DD244557A5 - PROCESS FOR THE PREPARATION OF 7-AMINO-3-PROPENYL-CEPHALOSPORANOSE ACID AND THEIR ESTERS - Google Patents

Abstract

The invention relates to a process for the preparation of novel cephalosprin compound, namely 7beta-amino-3 - [() - 1-propen-1yl -] - 3-cephem-4-carboxylic acid and the esters thereof, having the general formula wherein the Has 3-propenyl group configuration and R represents a hydrogen atom or a conventional carboxyl-protecting group. Also, the acid addition salts of these compounds and the metal salts of those compounds wherein R represents a hydrogen atom are provided by the process of the present invention. The methods obtainable according to the invention are useful wipe compounds for the preparation of orally active cephalosporins. formula

Description

- CH = PPh.

COOR

wherein R has the meanings given above and Ph represents a phenyl group,

in an inert organic reaction medium, such as dichloromethane, Ν, Ν-dimethylformamide, isopropanol or a mixture thereof, with acetaldehyde at a reaction temperature of ^{0 0} C to 25 ⁰ C to give a compound of the general formula

-CH = N

COOR

implements,

then removing the benzylidene group or both the benzylidene group and the carboxyl-protecting group, optionally separating the 3- (Z) - and 3- (E) -isomers, and, if desired, converting the resulting compound into an acid addition or metal salt, or

b) an intermediate compound of the general formula

^ CH = PPh

COOR

wherein R has the meanings given above and Ph represents a phenyl group, in an inert solvent with acetaldehyde to a compound of the general formula

-I-

PhCH ₂ CONH

COOR

then the phenylacetamido group or both the phenylacetamido group and the carboxyl-protecting group are removed,

if desired, separating the 3- (Z) and 3- (E) -isomers and, if desired, converting the compound obtained into an acid addition salt or metal salt.

2. The method according to item ', characterized in that one carries out in step a) the reaction with acetaldehyde in the presence of a lithium halide.

3. The method according to item 2, characterized in that is used as the lithium halide lithium chloride, lithium bromide or lithium iodide.

4. The method according to item 2, characterized in that lithium bromide is used as lithium halide.

5. Method according to one of the preceding points, characterized in that compounds in which R is a hydrogen atom or a methoxymethyl - trichloroethyl - ^ - iTrimethylsilyll-ethyKt-butyl, benzyl, diphenylmethyl, o-nitrobenzyl-, p-nitrobenzyl, trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, allyl or 2-chloroallyl group,

or acid addition salts thereof.

6. The method according to item 5, characterized in that one produces acid addition salts, which are the hydrochlorides, sulfates, p-toluenesulfonates or phosphates.

7. The method according to any one of items 1-4, characterized in that one produces metal salts, which is the sodium, potassium, calcium or aluminum salt.

8. The method according to item 5, characterized in that one Diphenylmethyl ^ ß-amino-S-KZM-propen-i-yl-S-cephem ^ - carboxylate or 7/3-amino-3 - [(Z) -1-propene 1-yl] -3-cephem-4-carboxylic acid or the hydrochlorides thereof.

9. The method according to item 7, characterized in that one prepares sodium ^ -amino-S-KZl-i-propen-i-yl-S-cephem ^ -carboxylate.

Field of application of the invention

The invention relates to a process for the preparation of 7/3 amino-3 - [(Z) -1-propen-1-yl] -3-cephem-4-carboxylic acid and its esters. The compounds obtainable according to the invention are intermediates for the preparation of orally active cephalosporins.

Characteristic of the known technical solutions

GB-PS 1342241 (published on 3.1.1974, corresponds to ÜS-PS 3769277 and 3994884) describes the compound Vl shown below

CH = CH-CH.

COOH

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

U.S. Patent 4,409,214 describes the preparation of Compound VII, shown below, via the Wittig reaction with diphenylmethyl ^ -benzylideneamino-S-triphenylphosphoniummethylceph-S-em -carboxylate in Preparative Examples 38 and 39. However, there is no description of Figure 7 -Amino-3 - [(Z) -1-propen-1-yl] -3-cephem-4-carboxylic acid or another 3- (1-propen-1-yl) cephalosporin compound.

