IE59014B1

IE59014B1 - Cephalosporanic acid derivatives

Info

Publication number: IE59014B1
Application number: IE104886A
Authority: IE
Original assignee: Bristol Myers Squibb Co
Priority date: 1985-04-22
Filing date: 1986-04-21
Publication date: 1993-12-15
Also published as: YU43697B; HK106290A; GR861065B; CS287286A2; FI84268C; ZW9086A1; HUT41033A; DK182486A; DK163584C; AU5616886A; OA08245A; HU195223B; BE904646A; NL192205B; IT1228241B; GB8609661D0; LU86402A1; CY1571A; NO861430L; ZA862985B

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

This application relates to 7-amino-3-propenyl cephalosporanic acid and esters thereof..

British Patent Specification No. 1,342,241 published January 3, 1974 (corresponding-D-S. Patent Nos, 3,769,277, and 3,994,884, granted October 30, 1973, and November 30, 1976) discloses the Compound VI but there is no description of 7j3-amino-3ί (2)-l-propen-l-yl]-3-cephem-4-carboxylic acid as an intermediate in the preparation thereof. «9« U.S. Patent Wo. 4,,409,.214 patented October 11, 1983 discloses the preparation of Compound VII via the Wittig reaction on diphenylmethyl 7 -benzylideneaxnino-3-tripheny 1phosphoniomethylceph-3-em"4-carboxylate in Preparations 38 S and 39, but there is no description of ΐβ-&αάτίο-3-[(Ζ)1~ propen-l-yl)-3-cephexn-4-carboxylic acid, nor of another 3 (1-propen-l-yl)cephalosporin compound.

U.S. Patent No.. 4,110,534 patented April 29, 1978 is XO particularly concerned with preparation of compounds such as 571 and vii by the Wittig reaction. Refer particularly to columns 8, 9, and 49 (Example 21).

E- O„ House et al. Jour. Org. Chem.. 29, 3327-3333 (1964) have ‘studied the effect pf solvents and additives including lithium salts on the proportions of cis- and trans- olefins produced in tha Wittig reaction with aldehydes.

This invention relates to- cephalosporin intermediates having Formula I, the synthetically useful acid, addition and metal salts thereof, and to processes for their preparation -3In th© compounds of Formula I, the configuration of 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 groups such as benzyl, p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, and diphenyImethyl (benzhydryl), alkyl groups such as t-butyl; haloalkyl groups such as 2,2,2-trichloroethyl, alkenyl groups such as allyl, 2-chloroallyl, alkoxymethyl groups such as methoscymethyl, 2- (trimethylsilyl) ethyl, trimethylsilyl, tert. -buty Idimethylsilyl, tert. -butyldiphenylsilyl, and other carboxyl protecting groups described in the literature, for instance, in British Patent Specification No. 1,399,086. We prefer to utilise carboxyl-protecting groups which are readily removed by treatment with acid, particularly benzhydryl or t-butyl. The acid addition, salts and the metal salts of the foregoing substance where M is hydrogen are also part of the present invention.

The or cis- configuration of the 3-propenyl group is a critical aspect of the present compounds. This is the characteristic which determines the advantageous Gram negative antibacterial properties of the cephalosporin end products which are the subject of U.S. application Serial No- 564,604.

The synthetically useful acid addition salts Include the -salts of 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 acids known and used In the cephalosporin arts.

Those substances of Formula I wherein R is hydrogen also form metal salts- Synthetically suitable metal salts include the sodium, potassium, calcium, magnesium, aluminum, and sine salts-4™ The mosh preferred compounds of the invention are: 1. Dipheny lmethyl 7 )3-amino-3- ((Z) -1-propen-l-yl] -3-cephem-4carboxylate. j 2, Dipheny lme thyl 70-amino-3-[ (2) -1-propen-l-yl] -3-cephem-45 carboxylate hydrochloride» 3. Dipheny lmethyl 7)S-amino-3" [(2) -1-propen-1-yl] -3-cephem-4carboxylate sulfate. 4. Sodium 7/3-amino-3- [(2) -1-propen-1-yl] -3-cephem-4-carboxylate . Potassium 7/3~aiaino-3-[ (2)-1-propen-l-yl)-3~cephem-410 carboxylate.

