IL32383A - Process for preparing acylated derivatives of ypsilon-lactams of cephalosporin and compounds of this type - Google Patents

Description

■ Ϊ7Ρ3 1 Ί1ΒΡ17ΝΡ¾ 701 ΡΚΡΡ7·» V im71P Β33Π7 8ΠΠ Ί»7ηΠ n't ai p murin map-mi I»PIIP 'NEW PROCESS FOR PREPARING ACYLATED DERIVATIVES OF V- LACTAMS OF CEPHALOSPORIN AND NOVEL COMPOUNDS OF THIS TYPE it' 32383/2 The present invention has as object a new process for^ preparing acylated derivatives of cephalosporin* The invention has more particularly as object a new process for preparing the raoemic or optically active acylated derivatives of cephalosporin* of general formula It I As it has been indicated in this application, those compounds are endowed with interesting antibiotic properties* ; According to the said application, one prepared the acylated derivatives of cephalosporin of formula I by hemi-synthesis, that is to jay starting from products of whichoone part of the molecule was pre-existent# The present lnveniton makes possible the preparation of the acylated derivatives of eephalosporin of formula I - p.-sulphophenylacetyl - p,-nitrophenylacetyl, etc.

The starting products of the process of the invention, the compounds of formula I', are obtained according to a Israel process described, as indicated above, in the /application «£ According to the said process one causes an amino acid of formula II: R,HN - CH~ - CH~ - COOH 1 d ■ II to react with benzyl alcohol in the presence of an acid agent, of formula ΧΉ, X being a halogen, sulphuric or sulphonic anion, obtains an ester salt of formula III: which one condenses with an alkyl or aralkyl oxalate obtains a benzyl 2,3-dioxopyrrolidine-4—carboxylate enolic formula IV: which, by hydrogenolysis, gives the corresponding -carboxyl derivative of formula IV : IV« 2-(a-R-oxy-car' onyl-a-Y-methyl)-5-aniinomethyl-2,3-dihydro-1 thiazine- -carboxylic acid, of formula VIII: which appears in the form of a mixture of threo and erythro isomers, or in the form of one of the two, splits off the imido group or the acylamino group, Y, by an exchange of function using hydrazine, by an acid hydrolysis or by , of being able to exist in the form of threo and erythro isomers, of which one liberates the carboxyl group by the action of an acid agent, obtains a Y-lactam of 2-(a-carboxy -a-ajsiinomethyl)-5-aminomethyl--2,3- One introduces 106 mg. of Y-lactam of DL-6H.7H-cis 7- amino 3-aminomethyl ceph.-3-emff 4-carboxylic acid into 1 c.c. of dimethylformamide, adds 125 mS» of homophthalic anhydride and agitates at ambient temperature for one night. The next day, one adds 10 c.c. of water, agitates for 5 minutes, suction-filters, washes with water, dries and purifies the product by dissolution in 1 c.c. of dimethylsulphoxide.

One filters, adds to the filtrate 1 c.c. of methanol, then 1 c.c. of water. One suction-filters, washes the product with aqueous methanol and with ether and obtains 120 mg. (being 70%) of product melting above 260°C. It appears in the form of colourless crystals, soluble in dimethylformamide and dimethylsulphoxide as well as in aqueous alkalis, slightly soluble in the usual organic solvents.

Analysis : C^H^O^S = 373.37 Calculated : C% 5 .68 E% .0 N% 11.26 S% 8.58 Found : 5^.9 .2 n.o 8.7 I.R.. Spectrum in nujol: Bands at 1767 cm"*1 β-lactam 1678 cm"1 1704-1658 cm"1 Y-lactam .+ amide - acid 1532 cm"1 2nd amide absorption in the associated OH/NH region and OH aromatic acid As far as is known, this compound is not described in the literature.

