DK151338B - METHOD OF ANALOGUE FOR THE PREPARATION OF RACEMIC OR OPTICALLY ACTIVE PENICILLIN OR CEPHALOSPORINES - Google Patents

Description

* * · \ 151338

The invention relates to an analogous process for the preparation of novel penicillins or cephalosporins of the general formula (I) as set forth in claim 1.

The compounds of the present invention have a broad antibacterial spectrum against Gram-positive and Gram-negative bacteria, and are particularly effective against the species Pseudomonas aeruginosa, Klebsiella pneumoniae and Proteus. Furthermore, the compounds of the invention have a high resistance to (3-lactamase produced by bacteria) and they have an effective antibacterial activity even against clinical isolates of bacteria, which are clinically significant. compounds quite effective as therapeutic agents for humans and animals having infectious diseases caused by the aforementioned pathogenic microorganisms.

It is already known that 6-aeylaminopenicillanic acid and 7-aeylamino cephalosporanoic acid with an amino group at the α-position of the acyl group exhibit potent antibacterial activity not only against gram-positive bacteria but also against gram-negative bacteria. However, the known compounds described suffer from the disadvantage that they not only have no effective antibacterial activity against Pseudomonas aeruginosa, Klebsiella pneumoniae and Proteus species, which have caused many clinically serious infectious diseases, but also against resistant bacteria that are frequently isolated in many clinical hospitals. Furthermore, they tend to be hydrolyzed by β-lactamase, which is produced by many drug-resistant bacteria.

The compounds prepared by the process of the invention exhibit a broad antibacterial spectrum, have high resistance to β-lactamase produced by bacteria, and are effective against clinical isolates of bacteria.

The excellent properties of the compounds of general formula (I) and their non-toxic salts are derived from the following part of the molecule (0) / Ή A-N N - C-NH-2

RZ K

2 wherein A, R, R and n are as defined in claim 1. It is clearly seen that these compounds have an ureido bond represented by the formula

/ «I

ISLAND

and is characterized in that this ureido bond is formed in association with the oxo or dioxopiperazine ring above.

3 151338

Some ureido-type penicillin compounds are known, e.g. Mezlocillin sodium of formula JK (01 -c. / 00¾ CH, SO, lf N-CONHCHCONH-i- \ / A 1 I 3 V / [Q] cr COONa

This compound contains an ureido bond and is the most closely related in chemical structure to the compounds of the invention, although there are also crucial differences as explained below. The Mezlocillin-type compounds contain the following group 0 0 '-ncnc-nh-I-10 0 V', namely an ureido bond represented by the formula -> NC-NH- and also a cyclic ureido bond represented in the 2-oxoimidazolidine ring by the formula -b-

That is, a biureido bond is formed and the characteristic feature of this type of compound lies in this chemical structure. Therefore, the compounds of the invention and the Mezlocillin type ureido compounds are decidedly different.

Furthermore, by comparing the useful effect of the penicillins of this invention with the action of Mezlocillin, which is a typical representative of the biureido-type compounds, it has been found that the compounds of the invention, e.g. Piperacillin of formula (I) wherein A is ethyl, R 2 and R are H, and R is phenyl, have a much broader anti-bacterial spectrum than Mezlocillin, as shown in the 18th Interscience (1- October 4, 1978), Session 6, no. 39 and Session 12, no. 116th

It goes without saying that the cephalosporins of formula (i) here are quite different in chemistry from Mezlocil. The present cephalosporins have excellent properties which have never been achieved by conventional cephalosporins.

The present compounds of formula (I) have their optical isomers and all D-isomers, L-isomers and racemic compounds thereof can be prepared by the process of the invention.

The process according to the invention is characterized by the characterizing part of claim 1.

In formulas (II), (IV) and (VI), R is a hydrogen atom, a salt-forming cation, or a protecting group known in the art of penicillin or cephalosporin. More specifically, the protecting groups may be (1) ester-forming groups which can be removed by catalytic reduction, chemical reduction or hydrolysis under mild conditions, e.g. arylsulfonylalkyl groups such as toluene sulfonylethyl; substituted or unsubstituted aralkyl groups such as benzyl, 4-nitrobenzyl, diphenylmethyl, trityl or 3,5-di- (tert-butyl) -4-hydroxybenzyl; substituted or unsubstituted alkyl groups such as tert-butyl or trichloroethyl; phenacyl groups; alkoxyalkyl groups such as methoxymethyl; or unsubstituted or alkyl-substituted cyclic aminoalkyl groups such as piperidinoethyl, 4-methylpyperidinoethyl, morpholinoethyl or pyrrolidinoethyl; (2) ester forming groups which can be easily removed by enzymes in living organisms, e.g. acyloxyalkyl groups such as pivaloyloxymethyl; phthalidyl or indanyl; (3) silicon-containing groups, phosphorus-containing groups or tin-containing groups, which are readily removed by treatment with IO or an alcohol such as (CH CH) -₂Si, -CLCL, Η, -Ο.

P-, ^ P- or (C.H0), Sn-.

// 4 y 3 0 C2H5 °

The protecting groups mentioned above under (1), (2) and (3) are typical, and other examples are set forth in U.S. Pat.

3 499 909, 3 573 296 and 3 641 018 and DE Publication Nos. 2 301 014, 2 253 287 and 2 337 105. The salt-forming cation can be of the same kind used in penicillin or cephalosporin compounds ·, preferably those which form non-toxic salts. The salts may be alkali metal salts such as sodium salts or potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, ammonium salts and salts with nitrogenous organic compounds such as procaine, dibenzylamine, N-benzyl - $ - phenethylamine, 1-ephenamine and. dibenzylethylenediamine. In addition to the above cations, such cations which are capable of forming salts with other nitrogenous organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine and dicyclohexylamine may be used. . The cation may also be a quaternary ammonium group formed at the 3-position of the cephalic ring, such as pyridinium, quinolinium, isoquinolinium or pyrimidinium. In this case, a betain structure is formed in the molecule.

In formulas (II) and (IV), R means hydrogen or a conventional protecting silicon-containing or phosphorus-containing group which can be easily removed by treatment with water or an alcohol. These groups can e.g. be the same as mentioned for R above under (3).

In formula (VI) under variant (c) of the process, B represents a substituent readily replaced by a nucleophilic reagent and examples thereof are halogen atoms such as chlorine and bromine; lower alkanoyloxy groups such as formyloxy, acetoxy, propionyloxy, butyloxy and pivaloyloxy; arylcarbonyloxy groups such as benzoyloxy or naphthoyloxy; arylcarbonylthio groups such as benzoylthio or naphthoylthio; carbamoyloxy groups; heteroaromatic amine N-oxide thio groups having a thio group at the carbon atom up to the N-oxide group of the molecule, such as pyridin-1-oxide-2-ylthio or pyridazine-1-oxide-6-ylthio.

Each of the above groups for B may be substituted by any of such substituents as, for example, halogen atoms, nitro groups, alkyl groups, alkoxy groups, alkylthio groups or acyl groups.

As compound (II) under the variant (a) of the process, any D-isomer, L-isomer or racemic compound can be used.

6 151338

As a reactive derivative of the carboxyl group of the compound of formula (III), a reactive derivative of a carboxylic acid which is usually used for the synthesis of acid amide compounds may be used. Examples of such reactive derivatives are acid halides, acid azide, acid cyanide, mixed acid anhydrides, active esters and active amides. Particularly preferred examples thereof are acid halides, such as acid chlorides and acid bromides, and active esters such as cyanomethyl ester or trichloromethyl ester.

The reactive derivative of the carboxyl group of the compound of formula (III) can be readily obtained by e.g. reacting an oxopiperazine of formula A-U] JH (VIII) 2/3 3

R

Wherein A, R, R and n are as defined in claim 1, synthesized in a manner known per se as set forth in the subsequent literature references, with the phosgene or trichloromethyl ester of chloroformic acid.

Literature References: V.G. Granik, Khim-Farm. Zh., KV), 16-19 (1967) (Russ);

Samuel R. Aspinall, J. An. Chem. Soc., 62, 1202-V (19V0);

Kuniyoshi MASUZAWA, Pharm. Bull. (Japan), 38 2078-2081 (1966);

Arthur P. Phillips, Ger. 1135V72, Aug. 30 (1962); J. L. Riebsomer, J. Org. Chem., £ 68-73 (1950); 151338 7

Literature Reference: (continued)

Boy, Rec. trot. Chim., £ 2 305;

Patric T. Izzo, J. Am. Chem. Soc., 8l k668-k670 (1959); and B. H. Chase & A. M. Downes, J. Chem. Soc., 387-3877 (1953).

Specific examples of compounds of formula (VIII) and the reactive derivatives of the carboxyl group of the compound of formula (III) are given in Table 1 and Table 2, respectively.

8 151338

Table 1

Compounds of formula (VIII) ---,

Mp. (omkrystal-

Connection agent) (cm-1) 1

0 o Jc = 0 1640 I

rA 136 ° C (()), ΗΪΓ ^ ΝΗ. 0 Vhh '3450 - 3250 0 kp. 122 -, V-% 125 ° C / 2 mmHg In = 0 1650 - 1630! mm.

140 - 14-1 ° C (IPA) Vuh 3260, 3170 CH3 0 _ ^^ G = Q 1645 '1625 A 112 - 113 ° C ((O))) ° CH3COF ^ JIH ^ YM 3380, 3220 o γ * π_η 1650, 1630 A 129 - 130 ° C (IPA), cicHaCQE ^ m m vm 3270 0 ^ 0 = 0 1660-1630 r <134 - 135 ° C (IPA) j C12CHC0N HH Vm 3280 0 Vc = 0 1670, 1640, λ A 96 - 97 ° C (CC1J j 0Η5 (0Η2) ΐ30Η200Ι ^ Μ ^ YM 3200 0 / n_n 1660, 1620 A 80 - 8l ° C (IPE), 0Η3 (0Η2) 50Η200ΪΓ ^ ΚΗ vm 3250 0. Vp_ri 1660, 1620

,. A 83 - 84 ° C (IPE) J

CH3 (CH2) 4CH2C01Sr HH) / m 3250 0 Vn = n 1660, 1620. . A 99 - 100 ° C (CC14), ch3 (ch2) 3ch2copv_jih 4 vM 3250 o = 0 0680 A 167 - 168 ° C (EtOH) Vim 3200

CH ^ SOpU HH

2 2 w_ Vs02N <1310, 1140 9 151338

Table 1 (continued) /? o Vn_o 1650, 1620 rA 189 - 190 ° c (IPA), u (ΟΗ · ^) 3 TCH2-, NH V jjj-g 525Ο 0 Vc = 0 1650 - 1650 r4 oily material, CH3 (CH2) 4CH2-N NH ale 3270 P 3250 rJ (oily material.

CH3 (CH2) 2CH2-N_NH all Yc = 0 1650 - 1630 - - ...... - A '^ ^. 4 = 0 1650 - 1620 CH, (CHo) 0Ho-N NH oily food 5 2 2 2 all _cb____ 0 fe, 1650 - 16J0 rA oily material- Hydrochloride CH3 (CH2) 6CH2-N NH all Vc = o 1680 '' Vjjjj 3200, 3080 ______ _______ - - - ---- «- ......... M ---- 1 o ^ c = o 1620 V \ kp · 104 ° C / 4 mmHg, ch3nwnh vm 5275 0 Vq-o 1610} ~ y oily matter, CH3CH2-N NH ale VNH 3250 oily matter- ^ 0 = 0 ^ 10 ch3 (ch2) 2ch2 - \ _ nh ale v'jju 3250 ..... .. .. ... .. .... .... - 1 —ft - -.....—— - 0 oily matter— V ^ O 1610 V- \ all. 1 (CH3) 2CH-N_jm vm 3400 - 3200 0 ,. 4..4. 4.. vL0 1620 ^ oily material- CH3 (CH2) 3CH2-N__NH ale ') lm 3270 0 ^. ^ 0-0 1620 CH rA oily material- ^ CHCH2CH2-N NH ale Vjjh 3270 CH3 "j _: _____ _: _! 10 151338

Table 1 (continued) 0, Vc = 0 1620 oily material, CH5 (CH2) 4CH2-N_JIH all Vm 3270 ^ oily material- ^ 0 = 0 1620 CH5 (CH2) 5CH2-N NH all 3270 0 _. ..,. Vn-n 1620 oily material CH3 (CH2) 6CH2-FJJH al® '\) m 3270 0 oily material- V0_o ^ 20 y-N. all in CH3 (CH2) 10CH2-NJJH Vm 3270 0 Vn n 1620 V oily material Vrø 5300 0 · i K V1630 CH-z (CHp) nCHp-U NH oily material 2 2 2 H ale J 3300 ch5 m

0 I

. . ^ oily matter- ^ C = 0 1630 CH3 (CH2) 2CH2-E ER all -) M From 3200 ch5 0 or'0 ', ^ C = 0 1650 / - \ K 157 - 158 ° C (Γ J) j ( O / -0H2-] i ffl Ό Vjih 3300 0 i ^ pp. 183- l85 ° C / 2mmHg ^ 0 = 0 1620 HOCHgCHg-F BH * JJ '6 ° N oily matter- ^ 0 = 0 1650 y — s. 'pip -) CH2 = CHCH2-ir MH Vm 3300 n 151338

Table 1 (continued) ° K ^ 0 = 0 1620 0Η? = 0Η0Η-1ί EH oily matter, I ^ all Vm 3300 CH3 Vn ^ 0 = 0 1640 CHp = CCH2-E EH oily matter, I ^ all Vjjjj 3300 CH3 0, 0H = 0HCH2-H ra Oily material- 0 = ° 1660 I wm Vm 3350 CH5 0 0 ^ 0 = 0 1695, 1660 Vf. 158 ° C (IPA) CH CH ^ -EMffl Vlffi 3220 °, ° oily material = C = 0 I730 - 1650

alp I

CH5C00CH2CH2-H HH Υ ^ Η 3300 - 3200 00 n, 0s ^ 0 = 0 1680, 1650 W 124 ° C ((]), CH ^ CHp-E EH 0 ^ V ^ j 3250 00 Vp = o 1680, 1650 V / 98 - 100 ° C {(j), CH3CH2CH2-N HH 0 VNH 3200, 3100 00 n VC = o 1695, 1670 W7 H1 - 113 C (CClr), CH5 (CH2) 2CH2-N HH ^ YNH 3240, 3150 0 0 C-0 1650 S-4 166 - 167 ° C ((]), (CH 5) 2CH-H HH ^ 0 ^ Vm 3300 - 3200 0 0 VC = 0 1700, 1660

Vf 104 - 106 ° C (IPE), CH3 (CH2) 3CH2-N HH vm 3200, 3100 12 151338 _Table 1 (continued) 0 0 Vq_q 1700, 1660

'M' 111 - 115 ° G (ΙΡΞ) I

ΟΗ5 (ΟΗ2) 4ΟΗρ-Ν HH VM 3200, 3100 0 0 Vc = o 1700, 1660

YJf 112 - Π 5 ° Π (TPP) I

CH5 (CH2) 5CH2-N ^ NH Vhh 3200, 3100 00 n Vn = 0 1700, 1660 \ -4 116 - 120 ° C (IPE) \ CH5 (CH2) 6CH2-H H Vm 3225, 3100 OO ^ C = 0 1680, 1655 VT 136 - I37 ° C »CH2 = CHCH2-NJM (Acetone) 3200, 3100 ° C = o 1690, 1645 ° C 202 - 20H- ° C (IPA).

(0) -NJSIH VkH 3260 j OO ^ 0 = 0! 700 - I650 M 128 - 129 ° C (EtOH), CICHgCHglSr HH Vjjfj 3200 - 3100 OO} 'M' 0 »0 = 0 1660 CH5CH2-N HH 127 - I280C (AcOEt), M Vm 3200, 3080 CH3 OO) M a * 0 = 0 1660 CH3-N NH 146 - 1 ^ 7 C (il).

M Oy Ask 3200, 3100 -ch5 --- j-J- "-------

Note: IPA = (CH5) 2CH0H

ipe = (ch3) 2choch (ch3) 2

AcOEt = CH3C00CH2CH3

EtOH = CH 3 CH 2 OH

13 151338

Table 2

Reactive derivatives of compounds of formula (III)

Connection. Physical Properties I * R · (cm-1) 0 ·, rA ....... V0_0 1790, 1710, CH ^ CO-N N-COC1. Oily material- ^ w · all 1640 0 '^ C = 0 1790

raw

ciCH2oo-ir ir-coci 1730 - 1650 o 4 = 0 1790, Λ C12CHCO-N N-COC1 1730 - 1650 0 Vc = 0 1740, 1.660, CH3 (CH2) 13CH2CO-Nwli-COCl "1640 0 Vc = 0 1740, rA "ch5 (ch2) 5ch2co-it w-σοσι i680 - 1640 o 1 = 0 1740, iH" CH5 (CH2) 4CH2C0-N_ ^ N-C0C1 1680 - 1640 \ o Vc = o 1790, 1710,

raw

CH5 (CH2) 3CH2CO-li N-COC1 1640 -, 0 Vc = o 1790, 1700 CE5S02-ir N-COC1 f VSo2 2.320, 1140 14 151338

Table 2 (continued) 0 VC = 0 1740 - 1720, oily (CH5) 3CC00CH2-N N-COC1 material 1670 "^ 0 = 0 1790, 1720 CH5 (CH2) 4CH2-I'Tjl-COCl 0) A" VC = 0 1790, 1720 CH 2 (CH 2) 2 CH 2

A

CH3 (OH) 2CH2-K 1T-COC1 "YCz = Q 1790, 1720

M

ch5 0 \ A "Vc = 0 1790, 1720 CH5 (CH2) 6CH2-1'I_rl-COCl 0 m.p. = 115 - 116 ° C j (decomp.) M1 = 0 1720, 1660" U'0001 (from (6 )) 0 ^) HN N-COC1 crystal Yc =; q 1720, 1660 ge3 K oily m0 16; 0 CH ^ -F K-COC1 material 0 your 0 K "VG = 0 1750, 1650 CH5 (CH2) 2CH2-N N-COC1 -1-1-1 15

Table 2 (continued) K oleactict ^ C = 0 ^ 30, 1650 ch3ch2-hwij-coci 0) K "vc = 0 1720, 1640 (CH ^ CH-I ^ Ji-CGCl 0) K« vq_o 1730, 1640 ch3 ( 0H2) 5ch2-n N-COC1 0) K "VC = 0 1720, 1640 (ch3) 2CHCH2CH2-N N-COC] 0) K" vc = 0 1730, 1640 ch3 (CH2) 4CH2-N N-COC1 0 j \ -y "Vc = 0 1730, 1640 ch3 (ch2) 5CH2-N N-COC1 0) K" YC = 0 1720, 1640 CH3 (CH2) gCH2-lT_N-COC1 0 in K "VQ-π 1720, 1640 CH3 (CH2) 10CH2-N N-COC1 - \ K ”Vc = o 1730, 1640 H> -1 1T-COC1 - '\ _f 16 151338

Table 2 (continued)

0 r H

0¾ (CHo) oCHo-H N-COCl oily} 7 y-t material Yq = q 1720, 1540 CH

S

0

Υ “λ” I

CH5 (CH2) 2CH2-W BT-COCl vc = o 1730, 1650 CH3 y-, · '"C = 0 1720, 1645 (O / -CH2-N_N-COCl 0 Vc = 0 1730,) -Λ" HOCH2CH2 -IT Έ-COC1 '1660 - 1630 0) K "Vq_o 1720, 1640 CH2 = CHCH2-N N-COC1 0 K ·) CH2 = CHCM N-COC1" Vc = o 1730, 1650 I v-1 CH3 0 ^ - v) CH2 = CCH2-ir IT-COC1 "Vc = 0 1730, 1650 CH3 CH-zCH 0 CHCH ^ N ^ JT-COCl 'Vc = 0 173Ο, 1650 (trans) 17 151338

Table 2 (continued) π η m.p. 94 - 95 ° C, 0 (decqmp.) ^ 0 = 0 1790, 1680 CH3-N_N-COC1 (from CH2Et | 0) oily material- ^ C = 0 Π90, 17 ^ 0, / \ o '] λ CH5C00CH2CH2- N N-C0C1 ax 1670 O π snip. 95 - 96 ° cuu (decomp.) Vc = 0 1780, 1660 ch3ch2-n ^ n-coci (from Ac0Bu ^ oily material- ^ C = 0 4780> CH3CH2 CH2-C0C1 all 1710 - 1640 0 0 j "Vc_0 1780, 1660 CH3 (CH2) 2CH2-N N-G0C1 0 0 mp 130 - 131 ° C \ M VC = 0 1780, 1660 (CH3) 2CH-N N-COC1 (decDmp.) Oily material- 0 = 0 1790, CH3 (CH2) 3CH2-Njr-COCl all 1720 _ 1665 0 0 Fr_n 1780,

M

CH3 (CH2) 4CH2-I-ir-COCl 1720 - 1640 0 0 Vq = 0 1780, M 'CH5 (CH2) 5CH2-N N-COCl 1720 - 1640 i8 151338

Table 2 (continued) 0 0 Vc = 0 1780, CH3 (CH2) 6CH2-hMt-COC1 1720 - 1640 0 0 V ^ o 1775, i (crystal CH2 = CHCH2-N ^ N-COC1 1660 - 1620 in OO \ ic = 0 1785, / - \ crystal (OZ-N ^ JT-COCl 1720 - 1650 oily matter- ^ c = 0 1790 * 1720 'C1CH2CH2-N N-C0C1 a ± e 1680 00 hi mp 65 - 70 C.

CH3CH2-F N-COC1 VC = Q 1785, 1680 ^ - (. (Decomp.) Ch5

Note: Et20 = CH3CH20CH2CH3

AcOBu = CH3C00 (CH2) 3CH3 19 151338

The compound of the general formula (V) under the variant (b) of the process can easily be obtained by reacting e.g. an alkali metal or alkaline earth metal salt or salt having a nitrogenous organic base of an amino acid (any D-isomer, L-isomer or racemic compound) of the general formula (IX): H + N-CH-COOH (IX)

Δ 15 R

5 wherein R is as defined in claim 1, with a reactive derivative with respect to the carboxyl group of a compound of general formula (III) in a solvent inert to the reaction, in the presence of an acid binding agent.

As a reactive derivative with respect to the carboxyl group of the compound of the general formula (V), a reactive derivative of a carboxylic acid is usually used for the synthesis of acid amides. Such reactive derivatives include, for example, acid halides, acid anhydrides, mixed acid anhydrides with organic or inorganic acids, active acid amides, acid cyanides and active esters. Particularly preferred are acid chlorides, mixed acid anhydrides and active acid amides. Examples of mixed acid anhydrides are mixed acid anhydrides with substituted acetic acid, alkyl carbonic acid, aryl carbonic acid and aralkyl carbonic acid; examples of the active esters are cyanomethyl esters, substituted phenyl esters, substituted benzyl esters, substituted thienyl esters; and examples of active acid amides are N-acyl saccharins, N-acylimidazoles, N-acyl benzoyl amides, N, N-dicyclohexyl-N-acylureas and N-acylsulfonamides.

Compounds of formula (VI) under the variant (c) of the process can be obtained e.g. according to variants (a) or (b). Some of the compounds formed by variant (c) can be further used as starting material by variant (c). Any D, L and racemic compound of formula (VI) may be used.

The practical implementation of process variants (a), (b) and (c) is explained below.

The variants (a) and (b) can be performed under substantially the same conditions. Thus, the compound of formula (II) or (IV) can be dissolved or suspended in at least one of the solvents: water, acetone, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, methanol, ethanol, methoxyethanol, diethyl ether, isopropyl ether, benzene, toluene, methylene chloride, chloroform , ethyl acetate and methyl isobutyl ketone. The resulting solution or suspension is reacted with a reactive derivative of the compound of formula (III) or with the compound of formula (V) or a reactive derivative with respect to the carboxyl group of the compound of formula (V) in the presence or absence of a base at a temperature between -r60 ° and 80 ° C, preferably between -t40 ° and 30 ° C. The reaction time is usually 5 minutes to 5 hours. Examples of bases used in the above reaction are inorganic bases such as alkali hydroxides, alkali hydrogen carbonates, alkali carbonates and alkali acetates; tertiary amines such as trimethylamine, triethylamine, tributylamine, pyridine, N-methylpiperidine, N-methylmorpholine, lutidine or collidine; and secondary amines such as dicyclohexylamine or diethylamine. When the compound of formula (V) is used in the form of a free acid or salt in the process variant (a), the reaction of variant (a) can be carried out in the presence of a dehydrating condensing agent such as Ν, Ν-dicyclohexylcarbodiimide, N-cyclohexyl-N N-N1-diethylcarbodiimide, N, N1-carbonyl- (2-methylimidazole), a trialkyl ester of phosphoric acid, ethyl ester of polyphosphoric acid, phosphorus oxychloride, phosphorous trichloride, 2-chloro-1,3,2-dioxaphospholane . The salt of the compound of formula (V) comprises alkali metal salts, alkaline earth metal salts, ammonium salts and salts with organic bases such as trimethylamine or dicyclohexylamine.

Practical embodiments of variant (c) are as follows: When B of formula (VI) is different from a hetero-aromatic N-oxide thio group with a thio group at the carbon atom next to the N-oxide group in the molecule, the compound is reacted of formula (VI) having a compound of formula (VII) or a tertiary amine in at least one solvent, e.g. water, methanol, ethanol, propanol, isopropanol, butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, dioxane, acetonitrile, ethyl acetate, methoxyethanol, dimethoxyethane, dimethylformamide, dimethylsulfoxide, dichloromethane, chloroform or dichloro. The above reaction is preferably carried out in a highly polar solvent such as water. In this case, it is convenient to adjust the pH of the reaction mixture to 2-10, preferably 4-8. The desired pH value can be obtained by adding a buffer solution such as sodium phosphate. The reaction conditions are not very limited, but the reaction is usually carried out between 0 ° C and 100 ° C over several hours up to 10 hours. When B in the formula (Vi) is a heteroaromatic N-oxide thio group with a thio group at the carbon atom near the N-oxide group of the molecule, the compound of formula (VI) is reacted with the compound (VII) in the above solvent in the presence of a cupriforbindelse. This reaction is particularly suitable if an alcohol such as methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, n-butyl alcohol, benzyl alcohol or ethylene glycol is used as the compound of formula (VII).

In this case, the reaction proceeds smoothly using excess alcohol as it also acts as a reaction medium. The cupric compound used in the process may be organic or inorganic, such as cuprichloride, bromide, fluoride, nitrate, sulfate, borate, phosphate, cyanide, formate, acetate, propionate, citrate, tartrate , benzoate or salicylate. Preferably, the amount of cupric compound used is half a mole per minute. moles of the compound of formula (VI). The reaction temperature and reaction time can be varied depending on the nature of the compound of formula (VI), the cupric compound and the compound of formula (VII), but temperatures are preferably between 0 ° C and 100 ° C, and the reaction time may conveniently be between several minutes and more. days.

The reaction conditions of process variants (a), (b) and (c) are not limited to the above, but can be varied depending on the nature of the reagents.

Furthermore, one can readily prepare non-toxic salts of the above formula (I), which is a salt-forming cation, known per se from compounds of formula (I) wherein R 1 is a hydrogen atom or a blocking group.

22 1 5 1 3 3 8

Among the compounds of formula (I), the penicillins can be readily obtained by one of the aforementioned process variants (a) and (b), while the cephalosporins can be readily obtained by any of the variants (a), (b) or (c).

In the following, the study method for the activity of the compounds of the invention is described.

(1) The minimum inhibitory concentrations (MICs) of the compounds against different standard strains are shown in Tables 3 and 4.

The minimum inhibitory concentration (MIC) was determined by a plate method published in "Chemotherapy" (Japan),

Vol. 16, (1968), pages 98-99. The culture medium was cardiac infusion agar (pH = 7.4). Number of cells per cell plate in the seed material was ΙΟ4 (106 cells / ml).

23 151338

&Quot; "

ft ft 'θ' Ο m I- 1 Φ cd ηι ο +3 ί) (Ο ι \ | ιΗ Ο OH, η ft 3 Λ \ /

ft ί> S V

_Ο _____ ft Φ γΗ Cd ι —I · Η φ ft ο ο · ο • γ-Ο Ο ο in ο ο 03 <S ™ <Μ Φ φ κ, Λ Λ ^ ft ^ Μ 2J___ ω cd cd f5 m ο ο " „A so ο ο ο · Η · Ο ιη m

If tiflfe OJ

3 3 · Φ ίπ Μ Λ CQ Φ Ρη cd cd • ri * “3 jft t ri OH C- C- t> ft a tn m m φ ·

Λ ί-F Η Η H

03 G \ / V

bold V V _ ft cn 1 o ^ O C \ 1 c- c-

H in tn H

> 5 03 0C3 · ·. * Λ 3 3 Η H tn ft O Φ

Cd O ft w \ /

43 O 3 V V

cn o cd tn

rh

03. r—> - -, Q ft ft

cd · Η -H

£ 4 - '• HH

ft Η H

«Η * H * H

, Η I O I O

breath g 3 | 3 tj-h "£ .2" ^ 5 fd ft 43% id | 4 IS gray

H

(1) e n O cd cd ft iw! 2i a ft tn tno tn tno tn tno

ft a BO a BO a W O

jj 000 000 000 3 V-f νγ

Jj CQ I CQ I CQ I

+ J \ - & N-fe pl · Λ · 1 o o 1 o o a o a o od 00 o tn a a a o a o

O - a 0 - 0 C3 - CQ

(O) Co) Cot -Γ-1 - * --- 0) '(xoaq-TOH) fea x> I -, - 1 -—; -—- 1-1-.151338, = I · -to o ff)!> .0). In g according to CM. Ln - 5 ™ ft -ilt «'- -"> - ti> 0

^ £. V

ω co O. .

I S § 02 w u. + Tf £ • l-fg «- - o. . d o “

fl. > ^ V V V

'3 d -.

§ o £ Lo Lq Jo Lo

S.E O. lo .- ^ N · CN (M (M

- ^^ 'li. Csl "Ό ^ sO so sO J-0 ω αϊ ^ ^ Æ« 'ci-.

“S l_ t> t> _ _ F> '£ - l2 Lo lo Lo -. Lo O) ~ Q X _1 _1 O o o Ίδζνν V V V V v

UJ

J11 £. '£ & t - ^ *' g §- «Έ VVV v 'ft * -__ · X · Z 2 χ 2 z 2 xx ° £ £ · 2 xx9 · £ -P o .p -P o - P-Po "> -> 'o * .5X8 ajs. 5Sa sjs 5ja 5ja Xs - ti · ·?. T' t_ X» '· s —i lT li Ρΐ Vi Vi Vi' Μ V. - <%. —K_ —Is —k —k ~ —k_ 0 o nq ooooo

ή X X X X x x X

li iil I is 1 a 3- © g §- © § 5- © S | - @ § §- © s 5- @ § 5- © 4JZ 2 ZZ 2 X 2 “8 S 8 8 8 8 I '<) £ »X>» X) X.

o * & af. d d X § co 0 ϋ 5 5 o. x! 0 -5 3? x ί § u ϋ o S £ i c -η ω ,.

-0. ™ CO - cl 0Q xf- Lo sD

m i — t * n sj o cd m i 3 π fa Ti c I ______ _ 25 __ 151338 «s t> 5 Q in t> O _L In ^ Olo ^ k 'Lr> O N. lo

0] = I. u \ - - - N

-ώ 3 V- so _ - o o W

i I r v v ~ v ~ a.

w u) O ^ ί «° E & ^^ 5 y £ z - - - ό ο _ ο

oli ^ v V V V V

! t -------- 1- S!

How. s K; «A a a - | ^ Ll N vo 'so <n vo so so 0 ¢) ~ * Æ «__ | .. b 5 B' 6 - - B t 0) I A - - °, ® - o

Ο δ 7 X / V V V V V V

W Z V -

LU

1 0- J δ S £ £ ^ t> y - ^ * Ί- if v .y v v ω ^ _________.

id 4 4 * ddd cf zz „zzzzz <^ .5 ^ 5 58 ξ & 3 Sig ψβ Sig ϊβ-Ρ Q) (/ jw tø (/) (λ ω tø µ VZ V-;: V :: V: - VZ V ":: V" :: · tj Ko - Ko Ko Ko Ko K ° Ko

% X X x X 5 XX

.rS z. xx SS zz gS 'S 8 8 o 8 8 ΰ s S- @ § §- <3> § §- © § S-® S S- @ sg 5- @ i “izi 2 gzz 8 8 8-8 § § 8

X X) X X x X X

5 X x "f f g ·. F! © Ϊ 5 5 § ° s § s s s s 3 s -1 ---- _ rt · • Η Φ • S" -o 00 o- £ - £! 2

O (DU

foTj ΰ 26 15 1338 g "ο I δ ^ 'Ν.' Φ. S '

Jl * ei "*?. Get S ° ft ^ S- W V) t>

ir n fs 0s *. O O o CN

O n 'Lo O · O IS

K O o, d o 6

£ L § & V V

§ c? s: w i /) · Ln.

