IL32379A - Process for preparing derivatives of cephalosporin and gamma-lactam of 6h,7h-cis-7-aminomethyl-ceph-3-em-4-carboxylic acid - Google Patents

Description

32379/2 PROCESS FOR PREPARING NEW DERIVATIVES OF CEPHALOSPORIN AND NEW fl - LACTAM OF 6H.7H÷ CIS- 7÷ AMINO ETHYL- C EPH- 3- EM- »- CARBO XYLIC ACID jni.Di'is. ηΐΐΐπ nn^in n- n I ' i-rocess for preparing new derivatives of cephalosporin Company named. : RO'USSEL-UCLA? The present invention relates to a process for preparing new derivatives of cephalosporin .

The invention has more particularly as object a process for preparing the racemic or optically active derivatives of cephalosporin, of general formula I: H .11 .a which- R— rgpmgbSnt g- hy4gpg ¾'r»j¾n 'alky1 raaioal -aadioalv theco radioalo boing able- ¾ο· be Gubo itutaa cr nsti The new derivatives of cephalosporin . of general formula I are useful as intermediates in the preparation of the racemic or optically active derivatives .of cephalosporin of general formula I': in which R2 represents an'acyl radical substituted or not i'lgy iii '.yadical',- -thecQ " ■radioalc boing "a lo to "oo ou'ootitutou -o The compounds of formula I' are described in the published JDutch Patent Application No. 68-00751. As it has been indicated in this application, the derivatives of cephalosporin of formula I1 are endowed with interesting antibiotic properties.

According to this application, one prepared the compounds I' by hemisynthesis , that is to say starting from products of which one part of the molecule was .pre -existent .

Now, the present invention makes possible, by the route of total- synthesis , preparation of the derivatives of cephalosporin of formula I, that is to say products including at the 7-position of the cephalosporanic skeleton a free ijrimary amine function, the compounds I being able ΐο· be converted, by acylation of .this primary amine function, into derivatives of cephalosporin of formula I1.

Israel This acylation is described in the/patent- application of tho oamo day ( 136$ B.) Λ°.·. 32383.

The process for preparing the new derivatives of cephalosporin of general formula I, the object of the present invention, is represented on the annexed . diagram.

The said process is characterized in that one causes an amino acid of formula II: to react with benzyl alcohol in' the presence of an acid agent, of formula XH, X being a halogen or sulphuric or sulphonic anion, obtains an ester salt of formula III: III which one condenses with an alkyl or aralkyl oxalate, obtain a benzyl 2, 3-dioxo-pyrrolidine- -carboxylate of enolic formula IV: which, by hydrogenolysis , gives the corresponding -carboxyl derivative of formula IV" : subjects this compound to aminomethylation according to the reaction of Mannich, obtains a 2>3-dioxo- -(R' ,R") -amino-methyl-pyrrolidine , 'of formula V: · i which R' and R" represent alkyl or aralkyl radicals or together in this com thioacyl ' group , obtains a 2,3-dioxo- -acyl-thiomet yl-pyrrolidine of formula VI: VI s n e a y ra ca , frees the thiol function by an acid alcoholysis, obtains a mercaptan of formula VI': condenses this latter with an enamine of formula VII: VII in vmic R represents a lower alkyl radical or a lower aralkyl radical and .

Y represents an imido group or an acylamino group where the term acyl means the residue of a lower carboxylic organic acid, obtains a γ-lactam of 2-(a-R-oxy-carbonyl a-Y-methyl) -5-aminomethyl-2, 3-dihydro-l,3-thiazine- -carboxylic acid, Of formula VIII: 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 hydrogenolysis , obtains the corresponding Y-lactam, of formula VIII' : e ng a e o ex s n e orm o reo anc or ery ro isomers, of which one frees the carboxyl group by the ac of an acid agent, obtains a -lactam of 2-(a-carboxy-a- amino-methyl) -3-aminomethyl-2 , 3-dihydro-l , 3-thiazine- - carboxylic acid of formula IX: being able erythro isomers which one treats with a tritylation agent, obtains a Y-lactam of 2-(a-carboxy-a-tritylaminomethyl) -5-amino-methyl-2, 3-dihydro-l , 3-thiazine- -carboxylic acid of formula IX' : .( being able to exist in the form of threo and' or erythro isomers, converts the erythro isomer by treatment with an alkaline agent into threo isomer, subjects the threo . isomers to cyclization by the action of a dialkyl- or dicycloalkyl-carbodiimide , in the presence of a polar solvent and a tertiary amine, obtains the Y-lactam of DL-6H, 7H-cis 7-ti'itylamino-3-aminomethyl-ceph-3-em^- -carboxylic acid of formula X: which one detritylates by the action of an acid agent and obtains the Y-lactam of DL-6H? 7H-cis 7-amino-^-aminomethyl ceph-3-eme- -carboxylic acid of formula I: H H which one resolves, if necessary by means of an optically' active organic carboxylic or sulphonic acid and isolates , the desired optically active .derivative .

