Note: Descriptions are shown in the official language in which they were submitted.
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TITLE OF THE INVENTION
CARBAPENEM ANTIBACTERIAL COMPOUNDS, COMPOSITIONS AND METHODS OF TREATMENT
BACKGROUND OF THE INVENTION
The present invention relates to carbapenem
antibacterial agents in which the carbapenem nucleus is substituted
at the 2-position with a naphthosultam linked through a CH2 group.
The naphthosultam is further substituted with various substituent
groups including at least one cationic group -A-(a-L-B.
The carbapenems of the present invention are useful
against gram positive microorganisms, especially methicillin
resistant Staphylococcus aureus (MRSA), methicillin resistant
Staphylococcus epidermidis (MRSE), and methicillin resistant
20 coagulase negative Staphylococci (MRCNS), and are also active
against Gram negative bacteria. 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. The
antibacterial compounds of the present invention thus comprise an
important contribution to therapy for treating infections caused by
these difficult to control pathogens.
SUMMARY OF THE INVENTION
The present invention relates to a compound represented
by formula I:
tR)2
P H H R
H3C ~ CH2-N \
/~- N ~ i
C02M ~=S \ J
O A-Q-L-B
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as well as pharmaceutically acceptable salts thereof, wherein:
R1 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;
P represents hydrogen, hydroxyl, F or hydroxyl protected
by a hydroxyl-protecting group;
A-Q-L-B represents a side chain wherein:
A is a C 1-6 alkylene group, straight or branched, and
10 optionally interrupted or terminated by 1-2 of -O-, -S-, NRa-, -C(O)-
and -CH=CH-;
fa represents
R ~ ~ /Rb
~N~ H ~~~
2)b
X
in which:
bis2or3;
and X- is a charge balancing counterion;
L represents a C1-g alkylene group, unsubstituted or
substituted with 1-3 Rc groups, and is interrupted or terminated by 1-
3 of -CH=CH-, -C(O)- , -C(O)NRd-, -Het(Re)- , -C(O)-Het(Re)- ,
_C(O)NR,a_get(Re)- , -O- , -S- , -S(O)-, -S02-, -C02- , -NRa- ,
-N+(Ra)z_
-C O ~ ~ -C O N Ra
~I ~I ~ ) ~I
Re . Re and Re
Het is a heteroaryl group;
B represents
-~NRfR9Rh or -NRfR9
or
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~Re~2 (Re)2
I \~ ~ I
N -~- R b )o-1 N
2) or
N
wherein represents a 5-10 membered mono- or bicyclic, N-
containing heteroaryl group, optionally containing 1-4 additional
heteroatoms selected from O, S and N;
Ra is H or C1_g alkyl;
Rb is NH2 or C1_6 alkyl unsubstituted or substituted with
1-3 groups selected from halo, OH, CN and C(O)NH2;
Rc is independently selected from halo, ORa, SRa,
OC(O)Ra, C02Ra, CN, C(O)N(Ra)2 and C(O)Ra,
Rd is H or C1_g alkyl, or Rc and Rd taken together with
any intervening atoms represent a 4-6 membered ring;
Re is H; Rc; N02 ; N(Ra)2 ; S02N(Ra)2 or C1_4 alkyl,
unsubstituted or substituted with 1-3 groups selected from halo, OH
and C(O)NH2;
15 Rf Rg and Rh are independently selected from H; C1-6
straight or branched chain alkyl, unsubstituted or substituted with 1-
3 Rc groups; C3_g cycloalkyl, unsubstituted or substituted with 1-3 Rc
groups; phenyl, unsubstituted or substituted with 1-3 Re groups and
Het, unsubstituted or substituted with 1-3 Re groups,
or
Rf and Rg taken together with the intervening N atom
form a 4-6 membered ring, optionally interrupted by 1-2 of O, S, C(O)
or NRh, and optionally substituted by 1-3 Rc groups;
and each R independently represents H; N02 ; N(Ra)2;
25 S02N(Ra)~ ; Rc or C1_4 alkyl, unsubstituted or substituted with 1-3
groups selected from halo, OH, C(O)NH2~
or
R together with A of the group -A-Q-L-B and any
intervening atoms represent a 5-6 membered carbocyclic ring.
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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.
Carboxylate anion refers to a negatively charged group
-COO-.
The term "alkyl" refers to a monovalent alkane
10 (hydrocarbon) derived radical containing from 1 to 15 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 substituted, alkyl groups
may be substituted with up to four substituent groups, selected from
15 Rc, Rf and Rg, or as otherwise 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". When a bond appears without a group attached, this
signifies the presence of a methyl group.
20 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.
The term "alkenyl" refers to a hydrocarbon radical
25 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.
The term "alkynyl" refers to a hydrocarbon radical
straight or branched, containing from 2 to 10 carbon atoms and at
30 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,
phenanthrenyl and the like. An aryl group thus contains at least one
35 ring having at least 6 atoms, with up to five such rings being present,
containing up to 22 atoms therein, with alternating (resonating)
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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.
5 The term "heteroaryl" (Het) 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, O, S or N, and in which 1-2 additional carbon atoms are
optionally replaced by a heteroatom selected from O or S, and in
which from 1-3 additional carbon atoms are optionally replaced by N,
said heteroaryl group being optionally substituted as described
herein. Examples include the following:
CNH ~NH ~S
pyrroie (pyrrolyl) imidazole (imidazoly!) thiazole (thiazolyl)
N ~O CO CS
oxazole (oxazolyl) furan (furyi) thiophene (thienyl)
N~NH .~ ,NH ~ ,O
N N
triazole (triazolyl) pyrazole (pyrazolyl) isoxazoie (isoxazolyl)
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N
~s I~ I
N N N
isothiazole (isothiazolyl) pyridine (pyridinyl) pyrazine
(pyrazinyl)
~~ N
I :N I NJ
N
pyridazine (pyridazinyl) pyrimidine (pyrimidinyl)
N~N
~NJ
triazine (triazinyi)
Heteroaryl includes protonated forms as well. It thus
includes positively charged as well as non-charged groups.
Examples include the groups shown above, having an additional H
attached to a nitrogen atom.
The group A-Q-L-B is attached to one of the two phenyl
rings shown.
Heteroarylium refers to heteroaryl groups bearing a
quaternary yr protonated atom and thus a positive charge.
Examples include the following:
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~N~/N-CH3 ~-N~/S
~~ N + +
.~N~~ ~ ,N CH3 ~ ,O
+ i + ;+
+ N
~N~ i \
~ \ N-CH3
N~/ + N N +
CH3 CH3
~N/ ~ ~N
,S ~ J + ~L J
i+ N N
\ NnN.CHs
~N.N ~N~
,+
CH3
When a charge is shown on a particular nitrogen atom
in a ring or in a nitrogen containing non-ring moiety which contains
5 one or more additional nitrogen atoms, it is understood that the
charge may reside on a different nitrogen atom than that shown in a
particular drawing by virtue of charge resonance that occurs.
~N~ ~N~ +
NON-CH3 ~ N~N_.CHs
10 and
~N~N-CHs ...--~ ~N ~ CH3
+ iNw/
Likewise, when a basic nitrogen containing moiety is
provided at an appropriately acidic pH, the moiety becomes
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wo ~no62~ -$- pcTn~s9sn2mo
protonated due to acid base reactivity. Both the protonated and non-
protonated forms of the compounds of formula I are included in the
present invention.
The term "heterocycloalkyl" refers to a cycloalkyl group
5 (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.
The terms "quaternary nitrogen" and "positive charge"
refer to tetravalent, positively charged atoms including, e.g., the
10 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 well as basic nitrogens which are
15 protonated at physiologic pH.
The term "heteroatom" means O, S or N, selected on an
independent basis.
Halogen and "halo" refer to bromine, chlorine, fluorine
and iodine.
20 Alkoxy refers to C1-C4 alkyl-O-, with the alkyl group
optionally substituted as described herein.
When a group is termed "substituted", unless otherwise
indicated, this means that the group contains from 1 to 4 substituents
thereon.
25 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,
30 and with reference to standard textbooks, such as Greene, T. W. et al.
Protective Groups in Organic Synthesis Wiley, New York (1991).
Examples of suitable protecting groups are contained throughout the
specification.
In some of the carbapenem compounds of the present
35 invention, M is a readily removable carboxyl protecting group, and/or
P represents a hydroxyl which is protected by a hydroxyl-protecting
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group. Such conventional protecting groups consist of 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
5 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
10 catalytic hydrogenation.
Examples 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
15 and t-butyl.
Examples of suitable hydroxyl protecting groups include
triethylsilyl, t-butyldimethylsilyl, o-nitrobenzyloxycarbonyl,
p-nitrobenzyloxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl,
t-butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl and the like.
20 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
25 compounds of the present invention which would be apparent to the
pharmaceutical chemist. i.e., those which are substantially non-toxic
and which may favorably affect the pharmacokinetic properties of
said compounds, such as palatability, absorption, distribution,
metabolism and excretion. Other factors, more practical in nature,
30 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
35 acceptable carriers. Thus, the present invention is also concerned
with pharmaceutical compositions and methods of treating bacterial
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infections utilizing as an active ingredient the novel carbapenem
compounds.
With respect to -C02M, which is attached to the
carbapenem nucleus at position 3, this represents a carboxylic
5 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 take the
10 form -LOOM, where M is a negative charge, which is balanced by a
counterion, e.g., an alkali metal cation such as sodium or potassium.
Other pharmaceutically acceptable counterions may be calcium,
magnesium, zinc, ammonium, or alkylammonium cations such as
tetramethylammonium, tetrabutylammonium, choline,
15 triethylhydroammonium, meglumine, 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.
20 Included among such salts are the following: acetate, adipate,
alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,
citrate, camphorate, camphorsulfonate, cyclopentanepropionate,
digluconate, dodecylsulfate, ethanesulfonate, fumarate,
glucoheptanoate, glycerophosphate, hemisulfate, heptanoate,
25 hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-
hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-
naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate,
persulfate, 3-phenylpropionate, picrate, pivalate, propionate,
succinate, tartrate, thiocyanate, tosylate and undecanoate.
30 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
35 pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and
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methoxymethyl, and others described in detail in U.S. Pat. No.
4,479,947. These are also referred to as "biolabile esters".
Acid addition salts of the compounds of formula I are
likely protonated at physiological pH, as mentioned above.
5 Compounds such as those containing a basic N-containing moiety
are capable of protonation in water at or near pH 7, so that the moiety
can exist in its neutral form or as an acid addition (protonated) form.
X- is a charge balancing group.
Biolabile esters are biologically hydrolizable, and may be
suitable for oral administration, due to good absorption through the
stomach or intenstinal mucosa, resistance to gastric acid
degradation and other factors. Examples of biolabile esters include
compounds in which M represents an alkoxyalkyl,
alkylcarbonyloxyalkyl, alkoxycarbonyloxyalkyl, cycloalkoxyalkyl,
15 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-
20 acetoxyethyl, 1-acetoxypropyl, pivaloyloxymethyl, 1-
isopropyloxycarbonyloxyethyl, 1-cyclohexyloxycarbonyloxyethyl,
phthalidyl and (2-oxo-5-methyl-1,3-dioxolen-4-yl)methyl.
For the purposes of this invention, all compounds which
have one or more cations are balanced with one or more, as
25 necessary, of a charge balancing group X-. Examples of cases where
a charge balancing group is required are quarternized substituents
such as heteroarylium or C(=N+RHR')RA, where Ra and Rf are not H.
Additionally, all compounds having one or more anions are counter
balanced with one or more, as necessary, charge balancing cations.
30 When a group is interrupted by 2-3 of O, S, or N they
cannot form O-O, O-O-O, O-S, O-S-O, S-S, or S-S-S bonds. This is
exemplified in the case when L or A is an alkylene interrupted or
terminated by 1-3 of O, S, -S(O)-, -SOZ-, NRa, COZ C(O)NR~,...and the
like.
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X' can be present or absent as necessary to maintain the
appropriate charge balance. When present, these represent
pharmaceutically acceptable counterions. Most anions derived from
inorganic or organic acids are suitable. Representative examples of
5 such counterions are the following: acetate, adipate,
aminosalicylate, anhydromethylenecitrate, ascorbate, aspartate,
benzoate, benzenesulfonate, bromide, citrate, camphorate,
camphorsulfonate, chloride, estolate, ethanesulfonate, fumarate,
glucoheptanoate, gluconate, glutamate, lactobionate, malate,
10 maleate, mandelate, methanesulfonate, pantothenate, pectinate,
phosphate/diphosphate, polygalacturonate, propionate, salicylate,
stearate, succinate, sulfate, tartrate and tosylate. Other suitable
anionic species will be apparent to the ordinarily skilled chemist.
Likewise, when more than one negative charge is
15 necessary to maintain charge neutrality, the counterion indicator X'
represents a specie with more than one negative charge, such as
malonate, tartrate or ethylenediaminetetraacetate (EDTA), or when a
multivalent negatively charged counterion is present with a
carbapenem which bears a net single positive charge, an appropriate
20 number of carbapenem molecules can be found in association
therewith to maintain the overall charge balance and neutrality.
Numbering and nomenclature using in naming the
naphthosultams are as follows:
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Naphthosultam Nomenclature
Chemical Abstracts
5 4
6 / \ 3
~/ 7 \ ~ / 2
HN -O~ O '~~N O, O
1,8-naphthosultam 1,8-naphthosultamyl
5 6
\ 4 / ~ \ 7
\ / 3 \ / 8
H N -S,' ~N -S,1
z ~ O '~2 ~ O
2H naphth[1,8-cdJisothiazole, 1,1-dioxo-2H naphth[1,8-cdJisothiazol-2-yl
1, i -dioxide
I~JPAC (from Beilstein's Autonomy
5 6
4 / \ 7
/ 3 \ ~ / 8
l
HN-S: ~N-S:
z ~' O ''~,~ z ~' O
2 H~1-thia-2-aza-acenaphthalene, 1,1-dioxo-2H-1-thia-2-aza-acenaphthalen-2-yl
1,1-dioxide
The -A- portion of the side chain is a C1_6 alkylene group
5 which is straight or branched, and is optionally interrupted or
terminated by 1-2 of O, S, NRa, C(O), and -CH=CH-. The interrupting
groups can be separate or together, and can terminate the C1_6
alkylene group. Also, the interrupting or terminating moiety can be
between the alkylene group and the naphthosultam or -Q-. For
10 example, A can represent -p_C 1-6 alkyl- , -C 1_g alkyl -O- ,
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-NRa-1-6 alkyl- and the like.
~,l represents
~Rb
~N~ H ~O~
2)b
X
in which:
bis2or3;
and X- is a charge balancing counterion.
L represents a C1_g alkylene group, unsubstituted or
substituted with 1-3 Rc groups, and is interrupted or terminated by 1-
3 of -CH=CH-, -C(O)- , -C(O)NRd-, -Het(Re)- , -C(O)-Het(Re)- ,
-C(O)NRa- , -Het(Re)- , -O- , -S- , -S(O)-, -S02-, -C02- , -NRa- , -
N+(Ra)2_
-CO ~ ~ -CONRa
)
Re , Re and Re .
These interrupting or terminating moieties can be separate or
15 together. As described above with respect to A, the moieties can be at
the ends of the C1_g alkylene group, and between the C1_g alkylene
moiety and Q or B.
B represents
~RfRgRh or -NRfR9
or
~Re)2 ~Re)2
I \~+ ~ I
N -~-Rb)o-~ N
or
N
wherein represents a 5-10 membered mono- or bicyclic, N-
containing heteroaryl group, optionally containing 1-4 additional
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heteroatoms selected from O, S and N. These include positively
charged as well as neutral moieties, many of which become positively
charged at neutral to acidic pH. All are included in the present
invention.
5 When Rb represents C1_g alkyl, it may be unsubstituted
or substituted with 1-3 groups selected from halo, OH, CN and
C(O)NH2.
When Rc and Rd both appear, they may be taken in
combination with any intervening atoms to farm a 4-6 membered
i 0 ring.
When Rf and Rg are both present, they can be taken
together with the intervening atoms to form a 4-6 membered ring,
which is optionally interrupted by 1-2 of O, S, C(O) and NRh. The
ring can be unsubstituted or substituted with 1-3 Rc groups.
15 When one of the R groups is taken in combination with A
from the side chain A-Q-L-B, along with the intervening atoms, it
represents a 5-6 membered carbocyclic ring.
A subset of compounds of formula I which is of interest
relates to those compounds where Rl represents methyl. Within this
20 subset, all other variables are as originally defined.
Another subset of compounds of formula I which is of
interest relates to those compounds where COZM represents a
carboxylate anion. Hence, M in this instance represents a negative
charge which is balanced by a positively charged group, such as in
25 the positively charged Q group.
Another subset of compounds of formula I that is of
interest relates to those compounds where P represents hydroxyl or
hydroxyl protected by a hydroxyl protecting group. Within this
subset, all other variables are as originally defined.
30 Another subset of compounds of formula I that is of
interest relates to compounds of formula I wherein A represents C1-3
alkylene. Within this subset, all other variables are as originally
defined.
Another subset of compounds of formula I that is of
35 interest relates to compounds where L is C 1-5 alkylene that is
interrupted or terminated by -C(O)NRd-, -C(O)NRa-Het(Re}-, -NRa-
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-C(O) N Ra
, -N+(Ra)2 or RQ . Within this subset, all other
5
variables are as originally defined.
Another subset of compounds of formula I that is of
interest relates to compounds where B represents
O
1) -NRiRsRh or -NRfR9.
