Note: Descriptions are shown in the official language in which they were submitted.
~L07~
This inventlon relates to an improved process for the preparation
of certain esters of 7-aminocephalosporanic acid and derivatives. Our sritish
Patent Specifica~ion No. 1~377,817 discloses, inter alla a process for the
preparation of a class of compounds of formula (I):
Rl ~--S ~
o~ N ~ ~ 2 (I)
~C-O-C--Z
, X~
~herein X and Y are the same or d-lferent and each rÇpresents oxygen or
sulphur;
Z represents the residue of a lactone, thiolactone or dithio-
lactone ring system;
R represçnts hydrogen or an alkyl, alkenyl, alkynyl9 aryl or
aralkyl group 9 or a functional substituent;
B represents hydrogen, an acetoxy group or a pyridinium group;
and
R i6 an organic acyla~ino group, a group o~ ~or~ula (II):
CH - C ~
(II)
,/
/\
C~3 CH3
,. 1 --
.
.. ..
. . , ,
- .
, . -
: .:- '
, .
: .:- : - . - . . . ~:
.. .. . : :
..
.
` :
[D7~6Z
or a group of ~ormula (III):
N -CH = N (III)
R3 /
wherein R2 and R3 each represent a lower alkyl group~ or R2 and R3 taken
together with the nitrogen to which they are attached form a monocyclic ring;
which process comprises reacting a compound of formula ~IV):
Rl ~S
N ~ ~ - CH2B
C OH (I~)
or a reactive esterifying derivative thereof, with a compound of fonmula (V):
HO - C - Z
(V) '~
or a reactive esterifying derlvative thereof.
Although such a process, being a con~entional esterification
process, is simple and efficient, it does suffer from ~he disadvantage that
migration of the double bond occurs during the reaction to a marked extent
to produce a proportion of antlbacterially inactive 2-cephem, Reactive
esterifying derivatlves of the compound (V) which are known ~ro~ other
cephalosporin esteriflcation procedures to reduce this migration to a minimum
- 2 -
.
- ,. .:
- ~ ,
6Zl
include diazo derivatives and the reactiVe intermediate formed on reaction in
situ with a carbodi-imide. However, neither of these procedures may be
satisfactorily applied to the case of the particular class of esters described
above.
We have now found that the double bond migration during the
esterification process can be substantially reduced by employing, as the
reactive esterifying derivative of the compound (V), the corresponding iodide.
Accordingly, the present invention provides a process for the
preparation of a compound of formula (IA), wherein X,Y,Z and R are as defined
with respect to formula (I) above,
~,1 /S~
J N\ ~ CH2~
¦ R
~ F
Il
A is hydrogen, acetoxy, a carbon, nitrogen or sulphur nucleophile, or carba-
moyloxy, and R is an amino group or a group as defined with respect to
formula I, which process comprises reacting a compound of formula (IV) or a
reactive esterifying derivative ~hereof with a compound of formula (VA).
I - C - - Z (VA)
X--If
Y
3 -
. - , '. . ~ '
- : .. . , . : ,
,
~L~7~
~herein R,X,~ and Z are as deflned ~ith respect to formula (I) above.
Suitable examples of the groups R,X,Y and Z are disclosed in
British Speclfication No. 1,377,817.
The group A may be inter alia a strong carbon, nitrogen or
sulphur nucleophile. Such nucleophiles displace the acetoxy group from the
nucleus of 7-aminocephalosporanic acid and such displacement has been observed
with various pyridines (Hale et.al. siochem J. 79, 403, (1961) and Spencer
et.al., J.Org. Chem (US~) 32 500, (1967)); other aromatic heterocycles (Hale
et.al loc cit;) Kariyone et al J. ~ntibiotics~ 23, 131 (1970); and Spencer et.
al. loc.cit.); Xanthates and dithiocarbamates Van Heyningen et. al.
J.Chem.Soc. (London) 5015 (1965)) and anilines (Bradshaw et.al.
