CS270435B2 - Method of 7-amino-3-propenylcephalosporanoic acid and its esters production - Google Patents

Description

The present invention relates to novel intermediates for the preparation of cephalaporins, namely 7H-amino-3 / (Z) -1-propen-1-yl-7-cephem-4-carboxylic acid and its esters of formula I

wherein the configuration of the 3-propenyl group is Z (sometimes referred to as cis) and R represents a hydrogen atom or a common ester protecting group of the carboxyl function, and their acid and metal addition salts of the above compound wherein R is hydrogen. The disclosed compounds are useful as intermediates for the preparation of cephalosporins effective when administered orally.

In the British patent specification δ. No. 1,342,241, issued Jan. 3, 1974 (corresponding to U.S. Patent Nos. 3,769,277 and 3,994,884, issued Oct. 30, 1973 and Nov. 30, 1976) discloses a compound of Formula VI.

(VI), however, there is no mention of 7B-amino-3-Z (Z) -1-propen-1-yl-7-cephem-4-carboxylic acid as an intermediate used in the preparation of the above compound.

U.S. Patent No. 4,409,214, issued October 11, 1983, describes the preparation of a compound of formula VII

(VII)

By Wittig reaction using diphenylmethyl-7-benzylidemamino-3-triphenylphosphoniomethylaef-3-em-4-carboxylate (see Preparations 38 and 39), however, the 7-amino-3-Z (Z) -1-propene-1- N-3-cephem-4-carboxylic acid, and no other 3- (1-propen-1-yl) cephalosporanic compound.

U.S. Pat. No. 4,110,534, issued April 29, 1978, and in particular relates to the preparation of compounds such as those of the above formulas VI and VII by the Wittig reaction. Particular reference is made to columns 8, 9 and 49 (Example 21).

H. House et al., Jour. Org. Chem. 22, 3327-3333 (1964), studied the effect of solvents and additives, such as lithium salts, on the ratio of cis- and trans-olefins produced by the Wittig reaction to β aldehydes.

The invention relates to cephalosporin intermediates of formula (I)

(1) their synthetically usable acid addition salts and metal salts.

In the compounds of Formula I, the 3-propenyl group has the Z (or cis) configuration. The symbol R represents a hydrogen atom or a common ester protecting group for a carboxyl function. The term refers to a protecting group commonly used to protect amino or carboxyl groups in the synthesis of cephalosporin compounds, selected from the group consisting of C7-14 aralkyl groups optionally substituted by nitro; C 1 -C 4 alkoxy, C 1 -C 6 alkyl optionally substituted with 1 to 3 halogen atoms, C 2 -C 6 alkoxymethyl, C 1 -C 4 trialkylsilyl in each alkyl moiety, and C 1 -C 4 diphenylalkylsilyl Examples of suitable protecting groups within the above range include benzyl, p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl diphenylmethyl (benzhydryl), target, butylo and 2,2,2-trichloroethyl, methoxymethyl, 2- (trimethylsilyl) ethyl, trimethylsilyl, tert-butyldimethyleilyl and tert-butyldiphenylsilyl. These and other suitable carboxyl function protecting groups are described in the literature, e.g. In the present case, preference is given to those carboxyl-protecting groups which are readily cleavable by acid treatment, in particular benzhydryl group * or tert-butyl group. The invention also includes acid addition salts of the above compounds with acids and the metal salts of those compounds in which R represents a hydrogen atom. The Z-configuration (or cis-configuration) of the 3-propenyl groups is of critical importance for this invention. This characteristic aspect determines the beneficial antibacterial properties of the final cephalosporins against gram-negative organisms.

Synthetic acid addition salts of the compounds of formula (I) include salts with mineral acids such as hydrochloric acid, sulfuric acid as well as phosphoric acid, salts of 8 organic sulfonic acids such as β-toluenaulfonic acid, and salts with other acids used in chemistry cephalosporins.

CS 270439 B2

The compound of formula (I) in which R is a hydrogen atom is also an β metal. Synthetic metal salts include sodium, potassium, calcium, magnesium, aluminum and zinc salts.

