Note: Descriptions are shown in the official language in which they were submitted.
L2Z595~
-- 2 --
HOE 83/F 079
The invention relates to a process for the pre-
~ parat;on of 7-amino-cephalosporanic acid derivatives of
; the general formula I
R1
H2N
l (I)
o ,~ ~ CH 7,A
co2e
S- wherein
R1 ~denotes hydrogen or methoxy and
A denotes a pyridlnium rad7cal 0 N ~ , ~hich
can be monosubstituted or polysubstituted by
identical or different substituents;from the group
~10 ~ compr;sing opt;onally subst;tuted C;-C6-alkyl, it
`bei~ng possible for two alkyl groups in the ortho-
; ~ pos;tion also to be llnked to form an optionally
~ subststuted di- to deca-methylene ring, in which
; ~ one ring carbon atom can be replaced by a hetero-
atom and wh;ch can furthermore also contain one
or two double bonds, optionally substituted C2-C6-
alkenyl, C2-C6-alk;nyl and C3-C7-cycloalkyl and
:
C3-C7-cycloalkyl-methyl, it being possible for the
ring also to be subst;tuted in the last two sub-
stituents; C4-C7-cycloalkenyl, optionally substi-
tuted C1-C6-alkoxy, C2-C6-alkenyloxy and C2-C6-
` alkinyloxy, halogenr trifluoromethyl and hydroxyl,
.. .
~r~
~4
.
,~ ~LrZ2~;i9~i4
- 3 -
and optionally substituted phenyl, benzy1 and
heteroaryL, and where;n, furthermore,
A denotes a quinol;nium ~ or an isoquinol;-
n;um - ~ ~ rad;caL, each of which can also
be monosubstituted or polysubstituted by identi-
cal or different substituents from the group com-
prising opt;onally substituted C1-C6-alkyl, C1-C6-
alkoxy, halogen, trifLuoromethyl and hydroxyl.
The present invention particularly relates to com-
pounds in wh;ch A denotes a pyr;d;nium rad;cal - ~ ,
which can be monosubstituted or polysubstituted by iden-
ticai or different substituents from the group compris-
; ;ng C1-C6-alkyl, which can be monosubstituted or poly-
~ s~u~bsti~tuted~by hydroxyl or sulfo; and C1-C6-alkoxy and
h;ydroxy-C1-C6-aLkoxy, it being possible ~or two alkyl
gr;oups also ~o be~linked to form an optiona~lly substitu-
~ted di~-`to de~ca-m~ethylene ring, in which one ring carbon
; atom can be replaced by a heteroatom and which can fur-
:
thermore~also contain one or two double bonds,
C2-C6-alkenyl, which can be substituted by hydroxyl,
C2-C6-alkinYl~
C3-C7-cycLoalkyl and C3-C7-cycloaLkyl-methyl, it being
poss;bLe for the ring also to be subst;tuted by hydroxyl
or halogen in these two substituents,
C4-C7-cycloalkenyl,
C1-C6-alkoxy~ which can be substituted by hydroxyl,
C~-C6-alkenyloxy and c2-c6-alk;nYloxy,
halogen, ~r;fluoromethyl and hydroxyl, and phenyl, benzyl
..
.
'
Z2S~3$~
-- 4 --
or heteroaryl, wh;ch can also be subst;tuted by halo~en,
or in which A denotes a qu;nol;n;u~ or ;soquinolinium
rad;cal, each of which can also be monosubstituted or
polysubstituted by identical or different substituents
from the group compris;ng C1-C6-alkyl, wh;ch can be sub-
st;tuted by hydroxyl, and c1-C6-alkoxy, halogen, tr;flu-
oromethy~ and hydroxyl.
- ~ossible optional substituents of the di- to deca-
methylene ring mentioned under A, in which one ring car-
bon atom can be replaced by a heteroatom and which can
furthermore also contain one or two double bonds, are, ;n
; part;cular, the follow;ng substituents, wh;ch may occur
singly or in combinat;on, but preferably singly: C1-C6-
; alkyl, C1-C4-alkoxy, hydroxymethyl, halogen, hydroxyl, oxo
and exome~thylene.
These substituents can occur on the above rings
fused ont~o the pyridinium rad;cal, ;ndependently of whe-
t~her the particular ring is saturated, unsaturated or
also ;nterrupted by a heteroatorn.
The ring fused onto the pyridinium radical can
contain two to ten r;ng members Sd;- to deca-methylene),
but preferably three to five ring members, and thus is,
for example, a cyclopenteno, cyclohexeno or cyclohepteno
ring. lf such a fused-on ring contains a double bond,
examples which may be mentioned are the dehydrocyclopen-
tadieno, dehydrocyclohexadieno and dehydrocycloheptadieno
r;ng. If one carbon atom ;n such a r;ng is replaced by a
heteroatom, poss;ble heteroatoms are, ;n particular~ oxy-
:
~ gen or sulFur. Examples wh1ch may be mentioned of fused-on
.
2~i954
- 5 -
r;ngs wh;ch contain an oxygen atom and two or one doubLe
bond are furo, pyrano, dihydrofuro and dihydropyrano;
examples of fused-on rings containing a sulfur atom and
t~o or one double bond are thieno, thiopyrano, dihydro-
thieno and dihydropyrano. Of the fused-on rings contain-
;ng a~heteroatom, those rings wh;ch contain only one
double bond are particularly suitable for subst;tution,
especially by the abovementioned substituents.
The following substituents are examples of parti-
cularLy pre~erred substituents:
A: a quinolinium or an ;soquinolinium radical, each of
~h;ch can also be monosubstituted or polysubstituted
-,
by identical or d;fferent substituents from the group i
compri~slng C1-C6~alkyl, such as, for exampLe, methyl,
.
ethyl and propyl, preferably methyl, methoxy, hydroxyl,
halogen and tr;fluoromethyl, or a pyridinium radical,
~hich can be~monosubstituted or polysubstituted, pre-
ferabLy mono-, di- or tr;-substituted, in particular
~ mono- or~ di-s~ubstituted, for example by C1-C4-alkyl,
such as, in particular, methyl, ethyl, propyl, isopro-
pyl, n-butyl, sec.-butyl, tert.-butyl, dim~thyl, tri-
methyl, methyl and etbyl, methyl and propyl, methyL
and isopropyl or ethyl and ethyl; or hydroxy-C1-C4-
~ alkyl, such as, i~n particular, hydroxymethyl, hydroxy-
ethyl, hydroxypropyl, hydroxyisopropyl, hydroxybutyl,
hydroxy-sec.-butyl or hydroxy tert.-butyL~ it also be~
;ng possible, for example, for the alkyl radical to
carry two or three hydroxyl groups; C3-C4-alkenyl,
such as, ;n part;cular, allyl~ 2-methallyl and buten-
.
~ '
,.
;9~;4
-- 6 --3-yl, which can also be substituted by hydroxyl, such
as, in part;cular, hydroxyallyl and hydroxybutenyl;
C3-aLkinyl, such as, in particular, propargyl~ C3-C6-
cycloalkyl or C3-C6-cycLoalkyl-methyl, the carbon num-
ber relat;ng to the cycloalkyl part, such as, in par-
ticular, cyclopropyl, cyclobutyl, cyclopentyl, cyclo
hexyl and cyclopentylmethyl, it be;ng possible for the
r;ngs also to be subst;tuted, for example by hydroxyl,
such as, in particular, 1-hydroxy-cyclopentyl and 1-
hydroxy-cyclohexyl, or by halogen, preferably chlorine;
C5-C6-cycloalkenyl, such as, ;n particular, cyclo-
penten-1-yl and cyclohexen-1-yl;
C1-C6-alkoxy, such as, in particular, methoxy and eth-
oxy;
halogen, such as, in particular, 3-fluoro, 3-chloro,
3-bromo or 3-iodo; hydroxyl, in particular 3-hydroxyl;
tr;fluoromethyl, in part;cular 3-~rifluoromethyl; phe-
nyl and benzyl, which can also be subst;tuted, for ex-
ample by halogen, in particular chlorine, such as, for
example, 4-chlorobenzyl; or Z'-th;enyl or 3'-thienyl.
