CA1161429A - 2-(2-aminothiazol-4-yl)-n-(imidazolidin-2-on-1-yl)-2- imino-acetylaminocephalosporanic acids in pure syn- form, a process for their production and syn-acid used in such a process - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
A pure syn-form cephalosporin of the formula in which n is 2, 3 or 4, R1 represents a hydrogen atom, a pharmaceutically acceptable metal cation, an ammonium cation of a pharmaceutically acceptable nitrogen base, a radical of an ester of, if another part of the molecule contains a positive charge, a negative charge, T denotes -CH3, -CH2-O-CO-CH3, [in which Z denotes O or S), -O-CO-NH2, or and Y denotes -S- or -?-, is produced by reacting aminothiazolylglyoxylic acid of the formula ABSTRACT:

with the hydrazine compound of the formula to give a syn-acid of the formula and reacting the syn-acid with a halogenating agent, and then in the absence of a base with a 7-aminocephalosporanic acid derivative of the formula

Description

The present invention relates to certain cephalosporins in pure syn-form and to a process for their production.
In DE-OS (Gerrnan Published Specification) 2,818,263, in addition to other compounds, the compound of the formula:

H2N ~ S H
~ C / ~ S ~

i ~ N ~ CH2-O-CO-CH3 (I) O ~ H]

is descri.bed.
It can exist either in the syn-form (the imidazolidinone ring points towards the cephem skeleton) or in the anti-form.
However, in the process deseribed in DE-OS (German Published Specifieation) 2,818,263 for the preparation of these eompounds, the aeid used for the reaction with 7-aminocephalosporanie aeid, if it eontains an amino group, is always first provided with a proteetive group on the amino group, as for ex-ample in the compound of the formula:
(cH3)3c-O-CO-NH S

(Ia) C -COOH
~ / N
HN~_JN

~ fter coupling this acid with 7-aminocephalosporanic acid, the pro-tective group is then split off by means of trifluoroacetic acid and, at the same time, under the action of this strong acid, the anti-form is partly converted into the syn-form. Under the action of the trifluoroacetic acid, an equilibrium . ~

is established between the syn-form and the anti-Eorm, approximately equal parts of the two forms being present. That this is an equilibrium, is recognised because the same mixture is also given by the pure anti-form in trifluoroacetic acid in a few moments. Furthermore, the cephalosporins according to the DE-OS
(German Published Specification) 2,818,263 are always obtained in amorphous form.
It has now been found, surprisingly, that pure, and in some cases crystalline, syn-cephalosporins of the general formula N ~ - Y

N N ~ T (II) ~ CO ~ COORl N NH
(CH2)n (syn-form) can be prepared directly precisely in the presence oE a strong acid, for example hydrochloric acid, and in the absence of any ~ases.
The pure syn-form has proved to be considerably more active than the anti-form.
According to the present invention we provide cephalosporins, in pure syn-form, of the general formula (II) tas mentioned above) in which n i5 2, 3 or 4, Rl denotes a hydrogen atom, or if another

- 2 . . .

part of th~e molecule contains a positive charge, a negative charge; T denotes -CH3~ -CH2-0-C0-CH3, N -N
-CH2-S ~ ~ CH3 , (ir. which Z denotes 0 or S) N _ N
-o-co-l~H2, -C}~ -s~

and Y denotes -S- or -~-. As indicated the compounds of the general formula (II) can also be in the form of inner salts, in which case Rl is absent~ and instead, the carboxyl group carries a negative charge, whilst another grouping in the molecule carries a positive charge. Preferred compounds of general formula (III) are those in which Rl represents a sodium cation and T
represents a -CH2-0-C0-CH3 radical.
According to the present invention we also provide a process for the production of pure syn- orm cephalosporins of the invention in which a 7-aminocephalosporanic acid derivative of the general formula NH2----~ Y~
N ~ -T (III) COORl in which Y, Rl and T have the same meaning as in claim 1, is reacted, in the absence of a base, with an acid halide of the general formula HX --H N S
2 ~ ~ COX
--C /
N~ ,CO~NH (IV) ~ ~CH2~n Le A 20 342 in which n is 2, 3 or 4, and X represents a halogen atom, preferably a chlorine atom and, where a 7-aminocephalosporanic acid of formula (III) in which Y denotes -S- is used o and a compound in which Y denotes -~- is required, the product is treated with an oxidising agent.
The reaction is preferably carried out in an inert solvent, for example tetrahydrofuran (THF). In general, the reaction is carried out at a temperature of -~0 to +25C, and preferably of -50 to O C.
Preferably, the cephalosporanic acid derivative of formula (III) is silylated on the amino group and the carboxyl group (when Rl denotes a hydrogen atom) so that, for example, trimethylsilyl, triethylsilyl or other silyl radicals are introduced, before the reaction with the acid halide of the formula (IV).
The reaction of compounds of formulae (III) and (IV) must be carried out in the absence of bases. This is particularly necessary because the acid halides of formula (IV) are sensitive to bases. However, under these reaction conditions, it must be regarded as particularly surprising that the desired compounds are obtained in the pure syn-form, since, as described above, an equilibrium mixture of the syn-compound and anti-compound is obtained from the anti-compound under the action of a strong acid, such as trifluoroacetic acid.
The syn-acid halides of the formula (IV) employed as the starting material are novel, these acid halides may be prepared by a process in which aminothiazolylglyoxylic acid of the formula ~ ~ COOH
/
CO

is reacted a hydrazine compound o~ the general ~ormula Co H2N-N' ~H
in which ~ 2)n n is 2, 3 or 4~
to give a syn-acid of the general formula " ( V ) N~ ,co~
N NH
~ CH2)n in which n has the abovementioned meaning, and the syn-acid o~ formula (V) is then reacted with a halogenating agent, preferably thionyl chloride.
It is surprising that the syn-form is formed in this reaction, since in the case of the reaction of a corresponding aminothiazolyl~lyoxylic acid which only carries a protective group ( a BOC radical in which BOC
denotes (CH3)3C-O-CO-) on the amino group, with an appropriate hydrazine compound, the anti-form BOC-NH S
r~ / COOH
~- (anti) ~C~ N
HN\__~N~

is obtained.
The syn-form and anti-form can be differentiated with the aid of the NMR spectrum. For example, the -CH2-CH2- group in the imidazolidinone part gives two multiplets in the syn-form, whilst the anti-form shows a pseudo-singlet.

