Note: Descriptions are shown in the official language in which they were submitted.
' ~ 13~058~
3-UNSATURATED ALKYL CEPHEMS FROM 3-TRIFLYL CEPHEMS
BACKGROUND OF THE INVENTION
Field of the Invention
The present invention relates to a process for the
production of a 3-hydrocarbyl-3-cephem derivative by
providing a 3-~triflyloxy-3-cephem intermediate,~reacting the
intermediate with a 1-alkenyltributylstannane in the
presence of b3.s(dibenzylideneacetonyl)-palladium and a
phosphine and a metal halide. The resulting 3-unsaturated
alkyl-3-cephems are useful as broad spectrum antibacterial
agents.
Background Art
Hoshi et al., U.S. Patents 4,591,641 (5/86) and
4,520,022 t5/85), both of which are owned by the assignee of
the present invention, disclose vinyl-substituted
cephalosporins having the 3-((Z)-1-propenyl) and
7-phenylglycy:lamido groups represented by the structural
formula, A,
~S
/ cHCONH
I
NH2 ~ N ~ 1!=CHCH3
R ~ O ..
' Rl COZIi
Formula A
- 2 -
134Q583
wherein the 3-propenyl group has the (Z) configuration.
These patented compounds were produced by forming a
substituted viny:L group in the 3-position of the
cephalosporin nucleus by reacting a 3-halomethyl
cephalosporin or an alkyl halide (e. g., methyl halide) with
a triarylphosphine to yield a phosphoranyl intermediate
which is then treated with a alkylhydrogencarbonyl reagent
or a 3-hydrogencarbonyl cephalosporin, respectively. The
_ foregoing compounds were produced by application of the
synthetic routes disclosed in U.S. Patents 3,769,277
(10/73), 3,994,8B4 (11/76), and 4,107,431 (8/78).
Long et al., U.S. Patent 3,769,277 (10/73)disclose
~ 3-4-carboxy cephalosporins of the formula
S
H1NFI
1 3
R
I~-~ ~ 4
R
COON
by reacting a 3-formyl (i.e. a 3-hydrogencarbonyl)-
cephalosporin With a phosphorane of the formula R3P=CR3R4
Weir, U.S. Patent 3,994,884 (11/76) discloses the
preparation of -~A3-4-carboxy cephalosporin having a 3-vinyl
group by reactir,~g the corresponding 3-halomethyl
cephalosporin compound with a phosphine to obtain the
phosphonium intermediate, converting the phosphonium
- 3 -
-~ ~34Q~83
' , intermediate t:o the corresponding phosphoranylidene
intermediate, and coupling the phosphoranylidene
intermediate with formaldehyde.
Clark, et. al., U.S. Patent 4,107,431 (8/78)
(G81342241), disclose the preparation of A 3-vinyl or
substituted vinyl-4-carboxy cephalosporins by reacting a
3-phosphoranyl,idene cephalosporin with a carbonyl compound
of the formula. R3COR4 or by reacting a 3-formyl
cephalosporin with a phosphorane of the formula R3P=CR3R4
O'Callagh.an et al., U.S. Patent 3,830,700 (8/74),
disclose certain 3-arylvinvyl cephalosporins useful as
chromogenic agents for the detection of ~-lactamase
activity. The compounds useful in the patented method were
prepared by reacting a 3-phosphoranylidene cephalosporin
with a hydrogencarbonyl aryl (aryl aldehyde) compound or by
reacting a 3-h.ydrogencarbonyl cephalosporin with a
phosporane of the formula ( R ) 3P=CFiAr .
Beeby, U.S. Patents 3,983,113 (9/76), 4,049,806 (9/77),
and 4,139,618 (2/79) disclose 3-(heterocyclothio)propenyl
cephalosporins represented by the formula
O ii
11 1 S
1t3-C:li2-C-N
S-R1
N
O
C02R2 trans
- 4 -
,,.
13405g3
wherein the compounds were prepared by reacting the starting
3-formyl cepha:Losporin with a suitable vinyl Grignard
reagent to obtain a mixture of a- and ~-hydroxy isomers of
the corresponding 3-(1-hydroxyprop-2-enyl) cephalosporin
followed by treating the foregoing intermediate with a
mercapto substituted heterocycle corresponding to the SR1
substituent in the presence of a small amount of strong
acid. Beeby, U.S. Patent 4,112,087 (9/78) discloses
. compound having the formula shown above except that "OR" is
substituted fo:r "S-Rl"
Webber, U.S. Patent 4,065,620 (12/77) discloses
3-(substituted) vinyl cephalosporins prepared by reacting a
3-formyl cephalosporin compound with a phosphorane of the
formula RiR2R3P=CH-Y under conventional Wittig reaction
conditions.
Takaya et al., EP App. Publn. 0,030,630 (6/81) disclose
7-acylamino-3-vinylcephalosporanic acid derivatives prepared
by reacting a 3-formyl cephalosporin compound with a
suitable phosphorane.
Miyadera et al., U.S. Patent 4,147,863 (4/79) disclose
cephalosporin derivatives having a (1-alkyl-1H-tetrazol-
5-yl)vinyl group at the 3-position of the cephem nucleus.
The patent discloses preparation of the intermediate having
- 5 -
134083
the given 3-vinyl substituent by reacting a known 3-formyl
cephalosporin with a Wittig reagent (phosphorane).
Beattie et al., U.S. Patent 4,255,423 (3/81) disclose
cephalosporin compounds having a substituted or
unsubstituted vinyl group at the 3-position of the
cephalosporin nucleus prepared by the reaction of a
phosphoranylidene compound with a compound containing a
carbonyl group. More particularly, a phosphoranylidene
compound of the formula
S
R4N!!
r7 ~ CH=P (R) 3
C OOR6
may be reacted with a carbonyl compound of the formula
R2-CO-R3 to obtain the -CH=CR2R3 substituent at the
3-position of the cephem nucelus.