CH = CH.

COOH

The US-PS 4110 534 is particularly concerned with the preparation of compounds, for. As the above Vl and VII, on the Wittig reaction, see. 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 are formed in the Wittig reaction with aldehydes.

Object of the invention

The novel intermediates obtainable according to the invention can be further processed into orally active, anti-bacterial cephalosporin end products.

Explanation of the essence of the invention

The invention has for its object to provide new processes for the preparation of intermediates that can be used in the production of antibacterial cephalosporins.

According to the invention, a process for the preparation of the new and valuable intermediates of the general formula (I):

-CH = CH-CH ₃

COOR

and the synthetically useful acid addition and metal salts thereof.

The 3-propenyl group of the compounds of general formula I obtainable according to the invention have Z or cis configuration. R represents a hydrogen atom or a conventional carboxyl-protecting group. The latter group refers to protecting groups commonly used in the synthesis of cephalosporin compounds for amino or carboxyl groups. Suitable carboxyl protecting groups are alkyl 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, trimethylsilyl, tert-butyldimethylsilyl and tert-butyldiphenylsilyl, and other carboxyl protecting groups described in the literature, for example, in British Pat. No. 1,399,086. Preferably, carboxyl protecting groups are employed which can be easily removed with the help of an acid. These include in particular benzhydryl and t-butyl groups. The acid addition salts and the metal salts of those compounds wherein 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 to the compounds of the invention. This is a feature that determines the beneficial gram-negative antibacterial properties of cephalosporin end-products.

Synthetically useful acid addition salts include the salts of the compounds of general formula I with mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid, with organic sulfonic acids such as p-toluenesulfonic acid and other acids known and used in cephalosporin chemistry. Those compounds of general formula I in which R represents a hydrogen atom also form metal salts. Synthetic metal salts are the sodium, potassium, calcium, magnesium, aluminum and zinc salts. The most preferred compounds of the invention are the following:

1. Diphenylmethyl ^ / ß-amino-S-tiZl-i-propen-i-yl-S-cephem ^ -carboxylate.

2. Diphenylmethyl-β-amino-S-ItZl-i-propene-i-yl-S-cephem ^ -carboxylate hydrochloride.

3. Diphenylmethyl-Tβ-amino-S-IfZl-i-propene-i-ylJ-S-cephem-i-carboxylate sulfate.

4. Sodium / S-amino-S-KZl-i-propen-i-yl-S-cephem ^ -carboxylate.

5. Potassium Tβ-amino-S-HZl-i-propene-i-yn-S-cephem ^ -carboxylate.

6. 7/3-Amino-3 - [(Z) -1-propen-1-yl] -3-cephem-4-carboxylic acid.

The process according to the invention is explained in more detail below with reference to 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 may be used which are well known to those skilled in the art

It has been found that in the Wittig reaction of the compound IM 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 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, preferably containing a cosolvent, such as dimethylformamide or isopropanol, in minor proportions of about ¹ to about ¹ volume percent by volume of methylene chloride. The reaction temperatures are from -10 ° C to +25 ⁰ C and preferably at ⁰ C to 25 ⁰ C. DasWittig product Ha 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 1a of the present invention. Reaction 3 in the scheme mentioned.

Thereafter, la is treated with trifluoroacetic acid (TFA) and 7: 3-amino-3 - [(Z) -1-propen-1-yl] -3-cephem-4-carboxylic acid (I b, reaction 7) in the ratio Z / E = 9/1. After acylating I b with p-hydroxyphenylglycine by a conventional "acid chloride method" or an "activated ester method", the orally active cephalosporin V is obtained.

Alternatively, the 7/3 amino-3-propen-1-yl cephalosporin ester Ia may be acylated with N-BOC (tert-butoxycarbonyl) blocked p-hydroxyphenylglycine in the presence of DCC (dicyclohexylcarbodiimide). Then deblocked with TFA (trifluoroacetic acid) and receives the cephalosporin V.

