DK147235B - METHOD OF ANALOGUE FOR PREPARING PENICILLIN OR CEPHALOSPORIN COMPOUNDS OR PHARMACEUTICAL ACCEPTABLE SALTS THEREOF - Google Patents

Description

.1 147235

The invention relates to an analogous process for the preparation of penicillin or cephalosporin compounds of the formula (I) of claim 1 or pharmaceutically acceptable salts of the compounds wherein hydrogen is.

The compounds of the present invention are semi-synthetic penicillins and cephalosporins which have an effective antibacterial activity against Gram negative bacteria, especially Pseudomonas aeruginosa, Klebsiella pneumoniae and Proteus species, and a high resistance to β-lactamase produced by 2 147236, which is significant from a chemical point of view. These compounds are disclosed in Danish Patent Application No. 2019/75 and can be prepared by the process set forth therein.

It has now been found that the compounds of formula (I) can also be prepared by the analogous process according to the invention, which is characterized by the characterizing part of claim 1.

In the following, the invention will be further explained.

The compounds of formula (I) include optically active compounds and racemic compounds.

When the general formula (I) R 1 is an ester-forming group, it is selected from methoxymethyl, pivaloyloxymethyl, phthalidyl, 2-piperidinoethyl and 2-morpholinoethyl, which can be readily removed by enzymes in a living body.

In general formula (II), the carboxyl protecting group R may be any of the groups heretofore used in the field of penicillin or cephalosporin compounds. ; the carboxyl protecting group (1) includes ester forming groups which can be removed by catalytic reduction, chemical reduction or treatment under mild conditions, e.g. aralkyl groups such as benzyl, 4-nitrobenzyl, diphenylmethyl, trityl and 3,5-di (tert-butyl) -4-hydroxybenzyl; alkyl groups such as tert-butyl and trichloroethyl; phenylcarbonylalkyl groups such as phenacyl; alkoxyalkyl groups such as methoxymethyl; and unsubstituted or alkyl-substituted cyclic aminoalkyl groups such as piperidinoethyl, 4-methylpiperidinoethyl, morpholinoethyl and pyrrolidinoethyl; (2) ester forming groups which can be readily removed by enzymes in a living body, e.g. acyloxyalkyl groups such as pivaloyloxymethyl; and the phthalidyl group; (3) silicon, phosphorus or tin-containing groups which can be easily removed by treatment with water or an alcohol, such as (CH3) 3Si, (CH3) 2siC, δo / -, 0V-c2h5o'P '08 (C ^ Hg) ^ Sn. These examples of carboxyl protecting groups are only typical and other examples are cited in the US. U.S. Patent Nos. 3 147235 Nos. 3 499 909, 3 573 296 and 3 641 018 and in DE Publication Nos. 2 301 014, 2 253 287 and 2 337 105 and may also be used in the process of the invention.

The pharmaceutically acceptable salts of the compounds of general formula (I) contain cations which have heretofore been known in the art of penicillin or cephalosporin compounds and which form non-toxic salts. The salts include alkali metal salts such as sodium salts and potassium salts; and alkaline earth metal salts such as calcium salts and magnesium salts. In addition to the above cations, cations capable of forming salts with other nitrogenous organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine and dicyclohexylamine can be used.

In general formulas (I) and (III), R and R each represent a hydrogen atom or an alkyl group of 1-8 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl, hexyl and octyl.

In the general formulas (I) and (III), A represents a hydrogen atom, an alkyl group of 1 to 12 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl and dodecyl, an alkenyl group having 2 4 carbon atoms such as vinyl, propenyl and butenyl, a cycloalkyl group of 5-7 carbon atoms such as cyclopentyl, cyclohexyl and cycloheptyl, a phenyl group, a benzyl group, an acyl group of 1-18 carbon atoms such as formyl, acetyl, propionyl, isovaleryl, caproyl, enanthoyl, capryloyl, palmitoyl, stearoyl, acryloyl, cyclohexanecarbonyl, benzoyl, phenylglycyl, furoyl and thenoyl, an acyloxyalkyl group having 1-7 carbon atoms in the acyl moiety and 1-4 carbon atoms in the alkyl moiety, such as acetyloxyethyl , or an alkylsulfonyl group having 1-4 carbon atoms such as methanesulfonyl, ethanesulfonyl, propanesulfonyl and butanesulfonyl. Each of the above groups represented by A may be substituted by chloro, hydroxy or alkoxy of 1-4 carbon atoms.

Further, R 4 represents a hydrogen atom, an azido group, an alkoxy group of 1-4 carbon atoms such as methoxy, ethoxy and propoxy, an acyloxy group of 1-4 carbon atoms such as acetyloxy, propionyloxy and butyryloxy, an isoxazolylcarbonylthio group, an oxazole, an oxazole thiazolylthio group, a thiazolinylthio group, an imidazolylthio group, a pyridazinylthio group, a pyrimidinylthio group, an oxadiazolylthio group, a thiadiazolylthio group, a triazolylthio group, a tetrazolylthio group or a tetrazolylthio group triazinyl) thio group. Each of the above heterocyclic groups may be substituted by alkyl of 1-4 carbon atoms.

The compound of formula (III) may be prepared according to the method disclosed in Belgian Patent Specification No. 828,692.

The reactive derivative in the carboxyl group of the compound of formula (III) is e.g. an acid halide, an acid anhydride, a mixed acid anhydride with an organic or inorganic acid, an active acid amide or an active ester. Specifically, the reactive derivatives e.g. an acid chloride; an acidic acid; an acid cyanide; a mixed acid anhydride with an aliphatic carboxylic acid, aromatic carboxylic acid, alkyl carboxylic acid, aralkyl carboxylic acid, dialkylphosphoric acid, diphenylphosphoric acid, methanesulfonic acid or p-toluenesulfonic acid; an acid amide with one. imidazole, 4-substituted imidazole, dimethylpyrazole, triazole, tetrazole or saccharin; a cyano methyl ester; a substituent et-phenyl ester; or a substituted-phenylthioester.

Furthermore, as the reactive derivative in the carboxyl group of the compound of formula (III), a reactive derivative prepared by reacting the compound of formula (III) with an activating agent such as NjN'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N, N'-diethylcarbodiimide, N, N * -carbonyl-di- (2-methylimidazole), dimethylchloroformiminium chloride, dimethylethoxyformiminium chloride, trialkyl ester of phosphoric acid, phosphorus oxychloride, phosphorus trichloride, thionyl chloride and oxalyl chloride.

Various embodiments of the process of the invention are explained below with reference to the following reaction scheme.

. 147235 5 a Φ ti 01 φ Φ S «

0) Φ • o-p <H-P

i-i ^ hi -p. «

/ N-v O bOW

f \ O «ri Φ EQ} - O 'd, Ο \ / β I Φ

—'3 ΦγΙ W

_i ΑΧ® H

ω xo h i § a co S> »

£ g O O above K

β - Ρί m tt j w ^^

Si ω n cm

O g W

® * - p to 5 • = i β o

• H

• P

* § h s cd about, ^ OH '- g t £ w W) (H o cd Ph JS'

O Ή> i B

hey? § s s «s« * j? i -p β to o a ^ cq> c · ^ V «^ an a S S c II SS ^ ~ φ ® 2 β β φ φ ^ W) b0 Τ * Ο Ο &

Η Η S

3 3 C ~~ -Ρ C- C- Ο Pi ® g (¾ Ο Ο / Ν \ ο / Ν \ ο / Ν> \ ο a a ra ο ^ 02 “vi-0 a5 VB 5 Vf

-4, H—- K - »R. S

ω o ii s pj il g o — o o o — o

I I> I

CO in ό uo

Pi Pi Pi Pi 6 147235

Q

In general formula (IV), R is an acyl group represented by r 5_co-, wherein R · * is a residue of the acyl group without a carbonyl group.

The acyl group may be any of the acyl groups known heretofore in the art of penicillin or cephalosporin compounds. Examples of the acyl group include acyl groups derived from various aliphatic, aromatic, araliphatic, alicyclic and heterocyclic compounds. Acyl 12 is preferred. 11 groups of the formula R 1> CH-CO- wherein R represents an alkyl R 11 group such as methyl, ethyl, propyl and butyl, an aryl group such as phenyl and naphthyl, an aralkyl group such as benzyl and phenethyl, an aryloxy group such as phenoxy and naphthoxy, or a YN-protected-amino-y'-protected carboxypropyl group such as Y-N-ethoxycarbonylamino-γ ^ -benzhydryloxycarbonylpropyl, Y Y-N-ethoxycarbonylamino-γ-trimethylsilyloxycarbonylpropyl, YN-phenylcarbyl β-Benzysilyloxycarbonylpropyl, N-phenylcarbamoylamino-trimethylsilyloxycarbinylpropyl, and R 12 means a hydrogen atom, a hydroxy group, a halogen atom such as chlorine and bromine, or a lower alkyl group such as methyl, ethyl and propyl. Each of the aforementioned groups— 111? per represented by R and R may have one or more substituents selected from halogen, hydroxy, nitro, alkyl, alkoxy, alkylthio and acyl.

The iminohalogenation reaction, which is a reaction of the compound of formula (IV) with an iminohalogenating agent, is carried out to form the corresponding iminohalide compound. As imino halogenating agents, e.g. phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride and phosgene. This reaction is carried out in a solvent or a mixture of solvents. As solvents, e.g. methylene chloride, chloroform, benzene, dichloroethane, trichloroethane and tetrachloroethane. Furthermore, other inert solvents such as tetrahydrofuran, dioxane and dimethoxyethane can be used. The reaction conditions for the imino halogenation are not particularly limited, although the reaction is usually carried out under cooling of the reaction medium.

The imino halide compound thus obtained is reacted with an imino etherifying agent to form the corresponding imino ether compound (imino etherification reaction). The imino etherifying agent is a compound of the formula R 1 -OM wherein: represents an alkyl, aralkyl or alkoxyalkyl group, and M represents a hydrogen atom or an alkali metal atom. More specifically, the imino etherifying agent comprises e.g. alcohols such as methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, isobutyl alcohol, tert-butyl alcohol, benzyl alcohol and methoxymethyl alcohol, and alcoholates of such alcohols with alkali metals.

The reaction conditions for the imino etherification are not very limited, although the reaction is usually carried out while the reaction medium is cooled or heated. The imino etherification reaction mixture may be concentrated by evaporation under reduced pressure to remove the imino halogenating agent and imino etherifying agent, or the reaction mixture may be used for the next reaction as is.