It is known in the art to which this invention and the
compounds thereby produced relate that the compounds having
the cis(Z)-stereoisomeric configuration are preferred over
the compounds having the trans(E)-stereoisomeric
configuration because the former compounds possess. greater
antibacterial activity,. (See U.S. Patent 4,520,022,
- 6 -
1340583
col. 16, lines 23-29).
The processes heretofore known and reported in the
literature for producing 3-(1-propenyl)-3-cephems afford a
mixture of the cis(Z)- and trans(E)-isomers which requires
costly separation to obtain the preferred, more
antibacterially active cis(Z)-isomer and, accordingly, the
overall yield of desired cis(Z)-isomer based on starting
material is relatively low.
Scott, Crisp and Stille, J. Amen. Chem. Soc., 106,
4630(1984) desr_ribed the palladium-catalyzed coupling of
organotins with electrophiles facilitated by the addition of
zinc chloride.
Scott and Stille, J. Amer. Chem. Soc., 108, 3033(1986)
described the palladium-catalyzed coupling reaction of
several vinyl triflates with organostannanes such as, for
example, vinyltributylstannane to yield a product having the
vinyl group bonded to the carbon atom which has been vacated
by the triflate group.
In view of the desirability to improve the processes to
produce 3-viny:Lcephem derivatives having the preferred
cis(Z)-stereoisomeric configuration, it has been conceived
to apply a stereospecific synthetic route for constructing
-
134083
the Z-propenyl side chain at C(3) of the cephem nucleus
utilizing the palladium-catalyzed coupling of a suitably
functionalized cephem with cis(Z)-propenyltributyl-
stannane.
Starting with the readily available 3-hydroxycephems
and derivatives thereof, including the trif luoromethyl-
sulfonate (triflate) and methanesulfonate and chloro and
diphenylphosphat~e derivates, coupling with the
above-mentioned ~organometallic agents was explored. It was
found that the above coupling reactions were unsatisfactory
when carried-out according to conditions reported by Scott
and Stille (loc. cit.). The coupling between diphenylmethyl
7-(phenylacetamido)-3-triflyloxy-3-cephem-4-carboxylate and
stannanes was unsatisfactory when carried out under
literature conditions. The use of PdP~3)4-LiCl in THF led
largely to the 3-chloro derivative of the above-mentioned
cephem, which readily isomerized to the A2-cephem while
giving only trace amounts of the desired cephem. Use of
ZnCl2 in place of LiCl did not yield any of the D2-cephem
by-product. However, conversion to the desired product was
so slow when carried out in refluxing THF that extensive
decomposition of the starting triflate took place.
Consequently the desired product, diphenylmethyl 7-(phenyl-
acetamido)-3-(Z-1-propenyl)-3-cephem-4-carboxylate, was
obtained only in very poor yield.
- 8 -
134058
SUN~IARY OF THE INVENTION
It has been discovered that coupling between
3-triflyloxycephems and certain unsaturated hydrocarbyl-
stannanes (unsaturated hydrocarbyltrialkyl stannanes) can be
induced to form a carbon-carbon bond at the 3-position of
the cephem nuc:Leus in satisfactory yield and, in the case of
the 1-alkenyl and 1-polyalkenyl derivatives, with
- substantially complete stereospecificity (i.e., greater than
99% stereospec:Lficity). This is accomplished by carrying
out the coupling reaction at room temperature in the
presence of a relatively polar aprotic solvent, a Pdo or a
PdII compound, certain metal halides, and a phosphine.
DETAILED DESCRIPTION OF THE INVENTION
This invention is a process for the production of a
3-hydrocarbyl-:3-cephem derivative represented by the formula
13
1 S
Q-o
/ ~1 Formula I,
0
COOH
- g _
;130583
wherein Rl rep:resents a hydrocarbyl group selected from
unsubstituted and substituted 1-alkenyl, conjugated and
unconjugated 1~-polyalkenyl, 1-alkynyl, and carbocyclic and
heterocyclic aryl and wherein Q represents a group selected
from H; an acy:L group, R-CO-, wherein R is an organic group
having 1-20 carbon atoms and is selected from (a)
unsubstituted and substituted carbocyclic and heterocyclic
aryl, (b) unsubstituted and substituted, straight-chain and
branched-chain,, alkyl, (c) unsubstituted and substituted
carbocyclic and heterocyclic aralkyl, (d) unsubstituted and
substituted cai:bocyclic and heterocyclic cycloalkyl, ( c )
unsubstituted and substituted alkenyl, (f) unsubstituted and
substituted cyc:loalkenyl, and (g) unsubstituted and
substituted alkynyl; an unsubstituted and substituted
trialkylsilyloxycarbonyl and triarylsilyloxycarbonyl; and
trialkysilyl and triarylsilyl groups, wherein, when
substituted, the alkyl, cycloalkyl, alkenyl, cycloalkenyl
and alkynyl group may be substituted with 1 to 3
substituents selected from halo, hydroxy, alkoxy, amino,
mono- and dialkylamino, vitro, carboxyl, alkoxycarbonyl,
oximino and cyano groups and the aryl group may be
substituted with 1 to 3 alkyl, hydroxy, alkoxy, halo, amino,
mono- and dialkylamino, vitro, carboxyl, alkoxycarbonyl, and
cyano groups and pharmaceutically acceptable acid addition
and base salts and esters thereof, comprising the steps of:
- 10 -
F
1340583
' _ (a) providing a 3-trifluoromethanesulfonyloxy-3-
cephem starting compound in a relatively polar aprotic
solvent;
(b) contacting the starting compound from step (a)
above with at least an equimolar amount of a hydrocarbyl-
trialkyl stannane in the presence of about 1-10 mole % of a
palladium compound and about 3-30 mole % of a phosphine
reagent and 0-7 molar equivalents of a metal halide under
conditions effective to induce chemical reactivity; and
(c) recovering the 3-hydrocarbyl-3-cephem product from
the reaction mixture from step (b).
By use of the process according to this invention, we
have obtained several novel compounds which we were
unsuccessful in obtaining when employing procedures known
and reported previously.