It is convenient to note that in this process the compounds VIII, VIII', IX and IX' possess 2 asymmetric carbons and can therefore exist in the form of threo isomer and erythro isomer. In fact, these 2 isomers have been observed. In addition, it seems that it is possible, as a/ function of the operative conditions, to vary the threo/erythro proportion and possibly to obtain one of the isomers in a preferential or even practically exclusive the case/ way. This is /at the time of the formation of the compound VIII, where one can. obtain almost exclusively the erythro isomer by using certain operative conditions. It has however been observed that the erythro isomer of compound VIII can be converted into a mixture of threo and erythro isomers of compound VIII 1.

, Thus it is not necessarily advantageous, in order to convert VIII into IX', by the intermediate of the compounds VIII' and. IX, to isolate a pure isomer at each stage; the mixture of the two isomers can very well be used to conduct the following stage. .However, onl one of the two isomers of XI' , the threo isomer, leads, by cyclization, to the compound X possessing the desired 6H, 7H-cis configuration, s ere ore necessary to o a n a eas partially in the form of threo isomer. This seems to be so whatever the operative conditions may be. In addition, it has been shown that it was possible to isomerize the erythro form of. IX' into the corresponding threo form. It ■ is there a question of one of the essential particularities of the process of the invention.

The process for preparing the derivatives of cephalosporin of general formula I, such as has been defined above, includes more particularly two remarkable and unexpected aspects: 1) The hydrogenolysis of benzyl 2, 5-dioxo-pyrrolidine- - carboxylate of enolic formula IV by catalytic hydrogena- tion which respects the 2,3 double bond, this hydrogenolysis being followed by a decarboxylation in an.aminomethylating medium.

. . It is advisable to note that in the particular case .where = H, the simple elimination of the carboxylic group useful for the creation of an activated (therefore alkylatable) methylene at 4 had not until now been able to be effected without breaking the heterocyclic • chain .[cf. SOUTHWIC et_al, J. Org. 21, 1086 (1956)]. 2) The isomerization of the erythro form of the .Y-lactarn of . 2-(a-carboxy-a-tritylamino-methyl) -5-aminomethyl-2, ~>- dihydro-1 , 3-thiazine- -carboxylic acid of formula IX' in the. threo form under the effect of the action of an alkaline agent. One obtains in this way an intermediate product prefiguring the cephalospor.anic structure of natural origin.

As. has been indicated above, one will use as s-tarting material of the above process β-alanine or even - if one wishes to obtain a final compound substituted at the - - -~- on the nitrogen. It is likewise possible to proceed to this substitution once the synthesis is completed, that is to say at the level of the final structure of formula I.

A preferred, but not limitative ,. method for carrying out the process of the invention can be characterized in particular by the following points: - the reaction of benzyl alcohol with the starting product of formula II is effected in the presence of a sulphonic acid such as p_-toluenesulphonic acid or methanesulphonic acid, or in the presence of a mineral acid, such as hydrochloric acid or sulphuric acid.

- The condensation of the ester salt of formula III with an · alkyl or aralkyl oxalate is effected in the presence of an alkaline agent, such as an alkaline alcoholate like potassium or sodium t-butylate, or potassium or sodium benzylate. As oxalate, one uses advantageously benzyl ' oxalate or ethyl oxalate. . · - The hydrogenol sis of benzyl 2 , 3-dioxo -pyrrolidine -4- . carboxylate of enolic formula IV is conducted in the presence of a palladium or platinum based hydrogenation catalyst.

- The a inomethylation of the hydrogenolysis product is · the/ realized by the action of formaldehyde and of/Hydrochloride of the chosen amine by operating in a hydrochloric medium.

. As examples of amines, one will mention morpholine , pyrrolidine, dimethylamine , diethylamine , etc.

- The' displacement of the amine group of the product resulting from the aminomethylation is obtained by the action of a thiocarboxylic acid, such as thio-acetic. acid or thio- propionic acid, in the presence of the corresponding alkali- metal, such as sodium or potassium, thiocarboxylate , which leads to 2 , ~dioxo- -acyl-thiomethyl-pyrrolidine * of e th o function of , - oxo- -acyl-th omet y - pyrrolidine of formula VI is freed by methanolysis in the presence of an acid agent, such as a mineral acid like hydrochloric acid or sulphuric acid, or a sulphonic acid like p_-toluenesulphonic acid or methane sulphonic acid, and one obtains the mercaptan of formula VI'.

The methanol reaction medium containing the mercaptan of formula VI1 is, after neutralization at low temperature, the/ admixed with an enamine of formula VII, such as /t -butyl- .. ·: phthalimido malonaldehydate enamine. The methanol solution is taken to dryness by distillation in vacuo and the residue thus obtained is taken up again by anhydrous benzene; the reaction mixture is heated to reflux, possibly,' with azeotropic entrainment of the water thus formed, for 12 hours, and one thus obtains the thiazine of formula VIII, which appears, in these conditions, essentially in the form of er hro isomer.

One eliminates the phthaloyl group of the γ-lactam of 2- ( a-R-oxy-carbonyl a-phthalimido)-methyl-5-aminomethyl-2,3-dihydro-1 , 3-thiazine-4-carboxylic acid, of formula VIII (with Y = phthalimido) by hydrazinolysis in the presence of an organic solvent, such as a disubstituted amide like dimethylformamide , or a cyclic ether such as dioxan.

