Note: Descriptions are shown in the official language in which they were submitted.
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
ARYLOXYMETHYL CARBAPENEM ANTIBACTERIALS
BACKGROUND OF THE INVENTION
The present invention relates to carbapenem
antibacterial agents in which the carbapenem nucleus is
substituted at t;he 2-position with an aryl platform, linked through
a CH2-O- group. The aryl platform is further substituted with
various substit,uent groups, typically including at least one
cationic group.
Th.e carbapenems of the present invention are useful
against gram positive microorganisms, especially methicillin
resistant Stapl:~ylococcus aureus (MRSA), methicillin resistant
Staphylococcus epidermidis (MRSE), and methicillin resistant
coagulase negative Staphylococci (MRCNS). The antibacterial
compounds of t:he present invention thus comprise an important
contribution to therapy for treating infections caused by these difficult
to control pathogens.
There is an increasing need for agents effective against
such pathogens (MRSA/MRCNS) which are at the same time
relatively free from undesirable side effects.
SUMMARY OF' THE NTION
The present invention relates to a compound represented
by formula I:
(R)s
P H H R
CH2 O
N~ X
O
C 02M '''
i
I ~R)s
or a salt or hydrate thereof, wherein:
CA 02304267 2000-03-14
WO 99/14217 PGT/US98/190I5
Rl represents H or methyl;
C02M represents a carboxylic acid, a carboxylate anion,
a pharmaceutically acceptable ester group or a carboxylic acid
protected by a protecting group;
1' represents hydrogen, hydroxyl, F or hydroxyl protected
by a hydroxyl-protecting group;
X is present or absent, and when present, represents
members selected from the group consisting of CH2, C(R) 2, C=CR2,
O, S(O)x, with x equal to 0, 1 or 2, C(O), C02, OCO and NR;
each R group is independently selected from: hydrogen;
halo; -CN; -NO2; -NRaRb; -ORc; -SRc; -C(O)NRaRb; -C(O)ORh; -
S(O)Rc; -S02Rc; -SO~NRaRb; -NRaS02Rb; -C(O)Ra; -OC(O)Ra; -
OC(O)NRaRb; -NRaC(O)NRbRc; -NRaC02Rh; -OCOZRh; -
NRaC(O)Rb; -~C1-g straight- or branched-chain alkyl, unsubstituted or
substituted with one to four Rd groups; -A-(CH2)n-Ca and -Cg-7
cycloalkyl, un~substituted or substituted with one to four Rd groups;
A represents O, S or -CH2-;
n represents an integer 0-3;
each Ra, Rb and Rc independently represents hydrogen,
-C1_g straight,- or branched-chain alkyl, unsubstituted or substituted
with one to four Rd groups, or -Cg_7 cycloalkyl, unsubstituted or
substituted with one to four Rd groups;
or Ra and Rb taken together with any intervening atoms
represent a 4-6 membered saturated ring optionally interrupted by
one or more of O, S, NRc, with Rc as defined above, or -C(O)-, said
ring being unsubstituted or substituted with one to four Ri groups;
o:r Rb and Rc taken together with any intervening atoms
represent a 4-6 membered saturated ring optionally interrupted by
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-3-
one to three of O, S, NRa, with Ra as defined above, or -C(O)-, said
ring being un.substituted or substituted with one to four Ri groups;
Each Rd independently represents halo; -CN; -N02; -
NReRf -ORg; -SRg; -~CONReRf -COORg; -SORg; -SOZRg; -S02NReRf
-NReSO2Rf -CORe; -NRe CORf -OCORe; -OCONReRf -
NReCONRfR.g; -NReCOZRh; -OC02Rh; -C(NRe)NRfRg; _
NReC(NH)NRfR,g or -NReC(NRf)Rg;
Re, Rf and Rg represent hydrogen; -R*; -C1-6 straight- or
branched-chain alkyl unsubstituted or substituted with one to four Ri
groups;
or Re and Rf taken together with any intervening atoms
represent a 4-6 membered saturated ring optionally interrupted by
one to three of O, S, -C(O)- or NRg with Rg as defined above, said ring
being unsubstituted or substituted with one to four Ri groups;
each Ri independently represents halo; -CN; -N02;
phenyl; -NHS02Rh; -ORh, -SRh; -N(Rh)2; -N+(Rh)3; -C(O)N(Rh)2; -
S02N(Rh)2; heteroaryl; heteroarylium; -C02Rh; -C(O)Rh; -OCORh; -
NHCORh; gu.anidinyl; carbamimidoyl or ureido;
each Rh independently represents hydrogen, a -C1-6
straight or branched-chain alkyl group; a -C3-C6 cycloalkyl group or
phenyl, or when two Rh groups are present, said Rh groups may be
taken in combination and represent a 4-6 membered saturated ring,
optionally interrupted by one or two of O, S, S02, -C(O)-, NH and
NCHg;
f~ is selected from the group consisting of
(CH2)b
o,s~a ~- o,b,~
-N i , -~N ii , ~--N~ a , ~..No N_Rx and ~NRXRyRZ
w~ ~ a~~
L~ (CH2)a
wherein:
a and b are 1, 2 or 3;
CA 02304267 2000-03-14
WO 99/14217 PCTNS98/19015
-4-
L. is a pharmaceutically acceptable counterion;
a, represents O, S or NRs;
Vii, b, ~,, ~, and a represent CRt, N or N+Rs, provided that
no more than one of ~3, 8, ~., ~. and a is N+Rs;
each Rs independently represents hydrogen; phenyl or -
C1_g straight- or branched-chain alkyl, unsubstituted or substituted
with one to four Ri groups;
each Rt independently represents hydrogen; halo;
phenyl; -CN; -N02; -NRuRv; -ORu; -SRu; -CONRuRv; -COORh; -
SORu; -S02Rt1; -S02NRuRv; -NRuS02Rv; -CORu; -NRuCORv; -
OCORu; -OCONRuR~'; -NRuC02Rv; -NRuCONRvRw; -OC02Rv; -C1_
g straight- or lbranched-chain alkyl, unsubstituted or substituted with
one to four Ri groups;
Ru and Rv represent hydrogen or -C 1_6 straight- or
branched-chain alkyl, unsubstituted or substituted with one to four Ri
groups;
or Ru and Rv together with any intervening atoms
represent a 4-6 membered saturated ring optionally interrupted by
one or more of O, S, NRw or -C(O)-, said ring being unsubstituted or
substituted with one to four Ri groups;
each Rw independently represents hydrogen; -C 1-6
straight- or branched-chain alkyl, unsubstituted or substituted with
one to four Rl groups; C3-g cycloalkyl optionally substituted with one
to four Rl groups; phenyl optionally substituted with one to four Ri
groups, or hete~roaryl optionally substituted with 1-4 Ri groups;
or' Rh and Rw taken together with any intervening atoms
represent a 5-Ei membered saturated ring, optionally interrupted by
one or two of O, S, 502, NH or NCHg;
R~'~ represents hydrogen or a C1_g straight- or branched-
chain alkyl, optionally interrupted by one or two of O, S, SO, 502,
NRw, N+RhR~~, or -C(O}-, said chain being unsubstituted or
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/190I5
-5-
substituted with one to four of halo, CN, N02, ORw, SRw, SORw,
S02Rw, NRhR~'~', N'f'(Rh)2R"°, -C(O)-R"", C(O)NRhRw, S02NRhRw,
C02Rw, OC(O)Rw, OC(O)NRhRw, NRhC(O)Rw, NRhC(O)NRhRw, or
a phenyl or heteroaryl group which is in turn optionally substituted
with from one to four Rl groups or with one to two C1_g straight- or
branched- chain alkyl groups, said alkyl groups being unsubstituted
or substituted with one to four Ri groups;
RY and RZ represent hydrogen; phenyl; -C 1-g straight or
branched chain alkyl, unsubstituted or substituted with one to four Ri
groups, and optionally interrupted by O, S, NRw, N+RhRw or
-C(O)-;
or RX and RY together with any intervening atoms
represent a 4-~6 membered saturated ring optionally interrupted by O,
S, 502, NRw , N+RhRw or -C(O)-, unsubstituted or substituted with
1- 4 Rl groups,
and when Rx and RY together represent a 4-6 membered
ring as defined above, RZ is as defined above or RZ represents an
additional saturated 4-6 membered ring fused to the ring represented
by RX and RY taken together, optionally interrupted by O, S, NRw or -
C(O)-, said rings being unsubstituted or substituted with one to four
Ri groups.
Pharmaceutical compositions and methods of treatment
are also included.
DETAILED DESCRIPTION OF THE INVENTION
The invention is described herein in detail using the
terms defined below unless otherwise specified.
C%arboxylate anion refers to a negatively charged
group -COO-.
The term "alkyl" refers to a monovalent alkane
(hydrocarbon) derived radical containing from 1 to 10 carbon
atoms unless otherwise defined. It may be straight, branched or
cyclic. Preferred alkyl groups include methyl, ethyl, propyl,
isopropyl, butyl, t-butyl, cyclopentyl and cyclohexyl. When
CA 02304267 2000-03-14
WO 99/14217 PGTNS98/19015
-6-
substituted, alkyl groups may be substituted with up to four
substituent groups, selected from Rd and Ri, as defined, at any
available point of attachment. When the alkyl group is said to be
substituted with an alkyl group, this is used interchangeably with
"branched alkyl group".
~Cycloalkyl is a specie of alkyl containing from 3 to
carbon atoms, without alternating or resonating double bonds
between carbon atoms. It may contain from 1 to 4 rings which are
fused.
10 The term "alkenyl" refers to a hydrocarbon radical
straight, branched or cyclic containing from 2 to 10 carbon atoms
and at least one carbon to carbon double bond. Preferred alkenyl
groups include ethenyl, propenyl, butenyl and cyclohexenyl.
'.Che term "alkynyl" refers to a hydrocarbon radical
15 straight or branched, containing from 2 to 10 carbon atoms and at
least one carbon to carbon triple bond. Preferred alkynyl groups
include ethynyl, propynyl and butynyl.
Aryl refers to aromatic rings e.g., phenyl, substituted
phenyl and the like, as well as rings which are fused, e.g.,
naphthyl, phE:nanthrenyl and the like. An aryl group thus
contains at least one ring having at least 6 atoms, with up to five
such rings being present, containing up to 22 atoms therein, with
alternating (resonating) double bonds between adjacent carbon
atoms or suitable heteroatoms. The preferred aryl groups are
phenyl, naphthyl and phenanthrenyl. Aryl groups may likewise
be substituted as defined. Preferred substituted aryls include
phenyl and naphthyl.
The term "heteroaryl" refers to a monocyclic aromatic
hydrocarbon group having 5 or 6 ring atoms, or a bicyclic
aromatic group having 8 to 10 atoms, containing at least one
heteroatom, C>, S or N, in which a carbon or nitrogen atom is the
point of attachment, and in which one or two additional carbon
atoms is optionally replaced by a heteroatom selected from O or S,
and in which from 1 to 3 additional carbon atoms are optionally
replaced by nitrogen heteroatoms, said heteroaryl group being
optionally substituted as described herein. Examples of this type
are pyrrole, pyridine, oxazole, thiazole and oxazine. Additional
CA 02304267 2000-03-14
WO 99/14217 PCT/IJS98/19015
nitrogen atoms may be present together with the first nitrogen
and oxygen or sulfur, giving, e.g., thiadiazole. Examples include
the following:
CN H N~/N H N ~/S
pyrrole (pyrrolyl) imidazole (imidazolyl) thiazole (thiazolyl)
N~4 CO CS
oxazole (oxazolyi) furan {furyl) thiophene (thienyl)
N~NH ~ ,NH ~ ,O
N N
triazole (triazolyl) pyrazole (pyrazolyl) isoxazole (isoxazolyl)
.S . C
C-, ~ N
N N
isothiazole (isothiazolyl) pyridine (pyridinyl) pYrazine
(pyrazinyl)
~N
~. -.N
N N
pyridazine (pyridazinyi) pyrimidine {pyrimidinyl)
N'~ N
~.NJ
triazine (triazinyl)
»eteroarylium refers to heteroaryl groups bearing a
quaternary nitrogen atom and thus a positive charge. Examples
include the following:
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
~N~N CH3 'NHS
~~ N + +
~N~O ~ N-CH3 ~ ,O
+ ~+
+ N
~N%~
N~ N'~CH3
+ N N+
CH3 CH3
''~S I ~N/ ~N~N
f,N J ~ J
+ N
~~+ .CH3
~.N
N+ N
CH3
'When a charge is shown on a particular nitrogen
atom in a ring which. contains one or more additional nitrogen
atoms, it is understood that the charge may reside on a different
nitrogen atoms in the ring by virtue of charge resonance that
occurs.
i s
~IIV%'~N-CH \N~N ~ CH
INS 3 N~/
and
'NON-.CHs .E-~ ~N ~ CH3
i
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-9-
'The term "heterocycloalkyl" refers to a cycloalkyl
group (nonaromatic) in which one of the carbon atoms in the ring
is replaced by a heteroatom selected from O, S or N, and in which
up to three additional carbon atoms may be replaced by hetero
atoms.
'fhe terms "quaternary nitrogen" and "positive
charge" refer to tetravalent, positively charged nitrogen atoms
including, e.~;., the positively charged nitrogen in a
tetraalkylammonium group (e. g. tetramethylammonium),
heteroarylium, (e.g., N-methyl-pyridinium), basic nitrogens
which are protonated at physiological pH, and the like. Cationic
groups thus encompass positively charged nitrogen-containing
groups, as wE~ll as basic nitrogens which are protonated at
physiologic p:H.
7Che term "heteroatom" means O, S or N, selected on
an independent basis.
Halogen and "halo" refer to bromine, chlorine,
fluorine and :iodine.
E~lkoxy refers to C1-C4 alkyl-O-, with the alkyl group
optionally substituted as described herein.
(xuanidinyl refers to the group: H2NC(NH)NH-.
Carbamimidoyl refers to the group: H2NC(NH)-.
Zlreido refers to the group: H2NC(O)NH-.
When a group is termed "substituted", unless
otherwise indicated, this means that the group contains from 1 to
4 substituents thereon. With respect to R, Ra, Rb and Rc, the
substituents available on alkyl groups are selected from the values
of Rd. Many of the variable groups are optionally substituted with
up to four Ri groups. With respect to Re, Rf and Rg, when these
variables represent substituted alkyl, the substituents available
thereon are selected from the values of Ri.
When a functional group is termed "protected", this
means that the group is in modified form to preclude undesired
side reactions at the protected site. Suitable protecting groups for
the compounds of the present invention will be recognized from
the present application taking into account the level of skill in the
art, and with reference to standard textbooks, such as Greene, T.
CA 02304267 2000-03-14
WO 9/14217 PCT/US98/19015
W. et al. Protective ~rou~s in Orga is y h~'.,~ Wiley, New York
(1991). Exar~ciples of suitable protecting groups are contained
throughout the specification.
When a group is "optionally interrupted", this
includes one or more of the interrupting moieties in combination,
as well as sari moieties located at either or both ends of the chain.
Thus, it includes terminating the group as well.
In some of the carbapenem compounds of the present
invention, M :is a readily removable carboxyl protecting group,
and/or P represents a hydroxyl which is protected by a hydroxyl-
protecting group. Such conventional protecting groups consist of
known groups which are used to protectively block the hydroxyl or
carboxyl group during the synthesis procedures described herein.
These conventional blocking groups are readily removable, i.e.,
they can be removed, if desired, by procedures which will not
cause cleavage or other disruption of the remaining portions of the
molecule. Such procedures include chemical and enzymatic
hydrolysis, treatment with chemical reducing or oxidizing agents
under mild conditions, treatment with a transition metal catalyst
and a nucleophile and catalytic hydrogenation.
E'~xamples of carboxyl protecting groups include
allyl, benzhydryl, 2-naphthylmethyl, benzyl, silyl such as
t-butyldimethylsilyl (TBDMS), phenacyl, p-methoxybenzyl,
o-nitrobenzyl, p-methoxyphenyl, p-nitrobenzyl, 4-pyridylmethyl
and t-butyl.
Examples of suitable C-6 hydroxyethyl protecting groups
include triethylsilyl, t-butyldimethylsilyl, o-nitrobenzyloxycarbonyl, p-
nitrobenzyloxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, t-
butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl and the like.
The carbapenem compounds of the present invention
are useful per se and in their pharmaceutically acceptable salt
and ester forms for the treatment of bacterial infections in animal
and human subjects. The term "pharmaceutically acceptable
ester, salt or hydrate,"' refers to those salts, esters and hydrated
forms of the compounds of the present invention which would be
apparent to th.e pharmaceutical chemist. i.e., those which are
substantially non-toxic and which may favorably affect the
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-11-
pharmacokin.etic praperties of said compounds, such as
palatability, .absorption, distribution, metabolism and excretion.
Other factor.., more practical in nature, which are also important
in the selection, are cost of the raw materials, ease of
crystallization, yield, stability, solubility, hygroscopicity and
flowability of the resulting bulk drug. Conveniently,
pharmaceutical compositions may be prepared from the active
ingredients in combination with pharmaceutically acceptable
carriers. Thus, the present invention is also concerned with
pharmaceutical compositions and methods of treating bacterial
infections utilizing as an active ingredient the novel carbapenem
compounds.
kith respect to -C02M, which is attached to the
carbapenem nucleus at position 3, this represents a carboxylic
acid group (M represents H), a carboxylate anion (M represents
a negative charge), a pharmaceutically acceptable ester (M
represents an. ester forming group) or a carboxylic acid protected
by a protecting group (M represents a carboxyl protecting group).
The pharmaceutically acceptable salts referred to
above may tale the form -COOM, where M is a negative charge,
which is balanced by a counterion, e.g., an alkali metal cation
such as sodium or patassium. Other pharmaceutically acceptable
counterions may be calcium, magnesium, zinc, ammonium, or
alkylammonium cations such as tetramethylammonium,
tetrabutylam~monium, choline, triethylhydroammonium,
megiumine, triethanolhydroammonium, etc.
The pharmaceutically acceptable salts referred to
above also include acid addition salts. Thus, the Formula I
compounds can be used in the form of salts derived from
inorganic or organic acids. Included among such salts are the
following: acetate, adipate, alginate, aspartate, benzoate,
benzenesulfon.ate, bisulfate, butyrate, citrate, camphorate,
camphorsulfonate, cyclopentanepropionate, digluconate,
dodecylsulfatE~, ethanesulfonate, fumarate, glucoheptanoate,
glycerophosphate, hemisulfate, heptanoate, hexanoate,
hydrochloride" hydrobromide, hydroiodide, 2-
hydroxyethan~esulfonate, lactate, maleate, methanesulfonate, 2-
CA 02304267 2000-03-14
WO 99114217 PCT/US98119015
-12-
naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate,
persulfate, 3-phenylpropionate, picrate, pivalate, propionate,
succinate, tartrate, thiocyanate, tosylate and undecanoate.
The pharmaceutically acceptable esters are such as
would be readily apparent to a medicinal chemist, and include, for
example, those described in detail in U.S. Pat. No. 4,309,438.
Included within such pharmaceutically acceptable esters are
those which are hydrolyzed under physiological conditions, such
as pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and
methoxymeth;yl, and others described in detail in U.S. Pat. No.
4,479,947. These are also referred to as "biolabile esters".
>:3iolabile esters are biologically hydrolizable, and may
be suitable for oral administration, due to good absorption through
the stomach or intestinal mucosa, resistance to gastric acid
degradation and other factors. Examples of biolabile esters
include compounds in which M represents an alkoxyalkyl,
alkylcarbonyloxyalkyl, alkoxycarbonyloxyalkyl, cycloalkoxyalkyl,
alkenyloxyalkyl, aryloxyalkyl, alkoxyaryl, alkylthioalkyl,
cycloalkylthioalkyl, alkenylthioalkyl, arylthioalkyl or alkylthioaryl
group. These groups can be substituted in the alkyl or aryl
portions thereof with acyl or halo groups. The following M species
are examples of biolabile ester forming moieties.: acetoxymethyl,
1-acetoxyethyl., 1-acetoxypropyl, pivaloyloxymethyl, 1-
isopropyloxycarbonyloxyethyl, 1-cyclohexyloxycarbonyloxyethyl,
phthalidyl and (2-oxo-5-methyl-1,3-dioxolen-4-yl)methyl.
L- can be present or absent as necessary to maintain
the appropriate charge balance. When present, L- represents a
pharmaceutic<~lly acceptable counterion. Most anions derived
from inorganic or organic acids are suitable. Representative
examples of such counterions are the following: acetate, adipate,
aminosalicylai~e, anhydromethylenecitrate, ascorbate, aspartate,
benzoate, benzenesulfonate, bromide, citrate, camphorate,
camphorsulfonate, chloride, estolate, ethanesulfonate, fumarate,
glucoheptanoa.te, gluconate, glutamate, lactobionate, malate,
maleate, mandelate, methanesulfonate, pantothenate, pectinate,
phosphate/dip:hosphate, polygalacturonate, propionate, salicylate,
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
stearate, succinate, sulfate, tartrate and tosylate. Other suitable
anionic species will be apparent to the ordinarily skilled chemist.
