FI84268B - 7 -AMINO-3-PROPENYLCEFALOSPORANSYRA OCH DESS ESTRAR OCH ETT FOERFARANDE FOER FRAMSTAELLNING AV DESSA. - Google Patents

Description

1 84268 7-Amino-3-propenylcephalosporanic acid and its esters and method for their preparation

The invention relates to novel cephalosporanic acid derivatives of the formula

H, N-j / X

h n ^^> - CH = CH-CH. (i) 0v j

10 COOR

wherein the 3-propenyl group has the Z configuration and R is hydrogen or a conventional carboxy protecting group, and their acid addition and metal salts. These compounds are useful as intermediates in the preparation of orally active cephalosporins.

GB 1 342 241 (corresponding to U.S. Patents 3,769,277 and 3,994,884) describes compound VI but does not describe 7β-amino-3 - [(Z) -1-propen-1-yl] - 3-Cephem-4-carboxylic acid as an intermediate in the preparation of compound VI.

25 O-CH 2 CO ™ T-fS ^ ^ N CH = CH-CH 2

COOH

U.S. Patent No. 4,409,214 describes the preparation of Compound VII in Examples 38 and 39 by a Wittig reaction using diphenylmethyl 7-benzylideneamino-3-triphenylphosphonomethylcef-4-em-4-carboxylate as the starting material, but does not describe 73-amino-3- [(Z) -1-Propen-1-yl] -3-cephem-4-carboxylic acid and no other 3- (1-propen-1-yl) cephalosporin compound.

2 84268 a2 »l-f I It vh <y—

5 COOH

U.S. Patent No. 4,110,534 specifically discusses the preparation of compounds such as compounds VI and VII by the Wittig reaction. See. in particular columns 8, 9 and 49 (Example 21).

In Jour. Org. Chem. 29, 3327-3333 (1964) describes the use of solvents and additives, e.g. the effect of lithium salts on the ratio of cis- and trans-olefins formed in the Wittig reaction with aldehydes.

In the compounds of the present invention, the 3 proponyl groups have the Z or cis configuration. R is hydrogen or a conventional carboxy protecting group. The latter term refers to a protecting group 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 (benzhydryl), alkyl groups such as tert-butyl, halo-alkylalkyl groups such as 2,2,2-trichloroethyl, alkenyl groups such as 2-chloroallyl, alkoxymethyl groups such as methoxymethyl, 2- (trimethylsilyl) ethyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl and other carboxyls in the literature, e.g. in GB Patent Protections 1,399,086. Preferred protecting groups are those which are readily removed by acid treatment, especially benzhydryl or tert-butyl.

In the compounds of the invention, the Z or cis configuration of the 3-propenyl group 35 forms a critical point.

3,84268 This is a characteristic that determines the preferred gram-negative antibacterial properties of the cephalosporin end products.

Acid addition salts useful in synthesis are those formed with mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid, organic sulfonic acids such as p-toluenesulfonic acid and other acids used in cephalosporin chemistry.

Compounds of formula I in which R is hydrogen also form metal salts. Suitable metal conditions for the synthesis include sodium, potassium, calcium, magnesium, aluminum and zinc salts.

The most preferred compounds of formula I are: 1. Diphenylmethyl 76-amino-3 - [(Z) -1-propen-1-yl] -3-cephem-4-carboxylate 2. Diphenylmethyl 76-amino-3 - [ (Z) -1-propen-1-yl] -3-cephem-4-carboxylate hydrochloride 3. Diphenylmethyl 76-amino-3 - [(Z) -1-propen-1-yl] -3-cephem-4-carboxylate sulfate 20 4. Sodium 7β-amino-3 - [(Z) -1-propen-1 -yl] -3-cephem-4-carboxylate 5. Potassium 7B-amino-3 - [(Z) -1-propen-1-yl] -3-cephem-4-carboxylate 6. 7B-amino-3- [(Z) -1-propen-1-yl] -3-cephem-4-carboxylic acid.