IN.? O li) ·. . Μ i /) · £ N Lo H

"In t * H -" il fN ^^ si <U (U; "Æs Λ Ί-h 'g;. G: t> + 4« - "• S 8 g ώ $ V“ 5 d 6

LU

O n

o y o *. Qx (S O CS

t. ^. [> ES £ κ ~ X ir ^ ° ° o - o O o

Ί- tf g V V _V

^ = - ..,.

'x-. I n Q · Q · (o) I δ 2 5 -f 3 M ° o g o o.-¾ - o <| x ^ Si -p P x o- | ° 5 5 o o · .¾

-g -P o P P O -g -P o m "0" "O« «c *> ·? O

. “Χδ“ Lp ^ Xs “Yes 5Χδ 5 | s 5j5S

u \ i il il Q u il .; 1 Ko .'i Ko Ko Ko Kq Ko Ko X- 'Χ X X -X X x

S 8 8 I 1.1 I S

I of © §§- © Sf® §f® §f® §f® §5-® 3 ZO 2 ° 8 OO · s K 50 50 50 S 50 Si x "> £ ^ f> £ 'Ί x1 ooo UO 5 o ro 'X 3? O 6 i' “" 1:

C

-Hq) ·.

m ". L {£) ^ 0 I> OO o- O

O 0) U ~ CN

C___ _! ____ 27 —.__ 151338 —'2 o · i ^^

<0 o S 1Λ, ~ LO. FNJ

-If) 1- d ^ w - ft

Si v t r —- ^ - --1 1 i j ω co t> ['-. (V.

| X§ 2 £ 2 2 2 B £ 2 i O w v ° ^ I CL> ^ v i ——- w a a o § o. . . ίο lo S.EOlr) io lo CM CM N io ~ 1 ϊΓ H ° * ^ - νό I vO J \ £) I £ 4 tl) QJ * & s% ._ b 3j-. C> L /> ^ ~ L)

Qj- ^ Xo d - 0 - m -

-50.5 V V V V V V

w <c v LU. · ^ T>, 4 .-- c- _ 0 g 3 0 t> in x lo. ίο d 6 - 0 -_i 0 ^

"A. g V V v ^ V V V

£ Ll if)

. φ 'I

N

5 I 4 -Sf «i -5 ci ο X x z ^ x 2

»JJ o J5 ί> O"> <50 4? .2 Q "" O J2 J? O J? J? O

SXs 5J8 5AS ^ 5 ^ 8 Jig 5 ^ 8

Vj, * 0 Q * O C-l WW:

H "ί-o H * o · Ko |" ^ o K

2 IIX 5 5 χχ · oR 8-8 S § 8 8 § 5- © § oO a ο-ζΡ e o- <g) g | - <g> s 5- <§> -o § PZZ .2 Z 2 2 z 0 8 8 8 8 ^ 8 8 0

5 -JO X) X X> "X X X

Ί £ ί α Ϊ 5 "· δ .¾ U χ * υ ϋ 5 ° j C! ·! Q w - cm 00 4- in. V £> t>

Mr-t.N <N CM 04 CN CM (M

0 a; m fe xs c: _____ | ___ ϋ__ 151338 c5 v -; '5 q m ,. O „o-, i / i

i O Ifl ~ / Φ t> [> <N

-S 3 y- οο ό o o ^ c \ | Μ a_ j ----------: - I.

! ω <0 1>! 'Ffl k O bl Γ0 O "£ * t> C"?> Il «, v d 6 ~" v g d

. 11 o io 2 C2 52 lo S

Ί 15¾ ^ "ϊ Λ3 Λ) N iQ> 0 Φ at - 1-b 5 · s - 5 B B 5 g) ~ q X _ <O O O - __

-f8zv V .V V V V V

lil.

1 £ L

8 il I i t t "B. Eph. B

| S2 v d ° ° v v v & * -_____ i_ p>

X

S

o (8> 8

4 ~ r $ r? ° <| 5 <S.

Z z z Z o- | 5 z "? J? O -P-PS -P -ro ·? -? O 4? -5 o" «o *>" o 5Xa ^ £ s ψ & πβ & sfa sis W wi tø co c / ι cø w ^ ww 'yf y? y? y? i Ko Ko Ko Ko Ko K ° Ko

nx X 'x x X 5 X

° ZX ΖΓ Z Z Z ^ 8 o o o g g I s | J? § g-® s | ® §f® § | ® § "- © §1-®" * d5 K K K: ΰ s 1 Λ ^ χ1 A χ O O fil u o o

Si, j ^ i <P ">

5 5 & 3 S

___I______ i β Λ ra OO O o - ol Γ0 xf · nin · CM Csi ro ro ro to ro 0, (U St 1¾¾ s _ ___ 29, ___ ^ -! __, .. taJ338 β g "ai 8 in ^ Μ m to t * vd * 8 5 J {5 N vO 'w> 10 ^ ii | r; v ~ j ^ 3- j__ ~ ______ i 1 Γ ~ jjw V) l>! li% as s s. £ .. 5 5 s I? Δ - - - ^ VV ° 8 d '- sz o I · - O io 10 · ΙΌ.,. ΙΛ "ijji cvi <N £ 4 (¾ NN ft

Q) QJ

(£ «d ~ h O 'O' g P ~ P * O '.

Z χ rø Λ7 W ^ ^ ^ ° 2

Γ2 °. · ° V V V

HI

i q.

J lag £ s P'S 5 & '

° ° V V V

<8 ^ · _____] ___ [___ z z: z 2 Z Z z

;; o irS ÆxS £ χο xxS -r-Ps xxS

5Xs sia 5Sa s yes s Ss $ IJ ^ §a

(/) W W <0 CO I (0 CO I

y-z w yi 'yi y? yi µ: Ht rs = ns H »o H * on ° 1¾ g II 'xx 5 .5 x 8 8 i IIII 8 fj §y @ § s.® § | h @' §s-® § §- © § f®. §

5: Z Z 2 Z 2 * Z Z

t <50 o O Q o O

gSoooOoo * X X) X X) X Ό Ό J3 x 5 3? Of. 0 o ^ s ^ S 5 A, 5 3 "g 3 'S' <sl.

__ -; ~ 7 · • rl <U. ^ Λ in in vD £ r- 00 o- 0 - M H · CO CO CO 10 ro ip xh 0 0) u '1¾¾ gj_______, ___: _ I _: _ 30 _ ^ __ 151338 ί is

I O I g io 10 ^ rø lo lo H

! J |> - ^ N> 0 ti d ^ ri m S- ί; ___________ ... - ....> .. -........ — .—. - —Ϊ i. -.

i ιο ϋ) t> SSS fi £ 2 j £ | g «- --- - - 7» i________ • If £ {Q "Ϊ} 'oj. Ί S 5 QJ G) £ see“ S h 00 00 o ~ - C- r> "£ IZ -2 ^ C> t> m CO lo Lr) 185v °. o ° ° v f LLi in. 1 o.

i i s i ε s g g g e «

Ils v ° d · ό v å 1, __ i i. i i i i i i

4? -P O T-rS ΓΤ O · £> -? O -P -P O -P-Po "" O

SXs Ά £ β 5 ^ 8 δ S s sgg 5 g§ 5X8 tø w tø co µ ω w W V -; - V-; r * V- :: \ _Z \ -: i \ —2 1 Ko Ko Ko Ko Ko Ko K ° - Ko ol 5 ·. i έ Ι i i Ή 8 8 8 8 8 8 8 S S ^ g> §S ^ gf- <g> § §5 ^ 5) § „- © §5- @

z 2 Z 2 2 2 Z

Γ.Ο o o O * 7 O O

W O O O O o o * * 0 ° 0 Ό * 0 \) “0 Q o o o o oN ^

cl O o Cj W · I

5 g 3 * $ xn in S

o H 3 U · -O O £ ___o 1 g g ι a ___ ° 15. i? $ $ # $ $ O Cl) 5-1 (¾¾ c · _______ JL _: _ L —___ _____, _-. 31 _ 15133ft

'- I

j | 6> f \ of L ·) Lo Ln Ui! J! ^ * νό * ΰ - - d; ^ S.

I --------! Ill - B = S g 2! Ifδ v - ° i 'i> ____________________________.

8 d 11 o *> u, JQ 2 -§'fX X 2- ft ΰ s6 j ft qj <u & a £ ~ 0 i_ O- t> Ο £ - _rto r - 5 b) w Lo u) -, £ <d * nx _: -i __: _i ο o

-§Andv v v V V V Q

LU

111¾ B § '' <? > g g | ls V V V v · ° '° ώ _l _ ^ ______ <d 4 _ £ <i 4 d 4 z z z z 2 2; x

<P "? 0 • r'-rS -P -r ° - £ -? Ο -P -P O -r-? 0 -τ'-PS

i 5X8 sXa 5Χδ <Xs 5Xa sXa ^ ls i vi · W v-l ·· V :: γΐ \ -: ι V :: 6 ί Ro Ro Ko Ko "Ro Ro Ro

£ j X X. X X x X X

S] I I I I I I I I

In e 5h§) g §- @ § S- @ g §-® S 5-® g $ - <5) § S - @>

ί 5 2 2 Z Z Z Z

] j o 8 8 8 § O o - £ jO «0 Æ 10 XiSi 3X 00 i 'S ϊ X g ~ g € s a A L-J j? 3? £ ¥ i @ ° u S 4 υ o υ i: p • H 0) -P “cr · P T- M <Y) d * lo ^ ^ Ψ ^^ lo JO ft ^

1¾¾ G

__32 __151338 _ί S \ il 82 ™ ί2 ft ™ i. \ V) § I, - \ φ> * ^ ΓΟ 09 νθ (Υ) Η \ - \! ________ \ | οι to ΐ> \ i lp iå 2 2. 2 ™ ft \ ί ε 3 Φ - ή 'ri ri ni S0 \ | 11> υ' · \ | ------ --- “-: ----—-> ------- S d \

Il O 52 '2 52% L ·) \ "§? H.-Ri ri ri vi ^ ri \ Æs \ d \ 1 = 5 N.» «S a E \ U z v \

LU V

____; ______ \ p fl_ r · \

Jfli £ S S. IS 'tg - E \ | asi 6 - - - - v \ å h. \ I -rm- i i \ i · \! dd 4 (S 4. \ i Z z ZZ z 4 \ i <5 ^ 0 -P -? O -5-? O -p -2 oppo P "0 \ |. ^ XS SXp 5Ss 5js 5 * 8 \ ( I vi Cl y 'v:. Cj Cl \ (D «o I' o I so I oo \ six r X x ac x \ M! Zzzzzz \ 0; g QOO 8 O \ 1; 8S- © §f-® S§-® S§® S | - <§> s | ® \ i li gi it s € 1 g \ 8 i ^ Sr ^ Xr ^ Xi85 j:; jO \ rs "s1 io § X \! Ϊ ί δ 5 * f ^ \ i _____ | ___, _}

«X

• Η Φ _ \ Ethno r> Qa cn o - \ S- <I — 1 · -Lo Dj X / J lo vO vO N.

O 0) H \ fa tj d ____ [_ [_____ s ^ "ΤΓΊ - ^^ - Π13 ..... I-. I 151336! (? & & 'Ε 2 2 2 κ ΙΐΛ · V ν - ^ m 3 g „22« & <d / το Ο OO> '· £ -fz £ o O Ο Λ, W Λί

• £ L> <& NN

See s: i .§ o g o § S * 0 '1Λ o §§ · & S 8 N ^ w N · β 1¾ Λ Λ Α / «·“ 5 Hj [> £> fO. _ o- r - I uo 'Lo Lb' ~ ". -. J> - o m _i _j. _i to c>. q ^ • 5 ° z v V V λ V V V · • m -_ ·..,.

: r: - ..

£ l.

8¾ O '£ r t> D ~ t> .O' 'r ^ O ·. ·

J g § ^ · * -0 ^ Lo I> - · R O

"ti to V -V v V ° ° +» LL 09 e1 X * "> o 5 § 5 S li, j ^ s g 5 -Ti, g. 8 8 H @ 8 8 H.

oo (b © Z oo (/) -rt * _H _ * «ri f« rt? zz y ~ £ P z® p © S zÉ .o 2 ^ (0 y-8 (oy-8 M 'yS ifly- 3 W y-υ w y- SU) y-δ 1 ft 'ft ft ft ft ft ft B x ° x ° x ° x ° x ° x ° ± °

SgESSSSS

H O · O O O O O O

I §! - <§> έ i $ “& s-®. gs ^ §! _ © -s 3? µ i J g i 'i u Jj u JJ 55.

f δ ί o g I = 4 cd cd t C O Z ““ 7 V "" 7 ^ • H 0) _> N I Ίµ, O,? 85. J i J '* j -. <N ro g-cfl 1 3 1 j 1 o 1 ^ 1 ___ '_ 34 _ 151

_d S

i »I e s: r w o- s: vo -g a> O .. -: Λ9 o 5 v - 55 ·· v v 3 ^ n t> _ l> ^ ov ^ | £ S ^ ^ 2 R & R t> p Ji ° x - 'ή' ~ - ° d

ί I *. Μ ^ V V V

1 g ^

Jig s ft ft ft. d 5 1 if * __ ci h> -O'- _ o 0 "Ov O'- f.

r ~ i t * 'S' o t> R

ί (fi. H o ° - o 6 o ^ | ° Z · V V ° v V v hi '%'

§ CL

8 ^ o ?: R µ 't> s- £ 8 K r> - J> Lr> · t> c>

> v_> C) '' rv ό O

-fig v ° vv '~ vv $ ^ _I_i __ ^ _ ψ ζ · £ H au * 3 3% a © "2 3 g, _ ° ί yi, ® 4. 5 ί _J> ® /" z, 5 ^ co y-8 to y-8 w Ny-8 to ^ -8 to y-8 w y-8 w y-8 1 ft ft R ft ft ft ft g x ° X ° x ° x ° X ° X ° x ° * 2 g § I g- II § I g O-® ee 5 ~ <o> § oRo) § 5Ro> § §- <o> § | -® szzzzzzz

MO Q Ο Ο Ο Ο O

+ jo S> 2 Οχ1 ο ο o β JO X »Tf X> X 5? ". g □? £> x * nf

So O o O «5 5 5. 1 1 'c -H (!) Fj'. ψ L0 vD [> CO 2.

0 CD M 1¾¾ fi __ 35 '_ 151338 j <ϋ _β _α ϋ § S sO. Ρ ~ £>, ηΟ '^ § | L0 Lo Ln to sf- "~ -g S> -: - - o <=> trj it VV Ό"? 2 J i> ot> c> ^ o · £ SL 07 · * · ° Lo Lo!> ^ Li) £ ~ ^. °. - - —1 d O -

£ L> * V V

3 * I O lo s c o. ,, N lo • fffc β 5¾ M. ^ CL ft i§ [_ "5 Η cn _ i> · t · ·, <>. O 'C - Z t> / Lo lo ^ Jj, x fi H ό - . °. - - d Q - * 5 ° zv vvvvv 111> ___ -o H.

Q V cs I ** CN D *

Lo B) Z ^ w ^ § ^ ° d - -. ° '° -

t- <S ^ V V v v V

+> LL

ω -τ 'm η Η_ 5 5 | = ^ Ζ = (Ζ = <ζ = ^ ί Ζ = \? = \ £? = \ X1 W | Λ] «I ζ-ο Ο I ζ-δ Ι_?" υ ζΐ η η η * 1 η Λ jfi Ji Jé Ji J4 Ji Jt, co y-δ iTiu w γ-8 w yo w V-δ ω y-δ t0 \ δ v-2 y · / Vf γ-f Y ~ f Yf Vf S x ° x ° x ° x ° i ° i ° x °.

o | 11 § I 1 I

H § §- © § §- © s g-® § §-® § §- © S 5- © s Λ1 z z z z z z z ίο O O O o o o o

MOOOOOCJO

s Λ 55 35 55 30 55 55 *! i> é! I é -1 --- ri 'H d) -g ® _ - cm oo · φ in · l>

OtUri __ ~.

1¾¾ ri _ · _ 36 _ 151538 d ϋ <u § ίο - ^ ™ IT 'ηα ii ξι. ·', Lo - ^ Ν i | v ™ 00 V ° d 'Γ S _L mm F' rr> i> r > # ± m T - - In - lo f>

£ -5 ^ 0 ^ no - r> - Z

fl_ I * 3 «1 s: <ooo Lo, _ S £ p Λ, ^ i / 7 iiwvi ^ (M - SN ^ 1 sd“ 5 HO r> [> t> r ~ I ~ ^ Lo b? ^ Lo - «Jomo - z __: - o

ϋ ° z v v v v v v V V

ill t __; 8 a_ i o 2 E> £> [Τ 't ~ C ~ O t-'.

£ 2> § Lo b) Lo Lo Lo Lo LO

~ §-0 V 'V V V' V V

P LL LO

J

fU f> x fix Π = fi r-, ll-l ± = (i = (M i = <L = K to) ± = Ρ 3 j. S 3. 3 ®? 3 _? 2 _y Ί _i zpz _S g / S ©, δ ^ «ΓΪ8 <Ty§« '"is tTVl'« TVS cTt§ cTi§ Vz Vz V? Vz Vz \ ~ i Vz i λ 4 -I 4 4 R 4 5 g S i | · iii

In § §Ko> - £ s | ^ o> e o- {o> § 5- <o> s 5h @> § | - <g> S

pzxxxzzz lhq o o o q o o -u o o o o8 o o "» »» »S» »X · n? x" g "af0 3? 5"

$ ° ° x „3 ° £ S

δ ° δ a? o! : s' -H 0 X ^ OQ (Y- O - CM Γ0 <4- g ^ - - S N CN CM ^

fet3 S

___ 37 · _ 151338

J <u ¢ 5 O

"i o fi ί- 0“ ~., Λ. ro -¾ 5 »O c- ^^ l> - -g«> o O 6 o o 6 Λ) 5 §- w «gr.

lis fe 2 fe fe £ = S

di 3 · '«'" S «i § Lo ro E * o lo, ^ - if-fc d g ^ n i! 8

r £ § I

i ^, jj £ 2 o o 6 O 6 6

• 5 ° z ° V V V V V

to lii, __.

C3 ti.

8 ^ o n> t> £> ro t> £ * _Ξ p § lo LO in iO - ^ t> - - - -. «) - ° 11 ·« £ 1¾ _____ 5 ~ i ί i 2 = Z -p Z = K Z =? S Z =? 9 Z =? · 5 2 = \ T? -5 I y> I z-5 I 2-o I z-o m m 2 = (i = {± = <- H z = <5 a% s a. A a s

δ J p- £ 1 fl δ ^ 5 2 * £ I

«ΓΥ8« fyS «ys <TU« ΓΥ§ «Tys cTyå.

: - tf p µ ft ft ft · ft 1 § I I I 1 Γ r B § | - @ § e § | ~ ® § 5-®-δ e | -® ~ £ § 5- ©

I ~ Z 2 z É z Z Z

Po 0 Ci O o o o • M d o o α α o o

s & X X Yj X X X

0 3 ·. 3? x * <£ 2 * 2 3, o o o o '-i. o S 2 1? X * x> 3? 3? of q 000 O o 1 -I ______ β p $ lo> o C- 00 0.0 - CN (N fM fM N ro ro o α) μ

β _L ______... ------- J

38 _ 151338 ^ Μ 15! β Ο- J> C ~ er- V I I L „t> lo iq in Lo iq

So) · o "d - ~ ~ - ~

5 &. V V V V

o ^ <3- £: t> r> j>

N «> E> ^ &> 10 [λ LP

£ - ^ 2 ¢ 5 6 - '- -' - β_ | & v V [V ~ v c w i C o, In · in f I w. (s ^ <> i - (N <n ci £

1-5 - - B 5 & B B

<u a n o ° - _l _L - -

I ϋ2 v V V v V V

in

111 & & 5 ζ ζ ·. B E

~ - - V 'V v v * ____ £ f = l £ 2 = 1 ^^ X 2 = 1 x Ο I 2-0 ° 2 2Γ z-o 8 ^ 8 8 8 = (

O CO (rt O O O CO

-J * _ £ * _Jt N ft M

δ 4 y-i f z, 5 2rf 5 ^, s ^ P Z

. .gry · «ryS ai <riB ciys <ry§ cTyg 1 W w W V-z V-z V-z Vz 14 4 4 4 4 4 4 4 Ϊ i ° i i ° i ° i ° 5 ° i ° 2 g. δ ο ο ο o

I S3-® 8½ eo-§-5 s 54o> S §5 - @> §5- ^ 5 § 5-®-S

- ^ QOOOoOO

ωοοοοδοο »J? »^» 3Q X> a? · I X or1 a? a? a? S o U «ϋ ο a ΐ p δ K 5 · f ί g S S ° o u g i X ϋ ° c

nm 01 00 Th in Ή £ ~ 0O

^ of) · no no no no no no oa) m _1¾¾ a _______J_ i_1_1_f_ 39 · 151338 - - \ \ \ \ i £ SF "£ \ \ \ \ v - ° \ \ \ \ 5" · _, ____ \ _ \ 1 \ 1 \ aS & r> O '\ \ \ \ I å g &> m \ \ \ \ £ ^ "2 - od \ \. \ \ Η. I * v \ \. \ \ 3 * \ \ \ \ 'o | io. \ \ \ \ N' d ^ \ \ \ <U m N.

æ * \ | \ \ | \ "5> -> r> 'N. NS'S \ VS ^ \ l ~ I k>” ~ \ \ \ \ ~ S ° Z vv V \ \ \ \ ω \. \ · \] \ 0 CL \ \ \ \ δΗ & £ t> \ \ \ '\ -2 £ cs P ·>. k> \ · \ \ \ i'i 0 - \ \ \ \ t - «* SV. \ \ \ \ W \ · \ \ \ 2 .- == 2. n 2—2 "> Z — Z * \ \ \ \ I 1-5 T> -5 I z-5 \. \ \ \ z = (z = (\ \ \ \ 'J * Ji. Ji \ \ \ \ «KRR \ \ \ \ will l \ \\ \ S g S - @ - 5 g | - @ § 5- < 5> \ \ \ \ 44 ZZ · I \ \ \ \ μυ ^ υ \ \\ \ • d z. «V2 ^, ° · ^ · X. \ \ \ \ • β ΰ \ \ \ \ 0 'X Ϊ \ \ \ \ 5 0 \ \ \ \,. G1 \ 1 \ -p ® Cr ~ o “X ^ X.

Odih ^^ \ X \ X

feu c \ \ \ _X

(2) The minimum inhibitory concentrations (MICs) of the compounds against clinical isolates of bacteria are shown in Tables 5 and 6, where the numbers in Table 5 refer to the compounds in Table 3 and the numbers in Table 6 refer to the compounds in Table .

4th

The MIC was determined in the same way as described in the above paragraph (1).

41 ___ 151338 tn O O O O O o o o

ItnOOOOOOO

Pm cm - nj cm ni cm Η H

Λ Λ Λ ____ m in m in in m - ^ - ιηιηοιηιηιηιηιΗ. pt, CM CM CO CD CD CD CD K \

Η H

m in ^ tn H cm C- | pL | m CD o m m tn m c— c— crv m cm C "Η H iH in m · c ~~ I ······ * pq o m m m Η Η o o in m m

H in cm cm inside H

I ..... ...

(icMCOCOCMCMniCDfn

Η Η Η H

oo cd in m- m m m m c— 03 cd in CM H H H i — I H in ^ oo · '·····

φ H cd m m m m m H

m to * s CC _______; __ 02

d CD

Η o m co m m m m m m ο ι o in CM Η Η Η Η H m in o co · · · * · '* *

o HcDmmmmmH

how Φ H S.

_0>: _______- H ------ +3 H m m m m m m m c— C72 C— H CM Η H H H H in 00 .... ··· ·

m cd m m m m m H

m g 00 coininmtnmm mo

Li ^ CMCMHCMHHH in oo ····· ·

cd cd m cd m .m m H

m g H m m c- cr \ cn 'co ^ ι> H in c ~ - ^ ^ 00 o o m h "o o o o

g V V V

/, m σ \ oo o esc / in S CO Γ0 'S'

/ -Η * H

/ HH * / ΰ Η H Sh / Η Ή · Η β · / Η ο ϋ / CD I Η I -Η I · Η 03

/ Kl S · Η S ί3 g f! W

/ Ή 3 ° 3 '2 “2 Η / CD Ή Η · γΊ η Ή Π CD _ _ /' ΰ = - - / γ | +3 b 4 ° 10 -Ρ ^ d / η cd ^ cd ° cd ra · Η1 / - ° S | S jg £ j o. Iojq.uo% o 151338 ---- ·. 42 - [--- oo oooooo o o o o o o o o

CM CM CM CM CM CM CM CM CM

ΛΑΛΑ Λ Λ Λ Λ

LO LO LO LO LO LO LO. LO

CM CM CM CM CM * CM CM lO

CO 'CO MD CO CO CD CO CM

H

O CO CJV "" CTC C "- cre C— lo i — I c-Lo ^ -Lotr-in h'coohohoh to o 0 to c- tr- c—

rH LO LO LO rH LO LO LO

• · · ·. · · · ·

CO Η Η H CO'H Η H

LO LO lo LO LO LO LO

LO LO CM CM CM CM CM CM CM

• · · · · · ·

CM CM CO CO CD - CO CO CO

Η H

COCOCOCOCOCOCOt'-CO — I in — I in — I in — I in — in I — I LO t — I

CO CO CO CO CO CO H CO

P

CD

CQ

-p --------- β 0

& JIOCOCOO-COCOCOCO

'HHHloHHHiH

CO CO CO H COCOCOCO

i-1 LO________

H

® LO LO CO LO CO CO

ROCMLOCMHlOCMCMCM Cu ········

E-Ico CM CO CO CM CO co CO

r — I H

CO CO. CO C— CO CO C „- CO

i- | rH rH LO iH tH LO rH

CO CO CO H KM CO H CO

0Ί CT \ CO CO CO CO CO

C— to— c ~ - c: - c— c— oooooooo

V V

CM r-l M • M4 LO O rH CM

# 1-4 rM rH

u β

<D

Μ

H

CD

β

• H

S

o I _____ 43 1 5 1 3 3 8 * - · - ----

LO LO LO tO

LO LO OI LO CM OJ H LO

i .... ··· ·

• M CM OJ LO OJ LO LO tO CM

HH H H

fO O O O o o O o O

lOOOOOOtoO} * j CM CM OI OJ H OI OJ

A Λ Λ Λ _____ A_ ΙΟ LO ΙΟ ro

OJ ΟΙ OJ LO CM LO H

I · · · · · ·

O LO LO CM LOLO CM tOLO

^ H CM H__oi lo lo lo lo ro ro C "

HCMOJOIOJHH LOLO

I · · · · · · · ·

LO LO LO LO LO tO tO i I CM

rh

H

LO O O O o

ro O O O O

• H oi OI CM CM

o § Λ ΛΑ a o --------- CD

• H LO

Λ LO ^

• H o o O LO O OJ O

L. O O O OJ LO H LO

φ Js; CM CM CM

1 7 3 & A Λ LO CQ -------- pq φ LO LO. to LO O-

H „OJ LO LO LO i I CM LO

cri to * · · ·

(S LOOlOJ OjrOLQHLO

H S Η Η H OJ

CD

tOrOLOLOLOtOLOlO-

W h cm OJ OJ H Ol lO LO

to * · · · · '* * tOLOLOLOtOLOHOl

fe H

ci3 CO LO LO LO LO LO to

H-OJ CM LO LO CM CM H

thaw ...··* ·

LO LO CM CM LO LO tO LO

iz; HH ^

Ci3

j CM OL 00 O OL

/ * 3 «CO CO" Φ * -Γ / ΰ d / * H · Η · / Sh hh / HH H S5 / ri Ή · Η / Irl ΙΟ ΙΟ Φ / Φ å-rl 0 · Η S · Η Μ / cQ3ci) 3dPfiH / Η Η Η · Η Φ Η Φ Φ / (D, ππ ft ί-η, Ω PrQ Ό =: = -

/ Ό -Ρ Si -Ρ -PH S

/ s cti-¾ cd cd tdp · η

J «Η S fe O feco, Q

%, 10 JQ.U03 O

'fa I' ιιιι — J ----- 151338 44 f- to cr> cn and cn m 'mHi> -iHC-i> -H - [> - H · m o o o o o ._______ V__ oooooooo O O O O O O m o

CM CM <M CM CM CM H

A Λ Λ A A_____ tommC'-cnc - Cj '> r ~ - HCMHinHmc-m ········

two vd m h m Η ο H

to to c- c— cn σι Γ Η - in H m m C- C- 'm «·· · · · · ·

two cm to Η H O O H

r — 1l oooooooo o o o o o o o o

CMCMCMCMCMCMCMCM

^ λ αααλλαλ -p _____ cd --- J2 mm t w. w.

c2o O O m O m M3 md Ο o m cm m cm H cm

CM

1 -: ------- in H to tocnc-t ^ cnc— ®H m H c— m m t- m

Q

CdtOCMCOOHHOH

^ H

c— m cn cn cti cn and

m H tH C—. C— C— H— IH

H CO Ο Ο o 'O O O

V

to m m r— ir- D- m c— H cm H m m m H m • · · · · * · · ·

toMjmHHHmH

(Mi — i n << in o i — i cm r— (r — l i — t Λ

(D

01

H

5 «o fa ______! __ 45 1 5 1 3 3 8

I ~ F1 - ^^ - "V —I— I

00

rn O O o o (._> o u4 O

O m IC \ in U \ 1 (4 IM in fe cm ώ Λ ·

CMOOOinOOCMO OininCMininHin 1¾ CM

J ^ _A _____-_____ co in \ o _ HOOOLna ^ LPvfMin Otninc \ jc \ ic \ iHoj {25 c \ j _ ^ __ A________ O tn 00 in in H in CT4 „....

cm O O in m cm c \ i cn cm

O LT> CM CM Η Η H

fe cm _f__A_____l___ cfl m CQ io in o m ·

CjCMOOOOO OCMO

• H ΟΟΟιηιηιη Ηιη

M fe <M OJ H

d ώ * P <Λ φ td ---------- “Η ram in css O · s3 h o O o in in cm m 0 o O. in cm cm cm H cm

and fe cm H

-.§ ^ Λ 3 _____: ------- ω

ra H

PM CM

cm O inintnO in a o K \ OCMCMCMinCMCVlin

I fe PM

^ __Λ ____._____ r φ '£ j. »Q ^ iS ooo O O in O tnio in ^ OOinnjincM cm fe CM H.

__Λ __________ vo C— tn O o o m o O in o O m in oil tn in cm in fe cm _f__A __-___; _____. in tn o

H. O O O o O O in O

O O O o tn in cm m fe cm cm H h ° Λ Λ j cm σ \ oo o σι / p; L η n m ·

/ i ri '3 S

/ * frl Ή vi · / / Φ I irl. I O - ί 'O Φ /. «Id li' 1¾ a: / ΦΗΟ Ή Φ. · Η Φ Φ / «SM * H U & U & 'ϋ. - - - -

/ W fij G

/ fi 0 (8 ίΗ5 Λ3 »I

/ Λ fe · *? fe.a fe tQ 43 1 ____ / £. loj ^ trøa £ 46 151338 1 (Λ Ιί * \ ΙΟ 'ΙΟ (\ J t \ l CM ΟΙ • * · · KO Ιΐλ V.O νο νϋ LO ΙΟ Ο CM <Μ (Μ ΙΟ

Lf \ LO LO

LO CM CM CM '-Ο • · · * ·

CMOVOVOVOIOCMLO

Η in CM Η OJ

ir \ to in in cm in i — I rH cm in cm

VOCMtOtOVOCMVOCM

Η Η H

in to to lo in cm H i-l in cm in

cm in co to CM vo CM

H CM Η H

in in in in

inmCMCMCMlOCMlO CM CM rH r-I r-I CM rH CM

in to m CM LO H H CM LO in to / - «·······

-P VO CM to tO VO CM CM CM

cO Η Η Η H

M

• P

--------- 0 cu to lo in to in to

wHCMCMHCMHLO

(Otovo vo tovo to CM io

1 H CM

ΙΛ J_1 --- - - S in to to to in lo

. jjjCMCM.HHCMlOCMLO

E- * VO VO totovo CM VO CM

Η H

io to io to

CM ΙΟ H CM H

VO CM tO VO CO LO ΙΟ O

H CM CM in

LO IO

LO O CM CM LO Ο O LO

CM ΙΟ Η H CM 'IO IO CM

OI rH n in O i — I CM |

'<I — I rH rH

• - .- s 0)

CO

H

<1> _.

