ANTIBACTERIAL AZETIDINONE DERIVATIVES

DERIVES ANTIBACTERIENS DE L'AZETIDINONE

English Abstract

ABSTRACT OF THE DISCLOSURE
The present invention relates to novel .beta.-lactam containing compounds
and to their preparation, and the applicant has previously disclosed that
compounds of the formulae (I) and (II):
<IMG>
(I) (II)
and their salts and esters are .beta.-lactamase inhibitors. A further group of
compounds which have intrinsic .beta.-lactamase inhibitory properties has now been
discovered and the new compounds are also useful intermediates in the prepara-
tion of the compound of the formula (II) and its salts and esters. Hence the
present invention provides compounds of the formula (III):
<IMG>
(III)
wherein R1 is an acyl group and salts and esters thereof.
The group R1 in the above formula may represent a wide variety of
acyl groups of the formula R2CO which may contain up to 16 carbon atoms,
although in general, it more suitably contains up to 12 carbon atoms and is
an acyl group found in the acylamino side chain of the known antibacterially
active penicillins and cephalosporins.
The present invention also provides a process for the preparation
of compounds of the formula (III) as hereinbefore described and salts and
esters thereof which process comprises acylation of the corresponding compound
of the formula (I) as hereinbefore described or salt or ester thereof with
a compound of the formula (V):

R2 - CO2H (V)
or a reactive acylating derivative thereof wherein R2-CO2H is an organic
carboxylic acid.

Claims

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 the
general formula (III)
<IMG> (III)
and pharmaceutically acceptable salts and esters thereof wherein
R1 is an acyl group of the formula R2CO which may contain up to
16 carbon atoms which comprises
(a) the acylation of a compound of the formula (I)
<IMG>
(I)
or a pharmaceutically acceptable salt or ester thereof with a
compound of the formula (V)
R2-CO2H or an acylating derivative thereof R2-CO-X
where X is halogen, pseudohalide, acyloxy, sulphonyloxy or a group
formed by condensation of R2-CO2H with a carbodiimide, and R2-CO2H
is an organic carboxylic acid of up to 16 carbon atoms and
recovering said compound of formula (I) or a pharmaceutically
acceptable salt or ester thereof, or
(b) to prepare a compound of formula (III) or a
pharmaceutically acceptable salt thereof, the hydrogenation of
a compound of the formula (VI)
<IMG> (VI)
16

wherein R2CO is an acyl group containing up to 16 carbon atoms
and R12 is benzyl, methoxybenzyl, benzhydryl, or dimethoxybenz-
hydryl, in a solvent containing an ether, and recovering said
compound of formula (III) or where required preparing a
pharmaceutically acceptable salt thereof.
2. A process as claimed in claim 1 (a) which comprises the
reaction of an ester of the compound of the formula (I) with the
acid of the formula (V) in the presence of a condensation promoting
agent.
3. A process as claimed in claim 2 wherein the condensation
promoting agent is a carbodiimide or a carbodiimidazole.
4. A process as claimed in claim 2 wherein the condensation
promoting agent is dicyclohexyldicarbodiimide.
5. A process as claimed in claim 1 (a) which process
comprises the reaction of a salt of the compound of the formula
(I) with an acid anhydride of the formula R2.CO.O.COR2.
6. A process as claimed in claim 1 (b) wherein the ether
is tetrahydrofuran.
7. A process as claimed in claim 6 wherein the hydro-
genolysable group is a benzyl group.
8. A compound of the formula (III)
<IMG> (III)
wherein R1 is an acyl group of the formula R2CO which may contain
up to 16 carbon atoms, and pharmaceutically acceptable salts
thereof when prepared by the process of claim 1 (a) or 1 (b) and
esters thereof when prepared by the process of claim 1 (a) or an
obvious chemical equivalent.
17

9. A compound of the formula (III)
<IMG> (III)
wherein R1 is an acyl group of the formula R2CO which may contain
up to 16 carbon atoms and pharmaceutically acceptable salts
and esters thereof when prepared by the process of claim 3, 4 or
5 or an obvious chemical equivalent.
10. A compound of the formula (III)
<IMG> (III)
wherein R1 is an acyl group of the formula R2CO which may contain
up to 16 carbon atoms and pharmaceutically acceptable salts thereof
when prepared by the process of claim 6 or 7 or an obvious
chemical equivalent.
18

