FI85376C - FOERFARANDE FOER FRAMSTAELLNING AV TERAPEUTISKT AKTIVA 6- (SUBSTITUERAD METYLEN) PENICILLANDERIVAT. - Google Patents

Description

1 ^ 5376

Process for the preparation of therapeutically active 6- (substituted methylene) penicillan derivatives

The invention relates to a process for the preparation of novel 6- (substituted 5 methylene) penicillanic acid derivatives.

These compounds can be used as β-lactamase inhibitors.

One of the best known and widely used groups of antibacterial agents is the group known as β-lactam antibiotics. These compounds are characterized in that they have a nucleus formed by a 2-azetidinone or β-lactam ring fused to either a thiazolidine or dihydro-1,3-thiazine ring. When the nucleus has a thiazolidine ring, compounds 15 are usually commonly referred to as penicillins, while when the core contains a dihydrothiazine ring, the compounds are referred to as cephalosporins. Typical examples of penicillins commonly used in clinical practice include benzylpenicillin (penicillin-20 line G), phenoxymethylpenicillin (penicillin V), ampicillin and carpenicillin; typical examples of common cephalosporins are cephalothin, cefalexin and cefazoline.

However, despite the widespread use and general acceptability of β-lactam antibiotics as valuable chemotherapeutic agents, their significant drawback is that some of them do not act against certain microorganisms. It is believed that in many cases, this resistance of a particular microorganism to a particular β-lactam antibiotic is due to the production of β-lactamase by the microorganism. The latter substances are enzymes that cleave the β-lactam ring of penicillins and ____ cephalosporins to form products that lack antibacterial activity. 35 However, certain agents have the ability to inhibit β-lactamase 2, and when a β-lactamase inhibitor is used in combination with penicillin or cephalosporin, it may increase or enhance the antibacterial efficacy of penicillin or cephalosporin against certain microorganisms.

5 An increase in the antibacterial effect is considered to occur when the antibacterial effect of the combination of a β-lactamase inhibitor and a β-lactam antibiotic is significantly greater than the sum of the antibacterial effects of the individual components.

Thus, according to the invention, novel compounds are prepared which are 6- (substituted methylene) penicillanic acids, their 1-oxides, 1,1-dioxides and their esters which are easily hydrolyzed in vivo. These novel penicillanic acids and their readily hydrolyzable esters in vivo are potent inhibitors of microbial β-lactamases.

European patent application 50 805 describes compounds of the formula: 20 ° ° n Λ J-N_L <CN> // C00R3 1 2 3 4 5 6 7 8 9 10 11 2 where n is zero, 1 or 2, R3 is CN or certain carbonyl groups, R 2 is hydrogen, lower alkyl or halogen and R 3 is 4 hydrogen or a readily hydrolysable group, compounds 5 being useful as β-lactamase inhibitors The same reference 6 describes 6-oxopenicillanic acid esters, the corresponding sulphoxides and sulphoxides. as well as a process 8 for their use in the preparation of compounds of formula (III) by reacting with a phosphorane of formula R 3 R 2 C = P (C 6 H 5) 3.

11 GB patent application 2 053 220 describes, inter alia, 3 853/6 certain 6-methylene-1,1-dioxopenicillanic acids and esters of the above formula (III) in which n is 2 and Rx and R2 independently of one another are hydrogen, optionally substituted alkyl, aryl, optionally substituted cycloalkyl, aralkyl, or an optionally substituted amino group, or together with the carbon atom to which they are attached, Rx and R2 form a 3-7 membered carbocyclic or heterocyclic ring.

U.S. Patent 4,287,181 describes certain 6-substituted penicillanic acid 1,1-dioxides and esters thereof, wherein the 6-substituent is or3 i r4-ch 15 and, inter alia, R3 is H or alkanoyl and R4 is H, (C C 1 -C 4 alkyl, phenyl, benzyl or pyridyl, which compounds are useful as β-lactamase inhibitors.

According to the present invention, novel 6- (substituted methylene) penicillanic acid derivatives of formula R2 are prepared.

3 / l “'n CH (I) rM> -f 25 —N - /// coori where n is zero, 1 or 2; R 1 is Ra or R b, which Ra is a carboxyl protecting group selected from tetrahydropyranyl, allyl, benzyl and benzhydryl, and R b is hydrogen or R 4 -COCOR 6 I c: .35 rd 4 35376 wherein R 4 and R 5 are each is hydrogen or CH 3 and R 6 is (C 1 -C 6) alkyl; one of R 2 and R 3 is hydrogen and the other is Cl, CH 2 OH, vinyl, () -alkylthio, () -alkylsulfonyl, furyl, thienyl, N-methylpyrrolyl, N-acetylpyrrolrolyl, R 7 C 6 H 4, R 7 C 6 H 4 S, R 7

<0) p <0) P

IR7! R7 — ff- -¾— (R7) *. ^ r 15 't — F X- · N - ^ - xi X1

RlHTir 1. r7-r11-cf%. , N ^ N '20 (R7) t-fW or RH_r ^ _R8 1 2 3 4 5 6 7 8 9 10 11 and p is zero or 1, t is zero, 1 or 2, X3 is S, O or 2 NR11 , R 7 is hydrogen, (C 3 -C 4) alkyl, (C 1 -C 4) alkoxy, allyloxy, hydroxyl, carboxyl, (C 2 -C 5) alkoxycarbonyl, 4 (C 1 -C 5) alkylcarbonyl, phenyl, benzyl. Cl, Br or 5 CF3; R 8 is hydrogen, (C 1 -C 4) alkyl, phenyl or benzyl; and 6 R 11 is hydrogen, CH 3, C 2 H 5 or CH 3 CO and their pharmaceutically acceptable acid addition salts if 8 in R 2 or R 3 has a basic nitrogen atom, and their pharmaceutical 9 for the preparation of pharmaceutically acceptable cationic salts if R 1 is hydrogen or R 2: or R3 has a carboxyl group.

5 B 5 376

Particularly preferred compounds of formula (I) are those wherein n is zero or 2 and one of R 2 and R 3 is hydrogen and the other is furyl, thienyl, CH 2 OH, phenyl, methylsulfonyl, N-methylpyrrolyl, 0 'R7- € Cl' \ (O) (0)

F P

10

(R7) r — f-f "^ ί1, (R7) 1— I ,,, - X

VA) fc γ * ι '' 15 -i 'r7) <j; v ·

Particularly preferred carboxyl protecting group R * is allyl due to the relative ease with which it can be selectively prepared and removed.

A particularly preferred in vivo readily hydrolyzable ester group residue Rb is -CH2OCOR6 (i.e., R4 and R5 in the above formula for Rb are each hydrogen atoms).

The compounds of formula (I) are useful as inhibitors of β-lactamase enzymes. By this mechanism, these compounds increase the activity of β-lactam antibiotics (penicillins and cephalosporins), in particular against microorganisms that are resistant or partially resistant to the β-lactam antibiotic by producing enzymes (β-lactamases) that are otherwise in this case, destroy or partially destroy the β-lactam antibiotic. In this way, the activity spectrum of the β-lactam antibiotic is broadened.

35 Although these compounds act by increasing the activity of β-6 35376 lactam antibiotics in general, their primary use has been found to be a combination of penicillin or cephalosporin permanently approved for clinical use, namely Amoxicillin, ampi-5cillin, apalcillin, azlocillin, azthreonam, azthreonam, carbenicillin, carbenicillin indanyl, carbenicillin phenyl, cefaclor, cefadroxil, cephaloram, cefamandole, cefamandole, cefamandole nafate, cefaparole, cefatrizine, cefazolin, cefbuperazone, cefonicid, cefmenoxime, cefmenoxime, cefmenoxime, cefoxitin, cefpiramide, cefpirome, cefsulodine, ceftazoxime, ceftriaxone, cefuroxime, cephacetrile, cephalexin, cephaloglycine, cephaloridine, cephalothin, cephapirin, cephradine, cyclacillin, cyclacillin penicillin G, penicillin V, phenethi-cillin, piperaci llin, pirbenicillin, pivampicillin, sarmo-xicillin, sarpicillin, suncillin, talampicillin and ticarcillin, including pharmaceutically acceptable salts thereof. The names used for these S-lactams are generally USAN (ie United States Adopted Names).

Such useful combinations also include combinations of β-lactamase inhibitors of formula (I) 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3- (5,6-dihydro-4 -pyrindenium) methyl 3-cephem-4-carboxylate (HR-810); 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3- (N-methylpyrrolidinium) methyl 3-cephem-4-carboxylate (BMY-28, 142) and 7- [D- (2- [4-Carboxy-5-imidazolecarboxamido]) -2-phenylacetamido] -3- [4- (2-sulfonateethyl) pyridinium] -3-cephem-4-carboxylic acid.

Although the compounds of formula (I) may be administered separately without a β-lactam antibiotic, combination dosage forms are preferred. The pharmaceutical composition for oral or parenteral administration contains, in a weight ratio of 1: 3 to 3: 1, a β-lactamase inhibitor of formula (I) and a β-lactam antibiotic, in total amounts which sufficient to successfully treat a mammalian bacterial infection in a single or, more commonly, multiple doses.

Compounds of formula (I) in which R 2 or R 3 has a basic nitrogen atom are capable of forming acid addition salts. The preparation of such salts with pharmaceutically acceptable acids is within the scope of 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, gluconic acid, sugar acid, benzenesulfonic acid, chlorosulfonic acid, p-toluic acid, p-toluene, p-toluene

Further, compounds of formula (I) wherein R 1 is hydrogen or R 2 or R 3 is a carboxyl group form cationic salts and the preparation of salts formed with such pharmaceutically acceptable cations is within the scope of the invention. Examples of such cations are sodium, potassium, ammonium, calcium, magnesium, zinc; and substituted ammonium salts formed with amines such as diethanolamine, choline, ethylenediamine, ethanolamine, N-methylglucamine and procaine.

This invention relates to penicillanic acid derivatives represented by the following structural formula: \ -N-1 'COOH 1

In penicillanic acid derivatives, the dashed (85) attachment of the substituent to the bicyclic nucleus indicates that the substituent is below the level of the nucleus. Such a substituent is said to be in the α-configuration. Conversely, the broad line attachment (^) of the substituent to the bicyclic core indicates that the substituent is above the plane of the core. This latter configuration is called the β-configuration. As used herein, a solid bond line (-) to a bicyclic core of a substituent indicates that the substituent may be in either the α-configuration or the β-configuration.

Compounds of formula (I) are prepared according to the invention by a) when n is zero, 1 or 2, the starting compound of formula of the formula wherein R1 is as defined above, preferably R ", is reacted with a Wittig reagent. with the formula R 2 R 3 C = P (C 6 H 5) 3 in the presence of a reaction-inert organic solvent at a temperature in the range of -100 to + 50 ° C to give a compound of formula (I) wherein n is zero; and, if desired, a compound of formula (I) wherein n is 1 or 2, oxidizing the corresponding compound wherein n is zero, preferably with an alkali metal or alkaline earth metal permanganate, 3-chloroperbenzoic acid or peracetic acid; and, if desired, removing a carboxy protecting group Ra of a compound of formula (I) wherein R 1 is R b to give a compound of formula (I) wherein R 1 is H, and then, if desired, then reacting the obtained compound with a compound of formula RbQ, wherein R b is other than hydrogen as defined above and Q is chlorine, bromine or iodine, in the presence of a polar organic solvent, or b) when n is zero or 2 and one of R 2 and R 3 is hydrogen and the other is vinyl, () alkylsulfonyl 1, furyl, thienyl, N-methylpyrrolyl, N-acetylpyrrolyl, R 7 -O.

(0) p (0)

15 F P

(R7) R7 — ff - + 1— <R?) T — t and X1 20 "-Ö1 '"' -ζτ · -'- 0Γ ”“ '--CXV “p is zero or 1, t is zero, 1 or 2, X 1 is S, O or NR 11; R 7 is hydrogen, (C 1 -C 4) alkyl, () alkoxy, allyloxy, hydroxy, carboxyl, (C 2 -C 5) alkoxycarbonyl, (C 1 -C 3 alkylcarbonyl, phenyl, benzyl, Cl, Br or CF 3), and R 8 is H, (C1-C4) alkyl, phenyl or benzyl, and R11 is H, CH3, C2H5 or CH3CO a compound of formula

Br Br (° n CH, y) -nL, 5 O 'COOR1 where R1 is other than H and n is zero or 2 are contacted with equimolar amounts of (C1-C *) alkylmagnesium halide or (C1-C4) an alkyllithium reagent and an aldehyde of the formula R 2 R 3 CO, wherein said halide is Cl, Br or J and R 2 and R 3 are as defined immediately above, in the presence of a reaction-inert solvent at a temperature in the range of -100 to + 25 ° C to give a compound of Formula 13; P * C ^ n CH3 i »f-r fc; Wherein R 12 and R 13 are the same as R 2 and R 3 as defined above, and optionally converting a compound of formula (XI) to a carboxy-protected derivative wherein R 1 is as defined above and acylating with acyl chloride or acyl bromide of formula R 18 Cl or R18Br, wherein R18 is acetyl, in the presence of an equimolar amount of a tertiary amine, and in the presence of a reaction-inert organic solvent, is hydrogenolyzed in the presence of a reaction-inert solvent with an organic tin hydride or hydrogen in the presence of a noble metal catalyst; and dehydrating or deacetylating the resulting compound, or c) when n is 2 and R 2 and R 3 are as defined in b) above, a compound of formula 11 3 5376

H 0 P

BSf> Vh3 PCH3 5 O 'Noor1 (IX) wherein R1 is other than H is reacted with equimolar amounts of (C1-C4) alkylmagnesium halide and aldehyde of formula R2R3CO where R2 and R3 are in b) above) as defined, in an ether solvent at a temperature in the range of -80 to + 25 ° C to give the first product of formula 15 OH 0 0 13 · \ / CH „RXJ-C ////. Wherein R12 and R13 are the same as R2 and R3 as defined immediately above, optionally reacting said first product with an acyl chloride or acyl bromide of the formula R18Cl or R18Br, wherein R18 is acetyl in the presence of an equimolar amount of a tertiary amine and a reaction-inert organic solvent; and dehydrating said first product or deacetylating an acetylated derivative of said first product.

30 These methods are illustrated by the following reaction schemes.

12 85376

Method a) H% [= r ^ 5_γ — γγξ, IV. ^ COOR1 N "'' COOR1

Vlvl (v) 10 2 3®® RZRJCP (0) 3 15 R oo r3 ▼ • \ / rH, C <N 3 cc CH- tTJl "· .._ ^ rr>; ^ COOR1 0 ^ N ^ 'COOR1 20 (VII) R = Ra (VI) R ^ R3 25 vv (VH) R1 = Rb <—- (VI) R1 = Rb 0 = C6H5 30 i3 8 5 376

Method c)

H O P OH o O

Br 1 s vCH3 t> 13 · y CH, 5 "- rVc« 3> r— <O * - „- ^ 2.KK CO o ^ id-lw (IX> R ^ H (H R3yH, 10 p13 0 0 ,. y ch ^ (I) R1 = Rb Λ-? ££ | -f VcHj x, -N-1 15 - ^ COOR1 (I) R1 ^

Method b) 20

l.CH-MgBr QH

Br ΒΓ (S) n / CH3 or R13-C, Br (S) n / CH3 “'—6 Γ Vch3 N% οοκι2 · Κ R C = 0 o * N -" "coor1 25 1 1

(X) R 2 H, n = 0 (XI) R 2 * H

or 2 'OR18 (OR18 ▼ (0) R13-i ^ Js ^ / CH3 R13-C. fr Js ^ VCH3 K0'-Γ rCH3, έ1 ^ - ^ CH3 O ^ N ^ -COOR1' Br O * N VoOR1 (II) (XII)

35 j R18? IH

(I) 14 ö 5 3 7 6

The Wittig salts of formula R2R3CHP + (C6H5) 3Cl 'used in process a) are either known compounds or can be readily prepared from commercially available starting materials by general synthetic methods, for example as shown below.

Preparation of Wittier salts 10 a)

► Pί P ((ZI) 3 W

Na2S20g * -► - = -> N ^ Vn 15 ° H ^ P03C1® AA -► k Π <ch3co> 20 | f7 | C1 \ H Cl ΐΛ - 3 C1 o CH3 ci. 'ch.OCOCH, J · 2 j 20 <1 i ·: “A.

0 p®

Cl9 C)

30 r ^ N

-3 Ao ΑΑοΓ * A ^ \ a2? 03

Cl® is 8 5376

The primary alcohols of formula R 3 CH 2 OH are typically converted to the corresponding chloromethyl compounds by reacting the alcohol with an equimolar amount of thionyl chloride in a reaction-inert solvent, e.g.

5 in the presence of chloroform or methylene chloride at room temperature or about room temperature. The product is isolated, for example, by neutralizing the reaction mixture and extracting.

The chloromethyl compound, R 3 CH 2 Cl, is then converted to the desired Wittig salt, e.g., by reacting it with an equivalent amount of 10 molar triphenylphosphine. This step is typically performed in a solvent such as toluene at a higher than normal temperature, preferably at boiling temperature. The desired product forms a precipitate which is then collected by filtration.

6-α-Hydroxypenicillanic acid is a known compound, see e.g. Hauser et al., Helv. Chim. Acta, 50, 1327 (1967). The acid is converted to the carboxy-protected derivative of formula (IV). The identity of the carboxy protecting group is not critical. The only requirements for the carboxy protecting group are: (i) it must be stable under the oxidation conditions used to form the 6-oxopenicillanate ester (V) and its subsequent reaction with Wittig's reagent to form the 6- ( substituted methylene) penicillanate; (ii) it must be selectively removable from a compound of formula (VI, R1 = Ra) under conditions in which both β-lactam and 6- (substituted methylene) groups remain substantially intact; (iii) it must be stable upon oxidation of compound (VI, R 1 = Ra) to form sulfones of formula (VII) or similar sulfoxides. Such carboxy protecting groups which meet the above requirements include a tetrahydropyranyl group, a benzyl group, a benzhydryl group and an allyl group. Particularly preferred such groups are allyl and benzyl, and allyl is most preferred due to its ease of selectivity and selective removal.

The oxidation of the carboxy-protected 6-α-hydroxypenicillanate (IV) to the corresponding 6-oxopenicillanate ester (X) is typically performed with approximately equimolar excess of trifluoroacetic anhydride and a molar excess of dimethyl sulfoxide in the presence of a reaction-inert solvent or e.g. chloroform. The reaction is preferably carried out at a temperature between about -80 ° C and -70 ° C. The reaction mixture is neutralized, e.g., by the addition of a tertiary amine such as triethylamine, followed by isolation, e.g. by partitioning between water and a water-immiscible solvent, and evaporating the organic layer to dryness.

The 6-oxopenicillanate ester of formula (V) is then reacted with a Wittig reagent of formula R2R3, CP (C6H5) 3. This reaction is carried out primarily in a reaction-inert organic solvent, for example, a hydrocarbon such as pentane, hexane, benzene, toluene or xylene; a halogenated hydrocarbon such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,2-dibromoethane or chlorobenzene; in the presence of an ether such as tetrahydrofuran, dioxane, diethyl ether, 1,2-dimethoxyethane or t-butyl methyl ether. Although this reaction can be carried out over a wide temperature range of -100 ° C to + 50 ° C, the preferred temperature is in the range of about -78 ° C to + 25 ° C.

The desired product of formula (VI, R1 = Ra) is isolated by known methods, for example by quenching the reaction by adding aqueous ammonium chloride solution, extracting with water as an immiscible solvent and evaporating the solvent. If desired, the product obtained is purified by conventional methods known to those skilled in the art, for example, by column chromatography on silica gel.

An ester of formula (VI, R1 = Ra) wherein Ra is a carboxy protecting group as defined above may then be converted to the corresponding acid or ester of formula (VI, R1 = Rb) wherein Rb is hydrogen or an ester forming group as defined above. . The carboxy protecting group is typically removed from a compound of formula (VI, R1 = Ra) to form the corresponding carboxylic acid. The specific method chosen to remove the carboxy protecting group depends on the nature of the R * group, but one skilled in the art will readily determine the appropriate method.

As mentioned above, a particularly preferred carboxy protecting group R * is allyl. Although this group can be removed most satisfactorily by hydrolysis with dilute acid or alkali, a particularly preferred process for removing it uses a soluble palladium (0) complex, tetrakis (triphenylphosphine) palladium (0) as a catalyst, a method previously described by Jeffrey and McCombie, J. Org. Chem., 47, 587-590 (1982). In a typical process, an allyl ester in a reaction-inert solvent, e.g. ethylene di-chloride, chloroform, ethyl acetate, and a catalytic amount of tetrakis (triphenylphosphine) palladium (0), for example about 1-5 mole percent based on the allyl ester, and in an amount equal to triphenylphosphine is combined under the protection of a nitrogen atmosphere. To this is added an equimolar amount of the sodium or potassium salt of 2-ethylhexanoate relative to the allyl ester and the resulting mixture is stirred at ambient temperature until the desired salt, e.g. the salt of formula (VI) wherein R 1 is Na or K, is completely precipitated. Usually, the reaction is substantially complete within about two to twenty hours. The salt is then collected, e.g. by filtration.

If desired, sulfoxides or sulfones of formula (I), i.e. the sulphides corresponding to the compounds of formula (I) in which n is 35 l or 2 are oxidized using any of a wide variety of oxidants known in the art to be used to oxidize sulphoxides to sulfones. However, particularly convenient reagents are metal permanganates such as alkali metal permanganates and alkaline earth metal permanganates, and organic peroxyacids such as organic peroxycarboxylic acids. Suitable reagents include sodium permanganate, potassium permanganate, 3-chloroperbenzoic acid and peracetic acid.

A particularly preferred group of oxidants are organic peroxyacids and the preferred organic peroxyacid 10 is 3-chloroperbenzoic acid.

When the desired oxidation product is a sulfoxide of formula (I) wherein n is 1, approximately molar equivalents of starting material sulfide (n is zero) and an oxidant are used. When the desired product is a sulfone, i.e. a compound of formula (I) wherein n is 2, the sulphide is contacted with two or more molar equivalents of an oxidant. Alternatively, the sulfoxides may, of course, serve as starting materials for the preparation of the corresponding sulfone, in which case the oxidant is used in at least about 20 equimolar amounts.

For example, when a compound of formula (VI, R 1 = R ") wherein Ra is as previously defined is oxidized to the corresponding compound of formula (VII) using an organic peroxyacid, e.g. peroxycarboxylic acid, the reaction is usually carried out by treating a compound of formula (VI, R 1 = R"). *) with about 2 to about 4 molar equivalents of an oxidizing agent in a reaction-inert organic solvent Typical solvents include chlorinated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, and ethers such as diethyl ether, tetrahydrofuran and 1,2-dimethoxyethane. The reaction is normally carried out at a temperature of about -20 ° C to about + 50 ° C, and preferably about 25 ° C. The reaction times used at about 25 ° C are usually about 2 to about 16 ° C. The product is usually isolated by removing the solvent by evaporation in vacuo. by conventional methods well known in the art.

The above-mentioned oxidation methods preferably use a starting material in which the carboxy group is protected by the above-mentioned carboxy protecting group, Ra. Deprotection of the carboxy 5 from the sulfoxide or sulfone product is carried out in the usual manner depending on the particular protecting group used in each case, for example as described above for the compounds (VI, R1 = Ra).

