These important intermediates are usually prepared from 4-acetoxy azetidinones by reaction with a suitable thioacid in an aqueous or organic-aqueous medium in the presence of a base, but this methodology is often unsuitable, especially when sensitive thioacids are used. Moreover high amount of impurities are often present in the above conditions, and therefore an additional chromatographic purification step is needed.

The present invention relates to a procedure which provides mild conditions necessary for sensitive thioacids and gives a high yield (up to 95%) of the desired thioesters having the desired stereochemical configuration with only negligible amounts of by-products. Moreover this procedure is general and gives high yields with a wide range of thioacids in mild and safe conditions.

The present invention provides a process for preparing a compound of formula (I)

wherein R is H or a hydroxy protecting group, R ₂ is:

(i) a linear, branched or cyclic C,-C ₆ alkyl group optionally substituted by one or more groups chosen from free and protected hydroxy and amino groups and alkoxy, thioalkyl, acyloxy and carbamoyloxy groups; or

(ii) a 2-pyridyl ring or a 2-tetrahydrofuranyl ring or an aromatic group, optionally substituted by one or more groups chosen from free and protected hydroxy and amino groups and alkoxy, acyloxy, carbamoyloxy and linear or branched C ₁ -C ₄ alkyl groups, the alkyl groups being, in turn, optionally substituted by a free or protected hydroxy or amino group, an alkoxy, acyloxy, carbamoyloxy group, or a quaternary onium derivative with an optionally substituted heterocyclic base; and R ₃ is H or a nitrogen protecting group; which process comprises reacting together a compound of formula

wherein R, is a linear or branched C,-C ₄ alkyl group or a phenyl group and R and R ₃ are as defined above, a compound of formula (III)

wherein R ₂ is as defined above and X is a cation or a silicon- containing residue, and a salt of a group Ila, ib or transition element.

The configuration of the compound of formula I is l'R,3S,4R so that the desired (5R,6S,1 ^, R) stereochemistry of the penem end-product is achieved.

In one embodiment the process of the invention comprises mixing together, in an organic solvent, the compound of formula II and the compound of formula III and then adding thereto the said salt.

In another embodiment the process of the invention comprises mixing together, in an organic solvent, the compound of formula III and the said salt and then adding thereto the compound of formula II.

Typically, the reaction is carried out in an organic solvent with from 1 to 5 molar equivalents, preferably from 1 to 3 molar equivalents, of the compound of the formula (III) . The salt of the group Ila, lib or transition element is typically present in an amount of from 0.1 to 5 molar equivalents, preferably from 0.1 to 3 molar equivalents. The reaction temperature is typically from -20'C to 60 ^C C, preferably from O'C to 40*C. The reaction is typically conducted for a time of from 1 hour to 3 days, preferably from 4 hours to 1 day.

A linear or branched C ₁ -C ₆ alkyl group is typically a linear or branched C,-C ₄ alkyl group. Examples of a C,-^ alkyl group are methyl, ethyl, propyl, i-propyl, butyl, ^" sec butyl and tert butyl, in particular methyl or ethyl.

R is preferably H or a hydroxy protecting group.

R-, is preferably:

(i) a linear or branched C,-C ₄ alkyl group optionally substituted by a free or protected hydroxy or amino group, or a

linear, branched or cyclic 0,-0 ₄ alkoxy, thioalkyl or C.,-C ₅ alkanoyloxy group, or a carbamoyloxy group, (ii) a 2-tetrahydrofuranyl or a 2-pyridyl group optionally substituted by one or more groups chosen from free and protected hydroxy and amino groups, and alkoxy and acyloxy groups;

(iii) a phenyl ring optionally substituted by one or more groups chosen from: a free or protected hydroxy group, a C,-C ₄ alkyl group which is optionally substituted by a free or protected hydroxy or amino group or a quaternary onium derivative with an optionally substituted heterocyclic base. Examples of suitable quaternar onium derivatives include pyrrolidiniu and pyridinium groups. When R ₂ is a substituted linear or branched C.-C ₄ alkyl group the substituent is most preferably selected from a carbamoyloxy, acetoxy, methoxy, free or protected hydroxy, and free or protected amino group.

