LU86402A1 - 7-AMINO-3-PROPENYLCEPHALOSPORANIC ACID AND ITS ESTERS - Google Patents

Description

7-AMIN0-3-PR0PENYLCEPHAL0SP0RANIC ACID AND ITS ESTERS

The subject of the present invention is new intermediates in the cephalosporin consisting of 7-amino-3-propenylcephalospora-5-nic acid and its esters.

Description of the Prior Art

UK Patent No. 1,342,241 issued January 3, 1974 (corresponding to U.S. Patents 3,769,277 and 3,994,884, issued October 30, 1973 and November 30, 1976) describes compound VI 10 but it does not 7ß-amino-3 - [(Z) -1-propen-1-yl] -3-cephem-4-carboxylic acid is not described therein as an intermediate in the preparation of this compound VI.

15 ^ CH-CONH-t-S * S N

2 J VI

COOH

20

U.S. Patent No. 4,409,214 published October 11, 1983, describes the preparation of compound VII via a Wittig reaction on 7-benzylidineamino-3-triphenyl-phosphoniomethylceph-3- diphenylmethyl em-4-carboxylate in the examples of preparations 38 and 39, but there is no description of the acid 7ß-amino-3 - [(Z) -l-propen-1-yl] - 3-cephem-4-carboxylic, nor another 3- (l-propen-l-yl) cephalosporin.

2 82 jXp-CH-CH,

COOH

United States Patent No. 4,110,534 issued April 29, 1978, particularly relates to the preparation of compounds 10 such as VI and VII by the Wittig reaction. Reference will be made in particular to columns 8, 9 and 49 (example 21).

H.O. House et al. Day. Org. Chem. 29, 3327-3333 (1964) studied the effects of solvents and additives including lithium salts on the proportions of cis- and trans-olefins in the Wittig reaction with aldehydes.

Summary of the invention

This invention relates to cephalosporin intermediates having the formula I, their acid addition salts and their metallic or synthetic salts, and the process for their preparation.

20 ντΥ5Ί N y ^ h-ch-ch3

25 COOR

In the compounds of formula I, the configuration of the 3-propenyl group is Z- or cis-.

R is a hydrogen atom or a conventional protecting group for the carboxy group. The last expression refers to the protective group of the species conventionally used for amino or carboxyl groups in the synthesis of cephalosporin compounds.

Suitable carboxyl protecting groups include aralkyl groups, such as benzyl, p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, and diphenylmethyl (benzhy-dryl) groups, alkyl groups such as t-butyl; haloalkyl groups 3 such as 2,2,2-trichloroethyl, alkenyl groups such as allyl, 2-chloroallyl, alkoxymethyl groups such as methoxymethyl, 2- (trimethylsilyl) ethyl, trimethylsilyl, tert.-butyldimethylsilyl, tert.-butyld1phenyls1lyl , and car-5-boxyl protecting groups described in the literature, for example, in the description of British Patent 1,399,086.

It is preferable to use as carboxyl protecting groups groups which are easily removed by acid treatment, in particular the benzhydryl or t-butyl groups. Acid addition salts and metal salts of the foregoing substance, where R is a hydrogen atom, are also covered by the present invention.

The Z- or ci s- configuration of the 3-propenyl group is a critical aspect of the compounds present. It is the characteristic which determines the interesting Gram-negative antibacterial properties of the 15 cephalosporin end products which are the subject of parent application No. 564 604.

Acid addition salts of synthetic use include salts of formula I with mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid, with organic sulfonic acids such as acid para-toluenesulfonic and with other acids known and used in the art relating to cephalosporin.

The substances of formula I in which R is hydrogen also form metal salts. Suitable synthetic metal salts include the sodium, potassium, calcium, magnesium, aluminum and zinc salts.