Example 2 ' : Preparation of the Y-lactam of DL-6H. 7H-cis 7-Ρ» -sulphonyl phenylacetamido 3-aminomethyl ceph-3-emj& -carboxylic of Ν hydrochloric acid and extracts with ether. One evaporates the extracts to dryness in vacuo , dries and dissolves the residue in ethyl acetate. One adds diethyl-, amine and starts crystallization by scratching. One adds · ether, suction-filters, introduces the residue into an ether-water mixture, adds acetic acid until the product is dissolved, washes with water, dries, filters and concentrates, the filtrate to dryness in vacuo.

The product crystallizes in petroleum ether and one obtains 1.15 g. (being 60%) of p.-tritylamino phenylacetic acid.

One introduces 786 mg. of p.-tritylamino phenylacetic acid into 8 c.c. of anhydrous methylene chloride placed under an atmosphere of nitrogen, adds 250 mg. of carbodiimide and agitates while cooling to 10° for 1 hour.. One suction-filters the urea, concentrates the filtrate to dryness and dissolves the residue which is constituted by the anhydride of p.-tritylamino phenylacetic acid in 4 c.c. of dimethylformamide.

To the above solution, one adds 106 mg. of Y-lactam of DL-6H, 7H-cis 7-amino 3-aminomethyl ceph-3-em/ii 4—carboxylic acid and agitates at ambient temperature for one night.

One then adds methylene chloride, washes with water, extracts the washin waters with ether, combines the organic phases, dries and reduces to small volume in vacuo, without heating. One precipitates with ether, suction-filters, washes with ether and obtains 233 m . of Y-lactam of DL-6H, 7H-cis 7-p.-tritylamino phenylacetamido 3-aminomethyl ceph-3-em/§ 4-carboxylic acid.

One saturates 10 c.c. of nitromethane with gaseous minutes at ambient temperature, drives off the excess hydrochloric acid, suction-filters and obtains 5 0 mg. of product melting above 250° . One purifies 210 mg. of this product in the following way: of product of which the purity is confirmed by thin layer chromatography, Rf 0.62 identical to the product obtained (c = 1%, dimethylformamide) .

The I.R. spectrum in nujol can be superimposed on that of theSemisynthetic product.

In an analogous way, by operating according to example .3» one obtains the Y-lactam of L(+)-6H, 7H-cis 7-(p. -amino phenylacetamido) 3-aminomethyl ceph-3-em^ -carboxylic acid, Ca] ° = + 14?° + 3.5° (c = 0.7%, dimethylformamide) .

As far as is known, this compound is not described in the literature.

Exam-pie 5 : "Preparation of the V-lactam of L(+)-6H» 7H-cis 7-(p-nitrophenyiacetamido) 3-amino- methyl ceph-3-emj/ -carboxylic acid One mixes under agitation and under nitrogen, 30 c.c. of nitromethane, 3.65 g. of p-nitrophenylacetic acid and. 2.25 g» of dicyclohexyl carbodiimide ; one maintains the agitation for one hour, adds 1.055 g. of Y-lactam of L(+)-6H 7H~cis 7-amino 3-aminomethyl ceph-3-em^ 4-carboxylic acid and 2 drops of pyridine and continues agitation for 15 minutes, at ambient temperature; one suction-filters and collects 1.75 6· of crude compound of which one takes up 0.67 g. in c.c. of dimethylsulphoxide, suction-filters and recrystallizes in ethanol; one obtains 0.43 . of V-lactam of L(+)-6H, 7H-cis 7-(p-nitrophenylacetamido) 3-aminomethyl ceph-3-em^ 4-carboxylic acid.

The product appears in the form of colourless crystals, soluble in dimethylformamide, insoluble in water and ethanol; its melting point is higher than 250°.

As far as is known, this compound is not described in the literature .