Scheme 1

Scheme 2

PHCH

= N η S

'-CH = PPh ₃

COOCHPh ₂ III

Implementation 3

PhCH = N.

/ -N

CH = CH-CH.

COOCHPh,

Ha

Implementation 3

PhCH ₂ CONH η S ^ö N ₁

A-is

sy ~

CH = PPh.

COOCHPh,

Implementation 10

VIII

PhCH ₂ CONH

CH = CHCH.

COOCHPh,

Implementation 11

IX

-CH = CH-CH.

Implementation 5

COOCHPh. Ia implementation 7 or 8

HO-T V-CHCONH

NHBOC

N, J-CH = CH-CH-

^IV COOCHPh, COOH

CH = CH-CH.

Implementation 6

Implementation 9

HO

J / - V-CHCONH _ S ^S

NH, CH = CH-CH.

COOH

BMY-28100

The invention will be explained in more detail below with reference to the examples. The following abbreviations are used:

Ph = Phenyl BOC = -COOC (CH ₃ I ₃ DCC = Dicyclohexylcarbodiimide TFA = Trifluoroacetic acid EtOAc = Ethyl acetate DMF = Dimethylformamide

Implementation 1

Diphenylmethyl ^ -benzylideneamino-S-triphenylphosphoniomethyl-S-cecommerM-carboxylate chloride To a suspension of diphenylmethyl-amino-S-chloromethyl-S-cephem-1-carboxylate hydrochloride (200 g, 0.44 mol) in 940 mL of CH 2 Cl 2 440 ml of 1N NaOH at room temperature. The mixture is shaken for 10 minutes and the organic layer is separated off. To this organic layer are added MgSO ₄ (75 g) and benzaldehyde (51 g, 0.48 mol), and the mixture is allowed to stand at room temperature for 3 hours. The reaction mixture is filtered and the insoluble constituents are washed with 200 ml of CH ₂ Cl ₂ . To the filtrate, which is combined with the solvent used for washing, is added triphenylphosphine (126 g, 0.48 mol). The mixture is concentrated under reduced pressure to about 400 ml and allowed to stand for 4 days. The resulting viscous oil is diluted with 11% ethyl acetate and triturated to separate the title compound as a pale yellow crystalline powder, which is filtered off and dried in vacuo, yield 322g (96%); Schmp. 185-190 ⁰ C (Zers.).

KBr

IR: νcm " ¹ 1 780.1 720.1 630.

Max

CH ₂ Cl ₂

UV: λ nm (ε) 260 (24100).

Max

Implementation 2

Diphenylmethyl ^ -benzylideneamino-S-ktriphenylphosphoranylidene] -methyl-S-cephem ^ -carboxylatill) A mixture of diphenylmethyl ^ -benzylideneamino-S-triphenylphosphoniomethyl-S-cephem ^ -carboxylate chloride (322g, 0.42 mol) and 252 ml of 5N Na ₂ CO _{3 in} 1.61 CH ₂ Cl ₂ is stirred vigorously for 15 min at room temperature. The organic layer is separated, dried over MgSO ₄ and concentrated to about 500 ml. The concentrate is diluted with stirring with 11 acetone to give a pale yellow crystalline powder, which is filtered off, yield 237 g (78%) of III with mp 195-198 ° C (dec.).

KBr

IR: ν cm " ¹ 1 770.1 620.

Max

CH ₂ Cl ₂

UV: λ nm (ε) 254 (23,000), 389 (22,000).

Max

NMR: 5 ^CDCl 3 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 = 22Hz); 6.95 (1H, s); 7.2 ~ 7.8 (3OH, m); 8.55 (1H, s).

