DE1545922A1 - Process for the preparation of cephalosporin derivatives - Google Patents

Description

Dr. Ψ. Do Zurottafn . - Dr. E Attmann Dr. R. Ko * n'g »bereer - DIpI. Phy ·. R. Holzbauer

Dr. F. Zumeleln jun. Ntmlanwilli I Munich 2, Irflubauiitrcö · 4 / III 4Ό / Κ
C 56
2/2/1
P 15 4 * 922.0 Naue full tlndiag

Glaxo laboratories Li nit ed, öreenford, Middlesex / England

as

7öX'fa.areri 2jur production of cophaloaporin derivatives

(Removed from P * tent 1 228 264)

The invention relates to a process for the production of new? Η D β egg derivatives of the 7-amiaoeepMlospor? Uic acid (7-Λ0Α), ie, h, ö.in-ar compound, the structure of which is normally white by the iwichütöhonde Formula is shown:

C CH ₀ OAc

Il

= C V

QO ₂ II

A derivative of 7-ACA, in which a useful an.tib ic table Afcfc.lvI.tHt inobosonderö against grampo-positive organisms as well resistance to attack by penicillins e er ~ It has been found that the bacteria are Ii- (7-Phenylacetamidocf3pb-3 "~ c5j" -3-y2j3etbyl) -pyridinium-4-carboxylate the sewed

BAD OFiIGfWAL

90 9 850 / $ 1 93

m. O mm

, S.

It has now been found that some boron derivatives of this ycrbinlung "Ia Kuaätzltoh ku liejer" Deatilndir ^ koit gCi. ^ EnUber de ^ n In-; r? 1.i'f of? Eniüillir ^ se orsrvagoti'len SfcaykylokoLk ^ n in the i. oiiissii a common activity
i; rauipossitiven or granaegaciven. Own oig-aninmen. Some of these derivatives are also cooked against the attack of the ptjnieilliiiiiae 'otaph, eyed by iitiphylckocci. loccccal pcnicllliiiaae) beotändi ^ er than the compound Ia,

According to the invention are therefore new compounds of the general formula

vurgosohen, in which R ^ is an alkoxy, alkylthio, acyloxy, Acyl, carboxyalkyl, cartaiioyl. Alkyl, hydroxy, amino or substituted Amnosx'uppG or an Ilalogenatom, Rg a hydrogen or a halogenated or an alkoxy, alkylthio, Acyloxy, acyl, carbocyalkyl, carbanoyl, alkyl, hydrocyclic, Amino or substituted amino group and R, üln Vaaserritoffatca or an alkyl, hydroxyalkyl, N-hydroxyallrylcarbamoyl, or

90 98 50/18 9 0 ^{& AD}

Alkanoyloxy groups, where the alkyl units contain at most 4 carbon atoms, and χ denotes 1 or 2, where, when χ = 2, the IU groups do not have to be the same, and when R ₀ does not represent a V ^ oxygen atom, the radicals R ^ and R ~ can be the same or different.

Compounds in which R- is an © amino, hydroxy, carbanoyl, Carboxyalicyl or '^ yloxy group and R ^, hydrogen are particularly important in terms of their activity of interest against gram-negative organisms.

Further compounds according to the invention, which a special applies, nind those of the general formula:

R ₂ tf ^

in which R ₁ - represents an acyloxy or li-hydroxyalkylcarbauoyl group and R .., Rp and χ have the above meaning.

The compounds according to the invention can be prepared by making a connection of the general ϊοπηβΐ

Among other things

8AD

909850/16

- 4 -

(or a water-soluble salt thereof) in which R is hydrogen or the group R ₁ - <^ ^> - CH ₂ -CO-, where R ₁ and R ₂

have the meaning given above, with the exception that instead of amino groups nitro groups are present, with a nucleophilic compound of the general formula

IV

in which R, and ι have the meaning given above, in a strongly polar medium, the resulting compound being reacted with a suitable phenylacetylationa is phenylacotylated medium, if R is hydrogen »and if necessary, the nitro group is reduced to an amino group will·

The preferred embodiment of the method according to FIG. invention comprises the reaction of a compound of the general formula

-CH ₀ -CO-NH-CH,

² 111 III

0 m G Ii ^ i -CUoOAc

in which R. and R.sup.1 have the meaning given above, or a water-soluble salaea thereof, with a nucleophilic compound of the above formula IV in a strongly polar medium. Palis salts ypi \ _XerWind_un ^ cn of Ponael III

909850/1099

been used, β Lud ζ, 13 * iiafcrima--, Ki-. II mn λ; <üulzt) suitable, »J); _: y £ an £ all-'sjn ^ lii gcoi ^ nwfco Mr.-diuu la fc vfiiübvj'vi wtmii however dia uuJcloöphll-j: 7erbi, iiuUii. ·? in Vm. j der i? i.ohä oehr t (): ji L ^ n iijfei kum a uit V / a: ^ sex * iaioohburoti ι. r ;; :, U, .3C> .aj

: -jcii ia generally within YO ⁰ O,

id velclier d & u Povliicbxuln ^ i Λ sz Iloaktton a Jijan ^ -n- shall be, üiiiigt 70η des ¹ aii ;; ev /; ii; viet; uji T ^ ipoxatUi ¹ ab nvä) i - mi , eüo ^ h 'isircii yot / versu ·. Le 1>ΐ> ο f; ίιγιτ, χΐ:; ■ / «> · idem.