If A is a pyridinium radical which is substitu-
ted by two alkyl groups linked to form a di- to deca
methylene ring which can ;n turn be monosubstituted or
polysubst;tuted, preferably monosubstituted, and can con-
ta;n one or two double bonds, the following fused~on ringsystems are very particularly suitable here:
cyclobuteno, cyclopenteno, hydroxycyclopenteno, oxocyclo-
penteno, hydroxymethylcyclopenteno, exomethylenecyclopen-
teno, carboxycyclopenteno and carbamoylcyclopenteno,
,
` ~2~:;95
-- 7 --
cyclohexeno, hydroxycyclohexeno, oxocyclohexeno, hydroxy-
methyl-cyclohexeno, exomethylene-cyclohexeno, carboxycyclo-
hexeno and carbamoylcyclohexeno,
cyclohepteno, hydroxy-, oxo-, hydroxymethyl-, exomethyl-
ene- and carboxy~cyclohepteno and carbamoylcyclohepteno;
and dehydro-cyclopenteno, dehydro-cyclohexeno and dehydro-
cyc lohepteno.
If a ring carbon atom in the abovement;oned fused-
on ring systems is replaced by a heteroatom, in particu-
lar oxygen, the foliowing ring systems are particularlysultable: furoC2,3-b]pyridine, furo~3,2-b3pyridine, furo-
C2,3-c~pyridine, furo~3,2-c]pyridine, thieno~2,3-b]pyrid-
;ne, th;eno~3,2-b]pyrid;ne, th;eno~2,3-c3pyridine, thieno-
C3,2-c3pyridine, thieno~3,4-b3pyr;d;ne and th;eno~3~4~c3-
pyrid;ne.
The process according to the ;nvention for thepreparat;on of compounds of the formula I comprises reac-
ting a compound of the general formula II, or salts thereof,
R1
R3CONIl = ,~S
~:H2R ~II)
COO~ .
wherein
R1 denotes hydrogen or methoxy,
R2 denotes a group which can be replaced by the
base corresponding to the radicals A of formula I,
~. 7
and in which RJC0 represents an acyl radical, for
example a formyl radical or an acyl radical which
is generally known from cephaLosporin and peni-
~` `f'
'' ' '
- 1~259S4
. - 8 -
cill;n chem;stry,
with the base on which the radical A defined above in for-
mul:a I is based, to form the compound of the general for-
mula III
~R1
R3CoN~I~5~
5 ~ o ~ ~ ( I I I )
in ~hich
~ A, R1 and R3 have the abovement;oned meaning,
and then spl;tt;ng off the acyl radical by general chemi-
cal or enzymatic methods known from cephalosporin and
:
penicillin chemistry, to form the compound I.
: Particularly su;table radicals R2 are acyLoxy
: radicaLs of lower aliphatic carboxylic acids, preferablywith 1 tD 4 carbon atoms, such as, for example, acetoxy
or propionyloxy, in particular acetoxy, which can opt;on-
; 15 ally be substituted, such as, for example, chloroacetoxy
or acet~o~acetoxy. Other ~roups are aLso suitable for R2,
such as, for example, carbamoyloxy.
In the acyl radicals R3Co-, R3 denotes hydrogen or
the group R4-~CH2)n-, in which n = O or 1 and R4 denotes
` 20 a C~-C1û-alkyl radical, preferably a C1-C4-alkyl rad;-
caL, whlch can be monosubstituted or polysubstituted by
identi~cal or different substituents from the group com-
`pr;sing optionally substituted carbocyclic or heterocyc~
I;c aryl, such as, for example, phenyl and thienyl, opti-.
onally substituted aryloxy or heteroaryloxy, such as~ for
example, phenyloxy, optionalLy substituted arylthio or
:. ~l225954
_ 9 _
heteroarylthio~ such as, for example, phenylthio and imi~
dazolylthio, C3-C6-cycloalkyl and C4-C~-cycloalkenyl, op~
tionally subst;tuted c1-c6-alkoxY, opt;onally subst;tu-
ted Cl-c6-alky~thio~ cyano, haLogen, trifluoromethyl, sul-
fo, hydroxyl, amino and carboxyl, it being possible forhydroxyl, am;no and carboxyl groups also to be protected
or blocked, for example the group
, 2 3 '
CO01~
;n which Z represents optionally substituted arylcarbonyl,
such as, for example, phenylcarbonyl or heteroarylcarbonyl,
such as, for example, th;en-2-yl-carbonyl, opt;onally sub-
stituted C1-C4-alkoxycarbonyl or the group
; -CH=C(C02C2H5)~, opt;onally subst;tuted C1-C6-alkyl-sul-
fonyl or opt;onally subst;tuted phenylsulfonyl, such as,
for example, 4-methyl-phenylsulfonyl or 4-chloro-phenyl-
sulfonyl, or R4 denotes an opt;onally substituted car-
bocycl;c or heterocyclic aryl radical, such as, for ex-
ample,~phenyl, th;enyl or furyl.
R3 furthermore denotes the group R4-C~
~oR5
wherein RS denotes hydrogen or an opt;onally subst;tu-
ted C1-C6-alkyl rad;cal and R4 has the above mening,
or R3 denotes the rad;cal R6CO-~C,- , in which R6 de-
oR5C1-C6-alkyl~
Particularly preferred starting compounds are
those in which the acyl radicals R3Co- denote a thienyl-
acetyl or phenylacetyl radical whictl can be split off
~225~5
- 10 ~
enzymatically by means of pen;c;llin G am;dohydrolase.
Start;ng compounds wh;ch are readily access;ble preparat-
ively and are thus inexpensive and in which R3Co- can be,
for example, thienylacetyl~ phenylacetyl or phenoxyacetyl
S are also preferred. The radicals of the natural product
cephatosporin C and blocked and protected derivatives
thereof, of the formula Z-NH-CH~CH2)3 CO-, in wh;ch
COOH
Z has the abovementioned meaningy are furthermore parti-
cularly preferred. The startiny compounds are thus known
from the literature or can eas;ly be prepared by proces-
ses which ire known from the literature.
The react;on of compounds of the general formula
II w;th the bases which correspond to the radicals A ;n
the general formula I can be carried out in water or in
~a mixture of water and a readily water-m;scible organ;c
solvent, such as, for example, acetone, d;oxane, aceto-
~nitrile, d;methylformam;de, dimethylsulfoxide or ethanol.
::
The reac~t;ion temperature ;s ;n general in the range from
about 10~to about 100C, and is preferably between 20 and
80C. The base ComponQnt is added in amounts between
approximately equimolar amounts and up to a 5-fold excess.
Replacement of the radical R2 is facilitated by the pre-
sence of neutral salt ;ons, preferably of iodide or thio-
cyanate ions, ln the reaction medium. In particular,
about 10 to about 30 equivalents of potassium iodide~
sodium iodide, potassium thiocyanate or sodium thiocyanate
are added. The reaction is advantageously carried out
close to ~he neutral po;nt, preferably at a pH value in the
~ ~ . . . . .