When R ₂ is an optionally substituted 2-pyridyl group it is preferably an unsubεtituted 2-pyridyl group or a 2-pyridyl group substituted by one or more free or protected hydroxy groups. When R ₂ is an unsubstituted 2-tetrahydrofuranyl group the asymmetric carbon atom has the (R) configuration.

Particularly preferred R ₂ groups are carbamoyloxymethyl , acetoxy ethyl, methoxymethyl, free or protected hydroxymethyl, 2-tetrahydrofuranyl and free or protected aminomethyl groups. When R ₃ is a nitrogen protecting group it is preferably chosen from t-butyldimethylsilyl, trimethylsilyl C*-C ₄ alkyl and triethylsilyl groups.

When the hydroxy or amino groups referred to herein are

protected, they may be protected by any group known to be suitable for protecting the hydroxy or amino moiety. Preferably the protecting group is chosen from t-butyldi- ethylsilyl, trimethylsilyl, triethylsilyl, pyranyl, acyl, p- nitrobenzyloxycarbonyl and 2,2,2-trichloroethoxycarbonyl groups.

When the X group represents a cation it is preferably an alkali or alkaline-earth metal cation, an ammonium cation or a tri- or tetra-alkylammonium cation. Preferably, X is a sodium, potassium or trialkylammoniu cation.

X acts as an activating residue, giving a reactive form of the compound of formula (III) which can then replace the group -OCOR.* in the compound of formula (II) . When X is a silicon-containing residue, it is typically a group -SiR'R"R' ' ' wherein each of R' , R" and R" ' is, independently, a linear or branched C,-^ alkyl group. Preferred examples of SiR'R"R' ' ' are a trimethylsilyl and a t- butyldimethylsilyl group.

Preferably the salt of a group Ila, lib or transition element is a halogenide, such as a chloride, bromide or iodide, or a carboxylate, such as an acetate, or a salt with an inorganic anion, such as a carbonate. A group Ila element is preferably Mg and a group lib element is preferably Zn.

The transition element is a first-, second- or third-row transition element, typically a first-row transition element. Preferably it is selected from Fe, Co and Ni. The salt of a transition element is preferably an iron trihalogenide such as FeCl ₃ , FeBr ₃ and Fel ₃ .

Suitable organic solvents include polar solvents, such as

acetonitrile, tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate and mixtures thereof. Preferred solvents are dioxane, tetrahydrofuran, dimethoxyethane and ethyl acetate.

The salt of the group Ila, lib or transition element may be, if desired, recycled by removal them from the reaction media by usual methods, such as filtration or water extraction, and then recovering the starting salt.

Optionally the said salt may be used in catalytic amounts (e.g. 10 to 20% by mole of the starting material) , provided that a suitable silicon derivative of the abovesaid thioacid is used, i.e. provided X in formula (III) is a silicon-containing residue.

Optionally a complex may be formed in situ, y mixing together the compound of formula (III) and the sail salt in an organic solvent, and reacted with a compound of formula (II) . The starting compounds of the formula (II) are known compounds and some are commercially available. Two isomers, namely (l'R,3S,4S) and (I'R,3S,4R) of the compounds of formula (II) may be present. Either isomer, or a racemic mixture thereof, can be used as starting material in the process. The compounds of formula (III) are known or may be prepared by known methods. Due to the low cost of the reagents and to high yields, and easy and mild reaction conditions the process of the invention is particularly useful for the preparation of compounds of formula (I) on a large scale.

As stated above, the compounds of the formula (I) are key intermediates in the synthesis of many useful pene antibiotics. The process of the invention may therefore be particularly useful in the industrial production of penem

SUBSTITUTESHEET

antibiotics.