The most preferred compounds of the invention are:

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

2. Diphenylmethyl-70-amino-3 - [(Z) -1-propen-1-yl] -3-cephem-4-carboxylate hydrochloride;

3. Diphenylinethyl-1 H -amino-3 - [(Z) -1-propen-1-yl] -3-oephem-4-carboxylate sulfate;

4. Sodium-70-amino-3 - [(Z) -1-propen-1-yl] -3-cephem-4-carboxylate;

5. calliin-70-amino-3 - [(Z) -1-propen-1-yl] -3-oephem-4-carboxylate; and

6. 70-Alno-3 - [(Z) -1-pren-1-yl] -3-cephem-4-carboxylic acid.

Preferred processes for the preparation of the compounds of formula (Z) according to the invention are outlined in Reaction Schemes 1 and 2;

Diagram. 1 Scheme 2

PhCH

COOCHPh ₂

PhCH ₂ COHH <

Example 3

PhCH-N

COOCHPh

CH-CHCH ₃ Example ³⁰ COOCHPh (XX) Example 5

HIM

(XV) Example 11

COOCHrn

CX <)

CH-CH-CH

CH-CH-CH ₃

I NHBOC

or 8 (Ib) example 6

HIM

^ / example 9

CONH

NH

H «CH-CH ₃ (v)

COOH

In the above formulas, Ph represents a phenyl group.

CS 270435. B2

In Scheme 1, diphenylmethyl is mentioned as the preferred carboxyl-protecting group, but it is understood that other carboxyl-protecting groups known in the art may be used in the present case.

It has been found that in the Wittig reaction of a compound of formula XII with acetaldehyde, the addition of a suitable lithium halide such as lithium chloride, lithium bromide or lithium iodide results in improved yield and Z / E isomer fraction in the reaction product of formula IIIa. 5 to 15 equivalents, preferably 10 equivalents of lithium bromide

The preferred reaction medium is methylene chloride containing preferably a certain amount (about 1/10 to 1/3 volume by volume for each part of methylene chloride) of a co-solvent such as dimethylformamide or isopropanol. 25 ° C, preferably from 0 to 25 ° C. · The Wittig reaction product (IIIa) is extracted with a suitable organic solvent, such as ethyl acetate, and the extract is treated with Girard reagent T to form

7-aminoceph * 3-enderivative of formula (Ia) according to the invention This procedure is described in Example 3. 3-cefem-4-carboxylic acid of formula 1b (Example 7) »wherein the Z / E isomer ratio is &gt; 9/1 Acylation of the compound of formula 1b with p-hydroxyphenylglycine using a conventional method of acylation with acid chloride or activated ester then yields cephalosporin V, effective for oral administration ·

Alternatively, the cephalosporin of formula V is obtained by acylating the ester of formula Ia with a p-hydroxyphenylglycine protected with nitrogen by a tert-butoxycarbonyl group in the presence of dicyclohexylcarbodiimide followed by removal of the protecting group with trifluoroacetic acid.

The invention is illustrated by the following non-limiting examples. Ph is the phenyl group and the shapes of the signals in the NMR spectra are indicated by the usual abbreviations:

= singlet d «doublet t = triplet q = quartet □ = multiplet w = Broad signal ·

Example 1

Diphenylmethyl-7-benzylideneamino-3-triphenylphosphonomethyl-3-cephem-4-carboxylate chloride

To a suspension of 200 g (0.44 mol) of diphenylmethyl-7-amino-3-chloroethyl-3-cephem-4-carboxylate hydrochloride in 940 ml of dichloromethane is added at room temperature 440 ml of 1 N sodium hydroxide. then the organic layer was separated, 75 g of magnesium sulfate and 51 g (0.46 mol) of benzaldehyde were added thereto, and the resulting mixture was allowed to stand at room temperature for 3 hours. The reaction mixture was filtered and the insolubles were washed with 200 ml of dichloromethane. Combine with the washings, add 126 g (0.46 mol) of triphenylphosphine, concentrate under reduced pressure to about 400 ml and allow to stand for 4 days. The resulting viscous oil is diluted with 1 liter of ethyl acetate and triturated to yield The title compound is obtained in the form of a pale yellow crystalline powder, which is filtered off and dried in vacuo. The product melting under decomposition at 185-190 ° C yields 322 g (96%).