The acylation reaction, which is a reaction of the compound of formula (II) with the reactive derivative in the carboxyl group of the compound of formula (III), is generally carried out while the reaction medium is cooled or heated. When the acylation reaction is carried out in the presence of an additional solvent, such as dimethylformamide, satisfactory results can be obtained. However, the reaction conditions for the acylation are not particularly limited.

The iminohalogenation reaction, the iminoetherification reaction and the acylation reaction can, as is known, be carried out in the presence of one or more organic bases such as såsom, Ν-dimethylaniline, pyridine, quinoline, picoline, lutidine, trialkylamine and dialkylbenzylamine.

The reaction product thus obtained is hydrolyzed to remove

Q

the acyl group R. In this case, the hydrolysis proceeds satisfactorily by pouring the reaction mixture from the previous reaction into water. The carboxyl protecting group R may also be hydrolyzed simultaneously, depending on the nature of the carboxyl protecting group, and converted to a hydrogen atom. Furthermore, the residual carboxyl-protecting group which has not been hydrolyzed can be removed if necessary or desired. The reaction to remove the carboxyl protecting group varies depending on the nature of the carboxyl protecting group and the reaction is carried out by a commonly known procedure such as catalytic reduction, chemical reduction or treatment under mild conditions. Especially when R is a phenacyl or benzhydryl group, the carboxyl protecting group can be easily removed by treatment with sodium benzene thiolate in dimethylformamide or tetrahydrofuran or with trifluoroacetic acid in anisole.

The penicillin or cephalosporin thus obtained is isolated by commonly known procedures.

Pharmaceutically acceptable salts of the compounds of general formula (I) containing a non-toxic salt-forming cation are readily obtained by the usual procedure from compounds of general formula (I) wherein there is a hydrogen atom or a carboxyl protecting group.

The compounds of the general formula (I) of the invention have a broad antinacterial spectrum and are ureido-type compounds which have been found particularly useful in the treatment of infectious diseases due to Gram-negative bacteria which have been considered difficult to cure. They have an extremely high antibacterial activity against Pseudomonas aeruginosa,

Klebsiella pneumoniae and Proteus species.

One of these compounds produced by the process of the invention, namely piperacillin sodium having the following structure, has already been marketed in Japan and the Federal Republic of Germany: 0 0

} ~ Λ S CH

CH₂, CH „N NCONHCHCO0N3 - -

3, w | T-ch3 1_N-i-COONa

P <T

9 147235 (This is compound # 2 in Table I below).

Cefoperazone sodium with the following structure will also soon be marketed in Japan: • 0X .0 M -s CK, CH „N BCOHHCHCCNK - (- T 'Ί 3 2W T I f-f' O h-

I ° COOKa L

OH .3 (This is compound # 12 in the table n below).

The excellent properties of the compounds of the invention are due to the group (0), Δ \ A-N N-C-NH- 3

R R

in the molecule, namely the mono- or dioxopiperazine ring and the ureido bond.

Danish Patent Application No. 3118/74 and AT Patent No. 307,617 disclose ureido-type compounds, but only azlocillin and mezlociline with the following chemical structures are reported to be under commercialization.

Jk <D1 S xCH3 • H-N N-C0NH-CH-C0NH ~] - (v_y i I C, I3 X J-u— v KJJ 0 COONa

Azlocillin sodium 10 147235 o

(D) S · CH

CH SO-N N-CONH-Cir-CONH-i-f N '\ Λ 3 w X Tj_J 3 LQJ o COONa

Mezlocillln-natrjum

It is apparent from the above structures that mezlocillin and azlo-cillin containing a ureido bond as shown by

ISLAND

'Sn-CO-NH- in the group -N N-CO-NH-,

W

also contains a 2-oxo-imidazolidine ring with a cyclic ureido bond represented by the formula

ISLAND

• -N li- V.7

These two form a biureido bond. These are the structural features of mezlocillin and azlocillin. The difference between the ureido bond in the penicillins prepared according to the invention and the biureido bond in the above known penicillins is quite clear.

It is reported in the 18th Interscience (1978, Oct. 1-4),

Session 6, No. 39 and Session 12, no. 116, that piperacillin, which is representative of the compounds of the present invention, has a wider antibacterial spectrum than mezlocillin and azlocillin. Furthermore, these literature sites show that mezlocillin overall is better than azlocillin. Therefore, results of comparative tests of mezlocillin and the compounds of the invention are listed in the attached Table I. It is clear from the test results that the compounds of the invention are much better than mezlocillin.

The cephalosporins prepared according to the invention containing the group n 147235 in n

HK

A-N N-C-NH-

ks

R IT

in the molecule are quite different from the known cephalosporins in chemical structure. However, to clearly demonstrate the utility of the cephalosporins of the present invention, results of comparative tests between conventional cephalosporins whose utility is recognized and cephalosporins prepared by the method of the invention are set forth in the attached Table II.

table in '12 .147235

Conn. Staff ^ coCtøi EscW / tiJo. Pseu / W / AS Iplk ^ e ^ n ^ 'uctural formula aureas ^ oA cofr VUl ^ acris ps-eB-WMe --ή "______ 2 °? F __IF0_ G-N301T Y-50' C ^ SOj-j '^ JCDA / HdHCom-rf '^ y & fc Φ && <' · ^ <'* ^ / ζε 1 </. R? 1 ΖΡ ~ ΊΖΠΐτ ^ _ ^ 0 tOOAfn.' 6 '^% -fc O) c rH ~ · --- --1-

. ; «« <* · <, «<UT

3 «« / "« Γ7ΓΤΓ ω> n /> Μ! '------ 4- wsttøcum & «p £ fa ____Co3 0 CODAffl. · 3./5

Vf ^ ~~ 7 ~ ίΓ '- “- ___ ~ t CHpocHJ ^ Ji ^ ZQN ^ CHCONHr-f ^ .3.

y <™ v. << ir ** - 6 w ^ w | (cc / ^: .iiiy ~ _ _ ^ 0 _coofk <ir </. S7 6.ZS- 7 <3> jHco ^ chcp% SvJ {5 . ~ = —— * J- / v— (^ 4. J. & 7 </ 57 r ^ t- __ ^ ° COOAIql '7 *' 2Sr </. 57 / „fy / 0 ~~: L-- ' · Φ) a * <0 / - · _ C-OOA / ^ * 0.4 0.4 \ ^ P cd) · ~~ ----;.

• · // CH3CcHaTNiNCDAWCWCOAifWSy. * Full </ .s? // 57 C y c kJ c% S 'Y </ 57 </. 57 _ 13____________ 147235 porb S'tafi / lococcus EscIiericfJa. PstuJowyjiS ProtemS IddeiiSelift.

No. Structural Formula to TdU-SF "dA CoI i ΝΕΗΓ cusYUfliwiSOi ViLtgciviS pjiew ^ iie

_. _ 2o? P IF0 & 1WT Y-EQ

% ~ i ° '· («c M

IZ tH ^ tONHWC0Mj ££ vi3 <0.4 <0Λ fiZS <0.4- Z5 __ύΗ C-OOWlk .____.__ · _____ \ _J> CD) ς 03 '' / 3 C.H <0.4- 0.7? / 2.5 · / 57 / 2.5 ίθ) 0 CDDJ-JOJ ·% -J '0 »s03 / 4 ίΙ! 3 ^ 0ΝΗ <Μί0ΝΗτ £ ^ Η3 <β7? <Ø.7? M <M? 4.45 (2J 0 zooc / h> h / 3 ').

'..... 1 i ,, - „. 1, 1 I. "1". VV3 C 03 ft ztl ^ COØWMN ^ y-cHs 0.7? 17? Z5 /.57 Z5 (o) t> Qom ^ tocm ^ x. crø c tJta / 6 c // ^ comHco ^ / jrj <(i ^ 0.7? <0.4- βζ5 o, 7? Z5 (33 o toom £> W3 co) ς Mh / 7 c ^ Njn / C 0NHCHCDN5j- ^ m 0.7? O, 4- 4.25 0.7? Z5 C ^} O - cootyjyfji)

OxA ° <W rsS ^ 3 ft CH3N hcOWMCMfåiJicH * <0.7? <0 7? 72 5 “3./5 /Z./r w Q cr cow4 'W3 CD) π xM * /? CH3N ^ CO // 4CHCO // 4j ^ J ^ H3 <ίεγ </. 77 jZS 3.13 Z5- s3 O COO / Jcl% -P CD) ς. / ¾ · i zø ø3cHj ^ comcHtomr ^ Ycfj3 <0.4. <0.4 3./3 3./3 CM, (P) t> OW4

». t _ I

To) o CH3- 'zl cm ^^ OMCOmr ^ uts <0J 3., 3 425- 0.7? Z5 Φ CØiWil _OH _____ [_____ - ~ (W „rH3 a, 3» W «7? ^ (Ο) υ COO / V«. S '

Vf0 C «c 03 23 © CHaNJ ^ 0.4 <<> ./ 3 </ i? ^ 7? island, 7? (g) ^ co0 / 4 .147-2.35 _ X4__ · - 'S'tapWococcus Eschjerickia. Pseuioirto'WS Proteu-S Kleksielta-

Conn. '' - No. Structural formula diiwS F ^ A coll ΝΕΗΓ oueYtwiimSa. VtfigariS preuwortue

'20? P _ i FO 4N30 ^ T Y-5Q

fO (d) c Jill 24. w * wftT? <u ejts i31 t „ch3cr) L $> j u tmk

Vt ° cw -c <% 2S Cfl3CH, N AJCO / WCWCoNfhrf ^ <M 3J3 0.1 $ f ^ g

. ^ h3 lo] I

CD) rt .0 / ¾ • 2 £ </. Γ7 </ Λ7 2.T '<Λ · $ 7 J./3 •' i ° D 0 · cøøMn f — fP c °) c, cH> 21 CH3CON_W < / Srf </ <f7 ^. 9/3 /2.Γ iO] Q 'c ^ oojVft 2 ?. cHjSd <, i £ -r </ tf7 ^ << J7 /2.r [O] · 0 COoMl

What cw '<? a Ί: p ~ 2 (\% mt $! WCO / WeO // ^ Y (^ </, 4-7 <Ai7 Us <! si £ .25- ® 0 arøfc 30 <^ tfLlTibcO / '/// ScOA% ^^ </ ^ 7 </.- 77 27- 3,, 3 ^ w __L_L_

CD) "M

31 [ffV-Ν ^ C0A /// CHC0 /% r / C / 4 </ 457 </. 57 /-?.£ "r.25 * / 2. s *

~ W to] g ^ ~ Wa I

) TABLE · II_ 15 _ 147235

Forb> S'tfl |! ^ Iococais bctar / dJa. PseiuWstfAS Pr & teuuS {CieliSiel ^ No. Structural Formula oiLr ^ u-SFPA ccli NlHT CLe ^ inoSO. Vili.oa.riS ρηςίχίΜ'ώζ _______ _ I FO 6-N30.2T y ^ rn

Cefa- (M · c ~ -------__

• loglv- 'HiNCHCOA /// - rr'X

i <S [* i </. irf O.ST> 200, 00 '-Na ___' £ oOMjl. _. '1 ^ <m <ttJ> 200 ./io.