This compound can be converted into hydrochloride of One nixes 900 mg. of active charcoal, 0.75 c.c. of an aqueous 20% solution of palladium chloride and 10 c.c. of water, under agitation and causes a current of hydrogen to pass until complete reduction of the palladium, one suction-filters the charcoal which one washes with water until neutrality of the washing waters. One puts in suspension the palladinized charcoal thus obtained in 10 c.c. of dimethylformamide with 980 mg. of Y-lactam of L(+)- 6H, 7H-cis 7-(p-nitrophenylacetamido) 3-aminomethyl ceph-3- eme -carbox lic acid and 3 c.c. of N hydrochloric acid, under agitation and causes a current of hydrogen to pass at ambient temperature for 2 hours; one filters the catalyst, suction-filters it, rinses the filter with 50% aqueous ethanol containing 1 drop of hydrochloric acid and distills the combined filtrates, under strong vacuum, one takes up the dry residue with ethanol, filters, washes the residue with ethanol, then with ether and dries. One obtains 875 ^ . °? hydrochloride of Y-lactam of L(+)-6H, 7H-cis 7-(p-amirophenylacetamido) 3-aminomethyl ceph-3-eme 4—carboxylic acid, in the form of a solid product soluble in water, insoluble in alcohol and melting_ above 250°C. (Yield 88%). Its rotatory power is Ca] ° = + 1 7 + 3° (c = 0.7%, dimethylformamide).

As far as is known, this compound is not described in the literature.

By treating the hydrochloride obtained above with a mineral or organic base, one obtains the Y-lactam of L(+)-6Ξ, ?H-cis 7-(p-&iai&opkeayl&cetamido) 3-aminomethyl ceph-3-emy 4—carboxylic acid described in example .

By operating in the same way and by using as raw material the Y-lactam of DL-6H, 7H-c s 7-amino 3-amino filters, dries and collects 350 g« (being a quantitative yield) of crystals, m.p. 142°.

The product thus obtained is identical to that described by Nobuo Yzumiya et al., Nippon agaku Zasshi 78. 66 (1957) .

Stage B : Benzyl 2, 5-dioxo-pyrrolidine -carboxylate » IV ..with R∑ — H ■ One introduces 225 g. of potassium t-butylate into p. -toluene sulphohate β-alaninate.

One dissolves, on the other hand, J00 g. of benzyl oxalate in 600 c.c. of hot benzene, allows it to return to ambient temperature and neutralizes the slight acidity ■ of the solution by the addition of 0.4 c.c. of triethyl- amine. This solution is admixed with the mixture formed above and still maintained in the refrigerating bath.

One reheats to ambient temperature and takes to reflux for five hours.

One drives off the benzene in vacuo, adds successively first 2 litres of water containin 15 c.c. of acetic acid, then.1.5 litres of isopropyl ether and finally 110 c.c. of concentrated hydrochloric acid (until pH = 1 is obtained).

One ice-cools while agitating for 2 and a half hours. One suction-filters, washes with water, with isopropyl ether and recrystallizes by dissolution in dimethylformamide and precipitation by water. One obtains 150.5 g. (being 56% of product, m.p. 186°C, soluble in the alcohols, ethe and acetone, insoluble in benzene and water.

Analysis . : ¾2Ηΐι0 Ν = 255.24 Calculated : C% 61.8 Ή% 4.76 JS% 6.01 Found : 62 5.1 6.5 I.R. Spectrum; ^ o maxima in the carbonyl region 1729 cm"~^ and 1695 cm"*^ Absorption in the associated OH/NH region Presence of monosubstituted aromatic ring As far as is known, this compound is not described in the literature.

Stage C : 2 , 5-dioxo-pyrrolidine- -carboxylic acid , IV with a) Preparation of the hydrogenation catalyst saturation of the catalyst, one suction-filters it protected . from the air and rinses several times with anhydrous dimethylformamide. b) Hydrop;enation One dissolves 9.52 g. of benzyl 2,3-dioxo-pyrrolidine- 4-carboxylate in 5° c.c. of anhydrous dimethylformamide, adds the catalyst prepared above. One places the whole under an atmosphere of hydrogen, then agitates while cooling from time to time in order to avoid any appreciable rise in temperature. One filters off, adds to the filtrate 500 c.c. of isopropyl ether, suction-filters and dries.

One obtains 4.618 g. (being 96%) of product which one uses as it is for continuing the synthesis. For analysis, one redissolves them in 6 volumes of dimethylsulphoxide -and 4 volumes of methanol. One filters off and again adds 4 volumes of methanol. There is formed a white precipitate which one suction-filters and dries. Yield from purification : 60%.