11. A process as claimed in claim 1 for the preparation of
a compound of the general formula (III) as set forth therein and
pharmaceutically acceptable salts thereof, wherein R1 is selected
from groups of the formula CO-R2, wherein R2 is an alkyl, alkenyl
or alkynyl group of up to 12 carbon atoms or such a group substitut-
ed by one, two or three inert substituents selected from phenyl,
phenoxy or inertly substituted phenyl or phenoxy groups or by
C2-8 ester, or lower alkoxy groups or by fluorine or chlorine
atoms, wherein the reactants are chosen such that R2 is as defined
above, X and R12 are as defined in claim 1.
12. A process as claimed in claim 1 for the preparation
of a compound of the general formula (III) as set forth therein
and pharmaceutically acceptable salts thereof, wherein R1 is
selected from groups of the formula CO.R2, wherein R2 is an acyl
group of the formula (a)
<IMG> (a)
wherein n is 0 or an integer from 1 to 6; R3 is a hydrogen atom
or a phenyl or phenoxy group; R4 is a hydrogen or halogen atom or a
lower alkyl, lower alkoxy or -CO2R5 group, where R5 is a hydrocarbon
group of 1 to 8 carbon atoms, wherein the reactants are chosen
such that R2 is as defined above and X and R12 are as defined in
claim 1.
13. A process as claimed in claim 12 for the
preparation of a compound of the general formula (III) as set
forth therein and pharmaceutically acceptable salts thereof,
wherein the formula (a) is defined so that n is 0 or an integer
from 1 to 3; R3 is a hydrogen atom or a phenyl or phenoxy group
and R4 is a hydrogen atom or CO2R5 group, where R5 is a phenyl,
19

benzyl or benzhydryl group and the reactants are chosen such that
R2 is defined in accordance with the above definition and X and
R12 are as defined in claim 12.
14. A process as claimed in claim 1 for the preparation of
a compound of the general formula (III) as set forth in claim 1
and pharmaceutically acceptable salts thereof, wherein R1 is
selected from groups of the formula -CO-R6, wherein R6 is a
methyl group or a methyl group substituted by a C1-3 alkyl group,
a phenyl or a phenoxy group or by a phenyl group and an ester group
-CO2R7, wherein R7 is a phenyl, benzyl or benzhydryl group and the
reactants are chosen so that R2 has the meaning of R6 and X and
R12 are as defined in claim 1.
15. A process as claimed in claim 1 wherein the pharmaceutic-
ally acceptable salts of the compounds of the formula (III) set
forth and defined therein are selected from sodium, potassium,
calcium and magnesium salts and these salts are recovered or the
free compounds of formula (III) are converted thereto.
16. A process as claimed in claim 1 for the preparation of
compounds of the formula (IV)
<IMG> (IV)
and pharmaceutically acceptable salts thereof, wherein R1 is as
defined as it is for formula (III) in claim 1 and R8 is selected
from C1-4 alkyl groups, phenyl, benzyl or benzhydryl groups or
those of the formula -CH2R , wherein R9 is pivaloyloxy or
phthalimidyl or C1-4 alkyl group substituted by a thioalkyl group

containing up to 4 carbon atoms or by a sulphonic acid group
-SO2R10, wherein R10 is a methyl, phenyl or tolyl group, wherein
the reactants are chosen so that R2CO is as defined in claim 1
and R12 has the same meaning as R8.
17. A process as claimed in claim 16 for the preparation
of compounds of the formula (IV) set forth therein and
pharmaceutically acceptable salts thereof, wherein R8 is selected
from phenyl, benzyl, benzhydryl, phthalimidylmethyl or pivaloyloxy
methyl groups and those of the formula CH2CH2SR11, wherein R11 is
a C1-4 alkyl group and CH2CH2SO2R10, wherein R10 is a methyl,
phenyl or tolyl group and the reactants are chosen so that R2CO
is as defined in claim 1 and R12 has the same meaning as R8.
18. A process for the preparation of benzyl phenoxyacetyl-
clavulanate which comprises treating benzyl clavulanate with
phenoxyacetic acid and subsequently with dicyclohexyldicarbodiimide.
19. A process for the preparation of compounds of the
general formula
<IMG>
wherein R00 and R0 are selected from the following combinations:
21

<IMG>
which comprises reacting a clavulanic ester of the formula
<IMG>
wherein R00 is as defined above, in the presence of dry methylene
chloride with a compound of the formula RO.CO2H wherein R0 is as
defined above, in the presence of dicyclohexylcarbodiimide.
22