The preferred compounds of the invention are: 1. diphenylmethyl 7β-amino-3 - [(Z) -1-propen-1-yl] -3-cephem-4-carboxylate; 2. 7B-amino-3 - [(Z) -1-propen-1-yl] -3-cephem-4-carboxylate diphenylmethyl hydrochloride; 3. 7ß-amino-3 - [(Z) -1-propen-1-yl] -3-cephem-4-carboxy-late diphenylmethyl sulfate; 4. sodium 7B-amino-3 - [(Z) -1-propen-1-yl] -3-cephem-4-carboxylate; 5. potassium 7β-amino-3 - [(Z) -1-propen-1-yl] -3-cephem-4-carboxylate; 6. 7ß-amino-3 - [(Z) -l-propen-1-yl] -3-cephem-4-carboxylic acid.

4

Detailed description of the invention

Furthermore, this invention relates to the process for the preparation of the compounds of formula I. The preferred processes are shown in reaction schemes 1 and 2.

In reaction scheme 1, the diphenylmethyl group is shown as the preferred carboxy protecting group. Those skilled in the art will understand that other protecting groups for the carboxyl, well known in the art, can be used.

In the Wittig reaction of compound III with acetaldehyde, it has been found that the addition of a suitable lithium halide, such as lithium chloride, lithium bromide or lithium iodide, improves the yield and the Z / E proportion of the isomer of the reaction product 11a. The reaction is preferably carried out with 5 to 15 equivalents, preferably 10 equivalents of lithium bromide.

Methylene chloride is the preferred reaction medium; it can preferably be combined with a cosolvent such as dimethylformamide or isopropanol, in minor proportions of approximately 1/10 to 1/3 by volume per part of methylene chloride.

Reaction temperatures in the range of -10 ° C to + 25 ° C are suitable, temperatures of 0 ° to 25 ° C being preferred.

The Wittig reaction product (11a) is extracted into a suitable organic solvent such as ethyl acetate, and the extract is treated with the Girard T reagent to yield the compound 7-amino-ceph-3- th of the present invention (la). Reference may be made to method 3.

Subsequent treatment of (la) with trifluoroacetic acid (TFA) produces 7p-amino-3 - [(Z) -l-propen-l-yl] -3-cephem-4-carboxyüque acid (Ib, process 7) in the ratio of Z / E = 9/1. The acylation of (Ib) by p-hydroxyphenylglycine according to a conventional method ut111-30 sant acid chloride or an activated ester produces cephalosporin V orally active from US Serial Application No. 564,604.

Alternatively, the acylation of the ester (la) of 7p-amino-3-propen-1-yl-cephalosporin with p-hydroxyphenylglycine blocked by tert.-butoxycarbonyl in the presence of DCC (dicyclohexylcarbodiimide) 35 deblocking with TFA (trifluoroacetic acid) also produces cephalosporin V.

5

Diagram 1 Diagram 2

PHCH = N- | - | ^ SV> | PhCH2CONH- | S N

5 ^ j — Nv ^ J-CH-PPh3 J ~ -NvJ ^ H-PPh3 COOCHPh- III O '2 COOCHPh2

Method 2 _ VIII

^ Process 10 r \ · * 10 PhCH ^ N ^ _ \ | | PhCH-CONEH- * SS N.

J — Nv ✓> -CH = CH-CH, I I

// γ- J / -n ^ Lch-chch, COOCHPh2 0 COOCHPh, lia 2 15 \ Method 3 / Ix \. / Process 11 v-j-rSN) ^ // CH-CHrCH3 20 COOCHPh-

Method 5, 2 V ^ Method 7, or 8

H ° ^) - ÇHCONH-j - „» ^ SN

25 NHB0C CH * CH-CH3 J-Mx ^ LcH-CH-CHg

IV COOCHPh 2 COOH

[Method 6 \ X

30 1 y__ ^ Process 9 H X— / CHCONHr-j-f'S N.

NH2 J — Nv ^ L-CH »CH-CH3 y

COOH

35 BMY-28100

Description of specific implementations

The following abbreviations are used in the examples above and have the meanings indicated below: 6

Ph = phenyl BOC = -COOC (CH3) 3 DCC = dlcyclohexylcarbodiimide TFA = trifluoroacetic acid 5 EtOAc = ethyl acetate DMF = dimethylformamide.