Within this subset, all other variables. are as originally defined.
A preferred subset of compounds of formula I which is of
interest relates to those compounds wherein:
10 Rl represents methyl;
C02M represents a carboxylate anion;
P represents hydroxyl or hydroxyl protected by a
hydroxyl protecting group;
A represents C1_3 alkylene;
15 Q represents
R~ ~ ~Rb
N O+
OU
X-
in which:
bis2or3,
and X- is a charge balancing counterion;
20 L is C 1-5 alkylene, interrupted or terminated by
-C(O)NRd-, -C(O)NRa-Het(Re)-, -NRa- , -N+(Ra)2 - or
-C(O)NRa
Re
and B represents: -ORfR9Rh or -N RfR9.
All other variables are as originally defined.
25 Representative examples of compounds of the invention
are found in Tables I - III.
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wo ~no62~ -17- Pcr~rs9gnzmo
Table I
Q-L-B
OH CH3 \
H H
'S
~2
O ~ 2-3 X
C02-
wherein Q-L-B is selected from:
\ /'~ \ 1 \ n ~--N N+ NH3+
~N+ N+~N+~ ~N ~N+
~/ \ \
\ ~ N~ ,~~, NH3+
\ S N+~~N+ ~.: N+~
\ /~'-\ N N~ \ ~----1 N ~ IV
N+ N+ ~ \- N+w ~ N+ N+ --~ ~= N+~
\ ~ ~- ~ 1 \ ~-\ 1
~. N V + \, N+~ ~ N+ N+ ~ N- N+~
\ ~/ \
\ !~ ~"-N ~ N
~N+ N+ ~=N+~'NH3+ ~ \ N+-
~/ \ ~/ U \
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N [~ N\_-.. N+~/NH3+
\ ~---1 \ N+~ \
- N+ +~
~N ~+ ~i \
NH3+
N I N /~
_ ~ \~N+~NH3+ ~ _ ~ ~-N+~
N ~/ + ~ N ~/ \
N
N, ~ N/~N
N N+ ~ ~ N+~ ~ ~ ~ ~ N+~
N ~/
~N ~+
~1
\ ~'\ ~N . N+~
~- N+ N+
~N
\ ~ ~N
\_-. N+~NH3+
N+ N+
NH3+
N N+~ N \
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NH3+ - N+
\ n J--
~N ~ ~ \ N
N+~
S N N+~ ~ Nj
'-~ ~ 'N
n
N~-N+
N+
v ~ ~ N
N J
N+~~N ~ ~ ~ 'N+
~N~ \
-N+
% U
/-\ . /
N+
~-\ N~ -
N+ N+~ \
\ n ~ +- S N N+-' N !iN
N+ N+ ~~ a \ +
a
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NH3+
NH3+ p
~N N+~~
N+ N+~ / U
H2N~ U H2N
~NH3+
0
~NH3+
~N N~~/ ~-N~+
H2N~ ~ H NI
2
~NH3+
NH3+ ~~./p
NH~ H2N
N N+
-N N+~~
a ~ / ~/
~NH3+
/--\ NH2 NH3+ H N p
~- N+ N+~
N NI+~
U
NH3+ ~NH3+
~i ~i +.f b2+ ~- N N /-~ b2+
i~
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Table iI
2-3 X -
C02-
wherein Q-L-B is selected from:
I
\ /-'~ f--~1 \ n ~N N+ NH3+
~- N+ N+ N+~ ~ N+ N+
~/\ U\
\ ~ N~ NH3+
~N~+~ ~N+fNH3+ \ ~ J.-.N~
\ ~ N~+ ~N+~
\ ~ N N~ \ ~--~ N ~ IV
~N+ N+~ \-N+y-N+ N+-~ ~=N+~
\ ~--\ J- ~ 1 \ n 1
N+~~N+ ~- N+~ ~- N+ N+ ~ N- N+~
\ U
\ /-\ J---N ~ N
~N+ N+ '=N+f NH3+ ~ \ N+-
U \ ~/ U ~
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N\, N+~/NH3+
~N ~+ NU \
NH3+
N I N /~
N+~ NH3+ ~ _ ~ ~- N+~
N~ \
N ~.-/ ~
N
N ~ NON
N+~ ~ ~ ~ ~ N+~
N+ N+ ~ N ~ +
S
\/
~N ~/ ~ ~ N, N+~
~N ~ ~
~N
N
~N+~NH3+
-N ~+
_ NH3+
\ ~\ ~- N+'~
~N~iv ~
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NH3+ - N+
\/
~- N+~~N \ N
N+~ ,
S N N+ ~ ~ N j
'--~ ~ --N
n
N~ N+
N+
N
\ ~--~ '~ I
~N~+ \~ ~N J
\ ~N ~--N~
-N+
n . /
~~ ~ + N+
~' ~' Nv /
~ ~+
w
\ ~--y--~~N+ - ~ N+ N+ N+
~N ~N+ N~
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NH3+
NH3+ O
~- N N+~
N+ N+~ I U
H2N~ ~.-/ H2N
.NH3+
/~/O
NH3+
~N N+ ~N~+
r
H2N
H2N
NH3+
NH3+ O
NH~ H2N
1
N ~N+ - N N+~
~NH3+
N NNH~ NH3+ H2N O
/ N N~+~
U
NH3+ ,-NH3+
~ ~+
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Table III
OH CH3 ~ ~ ~ Q-L-B
H H
_ ,Oz
N
O
C02- 2-3 X
wherein Q-L-B is selected from:
\ /~ ~ ~ ~ n ~ N N+ N H3+
~- N+ N+ ~ N+~ ~ N ~N+
\-/~ \
N~ NH3+
N ~ + ~ ~ N+ f N H3+ \ ~--~ ~--.N
S N+~~N+ N+~
\ ~1 N N~ \ ~--~ N~ N
N+ N+ --~ \- N+w ~ N+ N+ -~ ~= N+~
~ y 1 \ ~\ vs1
~.N~+-~~N+~ ~-N+ N+~ N-N+~
~N
~N N+~N~=N+f NH + ~ ~ N+
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N\ N~ ~NH3+
\ Nl+~ _\ /~\
~N ~+ N~/ \
NH3+
N I N
\. N+~ NHg+ ~ _ ~ ~ N+~
N~ \
NU \
N
N, ~ N/~N
\ ~ ~ ~ N+~ ~ ~ ~ ~ N+~
N \~ ~ ~ N ~% +
\ S
\ ~\ ~' ~ \ 1
~N ~/ ~ ~--1 N.N+~
~N ~ ~
~N
\ ~\ ~N
\, N+~NH3+
~N V+
_ NH3+
N+ N+ \
\ ~\ ~' N+~~
U \
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NH3+ -N+
\ n
/ ~N U \ N
N+~
N N+ ~ ~ Ng
'-~ ~ 'N
n
N~ N+
N+
N ~- N
\n
~N~+ \ ~ 'N J
\ ~N~N+
-N+
\/
~~ ~ + N+
~N \
~ ~+
\ n f--~~N+- ~ N+ N+ N+
N+~~N+ N-l a
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NH3+
NH3+ O
/ ~ N N+~
-N+ N+~ I U
H2N~ ~/ H2N
~NH3+
O
NH3+
-N~+ ~-N~+
H2N H NI
NH3+
NH3+ O
HN
~NH
N+ N+~
~--/ ~ % ~i +
-NH3+-
NH //
/--~ I ~ NH3+ H2N O
~~U+ n~ b
~~~+
~NH3+ ,--NH3+
2+ ~N N~~~2+
/ U
The process is illustrated by the following generic scheme:
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FLOW SHEET A
p R~ 1) Activate hydroxyl group for displacement
H H 2) React with side chain group
H tR)z
-X'
O N
COZP"
N _~ ~R)z
2
1 ) Convert X' to X
2) Q-L-B,
-L-B,
1 ) if necessary, modify R
2)deblock P and P"
3) If necessary, convert or
deblock B' to the basic or
cationic functionB
Steps 2 and 3 can be carried out
separately, simultaneously or
their order can be reversed.
/O -i-B
I /A
pH Rr ~~~ P =OH or hydroxyl protecting group
H H N, ~R)z p~~ = carboxyl protecting grou
= S p
N ~
O X' = Precursor to X
X = a leaving group on A
A4
Q' = monoalkylated monocationic precursor
to the dialkylated, dicationic group p
R , A, D, L and B as defined in the scope of the invention
B'is a protected form of B, a precursorto B, or B' = B
With reference to Flow Sheet A above, P, R1, R, and M,
are as defined with respect to the compounds of formula I.
5 P** represents a carboxyl protecting group.
~,1* represents a group which reacts with intermediate
~2 (upon activation of A~) in a manner which results in the
incorporation in the final product of a member of the group defined as
Q above, thus Q* may be viewed as a precursor for Q.
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The naphthosultam side chain group used in the
synthesis of the compounds of the present invention have, in some
cases, been described in the chemical literature. In other cases,
precursor compounds which may be readily converted to the requisite
5 naphthosultam have been described in the literature. In cases where
the requisite naphthosultam is not known in the literature it is
neceessary to synthesize the naphthosultam by a newly developed
synthesis. One skilled in the art can adapt a previously published
synthesis of an analogous naphthosultam to prepare the requisite
10 compound in a straightforward manner without undue
experimentation. Examples of naphthosultam synthesis are
described herein (see below).
The naphthosultam side chain group is initially reacted
with a suitably protected carbapen-2-em-3-carboxylate having an
15 activated hydroxymethyl group at the 2-position.
The carbapenem nucleus having a -CH20H substituent
at position 2 can be obtained in accordance with Schmitt, S. M. et al.,
J. Antibiotics 41(6): 780-787 (1988), the teachings of which are
incorporated herein by reference. The carboxylic acid group at C-3 of
20 the carbapenem 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 optionally protected with a hydroxyl
protecting group such as trimethylsilyl (TMS), triethylsilyl (TES),
25 tent-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS),
acetyl, allyloxycarbonyl, 2-trimethylsilylethoxy carbonyl, 2-
trichloroethoxycarbonyl and the like.
The addition of the naphthosultam side chain group
to the carbapenem is accomplished by treating a solution of the
30 hydroxymethyl-carbapenem and the naphthosultam side chain
group in a suitable solvent such as tetrahydrofuran (THF), ether,
acetonitrile, dimethylformamide (DMF), benzene, dimethylsulfoxide
(DMSO), and the like with a (premixed) suitable activating reagent
such as diethyl azodicarboxylate (DEAD) / triphenylphosphine,
35 diisopropyl azodicarboxylate (DIAD) / tributylphosphine, and the like,
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at a temperature between about -20 °C and 35 °C for about 5 to
90
minutes.
Alternatively, the naphthosultam and carbapenem can
be mixed together with either the azodicarboxylate or the phosphine
5 reagent in a suitable solvent and the other component of the
activating reagent (the phosphine or the azodicarboxylate,
respectively) can be added to that mixture. Once the naphthosultam,
carbapenem, and activating reagents) have been mixed, the reaction
is allowed to proceed at a temperature between about -20 °C and 35
°C
IO for about 5 to 90 minutes.
The resulting mixture is then subjected to a standard
work-up procedure familiar to those skilled in the art to afford a
crude 2-naphthosultam-methyl substituted carbapenem which is
purified, if necessary, by recrystallization or by chromatography on
15 silica gel, eluting with a suitable solvent or mixture of two or more
solvents, such as hexane, ethyl acetate, ether, benzene,
dichloromethane, chloroform, acetone, methanol and the like.
Modification of the naphthosultam side chain of
compounds A2, which is generally necessary to introduce the
20 charged substituent of A4, is best accomplished before removal of the
protecting groups. For compounds which contain a hydroxyl group
(X') in the side chain, a positively charged substituent may be
introduced into the side chain by first activating the hydroxyl group
by converting it to a suitable leaving group (X) such as a triflate,
25 mesylate, tosylate, iodide, chloride, bromide, and the like, and then
displacing the resulting leaving group with a compound Q*, such as
a suitably substituted diazabicyclooctane or a suitably substituted
N,N-dimethylpiperazine. Alternatively,
in some cases, the charged substituent may be incorporated in the
30 naphthosultam side chain before addition of the naphthosultam to
the carbapenem or may be introduced after deprotection of A2.
However, introduction of the charged substituent by modification of
A2 before deprotection is greatly preferred.
In some cases, activation of the hydroxyl group and
35 displacement by Q* to produce A3 may be accomplished in a single
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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
5 compound in a suitable solvent such as dichloromethane, tetrahydro-
furan, ether, benzene, and the like with an activating reagent, such
as trifluoromethanesulfonic anhydride, methanesulfonic anhydride,
toluenesulfonic anhydride, methanesulfonyl chloride,
benzenesulfonyl chloride, toluenesulfonyl chloride, and the like in the
10 presence of a suitable base such as triethylamine, tributylamine,
diisopropylethylamine, 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
15 intermediate in a suitable solvent such as acetone, methyl ethyl
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
20 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
25 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,
tetrahydrofuran, ether, DMF, benzene, acetonitrile, DMSO, and the
like as described in the preceding paragraphs. The resulting
30 activated intermediate is treated with 1-3 molar equivalents of
compound Q* at 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
35 solvent. In other cases, the displacement may be conducted without
isolation of the intermediate and, in cases where Q* is also used as a
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WO 99/20627 -33- PCT/US98/22110
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 f~*. A silver salt of a non-nucleophilic acid,
such as silver trifluoromethanesulfonate, silver tetrafluoroborate and
the like is then added. Although the reaction will proceed in the
absence of the silver salt, the reaction proceeds more rapidly in the
10 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 efficiency 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.
The synthesis of the target compound is completed by
removing any protecting groups which are present in the
penultimate intermediate using standard techniques which are well
known to those skilled in the art. The deprotected final product is
20 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 or by recrystallization.
The 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
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.
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Using standard susceptibility tests, the compounds of the
invention are determined to be active against MRSA.
The invention is illustrated with the following non-
limiting examples.
PREPARATIVE EXAMPLE 1
SYNTHESIS OF 4-(2-TRIETHYLSILArTYLOXY-ETHYL)-1 8
NAPHTHOSULTAM
~OH ~OAc
\ AcCI / I \ 1 ) CIS03H
\ / Et3N \ / 2) K2C03
OAc OAc
\ SOC12 / I \ HN03
\ / \
S03K ~ S02C1
_OAc -OH
/ \ NH3 / \ Cs2CO3
/ \
N02 S02CI N02 S02NH2
~OH ~OTES
\ TESCI /
\ / \ /
HN-O,O HN-o.0
Sit n 1: 1-(2-Aceto~~vl)-naphthalene
10 Triethylamine (691 mL, 4.96 mol) was added to an ice
cold solution of 1-(2-hydroxy-ethyl)-naphthalene (569 g, 3.30 mol) in
dichloromethane (2.2 L). Acetyl chloride (282 mL, 3.97 mol) was
added dropwise over 90 minutes. After the addition was complete,
the reaction mixture was stirred for an additional 30 minutes with
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ice-bath cooling. The reaction mixture was washed sequentially with
water (2 x 1 L), 1N HCl ( 1 L, 500 mL), water ( 1 L), 5% aqueous
NaHC03 (500 mL), water (I L), and brine (500 mL), then dried over
magnesium sulfate, filtered, and evaporated to afford 1-(2-acetoxy-
ethyl)-naphthalene (723.2 g) as a yellow oil that slowly crystallized.
tep 2: Potassium 4-(2-acetoxy-ethyl)-naphthalene-1-sulfonate
Chlorosulfonic acid (69.3 g, 590 mmol) was added
dropwise over 17 minutes to a solution of 1-(2-acetoxy-ethyl)-
10 naphthalene (105.5 g, 490 mmol) in dichloromethane (200 mL). The
reaction was exothermic and periodic ice-bath cooling was employed
to maintain the internal temperature at 25-30°C. Approximately 10
minutes into the CLS03H addition, voluminous evolution of HCl gas
was observed. After the addition was complete, the reaction mixture
15 was stirred at room temperature for 3 hours then cautiously added to
ice (400 g). After shaking, the layers were separated. The aqueous
layer was washed with dichloromethane then slowly neutralized by
addition of a solution of potassium carbonate (77 g, 560 mmol) in
water (200 mL). The precipitate was collected by filtration, washed
20 with cold water (100 mL), then dried under vacuum at 60 °C to afford
potassium 4-(2-acetoxy-ethyl) naphthalene sulfonate (102.39 g) as a
white solid. This material contained ca. 6% of the isomeric
potassium 5-(2-acetoxy-ethyl)-1-naphthalene sulfonate as determined
by 1H NMR. The filtrate was concentrated under vacuum to afford a
25 white suspension (355 g) which was stored in a refrigerator
overnight. The solid was collected by filtration, washed with cold
water (100 mL), then dried under vacuum at 60 °C to afford a second
crop of potassium 4-(2-acetoxy-ethyl)-naphthalene-1-sulfonate (10.67
g) as a white solid. The second crop contained ca. 14% of the isomeric
30 potassium 5-(2-acetoxy-ethyl)-1-naphthalene sulfonate as determined
by 1H NMR.