- J.Chem.Soc.(London) 801 (1968)).
The group A may advantageously be a group o~ formula
S - Het
wherein 'Het' is a five o~ six membered heterocyclic ring containlng from one
to four atoms selected ~rom N, O and S unsubstituted or substituted with one
or two groups selected from lower alkyl, lower alkenyl, lower alkoxy, hydroxy-
alkyl, alkoxyalkyl, carboxgalkyl, trifluoromethyl, hydroxy, or halogen.
Examples of the group 'Het' include unsubstituted and substituted
1,2,3-triazolyl, 1,2,4-triazolyl9 1,2,3,4-tetrazolyl, oxazolyl, thiazolyl,
1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl or 1,2,4-thiadiazolyl.
Preferably A is 2-methyl-1,3,4-thiadlazolyl-5-thio, l-methyl-
(lH)-1,2,3~4-tetrazolyl-5-thio, Z-methyl-1,3,4-oxadiazolyl-5-thio or (lH)-
1,3,4-triazolyl-5-thio.
The group R1 in ~ormula (lA) has been de~ined as an organlc
acylamlno group. The ~ast major:lty of antimlcrobially actlve ceph-3-ems wh:lch
-- 4 --
:. :
.
.
2~
have been reported to date in the literature carry a 7-acylamino group. It
has been found over the years that by varying the identlty of the 7-acylamino
group, the speetr~ and/or level o~ antibaeterial aetivity of any given eeph-3-
em can be modified. Similarly, in the present case a very large number of
7-aeylamino groups ean be introdueed producing a range of eompounds of widely
differing spectra and levels o~ acti~ity. In general, however, whatever the
identity of the aeylamino group Rl, the eompounds of formula ~lA) possess some
activity and those who are fa~iliar with ~he cephalosporin art will be aware
of the range o~ acylamine groups Rl which may be introduced.
In general, therefore, ~1 in formula (1~) may be any of the
organic acylamino groups which are present in the reported natural and semi-
synthetie penieillins and eephalosporins.
~xamples inelude aeylamine groups of the following general
formulae (i~, (ii) and (iii):-
(i) R (CH2)n-CH-(CH2)m C0 NH-
Xl
wherein R represents hydrogen or an alkyl, eycloalkyl ~especially C3 to C6
; 20 eyeloalkyl), cycloalkenyi (especially cyclohexenyl or eyclohexadienyl) 7 aryl
(espeeially phenyl or substituted phenyl e.g. ~-hydroxy-phenyl), he~erocyclie
(e.g thienyl, pyridyl, substituted isoxazolyl sueh as 3-0-ehlorophenyl-5-
methyl isoxazol-4-yl, sydnonyl, tetrazolyl); -CH(NH2)C02H; Xl represents
hydrogen, a hydroxyl group, a halogen ato~ (espee~ally ehlorine), a carboxylie
aeid group or carboxylic acid ester group (e.g. a phenyl or indanyl ester),
an azido group, an amino group or substituted amino group (includlng ureido,
substituted ureido, guanLdino and substituted guanidino groups), a triazolyl
- 5 -
~ -- . , ,
.. . .
L6Z~
group, a tetrazolyl group, a cy~no group, an acyloxy 8roup (e.g. formyloxy or
lower alkanoyloxy group) or an esterified hydroxy group; and n and m each
separately represent 0, 1, 2 or 3.
(ii)
CH2 ~ C0-NH-
(CH2)n C /
~ 2 - X
~herein n is an integer ~rom 1 to 4 and Xl is as defined in (i) above.
(iii)
R4 Z-C-C0-NH-
wherein R4 is an alkyl, aralkyl, aryl (especialIy phenyl or subs~ituted phenyl
g~oup), cycloalkyl (especially a C3 to C6 cycloalkyl or substituted cycloalkyl
group, cycloalkenyl (especially a cyclohexenyl or cyclohexadienyl group) or a
heterocyclic group (especially a thienyl or pyridyl group); R5 and R6 are each
hydrogen lower alkyl, phenyl, benzyl or phenylethyl groups; and Z is oxygen or
sulphur.