PROCESS 1

7-Benzylideneamino-3-triphen chloride, diphenylmethyl methylphosphoniomethyl-3-cephem-4-carboxylate 10 A suspension of diphenylmethyl 7-amino-3-chloromethyl-3-cephem-4-carboxylate (200 g, 0 , 44 mol) in methylene chloride (940 ml), IN sodium hydroxide solution (440 ml) is added at room temperature. The mixture is stirred for 10 minutes and the organic layer is separated. To this organic phase, magnesium sulfate (75 g) and benzaldehyde (51 g, 0.48 mole) are added and the mixture is left for 3 hours at room temperature. The reaction mixture is filtered and the insolubles are washed with methylene chloride (200 ml). To the combined filtrate with the washes with methylene chloride, triphenylphosphine (126 g, 0.48 mole) is added. The mixture is concentrated to about 400 ml, under reduced pressure, and left for 4 days. The resulting viscous oil is diluted with ethyl acetate (1 liter) and triturated to separate the compound indicated above, which is in the form of a pale yellow crystalline powder which is obtained by filtration and dried under vacuum . Yield: 322 g (96¾). Melting point: 185-190 ° C (decomposition).

IR: vmax 1780 ’172 °’ 1630 UV: X ^ C12 nm U) 260 (24100).

30 PROCEDURE 2 7-benzylideneamino-3 - [(triphen, ylphosphoranylldene) methyl] -3-cephem-4-carboxylate of diphenylmethyl (III) 33 A mixture of 7-benzylideneamino-3-triphenylphosphonio-methyl-3-cephem chloride Diphenylmethyl 4-carboxylate (322 g, 0.42 mole) and 5N sodium carbonate (252 ml) in methylene chloride (1.6 liters) is stirred vigorously for 15 minutes at room temperature. The organic layer is separated, dried over magnesium sulfate and concentrated to about 500 ml by volume. The concentrate is diluted with acetone (1 liter), with stirring, to give a light yellow crystalline powder which is obtained by filtration to give 237 g 5 (78%) of 3, melting at 195-198 ° C (decomposition ).

IR: vmax 1770 ’1620 * UV: Xmf2 nm 254 (23000)” 389 (22000).

10 NMR: 6CDC13 ppm 2.56 and 3.16 (2H, Abq), 5.00 (1H, d, I * 4 Hz), 5.23 (1H, d, I = 4 Hz), 5.47 ( 1H, d, I = 22 Hz), 6.95 (1H, s), 7.2-7.8 (30H, m), 8.55 (1H, s).

PROCESS 3 15 7-amino-3-C (Z) -1-propen-1-yl] -3-cephem-4-carboxylate hydrochloride (hydrochloride la) To a cold solution of lithium bromide (19 g, 216 mmol) in a mixed solvent of dry dimethylformamide (100 ml) and methylene chloride (300 ml), acetaldehyde (20 ml, 360 mmol) and 7-benzylideneamino-3 - [(triphenylphosphoranylidene) methyl are added ] -3-cephem- 4-diphenylmethyl (III) carboxylate (15 g, 20 mmol) at -5 ° C. The mixture is kept for 20 hours at -5 ° -10 ° C, then 5 hours at room temperature. The resulting light brown solution is concentrated to about 100 ml by volume in vacuo and added to a two-layer solvent of ethyl acetate (400 ml) and water (400 ml). The upper layer is separated and diluted with Isopropyl ether (400 ml). Silica gel (Wako gel C-100, 40 g) is added to the mixture. The mixture is stirred for 5 minutes then filtered through a layer of diatoms. The insolubles are washed with a mixed solvent consisting of ethyl acetate and isopropyl ether, in the proportions 1/1 (200 ml). The filtrate is and the combined washing waters are concentrated to a volume of approximately 400 ml. A 0.5M solution of Girard's reagent T in methanol (60 ml) and acetic acid (6 ml) is added to the above concentrate and the mixture is stirred for about 15 minutes at room temperature. The mixture is evaporated to a volume of 200 ml, washed with water (200 ml), with a saturated solution of sodium bicarbonate (3x20 ml) and with salt water (20 ml) successively, dried over sulphate magnesium, treated with charcoal and concentrated to approximately 50 ml. At ! 8 concentrate, normal hydrochloric acid in methanol (40 ml) is added at room temperature and left for about 15 minutes. The mixture is evaporated to about 30 ml and diluted by adding ether (300 ml). The precipitate is collected by filtration and dried over P205 to give 7.9 g of a light yellow powder. A solution of the powder (7.3 g) in a mixed solvent consisting of methanol (80 ml) and ethyl acetate (80 ml) is treated with charcoal, concentrated to approximately 100 ml, seeded with crystallized hydrochloride of the title compound, diluted slowly with ether (80 ml) and stirred for 1 hour. The separated colorless crystals are collected by filtration and dried over P20g under vacuum, to give 6.3 g (75¾) of the title compound. This product is a mixture of the Z and E isomers with reference to the propenyl group at position 3 (Z / E = 9/1 by HPLC) (Lichrosorb RP-18, 80¾ methanol. Phosphate buffer S pH 7.2, 254 nm, 1 ml / min.).

