CA1128931A - Process for the preparation of cyano acetamide derivatives - Google Patents

Abstract

Abstract of the Disclosure Process for the preparation of acid amide derivatives of the general formula (I) wherein R1 represents hydrogen, or C1-6 alkyl, R2 is hydrogen, optionally a substituted aromatic or heteroaromatic preferably phenyl, furyl, thienyl, pyridyl, or optionally substituted C1-6 alkyl, preferably furylalkyl or phenylalkyl group or R1 and R2 together form alkylene, which is optionally substituted, preferably furylalkylene or phenylalkylene, R3 represents hydrogen or an easily cleavable esterifying group. preferably trialkyl-silyl or tri-chloroethyl, is or or and salts thereof by acylation of amines of the general formula II

(II) - wherein R3 and A are as given above-which comprises reacting amines of the general formula II or salts thereof - wherein R3 and A are as defined above - with an ester of the general formula (III) >

wherein Rl, R2 and R3 are as defined above and X is halogen, preferably chlorine or fluorine - and, if desired, splitting off the R3 protecting group of the ester group in positions 3 or 4 and/or setting free the product, if desired, from the salt thereof and/or converting it to salt. The compounds are valuable antibiotics.

Description

~2893~

, ~

,?o:na~l-3--on:rl)o:~Jl:i.c ac:Ld, 3-motily:l.-ce~ -3-~ c,~rl~o. yli.c ;lold ..l.n~l 3-.~oeto~;y-l~lo~ ,rl-co~,?1l~3~ carbo.{yli.c aci cl der'~v~lt:ives acyl.lte('l~rit'l cyal-lo acc-tic acicl cder,i,vatives aro l~nolr.-l to be valur~ le ~.U~ b:LO tics ~ wnicll ma}r be cmployecl in human tl~erap~ Ie-t'lods for tlle preparatioll OL' the above mentioned clerivat~ve3 have been clescribed accorclillg to ~ieh -the amille to be acylatecl is acylatecl ~Ji-th aced halides or mi-,recl a~lvdrldes ol carbo~ylic acids substituted l~ith a cyano group in the alpha position. ~ccording to another l~lo~m process th~ carboxylic acid substituted ~iitll CyanO
in the alpha position is reactecl~:~ith the a~ine in the presenee o~ a ~Jater abstracting agent, such as clicyclo-hexylcarbodiimide, ¦S~JiSS Pa-tent Speeifications No~.:
L~80.365, ~l~2,236, ~07,292,) T'ae disadvantage of the nown processes is, tlla-t the preparat:ion of pure product is generally only possible by chromatogræphic ~e-thods, - aeeompaniecl by other technological disadvRntages ~ncl ' problems, One of such problems occurs ~hen usi~g an acid '~ ehloride, as the pure acid chloricle ~nay only be prepared by a distillation accompaniecl by losses ancl the acid ehloride has to be worl~ed up in.~ediately because of the damage of pol~nerisation, ~hen using a erL~de acid ehloride to acylate molecules containing other racLicals sensitive to nucleophilic a~ents - as it is the case Irith

2~ eephem and pena~ derivatives - !nany side reaetions ~ay ' oceur.
1~1so many by-products are for~ed ~/hen enploying ~he l~nolm mi~ed anhydrides, thus one should Irorl- at a rather low temperature, Tlle pure end-produet can be recovered 30 ffven uncler suell circ~stances only by cllro~llato~raphy, A lL~64-77 /~né
' q~
~ .

,Z893~

Processes employing water abstractlng agents are rather complicated in indust-ry, and yields of only 65% can be achieved. It is dificult to remove the formed by-product: N-acyl ureas.
The disadvantages mentioned above are eliminated in the process of the present invention.
The present invention relates to a process for the preparation of acid amide derivatives of the general formula Rl C0 - NH ~ S

? C\

CN
R Co-oR3 - wherein R is hydrogen or Cl 6 alkyl, R2 is hydrogen, an aromatic or heteroaromatic ring which is unsubstituted or is substituted by one or more substituents selected from the group consisting of halogens, lower alkyl, lower alkoxy, halogenoalkyl, amino, mono- and di-- lower alkylamino and nitro groups, or R2 is a Cl 6 alkyl which is unsubstitut-ed or is substituted by a furyl or a phenyl group, or Rl and R2 together form a benzylidene group or an alkylene group which is un-substituted or is substituted by a phenyl, furyl, thienyl or pyridyl ring, R3 is hydrogen, or a readily cleavable esterifying group, preferably trialkyl-silyl, or trichloroethyl, ,- '\ ~