The invention also relates to a process for the preparation of compounds of formula I. The process is characterized in that the compound of formula 30 - N vv ^> J ”CH = p? H3

35. C00R

4,84268 wherein R is hydrogen or a conventional carboxy protecting group, and Ph is a phenyl group, is reacted with acetaldehyde in an inert organic reaction medium which is dichloromethane. N, N-dimethylformamide, isopropanol or a mixture thereof, at a reaction temperature of 0-25 ° C to give a compound of formula <¥ n \ ^^ ch = gh-ch3

COOR

After which the benzylidene group or both the benzylidene group and the carboxy protecting group are removed and, if desired, the 3- (Z) and 3- (E) isomers are separated to give a compound of formula 20 - —S '^ ^ CH = CH_CH3

COOR

25 wherein R is as defined above. Preferred embodiments are shown in Reaction Schemes 1 and 2.

In Reaction Scheme 1, the carboxy protecting group is preferably a diphenylmethyl group. It will be apparent to those skilled in the art that other known carboxyl protecting groups may be used.

It has been found that the addition of an appropriate lithium halide 35 such as lithium chloride, lithium bromide or lithium iodide in the Wittig reaction of compound III and acetaldehyde can improve the yield of the reaction product Ha and the Z / E isomer ratio. The reaction is preferably carried out with 5 to 15 chemical equivalents, more preferably 10 equivalents of lithium bromide.

Methylene chloride is the preferred reaction medium and preferably contains a co-solvent such as dimethylformamide or isopropanol in small amounts, i.e. about 1/10 to 1/3 volume per part of methylene chloride. The reaction temperature is suitably in the range of -10 to + 25 ° C and preferably 10 to 25 ° C. The Wittig product Ha is extracted into a suitable organic solvent, e.g. ethyl acetate, and the extract is treated with Girard reagent T to give the 7-aminocef-3-eme compound Ia of the invention. See. 3. Treatment of compound Ia with trifluoro-acetic acid (TFA) affords 76-amino-3 - [(Z) -1-propen-1-yl] -3-cephem-4-carboxylic acid (Ib, procedure 7). ) 9: 1 Z / E ratio. By acylation of compound Ib with p-hydroxyphenylglycine by a conventional acid chloride procedure or by an activated ester procedure, cephalosporin V is activated.

An alternative route to cephalosporin V is also obtained by acylation of 7e-amino-3-propen-1-ylcephalosporin ester Ia with N-Boc (tert-butoxycarbonyl) protected p-hydroxyphenylglycine in the presence of DDC (dicyclohexylcarbodiimide) followed by deprotection. TFA (with trifluoroacetic acid).

6 84268

Scheme 1 Scheme 2 PBCH = N-j-f N PhCH2CONH-r- ^ s \ 5 / Mv ^ J-ca-PPh 3 J-NsJ ^ H = PPh3 COOCHPh, XII O coocH? H ^

Procedure 3 _ VIII

^ Procedure 10 ^ ^. sL · 1 o f \

lu PhCH = N __ ^ s \ I

j j PhCH2CONHn-fN

L o ^ T J / -NnJ-ch = chch3 COOCHPh2 O COOCHPh2

Ha 15 \ / Ix \ Procedure 3 / Procedure 11 // - CH = CHrCH3 20 COOCHPh2

Procedure V \ Procedure 7 or 8 vT xa V -

Η · ° \ _) - iHC0NHT-I ^ SX | H ^ -p j-'S'N

25 NHBOCC Jr — N 2 x J-CH = CH-CH 3 CH = CH-CH 3 O COOCHPh 2 COOH Ib

Procedure 6 \, / Procedure 9 30 ^ / - \ ^ H0 v_y "fHC0NHn — rs ^

nh2 ^ -nnJ-ch = ch-ch3 V

COOH

35 BMY-28100 7 84268

The following abbreviations have been used:

