CH671399A5 - - Google Patents

Description

The invention relates to cephalosporin intermediates and a process for their preparation.

GB Patent 1,342,241 (published January 3, 1974; corresponds to U.S. Patents 3,769,277 and 3,994,884) 45 describes Compound VI shown below

wherein R has the meanings given in claim 1 and Ph represents a phenyl group, in an inert organic reaction medium with acetaldehyde at a reaction temperature of -10 to 25 ° C to a compound of the general formula

CH = CH-CH,

COOR

reacted, then removed the benzylidene group, and the 3- (Z) - and 3- (E) -isomers separated.

8. A process for the preparation of the compounds according to claim 1, in which R represents a hydrogen atom, characterized in that an intermediate compound of the general formula

50

-CH2CONH

CH = CH-CH_

COOH

VI

55

However, it is not described that 7β-amino-3 - [(Z) -1-propen-l-yl)] - 3-cephem-4-carboxylic acid was used as an intermediate for the preparation of the compound mentioned.

US Pat. No. 4,409,214 describes the preparation of compound VII shown below via the Wittig reaction with diphenylmethyl-7-benzylideneamino-3-triphenylphosphonium methylceph-3-em-4-carboxylate in Preparation 65, Examples 38 and 39. However, there is no description of the 7β-amino-3 - [(Z) -l-propen-l-yl] - 3-cephem-4-carboxylic acid or any other 3- (l-propen-l-yl ) -cephalo-sporin compound.

3rd

671 399

CH = CH,

VII 5

COOH

U.S. Patent 4,110,534 is particularly concerned with the preparation of compounds e.g. VI and VII shown above, on the Wittig reaction, cf. in particular columns 8, 9 and 49 (example 21).

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

The invention relates to cephalosporin intermediate compounds of the general formula I, the synthetically useful acid addition and metal salts thereof and processes for the preparation of these compounds.

CH = CH-CH.

10th

15

20th

25th

COOR

30th

The 3-propenyl group of the compounds of the general formula I according to the invention have a Z or cis configuration. R represents a hydrogen atom or a conventional carboxyl protecting group. The latter group denotes protective groups which are usually used in the synthesis of cephalo-sporin compounds for amino or carboxyl groups. Suitable carboxyl protecting groups are aralkyl groups such as benzyl, p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl and diphenylmethyl (benzhydryl), alkyl groups such as t-butyl, haloalkyl groups such as 2,2,2-trichloroethyl, alkenyl groups such as Allyl and 2-chloroallyl, alkoxymethyl groups such as methoxymethyl, 2- (trimethylsilyl) ethyl, tri-methylsilyl, tert-butyldimethylsilyl and tert-butyldiphenyl-silyl, and other carboxyl protecting groups described in the literature, for example in GB-PS 1 399 086. Carboxyl protecting groups which can be easily removed with the aid of an acid are preferably used. These include in particular benzhydryl and t-butyl groups. The acid addition salts and the metal salts of those compounds in which R represents a hydrogen atom are also included in the invention.

The Z or cis configuration of the 3-propenyl group is of essential importance for the compounds according to the invention. This is a feature that determines the beneficial gram-negative antibacterial properties of the cephalo-sporin end products.

The synthetically useful acid addition salts include the salts of the compounds of the general formula I with mineral acids, such as hydrochloric acid, sulfuric acid and phosphoric acid, with organic sulfonic acids, such as p-

35

40

45

50

55

60

Toluenesulfonic acid, and other acids that are known and used in cephalo-sporine chemistry.

Those compounds of the general formula I in which R represents a hydrogen atom also form metal salts. Metal salts suitable for synthetic purposes are the sodium, potassium, calcium, magnesium, aluminum and zinc salts.

The most preferred compounds according to the invention are the following:

1. Diphenylmethyl-7ß-amino-3- [(Z) -l-propen-1-yl] -3-ce-phem-4-carboxylate.

2. Diphenylmethyl-7ß-amino-3 - [(Z) -l-propen-l-yl] - 3-ce-phem-4-carboxylate hydrochloride.

3. Diphenylmethyl-7ß-amino-3 - [(Z) -l-propen-l-yl] - 3-ce-phem-4-carboxylate sulfate.

4. Sodium 7β-amino-3 - [(Z) -1-propen-1-yl] -3-cephem-4-carboxylate.

5. Potassium 7ß-amino-3 - [(Z) -l-propen-l-yl] - 3-cephem-4-carboxylate.

6. 7β-amino-3 - [(Z) -l-propen-1-yl] - 3-cephem-4-carboxylic acid.

