FI82698B - FOERFARANDE FOER FRAMSTAELLNING AV PENEMFOERENINGAR. - Google Patents

Description

1 82698

This invention relates to a process for the preparation of penem compounds of formula I.

OH

SN— SR

(R) wherein R is hydrogen, lower alkyl, -CH2-CF3, -CH2-CH2F, -CH2-CH (OH) -CH2-OH, -CH2-CH2-OH, -1-methylimidazolyl -2-yl-methyl, -CH 2 "CH 2" NH "CO" CH 2 -NH 2, -CH 2 "CH 2" CO-NH-CH 3, -CH 2 -CH 2 -NH 2, benzyl, -CH 2 CH 2 -Cl, phenylthioethyl,

, N I

-CH2 "CH2S-^, cyanomethyl, -CH2-CO-CH3, -CH2CO2CH3, -CH2" CH2 "CN, -CH2 * \ S ~~ · ** CH2" COONa, -CH2CH2COONa, -CH2-CH <OH) COONa, -CH 2 -CH (OH) -CH 3, -CH 2 -C (NH) -N (CH 3) 2,

N — N —I

-CH2-jj-CH3, -CH2S- ^ f, -CH2-CH2-S, -CH2CH2S ° \ NOH, N-N'N-''S-L / II ^ CH2 ch3 -Q ", .... C..C.XQ.

2,82698 X is hydrogen, sodium or a carboxy protecting group, and tautomers thereof when R is hydrogen.

Penems, a recent addition to the genus of synthetic β-lactams, have potent anti-bacterial activity. To date, they have been prepared in laboratories, using time-consuming, multi-step methods with low yields and are thus uneconomical.

The new method according to the invention differs in several respects from previously known penem combinations, for example as described in patent publication FI-67853.

(1) The method presented in the application is stereospecific for the asymmetric carbon atom in the 5-position of the penem molecule. Previous methods have yielded stereoisomeric mixtures of 5R and 5S which are difficult to separate. A stereospecific extract of previously known methods is described, inter alia, in Tetrahedron Letters, Vol. 22, no. 56, pages 3485-3488 (1981).

(2) Even if it is not intended to form a stereostructured product, the method of the invention gives the penem compound in a higher yield than known methods.

(3) The method according to the invention can be used to prepare basic penem compounds, i.e. those containing imidazolyl groups. It has not been possible to prepare such compounds by known methods.

(4) The process according to the invention is generally simpler than the known processes, i.e. the process according to the invention requires fewer reaction steps.

(5) The process according to the invention also produces products of the formulas Va and Vb. These intermediate tautomers can be easily converted to 3,86698 thiopenem compounds having any desired group at the 2-position. No such intermediates have been formed by known methods. Using known methods, it has been necessary to repeat several steps to prepare penem compounds having different groups in the 2-position.

According to the invention, compounds of formula I can be prepared as a compound of formula VI

OH S

S-C-Y

(R) is a protected carboxy group and Y is a leaving group is cyclized intramolecularly in an anhydrous organic solvent in the presence of a non-nucleophilic strong base at a temperature of -50 ° to -100 ° C to give a tautomeric compound [ (Va), (Vb)]

OH OH

-— Rv5 "„ Λ — t * ys J- N - * - «2 ^ (Va) (Vb) wherein R 2 is as defined above and, if desired, converting such tautomeric compound to formula I, wherein by attaching the group R: 4 82698 (i) reaction of the formula

RZ

wherein R is as defined above and Z is a leaving group; (ii) (for the preparation of a compound of formula I wherein R is an unsubstituted or substituted C 2 -C 6 alkyl group) by the addition of an olefin using 1,2-unsaturated substituted or unsubstituted C 2 -C 6 alkylene; (iii) (for the preparation of a compound of formula I wherein R is a C 2 -C 6 alkyl group having a hydroxy group attached to another carbon starting from a sulfur atom and optionally containing one or more other substituents), by reaction-substituted or unsubstituted 1,2-epoxy-C 2 -C6 alkane, wherein any functional groups of the reactants may be protected protecting groups which are removed at any suitable stage in the process, and the compound of formula I thus obtained, if desired, deprotected with a protected carboxyl group R2 (if present) and isolated as the free acid, pharmaceutically acceptable. as an acceptable salt or pharmaceutically acceptable ester.

For convenience, the tautomeric compound [(Va), (Vb)] is simply referred to below as compound V.

The process defined above is a new inventive process which makes it possible to prepare known and novel penem compounds in high yields.

Suitable carboxyl protecting groups are those which can be removed under conventional conditions without reaction with other functional groups present in the S-lacam, e.g.

For example, a preferred protecting group on R 2 = allyl; and in Rv and R2, in Compound II, preferred protecting groups are preferably lower alkylsilyl lower alkyl and allyl, respectively.

Unless otherwise indicated, the term "lower alkyl" embraces branched and straight chain alkyl groups having 1 to 6, preferably 1 to 4, carbon atoms and includes, e.g., methyl, ethyl, n-propyl, isopropyl, t-butyl, pentyl and hexyl.

The term "removable hydroxy protecting group" means any group conventionally used for this purpose, with the sole requirement of compatibility with hydroxy substituents in penems and β-1-lactam intermediates and removability using elemental zinc or any other conventional agent used for this purpose that does not adversely affect -alkamam to the structure of intermediates. Preferred hydroxy protecting groups include trichloroethoxycarbonyl, dimethylributylsilyl, trimethylsilyloxycarbonyl and trimethylsilyl.

The method of this invention can be used to prepare penems of any desired stereochemistry. The most preferred stereochemistry of the final penem compounds is (5R, 6S, 8R), less preferred is (5R, 6R, 8S). The final penems with the desired stereochemistry can be obtained by selecting the starting material having the appropriate stereochemistry.