IR: 0 178 ° »1720, 163 ° cm @ ^-1 .

UV: 1 ^{μm λ} 1,260 µm (g 24100).

шах

Example 2

Diphenylmethyl-7-benzylenenamino-3 - [(tri- enylphosphonated lidene)] motba 1 -3-cis-4-carboxylate (III)

Зтёв 322 g (0.42 mol) of dienylmethyl-7-benzylldenamino-3'-triphenyl-phosphonomethyl-5-methyl-4-carboxylate chloride and 252 ml of a 5N solution of sodium carbonate in 1.6 liters of dichloromethane. at room temperature for 15 minutes vigorously stirring. The organic layer was separated, dried over magnesium sulfate and concentrated to about 500 mL. The concentrate was diluted with 1 liter of acetone with stirring to give a pale yellow crystalline powder which was filtered off to give 237 g (78%) of the compound of formula III, melting at 195-198 ° C with decomposition.

ID ^:) КВг 1770,1620 0т ·· ¹ .

* max

UV: CH ₂ Cl 2 _{254 am} (g 23000), 389 nm (f 22000).

** max

NMR (CDCl3, 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, a), 7.2-7.8 (ЗОН, m), 8.55 (1H, a) ·

Example 3

Phenylmethyl 1-7 -amino-3 - [(Z) -1-propen-1-yl] -3-methyl-4-carboxylate hydrochloride (Ia, hydrochloride)

20 ml (360 mmol) of acetaldehyde and 15 g (20 mmol) of diphenylmethyl-7- are added to a cold solution of 19 g (216 mmol) of lithium bromide in a mixture of 100 ml of anhydrous dimethyl amide and 300 ml of dichloromethane at -5 ° C. benzylideneamino-3-7-triphenylphosphoranylidene) methyl 3-cephem-4-carboxylate (III). The mixture was left to stand at -5 to -10 ° C for 20 hours and then at room temperature for 5 hours. The resulting brownish solution was concentrated to about 100 mL in vacuo and the concentrate was added to a mixture of 400 mL of ethyl acetate and 400 mL of water. The upper layer is separated, diluted with 400 ml of isopropyl ether and 40 g of silica gel are added. The resulting mixture was stirred for 5 minutes, then filtered through a pad of diatomaceous earth and the insoluble matter was washed with 200 mL of a mixture of equal parts of ethyl acetate and isopropyl ether. The filtrate is combined in the washings and concentrated to a volume of about 400 ml. To this concentrate was added a solution of 0.5M Oirard reagent T in 60 ml of methanol and 6 ml of acetic acid, stirred at room temperature for 15 minutes and then evaporated to a volume of about 200 ml. The concentrate is washed successively with 200 ml of water, three times with 20 ml each of saturated aqueous sodium bicarbonate solution and 20 ml of sodium chloride solution, dried over magnesium sulfate and, after decolorizing with charcoal, concentrated to a volume of about 50 ml. 40 ml of 1N methanolic hydrochloric acid are added to the concentrate at room temperature, the mixture is allowed to stand for 15 minutes, then evaporated to a volume of about 30 ml and the concentrate is diluted with 300 ml of ether. The precipitate formed is filtered and dried over phosphorus pentoxide to give 7.9 g of a yellowish powder.

Dissolve 7.3 g of this powder in a mixture of 60 ml of methanol and 80 ml of ethyl acetate, decolorize with charcoal, concentrate to a volume of about 100 ml, inoculate the concentrate with crystalline hydrochloride of the title compound, slowly dilute with 80 ml of ether and Stir for one hour. The precipitated colorless crystals are filtered off and dried in vacuo over phosphorus pentoxide. This afforded 6.38 (71%) of the title compound. This product consists of a mixture of Z- and E-isomers on the propanyl residue at the 3-position. According to HPLC, 80% methanol with phosphate buffer pH 7.2 (254 µl, flow rate 1 ml / min) as eluent Z / E »9/1. ^IR! ) max · ^2β 5θ / 17β5, 1725cm ” ¹ .