Compounds of formula (I) in which R 1 is an ester-forming hydrolysable residue in vivo, i.e. compounds in which R 6 is other than hydrogen, may be prepared directly from the corresponding compound in which R 1 is hydrogen by conventional esterification methods. The specific method selected will depend on the exact structure of the ester-forming residue, but the appropriate method will be readily selected by one skilled in the art. Compounds wherein R 1 is R 4 -COCOR 6 R 5 wherein R 4 and R 5 are as defined above can be prepared by alkylation of the corresponding compound of formula (I) wherein R 1 is hydrogen with a halide of formula RbQ wherein Rb is as defined above except hydrogen and Q is halogen. The terms "halide" and "halogen" refer to derivatives of chlorine, bromine and iodine. The reaction is typically carried out by dissolving a salt of a compound of formula (I) wherein R 1 is hydrogen in a suitable polar organic solvent, for example N, N-dimethylformamide, and then adding about a molar equivalent of the appropriate halide (RbQ). After the reaction is substantially complete, the product is isolated by conventional methods. It is often sufficient to dilute the reaction medium with excess water and then extract the product into a water-immiscible organic solvent and recover 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-ethyl-5-lipiperidine, N, N-dimethylaniline and N-methylmorpholine salts, and quaternary ammonium ammonium salts such as tetramethylammonium. and tetrabutylammonium salts. The reaction is carried out at a temperature in the range of about 0 to about 100 ° C, and usually about 25 ° C. The length of time required to complete the reaction will vary depending on various factors such as the concentration of the reagents and the reactivity of the reagents. Thus, in the case of a halogen compound, iodide reacts faster than bromide, which in turn reacts faster than chloride. In fact, when using a chlorine compound, it is sometimes advantageous to add at most one molar equivalent of alkali metal iodide. This has an accelerating effect on the reaction. When all of the above factors are taken into account, commonly used reaction times range from about 1 to about 20 hours.

The 6-α-bromo-1,1-dioxopenicillanate ester starting material (IX) required in process c) above is converted to a Grignard reagent by reacting it with an equimolar amount of a low molecular weight Grig-25 nard reagent, e.g. methylmagnesium bromide, ethylmagnesium chloride -butylmagnesium iodide, in an ether solvent, preferably tetrahydrofuran or ethyl ether, at a temperature in the range of -80 ° C to + 25 ° C, typically at -78 ° C. After stirring for a few minutes, an equimolar amount of the appropriate aldehyde of formula R12R13C * 0 is added and stirring is continued until the reaction is substantially complete, usually about 10 minutes to about four hours at the same temperature. The ester of formula (II) can be isolated by conventional methods. For example, the reaction is quenched with aqueous ammonium chloride solution and the product is extracted with water as an immiscible solvent. The product (II) obtained can be further purified, e.g. by chromatography on silica gel.

The secondary alcohol of formula (II) is then dehydrated to the corresponding 6-5 (substituted methylene) -1,1-dioxopenicillanate compound of formula (I). Although various methods known in the art for dehydrating secondary alcohols to olefins can be used to successfully complete this step, the preferred method uses conversion of the alcohol 10 to acetate by reacting it with at least equimolar amounts of acetic anhydride and pyridine to stir at room temperature for one to ten hours. The reaction is usually quenched with water and the desired product (I, n = 2) is isolated by extraction methods and purified if desired.

The products of formula (I) obtained as described above are esters in which R 1 is either a carboxy protecting group R * as defined above or an easily in vivo hydrolysable ester group Rb as defined above. These esters where R 1 is Ra are converted to the corresponding carboxylic acids (R b is hydrogen) by the methods described above. If desired, the carboxylic acids of formula (I) may, of course, also be converted by the methods described above to the corresponding compound in which R 1 is the in vivo hydrolysable ester group Rb.

The starting 6-α-bromo-1,1-dioxopenicillanate esters (IX) are typically prepared from 6,6-dibromo, 1-dioxopenicillanic acid by treatment with sodium bicarbonate and sodium bisulfite followed by acidification. The 6-o-bromo-1,1-dioxopenicillanic acid formed is then converted to the ester of formula (IX).

The starting esters of formula (X) used as starting materials in process b) above are known compounds, see e.g. U.S. Patent 4,234,579. In a typical treatment according to this process, the starting ester (X) is contacted in a reaction-inert solvent, e.g. toluene, xylene, pentane, tetrahydrofuran, ethyl ether or mixtures thereof, at low temperature for contacting with an equimolar amount of an alkyllithium reagent, e.g. . This is immediately contacted with an equi-10 molar amount of aldehyde R12R13CO. wherein R 12 and R 13 are as previously defined, and the mixture is stirred at -100 ° to -50 ° C, preferably -78 ° C, for about 1-4 hours. The reaction is then quenched and the bromo-hydrine intermediate of formula (XI) is isolated, for example, by partitioning between water and solvent and purifying the extract by column chromatography on silica gel or Florisil (magnesium silicate).

Alternatively, the dibromoester starting material of formula (X) above is reacted with an equimolar amount of equimolar low molecular weight Grignard reagent using the same reagents and conditions as described above for method c) to give the bromide of formula (XI).

The hydroxyl in the 6-position substituent of bromohydrin (XI) can be acylated to give the corresponding compound of formula (XII) shown in the reaction scheme, wherein R 18 is acetyl. The acylation is typically carried out by reacting equimolar amounts of acetyl chloride or acetyl libromide with a bromohydrin intermediate of formula (XI) and a tertiary amine, for example pyridine, N-methylmorpholine or the like in the presence of room at or below. The diester of formula (XII) can then be isolated by well known methods such as extraction and evaporation of the solvent and purification, if desired, e.g. by flash chromatography.

The bromohydrin ester intermediate (XI) or bromide di-5 blades (XII) are then treated under hydrogenolysis conditions to remove the bromine atom. This is accomplished by treating the bromohydrin with hydrogen in the presence of a noble metal catalyst or by reduction with certain organic tin hydrides. Preferred organic tin hydride reducing agents are dialkyltin dihydrides, trialkyltin hydrides having 1 to 6 carbon atoms in each alkyl group, and triaryltin hydrides in which aryl is phenyl which may be substituted as a nitro group or a trihydryl group with an alkyl group having 1 to 3 carbon atoms. -n-butyltin hydride, the latter being particularly preferred for economic and efficient reasons.

When said tin hydrides are used, the reaction is usually carried out in the presence of a reaction-inert solvent. Suitable solvents for use with organic tin hydride reducing agents are those which substantially dissolve the starting material of formula (XI) or (XII) but do not themselves react with the hydride reducing agent. Examples of such solvents include aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene and naphthalene; and ethers such as ethyl ether, isopropyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane. Particularly preferred solvents for economic and efficient reasons are benzene and toluene.

When carrying out the hydrogenolysis using organic tin hydride reducing agents, equimolar amounts of bromohydrin (XI) or bromide ester (XII) and hydride are theoretically required. In practice, in order to ensure the completeness of the reaction, the hybrid is often used in excess, e.g. 5-50% molar excess of hydride.

24 8 5376

The hydrogenolysis with organic tin hydrides is substantially complete under the preferred conditions described above without a catalyst. However, the reaction is accelerated by a free radical generating source 5, e.g. ultraviolet light, or by a catalytic amount of azobisisobutyronitrile or peroxides such as benzoyl peroxide. The preferred free radical source for this reaction is a catalytic amount of azobisisobutyronitrile.

The compound of formula (XI) or (XII) is typically dissolved in a reaction inert solvent, the solution is kept under an inert atmosphere, e.g. nitrogen or argon, and an appropriate amount of organic tin hydride and optionally a free radical source, e.g. azobisisobutyronitrile, is added. and the resulting mixture is stirred at a temperature, preferably between about 0 ° C and the boiling point of the solvent. The reaction is usually complete within a few minutes to about a few hours, e.g., from 5 minutes at the boiling point of benzene to about 20 hours at 0 ° C. The resulting compound of formula (II) is then converted to the compound of formula I by dehydration or deacetylation as described above in connection with method c).

The compounds of formula (II) formed by debromination with organic stannous hydride as described above have been found to be predominantly 6-α-isomers, i.e. the 6-R 12 R 13 C (OH) substituent is in the α-configuration.

When the hydrogenolysis step is performed using Hydrogen in the presence of a noble metal catalyst, a convenient method to accomplish this change is to stir or shake a solution of a compound of formula (XI) or (XII) in a hydrogen atmosphere or a mixture of hydrogen and an inert diluent such as nitrogen or argon in a noble metal hydrolysis catalyst. Suitable solvents for this hydrogenolysis reaction are those which essentially dissolve the starting material of formula (XI) or (XII) but which do not themselves participate in the hydrogenation or hydrogenolysis reactions. Examples of such solvents include ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane; low molecular weight esters such as ethyl acetate and butyl acetate? tertiary amides such as -N, N-dimethylformamide, -N, N-dimethylacetamide and -N-methylpyrrolidone; water; and mixtures thereof. In addition, it is often desirable to buffer the reaction mixture so that the work takes place in a pH range of about 4-9, preferably about 6-8. Commonly used are borate, bicarbonate and phosphorus buffers. The introduction of hydrogen gas into the reaction medium is usually carried out by carrying out the reaction in a closed vessel containing a compound of formula (XI) or (XII), a solvent, a catalyst and hydrogen. The pressure inside the reaction vessel can range from about 1 to about 100 kg / cm 2. The preferred pressure range, with the atmosphere inside the reaction vessel being predominantly pure hydrogen, is from about 2 to about 5 kg / cm 2. The hydrogenolysis 20 is usually performed at a temperature of about 0 ° C to about 60 ° C, and preferably about 25 ° C to about 50 ° C. When using preferred temperature and pressure values, the hydrogenolysis usually takes place within a few hours, e.g. about 2-20 hours. Preferred noble metal catalysts for use in this hydrogenolysis reaction are the types of materials known in the art for this type of conversion, for example nickel, palladium, platinum and rhodium. Palladium is particularly preferred. The catalyst is usually present in an amount of from about 0.01% to about 25% by weight, and preferably from about 0.1% to about 10% by weight, based on the compound of formula (XI). It is often desirable to suspend the catalyst on an inert support, a particularly suitable catalyst being palladium suspended on an inert support such as carbon.

After complete hydrogenolysis, the compound of formula (II) is then converted to the compound of formula 26 85376 (I) as described above.

When the starting compound of formula (XI) or (XII) is a benzyl ester (R1 = Ra = benzyl), the above catalytic hydrogenolysis process can also cause cleavage of the benzyl group to give a compound of formula (II) wherein R1 is hydrogen.

The starting aldehydes of formula R12R13CO, wherein R12 and R13 are as defined above, are either obtained from commercial sources or are readily prepared from available starting materials by methods well known in the art, for example: 1. Oxidation using the corresponding primary alcohols obtained above as Wittig reagent precursors e.g. oxidants such as potassium dichromate, chromic acid / pyridine mixture, catalytic oxidation in the presence of precious metals, manganese dioxide.

2. The corresponding methyl-substituted aromatic hydrocarbon is reacted with e.g. selenium dioxide.

3. The corresponding C1-C4 alkoxycarbonyl compound is reduced with a metal hydride at low temperature in the presence of ether solvents. Examples of suitable metal dihydrides are lithium aluminum hydride and diisobutylaluminum hydride (DIBAL-H).

4. A suitable aromatic hydrocarbon precursor is reacted with n-butyllithium and dimethylformamide.

As mentioned above, the compounds of formula (I) wherein R 1 is H and their salts show a synergistic effect in combination with β-lactam antibiotics in in vitro antibacterial experiments. Such activity is demonstrated by measuring the minimum inhibitory concentrations (MICs) in mg / ml against various microorganisms. The method to be followed is the method 35 recommended by the International Collaborative Study on Antibiotic Sensitivity Testing [Ericcson & Sherris, Acta 27 8 5 376

Pathologica et Microbiologia Scandinav., Supp. 217, Section B (1971) pp. 64-68] and using brain-heart infusion agar (BHI agar) and an inoculum repeater. Tubes incubated overnight are diluted 100-fold for use as a standard inoculum (20,000 to 10,000 cells in approximately 0.002 ml are transferred to an agar surface; 20 ml BHI agar / plate). Twelve-fold dilutions of test compound are used at an initial concentration of 200 pg / ml. Individual colonies are disregarded when surfaces 10 are examined after 18 hours at 37 ° C. The susceptibility (MIC) of a test organism is considered to be the lowest concentration of the test compound or combination of compounds that produces complete inhibition of growth as judged to the naked eye.

The compounds of formula (I) wherein R 1 is H and their salts in combination with known β-lactam antibiotics are useful as industrial antimicrobial agents, for example in water treatment, slime control, paint protection and wood protection, as well as for topical application as disinfectants. When using these compounds 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 emollient cream. Similarly, they may be dissolved or dispersed in liquid diluents or solvents such as water, alkanols, glycols, or mixtures thereof. In most cases, it will be convenient to use concentrations of from about 0.1% to about 10% by weight of the active ingredient, based on the total amount of the combination.

As also mentioned above, the compounds of formula (I) in which R 1 is R b are of particular value as potent inhibitors of microbial β-lactamases. Thanks to this mechanism, they increase the bacterial efficacy of β-lactam antibiotics-35 (penicillins and cephalosporins) against many microorganisms, especially B-28 8 5 3 7 6 lactamase-producing microorganisms. The ability of compounds of formula (I) to increase the efficacy of a β-lactam antibiotic can be evaluated by experiments in which the MIC values of the antibiotic alone and the MIC values of the compound of formula (I) wherein R 1 is hydrogen are determined. These MIC values are then compared to the MIC values obtained with a combination of a particular antibiotic and a compound of formula (I) wherein R 1 is hydrogen. When the antibacterial efficacy of a combination is significantly greater than would be expected from the efficacy of the individual compounds, this is considered to indicate an increase in activity.

The 6-lactamase inhibitory activity of the compounds of formula (I) was determined by the method described above, comparing the results obtained using the compound of formula (I) in combination with the well-known β-lactam antibiotic, ampicillin. B-lactamase inhibition manifests itself as a strength of the synergism of the combination compared to ampicillin alone. The results obtained in this experiment are shown in the following Table I. For comparison, the same experiment was also performed using compounds known from EP-A-50805. The results obtained in this case are shown in the following Table II. The experimental results show that the compounds according to the invention have surprisingly valuable properties compared to these known compounds.

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Compounds of formula (I) wherein R 1 is hydrogen or a residue of an ester group which is readily hydrolysed in vivo increase the antibacterial efficacy of β-lactam antibiotics in vivo. That is, they reduce the amount of antibiotic required to protect mice from the otherwise lethal implant of certain β-lactamase-producing bacteria. In determining such activity, mice are induced by acute experimental infections by inoculating mice intraperitoneally with a standardized culture of the test organism suspended in 5% porcine abdominal mucin. The severity of the infection is standardized so that the mice receive a lethal dose of the organism (the lethal dose is the smallest implant of the organism required to continuously kill 100 percent of the infected, untreated mice). The test compound is administered in combination with an antibiotic at different doses, po or ip) to infected groups of mice. At the end of the experiment, the activity of the mixture is assessed by counting the number of survivors from the animals treated with a given dose. Activity is expressed as the percentage of 20 animals that survive a given dose or is calculated as the PD50 (the dose that protects 50% of the animals from infection).

The ability of the compounds of formula (I) to increase the efficacy of a β-lactam antibiotic against β-lactamase-producing bacteria makes them valuable for administration with β-lactam antibiotics for the treatment of bacterial infections in mammals, especially humans. In the treatment of a bacterial infection, a compound of formula (I) may be mixed with a β-lactam antibiotic. Alternatively, a compound of formula (I) or (II) may be administered as a separate agent during β-lactam antibiotic treatment. In some cases, it is preferred to administer a compound of formula (I) to a patient as a pre-treatment prior to initiating treatment with a β-lactam antibiotic.

When a compound of formula (I) wherein R 1 is Rb as defined above is used to increase the efficacy of a β-lactam antibiotic, a mixture of said compound with a β-lactam antibiotic is preferably administered in combination with standard pharmaceutical carriers or 40-0.

a 5 with 6/6 diluents. A pharmaceutical combination comprising a pharmaceutically acceptable carrier, a β-lactam antibiotic and / or said compound of formula (I) will usually contain from about 5% to about 80% by weight of a pharmaceutically acceptable carrier.

When said compounds of formula (I) are used in combination with another β-lactam antibiotic, said compounds may be administered orally or parenterally, i.e. intramuscularly, subcutaneously or intraperitoneally. Although the prescribing physician will ultimately determine the amount of dose to be administered to a human patient, the daily weight ratio of the compound of formula (I) wherein R 1 is R b to the β-lactam antibiotic will normally be in the range of about 1: 3 to 3: 1. In addition, when the compounds of formula (I) are used in combination with a β-lactam antibiotic, the daily oral dose of each component will normally be in the range of about 10 to about 200 mg per kilogram of body weight and the daily parenteral dose of each component will normally be about 10 - about 40 mg per kilogram body weight. These daily doses are usually in divided doses. In some cases, the prescribing physician may decide on the required dosage amounts outside these limits.

As will be appreciated by those skilled in the art, some β-lactam compounds are effective when administered orally or parenterally, while others are effective only when administered parenterally. When a compound of formula (I) is to be used concomitantly (i.e. mixed with) a β-30 lactam antibiotic which is effective only when administered parenterally, a combination composition suitable for parenteral use is required. When a compound of formula (I) is to be used concomitantly (mixed with) a β-lactam antibiotic which is effective orally or parenterally, combinations suitable for either oral or parenteral administration may be prepared. In addition, preparations of the active compounds of formula (I) may be administered orally by concomitant administration of a parenteral other β-lactam antibiotic; and it is also possible to administer preparations of said compounds of formula (I) or (II) parenterally by co-administration of another β-lactam antibiotic.

The present invention is illustrated by the following examples. It is to be understood, however, that the invention is not limited to the specific details of these examples. Proton and C13 nuclear magnetic resonance spectra were determined at 60, 90, 250 or 300 MHz for solutions in deuterochlorophore (CDCl3), deuterium oxide (D20), perdeuteroacetone (CD3COCD3) or perdeuterodimethylsulfoxide (DMS0-pi expressed in parts per million (ppm) downfield from tetramethylsilane. The following abbreviations have been used: s, singlet; d, doublets; dd, 15 doublets of doublets; t, triplets; q, quartet; m, multiplet; b, wide.

Example 1 6-α-Hydroxypenicillanate esters A. Allyl ester 20 To a solution of 85 g of 6-α-hydroxypenicillanic acid (prepared by the method of Hauser et al., Helv. Chim. Acta, 50, 1327, 1967) (0.39 moles) in 300 ml of dimethylformamide were added 34 ml (0.39 moles) of allyl bromide, 54 ml (0.39 moles) of triethylamine and 2 g of sodium hydrogen carbonate, and the mixture was stirred at room temperature for 15 hours. After quenching the reaction with water and extracting with ethyl ether, the combined ether layers were washed with saturated sodium bicarbonate solution, water, dried (MgSO 4) and evaporated to dryness in vacuo to give 43 g of crude product. The crude material was purified by silica gel column chromatography eluting with chloroform / ethyl acetate 9: 1 to give 22.75 g (23%) of allyl ester. 1 H-NMR (CDCl 3) ppm (delta): 1.42 (s, 3H), 1.60 (s, 3H), 4.45 (s, 1H), 4.5-5.0 (m, 3H ), 5.2-6.2 (m. 4H).

B. Pivaloyloxymethyl ester

A mixture of 9 g (0.041 mol) of 6-α-hydroxypenicillanic acid, 40 ml of dimethylformamide, 7.4 ml (0.041 mol) of diisopropylethylamine, 6 ml (0.041 42 8 5 37 6 mol) of chloromethyl pivalate and 6.15 g (0.041 mol) of sodium iodide were stirred at room temperature for 15 hours. Water was added, the mixture was extracted with ethyl ether, the extracts dried and evaporated to dryness to give 9 g of crude ester which was purified on a silica gel column eluting with chloroform / ethyl acetate (9: 1). The amount of combined product fractions was 4.384 g (32%).

C. Benzyl Ester 10 To a mixture of 20 g (0.092 moles) of 6-α-hydroxy-penicillanic acid, 12.9 mL (0.092 moles) of triethylamine, 1.105 g (0.013 moles) of sodium bicarbonate, and 200 mL of dimethylformamide (DMF). 12.0 ml (0.101 mol) of benzyl bromide were added. The mixture was stirred at room temperature for 20 hours, partitioned between ethyl ether and water-soluble portions, and the pH of the aqueous phase was adjusted to 2.0 6-norm. hydrochloric acid. The layers were separated, the aqueous layer was re-extracted twice with ether, the combined ether layers were washed with sodium bicarbonate solution, water, dried and the solvent was evaporated. The residue was crystallized from hot chloroform / hexane to give 9.1 g of colorless crystals, mp 165-167 ° C.

D. (5-Methyl-2-oxo-1,3-dioxol-4-yl) methyl ester

A mixture of 15 g (0.078 mol) of (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl bromide, 18.7 g (0.078 mol) of sodium 6-α-hydroxypenicillanate in 225 ml of DMF is stirred at room temperature for 4 hours, poured onto ice and worked up as described above to give the desired ester.

Example 2 6-Oxopenicillanate Esters A. Allyl 6-Oxopenicillanate 35 A mixture of 2.84 ml (0.04 mol) of dimethyl sulfoxide, 3.67 ml (0.026 mol) of trifluoroacetic anhydride and 50 ml of methylene chloride was stirred - At 78 eC for ten minutes. At -78 ° C, a solution of 5.14 g (0.02 mol) of allyl 6-α-hydroxypenicillanate in 10 ml of methylene chloride was added and the resulting mixture was stirred for 40 minutes. At this temperature, triethylamine (7.24 mL, 0.052 mol) was added and the mixture was gradually warmed to room temperature and quenched with water. After extraction with methylene chloride, the combined organic layers were washed with water (3x), dried and the solvent evaporated in vacuo to give the title compound as a yellow oil, 5.1 g (100%).

1 H-NMR δ CDCl 3 (delta): 1.60 (s, 6H), 4.75 (m, 2H), 4.82 (s, 1H), 5.1-6.3 (m, 3H), δ .82 (s, 1 H).

B. Pivaloyloxymethyl ester

A mixture of 0.36 mL (5.06 mmol) of dimethyl sulfoxide, 0.47 mL (3.29 mmol) of trifluoroacetic acid anhydride, 839 mg (2.53 mmol) of pivaloyloxymethyl 6-α-hydroxypenicillanate and 5 ml of methylene chloride was stirred at -78 ° C for 30 minutes and 0.92 ml (6.58 mmol) of triethylamine was added. Further work-up of the product as described in Part A above gave 788 mg of 20 (95%) of the desired ketone. 1 H-NMR (CDCl 3) ppm (delta): 1.3 (s, 9H), 1.65 (s, 6H), 4.85 (s, 1H), 5.8 (m, 3H).

Example 3

Allyl 6 (E) - (2-pyridyl) metyleenipenisillanaatti

A mixture of 2.64 g (6.8 mmol) of 2-picolyl-25-triphenylphosphonium chloride and 0.265 g (6.8 mmol) of sodium amide in 6 ml of dry tetrahydrofuran (THF) was stirred at room temperature for 30 minutes. The resulting brown suspension was cooled to -78 ° C, a solution of 1.8 g (7.0 mmol) of allyl 6-oxopene-30 branate in 4 mL of dry THF was added in one portion and the mixture was stirred at -78 ° for three minutes. C. The reaction was quenched by the addition of saturated ammonium chloride solution, extracted with ethyl acetate and the combined organic layers were washed with water (3x), dried (MgSO 4) and evaporated to dryness in vacuo to give 3.3 g of a red oil. The oil was purified by silica gel column chromatography to give 1.35 g (60.7%) of the desired product as a yellow oil.

44 δ 3776 1 H-NMR (CDCl 3) ppm (delta): 1.50 (s, 3H), 1.58 (s, 3H), 4.57 (s, 1H), 4.65 (d, 2H) , 5.15-6.15 (m, 3H), 6.17 (d, IK, J = 1 Kz), 6.87 (d, 1H, J = 1 Kz), 7.2-7.4 ( m, 2H), 7.60 (from td, 1H), 8.62 (from dd); Δ 13 C-NMR (CDCl 3) ppm (delta): 26.04, 32.99, 62.77, 65.75, 70.01, 70.54, 119.10, 123.24, 124.02, 125, 86, 131.06, 136.34, 144.66, 149.94, 152.13, 167.54, 168.73.