____ eooA / a .__. __ * _ '' -Sin </ · 5'7 </, r ^> Z60 zoo '-Na. cooMl 7 · · .g? - <rn> * · »'W *,» 1 ^ uMcHUMrj / 7 ft7? <0J zs. - <______ ^

Vf0 cw c T ~ ---- '

? CftptN titOMHCHLQMH-r-f '^ s 0 rro, η7η' ---J

w é} <p · 71 v ^ booNf ^ '3

Vf ° W o _ 3, n <*, ^ A> 9 __ ^ 0 toof / n ~ W5 cw ca / - // · - _______ 4 <0.79 <0.79 ZS - ^ 8 lom, lu, · 7 < o.7f 5 0.79 <ol zs- ~ ZT ^^ ε <«7f«. *, 7Γ ^ ~~ η _® i00Na.k »3 << V? <>. * T ch ^ coA <, 79 <0.79

__ ^ Coo / Vft .__ '7 ^ (T

Vf0 CD) ς '"" • - i cmj} <^ * Fåxsr wi <oj 7ir fol. zt / tn

^ C.00 / 4. 'F ^ T

__16__

14723S

jForb S'toik / lococcuc Escker / ckla. Pseiubmo'iÆS Proteu ^ Kie'oSieU0- jnr. Structural formula au.r «.u.S FDA co! I NEHT OÆttUtfitoSa. Vtfl ^ ariS pneu? W »clothing

__'_ zrtp__i FQ G-N30-2T r ~ 5Q

tL ·? 0 - m ~ ί <'· ** ** / -i7 <** t __' ^ tOOik. tHa ____.__ ^ ___ 1 ^ · J / »'«,. / 0Λ S.ZS 0.71 0.1 Γ V? ^ 77. | // cHA ^ co / Wco // ^ 6 '] <o, 7 <! <0.7 * 1} z. $ <O.7f <44 Θ ^ Xook t% O fe ~ iz a, M3 ^ XCMpL · Si <isr <»./ i,» 0.4. <o.i 1 · ^ irn. b &. 1 IW * (® ,,,, SN fefe Ί i / 3 «V </. 77 </. 37 ζί A / 3 3./3 Γ {Ti · 0 w __ ^ CPO / Vg, W - ____ (P ? OX, As / 4 </ s7 </ s7 iZ; ir / 's? / ,, rf I \ -J * CD) c / s <υπ </.*? * · ** 3J3.

__ ^ CQgAfo, 3_____ / £ Arr <0.4 ro 3./3 0.7! IN__. coo / fir, _____.

I ^ -f ^ E.P). ς> μ— / ν.

/ 7 WL / co ^ cc ^^ ii /.^ /.rr <e. / /.*7 44 __føp / fu. kpj3 _______ ^ ___ U (W <, a / Jaj ...

12 ^ jQJ ^^ CDØ / J ^^ Cfijis ^ A ^ <A / 5-75 J75 __CPPMl_______

Fr ° cp> c I

Il mWM $! 00plajct / 3 0.71 <0.1 M c.zr s./s j __feWa .______! \ jp CP) c.

H0CH £ H, N bcQtfHCHC.Oflfi-r-fJ \ tf 7 _ zo. fez /, i7 </. 37 z3 </. 37 <I.Sf fe «« Λ - - ____ ^ * 147235 _ 17_

Conn. ^ taf ^ coccus EscKericKlo. PseuJojtøftiiS Proteu.S

No. Structural Formula aiLrellS jtdA coli NIHI ΟέΥΜ ^ α. VOi ^ oriS piieuwae I_J ___ 20? P_i FQ tøWT Y-50

Vf ° ·. CW ς z / »-jiLj </.* <m, z.t Utr? <> *? __ · Ori 'CPOfi / tL ______.____ β ζρ) Λ - 22 arøjUico <Ι. * 7 </.^ 7 / ^ r <^ 7 <t. * 7 (ff) ~ ο Zvv 23 cH ^ fc ^ co / V ^ </, 5-7 <447/2 3- </. 3-7 c / 'Sf __Jfj' cooflx b / 3 ___ —_ j Ί! r 2i hQj 0.7 * 1 <^ f Λ 2Γ 0.77 t.sj i _ ^ ° tooNd bf3________ j _; _ i_______ i. .

Is i i 'i i i I t.

18 147235

The process according to the invention is further illustrated by the following examples. In the examples, the compounds prepared using the reactive derivative of the D (-) isomer of the compound of formula (III) are designated as D (-) or D (-) isomer.

Example 1 2.9 g of triphenyl methyl ester of 6- (phenylacetamido) penicillanic acid and 2.06 ml of N, N-dimethylaniline were dissolved in 30 ml of methylene chloride and 1.15 g of phosphorus pentachloride was added to this solution at -25 ° C. The mixture was allowed to react at between -30 and -20 ° C for 1.5 hours, followed by the dropwise addition of 20 ml of methyl alcohol while maintaining the temperature at -30 to -20 ° C. The reaction mixture was further allowed to react at the same temperature for 2.5 hours, followed by the addition of 3> 43 ml of N, N-dimethylaniline.

On the other hand, 1.76 g of D (-) - oc- (4-ethyl-2,3-dioxo-1-piperazino-carbonylamino) phenylacetic acid and 0.76 ml of N, N-dimethyl-aniline were dissolved in a mixed solvent. consisting of 8 ml of methylene chloride and 4 ml of dimethylformamide. The solution was cooled to -10 and -5 ° C followed by dropwise addition of 0.65 g of ethyl chlorocarbonate and stirring at the same temperature for 30 minutes.

After the reaction mixture was cooled to -25 ° C, it was added to the previous reaction mixture.

The resulting mixture was allowed to react at -25 ° C for 2 hours and then freed from the solvent by evaporation gaining reduced pressure. The residue was dissolved in a mixed solvent consisting of 30 ml of water and 50 ml of ethyl acetate. The solution was adjusted to pH 1.0 by adding dilute hydrochloric acid under ice-cooling and stirring for 15 minutes. The organic layer was separated from the aqueous layer, then 20 ml of water was added and adjusted to pH 7> 0 by the addition of sodium hydrogen carbonate under ice-cooling. The resulting aqueous layer was separated from the organic layer, then 20 ml of ethyl acetate was added and then adjusted to pH 2.0 by adding dilute hydrochloric acid with stirring. The mixture was further stirred at 15-20 ° C for 3 hours to precipitate crystals which were collected by filtration to obtain 1.2 g of a monohydrate of 6 - Γ D (-) - 19 147-296 α 4-ethyl-2,3-dioxo-1-piperazino-carbonylamino) -phenylacetamido] -penicillanic acid, m.p. (decomp.) 154 ° - 156 ° C, yield 45%.

IR (EBr) cm ”1: γ ^ = 0 1775 (lactam), 1735 (-C00H), 1705, 1680, 1665 (-C0nO RMR ((0 05) 2SO) T values: 0; 20 (1H, d), 0.76 (1H, d), 2.69 (5H, s), 4.32 (1H, d), 4.53 (1H, q), 4.64 (1H, d), 5, Δ (3H, br), 5.83 (1H, s), 6.13 (2H, bs), 6.49 (2H, bs), 6.62 (2H, q), 8.44 (3H, s) ), 8.58 (3H, s), 8.91 (3H, t) In the same manner as above, the compounds of the general formula (I) listed in Table 1 were prepared.

20 ΐ A 7 2 3 5

Table 1 I Compounds Compound of the General Formula _ (I) __ D (-) -

P

CH2 (CH2) 5CH2C0-N H-COMHCHCONH-i-f Aj 3

(ISLAND). COOH

mp. (decomp.) 151 ° - 153 ° C

D (-) - CICHpCO-H H-CONHCHCONH-j-rsVCH5 w Kl j-KK3

KJj 0 COOH

mp. (decomp.) 215 ° C D (-) - 0 yQVcO-H N-COKHCHCOKH ^ CH3 w K J-h-a033

KJJ 0 COOH

mp. (decomp.) 120 ° - 124 ° C D (-) - ch3o / 0 CH2 oJa) VcO-H ^ ίΓ-COKHCHCOMH-i-ASVCH3 'r * w <&> K ^ -K3

CH2 O KJJ 0 COOH

mp. (decomp.) 120 ° - 124 ° C

continued 21 147235

Table 1 (continued) vcl ^

Cl-UjVcO-N N-CONHCHCONH —i- ^ SV ^ CH3 W Ι ^ Λΐ Λ-Η — k ™ 3

KJJ o COOH

mp. (decomp.) 130 ° - 133 ° C

D (-) - CH 3 OH 0 II) - \ <3 λΗ „HCCH? -II N-C OKHCHC GNH -S ^ w rft,

KJJ οκ COOH

mp. (decomp.) 95 ° C D (-) - 0 H Will N-CONHCHCONH — ϊ- / S \ / CH

. KJJ O COOH

mp. (decomp.) 134 ° C D (-) -

0 P

Y — K c! OH

CH3-N N-C OKHCHC OHH — j-ΛΥ} w rrVi J ~ N— \ 3 KJJ g cooh ·

mp. (decomp.) 156 ° - 157 ° C

continued 22 147235

Table '(continued) D (-) -

W

CHx-F N-COHHCHDOHH 7-CH5

O COOH

mp. (decomp.) 84 ° - 87 ° C

D (-) - 0 0) - ^ q ph, CH3-H N-CONHCHCOHH-j-j '' jx ^

I O COOH

t

m.p., (decomp.) 185 ° C

i ___________ i- dm · Vf ^ NCONHCHCOKH—

O 1 COOH m.p. (decomp.) 154 ° - 155 ° C

D <“> - O O

M. CH

CH_CH_N NCONHCHCONHt-f 6 3 2 \ _ / r I ch (fV | Jr-- N-1

CH3 (R) K) J o COOH

m.p. (decomp.) 150 ° - 152 ° C

continued 23 147235

Table (continued) D (-} - 0 0 H c "3 CH3CH2N NCONHCHCONH-T-Γ | \ CH3

<^ 3 0) O ^ -HoOH

m.p. (decomp.) 156 ° - 157 ° C

D (-) - 0 y ^ c ^ ch CH- (CH0)., N NCONHCHCONH-i- <b> <3 3 2 11 cf I "CH3

O o N

COOH

m.p. (decomp.) 106 ° C

EXAMPLE 2 (1) 2.26 g of phenyl ester of 6- (phenylacetamido) penicillanic acid and 2.06 ml of Ν, Ν-dimethylaniline were dissolved in 30 ml of methylene chloride, and 1.15 g of phosphorus pentachloride was added to this solution. 25 ° C. The mixture was allowed to react at between -30 and -20 ° C for 1.5 hours, followed by the dropwise addition of 20 ml of methyl alcohol while maintaining the temperature at -30 to -20 ° C. The reaction mixture was further allowed to react at the same temperature for 3 hours, followed by the addition of 3> 43 ml of Ν, Ν-dimethylaniline.

