Process for the preparation of 3-exomethylenecepham derivatives

Abstract: A process is provided for the preparation of 3-­ methylene and 3-halomethylene cepham derivatives via 3-phos­ phoniomethyl-3-cephem derivatives, which in turn can be prepared from 3-halomethyl-3-cephem derivatives. The prepa­ ration can be carried out with or without isolating the intermediate phosphonium cephem compounds. The 3-methylene and 3-halomethylene cepham derivatives and in particular the 1-oxo and 1,1-dioxo cepham compounds are also prepared by reducing a 3-halomethyl-3-cephem derivative with activated metal, preferably zinc or magnesium.

Description: The invention relates to a new process for the preparation of 3-exomethylene cepham derivatives. These 3-exomethylene cepham compounds (also referred to hereinafter as 3-methylene cepham compounds) are valuable intermediates in the semi-synthetic preparation of various therapeutically useful antibiotics. For example, 3-methylene cepham sulfoxides (also named: 3-methylene-1-oxocepham compounds) can be converted into 7-ADCA and derivatives thereof, into 7-ACA and other 3-acyloxymethyl cephalosporins, and into 3-heteroarylthiomethyl cephalosporins. Some of these compounds can be used as such in pharmaceutical preparations, others have to be converted further before they are suitable for therapeutic use. Several routes have been known sofar to produce 3-methylene cepham compounds, but these routes are almost entirely limited to the preparation of 3-methylene cepham sulfides. U.S. Patent No. 4,354,022 discloses a process for preparing 3-methylene cepham sulfides by reacting inter alia 3-halomethyl-3-cephem sulfides with a combination of a metal (zinc, tin or iron) and certain ammonium salts (ammonium halides, ammonium carbonate and ammonium acetate). It is noted that of the 3-halomethyl-3-cephem compounds only chloromethyl is exemplified in this reference. In Chem. Pharm. Bull. 36 (2) 528-591 (1988) the preparation of 7-amino-3-methylene-cepham-4-carboxylic acid is described, by reduction of the corresponding 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem compound with zinc either in aqueous acidic or in anhydrous neutral medium. Other known methods for the preparation of 3-methylene cepham sulfides include the conversion of 3-acetoxymethyl, 3-thiomethyl and 3-carbamoyloxy cephem sulfides. In Synth. Comm. 16 (6) 649-652 (1986) the preparation of 3-methylene-1-oxocepham compounds is described, by reduction of the corresponding 3-acetoxymethyl cephem compounds with activated zinc dust and ammonium chloride. The present invention now provides a new process for the preparation of 3-methylene cepham compounds of high purity and in good yields. It has now surprisingly been found that such 3-methylene cepham compounds can be advantageously obtained from the corresponding 3-phosphoniomethyl-3-cephem compounds. Therefore, according to one aspect of the invention, there is provided a process for the preparation of 3-methylene cepham derivatives of the general formula 1: wherein A is an amino group or a protected amino group, B is a carboxy group or a protected carboxy group, or a salt thereof, and n is 0, 1 or 2, which comprises converting a 3-phosphoniomethyl-3-cephem derivative of formula 2: wherein A, B and n are each as defined above, Y is chloride or bromide, Z is Y or hydrogen, and R₁, R₂ and R₃ represent the same or different alkyl, aryl or aralkyl groups, into a compound of formula 1, in alkaline medium. Suitable "protected amino groups" as used in this specification include amino groups substituted with a suitable protective group which are conventionally used in cephalosporin and penicillin chemistry as protective groups at position 7 and position 6, respectively, such as acylamino, phenyl(lower)alkylamino, (cyclo)alkylamino, (cyclo)alkylideneamino. Suitable "acylamino" groups include aliphatic, aromatic and heterocyclic acylamino groups, the acyl group being for example formyl, acetyl, propionyl, butyryl, valeryl, hexanoyl, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, benzoyl, toluyl, phenylacetyl, phenylpropionyl and phenoxycarbonyl. Basically, the same groups as mentioned in U.S. Patent No. 4,354,022, and other groups known to persons skilled in the art of cephalosporin and penicillin chemistry are included within the scope of this invention. Suitable "protected carboxy groups" as used in this specification include carboxy groups substituted with a suitable protective group, which are conventionally used in cephalosporin and penicillin chemistry as carboxy-protective groups at position 4 and position 3, respectively. Suitable examples of such protected carboxy groups include esters, such as the methyl ester, ethyl ester, propyl ester, butyl ester, in particular the t-butyl ester, benzyl ester, optionally substituted, such as the 4-nitrobenzyl ester and diphenylmethyl ester. See also U.S. Patent No. 4,354,022, referred to above. Suitable "salts" of the compounds of formula 1, and the starting compounds (and intermediates) for preparing these compounds, include conventional non-toxic salts, such as those listed in U.S. Patent No. 4,354,022, referred to above. Preferred compounds of formula 1 which can be made by the method according to the present invention are 3-methylene cepham derivatives, and especially the 3-methylene 1-oxo-cepham (most preferred) and 3-methylene 1,1-dioxocepham compounds. The reaction defined above is suitably carried out by adding a previously prepared suspension or solution of an inorganic salt in water which is adjusted to a pH above 7, to the phosphonium salt of formula 2. Suitable inorganic salts include tin salts, such as stannous or stannic halides; stannites, e.g. sodium stannite; sodium, potassium, aluminium, boron, phosphorus, zinc and tellurium salts, especially halides; and combinations thereof. Of these, stannous chloride and bromide, and stannites are preferred, stannous chloride being most preferred. The inorganic salt is preferably suspended or dissolved in a little water. The pH is then preferably adjusted to values of 9 and higher by adding a strong hydroxide solution. The suspension or solution is then added to the phosphonium cephem compound, which is preferably in solution. Suitable solvents are, for example, tetrahydrofuran (preferred), methylene chloride and acetonitrile. The reaction takes also place when adding a strong base without an inorganic salt. The reaction conditions are not very critical and may be optimized experimentally. Suitable temperatures are usually in the range of between 0°C and the boiling point of the reaction mixture, and preferably at about 40°C. The reaction time may vary widely, but is suitably in the range of between some minutes and several hours, usually between 1-2 hours. Isolation and purification is suitably carried out by usual techniques, for example by adjusting the pH to neutral, pouring out the reaction mixture in an organic solvent which is poorly miscible with water, extracting, separating, washing, evaporating and redissolving. The conversion of the phosphonium salt into the