In another aspect, this invention is the novel starting
3-trifluoromethanesulfonyloxy-3-cephem having the formula
H S
QN
Z~ Formula II,
O I~ O~ht
COON
wherein
- 11 -
...,
134o~s3
Tf represents the trifluoromethanesulfonyloxy,
CF3S(0)2-, group; and
Q represents a group selected from H; an acyl group,
R-CO-, wherein R is an organic group having 1-20 carbon atoms
and is selected from (a) unsubstituted and substituted,
carbocyclic and heterocyclic aryl, (b) unsubstituted and
substituted, straight-chain and branched-chain, alkyl, (c)
_ unsubstituted and substituted carbocyclic and heterocyclic
aralkyl, (d) unsubstituted and substituted carbocyclic and
heterocyclic cyc:loalkyl, (e) unsubstituted and substituted
alkenyl, (f) unsubstituted and substituted cycloalkenyl, and
(g) unsubstituted and substituted alkynyl; an unsubstituted
and substituted trialkylsilyloxycarbonyl and
triarylsilyloxycarbonyl; and trialkylsilyl and triarylsilyl
groups, wherein, when substituted, the alkyl, cycloalkyl,
alkenyl, cycloalkenyl and alkynyl group may be substituted
with 1 to 3 substituents selected from halo, hydroxy, alkoxy,
amino, mono- and dialkylamino, vitro, carboxyl,
alkoxycarbonyl, oximino, and cyano groups and the aryl group
may be substituted with 1 to 3 alkyl, hydroxy, alkoxy, halo,
amino, mono- and dialkylamino, vitro, carboxyl,
alkoxycarbonyl, and cyano groups and pharmaceutically
acceptable acid addition and base salts and esters thereof.
By way of example but without limitation, Q in the above
- 12 -
. ,,....
1340583
formulas I and II may be unsubstituted and substituted
hydrocarbyl such as phenacyl (NCO); phenacetyl (~CH2CO),
t-butyloxycarbon~yl (t-BuOCO); a group represented by the
formula G-iH- wherein G is 2- or 3-thienyl or unsubstituted
G'
and substituted phenyl and G' is hydroxy, formyloxy, acetoxy,
carboxy, sulfo, or amino and substituted amino; a group
represented by the formula G-~- wherein G has the meaning
- N ~wOY
given above and 'Y is H, methyl or acetyl; a group represented
by the formula G~-(Z)m CH2- wherein G has the meaning given
above, m is 0 (zero) or 1, and Z is O (oxygen) or S (sulfur);
a group represented by the formula G-(Z)mCH2=1[-NH-CH2- wherein
NH
G, Z and m have the meanings given above; and G-CH-CO- wherein
l
NHP
and P is any one of well known protecting groups
conventionally used in cephalosporin chemistry with amino,
hydroxy and carboxyl groups such as, for example, benzyl,
diphenylmethyl, and the like.
The starting 3-trifluoromethanesulfonyloxy-3-cephem (also
referred to as 3~-triflyloxy-3-cephem wherein the acronym
"triflyl" or "tr:iflate" is used to designate the
trifluoromethanesulfonyl group) can be readily obtained
starting from the known 3-hydroxycephems. The starting
- 13 -
134o~s~
3-trif lyloxy-3-cephem may bear various substituents on the
3-cephem nucleus as are known to those skilled in the art to
which this invention pertains. The carboxyl group at the
4-position may be in the form of an ester or salt derivative
thereof. The 7-position of the 3-cephem nucleus may bear an
unsubstituted or substituted amino group wherein. the
substituent may be selected from any substituent known and
reported in the 7.iterature. By way of example but without
limitation, the 4-carboxyl group may be present as the
diphenylmethyl carboxylate ester and the 7-position
substituent may be the phenylacetamido or t-butyloxy-
carbonylamino graup.
The aprotic solvent used in the process of this
invention should be relatively polar. Thus, the solvent
may be selected from 1-methyl-2-pyrrolidinone,
tetrahydrofuran (TIiF), nitriles such as acetonitrile,
dimethylsulfoxide (DMSO), dimethylformamide (DMF), ethers
such as glyme and dioxane, hexamethylphosphoric amide
(HMPA), acetone, nitromethane and nitrobenzene. Preferably,
the solvent is selected from 1-methyl-2-pyrrolidinone, THF,
acetonitrile, DMSO and DMF. More preferably, the solvent is
selected from N-methylpyrrolidinone, TIiF and acetonitrile.
Most preferably, the solvent is 1-methyl-2-pyrrolidinone.
By the expression "hydrocarbyl" with reference to the
- 14 -
1340583
3-hydrocarbyl substituent on the cephem nucleus derived from
the hydrocarbyltrialkylstannane is meant unsubstituted and
substituted alkenyl, unconjugated and conjugated
polyalkenyl, alkynyl, and aryltrialkylstannanes, for
example, 1-alkenyl- and 1-dienyl, 1-alkynyl- and
aryltributylstannanes. Although the 1-alkenyl, 1-dienyl,
1-alkynyl and aryl group may be any such group, preferred
are the C2-C4 1-alkenyl and 1-alkynyl groups including, for
( example; -C(CH3)=CH2, H2C=CH-, CH3CH=CH-, (CH3)2C=CH-,
CH3-C=C-, and H2C=C(OC2H5)- bonded to the -Sn(C4H9)3
(or -SnBu3) group. Representative of the 1-polyalkenyl
group are the CH3-CH=C=CH- and H2=CH-CH=CH- groups. With
reference to heterocyclic aryl and heterocyclic aralkyl as
the "hydrocarbyl" group by the expression "hydrocarbyl" is
meant 2-, 3- or 4-pyridyl and -pyridylmethyl, 2-
imidazolyl and .imidazolylmethyl, and 2-thiazolyl
and -thiazolylmethyl, 2- or 3-furyl and -furylmethyl,
2-pyrryl and -pyrrylmethyl, 2-thienyl and -thienyl methyl
and salts thereof. More preferably, the process of the
invention is useful to produce the 1-alkenyl and 1-alkynyl
cephem derivatives. Most preferably, the process of the
invention is especially useful to produce the
3-(Z-1-propenyl)-, i.e. 3-(Z-CH=CHCH3)-, 3-cephem, the
3-(propen-2-yl)~-3-cephem, and the -3-(1-propynyl)-3-cephem
derivatives.
