Note: Descriptions are shown in the official language in which they were submitted.
3~ ~
Reference to Related A~lications
.
This appli~ation is related to our co-pending U.S.
application Serial No. 564,604 filed December 28,
1983 and now U.S. Patent No. 4,520,022, patented May 28, 1985,
which ~s related to U.S. Application Serial No. 461,833
filed January 28, 1983, and now abandoned, corresponding
to Canadian Serial No. 444,731 filed January 5, 1984 and
issued ~arch 8, 1988 as Patent No. 1,233,815.
1 Descr~etion of the Prior Art
.
U.~. Patent Specification 1,342,241 published January 3,
1974 (corre~ponding ~.S. Patent Nos~ 3,769,277, and 3,934~884,
granted October 30, 1973, and No~ember 30, 1976) di~closes
the Compou~d VI but ~here is no desoriptlon of 7~-amino~3-
[~Z)=l-propen-l-yl~3 cephem-4-carboxylic acid as an
~ntermediate in ~he preparation thereof.
~ C~2CONE ~ ~ V~
p7 ~?=C~_~3
COO~
i ~ ~
r
~ ~,
A. ?
~73~
U.S. Patent No. 4,409/214 patented October 11, 1983
discloses the preparation of Compound VII via the Wittig
reaction on diphenylmethyl 7-benzylideneamino-3 triphenyl-
phosphoniomethylceph-3-em-4-carboxylate in Preparations 38
and 39, but there is no description of 7~-amino-3-[(Z)-l-
propen-l-yl]-3~cephem-4-carboxylic acid, nor of an other 3-
(l-propen-l-yl)cephalosporin compound.
2 ~ S ~
=C~2 ~II
~:oolI
U.S. Patent No. 4,110,534 patented April 29, 1~78 is
particularly concerned with preparation of compounds such as
VI and VII by the Wittig reaction. Refer particularly to
col~mns 8, 9, and 49 (Example 21).
H. O. House et al. Jour. Org. Chem. 29, 3327-3333
(1964) have studied the effect of solven~s and additives
including lithium salts on the proportions of cis- and
trans- olefins produced in the Wittig reactio~ with aldehydes.
Summary of the Invention
This invention relates to cephalosporin intermediates
having Formula I, the synthetically useful acid addition
and metal salts theresf, and to processes ~or their preparation.
2 ~ S ~ I
C~-C~3
COOR
36~
In the compounds o~ Formula I, the configuration o~ the
3-propenyl group is Z- or cis-. R is hydrogen or a conventional
carboxy-protecting group. The latter expression refers to
protecting group of the sort conventionally used for amino
or carboxyl groups in the synthesis of cephalosporin compounds.
Suitable carboxyl protecting groups include Aralkyl gxoups
such as benzyl, p-methoxybenzyl, o nitrobenæyl r p-~itrobenzyl,
and diphenylmethyl (benzhydryl3, alkyl groups such as t-butyl;
haloalkyl gxoups such as 2~2,2-trichloroethyl, alken.yl.groups
su~h as allyl, 2-chloroallyl, alkoxymethyl groups such as
m thoxymethyl, 2-(trimethylsilyl)ethyl, trimethylsilyl,
tert.-butyldimethylsilyl, ert.-butyldiphenylsilyl, and
o~her carboxyl protecting groups described in the literature,
~or instance, in ~ritish Specificatio~ 1,399,086. We pre~er
to utilize ~arboxyl-protecting groups which are readily
xemoved by treatment with acid, particularly benzhydryl or
t-butyl. The acid addition salts and the metal salts of the
foregoing substance where R is hydroge~ are also part of the
present in~ention.
The Z-, or cis- confisuration of the 3-propenyl group
is a criti~al aspect of the pres~nt compounds. This is ~he
characteristic which determines th~ advantageous Gram
negative a~tibacterial properties of the cephalosporin end
products which are the subject of U.S. Patent No. 4,520,022
issued May 2 8, 19 85 .