exomethylene group in the presence of a base was surprising because the formation of a phosphorane group was expected. The phosphonium cephem compounds (sulfides, sulfoxides and sulfones) of formula 2 are believed to be novel and form an aspect of the invention. Some specific corresponding iodine sulfide compounds prepared from a 3-hydroxymethyl cephem compound have been mentioned in U.S. Patent No. 4,705,851. The compounds found can be conveniently prepared by reacting a corresponding (2-halo)-3-halomethyl-3-cephem compound of the general formula 3: wherein A, B, Y, Z and n are each as defined above, with a phosphine compound of formula 4: wherein R₁, R₂ and R₃ are as defined above, in a suitable solvent. Suitable phosphines are, inter alia, trialkyl (C₁₋₆, straight or branched), triaryl or triaralkyl (both unsubstituted or substituted by one or more groups) phosphines, of which triphenyl phosphine is preferred. Preferably, the carboxy group at position 4 is protected by a suitable protecting group. Suitable solvents include tetrahydrofuran, which is preferred. Although the reaction conditions are not very critical, the reaction is conveniently carried out at slightly elevated temperature (about 40°C) for several hours (usually about 3 hours) in an inert atmosphere. The desired phosphonium cephem compounds may also be prepared from other phosphonium cephem compounds, by converting one or more groups of the molecule. For example, a 3-phosphoniomethyl-3-cephem sulfide derivative can be prepared from the corresponding 3-phosphoniomethyl-3-cephem sulfoxide derivative, for example by reacting the sulfoxide with PCl₃. Isolation and purification of the resulting phosphonium cephem compounds may be carried out by usual techniques (e.g. centrifugation, washing and drying). Preferred phosphonium cephem compounds are such compounds of formula 2 in which Z is hydrogen and Y is bromine. Most preferred are those compounds in which, moreover, n is 1 and R₁, R₂ and R₃ are phenyl. The starting (2-halo)-3-halomethyl-3-cephem derivatives (sulfides, sulfoxides and sulfones) are either known compounds or may be prepared by methods known for the preparation of analogous compounds. See, for example, EP-A-0015629 and EP-A-0034394. Preferably, 3-bromomethyl-3-cephem derivatives are used as starting compounds. Such 3-bromomethyl-3-cephem derivatives are suitably prepared, for example, by bromination of the corresponding 3-methyl-3-cephem compounds. The bromination is suitably carried out with N-bromosuccinimide (NBS) in a non-hydrolytic solvent, for example methylene chloride or methylene chloride/acetic acid, preferably using an initiator and most preferably light (irradiation). Preferably, the bromination reaction with NBS and light is carried out at low temperature (about 0°C), usually for a time between some minutes and several hours, for example between about 1 and 4 hours. If desired, by-products which may be formed during the bromination reaction, such as 2-bromo-3-bromomethyl-3-cephem derivatives may be debrominated at the 2-position by the addition of a suitable debrominating agent, for example a phosphite, such as tributyl phosphite. After the bromination the reaction mixture is isolated and purified according to usual techniques to give the desired 3-bromomethyl-3-cephem compounds. Similar techniques can be applied for the preparation of other (2-halo)-3-halomethyl-3-cephem compounds, which are all within the skill of the average expert. According to another preferred embodiment of the invention the 3-methylene compounds of formula 3 can also be directly prepared from the 3-halomethyl-3-cephem derivatives of formula 3 via the intermediate phosphonium cephem compounds of formula 2, but without isolating said intermediates. The reaction conditions are substantially identical to the conditions described above for the separate preparation of the compounds of formula 1 from the 3-phosphoniomethyl-3-cephem derivatives of formula 2 and the preparation of the latter compounds from the 3-halomethyl-3-cephem derivatives, respectively. The following Examples are offered by way of illustration of the invention. No attempts were made to optimize the yields. Examples 1-6 show the preparation of certain new 3-bromomethyl cephem derivatives. Examples 7-13 illustrate the preparation of 3-phosphoniomethyl cephem compounds and Examples 14-22 the preparation of 3-exomethylene cephams from such phosphonium compounds. Finally, examples 23-30 show "one-pot" syntheses of 3-exomethylene cephams via phosphonium salts, but without isolating these intermediates. EXAMPLES Example 1 Preparation of tert-butyl (6R,7R)-3-bromomethyl-1,1-dioxo-7-phenylacetamido-3-cephem-4-carboxylate from tert-butyl (6R,7R)-3-methyl-1,1-dioxo-7-phenylacetamido-3-cephem-4-carboxylate A solution of 6 g (14.27 mmoles) tert -butyl (6R,7R)-3-methyl-1,1-dioxo-7-phenylacetamido-3-cephem-4-carboxylate in 90 ml of methylene chloride was stirred at 0°C under dry nitrogen with 3.5 g (19.66 mmoles) of N-bromo-succinimide and irradiated with 26 fluorescent tubes (Philips 03T; 20 W) for 60 minutes. The solution was washed with water (pH = 7), combined with a methylene chloride backwash of the aqueous phase, dried and evaporated to low volume. The residue was chromatographed on Kieselgel H type 60 with a preparative Jobin-Yvon column. Eluation with toluene/ethyl acetate (5:1) gave after trituration with ether 1.43 g of the title compound with a purity of 94%. IR-spectrum (KBr-disc; values in cm⁻¹): 3420, 3000, 1790, 1720, 1680, 1600, 1500, 1260, 1230, 1040, 1020, 990, 820, 700 and 680. PMR-spectrum (360 MHz; CDCl₃; tetramethylsilane as an internal reference; δ-values in ppm): 1.54 (s, 9H); 3.64 (s, 2H); 3.72 and 4.08 (ABq, 2H; J = 19.0 Hz); 4.19 and 4.48 (ABq, 2H; J = 10.8 Hz); 4.81 (d, 1H; J = 4.6 Hz); 6.13 (dd, 1H; J = 4.6 and 10.2 Hz); 6.78 (d, 1H; J = 10.2 Hz); 7.3 (m, 5H). Example 2 Preparation of 4-nitrobenzyl (1S,6R,7R)-3-bromomethyl-1-oxo-7-phenylacetamido-cephem-4-carboxylate from 4-nitrobenzyl (1S,6R,7R)-3-methyl-1-oxo-7-phenylacetamido-3-cephem-4-carboxylate A solution of 1 g (2.1 mmoles) of 4-nitrobenzyl (1S,6R,7R)-3-methyl-1-oxo-7-phenylacetamido-3-cephem-4-carboxylate in 100 ml of methylene chloride and 100 ml of acetic acid was stirred at 4°C under dry nitrogen with 620 mg (3.4 mmoles) of N-bromosuccinimide and irradiated with a 150 W tungsten lamp for 90 minutes. After evaporating the solvents while adding some toluene, the residue was washed with a cold sodium bisulphite solution, giving 1.0 g of the title product. PMR-spectrum (360 MHz; CF₃COOD; tetramethylsilane as an internal reference; δ-values in ppm): 3.59 and 4.05 (ABq, 2H; J = 19 Hz); 3.65 (s, 2H); 4.22 (s, 2H); 4.84 (d, 1H; J = 4.5 Hz); 5.31, 5.38 (ABq, 2H; J = 15.6 Hz); 6.05 (d, 1H; J = 4.5 Hz); 7.0 - 8.2 (m, 9H). Example 3 Preparation of 4-nitrobenzyl (1S,6R,7R)-3-bromomethyl-1-oxo-7-phenoxyacetamido-3-cephem-4-carboxylate from 4-nitrobenzyl (1S,6R,7R)-3-methyl-1-oxo-7-phenoxyacetamido-3-cephem-4-carboxylate A solution of 2.6 g (purity 82%; 4.27 mmoles) of 4-nitrobenzyl (1S,6R,7R)-3-methyl-1-oxo-7-phenoxyacetamido-3-cephem-4-carboxylate