Specific examples of organic acylamino groups R which may be
present in the compounds prepared by the process of this invention include
2-thienylacetamido, phenylacetamido, 2-hydroxyphenylacetamido, 2-aminophenyl-
acetamido, 4-pyridylacetamido, 2-amlno-~-hydroxyphenylacet~mido and l-tetra-
~olylacetamido and w~aminoadipamido.
- 6
.. ~. , ~
, ... .. ..
~ .
~L~'7~ ~Zl
By the term "reactive esterifylng ~erivative" in relation to
compounds (IV) above, we mean derivatives of (IV) which when reacted with the
iodo compound (VA) take part in a reaction wlth the consequent formation of an
ester linkage:
C00 R
C
X Z
\C/
Il
Y
Many methods of esterification using several different reactive esterifying
derivatives are known from the li~erature. For example, the esterification
reaction defined above may be achieved by reacting a compound (VA) with a
compound of formula (IV ~):
Rl ---r~ ~~ j
0 ~ --CH2A (IVA~
CO ,O~U
~herein Rl and A are as defined wlth reference to formula (lA) above under
conditions which cause the elimination of the elements of compound UI wlth the
consequent formation of the ester of formula (lA). Thus, for example, U may
represent hydrogen or a salt-forming ion such as sodium or potassium, or a
triallcyl ammonium ion, particularly triethylammonium. ~hen the group R in
compound (IV) contains a free amino group, or when R is ltself amino, it is
preferable that the amino group should be protected prior to the esterification
reaction.
- -, . ' ' ~ ' ' '
' ~ ' . . :
. . .. : . .. . . .
.. . .
. .
. - -. ~ , . . , ~ ~ .
.
Examples o~ protected amino groups include the protonated amino
group (NH3) which after the acylation reac~ion can be converted to a free
amino group by simple neutralisation; the benzyloxycarbonyla~ino group or
substituted benzyloxycarbonylamino groups which are subsequently converted to
NH2 by catalytic hydrogenation; and various groups whieh after the acylation
reaction regenerate the amino group on mild acid hydrolysis.
(Alkaline hydrolysis is not generally useful since hydrolysis
of the ester group takes place under alkaline conditions.)
Examples of a protected amino group which may subsequently be
con~erted to NH2 by mild acid hydrolysis include enamine groups of general
formula (VI) or tautomeric modifications thereof, and ~-hydroxyarylidene
groups of general formula (VII) or tautomeric modifications thereof:-
R7
I
~ C / CH
R - C N - C N -
R9 - C 1 ~ C H
~ ~ \ /
(VI) (VII)
In structures (VI) and (VII) the dotted lines represent hydrogen
bonds. In structure (VI) R ~s a lower alkyl group, R is either a hydrogen
- atom or together with R7 completes a carbocyclic ring, and R9 is a lower alkyl,
aryl, or lower alkoxy group. In ~tructure (VII) ~1 represents the residue of
a substituted or unsubstituted ben~ene or naphthalene rlng.
. . .
6~
An ex~mple o~ a "protected amino~l which can be converted to NH2
after the esterification reactlon ls the azido group. In this case, the final
conversion into NH2 may be brought about by eitheF catalytic hydrogenation
or electrol~tic reduction.
The advantage of the process of this invention is that double
bonded migration during the reaction is minimised. It is likely that the
speed of the reaction is an important factor in this reduced isomerisation,
which may be caused by the carboxylate of starting m~terial.
The speed of the process also allows a convenient synthesis of
the compounds of formula (I) ~herein R1 is amino, which are often difficult
to prepare by previously kno~n methods.
The following examples illustrate the process of the invention.