Implementation 3

Diphenylmethyl ^ -amino-S-KZJ-i-propen-i-yl-S-cephem ^ -carboxylate hydrochloride (la hydrochloride) To a cold solution of LiBr (19q, 216 mmol) in a mixed solvent of dry dimethylformamide (100 ml) and CH ₂ Cl ₂ (300ml) are added at ⁰ -5 C acetaldehyde (20 mL; 36OmMoI) and diphenylmethyl ^ -benzylidenamino-S - [(triphenylphosphoranylidene) methyl] -3-cephem-4-carboxylate (III) 15g; 2OmMoI). The mixture is allowed to stand for 20 h at -5 ° C to -1O ⁰ C and then for 5 h at room temperature. The resulting pale yellow solution is concentrated in vacuo to about 100 ml and placed in a solvent (two layers) of ethyl acetate (400 ml) and H ₂ O (400 ml). The upper layer is separated and diluted with 400 ml of isopropyl ether. Silica gel (Wakogel C-100, 40g) is added to the mixture. The mixture is shaken for 5 min and then filtered through a pad of diatomaceous earth (filter aid). The insoluble constituents are washed with a solvent mixture 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 are added to the above concentrate 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 H ₂ 0.3 χ 20 ml of saturated aqueous NaHCO ₃ solution and 20 ml of brine, dried over MgSO ₄ , treated with carbon and concentrated to about 50 ml on. The concentrate is added at room temperature 40 ml of N HCl in methanol and allowed to stand for 15 min. The mixture is concentrated to about 30 ml and diluted by adding 300 ml of ether. The precipitate is filtered off and dried over P ₂ O ₅ , to give 7.9 g of a pale 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, is seeded with a crystalline hydrochloride of the title compound, slowly diluted with 80 ml of ether and stirred 1 h. The deposited colorless crystals are filtered off and dried in vacuo over P ₂ O ₅ to give 6.3 g (71%) of the title compound. This product is a mixture of the Z and Ε isomers relative to the propenyl moiety at the 3-position (Z / E = 9/1 by HPLC) (LichrosorbRP-18.80% methanol - pH 7.2 phosphate buffer, 254nm, 1ml / min ).

-6- 244 Öt> /

KBr

IR: ν cm " ¹ 2 850.1785, 1725.

Max

EtOH

UR: λ nm (ETem) 287 (173).

Max

NMR: s ^DMSOd 6 ppm 1.47 (27/10 H, dd, J = 7, 2Hz, = CHCH ₃ , ice); 1.74 (3 / 10H, d, J = 7Hz, = CHCH _3, trans); 3.47 and 3.8 (each 1H, d, J = 16Hz); 5.13 (1H, d, J = 4.5Hz, 6-H); 5.23 (1H, d, J = 4.5Hz, 7-H); 5.62 (1H, dq, J = 10 and 7Hz, 3-CH = CH); 6.24 (1H, dd, J = 10 and 2Hz, 3-CH); 6.81 (1H, s, CHPH ₂ ); 7.35 (1 OH, m, Ph-H).

Implementation 4

Diphenylmethyl ^ -amino-S-IfZM-propene-i-yD-S-cephem ^ -carboxylate (la)

To a stirred suspension of the hydrochloride of diphenylmethyl ^ -amino-S-lfZJ-i-propene-i-ylJ-S-cephem ^ -carboxylate (5 g; 11.3 mmol) in 20 mL H ₂ O and 40 mL of ethyl acetate is added NaHCO ₃ , to the pH of the mixture becomes 8. The organic layer is washed with 5 ml of saturated aqueous NaCl solution, dried over MgSO ₄ and concentrated to about 20 ml. The resulting solution is diluted with 10mI isopropyl ether and seeded with the crystalline compound I a. Additional isopropyl ether (30 ml) is slowly added to the mixture with stirring. After 15 min, the precipitated colorless crystals are filtered off, washed with 10 ml of isopropyl ether and dried in vacuo over P ₂ Os to give 4.3 g (94%) of the title compound (Z / E = 9/1 by HPLC) (Lichrosorb RP-18.80% methanol - pH 7.2 phosphate buffer, 254nm, 1ml / min).

KBr

IR: ν cm " ¹ 3 450.1765, 1730.

Max

EtOH

UV: λ nm (E Tom) 289 (185).