X) - - - - «o fa _I_1_I_I_1_1_ I '" · - * · "* s

47 I

., __, _, _ - _, - i- 151338

"LP LP

c— · ·

HlPOOlPCMLPCMLP CPCMOOPJH CMHPJ

CM CM

§ Λ Λ

- CD LP tP

Cd O CM LP H

• H IP ...

£ CO O O LP MD CM LP IP

O tP LP O CM H PI

g CM

ω § A

she and ______.____ cd

Η H rH CO

(DO O O O O LP · O IP O

• Η -Μ- O O O O CM IP CM O

CQ CM CM CM CM H

ω § A A A A.

rh

m ____; ___; ___ t-

H

HOOoOlpOlpO • ^ f-O Ο Ο O CM LP CM O

CM CM CM CM H

g A A A

^ OOOOOOLPO

lOOOlPLPLPCMLP

CQ CM CM H

C- rt A

I to IP 0 --------- £ H · * <j)

.Ω p tP Ο Ο Ο Ο Ο Ο Ο O

cd ft ι o o o ip ο o ip o

EH ^ mcMCMH HH I H

"Λ to <d ----- 1 ----- £! O s Λ 0 CM O O O O O O lp o

Ό 'I O O o O LP LP CM; LP

£ ra CM PI H H

Φ Λ

to A

PL | ______; ____

LP

HO o o o O O PI O

I o o O LP '. LP LP H LP

m CM. CM H

A

j cm cp oo o cn / =,. «rnroM *! ^ / HH i / · Η Ή · / £ Η Η ζί / · Η · Η · Η! I Η ίο ΙΟ Φ / ® SH SH SH to / ® 3 -Η 3 «Η Η Η / Η · Η Ο · Η Φ · Η Φ / φη · η η, ω U & · ϋ / ^ -PH-Pin -PH Η γ = r = / η cd S 'cd cd cd 3 · η / £ SC SO SW Æ / O I0JQ.U03 | g

/ _SJ ____] ____ I

.48 1 5 1 3 3 8 lp, ίο, ip- lp, ir- cn t-. cm in H m nj in r- in • • III ···

VO'lMiPlr-LLPR HOH

I-I

lp, tn tn c— tn

lp, c \ i H m H in H

. ······ pjinvotnmtnHtn

H never H

in in • ·

O O O in o m-m ni OOinmoniHH H ni H

in a ΟΟΟίηοιηηιηι

ooinnimniHH

HH

-P

d________

CO

-P

L.

0 in in

O o never never in o o

ιηΟΗΗΗηιιηιη <t H

in --------

H

Φ m «2 *

cdLnO ni in a O O O

E-ini inH ni ni in in in in in in in • • · · CMinmmininoo

HniHHmniinin in m n • · · O-Omniniinoo ιηΟΗΗΗηιιηιη ni cd r-1 η ^ m o r-ι m

. r-J i-l (H

U

S

<D

CO

H

(!)

Ti _ _ _ _ _ - - a "\ ~" 'fi

ISLAND

'_______ 49 ___ 151338 co n σο c- t-

LT \ H LA LA r- LA LA

d ω · · · *

oj3 la cm la cm Ο Η H

H τ-L H H CM H

H ft) CQ CD B

rf d_______ 0 i ------

, B VO

01 ft CO „_ ra >> HO ο ο ο ο o -pcmo o o o o.o o

CM CM CM CM CM CM H

m Λ Λ Λ · Λ

• H CFO

d H VO LA LA LA LA LA LA

P CO LA CM CM CM CM CM H

J>. * ·····

-μ Η H CO VO VO VO VO LA

CQ cd H _ _______

1 — In CD

d C50

OVOC0 CA A- LA tA tA ΑΡΗ t> H in CM H H LA

H CM ...... *

<jj O tA · H VO tA tA H

tol H

co

H OO A- tA A- tA CO

ft) [A LA LA ΙΑ H LAH A ~ <D 00 ...... ·

Sj i — I i — I CM CM tA H tA O

Η Η Η H

CD

H CQ

l ·) H

LA CD —-----: ---- I H i-

L rl LA LA

φ H LA CM

rH ia £ CM ·

φ Η H O O O CM LA VO

s £ H

EH “A A

Φ CM la

B to LA CM

d CM · ·

OHO O O O CM LA LO

CQ Η Ο Ο Ο Ο H CM

CM CM CM CM

$ £ A A A A

rh

CD -------- • H LA LA CA LA A ~

, dj LA CM LA LA H CM LA

cq a- · · „· * ·?

Hvo CM O CM LA VO H

Ο Η Ο H

CM

ξ A

/ r * rj CN GO 00 O

/ .Η -H η O -a * / Η H, / a Η H k / -Η · Η -H 2

/ CD I 3 «£« H

/ “I-H jaa § si $

/ Ή? o p CD p CD “J

/ CD · Η -Η Ή, Ω Ή, Ω Η / ij fti a f) ft ft) H ® / β -Pa · µ «ι · Ρί · ΰ = = = / · η cd -¾ cti ο cd ο ΰ

/, D S S5 £ * H

/. & Ioaq.uo3 £ i___E ti. .1 ___ 50 151338 in tn crv in cr> cMinHC-cMir-H - ^ -, · · · · f «·

"vo cm in O vo Ο Ο O

H -V V

0 o o o o o o o

OOOOOO.inin C \ J CM CM H CM 'CM

Λ A Λ t— m c— σ ^ ι .r ~ - cn

mcM in c— in in H

·. ···· * ·· H vo H O Η Η H tn C'-tno'iOvD-cyva'iC- inHC-c-tnc-n-in • · · · · · ·

rH tn ΟΌ H O Ο H

*! p tn m c— cn tn £ - cn c— Φ H cm in 'c- H m IH m

P tn vo Η O tn Η Ο H

β 0 m 1 in

tn CM CM

Ho O in η o mvovo

0) o O CM CM in CM

& H CM

CD.

EH Λ in in cm O O O m o m cm vo

in O in cm in cm H

H

tnintni> tn [r— cncn H cm H in H in c- c- · · · * * * · ·

mvocnHtnHOO

CM i — I ΓΟ · Μ * m O i — 1 m

t! r-i rH

»S Φ

01 H CD

...... β

• Η fi Ο fa _L__J___1___ 51 151338 Η

• <L) LO

φ CM LfC LPi W) ...

-pOOO cOCMCMLf \

-P O O O rH r-l CM

φ CM CM CM

* Λ Λ 3 SHircOOH-GOr-ΐΗ-Η- ca ......

MHOOOC ^ OO

fl V V V V

xa ri CD -H ^

P -H [> CO t <~ \ CJI

o ri m H- h · ir \ · H 'S · o

Cj cd · · · · · · ·

P4WH O O H t ^ O O

I V V v a -: ------- i LT \ H 2 ϊ H c- cn co σ> · ι-ΙΙθΟΟ (Γ-ΙθΗΗ- [Η TO JO · · · * · · · E- * φΗΟΟΗΚΛΟΟ

• g V V

/, Η O OC CM pl / H § «φ rp / rH rH '· / ri Η H ri / -Η -Η · Η rt / φ i H i O i O ^ / to ah g-Η å -d φ / 'ri § · η g ri g. £ cq

/ 5 2 -H g 4 ® H

/ tti2 Sj ri Φ / ti - - r

/ -HdJca ^ cdcQ S

/ a s ^ s ° a “-η / (S TO.1q.119a o i __: _ i fa i i i_i 52 151338 LTv LPi Lf \ t <~ \ CTi LTV CM CM CM Η C ~ - ····« ·

CM VO V £> MD ΚΛ O

r ~ \ ^ ^ ^ * ··· «· o o o o o o o

V V V V V V

-p d cq m jj cr> cn £ j o o o o o o

w V V V V

VO

m______

H

Φ, Ο d

EH

* vh ^ -vt- ^ 'Φ ^ ····· * 0 o 0 0 0 0

V V V V V V

co in 0 ι-i cm r-l I-1 i-l .§

(D

raw

H

0)

Ti = r = = = s

• H

«

ISLAND

_Efa______ 151338 - -.-. * · 'I _____ ii ------- Γ "- -κ * —1-¾ .1 ud on οο ω oo

LH t— C ~ - m in C— Εν in H OOOOiMOJOO

pt) C \ J LT \ LT \ Η H

N> VD Cn VQ Ή3 in tn

, φρ-) - ^ f ^ Tf in rH Ln in CM pH

pi, tn O O O rH KN Η H MD tn ___V V V_________ V, o vjo VO VO VO € 0 00 fOiLH Tf Tf Tf in in in in t- l>

pt) f — i O O O Η H rH H O O

___V V V_______

UD oo VO 00 00 vo VO

C \] m Tf "Tf C— LT \ C C— in in

p, h O OOOrHOOrHH

____V V V_______ N-N O0 tn K "\ tn tn M3 tn

, I, (Tf C— ^. I — I Η Η H. M rH

* j I · - · · · · · · * P4 to, O O O tn tn cn cn H tn ___ V ___ v _.______ S CO u3 'IQ M0 MD M3 M3 M3 Φ MD in Tf Tf Tf LTD LT \ in LTD LTD LT \

SjOO · · ·. · · · · · 3., - 1 O O ΟΗΗγΗΗΗγΗ

03 s V V V

CQ

-------- o

'"I * O OY MD CO M> 00 M3 MD MD

O LTD LTD Tf Tf Tf C— in C— in LO in

H h °° H O O O O pH Ο Η Η H

jS å I v v v g S '----------- in .p w tn c0 md md m> cn md

Tf 'if Tf C— in LTi in pH in 00 · · · ·······

tn O OOOHrHHf ^ H

S v v v '_____

00 (θ \ VD V £) VO vD VD VD

Lp ^, _ | -Sj "ΙΓ \ ΙΓ \ lT \ LO Lf \ ΓΠ · · · ······

O O OHHH HHH

s V V V

H- OUT 00 MD 00 00 00 00 ud in Tf Tf Tf c- in c ~ - c ~ - O'- c- cn · · · ·· # ····

H o O O O pH O O O O

S V V V

/ * rf oj η "ϋ * oo od / JO Si rH S ^ /> 5 · Ή Si · Η rj / pH X! -ri N ^ / Φ SO go go Sh $ / µ3η3ηρνο ^ / pH os · Η c« · Η cd H Cj / Φ U St UA UA g $ / SA f ft f ft Λ ό / cj (ή φ cd c) cd oi — 1 □ - - ”~ ~

/.Hsoao ao®-H

/ g ° _ t / _o 'loag-noH_ tS__J_l__ 54 151338 to tn in in tn H cm c \ i Ln cm V · · ...

1 CM Ln tn CO LO CO LM CO

| —I CM CM H

tn in O OOOOOO

I CM O O O 0.0 O m

H CM CM CM H CM

Λ co in co m m in cMtn cm in H in cm in cm y H co (H tn cm co cm cd

Η H

co m co tn in tn in tn

H m cm in H cm h cm H

I.. . . · «· · · Y H co h tn- co tn co tn r — 1 co m O icc Ο Ο O 0.0

tn cm in cm OOOOO

, H H CM CM CM r-i H 1¾ λ

Ο O / N

ISLAND

cd • H in your co in o 'si- in cm • H tn · ο cm LncoOOOLnin aj 5¾ H cm m O in cm cm

cb H

CM o I m --------- co fe

CM

, t Lf \ DO 'sD tO LT \ LPi H LO LO H LO c \ j t \ J Lf \ o DO · · ····· ti DO C \ J Η ίΟ C \ J VO C \ i

«G Η Η H

in tn co in co. tn in tn in tn

<3- in CM m H CM H cm H

tn · · · * H co H tn co tn co cn g 00 tn co tn in tn in tn

h in m — I cm H cm H

tn · · '· · ·· tn cm H tn co tn co tn

and H

ci? / r-l CM 00

/ S

/ Ή 9 / ° 3. g u / ΰ Λ -Η N fl / s I S 'I? 1¾ t «/ -W in ΪΗ §N O“

/ Η P ω P cd P cd H i-J

/ <D · Η · Η, ij · Η jil l \) Φ / £] -P φ -P Φ -Ρ φ Ρι S3 - - = / · η cd ο cd ο cd ο φ · η / & aaa ο λ / Ο ο / fe χΌΛΟ-ΐΙΟχ fe 55 151338 æ ^ 11 '"g 8 8 8 SS § K a; i;

te CM CM CM CM H cxl M

Λ Λ Λ Λ ________ 5ο ο Ο ο ιη Ο, γν ιτ \ -8 S 8 8 ^^ 88 ^ - § Λ AA Λ VD Ιβ in HO Ο Ο Ο Ο ΙΓ \ Ο 'Ο ο Ο Ο ir \ cm ιια . £> ™ ^ C \ | CM CVJ CM CM CM ιΗ r-l ώ Λ A A A ___ ω ιη in σ> ο ο ο οlt \ ο "^ CM Ο Ο Ο LTv CM Lf \ I_j 1-1 CM C \ J OJ OJ CM H r-1

§ A A A A

cfl m 0 i? i · Ο ο ο ο o o So ο o 5 ™ S 8 8 8 8 ^ 3 °°° gg Λ Λ Λ Λ U --- dj --—--; ----: Cå ^ 1 S g Ο O 8. & CM g © CM Oj

o CM CM CM CM HinHH

o § A A ΛΑ χί ___- -. - -_____ I___ 3 --—— —— Φ} £> to in

CQ H LTV CVJ, -J CVJ

Qj OJ · *. .

7 N 8 8 δδΒ ^ δ, κϊ ^ «·

Jj a. CM CM CM CM, 1X1 ^ * A A A Λ i ω ---------;

, Ο In CCA

φ CM. ΙΓι ε · * ωο ο ο ο ιπ · ο 0 * ^ · Ο Ο OinCMO ° vox3 a CM CM CM CM H ^ ® A A A A ___ Ό ^. into a CCA Ο Ο Ο Ο O CM O, —i λ. λι Ο O OOtnHOO ^^

and CM CM CM CM HlTArHM

ώ A A A A

in, o o o S o o o 0 0 o H 8 ° S SSSSs '"1"' g Λ Λ Λ Λ j r-c cm ο ^ οο σ>.

/ ri / O s) ri c!

/> S H S3 · Η g I

/ Η Λ -ri N »/ I W), -P I Η H g.

/ <d Not o Ιο i o u ®: / .ta 3 h In o / φ Τί'Λ · Η'λ3 · ηλ λ., ¾1. '/ ϊ s-s · * «£«' 3 3 8 8 *, '/ 5 a · ο «3 ο do φ η s, / £ S £ S ο, ω / ^ ---- £

j ο_, Toj ^ uoa_I g I

56 1 5 1 3 3 8 p— vo to vo to LO ΙΟ LO CO v0 00 φ · H to H LTV H CM CM CVJ H in o- m · · · …….

“Η to H - to vo vo to Η o S S3 o cb ω ---- £, Q (—1 3 tO to IT)

CSOH LO H LO tO LO CM

»—I · · · · * · · I I

□ to CM to CM LO CM CM VO

φ ^ Η H CM Η H

• H Cb m ___, Ω <D --------- d t-

rH tO tO tO

Η H CM H LO LO CM

«E- · · * · · · ιι

to * VO to CM LO CM LO VO

Jg rH CM rH CVJ

cb

-si-O o O O O O 0-0 to O

ί ο o o o o to o; o cm two

m CM CM. CM CM H CNJ H

: Λ A A Λ πΓ.

tQ; ___: __: ----------- 0 .JL & to o o o o o ο ο o to o

H | o O O o O to O O CM LO

. S-iGQ CM CM CM. CM H CMH

® S Λ Λ Λ A

rP ---------- ♦ --- ** ti

Si

§I CM o o O O Ο O 0 .0 to LO

5: ι Ο Ο Ο Ο O to Ο O CM CM

, 01 02 CM CM CM CM H CM .H

gf A A A A

tnj ---: -; --------- fv

HO ο O 0 0-0 0 0 to LO

i o O O O O LO Ο O CM CM

£ / 2 CM CM CM CM. CM CM H

A A A A

/ rH CM O. CO 02 / s / · Η / O S _ S. · - ·

/> s -H S · Η H

/ rH * S -H C3 W

/ ElO + = Η -H

/ Φ I Ο I Ο I Ο ΪΗ Φ / 03 § | H S'-1 S. μ ο ω

/ H PcC p®. ραί Η H

/ φ Hil ή, s φ ω 7 -d kft ίιΆ U Ά Λ 'd. _, _ / d -Ρ ω -Ρ ® -ρω ft d - “- - * / · Η cdo ctfO £ ΰ · ο ω · Η / Ρ S S ί3- ° '<? / £. I0Jq.U02 £,

- '' ........ '' I

57 151338 _Table 6-5_

Proteus

Compound mirabilis morganii vulgaris trial

Nairiv ™ r, 3.13 1.56 50 50

Cephaloglycm J

Compound No. · 1 3-13 3.13 1.56 6.25 ". 2 1.56 1.56 0.8 3.13" "3 6.25 3.13 3.13 6.25" 4 3.13 3.13 1.56 3.13 (3) Resistant activity against β-lactamase, Pseudomonas aeruginosa GN 238:

The resistant activity of each compound to β-lactamase was measured as described below, β-lactamase was prepared from Pseudomonas aeruginosa CEN 238,

This microorganism was grown in 100 ml of a culture medium containing 2 g yeast extract, 10 g polypeptone, 2 g glucose, 7 g disodium hydrogen phosphate, 2 g potassium dihydrogen phosphate, 1.2 g ammonium sulphate and 0.4 g magnesium sulphate. liter in a 500 ml conical flask for 6 hours by shaking at 37 ° C. The cells formed were collected by centrifugation (5,000 rpm for 10 minutes), washed 3 times with 0.1 M phosphate buffer (pH = 7.0). Then, the cells were subjected to sound processing (20 KHz, 20 minutes) and then centrifuged at 15,000 rpm. for 60 minutes. Using the above enzyme fluid, the resistance of each compound to β-lactamase was determined by iodometric sample. The results obtained are given in Table 7, where the numbers refer to the compounds in Table 3. Each number in Table 7 indicates a relative activity value calculated by assuming an activity of 100 for potassium penicillin G used as a control.

'"* · ** —-' -, r 58 1 5 1 3 3 8

Table 7

Comparison of resistant activity to β-lactamase

Compound Relative Activity (%)

Potassium Penicillin G 100

Sodium Amp in c illin 115

Sodium Carbenicillin 116

Sodium Sulbenicillin 50

Compound No. 49 3 »» 2 14 »» 1 15 »» 3 15 n η 4 15 Η tf. 5 15 »» 10 16 i ». ·» 11 1 12 »« 12, 1

From Tables 3-6, it is understood that the compounds of this invention have a broader antibacterial spectrum and a higher antibacterial activity against not only Pseudomonas aeruginosa, Klebsiella pneumoniae and Proteus species, but also many drug resistant bacteria than is the case with ampicillin and cephaloglycine used. for control, ie in conjunction with an amino group at the α-position of the acyl group. It is also apparent from Table 7 that the compound of the invention has a much higher resistance to β-lactamase than the comparison compounds.

It is evident from the above results that the compounds of formula (I) containing two oxygen atoms attached to the 2 and 3 positions of the piperazine ring, respectively, exhibit particularly excellent properties, and particularly preferred compounds are those wherein A represents a hydrogen atom, a (C2-4) alkenyl group, a phenyl group, a benzyl group or an) alkyl group which may be substituted by chloro, hydroxy or carboxyl; and 3 and R each independently represent a hydrogen atom or a (C 1-6) alkyl group. The most preferred compounds are 6-Q) (-) - O & - (4-ethyl-59 1 5 1 3 3 8 2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamide] penicillanic acid and 7- £ p (- ) -dr (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -p-hydroxyphenylacetamidoj-3- [5- (1-methyl-1,2,3,4-tetrazolyl) thio-methyl] - cephem-4-carboxylic acid and pharmaceutically acceptable acid addition salts thereof.

The present penicillins and cephalosporins usually have low toxicity. Eg. have 6- [D (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] penicillanic acid and 6- [D (-) - α- (4-ethyl-2, 3-Dioxo-1-piperazinocarbonylamino) phenylacetamido] -penicillanic acid an LD 50 (iv in mice weighing 19-1 g) greater than 5 g / kg

The compounds of formula (i) can be administered either in the form of the free acids or in the form of non-toxic salts or physiologically acceptable esters. Furthermore, those compounds which are in the form of physiologically unacceptable esters can usually be used by conversion to the free acids or non-toxic salts by removal of the ester-forming group in a manner known per se.

The compounds of the invention can be administered to humans and animals in the form of tablets, capsules, syrups or injections, in the same manner as the known penicillins and cephalosporins.

The process according to the invention is further illustrated by the following examples.

EXAMPLE 1 (1) To a mixture of 2.5 g of 1-acetyl-3-oxo-piperazine, 3.45 g of triethylamine and 20 ml of anhydrous dioxane was added a solution of 3.71 g of trimethylchlorosilane in 10 ml of anhydrous dioxane. The resulting mixture was refluxed for 17 hours and cooled to precipitate triethylamine hydrochloride, which was then filtered off. The filtrate was dripped at T40 ° C to -30 ° C to a solution of 1.8 g of phosgene in 30 ml of anhydrous methylene chloride. After the dripping, the temperature of the resulting mixture was raised to room temperature, which was maintained for 30 minutes. Then, excess of phosgene and solvent were removed by distillation under reduced pressure to give 3.5 g of light brown oily 4-acetyl-2-oxo-1-piperazinocarbonyl chloride.

IR (film) cm -1: C = o 1790 »1710» 1640 · (2) A suspension of 1.0 g of 6- [D (-) - α-aminophenylacetamido] penicillanic acid in 20 ml of tetrahydrofuran containing 20% by volume of water , was adjusted to pH = 8.0 to 8.5 by the gradual addition of triethylamine with stirring and then cooled to 0 ° C. To the suspension thus treated, a solution of 900 mg of the above-mentioned 4-acetyl-2-oxo-1-piperazinocarbonyl chloride was dropped into 5 ml of tetrahydrofuran at said temperature over 30 minutes. During this time, the pH of the suspension was maintained at 7.5 to 8.0 by the gradual addition of triethylamine. Then, the temperature of the resulting mixture was raised to 5 ° C to 10 ° C and the mixture was reacted at said temperature for 1 hour while maintaining the pH of 7.5 to 8.0 by the addition of triethylamine. After concentration, the tetrahydrofuran was distilled off at reduced pressure and the residue was dissolved in a mixed solvent consisting of 30 ml of ethyl acetate and 10 ml of water. The resulting solution was adjusted to a pH of 1.5 to 2 by the addition of dilute hydrochloric acid under ice-cooling, and then the organic layer was separated. The aqueous layer was re-extracted with 20 ml of ethyl acetate and the resulting organic layer was combined with the above organic layer. The combined organic layers were washed with water, dried over anhydrous magnesium sulfate and then ice-cooled. In this organic layer was added a solution of 470 mg of a sodium salt of 2-ethylhexanoic acid in 20 ml of ethyl acetate to precipitate white crystals. The precipitated crystals were collected by filtration, washed with ethyl acetate and then dried to give 1.4 g of sodium salt of 6 - [D (-) - α- (4-acetyl-2-oxo-1-piperazinocarbonylamino) phenylacetamido] penicillanic acid, mp: 2050 ° C (decomp.), yield: 94%.

IR (KBr) cm ”1; γc = Q 1760 (lactam), 1600 - 1700 (-C00®, -CON <0 NMR: [(CD2) 2SO + D20] + values: 2.73 (5H), 4.35 (1H), 4, 75 (2H), 5.75 (1H), 5.84 (2H), 6.42 (4H), 8.03 (3H), 8.52 (3H), 8.64 (3H).

The above operation was repeated with the change that 4-acetyl-2-oxo-1-piperazinocarbonyl chloride was replaced with the reactive derivatives of compounds of formula (III) listed below to give the compounds listed in Table 8. The structure of each of the final products formed was confirmed by IR and NMR.

62 151338

Γ S S

S. O (C

o o o so 00 c- y_y ^

cS ^ ra L in ^ -P

and t * '-fe £ * E

fCN fOiO 4? I oo and T

M K O!> I —1 KN KNO £?> O o o, α> ω awo. · Fl v_y o +1 000¾.

r- [3 W -p y_ / 3 eq I * a >> Jn • Y? §> O _ g \ a o ° "i o S- (o) * _1 o <D O CM BO / cm κι m a, .- °.

_i a i on g I

tu o o o a i «O, _„ KN I CM O K 'I f® ~ ° φ! | ^>! n O · I · a £ o a o ft o ft ^ i a o a o · a

-Jj Ov and O CM Q I O

-¾ T Ί X Η X o ^ a λ ^ l J ω o ω T 1 5 ^^ aa ft l J ft ji - '' - '-'! Si '- co .TJ ° cm ihg · § p. < S ft Λ ° έ O 2 I ra I jg 'mi / JjS to i ft

• H

? hH _i OH o 'WH § "S Vi

G! V

>? h O I co

• H O o O O

Ih CH [O O

® - Ov a 'CM I

10 s T). s We take *? ^ laj • H S O cm. 1

4J φ O K O

5 co a o o 3.3 I I é 63 151338

κί ώ S

S25 S - ίΛ ΚΛ> ftfvO m Ο tu Ο., WMO S 'ο ο ο © ο ο ο £ cd * y ~ f £ VV b ja O ral ·!> »Ra I 5 CT \ cc \ o CO \ jg jb \ _j2j ^ tt wo 1 13 I p 0 oo © —k S —k.

V / 40 ^ / 1 -p o o ra I>, M o W o tf I 8 I- 8 £ J | - <° K g-® "

O "" CTi OH O CD

o CF * O C ~ - O ir \

ffi / 7Λ H IH I H

SA °) ~ V3-, ~ ° ΤΒ] - g ά W g. Y & o a i a ii

10 CV1 O CM Q

O ^ B 1¾ M tM W% V ί ω o © o © 1 J ^ H "^ CM Tj 5> * 3 g cm» tU »M ·" I o ft I O ft I O g, -P ^ ra g ^ g

P I jo, · $ I ff \ tø 1 M

u - j £ - m - pr;

JH P O P U P O

00

rh

© ©

Eh i

Η H

ISLAND ISLAND

ISLAND ISLAND

8 2 h ° r ^ ° r} 8 y y o I 1

In CM CM

γΊ 8 8 w ^^

In CM CM

cm tu fi ° ° o.

tc \ tf *

ftj · W W

O O O

64 1 5 1 3 3 8 ώ Η $ ^ [§ am to too

to too ra totoo ^ a a O

ggg · gg§ $ ° v2, ° yf I yr I iri * “J, I1 mJ = i Tf § 4, 3 -i 3 -A sx> vq 43 OO a 4s aoaoa · >> ac> aoo ft oo oh- o 'do __ crv o __ „to a f7 \ d% <§> 1 i · ®, oaaooo oo o cvj o oo

O to 00 o to I H

i a h i h o., a ^ cm rr ΐ o 2 v - a ft a s * i ft i a i a oj a CVJ · Q cvi o M o a «a o O ω O Φ O <1>

-P cvj a vo ri o H

ra cvi cvi o +5 a · a * to · T. i ο ft i o ft i - ft q ^ a - to a is! i to ω i to ra i a ra w ^ w tt a ^ o ο o a o «^ 00

H

0) ft «

EH

H H o

O O O

o O o

O to O I

r a i o> a

° tT Ύ) V

^ a & i I I cvj OJ CM a a a o o 0.0 o CM VO o, -v o CM CM o a a to o o ^.

EXAMPLE 2 (1) In a solution of 1.74 g of sodium salt of D (-) - α-aminophenyl acetic acid in 30 ml of tetrahydrofuran containing 20% by volume water, cooled to 0 ° C, a solution of 2.5 g of 4-acetyl-2-oxo-1-piperazinocarbonyl in 5 ml of tetrahydrofuran was dropped at said temperature over 30 minutes. During this time, the pH of one of the reaction solution was kept between 11.0 and 12.0 by gradually adding a 10% aqueous sodium hydroxide solution. Then the temperature of the resulting mixed solution was raised to 5 - 10 ° C and the solution was reacted at room temperature for 2 hours while maintaining a pH between 10.0 and 11.0 by adding 10% aqueous sodium hydroxide solution. After the reaction, the tetrahydrofuran was distilled off at reduced pressure. The residue was dissolved in a mixed solvent containing 20 ml of water and 50 ml of ethyl acetate and the resulting solution was adjusted to a pH of 1.0 to 1.5 by adding dilute hydrochloric acid under ice-cooling. Then, the organic layer was separated, washed with water and then dried over anhydrous magnesium sulfate. To this organic layer was added a solution of 1.66 g of sodium salt of 2-ethylhexanoic acid in 20 ml of ethyl acetate to precipitate white crystals. The precipitated crystals were collected by filtration, washed thoroughly with ethyl acetate and then dried to give 1.89 g of a sodium salt of D (-) - α- (4-acetyl-2-oxo-1-piperazinocarbonylamino) phenylacetic acid, m.p. : 115 ° C (decomp.), Yield 52%.

IR (KBr) cm -1: 1690, 1650 - 1600 (2) For a suspension in 15 ml of anhydrous acetone of 833 mg of the above sodium salt of D (-) - α- (4-acetyl-2-oxo-1-piperazinocarbonyl -amino) phenyl-acetic acid was added 10 mg of N-methylmorpholine. The resulting mixture was collected at -20 ° C to -15 ° C and a solution of 286 mg of ethyl chlorocarbonate in 5 ml of anhydrous acetone was added dropwise over 5 minutes. Then the mixture was stirred at said temperature for 60 minutes. In the thus treated mixture, a solution of 646 mg of triethylamine salt of 6-aminopeniacillanic acid in 30 ml of anhydrous methylene chloride was dropped at -40 ° C to -30 ° C over 10 minutes. Then the mixture was reacted with stirring at -30 ° C to -20 ° C for 60 minutes and at -20 ° C to -1.0 ° C for 30 minutes and at -10 ° C to 0 ° C for 30 minutes. After the reaction, the organic solvent was distilled off under reduced pressure. The residue was dissolved in a mixed solvent consisting of 50 ml of ethyl acetate and 20 ml of water and the resulting solution was adjusted to a pH of 1.5 to 2.0 by the addition of dilute hydrochloric acid under ice-cooling. Then, the organic layer was washed thoroughly with water and then dried over anhydrous magnesium sulfate and the ethyl acetate was distilled off at reduced pressure. The residue was dissolved in 50 ml of acetone and the resulting solution was mixed with a solution of 340 mg of sodium salt of 2-ethylhexanoic acid in 20 ml of acetone under ice-cooling to precipitate white crystals. The precipitated crystals were collected by filtration, washed thoroughly with acetone and then dried to give 1.16 g of sodium salt of 6- [D (-) - α- (4-acetyl-2-oxo-1-piperazinocarbonylamino) phenylacetamido] penicillanic acid, mp: 205 ° C (decomp.), yield 94%.

in Example 5

Cl) To a mixture of 1.0 g of 1-palmitoyl-3-oxo-piperazine, 0.6 g of triethylamine and 20 ml of anhydrous dioxane was added a solution of 0.65 g of trimethylchlorosilane in 10 ml of anhydrous dioxane. The resulting mixture was refluxed for 16 hours and cooled to precipitate triethylamine hydrochloride which was then filtered off. The filtrate was dripped at -40 ° C to -30 ° C in a solution of 0.6 g of phosgene in 30 ml of anhydrous methylene chloride. After the drip, the temperature of the resulting mixture was raised and the mixture was reacted to room temperature for 30 minutes. Then, excess phosgene and solvent were distilled off at reduced pressure to give 1.1 g of pale yellow oily 4-palmitoyl-2-oxo-1-piperazinocarbonyl chloride.

IR (film) cm “:: Y ^ c = 0 - * - 740, 1660, 1640 (2) A suspension of 1.0 g of 6- [D (-) - α-aminophenylacetamido] penicillanic acid in 20 ml of tetrahydrofuran containing 20% by volume of water was adjusted to a pH of 8.0 to 8.5 by the gradual addition of triethylamine with stirring and then cooled to 0 ° C.