The cyclization of a compound of formula VI to a tautomeric compound V is carried out in the usual manner in an anhydrous inert organic solvent, for example tetrahydrofuran, and a non-nucleophilic strong base, for example, lithium diisopropylamide (LDA) and lithium amine ethyl pulse rate. Usually the cyclization is carried out at about -50 ° C to -100 ° C, and preferably at about -70 ° C, and is usually complete within about 5 minutes to 24 hours. Usually a substantially equimolar amount of strong base is used.

The conversion of tautomeric compound V to another compound of formula I is carried out in a conventional manner in an anhydrous inert organic solvent, for example tetrahydrofuran, ethyl ether or dioxane, at a temperature between about -10 ° C and about 45 ° C, preferably at room temperature (about 25 ° C).

In the case where this conversion is carried out on the resulting tautomeric compound V, it should be noted that deprotection of the hydroxy group at the 8-position may have been done previously using suitable reagents, as described later, in similar solvents and at a similar temperature range.

Thus, the conversion can be performed as a follow-up to such a deprotection step, namely without isolating the tautomeric compound V.

Thus, the same solvents can be used in both steps, and it is also common to carry out the reactions in both steps at approximately the same temperature or at least in the same temperature range mentioned above. If the tautomer is first isolated, a different solvent and temperature can be used in this step than in the previous step, however, they are preferably the same.

The conversion using RZ is usually carried out in the presence of a base or an acid acceptor. Bases or li τ 82698 acid acceptors known for such a reaction can be used e.g. inorganic bases such as alkali metal carbonates or bicarbonates, or organic bases such as triethylamine. Where tetraburylammonium fluoride has been used previously (to remove R 1 in process (a)) and where it remains in the reaction solution, it also acts as a base in this reaction.

For example, the alkylation step may be carried out in one embodiment by reacting a compound of formula X with CH 3, SO 3 R (X) wherein R is as defined above, but not hydrogen, with a tautomeric compound of formula V. This particular reaction is carried out in the usual manner in a suitable organic solvent, for example, tetrahydrofuran. A substantially equimolar amount of an acid acceptor, for example an inorganic carbonate, facilitates the reaction. Typical reaction temperatures range from about -5 ° C to about 30 ° C, and the reaction is usually complete within 1-24 hours.

The addition of the olefin is usually carried out using a radical scavenger, for example AB] 2,2'-azobis (2-methylpropion-n i tri i 1 i)].

Deprotection of the protected carboxyl group R2 can be carried out by conventional methods selected according to the nature of the protecting group. The preferred protecting group is an allyl group, preferably allyl, and its removal can generally be accomplished under catalytic conditions in the presence of a base, preferably using the methods described in our EP Application No. 0 0123 663. Thus, allyl groups are preferably removed using a suitable aprotic solvent. such as tetrahydrofuran, diethyl ether or methylene chloride, an alkali metal alkyl carboxylate, preferably potassium or sodium 2-ethylhexanonate (to give penem an early metal salt, preferably penem sodium or potassium salt as a catalyst) and with a mixture of the palladium compound used and trimethylphosphine). Most preferably, this step proceeds by removing the allyl protecting group and forming the early metal salt of the penem in situ.

If the reaction product is an amphoteric ion, removal of the allyl group requires only a catalyst and any weak nucleophiles (e.g., H2O or alcohol).

This method usually produces the free acid of the penem product. The formation of the metabolite and the metabolizable ester can be carried out by treating the free acid by conventional methods. For example, the free acid can be reacted with a stoichiometric amount of the appropriate non-toxic base in an inert solvent, followed by isolation of the desired salt by lyophilization or mixing. Or, the metabolizable ester can be formed by reacting the penem a 1 ka 1 with a reactive derivative of the desired ester group; for example, phthalidyl ester or pivaloyloxymethyl ester can be prepared by reacting the corresponding penem alkali metal salts with chlorophthalide or pivaloyloxymethyl chloride in a solvent such as dimethylformamide, preferably with a catalytic amount of sodium iodide.

9,82698

Reaction formula »

OH OH

CH, C -, - r-SR * CH, C -—SR *

3 I A * 3 I

K

XX XXIII XXII

B '<j> H t CH, -C -— SMet A Γ' /) - c · / u xch2r2

/ XXI

OH * CH, - £ - - ^ c ^

3 4 [S

·. VI

10 82698

The intermediates of formula VI can be prepared, for example, according to the attached reaction scheme. It will be appreciated that any functional group in any intermediate may be protected and is necessary or desirable.

Step A '

The reaction of azitidone XX with α-substituted acetate XXIII is preferably performed in the presence of an acid acceptor, preferably at a temperature of about 15 ° C to about 30 ° C.

W is a leaving group preferably tosyl, mesyl, chlorine, bromine, iodine or trifluoromethylphenyl, most preferably iodine or bromine.

In acetate XXIII, R 2 is preferably allyl oxycarbonyl, most preferably allyloxycarbonyl.

If the solvent is also an acid acceptor, e.g. pyridine, no additional acid acceptor is required. Alternatively, an organic solvent other than an acid acceptor, e.g. acetonitrile, may be used. In these cases, a separate acid acceptor, organic or inorganic, must be used. Preferably, the reaction is performed in acetonitrile using cesium carbonate or tetraalkylammonium hydroxide as the acid acceptor.

Step B * can be performed in a polar solvent, for example methanol, ethanol, dimethylformamide, tetrahydrofuran or water. Suitable reactive salts of thiopholic metals include, for example, any reactive salts of copper, mercury, silver, lead, nickel and thallium in which the reaction is not affected by the anion. It is preferred to use Cu (II), silver (I) and mercury (II), with silver (I) being most preferred. The salts may be salts of organic or inorganic 11,82698 acids, and suitable salts include, for example, silver nitrate, silver fluoroborate and silver acetate. Silver nitrate is the preferred salt. Typical copper salts are copper (II) acetate and copper (II) nitrate. A typical suitable mercury salt is mercury acetate. Lead salts have been found to give much slower reaction rates.

Silver salts are the most preferred, due to their readiness for re-use and their relatively non-toxic nature.