The liberation of the carboxyl group of the Y-lactam of 2-(a-R-oxy-carbonyl a-aminomethyl)-5-aminome hyl-2 ,3-dihydro 1 , 3-thiazine-^-carboxylic acid,, of formula VIII', is effected b . an acid agent., such as a mineral or organic acid, like hydrochloric acid, hydrobromic acid, p_-toluene sulphonic acid, a mixture of hydrobromic and acetic acids, or trifluoroacetic acid, in an anhydrous organic solvent, such as benzene, toluene, ether, dioxan, nitromethane , or a polyhalogenated hydrocarbon like chloroform or methylene • e r y a on o e - ac am - - ar -.- - methyl) -5-aminomethyl-2, J-clihydx^o-l , 3-thiazine-4-carboxylic acid of formula IX is effected by the action of trityl chloride and by operating in the presence of an alkaline agent like triethylamine . he conversion of the erythro form of the Y-lactam of 2- (a-carboxy-a-tritylamino -methyl) -5-arninomethyl-2, 2-dihydro- 1 , 3-thiazine- -carboxylic acid, of formula IX', into the' threo form is realized by the. action of an alkaline agent, such as an alkali -metal hydroxide like sodium, hydroxide or lithium hydroxide, in an alkanol , such as methanol or ethanol.

The cyclization of the Y-lactam of 2-(a-carboxy-a-trityl- aminomethyl) -5-aminomethyl-2, 3-dihydro-l , 3-thiazine-4- carboxylic acid, threo isomer, of formula IX* is obtained by the action of a dialkyl or dicyclalkyl-Oarbodiimide , such as dicyclohexylcarbodiimide or diisopropylcarbodiimide in the presence of a polar solvent, such as a nitroalkane like nitromethane , a disubstituted amide, a sulphoxide, acetone or acetonitrile , and in the presence of a tertiary amine like pyridine, a collidine or a dialkylaniline , this medium being able to include an additional solvent like methylene chloride or chloroform.

•The detritylation of the Y-lactam of DL-6K, 7H-cis 7-tri- tylamino 3-aminomethyl ceph-3-eme-4--carboxylic acid, of formula X, is obtained by the action of an acid agent, such as a mineral or organic acid like hydrochloric acid, hydrofluoric acid, acetic acid or trifluoroacetic acid, by operating in an organic solvent like nitrcmethane , chloroform, methylene chloride or methanol.

The resolution of the Y-lactam of DL-6H, 7H-cis 7-a in° 3-aminomethyl ceph-5-eme- -.carboxylic acid of formula I is . , , carn'phosulphonic or glutamic acids, the decomposition of the salt thus obtained being effected by means of a mineral base such as sodium or potassium hydroxide, or an organic base such as a tertiary amine like triethyl- amine .

. "': The following examples illustrate the invention without however limiting it.

, .EXAMPLE 1 :' Preparation of the Y-lactam of DL-6H.7H-cis 7-amino 5-aminomethyl ceph-3-em^ -carbox.ylic acid , I w- Ul1) Ιΐ^ - Stapre A .: .Benzyl p-toluene sulphonate β-alaninate , III with ¾p^-il»md X = p-toluenesulphonyl In an apparatus provided with a system for separating water formed in the reaction and azeotropically entrained y the solvent, one heats at reflux for 5 hours the . following mixture-: - β-alanine 89 g. - monohydrated p_-toluene sulphonic acid 210 g. - benzyl alcohol 5Ο cc. - carbon tetrachloride 500 cc.

During this time One has separated about 5 c.c. of water. The reaction liquor is then reduced to small volume by distillation in vacuo. One cools and crystallises the product thus formed in ether. One ice-cools, suction-filters, dries and collects 55Ο 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 Kagaku Zasshi 76 , 662 (1957) . ' · . ' tapre : enzy ,-- oxo -pyrro ne - -ca ox a e iv 'iiti II One introduces 225 g. of potassium t-butylate into · 9CO c.c. of anhydrous benzene, adds 50° c.c. of benzyl alcohol, cools the mixture with an ice -methanol bath and> without exceeding 30°, incorporates 351 έ· °f benzyl p_-toluene sulphonate 3-alaninate .

One dissolves, on the other hand, 300 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 triethylamine . 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 containing 15 c.c. of acetic acid, . the 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 13O.5 g. (being 5 %); of product, m.p. 186°C, soluble in the alcohols, ether and acetone, insoluble in benzene and water.