Tortel'lhaiic la a variety of 'Ua! il \>! equivalent ö'-c connection III aul ¹ 1 Did ίΰ HoluiUiAv "ilen.be der imklaüphlleii Vorbinduuf, IV rerwendöt;. Dex * Wrirt the T / iirmfi becomes' /» rteiihafi; within do · "· Bereliilum ^c i biu 8, possibly 6 lilac 7 »upright: - !!. Srforderlielienfallß aoll the pj.-V / type of löaung duroli i-> u ^ abe öLnos PuJffermittele, s "B, Ammonlumaoetat or Falla a Alkalieala the ¹ / '> ^ represents ibindun general Fomel III is used, by, for example, to display Esöigaüure to the "respect" n. Worth olr _ib -ei; to be leveled.

D: ut fteaktio-naurodukt can from the Reaktiouamiijchun ^, the beiurmmgeaetate Connection of the Ji'ormül III uml andare

BATH

909850/1199

xi contain ι. k-üin, with -UiIu gobiauchliciher work »- "Reitien, like Kriiital / liaation,!", Lek ^ i / oohnr ^ ae, Papissrchromato- *

iivtiyiil-ά or duroh LoheiuUu »/ '-. j! tt ^ ig rtrtmttt

; ;] fi wi'l ün is practicing

uui ^ / on ϊ · 0Γ: · '- ι] Γ ^Γ ii) L *, lei ¹ '/.i/bi.nd'.iu;:'αα FotüJjl III λιι ^ iijje: ¹ U'jigisnotL. ^! _a , hi j t'.i: ", · ■■ κ *; ·; ilü Auc'i'Uto nn dej · Vorhtn« <iun.;i; iet erwiiuaohfcun Verb? αlun-t II received iab, D ^ r Excess ■ / Oü Yurbiitduiii-, IV tmd f?!; - fii. "Uini.i = -; oactstj connection HT wüedyn ■ ' ⁿ .u'i 1.1 i h oiuem urgajii.MCiu> a LiiMU _; ;; Jii; it to.l, 2.ß, Hv uiy lurrhJcrii, '.ii'.i-'iihiept and the reiiilLoiie glueing üur h ei.n \ ii.loiieiiuusbauiichhü » ^!; :;, 3,1), in an Aoefc-iliormr durühoL- krern ^ elaooen, um irgen <l · * .floh »; ; Teia Carupnaäurtj / erbindungen, e'.nochl iess-Ic h dem Reot dar uauir. ^ Iäoetaten. Compound III. The zurüokblöi · - Louun ^ will then beiapieJ.rH / oisd in eiiioia Rot'iry-Ver-lampfer

and (Tei.L'ior / ^ jtrockriot The residue can then \\ _w;.> iiüin suitable Loei-Rinßsmitfcel, for example, methanol crystallized ■ xiör ilit, teis Auofällung, belBpteloweiae ouch a methanoliachen L5aung by Zuaats tone acetone, cleaned .

The previous formulas of the formula III given above can can be produced by reacting 7-ACA with a ceoign besides Pheny Iac control agent. Suitable phonylacetylation ambel are in general oolchö, which Eur Phenylacetyll «h ~ tion of. Aminoainiden., E.B. Psptidoii, are suitable, odor inalogan and include in particular Phenylacefcy! halideβ,

909850/1699

preferably) the chloride or bromide, and mixed anhydrides, which 2.B. derived from phenylacetic acid and an alkyl haloformate. The acylation is conveniently carried out in an aqueous medium. for example an aqueous, water-miscible ketone, for example acetone or aqueous tetrahydrofuran, preferably also in the presence of an acid-binding agent, for example lithium bicarbonate. The p ^ -Vert is preferably in the range between 5 and 7 during the reaction which can be carried out at temperatures from 0 ° to 25 ⁰ C, is maintained. The acylation can also be carried out in a medium consisting of an organic solvent, for example ethyl acetate, for example by maintaining reflux conditions.

The compounds according to the invention can, on the other hand, be prepared be done by first making 7 "ACA with the chosen nucleophyll Compound of the formula IV to form a compound of the general formula

reacted, in which R, and χ have the meaning given above, whereupon the compound obtained is acylated with a suitable Pfcenylacetylierungsmittol. These reactions can generally be carried out under the conditions described above for the nucleophilic compound wetting and acylation reaction, with the preferred order of execution being used.

909850/1699

Alternatively, the compounds of Pormel V can be made from a compound the general formula

HOOC-CH- (CH,), -CONH-ClI-.
ι 2 5 j]

0 »C --— Ν • J-.CH ₀ F ^ ^ TI

are prepared, in which R, and χ the meaning given above, using known procedures for the conversion of cephalosporin C to V-ACA. The compound of the formula VI can also be prepared by reaction with nucleophilic compounds of the formula IV according to procedures which are analogous to those described for the reaction of compounds of the formula III with compounds of the formula IT.