Le A 20 342 2~

~ he syn-acid of the ~ormula (~) in which n is 2 can be converted into the syn-acid chloride hydrochloride o~
the formula (IV) with thionyl chloride only under certain conditions. One of these conditions is that the water of crystallisation contained in the syn-acid of the formula (V) is not removed9 and more water is added to the solvent, before the addition of the thionyl chloride, in an amount such that the reaction mixture contains 2 to 4 molar equivalents of water, relative to the syn-acid of formula (V). The syn-acids of the formula (V) in which n is 3 or 4 can be converted in the dry form (0.4 molar equivalent of H20) or in the undried form (1.7 molar equivalents of H20) into the syn-acid chloride hydrochloride of the formula (IV) with thionyl chloride.
Acetonitrile or a Cl to C6 nitro-alkane, for example nitromethane, is generally used as the solvent. A
large excess of thionyl chloride must be employed in this reaction, i.e. the molar ratio of the syn-acid of formula (V) to thionyl chloride is at least 1:3, preferably 1:1~.
It is also possible to use thionyl chloride itself as the diluent, but the acid chloride hydrochloride is then not obtained in the same purity.
The halogenation of the syn-acids of ~ormula (V) is in general carried out at a temperature from O to 30C, preferably at 15 to 25C.
2-Aminothiazole radicals are also referred to herein as 2-imino-4-thiazoline radicals.
Figure 1 shows the IR spectrum of the compound according to Example 3b in Nujol.
Figure 2 shows the IR s~ectrum of the compound according to Example 4 in ~ujol.
The following Examples, 3a to 3d, 4 to 12, 13c and 14 to 16 illustrate processes for the production of compounds of formula (II) according to the present invention, Examples 2a to 2e and 13b illustrate processes for the production of ~ ~rade rn~rk Le A 20 342 . _ _ 4~

compounds of formula (IV) according to the present inven~ion and the remaining Examples illustrate the production of intermediates therefor.
Example 1 2-(2-Imino-4-thiazolin-4-yl)-N-(imidazolidin-2-on-1-yl)-2-iminoacetic acld (syn-form) 10 g of 2-(2-imino-4-thiazolin-4-yl)-glyoxylic acid were added to a solution of 7.6 g of 1-amino-2-oxo-imida201idine in 90 ml of water and the mixture was stirred at 20C overnight. The product which had crystallised out was filtered off, washed with water and dried in a desiccator.
Yield: 7.2 g, melting point: > 240C.
C8H9N503SX~I2 calculated: C 35.2 H 4.0 N 25.6 S 11.7 found: C 35.2 H 4.1 N 25.3 S 11.5 NMR (100 MHz; ~ in d6-DMSO/CD3 OD): 6.8$ (s; thiazoline-5-H); 3.9-3.7 (m; N-CH2-CH2-N) and 3-5-3-27 (m;
N-CH2-CH -N) Example 2a 2-(2-Imino-4-thiazolin-4-yl)-N ~ midazolidin-2-on-1-yl)-2-iminoacetic acid chloride hydrochloride 4.65 g of 2-(2-imino-4-thiazolin-4-yl)-N-(imid-azolidin-2-on-1-yl)-2-iminoacetic acid in the syn-form with respect to their carboxyl group (98Z with a particle size of ~ 5~; the substance contained 1.8 molar equivalents of water) were suspended in 96 ml of acetonitrile (water content: 0.30%), and 16 ml of thionyl chloride were added at 20C under dry N2. The mixture was stirred at 20C
for 1~ hours and the crystalline yellow precipitate which had separated out was then filtered off, with exclusion of moisture, and washed twice with absolute acetonitrile ~
After drying in a desiccator, the yield was: 5.0 g (about 100% of theory).
IR spectrum (Nujo~ (carbonyl range): 1810 (CO-Cl), 35 1660-1685 and 1625 (finger print region): 975, 890, 855, 800, 775 and 725 cm 1.

Le A 20 3~2 14~

The substance~was very sensitive to moisture.
Even after several weeks, it remained unchanged at a temperature of 0C if moisture was absolutely excluded.
Example 2b A mixture o~ 5 g of the acid used in Example 2a, 100 ml of nitromethane (water content: 0.17%) and 50 ml of nitromethane (water content: 0.02%), as well as 5.7 ml of thionyl chloride was stirred at 20C for 24 hours with exclusion of moisture. The precipitate which had separated out was then filtered off, washed with absolute nitromethane and dried in a desiccator.
Yield: 5.3 g IR spectrum: identical to that of Example 2a.
Exam~le 2c If in each case 0.5 g of the acid employed in Example 2a, 15 ml of l-nitropropane, as the solvent, and 1.72 ml of thionyl chloride were used, after carrying out the experiment as in Example 2, the acid chloride hydro-chloride of Example 2a was obtained in almost ~uantitative yield if the water content of the l-nitropropane was 0.19%.
If the l-nitropropane used contained only 0.04% of water, virtually no acid chloride was formed (according to the IR spectrum).
Example 2d If in each case 0.5 ~ of the acid employed in Example 2a, 15 ml of nitromethane, as the solvent, and o.6 ml of thionyl chloride were used, after stirrin6 the mix-ture at 20C for 24 hours, the acid chloride hydrochloride of Example 2a was obtained in very good yield if the water content of the nitromethane was 0.17%. If the water content of the solvent was 0.02%, no band occurred at 1810 cm 1 in the IR spectrum of the reaction product, that is to say virtually no acid chloride had been formed.

If a mixture of 10 g of the acid employed in Example Le A 2~ 342 .