\ / or C-CH
/ C \ ~ 3 ~ ( -CH20COCH3 and salts thereof - by ,, , ' ~i l:~Z8931 acylating amines of the general Formula S\
H N ~ CII) / ~ N ~

co-oR3 wherein R3 and A are as defined above which comprises reacting an amine of the general formula II or~a ~alt thereof - wherein R3 and A are as defined above -with an ester of the general formula Rl~ ~ COO~\~ X

-- ~ X

wherein Rl, R2 and R3 are as defined above and X stands for halogen, preferably - chlorine or 1uorine, and thereafter optionally splitting off the protecting group R3 of the ester group in position 3 or 4 and/or setting free the product, if required, from its salt and/or converting it to a salt thereof.
When R2 is an aromatic radical it is preferably a phenyl, thienyl, 20 furyl or pyridyl radical. When it is a substituted Cl 6 alkyl radical it is preferably a furalkyl or phenylalkyl radical. When Rl and R2 form a substit-; uted alkylene group it is preferably furylalkylene or phenylalkylene.
The term "alkyl group" as used herein means Cl 6 straight or branched saturated aliphatic hydrocarbons, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl etc.
The term "aromatic group" stands for mono or bicyclic aromatic ring systems ~such as a phenyl or naphthyl group).
The term "heteroaromatic radical" stands for aromatic ring systems consisting of one or several rings, containing one or several heteroatoms 30 ~nitrogen, oxygen and/or sulphurl, ~' s~lol~ ~l!3 ~ i.oll~rl~ r~ yr:L~ .n~ no iso~l:ixlolyl ~roup3 QtC, L~llc arOnlQtic and hotolo.lro.-latic r~ s ~llay op~iollally be s~lbstituted -~itll one or sovoral 5ub5titucntC,~ ,~7~c'n as. 'lalOgO}l, (SUCil a5 chlorillc, bror.linc 5 or iodille), or lower all~yl (9uch as ~letnyl, otlr~l~, lower all~oxy~ suc}.~ as netllo}~y~ etllo~y, l~alo~cnoall;yl, suc~ as trifluoro~.letllyl, ~lino~ substituted arlino~ such as .~ethyl-~mino, e-t~lyla~nino~ or nitro. rile ter.~ "furyl-all.~yl gro~pl' stancls for fulyl~ et,l-jrl, :Puryl-ethyl, and the tel~ "phenyl-alkyl" may stalld for benzyl, beta-phenyl-ethyl, etc.
R and 1~ together forl-l an alkylelle c~roup, such as Cl 1, all~ylene, preferably ~ethylene, or ethyle~e, optionally substituted by phonyl, furyl, ~hienyl, pyriclyl etc. '~ may stc~lcl for chlorine, fluorine, or iocline, 1~ prePerably for chlorine or fluorine.
The ester ~roup in the place o~ R3 may be any of the easily re~navable esterifyillg groups Lnown in the chenistry of penicillin~ and cephalosporins~ SUCll as tri-lower all~yl-silyl or trichloroethyl. As salts of the coA.Ipounds of the general fo~mula I al~ali metal salts (such as sodi~L~l or potassium salts), or sa'ts fol~ed ~-~ith organic a;-ilines (such as tri-lower allcrl a~ines e.~, triethylanine) may be mentioned, 'rhe clefinitioll of the substituents ~Yill not change in 2~ tlle course of the specification, thus we silall lOt repeat it hereinafter, As starting l~aterials, pre.erably a narro~er group of thc acylatillg age~nts of the ~eneral for~lula III, cyanoacetic acicl pentachloroplanylester~ alpha cyano-phenylacetic acid pentachloroplenyl cster, alpila cy.~no-beta-phel~yl acrylic acid pontach'oropnenyl cster or tile ~2893 c0~ '09po~ )e.t~ OI~> ~`~ l;0'1'.5 ';I;-y 1~0 u~
~ onpo~ ls o~ tllo ~-ellcr;ll fo:~mula II are proferaDl~J
e;tlplo~ed ~ t;hc :Eori~l o~ tlle:;I salts, proferably in t'no îorn o~ socli~tl, potassittm, litl~ uil 5alts, or a ~alt ~or~led ~-Jitl triall~ylalllille ~ such as trietllyl~mine.
Tlle reaction l.s pre~erably carriecl ottt :in the presence o~ an aprotic solvent. I-Ialogenated hydrcearbons~ sucll as carbontetrachloride~ dechloromethane, chloroform, dichloro-ethane J.nay be entployed. Dipolar solvents, such as aceto-nitrile or other solvents may also be used.
'rhe reaction ~tay preferably be perforined in thepresence o:E a tertiary base~ Suitable basee are triaLkyl amines~ such as triethyla~tine~ or h0teroeyelic antines, such as pyridine or N-~netllyl-morpholine.
1~ ~le active esters e~tployed aecorclin~ to the present in~ention may be prepa~ecl by reac-ting the suitable cyano-~ acetic acid chloride with pentahalogenophenol or salts thereof, ~he acylation tal~es generally place ~mder mild reaction conclitions at a temperature o~ 0 to 20 C.
~le product is obtained ~lith a good yield, chron~atographic purifica-tion is not necessary, ~e details of the process are illustrated by the following Exa~nples.
:3xamples 2~ The chro~latograpllic tests ~ere carried out o~ thin layer using ~ieselgel ~Ierck F-2~4, cleveloping solvent:
1. Ben3ene-ethyl acetate = 2:1 2. Butanol-acetie acid = 3~

