DK174517B1 - 3-Unsatd. hydrocarbyl 3-cephem 4-carboxylic acids prepn. - by treating 3-triflyl cpd. with hydrocarbyl tri:alkyl stannane in presence of palladium cpd. and phosphine - Google Patents

Abstract

Prepn. of 3-hydrocarbyl-3- cephem-4-carboxylic acids of formula (I) or their salts or esters comprises: (i) providing a 3-trifjluromethane su,lsulphonloxy-3-cephem (II) starting cpd. in a relatively polar aprotic solvent; (ii) contacting this with an at least equimolar amt. of R1-trialkyl stannane (III) in presence of 1-10 mole% of a Pd(O) or Pd (II) cpd. and 3-30 mole.% of tri(2-furyl)phosphine at 25-65 deg.C, protected from atmos.oxygen, for 1-75 hrs; and (iii) recovering (I) from the reaction mixt. R1 = opt. substd., 1-alkyl, opt. conjugated 1-polyalkenyl, 1-alkynyl, phenyl, Het or Het-CH2; Het = 2-, 3- or 4-pyridyl, 2-iomidazolyl, 2-thiazolyl, 2- or 3- furyl, 2-pyrryl 2-thienyl; Q = H, t-butoxycarbonyl, a silyl protecting gp.; or the acyl gp. of a known 7-acylamino cephalosprin antibiotic; aryl and heteroaryl gps. may be substd. by 1-3 alkyl, OH, alkoxy, halo, amino,alkylamino, dialkylamino, NO2, COOH, alkoxycarbonyl and CN gps.

Description

DK 174517 B1

BACKGROUND OF THE INVENTION

The present invention relates to a process for preparing a 3-hydrocarbyl-3-cephem derivative by providing a 3-triflytoxy-3-cephem intermediate, reacting the intermediate with a 1-hydrocarbyltributyl stannane in the presence of a palladium compound and a phosphine, and optionally a metal halide. The resulting 3-unsaturated alkyl 3-cephemes are useful as broad-spectrum antibacterial agents.

Prior art

Hoshi et al., U.S. Patent Nos. 4,591,641 (5/86) and 4,520,022 (5/85), both owned by the transferor of the present invention, describe vinyl-substituted cephalo-sporins with 3 - ((Z -1-propenyl) and 7-phenylglycylamido groups of structural formula A

I ^ J ^ NlcHCONH - * - 15 H “2

R *, Formula A CO 2 H

wherein the 3-propylene group has Z configuration. These compounds are prepared by forming a substituted vinyl group at the 3-position of the cephalosporin nucleus by reacting a 3-halomethylcephalosporin or an alkyl halide (e.g., methyl halide) with a triphenylphosphine to give a pbosphoranyl intermediate, which is then reacted with respectively. an alkyl hydrogen carbonyl reagent or a 3-hydrogen carbonyl cephalosporin. The above compounds were prepared using the methods described in U.S. Patent Nos. 3,769,277 (10/73), 3,994,884 (11/76) and 4,107,431 (8/78).

Long et al., U.S. Patent No. 3,769,277 (10/73), discloses the preparation of A3-4 carboxy-cephalosporins of the formula 30 R1KU J- ^ oi-Nv ^ Au <* 4

COOH

By reacting a 3-formyl · (i.e., 3-hydrogencarbonyl) cephalosporin with a phosphorus of formula R3P = CR3R \

Weir, U.S. Patent No. 3,994,884 (11/76) discloses the preparation of -A3-4-carboxycephalosporin containing a 3-vinyl group by reacting the corresponding 3-halo-methylcephalosporin compound with a phosphine to obtain a phosphonium flour. intermediate product, conversion of the phosphonium intermediate to the corresponding phosphoranylidene intermediate and coupling of the phosphoranylidene intermediate with formaldehyde.

10

Clark et al., U.S. Patent No. 4,107,431 (8/78) GB No. 1342241), discloses the preparation of A3-vinyl or substituted vinyl-4-carboxycephalosporins by reacting a 3-phosphoranylidene cephalosporin with a carbonyl compound of the formula R3COR4 by reacting a 3-formyl cephalosporin with a phosphorane of the formula R3P = CR3R4.

O'Callaghan et al., U.S. Patent No. 3,830,700 (8/74), disclose certain 3-arrhytvinylcephalo-sporins useful as chromogenic agents for the detection of β-lactamase activity.

The compounds useful in the present method are prepared by reacting a 3-phosphoranylidene cephalosporin with a hydrogencarbonylaryl (arylaldehyde) compound or by reacting a 3-hydrogencarbonylcephalosporin with a phosphorane of formula (R) 3P = CHAr .

Beeby, U.S. Patent Nos. 3,983,113 (9/76), 4,049,806 (9/77) and 4,139,618 (2/79), disclose-25 ° li-r3-ch2-c-n ^ -λ.

I | In the case of C02R2 jtrangl wherein the compounds were prepared by reacting the 3-formylcephalosporin starting compound with a suitable vinyl-Grignard reagent to obtain a mixture of α- and 35β-hydroxy isomers of the corresponding 3- (1- hydroxy-prop-2-enyl) cephalosporin, followed by treatment of the above intermediate with a mercaptosubstituted hetero-cyclic compound corresponding to the SR1 substituent in the presence of a small amount of strong acid. Beeby, U.S. Patent No. 4,112,087 (9/78), discloses compound of the same formula as described above except that "SR1" is replaced by "OR".