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

5 Procedure 1

Of diphenylmethyl 7-benzylideneamino-3-triphenyl-phosphoniomethyl-3-cephem-4-karboksylaattikloridi_

To a suspension of 200 g (0.44 mol) of diphenylmethyl 7-amino-3-chloromethyl-3-cephem-4-carboxylate-10 hydrochloride in 940 mL of CH 2 Cl 2 was added 440 mL of 1 N NaOH. at room temperature. The mixture was shaken for 10 minutes and the organic layer was isolated. To this organic layer were added 75 g of magnesium sulfate and 51 g (0.48 mol) of benzaldehyde, and then the mixture was allowed to stand for 15 hours at room temperature. The reaction mixture was filtered and the insoluble material was washed with 200 mL of CH 2 Cl 2. To the combination of filtrate and washings was added 126 g (0.48 mol) of triphenylphosphine. The mixture was concentrated to about 400 mL in vacuo and allowed to stand for 4 days. The resulting viscous oil was diluted with 1 liter of ethyl acetate and triturated to give a pale yellow crystalline powder which was isolated by filtration and dried in vacuo. Yield 322 g (96%), m.p. 185-190 ° C (decomposes).

25 IR:?) ™ Z cm -1 1780, 1720, 1630.

ch2ci2 UV: λ nm (ε) 260 (24100).

max

Procedure 2

Diphenylmethyl 7-benzylideneamino-3 - [(triphenylphosphoranylidene) methyl] -3-cephem-4-carboxylate (III)

A mixture of 322 g (0.42 mol) of diphenylmethyl-7-benzylideneamino-3-triphenylphosphonomethyl-3-cephem-4-carboxylate chloride and 252 ml of 5 N Na2CO3 solution in 1.6 liters of CH2Cl2, stirred vigorously for 15 minutes to 8,44268 minutes at room temperature. The organic layer was isolated, dried over magnesium sulfate and concentrated to a volume of about 500 mL. The concentrate was diluted with stirring with 1 liter of acetone to give a pale yellow crystalline powder which was isolated by filtration to give 237 g (78%) of compound 3, m.p. 195-198 ° C (decomposes). IR: cm-1 1770, 1620.

UV:> CH 2 Cl 2 nm (,) 254 (23000), 389 (22000).

λmax NMR: δ CDCl3-3 ppm 2; 56 & 3.16 (2H, ABq), 5.00 (1H, d, J = 4

Hz), 5.23 (1H, d, J = 4 Hz), 5.47 (1H, d, J = 22 Hz), 6.95 (1H, s), 7.2, 7.8 (30H, m ), 8.55 (1 H, s).

Procedure 3

Diphenylmethyl 7-amino-3 - ((Z_) -1-propen-1-yl) -15,3-cephem-4-carboxylate hydrochloride (Ia hydrochloride)