Analysis V C12H11° N = 2^'2^ ' ' ' Calculated : C 61.8 11% .76 N% 6.01 Pound : 62 5.1 6.3 ■I.R. Spectrum:' . " wo maxima in the carbonyl region 1729 cm"*"1" and 1693 crn"*^ Absorption in the associated . OH/ H region Presence of monosubstituted aromatic τΓ ι As far as is known, this compound is not described in the a) Preparation of the hydropenation catalyst .One agitates under an atmosphere of hydrogen a suspension of 0.3 g. of animal charcoal in 4 c.c. of an aqueous solution containing 2% of palladium chloride. After saturation of the catalyst , one suction-filters it protected from the air and rinses several times with anhydrous dimethylformamide . b) Kydroprenation One dissolves 9-32 g. of benzyl 2, 3-dioxo-pyrrolidine - 4-carboxylate in 50'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 $00 c.c. of isopropyl ether, suction- ilters 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 dimethylsulphoxide and dimethylformamide , insoluble in isopropyl ether and in water. Ί.Ί . Spectrum (in nujol) Absorption in the associated OH/JNH region . · Complex and strong absorption in the carboxyl region : inflection 1708 cm"1 max. 1677 cm"1 • Analysis : ' C^H^O^ Calculated : C% 41.96 11% 3.5 N% 9.79' , the literature hydrochloride, V with R' + R" = One adds 2 drops of N hydrochloric acid to 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% formaldehyde, 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 from ethanol. 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%^ product which appears in the form of white crystals, slightly soluble in ethanol and ether, soluble in water.

Analysis : 23 .7 Calculated : 0% 46.06 H% 6.4 W/o 11.9 01% i5.ll Found : 45.8 6.4 . 11.8 . I.5.2 I.R. Spectrum: (in nujol) Absorption bands at 3210 cm'"1" and from 3.6 to 4.1 μ 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-4-morpholino-me hyl -pyrrolidine hydrochloride can be Obtained starting from benzyl 2,3-^ioxo- - - One introduces 50.35 g. of benzyl , 3-dioxo-pyrrolidine 4-carboxylate into 300 c.c. of dioxan containing 10 water, heats slightly to dissolve the product, adds 3 g- of animal charcoal and 1 c.c. of an aqueous solution of 20% palladium chloride, one places under an . atmosphere of hydrogen and agitates very energetically. In 1 hour 40 mins. one has absorbed 2?00 c.c. of hydrogen (volume predicted by theory 2912 c.c). One cools, purges with nitrogen, then introduces 130 c.c. of mixture thus composed: , morpholine 3.5 £· water' 100 c.c. concentrated hydrochloric acid ·.· 40 c.c.

N hydrochloric acid ' 15 c.c. formaldehyde . 50 c.c. water to make $00 c.c.

One heats the reaction mixture to about 0° and collects in 1 hour 325 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 a product identical to that described above.

'. Stage E :. , 5-dioxo- -acetyl -thiometh l -pyrrolidine , · VI with Ac = acetyl and Rj—=-ff 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 sodium bicarbonate, agitates for 5 minutes, then adds 46.8 g. of 2,3-dioxo - mixture is agitated at aribient teinperature for.3 hours and a half', with the addition of a little ether at the end of half- an-hour in order to suppress the froth which, is formed. One then acidifies to pl-l - 1 by the addition of 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 l'50 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 6· of product, identical to that of the first yield. Total yield : 72.5%.

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

For analysis, one recrystallizes it from 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 : 0% . 1 H 4.85 7. 9 S% 17.13 Found . : 44.7 4.9 7.6 . . 17.1 U. V.-■. Spectrum a) in ethanol/O. I N hydrochloric acid · Max. 225 ·κμ E¾m = 666 Max. 251 πη,ι E^. = ^6'+ / I.R. Spectrum (in chloroform) . . .

Carbonyl absorption -max 1689 cm""1 Wd fine band at 5 60 cm"1 OH. max. at about 3210 cm"1 As far as is known, this compound is not described in the literature.

Stage ? : γ-lactam of 2- a-t-butoxy-carbonyl a-phthali- mido-methyl] -3-air.inomethyl-2, -dihydro-l , 3- •thiazine- -carbox ic acid , VIII with R = t-bu, -R^ '- H- and Y = phthalimido One dissolves 18.72 g. of 2,3-dioxo-4-acetylthio- me h l-pyrrolidine in 300 o,c. of a methanol solution of 5% ^-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 -5O0 and admixes it drop by drop with 39.5 c.c. of a 2 ammonium acetate solution in methanol. One then adds while operating under an atmosphere of nitrogen, 30 g. of -butyl phthalimido malonaldehydate enamine and leaves under agitation for a fev/ 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 0;i) of product, m.p. 25>0° , which. appears in the form of white crystals soluble in the methahol/chloroform mixture, slightly soluble in pure methanol, insoluble in benzene and ether.

Calculated ' C% 57.S E 5.10 N 10.11 S% 7.72 Pound 57.7 5 ·^ 9.9 7.9 As far as is known, this compound is not described in the literature.