Example 4 Using the procedure of Example 3, but instead of the appropriate Wittig reagent of formula (CgH, j) 3P Cf ^ R Cl, instead of 2-picolyl-triphenylphosphonium chloride, the following compounds are obtained.

3 CM

R3CM ^ .S “M3 15 -f ^ Y ^ CII3 / -H-1 '' Όοοα ^ οιι-α ^ R3 Time Thermal Elution Yield f 1 H-NMR (CDCl 3 J ppm (delta):„ min. state solvent x)% 20 oc —----

Cl 30 -78- A 13 (E) E-isomer: 1/5 (s, 3H), 1.6 +25 +3.2 (Z) 3U) ^ 4 7 5 (s, lii), 4.65 (d, 211), 5.1-6.2 (m, 3Π),; 5.7 (d, H1), 6.82 (d, IM).

: 25 Z-isomer: 1> 5 (s, 311), 1.6 - ·. (s, 311), 4.57 (s, 1H), 4.7 (d, 211), 5.15-6.24 (m, 311), 5.77 (s, 1H), 6.37 ( s, lii).

α1S1 -78B16 (E) Z isomer: 1.48 (s, 311), 1.60 (2) (Z) (s, 311), 2.58 (s, 311), 4.42 ( E + Z) (s, lii), 4.60 (d, 211), 5.0-6.1 (m, 311), 5.58 (s, lii), 6.42; (S,. III) 45 85376

Time Thermal Elution Yield + 1 H-NMR (CDCl 3) ppn (delta): min min ° C solvent x)% ___ E-isomer: 11 45 (s, 311), 1.60 (s, 311) , 2.40 (s, 3H), 4.60 (s, 1H), 4.80 (d, 2H), 5.0-6.1 (m, 311), 5.72 (d, li) , 6.90 (d, 1 H).

CI10 * a * 10 25 B 32 (E) 1.50 (s, 311), 1.60 (s, 3H), 4.5.

(s, lii), 4.62 (d, 211), 5.1-6.0 (m, 311), 5.90 (d, 1H), 6.80 (d, lii), 9.73 (d, H1).

^ Carried out with formylmethylene-triphenylphosphorane in benzene.

2 2-quino-3-78 B 30 (Z) 1.5 (s, 311), 1.62 (s, 311), 4.6 lyyl (s, lii), 4.7 (d, 211), 5.1-6.2 (m, 3II), 6.35 (d, Iti), 7.0 (d, lii), 7.2-8.2 (m, 611).

C 9 H 5 S 1 -70 B 12 (E, Z) 1.5 (s, 2.211), 1.55 (s, 0.811), 1.65 (s, 2.211), 1.7 (s, 0.811), 4, Δ (s, III), 4.5-4.8 (m, 211), 5.1-6.1 (m, 411), 6.0 (s, 0.2611), 7.15 (d, 0, 7411), 7.4 (m, 511).

25 3 "78 B 20 (E) 1.45 (s, 311), 1.55 (s, 3H), 4.5f

Cl (s, lii), 4.65 (d, 211), 5.2-6.1 (m, 3II), 6.15 (d, H1), 6.75 (d,: lii), 7, 05-7.75 (m, 311).

30 CgH5 5 -78 A 4 (Z) 1.5 (s, 311), 1.6 (s, 311), 4.6 (s, lii), 4.68 (d, 211), 5 * 1- 6.1 '. On, 3II), 5.77 (s, UI), 6.57 (s, 1 ') # 7.2-7.64 (m, 311), 7.64-8.16 (m, 211).

35 46 85376 3 1 R Time Thermal Elution Yield 1 H-NMR (CDCl 3 ppm (delta): min min ° C solvent x) _% ____________ _ 30 (E) 1.52 (s, 3H), 1.62 ( s, 311), 4.60 (s, 1H), 4.69 (d, 2H), 5.1-6.3 δ (m, 311), 6.1 (d, li), 7.03 ( d, 1H), 7.4 (s, 5 H).

3-78 C 14 (E) 1.55 (s, 311), 1.65 (s, 311), 2.55 cm-dl 611), 4.65 (s, lii), 4.75 (d, W 3) 211), 5.1-6.1 (m, 311), 6.25 (d, 1H), 6.9 (s, 1H), 7.0 (d, lii).

(E, Z) 3-78 D (E) OC11 1.5 (s, 3H), 1.6 (s, 311), 3.85 fpY "(s, 311), 4.55 (s, lii) ), 4.7 (d, 15Sa 211), 5.1-6.1 (m, 3H), 6.2 (d, 1i), 7.0-7.5 (m, 311), 8 .2 (t, 1H).

Δ -78 A1 (E) OClClCl = CHO 1/5 (s, 3H), 1.6 (s, 3H), 4.4-4.8 ip'l (m, 5H), 5.1-6, 3 (m, 611), 6.2 (d, 1H), 7.15 (d, 2II), 7.4 (d, 1H), 8.15 (t, 1H).

3-70137 E-isomer: 1.5 (s, 311), 1.6 (s, 311), 2.6 (s, 3H), 4.6 (s, 1H), 4.65 (m , 211), 5.1-6.2 (m, 311),: 'v 25 CU3 6.2 (d' lu) 'M1 2 <d'! ») · 3 / ° - 7.7 (m, 3II).

-78 C 50 E isomer: lf5 (s # 3H), 1.6 (s, a3II), 4.55 (s, lii), 4.67 (m, 211), 5.0-6.2 ( m, 3H), 6.15 (d, 1H), 6.95 (d, III), 8.4-8.8 (m, 311).

Δ -78 C 13 E-isomer: 1.5 (s, 3H), 1.7 (s, 3 OClI 311), 4.55 (s, lii), 4.7 (m, 2H), 35 , 1-6.2 (m, 311), 6.2 (s, lii), 11 NA 6.5-7.0 (m, 311), 8.5 (d, lii).

X) 47 85376 A = hexane / ethyl acetate (9: 1), A1 = hexane / ethyl acetate (7: 3), B = chloroform, C = chloroform / ethyl acetate (9: 1), 5 D = chloroform / ethyl acetate (99: 1).

t 3 E-isomer (R is relative to anti-β-lactam) 3 Z-isomer (R is relative to syn γ-lactam)

Example 5 Sodium 6 (E) - (2-pyridyl) methylene penicillanate

A mixture of 0.120 g (0.38 mmol) of allyl 6- (E) - (2-pyridyl) methylene penicillanate, 20 mg of tetrakis (triphenylphosphine) palladium (0) and 20 mg of triphenylphosphine was dissolved in 3 To 0.7 ml of ethyl acetate and to this was added 0.76 ml (0.38 mmol) of a 0.5 molar solution of sodium 2-ethylhexanoate in ethyl acetate under a nitrogen atmosphere. The mixture was stirred at room temperature for two hours, the precipitate was collected by filtration, washed with ethyl acetate and dried in vacuo to give 57 mg (48%) of the title compound as a yellow solid. 1 H-NMR (D 2 O) ppm (delta): 1.55 (s, 6H), 4.33 (s, 1H), 6.17 (d, 1H, J = 0.5Hz), 7.03 (d, 1H, J = 0.5 Hz), 7.17-8.07 (m, 3H), 8.57 (m, 1H); Infrared spectrum (KBr): 3433, 1756, 1605 cm-1.

Example 6 Using the appropriate starting material selected from the allyl esters obtained in Example 4 in the process of Example 5, the following sodium salts are obtained in a similar manner.

30 48 8 5 376 r3cho ^ sn ^ CH3 I-1 rCH3 Λ-N-1 // 0 '' ISON 3% R_Isomer_Yield__Physical properties

Cl (E) 95 Yellow solid (1 H-NMR (δ) ppm (delta): 1.50 (s, 10 ", 3H), 1.58 (s, 3H), 4.3 (s, 1H), 83 (d, 1H), 7.1 (d, 1H), infrared spectrum (KBr) cm-1: 1573, 1607, 1688, 1775, 3460.

15 Cl (Z) 89 Infrared spectrum (KBr) cm-1: 1580, 1609, 1679, 1753, 3491.

White solid CH 3 S (E) 80 tea, 1 H-NMR (D 2 O) δ PPm (delta): 1.48 (s, 3H), 1.56 (s, 3H), 2.50 (s, 3K) , 4.20 (s, 1H), 5.88 (s, 1H).

7.2 (s. 1H); infrared spectrum (KBr) cm-1: 1396, 16060, 1749, 2926, 2963, 3552.

· CgII ^ (Z) 60 pale yellow powder C6H5 (E) 80 white powder 1 H-NMR (DO / DMSO) - ppm (delta: 1.5 (s, 6HJ, 4.25 (s, 1H), 6.1 (d, 1H), 7.0 (d, 1H), 7.4 (s, 5H); infrared (KBr) spectrum: 1626, 1642, 1655, 1742, 3434.

49 85376

Example 6A

Fenyylitiometyleeni-6-penicillanic

A mixture of 93 mg (0.26 mmol) of allyl 6-phenylthiomethylene penicillanate (mixture of isomers) and 10 mg of tetrakis (triphenylphosphine) palladium (0) and 10 mg of triphenylphosphene was dissolved in 1 ml of ethyl acetate and 0.52 ml was added. A 0.5 molar solution of sodium 2-ethylhexanoate in ethyl acetate at room temperature and the resulting mixture were stirred for 10 hours under a nitrogen blanket. Since very little salt precipitated, the mixture was quenched with water and extracted with methylene chloride. The aqueous layer was acidified (pH 3.5) and extracted with methylene chloride. The dried extracts were concentrated in vacuo to give 63 mg (75 Z) of the free acid as a mixture of isomers. 1 H-NMR (CDCl 3 ppm (delta: 1/5 (s, 2.1H), 1.55 (s, 0.9H), 1.6 (s, 2.1H), 1.65 (s, O , 9H), 4 r 4 (s, 0.7H), 4.5 (s, 0.3H), 54.33 (d, 0.7H), 5; 7 (s, 0.3H), 6.7 (s, 0H3H), 7.1 (d, 0.7H), 7.5 (m, 5H).

20

Example 7

Allyy1i-1,1-dioxo-6 (E) - (2-pyridyl) -metyleeni-; Penicillanate: To a solution of 1.30 g (4.09 mmol) of allyl: 25-E (-) - (2-pyridyl) methylene penicillanate in 15 mL of methylene chloride was added 1.70 g (8.2 mmol) of ) 80-85% pure m-chloroperbenzoic acid and a mixture were stirred under nitrogen for three hours at room temperature. After quenching with saturated sodium thiosulfate solution ____: 30 and water, the mixture was extracted with methylene chloride, the organic layer was adjusted to pH 7.5 with saturated sodium hydrogen carbonate solution, washed with water, dried (MgSO 4) and the solvent evaporated in vacuo to give 1.4 g (98 g). %) product yellow. . ·. 35 as an oil. The oil was purified by chromatography on a silica gel column eluting with hexane / ethyl acetate 7: 3 to give 0.78 g (55%) of the title sulfone as colorless crystals.

1 H-NMR (CDCl 3) ppm (delta): 1.48 (s, 3H), 1.63 (s, 3H), δ 4.45 (s, 1H), 4.73 (d, 2H), 5.1- 6.2 (m, 3H), 5.77 (d, 1H, J = 0.5Hz), 7.27 (d, 1H, J = 0.5Hz), 7.1-8.1 (ra, 3H) Δ 8.6 (m, 1 H); 13 C-NMR (CDCl 3) ppm (delta): 18.53, 20.43, 63.18, 64.25, 66.63, 72.04, 119.91, 124.64, 126.03, 130.68 , 132.83, 136.77, 150.31, 166.86, 168.11.

L0 Infrared red-1: 1323, 1586, 1759, 1783, 3437.

Example 8

Allyl 1,1-dioxo-6 (E) - (2-hydroxyethylidene) penicillanate To a solution of 0.190 g (0.61 mmol) of allyl 1,1-dioxo-6 (C) -formylmethylene penicillanate in 4 ml in dry tetrahydrofuran at -78 ° C was added 0.61 ml (0.61 mmol) of 1 mol. hexane solution of diisobutylaluminum hydride. The mixture was stirred at -78 ° C for ten minutes, quenched with methanol, stirred at room temperature for 20 minutes and filtered. The filtrate was concentrated in vacuo to give 0.258 g of a crude product which was diluted with water, extracted with chloroform and the organic layer dried (MgSO 4). Evaporation of chloroform gave 160 mg of material which was further purified by column chromatography on silica gel eluting with chloroform / ethyl acetate 4: 1 to give 113 mg (60%) of the title compound. 31 H-NMR (CDCl 3) ppm (delta): 1.40 (s, 3H), 1.60 (s, 3H), 2.60 (bs, 11), 4.3 (m, 211), 4 , 4 (s, 1H), 4.7 (d, 2H), 5.1-6.0 (m, 3II), 5.25 (d, 1H), 6.38 (m, 1H).

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Example 9A

Allyl 6 (E) - (11-oxoquinolin-2-yl) methylene] -1,1,1-dioxopenicillanate

Allyl 6 (E) -N- (quinolin-2-yl) methylene / -1-oxo-5 penicillanate (obtained as a by-product in the preparation of the corresponding sulfone, see previous example, star) (124 mg, 0.313 mmol) was dissolved in 5 mL of methylene chloride and 195 mg (0.904 mmol) of 80% m-chloroperbenzoic acid were added. The mixture was stirred at room temperature for 48 hours, quenched with water and extracted with methylene chloride. The extracts were washed with saturated sodium bicarbonate solution, water, dried and concentrated in vacuo to a yellow oil, the oil was purified by column chromatography on silica gel to give 45 mg (35%) of the title N-oxide as a yellow solid.

1 H-NMR (CDCl 3) ppm (delta: 1.45 (s, 3H), 1.6 (s, 3H), 4.45 (s, 1H), 4.7 (m, 2H), 5.0- 6.0 (m, 3K), 5.85 (d, 1H), 7.3-8.0 (m, 7H).

20 Example 10

Sodium 1,1-dioxo-6 (E) - (2-pyridyl) methylene penicillanate

A mixture of allyl 1,1-dioxo-6 (E) - (2-pyridyl) methylene penicillanate (0.14 g, 0.4 mmol), 20 mg tetrakis (triphenylphosphine) palladium (0) and 20 mg of triphenylphosphine was dissolved in 2 ml of ethyl acetate and 0.8 ml (0.4 mmol) of 0.5 mol was added under nitrogen. ethyl acetate solution of sodium 2-ethylhexanoate. The resulting mixture was stirred at room temperature for 3 minutes. The resulting precipitate was filtered off, washed with ethyl acetate and dried to give 0.13 g (95%) of the sodium salt as a yellow solid.

1 H-NMR (D 2 O) ppm (delta): 1.50 (s, 3K), 1.60 (s, 3H), 4.23 35 (s, 1H), 5.90 (d, 1H, J = 1Hz ), 7.1-8.0 (m, 4H), 8.57 (m, 1H), infrared spectrum (KBr) cm-1590, 1621, 1770, 3454.

56 85376

Example 11

Allyl 1,1-dioxo-6 (E) - (1-oxo-2-pyridyl) methylene penicillanate

A solution of allyl 1,1-dioxo-6 (E) - (2-pyr-5-ylidyl) methylene penicillanate (100 mg, 0.286 mmol) in 5 mL of methylene chloride was treated with m-chloroperbenzoic acid (120 mg, 0, 59 mmol) and stirred at room temperature for three days. The mixture was quenched with saturated sodium thiosulfate solution and extracted with methylene chloride. The organic layer was neutralized with saturated sodium hydrogen carbonate solution, washed with water, dried and evaporated to dryness to give 82 mg of a yellow oil. The yellow oil was purified by column chromatography on silica gel using ethyl acetate as eluent to give 22 mg (21%) of the title compound and 14 mg (13%) of the by-product, 2,3-epoxypropanyl-1,1-dioxo-6 (E) - (l-oxo-2-pyridyl) -metyleenipeni-sillanaattia.

Allyl 1,1-dioxo-6 (E) - (1-oxo-2-pyridyl) methylene-20 penicillanate: 1 H-NMR (CDCl 3) ppm (delta): 1.5 (s, 3H), 1.6 (s, 3H), 4.45 (d, li), 4.7 (d, 2H), 5.1-6.0 (m, 3H), 5.8 (s, 1H), 7.1- 8.4 (m. 5H).

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Example 13

Pivaloyloxymethyl 6 (E) - (methylthio) methylene-nipenisillanaatti

A mixture of 2.4 mmol (methylthiomethyl) -5 triphenylphosphonium chloride, 2.4 mmol of sodium amide in 5 ml of dry tetrahydrofuran (THF) was stirred at room temperature for 20 minutes. To the resulting yellow solution was added at -78 ° C a solution of 788 mg (2.4 mmol) of pivaloyloxymethyl-6-oxopenicillanate-10 in 10 mL of dry YHF. The mixture was stirred at -78 ° C for one minute, poured into saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried (Na 2 SO 4) and the solvent evaporated in vacuo to give 774 mg of crude product, which was purified by silica gel column chromatography eluting with chloroform to give 220 mg (24.5%) of pure product.

1 H-NMR (CDCl 3) ppm (delta): 1.25 (s, 9H), 1.50 (s, 3H), 1.65 (s, 3H), 2.45 (s, 3H), 4.45 (s, 1H), 6.85 (m, 3H), δ 7.0 (d, 1H).

Example 14

Pivaloyloxymethyl 6- (E) -methylsulfonylmethylcenipenicillanate-1-oxide (A) and the corresponding 1,1-dioxide (B) To a solution of 215 mg (0.58 mmol) of pivaloyloxymethyl-6 (E) - ( methylthiomethyl) methylene penicenate In 5 mL of methylene chloride was added 375 mg (1.74 mmol, 3 equivalents) of 80% m-chloroperbenzoic acid. The mixture was stirred at room temperature for 4 hours, quenched with water, saturated sodium thiosulfate solution, sodium hydrogencarbonate and extracted with chloroform. The organic phase was washed three times with water, dried (MgSO 4) and evaporated to dryness in vacuo to give 200 mg of a mixture of products. The crude mixture was purified by chromatography on silica gel eluting with

II

63 85376 with chloroform / ethyl acetate (9: 1) to give 25 mg of 1-oxide (A) and 45 mg of 1,1-dioxide product (B).

(A): 1 H-NMR (CDCl 3) ppm (delta): 1.21 (s, 9H), 1.3 (s, 3H), δ 1.7 (s, 3II), 3.1 (s, 3H ), 4.7 (s, 1H), 5.8 (AB quartet, 2H), 5.85 (d, 1H), 7.1 (d, 1H); infrared spectrum (CHCl 3) cm -1: 1333, 1759, 1807, 2927, 2960.

(B): 1 H-NMR (CDCl 3) ppm (delta): 1.2 (s, 9H), 1.45 (s, 3H), 1.6 (s, 3H), 3.15 (s, 3H) , 4.5 (s, 1H), 5.6 (d, 1H), 5.8 (AB quartet, 2H), 7.2 (d, 1H); infrared spectrum (CHCl 3) cm -1: 1324, 1758, 1800, 2929, 2956.

Example 15

Allyl 6-o (.- (N-methylpyrrol-2-yl) hydroxymethyl 1,1-dioxopenicillanate Allyl 6-o (.-Bromo-1,1-dioxopenicillanate (520 mg, 1.48 mmol) ) was dissolved in 10 ml of dry tetrahydrofuran (THF) and cooled to -73 [deg.] C. A solution of methylmagnesium bromide (0.52 ml, 2.85 mol in THF) was added and the mixture was stirred for 5 minutes. -78 [deg.] C. N-methylpyrrole-2-carboxaldehyde (162 mg, 0.16 ml) was added and stirring was continued at -78 [deg.] C. The mixture was poured into saturated ammonium chloride solution, extracted with ethyl acetate and the organic layer dried ( Evaporation of the solvent in vacuo gave 466 mg of crude product which was purified by chromatography on silica gel eluting with chloroform / ethyl acetate (9: 1) to give 180 mg (32%) of pure title compound.

1 H-NMR (CDCl 3) ppm (delta): 1.4 (s, 3H), 1.62 (s, 3H), 3.68 (s, 311), 4.0-4.4 (m, 1H ), 4.42 (s, 1H), 4.5-4.8 (m, 3H), 5.0-6.0 (m, 4H), 6.0-6.7 (m, 3H).

Example 16

Allyl 6 (E) - (N-methylpyrrol-2-yl) methylene 1,1-dioxopenicillanate Allyl 6- (N-methylpyrrol-2-yl) hydroxymethyl 1,1-dioxopenicillanate (180 mg, 0.47 mol) 64 8 5 376 were dissolved in 3 lanes of tetrahydrofuran and 0.15 ml of acetic anhydride and 0.2 ml of pyridine were added.

The mixture was stirred at room temperature for one hour. The reaction was quenched with water and extracted with ethyl acetate-5. The organic layer was dried and the solvent was evaporated in vacuo to give 162 mg of material which still contained starting material. This was dissolved in methylene chloride (3 ml) and 0.15 ml of acetyl chloride and 0.2 ml of pyridine were added. The mixture was stirred for two hours at room temperature and worked up as above to give 140 mg of crude product which was purified by chromatography on a silica gel column to give 72 mg (42%) of pure product. Recrystallization from ethyl acetate gave colorless needles.

1 H-NMR (CDCl 3) ppm (delta): 1.45 (s, 3H), 1.65 (s, 3H), 3.7 (s, 3H), 4.4 (s, 3H), 4, 6-4.9 (m, 2H), 5.1-6.4 (m, 4H), 6.6-7.0 (m, 2H), 7.5 (dd, 1H).

Example 17

Sodium 6 (E) - (N-methylpyrrol-2-yl) methylene-1,1-dioxopenicillanate

A solution of 46 mg of allyl 6 (E) - (N-methylpyrrol-2-yl) methylene-1,1-dioxopenicillanate, 5 mg of tetrakis (triphenylphosphine) palladium (0), 4 mg of triphenylphosphine and one mL of methylene chloride was stirred under a ty-25 pen for five minutes. The resulting mixture was diluted with one ml of ethyl acetate and 0.25 ml of sodium 2-ethylhexanoate in ethyl acetate was added. After stirring for 1 hour at room temperature, the mixture was filtered and the precipitate was washed with ethyl acetate and ethyl ether to give 30 mg of a yellow solid. 1 H-NMR (D 2 O) ppm (delta): 1.50 (s, 3H), 1.60 (s, 3H), 3.65 (s, 3H), 4.10 (s, 1H), 5.4 (s, 1H), 6.1-6.5 (m, 1H), 7.0 (s, broad, 2H), 7.2-7.4 (m, 1H); infrared (KBr) cm-1: 1568, 1616, 1660, 1745, 3465.

65 85376

Example 18 Using the appropriate aldehyde of the formula R 1 CHO in the process of Example 15, the corresponding compounds of the formula below 5 OH 0 O are obtained.

R13-CH V CH

R CH3- ^ S \ / 3 i-f rCH3

J-N-L

δ // COOCH2CH = CH2 10 R ^ 3 Yield% Silica gel (1 H-NMR (CDCl 3) ppcn (delta); _elute x) __ _ 30 A 6-0 ε-isomer: 1.4 (s ^ θΛ 0.39H), 1.5 (s, 2.61H), 15 1r 62 (s, 0.39H), 1.7 (s, 2.61H), 3.0 (bs, 1H), 4.0-4.4 (m, 1H), 4.45 (s, 1H), 4.5-4.9 (m, 2H), 5.1-6.1 (m, 4H), 6.3-6.6 (m, 2H), 7.45 (m, 3-H).

a 6 A Isomers 6-O, 8R and 6-c (.8S

O mixture r — Π 38 A 1.4 (s, 3H) lr60 (s, 25 '' UiA 3H), 2.50 and 2.60 (s, CCCH3 3H), 4.1-4.4 (m, 1H), 4.4 and 4.5 (s, 1H), 4.6-5.0 (m, 3H), 5.1-6.0 (m, 4H), 6.0-7.2 (m, 4H).

