with ethyl acetate, the organic layer is washed twice with water, dried (MgSO4), and concentrated under reduced pressure to obtain a red oil of 3.31. The oil was purified by silica gel column chromatography to yield 1.35 jl (6G, 7
．． 9 g) of the desired product are obtained.

”H-NMRCCDCIs)jIF倶(J):L50(
g, 3H), 1.58 (g, L &), 457 (a, 1j
r), 4.65 (4°2H), 5.15-6-15 (
3H), 6.17 (d.

lH, /==1#g), 6.87 (d, ljr
, J=IHs), 7.2-7.4 C poison, 2H),
7.60 (d of d, 1ff), 8.62 (dl of d
lH); C Otori”-NMRCCDCI@) pp collection (δ): 26.
04,32.99.62.77.65.75.70.0
1.70.54, 119.10.123.24.124
．． 02, l 25.86.131.66.136.06
．． 136.34, 144.66.149.94.152
．． 13.167.54.168.73゜Example by applying the procedure of Example 3, but instead of 2-picolyltriphenylphostuonium chloride, structural formula tc@H,)
sepCH, Il"Ole te show tl, le'1iXk
9 (Tich<wtttiy) reagent to obtain the following compounds.

125 +3.2 (J) (-formylmethylenetriphenylphosphorane benzene rice"H-NME (CDCJs) P'I' (δ): 5.7
3 (4,1ff), 6.82 (d, IJf) 2-isomer: 1.5 (a, 3ff), L6 (a, 3H), 4.57
(a, lH), 47(4,2H), 5.15-6.24
(me 3H), 5.77 (s, 1ff), 6
．． 37 (s, 1 g) using E solution.

Example 4 (string) 2-quinolyl 3-78
EC, HsS 1-78
B2O(J7) 1.5 (a,
3M), 1.62 (s, 3ff), 4-6 (a, xH)
, 4.7<4.2H), 5.1-6.2 (inertia, 3H)
, 6.35 (d.

lH), 7.0 (d, IH), 7.2- & 2 (inertia,
6B) 12φ, Z 4.5 (Jl, 1ff), 4.5-4.8 (Poison, 2B)
, 5.1-6.1 (m, 4H), 6.8 (8, α2
6B), 7.15 (d, 0.74ff), 7.4 (appreciation,
5H) 1.45 (s, 3B), 1.55 (a, 3ff)
, 4.55 (Jl, IH), 4.65 (d, 2H), 5
．． 2-6.1 (Kan, 3H), 6.15 (d, I
H), 6.75 (d, 1H), 7.05-7.7
5 (tn.

3H) Example 4 (Continued) B&A) °C Elution solvent 4''
(j)6)C6H,5-78A 4(J)3
0 (J) 10 (E, I;) "H-NMR (CDCIs) PP (δ): 1.5 (j
, 3ff), 1.6 (#, 3H), 4.6 (a
, Iff), 468(d, 2ff), 5.1-6.
1 (m, 3H), 5.77 (11.

IH), 6.57 (s, 1ff), 7.2-7.64
(regular, 3H), 7.64-8.16 (k, 2H) 1.52 (s, 3ff), 1.62 (t, 3H), 46
0(s, iH), 4.69<d, 2H), 5.1-6.
3 (ind., 3H), 6.1 (d.

IH), 7.03td, LH), Z4 (s e5H) 1.55 (t, 3ff), L65 (s, 3ff),.

2.55 (s, 6ff), 4.65ta, IH), +,
75(d, 2H), 5.1-6.1 (Concern.

3H), 6.25 (d, If), 6.9 (s ei
ff), 7.0 (d, iff) Example & 6(J)-(2-Bi!Jzyl)methylenepenicillane in 0.120 N (0.38 mm 4&l) of 6(J)-
(2-pyridyl) methylenepenicillane allyl, 20~
Tetrakis (triphenylphosphine cobaladium (
A mixture of 0) and 20M9 triphenylphostuin was dissolved in 3 mg of ethyl acetate, and to this solution was added 0.5 mol of 0.76 m (0.38 mmol) of sodium 2-ethylhexanoate under a nitrogen atmosphere. Add ethyl vinegar solution. The mixture was stirred at room temperature for 2 hours, and the precipitate was subjected to FHL, washed with ethyl acetate, and dried in vacuo to give 57 Da (48N) of the title compound as a yellow solid.

'H-NMR<Dn)'IJptnC8): 1.5
5 (#, 6H), 433 (a, LH), 6.17
(d, IH,!=0.5Hz), 7.03(
d, ljr, J=O, SHg), 7.17-
8.07 (m.

3M), 8.57 (Raku #1f); Infrared absorption spectrum (fJr): 3433.1756.1605tx-”
@Example 6 Applying the appropriate starting materials selected from the allyl esters obtained in Example 4 to the procedure of Example 5, the following sodium salts are obtained in a similar manner.

C-CB) 95 Yellow solid, “H-N
MR(J)*0)jj)fls('): L50Ca,
3M), LS8Ca.

3M), 43(a, 1ff), 5.83 (4,1#), 7.1 (d, 1ff): infrared absorption Spectrum (fly)aIL-: 1573.1607. 1688.1775° 346 G.

C1(J) 89 Infrared absorption spectrum CK
Br)z-”: 1580. 1609.1679. 1753.3491°Beak S (J) 80 White solid, 'H-N
MECD, 0)pp(δ) 148 (g, 3ff), 1.56 (a.

3M), 2.50 (s, 3Jf), 4.20 (#, 1ff), 5.88 (s, 1jr), 7.2 (jl IJir) Door outside line absorption spectrum (Kjir) cIL': 1396.1606 .17
49. 2926.2963゜a s 5 L C6H*' (Z) 60 Pale yellow powder 1
．． 5 (a, 6ff), 425 (a, if), &1 (d.

1ff), 7.0 (d, IN), 7.4 (a, 5H) p Infrared absorption spectrum v (KB de) ax-: 1626.1642. 1655.1742. 3434゜93q (0-26 mmol) of 6-phenylthiomethylenebeesilane allyl (isomer mixture*) and 10JII9
Tetrakis(triphenylphosphine)palladium (
O) A mixture of sP and 10q of triphenylphosphine is dissolved in 1-ethyl acetate, and a 0.5M solution of o,sz-sodium 2-ethylhexanoate in ethyl acetate is added at room temperature 1, resulting in the formation of The mixture was heated under a nitrogen stream for 1
Stir for 0 hours.

#1 When no more salt is produced, add water to the mixture and extract with methylene chloride. The aqueous layer is made aqueous (43,5) and extracted with methylene chloride. The dried extract is concentrated under reduced pressure to yield 63 Da (75N) of the free acid as a mixture of isomers.

”H-Null (C1)Cds) P pw(δ)
:L5<a, 2.1H), 1.55(s, 0.9ff)
, 1-6Cj, 2.1#), 1.65*, 0.9ff
), 4-4 (a, 0.7H), 4.5 C&,
03H)%5.38(d, 0.7ff), 5.7(s,
0.3ff), 6.7 (s * 0.3
K ), 7.1 (d, 0.7ff), 7.5 (ind., 5
H) x, 6 of 3ofIC4,09 cells (J) -(
2-PyridiAl) Methylenepenicillane Allyl methylene chloride IS- in the fII solution, 1.70 ti (8-2
80-85X purity (mmol) of inertia-chloroperbenzoic acid is added. The mixture is further stirred at room temperature for 3 hours under nitrogen flow. After terminating the reaction with a saturated aqueous sodium thioate solution and water, the ff1 l stock is extracted with methine chloride. 1! The liquid layer was saturated with hydrogen carbonate (pH 7) with an aqueous solution of
After washing with water and drying (<MeSO4), the solvent was distilled off under reduced pressure to obtain the product L4jl (98X) as a yellow oil. The oil was purified by silica gel column chromatography and eluted with a mixed solvent of hexane-ethyl acetate (7:3) to give 0.78 JP (55X) as colorless crystals.
The title sulfonic compound is obtained.

"H-NMECCI)Cds)ttmcdelme);L4
g(j.

3K), 1J3 (s, 3H), 4.45 (j, 1ff)
, 473(d, 2Jr), 5.1-6.2 (w, 3
Jf), 5.77 (tL, 1M, J = 0.5
Hz), 7.27 (d, 1f, /=0.5Hg), 7.1-8.1 h+s, 3f), 8-6 (s
-IH)z”C-#&ffi(Cj)Cjs)plm(
J): l&S 3.2 G, 43.63.18
; 64.25.66.63.72.04.119.
91.12464.126.03.130.6 g, 1
32.83°136.7? , 15G, 31.166.
8 ti, 168.11° infrared absorption spectrum <KB
r)am-”: 1323.1586.1759.
1783.3437゜Example a Hydrogenation of 0.6 l (0.61 mmol) of Killer-6(E)-pro-#ξ-lamethylenepenicinic acid in a solution of 1 mg of anhydrous tetrahydrofuran at -78°C. Add the diisoptylaluminium IM hexa/solution.

The mixture is stirred at -78C for 10 minutes, then quenched with methanol, stirred at room temperature for 10 minutes, and then filtered. Fi [ was concentrated under reduced pressure to obtain a crude product of 0.25B, i9, which was purified using silica gel column chromatography. Elute with a mixed solvent of no-form-ethyl acetate (4:1), 111
9 (63N) of the title compound is obtained.

1H-Null (CDCIm)99ri1(δ):
11-40 (, 3ff), 1.60 (#, 3f), 2.
60C6#IIH), 4.3 (apprehension.

2M), 4.4Ca, LH), 4.7 (4, 2H),
5.1-6.0 (groove, 3H), 5.25 (d, LH),
6.38 (Inertia.

IH).

Example a The procedure of Example 7 is carried out using jI'J: 6-methylenepenicillanic acid ester (%=0) obtained in Example 4 as a starting material to obtain the following compound.

Example 9A 6 (J) -C(quinolin-2-yl)methylenecous 1-oxopenicillanate (124 Da).

0.313 mmol) (to produce the corresponding sulfonate @obtained nrua product, see cost stamp of previous example) in methylene chloride 5- and 195 ag (0.904 mmol) of 80X methane. - Add chloroperbenzoic acid. The mixture was stirred at room temperature for 48 hours, quenched with water and extracted with methylene chloride. The extract was washed with a saturated aqueous solution of hydrogen carbonate and water, dried, and concentrated under reduced pressure to obtain a yellow oil. The oil was purified by silica gel column chromatography to obtain 45m9 (35N) of the title N-oxide compound as a yellow solid.

Breath H-NMINCDCIs) PPtyh (δ): 1-4
5(a, 3ff).

1.6 (a, 3H), 4.45 (J, IH), 4
7 (fossa.

2M), 5.0-6.0<m, 3H), 5.85Cd,
IH), 7.3-8.0 (Umugi, 7H).

Example 1α Allyl 1,1-dioxo-6(J)-(2-pyridyl)methylenepenicillanate (0,14,p, 0.4 mmol), 20as>tetrakis(triphenylphosphine)palladium(0) and 20 triphenylphosphine were dissolved in 2 m of ethyl acetate.

And under nitrogen flow 0. 2- of J3d (0.4 mmol)
Add a 0.5 molar solution of ethylquinatricum in ethyl acetate.

The reaction mixture is stirred at room temperature for 5 minutes. The resulting precipitate is collected, washed with ethyl acetate and dried to obtain the sodium salt of 0.13195X) as a yellow solid.

'H-NMIt (DtO) Pptn<δ): 1.5
G (#, 3H), 1.60 (a, 3H), 4.23 (
a, IH), 5.90 (d.

IH, J=IHz), 7.1-&O (鵠, 4H),
&57(m,1Ii)-1,1-dioxo-6(#)-(1-oxo-2-1,
1-dioxo-6(J)-(2-pyridyl)methylenepenicillane IC10G! , 0.286 mmol) in methylene chloride (5d) was diluted with meta-chloroperbenzoic acid (1
201IQ, 0.59 mmol) and stirred at room temperature for 3 days. A saturated aqueous sodium thiosulfate solution was added to the mixture to stop the reaction, and the mixture was extracted with methylene chloride. The organic layer was neutralized with a saturated aqueous sodium hydrogen carbonate solution, dried, and concentrated.
82 m9 of yellow oil are obtained.

Dilute the yellow oil with silica gel column chroma dog 2fee.
Elution with ethyl acetate yields the title compound of 22119 (219) and a by-product of 14 da (13X), 1.1-
Dioxo-6(A')-(1-oxo-2-pyridyl)methylenepenisilane 92.3-epoxypropyl is obtained.

1.1-dioxo-6(J)-(1-oquino-2-pyridyl)methyl/allyl benicilate: "H-NMR (C
DCIs)F pi(δn 1.5<s, 3Hha1J3
(a, aH), 4.45 (d, IH), 4.7 (d
.

2H), 5.1-6.0 Cm, 3H), 5.8 (a
, IH), 7l-84 (pseudo, 5H) Compounds having the following structural formula can also be obtained by hydrolyzing the appropriate allyl ester by the method of Example 1O.

Potassium 2-ethylhexanoate is used in place of sodium 2-ethylhexanoate to obtain potassium salts corresponding to each of the above structural formulas.

Bh isomer yield (,96)HOCH,
(Al') 53 2-quinolyl (J) 76 rhochloro (E) 862-pyridyl (a, 3ff), 4.24 (8, 1H), 4.30C
dd, 2K), 5.75 (s, IH), 7.20
(d, 1ff);”H-NMRC250MHz, DME
O) ppm (δ): Infrared absorption spectrum <KBr)
cIr': 1619,'l 771.3437"H-NMR (250MHz, DMsO) pp
tn (δ): 1.56 (s, 3B), L64 (t, 3H
), 4a4 (g.

1ff), 6.18 (a, IH), 7.45-8
．． 0 (normal, 4H); infrared absorption spectrum (KBr)C
11'':1624.1771,3433' H-NMR (250MHz -DtO) pP inertia (
δ): 1.52 (t.

7.65 7.75 (WL, LH) p Infrared absorption spectrum (KB de) 1:1629.1781.34
03 Example 1a A mixture of 2.4 mmol of chloride (methylthiomethylcotriphenylphosphonium chloride, 2.4 mmol of sodium amide) in anhydrous tetrahydrofuran (THE') (5-) is stirred at room temperature for 20 minutes. To the resulting yellow solution at -78°C was added 78859 (2.4 mmol) of 6-oxinobenicilane a!hibaloyloxymethyl in anhydrous THF (10 mg)! The mixture was stirred at -78°C for 1 min. After that, it was poured into a saturated ammonium chloride aqueous solution and extracted with ethyl acetate.The organic layer was dried (7
1/al,! 104) and the solvent was distilled off under reduced pressure, 744
Purify this product using silica gel column chromatography and elute with chloroform to obtain 2.
A pure product of 20# (24,5N) is obtained.