You special quaternary ammonium compounds here are described with reference to the substance cepham (cf. J.A.C.S. 1962, 84, 3400).

The invention is explained in more detail below by means of examples ringing place. Ultraviolet absorption refers to solutions in water or aqueous phosphate buffer at p "6.0.

a.

The paper chromatography in Examples 1b and 8 was used on Vhatman Hr. 1 paper, buffered with 0.1m liatrium acetate (Pjj 5) executed, üaa solution system consisted of (volume parts in brackets) ethyl acetate (3), n-eutanol (1), 0, Im-Natriuiaacet & t (8th); the direction of travel was downwards.

90flAfiiWiftOö ^BAD

On the other hand, papiorcliromatography * 3bf »rifal3-B was performed on Whatman No. 1, where L enbv / edor on Pjj 6 using ώίηο» solvent iijra'jßJBn from n-butanol (4, * f Wiiseaρ (5) »Ethanol (I) or on p _a >> using

tfiL buffered w & l *.

] *). 1'ϊ Εΐ-ϊΐ ¹ ; fcrophorooo wiirdu * on / ha transformer 3MH-PiI pi er -en 1) lI a fall or gradient of 10 to 30 V / oui on ^ e trip; Bio i'u.t'ftn.'lungen were (VoLn'iaenteLlo in KlaraMern): ^) Pjj l »9i acetic acid (Ω4), Aiii-iLiJüiinäurö (17)» acetone (103) imd Vaifjjjor (495) and b) p "7i 0.05 Bi-Diniitrlumiiydro ^ enphoopliat, where bat d for p""value. with Phoaphorfj / uire ö ing 'ml? llt w: ar.

* io ΡλϊΙγ i? '- τ "in ttvf PapiHi'iiliromabograatmon t Eiektrophoreto- ^ nd ^ .iv Ken were άΙβ dunkl" Flöokon feetgoflteilt when the patent iteve were irradiated with ui ^ ra ^ tolettem Idchfc.. Zwitterionon yeasts a? If- the basis in electrophoresis with a p ^ word voii 1, ¹ Jj. aic were not moved if the p »j ~ ¥ ert 7

Stirring turned into a solution γόη 7 -'- ΓΑ (20 g) and 25 g

bio-carbonate in aqueous icetone (60 $, 400 ml), - ■ which was kept at 0 ⁰ C., ^ Hethoryphenylacetylchlorid (15 g) in (JO?) ei) added for a period of τοη 10 Hinaten *

DIo Roakt; v-ni ?? ai «<5haiag mirde for another 40 minutes at 0 I iitvw I» ? itifi at Ra au tempera door, whereupon the acetone

Bruek was removed, BIq aqueous solution

90985 0/1699 BAD original

v / uai ·.) washed with DläthyiHt'i - 3r (100 ml) and with concentrated hydrochloric acid to a value of 1 ai? (three! I 50 ml), dao Atu.yiaeet, i :, vnu Ie jjut with V / asaei * gevr-inchen and About NaferLuiisnuICal. ^ jt: uoknet- 'kin [r5f.un.goiali, t9L rfiirdt i * bdefSinhiiu , ^v ^ i.iJ -: 1a! J VoIu lsn 100 ml botfa _; j ui.d diü Lönu / ΐέξ vmrdo boi O ' ^J ''i ti tohoxi ^ ü La j Hm, K.ri- «ballo of V-Cp-Mothoxypiienylaceta.'tiiltj) ■ • 4iepiirvlt-.' ^ oi. \ Ani '' ■■ '. ir «are gel; .ii _t i: a> jl, t iitid 1 hour long sr I -VO ⁰ O dried,

Outside office U ₁ O ä (4Y = 2 p)

(using TittatLo ^) s · - 1-20: 0,. H ₀ ^ u ₇ K ₉ G

requires 420

lL ^{at 262 ra} / ^{L (E} Ü ^K

The next few hours of substituted l-honylacetamidocephalooporanic acids were produced in UhnlLoher V / oLse & un T-AGk

Example! Aua- R- ^yA nax _E 1> i equiir

lir. Subotituent booty for rough. 1cn ber.

rough.

2a p-acetoxy 84.5 0.63 260 190 448 454

3a p-Pluor 82.2 0.75 260 204 408 409

4a p-chlorine 90 0.70 260 204 425 427

5a p-bromine 84 0.85 (§25 (333 469 470

432

6a p ~ Acotyl 76 0.7? -? -52 5bt 551 445 7a 3.4-ltt! S3thoxy 73.3 0.53 |||| [| ^ f 450 450

¹ butanolaysten

Example l 1b

!! - / "'T-Cp-Me
pyridirLLiun-4-carboylate

4.73 ml of pyridine (5 equiv.) Were added with stirring to a suspension of 7- (p-methojcyphenylacetamido) -cephalospioanic acid (5 g) in 45 ml of water. The acid dissolved to yield a solution with a PJJ of 5 »7 · This solution was maintained for 16 hours under STII Vstoff at 46 ⁰ C and then with methylene chloride (4 x 20 mL) extracted. The solution, after concentrating in a rotary evaporator at 40 °, when all methylene chloride had been removed, was passed downwardly through a column of Dowex-1 ion exchange in the acetate circulation or cycle. The eluates containing the desired pyridine derivative (as determined by polarimetry) were pooled and subjected to freeze-drying. Trituration of the freeze-dried solid with methanol (approx. 5 icJL) gave the pyridine derivative in the form of a white solid (1.174 g, 258 m / i (E ₁ ¹ J _1n 327), ^ Z- + 70 ° (c 1.0), .