:Likewise, when L- represents a specie with more
than one negative charge, such as malonate, tartrate or
ethylenediaminetetraacetate (EDTA), an appropriate number of
carbapenem molecules can be found in association therewith to
maintain the overall. charge balance and neutrality.
'i~hen the side chain is neutral, and the 3-carboxylate
is in the form of an anion, the molecule is charge balanced by the
presence of a:n apprapriately charged group, such as L'' . Suitable
positively charged groups include cations, such as sodium,
potassium, calcium, magnesium and the like. Protonated
moieties are .also acceptable, such as tetraalkylammonium and
the like.
A subset of compounds of the invention which is of
particular interest is described with reference to formula I
wherein Rl represents methyl. Within this subset, all other
variables are as originally defined.
Another subset of compounds of the invention which is of
particular interest is described with reference to formula I wherein
C02M represents a carboxylic acid or a carboxylate anion. Hence, M
in this instance represents a negative charge which will be balanced
by a positivel;~ charged group, such as in the positively charged R
group. Likewise, if t:he positively charged R group contains more
than one positive charge, a negatively charged counterion may be
present which in combination with the carboxylate anion, provides
overall chargE: neutrality.
Another subset of compounds of the invention which is of
particular interest is described with reference to formula I wherein P
represents hydroxyl or hydroxyl protected by hydroxyl-protecting
group. Within this subset, all other variables are as originally
defined.
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-14-
Another subset of compounds of the invention which
is particular :interest is described with reference to formula I
wherein at least one of the R groups attached to the phenyl ring
contains a positively charged moiety. More particularly, one of the
R groups represents -A-(CH2)n-Q, and the remaining R groups
represent hydrogen ar another value of R other than -A-(CHZ)n-(d.
Within this subset, A, n, Q and all other variables are as
originally defined.
Another subset of compounds of the invention which is of
particular interest is described with reference to formula I one of the
R groups represents -A-(CHZ)n-Q, and A represents -CH2 -. Within
this subset, all other variables are as originally defined.
Another subset of compounds of the invention which is of
particular interest is described with reference to formula I wherein
one of the R groups represents -A-(CHZ)p-Q, and n represents 0 or 1.
Within this subset, all other variables are as originally defined.
Another subset of compounds of the invention which is of
particular interest is described with reference to formula I wherein
one of the R groups represents -A-(CHZ)n-Q, and Q represents
, ~O.S,a
or ~ N a
a. represents O, S or NRs;
and Vii, 8, ~,, ~, and a represent CRt, N or N+Rs, provided
that no more than one of (3, b, ~,, ~. and a is N+Rs, balanced by L-
which is a pharmaceutically acceptable counterion, and Rs is as
originally defined. Within this subset, all other variables are as
originally defined.
Another subset of compounds of the invention which is of
particular interest is described with reference to formula I wherein
CA 02304267 2000-03-14
WO 99/14217 PCT/US9$/19015
-15-
one of the R groups represents -A-(CH2)n-Q, and Q is selected from
the group consisting of
l(CH2; O
SrN~ ON_Rx and ~-NRXRyRZ
O
L (CH2)a
a and b are 2;
L- is a pharmaceutically acceptable counterion;
and Rx, RY and RZ are as originally defined. Within
this subset, a:ll other variables are as originally defined.
A more preferred subset of compounds of the invention
which is of interest is described with reference to formula I wherein
one of the R groups represents -A-(CHZ)p-Q, and Q is
(CH~b
NCO ON_Rx
L~ (CH~a
Within this subset, all other variables are as originally defined.
Another subset of compounds of the invention which is of
particular interest is described with reference to formula I wherein
one of the R groups represents -A-(CHZ)~-Q, and Q is
N~~ i 6
wherein:
a represents O, S or NRs;
~3, S, ~,, ~. and a represent CRt, N or N+Rs, provided that
no_more than one of Vii, 8, ~,, w and a is N+Rs, balanced by L-,which is
a pharmaceutically acceptable counterion, and
CA 02304267 2000-03-14
WO 99/14217 PCT/US98119015
-16-
all other variables are as originally defined.
Representative examples of compounds of the
invention are as follows:
TABLE 1
Na
' ~S
al1y102C0 H H
o ~
N
O C02allyi
/
_S
HO H H
O
N
O C 02 X+
~~N~
/ 1 U
1 \
allyl-O H H
O
N~ X_
O C02-allyl
CA 02304267 2000-03-14
WO 99/14217 PCTNS98/19015
-17-
OH
' S
allyl-02C0 H H
O
N
O C02allyl
~-=J
'- 's
HO H H
O
N
O
CO ~
N~~ CONH2
/ ~ O
_ _S x
7 HO H H
O ~ /
N
O COO
+ ,..1
O ~N~CONH2
p
'" S
allyl-O H H
O
N
O C 02-allyl
CA 02304267 2000-03-14
WO 99/14217 PCT1US98/19015
-lg_
OH
/ ,
'' S
al1y102C0 H H
O ~ /
N
O C02ailyl
O Z~~CONH2
/ ~ x0
to ' -s
HO H H
O \ /
N
O COO
s ,O
HO H H
11 O \ /
N
O
C02 X+
/ ' S O
HO H H
\ /
N
O
C02' x+
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-19-
0
N~~J~CONH2
/
"_ S ~O X
HO H H
O
N
O
CO~
O
~NO~CONH2
0O
-s S ~O
2
al1y102C0
H H
14 O
N
O
C02allyi
O
N~~J~CONH2
/ ' O
'_ g~,O OX
HO H H
15 O ~ /
N
O
CO ~
O
HO H H
16 O ~ /
N
O CO~ X
CA 02304267 2000-03-14
WO 9/14217 PCT/US98/19015
-20-
O
N~~J~CONH2
O
'o x
HO H H
17
N
O
CO ~
CH2=CHCHZOzCO H H
C02CHzCH=CH2
1g H O H H
IV
O
C 02 X+
OSiPh~M~
CHr-CHCH202C H H
N
O
C02CHzCH=CH2
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/I9015
-21-
OH
C H2=C H C H202C O H H
N
O C 02C H2C H=C H2
~ ~NMe
N
~XJQ
CH2=CHCH202C0 H
O
N
O C OZCH2CH=CH2
+ /r~NMe
HO H H
O ~
O
CHrCHCH202C
24
N
O C02CHzCH=CH2
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-22-
/ O
HO H H
O
N
O
C 02 X+
I ,
CHz=CHCH202C H H
N
O CO CH
z 2CH~H2
HO H H
O
N
O
C 02- X+
I ~ CO2CHs
02C0 H H
2$
~02CH2CH=CH2
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-23-
C 02C H3
HO H H
O
y
N
O C 02 X+
I ~ COzCH3
~02C0 H H
30 \ /
O ~ H2CH=CH2
C OZC H3
31 HO H H
N
O
C 02 X+
I ~ oTBs
2 N
\ /
N
O C02CH2CH=CH2
CA 02304267 2000-03-14
WO 99/14217 PCTNS98/19015
-24-
off
w
33 ~2~ H H
O
IV~
O CC~2CH2CH=CH2
C
<N
N
O
34 ~2C O H H X O
O
N
O
C 02C H2CH=CH2
C H3
w ~N
N
35 H O H H
O
N
~ p2 O
f ~ onns
w
~2C0 H H
O
N
C02CHZCH=CH2
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-25-
I ~ t
37 ~2 H H
O
N
O C02CH2CH=CH2
w ~N~CONH2
2X-
~'/~02C0 H H O
IV~
O
C 02CH2CH=CH2
~N~CON H2
O+ X
/ N _
HO H H
O
O
C 02
H20TBS
~ 02C H H
O ~
N
O
C02CH~H_CHz
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-26-
HzOH
02C0 H H .
N
O
C02CH2CH=CH2
/ '"C H20 H
HO H H
O ~ ~
N
O
C 02 X+
TBs
I~
43 CH2=CHCHz02C
N
O
C02CHzCH=CH2
H
44 CH2=CHCHz02C
H
N
O
C02CH2CH=CH2
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-27-
Ms
45 CH 2=CHCH20~
N
O
C02CH2CH=CH2
w
46 CH2=CHCHz02C
N
O
C02CH2CH=CH2
CH3
O ~/
O
/ O
47 C H2=CHCH202C O H H
N
O
C 02C H2CH=CH2
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-28-
~~CONH2
O
NJ _
2
O
C H2=CHCH202C O H H
N
O
C 02CH2CH=CH2
~N
N
~'J
w
O
C H2=C HCH202C O H _
O ~ /
N
O C 02C H2CH=CH2
CH2CH2CONH2
Q+ N
O
CH2=CHCH202C H H
/
N
O C02CH2CH=CH2
CA 02304267 2000-03-14
WO 99/14217 PGT/US9$/19015
-29-
CHa
o ~J
~i O
51 HO H H
O
N
O C02 O
~N~CONH2
oNJ
O
52 H O H H
O
O N~O
C02
o ~J
i O
HO H H
N
O 02 O
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-30-
CHzCHzCONH2
O ~/
/ O
r~ HO H H
O
O
Co2 0
OH
/ O
55 ~ 02C0 H H
O 1
C02CH2CH=Cf-h
~N~CONH2
2 X~ NJ
O
56 I / O
~'~02C O _
H
N
O
C 02C H2CH=CH2
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-31-
O
~N~CONH2
Xo NJ
0
O
57
HO H H
N
O
C 02
C H3
X NJ
0
5s ~ i O
~02C O H H
O
N
O
C02C H2CH=CH2
CA 02304267 2000-03-14
WO 99/14217 PC"T/US98/19015
-32-
CH3
NJ
0
~i O
HO H H
O ~
1V~
O _
C020
OH
O ~ HCO2CHs
H H
60 O
N
O
C02CH2CH=CH2
~~CONH2
2 X~ NJ
0
61
~H
C 02C H3
H H
O ~
N
O
C OZC H2CH=CH2
CA 02304267 2000-03-14
WO 99/14217 PCf/US98/19015
-33-
O
~N~CON H2
o NJ
x o
~ ~C 02C H3
HO H H
O
o N~O
C 02
CH3
O
NJ
0
y
~O C O ~ HC02C H3
2 ~ -
N
O C02CH2CH=CH2
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-34-
CHa
NJ
0
~ ~'C02CH3
HO H H -
O
O
N CO O
02C H O
O ~
O
COzCHzCH=CHz
O
HO H H
O
N
O
C02' X+
X + and X- represent appropriately charged counterions
which are present to provide overall charge balance.
Z'he compounds of the present invention are prepared by
5 reacting a suitably protected, activated 2-hydroxymethyl-carbapen-2-
em-3-carboxylate with an appropriately substituted phenyl ring, and
then removing any protecting groups which are present to afford the
CA 02304267 2000-03-14
WO 99(14217 PCT/US98/19015
-35-
desired final product. The process is illustrated by the following
generic schemes:
FLOW SHEET A
P H H R1 OH ..-/ (R)s
HsC OH
-N ~ + (R)s
O " X
C02P A2
P H H R~ ~ (R)s
Mitsunok~u Reaction HsC O
R02CN= NC02R N
R'.vP O X
..
Solvent ~ C02P
i (R)s
HO H H R~ ~ (R)s
Denrotection H C O ~ /
(Ph~p~Pd
Ph3P
O X
C02Na ~ C02.
i (R)a
n. C02H
CH2CI2'EtOAc
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
_36
FLOW SHEET B
P H H Ri OH -..,._/ (R)2
H3C OH \
/ + (R)3 ~ \ ' \A CH2 nOSiR
~ r ( ) a
O ~ X
A1 COzP"
j A(CH2)nOSiR3
X
P H H Ri
Mitsunobu Reaction HsC O
R02CN=NC02R / ~ (R)s
R'sP
Solvent O A6 C02P'. R)2
~~ j A(CH2)nOH
~ X
P H H Ri
Desilylation H3C O ~
(R)s
Bu4NF N /
HOAc O
Solvent ~ C02P"
CH2)nQ+
Activation
Displacement
Deprotection HsC
R)3
a~
With reference to the Flow Sheets above, P, R, R1, A, Q
and n are as defined with respect to the compounds of formula I. P**
is a carboxyl covering group.
The side chain ,~,2 or ~ is initially reacted with a
suitably protected carbapen-2-em-3-carboxylate having an activated
hydroxymethyl group at the 2-position.
The carbapenem nucleus having a hydroxymethyl
substituent at position 2 can be obtained in accordance with Schmitt,
CA 02304267 2000-03-14
- WO 99/14217 PGTNS98/19015
S. M. et al., J_. Antibiotics 41(6): 780-787 (1988), the teachings ofwhich
are incorporated herein by reference. The carboxylic acid group at C-
3 of the carba~penem is generally protected as a carboxyl protecting
group such as p-nitrobenzyl (PNB), allyl, p-methoxybenzyl,
trichloroethyl., 2-trimethylsilylethyl and the like. Furthermore, the
hydroxyl group of the 6-(hydroxyethyl) side-chain is protected with a
hydroxyl protecting group such as trimethylsilyl (TMS), triethylsilyl
(TES), tert-bu.tyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl
(TBDPS), acetyl, allyloxycarbonyl, 2-trimethylsilylethoxycarbonyl, 2-
trichloroetho~;ycarbonyl and the like.
7.'he addition of the side chain to the carbapenem is
accomplished by treating a solution of the hydroxymethyl-
carbapenem ~~ and the side chain ~ or ~5 in a suitable solvent
such as tetrallydrofuran (THF), ether, acetonitrile,
dimethylformamide (DMF), benzene, dimethylsulfoxide (DMSO), and
the like with .a combination of reagents that comprise the Mitsunobu
reaction ( for a review see: Hughes, D.L. Organic Reactions,
Paquette, L. ed., Vol. 42, John Wiley & Sons, USA, 1992. ) such as an
azodicarboxyl;ate like diethylazodicarboxylate (DEAD),
diisopropyldiazodicarboxylate(DIAD), and
tetramethyldiazodicarboxamide (TMAD), or the like, and a tri-
substituted phosphine, such as triphenylphosphine, tri-n-
butylphosphine, and the like, at a temperature between about -20 °C
and 35 °C for ~~bout 5 to 90 minutes.
Alternatively, the naphthosultam and carbapenem can
be simultaneously added to a preformed complex of the
diazocarboxyl;~te and phosphine. Once the naphthosultam,
carbapenem, find activating reagents) have been mixed, the reaction
is allowed to proceed at a temperature between about -20 °C and 35
°C
for about 5 to 90 minutes.
The resulting mixture is then subjected to a standard
work-up procedure to afford a crude methyl substituted carbapenem
which is purified, if necessary, by recrystallization or by
chromatography on silica gel, eluting with a suitable solvent or
mixture of two or more solvents, such as hexane, ethyl acetate, ether,
benzene, dichl.oromethane, chloroform, acetone, methanol and the
like.
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-38-
lModification of the side chain, which is generally
necessary to introduce the charged substituent, is best accomplished
before reacting the carbapenem and the side chain, as in Flow Sheet
B. Afterwards, the removal of protecting groups on the hydroxyethyl
side chain and/or 3-carbapenem carboxylate can be accomplished.
For compounds which contain a hydroxyl group in the side chain, a
positively charged substituent may be introduced into the side chain
by first activating the hydroxyl group. This entails converting it to a
suitable leaving group such as a triflate, mesylate, tosylate, iodide,
chloride, broxr~ide, and the like, and then displacing the resulting
leaving group with a compound Q, such as N-methyl-imidazole, N-(2-
hydroxyethyl)-imidazole, N-methyl-diazabicyclooctane, 1-
(carbamoylmethyl)-4-aza-1-azoniabicyclo[2.2.2]octane, 1-(3-
hydroxyprop-7.-yl)-4-aza-1-azoniabicyclo[2.2.2]octane, pyridine,
morpholine arid the like which contains a nitrogen atom that can act
as a nucleophiile. Alternatively, in some cases, the charged
substituent m;ay be incorporated in the side chain after addition of the
side chain to the carbapenem, or after deprotection. Introduction of
the charged moiety Q before deprotection is greatly preferred.
In some cases, activation of the hydroxyl group and
displacement by Q to produce ~8 may be accomplished in a single
step by taking advantage of the basic character of compound Q and
using it as a base in the activation reaction.
The conversion of the hydroxyl group to a suitable
leaving group is accomplished by treating the hydroxyl substituted
compound in a suitable solvent such as dichloromethane, tetrahydro-
furan, ether, benzene, and the like with an activating reagent, such
as trifluorome~thanesulfonic anhydride, methanesulfonic anhydride,
toluenesulfonic anhydride, methanesulfonyl chloride,
benzenesulfon;yl chloride, toluenesulfonyl chloride, and the like in the
presence of a .suitable base such as triethylamine, tributylamine,
diisopropyleth;ylamine and the like at a temperature between about
-100°C and 0°C: for about 5 to 120 minutes. The intermediate
thus
obtained contains a leaving group, which may be converted to an
alternative leaving group, iodide, by treating a solution of the
intermediate in a suitable solvent such as acetone, methyl ethyl
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-39-
ketone, and the like at about -10°C to 50°C with an excess of
sodium
iodide or potassium iodide for about 0.25 to 24 hours.
In many cases, the iodide is obtained in sufficiently pure
form that it may be used without further purification. For ease of
S handling, the iodide, if not crystalline, may be lyophilized from
benzene to afford an amorphous, easily handled, solid.
The activated hydroxyl group or iodide is displaced by
reacting the activated intermediate with reagent Q. In some cases,
activation and displacement of the hydroxyl group may be
accomplished in a single step. The activating reagent is added to a
solution of thE~ hydroxyl substituted compound in the presence of a
suitable base in a suitable solvent such as dichloromethane,
tetrahydrofur;an, ether, DMF, benzene, acetonitrile, DMSO and the
like as described in the preceding paragraphs. The resulting
activated intermediate is treated with 1-3 molar equivalents of
compound Q a.t a temperature between about -78°C and 50°C for
about
15 to 120 minutes. In some cases, it is desirable to form the activated
intermediate in one solvent, isolate the activated intermediate, and
conduct the displacement reaction in a different solvent. In other
cases, the displacement may be conducted without isolation of the
intermediate and, in cases where fl is also used as a base, may even
be concurrent with the formation of the activated intermediate.
In cases where the displacement reaction is best
accomplished by using the iodide, a solution of the iodide is combined
with an approximately equivalent amount (0.9 - 1.05 molar
equivalents) of compound Q. A silver salt of a non-nucleophilic acid,
such as silver trifluoromethanesulfonate, silver tetrafluoroborate and
the like is them added. Although the reaction will proceed in the
absence of the silver salt, the reaction proceeds more rapidly in the
presence of the silver salt. In addition, the silver salt assists in the
removal of thE~ displaced iodide from the reaction mixture which can
improve the ei.~"-iciency of subsequent steps. The resulting mixture is
then subjected. to a standard work-up procedure familiar to those
skilled in the art to afford a crude product which is purified, if
necessary, by recrystallization or chromatography.
An alternative method for introducing a positive charge
into the side chain may be applied to side chains that contain a
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-40-
nitrogen atom which may be quaternized by reaction with a suitable
alkylating reagent, such as methyl iodide, methyl bromide, benzyl
trichloroacetimidate, methyl trifluoromethanesulfonate,
triethyloxoniLUn tetrafluoroborate, and the like. Quaternization of the
nitrogen atoms in the side chain is effected by treating a solution of the
compound with a slight excess (1.05 to 1.2 molar equivalents) of the
alkylating reagent.
The synthesis of the target compound is completed by
removing any protecting groups which are present in the
penultimate intermediate using standard techniques: The
deprotected final product is then purified, as necessary, using
standard techniques such as ion exchange chromatography, HPLC
on reverse phase silica gel, MPLC on reverse phase polystyrene gel,
and the like o:r by recrystallization.
T'he final product may be characterized structurally by
standard techniques such as NMR, IR, MS, and UV. For ease of
handling, the final product, if not crystalline, may be lyophilized
from water to afford an amorphous, easily handled solid.
The compounds of the present invention are valuable
antibacterial agents active against various Gram-positive and to a
lesser extent Gram-negative bacteria, and accordingly find utility
in human and veterinary medicine.
Many of compounds of the present invention are
biologically active against MRSA/MRCNS. In vitro antibacterial
activity is predictive of in vivo activity when the compounds are
administered to a mammal infected with a susceptible bacterial
organism.
Using standard susceptibility tests, the compounds of
the invention are determined to be active against MRSA.
T:he compounds of the invention can be formulated in
pharmaceutical compositions by combining the compound with a
pharmaceutically acceptable carrier. Examples of such carriers
are set forth below.
Tike compounds may be employed in powder or
crystalline form, in liquid solution, or in suspension. They may be
administered by a variety of means; those of principal interest
CA 02304267 2000-03-14
- WO 99/14217 PCT/US98/19015
-41-
include: topically, orally and parenterally by injection
(intravenousl;y or intramuscularly).
Compositions for injection, a preferred route of
delivery, may be prepared in unit dosage form in ampoules, or in
multidose containers. The injectable compositions may take such
forms as suspensions, solutions, or emulsions in oily or aqueous
vehicles, and may contain various formulating agents.