"H-NMRCCDCIs) 9p(Delta): 1.2
5 (a.

9H), 1.50 (a, 3ff), 1.65 (g
, 3H), 2.45 (A, 3B), 445 (a, lB)
, 6.85 (m, 3#), 7.0 (4,1ff).

215II9 (0,58 mmol) of 6 (A') −
Add 375q of (methylthiomethyl)methylenepenicillanate to a methylene chloride (5-) solution of pivaloyloxymethyl penicillanate.
(1.74 mmol, 3 equivalents) of 80% normal cuchloroperbenzoic acid. After the mixture was stirred at room temperature for 4 hours, water, a saturated aqueous sodium thiosulfate solution and sodium hydrogen carbonate were added to stop the reaction, and the mixture was extracted with chloroform.

The organic layer is washed with water three times, dried (Myom 4), and concentrated under reduced pressure to obtain a mixed product of 200 Da. The crude mixture was purified by silica gel column chromatography, eluted with a mixed solvent of chloroform-ethyl acetate (9:1), and 1-
Oxide (A) and 1,1-dioxide product (J) of 45I9 are obtained.

(A): Kame H-NMRtCDC, -7s) ppm (δ
): x, 21 (s.

9H), IJ (a, 3H), 1.7 (a, 3ff
), 3.1 (a, 3ff), 4.7 (s, iH)
, 5.8CAB q, 2K), 5.55 (4.1g)
,? , 1(d, 1f); infrared absorption spectrum CCHC
Is) am-”: 1333.1759.1807.2
927.2960° (J7: "H-NMR (CDCIs) j pi (δ n: l-2 (J a9H), 1.45 (a,
3H), 1.6 (a, 3H), 3.15 (a, 3
H), 4.5 (a, lH), 5.6° (d, IH
), 5.8(,4J q, 2H), 7.2(d, If
); Infrared absorption spectrum CCHCl5)C11-':
1324.1758.180G, 2929,2956°C allyl 6-altazpromo 1,1-dioxobenyl 22-functional allyl (520D, 1.48mmol) was dissolved in anhydrous tetrahydrofuran tTBF>10sd and heated to -78°C. Cool. Methylmagnesium bromide (0.52 mg,
2.85 molar THF solution) is added and the mixture is stirred for 5 minutes at -78°C.

N-methylpyrrole-2-carboxaldehyde (162
mg, 0.16 m) and continue stirring at -78°C for 20 minutes. The mixture was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic layer was dried (M g !l
04), the solvent was distilled off under reduced pressure to obtain 466 mg of a crude product, which was purified using silica gel chromadog 2 filter and eluted with a mixed solvent of chloroform-ethyl acetate (9:1) to give a concentration of 180 to 32%. ) to obtain the pure title compound.

Supervision H-NMR (C1) CIs) Pj' scratch (δn:
1.4 (a, 3B), 1.62 (a, 3H), 3.68
(#, 3B), 4.0-4.4 (wind, IH), 4.42
(#, lH), 4.5-4.8 (Fable.

3H), 5.0-6.0 (m, 4H), 6.0-
6.7 Lm, 3g>.

6-alpha CM-j tilvirol] human-oxymethyl-1,1-dioxopenicilane dispersion (180 Da,
0.47 mmol) with 3-tetrahydrofuran and 0.47 mmol).
Dissolve in 15m acetic anhydride and 0.21st pyridine.

Water is added to stop the reaction, and the mixture is extracted with ethyl acetate. The organic skin is dried and the solvent is distilled off under reduced pressure to give 162.mu. of material still containing the starting material. This was methine chloride y (3gg
Dissolve 0.15 g of acetyl chloride and 0.15 g of acetyl chloride.
Add 2- pyridine. The mixture is stirred for 2 hours at room temperature and treated as described above to give 140 ~ crude product.

Purified by column raftography, 72IR9<4z
Obtain a pure product of circle).

Recrystallization from ethyl acetate gives colorless needle-like crystals.

'H-NMRCCDCIs)' Ijt regret (δ): 1.4
5(1,3H), 1.65<8,3H), 3.7(s,
3g), 4.4 (a, 3H), 4.6-4.9
(m, 2H), 5.1-6.4 (m, 4H), 6.
6-7.0 (scratch, 2H), 7.5 (dd, 1M)
46M9's 6(J)-(#-methylvia-/l/-2-
A solution of allyl)methylene-1,1-dioxopenicillanate, 5J1g of tetrakis(triphenylphosphine)palladium(0), 4IIg of tri7ylphosphine, and 1-methylene chloride is stirred for 5 minutes under a stream of nitrogen. . The resulting mixture is diluted with IIIg of vinegar and ethyl acetate and 0.25-g of sodium 2-ethylhexanoate in ethyl acetate is added.

After stirring at room temperature for 1 hour, the mixture was filtered and the precipitate was washed with ethyl acetate and ethyl ether to obtain a yellow solid.

凰H-Null (DtO)F pt(δ)
1.50 (s, 3H), 1.60 (J, 3#), 3.6
5 (s, 3H), 4.10 (s.

IB), 5.4 (s, 17), 6.1-6.5 (m,
IH), 7.0 (a, IIA broad peak, 2H),
7.2-7.4 (tn.

lH); Infrared absorption spectrum (KBr) cf': 15
6B.

Example 1a 6-alpha (
Furan-2-yl)hydromethyl-1,1-dioxo-
Venicilla/l! In the bath solution of allyl methylene chloride, Q
, 14 sd (1 mmol) of triethylamine and O,
Add 1 m (0,924 mmol) of trifluoromethylsulfonyl chloride. The mixture was further stirred for 2 hours at a temperature of 100 ml of concentrated air. The reaction was stopped with water, extracted with methylene chloride, and the extract was dried (MgJ04), and the solvent was distilled off under reduced pressure to obtain a crude product of 33Q-9. Purification by silica gel chromatography and elution with chloroform gives a product of 130 Da. This product was confirmed by HP-LC to be a 4:1 mixture of (A') isomers.

'H-NMRLCD, C15)pp(δ): 1.47
(s, 3ff), 1.51 (n, 3ff), 4.47 1,1ff), 4.7SC4°2ff), 5.1-6.
2 (s, 4H), 5.52 (dd, if), 6.8
(m, IH), 7.15 (d, IH), 7.6Cd, I
H>Example 2α Allyl 6-(N-acetylpyrrol-2-yl)P-droxymethyl-1,1-dioquine penicillanate (210
JIg, 0.51 mmol) is dissolved in 3-tetrahydrofuran, and 0.16 g of acetic anhydride and 0.3 g of pyridine are added. The mixture is then stirred at room temperature for 24 hours. The reaction was stopped with water, extracted with methylene chloride, and the extract was dried. 1 to obtain 171 Da (75X) yellow crystals.

"H-NMECCDCIs)911mC delta): 1.
4 (s, 3H), 1.6 (a, 3f), 2.15
(s, 3ff), 2.55 (a.

3ff), 4.15-4.3 (dd, Iff),
4.4 (#, If), 4.6-4.8 (rinsing, 3
B), 5.1-6.0 (inertia, 3H), 6.1-6.6
(Ang, 2H), 5.5-7.4 (tn, 2H).

B5 N,O-diacetate product 1 obtained in part A
7 Dissolve GII9 (0,38i IJ solution) in methylene chloride and add 47# (0,38 mmol) of 1,5-diazabicyclo[4,3,O]non-5-ene (DBN). The mixture is stirred at room temperature for 1 hour. Water is added and the mixture is extracted with methylene chloride. Drying and concentrating the extract yields 158 I kg of oil. This product was subjected to silica gel column chromatography and eluted with dichloroform-ethyl acetate (9B:2).

The product 108II9 is obtained as a pale yellow oil.

H-NMRCCDCI, ) 119 (δ): 1.5 (g
, 3N), 1.6 (a, 3ff), L55 (+, 3ff
), 4.4 (s, 1ff), 4.65 (d, 2#), 5
．． 0-6.0 (Yu, 4B), 6.3 (t, 1#), 6
．． 8 (dd, IH), 7.2 (m, IH), 8.2
(d, 1#).

A, Example Part A method as described above using 1.98 mmol allyl 6-2enylhydroxymethyl-1,1-dioxypenicillanate, 4.2 mmol acetyl chloride and 0.4+d pyridi/ By applying 0.711C84
%) of allyl 6-fuynylacetoxymethyl-1,1-dioquinobenicila heptadate.

”H-NME (CDCIs) FF information (δ): 1.3
and 1-4 (j, 3ff), 1.12 (g, 3ff), 2
．． 08 and 2.2 (s, 3ff), 4.2 (dd, 1jr
), 44 (s, 1ff), 4.5 (d, 1ff), 4.
65 (d, 2ff), 6.25 (took, if), 7.3 (
m.

5H).

B, 0.25 m of the product of Part A (0.7, 9, 1,66 mmol) in methylene chloride! (1,67 milliJ
mol) of 1,5-diazabisipha(S,4.O)cundeca-5-ene (DBU) is added. The mixture is then stirred at room temperature for 10 minutes. Add water and methylene chloride, separate the two layers, and reduce the organic layer to 0.1 NjILa! , then wash with salt, water and water. Dry the extract (Nap!104
), the solvent is removed to obtain 660 m9 of crude product.

This product was purified by column chromatography packed with 1001 silica gel and eluted with chloroform.
The (f)-isomer of ~(IIN) is obtained.

"H-NMRCCDCIs)pptncδ): 1,45
(+, 3H), 1.60 (a, 3f), 4.45 (a+
IH), 4.68 (d.

2H), 5.37 (d, LH), &l-6.05 (t
n, 3#), 7.35 (4, 1ff), 7.45La
, 1#).

From the next elution, (E) of the title compound was obtained as a colorless oily substance.
- isomer 100Ik100I, 96)') obtained. If left alone, the main island will crystallize.

Otori H-NMRCCDCIs)pptn(δ): 1.4
5 (a, 3ff), 1.58 (a, 3ff), 4.45
(j, 1ff), 4.75 (d.

2M), 5.45 (d, 1ff), 5.2-6.2 (
s, 2H), 7.36Cd, IH), 7.45(#
, 5jr).

Example 22 The procedure of Example 19 is carried out using a compound having an appropriate water-degradable group selected from the compounds prepared in Example 18 to obtain the following compounds.

Example 2a The method of Example 17 was carried out using the esters prepared in Examples 19-22, allyl No. 6-8-methylene-1,1-dioxopenicillanate as starting materials (S.

The following sodium salts are obtained. Corresponding potassium salts c,
Example 23 obtained using potassium 2-ethylhexanoate-1
(continued: Infrared absorption BS isomer yield (X) spectrum (KB
r) (Kariu 4) (Kariu 4) if-NME (Ds0) pP (δ) 1.55 (t
, 3B), 1.60 (a, 3ff), 4.2 (s, LH
), 5.8 (8, 1ff), 7.0-7.9 (regular, 4
B) 1.59 (a, 3ff), 1.60 (a, 3ff), 4
．． 22 (s, 0.6M), 4.3 (s, 0
．． 4H), 5.53(a, 0.4H), 5.75(
a, 0.6ff), 5.5-62 (倶, 3H) 1.5 (a, 3M), L, S (s, 3B)
, 2.5 (s e3ff), 4.28 (a, 1ff)
, 6.05 (d, IH), 7.2-7.35 (倶, 2H
), 7.4 (d, LH), 767Ct, LH) "C-NME (DtO) 991n (δ): 20.
719.22.436.26.032.68.386.
6 g, 533.74.489.120.794.12
&334.132.843.14-0.670.152
．． 549.163.012.174.041.175.
657CDxO+DNS O): l-5(s,
3H), 1-6 (s e3H), 4.1 (s,
LH), 5.9 (d, If), 7.5 (d, I
ff), 8.5-9.0 (γn, 3Hn) Example 2 Allyl 6(E)-7 enylmethylene-1,1-dioquine penicillanate of 0.177 (0.28 mmol) of 1-dioxide, 2
To a 3d ethyl acetate solution of triphenylphosphine and tetrakis(triphenylphosphine) baladicum (O) of 019 is added 0.57 mg of 0.5 mole sodium 2-ethylhexanoate. The mixture is stirred at room temperature for 1 hour. After cooling for 65 hours, no precipitate is formed.

The mixture is diluted with ethyl inate and water, the separated aqueous layer is adjusted to pH 8 with dilute hydrochloric acid, and extracted with additional ethyl acetate. After drying the extract (Nα, SO,), the solvent was distilled off under reduced pressure to obtain 62519 (62519) as yellow crystals (recrystallized from a7ton).
9X) generation g! Get J.

'H-Null (CDs COCDs) j j
ML (δ): 1.55 CM, 3K), 1.65
(g, 3H), 4.43 (a, 1#), 5.93 (d
.

lH), 7.3-7.9 (chicken, 6B), 8-'I (b
a-1ff) pInfrared absorption spectrum CKEr)m
-': 1327.1685.1737.1772.
2929.61.3108.3477゜fruit 6 (z Methi soil A.

Allyl 6-(1-methylimidazol-2-yl)hydroxymethyl-1,1-dioquine penicillanate (472
mg, 1.23 mmol) is acetylated by the method of Example 20.14-)A to obtain 392 Da (75%) of the acetoxy compound as a mixture of two isomers.

' jr-Hull (CDCjs) j F@ (
δ): 1.4 (a, 1.51), 1.5 (a
, 1.5ff), 1.6 (x, LBH),
1.7 (s.

1ff), 2-2 (s, 3ff), 3.7 (a,
1.5jr), 3.75*, 1.5ff), 4.0-
6.0 (m, BM), 6.3-6.5 (m, 1f
), 66-8 (,1ff), ? , 0(m, lB).

8, 6 Allyl (J)-(1-methylimidazole-2-ioic acid) Product obtained in Part A above (3921Ig, 0J2
0 mmol), 51d of methine chloride/and 0.11
5d 1,5-diazabicyclo(4,3,0)non-5
-non-CDIN) by the method of Example 20, Part B and is converted to the title ester in a yield of 53 days.

'H-NMRLCDCIs)pptfLcδ): 1.5
(a, 3ff), 1.6 (a, 3ff), 3.7 (s
, 3ff), 4.35 (a, 1J included 4.7 (groove, 2
H), 5.0-6.1 (apprehension, 3H), 5.7 (d.