l L~ ~9 2a, 300 ml of 2-nitropropane (water content: 0.19%) and 34.4 ml of thionyl chloride was stirred at 20C for 24 hours, the acid chloride hydrochloride of Example 2a w~s obtained, as a precipitate, in virtually quantitative yield.
However, if only the amount of 2~nitropropane was reduced to 150 ml (with the same water content of 0.19~) in this experiment, the reaction product which had pre-cipitated showed no acid chloride band at 1810 cm 1 in the IR spectrum.
Example_3a Sodium 7-[(2-aminothiazol-4-yl)-N-(imidazolidin-2-on-1-yl)-2-iminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxy-late (syn-form) (amorphous) 32 ml of bis-trimethylsilylacetamide were added to a mixture of 16.1 g of 7-aminocephalosporanic acid (94%
pure) and 110 ml of dry tetrahydrofuran at 20C, whilst stirring. The solid dissolved in the course of about 2 minutes with a slight increase in the temperature.
The solution was cooled to -50C and 20.2 g of the acid chloride hydrochloride prepared according to Example 2a were added, under M2. The mixture was stirred in the cooling bath for a further 10 minutes, during which the temperature fell to -65C. The cooling bath was then removed. After about 20 minutes, the temperature had risen to 0-5C and everything had dissolved. The react-ion solution was then poured into 3 litres of ether, whilst stirring, and the mixture was stirred in an open vessel for about 30 minutes. The precipitate which had then separated out consisted of the amorphous hydrochloride of the cephalosporin (syn-form) mentioned in the title of this Example. The precipitate was filtered off, washed with ether and then introduced in portions into 1.2 litres of water of 0-5C in the course of 20 minutes, whilst stirring. The pH of the mixture was kept at about 3 by simultaneously adding solid NaHC03 or sodium hydroxide Le d 20 342 4~

solution. The pH was then adjusted to 3.2, the mixture was stirred for a further 15-20 minutes and a somewhat gelatinous precipitate, which essentially contained impurities, was then filtered off. During this filtration, the filtrate was kept at pH 5 by appropriate addition of 2 N sodium hydroxide solution, and was cooled. The gelatinous precipitate was washed thoroughly with ice-water (200 ml). The combined aqueous filtrates were adjusted to pH 6.5 and ~reeze dried. The amorphous sodium salt of the cephalosporin (syn-form) mentioned in the title was thus obtained.
The yield varied between 24.2 and 32.7 g over sev-eral batches.
According to high performance liquid chromatography, the content of syn-form was about 75%. The anti-form was present only to the extent of C 1%. The crude product contained NaCl (about 5%), acetamide (about 1 molar equivalent) and water (about 1 to 2 molar equivalents).
NMR (100 MHz: ~ in CD30D-d6DMS0): 6.78 (s; thiazoline 5-H);
5.75 (a;B-lactam; I ~ 4.7) and 5~ lactam; I - 4.7).
Example 3b Sodium 77 [(2-aminothiazol-4-yl)-N-(imidazolidin-2-on-1-yl)-2-iminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylate.
(syn-form) (crystalline) (ethanolate) (readily water-soluble form).
62.6 g of an amorphous syn-cephalosporin sodium salt prepared according to Example 3a were dissolved in 250 ml of water at 20C. 600 ml of ethanol were first added to this solution, whilst swirling, and, after crystallisation had been started by trituration, a further 400 ml of ethanol were added. The suspension was left to stand at 20C
for 5 minutes and the solid was filtered off and rinsed with aqueous ethanol (water/ethanol ~ 1/4). Yield: 40.4 g.
The substance was crystalline and, according to analysis and the NMR spectrum, contained about 1 mole of Le A 20 342 . . _ .

1~ 9 water of crystallisation and about 1 mole of ethanol of crystallisation.
I~MR (1H-360 MHzj in D20; ~ in ppmj I in Hz): 3.210 and~ 3-5 (-A-CH2-; IAB = (~) 18.0), 5.040 (~-lactam;
I = 4.7), 5.710 (~-lactam; I = 4.7), 4.727 and 4.560 (-CH2-0-CO-; IAB = (~) 12.6), 1.910 (-0-CO-CH3), 6.810 (thiazole), 3.737 and 3.393 (-N-CH2-CH2-N-), 3.460 (CH2 EtOH~ and 0.982 (CH3 EtOH) NMR (13C-25.2 MHz, ~ in ppm, relative to TMS = O; in D20 ) C atoms (ppm) 2 26.608

3 117.126

4 132.303 15 6 58.244 7 59.622 8 167.582 170.820 CH2 on C3 64.974 20 CO of OAc 174.564 CH3 of OAc 21.181 CH2 d to N(N)46.635 CH2 d to NH 37.867 CO (urea) 161.631 25 CH2 of EtOH 57.890 CH3 of EtOH 17-784 d values and the associated intensities of an X-ray diffraction analysis in accordance with the method of Debye-Scherrer (demonstration of the crystallinity):

Le A 20 342 .

.~ 29 14 4 ~3--97_11S.1 590!8d 100 1 100 1 ~0 2 A = 1.5418 R d~I hkll dR II ¦hkl d~ _ I
Filter: Ni17.48 23.81 2l 2.107 2 15.13 53.66 25 (2.053 5 13.29 13.53 10 B~2.006 5 Intensity:9.57 13.42 5 estimated8.68 13.24 15 8.01 253.08 10 B = band6 87 150B ~22 9 o32l0 6.12 252.787 3

5.85 102.666 15 5.54 52.559 10 4.74 302.473 8 4.51 152.353 1 ] 3 4.04 002.269 20 ~ 3.97 pO0 2.180 5 Example 3c Sodium 7-[(2-aminothiazol-4-yl)-N-(imidazolidin-2-on-1-yl)-2-iminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxy-late (syn-form) (crystalline).
67.3 g of 7-aminocephalosporanic acid (94% pure), 450 ml of dry tetrahydrofuran and 134 ml of bis-trimethyl-silylacetamide were brought together, in this sequence, under dry N2 and whilst stirring. After a clear solution had been formed (in the course of a few minutes), this was cooled to -50C and 84.5 g of the acid chloride hydrochloride prepared according to Example 2a was added, whilst stirring. The mixture was then stirred at the same temperature for about a further 10 minutes, the cooling bath was subsequently removed and the temperature was allowed to rise to about 0 by itself. When every-thing had dissolved, the solution was poured into a mixture of 4,000 ml of tetrahydrofuran and 3 ml of water, whilst stirring, and the precipitate which separated out was filtered off. This precipitate, in the moist form on the filter, was introduced into 2,000~) ml of ice-water, whilst stirring and cooling further with ice, the pH being kept Le A 20 342 _ . .