To a cold solution of 19 g (216 mmol) of LiBr in a solvent mixture of 100 mL of dry dimethylformamide and 300 mL of CH 2 Cl 2 was added at -5 ° C 20 mL (360 mmol) of acetaldehyde and 15 g (20 mmol) of mmol) diphenylmethyl 20-1-benzylideneamino-3 - [(triphenylphosphoranylidene) methyl] -3-cephem-4-carboxylate (III). The mixture was allowed to stand at -5 for 20 hours. At -10 ° C and then for 5 hours at room temperature. The resulting light brown solution was concentrated to a volume of about 100 mL in vacuo and added to a two to 25 layer solvent of 400 mL of ethyl acetate and 400 mL of water. The upper layer was isolated and diluted with 400 mL of isopropyl ether. To the mixture was added 40 g of silica gel (Wako gel C-100). The mixture was shaken for 5 minutes and filtered through a pad of diatomaceous earth filter aid. The insoluble matter was washed with 200 ml of a 1: 1 mixture of ethyl acetate and isopropyl ether. The combination of filtrate and washings was concentrated to a volume of about 400 ml. To the above concentrate was added a 0.5 M solution of Girard's Reagent T in 60 ml of 35 methanol and 6 ml of acetic acid, and the mixture was stirred at 9,84268 for 15 minutes at room temperature. The mixture was evaporated to a volume of about 200 ml, washed successively with 200 ml of water, 3 x 20 ml of saturated aqueous MaHCO 3 solution and 20 ml of water, dried over magnesium sulfate, treated with activated carbon and concentrated to about 50 ml. To the concentrate was added 40 ml of 1 N HCl in methanol at room temperature and allowed to stand for 15 minutes. The mixture was evaporated to about 30 ml and diluted by adding 300 ml of ether. The precipitate was isolated by filtration, dried over P 2 O 5 to give 7.9 g of a pale yellow powder. A solution of 7.3 g of this powder in a solvent mixture of 80 ml of methanol and 80 ml of ethyl acetate was treated with activated carbon, concentrated to about 100 ml, seeded with the hydrochloride crystals of the title compound, slowly diluted with 80 ml of ether and stirred for one hour. The precipitated colorless crystals were isolated by filtration, dried over P 2 O 5 to give 5.3 g (71%) of the title compound. This product was a mixture of the Z and E isomers with respect to the propenyl group in the 3-position (Z / E = 9: 1 by HPLC) (Lichrosorb 20 RP-18, 80% methanol - pH 7.2 phosphate buffer, 254 nm, 1 ml / min).

IR: v H1 cm-1 2850, 1785, 1725.

UR: λ nm (E i * J 287 (173).

NMR: δ DMSO-d 6 ppm 1.47 (27 / 10H, dd, J = 7.2 Hz, = CHCH 3, 25 cis), 1.74 (3 / 10H, d, J = 7 Hz, = CHCH 3, trans) , 3.47 & 3.8 each 1H, d, J = 16 Hz), 5.13 (1H, d, J = 4.5 Hz, 6-H), 5.23 (1H, d, J = 4 , 5 Hz, 7-H), 5.62 (1H, dq, J = 10 & 7 Hz, 3-CH = CH), 6.24 (1H, dd J = 10 & 2 Hz, 3-CH), 6.81 (1H, s, CHPH 2), 735 (10H, m, Ph-H).

30 Procedure 4

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

To a stirred suspension of 5 g (11.3 mmol) of diphenylmethyl 7-amino-3 - ((Z) -1-propen-1-yl) -3-cephene-35 ml-4-carboxylate in 20 ml of water and in 40 mL of ethyl 84268 acetate, enough NaHCO 3 was added to bring the pH of the mixture to 8. The organic layer was washed with 5 mL of saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated to a volume of about 20 mL. The resulting solution was diluted with 10 ml of isopropyl ether and seeded with crystals of compound Ia. 30 ml of isopropyl ether were added slowly and with stirring. After 15 minutes, the precipitated colorless crystals were isolated by filtration, washed with 10 ml of isopropyl 10 ether, dried over P 2 O 5 in vacuo to give 4.3 g (94%) of the title compound (Z / E = 9: 1 by HPLC) (Lichrosorb RP -18, 80% methanol - pH 7 phosphate buffer, 254 nm, 1 ml / min).

IR: 'm® * cm -1 3450, 1765, 1730.

UV: λmax nm (E 'J 289 (185).

NMR: δCDCl, ppm 1.43 (3H, dd, J = 2 & 7 Hz, CH = CHCH 3), 1.66 (2H, broad, s, D 2 O-covered, NH 2), 3.23 S. 3, 55 (1H, d, J = 17 Hz, 2-H each), 4.73 (1H, d, J = 4.5 Hz, 6-H), 4.96 (1H, d, J = 4.5) Hz, 7-H), 5.46 (1H, dq, J = 10 6 7 Hz, 3 3-CH = CH), 6.06 (1H, broad, d, J = 10 Hz, 3-CH), 6.94 (1H, s, CHPh 2), 7.3 (10H, m, Ph-H).