The.synthetically u5eful acid addition salts include
the salts o~ Formula I with mineral acids such as hydrochloric
acid, sulfuric acid and phosphoric acid, with organic
sulfonic acids such as p-toluenesulfonic acid and other
a~ids know~ and used in the cep~alosporin arts.
Those substances of Formula I wherein R is hydrogen
also form metal salts. 5ynthetically suitable metal s?lts
include th~ sodium, potassium, calcium, masnesium, alufflinum,
and zinc salts.
'3~
In another aspect the present invention provides a
process for preparing compounds having Formula I as shown
above, which process comprises reacting the intermediate
of the formula
~ fS~
~ ~ C~=~Ph3
wherein R has the same meaning as shown above, Ph is the
phenyl group with acetaldehyde in an inert organic
reaction medium comprising dichloromethane, N,N'-
dimethylformamide, isopropanol or a mixture thereof at a
reaction temperature between 0C and 25C to provide a
compound of the formula
~-N ~
N ~ ~=C~-C~3
~0~
and thereafter removing the benzylidene group to give the
compound wherein R is a carboxyl-protecting group and, if
desired, separating the 3-(Z) and 3-(E) isomexs or
removing-both the benzylidene group and the carboxyl-
protecting group to provide the desired compound.
- 4a -
~3~
The most preferred compounds of the invention are~
1. Diphenylmethyl 7~-amino-3-[(Z)-l-propen-l-yl~-3-cephem-4-
carboxylate.
2. Diphenylmethyl 7~-amino-3-~Z)-l-propen-l-yl~-3-cephem-4-
caxboxylate hydrochloride.
3~ Diphenylmethyl 7~-amino-3-[(Z)-l-propen-l-yi]~3-cephem~4-
carboxylate sulfate.
4. Sodium 7~-amino-3-[(Z)-l-propen-l-yl]-3-cephem-4-carboxylate~
5~ Potassium 7~-amino-3-[(Z)-l-propen-l-yl~-3-cephem-4-
carboxylate.
6. 7~-Amino-3-[(Z)-l-propen-l~yl3-3-cepehm-4-carboxylic
acid.
Detailed Description of the Invention
In a~other aspect, this in~ention relates to processes
i5 for the preparation of the compounds of Formula I. Preferred
procedures are shown in Reaction Schemes 1 and 2.
In Reaction Scheme 1, the diphenylmethyl group is shown
as the preferred carboxy-pro~ecting group. I~ will be
appreciated by those skilled.in the art that other carboxyl-
protecting groups, well-known in the art, may be used.
In the Wittig reaction of Compound III with acetaldehyde,
we have found that addition of an appropriate lithium halide
such as lithium chloride~ lithium bromide or lithi~m iodide
improves the yield and proportion of Z/E isomer of the
reaction product IIa. The reaction is preferably carried
~2~36~
.
out with 5 t~ 15 chemical equivalents, preferably 10 equivalents~
of lithium bromide.
M~thylene chloride is the preferred reaction medium
preferably containing a cosolvent such as dimethylformamide
or isopropanol in minor proportions o~ ~rom about 1/10 to
1/3 part by volume per paxt of me~hylene chloride. Reaction
temperatures in the range of -10~C to t25C are appropriate
with 0 to 25C being preferred. The Wi~tig product IIa is
extracted into a suitable organic solvent such as ethyl
acetate and the extract is treated with Girard's reagent T
to afford the 7 aminoceph-3-em compound of the presen~
invention, Ia. Refer to Procedure 3 hereof. Subsequent
treatment of I~ with trifluoroacetic acid (TFA) yields 7~-
ami~o-3-[~Z)~l-propen-l-yl~-3-cephem-4-carboxyiiC acid (Ib,
Procedure 7) in the ratio of Z/E = 9/1. Acylation of Ib
with p-hydroxyphenylglyci~e by a conventional acid chloride
method or an activated ester me~hod yields the orally ef~2ctive
cephalo~porin V of the parent application Serial No.
564, 604, now U. S. Patent 4, 520, 022.