The invention furthermore relates to processes for the preparation of the compounds of the general formula I. Preferred procedures are shown in reaction schemes 1 and 2.

In the reaction shown in Reaction Scheme 1, the diphenylmethyl group is used as the preferred carboxyl protecting group. Of course, other carboxyl protecting groups which are well known to the person skilled in the art can also be used.

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

Methylene chloride is the preferred reaction medium, which preferably contains a co-solvent such as dimethylformamide or isopropanol in minor proportions of about 1/10 to 1/3 parts by volume per part by volume of methylene chloride. The reaction temperatures are from -10 ° C to +25 ° C and preferably 0 ° C to 25 ° C. The Wittig product IIa is extracted into a suitable organic solvent, such as ethyl acetate. The extract is treated with Girard's reagent T to give the 7-amino-ceph-3-em compound Ia of the present invention, cf. Implementation 3 in the above scheme. Then Ia is treated with trifluoroacetic acid (TFA) and 7ß-amino-3 - [(Z) -l-propen-l-yl] - 3-cephem-4-carboxylic acid (Ib, reaction 7) is obtained in the ratio Z / E = 9/1. After acylation of Ib with p-hydroxyphenylglycine using a conventional “acid chloride process” or an “activated ester process”, the orally active cephalosporin V is obtained.

Alternatively, the 7β-amino-3-propen-1-yl-cephalosporin ester la can be acylated with N-BOC (tert-butoxycarbo-nyl) blocked p-hydroxyphenylglycine in the presence of DCC (dicyclohexylcarbodiimide). Then you deblock with TFA (trifluoroacetic acid) and get the cephalosporin V.

671 399

Scheme 1

4th

Scheme 2

PhCH = N

■ CH = PPh-,

COOCHPhj III

Implementation 3

PhCH = N_

TJ 1

0 y

COOCHPh,

Implementation 3

CH.

IIa

PhCH2CONH ^ s

COOCHPh.

ny

Position 10

Vili

PhCH2CONH.

Nv ^ J-CH = CHCH3

COOCHPh,

Implementation 11

IX

- CH = CH-CH-

COOCHPh,

t

Yes

"Ox = 7- CHCONH

CH = CH-CH

COOCHPh.

COOH

Ib

Implementation 6

H0Ì. ' xhCHCONH

\ = / i

BMY-28100

Implementation 9

COOH

The invention is explained in more detail below with the aid of the examples. The following abbreviations are used: Ph = phenyl BOC = -COOC (CH3) 3 DCC = dicyclohexylcarbodiimide TFA = trifluoroacetic acid EtOAc = ethyl acetate DMF = dimethylformamide

Implementation 1

Diphenylmethyl-7-benzylidenamino-3-triphenylphosphonio-methyl-3-cephem-4-carboxylate chloride

440 ml IN NaOH are added at room temperature to a suspension of diphenylmethyl-7-amino-3-chloromethyl-3-cephem-4-carboxylate hydrochloride (200 g; 0.44 mol) in 940 ml CH2C12. The mixture is shaken for 10 minutes and the organic layer is separated off. MgSO4 (75 g) and benzaldehyde (51 g; 0.48 mol) are added to this organic layer and the mixture is left to stand at room temperature for 55 hours. The reaction mixture is filtered and the insoluble constituents are washed with 200 ml of CH2C12. Triphenylphosphine (126 g; 0.48 mol) is added to the filtrate, which is combined with the solvent used for washing. The mixture is concentrated to about 60 400 ml under reduced pressure and left to stand for 4 days. The viscous oil obtained is diluted with 11 ethyl acetate and triturated to separate the title compound as a light yellow crystalline powder, which is filtered off and dried in vacuo, yield 322 g (96%); Mp 185-190 ° C (dec.).

65 K "Rr

IR: v r cm-1 1780.1720.1630.

max uv: xmscl2 nm (s) 260 (2410 °) -

5

671 399

UR: A. 0 nm (E JA) 287 (173). max 1 cm

Implementation 2

Diphenylmethyl-7-benzylideneamino-3- [(triphenylphosphoronylidene) - methylJ-3-cephem-4-carboxylate (III)

A mixture of diphenylmethyl-7-benzylidenami-no-3-triphenylphosphoniomethyl-3-cephem-4-carboxylate chloride (322 g; 0.42 mol) and 252 ml of 5N Na2C03 in 1.61 CH2C12 is stirred vigorously for 15 min Room temperature. The organic layer is separated off, dried over MgSO4 and concentrated to about 500 ml. The concentrate is diluted with 11 acetone while stirring and a light yellow crystalline powder is obtained, which is filtered off, yield 237 g (78%) of III with mp. 195-198 ° C. (dec.)