15 iR: cm'1 2850, 1785, 1725.

uv: c ™ ιυ287 <ΐ73> · 20 NMR: iDMS0_d6 ppm 1.47 (27 / 10H, d-d, I = 7.2 Hz, -CHCH3, cis); 1.74 (3/10 H, d, I = 7 Hz, -CHCH3> trans); 3.47 and 3.8 (for each 1H, d, I = 16 Hz); 5.13 (1H, d, 1 = 4.5Hz, 6-H); 5.23 (1H, d, I = 4.5Hz, 7-H); 5.62 (1H, d-q, I = 10 and 7 Hz, 3-CH = CH); 6.24 (1H, d-d, I = 10 and 2 Hz, 3-CH); 6.81 (1H, s, CHPH2); 7.35 25 (10H, m, Ph-H).

PROCESS 4 7-amino-3 - [(Z) -l-propen-1-yl] -3-diphenylmethyl-4-carboxylate (la) To a stirred suspension of 7-amino-3 hydrochloride - [(Z ) -l-30 propen-l-yl] -3-cephem-4-diphenylmethyl carboxylate (5 g, 11.3 mmo-les) in water (20 ml) and ethyl acid (40 ml ), sodium bicarbonate is added until the pH of the mixture reaches 8. The organic layer is washed with a saturated aqueous solution of sodium chloride (5 ml), dried over magnesium sulfate and concentrated to one volume. about 20 ml. The resulting solution is diluted with isopropyl ether (10 ml) and seeded with the crystallized compound. An additional amount of isopropyl ether (30 ml) is added slowly to the mixture with stirring. After 15 minutes, the separate colorless crystals 9 are collected by filtration, washed with isopropyl ether (10 ml) and dried over PgOg under vacuum, to give 4.3 g (94¾) of the title compound (Z / E = 9/1 by HPLC) (Lichrosorb RP-18, 80% methanol, phosphate buffer of pH 7.2, 254 nm, 1 ml / ml.).

5 IR: vmax cm-1 345 ° * 1765> 1730 UV: λ ™ nm (ε} *) 289 (185). max 1 cm 10 NMR: 6CDC13 ppm 1.43 (3H, d-d, I = 2 and 7 Hz, CH = CHCH3); 1.66 (2H, br, s, disappears in the presence of DgO, NH ^); 3.23 and 3.55 (for each 1H, d, I = 17 Hz, 2-H); 4.73 (1H, d, I = 4.5Hz, 6-H); 4.96 (1H, d, I = 4.5Hz, 7-H); 5.46 (1H, d-q, I = 10 and 7 Hz, 3-CH = CH); 6.06 (1H, br, d, I = 10 Hz, 3-CH); 6.94 (1H, s, 15 CHPh2); 7.3 (10H, m, Ph-H).