In the suspension thus treated, a solution of 1.27 g of the above-mentioned palmitoyl-2-oxo-1-piperazinocarbonyl chloride was dripped into 5 ml of tetrahydrofuran at the said temperature over 30 minutes. During this time, the pH of the suspension of 7.5 to 8.0 was maintained by the gradual addition of triethylamine. Then the temperature of the resulting mixture was raised to 5 ° C to 10 ° C and the mixture was reacted at said temperature for 1 hour while maintaining the pH of 7.5 to 8.0 by the addition of triethylamine. After the reaction, the tetrahydrofuran was distilled off at reduced pressure and the residue was dissolved in a mixed solvent containing 30 ml of ethyl acetate and 10 ml of water. The resulting solution was adjusted to a pH of 1.0 to 2.0 by adding dilute hydrochloric acid under ice-cooling, and then the organic layer was separated. The aqueous layer was re-extracted with 20 ml of ethyl acetate and the resulting organic layer was combined with the above organic layer. The combined organic layer was washed with water and dried over anhydrous magnesium sulfate. This organic layer was concentrated under reduced pressure to remove the solvent and the concentrate was introduced into 10 ml of diisopropyl ether to precipitate crystals. The crystals were then collected by filtration to give 1.65 g of white crystals of 6- [D (-) - α- (4-palmitoyl-2-oxo-1-piperazinocarbonylamino) phenylacetamido] penicillanic acid, mp: 121 - 123 ° C (decomp.), yield 80%.

IR (KBr) cm -1: C = Q 1770 (lactam), 1730 (-C00H), 1660 - 1630 (-CON O-

The above operation was repeated with the change that the 4-palmitoyl-2-oxo-1-piperazinocarbonyl chloride was replaced with the reactive derivatives of compounds of formula (III) shown in Table 9 to form the end products also shown in Table 9. The structure of the compounds formed was confirmed by IR and NMR.

ee 151358

M M KS

(TV DAO o | to too · * O

g g 8 «goo - g ®

π 5 y- [i s I

CQ I ι_> GQ 1 .p ηηλ i3 I 'Vf · £ $ js I s 1 SME «) 1¾¾

N ^. Ώ M fi Ο Ο O tft ΚΛΟ H

mo 3 O ^ V / ω mmo p ® td M 3 rn + - ο ο o “B - b - - ra I if γ- 3 '§ o ° 8 o ° Ml'« Π 'o ° 1 gÆ> K gÆ > £ -A 3 ti «3 g ^ H g ^ 7 -1 B ° - K, -1 8 I '8' § g» HI hi. C- O If} 0.0

Ο Ϊ3 LTv O S LTv fi / 7 \ Η O OJ

in t] H X) H §λ °> w g- / o> H

a V - .. V ~ § "g ^ ~ WO ft O ft O ft O ft + joaoa ia oa ca (Μ o CM o o a, S io ε mm. * ο ^ ΐ5κ # 0) ο ω ο ω I__J ® Y l ω M in m Ό ^ sr Ό. LJ Ό --- - --- I ^ B -

<M CM ο I

Μ Μ * ο · o IO * 'O .gc lft & o and ft 9 --- Μ S i g1 im SI ra i ο ra MYi § H' - M cq - {xj χ- H LO J 1 ω ο o ft P ft o 33 & ca eh _; __.___

r "N

I H

g a h 8 8 <s o ^ o 2 H <Yj ° f)

B'Η ^ B7 B ^ Ο H

• -p Ο T i Ο o 1 ecu o o-Ο o>. o o _ i o

H-ti CM CM o B ^ I

j · «® w Ή Y Ί o.b.

: s a ο o LJ Ύ Ί

φ in tn B I J

--- --- I B

Φ φ CM CM Ο I

i> to · B M O, O

• hh 3 3 B?

P φ K

vj> τ) and m o f / nl

cad M M H OJ

φ Η ο Ο o Μ, Ω 69 15133a ---- Η -—--

JR

VO

3 ® «σ \ co. σ \

HJH

ffi (D too (¾ ixj Φ tOitOO -P WWO -P; tfVtfO +? ωωο -p ooo -P 'WKo -p OOO >> \ V_ / κ * ν OOO> 5 γ-γ gm \ s vf <§ “ U = y * i 3 ° \ i 3 _J o - ^ o -1 o ο ο o o W 00 _ O to goj SO Μ ΚΛ

13 Ο H 13 H

O O __ O

O I &} I O _ I

| - <2> 8 S 1 ^ 2) R-

g i — i O H g H

ΐ ΐ ° ΰ 1 ° Å f «. 3 t λ Sr 44 p I Φ O <D I d) k Ο O τί Ο 5 λΦ i λΦ 1 / φ ί σ> i y 1 1 μ 'L a

w H ′ Μ φΗ H

H f =) O O O Q O

<D rQ

(ΰ EH --- "-

rh

I Ο Η Ο Ο Ο Ο I I ο

I Ο ν g I

Τ) υ ° Φ 1 ° Λ ο ο ο

ο A HO

φ φ> Η ώ ρτ * Ο Ο Ο 70 EXAMPLE 4.

(1) To a solution of 6.4 g of 1-formyl-3-oxo-piperazine in 10 ml of anhydrous dimethylformamide was added 2.7 g of sodium hydride (purity 53%) under ice-cooling and the resulting mixture was reacted at room temperature for 1 hour. Then the mixture was introduced into 7.1 g of methyl iodide and reacted for 10 hours. After the reaction, the dimethylformamide was distilled off under reduced pressure to give 1-formyl-4-methyl-3-oxo-piperazine. This piperazine compound is dissolved in 70 ml of a 50% aqueous acetone solution containing 2.2 g of sodium hydroxide and the resulting solution is reacted at room temperature for 3 hours. Then, the solvent was distilled off under reduced pressure and the residue was introduced into acetone to precipitate insoluble matter. The insolubles were filtered off and the acetone was distilled off from the filtrate under reduced pressure. Then the residue was subjected to distillation at reduced pressure to give 5.2 g of 1-methyl-2-oxo-piperazine, b.p. 104 ° C / 4 mmHg, yield 91%.

(2) In a solution of 1.9 g of phosgene in 20 ml of anhydrous dioxane, drop at 10 ° C 20 ml of anhydrous dioxane solution containing 2.0 g of 1-methyl-2-oxo-piperazine and 1.95 g triethylamine, after which the reaction proceeded to precipitate white crystals of triethylamine hydrochloride. The precipitated crystals were filtered off and the filtrate was evaporated to dryness to give 3.0 g of pale yellow oily 4-methyl-3-oxo-1-piperazinocarbonyl chloride.

IR (film) cm ”:: 1710, 1630 (3) A suspension of 4.0 g of 6- [D (-) - α-aminophenylacetamido] penicillanic acid in 40 ml of tetrahydrofuran containing 20% by volume of water was adjusted to a pH value of 8.0 to 8.5 by gradual addition of triethylamine with stirring, and then cooled to 0 ° C. To the suspension thus treated was added 10 ml of a tetrahydrofuran solution containing 2.2 g of the above 4-methyl-3-oxo-1-piperazinocarbonyl chloride. During this time, the pH of the suspension was maintained at 7.5 to 8.5 by the gradual addition of triethylamine. Then, the resulting mixture was reacted at said temperature for 30 minutes, and the temperature was raised to 10 ° C to 15 ° C, then the mixture was further reacted at said temperature for 90 minutes while maintaining the pH of 7.5 to 8.0 µl. 151338 by the addition of triethylamine. After the reaction, the tetrahydro uranium was distilled off under reduced pressure and the residue was dissolved in 30 ml of water. The resulting solution was washed with ethyl acetate and the aqueous layer was separated. This aqueous layer was ice-cooled and then adjusted to a pH of 1.5 by the addition of dilute hydrochloric acid to precipitate white crystals. The precipitated crystals were collected by filtration, washed several times with small amounts of water, dried and then dissolved in 100 ml of acetone. To the resulting solution was added 1.9 g of a sodium salt of 2-ethylhexanoic acid under ice-cooling to precipitate crystals, which were then collected by filtration to give 5.4 g of a sodium salt of 6- [D (-) - α- ( 4-methyl-3-oxo-1-piperazinocarbonylamino) phenylacetamido] penicillanic acid, mp: 195 ° C (decomp.), Yield 92%.

IR (KBr) cm "1: C = Q 1760 (lactam), 1600-1660 (-CON, -C0000), NMR [(CD CD ^^ SO + D₂O] values: 2.62 (5H), 4.48 (1H) ), 4.56 (2H), 5.97 (3H), 6.63 - 6.39 (4H), 7.13 (3H), 8.46 (3H), 8.55 (3H).

The above operation was repeated with the change that 4-methyl-3-oxo-1-piperazinocarbonyl chloride was replaced with each of the reactive derivatives of formula (III) listed in subsequent Table 10 to give the end products. The structure of each of the compounds formed was confirmed by IR and NMR.

72 151338 in S å

tA tAO m hiT'iT'S

ooofi vs 0v „OOO

> f g a S KV ^ S I n 1 ral a ^ a a o 00 colg ^

Ro tA tAO., O o o., Ya! m I> r I. -λ g

. : a o 02 I £ i £ S '^ D

a tr— Va _L 'd S - £ j $ g "8. -i 3 Ho =: 8 _ 1 a) ο - / <5 \ 1 ο a § o §" ^ P) "Ό ϊΰ \ - / Mo oo W '- <o G a co a o- o, _. oo Mo rl OOOOB / 7 \ ooo -g 8 S / ΤΛ ~ 8Λ °> ™ 2 8 fi ΓΒΊ ~ IA °> 7 8 2: r * Ί ~ 4J o ^ & r a * oa 7. ao ^ a ft mi ο oo .a ^ qia rt w js i ™ °

γη K a) .a ^ ω 1 J ω B

-h o -o 'f a o ^ a -d Ο Φ 0 +> cm ^ 1. J ^ I ^ J? 3 o {q '- ^ o a a -o, h g <m · i · ο · i cm § a ft cm a cm ft ;, a.

ngio s i a si— s io © £ ^ w to ^ ~ v o to ^ iA co ·· - 5 *, Q I tA I tA I a I a § co ^ a. —A —o χ a

EH ftO P ϋ P - PO

/ -s

H H I H

in'- ', -1' η a § d «5? 8

ώ S £ Η I

/, ¾ f] η o .a.

Po 1 J ο o f Ί

cdSH o ^ a o. O _JLJ

!> _ i o. I ° a • h a cm i .a. i u ω a a. f Ί «μ <us o r 1 i, J a 3 cm J J o ^ a 'o a - o ^ a i a +5 Φ CM I a i> w a cm o ^

• hh o a ™ H

4j Φ v-- O - ~ 1 O

id a ia a yes w a a a a a a S a ο ο o a bp ° 73 151338 cd

KN KNO cd ^ 'Cd cR

K K O> 25 ro s ffl o O O KN KNO ON KN KNO 00 V7 B B O B B O '

ΓΊ O O O © 'O O O CD

CQ I v_y -P V- / -P

y? i <1 & «Π fe -4, σι Y-S £ Y-B £ κ ° ® 'p4 0 —k 3 S ij 1 o o S t? B O B o

o K5 B O S O

Κ / ΖΛ jS o cnj o 'd-

ο- (Ω> ^ o _ o O ___ ON

s i ^ °> 7 mi _ o o 3 3

O I LfN O ON OH

-p [sl 00 O ΟΝ O KN ON

cd ^. — 1 I H I B 'H

t ° Ύ x XV χ X 7 ° χ O Cd ft oXsXo ft 0 * ^ 3 ^ ft «Η - ixj a · S I a

- o o (M O CM O

c \ i Μ B Λ KM

O K o O CD O CD

H OH cnj H CNJ H

H O CNJ ·, _ £ ^ · CD OJ. K ø | . . hh 0, p 1 "" ft'3 & JL S sr PH T k "É I KN ^ .IKN ®

H X δ ra - B ^ K

p W P O P o

rh

O H H

7 8 8 Λ, 2, Xe

° t 0yf oJX

K I 1

o CNJ CNJ

cnj K S

K o o o CNJ Cd

o Xl X

CNJ K B

^ o o KN ^ 'ti

K KN KN

o B B

o o 151338 74 || Il I ...... ...... * TI ............ '------- O!> T "- <3 \ VO 00 <D cd Q> ω oi -P έι +3 +3

. K p to ro +3 ^ P

kokoo h KWO j>, O is KW on o o o p is- p

o o o p y / p P

y-f 3 ran s 5 3. cq I - · “cd P cd

y-K o i O K>, KO

i O 1 O ΝΛ p ko koo o _i uo ^ uo WMO 5 WKooq

V- O O O OOO p O O O H

O H g H y_y ^ γ_ / CM

§ I O I CQ 1 O CQ I I

O _ O W _n \ O - V? ° K0 Y ^ να

§- ^ θ) h g v?) Η „i w | 4o W

Hj '^ O ^ K ° K ^

O O · K · K

0 o ft i 91 o ft o Pi +3 i a κ. a o a and 1 Xs) i «λ? i mi ih® «

P O ^ K P I P K P KP

O I w C \ 1 ^ o '- * O'—

«Η coj. K O O

^ K 'q,, O · I · I · I O g * I ™ ft .K. Pi i / K. Pi ° id) ra2is oU g §

Η P V P K W P K

Φ 3 EH--

H

h S

Island Island

Island Island

X) ° Η H

° »? at - 8 8 ki W o o

K O.I I

O OO K

Example 5 (1) In a solution of 0.5 g of phosgene in 10 ml of anhydrous dioxane, at 10 ° C 10 ml of anhydrous dioxane containing 0.56 g of 1-allyl-2-oxo-piperazine and 0 5 g of triethylamine, thereby initiating a reaction to precipitate white crystals of triethylamine hydrochloride. The white crystals were then collected by filtration and the filtrate was evaporated to dryness to give 800 mg of pale yellow oily 4-allyl-3-oxo-1-piperazino carbonyl chloride.

IR (film) cm to a pH of 8.0 to 8.5 by gradual addition of triethylamine with stirring and then cooled to 0 ° C. In the thus treated 10 ml of tetrahydrofuran solution containing 800 mg of the above 4-allyl-3-oxo was added dropwise. During this time, the pH of the suspension was maintained at 7.5 to 8.5 by the gradual addition of triethylamine, then the resulting mixture was reacted at said temperature for 30 minutes and the temperature was raised to 10 ° C. The mixture was further reacted at said temperature for 90 minutes while the pH was adjusted to 7.5 to 8.0 by the addition of triethylamine. After the reaction, the tetrahydrofuran was distilled off under reduced pressure and the residue was collected in 20 ml of water. The resulting solution was washed with ethyl acetate, and other layers were separated. This aqueous layer was ice-cooled and adjusted to a pH of 1.5 by the addition of dilute hydrochloric acid to precipitate white crystals. The precipitated crystals were collected by filtration, washed thoroughly with water and then dried to give 1.8 g of 6- [p (-) - (K- (4-allyl-3-oxo-1-piperazinocarbonylamino) phenylac etamido] penicillanic acid , mp 92 ° C (decomp.), yield 90%.

IR (KBr) cm -1; V c = 0 1760 (lactam), 1720-1620 (-C00H, -CONC)

- ------ J

76 151338

The above operation was repeated with the change that the 4-allyl-3-oxo-1-piperazinocarbonyl chloride was replaced by each of the reactive derivatives of formula (III) listed in Table 11 to form the respective end products also shown. in Table 11 <> The structure of each compound was confirmed. by IR and NMR.

77 151338

Κ'ΚΛ Ο k \ co§ 'SR W

66 8 § S68 S i «g 3" Y-f φ Yi o φ "amber ^ i i amber £ <1 £ 3 Hg Hg _i g S and. · O g 3! Q M p kp, -, °

-p fe ·. fe W

P O O O g ~

O O O O O O O

m ω / T \ cm ffi / ~ \ o o o

Ϊ i ^> 3 | ^> S g- © S

rH O O} Si '-'

rH O · O O

p fe i * s a J a

§ X) s x) 5 AS

S ° isf K. 5 ° T 5 cAe1 5

Eli hri tti - C \ 1 - I '' '

0—0 Μ (Λ CM I

W. O fe. , _ W 2 · X “& X“ - ° & A g = o § § η j, ^ S i »" § λ “£ ® H po O O O O'— 'H / ~ v

Φ H

O H -----

03 H

Eh β

<D

H

a &

Ή Oh

Η H

p-ri o o

+ 1 ^ 0 O H

ξ 2 o o o

> S I I O

Ή. then fairy O

fe § i) i) a

* 3 ° 7 1Λ ° Ύ JJ

-P Φ W W cm o fe> · ϋ o - o jxj to i ^

H S3 W O M CM I

+5 · η o O - o wra

, y O il il W_ o S

riSU CM CM 0 = 0 03

So W W ^ w £

ECHY o o g -P

78 1 5 1 3 3 8 w £:. w w

ΚΛ fT \ Q {Τ '[Ov fOO tf> tfO

W W O _ W W O M WO

ooo $ ooo ooo

Yi S y-f I yy fe 02 I, >> cq I cr \ ca I {Ti

US 4 US VS

4.? 4! 4! O ** O! >> i_rW ^ w o S θ S £ a o S t) S ti Ο Ο O p o p o o __O _ ^. mi i- © »i-®» g g o S o o 00 o o o o

U CM O c \ j Ο H

I Η I Η I H

-P „S. 4¾. ^ “O ^ V ft o ^ ft o ^ w ft

Li i a i i a i s 0 CM O CM O CM o £ W Λ W -¾ Μ Λ

JT ο ω ο a) o <D

<3- -ri m 'ti co' ϋ

V cm CM CM

H W · W «W * h i o; 1 o ft o p, 1 2 I ϊί §5 «§ cd no no no

i — I rH rH

OOO OOO OOO

Λ ή Λ 0 * Sr O ^ ÉT o * Ss i i i

CM CM CM

W W W

OOO ^ LTV CO

CM CM CM

WWW

OOO tA to ΚΛ

WWW

ooo 79 1 5 1 3 3 8 Μ ΚΛ ΚΛΟ ΜΚ Y f f Yf ^ £ CQ I '«Ο £ ~ y Μ 00 Κω μ ω +5 to too -ρ ο -μ Μ ο -Ρ Μ>, ο ο ο >> and γγ g ο g ο I ο μ / 7λ Vs | Λ2) - Λ - g ο "ο ο ο _ ο Ο Μ Μ ^ ο in two

/ -s s H OH

Ϊ XJ ~ ~ 5 ° T i S <2 / i

U O) S S S

O tti · O O Q

cS o, y o ο O ω i ω

Η H H

d w X J ~ H Mi cy'tt ft, i o o i. a i 2 # § 2 ώ ra ® P O P '-

H 'O

o o ό cT-ts

C \ J H

M O.

ISLAND ISLAND

ISLAND ISLAND

Η I

g oV

EXAMPLE 6 (1) To a mixture of 8 g of diethyl ester of oxalic acid and 8 ml of ethanol, 4.4 g of N-ethyl-ethylenediamine was dropped at room temperature. The resulting mixture was allowed to react for 3 hours and then heated to remove the ethanol. Then, the residue of 10 ml of dioxane was recrystallized to give 5.4 g of 1-ethyl-2,3-dioxopiperazine, m.p. 124 ° C, yield 76.0%.

(2) To a suspension of 0.71 g of the above-mentioned 1-ethyl-2,3-dioxo-piperazine in 15 ml of anhydrous dioxane was added with stirring 0.70 g of trimethylsilyl chloride and 0.83 ml of triethylamine. The resulting mixture was stirred at room temperature for 20 hours to precipitate triethylamine hydrochloride. This hydrochloride was filtered off and the filtrate was dripped at 5 ° to 10 ° C in a solution of 0.70 g of phosgene in 10 ml of anhydrous tetrahydrofuran. Then, the resulting mixture was reacted at 5 ° to 10 ° C for 30 minutes and at room temperature for 2 hours, after which the solvent was distilled off under reduced pressure to give 1.0 g of light yellow crystals of 4-ethyl-2,3-dioxo-1 piperazinocarbonylchlorid.

(3) A suspension of 1.75 g of 6- [d (-) - α-aminophenylacetamide-Chippenicillanic acid in 50 ml of tetrahydrofuran containing 20% by volume of water was adjusted to pH 8.0 to 8.5 by addition of triethylamine with stirring. forming a solution. This solution was cooled to 0 ° to 5 ° C and then 7 ml of anhydrous tetrahydrofuran solution containing 1.0 g of the above 4-ethyl-2,3-dioxo-1-piperazinocarbonyl chloride was dripped into the solution. During this period, the pH of the reaction solution was maintained at 7.5 to 8.0 by the gradual addition of triethylamine. The resulting mixed solution was reacted at said temperature for 30 minutes and then at 5 ° to 10 ° C for one hour while maintaining the pH at 7.5 to 8.0. After the reaction, the tetrahydrofuran was removed by distillation under reduced pressure and the residue was dissolved in 20 ml of water and then washed twice with 20 ml of ethyl acetate. 50 ml of ethyl acetate was again added to the aqueous layer and the resulting mixture was adjusted to a pH of 1.5 by gradually adding dilute hydrochloric acid under ice-cooling. Then, the ethyl acetate layer was separated, which was washed thoroughly with water and then dried over anhydrous magnesium sulfate. To the thus treated layer was added 10 ml of an ethyl acetate solution containing 0.85 g of sodium 2-ethyl hexanoate to precipitate white crystals. The precipitated crystals were collected by filtration, washed thoroughly with ethyl acetate, then washed with diethyl ether and dried to give 2.4 g of sodium salt of 6- [D (-) - α- (4-ethyl-2,3-dioxo-1 piperazinocarbonylamino) phenylacetamido] penicillanic acid, m.p. 183-185 ° C (decomp.), Yield 89%.

IR (KBr) cm ”1: V ^ c = O (lactam), 1720 - 1670 (-CON <), 1600 (-C00®) NMR ((01) 3) 280 + D20) Έ values: 2.62 (5H) , 4.31 (1H), 4.50 (1H), 4.70 (1E), 6.05 (1H), 6.35 - 6.65 (6H), 8.49 (3H), 8.60 (3H), 8.91 (3H)

The above operation was repeated with the change that 4-ethyl-2,3-dioxo-1-piperazinocarbonyl chloride was replaced with each of the reactive derivatives of formula (III) listed in Table 12 to give the end products also listed in Table 12. The structure of each compound produced was confirmed by IR and NMR.

82 1 5713 33 d Μ pa pao

d M M O

g O o o § pa tao cS. y_ / oo oo o oo ra I co d © Y ~ f © ω © SP ca I p · _l +3 to ta tao -p VS 'P> +3 J ggg έ -J £ 8 5 c 4 3 r ° 1 I 3 s = sug © o 'SE 5 g ^ -7 H 2 s ® O o ° y! 2L ^ 3 I- © 1 § Vs § ° S img - o] J o cm o

g OX o ^ isT X MX

© o © T © o © M I rtf CM Tj cm -¾ h o. S. ^ M 4, ^ T) 4 ai. M i.

Λ ° Τ θ Λ B & Λ E § · ^ ”Em ^ w MO MO MO ·

rh

CD ______

E- * P

P

? H

I h

Wed, S

• erf c Η O

ro. £ O O

; ©. · £ S ° * A

: jhj Η ° γ ^ Ί • 5.1 g oV k ® φ 8 k g

CM tt Ον Μ M CM

r- V Ί O -

© © J J CM CM

> rti O ^ B Μ M

• Η 'β I Ο O

Take XM Μ M

d ο ο M

© o o

M * H

83 1 5 1 3 38 SR.

m a ^ d ® <s3 Ο Ο O. "A +?

Jzj \ / j to tOO -P

to too m 7 ~ i cn a a o >>

Kao co ral t> - uooig ο ο o v- ^ „V- / 's y-f i _i ί ®i 3 W I +3 V -P y-a Λ f I! K0 <go 3 opao Θ - 8- (3) - .8 -7 ο oa V— / oqi ο oaoa at \ _ a AT \ Ο LO o- (0) 00 g <°> asi ^ -7 s § „ γΊ .-. 8 ~ +3 ^ a o ^ a a g <d o ^ .aN a i a T Ί a

to Y 1 O CM o J J Q

-P 1 J ^ a At o ^ ar λ T on? CD ο ω I ω o. I ^ cvi - * ™ ch a - a ^ a - wo CM é O · hh, ·., 1 --- ft I o ft I o ft ™ -—to g - u 3-7-11 a ^ 1 am 1 jn ra · ™ ra w · 0 a 'r' a ^ O v_- fl 0 00 £> cd

Eh ---

H

ISLAND

ISLAND

O H

Η I O

8 ° γΒΊ 8 ° o <Sc ° ^ b-,

° Λ A ·· oV

° v% k, 8 8 8 cm o a - 0 0

to Ο II

K to CM

0 a a w 0 0..

in! 84 15133¾

ω $) R

oo c- σ \ ω φ +3 μ -Ρ φ t å ^ t £ ►?> ο £) · cd! >> Υ β ΜΜ ο Ε 00 Ε3 Ρ Κ * ^ ο ο κν tno tJ. · 9 cd 3 V / ω W Κ ο ø ° 3 ^ 1¾ / —ί -Ρ ο ο ο § ρ ΚΛ ΚΛΟ CQ I -μ V / ggg ο V? £ «Π ο @ 68 ο y-f <*. A y * ° * - v-f% cq 1 ω o 3 _i ^ 7 o? I c- l i ο ο W I _J ·

n o lt \ W / ΤΛ Ο O ir \ ° [T

8 * l ^ 71 | Ao) A g A

ξ 6- (o) έ 2 & I & | Ao) έ

s g ^ 71 vs § “« I I I

-Ρ o -¾ 11, ¾ 0, ¾, o / 2} 0 / ¾

Ih ο ω oA ^ Y ω YT ® O φ OI · ϋ I "d 1 -d ^ T 1¾ -S- ΰ, ° r ^ wm ^ ° ^? A ° γ ^ γ ° ~ Λ ° ^ τ ft Λ ^ ft 'Ag a A ° * V é

A @ A o AS AS

S

EH __.______

H

ISLAND

Ο H

ISLAND ISLAND

e3 ° yS Ί $ g 8 ° V ° γγϋ o $ o i y ° V ο B o

° iBJ 8o g ° V

fAil o r, £ *

@ o 6 S

I ..... I - - I b ----- ------

Example 7 85 151338

A suspension of 1.4 g of 6-jp (-) - oc-aminophenylacetamidoj [penicillanic acid in 30 ml of tetrahydrofuran containing 20% by volume of water was adjusted to pH = 8.0 to 8.5 by addition of triethylamine with stirring to give a resolution. This solution was cooled to 0 ° to 5 ° C and 10 ml of a tetrahydrofuran solution containing 1.2 g of 4-n-pentyl-2,3-dioxo-1-piperazinocarbonyl chloride was added to the solution. During this period, the pH of the reaction mixture was maintained at 7.5 to 8.5 by the gradual addition of triethylamine. Then, the resulting mixture was reacted at said temperature for 30 minutes and then at 10 ° to 15 ° C for 90 minutes while maintaining the pH of 7.5 to 8.5. After the reaction, the tetrahydrofuran was distilled off under reduced pressure and the residue dissolved. in 20 ml of water and then washed twice with 20 ml of ethyl acetate. To the aqueous layer was added an additional 30 ml of ethyl acetate and the resulting mixture was adjusted to a pH of 1.5 by adding dilute hydrochloric acid under ice-cooling. Then, the ethyl acetate layer, which was thoroughly washed with water, was separated, dried over magnesium sulfate and then freed of the solvent by distillation under reduced pressure. The residue was recrystallized by the addition of diisopropyl ether to give 1.8 g of crystals of 6- O (-) - α- (4-pentyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] penicillanic acid, m.p. 96 ° C (decomp.), Yield 80.5%.

IR (KBr) cm -1; C = Q i770 (lactam), 1720 - 1660 (-CroC, -C00H) MR ((CD2 SO + D20) T values: 2.62 (5H), 4.31 (1H), 4.51 - 4.69 (2H), 6.04) IH), 6.20 - 6.90 (6H), 8.50 (3H), 8.60 (3H), 8.75 (6H), 8.90 (3H) 86 151338

The above operation was repeated with the change that 4-n-pentyl-2,3-dioxo-1-piperazinocarbonyl chloride was replaced with any of the reactive derivatives mentioned in Table 13 below to form compounds of formula (III) said end products. The structure of the compounds formed was confirmed by IR and NMR.

c 87 15133¾ I j-j HjH jrj kn JT ^ JTS Vo

Sgg ggg * ggg fc w * xV “i h;

02 I CO 03 I 00 03 i IN

\ _! S; V-fc 00 V-S

A I -Λ ® £ 3 § 3 1 ^ 1 I ^ 5 • I! -®o S- © - · | · © ο jh! Zi o SO So O Sc- O o O LT; IW ο Ο O c \ l O CTi i Η i σ>. in S ° fl - ° r *) ~ YS - 3 ° V & oiS & ° t t

+) C \ J O CM O CM O

7n fi id WX a, ¾ g Ο ^ ο Ώ ο ω

A ^ a LT \ 70 CO

£ ST'S1 "" S ^ 10 p, 1 0 ft Λ 3 a 2 s §15 "® ~ n a o O 0 p 0

pH

H ^ __________

2 H

3 tj H 3

. H

«Η <0. H

¢ 0 S Ο Η Ή

"go O O

p Ο Ο Ο O

Φ <Η Ω fe 7 7 1¾ X) ° f) Y) • H S 7 O ^ S ^ O ^ S ^

M CM I I

© © and CM CM

d «0 a w

Η τ ^ · O O

ω ω ^ lo. co>> d cm ^^

H <3 and CM CM

-P -H 0 and w

w O O

cd P to ^ - <φ ° a r \ JT1 a'H 0 0 0 «151338 '

Example $

With 1.7 g of triethylamine salt of 6- [p (-) - α-amino-p-hydroxyphenyl-acetamidojpenicillanic acid and 0.7 g of 4-methyl-2,3-dioxo-1-piperazino carbonyl chloride were repeated in the procedure of Example 7 to give 1.2 g of sodium salt of 6-jD (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -p-hydroxyphenylacetamido] penicillanic acid, m.p. 170-172 ° C (decomp.), Yield 75%.

IR (KBr) cm -1: vF 1760 (lactam), 1710 - 1660 (-COIRO, 1600 (-000 °) fflR ((CD4) 2 SO) x values: 2 * 8 - 3.3 (4H), 4.45 (1H), 4.65 (2H), 6.05 (1H), 6.2 (4H), 6.97 (3H), 8.48 (3H), 8.60 (3Ξ) In the same manner as indicated above, the sodium salt of 6- [d (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -β-hydroxy-phenylacetamidojpenicillanic acid, mp 175 ° C (decomp.), yield 72%, from 4-ethyl-2,3-dioxo 1-piperazinocarbonyl chloride and a triethylamine salt of 6- [p (-) - α-amino-p-hydroxyphenylacetamidoj penicillanic acid.

Example 9

To a solution of 0.8 g of phthalide ester of 6- [p (-) - α-aminophenyl-acetamidoj penicillanic acid in 10 ml of tetrahydrofuran was added 0.25 ml of triethylamine. In the resulting mixture, 0.32 g of 4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride was dripped with ice cooling and the mixture was reacted at room temperature for 2 hours. After the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in a mixed solvent consisting of 20 ml of ethyl acetate and 20 ml of water and the resulting solution was adjusted to pH 2 by the addition of dilute hydrochloric acid. Then, the organic layer which was washed with water was separated, washed with a 2% aqueous sodium bicarbonate solution, washed with water, dried over magnesium sulfate and then evaporated to a 2 ml liquid. To the concentrate was added 20 ml of diisopropyl ether to precipitate crystals, which were then collected to give 0.95 g of phthalide ester crystals of 6- [ioD (-) -oc- (4-methyl 1-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] penicillanic acid, m.p. 157-160 ° C (decomp.), Yield 90.0

IR (KBr) cm - in V₂, q 1780 (lactam), 1715 (ester), 1680 (-COnC) MR ((01) 3) 200 + D₂O) 71 values: 2.12 (4H), 2.40 (1H) ), 2.58 (5H), 4.25 - 4.60 (3H), 5.45 (1H), 5.85 - 6.42 (4H), 6.90 (3H), 8.50 (6H)

The above operation was repeated with the change that: 4-methyl 1-2,3-dioxo-1-piperazinocarbonyl chloride was replaced with each of the reactive derivatives of compounds of formula (III) listed in Table 14 to give the Table 14 end products mentioned. The structure of the compounds formed was confirmed by IR and NMR.

90 151338 @> ·> §. r- \ Ο νο 6 (Ο) w ο4 / - \ σ> yd / ω νγ ω 0 = \ $ η no α, ° <S ° - I Η °° £ \ β WWO fi docoo 'dooo' o \ Jsi fi go 8 3 Yi 3 -13 v / 02 I ^ / I ~ vs - o O) 02 IOIOW o tn VS o —λ o S o

rH I O \ O O

0) -4 H O DO o h

> d \ ί Η S H W _ / r \ H

a. o s, 2λΟ>.