The reaction is facilitated by the use of an acid acceptor, e.g. pyridine or triethylamine. Preferably the reaction is carried out in an inert atmosphere, e.g. nitrogen.

It is highly preferred that in carrying out the above reactions, the β-lactam intermediates prepared in each step are not isolated but left in the reaction vessel and treated according to the next reaction step. This greatly facilitates the process because several steps can be performed in the same solvent regardless of the separation of the desired product.

Step C 'can be performed in a suitable solvent. The temperature is usually between 10 ° C and 45 ° C, about 25 ° C is recommended.

Usually, the intermediate of the metal salt of formula XXI is treated

To protect the hydroxy group in the 5-position (if not already protected) before step C is carried out. The resulting protective. . the group may be deprotected, if desired, of formula VI

after cyclization of the product of formula V, i.e. deprotection, can be carried out, for example, on a compound of formula V. Conventional hydroxy protection methods and deprotection methods can be used, as described below.

In a preferred form of this process, the intermediate of formula XXII is used immediately in the reaction of step B 'without isolating it from the reaction mixture where it is formed (step A') and the compound of formula XXI thus formed is treated directly in step C 'without isolating it from the reaction step.

If the 5-hydroxy group in the intermediate of formula XXII formed in step B is protected before step C ', protection can similarly be carried out directly on the intermediate of formula XXI without isolating it from the reaction mixture where it is formed. And similarly, the intermediate thus formed can be treated in step C 'without isolating it from the reaction mixture.

Similarly, cyclization of an intermediate of formula V and removal of the 8-hydroxy protecting group from the resulting compound can be performed sequentially without separating the cyclized product from the reaction vessel where they are formed. In the resulting penem compound, the 8-hydroxy group is protected, which is then removed by conventional methods. Subsequent deprotection of the carboxyl at the 3-position and formation of the free acid, salt, or metabolizable ester can be performed using the methods described above.

Suitable hydroxy protecting groups are well known in the context of penem compounds and methods for attaching them to hydroxy groups are also well known. A particularly preferred method of protection, for example to protect a 5-hydroxy group in compounds of formula XXI, comprises reacting a suitable intermediate (e.g. formula XXI) having an unprotected hydroxy group with bis-silylacetamide which immediately forms a trimethylisyl protecting group to the desired hydroxy group. group. Protection of the 5-hydroxy group of azitidone intermediates in the methods discussed above can be accomplished without isolating the product.

The inert solvent thus used may be the same as, for example, DMF used in the previous step. Other solvents, such as chloroform and methylene chloride, may also be used. Temperatures in hydroxy protection processes are typically from about 0 ° C to about 30 ° C.

Methods for deprotecting a 5- or 8-hydroxy group are well known in the context of penem compounds. Preferably, when the hydroxy protecting group is trimethylsilyl, the addition of a dilute aqueous solution of the acid, such as acetic acid, to the solution in which the deprotected intermediate is prepared causes removal. Thus, for example, it is not necessary to isolate a protected derivative of a compound of formula IV before deprotection of the 8-hydroxy group.

The following examples illustrate in detail the methods of the present invention, methods for preparing the starting material, and the use of intermediates prepared by a direct process. In these examples, "NMR" means nuclear magnetic resonance spectrum, "rotation" means the optical rotation of a compound in a suitable liquid; "MS" means mass spectrum; UV denotes u1 travio1 etspectrum; and "IR" means infrared spectrum; chromatography was performed on silica gel unless otherwise noted. The term at room temperature refers to about 18 ° C to about 25 ° C.

’4 82698

Preparation of starting materials Preparation Example A

(3S, 4R, 5R) -3- (1-Trichloro-ethoxycarbonyloxy-ethyl) -4- (triphenylmethyl-thio) -azetidin-2-one

To a 250 mL flask add 7.8 g (0.0223 M) of 3- (1-trichloroethoxycarbonyloxyethyl) -4-acetoxyazetidin-2-one, 220 mL of acetonitrile, 2.6 g (0.252 M) of cesium carbonate, and 5 , 2 g (0.0188 M) of triphenylmethane thiol (tritylthiol). After stirring for 5 hours, add a further 1.0 g (0.0036 M) of triphenyl imethanethio and stir the mixture for a further half hour. Store overnight in the refrigerator, then remove solids by filtration and solvents under reduced pressure to give the crude reaction product. Chromatograph this crude product on crude silica gel eluting with methylene chloride to 10 * and 20 * ethyl acetate / methylene chloride to give 7.89 g of (3S, 5R, 5R) -3- (1-trichloroethoxycarbonyloxyethyl). ) -4- (triphenylmethylthio) azetidin-2-one having the following spectrum: NMR = 7.7 - 7.1.16H; 5.05, 1 H, m; 4.85, 2H, q (J = 18Hz); 4.45, 1H, d (J = 1.5 Hz); 3.3: 1H: dd (J = 1.5: 9Hz); 1.5.3H, d (J = 9Hz).

Preparation Example B

1-methyl-2-chloromethylimidazole

Place 10 g of 1-methylimide and 100 mg of an aqueous solution of 37,515 formaldehyde in a 150 ml Parr bomb and heat to 125 ° C in an oil bath. Remove the water and evaporate the residue to a gel. Extract the gel in solution with methanol. Remove the methanol. Isolate the product, 1-methyl-2-hydroxymethylimidazole, on a coarse silica column, and crystallize from Celesta. Mix 4.4 g of 1-methyl-2-hydroxymethyl-1-imidazo 1 and 5.7 ml of SOCl 2 in 50 ml of 5,82698 CHCl 3 in a reaction flask. Stir for 18 hours and remove the solvent and excess SOCl 2 in vacuo. Evaporate to dryness to give the product 1-methyl-2-chloromethylimide.