Stape G ': Y-lactam of 2-f o-t-butoxy-carbonyl ,g-arnino~ methyl hydrochloride] -5-aminomefth l-2, dihydro-l , 3-thiazine- -carboxylic acid , Oil1 (hydrochloride) with H = t-But, One introduces 16.6 g. of Y-lactam of 2-( -t-butoxy- carbonyl †a-phthalimido-methyl)-5-aminomethyl-2, 3-dihydro 1 ,3-thiazine-4-carboxylic acid in 32 c.c. of dimeth lformamide , then one adds very slowly, while operating under agitation- and an atmosphere of nitrogen, 22 c.c. of 2 resolution of hydrazine hydrate in dimethylformamide and agitates for $~0 minutes at ambient temperature. One then adds in a. space of 30 minutes, 4 c.c. of hydrochloric acid, agitates for 30 minutes, then ice-cools and filters. The filtrate is evaporated to dryness in vacuo and the residue, dissolved in 3 c.c. of water, is treated with animal charcoal. One filter,' 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 crystallization from 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.R. or U..V. spectral characteristics, but in fine zone chromatography, the erythro form appears most mobile (Kieselgel 'G? wate 20%) . ?or each pure stereoisomeric hydrochloride (or . '' their mixture) dissolution in the minimum of an aqueous solution of sodium bicarbonate liberates the free base (or the mixture of free bases) which one can extract with ethyl • acetate .

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

'-'Stape H ■ ' : -lactam of 2-(a-carboxy-a-trity lamino) - ' meth l-17-3minomethyl-2, - ihydro-l , 3- thiazine- -carboxylic acid 1) -1actam of 2-(a-ca b 0 / -«.-3ruinomethy1 ) -cj-a inomethy1-2,5- ' dihydro-1 , 5-thiazine—!--carboxyIic acid, IX, ■wi-¾i'^~=-HT One introduces 12.88 g. of- the mixture of threo and erythro isomers corresponding to the Y-lactam of .2-(a-t-buto y- carbonyl aminometh l hydrochloride) -^-aminometh l-2, 3-di ydro- 1,3-thiazine-^-carboxylic acid into 320 c.c. of nitromethane, saturated v/ith 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 fift ,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-(o,-carboxy-a-tritylaminomethyl) - -amino- me h 1-2, -dihydro-1 , 3-thiazine- -carboxylic acid, IX1 ,..' 'One - places the mixture ..obtained above under ah atmosphere ' of nitrogen, -cools with a' bath of iced water and introduces 28 c.c. of triethylamine and 2 g. of tri'tyl chloride into 80 c.c. of methylene chloride. One leaves at ambient ' tempe at re under nitrogen for one night and evaporates to dryness in vacuo. One dissolves the residue in a mixture and adds 16 c.c. of acetic acid. One concentrates to half volume, agitates -for half an hour at ambient temperature, suction-filters, dries and collects 7.16 Ε· (being 38½) of tritylated product, a practically pure threo 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 LV hours at ambient temperature. One suction-filters, washes with ether, then with water and Obtains 8. $68 g. of tritylated product, the erythro form containin a little threo isomer.

As far as is known, this compound is not described. in the literature. 4) Isomeri zation of the erythro form into threo One suspends 8.568 g. of erythro form tritylated derivative in' I70 c.c. of methanol, cools to 10°, adds 11.8 c.c. of aqueous N lithine, keeps fo 3 minutes at ambient temperature. One then adds acetic acid (about .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 .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 v/hich 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, suctio -filters which, one isomerizes as described above to obtain thus 0.887 g. .of threo form, derivative.

) 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 ethe 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 2 0° (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 : = 471.55 Calculated : C 68.77' N% 8.91. S 6.80' K% 5.35 Found ' : 69. 8.6 7-1 5.3 'Sta e I ' : -lactam of PL '6H, 7H-cis 7-tritylamino 3'-a i.nomethy1 ceph-3-ern0 4-carboxylic acid, • X, with R = II. i One puts in suspension 14.15 g. of Y-lactam of 2-( - ' j carboxy-ct-tritylamino).-methy1-5-aminomethy1-2, 3-dihydro-1 , 3- thiazine-4-carboxylie acid, threo form, in 140 c.c of anhydrous · pyridine placed under an atmosphere of nitrogen.

One adds 10.2 g. of dicyclohexyl carbodiimide , agitates for minutes, and introduces 300 c.c. of anhydrous methylene chloride, then 300 c.c. of anhydrous nitro ethane . The resulting white suspension is left sheltered from the light at ambient temperature for 65 hours; ' one suction-filters the dicyclohexylurea which had crystallized, rinses the crystals with . methylene chloride, concentrates filtrate and washings in vacuo until.1/4 of volume., treats with animal crystallizes the residue by triturating in ether,- suction- filters and keeps the mother liquors of washing.

The crystalline product is dissolved in $ ~0 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 g. of colourless crystals, solvates with a half molecule of water, melting in the region of 200° (with decomposition). 3y the addition of v/ater 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 24-0° with decomposition.

Analysis of the product solvated with ½ mol. of water.' C27¾°2N3S 1/2 H2° = 62 · 5 Calculated : C% 70.16 K 5.23. ' % 9.08 S% 6.93 Found : 69.9 5-5 9.1 : 6.8 1.5. Snectrum in chloroform: free NH 0 cm"^" + associated β -lactam 1777 cm -lactam 1698 cm -.1- C = C 1663. cm aromatic U.V. Spectrum 1)' in ethanol - Inflex.'a about .226. my. ∑ ^m = ιημ . Ξ ^ = 125 - 259-260 ra . E ^ = 121 2)· in ethanol containing.0.1 N hydrochloric acid Inflex. at about 225-6 πιμ E J = 425 . · · 259-60 πιμ Ε jj^ = 123 3) in ethanol containing 0.1_N caustic soda λ max. 260 ιημ E 'frn = 78 Nuclear magnetic .resonance 60 Mhz in CDCl^.