An alternative xoute, acylation of 7~-amino~3-propen-1-
yl cepha}ospsrin ester Ia with the N-BOC (tert.-butoxycarbonyl)
blocked p-hydroxyphenylglycine in the presence o DCC
(dicyclohexylcarbodiimide) and followed by deblocking wi~h
TFA (trifluoroacetic acid)~also yielas the cephalosporin vO
-6-
,' '
.. ~ . . . .
1~73~
Scheme 2
Scheme 1 - -
PhC~=N ~ ~ PhCH2CONH ~ S ~
H=PPh3 ~ ~ H=PPh3
COOCHPh2 III COOCHPh~
VIII
~ Procedure 3 Procedure 10
r PhCH=N ~ ~ ~ PhC~2CONH S
CH=CH-CH3 J~ CH=CHCH3
COOCHPh2 COOCHPh2
IIa IX
~Procedure 3~ Procedure 11
r~ ~
N ~ CH=CH-C~3
COOCHPh2
Procedure 5 /\ Procedure 7, or 8
\~ I a
HO~ C~lCONH~S~ 2 ~ ~
N~BOC k~ CH=CH-cH30 ~ ~ CH=CH-C~3
IV o COOCHPh2 COOH Ib
Procedure 6\ ~
\ Prvcedure 9,
~IO ~ HCONH~
O ~f~CH=CH-CH3
COOH
BMY-28100
~7~
Description of Specific ~mbodiments
The following abbreviations which appear in the experimental
procedures have the meaning indicated below:
Ph = phenyl
BOC = -COOC(CH3)3
DCC = dicyclohexylcarbodiimide
T~A = trifluoroacetic acid
EtOAc c ethyl acetate
DMF a dimethylformamide
Procedure 1
.
Diphenylmethyl 7-Benzylideneamino-3-tripheny~phosphoniomethyl~3-
cephem-4-carboxy~te Chloride
To a suspension of diphenylmethyl 7 amino-3-chloromethyl-3-
cephem-4-c~rboxylate hydrochloride ~200 g, 0.4~ mole) in
C~2C12 (940 ml) was added 1 N NaOH (440 ml) at room temperature.
The mixture was shaken for 10 minute~ and t~e oxganic layer
was separated. To this organic ~ayer were added MgSO4 (75
g) and benzaldehyde (51 g, 0.48 mole) and the mixture was
allowed to stand for 3 hours at room temperature. The
20reaction mixture was filtered and the insolubles were washed
with CH2C12 (200 ml). To ~he combined filtrate and washings
was added triphenylphosphine (126 g, 0.48 mole)~ The mixture
was concentrated to about 400 ml under reduced pressure and
allowed to stand for 4 days. The resulting viscous oil was
25diluted wi~h ethyl acetate tl 1) and triturated to separate
the title compound~ a pale yellow crystalline powder which
was collected by filtration and dried in vacuo Yield 322 g
(96%). M.p. 185~190C (dec.3.
~ ~8-
~'7~
IR: vKBr cm 1 1780, 1720, 1630.
W ~C~2C12 nm (E) 260 (24100).
Procedure 2
Diphenylmethyl 7-~enzvlideneamino-3 ~(triphenY~phosphoranylidene~
methyl~-3-cephem-4-carboxylate (II~)
mixture of diphenylmethyl 7-benzylideneamino-3-
triphenylphosphoniomethyl-3-cephem-4-carboxylate chloride
~322 g, 0.42 mole) and 5 N Na2CO3 (252 ml) in CH2C12 (10 6 1)
was stirred vigorously for 15 minute~ at room temperature~
The organic layer was separated, dried over MgSO4 and concentrated
to abo~t 500 ml of volume. The concentrate was dilu~ed
with acetone (1 1), with stixring, to give a light yellow
cxystalline powder which was collected by filtration to
yield 237 g (78~) o 3, melting at 195-198C (dec.).
lS IR: vKBar cm 1 1770, 1620.