Alternatively, the active ingredient may be in powder (lyophilized
or non-lyophilized) form for reconstitution at the time of delivery
with a suitable vehicle, such as sterile water. In injectable
compositions, the carrier is typically comprised of sterile water,
saline or another injectable liquid, e.g., peanut oil for
intramuscular injections. Also, various buffering agents,
preservatives .and the like can be included.
Topical applications may be formulated in carriers
such as hydrophobic or hydrophilic bases to form ointments,
creams, lotions, in aqueous, oleaginous or alcoholic liquids to
form paints or in dry diluents to form powders.
Oral compositions may take such forms as tablets,
capsules, oral suspensions and oral solutions. The oral
compositions rnay utilize carriers such as conventional
formulating agents, and may include sustained release properties
as well as rapi:d delivery forms.
Tlhe dosage to be administered depends to a large
extent upon the condition and size of the subject being treated, the
route and frequency of administration, the sensitivity of the
pathogen to the particular compound selected, the virulence of the
infection and other factors. Such matters, however, are left to the
routine discretion of the physician according to principles of
treatment well known in the antibacterial arts. Another factor
influencing th<: precise dosage regimen, apart from the nature of
the infection and peculiar identity of the individual being treated,
is the molecular weight of the compound.
The compositions for human delivery per unit
dosage, whether liquid or solid, may contain from about 0.01% to
as high as about 99% of active material, the preferred range being
from about 10-60%. The composition will generally contain from
CA 02304267 2000-03-14
WO 99/14217 PCTNS98/19015
-42-
about 15 mg to about 2.5 g of the active ingredient; however, in
general, it is preferable to employ dosage amounts in the range of
from about 2.50 mg to 1000 mg. In parenteral administration, the
unit dosage will typically include the pure compound in sterile
water solution or in the form of a soluble powder intended for
solution, which can be adjusted to neutral pH and isotonic.
'hhe invention described herein also includes a
method of trE~ating a bacterial infection in a mammal in need of
such treatment comprising administering to said mammal a
compound of formula I in an amount effective to treat said
infection.
'.fhe preferred methods of administration of the
Formula I antibacterial compounds include oral and parenteral,
e.g., i.v. infusion, i.v. bolus and i.m. injection.
1! or adults, about 5-50 mg of Formula I antibacterial
compound per kg of body weight given one to four times daily is
preferred. Th.e preferred dosage is 250 mg to 1000 mg of the
antibacterial given one to four times per day. More specifically,
for mild infections a dose of about 250 mg two or three times daily
is recommended. For moderate infections against highly
susceptible gram positive organisms a dose of about 500 mg three
or four times daily is recommended. For severe, life-threatening
infections against organisms at the upper limits of sensitivity to
the antibiotic, a dose of about 1000-2000 mg three to four times daily
may be recommended.
F~'or children, a dose of about 5-25 mg/kg of body
weight given 2, 3, or 4 times per day is preferred; a dose of 10
mg/kg is typically recommended.
Z'he compounds of Formula I are of the broad class
known as carbapenems. Many carbapenems are susceptible to
attack by a renal enzyme known as dehydropeptidase (DHP). This
attack or degradation may reduce the efficacy of the carbapenem
antibacterial agent. Many of the compounds of the present
invention, on the other hand, are less subject to such attack, and
therefore may not require the use of a DHP inhibitor. However,
such use is optional and contemplated to be part of the present
invention. Inlhibitors of DHP and their use with carbapenems are
CA 02304267 2000-03-14
WO 99/14217 PCf/US98119015
disclosed in, e.g.,[European Patent Application Nos. ?9102616.4,
filed July 24, 1979 (Patent No. 0 007 614); and 82107174.3, filed
August 9, 1982 (Publication No. 0 072 014)] .
'The compounds of the present invention may, where
DHP inhibition is desired or necessary, be combined or used with
the appropriate DHP inhibitor as described in the aforesaid
patents and published application. The cited European Patent
Applications define the procedure for determining DHP
susceptibility of the present carbapenems and disclose suitable
inhibitors, combination compositions and methods of treatment.
A preferred v~eight ratio of Formula I compound: DHP inhibitor
in the combination compositions is about 1:1.
A preferred DHP inhibitor is 7-(L-2-amino-2-carboxy-
ethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptenoic
acid or a useful salt thereof.
The invention is further described in connection with the
following non-limiting examples.
EXAMPLE 1
PREPARATION OF 1-HYDROXYDIBENZOTHIOPHENE
OH
S
Step A:
A stirred mixture of 3-methoxy benzenethiol (0.5 g, 3.6
mmoles), 1-fluoro-2-nitrobenzene (0.5 g, 3.6 mmoles), 37% KF/A1203
(1.4755 g, 3 w,/w) , and 18-crown-6 (0.1255 g, 0.36 mmoles) in sieve-
dried acetonit~rile (5 mL) was refluxed at 90°C under a N2 atmosphere
fox 1 hr. The reaction was allowed to cool to ambient temperature.
The insoluble solids present in the reaction were filtered off and
washed with EtOAc. The filtrate was collected and concentrated in
vacuo to give a black/red solid (1.1487 g). The product was purified by
plate layer chromatography with a mixture of 2:1 hexane/CH2C12 to
afford the desired product as a yellow solid (0.7095 g).
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
1H NMR (CDCl3) b: 3.82 (s, 3H), 6.90 (dd, 1H), 7.01 (dd,
1H), 7.12-7.23 (m, 3H); 7.33-7.39 (m, 2H), 8.22 (dd, 1H).
Step B:
To a stirred solution of the product obtained from Step A
(0.7095 g, 2.7 ~nmoles) in absolute EtOH (7 mL) was added SnCl2~H20
(1.8563 g, 8.1 :mmoles). The resulting mixture was refluxed at 90°C
for 1.5 hrs under an atmosphere of N2. The reaction was cooled to
ambient temperature, poured into a mixture of ice, brine, and 5 N
NaOH, and extracted with EtOAc (2X). The organic layers were
combined, wae;hed with brine, and dried over Na2S04. Concentration
in vacuo ail'orded the desired product as a yellow oil (0.6826 g). The
product was purified by plate layer chromatography with 1:1
CH2C12/hexane to give the desired amine (0.52 g, quantitative yield).
113 NMR (CDCl3) 8: 3.72 (s, 3H), 4.29 (br s, 2 H), 6.62-6.69
(m, 3H), 6.73-6.80 (m, 2H), 7.11 (t, 1H), 7.21 (t, 1H), 7.44 (dd, 1H).
Step C:
To a thick slurry of the amine (0.277 g, 1.74 mmoles)
from Step B in 2 N HCl (1.76 mL) and HOAc (0.54 mL) was added
absolute EtOH (1.?6 mL) to solubilize the mixture. The stirred
mixture was cooled to 0°C and a solution of NaN02 (0.1552 g, 2.09
mmoles) in water (0.2 mL) was added under N2. The resulting light
brown solution was stirred at 0°C for 20 min. before adding a 93.1
mg/mL aqueous solution of KPF6 (2.7 mL). Upon addition, yellow
solid immediately precipitated out of solution. The yellow/brown solid
was collected by vacuum filtration and washed with cold water (2X)
and cold Et20 (3X). After drying in vacuo over 18 hrs, the diazonium
salt was collected as a yellow solid (0.3149 g).
1H NMR (d6-acetone) b: 3.83 (s, 3H), 7.16 (dd, 1H), 7.27 (s,
1H), 7.27-?.30 (dd, 1H), 7.47 (t, 1H), 7.79 (d, 1H), 7.88 (t, 1H), 8.18 (t,
1H), 8.84 (dd, 1H).
Step D:
A solution of FeS04~7H20 (0.2258 g, 0.81 mmoles) in
distilled water (3 mL) was heated to 100°C. The diazonium salt from
Step C was added in one portion and the resulting mixture was
CA 02304267 2000-03-14
WO 99114217 PCT/US9$/19015
-45- -
stirred at 10f1°C under N2. Gas evolution was observed for the first 5-
min. of the reaction. With time, the product oiled out of solution.
After 30 min., the reaction was partitioned between EtOAc and
ice/brine. The organic layer was collected, dried over Na2S04, and
5 concentrated in vacuo to give a green/brown oil (0.331? g). The crude
material was purified by plate layer chromatography with 20%
CH2C12/hexane to afford the desired product as a white solid (0.040 g).
-~H NMR (CDC13) 8: 4.07 (s, 3H), 6.89 (d, 1H), 7.36-7.45 (m,
4H), 7.80 (dd, 1H), 8.64 (dd, 1H).
Step E:
':~o a stirred solution of the dibenzothiophene (0.040 g,
0.19 mmoles) isolated from Step D in HOAc (2.5 mL) was added 40%
HBr (0.65 mL~, 5.6 mmoles) under N2. The reaction was heated to
130°C for 20 hrs. The resulting green solution was partitioned
between EtOAc and ice/brine. The organic layer was washed with
sat. NaHC03 (2X) and brine. The EtOAc extract was dried over
Na2S04 and concentrated in vacuo to give an ofd white solid (0.0366 g).
Purification by plate layer chromatography with 1:1 hexane/CH2Cl2
afforded the desired phenol as a white solid (0.0294 g).
~~H NMR (CDC13) 8: 5.53 (s, 1H), 6.77 (d, 1H), 7.26 (t, 1H),
7.43-7.49 (m, 3H), 7.82 (dd, 1H), 8.63 (dd, 1H).
EXAMPLE 2
PREPARATION OF CARBAPENEM 1
auy~2c
A, solution of 1-hydroxybenzothiophene (0.0294 g, 0.15
mmoles), the bis-allyl protected carbinol (0.0684 g, 0.19 mmoles), and
triphenylphos;phine (0.0592 g, 0.22 mmoles) in distilled THF (1.5 mL)
was cooled to ~0°C and placed under a N2 atmosphere. To this stirred
c o~y
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-46- ' -
solution was added dropwise diisopropylazodicarboxylate (0.06 mL,
0.22 mmoles). The reaction was stirred for 1 hr, and concentrated in
vacuo. The residue was purified by plate layer chomatography with
double elution using 20% hexane/CH2C12 to afford the coupled
product as a yellow oil (0.037 g).
»H NMR (CDC13) S: 1.28 (d, 3H), 1.43 (d, 3H), 3.40 (m,
2H), 4.18 (dd,1H), 4.58-4.63 (dd, 2H), 4.74-4.93 (m, 2H), 5.00 (d, 1H),
5.09 (m, 1H),1p.22-5.52 (m, 4H), 5.84-6.07 (m, 3H), 6.87 (d, 1H), 7.33 (t,
1H), 7.43-7.50 (m, 3H), 7.83 (dd, 1H), 8.57 (dd, 1H).
EXAMPLE 3
PREPARATION OF CARBAPENEM 2
/ 1
'- 's
HO H H
O
N
O
C 02Na
To a solution of carbapenem 1 (0.037 g, 0.068 mmoles) in
1:1 CH2C12/EtOAc (1 mL) was added under N2, 2-ethylhexanoic acid
(0.01 mL, 0.0 i'4 mmoles), 0.5 M solution of sodium-2-ethyl-hexanoate
(0.15 mL, 0.0f4 mmoles), triphenylphosphine (0.0115 g, 0.004
mmoles), and Pd(PPh3)4 (0.0175g, 0.001 mmoles) in that order. The
reaction was ,stirred at ambient temperature for 5 min. and then
stirred at 0°C for another 30 min. The product was precipitated out of
solution with .addition of Et20 (5 mL). The resulting mixture was
centrifuged and the supernatent discarded. The product was
triturated with additional Et20 (5 mL) and dried in vacuo to give a
white%range .solid (0.0146 g). The crude material was purified by
reverse phase plate layer chromatography with 7:3 H20/CH3CN. The
desired produ<;t was eluted off the silica gel with 4:1 CH3CN/H20.
Lyophilization. gave the final compound as a white solid (0.023 g).
CA 02304267 2000-03-14
WO 99/i4217 PCT/US98/19015
-47-
~~H NMR (5:2 D20/CD3CN) 8: L43 (t, 6H), 3.59-3.63 (m,
2H), 4.36-4.49: (m, 2 H), 5.24 (d, 1H), 6.05 (d, 1H), 7.35 (d, 1H), 7.70-7.83
(m, 4H), 8.19 (dd, 1H), 8.93 (dd, 1H).
EXAMPLE 4
PREPARATION OF 1-HYDROXY-5-T
BUTYLDIMETHYLSILYLOXYMETHYL DIBENZOTHIOPHENE
OH
s~
OTBS
Step A:
2;-Bromo-3-nitrotoluene and 3-methoxy benzenethiol were
coupled using the procedures described in Example 1 (Step A) to
afford the desired product as a yellow oil.
1H NMR (CDC13) 8: 2.38 (s, 3H), 3.73 (s, 3H), 6.62-6.66 (m,
2H), 6.68 (dd, 1H), 7.11 (t, 1H), 7.39 (m, 2H), 7.53 (dd, 1H).
Step B:
The coupled product from Step A was reduced to its
corresponding' amine using the procedures described in Example 1
(Step B). The amine was obtained as a green/yellow oil.
IH NMR (CDC13) 8: 2.39 (s, 3H), 3.71 (s, 3H), 6.58-6.65 (m,
3H), 6.71-6.76 (m, 2H), 7.09 (q, 2H).
Step C:
'C~tilizing the procedure described in Example 1 (Step C),
the amine from Step B was converted to its diazonium salt. The
product was isolated as a green/yellow solid.
1:H NMR (d6-acetone) $: 2.49 (s, 3H), 3.78 (s, 3H), 6.97-7.02
(m, 3H), 7.35 (it, 1H), 8.04 (t, 1H), 8.31 (d, 1H), 8.87 (d, 1H).
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
_48_
Step D:
'to a solution of the diazonium salt (0.9275 g, 2.3 mmoles)
obtained from Step C in anhydrous DMSO (20 mL) was added 3A
molecular sieves. The mixture was heated to 60°C and stirred for 1
hr. The orange mixture was filtered and the molecular sieves
washed well with EtOAc. The filtrate was collected and washed with
H20 (4X) followed by brine. The organic layer was dried over Na2S04
and concentrated in vacuo to give a dark red/orange oil. The crude
material was purified by plate layer chromatography with 2:1
hexane/CH2C12 to give the desired dibenzothiophene as a white solid
(0.1047 g).
»H NMR (CDCl3) 8: 2.58 (s, 3H), 4.08 (s, 3H), 6.91 (d, 1H),
7.25 (d, 1H), 7.36 (t, 2H), 7.47 (d, 1H), 8.50 (d, 1H).
Step E:
jJtilizing the procedure described in Example 1 (Step E),
the product from Step D was demethylated to give the phenol as a
white solid.
~~H NMR (CDC13) b: 2.58 (s, 3H), 6.77 (d, 1H), 7.24-7.31 (2d,
2H), 7.38 (t, lla), 7.43 (t,1H), 8.48 (d, 1H).
Step F:
To a solution of the phenol (0.076 g, 0.35 mmoles) from
Step E in CH2C12 (1 mL) was added NEt3 (0.059 mL, 0.42 mmoles) at
0°C under N2. The reaction was stirred for 10 min. before adding
acetyl chloride (0.027 mL, 0.39 mmoles). The reaction was then
stirred at 0°C for another 15 min. and poured into ice/H20. The
mixture was Extracted with EtOAc. The organic layers were washed
with 1 N HCl followed by brine, and dried over Na2S04.
Concentration. in vacuo gave the desired product as a light brown oil
(0.1163 g, quantitative yield).
1H NMR (CDC13) b: 2.53 (s, 3H), 2.57 (s, 3H), ?.19 (d, 1H),
7.27 (d, 1H), 7.38 (t, 1H), 7.43 (t, 1H), 7.73 (d, 1H), 8.08 (d, 1H).
Step G:
The acetylated product (0.0902, 0.35 mmoles) obtained
from Step F was dissolved in CC14 (0.5 mL) and placed under a N2
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-49-
atmosphere. NBS (0.0817 g, 0.46 mmoles) was added followed by a
crystal of AIBN. The reaction was heated to 80°C for 23 hrs. The
reaction was poured into ice/brine and extracted with EtOAc. The
organic layers were washed with 5% Na2S203 and brine.
Concentration in vacuo gave the crude product as a yellow oil (0.2085
g). The oil was purified by plate layer chromatography with 1:1
hexane/CH2C;12 to afford the alkyl bromide as a yellow solid (0.0895 g).
~1H NMR (CDC13) S: 2.53 (s, 3H), 4.77 (s, 2H), 7.23 (d, 1H),
7.46-7.52 (m, 3H), 7.76 (d, 1H), 8.22 (dd, 1H).
Step H:
'.Che alkyl bromide (0.0895 g, 0.27 mmoles) from Step G
was combined with KOAc (0.0541 g, 0.53 mmoles) in sieve-dried DMF
(1 mL) and hE:ated to 100°C for 1 hr. The reaction was poured into
icelH20 and extracted with EtOAc. The organic layers were washed
with additional H20 (2X) and brine, and dried over Na2S04.
Concentration in vacuo gave an orange/red oil (0.114 g). The oil was
purified by plate layer chromatography with 3:1 CH2Cl2lhexane to
give a pale yellow solid (0.0635 g).
~-H NMR (CDC13) b: 2.17 (s, 3H), 2.55 (s, 3H), 5.38 (s, 2H),
7.21 (d, 1H), 7.44-7.49 (m, 3H), 7.73 (d, 1H), 8.22 (dd, 1H).
Step I:
A yellow mixture of the product (0.0635 g, 0.2 mmoles)
from Step H, ;i N NaOH (0.1 mL, 0.42 mmoles), and absolute EtOH (1
mL) was heated to 70°C under N2 for 15 min. The reaction was
partitioned bEaween EtOAc and iceJl N HCI. The organic layer was
washed with hrine, dried over Na2S04, and concentrated in vacuo to
give an orange solid (0.0637 g). The solid was purified by plate layer
chromatography with 5% EtOAc/CH2C12 to give the desired product
as a slightly orange solid (0.0335g).
lH NMR (CDC13+CD30D) 8: 4.76 (s, 2H), 6.71 (d, 1H), ?.07
(t, 1H), 7.17 (d., 1H), 7.24-7.28 (m, 2H), 8.45 (d, 1H).
Step J:
To a flask charged with the phenol (0.0335 g, 0.16
mmoles) from Step I was added a solution of TBSCl (0.0305 g, 0.17
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-50-
mmoles) in D:MF (0.5 mL) under N2. The reaction was cooled to 0°C
and stirred for 10 min. before adding dropwise a solution of imidazole
(0.0137g, 0.19 mmoles) in DMF (0.25 mL). The solution was stirred at
0°C for 1 h. ~'he reaction was partitioned between EtOAc and ice/1 N
HCI. The organic layer was washed with brine, dried over Na2S04,
and concentrated in vacuo to give a light brown oil. The oil was
purified by plate layer chromatography with 3:1 CH2C12/hexane to
afford the TBS-protected alcohol as a light yellow solid (0.0416 g).
1H NMR (CDCl3) 8: 0.15 (s, 3H), 0.98 (s, 6H), 4.97 (s, 2H),
6.76 {d, 1H), 7.26 (t, 1H), 7.45-7.48 (m, 3H), 8.55 (dd, 1H).
EXAMPLE 5
PREPARATION OF CARBAPENEM 3
OH
' ~S
allylz0 C O H H
O
N
0
C02a0y1
Step A:
L7tilizing the procedure from Example 2, 1-hydroxy-5-t-
butyldimethylsilyloxymethyl dibenzothiophene was coupled with bis-
allyl carbinol i;o afford the desired product as a yellow/orange oil after
plate layer chromatography with 3:1 CH2C12/hexane.
1:H NMR (CDC13) b: 0.15 (s, 3H), 0.98 (s, 6H), 1.27 (d, 3H),
1.41 (d, 3H), 3.41-3.44 (m, 2H), 4.14 (dd, 1H), 4.56-4.58 (m, 2H), 4.75-4.85
(m, 2H), 4.96 (s, 2H), 4.98 (d, 1H), 5.08-5.12 (m, 1H), 5.21-5.48 (m, 4H),
5.80-6.03 (m, 3H), 6.86 {d, 1H), 7.32 (t, 1H), 7.46-7.49 (m, 3H), 8.51 (dd,
1H).
Step B:
To a solution of the adduct (0.0572 g, 0.083 mmoles)
obtained from Step A in distilled THF (1 mL) was added HOAc (0.028
mL, 0.496 mmoles) followed by 1 M TBAF in THF (0.25 mL, 0.248
mmoles). The reaction was stirred at ambient temperature for 3 hrs.
CA 02304267 2000-03-14
WO 99/14217 PCT/I1S98/19015
-$1-
The reaction was partitioned between EtOAc and H20/brine. The
organic layer was washed with sat. NaHC03 (2X) and brine, and
dried over Na2S04. After removing the solvent in vacuo, a yellow oil
was obtained (0.053 g). The oil was purified by plate layer
$ chromatography with double elution using 5% EtOAc/CH2C12 to
afford the desired phenol as a yellow/orange oil (0.0349 g).