Pyridine ^1f0 ^ ^#

Analysis t (C ₂₂ H ₂₁ H ₅ O ₅ SOjSH ₂ O)
found i C 58.4 H 4.9 H 8.8 S 7.1 %
ber.s 58.9 4.95 9.4 7.15 Ji.

Similarly, the following pyridinium derivatives were prepared from substituted phenylacetamidocephalosporanic acids.

09850/1699

Example yield -Λ max E ₁ ^

No. Substituent $ rough

2b p-acetoxy 49 258 198 0.00 0.70 3b p-fluoro 13.6 260 200 0.00 0.65 4b p-chlorine 23.2 259 170 0.00 0.52

5b p-bromo 37 [|| § [H \ 0.00 0.40

6b p-acetyl '2.3 251 551 0.00 0.18

7b 3,4-dimethoxy 42 [i; 30 [^ O _{OJOO Q} ^ ₃

it)

'Ethyl acetate system

'R- the original CephalOBporanaaure

Example 8

-£ ~ 7- (p-lle thoxypheny Iac etamido) -ceph-3-em-3-ylnethyl_ _p 7-2 'methylpyridinium-4-carboxylate

ot-Picoun (5.55 ml »about 5 equiv.) was added with stirring to a suspension of 5 g of 7- (p-kethoxyphenylacetamido) -cephaloaporanaic acid (prepared as described in Example 1a) in 45 ml of water; the acid dissolved to form a solution with a p "of 6.6. This solution was left to stand under nitrogen for 16 hours at 46 ° C. and then extracted with methylene chloride 4- χ 20 ml). After concentration, the solution was passed into a rotary evaporator <T40 ° C. through a column of Dowex-1 ion exchange resin in the acetate circulation stage or in the acetate cycle downwards. Pie eluates which contained the desired * -picoline derivative (determined polarimetrically) were torn down and subjected to freeze-drying. A solution

909850/1699

Ate freeze-dried material in one mlnUiiaen volume of ethanol (about 2 ml) was slowly increasing . a large volume of acetone (about 500 al) which was stirred magnetically. As a result of this work, the ec-pieoline derivative required was precipitated in the form of a fine, white-discolored peatatoffea (937 mg, 17.9 *>, X _mx 265 nyi, (e] ^ 316), f * J _D + 122 ° (c , 0.96), R ₇ ^ _pACA

Analysis.; (.Co ₃ Hg ₃ IT ₃ OrS · PlI ₉ O)

ber .: C 56.4- ZI 5.5 IT 8.6 S 6.5 Ji

gof.i 56.3 5.5 3.8 £ 6.8

Beiopiel ^ g

^ "" C 7-p - ÄJainophenyla cet ami do) -c eph-3- em-3-y Ims t hy 1_7-pyr idlniuia- 4- car boxyla t

a) p-nitrophenylessig3 acid was converted into its acid chloride and condensed with 7-ACA to form 7- (p-ftitrophenylacetamido ·) -cephalosporanic acid to achieve in 85/6 yield,

b) 7- (p-Hitrophenylacota! aido) -cephalosporanBäure (5.0 g) was dissolved in wäJßrigem pyridine (10 Ji, 50 ml) and reacted at 50 ° for 16 hours · The resulting solution was χ with Dichlornjethan (2 30 nl) washed and applied to a column of ion exchange resins (Dowex-1, acetate circulation or cycle, 100 ml). The column was removed with water-washed and the Eluatö, which accounted for a total of 350 ml, were pooled and subjected to freeze-drying, wherein said pyridinium derivative (1.80 g, 34 ^) was obtained _t

BATH ORIGINAL 90 9 8 §0 / 1 6 9 9 '

262 to 263 m / i _for JJ * «300 (aqueous solution 0.002

/ ι CuI

R- (ethyl acetate system) * 0.00.

c) K- £ ~ 7-

Nium-4-carboylcylate (1.0 g) was dissolved in water (20 ml) and the solution was in the presence of hydrogen at a pressure of about 4.22 kg / cm '"(GO p, ji) of palladium on charcoal (5 £> 1 | 0 g) for 5 hours. The catalyst was removed by filtration and the clear filtrate was freeze-dried, whereby !! - / ^ - "(p-Aainophenylacetainida) ceph-3- em-3-ylethylethyl pyridine-4-carboxylate (400 mg 42.8 %.

■ ^ 242 m / u max E] J _1n * 250

χ ^{; lcm} .-> (aqueous solution 0.003 %)

^A 268 m / U inflexion E ^ = 168

R- (butanol and ethyl acetate systems) «0.00

Example 10

N-2C7- (p-Hydroxyphenylacetamido) -ceph-3-em-3-ylmethyl-7-pyridinium-4-carboxylate

7- (p-Hydroxyphenylacetamido) -cephalosporan3 acid was, as described in Eeiflpiel 9, converted into the pyridinium derivative, a yield of 24.5 / * being obtained. ^ 258 a / i max. BJ ^ * 215 (aqueous solution 0.0025 "" R- (XthylacetÄtsyatem) »0.00.