The coupling constant between the two protons of the (3-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 '. lit erature .

Stage J : Y-lactam of DL-6H, 7H-cis 7-amino -amino- methyl ceph-3-erojf. -carboxylic acid, I , wi h Rj^ = H One introduces 6 g. of Y-lactam of DL-6H, ?E-tra s 7-tritylamino 3-afflinomethyl ce h-3-emJ -carb oxylie acid into 2 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, adds 60 c.c. of ether, suction-filters, washes with ether and dries. The hydrochloride thus obtained is introduced into 3 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 fran 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.

Calculated : Cfr 5. K# 4.30 Ni 19. 0 S?i 15.18 Pound : , 5.7 .5 20..0 ' 14.9' I.R. Spectrum. in nujol . -lactam at 175 cm-1 -lactam at 168 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 -arninomethyl ceph-5-em$.4-carbox;ylic acid One dissolves 3 g. of pure D(-) -tartaric, acid in 15 c.c. of water, introduces J.17 g. of the Y-lactam of DL-6H, 7H-cis 7-amino 3-aminomethyl ceph-3-emi¾-4-carboxylic acid, then adds I c.c. of methanol. The tartrate crystallizes. One again' adds 15.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, [αϋ 2^0 =' + 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 ' minutes, suction-filters, washes with ethanol and with ether and obtains 1.2 g. of Y-lactam of L(+)~6H, 711-cis 7-amino 3-aminomethyl ceph-3-emj¾-4-carboxylic acid, [a] 20 = + 226° + 3° (c = 1%, water).

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

■Startin from the mother solution of the above tartrate, one can obtain the other isomer. ' ' with triethylamine until a slightly alkaline pH is obtained, one concentrates over a water bath at 55° > 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 . ceph-3-eme -carboxylic acid.

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

■ '· . Examples of acylation of1 the compounds of formula I : ■ Preparation " of compounds of formula I1 Example 1 ' : Preparation O 'the Y-lactam of DL-6H, 7K-cis 7-Q . -carboxyl phenylacetarnido 3-aminomethyl ceph-3-em$- -carbox lie ■ acid . One introduces 106 mg. of Y-lactam of DL-6H, 7H-cis 7-amino 3-aminomethyl ceph-3-em<5j- -carboxylic acid into 1 c.c. of dimethylformamide, adds 125 ^δ· 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 l.c.c. of water. One suction filters, washes the product with aqueous methanol and with ether and obtains 120 mg. (being 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 : 6% 54.68 E% .05 'N% 11.26. S% S.58 Found · : 5 .9 · 4.2. 11.0 8.7 Bands at 1767 cm"1 -lactam .1678 cm"1 1704-1658 cm"1 Y-lactam + amide + acid 1552 cm"1 2nd amide absorption in the associated OH/BHregion and OH aromatic acid As far as is known, this> compound is not described in the literature'.

·" Exam le 2' : Preparation of the Y-lactam of DL-6H, 7H-cis 7-P . -sulphonyl phenylacetamido 3-aminometh l ceph-5-ero¾ -4-carboxylie acid One puts in suspension while agitating 106 mg. of Y-lactam of DL-6H, 7H-cis 7-amino 3-aminomethyl ceph-3-em^_ 4-carboxylic acid in 1 c.c. of dimethylformamide , adds 277 mg. of sodium salt of p. -sulphonyl phenylacetic acid and 115 mg. of dicyclohexylcarbodiimide . The reaction mixture is agitated at ambient temperature for two hours, one suction-filters the dicyclohexylurea , adds 3 c.c. of dioxan and suction-filters the product thus formed. One recrystallizes itfrcma water-dioxan mixture.^ One obtains 162 mg. -(being 70%) taking account of the fact that the product is solvated with 2 molecules of dioxan. It loses 18.6% of its weight at 100° in vacuo. The values . of the microanalysis below. have been calculated for a solvation- with 1/2 molecule of dioxan.

Analysis : C^H-^O^NjS^a = 5. 6 Calculated.: C% 45.44 ¾¾ 3.82 N% 8.84 S% 13.48 Pound ■ ' : · 45.1. 4.0 . 8.8 .13.2 I.R. Spectrum in nujol Bands at 1781 cm"1.3-lactam 1698 and 1655 cm"1 · C=0 of amide . 156O cm"1 2nd amide absorption in the associated OH/NH region. the literature.

.Example V ·* Preparation of the -lactam of DL-6H, 7H-cis 7-P. -amino -phenylacetamido 5 -amino One prepares first of all the anhydride of p. -amino phenyl acetic acid, beforehand protecting the amine function by tritylation.

One introduces 5 of p. -amino phenylacetic acid into 13.5 c.c. of an aqueous N solution of diethylamine, adds 2.25 g. of trityl chloride and agitates for one half-hour. One decants, adds 10 c.c. of ethyl acetate and 5 c.c. of N hydrochloric acid and extracts with ether. ■ One evaporates the 'extracts to dryness in vacuo, dries and dissolves the residue' in ethyl acetate. One adds diethylamine and starts crystallization by' scratching. One adds ether, suction-filters introduces the residue into an ethe -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 c.c. of dimethyl-formamide.