in 150 ml of methylene chloride and 150 ml of acetic acid was stirred at 0°C under dry nitrogen with 1.85 g (10.39 mmoles) of N-bromosuccinimide and irradiated with a 150 W tungsten lamp for 200 minutes. After evaporating the solvents the residue was dissolved in methylene chloride, the methylene chloride solution was washed with water and phosphate buffer and evaporated. Trituration with ether/petroleum ether 40-60°C gave 2.17 g of the title product with a purity of 67% (yield 48%). PMR-spectrum (360 MHz; DMSO-d₆; internal reference tetramethylsilane): 3.81 and 4.02 (ABq, 2H; J = 18.5 Hz); 4.53 and 4.59 (ABq, 2H; J = 9.8 Hz); 4.67 (s, 2H); 5.06 (d, 1H; J = 4.4 Hz); 5.48 (s, 2H); 6.11 (d, 1H; J = 4.4 and 9.8 Hz); 6.96 and 7.16 (m, 5H); 7.73 and 8.25 (ABq, 4H; J = 8.3 Hz) 8.19 (d, 1H; J = 9.8 Hz). Example 4 Preparation of methyl (1S,6R,7R)-3-bromomethyl-1-oxo-7-phenoxyacetamido-3-cephem-4-carboxylate from methyl (1S,6R,7R)-3-methyl-1-oxo-7-phenoxyacetamido-3-cephem-4-carboxylate A solution of 2.3 g (6.1 mmoles) of methyl (1S,6R,7R)-3-methyl-1-oxo-7-phenoxyacetamido-3-cephem-4-carboxylate in 50 ml of methylene chloride and 50 ml of acetic acid was stirred at 0°C under dry nitrogen with 1.5 g of N-bromosuccinimide and irradiated with a 150 W tungsten lamp for 60 minutes. After adding 0.3 ml of tributylphosphite and stirring for 4 hours at -5°C the reaction mixture was poured out into 500 ml of methylene chloride and 100 ml of water. After separating the layers the organic layer was washed with water (4 x 100 ml), combined with a methylene chloride backwash (100 ml) of the aqueous phases, dried and evaporated. Trituration of the residue with ether gave 2.55 g of the title compound with a purity of 58%. Yield 53%. IR-spectrum (KBr-disc, values in cm⁻¹): 3380, 2955, 1790, 1728, 1697, 1599, 1522, 1495, 1435, 1375, 1305, 1240, 1174, 1098, 1065, 1020, 735 and 690. PMR-spectrum (360 MHz; CDCl₃/DMSO-d₆ (3:1); tetramethylsilane as an internal reference; δ-values in ppm): 3.81 and 3.90 (ABq, 2H; J = 18.0 Hz); 3.91 (s, 3H); 4.41 and 4.59 (ABq, 2H; J = 10.1 Hz); 4.60 (s, 2H); 4.99 (d, 1H; J = 4.5 Hz); 6.10 (dd, 1H; J = 4.5 and 10.1 Hz); 6.9 - 7.3 (m, 5H); 8.04 (d, 1H; J = 10.1 Hz). Example 5 Preparation of 4-nitrobenzyl (1S,6R,7R)-3-bromomethyl-7-formamido-1-oxo-3-cephem-4-carboxylate from 4-nitrobenzyl (1S,6R,7R)-7-formamido-3-methyl-1-oxo-3-cephem-4-carboxylate A solution of 2 g (5.84 mmoles) of 4-nitrobenzyl (1S,6R,7R)-7-formamido-3-methyl-1-oxo-3-cephem-4-carboxylate in 150 ml of methylene chloride and 150 ml of acetic acid was stirred at 0°C under dry nitrogen with 1.4 g (7.8 mmoles) of N-bromosuccinimide and irradiated with a 150 W tungsten lamp for 90 minutes. After adding 0.2 ml (0.7 mmoles) of tributylphosphite and stirring for 15 minutes at -5°C the solvents were evaporated. After dissolving the residue in a mixture of methylene chloride and ethyl acetate and washing with water the solution was concentrated. The crystals were filtered off and washed with ether and petroleum ether 40-60°C and dried giving 1.6 g of the title compound with a purity of 79%. Yield 61%. IR spectrum (KBr-disc, values in cm⁻¹): 3280, 1780, 1730, 1720, 1665, 1522, 1386, 1350, 1260, 1242, 1172, 1030, 852, 739, 696 and 620. PMR spectrum (360 MHz; DMSO-d₆; tetramethylsilane as an internal reference; δ-values in ppm): 3.82 and 3.99 (ABq, 2H; J = 18.6 Hz); 4.52 and 4.62 (ABq, 2H; J = 10.2 Hz); 5.03 (d, 1H; J = 4.9 Hz); 5.46 and 5.50 (ABq, 2H; J = 13.6 Hz); 6.04 (dd, 1H; J = 4.9 and 9.8 Hz); 7.73 and 8.25 (ABq, 4H; J = 8.7 Hz); 8.16 (s, 1H); 8.44 (d, 1H; J = 9.8 Hz). Example 6 Preparation of tert-butyl (1S,6R,7R)-3-dibromomethyl-7-formamido-1-oxo-3-cephem-4-carboylate from tert-butyl (1S,6R,7R)-3-methyl-7-formamido-1-oxo-3-cephem-4-carboxylate A suspension of 6.3 g (20 mmoles) of tert -butyl (1S,6R,7R)-3-methyl-7-formamido-1-oxo-3-cephem-4-carboxylate in 150 ml of methylene chloride was stirred at 4°C under dry nitrogen with 9.8 g (55 mmoles) of N-bromosuccinimide, gradually added, and irradiated with a 150 W tungsten lamp for 5.5 hours. After washing the reaction mixture with water, treatment with decolourizing carbon and drying, 6.7 g of a crude mixture of brominated products was precipitated with petroleum ether 40-60°C. The precipitate was chromatographed with a Jobin-Yvon column on Kieselgel H in methylene chloride/ethyl acetate (7:3). The appropriate fractions were combined and evaporated, and the residue was triturated with ether to give 2.4 g of the title product. IR-spectrum (KBr-disc, values in cm⁻¹): 3320, 3092, 1798, 1718, 1678, 1610, 1500, 1397, 1373, 1152, 1000, 646. PMR-spectrum (60 MHz; DMSO-d6; tetramethylsilane as an internal reference: δ-values in ppm): 1.51 (s, 9H); 3.77, 407, 4.17 and 4.47 (ABq, 2H; J = 18 Hz); 5.14 (d, 1H; J = 5 Hz); 6.08 (dd, 1H; J = 5 and 9.5 Hz); 7.32 (s, 1H); 8.26 (S, 1H); 8.65 (d, 1H; J = 9.5 Hz). Example 7 Preparation of (6R,7R)-4-tert-butoxycarbonyl-1,1-dioxo-7-phenylacetamido-3-triphenylphosphoniomethyl-3-cephem bromide from tert-butyl (6R,7R)-3-bromomethyl-1,1-dioxo-7-phenylacetamido-3-cephem-4-carboxylate A mixture of 1 g (2 mmoles of tert -butyl (6R,7R)-3-bromomethyl-1,1-dioxo-7-phenylacetamido-3-cephem-4-carboxyl ate (see Example 1), 20 ml of tetrahydrofuran and 800 mg (3.1 mmoles) of triphenylphosphine was stirred at 40°C for 3 hours under nitrogen. Centrifugation, washing with ether and drying gave 1.54 g of the title compound with a purity of 85%. Yield 91%. IR-spectrum (KBr-disc; values in cm⁻¹): 3400, 2980, 2855, 1800, 1710, 1690, 1500, 1440, 1370, 1335, 1300, 1155, 1135, 1110, 1000, 840, 750, 720, 692, 540 and 500. PMR-spectrum (360 MHz; CDCl₃; tetramethylsilane as an internal reference; δ-values in ppm): 1.24 (s, 9H); 3.29 (d, 1H; J = 19 Hz); 3.62 (s, 2H); 5.13 and 5.75 (2xt, 2H; J = 14.4 and 14.4 Hz); 5.14 (d, 1H; J = 4.5 Hz); 5.49 dd, 1H; J = 19.0 and 5.4 Hz); 6.12 (dd, 1H; J = 4.5 and 10.1 Hz); 6.92 (d, 1H; J = 10.1 Hz); 7.2 - 7.8 (m, 20 H). Example 8 Preparation of (1S,6R,7R)-4-nitrobenzyloxycarbonyl-1-oxo-7-phenylacetamido-3-triphenylphosphoniomethyl-3-cephem bromide from 4-nitrobenzyl (1S,6R,7R)-3-bromomethyl-1-oxo-7-phenylacetamido-3-cephem-4-carboxylate A mixture of 447 mg of 4-nitrobenzyl (1S,6R,7R)-3-bromomethyl-1-oxo-7-phenylacetamido-3-cephem-4-carboxylate (see Example 2), 600 mg of triphenylphosphine and 15 ml of tetrahydrofuran was stirred at 40°C for 3 hours. After evaporation of the solvent and addituon of ether the precipitate formed was filtered off giving 600 mg of the title product with a purity of 57%. IR-spectrum (KBr-disc, values in cm⁻¹): 3400, 1795, 1724, 1680, 1520, 1438, 1349, 1255, 1170, 1111, 1030, 853, 739, 720, 690 and 500. PMR-spectrum (360 MHz; CDCl₃; tetramethylsilane as an internal reference; δ-values in ppm): 3.50 (d, 1H; J = 19.4 Hz); 3.60 (s, 2H); 4.84 (dd, 1H; J = 19.4 and 4.5 Hz); 4.98 and 5.11 (ABq, 2 H; J = 13.3 Hz); 5.10 (d, 1H; J = 4.4 Hz); 5.11 and 5.45 (2xt, 2H; J = 14.4 and 14.4 Hz); 6.06 (dd, 1 H; J = 4.4 and 10.1 Hz); 6.94 (d, 1H; J = 10.1 Hz); 7.2 - 8.3 (m, 24H). Example 9 Preparation of (1S,6R,7R)-4-nitrobenzyloxycarbonyl-1-oxo-7-phenoxyacetamido-3-triphenylphosphoniomethyl-3-cephem bromide from 4-nitrobenzyl (1S,6R,7R)-3-bromomethyl-1-oxo-7-phenoxyacetamido-3-cephem-4-carboxylate To a solution of 1.73 g (purity 67%; 2 mmoles) of 4-nitrobenzyl (1S,6R,7R)-3-bromomethyl-1-oxo-7-phenoxyacetamido-3-cephem-4-carboxylate (see Example 3) in 55 ml of tetrahydrofuran, 1.58 g (6 mmoles) of triphenylphosphine were added and the mixture was stirred at 40°C for 3 hours under nitrogen. After standing overnight precipitaion with ether gave 2.29 g of the title product with a purity of 59%. Yield 80%. IR-spectrum (KBr-disc, values in cm₋₁): 3400, 1800, 1725, 1700, 1605, 1592, 1524, 1495, 1442, 1390, 1350, 1300, 1245, 1175, 1114, 1070, 1035, 755, 695 and 510. PMR-spectrum (360 MHz; CDCl₃; tetramethylsilane as an internal reference; δ-values in ppm): 3.51 (d, 1H; J = 19.5 Hz); 4.54 (s, 2H); 4,97 (dd, 1H; J = 19.5 and 5.9 Hz); 5.00 and 5.14 (ABq, 2H; J = 13.2 Hz); 5.13 and 5.51 (2xtr, 2H; J = 14.6 and 17.1 Hz); 5.21 (d, 1H; J = 4.9 Hz); 6.16 (dd, 1H; J = 4.9 and 10.7 Hz); 6.94, 7.02 and 7.29 (m, 5H); 7.44 and 8.18 (ABq, 4H; J = 8.8 Hz); 7.5 - 7.9 (m, 15H). Example 10 Preparation of (1S,6R,7R)-4-methoxycarbonyl-1-oxo-7-phenoxyacetamido-3-triphenylphosphoniomethyl-3-cephem bromide from methyl (1S,6R,7R)-3-bromomethyl-1-oxo-7-phenoxyacetamido-3-cephem-4-carboxylate A mixture of 1.37 g (purity 58%; 1.74 mmoles) of methyl (1S,6R,7R)-3-bromomethyl-1-oxo-7-phenoxyacetamido-3-cephem-4-carboxylate (see Example 4), 1.18 g (4.5 mmoles) of triphenylphosphine and 15 ml of tetrahydrofuran was stirred at 40°C for 3 hours. After addition of ether the precipitate formed was isolated by centrifugation, giving 1.93 g of the title product with a purity of 64%. Yield 99%. IR-spectrum (KBr-disc, values in cm⁻¹): 3390, 1795, 1720, 1691, 1530, 1490, 1438, 1370, 1297, 1260, 1240, 1170, 1110, 1028, 750, 720, 690 and 500. PMR-spectrum (360 MHz; CDCl₃; tetramethylsilane as an internal reference; δ-values in ppm): 3.56 (s, 3H); 3.57 (d, 1H; J = 19.0 Hz); 4.54 (s, 2H); 4.88 (dd, 1H; J = 19.0 and 5.9 Hz); 5.09 and 5.52 (2xt, 2H; J = 14.6 and 17.1 Hz); 5.20 (d, 1H; J = 4.9 Hz); 6.13 (dd, 1H; J = 4.9 and 10.3 Hz); 6.93, 7.02 and 7.29 (m, 5H); 7.6 - 8.0 (m, 15H). Example 11 Preparation of (1S,6R,7R)-4-diphenylmethyloxycarbonyl-1-oxo-7-formamido-3-triphenylphosphoniomethyl-3-cephem bromide from diphenylmethyl (1S,6R,7R)-3-bromomethyl-7-formamido-1-oxo-3-cephem-4-carboxylate A mixture of 2 g (purity 74%; 2.94 mmoles) of diphenylmethyl (1S,6R,7R)-3-bromomethyl-7-formamido-1-oxo-3-cephem-4-carboxylate (see U.S. Patent No. 3,769,277), 3 g of triphenylphosphine and 50 ml of tetrahydrofuran was stirred at 40°C under nitrogen for 16 hours and treated with ether, giving 2.97 g of the title product with a purity of 73%. Yield 96%. IR-spectrum (KBr-disc; values in cm⁻¹): 3400, 3060, 2970, 2860, 1795, 1690, 1500, 1460, 1370, 1250, 1160, 1110, 745, 690 and 500. PMR-spectrum (360 MHz; CDCl₃; tetramethylsilane as an internal reference; δ-values in ppm): 3.60 (d, 1H; J = 19.1 Hz); 4.97 (dd, 1H; J = 19.1 and 5.4 Hz); 5.17 and 5.49 (2xt, 2H; J = 14.7 and 14.1 Hz); 5.21 (d, 1H; J = 4.9 Hz); 6.14 (dd, 1H; J = 4.9 and 10.3 Hz); 6.48 (s, 1H); 7.02 (d, 1H; J = 10.3 Hz); 7.1 - 7.9 (m, 25H); 8.17 (s, 1H). Example 12 Preparation of (1S,6R,7R)-4-tert-butoxycarbonyl-1-oxo-7-phenylacetamido-3-triphenylphosphoniomethyl-3-cephem bromide from tert-butyl (1S,6R,7R)-3-bromomethyl-1-oxo-7-phenylacetamido-3-cephem-4-carboxylate 24.2 g (purity 89%; 44.6 mmoles) of tert -butyl (1S,6R,7R)-3-bromomethyl-1-oxo-7-phenylacetamido-3-cephem-4-carboxylate was heated in 250 ml of tetrahydrofuran at 40°C. After addition of 14.4 g (55 mmoles) of triphenylphosphine stirring was continued for 2 hours and then 250 ml of diethylether was added. Filtration of the precipitate, washing with diethylether and drying gave 37.3 g of the title compound with a purity of 84%. Yield 94%. IR-spectrum (KBr-disc; values in cm⁻¹): 1795, 1710, 1690, 1620, 1505, 1445, 1365, 1310, 1280, 1265, 1160, 1115, 1040, 1005, 840, 745, 725 and 700. PMR-spectrum (360 MHz; CDCl₃; δ-values in ppm; tetramethylsilane as an internal reference): 1.23 (s, 9H); 3.41 (dd, 1H; J = 18.7 and 2.0 Hz); 3.58 (s, 2H); 4.87 (dd, 1H; J = 18.7 and 5.4 Hz); 4.95 (d, 1H; J = 5.0 Hz); 5.14 (dd, 1H; J = 14.4 and 17.6 Hz); 5.48 (dd, 1H; J = 14.4 and 13.7 Hz); 6.06 (dd, 1H; J = 5.0 and 10.1 Hz); 6.76 (d, 1H; J = 10.1 Hz); 7.2 - 7.9 (m, 20H). Example 13 Preparation of (6R,7R)-4-tert-butoxycarbonyl-1-oxo-7-phenylacetamido-3-triphenylphosphoniomethyl-3-cephem bromide from (1S,6R,7R)-4-tert-butoxycarbonyl-1-oxo-7-phenylacetamido-3-triphenylphosphoniomethyl-3-cephem bromide To suspension of 1.85 g (2.23 mmoles) of (1S,6R,7R)-4- tert -butoxycarbonyl-1-oxo-7-phenylacetamido-3-triphenylphosphoniomethyl-3-cephem bromide (see Example 12) in 25 ml of tetrahydrofuran was added 0.35 ml (4 mmoles) of phosphorus trichloride at 0°C. After 30 minutes 20 ml of water was added to the clear reaction mixture, the pH was adjusted to 5 with a 4 N sodium hydroxide solution and stirring was continued for 45 minutes maintaining the pH at 5. After adding 20 ml of ethyl acetate, separation of the layers and extracting the water layer with 2 x 10 ml of ethyl acetate, the combined organic layers were dried (magnesium acetate) and evaporated to dryness. Isolation by trituration and drying gave 1.73 g of the title product. Purity 82%. Yield 87%. IR-spectrum (KBr-disc; values in cm⁻¹): 1786, 1710, 1676, 1630, 1540, 1445, 1380, 1310, 1280, 1160, 1115, 1010, 845, 730 and 700. PMR-spectrum (360 MHz; CDCl₃; δ-values in ppm; tetramethylsilane as an internal reference): 1.22 (s, 9H); 3.10 (dd, 1H; J = 18.9 and 2.1 Hz); 3.98 (dd, 1H; J = 18.9 and 5.9 Hz); 3.63 and 3.70 (ABq, 2H; J = 14.7 Hz); 4.79 (d, 1H; J = 4.6 Hz); 5.01 and 5.29 (2xtr, 2H; J = 14.6 and 14.7 and 13.9 Hz); 5.62 (dd, 1H; J = 4.6 and 8.8 Hz); 7.1 - 7.8 (m, 20H). Example 14 Preparation of tert-butyl (1S,4R,6R,7R)-3-methylene-1,1-dioxo-7-phenylacetamido-cepham-4-carboxylate from (6R,7R)-4-tert-butoxycarbonyl-1,1-dioxo-7-phenylacetamido-3-triphenylphosphoniomethyl-3-cephem bromide A suspension of 385 mg of stannous chloride dihydrate in 5 ml of water, of which the pH was adjusted to 9 with a 4 N sodium hydroxide solution was added to a suspension of 765 mg (purity 85%; 0.85 mmoles) of (6R,7R)-4- tert -butoxycarbonyl-1,1-dioxo-7-phenylacetamido-3-triphenylphosphoniomethyl-3-cephem bromide (see Example 7) in 15 ml of tetrahydrofuran. The reaction mixture was stirred at 40°C for 90 minutes, while maintaining the pH at 9 and adjusting the pH to 7 when the reaction was terminated, and poured out into ethyl acetate. After washing the organic layer with brine the solvents were evaporated. The residue was dissolved in acetone and ether and petroleum ether 40-60°C were added giving 510 mg of a mixture of the title compound (yield 45%) and the starting compound (25%), as confirmed with PMR spectroscopy. Example 15 Preparation of 4-nitrobenzyl (1S,4R,6R,7R)-3-methylene-1-oxo-7-phenylacetamido-cepham-4-carboxylate from (1S,6R,7R)-4-nitrobenzyloxycarbonyl-1-oxo-7-phenylacetamido-3-triphenylphosphoniomethyl-3-cephem