909850/1699

Example 11

K ~ / ~ 7 ~ (p-methylphenylac ο tami do) -c epli -? - a-j5-yliae thyI _- T-pyrIdinium-4-carboxylate

p-Methylplicnylessißoäure (0.55 g) was converted into its acid chloride and condensed with 7-ACA (1.0 g) in aqueous solution in the presence of excess sodium bicarbonate to give 7- (p-Methylphenylscetamido) -cephaloflporanic acid (1.10 g To give 73 1A.

^ • 255 m / u max. E ^ _n , = 255 (Hethanol solution 0.003 f) R _£ (Butanolayotem) = 0.79

7- (p-Methylphenylacetauiido) -eephalosporanoic acid (0.9 g) was added to dac pyridiniunderivat converted in the manner described in Example 9, a yield τοη 21> »was obtained.

in / U max. E ₁ ^ «= 255 R ^ (ithylaeetatsystem) ■ 0.00

Example 12

y- / ^r * 7- (p-carbamoylp, henylacetamido) »ceph» 3-em-3 ~ y! methyl 7-pyridinium-4-carboxylate

p-Carbamoylphenyl acetic acid was produced by the method given by Mellinghoif, Bor. 2g, 3207 (1889). The reaction with thionyl chloride gave an impure acid chloride which 7- (p-Carbamoylpheny / acetamido) -cephalO3poranäure ale crystalline Peetetoff (15.7 2) on reaction with 7-AOA.

BAO ORIGINAL 909850/1699

Λζ34 mix max. Bl ^ _n ■ 434 (Hatriumsale in

_λ ' ^1cm _Λ4 Waseer 0.002 <f> ^ 260 n.fx height (plateau) Ej £ _a * 243

R _f (butanol syotem) »0.39

7- (p-Car1) amoylphenylacetaiaido) -cep3ialoeporaneäure was, like described in Example 9, converted into the pyridinium derirate, a 34 # yield was obtained

0 myu max E ^ _m a 412 (aqueous solution 0.002 <f>) (ethyl acetate ytem) «0.00.

Example 13

H "/" * 7- (p-methylmercap tophenyla.c etamido) -c eph-3-eia-3-ylmethyl _- 7-pyridine-4-carboxylate

1.6 g of p-Methylmercaptophenylessigsäure (P 99 to 100 ⁰ C) was converted to the acid chloride with thionyl chloride and 1-old KCK (2.0 g) is condensed in aqueous acetone in the presence of excess ITatriumbicarbonat. 2.7 g of 7 ~ (p ~ methyl mercaptophen / laoetamido) «cephaloiporanoic acid were obtained in 84.4% yield.

■ ^ 260 ayu maz. l] J _a - 505 (tfatrlume & ls in water 0.002 Jt) R ^ (butanol system) «0.82

7 ~ (p-Hethylxaercaptophenylacetamido) -cephalosporaneaur · was converted into the tyridinium derivative in a yield of 31 % »

Λ256 Ä ^ a max. E ^ _m «395 (aqueous solution 0.002 Jt) & £ (ithylacatatsystoa) * 0.00 ·

90 98 50/1699

Example 14

lT- ^ ~ 7-Carboxymetbylpliönylacetaniido) -ceph - 3-eEi-3-ylittetliyl _- 7- 'pyridinirm-4-carboxylate

Benzene-p-dieesiga acid (3.4 g) was refluxed with dhionyl chloride heated for 2.5 hours and the thional chloride was removed. The acid chloride was mixed with 7-ACA (4.0 g) in Presence of a supernatant τοη ETatriuiübiearbonat in aqueous Acetone condenses, leaving 3.6 g of 7- (p-carboxyniethylphenylacetamido) -cephalosporanic acid (54 »7 ^) in" form of a white kriatallinen Pestatoffes were obtained.

• ^ 262 m / a max. BJCL ^{a 220} (liatrium salt in water 0.005 ^) / ι cd

R _f (butanol system) «0.19

7- (p-Carboxymothylphenylacetaiaido) -ceplialossporansUure was converted into the pyridine derivative, as described in Example 9, (omitting the ion exchange treatment) with a yield of τοη 73 f » .

^ 256 m / u aax. EJJ _n «185 (aqueous solution) R ^ (Butaliisystem) == 0.10.

£ eJ3plel 15

% ~ £ ~ 7 ~ (p-Ac etoxyphenylacetaoido) -ceph-3- ^ m-3 ~ yl ^ et '^ yl7-4 * -

4.0 g of 7 ~ tp ~ acetoxypheny! Acetamido) -cephaloeporan £ äüx @, "Flcolin (4> 0 ml) and 36 ml Uaoaer \ * urden at 50 ⁰ C for 16 hours UTBgsfletst, The cooled solution was diluted with Waoser ( 20 ial) and washed with liethylencülorid (2 χ 30 al). The aqueous phase

90 9 8 50/1699 BAD ORIGINAL

was separated from a small amount of gum and placed on a Column of Dowox-1 ion exchange hara in the acetate cycle brought; the column was washed with water, the eluates were collected (total amount 250 ml) and boiled to 5 ml under reduced pressure. The concentrated aqueous solution was made with methanol (5 ml) and poured into acetone (500 nl). The white precipitate was collected with acetone and diethyl ether washed and dried in a desiccator.