Ml o I W \ - {I

jQ S O S

g g S SÆ) S 8 S

"SÆ) H S ^ -7 H °, A H

V M \ _ / O ^ Τ Ί “& å” g. oV ft

s? ι vs I ™ I

3 ° γ · ΒΊ% oU I s I

I <A4 S are S ™ 3

u I o CM

£ CM · CM ·. ffi · 1 W P. 1 ^ ft I O ft

_ I DO g I M CO I DO CQ

^ ν_ ^ ωυ ·· ν_ ^ ο wM

1-1 SO ft w P O

Γ-1

<D

5 —-----

® H

Η H

H ·

H

<Η Φ, ag s P o g

© «M J I

i «H § ° Y ^

, J d O O X J

f1 W O I O ^ S

g «'f vs i,

'ft tQ o. M J I M

• <U CD J J I CM

> ft O ^ S M -

• H fl I O CM

-P · Η CM CM M

a p m. - o På do χ-i

φ o CO M DO

«Ή g 3 g I_l_l_i 91 151338.!

Example 10

A solution of 0.86 g of hydrochloric acid! of methoxymethyl ester of 6- [d (-) - α-aminophenylac etamido] penicillanic acid in 15 ml of tetrahydrofuran containing 20% by volume of water was adjusted to a pH of 8.0 to 8.5 by addition of triethylamine at 0 ° to 5 ° C. To this solution was added a solution of 0.38 g of 4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride in 10 ml of tetrahydrofuran over 10 minutes. During this period, the pH of the reaction mixture was maintained at 7.5 to 8.0 by the gradual addition of triethylamine. The resulting mixed solution was reacted for 30 minutes while maintaining the pH to 7.5 to 8.0. After completion of the reaction, the tetrahydrofuran was removed by distillation under reduced pressure. The residue was dissolved in a mixed solvent containing 50 ml of water and 50 ml of ethyl acetate and the resulting solution was adjusted to a pH of 1.5 by adding dilute hydrochloric acid under ice-cooling. Then, the organic layer which was washed with water was separated, dried over anhydrous magnesium sulfate and then freed of the solvent by distillation under reduced pressure to form crystals.

The crystals thus formed were washed with diethyl ether to give 0.9 g of methoxymethyl ester of 6- {p (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] penicillanic acid, m.p.

111-115 ° C (decomp.), Yield 82.5%.

IR (KBr) cm -1; 1780 (lactam), 1740 (ester), 1700 - 1660 '(-CONCC) NMR ((CD₂) 200)' Z value: 0.15 (1H), 2.0 (1H), 2.67 (5H), 4.3 - 4.5 (3H) ), 4.75 (2H), 5.7 (1H), 6.55 (4H), 6.97 (3H), 7.25 (3H), 8.84 (3H), 8.60 (3H) 92 1 5 1 3 3 8

The above operation was repeated with the change that 4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride was replaced with each of the reactive derivatives of formula (III) shown in Table 15 to give the final product also shown in Table 15. ter. The structure of each of the compounds formed was confirmed by IR and NMR.

93 1 5 1 3 3 8 to

tU

ο Ο νρ VP CNJ CO, ^ trj ώ ^ ΚΛ Ο νρ Ο * W rT two, too Ο ° γλ and W Ko g ™ ω o ω o o o w Μ t ^ 1 © y ~ (s two, too

o -jf ra I if tU tU o -P

to \ too f \ _a if o o o>, tu iu o i o1 y- {s m o o o β —k B, / ¾ S; v / <& \> 'd co i 3 5 ^ 3 g ° s ri SHO So [Λ o 5 _I O o OI ° ° • H - ^ lp, M / - \ O tU LO, • 8 a ° ω | λ2) 00 I m S gg 1 S λ = ν 1, O _ to, O 00 0- (0) to P tU / TTv oo io tu \ - / cn

5 | Λ2> ~ ° ν ^ - I

. — I g · J I o H O PM O ^ SsT ft I g <+> od i a ovs a 1 ° ν ^ ι I beer oXzP # H 1 J -d <aj -d l d · fe ^^ -w tu ^

In CM O

CM tu · CM

i tu ØH i o Øi i ft. ^ o a ^^ S '-' to g i to ,. µ i- to, or i tu ta

—— i ± J —— jxj —— O.

a p o p o P ^

H

φ ----

S H

S H

H H

l

Η H

H CD O

cd a o u. island

U O _ I

H ° tB1 O

are given 8 oKs g

.Jj not O I I

u - 0> £ ° V ^

® ® ° vsi g I J

p * i ^ i 5¾ CM tu o S3 gs ™ tc \ tov CO, • S te tu tu tu © oooo (U 'H - 0, 151338 94 ΚΛ Μ Ο O vp CM ^ w 7 ο * ία WKO »- ο ο ο Υ-Υs ca I -Ρ V125 s ° ί ο ο ο ο | - {θ)? ο ο ο I C- Τ> ~ cYlzT ft * ι ύ Ο * cm ο ώ ο <ø

νχ \ 0 tJ

£ η CM ο Ο Η ft 3 '3 s 7 Υι Μ

in - W

r-) p o i-l ω, ω - a)

Bi Η

ISLAND

ISLAND

C \ 1 w o in c \ i

W

OK\

W

ISLAND

Example 151538

With 1.5 g of hydrochloride of pivaloyloxymethyl ester of 6- [l) (-) - α-aminophenylacetamido] -penicillanic acid and 0.6 g of 4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride, the procedure of Example 10 was repeated. a pivaloyloxymethyl ester of 6- [d (-) - oc- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] penicillanic acid, m.p. 108-111 ° C (decomp.), Yield 75%.

t IR (KBr) cm -1: Vc-O 780 (lactam), 1750 (ester),

1710 - 1660 (-CORO

The above procedure was repeated with the change that the 4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride was replaced with each of the reactive derivatives of compounds of formula (III) shown in Table 16 to give the respective compounds shown in Table 16. The structure of each compound was confirmed by IR and NMR.

96 151338 to two

W

o to o o to o w o

o CM

o N · to too cm

o IN · W W O IN

O o o o cm © \ / / ώ +1 / 1 '+3 o -P ml f

to too N, V-SZ5 N

S 888 € J É Ϊ Nf 3 Γ \> 3 1 ° vi - 8 -

• S I O O O

2 __i o o o £ - \ 00 W / 4Λ j £> O o O- (0) ^

* »G I i I

Jj O o ® ®_ / nS ^ o i ™ 3 | ^> ~ ° fi - +? Often ft «o a i a s I o cm o © Ov g Js! ixj ^ U T Ί © o © 1¾ J J MD> d o ^ fer - - - 1 ^ ΙΛ C \ J O W · 2 IK ft I O ft ^ ^ o g1 ^ ^ g Η Λ ^ B S & © no n o cd

EH

-7 — Τ '------ ---------

H

H

H

's-τ' • H ^ 'H © 3 os S o

Μ Oh

Ο I

© <Η Ον ia lefl g T)

31 ° C

k 1 CM

© CD ο ν S W

%)%

gS ° T S

S3 å1 8 as # © o w w ffj <H ° ° __J_I-

Example 12 97 15.1338

With 0.81 g of hydrochloride of β-piperidinoethyl ester of 6- [ρ (-) - α-aminophenylacetamidojpenicillanic acid and 0.3 g of 4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride, the procedure of Example 10 was repeated. 75 g of β-piperidinoethyl ester of 6- [p (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamidojpenicillanic acid, m.p. 1666-169 ° C (decomp.), yield 78%.

IR (KBr) cm "l; qq · q · 1780 (lactam), 1740 (ester),

1710 - 1670 (-C0nO

HMR (CDCl3) λ values: 2.7 (5H), 4.5 - 4.6 (3H), 5-7 (1H), 5.75 (2H), 6.0 (2H), 6.4 (2H), 6.9 (3H), 7.45 ( 2H), 7.6 (4H), 8.5 (12H)

The above procedure was repeated with the change that the 4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride was replaced with 4-n-octyl-2,3-dioxo-1-piperazinocarbonyl chloride to give β-piperidino-ethyl ester of 6- [b (-) -α- (4-n-octyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] penicillanic acid, m.p. 110-115 ° C (decomp.), Yield 73.58%.

Example 13

With 0.93 g of hydrochloride of β-morpholinoethyl ester of 6- [p (-) ~ α-amino-phenylacetamido] -penicillanic acid and 0.39 g of 4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride, the same procedure was repeated. Example 10 to give 0.8 g of β-morpholinoethyl ester of 6- {p (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamidoJ-penicillanic acid, m.p. 150-153 ° C (decomp.), Yield 73%.

98 (IR) (KBr) cm -1: δ q ~ q 1780 (lactam), 1740 (ester),

1710 - 1680 (-COtfO

MMR (CDCl3) X values; 2.55 (5H), 4.5 - 4.55 (3H), 5.6 (1H), 5.7 (3H), 6.0 (2H), 6.3 (2H), 7.4 (2H), 7.5 (4Ξ), 8.5 (6H)

The above procedure was repeated with the change that the 4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride was replaced with 4-n-octyl-2,3-dioxo-1-piperazinocarbonyl chloride to give β-morpholino ethyl ester of 6- [ D (-) - α - (4-n-octyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamidojpenicillanic acid, m.p. 103-105 ° C (decomp.), Yield 70%.

Example 14 <D - - # λ

To a solution of 8.7 g of sodium salt of D (-) - α-phenylglycine in 50 ml of water was added 50 ml of ethyl acetate and 5.05 g of triethylamine. To the resulting mixture was gradually added 9.5 g of 4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride at 0 ° to 5 ° C over 15 minutes, after which the mixture was reacted at 5 ° to 15 ° C for 30 minutes. After the reaction, the aqueous layer washed with diethyl ether was separated and then the pH was adjusted to 1.5 by adding dilute hydrochloric acid to precipitate crystals. The precipitated crystals were collected by filtration, washed with water and dried to give 14.1 g of D (-) - oc- (4-methyl-2,3-dioxo-1-piperazino-carbonylamino) phenylacetic acid, mp. 138-14 ° C (decomp.), Yield 87%. The recrystallization of aqueous butanol gave white crystals, m.p. 14 DEG-142 DEG C. (decomp.).

99 '151338

Elemental Analysis - (for:

Calculated -: {<? ») C: 52.01 H: 5.30 Ή: 13.00 Found- (<fo) C: 52.24 H: 5-32 N: 12.87 IR (KBr) cm -1: Vq = q 1710, 1700, 1660 .

(2) In a solution of 10 g of the above D (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetic acid in 200 ml of acetone, a solution of 5.2 g of sodium salt of 2- ethyl hexanoic acid in 50 ml of acetone with stirring to precipitate crystals. The precipitated crystals were collected by filtration and then washed with acetone to give 9.6 g of sodium salt of D (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetic acid, m.p. 165 ° C (decomp.), Yield 95% · (3) To a suspension of 8.8 g of the above sodium salt of D (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetic acid In 80 ml of methylene chloride 20 mg of N-methylmorpholine was added. To the resulting mixture, a solution of 3.1 g of ethyl chloro carbonate in 20 ml of methylene chloride was dropped at -r20 ° to -HL5 ° C over 5 minutes and the mixture was reacted at said temperature for one hour.

To this reaction liquid was added a solution of 9.4 g of a triethylamine salt of 6-aminopenicillanic acid in 40 ml of methylene chloride at -r40 ° to -i-30 ° C over 10 minutes, and the resulting mixture was reacted at -f40 ° to -r20 ° C within an hour. After the reaction, the temperature of the reaction liquid was gradually raised to 0 ° C over one hour and the mixture was extracted with 100 ml of water. The aqueous layer was then separated and the methylene chloride layer was subjected to further extraction with 50 ml of water and the resulting aqueous layer was combined with the above aqueous layer. The combined aqueous layers were adjusted to a pH of 2 by the addition of dilute hydrochloric acid under ice-cooling to precipitate crystals. The precipitated crystals were collected by filtration, washed thoroughly with water, dried and then dissolved in 200 ml of acetone. To the resulting solution, a solution of 4 g of sodium salt of 2-ethylhexanoic acid in 40 ml of acetone was added dropwise over 10 minutes to precipitate crystals. The precipitated loo 151338 crystals were collected by filtration, washed with acetone and then dried to give 11.4 g of sodium salt of 6-Qd (-) - (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamidoj penicillanic acid , m.p. 170 ° C (decomp.), Yield 80.8%.

The above operation was repeated with the change that the (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetic acid was replaced with the compounds of formula (V) listed in Table 17 to give the final products also shown in Table 17. The structure of the compounds formed was confirmed by IR and NMR.

ιοί 151338 cd

S

ΝΛ ΙΛΟ cd W W o 1¾ o o o t <- \ t <AO V- / cd K W o is? o o o cq! ΚΛ KXD V / Vs

Μ Μ O Π I

o o o m i —A

g 21 R | T0 I ti i ° § i r ° s „m g 1 §l2> 8

Ή K / “λ g I

«R®? T) 3 § ° ϊβ3 ° t ϊ γΊ ° V g S 1) c \ i c \ l 0) on W ~

Ml O CM

fe CM CM M

i ill I td i o ^ O '- "O v_ ^ I JO I tfv i - p —-- W · χ · w £ O O o O fi o

H

Q) -----

P

CD

EH

[> W

island

ISLAND

_I hear O

1 „§ m s i -mi 1, t® s ° v ^

Ξ I ° YS ° V

ra i 11 cm H O-! 3 O ^ tsr w φ V ^ r o

d 1 J cm CM

Hl O CM

XI CM CM w

fe Ag g Ag AS

* A ff A tT A ff 'p o p o p o

Example 15 102 151338 (1) To a solution of 2.28 g of D (-) - α-amino-1,4-cyclohexadienyl acetic acid in 15 ml of N NaOH was added 20 ml of ethyl acetate and 2.1 ml of triethylamine, and the resulting mixture was cooled to 0 ° C. To this mixture was gradually added 1.69 g of 4-methyl-2,3-dioxo-1-piperazino-carbonyl chloride over 10 minutes. Then, the mixture was reacted for 30 minutes under ice-cooling and the aqueous layer separated. An additional 20 ml of ethyl acetate was added to the aqueous layer. The resulting mixture was adjusted to a pH of 2 by the addition of 2N hydrochloric acid under ice-cooling and the ethyl acetate layer was separated. The organic layer was thoroughly washed with water, dried over anhydrous magnesium sulfate, freed of solvent by distillation under reduced pressure and then introduced into isopropanol to precipitate crystals. The precipitated crystals were collected by filtration to give 2.5 g of white crystals of D (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -1,4-cyclohexadienyl acetic acid, m.p. 140-145 ° C (decomp.), Yield lk%.

IR (KBr) cm ”1: 3300, Q Q = 0 1715, 1660 MR (dg-DMSO) Z values 0.57 (1H, d), 4.26 (1H, s), 4.36 (2H, s), 5.29 (1H, d), 6.07 - 6.18 (2H, m), 6.38 - 6.49 (2H, m), 7.05 (3H, s), 7.35 (4H, s) (2) For a suspension of 0.45 g of the above D (- ) -cc- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -1,4-cyclohexadienylacetic acid in 15 ml of anhydrous methylene chloride was added 0.24 ml of N-methyl morpholine with stirring to form a solution. After cooling the solution to -HLO ° C, 3 ml of anhydrous methylene chloride solution containing 0.4 g of ethyl chlorocarbonate was added dropwise and the resulting mixture was reacted at said temperature for 90 minutes. Then, the reaction liquid was cooled to t20 ° C and 5 ml of a methylene chloride solution containing 0.70 g of triethylamine salt of 6-aminopenicillanic acid and 0.31 ml of triethylamine was gradually dropped into the reaction liquid. The resulting mixture was reacted at + 20 ° C for one hour, at - ^ 20 ° to 0 ° C for one hour, and at 0 ° to 5 ° C for one hour. Then, the reaction liquid of the solvent is distilled off under reduced pressure. The residue was dissolved in 10 ml of water and then washed with 10 ml of ethyl acetate. The aqueous layer was again introduced into 15 ml of ethyl acetate and the mixture was adjusted to a pH of 2.0 by the addition of 2N HCl under ice-cooling. Then the ethyl acetate layer which was washed with water was separated, dried over anhydrous magnesium sulfate and freed from the solvent by distillation under reduced pressure to give 0.74 g of white crystals of 6- [d (-) -oc- (4-methyl-2.3). -dioxo-1-piperazinocarbonylamino) -1,4-cyclohexadienylacetamide-Cyptenicillanic acid, 84-87 ° C (decomp.), Yield 87%.

UMR (dg-DMSO) X values: 0.55 (1H, d), 0.95 (1H, d), 4.22 (1H, s), 4.35 (2H, s), 4.41 - 4.61 (2H, s), 4.92 (1H, d), 5.75 (1H, s), 6.05 (2H, bs), 6.40 (2H, bs), 7.03 (3H, s), 7.35 (4H, s), 8.40 (3H, s), 8.52 ( 3H, s)

The product thus formed was adjusted to a pH of 7.0 by neutralization with aqueous sodium hydrogen carbonate solution and then subjected to filtration and freeze-drying to form the sodium salt thereof.

The above operation was repeated with the change that D (-) - oc- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -1,4-cyclohexa-dienylacetic acid was replaced with each of the ones in Table 18 compounds of formula (V) to form the end products also shown in Table 18. The structure of each of the compounds formed was confirmed by IR and NMR.

104 151338 ·

o3 K

to coo

cd K K O

S o o o CO ΚΌ V_ / cd K K o 1¾ o O O CQ 1 CO [ΛΟ V / Y-E3 S S S il -4, H t5 r °

in G Γ "S

1 o 1 so dg κ / ΓΛ g ^ o κ \ _y 9

0 jxj λ — v g I

: rO e γγ 2 g 0ΥΒ-, ° ΐ

r-l I i J CM

• H O K 0 ^ * f g m J 1 cm cm § ° *? @ 3 ® ϋ, i «. §> - <- o ^ o ^ 'i two i co 1 co

H ^ M - {Xi K

CD fi U fi O o O

s EH____>

W M

si o ω k o H oK / T \ S o o - (/ /) k K o _ K \ _jy 5 § IO g 1 1 ^ 0 1 ° r ^ Φ o os

Y ^ Y) CM

• S Ϊ 3 CM ° • 3 oiV § 'S.

P CM CM K

fe I K I K l o 0 ^ 0 ^ o "" ^

& 4 | CO I CO I CO

^ K - K K

fi o O O P O

Example 16 105 151338 (1) To a solution of 2.2 g of DL-oc-amino-2-thienyl acetic acid in 14 ml of N sodium hydroxide solution was added 2.2 g of triethylamine at 0 ° C.

To the resulting mixture was added an additional 3.6 g of 4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride little by little at said temperature. Then the mixture was reacted at 0 ° C for 30 minutes and then at room temperature for 30 minutes. After the reaction, the reaction liquid was adjusted to a pH of 1.0 by the addition of dilute hydrochloric acid to precipitate crystals. The precipitated crystals were collected by filtration, washed with water and then dried to give 3.5 g of DL-α- (4-methyl-2,3-dioxo-1-piperazino-carbonylamino) -2-thienylacetic acid, m.p. 2.14-215 ° C (decomp.), Yield 80.5 # IR · KBr) cm "1: \ c = 0 ^ 10 ^ 80" (2) In a solution of 3.5 g of the above DL -oc- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -2-thienylacetic acid in 100 ml of acetone was added a solution of 1.86 g of sodium salt of 2-ethylhexanoic acid in 50 ml of acetone and the crystals precipitated. The precipitated crystals were collected by filtration and then washed with α-cetone to give 3.5 g of sodium salt of DL-oc- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -2-thienylacetic acid, m.p. 175-176 ° C (decomp.) (3) To a suspension of 3.3 g of. the above sodium salt of DL-α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -2-thienylacetic acid in 50 ml of methylene chloride was added 30 mg of N-methylmorpholine and the resulting mixture was cooled to -ί-20ο to -HL5 ° C. To the resulting mixture was added a solution of 1.3 g of ethyl chlorocarbonate in 20 ml of methylene chloride over 5 minutes and the mixture was stirred at said temperature for 90 minutes. Then, a solution of 3.3 g of triethylamine salt of 6-aminopenicillanic acid in 50 ml of methylene chloride in the mixture was dropped at -r50 ° to -r40 ° C over 20 minutes and the resulting mixture was reacted with stirring at -f40 ° to -r30 ° C for 30 minutes, at - ^ 30 ° to -r-20 ° C for 30 minutes 106 1 5 1 3 3 8 and then at τ · 20 ° to 0 ° C for 30 minutes. After the reaction, the solvent was distilled off under reduced pressure and the residue dissolved in water. The aqueous solution formed was adjusted to a pH of 2.0 by the addition of dilute hydrochloric acid under ice-cooling to precipitate crystals. The precipitated crystals were collected by filtration, washed thoroughly with water and then dried to give 4.1 g of 6-jl of (1- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -2-thienylacetamidoj penicillanic acid, mp.

185 ° C (decomp.), Yield 80.5%.

IR (nujol) cm -1: Vc = 0 1780 (lactam), 1715 (-C00H), 1685 - 1675 (-CONO MR ((CD3) 2CO) T values: 0.5 (1H), 1.8 (1H), 2.6 ( IH), 2.85 - 3.05 (2H), 4.0 (IH), 4.2 - 4.5 (2H), 5.7 (IH), 5.8 - 6.0 (2H), 6.2 - 6.4 (2H), 6.95 (3H), 8.4 (3H) , 8.45 (3H)

The product thus formed was adjusted to a pH of 7.0 by neutralization with an aqueous sodium hydrogen carbonate solution and then filtered and lyophilized to give the sodium salt thereof.

The above operation was repeated with the change that the sodium salt of DL-oc- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -2-thienylacetic acid was replaced with each of the compounds of formula (V) to form the end products also shown in Table 19. The structure of each of the compounds formed was confirmed by IR and NMR.

iG7 151338 cd a [Λ too ffi W o cd o o o S3 \ / j cd to too / f a a o ra l fo, too o o o ya

W «o V- / I

(ϋ RP® oH H

Ϊ ^ ti 's ° h y ~ ^ f \ v °

λ I ° §JO

-p o o o ra s g sjrn g * n o p-Njt o 41 g n b 2

^ gV 8 ° fS

• ri O

£ 8 I J k i ° yS g

} _, JL J cm CM

* ° V § w

CM CM W

W W o ev o o - S L to I to I to

^ P M P a ^ M

Η P O P O P O

CD

3 ________ EH-- - · ο> CD

> S

v_ ^ O

cd o S § sxi H & 9 8 ra ® o aj Π a £ S i — n a = ° o «ri § i 1:. I ^ § ° Y *) s o o.a_ ® 8 ϊ 1 Jm H ° V ^ ° "Y g -d o ^ a 'a -

fl i o CM

• ri CM CM a p a a o u o o - O I to I to I to a p a p a p a p o · p o p o

Example 17 108 151338

To a suspension of 0.9 g of 6- [d (-) - ct-aminophenylacetamidoj penicillanic acid in 30 ml of anhydrous ethyl acetate was added at 5 ° to 10 ° C 0.55 g of triethylamine and 0.6 g of trimethylsilyl chloride. The resulting mixture was reacted at 15 ° to 20 ° C for 3 hours to form trimethylsilylated 6- µD (-) -α-aminophenylacetamidojpenicillanic acid.

To this acid was then added 1 g of 4-ethyl-2,3-dioxo-1-piperazino carbonyl chloride and the resulting mixture was reacted at 15 ° to 20 ° C for 2 hours. After the reaction, a precipitate of triethylamine hydrochloride was separated by filtration and the filtrate was introduced into 0.4 g of n-butanol to precipitate crystals. The precipitated crystals were collected by filtration to give 1.25 g of white crystals r * of 6- [D (-) - o- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamidojpenicillanic acid. In a solution of the said crystals in 30 ml of tetrahydrofuran, a solution of 0.38 g of the sodium salt of 2-ethylhexanoic acid in 10 ml of tetrahydrofuran was dropped and white crystals precipitated. The precipitated crystals were collected by filtration, washed thoroughly with tetrahydrofuran and then dried to give 1.25 g of sodium salt of 6- [p (-) - oc- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] penicillanic acid , m.p. 183-185 ° C (decomp.), Yield 90%.

Example 18

To a suspension of 4 g of trihydrate of 6- [i) (-) - α-aminophenylacetamido penicillanic acid in 40 ml of water was added 20 ml of ethyl acetate and the resulting mixture was cooled to 2 ° C. Then, the mixture was combined with 1.37 g of potassium carbonate and stirred at 2 ° to 3 ° C for 2 minutes. Then 1.89 g of 4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride was added to the mixture at said temperature over 10 minutes and the resulting mixture was reacted at said temperature for 15 minutes. After the reaction, small amounts of insoluble matter were separated by filtration and the filtrate was introduced into 80 ml of ethyl acetate. In the resulting mixture, 5 ml of 2N hydrochloric acid was dripped at 20 ° to 22 ° C over 5 minutes and the mixture was stirred at said temperature for 5 hours to precipitate crystals. The precipitated crystals were collected by filtration, washed twice with 4 ml of water, washed twice more with 4 ml of isopropanol and then dried to give 4.0 g of dihydrate of 6- {jD (-) - α- (4- methyl 2,3-dioxo-1-piperazinocarbonylamino) phenylacetamidoj penicillanic acid, m.p. 156-157 ° C (decomp.), Yield 75.4% · IR (KBr) cm-1j JQ = Q 1775, 1740, 1695, 1670 MR (ds-DMSO) T values: 0.18 (1H, d), 0.77 (1H, d), 2.66 (5H, s), 4.30 (1H, d), 4.40 (3H, br), 4-48 (1H, g), 4.65 (1H, d), 5.80 (1H, s), 6.12 (2H, bs), 6.45 (2H, bs), 7.06 (3H, s), 8.48 (3H, s), 8.60 (3H, s)

The above procedure was repeated as the 4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride was replaced with 4-ethyl-2,3-dioxo-1-piperazinocarbonyl chloride to form a monohydrate of 6- {d (-) - (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamidoj penicillanic acid, mp · 154-156 ° C (decomp.), Yield 84.8% IR (KBr) cm -1: J = Q 1775, 1735, 1705, 1680, 1665 NMR (dg-DMSO) Z 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), 5.00 (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)

The monohydrate thus formed was neutralized with an aqueous sodium bicarbonate solution and then the mixture was filtered and the filtrate was freeze-dried to give the sodium salt of 6- [p (-) - <x- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamidoj -penicillanoic acid · 110 151338

Further, a solution of 2 g of the above dihydrate of 6- [p (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamidojpenicillanic acid for 18 hours was precipitated to precipitate crystals which were filtered off to form of 2 g of monohydrate of a nitromethane addition product of 6- [p (-) -a- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamidoj | penicillanic acid, m.p. 128-130 ° C (decomp.), Yield 92.2%.

Elemental Analysis (for 022 ^ 25 ^ 5 ^ 7 ^ 0 ^ 1 ^ 02 '^ O):

Calcd. (%) C: 47.42 Η: 5 · 19 H: 14.43 Found - (%) C: 47-94 H: 5.13 N: 14.53 IR (KBr) cm -1: 0 = 0 1770 '1755' 1700 ' 1680 NMR (d6-DMSO) λ values: 0.22 (1H, d), 0.80 (1H, d), 2.69 (5H, s), 3.3Ο (3H, hr), 4.30 (1H, d), 4.46 - 4.70 ( 2H), 5.67 (3H, s), 5.81 (1H, s), 6.13 (2H, bs), 6.46 (2H, bs), 7.07 (3H, s), 8.45 (3H, s), 8.58 (3H, s) )

Example 19

To a suspension of 1.6 g trihydrate of D (-) - α-aminobenzyl-penicillin in 20 ml of water was added 0.52 g of potassium carbonate at 2 ° to 3 ° C and the resulting mixture was stirred for 3 minutes. To the mixture was gradually added 0.81 g of 4-ethyl-2,3-dioxo-1-piperazinocarbonyl chloride at said temperature over 10 minutes and the mixture was reacted for 15 minutes. After the reaction, small amounts of insoluble matter were filtered off and the filtrate was introduced into 10 ml of methyl n-propyl ketone. To the resulting mixture, 1.98 ml of 2N hydrochloric acid was added dropwise at 15 ° to 20 ° C over 2 minutes, and the mixture was stirred at said temperature for two hours to precipitate crystals. The precipitated crystals were collected by filtration, washed twice with 2 ml of water, washed twice more with 2 ml of methyl-n-propyl ketone, and then dried to give 1.7 g of monohydrate of D (-) - a- ( 4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) benzylpenicillin, m.p. 152-154 ° C (decomp.), Yield 80.2%.

The product thus formed was neutralized with an aqueous sodium hydrogen carbonate solution and then subjected to filtration and freeze-dried to give a sodium salt of said product.

Example 20

A suspension of 4.0 g of monohydrate of 7- (D (-) - α-aminophenylacetamido-3-methyl-Δ-cephem-4-carboxylic acid in 60 ml of tetrahydrofuran containing 20% by volume of water was adjusted to a pH value. -di of 8.0 to 8.5 by gradually adding triethylamine with stirring to form a solution which was then cooled to 0 ° C. To this solution was gradually added 2.5 g of crystals of 4-methyl-2,3- dioxo-l.piperazlino-carbonyl chloride over 10 minutes ter During this period the pH of the reaction mixture was maintained at 7.5 to 8.0 by the gradual addition of triethylamine and then the resulting mixture was reacted at 0 ° to 5 ° C. for 15 minutes while maintaining the pH at 7.5 to 8.0 After the reaction, the reaction mixture was stirred with 60 ml of diethyl ether and 70 ml of water and then the aqueous layer was separated. The aqueous layer thus formed was washed with 30 ml of ethyl acetate. cooled to 0 ° to 5 ° C and then adjusted to a pH of 1.5 by adding dilute hydrochloric acid to precipitation of white crystals.

The precipitated crystals were collected by filtration, washed thoroughly with water and then dried to give 4.7 g of white crystals of 7- (p (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) - phenylacetamido] -3-methyl-Δ-cephem-4-carboxylic acid, mp 185-186 ° C (decomp), yield 86%

r 112 151338 IR (KBr) cm -1: v = j = 0 1770 - 1760 (lactam), 1720 - 1660 (-COUCT-C00H) MR (dg-DMSO) T values: 0.1 (1H, d), 0.56 (1H, d), 2.62 (5H, s), 4.26 - 4.37 (2H, dd), 5.05 (1H, d), 6.1 (2H, bs), 6.47 (2H, bs), 6.63 (2H, s) , 7.05 (3H, s), 8.02 (3H, s)

The above operation was repeated with the change that the 4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride was replaced with each of the reactive derivatives of compounds of formula (III) shown in Table 20 to form the ones also shown in Table 20. end products. The structure of each of the compounds formed was confirmed by IR and NMR.

113 151338 tOl «m ^ in ο M vo S 'MO ΓΛ o V £> CO O M CO CQ Vo D- k \ __i o y-iz; Μ Φ ® I ®

ο K -p co Vo -p _i -P

i ° V> V-izi -P -P

ri °>> i> »^ ° b

co Vo h4 _i p g P

ω 13 µ ° 3 g 3 ". § gYo> - ω ω ο ο ω \ y / ο Ό g ο fcri Γ ~ \ ο § ο β g οο ο - (0) ° ° ο ρ ό ο frj \ _ / νο ο m 2 gVo) Η § Η oJ, ο g'η- / ~ ο 'Τ X) ", ο ft ft ft + · ο a τ iais <uio 1 J o cm o

rH o ώ M CVS, ¾ K .M

, h t i 'S I ω o ω

• H I I T3 CM 'Ti CM P

+1 crSg - K "-

IQ 7 O. CM

S CM. CM 0. W i φ i g ρ ^, Λο s 3 &

° έ! 7 § i ^ ra m I

M vSk ω - K W

p o p o o

rH <D

P

ø ---- EH ^

H

H

H

s__ '£ ω

CH P P

Cd a o

fH O

ίπ O H o

® <H O I

tP O

ctCd p o T Ί

S s g oV

s «g l) ™« 5 o a °> f g ω $ „XJ & y £ * g ° ^ S cm

Sp i i § lay if i i __I-- • 114 151338

Example 21 (1) To a solution of 0.92 g of 1-n-pentyl-2,3-dioxo-piperazine in 15 ml of anhydrous dioxane was added 1.1 ml of triethylamine and 1.08 g of trimethylsilyl chloride. The resulting mixture was stirred at room temperature for 20 hours to give triethylamine hydrochloride. This hydrochloride was filtered off and the filtrate was dripped at 0 ° to 5 ° C in a solution of 0.6 g of phosgene in 10 ml of anhydrous tetrahydrofuran. Then, the resulting mixture was reacted at 5 ° to 10 ° C for 30 minutes and then at room temperature for 2 hours. The solvent was then distilled off under reduced pressure to give 1.21 g of pale yellow oily 4-n-pentyl-2,3-dioxo-1-piperazinocarbonyl chloride.