Procedure 5

Diphenylmethyl-7 - [(D) -α- (tert-butoxycarbonylamino) -g- (4-hydroxyphenyl) acetamido] -3 - ((Z) -1-propen-1-25yl) -3-cephem- 4-carboxylate (IV)

A mixture of 4.2 g (10.4 mmol) of diphenylmethyl-7-amino-3 - ((Z) -1-propen-1-yl) -3-cephem-4-carboxylate (Ia) , 3.3 g (12.5 mmol) of (D) -α- (tert-butoxycarbonylamino) -α-4-hydroxyphenyl) acetic acid and 2.6 g (12.5 mmol) of DCC in 104 ml: ethyl acetate, stirred for 1.5 hours at room temperature. The mixture was filtered and the insoluble material was washed with 20 ml of ethyl acetate. The filtrate and washings were combined and washed successively with 3 x 5 mL of saturated aqueous NaHCO 3, 5 mL of brine and 5 mL of 10% HCl, dried over magnesium sulfate, treated with charcoal and filtered. The filtrate was then concentrated to about 10 mL and diluted with 20 mL of n-heptane. The precipitate was isolated by filtration and dried over P 2 O 5 in vacuo. 7.8 g (purity 90%, quantitative by weight) of a colorless powder (Z / E = 9: 1 by HPLC) were obtained (Lichrosorb RP-18, 80% methanol - pH 7.2 phosphate buffer, 254 nm, 1 ml / min).

IR: νmax cm-1 3400, 1790, 1720, 1690 10 UV: λmax nm (E 278 (113), 289 (115), 295 (95)).

NMR: δ (CDCl 3) ppm 1.3-1.45 (12H, m, BOC-H and = CH-CH 3), 3.08 and 3.33 (1H, d, J = 18 Hz, 2-H ), 4.92 (1H, d, J = 4.5 Hz, 6-H), 5.06 (1Hm d, J = 6 Hz, s, covered by D 2 O, CHN), 5.5 (1H, dq, J = 10 and 7 Hz, 3-CH = CH), 5.68 (1H, dd, J = 4.5 and 8 Hz), d, J = 4.5 Hz covered by D 2 O, 7- B). 6.01 (1H, d, J = 10 Hz, 3-CH), 6.65 and 7.08 (2H, d, J = 8 Hz each), 6.71 (1H, d, J = 8 Hz) ,

H H

20 D 2 O-coated, 7-NH 4), 6.88 (1H, s, CHPh 2), 7.3 (10H, m,

Ph-H).

Procedure 6 BMY-28100; __ 7 - [(D) -2-amino-2- (4-hydroxyphenyl) acetamido] -3- (propen-1-yl) -3-cephem-4-carboxylic acid 25 m

A mixture of 7.7 g (10.6 mmol), purity 90%) of the 7 - [(D) -α- (tert-butoxycarbonylamino) -α- (4-hydroxyphenyl) acetamido] -3 prepared in Example 5 was prepared. - ((Z) -1-propen-1-yl) -3-cephem-4-carboxylate (IV), 7.7 ml of anisole 30 and 77 ml of trifluoroacetic acid, were stirred for one hour at room temperature. The mixture was concentrated in vacuo. To the concentrate was added 50 ml of toluene and the mixture was evaporated in vacuo. To the remaining oil was added 200 ml of ether. The precipitated solid was isolated by filtration, washed with 20 mL of ether, dried over KOH in vacuo to give 5.3 g of the trifluoroacetic acid (TFA) salt of BMY-28100. The salt (5.3 g) was dissolved in 100 ml of water, treated with activated carbon and poured onto a column of 0.6 liters of HP-20. The column was washed with 4 liters of water 5 and eluted with 40% aqueous MeOH. The methanol fractions containing the desired product (1.7 liters) were collected and evaporated to a volume of about 20 ml. The concentrate was slowly diluted with 100 ml of acetone. The precipitated colorless crystalline powder was isolated by filtration, washed with 20 ml of acetone, dried over P 2 O 5 in vacuo to give 4 g (97%) of BMY-28100 (Z / E = 9: 1, two-ision) (Lichrosorb RP-18, 20% methanol - pH 7.2 phosphate buffer, 254 nm, 1 ml / min).