In these examples, the following abbreviations are used:
Cephalothin : 2-thienylace~amidocephalosporanic acid
BOC : t-Butyloxycarbonyl
DMSO : Dimethylsulphoxide
Cephaloglycin : D-~-aminophenylacetamidocephalosporanic acid
~CA : 7-aminocephalosporanic acid
Example 1
Phthalidyl 2-thienylacetamidocephalosporanate
Iodophthalide was prepared immediately prior to use by mixing
acetonitrile solutions of sodium iodide (l.Sm mole) and bromoph~halide
(1.5 m mole) and stirring for 3 minutes. This solution was filtered ~to
remove precipitated sodium bro~ide) into an ice cooled DMSO solution of
~cephalothin (1 ~ mole~, stirred 10 minutes and poured into ice water to pre-
cipitate the required este~. ~ield o~ crude, neutral product after work up - 90%.
~ .. . .... ' ., ' . .. ' , ! ' .. .. , . ' ,
``' ' " ~' " ' ' ' '` ` ' , ~ ~ " ' " '' "' , '" . ' ', " ', ' ' ' ' '' ' ' ' . ' ' ' '
` " " '' `' . " ' ' '" ' ' ' .' .' ' .. , , .. ' " ' ' . ' .' . " . ' .
' ' ' ' ' ' . . ' ' . , . . ' . ' . . , , . ' ' ` ' '
. '.` .` ' . " . '' `'. `' ' ,'. ' . ' ' '`
, ~ . '
' ' ,', ' ' ' '` ' '" '' ' ` , ,
~L~7~
TLC and MMR indicate ~ 90% ceph-3 e~ ester. ~ (CDC13/trace D~So) = 2.08 (d,
3H, -OCOCH3), 3.61 (broad s, 2H, C2-H), 3.88 (s, 2H, ~-CH2~, 4.6 - 5.4 (ABq ~ d,
3H, -CH20- ~ C6), S.6 - 6.0 (m, lH, C7) 6.9 - 7.~ (d~ ~ t, 3H, thienyl aro-
matics), 7.5 - 8.2 (m, ca. 5H, phthalidyl aromatics and -OCHO-)~ 8.2 - 8.6
~2d~ lH, amide N-H)- ~max (CHC13) 3370, 2960, 1793, 17~3, 1682, 1505, 1230,
982cm ; ~ max (~tOH) 275nm (~ ,7000)
Phthalidyl N-t-Butyloxycarbonylcephaloglyclnate
N-t-BOC cephaloglycin (l.lm mole) in D~SO was treated with Et3N
(lm mole) at room temperature and a solution of iodophthalide (1.5 m mole) in
acetonitrile was filtered into this. The mixture was stirred 15 minutes at
room temperature and poured into ice water to precipitate the phthalidyl ester.
~ield 77%. tlc and NMR indicate > 90% pure ceph-3-em ester. ~ (CDC13) 1.40
(s, 9H, Bu-H), 2.10 (d, 3H, -OCOCH3), 3.48 (broad s, 2H, C2-H), 4.6 5.6
(m, 4H, C6 ~ -CH20- ~C~), 5.7 - 6.1 (m, 2Hg C7 ~ NHBOC), 7.2 - 8.2 (m, llH7
~phenyl ~ phthalidyl aromatics and -OCHO- ~ amido NH). ~m (CHC13), 3400,
2960, 1792, 1693, 1495, 12309 981cm 1; ~ max (EtOH) 270nm ( ,7400)-
Example 3
Phthalidyl 7-aminocephalosporanate
(a) Sodium 7-N-(3-metho~ycarbonyl-prop-2-en-2-yl)-aminocephalosporanate
ACA (3.68mmole) was suspended in dry methanol and a solution o~
sodium (3.68m mole) in dry methanol added dropwise. On completion o~ the
addition, methyl acetoacetate (4m mole) was added and the solution stirred
~ hours with molecular sieye (4~ iltered and evaporated. Residue was ether
washed, Yield 69%. ~ (D~SO) 2.03 (s~ 6H, CH3-C=CH ~ -OCOCH3), 3.56 (bs, 5H,
-COOCH3 ~ C2 - H), 4.67 (s, lH, q~CH-), 4.7 ~ 5.3 (m, 3H, -OCH20~ ~ C6), 5.5 -
5.9 (m, lH, C7, 9.00 (d, lH, N~l), ~ma~ (nu~ol ) 1762, 1665, 1620, 1280cm 1
; *Trademark
~ - - 1 0
..