IR: v ^ cm-1 1770, 1620.

Max

UV: nm (£) 254 (23000), 389 (22000).

NMR: 8 CDC13 ppm 2.56 and 3.16 (2H, Abq); 5.00 (1H, d, J = 4Hz); 5.23 (1H, d, J = 4Hz); 5.47 (1H, d, J = 22 Hz); 6.95 (1H, s); 7.2 ~ 7.8 (30H, m); 8.55 (1H, s).

Implementation 3

Diphenylmethyl-7-amino-3 - ((Z) l-propen-1-yl) - 3-cephem-4-carboxylate hydrochloride (Ia hydrochloride)

To a cold solution of LiBr (19 q; 216 mmol) in a solvent mixture of dry dimethylformamide (100 ml) and CH2C12 (300 ml), acetaldehyde (20 ml, 360 mmol) and diphenylmethyl-7 are added at -5 ° C -benzylidenamino-3- [triphenylphosphoranylidene) methyl] -3-ce-phem-4-carboxylate (III) (15 g; 20 mmol). The mixture is allowed to stand at -5 ° C to 10 ° C for 20 h and then at room temperature for 5 h. The light yellow solution obtained is concentrated in vacuo to about 100 ml and placed in a solvent (two layers) of ethyl acetate (400 ml) and H20 (400 ml). The upper layer is separated off and diluted with 400 ml of isopropyl ether. Silica gel (Wakogel C-100; 40 g) is added to the mixture. The mixture is shaken for 5 minutes and then filtered through a cushion of diatomaceous earth (filter aid). The insoluble constituents are washed with a mixed solvent of ethyl acetate / isopropyl ether (1/1; 200 ml). The filtrate is combined with the solvent used for washing and concentrated to 400 ml. A 0.5 M Girard Reagent T solution in 60 ml of methanol and 6 ml of acetic acid is added to the concentrate mentioned above and the mixture is stirred for 15 minutes at room temperature. The mixture is concentrated to about 200 ml, washed successively with 200 ml of H20, 3 × 20 ml of saturated aqueous NaH-C03 solution and 20 ml of brine, dried over MgS04, treated with coal and concentrated to about 50 ml. 40 ml of N HCl in methanol are added to the concentrate at room temperature and the mixture is left to stand for 15 minutes. The mixture is concentrated to about 30 ml and diluted by adding 300 ml of ether. The precipitate is filtered off and dried over P205, giving 7.9 g of a light yellow powder. A solution of this powder (7.3 g) in a solvent mixture of 80 ml of methanol and 80 ml of ethyl acetate is treated with charcoal, concentrated to about 100 ml, inoculated with a crystalline hydrochloride of the title compound, diluted slowly with 80 ml Ether and stir for 1 h. The deposited colorless crystals are filtered off and dried in vacuo over P205, giving 6.3 g (71%) of the title compound. This product is a mixture of the Z and E isomers with respect to the propenyl unit in the 3-position (Z / E = 9 / l by means of HPLC) (Lichrosorb RP-18, 80% methanol pH 7.2 phosphate buffer, 254 nm, 1 ml / min).

IR: vKBr cm "1 2850, 1785, 1725.

Max '

5 NMR: 5 ° MSO-d6 ppm 147 (27/10 H, d-d, J = 7.2 Hz, = CHCH3, ice); 1.74 (3/10 H, d, J = 7 Hz, = CHCH3, trans); 3.47 and 3.8 (1H, d, J = 16 Hz each); 5.13 (IH, d, J = 4.5 Hz, 6-H); 5.23 (1H, d, J = 4.5 Hz, 7-H); 5.62 (1H, d-q, J = 10 and 7 Hz, 3-CH = CH); 6.24 (1H, d-d, J = 10 and 10 2 Hz, 3-CH); 6.81 (1H, s, CHPH2); 7.35 (10H, m, Ph-H).