PROCESS 5 7 - [(D) -a- (t-butoxycarbonylamino) -a- (4-hydroxyphenyl) acetamido] -3 - [(Z) -l - propen-1-yl] -3-cephem-4- dlphenylmethyl (IV) carboxylate

A mixture of 7-amino-3 - [(Z) -l-propen-1-yl] -3-cephem-4-carboxylate 20 of diphenylmethyl (la) (4.2 g, 10.4 mmol), (D) -a- (t-butoxy-carbonylamino) -ct- (4-hydroxyphenyl) acetic acid (3.3 g, 12.5 mmol) and DCC (2.6 g, 12.5 mmol) in the ethyl acetate (104 ml) is stirred for 1.5 hours at room temperature. The mixture is filtered and the insolubles are washed with acetic acid (20 ml). The filtrate and the washings are combined and washed with a saturated sodium bicarbonate solution (3 × 5 ml), brine (5 ml), 10% hydrochloric acid (5 ml) and water. salted successively, then dried over magnesium sulfate treated with charcoal and filtered. The filtrate is concentrated to approximately 10 ml and diluted with normal heptane (20 ml). The precipitate is collected by filtration and dried over PgOg under vacuum. 7.8 g (90% purity, quantitatively by weight) are thus obtained in the form of a colorless powder (Z / E = 9/1 according to HPLC) (Lichrosorb RP-18, 80% methanol, phosphate buffer pH 7.2, 254 nm, 1 ml / min.).

35 IR: cm'1 3400, 1790, 1720, 1690.

UV: xmaxH nra (ε l% cm '278 (113) * 289 (115)' 295 (95) -! 5 10 NMR: 6CDC13 ppm 1,3-1,45 (12H, m, BOC-H and = CH -CH3); 3.08 and 3.33 (for each 1H, d, I = 18 Hz, 2-H); 4.92 (1H, d, I = 4.5 Hz, 6-H); 5, 06 (1H, d, I "* 6 Hz, disappears in the presence of D ,, 0, CJHN); 5.5 (1H, dq, I = 10 and 7 Hz, 3-CH * CH); 5.68 ( 1H, dd, I = 4.5 and 5 8 Hz, d, I = 4.5 Hz, disappears in the presence of D20, 7-H); 6.01 (1H, d, I = 10 Hz, 3-CH ); 6.65 and 7.08 (for each 2H, d, I = 8 Hz, H0- ^ 3-); 6.71 (1H, d, I = 8 Hz, disappears in the presence of 10 D20 , 7-NH2); 6.88 (1H, s, CHPh2); 7.3 (10H, m, Ph-H).

PROCESS 6 BMY-28100; acid 7 - [(D) -2-amino-2- (4-h.ydrox.yphenyl) acetamido] -3- (propen- 1-yl) -3-cephem-4-carbox, yl ic (V)

A mixture of 7 - [(D) -a- (t-butoxycarbonylamino) -a- (4-hydroxyphenyl) -15 acetam1do] -3-C (Z) -l-propen-1-yl] -3-cephem- Diphenyl-methyl (IV) 4-carboxylate which is prepared in process 5 (90% purity, 7.7 g, 10.6 mmol), anisole (7.7 ml) and trifluoroacetic acid (77 ml), is stirred for 1 hour at room temperature. The mixture is concentrated in vacuo. Toluene (50 ml) is added to the concentrate and the mixture is evaporated in vacuo. 200 ml of ether are added to the residual oil. The separated solid is collected by filtration, washed with ether (20 ml) and dried over potassium hydroxide under vacuum to give 5.3 g of trifluoroacetic acid salt (TFA) of BMY-28100. The salt (5.3 g) is dissolved in water (100 ml), treated with charcoal and placed on a column 25 filled with Diaion HP-20 (0.6 liter). The column is washed with water (4 liters) and eluted with 40% aqueous methanol. The methanolic fractions (1.7 liters) containing the desired product are collected and evaporated to a volume of about 20 ml. The concentrate is diluted slowly with acetone (100 ml). The separated colorless crystalline powder is collected by filtration, washed with acetone (20 ml) and dried over P20g under vacuum to give 4 g (97%) of BMY-28100 (Z / E = 9/1, Zwitterion) (Lichrosorb RP-18, 20% methanol, phosphate buffer of pH 7.2, 254 nm, 1 ml / min.).