20. A process for the preparation of compounds of the
general formula
<IMG>
wherein R00 and R0 are selected from the following combinations:
<IMG>
which comprises reacting a clavulanic ester of the formula
<IMG>
wherein R00 is as defined above, in the presence of dry methylene
chloride or dry acetone with a compound of the formula R0.CO2H,
wherein R0 is as defined above, in the presence of pyridine and
dicyclohexylcarbodiimide.
21. A process for the preparation of sodium 3-(2'-
acetoxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3,2,.0]heptane-2-
carboxylate which comprises reacting sodium clavulanate with
acetic anhydride.
22. A process for the preparation of 3[2'-(phenylmonophenyl-
malanoxy)ethylidene]-7-oxo-4-oxa-1-azabicyclo[3,2,0]heptane-2-
carboxylic acid and its methyl ester which comprises hydrogenating
an ester of the formula
23

<IMG>
and when the methyl ester is required, the hydrogenation product
is treated with diazomethane.
23. A compound of the general formula (III) as set forth
in claim 1 and defined in claim 11 and pharmaceutically acceptable
salts thereof whenever prepared by the process of claim 11 or an
obvious chemical equivalent thereof.
24. A compound of the general formula (III) as set forth in
claim 1 and defined in claim 12 and pharmaceutically acceptable
salts thereof whenever prepared by the process of claim 12 or an
obvious chemical equivalent thereof.
25. A compound of the general formula (III) as set forth in
claim 12 and defined in claim 13 and pharmaceutically acceptable
salts thereof whenever prepared by the process of claim 13 or an
obvious chemical equivalent thereof.
26. A compound of the general formula (III) as set forth in
claim 1 and defined in claim 14 and pharmaceutically acceptable
salts thereof whenever prepared by the process of claim 14 or an
obvious chemical equivalent thereof.
27. Pharmaceutically acceptable salts of the compounds of
the general formula (III) as set forth and defined in claim 1
selected from sodium, potassium, calcium and magnesium salts
whenever prepared by the process of claim 15 or an obvious
chemical equivalent thereof.
28. Compounds of the formula (IV) as set forth and defined
in claim 16 and pharmaceutically acceptable salts thereof
24

whenever prepared by the process of claim 16 or an obvious chemical
equivalent thereof.
29. Compounds of the formula (IV) as set forth in claim 16
and defined in claim 17 and pharmaceutically acceptable salts
thereof whenever prepared by the process of claim 17 or an obvious
chemical equivalent thereof.
30. Benzyl phenoxyacetyl-clavulanate whenever prepared by
the process of claim 18 or an obvious chemical equivalent thereof.
31. Compounds of the general formula set forth and defined
in claim 19 whenever prepared by the process of claim 19 or an
obvious chemical equivalent thereof.
32. Compounds of the general formula set forth and defined
in claim 20 whenever prepared by the process of claim 20 or an
obvious chemical equivalent thereof.
33. Sodium 3-(2'-acetoxyethylidene)-7-oxo-4-oxa-1-
azabicyclo[3,2,0]heptane-2-carboxylate whenever prepared by the
process of claim 21 or an obvious chemical equivalent thereof.
34. 3[2'-(phenylmonophenylmalanoxy)ethylidene]-7-oxo-4-
oxa-1-azabicyclo[3,2,0]heptane-2-carboxylic acid and its methyl
ester whenever prepared by the process of claim 22 or an obvious
chemical equivalent thereof.

Description

1053681
The present invention relates to novel ~-lactam containing
compounds and to their preparation,
Canadian Patent Application Nos, 224,970 and 250,165 disclose
inter alia that compounds of the formulae (I) and (II):
~O > ~ H20H
N
C02H C02H
(I)
and their salts and esters are ~-lactamase inhibitors, A further group of
compounds which have intrinsic ~-lactamase inhibitory properties has now been
discovered, These new compounds are also useful intermediates in the prepara-
tion of the compound of the formula (II) and its salts and esters.
The present invention provides compounds of the formuls (III):
~-- > f :H2-OR
N
C02H (III)
wherein R1 is an acyl group and salts and esters thereof.
The group Rl in the above formula may represent a wide variety
of acyl groups of the formula R C0 which may contain up to 16 carbon atoms,
although in general, it more suitably contains up to 12 carbon atoms and is
an acyl group found in the acylamino side chain of the known antibacterially
active penicillins and cephalosporins.
Most suitably the group R1 does not contain any highly reactive
substituents, Thus particularly suitable values for R include groups of the