Webber, U.S. Patent No. 4,065,620 (12/77), discloses 3- (substituted) vinyl cephalo-sporins prepared by reacting a 3-formyl cephalosporin compound with a phosphorane of formula R 1 R 2 P = CH-Y under conventional Wittig reaction conditions .

Takaya et al., Published EP Application No. 0.030,630 (6/81), disclose 7-acylamino-3-vinylcephalosporic acid derivatives prepared by reacting a 3-formylcephalo-sporine compound with a suitable phosphorane.

Miyadera et al., U.S. Patent No. 4,147,863 (4/79), disclose cephalosporin derivatives having a (1-alkyl-1H-tetrazol-5-yl) vinyl group at the 3-position of the cephemic chem. Also described is the preparation of the intermediate with the given 3-vinyl substituent by reacting a known 3-formylcephalosporin with a Wittig reagent (phosphorane).

Beattie et al., U.S. Patent No. 4,255,423 (3/81), disclose cephalosporin compounds having a substituted or unsubstituted vinyl group at the 3-position of the cephalosporin germ, which compounds are prepared by reacting a phosphoranylide compound with a compound containing a carbonyl group. Specifically, a phosphoranylidene compound of formula 25 V - - - - ^ vL_ ch = p (R) 3 o cook6 can be reacted with a carbonyl compound of formula R2-CO-R3 to give the -CH = CR2R3 substituent in cephem chem 3 -position.

It is known in the art that the cis (Z) stereoisomer configuration compounds are preferred over compounds with the trans (E) stereoisomer configuration, since the former DK 174517 B1 4 possesses greater antibacterial activity (See US Patent No.

4,520,022, column 16, lines 23-29).

The methods known in the art and described in the literature for the preparation of 3- (1-propenyl) -3-cephemes provide a mixture of cis (Z) and trans (E) isomers which requires costly separation to obtain the preferred, more antibacterially active, cis (Z) isomers, and the overall yield of desired cis (Z) isomer based on starting material is therefore relatively low.

Scott, Crisp & Stille, J. Amer. Chem. Soc., 106, 4630 (1984), describe the palladium-catalyzed coupling of organotin compounds with electrophilic compounds facilitated by the addition of zinc chloride.

Scott & Stille, J. Arner. Chem. Soc., 108, 3033 (1986), describe the palladium-catalyzed coupling reaction between various vinyl triflates and organostannans, such as e.g. vinyl tributyl stannane, to obtain a product in which the vinyl group is bonded to the carbon atom left by the triflate group.

Because of the desirability of improving the methods of preparing 3-vinyl-20 cephem derivatives with the preferred cis (Z) stereolomer configurations, it has been contemplated to use a stereospecific synthesis pathway to build the Z-propenyl side chain of the cephem chem. 3-position using palladium-catalyzed coupling of appropriately functionalized cephem with cis (Z) -propenyltributylstannan.

Based on the readily available 3-hydroxycephemes and derivatives thereof, including trifluoromethylisulfonate (trifiat) and methanesulfonate and chlorine and diphenylphosphate derivatives, coupling with the above-mentioned organometallic agents was investigated. It was found that the above coupling reactions were unsatisfactory when performed in accordance with the conditions stated by Scott & Stille (loc. Cit.). The coupling between di-phenylmethyl-7- (phenylacetamido) -3-triflyloxy-3-cephem-4-carboxylate and stannanes was unsatisfactory when carried out under conditions described in the literature. The use of Pd ((C6H5) 3P) 4-UCI in THF mainly led to the 3-chloro derivative of the above cephem, which was easily isomerized to the A2 cephem, while only trace amounts of the desired cephem were obtained. Use of ZnCl2 in place of LiCl does not yield any 35 A2 cephem by-product. However, the conversion of the desired product proceeded so slowly upon refluxing THF that extensive decomposition of the starting triflate occurred. The desired product, diphenylmethyl-7- (phenylacetamido) -3- (Z-1-propenyl) -3-cephem-4-carboxylate, was therefore obtained only in very poor yield.

SUMMARY OF THE INVENTION 5 It has now been found that coupling between 3-triflyloxycephemes and certain unsaturated hydrocarbyl stannans (unsaturated hydrocarbyl tributyl stannanes) can result in the formation of a carbon-carbon bond at the 3-position of the cephem chem in satisfactory yield. of the 1-alkenyl and 1-dienyl derivatives to achieve virtually complete stereospecificity (i.e., more than 99% specificity). This is accomplished by carrying out the coupling reaction at room temperature in the presence of a polar aprotic solvent, a Pd ° or Pd 'compound, certain metal halides and a phosphine.

Detailed description of the invention

Thus, the present invention relates to a process for preparing a 3-15 hydrocarbyl-3-cephem derivative of formula (I)

20 I

λ-N i O '»

COOH

Formula I wherein R 1 is a hydrocarbyl group selected from unsubstituted or substituted 1-alkenyl of 2-4 carbon atoms, 1-dienyl, 1-alkynyl of 2-4 carbon atoms, phenyl or heteroaryl selected from 2-, 3-, or 4 -pyridyl, 2-imidazolyl, 2-thiazolyl, 2- or 3-furyl, 2-pyrryl, 2-thienyl, wherein the phenyl and heteroaryl groups may be substituted with 1-3 alkyl, hydroxy, alkoxy, halogen, amino, mono and dialkylamino, nitro, carboxyl, alkoxycarbonyl and cyano groups and Q is selected from t-butyloxycarbonyl, a silyl protecting group or the acyl group of a known 7-acylaminocephalosporin antibiotic and pharmaceutically acceptable acid addition and acid addition and esters thereof, characterized by reacting a 3-trifluoromethanesulfonyloxy-3-cephem starting compound of formula (II) DK 174517 B1 6