In one embodiment, the process of the invention includes the additional step of converting the compound of formula (I) into a penem antibiotic. For example the penem antibiotic produced may be a compound of the following formula (la) :

wherein R' ₂ is a carbamoyloxymethyl, methoxymethyl group or 2(R)tetrahydrofuranyl group and R' ₄ is a hydrogen atom, an acetoxymethyl or (5-methyl-2-oxo-l,3 dioxolen-3-yl) ethyl group, or a pharmaceutically acceptable salt thereof.

The conversion of a compound of formula (I) into a penem antibiotic, such as a compound of formula (la) , is carried out by performing conventional reactions well known in the chemistry of penem compounds. The conversion typically comprises cyclization and removal of the optionally present protecting groups. It may further include the optional introduction of a substituent to form an ester group at position 3 of the penem nucleus, for example the introduction of the group R' ₄ in formula (la) defined above.

The resulting penem antibiotic, for example a compound of formula (la) , may then, if desired, be converted into a pharmaceutically acceptable salt thereof.

The penem antibiotic, such as a compound of formula (la) or a pharmaceutically acceptable salt thereof, may then be formulated together with a pharmaceutically acceptable carrier or diluent. The resulting pharmaceutical composition may be

SUBSTITUTESHEET

for oral or parenteral administration.

The following examples further illustrate the process of the invention.

SUBSTITUTE SHEET

Example 1

4 (\ )-carbaraovloxvacetvlthio-3 rs^-r1 ( R)t-butvldinethvlsi v oxv- ethvl1azetidin-2-one

To a solution of 4-acetoxy-3(R)-[1(R)t-butyldimethylsilyloxy- ethyl]azetidin-2-one (2.87 g) in dioxane (40 ml) the potassium salt of carbamoyloxythioacetic acid (2.1g) was added. Zinc bromide (2.7g) was added to the resulting suspension and the reaction mixture was stirred for 4 hours at 40*0. The reaction mixture was then cooled at room temperature and poured in a mixture of ethyl acetate and water. The organic layer was separated, washed twice with water, dried over anhydrous sodium sulfate, and evaporated in vacuo. The solid residue was taken-up with CH ₂ C1 ₂ . Upon addition of hexanes and cooling a white solid was precipitated, and collected by filtration to give 3.26g of the title product (90% yield).

NMR (CDC1 ₃ ) δ(ppm): 0.1 (6H, ε) ; 0.75 (9H, s) ; 1.18 (3H, d) ; 3.18 (1H, dd) ; 4.23 (1H, m) ; 4.75 (2H, ABq) ; 5.35 (1H, d) ; 5.45 (2H, br s) ; 7.05 (1H, s)

Example 2 fR>-carbamovloxvacetvlthio-3(S>-rifR^t-butvldimethvlsi lvloxv- ethvll zetidin-2-one

The reaction was carried out as described in example 1, except that ethyl acetate was used as solvent. After 3 hours the reaction was cooled and, after the usual work-up and crystallization the title product was obtained in 85% yield.

SUBSTITUTESHEET

- 1 0 -

Example 3 tR1-carbamovlowacetvlthio-3(S)-rifR t-butvldimethvlsilvloxv- ethvnazetidin-2-one

The reaction was carried out as described in example 1, except that the reaction was run at room temperature for 8 hours. After the usual work-up and crystallization the title product was obtained in 90% yield.

Example 4

4 (K)-carbaπovloxvacetvlthio-3 fS> ^• -T1fmt-butvldinethvlsilvloxv- ethvnazetidin-2-one

The reaction was carried out as described in the previous examples, except that zinc chloride was used instead. After the usual work-up and crystallization the title product was obtained in 75-80% yield.