S - 7β-Amino-3- [(2) -1-propen-l-yl] -3-cerhem-4-carboxylic acid.

In another aspects this invention relates to processes for the preparation of the compounds of Formula I. Preferred procedures are shown in Reaction Schemes 1 and 2, In Reaction Scheme 1» the dipheny lmethyl group is shown as the' preferred carboxy-protecting group,.. It will be appreciated by those skilled. in the art that other carboxylprotecting 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 lithium iodide j improves the yield and proportion of Z/E isomer of the reaction product Ila. The reaction is preferably carried »5out with 5 to 15 chemical equivalents, preferably 10 equivalents, of lithium bromideMethylene chloride is the preferred reaction medium preferably containing a cosolvent such as dimethylformamide or isopropanol in minor proportions of from about 1/10 to 4 1/3 part by volume per part of methylene chloride. Reaction temperatures in the range of -10®C to +25&C are appropriate with 0® to 25°C being preferred. The wittig product Ila is extracted into a suitable organic solvent such as ethyl acetate and the extract is treated with Girard’s reagent T tb afford the 7-aminoceph-3-em compound of the present invention, la. Refer to Procedure 3 hereof. Subsequent treatment of la with trifluoroacetic acid (TFA) yields 7β~ amino-3- [(2) -l-propen-l-yl] -3-cephem-4-carboxylic acid (Xb e Procedure 7) in the ratio of 2/E = 9/1. Acylation of Xb with p-hydroxyphenylglycine by a conventional acid chloride method or an activated ester method yields the -orally effective cephalosporin V of U.S. application Serial. No. 564,604.

An alternative route, acylation of 7^-amino-3-propen-l20 yi cephalosporin ester la with the N-30C (tert.-butoxycarbonyl) blocked p-hydroxyphenylglycine in the presence of DCC (dicyclohexylcarbodiimide) and followed by deblocking with TFA (trifluoroacetic acid) also yields the cephalosporin V. -6PhCSoC0NH« Scheme 1 Scheme 2 N. ,«,< // -]_ΓΗ=ΡΡΗ COOCHPh,»·., vJL i i Z \ Procedure 3 v PhCH^CONH Procedure 10 ~C3=C5CH~ COOCHPh, IX /Procedure 11 Procedure 5 HOV^ A_ CHCONI \=/ I NHBOC IV \ procedure 6 A/ ce=ch-ce3 COOCHPh, xy-X’S’X, ji ! 1 ί. y ZL /} I COOE -CH-CBMCS.

HO-/* / K. Procedure 9 ·' L v 'CHCON5 ! NH —^s· / COOH BMY-28100 The following abbreviations which appear In the experimental procedures have the meaning indicated below: Ph = phenyl BOC = ~CQOC(GH3)3 DCC = dicyclohexylcarbodiimide TPM, = txifluoroacetic acid EtOAc = ethyl acetate DMF = dimethylformamide Procedure 1 Dipheny Ime thyl._7-^enzylideneaaiino-3-triphenylphosphoni<»aethyl-3cephem-4-carboxylate Chloride To a suspension of dipheny Imethyl 7"amino-3-chloromethyl-3cephem-4-carboxylate hydrochloride (200 g, 0.44 mole) in CH^Cl? (940 ml) was added 1 M NaOH (440 ml) at room temperature The mixture was shaken for 10 minutes and the organic layer was separated. To this organic layer were added MgSOz (75 g) and benzaldehyde (51 g, 0..48 mole) and the mixture was allowed to stand for 3 hours at room temperature. The reaction mixture was filtered and th®. insolubles were washed with CH^Cl«j (200 ml) ... To the 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 diluted with ethyl acetate (1 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 ί (96%). M.p. 185~190eC (dec.). -8IRi KBr 1/ max cm 1780,, 1720,, 1630» UV: xCH2C12 max nm (ε) 260 (24100).