,
f` ~ 9S4
- 11 -
range from about 5 to about 8~
The react;on can also preferabLy be carried out
;n non-aqueous solut;on ;n the presence of tr;-C1-C4-alkyl-
. iodosilane, such as, for example, trimethyl- or triethyl-
;odos;lane. The react;on of compounds of the general for-
mula II with pyr;d;ne bases ;s known. Thus, for example,
it is reported in the literature tEuro~pean Patent 60,144)
that 3-iodomethyl-cephalosporin deriva~ives, for example
compounds wh;ch correspond to those of the formula I,
1û ~here A - I, react with pyridine bases to give the corre-
spond;ng pyridinium compounds. Such iodoalkyl compounds
can generally be prepared from esters, for example acet-
ates, wlth trimethyliodosilane (J. Amer. Chem. Soc. 99,
968, 1977; and Angew. Chem;e 91, 648, 1979)~ a reaction
wh;ch has~subsequently been applled to cephalosporins
(European Patent 34,924, U.S. Patent 4,266,049, Tetra~
hedron Letters 1981, 3915 and European Patent 70,706).
According to the two-stage process described in
European~Patent 60,144, for example, the acetates corre
2a sponding to those of the forwuLa II (R2=OCOCH3) are first
converted into the 3-iodomethylcompounds, and these are
;solated and then reacted with the desired pyridine bases.
Purification by chromatography is necessary to isolate
the end products, and the maximum yield of pure end product
is below 10% o~ theory. Even in a var;ant described in
European Patent 70,706, Example 5, in which the 3-iodo-
methyl compounds are not isolated, after reaction with
pyridine, the title compound, besides several components~
can be identified only by chromato~raphy.
2S9S~
- 12 -
It is surprising that the yields of end products
of the formula I are ;ncreased up to more than ten-fold
~hen the nucleoph;l;c replacement react;on ;s carried out
from the start ;n the presence of an excess of the corre-
sponding bases on which the radical A in formula I is based,i.e. a tr;-C1-C4-alkyl;odos;lane, preferably trimethyl-
iodos;lane~ after addition of the base to the react;on
mixture.
The process ;s carr;ed out by a procedure in which
the base corresponding to the rad;cal A ;s added to a
solut;on or suspension of the compound II ;n a suitable
solvent, followed by tr;methyliodosilane. It is also
poss;ble, for example, for a reaction mixture of iodine
and~hexamethyldisilane, which have first been reacted at
temperatures between about 60 and 1Z0C in a manner
known from the L;terature, tr;methyl;odos;lane being
formed, to be used instead of trimethyliodosilane. In-
stead of trimethyliodosilane, triethyl;odosilane which
has been prepared in a manner which is known from ~he
literature can also be used with the same good results.
The reaction ;s carried out at temperatures between about
-S and ~100C, preferably between +10 and t80C.
Examples of su;table inert aprotic solvents are
chlorinated hydrocarbons, such as methylene chloride~
chloroform, d;chloroethane, trichloroethane and carbon
tetrachlor;de, or lower alkyl-n;tr;les, such as aceton;t-
rile or propion;trile, or fr;gens; ;n part;cular, methyl-
ene chlor;de ;s an outstand;ng solvent.
At least the stoichiometric arnount up to a twenty-
' ' .
- ~.2Z595~
- 13 -
fold excess of the base corresponding to the radical A is
added, and the react;on ;s preferably carr;ed out with
amounts such that the quant;ty of hydrogen ;od;de l;ber-
ated ;s bonded and at least 1 mole, preferably 2-5 moles,
of the base are still ava;lable for the replacement reac-
tion~
Since, besides the group R2 to be replaced in the
start;ng compound II, other funct;onal groups present,
such as the am;no, carboxyl or am;de group, react w;th
trimethyl~iodos;lane, the latter ;s added ;n at least a
four-fald up to a twenty-fold excess, preferably in a
f;ve- to ten-fold excess.
Carboxyl and N-am;no groups ;n the compound II
i can also be pres;lylated by add;t;on of a silylating
`15 agent,~such as, for example, b;strimethyls;lylacetam;de,
bistr;met~hylsilyltr;fluoroacetamide, trimethylchloros;l-
i
ane~, hexamethyldisilazane or bistrimethylsilylurea, eitherin the absence of or in the presence of a base, preferably
;the desired bsse on wh;ch the group A ;s based, in the
amount descr;bed above. At least the stoichiometr;c amount
or an excess of tr;methyl;odos;lane, preferably a two-
~ :
fold up to a ten-fold excess, is then added~
If the base on wh;ch the radical A in formula I
;s based contains funct;onal groups, such as, for example,
hydroxyl groups and the l;ke, these are preferably pre-
silylated with one of the abovementioned silylat;ng agents
and then used ;n tl1e react;on.
The reaction products of the formula III can be
isolated from the aqueous phase obtained by adding watcr
. ' .
5~354
- 14 -
or aqueous mineral ac;ds, for example d;lute HCl, HBr, HI
or H2S04~ in the customary manner, for example by freeze-
dry;ng the aqueous phase, chromatography and the l;ke~
The polar reaction products are preferably precipitated
from the aqueous soLut;on in the form of a sparingly sol~
uble salt, for example a hydr;od;de salt.
~ he acyl group R C0 in the result;ng compounds
of the generaL formula III iS then split off by generally
known chemical methods - for example by hydrolysis with
d;lute mineral ac;ds, such as, for example, hydrochlor;c
acid or sulfuric acid, or by imide chlorides - or enzym-
at;c methods, such as are described, for example, ;n
6erman Offenlegun~sschr1ft 3,019,838.
If imide chloride splitting is used, the compound
15 :~III ;s reacted with, for example, phosphorus pentachloride,
the imide chlor;de formed is converted into the imino-
ether by~addition of an alcohol and this ether is then
~split~by~hydrolysis~or alcoholysis. The reaction is ad-
vantageously carried out in the presence of a silylating
agent, such as trimethyLchlorosiLane. After hydrolysis
of the reaction mixture by addition of water, the compound
of the general formula I formed is isolated from the
aqueous p;hase in the customary manner, for example by
freeze-drylng or chromatography over silica gel or the
like~ The~rea~ction products are preferably isolated from
the reaction solution directly as spar;ngly soluble salts,
for exampLe a hydrochloride or hydr;od;de~
If enzymatic splitting is used, for example, the
acyl radical in compounds of the formula III in which
X~i9S4
- 15 -
R3co denotes C6H5CH2CO- or ~ ~ c~ CO_ is spljt off
with fixed penicillin G am;dohydrolase. The reaction is
carried out ;n aqueous solut;on at a temperature of about
25-40C, preferably 35-37C, and a pH value of about
6.5-8.0, preferably 7~2-7.8. The pH value ;s kept con-
stant-by addition of 1 N NaOH. When the react;on has
ended, the f;xed enzyme ;s separated off by filtration.
The react;on products of the formula I thus ob-
tained are ;solated from the aqueous phase ;n the custom-
ary manner, for example by freeze-drying, chromatography
or precip;tation in the form of a spar;ngly soluble salt.