1ff), 6.9 (groove, IH), 7.1 (d, 1ff)
, 7.2 (groove, IH) C, allyl ester obtained in part B (163~,
0.45 mmol) in Example 17 using the corresponding potassium salt instead of sodium 2-ethylhexanoate.
It is converted to the title potassium salt using the method described in . The product is
Only the single (J) isomer was obtained, 143J9 (yield 879).

'H-NMRCDM! 10) ppfnc delta):
1.38 (s.

3H), 1.45 (a, 3H), 3.8Cs, 4
H), 5.68 (s, 1f), 7.15 (a, LH),
7-35 (tn, 2H) + Tsuta”C-NMR (DM
E O) p ptν1(δ): 18.5, 20.2
．． 32.5.64.4.66.2.70.55.115
．． 2.124.6.129.9.13G, 6,141.
2,167.9.169.0. Infrared absorption spectrum C
KBde)cIL-Otori: 1614.1762.3428 Example 2a Example 1O using 50 mg (0.12 mmol) of allyl 6-(3-allyloxy-2-pyridyl)methylene-1,1-dioquine penicilane Repeat the process of 5.24 triphenylphosphine, 5.2j9 tetrakis(triphenylphosphine)palladium (and α24 mmol potassium 2-ethylhexanoate (starting material), molar equivalent)
A solution of 1.5-ethyl acetate was added to reduce the reaction mixture to 18
After stirring for an hour, remove the ethyl acetate with a pipette and wash the residue with two 1 m portions of ethyl acetate to obtain a dark solid. Honjima was found to be the dipotassium salt of 6(J)-(3-w droxy-2-pyridyl)methylene-1,1-dioxopenicilane.

”H-NMRCDtO)99%<Delta): 1.56(
s, 3jr), 1.62 (#, 3ff), 4.27 (8
, 1ff), 6.00 (d.

1ff), 7.29 (Raku, 2B), 7.80 (d, 1f
f), &04Cd, IH).

Example 2? 6U)-(2-pyrimidinyl)methylenepenicillanic acid allyl 2-hydroxymethylpyrimidine 7.44.1323 mmol) and 30
A suspension of sodium chloride in sodium ether prepared from anhydrous ethanol was cooled to room temperature and mixed with 18!1 (163 mmol) of hydroxyacedoazidine hydrochloride for 8.06 s.
d (151 mmol) of 3-dimethylamino-acrolein are added and the mixture is heated to reflux. The dimethylamine is distilled off while adding ethanol until the amount of solvent is reached.

After refluxing for 9 hours, the mixture is further stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, and the residue was applied to a silica gel column and eluted with a mixed solvent of ethyl acetate-methanol (19:1) to obtain a product of 4.11 (yield: 46X).

Sphonium 2-hydroxymethylpyrimidine 4.096.9 (37
, 2 mmA/) was dissolved in 80 d of methylene chloride, and 8
．． 6 gIt (37.2 mmol) of thionyl chloride are added dropwise. (Rapid reaction) The mixture is stirred for 15 minutes, neutralized with saturated aqueous sodium bicarbonate solution and extracted with methylene chloride. After drying the extract, the solvent is distilled off to obtain 2-chloromethylpyrimidine 3.67.9.

"H-NMR (CDCIj) P9flL (δ): 4.8
2 (a, 2ff), 7J (t, 1ff), 8.9 (d,
2f) A solution of 3.5651 (27.7 mmol) of 2-chloromethylpyrimidine in 30 toluene and 7.26
A mixture of triphenylphosphine of 9, p (27,7 mSoles) is heated under reflux for 18 hours. The resulting precipitate was removed from F and dried. 9.06. p (yield in two steps is 6556).

C0 Wittg reagent of 2,187, p (5,6 mmol) obtained in Part B above, 2.1849 (i5.3
2 mmol) of sodium amide and 30-mg of anhydrous tetrahydrofuran (THF) were stirred at room temperature for 5 minutes.

Pour into saturated aqueous heptammonium chloride solution and extract with chloroform. The organic layer was washed with a saturated aqueous ammonium chloride solution and then with brine, dried (MσSO,), and the solvent was distilled off under reduced pressure. The resulting oil was eluted with silica gel column chromatography using a mixed solvent of WIIH and ethyl acetate-chloroform (9:1) to obtain a pure product of 560 Da.

"H-NMR (CDCIs) pPWLCa): 1-5
(a, 3ff), 1.6 (j, 3H), 46(
a', Lff), 4.7 (n, 2K), 5.1-6.3
(yx, 3ff), 6.2 (d, Iff),
7.0 (!

iH), 7.0-7.35 (inertia, IK), 8.8 (d
, 2H) Allyl 6(E)-(2-pyrimidyl)-methylenepenicillanate (560 Da, 1.69 mmol) and 3-chloroperbenzoic acid R730 Da (3,38 mmol) in 10- Water is added to the reaction mixture, which is dissolved in methylene chloride and stirred for 4 hours under nitrogen flow, and extracted with methylene chloride. The extract was washed with aqueous sodium thiosulfate solution,
After neutralization with saturated sodium bicarbonate, the mixture was washed with brine, dried, and concentrated under reduced pressure to obtain a crude oil with a weight of 460 Da. The oil was purified by silica gel column chromatography using Wag 9.
Elution with :1 of chloroform-ethyl acetate yields 180 m9 of the desired allyl ester as a pale yellow solid.

”g-yxx(cncls)ppnShukuδ)21.45
(J, 3ff), 1.650* m 3 H), 4.
5 (a, if), 4.75 (m.

2K), 5.2-6.3 (s, 3K), 5.75 (
J, 1ff), 7.1-7.5 (sad, 2H), 8.9
(4,2ff)B, when the above 7') ester is reacted with tri7enylphosphine, tetrakis(triphenylphosphine)palladium(0) and potassium 2-ethylhexanoate by the method of Example 10, a pale yellow color is obtained. The desired potassium salt is obtained as a solidified product with a yield of 89X.

"H-NMR (D, 0) ppm (delta): L6 (s,
3ff), IJ8 (#, 3ff), 4.4 (#, IH)
, 6.1 (j, 1ff), 7.48 (s, 1ff
), 7.54 (t, Iff), a, as(d.

2H): "C-NMR (D, 0)pp(delta): 20-
9.22.7.68.8.68.9.74.6.124
．． 5.132.5.139.9.160.9,163.
2,172.5°175.5 Infrared absorption spectrum CKBr>cm-”: 1560.1615.1771.
3439゜Example 21 Le 1. To a solution of OjL 6-alphahydroxypenicillanic acid in 25-methylene chloride is added 50M9 diisopropylcarbodiimide and 0.5-2,2-trichloroethanol. After stirring the mixture overnight, the solvent was distilled off under reduced pressure, and the crude product was purified by silica gel column chromatography 2E to obtain 6-alpha-droxypenisilane powder 2,2.2-)rifsugaloethyl.

B. A solution of 1.0 J of 6-alpha-hydroxypenicillanic acid in 50 sd of dioxane with p-
Toluenesulfonic acid and 0.14.9 of dihydropyran are added and the mixture is warmed to 50°C. Distill the solvent,
Sla by silica gel column chromatography, 6-
Alpha hydroxypenicillanic acid 2-tetrahytomipyran is obtained.

To a solution of 1.8 m (0.025 mol) of dimethyl sulfoxide in 2 methylene chloride, a solution of anhydrous trifluoroacetic acid powder in 5 m of methylene chloride is added dropwise at -60°C. The mixture was stirred at -60°C for 20 minutes, a solution of 350 Da (1,14 m7) of benzyl 6-alpha-hydroxypenicillanate in 5-methylene chloride was added, and the mixture was stirred at -60°C for 60 minutes.
Continue stirring for a minute. Triethylamine (0.50 m) is added, the cooling bath is removed and the mixture is brought back to 0° C., then poured into ice water and extracted with methine chloride/. The organic layer is dried and reduced to a small volume under reduced pressure. The concentrated solution was then diluted with benzene and washed three times with ice water. The benzene layer was dried, the solvent was distilled off under reduced pressure, and 230 mg (
67X) is obtained. Proton NME spectrum (
CDC4) revealed that raw fi+ has high purity.

Benzyl acid 9-0! 1 (0.02 mol) of benzyl 6,6-dibromopenicilane is dissolved in 200 °C of freshly distilled toluene and cooled to -78°C. Then, a pentane solution of tertiary butyl lithium equivalent to 2.2 moles of 9- was added dropwise.

The mixture was stirred for 30 minutes and added 2.14 JF (
0.02 mol) of 2-pyridine-carboxinaldehyde was added, and after further stirring for 40 minutes, the cooling bath was removed and the reaction mixture was returned to -10°C and diluted with 200°C of toluene.
Wash with water (5 times) and dry (NalSO4). The toluene solution was packed into a fluorosil column (1#) and eluted with a mixed solvent of toluene and ethyl acetate (2:1). The combined eluted portions of the product were distilled off under reduced pressure until a brown syrup was obtained. Use it in the next step.

B. Brown syrup obtained in part A (4,21
1) 850 sd nohe 7 seytc dissolved, Z65y
of tributyltin hydride is added. The mixture was heated under reflux for 2 hours and further added with tributyltin hydride (1,65,9
) and then continue heating to reflux overnight. The solvent was distilled off under reduced pressure, and the residue was washed with hexane and packed into a 500 yen silica gel column, and toluene-acetate ether (2:
Elution with a mixed solvent of 1) yields 425 mg of the title compound.

"H-NMRCCDCIs)P'lJ倶(δ):L35
C8,3H), 1.7 (a, 3H), 4.0 (d
d, 11.4.5 (s, 1#), 5.1 (8,
2H), 5.2 (d, If), 5.4 (d
, IH), 7.0-7.8 (Raku, 3H), 8.5 (Kan,
IH) in a solution of 0.40II of benzyl 6-(2-pyridyl)-hydroxymethylpenicillanate in methylene chloride,
0.2011 h-chloroperbenzoic acid is added and the mixture is stirred at room temperature for 1 hour. The mixture was identified by thin layer chromatography to contain several sulfoxides. An additional 0.21 g of air-chloride perbenzoate a is added and the mixture is further stirred overnight. The mixture is diluted with methylene chloride and washed successively with saturated aqueous sodium thiosulfate solution, water, and saturated aqueous sodium hydrocarbon solution. The organic layer is then concentrated under reduced pressure. Dissolve the residue with ethyl vinegar,
Wash with sodium bicarbonate wash, water and saline;
Dry (NalSO4). The solvent was distilled off to obtain the desired benzyl ester 330I9 as a brown oil.

The main island was purified by silica gel column chromatography,
Elution with a mixed solvent of ethyl acetate-hexane (11:9) gives 60 mg of a yellow oil.

“H-NMII(CDC)s) pp Satori(δ): 1.25
(g, 3H), L52 (J, 3ff), 41 (dd,
If), 4.5 (a +1ff), 4.72 (d,
i#n, 5.5 (d, 2H), 5.8 (d, 1ff)
, 7.1-8.0 (m, 3H), 8.5 (m.

IH).

1. In a mixed solvent of 10-tetrahydrofuran (T, H,!, ) and 4d water, 10% palladium-
The carbon catalyst is suspended and pre-hydrogenated for 20 minutes at 3 atmospheres of hydrogen pressure. Add to this the 1 obtained in Bart A above.
Add 30 IIg of benzyl ester and add 50 pat
(Hydrogenate for 30 minutes at 3.5 Kmlcm.
Add 2919 palladium on carbon and continue hydrogenating at 50 psi for 2 hours. The catalyst was separated from F, the solvent was distilled off under reduced pressure, and the residue was partitioned between water and ethyl acetate. Freeze-drying the aqueous layer yields the desired 85I9.

"H-NMECD, 0) ppm (δ): 1.3 (g, 3
ff), 1.5 (a, 3ff), 4.4 (a, I
H), 5.0-5.35 (T1%.

2H), Fh9Cd, 111); Infrared absorption spectrum (KBr)cst-': 1620.1731
．． 3407C, par) In the method of A, using a total amount of 175 to (equimolar amount) of metaku μ-perbenzoic acid,
When the above procedure is carried out, the product separated is a mixture of alpha and beta sulfoxides.

Example 3a The following ingredients are mixed to obtain a powder of uniform composition in the weight ratios shown below.

(6) Ampicillin trihydrate 1m h
.

(C) Lactose α5
The mixture (1375M9) is filled into appropriately sized capsules to obtain capsules with 250 ag potency of each active ingredient. If preparing capsules of higher or lower potency, over-adjusting the capsule size or filling amount. If obtaining capsules with a weight ratio of active ingredients different from 1, the relative Prepare the appropriate weight. For example, the above component classes are 0.75.1.5.0.5 and 3, respectively.
．． When mixed to a weight ratio of 0 and filled with 170011g,
(Obtain capsules with a titer of 225η for (L) and a titer of 4509 for (6).

In a similar manner, other β-lactamase inhibitors of the present invention can be used in combination with other commercially available β-lactamase inhibitors used in oral preparations.
-Prescribe with lactam antibiotics. In addition, in the above formulation, component (- and component (63% 6-(2-pyridyl)methylene-1,1-dioxobenicilla 7-(D-(2-
-Amino-2-phenylacetamide)] Prepared by replacing the number of penicillanoyloxymethyl salts with twice the amount.

Example 34 Preparation of Injection Equal weights of hepphalosporin sodium and potassium 1,1-dioxo-6(E)-(2-pyrazinyl)methylenepenicillanate were combined with 20 times the amount of water per weight.

The solution is sterilized using common methods in pharmaceutical technology.
Fill with NF, fill into a vial, and loosen the vial.
'Do A&. Then, the vial is lyophilized on a tray and the vial is stoppered under vacuum. Freeze-dried vials are s
The amount of oollg containing each active ingredient is the filling amount. Prior to injection, add 10 d of sterile water for injection to each vial through a rubber i& and shake until dissolved. The 1-10 d of injection solution required for the injection is collected through a rubber stopper using a hypodermic needle.

0-511 (1-29 mmol) of 6-(2-thiazolyl)hydroxydimethyl-1,1-dioquinosialyl dispersion (prepared in Example 18) and 0.396 fI
(3,88 mmol) of acetic anhydride and 0.307 g
Acetylation is carried out by the method of Example 20, Part A of 5d (3.88 mmol) of pyridine in t% tetrahydrofuran. The mixture was then diluted with methylene chloride and
After washing with water until the pH becomes neutral (pH 6.0-6.5), the solvent is distilled off to obtain the desired acetate of 0.688j'.