~~H NMR (CDCl3) 8: 1.27 (d, 3H), 1.41 (d, 3H), 3.41-3.44 (m,
2H), 4.14 (dd, 1H), 4.56-4.58 (m, 2H), 4.75-4.85 (m, 2H), 4.96 (d, 2H),
4.98 (d, 1H), 5.08-5.12 (m, 1H), 5.21-5.48 (m, 4H), 5.80-6.03 (m, 3H), 6.86
(d, 1H), 7.32 (t , 1H), 7.46-7.49 (m, 3H), 8.51 (dd, 1H).
EXAMPLE 6
PREPARATION OF CARBAPENEM 4
O,~N~
-- 's
HO H ~
O
N
O
CO ~
1$
Step A:
To a solution of carbapenem 3 (0.0349 g, 0.060 mmoles) in
sieve-dried CH2Cl2 (1 mL) was added 1-methyl imidazole (0.011 mL,
0.13 mmoles) ,at -20°C followed by Tf20 (0.011 mL, 0.066 mmoles). The
reaction was stirred at -20°C for 1.5 h and then partitioned between
ice/H20 and CH2Cl2. The organic layer was washed with brine,
dried over Na;2S04, and concentrated in vacuo to give a pale yellow oil
(0.0562 g). Tl:~e oil was redissolved in CH2C12 (0.5 mL) and the
product was precipitated out with Et20 as an oil. The mixture was
2$ centrifuged and the supernatent discarded. The oil was washed with
Et20 and dried in vacuo (0.0462 g, quantitative yield).
1H NMR (CDC13) S: 1.27 (d, 3H), 1.42 (d, 3H), 3.36-3.47 (m,
2H), 3.96 (s, 3H), 4.17 (dd, 1H), 4.56-4.60 (m, 2H), 4.71-4.90 (m, 2H), 4.99
(d, 1H), 5.06-5.16 (m, 1H), 5.21-5.49 (m, 4H), 5.62 (s, 2H), 5.79-6.05 (m,
CA 02304267 2000-03-14
WO 99/14217 PGT/US98/19015
-52-
3H), 6.89 (d, 1H), 7.23-7.2? (m, 2H), 7.35 (t, 1H), 7.44 (d, 1H), 7.49-7.60
(m, 2H), 8.57 (dd, 1H), 9.31 (s, 1H).
Step B:
The product from Step A was deblocked using the
procedures dE;scribed in Example 3 to afford the final compound as a
white solid after lyophilization.
~-H NMR (5:2 D20/CD3CN) 8: 1.42-1.46 (2d, 6H), 3.57-3.62
(m, 2H), 4.07 Ia, 3H), 4.33-4.43 (m, 2H), 5.23 (d, 1H), 5.88 (s, 2H), 6.02
(d, 1H), 7.37 (d, 1H), 7.67-7.91 (m, 6H), 8,98 (d, IH).
EXAMPLE 7
PREPARATION OF CARBAPENEM 5
/ ~N~~~CONH2
S ~C, I/~
HO H H
O
N
1S ~ CO~
Step A:
To a stirred solution of carbapenem 3 (0.0895 g, 0.16
mmoles) in sieve-dried CH2C12 (1.5 mL) was added NEt3 (0.032 mL,
0.23 mmoles) at -6°C under N2 followed by dropwise addition of MsCl
(0.016 mL, 0.2.0 mmoles). The reaction was stirred at -6°C for 15 min.,
and then poured into ice/1 M HCI. The resulting mixture was
extracted with EtOAc. The organic layer was washed with brine,
dried over Na;,S04, and concentrated in vacuo to give a pale yellow oil
(0.1027 g, 98%~ yield). The crude mesylate was dissolved in acetone (2
mL) and cooled to 0°C. NaI (0.0465 g, 0.31 mmoles) was added in one
portion under N2. With time the reaction became increasingly
yellow. The rE~action was stirred at 0°C for 1 hr and then partitioned
between ice/brine and EtOAc. The organic layer was dried over
Na2S04 and concentrated in vacuo to afford the alkyl iodide as a
yellow oil (0.1045 g).
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-53-
~~H NMR (CDC13) 8: 1.27 (d, 3H), 1.41 (d, 3H), 3.35-3.42 (m,
1H), 3.43 (dd, 1H), 4.14 (dd, 1H), 4.57-4.59 (m, 2H), 4.68 (s, 2H), 4.71-
4.89 (m, 2H), 4.99 (d, 2H), 5.06-5.13 (m, 1H), 5.21-5.51 (m, 4H), 5.80-6.03
(m, 3H), 6.86 t d, 1H), 7.32-7.52 (m, 4H), 8.49 (d, 1H).
Step B:
To a solution of the alkyl iodide (0.1045 g, 0.15 mmoles)
obtained from Step A in sieve-dried acetonitrile (2 mL) was added
dabco acetamide triflate salt (0.0481 g, 0.15 mmoles) followed by
Ag4Tf (0.039~E g, 0.15 mmoles) at ambient temperature under N2.
Upon addition of AgOTf, a yellow precipitate formed. The resulting
mixture was stirred for 40 min. and filtered through a celite pad.
The celite wa.~ washed well with acetonitrile and the filtrate
concentrated i.n vacuo. The residue was dissolved in acetone (4 mL)
and filtered tlxrough a cotton plug into a centrifuge tube. The solution
was reconcentrated under a stream of N2 to give a rose-colored oil
(0.1585 g, quantitative yield).
1:H NMR (dg-acetone) 8: 1.35-1.41 (2d, 6H), 3.56-378 (m,
2H), 3.34 (dd, 1H), 4.34 (dd, 1H), 4.52-4.88 (m, 18H), 5.01-5.57 (m, 8H),
5.80 (d, 1H), 5.87-6.05 (m, 2H), 7.18 (d, 1H), 7.20-7.25 (bs, 1H), 7.53 (t,
1H), 7.62-7.71 (m, 3H), 7.86 (d, 1H), 8.91 (d, 1H).
Step C:
The product (0.0696 g, 0.068 mmoles) from Step B was
deblocked using the procedure described in Example 3 with the
exception of sieve-dried DMF as the solvent. The reaction became
increasingly cloudy over time. After 1 hr, the reaction was cooled to
0°C and the product was further precipitated with the addition of
acetone. The crude material (0.0377 g) was collected as a hexanoate
salt after washing with acetone and centrifugation. The compound
was dissolved in a minimal amount of H20 and purified via a
reverse-phase HPLC equipped with a 10 mL column of MacroPrep ion
exchange resin in conjunction with a 10 mL column of Amberchrom
CG 161.
The following :EiPLC conditions used are listed below:
CA 02304267 2000-03-14
WO 9Q/14217 PCT/US98/19015
-54-
Macroprep column
Timefminl Flow ratefmL/minl
_ 1 an
0-5 10 water
5-10 10 5% NaCI
10-30 15 5% NaCl
Amberchrom CG 161 column
Timefminl Flow ratejmlJminl ant
(linear gradiE~t
0-15 10 water
15-20 10 100% H20 to 60:40
CH3CN/H20
1 S After lyophili:zation, the final compound was obtained as a white solid
(0.0155 g).
~~H NMR (5:2 D20/CD3CN) 8: 1.47 (d, 6H), 3.60-3.67 (m,
2H), 4.33-4.82 (m, 16H), 5.24-5.31 (m, 3H), 6.02 (d, 1H), 7.42 (d, 1H),
7.78-7.96 (m, 4H), 9.07 (dd, 1H).
EXAMPLE 8
PREPARATION OF 1-HYDROXY-5-T
BUTYLDIMETHYLSILYLOXYPROPYL DIBENZOTHIOPHENE
OH
Step A:
The acetylated dibenzothiophene (0.3985, 1.55 mmoles)
obtained from Example 4 (Step F) was dissolved in CC14 (5 mL) and
place under a N2 atmosphere. Recrystallized NBS (0.3051 g, 1.7
mmoles) was added followed by a crystal of AIBN. The reaction was
heated to 80°C; for 23 hrs. Additional NBS (0.3067 g, 1.7 mmoles) was
CA 02304267 2000-03-14
- WO 99/14217 PCT/US98/19015
-55-
added to the reaction and the mixture was stirred at 80°C for another
6.5 hrs. The reaction was poured into ice/brine and extracted with
EtOAc. The organic layers were washed with 5% Na2S203 and brine.
Concentration in vacuo gave an orange solid (0.5974 g). By 1H NMR
5 analysis, the crude product contained a 3:1 mixture of the desired
dibrominated product to the monobrominated product or 74% yield of
dibrominated product.
~-H NMR (CDC13) S: 2.55 (s, 3H), 6.96 (s, 1H), 7.25 (d, 1H),
7.48-7.50 (m, 2H), 7.76 (t, 2H), 8.24 (d, 1H).
Step B:
~'he crude alkyl bromide (0.4670 g, 1.1 mmoles) from Step
A was dissolved in sieve-dried DMF (5 mL) and placed under N2.
KOAc (0.3396 g, 3.4 mmoles) was added in one portion and the
reaction was heated to 100°C. After 1.5 hrs, The reaction was
partitioned beaween EtOAc and H20. The organic layer was washed
with water (3:K) and brine, dried over Na2S04, and concentrated in
vacuo to give ;~ brown/yellow oil (0.6382 g). The oil was purified by
plate layer chromatography with 4 elutions using 3:2 CH2C12/hexane
to give 2 major fractions: 1) the triacetate compound (0.1403 g) and 2)
a mixture of tlhe diacetate compound and the aldehyde (0.2077 g).
1H NMR (CDC13) 8: 2.18 (s, 6H), 2.55 (s, 3H), 7.23 (d, 1H),
7.47 (t, 2H), 7.61 (d, 1H), ?.75 (d, 1H), 7.93 (s, 1H), 8.31 (dd, 1H).
Step C:
Z'he fraction from Step B containing the triacetate
compound (0.7.255 g, 0.4 mmoles) was suspended in absolute EtOH (2
mL) and 5 N NaOH (0.15 mL, 0.8 mmoles) was added under N2. The
reaction was heated to 70°C for 20 min. then poured into ice/1 M HCl.
The mixture was extracted with EtOAc. The organic layer was
collected, washed with brine, dried over Na2S04, and cocentrated in
vacuo to give an orange solid (0.1065 g). The solid was purified by
plate layer chi°omatography with 5% EtOAc/CH2Cl2 to afford the
clean aldehyde as a yellow solid (0.0756 g).
1:H NMR (CDC13+d6-acetone) S: 6.73 (d, 1H), 7.0? (t, 1H),
7.21 (d, 1H), 7.40 (t, 1H), 7.73 (d, 1H), 8.78 (dd, 1H), 9.00 (bs, 1 H), 10.04
(s, 1H).
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-56-
Step D:
'The fraction from Step B containing a mixture of the
diacetate compound and the aldehyde (0.2077 g, 0.77 moles) was
submitted under the same reaction conditions described in Step C.
The resultin~; mixture of aldehyde and diol was separated by plate
layer chromatography with 5% EtOAc/CH2Cl2 to give 0.0895 g of
clean aldehy~de.
Step E:
'rhe aldehydes from Step C and Step D were combined
and acetylated using the procedures described in Example 4 (Step F).
The reaction was stirred at 0°C for a total of 30 min. The desired
product was isolated as tan solid.
-~H NMR (CDCl3) 8: 2.57 (s, 3 H), 7.29 (d, 1 H), 7.50 (t, 1 H),
7.65 (t 1 H), 7.32 (d, 1 H), 7.99 (dd, 1 H), 8.54 (dd, 1 H), 10.29 {s, 1 H).
Step F:
The acetylated product (0.1572 g, 0.58 mmoles) from Step
E was dissolved in CH2Cl2 (3 mL) and methyl
(triphenylphosphoranylidene)-acetate (0.2141 g, 0.64 mmoles) was
added under :~T2. The mixture was stirred at ambient temperature
for 1.5 hrs. T'he reaction was concentrated in vacuo to give a
white/yellow solid. The solid was purified by plate layer
chromatography with 5% hexane/CH2C12 to give the desired ester as
a white solid (0.1688g).
~~H NMR, (CDC13) 8: 2.54 (s, 3 H), 3.86 (s, 3H), 6.6? (d, 1H),
7.24 (d, 1H), 7.48 (t 2H), 7.66 (d, 1H), 7.77 (d, 1H), 7.95 (d, 1H), 8.28 (d,
1H).
Step G:
To a solution of the ester obtained from Step F (0.1688 g,
0.51 mmoles) :in 1:1 EtOAc/EtOH was added 10% Pd/C (0.0186, 10%
w/w). The resulting mixture was degassed with N2 and
hydrogenated under atmospheric H2 pressure for 3 hrs. The reaction
was degassed with N2 and the catalyst removed by filtering through a
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-57-
celite pad. The filtrate was concentrated in vacuo to give a
white/yellow solid (0.1595 g).
1H NMR (CDC13) 8: 2.53 (s, 3 H), 2.80 (t, 2H), 3.21 (t, 2H),
3.70 (s, 3H), 7.21 (t, 1H), 7.31 (d, 1H), 7.40-7.49 (m, 2H), 7.73 (dd, 1H),
8.12 (dd, 1H).
Step H:
'hhe alkyl ester isolated from Step G (0.1595 g, 0.49
mmoles) was dissolved in absolute EtOH (2 mL), and 5 N NaOH (0.29
mL, 1.5 mmoles) was added under N2. The resulting yellow mixture
was heated to 70°C. After 1 hr, the reaction was partitioned between
ice/1 M HCl and EtOAc. The organic layer was washed with brine,
dried over Na~2S04, and concentrated in vacuo to afford the desired
acid as a pale yellow solid (0.1614 g, quantitative yield).
-~H NMR (CDC13+d6-acetone) 8: 2.77 (t, 2H), 3.15 (t, 2H),
6.81 (d, IH), T.18-7.26 (m, 2H), 7.32 (t, 1H), 7.32 (d, 1H), 8.52 (d, 1H).
Step I:
To a solution of the carboxylic acid generated in Step H
(0.1614, 0.49 :mmoles) in distilled THF (5 mL) was added dropwise a 1
M solution of BH3~THF in THF (0.98 mL, 0.98 mmoles). Upon
addition, gas evolution was observed. With time, the reaction became
a cloudy green mixture. The reaction was stirred at ambient
temperature i:or a total of 2 hrs. The reaction was quenched with
dropwise addition of MeOH until no further gas evolution was
observed. The reaction mixture was concentrated in vacuo and the
residue was purified by plate layer chromatography with 5%
EtOAc/CH2Cl2 to give the desired diol as a white solid (0.1065 g).
~~H NMR (CDCl3+d6-acetone) 8: 1.88 (m, 2H), 2.81 (t, 2H),
3.5? (t, 2H), 6.74 (d, 1H), 7.08 (t, 2H), 7.10 (d, 1H), 7.21-7.27 (m, 2H),
8.42
(d, 1H), 8.69 (bs, 1 H).
Step J:
tJtilizing the procedure described in Example 4 (Step J),
the diol obtained from Step I was selectively protected at the primary
alcohol position to give the desired TBS-protected product as a yellow
oil after plate layer chromatography with 5% EtOAc/CH2C12.
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-58-
~~H NMR (CDC13) 8: 0.07 (s, 3H), 0.92 (s, 6 H), 1.99 (m,
2H), 2.92 (t, 2:H), 3.70 (t, 2H), 6.74 (d, 1H), 7.24-7.27 (m, 2H), 7.38-7.43
(m, 2H), 8.48 (d, 1H).
EXAMPLE 9
PREPARATION OF CARBAPENEM 6
OH
S
allyl20 C O H H
O
N
O
C 02allyl
Step A:
1-Hydroxy-5-t-butyldimethylsilyloxypropyl
dibenzothioph.ene was coupled with the bis-allyl protected carbinol
using the procedure described in Example 2 to give the adduct as a
yellow oil after plate layer chromatography with 3:1 CH2C12/hexane.
1H NMR (CDC13) 8: 0.09 (s, 3H), 0.94 (s, 6H), 1.29 (d, 3H),
1.43 (d, 3H), 1..98 (m, 2H), 2.93 (t, 2H), 3.35-3.48 (m, 2 H), 3.70 (t, 2H),
4.17 (dd, 1H), .4.58-4.63 (m, 2H), 4.74-4.93 (m, 2H), 5.00 (d, 1H), 5.09-5.18
(m, 1H), 5.22-5.52 (m, 4H), 5.84-6.07 (m, 3H), 6.87 (d, 1H), 7.26-7.51 (m,
4H), 8.43 (dd, 1H).
Step B:
The adduct from Step A was desilylated following the
procedures presented in Example 5 (Step B) with the exception that
the reaction was stirred for 4.5 hrs. The desired alcohol was isolated.
1:H NMR (CDC13) 8: 1.29 (d, 3H), 1.43 (d, 3H), 1.98 (m,
2H), 2.93 (t, 2H), 3.35-3.48 (m, 2 H), 3.70 (m, 2H), 4.17 (dd, 1H), 4.58-
4.63 (m, 2H), 4.74-4.93 (m, 2H), 5.00 (d, 1H), 5.09-5.18 (m, 1H), 5.22-5.52
(m, 4H), 5.84-E~.07 (m, 3H), 6.87 (d, 1H), 7.26-7.51 (m, 4H), 8.43 (dd, 1H).
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-59-
EXAMPLE 10
PREPARATION OF CARBAPENEM 7
H2
C 02v
Step A:
To a solution of carbapenem 6 (0.0561 g, 0.093 mmoles} in
sieve-dried CFi2Cl2 (1 mL) at -8°C was added 2,6-lutidine (0.016 mL,
0.14 mmoles) under N2 followed by Tf20 (0.017 mL, 0.10 mmoles).
After 25 min., additional Tf20 (1.1X) and 2,6-lutidine (1.5X) was
added to the reaction. The reaction was stirred for another 10 min
before partitioning the reaction between EtOAc and ice/1 M HCI. The
organic layer was washed with brine, dried over Na2S04, and
concentrated in vacuo to give the crude triflate as a yellow oil (0.0778
g, quantitative yield).
1:H NMR (CDC13) 8: 1.29 (d, 3H), 1.43 (d, 3H), 2.31 (m,
2H), 3.02 (t, 2Ii), 3.35-3.48 (m, 2 H), 4.17 (dd, 1H), 4.58-4.63 (m, 4H),
4.74-4.93 (m, 2H), 5.00 (d, 1H), 5.09-5.18 (m, 1H), 5.22-5.52 (m, 4H),
5.84-6.07 (m, 3H), 6.89 (d, 1H), 7.26-7.52 (m, 4H), 8.44 (dd, 1H).
Step B:
To a solution of the triflate obtained from Step A (0.0778
g, 0.093 mmoles) in sieve-dried CH3CN was added dabco acetamide
triflate salt (0.0298 g, 0.093 mmoles) under N2. The reaction was
stirred at ambient temperature for 1 hr and 20 min. The reaction
was concentrated in vacuo to give a rose-colored oil (0.106 g). The oil
was dissolved in acetone (2.5 mL) and the product was precipitated
out of solution with the addition of Et20 (8 mL). The solid was
isolated by centrifugation and rewashed with Et20 to give the desired
product (0.078.'3 g).
CA 02304267 2000-03-14
WO 99/14217 PGT/US98/19015
-60-
1~H NMR (d6-acetone) 8: 1.38 (d, 6H), 2.51 (m, 2H), 3.05 (t,
2H), 3.54 (m, :lH), 3.69-3.77 (m, 2H), 4.00 (m, 2H), 4.32-4.88 (m, 19H),
5.10-5.51 (m, EiH), 5.78 (d, 1H), 5.87-6.06 (m, 2H), 7.09 (d, 1H), 7.23 (bs,
1H), 7.43-7.51 (m, 3H), 7.57 (d, 1H), 7.68 (bs, 1H), 8.59 (dd, 1H).
Step C:
Z'he dabco quat from Step B was deallylated following the
procedures described in Examples 7 (Step C) to afford the desired
product as a vvhite solid.
1H NMR (5:2 D20/CD3CN) 8: 1.40 (d, 6H), 2.44 (m, 2H),
3.16 (t, 2H), 3.60-3.69 (m, 2H), 3.78 (m, 2H), 4.09-4.82 (m, 16H), 5.28 (d,
1H), 5.97 (d, 1~H), 7.31 (d, 1H), 7.59 (d, 1H), 7.67-7.79 (m, 3H), 8.78 (d,
1H).
EXAMPLE 11
PREPARATION OF CARBAPENEM 8
C02Na
Step A:
A solution of carbapenem 1 (0.099 g, 0.18 mmoles) in
CH2C12 (2 mL) was cooled to 0°C and a solution of 85 wt% MCPBA
(0.0436 g, 0.20 mmoles) in CH2C12 (2 mL) was added over 10 min. via
a dropping funnel. The reaction was allowed to stir at 0°C for 30 min.
The reaction v~~as quenched with 5% Na2S203 and extracted with
EtOAc. The organic layer was washed with 5% Na2S203 and brine,
dried over Na~;S.04, and concentrated in vacuo to give a yellow oil
(0.093 g). The oil was purified by plate layer chromatography with
10% EtOAc/CH2Cl2 to afford the sulfoxide as a mixture of
diastereomers (0.0496 g).