Max

NMR: 8 ^CDCl 3 ppm 1.43 (3H, dd, J = 2 and 7Hz, CH = CHCH ₃ ); 1.66 (2H, br, s, disappeared with D ₂ O, NH ₂ ); 3.23 and 3.55 (each 1 H, d, J = 17Hz, 2-H); 4.73 (1H, d, J = 4.5Hz, 6τΗ); 4.96 (1H, d, J = 4.5Hz, 7-H); 5.46 (1H, dq, J = 10 and 7Hz, 3-CH = CH); 6.06 (1 Hbr, d, J = 1 = Hz, 3-CH); 6.94 (1H, s, CHPh ₂ ); 7, a (1 = H, m, Ph-H).

Implementation 5

Of diphenylmethyl 7 - [(D) -a- (t-butoxycarbonylamino) -a- (4-hydroxyphenyl) acetamido] -3 - [(Z) -1-propen-1-yl] -3-cephem-4- carboxylate (IV)

A mixture of the diphenylmethyl ^ -amino-S-KZt-i-propene-i-yD-S-cephenrM-carboxylate (1a) (4.2g; 10.4 mmol), (D) -a- (t-butoxycarbonylamino) - a- (4-hydroxyphenyl) -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 has been combined with the solvent used for washing, is washed successively with 3 x 5 ml of saturated aqueous NaHCO ₃ solution, 5 ml of brine, 5 ml of 10% HCl solution and brine, dried over MgSO ₄ , treated with Coal and filtered. The filtrate is concentrated to about 10 ml and diluted with 20 ml of n-heptane. The precipitate is filtered off and dried in vacuo over P2O5. 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).

KBr

IR: νcm " ¹ 3400, 1790, 1720, 1690.

Max

EtOH

UV: λ nm (E) ° cm) 278 (113), 289 (115), 295 (95).

Max

NMR: 6 ^CDCl 3 ppm 1.3-1.45 (12H, m, BOC-H and = CH-CH ₃ ); 3.08 and 3.33 (each 1 H, d, J = 18Hz, 2-H); 4.92 (1H, d, J = 4.5Hz, 6-H); 5.06 (1H, d, J = 6Hz, s for D ₂ O, CHN); 5.5 (1H, dq, J = 10 and 7Hz, 3-CH = CH); 5.68 (1H, dd, J = 4.5 and 8Hz, d, J = 4.5Hz for D ₂ 0.7-H); 6.01 (1H, d, J = 1 = Hz, 3-CH); 6.65 and 7.08 (each 2H, d, J = 8Hz,

H 6.71 (1H, d, J = 8Hz, disappeared for D ₂ 0.7 -NH ₂ ); 6.88 (1H, s, CHPh ₂ ); 7.3 (10H, m, PhH).

Implementation 6

BMY-28100; 7 - [(D) -2-amino-2- (4-hydroxyphenyl) -acetamido] -3- (propen-1-yl) -3-cephem-4-carboxylic acid (V) A mixture of diphenylmethyl ^ -tlDi-a -ft-butoxycarbonylaminol-α-hydroxyphenyl o-acetamidol-S-HZl-i-propene-i-yl-S-cephem-4-carboxylate (IV) (prepared according to Reaction 5) (90% pure, 7.7 g; 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 to concentrate

and concentrate the mixture in vacuo. 200 ml of ether are added to the residual oil, the precipitated solid is filtered off, washed with 20 ml of ether and dried in vacuo over KOH to give 5.3 g of the trifluoroacetic acid (TFA) salt of BMA-28100. 5.3 g of the salt is dissolved in 100 ml of H ₂ O, treated with charcoal and applied to a column packed with Diaion HP-20 (0.6 L). The column is washed with H ₂ O (4I) and eluted with 40% MeOH, and the methanol fractions (1.7I) containing the desired product are collected and concentrated to approximately 20 ml, and the concentrate is diluted The precipitated colorless crystalline powder is filtered off, washed with 20 ml of acetone and dried over P ₂ O ₅ in vacuo to give 4 g (97%) of BMY-28100 (Z / E = 9/1) , Zwitterion) (Lichrosorb RP-18, 20% methanol-pH 7.2 phosphate buffer, 254nm, 1ml / min).