Procedure 7 15 7-Amino-3 - [(-Z) -1-propen-1-yl] ceph-3-em-4-carboxylic acid Ib

To a stirred solution of 260 mL of anisole and 1.38 liters of trifluoroacetic acid (TFA) cooled to 0 ° C was added 149.7 g (0.338 mol) of diphenylmethyl-20 7-amino-3 - [(Z) -1-propene -1-yl] -3-cephem-4-carboxylic acid hydrochloride (Procedure 3 or 11). The resulting slurry was then stirred for one hour at room temperature. The TFA was removed for the most part on a rotary evaporator in vacuo. The remaining supernatant solution was removed by decantation and the remaining slurry was triturated for one hour in 1.5 liters of dry ether. The crystalline product was isolated by filtration, dried over P 2 O 5 to give 87.24 g of Ib trifluoroacetate. These 87.24 g of trifluoroacetate were suspended with stirring in 900 ml of water (Ph. About 2.5). The mixture was cooled to + 5 ° C and the pH was adjusted to 0.6 with 12 N HCl. The yellow solution was treated with activated carbon and the slurry was filtered through a pad of diatomaceous earth filter aid. The resulting solution was cooled to + 5 ° C and the pH was adjusted to 2.0 with 20% NaOH solution. The suspension was kept for one hour in a refrigerator to promote crystallization. The crystals were isolated, washed with 800 ml of water and 800 ml of acetone and dried in vacuo at room temperature. Yield 69.4 g (85.5%) containing 9.7% of the trans isomer (by HPLC, column RP 18 Merck, H 2 (NH 4) PO 4, 0.1 mol 95 ml + CH 3 CN 5 ml, determined at 290 nm).

Procedure 8 7-Amino-3 - ((Z) -1-propen-1-yl) -3-cephem-4-carboxylic acid Ib 10 A solution of 50.0 g (68.7 mmol) of the compound prepared in Example 2. phosphoranyl compound III in 500 mL of CH 2 Cl 2 was mixed with a solution of 29.8 g (343 mmol) in 170 mL of dry DMF with a small amount, i.e. 10 mL of CH 2 Cl 2, and then with 39 mL (687 mmol) of with 15 anhydrous acetaldehyde prepared by distillation from paraldehyde and toluenesulphonic acid NL Drake and G.B. Cooke, Org. Syn. Col. Butter. II, p. 407 according to the method. The mixture was placed in a sealed vessel and kept at 20 ° C for 2 days. The reaction mixture was evaporated and the remaining liquid was diluted with 800 ml of EtoAc, washed with 3 x 300 ml of water and 300 ml of saturated NaCl solution, evaporated to give 34 g of the protected 3-propenyl derivative Ha as a foamy solid which was used as a foamy solid. in the next reaction.

The crude Ha obtained above was treated with 35 mL of 98% formic acid and 17 mL (206 mmol) of concentrated HCl for 1 hour at room temperature. To the reaction mixture was added 350 mL of water and an oily layer separated which was removed by washing with 3 x 100 mL of EtOAc. The pH of the aqueous layer 30 was adjusted to about 3 with about 65 mL of 4 N NaOH with stirring to give a crystalline solid which was isolated by filtration and washed with 50 mL of water to give 9.7 g (59%) of the title compound Ibm HPLC ( Lichrosorb RP-18, 4 x 300 mm, MeOH phosphate buffer (pH 35 7) = 15:85) showed that this product was a 14:4268 83:17 mixture of Z and E isomer with respect to the double bond of the 3-propenyl group, m.p. 200 ° C (decomposes).