Procedure 2 Diphenylmethyl 7-Benzylideneamino-3- [(triphenylphosphoranyiidene) methyl]3-cephem-4-carboxylate (Ill) A mixture of dipheny lmethyl 7-bensylideneamino~3triphenylphosphoniomethyl"3-cephem-4-carboxylate chloride (322 g, 0.42 mole) and 5 N (252 ml) in CH9C19 (1.6 1) was stirred vigorously for 15 minutes at room temperature.

The organic layer was separated, dried over MgSO^ and concentrated to about 500 ml of volume.. The concentrate was diluted with acetone (1 1) , with stirring,, to give a light yellow crystalline powder which was collected by filtration to yield 237 g (78%) of 3, melting at 195—19.8^0 (dee.).

IS IR: cm"1 1770, 1620. max UV: 10¾¾ nm (E) 254 (23000) , 389 (22000) . max NMR: 5CDC13 ppm 2.56 & 3.16 (2H, ABq) , 5.00 (IH, d, J=4 Hz), 5.23 (1H, d, >4 Hz), 5.47 (IH, d, J=22 Hz), 6.95 (IH, s), 7.2-7.8 (30H, m) , 8.55 (IH, s). -9Procedure 3 Diphenylmethyl 7-Amino-3-( (2)-1-propen-l-yl) -3-cephem-4carboxylate Hydrochloride (la Hydrochloride) To a cold solution of LiBr (19 g, 216 m moles) in a 5 mixed solvent of dry dimethylformamide (100 ml) and CH2C19 (300 ml) were added acetaldehyde (20 ml, 360 m moles) and diphenylmethyl 7-benzylideneamino-3-[(triphenylphosphoranylidene)methyl] -3-cephem-4-carboxylate (III) (15 g, 20 aa moles) at. -5°C. The mixture was allowed to stand for 20 hours at ιθ -5·^-10°Ο and then 5 hours at room temperature. The resulting light brown solution was concentrated fo ca. 100 al 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 isopropyl ether (400 ml) . Silica gel (Wako gel OlOG, 40 g) was added to the mixture. The mixture was shaken for 5 minutes and filtered through a pad of diatomaceous filter aid. Insolubles were washed with a mixed solvent of ethyl acetate-isopropyl ether (1/1, 200 ml)The combined filtrate and washings were concentrated fo ca. 400 ml of volume. A 0.5 M Girard reagent T solution in methanol (SO ml) and acetic acid (S al) was added to the above concentrate and the mixture was stirred for 15 minutes at room temperature. The mixture was evaporated to ca. 200 ml of voluae, washed with H?O (200 ml) , sat. aq.

NaSCO^ (3x20 ml) and brine (20 ml) successively,, dried over MgSO^, treated with charcoal and concentrated to ca. SO ml.