IR (film) cm -1: Vc = 0 1790 1720 ~ 1665 (2) A suspension of 1.70 g monohydrate of 7- {p (-) -? -Aminophenyl-acetamido] -3-methyl-A? - cephem-4-carboxylic acid in 50 ml of tetrahydrofuran containing 20% by volume of water was adjusted to a pH value of 8.0 to 8.5 by the addition of triethylamine, stirring to form a solution. This solution was cooled to 0 ° to 5 ° C and 7 ml of anhydrous tetradydrofuran solution containing 1.21 g of 4-n-pentyl-2,3-dioxo-piperazinocarbonyl chloride from step (1) was dripped into the solution. During this period, the pH of the solution was adjusted to 7.5 to 8.0 by the addition of triethylamine. Then the resulting mixture was reacted at 0 ° to 5 ° C for 1 hour and then at 5 ° to 10 ° C for 2 hours. while maintaining the pH of 7.5 to 8.0. After the reaction, the tetrahydrofuran was distilled off under reduced pressure and the residue was dissolved in 20 ml of water and then washed twice with 20 ml of ethyl acetate. The aqueous layer was then mixed again with 40 ml of ethyl acetate and adjusted to a pH of 1.5 by gradually adding dilute hydrochloric acid to ice-cooling. Then, the ethyl acetate layer was separated, which was washed with water and then dried over anhydrous magnesium sulfate. Then, 10 ml of an ethyl acetate solution containing 0.75 g of sodium 2-ethyl hexanoate was dropped into the layer at 0 ° to 5 ° C to precipitate white crystals. The precipitated crystals were collected by filtration and washed with ethyl acetate and then with diethyl ether to give 1.95 g of sodium salt of 7- [p (-) - α- (4-n-pentyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] -3-methyl-β-cephem-4-carboxylic acid, m.p. 164-166 ° C (decomp.), Yield 75%.

IR (KBr) cm -1: VC = Q 1750 (lactam), 1720 - 1660 (-COO, 1-590 (-C009)) NMR (dg-DMSO + D20) T values: 2.58 (5H, · s), 4.33 (1H, s), 4.49 (1H, d), 5.17 (1H, d), 6.10 (2H, bs), 6.42 - 6.87 (6H, m), 8.09 (3H, s), 8.60 - 8.90 (6H, bs), 9.12 (3H, t) 1

The above operation was repeated with the change that the 4-n-pentyl-2,3 ”dioxo-1-piperazinocarbonyl chloride was replaced with each of the reactive derivatives of compounds of formula (III) shown in Table 21 to give the end products listed in Table 21. The structure of the compounds formed was confirmed by IR and NMR.

n «151338 ΚΛ. ΚΝ ΚΝ ώ CO Μ ^ ώ C0

ο S Ν 0¾ ο S

, _ι Ο '«__I Ο cS i Ο cR

/ \ ο is- 1 \\ ο ω / —i. ο 00 CQ 7-0 ι> - m VO 1ST CQ'VolS- • VB y-3 V® i CD I 0) I ω ® Ά £ ^ £ -Λ. £ m W $ ω, Ω M £> «1¾ id g -d g S3 'o o w o 3 o η 3 l <2> | Xo> 0- | xo) p o o o oo o -tr o vo o m o lo

4-> I Η I Η I H

^ ° f) ~ TD ~ ° I) O

• rt o'ST a Ciw a o ^ s ft 4J ι a ι a ι a

ra CM o CM O CM O

S W Λ Μ A! w Λ ο ϋ ο ω ο ο> 4- r ^ j m <d co Ό

^^ "c \ J CM CM

K · W * frj · I o p, I o ft Λ S ft 3 § Λ §

Η P Ο P Ο P O

Φ & 05____

EH

L->

H

H

H

V>

S

<D

* H Η Η Η H

CO S ο ο o p o o o

POO o O

(Dpi I I

P O OvB

il 0y oV oU

'58 g S $ <d $ * j? ^

!> 'd CM CM CM

3 w w w -P -H o o o (0 p fPv fcs na

(DO B M W

Dip ο ο o __I -! - 117 151338 __

CVJ

'V

σ \ fc-

toe

W ti ® o a f J ° f

ra Vo P

y a · ϋ Λ 3 o W ο a o o r- o ΝΛ 1 <2) 7

Oh LA

Oh LA

I H

° fj ~ ka p.

^ 1 S

77 oj o

+1 ώ X

S o ω • P ^ 0 ώ * - Λ 3 g · I LA 03 ι-l w jxj

OJ Q O

I-I

(1) Λ-- (d

Eh

H

ISLAND

ISLAND

ISLAND

Ύ) 'Oh

M

o c \ j

K

ISLAND

LA

K

ISLAND

118 151338

Example 22

With 1.5 g of hydrochloride of methoxymethyl ester of 7- [D (-) - α-amino-phenylacetamido3-3-methyl-A? -Cephem-4-carboxylic acid and 0.65 g of 4-methyl-2,3-dioxo- 1-Piperazinocarbonyl chloride was repeated in the procedure of Example 20 to give 1.6 g of methoxymethyl ester of 7 * [b (-) -a- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] -3-methyl / \ ^ - cephem-4-carboxylic acid. mp. 146-148 ° C (decomp.), Yield 86%.

IR (KBr) cm "l: ^ q__ · 1770 (lactam), 1710 (ester),

1680 - 1600 (-CO0HO

Example 23

To a suspension of 0.20 g of 7- [p (-) - α-aminophenylacetamidoj-3-acetoxymethyl-Δ-cephem-4-carboxylic acid in 15 ml of anhydrous chloroform was added 0.17 ml of triethylamine with stirring to form a solution which was then cooled to 0 ° C. To this solution was added 0.11 g of 4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride and the resulting mixture was reacted at room temperature for 2 hours. Community. After the reaction, the liquid reaction mixture was evaporated under reduced pressure and the residue was dissolved in 15 ml of water. The resulting solution was washed with 10 ml of ethyl acetate. The aqueous layer was again combined with 20 ml of ethyl acetate and then adjusted to a pH of 1.5 by the addition of 2N hydrochloric acid under ice-cooling. Then, the ethyl acetate layer was separated which was washed successively with water and a saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was then distilled off under reduced pressure to give 0.22 g of white crystals of 7- [D (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -phenyl-acetamido-3-acetoxymethyl] ? -Cephem-4-carboxylic acid, m.p. 175 DEG C. (decomp.), Yield 76%.

115 151338 IR (XBr) cm -ΐϊ yΐϊ = 0 177O (lactam), 1720 - 1650 (-00Ν <, -COOH) MR (dg-DMSO) T values: 0.25 (1H, d), 0.65 (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 (2Ξ, bs) , 6.57 (2H, bs), 7.0 (3H, s), 8.0 (3H, s)

The above operation was repeated with the change that 4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride was replaced with each of the reactive derivatives of compounds of formula (III) shown in Table 22 to give the final products shown in Table 22 . The structure of each of the compounds prepared was confirmed by IR and NMR.

120 151338 to »

M

o W

ο ίο ο Ο = § · W Ο Ο -ί ϋ so Ο -νΟ (Μ »Ο Ο ΙΛ Ο m Ο Μ 00 OCO Μ 00 _ (Ο CM Ο Μ .. / Λ ο Φ Μ I _I Ο Φ Φ Μ y -— U +3 Ο jxj -Ρ * Υι Ο -Ρ Μ VS Ρ I Ο -ρ C0} -ϋ -ρ m 1 >> / Vv ° >> b 3 ^ g v_g s .4¾ • η ω ° 3 1 3 Γ ^ ο 3 f S "Μ g g g Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ <<<<2 2 2 8 8 8 8 8 8 8 8 Η η 8 ~ Ι ^ -7 'Τ 8 ~

I ° r * i ^ g & ο α I

φ o ^ -g ^ Μ and, Μ X) & U ι Φ Τ 1 φ And φ & ι CM Η 1 J 'ΰ · 5 * gw dnsr - Μα · I ο CM ft (Μ · CM · I hrt S' I ώ ft I ^ Pi - ow— OB ^ & s tv] 1 KV I ί <Λ tø IK 02

cm ^ Μ ^ K „X O

Ρ O ρ o p -

rH Φ P

CD ----

B

✓- ·.

H

H

H

P

Φ

PH

CDS

P H

uo 3 h

Φ <Η ο O

-Ρ ο Η Oh

cdTj ι ο o> Φ and ο ι η a T j g ° Υ ^ Ί ΦΦ θ4ι O ^ g,, -, 44 dia ι Ti o ^ g H about td

ΦΦ W O g P

ί> Η O I o HP ™ ™ J?

Sp § § ^ S 4 ^ g SS § g ~ 121 151338

The above 7- [ρ (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] -3-acetoxymethyl-Δ ^ -cephem-A-carboxylic acid 175 ° C (decomp.) Was recrystallized from aqueous acetone to give white crystals which exhibited a melting point of 198 - 200 ° C (decomp.).

Example 24 (1)

To a solution of 28.2 g of sodium salt of D (-) - phenylglyc in 150 ml of water was added 200 ml of ethyl acetate and 18.2 g of triethylamine and the resulting mixture was cooled to 0 ° C. To this mixture was added 34.3 g of 4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride over 15 minutes and the mixture was reacted at 5 ° to 10 ° C for 15 minutes. Then, the aqueous layer was separated, which was adjusted to a pH of 0.5 by the addition of 2N hydrochloric acid under ice-cooling to precipitate crystals. The precipitated crystals were collected by filtration and then dried to give 42 g of white crystals of D (-) - α- (4-methyl-2,3-dioxo-1-piperazino-carbonylamino) phenylacetic acid, m.p. 195 ° C (dec.).

IR (KBr) cm -1; y) c = 0 1700, 1660 NMR (d 6 -DMSO) T values: 0.1 (1H, d), 2.65 (5H, s), 4.60 (1H, d), 6.10 (2H, bs), 6.50 (2H, bs) ), 7.0 (3H, s) (2)

To a suspension in 15 ml of anhydrous methylene chloride of 0.31 g of D (-) -oc- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetic acid formed in the above step (1) was added 0.11 g N-methylmorpholine mites stirring to form a solution which is then cooled to 20 ° C. To this solution was added 3 ml of anhydrous methylene chloride solution containing 0.13 g of ethyl chlorocarbonate and the resulting mixture was reacted at -10 to 20 ° C for 60 minutes to form a mixed acid anhydride. In the acid anhydride thus formed was added a solution formed by adding 0.50 ml of triethylamine to a suspension in 5 ml of methanol of 0.41 g of 122 7-amino-3- [2- (5-methyl-1,3, 4-thiadiazolyl) -thiomethylj-A 2 -cephem-4-carboxylic acid. After drip, the resulting mixture was reacted at -ί-500 to -r30 ° C for 30 minutes, at -30 ° to 4-20 ° C for 30 minutes, at -r20 ° to 0 ° C for 60 minutes, and then at room temperature for 30 minutes. 30 minutes. The reaction liquid was then evaporated under reduced pressure and the concentrate dissolved in 10 ml of water, washed with 5 ml of ethyl acetate, again combined with 15 ml of ethyl acetate and the mixture adjusted to a pH of 1.5 by adding 2N hydrochloric acid under ice-cooling. Then, insoluble matter was filtered off and the ethyl acetate separated, washed successively with water and a saturated sodium chloride solution, dried over magnesium sulfate and then freed of the solvent under reduced pressure to give 0.58 g of light yellow crystals of 7- µg (-) - a - (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido3 -3- [2- (5-methyl-1,3,4-thiadiazolyl) -thiomethyl] - Δ-cephem-4-carboxylic acid . 160 DEG C. (decomp.), Yield 91%.

IR (KBr) cm -1: i780 (lactam), 1650-1720 (-CON <, -C00H) RMR (d6-DMSO) T values: 0.2 (1H, d), 0.6 (1H, d), 2.60 (5H , s), 4.35 (1H, q), 4.40 (1H, d), 5.0 (1H, d), 5.70 (2H, q), 6.10 (2H, bs), 6.25 - 6.55 (2H, 2H, bs), 7.0 (3H, s), 7.30 (3H, s)

The above operation was repeated with the change that D (-) - α- (4-methyl-

The 2,3-dioxo-1-piperazinocarbonylamino) phenylacetic acid was replaced with the compounds of formula (V) shown in Table 23 to give the final products also shown in Table 23. The structure of each of the compounds formed was confirmed by IR

and NMR.

123 151338 iiil ^ o K * to = ^ g I ra V * = <o ra ra * T to ra S to to ^ H ^ 8 & 03 o to> KI Vo »CM _J o LT \ Vs m WHO 00 I 00 o to m to yo —λ φ J Ο ί V-to ω Φ ω Γ \ ο ω i -P., ° +>, -i or Vto +3 -Λ. -P g if

1 4. j? g l 1 / ->, I

s "os I I-® 9 ° § £ - I® o" f of • m S 8 3 γ ~] 3 3 g "° A ~ ° i" PI Qj JJ CL CM ft I cx, to ao ^ to ^ a to aa -y> oioco Φ TJ CM, ¾ CM iis1 P CD to CD Φ

Qrd CM to C \ J '-' CM '- to "- η I W I to I to.

fM '-'O. 'O é - ft i r ° i ft i fpc ft 1 jp a

, '-'to f' - 'to S4 "W CQ

H P O gpo gRO

P

CD

Eh ---- to

I * I

In § -s-® § • g | ^ °) 8 ° rB) S o o ^ to.

® 8 I) k, Ά vs ° V g

CD. J J CM CM

P o ^ to w ^

ri I O CM

• H CM CM to P I to I to I to P - O O w ο i eft I eft I eft [x, ^ to - to '-'to P O P C P o 124 151338 m o V.

* W s

CQ

CM CD

W µ. "P

o W 43 _J 0 i>, ra ~ Vo! § V-S 3 -l.

0 0 w 0 a c- 0 vo tQ 5¾ Pi -p o a δ å S ° A 5

CO Λ W

H ^ (¾ & a) * -> «5 fi EH _

W

° A

1 to 5 §

Example 25 125 151338

With 0.3 g of D (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetic acid and 0.33 g of 7-amino-3- [5- (1-methyl-1,2 3,4-Tetrazolyl) -thiomethyl: QA 4 -cephem-4-carboxylic acid was repeated the procedure of Example 24 to give 0.5 g of 7- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido3-3- [alpha] - (1-methyl-1,2,3,4-tetrazolyl) -thiomethyl] -cephem-4-carboxylic acid, m.p. 161-163 ° C (decomp.), Yield 76%.

IR (nujol) cm -1:. y) c = Q 1775 (lactam), 1720 - 1660 (~ CQN \, -C00H) NMR (dg-DMSO) T values: 0.02 (1H, d), 0.34 (1H, d), 2.48 (5H, s) , 4.17 (1H, q), 4.26 (1H, d), 4.92 (1H, d), 5.66 (2H, s), 6.01 (5H, s), 6.35 (4H, s), 7.0 (3H, s)

The above operation was repeated with the change that D (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetic acid was replaced with each of the compounds of formula (V) to form of the end products also shown in Table 24. The structure of each of the compounds formed was confirmed by IR and NMR.

126 151338 r \ £ a = f S ^ pT ^ wf GQ »K-0> R S-Ov *

iS1 '5' »H $ = W S

OK CQ CQ

f Ο Φ CM <D CM φ

-. / Vi O-P K .. * P * W -P

v CQ Vo +> OK-P OK-p ffl V «>, I O V _l o S>» Ή I n2 Ο η2 ΓΛ O £ * φ _I ft cq Vo ft cq Λ) -ο ft

• ο “Λ Ώ yj * 3 - 3 I

c: o p I p i - g

-η k —1 _L «J

Q ^ * vv · * v ^ M O O O O _ 0 O g 0 oo K ° Ko o lu K / —V Ο K t ° v K to oYo) ^ o C- o ^

V K \ __ / H OH Ο H

5 JL ^> ® ~ m ~ «Η I K ft g & o jj o, j2L .o a o a. o a c p V ^ Y o o 9 o o s

g ° V I ° AS 1 Vs 5 I

I Κ * W I · I O ^ isr 5

- o i "~ 'l p, ^ I * U

«Φ i κλ ft i cq * g i / V η, n" ft § * § ft o ra ft (g) g ^ 3 $ Λ __; __ ^ <ΰ - --- tu

Eh 4J

raw

H

> -H

γ u · I 0-¾1

Φ M d M

fj O u rH

So M W g g <2 K / - \ O O Q) ft ^ ο- / π) o o r-ι g π-i K \ Y / Ο o> i a) 1 1, r <°>. m 11 iK s s a

® o K_0 ο Ο H

cq yV ο ιλ o + j Η I J IK- i -H cn I ° r ° rY °. Vs a s • H I K ^ I CT '^ t I Cr' & T β β, ω -'- 'Ο' T'L ΎΛ. to tu δ ^ pT ^ w ^ fol>> ft ft O ft O ft 'V / _ «

Example 26 127 f 51338

With 0.30 g of D (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetic acid and 0.34 g of 7-amino -> (5- (1 »3,4-thiadiazolyl)) -thiomethylJ - [beta] -cephem-4-carboxylic acid was repeated the procedure of Example 24 to give 0.47 g of 7- * jD (-) - oc- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino ) pienylacetamidoj-3- [~ 5- (1,3 »4-thiadiazolyl) -thiomethyl Ι-β-cephem-4-carboxylic acid, mp 158-159 ° C (decomp.), yield 71.5%.

IR (nujol) cm -1: Vc = 0-75 (lsctam), 1720-1660 (-CON <, -C00H)

The above procedure was repeated, replacing D (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetic acid with D (-) - et- (4-ethyl-2,3-dioxo-1- piperazinocarbonylamino) phenylacetic acid to give 7- [p (") - α- (4-ethyl-2,3-dioxo-1-piperazino-carbonylamino) phenylacetamide] -3- [5- (1,3,4-thiadiazolyl) - thio-methyl-α-Cephem-4-carboxylic acid 123 ° C (decomp.), Yield 64.5%.

Example 27

With 0.31 g of D (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetic acid and 0.39 g of 7-amino-3- {2- (1-methyl-1,3) 4-Triazolyl) -thiomethyl-3-AP-cephem-4-carboxylic acid was repeated according to Example 24, however, the methanol was replaced with anhydrous methylene chloride to give 0.43 g of 7-jp (-) - α- (4-methyl) -2,3-dioxo-1-piperazinocarbonylamino) phenylacetamidoJ-3 {2- (1-methyl-1,3,4-triazolyl) -thiomethyl-A2-cephem-4-carboxylic acid, yield 70%.

IR (nujol) cm -1; 'J q = q ^ 80 (1ειο1: ειιη)> 1720 "1650 (-CO1 <, -C00H) 128 151338

The above operation was repeated with the change that D (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetic acid was replaced with each of the compounds of formula (V) to forming the end products also listed in Table 25. The structure of each of the compounds mentioned was confirmed by IR and NMR.

129 151338 T \ * I ψ — υ ly. ν to cR.

1 * Τ = \ a ^

02 1Γ> I a-O

W οο IS

ο tu νο μ _I S CM φ / ν. Ο φ a -Ρ Λ1 02 Vo +5 Ο W +5 ® ya 5 ν R ^ “ι> 5 γλ ο ρ 'Η I ο1 02 Vo Ed <σ ο S. ι ^ ΰ a 3 _4 Η | Ζ! 22ν 22 Ο Ο Ο Ο Μ Ο Ο a a / - \ c- g oo «Η« - (Ο / ^ Ο U} a \ r7 Η ο Η + »aa / 7Λ 3 8 7 | Λ °> 7 η ο 4 a ο +3 Υ 1 ο ο ο η 1 J Λ ι Λ I ° τ å We s S ι aio * ar ID ^ ° '· ^ li - vi a "g1 ~ fol i

h n- o and Ay S

φ a> CO___> V * / ha Φ o ^ oa 5 IRo) § i § i ^ ® wias ° ra] § Φ ° 7 sia ™ i cAa a 7 A 7 Av, o "ponv / P4 EXAMPLE 28. X30 151338

The procedure of Example 24 was repeated with the change that D (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetic acid was replaced with each of the compounds of the formula ( V) to form the end products also listed in Table 26. The structure of each of the compounds formed was confirmed by IR and NMR.

131 151338 ΚΛ κ \ a trj ο Ο fe / ^ I ο \ r * w

& 2 CQ

CQ CM iW

CM W t

tri ο a CQ

Μ Μ I ο CM

_I Ο / O W

0) / -Λ. o CQ V-o o a

tn gq y-u ya / -4 S

3 α Λ ”ear 8

c HH ° I

H 'o W —k p a s V, o o o ___ a ^ a / - \ o- / o) o P g-fo) µΛ ^ / o «gw g @ 45) d 8?

P 'ο <ν ^ - R

ω o. a 7 1 7 j V i T) ω fod i o i o i a

CM * i o --- CQ - I

I [Οι I IJCN I IP

_i w η --- a - a ^ P o p o p o

P

(0 EH______

N

>., Ν ^ 'φ a na o • so o? H o o a 0 o _ a / 7 \ o S I-® f® i® a o o a w o i a <D _ · ° <νΐ2ίχ £? 1 χί ° ή s i o io i ^ a

H --— O - "- CQ I

P I ro, I CP I IP

-¾ - 'a w a ^ a Ορο P o p o pt) 132 151338 Ν "\ Γ <Λ κ κ ο ο a4 κ i ra Ο ra οα o w CM. S = / CM.

K I κ

OK ok ok

_ I o ™ i o / ^ λ ° 'W M ^ \ _ o ra v> —o OK gq y-o

Vs / ^ 4. £ V * 3 4 ° 0hg 4 k __L k K ^ Κ s i-® L I®

ω a id / ΤΛ K

p o S- (0) o

M O W \ —I O

0 1 Κ I

- T) 7 f)

VD Sar 42 ^ o ^ SjT

01 CM, 1J CM

ι-t i k i o ^ a i k (1) ^ o ^ I ^ -n o

8 I ΚΛ 1 I

^ p ο «o p o

K K

I® 1 I® i i® 1 1 § 1 o a o, V Λ

CM, CM

i k i o ^ a i k ο 'Τ' 1 "" o I ΚΛ I Jf \ I Κλ

^ K ^ K ---- K

P O · «o p o _J - 1 133 EXAMPLE 29

The procedure of Example 25 "was repeated with the change that D (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetic acid was replaced with each of the compounds of formula 27 (V) to form the end products also listed in Table 27. The structure of each of the compounds formed was confirmed by IR and NMR.

134 151338 '"125 = ¾ to

125 = 13 tp »I. \ M

I \ W £ 5-0 „p.

In B-o S = f S '

! ^ i = f GO I jZI-O

CO CM 13 =! and O K m

o W o CM

/ ~ i § afV-O oa «mvS" ° V? 48 «'7 I 03 Vo il K0 y? β n ° g Λ ΐ § 8 _ w ° S- 8 / 3Λ SÆ \ 8 ·" §Λ °> g ^ g / -, φ o 8 § \ 9 / ho ia rt in Oj2L o 3 vs t J ^ a VV vs

u I o I I W

1¾ - o —- go - i r- i κλ i tn I ΚΛ cm '^ a a yy a p o p o p o H Φ fi ---—--

H

> N *> *

! ^ L

S g ^ s @ 45) a ο o a \ ry o i a * = <A T)? s W t 'Y's h i o i o i a S - o - ro - i

7 * I fr \ I ΚΛ I

δ ^ a - ~ a - a £ P o p o p o 135 151338 ψΗ & ': ψ% a a-o I a-o w: B = ^ ra I a-o j cq

a · W

o a ra o a _i o cm, _i o

€ ^ §? o \ RS

i R i! - <§> 1 g® i ° S- {o) ° <ti o a \ - / o cq i a i p o a o IV Λ ° t

CM in J CM

- Λ g JL ° V Λ g. w & Γ aT - a ^^ p o P o p o 3 b_____ a a o o O ° o a o m i | ^> § p g

vS s A

R jL cAa iai oRJ i a1 ^ O i —- I ^ o II ΡΛ I [<Λ awa ^ apo · popo EXAMPLE 30 136 151338 In the same manner as given in Example 27, 7- [D (-) - a- ( 4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -p-hydroxyphenyl-acetamido] -3 - [- 5- (1-methyl-1,2,3,4-tetrazolyl) -thiomethyl] -Δ cephem-4-carboxylic acid from 7-amino-3 - [- 5- (1-methyl-1,2,3,4-tetrazolyl) -thiomethyl] -Aβ-cephem-4-carboxylic acid and D (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -p-hydroxyphenylacetic acid.

Mp: (decomp.), 147 - 9 ° C; dividend $ 62.0.

IR (KBr) cm -1: 1765 (lactam), 1720-1660 (-CON-, -C00H) In the same manner as above, 7- [D (-) - α- (4-ethyl-2,3-dioxo) was prepared -1-piperazinocarbonylamino) -β-hydroxyphenylacetamido] -3- [5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] -Z ^-cephem-4-carboxylic acid, m.p. 188-190 ° C (decomp.), Yield 80.7%, from 7-amino-3- [5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] - 4-carboxylic acid and D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -p-hydroxyphenylacetic acid.

EXAMPLE 31 In the same manner as in Example 24, 7 ~ [D (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] -3-azidomethyl-cephem-4-carboxylic acid was formed from D (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetic acid and 7-amino-3- "5 azidomethyl-Δ-cephem-4-carboxylic acid.

Mp: (decomp.), 185 - 8 ° C; yield 68.0% IR (KBr) cm -1: jc = Q 1775 (lactam), 1720-1660 (-CON-, -C00H) 2090 EXAMPLE 32 In 10 ml of phosphoric acid buffer with pH = 6.3 was suspended 0, 57 g of 7- [D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] -3-acetoxymethyl-Z Z-cephem-4-carboxylic acid, and O 07 g of sodium hydrogen carbonate was dissolved herein. To this solution was then added 0.12 g of 1-methyl-5-mercapto-1,2,3,4-tetrazole to dissolve the latter in the former and the solution was subjected to a reaction for 24 h. The pH of the solution was maintained at 6.5- 6.7 using dilute hydrochloric acid and sodium hydrogen carbonate, and after the reaction, the reaction liquid was collected, which was then adjusted to a pH of 5.0 by the addition of dilute hydrochloric acid. The reaction mixture was washed with sufficient ethyl acetate, then the aqueous layer was separated and then adjusted to a pH of 1.5 by adding dilute hydrochloric acid.

The precipitated crystals were collected by filtration and dried, then the dried crystals were washed with ethyl acetate to give 0.40 g of 7- [D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] -3- [5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl-Δ-cephem-4-carboxylic acid, mp: 163-165 ° C (decomp.) 74.5%.

IR (KBr) cm "1: gc = Q 1775 (lactam), 1720-1660 (-CON ^T, -C00H) NMR (d d-DMSO) values: 0.18 (1H, d), 0.55 (1H) , d), 2.64 (5H, s), 4.3 (1H, q), 4.4 (1H, d), 5.0 (1H, d), 5.75 (2H, s), 6 , 05 (5H, s), 6.3 - 6.8 (6H), 8.92 (3H, t).

In the same manner as above, the compounds shown in Table 28 were prepared from 7- [D (-) - o- (4-methyl-2,3-dioxo-1-piperazinocarbonyl) phenylacetamido] -3-acetoxymethyl-Δ ? -cephem-4-carboxylic acid or 7- [D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamido] -3-acetoxymethyl-5-Cephem-4-carboxylic acid and those of Table 28 showed compounds of formula (VII). All the compounds prepared were D (-) - isomers and the structure of the compounds was confirmed by IR and HMR.

138 1 5 1 33 8

tO VO

M R

vo o;

£ * = <CO

CO | h ^ ψη tT ® ^ ~ ϊ § f = \ ® I jj m I ψ £ Q) I ^ —i 'j> s fr * to> i ω GQ, Q ο Μ N ra, 0 S' «3 H8. "". 1

'O O W CO \ —O -P O K

c! _i 5 vs P ', _I o • ri o o 1 ^, r \ o o Λ ra Vo ο 1 p ra V-o o g VI ° Γο 1 V! p

· * - \ H @. -A H

-P O I O O., ° 1 <u o o W _ ih s oo W / T \ o a oo - <o vo 0- (0) ^ ° 10

• Η, Ο H W V— / Η o - H

s · i i-® - i - m ~ - g ft I ft S & | *? IT) Λ *? fl- S ° rsV 5 ° V 5 vs% oAr "'a w cAb ·" 1 “I. O «I ·: tov ft JO ft ft M a M S w a o m Ora o ra x) φ tu a w m n m CO ra Μ H ft = V ^ jj-3. I as-8 ra “

Ih * = * '= <„^ Ή © ίχΐ se g o o __I__L- 139 151538

JR

<1 · ^^

ΚΛ (Μ -VO

IS j £ K Ώ K = \ <D '^ z ^ \ © ^;: =: ί ,, © i fem s Ι3Μ s ®N f * 1 s = fuu & m S ra jg o K 5 (ΛΙ KC \ 1 K, io κ · K 3 W 3 / Vi o 3 0 K OK CQ Vo

1 o, [θ '· V-K

ΓΛ o o 4 o O o

GQ 7 — O O 02 JT-O O -i O

§ Vt 2 jp s 5 4 H Λ H g cd o i o i o i or q K K S,, -p K LTv K ^ K fZ \

O 8 Η O Η KV?) H

ϋ m ~ m ~ § ~ oo S P <K ft I Pi S o a o a os. a

% γ-) I ° ή I ° ^ I

IH i · | · O * ft cfN ft p & k a k a k s o ra o © o vi g g g b4 p p

KK j KK SK

k = / K = K s = ^ 140 151338 '£ cT' £ cR o ».

O- U2 I_ 00, g ω g VO * O ^ s = V 5 SvAb ^ V 5 * = (II £ & tf UI riB s ο Μ ο M ^ CO Vo _i O ~ _J O 3 \ _ ^.-Γ / -4. O 02 Π \ Ο I o

02 VO O 02 Vo - _L O

\\ z <3 \ V-js; O n> o V I CM I o o oo

I H _I GO M H

^^ X · <Ti s

-p O I o O I

n. S oo S 'Μ / ΊΛ Ln +3 o cm o £ o4 O)

fj ο H O 02 W X— / H

in m ~ m 2 s ^

»8 i · g & cxA I

5? 5 Ί a 1} a »Ϊ) s Ϊ J s k. S 3 ° V ° V g E * <KN * ΚΛ rt Q.

w g <m & m S '

° g ° § - ° I

K2 W

M M W 02 02 02 O _ / V B = <Ο I I ° • B = Cv <n g g g 141 151338 1§ * *

^ K \ IN

η Λ tr * Ό / - \ Ο 00 g φ ^

t = l £ £ £ ΓΛ I

έκ jn> 1 CM -P s CQ -P

V, Q η> »V> -> 03> CJ DWfl CQ, Ο

cm h I ο τ3 cm tJ

ixj H r \ oh K 2

oK m Vo ^ oK

_i o - V-K - I o r ~ \ o o i o / ^ ¾. ο o ra Vo o I o ra Vo o V “ϊ; Vi 8 Vi 8 4 H g H 4 • P o I Ο I O 1 m K CD K f7 \ 0- K o

So Ln a- (0) ° ® £ m ~ i ~ i <°> ^ ν 'K ft I ft K Pi _ oaq ^ kaoac ° o O Yl ooo CM IM i J Λ I 3d, c> κ φ oVsf φ ovs Φ s XJ s !, s I 3 3

P o ^ Sv K OK

aj i »ο» I · eh 4 ft 4 pi ft k a k a k s o IQ o ra o ra

K K K

ra CQ 03 K = ^ / {ra (Qa-> ° ο

K

o 142 151338

VP VQ

hi os [C \ Ho 00., / \ CM Κλ * Jpk ίφ a F \ ® ϊ I X j}

ο-s .¾ -p cm if p -P

^ ixj> ΐ M> »02, α ΟΜΛ ϋ K 5 cm tJ, _ι o tJ _ / 0¾ W 3 / \. o 3, 'Λ O 3 0 K 02 v — o 02' V-o 1 S - \ j & ·> ya

/ Ά Ο Ο I O IP

02 7— O _L O _L O

v a J- ^^ co I I oo o cn O [> ·

^ K H B H

«N ° '8 1 8 1 1¾ cm a rr \ cm k / r \ lπ £ g S i <2) 3 | λ2) 5 <M oYo') ^ -O ^ O ^^ w VV ο · o co Si1 i1 ° VS i *

„8 5 Ϊ) 3 Ϊ J I

H O S »° V 5 ° *?