Implementation 7

7-amino-3 - [(Z) -1-propen-1-yl] -ceph-3-em-4-carboxylic acid, I b

To a stirred solution of 260 ml of anisole and 1.381% trifluoroacetic acid (TFA) cooled to ⁰ ° C is added 149.7 g (0.338 mol) of diphenylmethyl ^ -amino-S-KZl-i-propen-i-yl- S-cephem ^ -carboxylic acid hydrochloride (0.338 moles, reaction 3 or 11). The resulting slurry is then stirred for 1 h at room temperature. 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 for 1 h with 1.5 l of dry ether. The crystalline product is filtered off and dried over P ₂ O ₅ to give 87.24 g of I b-trifluoroacetate. This 87.24 g of the trifluoroacetate is suspended in 900 ml of water (pH about 2.5) and stirred. The mixture is cooled to + 5 ° C and then the pH with 12 N HCl to 0.6. The yellow solution is treated with charcoal and the slurry is filtered with a diatomaceous earth filter aid pad. Cool the resulting solution to + 5 ° C and adjust the pH to 2.0 with 20% NaOH. The suspension is allowed to stand in a refrigerator for 1 h to aid crystallization. Collect the crystals, wash with 800 ml of water and 800 ml of acetone and dry in vacuo at room temperature, yield 69.4 g (85.5%). The product contains 9.7% of the trans-isomer (determined with a HPLC column RP18 MERCK; H ₂ (NH ₄ ) PO ₄ ; 0.1 mol 95 ml + CH ₃ CN 5 ml, detected at 290 nm).

Implementation 8

7-amino-3 - [(Z) -1-propen-1-yl] -3-cephem-4-carboxylic acid, Ib

A solution of phosphoranyl compound III (prepared according to Reaction 2: 50.0 g, 68.7 mmol) in 500 mL of CH ₂ Cl _{2 is} mixed with a solution of lithium bromide (29.8 g, 343 mmol) in 170 mL of dry DMF containing a small amount of CH _{2 2} CI ₂ (10 ml) and then with anhydrous acetaldehyde (39 ml, 687 mmol, prepared from paraldehyde and toluenesulphonic acid by distillation according to the method of NLDrake and GB Cooke, Org. Syn CoI, Volume II, p.407). The mixture is placed in a sealed container and allowed to stand for 2 days at 20 ° C. 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 II a as a foamy solid (34 g) used for the next reaction without further purification.

The resulting crude product IIa 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, whereupon an oily layer separates out, which is washed with 3 × 100 ml EtOAc. The pH of the aqueous layer is adjusted to about 3 with 4N NaOH (about 65 ml) while stirring to give a crystalline solid, which is filtered off and washed with 50 ml of water to give the title compound (Ib; 7g; 59%). HPLC (Lichrosorb RP-18.4 x 300mm, MeOH: phosphate buffer [pH 7] = 15:85) shows that this product is a 83:17 mixture of the Z and Ε isomers with respect to the double bond of the 3-propenyl group; M.p. 200 ⁰ C (Zers.).

IR: ν (KBr) in cm " ¹ 3420.1 805.1 620.

Max

UV: (pH 7 phosphate buffer) in nm (ε) 283 (8,900).

Max

NMR: δ (D ₂ O + NaHCO ₃ ) in ppm 1.69 and 1.88 (3H, each d, J = 6.0Hz, Z and E of -CH = CH-CH ₃ ); 3.38 and 3.72 (2H, Abq, J = 17Hz, H-2); 5.18 (1H, d, J ₆₇ = 5.0Hz, H-6); 5.51 (1H, d, H-7); about 5.8 (1 H, m, -CH = CH-CH ₃₎ and 6.06 (1 H, d, J = 11 Hz, -CH = CH-CH _3).