W : ~C~2C12 nm (~) 254 (23000), 389 (22000)~
max
NMR: ~CDC13 ppm 2056 & 3.16 (2H, ABq), 5.00 ~lH, d,
J=4 Hz) ~ 5.23 .(1~ d~ J=4 Hz) r 5.47 (lH~ d~ J=22 Hz)
6.95 (lH~ s), 7.2--7.8 (30~, m), 8.55 (1~ s)O
~ s,3
Procedure 3
Diphenylmethyl 7-Amino-3-( tZ)-l-propen-l-yl)-3~c~ph~n-4-
carboxylate Hydrochloride (Ia Hydrochloride)
To a cold solution of LiBr (19 g, 216 m moles) in a
mixed sol~ent of dry dimethylformamide (100 ml) and
CH2C12 (300 ml) were added acetaldehyde (20 ml, 360 rn rnoles)
and diphenylmethyl 7-benzylideneamino-3-~(triphenylphosphor-
anylidene)methyl]-3-cephem-4-car~oxylate (III) (15 g, 20 m mo~s)
at.-5C. The mixture was allowed to stand for 20 hours at
-5~ -10C and then 5 hours at room ternperature. The resulting
light brown solution was concentrated to ca. 100 ml of volume
in vacuo and added to a two layer solvent of ethyl acetate
(400 ml) and H2O (400 ml). The upper layer was separated
and diluted with isopropyI ether (400 ml). Silica gel-
-15 (Wako gel C-100, 4 n g) was added to the mixture . The mixture
was shaken for 5 minutes and filtered through a pad o~
diatomaceous filter aid. Insolubles were washed with a
mixed solverlt of ethyl acetate-isopropyl ethèr ~1/1, 200 ml).
The cor~ined filtrate and washings were concentrated to
ca. 400 ml of volume. A 0.5 M Girard reagent T solution
in methanol ( 60 ml) and acetic acid ( 6 ml) was added to
the above concentrate and the mixture was stirred for lS
minutes at room temperature. The mixture was evaporated to
ca. 20û ml of volume, washed with H20 (200 rnl), sat. aq.
NaHC03 (3x20 ml) and brine (20 rnl) successivelv, dried over
MgSO4, treated with charcoal and concentrated to ca. 50 ml~
To the concentratP was added N HCl in rnethanol (40 ml) at
room temperature and left standislg for 15 minutes. The
mixture was evaporated to ca . 3 0 ml and diluted by addition
of ether (300 ml). The precipitate was collected bv filtratioa
and dried over P2O5 to yive 7 . 9 g of light yellow powder. A
solution of the powder (7 . 3 g) in a mixed solverlt of rnethanol
(80 ml) and ethyl acetate t80 ml) was treat~d with char oal,
--10 ~
.
736~9
coneentrated to ca. 100 ml, seeded with crystalline hydrochloride
of the title compound, diluted slowly with ether (80 ml~ and
stirred for 1 hour. The separated colorless crystals were
collected by filtra~ion and dried over P~05 in vacuo to give
S 6.3 g (71~ of the title compoundO This product is a mixture
of thP isomers Z and E with reference to the propenyl moiety
at the 3 position (Z/E=9/1 by HPLC) (Lichrosor~ RP-18, 80% metha-
nol - p~ 7.2 phosphate buffer, 254 nm, 1 ml/min.)~
IR vKBr cm 1 2850, 1785~ 1725.
max
UR: ~E~O~ nm (E l~cm) 287 ~173).