PROCESS 7 35 7-amino-3 - [(Z) -l-propen-1-yl] -ceph-3-em-4-carboxylic acid (Ib) To a stirred solution of 260 ml of anisole and 1, 38 1 of trifluoroacetic acid (TFA) cooled to 0 ° C., 149.7 g (0.338 mol) of 7-amino-3 hydrochloride - [(Z) -l-propen-1-yl3-3-cephem are added -4-carboxylate 11 "of diphenylmethyl (0.338 mol, method 3 or 11). The resulting suspension is then stirred at room temperature for 1 hour. Most of the excess trifluoroacetic acid is removed in vacuo by evaporation on a rotary device. The residual supernatant solution is decanted and the residual suspension is triturated with 1.5 liters of anhydrous ether for 1 hour. The crystalline product is filtered and dried over PgOg to give 87.24 g of Ib, which is trifluoro-roacetate. These 87.24 g of trifluoroacetate are suspended and stirred in 900 ml of water (pH of the order of 2.5). The mixture is cooled 10 to + 5 ° C. and then adjusted to pH 0.6 with 12N hydrochloric acid. The yellow solution is treated with charcoal and the suspension is filtered through diatoms. The resulting solution is cooled to + 5 ° C and the pH is adjusted to 2 with 20¾ sodium hydroxide. The suspension is kept for 1 hour in a refrigerator to allow crystallization. The crystals are collected, washed with 800 ml of water, 800 ml of acetone and dried under vacuum at room temperature. The yield is 69.4 g (i.e. 85.5%). The product contains 9.7¾ of trans isomer (determined by an HPLC column of the RP-18 MERCK type, with a phosphate buffer ^ (NH ^ JPO ^, 0.1 mole 95 ml + CHgCN 5 ml, detected at 290 nm) .

20 PROCESS 8

7-amino-3 - [(Z) -l-propen-l-, y1] -3-cephem-4-carboxylic acid, yl ic (Ib)

A solution of compound III phosphoranyl prepared according to method 2 (50 g, 68.7 mmol) in methylene chloride (500 ml) is mixed with a solution of lithium bromide (29.8 g, 343 mmol) in 25 ml Anhydrous DMF (170 ml) containing a small amount of methylene chloride (10 ml) then with anhydrous acetaldehyde (39 ml, 687 mmol), prepared from paraldehyde and toluenesulfonic acid by distillation according to the NL process Drake and G.B. Cooke, Org. Syn.

Collar. Flight. II, p. 407. The mixture is placed in a sealed container and kept at 20 ° C for 2 days. The reaction mixture is then evaporated, the residual liquid is diluted with ethyl acetate (800 ml), washed with water (3x300 ml) and with a saturated solution of sodium chloride (300 ml), then evaporated to give the blocked 3-propenyl derivative 11a as a foamy solid (34 g), which is used for the next reaction without further purification.

The crude product 11a obtained above is treated with 98¾ formic acid (35 ml) and concentrated hydrochloric acid (17 ml, 206 mmol) at room temperature for 1 hour. To the mix! 12 reaction is added water (350 ml) to separate an oily layer which is extracted with ethyl acetate (3x100 ml). The pH of the aqueous layer is adjusted to about 3 with 4N sodium hydroxide (about 65 ml) with stirring to give a crystalline solid which is collected by filtration and washed with water (50 ml) to give the title compound (Ib, 9.7 g, 59%). The HPLC (Lichrosorb RP-18, 4x300 mm, MeOH: phosphate buffer (pH 7) - 15/85) shows that this product is an 83/17 mixture of the Z and E isomers, relating to the double bond of group 3- propenyl. Melting point: 200 ° C (decomposition).

1 ° IR: (KBr) in cm "1 3420, 1805, 1620.