bromide A suspension of 265 mg of stannous chloride dihydrate in 5 ml of water, of which the pH was adjusted to 9.5 with a 4 N sodium hydroxide solution was added to a solution of 548 mg (purity 57%; 0.38 mmoles) of (1S,6R,7R)-4-nitrobenzyloxycarbonyl-1-oxo-7-phenylacetamido-3-tri-phenylphosphoniomethyl-3-cephem bromide (see Example 8) in 15 ml of tetrahydrofuran. The reaction mixture was stirred at 40°C for 90 minutes, while maintaining the pH at 9 and adjusting the pH to 7 when the reaction was terminated, and poured out into ethyl acetate. The organic layer was washed with water (4x) and brine, combined with an ethyl acetate backwash of the aqueous phase and evaporated. The residue was dissolved in acetone and treated with ether and petroleum ether 40-60°C, giving the title product after centrifugation. The structure was confirmed by PMR spectroscopy. PMR-spectrum (360 MHz; DMSO-d₆; tetramethylsilane as an internal reference; δ-values in ppm): 3.51 and 3.64 (ABq, 2H; J = 15.6 Hz); 3.71 and 3.89 (ABq, 2H; J = 14.4 Hz); 5.01 (d, 1H; J = 4.5 Hz); 5.32, 5.39 and 5.72 (3xs, 3H); 5.47 (s, 2H); 7.1 - 8.3 (m, 10H). Example 16 Preparation of 4-nitrobenzyl (1S,4R,6R,7R)-7-phenoxyacetamido-3-methylene-1-oxocepham-4-carboxylate from (1S,6R,7R)-4-nitrobenzyloxycarbonyl-1-oxo-7-phenoxyacetamido-3-triphenylphosphoniomethyl-3-cephem bromide A suspension of 385 mg of stannous chloride dihydrate in 5 ml of water, of which the pH was adjusted to 9 with a 4 N sodium hydroxide solution was added to a suspension of 840 mg (purity 59%; 0.59 mmoles) of (1S,6R,7R)-4-nitrobenzyloxycarbonyl-1-oxo-7-phenoxyacetamido-3-triphenylphosphoniomethyl-3-cephem bromide (see Example 9) in 15 ml of tetrahydrofuran at 40°C, and after stirring for 90 minutes maintaining the pH at 9 the mixture was poured out into ethyl acetate. After evaporating the solvent the residue was dissolved in acetone. After adding ether and petroleum ether 40-60°C the precipitate formed was centrifugated (330 mg). The structure was confirmed by PMR spectroscopy. PMR-spectrum (360 MHz; DMSO-d₆; tetramethylsilane as an internal reference; δ-values in ppm): 3.77 and 3.97 (ABq, 2H; J = 14.4 Hz); 4.67 (s, 2H); 5.12 (d, 1H; J = 4.4 Hz); 5.34, 5.53 and 5.67 (3xs, 3H); 5.42 (s, 2H); 5.84 (dd, 1H; J = 4.4 and 10.2 Hz); 6.9 - 8.3 (m, 10 Hz). Example 17 Preparation of methyl (1S,4R,6R,7R)-7-phenoxyacetamido-3-methylene-1-oxocepham-4-carboxylate from (1S,6R,7R)-4-methoxycarbonyl-1-oxo-7-phenoxyacetamido-3-triphenylphosphoniomethyl-3-cephem bromide A suspension of 385 mg of stannous chloride dihydrate in 5 ml of water, of which the pH was adjusted to 9.5 with a 4 N sodium hydroxide solution was added to a suspension of 720 mg (purity 64%; 0.64 mmoles) of (1S,6R,7R)-4-methoxycarbonyl-1-oxo-7-phenoxyacetamido-3-triphenylphosphoniomethyl-3-cephem bromide (see Example 10) in 15 ml of tetrahydrofuran. The reaction mixture was stirred at 40°C for 90 minutes, while maintaining the pH at 9 and adjusting the pH to 7 when the reaction was terminated, and poured out into ethyl acetate. The organic layer was washed with water (4x) and brine, combined with an ethyl acetate backwash of the aqueous phase and evaporated. The residue was dissolved in acetone and treated with ether and petroleum ether 40-60°C, giving the title product after centrifugation. The structure was confirmed by PMR spectroscopy. PMR-spectrum (360 MHz; DMSO-d₆; tetramethylsilane as an internal reference; δ-values in ppm): 3.70 (s, 3H); 3.79 and 3.93 (ABq, 2 H; J = 14.2 Hz) 4.62 (s, 2H); 5.11 (d, 1H; J = 4.4 Hz); 5.34, 5.41 and 5.71 (3xs, 3H); 5.80 (dd, 1H; J = 4.4 and 10.2 Hz); 6.9 - 7.6 (m, 5 Hz); 8.27 (d, 1H; J = 10.2 Hz). Example 18 Preparation of diphenylmethyl (1S,4R,6R,7R)-7-formamido-3-methylene-1-oxocepham-4-carboxylate from (1S,6R,7R)-4-diphenylmethyloxycarbonyl-1-oxo-7-formamido-3-triphenylphosphoniomethyl-3-cephem bromide A suspension of 385 mg of stannous chloride dihydrate in 5 ml of water, of which the pH was adjusted to 9.5 with a 4 N sodium hydroxide solution was added to a suspension of 765 mg (purity 73%; 0.73 mmoles) of (1S,6R,7R)-4-diphenylmethyloxycarbonyl-1-oxo-7-formamido-3-triphenylphosphoniomethyl-3-cephem bromide (see Example 11) in 15 ml of tetrahydrofuran. The reaction mixture was stirred at 40°C for 90 minutes, while maintaining the pH at 9 and adjusting the pH to 7 when the reaction was terminated, and poured out into ethyl acetate (100 ml). The organic layer was washed with water, combined with an ethyl acetate backwash of the aqueous phase and evaporated. The residue was dissolved in acetone and treated with ether and petroleum ether 40-60°C, giving after centrifugation 260 mg of a mixture of the title product and triphenylphosphine oxide containing 53.4% of the title product. Yield 45%. Example 19 Preparation of tert-butyl (1S,4R,6R,7R)-3-methylene-1-oxo-7-phenylacetamido-cepham-4-carboxylate from (1S,6R,7R)-4-tert-butoxy-carbonyl-1-oxo-7-phenylacetamido-3-triphenylphosphoniomethyl-3-cephem bromide in the presence of stannous chloride dihydrate To a suspension of 750 mg (purity 84%; 0.84 mmoles) of (1S,6R,7R)-4- tert -butoxycarbonyl-1-oxo-7-phenylacetamido-3-triphenylphosphoniomethyl-3-cephem bromide (see Example 12) in 15 ml of tetrahydrofuran was added a suspension having a pH of 9 prepared by adding a 4 N sodium hydroxide solution to 385 mg of stannous chloride dihydrate in 5 ml of water. After heating the reaction mixture to 60°C and maintaining the pH at 9 with a 1 N sodium hydroxide solution the reaction mixture was stirred for 20 minutes and cooled down to room temperature. After adjusting the pH to 7 and pouring out the reaction mixture into 60 ml of ethyl acetate the layers were separated, the water layer extracted with 3 x 30 ml of ethyl acetate and the combined organic layers were washed with brine. The ethyl acetate solution, containing 96% of the title compound as determined by HPLC analysis, was concentrated to dryness. The residue was then dissolved in acetone and precipitated with diethylether and petroleum ether 40-60°C. Isolation by centrifugation, washing and drying gave 470 mg of the title compound with a purity of 68%. Yield 94%. Example 20 Preparation of tert-butyl (1S,4R,6R,7R)-3-methylene-1-oxo-7-phenylacetamido-cepham-4-carboxylate from (1S,6R,7R)-4-tert-butoxycarbonyl-1-oxo-phenylacetamido-3-triphenylphosphoniomethyl-3-cephem bromide A. The process according to Example 19 was repeated without addition of stannous chloride dihydrate. The reaction was carried out at 35°C for 2 hours while maintaining the pH at 9. The yield in solution was 39%. After isolation 200 mg of the title compound was obtained with a purity of 20%. Isolated yield: 12%. B. The process according to Example 19 was repeated but, instead of stannous chloride dihydrate, 400 mg of stannic bromide was used. The reaction was carried out at 35°C for 90 minutes. The yield in solution was 92%. After isolation 540 mg of the title compound was obtained with a purity of 55%. Isolated yield: 87%. C. The process according to Example 19 was repeated but, instead of stannous