~ 13 -at about 5 to 5.5 by means of 2 N sodium hydroxide solution during this addition, and finally being adjusted to 6.5.
: The resulting solution was then concentrated,from a bath OL
about 30 to ~5C, to a volume of 800 to l~000 ml in vacuo by means of a ro~ary evaporator, and about ~,000 ml of ethanol were then gradually added, whilst stirring.
During this addition, the mixture was seeded from time to time with crystalline material. The resulting suspension was then stirred for about a further 30 minutes and the solid was filtered off, washed with ethanol/water (4/1) and ethanol and dried in vacuo.
Yield: 109.4 g (74% of theory, relative to Cl8Hl8N7Nao7s2xH2oxc2HsoH) (syn-form; crystalline) The IR spectrum and NMR spectrum were identical to those of the substance described in Example 3b. The ethyl alcohol obtained in the crystals could be removed by drying, for example at 40 to 70C in a circulating air drying cabinet. The substance thus kept the crystalline state and the syn-form. The IR spectrum of the solid substance changed slightly.
*) As an alternative, it was also possible to dissolve the precipitate in less water tabout 1,000 ml) and then to add about 3,000 ml of ethanol. In this case also, the cephalosporin was obtained in a corresponding purity and yield.
Example 3d Sodium 7-~(2-aminothiazol-4-yl)-N-~imidazolidin-2-on-1-yl)-2-iminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxy-late (syn-form) (crystalline).
A mixture of 6 g (0.022 mole) of 7-aminocephalo-sporanic acid, 60 ml of acetonitrile (dried over a mole-cular sieve) and 5.4 ml (0.026 mole) of hexamethyldi-silazane was i~mersed in an oil bath, which had been pre-heated to 100C, whilst stirring, and a weaX stream of N2 was passed over the suspension, which soon boiled under Le A 20 342 ~ 14 ~
reflux. After about 15 minutes, a clear solution had formed, and after a total of about 1 hour, ammonia could no longer be detected with indicator paper in the vapour space above the reaction mixture. The reaction solution was then cooled to 30C and, whilst stirring, was concentrated to a volume of about 30 ml by means of an oil pump, preceded by a cold trap (liquid N2), the reaction flask being immersed in a water bath of room temperature in order to restore the heat lost. The reaction solution which remained was then cooled to 5C in ice/water.
5.88 g (0.019 mole) of the acid chloride hydrochloride:
S_' ~ N ~ CO-C-C
N
.l~
, l were then added all at once. The internal temperature thereby rose to 26C. When the internal temperature had fallen again to 20C, the ice-bath was removed and stirring was continued at room temperature for a further 3 hours and 40 minutes. The reaction mixture was then poured into 600 ml of ether (~2 content < 0.1%), which was stirred in an open vessel, and the mixture was subse-quently stirred for 30 minutes, and the precipitateformed was filtered off through a glass frit, washed once with ether on the filter, pressed off and introduced, from the filter, into 60 ml of ice-water, the pH at the same time being kept between 5 and 7 by appropriate addition of 2 N sodium hydroxide solution. The mixture was then subsequently stirred at p~I 7.5 for a further 10 minutes, during which the lumps of the filter cake were broken up.
A small amount of undissolved material (impurity) was filtered off and the clear filtrate (if necessary) was Le A 20 ~42 again adjusted to ph '7.5 ~the' volume was then' about 120 ml), 350 ml of EtOH were then added, the mixture was triturated, a further 150 ml of EtOH were added, the mixture was stirred at room temperature for about 30 minutes and the crystalline sodium salt was then filtered off. The salt was washed on the filter twice with 20 ml of EtOH/H20 = 5/1 and then once with 20 ml of EtOH.
Yield (after drying over P205 in a desiccator) = 4.7 g (45% of theory) (crystalline).
Purification of the crystalline crude'product 4.5 g of the crude product were dissolved in 45 ml of water at room temperature, whilst stirring (dissolved rapidly), and 120 ml of EtOH were then immediately added to the clear solution. A few brown flakes thereby separated out. These were removed by filtration. The flakes were rinsed with some ~tOH. A further 280 ml of EtOH were then added to the filtrate, whilst stirring, and the mixture was triturated, and stirred at room temperature for a further 40 minutes. The solid was then filtered off and washed twice with 10 ml of EtOH/H20=5/1 and once with EtOH.
Yield: (desiccator, P205): 3.2 g (crystalline) (corres-ponding to a total yield of 32% of theory).
NMR (250 MHz; ~ in CD30D/D20): 6.77 (s, thiazoline-5 5.77 (d; lH; ~-lactam); 5.07 (d; lH; ~-lactam); and 3.85 - 3.22 (m; 6H; C-2; imidazolidinone).
Example 4 Sodium 7- ~(2-aminothiazol-4-yl)-N-(imidazolidin-2-on-1-yl)-2-iminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxy-late (syn-form) (crystalline) (sparingly water-soluble form).
20 g of the readily water-soluble, crystalline, ethanol-containing sodium salt described under Example 3b were dissolved in 100 ml of water of 20C, whilst stirring, and, after seeding with the sparingly water-soluble form, this solution was stirred for a further 30 minutes. The Le A 20 342 . . .

sparingly water-soluble, crystalline form had then separated out. The precipitate was filtered off and dried in the desiccator over P401o. The substance contained no ethanol, but about 2 molar equivalents of water.
Yield: 11.65 g NMR (250 MHz; ~ in d6-DMS0): 9.82 (d, J 7.5 Hz, C-C0-NH), 7.5 (s, N-C0-NH); 7.5 (d, H2N-thiazole); 6.73 (s, thia-zole-5-H); 5.7 (dd, J 5Hz and 7.5 Hz, C7-H); 5.03 (d, 5 Hz, C6-H); 5.01 and 4.79 (AB, J 12.5 Hz, CH2-0-C0); 3.9-3.2 (m, S-CH2, N-CH2-CH2-N, H20), and 2.02 (s, -C0-CH3).
d values and the associated intensities of an X-ray diffraction analysis in accordance with the method o~
Debye-Scherrer (demonstration of the crystallinity):
, .. ._ 9.6 4.35 3.70 16.99 ., . ._ _ 598/80 10 7o 7 5 . __ . - __ .~
d~ 1 hkl dR I hkl d~ I
= 1.5418 ~ 16.99 53.52 5 2.179 9.61 100 3.41 15 2.150 15 Filter; Ni 8.5310 3.27 0 7.44 203.11 15

6.86 32.956 15 Intensity:
estimated 6.42 152.864 15 3 (5.64 202.ôl4 3 B = band (5 041 125(22 700 18 4.75 40B (2.648 8 4.52 102.549 5 4~35 7o2.467 20 4.00 602.381 10 3.90 302.312 8 3.70 7020259 8 15 Example 5 L-lysine 7-[(2-aminothiazol-4-yl)-N-(imidazolidin-2-on-1-yl)-2-iminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxy-late (sYn-form) The mixtureof 100 g of "Lewatit" S 100~ (~rade Mark) (H form) and 500 ml o~ water was cooled to C. 10 g Le A 20 342 . _ _ _ .