NMR ~DMSO d6 ppm 1.47 (27/lOH, d-d, ~=7, 2 ~z, ~CHC~3,
cis), 1.74 (3JlOH, d~ 3=7 ~z, aCHC~3, trans), 3.47 & 3.8
(each 1~, d, J=16 Hz), 5.13 (1~, d, J=4.5 ~z, 6-~, 5.23
(1~, d, J-4.5 Hz, 7-~), 5.62 (1~, d-q, J=10 ~ 7 ~z,
3-C~=C~), 6.24 (1~, d-d J=10 ~ 2 ~z, 3-C~j, 6.81 (1~, s,
-P~2), 7.3~ (10~, m, Ph-~)
Pxocedure 4
DiPhenylmethyl 7-Ami~o-3-((z2-l-propen~ 3-ce~h=~n-~ ca=~ e
(_
To a stirred suspension of ~he hydrochloride of
diphenylmethyl 7-amino 3-t~Z)~ ropen-l-yl) 3-cephem-4-carboxylate
(5 g, 11.3 m moles) in ~2 (20 ml) and ethyl acetate (40 ml)
was added NaHC03 until the pH of the mixture became 8.
The organic layer was washed with sat. aq. NaCl (5 ml), dried
over MgS04 and concentrated to ca. 20 ml of volumeO The
resulting solution was diluted wi~h isopropyl ether tlO ml)
and seeded with crystalline Ia. Additional isvpropyl ether
~11--
73~
(30 ml) was added slowly to the mixture wit~ stirring. ~ter
15 minutes the separated colorless crystals wer~ collec~ed
by filtration, washed with isopropyl ether (10 ml~ and
dried oYer P;2O5 isl ~racuo to gi~e 4 . 3 g (94%) of ~che
title compound (Z/E=9Jl by EIPLC) (Lichrs:~sorb RP 18 80P~
metha~aol - p~I 7.2 phospha~e bufXer,- 254 ~mj 1 ml/min.~.
IR: v~3r cm 1 345û, 1765, 1730~.
W ~Eto}I a~m ~E 14 ) 289 ~185)-
NMR:~CDC13 pp~ 1.43 (3H, d-d, J=2 & 7 ~37~ C~=C~C:E3), 1.66
(2~, br, s, disappeared by D;~O, N~I2), 3.23 ~ 3.5S (each
lH, d, J--17 ~z, 2-~), 4.73 (1~, d, J--4.5 Hz, 6-~3, 4.96
(1~, d~ J=4.5 ~z, 7-H~, 5.46 (i~, d-q, J=10 & ~ EIz,
3-CH=C~ 6.06 tl~l, brr d, J=10 ~Iz, 3-C~), 6.94
~, CE[Ph~), 7.3 ~10~, m, }?h~
Procedure 5
carboxylate (IV)
A mixt~re of diphenylmethyl 7-~no-3-~(Z3-l~propen-1-
yl)-3-cephem-4 carboxylate (Ia) t4.2 g, lOo4~ m moles) j
tD) -a- ~tbutc~xycarbonyl~no) -a- ~4~hydroxyphenyl) acetic
acid (3O3 g, 12.5 m mol~s) and DCC ~2.6 g, 12.5 m moles~
in e~:hyl acet~ts (104 ml)~ was stirred for l.S hour~ a~
room temperature- The mixture was filtexed and insol~le~
wexe washed with ethyl acetate. 52û ml), The filtrake ~d
th~ washings were coIa~ine~ and washe~ with sat, a~, NaElCO3
(3x5 ml), brine ~5 ml), lû96 ~C1 ~5 ml) and ~sine su~cessi~ely9
dried o~Ter MgS04, treate~ wi~ charcoal and f iltered ~, The
-12-
~273~
filtrate was concentrated to ca~ 10 ml and diluted with n-
heptane (20 ml). The precipitate was collected by filtration
and dried over P205 in vacuo. Yield 7.8 g (9o% pure,
quantitative in weight) as colorless powder (Z/E=9/1 based
S on BPLC) (Lichrosorb RP-18, 80~ methanol-pH 7.2 phosphate
buffer, 254 nm, 1 ml/min.).
B o v~BS c~-l 3~D, 179D, ~720~ 1~90.
~B~ S ) 27~ 3~, 28~ ), 2~5 (95)
R~R : ~ 3 py~ 1.3-~5 (12~ =C~-CE3~, 3.Da ~ 3.33 ~e~
, J-18 P~ 2 (1~, ~, Js~.5 ~, 6-~), 5.~ (1~ ~, J~6 ~z.
s by D2~, C$N), 5.5 (1~, d-~, J~10 ~ 7 ~, 3-~=~), ~.68 (~,d-d, J=.6 ~z.