3. Butallol-acetic acicl - water - pyridine = 30:3:12:10 developer: chlorino/toluidine/~J.

, ~

~lZ8931 6-B(~-Cyano)-acetyl.~ iclo-penc~l-carbo~ylic acid 2,1 g" (O,01 mole) of 6-~1lino-penicillanic acid (6-APA) are cli5901ved in 30 ml, of dichloromethano by ~clding 2.8 5 ml. (0,02 moles) of triethyl~lina and at 0 C 3.3 g, (0.01 mole) of cyanoacetic acid pentachlorophenylester are added.
The mixture is stirred for 2 hours, ~rhereafter it is decomposed with a pllosphate buffer of pH = 7. The mixture is then acidified to ethyl acetate by adding 1:3 phosphoric acid. The organic layer is dried above magnesium sulfate~
and e~aporated~
The residual crystalls are triturated with diiso-propyl ether, 2 g, of the product are obtained (77 C,~).
1~ Analysis:
calculated C 46.64 ,~ N 4,62 ~ N 14.83 G~;
found : C 46,72 ',~ N 4.~8 ~ N 14.72 G~G~
dff~eloping solvent system: 3, Rf = o.64 lactam C=0 group: 17S3 cm 1 Example 2 7-B(~-Cyano)-acetylamino-3-acetoxymethyl_3-cephem--carboxylic acid 2.7 g, 7-amino-3-acetoxymethyl-3-cephem-aarboxylic acid (7-ACA) are suspended in ~0 ml. of dichloromethane - 2~ and 3.~ ml, of triethylamine are added dropwise~ The obtained clear solution is cooled to 0 C and 3.3 g.
(0,01 mole) of cyanoacetic acid pentachlorphenyl ester are aclded. The mixture is stirred for 2 hours at 0 to ~ C, and i9 decomposecL with a buffer of pH = '7, The . ~

~ ~z~93~

aqueous layer is washed with ethrl aoetate, the basio solution acidlfied with 2n ~ICl to pH = 2 to ethyl aoetate. 'I`he ethyl aoetate is dried and evaporated.
The produot is triturated ~ith diisopropyl ether. Yield 1.9 g, (88 ']0), m.p, 168-170 C.
Analysis:
oaloulated: C 46.02 ~o EI 3.86 % N 12.38 ~;
found: C 46.o8 ,% H 3.93 ~,1 N 12.25 ~.
developing solvent system: 3, Rf = o,637 - 10 lactam C=0 group: 1792 cm 1 Example 3 7-B(~-Cyano)-acetylamido-3-methyl_3-cephem_carboxrlic acid 2,2 g. (0.01 mole) of 7-ADCA are dissolved in 2~ ml.
1~ of acetonitrile by adding 1-2 drops of water and 4.2 ml.
(0,03 moles) of triethylamine. The clear solution is cooled to 0 C and 3.3 g. (0.01 mole) of cyano acetic acid pentachlorophenyl ester are added. The mixture is stirred for 2 hours and the aoetonitrile is distilled off.
The residue is taken up in 20 ml. of ethyl aoetate and washed with 20 ml. of saturated sodium hydrogen oarbonate.
The product is acidified i~to ethyl acetate by adding 10 % hydroohlorio acid to the aqueous layer. The organic layer is dried and ffvaporated and the precipitated 2~ produot is triturated with petrol ether.
Yield: 2.0 g. (71 ~,~0), m.p.: 182-184 C.
Analysis:

oaloulated: C 46,96 %, II 3.94 ',' N 14.94 ~jlo;
found: C 46.71 ~iO H 3.90 ~0 N 14.77 ,~o.