'f'A~3 (0.017 mole) of the 'subs'tance'prep'ared accordin~ to Example 3b were then added all at once, whilst stirring, and stirring was continued at the same temperature. After 6 minutes, the pH had fallen from an initial value of 4.85 to 3.39.
The ion exchanger was then immediately filtered off over a G-4 filter and the clear filtrate was adjusted to pH 6.55 with 2.15 g (0.015 mole) of L-lysine in the course of 20 minutes. This solution was then subjected to freeze-drying.
Yield: 9.6 g (87% of theory) (amorphous).
NMR (250 MHz; ~ in CD30D ~ D20): 6.96 (s, thiazoline-5-H); 5.91 (d; lH; ~-lactam); 5.23 (d, lH; ~-lactam), 5.0 - 4.77 (AB, 2H; -CH2-0-CO-; exchangeable); 4.1 -3.38 (m; 7H; C-2; imidazolidinone; lysine-a-H); 3.0 (t, 2H; lysine H2N-CH2-); 2.1 (s; 3H; -OCO-CH3); and 1.96-1.45 (m, 6H; lysine).
Strongly acid ion exchanger.
Example 6 L~lysine 7-[(2-aminothiazol-4-yl)-N-(imidazolidin-2-on-1-yl)-2-iminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylate (sYn-form) ' '' '' . _ 1 g tO.0017 mole) o~ the substance from Example 3b was added to a mixture, cooled to 0 to 5C, of 10 g of Lewatit S 100 (H~ form) and 30 ml of water (pH 3.4), whilst stirring, and the mixture was stirred for 10 minutes (the pH was then constant at 3.4) and the ion exchanger was subsequently filtered off. The filtrate was adjusted to pH 6.7 with L-lysine and the solution was then poured into 200 ml of isopropanol, whilst stirring.
A pulverulent precipitate separated out and, after 3 minutes, was filtered off. At the end of this filtrat-ion, the precipitate became tacky on the frit. After trituration with fresh isopropanol, the precipitate could be suction-dried.
Yield: 0.6 g (50% of theory) (amorphous).

Le A 20 342 NMR: identical to those of'Example 5.
E'xamp'l'e 7 Using the following bases~ the corresponding salts were obtained from in each case 1 g of the substance from Example ~c, in a manner corresponding to that in Example 5:

Le A 20 342 .

5, ~

5: 1: N ~ ,~
g _ N ~ ~~I N UI:
N tl3 N N O-- N O ~
~ ~ U 5~ ~: N N ::~ NU N U
U U I U ~ ~ ~ U
,1 O ZN ~ O;C U O ~ Z U N
~ ~' ~ X ~ 51 X ~ ~ N . ~
.~ N N ~ N ~ N In N ~ ` O
X ~J ~ ~ ~U7 ~ ~ U~ ~ : U7 U~
~ _ _ ~, _ _ _ _ ~ _ _ _ _ ~
O C~ O N In O ~ ~ O N~r O ~r 1~
tY; n ~ ,I N a) a~ ~ N ,1 ~;r ,1 n ~ o o ~ ~ ~ ~ ~ oo ~
.~ O O o o O O

N N ~
_ ~ ~ U
N I O N Z
U UN N U

U I ~ ~ U ~
;n z ~ u æ ~ z 11:1 N Z -- NU N

` iï '`~

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Exa~'p'l'e 8 ~he l-oxide of sodium 7-[(2-aminothiazol-4-yl)-N-(imidaæolidin-2-on-1-yl)-2-iminoacetamido]-3-acetoxy-methyl 3-cephem-4-carboxylate (syn-form).
As described in Example 3c, 2.88 g o~ the S-oxide of 7-aminocephalosporanic acid were silylated by means of bis-trimethylsilylacetamide in tetrahydrofuran and the silylation product was reacted with the acid chloride hydrochloride prepared according to Example 2a. The reaction mixture was then poured into a large quantity of absolute ether, the precipitate which had separated out was filtered off and dissolved in water a~ pH 6.5~ with the addition of sodium hydroxide solution, and the solution obtained was freeze-dried.
Yield: 2~0 g NMR (250 MHz, ~; in CD20D/D20): 6.98 (s; lH; thiazoline-5); 6.4 (d; lH; J = 5Hz; ~-lactam); 5.1 and 4.7 (AB;
2H; -CH20Ac; J - 13.5 Hz); 4.94 (d; lH, J = 5Hz; ~-lactam); 4.0-3.8 (m; 3H; CH2NH and 2-CH); 3.6-3.46 (m;
3H; N-N-CH2 and 2-XH); and 2.1 (s; 3H; CH-CH3).
This substance could also be obtained from the substance of Example 3a-d by direct oxidation with m-chloroperbenzoic acid in water.
The S-oxide of aminocephalosporanic acid was prepared from the S-oxide of phenylacetylaminocephalosporanic acid by splitting ofP the phenylacetyl radical enzymatically.
Example 9 Sodium 7-[(2-aminothiazol-4-yl)-N-(imidazolidin-2-on-1-yl)-2-iminoacetamido3-3-methyl-3-cephem-4-carboxylate (syn-form).
As in Example 3d, 5 g of 7-aminodeacetoxy-cephalosporanic acid were silylated by means of hexamethyl-disilazane in acetonitrile and the silylation product was then reacted with the acid chloride hydrochloride prepared according to Example 2a. Finally, the reaction mixture Le A 20 342 1 1~ 3 was stirred at 20C ~or a further 4 hours and then poured into 600 ml of ether. The mixture was stirred for 20 minutes and the precipitate which had separated out was filtered o~f and dissolved in ice-water (60 ml) at pH 6.5~ with the addition of 2N sodium hydroxide solution.
This solution was clarified by filtering off small amounts of impurities, and a total o~ 600 ml of EtOH were then added gradually. The gelatinous precipitate which thereby formed was filtered o~f, w shed thoroughly with EtOH and dried.
Yield: 2.15 g NMR (250 MHz; ~; in CD30D/D20): 6.86 (s; lHj thiazoline-5); 5.72 (d; lH; J = 5Hz; ~-lactam); 5.06 (d; lH, J =
5Hz; 3-lactam); 3.87 (t; 2H, N-N-CH2); and 1.87 (s; 3H;
3-CH3).
Exa ple 10 The l-oxide of sodium 7-[(2-aminothiazol-4-yl)-N-(imida-zolidin-2-on-1-yl)-2-iminoacetamido]-3-methyl-3-cephem-4-carboxylate (sy.n-form).
As in Example 3c, 2.14 g of the S-oxide of