On the other hand, 1.76 g of D (-) - α- (4-ethyl-2,3-dioxo-1-piperazino-carbonylamino) phenylacetic acid and 0.76 ml of Ν, Ν-dimethylaniline were dissolved in a mixed solvent consisting of 8 ml of methylene chloride and 4 ml of dimethylformamide. The solution was cooled to between -15 and -10 ° C, followed by the dropwise addition of 0.65 g of ethyl chlorocarbonate, and stirred at the same temperature for 40 minutes. After the reaction mixture was cooled to -25 ° C, it was added to the previous reaction mixture at 24 ° C.

The resulting mixture was allowed to react at ~ 25 ° C for 3 hours and then freed from the solvent by evaporation under reduced pressure. The residue was dissolved in a mixed solvent consisting of 20 ml of water and 40 ml of ethyl acetate. The organic layer was separated from the aqueous layer, washed with saturated aqueous sodium chloride solution, dilute hydrochloric acid and a 5% aqueous sodium hydrogen arbonate solution and then dried over anhydrous magnesium sulfate. Ethyl acetate was removed by evaporation under reduced pressure and the residue was solidified by the addition of 50 ml of diethyl ether. The white powder thus obtained was filtered off and washed with diethyl ether to give 2.29 g of phenacyl ester of 6 [D (-) -a- (4-ethyl-2,3-dioxo-1-piperazino-carbonylamino) phenylacetate. amido] pencillic acid, yield 72%.

IR (KBr) cm ”1; qq 1775 (l & ctam), 1760 (ester), 1710 - 1665 (-CON <, -00- (5)) (2) 2 g of the above-mentioned phenacylic ester of 6- [D (-) - oc- (4-ethyl) - 2,3-Dioxo-1-piperazino-carbonylamino) phenylacetamido] penicillanic acid was dissolved in 30 ml of tetrahydrofuran and 0.42 g of sodium benzene thiolate was added to this solution at 15-20 ° C. The mixture was stirred for 1 hour to precipitate crystals, which were collected by filtration, and the filtrate was concentrated by evaporation under reduced pressure to obtain a further quantity of crystals. The first amount of crystals and the second amount of crystals were combined and dissolved in 10 ml of water. To this solution was added 15 ml of ethyl acetate and the mixture was then adjusted to pH 2.0 by adding dilute hydrochloric acid with stirring at 18-20 ° C. The solution was further stirred at 18-20 ° C for 5 hours to precipitate crystals which were collected by filtration to give 1.47 g of monohydrate of 6- [D (-) - α- (4-ethyl-2) 3-Dioxo-1-piperazino-carbonylamino) phenylacetamido] penicillanic acid, yield 87%.

This was consistent with the compound prepared in Example 1 with respect to the analytical data for IR, NMR and melting point.

The above working steps (1) and (2) were repeated except that the phenacyl ester of 6- (phenylacetamido) penicilanoic acid used in step (1) was replaced with a phenacylic ester of 6- (butyramido) penicilanoic acid, whereby a monohydrate of 6 [D (-) - α- (4-ethyl-2,3-dioxo-1-piperazino-carbonylamino) phenylacetamido] -penicillanic acid was obtained, yield 65%.

(3) 1.0 g of the above monohydrate of 6- [D (-) - α- (4-ethyl-2,3-dioxo-1-piperazino-carbonylamino) phenylacetamido-diphenicillanic acid was dissolved in 20 ml of acetone. To the solution was added 3 ml of an acetone solution containing 0.33 g of sodium 2-ethyl hexanoate to precipitate white crystals. The precipitated crystals were collected by filtration, washed sufficiently with ethyl acetate, washed with diethyl ether and then dried to give 1.02 g of sodium salt of 6- [D (-) - α- (4-ethyl-2,3-dioxo) -1-piperazino-carbonylamino) phenylacetamido] penicillanic acid, m.p. 183 - 185 ° C (decomp.), Yield 98%.

IR (KBr) cm ”1: γc = 0 1765 (lactam), 1720 - 1670 (-CONO, 1600 (-C00")) tube ((CD3) 2S0 + D20) T values: 2y62 (5H), 4.31 (1H), 4.50 (1H), 4.70 (1H), 6.05 (1H), 6.35 - 6.65 (6H), 8.49 (3H), 8.60 (3H), 8.91 (3H).

Using the phenacyl ester of 6- (phenylacetanidojpenicillanic acid and a compound of formula (III) as given in Table 2), the above working steps (1), (2) and (3) were taken to obtain the respective compounds listed in Table 2. The structure of each compound prepared was confirmed by IR and NMR All the compounds prepared were D (-) - isomers.

26 147235 -p

CO

ω

-P

U

o «η

CO

cO £ 3 a ιλ (Λ o tn tn o W M o K K O vo OOOvg ® ° ^ ys j £ ra \ / / vo / j m 0 S o - ω

a £ V * S

1 T? I i & "S —1 £% <8 g \> 3 g ° 3 s · o -pooa / —vo <D oi, OW / s- \ ° g i- © si <o> s -PS '- < omo ^ o 'goi S i ft 01¾ ft t υί t) i kJ ® W <3 nt a> d nt I O- c \ J -'. oo ^ om S tn. · tn · -2 Cd g «Cd ft goaoa

tQ CQ

H

H

H

in!

<D

H

S l-i-t it ts 0 W o 1 te 'te. S '-' o

M O O

<D O I

3 «ys ΎΊ i V γ £ t I ni

£ j- O O

o o CQ

(i, cn tn W w o o 27 1A7235 --------- -p

Cd οι

• P

ISLAND

cd cd fe

> 2; Γ <Λ ί <Λ Oh

! ιΡ | ιΓ o ooo ° \ Z / ° R cd s yv / (o! Λ (OlO ® 02 'τη +? K fe o +? \ _' \ f OOO -P Ϊ - fe f £ W £ i οϊ -1 § ώ f 1 Hk ** i °. Vt * 1 ^ 8 _ o ° —1 o ° fe / ^ λ £ κ / ^ Λ η! £ s - ((J> 5

§Λθ) S g ° g g ^ / S

§ \ —— f O o O I O> -V I ° * 8 o SYn> o o i

ί ° vS S o T S

cd T H o ™ J cxj ra L J o fe - 43 ^ fe g k i ° γκΊ έ «&

ϋ 8 I l J I 8 I

c \ io ^ fer ooo -—- φ IOO ω C \ j Ό O fe O fe CM fe O s "''% & i ή i S é '3 ° s [<ysn ir> ___ fe fe 0 I © B I- © fe '-' oooo, -, o • Λ p Ό vfeT I 1 k ° γΒ-, si1 8 'XJ 8

<M Sfe ^ O

1 O

fe ^ 8 8 ^

S

(1 fe B I5J .s 28 147235

-P

n3 tn -p u o «Ρ 05, ¾ S U3.

tn tn o g ώ M O Q) 5

Γ5 O O -P ΝΛ N "\ O

\ / / £ W W o ^ V— /! >> o o o oo

/ W C "· V / UD

ra -ti cd, vd X — f

i— ^ Jf'tf'O © °? -P

KW W O +3 \ '+3 - 0 0 0 +3 ~ H to 0 ° vy * i a I g ° § - I r \ * 5 I®.; · U «

N O O W O H O

o CM S CM S ^ 0 g; ^ o -, ^ O ^ 5 f Ί 0 · O-ZrSS gt &

^ A. J s w y - '/ s Γ i S

O g o g - 'o I O

1000 r-A-t ^ m CM 0 O 0 ° δ ©

W -tf I ^ k, S

? W

xS,. (i. o ft ft ►if 'Q,

IJJ g * o s I * g i *

S

° o §- / q \ I / -x g I © Λ | ® 2 ° v i u CM O ° δ w i 1 © i ° y i i 29 147235 ..... -µ cd m μ o «μ cd

W

(Λ (ΛΟ cd W H o 1¾ o o o ΙΛ IA O \ / y WHO · 'Y — f $.