66 8 5 376

Example 18 (continued)

Silica gel R13 Yield% eluent x) 1h-N> IR (CDCl 3) drill (delta):

C 9 H 5 78 A 1 T 4 (s, 3H), 1.6 (s, 3H), 3.28 (bs, 1H), 3.8-4.2 δ (ra, 1H), 4.35 (s, 1H ), 4.45-4.8 (m, 3H), δ; -6-6 (m, 4H), 7.3 (s, 5H).

fpY '33 B 1.3 (s, 3H), 1.55 (s, 3H), 4.04 (bs, 1H), 4.35 10 (s, 1H), 4f 5-4.85 (ra , 3H), 5.1-6.1 (m, 4H), 7.1-7.4 (m, 1H), 7.6-8.0 (m, 1H), 8.2-8.7 (m, 2H), ).

S 35 B 1.3 (s, 3H), 1.55 (s, 3H), 4.0 (ra, 1H), 4.35 (s, 1H), 4.4-6.8 (ra , 3H), 5.1-6.2 (m, 4H), 7.2-7.5 (m, 2H), 8.2-8.6 (m, 2H).

Π Π 50 B 1.25 (s, 0.75H), 1.35 (s, 20 ^ sA 2.25H), 1.55 (s, 3H), 3.3 (bs, 1H), 4.05 (dd, 1H), 4; 3 (s, 1H), 4.3-4.8 (m, 3H), 5.0-6.2 (m, 4H), 6.8-7.4 (m, 3H); .

67 85376

Example 18 (continued)

Silica gel R13 Yield% eluent x) 1 H-NMR (CDCl 3) ppm (delta): CH -, = CH 21 1.4 (s, 3H>, 1.6 (s, 3H), 3.0 (bs , 1H), 3.7-4.0 (m, 5H), 4.4-4.8 (m, 4H), 5.0-6.3 (m, 6H).

jj — p 25 D 1.36 (s, 1.5H), 1.40 (s, 1.5η), 1.60 (s, 1V5H), CH3 1.65 (s, lt5H), 3.7 ( s, 3 3 H), 4.0-4.5 (m, 2H), 4.4 (s, 1H), 4.5-4.3 (m, 2H), 5.0-6.0 (m , 4H), 6.7 (s, 1H), 6.85 (s, 1H).

] D 5 -vt 52 D 6 -O, 8S isomer: 1.4 H ii (s, 3 H), 1.6 (s, 3 H), 4.38 (dd, 1 H), 4.43 (s , 1H), 4.67-4.75 (m, 2H), 4.76 (d, 1H), 5.3-5.5 (m, 2H), 5.63 (d, 1H), , 85-6.05 (m, 1H), 7.4 (d, 1H), 7.8 fd.

- 6-c, 8R-isane: 1.36 (s, 3H), 1.60 (s, 3H), 4.22 (d, 1H), 4.4 (s, 1H), 4f65 (m , 2H), 4.88 (s, 1H), 5.25-5.5 (m, 2K), 5.55 (d, 1H), 5.8-6 (m, 1H), 7.35 ( d, 1H), 7.75 (d, 1H).

68 8 5376

Example 18 (cont.) 13% Yield Silicate gel R (eluent x) (MMRtcpcl ^ ipDmtd)): ^ 6 ^ 5- ^ * E 6-of, 8S isomer: 1.44 (s, 3H), 1.62 ( s, 3H), δ 3.68 (bs, 1HJ, 4.31 (dd, 1H), 4.5 Cs, 1H), 4.74 (d, 2H), 4.86 (d, 1H), δ , 4 (m, 3H), 5.9 (m, 1H), 7/5 (m, 3H), 8.02 (s, 10H), 8.14 (m, 2H), IR: 3482, 1802 en-1.

, a, t · x. Porate without 6-o (, 8S-N 57 crude A (polar isomer, 41 (s 3H) \ tcmarnpi ° isomer) 1.6 (s, 3H), 4.45 (s, 1K), 8 MP F ( polar-cern isomer) 4.4-4.8 (m, 4H), 5 / 2-5 {6 (m, 3H), 3, -O, 3 (m, 1H), 7.35 ( t, 1H),

More polar 6-o (8R-iso-iodide: 1.45 (s, 3H), 1.6 (s, 3H), 4.4 (s, 1H), 4> 45 (dd, 1H), 4 (7-4.9) (m, 2H), 4.95 (d, 1H), 5.2-3.6 (m, 3H), 3.7-25, 6.3 (m, 1H); ), 7.35 (t, 1 H), 8.85 (d, 1 H).

69 85376

Example 18 (continued), 7a Silica silica RX Baan ° ~ ° eluent x) ____ 1 H-NMR (CSCl 3) .ppm (delta): a 25% l.frak- D 1. Fraction: 1.4 (s, 3K) , thio (one iso-, _, ter) ^ s' 3H ^ '4 <-2 "- ·» 4 (m' 5 12% 2.fraction 2K), 4.5-5.0 (m, 3H) , 5.1- (mixture of 2 isomers), 5.1 (t 1 / 6H), 7.6 (d / 1λ) / 8T 37 Cd, 1H), 9.23 (s, 1H).

& 56 D 1.4 (s, 3H), 1T57 (s, 3K), 70:30 isonee- 4.25 (m, 1H), 4.37 (s, 10 alloy 0.7H), 4.42 (s, 0.3η), 4.75 (m, 2K), 4.8 (d, 0.3K), 4.35 (d, 0.7H), 5.25-5.5 (m, 3K), 5 ., 9 (m, 1K), 852 (m, 2H), 8.34 (m, 1H).

B

22 D 1.4 (s, 1H), 1.46 (s, 2K), LLr> isomers 1.6 (e, 1H), 1.63 (s, 2H), 4.12 (m, 1H), 4.22 (n, 1K), 4.41 and 4.46 (s, 1H), 4.6-4.3 (m, 2H), 4.95 (d, 1H), Δ (m, 3H), 5.9 (m, 1H), 6.95 and 7.05 (s, 1K), 7.23 and 7.36 (s, · · 1H).

1-Diethoxymethylimidazole-2-carboxaldehyde 70 85376 was used as the starting aldehyde.

Example 18 (continued)

Silicate 13 Yield% eluent x) -t - ± ------- 1 H-NMR (CDCl 3) drill (delta): 35 G 1.33-1.40 (d, 3H), l 56-5 two i, 57 (d, 3H), 4.20-4.40 isomer 1 (m, 2H), 4.59-4.72 (m, 2H), 4.86-4 ^ 88 (d, 0H) , 5H), 5j 04-5.06 (d, 0.5H), 5.26-5.42 (m, 2H), 5.50-10.62 (m, 1H), 5.32-6 , 00 (m, 1H), 7.50-7.86 (m, 1H), 7.90-9.03 (π, 1H), 9.02-9.10 (m, 1H)

Infrared spectrum: 15 L - x 1800 cm x) Λ - chloroform / ethyl acetate (9: 1) 20 B - ethyl acetate / chloroform (7: 3) O - chloroform / ethyl acetate (19: 1) D - chloroform / methanol (19: 1) ) E - chloroform - _ F - chloroform / ethyl acetate (1: 1) 25 G - ethyl acetate

Example 19

Allyl 6- (furan-2-yl) methylene-1,1-dioxopenicillanate, (E) - and (Z) -isomers

To a solution of 310 mg (0.84 mmol) of allyl 30- [6- (furan-2-yl) hydroxymethyl 1,1-dioxopenicillanate in 5 mL of methylene chloride was added 0.15 mL (1 mmol) of methylene chloride. triethylamine and 0.1 ml (0.924 mmol) of trifluoromethylsulfonyl chloride and the mixture was stirred under nitrogen at room temperature for two hours. Reaction -35 was quenched with water, extracted with methylene chloride,

II

71 85376 teas were dried (MgSO 4) and the solvent evaporated in vacuo to give 330 mg of crude product. Purification by chromatography on a silica gel column eluting with chloroform gave 130 mg of product, which was estimated by HPLC to be a 4: 1 mixture of (E) and (Z) isomers.

1 H-NMR (CDCl 3) ppm (delta): 1.47 (s, 3H), 1.61 (s, 3H), 4.47 (s, 1H), 4.75 (d, 2H), 5.1 -6.2 (m, 4H), 5.52 (dd, 1H), 6.8 (m, 1H), 7.15 (d, 1H), 7.6 (d, 1H).

10 Example 20

Allyl 6 (E) - (N-acetylpyrrol-2-yl) methylene 1,1-dioxopenicillanate A. Allyl 6- (N-acetylpyrrol-2-yl) acetoxymethyl 1,1-dioxopenicillanate 6- (N-Acetylpyrrol-2-yl) hydroxymethyl 1,1-dioxopenicillanate (210 mg, 0.51 mmol) was dissolved in 3 ml of tetrahydrofuran and 0.16 ml of acetic anhydride and 0.2 ml of pyridine and a mixture were added. stirred at room temperature for 24 hours. The reaction was quenched with water, extracted with methylene chloride, dried and evaporated to dryness to give 171 mg (75%) of yellow crystals.

1 H-NMR (CDCl 3) ppm (delta): 1.4 (s, 3H), 1.6 (s, 3H), 2.15 (s, 3H), 2.55 (s, 3H), 4.15 -4.3 (dd, 1H), 4.4 (s, 1H), 4.6-4.8 (m, 3H), 5.1-6.0 (m, 3H), 6.1- 6.6 (ra, 2H) 6.6-7.4 (m, 2H).

B. The product of Part A, Ν, Ο-diacetate, 170 mg (0.38 mmol), was dissolved in methylene chloride and 47 mg (0.38 mmol) of 1,5-diazabicyclo / 4.3.07-non-5-ene (DBN) was added. .

The mixture was stirred at room temperature for one hour. Water was added and the mixture was extracted with methylene chloride. The extracts were dried and evaporated to dryness to give 158 mg of an oil which was purified by chromatography on silica gel using 2% ethyl acetate in chloroform as eluent to give 108 mg of product as a pale yellow oil.

72 85376 1 H-NMR (CDCl 3) ppm (delta): 1.5 (s, 3H), 1.6 (s, 3H), 2.55 (s, 3H), 4.4 (s, 1H), 4 , 65 (d, 2H), 5.0-6.0 (m, 4H), 6.3 (t, 1H), 6.8 (dd, 1H), 7.2 (m, 1H), 2 (d, 1 H).

Example 21 Allyl 6 (E) -phenylmethylene-1,1-dioxopenicillanate and the corresponding (Z) -isomer A. Using 1.98 mmol of allyl 6-phenylhydroxymethyl 1,1-dioxopenicillanate in the procedure of Part A of the above example , 4.2 mmol of acetyl chloride and 0.4 ml of pyridine gave 0.7 g (84%) of allyl 6-phenylacetoxymethyl 1,1-dioxopenicillanate as a pale yellow resin.

1 H-NMR (CDCl 3) ppm (delta): 1.3 and 1.4 (s, 3H), 1.62 (s, 3H), 2.08 and 2.2 (s, 3H), 4.2 ( dd, 1H), 4.4 (s, 1H), 4.5 (d, 1H), 4.65 (d, 2H), 6.25 (m, 1K), 7.3 (m, 5H) .

B. To a solution of the product of Part A (0.7 g, 1.66 mmol) in methylene chloride was added 0.25 mL (1.67 mmol) of 1,5-diazabicyclo / 5.4.07undek-5-ene (DBU). and the mixture was stirred at room temperature for ten minutes.

Water and methylene chloride were added, the layers were separated and the organic extracts were washed with 0.1 N hydrochloric acid, brine and water. The extracts were dried (Na 3 SO 4) and the solvent evaporated to give 660 mg of crude product which was purified by column chromatography on 100 g of silica gel eluting with chloroform to give 68 mg (11%) of the (Z) -isomer; 1 H-NMR (CDCl 3) ppm (delta): 1.45 (s, 3H), 1.60 (s, 3H), 4.45 (s, 1H), 4.68 (d, 2H), 5.37 (d, 1H), 5.1-6.05 (m, 3H), 7.35 (d, 1H), 7.45 (s, 1H).

The following eluate fractions gave 100 mg (16.7%) of the (E) -isomer of the title compound as a colorless oil which formed crystals on standing.

1 H-NMR (CDCl 3) ppm (delta): 1.45 (s, 3H), 1.58 (s, 3H), (s, 1H), 4.75 (d, 2H), 5.45 (d, 1H), 5.2-6.2 (m, 3H), 35.36 (d, 1H), 7.45 (s, 5H).

73 85376

Example 22

By the method of Example 19, the following compounds were prepared from the appropriate hydroxy compounds obtained in Example 18.

5 0 0

3 W CH

R γ — rsY «3 0 ^ ^ 'COOCH-CHCH- 10 ^ ^ 3 Yield Silica gel> R _ eluent_ H-NI-1R (CDCl3,) pam (delta): 22 (E) Ethyl ether- (E) isomer: 1.5 (s, 3H), 19 (2) 1 (7 (s, 3H), 4r5 (s, 1H), 4.7 (d, 2H), 5.5 (d, 1H) , 5.1-6.2 (m, 3H), 7.3-7.5 (m, 2H), 7.7-3.0 (m, 1H), 8.53-8.83 (m, 2H) (Z) -isane: 1.48 (s, 3H), 1.6 (s, 3H), 4.5 (s, 1H), 4.7 (d, 2H), 5.25 (s, 1K), 5.1-6.2 (m, 3H), 6.88 (s, 1H), 7.2-7.5 (m, 1H), 08.43-9.0 (m, 3H).

36 Ethyl-isomer mixture: 1.45 (s, tate / cyano (1: 1) 3H), 1.62 (s, 3H), 4.5 (s, 1H), 4.7 (d, 2H ), 5.2-6.2 (m, 4H), 6.75 (s, 20H, 0.3H), 7.2-7.5 (m, 1.7H), 7.6-7.35 ( m, 1H), 8.5-8.83 (m. 2H).

74 85376

Example 22 (continued)

Silica gel r3 Yield% eluent 1 H-NMR (CDCl 3) ppm (delta): δ 14 CHCl 3 1.45 (s, 3H), 1.6 (s, 3H), 4.4 (s, 3H), 4.7 ( d, 2H), δ 5.0-6.2 (m, 3H), 5.25 (d, 1H), 7.0-7.65 (m, 4H).

CH 2 = CH- 18 CHCl 3 1.45 (s, 3H), 1.65 (s, 3K), 3.7-4.2 (m, 1H), 4.45 (s, 0.6H), 4.5 ( s, 0.4η), 4.75 (d, 2H), 5.1-6.4 (m, 7H).

75 85376

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Example 24 6 (E) -Phenylmethylenepenicillanic acid 1,1-dioxide

To a solution of 0.1 g (0.28 mmol) of allyl 5-6 (E) -phenylmethylene-1,1-dioxopenicillanate, 20 mg of triphenylphosphine and 20 mg of tetrakis (triphenylphosphine) palladium (0) In 3 ml of ethyl acetate, 0.57 ml of 0.5 mol of sodium 2-ethylhexanoate was added, and the mixture was stirred at room temperature for 1 hour. After stirring in place in the refrigerator for 65 hours, no precipitate had formed. The mixture was diluted with ethyl acetate and water, the pH of the separated aqueous layer was adjusted to 1.8 with dilute hydrochloric acid, extracted with fresh ethyl acetate, the extracts dried (Na 2 SO 4) and the solvent evaporated in vacuo to give 62 mg (69%) of product as yellow crystals (acetone). ).

1 H-NMR (CD 3 COD 3) ppm (delta): 1.55 (s, 3H), 1.65 (s, 3H), 4.43 (s, 1H), 5.93 (d, lii), 7.3 -7.9 (m, 6 H), 8.7 (bs, 1 H); Infrared spectrum (KBr) cm-1327, 1685, 1737, 1772, 2961, 20 3108, 3477.

Example 25

Potassium 6 (E) - (1-methylimidazol-3-yl) methylene 1,1-dioxopenicillanate A. Allyl 6- (1-methylimidazol-2-yl) acetoxy-25-methyl- 1,1-Dioxopenicillanate 6- (1-methylimidazol-2-yl) hydroxymethyl 1,1-dioxopenicillanate (472 mg, 1.23 mmol) was acetylated by the method of Example 20 Part A to give 392 mg (75% ) acetoxy as a mixture of two isomers.

1 H-NMR (CDCl 3) ppm (delta): 1.4 (s, 1.5H), 1.5 (s, 1.5H), 1.6 (s, 1.5H), 1.7 (s, 1H), 2.2 (s, 3H), 3.7 (s, 1.5H), 3.75 (s, 1.5H), 4.0-6.0 (m, 8H), 6.3 -6.5 (m, 1 H), 6.8 (m, 1 H), 7.0 (m, 1 H).

35 B. Allyl 6 (E) - (1-methylimidazol-2-yl) methylene 1,1-dioxopenicillanate 80 85376

The product from Part A above (392 mg, 0.920 mmol), 5 mL of methylene chloride, and 0.115 mL of 1,5-diazabicyclo [4.3.0] non-5-ene (DBU) were reacted to give the title ester by the method of Example 20, Part B. 53% I get-5 approx.

1 H-NMR (CDCl 3) ppm (delta): 1.5 (s, 3H), 1.6 (s, 3H), 3.7 (s, 3H), 4.35 (s, 1H), 4.7 (m, 2H), 5.0-6.1 (m, 3H), 5.7 (d, 1H), 6.9 (m, 1H), 7.1 (d, 1H), 7.2 ( m, 1H).

C. The allyl ester from Part B (163 mg, 0.45 mmol-10) was converted to the title potassium salt by the method of Example 17, however, using potassium 2-ethylhexanoate instead of the corresponding sodium salt. The amount of the obtained product was 143 mg (yield 87%) of one (E) -isomer.

1 H-NMR (DMSO) ppm (delta): 1.38 (s, 3H), 1.45 (s, 3H), 3.8 (s, 4H), 5.68 (s, 1H), δ, 15 (s, 1 H), 7.35 (m, 2 H); 13 C-NMR (DMSO) ppm (delta): 18.5, 20.2, 32.5, 64.4, 66.2, 70.55, 115.2, 124.6, 129.9, 130.6 , 141.2, 167.9, 169.0.

Infrared Spectrum (KBr) cm-1614, 1762, 3428.

Example 26 The procedure of Example 10 was repeated with 50 mg (0.12 mmol) of allyl 6- (3-allyloxy-2-pyridyl) methylene-1,1-dioxopenicillanate using 5.2 mg of triphenylphosphine, 5.2 mg of tetrakis ( triphenylphosphine) palladium (0) and 0.24 mmol of potassium 2-ethylhexanoate 25 (2 molar equivalents relative to the starting allyl ester in 1.5 ml of ethyl acetate and stirring the resulting mixture for 18 hours) The ethyl acetate was aspirated off with a pipette and the residue was washed twice with 1 ml. ethyl acetate to give a dark solid, 43 mg, which was found to be the dipotassium salt of 6- (E) - (3-hydroxy-2-pyridyl) methylene-1,1-dioxopenicillanic acid.

1 H-NMR (D 2 O) ppm (delta): 1.56 (s, 3H), 1.62 (s, 3H), 4.27 (s, 1H), 6.00 (d, 1H), 7.29 (m, 2H), 7.80 (d, 1H), 8.04 (d, 1H).

81 65376

Example 27

Allyl 6 (E) - (2-pyrimidinyl) methylenepenicillanate A. 2-Hydroxymethylpyrimidine A slurry of sodium ethylate prepared from 7.44 g (323 mmol) of sodium metal and 300 mL of absolute ethanol was cooled to room temperature. , 18 g (163 mmol) of hydroxyacetamidine hydrochloride and 8.06 ml (81 mmol) of 3-dimethylamino-10 acrolein were added and the mixture was heated to boiling. Dimethylamine was slowly distilled off with occasional addition of ethanol to keep the volume of solvent the same. After boiling for nine hours, the mixture was then stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was applied to a silica gel column and eluted with ethyl acetate / methanol 19: 1 to give 4.1 g of product (46% yield).

B. 2-Pyrimidinylmethyltriphenylphosphonium chloride 2-Hydroxymethylpyrimidine, 4.096 g (37.2 mmol) was dissolved in 80 ml of methylene chloride and 8.6 ml (37.2 mmol) of thionyl chloride were added dropwise (exothermic reaction). The mixture was stirred for 15 minutes, neutralized with saturated sodium hydrogen carbonate solution and extracted with methylene chloride. The extracts were dried and the solvent evaporated to give 3.67 g of 2-chloromethylpyrimidine.

1 H-NMR (CDCl 3) ppm (delta): 4.82 (s, 2K), 7.3 (t, 1H), 8.9 (d, 2H).

A mixture of 3.565 g (27.7 mmol) of 2-chloromethylpyrimidine in 30 ml of toluene and 7.269 g (27.7 mmol) of triphenylphosphine was heated at reflux for 18 hours. The resulting precipitate was collected by filtration and dried to give 9.06 g (65% over two steps).

82 8 5376 C. A mixture of 2.187 g (5.6 minol) of the Wittig reagent obtained in Part B above, 218.4 mg (5.32 mmol) of sodium amide and 30 ml of dry tetrahydrofuran (THF) was stirred at room temperature for 1 hour. , 5 hours.

At 5-78 ° C, a solution of 1.44 g (5.65 mmol) of allyl 6-oxopenicillanate in 10 mL of dry THF was added in one portion, the resulting mixture was stirred for five minutes, poured into saturated ammonium chloride solution and extracted with chloroform. The organic phase was washed with saturated ammonium chloride solution, brine, dried (MgSO 4) and the solvent evaporated in vacuo. The resulting oil was purified by silica gel column chromatography eluting with chloroform / ethyl acetate 9: 1 to give 560 mg of pure product.

1 H-NMR (CDCl 3) ppm (delta): 1.5 (s, 3H), 1.6 (s, 3H), 4.6 (s, li), 4.7 (m, 2H), δ, 1-6.3 (m, 3H), 6.2 (d, 1H), 7.5 (d, 1H), 7.0-7.35 (m, 1H), 8.8 (d, 2H) .

Example 28 Allyl 1,1,1-dioxo-6 (E) - (2-pyrimidinylmethylenepenisil-20-sanoic acid and potassium salt A. Allyl 6 (E) - (2-pyrimidinyl) methylene penicillanate (560 mg, 1.69 mmol) and 3-chloroperbenzoic acid (730 mg, 3.38 mmol) were dissolved in 10 mL of methylene chloride and stirred under a nitrogen atmosphere for 4 hours, quenched with water, extracted with methylene chloride, washed with sodium thiosulfate, neutralized with sodium thiosulfate, neutralized with sodium thiosulfate. washed with brine, dried and concentrated in vacuo to give 460 mg of a crude oil, the oil was purified by 3Q chromatography on a silica gel column eluting with chloroform / ethyl acetate 9: 1 to give 180 mg of the desired allyl ester as a pale yellow solid.

1 H-NMR (CDCl 3) ppm (delta): 1.45 (s, 3H), 1.65 (s, 3H), δ 4.5 (s, 1H), 4.75 (m, 2H), δ, 2-6.3 (m, 3H), 5.75 (s, 1H), 7.1-7.5 (m, 2H), 8.9 (d, 2H).

I; 83 85376 B. Reaction of the allyl ester obtained above with triphenylphosphine, tetrakis (triphenylphosphine) palladium (0) and potassium 2-ethylhexanoate according to the procedure of Example 10 gave the desired potassium salt in 89% yield as a pink solid.

1 H-NMR (D 2 O) ppm (delta): 1.6 (s, 3H), 1.68 (s, 3H), 4.4 (s, 1H), 6.1 (s, 1H), 7.48 (s, 1H), 7.54 (t, 1H), 8.88 (d, 2H); 13 C-NMR (D 2 O) ppm (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 Spectrum (KBr) cm-3: 1560, 1615, 1771, 3439.