You-r ^

Jr— N

° ^ y ^ OTt (ll>

COOH

Wherein Tf is the trifluoromethanesulfonyloxy group CF3S (0) 2- and where Q is selected from t-butyloxycarbonyl, a silyl protecting group or the acyl group of a known 7-acylamino-cephalosporin antibiotic, or the diphenylmethyl ester or pivaloyoxymethyl ester thereof, with the at least one equimolar amount 10 of a R1-tri-butyl stannane in the presence of 1-10 mole% of a Pd ° or PdM compound and 3-30 mole% of tri- (2-furyl) phoshine and 0-7 molar equivalents of a metal halide at 20-65 ° C, protected from atmospheric oxygen for 1-75 hours and recovering the cephem product from the reaction mixture.

Using the process of the present invention, several novel compounds have been obtained which have not been possible to obtain using known methods.

By way of example, Q of the above formulas (I) and (II) may be benzoyl (<t> CO), phenylacetyl (d> CH 2 CO), tert-butyloxycarbonyl (tert.-BuOCO) and G-CH-CO. -

NHP

Wherein G is 2- or 3-thienyl or unsubstituted or substituted phenyl and P is any of the protecting groups used in the cephalosporin chemistry to protect amino, hydroxy and carboxyl such as benzyl, diphenylmethyl and the like.

The 3-Trifluoromethanesulfonyloxy-3-cephem starting compound (also referred to as 3-trifly-ioxy-3-cephem, where the acronym "triflyl" or "'triflate1" is used to designate the trifluoro-methanesulfonyl group) can be readily obtained from known 3-hydroxyc. The carboxyl group at the 4-position can be in the form of the diphenylmethyl ester or the pivaloyloxy-methyl ester and the substituent at the 7-position can e.g. be the phenylacetamido or tert-butyloxycarbonyl group.

7 DK 174517 B1

The aprotic solvent used in the process of this invention should be polar. Thus, the solvent can be selected from 1-methyl-2-pyrrolidinone, tetrahydrofuran (THF), nitriles such as acetonitrile, dimethylsulfoxide (DMSO), dimethylformamide (DMF), ethers such as glyme and dioxane, hexamethylphosphoric acid amide (HMPA), acetone, nitromethane and nitrobenzene. The solvent is preferably selected from 1-methyf-2-pyrrolidinone, THF, acetonitrile, DMSO and DMF. The solvent is especially selected from N-methylpyrrolidinone, THF and acetonitrile. Most preferably, the solvent is 1-methyl-2-pyrrolidinone.

The substituent R1 means unsubstituted or substituted 1-alkenyl with 2-4 carbon atoms, 1-dienyl, 1-alkynyl with 2-4 carbon atoms or phenyl, including e.g.

-C (CH3) = CH2, H2C = CH-, CH3CH = CH-, (CH3) 2C = CH-, CHa-CsC- and H2C = C (OC2H5) -bound to -Sn (C4Hg) 3- (or - The SnBu 3) group, or heteroaryl selected from 2-, 3- or 4-pyridyl, 2-imidazolyl, 2-thiazolyl, 2- or 3-furyl, 2-pyrryl, 2-thienyl. The process 15 of the invention is preferably used to prepare 1-alkenyl or 1-alkynylcephem derivatives. More preferably, the present process is used to prepare the 3- (Z-1-propenyl) -3-cephem derivative, i.e. The 3- (Z-CH = CHCH 3) -3-cephem derivative, the 3- (propen-2-yl) -3-cephem derivative, or the 3- (1-propynyl) -3-cephem derivative.

20

The Pd compound is a Pd ° compound such as bis (dibenzylidene-acetonyl) palladium (Pd (dba) 2), or a Pd 'compound such as Pd (OAc) 2, or PdCl 2. The former Pd reagent (Pd (dba) 2) is particularly advantageous in the process of the invention.

The meta halide used in combination with the Pd compound in the process of the present invention is selected from ZnCl2, ZnBr2, LiCl, LiBr,

Lil, MgCl2, MgBr2, HgCl2, and boron, aluminum or cadmium halides (Cl and Br). The metal halide is preferably selected from ZnCl2 and ZnBr2, especially ZnCl2.

The following reaction scheme shows a typical embodiment of the process of the present invention: Z "C"; gg coocH ^ h, [O], III iv DK 174517 B1 8

A general experimental method for carrying out the process of the invention in relation to the above reaction scheme is the following:

Triflate III (107 mg, 0.169 mmol) in dry 1-methyl-2-pyrrolidinone (3 ml) was treated with a suitable stannane (0.20 mmol, in 1 ml of 1-methyl-2-pyrrolidinone). Zinc chloride (52 mg, 0.38 mmol), Pd (dba) 2 (2.45 mg, 0.0042 mmol) and tri ~ (2-furyl) phosphine (2.0 mg, 0.0085 mmol) were then added. The dark solution was stirred under argon at 25-50 ° C for approx. 25 hours. The product was isolated by flash chromatography on SiO 2 and characterized by elemental analysis, 1 H-NMR and mass spectroscopy.