Sten 3: 4-(2-Acetoxv-eth lv )-naphthalene-1-sulfonvl chloride
Potassium 4-(2-acetoxy-ethyl)-naphthalene-1-sulfonate
35 (102.3 g, 308 mmol) was added in portions over 15 minutes to a room
temperature solution of dimethylformamide (2.4 mL, 31 mmol) in
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WO 99/20627 ~~ PCT/US98/22110
thionyl chloride (112 mL, 1.54 mol). The reaction mixture was
gradually brought to 80 °C (oil bath temperature) over 30 minutes and
heated at 80° C for 90 minutes, then cooled to room temperature and
stirred at room temperature for 60 minutes. The reaction mixture
5 was partitioned between ice water (500 mL) and ethyl acetate (500
mL). The organic layer was washed with water (200 mL) and brine
(200 mL), dried over magnesium sulfate, filtered, and evaporated
under vacuum to a cream colored solid. The crude product was
triturated with pet ether to afford 4-(2-acetoxy-ethyl)-naphthalene-1-
sulfonyl chloride as a pale tan solid (77.47 g).
Step 4' 4-(2-Acetoxv-ethyl,}-8-vitro-naphthalene-1-sulfonyl chloride
4-(2-Acetoxy-ethyl)-naphthalene-1-sulfonyl chloride
(76.96 g, 246 mmol} was added portionwise over 12 minutes to 90%
15 nitric acid (154 mL, 3.278 mol) cooled in an ice-methanol bath (-
20°C).
After the addition was complete, the reaction mixture was stirred at -
°C for an additional 15 minutes. The reaction mixture was
partitioned between ice water (800 mL) and chloroform (800 mL). The
aqueous layer was extracted with chloroform (100 mL). The
20 combined organic layers were washed with brine (400 mL, 200 mL),
then dried over magnesium sulfate, filtered, and evaporated to a
golden oil. Diethyl ether (300 mL) was added to the crude product and
the mixure was shaken vigorously to afford an off white solid. The
solid was collected by filtration, washed with ether (2 x 50 mL), and
25 dried under vacuum to afford 4-(2-acetoxy-ethyl)-8-vitro-naphthalene-
1-sulfonyl chloride (41.85 g) as an off white solid.
Sten 5: 4-(2-Hvdroxv-ethyl)-.8-vitro-naphthalene-1-sulfonamide
Solid 4-(2-acetoxy-ethyl)-8-vitro-naphthalene-1-sulfonyl
chloride (39.64 g, 111 mmol) was added to an ice-cold, 6.8 M solution
of ammonia in methanol (408 mL, 277 mmol). The cooling bath was
removed, the reaction flask was stoppered, and the reaction was
stirred at room temperature. After 4 days, the dark amber solution
was concentrated under vacuum to a dark gum. The residue was
35 triturated vigorously shaken with water (300 mL) to give a solid
which was washed with water ( 150 rnL) then ether ( 150 mL) and
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dried under vacuum. The resulting brown solid was recrystallized
from isopropanol (300 mL) to afford 4-(2-hydroxy-ethyl)-8-nitro-
naphthalene-1-sulfonamide (27.79 g) as tan flakes.
Sten 6: 4-(2-Hydroxv-ethyl)-1.8-naphthosultam
Powdered cesium carbonate (76.8 g, 236 mmol) was
added to a solution of 4-(2-hydroxy-ethyl)-8-nitro-naphthalene-1-
sulfonamide (30.77 g, 94.3 mmol) in anhydrous dimethylformamide
(470 mL). The mixture was placed under a nitrogen atmosphere,
10 sonicated for 10 minutes, then stirred at room temperature for 20
minutes. The mixture was then placed in a 100 °C oil bath and
stirred vigorously. After 3.5 hours, the reaction mixture was
removed from the heating bath, allowed to cool to room temperature,
and left at room temperature overnight. The mixture was then
15 filtered and the collected solid was washed with dimethylformamide.
The combined filtrate and washings were evaporated to a dark oil.
This material was dissolved in water (400 mL), treated with activated
charcoal (5 g), and the resulting mixture was heated on a hot water
bath for 5 minutes. The mixture was cooled slightly then filtered
20 through a pad of super-cel. The filtrate was diluted with 2-butanone
(450 mL), brine (300 mL), and 1M pH 1 aqueous phosphate (150 mL).
The mixture was shaken vigorously and the layers were separated.
The aqueous layer was extracted with 2-butanone (2 x I50 mL). The
combined organic layers were washed with brine (2 x 300 mL), dried
25 over magnesium sulfate, filtered and evaporated to a brown solid
(21.4 g). The solid was treated with ethyl acetate (100 mL), sonicated
for 15 minutes and filtered. The collected solid was washed with cold
ethyl acetate (50 mL) and dried under vacuum to afford 4-(2-hydroxy-
ethyl)-1,8-naphthosultam as a pale brown powder (16.68 g).
30 IH NMR (DMSO-dg, 500 MHz) d 3.25 (t, ArC I~CH20H), 3.73
(m, ArCH2CH20H), 4.77 (t, ArCH2CH20I-~), 6.90 (d, H-7), 7.58 (dd, H-
6), 7.69 (d, H-5), 7.69 (d, H-3), and 8.03 (d, H-2}.
Sten 7~ 4-(2-Triethy~silanvlox~~vl)-1 8-naphtho~ultam
35 Chlorotriethylsilane (13.57 mL, 80.86 mmol) was added
dropwise over 1 minute to a vigorously stirred suspension of 4-(2-
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hydroxy-ethyl)-1,8-naphthosultam (17.53 g, 70.32 mmol) and
imidazole (5.99 g, 87.90 mmol) in dichloromethane (351 mL). The
reaction mixture was stirred under a nitrogen atmosphere at room
temperature for 15 minutes, then water (350 mL) was added. The
5 organic layer vas washed sequentially with 0.2 N HCl (350 mL) and
water (350 mL) then dried over magnesium sulfate, filtered, and
evaporated under vacuum to a dark oil (29.07 g). The crude product
was purified by flash column chromatography on silica gel (5 x 27 cm
column, eluted with 4:1 hexanes-EtOAc followed by 3:1 hexanes-
EtOAc) to afford a deep red oil (23.9 g). The oil was mixed with
hexanes (225 mL), sonicated to start crystallization, and stirred at
room temperature. The mixture was filtered and the collected solid
was washed with hexanes (3 x 15 mL) and vacuum dried to afford 4-
(2-triethylsilyloxy-ethyl)-1,8-naphthosultam (19.78 g) as a light pink-
white solid.
1H NMR (CDC13, 500 MHz) d 0.54 (q, SiC~i2CHg), 0.88 (t,
SiCH2C~g), 3.34 (t, ArCH2CH20), 3.95 (t, ArCH2C~-I20), 6.89 (d, H-7),
7.14 (s, NH), 7.50 (dd, H-6), 7.62 (d, H-3), 7.66 (d, H-5), 7.89 (d, H-2)
mp 68.5-70.0°C
PREPARATIVE EXAMPLE 2
SYNTHESIS OF ALLYL (1S.5R,6S)-6-f(1R)
(ALLYLOXYCARBONYLOXY)-ETHYLI-1-METHYL-2-(4-f2
(TRIFLUOROMETHANESULFONYLOXY)-ETHYLI-1,8
25 NAPHTHOSULTAMYL-METHYLI-CARBAPEN-2-EM-3-
CARBOXYLATE
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OTES
0
ROCO H H Me \
Me OH HN-S:O
" O
N O
O ~ PPh3 DIAD, PPh3
C02R
R = ailyl
O
I I \
ROCO H H Me
OTES heat ~
Me ~ \ /
N O \
O ~ PPh3 isy
O O
C02R
-OTES
~OH
/ \
pll Me \ ~ / / ~ \
ROCO H H
Me N-S .O TtOH~ \ / Tf
N~ O 'i,/N-S.O
O O
C02R
OTf
/ ~ \
O \ /
ROCO H H Me
Me N SII~~O
O
O
C02R
~~vl (3-f1(R)-(all,~ycarbon~~)-ethyll-2-tl(R)-methyl-2-oxo-
3-f4-(2-trieth ls~ ilanyloxv-eth lY )-1,8-naphthosultam~l_- rop 1~,35)-
4-oxo-azetidin-1-yll-(trinhenylnhosphoranylidene)-acetate
A solution of allyl (3-[1(R)-(allyloxycarbonyloxy)-ethyl]-2-
[3-hydroxy-1(R)-methyl-2-oxo-propyl)-(2R,3S)-4-oxo-azetidin-1-yl}-
(triphenylphosphoranylidene)-acetate (74.8 g, 116.2 mmol), 4-(2-
triethylsilanyloxy-ethyl)-1,8-naphthosultam (38.03 g, 104.6 mmol),
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and triphenylphosphine {45.72 g, 174.3 mmol) in anhydrous
tetrahydrofuran (582 mL) was placed under a nitrogen atmosphere
and cooled in an ice bath. Diisopropyl azodicarboxylate (34.3 mL,
174.3 mmol) was added over one minute. The resulting solution was
5 sirred at 0°C for 60 minutes followed by 30 minutes at room
temperature. The mixture was filtered to remove a small amount of
solid. The filtrate was diluted with ethyl acetate (300 mL) and washed
with brine (300 mL). The organic phase was dried over magnesium
sulfate, filtered and evaporated under vacuum to a dark red oil (220.1
10 g). The crude product was purified by chromatography on silica gel
(5 kg), eluting with 7:3 hexane-ethyl acetate followed by 1:1 hexane-
ethyl acetate. The product containing fractions were combined and
evaporated under vacuum to afford the title compound (94.7 g) as a
viscous oil. In order to determine an accurate yield for the reaction,
15 an aliquot of this material (508.8 mg of 263.5 g of a solution of the
product in toluene) was lyophilized from benzene to afford an off
white fluffy solid (144.1 mg). The actual yield of product was
calculated as 74.62g.
20 Step 2' ,All, 1~ (1S,5R,6S)-6-((1R)-fallyloxycarbonyloxy)-ethyll-1-methyl-
2- f 4-( 2-triethylsilanvl oxv-ethyl)-1.8-naphthosultamvl-methyll -
carbapen-2-em-3-carboxvlate
A solution of allyl [3-[1(R)-(allyloxycarbonyloxy)-ethyl]-2-
{ 1(R)-methyl-2-oxo-3-[4-(2-triethylsilanyloxy-ethyl)-1,8-
25 naphthosultamyl]-propyl)-(2R,3S)-4-oxo-azetidin-1-yl}-
(triphenylphosphoranylidene)-acetate (74.6 g, 75.4 mmol, see step 1)
in toluene (750 mL) was placed under a nitrogen atmosphere and
refluxed for 2.5 hours. The reaction mixture was allowed to cool to
room temperature and evaporated to a paste which was stored
30 overnight in the freezer as a suspension in dichloromethane. The
crude product was purified by chromatography on silica gel (1.8 kg),
eluting with 85:15 hexane-ethyl acetate followed by 4: hexane-ethyl
acetate. The product containing fractions were combined and
evaporated under vacuum to afford the title compound (42.4 g) as a
35 viscous tan oil.
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IR (thin film on NaCl) 2955, 2876, 1784, 1746, 1716, 1258,
and 661 cm-1
IH NMR (CDC13, 500 MHz) d 0.52 (q, SiCH2CH3), 0.88 (t,
SiCH2CI~- 3) 1.29 (d, 1-CH3), 1.43 (d, C~gCHOC02), 3.34 (t,
5 ArCH2CH20), 3.37 (dq, H-1), 3.43 (dd, H-6), 3.94 (t, ArCH2C~0), 4.14
(dd, H-5), 4.56-4.60 (m, OC02CH2), 4.67 (d, 2-CHaHb), 4.81 and 4.92
(two dd, C02CH2), 5.11 (dq, CH3CHOC02), 5.24 (d, vinyl-H) 5.30-5.34
(m, 2 vinyl-H), 5.37 (d, 2-CHa~), 5.50 (d, vinyl-H), 5.86-5.89 (m, vinyl-
H), 6.00-6.04 (m, vinyl-H), 6.69 (d, Ar H-7), 7.50 (t, Ar H-6), 7.61 (d, Ar
10 H-5), 7.63 (d, Ar H-3), 7.90 (d, Ar H-2)
HRMS (FAB) calculated for C36H47N2OgSiS (MH+)
711.2771; found 711.2690.
Step 3' Allvl (1S,5R 6S)-6-f(1R)-(allyoxycarbonvloxy)-ethvll-2-f4-(2-
15 hvdrox~ roRyl)-1,8-na~hthosultamvl-methvll-1-methyl-carba ep n-2-
em-3-carboxvlate
A solution of allyl (1S,5R,6S)-6-[(1R)-
(allyloxycarbonyloxy)-ethyl]-1-methyl-2-[4-(2-triethylsilanyloxy-ethyl)-
1,8-naphthosultamyl-methyl]-carbapen-2-em-3-carboxylate (45.2 g,
20 63.6 mmol) in tetrahydrofuran (500 mL) was diluted with water (125
mL) and treated with 1M aqueous trifluoromethanesulfonic acid (6.4
mL, 6.4 mmol). The resulting mixture was stirred at room
temperature for 15 minutes, then partitioned between 5% aqueous
sodium bicarbonate (200 mL), brine (25 mL), and ethyl acetate (500
25 mL). The organic phase was washed with dilute brine (200 mL),
dried over magnesium sulfate, filtered and evaporated under
vacuum to an oil (50.2 g). The oil was evaporated under vacuum from
toluene (3 x 50 mL) to afford the title compound (42.9 g) as a tacky
foam. This material was used without purification in the next step.
30 1H NMR (CDC13) d 1.31 (d, 1-CH3), 1.45 (d,
C i~3CHOC02), 3.41 (t, ArCH2CH20H), 3.41 (dq, H-1), 3.45 (dd, H-6),
4.04 (dt, ArCH2CH20H), 4.16 (dd, H-5), 4.59 (m, OC02CH2), 4.69 (d, 2-
C -~aHb), 4.89 (m, C02CH2), 5.14 (dq, CH3C~- OC02), 5.26, 5.33, 5.35
and 5.53 (four m, 4 vinyl-H), 5.41 (d, 2-CHaHb), 5.91 and 6.05 (two m, 2
35 vinyl-H), 6.73 (d, Ar H-7), 7.54 (dd, Ar H-6), 7.63 (d, Ar H-5), 7.68 (d,
Ar H-3), 7.95 (d, Ar H-2)
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Sten 4: Allyl (1S.5R.6S)-6-f(1R)-(allyloxvcarbonvloxy)-ethyll-1-meth ~~l-
2-(4-f2-(trifluoromethanesulfonylo~c )-et 11-1,8-nanhthosultam ~~l-
methyll-carbapen-2-em-3-carboxvlate
5 A solution of allyl (1S,5R,6S)-6-[(1R)-
(allyloxycarbonyloxy)-ethyl]-2-[4-(2-hydroxy-propyl)-1,8-
naphthosultamyl-methyl]-1-methyl-carbapen-2-em-3-carboxylate
(63.58 mmol, amount teoretically present in the unpurified product of
the previous step) in anhydrous methylene chloride (750 mL) was
10 placed under a nitrogen atmosphere, cooled in an ice-methanol bath
(-15°C), and treated with 2,6-lutidine (22.2 mL, 190.7 mmol). The
resulting mixture was aged at -15°C for 8 minutes then
trifluoromethanesulfonic anhydride (16.0 mL, 95.4 mmol) was added
over a period of 4 minutes. After 30 minutes at -15°C, the reaction
15 mixture was diluted with methylene chloride (1.25 L) and washed
sequentially with water (1.8 L), 0.2N hydrochloric acid (2 x 1.8 L) and
water (1.8 L), then dried over magnesium sulfate, filtered, and
evaporated under vacuum to give the title compound as an oil.
1H NMR (CDC13, 500 MHz) 8 1.31 (d, 1-C~- 3), 1.44 (d,
20 C~CHOH), 3.39 (m, H-1), 3.45 (dd, H-5), 3.67 (CHzCH20Tf), 4.16 (m,
H-6), 4.58 (t, CHZOTfj, 4.67 (d, 2-CHaHb), 4.82 (m, CHZCH=CH2), 4.93
(m, CH2CH=CH2), 5.12 (m, CI-~CH30), 5.24 (d, C~- 2CH=CH2), 5.32 (m,
CH2CH=CH2), 5.41 (d, CH2N), 5.52 (d, CHZCH=CHZ), 5.88 (m,
CHZCH=CHZ), 6.03 (m, CHZC~=CH2), 6.77 (d, ArH-7), 7.54 and 7.58 (2
25 m's, ArH-5 and Ar H-6), 7.67 (d, Ar H-2), 7.96 (d, Ar H-4).
PREPARATIVE EXAMPLE 3
SYNTHESIS OF 3-(2-TRIETHYLSILArTYLOXY-ETHYL)-1,8
NAPHTHOSULTAM
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Br
/ I \ ~ _ NBA / I \ ~ AcC
\ / OH \ / OH Et3N
Br Br
/ \ ~ 1 ) CIS03H / \ ~ SOC12
\ I / OAc 2) K2CO3 \ ( / OAc
S03K
Br Br
\ ~ -HN~ / I \ ~ NH
\ / OAc \ / OAc
S02CI N02 S02CI
Br Br
/ I \ 1 Nab / I \ ~ Cs2- CO~
\ / OAc \ / OH
N02 S02NH2 N02 S02NH2
Br
/ \ ~ H2 / \ TESCI
\ I / OH Pd(OH)2/C (
\ / OH
HN-OHO HN-O'O
/ \
\ I / OTES
HN-~.O
O
Stew 1 ~ 1-Bromo-2-(2-hvdroxy-eth lv )-naphthalene
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A solution of 2-(2-hydroxy-ethyl)-naphthalene (58.5 g,
0.34 mol) in anhydrous acetonitrile (500 mL) was treated with N-
bromo-succinimide (66.5 g, 0.37 mol). The resulting solution was
stirred at room temperature under a nitrogen atmosphere and
5 protected from light for 30 minutes, then heated in an oil bath at
50°C
for 2 hours. After cooling to room temperature, the reaction mixture
was evaporated under vacuum to a viscous oil. The oil in diethyl
ether (350 mL) was washed with water (350 mL}, dilute aqueous
sodium thiosulfate (300 mL), water (300 mL) and brine (200 mL),
10 dried over magnesium sulfate, filtered, and evaporated under
vacuum to an oil (89.5 g) that solidified on standing. The crude
product was chromatographed on a column of EM silica gel 60,
eluting with methylene chloride, to afford a yellow solid (78.2 g).