l~Z8931 Developir~ solvent sy~to~ 3, i~ = o,G67 lact~n C=0 grollp: 17cJ~ o `~a~plO t~
7-B(~-Cyano)-~cetyl~llido-3-motl~yl-3-cephe7n-carboxylic acid trichloroethyl estor 3,8 g. (0.01 mole) of 6-ADCA-trichloroethyl oster hydrochloride are dissolved in ~0 ~ll. of cliehloromethane by aclding 1,6 ml. of (0.02 moles) of pyricline and 20 ml, of l~ator, The layers are separated ancl the clichloromethane is dried over magnesi~un sulfate, 0,8 ml, (0.01 mole) of pyridine and 3.3 g, (0.01 mole) of eyanoaeetic acid penta-ehlorophenyl ester are added, ~le mixture is stirred for 2 hours at room temperature and l~hen the reaetion is eompleted, it is washed with 2n HCl (20 ml,) and with 1~ ml, of saturated 1~ NaCl-solution and the dichloromethane is dried and the obtained product is triturated with diisopropyl ether, YieLd: 4,12 g. (90 ~0); m,p, 1~8-160 C.
Analysis:
ealeulated: C 37,83 (~iJ H 2.93 ~j~ N 10,18 ,0 Cl 2~.77 ',~
20 found: C 37.63 c~ II 2.76 ~/~ N 9.9~ Cl 2~.7~ ~
Developing solvent system: 1~ Rf = 0.~87 laetam eC=0 group: 179~ em 1.

3xample ~
7~ Cyano)-acetamido-3-methyl-3-cephem-earboxylie 2~ aeid 3.0 g. (0,007 moles) of 7B-(x-Cyano)-aeetamiclo-3-methyl-3-eephem-carboxylic acid trichloroethylester are dissolved in 25 ml, of formic aeid and the solution is oooled to 0 C and 1 g, of zinc aetivated previously ~i-th ~ ., ~lZ893~

2n IICl is addccl. Tllc mixturo i3 stlrrod for 2 hour3 at room tomperature, 'Nlo ZillO iS fil-terecl off ancl the formic acid i9 distillQd off. The ro~idual oily sub-~tance is talcon up in water ancl shalcen out into ethyl acetate, Tlle or~anic layer ls dried over ma~lesium sulfate and distilled of-f, The precipitated substance is triturated with diisopropyl ether.
Yield: 2,0 g, (98 ~,1); m.p,: 180-182 C.
-` Analysis:
10 calculated: C 46,96 % H 3,94 % N 14,94 '~
; found: C 46.52 % H 3.44 7~ N 14,63 '~0, Developing solvent system: 3,R~ = o.667, lactam C=0 group: 178~ cm - Example 6 ; 1~ 7-B(~-Cyano)-acetylamido-3-acetoxymethyl-3-cephem-carboxylic acid triethylamine salt.
1,7 g. (0,00~ moles) of 7~-(~-Cyano)-acetamido-3-acetoxymethyl-3-cephem-carboxylic acid are taken up in 10 ml. of acetone, whereafter 0.7 ml, ~0,005 moles) of triethylamine are added dropwise, Clear solution is obtained, The mixture is stirred at room te~perature, The triethylamine salt is precipitated in about 10 minutes. The mixture is stirred for 1 hour and the orystals are filtered.
2~ Yield: 2,1 g. (89 ,~); m.p.: 16~-167 C.
Analysis:
, calculated: C ~l.X0 'j~ H 6.64 (,~ M 12,72 ~0;
-~ found: C ~1.72 ~ EI 6.46 (p N 12,42 '~0.