8 ~z. ~, J=~.5 z by D20~ 7 ~), 6.01 (~Xt a, J~lo ~z, 3-CE), 6.~5 ~ 7.~8
(ea~h 2B. ~, J-8 ~zy ~ ~ ) ~.71 tl~ J-8 ~2, ~iS~ ea ~q D20, 7
6.88 (1~, 59 ~)~ 7.3 t
Procedure 6
BMY-28100; 7-~(D)-2-Amino-2-(4-hydroxyphenyl)acetamido~-3
(propen-l-yl)-3-ce~em-4-carboxyllc Acid (V)
A mixture of diphenylmethyl 7-[(D)_a_(t butoxycarbonyl-
amino)-a-t4-hydrox~phenyl)acetamido]-3-((z)-l-propen-l-yl-3
cephem-4-carboxylate (IV) which was prepared in Procedure 5
(90% pure, 7.7 g, 10.6 m moles), anisole (7.7 ml) and
trifluoroacetic acid (77 ml) was stirred for 1 hour at room
temperature. The mixture was concentrated in vacuo.
To}uene (50 ml) was added to the concentrate and the mixture
was evaporate~ in vacuo. Ether (200 ml) was added to the
residual oil. The separated solid was collect~d by filtration,
washed with ether (20 ml) and dried over KOH in vacuo to
-13-
3~
afford 5.3 g of trifluoroacetic acid (TFA) salt of BMY-
28100. The salt (5.3 g) was dissolved in H2O (100 ml),
treated with charcoal and placed on a column packed with
Diaion ~P-20 (0.6 l). The column was washed with H20 (4 l)
and eluted with 40% aqueous MeOH. The methanolic fractions
(1.7 13 containing the desired product were collected and
evaporated to ca. 20 ml of volume, The concentrate was
diluted slowly with acetone (100 ml). The separated colorless
crystalline powder was collected by ~iltxation, washed with
acetone (20 ml) and dried over P205 ln vacuo to gi~e 4 g
(97~) of BMY-28100 ~Z/E=9/l, Zwitterion) (Lichrosor~ RP-18,
20% methanol - p~ 7.2 phosphate buffer, 254 nm, 1 ml/mi~.
Procedure 7
7-Amino-3-[_(Z)-l-propen-l-yl]ceph-3-em-4-carboxylic Acid, Ib
To a stirred solution of 260 ml anisole and 1.38 l of
trifluoroacetic acid (T~A) cooled to 0~C was added 149.7 g
(0.338 mole) of diphenylmethyl 7-amino-3-E(Z)-1-propen-l-
yl]-3-cephem-4-carboxylic acid hydrochloride (0.338 mole,
Procedure 3 or ll). The resulting slurry was then stirred
at room temperature for l hour. Most excess of TFA was
removed in acuo on the rotary evaporation. The residual
supernatant solution was decanted and the residual slurry
was triturated with 1.5 l of dry ether during l hour. The
crystalline product was filtered and dried over P2O5 to
give 87.24 g Ib trifluoroacetate. These 87.24 g of the
trifluoroacetate were suspended and stirred into 900 ml of
water (pH ca. 2.5). The mixture was cooled to ~5C and
the~ adjusted to pH 0.6 with 12 N HCl. The yellow solution
was charcoal treated and the slurry was filtered on a diatomaceous
3~ filter aid pad. The resulting solution was cooled to ~5~C and the
pH wa adjusted to 2.0 with 20% NaOH . The suspension was
kept l hour in a refrigexator to aid crystallization. The
~ I -14-
~ ~'73~
.
crystals were collected, washed with 800 ml of water, 800 ml
of acetone and vacuum dried at room temperature. Yield ~9.4
g (85.5~). Contains 9.7% of trans isomer (determined by
HPLC colu~n RP 18 MERCK; ~2(N~4)P04, 0.1 mole 95 ml + CH3 CN
5 ml; detected at 290 nm).