Recrystallization of this material from carbon tetrachloride provided
15 the title compound (46.5 g) as a pale yellow solid.
Step 2: 2-(2-Acetoxy-ethyl)-1-bromo-naphthalene
A solution of 1-bromo-2-(2-hydroxy-ethyl)-naphthalene
(46.5 g, 0.185 mol) in methylene chloride (370 mL) was placed under a
20 nitrogen atmosphere, cooled in an ice bath, and stirred.
Triethylamine (32.3 mL, 0.232 mol) was added followed by acetyl
chloride (15.8 mL, 0.222 mol) dropwise over 5 minutes. The reaction
mixture was removed from the ice bath and stirred at room
temperature for 15 minutes. The reaction mixture was washed with
25 water (300 mL), 1N hydrochloric acid (200 mL) and water (250 mL),
dried over magnesium sulfate, filtered, and evaporated under
vacuum to afford the title compound as an oil (55.1 g).
Sten 3' Potassium 3-(2-aceto~c ~-ethyl)-4-bromo-naphthalene-1-
30 nat
A solution of 2-(2-acetoxy-ethyl)-1-bromo-naphthalene
(32.5 g, 0.111 mol) in trifluoroacetic acid (112 mL) was stirred under a
nitrogen atmosphere and cooled in an ice bath while chlorosulfonic
acid (8.9 mL, 0.130 mol) was added dropwise over 5 minutes. The
35 resulting solution was heated in an oil bath at 50°C for 90 minutes
then cooled to room temperature and evaporated under vacuum to
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dark oil. The oil was partitioned between methylene chloride (150
mL) and water (150 mL). The aqueous phase was washed with
methylene chloride (150 mL), briefly pumped under vacuum, then
brought to pH 8 with 3M aqueous potassium hydroxide (30 mL)
5 followed by 4M aqueous potassium carbonate (35 mL). The resulting
mixture was stirred in a cold room (5°C) for 2 hours and filtered to
remove the product. The recovered white solid was vacuum dried to
afFord the title compound (11.21 g).
10 ten 4~ 3-(2-Acetoxy-ethyl)-4-bromo-naphthalene-1-sulfon~rl chloride
Potassium 3-(2-acetoxy-ethyl)-4-bromo-naphthalene-1-
sulfonate (17.75 g, 43.2 mmol) was added at room temperature to a
stirred solution of N,N-dimethylformamide (0.334 mL, 4.31 mmol) in
thionyl chloride (63 mL, 863 mmol). The resulting mixture was
15 placed in an oil bath at 70°C and stirred. After 10 minutes,
additional
thionyl chloride (20 mL) was added to facilitate stirring. After 40
minutes at 70°, the reaction flask was fitted with a distillation head
and excess thionyl chloride was removed under vacuum. The
residual brown solid was mixed with diethyl ether (300 mL) and
20 added to an ice-cold, stirred mixture of water (I00 mL) and ether (100
mL). The organic phase was separated, washed with water (200 mL)
and brine (100 mL), dried over magnesium sulfate, filtered, and
evaporated under vacuum to afford the title compound (14.63 g).
25 Step 5' 3-(2-Acetoxv-ethyl)-4-bromo-8-nitro-naphthalene-1-sulfonXl
chloride
An ice-cold, stirred solution of 3-(2-acetoxy-ethyl)-4-
bromo-naphthalene-1-sulfonyl chloride (17.66 g, 45.1 mmol) in
trifluoroacetic acid (150 mL) was treated with 96% sulfuric acid (12.5
30 mL, 225 mmol) and with 90% nitric acid (2.65 mL, 56.4 mmol) added
dropwise over 3 minutes. The reaction mixture was removed from
the ice bath, stirred at room temperature for 15 minutes, re-cooled in
an ice bath, and treated with water (850 mL) added dropwise. The
resulting mixture was filtered through a celite pad to collect the solid
35 which was washed with water (100mL) and dissolved in methylene
chloride (350 mL). The methylene chloride solution was washed with
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water (500 mL) containing brine (100 mL), dried over magnesium
sulfate, and evaporated under vacuum to an oil (21.23 g). This
material was shown to be a 42:58 mixture of the 5-N02 to 8-N02
products by 1H NMR}. The crude product was mixed with ethyl
5 acetate (20 mL) and sonicated to provide a crystalline precipitate.
This material was collected, washed with ethyl acetate, and dried
under vacuum to afford the title compound (8.llg) as an off white
solid. The mother liquors yielded an additional 1.47 g of the title
compound following flash chromatography on silica gel (eluting with
10 30-35% ethyl acetate in hexane) and crystallization from diethyl ether.
Step 6: 3-(2-Acetoxv-ethyl)-4-bromo-8-vitro-naphthalene-1-
sulfonamide
Solid 3-(2-acetoxy-ethyl)-4-bromo-8-vitro-naphthalene-1-
15 sulfonyl chloride (5.00 g, 11.45 mmol) was added at room temperature
to 0.5M ammonia in dioxane (92 mL, 46 mmol). After stirring at
room temperature for 40 minutes, the mixture was evaporated under
vacuum to a residue which was mixed with water (100 mL),
sonicated, and filtered. The collected pale-yellow solid was washed
20 with water (2 x 20 mL) and vacuum dried to afford the title compound
(4.75 g).
Step 7: 4-Bromo-3-(2-hydroxy-ethyl)-8-vitro-naphthalene-1-
sulfonamide
25 Sodium methoxide in methanol (23.7 mL of a 0.5M
solution, 11.8 mmol) was added to a suspension of 3-(2-acetoxy-ethyl)-
4-bromo-8-vitro-naphthalene-1-sulfonamide (4.70 g, 11.3 mmol) in
methanol (33 mL}. The mixture was stirred under a nitrogen
atmosphere at room temperature for 90 minutes, then concentrated
30 under vacuum to approximately half volume, diluted with ethyl
acetate (200 mL), and washed with 2N hydrochloric acid. The oganic
solution was washed with water (100 mL) and brine (50 mL), dried
over magnesium sulfate, filtered, and left to stand at room
temperature. The organic solution deposited a solid which was
35 collected by filtration, washed with ethyl acetate (2 x 15 mL), and
vacuum dried to give the title comound ( 1.78 g). Additional poduct
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{ 1.88g) was obtained from the mother liquors after concentration
under vacuum and crystallization from diethyl ether.
~n 8' 4-Bromo-3-(2-hydrox -y eth ly )-1,8-nanhthosultam
5 A solution of 4-bromo-3-(2-hydroxy-ethyl)-8-nitro-
naphthalene-1-sulfonamide (3.61 g, 9.62 mmol) in anhydrous N,N-
dimethylformamide (96 mL) was treated with cesium carbonate (7.84
g, 24.1 mmol). The resulting mixture placed under a nitrogen
atmospere, sonicated at room temperature for 10 minutes, stirred at
10 room temperature for 5 minutes, and then heated in an oil bath at
100°C for 2 hours. The mixture was evaporated under vacuum to a
brown residue which was partitioned between ethyl acetate (100 mL)
and 2N hydrocloric acid (20 mL). The organic phase was washed
with water (20 mL) and brine (20 mL), dried over magnesium sulfate,
15 filtered, and evaporated under vacuum to a solid (2.83 g). This
material was mixed with diethyl ether (30 mL), sonicated, stirred,
and filtered. The collected solid was washed with ether (20 mL) and
vacuum dried to give the title compound (2.21 g) as a tan powder.
20 step 9: 3-(2-Hydro~-ethyl)-1,8-naphthosultam
A solution of 4-bromo-3-(2-hydroxy-ethyl)-1,8-
naphthosultam (2.10 g, 6.4 mmol) in ethanol (105 mL) was treated
with triethylamine (2.68 mL, 19.2 mmol) and 20% palladium
hydroxide on carbon (0.84 g). The mixture was hydrogenated (45-50
25 psi H2) on a Parr shaker for 6.5 hours at room temperature, then
filtered through a celite pad to remove the catalyst which was washed
with additional ethanol (3 x 5 mL). The filtrate and washings were
evaporated under vacuum to a residue which was partitioned
between ethyl acetate (60 mL) and 1N hydrochloric acid (50 mL). The
30 organic phase was washed with brine (25 mL), dried over
magnesium sulfate, filtered, and evaporated under vacuum to afford
the title compound (1.32 g) as a brown solid.
~tgp 10' 3-(2-Triethylsilanyloxy-eth~1 8-nanhthosultam
35 A mixture of 3-(2-hydroxy-ethyl)-1,8-naphthosultam (1.44
g, 5.78 mmol) and imdazole (0.495 g, 7.27 mmol) in anhydrous
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methylene chloride (39 mL), at room temperature and under a
nitrogen atmosphere, was treated with chlorotriethylsilane (1.12 mL,
6.69 mmol). After stirring at room temperature for 30 minutes, the
mixture was diluted with methylene chloride (60 mL), washed with
5 water (I00 mL), 0.2N hydrochloric acid (50 mL) and water (100 mL),
dried over magnesium sulfate, filtered, and evaporated under
vacuum to a dark oil (2.15 g). The oil was purified by flash
chromatography on EM silica gel 60 (4 x 15 cm column), using 3:1
hexane-ethyl acetate as eluting solvent, to give an oil (2.09 g). This
10 material was mixed with hexane ( 10 mL) and sonicated to afford a
crystalline solid. The solid was collected, washed with hexane (3
mL), and dried to afford the title compound (1.73 g).
MP. 97.5-98.0°C.
1H NMR (CDC13) d 0.54 (q, SiC i~CHg), 0.88 (t, SiCH2C~-I3), 3.08
15 (t, ArCH2), 3.90 (t, CH20), 6.84 (m, H-7), 7.24-7.47 (m, H-5 and H-6),
7.84 and 7.90 (two d's, H-2 and H-4).
PREPARATIVE EXAMPLE 4
SYNTHESIS OF ALLYL (1S Rf6S)-6-f(1R)
20 (ALLYLOXYCARBQNYLOXY)-ETHYLI-1-METHYL-2-(3-f2-
(TRIFLUOROMETHANESULFONYLOXY)-ETHYLI-1~8-
NAPHTHOSULTAMYL-METHYLI-CARBAPEN-2-EM-3-
CARBOXYLATE
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~I
ROC H H Me ~ / OTES
Me ~ OOH HN-S:O
O O
O ~ PPh3 DIAD, PPh3
C02R
R = allyl
Q
ROC Me I \
H H
w
Me / heat
N O N\ \
O ~ PPh3 iSv OTES
O O
C02R
/ \
ROC \ I / OTES / \
H H Me I
Me N-S~~O TfO~ \ / OH Tf
N~ O ~~N S~~O
O O
C02R
/ \
ROC \ I / OTf
H H Me )'
Me N
/j-" O
~'~(O
COZR
Step 1Allvl (3-f 1(R)-(al~,vlo~cycarbonylox )-et rll-2-11(R)-methyl-2-oxo-
3-f3-(2-trieth ly silanyloxy-eth 1~ 8-na~hthosultamyll-prop, 1~,,
4-oxo-azetidin-1-yll-(tripheny_lphosphoranylidene)-acetate
A solution of allyl {3-[1(R)-(allyloxycarbonyloxy)-ethyl]-2-
[3-hydroxy-1(R)-methyl-2-oxo-propyl]-(2R,3S)-4-oxo-azetidin-1-yl}-
(triphenylphosphoranylidene)-acetate (3.81 g, 5.91 mmol), 3-(2-
triethylsilanyloxy-ethyl)-1,8-naphthosultam (1.72 g, 4.73 mmol), and
triphenylphosphine (2.32 g, 8.87 mmol) in anhydrous
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tetrahydrofuran (30 mL) was placed under a nitrogen atmosphere
and cooled in an ice bath. Diisopropyl azodicarboxylate (1.75 mL, 8.$7
mmol) was added over one minute. The resulting solution was sirred
at 0°C for 60 minutes followed by 30 minutes at room temperature,
5 then diluted with ethyl acetate (100 mL) and washed with brine (50
mL). The organic phase was dried over magnesium sulfate, filtered
and evaporated under vacuum to a viscous, dark oil. The crude
product was purified by flash chromatography on EM silica gel 60 (5 x
19 cm column), eluting with 2:1 hexane-ethyl acetate. The product
containing fractions were combined and evaporated under vacuum to
afford the title compound (3.48 g) as a foam.
Step 2: Allyl (1S.5R,6S)-6-f(1R)-(all~vcarbonvlox~~)-ethyll-1-methxl-
2-[3-(2-triethylsilanyloxv-eth lv )-1,8-naphthosultamvl-methyll-
carbapen-2-em-3-carboxylate
A solution of allyl {3-[1(R)-(allyloxycarbonyloxy)-ethyl]-2-
{1(R)-methyl-2-oxo-3-[3-(2-triethylsilanyloxy-ethyl)-1,8-
naphthosultamyl]-propyl)-(2R,3S)-4-oxo-azetidin-1-yl}-
(triphenylphosphoranylidene)-acetate (3.47 g, 3.50 mmol) in
20 anhydrous toluene (35 mL) was placed under a nitrogen atmoshere
and heated at reflux for 3.5 hours. The solution was concentrated
under vacuum to 10 mL and applied to a column (4 x 20 cm) of EM
silica gel 60. The column was eluted with 3:1 hexane-ethyl acetate (28
x 20 mL fractions) followed by 2:1 hexane-ethyl acetate (20 mL
25 fractions). The product containing fractions were combined and
concentrated under vacuum. The residue was lyophilized from
benzene to give the title compound (1.894 g) as a gum.
1H NMR (CDCl3) d 0.57 (q, SiCH2CH3), 0.92 (t,
SiCH2C~,3)~ 1.31 (d, 1-CH3), 1.45 (d, CH3CHOC02), 3.11 (t,
30 ArC i~CH20), 3.41 (dq, H-i), 3.45 (dd, H-6), 3.93 (t ArCH2C~0), 4.17
(dd, H-5), 4.59 (m, OC02CH2), 4.67 (d, 2-CHaHb), 4.81-4.95 (m,
C02CH2), 5.14 (dq, CH3C -~iOC02), 5.25-5.36 (m, 3 vinyl-H), 5.39 (d, 2-
CHaH~), 5.50-5.54 (m, vinyl-H), 5.88-5.93 (m, vinyl-H), 6.01-6.07 (m,
vinyl-H), 6.66 (d, Ar H-7), 7.43 (d, Ar H-5), ?.48 (dd, Ar H-6), 7.90 and
35 7.93 (two s, Ar H-2 and Ar H-4).
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Step lyl_(_1_S_ R,6S)-6-f(1R)-(allyloxycarbonyloxv)-ethxll-2-f3-(2-
h droxv-Rropyl)-1.8-naphthosultamvl-methvll-1-methyl-carba ep n-2-
em-3-carboxylate
A solution of allyl (1S,5R,6S)-6-[(1R)-
5 (allyloxycarbonyloxy)-ethyl]-1-methyl-2-[3-(2-triethylsilanyloxy-ethyl)-
1,8-naphthosultamyl-methyl]-carbapen-2-em-3-carboxylate (0.502 g,
0.706 mmol) in tetrahydrofuran (5.6 mL) was diluted with water (1.4
mL) and treated with 1M aqueous trifluoromethanesulfonic acid
(0.071 mL, 0.071 mmol). After stirring at room temperature for 15
10 minutes, the solution was treated with 2% aqueous sodium
bicarbonate (5 mL) and extracted with ethyl acetate (25 mL). The
organic phase was washed with brine (25 mL), dried over
magnesium sulfate, filtered and evaporated under vacuum to provide
the title compound (0.473 g) as an oil.
15 1H NMR (CDCl3) d 1.31 (d, 1-CH3), 1.45 (d,
CH3CHOC02), 3.16 (t, ArCH2CH20H), 3.40 (dq, H-1), 3.45 (dd, H-6),
4.01 (q, ArCH2C~20H), 4.16 (dd, H-5), 4.59 (m, OC02CH2), 4.67 (d, 2-
CH~Hb), 4.81-4.95 (m, C02CH2), 5.13 (dq, CH3CHOC02), 5.25-5.36 (m,
3 vinyl-H), 5.40 (d, 2-CHaI~), 5.50-5.54 (m, vinyl-H), 5.88-5.93 (m,
20 vinyl-H), 6.02-6.07 (m, vinyl-H), 6.68 (d, Ar H-7), 7.45 (d, Ar H-5), 7.50
(dd, Ar H-6), 7.91 and 7.96 (two s's, Ar H-2 and Ar H-4).