To the concentrate was added N HCl in methanol (40 ml) at <Λ=Ϊ room temperature and left standing for 15 minutes. The mixture was evaporated to ca. 30 ml and diluted by addition of ether (300 ml) . The precipitate was collected by filtration and dried over ~2°5 to give 7.9 g of light yellow powder. A solution of the powder (7.3 g) in a mixed solvent of methanol (80 ml) and ethyl acetate (80 ml) was treated with charcoal, -10concentrated 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 filtration and dried over in vacuo to give -6...3 g (71%) of the title compound. This product is a mixture of the isomers 2 and 2 with reference to the propenyl moiety at the 3 position (2/2=9/1 by HPLC) (Lichrosorb RP-18, 80% ch3" OH - pH 7.2 phosphate buffer, 254 nm, 1 ml/min.)» ca"A 2850, 1785, 1725» 10 °®! λϊ£Η (E ϊ*™’ 287 tl73)· NMR: gDMS0~d5 ppm 1.47 (27/10H, d-d, J=7, 2 Hz, .=CHCH3, cis), 1.74 (3/10Ξ, d, J=7 Hs, =CHCH3, trans), 3-47 & 3.8 (each IH, d, J=16 Hz) ,. 5.13 (IH, d/J=4»5 Ss, 6-H) ,· 5.23 (IH, d, J=4.5 Hs, 7-Ή) , 5.62 (IH, d-q, J=10 £7 Hs, 1S 3~CH=CH), 6.24 (IS, d-d J=l0 S 2 Hs, 3-(¾) , 6.81 (IH, s, CHPH2), 7»35 (1033, m, Ph-H)» Procedure 4 Dipheny lmethy1 7-Amino-3-((Z)-l-propen-l-yl)-3-cephem-4-carboxylate (la? To a stirred suspension of the hydrochloride of diphenvImethy1 7-amino-3— {(Z) -l-propen-l-yl) -3-cephem-4-carboxylate (5 g, 11.3 m moles) in H^O (20 ml) and ethyl acetate (40 ml) 4 was added NaHCO^ until the pH of the mixture became 8» The organic layer was washed with sat. aq. NaCl (5 ml), dried J25 over MgSOj and concentrated to ca. 20 ml of volume. The resulting solution was diluted with isopropyl ether (10 ml) and seeded with crystalline ia. Additional isopropyl ether -11(30 ml) was added slowly to the mixture .with stirring. After' minutes the separated colorless crystals were collected by filtration, washed with isopropyl ether (10 ml) and dried over P90„ in vacuo to give 4.,3 g (94%) of the β title compound (S/E-9/I by HPLC) (Lichrosorb RP-18 80% methanol - pH 7,.2 phosphate buffer, 254 nm, 1 ml/min3 .

IB: cm1 3450, 1765, 1730.

UV:. λ^°Ξ nm (32 15 ) 289 (185) . max 1 cm mn NMS:5 3 ppm 1.43 (3H, d-d, J-2 δ 7 Hz, CH=CHCH3) , 1.66 10 (2E, br, sf disappeared by D^O, NH,) , 3.23 δ 3.55 (each IH, d, J-17 Hr, 2-3), 4.73 (IS, d, J=4.5'Hz, 6-3), 4.96 (IS, a, J=4.5 Hz, 7-H) , 5.46. (IH, d~q, J-10 & 7 Hz, 3-CH-CH), 6.06 (IH, br, d, J«lO Hz, 3-GH), 6.94 (IE, s, CH3?h9) , 7.3 (10Ξ, m, Ph-3).

IS Procedure 5 Dipheny Imethyl 7-[(D)-a-(t-butoxyearbonylamino)-a-(4hydroryphenyl) acetamido] -3-( (Z) -l-propen-l-yl) -3-cephem-4-carbcgylate_ (IV) A mixture of dipheny Ime thyl 7-amino-3-{ (Z) -1-propen-l20 yl)-3-cephea-4-carboxylate (la) (4.2 g, 10.4 mmoles), (D) (t-butoxycarbonylamino)(4-hydroxyphenyl)acetic acid (3.3 g, 12,5 a moles) and DCC .(2.6 g, 12.5 s moles) in ethyl acetate (104 sal) was stirred for 1.5 hours at room temperature. The mixture was filtered and insolubles were washed with ethyl acetate (20 ml) . The filtrate and the washings war© combined and washed with sat. aq. NaHCO^ L (3x5 ml) , brine (5 ml), 10% SCI (5 ml) and brine successively, dried over MgSO^, treated with charcoal and filtered. The -12filtrate was concentrated to ca.. 10 ml and diluted with nheptane (20 ml). The precipitate was collected hy filtration and dried over ?2θ5 ip vacuo. Yield 7.8 g (90% pure, quantitative in weight) as colorless powder (Z/E=9/l based on HPLC) (Lichrosorb HP-18, 80% methanol- pH 7.2 phosphate buffer, 254 nm, 1 ml/min-).

HR - c-Γ1 33-00, 1790, 1720,, l6©0.