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-61-
1H NMR (CDC13) b: 1.26 (d, 3H), 1.41 (dd, 3H), 3.25-3.49
(m, 2H), 4.17 (m, 1H), 4.57 (m, 2H), 4.71-5.51 (m, 8H), 5.76-6.05 (m,
3H), 7.06 (t,1H ), 7.40-7.64 (m, 4H), 7.97 (d, 1H), 8.16 (dd, 1H).
Step B:
The final compound was isolated in 60% yield after
submitting thE~ sulfoxide obtained in Step A to the conditions
described in Example 3.
1E3 NMR (5:2 D20/CD3CN) 8: 1.45 (d, 6H), 3.52-3.63 (m,
2H), 4.36-4.44 (m, 2 H), 5.20 (dd, 1H), 6.03 (dd, 1H), 7.63 (d, 1H), ?.81
7.93 (m, 3H), 7.98 (t, 1H), 8.28 (d, 1H), 8.60 (d, 1H).
EXAMPLE 12
PREPARATION OF CARBAPENEM 9
0
1
HO H H
O
N
O
C02Na
The sulfone was prepared in an analogous manner to
Example 11 using 3 equivalents of MCPBA in the oxidation step
(Example 11, ~~tep A). The final compound was isolated as a white
solid.
1H NMR (5:2 D20/CD3CN) 8: 1.50 (2d, 6H), 3.59 (m, 1H),
3.67 (dd, 1H), 4.43 (dd, 1H), 4.45 (m, 1H), 5.30 (d, 1H), 6.11 (d, 1H), 7.77
(d, 1H), 7.80 (d, 1H), 7.92 (t, 2H), 8.10 (t, 1H), 8.21 (d, 1H), 8.69 (d, 1H).
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-62-
EXAMPLE 13
PREPARATION OF CARBAPENEM 10
O+~CONHp
7 CI~
C02
T'o a solution of carbapenem 5 (0.0100 g, 0.016 mmoles) in
1:1 acetone/H~;O (1 mL) was added 0.44 mL of a stock solution (0.024
g/mL) of dimethyl dioxirane in acetone at 0°C under N2. The reaction
was followed by reverse-phase HPLC. After 50 min., an additional
0.040 mL of dimethyl dioxirane was added to the reaction. The
reaction was stirred for another 20 min., then concentrated in vacuo.
The aqueous residue was lyophilized to give the sulfoxide in 54%
purity by l:Ei NMR and W as a white solid (0.0071 g).
1JH NMR (5:2 D20/CD3CN) 8: 1.45 (m, 6H), 3.27-3.61 (m,
2H), 4.28-4.82 ~;m, 16 H), 5.04-5.46 (m, 3H), 5.73-5.93 (m, 1H), 7.53-8.15
(m, 5H), 8.62-Ft.? 1 (m, 1H).
EXAMPLE 14
PREPARATION OF CARBAPENEM 11
0
~~~CONH2
~../O
0 2 ~OTf
al1y120C0 H H
O
N
O
, c o2l~l
Step A:
Carbapenem 3 was treated with 3 equivalents of a 0.057
M solution of dimethyl dioxirane in acetone in the same manner
CA 02304267 2000-03-14
WO 99/14217 PCTNS98/19015
-63-
described in Example 13 with the exception that the reaction was
complete within 20 min. Purification of the crude material by plate
layer chromatography with 15% EtOAc/CH2C12 gave the desired
sulfone in quantitative yield.
lH NMR (CDC13) 8: 1.23 (d, 3H), 1.43 (d, 3H), 3.27 (m,
1H), 3.45 (dd, 1H), 4.19 (dd, 1H), 4.58-4.91 (m, 4H), 4.94 (d, 1H), 5.08-
5.51 {m, 7H), 5.78 (d, 1H), 5.83-6.05 (m, 2H), 7.11 (dd, 1H), 7.44-7.66 (m,
4H), 8.12 (d, 1:H).
Step B:
T'he sulfone generated in Step A was converted to the
alkyl iodide following the procedures described in Example 7 {Step A)
with the exception that initial mesylation was complete after 35 min.
and 5 equivalE:nts of NaI at ambient temperature for 4.5 hrs was
necessary to drive the reaction to completion. The iodide was isolated
in quantitative yield as a red/orange oil.
I:H NMR (CDCl3) b: 1.23 (d, 3H), 1.41 (d, 3H), 3.24 (m,
1H), 3.45 (dd, :lH), 4.19 (dd, 1H), 4.58-4.90 (m, 4H), 4.78 (s, 2H), 4.93 (d,
iH), 5.07-5.51 (m, 5H), 5.78 (d, 1H), 5.83-6.05 (m, 2H), 7.I1 (m; 1H),
7.44-7.59 (m, 4H), 8.06 (d, 1H).
Step C:
Utilizing the procedure from Example 7 (Step B) with the
exception that the reaction was stirred at ambient temperature for 19
hrs, the dabco quaternized carbapenem was prepared by reacting the
alkyl iodide isolated from Step B with the dabco acetamide triflate
salt.
IH NMR (d6-acetone) 8: 1.35 (d, 6H), 3.50 (m, 1H), 3.72
(dd, 1H), 4.34 (dd, 1H), 4.58-4.87 (m, 18H), 5.09-5.50 (m, 8H), 5.77 (d,
1H), 5.89-6.05 I;m, 2H), 7.22 (bs, 1H), 7.52 (t, 2H), 7.66-7.76 (m, 3H), 7.93-
$.02 (m, 2H), 8.69 (dd, 1H).
CA 02304267 2000-03-14
WO 9914217 PCT/US98/19015
EXAMPLE 15
PREPARATION OF CARBAPENEM 12
~~NO~C O N H2
O
..._ 1 S,O ~OTf
HO H H
O
N
O
C02~
A mixture of carbapenem 11 (0.0761 g, 0.072 mmoles),
triphenylphosphine (0.028 g, 0.011 mmoles), Pd(PPh3)4 (0.0047 g,
0.036 mmoles), and dimedone (0.0302 g, 0.20 mmoles) in sieve-dried
DMF (1 mL) vvas sparged with N2. iPr2NEt (0.037 mL, 0.20 mmoles)
was then added. The reaction was stirred at ambient temperature for
1 hr. The product was precipitated out of solution with Et20 (6 mL).
The mixture was centrifuged and the supernatent was discarded.
The solid pellet was washed with Et20 and recentrifuged. The pellet
was collected .and dried in vacuo to give an off white solid (0.050 g).
0.012 g of the crude material was purified on reverse phase HPLC by
eluting the compound through a 10 mL column of Amberchrom CG
161 with a linear gradient (100% water to 40:60 CH3CN/H20 over 35
min). The aqueous fractions were lyophilized to give the desired
product in 82°o purity (0.0082 g).
1H NMR (5:2 D20/CD3CN) S: 1.44 (t, 6H), 3.52-3.61 (m,
1H), 3.66 (dd, 1H), 4.49-4.86 (m, 16H), 5.29-5.40 (m, 3H), 6.03 (d, 1H),
7.79-7.84 (2d, 2H), 7.95-8.03 (m, 2H), 8.21 (t, 1H), 8.90 (d, 1H).
EXAMPLE 16
PREPARATION OF 1-HYDROXY-5-T-
BUTYLDIMETHYLSILYLOXYMETHYL DIBENZOFURAN
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-65-
Step A:
To a mixture of 2,6-difluoronitrobenzene (1.0 g, 6.3
mmoles) in MeOH (10 mL) was added a 4.4 M solution of NaOMe in
MeOH (1.57 mL, 6.9 mmoles). The mixture was heated to 70°C for 20
min. The resulting orange reaction mixture was concentrated in
vacuo. The residue was dissolved in EtOAc and washed with H20
and brine. The organic layer was dried over Na2S04 and
concentrated in vacuo to give a pale yellow solid. The solid was
purified by plate layer chromatography with 1:1 hexane/CH2Cl2 to
give clean prodluct as a pale yellow solid (1.0559 g).
1H NMR (CDCl3) 8: 3.89 (s, 3H), 6.77-6.85 (m, 2H), 7.36-
7.41 (m, 1H).
Step B:
The methoxy nitrobenzene isolated from Step A was
coupled with o-cresol (0.64 mL, 6.2 mmoles) using the procedures
described in E~;ample 1 (Step A) with the exception that the reaction
time was 3 hrs. After purification by plate layer chromatography
with 1:1 hexane/CH2C12, the desired adduct was obtained as a pale
yellow solid.
1H NMR (CDCl3) S: 2.18 (s, 3H), 3.91 (s, 3H), 6.27 (d, 1H),
6.66 (d, 1H), 6.98 (d, 1H), ?.10-7.27 (m, 4H).
Step C:
The adduct from Step B ( 1.3924 g, 5.4 mmoles) was
hydrogenated under 40-46 psi of H2 in a Parr Shaker for 5 days using
10% Pd/C (0.139 g, 10 w/w) in 1:1 EtOH/EtOAc. The catalyst was
filtered off through a celite pad and the filtrate was concentrated in
vacuo. The product was obtained as a yellow oil ( 1.2833 g, quantitative
yield).
1H NMR (CDCl3) b: 2.30 (s, 3H), 3.88 (s, 3H), 6.36 (m,
1H), 6.60 (m, 2H), 6.79 (d, 1H), 6.97 (t, 1H), 7.08 (t, 1H), 7.21 (d, 1H).
Step D:
The amine from Step C was converted to its KPF6
diazonium salt using the procedures described in Example 1 (Step C).
The product was isolated as a yellow solid.
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/I9015
-66-
1H NMR (ds-acetone) 8: 2.26 (s, 3H), 4.36 (s, 3H), 6.57 (d,
1H), 7.25 (d, l:Ei), 7.32 (d, 1H), 7.38 (t, 2H), 7.46 (dd, 1H), 8.17 (t, 1H).
Step E:
A mixture of 0.438 g (0.48 mmoles) of Pd2(dba)3 in
anhydrous DMSO (30 mL) was heated to 100°C under N2 and the
diazonium salt from Step D ( 1.8489 g, 4.8 mmoles) was added in one
portion, resulting in significant gas evolution: The reaction was
stirred at 100"C for 40 min and then filtered through celite. The
filtrate was paritioned between EtOAc and water. The organic layer
was washed well with H20 (2X) followed by brine. The organic layer
was dried over Na2S04 and concentrated in vacuo to give a black
solid. The solid was purified by plate layer chromatography with 2:1
hexane/CH2C:l2 to give the desired product as a white solid (0.4335 g).
1H NMR (CDC13) 8: 2.59 (s, 3H), 4.05 (s, 3H), 6.77 (d, 1H),
7.20-7.27 (m, 3.H), 7.35 (t, 1H), 7.95 (dd, 1H).
Step F:
The dibenzofuran from Step E was demethylated and
acetylated usi:ng the procedures described in Example 1 (Step E) and
Example 4 (Step F) respectively. The desired product was obtained as
a white solid over the 2 steps.
l:Ei NMR (CDCl3) b: 2.50 (s, 3H), 2.58 (s, 3H), 7.11 (dd,
1H), 7.21-?.30 (m; 2H), 7.41-7.50 (m, 2H), 7.64 (dd, 1H).
Step G:
0,1126 g (0.49 mmoles) of acetylated dibenzofuran from
Step F, recryst;allized NBS (0.0970 g, 0.54 mmoles), benzoyl peroxide
(0.0271 g, 0.099 mmoles), and CC14 (3 mL) were combined under N2
and heated to 100°C. In addition to heating, the reaction was
illuminated with a sun lamp. Within 30 min., the reaction became
dark purple. After 2 hrs, another 0.3 equivalents of NBS and 0.0312 g
of benzoyl peroxide were added. The reaction was heated for another
2 hrs, and then partitioned between EtOAc and 5% Na2S203. The
organic layer was washed with H20 and brine, dried over Na2S04,
and concentrated in vacuo to give a dark purple solid. The solid was
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
purified by plate layer chromatography with 2:1 CH2Cl~hexane to
afford the desired alkyl bromide as an off white solid (0.081 g).
~~H NMR (CDC13) b: 2.50 (s, 3H), 4.84 (s, 2H), 7.16 (dd,
1H), 7.30 (t, lIEI), 7.47-7.55 (m, 3H), ?.77 (dd, 1H).
Step H:
The diacetate was prepared after plate layer
chromatography with 2:1 CH2C12/hexane, from the alkyl bromide of
Step G using the procedures described in Example 4 (Step H).
~~H NMR (CDC13) b: 2.14 (s, 3H), 2.51 (s, 3H), 5.49 (s, 2H),
7.15 (dd, 1H), 7.32 (t, 1H), 7.44-7.52 (m, 3H), 7.80 (dd, 1H).
Step I:
Z'he diacetate from Step H was treated under the same
conditions as :Example 4 (Step I) to give the crude diol.
1H NMR (CDCl3+CD30D) 8: 5.00 (s, 2H), 6.67 (d, 1H),
7.03 (d, 1H), 7.19-7.30 (m, 2H), 7.38 (dd, 1H), 8.02 (dd, 1H).
Step J:
Z'he diol from Step I was selectively protected at the
primary position using the procedures described in Example 4 (Step
J) to give the desired product as a white solid after plate layer
chromatography with 2:1 CH2C12/hexane.
1H NMR (CDC13) 8: 0.15 (s, 3H), 0.97 (s, 6H), 5.15 (s, 2H),
6.68 (d, 1H), 7.15 (d, 1H), 7.25 (t, 1H), 7.33 (t, 1H), 7.53 (d,1H), 7.98 (d,
1H).
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-b8-
EXAMPLE 17
PREPARATION OF CARBAPENEM 13
O~~~CONH2
o ~/
HO H H
O
N
O
C 02~
Step A:
~'he carbapenem adduct was prepared by coupling 1-
hydroxy-5-t-butyldimethylsilylmethyl dibenzofuran with bis-allyl
protected carbinol in an analogous manner to Example 2 to give the
desired product as a light purple oil.
1H NMR (CDC13) 8: 0.15 (s, 3H), 0.97 (s, 6H), 1.30 (d, 3H),
1.44 (d, 3H), 3.,46 (dd, 1H), 3.49 (m, 1H), 4.20 (dd, 1H), 4.60 (dd, 2H),
4.72-4.91 (m, ~;H), 4.96 (d, 1H), 5.09-5.51 (m, 5H), 5.13 (s, 2H), 5.73 (d,
1H), 5.85-6.07 (m, 2H), 6.77 (d, 1H), 7.21 (t, 1H), 7.31-7.40 (m, 2H), 7.52
(t, .1H), 7.92 (d, 1H).
Step B:
Desilylation of the carbapenem from Step A was
accomplished using the procedures described in Example 5 (Step B) to
give the desirE~d alcohol as a yellow oil.
1:H NMR (CDCl3) S: 1.30 (d, 3H), 1.44 (d, 3H), 3.46 (dd,
1H), 3.49 {m, 1H), 4.20 (dd, 1H), 4.60 {dd, 2H), 4.72-4.91 (m, 2H), 4.96 (d,
1H), 5.08 (s, 2H), 5.10 (m, 1H), 5.24-5.51 (m, 4H), 5.73 (d, 1H), 5.85-6.07
(m, 2H), 6.70 (.d, 1H), 7.23-7.50 (m, 4H), 8.03 (dd, 1H).
Step C:
The alcohol from Step B was converted to its
corresponding alkyl iodide following procedures presented in
Example 7 (Step A).
1:H NMR (CDC13) b: 1.30 (d, 3H), 1.44 (d, 3H), 3.46 (dd,
1H), 3.49 (m, 1H), 4.20 (dd, 1H), 4.60 (m, 2H), 4.71-4.89 (m, 2H), 4.75 (s,
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-69-
2H), 4.95 (d, 1H), 5.09-5.49 (m, 5H), 5.73 (d,1H), 5.85-6.07 (m, 2H), 6.77
(d, 1H), 7.23-7.48 (m, 4H), 7.92 (d, 1H).
Step D:
Lltilizing the procedures presented in Example? (Steps B
and C), the al:l~yl iodide from Step C was displaced by dabco acetamide
triflate salt and deallylated to afford the final compound. Purification
of the crude product was achieved on reverse-phase HPLC by eluting
the compound. through a 10 mL column of Amberchrom CG 161 with
a linear gradient (100% water to 40:60 CH3CN/H20 over 45 min).
1H NMR (5:2 D20/CD3CN) 8: 1.41 {d, 6H), 3.59-3.70 (m,
2H), 4.23-4.82 (m, 16H), 5.16 (d, 1H), 5.29 (s, 2H), 5.89 (d, 1H), 7.24 (d,
1H), 7.53 (d, lJEi), 7.73-7.89 (m, 3H), 8.51 (d, IH).
EXAMPLE 18
PREPARATION OF CARBAPENEM 14
Step A: Preparation of 3-hydroxybiphenyl
A stirred mixture of 660mg(3mmo1) of 3-iodophenol,
439mg (3.6mmo1) phenylboronic acid, and 173mg (0.15mmo1)
tetrakistriphenylphosphine in lOmL of toluene, 5mL ethanol, and
6mL 2M sodium carbonate (aqueous) was heated at IOOoC in an inert
atmosphere of nitrogen for 15 minutes. The cooled mixture was
partitioned between EtOAc, ice, and brine and the organic phase was
separated, washed with brine, dried over anhydrous Na2S04, filtered
and evaporated. The residue was purified by plate layer
chromatography (PLC) using CH2Cl2 as the eluant to give 430mg of
the title product.
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-70- _
Step B:
Following the procedure outlined in Example 2 and
using 28.2mg (0.165mmo1) of 3-hydroxybiphenyl there was obtained
after plate layer chromatography using methylene chloride as the
eluant, 58.9mg of carbapenem 14, containing some 3-
hydroxybiphenyl, which was used without further purification.
1H NMR (CDC13) 8: 1.26 (d, J=7.3Hz,3H), 1.47 (d,
J=6.3Hz, 3H), 3.47 (dd, J=3.0, llHz, 1H-6), 3.50 (m, 1H-1), and 4.2 (dd,
J=3.0, lOHz, 1H-5).
EXAMPLE 19
PREPARATION OF CARBAPENEM 15
Following the procedure outlined in Example 3 and
using the carbapenem derivative prepared in Example 18, 9.4mg of
carbapenem 15 was obtained after purification by reverse phase plate
layer chromatography using water-acetonitrile (7:3) as eluant and
lyophilization.
IR (nujol) : 1750 and 1596 cm-1;
1H NMR (D20-CD3CN,5:2) S: 1.43 (d, J=7.3Hz, 3H), 1.5 (d,
J=6.3Hz, 3H), 3.56 (m, 1H-1), 3.62 (dd, J= 2.8, 5.7Hz, 1H-6), 4.36 (dd, J=
2.6, 9.9Hz, 1H-5), 4.45 (m, 1H-8), 5.06 (d, J=13.8Hz), 1H), 5.85 (d,
J=13.8Hz, 1H), 7.28-?.96 (m, 9 ArH);
L;rV: ~,max 252nm(H20).
CA 02304267 2000-03-14
WO 99/14217 PCT/US98J19015
EXAMPLE 20
PREPARATION OF CARBAPENEM 16
OSiPh2CMe3
Step A: Preparation of 4'-t-butyldiphenylsilyloxymethyl-3-
hydroxybiphE~nyl
A.s described in Example 18, step A, 391mg ( 1 mmol) of 4-
t-butyldiphenylsilyloxymethylboronic acid (prepared as exemplified
in US 5,192,758) and 220 mg (1 mmol) of 3-iodophenol gave 354.3mg of
the title compound.
Step B:
I! ollowing the procedure of Example 2, 153.5mg
(0.35mmo1) of 4'-t-butyldiphenylsilyloxymethyl-3-hydroxybiphenyl
was utilized to prepare 89.2mg of carbapenem 16 containing some of
the latter which was used without further purification.
EXAMPLE 21
PREPARATION OF CARBAPENEM 17
7.'o a stirred solution of carbapenem 16, prepared in
Example 20, i:n 1mL of THF at OoC was added sequentially 19.5mL
(0.34mmo1) of acetic acid and 227mL (0.23mmo1) of a 1.0 M solution of
tetrabutylam~nonium fluoride in THF. The resulting mixture was
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
stirred with t:he ice-water bath removed for six hours. The mixture
was partitioned between ether, ice-water, and saturated NaHC03
solution and t;he organic phase separated, washed with brine, dried
over Na2S04, filtered, and evaporated. Purification by plate layer
chromatography using CH2Cl2-EtOAc(10:1) as eluant provided
19.7mg of carbapenem alcohol.
I:R (CH2Cl2): 3604,1779, 1746, and 1719cm-1;
1H NMR (CDC13) 8: 1.26 (d, J=7.2Hz,3H), 1.46 (d,
J=6.3Hz, 3H), 1.72 (t, J=5.7Hz, 1-OH), 3.45 (dd, J=3.0, 8.lHz, 1H-6),
3.50 (m, 1H-1), 4.19 (dd, J=3.0, lOHz, 1H-5), 5.13 (m, 1H-8), 4.75 (d,
J=5.7Hz, 2H), 6.86-7.6 (m, 8 ArH).