Preparation Example C

2- (N-allyloxycarbonyl-lysyl-amino) -ethane

Add pivaloyl chloride (2.4 mL) in CH 2 Cl 2 (10 mL) to a cooled (0 ° -5 ° C) and stirred solution of N-α-yloxycarbonyl-1-ysin (2.18 g) and triethylamine (2.8 mL) in dry CH 2 Cl: Ssa (50 ml). Stir the mixture at 0 ° -5 ° C for 15 minutes and then add a solution of 2-aminoethanethiol hydrochloride (2.4 g) and triethylamine (2.8 mL) in ethanol (15 mL) and CH 2 Cl 2 (40 mL). Stir at room temperature for 1 hour, wash the mixture with aqueous 2N-H 2 SO 4 and aqueous NaHCO 3, dry and evaporate. Grind the resulting solid with ether to dust, filter and dry to give the title product. PMR (CDCl 3: δ 1.42 (t, J = 8Hz, D 2 O as 1H), 2.61 (m, 2H), 3.50 (q, J = 7Hz, 2H), 3.88 (d, J = 7Hz, 2H), 4.57 (m, 2H), 5.1-5.5 (m, 2H), 5.6-6.2 (m, 2H; 1H as D2O and 7.0 (br)); , S, 1H, as D2O).

Preparation Example D

Allyl (5R, 6S, 8R, 2'RS) - (ethanesulfinyl) -6- (1-hydroxyethyl) penem-3-carboxylate

Stir a solution of allyl (5R, 6S, 8R, 2'RS) -2- (ethylthio) -6- (1-hydroxyethyl) penem-3-carboxylate (31.5 g) in ethyl acetate (200 mL) and dichloromethane (100 ml) at 0 ° -5 ° C. Add a solution of m-chloroperoxybenzoic acid (80-85%, 22 g) in ethyl acetate (120 mL) over 0.5 h. 0.5 h after the addition, add the solution to a stirred mixture of ethyl acetate (150 mL), water (125 mL) and 16,82698 sodium bicarbonate (15 g) and stir rapidly for 15 minutes. Dry the organic phase over MgSO 4, evaporate and chromatograph on silica gel rapidly, eluting with 1: 1 hexane-ethyl acetate, then with pure ethyl acetate. Evaporate the product fractions and treat the residue in vacuo to give the title product as a thick yellow oil.

PMR (CDCl 3): δ 1.2-1.6 (m, 6H), 3.0-3.35 (m, 2H), 3.38 (br.s, 1H, as D 2 O), 3.38 (m, 1H), 4.18 (m, 1H), 4.75 (br.d, J = 6.5 Hz), 5.2-5.6 (m, 2H), 5.73 and 5.89 (both d, J = 1.5 Ha, total 1H) and 5.8 to 6.2 (m, 1H).

Example 1

Allyl- (5R, 6S, 8R) -2-thiol-6- (1-hydroxyethyl) penem-3-carboxylate and allyl- (5R, 6S, 8R) -2-thione-6- (1- Preparation of hydroxyethyl) -penem-3-carboxylate A. Preparation of (3S, 4R, 5R) -1-allyloxycarbonylmethyl) -3- (1-hydroxyethyl) -4- (triphenylmethylthio) azetidin-2-one.

Add 3 g of (3S, 4R, 5R) -3-1-hydroxyethyl) -4- (triphenylmethylthio) azetidin-2-one to 10 ml of acetonitrile containing 0.286 g of cesium carbonate. To the mixture add 0.2 g of α-iodine 11yl acetate. Stir the mixture at room temperature for 16 hours. Dilute with ether (50 mL), filter and wash the ether layer with 1 * aqueous phosphoric acid, then water. After drying over sodium chloride, remove the solvent to give a foamy solid.

NMR: = 8.4, 1H, s; 7.65, 1H, d (J = 1Hz); 7.05, 1H, d (J = 1Hz); 5.95, 1H, d (J = 2Hz); 5.8: 1 H, m; 5.45 - 5.1, 2H, m; 4.3: 1H: m; 4.1, 2H, Q (J = 16Hz); 3.5, d d (J = 2.6); 1.35; 3H, d (J = 6Hz).

17 82698 B. Preparation of Silver (3S, 4R, 5R) -3-1-hydroxyethyl) -1-allyloxycarbonylmethyl azetidin-2-one 4-thiolate

To a 50 mL flask containing a nitrogen atmosphere, add 10 mL of methanol and 460 mg of (3S, 4R, 5R) -1-allyloxycarbonyl) -3- (1-hydroxyethyl) -4- (triphenylmethylthio) azetidine. 2-one. To this mixture add 160 mg of silver nitrate and 0.15 ml of pyridine. Stir the mixture at 20 ° C for one hour. Stop the reaction and remove the methanol by stripping to give the title product.

C. Preparation of Silver (3S, 4R, 5R) -3- (1-trimethylsilyloxyethyl) -1-yl-1-oxycarbonylmethyl azetidin-2-one 4-thiolate

Add all the silver (3S, 4R, 5R) -3-hydroxyethyl) -1-allyloxycarbonyl-methyl-azetidin-2-one-4-thiolate obtained in step (B) above to 25 ml of methylene chloride. To this mixture add 1.1 ml of bis-silylacetamide. Stir the mixture at room temperature for 15 minutes to give the title product.

D. Preparation of (3S, 4R, 5R) -1- (allyloxycarbonylmethyl) -3- (1-trimethylsilyloxymethyl) -4- (1'-imidazolylthiocarbonylthio) azetidin-2-one

After completion of step C above, add 350 mg of thiocarbonyldiimidazole to the same solution. Stir the mixture at room temperature for 3 hours. Filter the solution, wash the precipitate with methylene chloride1 la. Collect the filtrate and remove the methylene chloride by stripping. Chromatograph the residue on silica gel eluting with 20 * ethyl acetate / methylene chloride to give 335 mg of the title product.