7-aminodeacetoxycephalosporanic acid were silylated by means of bis-trimethylsilylacetamide in tetrahydrofuran and the silylation product was then reacted with the acid chloride hydrochloride of Example 2a. The reaction mixture was poured into a large amount of ether, the pre-cipitate which had separated out was dissol~ed in ice-water of pH 6.5 and this solution was freeze-dried.
Yield: 1.0 g NMR (250 MHz; ~; in CD30D/D20): 7.0 (s; lH; thiazoline-5); 6.o (d; lH; ~-lactam; J = 5Hz); 4.92 (d; lH; ~-lactam; J = 5Hz); 4.0-3.5 (m; N-CH2-CH2-N and 2-H); and 1.97 (s; 3H; 3-CH3).
This substance could also be prepared from the substance o~ Example 9 by direct oxidation with m-chloro-perbenzoic acid in water.

Le A 20 342 The S-oxide of aminodeaceto~ycephalosporanic acid was prepared from the S-oxide of phenylacetylaminodeace-toxycephalosporanlc acid by splitting of~ the phenylacetyl radical enzymatically.
~xample_ll Sodium 7-~(2-aminothiazol-4-yl)-N-(imidazolidin-2-on-1-yl)-2-iminoacetamido]-3-aminocarbonyloxymethyl-3-cephem-4-carboxylate (syn-form) (crystalline).
A mixture of 1.68 g of sodium 7-amino-3-amino-carbonyloxymethyl-3-cephem-4-carboxylate, 20 ml of tetra-hydrofuran and 0.42 ml of trifluoroacetic acid was stirred at 20C for 20 minutes. 20 ml o~ acetonitrile and then 6.2 ml o~ bis-trimethylsilylacetamide were subsequently added and the mixture was stirred for a further 50 minutes.
It was then cooled to -50C, 1.77 g of the acid chloride hydrochloride of Example 2a were added and the mixture was then stirred at -50C for 10 minutes. After removing the cooling bath, the temperature rose to ~10C in the course of 30 minutes. The reaction mixture was then poured into 200 ml of ether andstirred for 10 ~inutes.
The precipitate which had separated out was then ~iltered off, washed with ether and dissolved in 20 ml of ice-water at pH 6.5, with the addition o~ 1 N sodium hydroxide solution. Small amounts of impurities were filtered off and a total of 200 ml of EtOH were added gradually to the ~iltrate ~40 ml). The sodium salt thereby separated out as a crystalline precipitate.
Yield: 1.8 g NMR (250 MHz; ~; in CD30D/D20): 6.85 (s; lH; thiazoline-5); 5.8 (d; lH; ~-lactam; J = 5Hz); 5.1 (d, lH; ~-lactam;
J = 5Hz); 4.82-4.59 (AB; CH20CONH2, exchangeable);
3.86 (t; 2H; =N-N-CH2; J - 8Hz); and 3.59-3.24 (m; 4H;
CH2-NH and C-2).
~he sodium 7-amino-3-aminocarbonyloxymethyl-3-cephem-4-carboxylate was prepared from sodium 7-phenyl-Le A 20 342 s.' -- 24 --acetyIamino-3-'aminocarbonyloxymethyl-3-cep'hem-4-carboxylate by splitting of~ the phenylacetyl radical enzymatically.
E~xample 12 7-[(2-Aminothiazol-4-yl)-N-(imidazolidin-2-on-1-yl)-2-iminoacetamido]-3-pyridiniomethyl-3 cephem-4-carboxylate (syn-form)~
1.68 g of 7-amino-3-(1-pyridinium)-methyl-3-cephem-4-carboxylate, 20 ml of tetrahydrofuran, 6.15 ml of bis-trimethylsilylacetamide, 0.43 ml of trifluoroacetic acid and 20 ml of acetonitrile were brought together in this sequence at 20C, whilst stirring. The clear solution was stirred for a further 10 minutes and then cooled to -50C and 1.8 g of the acid chloride hydro-chloride described in Example 2a were added. The cool-ing bath was then removed. After 25 minutes, the temperature had risen to +8C and a clear solution had formed.
This was poured into 200 ml of ether and the mixture was stirred in an open vessel for 20 minutes. The precipi-tate which had separated out was filtered off, washed thoroughly with ether and dissolved in 20 ml of ice-water at pH 7, with the addition of 1 N sodium hydroxide solution.
A small amount (0.1 g) of an impurity was filtered off and a total of 600 ml o~ ~tOH were added gradually to the filtrate. After leaving the mixture to stand overnight, the product was filtered off, washed with EtOH and dried.
Yield: 1.2 g NMR (250 MHz; ~; in d-6-DMSO): 6.70 (s; lH; thiazoline-5); 9.5 (d; 2H; pyridinium); 8.6 (m; lH; pyridinium);
and 8.2 (m; 2H; pyridinium).
Exam~le 13a 2-(2-Imino-4-thiazolin-4-yl)-N-(perhydro-1,3-diazin-2-on-l-yl)-2-iminoacetic acid (syn-form).
2 g of 1-amino-perhydro-1,3-diazin-2-one were dis-solved in 30 ml of water. After adding 3 g of 2-(2-imino-4-thiazolin-4-yl)-glyoxylic acid, the mixture was Le A 20 342 ~ 9 stirred at 20C for 5 hours and t~e yellow precipitate was filtered off, washed with water and dried over P205 in a desiccator.
Yield: 4.3 g Melting point:~ 260C.
IR (Nujol; carbonyl range): 1640; 1600; and 1490 cm 1.
Water content (by Fischer method) = 11.3%.
NMR (250 MH~; ~, in NaOD(D20): 7.13 (s; lH; thiazoline-5); 3.72 (t; 2H; N-N-CH2); 3.32 (t; 2H, NH-CH2); and 10 2.9-1.99 (m; 2K; perhydrodiazine-5-H).
The aminoperhydrodiazinone was obtained from perhydro-1,3-diazin-2-one by nitrosation (NaN02, H2S04) and reduction with zinc dust (melting point - 114 - 117).
Example 13b 15 2-(2-Imino-4-thiazolin-4-yl)-N-(perhydro-1,3-diazin-2-on-l-yl)-2-iminoacetic acid chloride hydrochloride.