- 15 -
.~
1340g3
The phosphine reagent may be selected from phosphine
compound such as, for example, triphenylphosphine,
tri-(3-fluorophenyl)-phosphine, tri-(3-chlorophenyl)-
phosphine, tri-(:3-methoxyphenyl)-phosphine, diphenyl-
methylphosphine, dimethylphenylphosphine, tributyl-
phosphine, tri-(2-thienyl)-phosphine,and tri-(2-furyl)-
phosphine. Phosphite compounds such as, for example,
trimethyl and tr:Lethyl and triphenyl and tri-isopropyl
_ phosphites may be substituted for the above-mentioned
phosphine compounds. Also, chelating phosphines such as, for
example, bis-diphenylphosphinoethane and
bis-diphenylphosphinopropane may be substituted for the above
phosphines. Preferably, the phosphine is
tri-(2-furyl)-phosphine.
Although amT Pd compound may be used in the process of
this invention, preferably the Pd compound is selecte~ from
a Pd~ compound such as bis(dibenzylidene-acetonyl)palladium
[Pd(dba)2] and a PdII compound such as Pd(OAc)2, and PdCl2 The
first-named Pd reagent [Pd(dba)2] is especially advantageous
in the process according to this invention.
The metal halide used in combination with the Pd
compound in the process according to this invention is
selected from ZnCl2, Zner2, LiCl, LiHr, LiI, MgCl2, MgBr2,
HgCl2 and boron and aluminum and cadmium halides (Cl and
- 16 -
134083
Br). Preferably,, the metal halide is selected from ZnCl2
and ZnBr2, most preferably, ZnCl2
Representative of the process according to the present
invention is the following equation:
0
1'A~ .N . O
N S ~' ~S~S~) Ih
N
/ 'fl ZnClt i 1~~1~s,t N
COOGNPht
1 COOCHmnf
t
III IV
A general experimental procedure for carrying out the
process of this invention, with reference to the foregoing
equation, follows:
Triflate III (107) mg, 0.169 mmol) in dry 1-methyl-2-
pyrrolidinone (3 mL) was treated with the appropriate
stannane (0.20 mmol, in 1 mL 1-methyl-2-pyrrolidinone).
Zinc chloride (5~: mg, 0.38 mmol), Pd(dba)2 (2.45 mg, 0.0042
mmol) and tri-(2-~furyl)phosphine (2.0 mg, 0.0085 mmol) were
then added. The dark solution was stirred under argon at
25~-50~C for about 25 hr. The product was isolated by flash
chromatography on Si02 and characterized by elemental
analysis, 1H-NMR and mass spectroscopy.
The final product may be recovered from the coupling
reaction mixture by techniques which are convention in the
- 17 -
'134083
cephalosporin and penicillin arts, such as by that procedure
described above :Ln the general experimental procedure.
The following table illustrates but a few representative
hydrocarbyltributylstannanes, resulting products from reaction
thereof with the triflate, III, illustrated above, reaction
time and yield (~) of product according to the process of this
invention.
Example 5 illustrating the preparation of a
3-(desmethyl)-3-cephem is outside the scope of the invention
described and claimed herein but is included to illustrate
the utility of the process according to the invention.
In view of the results obtained as illustrated in the
examples, the time and temperature of the reaction in step
(b) of the process according to this invention are not
believed to be critical and may range from about 20~C to
about 65~C for about 1 h to about 75 h, preferably about
25-50~C for about 1-72 h, depending on the selection and
reactivity of the particular reactants and catalyst system.
- 18 -
134083
TABLE '
Palladium-Catalyzed Coupling of III With Stannanes
- r Temperature - x 7lield
Fx. No. Stannane Produet (Time) -(isolated)
0
~e~ w
6 ~s"w, '~ s Z5'C) 79
o . 1 h
C00CN1A)
- ~~~ /N
w s
1 . ~ w.(a) o i 25'C. 65
- coocw,, 16 h
0
re~a~N
s
25'C) 66
.,s,., o
COOCNM, 72 h
0
. ~~'AH N s
Z cN; c=c-s~e~) ~~csc-cN) 50'C, 50
0
coocNr~) 1 h
~~~ ~N
N~S
II1~~,N
wo-~--s~s~,
0 50'C) 57
COOCNIe, 0Me
6 h
o
~~~~
s
7 ' o i a~ 25'C,.. 52
16 h
CoOCNIA
0
1A~ N
N~ f
os.,w, (b) o~ 65'C) 68
1 h
C00CwA
a
~b~98Z _Z-Stannane Gave 97Z _Z product.
THF vas uscd as a solvent, with 5 squivalents of tin hydride.
- 19 -
1~40~83
,...
The following examples, 1-4 and 6-14, illustrate but a
few representative actual procedures for carrying-out the
process according to this invention and are not to be
construed as limiting the invention in scope. Examples A
and H show the preparation of a representative starting
material. A11 parts and percentages are by weight and
temperatures are in degrees Celsius unless otherwise
indicated.
EXAMPLE A:
Diphenylmethyl
7-(phenylacetamido)-3-hydroxy-3-cephem-4-carboxylate.
A solution of 3.:38 g (0.006 mole) of diphenylmethyl
7-amino-3-hydroxy-3-cephem-4-carboxylate p-toluene sulfonic
acid saltl and 1"87 g (0.018 mole) of sodium bisulfate in
120 mL of tetrahydrofuran and 30 mL of water was treated
dropwise with a solution of 1.41 g (0.009 mole) of phenyl
acetyl chloride in 10 mL of tetrahydrofuran. After addition
of the acid chloride was complete, the reaction mixture was
stirred at room temperature for 2 hrs. The tetrahydrofuran
was then removed from the reaction mix at reduced pressure
and the aqueous concentrate extracted with ethyl acetate.