O O O / 'H

\ / / EC! CO JO O

V_ / «\> vo wwo ^ / 5] —W e ?. o o o <ξ · \ VO vø Y __ / Ό RO) CD ΪΟ Φ µ w o µ vi µ µ w µ. χ— w μ ί >> Ο ί >> ι ί >> Η Ο Η ο, -. µ _ [µ i ^ * ιγ> * * Η / 4Γ \ Η s 0- / ΓΥ ·> ο - ο Η \ ν _ // Ο ο ο, —ν ο _ S '-' ο I Ο Η / yv \ ο

1? R Υί 5 S

t ° γΥ - - ο - ο i J a c \ j Ρ- ο. s. w * n cYY s m a v ^ s ^ I o o o o OJ O OJ O Y J ϋ K <D Η ω O ^ W ω (M o W o Td l w cm - o ^ W ^

HH O O

<D O O / \ w to · -40 · 4? Y · & cd M&W 81¾¾¾ eh o S o goom to · ra - _ w o o 1 §Y) g i © s i „? ° r ") i-® ° vS ο ^ ϊξΓ o

° V 'g- Y

OJ OJ in J

W W O ^ ST

o o i

CM O W

W o o o o / \

CO CO (O (O

w W W W

o o o o 147235 3η ρ et m • Ρ ο «Η et ώ

Β S

to two [ΑΟ ίο ιο ίο D3 ΠΚΟ W W Ο Ο Ο γ γ γ

V-B V-lf "iR '' - to ^ R

i 1Γ \ VD I VD

I.. Κ η -Λ m g ° p ΐϋο · £ g ° · ® Ι ^ ϊ | -®Ι | -®f ο ο> ο ο ο Ο ΙΟ ο ο Ο Ο Ο Ο. Β ^ Ο Ο, Β ^ ίη 4? τ 1 "Υ Ί a Υ Ί s Ρ I · I · I · Τ Cd Ρί OJ ft OJ Λ o w a w s w g i; o o o o o o

RR tO o * 5f O UD O

w ^ φ -—> <D Φ

Cd Ό OJ Ό Cd * 3 H ^ W ^ W - · w o o o 3 ^ ft ^ ft ΪΡ &

p g a o s o S

¢) to ra ra

Ed ---- W g g 'Ib Ϊ®' jb o o o

“RS ° yS ° rS

cAb ^ o ^ b ^ o ^ b '"'

I I I

Cd OJ Cd

Μ B W

O o o

tc \ <- VO

CD OJ CVI

W Sti Sti o o o tov tov * to

Path Path Path Path o o o 31 147235 - - -µ cd

CQ

µ o «Η

sR

island! ro cR

) ¾ -cf H cd

ΙΛ [ΛΟ IS S

B M o ® [Λ to o

O O O -P <1) W W O

w, -P cd +5 o o o /] j? tA K \ S>, V- / oa £ W fn) o Jo J 5 v Ϊ o o o * co vo

rA o * Ά o —II

g 8 I æ S ° I

Oh,. OJ -k H O ^ IV 'i “s · ® #

O OO o J—. in S '-' O.

o cn m / 7 ~ Λ oo o H

I Η b2 ~ (C)> H ° w -p o ¾ w i

w T I S · V S

-P 1 J ft o ft & k 0 ^ ¾ ^ ais λ) a 0 io ov ^ oo <H cm α v ^ ° · ° w ω cd I φ cm ω g 3 cAY S g 5 w ^ · H * 1 i i1 O i * gi *

il ° CQ \ / CQ ° OJ

cd Ε-Γ ---: -

K

O g i © § i © 0 O r '- ^^ V g- / Q \ 8 ° TB1 ^ vs

° V 'ov2 JJ

1 X) i O i cm π Α κ § | © I § 32 147235 - ^ cd w

P

ISLAND

in o vo is £ 0 cd <D 0) g

g .p .p {O (Λ O

t n t n o +3 cd -p B? W o wmo >> .g ·>, ooo in open tn jn o PV / vo \ / / ij Ed K o ij r— (ri 3 ϋΧ / 0 / ϋ? Αί $ ® Π t) -¾ o CQ OI ff U ε V-. V 'Η 1' v H I r-1 id o pd o - <k g gi I o o g o o, —s p 0 j— \ o g o Ed / s - \\ Ed o

Ed / TnV vo 8 o P \ () Vo in

01 ()) vo O, - C- Eti Y '-' / Y

Λ Ed γ - '/ H Ed / r ~ \\ Ed H g' —J H

p g N— 'o- ((j Vo o cd o - Ed \ ^ / - o ^ ra o · g' - '· l · P i ft o ft c> gv gi £ ovg s o a γ i s S V Y o i o o

il i o o 'g o X J O

£ n 5 ° ·? -s X. w w g "i CsJ § · g" i1 g "i-

, Ω KJ ^ CQ CQ

M: ---

S

Ed o

Island Island

O g g / -V _. 1 # joints, I® °

? § O-A

° rX Ί TI

°, I J k.

x g Γ tu tn tn - 'X1 S g 33 147235 ό

COW

ώ α> «g +> to ο Ε Μ K O b-, O O O j? yy i

CQ

\ —S i °

K

g O H

O I

0 __, Ϊ s · ® „s a o u 9 ^

+5 I W

U O »· o & 4 'JJ! I "d c \ i ---

CM M

_1 o H to · S W &

rO o S

cd co EH _

W

ISLAND

o to 1 a

O fe! ISLAND

r r

O ^ FET

CM

W

ISLAND

EXAMPLE 3 34 347235 3.72 g of potassium salt of 6- (phenylacetamido) penicillanic acid was suspended in 30 ml of methylene chloride and 0.25 ml of N, N-dimethyl-aniline was added to this suspension. Then 1.52 ml of trimethylsilyl chloride was added at 10 ° -15 ° C and the mixture allowed to react for 30 minutes. After the reaction mixture was cooled to t50 ° C, 4.12 ml of Ν, Ν-dimethylaniline and 2.3 g of phosphorus pentachloride were added. The resulting mixture was allowed to react at -r45 ° to 4-40 ° C for 1.5 hours, followed by the addition of 13.7 ml of isobutyl alcohol. The reaction mixture was further allowed to react at between -5-45 ° and * r40 ° C for three hours, followed by the addition of 6.86 ml of N, N-dimethylaniline.

On the other hand, 3.52 g of D (-) - 0 (, - (4-ethyl-2,3-dioxo-1-piperazino-carbonylamino) phenylacetic acid and 1.21 g of triethylamine were dissolved in a mixed solvent consisting of 20 ml of methylene chloride and 10 ml of dimethylformamide To the solution was added dropwise 1.3 g of ethyl chlorocarbonate at between 4-15 ° and 4- 10 ° C and the mixture was stirred at the same temperature for 30 minutes. After the reaction mixture was cooled to 4-40 ° C, it was added to the previous reaction mixture.

The resulting mixture was allowed to react at between 4-40 ° and -r30 ° C for two hours and at -KL5 ° C overnight and was then liberated from the solvent by evaporation under reduced pressure. The residue was treated in the same manner as in Example 1 to give 1.72 g of monohydrate of 6- / 5 (-) - oC- (4-ethyl-2,3-dioxo-2,3-dioxo-1- piperazino-cabonylamino) phenylacetamido7penicilic acid, yield 32%. This compound was consistent with that prepared in Example 1 with respect to them. analytical data for IR, NMR and melting point. ·

The above procedure was repeated, the wind day replacing the 1.52 ml trimethylsilyl chloride with 0.82 ml phosphorus trichloride to give 2.1 g monohydrate of 6- / 5 (-) - 0 - (4-ethyl-2.3) -dioxo-1-piperazino-carbonylamino) phenylacetamido7penicillanic acid, yield 39%.

EXAMPLE 4 147235

Using (4-methyl-2β-dioxo-1-piperazinocarbonylamino) phenylacetic acid and a compound of formula (IV) as set forth in Table 3, the same procedure as in Example 2- (1) was repeated to obtain the respective compounds as listed in Table 3. The structure of each compound prepared was confirmed by IR and NMR.

36 147235 -µ (Ο -__ Ι --------- - --Μ • µ u ο <Η Ε <Λ ΓΌ ηη Η-1 Ο κ \ ο Κ ο ο '' '%% s = S ο Γ ρΓρΓο. 8 ® ο ο ο ο ο 1 f f. YS.

c? ra ο cq ο ο \ - {3 ιη | —S Η J Η _1 3 t r- \ ,. hA, 3 § ° ο É ° ο • Η Ο Η O C0 2 ο, —ν 1-1 2 / - ^ ο ι §- <§> - mi} * Ο ft Ο ft ^ ο a. ο s I Ο Ι Ο Ο. 13 Ο 0 13 Ο Τ Ί «τ ϊ 5 I c / V“. cAt ^

Η ^ I ^ I

.2 w w "& - & Γ έ |« ° § «ι ΡΛ Ε * Λ Μ ο (Ο Μ Ο ο ο ο ο ο ο

> CM OJ

SU W SU

w Ο -Ο β Κλ to Ο ΙΟ ιοο ω Μ ο Κ Η Η Ο I I I yy> y

«Η CQ CQ

13 Ν 13 13 ΐ Κ Κ Η Η κ κ ο g ° ° °

Sk κ 2 3? ? I (ύ) ίρ} 37 147235

© O O

/ I I

'£ o—' o o

CM CM

K K

Island Island

[o, [ΛΟ [Λ (ΛΟ tO tO O

K Hi O M M O W a O

o OO ooo ooo y ~ (y ~ (y ~ (mo co o co o \ o \ O \ io V-SOX-a CT.) -¾ £ | CD I CO i K 1 Η 1 hp 1 ko ko K o „KO so K ° OC— O co 0-0 O y- \ LO O / -l 'OO / -V ^ Ι ©; -I- ©; i © ~ O ft O ft and <oaoaoas ° rS! ° yS 1 VS 1 I Λ 0 <T. - ° * T. Λ <HI tO Cl I to C> | to ft - f «Sf ^ KB * - ma to ft O g P) o ° w H --- Q) 1 @ 9 9 ° Λ κ o— oo

CM CM

K K

O o (O (O o totoo to o WMO W K O WMo ooo ooo ooo.

y- 'YY YY

m co cq Y-a \ —a \ - a ~ A —l g o .go g o ooo o o o

CM CM CVJ

K W K

OOO

EXAMPLE 5 38 387235 3 1.95 g of 7-phenylacetamido-3-acetoxymethyl / 1-cephem-4-carboxylic acid was suspended in 20 ml of methylene chloride and successively 0.72 ml of triethylamine and 0.48 ml of phosphorus trichloride were added successively. for this suspension at 15 ° -20 ° C. The mixture was stirred at 15 ° -20 ° C for one hour, followed by the addition of 2.06 ml of Ν, Ν-dimethylaniline and 1.15 g of phosphorus pentachloride while maintaining the temperature at between -5-20 ° and -15 ° C. C. Then, the reaction mixture was further allowed to react for three hours at the same temperature, followed by the dropwise addition of 6.85 ml of isobutyl alcohol at the same temperature and then stirred at -r15 ° C for seven hours. After the solvent was removed by evaporation landing at reduced pressure, the residue was dissolved in 20 ml of methylene chloride, followed by the addition of 3 »43 ml of N.N.-dimethylaniline and cooled to -1 ° C.