1053681
formula CO.R where R is an hydrocarbon group of up to 12 carbon atoms which
is unsubstituted or substituted only by inert groups such as lower alkoxy, lower
acyloxy, fluorine or chlorine atoms or the like. Most suitably R2 is an alkyl,
alkenyl or alkynyl group of up to 12 carbon atoms or such a group substituted
by one, two or three inert substituents such as phenyl, ph-enoxy or inertly
substituted phenyl or phenoxy groups or by C2 8 ester, or lower alkoxy groups
or by fluorine or chlorine atoms.
Suitable acyl groups include these of the sub-formula (a):
- co - fH - (CH2)n - R (a)
R
wherein n is 0 or an integer from 1 to 6; R3 is a hydrogen atom or a phenyl or
phenoxy group; and R4 is an hydrogen or halogen atom or a lower alkyl, lower
alkoxy or C02R5 group where R5 is an hydrocarbon group of 1 to 8 carbon atoms.
Suitably n is O or an integer from 1 to 3; R3 is an hydrogen
atom or a phenyl or phenoxy group and R is an hydrogen atom or C02R5 group
where R5 is a phenyl, benzyl or benzhydryl group.
Preferred acyl groups include those of the sub-formula
- CO - R6, wherein R6 is a methyl group or a methyl group substituted by a
Cl 3 alkyl group, a phenyl or a phenoxy group or by a phenyl group and an
ester group Co2R7 wherein R7 is a phenyl, benzyl or benzhydryl group.
When used herein the term "lower" means that a group has 1 to
6 carbon atoms.
The compounds of the formula (III) and their pharmaceutically
acceptable salts form a highly suitable aspect of this invention.
Suitable salts of the compounds of formula (III) include the
sodium, potassium, calcium, magnesium and other conventional pharmaceutically
acceptable salts.
-- 2 --

1053681
The sodium and potassium salts of the compounds of formula (III)
are particularly suitable.
Suitable esters of the compounds of the formula (III) include
those of the formula (IV):
,,J~--> /~ H2-R
N ~ (IV)
C02R
wherein R1 is as defined in relation to formula (III) and R is an organic
group.
Suitable groups include hydrocarbon groups of 1 to 12 carbon
atoms optionally substituted by halogen, lower alkoxy, lower acyloxy, or the
like.
Highly suitable groups R8 include C1 4 alkyl groups, phenyl,
benzyl or benzhydryl groups or those of the formula -CH2R9 wherein R9 is
pivaloyloxy or phthalimidyl or Cl 4 alkyl group substituted by a thioalkyl
group containing up to 4 carbon atoms or by a sulphonic acid group -S02R
wherein R10 i8 a methyl, phenyl or tolyl group.
Preferred groups R8 include phenyl, benzyl, benzhydryl,
phthalimidylmethyl or pivaloyloxymethyl groups and those of the formula
CH2CH2SR11, wherein Rll_is a Cl 4 alkyl group and CH2CH2S02R10 wherein R10 is
a methyl, phenyl or tolyl group.
The present invention also provides a process for the prepara-
tion of compounds of the formula (III) as hereinbefore described and salts and
esters thereof which process comprises acylation of the corresponding compound
of the formula (I) as hereinbefore described or salt or ester thereof with a
compound of the formula (V):
:

1053681
R - C02H (V)
or a reactive acylating derivative thereof wherein R2-C02H is an organic
carboxylic acid.
The acylation reaction may be carried out by conventional mild
acylation techniques such as by the reaction with the free acid (V) in the
presence of a condensation promoting agent or by the reaction with an acylating
derivative R2-C0-X in conventional solvent where R2 is as defined in relation
to formulae (V) and X is a good leaving group readily displaced by a nucleophile.
Suitable groups X include halogen atoms, pseudohalides, acyloxy
groups, sulphonyloxy groups or groups formed by condensation of a compound of
the formula (V) with a carbodiimide or like dehydrating agent.
Suitable acylating agents will be similar to those used in the
preparation of penicillins or cephalosporins from 6-aminopenicillanic acid or
7-aminocephalosporanic acid. However, the ~-lactam ring in compounds of
formula (III) are frequently more reactive than those of many penicillins or
cephalosporins so that in general particularly mild reaction conditions are
preferred.
Generally the acylation reaction of this invention is carried
out in an inert organic solvent. Suitable solvents include chloroform,
methylene chloride, tetrahydrofuran, dimethylformamide, dimethysulphoxide,
acetone and the like.
Generally the acylation reaction of this invention is carried
out at a non-extreme temperature, for example, at ambient or slightly depressed
temperatures, such as in the range -20C to +20C, for example, -5C to +5C.
Acylation reactions are often carried out in the presence of
an acid acceptor which serves the purpose of removing any acid generated during
the reaction. The choice of acid acceptor will be determined by the desire to
''
'