; E. (5R, 6S, 8R) Allyl-2-thio-6- (1-trimethylsilyloxymethyl) penem-3-carboxylate and (5R, 6S, 8R) α-yl-2-thione-6- (1-trimethylsilyloxymethyl) ) preparation of an equilibrium mixture of penam 18 82698

Add 170 mg of (3S, 4R, 5R) -1- (allyloxycarbonylmethyl) -3- (1-trimethylsilylmethyl) -4- (1'-imidazolylthiocarbonylthio) azetidin-2-one 40 ml of anhydrous tetrahydrofuran under a nitrogen atmosphere. Cool the mixture to -78 ° C and then add dropwise 0.6 mL of 1 M lithium di- (trimethylsilyl) amine in hexane. Stir the mixture at -78 ° C for 5 minutes. Add 0.2 ml of acetic acid to the mixture. Dilute the mixture to 200 mL of methylene chloride. Wash the organic solution with water, aqueous sodium bicarbonate solution and then again with water. Purify the product rapidly by chromatography eluting the sample through silica gel with 5% ethyl acetate / methylene chloride to give 125 mg of the desired product and the desilylated product.

F. (5R, 6S, 8R) Allyl-2-thiol-6- (1-hydroxyethyl) penem-3-carboxylate and (5R, 6S, 8R) allyl-2-thione-6- (1-hydroxyethyl) penam equilibrium mixture preparation

Add 25 ml of the mixture obtained in step (E) in its entirety together with 5 ml of tetrahydrofuran, 1 ml of water and 1 ml of acetic acid. Stir the mixture at room temperature for 2 hours. Add ethyl acetate to the solution and wash the organic phase with sodium bicarbonate solution 11a, water and then brine. Dry the organic phase over anhydrous sodium sulfate, filter and remove the solvent by stripping to give the title product.

The product of step F can then be treated, if desired, to give α-yl (5R, 6S, 8R) -2-ethylthio-6- (1-hydroxyethyl) penem-3-carboxylate.

Example 2 Preparation of (5R, 6S, 8R) Allyl 2- (2 ', 2'-2'-trifluoroethyl) -6- (1-hydroxyethyl) penem-3-carboxylate 19,82698 1. Dissolve 0.735 ml of pyridine in 25 ml of dry toluene and cool to -20 ° C under nitrogen. Add 1.45 mL of trifluoromethanesulfonic anhydride followed by 0.703 mL of 2,2,2-trifluoroethanol and allow to warm to room temperature. Wash the resulting residue with water, dry over anhydrous sodium sulfate, and distill to collect all fractions having a boiling point of less than 100 ° C to give trifluoromethyl 2,2,2-trifluoroethylphonate a.

2. Add (5R, 6S, 8R) Al 1 -2-thiol-6- (1-hydroxyethyl) penem-3-carboxylate, (5R, 6S, 8R) α-yl-2-thione-6- (1R -hydroxyethyl) -penam-3-carboxylate in 3 ml of tetrahydrofuran and 5 ml of trifluoromethyl 2,2,2-trifluoroethylphonate. Add 1 equivalent of potassium carbonate (powder) to the mixture. Keep the reaction mixture at room temperature for 1-1.5 hours and stir at room temperature for 1 hour. Filter the solution and wash with methylene chloride or 2% phosphoric acid. Evaporate the solvent. Dissolve the residue in warm 1: 1 chloroform: Petro 1 ether and cool. The product crystallizes in solution, yield 168 mg of the title product.

Example 3

Sodium (5R, 6S, 8R) -2- (2,3-dihydroxy-1-propylthio) -6- (1-hydroxyethyl) penem-3-carboxylate

A

OH h, 0H? 0H

H.C — C in._P "SN = S H3C“? "| - A f -> Jj JJ« o (I) (II)

° 'X

20 82698

To a 100 mL flask add 400 mg (0.000696 M) of an equilibrium mixture of thion I and the corresponding thiol tautomer 10 mL of distilled tetrahydrofuran, 154 mg (0.00208 M) (3 eq.) Of glycide, and 25 mg of potassium carbonate. Stir until a thin layer chromatograph indicates that no starting material is present. Acidify to pH 7 with 10% phosphoric acid, remove tetrahydrofuran by rotary evaporation and chromatograph the residue on crude silica gel with 100% ethyl acetate, yield after isolation 160 mg of product II (61% yield).

B. To a 50 mL flask, under a nitrogen atmosphere, add a solution of 160 mg of the product II obtained in Step II in 2 mL of ethyl acetate, 73 mg (0.000442 M) of sodium ethyl 2-hexanoate, 10 mg of triphenylphosphine, and 5 mg of Pd (Ph3) p4. Stir the reaction mixture for 3 hours, refrigerate overnight, add water and extract the product on an HPLC column with 100% water, yield after isolation 32 mg of the title product as a white amorphous solid.

Example 4

Sodium (5R, 6S, 8R) -2- (2,3-dihydroxypropylthio) -6- (1-hydroxyethyl) penem-3-carboxylate A. Add to a solution of 20 g of allyl. - (5R, 6S, 8R) -6-hydroxyethyl) -2-thione and α-yl- (5R, 6S, 8R) -6- (1-hydroxyethyl) -2-thiol-penem-3-carboxylate equilibrium mixture and diisopropylethylamine (0.15 g) in dry acetonitrile (4 ml), 2,3-dihydroxy-1-bromopropane (0.2 g). After about 1 hour at 25 ° C, dilute with aqueous tartaric acid and dry over magnesium sulfate. Evaporate and partition the residue from dichloromethane to give allyl (5R, 6S, 8R) -6- (1-hydroxyethyl) -2- (2,3-dihydroxypropylthio) penem-3-carboxylate.

21 82698 B. Treat 160 mg of the reaction compound of Step A in exactly the same manner as in Example 30 Bf to give 32 g of the title product after isolation.