The organic extract was washed twice with 5% sodium
bicarbonate and twice with brine. Finally, the organic
solvent was remo~red at reduced pressure leaving a solid foam
- 20 -
1340583
residue. The reside was chromatographed on l00 g of silica
gel yielding 1.8!5 g (61.6%) of diphenylmethyl
7-(phenylacetamido)-3-hydroxy-3-cephem-4-carboxylate. The
nuclear magnetic resonance spectrum was consistent for the
desired structure.
lE. Scartazzini, and H. Nickel, Helv. Chim. Acta, 1974, 57,
1919.
EXAMPLE B:
Diphenylmethyl
7-( henvlacetamidol-3-(trifluoromethylsulfonyloxy)-3-cephem-
4-carboxylate.
To 1.57 g i0.00313 mole) of diphenylmethyl 7-(phenyl-
acetamido)-3-hydroxy-3-cephem-4-carboxylate in 63 mL of
methylene chloride was added 0:546 mL (0.00313 mole) of
N,N-diisopropylethyl amine and the mixture stirred at -20o for
min. under a :nitrogen atmosphere. Then 0.633 mL (0.00376
mole) of trifluoromethanesulfonic anhydride was added to the
mix and stirring at -20~ continued for 20 min. The reaction
mix was diluted to 400 mL volume by the addition of methylene
chloride. To the organic solution was added 100 mL of 0.25 N
hydrochloric acid. The phases were separated and the
methylene chloride phase was washed successively with water,
dilute sodium bicarbonate, 0.25 N hydrochloric acid and water.
- 21 -
134083
t
The organic layex was dried over magnesium sulfate. The
sulfate was remo~red by filtration and the solvent removed at
reduced pressure yielding 1.37 g (69.2%) of diphenylmethyl
7-[phenylacetamido]-3-(trif luoromethylsulfonyloxy)-3-cephem-
-4-carboxylate. The nuclear magnetic resonance spectrum was
consistent for the desired structure.
Anal. Calcd. for C29H23N207S2F3: C, 55.06; H, 3.66; N,
4.43; S, 10.14.
Found: C,, 55.28; H, 3.66; N, 3.94; S, 10.68.
EXAMPLE 1:
Diphenylmethyl 7-~[phenylacetamido]-3-(Z-1-propenyl)-3-
cephem-4-carboxylate.
A solution of 0..>.26 g (0.00358 mole) of diphenylmethyl
7-[phenylacetamido]-3-(trifluoromethylsulfonyloxy)-3-cephem-
-4-carboxylate, 0.130 g (0.00039 mole) of Z-1-propenyl
tri-n-butylstannane, 0.0033 g (0.000014 mole) of
tri(2-furyl)phosphine and 0.0041 g (0.000007 mole) of
palladium(0) bisl;dibenzylidene acetone) in 4 mL of
tetrahydrofuran, under an argon atmosphere, was degassed at
reduced pressure for 30 seconds. Then a solution of 0.097 g
(0.00072 mole) of zinc chloride in 1 mL of tetrahydrofuran
was added all at once. The reaction mixture was stirred at
room temperature for 16 hrs. The mix was then diluted with
ethyl acetate and washed with dilute ammonium chloride
solution. The organic solvent was removed at reduced
- 22 -
1340y83
pressure and replaced with acetonitrile. The acetonitrile
solution was washed three times with n-pentane and the solvent
again removed at reduced pressure. The residue was
chromatographed on silica gel to yield 0.l23 g (65%)_of
diphenylmethyl 7--[phenylacetamido]-3-(Z-1-propenyl)-3-
cephem-4-carboxylate. The nuclear magnetic resonance
spectrum was consistent for the desired structure.
EXAMPLE 2:
DiphenYlmethyl 7-[phenYlacetamido]-3-(1-propynyl)-3-cephem-
4-carboxylate.
A mixture of 1.03 g (0.00162 mole) of diphenylmethyl
7-[phenylacetyl]-3-(trifluoromethylsulfonyloxy)-3-cephem-4-
carboxylate, 0.533 g (0.00162 mole) of (1-propynyl)-tri-n-
butylstannane, 0..665 g (0.00488 mole) of zinc chloride,
0.030 g (0.00013 mole) of tri(2-furyl)phosphine and 0.00727
g (0.000032 mole) of palladium(II) acetate in 30 mL of dry
N,N-dimethylformamide was heated at 65~C for 2 hrs and at room
temperature for 7.9 hrs under a nitrogen atmosphere. The
reaction mixture was diluted with ethyl acetate and the
organic solution washed five times with water. The ethyl
acetate was removed at reduced pressure and the residue
dissolved in acet:onitrile. The organic phase was washed two
times with n-pentane and the acetonitrile removed at reduced
pressure. The residue was purified by reverse-phase
chromatography to yield 0.281 g (30%) of diphenylmethyl
- 23 -
,~ 1344583
7-[phenylacetamido]-3-(1-propynyl)-3-cephem-4-carboxylate.
The nuclear magnetic spectrum was consistent for the desired
structure.
Anal. Calcd. for C31H26N2~4S~ C, 7l.24; H, 5.02; N, 5.36;
S, 6.l4.
Found: C, 71.23; H, 5.02; N, 5.30; S, 6.l1.
EXAMPLE 3:
Diphenylmethyl
_ 7-[phenylacetamido]-3-(2-methyl-1-propenyl)-3-cephem-4-carb-
oxylate.