1053681
cause minimal reaction between the acid acceptor and the com~ound being acylated
and such a choice will be routine to those skilled in the art.
Pyridine has been found to be a suitable acid acceptor for use
in the preparation of several of the compounds of the formula (III).
A particularly convenient method of acylating esters of the
compounds of the formula (I) comprises the reaction of the ester of the compound
of formula (I) with an acid R C02H in the presence of a condensation promoting
agent such as a carbodiimide, carbodiimidazole or the like agent.
A particularly suitable condensatio~ promoting agent is
dicyclohexyldicarbodiimide.
Such reactions are generally carried out in inert solvents at
non-extreme temperatures, for example, in methylene chloride at ambient or a
slightly depressed temperature.
A particularly convenient method of acylating salts of the
compounds of the formula (I) comprises the reaction of the salt of the compound
of the formula (I) with an acid anhydride of the formula R .CO.O.CO.R .
Such reactions are normally carried out at a depressed tempera-
ture, for example, about 0C. When the anhydride is liquid at such temperatures
it may be used as the solvent for the reaction, excess anhydride being evaporated
off after the completion of the reaction. If the anhydride is not liquid at
the desired temperature an inert organic solvent may be employed.
A particularly suitable method of providing the compounds of
the formula (III) or their salts comprises the hydrogenation of a compound of
the formula (VI):
~ f H20 - CO - E~
(Vl)
C0 - O - R
' '' ' ' ~
' ' .

105368~
wherein Rl is a hydrogenolysable group in a solvent containing an ether.
Most suitably the solvent contains tetrahydrofuran.
Preferably the solvent consists of tetrahydrofuran.
Typical hydrogenolysable groups include benzyl, inertly sub-
stituted benzyl such as methoxybenzyl, benzhydryl, dimethoxybenzhydryl and
like groups.
The preferred group R is the benzyl group.
The reaction is most suitably carried out at a non-extreme
temperature such as 0 - 30C, more suitably 5 - 20C.
The hydrogenation normally takes place in the presence of a
transition metal catalyst such as palladium, for example 10% palladium on
charcoal. The catalyst is usual]y present at about 1/3 the weight of compound
of the formula (VI).
The salts of the compounds of the formula (III) may be pre-
pared by careful treatment with base in conventional manner.
In a composition aspect the present invention provides a pharma-
ceutical composition which comprises a compound of the formula (III) as herein-
before defined or a salt or ester thereof. Such compositions will also comprise
a pharm8ceutically acceptable carrier in accordance with conventional pharma-
ceutical practice.
Such compositions may also include penicillins or cephalosporins
if desired such as ampicillin, amoxycillin and the like.
The compositions of this invention will normally be adapted for
administration to humans and other mammals, for example, in conventional modes
of treatment of diseases of the skin or of the urinary tract.
Suitable forms of the compositions of this invention include
tablets, capsules, solutions or creams for topical application, syrups,
suspensions, reconstitutable powders and sterile forms suitable for injection
- 6 -

1053681
or infusion. Such compositions may contain conventional pharmaceutically
acceptable materials such as diluents, binders, colours, flavours, preservatives,
disintegrants, and the like in accordance with conventional pharmaceutical
practice.
EXAMPLE 1
Benzyl phenoxyacetylclavulanate
Benzyl clavulanate (57.8mg) in dry methylene chloride (2ml)
was treated with phenoxyacetic acid (30.5mg) and the solution was cooled to
O C. Dicyclohexyldicarbodiimide (90.6mg; 2 equiv.) was added and the stirred
solution was allowed to warm to room temperature. The reaction mixture was
stirred for a further 15 hours at ambient temperature. Fractionation on silica
gel, eluting with ethyl acetate-hexane (1:4) gave benzyl phenoxyacetylclavulanate
(23mg) as a colourless oil; ir (film) 1800, 1750, 1690 cm , n.m.r. (CDC13) as
in Figure 1. Further elution with ethyl acetate gave recovered starting
material (29mg).
A sample of the above prepared material was found to have the
following I50 values against ~-lactamases on a standard enzyme inhibitory
asOEay:
Organism: E. coli JT4 E. coli JT410 staph. aureas Russell
Iso ~g/ml): 2.5 1.5 7.5
EXAMPLE 2
General Method B
~ CUzO~