Example 5

4 fR -carbamovloxvacetvlthio-3 fSI-r1(RIt-butvldinethvlsilvloYv- ethylla2e idin-2-one

The reaction was carried out as described in the previous examples, except that magnesium chloride was used instead. After the usual work-up and crystallization the title product was obtained in about 50% yield.

Example 6

4 (I - -carbaτnovloxvacetvlthio-3 (S 1 CR)t-butvldimethvlsi vloxv- g hyngse din-Z-pne The reaction was carried out as described in the previous examples, except that iron trichloride (1.5 equivalents) was used' instead. After the usual work-up and crystallization the title product was obtained in 60% yield.

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Example 7

4fR>-carban.ovloxγacetvlthio-3fS 1fR)t-butv dimethvlsllvloxv- ethv 1 zetidin-2-ona

Ine reaction was carried out as described in example 1, except that 2.6g of the starting thioacid salt and 3.4g of zinc bromide were used instead. After 1.5 hours heating and the usual work-up and crystallization the title product was obtained in 95% yield.

Example 8 fR1- ^* τ.ethoxvacetvlthio-3f5 r fR1t-butvldi-ethvlsilvloyv- ethvllazetidin-2-one

To a solution of 4-acetoxy-3(R)-[1(R)t-butyldimethylsilyloxy- ethyl]azetidin-2-one (2.87 g) in dioxane (40 ml) the potassium salt of methoxythioacetic acid (1.7g) was added. Zinc bromide (2.7g) was added to the resulting suspension and the reaction mixture was stirred for 4 hours at 40 ^* C. The reaction mixture was then cooled at room temperature and poured in a mixture of ethyl acetate and water. The organic layer was separated, washed twice with water, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by column chro atography to give 2.99g of the title product (90% yield). NHR (CDClj) δ(ppm): 0.1 (6H, s) ; 0.83 (9H, s) ; 1.16 (3H, d) ; 3.13 (1H, dd); 3.42 (3H, s) , 4.01 (2H,s) 4.20 (1H, a) ; 5.22 (1H, d); 6.55 (1H, s)

Example t fRl -acetvltM _Q .!W-<n -ri rR>t-butvldimβthvlsllvloxvethvlϊ azatldin-2-ona

To a solution of 4-acetoxy-3(R)-[1(R)t-butyldimethylsilyloxy- ethyl]azetidin-2-one (2.87 g) in dioxane (40 ml), the sodium salt of thioacetic acid (1.2g) was added. Zinc bromide (2.7g) wps added to the resulting suspension and the reaction mixture was stirred for 4 hours at 40*C. The reaction mixture was then cooled at room temperature and poured in a mixture of ethyl acetate and water. The organic layer was separated, washed twice with water, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography to give 2.7g of the title product (89% yield). NKR (CDC1 ₃ ) δ(ppm): 0.1 (6H, s) ; 0.86 (9H, ε) ; 1.19 (3H, d) ; 2.37 (3H, s) ; 3.14 (1H, dd) ; 4.24 (1H, m) ; 5.31 (1H, d) ; 6.31 (1H, s).

Example 10 4rR1-r -rt-butvldiDhβnvlsilvloxvmethvinbenzovlthio-3f5>- ri CR)t-butyldicethylsilyloxyethvH lazetidin-2-one To a solution of 4-acetoxy-3(R)-[1(R)t-butyldimethylsilyloxy- ethyl]azetidin-2-one (2.87 g) in dioxane (40 ml), the potassium salt of [4-(t-butyldiphenylsilyloxymethyl) 3-thiobenzoic acid (4.99g) was added. Zinc chloride (1.64g) was added to the resulting mixture and the reaction mixture was εtirred for 4 hours at 40*C. The reaction mixture was then cooled at room temperature and poured in a mixture of ethyl acetate and water. The organic layer was separated, washed twice with water, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography to give 5.13g of the title product (85% yield).