The product appears in the form of white crystals, scarcely stable by reason of decarboxylation. It is soluble in' di ethylsulphoxide and dimethylformamide, insoluble in isopropyl ether and in water.

I.R. Spectrum (in nujol) Absorption in the associated OH NH region Complex and strong absorption in the carboxyl region : •Shoulder ' , 1708 cm"1 max..1677 cm"" Analysis C5H50 N Calculated C% 41.96 H% 3.52 N% 9.79 Found 41.7 3.8" 9.9 As far as is known, this compound is not described in the literature.

Stage P.- : 2 '-dioxo- -morpholino-me hyl-pyrrolidine . 10 c.c. of a., morpholine hydrochloride solution prepared by ..neutralization of 8.71 g. of morpholine by concentrated hydrochloric acid and addition of 50 c.c. of water.. One adds 2 c.c. of 30% ormaldehyde, then introduces 2.83 g. of 2 , 3-dioxo-pyrrolidine-4—carboxylic acid. The reaction mixture is heated to 60-65° under agitation for 30 hours. One evaporates to dryness and recrystallizes the residue framethanol. One obtains 2.986 g. of product directly usable for continuing the synthesis.

For analysis, one dissolves the product in one . volume of hot water and adds three volumes of ethanol.

One ice-cools, suction-filters and obtains, with a yield of 80%, a product which appears in the form of white crystals, slightly soluble in ethanol and ether, soluble in water.

Analysis : C^H-^O^Cl = 234.7 Calculated : C% 46.06 H% 6. N% 11.94 01% 15.11 " Found : 45.8 6.4 11.8 . 15.2 I.R. Spectrum; (in nujol) Absorption bands at 3210 cm"*1 and from 3.6 to 4.1 Triplet in the carbonyl region 1711 cm"1 1691 cm"1 1664 cm"*1 As far as is known, this compound is not described in the literature.

The 2 , 3-dioxo-^-21°rpholinOHnethyl-pyrrolidine hydrochloride can be obtained starting from benzyl 2 , 3-dioxo-pyrrolidine- -carboxylate without isolation of the free intermediate acid in the following way: One introduces 30.33 g. of benzyl 2 , 3-dioxo-pyrrolidine-4-carboxylate into 300 c.c. of dioxan containing 10% water, heats slightly to dissolve the product, adds of hydrogen and agitates very energetically. In 1 hour 40 mins. one has absorbed 700 c.c. of hydrogen (volume predicted by theory 2912 c.c). One cools, purges with nitrogen, then introduces 150 c.c. of mixture thus composed: morpholine ' 4-3.5 6· water 100 c.c. concentrated hydrochloric acid .· 40 c.c.

IT hydrochloric acid 15 c.c. . formaldehyde 5° c.c. water to make 50 c.c.

One heats the reaction mixture to about 5°° and collects in 1 hour 2325 c.c. of carbonic gas. Theory predicts a release of carbonic gas equal to that of the hydrogen absorbed initially in the reaction. One therefore expects here, at least, the liberation of 2700 c.c. of carbonic gas. One agitates lightly for a few minutes, filters and evaporates to dryness in vacuo. The residue can be used as it is for continuing the synthesis.

For analysis, one pastes the product thus obtained with ethanol, rinses with ether, dries and obtains, with a yield of 63.5%» a product identical to that described above.

Stage E : 2, 3-dioxo- -acetyl-thiomethyl-pyrrolidine, VI wi h Ac = acetyl ^aml =^S=? In a container cooled with the ice-methanol bath, one introduces 140 c.c. of water, 24 g. of monosodium phosphate, 60 c.c. of thioacetic acid and 67.2 g. of bicarbonate of soda, agitates for 5 minutes, then adds 46.8 g. of 2,3-dioxo-4-morpholino-methyl-pyrrolidine hydrochloride. The reaction mixture is agitated at ambient temperature for 3 hours and a half, with the addition of a little ether at the 80 c.c. of concentrated hydrochloric acid and drives off the excess thioacetic acid by evaporation in vacuo.