Step 4: All 1~,5R~6S)-6-f(1R)-(all loxycarbonvloxy)-ethyll-1-methyl-
2-(3-f2-(trifluoromethanesulfon~oxy)-eth 1~,8-naphthosultamyl-
25 methyll-carbapen-2-em-3-carboxylate
A solution of allyl (1S,5R,6S)-6-[(1R)-
(allyloxycarbonyloxy)-ethyl]-2-[3-(2-hydroxy-propyl)-1,8-
naphthosultamyl-methyl]-I-methyl-carbapen-2-em-3-carboxylate
(0.706 mmol) and 2,6-lutidine (0.246 mL, 2.12 mmol) in anhydrous
30 methylene chloride (9.4 mL) was placed under a nitrogen atmosphere
and cooled in a CC14-dry ice bath (-23°C).
Trifluoromethanesulfonic anhydride (0.178 mL, 1.06
mmol) was added and the resulting solution was stirred in the cold
for 30 minutes. The solution was diluted with methylene chloride (20
35 mL) and water (20 mL) and shaken. The organic phase was
separated, washed with 0.2N hydrochloric acid (20 mL) and water (20
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mL), dried over magnesium sulfate, filtered and evaporated under
vacuum to give the title compound as a foam (0.531 g).
1H NMR (CDC13) d 1.32 (d, 1-CHg), 1.46 (d,
C~3CHOC02), 3.41 (dq, H-1), 3.44 (t, ArCH2CH20), 3.45 (dd, H-6), 4.18
(dd, H-5), 4.56-4.64 (m, OC02CH2), 4.63 (d, 2-CH~Hb), 4.83 (t,
ArCH2CH20), 4.8-4.96 (m, C02CH2), 5.14 (dq, CH3CHOC02), 5.25-
5.36 (m, 3 vinyl-H), 5.42 (d, 2-CHaHb), 5.51-5.54 (m, vinyl-H), 5.86-5.95
(m, vinyl-H), 6.02-6.09 (m, vinyl-H), 6.73 (d, Ar H-7), 7.48 (d, Ar H-5),
7.55 (dd, Ar H-6), 7.86 and 7.97 (two s's, Ar H-2 and Ar H-4).
PREPARATIVE EXAMPLE 5
SYNTHESIS OF 4-(TRIETHYLSILYLOXY-METHYL)-1 8
NAPHTHOSULTAM
Br Br Br
/ ~ \ ClS03H~ / I \ HNO~ / I \ SnCl2-
\ / \ / \ /
S03K N02 S03H
Br Br CHO
\ P~ / I \ BuLi~ / ( \ Nab
\ / \ / HC02Et \ /
NH2 S03Na H,N-O,O H,N-O ~
OH OTES
\ TESCI /
\ / ~ \ /
H'N ~'~O H'N 0~0
Step 1: Potassium 4-bromo-naphthalene-1-sulfonate
A solution of 1-bromonaphthalene (19 mL, 137 mmol) in
carbon tetrachloride (24 mL) was cooled in an ice bath under
nitrogen. Chlorosulfonic acid (9.1 mL, 137 mmol) was added
dropwise over 20 minutes. After an additional 5 minutes, the heavy
CA 02306565 2000-04-17
wo ~no62~ -53_ PCT/US98/22110
grey suspension was removed from the ice bath and was stirred at
room temperature for 16 hours to give a grey paste. The mixture was
partitioned between methylene chloride (100 mL) and water (300 mL).
The aqueous layer was made basic with potassium carbonate and the
5 resulting suspension was filtered. The collected solid was washed
with methylene chloride (50 mL) and water (50 mL), and dried under
vacuum to give the title compound as a white solid (30 g).
1H NMR (DMSO-d6) d 7.61 (m, ArH), ?.65 (m, ArH)~ 7.82
(m, 2AxH), 8.14 (dd, ArH), and 8.90 (dd, ArH).
Step 2: 4-Bromo-8-nitro-naphthalene-1-sulfonic acid
Potassium 4-bromo-naphthalene-1-sulfonate (1.38 g, 4.24
mmol) was added portionwise over 20 minutes to 90% nitric acid (2
mL), which was cooled in a methanol/ ice bath to approximately -15
15 °C. After 1.5 hours, the mixture was placed in a refrigerator for 20
hours. Diethyl ether (20 mL) was added and the precipitated solid
was filtered, washed with ether (I00 mL) and isopropanol (20 mL),
and dried under a stream of nitrogen to give the title compound as an
approximately 4:1 mixture of the 5- and 8-nitro isomers (1.25 g).
1H NMR (D20) d 7.70 (dd, ArH), 8.09 (d, ArH), 8.20 (d,
ArH)~ 8.21 (dd, ArH), and 8.63 (d, ArH).
ten 3: Sodium 4-bromo-8-amino-naphthalene-1-sulfonate
4-Bromo-8-nitro-naphthalene-1-sulfonic acid (1 g, 3.01
25 mmol) and tin chloride dehydrate (1.83 g, 8.I mmol) were suspended
in a mixture of water (10 mL) and ethanol (10 mL). The resulting
mixture was heated for 3 hours in a 100 °C oiI bath. The mixture was
cooled to room temperature and filtered. The collected solid was
suspended in water (20 mL) and the mixture was made basic with
30 sodium carbonate then placed on a CG-161 amberchrom resin
column (3 x 9 cm). The column was washed with water (300 mL) and
was eluted with 25% MeCN/ H20, collecting 12 mL fractions.
Fractions 17-19 were combined and evaporated to give the title
compound as a solid (0.33 g).
35 1H NMR (D20) d 7.07 (dd, ArH), 7.49 (t, ArH)~ 7.83 (d,
ArH), 7.85 (dd ArH) and 8.08 (d, ArH).
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Step 4: 4-Bromo-1.8-naghthosultam
Sodium 4-bromo-8-amino-naphthalene-1-sulfonate (1.2 g,
3.70 mmoi) was suspended in phosphorous oxychloride (10 mL, 107
5 mmol) and the mixture was refluxed for 1 hour to give a thin
suspension. The mixture was cooled to room temperature and was
added to ice (100 mL). The precipitate was collected and washed with
water (20 mL) then dried under vacuum (0.675 g). A second crop was
obtained from the filtrate (0.186 g). The combined solids were
10 dissolved in 5% methanol in methylene chloride and were placed on a
silica gel column (29 x 3.5cm, packed and eluted with 5% methanol in
methylene chloride), collecting 8 mL fractions. Fractions 27-39 were
combined and evaporated to give the title compound as a solid (0.55 g).
1H NMR (0.14 mL CDC13 and 0.01 rnL CD30D) d 6.89 (d,
15 ArH), 7.58(dd ArH), 7.68 (d, ArH), 7.73 (d, ArH) and 7.95 (d, ArH).
Step 5: 4-Formvl-1,8-naphthosultam
A solution of 4-bromo-1,8-naphthosultarn (0.24 g, 0.845
mmol) in anhydrous tetrahydrofuran (5 mL) was cooled in a dry ice/
20 acetone bath under nitrogen. n-Butyllithium (1.32 mL of a 1.6 M
solution in hexanes, 2.11 mmol) was added and the mixture was
stirred for 5 minutes. Ethyl formate (1 mL, 12.4 mmol) was then
added, and after an additional 5 minutes, 2N aqueous hydrochloric
acid (3 mL) was added. The flask was removed from the bath and the
25 yellow solution was partitioned between ethyl acetate (30 mL) and
water (30 mL). The ethyl acetate layer was washed with saturated
aqueous sodium chloride (20 mL), dried over magnesium sulfate,
filtered, and evaporated. The residual oil was purified on preparative
silica gel plates (3 x 1000 micron/ developed and eluted with 5%
30 methanol/ methylene chloride) to give the title compound as a red
solid (0.035 g).
1H NMR (CDCl3) d 7.09 (d, ArH), 7.78 (dd, ArH)~ 8.12 (d,
ArH), 8.30(d, ArH), 8.70 (d, ArH) and 10.5 (s, CHO).
35 step 6: 4-H dy rox~~ethvl-1.8-nanhthosultam
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A solution of 4-formyl-1,8-naphthosultam (0.035 g, 0.15
mmol) in anhydrous methanol (1 mL) was cooled in an ice bath
under nitrogen. Sodium borohydride (0.011 g, 0.3 mmol) was added
and the solution was stirred for 30 minutes. The mixture was
5 partitioned between methylene chloride (10 mL) and 0.2N aqueous
hydrochloric acid (10 mL). The aqueous layer was extracted with 5%
methanol in methylene chloride (2 x 10 mL), and the combined
organic layers were evaporated to give the title compound as a yellow
solid (0.032 g).
10 1H NMR (0.14mLCDCl3and O.OlmL CD30D) d 5.13 (s,
C~i20H), 6.85 (d, ArH), 7.50 (dd, ArH), 7.57 (d, ArH), 7.82 (d, ArH)
and 7.88 (d, ArH).
4-(Triethvlsilvloxv-methvl)-1,8-nanhthosultam
15 A mixture of 4-hydroxymethyl-1,8-naphthosultam (2.92
g, 8.7 mmol), imidazole (0.74 g, 10.9 mmol), and triethylsilyl chloride
(1.68 mL, 10.0 mmol) in dichloromethane (40 mL) was stirred at room
temperature under a nitrogen atmosphere for 30 minutes. The
reaction mixture was then washed with 0.1 N HCl (80 mL), water (40
20 mL), and brine (40 mL), then dried over MgS04 and concentrated to a
brown oil. The oil was stored at 0° C for 72 hours. The crude product
was purified by flash chromatography on EM silica gel 60 (5 x 15 cm)
eluting with 4:1 hexane-ethyl acetate (200 mL) followed by 2:1 hexane-
ethyl acetate (1000 mL). The product-containing fractions were
25 combined and concentrated to give a light brown solid (2.3 g). The
product was further purified by recrystallization from 15:1 hexane-
ethyl acetate (80 mL) to give the title compound (1.48 g) as large white
needles. The mother liquor was concentrated and washed with cold
hexane (10 mL) to provide additional title compound (0.50 g) as
30 smaller white needles.
1H NMR (CDC13) d 0.73 (q, SiCH2CH3), 1.03 (t,
SiCH2CH3), 5.26 (s, ArCH2), 6.92 (d, ArH-7), 7.53 (dd, ArH-6), 7.59 (d,
ArH-5), 7.93 and 7.96 (two d's, ArH-2 and ArH-3)
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PREPARATIVE EXAMPLE 6
SYNTHESIS OF ALLYL (1S.5R,6S)-6-f(1R)
(ALLYLOXYCARB O NYLOXY)-ETHYLI -1-METHYL-2- f 4
(~ODOMETHYL)-li8-NAPHTHOSULTAMYL-METHYLI
5 . CARBAPEN-EM-3-CARBOXYLATE
OTES
R
\ \
HN-~O O
DIAD, PPh3
n=auyi
O
CH3
~OTES HBa
~N
~PPh3 ~
C02R
H
TfOH \ \
OH
R OJ
\ \ ~ 1 MsCI
2) Nal
~/N-~O~O
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Step 1-Allvl t3-f 1(R)-(allyloxvcarbonyloxy)-ethyll-2-f 1(R)-methyl-2-oxo-
3-f4-(2-triethylsilanyloxy-methyl)-1~8-nar~hthosultamyll-prop
2R.3S)-4-oxo-azetidin-1~r11-(tripthenylphosphoranylidene)-acetate
A solution of allyl {3-[1(R)-(allyloxycarbonyloxy)-ethyl]-2-
[3-hydroxy-1(R)-methyl-2-oxo-propyl]-(2R,3S)-4-oxo-azetidin-1-yl}-
(triphenylphosphoranylidene)-acetate (2.76 g, 4.3 mmol), 4-(2-
triethylsilanyloxy-methyl)-1,8-naphthosultam (1.38 g, 3.9 mmol), and
triphenylphosphine (1.53 g, 5.9 mmol) in anhydrous THF (20 mL) was
placed under a nitrogen atmosphere and cooled in an ice bath.
10 Diisopropyl azodicarboxylate (1.2 mL, 5.9 mmol) was added over one
minute. The resulting orange solution was stirred at 0° C for 30
minutes and then an additional 30 minutes at room temperature,
after which the reaction mixture wad partitioned between ethyl
acetate (80 mL) and brine (80 mL). The organic phase then dried over
15 MgS04 and concentrated. The concentrated solution was stored at 0°
C for 17 hours. The crude product was purified by flash
chromatography on EM silica gel 60 (5 x 15 cm), eluting with 7:3
hexane-ethyl acetate (200 mL) followed by 1:1 hexane-ethyl acetate
( 1000 mL). The product-containing fractions were combined and
20 concentrated to yield the title compound (3.2 g) as an. off white foam.
Step 2: All lY (1S,5R,6S)-6-f(1R)-(allvloxvcarbonyloxy)-ethvll-1-methyl-
2-f4-(2-trieth ls~ iianyloxv-meth 1~,8-naphthosultamyl-met~yll-
carbapen-2-em-3-carbox- lv ate
25 A solution of allyl (3-[1(R)-(allyloxycarbonyloxy)-ethyl]-2-
{1(R)-methyl-2-oxo-3-[4-(2-triethylsilanyloxy-methyl)-1,8-
naphthosultamyl]-propyl}-(2R,3S)-4-oxo-azetidin-1-yl}-
(triphenylphosphoranylidene)-acetate (3.2 g, 3.3 mmol) in anhydrous
toluene (40 mL) was placed under a nitrogen atmoshere and heated
30 at reflux for 2.75 hours. The reaction mixture was allowed to cool to
~40° C and then concentrated to an orange oil. The oil was dissolved
in dichloromethane (3 mL) and then stored at 0° C for 17 hours. The
crude product was purified by flash chromatography on EM silica gel
60 (5 x 15 cm) eluting with 4:1 hexane-ethyl acetate (400 mL) followed
35 by 2:1 hexane-ethyl acetate (850 mL). The product-containing
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fractions were concentrated to give the title compound (1.6 g) as an
off white foam.
1H NMR (CDC13) d 0.73 (q, SiCH2CH3), 1.02 (t,
SiCH2C~g), 1.31 (d, 1-CH3), 1.45 (d, C I~CHO), 3.40 (dq, H-1), 3.44 (dd,
H-6), 4.16 (dd, H-5), 4.59 (m, OC02CH2), 4.67 (d, 2-CHaHb), 4.88 (m,
C02CH2), 5.13 (dq, CH3CH0), 5.26 (m, ArCH20 and 1 vinyl-H), 5.32-
5.36 (m, 2 vinyl-H's}, 5.40 (d, CHa~, 5.50-5.54 (m, vinyl-H), 5.86-5.96
(m, vinyl-H), 6.00-6.10 (m, vinyl-H), 6.72 (dd, Ar H-7), 7.52 (m, Ar H5
and Ar H6), 7.94 and 7.98 (two d's, Ar H2 and Ar H3)
Stgp 3' Allvl (1S,5R,6S)-6-f(1R)-(all~ycarbonyloxv)-ethyll-2-f4-
(hvdroxvmethyl)-1.8-naphthosultamvl-methvll-1-methyl-carba ep n-2-
em-3-carbox, 1
A solution of allyl (1S,5R,6S)-6-[(1R)-
15 (allyloxycarbonyloxy)-ethyl]-1-methyl-2-[4-(2-triethylsilanyloxy-
methyl)-1,8-naphthosultamyl-methyl]-carbapen-2-em-3-carboxylate
(1.50 g, 2.15 mmol) in tetrahydrofuran (32 mL) was diluted with water
(16 mL) and treated with 1N aqueous triflouromethanesulfonic acid
(301 mL, 0.301 mmol). After stirring at room temperature for 20
20 minutes the reaction mixture was partitioned between
dichloromethane (200 mL) and 5% aqueous bicarbonate (60 mL). The
aqueous phase was extracted with dichloromethane (30 mL) and the
combined organic phase was concentrated to yield the title compound
(1.56 g) as a white foam.
Sten 4: Allvl (1S.5R.6S)-6-f(1R)-(allvloxvcarbonvloxv)-ethvll-2-f4-
(iodomethvl)-1.8-nanhthosultamvl-methvll-1-methyl-carbauen-2-em-
3-carbox~rlate
Allyl (1S,5R,6S)-6-[(1R)-(allyloxycarbonyloxy)-ethyl]-2-[4-
30 (hydroxymethyl)-1,8-naphthosultamyl-methyl]-1-methyl-carbapen-2-
em-3-carboxylate was dissolved in dichloromethane (49 mL) and
cooled in an ice bath under an atmosphere of nitrogen.
Triethylamine (0.524 mL, 3.8 mmol) followed by methanesulfonyl
chloride (0.258 mL, 3.23 mmol) was added and the reaction mixture
was allowed to stir at 2° C for 40 minutes. The reaction mixture was
then partitioned between dichloromethane (250 mL) and 0.1 N
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aqueous HCl (200 mL), and the organic phase dried over MgS04 then
concentrated and dried under vacuum for 20 hours. The resulting
mesylate (1.7 g, quant.) was dissolved in acetone (60 mL) and sodium
iodide (1.95 g, 13 mmol) was added. This suspension was stirred for
5 80 minutes at room temperature under a nitrogen atmosphere. The
reaction mixture was then partitioned between dichloromethane (200
mL) and water (200 mL). The aqueous phase was extracted with
dichloromethane (50 mL) and the combined organic phase was
washed with 5% NaHS03 (2 x 75 mL), dried over MgS04 and then
10 concentrated. The resulting yellow oil was lyophilized from benzene
(40 mL) to afford the title compound (1.5 g, quant.) as an amorphous
yellow solid.