Procedure 8
7-Amino-3-t~Z1-1-propen-1-yl)-3-cephem-~-carboxylic Acid, Ib
A solution of the.phosphoranyl compound III as produced
by Procedure .2 (50.0 g, 68.7 m mole) in CH2C12 (500 ml) was
mixed with a solution of lithium bromide (~9.8 g, 343 m
mole) in dry DMF (170 ml) containing a small amount of
CH2C12 (10 ml) and then with anhydrous acetaldehyde (39 ml,
687 m mole; prepared from paraldehyde and toluenesulfonic
. acid by distillation, according to the procedure of N.L.
Drake and G.B. Cooke, Org. Syn. Col. Vol. II, p~ 407). The
mixture was placed in a sealed vessel and kept at 20C for
days. The reaction mixture being evaporated, the residual
liquid was diluted with EtOAc (800 ml), washed with water
(3x300 ml) and a saturated NaCl solution (300 ml), and
e~aporated to give the blocked 3-propenyl derivati~e IIa as
foamy solid (34 g), which was used for the next reaction
without further purification.
The crude IIa obtained above was treated with 98%
formic acid (35 ml) and concentrated HCl (17 ml, 206 m mole)
at room temperature for 1 hour. To the reaction mixture was
added water (350 ml) to separate an oily layer, which was
washed out with EtOAc (3x100 ml)~ The pH o the a~ueous
layer was adjusted to about 3 with 4N NaO~ (ca. 65 ml) under
stirring to give cryst~lline solid, which was csllected by
filtration and washed with water ~50 ml) to afford the title
-15-
~;~736~
.
compound (Ib, 9.7 g, 59%). HPLC [Lichrosorb RP-18, 4x300
mm, MeOH: phosphate buffer (pH 7) = 15 : 85~ showed that
this product was an 83:17 mixture of Z and E isomers about
the double bond of the 3-propenyl group. M.p. 200C (dec~).
IR: vmax (KBr) in cm 1 3420, 1805, 1620.
W: ~max (pH 7 phosphate buffer) in nm (~) 283 (8900).
PMR: ~ (D2O f NaHCO3~ in ppm 1.59 and 1.88 (3H, each d,
J=6.0 Hz, Z and E of -CH=CH-CH3), 3.38 and 3.72 ~H, Abq,
J=17 Hz, H-2)~ 5.18 (lH, d, J6 7=5 Hz, ~-6~, 5.51 (lH, d,
H-7), ca. 5.8 (lH, m, -CH=CH-CH3) and 6.06 (lH/ d, J-ll
Hz, -CH=CH-CH3)-
Anal. Calcd. for CloH12N2O3S:. C, 49.99; H, 5.03; N, 11.66;
S, 13.34%.
Found: C, 50.20; H, 4.94; N, 10.93;
S, 12.82%.
Procedure 9
7-r(D)-2-Amino-2-(4-hydroxyphenyl?acetamido~-3-((Z)-1-
propen-l-Yl)-3-cep em-4-carboxYlic A_id, V
Dimethylaniline (1.7 ml, 13.1 m mole3, trimethylsilyl
chlaride (2.1 ml, 16.4 m mole) and triethylamine (TEA, 2,3
ml, 16.4 m mole) were added successively to a suspension of
Ib produced by Procedure 8 ~1.58 g, 6.56 m mole~ in CH2C12
(16 ml~ under ice-cooling. The mixture was stirred at room
temperature for 30 minutes. To the mixture was added portionwise
under stirring D-p~hydroxyphenylglycyl chloride hydrochloride
(1.46 g 6.56 m mole) and the reac~ion wa~ monitored by HPLC
-16-
~L~736~
[Lichrosorb RP-18, 4x300 mm, MeOH: phosphate buffer (pH 7~ -
25:75]. An additional amount of the glycyl chloride was
added to the mixture 3 times at 15 minute intervals (291 mg
each) to complete the acylation. After the addition of dry
MeOH (2.0 ml) containing dry D~F (0.1 ml), the resulting
clear solution was neutralized with ~EA (3.2 ml) to pH 6 and
then diluted with CH2C12 ~30 ml) to give a precipitate,
which was collected by filtration and washed with CH2C12 (10 ml)
to give the title compound as the dimethylformamide solvate
lQ (2.39 g, yield 94%; ca. 50% pure; Z/E = 47-12 by HPLC).