'HNMR (CDCl5) 9'ljmCδ1.5
2(t, 3H), t, 7o(a, 3ff), z, as(
j, aff), 4.4-4.6 (door, 2H), 4.6-
5.0 (corner, 3H), 5.2-6.4 (m, 3H),
a65 (d, IH), 7.4 (d, IB), 7.
8Cd, LH>.

The above acetoyl ester (0,68811, L29
29 mmol) and 0.16 g (1.29 mmol) of 1.
5-diazabifucro(4,3,0)-non-5-ene (
DBN) and 5d of methylene chloride and stirred at room temperature for 1 hour. The mixture was diluted with methylene chloride and washed with water (
After drying (NatSO4) and evaporation of the solvent, an oil is obtained. This was subjected to silica gel chromatography and eluted with a mixed solvent of ethyl acetate-hexane (1:1), yielding 0.189. f (39%) is obtained as a pale yellow oil.

'H-NMRCCDCIs) p9rnCδ): 1.5
3 (a, 3B), 1.65 (a, 3H), 4.3
3 (s, 3H), 4.55 (d.

2H), 5A-54 (door, 2H), &45 (g, IH)
, 5.4-5. Q(a, 1ff),? −1(s, lH
), 7.75 (m, xH), 7.65 (d, lH).

B. By the Part C method of Example 25, the allyl ester obtained above was hydrolyzed to give 6- as a yellow solid.
Allyl (2-thiazolyl)methylene-1<1-dioquine penicillanate 1 was obtained in a yield of 84.7%.

'H-NMR250MHzCDMSO-Da)99mC
δ): 1.40 (a, 3H), 1-45 (a, 3
H), 3.80 (a, IH), 5.83 (s, I
H), 7.66 (g, IH), 8.04 (H2
H).

6-I of 39.3.9' in chloroform of 膓-3QQag
J)-(2-amino-2-phenylacetamide)]y-7ranic acid trihydrate was added, and then 5o- water was added, and then a 40% aqueous solution of tetrabutylammonium hydroxide was added to dilute the mixture. Adjust to pHt-8.5. The two layers are separated and the aqueous layer is saturated with sodium sulfate and extracted with additional chloroform. The extract and the first chloroform layer are combined and concentrated until the total amount of solvent is about 250 Mt.

To this solution are added 150-methyl acetoacetate and 301 anhydrous magnesium sulfate. After the mixture is heated to reflux for 3 hours, a precipitate forms when the mixture is allowed to stand. Then, take the supernatant liquid of the heated organic layer. The clear loloform solution is left under cooling to obtain crystals of the title compound in a yield of 52%. The melting point of this product is 182-184℃ (decomposed).

'H-NMR (CDC/A) pF fi (, δ):
0-8-2.0 (yIL, 4H), 1-88 (j, 3H
), 3-1-3-6 (m, 8H), 3.6 (s
, 3H), 44-17 (, lH), 44-58 (.

iH), 5.05 (d, IH), &38-5.6 (shoulder,
2ffi, 6.78 (d, 1ff), 7.35 (a
, 5H), 9.4 (d.

IH).

Example 38 4L9JiF 6-(2
-Amino-2-(4-ζ-drokycuphenyl]acetamide)-e disila/acid trihydrate and 50 m of water were added, and 40
pH using % tetrabutylammonium hydroxide aqueous solution
8.5Kv14 verses. Separate into three layers, take the top layer, saturate with sodium sulfate, and then extract with dichloromethane. Combine the extract with the middle layer and lower layer,
The mixture is concentrated under reduced pressure to obtain an oil, which crystallizes when added dropwise to the product. This crystal is 44
．． 61 of 6-(2-amino-2-[4-hydroxyphenyl]acetamido)-penicillanic acid tetrabutylammonicum salt is obtained.

The above salt is added to 150 mj of methyl acetoacetate and the suspension is heated at about 65° C. until a clear solution is obtained (8 minutes). The mixture is allowed to cool, and then the solidified material is removed.

The solidified product was washed with methyl acetoacetate and then with diethyl ether.49.2! 6-(2-(1-methyl-2-
Methoxycarbonylvinylamino)-2-(4-hydroxyphenyl]acetamido)-e dilanic acid tetrabutylammonium salt is obtained.

300 Da (0.79 mmol) of ethyl acetate of the first eluting isomer of allyl 6-alpha(pyrimidin-2-yl)human Q-oxymethyl-1°1-dioquine penicillanate (obtained in Example 18) 4m solution K, 309 tetrakis(triphenylphosphine)palladium<0>
and 309 triphenylphosphine. The mixture was stirred under a stream of nitrogen until the reagents were dissolved, at 1.57 d (0
, 79 mmol and 17 mol) of potassium 2-ethylhexanoate in ethyl acetate. After stirring at room temperature for 20 minutes, the mixture was t-filtered, the slurry was washed with ethyl acetate, dried,
Obtain 53 mg of a yellow solid. The F solution is treated with ethyl acetate to precipitate the second product 152. Yield in full view is 69
%.

'H-NMR, 250MHz, CDMSO-dJ'19
rnc'): 1.33 (s, 3H), 1.44 (a, 3
H), 3.77 (s.

IH), 3.95 (d or d, J-2, J-6,
IH), 4.89 (d, J-2, 1H), 5.1 (d
, J 謬6, 'LH), 6.33(s, IH),
7.48 (t, J-4, 1H), 8.84 (d
, J proverb 4.2H).

A solution of the second leached isomer of allyl 6-alpha(pyrimidin-2-yl)hydroxymethyl-1゜1-dioquininisilane (obtained in Example 18) in aOO* (α 79 mmol) was added as above. Treated in the same manner as the procedure, the potassium salt 236J! p (79%).

'HNMR* 250 MHg, CDuSQ-d
s) pF TrL(δ): 1.30 (s, 3
H), 1.42 (g, 3B), 3.65 (s.

IH), 4.60 (dd, J Snow 2, J-8
, xH), 475 (d, J cod 2.IH), 5.15 (d
,, /-8, iB), 7.47(t, J飄4.1M>,
8.85Cd, J-4, 2H).

The first eluting isomer of 6-alpha(pyridi/-2-yl)human axymethyl-1,1-diogysopenicilla/allylic acid (obtained in Example 1B) of 785η (obtained in Example 1B) was dissolved in methylene chloride 4d and this solution , 0.45au (5
, 6 mmol) of viridi/ and 0.53 lj (5.6 mmol) of acetic anhydride are added. Then mix the mixture at room temperature 2
．． Stir for 5 hours. The mixture is diluted with 3014 methylene chloride, extracted with water (LC7X60Jlj), dried over anhydrous magnesium sulfate, and filtered. Distilled under reduced pressure, 813J
v (92%) of the title compound.

"H-NMRCCDCIs)zz+m(a):1.4(
s, 3H), 1.6 (s, 3H), 2.2 (s
, 3H), 4.45 (s, 3B), 4.45
(dd, LH), 4.75 (m, 2H), 4.95 (d
, IH), 5.2-5.6 (m, 2H), 5.7-6.
3 (1rL, 1ff), 6.45 (d, IH), 7.3
5 (t, IH), 8.85 (d, IH) - KJ of allyl 6-alpha(pyrimidi:/-2-yl)hydroxymethyl-1,1-dioxopenicillanate
The isomer B (obtained in Example 18) is acetylated by the pearl method to obtain the title compound in a yield of 88%.

'H-NMR (CDCjig) pT)2F1 (
δ)? 1.4 (s, 3H), 1.6 (a, 3H), 4.
45 (a, iH), 4.50 (dd.

J-1, J-8, 1ff), 4.75 (door, 2H),
4.8Cd,! -1,1H), 5.25-5.6 (m
, 2H), 5.7-6.3 (rfL, IH), 6
．． 4 (d, J-8, lH), 7.35 (t,, 7
-6, IH), s, s (ct, /-6, xH)-
A solution of allyl (6-alpha, 8S)-6-(pyrimidinol-2-yl)acetoxymethyl-1,1-dioquinoinisilanate 789Iv (L86 mmol) in ethyl acetate 4- was reacted according to the procedure of Example 54. and 34219(
The target potassium salt (43%) was obtained and the assembled MPL
C" and eluted with a mixed solvent of water-acetonitrile (9:l) to obtain iosmg product (85% purity by HPLC analysis) (6-alpha, 8B)-6-(pyrimidine) -2-yl)acetoxymethyl-1,1-dioxoinisila/allyl acid 666η (1,57 mmol) was reacted using the same procedure to obtain a crude product of 339IIJi (51%).Assembling this product The product was purified by MPLC' method and eluted with a mixed solvent of water-acetonitrile (9:1) to obtain single isomers of 162~.

'HNMR-250MHz, CDMSOdo)
pp7K (δ): 1.34 (a, 3ff), 1.44 (
g, 3H), 2.17 (g.

3H), 3.65 (#, iH), 4.15 (dd, J-
2゜J-8, IH), 4.95 (d, J■2.i
H), 6.27 (d, J-8, IH), 7.50 (t,
J■5.1H), 8.85 (d, J proverb 5.2H)
.

MPLC is medium-performance liquid chromatography HPLC is high-performance liquid chromatography Example 42 6-B'''- of the appropriate starting material obtained in Example 18
The method of Example 20 or 25 is carried out using CHoH-substituted-1,1-dioquininini-7lanic acid ester to obtain the following acetic acid esters.

Example 43 The 8-acetoxy-3-carbonyloxyallyl esters obtained in Examples 25A and 57 are converted into potassium salts of the following structural formula by the method of Example 54.

C6,C.

818 x-body chemistry Yield C56) C5a (C8s is monooctadecylsilane) Ka”H
-NMII (DME O-46) 31 voices (δ): 1
．． 3 (s, 2.IH), 1.34 (s, 0
．． 9H), 1.42 (s, 3ff), 2.13 (a
, 0.9H), 2.2 (s.

2, IH), 3-66 (a, o-7ff), 3.7
(8, 0, 3H), 4.1 (dd, 0.3H), 4
．． 95Cd, 0.7H), 5.07(d, 0.3K
), 6.24<d, 0.3H), 6.36(4,0,7
ff), 8.7 (a, 2H), 8.8 (8.

0.7 H), 8.83 (a, 0.3ff) IE (HE
D) 2 3468, 1781, 1746.1623
Uses cIrl ram.

Example 44 The 8-acetoxy esters obtained above and below are converted into the corresponding 6-methylene compounds by the method of Example 20, Part B, and then the allyl group is removed by the method of Example 54, resulting in the following structural formula: potassium salt (R1 is potassium)
is obtained.

M” Yield (%) “H-NMR (CD
Cl5) LPy;), (d 2B), 5.30 (#, iH), 5° (Tai・2M), 6.00 (倶, lff7.10 (a,
1ff), 7.5 (ss3H), &02 (j, 0.5
H), 8.25 (usually 2H), L87 (sO,5H) A is a l=1 mixture of E and 2 isomers 8, 42 E isomer only 1.53 (1,3ff), 1,63 (
s, 3H), 4.3 (a * 50 IH), 5.7 (s, 1
ff), ), 7.2 (a
, IH), 7.4-8.0 (m, 5M), 8.7 (s, iff) R1 = = allyl R1 yield α) ”H-NMR (CDCIs) p
Voice (δ): (ffi family 5.3
1-5.44 (inertia, 2H), 5.74 Meiji 6BB)
(s, lE8, 87-6.0
1 (K, IB), 7.59 (4, 1#), 8.76 (s
, IH) (raw material (a, 1ff), 5.
80-6.02 Example 68B)
(Wound, IH), 7.38-7.42 (Jō.

2H), 871 (m, IH) Infrared absorption spectrum: 1795 cm-'' R1=Potassium Example 58 1.55 (g, 3ff), 165 corresponding compound <8,3H), 4.35 (a.

By-products IH), 5.12 (d, LH), 7.52td, IH), 7.68
(d, IH), 8.85 (inert.

1ff), 92 (inertia, IH) 39 (yellow side 1.38 (a, 3B), 1fi40
compound) <s, 3H), 419 (a.

if), 5.92 (J, 1ff), 7.76 (J, IH), 9.13 (s, 1ff) Infrared absorption spectrum: μr) 1775.1620 150 (MP: 1.40 (a, 3H), 1.48
LP isomer (s, 3H), 4.20 (s.

The ratio is 1ff), 5.91 (a, 1ff).

3.5:1) 7.40-7.60 (apprehension, 2M)
.

8.89 C%, Iff) Infrared absorption spectrum 03 de) = 1760.1610 1 R1 = Allyl Bs Yield "4 (36) ' H-
NME (CDCl5) Fpf7L (S: CM,
(m, 2H), s, a
4-546 (K, 2H), 5.65 (s, lH
), &0 (IH), 7.16 (a.

1ff), 7.34 (a, 1H) Infrared absorption spectrum: 1790.1760, 1680aa-'] Example 18-8 5.45 (m, 2H)
, 5.96-6.02R1=potassium 84 1.38 (s, 3H), 1.46 (a, 3
H), 2.33 (s.

3B), 4.16 (g, lH), 5.89 (J, 1ff), 7.3 Ca, lH), 7.46 (Jl.

1ff) Common line absorption spectrum (KA Den: 1773. 1683.1619 儂-1 20 Infrared absorption spectrum: 1780, l 625cf - R1 = Allyl R8 Yield C%) "H-NMR (CDCIs
) ppm (δ): 5.46 (normal, 2H), 5.62
(s.

Lff), 5.80-6.92 (employment.

1ff), 7.32 (s, IH) infrared absorption spectrum: 1805 cm-"R1±potassium"H-NMR (D, 0 or harvest (X) da-acetone) 2% (S: 58
1.42 (s, 3ff), 1.48 (a, 3H
), 2.52 (11.

3H), 425 (#, LH), 5.87 (#, 1ff), 7.18 (a, IH) Infrared absorption spectrum (KEr): 1785aa-' Example 45 141aFC0.38 mmol) of 6-(imidazole) -2-yl)hydroxymethyl-xax-dioxoinisila7! ! ! Allyl [isomer mixture obtained in Example 18], 1219 tetrakis(triphenylphosphine)palladium(0), 121 Ig of triphenylphosphine, 0.76 id (0.38 mmol) of potassium 2-ethyl-hexanoate and The mixture of 2d and ethyl acetate is stirred under nitrogen for 1 hour. The precipitated product was purified to obtain a yellow solid containing 143 Mg (100%).The main island was analyzed by high performance liquid chromatography and found to contain two types of isomers. Infrared absorption spectrum (KBr)
: 3382.1780.1728 and 1615CI
+-'.