A mixture of 0.105 g (0.000166 mole) of diphenylmethyl
7-[phenylacetamido]-3-(trifluoromethylsulfonyloxy)-3-cephem-
-4-carboxylate, 0.070 g (0.0002 mole) of
(2-methyl-1-propenyl)tri-n-butylstannane, 0.052 g (0.00038
mole) of zinc chloride and 0.0039 g (0.000016 mole) of
tri(2-furyl)phosphine in 4 mL of dry 1-methyl-2-pyrroli-
dinone, under an Argon atmosphere, was degassed for 30
seconds. Then 0.0049 g (0.000008 mole) of palladium(0)
bis(dibenylidene acetone) was added a11 at once. The
reaction mix was stirred at room temperature for 19 hrs.
The reaction mix was then diluted with ethyl acetate and the
organic phase washed with dilute ammonium chloride. The
ethyl acetate was removed at reduced pressure and replaced
with acetonitrile. The organic solution was washed with
n-pentane and the acetonitrile removed at reduced pressure.
The residue was chromatographed on silica gel yielding 0.0603
- 24 -
134083
g (66~) of diphenylmethyl 7-[phenylacetamido]-3-
(2-methyl-1-propenyl)-3-cephem-4-carboxylate. The nuclear
magnetic resonance and mass spectra were consistent for the
desired structure.
Anal. Calcd. for C32H30N2~4S= C, 71.35; H, 5.61; N, 5.20;
S, 5.95.
Found: C, 70.97; H, 5.67; N, 5.07; S, 5.42
_ EXAMPLE 4:
Diphenylmethyl
7-[phenylacetamido]-3-(E-methoxYphenyl)-3-cephem-4-
carboxylate.
A mixture of 0.1029 g ((0.000163 mole) of diphenylmethyl
7-[phenylacetamido]-3-(trifluoromethylsulfonyloxy)-3-cephem-
-4-carboxylate, 0.0775 g (0.000195 mole) of
(p-methoxyphenyl;~ tri-n-butylstannane, 0 . 044 g ( 0. 00032
mole) of zinc chloride and 0.00378 g (0.000016 mole) of
tri(2-furyl)-phosphine in 4 mL of dry 1-methyl-2-pyrroli-
dinone, under an argon atmosphere, was degassed for 30
seconds. Then 0.0047 g (0.000008 mole) of palladium(0)
bis(dibenzylidene acetone) was added a11 at once. The
reaction mix was stirred at 50~ for 5.5 hrs and room
temperature for 16 hrs. The reaction mix was then diluted
with ethyl acetate and the organic solution washed with dilute
ammonium chloride. The ethyl acetate was removed at reduced
pressure and replaced with acetonitrile. The organic phase
- 25 -
F
1340583
was washed with n-pentane and the acetonitrile removed at
reduced pressure. The residue was chromatographed on silica
gel to yield 0.0548 g (57%) of diphenylmethyl
7-[phenylacetamido]-3-(p-methoxyphenyl)-3-cephem-4-carboxylate.
The nuclear magnetic resonance spectrum was consistent for the
desired structure. .
Anal. Calcd. for C35H30N2~5S: C, 71.16; H, 5.12; N, 4.74
Found: C, 70.95; H, 5.18; N, 4.70.
EXAMPLE 5 (Comparison
Diphenylmethyl 7-[phenylacetamido]-3-(desmethyl)-3-cephem-
4-carboxylate.
To a mixture of 0.100 g (0.000158 mole) of diphenylmethyl
7-[phenylacetamido]-3-(trifluoromethylsulfonyloxy)-3-cephem-
-4-carboxylate, 0.065 g (0.00047 mole) of zinc chloride,
0.00293 g (0.000012 mole) of tri(2-furyl)-phosphine and
0.0007 g (0.000003 mole) of palladium(II) acetate in 3mL of
dry tetrahydrofuran under an Argon atmosphere was added 0.216
g (0.00074 mole) of tri-n-butyl-tin hydride portionwise. The
reaction mix was stirred at 65~ for 2 hrs. The reaction mix
was then diluted 'with methylene chloride and the organic
solution washed with n-pentane and the solvent removed at
reduced pressure. The residue was chromatographed on silica
gel to yield 0.053 g t68.5%) of diphenylmethyl
7-[phenylacetamido]-3](desmethyl)-3-cephem-4:-carboxylate. The
- 26 -
F
134083
nuclear magnetic resonance spectrum was consistent for the
desired structure.
Anal. Calcd. for C28H24N204S: C, 69.40; H, 4.99; N, 5.78;
S, 6.62
Found: C, 68.04; H, 4.96; N, 5.52; S, 6.60
EXAMPLE 6:
Diphenylmethyl 7~-tphenYlacetamido]-3-ethenyl-3-cephem-4-
carboxylate.
A mixture of 0.4645 g (0.00073 mole) of diphenylmethyl
7-[phenylacetamido]-3-trifluoromethylsulfonyloxy)-3-cephem-
4-carboxylate, 0.279 g (0.00088 mole) of ethenyl
tri-n-butylstannane, 4.200 g (0.00146 mole) of zinc chloride
and 0.0068 g (0.'D00029 mole) of tri(2-furyl)phosphine in 6
mL of dry 1-methyl-2-pyrrolidinone, under an Argon
atmosphere, was degassed for 30 seconds. Then 0.0084 g
(0.000014 mole) of palladium(0) bis(dibenzylidene acetone)
was added a11 at once. The reaction mixture was stirred at
room temperature for 1 hr. The reaction mix was then
diluted with ethyl acetate and the organic solution washed
with dilute ammonium chloride. The ethyl acetate was
removed at reduced pressure and replaced with acetonitrile.
The organic phase was washed with n-pentane and the
acetonitrile removed at reduced pressure. The residue was
crystallized from ethanol/methylene chloride yielding 0.320
g (85%) of diphenylmethyl 7-[phenylacetamido]-3-ethenyl-3-
- 27 -
13~0~83
cephem-4-carboxylate. The nuclear magnetic resonance
spectrum was consistent for the desired structure.
Anal. Calcd. for C30H26N2~4S~ C, 70.56; H, 5.13; N, 5.49;
S, 6.28.
Found: C, 70.22; H, 5.13; N, 5.21; S, 6.41.