To the 'above solution, one adds 106 mg. of Y-lactam of DL-6H, 7H-cis 7-a^i o J-aminomethyl c'eph-3-em^-, -carboxylic acid and agitates at ambient temperature for one extracts the washing waters with ether, combines the organic phases, dries and reduces to small volume in vacuo, withou . heatin . One precipitates with ether, suction- filters, washes with ether and obtains 233 mg. of Y-lactam of DL-6H, 7H-cis 7-p. -tritylamino phenylacetamido 3-ainino-■ methyl ceph-^-em^^-c rbox lie acid. <· .

One saturates 10 c.c. of nitromethane with gaseous hydrochloric acid , ice-cools and introduces the 1.0 5 g. of the above tritylated derivative. One agitates for 5 minutes at ambient tempera'ture , drives off the excess hydrochloric acid, suction-filters and obtains 570 mg. of product melting above 250°. One purifies 210 mg. of this product in the following way : One introduces it into a dilute aqueous solution of hydrochloric acid, neutralizes by the addition of triethylamine, suction-filters', washes with methanol, then with ether.

One obtains 1 0 mg. of v -lactam of DL-6H, 7H-cis -Ρ·-&πα ο phenylacetamido 3-amiriomethyl ceph-3-em^-4-carbox lic acid. The product melts above 250°, it appears in the form of ■straw-yellow crystals.

Analysis :. C^H^O^S = 3 .39 ' Calculated : C '55.8 H% 4.7 JN% 16.26 S% 9.3 Pound . ■ : 55-5' . 16.1 9.1 As far as is known, this compound is' not described 'in the literature.

ExamOle 4 ' : Prepara ion, of the Y -lactam of L( + )-6H, methyl ceph-3-eme 4-carboxy lie acid One puts in suspension 0 mS« of Y -lactam of L(+)-6H, 7K-cis 7-amino 3i-amiiiomethyl · ceph-3-eme 4-carboxylic acid in 4 c.c. of -.iced water, adds 0.5' c.c. of an aoueous 1Q of/ solution of sodium .bicarbonate , then 5 drops/thienyl acetyl bicarbonate solution and continues the agitation for another 15 minutes.

One suction-filters, washes with water, pastes with methanol, then with ether. One obtains 57 ra . (being 7 0 of product of which the pur.! ty is confirmed by thin layer chromatography, Sf 0.62 identical to the product obtained by hemisynthesis .

The product melts above 260°, [α]^° = + 145· 5 + 2.5° (c = 1/i. dimethyIformamide) .

The I.E. spectrum in nujol can be superimposed' on that- of the hemisynthetic product.

' In an analogous way, by operating according to example. 5'·, .one obtains the Y-lactam of L(+ )-6H, 7K-cis 7-(p. -amino phenylacetamido) 3-aniinomethyl ceph-3-eme -carboxylic acid, ■ [α]^° = + 1 7° ± 3.5° (c = 0.7%,, dimethylformamide) .

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

Example 5' : Preparation of the -lactam of L(+)-6PI, ■ 7H-cis 7-( >-nitrophenylacetamido) 5-amino- methyl ceph.-3-em^ 4-carbox lic acid s One mixes under agitation, and under nitrogen, 30 c.c. of riitromethane , 3.65 g. of p-nitrophenylacetic acid and 2.25 g. of dicyclohexyl carbodiimide ; -one maintains the agitation for one hour, adds I.O55 g. of Y-lactam of L(+)-6H, 7H-cis 7-sm:ino 3-aminoiaethyl ceph-3-eme -carboxylic acid and 2.drops of pyridine and continues agitation for 15 minutes, at ambient temperature; one suction-filters and collects 1.75 6· °f crude compound of which one takes up 0.6 g.with 4. c.c. of dimethylsulphoxide , suction-filters and recrystallizes franethanol ; one obtains 0.43 g. of j Y-lactam of L(+)-6H, 7H-cis 7-(p-nitrophenylacetamido ) 3-aminomethyl ceph-3-em 4-carboxylic acid. crystals, soluble in dimethylformamide , insoluble in water and ethanol; its melting point is higher than 250°C.

•As far as is known, this compound is not described in : the literature. ■ .' This compound can be converted into hydrochloride of the Y -lactam of. L(+)-6E, 7H-cis 7-(p-aminophenylacetamido ) 3- aininomethyl ceph-3-em^- -carboxylic acid by operating as follows:' One mixes 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-' ci s 7-(p-nitrophenylacetar.oido ) 3-aii'in.ometh l ceph-J-em^' - carboxy lie. acid and 3 c.c. of I\T 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 w th ether and dries. One obtains 875 ^ . of hydrochloride of Y-lactam of L(+)-6H, 7H-cis 7-(p-amino-phenylacetamido.) '3-aminomethyl ceph-3-em¾ -c rbox lie 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 [a]^° = + 147° + 3° (c = 0.7%, dimethylformamide) .. the literature.