IR: ν max (KBr) cm-1 3420, 1805, 1620.

UV: A max (PH 7 phosphate buffer) nm (t) 283 (8900).

Δ PMR: δ (D 2 O + NaHCO 3) ppm 1.69 and 1.88 (3H, each d, J = 6.0 Hz, Z and E -CH = CH-CH 3), 3.38 and 3.72 (2H , Abq, J = 17 Hz, H-2), 5.18 (1H, d, J 6.7 = 5.0 Hz, H-6), 5.51 (1H, d, H-7), n. 5.8 (1H, m, -CH = CH-CH 3) and 6.06 (1H, d, J = 11 Hz, -CH = CH-CH 3).

10 Analysis for C10H12N2O3S

Calculated: C 49.99 H 5.03 N 11.66 S 13.34%

Found: C 50.20 H 4.94 N 10.93 S 12.82%

Procedure 9

7 - [(D) -2-amino-2- (4-hydroxyphenyl) acetamido] -3-15 ((Z) -1-propen-1-yl) -3-cephem-4-carboxylic acid V

1.7 ml (13.1 mmol) of dimethylaniline, 2.1 ml (16.4 mmol) of trimethylsilyl chloride and 2.3 ml (16.4 mmol) of triethylamine (TEA) were added successively and under ice-cooling to a suspension of 1 .58 g (6.56 mmol) of compound Ib prepared in Example 8 in 16 mL of CH 2 Cl 2. The mixture was stirred for 30 minutes at room temperature. To the mixture was added portionwise and with stirring 1.46 g (6.56 mmol) of D-p-hydroxyphenylglycyl chloride hydrochloride and the reaction was monitored by HPLC (Lichrosorb RP-18, 4,300 mm, MeOH-25 phosphate buffer (pH 7) = 25:75). To complete the acylation, additional glycyl chloride (291 mg) was added to the mixture three times every 15 minutes. After the addition of 2.0 mL of dry MeOH with 0.1 mL of dry DMF, the resulting clear solution was neutralized with 3.2 mL of 30 TEA to pH 6 and then diluted with 30 mL of CH 2 Cl 2. and a precipitate was obtained which was isolated by filtration and washed with 10 ml of CH 2 Cl 2 to give 2.39 g (yield 94%, purity ca. 50% Z / E = 47:12 by HPLC) of the title compound as a dimethylformamide solvate.

35 15 84268

Procedure 10

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

s / TA_CH2 "

Yzz / j j CH 2 CHO

,, - N Jv CCl./CSjOE'* 0y CE = P (Ph) 2

COODPM

10 MP- = 758f8 _ / S \ 15 0

1_ sec. _ 524.6 COODPM

A stirred solution of 18 liters of CCl 4, 1.8 liters of methanol and 12 g of p-benzosylbenzoic acid was cooled to 8 ° C and 970 ml of acetaldehyde were added. The temperature of the resulting solution rose to + 14 ° C. After 5 minutes, 588 g (0.7749 mol) of diphenylmethyl 7-phenylacetamido-3 - [(triphenylphosphoranylidene) methyl] -3-cephem-4-carboxylate were added. The cooling bath was removed and the mixture was stirred vigorously for 4 hours at 35 ° C under protection from light under nitrogen until complete dissolution of the phosphorane.

The resulting solution was concentrated in vacuo, the residue was dissolved in 2 liters of ethanol, and the solution was concentrated in vacuo to a semi-crystalline residue which was slurried in 3 liters of ethanol.

The mixture was stirred for 2 hours at + 5 ° C and allowed to stand overnight and the crystals were isolated twice, washed with ethanol and dried in vacuo at room temperature.

Yield 191 g (47%), m.p. 124-128 ° C. The sample contained 7.5% trans isomer (determined by HPLC, Lichrosorb Si 60 5 164268 μm Merck, eluent: 85% toluene, 15% ethyl acetate).