Implementation 4

Diphenylmethyl-7-amino-3- ((Z) -l-propen-l-yl) -3-cephem-4-carboxylate (Ia)

15 To a stirred suspension of the hydrochloride of diphenylmethyl-7-amino-3- ((Z) -l-propen-l-yl) -3-cephem-4-carboxylate (5 g; 11.3 mmol) in 20 ml H20 and 40 ml of ethyl acetate are added to NaHCO 3 until the pH of the mixture becomes 8. The organic layer is washed with 5 ml of 20 saturated aqueous NaCl solution, dried over MgSO4 and concentrated to about 20 ml. The solution obtained is diluted with 10 ml of isopropyl ether and inoculated with the crystalline compound Ia. Additional isopropyl ether (30 ml) is slowly added to the mixture with stirring. After 15 min fil-25, the separated colorless crystals are separated off, washed with 10 ml of isopropyl ether and dried in vacuo over P205, giving 4.3 g (94%) of the title compound (Z / E = 9/1 by means of HPLC) (Lichrosorb RP-18, 80% methanol pH 7.2 phosphate buffer, 254 nm, 1 ml / min).

30 IR: vKBr cm-1 3450, 1765, 1730.

Max

UV: ^ EtOH nm (E -) 289 (185).

max 1 cm

35

NMR: Ô CDC13 ppm 1.43 (3H, d-d, J = 2 and 7 Hz, CH = CHCH3); 1.66 (2H, br, s, disappeared with D20 NH2); 3.23 and 3.55 (each 1H, d, J = 17 Hz, 2-H); 4.73 (1H, d, J = 4.5 Hz, 6-H); 4.96 (1H, d, J = 4.5 Hz, 7-H); 5.46 (1H, d-q, 40 J = 10 and 7 Hz, 3-CH = CH); 6.06 (1H, br, d, J = 1 Hz, 3-CH); 6.94 (1H, s, CHPh2); 7.3 (1 = H, m, Ph-H).

Implementation 5

Diphenylmethyl-7 - [(D) -a- (t-butoxycarbonylamino) - a- (4-45 hydroxyphenylj-acetamidoj- 3- ((Z) -l-propen-l-yl) - 3-ce-phem-4 -carboxylate (IV)

A mixture of diphenylmethyl-7-amino-3- ((Z) -l-propen-l-yl) -3-cephem-4-carboxylate (Ia) (4.2 g;

10.4 mmol), (D) -a- (t-butoxycarbonylamino) -a- (4-hydroxy-50 phenyl) -acetic acid (3.3 g; 12.5 mmol) and DCC (2.6 g;

12.5 mmol) in 104 ml of ethyl acetate are stirred for 1.5 h at room temperature. The mixture is filtered and the insoluble constituents are washed with 20 ml of ethyl acetate. The filtrate, which one with the solvent used for washing

55 has combined, washed successively with 3 x 5 ml of saturated aqueous NaHC03 solution, 5 ml of brine, 5 ml of 10% HCl solution and brine, dried over MgS04, treated with coal and filtered. The filtrate is concentrated to about 10 ml and diluted with 20 ml of n-Hep-60 tan. The precipitate is filtered off and dried in vacuo over P205. Yield 7.8 g (90% pure, quantitative by weight), colorless powder (Z / E = 9/1 according to HPLC) (Lichrosorb RP-18, 80% methanol pH 7.2 phosphate buffer, 254 nm, 1 ml / min).

65 IR: vKBr cm-1 3400, 1790, 1720, 1690.

Max

UV: nm (E-278 (113), 289 (115), 295 (95).

max 1 cm

671 399

6

NMR: 8 CDC13 ppm 1.3-1.45 (12H, m, BOC-H and = CH-CH3); 3.08 and 3.33 (each 1H, d, J = 18 Hz, 2-H); 4.92 (1H, d, J = 4.5 Hz, 6-H); 5.06 (1H, d, J = 6 Hz, s at D20, CHN); 5.5 (1H, d-q, J = 10 and 7 Hz, 3-CH = CH); 5.68 (1H, d-d, J = 4.5 and 8 Hz, d, J = 4.5 Hz at D20, 7-H); 6.01 (1H, d, J = 1 Hz, 3-CH); 6.65 and 7.08 (2H, d,

J = 8 Hz, HO);

6.71 (1H, d, J = 8 Hz, disappeared at D20, 7-NH2); 6.88 (1H, s, CHPh,); 7.3 (10H, m, Ph-H).