10

The final product can be recovered from the coupling reaction mixture by methods conventional in the cephalosporin and penicillin preparations, such as by the general experimental method described above.

The following table illustrates only a few representative hydrocarbyl tributyls, products resulting from the reaction thereof with triflate III as illustrated above, reaction time and yield (%) of the product of the present invention.

Example 5, which illustrates the preparation of a 3- (desmethyl) -3-cephem compound, falls outside the scope of the present invention but is included to illustrate the utility of the process of the invention.

On the basis of the results obtained from the examples, the reaction time and temperature in step (b) of the process according to the invention are not considered to be critical and may vary in the range from about 20% to about 20%. 20 to approx. 65 ° C for approx. 1 to approx. 75 hours, preferably approx. 25-50 ° C for approx. 1-72 hours, depending on the choice and reactivity of the particular reactants and the catalyst system.

9 DK 174517 B1

Table

Palladium-catalyzed coupling of III with stannanes

Temperature ·% yield

Ex. No. Stannan product (time) - (isolated) *> ^ 85 • eocxHrs 1 Oi *. (a> 25 * C. 65

Xoc ~ *. 16 ti * 16 * O u ^ h ',, - 25'C. 66 19 hours O u 2 c * vc * c-s «b«, i — H.. ^ »* - c * e-CM 65 C 2 hours, 30 ° <7_-. 25 ° C 19 hours COOCHP *.

s i ° Y ^ L 50 ° C 5.5 hours, 57 w wt% 25 ° C16 hours.

o ΛΛ /, 7 25 * C, 52 * «·«. ? ioocMm, 19 hours V \ V,

5 <b) ΓΟ «'c · W

° f 2 hours cooc * «> (S S Z'Stan2an 9av» 7% 2 product DK 174517 B1 10

The following Examples 1-4 and 6-14 illustrate only a few representative actual embodiments of the method of the invention. Examples A and B illustrate the preparation of a representative starting material. All parts and percentages are by weight unless otherwise stated.

5

Example A

Diphenylmethyl-7- (oenylacetamido) 3-hydroxy-3-cephem-4-carboxylate A solution of 3.38 g (0.006 mol) of diphenylmethyl-7-amino-3-hydroxy-3-cephem-4-carboxylate-p-toluenesulfonic acid salt (E Scartazzini & H. Bickel, Helv. Chim. Acta, 1974, 57, 1919) and 1.87 g (0.018 mole) of sodium bisulfite in 120 ml of tetrahydrofuran and 30 ml of water were treated dropwise with a solution of 1.41 g (0.009 mole) phenylacetyl chloride in 10 ml of tetrahydrofuran. After the addition of the acid chloride, the reaction mixture was stirred at room temperature for 2 hours, then the tetrahydrofuran was removed from the reaction mixture at reduced pressure and the aqueous concentrate extracted twice with the organic extract. Finally, the organic solvent was removed at reduced pressure to give a solid, foamy residue, The residue was chromatographed on 100 g of silica gel to give 1.85 g (61.6%) of diphenylmethyl-7- ( phenylacetamido) - 3 -hydroxy-3-cephem-4-cart> oxylate. The nuclear magnetic resonance spectrum was consistent with the desired structure.

Example B

Diphenylmethyl-7-phenylacetamido-3-trifluonomethylsulfonylphoxy-3-cephem-4-carboxylate To 1.57 g (0.00313 mole) of diphenylmethyl-7- (phenylacetamido) -3-hydroxy-3-cephem-4-carboxylate To methylene chloride 0.546 ml (0.00313 mol) of N, N-diisopropyl-ethylamine was added and the mixture was stirred at -20 ° C for 10 minutes under a nitrogen atmosphere.

Then, 0.633 ml (0.00376 mol) of trifluoromethanesulfonic anhydride was added to the mixture and stirring at -20 ° C was continued for 20 minutes. The reaction mixture was diluted to a volume of 400 ml by adding methylene chloride. To the organic solution was added 100 ml of 0.25 N hydrochloric acid. The phases were separated and the methylene chloride phase was washed successively with water, dilute sodium bicarbonate, 0.25 N hydrochloric acid and water. The organic layer was dried over magnesium sulfate. The sulfate was removed by filtration and the solvent was removed at reduced pressure to afford 1.37 g (69.2%) of diphenylmethyl-7-phenylacetamido-3- (trifluoromethylsulfonyloxy) -3-cephem-4-carboxylate. The nuclear magnetic resonance spectrum was consistent with the desired structure.

11 DK 174517 B1

Analysis for

Calculated: C: 55.06%, H: 3.66%, N: 4.43%, S: 10.14%.

Found: C: 55.28%, H: 3.66%, N: 3.94%, S: 10.68%.

Example 1

Diphenylmethyl-7-phenylacetamido-3-fZ-1-propenyl-3-cephem-4-carboxylate A solution of 0.226 g (0.00358 mol) of diphenylmethyl-7-phenylacetamido-3- (trifluoro-methylsulfonyloxy) -3-cephem 4-carboxylate, 0.130 g (0.00039 mole) of Z-1-propenyl-tri-n-butyl stannane, 0.0033 g (0.000014 mole) of tri (2-furyl) phosphine and 0.0041 g (0.000007 mol) 10 Paliadium (0) bis (dibenzylidene acetone) in 4 ml of tetrahydrofuran was degassed under argon atmosphere at reduced pressure for 30 seconds. Then a solution of 0.097 g (0.00072 mol) of zinc chloride in 1 ml of tetrahydrofuran was added at once. The reaction mixture was stirred at room temperature for 16 hours. The mixture was then diluted with ethyl acetate and washed with a dilute ammonium chloride solution. The organic solvent was removed at reduced pressure and replaced with acetonitrile. The acetonitrile solution was washed 3 times with n-pentane and the solvent was again removed at reduced pressure. The residue was chromatographed on silica gel to give 0.123 g (65%) of diphenylmethyl-7-phenylacetamido-3- (Z-1-propenyl) -3-cephem-4-carboxylate. The nuclear magnetic resonance spectrum was consistent with the desired structure.