On the other hand, 1.68 g of D (-) - 0 (, - (4-methyl-2,3-dioxo-1-piperazino-carbonylamino) phenylacetic acid and 0.84 ml of triethylamine were dissolved in 20 ml of methylene chloride, followed by dropwise addition of 0.65 g of ethyl chlorocarbonate at between -20 ° C and -Cl5 ° C, and the mixture was stirred at the same temperature for 1.5 hours. After the reaction mixture was cooled to -r25 ° C, it was added to the previous reaction mixture .

The resulting mixture was allowed to react at -r-20 ° and -KL5 ° C for two hours and then at between -KLO0 and -r5 ° C for one hour. The solvent was removed by evaporation under reduced pressure and the residue was dissolved in a mixed solvent consisting of 30 ml of ethyl acetate, 3 ml of acetone and 10 ml of water. The solution was adjusted to pH 2.0 by the addition of dilute hydrochloric acid and divided into an organic layer and an aqueous layer. The aqueous layer was extracted with 10 ml of ethyl acetate. The organic layer and ethyl acetate extract were combined, followed by the addition of 10 ml of water, and adjusted to pH 7.0 with the addition of sodium hydrogen carbonate under ice-cooling. The resulting aqueous layer was separated from the organic layer, washed with 20 ml of diethyl ether and then adjusted to pH 2.0 by the addition of dilute hydrochloric acid to precipitate crystals which were collected by filtration to give 1.62 g of 7 D (-) - o (- (4-methyl-2,3-dioxo-1-piperazinocarbonyl-amino) phenylacetamido / -3-acetoxymethyl-cephem-4-carboxylic acid, mp 175 ° C, yield 58%.

IR (KBr) cm "": V ^ C = 0 1770 (lactam) χ 720 -1650 (-CON ^, -C00H) NMR ((CD3) 2SO) (1H, d), 2.66 (5H, s), 4.32 (1H, q), 4.43 (1H, d), 5.05 (1H, d), 5.21 (2H, q) , 6.15 (2H, bs), 6.40 (2H, bs), 6.57 (2H, bs), 7.0 (3H, s), 8.0 (3H, s).

In the same way as above, the compounds were prepared in Table 4. The structure of each compound prepared was confirmed by IR and NMR.

40 147235

Table 4 prepared compound of the general formula (I) D (-) - 0 0, (g W w

(OVEN N-COHHCHCOHH-j / 0 j, I

W (θ 'o ^ b-Y ^ -CH2sAirli

COOH

In m.p. (decomp.) 163 ° C D (-) -

0 O

CH5CH2-K N-COHHCHCCSH- | -1 / ^ ®, | j W fO] ο / -Ν0εΗ234-Η, Κ j cooh; E ^ I 2 |

j mp. (decomp.) 163 ° - 165 ° C

in 1- D (-) -

0 O

CH3CH2-F H-CGNHCHCOKE —i- |

w rcD 0 ^ -> r „^ sV

cooh 11 .mp., * (decomp.) 159 ° - 160 ° 0.

B (-) - 'O, 0

y ~ <c * K

CHj-iT H-C0MCHC0M- | —0 '^ j, 1

^ (O) 0 ^ "T CH2S ^ J

COOH

mp. (decomp.) 180 ° - 182 ° C · continued 41 147235

Table 4 (continued) D (-) - 0, 0 CH-sj-IT N-C ONHCHC ONH —i * r_,

COOH 'I

ch5

mp. (decomp.) 182 ° - 184 ° C

D (-) -

0 O

CH2-S N-CONHCHCONH-j- ^ w (é) J- * · / - '** · ®

COOH

mp. (decomp.) 192 ° - 194 ° C

D (-) - 0 O j- <r CH ^ -N K-CONHCHCOMH-i -__ mr W rAl HJ- ^ sc-fT 3

IUJ 0x T II O-N

COOH O.

mp., (decomp.) 183 ° C

D (-) -

0 O

CH3CH2-F N-CONHCHCONH ~ i-r ^ & vi v ~ y, ^ - nv ^ -ch? Also, 11Uj 0 1 ^

COOH

mp ,. (decomp.) 162 ° - 166 ° C

continued 42 147235

Table 4 (continued) D (-) -.

0 0 ^ - <('CH 5 CH 2 -N N-COHHCHCOHH-j- W (Q)

COOH H

mp. (decomP ·) 177 ° ~ 18 °° C

D (-) - 0 0 s w_w CH5CH2 ~ K F - C0HHCHC0KH - π | V-7 λ-isrv ^ -CEpS-Us ^ iir

add 0- / i V

^ C00H ch2ch3

mp (decomp.) 171 ° - 175 ° C

D (-) - 0 0 CEfeCHp-N K-COKHCHCOlSH-i- ^ Ί i, -f? 'w iéi Λi · f: L'¾ · i' = ·,

COOH

OH

mp (decomp.) 183 ° - 185 ° C D (-) - 0 0 'i-C? '\ S w-to H0CH2CH2-E II-COEHCHCOKH -i-j, j |

W i ~ Nx ^ -CH2sA, rH

[QJ oy I f

COOH

OH CH3 · §mp. (decomp.) 170 ° - 173 ° C is continued 43 147235

Table 4 (continued) D (_} _ '~~~ “0 .0 g w_w

C1CH2CH2-N N-COHHCHC0NH- ^ Dv) jj J

W (O) o OH C00H CH 2

mp. (decomp.) 193 ° - 195 ° C

D (-) - '0 .0 g i — n

CH2 = CHCH2-1T K-COKHCHCONH -i-I II

W (Q) 0 <^ - I, Y! L'GH2sJ ^ K''H

V ° C00H ch5

mp .. (decomp.) 185 ° - 185 ° C

B (-) - o Ρ

s h_N

OT N-COHHCHCOHH-j- ^> l JJ

W i'q ') Νγ ^ -0Η28ΛΚ ^ Γ ^ C00H ch3 «“ P. * (decomp.) 153 ° - 157 ° C D (-) - 0 0 y ~ i-

GH3CH2-I N-CONHCHCONH —— ^ ff — N

w ίο)

CQOH

mp, ·· (decomp.) 175 ° - 178 ° C

continued 44 147235

Table 4 (continued) 0 y ° y ~ <s o CHj-IT! T-C OiTHCHCQKH -j] J— W e2s ~ <{/> - ch3 lUJ o T n — i

CO OH I

ch5 m.p. (decomp.) 95 ° - 98 ° 0 D (-) - 0, °

^^ T

CHxCHq-H jr-COHHCHCOHH-i- ^ 3 ^^ f

w 0j- »y- = H2s-lj, J

^ OOOH ig,

mp. (decomp.) 147 ° C

EXAMPLE 6 (1) 1.58 g of benzhydryl ester of 7-phenylacetamido-3- [2- (5-methyl-1,3,4-thiadiazolyl) thiomethyl] -4-cephem-4-carboxylic acid and 1.03 Na The β-dimethylaniline was dissolved in 20 ml of methylene chloride and 0.63 g of phosphorus pentachloride was now added to this solution at between 4-30 ° and -20 ° C. The mixture was allowed to react at between 4-30 ° and -20 ° C for two hours and at between 4-20 ° and 4-15 ° C for three hours and then cooled to between 4-30 ° and 4-20 ° C, followed by the addition of 3.5 ml of isobutyl alcohol. This reaction mixture was further allowed to react at between 4-30 ° and 4-20 ° C for three hours, followed by the addition of 2.2 ml of N, N-dimethylaniline.

On the other hand, 0.48 g of D (-) - oC- (4-methyl-2,3-dioxo-1-rpiperazino-carbonylamino) phenylacetic acid and 0.38 mo N, N-dimethylaniline were dissolved in a mixed solvent consisting of 6 ml of methylene chloride and 3 ml of dimethylformamide were added dropwise 0.33 g of ethyl chlorocarbonate to this solution at between 4-10 ° and 4-5 ° C. After the mixture was stirred at the same temperature for 30 minutes, it was cooled to between 4-30 ° and 4-20 ° C and added to the previous reaction mixture »

The resulting mixture was allowed to react at between 4-30 ° and 4-20 ° C for two hours and then at 4-15 ° C overnight. After completion of the reaction, the solvent was removed by evaporation under reduced pressure and the residue dissolved in a mixed solvent of 30 ml of ethyl acetate and 10 ml of water. The organic layer was separated from the aqueous layer, washed successively. a saturated aqueous sodium chloride solution, dilute hydrochloric acid, and a 3% aqueous sodium hydrogen carbonate solution, and then dried over anhydrous magnesium sulfate. The ethyl acetate was removed by evaporation under reduced pressure, and the residue was crystallized by the addition of 30 ml of diethyl ether to give 1.33 g of benzhydryl ester of 7 -, / 5 (-) - θζ- (4-πιβ thyl-2,3 -dioxo-1-piperazino-carbonylamino) phenylacetamido7-3 "/ 2- (5-methyl-1,3,4-thiadiazolyl) thiomethylT7-6 cephem-4-carboxylic acid, m.p. (decomp.) 148 ° - 150 ° C, yield 68%.

IR (KBr) cm -1: C = 0.1775 (lactam), 1750 (ester),

1710 - 1660 (-C0NO

(2) 1.0 g of the above-mentioned baizhydryl ester of 7- / 5 (-) - o- (4-methyl-2,3-dioxo-1-piperazino-carbonylamino) phenylacetamido7-3 - / - 2- (5- methyl-1,3,4-thiadiazolyl) -thiomethyl7-Δ-cephem-4-carboxylic acid was dissolved in a mixture of 10 ml of methylene chloride and 1 ml of anisole, and 0.5 ml of trifluoroacetic acid was added to this solution at 15 ° to 20 ° C. ° C. The mixture was allowed to react for three hours and then freed from the solvent by evaporation under reduced pressure. The residue was pulverized by adding 10 ml of ethyl acetate to give 0.69 g of 7- / 5 (-) - 04 - (4-methyl-2,3-dioxo-1-piperazino-carbonylamino) phenylacetamido7-3 - 2- (5-methyl-1,3,4-thiadiazolyl) thiomethylT7- / X-cephem-4-carboxylic acid, m.p. (decomp.) 158 ° - 162 ° C. Yield 88%.