One filters and keeps the filtrate. The suction- filtered product is washed with water, then one dissolves it in I50 c.c. of hot chloroform, one decants the water contained in the product and extracts the aqueous phase with chloroform. The combined organic phases are dried on sodium sulphate and evaporated to dryness in vacuo.

The residue is pasted with ether and. provides 25 g. (being 67%) of product m.p. 136°.

One extracts, on the other hand, the filtrate obtained above with chloroform, dries the extracts on sodium sulphate, filters and evaporates to dryness in vacuo. The residue is dissolved in a mixture of 10 c.c. of ethyl acetate and 10 c.c. of ether. One leaves. for 1 night in an icebox, suction-filters and obtains 2.5 g. of product, identical to that of the first yield. Total yield : 72.5%.

The product is usable without another purification for continuing the synthesis.

For analysis, one recrystallizes itfrom ethyl acetate, the melting point remains constant. It appears in the form of white crystals, soluble in water, slightly soluble in ether and ethyl acetate.

Analysis : C^O^NS = 187.21 Calculated : C% .91 H% 4.85 W° 7A9 S% 17.15 Pound : 44.7 4.9 7.6 17.1 U.V. Spectrum a) in ethanol/0.1 N hydrochloric acid Max. 225 mu · E¾m = 666 ■ b in ethanol/0,1 N caustic soda Max. 25I m = 56 : I.R., Spectrum (in chloroform) OH max. at about 3210 cm . As far as is known, this compound is not described in the literature.

Stafge F γ-lactam of 2-/a-t-butoxy-carbonyl-K-phthali- mido-methyl 7-5-aminome hyl-2 , 5-dihydro- 1 ,3- hiazine-4-carboxylic acid, VIII with One dissolves 18.72 g. of 1 , 3-dioxo-4-acetyl- thibmethyl-pyrrolidine in 300 c.c, of a methanol solution of % p. -toluene sulphonic acid and takes to reflux for two and a half hours. One then leaves the mixture thus formed to return to . ambient temperature, cools to -50° and admixes it drop, by drop with 59.5 c.c. of a 2 N ammonium acetate solution in methanol. One then adds while operating under an atmosphere of nitrogen, JO g. of t-butyl phthalimido malonaldehydate enamine and leaves under agitation for a few minutes at ambient temperature.

One evaporates the solvents by distillation in vacuo, takes up the residue with anhydrous benzene and heats it to reflux, with continuous separation of water, for twelve hours. One takes up the residue, formed essentially of er thro isomer, with 200 c.c. of methanol and suction-filters the crystals. One purifies by successive pasting with water, methanol, ether, dissolution in dimethyl-formamide and addition of methanol.

One obtains 16.6 g. (being.40%) of product, m.p. 250° , which appears in the form of v/hite crystals soluble in the methanol/chloroform mixture, slightly soluble in pure methanol, insoluble 'in benzene and ether.

Analysis : C^H^O^N.S = 15. 7 Calculated : C% 57.8 H% 5-10 N% 10.11 S% 7.72 Stage G : -lactam of 2-ra-t-butoxy-carbonyl ,(X-aroino- methyl hydrochloride] -5-aminomethyl~ , 5- dihydro-1 , 3-thiazine-4--carboxylic acid , VIII' (hydrochloride) with R = t-But, One introduces 16.6 g. of Y-lactam of 2-(a-t-butoxy- carbonyl ,α-phthalimido-methyl) -5-aminomethyl-2 , 3-dihydro-l , 3- thiazine- -carboxylic acid into 32 c.c. of dimethylformamide , then one adds very slowly, while operating under agitation and an atmosphere of nitrogen, 22 c.c. of a 2 M solution of hydrazine hydrate in dimethylformamide and agitates for 0 minutes at ambient temperature. One then adds in a space of ' 30 minutes, c.c. of N hydrochloric acid, agitates for 30 minutes, then ice-cools and filters. The filtrate is evaporated to dryness in vacuo and the residue, dissolved in 30 c.c. of water, is treated with animal charcoal. One filters, evaporates to dryness and crystallizes this product thus obtained in methanol. One washes with ether and obtains 12.5 g« (being 97%) of product which, although formed from a mixture of threo and erythro isomers, is nevertheless usable as it is for continuing the synthesis.