Example 2

Diphenylmethyl-7-phenylacetamido-3- (1-propynyl) -3-cephem-4-carboxylate A mixture of 1.03 g (0.00162 mol) of diphenylmethyl-7-phenyl-acetyl-3- (trifluoromethyl-sulfonyl) xy) -3-cephem-4-carboxylate, 0.533 g (0.00162 mol) (1-propynyl) tri-n-butyl stannane, 0.665 g (0.00488 mol) zinc chloride, 0.030 g (0.00013 mol) ) Tri (2-furyl) phosphine and 0.00727 g (0.000032 mol) of palladium (II) acetate in 30 ml of dry N, N-dimethylformamide were heated at 65 ° C for 2 hours and at room temperature for 19 hours under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate and the organic solution was washed 5 times with water. Ethyl acetate was removed at reduced pressure and the residue dissolved in acetonitrile. The organic phase was washed twice with n-pentane and the acetonitrile removed at reduced pressure. The residue was purified by reverse phase chromatography to give 0.281 g (30%) of diphenylmethyl-7-phenylacetamido-3- (1-propynyl) -3-cephem-4-carboxylate. The nuclear magnetic resonance spectrum corresponded to the desired structure.

Analysis for C3.1H26N2O4S: DK 174517 B1 12

Calculated: C: 71.24%, H: 5.02%, N: 5.36%, S: 6.14%.

Found: C: 71.23%, H: 5.02%, N: 5.03%, S: 6.11%.

Example 3 DiDhenylmethyl-7-phenylacetamido-3- (2-methylM-propenyl) -3-cephem-4-carboxylate A mixture of 0.105 g (0.000166 mol) of diphenylmethyl-7-phenylacetamido-3- (trifluoro-methylsulfonyloxy) -3-cephem-4-carboxylate, 0.040 g (0.0002 mol) (2-methyl-1-propenyl) tri-n-butylstannane, 0.052 g (0.00036 mol) zinc chloride and 0.0039 g (0 , 000016 moles of tri (2-fury) phosphine in 4 ml of dry 1-methyl-2-pyrrolidinone was degassed for 30 seconds under 10 argon atmosphere. Then, 0.0049 g (0.000008 mole) of palladium (O) bis (dibenzylideneacetone) was added at once. The reaction mixture was stirred at room temperature for 19 hours. The reaction mixture was then diluted with ethyl acetate and the organic phase was washed with dilute ammonium chloride. The ethyl acetate was removed at reduced pressure and replaced with acetonitrile. The organic solution was washed with n-pentane and the acetonitrile was removed at reduced pressure. The residue was chromatographed on silica gel to give 0.0603 g (66%) of diphenylmethyl-7-phenylacetamido-3- (2-methyl-1-propenyl) -3-cephem-4-carboxylate. The nuclear magnetic resonance spectrum and the mass spectrum matched the desired structure.

Analysis for C 32 H 30 N 2 O 4 S: Calculated: C: 71.35%, H: 5.61%, N: 5.20%, S: 5.95%.

Found: C: 70.97%, H: 5.67%, N: 5.07%, S: 5.42%.

Example 4

Oiphenylmethyl-7-phenylacetamido-3- (D-methoxyphenyl) -3-cedhem-4-carboxylate A mixture of 0.1029 g (0.000163 mol) of diphenylmethyl-7-phenylacetamido-3- (trifluoro-methylsulfonyloxy) 3-cephem-4-carboxylate, 0.0775 g (0.000195 mole) (p-methoxyphenyl) tri-n-butyl stannane, 0.044 g (0.00032 mole) zinc chloride and 0.00378 g (O, 000016 mole of tri (2-furyl) phosphine in 4 ml of dry 1-methyl-2-pyrrolidinone was degassed for 30 seconds under an argon atmosphere and then 0.0047 g (0.000008 mole) of palladium-30 (O) bis was added at once. The reaction mixture was stirred at 50 ° C for 5.5 hours and at room temperature for 16 hours, then the reaction mixture was diluted with ethyl acetate and the organic solution was washed with dilute ammonium chloride, the ethyl acetate was removed at reduced pressure and replaced with the acetonitrile. n-pentane and acetonitrile were removed at reduced pressure. The residue was chromatographed on silica gel to give 0.0548 g (57%) of diphenylmethyl -7-phenylacetamido-3- (p-methoxyphenyl) -3-cephem-4-carboxylate.

DK 174517 B1 13

The nuclear magnetic resonance spectrum was consistent with the desired structure.

Analysis for C3sH3oN₂O5S:

Calculated: C: 71.16%, H: 5.12%, N: 4.74%.

Found: C: 70.95%, H: 5.18%, N: 4.70%.