Example 29 A. To a mixture of 1.0 g of 6-o-hydroxypenicillanic acid in 25 ml of methylene chloride are added 50 mg of di-isopropylcarbodiimide and 0.5 ml of 2,2,2-trichloroethanol. The mixture is stirred overnight, the solvent is removed by evaporation in vacuo and the crude product is purified by column chromatography on silica gel to give 2,2,2-trichloroethyl 6-o-hydroxypenicillanate.

B. To a mixture of 1.0 g of 6-o {-hydroxypenicillanic acid in 50 ml of dioxane are added 0.5 g of p-toluenesulfonic acid and 0.4 g of dihydropyran and the mixture is heated to 50 ° C, then stirred overnight at room temperature. Evaporation of the solvent and purification by column chromatography on a silica gel column gives 2-tetrahydropyranyl-6-o (-hydroxypenicillanate).

Example 30

Benzyl-6-oksopenisillanaatti

To a solution of 1.8 ml (0.025 mol) of dimethyl sulfoxide in 2 ml of methylene chloride at -60 ° C was added dropwise a solution of 2.12 ml (0.015 mol) of trifluoroacetic anhydride in 5 ml of methylene chloride. The mixture was stirred at -60 ° C for 20 minutes, a solution of 350 mg (1.14 mmol) of benzyl 35-hydroxypenicillanate in 5 ml of methylene chloride was added and stirring was continued at -60 ° C for 60 minutes. Triethylamine (0.50 ml) was added, the cooling bath was removed, the mixture was warmed to 0 ° C, poured into ice water and extracted with methylene chloride. The organic layer was dried, concentrated to low volume in vacuo, diluted with benzene and washed three times with ice water. The benzene layer was dried, and the solvent was evaporated in vacuo to give 230 mg (67%) of the product as yellow crystals. The proton NMR spectrum in CDCl 3 showed the product to be very pure.

Example 31

Benzyl 6- (2-pyridyl) hydroxymethylpenicillanate A. Benzyl 6-bromo-6- (2-pyridyl) hydroxymethylpenicillanate

A solution of 9.0 g (0.02 mol) of benzyl 6,6-dibromopenicillanate in 200 ml of freshly distilled toluene is cooled to -78 ° C and 9 ml of 2.2 mol are added dropwise. t-butyllithium pentane solution. The resulting mixture was stirred for 30 minutes, 2.14 g (0.02 mol) of 2-pyridinecarboxaldehyde was added and stirring was continued for another 40 minutes. The reaction was quenched by the dropwise addition of acetic acid in toluene. After stirring for 1 hour, the cooling bath was removed, the mixture was warmed to -10 ° C, diluted with 200 mL of toluene, washed with water (5 times) and dried (Na 2 SO 4). The toluene solution was applied to a Florisil column (1 kg) and eluted with toluene / ethyl acetate 2: 1. The product fractions were combined and evaporated in vacuo to a brown Siira-30 pitch, 4.2 g, which was used in the next step.

B. The brown syrup obtained in Part A (4.2 g) was dissolved in 50 ml of benzene and 2.65 g of tributyltin hydride was added. The mixture was heated at reflux for 2 hours, more tributyltin hydride (1.65 g) was added and heating at reflux was continued overnight. The solvent was evaporated in vacuo, the residue was washed with hexane and applied to a column of 500 g of silica gel, eluting with toluene / ethyl acetate 2: 1 to give 425 mg of the title compound.

1 H-NMR (CDCl 3) ppm (delta): 1.35 (s, 3H), 1.7 (s, 3H), 4.0 (dd, 1H), 4.5 (s, 1H), 5.1 ( s, 2H), 5.2 (d, 1H), 5.4 (d, 1H), 7.0-7.8 (m, 3H), 8.5 (m, 1H).

Example 32 6- (2-Pyridyl) hydroxymethylpenicillanic acid 1,1-dioxide A. Benzyl 6- (2-pyridyl) hydroxymethyl 1,1-dioxopenishanate

To a solution of 0.40 g of benzyl 6- (2-pyridyl) hydroxymethylpenicillanate in 5 ml of methylene chloride was added 0.20 g of m-chloroperbenzoic acid, and the mixture was stirred at room temperature for 1 hour. Oh-chromatographic analysis showed the mixture to contain some sulfoxide. An additional 0.2 g of m-chloroperbenzoic acid was added and the mixture was stirred overnight. The mixture was diluted with methylene chloride, washed alternately with saturated sodium thiosulfate solution, water, saturated sodium hydrogen carbonate solution, and the organic layer was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with sodium bicarbonate solution, water, brine, and dried (Na 2 SO 4).

Evaporation of the solvent gave 330 mg of the desired benzyl ester as a brown oil which was purified by column chromatography on silica gel eluting with ethyl acetate / hexane 11: 9 to give 60 mg of a yellow oil.

1 H-NMR (CDCl 3) ppm (delta): 1.25 (s, 3H), 1.52 (s, 3H), 4.1 (dd, 1H), 4.5 (s, 1H), 4.72 (d , 1H), 5.5 (d, 2H), 5.8 (d, 1H), 7.1-8.0 (m, 3K), 8.5 (m, 1H).

B. A suspension of 118 mg of 10% 35 Pd / C catalyst in 10 ml of tetrahydrofuran (THF) and 86 85376 4 ml of water was prehydrated for 20 minutes under 3 atmospheres of hydrogen pressure. To this was added 130 mg of the benzyl ester obtained in Part A above in 4 mL of the same THF / water mixture. This was hydrogenated at 50 psi (3.5 kg / cm) for 30 minutes. A further 129 mg of 10% Pd / C was adjusted to Li-5 and hydrogenation was continued at 50 psi for two hours. The catalyst was removed by filtration, the solvent was evaporated off in vacuo and the residue partitioned between water and ethyl acetate. The aqueous layer was lyophilized to give 85 mg of the desired acid.

1 H-NMR (D 2 O) ppm (delta): 1.3 (s, 3H), 1.5 (s, 3H), 4.4 (s, 1H), 5.0-5.35 (m, 2H) Δ 5.9 (d, 1 H):

Infrared Spectrum (KBr) cm 1620, 1731, 3407.

C. However, when the above procedure is carried out, using only a total of 175 mg of m-chloroperbenzoic acid (equimolar) in Part A, the isolated product is a mixture of the corresponding o- and β-sulphoxides.

Example 33

The following substances are mixed together to give a powder having a uniform composition in the following ratios: (a) Potassium (6-, 8R) -6- (thiazol-2-yl) acetoxymethyl-1,1- dioxopenicillin 1.0 N (25) Ampicillin trihydrate 1.0: (c) Lactose 0.5 (d) Polyethylene glycol, average molecular weight 4000 3.0

The mixture (1375 mg) is filled into suitably sized hard gelatin capsules to give capsules containing 250 mg of effective each active ingredient. More potent or dilute capsules are made by adjusting the capsule size and fill weight to suit. The relative weights of the active ingredients are adjusted so as to obtain capsules in which the weight ratio of the active ingredients is other than one, e.g. the ingredients are mixed in a weight ratio of 0.75, 1.5, 0.5 and 3.0, respectively. with a fill weight of 1700 mg / capsule to give capsules with 225 mg of effective (a) and 450 mg of effective 5 (b).

Similarly, other β-lactamase inhibitors of this invention are compounded with other common β-lactam antibiotics for oral use.

Alternatively, ingredients (a) and (b) are replaced in the above recipe by 2 parts by weight of 6- [b- (2-amino-2-phenylacetamido) -7-penicillanoyloxymethyl-6- (2-pyridyl) methylene-1,1] -dioksopenisillanaatti hydrochloride. Example 34 Injectable Preparation 15 Equal parts by weight of cefoperazone sodium and potassium 1,1-dioxo-6 (E) - (2-pyrazinyl) methylene penicillanate are combined with 20 parts by weight of water. Using standard pharmaceutical methods, the solution is sterile filtered, filled into small vials, the vials are loosely closed with rubber stoppers, and the vials are lyophilized with plates. The filling volume is such that each lyophilized vial, now sealed in vacuo, contains 500 mg of each active ingredient. Prior to injection, each small vial of medicament is pretreated by injecting 10 ml of sterile water for injections through a rubber stopper and shaken to dissolve the contents. Take 1-10 ml of the solution to be injected through a rubber stopper with a hypodermic needle. Example 35 Allyl 6- (2-thiazolyl) acetoxymethyl-1,1-dioxopenis illanate

Acetylation in which 0.5 g (1.29 mmol) of allyl 6- (2-thiazolyl) hydroxymethyl 1,1-dioxopenicillanate (obtained in Example 18) was acetylated with 0.396 g (3.88 35 mmol) of acetic anhydride and 0.307 g of 88 85,376 (3.88 mmol) of pyridine in 5 ml of tetrahydrofuran was carried out by the method of Example 20, Part A, with stirring at room temperature for four hours. The mixture was then diluted with methylene chloride, washed with water until neutral (pH 6.0-6.5), the organic phase dried (Na 2 SO 4) and the solvent evaporated to give 0.688 g of the desired acetate.

1 H-NMR (CDCl 3) ppm (delta): 1.52 (s, 3H), 1.70 (s, 3H), 2.35 (s, 3H), 4.4-4.6 (m, 2H ), 4.6-5.0 (m, 3H), 5.2-6.4 (m, 3H), 6.65 (d, 1H), 7.4 (d, 1H), 7.8 (d, 1 H).

Example 36

Allyl 6- (2-thiazolyl) methylene-1,1-dioxopenicillanate and its hydrolysis to the potassium salt A. The above acetoxyester (0.688 g, 1.29 mmol) was mixed with 0.16 g (1.29 mmol) of 1 , 5-diazabicyclo [4.3.0] hon-5-ene (DBN) and 5 ml of methylene chloride, and stirred for 1 hour at room temperature. The resulting mixture was diluted with methylene chloride, washed with water (2 x 50 mL), dried (Na 2 SO 4) 2 O and the solvent evaporated to give an oil.

This was chromatographed on a silica gel column eluting with 1: 1 ethyl acetate / hexane to give 0.189 g (39%) of a pale yellow oil.

1 H-NMR (CDCl 3) ppm (delta): 1.53 (s, 3K), 1.65 (s, 3H), 4.33 (s, 1H), 4.55 (d, 2H), 5.0-5.4 (m, 211), 5.45 (s, 1H), 5.4-6.0 (m, 1H), 7.1 (m, 1H), 7.75 (m, 1H), 7.65 (d, 1H), B. Hydrolysis of the allyl ester obtained above by the method of Example 25, Part C, afforded potassium 6- (2-thiazol-3'-solyl) methylene-1,1-dioxopenicillanate in 84.7% step yield. as a yellow solid.

1 H-NMR 250 MHz (DMSO-d 6 (delta)): 1.40 (s, 3H), 1.45 (s, 3H), 3.80 (s, 1H), 5.83 (s, 1H), δ .66 (s, 1H), 8.04 (m, 2H).

89 85376

Example 37

Tetrabutylammonium 6- {D- (2- (1-methyl-2-methoxycarbonylvinylamino) -2-phenylacetamido) -7-penicillanate To 300 ml of chloroform was added 39.3 g of 6- (D- (2-amino) -2-phenylacetamido) penicillanic acid trihydrate, 50 ml of water was added and the pH of the mixture was adjusted to 8.5 by adding 40% aqueous tetrabutylammonium hydroxide. The layers were separated, the aqueous layer was saturated with sodium sulfate and extracted with fresh chloroform. The extracts and the original lower layer were combined and the solvent was evaporated off until the total volume was about 250 ml.

To this were added 150 ml of methyl acetoacetate and 30 g of dry magnesium sulfate. The mixture was heated at reflux for three hours, allowed to settle and the warm organic layer was decanted off. The clear chloroform solution was allowed to cool to give crystals of the title compound in 52% yield, mp 182-184 ° C (dec).

1 H-NMR (CDCl 3) ppm (delta): 0.8-2.0 (m, 4H), 1.88 (s, 3H), 3.1-3.6 (m, 8H), 3.6 ( s, 3H), 4.17 (s, 1H), 4.58 (s, 1H), 5.05 (d, 1H), 5.38-5.6 (m, 2H), 6.78 (d , 1H), 7.35 (s, 5H), 9.4 (d, 1H).

25 Example 38

Tetrabutylammonium 6- [D- (2- {1-methyl-2-methoxycarbonylvinylamino] -2- [3-hydroxyphenyl] acetamido) 7-penicillanate To 300 ml of dichloromethane is added 41.9 g of 6- (2-30 amino-2 (3-hydroxyphenyl) acetamido) penicillanic acid trihydrate and 50 ml of water, and then the pH is adjusted to 8.5 using 40% aqueous tetrabutylammonium hydroxide solution. Three layers are obtained. The upper layer is removed, saturated with sodium sulfate and then extracted with dichloromethane. The extracts are combined with the middle layer and the lower layer, and the resulting mixture is evaporated to dryness in vacuo to give an oil which crystallizes on trituration with acetone. 44.6 g of tetrabutylammonium 6- (2-5 amino-2- [4-hydroxyphenyl] acetamido) penicillanate are thus obtained.

The salt obtained above is added to 150 ml 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 solid is collected on a filter-10 rack. The solid is washed with methyl acetoacetate followed by diethyl ether to give 49.25 g of tetrabutylammonium 6- (2- [1-methyl-2-methoxycarbonylvinylamino] -2- [4-hydroxyphenyl] acetamido) penicillanate crystals.

Example 39 A. Potassium (6 o (8S) -6-pyrimidin-2-yl) hydroxymethyl 1,1-dioxopenicillanate

To a solution of 300 mg (0.79 mmol) of the first eluted allyl 6-oi- (pyrimidin-2-yl) hydroxy-20-methyl-1,1-dioxopenicillanate (obtained in Example 18) in 4 ml of ethyl acetate was added 30 ml of ethyl acetate. mg of tetrakis (triphenylphosphine) palladium (0) and 30 mg of triphenylphosphine. The mixture was stirred under nitrogen to solvate the reagents (5-10 minutes) and 1.57 mL (0.79 mmol) of potassium 2-ethylhexanoate in ethyl acetate was added. After stirring at room temperature for 20 minutes, the mixture was filtered and the filter cake was washed with ethyl acetate and dried to give 53 mg of a yellow solid. The filtrate was treated with ethyl ether 30 to precipitate a second crop, 152 mg; total yield 69%.

1 H-NMR, 250 MHz, (DMSO-d 6) ppm (delta): 1.33 (s, 3H), 1.44 (s, 3H), 3.77 (s, 1H), 3.95 (d or d, J = 2, J = 6, 1H), 4.89 (d, J = 2, 1H), 5.1 (d, J = 6, 1H), 6.33 (s, 1H), 7, 48 35 (t, J = 4, 1H), 8.84 (d, J = 4, 2H).

li 9i 85376 B. Potassium (6-ol, 8R) -6- (pyrimidin-2-yl) hydroxymethyl 1,1-dioxopenicillanate A solution of 300 mg (0.79 mmol) of the second eluted allyl The -6-o- (pyrimidin-2-yl) hydroxymethyl-5'-1,1-dioxopenicillanate isomer (obtained in Example 18) was converted to its potassium salt by the above procedure to give 236 mg (79%) of the product. 1 H-NMR, 250 MHz, (DMSO-d 6) ppm (delta): 1.30 (s, 3H), 1.42 (s, 3H), 3.65 (s, 1H), 4.60 (dd, J = 2, J = 8, 1H), 4.75 (d, 10 J = 2, 1H), 5.15 (d, J = 8, 1H), 7.47 (t, J = 4, 1H) , 8.85 (d, J = 4.2H).

Example 40 A. Allyl (6-o (8S) -6- (pyrimidin-2-yl) acetoxymethyl 1,1-dioxopenicillanate 15 To a solution of 785 mg (2.1 mmol) of allyl eluted from the first sex -6-o- (pyrimidin-2-yl) hydroxymethyl-1,1-dioxopenicillanate isomer (obtained in Example 18) in 4 ml of methylene chloride, 0.45 ml (5.6 mmol) of pyridine and 0, 53 ml (5.6 mmol) of acetic anhydride and the mixture were stirred at room temperature for 2.5 hours, diluted with 30 ml of methylene chloride, extracted with water (7 x 60 ml), dried over anhydrous magnesium sulphate and filtered. 813 mg (92%) of the title compound.

1 H-NMR (CDCl 3) ppm (delta): 1.4 (s, 3H), 1.6 (s, 3H), 2.2 (s, 3H), 4.45 (s, 3H), 4.45 (dd, 1H), 4.75 (m, 2H), 4.95 (d, 1H), 5.2-5.6 (m, 2H), 5.7-6.3 (m, 1H), 6.45 (d, 1 H), 7.35 (t, 1 H), 8.85 (d, 1 H).

B. Allyl (6,8R) -6-pyrimidin-2-yl) acetoxymethyl 1,1-dioxopenicillanate

Acetylation of the second eluted allyl 6- (pyrimidin-2-yl) hydroxymethyl 1,1-dioxopenisilanate isomer (obtained in Example 18) by the above method gave the title compound in 88% yield.

92 8 5376 1 H-NMR (CDCl 3) ppm (delta): 1.4 (s, 3H), 1.6 (s, 3H), 4.45 (s, 1H), 4.50 (dd, J = 1 , J = 3, 1H), 4.75 (m, 2H), 4.8 (d, J = 1, 1H), 5.25-5.6 (m, 2H), 5.7-6.3 (m, 1H), 6.4 (d, J = 8, III), 7.35 (t, J = 6, 1H), 8.8 (d, J = 6, 1H).

5 Example 41 Δ. Potassium (6-o (8S) -6- (pyrimidin-2-yl) acetoxymethyl 1,1-dioxopenicillanate A solution of 789 mg (1.86 mmol) of allyl (6-β (8S) ) -6- (pyrimidin-2-yl) acetoxymethyl 1,1-dioxo-10 penicillanate in 4 ml of ethyl acetate was reacted according to the procedure of Example 39 to give 342 mg (43%) of the desired potassium salt, which was purified from the preparative solvent. Using MPLC, eluting with water / acetonitrile 9: 1 to give 105 mg of product (purity 85% by HPLC analysis).

B. Potassium (6-o (, 8R) -6- (pyrimidin-2-yl) acetoxymethyl 1,1-dioxopenicillanate A solution of 666 mg (1.57 mmol) of allyl- (6-8R) -6 - (pyrimidin-2-yl) acetoxymethyl 1,1-dioxopenicillanate was reacted by the same procedure to give 339 mg (51%) of crude product, which was purified by M) preparative MPLC using water / acetic acid. with a 9: 1 mixture of tonitrile to give 162 mg of pure isomer.

1 H-NMR, 250 MHz, (DMSO-d 6) (delta): 1.34 (s, 3H), 1.44 (s, 3H), 2.17 (s, 3H), 3.65 (s, 1H ), 4.15 (dd, J = 2, J = 8, 1H), 4.97 (d, J = 2, 1H), 6.27 (d, J = 8, 1H), 7.50 (t , J = 5, 1H), 8.85 (d, J = 5, 2H).

x ^ MPLC is a medium pressure liquid chromatographic method M) HPLC is a high pressure liquid chromatographic method I: 93 85376

Example 42 Using the appropriate starting material from Example 18, 6-R, CHOH-substituted 1,1-dioxopenicillanate road ester, the following acetate esters are prepared by the method of Examples 20 or 40.

OCOCH. O O

i * * J \ I CH

1 H-NMR (CDCl 3) δ (delta): R C'6, Cg stereochemistry Yield-S - (^ 3H) ^ 1 ^ g3 15 C HN / NCrf 6 ° (.8S and 100 3H), 2.25 (s, 3H), 4.51 5 3 6-o (, 8R mixture (m, 2H), 4.79 (m, 2K ), 5.43 (m, 2H), 5.98 (m, 1H), 6.65 (d, 1H), 7.5 (m, 3H), 7.98 (s, 1H), 8.20 ( m, 2H).

1.4 (s, 1.8H), 1.43 (s, N 2 S 60:40 69 1.2H), 1.56 (s, 1.2H), 6 ° / 8S and 1.62 (s, 1.8H), 2.2 (s, 6-Of, 8R mixture 1.2Η), 2.3 (s, 1.8H), 23 4.35 (m, 1H), 4.4 (s , 0.6H), 4.43 (s, 0.4H), 4.78 (d, 0.6H), 4.8 (d, 0.4H), 5.3-5.5 (m, 2H), 5.8-6.05 (m, 1H), 6.3 (m, 1H), 7.45 (d, 1K), 8.82 (d, 1H), 9.25 (m, 1H).

94 85376

Example 42 (continued) C 6 -C 8 R 13 Stereochemistry Yield% _ 1 H-NMH (CPCl 2) ppm (delta); GO: 40 66 lf4 (s, 1.8H), 1.5 (s, [(JJ ^ 6-, 8S and 1.2H), 1.6 (s, 1.8E), 5 "6- ΔR mixture 1.65 (s, 1.2HJ, 2.2 (s, 1.2K), 2.26 (s, 1,3H), 4.23 (dd, 0.4H), 4, 35 (dd, 0.6H), 4.4 (s, 0.6H), 4 T45 (s, 014H), 4.63 (m, 2H), 4.74 (d, 0.6K), 5 .0 (d, 0.4K), 5.35 (m, 2H), 5.9 (n, 1H), 6.45 (m, 1H), 8.6 (m, 2H), 8.75 ( m, 1H).

95 85376

Example 43

The 8-acetoxy-3-carbonyloxyallyl esters obtained in Examples 25A and 42 are converted to the potassium salt of the formula below by the method of Example 54,

OCOCH O O

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en 3

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0 '' COOK

C6 'C8 R13 stereochemistry Yield% 1 H-NMR (PO) cpm (delta): 65:35 57 Purified: 1.45 (s, 3H),?, A 6 - «, 8S (crude) 1> 58 (s # 3H ) 'lr25 (s, 6_ ° i'8R 21 1.05H), 1.32 (s, 1 f 95K), 10 (purified 4 25 (s # o 65h) 4 28 by chromatographic analysis of iso- (s , 0.3 5 K), 4.37 (dd, mixture of mers) 35H), 6.25 (d, 0.65H), 6.35 (d, 0f35K), 7.73 (m, 1H), 8.85 (m, 1H), 9f15 (m, 1H).

r-N. 6: 1 64 1.44 (s, 3H), 1.5 (s,

Il 6-o <, 8S 1 '6-o <, 3R 3H), 1 \ 62 (s, 3H), 2.2-20 6h3 is, 0.4H), 2.24 (s, 2.6H), 3.8 (s, 3H), 4.27 (s, 1H), 4.4 (dd, 1H), 4.96 (d, 1H), 6.45 (d, 0.15H), 6.5 (d, 1H), 3.55 H), 7.07 (s, 25.0H), 7.1 (d, 0.85H), 7.16, 0.15H), 7.2 (d, 0.35H).

IR (XBr): 3409, 1786, 1740, 1620 cm -1.

96 85 376

Example 43 (continued) C 6 H 8 Stereo Chemistry Yield 1 H-NMR (DMSO-d 6) δόιπ (delta 1; - ----- O - ** - - - ^ 0; 7 0 , 84 13 (s, 2.1H), 1.34 (s, LI 6-ol, bS (crude) A <A 6-ck, 8R 43 £> ι9Η), 1.42 (s, 3H), 2 , 13 9 chromatograph (0.9η), 2.2 (s, 2.1H), fusion 3.66 (s, 0.7H), 3.7 (s, after 0.3H>, 4.1 (dd, 0, 3H), 4.95 (d, 0H, 7H), 5.07 (d, 0.3H), 6.24 (d, 0.3H), 6.36 (d, 0.7H), 8? Δ (s, 2H), 8.8 (s, 0.7η), 3.83 (s, 0.3H).

IR (K3r): 3463, 1731, 1746, 1623 cm-1.