The compounds of the formula I according to the
~;nvent;on are starting substances for the preparation of
numerous h;ghly act;ve ant;b;ot;cs of the general formula
1~5 III' ~ R1
R CO-l~H ~--~S ~
o) ~ ~ 2
C2 ( I I I ' )
in wh;ch, for example, R1 denotes hydrogen or methoxy and
`~' R3 CO denotes, ;n part;cular, a 2-(aminoheterocyclyl)~2-
~ oxy;m;noacetyl radical, for example the 2-~2-aminothia-
zolyl~-2-oxyimino-acetyl radical, which are described in
German Patent Applications corresponding to German Offen
legungsschrift 3,118,732, P 32 07 840.4, P 32 47 614.0
and P 32 47 613.2~
~` The following embodiment examples for the com-
pounds which can be prepared by the process according to
the invention serve to further illustrate the invention,
.
'' '
.~ 2S9~L
- 16 -
but do not restrict it thereto.
Preparation of the starting materials
Example 1
3-[(2 3-C clo enteno 1- ; erid;n;o)methYl]-7-(2~th;enyl)~
,~ Y P _P P
acetalnido)-ceph-3-em-4 carboxylate
Variant a
A mixture of 150 g (0036 mole).of sod;um 7-t2
thienylacetamido)-cephalosporinate ~cephalothin), 680 g
(7 moles) of potasslum thiocyanate, 66.5 g (65 rnl, 0.56
mole) of 2,3-cyclopentenopyr;dine, 150 mL of water and
30 g of 85 per cent strength phosphoric acid ;s stirred
at 66-68C for 4 hours. During this time, the pH value
drops from 6.6 to pH 6Ø The yellow-colored viscous
solution is diluted with 3 liters of water and extracted
wlth ~our 400 ml por~ions of methylene chloride. 110 ml
of 18 per cent strength hydrochloric acid are then added
dropwise at 5-10C in the course of 30 mlnutes, wh;le
cooling and stirring, whereupon a voluminous precipitate
forms. The mixture is left in an ice-bath for 2 hours
and the precipitate is filtered off with suction, washed
w;th three 500 ml portions of water and dried in vacuo.
~-~ Yield: 130 g (0.245 mole) of light yellow-colored crys-
tflls (68X of theory) of decomposition point
156-1 58C.
C22H21N34S2 x HSCN x H20
Calculated C 51.86 H 4.54 N 10052 S 18.06 H20 3.38%
Found C 51.8 H 4.3 N 10.2 S 18.0 H20 2.9 %
IR (KBr): 1775 ~lactam C0); and 2040 cm 1 (SCN)
H-NMR (CF3C02D): S = 2.3-2.8 (m, 2H, cyclopentene H);
2S~3~;4
- 17 -
3.15-3.95 (m, 6H, 4 cyclopentene H
and SCH2); 4.06 ts, 2H, CH2CO);
5.2-6.2 (m, 4H, CH2Py and 2
lactam H); 6.8-7.4 (m, 3H, th;o-
phene) and 7.65-8.70 ppm ~m, 3H,
PY).
Varlant b
3.96 9 (10 mmol) of 7-(2-thienylacetamido)-cepha-
losporanic acid are dissolved in 90 ml of methylene chlor-
ide, and 10.2 9 (10 ml, 86 mmol~ of Z,3-cyclopentenopyri-
dine are added. 14 g (10 ml, 70 mmcl) of trimethyliodo-
silane are then added dropw;se, while stirring and cool-
;ng, and the solution ;s heated under reflux for 2 hours.
It is cooled to -15C, 25 ml of 2 N hydrochlor;c acid
~: ~
are added and the organic phase is separated off. The
aqueous phase is adjusted to pH 6.0 by addition of sod;um
~bi~carbonate and ;s chromatographed over sllica gel (Grace,
~ : : : ~ ~ . : :
` 0.1 mm) us;n`g acetone:water (3:1). After freeze-drying
the pro~duct fractlons, the t;tle compound ;s obtained ;n
20~ the for~m~of a l;ght yellow amorphous solid. ~
Yield; 3.2 g (70.5% of theory) ~,
IR (KBr):~ 1775 cm~1 (lactam C0)
~MR `(CF3C02D): ~ - 2 .3-2.8 (m, 2H, cyclopentene H);
3.1-3.~5 (m, 6H, 4 cyclopentene H
and SCH2); 4.09 (s, 2H, CH2C0);
5.2-6.2S ~m, 4H, CH2Py and 2 lactam H);
6.8-7.4 (m, 3H, thiophene); and
7.65-8.85 ppm ~m, 3H, Py).
'` ', :
' " ' '
.
: '
S9~;4
~ 18 -
Example 2
3-C~2,3-Cyclopenteno-1-pyr;d;n;o)methyl~-7-phenylacetam-
ido-ce h-3-em-4-carboxylate
P
Vari ant a
The t;tle compound is obta;ned from 14.l~ g of
sod;urn 7-phenyLacetamido-cephalospor;nate, ~8 g of pot-
assium thiocyanate, 6.5 ml of 2,3-cyclopentenopyridine,
15 ml of water and 3.4 g of 85 ~er cent strength phospho-
ric acid analogously to Example 1a. The react;on m;xture
is diluted with 120 ml of acetone and chromatographed over
500 9 of silica gel (Grace, 0.1 mm) using acetone:water
(8:1) and then acetone:water (2:1). After freeze-drying,
the product fractlons give 7a5 g (48% of theory) of a
light grey-colored amorphous solid.
15 IR tKBr): 1770 cm 1 (lactam C0)
H-NMR (CF3C02D~: S = 2.25-2.85 (m, 2H, cyclopentene H);
3.1-3.75 (m, 6H, 4 cyclopentene H
and SCH2); 3.87 (s, 2H, CH2C0);
3.2-6.25 (m, 4H, CH2Py and 2 lac- ;
tam H); 7.38 (s, 5H, phenyl); and
`~`~ 7.6-8.7 ppm (m, 3H, Py).
~~ Variant b
The title compound is obtained from 3.9 g of 7-
phenylacetam;do-cephalosporinate, 10 ml of 2,3-cyclopen-
tenodpyridine and 10 ml of trimethyliodosilane ;n 90 mlof methylene chloride analogously to Example 1b. After
the hydrolys;s, the rnixture is chromatographed as above,
over silica gel using acetone:water (3:1).
Yield: 2.4 g (53.5%) of an arnorphous solid.
~L22~;9~i4
- 19 -
The compound is identicaL in all its properties
to that of Example 2a.
Examp le 3
,. 3-~(2r3-~enteno-1-pyridlnio)lnethyl]-7~phenoxy-
acetam;do~ceph-3-em-4-carboxylate
Var;ant a
The title compound is obtained~ from 21.4 g oF
sodium 7-phenoxyacetam;do-cephalosporinate, 95 g of pot-
ass;um thiocyanate, 9 ml of 2,3-cyclopentenopyr;dine and
1.5 g of 85 per cent strength H3P04 in 21 ml of water ana-
logously to Example 1a. After dilution with acetone, the
m;xture is chromatographed over 600 g of silica gel using
acetone:water (8-1) and then using acetone:water (2:1).
The product fractions are freeze-dried. 11.9 g (51% of
theory) of a colorless amorphous sol;d are obta;ned.
IR; ~KBr)~: 1770 cm 1 (la~ctam C0)
H-NMR ~CF3C02D): ~ = 2.25-2.85 ~m, 2H, cyclopentene H);
3.15-3.9 (m, 6H, cyclopentene H and
SCH2); 4.~31 (s,. 2H, CH2CO); 5.25-
6.20 (m, 4H, CH2Py and 2 lactam H);
: ;,
6.8-7.5 ~m, 5 phenyl H); and 7.65-
8.7 ppm (m, 3H, Py).