. . : . ~, . .
. .: . .
. .
: . : .
, .
, - ,.. :
.. .....
,, ':
1~7~
(b) Phthalidyl 7-N~(3-~ethoxy~a~bo~ylp~op-2-en-2-yl)amino ~ephalosporanate
The above sodium salt was esterified by the same method as Example
1 using DMSO/acetonitrile solvent at 0-5C. Yield 83% of pure ceph-3-em ester.
~(CDC13) 2.05 (s, 3H9 -OCOCH3). 3.2 - 4.0 (s at 3.68 ~ m, 5H, OCH3 ~ C2-H),
4.6 - 5.8 (m, 5H~ C=CH- ~ C6 ~ C7 ~ -C~ o-)~ 7.4 - 8.2 ~m ca 5H, phthalidyl
aromatics and -OCHO-), 9.30 (d, lH, N~ .~'max tCHC13), 3540, 3020, 1800,
1750, 1667, 1630, 1230, 995cm 1; ~max (EtOH) 279nm ( ,14800). The above
crude product was deprotected (HCl/acetone) to form ~CA phthalidyl ester in
70% yield. ImpuritiPs in the N-pro~ected co~pound were washed out after
deprotection.
Example 4
(a) Sodium 7-N-(3-methoxycarbonylprop-2-en-2-yl)-amino-3(1-methyl-
tetrazol-5~-yl-thiomethyl)-ceph-3-em-4-carboxylate
Prepared similarly to Example 3(a) from te~razole ~CA
Yield 74%. ~ (DMSO) 2.02 (s, 3H, CH3-C+CH~, 3.60 (s, 3H, -COOCH3), 4.00
(s, 3H, -NCH3), 3.2 - 4.9 (m, 4H, C2-H ~ CH2S), 4.68 (s, lH, C=CH), 5.16
(d, lH, C6, 5.4 - 5.8 (m, lH, C7), 9.01 (d, lH, NH), ~max tnuJol) 3300, 1757,
1650 (shoulder), 1610, 1275cm
(b) Phthalidyl 7-N-(3-methoxycarbonylprop-2-en-2-yl)amino-3 l' methyl-
tetrazol-5'-yl-thiomethyl)-ceph-3-em-4-carboxylate
Esterification was carried out as in Example 3(b) in 57% yield
of pure ceph-3-em ester. ~ (CDC13) 1.98 (s, 3H, CH3-C+CH), 3.68 (s, 3H, OCH3),
4,02 (d, 3H, N-CH3) 3.3 - 5.0 (m9 5H, C2-H ~ 3 -CH2S- ~ ?C=CH-), 5.10 (d, lH,
C6) 5.40 (q, lH, C7), 7.3 - 8.2 (m, 8H, phthalidyl aromatics and -OCHO-
impurity), 9.28 (d, lH, N~), Y max (CHC13) 3540, 3000, 1780, 1740, 1653,
1610, 1260, 1210, 1155~ 970. ~ ~ax (EtOH) 283nm (~ ,17500). This crude
p~oduct was deprotected with HCl/acetone to yield tetrazole ACA phthalidyl
ester hydrochloride (52%).
11 -
' ': ' ' '
..
. . ............................... .
' ' ., ' ` . ' ' ' . ''.' ' ' ' ~ ', ~' ' ''' '
- : . - .
.: - : .
.
.