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u 101 85376

Example 45

Potassium 6- (imidazol-2-yl) hydroxymethyl 1,1-dioxopenicillanate

A mixture of 141 mg (0.38 mmol) of allyl 6-5 (imidazol-2-yl) hydroxymethyl 1,1-dioxopenicillanate. / A mixture of isomers obtained in Example 18 7, 12 mg of tetrakis (triphenylphosphine) palladium ( 0), 12 mg of triphenylphosphine, 0.76 ml (0.38 mmol) of potassium 2-ethylhexanoate and 2 ml of ethyl acetate were stirred under nitrogen for 1 hour. The precipitated product was collected by filtration to give 143 mg (100%) of a yellow solid which was found to contain two isomers by high pressure liquid chromatographic analysis. Infrared (KBr): 3382, 1780, 1728 and 1615 cm Example 46 A. Benzyl 6- (2-thiazolyl) hydroxymethyl 1,1-dioxopenicillanate

A solution of 17.79 g (44 mmol) of benzyl 6 -? - bromo-1,1-dioxopenicillanate in 250 ml of dry tetrahydrofuran was reacted with an equimolar amount of methylmagnesium bromide at -78 ° C, then after stirring for one minute an equimolar amount of thiazole-2-carboxaldehyde was added and stirring was continued for 10 minutes. An equimolar amount of acetic acid was then added, and after stirring for 5 minutes, the mixture was poured into 500 ml of water. Extraction with ethyl acetate, washing of the extracts with water, drying (MgSO 4) and evaporation of the solvent in vacuo gave 16.93 g (89%) of crude product which showed two spots on TLC. The crude product was purified by silica gel column chromatography eluting with chloroform / ethyl acetate 96: 4 to give 4.72 g of the more polar isomer, 2.98 g of the more polar isomer and 0.5 g of a mixture of isomers (total yield 43%). . More polar isomer: 1 H-NMR (CDCl 3) ppm δ (delta): 1.25 (s, 3H), 1.55 (s, 3H), 4.3 (dd, 1H), 4.45 102 8 5 3 76 (s, 1H), 4.65 (bs, 1H), 4.9 (d, 1H), 5.2 (m, 2H), 5.55 (d, 1H), 7.35 (m, 6H) , 7.75 (d, 1H).

Non-polar isomer: 1 H-NMR (CDCl 3) ppm (delta): 1.2 (s, 3H), 1.5 (s, 3H), 4.35 (m, 2H), 4.75 (d, 1H), δ .15 (m, 2H), 5.55 (d, 1H), 7.2 (m, 6H), 7.6 (d, li).

B. Diphenylmethyl 6- (2-thiazolyl) hydroxymethyl 1,1-dioxopenicillanate By repeating the above procedure with diphenylmethyl 6-06-bromo-1,1-dioxopenicillanate in an amount of 20-10 mmol and purifying by chromatography on silica gel eluting with with chloroform / ethyl acetate 9: 1, 2.464 g of the more polar (LP) isomer and 3.029 g of the more polar (MP) isomer were obtained.

More polar isomer: 1 H-NMR (CDCl 3) ppm (delta): 1.06 (s, 3H), 1.52 (s, 3H), 4.1-4.3 (m, 1H), 4, 42 (s, 1H), 4.76 (d, 1H), 5.45 (d, 1H), 6.82 (s, li), 7.05-7.3 (m, 1H), 7.56 (d, lii).

More non-polar isomer: 1 H-NMR (CDCl 3) ppm (delta): 1.2 (s, 3H), 1.65 (s, 3H), 4.35 (dd, 1H), 4.55 (s, 1H), 4.83 (d, 1H), 5.65 (dd, 1H), 6.95 (s, 1H), 7.2, 7.4 (m, 1H), 7.75 (d, 1H).

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Example 48 A. (6-cis, 8R) -6- (Thiazol-2-yl) propionyloxymethyl-1,1-dioxopenicillanic acid A mixture of 1.89 g of 10% palladium / -5 carbon catalyst In 20 ml of a mixture of tetrahydrofuran (THF) and water (v / v 9: 7), saturated with hydrogen and a solution of 689 mg (1.4 mmol) of benzyl- (6-O, 8R) -6 -thiazol-2-yl) propionyloxymethyl 1,1-dioxoponisillanate in 13 ml of THF and 7 ml of water. The resulting mixture was hydrogenated at 3 bar for 20 minutes, then the catalyst was removed by filtration, the filtrate was extracted with ethyl acetate (3 x 200 ml) and the extracts were dried (MgSO 4). Evaporation of the solvent in vacuo gave 330 mg of a yellow solid.

B- (6 ', 8R) -6- (thiazol-2-yl) benzoyloxymethyl-1,1-dioxopenicillanic acid The title compound was obtained by the above procedure from the corresponding benzyl ester in 57% yield. 1 H-NMR (D 2 O) ppm (delta): 1.38 (s, 3H), 1.55 (s, 3H), 4.25 (s, 1H), 4.44 (dd, 1H), δ, 05 (d, 1H), 6.68 (d, 1H), 7.4 (t, 7H), 7.55 (t, 1H), 7.58 (d, 1H), 7.7 (d, 1H) ), 7.95 (d, 1 H).

Infrared (KBr): 3473, 1782, 1729, 1622 cm Example 49 25 A. (6H, 8S) -6- (thiazol-2-yl) ethoxycarbonyloxymethyl-1,1-dioxopenicillanic acid To a solution of 557 mg (0.954 mmol) diphenylmethyl, 8S) -6- (thiazol-2-yl) ethoxycarbonyloxymethyl 1,1-dioxopenicillanate in 5 ml of methylene chloride was added 0.62 ml (5.72 mmol) of anisole.

The mixture was cooled to -5 ° C and a mixture of 382 mg (2.86 mmol) of dry aluminum chloride and 2 ml of nitromethane was slowly added over 15 minutes. The reaction mixture was diluted with 50 ml of ethyl acetate, water was added and the pH was adjusted to 7.5. The aqueous layer was separated, acidified to pH 3 and extracted with ethyl acetate. Evaporation of the solvent left a glass which was dissolved in ethyl ether, filtered and hexane was added to the filtrate for precipitation. After filtration and drying to recover the solid, 211 mg (53%) of product were obtained. 1 H-NMR 300 MHz, (CDCl 3) ppm (delta): 1.40 (t, 3H), 1.53 (s, 3H), 1.67 (s, 3H), 4.28-4.42 (m, 3H), 4.50 (s, 1H), 4.92 (s, 1H), 6.58 (d, 1H), 7.53 (d, 1H), 7.93 (d, 1H) . Infrared (KBr): 3443, 1797, 1754 cm 10 B. Using the (6-, 8R) -isomer of the diphenylmethyl ester starting material obtained in Example 62 in the above procedure, the corresponding 6- (thiazol-2-yl) -ethoxycarbonyloxymethyl-1,1 -dioxopenicillanic acid (6-t, 8R) -isomer.

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ill 85376

Example 51 A. Allyl 6-bromo-6- (2-thiazolyl) hydroxymethyl 1,1-dioxopenicillanate

A solution of 8.84 g (20 mmol) of allyl 6,6-5 dibromo-1,1-dioxopenicillanate in 100 ml of dry tetrahydrofuran was cooled to -78 ° C, 7.02 ml (20 mmol) of methylmagnesium bromide were added. and the mixture was stirred for 5 minutes. At -78 ° C, a solution of 2.26 g (20 mmol) of thiazole-2-carboxaldehyde in 10 ml of the same solvent was added and the resulting mixture was stirred for 20 minutes. Acetic acid (1.2 ml) was added, the mixture was poured into silica and extracted with ethyl acetate and chloroform. The combined organic layers were dried (^ 28 () 4) and the solvent evaporated in vacuo to give 8.5 g of crude product as a glass. The crude glass was purified by silica gel column chromatography eluting with chloroform / ethyl acetate 89:11 to give 6.2 g (72%) of pure product, which was found to be one isomer.

1 H-NMR (CDCl 3) ppm (delta): 1.4 (s, 311), 1.6 (s, 311), 4.0 (bs, 1H), 4.42 (s, 1H), 4, Δ (d, 2H), 5.3 (s, 1H), 5.55 (s, 1H), 5.1-6.3 (m, 3H), 7.35 (d, 1H), 7.75 (d, 1 H).

B. Benzyl 6-bromo-6- (2-thiazolyl) hydroxymethyl 1,1-dioxopenicillanate Using benzyl 6,6-dibromo-1,1-dioxopenicillanate instead of the allyl ester in the above procedure, the title compound was obtained in orange. as a foam in quantitative yields.

1 H-NMR (CDCl 3) ppm (delta): 1.32 (s, 3H), 1.60 (s, 3H), 3Q 4.5 (s, 2H), 5.2-5.8 (m, 4H ), 7.3 (d, 1 H), 7.4 (s, 5 H), 7.8 (d, 1 H).

112 85376

Example 51 (cont'd) C. The following compounds were prepared in a similar manner by the method of Part A.

° H 00

13 ’CH

R -CHx / 3 ^ COOR3 5 Ra R13 Yield% 1 H-NMR (CDCl 3 ppm (delta): benzyl 100 1.25 (s, 3H), 1.54 (s, 3H), yellow 4 S (1H ), 502 (s, 2H), el. Room 5, 43 (s, 1H), 5.68 (s, 1H), 7.32 (m, 7H), 8.00 (m, 2H).

CH-

»J

10 benzyl ^ / | 88 lj4 (2s, 3H), 1.6 (s, 3H), νΝ · ^ \ kelelt. 40 (s, 1H), 4.9 (2, 1H), solid 5.18 (m, 2H), 5.5-5.8 (m / 2H), 7.5 (s, 5H), 3, 0 and 8.5 (2s, 1H).

Benzyl O 100 V5 <s '3> »' V3 <*" ™, 4.45 (s, 0.75H), 4.52 (s, 0.25H), 5.1-5.4 (m, 4H), 7.3 (s, 5H), 8.6 (m, 2H), 9.0 (m, 1H).

allyl δ N 2 N 38 1.38 (s, 3H), 1.60 (s, 3H), 4.38-4.73 (m, 3H), 5.0-6.0 (m, 5H), 7.10 (s, 1 H). 8.51 (s, 1 H).

113 85376

Example 52 A. Acylation of the compounds obtained in the previous example by the method of Example 42 or 47 in a similar manner gave the following compounds:

OR18 0 O

R13-CH / Λ '/ CH3 5 n TCH3

Oy ^ CCCR3 A. wherein Ra is allyl and R10 is C1-CO: R13 Yield% 1 H-NMR (CDCl 3) δem (delta): 2-thiazolyl 1H-β (s, 3H), 1 / · 6 (S / 3H), colorless 2.25 (s, 3H>, 4.45 (s, crystals of 10 1H), 4.65 (m, 2K), 5.4 (s, 1H), 5.2-6.3 ( m, 3H), 6.7 (s, 1K), 7.4 (d, 1H), 7.8 (d, 1H).

13 C-NMR (CCCl 3) δ (delta): δ 18.4, 19.8, 20.4, 60.7, 63.1, 64.4, 66.5, 66.9, 73.3, 120 , 3, 120.4, 130,, 6, 143.6, 163.7, 165.5, 166.2, 168/6.

20 59 1.40 (s, 3K), 1.60 (s,

S N

V / (+21% isomeric-3H), 2.25 (s, 3H), 4.48-k product) 4.70 3HK 5f2_6j2 5H), 6.92 (s, 1K), 8.33 (s, 1H).

Example 52 (cont'd) 114 85 376 18 B. wherein Ra is benzyl and R is CH3CO: R13 Yield% 1 H-NMR (CDCl 3) ν cm (delta): 2-thiazolyl 100 glassy 1.25 (s, 3H) , 1.55 (s, 3H). . , 5 ter 9: 1 4> 50 (s'0 -9H) '4> 5 = (s'0 j1H), 5.2 (m, 2H), 5.40 (s, 0t9H), 5 T 5 7 (s, 0.1H), 6.42 (s, 0.1H), 6.60 (s, 0.9H), 7.3 (m, 6H), 7.75 (d, 1H).

100 i, 3 (s, 3H), 1.52 (s, 3H), yellow 212 5 (s, 3H), 4.54 (s, 1H), foam 5> 02 <= '2H)' = f52 6.3 (s, 1H), 7.3 (m, 7H), 7.9 (m, 2H).

ch3 N: Λ 19 1.25 (s, 3K), 1.5 (s, 3E), 2.19 (s, 3H), 3.95 (s, 3H), 4.4 (s, 1H), 5, 15 (s, 2H), 5.45 (s, 1H), 6.3 (s, 1H), 7.35 (s, SH), 7.73 (s, 1K).

Δ 90 1.25 (s, 2.25H), 1.35 (s, 3.1, 0.75H), 1.4 (sr 2.25K), mixture 1j 4 2 (s, 0.75H), 2 , 2 (s, 2.25H), 2.3 (s, 0.75H), 4.45 (s, 0.75H), 4.55 (s, 0.25H), 5.1-5.3 (m, 2H), 5.3- (Sf 0.75H), 5.6 (s, 0.2wH), 6.25 (s, 0.25H), 6.4 (s, 0.75H) , 7.3 (m, 5H), 3.67 (π, 2H), 9.67 (s, 1H).

115 85376

Example 52 (continued) C. Alternatively, compounds of the above formula are prepared by carrying out the procedure of Example 51 by acylating the reaction mixture prior to isolating the product by the following general procedure: To a solution of 1.0 equivalent of 6,6-dibromopenicillanate ester in tetrahydrofuran at -78 ° C. 1.3 equivalents of methylmagnesium bromide dissolved in the same solvent were added and the mixture was stirred for 5-10 minutes. At -78 ° C to -68 ° C, 1.3 equivalents of the appropriate aldehyde 13 (R CHO) in the same solvent were added and the reaction mixture was stirred for 30-60 minutes. 1.3 equivalents of acetyl chloride were then added, stirring at -78 [deg.] C. was continued for 10 minutes and then the product was isolated by pouring into ice / water, extraction with ethyl acetate, a 15-dip plug and evaporation of the solvent in vacuo with C1-CO3 Yield% 1 H-NMR (CSCl 2) δ (delta):

2 0 .. J

benzyl C6 ^ 5 100 light yellow foam allyl ^ 35 (s, 3H), 1.56 (s, \ / yellow 3H), 2.22 (s, 3H), 4.42 25 ° oil (s, 1H), 4, 60-4.74 (m, 2H), 5.24-5.42 (m, 3H), 5.79-5f 96 (m, 1H), 6.52 (s, 1H), 7.32-7 .34 (d, 1H), 8.70-8.74 (d. 1H).

:: Infrared: 1810, 3 U _Ί 1760 cm.

116 8 5376

Example 52 (continued)

Ra R13 Yield-1 H-NMR (CDCl 3) cpm (delta); allyl (S '\ / 59!> 42 ^ s' 3H) '1.62 ^ s' \\ // yellow 3H), 2.28 (s, 3H), 2.48> -M oil 3 / ( s, 3H), 4.5 Cs, In), CH 3 4.6-4.8 (m, 2K), 5.28-5.47 (m, 2H), 5.82-6.0 (m, 1H), 6.3 (s, 1K), 6.97 (s, 1H),

Infrared. 1810, 1760, 1730 cm-1.

N "'S 59 1.6 (s, 3H), 1.3 (s, benzyl, 3H), 2.2 (s, 3H), 2.3 CH3 CH3 (s, 6H), 4, Δ (5, 1H), 5.2 (d, 2H), 5.3 (s, 1K), 6.4 (s, 1H), 7.3 (s, 5H).

CH 3 22 1.22 (s, 3H), 1.5 (s, benzyl-3H), 2> 18 (s, 3K), 2> 12 2 (s, 3H), 4.5 (s, 1H), 5.16-5.36 (m, 3H), 6.18 (s, 1H), 6.48 (s, 1H), 7.4 (s, 5H).

Example 52 (cont'd) 117 85376

Ra R13-1H-NMR (CDCl3) ppm (delta); benzyl n ^ S 44 1.26 (.s, 3H), lr5 {s, W-like 3η), 2.2 (s, 3H), 2r4 _ 'foam 5 CH3 (s, 3H), 4.4 (s , 1 H), 5.16 (d, 2 H); 5.3 (s, 1H), 6.6 (s, 1H), 6.3 (s, 1H), 7.3 (s, 5H).

N 36 1.40 (s, 3H), 1.60 (s, Allyl foam) H 2.27 (s, 3H), CK3 2.65 (s, 3H), 4.20- 4.3 (m, 3 H), 5.1-6.2 (m, 4 H) - 6.41 (s, 1 H).

Inf rapunain. 1313, 15 1760 cm-1.

Example 53 Λ. Benzyl 6- <3- (thiazol-2-yl) acetoxymethyl 1,1-dioxopenicillanate

To a solution of 74.6 g (134 mmol) of benzyl 20 6-bromo-6- (thiazol-2-yl) acetoxymethyl 1,1-dioxopenicillanate in 850 ml of benzene was added 43.99 g (151, 2 mmol) of tri-n-butyltin hydride. The mixture was heated at reflux for 5.5 hours and allowed to stand overnight. The solvent was evaporated in vacuo, the residue was dissolved in hexane and extracted with acetonitrile (2 x 250 ml). The acetonitrile layer was evaporated to dryness, the residue was slurried in ethyl ether, filtered and the filter cake was washed with ether to give 33.23 g of colorless crystals. Another 2.8 g was obtained by evaporation of the filtrate to dryness. The residue was dissolved in benzene and tri-n-butyltin hydride was added. The mixture was boiled for one hour and worked up as in the first batch; total yield 56.3 Z.

118 8 5376

The first batch obtained above was purified by chromatography on a silica gel column eluting with chloroform / ethyl acetate 9: 1. The product fractions were evaporated to dryness, slurried in ethyl ether / ethyl acetate-5 4: 1, filtered, washed with ether to give 22.6 g of a white solid.

1 H-NMR (CDCl 3) ppm (delta): 1.25 (s, 3H), 1.53 (s, 3H), 2.1 (s, 311), 4.53 (s, 1H), 4.80 (d, 1H), 5.2 (dd, 1H), 5.22 (q, 211), 6.75 (d, 1K), 7.35 (s, 5H), 7.4 (d, lii) , 7.8 (d, 1H).

13 C-NMR (CDCl 3) ppm (delta): 17.7, 19.9, 20.5, 54.5, 63.06, 63.6, 63.8, 64.5, 68.1, 121.8, 128.8, 128.9, 134.3, 142.6, 164.6, 166.5, 169.2, 170.5.

B. The following compounds were obtained in a similar manner by de-bromination of the other compounds obtained in Example 52.

15

Example 53 (cont'd) 119 8 5 3 7 6 5 OCOCH-. 0 0 R 13 -HH X / CH 3 -I TCH 3 0 * 1 //// J, C00Ra 10 Ra R13 Yield% 1 H-NMR (CDCl 3) δ (delta): 1 H -rv benzyl 39 1.3 (s, 3H) , 1.55 (s, 3H), 2.19 (s, 3H), 4.5 (s, 1H), 4.79 (d, 1H), 5.2 (m, 3H), δ 6.79 (d, 1H), 7.32 (π, 7H), 7.9 (m, 2H). ch3 'benzyl N-N 72 1.29 (s, 3H), 1.55 (s, 3H), 2.10 (s, 3H), 4.03 (s, 3H), 4.5 (s, 1H) , 4.73 (d, 1H), 4.87 (dd, 1H), 5.25 (q, 2H), 6.53 (d, 1H), 7.38 (s, 5H), 7.89 ( s, 1H).

Benzyl (T ^ 46 1.3 (s, 3H), 1.55 (s, 3H), N yellow 4.45 (s, 1H), 4.6-5.1 (m, solid _ _.

material 2H) (° t2 2H) '6/6 <dd (1H), 7T35 (s, SH), 8.6 (m, 2H), 8.83 (m, 1H).

30 120 85376

Example 53 (continued)

Ra R13 Yield% 1H-N1-iR (CDCl3.,) Ppm (delta): / nn allyl SJ \ N 70 lr44 (s, 3H), 1.62 (sT 3H), oil \ 2.10 ( s, 3H), 4.51 (s, 1H), δ 4.60-4.80 (m, 2H), 4.89-4.91 (d, 1H), δf26-5.42 (m, 3H ), 5.36-5.99 (m, 1H), 6.88-6.92 (d, 1H), 8.32 (s, 1H). Infrared: 10 1795, 1750.

/OF

allyl 1R - 511 (iMP MP isomer: 5.34-6.00 (m, isomer) 1H), 6.28-6.4 2 (m, 2H), 11 (LP 6.62-6, 77 (d, 1 H), 7.38-

isomerism) 7.43 (<3, 1H), 3y64-8? 7Q

15 (d, 1H). White crystals, infrared (KEr): 1807, 1760 cm -1 allyl H 31 1.46 (s, 3H), 1.64 (s, 3H), yellow 2.14 (s, 3H), 2.48 (s , 3H), δ 3 δ 4.5 (s, 1H), 4.6-4.9 (m, 3H), 5.2-5.26 (dd, 1H), 5.3-5.6 ( m, 2K), 5.36-6.1 (m, 1H), 6.7 (d, 1H), 7.0 (s, 1H) δ Infrap: 1810, 1760 cm benzyl S 43 1.3 ( s, 3H), 1.58 (s, 3H), (194 5-2.12 (s, 3H), 2.36 (d, 6H), CH 3 CS 3 195-5 ° C. 4.5 (s, 1H), 4.75 (d, 1H), 5.2-5.4 (dd, 3H), 6.6 (d, 1H), 7.4 (s, 5H).

121 85376

Example 53 (continued)

Ra R13 Yield 1 H-NMR (CDCl 3) δ (delta): FH 3 benzyl 9 ^ 16 ^ 28 (s' 3H) '^ 55 <*' 3 «), N = (colorless 2.1 (s, 3H ), 2.4 (s, 3H), - solid 1 ^) · 4.8 (dd, 1H), isomer 5f25 (q, 1H), 6.15 (s, 1H), 5.5 (d, 1H) ), 7, 4 (s, SH).

N 2 S 43 1.3 (S, 3H), 1.58 (s, 3H), benzyl / 2.14 (s, 3H), 2.48 (s, 3H), CH 2 O 3, 52 (s, 1H), 4.8 (d, 1H), 5.16-5.36 (AB quartet and dd, 3H), 6.7 (d, 1H), 7.0 (s, 1H), 7 .4 (s, 5H).

N 2 N 44 1.37-1.40 (d, 3E), 1.53-15 allyl ° C CH iscnirLn <a · 3l <> 2.12-2.14 (d, 3 mixture 3K), 2 .58 (s, 3H), 4.48 (s, 1H), 4.58-4.83 (m, 4H), 5.24-5.46 (m, 2H), 5.82-6.00 (m, 1H), 6.64-6.67 (d, 0.75H), δ 7.05-7.08 (d, 0.25H).

Infrared: 1810, 1765 en "'.

122 85376

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Example 54 (cont'd) B. The 6β- (thiazol-2-yl) -acetoxymethyl-1,1-dioxopenicillanic acid obtained in Part A above was converted to the corresponding potassium salt by treating an aqueous acid slurry with an equimolar amount of potassium hydrogen carbonate in water, and purifying by medium pressure liquid chromatography. On a C18 column eluting with water / acetonitrile 9: 1 to give the corresponding potassium salt in 60% yield.

1 H-NMR (DMSO-d 6) ppm (delta): 1.37 (s, 3H), 1.48 (s, 3H), 2.07 (s, 3H), 3.80 (s, 1H), 4.92 (dd, 1 H), 5.12 (d, 1 H), 6.55 (d, 1 H), 7.89 (m, 2 H).

Infrared (KBr): 3454, 1788, 1630 cm -1) C 18 g is octadecyl silicate.