^{1175 287 Н 287 Μ (E} lím ¹⁷³⁾ ·

NMR (perdeuterodimethylsulfoxide, values <1 ppm):

1.47 (27 / 1OH, dd-, J = 7.2 Hz, = CHCH ₃ , cis), 1.74 (3 / ЮН, d, J = 7 Hz, CHCH ₃ , trans), 3.47 and 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 a)

Hz, 3-CH3CH), 6.24 (1H, d-d, J &gt; 10 and 2 Hz, 3-CH), 6.81 (1H, s, CHPhg),

7.35 (M, m, Ph-H).

Example 4

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

To a stirred suspension of 9 in (11.3 mmol) diphenylaethyl-7-amino-3 - [(Z) -1-propenyl] -3-cephem-4-carboxylate hydrochloride in 20 ml of water and 40 ml of ethyl acetate, sodium bicarbonate was added to pH 8. The organic layer is washed with 9 ml of saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated to a volume of about 20 ml. The concentrate is diluted with 10 ml of isopropyl ether, seeded with crystalline compound Ia and the mixture is slowly added with stirring. After stirring for 15 minutes the precipitated colorless crystals are filtered off and, after washing with 10 ml of isopropyl ether, dried under vacuum over phosphorus pentoxide. high pressure liquid chromatography, 80% methanol-phosphate buffer pH 7.2, 294 nm, flow rate 1 ml / min) ^IR: 9mx 3450, 1765, 1730 cm ^-1 .

^UV: mmS ^{H 289} ““ ^(E 1 * cm ¹⁸⁵ > ·

NMR (CDCl3, value / vppu):

1.43 (3H, dd, J 2 and 7 Hz, CH 3 CHCH 2), 1.66 (2H, bs, not present in the spectrum, HHg), 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, dq, J and iq_a 7 Hz, 3-CH3CH), 6.06 (1H, bd, J = 10 Hz, 3-CH), 6.94 (1H, s, CH ν h ₂ ), 7.3 (MH +, Ph-H).

Example 5

Difenylmethy1-7 - / (D- ^and - (Boc) -Λ- (4-hydroxyphenyl) acetoamido / 3 - / (Z) -l-propen-l-yl / -3-cephem-4-carboxylate ( IV)

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 (0) - ^α - (tert-butoxycarbonylamino) -4- (4-hydroxyphenyl) acetic acid and 2.6 g (12.5 mmol) of dicyclohexylcarbodiimide in 104 ml of ethyl acetate were stirred at room temperature for 1.5 hours. rooms. The reaction mixture was filtered and the insolubles washed with 20 ml of ethyl acetate. The filtrate is combined with the washings

The liquid was washed successively with 5 ml each of 5 ml of saturated aqueous sodium bicarbonate solution, 5 ml of sodium chloride solution, 5 ml of 10% hydrochloric acid and sodium chloride solution, dried over magnesium sulphate and filtered after decolorizing with charcoal. the nitrate is concentrated to a volume of about 10 ml and the concentrate is diluted with 20 ml of n-heptane. The leached precipitate is filtered off and vacuum-dried over phosphorus pentoxide. 7.8 g (purity 90% by weight quantitative yield) of the title compound are obtained in the form of a colorless powder, in which the ratio of isomers Z / E · 9/1 (HPLC, 80% methanol-phosphate buffer pH 7), 2, 254 nm, flow rate 1 ml / nin).

IR: J 3400, 1790, 1720, 1690 cm ^-1 .