; Developing sol~ent system: 3, Rf = o.694 lactam C=0 group: 1790 cm 1, plo 7 7~,-(~-Cy~ulo)-acotyl~ ido-3-acetox~lletllyl-3-copllcnl-carboxyl:ic acid socliwll salt 1.6 ~. (0,003~ moles) of 7~ Cyano)-aee-tylamido-3-acetoxyme-tllyl-3-cep~lem-carboxylic aeid trie-tnylamine salt are milclly lleated ~ith 20 ml. of anh~drous ethanol ~nd thus the substanoe gets dissolved. 0,~ g. (0.003~ l~olcs) of diethylacetic acid sodium salt is added drop~ise, which had been dissolved in 6 ml. of clry ethanol, After the 0 additiOll i5 completed the socli~n salt is i~ediately precipitated~ The mixture is stirred for another 30 ; minutes and cooled to 0 to 5 C and the subst~nce is filtered, During the filtration the substance is washed ~ith 10 ml, of cold alcohol, 1~ Yield: 1,2 g. (9~ %).
Analysis:
ealeulated: C 43.22 p II 3.9~ $ N 11.63 -,";
found: C 43.12 c,~ H 3,~2 c,~ N 11,47 C,d~, Dffveloping solvent system: 3, ~f = o.6g~.
laetam C=0 group: 1792 e~~

~xample 8 6B-(~-Cyano)-aeetylamido-penam-carboxylic acid triethylamine salt 2,2 g, of 6-APA (0,01 mole) are dissolved 2~ in ~0 ml, of dichloromethane by adding 2,~ ml, of (0,02 ~noles) of triethylamine, The solution is filtered until a clear solution is obtained, ~hereafter the solu-tion is cooled to 0 C, 3,4 g, of cyanoacetic acid pentacllloro-phenyl oster (0,01 mole) are added, 'rhe ~lixture is stirred for 2 llours at 0 C, evaporated and tri-turated ~1 2893~

~ltih diisoprop~ her, Yi~lcl 3.~ ~" (~ p,: S5-90 C decomposition.
Analys i5:
calcul.ltocl: ~ ~3,12 ';~ M 7-34 (,~ M 14,5~
found: C ~3,33 (/o II 7,28 '~ N 11~,22 ,~, De~eloping solvent syst~m: 3, 1'~ = o,645 lactam C=O group: 17S5 c~ 1, ~xample 9 7~ Cyano)-acetamiclo-3-acetoxymetllyl-3-cephem-carboxylic acid 2,7 g, (0,01 mole) of 7-ACA are suspended in dichloro-methane and 2,8 ml, (0,02 moles) of triethylamine are added to get a solution, The mixture is cooled to 0 C
and 2,51 g, (0,01 mole) of cyanoacetic acid pentafluoro-1~ phenyl ester are added, The mixture is stirred for 2hours at room temperature and decomposed with saturated sodium hydrogen carbonate solution, The substance is acidified into ethyl acetate by adding 2n HCl. ~he organic layer is dried and e~aporated, The precipitated crystals are triturated witih diisopropyl ether, Yield: 2,9 g, (85 ~); m,p,: 16S-170 C, Analysis oalcul~ted: C 46,02 ,~ H 3,86 ~,~ N 12,3S ~,';
foun~: C 46,o9 /a~ H 3,S~ ~:' N 11,98 ~p, 2~ Developing sol~ent system: 3, R~ = o,637 lacta~l C=0 group: 1792 Cm~l, 28g3~
1, ""T'I- :3 LO
7-[~ Cyano)-aoot~ni~lo-3-~ilo~IIyl-3-cepIlem-carboxyllc ~cid 2,2 ~, (0~01 mole) of 7-ADCA are dissolvod in 25 t~
of ~cetonitrile by acIcling 1 to 2 drops of ~rater and 4,2 ml.
(0,03 mole9) of t-.riethylamine, Th.e pure ~olution is cooled to 0 C, 2,~1 g, (0,01 mole) of cyano-acetic acid penta-fluorophenyl ester are added, ~he mixture is stirred for 2 hours and the acetonitrile is distilled off, The residue is taken up in 20 ml. ethyl acetate and ~-ashed with 20 ml.
of sat~rated sodium bicarbonate, The subst.ance in the aqueous layer is acidified l~ith 20 fo HCl into 2~ ml, of ethyl aeetat0, The organic layer i5 dried, evaporated and the preeipitated substanee is triturated with petrol 1~ ether, Yield: 2,3 g, (81,~ ~lo) ~ m,p,: 183-lo~ C, Analysis:
ealeulated: C 46,96 ,~0 ~I 3,94 ~J0 IT 14,94 ~0;
found: C 46,9~ $ H 4,12 ~;~ N 1~,08 ',0, Developing solvent system: 3, R~ = 0,667 laetam C=0 group: 178~ em~l, æxample 11 6-B(~-Cyano)B-p'Ienylaerylamido-penatl-earboxylie acid 1,1 g, (0.00~ moles) of 6-~PA are dissolved in 30 ml, 2~ diehloromethane by adding 1,4 ml, (0,01 mole) of tri-ethylamine, After the dissolution is completed, 2.1 g, (0,00~ moles) of ~-cyano-B-phenyl-acrylic acid-pentaehlorophenyl ester are added at 0 C and the mixture is stirred for 2 hours at 0 C, TIIe mixture is wasIIed ~rith ~Z~3931 _ 14 _ saturatecl soclllull bLcarl~oIlato ~ulcl acidLfiecl into othyl aoetate ~:ith 1:3 phosphoric acicl. ~he othyl acetate i3 dried, e~aporatecl ~ld tho pre¢ipi-tated product is trlturatecl with cliisopropyl other.
Yi~ld: 1-35 ~. (72,~ b); m.p. 147-1~0 C, Analysis:
calculated: C ~8.20 'p H L~,61 ~0 N 11.32 ~;
found: C ~8.17 $ II ~-3 ~,~ N 11.14 ','.
Developing solvent system: 2, R~ = o.68 10 lactam C=0 group: 179~ cm 1.