SSSX W X m ) 273.(113)» 289 (115), 295 (95)« » CS Slffl S 5°^3 ppn 1.3-X-h5 (123» 3- 30C-3_ & MS-CHg)» 3.08 & 3.33 (e«3s 13» £.» J = l8 Hz» 2-3)» 1.92 &» J = 1-5 Ss, 6-3)» 5-θ6 (13» a, J«6 3s. by 3^0» CgyO ? 5-5 (IH, a-g» J = 10 & 7 Hr» 3-^3=¾)^ 5-68 (13» d-d, J=4.5 & 3s.- a, 1=15.5 Hr by 3^0» 7-3)» 6.01 (23» d, J = 10 Ss» 3-C3)» 6.65 « T-OS ' (ea=h zb. a, J-3 at. ao-Qb 5 .71 (13» 4» 3*8 Hs,disappeared by ^0» 7~3^)» 3, M, „88 (23» s, 1-3 (103» Ea-H).

Procedure 6 BMY-28100? 7- ( (D)-2-Amino-2- (4-hydroxyphenyl) acetamido] -3^ (propen- l-yll-3 ycephemy 4-carboxylie Ac id (V) A mixture of dipheny Ime thyl 7- ((D) -a- (t-butoxycarbonylamino) -«-(4-hydroxyphenyl) acetamido] -3- ((2) -l-propen-l-yl-320 cephem-4-carboxylate (IV) which was prepared in Procedure 5 (90% pure, 7-7 g, 10-6 m moles) , anisole (7..7 ml) and trif luoroacetic acid (77 ml) was stirred for 1 hour at room * temperature. The mixture was concentrated in vacuo.

Toluene (50 ml) was added to the concentrate and the mixture j was evaporated in vacuo« Ether (200 ml) was added to the residual oil. The separated solid was collected by filtration, washed with ether (20 ml) and dried over KOH in vacuo to -13afford 5-3 28100» The salt (5.3 g) was dissolved in H?0 (100 ml), treated with charcoal and placed on a column packed with Diaion HP-20 (0.6 1). The column, was washed with H,0 (4 1) and eluted with 40% aqueous MeOH. The methanolic fractions (1.7 1) 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 filtration, washed with acetone (20 al) and dried over P205 in vacuo to give 4 g (97%) of ΒΜΪ-23100 (2/E-9/1, Zwitterion) (Lichrosorb RP-18, % methanol - pH 7.2 phosphate buffer, 254 nm, 1 ml/min.

Procedure 7 7-Amino-3-J (Z)-1-propen-l-yl]ceph-3-em-4-carboxylic Acid, Xb To a stirred solution of 260 ml anisole and 1.38 1 of trifluoroacetic acid (TFA) cooled to 0®C was added 149.7 g (0.338 mole) of diphenylmethyl 7-amino-3~[(2)-l-propen-lyl]-3-cephem-4-carboxylic acid hydrochloride (0.338 mole, Procedure 3 or 11)„ The resulting slurry was then stirred at room temperature for 1 hour. Most excess of TFA was removed in vacuo on the rotary evaporation. The residual supernatant solution was decanted and th® residual slurry was triturated with 1.5 1 of dry ether during X hour. The crystalline product was filtered and dried·over ?2°5 to give 87.24 g lb 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 4-5aC and then adjusted to pH O.S with 12. N HCl. The yellow solution was charcoal treated and the slurry was filtered oa a diatomaceous filter aid pad. The resulting solution was cooled to 45 ®C and the pH was adjusted to 2.0 with 20% SaOH . The suspension was i kept 1 hour in a refrigerator to aid crystallization. The -14crystals were collected, washed with 800 ml of wafer, 800 ml of acetone and vacuum dried at room temperature- Yield 69.4 g (85-5%). Contains 9..7% of trans isomer (determined by HPLC column RP 18 MERCK? H, (NHJ PO,, 0-1 mole 95 ml t CH3 CN ml; detected at 290 nm) Procedure 8 7-Amino-3- ((2)-1-propen-l-yl) -3-cephem-4-carboxylic Acid, Ib . Κ A solution of the phosphoranyl compound III as produced by Procedure 2 (50-0 g, 68-7 m mole) in CH^Cl^ (500 ml) was mixed with a solution of lithium bromide (29-8 g, 343 m mole) in dry DMF (170 ml) containing a small amount of CH9Cl-, (10 ml) and then with- anhydrous acetaldehyde (39 ml, 687 m mole; prepared from paraldehyde and toluenesulfonic acid by distillation, according to th©.procedure of N.L. Drake and G-B- Cooke, Org. Syn. Col. Vol. II, p. 407). Th© mixture was placed in a sealed vessel and kept at 20®C for 2 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 evaporated to give th© blocked 3-propeny 1 derivative Ila as foamy solid (34 g) , which was used for the next reaction without further purificationThe crude Ila 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 al) » The ©H of the aqueous layer was adjusted to about 3 with 4N NaOH (ca- 65 ml) under stirring to give crystalline solid, which was collected by filtration and washed with water (50 ml) to afford the title -IS30 compound (lb, 9.7 g, 59%). HPLC [Lichrosorb RP-18, 4x300 ram, 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. 200°C (dec.)., IR: (KBr) in cm"1 3420, 1805, 1620.