UV: ^{278 µ (E1} * cm ^U3) ' ²⁸⁹ '' ^(E1 * cm ^U5) · ^{295 no (e1} * ⁹⁵⁾ ' cm

NMR (CDCl3):

1.3 to 1.45 (12H, m, H-butoxycarbonyl and »CH-CH _3), 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 =

Hz, in the presence of deutsium oxide s, CHN), 5.5 (1H, dq, J 10 and 7 Hz, 3-CH 2 CH), 5.68 (1H, dd, J 1, 4.5 and 8 Hz, d, J = 4.5 Hz in the presence of deuteriuron oxide · 7-H), 6.01 (1H, d, J = 10 Hz, 3-CH), 6.65 and 7.08 (each 2H, d, J) 8 Hz,

disappeared using deuteriuron oxide, 7-KHg), 6.88 (1H, s, CHFhg), 7.3 (10H, m, Ph-H).

Example 6

7-Z (D) -2-amino-2- (4-hydroxyphenyl) acetamido / -3- (px ^, open-1-yl) -3-oephom-4-carboxylic acid (V)

Mixture of 7,7 8 diphenylmethyl-7 - [(D - <* - (tert-butoxycarbonylamino) - * - (4-hydroxyphenyl) acetamido] -3 - [(Z) -1-propen-1-yl] -3 -cephem-4-carboxylate (IV) prepared in Example 5 (purity 90 10.6 mmol), 7.7 mL of anionic acid and 77 mL of trifluorootic acid are stirred at room temperature for 1 hour. The reaction mixture is concentrated in vacuo to a residue. 50 ml of toluene are added and the mixture is evaporated in vacuo. The oily residue is taken up in 200 ml of ether, the precipitated solid is filtered off and, after washing with 20 ml of ether, dried in vacuo over potassium hydroxide. with trifluoroacetic acid · 5.3 g of this salt are dissolved in 100 ml of water, the solution is clarified with activated carbon and applied to a column of 0.6 liters * with Diaion HP-20 ion exchange resin. The column is washed with 4 liters of water and then eluted with 40 liters. The methanolic fractions of 1.7 liters containing the desired product were evaporated to a volume of about 20 ml and the concentrate was The precipitated colorless crystalline powder is washed with 20 ml of acetone and dried in vacuo over phosphorus pentoxide to give 4 g (97%) of the title product in which the isomer ratio Z / E * 9/1 (zwitterionic) is obtained. ion) (high pressure liquid chromatography, Lichrosorb RP-18, 20% methanol, phosphate buffer pH 7.2, 254 nm, flow rate 1 ml / min) ·

Example 7

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

To a stirred solution of 260 ml of anisole and 1.38 liters of trifluoroacetic acid, cooled to 0 ° C, 0.338 mol (149.7 g) of diphenylmethyl-7-amino-3 - [(Z) -1-propen-1-yl] hydrochloride is added. The resulting suspension was stirred at room temperature for 1 hour, most of the excess trifluoroacetic acid was evaporated in vacuo on a rotary evaporator, the remaining supernatant was separated by decantation and the pellet was removed. Triturate with β 1.5 liters of dry ether for 1 hour. The crystalline product is filtered off and dried over phosphorus pentoxide. 87.24 g of trifluoroacetate 1b are obtained. The 87.24 g of trifluoroacetate are suspended in 900 ml of water (pH ca. 2.5) with stirring, the mixture is cooled to + 5 ° C and the pH is adjusted to 0.6 with 12N hydrochloric acid. activated carbon and the suspension is filtered through a pad of diatomaceous earth · The filtrate is cooled to * 5 ° C and adjusted to pH 2.0 with 20% sodium hydroxide solution · The resulting suspension is kept in the refrigerator for 1 hour to crystallize · Crystals are collected, washed with 600 ml of water and 800 ml of acetone, and dried under vacuum at room temperature. The yield is 69.4 g (85.5%). The product contains 9.7% of the trans-isomer (by HPLC on a HP 16 MERCK column). ; 95 ml 0.1M ammonium dihydrogen phosphate - 5 ml acetonitrile, detection at 290 nm / ·

Example 8

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

A solution of 50.0 g (68.7 mmol) of the phosphorousl compound of formula III, prepared as described in Example 2, in 500 ml of dichloromethane is treated with 8 solution of 29.8 g (343 mmol) of lithium bromide in 170 ml of dry dimethylformamide containing a small amount of dichloromethane ( 10 ml) and then with 39 ml of anhydrous acetaldehyde (667 mmol; prepared according to the procedure described by NL Drake and GB Cooke, Org · Syn. Col · Vol · II, p. 407, distillation from paraldehyde and toluenesulfonic acid) · Mixture The reaction mixture is evaporated, the liquid residue is diluted with 800 ml of ethyl acetate, the solution is washed three times with 300 ml of water and 300 ml of saturated chloride solution each time. Sodium, then evaporated. 34 g of protected 3-propenyl derivative of formula IIa are obtained in the form of a rigid foam, which is used without further purification for the following reaction.