chloride dihydrate, 0.2 ml of stannic chloride was used. The reaction was carried out at 35°C for 2 hours. The yield in solution was 82%. After isolation 370 mg of the title compound was obtained with a purity of 70%. Isolated yield: 76%. D. The process according to Example 19 was repeated but, instead of stannous chloride dihydrate, 250 mg of disodium hydrogen phosphate was used. The reaction was carried out at 35°C for 2 hours. The yield in solution was 88%. After isolation 360 mg of the title compound was obtained with a purity of 77%. Isolated yield: 82%. E. The process according to Example 19 was repeated but, instead of stannous chloride dihydrate, 680 mg of a solid residue containing sodium stannite was used which was prepared in the following manner: a solution of 450 mg of stannous chloride dihydrate in 80 ml of a 0.1 N sodium hydroxide solution was concentrated to dryness giving 800 mg of the residue mentioned. After treating a suspension of the starting material in tetrahydrofuran with 680 mg of this residue at 40°C for 1 hour, 570 mg of the title compound was obtained with a purity of 48% after isolation. Isolated yield: 80%. F. The process according to Example 19 was repeated but, instead of stannous chloride, sodium stannite was used which was formed in situ by adding to the suspension of the cephem bromide compound (750 mg) in 15 ml of tetrahydrofuran a solution of 385 mg of stannous chloride dihydrate and 100 mg of sodium chloride in 5 ml of water, of which the pH was adjusted to 9 with a 4 N sodium hydroxide solution. After heating the reaction mixture up to 40°C and maintaining the pH at 9 with a 1 N sodium hydroxide solution, the reaction mixture was stirred for 90 minutes and cooled down to room temperature. After adjusting the pH to 7 and pouring out the reaction mixture into 60 ml of ethyl acetate the layers were separated, the water layer extracted with 3 x 30 ml of ethyl acetate and the combined organic layers were washed with brine. The ethyl acetate solution, containing 92% of the title compound as determined by HPLC analysis was concentrated to dryness. The residue was then dissolved in acetone and precipitated with diethylether and petroleum ether 40-60°C. Isolation by centrifugation, washing and drying gave 490 mg of the title compound with a purity of 61%. Yield 88%. G. The process according to Example 19 was repeated but, instead of stannous chloride dihydrate, 175 mg of sodium bromide was used. The reaction was carried out at 35°C for 2 hours. The yield in solution was 86%. After isolation 360 mg of the title compound was obtained with a purity of 51%. Isolated yield: 79%. H. The process according to Example 19 was repeated but, instead of stannous chloride dihydrate, 100 mg of sodium chloride was used. The reaction was carried out at 35°C for 90 minutes. The yield in solution was 86%. After isolation 610 mg of the title compound was obtained with a purity of 44%. Isolated yield: 79%. I. The process according to Example 19 was repeated but, instead of stannous chloride dihydrate, 230 mg of aluminium chloride was used. The reaction was carried out at 40°C for 90 minutes. The yield in solution was 83%. After isolation 600 mg of the title compound with a purity of 46%. Isolated yield: 81%. J. The process according to Example 19 was repeated but, instead of stannous chloride dihydrate, 0.14 ml of boron trichloride was used. The reaction was carried out at 35°C for 2 hours. The yield in solution was 77%. After isolation 370 mg of the title compound was obtained with a purity of 65%. Isolated yield: 67%. K. The process according to Example 19 was repeated but, instead of stannous chloride dihydrate, 0.14 ml of phosphorus trichloride was used. The reaction was carried out at 35°C for 2 hours. The yield in solution was 84%. After isolation 380 mg of the title compound was obtained with a purity of 73%. Isolated yield: 82%. L. The process according to Example 19 was repeated but, instead of stannous chloride dihydrate, 250 mg of zinc chloride was used. The reaction was carried out at 40°C for 90 minutes. The yield in solution, determined according to HPLC, was 88%. After isolation 531 mg of the title compound was obtained with a purity of 53%. Isolated yield: 82%. M. The process according to Example 19 was repeated but, instead of stannous chloride dihydrate, 435 mg of tellurium tetrachloride was used. The reaction was carried out at 30°C for 2 hours. After isolation 302 mg of the title compound was obtained with a purity of 48%. Yield: 57%. N. The process according to Example 19 was repeated but the added suspension of stannous chloride dihydrate was adjusted to pH 12 by adding a 4 N sodium hydroxide solution to 385 mg of stannous chloride dihydrate in 5 ml of water and stirring this mixture for 15 minutes. After heating the reaction mixture to 40°C and maintaining the pH at 10.5 with a 1 N sodium hydroxide solution, the reaction mixture was stirred for 45 minutes and poured out into ethyl acetate. After adjusting the pH to 7, separating the layers and evaporating the organic solvent to dryness the residue was treated with acetone, diethylether and petroleum ether 40-60°C. After collecting and drying the solid 500 mg of the title compound with a purity of 68% was obtained. Yield 100%. Example 21 Preparation of tert-butyl (1S,4R,6R,7R)-3-methylene-1-oxo-7-phenylacetamido-cepham-4-carboxylate from (1S,6R,7R)-4-tert-butoxycarbonyl-1-oxo-7-phenylacetamido-3-triphenylphosphoniomethyl-3-cephem bromide A. To a solution of 750 mg (purity 84%; 0.84 mmoles) of (1S,6R,7R)-4- tert -butoxycarbonyl-1-oxo-7-phenylacetamido-3-triphenylphosphoniomethyl-3-cephem bromide (see Example 12) in 15 ml of acetonitrile was added a suspension having a pH of 9, prepared by adding a 4 N sodium hydroxide solution to 385 mg of stannous chloride dihydrate in 5 ml of water. After heating the reaction mixture to 40°C and maintaining the pH at 9 with a 1 N sodium hydroxide solution to reaction mixture was stirred for 90 minutes and cooled down to room temperature. After centrifugation and extracting the residue with ethyl acetate (2x), the organic solution, containing 66% of the title compound as determined by HPLC analysis, was washed with brine, dried and concentrated to dryness. Then the residue was treated with acetone, diethylether and petroleum ether 40-60°C. After collecting and drying the solid 540 mg of the title compound with a purity of 35% was obtained. Yield 56%. B. To a solution of 1.5 g (purity 84%; 1.68 mmoles) of (1S,6R,7R)-4- tert -butoxycarbonyl-1-oxo-7-phenylacetamido-3-triphenylphosphoniomethyl-3-cephem bromide (see Example 12) in 30 ml of methylene chloride was added a suspension having a pH of 9 prepared by adding a 4 N sodium hydroxide solution to 770 mg of stannous chloride dihydrate in 10 ml of water. After heating the reaction mixture up to 40°C and maintaining the pH at 9 with a 1 N sodium hydroxide solution the reaction mixture was stirred for 90 minutes and poured out into ethyl acetate. After separation of the layers the organic layer was washed with brine and concentrated to dryness. Then