UV: Xwav (pH 7 phosphate buffer) in nm (£) 28'3 (8900) .

PMR: δ (DoO.+ NaHCOg) in ppm 1.69 and 1.88 (3H, each d, J=S.Q Hz, 2 and E of -03=03-¾) , 3.38 and 3.72 (2H, &bq, J=17 Hz, H-2), 5.18 (IH, d, Jg"7=5-0 Hs, H-6) , 5.51 (IH, d, H-7) , ca. 5.8 (IH, m, -CH=CH-CH3) and 6.06 (IH, d, J=ll Hs, ~CH=CH-CB3).

Anal. Calcd. for C, z C, 49.99; Η, 5.03; Ν, 11.66; , 13.34%.

Founds C, 50.20; Η, 4.94; Ν, 10.93; S, 12.82%.

Procedure 9 7- F (D) -2-Amino-2-(4-hydroxyphenyl) acetamido] -3- ((2) -1propen-l-yl)-3-cephem-4-carboxylic Acid, V Dimethylaniline (1.7 ml, 13.1 m mole) e trimethylsilyl chloride (2.1 ml, 16.4 m mole) and triethylamine (TEA, 2.3 ml, 16.4 a mole) were added successively to a. suspension of lb produced by Procedure 8 (1.58 g, 6.56 m mole) in CH9C19 (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-hydxoxyphenylglycyl chloride hydrochloride ί (1.46 g 6.56 m mole) and the reaction was monitored by HPLC -1610 [Lichrosorb RP-18# 4x300 mm, MeOE: phosphate buffer (pH 7) « :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 BMP (0-1 ml), the resulting clear solution was neutralised with TEA (3.2 ml) to pH 6 and then diluted with CH^Cl, (30 ml) to give a precipitate, which was collected by filtration and washed with CH^Cl, (10 mlj to give the title compound as the dimethylformamide solvate (2.39 g, yield 94%t ca. 50% pure? S/B = 47:12 by HPLC).

Procedure 10 Dipheny Imethyl 7-Phenylacetamldo-3- ((Z)-propen-1-yl) ceph-3exa-4 -carboxylate, IX oS CH^CSO CC14/CH?OH A stirred solution of 18 1 of CCIdl, 1.8. 1 methanol arid 4 g o-benrovl foensoic acid was cooled to 8°C 970 ml of acetaldehyde were added. The temperature of the resulting solution rose to + 14°C. After five minutes, 588 g (0.7749 mole) of diphenyImethyl 7-phenylacetamido-3-[(triphenylphoranylidene)methyl]-3-cephem-4-carboxylate was added. The -17cooling bath was removed and the mixture vigorously stirred for 4 hours at 35°C shaded from light under an atmosphere until complete dissolution of the phosphorane had occurredThe resulting solution was vacuum concentrated and th© residue was dissolved ia 2 1 of ethanol, and the solution was vacuum concentrated to a semi~crystallized residue which was slurried with 3 1 of ethanol.