Var;ant b
The t;tle compound is obtained from 2.5 g of 7-
- 25 phenoxyacetamido-cephalospor;nate, S ml of 2,3~cyclopen-
tenopyridine and 5 ml of trimethyliodosilane ;n 45 ml of
methylene chlor;de analogously to Example 1b. After the
hydrolysis, the aqueous phase is chromatographed over
silica gel using acetone:water (3:1~ After freeze-drylng,
25g5
- 20 -
the product ~ractions give 1.8 g (61.5% of theory) of a
brown;sh-colored amorphous solid. The compound ;s iden-
ticaL in all its properties to that of Example 3a.
Example _
7-(D~5 B_ zam;do-5-carboxypentane-am;do)-3-rt2,3-cyclo~
Denteno-1-DYridinio)methyl]ceoh~3-em 4-carboxylate
Variant a
A solution of 5.2 g (10 mmol) of 7-tD-5-benzamido~
5-carboxypentane-amido)-cephalosporinate, 11.9 g (11~7 ml,
0.1 mole) of 2,3~cyclopentenopyridine, 66 g (0.4 mole) of
potassium iodide and 30 mg of ascorbic acid in 75 ml of
water and 25 ml of acetone is heated at 66-68C for 4
hours. After cooling, the mixture is diluted wi~h 500 ml
of acetone and chromatographed over 300 g of s;lica gel.
15 ~The sa~ts are eluted w;th acetone:water (7:1) and the
title~compound is eluted w~ith acetone:water t2:1). After
~freeze-drying of the product fractions, 3.2 g (55% of
theory) of a colorless amorphous solid are ob~ained~
IR (KBr): 1770 cm 1 (lactam C0)
1H-NMR (CF3C02D): ~ = 1.8-3.9 (m, 15H, 6 cyclopentene H,
SCH2 and pentane H); 4.8-602 (m~
4H, CH2Py and 2 lactam H); and 7.3-
8.7 ppm (m, 8H, Py and phenyl)0
Var;ant b
5.1 g ~4 ml, 28 mmol) of trimethyliodosilane are
added all at once to a mixture of 2.1 g (4 mmol) of 7- -~
(D-5-benzamido-5~carboxypentane aMido)-cephalospor;nate,
4.06 g (4 ml, 34 mmol) of 2,3-cyclopentenopyridine and
- 40 rnl of methylene chloride, wh1le cooling~ The mixture
- ~ ~Z2~i9~4
....~. - 21 - -
;s heated under reflux for 2 hours, cooled and hydrolyzed
by add;t;on of 5 ml of 2 N HCl. The aqueous phase ;s
separated off, adjusted to pH 6 with sodium bicarbonate
and chromatographed over 150 g of sil;ca geL using ace
tone:water (5:1) and then acetone:water (2:1~. After
~ freeze-drying, the produc~ fracti~ons give 1.9 g (47~5X of
; a light yellow amorphous solid. The compound is ;dent;-
cal in all its properties to that described above.
Example 5
7-tD-5-(4-Chlorobenzamido)~5-carboxypentane-amido)-3-
~(2,3-cyc~lopenteno-1-pyrid;nio)methyl]-ceph-3-em-4-car-
boxylate
Variant a
~The title compound is obtained as an amorphous
solid 1n 48% yield analogously to Example 4a from 5.5 g
t10 mmol) of 7-CD-5-(4 chlorobenzamido)-5-carboxypentane-
amido~-c~ephalosporinate, 11.9 9 (0.1 mole) of 2,3-c-yclo--
penten~opyridine, 66 g (0.4 mole) of potassium iodide and
30 mg of ascorbic acid in 100 ml of water:acetone (3:1).
.
20 IR (~Br): 1770 cm 1 (lactam C0)
H-NMR (CF3C02D): ~ = 1.9-2.9 (m, 8H, (CH2)3 and 2 cyclo-
pentene H); 3.1-3.8 (m, 7~, lt cyclo-
pentene H, SCH2 and CH); 4.9-6.3
(m, 4H, CH2Py and 2 lactam H); and
7.3-8.7 ppm tm, 7H, phenyl and Py).
Variant b
The title compound is obtained as an amorphous
sol;d analogously to Example 4b from 7-CD-5-~4-chlorobenz-
amido)-5-carboxypentane-arnido]-cephalosporinate, (Z.Z g),
.. .
.
-' ~ 2259S4
- 22
2,3-cyclopentenopyr;d;ne ~4.06 9) and tr;methyliodosilane
(5.1 g) ;n methylene chlor;de (40 ml), after chrorna-
tography. Yield: 51X of theory.
The compound is identical in all its propert;es
S to ehat described above.
The compounds of the following ~xamples 6~12 are
obtained from the correspond;ng cephalosporin derivatives
and 2,3-cycLopentenopyr;d;ne analogously to Example 4,
var;ant a ~replacement in water) or 4, variant b (tri-
methyliodosilane method).Example 6
7-(D-5-benzenesulfonamido)-5-carboxypentane-am;do)-3-
~(2,3-cyclopenteno-1-pyr;dinio~methyl]-ceph-3-em-4-car-
boxylate
Yield according to variant a. 45%, according to variant
b: 5ZX
.
1H-NMR (CF3C02D): ~ = 1.6-4.4 (m, 15H, 6 cyclopentene H,
- 7 pentane H and SCH2); 5.15-6.2
(m, 4H, CHzPy and 2 lactam H); and
7.4-8.65 ppm tm~ 8H~ phenyl and Py).
Example 7
7 CD-5-(4-MethylbenzenesuLfonamido)-5-carboxy-pentane-
amidoJ-3-~t2,3-cyclopenteno-1-pyridinio)methyl]-ceph-3-
em~4-carboxylate
Yield according to variant a: 38%
H-NMR tD6-DMS0): ~ = 1.2-4.1 tm~ 18H with s at 2.36-CH3,
6 cyclopentene H, 7 pentane H and
CH2S); 4.8~507 t4H, CH2 Py and
2 lactam H); and 7.2-9.4 ppm (~H,
.
~22~;95~
- 23 -
3 Py H, 4 phenyl H and 2NH).
7-~D-5~(4-chlorobenzenesulfonam;do)-5~carboxypentane
am;do~3-(2,3-cyclopenteno-1-pyridinio)methyl-ceph-3-em
4-carboxylate
~ rield according to variant a: 48%, accord;ng to variant
; b: 55%
H-NMR (CF3C02D): ~ = 1.6-4.4 ~m, 15H~ 6 cyclopentene H,
7 pentane H and SCH2); 5.1-6.25
(m, 4H, CH2Py and 2 lactam H); and
7.4-8.7 ppm (m, 7H, phenyl and Py)
Example 9
7-(D-S-Am;no~5-carboxy pentane-am;do-3-(2,3-cyclopenteno-
1-pyridinio)methyl-ceph-3-em-4-carboxylate
Yield (accord;ng to var;ant a): 19%
H-NMR (D2~0): ~ = 1.6-2.7 (m~ 8H, (CH2)3 and 2
cyclopentene H): 2.9-3.9 (m, 7H, 4
cyclopentene M; SCH2 and CH N); 5.9 5.95
(m, 4H, CH2Py and 2 lactam H); and 7~6-
8.7 ppm (m, 3H, Py)
Example 10
`- 7-(P-5-tert.-Butyloxycarbonylamino-5-carboxypentane-amido)-
3-t2,3-cyclopenteno-1-pyr;d;nio)methyl-ceph-3-em 4-car-
boxylate
Yield according to variant a: 15% of theory
H-NMR (D6-DMS0): ~ = 1.2-1.9 ~rn, 15H, ~CH2)3 and
C(CH3)3); 1.9-2.4 ~rn, 2 cyclo-
pentene H); 2.7-4.0 tln, 7H~ CHN,
SCH2 and 4 cyclopentene H); 4.~~
.