5

Example 5 (Comparative Example)

Diphenylmethyl-7-phenvlacetamido-3- (desrnethvO-3-cephem-4-carboxylate

To a mixture of 0.100 g (0.000158 mol) diphenylmethyl-7-phenylacetamido-3- (trifluoromethylsulfonyioxy) -3-cephem-4-carboxylate, 0.065 g (0.00047 mol) zinc chloride, 0.00293 g ( 0.000012 mole of tri (2-furyl) phosphine and 0.0007 g (0.000003 mole) of palladium (II) acetate in 3 ml of dry tetrahydrofuran under argon atmosphere was added portionwise 0.216 g (0.00074 mole) of tri -butyltinhydrid. The reaction mixture was stirred at 65 ° C for 2 hours. The reaction mixture was then diluted with methylene chloride and the organic solution was washed with n-pentane and the solvent removed at reduced pressure. The residue was chromatographed on silica gel to give 0.053 g (68.5%) of diphenylmethyl-7-phenylacetamido-3- (desmethyl) -3-cephem-4-carboxylate. The nuclear magnetic resonance spectrum was consistent with the desired structure.

Analysis for C2BH24N2O4S:

Calculated: C: 69.40%, H: 4.99%, N: 5.78%, S: 6.62%.

Found: C: 68.04%, H: 4.96%, N: 5.52%, S: 6.60%.

Example 6

Diphenylmethyl-7-phenylacetamido-3-ethenyl-3-cephem-4-carboxylate A mixture of 0.4645 g (0.00073 mol) of diphenylmethyl-7-phenylacetamido-3- (trifluoro-methylsulfonyloxy) -3-cephem-4 carboxylate, 0.279 g (0.00088 mole) of ethenyl tri-n-butyl stannane, 0.200 g (0.00146 mole) of zinc chloride and 0.0068 g (0.000029 mole) of tri (2-furyl) phosphine in 6 ml of dry 1-methyl-2-pyrrolidinone was degassed under an argon atmosphere for 30 seconds. Then, 0.0084 g (0.000014 mol) of palladium (0) bis- (dibenzylideneacetone) was added at once. The reaction mixture was then stirred at room temperature for 1 hour.

Then the reaction mixture was diluted with ethyl acetate and the organic solution was washed with dilute ammonium chloride. The ethyl acetate was removed at reduced pressure and replaced with acetonitrile. The organic phase was washed with n-pentane and the acetonitrile was removed at reduced pressure. The residue was crystallized from ethanol / methylene chloride to give 0.320 g (85%) of diphenylmethyl-7-phenylacetamido-3-ethenyl-3-cephem-4-carboxylate. The nuclear magnetic resonance spectrum was consistent with the desired structure.

DK 174517 B1 14

Analysis for C

Calculated: C: 70.56%, H: 5.13%, N: 5.49%, S: 6.28%.

Found: C: 70.22%, H: 5.13%, N: 5.21%, S: 6.41%.

Example 7

Diphenylmethyl-7-phenylacetamido-3- (1-ethoxy-1-ethenyl) -3-cephem-4-carboxylate A mixture of 0.200 g (0.00031 mole) of diphenylmethyl-7-phenylacetamido-3-trifluoro-methylsulfonyl (xy) - 3-aphem-4-carboxylate, 0.115 g (0.000318 mol) (1-ethoxyvinyl) tri-n-butyl stannane, 0.090 g (0.00066 mol) zinc chloride and 0.00293 g (0.000012 mol) tri 2-10 furyl phosphine in 6 ml of dry 1-methyl-2-pyrrolidinone was degassed for 30 seconds under an argon atmosphere. Then, 0.0036 g (0.000006 mole) of palladium (O) -bis (dibenzylideneacetone) was added at once. The reaction mixture was stirred at room temperature for 19 hours. The reaction mixture was then diluted with ethyl acetate and the organic solution washed with dilute ammonium chloride. The ethyl acetate was removed at reduced pressure and replaced with acetonitrile. The organic solution was washed with n-pentane and the acetonitrile was removed at reduced pressure. The residue was chromatographed on silica gel to give 0.092 g (52%) of diphenylmethyl-7-phenylacetamido-3- (1-ethoxy-1-ethenyl) -3-cephem-4-carboxylate. The nuclear magnetic resonance spectrum was consistent with the desired structure.

Analysis for O

Calculated: C: 69.29%, H: 5.45%, N: 5.05%, S: 5.78%.

Found: C: 69.24%, H: 5.54%, N: 4.89%, S: 5.60%.

Additional cephemic derivatives were prepared essentially by the methods described above in the description of the invention and in the above-mentioned actual examples except that the triflate (Tf) derivative used was replaced with 7- [2- (4-hydroxyphenyl) -2- aminoacetamido) or 7 - [(Z) -2- (2-aminothiazol-4-yl) -2-methoxyimino-acetamido] -3-hydroxy-3-cephem-4-carboxylic acid and certain esters thereof, and The hydrocarbyl tributyl stannanes listed below are used. The starting triflates (Tf) listed in the following table are the following compounds designated "V" and "VI (a, b)" wherein all acidic sites are protected using conventional techniques described in the invention. . After the coupling reaction to obtain the desired 3-hydrocarbyl substitution on the cephemic nucleus, the protecting groups can be removed using conventional techniques. Suitable carbonyl protecting groups include aralkyl groups such as benzyl, methoxybenzyl and diphenylmethyl (benzhydryl), alkyl such as tert-butyl, and haloalkyl such as 2,2,2-trichloroethyl or the like. Suitable amine and hydroxy protecting groups include trityl and acyl groups such as chloroacetyl, formyl, tert-butoxycarbonyl and carbobenzyloxy and the like. Evidently, "QH in the formula shown in the table denotes the cepheme nucleus derived from the triflates" V "and" VI (a.b) ", and R1 represents the unsaturated alkyl group from the stannane.