Example 5 (5R, 6S, 8R) -2- (1-Methyl-2-imidazolylmethylthio) -6- (1-hydroxyethyl) -penem-3-carboxylic acid A. (5R, 6S, 8R) -allyl 2- (1-methyl-2-imidazol-methylthio) -6- (1-hydroxyethyl) -penem-3-carboxylate

In a 250 ml flask under a nitrogen atmosphere, place 1.38 g of an equilibrium mixture of thionithiol, 50 ml of tetrahydrofuran (THF) and 1.2 g of 1-methyl-2-chloromethylimidazole (Preparation Example B). Cool to 0 ° C. Add dropwise over 3 minutes 1.5 g of NaHCO 3 as a 10 fc aqueous solution. Stir for about 45 minutes and allow to stand for one hour at 0 ° C. Remove the THF solvent and, after thorough purification, obtain the title product.

NMR - (CDCl 3) δ = 6.95, 1H, s; 6.86, 1 H, s; 5.9: 1 H, m; 5.73, 1 H, d; 5.32: 2H: m; 4.7: 2H: m; 4.3: 2H: s; 4.2: 1H: m; 3.7, 1H, dd (J = 1.5, 6Hz); 3.68, 3 H, s; 1.3: 3H, d (J = 6Hz).

B. Dissolve 1.05 g of the reaction product of Step A in 40 mL of ethyl acetate. React at room temperature with about 200 mg of Pd ° reagent, 200 mg of triphenylphosphine and 1.5 ml of caproic acid. Extract the resulting title product with water. Increase the yield by dissolving the unreacted starting materials in 15 mL of CH 2 D 2, 1 mL of hexanoic acid, 0.3 mL of pyridine, 1.50 mg of triphenylphosphine, and about 100 mg of Pd ° for 0.5 h. Extract the obtained title product with water and combine with the previous extract - the product has 22,82698 NMR - (D 2 O) = 7.3, 1H, s; 7.27, 1 H, s; 5.6, 1H, d (J = 1.6 Hz); 4.4: 1H: m; 3.85, 1H, dd (J = 1.5, 6Hz), 3.81, 3H, s; 1.24, 3H, d (J = 6Hz).

Example 6 (5R, 6S, 8R) -6- (1-hydroxyethyl) -2- (2-glycylaminoethylthio) -penem-3-carboxylic acid (not included in the claims) A. Allyl- (5R, 6S, 8R) -6- (1-hydroxyethyl) -2- (2-N- [allyloxycarbonylglycylamino] ethylthio) penem-3-carboxylate

Stir a solution of the reaction product of Preparation Example D (0.50 g) and the reaction product of Preparation Example C (0.58 g) at 0 ° -5 ° C in dichloromethane and add diisopropylamine (0.2 g). After 5 minutes, wash the solution with 10% aqueous tartaric acid, dry and evaporate and purify the residue by preparative TLC (eluting with EtOAc; reaction product Rf 0.4) to give the title product as a pale yellow foam.

PMR (CDCl 3): 1.35 (d, J = tHz, 3H), 3.16 (m, 2H), 3.4-40 (m, 6H), 4.24 (m, 1H), 4.60 (d, J = 7.5Hz, 2H), 4.63 (m, 2H), 5.2-5.6 (m, 4H), 5.75 (d, J = 1.5Hz, 1H), δ .7 - 6.2 (m, H) and 7.20 (br, 6t, J = 7Hz).

B. Stir the reaction product of Preparation Example C (0.225 g), 2-ethylcaproic acid (0.20 g) and triphenylphosphine (0.05 g) at 30 ° -35 ° C in CH 2 Cl 2 (20 mL) under nitrogen and add tetrakis ( triphenylphosphite) palladium (0.03 g). After 1.5 h, collect the precipitate by centrifugation after addition of ether (15 mL), wash with 3 x 10 mL of 4: 1 ether: CH 2 Cl 2 and dry under nitrogen to give the title product as a cream powder.

I.R. (nujoli): 3400, 1770, 1650 and 1590 cm-1.

23 82698

Example 7 A

OH OH

\ H S 'H

✓ '«) -V εΎ -Y

I 9 | nhcoch2nh

J- N -O 2 - N-V

O 7 co2_k co2- ^

Add allyl (5R, 6S, 8R) -6- (1-hydroxyethyl) -2-thione penam-3-carboxylate and allyl (5R, 6S, 8R) -6- (1-hydroxyethyl) -2-thiol penem To a solution of an equilibrium mixture of -3-carboxylate (0.20 g) and d'-sopropylethylamine (0.15 g) in dry acetonitrile (0.23 g). After 1 hour at room temperature, dilute with aqueous tartaric acid and dry over magnesium sulfate. Evaporate and partition the residue from dichloromethane to give allyl (5R, 6S, 8R) -6- (1-hydroxyethyl) -2- (2-H-allyloxycarbonylglycylaminoethylthio) penem-3-carboxylate as a pale yellow foam.

B. Treat the product of Step A closely following the procedure described in Example 6, Step B to give (5R, 6S, 8R) -6- (1-hydroxyethyl) -2- (glycylaminoethylthio) -penem-3-carboxylic acid. .

Example 8

Allyl (5R, 6S, 8R) -6- (1-hydroxyethyl) -2- [2-methylcarbamoyl) ethylthio] penem-3-carboxylate 82698 (Γ N i'co? V $ ζγ \?

Add allyl (5R, 6S, 8R) -6- (1-hydroxyethyl) -2-thione penem-3-carboxylate and allyl (5R, 6S, 8R) -6- (1-hydroxyethyl) -2-thiol an equilibrium mixture of penem-3-carboxylate (0.20 g) and sopτι sopropyl 1 iethyl 1 amine (0.15 g) in dry acetonitrile (4 ml) N-methyl-3-iodopropionamide (0.2 g) . Keep the solution at 25 ° C for one hour, then dilute with ethyl acetate (25 mL), wash with aqueous tartaric acid and dry (MgSO 4).

Evaporate and crystallize the residue from dichloromethane to give the title product.

The (5R, 6S, 8S) -isomers corresponding to the (5R, 6S, 8R) products obtained in the above example can be obtained by following the procedures described in the examples, but using a suitable stereospecific starting material, namely (3R, 4R, 5S) -3- (1 -tri-chlorocarboxyoxyethyl) -4- (triphenylmethylthio) -azetidin-2-one.

