NL192205C - Process for preparing 7-amino-3- (Z-1-propenyl) -3-cephem-4-carboxylic acid and esters thereof. - Google Patents

Description

1 192205

Process for the preparation of 7-amino-3- (Z-1-propenyl) -3-cephem-4-carboxylic acid and esters thereof

The invention relates to a process for preparing a compound of formula 1, wherein the 3-propenyl group has the Z-configuration and R represents hydrogen or a conventional carboxyl-protecting group, as well as acid addition salts thereof and metal salts of the substance in which R hydrogen, whereby an intermediate of formula 10, in which R has the above meaning and Ph represents a phenyl group, is reacted with acetaldehyde in an inert organic reaction medium comprising dichloromethane, Ν, Ν-dimethykimamide, isopropyl alcohol or a mixture thereof, in a reaction temperature between 0 and 25 ° C, whereby a compound of formula 11 is obtained, and then the benzylidene group or both the benzylidene group and the carboxyl protecting group are removed.

U.S. Pat. No. 4,110,534 discloses a high class 3 vinyl and substituted vinyl cephalosporins and their preparation. This class includes 7-amino-3- (Z-1-propenyl) -3-cephem-4-carboxylic acid and its esters. These fibers can be prepared by subjecting a 3- (triphenylphosphoranylidenemethyl) -cephalosporin to a Wittig reaction. In this publication, a number of ratios of Z and E isomers in the final product are mentioned. Example 21 of this patent discloses a yield of 17% consisting largely of the cis isomer and only 5-10% of the trans isomer. However, it is not stated how these relationships can be influenced.

Of the compounds prepared by the present method, the Z or cis configuration of the 3-propenyl group is a critical property. This configuration determines the beneficial properties against Gram negative bacteria of the cephalosporin end products that are the subject of U.S. Patent 4,520,022.

The object of the present invention is to realize a favorable Z- / E-isomeric ratio in combination with a high chemical yield.

This object is achieved by carrying out a Wittig reaction with suitable starting products in the presence of lithium bromide.

The process of the invention is characterized in that the reaction with acetaldehyde is carried out in the presence of lithium bromide and, optionally, the 3- (Z) and 3- (E) isomers are separated to obtain a compound of formula 1 wherein R is the same has meanings as before.

Incidentally, it is known from U.S. Pat. No. 4,065,620 that 3- (substituted) -vinylcephalo-30 spuns can also be prepared by carrying out the Wittig reaction with a 3- (substituted) -formyl-cephalosporin sulfide or sulfoxide and a phosphorane derivative.

British Patent 1,342,241 describes the compound of formula II, but there is no description of 7p-animo-3 - [(Z) -1-propen-1-yl] -3-cefem-4- carboxylic acid as an intermediate in its preparation.

U.S. Patent No. 4,409,214 describes the preparation of the compound of formula 3 via a Wittig reaction on drphenylmethyl-7-benzylideneamino-3-triphenylphosphoniomethylceph-3-em-4-carboxy plate in Preparation Examples 38 and 39, but there is no description of 7p-amino-3 - [(Z) -1-propen-1-yl] -3-cefem-4-carboxylic acid, nor of any other 3- (1-propen-1 - yl) -cephaiosporin compound.

40 By H.O. House et al. Jour. Oig. Chem. 29, 3327-3 333 (1964) has studied the effect of solvents and additives including lithium salts on the amounts of cis and trans olefins produced in the Wittig reaction with aldehydes. However, this publication does not mention a combination of a high chemical yield with a favorable Z / E isomer ratio anywhere.

In the compounds of formula 1, R represents hydrogen or a conventional carboxyl protecting 45 group. The latter expression refers to protecting groups of the type 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 t-butyl; haloalkyl groups such as 2,2,2-trichloroethyl, alkenyl groups such as allyl, 2-chloroallyl, alkoxymethyl groups such as methoxymethyl, 50 2- (trimethylsilyl) ethyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and other carboxyl protecting groups which the literature has been described, such as, for example, in British Pat. No. 1,399,086. Preferably, carboxyl protecting groups are used which can be easily removed by treatment with acid, in particular benzhydryl or t-butyl. The preparation of the acid addition salts and the metal salts of said substance wherein R represents hydrogen are also part of 55 of the present invention.

The synthetically useful acid addition salts include the salts of formula 1 with mineral acids such as hydrogen chloride, sulfuric acid and phosphoric acid, with organic sulfonic acids such as p-toluenesulfonic acid and 192205 other acids known and used in the field of cephalosporins.