One .can if necessary, separate the constituents of the mixture by fractional crystallizationfraa methanol containing 20% water where the erythro isomer is the least soluble. The two threo and erythro stereoisomeric hydrochlorides can hardly be distinguished by their I.E. or.U.V. spectral characteristics, but in thin, layer.. chromatography , GP column ethanol 20%, For each pure stereoisomeric hydrochloride (or their mixture of free bases) which, one can extract with ethyl acetate.

As far as is known, this compound is not described in the literature.

Stage H : Y-lactam of 2-(a-carboxy-a-tritylamino) - methyl-5-aminomethyl-2, 5-dihydro-l , 3- . thiazine-4--carbo ylic acid 1) v-lactarn of 2-( -carboxy- -amin.ome¾h,yl) - -amino]Tieth,yl-2.3- dihydro-l , ^-thiazine-^-carboxylic acid , IX, ¾ggS¾r~¾j-- One introduces 12.88 g. of the mixture of threo and erythro isomers corresponding to the Y-lactam of 2-(a-t-butoxy-carbonyl aminomethyl hydrochloride) -5-aminomethyl-2, 3-dihydro-1, 3-thiazine-4-carboxylic acid into 320 c.c. of nitromethane · saturated with gaseous hydrochloric acid and cooled by an ice-methanol mixture. In the suspension thus formed one causes a current of gaseous hydrochloric acid to pass for fifty minutes, then drives off the hydrochloric acid in vacuo.

As far as is known, this compound is not described in the literature. 2) Y-lactam of 2-(a-carboxy-a-tritylaminomethyl) -5-ainino- methyl-2, -dihydro-l , -thiazine- -carboxylic acid, IX' ¾ One places the mixture obtained above under an atmosphere of nitrogen, cools with a bath of iced water and introduces 28 c.c. of triethylamine and 24 g. of trityl chloride into 80 c.c. of methylene chloride. One leaves at ambient temperature under nitrogen for one night and evaporates to dryness in vacuo. One dissolves the residue in a mixture of 200 c.c. of methanol and 200 c.c. of methylene chloride and adds 16 c.c. of acetic acid. One concentrates form.

As far as is known, this compound is not described in the literature. 3) Isolating the erythro isomer One treats the mother solution obtained above with animal charcoal, filters and evaporates to dryness in vacuo on a water bath. One dissolves, the residual oil in 200 c.c. of ether, adds drop by drop 20 c.c. of water and agitates under an atmosphere of nitrogen for 4 hours at ambient · temperature. One suction-filters, washes with ether, then with water and obtains 8.368 g. of tritylated product, the erythro form containing a little threo isomer.

As far as is known, this compound is not described in the literature. 4) Isomerization of the erythro form into threo One suspends 8.368 g. of erythro form tritylated derivative in 170 c.c. of methanol, cools to 10°, adds 11.8 c.c. of aqueous 3.4 N lithine, keeps for 3 minutes at ambient temperature. One then adds acetic acid (about 2.5 c.c.) until a slightly acid pH is obtained, then heats with a bath of 60° for 10 minutes. One suction-filters, washes with methanol and collects 4.728 g. of threo form tritylated derivative · The mother solution is treated on the other hand with animal charcoal; one filters, washes the insoluble part with methanol which one joins to the filtrate and evaporates to dryness in vacuo. The residue is dissolved in 10 c.c. of ether, one adds 1 c.c. of acetic acid and 1 c.c. of water. One leaves for 2 hours at ambient temperature, suction-filters and obtains 1.673 g. of erythro form tritylated derivative which one isomerizes as described above to ) Purification of the threo isomer One combines the different quantities of the threo form product, being 12.77 g., adds 10 c.c- of methanol and heats to reflux. One filters, dries after washing with . ether and obtains 12.13 g. (being 95%) of product usable for continuing the synthesis.