(5R, 6S, 8R) -allyl-2-substituted thio-6- (1-hydroxyethyl) -penem-3-carboxylate can be readily converted to the corresponding time metal salts. In this process, the α 11 yl group can be removed using a suitable aprotic solvent such as tetrahydrofuran, diethyl ether or methylene chloride, potassium or sodium with 2-ethylhexanoate as a catalyst in a mixture of palladium and triphenylphosphine to give the corresponding penem sodium or potassium directly.

By following the experimental methods published above using the appropriate starting materials, the following compounds can be prepared.

OH

CH, -C-f -SR

3 I

H _f, _U

/ \

0 CO2M

M = hydrogen or an early metal salt (preferably a potassium or sodium salt).

Example no. R.

9 -CH 2 CH 3 Data (for the potassium salt of the 5R, 6S, 8R9 isomer NMR δ = 1.25 to 1.49, 6H; δ = 2.76 to 3.14, 2H; δ = 3.85 to 3.94, 1H; δ = 4.12 - 4.37, 1Η, δ = 5.65 - 5.67, 1Η, d (D20)

Rotation: [<*] q6 = -145.2 ° IR: 1600 cm-1 and 1770 cm-1 (nujol).

10 -CH2CH2CH3 Data for the sodium salt of the (5R, 6S, 8R) isomer.

Brown powder.

IR spectrum (nujol) max.

1770 and 1600 ~ 1 26 8 2 6 9 8

Es imerkki

Well. R

11 -CH2CH2F Information on the sodium salt of the (5R, 6S, 8R) isomer 11 e.

[α] D = + 150.8 ° [H 2 O] NMR, D 2 O 5.75, 1H, d (J = 1Hz); 5.05 and 4.4 (2 tr i p1 and i-CH2F) 2H, (J = 1.8Hz, 9Hz); 4.3, 1H, m: 3.95, 1H, dd, J = 1 and 8Hz; 3.3: 2H m; 2.2 1H alternative - OH); 1.3: 3H: d: J = 9Hz.

12 -CH2CH2OH Data for the (5R, 6S, 8R) isomer protection 1a.

Light brown powder Ή NMR (020): 1.24 (d, 3, J = 7), 3.0 (m, 2), 3.77 (t, 2, J = 7) 3.63 (dd, 1 , J = 6.2), 4.15 (m, 1) 5.60 (d, 1, J = 2).

The free acid of the 13 -CH 2 CH 2 NH 2 isomer (5R, 6S, 8R) is a cream powder.

The potassium salt of the 14 -CH 2 C 6 H 5 (5R, 6S, 8R) isomer is a light brown solid.

15 -CH 2 CH 2 Cl The data for the sodium salt of the (5R, 6S, 8R) isomer are as follows: D 2 O; δ 5.6 (1H, d), 4.2 (1h, t), 3.75 (3H, m), 3.2 ( 2H, m), 1.2 (3H, d).

27 8 2 6 9 8 16 The sodium salt of the CH2CH2-S-C6H5 (5R, 6S, 8R) isomer is a yellow powder.

D 2 O; δ 7.3 (5H, m), 5.5 (1H, d), 4.1 (1H, t), 3.75 (1H, d: nd), 3.1 (4H, m), 1.25 ( 3H, d) The sodium m * '-j salt isomer of the 17 (5R, 6S, 8R9 isomer) is an off-white 2 n2 \ ____ I solid.

S D 2 O; δ 5.58 (1H, s), 5.0 (1H, m), 3.8-4.5 (5H, m), 3.3 (4H, m), 1.2 (3H, d) .

18 -CH 2 CH The data for the sodium salt of the (5R, 6S, 8R) isomer are as follows: 90mHz NMR D 2 O / CD 3 CN 120ppm, D J = 6Hz, 3H 5.70 ppm, D J = 1 Hz, 1H.

$ 19 The data for the sodium salt of the (5R, 6S, 8R) isomer -CH 2 C-CH 3 are as follows: 90mHz NMR D 2 O 1.30ppm, D J = 6Hz, 3H 2.40ppm, s, 3H 3.90ppm, DD 6Hz, 1Hz, 1H,

4.25ppm, D J = 1Hz, 1H

Mass Spectrum

The molecular ion is 324 mass units

The highest peak at 117 mass units 20 The potassium salt of the CH2CO2CH2 (5R, 6S, 8R) isomer is a light brown solid 28 82698 21 -CH2CH2CN 3H 2.80 - 3.40ppm, m, 4H, 3.90ppm, dd J = 6, Hz, 1H, 4.20ppm, m, 1H,

5.70ppm, D J = 1Hz, 1H

The data for the (5R, 6S, 8R) isomer free acid are as follows: 90 mHz NMR (D2O) C H g C σ 3 NH δ = 6.52, 1H, S; c 5.52, 1H, d (J = 1.5 Hz); 4.28 - 4.04, 1 H, m; 4.0 - 3.87, 2 H, m; 1.19, 3H, d (J = 6Hz).

23 CH 2 CO 2 Na The data for the (5R, 6S, 8R) isomer double sodium salt are as follows: 90 mHz NMR (D 2 O) δ = 6.64, 1H, d (J = 1.5Hz); 4.3 - 4.06, 1H, m; 3.87, 1H, dd (J = 1.5, 6Hz); 3.62, 2 H, s; 1.25, 3H, d (J = 6Hz).

24 CH 2 CH 2 C 2 Na Data Disodium salt of the (5R, 6S, 8R) isomer 11 e (M = Na) [α] * 6 (H 2 O) = + 153.7 ° PMR (D 2 O): 1.36 (d, J = Hz, 2H ), 2.6 (m, 2H), 3.2 (m, 2H), 3.93 (dd, J = 8 and 2H *, 1H), 4.28 (m, 1H) and 5.71 (d, J). = 2HZ, 1H).