22S9~;A
-- Z4 --
5~7 (m, 4H, CHzPy and 2 lactam H);
6.0-6.3 (NH); 7.7-8.9 (m, 3H, Py):
and 9.1-9.4 ppm (NH)
Example 11
7-~(D-5-Carboxy-5-~2,2-diethoxycarbonyl)v;nylamino-pen-
tane-amido]-3-(2 3-cycLopenteno-1-pyridinio~methyl-ceph-
3-em-4-carboxylate
Yield accord;ng to variant a: 14X Of theory
1H-NMR ~D6-DMSO~: ~ = 1.0-1.4 (t, 6H, ethyl), 1.4-1.8
(m, 6H, (CHz)3); 1.9-2.4 tm, Z
cyclopentene H); Z.8-4.3 (m, 11H,
4 cyclopentene H), CHNH, SCH2 and 4
ethyl); 4.7-5.7 (4H~ CHzPy and 2
lactam H); and 7.6-9.8 ppm ~6H, 3
Py H, vinyl H~ 2 NH)
Example 12
7-t2 Acetyl-2-sYn-methoxyimino-acetam;do)-3-~2~3-cyclo-
penteno-1-pyridin;o)methyl-ceph-3-em-4-carboxylate
Yield according to variant a: 18% of theory
~ZO 1H-NMR (CF3C02D): ~ = 2.3-2.9 (m with s at 2n49~ 5H~
CH3CO and 2 cyclopentene H); 3.1-
~`~` . 3~ (m, 6H, SCH2 and 4 cyclopen-
tene H) 4~26 (s~ 3H~ NOCH3), 5.1-
6.Z ~m, 4H~ CH2Py and 2 lactam H~;
and 7~6-8.7 ppm (m, 3H, Py)
The compounds sho~n below, which correspond to
the general formula .
12;~9S4
25 -
C6115CO~ C13 (CH2) 3CONH~
~C~I2A
CO2
and ;n which A denotes the subst;tuent shown ;n the second
column of TabLe 1, are obtained ana~ogously to Example
4b (trimethyliodosilane method).
Table 1
Ex- A Yield 1H-NMR (CF3C02D): ~(ppm)
ample _ ~ of th.
13 ~ ~ 38 1.7-3.9 (m, 9H, SCH2, 7 pentane
-~ ~ H) 4.8-6.4 (m, 4H, CH2Py and
2 lactam H); 7.4-9.2 (m, 10H, Py '
and phenyl)
~ ' .
14 ~ ~ 22 1.7-3.9 (m, 9H, SCH2 and 7 pen-
tane H): 4.8-6.3 (m, 4H, CH2Py
\> and 2 lactam H) 7~3-8.6 (m, 10H,
\~/ phenyl and quinoline) 8.9-9.4
(m, 2 quinoline H)
26 1.8-3.1 (m, 7H, pentane); 3.39
~ ~ and 3.82 (AB, J = 19~1Z, SCH2);
4.8-6.3 (m, 4H, CH2Py and 2 lac-
\~/ tam H); 7.3-8.7 (m, 11H, ohenyl
and ;soquinoline); 9.5-9.85 (m,
1 isoquinoline H)
`` lZ2~i954
- 26 -
Ex- A Yield 1H-NMR (Cf3C02D): ~ ~ppm)
ample % of th
_ ........... __ _
16 ~ 32 1.6-4.1 (m, 17H, 8 cyclohexene
H, 7 pentane H and SCH2), 4.9-
6.4 (m, 4H, CH2Py and 2 lactam
-~ ~ H); 7.3-9.0 ~m, 8H, phenyl and
. Py)
: _
17 35 1.7-3.0 (m, 7H, pentane); 2.76
(s, 3H, CH3); 3.65 and 3.73
~ C~33 (AB, J = 19 Hz, SCH2); 4.7-6.3
I ~ (m, 4H, CH2Py and 2 lactam H);
7.3-8.9 (m, 9H, phenyl and Py)
. ' _
18 62 1.8-2.9 (m, 7 pentane H); 3.42
. C~T~5 and 3.76 (AB, J = 19 Hz, SCH2);
4.9-6.4 (m, 4H, CH2Py and 2
lactam H); 7.3-9.25 (m, 14H,
: ~ phenyl and Py)
:
.
~ .
.
59
-- 27 --
The compounds shown beLow, wh;ch correspond to
the general formula
~L C~2CO~il ~S
L~L--C~I2A
CO ~
and ;n which A denotes the substituent shown in the sec-
ond column of Table 2, are obtained analogously to
Example 1b (trimethyliodosilane method).
Table 2
Ex- A ¦Yield 1H-NMR (CF3C02D): ~ (ppm
ampl~ ¦% of th.
19 ~ 84 2.66 (s, 3H, CH3); 3.40 and
C~ 3.72 (AB, J = 19 Hzf 2H, SCH2);
4.06 (s, 2H, CH2C0); 5~05~6.40
: : ~ (m, 4H, CH2Py and 2 lactam H);
. ~ ~ ~ 6.8-7.4 (m, 3H, thiopene), 7.95-
: : ~ 9.20 (m, 4H, Py)
__ _ ~
3.38 and 3.72 (AB, J = 19 Hz,
C ~ SCH2); 4.10-(s, 2H, CH2C0);
~._ . 4.9-6.3 (m, 4H, CH2Py and 2 lac-
C~ tam H); 6.9-7.3 (m, 3H, thio-
~ ~ pene); 7.66 (s, 5H, phenyl);
: : 8.0-9.4 (m, 4H, Py)
"
.
.
~.
^ ~LZZ~ii954
-- 28 --
Ex- A ¦Yield 1H-NMR (CF3C02D): ~ (ppm)
ampl~e '~ of th.
- 21 ~ 35 1.7-2.4 (m, 4H, cyclohexene H);
2.8-3.8 (m, 6H, 4 cycLohexene H),
-~ ~ SCH2); 4.05 (s, 2H, CH2C0);
5.15-6.25 (m, 4H, CH2Py and
. 2 lactam H); 6.8-7.5 (m, 3H,
¦ th;opene); 7.6-8~8 (m, 3H, Py)
. . _ ~
; 22 ~ 38 3.40 and 3.78 (AB, J = 19 Hz,
2H, SCH2); 4.08 (s, 2H, CH2CO);
5.15-6.35 (m, 4H, CH2Py and
2 lactam H); 6.8-7.4 (m, 3H
thiopene); 7.9-8.8 (m, 6H,
isoqu;noline H); 9.5-9.8 (m,
1 soqu;noline H)
.. . . __ . ..... ~
23 Ci ~ 28 3.42 and 3n75 (AB, ~ = 19 Hz,
~1 ~ SCH2); 4.06 (s, 2H, CH2C0);
5.26-6.42 (m, 4H, CH2Py and
2 lactam H); 6.8-7.4 (m, 3H,
.
thiopene); 8.0-9.2 (m, 5H, Py)
: ~
~ 2~;9S4
-- 29 --
The compounds shown below, whir,h correspond to
the general formula
and in wh;ch R1 and R3 deno'ce the substi'cuents given
in Table 3, are obta;ned analogously to Example 1b (tri-
methyliodosilane method).