The product appears in the form of colourless crystals, melting with decomposition at about 240° (while the erythro isomer melts with decomposition at about 220°).

. It is soluble in aqueous alcohol, slightly soluble in dimethylformamide and dimethylsulphoxide, insoluble in the hydrophobic organic solvents.

Analysis .: C^H^N^SO^ = 1.55 Calculated :' C% 68.77 N% 8.91 S% 6.80 H% 5.55 Found : 69. 8.6 7.1 5.3 . , Starce I : Y-lactam of DL-6H, 7H-cis 7-tritylamino • 3-aminomethyl ceph-5-em 4-carboxylic acid, X, w-iUli II.

One puts in suspension 14.15 g. of Y-lactam of 2-(a-carbox -a-trity1amino) -methy1-5-aminomethy1-2,5- ihydro-1 ,3-thiazine-4-carboxylic acid, three form, in 140 c.c. of anhydrous pyridine placed under an atmosphere of nitrogen. One adds 10.2 g. of dicyclohexyl carbod-iimide , agitates for 5 minutes, and introduces 300 c.c. of anhydrous methylene chloride, then 300 c.c. of anhydrous nitromethane . The ' resulting white suspension is left sheltered from the light at ambient temperature for 65 hours; one suction-filters the dicyclohexylurea which has crystallized, rinses the crystals with methylene chloride, concentrates filtrate and washings in vacuo until 1/4 of volume, treats with animal charcoal, filters and evaporates to dryness in vacuo. One The crystalline product is dissolved in 30 c.c. of ethyl, acetate, one precipitates by the addition of 2 c.c. of water, dilutes with 35 c.c. of ether and suction-filters 9.3 2· of colourless crystals, solvated with a half molecule of water', melting in the region of 200° (with decomposition).

By the addition of water to the ethereal solution obtained above, one recovers a further 0.18 g. of product identical to that of the first yield.

The product obtained is usable for continuing the synthesis.

For analysis, one recrystallizes it in methyl acetate and obtains an anhydrous sample, m.p. about 240° with decomposition.

Analysis of the product solvated with # mol. of water.

C27H23°2N3S 1/2 ¾° ¾ ^62.5 Calculated : C% 70.16 E% 5.2 % 9.08 S% 6.93 Found : 69.9 5.5 9.1 6.8 I.R. Spectrum in chloroform: free, NH 3 0 cm"1 + associated NH β-lactam 1777 cm""1 Y-lactam 1698 cm"1 C = C 1663 cm"1 aromatic U.V. Spectrum 1) in ethanol ·. .

Inflex. at about' 226 ιημ E1^ = 424 2 4 *μ E ^ = 125 259-260 ημ Elcm = 121 2) in ethanol containing 0.1 N hydrochloric acid Inflex. ' at- about 425 127 3) in ethanol containing 0.1 N caustic soda λ max. 260 mu E¾m = 78 Nuclear magnetic resonance 60 Mhz in CDCl^.

The coupling constant between the two protons of the β-lactam cycle is 5 Hz, which confirms the cis configuration of two hydrogens .

As far as is known, this compound is not described in the literature.

Stage J : Ύ-lactarn of DL-6H, 7H-cis 7-amino 3-amino- methyl ceph-3-em^ 4--carbox,lic acid, I, One introduces 6 g. of Y-lactam of L-6H, 7H-trans 7-tritylamino 3-aminomethyl .ceph-3-em -carboxylic acid into 42, c.c. of nitromethane saturated with gaseous hydrochloric acid at a temperature of 20°. One agitates at ambient temperature for 10 minutes, then drives off the hydrochloric acid in vacuo ¾ adds 60 c.c. of ether, suction-filters, washes with ether and dries. The hydrochloride thus obtained is introduced into 30 c.c. of ethanol under an atmosphere of nitrogen, one adds quickly while agitating 2.3 c.c. of triethylamine and continues the agitation for 10 minutes. One ice-cools, suction-filters, washes with ethanol, then with ether and collects 2.6 g. (being 93%) of product usable without other purification for the formation of acylation derivatives or for resolution.