The crude product of formula IIIa above prepared at room temperature for 1 hour is treated with 35 ml of 98% formic acid and 17 ml of concentrated hydrochloric acid (206 mmol). After adding 350 ml of water, an oily layer is separated from the reaction mixture and removed by shaking three times. 100 ml of ethyl acetate in each case. · The pH of the aqueous layer is adjusted to approximately 3 (ca 65 ml) with 4N sodium hydroxide solution. During this alkalization with stirring, a crystalline product precipitates, which is filtered off and washed with water (50 ml). 9.7 g (? 9%) of the title compound (1b) are obtained. High pressure liquid chromatography (Lichrosorb RP-18, 4 x 300 mm, methanol-phosphate buffer pH 7 15 and 85) indicated that the product was a mixture of the Z- and E-isomers on the double bond of the 3-propenyl group, in a ratio of 83: 17. The product melts with decomposition at 200 DEG C. IR: KBr 3420, 1805, 1620 cm @ ^-1 .

Max max _UV; phosphate buffer pH 7 283 µm (89 8900).

> 1

CS 270435. B2

FMR (sodium bicarbonate deuterium oxide *, J * values in ppm): 1.69 and 1.68 (3H, ▼ D, Z = 6.0 Hs, Z and Z each respectively). 38 and 3.72 (2H, ABq, J 17 Hs, H-2), 5.18 (1H, d, J ₆ H, 5.0 Hs, H-6), 5.51 (1H, d, H-7), and 5.8 (1H, m, -CH 2 O-CH ₃ ) and 6.06 (1H, d, J 11 Hz, ₃ -s ₃ -s ₃ ).

Analysis for ^C io®12 ^ 2 ° 3 ^S calculated 49.99% C, 5.03% H, 11.66% N, 13.34% 8 · Found 50.20% C, 4.94% H , 10.93% N, 12.82 £ S,

Example 9

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

To a suspension of 1.58 g (6.56 mmol) of the compound 1b prepared in Example 8 in 16 ml of dichloromethane, 1.7 ml (13.1 mmol) of dimethylaniline, 2.1 ml (16.4 mmol) are added successively under ice-cooling. of trimethylailyl chloride and 2.3 ml (16.4 mmol) of triothylamine. The resulting mixture was stirred at room temperature for 30 minutes, then 1.46 g (6.56 mmol) of Dp-hydroxyphenylglycyl chloride hydrochloride was added portionwise and the reaction ee is monitored by HPLC (Liohrosorb RP-18, 4 x 300 mm, methanol-phosphate buffer (pH 7) 25: 75) · To complete completion of the assortment, 291 mg of the above glyoyl chloride are added to the mixture at 15 minute intervals, After addition of 2.0 ml of dry methanol containing 0.1 ml of dry dimethylformamide, the resulting clear solution is neutralized with triethylamine (3.2 ml) to pH 6 and then diluted with 30 ml of dichloromethane to precipitate which is filtered off and washed with 10 ml. ml of dichloromethane. 2.39 g of the title compound is obtained as an eolvate with dimethylfortamide (yield 94%, purity about 50%, Z / E &lt; 47/12 by HPLC).