Example 12 7-B(~-Cy~no)-phenylacrylamido-3-acetoxymethyl-3-cephem-carboxylic acid 1.4 g. (0.005 moles) of 7-ACE are dissolved in 30 ml.
1~ of dichloromethane by adding 1.4 ml. (0.01 mole) of triethylamine. The solution is filtered to get a clear solution, cooled to 0 C and 2~2 g. (0.0~ moles) of ~-cyano-~-phenyl-acrylic acid pentachlorophenyl ester are added. After stirring for 1 hour, it is decomposed with a buffer of pH=7 and the aqueous layer is acidified to ethyl acetate with 1:3 phosphoric acid. The ethyl acetate is dried~ evaporated and the precipitated product is triturated with diisopropyl ether.
Yield: 1.6 g. (72.~ %).
2~ Analysis:
calculated: C ~5.20 ,~ H 4,01 $ N 9.83 ~;
found: C ~6.44 u,~ II 4.20 ~pl N 10,03 ';~.
developing solvent system: 3, Rf=0.~78.

lactam C=0 group: 178~ cm~l.

l'lZ8931 ~--r~ C ~ o ) ~--pllolly l~ ~o ~ iclo--3--~u(3 l~llyl--3--c (3 p~ tl---carbo~-ylio ncid 2.~ g. (0.01 llole) of 7-~DCA are dissolve~l in 25 ml, of acetonitrile by adding 2 drops of wator and

4,2 ml. (0.03 moles) of trlethylaltline. 4.1 g (0,01 mole) of ~-cy~lo_~_phenyl_acryl:ic acid pentachloropllenyl ester are added at roo~ temperature. The mixture is stirred for 2 hours at room temperature ~hereafter the solvent is distilled off. The residual procluct i9 taken up in ethyl acetate and washed with saturated sodi~ bicarbonate. The product i.5 acidified from the aqueous layer into ethyl acetate. The organic layer is dried, evaporated and the precipitated product is triturated with ether.
Yield: 3,0 g. (80 a~); m~p~ 178-180 C.
1~ Analys i5:
calculated: C ~8.~2 $ H 4.09 /1 N 11.38 %
found: C ~8.76 5~ ~ 4,43 /~ N 11.27 $.
developing sol~ent system: 2, Rf = o.687 lactam C=0 group: 1790 cm l, Example 14 7-B(~-Cyano)-Bphenylacrylamido-3-methyl-3-cephem-carboxylic acid 2,2 g, (0,01 mole of 7-ADCA are dissol~ed in 2~ ml, of acetonitrile by adding 2 drops of water and 4,2 ml.
2~ (0.03 moles) of triethylamine. 3,4 g, (0.01 mole) of ~-cyano-~-phenyl-acrylic acid pentafluorophenyl ester are added at room temperature. The mixture is stirred for 2 hours at room temperature and the solvent is distilled off. The residue is tal~en up with ethyl acetate and washed ~ith sa-turated sodium bicarbonate, The l~Z8931 5ub9tano(3 i5 acldif Lod flo~ o basic laycl i~ltO Ct7il'y1 QCotato. '1`.71e Or,,~liC 11yor i3 dlie(l~ evaporate(l .lnll the preclpitatccl solid is triturated Wit}l etiler, ~leld: 3.~ l~,. (S6 'j~ ; m,p.: 17~-180 C, A~lalysis:
calculated C ~8,~2 tjto II 4,o9 ,t N 11,38 ~;
founcl C ~t3,67 5~' rI 4,25 ,;~ N 11,~6 ',', de~reloping solvent system: 2, I~~ ~ o,6g7 lactam C=0 ~roup: 1790 cm 1 Example 1~
7~ Cyano)-B-pllenylacrylailido-3-metllyl-3-ceph9m-carboxylic acid trichloromethyl ester 1,7 g, (0,00~ moles) of 7-ADCA-tricnloroethyl ester-hydrochloride are dissolved in 30 ml, of dichloromethane 15 by adding 1,4 ~nl, (O.01 ~ole) of triethyla~ine, 2.1 ~, (0,00~ moles) of cc-cyano-~3-phenyl-acrylic acid penta-chlorophenyl ester are added, The mixture i5 stirred for 3 hours at room temperature and the dichloromethane is clistilled off, The residue is dissolved in ethyl acetate 20 and washed with saturated sodi7~n bicar7,~onate, 2n I-ICl and saturated sodium chloride, The product is dried and evaporatecl, The preeipitated solic' is triturated with dry et7nanol, Yield: 2,0 g, (80 ',~); m,p,: 12~-130 C, 2~ r'~alys i S:
calculated: C 47,9~ 'ic' E 3,22 ~ N S,33 ',~ Cl 21,24 CpJ;
found: C 48.12 ,c' lI 3,30 C~t N 8~50 C~d Cl 21.36 ',', developing solvent system: 1, Rf = 0,710 laetam group: 17S~ cm ~2893~