A solution of 17.7 jl (44 mmol) of 6-alphabromo-1,1-dioquine heptalanic acid-free hydrofuran 250 was mixed with an equimolar amount of tilmagnesium and 7.
After reacting at 8° C. and stirring for 1 minute, equimolar amounts of thiazole-2-carpoxalde ζ are added and stirring is continued for 10 minutes. After adding a further equimolar amount of acetic acid and stirring for 5 minutes, the mixture was poured into 500 g of water. Extracted with ethyl acetate, washed the extract with water and dried (MgSO4).
The solvent was distilled off under reduced pressure to obtain 16.93 g (89%) of a crude product. This product was purified by silica gel column chromatography and eluted with chloroform/ethyl acetate. 2.
98#, a less polar isomer and a mixture of o, sy isomers are obtained.

(Overall yield 43%).

More polar isomers: 'H-NMR (CDCIs
) F jl rIL('): 1-25(a, 3H)
, 1.55(j, 3H), 4iH), 4.45(a, I
H), 465 (6g.

4.9 (d, lB), &2 (WL, 2H), a55H)
, 7.35 (rPL, 6H), 7.75 (d, 1
E).

Less polar isomers: 'HNMR (CDCIs) pp
R (δ): 1.2 (a, 3H), R5 (a, 3H), 4
．． 35 (m, 2H), 4.75 (d, IH), &1 (chicken, 2H), 5.55 (d, LH), 7.2 (milk, 6H)
), 7.6(d, Iff).

20; On a remolar scale, 6-ark-arp spider-1,1
- The above procedure was repeated using diphenylmethyl sobenisilanate in silica gel column chromatography, and chloroform/ethyl acetate (9
: Elute with a mixed solvent of 1) to obtain a less polar isomer (CLP) of 2.464JF and a more polar isomer (MP) of 3, o29N.

More polar isomer: 凰H-NMR (CDCIa)
j t m (δ): 1.06 (g, 3H), 1.52 (
g, 3H), 4. l-4-3C111, 1ff), 4.
42 (s, Iff), 4.76 (d.

1ff), &45 (d, IH), 6.82 (a,
iH), 15-R3 (vortex, 11#), 7.56 (d,
LH)-less polar isomer: Otori H-1vMR (CDC
15) j 71% (δ): 1.2 (s, 3H), R65
(s, 3H), 435 (dd, 1ff), 455 (a,
IH), 4.83 (d, 1H), 5.65 (dd
, IH), 6.95(a, IH), 7.2-7.4 (
n%, if), 7.75 (d, 1ff) -, m
An appropriate acid chloride or an acid anhydride corresponding to the acid chloride having the 4U structural formula gtct, and an appropriate 6-R1''- obtained above.
CHoH-substituted-1*1- sit*7'3-
Example 20 near f-) using y y7w1 ester
Following the AO method, compounds of the following formula are obtained.

11<ノE' R” R”
Stereo I of C@ C,H,CH,2-thiazolyl C,HIC(J)
(obtained from the more polar 8-hydroxy compound of 5f Example 6L4) C8) obtained) (R) obtained from the more polar isomer) -Q7chi-
S: 1.3 (t, 3H), '1.4Ca, IB)
, 1.65 (#, 1ff), zss (q.

2H), 4.5 (s, 1ff), 4.4-4.6 (m,
1ff), 485 (d, Lff), 5.27 (a,
2H), 6.65 (d.

If), '1.35<m, 6B), 7.75(d, 1
f) L2SCa, 3H), R3(t, 3H)% 1.75(
#, 3ff), 4.24 (9°2H), 4.36-46
0 (m, LM), 4.55 (a, 1ff), 5
．． 02Cd.

1ff), 6A3Cd, IH), 6.95(s, Iff
), 7.1-7.5 (tn, 1lff), ? 75(
d, 1ff) Pink, solidified object R (B Ru R
18 (GM,) Stereochemistry of C8 in HUB “H-NME (CDC1m)P
Voice (δ): ts) 14cm, zxn),
L5 (8, 0,9H), +1.6 (a, 2.1
H), 1.65 (8.

(R) o, 9m), 44 (a, 0.
1H), 45 (0, 3H), 4.5-5.0 C inertia, 4
B), 5.1-6.2 (Repentance, 3H), 6.9 (d
, if), 7.4 (m, 177), 7.8 (d,
If) (S) 1.37 (m, 3K
), L50 (m, 3ff), low polarity yield 1.6
5 (y, 3ff), 1.82 (8, 3H), 22,%
2.70 (as, IH), 4.61
(s, 1ff), 4.7 (m, lK), 4.9tf
n, 2H), s, x2 (d, IH), 5.41 (倶,
Iff), 5Jha, 1ff), 5.8-6.5 (m
elB), 6.75 (d, 14), 7.6 (d.

Lff), 7.97 (d, tg) (72) 1.18 (m, 3H), 1
．． 28 (m, 3ff), high polarity yield 1.33 (
a, 3ff), 1.52 (g, IH), 41.5%
2.6 (regret, IB), 4.3-4.7 (ina, 5H), 5-0-5.4 (tn, 2B), 5.
45-6.2 (horse, IB), 6.47 (d, If
f), 7.23 (d, 1ff), 7.63 (d, IH)
Rα 318 B
Audience C6H, CM, 2-thiazolyl C,X
ICC8 stereochemistry “H-NMRCCDCIs
) 1% (δ): (S) 1.4 (a, 3
#), 1.6 (a, 3H), low polarity 4
．． 5(s, IB), 4.4-4.6 <K.

if), 5.1 (d, IH), 5.2 (a).

2H), 6.7Cd, LH)1. ．． 7.2-8.2 (scratches, 12ff) (A)! , 3 ($, 3H), 1.
6 (s, 3H), highly polar 4.5 (a
, IH), 4.6 (dd, IH), 4.86 (d,
Lff), &2(g, 2ff), 6.85(d, IB)
, 7.3-7.7 (m *9H), '1.8td, I
H), 8.15tdd, 2H) Practical IM Example 48 10% of 1,89g dissolved in a mixed solvent of 20at/tetrahytomifuran (THF>) and water at 9Nia (V/F)
The palladium-carbon catalyst mixture was saturated with hydrogen and 13
6898v (1,
4 mmol) of (6-alpha,8R)-6-(thiazol-2-yl)propionyloxymethyl-1,1-
Add a solution of benzyl dioquine penicillanate. After hydrogenating the reaction mixture at 3 atmospheres for 20 minutes, the catalyst is separated by F,
Extract the P solution with ethyl acetate (axzood) L;, dry the extract with C MgSO4>, distill off the solvent under reduced pressure, and
A yellow solid of 30 cm was obtained.

Perform the above procedure using the corresponding benzyl ester,
The title compound ft is obtained in a yield of 57%.

"H-NMR (Ha's pp Todoroki ('): 1.38 (s
, 3H), 1.55 (#, 3H), 425 (s
, IH), 4.44 (dd.

IH), 5.05 (d, 17/), 6.68 (d, IH
), 7.4 (t, 7H), 7.55 (t, l/)
, 7.58 (d.

If),? , 7 (d, IH), 7.95 (d,
IH), infrared absorption spectrum (KEr): 3473.
1782.1729.1622CI+-Otori.

557■ ((L954 mmol) of (6-alpha, 8
S)-6-(thiazol-2-yl)ethoxycarbonyloxymethyl-1,1-dioquine (α62M (&72
Add millimoles of anisole. The mixture is cooled to -5° and a mixture of 382 η (2,86 mmol) of anhydrous aluminum chloride and 2d of nitromethane is slowly added over a period of 15 minutes. The reaction mixture is diluted with ethyl acetate and water is added to adjust the pH to 7.5.

The aqueous layer is separated, acidified to pH 3, and extracted with ethyl acetate. The flaky crystal residue from which the solvent can be distilled off is dissolved in ethyl ether, filtered, and hexane is added to Solution F until a precipitate is formed. After removing F and drying, 21119 (53%)
of the product is obtained.

'H-NMR, 300MHz, (CDCIs) ppm
(δ): 1,4G (t, 3H), 1.53 (s
, 3H), 1.67 (#, 3Hχ4.28-4.42
(expletive, 3H), 450 (a, IH), 4.92←5t
iH), &58 (d, lH), 7.53 (d.

1ff), 7.93 (d, lH). Infrared absorption spectrum (ABr): No. 34 3.1797.1754cv-'
.

B. Applying the above procedure to the (6-alpha, SR>n-type gold) of the diphenylmethyl ester obtained in Example 62 as a starting material, 6-(thiazol-2-yl)ethoxycarbonyloxymethyl-1゜l - The (6-alpha, 8R)-isomer of dioquine penicillanic acid is obtained.

“HNMR, 300MHz, (CDCIs)ptm
4-2-4.4 (m, 3H), 4.44 (g, LH)
, 5.04 (j.

lH), 6.67 (d, IH), 7.53 (d, lH)
, 7.90 (t, xH), infrared absorption spectrum (KEr): 3418.1803.1750 Example 50 The method of Example 60 using the appropriate allyl ester obtained in Example 62 as a starting material to obtain the corresponding potassium salts.

Example 51 8.8411 (20 mmol) of 6.6-dipromo 1
．． A 100 d anhydrous tetrahydrofuran solution of allyl 1-dioxopenicillanate was cooled to -78°C, and 7.02 d
After adding methylmagnesium bromide (C20 mmol), the mixture is stirred for 5 minutes.

A solution of 226Ii (2G mmol) in thiazole-2-carboxaldehyde dissolved in 101Lt of the same solvent was added to
Add at 8°C. The reaction mixture is then stirred for 20 minutes.

After adding vinegar* (L2jllj), the mixture is poured into water and extracted with ethyl acetate and chloroform. The organic layers were combined and dried (JVax S Qa) L% The solvent was distilled off under reduced pressure to obtain 8.5 Jl of flaky crude product.
, 89:11 chloroform-ethyl acetate mixture fI
Elution with ItlE gave a pure product of 6.2 JF (72%), indicating that the main island was a single isomer.

If-NMRCCDCI@) p9 chicken (δ): 1
．． 4 (a, yo), 1.6 (8, 3H), 4.0C
ba, IH), 4.42 (a.

1ff), 4.6 (4, 2ff), 5.3 (a,
Lff), 5.55 (g, IH), 61-6.3 (Shizu,
3H), 7.35 (d.

IJf), 7.75 (d, 1ff).

In the above operation, instead of the allyl ester, s, s-
Using benzyl x,x-dioquine heptalanate, the title compound is obtained quantitatively as an orange foam.

'H-NMRCCDCJb)jlj'l'(')
:1.32 (a, 3B), 1.60 (1,3#
), 4.5 (a, 2H), 5.2-&8 (fi.

4H), 7.3 (d, 1ff), 7.4 (a, 5
H), 7.8 (d.

If).

C. The following compounds are similarly obtained by the Part AO procedure.

Example 52 Acylation of the compounds obtained in the previous examples by the method of Examples 57 or 62 similarly yields the following compounds.

C6 Another compound in the above structural formula is prepared by following the method of Example 66.

That is, the method is the following common method of acylating the reaction mixture before separating the products.

A solution of 1.0 equivalent jl of 6,6-dipromoinisilane acid ester in tetrahydrochloride was cooled to -78°C, and 1 to 3 equivalents of methylmadanequum bromide dissolved in the same solvent were added. The mixture is stirred for 5-10 minutes. Then 1.3 equivalents of the appropriate aldehyde (R"CHO) are dissolved in the same solvent and added at a temperature ranging from -78 °C to -68 °C. The reaction mixture is then stirred for 30-60 minutes. Stir. Add acetyl chloride from 1.3 beans and continue stirring at -78°C for 10 minutes. Ethyl acetate is extracted from the separated product by pouring it into ice water, and after drying, the solvent is distilled off under reduced pressure.

Here, E” is B5 B 13 in case of CHsCo
Grass harvest (Sembenzil C, H,
100 CHs CH.

*H-NME(CDC)s)ppm(δ):Light''; 5(s-s3B), L56(s, 3K), 2.22
(s.

3), 4.42Ca, LH), 4.69-4.74C
tin.

Go), 5.24-5.42 C%, 3ff), 5
．． 79-5.96-s, IH), 6-52(s, 1ff
), 7.32-7.34 Go, IH), 8.70-8.7
4 (d, iff) Thin line absorption spectrum, tor: 18
101.1760cm', 2ts, aH), 1.62(
s, 3ff), 2.28 (j #3), 2.48Cs
, 3B), 4.5 (s, IH), Ra 48 (m,
2ff), &28-&47 (m, 2H), 32-6
．． 0 (tn, 1K), 6.3 (s, ljn, 6.9
7M # 1ff) External absorption spectrum: 1810.1760.730cx
t” 5(i, 3H), x, 8cs, 3H), 2.2 (a
*Go), 2.3 (s, 6ff), 4.4 (Jl,
If), 5.2go, 2H), 5.3(a, 1ff),
6.4 (a, 1ff), '13 (s, 5K) 16 B 1j Yield (X)''H
-NME (CDCIs) PP inertia (δ): 1.22 (g,
3f), 1.5(a, Lff), 2・18Cs, 3H)
, 2.42 (t, 3ff), 45 (a.

If), 5.16-5.36 (Chinese, 3H), 6.1
8 (s, IH), 6.48 (#, Iff), Z 4
(a w5H) L26 (#, 3ff), L5 (a, 3M), 2.2
(s, 3B), 2.4Cs, 3M), 4.4 (a *
Iff), 5.16 (d, 2B), 5.3 (s, IH)
, 6.6 (Jl, 1ff), 6.8Ca, LH)
, 7.3Cs, 5H) 1.40C1, 3ff), 1.60 (a, 3ff), 2
．． 27 (a, 3H), 2.65 (s, 3H),
420-4,8 (inertia, 3H), 5.1-6.2 (door,
4H), 6.41 (8,1ff) Infrared absorption spectrum: 1815,1760 6-promo 6-(thiazol-2-yl)acetoxymethyl-1,1 of Example 53 Njiru 74.1F (134 mmol) 43.9977 (151.2 mmol) of tri-butyltin hydride are added to the benzyl 850d solution of benzyl dioxopenicillanate. The mixture is heated under reflux for 5.54 hours and then heated overnight. The solvent was distilled off under reduced pressure, and the residue was dissolved in hexane and extracted with acetonitrile. (2
x250m) The acetonitrile layer was distilled off, and the residue was dissolved in ethyl ether Kll! The mixture is made cloudy, separated, and the cake is washed with ether to give 33.28N colorless crystals. When liquid F is concentrated to dryness, 2.81 is obtained. Dissolve the residue in benzene and add 10f of trimethyltin hydride. The mixture is refluxed for 1 hour and processed as the first crop was obtained; total yield is 56.
3%.