IDdX

UV: (phosphate buffer pH 7) in nm (ε) 283 (8900).

illaX

NMR: 6 (D ^ O = NaHCOg) in ppm 1.69 and 1.88 (3H, for each d, I = 6.0 Hz, Z and E of -CH = CH-CH3); 3.38 and 3.72 (2H, Abq, I = 17 Hz, H-2); 5.18 (1H, d, Ig y = 5.0 Hz, H-6); 5.51 (1H, d, 15H-7); about 5.8 (1H, m, -CH = CH-CH3) and 6.06 (1H, d, I = 11 Hz, -CH = CH-CH3).

Upon analysis, it can be seen that the product obtained has the formula:

C10H12N2 ° 3S

and we get the following values:

20 C H N S

- calculated ........ 49.99 5.03 11.66 13.34 - found ......... 50.20 4.94 10.93 12.82 PROCESS 9

Acid 7 - [(D) -2-amino-2- (4-hydroxypheny1) acetamido] -3 - [(Z) -l-propen-25 1-yl] -3-cephem-4-carboxylic acid (V)

Dimethylaniline (1.7 ml, 13.1) is successively added to a suspension of Ib prepared according to method 8 (1.58 g, 6.56 mmol) in methylene chloride (16 ml) mmol), trimethylsilyl chloride (2.1 ml, 16.4 mmol) and triethyl-amine (TEA, 2.3 ml, 16.4 mmol). The mixture is stirred at room temperature for 30 minutes. To the mixture, Dp-hydroxyphenylglycyl chloride hydrochloride (1.46 g, 6.56 mmol) is added per portion, with stirring, and the reaction is followed by HPLC (Lichrosorb RP-18, 4x300 mm, Methanol: phosphate buffer pH 7 = 25/75). Additional glycyl chloride is added to the mixture three times at 15 minute intervals (291 mg each time) to complete the acylation. After addition of anhydrous methanol (2 ml) containing anhydrous dimethylformamide (0.1 ml), the resulting clear solution is [t 13 neutralized with TEA (3.2 ml) at pH 6 and then diluted with methylene chloride (30 ml) to give a precipitate, which is collected by filtration and washed with methylene chloride (10 ml) to give the title compound as solvent with dimethylformamide (2.39 g, 5 yield 94¾. Degree of purity 50¾ approx; Z / E = 47/12 according to the HPLC). PROCESS 10 7-Phenylacetamido-3 - [(Z) -propen-1-yl] -ceph-3-em-4-carboxylate of diphenylmethyl (IX) 10 - CH-CON. / Sv

\ - / * η— (η CH ^ CHO

M ^ CCl, / CH, OH ^ θ '/ (Ph) 3 4 3

COODPM

15 MW “758.8 2o‘ 0J “NyKj

1 MW "524.6 COODPM

A stirred solution of 18 l of carbon tetrachloride, 1.8 l of methanol and 12 g of p-benzoyl-benzoic acid is cooled to 8 ° C, 970 ml of acetaldehyde are added. The temperature of the resulting solution is + 14 ° C. Five minutes, 588 g (0.7749 mole) of 7-phenylacetamido-3 - [(triphenylphoranyl idene) methyl] -3-cephem-4-carboxylate of phenyl-methyl are added. The cooling bath is removed and the mixture is vigorously stirred for 4 hours, at 35 ° C, protected from light, under nitrogen until complete dissolution of the phosphorane occurs.

The resulting solution is concentrated in vacuo and the residue is dissolved in 2 liters of ethanol, then the solution is concentrated in vacuo to obtain a semi-crystallized residue which is suspended in 3 liters of ethanol.

The mixture is stirred for 2 hours at + 5 ° C and left overnight, crystals are collected twice, washed with ethanol and dried in vacuo at room temperature. The yield is 191 g (47¾) and the melting point: 124-128 ° C it contains 7.5% of 14 the trans isomer (determined by HPLC with Lichrosorb column of silicon 60 of 5 pm Merck elution with toluene 85% and ethyl acetate 15%).