Implementation 6

BMY-28100; 7 - [(D) -2-Amìno-2- (4-hydroxyphenyl) -acetamì-do] - 3- (propen-l-yl) - 3-cephem-4-carboxylic acid (V)

A mixture of diphenylmethyl-7 - [(D) -a- (t-butoxycarbonylamino) - a- (4-hydroxyphenyl) acetamido] -3- ((Z) -l-propen-l-yl) -3 -cephem-4-carboxylate (IV) (prepared according to reaction 5) (90% pure; 7.7 g; 10.6 mmol), 7.7 ml of anisole and 77 ml of trifluoroacetic acid are stirred at room temperature for 1 h. The mixture is concentrated in vacuo, 50 ml of toluene are added to the concentrate and the mixture is concentrated in vacuo. 200 ml of ether are added to the remaining oil, the precipitated solid is filtered off, washed with 20 ml of ether and dried in vacuo over KOH, yielding 5.3 g of the trifluoroacetic acid (TFA) salt of BMA-28100. 5.3 g of the salt are dissolved in 100 ml of H20, treated with coal and placed on a column packed with Diaion HP-20 (0.61). The column is washed with H20 (41) and eluted with 40% MeOH. The methanol fractions (1.71) containing the desired product are collected and concentrated to about 20 ml. The concentrate is diluted slowly with 100 ml acetone. The colorless crystalline powder which has precipitated is filtered off, washed with 20 ml of acetone and dried in vacuo over P2O5, giving 4 g (97%) of BMY-28100 (Z / E = 9/1, zwitterion) (Lichrosorb RP-18 , 20% methanol pH 7.2 phosphate buffer, 254 nm, 1 ml / min).

Implementation 7

7-amino-3 - [(Z) -l-propen-l-yl] - ceph-3-em-4-carboxylic acid,

IB

149.7 g (0.338 mol) of diphenylmethyl-7-amino-3 - [(Z) -l. Are added to a stirred solution of 260 ml of anisole and 1.38 l of trifluoroacetic acid (TFA), which is cooled to 0 ° C. -pro-pen-l-yl] - 3-cephem-4-carboxylic acid hydrochloride (0.338 mol); Implementation 3 or 11). The resulting slurry is then stirred at room temperature for 1 hour. The majority of the excess TFA is removed in vacuo using a rotary evaporator. The remaining supernatant solution is decanted. The remaining slurry is rubbed with 1.51 dry ether for 1 h. The crystalline product is filtered off and dried over P205, giving 87.24 g of Ib trifluoroacetate. This 87.24 g of the trifluoroacetate is suspended in 900 ml of water (pH approx. 2.5) and stirred. The mixture is cooled to + 5 ° C. and the pH is then adjusted to 0.6 with 12 N HCl. The yellow solution is treated with coal and the slurry is filtered with a diatomaceous earth filter aid pad. The solution obtained is cooled to + 5 ° C. and the pH is adjusted to 2.0 with 20% NaOH. The suspension is left to stand in a refrigerator for 1 hour to aid crystallization. The crystals are collected, washed with 800 ml of water and 800 ml of acetone and dried in vacuo at room temperature, yield 69.4 g

(85.5%). The product contains 9.7% of the trans isomer (determined with an HPLC column RP 18 MERCK; H2 (NH4) P04; 0.1 mol 95 ml + CH3 CN 5 ml; detected at 290 nm.).

Implementation 8

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

A solution of the phosphoranyl compound III (prepared according to reaction 2; 50.0 g; 68.7 mmol) in 500 ml of CH2C12 is mixed with a solution of lithium bromide (29.8 g; 343 mmol) in 170 ml of dry DMF, which is a small amount Amount of CH2C12 (10 ml), and then with anhydrous acetaldehyde (39 ml; 687 mmol; made from paraldehyde and toluenesulfonic acid by distillation according to the method of NL Drake and GB Cooke, Org. Syn. Col. Volume II, p. 407) . The mixture is placed in a closed vessel and left to stand at 20 ° C. for 2 days. The reaction mixture is concentrated, the remaining liquid is diluted with 800 ml of EtOAc, washed with 3 × 300 ml of water and 300 ml of a saturated NaCl solution and concentrated to give the protected 3-propenyl derivative IIa as a foam-like solid (34 g) which is used for the next implementation without further cleaning.