Procedure 10
Diphenylmethyl 7-Phenylacetamido-3-((Z)-propen-l-yl)ceph-3-
em-4-carboxylate, IX
C ~ CO~ ~ 5 ~
N ~ C~ PtPh)3
COODPM
MW = 758.8
~ CH ~ - N ~ S
N
1 MW = 524.6 C~OD~M
A stirrçd solution of 18 1 of CC14, 1.8 1 methanol and
12 g ~-benzoyl benzoic acid was cooled to 8C 970 ml of
acetaldehyde were added. The temperatt~re of the resulting
solution rose to + 14~C. After five minutes, 588 g (0.7749
mole) of diphenylmethyl 7-phenylacetamido-3-~(txiphenyl-
phoranylidene)methyl]-3-cephem-4-carboxylate was added. The
. .
` '` ~2~362~
cooling bath was removed and the mixture ~igorously stirred
for 4 hours at 35C shaded from light under an N2 atmosphere
until complete dissolution of the phosphorane had occurred.
The resultlng solution was vacuum concentrated and th2
S residue was dissolved in 2 1 of ethanol, and the solution
was vacuum concentr~ted to a semi-crystallized residue which
was slurried with 3 1 of ethanol.
The mixture wa~ stirred for 2 hours at + 5C and let
stand o~ernight, crystals werP collected twice, washed with
ethanol, and vacuum dried at room temperature. Yield 191 g
(47%). M.p. 124-128C contains 7.5% of trans isomer (determined
by HPLC column Lichrosorb Si 60 5 ym Merck eluted with 85%
toluene, 15~ ethyl acetate).
Procedure 11
Diphenylmeth~l 7-Amino-3-((Z)-propen-l-yl)ceph-3-em-4-
carboxylate Hydrochloride, Ia
To a stirred solution of 159.7 g (0.767 mole) of
PC15 in 2.8 1 CH2C12 were added 56.7 ml (0.700 mole) of
pyridine in 280 ml CH2C12 over a 20 minute pexiod. Under a
nitrogen atmosphere the slurry was cooled to 2C while 256 g
of IX ~roduced by Procedure 10 (0.488 mole) was addedO The
mixture was stirred for 40 minutes and the resulting slurry
was poured rapidly into a vigorously skirred solution of 1.4 1
of CH2Cl~, and 209 ml ~2.33 moles) of-1,3-butanediol at ~20Cr
so that ~he temperature did not rise above -5C. The cooling
bath was removed and after 45 minutes the temperature rose
to 10C and was held there for 35 minutes. Water (1.0
liter) was added and stirring continued for 5 minutes after
which the layers were allowed to separate. The organic
layer was washed with 600 ml HCl 2N and then 400 ml saturat~d
-18-
brine. The combined aqueous extracts were back-washed with
2 x 600 ml of CH2C12 and combined with the original CH2C12 extract.
The solution was dried over anhydrous MgSO4. The
MgS04 slurry was filtered and the MyS04 washed with 2 x 500
ml C~2C12. The combined filtrates were concentrated in
vacuo on the rotary evaporator to a volume of 2.4 liters and
diluted with 2.5 liters of ethyl acetate. The solution was
concentrated again to a volume of ca. 1.3 liters. The
resulting crystal - slurry was filtered, washed with 3 x 300
ml ethyl acetate. ~fter air and vacuum drying over P2O5
~here was obtained 149.8 g of the title compound as beige
crystals. Yield 6g.3g.
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