Procedure 11

Diphenylmethyl 7-amino-3 - ((Z) -propen-1-yl) cef-5 3-em-4-carboxylate hydrochloride Ia

To a stirred solution of 159.7 g (0.767 mol) of PCl 5 in 2.8 L of CH 2 Cl 2 was added over 20 minutes 56.7 mL (0.700 mol) of pyridine in 280 mL of CH 2 Cl 2. The slurry was cooled under nitrogen at 2 ° C and 256 g (0.488 mol) of compound IX prepared in procedure 10 was added. The mixture was stirred for 40 minutes and the resulting slurry was quickly poured into a vigorously stirred solution of 1.4 liters of CH 2 Cl 2 and 209 mL (2.33 mol) of 1,3-butanediol at -20 ° C so that the temperature did not elevated above 15 -5 ° C. The cooling bath was removed and after 45 minutes the temperature rose to 10 ° C and maintained at this temperature for 35 minutes. 1.0 liter of water was added, stirring was continued for 5 minutes and the layers were then allowed to separate. The organic layer was washed with 600 mL of 2 N HCl and then with 400 mL of brine. The combined aqueous extracts were backwashed with 2 x 600 mL CH2Cl2 and combined with the CH2Cl2 extract initially obtained.

The solution was dried over anhydrous magnesium sulfate. The magnesium sulfate slurry was isolated by filtration and the magnesium sulfate was washed with 2 x 500 mL of CH 2 Cl 2. The combined filtrates were concentrated in vacuo on a rotary evaporator to a volume of 2.4 liters and diluted with 2.5 liters of ethyl acetate. The solution was reconcentrated to a volume of about 1.3 liters. The formed crystal slurry was isolated by filtration, washed with 3 x 300 ml of ethyl acetate. After drying in air and vacuum over P 2 O 5, 149.8 g of the title compound were obtained as sand-colored crystals, yield 69.3%.

Claims (8)

A cephalosporanoic acid derivative of the formula 5 K2N-1F N N. CH = CH-CH_O 3 C00R 10 wherein the 3-propenyl group has Z-configuration and R is hydrogen or a conventional carboxy protecting group, and acid addition and metal salts thereof. Cephalosporanoic acid derivative according to claim 1, characterized in that R is diphenylmethyl. Cephalosporanoic acid derivative according to claim 1, characterized in that the acid addition salt is hydrochloride. Cephalosporanoic acid derivative according to claim 1, characterized in that it is diphenylmethyl-7B-amino-3 - [(Z) -1-propen-1-yl] -3-cephem-4-carboxylate or its hydrochloride. Cephalosporanoic acid derivative according to claim 1, characterized in that it is 7B-amino - [(Z) - 1-propen-1-yl] -3-cephem-4-carboxylic acid or its hydrochloride. 6. A process for the preparation of a cephalosporanoic acid derivative according to claim 1, characterized in that a compound of the formula <RTI ID = 0.0> -C = N- </RTI> 35 Nvy ^ CH = PPh3 COOR 202626 where R is hydrogen or a carboxy protecting group and Ph is a phenyl group reacted with acetaldehyde in an inert organic reaction medium, which is dichloromethane, N, N-dimethylformamide, isopropanol or a mixture thereof, at a reaction temperature of 0-25ΛO to give a compound with the formula COOK 15 whereupon the benzylidene group or both benzylidene group and the carboxy protecting group are removed and, if desired, the 3- (Z) and 3- (E) isomers are separated to give a compound of formula 20 c 'TT Ί - N CH = CH-CH3 COOR where R is the same as above. 7. A process according to claim 6, characterized in that the reaction with acetaldehyde is carried out in the presence of lithium halide. 8. A process according to claim 7, characterized in that the lithium halide is lithium chloride, lithium bromide or lithium iodide, preferably lithium bromide.