Example 55 A. 6- (Benzothiazol-2-yl) methylene-1,1-dioxopenicillanic acid, mixture of E and Z isomers

To a solution of 400 mg (0.91 mmol) of 6- (benzothiazol-2-yl) -acetoxymethyl-1,1-dioxopenicillanic acid in 5 ml of water was added a solution of 0.15 g (1, 82 mmol) of sodium hydrogen carbonate in 2 ml of water and the resulting mixture was stirred for two hours. The reaction mixture was lyophilized (pH 7.55). The lyophilate was dissolved in 8 ml of water, the pH was adjusted to 3.5 with dilute hydrochloric acid, the mixture was extracted with ethyl acetate, the organic layers were dried (MgSO 4) and the solvent was evaporated off in vacuo. The product obtained was shown by its NMR spectrum to be a 60:40 mixture of its (E) and (Z) isomers.

1 H-NMR (CDCl 3) ppm (delta): 1.55 (s, 1.2H), 1.6 (s, 1.3H), 1.65 (s, 1.2H), 1.67 (s , 1.8H), 4.55 (s, 0.6H), 4.58 (s, 0.4H), 5.38 (s, 0.4H), 5.74 (s, 0.6H), 7.44 (s, 0.4H), 7.43 (s, 0.6H), 7.5 (m, 4H), 7.89 (d, 1H), 8.07 (d, 0.4H) , 8.15 (d. 0.6H).

B. Similar treatment of the corresponding 6-R-CH (OAc) -substituted-1,1-dioxopenicillanic acid 12-7636 obtained above gave a compound of formula below as a mixture of (E) - and (Z) -isomers.

O O

13 \ / CH

R -CH \ 5 * -Γ YCH3

The J-L

Oy '' CCOH

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15

Example 56 A. Potassium 6-bromo-6- (thiazol-2-yl) acetoxymethyl 1,1-dioxopenicillanate By administration of 96 mg (0.2 mmol) of allyl 6-bromo-6- (thiazol-2-yl) -yl) acetoxymethyl 1,1-dioxopenisilanate (obtained in Example S.2) was reacted according to the procedure of Example 60 for 10 minutes and worked up as described to give 46 mg (48%) of a yellow solid.

1 H-NMR (D 2 O) ppm (delta: 1.45 (s, 3H), 1.6 (s, 3H), 4.4 (s, 1H), 5.55 (s, 1H), 6.35 ( s, lii), 7.72 (d, 1H), 7.86 (d, 1H).

B. Potassium 6-bromo-6- (thiazol-2-yl) hydroxymethyl 1,1-dioxopenicillanate

Similarly, 220 mg of allyl 6-bromo-6- (thiazol-2-yl) hydroxymethyl 1,1-dioxopenicillanate (obtained in Example 51) was reacted according to the above procedure for 20 minutes to give 52% of 35%. I obtained the title salt as a pale yellow solid.

I: 127 85376 1 H-NMR (DMSO-d 6) ppm (delta): 1.35 (s, 3H), 1.47 (s, 3H), 3.75 (s, 0.4H), 3.83 ( s, 0.6H), 5.3 (d, 0.4H), 5.32 (d, 6H), 5.45 (s, 0.6H), 5.5 (s, 0.4H), 7 , 6-8.0 (m. 2H). Infrared (KBr): 3442, 1794, 1633 cm-5 Example 57

Potassium (6-β, 8S) -6- (thiazol-2-yl) hydroxymethyl lipenicillanate A. Allyl 6-bromo-6- (thiazol-2-yl) hydroxymethyl lipenicillanate To a solution of 9.971 g (24.99 mmol) of allyl 6,6-dibromopenicillanate in 150 ml of dry tetrahydrofuran cooled to -78 ° C under nitrogen, 8.77 ml of 2.85 mol were added. (24.99 mmol) in methylmagnesium bromide in THF and the mixture was stirred for 15 minutes. A solution of 2.824 g (24.99 mmol) of thiazole-2-carboxaldehyde in 5 mL of THF was adjusted to Li-15 and the mixture was stirred again for 20 minutes at -78 ° C. The reaction was quenched by the addition of 1.43 mL (24.99 mmol) of glacial acetic acid, stirred for 10 minutes, then allowed to warm to room temperature. It was then poured into water, extracted with 2 x 250 ml of ethyl acetate, the extracts washed with water (2 x 250 ml), dried (MgSO 4) and the solvent evaporated in vacuo to give 10.36 g of an orange oil, the oil was purified by chromatography on a silica gel column eluting with chloroform / ethyl acetate 9: 1 to give 4.54 g of a yellow solid (mixture of isomers) and 0.443 g of a yellow foam, only the more polar isomer, (total yield 46%). For the yellow foam: 1 H-NMR (CDCl 3) ppm (delta): 1.56 (s, 3H), 1.76 (s, 3H), 4.60 (s, 1H), 4.7 (m, 2H ), 4.9-6.4 (m, 6H), 7.45 (m, 1H), 7.8 (m, 1H).

::: B. Allyl 6-β- (thiazol-2-yl) hydroxymethyl penicillanate 35 The more polar isomer of Part A, 200 mg (0.426 mmol) was dissolved in 1 mL of benzene and 0.183 mL of 128 85376 (0.693 mmol, 1 .5 equivalents) of tri-n-butyltin hydride in benzene. The mixture was heated at reflux for three hours and then allowed to stand overnight at room temperature. The solvent was evaporated off in vacuo, the residue was dissolved in acetonitrile, washed with hexane and evaporated to low volume and applied to a silica gel column and eluted with chloroform to give 73 mg (45%) of the desired product.

1 H-NMR (CDCl 3) ppm (delta): 1.65 (s, 3H), 1.87 (s, 3H), δ 3.8-4.4 (m, 1H), 4.05-4.3 (dd, lii), 4.65 (s, 1H), 4.78 (m, 2H), 5.3-5.6 (m, 2H), 5.6-6.3 (m, 3H), 7.45 (m, 1 H), 7.85 (m, 1 H).

C. The product from Part B, 73 mg (0.206 mmol), was converted to the potassium salt by the method of Example 45 to give 58 mg (80%) of the title compound as a yellow solid.

1 H-NMR, 300 MHz, (D 2 O) ppm (delta): 1.36 (s, 3H), 1.55 (s, 3H), 4.13 (dd, 1H), 4.18 (s, 1H) , 5.32 (d, 1H), 5.41 (d, 1H), 7.56 (d, 1H), 7.60 (d, 1H).

Example 58 A. Using the appropriate aldehyde, R 1 CHO instead of thiazole-2-oxoxoxyaldehyde in the procedure of Example 57, Part A, the corresponding compounds of the formula below were obtained in a similar manner.

25 li 129 85376

Example 58 (continued)

c OH

R 13 -CH 3 S / CH 3 v -r rcH 3 IN-O 'COOCH 2 CH = CH 2 R 13 Yield; 1 H-NMR (CDCl 3) prm (delta); a 20, isane A Isan A: ( s, 3H), 1.64 (white ki- (s, 3H), 4.42 (d, 1H), 4.50 te) (s, 1H), 4.64 (m, 2H), 5.26- 13, Isane B 5.50 (m, 3H), 5.84 (s, 1H), OIL 5.8-6.0 (m, 1H), 8.58 (d, 2H), 8.9 (s, 1H), 13 C-NMR (CDCl 3): 26.4, 32.5, 64.4, 66.1, 69.8, 70.9, 73.7, 74.9, 119.6, 131.0, 143, 0.20 144.3, 144.6, 152.1, 166.8, 167.8 ppm

Isane B: 1.45 (s, 3H), 1.63 (s, 3H), 4.56 (s, 1H), 4.65 (m, 2H), 5.1-5.5 (m, 4H) ), 5.6-25 δ (m, 1H), 5.91 (s, 1H), 8.57 (m, 2H), 8.78 (m, 1H). 13 C-NMR (CDCl 3): 26.27, 32.57, 64 130, 66.19, 69.94, 70.77, 72.38, 74.73, 119.70, 130.98, 30 143.30 , 144.57, 144.70, 152.04, 166.99, 167.99 ppm.

130 85376

Example 58 (cont'd) 13 1 R_ Yield% 1 H-NMR (CSCl 2) ppm (delta): δ a 25, (isoraee- 1.52 (s, 3H), 1.70 (s, 3H), , 8S) 4.64 (s, 1H), 4.72 (m, 2H), δ 4 T86 (d, 1H), 5.34-5.48 (m, 3H), 5.91 (s, 1H ), 5.92-6.05 (m, 1 H), 7.39 (t, 1 H), 8.87 (d, 2 H).

a 40, (isomer - 1.52 (s, 3H), 1.71 (s, 3H), R 1 '8 R) 4.61 (s, 1H), 4.72 (m, 2H), 4.98 (d, 1H), 5γ30-5.52 (m, 3H), 5r90-6.04 (m, 1H), 6.10 (s, 1H), 7.40 (t, 1H), 8.85 ( d, 2H).

Cc H 2, 6 3 15 83, foam 1.49 (s, 3H), 1.69 (s, 3H), 1 H 3.56 (d, 0.7 H), 3.39 (d, 0.3H), 4.7 (m, 3H), 5.5 (m, 3H), 5.9 (m, 2H), 7.53 (m, 3H), 3.14 (m, 3H).

2o r ^ rr \\ _ 97 ^ crude ^ / mixture of isomers a O.

131 85376

Example 58 (cont'd) B. Debromination of the above compounds by the method of Example 57, Part B gave the following compounds.

OH

R13-CH2 ^ S ^ ^ CH3 I-1 l ^ CH3 /} - * - * / * o 'οοοοη, οη = οη2 oil 5 (s, 3H), 1.7 (s, 3H), 4.05 [1 J (dd, 1H), 4.35 (s, 1H), 4.5 N (d, 1H), 4, 55 (m, 2H), 5.25- (from Isomer A, .alpha.,...,. -5.0 (m, 1 H), 3.6 (m, 2 H), 3.35 (s, 1 H).

a 59 1.5 (s, 3H), 1.3 (s, 3H), 4.15 (dd, 1H), 4.25 (bs, 1H), 4.55 (s, 1H), 4.7 (m, 2H), δ (from isomer B 8 S) 5.2-6.2 (m, 5H), 8.67 (bs, 2H), 9.00 (bs, 1H).

a 35 oil 1.51 (s, 3H), 1T74 (s, 3H), 4.01 (dd, 1H), 4.44 (d, 1H), 4.60 (s, 1H), 4.70 ( d, 2H), 20 A, OS) 5.40 (m, 3H), 5.60 (d, 1H).

5.96 (m, 1 H), 7.34 (t, 1 H), 3.30 (d, 2 H).

a 65 1.52 (s, 3H), 1.78 (s, 3H), 4.123 (m, 2H), 4.64 (s, 1H), 25 1 (d, 2H), 5.30-5, 46 (m, J: (from isomer B, 8R) 3H), 5.53 (d, 1H), 5.90-6.04 to, 1H), 7.34 (t, 1H), 8.85 (d, 2H).

132 8 5 376

Example 58 (cont.) R13 Yield - 1 H-NMR (CDCl 3) δ (delta):

C 11 H 16 M / M 100 100 1.47 (s, 3H), 1.67 (s, 3H),. 4r16 (m, 2K), 4.64 (m, 3H), δ 5.47 (m, 4K), 5.94 (m, 1H), 7.43 (m, 3H), 8.02 (m , 3H).

81 1.42 (s, 3H), 1.7 (s, 3H), 4.4 (not purified), (s, 1H), 4.65 (m, 2H), 5.2-6.3 (8R) (m, 3K), 5.6 (d, J = 4, 1H), 5.6 (d, J = 8, IK), 7.2-7.6 (m, 2H), 7.8-8.1 (m, 2H).

36 1.45 (s, 3K), 1.55 (s, 3H), (after purification of 4? 13 (d "d '1H)' 4'5 (s '1H)'] _5) 4.65 (m, 2H), 5.2-6.4 (m, 5K), (3S) 7.2-7.6 (m, 2H), 7.3-3.2 (m, 2K).

;; a 133 85376

Example 58 (cont'd) C. The reaction of the allyl esters obtained above by the method of Example 45 gave the following potassium salts.

OH

R 13 -CH 2 S 2 / CH 3 5 f pCH 3

Qy "^ COOK

-.13 Yield% Stereochemistry 1 ^.

R 11 -H-HHR (DMSO-d) δem (delta): at C 0 75 8 R 1.46 (s, 3H), 1.56 (s, 3H), 3.76 (s, 1H), 4.13 (dd, 1H), 5.05 (d, 1H), 5.4 (d, 10 (Isaneen A) 1H), 8.53 (d, 2H), 3.72 (s, 1H). Infrared (KBr): 3473, 1761, 1607 cm -1.

a 82 8S 1.42 (s, 3H), 1.65 (s, 3K), 4.25 (s, 3H), 4.27 (dd, 15 (Isane B) 1H) '5'3 (d (1K) '5'35 (d / 1H), 8.6-8.7 (m, 2H), 3.8 (m, 1H).

Δ 94 S (D 2 O): 1.32 (s, 3H), 1.54 (s, 3H), 4.18 (s, 1K), δ (Isane Λ) 4.14-4.19 (m, 1H) , 5.19 (d, 1H), 5.25 (d, 1H), 7.45 (t, 1H), 8.75 (d, 2K).

95 8R (D 2 O): 1 * 44 <s '3 «), 1.58 (s' 3H) * 4» 12 (s, 1K), 4.13. (Isane B) {m, 1H), 5.22 (d, 1H), 5.49 (d, 1H), 7.46 (t, 1H), δ-75 (d, 2H).

134 85376

Example 58 (continued)

Stereochemistry H13 Yield at 6 ° 1 H-NMR (DMSO-d 6) corn (delta): ---- -0_k _ »-

CcH- i 6 3 / Nn 97 8R lr47 (s, 3K), 1.58 (s, 3H), \\ I? 3.79 (s, 1H), 4.13 (dd, 1K), 5 ', 5.2 (d, 1H), 5.4 (d, 1H), 5.95 (bs, 1H), 7.45 (t, 1H), 7.60 (t, 2H), 8.03 (d, 2H), 8.16 (s, 1H).

85 8S 1.48 (s, 3H), 1.67 (s, 3K), δ 4.27 (d ~ d 'J = 4 and 10' 1H), 4.3 (s, 1H), 5.45 (d, J = 4, 1H), 5.57 (d, J = 10, 1H), 7.45-7.65 (m, 2H), 8.04 (t, J = 8, 2H).

IR (KBr): 3424, 1765, 1746, 1592 cm -1.

91 8R 1f42 (s' 3H) '1f56 (s' 3H) r 4.16 (s, 1K), 4.25 (d - d, J = 4 and 8, 1H), 5.46 (d,

Li "J (4, 1H), 5.5 (d, J = 8, 1H), 7.4-7.6 (m, 2H), 7.3-3.05 (m, 2H).

S Cl

Cl 135 c <5 3 76

Example 59

Preparation of Pivaloyloxymethyl Esters A. To a solution of 470 mg (1.28 mmol) of potassium 6- (isothiazol-3-yl) methylene-1,1-dioxopenisilylate in 2 mL of dimethylformamide was added 0.18 mL (1.28 mmol) of mmol) chloromethyl pivalate at room temperature. The mixture was stirred overnight, then poured into water and extracted with ethyl ether (3 x 20 mL). The extracts were dried (Na 2 SO 4) and the solvent evaporated to give 500 mg (88%) of a dark orange oil. Chromatography on a silica gel column using chloroform / ethyl acetate 9: 1 as eluent gave pivaloyloxymethyl 6- (isothiazol-3-yl) methylene-1,1-dioxopenicillanate as a clear oil, yield 315 mg (55%). 1 H-NMR (CDCl 3) ppm (δ): 1.22 (m, 0.9H), 1.5 (s, 3H), 1.6 (s, 3H), 4.44 (s, 1H), 5.64 (s, 1H), 5.84 (AB quartet, 2H), 7.36 (s, 1H), 7.38 (d, 1H), 8.72 (d, 1H).

B. By the method described above, p-valoyloxymethyl 6 - [(3-methylbenzimidazol-2-yl) -20-hydroxymethyl] penicillanate was prepared from the potassium salt in 61% yield as a tan oil.

1 H-NMR (CDCl 3) ppm (δ): 1.2 (s, 9H), 1.42 (s, 3H), 1.64 (s, 3H), 3.84 (s, 3H), 4.5 (s, 1H), 4.58 (dd, 1H), 5.46 (d, 1H), 5.6 (d, 1H), 5.82 (AB quartet, 2H), 7.24 (m, 3H), 7.7 (m, 1 H).

Preparation A

6-Chloropyridin-2-ylmethyl-triphenylphosphonium chloride (i) 6-Chloro-2-methyl-pyridine-1-oxide To a solution of 5.1 g (40 mmol) of 6-chloro-136 85376 2-picoline in 50 ml: In methylene chloride, 8.625 g (40 nunoles) of 80% m-chloroperbenzoic acid were added and the mixture was stirred at room temperature for 15 hours. The reaction was quenched with 0.5 mL of saturated sodium thio-sulfate and the pH was adjusted to 7.5 with sodium hydrogen carbonate solution. The organic layer was washed with water, dried (Na 2 SO 4) and the solvent evaporated to give 4.84 g of N-oxide.

1 H-NMR 1 CDCl 3 / d 6 (delta): 2.6 (s, 3H), 7.0-8.0 (m, 3H).

(Ii) 6-chloro-2-acetoxymethylpyridine

A solution of 4.8 g (0.035 mol) of the N-oxide obtained above in 15 ml of acetic anhydride was named at 100 ° C for 1 hour and distilled in vacuo to give 2.39 g of the desired product, b.p. 125-15 128 ° / 0.7 mm, as a colorless oil.

1 H-NMR (CDCl 3) ppm (delta): 2.1 (s, 3H), 5.1 (s, 2H), 7.0-7.8 (m, 3H).

(iii) 6-chloro-2-pyridylmethanol

By hydrolysis of the product obtained in part (ii) in 20 ml of 2-norm. hydrochloric acid at 70 ° C for 1 hour, followed by neutralization (K 2 CO 3), extraction with chloroform and evaporation of the solvent from the dried extract gave 1.87 g of crude alcohol which was purified by silica gel column chromatography to give 0.982 g of pure material.

1 H-NMR (CDCl 3) ppm (delta): 4.8 (s, 2H), 5.3 (bs, 1H), 7.0-7.8 (m, 3H).

(iv) 6-Chloro-2-chloromethylpyridine 6-Chloro-2-pyridylmethanol, 0.982 g (6.84 mmol-30) was treated in 10 ml of methylene chloride with 0.814 grams of 137.85376 thionyl chloride at room temperature for 1 hour. The mixture was neutralized with saturated sodium hydrogencarbonate solution, extracted with methylene chloride, the extracts dried and the solvent evaporated to give 815 mg of product as colorless crystals.

1 H-NMR (CDCl 3) ppm (delta): 4.7 (s, 2H), 7.1-8.0 (m, 3H).

(v) Wittig reagent was prepared by dissolving 815 mg (5 mmol) of the product obtained in part (iv) and 1.318 g (5 mmol) of triphenylphosphine in toluene (10 ml) and heating the mixture at reflux for six hours. The precipitated product was collected by filtration to give 1.388 g (65%) of the title compound.

1 H-NMR (DMSO) ppm (delta): 5.5 (s, 1H), 5.8 (s, 1H), 7.2-8.2 (m, 18H), δ (vi) 4-methoxypyridine- 2-ylmethyltriphenylphosphonium chloride Using 2-methyl-4-methoxypyridine-1-oxide (2.1 g) as a starting material in the process of part (ii), 2.5 g of 2-acetoxymethyl-4-methoxypyridine with 20 as an impurity were obtained. about 25% 5-acetoxy-2-methyl-4-methoxypyridine. This mixture was dissolved in methanol (10 ml) containing 1.118 g (20.7 mmol) of sodium methylate and stirred at reflux for 1 hour. The methanol was evaporated off in vacuo, the residue was diluted with water, neutralized with dilute hydrochloric acid and extracted with chloroform. The organic layer was washed with brine, dried (MgSO 4) and evaporated to dryness in vacuo to give 853 mg (41%) of 2-hydroxymethyl-4-methoxypyridine.

3 H 1 H-NMR (CDCl 3) ppm (delta): 3.9 (s, 3H), 4.72 (s, 2H), 5.35 (bs, 1H), 6.7 (dd, 1H), δ, 95 (d, 1 H), 8.3 (d, 1 H).

The hydroxymethyl compound obtained above was converted to 2-chloromethyl-4-methoxypyridine by the method of part (iv) described above in a yield of 0.895 g (5.68 mmol). This was reacted with an equimolar amount of 138 85376 of triphenylphosphine in toluene (10 ml) boiling for 20 hours. The precipitated product was filtered off to give 860 mg of the title compound as a yellow solid.

5 Preparation B

2-Quinolinylmethyltriphenylphosphonium chloride A solution of 2-chloromethylquinoline, 6.26 g (0.035 mol), and 9.20 g (0.035 mol) of triphenylphosphine in 80 ml of toluene was heated at reflux for 3 hours. The precipitated solid was collected on a filter and dried in vacuo to give 3.5 g (23%) of product as a brown solid.

Preparation C

3-Allyloxy-2-pyridylmethyltriphenylphosphonium chloride (i) 3-Allyloxy-2-hydroxymethylpyridine

To a mixture of sodium methylate-methanol prepared from 1.43 grams (62 mmol) of sodium metal and 100 mL of methanol was added 5.9 g (31 mmol) of 3-hydroxy-20-oxy-2-hydroxymethylpyridine and the methanol was removed in vacuo. The resulting residue was dissolved in 80 mL of dimethyl sulfoxide (DMSO) and 3.0 mL (34.7 mmol) of allyl bromide in 20 mL of DMSO was added over 20 minutes at room temperature. The mixture was stirred for two hours, DMSO was distilled off in vacuo and the residue was partitioned between chloroform and water. The pH of the aqueous phase was adjusted to 7.5 and extracted three times with chloroform. The combined organic layers were washed with water, brine, dried (Na 2 SO 4) and evaporated to dryness to give 3.48 g (68%) of the desired ether.

(ii) 3-allyloxy-2-chloromethylpyridine

The product of Part A (3.43 g, 20.8 mmol) in 20 mL of methylene chloride was treated with 1.5 equivalents (2.5 mL) of thionyl chloride and the mixture was stirred under nitrogen for two hours. The volatiles were removed in vacuo; 139 85376 and the residue was partitioned between methylene chloride and water. The aqueous layer was adjusted to pH 7.5 and extracted with fresh methylene chloride. The combined extracts were washed with water, brine, dried (Na 2 SO 4) and the solvent evaporated in vacuo to give 3.28 g (86%) of the desired product which was used in the next step.

(iii) The product of part (ii) (3.28 g, 17.9 mmol) was dissolved in 30 mL of toluene and 4.69 g (17.9 mmol) of triphenylphosphine was added. The mixture was stirred at reflux for three hours, then kept at room temperature for 12 hours. The product was isolated by filtration, washed with toluene to give 3.89 g (49%) of the desired Wittig reagent.

15 Preparation D

Allyl 6-ol bromo-1,1-dioxopenicillanate (1) 6 - (- 1) romipenicillanic acid 1,1-dioxide

A suspension of 20.26 g (0.0517 moles) of 6,6-dibromopenicillanic acid-1,1-dioxide in 80 ml of 20 ° water was treated by the portionwise addition of 13 g (0.155 moles) of solid sodium bicarbonate. Vigorous gas evolution was controlled by the addition of ethyl acetate. Solid sodium hydrogen sulfite (6.76 g, 0.062 mol) was then added portionwise, the resulting mixture was stirred for 35 minutes and the pH was adjusted to 1.0 with concentrated hydrochloric acid. The acidified mixture was diluted with ethyl acetate, the organic phase was washed with brine, dried (Na 2 SO 4) and the solvent was evaporated off in vacuo. The residue was triturated with chloroform and filtered to give 6.72 g of a pale yellow solid. Another 3.2 g of product was obtained by concentrating the filtrate and treating the residue with chloroform.