105368~
The ciavulanic acid ester (200mg) was dissolved in dry methylene chloride or
dry acetone (lml) and cooled to 0C. Pyridine (1 equivalent) was added followed
by the acylating acid (1 equivalent) and dicyclohexylcarbodiimide (1 equivalent).
The reaction mixture was stirred for 15 hours at room temperature, filtered
and purified on a silica gel column (about 2g of silica per 100 mg of compound)
by gradient chromatography using petrol/ethyl acetate (4:1). Evaporation of
the solvents from the collected materials yields the desired product generally
as an oil.
General Method A
The clavulanic acid ester (200mg) was dissolved in dry methyleDe chloride (lml)
and cooled to -10C to 0C. The acylating acid (1 equivalent) was added
followed by dicyclohexylcarbodiimide (1 eguivalent) and the reaction stirred
for 15 hours at room temperature, filtered and purified either by gradient
chromatography as described above or by high pressure liquid chromatography
(h.p.l.c.) using cyclohexane/ethyl acetate (2:1) as eluant.
The following compounds were prepared by the preceeding processes.

1053681
~ ¢~^ ~ a~ ~ `D
R ____
R ,,
:~ R ,, ~sl ~ ~ o:l ~':
~o~yi L ¦ ~ ¦ R ¦ ¦ R
P~ 1~ ~ ~4 ~ ~0
- . - : . ' .: . ~ . - ' .
- ' ' ' . '~ . : - :
' ' ' '" ', - ' ' ' ' ,
' ' , '' - - :
~

1053681
i~
._ .
~r~ ~ ~ ~ U ~1
~ ~ ~0 ~0 O ~ ~ -01
C~ C~ ~ ~ :~
~0~
¢ ¢ ¢ ¢ ~tl
_ r ~ V
~ c~ C~ ~ C~ ~ F~
~ C~ 5:_0~ C C~_0~ C
o,y; ~_8
. . . _
o </~ ~ ~ ~ ~, r a
0~ O~ ~ ~~ ~N C~ C~ ~~
Z~ C N ~ i~ ~ ~ O
~ _
~ ~0 .C ~ ~r~ ~ _l O
-- 10 --

1053681
The physical characterising data for the preceeding compounds
is as follows:
a
Ir. (CIIC13) 1800 ~-lactam Cz0) 1750 (br. ester C=O and O-acyl C=0), 1695 (C=C)
n.m.r. (CDC13) 3.04 (lH, d, J = 17Hz, 6~-CH), 3.56 (lH, dd, J = 17Hz, J' =
2.5Hz, 6a-CH)~ 4.66 (2H, s, CH2OPh), 4.86 (3H, m, =CHCH2), 5.17 ~lH, s, 3-CH),
5.25 (2H, s, CH2Ph), 5.76 (lH~ d, J = 2.5Hz), 6.8 - 7.5 (lOH, m. CH2Ph and
OPh).
b
Ir. (CHC13) 1800 ~-lactam C=O), 1735 cm (br, ester C=0~ O-acyl C=0); n.m.r.
(CDC13) 3.08 (lH, d, J = 17Hz, 6~-CH), 3.55 (lH, dd, J = 17Hz, J' = 2.5Hz,
6~-CH), 4.79 (H, s, CHPh), 4.82 (3H, m, -C_C_2O), 5.13 (lH, s, CHC02Bz), 5.27
(4H, s, OCH2Ph x 2), 5.75 (lH, d, J = 2.5Hz, SCH), 7.50 (lSH, s, CH2Ph x 2
and CHPh); m.w. (mass spectrometry gave 542 which corresponds to C31H27HO8
(~+1)+.
c
Ir. (CHC13) 1800 ~-lactam C=0), 1735 cm (br, ester C=0 and 0-acyl C=0);
n.m.r. (CDC13) 3.03 (lH, d, J = 17Hz, ~-CH), 3.53 (lH, dd, J = 17Hz, J' =
2.5Hz, 6~-CH), 4.9 (4H, m, =C_C-2 and CHPh), 5.15 (lH, s, CHC02Bz), 5.23
(2H, s, CH2Ph), 5.75 (lH, d, J = 2.5Hz, 5-CH), 7.0 - 7.7~ (15H, m, aromatic
protons).
-
Ir. (CHC13) 1800 ~ lactam C-0), 1735 cm (br, ester C=0 and 0-acyl C=0);
n.m.r. (CDC13) 2.08 (3H, s, OC0CH3), 3.13 (lH, d, J = 17HZ, 6~-CH), 3.60
(lH, dd, J ~ 17Hz, J' = 2.5Hz, 6R-CH), 4.55 - 5.00 (3H, m, -C_CH2), 5.18
(lH, s, CHCO2Bz), 5.28 (2H9 s, CO2C_2Ph), 5.80 (lH, d, J = 2.5Hz, S-CH),
7-47S (5H, s, C02CH2Ph).
,. ,~ . ~. , , ., . , " ... . . ... . .