The substances of formula 1 in which R represents hydrogen also form metal salts. Synthetically suitable metal salts include sodium, potassium, calcium, magnesium, aluminum and zinc salts.

The compounds which are preferably prepared according to the invention are: 1. Diphenylmethyl-7p-amino-3 - [(Z) -1-propen-1-yl] -3-cephem-4-carboxylate, 2. Diphenylmethyl- 7p-amino-3 - [(Z) -1-propen-1-yl] -3-cephem-4-carboxylate hydrochloride, 3. Diphenylmethyl ^ -amino-3 - [(Z) -1-propen-1-yl] -3-cefem-4-carboxylate sulfate, 4. Sodium-73-amino-3 - [(Z) -1-propen-1-yl] -3-cefem-4-carboxylate, 5. Potassium-7β-amino-3 - [(Z) -1-propen-1-yl] -3-cephem-4-carboxylate, and 10 6,7p-Amino-3 - [(Z) -1-propen-1-yl] -3-cefem -4-carboxylic acid.

Preferred procedures are shown in reaction schemes A and B.

In reaction scheme A, the diphenylmethyl group is indicated as the preferred carboxyl protecting group. However, those skilled in the art will appreciate that other carboxyl protecting groups well known per se can be used.

in the Wittig reaction of the compound of formula 5 with acetaldehyde, it has been found that addition of lithium bromide improves the yield and ratio of Z / E isomer of the reaction product of formula 4a. The reaction is preferably carried out with 5-15 chemical equivalents, preferably 10 equivalents of lithium bromide.

Methylene chloride is the preferred reaction medium, which preferably contains a cosolvent such as dimethylformamide or isopropyl alcohol in minor amounts of 1/10 to 1/3 part by volume per part methylene chloride. Reaction temperatures in the range of from -10 ° C to + 25 ° C are suitable, with temperatures from 0 to 25 ° C being preferred. The Wittig product of formula 4a is extracted in a suitable organic solvent such as ethyl acetate and the extract is treated with Girard's reagent 25T to yield the 7-aminocef-3-em compound of formula 1a. See procedure 3.

In the experimental procedures, a number of abbreviations are used, which have the following meanings:

Ph = phenyl

EtOAc = ethyl acetate, DMF = dimethylformamide

Procedure 1

Diphenylmethyl-7-benzylideneamino-3-triphenylphosphoniomethyl-3-moiety-4-carboxylate chloride.

To a suspension of diphenylmethyl-7-amino-3-chloromethyl-3-cephem-4-carboxylate hydrochloride (200 g, 0.44 mol) in CH 2 Cl 2 (940 ml) was added 1N NaOH (440 ml) at room temperature. The mixture was shaken for 10 minutes and the organic layer separated. To this organic layer, MgSO 4 (75 g) and benzaldehyde (51 g, 0.48 mol) were added and the mixture was allowed to stand at room temperature for 3 hours. The reaction mixture was filtered and the insolubles were washed with 200 ml CH 2 Cl 2. 126 g of triphenylphosphine (0.48 mol) 40 was added to the combined filtrate and washings. The mixture was concentrated under reduced pressure to about 400 ml and left to stand for 4 days. The viscous oil obtained was diluted with 1 liter of ethyl acetate and triturated to yield the title compound as a pale yellow crystalline powder which was collected by filtration and dried under reduced pressure. Yield 322 g (96%). Melting point 185 to 190 ° C (decomposition).

45 IR: uijSc cm "1 1780, 1720,1630.

UV: λ £ & α * nm (e) 260 (24100).

Procedure 2

Diphenylmethyl-7-benzylideneamino-3 - [(triphenylphosphoranylidene) -methyl] -3-cephem-4-carboxylate (Formula 5).

50 A mixture of diphenylmethyl-7-benzylideneamino-3-triphenylphosphoniomethyl-3-cephem-4-carboxylate chloride (322 g, 0.42 mol) and 5N Na 2 CO 3 (252 ml) in CH 2 Cl 2 (1.6 liter) was left for Stirred vigorously for 15 minutes at room temperature. The organic layer was separated, dried over MgSO 4 and concentrated to a volume of about 500 ml. The concentrate was diluted with 1 liter of acetone, with stirring, to form a pale yellow crystalline powder which was collected by filtration. The yield of the title product was 237 (78%) with a melting point at 195-198 ° C (decomposition).

3 192205 IR: Umax cm -1 1770, 1620.

UV: λ ™ nrn (e) 254 (23000), 389 (22000).