EXAMPLE 22
PREPARATION OF CARBAPENEM 18
C;H
To a stirred solution of 19.7mg (0.036 mmol) of the
carbapenem 1'T from Example 21 and 6.3mL (0.079 mmol) of N-
methylimidazole in 1 mL of sieve dried CH2Cl2 at -23oC in an inert
atmosphere of nitrogen was added 6.7mL (0.0396 mmol) of neat triflic
anhydride. The resulting mixture was stirred at -23oC for 70 minutes
and then partitioned between water and CH2C12 and the organic
phase was separated, dried over Na2S04, filtered, and evaporated to
give 26.3mg of a colorless foam.
lla NMR (CDCl3) S: 1.25 (d, J=7.4Hz,3H), 1.45 (d,
J=6.2Hz, 3H), :3.45 (dd, J=3.0, 8.lHz, 1H-6), 3.50 (m, 1H-1), 3.97 (s, N-
CH3); 4.19 (dd, J=3.1, lOHz, 1H-5), 5.13 (m, 1H-8), 5.4 (s, 2H), 6.88-?.66
(m, 10 ArH), 9.32 (bs, 1H).
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-73-
EXAMPLE 23
PREPARATION OF CARBAPENEM 19
HO H H
O
O
Co2 0
Following the procedure outlined in Example 3, the
carbapenem 18 prepared in Example 22 was deallylated to provide
9.5mg of 19 afl;er purification by reverse phase chromatography (RP-
PLC) using wader-acetonitrile (7:3) as eluant and lyophilization.
IFL.(nujol): 1754, 1589cm-1;
1H NMR (D20-CD3CN,5:2) 8: 1.44 (d, J=7.3Hz, 3H), 1.5 (d,
J=6.5Hz, 3H), 3.54 (m, 1H-1), 3.62 (dd, J= 2.9, 5.7Hz, 1H-6), 4.14 (s, N-
CH3), 4.33 (dd, J= 2.6, 9.97Hz, 1H-5), 4.45 (m, 1H-8), 5.07 (d, J=14.3Hz),
1H), 5.68 (s, 21::f), 5.88 (d, J=14.3Hz, 1H), 7.3-8.02 (m, 10 ArH);
UV: ~.m~ 258:nm(H20).
EXAMPLE 24
PREPARATION OF CARBAPENEM 20
0
CH2=CHCH202C H t~
~N~
COzCH2CH=Chit
A.~ previously described in Example 2, 33.1mg
(0.168mmol) of commercially available 4-hydroxyfluoren-9-one gave
44.2mg of carbapenem 20 containing some of the latter which was
used without further purification.
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-74-
EXAMPLE 25
PREPARATION OF CARBAPENEM 21
0
HO H H
O ~
N
O
C02Na
Using the procedure described in Example 3,
carbapenem 20 prepared in Example 24 was deallylated to provide
12.5mg of carlbapenem 21 after RP-PLC and lyophilization.
IR (nujol): 1754, 1712, 1593cm-1;
1H NMR (D20-CD3CN,5:2) 8: 1.48 (d, J=7.3Hz, 3H), 1.49
(d, J=7.7Hz, 3:H), 3.62 (m, 1H-1), 3.65 (m, 1H-6), 4.42 (m, 1H-5), 4.47
(m, 1H-8), 5.lfi (d, J=13.5Hz), 1H), 5.95 (d, J=13.5Hz, 1H), 7.5-8.08 (m, 7
ArH);
LTV: ~,m~ 253nm(H20).
EXAMPLE 26
PREPARATION OF CARBAPENEM 22
I~
CHr-CHCH20zC H H
N
O CO CH
z 2CH=CHZ
Step A: Preparation of 4-Hydroxy-fluorene
A, partial solution of 196.2mg (1 mmol) of 4-hydroxy-
fluoren-9-one iin 2mL EtOAc and 3 mL EtOH with 40mg 10% Pd/C was
stirred under a balloon of hydrogen for 27.5 hours. The catalyst was
removed by filtration through celite, washed well with EtOAc, and
the filtrate ev<~porated. The residue was purified by plate layer
chromatography with CH2C12-EtOAc(50:1) to give 102.7mg of the title
substance.
1:H NMR (d6-acetone) 8: 3.88 (s, CH2).
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-75-
Step B:
ZJsing the procedure outlined in Example 2, 29.7mg (0.16
mmol) of 4-hydroxyfluorene, prepared above, provided 57.2mg of
carbapenem 2.2, which contained a small amount of the latter, and
was used witlZOUt further purification.
1H NMR (CDC13) S: 1.28 (d, J=7.3Hz,3H), 1.43 (d,
J=6.3Hz, 3H), 3.43 (dd, J=3.0, 7.9 Hz, 1H-6), 3.50 (m, 1H-1), 3.91 (s, 2H),
4.17 (dd, J=3.C1, lOHz, 1H-5), 5.13 (m, 1H-8), 4.91 (d, J=14.1Hz, 1H), 5.74
(d, J= 14.1 Hz), 6.83-8.05 (m, 7ArH).
EXAMPLE 27
PREPARATION OF CARBAPENEM 23
w
I ,
HO H H
O
N
O
C02Na
L7sing the deallylation procedure described in Example 3
and the material prepared in the above example, l9mg of
carbapenem 23 was produced after purification and lyophilization.
Ilk, (nujol): 1753, 1582cm-1;
1:H NMR (D20-CD3CN,5:2) S: 1.44 (app. d, 6H), 3.fi1 (m,
1H-1 & 1H-6), 4.17 (s, 2H), 4.33 (m, 1H-5), 4.42 (m, 1H-8), 5.16 (d,
J=13.8Hz), 1H), 5.99(d, J=13.8Hz, 1H), 7.27-8.42 (m, 7 ArH);
Z;rV: Amax 269nm(H20).
EXAMPLE 28
PREPARATION OF CARBAPENEM 24
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-76-
C02CHs
Step A: Preparation of 4-Hydroxy-9-carbomethoxy-fluorylidene
A, stirred mixture of 401mg (2 mmol) of 4-hydroxy-
fluoren-9-one and 1.378 (4.1mmo1) of methyl-
(triphenylphosphoranylidene)-acetate in lOmL of toluene was
refluxed under an atmosphere of nitrogen for 65.5 hours. The cooled
reaction mixture was evaporated and the residue purified by plate
Iayer chromatography using CH2Cl2-EtOAc (50:1) as eluant to give
433mg of the title compound as a mixture of isomers.
1H NMR (CDC13) S: 3.87 (s, 3H), 3.88 (s, 3H), 6.74-8.89 (m,
8H).
Step B:
A.s previously described in Example 2, 39.2mg
(0.156mmo1) of fluorylidene prepared in Step A was converted into
75.7mg of carbapenem 24 as a mixture of isomers and containing
some of the latter, which was used without further purification.
l:Ei NMR (CDC13) b: 1.25 (m, 3H), 1.42 (d, J=6.3Hz, 3H),
3.40 (m, 1H-1),, 3.43 (m, 1H-6), 3.85 (s, 3H), 3.86 (s, 3H), 4.18 (m, 1H-5),
5.11 (m, 1H-8), 6.7-8.88 (m, 8H).
EXAMPLE 29
PREPARATION OF CARBAPENEM 25
C02CHa
HO H H
C02Na
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
_77_
using the procedure described in Example 3 and the
material prepared in Example 28, 15.4 mg of carbapenem 25 was
produced as a, mixture of geometric isomers.
IJR (nujol): 1751, 1717, 1630, 1586cm-1;
S 1H NMR (D20-CD3CN,5:2) S: 1.48 (app. t, 6H), 3.63 (m,
1H-1 & 1H-6), 4.13 (s, 3H), 4.4(m, 1H-5), 4.46 (m, 1H-8), 5.16 (d,
J=13.9Hz), 1H), 5.97(d, J=13.9Hz, 1H), 7.08-8.88 (m, 8H);
L~~ Amax 330, 263nm(H20).
EXAMPLE 30
PREPARATION OF CARBAPENEM 26
C02CH3
O
Step A: Preparation of 4-Hydroxy-9-carbomethoxymethyl-fluorene
A stirred mixture of 348mg (1.38 mmol) of the
fluorylidene derivative prepared in Example 28, Step A, and 50mg of
10% Pd/C in lOmL of EtOAc-EtOH (1:1) was hydrogenated under
balloon pressure at ambient temperature for 2.5 hours. The catalyst
was removed by filtration through celite, washed well with EtOAc,
and the filtrate evaporated and dried in vacuo to give 348.5mg of the
title product.
113 NMR (CDC13) 8: 2.77 (d, J=7.3Hz, 2H), 3.79 (s, 3H),
4.42 (t, J=7.3Hz,1H), 5.6 (s, OH), 6.72-8.09 (m, 7ArH).
Step B:
As previously described in Example 2, 53mg (0.208
mmol) of the fluorene derivative prepared above provided after
purification by PLC eluting with CH2C12-EtOAc (50:1), 88mg of
carbapenem 2fi , as an equimixture of diastereomers, and containing
a little phenoli.c starting material, which was used without further
purification.
C02CH2CH=CH2
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
~~H NMR (CDC13) 8: 1.28 (d, J=7.3Hz, 3H), 1.44 (2d's, 3H),
2.75 (2d's, 2H;1, 3.43 (m, 1H-1 & 1H-6), 3.85 (s, 3H), 3.78 (2s's, 3H), 4.18
(2dd's, 1H-5), 4.41 (t, J=7.3Hz, 1H), 5.11 (m, 1H-8), 6.84-8.04 (m,
7ArH).
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-~9-
EXAMPLE 31
PREPARATION OF CARBAPENEM 27
C02Na
Using the procedure described in Example 3 and the
material prepared in the previous example, 28.3mg of carbapenem 27
was produced after RP-PLC purification and lyophilization.
IIt(nujol): 1754, 1?37, 1603, 1584cm-1;
1H NMR (D20-CD3CN,5:2) 8: 1.48 (app. d, 6H), 3.14 ( d,
J=6.9Hz, 2H), 3.65 (m, 1H-1 & 1H-6), 3.97 (s, 3H), 4.4 (m, 1H-5), 4.46
(m, 1H-8), 4.63 (t, J= 6.9Hz, 1H), 5.18 (d, J=13.9Hz), 1H), 5.99(d,
J=13.9Hz, 1H), ?.33-8.42 (m, 7ArH);
W: Amax 270nm(H20).
EXAMPLE 32
PREPARATION OF CARBAPENEM 28
Step A: Preparation of 4-Hydroxy-9-hydroxyethyl-fluorene
To a stirred solution of 277.5mg (1.09mmol) of the ester
prepared in Step A of Example 30 in 5mL of anhydrous THF at OoC
was added dro:pwise l.lmL (l.lmmol) of a 1M solution of lithium
aluminum hydride in ether. The resulting mixture was stirred at
OoC under nitrogen for 1.5 hours and then carefully quenched with
Glaubers salt. The mixture was partitioned between EtOAc, ice, 2N
HCl, and brine and the organic phase was separated, washed with
cozcH~H=CHz
CA 02304267 2000-03-14
WO 99/14217 PCTNS98/19015
brine, dried over Na2S04, filtered, and evaporated. The residue was
purified by PLC with CH2C12-EtOAc (10:1) to give 236.8mg of the title
compound.
1H NMR (CDC13) 8: 2.33 (q, J= 6.8Hz, 2H), 3.57 (t, J=
6.8Hz, 2H), 4.:13 (t, J=6.8Hz), 6.08 (s, OH), 6.68-8.13 (m, 7ArH).
Step B: Preparation of 4-Hydroxy-9-silyoxyethyl-fluorene
A mixture of 236.8mg (1.05mmo1) of carbinol, prepared
in the previous example, 173.5mg ( 1.15mmo1) of t-
butyldimethylchlorosilane, and 85.5mg (1.26mmo1) of imidazole in
5mL of sieve-dried DMF was stirred at OoC under nitrogen for 40
minutes. The mixture was partitioned between EtOAc, ice, 2N HCI,
and the organic phase was separated, washed twice with ice-water
and then with brine, dried over Na2S04, filtered, and evaporated. The
residue was purified by PLC with CH2C12-EtOAc (50:1) to give
325.1mg of the title compound.
1H NMR (CDC13) b: 0.03 (s, 6H), 0.88 (s, 9H), 2.19(m, 2H),
3.67 (t, J= 6.8Hz, 2H), 4.13 (t, J=6.4Hz), 5.12 (s, OH), 6:71-8.10 (m,
7ArH).
Step C:
Using the procedure described in Example 2 and the
material prepared in the above example, 478.1mg of carbapenem 28
was produced as an equimixture of diastereomers after PLC using
CH2C12-EtOAc (50:1) as eluant.
1:H NMR (CDC13) 8: 0.05 (s, 6H), 0.86 (s, 9H), 1.28 (d,
J=7.3Hz, 3H), 1.44 (d, 3H), 2.14 (m, 2H), 3.44 (m, 1H-1 & 1H-6), 3.65 (m,
2H), 4.11 (m, 1H), 4.20 (2dd's, 1H-5), 5.12 (m, 1H-8), 6.81-8.05 (m,
7ArH).
CA 02304267 2000-03-14
WO 991t4217 PCT/US98119015
-gl-
EXAMPLE 33
PREPARATION OF CARBAPENEM 29
Using the procedure outlined in Step B of Example 5 and
the material prepared in the above example, 220.9mg of the title
carbapenem was produced after purification by PLC using CH2Cl2-
EtOAc(10:1) a.; eluant.
1H NMR (CDC13) 8: 1.28 (2dd's, J=7.3Hz, 3H), 1.44 (app. t,
3H), 2.29 (m, 2H), 3.46 (m, 1H-1 & 1H-6), 3.56 (m, 2H), 4.12 (m, 1H),
4.20 (2dd's, 1H-5), 5.12 (m, 1H-8), 6.82-8.04 (m, 7ArH).
EXAMPLE 34
PREPARATION OF CARBAPENEM 30
CH3
N
To a stirred mixture of 51.5mg (0.09mmo1) of carbinol 29,
prepared in the previous example, and 16.2mg (0.2mmo1) of N-
methyl-imidazole in 1mL of sieve-dried CH2C12 at OoC was added
dropwise 27.9mg (0.99 mmol) of neat triflic anhydride. The mixture
was stirred at 0oC for 20 minutes and then with the ice-water bath
removed for 3 hours. The mixture was partitioned between H20 and
CH2C12 and tree organic phase was separated, dried over Na2S04,
filtered, evaporated, and dried in vacuo. The residue was taken up in
a minimum amount of CH2C12 and carbapenem 30 was precipitated
C02CH2CH=CH2
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
by the addition of Et20. After decantation of the supernatant and
drying in vacuo, 49.7mg of imidazolium salt 30 was obtained.
1H NMR (CDC13) S: 1.26 & 1.30 (2d's, J=7.3Hz, 3H), 1.42 &
1.45 (2d's, J=6.4Hz, 3H), 2.87 (m, 2H), 3.34 & 3.60 (2m's, 1H-1), 3.45
(2dd's, 1H-6), 3.72 & 3.73 (2s's, N-CH3), 3.76 (m, 2H), 4.15 & 4.31
(2dd's, 1H-5), 4.2 (m, 1H), 5.12 (m, 1H-8), 6.54-7.99 (m, 9H), 8.6 & 8.66
{2s's, 1H).
EXAMPLE 35
PREPARATION OF CARBAPENEM 31
CH3
N
N
O
C02 "
Using the procedure described in Example 3 and the
carbapenem prepared in the above example, 14.8mg of carbapenem
31 was produced.
IR (nujol): 1756, 1595, 1583cm-1;
11a NMR (D20-CD3CN,5:2) b: 1.5 (m, 6H), 3.1 (m, 2H), 3.6
(m, 1H-1), 3.7 {2dd's, 1H-6), 3.8{2s's, 3H), 4.05 (m, 2H), 4.35-4.45 (m,
3H), 5.18 & 5.2;5 (2d's, 1H), 5.98 (app. t, 1H), 7.2-8.42 (m, 7ArH);
UV: ~,m~ 271nm(H20).
CA 02304267 2000-03-14
WO 99/14217 PCTNS98/19015
-83-
EXAMPLE 36
PREPARATION OF CARBAPENEM 32
oMs
~2~ H H
O
N
O COzCH2CH=CH2
7.'o a stirred solution of 220.9mg (0.39 mmol) of
carbapenem carbinol 29, prepared in Example 33, in 3mL of sieve
dried CH2C12 at OoC was added sequentially 58.5mg (0.58 mmol) of
triethylamine and 57.4mg (0.5 mmol) of mesyl chloride. The mixture
was stirred further for 11 minutes, and the mixture was partitioned
between EtOAc, ice, 2N HCl, and brine and the organic phase was
separated, washed with brine, dried over Na2S04, filtered,
evaporated, and dried in vacuo to give 249.3mg of carbapenem 32
which was used without further purification.
1H NMR (CDC13) s: 2.760 & 2.765 (2s's, OS02CH3).
EXAMPLE 37
PREPARATION OF CARBAPENEM 33
A. mixture of 240.$mg (0.37 mmol) of carbapenem 32,
prepared in the previous example, and 249.6mg (1.6 mmol) of sodium
iodide in 3 mL~ acetone was stirred at ambient temperature for 55
hours. The mixture was partitioned between EtOAc, ice, 5% aqueous
sodium thiosulfate, and brine and the organic phase was separated,
washed with brine, dried over Na2S04, filtered, evaporated, and dried
C02CH2CH=CH2
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-84-
in vacuo to give 244.2mg of carbapenem 33 which was used without
further purification.
lH NMR (CDC13) 8: 2.53 (m, 2H), 3.0 (m, 2H).
S EXAMPLE 38
PREPARATION OF CARBAPENEM 34
O
~CONH2
OTf
A, mixture of 136.6mg (0.2mmol) of carbapenem 33,
63.9mg (0.2mxnol) of N-acetamidodiazoniabicyclooctane triflate, and
51.3mg (0.2mmo1) of silver triflate in l.SmL of acetonitrile was stirred
at ambient temperature for 25 hours. The insoluble AgI was removed
by filtration through celite, and the filtrate evaporated and dried in
vacuo. The re.;idue was taken up in acetone, refiltered, and the
filtrate concentrated. Upon the addition of Et20, the title compound
separated, and it was again reprecipitated from acetone, and dried in
vacuo to give JL50.2mg of 34, containing some of the starting salt,
which was used without further purification.
~-H NMR (d6-acetone) 8: 4.27 (m, 6H), 4.49 (m, 6H), 4.61
(m, 2H).
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-g$-
EXAMPLE 39
PREPARATION OF CARBAPENEM 35
O
~N~CONH2
N O
CI
HO
H H
O
N
O
C02 0
ZJsing the procedure described in Example 3 and
carbapenem 34, prepared in the foregoing example, 15.7mg of
carbapenem 35 was produced after purification on macroprep and
amberchrom 161 resins.
IR (nujol): 1749, 1695, 1583cm-1;
~-H NMR (D20-CD3CN,5:2) 8: 1.44 (m, 6H), 2.92 (m, 2H),
3.18 (m,2H), 3.5-3.75 (m, 1H-1 & 1H-6), 4.0(m, 6H), 4.35 (m, 6H), 5.07-
5.18 (2d's, 1H;1, 5.88-5.96 (2d's, 1H), 7.28-8.37 (m, 7ArH);
j~: Amax 271nm(H20).
EXAMPLE 40
PREPARATION OF CARBAPENEM 36
w
H20TBS
~ 02C H H
O ~
N
O
COzCH~H=CHz
Step A: Preparation of 4-Acetoxy-9-(2-t-butyldimethylsilyloxyethyl)-
fluorene
To a stirred solution of a mixture of 1.91g (5.6 mmol) of
the phenol, prepared in Step B of Example 32, and 736.6mg (7.28
mmol) of triet:hylamine in 20mL of CH2C12 at OoC was added 527.5mg
(6.72 mmol) of neat acetyl chloride and the mixture was stirred
further for 0.5 hour. The mixture was partitioned between EtOAc,
ice, 1N HCl, and brine and the organic phase was separated, washed
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
_g6_
with brine, dried over Na2S04, filtered, evaporated, and dried in
vacuo to give 2.14g of crude product which was used without further
purification.
1H NMR (CDC13) b: 0.86 (s, 9H), 2.47 (s, 3H).
Step B: Preparation of 4-Acetoxy-9-bromo-9-(2-t-
butyldimethylsilyloxyethyl)-fluorene
A mixture of 2.14g (5.6 mmol) of material prepared in
the previous step, 1.2g (6.72 mmol) of N-bromosuccinimide, and a
pinch of AIBTf in 20mL of carbon tetrachloride was refluxed under
nitrogen for 1.5 hours. The cooled mixture was partitioned between
EtOAc, ice, 5°o aqueous sodium thiosulfate, and brine and the
organic phase was separated, washed with brine, dried over Na2S04,
filtered, evaporated, and dried in vacuo to give the crude, title product
which was used without further purification.
1H NMR (CDC13) 8: 0.73 (s, 9H), 2.47 (s, 3H), 2.91 (m, 2H),
3.20 (m, 2H).