EXAMPLE 7:
DiphenylmethYl
- 7-[phenylacetamido]-3- ~ -ethoxy-1-ethenYl)-3-cephem-4-
carboxYlate.
A mixture of 0.2G0 g (0.00031 mole) of diphenylmethyl
7-[phenylacetamido]-3-trifluoromethylsulfonyloxy)-3-cephem-
4-carboxylate, 0.115 g (0.000318 mole) of (1-ethoxyvinyl)-
tri-n-butylstannane, 0.090 g (0.00066 mole) of zinc chloride
and 0.,00293 g (G.000012 mole) of tri(2-furyl)phosphine in
6 mL of dry 1-methyl-2-pyrrolidinone, under an Argon
atmosphere, was degassed for 30 seconds. Then 0.0036 g
(0.000006 mole) of palladium(0) bis(dibenzylidene acetone)
was added a11 at once. The reaction mix was stirred at room
temperature for 7.9 hrs. The reaction mixture was then
diluted with ethyl acetate and the organic solution washed
with dilute ammonium chloride. The ethyl acetate was removed
at reduced pressure and replaced with acetonitrile. The
organic solution was washed with n-pentane and the
acetonitrile removed at reduced pressure. The residue was
chromatographed on silica gel to yield 0.092 g (52%) of
- 28 -
1340583
,..,..
diphenylmethyl 7--[phenylacetamido]-3-(1-ethoxy-1-ethenyl)-
3-cephem-4-carboxylate. The nuclear magnetic resonance
spectrum was consistent for the desired structure.
Anal. Calcd. for C32H30N2~5S' C~ 69.29; H, 5.45; N, 5.05;
S, 5.78.
Found: C, 69.24; H, 5.54; N, 4.89; S, 5.60.
By following substantially the procedures described
above in the description of the invention and in the above
actual examples except for substitution of the given
triflate (Tf) derivative of 7-[2-(4-hydroxyphenyl)-2-amino-
acetamido]- and '1-[(Z)-2-(2-aminothiazol-4-yl)-2-
methoxyiminoacetamido]-3-hydroxy-3-cephem-4-carboxylic acid
and certain esters thereof and of the given hydrocarbyl-
tributylstannane shown in the following Table, additional
cephem derivatives were produced according to the process of
this invention. The starting triflates (Tf) referred to in
the following tables are those compounds designated "V" and
"VI (a, b)" below having a11 acidic sites protected using
techniques which are conventional in the art to which this
invention relates. Following the coupling reaction to obtain
the desired 3-hydrocarbyl substitution on the cephem nucleus,
the protecting groups can be removed using conventional
techniques. Suitable carbonyl protecting groups include
aralkyl groups such as benzyl, methoxybenzyl, and
diphenylmethyl (:benzhydryl); alkyl such as t-butyl; and
- 29 -
134083
haloalkyl such as 2, 2, 2-trichloroethyl and the like.
Suitable amine and hydroxy protecting groups include trityl
and acyl groups such as chloroacetyl, formyl,
t-butoxycarbonyl and carbobenzyloxy etc. It is to be
understood that, in the formula shown in the table, "Q"
represents the cephem nucleus derived from the triflates "V"
and "VI (a, b)" and R1 represents the unsaturated alkyl group
from the stannane.
N~ i o
I S
'(~~ N ~ orb Compound "V"
~nHi O
Coo H
G S
N ~~~1
i pT~r . Compound "VI"
OR ~
VI (a) : R'=R"=H
V I (b ) : R' =CH20COC (C~i3 ) 3 : R"=H
- 30 -
~~~o~s3
TABLE
Additional Examples of Palladium-Catalyzed Coupling of
Tri.flates ( Tf ) with Stannanes
C,~ ~ ~(
O 'coo H
Ex. No. Stannane Tf Product
8 _ VI(a) Q = 7-[2-(2-aminothiazol-4-yl)-
2 (Z)-hydroxyiminoacetyl]
SnHu R1 = CH=CH
mp: 170~C ~dec.)
9 _ VI(a) Q = 7-[2-(2-aminothiazol-4-yl)-
2-(Z)-hydroxyiminoacetyl],
SnBu3 p~valoyloxymethyl ester
R - CH=~H2
mp: 130 C (dec.)
CH3C=C-S:nBu3 VI ( b ) Q = 7- [ 2- ( 2-aminothiazol-4-yl ) -
21(Z)-hydroxyiminoacetyl]
R - C=C-CH
Pivaloylgxy~ethyl ester
mp: 115 C
11 ~ VI(a) Q = 7-[2-(2-aminothiazol-4-yl)-
2 (Z)-hydroxyiminoacetyl]
SnBu3 R1 = CH=C~CH )
mp: >160 C ~g~ad. dec.)
12 ~ VI(b) Q = 7-[2-(2-aminothiazol-4-yl)-
2 (Z)-hydroxyiminoacetyl]
SnBu3 . . R1 - CH=C(CH3)2
Pivaloyloxym~thyl ester
mp: 110-Q13 C
13 ~ V Q = 7-[D-2-amino-2-(4-hydroxy-
p~enyl)acetyl
SnBu3 R - CH=CHCH
mp: 213-218 C (dec.)
14 H3CH=C=CH V Q = 7-[D-2-amino-2-(4-hydroxy-
( ph enyl)acetyl]
SnHu3 RI = CH=C=CHCH3
- 3I -
F
1340583
The compounds of Formula I produced according to the
process of this invention may be provided as
pharmaceutically acceptable acid addition and base salts
wherein the anion or cation, respectively, does not
contribute significantly to the toxicity of the salt and
which salts are compatible with the standard and.
conventional pharmaceutically acceptable carriers and other
conventional adjuvants and excipients customarily employed
in producing pharmaceutical compositions adapted for oral or
parenteral administration. The acid addition salts are
formed by conventional techniques involving reaction for
compounds of Formula I with mineral acids such as, for
example, hydrochloric acid, hydrobromic acid, phosphoric
acid, and sulfuric acid, and with organic carboxylic and
sulfonic acids such as, for example, acetic acid, citric
acid, malefic acid, succinic acid, benzoic acid, tartaric
acid, ascorbic acid, methane sulfonic acid, ethanesulfonic
acid, p-toluenesulfonic acid, and the like.