IR (KBr) cm "1: γ? C = 0.1780 (lactam), 1650-1720 (-CONC, -COH) NMR ((OD5) 2 SO) values: 0.2 (1H, d), 0.6 ( IH, d), 2.60 (5H, d), 1.45 (1H, q), 4.40 (1H, d), 5.0 (1H, d), 5.70 (2H, q), 6.10 (2H, bs), 6.25 - 6.55 (4H, bs), 7.0 (3H, s), 7.30 (3H, s)

Using D (-) - 04 - (4-methyl-2,3-dioxo-piperazino-carbonylamino) phenylacetic acid, D (-) - o4 - (4-ethyl-2,3-dioxo-1-piperazino-carbonylamino) ) phenylacetic acid, or D (-) - (4-methyl-2,3-dioxo-1-piperazino-carbonylamino) -p-hydroxyphenylacetic acid, and a compound of formula (IV), as shown in Table .5 , the above work steps (1) and (2) were repeated to obtain the respective compounds of general formula (i) as set forth in Table 5. All the compounds prepared were D (-) isomers and the structure of each prepared compound was confirmed by IR and NMR.

47 147235 ra '_ _____________ ω 1 -μ +3 8 Μ -Ρ' ri Ο <Η to Κ Ο ο ο CO Ο

Μ CVJ

Κ Κ cg.

α> ι in ^ ο _ ο CQ, —Λ Ο to I W V0 ot 'Ο VO i - Λ 5 (!) m μ— ο / ν. ο ω S \ 'ω μ \\ - ο +>

5 Η £ Η I

. <8 s ° 1 g ° _ρ ο *> 6 a I "© s I #% ί ° Å f ° h f CAisf S 0) I d l d CM ^ CM --- w w o * o.

in JT * ft JP 9 *

g S ^ S

H o td u w

<D

, £) ---- cd

EH

^ co, “©♦ i <g> <o> (!) CO \ / CM \ / ~

η ω V B V

g o W ofr | C i o to g r \ _§ / ~ 4. 8

'S

® γΛ "Λ

™ W O M O

ot [g! g ® S δ do o

ri CM CM

• ri ΐϋ tn go o * i é ύ 147235 48 ---------------------— --— ra ω -p -p

tn S

K ra

0 -P

l J ^ é £ Sf == \ o s “i ^ -8 ^ | m ^ gi & = {5 ^ = 17 |

5 02 -P 02 "P

1 K & · CM g1 (M g1 __ | om ώ 5 ώ fi / \ OU'v O ^ O 'd and · \\ _ oi K 2. i K p \ / φ, - {o. -J o 6 -p / N \ O - / \ o *

U-P 02 7- O O 02 y-O O

ί >> \ / O \ / O

p -¾ O 1 — K σ>

M -d i c-r I

K O H _ H

o “Λ r.

Oh,. O KO K o K / r ~ \ o S o S o

0- <ι)> O O 02 O CC

K \\ y / m o, - vo o / —in lw ^ g-® "§- © :: i · ¾ '· S · ^ Qv ts ft, O p <O ft P Y Ί a O a O s

Cti O I O! ISLAND

ω 1 J o o .s. o ova. o e o <V 5 r Ί 5 r 1 å K1 W θ '"BT“ CT'tf v- / 0 * 1 * 1 · cr> v cl to η, ΓΟ n,

κ & κ W W W

in o w o οι o oi H --—-- 0

P

(ten

EH

cn

K

ok = (k = k s - = \ I 02 I ψ —o J γ B1§§ - <o) <o) CM \ - ('cmV = 7 V = y W y—' m \ / κ \ / K N /

o S o free OK

= r \ _l, rV_! '^ V in

Y- S V- K V — S

K K κ KO KO κ o K K g o O o O O o CM CM ni

K K W

o o o t§) | é tQ) 49 147235 _ .____ to φ

• P

• P

æ

CQ

-p

.... P

cn o κ ist = \ £ a g J $ I γ $ | \ k m I Xo m a = i I_ / φ Λ_ / φ o- * φ fc = f -p -P -p ra. ra r o _ r B S B | I g I '8 3 8' É r \ o 3 l K P | K p ra \ V— o 3

/ ~ \ 8 * / ~ i o - \ -K

m N) - o o co _o o i o

. \ / O \ / O _ O

o) —Κ CTi —k C \ J

Roo OJ V. f-

H H Κ O H

I \ I O I

KO KO O r —- V

K o K o K / ^ ~ v \ o o in o co o— (i)) o o, -. 0 o, -v oj K V-y c- i-®; g- ©; 1; x-K O ft O ft 0., ¾. ft + j o a o av ^ i a

Trt I O I O O

I- ° vN S ° v ^ Φ oK 'S I I J S T J - S k, 3 ^ tn ft tn ft tn «κ a uj a κ ft £ o8 or- o g *“ »m H - Φ 3

Eh tn

K

ISLAND

K = r> ¢ 23 = ^ 1¾ = \ | h K O | 0.2

OK OK o K

i O i O i O

/ “I 8 i i o / i o 02 - O O - O CO - o N— κ V-k. V ~ s rA γΛ γΑ ko ώο ko o o o o o o

CM OJ CM

κ κ K

o o o © [© ©.

50 U7235 Γ 2 +3 m -g m i o thø

1 U O.

1Z5—5¾ ^^ i ^ O ^ έ-g <1 · I ^^ ro ^ J, / ω * ?. ω ® "1 js g £ Y i ^ jo __i § P Μ ° £? M 3 ra '\ —g 3 ig 3 / -i 8. V * * A-" - "> ~ ϋ o ° io ° \ J O °

R - ^ - 00 ITV

H g O Η _l H

I O I _ I

o o- / PS \ 'tn o δ / ΤΛ tu h §' - 'h Iy ^ yN ^ I <0> ° - S - g <Y> - o ft o S1 o ft ^ ogv ^ aoa +> ioioios ° rB-] 3 ° VI ° rY 1

s cAY ff -cAY

lu | 0 * 1 * w ft tft ft M ft m SM s in o So ra ow Η ω ω _—------ Μ cd tn cn 8 · 5 sT “Ί ^ S - O 1“ t @> @ " ίββ ί'ββ

O HS OM OM

| O I O [O

/ V o r \ O / ^ o

CO o 02 ') - O 02 - O

\ —S v-s '' j— a

Ά I-i ("A

Μ O M O M O

S Μ M

O O O

O O O

OJ OJ CM

M M M

o o o tg) (§) 1 ^ C1 147235 51

Fe-S

«1 *

R W R

J8 | i jr> f g ft

5. £ -J g I

f K = "Ty-s 1 ri 8 'V-T 0- ° i V0 c? _I °° v- S3 .00 V ti

T H g ° H

shelter; i I® g i? 1 "\ Q) t" "I? 1 Yj! I Y) 1 ° Y 1 ° o ^ gi i * s ---

EH

s ixj

P "| ^ P

z-4 8 ^ -4! »R \ _s O — 8

VK

-Λ K

m o g 0 δ g r *> ii_ @

___L

EXAMPLE 7

Using the D (-) - O ^ - (4-ethyl-2,3-dioxo-1-piperazino-carbonylamino) phenylacetic acid ° β, ββ-trichloroethyl ester of 7-phenylacetamido-3- / 5- (1- methyl-1,2,3,4-tetrazolyl) thio-methyl7-λ-Cephem-4-carboxylic acid, the same procedure as in Example 6- (1) is repeated to prepare the βββ-trichloroethyl ester of 7- / 5 ( -) - oC - (4-ethyl-2,3-dioxo-1-piperazino-carbonylamino) phenyl-acetamido7-3- [5- (1-methyl-1,2,3,4-tetrazolyl) thio-methyl β-cephem-4-carboxylic acid, m.p. (decomp.) 125 ° - 135 ° C.

The obtained β, β, 3-trichloroethyl ester was treated with acetic acid / zinc powder to give 7- / D (-) - (1- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido7 ”3 - 5- (1-methyl-1,2,3,4-3 tetrazolyl) thiomethyl-A-cephem-4-carboxylic acid, m.p. (decomp.) 163-165 ° C.

EXAMPLE 8 (1) 3 »06 g of benzhydryl ester of 7-phenyl-acetamido-3-acetoxymethyl - -Δ-cephem-4-carboxylic acid was dissolved in 45 ml of methylene chloride and 2.73 g of Ν, Ν-dimethylaniline and 0 were added. 96 g of trimethylsilyl chloride for this solution. The mixture was allowed to react at room temperature for one hour and the oven then cooled to τ 45 ° C, followed by the addition of 1.49 g of phosphorus pentachloride. Then, the reaction mixture was further allowed to react with between * f40 ° and -i-30 ° C for one hour and at between 4-30 ° and -r20 ° C for three hours and then cooled to -r45 ° C, followed by addition of 6 ° C. in absolute methanol over ten minutes. The resulting mixture was allowed to react at -i-400 to -5-30 ° C for one hour and at between t30 ° and t20 ° C for two hours, followed by the addition of 3.60 g of dimethyl aniline.

On the other hand, 2.21 g of D (-) - olv (4-ethyl-2,3-dioxo-1-piperazino-carbonylamino) -p-hydroxy-phenylacetic acid was dissolved in a mixed solvent consisting of 18 ml of methylene chloride and 4 , 4 ml of dimethylformamide and 0.88 g of Ν, dim-dimethylaniline were added to this solution. The mixture was cooled to -5 ° C, followed by dropwise addition of 0.79 g of ethyl chlorocarbonate. After the reaction mixture was allowed to react at between + 15 ° and 53 ° C for two hours and then cooled to + 25 ° C, it was added to the previous reaction mixture.

The resulting mixture was allowed to react at between -5-25 ° and -r20 ° C for one hour and at between * 20 ° and τ · 10 ° 0 for fourteen hours and was then freed from the solvent by evaporation under reduced pressure, followed by of an addition of 150 ml of ethyl acetate and 50 ml of water to dissolve the residue. The organic layer was separated from the aqueous layer and successively washed with water, dilute hydrochloric acid, a 5% aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The ethyl acetate was removed by evaporation under reduced pressure and the residue was crystallized by addition of 50 ml of diethyl ether. The crystals were collected by filtration to give 4.0 g of benzhydryl ester of 7 "ZP (") - c - A3 ~ cephem-4-carboxylic acid, m.p. (decomp.) 143 ° -45 ° C, yield 96.4%.