5

Compound "V" U h Y

COOH

c Compound "VI" O _ ^ s Λ ΎΓί ^ Η; Ν S COOR 'VI (a) = K' = B "· *

VI (b): R '= CH2OCOC (CH3) j · - R'-H

DK 174517 B1 16

Table

Further Examples When palladium-catalyzed coupling of triflates (Tfl with stannanes

H

I s Q-N ~ i-f ^

0 * ~~ N

COOH - No. Stannan Tf Product 8 -> VI (a) Q = 7- [2- (2-Aminothiazol-4-yl) - \ 2 = (Z) -hydroxyiminoacetyl 3

SnBu., R = CH = CH2 and m.p. 170 ° C (dec.).

VI (a) Q = 7- [2- (2-aminothiazol-4-yl) - [2- (Z) -hydoxyoxyiminoacetyl],

SnBu_ pivaloyloxymethyl ester R1 = CH = CH9

Mp. 130 ° C (dec) CH-r: -SnBu., VI (b) Q = 7- [2- (2-aminothiazol-4-yl) -3J 2 = - (Z) -hydroxyiminoacetyl]

R = C = C-CH3 Pivaloyloxymethyl ester m.p. 115 ° C

11 V = \ VI (a) Q = 7- [2- (2-Aminothiazol-4-yl) - [2 = (Z) -hydroxyiminoacetyl)

SnBu, R = CH = CiCH, 7 J mp. > 160 ° C degree. dec ·) 12 y = 1 VI (b) Q = 7- [2- (2-Aminothiazol-4-yl) - [2 = · (Z) -hydroxyiminoacetyl 3

SnBu3 R1 = CH = C (CH3) 2

Pivaloyloxymethyl ester m.p. 110-113 ° C

13 t-- V Q = 7- [D-2-amino-2- (4-hydroxy- [4-phenyl) cycetyl]

SnBu'3 R = CH = CHCH3 '. mp. 213-21o C (dec.) 14 H_CH = C = CH V Q = 7- [D-2-amino-2- (4-hydroxy-1H-phenyl) acetyl]

SnBu3 R =, CH = C = CHCH3 f DK 174517 B1 17

The compounds of formula (I) prepared by the process of the present invention can be provided as pharmaceutically acceptable acid additions and base salts wherein the anion or cation, respectively, does not significantly contribute to the toxicity of the salt and the salts are compatible with conventional pharmaceutical acceptability. carriers and other conventional adjuvants and excipients commonly used in the preparation of pharmaceutical compositions for oral or parenteral administration. The acid addition salts are formed in a conventional manner by reacting compounds of formula (I) with mineral acids, such as e.g. hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or with organic carboxylic acids or sulfonic acids such as e.g.

Acetic acid, citric acid, maleic acid, succinic acid, benzoic acid, tartaric acid, ascorbic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid or the like.

in

Pharmaceutically acceptable base salts are formed in a conventional manner by reacting the compounds of formula (I) with alkali metal bases (Na, K) and alkaline earth metal bases (Ba, Zn, Mg), preferably with alkali metal bases such as e.g. dilute solutions of sodium hydroxide, potassium carbonate and sodium bicarbonate. Pharmaceutically acceptable base salts are also formed in conventional manner by reaction with amines such as e.g. triethylamine, dibenzylamine, Ν, Ν'-dibenzylethylenediamine, procaine or similar amines.

Pharmaceutically acceptable esters include such esters which are themselves active or act as prodrugs by being hydrolyzed in the body to obtain the active antibiotic. Suitable esters of the latter type include phenacyl, acetoxymethyl, pivaloyloxymethyl, O-acetoxybenzyl, 3-phthalidyl, 5-indanyl, methoxymethyl, benzyloxymethyl, glycyoxymethyl and other esters known in the cephalosporin and penicillin preparations.

The pharmaceutical compositions of compounds prepared by the process of the invention can be prepared by combining the compounds of the present invention with a solid or liquid pharmaceutically acceptable carrier, and optionally with pharmaceutically acceptable adjuvants and excipients using conventional methods. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. A solid support may comprise at least one component which may also act as a diluent, flavoring, solubilizing agent, lubricant, suspending agent, binder, tablet disintegrating agent and encapsulating agent, inert solid carriers comprising magnesium carbonate, magnesium stearate, talc, sugar, lactose, sugar, pectin, dextrin, starch, gelatin, cellulose material, low melting point wax, cocoa butter or the like. Liquid form preparations include solutions, suspensions and emulsions. For example, solutions of the compounds of the invention are provided in water or in water-propylene glycol or water-polyethylene glycol systems, optionally comprising suitable conventional dyes, flavoring agents, stabilizers and thickening agents.

The pharmaceutical composition is preferably provided in conventional manner in unit dosage form containing appropriate amounts of active component, i.e. the compound of formula (I) according to the invention.

The amount of active component, ie. the compound of formula (I) according to the invention, in the pharmaceutical composition or unit dosage form thereof can be varied or adjusted within certain limits depending on the particular application, the strength of the compound concerned and the desired concentration. Generally, the amount of active ingredient is between 0.5% by weight and approx. 90% by weight of the composition.