Yield 1.43 g ( $ 33.2>)

λ 256 m / U max "E ^ _a '" 242 (0.002 £ in 50% aqueous methanol)

H- (ethyl acetate system) * 0.00.

Example 16

H- / ~ 7- (p-Ace toxyphenylacetaido) -c epb-3-em-3-ylmethyl 1..7-2 'methylpyridinium-4-carboxylate

This compound was prepared according to the procedure described in Example 15.

Yield 35 » $ 1

- ^ 263 Π / U max. To ^ »260.5 ( $ 0.002 in 50% aqueous 1 ^cm methanol solution)

R- (Ethyl Acetate System) β ο, 00.

908350, '' 1S9S

Example 17

N - / "" 7- (p-AcetGxyohenylacetaaido) -ceph-3-em-3-ylinethyl_7-2 ', 4 * - dimethylpyridinium-4-carboxylate

This connection was made according to that described in Example 15 Working method established.

Yield 34.8 %

^ 262 m / i max. & _Λ '* »250 (0.001 $> in 50 ^ aqueous methanol)

R _f (ethyl acetate cystera) * 0.00

Belüpiel 18a

N - / "* 7- (p-Hitrophenylacetamido) -ceph-3-em-e-ylmethyl _- 7-N ^t , 4-hydroxymethylcarbamoylpyridiniuin-4-carboxylate

10.0 g of 7- (p-liitrophenylacetamido) -cephaloeporanoic acid were added in warn water (120 ml), welciise N-hydroxymethylisonicotinamide (7.0 g) contains, dissolved and the solution was kept at 50 ° for 17 hours. When the solution was cooled, it was with Methylene chloride (2 50 ml) and washed on a column of Dowex-1 ion exchanger applied in the acetate forum. she Column was washed with water (250 nl), the water except for 10 ml distilled off under reduced pressure and carefully in Poured ethyl alcohol (400 ml).

acid·
The K-hydroxymethylisonicotinamide derivative was collected, washed with ithanol and also with diethyl ether and then dried.

Yield 2.27 g (18.7 ^) - -

χ _H ßÄD ORIGINAL

267 »/ u nax. IqJ _n »327 (0.003 i> in Viaeoer)

909850/1699

R- (butanol system) * 0.40

R _f (Ethylacetateysteia) «0.00

Example 18b

N- / ~ 7- (p-Aminophenylacetatamido) ceph-3-em-3-ylniethyl _Ä 7-li · »4'-hydroxymeth.yicar'bamoylpyridinium-4-car'boxylat

N- / ~ 7- (p-llitroplienylacetaraido) -ceph-3-em-3-ylmethyl__7-H., 4'-hydroxymethylcarbamoylpyridinium-4-carboxylate (1.95 g) dissolved in water (100 ml) and in a Y / aeseratoffatmosphäre at a pressure of about 5.22 kg / cm · (GO paig) in the presence of palladium on carbon (10? 6 id, 2.2 g) for 5 hours shaken. The filtered solution (which was almost colorless, but slightly darkened when exposed to air) was freeze-dried, and the obtained Feotstoff was precipitated from aqueous acetone, whereby the amine was obtained «

Yield 880 mg (47.9 1>)

^λ 241 «yu max. E] J _m > 252 (0.005 t in Waeeer) .....

^ 260 to 270 mfx inflexion »215

R- (butanoleyetene) «0.07 Rf (ithylacetate system) ■ 0.00

3elopiel 19

N- / "7- (p-Hydroxy pheny Iac e tamido) -c eph-3-eE-3-yliae thyl _e 7-H '♦ 4-hydroxymethylcarbamoylpyridinium-4-carboxylate

7- (p-Hydroxyphenylacetamido) caphaloaporanoic acid (4.72 g) was obtained dissolved in acetone (5 ml) and added to a solution of 1-hydroxymethyliaon / cotinic acidoamide (3.66 g) in water (35 ml). Tue «

909850/1699>. ⁶ ^ ofu _Ginal

1-54592 *

Mixture was held at 50 ° for 27 hours and cooled calmly. After washing with methylene chloride (2 × 25 ml) was the aqueous solution is placed on a column of Sowex-1 ion exchange resin in the acetate form and then replenished with water rinsed (250 ml). The aqueous solution was collected, distilled to 10 ml under reduced pressure and converted to acetone (300 al) added, the ff-hydroxymethylisonicotinamide deriYat was obtained as a very fine precipitate.

Yield 0.783 g (13.5 t)

^λ 263 mja max.SJ ^ - 240 (0.003 t in water)

R _f (Äthylacetatsyatem) * 0.00 (starting material R ^ »0.09) Example 20

H - / * 7- (p-Ac e toxyphenylace tamido) -c eph-.3-em-3-ylnio thyl_7-lf ^f * 4 '-hydroxymethylcarbamoylpyridiniuiB-4-carboxylate

7- (p-acetoxyohenylacetamldo) -cephalosporanic acid (8.8 g) with N-hydroxymethylisonicotinic acid amide (6.15 g) as described in Example 18a, reacted to give the Jf-hydroxymethylisonicotinic acid amide derivative.