NMR: SCDC'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 = 22Hz), 6.95 (1H, s), 7.2? 7.8 (30H, m), 8.55 (1H, s).

5

Procedure 3

Diphenylmethyl-7-amino-3 - [(Z) -1-propen-1-yl] -3-cephem-4-carboxylate hydrochloride (1a hydrochloride).

Acetaldehyde (20 ml, 360 mmol) and diphenylmethyl-7 were added to a cold solution of LiBr (19 g, 216 mmoi) in a mixed solvent of dry dimethylformamide (100 ml) and CH2Cl2 (300 ml) at -5 ° C. -10 benzylidene-amino-3- (triphenylphosphoranylidene) methyl -3-cephem-4-carboxylate (of formula 5) (15 g, 20 mmol). The mixture was allowed to stand at -5 ° C to -10 ° C for 20 hours and then at room temperature for 5 hours. The resulting light brown solution was concentrated to a volume of about 100 ml under reduced pressure, and was added to a two-layer solvent of ethyl acetate (400 ml) and water (400 ml). The top layer was separated and diluted with 400 ml of isopropyl ether. Silica gel (Wako gel C-100, 40 g) was added to the mixture. The mixture was shaken for 5 minutes and filtered through a pad of diatomaceous filter aid. Insolubles were washed with a mixed solvent of ethyl acetate-isopropyl ether (1/1, 200 ml). The combined filtrate and washings were concentrated to a volume of about 400 ml.

A 0.5 M Girard reagent T solution in 60 ml of methanol and 6 ml of acetic acid was added to the above concentrate and the mixture was stirred at room temperature for 15 minutes. The mixture was evaporated to a volume of about 200 ml, washed with 200 ml of water, 3 x 20 ml of saturated aqueous NaHCO 3 solution and 20 ml of brine, in this order, and dried over MgSO 4, treated with charcoal and concentrated to about 50 ml . N HCl in 40 ml of methanol was added to the concentrate at room temperature and the resulting mixture was allowed to stand for 25 minutes. The mixture was evaporated to about 30 ml and diluted by adding 300 ml of ether. The precipitate was collected by filtration and dried over Pa05 to obtain 7.9 g of a pale yellow powder. A solution of the powder (7.3 g) in a mixed solvent of 80 ml of methanol and 80 ml of ethyl acetate was treated with charcoal, concentrated to about 100 ml, inoculated with crystalline hydrochloride of the title compound, diluted slowly to 80 ml of ether and Stirred for 1 hour. The separated colorless crystals were collected by filtration and dried over P2Os under reduced pressure to yield 6.3 g (71%) of the title compound. This product is a mixture of the isomers Z and E for the propenyl group in the 3-position (Z / E = 9/1 by HPLC) (Lichrosorb RP-18, 80% methanol - pH 7.2 phosphate buffer, 254 nm , 1 ml / min).

IR: cm-1 2850.1785.1725.

UV: nm (E} *,) 287 (173).

NMR: 8DMS ° -d 'ppm 1.47 (27/1 OH, dd, J = 7.2 Hz, = CHCH3, cis), 1.74 (3/1 OH, d, J = 7 Hz, = CHCH3 , trans), 3.47 & 3.8 (1H, d, J = 16 Hz each), 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, d -d J = 10 & 2 Hz .3 -CH), 6.81 (1H, s, CHPH2), 7.35 (10H, m, Ph-H).

Procedure 4

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

To a stirred suspension of the hydrochloride of diphenylmethyl-7-amino-3 - [(Z) -1-propen-1-yl] -3-45 cephem-4-carboxylate (5 g, 11.3 mmol) in H 2 O ( 20 ml) and ethyl acetate (40 ml) NaHCO 3 was added until the pH of the mixture became 8. The organic layer was washed with 5 ml of saturated aqueous NaCl solution, dried over MgSO 4 and concentrated to a volume of about 20 ml. The resulting solution was diluted with 10 ml of isopropyl ether and seeded with crystalline compound of formula 1a. A further 30 ml isopropyl ether was slowly added to the mixture while 50 was stirred therein. After 15 minutes, the separated colorless crystals were collected by filtration, washed with 10 ml of isopropyl ether and dried over P2 O5 under reduced pressure. 4.3 g (94%) of the title compound (Z / E = 9/1 by HPLC) were obtained (Lichrosorb RP-18 80% methanol - pH 7.2 phosphate buffer, 254 nm, 1 ml / min).

IR: v cm 1, 3450,1765,1730.

