Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~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,
,- '\ ~
CH2 C H2
\ / or C-CH
/ C \ ~ 3 ~ ( -CH20COCH3
CH3
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,
~'
-- 4 --
Z893
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
6 --
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~
-- 10 --
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,
8931
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~
- 12 -
~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~
7 --
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 ,~.