For analysis, one recrystallizes the product in water in the form of hydrochloride and liberates the base by the addition of triethylamine.

The product is' soluble in water, dimethylsulphoxide and dimethylformamide , slightly soluble in ethanol and insoluble in ether.

Analysis : = 211.24 Calculated : 0% 5. 9 H% 4. JO W/o 1 . 0 S%.15.18 Pound : . 4 . 4.5 20.0 14.9 I.3R. Spectrum in nujol β-lactam at ' 1754 cm-1 Y-lactam at t 1684 cm""1 double bond C = C 1647 cm"*1 and several other absorptions in the OH and NH regions.

As far as is known, this compound is not described in the literature.

Example 2' :' Resolution of the Y-lactam of DL-6H, 7H- • cis 7-amino -am omethyl ceph-J-em^ 4-carboxylic acid One dissolves 3 g. of pure D(-)-tartaric acid in 15 c.c. of water, introduces 3.1 g. of the Y-lactam of D1-6H, 7H-cis 7-amino 3-aminomethyl ceph -3-em/ 4-carboxylic acid, then adds 15 c.c. of methanol. The tartrate crystallizes. One again adds 1 c.c. of methanol, agitates for 5 minutes, suction-filters, washes with methanol, .then with ether. One obtains 2.16 g. (being 80%) of the diastereoisomeric salt, Ca] ° = + 77 + 1.5° (c = 1%, water).

One triturates the tartrate obtained above for five minutes in 17 c.c. of ethanol, then adds drop by drop 1.9 c.c. of triethylamine . One agitates at ambient temperature for 15 minutes, suction-filters, washes with ethanol and. ith ether and obtains 1.2 g. of Y-lactam of L(+)-6H, 7H~ is 4-carboxylic acid, [a] °'= + 226° + 3° (c = 1%, water).

As far as is known, this compound is not described in the literature.

Starting- from the mother solution of the above tartrate, One-proceeds thus: the mother solution is admixed with triethylamine until a slightly alkaline pH is obtained, one concentrates over a water bath at 35°» in vacuo, introduces the residue into 20 c.c. of ethanol, suction-filters, washes with ethanol and with ether. One obtains · 1.48 g. of Y-lactam of D(-)-6H, 7H-cis 7-amino 3-aminomethyl cep -3-emz^ -carboxylic acid.

As far as is known, this compound is no described in the literature ·

Claims (1)

1. WHAT IS CLAIMED Proceee for preparing the raoemio or optically active acylated derivatives of of general in which represents an radical substituted by an 2 aromatic radical or by these derivatives being characterized in that one subjects a raoemlc or optically active derivative of of general formulaι to the action of an lates the desired acylated derivative which one to the agent of a salifying Process according to claim characterized that acylatlon is a oarboxylic organic substituted or functional derivative of this suoh as the anhydride or a such as the Process according to 1 and characterized in that one prepares the of phenyiacetamido Process according to 1 and characterized in that one prepares of sulphonyl phenylacetamido Process according to Claims 1 and characterized that one prepared the of amino acid and its Process according to Claims 1 and characterised that one prepares of Process according to Claims 1 and characterised that one prepares of aminophenylacetamido acid and its Process according to Claims and characterized that one prepares the racemic or optically of Process according to Claim characterized in that addltiont one subjects the racemic or optically active of acid to a catalytic r Compounds of general wherein is an phenyl phenyl or phenyl with mineral acids or with organic The of phenylacetamldo The of amido The of phenylaeetamido acid and The of phenylaeetamido acid and its The raeemie or optically active of The mineral or organic acid salts of the raeemie or optically active of acetamldo The mineral or organic salts of the acylated racemic or optically active derivatives of cephalo of general formula as defined in claim For the Applicant insufficientOCRQuality