CA1273629A - 7-amino-3-propenylcephalosporanic acid and esters thereof - Google Patents

Abstract

ABSTRACT
This invention provides novel cephalosporin intermediates, 7.beta.-amino-3-[(Z)-1-propen-1-yl]-3-cephem-4-carboxylic acid and esters thereof having the general formula wherein the configuration of the 3-propenyl group is Z
sometimes referred to as cis- and R is hydrogen or a conventional carboxy-protecting group, and acid addition salts thereof and the metal salts of the foregoing substance wherein R is hydrogen. These compounds are useful as intermediates for preparation of orally active cephalosporins.

Description

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

,' ' .. ~ . . . .

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

~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 ~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 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 ~;~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

~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 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.

Claims (11)

What is claimed is:

1. A Compound of the formula wherein the 3-propenyl group has the Z-configuration and R
is hydrogen or a conventional carboxy-protecting group, and acid addition salts thereof and metal salts of the foregoing substance wherein R is hydrogen.

2. The compound of Claim 1 wherein R is a group selected from hydrogen, methoxymethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, t-butyl, benzyl, diphenylmethyl, o-nitrobenzyl, p-nitrobenzyl, trimethylsilyl, t-butyldimethyl-silyl, t-butyldiphenylsilyl, allyl, and 2-chloroallyl and acid addition salts thereof.

3. The compound of Claim 2 wherein the acid addition salts is selected from a group consisting of hydrochloride, sulfate, p-toluenesulfate, and phosphate.

4. The compound of Claim 1 wherein the metal salt is sodium, potassium, calcium, or aluminum salt.

5. The compound of Claim 2 which is diphenylmethyl 7.beta.-amino-3-[(Z)-1-propen-1-yl]-3-cephem-4-carboxylate and the hydrochloride thereof.

6. The compound of Claim 2 which is 7.beta.-amino-3-[(Z)-1-propen-1-y]-3-cephem-4-carboxylic acid and the hydrochloride thereof.

7. The compound of Claim 4 which is sodium 7.beta.-amino-3-[(Z)-1-propen-1-yl]3-cephem-4-carboxylate.

8. The process for preparing a compound as claimed in Claim 1 which comprises reacting the intermediate of the formula wherein R has the same meaning as in Claim 1, 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 0°C and 25°C to provide a compound of the formula 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) isomers or removing both the benzylidene group and the carboxyl-protecting group to provide the compound of the formula

9. The process of Claim 8 wherein the reaction with acetaldehyde is carried out in the presence of a lithium halide.

10. The process of Claim 9 wherein the lithium halide is lithium chloride, lithium bromide, or lithium iodide.

11. The process of Claim 9 wherein the lithium halide is lithium bromide.