1H NMR (CDC13) 1.28 (d, 1-CH3), 1.42(d, CH_gCHO), 3.36
(dq, H-1), 3.42 (dd, H-6), 4.13 (dd, H-5), 4.42-4.68 (m, OC02CH2), 4.63
15 (d, 2-CHaHb), 4.76-4.94 (m, C02CH2), 5.10 (dq, CH~CHO), 5.20-5.34
(m, 3 vinyl-H), 5.38 (d, ArCH2I), 5.38 (d, CHaH~, 5.49 (m, vinyl-H),
5.80-5.90 (m, vinyl-H), 5.94-6.06 (m, vinyl-H), 6.72 (dd, Ar H-7), 7.60-
7.64 (m, Ar H5 and Ar H6), 7.77 and 7.84 (two d's, Ar H2 and Ar H3)
20 PREPARATIVE EXAMPLE 7
SYNTHESIS OF 3-AZIDO-1(I,4-DIMETHYL-PIPERAZINIUM)
I?ROPANE TRIFLUOROMETHANESULFONATE
NaN3; Li CI, DMF N3 N~ N
CI~Br Cl~n
50°, 5 hrs Nal, 0.1 eq.,
CH3CN, 50°, 6 hr.
OTf-
N
'~ ~ N AgOTf, CH3CN - N N+~n s
n = 1, 2,3 and 4
Step 1: 1-Azido-3-chloronropane
25 Sodium azide (1.43 g, 22 mmol) and lithium chloride
(0.93 g, 22 mmol) are added to DMF (10 ml) under nitrogen. To this
was added 1,3-bromochloropropane (3.14g, 2.0 ml, 20 mmol) and the
reaction mixture is stirred and heated at 50° far 5 hours. The reaction
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mixture was diluted with water and extracted with petroleum ether.
The organic phase was washed twice with water, dried over MgS04
and evaporated to give 1,3-azidochloropropane.
Sten 2: 3-Azido-1(1.4-dimethyl-pinerazinium)-propane
trifluoromethanesulfonate.
The azidochloropropane from Step 1 is dissolved in
acetonitrile (8 ml) and treated with 1,4-dimethylpiperazine (1.12 g, 10
mmol). Sodium iodide (0.15 g, 1 mmol) is added and the reaction is
10 stirred under nitrogen at 50° for 6 hr. The solvent is removed under
reduced pressure and the residue is triturated with ether, the ether
solution is decanted off and the residue is taken up in acetonitrile (10
ml) and treated with silver trifluoromethane sulfonate (2.56 g, 10
mmol). After 10 min. the precipitated silver salts are filtered through
a bed of celite and washed with a little acetonitrile. The filtrate and
washings are evaporated to give the crude product which is
crystallized from EtOH/Et20 to give the product.
Following the above procedure and starting with the
20 appropriate chlorobromoalkane one obtains the following compounds
of Preparative Examples 8 to 10.
PREPARATIVE EXAMPLE 8
2-AZIDO-1(1,4-DIMETHYL-PIPERAZINITs7M)-ETHANE
TRIFLUOROMETHANESULFO~TATE.
OTf
' N N+~' N3
V \
PREPARATIVE EXAMPLE 9
4-AZIDO-1(1,4-DIMETHYL-PIPERAZINIUM)-BUTANE
TRIFLUOROMETHANESULFONATE.
OTf-
'N N+~'N3
~\
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WO 99PZ0627 -sl- PCT/US98/2Z110
PREPARATIVE EXAMPLE 10
~AZIDO-1(1,4-DIMETHYL-PIPERAZINIUM)-PENTANE
TRIFLUOROMETHANESULFONATE.
OTf-
-N N+'~ Na
'-
PREPARATIVE EXAMPLE 11
3-AZIDO-1(1.4-DIMETHYL-PIPERAZINIUM)-BUTANE
TRIFLUOROMETHANESULFONATE.
'N~ ' ,_~ B~ NaN3,Li CI, DMF
Br\~'Br -N N+ Br
CH3CN, 65°, 2 hr. ~ ~ 50°, overnight
OT
X
-N N+ N3 AgOTf, CH3CN N~ N ~ N3
Step 1: 3-Bromo-1(1,4-dimeth~-piperazinium)-butane bromide.
1,3-Dibromobutane (2.15 g, 1.2 ml, 10 mmol) is dissolved
in acetonitrile (2 ml). DABCO (1.23 g, 11 mmol) is added. The reaction
mixture is heated at 65° under nitrogen for 2 hr. The acetonitrile is
removed under reduced pressure to give the product.
Steu 2: 3-Azido-1(1,4-dimeth~l-piperazinium)-)-butane
trifluororaethanesulfonate,
The product from Step 1 is dissolved in DMF (5 ml).
20 Sodium azide {0.71 g, 11 mmol) and lithium chloride (0.5 g, 11 mmol)
are added followed by sodium iodide (0.149 g, 1 mmol). The reaction is
stirred at 50°, under nitrogen overnight. The DMF is removed under
reduced pressure with an external bath temperature of 40°. The
residue is taken up in acetonitrile (5 ml) and methanol (5 ml) and
25 treated with silver triflate (2.8 g, 11 mmol). After 0.5 hr the
precipitated silver salts are filtered off through a bed of celite and
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washed with a little methanol. The filtrate and washings are
evaporated to give an oil. Trituration with ether gives the product.
PREPARATIVE EXAMPLE 12
5 N-(4-AZIDOMETHYLPHENYL)-1-( 1,4-DIMETHYL-
PI~ERAZINIUM)ACETAMIDE TRIFLATE
C~I p MsCI/Et3N
H2N / \ CHzOH Py~H2Cl2 C 0 \ / H20H CH2CIz/T'HF C O \ / H20Ms
NaN3
DMF
-N~/N~~~ \ / CH2N3 ' ~ C ~ \ / H2N3
2. AgOTf
MeOH
Sten 1: N-(4-H.ydroxymethylphen~)chloroacetamide
A solution of 4-aminobenzyl alcohol (2 g, 16.3 mmol),
10 pyridine (1.3 mL, 16.3 mmol) in CH2Clz (50 mL) is treated with
chloroacetochloride (1.29 mL, 16.2 mmol) at 0°C. The mixture is
stirred for 0.5 hr and then washed with water, 1N HCI, water and
brine. It is dried over Na2S04 and concentrated. The residue is
chromatographed over silica gel (eluent: hexane:ethyl acetate v/v 2:1)
15 to give the product {0.54 g) as a white solid.
Step 2: 4-(1-Chloroacetamido)benzvl methanesolfonate
A solution of N-(4-
hydroxymethylphenyl)chloroacetamide (0.25 g, 1.25 mmol), Et3N (0.5
20 mL, 3.46 mmol), solvent CH2C12 (30 mL) and THF (10 mL) is treated
with methanesulfonyl chloride (0.1 mL, 1.29 mmol) at 0°C. The
mixture is kept at 0°C for 0.5 hr and more CH2C12 is added. It is then
washed with water and brine, dried over Na2S04 and concentrated to
give the product (0.313 g).
25
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Step 3: N-(4-Azidometh~phen ly )chlQroacetamide
A mixture of 4-(1-chloroacetamido)benzyl
methanesolfonate (0.313 g, 1.13 mmol), sodium azide (73 mg, 1.13
mmol), lithium chloride (48 mg, 1.13 mmol), DMF (10 mL) and
5 catalytic amount of sodium iodide is stirred at room temperature for 3
days. Most of the DMF is then removed under vacuum. The residue is
taken up in ethyl acetate and washed with water 3 times. The organic
layer is dried over Na2SOq and concentrated. The residue is
chromatographed over silica gel (eluent: Hexane:ethyl acetate v/v 2:1)
to give the product (77 mg) as a white solid.
Step 4: N-(4-azidomethYl_phenvl)-1-(1,4-dimeth3rl-
~iperazinium)acetamide triflate
A solution of N-(4-azidomethylphenyl)chloroacetamide
15 (77 mg, 0.343 mmol), 1,4-dimethylpiperazine (35 mg, 0.313 mmol) and
CH3CN (3 mL) is stirred at room temperature for 3 days. The Solent is
removed and the residue is dried under vacuum to give the product
(0.116 g) as chloride. This chloride is dissolved in MeOH (3 mL) and
treated with a solution of AgOTf (80 mg, 0.31 mmol) in CH3CN (0.5
20 mL). The mixture is stirred for 0.5 hr, then filtered to remove the
white precipitate. The filter cake is washed with CH3CN. The
combined filtrate is concentrated to give the product as a triflate salt.
PREPARATIVE EXAMPLE 13
25 N (4-(2-(ALLYLOXYCARBONYLAMINO)ETHYL)PHENYL)-1-(1,4-
DIMETHYL-PIPERAZINIUM)ACETAMIDE TRIFLATE
p~ H ~ CI
NH2 ~ Cr v
H2 \ / CH2CI2 H2 \ / ---
O Et3N/CH2CI2
H ~ H
CI~~ / \ CH3CN ~ + / \ H
2. AgOTf
O MeOH O
-OTf
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Step 1:N-(4-aminophenethyl)-O-ally 1 carbamate
To a solution of 4-aminophenethyl amine (2 g, 14.7
mmol) in CHZCl2 (20 mL) is added allyl chloroformate (0.533 mL, 4.89
mmol) at 0°C. The mixture is kept at 0°C for 0.5 hr and more
CHZCI2
5 is added. It is then washed with 5% NaHC03, water and brine, dried
over Na2S04 and concentrated. The residue is chromatographed over
silica gel (eluent: ethyl acetate:hexane v/v 1:1) to give the product (1.38
g) as a white solid.
Step 2: N-(4-(2-(Allyloxycarbonylamino)ethyl)phenyl)chloroacetamide
A solution of N-(4-aminophenethyl)-O-allyl carbamate
(1.38 g, 6.28 mmol), Et3N (1.5 mL, 10.4 mmol) in CHZC12 (30 mL) is
treated with chloroacetochloride (0.52 mL, 6.53 mmol) at 0°C. The
mixture is stirred for 20 min and then washed with water, IN HCl,
water and brine. It is dried over Na2S04 and concentrated to give the
product (1.58) as a white solid.
Step 3N-(4-(2-(Allvi_oxvcarbonvlamino)ethyl)phenyl)-1-(134-dimeth,~~l-
piperazinium)acetamide triflate
A solution of N-(4-(2-
(allyloxycarbonylamino)ethyl)phenyl)chloroacetamide (0.5 g, 1.68
mmol), 1,4-dimethylpiperazine (0.18 g, 1.61 mmol) and CH9CN (10
mL) is stirred at room temperature overnight. The solid is collected
by filtration and dried under vacuum to give the white crystal product
as chloride.
This chloride is dissolved in MeOH (10 mL) and treated
with a solution of AgOTf (0.31 g, 1.21 mmol) in CH3CN (2 mL). The
mixture is stirred for 0.5 hr, then filtered to remove the white
precipitate. The filter cake is washed with CH3CN. The combined
filtrate is concentrated to give the product as a triflate salt.
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PREPARATIVE EXAMPLE 14
N-(2-ALLYLOXYCARBONYLAMINO)ETHYL)-1-(1 4-DIMETH '~L
PIPER,AZINIUM)ACETAMI~7E TRIFLATE
~ 0
H2N~NH2 C~~ ~N ~ C~~ H O
H20/E1~OH, H2N ~ ~ Et3~~2 CI~~H~C
O
pH-3.8
-f~N
CH3CN
2. AgOTf
MeOH
_ r-. ~~.NJIo~
H
- -Off
step 1: N-(2-aminoethyl)-O-allyl carbamate
Ethelene diamine ( 1.8 g, 30 mmol) is dissolved in water
(5.8 mL) with 5 drops of bromocresol green indicator.
Methanesulfonyl chloride (c= 0.92 g/ mL H20) is added until the
solution turned to pale yellow (pH~3.8). The solution is diluted with
IO EtOH (16 mL), vigorously stirred, and treated simutaneously with
solutions of allylchloroformate (3.61 g, 30 mmol) in dimethoxyethane
(5.8 mL) and potassium acetate (c=50% w/v H20) by alternate
dropwise additions to maintain the pale yellow-green colouration of
the indicator. After the additions are complete the mixture is stirred
15 for 1 hr and the volatiles are removed under vacuum. The residue is
shaken with wetter and filtered to remove small quantities of the bis-
derivative. The filtrate is washed with benzene, basified with excess
40% aqueous NaOH, and then extracted with benzene. The organic
layer is washed with brine, dried over Na2S04 and concentrated to
20 give the product (0.6 g) as a yellow oil.
Step 2~ N-(2-Allvloxvcarbonylaminoethvl)chloroacetamide
A solution of N (2-aminoethyl)-O-allyl carbamate (0.6
g,4.17 mmol), Et3N (1.0 mL, 6.93 mmol) in CHZC12 (20 mL) is treated
25 with chloroacetochloride (0.35 mL, 4.17 mmol) at 0°C. The mixture is
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stirred for 20 min and then washed with water, 1NHC1, water and
brine. It is dried over Na2S04 and concentrated to give the product
(0.474 g) as a black solid.
Step 3N-(2-AllyloxYcarbonylamino)ethyl)-1-(14- imeth3il-
~perazinium)acetamide triflate
A solution of N-(2-
allyloxycarbonylaminoethyl)chloroacetamide (0.47 g, 2.13 mmol), 1,4-
dimethylpiperazine (0.167 g, 1.5 mmol) and CH3CN (20 mL) is stirred
10 at room temperature for 3 days. The solvent is removed and the
residue is dried under vacuum to give the product as the chloride.
This chloride is dissolved in MeOH (10 mL) and treated with a
solution of AgOTf (0.38 g, 1.48 mmol) in CH3CN (2 mL). The mixture
is stirred for 0.5 hr, then filtered to remove the precipitate. The filter
cake is washed with CH3CN. The combined filtrate is concentrated to
give the product as a triflate salt.
PREPARATIVE EXAMPLE 15
N-((3-ALLYLOXYCARBONYLAMINO)PROPYL)-1-(1,4-DIMETHYL-
PIPERAZINIUM)ACETAMIDE TRIFLATE
Following the procedure described in Preparative
Example 14, step 1 to step 3 and starting from 1,3-propanediamine,
the title compound is obtained.
30
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PREPARATIVE EXAMPLE I6
1V-(3-(2-ALLYLOXYCARBONYLAMINO)ETHYL)PHENYL)-1-(1,4
DIMETHYL-PIPERAZINIUM)ACETAMIDE TRIFLATE
02N I ~ 1. 02N ~ N3 1. Ph3P 02N ~ NH2 CI~~
H MsCI I ~
2. ~ 2. NaOH(2M)
NaN3 HCI(10%)
DMF
~I
02N w I N~ S~H 2N i I N~ CI ~'O
O EtOH ~ O
Et3N/CH~CI2
CI~~ ~ I N~ CH N ~ +~N i N
O ~ O ~ O
2. AgOTf
MeOH oTr
Step 1: 3-NitrQ,phene~;hyl azide
To a solution of 3-nitrophenethyl alcohol (2 g, 11.9?
mmol), Et3N (3.0 mL, 20.8 mmol) in CHZCl2 (40 mL) is added
methanesulfonyl chloride (1.0 mL, 12.9 mmol) at 0°C. After stirring
for 0.5 hr, more CHzCl2 is added. The solution is washed with water
10 and brine, dried over Na2S04 and concentrated. The residue is
dissolved in DMF (30 mL), sodium azide (0.8 g,12.3 mmol), lithium
chloride {0.53 g, 12.5 mmol) and catalytic amount of sodium iodide
are added. The mixture is stirred at room temperature overnight.
Most of DMF is then removed under vacuum and the residue is
15 washed with water and brine, dried over Na2S04 and concentrated.
The residue is chromatographed over silica gel (eluent: hexane:ethyl
acetate v/v 4:1) to give a pale yellow oil (1.8 g) as desired product.
Step 2: 3-Nitro henet ylamine
20 A mixture of 3-nitrophenethyl azide (0.9 g, 4.69 mmol),
triphenyl phosphine (1.22 g, 4.66 mmol) and CH2C12 (80 mL) is stirred
at room temperature for 3 days. Solvent is removed and the residue is
taken up in EtOH (20 mL). The solution is heated to 70°C, added 2M
NaOH aqueous solution (10 mL) and stirred at room temperature for
25 2 hrs. A 10% HCl aqueous solution (20 mL) is then added and
refluxed for 2 hrs. After the mixture cool to room temperature, it is
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washed with benzene, basified with 5N NaOH to pH~ 12, extracted
with ethyl acetate. The organic layer is dried over Na2S04 and
concentrated to give the product (0.63 g) as a yellow oil.
Step 3~ N (2-(3-Nitro~hen~~l)ethyl)-O-allyl carbamate
To a solution of 3-nitrophenylamine (0.62 g, 3.73 mmol)
and Et3N (0.8 mL, 5.54 mmol) in CH2C12 (20 mL) is added allyl
chloroformate (0.4 mL, 3.77 mmol) at 0°C. The mixture is kept at
0°C
for 0.5 hr and more CHZC12 is added. It is then washed with 5%
10 NaHC03, water and brine, dried over Na2S04 and concentrated to give
the product (0.9 g).
Step 4: N-(2-(3-Aminophen lv )ethyl)-O-allvl carbamate
A mixture of N-(2-(3-Aminophenyl)ethyl)-O-allyl
carbamate (0.9 g, 3.6 mmol), tin{II) chloride dehydrate (4.1 g, 18
mmol) in EtOH (50 mL) is heated at 70°C for 1 hr. The EtOH is
removed and the residue is added water, basified with 5N NaOH to
pH>10, extrated with CHzCl2. The organic layer is washed with water
and brine, dried over Na2S04, concerntrated to give the product (0.66
g).