.
Table 3
Ex- R1 R3 Yield l1H-NMR (CF3COZD): ~(PPm)
ample % of th.
_
24 H ~ ~ 28 2.1-2.9 (m, SH, CH3-
S~H - s;ng. at 2.33 and
N 2 2 cyclopentene H); 3.1-
3.9 (m, 6H, SCH2 and
4 cyclopentene H); 4.03
(S, 2H, CH2CO); 5.15-
6.25 (m, 4H, CH2Py and
2 lactam H); 7.3-8.7
~ I r (m, SH, Py and imidazole)
H CNCH2- 32 2.1-2.9 (m, 2 cyclopen-
tene H); 3.1-3.8 (m, 6H, -!
. SCH2 and 4 cyclopentene H);
3.88 (S, 2H, CH2CO3; 5.2-
6.25 (m, 4H, CH2PY and
2 lactam H); 7.65-8.7
(m, 3H, PY)
- - - - -
: : :
2sgs~ ~
- 30 -
Ex- R1 R3 Yield 1N-NMR (CF3C02D): ~S(PPm)
ample X of th.
26 H ~ 68 2.2-2.9 ~m, Z cyclopen-
~ 11 tene H); 3.15-3.85 (m, 6H,
N SCH2 and 4 cyclopentene H);
OC}13 5.2-6.Z5 (rn, 4H, CH2Py
. . and 2 lactam H); 6.60;
6.98 and 7.57 (one
. furan H each); 7.6-8.7
. . . ~m, 3H, Py)
_
27OCH3 ~ I 65 2.2-2.9 (m, 2 cyclopen-
CO tene H); 2.9-3.8 (m, 6H,
SCH2 and 4 cyclopentene
. H); 3.70 (s, 3H, OCH3);
4.10 (s, 2H, CH2CO);
5.25-6.20 (m, 4H, CH2Py
. and 2 lactam H); 6.7-
7.45 (m, 3 thiopene H);
~ : ~ ~.65-8.7 tm, 3H, Py)
' ,
.
.
` -
~ 2~s4
- 31 -
End products
Example 1
7-Am;no-3-C2,3-cyclopenteno-1-pyr;d;n;o)methyl]~ceph~3~
em-4 carboxylate
a) Chem;caL spl;ttin~
- 5~6 ml (44 mmol) of N,N-d;rnethylan;l;ne and 2.8 ml
~22.2 rnmol~ of trimethylchlorosilane are added to a stir-
red suspension of 5~6 g (10.5 mmol) of 3-C(2,3~cyclopen-
teno-1-pyr;d;n;o)methyl~-7-(2-thienylacetam;do~-ceph-3-
ern-4-carboxylate hydro~hiocyanate salt (Example 1) in 40 ml
of dry methylene chloride. When the temperature is in-
creased slightly to 27C, a clear solution is formed.
After the mixture has been stirred at room temperature
for 1 hour, it is cooled to -40C and 4.6 g (22.2 mmol)
of PCl5 are added all at once, whereupon the tempera-
ture r;ses to -25C. The dark brown solution is stir-
red at -30C for 1 hour and is then poured into a solu-
- t~on, cooled to -40C, of 9 ml of ;sobutanol in 18 rnl
of methy;lene chloride. A precipitate formsO After the
mixture has been left to stand overnight in a refriyera-
; tor, the precip;tate is f;ltered off w;th suction and
washed with methylene chloride. The rnoist crude product
is immed;ately dissolved in 15 ml of methanol of -5C,
and 80 ml of methylene chloride:ether ~1:1) are added drop-
wise~ After stlrring at -10C for 2 hours, the precipi-
tate formed is filtered off ~ith suction, washed with
acetone and dried over PzO5 in vacuo.
Yield: 3c3 g (78% of theory) of Light brown crystals.
16H17N33S x 2 HCl
.
2~g~4
- 3Z -
Calculated: C 47.41 H 4.97 Cl 17.49 N 10.37X
Found: C 46.2 H 5.6 Cl 16.6 N 9.8%
IR (Ksr): 1785 cm -1 (lactam CO)
1H-NMR(CF3C02D): ~ = 2~55-2.95 ~m, 2H cyclopentene H);
3.15-3.95 (mf 6H, 4 cyclopen-
tene H and S-CHz); 5~53 (s,
2H, lactam H); 5.55 and 6.03
(AB,J - 15 Hz, 2H~ CH2Py),
7.65-8.70 ppm (m, 3H, Py).
10 b) Enzymatic splitting
106 y (0.2 mole) of 3-C(2,3-cyclopenteno~1-pyri~
d;n;o)methyl~-7-(2-th;enyl-acetamido)-ceph~3-em 4-car-
boxylate hydrothiocyanate salt (Example 1) are suspended
;n 6CO ml of water, a solution of 150 ml of Amberl;te LA-2
.
(Rohm and~Haas) in 800 ml of ethylacetate are added and
; the mixture ;s stirred in an ice-bath for half an hour.
The phases are sPparated and the aqueous solution is ex-
tracted~w;th two 50 ml portions of LA-2 (acetate forrn) in
150 ml of methyl isobutyl ketone and the extract is also
washed with four 100 ml portions of methylene chloride.
The aqueous phase is made up to a volume of 500 ml and
adjusted to pH 7 with NaHC03 tO.2 g). 100 9 of fixed
pen;c;llin G am;nohydrolase enzyme are added and the mix-
ture is stirred at 37C and pH 7.1. The pH value is
; 25 kept constant by dropwise addition of 1N NaOH. After
2 hours, 90 per cent conversion is achieved (thin layer
chromatography system: acetone/H20 - 5:1, silica ~el plates)~
The fixed enzyme is filtered off and washed with three
100 ml portions of water and the aqueous phases are brought
~ 122~954
-- 33 --
to pH 6 ~ith 2N HCL and freeze-dried. The amorphous
lyoph;l;sate ;s stirred w;th 250 ml of methanol, a small
amount of unsoluble mater;al is filtered off and 300 ml
of 15 percent strength alcoholic hydrochloric acid and
S then 1 l;ter of ether are added to the f;ltrate. After
2 hours at 0C, this precipitate is filtered off with
suction, washed with ether:methanol ~4:1~ and dried in
vacuo.
Yield: 61 g of colorless product (75% of theory). The com-
pound is identical ;n all its properties to that
descr;bed above in Example 1a.
The compounds of the general formula I l;sted inthe following Table 4 are obtained from the corresponding
2-thienylacetamido-cephalosporine der;vat;ves analogously
15 to Example 1 (method a: chemical spl;tting; method b: en-
zymatic splitting).
:
Table 4
Ex- A ¦Method Yield ~ 1H-NMR(CF3C02D): ~(ppm)
; ample 1- ~ of th~
2 ~ ¦ a(b)72 1.7-2.4 (m, 4H, cyclo- 3
. ~ hexene H); 2.7-3~95 (m,
(69) 6H, 4 cyclohexene H and
. ~ SCH2); 5~35-6.25 (m,
4H, CH2Py and 2 lactam
_ _ H), 7.75-8 65 (m, 3H, Py)
.
,' .
-- ~X2~;95~
- 34 -
Ex- A Method Yield 1H-NMR(CF3C02D): ~(ppm)
ample % of th.
.