Yield 2.32 g (21.9 t)

^ 264 »AX max · E ^ _n « 218 (water 0.003 %)

R _r (Xthylacetateyatea) «0.00

^x (starting material B _f «0.70)

R _f (butanol system) »0.18

Example 21a 7 (jCp-Valeryloxyphenylacetamido) -cephalosporanic acid

p-Yaleryloxyphenylacetyl chloride (50 g) was dissolved in acetone (20 ml) dissolved and added dropwise during an acidic period of 5 minutes a solution of 7-ACA (5 * 0 g), I sodium bicarbonate (6.25 g) » Aoeton (42 ml) .in Wasaer (62 ml) added with stirring, whereby the solution was kept at 0 ° during the addition

The solution was stirred for 1 hour at 0 °, during one Allowed to warm to room temperature for a further hour and then the Acetone removed from the reduced bridge. The aqueous residue was washed with ethyl ether (2 25 ml) to a p ^ value of 2 adjusted with hydrochloric acid and then the cephalosporanic acid ii Ethyl acetate (3 x 100 ml) extracted. The ethyl acetate solution was washed twice with water and dried with sodium sulfate 25 ml concentrated under reduced pressure and poured into petroleum (b.p. 60 to 80 °, 500 ml). 7- (p-Valeryloxyphenylac.etamido) -cephalosporic acid 'was collected, washed with diethyl ether and dried

Yield 7.2 g (£ 00.0)

Λ 262 du max. Ε] £ _β * 183 (methanol 0.003 50

Rf (butanol system) * 0.88. (Ethyl acetate system) x 0.56

909850/1699

Example 21b

H- / f "7- (p-ValerylpxyphenyIacetaraido) -ceph-3-em-3-yinethy1-7-pyridiniuin-4-carboxylate

7- (p-Taleryloxyphenylacetaiaido) -cephälooporanic acid (7.0 g) was dissolved in water (63 ml) which contained pyridine (7.0 ml) and the solution was ^{reacted at 50 °} C. for 17 hours. When the suspension was cooled, it was washed with methylene chloride (2 × 30 ml) and the aqueous phase was separated off and poured onto a column of Dowex-I ^ ion exchange resins in the acetate cycle. The column was eluted with I / aucer, and the combined water eluates (250 ml) were distilled to dryness under reduced pressure. The residue was dissolved in methyl alcohol (15 ml) and poured into acetone (300 ml). The pyridinium derivative was mixed, washed with diethyl ether and dried.

Yield 0.430 g (6.0 ^)

^ 250 mAi max. EJ * _n «206 (water 0.003 fi)"

R _f (Äthylacetataystem) «0.00 (cp starting acid R * ■ 0.56)

R ^ (dutanolsyatom) «0.25

In the following. Table are the biological properties dor compounds prepared in the examples carried out. Dta staph. aureuB strains A and C were resistant to penicillin, while strain B was sensitive to penicillin was.

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Claims (23)