Step C: Prepay.°ation of 4-Acetoxy-9-E,Z-t-
butyldimethylsilyloxyethenyl-
fluorene
A mixture of the crude product from the previous step,
913mg (10.9 mmol) of NaHC03, and 1.54g (5.98 mmol) of silver triflate
in 25mL DMS~O was stirred at room temperature for 15 minutes. The
mixture was diluted with EtOAc, filtered through celite to remove the
insoluble materials, and washed thoroughly with EtOAc. The filtrate
was partitioned between EtOAc, ice, and brine and the organic phase
was separated, washed twice with ice-water, and then with brine,
dried over Na~;S04, filtered, evaporated, and dried in vacuo.
Purification by PLC eluted with CH2Cl2-hexanes (1:1) gave 1.22g of
product, as a mixture of geometric isomers.
113 NMR (CDC13) 8: 0.17 (s, 6H), 0.98 (s, 9H), 2.48 (s, 3H),
5.02 (m, 2H).
Step D: Preparation of 4-Hydroxy-9-E,Z-t-
butyldimethylsilyloxyethenyl-fluorene
To a stirred, warm solution of 1.19g (3.13 mmol) of
acetate, prepai~ed in the previous step, in 20mL EtOH was added
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
dropwise 0.77mL (3.85 mmol) of a 5N solution of sodium hydroxide in
water. The resulting dark solution was stirred further for 5 minutes
and then partitioned between EtOAc, ice, 1N HCI, and brine. The
organic phase was separated, washed with brine, dried over Na2S04,
filtered, evaporated, and dried in vacuo. Purification by PLC eluted
with CH2Cl2 ,gave 890.Omg of product, as a mixture of geometric
isomers.
1H NMR (CDC13) b: 0.15 (s, 6H), 0.96 (s, 9H), 4.98 (m, 2H);
5.18 & 5.22 (2;;'s, 1-OH), 6.68-8.1 (m, 8H).
Step E:
L;~sing the procedure outlined in Example 2 and 423.7mg
(1.25mmo1) of the mixture of phenols prepared in the previous step,
555mg of carbapenem 36 was produced which contained a little of the
starting phenol and was used without further purification.
1:H NMR (CDCl3) 8: 0.15 (s, 6H), 0.95 (s, 9H), 1.27 (d,
J=7.3Hz), 1.43 (d, 6.3Hz), 3.44 (m, 1H-1 & 1H-6), 4.17 (m, 1H-5), 5.12
(m, 1H-8), 6.7 i'-8.1 (m, 8H).
EXAMPLE 41
PREPARATION OF CARBAPENEM 37
CHzOH
02C0 H H
O ~
N
O
COzCHzCH=CHz
To a stirred solution of a mixture of carbapenem 36,
prepared in the prior example, and 292mg (4.86mmol) of acetic acid
in lOmL of THF was added 2.43mL (2.43mmol) of a 1M solution of
tetrabutylammonium fluoride in THF. The mixture was stirred
further for 1.2.5 hour, and then partitioned between EtOAc, ice,
saturated NaHC03 solution, and brine. The organic phase was
separated, washed with brine, dried over Na2S04, filtered,
evaporated, anal dried in vacuo. Purification by PLC eluted with
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
CH2C12-EtO.~c (10:1) gave 306mg of product 37, as a mixture of
geometric isomers.
1H NMR (CDC13) b: 1.27 (d, J=7.3Hz), 1.43 (d, J=6.3Hz),
3.44 (m, 1H-1 & 1H-6), 4.18 (m, 1H-5), 5.12 (m, 1H-8), 6.81-8.04 (m, 8H).
EXAMPLE 42
PREPARATION OF CARBAPENEM 38
l:Tsing the procedure described in Example 3, 27.6mg
(0.048mmo1) of carbapenem 37 in 1mL of CH2C12-DMF provided
16.2mg of carbapenem 38 after RP-PLC developed with water-
acetonitrile (c~:1).
I:R (nujol): 1747, 1599cm-1;
~=H NMR (D20-CD3CN,5:2) S: 1.49 (m, 6H), 3.65 (m, 1H-I
& 1H-6), 4.4 (gym, 1H)-5, 4.48 (m, 1H-8), 5.22(m, 3H), 6.03 (m, 1H), 7.17-
8.43 (m, 8H);
1;TV: ~,m~ 261nm(H20).
EXAMPLE 43
PREPARATION OF CARBAPENEM 39
Tss
1 ,
CH2=CHCH202C H
N
O
COZCH2CH=CH2
Step A: Preparation of 2-Methoxy-6-carbomethoxy-4'-t-butyi-
diphenylsilyloxymethylbiphenyl
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
_g9_
I:Tsing the procedure described in Step A of Example 18,
lO.Og (34.2mrnol) of methyl-2-iodo-3-methoxybenzoate (prepared as
outlined by V~~. M. Stanley, E. McMahon, and R. Adams, J. Amer.
Chem. Soc. 1933, 55, 706) was refluxed for 5 hours to give after
chromatography on silica gel with CH2C12-hexanes (2:1) l2.lg of the
title compound.
~~H NMR (CDC13) S: 1.14 (s, 9H), 3.57 (s, 3H), 3.78 (s, 3H),
7.1-7.77 (m, ArH).
Step B: Preparation of 2-Methoxy-4'-hydroxymethylbiphenyl-6-
carboxylic acid
A stirred mixture of 6.Og ( 11.7mmo1) of biphenyl
derivative prepared in Step A and 4.7mL of 5N NaOH in 100mL of
EtOH was refluxed in an inert atmosphere of nitrogen for 4 hours.
The mixture was partitioned between EtOAc, ice, 2N HCI, and the
organic phase was separated, washed with brine, dried over Na2S04,
filtered, evaporated, and dried in vacuo. Upon addition of a little
CH2C12 the product crystallized and after the addition of some
hexanes 1.95g~ of the product was collected by filtration and dried in
vacuo.
(m, 7ArH).
1H NMR (dg-acetone) b: 3.74 (s, 3H), 4.64 (s, 2H), 7.17-7.44
Step C: Preparation of 4-Methoxy-7-chloromethyl-fluoren-9-one
To a stirred suspension of 2.Og (7.74mmo1) of acid
prepared in Stxp B in 40mL of sieve- dried CH2C12 at OoC was added
all at once 3.55g (l7.Ommo1) of phosphorous pentachloride and the
mixture was stirred further for 5 minutes, and then for 1 hour with
the ice-water bath removed. The homogenous solution was retooled to
OoC, and 1.55; (11.6mmo1) of A1C13 was added all at once. The
resulting mixture was stirred further for 0.5 hour and then
partitioned between EtOAc, ice, and brine. The organic phase was
separated, washed with brine and saturated NaHC03, dried over
Na2S04, filtered, evaporated, and dried in vacuo to give 2.04g of the
title material as a yellow solid, which was used without further
purification.
IFi, (CH2C12): 1717.5cm-1;
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-90-
1H NMR (CDCl3) 8: 3.90 (s, 3H), 4.53 (s, 2H), 6.94-7.68 (m,
6ArH).
Step D: Preparation of 4-Methoxy-7-acetoxymethyl-fluoren-9-one
A mixture of 2.Og (7.7mmol) of material prepared in Step
C and 1.52g (115.5mmo1) of potassium acetate in 30mL of DMF was
stirred at 100'~C under nitrogen for 36 minutes. The cooled mixture
was partitionE:d between EtOAc and ice-water and the organic phase
was separated, washed twice with ice-water, and then with brine,
dried over Na;~S04, filtered, evaporated, and dried in vacuo to give
2.17g of the title material as a yellow solid, which was used without
further purification.
LR (CH2C12): 1742, 1718cm-1;
1H NMR (CDCl3) 8: 2.12 (s, 3H), 3.99 (s, 3H), 5.10 (s, 2H),
7.04-7.81 (m, EiArH).
Step E: Preparation of 4-Methoxy-7-hydroxymethyl-fluoren-9-one
A. stirred mixture of the acetate prepared above and
3.07mL (15.4mmol) of 5N NaOH in 100mL of EtOH was refluxed
under nitrogen for 10 minutes. The cooled mixture was partitioned
between EtOA~c, ice-water and 2N HCI, and the organic phase was
separated, washed with brine, dried over Na2S04, filtered,
evaporated, arid dried in vacuo to give 2.078 of the title material as a
yellow solid, which was used without further purification.
1:H NMR (CDC13) 8: 3.96 (s, 3H), 4.68 (s, 2H), 7.01-7.77 (m,
6ArH ).
Step F: Preparation of 4-Methoxy-7-formyl-fluoren-9-one
To a stirred suspension of 1.85g (7.69mmo1) of carbinol
from Step E in 50mL CH2C12 was added 270.1mg (0.769mmol) of
tetrapropylam.monium perruthenate. After stirring for 5 minutes,
1.35g (11.5mrnol) of solid N-methyl-morpholine-N-oxide was added all
at once, and tile resulting mixture stirred further for 5 minutes. The
dark solution was passed over a column of florisil eluted with
CH2C12-EtOAc (10:1) to give 1.42g of the title aldehyde as a yellow
solid.
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-91-
(s, 1H).
IR (CH2C12): 1720, 1698cm-1;
-~H NMR (CDC13) b: 4.02 (s, 3H), 7.09-8.1 (m, 6ArH), 10.0
Step G: Preparation of 4-Hydroxy-7-formyl-fluoren-9-one
A stirred mixture of the methylether from the previous
step and 30m:L of 48%HBr in l5mL of acetic acid was heated at 130oC
under nitrogen for 7 hours. The cooled mixture was poured onto ice-
water and the separated product collected by suction filtration,
washed well with water, and dried in vacuo to give 0.94g of the title
compound.
~~H NMR (d6-acetone) 8: 7.18-8.15 (m, 6ArH), 9.8 (s, 1-
OH), 10.07 (s, l-CHO).
Step H: Preparation of 4-Hydroxy-7-hydroxymethyl-fluoren-9-one
A stirred mixture of 405.2mg ( l.8mmo1) of aldehyde
prepared in Step G and 804.3mg (3.8mmo1) of sodium
triacetoxyborohydride in 27mL of anhydrous THF was refluxed under
nitrogen for 1 hour. The cooled mixture was partitioned between
EtOAc, ice-water and saturated NaHC03, and the organic phase was
separated, washed with brine, dried over Na2S04, filtered,
evaporated, and dried in vacuo. Purification by PLC with CH2C12-
EtOAc (2:1) yielded 303.7mg of the crystalline, title product.
1H NMR (d6-acetone) S: 4.66 (s,2H), 7.08-7.86 (m, 6ArH),
9.38 (s, 1-OH).
Step I: Preparation of 4-Hydroxy-7-t-butyldimethylsilyloxymethyl-
fluoren-9-one
A, mixture of 332.2mg (1.47mmo1) of the diol from Step H,
243.5mg (1.61mmo1) of t-butyldimethylchlorosilane, and 120mg
(1.76mmo1) of imidazole in 8mL of sieve dried DMF was stirred at O~C
for 45 minute;;. The mixture was partitioned between EtOAc, ice-
water and 2N HCI, and the organic phase was separated, washed
twice with ice-water, and then with brine, dried over Na2S04,
filtered, evaporated, and dried in vacuo. Purification by PLC using
CH2Cl2-EtOAc (50:1) gave 447.4mg of the title material.
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-92-
~~H NMR (d6-acetone) 8: 0.14 (s, 6H), 0.95 (s, 9H), 4.81
(s,2H), 7.08-7.86 (m, 6ArH), 9.35 (bs, 1-OH).
Step J:
ZJsing the procedure given in Example 2, 127.1mg
(0.37mmo1) of the phenol prepared in Step I provided 99.5mg of
carbapenem derivative 39 which contained a little of the latter and
some SN2' product and was used without further purification.
1H NMR (CDCl3) b: 0.1 (s, 6H), 0.93 (s, 9H), 1.27 (d,
J=7.3Hz), 1.43 (d, 6.3Hz), 3.44 (m, 1H-1 & 1H-6), 4.21 (dd, 1H-5), 5.12
(m, 1H-8), 6.811-7.76 (m~, 6H).
EXAMPLE 44
PREPARATION OF CARBAPENEM 40
H
I / O
CH2=CHCH20~
N
O
C02CHzCH=CH2
Using the procedure detailed in Example 5, Step B, the
carbapenem prepared in the previous example was desilylated to
provide 52.7mg of carbapenem 40 after PLC with CH2C12-EtOAc (2:1).
1:H NMR (CDC13) 8:1.29 (d, J=7.4Hz), 1.45 (d, 6.3Hz), 3.44
(m, 1H-1 & 1H:-6), 4.22 (dd, 1H-5), 5.13 (m, 1H-8), 7.0-7.78 (m, 6H).
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-93-
EXAMPLE 45
PREPARATION OF CARBAPENEM 41
Ms
O
CH2=CHCH202C
N
O
C02CHzCH=CHz
Using the procedure described in Example 36, the
carbapenem prepared in Example 44 was converted into the
corresponding' mesylate 41 (59mg).
1H NMR (CDC13) 8:1.27 (d, J=7.4Hz, 3H), 1.45 (d,
J=6.3Hz, 3H), 3.0 (s, 3H), 3.44 (m, 1H-1 & 1H-6), 4.22 (dd, 1H-5), 4.90 (d,
J=14.8Hz, 1H), 5.13 (m, 1H-8), 5.24 (s, 2H), 5.73 (d, J=14.8Hz, 1H),
?.03-7.82 (m, E~H).
EXAMPLE 46
PREPARATION OF CARBAPENEM 42
CH2=CHCH20~
N
O
C02CHzCH=CH2
Carbapenem 41 (58.7mg, 0.09mmo1) and 27.1mg
(0.18mmo1) of sodium iodide in 1mL of acetone was stirred at OoC for
1.25 hour. The mixture was partitioned between EtOAc, ice-water
and brine, anti the organic phase was separated, washed with brine,
dried over Na~;S04, filtered, evaporated, and dried in vacuo to give
63.3mg of cart>apenem 42; as a yellow foam, which was used without
further purification.
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-94-
1H NMR (CDC13) 8:1.30 (d, J=7.2Hz, 3H), 1.45 (d,
J=6.3Hz, 3H), 3.44 (m, 1H-1 & 1H-6), 4.22 (dd, 1H-5), 4.47 (s,2H), 4.90
(d, J=14.8Hz, 1H), 5.13 (m, 1H-8), 5.24 (s, 2H), 5.73 (d, J=14.8Hz, 1H),
7.01-7.78 (m, 6H).
EXAMPLE 47
PREPARATION OF CARBAPENEM 43
CHs
O ~~
OTf 0
/ O
CH2=CHCHzOzCO H H
O
N
cc::O
02CHzCH=CH2
lJsing the procedure described in Example 22, 40.5mg
(.07mmo1) of carbapenem 40 provided 55.5mg of salt 43.
-~H NMR (CDC13) 8:1.26 (d, J=7.3Hz, 3H), 1.41 (d,
J=6.2Hz, 3H), 3.44 (m, 1H-1 & 1H-6), 3.96 (s, N-CH3), 4.2 (dd, 1H-5),
5.13 (m, 1H-8), 5.39 (s, 2H), 5.65 (d, J=14.7Hz, 1H), 6.97-7.70 (m, 8H),
9.29 (s, 1H).
CA 02304267 2000-03-14
WO 99/14217 PC'T/US98/19015
-95-
EXAMPLE 48
PREPARATION OF CARBAPENEM 44
~~ coNH2
(O
O
2 OTf
/ O
CHr-CHCH20zC0 H H
O
N
C02CH2CH=CH2
Using the procedure of Example 38, the carbapenem 38
prepared in E;~cample 42 in 1mL acetonitrile after 0.5 hour was
converted to 8;g.2mg of carbapenem 44, which contained a little of the
dabco acetamide starting material and was used without further
purification.
1H NMR {d6-acetone) b: 1.38 (app t, 6H), 4.4 (m, 6H), 4.54
(m, 6H), 4.64 (s, 2H), 5.14 (s, 2H), 5.69 (d, J=13.8Hz, 1H), 7.3-8.05 (m,
6H).
EXAMPLE 49
PREPARATION OF CARBAPENEM 45
O N~
I / O
CH2=CHCH20~
H H
O
N
O
C02CHzCH=CH2
A mixture of 77.8mg (0.114mmo1) of carbapenem iodide
42 and 12.8mg (0.114mmol) of dabco in 1mL acetonitrile was stirred at
room temperature for 0.5 hour and then at OoC for 1.25 hour. The
acetonitrile waa evaporated and the residue partitioned between
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-96-
water and methylene chloride. The methylene chloride layer was
separated , dried over sodium sulfate, filtered, and evaporated to give
86.4mg of carbapenem 45.
1H NMR (CDC13) 5:1.29 (d, J=7.3Hz,3H), 1.44 (d, J=6.4Hz,
3H), 3.19 (m, 6H), 3.75 (m,6H), 3.44 (m, 1H-1 & 1H-6), 4.28 (dd, 1H-5),
5.45 (d, J=14.5Hz, 1H),5.65 (d, J=14.5Hz, 1H), 6.93-?.92 (m, 8H).
EXAMPLE 50
PREPARATION OF CARBAPENEM 46
CH2CH2CONH2
N
w
/ O
CHr-CHCH202C0 H H
O
C02CH2CH=CH2
To a solution of 102.2mg (0.15mmo1) of carbapenem
iodide 42 in 1mL of acetonitrile was added a solution of 22.9mg
(0.1S5mmo1) of N-2-carboxamidoethylimidazole in 0.275mL DMF and
0.085mL methanol and the mixture was stirred at room temperature
15 for 19 hours. The volatiles were evaporated and the residue taken up
in minimum amount of methylene chloride and the product
precipitated b~y the addition of Et20. Repetition of this process and
drying gave 116.1mg of carbapenem 46.
~'~H NMR (CDCl3) 5:1.28 (d, J=7.2Hz,3H), 1.44 (d, J=6.3Hz,
3H), 3.16 (m, 2H), 3.44 (m, 1H-1 & 1H-6), 4.27 (dd, 1H-5), 4.64 (m,2H),
5.59 (s, 2H), 6.21 (bs, 2NH), 6.93-7.8 (m, 8H), 9.82 (bs, 1H).
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-97-
EXAMPLE 51
PREPARATION OF CARBAPENEM 47
CHs
N
w
/ O
HO H H
O ~
N
O
C02 ~
Following the procedure outlined in Example 3, the
5 carbapenem 4~3 prepared in Example 47 was deallylated to provide
11.4mg of 47 .after purification by reverse phase chromatography (RP-
PLC) using water-acetonitrile (?:3) as the eluant and lyophilization.
IR (nujol): 1751, 1716, 1593cm-1;
lH NMR (D20-CD3CN,5:2) 8: 1.39 (d, J=7.4Hz, 3H), 1.45
10 (d, J=6.4Hz, 3:H), 3.54 (m, 1H-1), 3.59 (dd, J= 2.8 5.7Hz, 1H-6), 4.09 (s,
N-CH3), 4.45 (.m,lH-5 & 1H-8), 5.0 (d, J=13.6Hz, 1H), 5.58 (s, 2H), 5.78
(d, J=13.6Hz, 1H), 7.31-7.93 (m, 8ArH);
tTV: ~,m~ 256nm(H20).
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-98-
EXAMPLE 52
PREPARATION OF CARBAPENEM 48
~~ CONH2
OTf ~
/ O
HO H H
O
N.~
O
~O
Zlsing the procedure described in Example 7, Step C,
and carbapen~em 44, prepared in the Example 48, 7.6mg of
carbapenem 48 was produced with Et20 precipitation and
purification o:n amberchrom 161 resin.
IR (nujol): 1747, 1706, 1688, 1591cm-1;
1H NMR (D20-CD3CN,5:2) S: 1.47 (d, J=7.2Hz, 3H), 1.52
(d, J=6.3Hz, 3:H), 3.61-3.70 (m, 1H-1 & 1H-6), 4.27 (m, 6H), 4.47 (m, 6H),
5.07- 5.18 (2d';s, 1H), 5.88-5.96 (2d's, 1H), 7.28-8.37 (m, 7ArH);
Z~: Amax 268nm(H20).
EXAMPLE 53:
PREPARATION OF CARBAPENEM 49
N
~ ~,'J
O
HO H H
O ~
N
O
02 ~
I:~sing the procedure described in Example 3, except the
solvent was DMF, and carbapenem 46, prepared in Example 50, 20mg
of carbapenexr~ 49 was produced.
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-99-
I:R (nujol): 1754, 1711, 1595cm-1;
~-H NMR (D20-CD3CN,5:2) b: 1.43 (d, J=6.9Hz, 3H), 1.48
(d, J=6.3Hz, 3H), 3.37 (m, 6H), 3.62 (m, 6H), 4.68 (bs, 2H), 5.06 (d,
J=13.4Hz,lH), 5.83 (d, J=13.4Hz,lH), 7.38-8.0 (m, 6ArH);
Z1V: ~,m~ 257nm(H20).
E~~AMPLE 54
PREPARATION OF CARBAPENEM 50
CH2CH2CONH2
o ~~
N
/ O
HO H H
O
O
10 IJsing the procedure described in Example 3, except the
solvent was D~MF, and carbapenem 45, prepared in the Example 49,
34.8mg of car:bapenem 50 was produced.