Example 10

Diphenylmethyl-7-phenylacetamido-3 - [(Z) -propen-1-yl] -3-cephem-4-carboxylate (IX)

(1) mol · weight 524> 6

A solution consisting of 18 liters of tetrachloroethane, 1.8 liters of methanol and 12 g of p-benzoylbenzoic acid is cooled to 8 ° C and 970 ml of acetaldehyde is added thereto. The temperature of the resulting solution is raised to +14 ° C. 588 g (0.7749 mol) of diphenylmethyl-7-phenylacetamido-3 - [(triphenylphosphorated lidene) methyl] -3-cephem-4-carboxylate are added, the cooling bath is removed and the reaction mixture is dark and under nitrogen. Stirring at 35 ° C for 4 hours until complete dissolution of phosphorous ·

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

The mixture is stirred at + 5 ° C for 2 hours, then left to stand overnight, the crystals are filtered twice, washed with ethanol and dried under vacuum at room temperature. Yield: 191 g (47%), m.p. 128 ° C · High pressure liquid chromatography (Lichrosorb Si 60 5 µm, Merck, 85% toluene / 15% ethyl acetate as eluent) ·

Example 11

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

To a stirred solution of phosphorus pentachloride (159.7 g, 0.767 mol) in dichloromethane (2.8 L) was added pyridine (56.7 mL, 0.700 mol) in dichloromethane (280 mL) over 20 minutes. The resulting suspension was cooled to 2 ° C under nitrogen and 256 g of compound IX prepared according to Example 10 (0.488 mol) was stirred for 8 minutes, then the resulting suspension was quickly added to an intensively stirred solution of 209 ml (2 ml). , 33 mol)

Of 1,3-butanediol in 1.4 liters of dichloromethane cooled to -20 ° C · Addition at a rate such that the temperature does not rise above -5 ° C · The cooling bath is removed and the temperature rises to 10 ° C after 45 minutes , is kept at that level for 35 minutes. After the addition of 1.0 liter of water, stirring is continued for 5 minutes and the layers are allowed to separate. The organic layer is washed first with 600 ml of 2N hydrochloric acid and then with 400 ml of saturated sodium chloride solution. and these washings are combined with the original dichloromethane extract.

The organic solution is dried over anhydrous magnesium sulphate, the suspension is filtered and the magnesium sulphate collected on the filter is washed twice with 500 ml of dichloromethane each time. The combined filtrates are concentrated to 2.4 liters in a rotary evaporator and the concentrate is diluted with 2.5 liters. The solution is again concentrated to a volume of about 1.3 liters, the precipitated crystals are filtered off, washed three times with 300 ml of ethyl acetate and dried first in air and then in vacuo over phosphorus pentoxide. Yield 149.8 g (yield 69, 3%) title compounds, in the form of beige crystals ·

Claims (4)

Process for the preparation of 7-amino-3-propenylcephaloeporenoic acid and its esters of the general formula I ch = ch-ch ₃ (I) in which: The 3-propenyl group has the Z configuration R represents a hydrogen atom or an ester boundary group of a carboxyl function selected from the group consisting of C7 -C14 aralkyl groups optionally substituted by nitro or C1 -C4 alkoxy, C1 -C6 alkyl optionally substituted by 1 to 3 atoms halogens, (C 2 -C 6) alkoxymethyl, (C 1 -C 4) trialkylsilyl and (C 1 -C 4) diphenylalkylsilyl, their acid addition salts and the metal salts of the compound of formula (X), wherein R is a hydrogen atom, characterized in that the intermediate of formula (IXXa) wherein: R is as defined above and Ph represents a phenyl group, reacted with acetaldehyde in an inert organic reaction medium of dichloromethane, N, N'-dimethylformamide, isopropanol or the emission of these solvents, at a temperature between 0 ° C and 25 ° C, to give the compound of formula (IX) CH = CH-CH ₃ (II) wherein R is as defined above, the benzylidene group and optionally the carboxyl protecting group are cleaved off, the 3- (Z) - and 3- (E) isomers are optionally separated and the resulting product is optionally converted into its acid addition salt or acid or metal salt* 2. A process according to claim 1, wherein the reaction with acetaldehyde is carried out in the presence of lithium halide. 3. A process according to claim 2, wherein the lithium halide is lithium chloride, lithium bromite or lithium iodide. 4. The process of claim 2 wherein lithium halide is lithium bromide.