- 25 - Claims 1. Derivatives of 7-Phenylacetamidocephalosporinsaure the general my formula ^R i- <T ~> - ^CH ₂ - ^C0 - ^WH - wherein R ,. an alkoxy, alkylthio, acyloxy, acyl, carboxyalkyl, Carbamoyl, alkyl, hydroxy, amino or substituted amino group or a halogen atom, . Rp is a hydrogen or a halogen atom or a Alkoxy, alkyl thio, acyloxy, acyl, carboxyalkyl, Carbamoyl, alkyl, hydroxy, amino or substituted amino group, R ^ a hydrogen atom or an alkyl, hydroxyalkyl, N-hydroxyalkylcarbamoyl or alkanoyloxy group mean, wherein the alkyl parts do not have more than 4 carbon atoms included and χ the number 1 or 2 means, where, if χ = 2, the R groups are not the same must be, and if Rp does not represent a hydrogen atom, the radicals R ^ and Rp can be the same or different " 2. N- / ~ 7-Cp-methoxyphenylacetamido) ~ ceph ~ 3 ~ em-3 ~ y! Methyl 7-pyridinium-4-carboxyiate. 3 '. N- / 7- (p-acetoxyphenylacetamido) -ceph-3-em-3-ylmethyl 7- pyridiniuni-4-carboxylate. ^ __ ^ - - _{t Kl} ,,, .., BAD OHiGmAL New documents (Art. 7, Paragraph I, Paragraph 2, No. I, Clause 3 of the amendment from 4.9.19871 . 909850 / ί69 9. Ii * * t - 26 - 4. N- / ~ 7- (p-Fluorophenylacetamido) -ceph-3-eni-3-ylmethyl-7-pyridinium-4-carboxylate. 5. N- / 7- (p ~ chlorophenylacetamido) -ceph-3-em-3-ylmethyl 7-pyridinium-4-carboxylate. 6. N - / "" 7- (p-Bromophenylacetamido) -ceph-3-em-3-ylmethyl-7-pyridinium-4-carboxylate. 7. N - / "* 7- (p-Acetylphenylacetarnido) -ceph-3-em-3-ylmethyl_7- pyridiniurp-4-carboxylate. I. 8. N- / ~ 7- (3,4-Dimethoxyphenylacetamido} -ceph-3-em-3-ylmethyl-7-pyridinium-4-carboxylate. 9. N - / "" 7- (p-Methoxyphenylacetamido) -ceph-3-em-3-ylmethyl 7-2'-methylpyridinium-4-carboxylate. 10, N - / "" 7-p-aminophenylacetainido) -ceph-3-em-3-ylraethyl-7-pyridinium-4-carboxylate. ι 11. N- / ~ 7 (p-HydroxyphGnylacetamido) -ceph-3-em-3-ylmethyl_7 ~ pyridinium-4-carboxylate. 12. N - / "" 7- (p-Methylphenylacetamido) -ceph-S-em-S-ylmethyl 1-7-pyridinium -4-carboxylate. 13. N- / ~ 7- (p-Carbamoylphenylacetamido) -ceph-3-em ~ 3-ylmethyl 7-pyridiniuiTi-4-carboxylate. 14. N- / ~ 7- (p-Methylmercaptophenylacetamido) -c'eph-3-em-3-ylmethyl 7-pyridinium-4-carboxylate. . 15. N- / ~ 7-C? _l rboxymethylphenylacetamido) -ceph-3-em-3-ylmethyl_7-pyridinium-4-carboxylate. - 909350/169 16. N - / "* 7- (p-Acetoxyphenylacetamido) -ceph-3-em -3-ylmethyl_7-4'-methylpyridinium-4-carboxylate. 17. N- / "" 7- (p-Acetoxyphenylacetamido) -ceph-3-em-3-ylme thy 1__7- 2 · «methylpyridinium-4-carboxylate. j 18. N - / "" 7- (p-Acetoxyphenylacetamido) -ceph-3-em-3-ylmethyl__7- 2 ¹ _t 4'-dimethylpyridinium-4-carboxylate. ' 19. N - / "" 7- (p-Aminophenylacetamido) -ceph-3-em-3-ylmethyl-7-, N ¹ j4 '-hydroxymethylcarbanioylpyridinium-4-carboxylate. 20. N - / * "7- (p-Hydroxyphenylacetamido) -ceph-3-em-3.-ylmethyl__7-N ·, 4'-hydroxymethylcarbamoylpyridinium-4-carboxylate. 21. N- / ~ 7- (p - acetoxyphenylacetamido) -ceph-3-em-3-ylmethyl_7- N ', 4 ^l -hydroxymethylcarbamoylpyridinium-4-carboxylate. j 22. N- / ~ 7- (p-Valeryloxyphenylacetamido) -ceph-3-em-3-ylmethyl 7-pyridinium-4-carboxylate. 23. Process for the preparation of derivatives of 7-phenylacetamidocephalosporic acid the general formula o = - ^N -CH. -W ^ XN ₁ II wherein R .. is an alkoxy, alkylthio, acylcxy, acyl, carboxyallcyl, Carbamoyl, alkyl, hydroxy, amino or substituted amine or a halogen atom, ORIGINAL 909850/1699 Rp is a water or a halogen atom or a Alkoxy, alkylthio, acyloxy, acyl, carboxyalkyl, Carbamoyl, alkyl, hydroxy, amino or substituted amino group, R ~ a hydrogen atom or an alkyl, hydroxyalkyl, H-hydroxyalkylcarbamoyl or alkanoyloxy group · ■ - - - mean, wherein the alkyl parts do not have more than 4 carbon atoms included, and. χ the number 1 or 2 means, where, if χ = 2, the R., groups do not have to be the same, and if R ₂ does not represent a hydrogen atom, the radicals K. and Rp can be the same or different, characterized in that a compound of the general formula Ha -CH ₂ OAc wherein R is a hydrogen atom or the group -Cli ₂ -CO- means in which R _{1 is} an alkoxy, Alkylthic, acyloxy, acyl, carboxyalkyl, carbamoyl, alkyl, hydroxy, lutro or substituted amino group or a halocene atom, R- a hydrogen atom. Or a halo. a torn ocor cine alkoxy, alkylthio, acyloxy, acyl, carboxyallcyi, carbamoyl, alkyl, hydroxyl, nitro or substituted - .mino group or a water-soluble salt 909850 «699; ..; .- _:;! , represent thereof, preferably of a p n value of 5 to 8 in a strongly polar medium, preferably water, with 1 to 10 molar equivalents of a nucleophilic agent of the formula ■ <ΓΓ> (R-.) 3 χ wherein R ₃ and χ have the meaning given above, is reacted, the compound obtained, if R denotes a hydrogen atom, then with an acid of the general formula serving as a phenylacetylating agent or as a substituted phenylacetylating agent ¹ Vj = / XS-CH-COOH ^R 2 ft in which R ^ and R ~ have the meaning given above, or an acylating derivative of this acid, preferably an acid chloride or bromide, is reacted and then, if either the group R ^ or the group R _{2 is} a nitro group, this nitro group is reduced to an amino group, so that a compound of general formula II results. 909850/1 * 99