The above first product was subjected to silica gel column chromatography and eluted with a mixed solvent of chloroform-ethyl acetate (9:1). Concentrate the eluate of the product and convert it into an ethyl ether-ethyl acetate (4:1) mixed solvent! ! Make it muddy, V
It was taken and washed with ether to obtain a white solid of 22.6jF.

” H-NME (CDCIs) j) j m (
δ): 1.25 (g, 3H), 1.53 (a, 3H)%
2.1 (a, 3H), 4.58 (j.

IH), 4JO (d, lf), 5.2 (dd, lB),
s, 2z (a, zff), fi, 75 (d, iH), 7
．． 35 (g.

sH), 7.4 (d, 1#), 7.8 (d,
if),”C-NMECCDCla)j)jWL
(δ): 17.7.19.9.20.5.54.5.6
3.03.63.6.63.8.64.5.68.1.
121.8.128.8.128.9.134.3.1
Compounds of the formula 42.6.1646.1665.16&2.17α5°80 are obtained in the same manner by debromination of the neat compound tubes obtained in Example 67.

R, B 13 Collection vehicle (X) 195.5℃ ”H-NMR (CDCIs) pp(δ): 1.44C
8,3f), 1.62 (#, 3ff), 2.10Ca,
3H), 4.51 (s, Iff), 4.60-4.80
(Ya, 2B), 4g9-491 (d, 1ff), 5.2
6-5.42 (appreciation, 3H), 5.86-5.99 (appreciation, IH), 6.88-6.92 (d, 1ff),
8.82 (s, 1ff) infrared absorption spectrum: 179
5.1750MP isomer: 5.84-6.00(m,
IH), 6.28-6.42 (爲, 2H), 6.62
-6.77 (d, 1ff), 7.38-7.48
(d, 1ff), 8.64-&70 (d.

IH) White aryataLg infrared absorption spectrum (KEr): 1807.1760cm' x, 46 (a, 3ff), L64 (1,3H), 2.1
4 (s, 3H), 2.48 (s, 3H), 4.5
(s, IM), 446-49(,3H), &2-
&26 (dd, IH), 5.3-5.6 (regular, 2H
), 5.86-6.1 (K, IH), 6.7td, I
H), 7.0 (a, 1ff) Infrared absorption spectrum: 1810, 1760 cIf"1.3 (a, 3
H), 1.58 (a, 3H), 2.12 (a, 3ff)
, 2.36 (d, 6H), 4.5 (a, If)
, 4.75Cd, IH), 5.2-5.4 (dd,
3H), 6.6(d, 1#), 74Ca, 5H)
Juo7Rα E”Yield)Mixture”H-NMRCCDCIs)pp? FL(δ):1.
28 (a, 3H), L55 (s, 3H), 2.1
(II.

3H), 2.4 (a, 3H), 4.5 (8, 1
H), 4.8 (dd, LH), Fuzs (q, ig), 6
．． 15 (s.

IH), 6.5 (d, IH), 7.4 (s,
5H) 1.3 (a, :lf), 1.58 (g, 3ff
), 2.14 (t.

3H), 2.48 (s, 3H), 4.52 (8, If
), 4.8 (d, iH), 5.16-5.36
(AB qmrtet or dd, 3H), 6.7 (
d, Iff), 7.0 < s *1ff), 7.
4 (s, 5H) 1.37-1.40 (d, 3H), 1.58-1
．． 60 (d.

3H), Z12-2.14 (d, 3H), 2.58
(a.

3H), 4.48 (a, LH), 4.58-4.
88 (door, 4H), 5.24-5.46 (m, 2
H), 5.82-6.00 (hired, lH), 6.64-6
．． 67 (d, α75H), 7.05-7.08 (d
, 0.25H) Infrared absorption spectrum: 1810,1
765d" Example 54 A. The benzyl ester obtained above was hydrogenated by the method of Example 63 using a palladium □mu carbon catalyst to produce the corresponding carboxylic acid with the following structural formula where Hb is H. Convert to

R” R” Yi’! -(X
)”H-NMEtDMSO-d・orDtO)p voice (δ): (D20) L45 (s, 3f), 1.57
(a, 3B), 2.15 (g, 3ff), 4.33 (a
, lH), 5.24(d, LHha 475-&2(,-
-1ff D, blocked by 0 peak), 6
．． 55 (d, 1ff), &65-&8 (apprehension, 2H
) Infrared absorption spectrum ([Br): 3416.1
785.1618cf””C-NME: l 7.6.
19.8.20.4.54.4.64.1.65.7.
68.1.144.2.145.2.145.5.15
1.2.172.7. ．． 172.81.48 (Jl, 3
ff), 1.55 (s, 3H), 2.15 (a
.

66 (d, lf) Infrared absorption spectrum CKB de): 1787.1626
．． 161 Bar'' 1.48 (a, 3f), 1.6 (s, 3M), 2
．． 2 (s, 3H), 246C8, 3H), 4.3
5 (s, IK), 5.2 (d, iH), 1
．． 5 (s, 3#), 1.6 (s, 3 pieces),
2.2 C11, 3H), 2.45 (8, 3ff), 4
．． 35(a, 1ff), 4.9Cdd.

LH), 5.25<d, LH), 6.7(d, IK
763 (a, LH) Infrared absorption spectrum k (
KBr): 1787.1657.1626α-1 B, converting the 6-beta-(thiazol-2-yl)acetoxy mesol-1,1-dioquinopenicilanic acid obtained in Part A above into the corresponding potassium salt. The method consists of suspending the acid in aqueous solution, treating it with an equimolar amount of potassium bicarbonate eluted in water, and purifying it by medium-speed liquid chromatography using a C1 column, eluting with acetonitrile water. The corresponding potassium salt is obtained in yield.

Otori H-NMRCDMEO-da)'II F@(δ)
:L37(s, 3H), 1.48(J, 3H), 2
．． 07 (a, 3H”), &8゜(a, 1#), 4
52 (dd, lH), &12 (d, IH), 6J5 (d
, IB), 289 (m, 2H), infrared absorption spectrum &
(KBr): 3454.1788.163°CI4-1
゜mine CI is 400 Da (0.91 mmol) of octadecylsilane compound isomer mixture 6-(benzothia/-
α15 (L82 mmol) was added to a 5d aqueous solution of di-2-yl)acetoΦdimethyl-1,1-dioxopenicillanic acid.
After adding an aqueous solution of sodium bicarbonate (2117), the mixture is stirred for 2 hours. Reaction mixture (pH 7
, 55) is freeze-dried.

Take the freeze-dried product in 8-water and adjust the pH to 3 with dilute hydrochloric acid.
5 and extracted with ethyl acetate, the organic layer was dried (M
gSO4) and evaporate the solvent under reduced pressure.

The reaction product was identified by NMR spectral analysis and was found to be (A
') and (Z) isomers in a ratio of 60:40.

"HNMR (CDCjs)j9mCδ): 1.55 (#
, 1.2H), 1.6 (a, 1.8H), 1.6
5 (#, 1.2H), 1.67 (a.

1,8H), 4.55 (s, 0.6H), 4.
58 (a, α4H), 5.38 (a, 0.4
H), 5.74 (j, 0.6H), 7.44 (a,
(L4H), 7.48 (#, 0.6H), 7.5 (m
, 4H), 7.89 (d, IH), 8.07 (
d, 0.4H), 8.15 (d, 0.6H).

&6-R"-CH(OAa)-substituted-1,l-dioquine penicillanic acid obtained above was treated in the same manner to obtain a mixture of (A') and CZ) isomers of compounds with the following structural formula. obtain.

(//am) ') m compound 435 (#, l
H)% 5.7 (#, 0.6H), L95 (a, 0-4H), 7.26 (a, 0.6H), 7.55 (a, 0.4H), 8.09 (s , 2ff)-9619 (0.2 mmol) with allyl 7methyl-1,1-dioxoinisilanate (obtained in Example 67) in 6-promo-6-(thiazol-2-yl)acetate,
The reaction is carried out for 1° according to the method of Example 6o and worked up as described to give a yellow solidified product of 46η (48%).

Otori H-NMRCDtQ) ptnc δ): 1.45 (s
, 3H), 1.6 (s, Lff), 4.4 (z
, IH), 5.55 (8, IH), 6.85 (a
, IH), 7.72(d, IH), 7.86Cd, lH
).

Similarly to potassium acid, 220η of 6-promo-6-(thiazole-2
Allyl) hydroxymethyl-1,1-dioquine penicillanate (obtained in Example 66) was reacted for 20 minutes by the above method to obtain the title salt as a pale yellow solid with a yield of 52%.

”HNMRCDME Oda) p31- (δ)
:1.35 (a, 3H), 1.47 (a, 3H), 3.
75 (#, 0.4H), 3.83 (g, 0.6H), 5
．． 3 (d, 0.4H), 5.32 (d, 0.
6H), 5.45 (a, 0.6H), 5.5 (
a'+0.4H), 7.6-8.0 (rn, 2#
), infrared absorption spectrum (Kflr): 3442,
1794, 1633z-”.

A 150 d solution of allyl 6.6-dipromoiniglyate in anhydrous tetrahydrocufuran (1 unit - 9,97111C24,99 mmol) of potassium hydroxymethyl disilyl acid was cooled to -78°C under a nitrogen stream, and 2. 8.77 m of methylmagnesium bromide THF solution equivalent to 85 mol (
24.99 mmol) is added and the mixture is stirred for 15 minutes. A solution of thiazole-2-carboxaldehyde (24,99 mmol) in 5 ml of THF is added to the solution and the mixture is again stirred at -78 DEG C. for 20 minutes. 1.
The reaction is stopped by the addition of 43 M (2499 mmol) glacial acetic acid and the mixture is stirred for 10 minutes. After that, leave it to return to room temperature. 1. Next, pour into water, extract with ethyl acetate 2 x 259 m, wash the extract with water (2 x 250 m), and dry CM t.
i 5 () 4 ) and the solvent is distilled off under reduced pressure, lα3
An orange oil of 6I is obtained. This oil was purified by silica gel column chromatography, eluted with a mixed solvent of chloroform-ethyl acetate (9:1), and a yellow solid of 4.51 (isomer mixture) and only the more polar isomer were obtained. A yellow foam is obtained α4431. (Overall yield 46%).

Yellow foam @:”H-NMR (CDC1*) pptlL
(δ): L56 (a, 3H), 1.76 (J, 3H),
4.60 (a.

XH), 47 (m, 2H), 49-6.4 (m, 6H)
, 7.45 (s, iH), 7.8 (m, IH), the more polar isomer obtained in part A, 2204 (
0.462 mmol) was dissolved in 1d of benzene and 0.462 mmol) was dissolved in 1d of benzene.
A solution of 18117 (0,693 mmol, 1.5 eq.) hydrogenated tri-butylsf in benzene is added. The mixture is heated to reflux for 3 hours and left at room temperature overnight. The solvent was distilled off under reduced pressure, the residue was dissolved in acetonitrile, washed with hexane, concentrated to a small volume, and diluted with
The adsorbent was placed on a licagel column and eluted with chloroform to obtain 73 m9 (45%) of the desired product.

'B-NMR<CDCl5) ppm(J):'L6
5(a, 3H).

L87 (j, 3H), 3.8-4.4 (m, tH), 4
．． 05-4.3Cdd, LH>, 4.65(a, IH)
, 4.78 (+yL, 2B), 5.3-5.6 (m
, 2H), 5.6-6.3 (m, 3H), 7.45 (
m, IH), y, 5s (R, boxed.

C, 73 Da (α206 mmol) of the product obtained in Part B is converted to the potassium salt by the method of Example 60 (thus) to give the title compound as a yellow solid, ss* (80%).

"H-NMR, 300MHz, (DIO)ppm (δ)
: L36(+.

3ff), 1.55 (j, 3ff), 4.13 (dd,
iH), 4.18 (z, LH), 5.32 (d,
1ff), 5.41 (d.

lH), 7.56 (d, IH), 7.60 (d, IH)
Example 58 In the procedure of Part A of Example 72, thiazole-2
- an appropriate aldehyde in place of carboxaldehyde, R''
Using CHO, the corresponding compounds having the following structural formulas are similarly obtained.

Example 58 (Continued) B. Deprophylaxis of the above compounds by the method of Example 72, Part B provides the following compounds.

Example 58 (continued) C2 The allyl ester obtained above is reacted by the method of Example 60 to obtain the following potassium salts.

B Nishiki Pickup Car (X) C: Violent Stereochemistry “H-NMRCDMSO-ds) 22% (a): L
47 (8,3ff), 1.58 (s, 3g), 3.79
(a.

1ff), 4.13 (dd, 1ff), 5.2 (d, I
ff), 5.4(d, 1ff), Fs,, 95(b
s, IH), 7.45 (11H), 7.60 (t
, 2H), 8.03 (d, 2ff), 8.16 (#
, lffn 1.48 (s, 3ff), 1.67 (a, 3ff), 4
．． 27 (dofd, J = 4 atwl 1
0, IK), 4.3Ca, IH), 5.45(d,
, r=4, IB), 5.57(d, J=lo.

1ff), 7.45-7.65 (inertia, 2H), 8.0
4 (t.

Ct, J=8.2H) IRCKEr): 3424.1765.1746.15
92〆1 1.42 (s, 3ff), L56C8, 3H), 4.1
6 (a.

iH), 4.25 (d of d, J=4
and 8, 1H), 546Cd, J=4. IH)
, 5.5 (d, J=8.1ff), 7.4-7.6 (
7.8-&05(倶,2H)↓Preparation Example A A solution of 150d of 6-chloro-2-picoline chloride metele of 5.1g (40 mmol) of Cyto(,8,625JF (40 mmol)) 80% iso-chloroperbenzoic acid is added and the mixture is stirred at room temperature for 15 hours.

A saturated aqueous sodium thiosulfate solution of α5d was added to stop the reaction, and the pH was adjusted to 75 with an aqueous sodium bicarbonate solution. After washing the organic layer with water and drying (Nα!5O4), the solvent is distilled off to obtain 4.84.9 N-oxide.

'H-NMRCCDCnos)ppmcδ): 2.6(a
, 3H), 7.0-8.0on, 3H).

(ii) A solution of the above N-oxide (4.810.035 mol of 6-chloro0-2-acetoxymethylpyridine) in acetic anhydride of 15 M is heated at 100° C. for 1 hour. After that, it was distilled off under reduced pressure, b, 9.125-128℃ (0.7mH
g) 2.39190 of the desired product is obtained as a colorless oil.