nlple 1 (~
6-r~ Cy.~-lo)-p~lonyl.-1cct.uniclo-pcn~l-carbo~cylic acid 2.1 ~, (0,01 mole) of 6-~P~ are dlssol~od in ~0 Inl, of dic1l10rolilet11~1e by addin~ 4,2 ml. (0.03 moles) of tri-ethyl~2line, 4,0 ~, (0,01 ~lole) of ~-cyano-phonyl-aoetic acid pen-tacl1loropi1enyl ester are addecl~rhen -tlle dissolution is completocl, '~1e mixture is stirred for 1 hour at room temperature and the mixture is decomposed with sodi~ bicarbonat0 ~Ind acidified into ethyl acetate with 1:3 phosphoric acid, The mi~t~re is dried over magnesium sulfate and evaporated, The precipitated crystals are triturated with ether.
Yield: 3,1 g. (85 l~).
Analysis:
1~ calculated: C ~6.81 j~0 M 4.76 'jg N 11.69 ~;
fo~und: ~ ~6.70 G~ ~I 4.6~ C/o N 11.60 j~.
developing solvent system: 2, Rf = 0.~80 lactam C=0 ~roup = 1788 cm 1 E~ample 17 7~ Cyano)-pnenylacetaTnido-3-methyl-3-cephem-earboxylic acid 2.2 ~. (0.01 ~ole) of 7-~DCA are taken up in 40 ml.
acetonitrile by addin~ 2 drops of water and 4.2 ~
(0.03 mole) of triethyla~ine. 4,o ~. (O.Ol mole) of 2~ ~-cyano-phenylacetic acid pentachlorophenyl ester are added at 0 C. The mi~ture is stirred for 2 hours and the solvent is distilled off. The residue :is dissolved in ethyl acetate, washed with saturated sodi~ bicarbonate, tl1e product is acidified from the bicarbonate layer into 112893~

~thyl acet.~te by tllo adclitLorl O:r 1: ~ pilosphor:ic aCi.(l, Tlle so:lid ls drio(l, evaporcltecl.~ncl t]lC preoipitatocl solicl i3 tr:;turated w:;th ethor.
Yielcl: 2.9 g. (8~ ',;); m.p. 178-:L~0 C.
Analysis:
caleulated: ~7.14 ~t 'I 4.23 l~ N 11.76 'j~
found: ~6.91 ',~ II 4.27 ,' N 11.41 ,'.
developing solvent system: 2, I~ = o.67s laetam C=0 group: 1790 em 1.