Analysis for C ₁₀ H I ₂ N ₂ O ₃ S: H N S C 5.03 11.66 13.34% calc .: 49.99 4.94 10.93 12.82% Found .: 50,20

Implementation 9

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

Dimethylaniline (1.7 mL, 13.1 mmol), trimethylsilyl chloride (2.1 mL, 16.4 mmol) and triethylamine (TEA, 2.3 mL, 16.4 mmol) are added sequentially to a suspension of compound Ib (prepared according to Reaction 8, 1.58 g, 6.56 mmol) in CH ₂ Cl ₂ (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 and the reaction is monitored by means of HPLC (Lichrosorb RP-18, 4 × 300 nm, MeOH: phosphate buffer (pH 7) = 25:75 ). An additional amount of the glycyl chloride is added to the mixture three times at 15 minute intervals (291 mg each) to complete the acylation. After the addition of dry MeOH (2.0 ml) containing 0.1 ml of dry DMF, the resulting clear solution is neutralized with 3.2 ml of TEA to pH 6 and then diluted with 30 ml of CH ₂ Cl ₂ Precipitate obtained, which is filtered off and washed with 10 ml of CH ₂ Cl ₂ . The title compound is thus obtained as dimethylformamide solvate (2.39 g, yield 94%, about 50% pure, Z / E = 47:12 by HPLC).

Implementation 10

Diphenylmethyl-phenylacetamido-S-KZI-propene-i-yO-ceph-S-em-carboxylate, IX

-CH ₂ CON

COODPM

MW = 758.8

CH ₃ CHO

CH = P (Ph) ₃ CCl ₄ ZCH ₃ OH

1 MW = 524.6

COODPM

A stirred solution of 181 CCI ₄ , 1.81% methanol and 12 g of p-benzoylbenzoic acid, cooled to 8 ^° C., is added to 970 ml of acetaldehyde. The temperature of the solution obtained steigtauf + 14 ⁰ C. After 5 minutes, is 588 g (0,7749MoI) Diphenylmethyl ^ -phenylacetamido-S-Ktriphenylphoranylidenl-methyll-S-cephem ^ -carboxylatzu. The cooling bath is removed and the mixture is stirred vigorously for 4 h at 35 ° C and light and under a N ₂ atmosphere until the phosphorane is completely dissolved.

The resulting solution 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 31% ethanol.

The mixture is stirred for 2 h at + 5 ° C and allowed 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 by HPLC column LichrosorbSi 60 5p, m Merck, eluted with 85% toluene, 15% ethyl acetate).

Implementation 11

Diphenylmethyl ^ -amino-S-tfZl-propen-i-yl-ceph-S-em ^ -carboxylate hydrochloride, la

To a stirred solution of 159,7g (0,767MoI) PCI ₅ in 2.81 CH ₂ Cl ₂ is added over a period of 20 minutes 56.7 ml (0,700MoI) of pyridine in 280 ml CH ₂ CI. ₂ Under a nitrogen atmosphere, the slurry is cooled to 2 ° C 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 is poured quickly into a vigorously stirred solution of 1.44 ₂ CI ₂ and 209ml (2.33 mol) of 1,3-butanediol at -20 ⁰ C, so that the temperature does not exceed -5 ⁰ C is rising. Remove the cooling bath. After 45 minutes, the temperature rises to 10 ⁰ C. This temperature is maintained for 35 min. Add 1.01 water and stir for a further 5 min and then let the layers separate. The organic layer is washed with 600 ml of 2 N HCl and then with 400 ml of saturated sodium chloride solution. The combined aqueous extracts are washed back with 2 χ 600 ml CH ₂ Cl ₂ and combined with the original CH ₂ Cl ₂ extract. The solution is dried over anhydrous MgSO ₄ , the MgSO ₄ slurry is filtered and the MgSO _{4 is} washed twice with 500 ml of CH ₂ Cl ₂ . The combined filtrates are concentrated in vacuo with a rotary evaporator to 2.41 and diluted with 2.51 ethyl acetate. The solution is again concentrated to 1.31, the resulting crystal slurry is filtered, washed with 3 × 300 ml of ethyl acetate and dried in air and vacuum over P ₂ O ₅ to give 149.8 g of the title compound as beige crystals, Yield 69.3%.

Claims (1)

Invention claim: 1. Process for the preparation of the compound of the general formula: CH = CH-CH. COOR R represents a hydrogen atom or a conventional carboxyl-protecting group and the 3-propenyl group has Z configuration, and the acid addition salts thereof and the metal salts of the compounds wherein R represents a hydrogen atom, characterized in that a) an intermediate of the general formula