~7~Zl
Example 5
Phthalidyl 7-(D-~-t-butyloxycarbonyl aminophenyl acetamido?-3-
(l'methyl-tetrazole-5'-ylthiomethyl)-ceph~3-em-4-carboxylate
Esterification of the cephalosporin triethylammonium salt was
carried out similarly to example 2 ln 78% yield. ~(CDC13/trace DMSO) = 1.40
(s, 9H, Bu-ll), 3.59 and 3.70 (2 broad s, 2H7 C2-H), 3.90 and 3096 (2s, 3H,
N-CH3), 4.0 - 4.7 (m, 2H, 3-SCH2-), 4.87 (d, lH, C6), 5.38 (d, lH, C~-H),
5.5 - 5.9 (m, lH, C7) 6.04 (d, lH, NHBOC), 7.2 - 8.0 (m, lOH, ~-phenyl ~
phthalidyl aromatics and -OCHO-), 8.4 - 8.7 (m, lH, amide NH). ~max (CHC13) =
3420, 3010, 1785, 1690, 1490, 1230, 1160, 977cm . ~ ax (EtOH), 268nm
(= 8,300).
Example 6
Phthalidyl 7-(D-~-t-butyloxycarbonyl aminophenylacetamido)-3-(2'-methyl-1~,
31~ 4'-thiadiazol-5'-ylthiomethyl)ceph-3 em-4-carboxylate
Esterificatlon was carried out similarly to Example 2 in 67.1%
yield. ~ (CDC13/~race DMSO) = 1.40 (s, 9H, Bu-H), 2.70 (s, 3H, 2'-CH3),
3.60 and 3.67 (2 broad s, 2H, C2-H), 3.9 - 4.8 (m, 2H, 3-SCH2-), 4.85
(d, lH, C6) 5.40 (d, lH, Co~, 5.5 - 5.9 (m, lH, C7), 6.04 (d, lH, NHBOC),
7,2 - 8.0 (lOH, ~-phenyl ~ phthalidyl aromatics and -OCHO-), 8.5 - 8.8
(m, lH, amide NH). ~ max (CHC13) = 3330, 2930, 1785, 1733, 1690, 1492,
1220, 1160, 978cm 1. ~ max (~tOH) 274nm (~ = 11300).
Example 7
Phthalidyl 7-p-nitrobenzyloxycarbonylamino cephalosporanate
Sodium 7-p-nitrobenzyloxycarbonylamino cephalosporanate was
esterified by the method of Example 1 in 48% yield. ~ (CDC13) = 2.07 and
2,12 (2s, 3H, COCH3), 3.63 (broad, s, 2H, C2-H), 4.7 - 5.5 ~m, 3H, C6 ~ CH20-)
5.30 (s, 2H, -CH2 ~ =N02), 5.5 - 6.0 (m, 211, C7 ~ Nnl), 7.3 ~ 8.4 (m, 911,
- 12 -
-: , . . .
- -~ ,
-~ ~'.- ~. -, . .' : '
- - : , - - : : .
- ' , ' , ' '
~'71~c;;2~
aromatics ~ phthalidyl ~OCH0-), ~ (CHC13), a 3400, 1785, 1740, 1520, 1350,
1230, 1050, 980cm 1
Example 8
Phthalidyl N-(3-methoxycarbonylprop-2-en-2-yl)cephaloglycinate
(a) Sodium N-(3-me~hoxycarbonylprop-2-en-2-yl)cephaloglycinate
This was prepared by two methods:-
(i) Analogou~ly to example 3(a) with cephaloglycin
replacing ~C~. Yield 89%.
(ii) By acylation of ~CA sodium salt with an activated
derivative of D~~-N-(3-methoxycarbonylprop-2-en-2-yl)
aminophenylacetic acid (see J.Med.Chem. 9 749, 1966).
The aqueous solution was free~e dried-yield 50%.
(b) Phthalidyl N-(3-methoxycarbonylprop-2-en-2-yl)cephaloglycinate
The above sodium salt was esterified according to Example 1
in 53% yield.