By treating the hydrochloride obtained above v/ith a mineral or organic base, one obtains the Y-lactam of L(+)- . 6H, 7H-ci s 7-(p-aminophenylacetamido) 3-aminomethyl ceph-3- eni^-' -carbox lic acid described in example 4.' .

By operating in the same way and by using as startin ■ , material the Y-lactam of DL-6H, 7H-cis 7-amino J-aminomethyl ceph-3-em -4-carbox lic acid, one obtains the ' hydrochloride' of the Y-lacta -of DL-6K, 7H-cis 7-(p-aminophenylacetamido ). 3-aminometh l' ceph-3-eme -carboxylie acid of which the melting point is higher than 250°C.

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

Claims (1)

1. WHAT CLAIMED IS CLAIMS Process for racemic or optically active of cephalosporin of formula hydrogen ioalo boing to no characterized in that one an amino acid of formula II to react with benzyl alcohol in the presence of an acid of formula X being a sulphuric sulphonic obtains an ester salt of formula which one condenses with an alkyl aralkyl obtains a benzyl 2 enolic formula hydrogenolysis gives the corresponding derivative of formula subjects to aminomethylation according to the reaction of obtains a of formula in which and represent aralkyl radicals or together form the in this compound the thioac l obtains a of formula in which Ac represents the liberates the thiol function by an acid obtains a mercaptan of formula condenses this latter with an of formula Y VII in which R represents a lower radical or a radical and Y represents an imido group or an group where the term acyl means the residue of a lower carboxylic organic obtains a of formula which appears in the form of of threo and er t ro in the of one of the splits off the imido group or the acylamino by an exchange of function using by an acid hydrolysis or by hydrogeno obtains the corresponding of formula ί being able to exist in the form of threo and erythro of which one liberates the carboxyl group by action of an acid obtains of acid able to exist in the form o threo and erythro isomers which one treats with tritylation obtains a of acid of fprmula being able to exist in the form of threo and erythro the erythro treatment with an agent into threo subjects the threo isomer cyclization by the action of a or in the presence of a pola solvent and a obtains the acid of which one detritylates by the action of an acid and obtains the formula one if necessary by of an active organic or sulphonic acid arid isolates desired optically active Process for preparing the racemic or optically active of characterized in that one causes to react with benzyl alcohol in the presence of an acid obtains the corresponding salt of benzyl which one condenses with benzyl obtains benzyl by gives subjects latter to the action of and hydrochloride in the presence of aqueous hydrochloric obtains the chloride of one treats acid in the presence of sodium liberates the thiol function of the resulting by acid obtains condenses this latter with the phthalimido malonaldehydate enamine obtains the of which appears in the form of a mixture of threo and er or in the form of one of the eliminates the phthaloyl group by hydrazinolysis obtains after treatment with aqueous hydrochloric of chloride which appears in the form of threo erythro liberates the carboxyl group thereof by the action of an acid obtains the of carboxylic appears in form of threo erythro treats this compound with a tritylation obtains the am of which appears in the form of threo erythro converts the erythro by treatment with an alkaline into threo subjects this latter cyclization by the action of a or carbodiimide in the presence of a polar solvent and a tertiary obtains the of tritylamino acid which one detritylates by the action of an acid obtains the of s acid which one if b means of an optically active organic carboxylic sulphonic acid and isolates the desired optically active ccording to claim 1 or characterized in that hydrogenolysis of benzyl carboxylate is conducted in the presence of a palladium or platinum based hydrogenation Process according to claim characterized in that the aminomethylation is effected by means of formaldehyde and of ydrochloride of an amine such as morpholi e dimethylamine or Process according to claim characterized in that the thioacylation is effected by means of a thiocarboxylic acid such as thioacetic or thiopropionic in the presence of the corresponding such as sodium or thiocarboxylate Process according to claim characterized in the acid alcoholysis of is effected by methanolysis in the of an acid such as a mineral acid like hydrochloric acid or sulphuric or a sulphonic acid like sulphonic acid or sulphonic Process according to 1 and characterized in that the mercaptan resulting from the methanolysis according to 6 after neutralization at low temperature of the methanol reaction medium containing the said condensed with an such as phthali ido malonaldehydate Process according to claim characterized in that the conversion of the erythro form of the of carboxy acid into the threo form is realized by the action of an alkaline such as an hydroxide like sodium hydroxide or lithium in an such as methanol or Process according to claim characterized in that the cyclization of the of threo is obtained by the action of or such as or in the presence of a polar such as a nitroalkane like nitromethane a disubstituted a acetone or acetonitrile and in the presence of a tertiary amine like a or a dialkylaniline this medium being able include an additional solvent like methylene chloride or Process according to claim characterized in the resolution of of acid is effected by means of optically active organic carboxylic or sulphonic acid like camphosulphonic or glutamic the decomposition of the salt thus obtained being effected by means of mineral such as sodium or potassium hydroxide or organic base as a tertiary amine like trlethylamlne The of formula in which X is or The of formula The of The racemic or optically active derivatives of of formula n The of mino The of mino methyl o insufficientOCRQuality