IR (nujol): 1755, 1715,1688,1678,1592cm-1;
1H NMR (D20-CD3CN, 5:2) 8: 1.39 (d, J=6.2Hz, 3H), 1.45
15 (d, J=6.3Hz, 3:H), 3.08 (t, J=6.5Hz, 2H), 3.52 (m, 1H-1), 3.6 (dd, 1H-6),
4.4 (m, H-5 & H-8), 4.68 (t, J=6.5Hz, 2H), 5.0 (d, J=13.8Hz,lH), 5.58 (s,
2H), 5.75 (d, J=13.3Hz,lH), 7.28-7.9(m, 8ArH);
tTV: ~,max 257nm(H20).
CA 02304267 2000-03-14
WO 99/14217 PCT/US98119015
-100-
EXAMPLE 55
PREPARATION OF CARBAPENEM 51
OH
/ O
02C0 H H
O ~ /
O I
C02CH2CH=CH2
Step A: Preparation of 4-Acetoxy-7-formyl-fluoren-9-one
To a stirred suspension of 1.53g (6.83mmo1) of 4-hydroxy-
7-formyl-fluoren-9-one, prepared in Step G of Example 43, in 25mL
THF at OoC w;as added 1.24mL (8.88mmo1) of triethylamine and
0.58mL (8.2m~mo1) of acetyl chloride. The mixture was stirred further
for 0.5 hour and then partitioned between EtOAc, ice, 1N HCl, and
brine. The organic phase was separated, washed with brine, dried
over Na2S04, filtered, evaporated, and dried in vacuo. Purification by
chromatography on silica gel using methylene chloride as eluant
gave 1.46g of the title compound.
IR (CH2C12): 1772, 1724, 1702, 1618,1606cm-1;
1)H NMR (CDC13) 8: 2.48 (s, 3H), 7.38-8.15 (m, 6ArH), 10.0
(s, 1H).
Step B: Preparation of 4-Acetoxy-7-(E-2-carbomethoxyvinyl)-fluoren-9-
one
A mixture of 1.46g (5.49mmol) of aldehyde, prepared in
Step A, and 2.1)2g (6.04mmo1) of methyl-
(triphenylphosphoranylidene)-acetate in 25mL of methylene chloride
was stirred at room temperature for 1 hour, during which time
product precipitation was progressive. Ether-hexanes (2:1, 20mL)
was added and the yellow solid was collected by suction filtration,
washed with 60mL of ether-hexanes (2:1), and dried in vacuo to give
1.438 of the title material.
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-l~l-
1H NMR (CDC13) 8: 2.48 (s, 3H), 3.82 (s, 3H), 6.49 (d,
J=l6Hz, 1H), 7.30-7.87 (m, 6ArH), ?.68 (d, J=l6Hz, 1H).
Step C: Prept~.ration of 4-Acetoxy-7-(2-carbomethoxyethyl)-fluoren-9-
one
'fhe material prepared above in Step B, l.llg (3.45mmo1)
and 267mg of 5%Rh/C in 60mL methylene chloride and l2mL
methanol was stirred under balloon pressure of hydrogen for 5
hours. The catalyst was removed by filtration through celite, washed
well with methylene chloride, and the filtrate evaporated and dried in
vacuo to give l.lg of product which was used without further
purification.
1 H NMR (CDCl3) S: 2.46 (s, 3H), 2.65 (t, J=7.5Hz, 2H), 2.98
(t, J=7.5Hz, 2:H), 3.67 (s, 3H), 7.23-7.56 (m, 6ArH).
Step D: Preparation of 2-(4-Hydroxy-7-fluoren-9-one)propionic acid
A stirred mixture of 1.278 (3.92mmo1) of ester, prepared
in Step C above, and 2.43mL (12.2mmo1) of 5N NaOH in 30 mL of EtOH
was refluxed under nitrogen for 70 minutes. The cooled mixture was
partitioned bEaween EtOAc, ice, 2N HCl, and brine, and the organic
phase was separated, washed with brine, dried over Na2S04, filtered,
evaporated, a:nd dried in vacuo to give 1.04g of the title acid.
~-H NMR (d6-acetone) 8: 2.67 (t, J=7.5Hz, 2H), 2.97 (t,
J=7.5Hz, 2H), 7.08-7.80 (m, 6ArH), 9.37 (s, bs, 1H).
Step E: Preparation of 4-Hydroxy-7-(3-hydroxypropyl)-fluoren-9-of
7.'o a stirred suspension of the acid (905.1mg,3.38mmo1),
prepared above in Step D, in 30mL of anhydrous THF at ambient
temperature 'was added cautiously 10.1mL of 1M borane-THF in THF.
The resulting mixture was stirred further for 2 hours and carefully
quenched with methanol. The mixture was evaporated and the
residue partitioned between EtOAc, ice, saturated NaHC03, and
brine, and th<~ organic phase was separated, washed with brine,
dried over Na2S04, filtered, evaporated, and dried in vacuo to give
0.96g of the tii;le triol.
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-102-
1H NMR (d6-acetone) 8: 1.85 (m, 2H), 2.74 (t, J=7.4Hz,
2H), 3.60 (t, J-=7.4Hz, 2H),5.49 {d, J=6.lHz, 1H), 6.83-?.91 (m, 6ArH),
8.88 (s, 1H).
Step F: Preparation of 4-Hydroxy-7-(3-hydroxypropyl)-fluoren-9-one
A, stirred mixture of 870mg (3.38mmo1) of triol, prepared
in Step E, andl 958mg (13.5mmol) of manganese dioxide in 20mL of
acetone was r~efluxed for I7 hours. The cooled mixture was filtered
through celite, washed well with acetone, and the filtrate evaporated
and dried in vacuo to give 832.2mg of the title compound, as a brick-
red solid.
1H NMR (d6-acetone) 8: 1.85 (m, 2H), 2.74 (t, J=7.4Hz,
2H), 3.59 (m, 2H), 7.06-7.79 (m, 6ArH), 9.30 (s,lH).
Step G: Preparation of 4-Hydroxy-7-(3-t-butyldimethylsilyloxypropyl)-
fluoren-9-one
A. mixture of 832.2mg (3.28mmol) of diol, prepared in
Step F above, 543.2mg (3.6mmo1) of t-butyldimethylchlorosilane, and
267.7mg (3.9~uno1) of imidazole in lOmL sieve-dried DMF was stirred
at 0 oC for 45 minutes. The mixture was partitioned between EtOAc,
ice, and 2N HCI, and the organic phase was separated, washed twice
with ice-water and then with brine, dried over Na2S04, filtered, and
evaporated. The residue was purified by silica gel chromatography
using an elution gradient of methylene chloride-ethyl acetate (50:1 to
10:1) to give 1.~D5g of the title product.
1JH NMR (CDCl3) b: 0.04 (s, 6H), 0.89 {s, 9H), 1.84 (m, 2H),
2.68 (t, J=6.3Hz, 2H), 3.62 (t, J=6.3Hz, 2H), 5.25 (bs, 1H),5.7 (d, J=l5Hz,
1H), 6.98-7.61 (m, 6ArH)
Step H: Mitsunobu Reaction
Using the general procedure described in Example 2 and
109.8mg (0.3mmol) of phenol, prepared in Step G, 165.4mg of the
carbapenem adduct was produced.
Il~ NMR (CDC13) 8: 0.03 (s, 6H), 0.89 (s, 9H), 1.27 (d,
J=7.3Hz, 3H), :1.43 (d, J=6.3Hz, 3H), 1.84 (m, 2H), 2.68 (t, J=7.6Hz, 2H),
CA 02304267 2000-03-14
- WO 9,9/14217 PCT/US98/19015
-103- -
3.44 (m, 1H-1 & 1H-6), 3.62 (t, J=6.2Hz, 2H), 4.21 (dd, 1H-5), 5.12 (m,
1H-8), 5.7 (d, J=lSHz, 1H), 6.86-7.76 (m, 6H).
Step I: Desilylation
l:Jsing the general procedure outlined in Example 21, the
carbapenem prepared in the previous step provided 103.4mg of
carbapenem ;i 1.
»H NMR (CDC13) 8: 1.2? (d, J=7.3Hz, 3H), 1.43 (d,
J=6.3Hz, 3H), 1.8? (m, 2H), 2.72 (t, J=7.3Hz, 2H), 3.44 (m, IH-1 & 1H-
6), 3.67 (t, J=Ei.3Hz, 2H), 4.21 (dd, 1H-5), 5.12 (m, 1H-8), 5.7 (d, J=lSHz,
1H), 6.97-7.62. (m, 6H).
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-1 ()4-
EXAMPLE 56
PREPARATION OF CARBAPENEM 52
O
~~CONH2
(N~
20Tf O O
/ O
~~ 02C0 H
O ~
N
O
C02CH2CH=CH2
Step A: Triflat~e Formation
using the general procedure outlined in Step A of
Example 10, 58.2mg (0.097mmol) of alcohol 51, prepared in Example
55, was converted into 70.4mg of the corresponding triflate.
Step B: Displacement Reaction
Using the general procedure outlined in Step B of
Example 10, the crude triflate from Step A was converted into 81.3mg
of crude carbapenem 52, which was used without further
purification.
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-105-
EXAMPLE 57
PREPARATION OF CARBAPENEM 53
~CONH2
~~ o ~'J
0
O
HO H
O
N.~
O
~O
Using the general procedure outlined in Step C of
Example 7, the crude carbapenem salt 52 was converted into 20.3mg
of carbapenem 53, after resin chromatography on amberchrom CG
161.
JCR {nujol): 1753, 1704,1592cm-1;
~~H NMR (D20-CD3CN, 5:2) 8: 1.09 (m), 1.43 (d, J=7.4Hz,
3H), 1.48 (d, J=6.3Hz, 3H), 1.65 {m), 2.94 (m, 2H), 3.56 (m, 1H-1), 3.63
(dd, 1H-6), 3.83 (m), 4.2 (m), 4.45 (m), 5.01 (d, J=l4Hz,lH), 5.58 (s, 2H),
5.8 (d, J=l4Hz,lH), 7.36-7.83(m, 8ArH);
1-~: Amax 257nm(H20).
2
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/i9015
-1 Ob-
EXAMPLE 58
PREPARATION OF CARBAPENEM 54
CH3
N
~OTf NJ
O
I / O
0200 H H
O
O' 1
C02CH2CH=CH2
ZJsing the procedure described in Example 22, 48.7mg
(.08mmol) of carbapenem 51 provided 54.3mg of salt 54.
1H NMR (CDC13) 8:1.29 (d, J=7.4Hz,3H), 1.44 (d, J=6.3Hz,
3H), 2.25 (m, 2H), 2.72 (m, 2H), 3.44 (m, 1H-1 & 1H-6), 3.98 (s, N-CH3),
5.13 (m, 1H-8), 5.68 (d, J=14.9Hz, 1H), 6.99-7.65 (m, 8H), 9.2 (s, 1H).
EXAMPLE 59
PREPARATION OF CARBAPENEM 55
CH3
N
~~J
0
0
HO H H
O
N
O2~
Following the procedure outlined in Example 3, the
carbapenem 5~4 prepared in Example 58 was deallylated to provide
- l4mg of 55 after purification by reverse phase chromatography (RP-
PLC) using water-acetonitrile (7:3) as eluant and lyophilization.
Ilk, (nujol): 1753, 1709, 1594cm-1;
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-1 ~7-
1H NMR (D20-CD3CN,5:2) b: 1.43 (d, J=7.4Hz, 3H), 1.48
(d, J=6.3Hz, 3H), 2.38 (m, 2H), 2.87 (m, 2H), 3.54 (m, 1H-1), 3.62
(dd,lH-6), 4.OEi (s, N-CH3), 4.45 (m, 4H), 5.05 (d, J=14.3Hz, 1H), 5.84 (d,
J=14.3Hz, 1H), 7.36-7.81 (m, 8ArH), 8.9 (bs, 1H).
I:rV: ~,max 258nm(H20).
EXAMPLE 60
PREPARATION OF CARBAPENEM 56
2CHs
Step A: Preparation of 4-Hydroxy-7-(3-t-butyldimethylsilyloxypropyl)-
9-carbomethoxy-fluorylidene
A stirred mixture of 110.4mg (0.3mmo1) of fluorenone
derivative prepared in Step G of Example 55 and 250.8mg (0.75mmo1)
of methyl-(triphenylphosphoranylidene)-acetate in 3mL of p-xylene
was refluxed under nitrogen for 21 hours. The cooled mixture was
evaporated and the residue purified by PLC with CH2C12-EtOAc (50:1)
to give 90mg of the title compound as a mixture of geometric isomers.
lla NMR (CDC13) 8: 0.07 (s, 6H), 0.92 (s, 9H), 1.87 (m, 2H),
2.73 (m, 2H), 3.65 (t, 2H), 3.87 (s, 3H), 6.71-8.74 (m, 7H).
Step B: Mitsunobu Reaction
Using the general procedure described in Example 2 and
180.6mg (0.42mmo1) of phenol, prepared in Step A, 288.4mg of the
carbapenem was produced, as a mixture of geometric isomers.
1H NMR (CDC13) b: 0.04 (s, 6H), 0.89 & 0.90 (s's, 9H), 1.27
(2d's, 3H)), 1.43 (d, 6.5Hz,3H), 1.86 (m, 2H), 2.73 (m, 2H), 3.44 (m, 1H-1
& 1H-6), 3.66 (:m, 2H), 3.85 (s, 3H), 4.17 (2dd's, 1H-5), 5.12 (m, 1H-8),
5.45 (d, 1H), 5.'71 (d, J=lSHz, 1H), 6.69-8.74 (m, 7H).
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-108- -
Step C: Desilylation
Using the general procedure outlined in Example 21, the
carbapenem 1;268.9mg) prepared in the previous step provided
171.6mg (75°0) of carbapenem 56.
nH NMR (CDC13) 8: 1.27 (d, J=7.3Hz, 3H), 1.43 (d,
J=6.3Hz, 3H)., 1.95 (m, 2H), 2.78 (m, 2H), 3.44 (m, 1H-1 & 1H-6), 3.67 (t,
J=6.3Hz, 2H)., 3.86 (s, 3H), 4.21 (dd, 1H-5), 5.12 (m, 1H-8), 5.45 (d, 1H),
5.7 (d, 1H), 6.72-8.77 (m, 7H).
EXAMPLE 61
PREPARATION OF CARBAPENEM 57
O'~"'.~NH2
~O
Step A: Trifta.te Formation
15 ZJsing the general procedure outlined in Step A of
Example 10, 48.4mg (0.074mmol) of alcohol 56, prepared in Example
60, was converted into 65.6mg of the corresponding triflate.
Step B: Displacement Reaction
20 tJsing the general procedure outlined in Step B of
Example 10, t;he crude triflate from Step A was converted into 78mg of
crude carbapenem 58, which was used without further purification.
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-109-
EXAMPLE 62
PREPARATION OF CARBAPENEM 58
~~CONHZ
,~J
cc
H H H
O
O t
~O
ZJsing the general procedure outlined in Step C of
Example 7, the crude carbapenem salt 57 was converted into 1?.9mg
of carbapenern 58, after resin chromatography on amberchrom CG
161.
IR (nujol): 1751, 1699, 1584cm'1;
1H NMR (D20-CD3CN,5:2) 8: 1.09 (m), 1.5 (m, 6H), 1.65
(m), 2.94 (m, 2H), 3.56 (m, 1H-1 & 1H-6), 3.83 (m), 4.11 (s, 3H), 4.2 (m),
4.45 (m), 5.07 (d, J=13.6Hz,lH), 5.88 (d, J=13.6Hz,lH), 7.3-8.69(m, 7H);
Z1V: ~,m~ 330, 266nm(H20).
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-110- -
ExAMPLE s3
PREPARATION OF CARBAPENEM 59
CHs
~O:
t3sing the procedure described in Example 22, 70.2mg
(.Ollmmol) of carbapenem 56 provided 68.4mg of salt 59.
~~H NMR (CDC13) 8:1.28 (m, 3H), 1.44 (m, 3H), 2.25 (m,
2H), 2.72 (m, 2H), 3.44 (m, 1H-1 & 1H-6), 3.87 (s, 3H), 3.93 (s, N-CH3),
4.2 (m, 2H), 5.13 (m, 1H-8), 6.73-9.16 (m, 9H).
EXAMPLE 64
PREPARATION OF CARBAPENEM 60
CH3
HO H H
O
N
02~
Following the procedure outlined in Example 3, the
carbapenem 59 prepared in Example 64 was deallylated to provide
31.3mg of 60 :after purification by reverse phase chromatography (RP-
PLC) using water-acetonitrile (7:3) as the eluant and lyophilization.
I:R (nujol): 1753, 1715, 1587cm-1;
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-111-
1H NMR (D20-CD3CN,5:2) 8: 1.44 (m,6H), 2.38 (m, 2H),
2.87 (m, 2H), 3.54 (m, 1H-1 & H-6), 4.00, 4.02, 4.07, 4.09 (s's, 6H), 4.45
(m, 4H), 5.09 (d, J=l4Hz, 1H), 5.88 (d, J=l4Hz,1H), 7.28-8.84 (m, 9H).
W: ~,m~ 332, 268nm(H20).
EXAMPLE 65
PREPARATION OF CARBAPENEM 61
0
02C H O
O ~
O
C02CH2CH=CH2
Step A: Preparation of Methyl-2,2'-dimethoxy-biphenyl-6-carboxylate
10 Using the procedure outlined in Step A of Example 18,
201.7mg (0.6!~mmol) of methyl-2-iodo-3-methoxy-benzoate and
125.9mg (0.82mmo1) of 2-methoxy-phenylboronic acid gave after 27
hours of reflux a quantitative yield of the title substance.
~~H NMR (CDC13) 8:3.56 (s, 3H), 3.71 (s, 3H), 3.73 (s, 3H),
i 5 6.95-7.47 (m, 7H).
Step B: Preparation of 2,2'-dimethoxy-biphenyl-6-carboxylic acid
A stirred mixture of 188.4mg (0.69mmol) of ester
prepared in Step A and 0.28mL (1.39mmo1) of 5N NaOH in 2mL of
20 ethanol was ~..°efluxed under nitrogen for 1.5 hours. The mixture
was
partitioned between EtOAc, ice, 2N HCI, and the organic phase was
separated, washed with brine, dried over Na2S04, filtered,
evaporated, and dried in vacuo to give 171.6mg of the title acid which
was used without further purification.
25 »H NMR (d6-acetone) 5:3.66 (s, 3H), 3.71 (s, 3H), 6.79-7.48
(m, 7H).
Step C: Preparation of 12-Methoxy-3,4-benzocoumarin
To a stirred suspension of 171.6mg (0.67mmo1) of acid
30 prepared in Step B in 2mL of sieve-dried CH2C12 at OoC was added all
at once 173.1:mg (0.83mmo1) of phosphorous pentachloride and the
CA 02304267 2000-03-14
WO 99/14217 PCT/US98/19015
-112- -
mixture was stirred further for 5 minutes, and then for 1 hour with
the ice-water bath removed. The homogeneous solution was recooled
to OoC, and 133mg (0.99mmol) of A1C13 was added all at once. The
resulting mixture was stirred with the ice-water bath removed for 1
hour and then partitioned between EtOAc, ice, and brine. The
organic phase was separated, washed with brine, dried over Na2S04,
filtered, evaporated, and dried in vacuo. Purification by PLC with
hexanes-methylene chloride (2:1) provided 134.7mg of the title
compound.
1H NMR (CDC13) 8: 3.99 (s, 3H), 7.21-8.8? (m, 7ArH).
Step D: Preparation of 12-Hydroxy-3,4-benzocoumarin
Z'he methylether from Step C in 1mL acetic acid and
3.4mL 48%Hl3r was stirred at 130oC for 5 hours. The cooled solution
was treated with water and the insoluble product collected by
filtration, washed well with water, and dried in vacuo to give 131.3mg
of the title product, which was used without further purification.
1H NMR (d6-acetone) 8: 7.33-9.16 (m, 7H), 9.97 (s, 1H).
Step E: Mitsunobu Reaction
Llsing the general procedure described in Example 2 and
53mg {0.025mmo1) of phenol, prepared in Step D, 35.5mg of
carbapenem 61 was produced, which contained some of the C-3
isomer and was used without further purification.
EXAMPLE 66
PREPARATION OF CARBAPENEM 62
0
0
HO H H
O
O ~
C02Na
Llsing the procedure described in Example 3 and the
material prepared in Step E of the previous example, 6.6mg of
CA 02304267 2000-03-14
WO 99/14217 PCT/IJS98/19015
-113-
carbapenem Ei2 was produced after RP-PLC purification, elution with
water-acetonitrile (4:1), and lyophilization.
IR (nujol): 1754, 1726, 1598cm-1;
~-H NMR (D20-CD3CN,5:2) b: 1.41 (d, J=7.2Hz, 3H),1.45
5 (d, J=6.3Hz, 3H), 3.47(m, 1H-1), 3.61 (dd, 1H-6), 4.34 (dd, 1H-5), 4.42
(m, 1H-8), 5.2 (d, J=13.5Hz, 1H), 6.0 (d, J=13.5Hz, 1H), 7.56-9.18 (m,
7ArH);
t~~ Amax 332, 262nm(H20).