lOS3681
e
Ir. (CHC13) 1804 ~-lactam C~O~, 1765 (ester CeO and O-acyl CGO), 1695 cm
(C=C); n.m.r. (CDC13) 3.15 (lH, d. J = 17Hz, 6~-CH), 3.65 (lH, dd, J = 17Hz,
6a-CH), 4.7 (2H, s, CH20Ph), 4.75 - 5.4 (4H, complex pattern for -CH.C_2 and
CHC02Ph), 5.86 (lH, d, J = 2.5Hz, 5-CH), 6.85 - 7.7~ (lOH, m, aromatic protons).
f
Ir. (CHC13) 1805 ~-lactam C=O), 1760 and 1730 (ester C=O and O-acyl C=O),
1700 cm (C=C); n.m.r. 3.12 (lH, d, J = 17Hz, 6~-CH), 3.58 (lH, dd, J = 17Hz,
J' = 2.5Hz, 6q-CH), 4.7 - 5.2 (4H, m, -C_CH2 and CHPh), 5.28 (2H, s, C02CH2Ph),
5.33 (lH, s, CHC02Bz), 5.81 (lH, d, J = 2.5Hz, 5-CH), 7.05 - 7.7~ (15H, m,
aromatic protons).
g
Ir. (CHC13), 1805 ~-lactam C=O), 1790 (phthalimido C=O), 1740 cm 1 (br, ester
C=O and O-acyl C=O); n.m.r. 3.0 (lH, d, J = 17Hz, 6~-CH), 3.52 (lH, dd, J =
17Hz, J' = 2.5Hz, 6~-CH), 4.72 (lH, s, CHPh), 4.78 (3H, m, =CHC_2), 5.08 (lH,
s, 3-CH), 5-25 (2H, s, C02CH2Ph), 5.71 (lH, d, J = 2.5Hz, 5-CH), 5.82 (2H, s,
C02CH2Phth), 7.0 - 7.43 (lOH, m, aromatic protons), 7.65 - 8.2~ (4H, m, Phth).
h
Ir. (CHC13) 1805 ~-lactam C=O) 1755 (br, ester C=O and O-acyl C=O), 1700 cm 1
(CeC); n.m.r. 2.18 (3H, s, SC_3)? 2.78 (2H, t, J = 7.5Hz, CH2SCH3), 3-12
(lH, d, J = 17Hz, 6~-CH), 3.62 (lH, dd, J = 17Hz, J' = 2.5Hz, 6~-CH), 4.41
(2H, t, J = 7.5Hz, CH2CH2SCH3), 4.71 (2H, s, CH20Ph), 4.92 (3H, m, =C_CH2),
5.18 (lH, s, 3-CH), 5.81 (lH, d, J = 2.5Hz, 5-CH), 6.85 - 7.6J (5H, m, CH20Ph).
i
Ir. (CHC13) 1800 ~-lactam C=O), 1740 cm 1 (br, ester C=O and O-acyl C=O);
n.m.r. (CDC13), 2.13 (3H, s, SCH3), 2.74 (2H, t, J = 7.5Hz, CH2SCH3), 3.03
(lH, d, J = 17Hz, 6~-CH), 3.52 (lH, dd, J ~ 17Hz, J' = 2.5Hz, 6~-CH), 4.35 (2H,
t, J = 7.5Hz, CH2CH2SCH3), 4.72 (lH, s, CHPh), 4.82 (3H, m, =C_CH2),
- 12 -