-0 JO W ™ W

Π5 O s W W

Eh I * O 'O * ft S1 sT' & W S 0 pi s O KJ 03 O 03 «02

Sfl ffl.

m m glsS. s- £ s Jo) W „r ΝΛ

W

ISLAND

143 1 5 1 3 3 8 to io frj to «^ o a to? and r_ e 3. S '. =! S. i · $ Ί <f V ° oC B t to o = cq vjo 0 = 0 o = cq >>

of? cq cq O iS

oi> d oi <d, ^ 03

Mo M aj a + j M P

0 M 3 ο M £ ο M £ ο M

1 O ~ | O TL, I O X. _I o ·> r ~ i ο o r \ ο £ Γ \ o you / - \ ο o OQ Vo 0 CQ Vo a CQ Vo M CQ Vo o ya co y_a a V- !? g v-a ^ 2 H s -Λ: Λ. Λ s cd loi o o o o ^ o i

cq ώ ώ o Μ o M

+ 3gLOgCriatO | 2JH

ShOOOOOOOOOOOO

OOHOHOHOH

* m o m ~ iv> o m - co a a a a § a a ft

So aoaoaoaw - oooo O ooo jjj V, I ° rV IVI ° <A 1 o ^ a ^ o ^ a ^ o ^ a "1 o ^ -a ^ tn i I" I * I · CO rt CO i, CO si CO ft Μ & Μ & Μ & Μδ o § o § ogu co ._; ___, i-cd a and cd cd i cd a

o = CQ and CQ

In CQ I

0 1 o = CQ

0 = 0 o

I OJ

^ a co i r ° o

and CO to I CO

cd MM J = & ffl a o o o

____IN

EXAMPLE 33 In 10 ml of water, 1.15 g of 7- [D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] -3-acetoxymethyl-A 4-carboxylic acid and 0.17 g of sodium bicarbonate were then dissolved herein, after which 0.48 g of pyridine and 4.1 g of potassium thiocyanate were added. The resulting mixture was reacted at 60 ° C for 5 'hours while maintaining the pH of the mixture at 6.0 to 6.3 by the addition of dilute hydrochloric acid or sodium bicarbonate. After the reaction, 20 ml of water was added to dilute the reaction mixture, which was then washed with chloroform. The aqueous layer was then separated and adjusted to a pH of 1.5 by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration, dried and then washed with acetone to give 1.04 g (yield 79.6%) of thiocyanic acid salt of 7- [D (-) - α- (4-ethyl-2,3-dioxo) -l-piperazinocarbonylamino) phenylacetamido] -3- [z pyridine ppmethyl] -A-cephem-4-carboxylic acid betaine having a melting point (decomp) of 155-160 ° C, the product having the formula: AND.

\ V - ^

ΟΗτΟΗη-Ν ST-CONHCHCONH — i — Τ '"S.

^ é) 0 ^ Vch2-O

u cooh scar® IR (KBr) cm -1: JC_Q 1780 (lactam), 1720-1660 (-CO1 <J ^ SCN 2040) In the same manner as indicated above, a thiocyanic acid salt of 7- [D (-) - α- ( 4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] -3-pyridinomethyl-Δ-cephem-4-carboxylic acid betaine of 7- [D (-) - α- (4-methyl-2,3) -dioxo-1-piperazinocarbonylamino) phenyl-acetamido] -3-acetoxymethyl-Δ-cephem-4-carboxylic acid and pyridine, which product has the formula:

ISLAND ISLAND

)> - 'ζ σ CH 2 -N N-COKHCHCONH-ι-f] © ΓΛ w A 1-νΑοη2-νΑ 0 COOH SCAT®

Mp: (decomp.) 180 - 185 ° C; yield 82.0%.

Conventionally, the above two products were treated with an ion exchange resin to give the desired 7- [D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] -3-pyridino-methyl-ZsAcephem-4 -carboxylic acid betaine and 7- [D (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] -3-pyridino-methyl-Δ ^ - c ephem-4-carboxylic acid eb e tain .

Example 34 In 85 ml of anhydrous methanol was dissolved 1.5 g of sodium salt of 7- [D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] -3- [2-pyridyl-1 oxide) thiomethyl | -2V'-cephem-4-carboxylic acid. To the resulting solution was added 0.65 g of anhydrous cuprichloride, and the resulting mixture was stirred at room temperature for 15 minutes and reacted at 50 ° C for 14 hours. After the reaction, gaseous hydrogen sulfide was passed through the reaction solution under ice-cooling for 20 minutes. The insoluble substance formed was filtered off and the filtrate was evaporated under reduced pressure. To the residue was added 20 ml of a 5% aqueous sodium bicarbonate solution and the insoluble filter was filtered off, then dilute hydrochloric acid was added to the filtrate to adjust the pH to 6.5. The filtrate was then washed with 10 ml portions of ethyl acetate three times, then the aqueous layer was separated and then adjusted to a pH of 1.8 by adding dilute hydrochloric acid. The crystals thus precipitated were collected by filtration and then dried under reduced pressure and washed with 20 ml of an ethyl acetate chloroform mixture (1: 1 by volume) to give 0.40 g of 7- [D (-) - α- (4- ethyl 2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] -3-methoxymethyl-β-c ephem-4-carboxylic acid, mp: 16-26 ° C (decomp.), yield 30.5%.

146 151338 IR (KBr) cm "1: jQ = Q 1770 (lactam), 1700 (-C00H), 1666 (-COiO MR (dg-DMSO) H values: 0.13 (1H, d), 0.53 (1H, d ), 2.61 (5H, s), 4.31 (1H, q), 4.41 (1H, d), 4.96 (1H, d), 5.82 (2H, s), 6.10 (2H, bs), 6.33 (2H, 2H, 2H, bs), 6.79 (3H, s), 8.89 (3H, t).

EXAMPLE 35

To a solution of 3.2 g of D (-) - α- (4-ethyl-2,3-dioxo-1-piperazino-carbonylamino) phenylacetic acid in 20 ml of anhydrous methylene chloride and 5 ml of dimethylformamide was added 1.33 g Ν, Ν dimethylaniline. The resulting mixture was cooled to between -15 and -10 ° C and a solution of 1.14 g of ethyl chlorocarbonate in 5 ml of anhydrous methylene chloride was added dropwise over 5 minutes. The mixture was allowed to react at this temperature for 60 minutes.

To a suspension of 3.28 g of 7-amino-3- [5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] -1-cephem-4-carboxylic acid in 65 ml of anhydrous acetone nitrile, on the other hand, added 3.04 g of N, O-bis (trimethylsilyl) acetamide to give a solution. The solution was cooled to -20 ° C and poured into the aforementioned reaction mixture. Then the mixture was allowed to react at between -10 and -5 ° C for 60 minutes and at 5-10 ° C for 60 minutes. After completion of the reaction, 5 ml of methanol was added to the reaction mixture and the mixture was freed from insoluble material by filtration. Then, the solvent was removed by distillation under reduced pressure. The residue was dissolved in a mixed solvent consisting of 100 ml of water and 50 ml of ethyl acetate, and the resulting solution was adjusted to a pH of 7.5-8.0 by the addition of sodium bicarbonate, after which 80 ml of ethyl acetate and 20 ml of ethyl acetate were added. ml of acetone, and the resulting solution was adjusted to a pH of 1.5 by the addition of dilute hydrochloric acid.

Then, the organic layer was separated, washed sufficiently with water, and the solvent was removed from the ethyl acetate layer 1, by distillation under reduced pressure. The residue was dissolved in 15 ml of acetone and to this solution was added 60 ml of 2-propanol with stirring to precipitate white crystals. The precipitated crystals were collected by filtration, washed sufficiently with 2-propanol and dried to give 5.26 g of 7- [D - (-) - oc- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) ) phenylacetamido] -3- [5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] -4β-cephem-4-carboxylic acid, m.p. 163-165 ° C (decomp.), Yield 83.6%. The structure of this compound was confirmed by IR and MRI.

The above procedure was repeated except that D (-) - O (.- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetic acid was replaced with each of the compounds of formula (V) to obtain the respective desired compounds as shown in Table 29. The structure of each compound prepared was confirmed by ir and NMR.

·> 1! - ^ - 115! -! - IS1.31Å ry hk T * \ bP f = a \ bP $ Ύ P ~ 5 w ~ * κχ ί.

c \ iin cj in \ / okI

s: s: Vs p f> i s

-4 I! yÅJg I ir \ s ^ I

vr ° i V- 1 1 i K t i - æ ^ i 3 «Y k —Y O S o g / -Λ o i i ^ ;? r? o i i s-® ?. HH D Y i

3 VN i VY '1 »" | YOU I

3 J e L J 9% §o I §

8 T ° (Γ i 7 ° i £ Λ 8. K

fa «* S sP“ - * "I, g I

o po w Λ 3 m i m

σ \ '--'H

cm P O

AI 1 w m ri: i --------- E- <

M M

O §! h§> | jg> (D ht-1 Pi O r ~ \ «-i δ ooog SO o Λ O i ': | Ao> ih®-» H) n .1 \ A ys $ ..i xyy yy # suffer $ A ° g AS Ag

£ Q A sP A bP SbP

p o p o p o 149 EXAMPLE 36

The procedure of Example 35 was repeated using 3.1 g of D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenyl acetic acid and 3.0 g of 7-amino-3- [5- (1,2,3-triazolyl) thio-methyl] -α-cephem-4-carboxylic acid to give 4.5 g of 7 [D (_) _ α- (4-ethyl-2,3-dioxo) -1-piperazinocarbonylamino) -phenyl-acetamido] -3- [5- (1,2,3-triazolyl) thiomethyl] -Z ^ -cephem-4-carboxylic acid, m.p. 177-180 ° C (decomp.) »Yield 76.7% · IR (KBr) cm -1: 1> C = 0 1770 (lactam), 1703 (-C00H), 1680,

1667 (-CONO

EXAMPLE 37

The procedure of Example 35 was repeated using 1.9 g of D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetic acid and 2.2 g of 7-amino-3- [5 - (1,3,4-Thiadiazolyl) thiomethyl] - ^ - cephem-4-carboxylic acid to give 3.1 g of 7- [D (-) - oc- (4-ethyl-2,3-di oxo) -1-p ip era zino carbonylamino) phenyl-acetamido 3-3- [5- (1,3,4-thiadiazolyl) -thiomethyl] -β-cephem-4-carboxylic acid, m.p. 165-170 ° C (decomp.), Yield 82%.

IR (KBr) cm -1: j7c = 0.1775 (lactam), I705 (-C00H), 1685,

1675 (-CON O.

EXAMPLE 38

The procedure of Example 35 was repeated using 1.5 g of D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -p-hydroxyphenylacetic acid and 1.5 g of 7-amino-3- [5- (2-methyl-1,3,4-thiadiazolyl) -thiomethyl] -cephem-4-carboxylic acid to give 2.3 g of 7- [D (-) - oc- (4-ethyl) -2,3-dioxo-1-piperazino-carbonylamino) -p-hydroxyphenylacetamido] -3- [5- (2-methyl-1,3,4-thiadiazolyl) thiomethyl] - cephem-4-carboxylic acid, m.p. 172-177 ° C (decomp.), Yield 77.7%.

IR (KBr) cm ”1: C = 0 1780 (lactam) 17 1710 (-COOH) 1685, 1672 (-CONC) In the same manner as above, the compounds listed in Table 30 were prepared from D (-) -oc- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetic acid or D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -p-hydroxyphenylacetic acid and the compounds of formula (IV) shown in Table 30. The structure of each compound prepared was confirmed by IR and NMR.

151 151338

CN

ιτΐ Ο

OJ

;

! OJ

at rest E

in E

Krrs ° ft ^

I \. us I. \ ► — i <£ S

s ~ o ¥ * s-o ^ I. e \ * y ** b '"7 Oii £ ^ 4 * i-i ^ —i in- i is.

2 »I" w I

o + fo if ω / “A 8 '* § / r“ i 8 § «& o y-8 3 w yo s H Vs3' '· V" s • s I <PI °>' $ Jrte £ é § t clothes Π E rH ^^ d O £ -po ύ S c. S ft cs ft IT Ί § T) §

£ tes Φ cte O

> 5> 3 ο ✓Λ o o: 00 i - 'JT · a J E CL ^ - g H E Ο & E ^ m m cq C _' ____.

Eh -——----? R \

E

_ o> w H ^

rc \ E

CJ E O

H 5 “2 8 \ J EetS

g I V-g Wg ο I / J ._ / «Η ZC = / E- (I 1 - Ό CO K, (D CM ft a e ^ O °

φ I E I hC

3 «ryl« phys • h «te

^ i —L

O j E Ϊ3 o & 4 'CV ft

X E

* i

Isa 151338 Κλ w ο ft ro νλ η! S 3 s - = "ru 's-s ro - - = r \ ^.

Ϊ) = - § f | p ~ ° ^ i M P

«= Y · ^ S 85 = Y *,“ tv, WCV) Φ '5 ft -P g Ή o> »_I k i>,; _I ft + i. — F c · ^ o a. § g / y8 · 3 C2 y— o ^ CQ y-O. 3 07 y-o Ϊ2; '\ —S * \ —2 »i o ° \ <p i, .A> s Jr \> d + Λ. s 2ΰ H i i ^ ^ i-Ø-s -s 1-0§ s l ^ g s r — I J3 ϊ I a 1 i c c c o ^ O o ^ I · i · I ·

Cft X ft O. ft ft C. ft ft

~ p: I i 3 I X) I

Id eft a ¢ 5 cr ft ω cr ft ω WI Ό I "ft I Ό +5 CO ^ (\! 'Ft! ^ Έ jei ft ia 0- ^ 0 ^ o. ^ O <j_j I rC \ · I ΓΌ , Ql I * ft · w ^ o, away ^ s ft ft o. S ft O CQ ft c S.

o, 03 03 m I ___J_ i-1 rft

H K

'ffl o 5; ro B Qo

ΝΛ H

E O

O ^ a — ft co ft-x a co ft - = \

i \ e i \ W I

I »-o I + - ° l, M

ft .— / E = / i i i 03 02 W, cj ro ft 'ft ft ^^ ft' * f ft I ft / “i c o f ~ i o

10 y — O rQ y — O 02 y — O

U tt Uo

Cj ro ft

X E

___; --—— * —.—- * 153 151338 »1 i ΝΡ KN g · tM Λ ho. o tn § 8

jk o -P

_J o ffl f-i O g / Vs $ Ar8 3

Y-f% W

A i U ° * £ c g ° 5 i © i I © * ϊ d '-I £?

ISLAND ISLAND

ϋ Oh

§ X) S CXJ

-p cr s P c "t ii JL. I Ό * w O cm -, - ^ ~ <hi re * tt wo '-v * JK', · i S1 o ^ sa 5, 1 -no S.-i Oh my

CQ

H ____ pq -: c

EH

1Ό.

ffi

* \ O

K o

I I

If A§ \ —s \ - ^

[A U

zr. EXAMPLE 39 In a mixed solvent consisting of 80 ml of water and 40 ml of ethyl acetate, 4.0 g of 7- [D - (-) - α-aminophenylacetamide was suspended. do] -3-acetoxymethyl-β-cephem-4-carboxylic acid, and then 1.65 g of anhydrous potassium carbonate was dissolved therein under ice-cooling.

To this solution was added 7.3 g of 4- (α-hydroxyethyl) -2,3-dioxo-1-piperazinocarbonyl chloride at 0-5 ° C over 15 minutes, and the resulting mixture was allowed to react at 10-15 ° C for 30 minutes. After completion of the reaction, the aqueous layer was separated, 100 ml of acetonitrile was added and the resulting solution was adjusted to a pH of 1.5 by adding dilute hydrochloric acid and saturated with sodium chloride. The acetonitrile layer was then separated, washed twice with 30 ml of a saturated solution of sodium chloride and then dried at reduced pressure. The residue was dissolved in a mixed solvent consisting of 50 ml of acetone and 10 ml of ethanol and the insoluble material was separated. Then 100 ml of isopropyl alcohol was added to the resulting solution, which was concentrated to 2/3 volume at reduced pressure. The precipitated crystals were collected by filtration, washed with isopropyl alcohol and dried to give 4.5 g of 7- [D {-) - α- (4-fp-hydroxyethyl) -2,3-dioxo-1- piperazinocarbonylamino) phenylacetamido] -3-acetoxymethyl-Δ-cephem-4-carboxylic acid, m.p. 142-144 ° C (decomp.) Yield 76.3% · η ·. 1770 (lactam), 1708 (-COGH) IR (KBr) cm -1 J: S) C = 0 1680, 1665 (-CON <)

The above procedure was repeated except that 7- [D {-) - α-aminophenylacetamido] -3-acetoxymethyl-β-cephem-4-carboxylic acid was replaced with each of the compounds of formula (II) to preparation of the respective desired compounds as listed in Table 31. The structure of each compound prepared was confirmed by IR and NMR.

155 151338 fe in S = K two,

N "N I \ W

K K-O

o o ^ —1 · O I · O c \] CO <] · *

<u. $ JVI S

κ w O φ o ω! «. +> £ -p

r-Å c + »/ —d g -P

ω / V \ o f »> / o>, m CQ \ V- o _ £? ra y-o s ti V «? W § ti ίΛ o ° cHb p

, ¾ S IN S lA

0 C LI '»C ΊΓ,« Η O, _, ^ o -. ri% 1 ιΌ Η ϋ '- hog: t — 1 HO cf \ O • et * • H · O Ή O _ rt -prri ra os ^ ov s ^ 1 l) s J i ft os O oso IOI o CM Φ CM G) K Ό SX) o ^ ow

I CM I CM

^ S * s I O ft I O * ^ - o S w o ft

Ψ) SK CO s S · S

s ft pq <! „______ — ......—-- Έή: s — S ro

ΓΓ two, I \ K

£ j K s-o ~ O S = / ι-H O «'S o co

^ CM CM

d κ s p o o £ Λ ^ Λ, B ^ “4- ° 1 V" ° Y "§ 1—1 1 — l H K O g ° 1 I ©

s (MN- 'CM

£ ® w 151338

* »I

... 156

ϋ ~ = ΚΝ i \ K

i = / A

rl CO

* · * I r \ cv u '9 -— \ is φ

U 4J

I »5 / NX 8 § V-s / • 1

JrS> £ 2 PC \ k »8;

O IN

O Ή 1 ϊ 1 ir

.p O 53 O

t, I O

O CV 0) <H · K Ό O ^ I cv rH ^ K · rO l O ft ^ o a ηϊ «= w • S.

• 9 ·

EH

is zS

• ^ a j £ 2-0 co _jv- a

Ai

A

EXAMPLE 40 EXAMPLE 40. (1) To a solution of 0.63 g of D (-) - α- (4-ethyl-2,3'-oxo-1-piperazinocarbonylamino) phenylacetic acid in 10 ml of anhydrous methylene chloride was added 0.5 g of oxalyl chloride and a drop of N, N-dimethylformamide, and the resulting mixture was allowed to react at room temperature for 30 minutes. After completion of the reaction, the solvent was removed by distillation under reduced pressure. The residue was washed with anhydrous benzene to give 0.6 g of D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetyl chloride, m.p. 112-116 ° C (decomp.) Yield $ 88.8.

IR (KBr) cm "1: NH 3280 ~ ο = 0 179 ° - 1695 (2) To a suspension of 0.27 g of 7-aminocephalosporanoic acid in 6 ml of anhydrous methanol was added 0.24 g of triethylamine. The resulting solution was cooled to -40 ° C and to the solution was added a solution of 5 ml of anhydrous methylene chloride containing 0.34 g of D (-) - oc- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetyl chloride, and then the reaction liquid temperature was gradually raised to room temperature over 1 hour. After completion of the reaction, the solvent was removed by distillation under reduced pressure. The residue was filled with 20 ml of water and the resulting solution was washed twice with 5 ml of ethyl acetate. To the aqueous layer was added 20 ml of ethyl acetate and the solution was adjusted to a pH of 1.5 with the addition of 2N hydrochloric acid with stirring, then the organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate. , and the solvent removed by distillate ion under reduced pressure to give 453 mg of 7- [D (-) - oc- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamido] -3-acetoxymethyl-3-cephem-4 carboxylic acid, m.p.

165-166 ° C (decomp.), Yield 79.0 $.

In the same manner as above, 7- [D (-) - oc- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -p-hydroxyphenylacetamido] -3-acetoxy-λ-cephem-4-carboxylic acid, mp. 168-174 ° C (decomp.), Yield 72.3 $, from D (-) - α- (4-ethyl-2,3-dioxo-1-piperazino-carbonylamino) carbonylamino) - p-hydroxyphenylacetyl chloride and 7-aminocephalo-sporanoic acid.

EXAMPLE 41

To a suspension of 2.16 g of 6-aminopenicillanic acid in 20 ml of methylene chloride was added 2.02 g of triethylamine. To the resulting solution was added 3.4 g of D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetyl chloride at 10-15 ° C and the resulting mixture was allowed to react at 10 ° C. -15 ° C for 2 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure. The residue was filled with 20 ml of water and 30 ml of ethyl acetate were added to the resulting solution. The solution was adjusted to a pH of 2.5 by the addition of 2N hydrochloric acid and stirred for 4 hours to precipitate crystals.

The precipitated crystals were collected by filtration to give 4.4 g of 6- [D (-) - α- (4-ethyl-2,3-dioxo-1-piperazino-carbonylamino) phenylacetamido] penicillanic acid, m.p. 154-156 ° C (decomp.), Yield 82.2%.

In the same manner as above, 6- [D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -p-hydroxyphenylacetamido] penicillanic acid, m.p. 160-161 ° C (decomp.), Yield 70.5%, from 6-amino-penicillanic acid and D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -p-hydroxyphenylacetyl chloride .

EXAMPLE 42

The procedure of Example 35. was repeated using D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetic acid and 7-amino-3-carbamoyloxymethyl-A. 4-carboxylic acid to give 7- [D (-) - oc- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] -3-carbamoyloxymethyl - + - cephem-4-carboxylic acid , m.p. 175-180 ° C (decomp.), Yield 68.0%.

IR (KBr) cm -1: 0 NH? 3430 ° 3350 ° Cd 3300 ° c = 0 1778, 1710, 1670 159 151338 In the same manner as above, 7- (D (-) - α- (4-ethyl-2) was prepared 3-di oxo-1-piperazinocarbonylamino) -p-hydroxyphenylacetamido-3-carbamoyloxymethyl-α? -Cephem-4-carboxylic acid, mp 178-182 ° C (decomp.), Yield 65.090, from D (-) - α- (4-Ethyl-2,3-dioxo-1-piperazinocarbonylamino) -p-hydroxyphenylacetic acid and 7-amino-3-carbamoyl oxyme thi-ip-c ephem-4- c arb oxy 1 acid.

Example 43 (1) To a solution of 0.32 g of D (-) - o - (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetic acid in 15 ml of methylene chloride was added 0.1 g of N-methylmorpholine. . The resulting solution was cooled to -20 ° C and to the solution was added a solution of 0.11 g of ethyl chlorocarbonate in 2 ml of methylene chloride, after which the resulting solution was allowed to react at between -10 and -20 ° C for 1 hour. Then, the reaction liquid was added dropwise to a solution of 0.44 g of a benzhydryl ester of 7-amino-3-carbamoyloxymethyl-β-cephem-4-carboxylic acid in 5 ml of methylene chloride at -20 ° C. After drip, the resulting solution was allowed to react at between -1b and -20 ° C for 1.5 hours, after which the temperature was raised to room temperature. Then, the solvent was removed by distillation under reduced pressure and the residue was dissolved in 15 ml of ethyl acetate. Then, the resulting solution was successively washed with 10 ml of water, 5% by weight sodium bicarbonate solution and saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was then purified by column chromatography (silica gel / chloroform) to give 0.53 g of benzhydryl ester of 7- [D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] -3-carbamoyloxymethyl-Δ ^ -cephem-4-carboxylic acid, m.p. 120-125 ° C (decomp.), Yield 71.6%.

160 1 5 1 3 3 8 IR (KSr) cm "1: 34-80

Dconh 5500 ° C C = 0 1780 »1-718, 1680 KKR (CDCl3) <~ ζ '. Values -0.1 (1H, d), 2; 05 ClH, d), 2.64 (15H, bs), 3; 19 (1H, s), 4; 20 (2H, m), 4.86 (1H, d), 5.20 (2H, s), 5.25 (2H, bs), 6, 1 (2H, o), 6.3 - 6.9 (6H, m), 8.9 (3H, t) (2) To a solution of 0.2 g of the benzhydryl ester of 7- [D (-) - o- (4-Ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] -3-carbamoyloxymethyl-Δ-eephem-4-carboxylic acid in 5 ml of anisole was added 5 ml of trifluoroacetic acid, under ice cooling allowed to react for 30 minutes under ice-cooling. After completion of the reaction, the solvent was removed by distillation under reduced pressure. Then, the residue was dissolved in 15 ml of ethyl acetate and to the resulting solution was added 10 ml of water, after which the pH of the solution was adjusted to 7.5 by adding sodium bicarbonate with stirring. Then, the aqueous layer was separated, added to 20 ml of ethyl acetate and then adjusted to a pH of 2.0 by the addition of 2N hydrochloric acid. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to precipitate crystals. The precipitated crystals were collected by filtration to give 0.13 g of 7- [D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] -3-carbamoyloxymethyl-2 -cephem-4-carboxylic acid, m.p. 175-180 ° C (decomp.), Yield 83.8%.

IR (KBr) cm -1: pIHH 3450, 3350,]) COHH2 3500, pCm0 177S, 1710, 1670 161 151338 KKH (d d -DMSO) ητ Values 0.15 (1H, d), 0.55 (1H) , c), 2.60 (5H, b), 5-, 47 (2H, s), 4.28 (2H, c), 4; 95 (Hi, d), 5.25 (2H, q), 6.10 (2H, n>, 6; 25 - 6.90 (6H, m), 8.9 (3H, t) EXAMPLE 44 (1) To a solution of 0.32 g of D (-) - (4-Ethyl-2,3- (10-oxo-1-piperazinocarbonylamino) phenylacetic acid in 15 ml of anhydrous methylene chloride was added Q, 1 g of N-methylmorpholine. The resulting solution was cooled to -20 ° C and to the solution a solution of 0 , 11 g of ethyl chlorocarbonate in 1 ml of ethylene chloride, and the resulting mixed solution was allowed to react at -10 to -20 ° C for 1 hour, then a solution of 0.46 g of β, β, β-trichloroethyl ester of the reaction mixture was added dropwise. 7-Amino-3-cephem-3-carboxylic acid in 5 ml of methylene chloride at -20 C. After drip, the resulting mixed solution was allowed to react at between -10 and -20 ° C for 1 hour and at room temperature for 30 hours. After completing the re The reaction was removed by distillation under reduced pressure, the residue was washed successively with 5% by weight aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate.

Then, the solvent was removed by distillation under reduced pressure, the residue was purified by column chromatography (silica gel / benzene-ethyl acetate) to give 0.53 g of β, β, β-trichloroethyl ester of 7- [D (-) - α- ( 4-ethyl-2,3-dioxo-l-piperazinocarbonylamino) -phenylacetamido] -3- [5- (1-methyl-1,2,3> 4-tetrazolyl) thiomethyl] -A ^ -cephem-4-carboxylic acid, mp. 125-135 ° C (decomp.), Yield 69.6%.

IR (KBr) cm -1: C = 0 1780 '1715' 1680 162 151338 (2) To one solution-of 0.5 g of β, β, β-trichloroethyl ester of 7- [D - (-) - and (4-Ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] -3- [5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl-Δ-cephem-4-carboxylic acid 0.5 g of zinc dust and 0.5 ml of acetic acid were added and the resulting solution was allowed to react for 1.5 hours. After completion of the reaction, the reaction liquid was filtered and the filtrate was liberated from the solvent by distillation under reduced pressure. in 15 ml of water and the resulting solution was adjusted to a pH of 1.5 by the addition of 2N hydrochloric acid to precipitate crystals The precipitated crystals were collected by filtration, dried and then washed with ethyl acetate to give 7 - [D (-) - a- (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetamido] -3- [5- (1-methyl-l, 2,3,4-tetrazolyl) thiomethyl] - β-cephem-4-carboxylic acid, mp I63-I650C (decomp.), yield 82.1%.

TCK.qRMPKT. 10.0 g of D (-) -oc- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -p-hydroxyphenylacetic acid was suspended in 60 ml of anhydrous methylene chloride and 6.31 g was added. of trimethylsilyl chloride for this suspension. The mixture was cooled to 5 ° C followed by dropwise addition of 6.04 g of triethylamine at the same temperature over 15 minutes and stirring at 10 - 15 ° C for 90 minutes until the reaction was complete. Then, the reaction mixture was cooled to -20 ° C, 2.18 g of dimethylformamide was added and then 3.25 g of trichloromethyl chloroformate was added dropwise over 15 minutes. The resulting mixture was allowed to react at the same temperature for 120 minutes.

On the other hand, 10.0 g of 7-amino-3- [5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] -Z 2 -cephem-4-carboxylic acid was suspended in 90 ml. anhydrous methylene chloride and trimethylsilyl chloride was added to this suspension under ice cooling. To the mixture was added dropwise 7.40 g of triethylamine over 20 minutes and then allowed to react at the same temperature for 60 minutes. Then, this mixture was added dropwise to the above reaction mixture at between -15 and 10 ° C over 30 minutes, and the mixture was allowed to react at the same temperature for about 90 minutes. After the reaction temperature was raised to 0 ° C, 6.69 g of methanol was added. The mixture was allowed to react further at 0 ° C for 30 minutes and then poured into 280 ml of aqueous solution of 10.0 g of sodium bicarbonate. The resulting solution was separated into an aqueous layer and an organic layer. The organic layer was extracted with 20 ml of 3% aqueous sodium hydrogen carbonate solution and the extract was added to the above aqueous layer. To the combined aqueous solution was added 130 ml of acetonitrile. After the mixture was adjusted to pH 5.0 by the addition of 6N hydrochloric acid, 4 g of activated carbon was added and the mixture was filtered. The filtrate was heated to 40 ° C, adjusted to pH 2.0 by the addition of 6N hydrochloric acid, stirred at 35 ° C for 120 minutes and at 25 ° C for 60 minutes, and then cooled with ice to precipitate crystals. The precipitated crystals were collected by filtration, washed with 20 ml of 20% aqueous aononitrile solution and dried to give 15.9 g of crystals of 7- [D (-) - oc- (4-ethyl-2,3-dioxo- 1-piperazinocarbonylamino) -p-hydroxyphenyl-acetamido] -3- [5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] -α-cephem-4-carboxylic acid, m.p. 170 DEG-171 DEG C., yield 78.3%.

NMR (dg-acetone τ D 2 O) values 8.9 (3H, t), 6.8 - 6.3 (4H, m), 6.2 - 5.9 (7H, m), 5.78 (2H, ABq), 5.04 (1H, d), 4.58 (1H, s), 4.31 (1H, d), 3.08 (4H, A2B2q) EXAMPLE 46 in 70 ml of methylene chloride was suspended 3.5 g of - [D (-) - α-aminophenyl-acetamido] penicillanic acid, then 2.2 g of triethylamine was added to convert the suspension into solution. To the resulting solution was added dropwise a solution of 2.28 g of 4-ethyl-2-oxo-1-piperazinocarbonyl chloride in 10 ml of methylene chloride at 5-10 ° C. After the mixture was allowed to react for an additional hour, the solvent was distilled off and the residue dissolved in 30 ml of aqueous sodium chloride solution. To the resulting solution was added 50 ml of acetonitrile and the pH was adjusted to 3.0 with 2N hydrochloric acid. The acetonitrile layer was washed with an aqueous sodium chloride solution and the solvent was distilled off to obtain 2.61 g (yield 50%) of crude crystals. The crystals were dissolved in tetrahydroforan and then purified by "Sepha-dex (S) LH-20" (manufactured by Fine Chemical Company, developing solvent; tetrahydroforan) to give 6- [D (-) - α- (4) -ethyl-2-oxo-1-piperazinocarbonylamino) phenylacetamido] -penicillanic acid, m.p. 169 DEG-170 DEG C. (decomp.).