0.5 g of the substance from Example 13a (water content by Fischer method = 2.4%) was suspended in 15 ml of acetonitrile. A~ter adding 1.63 ml of SOC12, the 20 mixture is stirred at 20C for 3 1/4 hours. The pre-cipitate which had formed was then ~iltered off~ washed with acetonitrile and dried over P205 in a desiccator.
Yield: 0.55 g IR (Nujol; carbonyl range): 1800, 1665, 1625, 1560 and 25 1505 cm 1.
Example l~c Sodium 7-[(2-aminothiazol-4-yl)-N-(perhydro-1,3-diazin-2-on-l-yl)-2-iminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylate (syn-form).
A mixture of 5 g of 7-aminocephalosporanic acid, 30 ml of tetrahydrofuran and 9.8 ml of bis-trimethylsilyl-acetamide was stirred at 20C until a solution had formed (5 minutes) and the solution was then cooled to -50C and 5.3 g of the acid chloride hydrochloride prepared accord-ing to Example 13b were added. The cooling bath was Le A 20 3~2 then removed. A~ter 40 minutes (the internal tempera-ture is then + 18Cj, the reaction mixture was poured into 500 ml of ether. The mixture was stirred in an open vessel for 20 minutes and the precipitate was filtered off, washed with ether and dissol~ed in 50 ml of ice-water, the final pH being adjusted to 7.5 by means of 2 N sodium hydroxide solution. A very small amount of insoluble materia~ was filtered off and 500 ml of EtOH and then 500 ml of isopropanol were added to the filtrate (75 ml).
The mixture was stirred for a further 20 minutes and the product was filtered off and washed thoroughly with isopropanol.
Yield: 3.4 ~.
NMR (250 MHz; ~; in CD30D): 7.17 (s; lH; thiazoline-5);
5.87 (d; lH; J = 5 Hz; ~-lactam); 5.2 (d; lH; J = 5 Hz;
~-lactam); (CH2-O~c exchangeable); 3.76-3.6 (m; 3H;
N-N-CH2 and C-2); 3.45-3.28 (m; 3H; NH-CH2 and C-2);
and 2.11 (ps.s; 5H; perhydrodiazine-5-H and O-CO-CH3).
Ex~np~le _ 4 Sodium 7-[(2-aminothiazol-4-yl)-N-(perhydro-1,3~diazin-2-on-l-yl)-2-iminoacetamido~-3-aminocarbonyloxymethyl-3-cephem-4-carboxylate (syn-form).
A mixture of 4.03 g of sodium 7-amino-3-amino-carbonyloxymethyl-3-cephem-4-carboxylate, 40 ml of tetra-hydrofuran, 15.7. ml of bis-trimethylsilylacetamide, 40 ml of acetonitrile and 1.1 ~nl of trifluoroacetic acid was stirred at 20C for 40 minutes and the solution, which was then clear, was cooled to -50C. 4.27 g of the acid chloride hydrochloride prepared according to ~xample 13b were then added and the mixture was stirred at -50C for 10 minutes. The cooling bath was then removed and stirring was continued at room temperature until, after about 20 minutes at a temperature of +8C, a clear solution had formed. This was poured into 600 ml of ether, the mixture was stirred in an open vessel for 20 minutes and Le A 20 342 the precipitate which had separated out was filtered off, washed thoroughly with ~ether and then introduced into 50 ml of ice-water, the pH finally being adjusted to 7 - 7.5 by means of 2 N sodium hydroxide solution. A small amount of an impurity (1.2 g) was filtered off and a total of 850 ml of EtOH were then added gradually to the filtrate.
The mixture was subsequently stirred for a further hour at 20C and the product was filtered off, washed with EtOH
and dried over P205 in a desiccator.
Yield: 3.15 g NMR (250 MHz; ~; in CD30D/D20): 7.6 (s; lH; thiazoline-5); 5.84 (d; lH; J = 5 Hz; ~-lactam), 5.14 (d; lH; J =
5 Hz; ~-lactam); (CH20CONH2 exchangeable); 3.76-3.56 (m; 3H; N-N-CH2 and C-2); 3.42-3.22 (m; 3H; C~2-NH and 15 C-2); and 2.0 (m; 2H; perhydrodiazine-5-C).
Example 15 7-C(2-Aminothiazol-4-yl)-N-(perhydro-1,3-diazin-2-on-l-yl)-2-iminoacetamido]-3-pyridiniomethyl-3-cephem-4-carbonate (syn-form).
2.52 g of 7-amino-3-(1-pyridinium)-methyl-3-cephem-4-carbonate, 30 ml of tetrahydrofuran, 0.~4 ml of trifluoroacetic acid, 9.25 ml of bis-trimethylsilyl-acetamide and 30 ml of acetonitrile were brought together in this sequence at 20C and the mixture was stirred for 5 to 10 minutes. The solution, which was then clear, was cooled to -50C and 3.24 g (= 2.81 g of pure substance) of the acid chloride hydrochloride described in Example 13b were added. The cooling bath was then remo~ed and the mixture was stirred at room temperature for 2 hours.
The precipitate present was ~iltered off, washed with tetrahydrofuran/acetonitrile (1/1) and wlth ether and dried.
Yield: 2.7 g tA).
~he crude mother liquor was poured into 60o ml of ether3 the precipitate which had separated out was Le A 20 342 'J~f`~3 filtered off and dissolved in 25: ml of ice-water and a second fraction was precipitated by means of 300 ml of EtOH.
Yield: 1.5 g (B).
NMR (substance A) (250 MHz; ~; in CD30D/D20, based on MeOH): 9.13 (d; 2H) and 8.63 (t, lH) and 8.15 (m; 2H) pyridinium; 7.o6 (s; lH; thiazoline-5); 5.92 (d; lH;
J = 5Hz; ~-lactam); 5.73 and 5.35 (AB; 2H; CH2-pyridinium);
5.26 (d; lH; J = 5Hz; ~-lactam); and 2.07 (m; 2H;
perhydrodiazine-5-C) Example 16 .