PROCEDURE 11 5 7-amino-3 - [(Z) -propen-1-yl] -ceph-3-em-4-carboxylate hydrochloride (la) To a stirred solution of 159.7 g (0.767 mole) of PCI ^ in 2.8 liters of methylene chloride, 56.7 ml (0.700 mole) of pyri-dine in 280 ml of methylene chloride are added over a period of 20 minutes. 10 Under a nitrogen atmosphere, the suspension is cooled to 2 ° C while 256 g of IX, prepared by method 10, (0.488 mole) are added. The mixture is stirred for 40 minutes and the resulting suspension is quickly poured into a vigorously stirred solution of 1.4 liters of methylene chloride and 209 ml (2.33 moles) of 1,3-butanediol at 15 -20 ° C , so that the temperature does not rise above -20 ° C. The cooling bath is removed and, 40 minutes later, the temperature rises to 10 ° C and is maintained there for 35 minutes. Water (1 1) is added and stirring continued for 5 minutes, after which the layers are allowed to separate. The organic layer is washed with 600 ml of 2N hydrochloric acid and then with 400 ml of a saturated salt solution. The combined aqueous extracts are again washed with 2x600 ml of methylene chloride and then combined with the original methylene chloride extracts.

The solution is dried over anhydrous magnesium sulfate. The magnesium sulfate suspension is filtered and the magnesium sulfate is washed with 2 × 500 ml of methylene chloride. The combined filtrates are concentrated in vacuo on a rotary evaporator to a volume of 2.4 l, then diluted with 2.5 liters of ethyl acetate. The solution is concentrated again to a volume of approximately 1.3 liters. The resulting crystal suspension is filtered, washed with 3x300 ml of ethyl acetate. After drying in air and under vacuum over PgOg, 149.8 g of the title compound are obtained in the form of beige crystals. The yield is 69.3%.

Claims (13)

15 1. Compound of formula: 5 ΗζΝη — S 1— N CH »CH-CH3 QI COOR •% 10 in which: the 3-propenyl group has the Z configuration, and R is a hydrogen atom or a protecting group classic carboxyl, and the addition salts of acids and metal salts of said product in which R is hydrogen. 2. The compound according to claim 1, in which R is a group chosen from hydrogen, methoxymethyl, 2,2,2-trichloro-ethyl, 2- (trimethylsilyl) ethyl, t-butyl, benzyl , diphenylmethyl, o-nitrobenzyl, p-nitrobenzyl, trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, Vallyl and 2-chloroallyl and its acid addition salts. 3. The compound according to claim 2, in which the acid addition salts are chosen from the group comprising the hydrochloride, the sulphate, the para-toluenesulphate and the phosphate. 4. The compound according to claim 1, wherein the metal salt is a sodium, potassium, calcium or aluminum salt. 5. The compound according to claim 2 which is diphenylmethyl 7β-amino-3- [(Z) -1-propen-1-yl] -3-cephem-4-carboxylate and its hydrochloride. 6. The compound according to claim 2 which is 7β-amino-3 - [(Z) -1-propen-1-yl] -3-cephem-4-carboxylic acid and its hydrochloride. 7. The compound according to claim 4 which is sodium 7β-amino- 3 - [(Z) -1-propen-1-yl] -3-cephem-4-carboxylate. 8. A process for the preparation of the compound according to claim 1, which comprises the reaction between the intermediate of formula: t 16 "J, -N ^^ J-CH-PPhj 5 COOR wherein: R has the same meaning as in claim 1; 10 Ph is the phenyl group with acetaldehyde, in an inert organic reaction medium comprising dichloromethane, Ν, Ν'-dimethylformamide, isopropanol or a mixture thereof, at a reaction temperature between 0 ° C and 25 ° C, to provide a compound of formula: 15 <r ~ H "C HC H 3 C00R and then comprising removing the benzylidene group or both benzylidene groups and the carboxy protecting group, and if desired, separating the 3- (Z) and 3- (E) isomers to provide the compound of formula: h ^ -t — r ^ J- Nsy ^ -CH “CH" CH3 COOH wherein R has the same meaning as in claim 1. 9. The process according to claim 8, wherein the reaction with acetaldehyde is carried out in the presence of a lithium halide. "* 17 Αν 10. The method of claim 9, wherein the lithium halide is lithium chloride, lithium bromide or lithium iodide. 11. The method of claim 9, wherein the lithium halide is lithium bromide.