55 UV: XHm nm (E1 ° °m) 289 (185).

NMR: 8C0C, 3 ppm 1.43 (3H, d-d, J = 2 & 7 Hz, CH = CHCH3), 1.66 (2H, br, s, disappeared by DaO,

Claims (3)

192205 4 NH2), 3.23 & 3.55 (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, dq, J = 10 & 7 Hz, 3-CH = CH), 6.06 (1H, br, d, J = 10 Hz, 3-CH), 6.94 (1H, s, CHPha), 7.3 (10H, m, Ph-H). 5 Procedure 5 Diphenylmethyl-7-phenylacetamido-3 - [(Z) -propen-1-yl] cef-3-em-4-carboxylate, formula 9 (see reaction scheme C). A stirred solution of 18 liters of CCI4, 1.8 liters of methanol and 12 g of p-benzoyl benzoic acid was cooled to 8 ° C and 970 ml of acetaldehyde was added. The temperature of the obtained solution rose to + 14 ° C. After five minutes, 588 g (0.7749 mol of diphenylmethyl-7-phenyl-acetamido-3 - [(triphenylforanylidene) -3-10 cephem-4-carboxylate was added. The cooling bath was removed and the mixture was stirred at 35 ° for 4 hours C stirred vigorously, shielded from light under an N2 atmosphere, until the phosphorane was completely dissolved The resulting solution was concentrated under reduced pressure and the residue was dissolved in 2 liters of ethanol, and the solution was concentrated under reduced pressure to a semi- crystallized residue which was suspended with 3 liters of ethanol The mixture was stirred at + 5 ° C for 2 hours and left overnight The crystals were collected twice, washed with ethanol, and dried at room temperature under reduced pressure. was 191 g (47%). Melting point was 124-128 ° C and it contained 7.5% trans isomer (determined by HPLC column Lichrosorb Si 60 5pm Merck, eluted with 85% toluene, 15% ethyl acetate). 20 Procedure 6 Diphenylm ethyl 7-amino-3 - [(Z) -propen-1-yl] cef-3-em-4-carboxylate hydrochloride, formula 1a. To a stirred solution of 159.7 g (0.767 mol) PCI5 in 2.8 L CH2Cl2 was added 56.7 ml (0.700 mol) pyridine in 280 ml CH2Cl2 over a 20 minute period. Under a nitrogen atmosphere, the suspension was cooled to 2 ° C, while adding 256 g of the compound of formula 9 prepared according to procedure 10 (0.488 mol). The mixture was stirred for 40 minutes and the resulting suspension 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 was not above -5 ° C. The cooling bath was removed and after 45 minutes the temperature rose to 10 ° C, which was then maintained for 35 minutes. Water (1.01) was added and stirring was continued for 5 minutes after which the layers were allowed to separate. The organic layer was washed with 600 ml of HCl 2 N, then with 400 ml of saturated saline. The combined aqueous extracts were backwashed with 2 x 600 ml Ch2CI2 and combined with the original CH2CI2 extract. The solution was dried over anhydrous MgSO 4. The MgSO 4 suspension was filtered and the MgSO 4 washed with 2 x 500 ml CH 2 Cl 2. The combined filtrates were concentrated under reduced dark on a rotary evaporator to a volume of 2.4 liters and diluted with 2.5 liters of ethyl acetate. The solution was concentrated again to a volume of about 1.3 liters. The resulting crystal suspension was filtered and washed with 3 x 300 ml ethyl acetate. After air drying and under reduced pressure over P2Os, 149.8 g of the title compound were obtained as beige-colored crystals. 40 The yield was 69.3%. A process for preparing a compound of formula 1, wherein the 3-propenyl group has the Z configuration and R represents hydrogen or a conventional carboxyl protecting group, its acid addition salts and metal salts of the substance wherein R represents hydrogen, wherein an intermediate of formula 10, wherein R has the above meaning and Ph represents a phenyl group, is reacted with acetaldehyde in an inert organic reaction medium comprising dichloromethane, N, N-dimethylformamide, 50 isopropyl alcohol or a mixture thereof, at a reaction temperature between 0 and 25 ° C, whereby a compound of formula 11 is obtained, and then the benzylidene group or both the benzylidene group and the carboxyl protecting group are removed, characterized in that the reaction is carried out with acetaldehyde 192205 hyde in the presence of lithium bromide and if desired the 3- (Z) and 3- (E) isomers are separated to obtain a compound of formula 1 wherein n R has the same meanings as above. Hereby 2 sheets drawing