Example 9
Phthalidyl 7- CD~-N-(3'-methoxycarbonylprop 2'-en-2'-yl) amino~henylacetamid~ -
3- Cll'-methyltetra~ol-5"-ylthiomethyl]ceph-3-em-4-carboxylate
Sodium 7- [D-~-N-(3'-methoxycarbonylprop-2l-en-2l-yl) amino-
phenylacetamid~ -3- [1"-methyltetrazol-5"-ylthiomethyl]ceph-3-em-4-carboxylate
was prepared and esterified as for example 8.
Example 10
Phthalidyl 7-rD-X-N-(3'-methox~carbonylprop-2'~en-2~-yl) amino~henylacetamido~
3 r2"-methyl-1!'~ 311~ 4I-thiadiaZO1-5II-Y1thiOmethY~ ceph-3-em-4-carboxylate
Sodium 7-LD-X-N- (3'-methoxycarbonylprop-2'~en-2'-yl) amlnophenyl-
acetamido~-2-[2'l-methyl-1", 311, 4ll-thladiazol-5"-ylthiomethy~ ceph-3-em-4-
- carboxylate was prepared and ester:l~ied as ~or example 8,
- 13 -
' '
~ .
.
~7~
Example ll
Phthalidyl 7-~N-(3'-methoxycarbonylprop-2'-en~2'-~l)amino]-3-C2''-methyl~
3", 4''-thiadiazol-5"-ylthiomethyl~ ceph-3-em-4-carboxylate
Sodium 7-[N-(3'-methoxycarbonylprop~2'-yl)amin~ -3-t2"-methyl-1",
3",4"-thiadiazol-5"-ylthiomethyl-]ceph-2 em-4-carboxylate was prepared and
esterified analogously to example 3.
Example 12
Phthalidyl 7-rN-(3'-methoxycarbonylprop-2'-en-2'-yl)amino3-3-carbamoyloxy-
methylceph-3-em-4-carboxylate
Sodium 7-[N-(3'-methoxycarbonylprop-2'-yl)amino]-3-carbamoyloxy-
methylceph-3-em-4-carboxylate was prepared and esterified analogously to
example 3.
Example 13
Phthalidyl 7-(p-nitrobenzyloxycarbonylamino)-3-carbamoyloxymeth~lceph-3-em-4-
carboxylate
7-(p-nitrobenzyloxycarbonylamino)-3-carbamoyloxymethyl-ceph-3-
em-4-carboxylic acid was esterified according to example 2.
Example 14
N-phthaloylcephalosporin C bis-phthalidyl ester
N-phthaloylcephalosporin C as the di-sodlum salt (5m mole) was
esterified as ln example 1 using iodophthalide (from 15m mole of bromophthalide)0
After 10 minutes the bis phthalidyl ester (2.3g) precipitated on the addition
of ice-water.
Example 15
(a) Phthalidyl 7-D~-t-butyloxycarbonylam-l~ophenylacetamido-3-carbamoylo~y-
methyl-3-ce~hem-4~carboxylate
A solution of 7-D-~-t-butyloxycarbonylaminophenylacetamido-3-
- 14 -
.
,. : - ,
,
~L~'7~6~Zl
carbamoyloxymethyl-3-cephem-4-carboxyllc acld (1.02g., 2m mole) in dimethyl
sulphoxide (16 ml) ls treated with triethylamine (0.28 ml., 2m mole) and a
freshly prepared solution of iodophthalide (3m mole) in acetonitrile (8 mls)
is added. After 15 mins. at 20 ice-water is added and the solid collected.
A solution of the later in ethyl acetate is washed with dilute sodium bi-
carbonate, water, dried and evaporated. Precipitation of the residue from
ethyl acetate-petrol ether gives the desired ester (1.5g.).
(b) Phthalidyl 7-D-o~aminophenylacetamido-3-carbamoyloxy~ethyl-3-cephem-4
carboxylate
The foregoing crude ester (1.6g.) is treated with chilled tri-
fluoracetic acid (15 mls) over 40 mins. Evaporation and trituration with
ether gives the title compound as its trifluoracetate (1.5g.). This shows
one ma~or zone on biochromatography Rf = 0.75 in n-Butanol-ethanol-water.
'
~ 15