IR (KBr) cm "1; δ = 0 1765, 1700 - 1665 NMR (d 6 -DMSO) ppm values: 1.01 (3H, t, CH 3 CH 2), 1.40 (3H, s, C 2 -CH 3), 1, 55 (3H, s, C2-CH3), 2.50 (2H, m, CH3CH2), 2.70 (2H, m, piperazine ring C3-CH2), 3.28 (2H, s, piperazine ring C3-CH2J, 3 , 60 (2H, m, piperazine ring + Cg-CH2), 4.18 (1H, s, C3-H), 5.30 - 5.76 (3H, m, C5> 6_Ca aH) 7.35 (5H, s, C6H5), 9.20 (1H, d, NH), 10.1 (1H, d, NH),

The following compounds were prepared in the same manner as above by appropriate selection of starting compounds of formula (II) and reactive derivatives of compounds of formula (III): 6- [D (-) - α- (4-methyl-2-OXO- 1-piperazinocarbonylamino) -phenylacetamido] penicillanic acid,

Mp: 160 - 164 ° C (decomp.) IR (KBr) cm -1: γ C = 0 1765, 1700 -1665; 6- [D (-) - c1- (4-n-propyl-2-oxo) (1-piperazinocarbonylamino) -phenylacetamido] penicillanic acid,

Mp: 164 - 165 ° C (decomp.) IR (KBr) cm -1: γ C = Q 1765, 1700 -1665; 6- [D (-) - α- (4-ethyl-2-oxo-1) -piperazinocarbonylamino) -p-hydroxyphenylacetamidojpenicillanic acid,

Mp: 167 - 169 ° C (decomp.) IR (KBr) cm: γ c = 0.176.0> 0000665 6- [d (-) -cl- (4-ethyl-2-oxo- 1-piperazinocarbonylamino) -2-thienylacetamido) penicillanic acid, K5 151338

Mp: 164 - 167 ° C (decomp.) IR (KBr) cm 1:: c = 0 1770, 1700-1665 EXAMPLE 47 In 15 ml of 80% aqueous tetrahydrofuran, 1.0 g of 6- [D (-) - oc-aminophenylacetamido Jpenicillanic acid trihydrate, and triethylamine was added dropwise with stirring to adjust the pH to 8.0 - 8.5. The resulting solution was cooled to 10 ° C and 530 mg of 4-ethyl-3-oxo-1-piperazinocarbonyl chloride was added under the drop of triethylamine to keep the pH at 7.5 - 8.0. At the same temperature, the reaction was allowed to proceed for one hour, after which the tetrahydrofuran was distilled off and 10 ml of water and 15 ml of ethyl acetate were added to the residue and dissolved in the water. The resulting solution was added with dilute hydrochloric acid to adjust the pH to 2.0. Then, the ethyl acetate layer was separated, washed thoroughly with water and concentrated to 2/3 of the initial volume, then the precipitated crystals were collected by filtration to give 1.0 g (yield 80%) of 6- [D (-) - o- (4-ethyl-3-oxo-1-piperazinocarbonylamino) phenylacetamido] penicillanic acid m.p. 190 -191 ° C.

IR (KBr) cm -1: C = 0 1770 (µm), 1735 (-C00H), 1680 - 1620 (-CONH-).

In the same manner as described above, the following compounds were prepared by appropriate selection of starting compounds of formula (II) and reactive derivatives of compounds of formula (III): 6- [D (-) - α- (3-oxo-1-piperazinocarbonylamino ) -phenyl-acetamido] penicillanic acid e,

Mp: 172 - 173 ° C (decomp); 6- [Di -) - ex- (4-methyl-3-oxo-1-piperazinocarbonylamino) -phenylacetamido] penicillanic acid,

Mp: 196 - 197 ° C (decomp); 6- [D (-) - α- (4-n-propyl-3-oxo-1-piperazinocarbonylamino) phenylacetamido] penicillanic acid, 166 151338

Mp: I65 - 166 ° C (decomp); 6- [D (-) - α- (4-Benzyl-3-oxo-1-piperazinocarbonylamino) phenylacetamido) penicillanic acid e,

Mp: 148 - 149 ° C (decomp); 6- [D (-) - α- (4-n-butyl-3-oxo-1-piperazinocarbonylamino) phenylacetamido] penicillanic acid,

Mp: 144 - 146 ° C (decomp); 6- [D (-) -a- (4-ethyl-3-oxo-1-piperazinocarbonylamino) -p-hydroxyphenylacetamido] penicillanic acid,

Mp: 189 - 191 ° C (decomp.) IR (KBr) cm -1: C = Q 1775 (lactam), 1735 (-COGH), 1680 - 1620 (-CONH-); 6- [D (- ) - α- (4-Ethyl-3-oxo-1-piperazinocarbonylamino) -2-thienylate etamido] penicillanic acid,

Mp: 183 - 187 ° C (decomp.) IR (KBr) cm -1: γ C = 01775 (latam)> 1735 (-COQH), 1680-1620 (-CCMH).

EXAMPLE 48 In a mixture of 25 ml of anhydrous methylene chloride and 6 ml of dimethylformamide dissolve 3> 44 g of sodium salt of D (-) - α- (4-ethyl-2-oxo-1-piperazinocarbonylamino) -p-hydroxyphenylacetic acid and a drop of N-methylmorpholine was added. The resulting solution was cooled to between -15 and -10 ° C. To the solution was added dropwise 1.14 g of ethyl chlorocarbonate over 5 minutes and the reaction allowed to proceed for one hour at the same temperature. Then 1.22 ml of N, O-bis (trimethylsilyl) acetamide was added and the resulting mixture was cooled to -20 ° C.

On the other hand, 3.28 g of 7- amino-3- [5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] cephem-4-carboxylic acid was suspended in 50 ml of methylene chloride, and 3, 66 ml of N, O-bis (trimethylsilyl) acetamide were added to give a solution which was then cooled to -20 ° C. This solution was added to the above mixture cooled to -20 ° C and the resulting mixture was allowed to react at between 15 and -10 ° C for two hours and then at between -5 and 0 ° C for two hours.

167 1 5 1 3 38

Then, the solvent was distilled off and the residue was added to 30 ml of saturated aqueous sodium chloride solution and 50 ml of acetonitrile, and the resulting mixture was stirred for one hour, then sodium bicarbonate was added to adjust the pH to 3.0. The acetonitrile layer was washed with a saturated aqueous sodium chloride solution, the solvent was distilled off. Ether was added to the residue and the mixture was filtered to give 3.3 g (yield 52.1%) of 7- [D (-) -a- (4-ethyl-2-oxo-1-piperazinocarbonylamino) - p-hydroxy-phenylacetamido] -3- [5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] - cephem-4-carboxylic acid, m.p. 120 ° - 123 ° C (decomp.).

IR (KBr) cm -1: δ C = 0 1770, 1715 - 1660.

EXAMPLE 49 (1) In 20 ml of anhydrous methylene chloride, 1.72 g of 2,3-dioxo-1-piperazinoacetic acid were suspended and 2.38 g of trimethylsilyl chloride and 2.22 g of triethylamine were added dropwise in this order at room temperature. after which the resulting mixture was allowed to react for 1.5 hours at the same temperature. The reaction solution was then cooled to -50 ° C and 1.0 g of trichloromethyl chloroformate was added dropwise, after which the solution was allowed to react at the same temperature for 30 minutes and at -30 ° C for one hour. Then, the solution temperature was raised to room temperature over an hour to complete the reaction. The solvent was then distilled off under reduced pressure to obtain crystals.

On the other hand, 1.5 g of D8 -) - α-aminophenylacetic acid was suspended in 30 ml of anhydrous methylene chloride and 2.4 g of trimethylsilyl chloride and 2.1 g of triethylamine were added dropwise at room temperature. The resulting mixture was allowed to react at this temperature for one hour to complete the silylation. Then, the reaction solution was cooled to -40 ° C and a solution of the crystals obtained above in 40 ml of anhydrous methylene chloride was added dropwise. The resulting mixture was allowed to react at this temperature for 30 minutes and at 0 ° C for one hour, after which the temperature of the mixture was raised to room temperature over 30 minutes to complete the reaction.

168 1 5 1 3 38

Then, the reaction solution was introduced into 30 ml of water and the pH of the resulting mixture was adjusted to 1.0 with 2N hydrochloric acid. The organic layer was separated and 30 ml of water was added, after which the pH of the mixture was adjusted to 8.0 with a saturated aqueous sodium bicarbonate solution. The resulting mixture was allowed to stand and the aqueous layer was separated and added with 30 ml of ethyl acetate, then 2N hydrochloric acid was added to adjust the pH to 1.0. The organic layer was separated, washed with 20 ml of saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was treated with diethyl ether to give 3.0 g (yield 85%) of white crystals D (-) - α- (4-carboxymethyl-2,3-dioxo-1 piperazinocarbonylamino) phenylacetic acid, m.p. 70 - 75 ° C.

IR (KBr) cm "1: 3300 Y c = 01270 (" C00H)> 1710 -1685 (-CON C) NMR (dg-DMSO) ppm values: 3.45 - 4.30 (4H, m> CEZ x 2) 4.17 (2H, s, 3CH2), 5.38 (1H, d, 1CH), 7.40 (5H, s, aromatic proton), 9.80 (1H, d, 1H).

169 151338

The pH of the resulting mixture was adjusted to 8.0 with sodium bicarbonate. The aqueous layer was separated, 30 ml of methylene chloride was added and the pH of the mixture was adjusted to 1.0 with 2N hydrochloric acid. The organic layer was separated, washed with 20 ml of saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (eluted with benzene / ethyl acetate) to give 2.1 g (yield 34.8%) of white crystals of 7- [D (-) - oc- (4-carboxymethyl-2,3- dioxo-1-piperazinocarbonylamino) -phenylacetamido] -3-acetoxymethyl-Δ-cephem-4-carboxylic acid, m.p. 185 DEG-190 DEG C. (decomp.) IR (KBr) cm "1: δ NH 3300 V c = 0 1775, 1720 - 1665

Compounds of formula (IV) and reactive derivatives of compounds of formula (V) were selected and reacted in the same manner as described above to give the following compounds: 7- [D (-) -oc- [4- (2-carboxyethyl) ) -2,3-dioxo-1-piperazinocarbonylamino] phenylacetamido] -3-acetoxymethyl-Δcephem-4-earboxylic acid.

Mp: 150 - 155 ° C (decomp.) IR (KBr) cm -1: 177 (lactam), 1720-1685 (-CONO; 7- [D (-) - α- carboxymethyl-2,3-dioxo-1-piperazino-carbonylamino) phenylacetamido] -3- [5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] -α-cephem-4-carboxylic acid,

Mp: 170 - 175 ° C (decomp.) IR (KBr) cm -1: λ = δ = 0 (lac'tam)> 1720 - 1680 (-CON -); 7- {D (-) - α- [4- (2-carboxyethyl) -2,3-dioxo-1-piperazinocarbonylamino] phenylacetamido} 3- [5- (1-methyl-1,2,3,4 -tetrazolyl) thiomethyl] -Δ-cephem-4-carboxylic acid,

Mp: 162 - 165 ° C (decomp.) IR (KBr) cm -1: n n1770 (lactam) 1 υ = υ1710 - 1680 (-CON <); 7- (d (-) - α- [4- (3-carboxypropyl) -2,3-dioxo-1-piperazinocarbonylamino] phenylacetamido} -3- [5- (1-methyl-1,2, 3,4-tetrazolyl) thiomethyl] -cephem-4-carboxylic acid,

Mp: 145 ° C (decomp.) IR (KBr) cm -1: v / c = 01775 (lactam)> A ~ 1720 - 1680 (-CONC).

EXAMPLE 50 (1) In 70 ml of anhydrous methylene chloride, 3.4 g of D - (-) - phenylglycine was suspended and 6 ml of trimethylsilyl chloride were added and then 6.26 ml of triethylamine was added. The resulting mixture was allowed to react at room temperature for one hour. Then, 4-ethyl-6S-methyl-2,3-dioxo-1-piperazinocarbonyl chloride was added under ice-cooling, and the resulting was allowed to react at room temperature for 1.5 hours. To the reaction product was added 50 ml of water and the mixture was stirred for one hour. The precipitated crystals were collected by filtration, washed with water and dried, then subjected to azeotropic dehydration with 150 ml of toluene to give 6.2 g (yield 90.78%) of D (-) - α- (4- ethyl 6S-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetic acid, IR (KBr) cm -1:> / μϊι3300 1660 (2) in 10 ml of methylene chloride was suspended 0.6 g of D (-) - α- (4-ethyl-6S-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetic acid and 0.189 ml of N-methyl-morpholine was added. to form a solution. A mixture of 0.18 ml of ethyl chlorocarbonate and 1 ml of methylene chloride was added dropwise to the mixture at -15 ° C. The solution was allowed to react at the same temperature for 90 minutes and then cooled to -30 ° C. To the solution was added dropwise a solution of 0 7 g of the triethylamine salt of 6-aminopenicillanic acid in 10 ml of methylene chloride at between -25 and -30 ° C over 10 minutes. The resulting solution was allowed to react at between -25 and -15 ° C for 60 minutes and then at between -15 and 0 ° C for 30 minutes, after which the solvent was distilled off under reduced pressure and the residue was dissolved in 20 ml of 1% aqueous sodium hydrogen carbonate solution and washed with ethyl acetate. An additional 30 ml of ethyl acetate was added and the pH of the resulting mixture was adjusted to 2.0 with 2N hydrochloric acid under ice-cooling. The organic layer was separated, washed thoroughly with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to give 0.7 g (yield 72.4%) of 6- [D (-) - (4-ethyl-6 S-methyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetamido] -penicillanic acid.

IR (KBr) cm -1: VC = 0 1770 '1710' 1680 NMR (d 6 -DMSO) values: 8.88 (3H, t, CH 3), 8.75 (3H, d, CH 3), 8.58 ( 3H, s, CH 3), 8.44 (3H, s, CH 3), 5.85 - 6.85 (4H, m, CH 2 x 2), 5.84 (1H, s, CH), 4.60 ( 1H, m, CH), 4.48 - 5.85 (2H, m, CH x 2), 4.32 (1H, d, CH), 2.67 (5H, s, C6H5), 0.79 ( 1H, d, NH), 0.15 (1H, d, NH)

The same procedure as described above was repeated except that other reactive derivatives of compounds of formula (V) were used instead of D (-) - α- (4-ethyl-6S-methyl-2,3-dioxo-1- piperazinocarbonylamino) phenylacetic acid to give the following compounds: 6- [D (-) - α- (4-ethyl-6S-ethyl-2,3-dioxo-1-piperazino-carbonylamino) phenylacetamido] -penicillanic acid,

Mp: 156 ° C (decomp.) IR (KBr) vnf1: Yc = 0.1780, 1710 ° l67 ° + 6- [D (-) - α- (4-ethyl-6S-n-propyl-2, 3-dioxo-l-piperazine zinocarbonylamino) phenylacetamido] -penicillanic acid,

Mp: 150 ° C (decomp.) IR (KBr) cm -1: γQ = Q 1775, 1705, 1670; 6- [d (-) -oc- (4-ethyl-6S-n-butyl-2, 3-dioxo-l-piperazino-nocarbonylamino) phenylacetamido] -penicillanic acid,

Mp: 125 ° C (decomp.) IR (KBr) cm "1: 0 O = 01775, 1710» 1680; 6- [D (-) - α- (4-ethyl-6S-n-hexyl-2, 3-dioxo-l-piperazi-

. IN

172 (nocarbonylamino) phenylacetamido] -penicillanic acid,

Mp: 125 ° C (decomp.) IR (KBr) cm -1: γο = 0 1780, 1720 - 1680; 6- [D (-) - cc- (4-ethyl-5S-methyl) 2,3-dioxo-l-piperazino-carbonylamido) phenylacetamido] -penicillanic acid,

Mp: 156 - 157 ° C (decomp.) IR (KBr) cm "1: δ fc = 0 1770 '1705' 16705 6- [D (-) - oc- (4-ethyl-6R-methyl-2, 3-dioxo-1-piperazinocarbonylamino) phenylacetamido] -penicillanic acid,

Mp: 155 ° C (decomp.) IR (KBr) cm "1: δ c = 0 1780, 17 ° 5, 1680; 6- [D (-) - α- (4-ethyl-6R-ethyl-2 3-dioxo-1-piperazino-carbonylamino) phenylacetamido] -penicillanic acid,

Mp: 154 ° C (decomp.) IR (KBr) cm -1: yc = Q 1775, 1705, 1675; 6- [D (-) -a- (4-ethyl-6R-n-propyl-2, 3-dioxo-1-piperazinocarbonylamino) phenylacetamido] -penicillanic acid,

Mp: 155 ° C (decomp.) IR (KBr) cm -1: YC = Q 1780, 1705, 1670; 6- [D (-) - α- (4-ethyl-6R-n-butyl-2, 3-dioxo-1-piperazinocarbonylamino) phenylacetamido] -penicillanic acid,

Mp: 125 ° C (decomp.) IR (KBr) cm -1: YC = Q 1780, 1705, 1680, 1675; 6- [D (-) -oc- (4-ethyl-6R-n-hexyl) 2,3-dioxo-l-piperazino-nocarbonylamino) phenylacetamido] -penicillanic acid,

Mp: 121 ° C (decomp.) IR (KBr) cm -1: y "c = 0 1785» 1710 '1685; 6- [D (-) - α- (4-ethyl-5R-methyl-2,3-dioxo-1-piperazino-carbonylamino) -phenylacetamido] -penicillanic acid e,

Mp: 150 - 152 ° C (decomp.) IR (KBr) cm -1: γ C = Q 1780, 1710, 1670.

EXAMPLE 51

Compounds of formula (II) or (IV) and reactive derivatives of compounds of formula (III) or (V) were selected and reacted in the same manner as described under (1) or (2) in the above examples to obtain the following Compounds: 173 6- [D (-) - α- (4-Benzyl-2-oxo-1-piperazinocarbonylamino) -phenylacetamido-ypenicillanic acid,

Mp: 146 - 147 ° C (decomp); pivaloyloxymethyl 6- [D (-) - α- (4-acetyl-2-oxo-1-piperazinocarbonylamino) phenylacetamido] penicillanate,

Mp: 159 - 162 ° C (decomp.) IR (KBr) cm -1: (CaQ 1775 - 1740, 1710 - 1650; 6- [D (-) - α- (4-cyclohexyl-2,3- dioxo-l-piperazinocarbo-nylamino) phenylacetamido] penicillanic acid,

Mp: 166 - 167 ° C (decomp.) IR (KBr) cm ”1: C = 0 1780 '1730' 1710 '16705 6- [D (-) - α- (4-benzyl-2,3- dioxo-l-piperazinocarbonyl-amino) phenylacetamido] penicillanic acid,

Mp: 154 - 155 ° C (decomp.) IR (KBr) cm "1: / / Q = 0 1775, 1705, 1685, 1670; 6- [D (-) - α- (2,3-dioxo) 1-piperazinocarbonylamino) -phenylacetamido -penicillanic acid,

Mp: 154 - 156 ° C (decomp.) IR (KBr) cm -1: C = 0.1770, 1710, 1670; 6- [D (-) - α- (4-ethyl-2,3- dioxo-1-piperazinocarbonylamino-2-thienylacetamido -penicillanic acid,

Mp: 152 - 153 ° C (decomp.) IR (KBr) cm -1: (Q = Q 1775, 1720 - 1660 NMR (dgDMSO) TVs: 8.91 (3H, t, CH 3), 8.56 (3H, s, CH 2), 8.42 (3H, s, CH 3), 6.35 - 6.80 (4H, m, (¾ x 2), 5.95 - 6.20 (2H, m, CH 2)) ), 5.80 (1H, s, CH), 4.45 - 4.55 (2H, m, CH x 2), 4.05 (1H, d, CH), 2.89 - 3.13 (2H , m, CH x 2), 2.57 - 2.58 (1H, m, CH), 0.75 (1H, d, NH), 0.25 (1H, d, NH); KBr) om-1: yc = 01765, 1710-1630; 6- [d (-) -a- (4-n-dodecyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido

Mp: 114 - 116 ° C (decomp); indanyl-6- [D (-) - a- (4-ethyl-2,3-dioxo-l-piperazino-carbonylamino) phenylacetamido] penicillanate,

Mp: 95-100 ° C (decomp.) IR (KBr) cm -1: 3300 ° C = 0.1780, 1710, 1690-1670; 6- [D (-) -oc- (4-benz oyloxyethyl-2) , 3-dioxo-1-pip erazo-carbonylamino) phenylacetamido] penicillanic acid,

Mp: 175-180 ° C (decomp.) IR (KBr) about 1; yc = 0 ^ 73, .1730, 1720 -1660; 6 - [D (-) - α- (4-p-hydroxyethyl-2,3-dioxo-1-piperazino-carbonylamino) phenylacetamido-ypenicillanic acid,

Mp: 183 - 184 ° C (decomp); 6- [D (-) -a- (4-isovaleryloxyethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] penicillanic acid,

Mp: 105-110 ° C (decomp.) IR (KBr) cm -1: γσ = 0.1775, 1730, 1720-1640.

EXAMPLE 52

Compounds of formula (V), (IV) or (VI) and reactive derivatives of compounds of formula (III) or (V) or compounds of formula (VII) were selected and reacted in the same manner as described under (1), ( 2) or (3) in the above examples to give the following compounds: 7- [D (-) - α- (4-n-butylaminocarbonyl-2,3-dioxo-1-pipe-razinocarbonylamino) phenylacetamido] -3 - [5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] -A3-cephem-4-carboxylic acid,

Mp: 144 ° C (dec.); 7_ [d (-) (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] -3-n-propylthiomethyl-Δ ^ -cephem-4-carboxylic acid,

Mp: 155 - 157 ° C (dec.); 7- [D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] -3-carboxymethylthiomethyl-Δ3-cephem-4-carboxylic acid,

Mp: 135-137 ° C (decomp.); phthalidyl 7- [D (-) - a- (4-ethyl-2,3-dioxo-l-piperazino-nocarbonylamino) -p-hydroxyphenylacetamido] -3- [5- (1-methyl-1,2,3 4-tetrazolyl) -thiomethyl] -Aβ-cephem-4-carboxylate,

Mp: 152 - 155 ° C (decomp.) IR (KBr) cm -1: 3300 µc = 0 1780, 1715, 1670; 7- [D (-) - a- (4-ethyl-2,3-dioxo-l-piperazinocarbonylami-amino) -2-thionylacetamido] -3- [5- (1-methyl-l, 2,3,4 -tetrazolyl) thiomethyl] -α-cephem-4-carboxylic acid,

Mp: I60-162 ° C (decomp.) IR (KBr) cm -1: 1770, 1710-1660; 7- [D (-) - α- (4-p-chloroethyl-2,3-dioxo-1-piperazinocarbonylamino) -p-hydroxyphenylacetamido] -3- [5- (1-methyl-1,2 3,4-tetrazolyl) thiomethyl] - [beta] -cephem-4-carboxylic acid,

Mp: 193 - 195 ° C (decomp); 7- [D -) - α- (4-Allyl-2,3-dioxo-1-piperazinocarbonylamino) -p-hydroxyphenylacetamido] -3- [5- (1-methyl-1,2,3,4-dioxide) tetrazolyl) thiomethyl] - zs3-cephem-4-carboxylic acid,

Mp: 183 - 185 ° C (decomp); 7- [D (-) - α- (2,3-Dioxo-1-piperazinocarbonylamino) phenylacetamido] -3- [5- (1-methyl-1,2,3,4-tetrazolyl) -thiomethyl] -? -Cephem-4-carboxylic acid,

Mp: I53 - 157 ° C (decomp.); valeryloxymethyl-7- [D (-) - oc- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -p-hydroxyphenylacetamido] -3- [5- (1-methyl-1,2,3 4-tetrazolyl) thiomethyl] -Aβ-cephem-4-carboxylate,

Mp: 105 - 110 ° C (decomp.); pivaloyloxymethyl-7- [D (-) -a- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -p-hydroxyphenylacetamido] -3- [5- (1-methyl-1,2,3 (4-tetrazolyl) thiomethyl] -β-cephem-4-carboxylate,

Mp: 110 - 115 ° C (decomp); Isopropoxymethyl-7- [D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -p-hydroxyphenylacetamido] -3- [5- (1-methyl-1, 2,3,4-tetrazolyl) thiomethyl] -cephem-4-carboxylate,

Mp: 115-120 ° C (decomp.) Example 53 In 20 ml of anhydrous methylene chloride 1.72 g of 2,3-dioxo-1-piperazinoacetic acid was suspended and 3.25 g of trimethylsilyl chloride was added and then 2.93 g triethylamine at 5 ° C, after which the mixture was allowed to react at room temperature for one hour. The reaction solution was then cooled to -50 ° C, 1.1 g of trichloromethyl chloroformate was added and the temperature of the resulting mixture was raised to room temperature over one hour, after which the mixture was allowed to react at that temperature for one hour. The solvent was then removed by distillation under reduced pressure to give white crystals.

On the other hand, 3.49 g of 6- [D (-) - α-aminophenylacetamido] penicillanic acid were suspended in 40 ml of 50% anhydrous tetrahydrofuran and 1.85 g of sodium hydrogen carbonate was added to form a solution which was cooled to -5 ° C. To this solution was slowly added a solution of the crystals obtained above in 15 ml of tetrahydrofuran and the reaction was allowed to proceed for one hour at 5-7 ° C. Then the organic solvent was removed by distillation. under reduced pressure and 15 ml of ethyl acetate were added to the residue. After standing, the aqueous layer was separated, 50 ml of ethyl acetate added, and the pH of the mixture was adjusted to 2 by 2N hydrochloric acid, after which the organic layer was separated. This was washed with 10 ml of saturated sodium chloride solution and dried over anhydrous magnesium sulfate and the solvent then removed by distillation under reduced pressure. The residue was treated with diethyl ether to give 2.74 (yield 50.1%) of 6- [D (-) - α- (4-carboxymethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido Ipenicillanic acid, IR (KBr) cm -1: 1780, 1720, 1690-1670 177 151538 MR (dg-DMSO) ppm values: 1.4 (3H, s, CH 3), 1.55 (3H, s, CH ), 3.4-4.0 (4H, m, CH 2 x 2), 4.15 (1H, s, CH), 4.18 (2H, s, CH 2), 5.3-5.75 (3H , m, CH x 3), 7.32 (5H, bs, aromatic proton), 9.22 (1H, d, NH), 9.75 (1H, d, NH).

In the same manner as described above, the following compounds were prepared: 6- [D (-) - α- (4-carboxymethyl-2,3-dioxo-1-piperazino-carbonylamino) -p-hydroxyphenylacetamido] penicillanic acid,

Mp: 191 - 195 ° C (decomp.) IR (KBr) cm "1: δ c = 0 1770, 1715, 1700 - 1670; 6- [D (-) - α- (4-V-carboxy-n -propyl-2,3-dioxo-1-pipe-razinocarbonylamino) phenylac et amido] penicillanic acid,

Mp: 170 ° C (decomp.) IR (KBr) cm -1: C = Q 1775, 1715, 1710 - 1670.

KKftttMPEL 54

The compounds of formula (II) or (IV) and reactive derivatives of compounds of formula (III) or (V) were selected and reacted in the same manner as described under (1) or (2) in the above examples to give 6- [D (-) - α- (4-Ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] penicillanic acid having the following substituents as R 1 of formula (I)

R (decomp.) 0 C

-CH2O2H5 125 - 136 -ch2oc-> o .muo o -CH2O (CH2) 2CH3 135 - 137 -CH2O (CH2) 5CH5 90 - 95 -CH2OCH2CH <™ 3 95 - 97

Ull-7

D

7 ° ¾ -CH20CH2C ^ CH3 108 - 112

\ Cel

5 126. 130 nch3 -CH20CH <^ 3ch 80 - 83 IU- 179 151338 -CE ^ CR ^ 2 ^ 81 - 84 _ <¥ * 5__ / ¾ ~ CH2OC <-CH3 129 - 133 \ ch3 -CH 0 (CH2) 3CH3 65 - 67 ch3 / CH3 -ch-o-ch2ch <3 104.5 CH3 CH3 / CH, -CH-O-CH2CH 70 - 75 c2h5 3 -CH-OCH2CH3 gg

CH

ch3ch3 -CH-0 (CH2) 3CH3 CH 175 - 180 rv.

ch3ch3 / CH3 -CH-OCH-CH ^ 175 _ 1? 7

CH

/ \ CH, CH, 5 3 / CH, -CH9OCCH <5 185 - 189 2 0 -ch2oc (ch2) 3ch3 176 _ 1? 9 0 -CHOC (CH «), CB, I j 233 105 - 110 ΓΗ

Claims (5)

1. Analogous process for the preparation of racemic or optically active penicillins or cephalosporins of the general formula: (0) n z ™ ir ™ \ A-N N-C-NH-CH-CONH-j-f / -m u · JXj. wherein R 1 is hydrogen, a cation which forms a non-toxic salt, or a phthalidyl, indanyl, (C1-4) alkoxy (C1-4) alkyl, (C2_4) acyloXy- (c1-4) alkyl · - , piperidino (C1-4) alkyl or morpholino (C1-4) alkyl group, n is 1 or 2, the oxy group or groups may be arbitrarily attached to the 2- and 3-positions of the 2-piperazine group, R and R may be the same or different and each represents hydrogen or a (C1-6) alkyl group, A represents hydrogen, a (C2-4) alkenyl, (C5-7) cycloalkyl, phenyl, benzyl, (C1-4) alkylaminocarbonyl, (C -L_7) acyloxy- (C1-4) alkyl or (C1-4) alkylsulfonyl group, a (C1-6) acyl group which may be substituted by chlorine, or a (C1-4) alkyl group which may be substituted by chlorine, hydroxy or carboxyl, means ch3 V or | ch3 5 = c-ch2r ^ where R4 represents hydrogen, an azido group, a pyridinium group, a (C-L_Zf) alkoxy, (C-L_Zf) acyloxy or carbamoyloxy group, a (C-L_ ^) alkoxythiocarbonylthio group, a (C 1 -C 6) alkylthio group which may be substituted by carboxyl, or an oxazolylthio, thiazolylthio, thiazolinylthio, imidazolylthio, pyridazinylthio, pyrimidinylthio, oxadiazolylthioid, oxadiazolylthioid , tetrazolylthio, piperazinylthiocarbonylthio, isoxazolylcarbonylthio, (pyridyl-1-oxide) thio or (5-oxo-2,5-dihydro-1,2,4-triazinyl) thio group which may be substituted by (C ^ _ ^ alkyl) and R ° means a (C5_ (g) cycloalkadienyl, thienyl, phenyl or hydroxyphenyl group, characterized by, (a) a racemically or optically active compound of the general formula: R7 -NH-CH-CONE-rf S ^ (χχ) in R5 O in C00R1a 5a wherein R and Z are as defined above, R is hydrogen, a salt-forming cation or a protecting group known in the art the penicillin or cephalosporin region, and R is hydrogen or a conventional protecting silyl group or phosphorus containing group which can be easily removed by treatment with water or an alcohol, reacted with a reactive derivative in the carboxyl group of a compound of the general formula: <$> n AH HC-OH (ΠΙ) w II R 2 R 3 ° 2 3 wherein A, R, R and n are as defined above, or (b) a compound of the general formula: (it). C00Rla 182 151338 la 7 v, wherein R, R and ✓ Z have the above meaning, are reacted with a racemic or optically active compound of formula "". 0 '(V) AH SC-SH-CH-ξ-ΟΗ Jrfs0 * 5 ° R .R px 5 wherein A, R, r, r and n have the above meaning · or with a reactive derivative thereof in the carboxyl group or (c) a racemic or optically active compound of the general formula: v £ \ n δ A-NIJ-C-HHtCH-CONH-γ— (Λ · (VI) w * * 5 ° “K · COOR13 wherein A, Rla, R2, R3, R5 and n have the above meaning, and B represents a substituent which can be easily replaced by a nucleophilic reagent, reacted with a compound of the general formula: R8M (VII) wherein M is a hydrogen atom or an alkali metal or Q alkaline earth metal atom, and R is an azido group, a (C 1-4) alkoxy group, a (C thiazolylthio, thiazolinylthio, imidazolylthio, pyridazinylthio, pyrimidinylthio, oxadiazolylthio, thiadiazoylthio, triazolylthib, tetrazolylthio, piperazinylthiocarbonylthioc, isoxazylthioc (oxide) thio- or (5-oxo-2,5-dihydro-1,2,4-triazinyl) thio group, which may be optionally substituted with (C 1-4) alkyl, or reacted with pyridine, 183 1 5 1 3 388, where necessary removing the protecting group from a compound formed under (a), (b) or (c) wherein R · 1 "3 is a protecting group. Process according to claim 1, characterized in that the piperazine ring has oxygen atoms at positions 2 and 3 · Process according to claim 2, characterized in that A is hydrogen, a (C 2 -C) alkenyl, phenyl or benzyl group or a (C-, 5) alkyl group optionally substituted with -L-Xd 2 * chlorine , hydroxy or carboxyl, and R and each are hydrogen or (C1-6) alkyl. Process according to claim 3, characterized in that the compound of formula (i) prepared is 6- (N - (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamidoj penicillanic acid or a pharmaceutically acceptable salt thereof. Process according to claim 3, characterized in that the compound of formula (I) prepared is 7- {D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -p-hydroxyphenyl acetamido] -3- [5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl-3-cephem-4-carboxylic acid or a pharmaceutically acceptable salt thereof.