Sten 5: N-((3-(2-all ~loxycarbonvlamino)eth,~rl).phenvl)chloyoacetamide
A solution of N-(2-(3-Aminophenyl)ethyl)-O-allyl
carbamate (0.66 g,3.0 mmol), Et3N (0.65 mL, 4.5 mmol) in CH2C12 (20
25 mL) is treated with chloroacetochloride (0.26 mL, 3.2 mmol) at 0°C.
The mixture is stirred for 20 min and then washed with water,
lNHCI, water and brine. It is dried over Na2S04 and concentrated to
give the product (0.62 g).
ten 6' N-(3-(2-Al~,vloxycarbonvlamino)ethyl), .~henvl)-1-( la4-dimeth,~l-
~iperazinium)acetamide triflate
A solution of N-((3-(2-
allyloxycarbonylamino)ethyl)phenyl)chloroacetamide (0.32 g, 1.08
mmol), 1,4-dimethylpiperazine (0.121 g, 1.08 mmol) and CH3CN (10
mL) is stirred at room temperature overnight. The solvent is removed
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and the residue is dried under vacuum to give the product as
chloride. This chloride is dissolved in MeOH ( 10 mL) and treated with
a solution of AgOTf (0.27 g, 1.08 mmol) in CH3CN (1 mL). The
mixture is stirred for 0.5 hr, then filtered to remove the white
5 precipitate. The filter cake is washed with CH3CN. The combined
filtrate is concentrated to give the product as a triflate salt.
PREPARATIVE EXAMPLE 17
N-( 2-( 2-ALLYLOXYCARB ONYLAMINO )ETHYL) PHENYL)-1-( 1 4
IO DIMETHYL-PIPERAZINIUM)ACETAMIDE TRIFLATE
Following the procedure described in Example 16, step 1
to step 6 starting from 2-nitrophenethyl alcohol, the title compound is
obtained.
1 S PREPARATIVE EXAMPLE 18
(S)-f )- 3-AZIDO-1-(1,4-DIMETHYL-PIPERAZINIUM)-2-
METHYLPROPANE TRIFLATE
~. rt2o/2,6-lutidine
NaN3 CH2CI2
~H --~ N3~OH N3~N+ N-
DMF 2. ~ ~ U
-(~N-
CH3CN -OTf
~p 1: fR)-< )-3-azido-2-meth,~propanol
20 A mixture of (R)-()-3-bromo-2-methylpropanol (1 g, 6.53
mmol), sodium azide (0.47 g, 7.23 mmol), lithium chloride (0.31 g,
7.29 mmol) and DMF (10 mL) is heated at 50°C overnight. Most of
DMF is then removed. The residue is taken up in ethyl acetate,
washed with water and brine, dried over Na2S04 and concentrated to
25 give the product (0.64 g).
step 2~ fS)-< )- 3-Azido-1-(1 4-dimethvl-ninerazinium)-2-
methylpropane triflate
(R)-( )-3-azido-2-methylpropanol (0.64 g, 5.56 mmol) is
30 dissolved in CHzCl2 (40 mL). 2,6-lutidine (1.9 mL, 16.3 mmol) is added
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at -20°C followed by adding trifalic anhydride (1.4 mL, 8.32 mmol).
The mixture is kept in -20°C for 40 min, diluted with CHzCl2,
washed
with water, 0.1 N HCl aqueous solution, water and brine, dried over
NazS04 and concentrated to give the trifalte (1.33 g). The triflate (0.7 g,
5 2.83 mmol) is reacted with 1,4-dimethylpiperazine (0.31 g, 2.77 mmol)
in CH3CN for 3 hrs. The solvent is removed and the residue is dried
under vacuum to give the product.
EXAMPLE 1
10 ~1~, 5R 6S)- -2-t6-[2-(4-(3-AMMONIOPROPYL)- 14-DIMETHYL-
P~PERAZIN-1-IO)-ETHYLI-1,1-DIOXO-2-H-1-THIA-2-AZA
ACENAPHTHALEN-2-YL-METHYLI-6=[1(R)-HYDROXYETHYLI-1
METHYL-CARBAPEN-2-EM-3-CARBOXYLATE DICHLORIDE
OTf OTf-
3
CH2=CH-CH20C00 ~ -N~ ~ N
H H N,
~ ~2 CH3CN, rt, 1 hr, conc. soln
COOCH2-CH=CH2
2 OTf-
N ~ ~ N3
CHp=CH-CH20C00 ~ ~ ~ 1) DMF,[ (CgH5)3F14Pdo~
H H N- - CsH5SiH3, rt, 10 min.
2) H2, 5% Rh/C, 1.5 hr, 1 atm.
O N
COOCH2-CH=CH2
\N N ~ NH3+
OH 2 CI-
H H
N
~O
COO-
15 ~S~g~yl (1S,5R 6S)--6-[(1R)-(allylox~carbon~xy)-ethvll ~ (6 [2 (4
(3-azidop,~o_gvl)- 14-dimethyl~iperazin-1-iol-eth'~ ~ - ioxo-2-H-1-
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thia-2-aza-acenaphthalen-2-~1-methvll-1-methyl-carbapen-2-em-3-
carboxylate bis (trifluoromethanesulfonate).
Allyl (1S,5R,6S)--6-[(1R)-(allyloxycarbonyloxy)-ethyl]-2-[6-
(2-trifluoromethanesulfonyloxyethyl)-ethyl]- 1,1-dioxo-2H-1-thia-2-
5 aza-acenaphthalen-2-yl-methyl}-1-methyl-carbapen-2-em-3-
carboxylate from Step 4, Preparative Example 2, (150 mg,) is dissolved
in acetonitrile (1.5 ml), 3-Azido-1(1,4-dimethyl-piperazinium)-
propane trifluoromethanesulfonate (85 mg,) from Step 2, Preparative
Example 7, is added. The reaction is stirred 5 min. and the solvent is
10 evaporated under vacuum to give a thick oil which is stirred at room
temperature for 45 min. The residual solvent is removed to give the
product which is used in the next step without purification.
StP 2: (1 ,5R 6S)- -2-t6-f2-(4-(3-ammoniopropvl)- 1,4-dimethyl-
15 piperazin-1-io)-ethyll-11-dioxo-2-H-1-thia-2-aza-acenanhthalen-2-yl-
meth,-6-f 1(R)-hydroxvethyll-1-methyl-carbapen-2-em-3-carboxylate
dichloride.
Allyl (1S,5R,6S)--6-[(1R)-(allyloxycarbonyloxy)-ethyl]- 2-(6-
[2-(4-(3-ammoniopropyl)-1,4-dimethyl-piperazinium]-ethyl-1,1-dioxo-
20 2H-1-thia-2-aza-acenaphthalen-2-yl-methyl}-1-methyl-carbapen-2-em-
3-carboxylate bis (trifluoromethanesulfonate) from Step 1 is dissolved
in DMF (1.5 ml), Phenylsilane ( 115m1) is added, followed by
tetrakis(triphenylphosphine)palladium(0) (22.5 mg, 0.019 mmol). The
reaction is stirred at room temperature for 10 min. then diluted with
25 ether (5 ml) to precipitate the product. The ether solution is decanted
off and the residue washed with 2x7 ml ether. The combined ether
solutions are centrifuged and the precipitate combined with the
original precipitate is dissolved in acetonitrile/water 1/1 (2 ml). This
solution is applied to a column of Macro-Prep CM weak cation
30 exchange resin (5 ml). The column is eluted with 1:1 acetonitrile-
water (8 ml) followed by water ( 10 ml). The resin is eluted with 5%
aqueous sodium chloride (75 ml) and collected in 5x 15 ml fractions.
The first four fractions containing the product are combined and
treated with 5% rhodium on carbon (50 mg) and stirred under an
35 atmosphere of hydrogen. After 1 hour the catalyst is filtered off and
the filtrate is loaded onto a Rainin Microsorb C18 RP HPLC column
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(2x 30 cm). Gradient elution with acetonitrile/0.12M aqueous
ammonium chloride gives pure product containing fractions which
are combined and concentrated under vacuum. The concentrated
product is applied to a column of Amberchrome CG-161 4 ml) which
5 is eluted with water (10 ml) followed by 1:1 acetonitrile-water (10 ml).
The acetonitrile-water eluate is lyophilized to give the product.
EXAMPLE 2
(1S.5R,6S)- -2-f6-f2-(4-(2-AMMONIOETHYL)- 1,4-DIMETHYL-
10 PIPERAZIN-1-IO)-ETHYLI-1,1-DIOXO-2-H-1-THIA-2-AZA-
ACENAPHTHALEN-2-YL-METHYL)-6-~1(R)-HYDROXYETHYLI-1-
METHYL-CARBAPEN-2-EM-3-CARBOXYLATE DICHLORIDE.
N ~ +-~NH3+
2CI-
OH
H H N, ~ --
N
O
COO-
15 Substituting 2-Azido-1(1,4-dimethyl-piperazinium)-
ethane trifluoromethanesulfonate for 3-Azido-1(1,4-dimethyl-
piperazinium)-propane trifluoromethanesulfonate in Example 1,
Step 1 above, and following the procedure of Step 2 one obtains the
desired product.
20
EXAMPLE 3
(1SZ5R.6S)-2-(6-(2~4-(4-AMMONIOBUTYL)- 1.4-DIMETHYL-
PIPERAZIN-1-IO)-ETHYLI-1.1-DIOXO-2-H-1-THIA-2-AZA-
ACENAPHTHALEN-2-YL-METHYLI-6-f 1(R)-HYDROXYETHYLI-1-
25 METHYL-CARBAPEN-2-EM-3-CARBOXYLATE DICHLORIDE.
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N V \-~NH3+
2CI-
OH
H H N.O
N
~(O
COO-
Substituting 4-Azido-1(1,4-dimethyl-piperazinium)-
butane trifluoromethanesulfonate for 3-Azido-1( 1,4-dimethyl-
piperazinium)-propane trifluoromethanesulfonate in Example 1,
5 Step 1 above, and following the procedure of Step 2 one obtains the
desired product.
EXAMPLE 4
(1S 5R,6S)- -2-(6-f2-(4-(5-AMMONIOPENTYL)- 1,4-DIMETHYL-
10 PIPERAZIN-1-IO)-ETHYLI-1,1-DIOXO-2-H-1-THIA-2-AZA-
ACENAPHTHALEN-2-YL-METHYL)-6-f 1(R)-HYDROXYETHYLI-1-
METHYL-CARBAPEN-2-EM-3-CARBOXYLATE DICHLORIDE.
~n
N U ~~\'~ NH3+
~ 2CI-
OH
H H N~~ '
O N~ 2
COO-
Substituting 5-Azido-1(1,4-dimethyl-piperazinium)-
15 pentane trifluoromethanesulfonate for 3-Azido-1(1,4-dimethyl-
piperazinium)-propane trifluoromethanesulfonate in Example 1,
Step 1 above, and following the procedure of Step 2, one obtains the
desired product.
20
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EXAMPLE 5
(1S 5R 6S)- -2-f6-f2-(4-(3-AMMONIO-3-METHYLPROPYL)- 14
DIMETHYL-PIPERAZIN-1-IO)-ETHYLI-1 1-DIOXO-2-H-1-THIA-2
AZA-ACENAPHTHALEN-2-YL-METHYLI-6-f 1(R)-
5 HYDROXYETHYLI -1-METHYL-CARBAPEN-2-EM-3-
CARBOXYLATE DICHLORIDE.
N ~ ~ NH3+
OH ~ ~ ~ 2 CI-
H H N~ S
02
O
COO-
Substituting 3-Azido-1(1,4-dimethyl-piperazinium)-
butane trifluoromethanesulfonate for 3-Azido-1(1,4-dimethyl-
10 piperazinium)-propane trifluoromethanesulfonate in Example 1,
Step 1 above, and following the procedure of Step 2, one obtains the
desired product.
EXAMPLE 6
15 (1S,5R~6S)-6-(1(R)-HYDROXY-ETHYL)-1-METHYL-2-f 6-(2-(4-(3(R)-
AMO,~IO-2-METHYLPROPYL)- 1,4-DIMETHYL-PIPERAZIN-1-IO)-
ETHYL)-1.1-DIOXO-1H-1-THIA-2-AZA-ACENAPHTHYLEN-2-YL-
METHYL1CARBAPEN-2-EM-3-CARBOXYLATE DICHLORIDE
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Substituting 3-Azido-2-methyl-1(1,4-dimethyl-
piperazinium)-propane trifluoromethanesulfonate for 3-Azido-i(1,4-
dimethyl-piperazinium)-propane trifluoromethanesulfonate in
Example 1, Step 1, and following the procedure of Step 2, one obtains
the desired product.
EXAMPLE 7
(1S.5R.6S)- -2-(6-(2-(4-(3-METHYLAMMONIOPROPYL)- 14
DIMETHYL-PIPERAZIN-1-IO)-ETHYL)-1 1-DIOXO-2-H-1-THIA-2
AZA-ACENAPHTHALEN-2-YL-METHYL)-6-f 1(F)-
HYDROXYETHYLI -1-METHYL-CARBAPEN-2-EM-3
CARBOXYLATE DICHLORIDE.
CH3
~N ~ Ni ~ NH2+
OH \ ~ \ 2CI-
H H
N. V2
O N
COO-
Starting with allyl N-[3-(1,4-
dimethylpiperazinium)propyl)-N-methylcarbamate
trifluoromethanesulfonate and the product of Preparative Example 2,
and following the procedure of steps 1 and 2 of Example 11, one
obtains the title compound.
EXAMPLE 8
(1S R.6S)-6-(1(R)-HYDROXY-ETHYL)-1-METHYL-2-(6-(2-(4-(3-
AMONIOPROPYL)AMINOCARBONYLMETHYL)- 14-DIMETHYL
PIPERAZIN-1-IO)-ETHYL)-1 1-DIOX(~-1H-1-THIA-2-AZA
ACENAPHTHYLEN-2-YL-METHYL) CARBAPEN-2-EM-3-
CARBOXYLATE DICHLORIDE
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WO 99/20627 -76- PCT/US98/22110
OH H ~ \
N ~ N \
O O,~S. ~,~ /
O O- +
O CN J
2ci N+
0
NH
N+H3
Substituting the products of Preparative Examples 2 and
15, in step 1 of Example lI, followed by step 2 of Example 11, provides
the title compound.
EXAMPLE 9
(1S R,6S)-6-(1(R)-HYDF~OXY-ETHYL)-1-METHYL-2-(6-(2-(4-(2-
AMONIOETHYL)AMINOCARBONYLMETHYL)- 1,4-DIMETHYL-
PIPERAZIN-1-IO)-ETHYL)-1,1-DIOXO-1H-1-THI -2-AZA-
~CENAPHTHYLEN-2-YL-METHYLICARBAPEN-2-EM-3-
CARBOXYLATE DICHLORIDE
OH H ~ \
N ~ N \
O O~~SO /.,.- N /
O O- +
2~~- C
0
NH
H3 N
Substituting the product of Preparative Examples 2 and
14 in step 1 of Example 11 followed by Step 2 of Example 11 provides
the title compound.
CA 02306565 2000-04-17
wo ~no62~ _77- Pcrivs9sn2>< ><o
EXAMPLE 10
S~'~[THESIS OF (1S,~5R,6S)-2-(3-(2-f4-(3-AMMONIO-PROPYL)-1,4-
DIMETHYL-PIPERAZIN-1-IOl-ETHYL?-1,8-
NAPHTHOSULTAMYL-METHYL)-6-f(1R)-HYDROXY-ETHYLI-1-
METHYL-CARBAPEN-2-EM-3-CARBOXYLATE DICHLORIDE
/ I \ OTf Tf~ N3
ROCO H H Me ~ /
_ \
Me N S,O ~NJ
O
O
C02R
R = ally)
1 ) Pd(0) deblock HO H H Me ~
/ N 2) H2, 5% Rh/C_ N- S,
3) purification Me . p O ~ Np
N-S,. C ~ N
p O /N, O O CO~ 2 CQ
2 Tf~ ~ Ns ~H3
Step 1' All (1S,5R,6S)-6-f(1R)-(allyloxvcarbonylox~yll-2-(3-(2-f4-
(3-azido-prop- lv )-11,~4-dimeth~l-~inerazin-1-ioi-ethvll-1 8-
nanhthosultamvl-methyl)-1-methyl-carbapen-2-em-3-carboxlate
bis(trifluoromethanesulfonate)
A solution of allyl (1S,5R,6S)-6-[(1R)-
(allyloxycarbonyloxy)-ethyl]-1-methyl-2-{3-[2-
(trifluoromethanesulfonyloxy)-ethyl]-1,8-naphthosultamyl-methyl]-
carbapen-2-em-3-carboxylate (0.141 mmol) in anhydrous acetonitrile
(1.0 mL) is added to 1-(3-azido-propyl)-1,4-dimethylpiperazinium
trifluoromethanesulfonate (51 mg, 0.144 mmol). The solution is
concentrated under vacuum to approximately 0.2 mL and let stand at
room temperature for 2 hours. The oil is triturated with diethyl
20 ether, the solvent decanted, and the residue dried under vacuum to
afford the title compound as an amorphous solid. It is used in the
next step without further purification.