IR (KBr) cm -1: C = 0.1775 (? -Lactam), 1710 (-C00-), 1680, 1670

(-C0NO

(2) 4.0 g of the above-mentioned benzhydryl ester of 7- / 5 (-) - (2 acetoxymethyl-JA 2 -cephem-4-carboxylic acid was added to a mixture of 8 ml of anisole and 32 ml of trifluoroacetic acid at 0-5 ° C. The mixture was allowed to react for 40 minutes and was then released to the solvent by evaporation under reduced pressure. followed by the addition of 20 ml of diethyl ether to precipitate crystals which were collected by filtration to give 2.9 g of 7- / 5 (-) - o (.- (4-ethyl-2,3-dioxo-1) (piperazino-carbonylamino) -p-hydroxyphenylacetamino7-3-acetoxymethyl-cephem-4-carboxylic acid, mp (decomp.) 168 ° - 174 ° C, yield 92%.

IR (KBr) cm -1: C C = 0.1770 (°3 ° + 3ΐη)> * 710 (-C00H),

1680, 1670 (-CO1

(3) 2.5 g of the above 7- / 5 (-) - oC- (4-ethyl-2,3-dioxo-1-piperazino-carbonylamino) -p-hydroxyphenylacetamido7-3-acetoxy-methyl- β-Cephem-4-carboxylic acid was dissolved in a mixed solvent consisting of 18 ml of an n-butyl alcohol solution containing 0.7 g of sodium 2-ethyl hexanoate for this solution. The mixture was stirred for one hour to precipitate crystals which were filtered off, washed with acetone and dried to give 2.36 g of sodium salt of 7- / 5 (-) - © C - (4-ethyl-2,3 -dioxo-1-piperazino-carbonylamino) -p-hydroxyphenyl-acetamido7-3-acetoxymethyl-β-cephem-4-carboxylic acid, yield 91¾.

EXAMPLE 9

The same procedure as in Example 8 was repeated except that the benzhydryl ester of 7-phenylacetamido-3-acetoxymethyl-Δ-cephem-4-carboxylic acid was replaced with the benzhydryl ester of 7-phenoxyac etamido-3-acetoxymethyl-ΛΛ-cephem-4 -carboxylic acid, the dibenzhydryl ester of 7 - (<N -ethoxycarbonylamino- • eS'-carboxy-valeramido) -3-acetoxymethyl-Δ ^ -cephem-4-carboxylic acid, or the dibenzhydryl ester of 7- (S Β-Carboxy-valeramido) -3-acetoxymethyl-Z 2 -cephem-4-carboxylic acid to prepare the sodium salt of 7- / 5 (-) - α- (4-ethyl-2,3-dioxo-1-piperazino) -carbonylamino) -p-hydroxyphenyl-acetamido7-3-acetoxy-methyl-cephem-4-carboxylic acid, yield 60-80¾.

EXAMPLE 10 (1) 3.06 g of benzhydryl ester of 7-phenylacetamido-3- [5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl7-6-cephem-4-carboxylic acid was dissolved in ml of methylene chloride and 2.5 g of N, N-dimethylaniline and 0.87 g of trimethylsilyl chloride were added to this solution. The mixture was allowed to react at room temperature for 1 hour and then cooled to -45 ° C, followed by the addition of 2.08 g of phosphorus penta chloride. Then, the reaction mixture was allowed to react further at between -40 and 30 ° C for 1 hour and at between -30 and -20 ° C for 3 hours, and then cooled to -45 ° C, followed by the addition of 5.5 ml. absolute methyl alcohol within 10 minutes.

The resulting reaction mixture was allowed to react at between -40 and -30 ° C for 1 hour and at -30 to -20 ° C for 2 hours, followed by the addition of 3.24 g of N, N-dimethylaniline.

On the other hand, 2 g of D (-) - cc- (4-ethyl-2,3-dioxo-1-piperazine-carbonylamino) -p-hydroxyphenylacetic acid was dissolved in a mixed solvent consisting of 17 ml of methylene chloride and 4 ml. dimethylformamide, and 0.8 g of Ν, Ν-dimethylaniline was added to this solution. The mixture was cooled to -15 ° C, followed by the dropwise addition of 0.71 g of ethyl chlorocarbonate, and then allowed to react at between -15 and -10 ° C for 2 hours. After the reaction mixture was cooled to -25 ° C, it was added to the previous reaction mixture.

The resulting mixture was allowed to react at between -25 and -20 ° C for 1 hour and at between -20 and -10 ° C for 14 hours and was then freed from the solvent by evaporation under reduced pressure, followed by addition of 150 ml. ethyl acetate and 50 ml of water. Then, the organic layer was separated from the aqueous layer, washed with water, dilute hydrochloric acid, a 5% aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The ethyl acetate was removed by evaporation under reduced pressure and to the residue was added 30 ml of diethyl ether to precipitate crystals which were collected by filtration to give 3.58 g of benzyhydryl ester of 7- / P (-) - a- ( 4-Ethyl-2,3-dioxa-1-piperazino-carbonylamino) -p-hydroxy-phenylacetamido7-5- [5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl7-A 4-carboxylic acid, m.p. (decomp.) 148 ° -150 ° C, yield 88.5%.

IR (KBr) cm ”1: C C = Q 1773 (lactam), 1710 (-C00-), 1680, 1670 (-CON )L) (2) 3 5 5 g of the above benzhydryl ester of 7- / D ( -) - α- (4- Ethyl-2,3-dioxo-1-piperazino-carbonylamino) -p-hydroxyphenylacetamido-3- [5- (-1-methyl-1,2,3,4-tetrazolyl) thiomethyl7β-cephem-4-carboxylic acid was added to a mixture of 7 ml of anisole and 30 ml of trifluoroacetic acid at 0-5 ° C. The mixture was allowed to react for 40 minutes and then freed of the solvent by evaporation under reduced pressure, followed by the addition of 20 ml of diethyl ether to precipitate crystals which were collected by filtration to give 2.53 g of 7- / C (-) - oc- (4-ethyl-2,3-dioxo-1β-ip erazinocarbonylamino) -p-hydroxyphenylac etamido7-3- / 3 - (- methyl-1,2,3,4-tetrazolyl) thiomethyl7-4L-cephem-4-carboxylic acid, m.p. (decomp.) 170 ° -171 ° C, yield 91.0%.

IR (KBr) cm X: y> c = () 1775 (lactam), 1705 (-COCH), 1680, 1670 (-CONCT) (3) 2.5 g of the above 7-5 (-) - a - (4-Ethyl-2,3-dioxo-1-pipe-razino-carbonylamino) -p-hydroxyphenylacetamido7-3- [5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl7 Carboxylic acid was dissolved in a mixed solvent consisting of 20 ml of acetone and 5 ml of n-butyl alcohol and 15 ml of an n-butyl alcohol solution containing 0.64 g of sodium 2-ethyl hexanoate was added to this solution. The mixture was stirred for 1 hour to precipitate crystals which were filtered off, washed with acetone and dried to give 2.2 g of sodium salt of 7- / 5 (-) - oc- (4-ethyl-2,3- di oxo-1-piperazino-carbonylamino) -p-hydroxyphenylac etamido7-3- [3- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl7-22β-cephem 4-carboxylic acid, yield 84% .

EXAMPLE 11

The same procedure as in Examples 10- (1) and (2) was repeated except that the benzhydryl ester of 7-phenylacetamido-3- / 5- (1-methyl-1.2.3.4-tetrazolyl) -thiomethyl7-Δ. cephem-4-carboxylic acid was replaced with the benzhydryl ester of 7-phenylacetamido-3- / 2- (5-methyl-1,3,4-thiadiazolyl) thiomethyl7- <4 ^ -cephem-4-carboxylic acid to give 7-/5 (-) - cc- (4-Ethyl-2,3-dioxo-1-piperazino-carbonyl-amino / -p-hydroxyphenyl-acetamido) -3- [2- (5-methyl-1,3,4-thiadiazole) zolyl) thiomethyl7-2β-cephem-4-carboxylic acid, mp (decomp.) 172 ° -177 ° C, yield 83.2%.

IR (KBr) cm 1t y yC = Q 178Ο (lactam), 1710 (-C00H), 1685, 1672 (-ΟΟΝΠ)

Claims (2)

Patent Claims: An analogous process for the preparation of penicillin or cephalosporin compounds of the general formula (0) n Al / r 2 - C-NH-CH-CONII · ι Α (I) K * 1 ', RR 0 COOR1 wherein R ^ means a hydrogen atom or ester forming group selected from methoxymethyl, pivaloyloxymethyl, phthalidyl, 2-piperidinoethyl and 2-morpholinoethyl, n is 1 or 2, and n oxygen atoms are attached to the carbon atom at the 2 and / or 3 position of the piperazine ring 2 3 R and R may be the same or different and each represents hydrogen or (C 1 -C 6) alkyl, A means hydrogen or a (C 2 -C 4 alkenyl, (C 2 -C 4) cycloalkyl, phenyl, benzyl, (C1-6) acyl, (C1-7) acyloxy- (C1-4) alkyl, (C1-4) alkylsulfonyl or (C1-6) alkyl group which may be substituted by chloro, hydroxy or (C1-4) alkoxy, Z means CHg \ .H \ / I 4 or C - CH, R, \ / x CH3 where R4 is hydrogen, an azido group, a (C1-4) alkoxy group, a (C1-4) acyloxy group or an oxazolylthio-, thiazolylthio-, thiazolylthio-, imidazolylth io-, pyridazinylthio-, pyrimidinylthio-. Oxadiazolylthio, thiadiazolylthio, triazolylthio, tetrazolylthio, isoxazolylcarbonylthio or (5-oxo-2,5-dihydro-1,2,4-triazinyl) thio group, the heterocyclic groups optionally substituted with (c And R is (C1-6) cycloalkadienyl, thienyl, phenyl or hydroxyphenyl, or pharmaceutically acceptable salts of the compounds in which hydrogen is characterized in that a compound of the general formula OR6 r5-c = nj-ly (II) COOR 7 c wherein R is a residue of an acyl group without the carbonyl group, which acyl group is known in penicillin and cephalosporin-type compounds, R 7 is alkyl, aralkyl or alkoxyalkyl, R is a carboxyl group. boxyl protecting group used in penicillin or cephalosporin type compounds and Z has the above meaning is reacted with a reactive derivative in the carboxyl group of a compound of formula (O) AN NC-NH-CH-C00H (III) * wherein R1, R3, R9, A and n have the above meaning and it formed compound is hydrolyzed and then the hydrolysis product is treated, if necessary or if desired, in a conventional manner to remove the carboxy1 protecting group R, and if desired a compound of formula (I) wherein R 2 is hydrogen is esterified to introduce a of the aforementioned ester forming groups or is converted to a pharmaceutically acceptable salt. Method according to claim 1, characterized in that 2