1053681
5.10 (lH, s, 3-CH), 5.25 (2H, s, CH2Ph), 5.71 (lH, d, J - 2.5Hz, 5-CH), 7.42
and 7.48 (lOH, 2 singlets, aromatic protons).
Ir. (CHC13) 1805 ~-lacta~ C=0), 1760 (br, ester C=O and acyl C=0(x 2)),
1700 cm (C=C); n.m.r. (CDC13) 1.22 (9H, s, C(CH3)3), 3.08 (lH, d, J = 17Hz,
6~-CH), 3.57 (lH, dd, J = 17Hz, J' = 2.5Hz, 6~-CH), 4.60 (2H, s, CH2OPh),
4.80 (3H, m, =C_CH2), 5.08 (lH, s, 3-CH), 5.72 (lH, d, J = 2.5Hz, 5-CH),
5.80 (2H, s, C020C0Bu+), 6.8 - 7.5S (4H, m, OPh).
k
Ir. (CHC13) 1805 ~-lactam C=O) 1755 (br, ester C=O and acyl C=O (x 2)),
1700 cm (C=C); n.m.r- (CDC13) 1.2 (9H, s, C(CH3)3), 3.00 (lH, d, J = 17Hz,
6~-CH), 3.50 (lH, dd, J = MHz, J' = 2.5Hz, 6~-CH), 4.67 (lH, s, CHPh), 4.75
(3H, m, -C_CH2), 5.05 (lH, s, 3-CH), 5.19 (2H, s, CH2Ph), 5.68 (lH, d, J =
2.5Hz, 5-CH), 5.78 (2H, s, CO2CH2oCOBu+j, 7.32 and 7.385 (lOH, 2 singlets,
aromatic protons).
Ir. (CHCl3) 1805 ~-lactam C=0), 1755 and 1735 (ester C=0 and 0-acyl C=0),
1700 (C-C), 1310 and 1150 (SO2); n.m.r. (CDC13) 3.08 (lH, s, J = 17Hz, 6~-OH),
3-5 (2H, t, J ~ 6Hz, CH2S02Ph), 3.55 (lH, dd, J - 17Hz, J' = 2.5Hz, 6~-CH),
4-53 (2H~ t, J ' 6Hz, CH2CH2S02Ph), 4-66 (2H, s, CH2OPh?, 4.82 (3H, m, =C_CH2),
4.89 (lH? s, 3CH), 5.72 (lH, d, J = 2.5Hz, 5-CH), 6.8 - 7.45~ (5H, m, CH2OPh),
7.5 - 8.2~ (5H, m, SO2Ph).
- 13 -
'

1053681
EXA~LE 3
Sodium 3-(2'-acetoxyethylidene)-7-oxo-4-oxa-1-azabicylo[3,2,0~ heptane-2-
carboxylate
CH20C CH3
N 1 0
C02Na C02Na
(e7) (e8)
Sodium clavulanate (e7)(250 mg) was added to acetic anhydride
(5 mls) cooled to 0 C and the mixture was stirred at 0 C for 2 hours and was
then left overnight at 0-5C. The acetic anhydride was evaporated under
reduced pressure and the residue chromatographed on silica gel (eluting with
BuOH/EtOH/H20; 16:4:7) to give the title compound (e8) as a white amorphous
solid.
The n.m.r. spectrum showed a shift in the signal due to the
ethylidene methylene protons and the appearance of a signal at~ 2.0 due to
o
the presence of a CH3 C-0- group.
EXAMPLE 4
3-~2'-(Phenylmonophenylmalanoxy)ethylidine~-7-oxo-4-oxa-1-azabicyclo[3,2,0~ -
heptane-2-carboxylic acid
H~-0-CO-cH-Co2c6Ns 0 CH~-0-C0-CH C0 C6N
CO - O - CH2C6H5 C02H
(e9) (elO)

1053681
The ester (e9) (60mgs) was dissolved in freshly distilled
tetrahydrofuran (5 mls). To this solution was added 10% palladium on charcoal
(20 mgs) and the mixture was hydrogenated at 15C under 1 atmosphere of hydrogen
for 15 minutes. The mixture was filtered at 0C and the filtrate evaporated
under reduced pressure to yield the title compound.
The methyl ester of the title compound may be prepared by
treating the filtered tetrahydrofuran solution with dia~omethane.
Description 1
Illustration of Use of Compound as Intermediates
The product of Example 1 (20 mgs) was dissolved in ethanol
containing 10% ethyl acetate (2ml total volume). Sodium bicarbonate (2 equi-
valents) was added and 10% palladium on charcoal (10 mgs). The solution was
then hydrogenated at ambient temperature and pressure for 15 minutes. The
catalyst was filtered off, washed well with water and the combined filtrate
plus washing evaporated to yield the sodium salt of deoxyclavulanic acid
! [the compound of formula (II~ in high yield.
.
'
-: . , - ~: : . -
. ~ , . - .
- . ~ -
': :"~ . ': '
, .