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Step 2: (1S R,6S)-2-(3-f2-f4-(3-Arnmonio-.~roR lv )-1,4-dimeth ~~1-
piperazin-1-iol-ethvll-1,8-naphthosultamvl-methyl)-6-f ( 1R)-l~vdrox~
ethyl-1-methyl-carbapen-2-em-3-carboxXlate dichloride
A solution of crude allyl (1S,5R,6S)-6-[(1R)-
5 (allyloxycarbonyloxy)-ethyl]-2-(3-{2-[4-(3-azido-propyl)-1,4-
dimethylpiperazin-1-io]-ethyl)-1,8-naphthosultamyl-methyl)-1-
methyl-carbapen-2-em-3-carboxylate bis(trifluoromethanesulfonate)
(0.141 mmol) in anhydrous dimethylformamide (1.4 mL) is treated
with 5,5-dimethyl-1,3-cyclohexanedione (dimedone, 59 mg, 0.423
10 mmol), triphenylphosphine (5.5 mg, 0.021 mmol) and
tetrakis(triphenylphosphine)palladium(0) (8.1 mg, 0.007 mmol). The
mixture is placed under a nitrogen atmosphere, treated with N,N-
diisopropylethylamine (0.074 mL, 0.423 mmol), and stirred at room
temperature. After 20 minutes, the mixture is added to diethyl ether
15 (13 mL) and centrifuged. The supernatant is decanted from the
orange colored solid which is washed with more ether (14 mL) and
dried under vacuum to afford crude (1S,5R,6S)-2-(3-{2-[4-(3-azido-
propyl)-1,4-dimethylpiperazin-1-io]-ethyl}-1,8-naphthosultamyl-
methyl)-6-[( 1R)-hydroxy-ethyl]-1-methyl-carbapen-2-em-3-carboxylate
20 trifluromethanesulfonate.
The deallylated product is dissolved in tetrahydrofuran
(2 mL), water (4 mL) and ethanol (3 mL), treated with 5% rhodium on
carbon (17 mg), and stirred under an atmosphere of hydrogen. After
65 minutes, the mixture is filtered and the filtrate applied to a
25 column of Macro-Prep CM weak cation exchange resin (3 mL). The
column is eluted with 1:1 acetonitrile-water (10 mL), water (12 mL),
and 5% aqueous sodium chloride (40 mL). The saline fractions are
concentrated under vacuum to 9 mL and loaded onto a Ranin
Microsorb Clg RP HPLC column (2 x 30 cm) which is gradiently
30 eluted with acetonitrile in 0.12M aqueous ammonium chloride. The
product containing fractions are concentrated under vacuum then
applied to a column of Amberchrom CG-161 which is eluted with
water (25 mL) followed by 20% isopropanol in water. The product
eluted sharply with isopropanol-water. The product containing
35 fractions diluted with water, concentrated under vacuum to 4 mL,
and lyophilized to afford the title compound.
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EXAMPLE 1I
SYNTHESIS OF (1S,5R 6S)-6-f(1R)-HYDROXY-ETI~~1-1-METHYL
2-(3-(2-f4-(3-METHYLAMMONIO-PROPYL)- 1,4-DIMETHYL
PIPERAZIN-1-IOl-ETHYLI-1,8-NAPHTHOSULTAMYL-METHYL)-
CARBAPEN-2-EM-3-CARBOXYLATE DICHLORIDE
/ I \ ~ Tf~ Me~N.C02R
ROCO H H Me \ / OTf
N- S,
Me " O --N
N~ O
O R = allyl
C02R
R = ally!
/ \
\ HO Me \ I / Nd
/ N~ 1 ) Pd(0) deblock Me H H N -S ,. C
~N-S, C ~ 2) purification ~~ O O /~
''',,~ ~ O / N~ O 2 GQ
N ~ C02R CO~ NH
2 Tf~ ~ ~ 2
Me Me
Sit .p 1' All lv (1S 5R,6S)-2-f3-(2-(4-l4-(al~il~cxvcarbonvll-4-aza-pent-1-,
1.4-dimeth ~~1-piperazin-1-io 1-ethyl)-1.8-naphthosultamyl-methyll-6-
I(1R)-(allyloxycarbon~oxv)-ethyll-1-methvl-carbapen-2-em-3-
carboxxlate bis(trifluoromethanesulfonate~
A solution of allyl (1S,5R,6S)-6-[(1R)-
(allyloxycarbonyloxy)-ethyl]-1-methyl-2-{3-(3-
15 (trifluoromethanesulfonyloxy)-propyl]-1,8-naphthosultamyl-methyl)-
carbapen-2-em-3-carboxylate (0.172 mmol) in anhydrous acetonitrile
(0.9 mL) is treated with allyl N-[3-(1,4-dimethylpiperazinium)-propyl]-
N-methyl-carbamate trifluoromethanesulfonate (76 mg, 0.188 mmol).
The solution kept at room temperature for one hour then stored in a
20 freezer at -10°C for 3.5 days. The solvent is evaporated under
vacuum. The residual oil is triturated with diethyl ether, the solvent
decanted, and the residue dried under vacuum to afford the title
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compound as an amorphous solid. It is used in the next step without
further purification.
Step 2~ (1S 5R,.,.65)-6-f~lR)-Hydroxy-ethvll-1-methyl-2-(3-(2-f4-(3-
5 methvlammonio-propyl)- 1,4-'methyl-Ri~erazin-1-iol-eth lv 1-_1,,8-
naphthosultamvl-meth3rl)-carbapenem-2-em-3-carbo~vlate dichloride
A solution of crude allyl (1S,5R,6S)-2-[3-(2-(4-[4-
(allyloxycarbonyl]-4-aza-pent-1-yl]-1,4-dimethylpiperazin-1-io}-ethyl)-
1,8-naphthosultamyl-methyl]-6-[(1R)-(allyloxycarbonyloxy)-ethyl]-1-
10 methyl-carbapen-2-em-3-carboxylate bis(trifluoromethanesulfonate)
(0.172 mmol) and tetrakis(triphenylphosphine)palladium(0) (10.0 mg,
0.086 mmol) in anhydrous dimethylformamide (0.86 mL) is placed
under a nitrogen atmosphere and treated with phenylsilane (0.191
mL, 1.55 mmol). After stirring for 20 minutes at room temperature,
15 the dark solution is added to diethyl ether (12 mL) to give a brown
precipitate. The supernatant is decanted and the residue dried under
vacuum to give a solid (246 mg).
The solid is dissolved in 1:1 acetonitrile-water (3 mL) and
applied to a column of Macro-Prep CM weak cation exchange resin (4
20 mL). The column is eluted with 1:1 acetonitrile-water (7 mL), water
(18 mL), 5% aqueous NaCI (9 mL), and 1:1 isopropanol-10% aqueous
NaCl (10 mL). The product containing fractions (5% NaCI and 1:1
iPrOH-10% NaCI) wre combined and concentrated under vacuum to
remove isopropanol. The resulting solution is applied to a column of
25 Amberchrom CG-161 resin (5 mL) which is eluted with water (20 mL)
followed by 20% isopropanol in water (6 mL). The product containing
fractions (20% iPrOH) are concentrated under vacuum, diluted with
water, reconcentrated, filtered, and lyophilized to give a pale yellow,
amorphous solid (43 mg, 35% yield). This material is further purified
30 by HPLC on a Ranin Microsorb Clg RP column (2 x 30 cm) which is
gradiently eluted with acetonitrile (0-30%) in 0.12M aqueous
ammonium chloride. The product containing fractions (30% MeCN
in 0.12M NH4Cl) are desalted on Amberchrom CG-161 (5 mL) as
described above and the final aqueous solution lyophilized to provide
35 the title compound as an amorphous, white solid.
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EXAMPLE I2
(1S.5R.6S)-6-(I(R)-HYDROXY-ETHYL)-1-METHYL-2-(6-(2-(4-(4-
AMONIOMETHYLPHENYL)AMINOCARBONYL)METHYL)-1,4-
DIMETHYL-PIPERAZIN-1-IO)-ETHYL)-1 1-DIOXO-1H-1-THLA-2-
AZA-ACENAPHTHYLEN-2-YL-METHYL)CARBAPEN-2-EM-3-
CARBOXYLATE DICHLORIDE
N / _.N \
O Q..S. ~ /
O O O ...- N+
C
O
2C1- NH
H3+N
Stet 1: All lY (_1-S_,5R,6S)--6-f(1R)-(all loxycarbonylox~~)-eth~L 1-methvl-
2-(6-(2-(4-(4-azidomethy~phenyl)aminocarbonvl)meth,~rl)- 1 4-dimeth,L
10 ~iperazin-1-io)-ethyl)-1,I-dioxo-1H-1-thia-2-aza-acenanhth lv en-2;y1-
methvllcarbapen-2-em-3-carboxvlate bis-trifluormethylsulfonate.
Starting with N-(4-azidomethylphenyl)-1-(1,4-
dimethylpiperazinium)acetamide triflate (1$.5 mg) from Preparative
Example 12 and reacting it with the product of Step 4, Preparative
15 Example 2, according to the procedure of Example 1, step 1, one
obtains the title product, which is used in the next step without
further purification.
~gp 2. (1S,5R,6S)-6-(1(R)-hydroxv-ethyl)-1-metal-2-(6-(2-(4-(4-
20 amoniomethylnhenvl)aminocarbon lv )meth ly )-1,4-dimethyl-
piperazin-I-io)-ethyl)-1.1-dioxo-1H-1-thia-2-aza-acenaphth ly en-2 ;~~1-
methyllcarba-pen-2-em-3-carboxvlate dichloride.
The product from Step 1 is dissolved in DMF (0.2 ml),
Phenylsilane ( 30 ml) is added, followed by
25 tetrakis(triphenylphosphine)palladium(0) (2 mg). The reaction is
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stirred at room temperature for 15 min. then diluted with ether (2 ml)
to precipitate the product. The ether solution is decanted off and the
residue washed with 2x2 ml ether. The combined ether solutions are
centrifuged and the precipitate combined with the original precipitate
5 is dissolved in acetonitrile/water 1/1 (1 ml). This solution is applied to
a column of Macro-Prep CM weak cation exchange resin {1.5 ml).
The column is eluted with 1:1 acetonitrile-water (3 ml) followed by
water (3 ml). The resin is eluted with 5% aqueous sodium chloride (6
ml) and collected in 1 ml fractions. The fractions containing the
10 product are combined and treated with 5% rhodium on carbon and
stirred under an atmosphere of hydrogen. After 1.5 hour more
catalyst is added and the reduction continued for 1 hr.The catalyst is
filtered off and the filtrate is loaded onto a Rainin Microsorb C18 RP
HPLC column (2x 30 cm). Gradient elution with acetonitrile/0.12M
15 aqueous ammonium chloride gives pure product containing fractions
which are combined and concentrated under vacuum. The
concentrated product is applied to a column of Amberchrome CG-161
1.5 ml) which is eluted with water (5 ml) followed by 1:1 acetonitrile-
water (5 ml). The acetonitrile-water eluate is lyophilized to give the
20 product.
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EXAMPLE 13
~1S.5R.6S)-6-(1(R)-HYDROXY-ETHYL)-1-METHYL-2-(6-(2-(4-(4-(2-
AMONIOETHYL)PHENYL)AMINOCARBONYL)METHYL)-14
DIMETHYL-PIP RAZIN-1-IO)-ETHYL)-11-DIOXO-1H-1-THIA-2
5 AZA-ACENAPHTHYLEN-2-YL-METHYL)CARBAPEN-2-EM-3-
CARBOXYLATE DICHLORIDE
Starting with the products of Preparative examples 2 and
13, and following the procedure of steps 1 and 2 of Example 11, one
10 obtains the title compound.
EXAMPLE 14
( 1S, 5R,6S)-6-( 1(R)-HYDROXY-ETHYL)-1-METHYL-2-(6-(2-(4-(2-(2-
AMONIOETHYL)PHENYL)AMINOCARBONYL)METHYL)-1,4-
15 DIMETHYL-PIPERAZIN-1-IO)-ETHYL)-1,1-DIOXO-1H-1-THIA-2-
AZA-ACENAPHTHYLEN-2-YL-METHYLI CARBAPEN-2-EM-3
CARBOXYLATE DICHLORIDE
OH H . I \
N ~ N \
O 0 .S~ ~ ~ /
O O O N
C
0
,_ ..
NH
N+Hs~ /
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Starting with the product of Preparative examples 2 and
17, and following the procedure of steps 1 and 2 of Example 11, one
obtains the title compound.
EXAMPLE 15
( 1S,5R,6S)-6-( 1(R)-HYDROXY-ETHYL)-1-METHYL-2-(6-(2-(4-(3-
(2-AMONIOETHYL)PHENYL)AMINOCARBONYL)
METHYL)- 1.4-DIMETHYL-PIPERAZIN-1-IO)-ETHYL)-1,1
DIOXO-1H-1-THIA-2-AZA-ACENAPHTHYLEN-2-YL-
METHYL)CARBAPEN-2-EM-3-CARBOXYLATE
DICHLORIDE
N / _N I \
O ~-S~ ~ /
O 00 O N+
C
0
2C1- NH
H3+N~J~
Starting with the product of Preparative Examples 16
and 2, and following the procedure of steps 1 and 2 of Example 11, one
obtains the title compound.
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EXAMPLE 16
SYNTHESIS OF (lSa5R 6S)-2-f3-f2-(4-f f4-(2 AMMONIO ETHYL)
PHENYLCARBAMOYLI-METHYL}-1~4-DIMETHYL PIPERAZIN 1
IO)-ETHYLI-1,8-NAPHTHOSULTAMYL-METHYLI-6-f(1R)-
HYDROXY-ETHYLI-1-METHYL-CARBAPENEM-2-EM-3
CARBOXYLATE DICHLORIDE
O / \ Tf~ H
f
ROCO H H Me \ I / OTf ~~ N ~ N
Me N-S~ ~NJ O ~ NHC02R
O
N~ O R = ally)
O
C02R
R = allyl
/ \
/ \ HO H ~ Me \ I / Nd
\ I / N~ 1 ) Pd(o) deblocl~e N-Y' O
/N-~: ~ ~ 2) Purification N ~ O ~~ O
O O i Np O ~ 2 GQ
2 Tf~ ~O / NH
HN / \
~~ NHC02R H N
Step 1~ Allvl (1S 5R,6S)-2-f3-f2-(4-ff4-(2-allvloxvcar~onvla_mino ethyl)
phenvlcarbamoyll-meth ly 1-1.4-dimethyl-piperazin-1-io)-eth. ly 1-1,8-
IO nanhthosultamvl-methyl)-6-f(1R)-allyloxvcarbony~g~ -v eth lv 1~1-
n~eth3~1-carbauenem-2-em-3-carboxylate
bis(trifluoromethanesulfonate)
A solution of allyl (1S,5R,6S)-6-[(1R)-
(allyloxycarbonyloxy)-ethyl]-1-methyl-2-{3-[3-
15 (trifluoromethanesulfonyloxy)-propyl]-1,8-naphthosultamyl-methyl}-
carbapen-2-em-3-carboxylate (0.172 mmol) in anhydrous acetonitrile
(0.9 mL) is treated with allyl N-(2-{4-[2-(1,4-dimethylpiperazinium)-
acetylamino]-phenyl}-ethyl)-carbamate trifluoromethanesulfonate (98
mcr (1 1 RtZ mtrl~~l Thn onl"tin» lrn,~+ ..+ ..,"",., +llw~rv/~N.1+~~NIO ~n.~
..r.,.
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ether, the solvent decanted, and the residue dried under vacuum to
afford the title compound as a foam. It is used in the next step
without further purification.
5 Step 2: (1S.5R.6S)-2-(3-f2-(4-(f4-(2-ammonio-eth~phenylcarbamovll-
meth 1~_)-1,4-dimeth ~~1-piperazin-1-io)-ethyll-1,8-naphthosultam3rl-
n~ethvll-6-((1R)-h3rdrox -v ethyll-1-methyl-carbapenem-2-em-3-
carboxvlate dichloride
A solution of crude allyl (1S,5R,6S)-2-{3-[2-(4-([4-(2-
10 allyloxycarbonylamino-ethyl)-phenylcarbamoyl]-methyl}-1,4-
dimethylpiperazin-1-io)-ethyl]-1,8-naphthosultamyl-methyl}-6-[(1R)-
allyloxycarbonyloxy-ethyl]-1-methyl-carbapenem-2-em-3-carboxylate
bis(trifluoromethanesulfonate) (0.172 mmol) and
tetrakis(triphenylphosphine)palladium(0) (10.0 mg, 0.086 mmol) in
15 anhydrous dimethylformamide (0.86 mL) is placed under a nitrogen
atmosphere and treated with phenylsiiane (0.191 mL, 1.55 mmol).
After stirring for 20 minutes at room temperature, the solution is
added to diethyl ether (13 mL) to give a precipitate. The supernatant
is decanted and the solid residue dried under vacuum.
20 The solid is dissolved in 1:1 acetonitrile-water (3 mL)
with added tetrahydrofuran (4 mL) and water (0.5 mL) and applied to
a column of Macro-Prep CM weak cation exchange resin (2.5 mL).
The column is eluted with 1:1 acetonitrile-water (7 mL), water (12
mL), and 1:1 isopropanol-10% aqueous NaCl (8 mL). The product
25 containing fractions (1:1 iPrOH-10% NaCI) are concentrated under
vacuum to a hazy suspension and applied to a column of
Amberchrom CG-161 resin (4 mL). The column is eluted with water
(15 mL) followed by 20% isopropanol in water (6 mL). The product
containing fractions (20% iPrOH) are concentrated under vacuum
30 and lyophilized to give the title compound.