01D6-chloro-2-pyridylmethanol part (1
) in 1011 Lt of 2N hydrochloric acid at 70°C.
Hydrolysis for 1 hour, then neutralization (C&C05), extraction with chloroform, drying and distilling off the solvent will result in 1.
This product, which yields 87jl of crude alcohol, is purified by silica gel column chromatography to obtain pure stomach of α9821.

"HNMR (CDC1a) FP island (δ): 4-8 (a,
2H), 5.3 (bs, lH), 7.0-7.8 (
m, 3H) -(]V) 6-chloro0-2-chloromethylpyridine 6-chloroa-2-pyridylmethanol, α982/l (6,84 mmol) of methylene chloride <10t> solution in 0.814 Ij of thionyl chloride at room temperature for 1 hour. The mixture was neutralized with aqueous sodium bicarbonate solution, extracted with methylene chloride, the extract was dried and the solvent was distilled off to give 815 da of product as colorless crystals.

'HNMR (CDCAs) ppm (δ): 4.7 (g
, 2H), 7.1-&O (conduct, 3H), M Wit t reagents are par) 815Iv (5 mmol) of the product obtained in (iv) and 3.5L of LaI
(5 mmol) of triphenylphosphine otoluene (
10-) and heating the mixture under reflux for 6 hours. The precipitated product was collected by F and IJ68y (6
5%) of the title compound is obtained.

'H-NMR (DMSO)-Tj 11 m (δ)
:L5 (g, Iff), 5.8 (s, IH), 7
．． 2-8.2Cm, 18H).

Using 2-methyl-4-methoxypyridine-1-oxide (2.1 g) as a starting material according to the procedure in part (il), 2-acetoxymesol-4-methoxypyridine of 2.1 is obtained. On the main island, a mixture containing about 25% of 5-acetoxy-2-methyl-4-methoxypyridine was prepared at 1.11%.
Dissolve in methanol (10v) containing 8f (20.7 mmol) of sodium methoxide and reflux with stirring for 1 hour. Methanol is distilled off under reduced pressure, the residue is diluted with water, and after neutralization with dilute hydrochloric acid. , extracted with chloroform. The organic layer was washed with brine and dried under reduced pressure after drying with CMrtSO4.
ix then 85311Q < 41%) (F) 2-:F
ooxymethyl-4-methoxypyridine is obtained.

'HNMRCCDCIs)rJpm<'):3-9(s
, 3H), 4.72 (j, 2H), 5.35 (6a, I
H), 6.7 (dd.

iH), 6.95 (d, iH), 8.3 (d, IH).

The methyl hydroxide compound obtained above was added to the above par) (I
Convert to 210 lometel-4-methoxypyridine using method V) to obtain 0.895 Jl (5,68 mm→)
This product is reacted with an equimolar amount of triphenylphosphine toluene solution (10M) under reflux for 20 hours. The precipitated product was filtered to obtain 860 ml of the title compound as a yellow solid.

A solution of triphenylphosphine containing 2-riowIffkdt/sy&261cO-035 mol) and 5L201I (α035 mol) in 80 ml of toluene is heated under reflux for 3 hours. The precipitated solidified product is collected by F and dried under reduced pressure to obtain a product of 3.5.1F (23%) as a brown solidified product.

1.43 g of lysine (462 mmol) of metallic sodium and 100
Sodium methoxide prepared from methanol in d; after adding 5.9 g (31 mmol) of 3-human axy-2-hydroxymethylpyridine to the methanol mixture;
Remove methanol under reduced pressure. The resulting residue was dissolved in 80 mg of dimethyl sulfoxide (DMSO) and then 3. A 20t DMSO solution of Od allyl bromide is added dropwise over a period of 20 minutes at room temperature. The mixture is stirred for 2 hours, TDMSO is distilled off under reduced pressure, and the resulting residue is partitioned into a chloroform-water mixed solvent. The aqueous layer is adjusted to eH 7.5 and extracted three times with chloroform.

The organic layers were combined, washed with water and brine, dried, and (H
a, So, ), concentrated, 3.481! (68%) of the desired ester form was obtained.

A solution of the product obtained in Zin Part A (3,43 L, 20.8 mmol) in 20 m of methylene chloride was added to 1.5 equivalents (t) of methylene chloride.
Sd) and thionyl chloride, and the mixture was heated under a nitrogen stream for 2 hours.
Stir for an hour. The volatiles are removed under reduced pressure and the residue is partitioned between methylene chloride and water. Adjust the aqueous layer to pH 7.5,
Extract with additional methylene chloride. The extracts were combined, washed with water and brine, dried (N6tSO4), and the solvent was distilled off under reduced pressure to obtain 3.28 g (86%) of the desired product, which was used in the next step. .

Product obtained in OiD part (I) (3.28 g, 1
7.9 mmol) was dissolved in 30117 toluene y,
．． 69 g (17,9 mmol) of triphenylphosphine are added. The mixture is refluxed under stirring for 3 hours. When the product was collected and washed with toluene, &8951 (49%
) to obtain the desired Wit t ig reagent.

Allyl lanate (1) 6-alpha-bromopenicillanic acid 1.1-
Dioxide 20.26 II (α517 mol) of 6,6-dipromopenicillanic acid 1,1-dioxide is suspended in 8011 t of water, and 1310.155 mol) of sodium bicarbonate is added little by little. Then 6-76 g of sodium thiosulfate (
'0.062 mol) is added in portions and the resulting mixture is stirred for 35 minutes and diluted with ethyl acetate. After washing the organic layer with brine and drying (Na2SO4), the solvent was distilled off under reduced pressure. When chloroform was added to the residue, crushed finely and treated with P, a pale yellow solidified product was obtained.6.72. ? get. Concentrate the F solution, treat the residue with chloroform, and add 3
．． 21 products are obtained.

(a) °Initial material obtained above & 352g
In a solution of 20 g of dimethylformamide, 1.76 m (
2α3 mmol) of allyl bromide, 2.83 m(20,3
(mmol) of triethylamine and 0.2.9' of sodium bicarbonate are added and the mixture is stirred at room temperature under nitrogen for 15 hours. Water was added, the mixture was extracted with ethyl ether, the extract was washed with water and dried (Nat S 04
) After that, the solvent is distilled off under reduced pressure to obtain the desired ester as an oily substance.

'H-NMR (CDCIs) 214 m (δ)
:1.4 (#, 3H), 1.6 (s, 3H),'
4.4 (s, IH), 4.6 (d, xH
>, 4.7 (d, zH), s, xs (d, xH), 5.
1-5.9 (n%, 3H)- (iii) Allyl 6.6-dibromopenicillanate α41
Esterification of 6°6-dibromopenicillanic acid by the procedure described above was carried out on a scale of 7 mol, yielding 140 g as an oil.
(84%) of allyl ester is obtained.

'HNMR (CDCis) 9 'II door (δ):
1.5 (a, 3H), 1.65 (1, 3ff), 4.6
(a, LH), 4.75 (m.

2H), 5.3-5J (m, 2H), &85 (g
, IH), 5.8-6.3 (m, IH).

Production example E Nitachi-50I! 1-methylimidazole and 3 of 10011t
7% formaldehyde (special grade, specific gravity Lo8') (r:)
Place the mixture in a stainless steel container (300 m);
Heat at 150°C (bath temperature) for 17 hours. Cool the container on ice,
The mixture was taken out and concentrated under reduced pressure, and the resulting residue was evaporated overnight.
Leave at ℃. The resulting mixture of crystals and oil is filtered and washed with ethyl acetate. The colorless crystals are dried under reduced pressure to yield 14.60 Il of product. Reprocess the mother liquor to obtain a second crystal of 6.48.9'. Total yield 21.01 (31%) (li) 2 of 4.96 jl (43.9 mmol)
- To a 59 m solution of human axymethyl-1-methylimidazole in dioxane was added 490 JF (44,1 mmol) of selenium dioxide and the mixture was stirred for 5 minutes at 85-90°C, then for 36 hours at room temperature and 85°C at 85°C. Stir for 15 hours and finally at room temperature for 15 hours. treating the reaction mixture with F;
When the solvent was distilled off under reduced pressure, a crude aldehyde of 4.811 was obtained.
The product 2.111 is obtained as colorless crystals of Hg).

Manufacturing example F.

6-methylpyridi/dissolved in 50sLt methanol
-2-carboxaldehyde (0.44 mmol) at 20
．． Using 6 mmol of sodium borohydride, O-
Reduce at 5°C. After the reduction is complete, the mixture is neutralized with 2N sulfuric acid (pH 7.5) and treated with F. Concentrate solution F and partition between chloroform and water.

3.22. The solvent of the organic layer was distilled off to form an oily substance. ! A product of 9 was obtained and used in the next step.

GiD 3,22Ii oil obtained in part (I), triphenylphosphine 5.91, is dissolved in 30d toluene and heated to reflux for 4 hours. When the precipitate is collected, a brown solidified substance is obtained as &9311 Wi t t
Obtain the i g reagent.

Production Example G 2-pyrazinylmethyltriphenylphosphonicum chloride (1) 2-hydroxymethylpyrazine 11.29. f (79.2 mmol) of 2-pyrazinecarbonyl chloride (obtained by treatment with the corresponding 2-carboxylic acid t1 molar excess of thionyl chloride at reflux temperature) is dissolved in 1001 of tetrahydrofuran and cooled to -78 °C, z,
52.6 mmol of lithium aluminum hydride (95% pure) is added in small portions over a period of 20 minutes. Stir for t-10 minutes during mixing and leave to return to room temperature. 2
The reaction is quenched by adding M sodium hydroxide, filtered and washed with methanol. The F solution was distilled off under reduced pressure, and 4.1
2 g of a dark solid was obtained and used in the next step.

(it) The above dark solidified product (4,12y, 37.
8 mmol) was dissolved in MedeleyK chloride and 2.8jlj
of thionyl chloride is added at 0°C. After the mixture was warmed to room temperature and stirred for 30 minutes, water was added to neutralize the mixture and extracted with methylene chloride to obtain 2.2911 as a yellow oil.
It was used in the next step.

(b) Dissolve the above oil, Z29jl, in 49d of toluene, add 4.70jF of triphenylphosphine,
The mixture is refluxed for 3 hours. When treated in a conventional manner, a shun reagent with Wi t of 1.9911 is obtained as a brown solidified substance.

Preparation Example H A solution of 4-formylpyrimidine (7 4-methylpyrimidine:/C101,0,106 mmol) in lQQMt dioxane is heated at room temperature with 11.8 fI of selenium difluoride, and the mixture is heated at 100° C. for 15 hours. Furthermore, add 2.5jl of selenium dioxide,
After continued heating for 1 hour, the mixture is cooled and filtered, and the cake is washed with ethyl acetate.

The solvent is distilled off from the solution F and the washing solution under reduced pressure until dry. The residual dark oil is dissolved in methylene chloride, filtered and the solvent is evaporated. The residue is recrystallized from a small amount of methylene chloride to obtain the title aldehyde.

'HNMR (CDCIs)' II pa (δ) near, 8
7 (dd, IH), &06 (d, IH), 9.43 (d
, IH), 1.0.0 (s.

IH).

31.21 (α1
6-alphapromo-1,1-dioquininisilane acid (mol) is added in small portions over a period of 30 minutes. The mixture was stirred for 1 hour, the solvent was evaporated and the residue was dissolved in ethyl acetate (s
ollt).

Ethyl ether (400M) is added and the resulting mixture is left at 4°C. No crystals are formed after 18 hours. The ff11 compound was subjected to flk condensation under reduced pressure, and S L2g
A yellow solid was obtained, and the main island was subjected to silica gel chromatography and eluted with chloroform to obtain a colorless product in the form of flakes.

"H--NMR (CDC1m) PPM (δ): 1.26
(g, 3H), 1.57 (g, 3H), 4.55 (#,
IH), 4.70 (d.

1H), 5.13(d, iH), s, s (s, I
H), 7.27 (g, xoH).

Production Example J Benzothiazole-2-carboxaldehyde 250d was added to tetrahydromifuran freshly distilled (b, p, s z ℃
, 2 toll) benzothiazole (10, p, 0.074
mol) and cooled to −78° C. in a nitrogen stream. Further, stir at this temperature for 15 minutes. 29.611J for this
(α074 mol) of 2.5 mol loop chillithium t-
Add dropwise over 15 minutes and continue stirring for an additional 25 minutes. Then &6d (0,111 mol) of dimethylformamide was added.

Stir the reaction mixture for 1 hour. The mixture is allowed to return to room temperature, zooy ice is added, and the solvent is distilled off under reduced pressure.

The aqueous residue was diluted with ethyl acetate (5X Zo.

After drying the extract with C&gSQ4), it was concentrated to a small amount, subjected to silica gel column chromatography, and eluted with a mixed solvent of chloroform-ethyl acetate (96:4). 8.4 g of the desired aldehyde compound having a temperature of 74.5-75°C is obtained.

"H-NMR (CDCIs) p31m (δ) near, 54
(WL, 2B), 7.97 (m, IH), 8.21 (s
+s, 17/), 1.01 (g.

IH).

The following aldehydes are prepared in the same manner as above.

-99 raw materials Aldehyde yield (%)
) 4f-IH-1,2,3,4-triasif and methyl iodide are reacted in the presence of 2 to produce a solid product with a yield of 37%! 1 Cvrtius et al., J. Org, C.
am, 45, 4038 (produced from 198 ml and ethyl orthoformate).

"H-NMR (CDCIm) 92m (δ): 4.2 (s
, 3B), 8.05 (a, IH), 10.00 (g, L
H).

1.2 (t, 6H), 3.6 (q, 2ff
), 3.64 (q, 2M), 6.95 (8, LH),
7.21 (d, 1ff), 7.55 (d, IH)
-&23 (d, 1ff).

Tanolic sodium ethoxide Ru.

In the imidazo production example, pyrazine-2-carboxaldehyde pyrazine-2-carboxylic acid was mixed with methanolic sulfuric acid and 5H?
Reflux between P and esterify. Methanol was distilled off under reduced pressure, diluted with methylene chloride, and neutralized with sodium hydrogen carbonate (
pH 7.5>. If the organic layer is dried and concentrated, 84
% yield of methyl pyrazine-2-carboxylate as an off-white solid, which was recrystallized from isopropanol and ethyl ether to give yellow needles.

'H-NMRCCDCIs)FpFIL(δ):41(
s, 3H), 8.93 (-92H), 147 (expletive,
LH).