the residue was dissolved in acetone and treated with petroleum ether. After collecting and drying the solid 1.08 g of the title compound with a purity of 21% was obtained. Yield 33%. Example 22 Preparation of tert-butyl (4R,6R,7R)-3-methylene-7-phenylacetamido-cepham-4-carboxylate from (6R,7R)-4-tert-butoxycarbonyl-7-phenylacetamido-3-triphenylphosphoniomethyl-3-cephem bromide To a stirred mixture of 729 mg (purity 79%; 0.79 mmoles) of (6R,7R)-4- tert -butoxycarbonyl-7-phenylacetamido-3-triphenylphosphoniomethyl-3-cephem bromide in 15 ml of tetrahydrofuran was added under nitrogen a solution of 385 mg of stannous chloride dihydrate in 5 ml of water, of which the pH was adjusted to 9. After raising the temperature to 40°C the pH was maintained at 9 - 9.5 for 90 minutes. The reaction mixture was poured out into ethyl acetate, the layers were separated and the amount of the title product formed was determined in the organic layer. Yield 95%. Example 23 Preparation of tert-butyl (4R,6R,7R)-3-methylene-7-phenylacetamido-cepham-4-carboxylate from tert-butyl (1S,6R,7R)-3-bromomethyl-1-oxo-7-phenylacetamido-3-cephem-4-carboxylate. To a solution of 5 g (purity 89%; 9.2 mmoles) of tert -butyl (1S,6R,7R)-3-bromomethyl-1-oxo-7-phenylacetamido-3-cephem-4-carboxylate in 150 ml of tetrahydrofuran was added 4 g (15.3 mmoles) of triphenylphosphine with stirring at 40°C. While stirring continuously at 40°C gradually a white precipitate, the phosphonium salt, was formed. After 2 hours the suspension was cooled down to 2°C and treated with 1.3 g (14.9 mmoles) of phosphorus trichloride. After stirring for 90 minutes at 2°C and adjusting the pH of the clear solution to 9.5 with a 4 N sodium hydroxide solution, the reaction mixture was stirred for 60 minutes at 30°C. After adjusting the pH to 6.8 with 1 N hydrochloric acid solution the reaction mixture was extracted twice with a total amount of 400 ml of ethyl acetate. Evaporation of the dried (magnesium sulphate) organic layer and purification of the organic residue by silica-gel chromatography (toluene/butyl acetate 4:1 (v/v)) gave two fractions. After evaporation to dryness and trituration with diethylether the second fraction gave 1.81 g (a yield of 50%) of the title product. IR-spectrum (KBr-disc; values in cm⁻¹): 3300, 1780, 17,42, 1670, 1550, 1382, 1340, 1280, 1160, 940, 735 and 710. PMR-spectrum (360 MHz; CDCl₃; δ-values in ppm; tetramethylsilane as an internal reference): 1.45 (s, 9H); 3.15 and 3.63 (2xd, 2H, J = 13.2 Hz); 3.61 (s, 1H); 4.92 and 5.17 (3s, 3H); 5.36 (d, 1H; J = 4.3 Hz); 5.64 (d, 1H; J = 4.3 Hz); 6.34 (d, 1H; J = 9.6 Hz); 7.30 (m, 5H). Example 24 Preparation of tert-butyl (1S,4R,6R,7R)-3-methylene-1-oxo-7-phenylacetamido-cepham-4-carboxylate from tert-butyl (1S,6R,7R)-3-bromomethyl-1-oxo-7-phenylacetamido-3-cephem-4-carboxylate To a clear solution of 3.85 g (purity 88%; 7.01 mmoles) of tert -butyl (1S,6R,7R)-3-bromomethyl-1-oxo-phenylacetamido-3-cephem-4-carboxylate in 150 ml of tetrahydrofuran was added 3.9 g (15 mmoles) of triphenylphosphine under nitrogen. After stirring for 3 hours at 40°C, a suspension having a pH of 9.5 prepared by adding a 4 N sodium hydroxide solution to 3.85 g of stannous chloride in 50 ml of water was added and stirring was continued for 90 minutes, the pH being maintained at 9.5 and the temperature at 40°C. After pouring out the reaction mixture into 200 ml of ethyl acetate, separation of the layers and extraction of the water layer (3x) with ethyl acetate, the combined organic layers were washed with brine. According to a quantitative HPLC-analysis the yield of the title compound in the ethyl acetate solution was 98%. After concentration of the solution in vacuo , treatment with decolourizing carbon and filter aid and evaporation of the solvent, the residue was dissolved in methylene chloride. Precipitation with diethylether and petroleum ether 40-60°C, filtration of the precipitate, washing and drying gave 6.31 g of the title product with a purity of 41.5%. The yield of the title product was 93%. Example 25 Preparation of tert-butyl (1S,4R,6R,7R)-3-methylene-1-oxo-7-phenylacetamido-cepham-4-carboxylate from tert-butyl (1S,6R,7R)-3-bromomethyl-7-[(2-bromo-2-phenyl)acetamido]-1-oxo-3-cephem-4-carboxylate To a suspension of 565 mg of tert -butyl (1S,6R,7R)-3-bromomethyl-7-[(2-bromo-2-phenyl)acetamido]-1-oxo-3-cephem-4-carboxylate in 15 ml of tetrahydrofuran was added 720 mg of triphenylphosphine under nitrogen. After stirring for 2 hours at 40°C a suspension having a pH of 9.5 prepared by adding a 4 N sodium hydroxide solution to 385 mg of stannous chloride dihydrate in 5 ml of water was added and stirring was continued for 90 minutes, the pH being maintained at 9.5 and the reaction temperature at 40°C. After pouring out the reaction mixture into ethyl acetate, separation of the layers and extraction of the water layer (3x) with ethyl acetate the combined organic layers were washed with brine. According to a quantitative HPLC-analysis the yield of the title compound in the ethyl acetate solution was 30%. After concentrating the solution to dryness the residue was dissolved in acetone. Precipitation with diethylether and petroleum ether 40-60°C, filtration of the precipitate, washing and drying gave 750 mg of the title product with a purity of 15%. The yield of the title product was 27%. Example 26 Preparation of tert-butyl (1S,4R,6R,7R)-3-methylene-1,1-dioxo-7-phenylacetamido-cepham-4-carboxylate from tert-butyl (6R,7R)-3-bromomethyl-1,1-dioxo-7-phenylacetamido-3-cephem-4-carboxylate To a solution of 240 mg (0.48 mmoles) of tert -butyl (6R,7R)-3-bromomethyl-1,1-dioxo-7-phenylacetamido-3-cephem-4-carboxylate (see Example 1) in 15 ml of tetrahydrofuran was added 262 mg (1 mmole) of triphenylphosphine. The reaction mixture was stirred at 40°C for 16 hours and then a suspension of 185 mg of stannous chloride dihydrate into 5 ml of water, of which the pH was adjusted to 9 with a 4 N sodium hydroxide solution, was added. After stirring for 90 minutes while maintaining the pH at 9 with a 1 N sodium hydroxide solution the pH was adjusted to 7. The reaction mixture was poured out into ethyl acetate. After washing the organic layer with water and brine the solvents were evaporated. The residue was dissolved in acetone and ether, and petroleum ether 40-60°C was added giving, after centrifugation and drying 190 mg of the title compound with a purity of 59%. Yield 60%. Example 27 Preparation of tert-butyl (1S,4R,6R,7R)-7-formamido-3-methylene-1-oxocepham-4-carboxylate from tert-butyl (1S,6R,7R)-3-bromomethyl-7-formamido-1-oxo-3-cephem-4-carboxylate To a stirred solution of 200 mg (0.5 mmoles) of tert -butyl (1S,6R,7R)-3-bromomethyl-7-formamido-1-oxo-3-cephem-4-carboxylate in 15 ml of tetrahydrofuran was added 400 mg of triphenylphosphine. After stirring for 5 hours at 40°C a suspension having a pH of 9 was prepared by adding a 4 N sodium hydroxide solution to 200 mg of stannous chloride dihydrate in 5 ml of water. Maintaining the pH at 9 with a 1 N sodium hydroxyde solution, the reaction mixture was stirred for 90 minutes at 40°C and cooled