For therapeutic use in the treatment or control of gram-negative and gram-negative battery infections in warm-blooded animals, the compounds are administered at a dose to obtain and maintain a concentration, i.e. an amount or blood level in the animal being treated that is antibacterial. Such an antibacterially effective dose amount is generally in the range of about 100 mg to approx. 5000 mg per day. Evidently, the dose may vary depending on the patient's needs, the severity of the bacterial infection to be treated, and the particular compound being used.

It is also evident that the first dose administered may be increased beyond the above-mentioned upper level to rapidly achieve the desired blood level, or the first dose may be lower than the optimum, and the daily dose may be increased progressively during treatment. depending on the situation in question.

The compounds of formula (I) prepared by the process of the invention 30 may advantageously be administered parenterally, i. by injection, e.g. by intravenous injection, or by other parenteral administration. Pharmaceutical compositions for parenteral administration generally contain a pharmaceutically acceptable amount of the compound of formula (I) as a soluble salt (acid addition or base salt) dissolved in a pharmaceutically acceptable liquid carrier, such as e.g. water for injection or a buffer to provide the appropriate buffered isotonic solution having a pH of approx. 3.5-7. Suitable buffering agents include, e.g. trisodium orthophosphate, sodium, bicarbonate, sodium citrate, N-methylglucamine, L (+) - lysine and L (+) - arginine, to name a few representative buffering agents. The compounds of formula (I) are generally dissolved in the carrier in an amount sufficient to provide a pharmaceutically acceptable injectable concentration in the range of from 1 mg / ml to approx. 400 mg / ml solution. The resulting liquid pharmaceutical composition is administered so as to obtain the above-mentioned antibacterially effective dosage range in the range of about 100 mg to approx. 5000 mg per day.

The following table illustrates the activity of several representative compounds prepared by the method of the invention.

Table

Antibacterial Activity H 1 C (i)

Organism - - '1

Ex. 2 Ex. 3 Ex. 1 Ex. 14 cefaclor cephalexin S. ptveua coatings S 0.03 0.03 2 0.13 0.3 S. pyocencs 4 0.03 0.016 2 0.13 0.23 S. faecalls 16 i 8> 63 02 63 S. aureus «0.06 0.13 & 0.23 0.3 S. aureus / 502 serun> χς 0.06 0.5 32 1 1 S. aureus / Fen.Res. g 0.5 1 63 1 6 S. aureus / Meth.Res. > 1 $> 125> 125> 63> 125> 125

E- eoll 16 2 1> 63 1 A

E. cell l6 32 4> 63 2 4 K. pneumoniae 4 - 0.5> 63 0.5 4 X. pncuaonlae> 16> i2S 63> 63 63 63 E. cloacae> l6 ¢ 3> 125> 63> 125> 125 • P. nlrabllis * 16 '4. 1 € 3 2 *

Claims (7)

A process for the preparation of a cephemic derivative of formula (I) 5 HI s QNjf "* o * ~~ NY ^^ R1 (I) COOH 10 wherein R1 is a group selected from unsubstituted and substituted 1-alkenyl of 2-4 carbon atoms, 1-dienyl, 1-alkynyl with 2-4 carbon atoms, phenyl or heteroaryl selected from 2-, 3- or 4-pyridyl, 2-imidazolyl, 2-thiazolyl, 2- or 3-furyl, 2-pyrryl, 2-thienyl, wherein the phenyl and heteroaryl groups can be substituted with 1-3 alkyl, hydroxy, alkoxy, halogen, amino, mono and dialkylamino, nitro, carboxyl, alkoxycarbonyl and cyano groups, and Q is a group selected from t-butyloxycarbonyl, a silyl protecting group or the acyl group of a known 7-acylaminocephalosporin antibiotic and pharmaceutically acceptable salts and esters thereof, characterized by reacting a 3-trifluoro-methanesulfonyloxy-3 -cephem starting compound of formula (II) QA "pfe> l 25 λ- Ν '(II) cr oTf COOH where Tf is the trifluoromethanesulfonyloxy group CF3S (0) 2- and wherein Q is selected from t-30 butyloxycarbonyl, a silyl protecting group or the acyl group of a known 7-acyl-aminocephalosporin antibiotic, or the diphenylmethyl ester or pivaloyloxy methyl ester thereof, in a polar aprotic solvent having at least one equimolar amount of tri-butyl-stannane in the presence of 1-10 mol% of a Pd ° or Pdu compound and 3-30 mol% of tri- (2-furyl) phoshine and 0-7 molar equivalents of a metal halide at 20-65 ° C , Protected against atmospheric oxygen for 1-75 hours, and recovered the cephemic product from the reaction mixture. DK 174517 B1 21 The method of claim 1, wherein the R1 tributyl stannane is selected from the group H2C = CH-SnBu3, CH3CH = CH-SnBu3, (CH3) 2C = CH-SnBu3, CHa-C ^ C-SnBus. CH30-C6H4SnBu3 and H2C = C (OC2H5) -SnBu3. 5 The method of claim 1, wherein the Pd compound is selected from Pd (dba> 2, Pd (OAc) 2 and PdCl2. The method of claim 1, wherein the Pd compound is Pd (dba) 2. 10 The method of claim 2, wherein the Pd compound is Pd (dba) 2. Process according to claim 1, characterized in that the metal halide is selected from zinc chloride and zinc bromide. 15 The process according to claim 6, wherein zinc chloride is used.