Methyl ester, 2011 (0,145 mol) to 600
1 in anhydrous tetrahydrofuran and cooled to -78°C. Thereafter, 5.8 g of 98% lithium aluminum hydride THF solution is added dropwise over 15 minutes. mix 30
After stirring at −78° C. for minutes and adding 20 m of acetic acid, the mixture is concentrated under reduced pressure. The residue was distributed in a mixed solvent of 2N*@(3ON) and chloroform, the organic layers were combined, washed with water, dried, and then distilled off. 8.53. A crude product of p was obtained, and this product was purified by passing it through a silica gel column, eluted with a mixed solvent of methylene chloride and ethyl acetate (4:1), and s,
Yellow needles of ozy are obtained.

” H-NMR (CDCls) p'I) door (δ):
8.3 B (door, 2H), &7 (6-cho iH), 9.7
(s, IH).

Production 2-Ferpoxa (1) 0.34 mol of acetone 2 carbo/acid aqueous solution (10(114)tα 58 mol of sodium nitrate is 0-
When the reaction was carried out at 10°C and dilute nitric acid was further added to the precipitate, the dioxime, l,3-
Dioxyimino-2-okynepropane is obtained as yellowish brown crystals.

(i) Dioxime (0
, 158 mol) is reacted with equimolar amounts of phenylhydrazine hydrochloride and sodium acetate at 70°C for 30 minutes. water(
170 m) was added, the mixture was heated to 85°C and 250 m
Concentrate with 1 to give 111j and cool. ! :, 24.7
．． 9' phenylhydrazo 7 bodies are obtained.

'H-NMI'1 (CDCIs) ppm (δ) near,
3 (m, 5H), 7.9 (s, IH), 8.6
(8, 1H), 10.5 (ha, IH), 11.4 (
bs, IH), 12.3 (s, IH).

011) The above dioxime pheni A hydrazone, 24.7
Il (0,119 mol) was mixed with 500 d of acetic anhydride and 30
Stir at room temperature for a minute. and pour the mixture into water,
After stirring for 20 minutes, filter. The resulting solidified product was recrystallized from a mixed solvent of benzene and ethyl acetate, and a yellow powder was obtained as a monoacetate HON-CHC (-N
NHC,H,)CM-NoCQCHs, 15.471
52%).

'H-Null (CDCIs), acetone):
L85 (a, 3H), 7.09 (s, 5ff), 7.
95(a, IH), &3(j.

IH), 1.09C6g, 1#), 12.25(s, I
H)-GV) Monoacetate 15A obtained above
OI (0-062 mol) and selenium dioxide 22.16II
(0,068 mol) in tetrahydrofuran (400 mol)
11+4) was stirred at room temperature for 1 hour, treated with P, and then concentrated to give a yellow residue. The residue was dissolved in 700 d of hot inpropyl ether-cyclohexane (1:2) and 20017'! When concentrated with
．． 41 g (80%) of 2-phenyl-1,2,3-thiazole-4-carboxylated dehydride Φsim was obtained and used in the next step.

(Vl oxime form, 9.4110.0497 mol)
, 4.489 of S-)lioxane and 300 jlj of 2N hydrochloric acid are heated to reflux for 3.5 hours. The aqueous layer was extracted with ethyl ether, and the ether layer was distilled off under reduced pressure to obtain 6 g of aldehyde as crystals.

'H-NMR (CDCIs) tpmcδ) near, 6 (r
IL, 3H), 8.25 (rn, 3ff), IQ, 25
(a, iH), rIL9.6 at 67°C.

LL (1) Ethyl 5-methylinxasil-3-carboxylate α 16 mol of ethyl 2.4-dioxovalerate, 0.08
A mixture of mol hydroxylamine sulfate, 50 d ethanol and 70117 mol toluene is stirred at 40° C. for 4 hours. Cool the mixture at 15-20°C, 1.8.
Add 9' concentrated ammonia water and stir at room temperature for 60 hours. The mixture was poured into a water-toluene mixed solvent (injected, the aqueous layer was extracted with toluene, the organic layers were combined, washed with brine, dried (N (hS)), the solvent was distilled off under reduced pressure, and the yellow liquid was extracted. Distill the six products obtained, b, 9. 120-124°C (
14.68 g of product (30 to dede) are obtained which crystallizes on standing.

(ii) Ethyl ester obtained above, 2.0
J (14.4 mmol) of toluene (75 t () + 8 liquid is reduced with an equimolar amount of diimbutylaluminum hydride in 1M hexane solution at -75-70°C under a nitrogen atmosphere. After stirring for 30 minutes, chloride After adding an ammonium aqueous solution to stop the reaction and returning the temperature to room temperature, the solvent is distilled off under reduced pressure. Hot methanol is added to the residue and extracted by grinding. When the solvent is distilled off, α851/
of the product is obtained.

Claims (1)

[Claims] Formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, n is 0, 1 or 2; R^1 is R^a or R^b, and R^a is tetrahydro pyranyl group,
is the residue of a carboxy protecting group selected from allyl group, benzyl group, 4-nitrobenzyl group, benzhydryl group, 2,2,2-trichloroethyl group, t-butyl group and phenacyl group; R^b is hydrogen , or 3-phthalidyl group, 4-crotonolactonyl group, gamma-butyrolactone-4-yl group, ▲Mathematical formulas, chemical formulas, tables, etc.▼, ▲Mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ and ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (Here, R^4 and R^5 are each hydrogen or CH_3
, R^6 is a (C_1-C_5) alkyl group, and R^1^4 is ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and R^1^5 is 2-phenylacetamide. group, 2-phenoxyacetamide group, D-2amino-2-phenylacetamide group, D-2amino-2-(4-hydroxyphenyl)
Acetamide group, 2-carboxy-2-phenylacetamide group, 2-carboxy-2-(2-thienyl)acetamide group, 2-carboxy-2-(3-thienyl)acetamide group, D-2-(4- ethyl-2,3-dioxopiperazinocarbonylamino)-2-phenylacetamido group or 2,2-dimethyl-4-phenyl-5-imidazolidinon-1-yl group). It is a residue of an ester group that is easily hydrolyzed in the body; one of R^2 and R^3 is hydrogen, and the other is Cl
, CH_2OH, vinyl group, (C_1-C_4) alkylthio group, (C_1-C_4) alkylsulfonyl group,
Furyl group, thienyl group, N-methylpyrrolyl group, N-acetyl-pyrrolyl group, R^7C_5H_4, R^7C_
5H_4S, -CH(R^4)NR^1^6R^1^7
, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Mathematical formulas, chemical formulas, There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
, ▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲Mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
, ▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲Mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
, ▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲Mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
, ▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲Mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
, ▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲Mathematical formulas, chemical formulas,
There are tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼; where m is 2 or 3, p is 0 or 1, t is 0, 1 or 2, and X_1 is S , O or NR^1^1, where R^7 is hydrogen, (C_1-C_4
) alkyl group, (C_1-C_4) alkoxy group, allyloxy group, hydroxy group, carboxyl group, (C_2
-C_5) alkoxycarbonyl group, (C_1-C_5
) Alkylcarbonyl group, phenyl group, benzyl group, naphthyl group, pyridyl group, NR^8R^9, CONR^8
R^9, NHCOR^1^0, NO_2, Cl, Br,
CF_3 or SR^5; R^3 and R^9 are each hydrogen, (C_1-C_4) alkyl group, phenyl group or benzyl group; R^1^0 is (C_1-C_
4) is an alkyl group, CF_3 or phenyl group; and R^1^1 is hydrogen, CH_3, C__2H_5 or CH_3CO; R^1^6 and R^1^7 are respectively H, (C_1-C_4)alkyl group, (C_2-C
_4) R^1^6 and R which are hydroxyalkyl groups or together with the nitrogen atom to which they are bonded
^1^7 forms a pyrrolidino group, piperidino group, morpholino group, thiomorpholino group or 4-methylpiperazino group], or the above compound in which R^2 or R^3 contains a basic nitrogen atom Pharmaceutically acceptable acid addition salts, or R^1 is hydrogen, or R^
A pharmaceutically acceptable cationic salt of the above compound, wherein 2 or R^3 contains a carboxyl group. 2) n is 2, one of R^2 and R^3 is H, and the other is a 2-pyridyl group, N-oxo-2-pyridyl group, 2-quinolyl group, 3-allyloxy-2- Pyridyl group, 3-methoxy-2-pyridyl group, 4-methoxy-
2-pyridyl group, 3-hydroxy-2-pyridyl group, 6
-Methyl-2-pyridyl group, 1-methyl-2-imidazolyl group, 2-thiazolyl group, 4,5-dimethyl-2-thiazolyl group, 4-methyl-2-thiazolyl group, 4-pyrimidinyl group, 2-pyrimidinyl group group, 4,6-dimethyl-
2-pyrimidinyl group, 2-pyrazinyl group, 2-methyl-
The compound according to claim 1, which is a 1,2,4-triazol-3-yl group or a benzothiazol-2-yl group. 3) One of R^2 and R^3 is H, and the other is a 2-pyridyl group, 3-allyloxy-2-pyridyl group,
The compound according to claim 2, which is a 2-pyrazinyl group, a 2-pyrimidinyl group, a 3-hydroxy-2-pyridyl group, a 4-methoxy-2-pyridyl group, or a 2-thiazolyl group. 4) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, n is 0, 1 or 2; X_3 is H or Br; R^1 is R^a or R^b, and here and R^a is a tetrahydropyranyl group, an allyl group, a benzyl group, a 4-nitrobenzyl group, a benzhydryl group, 2
, 2,2-trichloroethyl, t-butyl and phenacyl; and R^b is H or 3-phthalidyl, 4-crotonolact Nyl group, gamma-butyrolactone-4-yl group, ▲Mathematical formulas, chemical formulas, tables, etc.▼, ▲Mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ and ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (Here, R^4 and R^5 are hydrogen or CH_
3, R^6 is a (C_1-C_5) alkyl group, and R^1^4 is ▲There are mathematical formulas, chemical formulas, tables, etc.▼, but here R^1^5 is 2-phenyla Cetamide group, 2-phenoxyacetamide group, D-2-amino-2
-phenylacetamide group, D-2-amino-2-(4-
hydroxyphenyl)acetamide group, 2-carboxy-
2-phenylacetamide group, 2-carboxy-2-(2
-thienyl)acetamide group, 2-carboxy-2-(3
-thienyl)acetamide group, D-2-(4-ethyl-2
, 3-dioxopiperazinocarbonylamino)-2-phenylacetamide group or 2,2-dimethyl-4-phenyl-5-imidazolidinone-1-yl group). is the residue of an ester group that can be hydrolyzed into; and R^1^3 is H, (C_
2-C_3) alkanoyl group, (C_2-C_3) alkoxycarbonyl group, pyrazinecarbonyl group, benzoyl group, CF_3CO or CONR^8R^9;
One of R^1^2 and R^1^3 is hydrogen, and the other is a vinyl group, (C_1-C_4) alkylsulfonyl group, furyl group, thienyl group, N-methylpyrrolyl group, N-
Acetylpyrrolyl group, CH(R^4)NR^1^6R^
1＾7, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Mathematical formulas,
There are chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
, ▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲Mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
, ▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲Mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
, ▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲Mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
, ▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲Mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
, ▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲Mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼; However, provided that R^1^2 or R^1^3 is ▲ Mathematical formula,
There are chemical formulas, tables, etc. ▼ and when p is 0,
R^7 is a group other than H and CH_3; and m is 2 or 3, p is 0 or 1, t is 0, 1 or 2, and X_1 is S, O or NR^1^ 1; R^7 is hydrogen, (C_1-C_4) alkyl group, (C
_1-C_4) Alkoxy group, allyloxy group, hydroxy group, carboxyl group, (C_2-C_5) alkoxycarbonyl group, (C_1-C_5) alkylcarbonyl group, phenyl group, benzyl group, naphthyl group, pyridyl group, NR^8R^ 9, CONR^8R^9, NHCOR
^1^0, NO_2, Cl, Br, CF_3 or SR
and R^8 and R^9 are H, (C
_1-C_4) is an alkyl group, phenyl group or benzyl group; R^1^0 is a (C_1-C_4) alkyl group, CF_3 or a phenyl group; and R^1^1
is H, CH_3, C_2H_5 or CH_2CO; R^1^6 and R^1^7 are H, (C_1-C
_4) Alkyl group, (C_2-C_4) hydroxyalkyl group, or R^1^6 and R^1^7 together with the nitrogen atom to which they are bonded form a pyrrolidino group, piperidino group, morpholino group. or a pharmaceutically acceptable acid addition of the above compounds in which R^1^2 or R^1^3 contains a basic nitrogen atom. Salt or R^1 is H or R^1^2 or R^1^
A pharmaceutically acceptable cationic salt of the above compound wherein 3 contains a carboxyl group. 5) n is 0 or 2, R^1^2 and R^1^
One of 3 is H, the other is 2-thiazolyl group, 3-
isothiazolyl group, 5-methyl-3-oxazolyl group,
1,3,4-thiadiazol-2-yl group, pyridazin-3-yl group, 1,2,3-thiadiazin-4-yl group, 1,2,4-oxadiazin-3-yl group, 1,2,
4-oxadiazin-5-yl group, 1,3,4-oxadiazin-2-yl group, 1-phenyl-5-methyl-1
, 2,3-triazin-4-yl group, N-methyl-1,
2,3,4-tetrazin-5-yl group, 1-methyl-1
, 2-diazin-3-yl group, 4-pyrimidinyl group, 4
, 5-dimethylthiazol-2-yl group, benzothiazol-2-yl group or 1-benzylbenzimidazol-2-yl group; and R^1^6 is H or C
5. A compound according to claim 4, which is H_3CO. 6) Claim 5, wherein X_3 is H, one of R^1^2 and R^1^3 is H, and the other is a 2-thiazolyl group or a benzothiazol-2-yl group Compounds described in. 7) The compound according to claim 1 or 4, wherein R^a is an allyl group or a benzyl group. 8) R^b is H, its pharmaceutically acceptable cation salt, ▲Mathematical formulas, chemical formulas, tables, etc. are available▼, ▲Mathematical formulas, chemical formulas,
The compound according to claim 1 or 4, which has tables, etc. ▼ or ▲ has mathematical formulas, chemical formulas, tables, etc. ▼. 9) A composition for treating bacterial infections comprising a compound according to claim 8 and a beta-lactam antibiotic in a weight ratio of 1:3 to 3:1. 10) A pharmaceutically acceptable carrier and R^1 is R^b
A composition for treating bacterial infections, comprising the compound according to claim 1 or 4, wherein R^b is ▲a mathematical formula, a chemical formula, a table, etc.▼.