Il 29 82698 25 -CH2CH COONa Details of the (5R, 6S, 8R) isomer

sodium salt 11 a are as follows: 60 mHz NMR D 2 O 1.15ppm, d J = 6Hz, 3H

2.8 - 3.40ppm, m, 2H

3.85ppm, m, 1H

4.20ppm, m, 2H

5.60ppm, D J = 1Hz, 1H.

The sodium CH2-C-CH3 salt of the 26β (5R, 6S, 8R) isomer is a tan solid OH.

27 -CH 2 -C 'N (CH 3) 2 The data for the (5R, 6S, 8R) isomer NH sodium salt 11 e are as follows:

90 mHz NMR D 2 O 1.25ppm, D J = 6Hz, 3H 3.17ppm, s, 3H 3.30ppm, s, 3H

3.8-4.3ppm, m, 2H 5.70ppm, D J = 1Hz, H

28 -CH2-C-CH3 Sodium salt 11 a N is as follows: OH 60 mHz NMR D 2 O

1.20ppm, D J = 6Hz, 3H

1.95ppm, s, 3H

3.60ppm, s, 2 H

3.80ppm, DD J = 6Hz, 1Hz, 1H,

4.20ppm, m, 1H

5.60ppm, D J = 1Hz, 1H.

29 -N_N Sodium salt is a yellow .pu.ΛΠ // U solid.

D 2: δ 5.4 (1H, d); 4.1 (1 H, t); N - 3.8 (3H, s); 3.73 (1H, d: n d); | 2.9-3.6 (4 H, m), 1.13 (3 H, d).

:!. · Ch3 3o 82698 30 χΝ n Sodium salt is a brown solid -CH2CH2-S.

D 2 O: δ 7.1 (2H, d); 5.5 (1H, d), 4.1 (1H, t); 3.8 (3 H, s, 1 H, d); I 3.1 (4 H, m); 1.3 (3 H, d).

CH3 31 N_Data for the (5R, 6S, 8R) isomer rn ru c_ / y O> sodium salt 11 a are as follows: LW \, _ J S D2O: δ 7.8 - 7.0 (4H, m), b N / ' 5.25 (1H, d), 4.0 (1H, t), 3.5 (1H, d), 2.7-3.4 (4H, m), 1.3 (3H, d).

32 / - \ The data (5R, 6S, 8R) isomerization _ / NR sodium salt 11 a are as follows: \ _ / 90mHz NMR D20

1.20ppm, D J = 6Hz, 3H

1.5 - 2.3 ppm, m, 4H 2.7 - 3.5 ppm, m, 4H

3.75ppm, DD 6Hz, 1Hz, 1H 4.15ppm, m, 1H 5.60ppm, DJ = 1Hz, 1H

Mass Spectrum of Molecular Ion 348 (330 + 184)

The highest peak 152 33 m_ (sodium salt of the 5R, 6S, 8R9 isomer is a light brown solid * D 2 O; d 7.2 (1H, s), 6.95 (1H, s), 5.2 (1H, d) ), 3.95 (1H, m), (3H, 1H, d: nd), 1.05 (3H, d).

34 Data (5R, 6S, 8R) of the isomer HO — sodium salt 1 a 1 1 e, brown powder.

ΛΜ ru e 1 ° 2O: δ 7.75 (1H, m); 7.0 (2 H, d); * LM2LH2 * S 5.52 (1H, d); 4.1 (1 H, m); 3.78 (1 H, d); 3.1 84H, br); 1.17 (3 H, d).

Claims (3)

A process for the preparation of penem compounds of the formula OH -S S'V-SR (I) 2 -N 2 coox wherein R is hydrogen, a lower alkyl, -CH 2 -CF 3 -, -CH 2 -CH 2 F-, -CH 2 - CH (OH) -CH2-OH, -CH2-CH2-OH, - 1-methyl-imidazol-2-yl-methyl, -CH2-CH2-NH-CO-CH2-NH2, -CH2-CH2-CO-NH -CH 3, -CH 2 -CH 2 -NH 2, benzyl, -CH 2 CH 2 -Cl, phenylthioethyl, / N ~ | -CH2 "CH2S- ^," cyanomethyl, -CH2-CO-CH3, -CH2CO2CH3, -CH2-CH2-CN, -CH2- /, -CH2-C00Na, -C ^ C1- COONa, \ N ^ -CH2 CH (OH) COONa, -CH2 "CH (OH) -CH3, -CH2" C (NH) -N (CH3> 2, N-1N -CH2-C-CH3, -CH2S- <ff, -CH2-CH2 -S, -CH2 CH2 S0> noh nn_r \ nJ \ s xy CH2 ch3 -QnH, h (J U wherein a compound of Form In VI OH S cf SCY 2 <VI> Cr N 2 CH 2 -R 2 where R at a temperature of -50 ° C - -100 ° C, whereby a tautomeric compound [(Va), (Vb)] is obtained OH 0 (Δ-γγγ ^ ^Λ τγ5) - NL-R2 R2 R2 ° (va) where R2 is defined above and, if necessary, such a tautomeric compound is converted to one of formula I, wherein by linking the group R: (i) by a reaction with a compound having the formula R-Z where R is defined above and Z is a leaving group; (ii) (to prepare a compound of formula I wherein R is an unsubstituted or substituted C 2 -C 6 alkyl group) by the addition of an olefin using a 1,2-unsaturated substituted or unsubstituted C 2 -C 6 alkylene; (Iii) (for the preparation of a compound of formula I, wherein R is in a C 2 -C 6 alkyl group of a hydroxy group attached to then other carbon atoms of sulfur atoms and optionally containing all kinds of other substituents) unsubstituted 1,2-epoxy C when needed, the protected carboxyl group R 2 (if present) is removed and separated as free acid, pharmaceutically acceptable site or pharmaceutically acceptable aster. Process according to claim 1, characterized in that R 2 is a in lyloxycarbonyl. 3. A process according to claim 1 or 2, characterized in that a compound of formula I is prepared which has stereochemistry (5R, 6S, 8R) aller (5R, 6R, 8S). «Li