CA1071621A - Process for preparing 7-aminocephalosporanic acid derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
The use of an iodolactone as an esterifying derivative in the preparation of lactonyl esters of cephalosporins substantially reduces double bond migration during the esterification reaction.

Description

~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) 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 :. :
.
.

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 ~ -- . , , .. . .

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) 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.

.. ~. , ~
, ... .. ..

~ .

~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:

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:-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%).

' ': ' ' ' ..
. . ............................... .
' ' ., ' ` . ' ' ' . ''.' ' ' ' ~ ', ~' ' ''' ' - : . - .
.: - : .
.
.

~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, -: , . . .
- -~ , -~ ~'.- ~. -, . .' : ' - - : , - - : : .
- ' , ' , ' ' ~'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, ' ' ~ .
.

~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-.
,. : - , , ~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

Claims (13)

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

1. A process for the preparation of a compound of formula (IA) wherein X and Y are the same or different and cach represen-ts oxygen or sulphur;
Z represents the resiclue of a lactone, thiolactone or dithiolactone ring system;
R represents hydrogen or an al.kyl, alkenyl, alkynyl, aryl or aralkyl group;

A is hydrogen, acetoxy; carbamoyloxy or a group;
- S - Het, wherein 'Het' is a five or six membered heterocyclic ring con-taining from one to four atoms selected from N, O and S unsubsti-tuted or substituted with one or two groups selected from lower alkyl, lower alkenyl, lower alkoxy, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, trifluoromethyl, hydroxy, or halogen;
R1 is an amino group, an organic acylamino group, or a group of formula or a group of formula:

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 or a reactive esterifying derivative thereof, with a compound of formula:

and recovering the required compound of formula (IA).

2. A process as claimed in claim 1 wherein Z is 1,2-pheny]-ene which may carry one ox more substituents selected fro-m alkoxy, nitro or halogen.

3. A process as claimed in claim 2, wherein Z is 1,2-phenyl-ene.

.

4. A process as claimed in claim 3 wherein X and Y are both oxygen.

5. A process as claimed in any one of claims 1, 3 or 4 wherein the gxoup R is hydrogen, methyl or phenyl.

6. A process as claimed in claim 1 wherein 'Het' is an unsùbstituted or the substituted 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3,4-tetrazolyl, oxazolyl, thiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl or 1,2,4-thiadiazolyl.

7. A process as claimed in claim 6 wherein the group A is 2-methyl-1,3,4-thiadiazolyl-5-thio, 1-methyl-(lH)-1,2,3,4-tetrazolyl-5-thio, 2-methyl-1,3,4-oxadiazolyl-5-thio or (1H)-1,3,4-triazolyl-5-thio.

8. A process as claimed in claim 1 wherein R1 is an organic acylamino group.

9. A process as claimed in claim 8 wherein R1 is 2-thienyl-acetamido, phenylacetamido, 2-hydroxyphenylacetamido, 2-amino-phenylacetamido, 4-pyridylacetamido, 2-amino-p-hydroxyphenyl-acetamido 1-tetlazolylacetamldo or w-aminoadipamido.

10. A process for the preparation of the ester phthalidyl 2-thienylacetamidocephalosporanate which comprises reacting iodo-phthalide with 2-thienylacetamidocephalosporanic acid in a solvent and recovering the required ester.

11. A process for the preparation of the ester phthalidyl 7-aminocephalosporanate which comprises reacting iodophthalide with sodium 7-N-(3-methoxycarbonyl-prop-2-en-2-yl)aminocephalo-sporanate in a solvent to form phthalidyl 7-N-(3-methoxycarbonyl-prop-2-en-2-yl)aminocephalosporanate and after removal of the protecting group in the 7 position recovering the required ester.

12. A process for the preparation of N-phtahloylcephalo-sporin C bis-phthalidyl ester which comprises reacting iodo-phthalide in a solvent with the disodium salt of N-phthaloyl-cephalosporin C and recovering the required ester.

13. A process for the preparation of the ester phthalidyl, 7-D-.alpha.-t-butoxycarbonylatminophenylacetamido-3-carbamoyloxy-methyl 3-cephem-4-carboxylate which comprises reacting iodophthalide in a solvent with triethlammonium 7-D-.alpha.-t-butyloxycarbonylamino-phenylacetamido-3-carboyloxymethyl-3-cephem-4-carboxylate and recovering the required ester.