The crude product IIa obtained is treated with 98% formic acid (35 ml) and concentrated HCl (17 ml; 2 = 6 mmol) for 1 h at room temperature. 350 ml of water are added to the reaction mixture, an oily layer separating out, which is washed with 3 × 100 ml of EtOAc. The pH of the aqueous layer is adjusted to about 3 with 4N NaOH (approx. 65 ml) with stirring, giving a crystalline solid which is filtered off and washed with 50 ml of water, the title compound (Ib; 9 , 7 g; 59%). HPLC (Lichrosorb RP-18, 4 x 300 mm, MeOH: phosphate buffer (pH 7) = 15:85) shows that this product is an 83:17 mixture of the Z and E isomers with respect to the double bond of the 3- Is propenyl group; Mp 200 ° C (dec.).

IR: vmax (KBr) in cm-1 3420, 1805, 1620.

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

NMR: 8 (D20 + NaHCO3) in ppm 1.69 and 1.88 (3H, each d, J = 6.0 Hz, Z and E of -CH = CH-CH3); 3.38 and 3.72 (2H, Abq, J = 17 Hz, H-2); 5.18 (1H, d, J67 = 5.0 Hz, H-6); 5.51 (IH, d, H-7); about 5.8 (1H, m, -CH = CH-CH3) and 6.06 (1H, d, J = 11 Hz, -CH = CH-CH3).

Analysis for Ci0Hi2N2O3S:

C H N S calc .: 49.99 5.03 11.66 13.34%

found: 50.20 4.94 10.93 12.82%

Implementation 9

7 - [(D) -2-Amino-2- (4-hydroxyphenyl) acetamido] -3- ((Z 'j-1-propen-l-yl) - 3-cephem-4-carboxylic acid, V

Dimethylaniline (1.7 ml; 13.1 mmol), trimethylsilylchloride (2.1 ml; 16.4 mmol) and triethylamine (TEA; 2.3 ml; 16.4 mmol) are added successively to a suspension of the compound Ib (prepared according to reaction 8; 1.58 g; 6.56 mmol) in CH2C12 (16 ml), cooling with ice. The mixture is stirred for 30 minutes at room temperature. Dp-hydroxyphenylglycyl chloride hydrochloride (1.46 g; 6.56 mmol) is added in portions to this mixture with stirring and the reaction is monitored by HPLC (Lichrosorb RP-18; 4 x 300 nm, MeOH: phosphate buffer (pH 7) = 25:75). An additional amount of the glycyl chloride is added three times at 15 min intervals (291 mg each)

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

671 399

the mixture to complete the acylation. After the addition of dry MeOH (2.0 ml) containing 0.1 ml dry DMF, the clear solution obtained is neutralized with 3.2 ml TEA to pH 6 and then diluted with 30 ml CH2C12 Precipitate is obtained, which is filtered off and washed with 10 ml of CH2C12. The title compound is thus obtained as dimethylformamide solvate (2.39 g; yield 94%; approx. 50% pure; Z / E = 47:12 by means of HPLC).

Implementation 10

Diphenylmethyl-7-phenylacetamido-3- ((Z) -propen-1-yl) -ceph-3-em-4-carboxylate, IX

ch2con4

rf

ch3cho

CH = P (Ph).

cci4 / ch3oh

COODPM

mw = 758.8

ch2c-n.

/ 7th

1 mw = 524.6

coodpm

A stirred solution of 18 1CC14, 1.8 l of methanol and 12 g of p-benzoylbenzoic acid, which has been cooled to 8 ° C., is added to 970 ml of acetaldehyde. The temperature of the solution obtained rises to +14 ° C. After 5 minutes, 588 g (0.7749 mol) of diphenylmethyl-7-phenylacetamido-3- [(tri-phenylphoranylidene) methyl] -3-cephem-4-carboxylate are added. The cooling bath is removed and the mixture is stirred vigorously for 4 h at 35 ° C. and in the absence of light and under an N2 atmosphere until the phosphorane is completely dissolved.

The solution obtained is concentrated in vacuo. The residue is dissolved in 21 ethanol and the solution is concentrated in vacuo to a semi-crystalline residue which is slurried in 3 liters of ethanol.

The mixture is stirred for 2 hours at + 5 ° C. and left to stand overnight. The crystals formed are collected twice, washed with ethanol and dried at room temperature in vacuo. Yield 191 g (47%), mp 124-128 ° C. The product contains 7.5% of the trans isomer (determined using an HPLC column Lichrosorb Si 60 5 [in Merck, eluted with 85% toluene, 15% ethyl acetate).