- 13 -

Example 11 tR -nicotinovl _ ^-3 f S - r fR^ t-b _U tvl ifflethvlsilvloxv- gthylϊageti3in-2*-φne

To a solution of 4-acetoxy-3(R)-[l(R)t-butyldimethylsilyloxy- ethyl]azetidin-2-one (2.87 g) in dioxane (40 ml), the sodium salt of thionicotinic acid (1.94g) was added. Zinc chloride (1.7g) was added to the resulting mixture and the reaction mixture was stirred for 4 hours at room temperature. The reaction mixture was then cooled at room temperature and poured in a mixture of ethyl acetate and water. The organic layer was separated, washed twice with water, dried over anhydrous sodium sulphate, and evaporated in vacuo. The residue was purified by column chromatography to give 1.9g of the title product (52% yield) .

Example 12 rR1 -carbaτ?ovlowacetvlthio-3 (S l (R t-butvldipethvlsilvloxv- ethvl1a2etidin-2-one

The reaction was carried out as described in example 1, except that the triethylaoaonium salt of carbamoyloxythioacetic acid (3.04g) was used instead. After 4 hours the reaction was cooled and, after the usual work-up and crystallization the title product was obtained in 90% yield.

Example 13

4 (R) - h?χγ*??-?ty hio-3 f S) -n (R) t-butvl-*aittgthyl6llγloχγ- ethyl) agetiain-2-gιτθ

The reaction was carried out as described in example 8, except that methoxythioacetic acid (1.4g) was used instead, and triethylamine (1.82 ml) was added to the reaction mixture. After 4 hours the reaction was cooled and, after the usual

SUBSTITUTESHEET

- 1 4 -

work-up and crystallization the title product was obtained in 90% yield.

Example 14 fRl-carbaτnovloxvacetvlthio-3fS^rifR t-butvldimethvl6ilvloxv- tthvng iflin-g-on?

The reaction was carried out as described in example 1, except that the trimethylsilyl derivative of carbamoyloxythioacetic acid (5.6g) and 0.32g of zinc bromide were used instead in acetonitrile. After 15 hours stirring at room temperature the reaction was worked-up as usual. The title product was obtained in 70% yield.

Example IS

4 tRΪ-carbamovloxvacetvlthio-3(S lfRϊt-butvldimethvlBllvloyv- e hyna _? etidin-?->pe The reaction was carried out as described in example 1, except that zinc iodide was used instead. After the usual work-up and crystallization the title product was obtained in 80% yield.

Example 16

4 (R)-carbamovloxvacetvlthio-3fS -r (R)t-butvl

The reaction was carried out as described in Example 1, except that a mixture of 4(R and S)acetoxy-3(R)-[l(R)t- butyldimethylsilyloxy-ethyl]azetidin-2-one was used as starting material. The title product was obtained in 88% yield

5

- 15 -

Example 17

4(R)-(2-tetrahvdrofuranoylthio-3(S)-l l(R)t-butyldimethylsilyloxy- e-.hyll azetidin-2-one

To a solution of 4(R) acetoxy-3(R) -I 1(R)t- butyldimethylsilyloxyethyll azetidin-2-one (2.87 g) indioxane (40 ml) the potassium salt of tetrahydrofuran-2-thiocarboxylic acid (2.1 σ) was added. Zinc bromide (2.7 g) was added to the resulting suspension and the reaction mixture was stirred for 6 hours at 35 ^β C. After the usual work-up the title product was obtained in 92% yield.

NMR ⁽ CDCl ₃ ⁾ 4(ppm) 1.19 (d, 1.5 H) , 1.21 (d, 1.5 H) , 1.82-2.40 ⁽ m ⁴ H ⁾ , 3.15-3.20 (m, 1H) , 3.90-4.13 (m,2H), 4.17-4.33 (m, 1H) , ⁴ .48 ⁽ dd, 1H) , 5.18 (d, 0.5 H) , 5.23 (d, 05 H) , 6,28 (J, 1H ₎ .