3 ~_~ 3 a (b) 81 2.69 (s, 3H, CH3);
(78) 3.66 (s, 2H, SCH2);
5.25 6.39 (m, 4H,
CH2Py and 2 lactam H);
7.83-9.03 (m, 4 Py H)
... _ .. ___
4 ~ a (b) 77 3.4-3.9 (AB, 2H, SCH2);
~ (75) 5.2-6.4 ~m, 4H, CH2Py
-~ 9 and 2 lactam H); 7.9-
8.8 (m, 5 q~;nol;ne H);
8.85-9.2 (mJ2 qu;no-
l;ne H)
_~ .. .. ~ _
~ a (b) 80 3.5-4.0 (AB, 2H, SCH2);
-N ~ ~ J 5.1-6.6 (m, 4H, CH2Py
(74) and 2 lactam H); 7.9-
8.8 (m, 6 ;soqu;noline
H); 9.8-9.95 (bs, 1 ;so-
qu;nol;ne H)
. _ ~. _
:
: ~ :
::
:
:` :
-` ~L225!9S4
- 35 -
Example 6
7-Amino-3-(2,3-cyclopenteno-1-pyrid;n;o)methyl-ceph-3-
em-4-carboxylate
-
3 9 (5.2 mmole) of 7-(D-5-benzamido-5-carboxypen-
S tanamido)-3-(2,3-cyclopenteno-1-pyridinio)methyl-ceph-3
em-4-carboxylate (Starting Example 4) are suspended in
20 ml of methylene chloride. After addition of 3.9 ml
(31.2 mmole) of N,N-dimethylaniline and 3.9 ml (31.Z mmole)
of trimethylchlorosilane, the mixture is stirred at room
temperature for 1 hour. The clear solu~ion is cooled to
40C and 6.2 g (30 mmole) of PCl5 are added~ The solu-
tion ;s stirred at -30 for 1 hour and is then poured,
all at once, into a solution, cooled to -40C, of 4.1 ml
of isobutanol in lO ml of methylene chloride. The mix-
ture ;s left at 0 for 1 hour and the solvent is thenremoved in a rotary vacuum evaporator. The res;due is
d;ssolved in 5 g of ;ce-water and the solution is brought
to pH 6 by addition of NaHC03O It is chromatographed
over~a silica gel column using acetone:~ater (2:1). The
product fract;ons are fre~eze-dried.
Y;eid: 0.83 g (48% of theory)
H-NMR ~CF3C02D): ~ ~= 2.2-2.9 (m, 2H, cyclopentene
H); 3.15-3.93 (m, 6H, 4 cyclopen-
tene H and SCH2); 5.25 6.35 (m,
4H, CH2Py and 2 lactam H); 7.65-
8.0 (m, 1H, Py); 8.23-8~7 ppm (m,
2H, PY)
~he compound of Example 6 is obtained from the
. '
.
LX2S9S4
- 36 -
benzenesulfonamido compounds o~ startlng Examples 6, 7 and
8, ;n a manner analogous to that descr;bed ;n Example 6.
Y;eld: 55% from the compound of starting Example 6
62% from the compound of starting Example 7
58% from the compound of start;ng Example 8
The compound obtained in each case is ;dent;cal
in all its properties to that describe~d above in Example 6.
Example 6
a) 3-~(2,3-Cyclopenteno-1 pyridin;o)methyl]-7-for-
-
~ mylamino-ceph-3-em-4-carboxylate hydriodide
24 g (0.08 mole) of anhydrous 7-formyl-am;no
cephalosporanlc acid are suspended in 400 ml of dr;ed
methylene chloride, and 46~8 ml (0~4 mole) of cyclopen-
tenopyr;~dlne are added at room temperature. 45.6 ml
(0.32 mole) of trimethylsilyl iodlde are added dropwise
to the clear solution, ~Ihile stirriny and wi.h exclusion
of mo;sture, and the m;xture is heated under refLux for
two hours. Tbe reaction mixture is then cooled to 0C,
2ûO ml of water are added and tl1e mixture is neutralized
w;th about 400 ml of saturated sodium bicarbonate solutlon
~pH 6). The phases are separated and the organ;c phase
;s extracted by shaking with 80 ml of water. The comb;ned
aqueous phases are extracted with three 200 ml portions
; of methylene chloride and separated off, residues of
methylene chloride are removed from the aqueous phase in
vacuo and the aqueous phase is clar;fied with 4 g of
-~ act;ve charcoal. The filtered a~ueous solution is brought
to a pH value of about 1~5 with 200 ml of 1N HI and is
then concentrated to about 100 ml in vacuo on a rotary
,
2595A
-- ~i7 --
evaporator The prec;pitate is filtered off with suction,
~Jashed w;th acetone and dr;ed ;n vacuo over P20
Yield: 24.1 9 (59.6% of theory)
cl7ti17N304XHIXH20 (505 3)
Calculated: C 40.41 H 3.99 I 25.11 N 8.32 S 6.35 H20 3.56X
Found: C 40.1 H 4.1 I Z3O7 N 8.2 S ~.4 H20 4.2%
H-NMR (CF3)C02)D: aS = 2.3-2.8 ~m, 2H, cyclopen
tene H); 3.15-3.~5 (m, 6H, 4
cyclopentene H and SCH2); 5.25-
6.30 (m, 4H, CH2Py and Z lac-
tam H~; 7.65-8 75 tm, 4H, HC0
and 3 Py H)
b) 7~-hmino-3-~(Z,3-cyclopenteno-1~pyr;din;o)methyl]-
ceph 3-em-~-carboxylate
,
15 D;hydrochloride
20.2 g (0.04 mole~ of the product of Stage a are
suspended ;n 200 ml of 2N hydrochloric acid. The suspen-
s;on ;s warmed to ~60C, a cLear solution be;ng formed,
and the soLution ;~5 lef~ at th;s temperature for a fur~
20 ther S~ minutes. It is concent~rated to a volume of about
40 ml on a rotary vacuum evaporator. After addit;on of
120 ml of acetone, the dihydrochloride of the title com-
pound precipitates as crystals. The crystals are filtered
otf witl1 suction, washed with acetone and dried in vacuo
over P205.
Y;eld: 15.4 g ~B6% of theory~, decomposition 167C
C16H17N303S x 2 HCl x H20 (422~4)
Calculated: C 45.5 H 5.0 Cl 160~ N 9.9 H20 4.3%
Found: C 44~0 H 4~8 Cl 15.2 N 9~6 H20 3O3%
5954
~ .
The N.~R spectrum is identical in all its proper-
t;es to that of Example 1a.
-Monohydr;od;de and monohydrochloride
. 0.422 g (1 mmole) of the above dihydrochloride is
dissolved ;n 2 ml of water at room temperature. 84 mg of
sodium b;carbonate and 0.05 ml ~about 0.4 mmole) of 57 per
cent hydriodic acid are added. The mo.nohydriodide preci-
p;tates from the clear solut;on as crystal. The crystals
are f;ltered off w;th suct;on~ washed with a l;ttle water
10 and dried in vacuo over H2S04.
Yield 0-2 y
C16H17N33S x HI x H20 (4773)
Calculated: C 1~0.26 H 4.22 I 26.59 N 8.80%
Found: ~C 40.7 H 4.2 I 25.0 N 8.9%
The monochloride is obtained from the mother
~l;qor by adding~acetone until crystaLlization starts.
The crystallization of 200 mg from acetone: water (6:1)
gives 130 mg of pure monochloride monohydrate.
16H17N33S x HCl x H20 (385.9)
Calculated: C 49.80 H 5.22 Cl 9.18 N 10.89 S 8.31%
.
Found: C 50.1 H 5.6 Cl 8.8 N 10.9 S 8.9%
.
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