Pharmaceutically acceptable base salts are formed by
conventional techniques involving reaction of the compounds
of Formula I with alkali (Na,K) and alkaline earth (Ba, Zn,
Mg) metal bases, more preferably with alkali metal bases
such as, for example, dilute solutions of sodium hydroxide,
potassium carbonate, and sodium bicarbonate. Also,
pharmaceutically acceptable base salts are formed by
- 32 -
134U583
conventional techniques involving reaction with amines such
as, for example, triethylamine, dibenzylamine,
N,N'-dibenzylethylenediamine, procaine and equivalent
amines.
Pharmaceutically acceptable esters include those esters
which are active per se or which function as pro-drugs by
being hydrolyzed in the body to yield the active antibiotic
_ per se. Suitable esters of the latter type include the
phenacyl, acetoxymethyl, pivaloyloxymethyl, ~-acetoxybenzyl,
3-phthalidyl, 5-:~ndanyl, methoxymethyl, benzoyloxymethy,
glycyoxymethyl, and other esters known in the cephalosporin
and penicillin arts.
The pharmaceutical compositions of compounds produced
according to the process of this invention may be prepared
by combining the compounds of this invention with a solid or
liquid pharmaceutically acceptable carrier and, optionally,
with pharmaceutically acceptable adjuvants and excipients
employing standard and conventional techniques. Solid form
compositions include powders, tablets, dispersible granules,
capsules, cachets and suppositories. A solid carrier can be
at least one substance which may also function as a diluent,
flavoring agent, solubilizer, lubricant, suspending agent,
binder, tablet disintegrating agent, and encapsulating
agent. Inert solid carriers include magnesium carbonate,
- 33 -
1340583
magnesium stearate, talc, sugar, lactose, pectin, dextrin,
starch, gelatin, cellulosic materials, low melting wax, cocoa
butter, and the :like . Liquid form compositions include
solutions, suspensions and emulsions. For example, there may
be provided solutions of the compounds of this invention
dissolved in water and water-propylene glycol and
water-polyethylene glycol systems, optionally containing
suitable conventional coloring agents, flavoring agents,
stabilizers and thickening agents.
Preferably, the pharmaceutical composition is provided
employing conventional techniques in unit dosage form
containing appropriate amounts of the active component, that
is, the compound of Formula I according to this invention.
The quantity of active component, that is the compound
of Formula I according to this invention, in the
pharmaceutical composition and unit dosage form thereof may
be varied or adjusted widely depending upon the particular
application, the potency of the particular compound, and the
desired concentration. Generally, the quantity of active
component will range between 0.5% to about 90% by weight of
the composition.
In therapeutic use for treating, or combatting
Gram-positive and Gram-negative bacterial infections in
- 34 -
1340583
warm-blooded animals, the compounds will be administered at
a dosage to obtain and maintain a concentration that is, an
amount, or blood-level in the animal undergoing treatment
which will be ant.ibacterially effective. Generally, such
antibacterially effective amount of dosage will be in the
range of from about 100 mg to about 5000 mg per day. It is
to be understood that the dosages may vary depending upon
the requirement of the patient, the severity of the
. bacterial infection being treated, and the particular
compound being used. Also, it is to be understood that the
initial dosage administered may be increased beyond the
above upper level. in order to rapidly achieve the desired
blood-level or the initial dosage may be smaller than the
optimum and the daily dosage may be progressively increased
during the course of treatment depending on the particular
situation.
The compounds of formula I produced according to the
process of this invention are advantageously administered
parenterally, i.e. by injection, for example, by intravenous
injection or by other parenteral routes of administration.
Pharmaceutical compositions for parenteral administration
will generally cantain a pharmaceutically acceptable amount
of the compound according to formula I as a soluble salt
(acid addition salt or base salt) dissolved in a
pharmaceutically acceptable liquid carrier such as, for
- 35 -
134.0583
example, water for injection and a buffer to provide a
suitably buffered isotonic solution having a pH of about
3.5-7. Suitable buffering agents include, for example,
trisodium orthophosphate, sodium bicarbonate, sodium
citrate, N-methyl,glucamine, L(+)-lysine and L(+)-arginine to
name but a few representative buffering agents. The
compound according to formula I generally will be dissolved
in the carrier in an amount sufficient to provide a
pharmaceutically acceptable injectable concentration in the
range of about 1 mg/ml to about 400mg/ml of solution. The
resulting liquid pharmaceutical composition will be
administered so a,s to obtain the above-mentioned
antibacterially effective amount of dosage in the range of
from about 100 mg to about 5000 mg per day.
The following table illustrates the activity of several
representative compounds produced by the process according
to this invention.
- 36 -
,,~.-..
134058
TABLE
Antibacterial Activity
ORGANISM M I
C
(ug/ml)
Ex. Ex. Ex. Ex. 14 CEFACLOR CEPHALEXIN
2 3 1
S. pneumoniae 8 0.03 0.03 2 0.13 0.5
S. pyogenes 4 0.03 0.0l 2 0.13 0.25
S. faecalis. 16 4 6 >63 32 63
S. aureus 4 0.06 8 8 0.25 0.5
S. aureus/50~ >16 0.06 0.13 32 1 1
serum 8 0.5 0.5 63 1 g
S. aureus/Pen.Res. >16 >125 1 >63 >125 >125
S. 16 2 >125 >63 1 4
aureus/Meth.Res. 16 32 1 >63 2 4
E. coli 16 4 4 >63 0.5 4
E. coli >16 >125 0.5 >63 63 63
K. pneumoniae >16 63 63 >63 >125 >125
K. pneumoniae 16 4 >125 63 2 4
E. cloacae 1
P. Mirabilis
- 37 -