Sodium 7-~(2-aminothiazol-4-yl)-N-(perhydro-1,3-diazin-2-on-l-yl)-2-iminoacetamido]-3- [(1-methyltetrazol-5-yl)-thiomethyl]-3-cephem-4-carboxylate (syn-form).
1.75 g of 7-amino-~- [(1-methyltetrazol-5-yl)-thiomethyl]3-cephem-4-carboxylic acid, 20 ml of tetra-hydrofuran, 5.65 ml of bis-trimethylsilylacetamide and 20 ml of acetonitrile were stirred at 20C for 20 minutes.
The solution, which was then clear, was cooled to -50C, 2 g (= 1.73 g of pure substance) of the acid chloride hydrochloride described in Example 13b were added, the cooling bath was removed and the mixture was stirred at the ambient temperature for about 25 minutes. The solution, which was then clear, now had a temperature of +10C, and was poured into 400 ml of ether. The mixture was stirred in an open vessel for 20 minutes and the precipitate was filtered off and dissolved in 20 ml of ice-water at pH 7 - 7.5, with the addition of 2N sodium hydroxide solution. A small amount of an impurity was 3 filtered off and 700 ml of EtOH and then 500 ml of ether were added to the filtrate. The precipitate which had separated out was filtered off, washed with ether and dried.
Yield: 0.9 g.
NMR (250 MHz; ~;` in CD30D/D20; based on MeOH = 3.3 ppm):
7.05 (s; lH; thiazoline-5); 5.83 (d; lH; J = 5Hz; ~-Le A 20 342 g l.act'am); '5.13 (d; lH;' J = 5Hz,' ~ act'am); 4.38 and 4.28 (AB; 2H; CH2-S-tetrazole)~ 4.0 (s; 3EI; Me-tetrazole);
3 . 84-3 . 69 (m; 3H; N-N-CH2 and C-2, AB part ); 3 . 52 (AB
part of C-2; lH); and 2;~6 (rnj 2E~; perhydrodiazlne-C-5)~.

Le A 20~ 342

Claims (23)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the production of a cephalosporin, in the pure syn-form, of the general formula (II) in which n is 2, 3 or 4, R1 represents a hydrogen atom or, if another part of the molecule contains a positive charge, a negative charge, T denotes -CH3, -CH2-O-CO-CH3, (in which Z denotes O or S), -O-CO-NH2, or and Y denotes -S- or -?-or a pharmaceutically acceptable metal salt, amine salt, ammonium salt or ester thereof, in which 7-aminocephalosporanic acid derivative of the general formula (III) in which Y, R1 and T have the same meanings as above, is reacted, in the absence of a base, with an acid halide of the general formula (IV) in which n has the same meaning given above and X denotes a halogen atom and where a 7-amino-cephalosporanic acid of formula (III) in which Y denotes -S- is used, and a compound in which Y denotes -?- is required, the product is treated with an oxidizing agent, and where required a free carboxylic acid of formula II is converted into a pharmaceutically acceptable salt or ester thereof.

2. A process according to claim 1, in which the reaction is carried out in an inert solvent.

3. A process according to claim 2, in which X denotes a chlorine atom.

4. A process according to claim 1, 2 or 3, in which R1 denotes a hydrogen atom and the cephalosporanic acid derivative of formula (III) is silylated on the amino group and the carboxyl group prior to the reaction with the acid halide of formula (IV).

5. A process according to claim 1, 2 or 3, in which the reaction is carried out at a temperature of -50 to 0°C.

6. A process according to claim 1, wherein the product is recovered in crystalline form.

7. A process according to claim 1, 2 or 3, wherein the pro-duct is recovered as the triethanolamine salt.

8. A process according to claim 1, 2 or 3, wherein the product is recovered as the lysine salt.

9. A process according to claim 1, 2 or 3, wherein the product is recovered as the ornithine salt.

10. A process according to claim 1, 2 or 3, wherein the product is recovered as the ester of the alcohol having the formula

11. A process according to claim 1, 2 or 3, wherein in the starting material of formula (III) T represents -CH2-O-CO-CH3, and the product is recovered as the sodium salt.

12. A process according to claim 1, 2 or 3, wherein in the starting materials Y represents -S-, n is 2 and T is as defined in claim 1 with the exception of -O-CO-NH2, the product being recovered in the unoxidized form (where Y is -s-).

13. A process according to claim 1, 2 or 3, wherein in the starting materials T represents -CH2-O-CO-CH3, Y represents -S-, n is 2, and the product is recovered in the unoxidized form (where Y is -S-) as the sodium salt.

14. A process for the preparation of sodium 7-[(2-aminothiazol-4-yl)-N-(imidazolidin-2-on-1-yl)-2-iminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylate (syn-form) which comprises silylating 7-aminocephalosporanic acid, reacting the resultant product with 2-(2-imino-4-thiazolin-4-yl)-N-(imidazolidin-2-on-1-yl)-2-iminoacetic acid chloride hydrochloride (syn-form) and converting the product to the sodium salt thereof.

15. A process according to claim 14 wherein the silylation is effected by means of bis-trimethylsilylacetamide.

16. A process according to claim 14 wherein the silylation is effected by means of hexamethyldisilazane.

17. A process according to claim 14, wherein the sodium salt is recovered in crystalline form.

18. Cephalosporins, in the pure syn-form, of the general formula (II) defined in claim 1, and their pharmaceutically acceptable metal salts, amine salts, ammonium salts and esters, when prepared by the process of claim 1 or by an obvious chemical equivalent thereof.

19. Compounds according to claim 18 which are in crystalline form when prepared by the process of claim 6 or by an obvious chemical equivalent thereof.

20. Sodium 7-[(2-aminothiazol-4-yl)-N-(imidazolidin-2-on-1-yl)-2-iminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylate (syn-form), when prepared by the process of claim 14, 15 or 16, or by an obvious chemical equivalent thereof.

21. Crystalline sodium 7-[(2-aminothiazol-4-yl)-N-(imidazoli-din-2-on-1-yl)-2-iminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylate (syn-form), when prepared by the process of claim 17 or by an obvious chemical equivalent thereof.

22. A process for the preparation of L-lysine 7-[(2-amino-thiazol-4-yl)-N-(imidazolidin-2-on-1-yl)-2-iminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylate (syn-form) which comprises silylating 7-aminocephalosporanic acid, reacting the resultant product with 2-(2-imino-4-thiazolin-4-yl)-N-(imidazolidin-2-on-l-yl)-2-iminoacetic acid chloride hydrochloride (syn-form) and converting the product to the L-lysine salt thereof.

23. L-lysine 7-[(2-aminothiazol-4-yl)-N-(imidazolidin-2-on-l-yl)-2-iminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylate (sny-form), when prepared by the process of claim 22, or by an obvious chemical equivalent thereof.