(ii) To a mixture of 6.352 g of the first batch material obtained above in 20 ml of dimethylformamide was added 1.76 ml (20.3 mmol) of allyl bromide, 2.83 ml (20.3 mmol) of triethylamine. and 0.2 g of sodium bicarbonate and the mixture was stirred under nitrogen at room temperature for 15 hours. Water was added, the mixture was extracted with ethyl ether, the extracts were washed with water, dried (Na 2 SO 4) and the solvent evaporated in vacuo to give 4.60 g (64%) of the desired ester as an oil.

1 H-NMR (CDCl 3) ppm (delta): 1.4 (s, 1H), 1.6 (s, 3H), 4.4 (s, 1H), 4.6 (d, 1H), 4, Δ (d, 2H), 5.15 (d, 1H), 5.1-5.95 (m, 3H).

(iii) Allyl 6,6-dibromopenicillanate

Esterification of 6,6-dibromopenicillanic acid by the above procedure at a molar amount of 0.417 gave 15,140 g (84) of the 1-yl ester as an oil.

1 H-NMR (CDCl 3) ppm (delta): 1.5 (s, 3H), 1.65 (s, 3H), 4.6 (s, 1H), 4.75 (m, 2H), 5.3 -5.6 (m, 2 H), 5.85 (s, 1 H), 5.8-6.3 (m, 1 H).

Preparation E

2-Formyl-1-methylimidazole (i) 2-Hydroxymethyl-1-methylimidazole

A mixture of 50 g of 1-methylimidazole and 100 ml of 37% formaldehyde (m.p. 1.08) was placed in a stainless steel bomb (300 ml) and heated at 150 ° C (bath temperature) for 17 hours. . The bomb was then cooled on ice and the mixture was removed, concentrated in vacuo and the residue was stored overnight at 4 ° C. The resulting mixture of crystals and oil was filtered, washing with ethyl acetate. The colorless crystals were dried in vacuo to give 14.60 g of product. Reprocessing the mother liquor gave a second crop of product, 6.48 g. Total yield 21.08 g (31%).

(ii) To a solution of 4.96 g (43.9 mmol) of 2-hydroxymethyl-1-methylimidazole in 50 mL of dioxane was added 4.90 g (44.1 mmol) of selenium dioxide and a mixture of The mixture was stirred at 85-90 ° C for five hours, at room temperature for 36 hours, at 85 ° C for eight hours and finally at room temperature for 15 hours. The reaction mixture was filtered, the solvent evaporated in vacuo to give 4.81 g of crude aldehyde which was distilled to give

2.11 g of product as colorless crystals, b.p. 65 ° C / 2.8 mmHg. Preparation F

6-Methyl-2-pyridylmethyltriphenylphosphonium chloride 10 (i) 6-Methyl-2-hydroxymethylpyridine 6-Methylpyridine-2-carboxaldehyde (0.44 mmol) was reduced in 50 mL of methanol with 20.6 mmol of sodium borohydride. C. After the reduction was complete, the mixture was neutralized (pH 7.5) to 2-norm. with sulfuric acid, filtered, the filtrate evaporated to dryness and partitioned between chloroform and water. Evaporation of the solvent from the organic layer gave 3.32 g of a red-black oil which was used in the next step, (ii) 2-chloromethyl-6-methylpyridine The product obtained above, 3.32 g (0.27 mmol), was treated in 20 ml. methylene chloride with 1.94 mL (27 mmol) of thionyl chloride at room temperature for one hour. The mixture was neutralized (NaHCO-j) and extracted with chloroform. Evaporation of the solvent gave 3.22 g of product as an oil which was used in the next step.

(lii) A solution of 3.22 g of the oil obtained in part (ii), 5.96 g of triphenylphosphine in 30 ml of toluene was heated at reflux for four hours. Filtration of the precipitate gave 3.93 g of Wittig reagent as a brown solid.

30 Preparation G

2-Pyrazinylmethyltriphenylphosphonium chloride (i) 2-Hydroxymethylpyrazine

To a solution of 11.29 g (79.2 mmol) of 2-pyrazinecarbonyl chloride (prepared by treating the corresponding 2-carboxylic acid with a molar excess of thionyl-142 85376 chloride at boiling temperature) in 100 ml of tetrahydrofuran at -78 ° C, 2.0 g (52.6 nunols) of lithium aluminum hydride (95% purity) were added portionwise over 20 minutes. The mixture was stirred for 10 minutes and allowed to warm to room temperature. The reaction was quenched with 2M sodium hydroxide, filtered, washing with methanol. Evaporation of the filtrate to dryness in vacuo gave 4.12 g of a dark solid which was used in the next step.

(Ii) The dark solid obtained above (4.12 g, 37.8 mmol) was dissolved in methylene chloride and at 0 ° C 2.8 ml of thionyl chloride were added. The mixture was warmed to room temperature, stirred for 30 minutes, water was added, the mixture was neutralized and extracted with methylene chloride to give 2.29 g of a yellow oil which was used in the next step.

(iii) To the above oil, 2.29 g in 40 ml of toluene, 4.70 g of triphenylphosphine was added and the mixture was boiled for three hours. Further work-up in the usual manner gave 1.955 g of Wittig's reagent as a brown solid.

Preparation H

4-formyylipyrimidiini

A solution of 4-methylpyrimidine (10 g, 0.106 mol) in 100 ml of dioxane was treated with 11.8 grams of selenium dioxide at room temperature and the mixture was heated at 100 ° C for 15 hours. After the addition of 2.5 g of selenium dioxide, heating was continued for one hour, the mixture was cooled, filtered, and the filter cake was washed with ethyl acetate. The filtrate and washings were evaporated to dryness in vacuo. The residual dark oil was dissolved in methylene chloride, filtered and the solvent evaporated. The residue was crystallized from a small amount of methylene chloride to give the title alde-35 hydr.

143 85376 1 H-NMR (CDCl 3) ppm (delta): 7.87 (dd, 1H), 9.06 (d, 1H), 9.43 (d, 1H), 10.0 (s, 1H).

Preparation I

Diphenylmethyl 6-? -Bromo-1,1-dioxopenicillanate

To a solution of 21.557 g (0.1 mol) of diphenyldiazomethane in 400 ml of dry tetrahydrofuran was added portionwise over 30 minutes 31.2 g (0.1 mol) of 6- [4-bromo-1,1-dioxopenicillanic acid. The reaction was slightly exothermic. The mixture was stirred for 1 hour, the solvent was evaporated and the residue was dissolved in ethyl acetate (50 ml). Ethyl ether (400 mL) was added and the resulting mixture was stored at 4 ° C. No crystals formed during 18 hours. The mixture was then evaporated to dryness in vacuo to give 51.2 g of a yellow solid which was chromatographed on silica gel eluting with chloroform to give 14.86 g of a colorless product as a glass.

1 H-NMR (CDCl 3) ppm (delta): 1.26 (s, 3H), 1.57 (s, 3H), 4.55 (s, 1H), 4.70 (d, 1H), δ, 13 (d, 1 H), 6.9 (s, 1 H), 7.27 (s, 10 H).

Preparation J

Benzothiazole-2-carboxaldehyde

A solution of freshly distilled (b.p. 82 ° C, 2 torr) benzothiazole (10 g, 0.074 mol) in 250 mL of tetrahydrofuran was cooled to -78 ° C under nitrogen and stirred at this temperature for 15 minutes. To this was added dropwise over 15 minutes 29.6 ml (0.074 mol) of 2.5 mol. n-butyllithium, stirring was continued for 25 minutes, and 8.6 ml (0.111 mol) of dimethylformamide were added, and the reaction mixture was stirred for 1 hour. The mixture was allowed to warm to room temperature, 200 g of ice were added and the solvent was evaporated off in vacuo. The aqueous residue was extracted with 5 x 100 mL of ethyl 35 acetate, the extracts were dried (MgSO 4), evaporated to a small volume of 14485376 and chromatographed on a silica gel column eluting with chloroform / ethyl acetate 96: 4 to give 8.4 g of the desired aldehyde. , sp. 74.5 to 75 ° C. 1 H-NMR (CDCl 3) ppn (delta): 7.54 (m, 2H), 7.97 (m, 1H), 8.21 δ (m, lii), 10.1 (s, lii).

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Preparation K

The pyrazine-2-carboxaldehyde

The pyrazine-2-carboxylic acid was esterified with a methanolic solution of sulfuric acid by boiling for 5 hours. The meta-5 ol was evaporated off in vacuo, diluted with methylene chloride and neutralized with sodium hydrogen carbonate (pH 7.5). The dried organic layer was evaporated to dryness to give methyl pyrazine-2-carboxylate as an off-white solid in 84% yield, which was recrystallized from isopropanol / ethyl ether to give yellow needles.

1 H-NMR (CDCl 3) ppm (delta): 4.1 (s, 3H), 8.93 (m, 2H), 9.47 (m, 1H).

The methyl ester (20 g, 0.145 mol) was dissolved in 15,600 mL of dry tetrahydrofuran, cooled to -78 ° C, and a solution of 5.3 g of 98% lithium aluminum hydride in THF was added dropwise over 15 minutes. The mixture was stirred for 30 minutes at -78 ° C, 20 mL of acetic acid was added and the mixture was concentrated in vacuo. The residue was partitioned between 2N hydrochloric acid (30 ml) and chloroform, the combined organic layers washed with water, dried and evaporated to dryness to give 8.53 g of crude product which was purified by passing through a silica gel column eluting with methylene chloride / ethyl acetate. 4: 1 to give 5.02 g of pale yellow needles.

1 H-NMR (CDCl 3) ppm (delta): 8.38 (m, 2H), 8.7 (bs, 1H), 9.7 (s, 1H).

Preparation L

2-Phenyl-1,2,3-triazole-4-carboxaldehyde (i) By reacting 0.34 moles of acetone dicarboxylic acid in 100 ml of water with 0.58 moles of sodium nitrite at 0-10 ° C and adding thereafter, to precipitate the product with dilute nitric acid, 35 dioximes, 1,3-dioxoimino-2-oxopropane, were obtained in 46% yield as golden brown crystals.

n 147 85376 (ii) Dioxin (0.158 mol) in ethanol (170 ml) was reacted with equimolar amounts of phenylhydrazine hydrochloride and sodium acetate at 70 ° C for 30 minutes. Water (170 ml) was added, mixture 5 was heated to 85 ° C, reduced in volume to 250 ml and cooled to give 24.7 g of phenylhydrazone.

1 H-NMR (CD 3 COD 3) ppm (delta): 7.3 (m, 5H), 7.9 (s, 1H), 8.6 (s, 1H), 10.5 (bs, lii), 11.4 (bs, 1H), 12.3 (s, 1H).

(Iii) The dioximiphenylhydrazone obtained above, 24.7 g (0.119 mol), was stirred at room temperature with 500 ml of acetic anhydride for 30 minutes and the mixture was poured into water, stirred for 20 minutes and filtered. The resulting crude solid was recrystallized from benzene / -15 ethyl acetate to give 15.47 g (52%) of monoacetate, HON = CH-C (= NNHC 6 H 5) CH = NOCOCH 3, as a yellow powder.

1 H-NMR (CDCl 3, acetone): 1.85 (s, 3H), 7.09 (m, 5H), 7.95 (s, 1H), 8.3 (s, 1H), 10.9 (bs , 1H), 12.25 (s, 1H).

(Iv) A solution of 15.40 g (0.062 mol) of the monoacetate obtained above and 22.16 g (0.063 mol) of cesium carbonate in 400 ml of tetrahydrofuran was stirred at room temperature for 1 hour, filtered and the filtrates evaporated to dryness. to give a yellow residue.

The residue was dissolved in 700 mL of hot isopropyl ether / cyclohexane and concentrated to 200 mL to give 9.41 g (80%) of 2-phenyl-1,2,3-triazole-4-carboxaldehyde oxime as a yellow powder. , which was used in the next step.

(V) A mixture of 9.41 g (0.0497 moles) of oxime, 4.48 g of s-trioxane and 300 ml of 2-hydrochloric acid was heated at reflux for 3.5 hours. The aqueous phase was extracted with ethyl ether, the combined ether layers washed with water, dried (MgSO 4) and the ether evaporated in vacuo to give 6 g of crystalline aldehyde.

148 85 376 1 H-NMR (CDCl 3) ppm (delta): 7.6 (m, 3H), 8.25 (m, 3H), 10.25 (s, 1H); mp 66-67 ° C.

Preparation M

5-Methylisoxazole-3-carboxaldehyde 5 (i) Ethyl 5-methylisoxazole-3-carboxylate

A mixture of 0.16 moles of ethyl 2,4-dioxovalerate and 0.08 moles of hydroxylamine sulfate, 50 ml of ethanol and 70 ml of toluene was stirred at 40 ° C for four hours. The mixture was cooled to 15-20 ° C, 1.8 g of concentrated ammonium hydroxide was added and stirring was continued at room temperature for 60 hours. The mixture was poured into water / toluene, the aqueous layer was extracted with toluene, the organic layers were combined, washed with brine and dried (Na 2 SO 4). Evaporation of the solvent 15 in vacuo gave a yellow liquid which was distilled to give 14.68 g of product, b.p. 120-124 ° C / 30 torr, which crystallized on standing.

(ii) The ethyl ester obtained above, 2.0 g (14.4 mmol) in 75 ml of toluene, was reduced with an equimolar amount of 1 mol. diisobutylaluminum hydride in hexane under nitrogen protection at -75 ° C to -70 ° C. After stirring for 30 minutes, the reaction was quenched with ammonium chloride solution, warmed to room temperature and the solvent was evaporated in vacuo. The residue was triturated with hot methanol, evaporated to dryness to give 0.85 g of product as a colorless oil.

1 H-NMR (CDCl 3) ppm (delta): 2.4 (s, 3H), 6.3 (d, 1H), 9.0 (s, 1H).

Preparation M (continued) 30 (iii) Benzoxazole-2-carboxaldehyde

The title compound was prepared by the method of (ii) from methyl benzoxazole-2-carboxylate to the extent of 0.041 mol; yield 35% as a yellow oil. 1 H-NMR (CDCl 3) ppm (δ): 7.3-8.1 (m, 4H), 10.0 (s, 35H).

li 149 8 5 3 7 6

The above starting material was obtained from o-aminophenol by a two-step method. In the first step, o-aminophenol was reacted with an equivalent molar amount of oxalyl chloride in m-dichlorobenzene solvent at reflux temperature (= 185 eC) to give 2,3-dioxobenzoxazolidine in almost quantitative yields. This was then reacted with a small excess of thionyl chloride in benzene at reflux temperature and the resulting 3-chloro-2-hydroxy-10-benzoxazine was treated with an equimolar amount of sodium hydrogen carbonate in methanol which was refluxed overnight to give the desired benzoxazole-2-carboxazole-2-carboxylate; mp. 101 - 102 eC. 1 H-NMR (CDCl 3) ppm (δ): 4.05 (s, 3H), 7.3 - 8.0 (m, 4H).

15 Preparation N

(i) 6-Methoxy-2-methylbenzothiazole (10.0 g, 55.9 mmol) was oxidized with selenium dioxide (6.2 g, 55.9 mmol) in 300 mL of dioxane for 6 hours according to the procedure described in Preparation H to give 6.0 g of 6-methoxy-2-formylbenzothiazole were obtained after chromatography of the crude product on silica gel using chloroform as eluent. 1 H-NMR (CDCl 3) ppm (δ): 3.9 (s, 3H), 7.1-7.5 (m, 2H), 8.0-8.3 (m, 1H), 10.1 ( s, 1H).

Claims (7)

150 85376 A process for the preparation of a therapeutically active 6- (substituted methylene) penicillanic acid derivative of the formula J wherein N is zero, 1 or 2; R 1 is R "or R b, which Ra is a carboxyl protecting group selected from tetrahydropyranyl, allyl, benzyl and benzhydryl, and R b is hydrogen or R 4 is -COCR R 5 wherein R 4 and R 5 are each hydrogen or CH 3 and R 6 is (C 1 -C 6) alkyl; one of R 2 and R 3 is hydrogen and the other is Cl, CH 2 OH, vinyl, () alkylthio, (03-04) alkylsulfonyl, furyl, thienyl, N-methylpyrrolyl, N-acetylpyrrolrolyl, R 7 C 6 H 4, R 7 C 6 H 4 S, 30 R7 'r ^ CO ~' <0) p (0) p 35 _ m7) r ^ N r7 — ίΠ— (R7) f “Tr · Iy xl li 151 85376» '' - ^ '·' “-fjr »'- (> 5"' '• -OCr - - “- o-" 10 and p is zero or 1, t is zero, 1 or 2, X 1 is S, O or NR 11, R 7 is hydrogen, (C C *) alkyl, (C 1 -C 3) alkoxy, allyloxy, hydroxyl, carboxyl, (C 2 -C 5) alkoxycarbonyl, (C 1 -C 5) alkylcarbonyl, phenyl, benzyl, Cl, Br or CF 3; R 8 is hydrogen, ( C 1 -C 4) alkyl, phenyl or benzyl, and R 11 is hydrogen, CH 3, C 2 H 5 or CH 3 CO, or a pharmaceutically acceptable acid addition salt of said derivative wherein R 2 or R 3 has a basic nitrogen atom, or said derivative wherein R 1 is hydrogen or R 2 or R 3 has a carboxyl group for the preparation of a pharmaceutically acceptable cationic salt, characterized in that a) when n is zero, 1 or 2, a starting compound of the formula 25 ° <s_ 1 pCH 3 O 2 N 2 OOR1 wherein R1 is as defined above, preferably R1, is reacted with a Wittig reag with an enzyme of the formula R 2 R 3 C = P (C 6 H 5) 3 35 152 8 5 376 in the presence of a reaction-inert organic solvent at a temperature in the range of -100 to + 50 ° C to give a compound of formula (I) wherein n is zero; and, if desired, a compound of formula (I) in which n is 1 or 2, the corresponding compound in which n is zero is oxidized, preferably with an alkali metal or alkaline earth metal permanganate, 3-chloroperbenzoic acid or peracetic acid; and, if desired, removing a carboxyl protecting group Ra of a compound of formula (I) wherein R 1 is R b to give a compound of formula (I) wherein R 1 is H, and then, if desired, then reacting the obtained compound with a compound of formula RbQ, wherein Rb is other than hydrogen as defined above and Q is chlorine, bromine or iodine, in the presence of a polar organic solvent, or b) when n is zero or 2 and one of R2 and R3 is hydrogen and the other is vinyl, (C1- C4) alkylsulfonyl, furyl, thienyl, N-methylpyrrolyl, N-acetylpyrrolyl, 20 7 R '(0) P (0) p 25, νζ? - ιΛ'15 Xl ”-S3- -S3- · * '-O- .s "' '• -CCr„ 153 8 5 3 76 p is zero or 1, t is zero, 1 or 2, Xx is S, O or NR11; R7 is hydrogen, (C1-C4-alkyl) , (C 1 -C 4) alkoxy, allyloxy, hydroxyl, carboxyl, (C 2 -C 5) alkoxycarbonyl, (C 1 -C 3) alkylcarbonyl, phenyl, benzyl, Cl, Br or CF 3, and R 8 is H, (C 1 -C 4) alkyl, phenyl or benzyl, and R 11 is H, CH 3, C 2 H5 or CH3CO, a compound of formula ^ Br 'g'n CH, -N-1 O 2 COOR 1 wherein R 1 is other than H and n is zero or 2, is contacted with equimolar amounts of a (C 1 -C 4) alkylmagnesium halide or a (C 1 -C 4) alkyllithium reagent and an aldehyde of formula is R 2 R 3 CO, wherein said halide is Cl, Br or J and R 2 and R 3 are as defined above, immediately in the presence of a reaction inert solvent at a temperature in the range of -100 to + 25 ° C to give a compound of formula Br (O) CH * s) -NV //. 1 '' C00R 25 υ (XI) wherein R12 and R13 are the same as R2 and R3 as defined above, and optionally converting a compound of formula (XI) to a carboxy-protected derivative wherein R1 is as defined above and acylating with acyl chloride or acyl bromide. with a formula of R 18 Cl or R 18 Br wherein R 18 is acetyl in the presence of an equimolar amount of a tertiary amine and in the presence of a reaction inert organic solvent is hydrogenolyzed in the presence of a reaction inert solvent with an organic tin hydride or 154 85376 hydrogen in the presence of a noble metal catalyst; and dehydrating or deacetylating the resulting compound, or c) when n is 2 and R 2 and R 3 are as defined in b) above, a compound of formula 5 H 0 P 'f -, - ½ JJ -! ^ οορ1 10 (IX ) wherein R 1 is other than H, is reacted with equimolar amounts of a (C 1 -C 3) alkylmagnesium halide and aldehyde of the formula R 2 R 3 CO, wherein R 2 and R 3 are as defined in b) above, in an ether solvent at a temperature in the range - 80 to + 25 ° C to give the first product of formula OH 0 0 20 13 'W CH_RXJ-C //// y 3 R1Zi- \ r "CH3 (Ι1> j'-N-koOR1 25 where R12 and R13 are the same as R2 and R3 as defined immediately above, optionally reacting said first product with an acyl chloride or acyl bromide of formula R18Cl or R18Br, wherein R18 is acetyl, in the presence of an equimolar amount of tertiary amine and with respect to the reaction in the presence of an inert organic solvent, and dehydrating said first tu extract or deacetylated acetylated derivative of said first product. Process according to Claim 1, characterized in that in said starting material R 1 is R a, preferably allyl or benzyl, said reaction-inert solvent is tetrahydrofuran, said temperature being between -78 and + 25 ° C, one of R 2 and R 3 is H and the other is 2-pyridyl, N-oxo-2-pyridyl, 2-quinolyl, 3-allyloxy-2-pyridyl, 3-methoxy-2-pyridyl, 4-methoxy -2-pyridyl, 3-hydroxy-2-pyridyl, 6-methyl-2-pyridyl, 1-methyl-2-imidazolyl, 2-thiazolyl, 4,5-dimethyl-2-thiazolyl, 4-methyl-2 - thiazolyl, 4-pyrimidinyl, 2-pyrimidinyl, 4,6-dimethyl-2-pyrimidinyl, 2-pyrazinyl, 2-methyl-1,2,4-10 triazol-3-yl or benzothiazol-2-yl; and said compound of formula (I) wherein n is zero is oxidized to the corresponding compound where n is 2 by oxidation with 3-chloroperbenzoic acid or potassium permanganate. Process according to Claim 1, characterized in that the reaction mentioned in b) or c) with the aldehyde R 2 R 3 CO is carried out at -78 ° C in the presence of tetrahydrofuran or ethyl ether. Process according to Claim 3, characterized in that one of R 2 and R 3 is H 2 O and the other is 2-thiazolyl, 3-isothiazolyl, 5-methyl-3-oxazolyl, pyridazin-3-yl, 1,2,3- thiadiazol-4-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1-phenyl-5-methyl-1,2,3-triazol-4- yl, 1-methyl-1,2-diazol-3-yl, 4-pyrimidinyl, 4,5-dimethylthiazol-2-yl, benzothiazol-2-yl or 1-benzylbenzimidazol-2-yl. Process according to Claim 1, characterized in that one of the radicals R 2 and R 3 is H and the other is 2-pyridyl, 3-allyloxy-2-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 3-hydroxy-2-pyridyl, 4-methoxy-2-pyridyl or 2-thiazolyl. Process according to Claim 4, characterized in that one of the radicals R 2 and R 3 is H and the other is 2-thiazolyl or benzothiazol-2-yl. Process according to any one of the preceding claims, characterized in that in said starting compound R 1 is allyl and this allyl derivative is converted into the corresponding compound in which R 1 is H, Na or K by reacting the resulting allyl ester product in the presence of a reaction-inert solvent. With tetrakis (triphenylphosphine) palladium (0) and triphenylphosphine and with equimolar amounts of the sodium or potassium salt of 2-ethylcaproic acid. 157 85376