down to room temperature. After adjusting the pH at 7 and pouring out the reaction mixture into ethyl acetate the layers were separated, the water layer extracted with ethyl acetate (3x) and the combined organic layers washed with brine. Concentrating the ethyl acetate solution to dryness yielded 242 mg of the title product with a purity of 46% and containing 47% triphenylphosphine oxide. The yield was 52%. Example 28 Preparation of 4-nitrobenzyl (1S,4R,6R,7R)-7-formamido-3-methylene-1-oxo-3-cepham-4-carboxylate from 4-nitrobenzyl (1S,6R,7R)- 3-bromomethyl-7-formamido-1-oxo-3-cephem-4-carboxylate To a suspension, prepared by adding 530 mg (2.0 mmoles) of triphenylphosphine to 475 mg (purity 79%; 0.79 mmoles) of 4-nitrobenzyl (1S,6R,7R)-3-bromomethyl-7-formamido-1-oxo-3-cephem-4-carboxylate (see Example 5) in 15 ml of tetrahydrofuran and stirring for 6 hours to 40°C, was added a suspension of 385 mg of stannous chloride dihydrate in 5 ml of water, of which the pH was adjusted to 9.5 with a 4 N sodium hydroxide solution. The reaction mixture was stirred at 40°C for 90 minutes, while maintaining the pH at 9. Then after adjusting the pH to 7 the reaction mixture was poured out into ethyl acetate. The organic layer was washed with water (4x) and brine, combined with an ethyl acetate backwash of the aqueous phase and evaporated. The residue was dissolved in acetone and treated with ether and petroleum ether 40-60°C, giving after centrifugation the title product. Its structure was confirmed by PMR spectroscopy. PMR-spectrum (360 MHz; DMSO-d₆; tetramethyl-silane as an internal reference; δ-values in ppm): 3.82 and 3.95 (ABq, 2H; J = 14.4 Hz); 5.09 (d, 1H; J = 4.4 Hz); 5.34, 5.49 and 5.74 (3xs, 3H); 5.42 (s, 2H); 5.73 (dd, 1H; J = 4.4 and 10.2 Hz). Example 29 Preparation of methyl (1S,4R,6R,7R)-7-phenoxyacetamido-3-methylene-1-oxocepham-4-carboxylate from methyl (1S,6R,7R)-3-bromomethyl-1-oxo-7-phenoxyacetamido-3-cephem-4-carboxylate To a suspension, prepared by adding 390 mg (1.5 mmoles) of triphenylphosphine to 460 mg of methyl (1S,6R,7R)-3-bromomethyl-1-oxo-7-phenoxyacetamido-3-cephem-4-carboxylate (see Example 4) in 15 ml of tetrahydrofuran, was added a suspension of 385 mg of stannous chloride dihydrate in 5 ml of water, of which the pH was adjusted to 9.5 with a 4 N sodium hydroxide solution. The reaction mixture was stirred at 40°C for 90 minutes, while maintaining the pH at 9. Then after adjusting the pH to 7 the reaction mixture was poured out into ethyl acetate. The organic layer was washed with water (4x) and brine, combined with an ethyl acetate backwash of the aqueous phase and evaporated. The residue was dissolved in acetone and treated with ether and petroleum ether 40-60°C, giving after centrifugation the title product. Its structure was confirmed by PMR spectroscopy. PMR-spectrum (360 MHz; DMSO-d₆; tetramethyl-silane as an internal reference; δ-values in ppm): 3.70 (s, 3H); 3.79 and 3.93 (ABq, 2H; J = 14.2 Hz); 4.62 (s, 2H); 5.11 (d, 1H; J - 4.4 Hz); 5.34, 5.41 and 5.71 (3xs, 3H); 5.80 (dd, 1H; J = 4.4 and 10.2 Hz); 6.9 - 7.6 (m, 5H); 8.27 (d, 1H; J = 10.2 Hz). Example 30 Preparation of diphenylmethyl (1S,4R,6R,7R)-7-formamido-3-methylene-1-oxocepham-4-carboxylate from diphenylmethyl (1S,6R,7R)-3-bromomethyl-7-formamido-1-oxo-3-cephem-4-carboxylate To a mixture of 500 mg (purity 74%; 0.74 mmoles) of diphenylmethyl (1S,6R,7R)-3-bromomethyl-7-formamido-1-oxo-3-cephem-4-carboxylate (see U.S. Patent No. 3,769,277), 780 mg of triphenylphosphine and 15 ml of tetrahydrofuran, a suspension of 385 mg of stannous chloride dihydrate in 5 ml of water was added, of which the pH was adjusted to 9.5 with a 4 N sodium hydroxide solution. The reaction mixture was stirred at 40°C for 90 minutes, while maintaining the pH at 9. Then after adjusting the pH to 7 the reaction mixture was poured out into ethyl acetate (100 ml). The organic layer was washed with water, combined with an ethyl acetate backwash of the aqueous phase and evaporated. The residue was dissolved in acetone and treated with ether and petroleum ether 40-60°C, giving after centrifugation 550 mg of a mixture of the title product and triphenylphosphine oxide containing 37% of the title product. Yield 64%.

Claims: A process for the preparation of a 3-methylene cepham derivative of the general formula 1: wherein, A is an amino group or a protected amino group, B is a carboxy group or a protected carboxy group, or a salt thereof, and n is 0, 1 or 2, which comprises converting a 3-phosphoniomethyl-3-cephem derivative of formula 2: wherein A, B and n are each as defined above, Y is chloride or bromide, Z is Y or hydrogen, and R₁, R₂ and R₃ represent the same or different alkyl, aryl or aralkyl groups, into a compound of formula 1, in alkaline medium. Process according to Claim 1 which comprises adding a previously prepared suspension or solution of an inorganic salt in water which is adjusted to a pH above 7, to the 3-phosphoniomethyl-3-cephem derivative of formula 2. Process according to Claim 2 in which the inorganic salt is a sodium, potassium, aluminium, boron, phosphorus, zinc, tin or tellurium salt. Process according to Claim 2 or 3 in which the inorganic salt is stannous chloride or bromide, or a stannite. Process according to any one of Claims 1-4 in which the reaction is carried out at a pH above 9. A process for the preparation of a 3-phosphoniomethyl-3-cephem derivative of formula 2: wherein A is an amino group or a protected amino group, B is a carboxy group or a protected carboxy group or a salt thereof, Y is chloride or bromide, Z is Y or hydrogen, R₁, R₂ and R₃ represent the same or different alkyl, aryl or aralkyl groups, and n is 0, 1 or 2, which comprises reacting a 3-halomethyl-3-cephem compound of formula 3: wherein A, B, Y, Z and n are as defined above, with a phosphine compound of formula 4: wherein R₁, R₂ and R₃ are as defined above, followed, if desired, by converting the resulting compound into another compound of formula 2. Process according to Claim 6 in which a 3-phosphoniomethyl-3-cephem derivative of formula 2 is prepared wherein Z is hydrogen and Y is bromine. A process for the preparation of 3-methylene cepham derivatives of formula 1 as defined in Claim 1, which comprises reacting a 3-halomethyl-3-cephem compound of formula 3, as defined in Claim 6, with a phosphine compound of formula 4, as defined in Claim 6, and converting the resulting product into a compound of formula 1. Process according to any one of Claim 6-8 in which the phosphine compound is triphenyl phosphine. Process according to Claim 8 in which the resulting product is converted by adding a previously prepared suspension or solution of an inorganic salt in water which is adjusted to a pH above 7, to the reaction mixture. A 3-phosphoniomethyl-3-cephem derivative of formula 2, as defined in Claim 1.

Inventors: DE KONING JAN JACOBUS, VERWEIJ JAN, WITKAMP HENDRIK ADRIANUS, DE KONING, JAN JACOBUS, VERWEIJ, JAN, WITKAMP, HENDRIK ADRIANUS
Applicants: GIST BROCADES NV, GIST-BROCADES N.V.
Application year: 1988
Main classification: C07D501
IPC codes: C07F9, C07D501, A61K31