Implementation 11

Diphenylmethyl-7-amino-3- ((Z) -propen-l-yl) - ceph-3-em-4-carboxylate hydrochloride, Ia

To a stirred solution of 159.7 g (0.767 mol) of PC15 in 2.8 1CH2C12 is added over a period of

30 20 min 56.7 ml (0.700 mol) pyridine in 280 ml CH2C12. The slurry is cooled to 2 ° C. under a nitrogen atmosphere and 256 g of compound IX (prepared according to reaction 10; 0.488 mol) are added. The mixture is stirred for 40 min and the resulting slurry 35 is quickly poured into a vigorously stirred solution of 1.41CH2C12 and 209 ml (2.33 mol) of 1,3-butanediol at −20 ° C. so that the temperature does not exceed −5 ° C increases. The cooling bath is removed. After 45 minutes the temperature rises to 10 ° C. This temperature is maintained for 35 min.

40 1.01 water is added and the mixture is stirred for a further 5 min and the layers can then be separated. The organic layer is washed with 600 ml of 2N HCl and then with 400 ml of saturated saline. The combined aqueous extracts are washed back with 2 x 600 ml CH2C12 and 45 combined with the original CH2C12 extract.

Dry the solution over anhydrous MgS04, filter the MgS04 slurry and wash the MgS04 twice with 500 ml CH2C12. The combined filtrates are concentrated in vacuo to 50 2.41 using a rotary evaporator and diluted with 2.51 ethyl acetate. The solution is again concentrated to 1.3 l, the crystal slurry obtained is filtered off, washed with 3 × 300 ml of ethyl acetate and dried in air and vacuum over P205, giving 149.8 g of the title compound as beige crystals . 55 Yield 69.3%.

C.

Claims (11)

671399 2nd PATENT CLAIMS 1. Compounds of the general formula CH = CH-CH. COOR wherein R represents a hydrogen atom or a carboxyl protecting group and has the 3-propenyl group in Z configuration, as well as the acid addition salts thereof and the metal salts of those compounds in which R represents a hydrogen atom. 2. Compounds according to claim 1, wherein R is a hydrogen atom or a methoxymethyl, 2,2,2-trichloroethyl, 2- (trimethylsilyl) ethyl, t-butyl, benzyl, diphenylmethyl, o-nitrobenzyl, p-nitrobenzyl, tri-methylsilyl, t-butyldi-methylsilyl, t-butyldiphenylsilyl, allyl or 2-chloroallyl group and the acid addition salts thereof. 3. Compounds according to claim 2, wherein the acid addition salts are the hydrochlorides, sulfates, p-toluenesulfonates and phosphates. 4. Compounds according to claim 1, wherein the metal salts are a sodium, potassium, calcium or aluminum salt. 5. Compounds according to claim 2, namely: Diphenyl-methyl-7ß-amino-3 - [(Z) -l-propen-l-yl] - 3-cephem-4-carboxylate and 7ß-amino-3- [ (Z) -l-propen-l-yl] - 3-cephem-4-car-bonic acid and the hydrochlorides thereof. 6. Compounds according to claim 4, namely: sodium 7β-amino-3 - [(Z) -l-propen-l-yl] - 3-cephem-4-carboxylate. 7. A process for the preparation of the compounds according to claims 1 to 6, characterized in that an intermediate compound of the general formula ^ ~ ^ -CH = N - CH = PPh. COOR I. wherein R is a carboxyl protecting group and Ph is a phenyl-io group, in an inert organic reaction medium with acetaldehyde at a reaction temperature of -10 to 25 ° C to a compound of the general formula 15 20th CH = N * CH = CH-CH, COOR reacted, then the benzylidene group and the carboxyl protecting group removed and the 3- (Z) - and 3- (E) -isomers 25 separated. 9. The method according to claim 7 or 8, characterized in that one carries out the reaction with acetaldehyde in the presence of a lithium halide. 10. The method according to claim 9, characterized in that the lithium halide is lithium chloride, lithium bromide. mid or lithium iodide. 11. The method according to claim 9, characterized in that lithium bromide is used as the lithium halide. 12. The method according to any one of claims 7 to 11, 35 characterized in that the inert reaction medium is di-chloromethane, N, N'-dimethylformamide, isopropanol or a mixture thereof. - CH = PPh " COOR 40 DESCRIPTION