The mixture was stirred for 2 hours at + 5°C and let stand overnight, crystals were collected twice, washed with ethanol, and vacuum dried at room temperature- Yield 191 g (47%). M.p- 124-128°C contains 7-5% of trans isomer (determined by HPLC column Lichrosorb Si SO 5 pm Merck eluted with 85% toluene, 15% ethyl acetate).

Procedure 11 Dipheny lmethyl 7"Aminp»3» ((Z) -propen-l-yl) eeph-3-em-4" carboxylate Hydrochloride, la To a stirred solution of 159.7 g (0-767 mole) of PCl^ in 2.8 1 CEOC1O were added 56-7 ml (0.700 mole) of pyridine in 280 ml C3^C19 over a 20 minute period- Under a nitrogen atmosphere th® slurry was cooled to 2°C while 256 g of IX produced by Procedure 10.(0-488 mole) was added. The mixture was stirred for 40 minutes and the.resulting slurry was poured rapidly info a vigorously stirred solution of 1-4 1 of CS9C19, and 209 ml (2.33 moles) of 1,3-butanediol at -20°C, so that the temperature did not rise above -5°C. The cooling bath was removed and after 45 minutes the temperature rose to 10°C 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 saturated »18" brine- The combined aqueous extracts were back-washed with 2 x 600 ml of CH?Cl, and combined with the original CH,C17 extract.

The solution was dried over anhydrous MgSO„. The MgS04 slurry was filtered and the MgSO„ washed with 2 x 500 ml CH9Cl2> 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 ©thyl acetate. After air and vacuum drying over P9O„ there was obtained 149.8 g of the title compound as beige crystals. Yield 69.3%.

Claims

1. - A Compound of the formula wherein the 3-propenyl group has the 2-configuration and R 5 is hydrogen ox a conventional carboxy-protecting group,' or an acid addition salt thereof-or a metal salt · of the foregoing substance wherein R is hydrogen.

2. - The compound of Claim 1 wherein R is a group selected from hydrogen, methoxymethy 1, 2,2,,2-trichloroethyl, 10 2-(trimethylsilyl)ethyls t-butyl, benzyl, fiipheny lmethy 1, o-nitrobenzyl, w-nitrobenzyl t trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, allyl, and 2-chloroallvl or an acid addition salt thereof.

3. The compound of Claim 1 or 2 wherein the acid addition £5 salt is selected from hydrochloride,.· sulfate, p-toluenesulfate, and phosphate.

4. » The compound of Claim 1 or 2 wherein the matal salt is sodium, - potassium, calcium, or aluminum salt.

5. Diphenylmethy1 7β20 amino-3-((Z)-l-propen-l-yl]-3-cephem-4-carboxylate and the hydrochloride thereof.

6. .

7. B-Amino-3-[(Z)-1propen-l-yl]-3-cephem-4-rcarb0xylic acid and the hydrochloride thereof. 207,. Sodium 7B-amino-3[(2) -1-propen-l-yl] -3-cephem-4-carboxylate.

8. The process for preparing a Claim 1 which comprises reacting the formula compound as claimed In intermediate of the CS=PPh 3 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, 10 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 henrylidene group or both the bensylidene group and the carboxy-protecting group and, if 15 desired, separating the 3-(2) and 3-(E) isomers to provide the compound of the formula -21Ο COOH wherein R has the same meaning as in Claim 1.

9. - The process of Claim 8 wherein the reaction with acetaldehyde is carried out in the presence of a lithium 5 halide„

11. The process of Claim 9 wherein the lithium halide is lithium bromide. 10

12. A compound of the formula given and defined in Claim 1 or an acid addition salt or a metal salt thereof, substantially as hereinbefore described and exemplified.

13. A process for preparing a compound of the formula given and defined in Claim 1 or an acid addition salt or a 15 metal salt thereof, substantially as hereinbefore described and exemplified.

14. A compound of the formula given and defined in Claim 1 or an acid addition salt or a metal salt thereof, whenever prepared by a process claimed in a preceding claim.