~xample lS
7-~-(~-Cyano)-phenylacetamido-3-methyl-3-cep~em-earboxylie acid 2.2 g. (0.01 mole) o~ 7-ADCA are taken up in L~o ml, of acetonitrile by adding 2 drops of water and 4.2 ml.
1~ (0.03 mole ) triethylamine. 3,3 g. (0.01 mole) ~-cyano-phenylacetic acicl-pentafluorophenyl ester are added at 0 C.
The mixture is stirred ~or l hour, evaporated and ta~en up in ethyl acetate. The mixture is washed with saturated socliu~
biearbonate, and acidifiecl with 1:3 phosphoric acid into ethyl acetate. The solid is dried, evaporated and the precipitated crystals are precipi-tated with ethyl ether.
Yield: 3,2 g. (92 ~j~); m.p.: 178-180 C, Analysis ealeulated: C ~7.14 ~ E 4.23 5~, N 11.76 ',~;
2~ found C ~7.20 ~jo M 4,L~ 11,92 $.
cleveloping solvent system: 2, ~C = 0.678 laetam C=0 group = 1790 em l.

~2893~

'7~B-(~-Cyallo)-aco tylLuni(lo-3-acc tO~Cy-lllo tllyl-3-oopllom-oarl-ox~lio ao:id trie~llyI..LIline s~lt , (0.02 r~olo ) Or 7-AC~ are dissolvod in ~.6 ml.
(O,O~Inolcs) trie-tllylanlino contaill:in~ ~0 ml, ~:ichloro-methalle at room tempera-ture. 'I`lle mixture is coolecl to 0 C
and at this temperature 6.6 g. (0.02 mole) of cyc~noacetic acid pentachlorophenylester are added ancl-tl~e ~ixture is stirrecl ~or 30 minutes ~nd the so~vent is distilled o~f in vacuo, tlle resiclue is recrystalliæed from 2~ ml, of acetone and the precipitated ~ ite crystals are dilutecl l~ith acetone, oooled c~nd filtered.
Yiel~: 7.~ g. (S~ ~); m,p.: 128-130 C.
Analy~is:
1~ calculcatecl: C ~1,80 ~ H 6.46 'J' N 12.72 ,~;
founcl: C 51.40 % EI 6.23 '~ N 12,~0 ,~.

Claims (9)

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

1. Process for the preparation of acid amide derivatives of the gen-eral formula (I) wherein R1 represents hydrogen, or C1-6 alkyl, R2 is hydrogen, an aromatic or heteroaromatic ring which is unsubstituted or is substituted by one or more substituents selected from the group consisting of halogens, lower alkyl, lower alkoxy, halogenoalkyl, amino, mono- and di-lower alkylamino and nitro groups, or R2 is a C1-6 alkyl which is unsubstituted or is substituted by a furyl or a phenyl group, or R1 and R2 together form a benzylidene group or an alkylene group which is un-substituted or is substituted by a phenyl, furyl, thienyl or pyridyl ring, R3 represents hydrogen or an easily cleavable esterifying group, is or or and salts thereof by acylation of amines of the general formula II

(II) - wherein R3 and A are as defined above, which comprises reacting an amine of the general formula II or a salt thereof - wherein R3 and A are as defined above - with an ester of the general formula (III) wherein R1 and R2 are as defined above and X is halogen, - and, if required, splitting off the R3 protecting group of the ester group in positions 3 or 4 and/or setting free the product, if required, from the salt thereof and/or converting it to salt.

2. A process according to claim 1 wherein R2 represents a phenyl, furyl, thienyl or pyridyl ring or a furylmethyl, furylethyl, phenylmethyl or .beta.-phenylethyl group, or R1 and R2 together form a C1-4 alkylene group and X
stands for chlorine or fluorine.

3. A process according to claim 1 wherein R is a trialkyl-silyl or trichloroethyl group.

4. A process as claimed in claim 1,2 or 3 which comprises reacting compounds of the general formula II or sodium, potassium, lithium, or trialkyl-amine, salts thereof with .alpha.-cyano-.beta.-phenylacrylic acid pentachlorophenylester or .alpha.-cyano-phenylacetic acid-pentachlorophenyl ester, or cyanoacetic acid pentachlorophenyl ester.

5. A process according to claim 1, 2 or 3 which comprises carrying out the reaction in the presence of a tertiary base.

6. A process as claimed in claim 2 or 3, which comprises conducting the reaction in the presence of an aprotic solvent or a dipolar solvent.

7. A process as claimed in claim 1, 2 or 3 which comprises conducting the reaction in the presence of carbontetrachloride, dichloromethane, chloro-form, dichloroethane or acetonitrile.

8. A process as claimed in claim 1, 2 or 3, which comprises perform-ing the reaction in the presence of a trialkylamines.

9. A process as claimed in claim 1, 2 or 3 which comprises performing the reaction in the presence of triethylamine or pyridine or N-methyl-mor-pholine.