CS253565B2 - Method of 1-sulpho-2-oxoazetidine preparation - Google Patents

Description

The present invention relates to novel 1-sulfo-2-oxoazetidine derivatives having excellent antiniicrobial activity and ability to inhibit beta-lactamase and a process for their preparation.

Various 2-oxoazetidine derivatives have been synthesized and described in the prior art, see for example Tetrahedron 34, 1731-1767 (1978), Chemical Reviews 76, 113-346 (1976), Synthesis 1973, 327-346. However, it is not known that one of these described 2-oxaazetidines had a sulfo group at the 1-position and a substituent at the 4-position.

The invention relates to a process for the preparation of novel 1-sulfo-2-oxoazetidine derivatives of the general formula I

wherein is a group of formula

^(CH 2> n - ^{r 4} where n is an integer from 0 to 3,

3

R and R which are the same or different, hydrogen, alkyl, cycloalkyl optionally substituted, optionally substituted aryl or aralkyl, optionally substituted heterocyclic, alkoxycarbonyl or acyl, or together are oxo,

R ( ⁴⁾ is hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic, halogen, cyano, hydroxyl, alkoxy, optionally substituted aryloxy, aralkyloxy with optionally substituted alkyl, arsloxy, sulfamoyloxy, carbamino, alkylsulfonyloxy, arylsulfonyloxy with optionally substituted aryl, sulfooxy, nitro, amino, azido, carboxyl, alkoxycarbonyl, alkoxycarbonylalkyloxy, aminocarbonyl, alkylthiocarbonyl, alkylthiocarbonyl, acyloxy, acyloxy with an optionally substituted aryl moiety, optionally substituted or a cycloalkyl group, an alkenyl group, an alkynyl group, an alkynyl group, a cycloalkenyl group, an aryl or a heterocyclic group which are optionally substituted with one or more substituents, wherein the substituents of the optionally substituted alkenyl and alkynyl groups are selected from the group consisting of optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heterocyclic, alkoxycarbonyl, acyl, oxo, halogen, cyano, hydroxy, alkoxy, aryloxy with optionally substituted aryl, acyloxy, acyloxy , alkylsulfonyloxy, arylsulfonyloxy with an optionally substituted aryl moiety, nitro, amino, carboxyl, aminocarbonyl, alkylthiocarbonyl, mercapto, alkylthio, aminoalkylthio, acylaminoalkylthio, aralkylthio with optionally substituted alkyl, arylthio with optionally substituted aryl, optionally substituted with heterocyclyl, optionally substituted with heterocyclic thio, heterocyclic thio the above optionally substituted groups contain at least one substituent the same or different and the optional substituents of the substituted cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocyclic and quaternary ammonium groups are selected from the group consisting of alkyl, alkoxy, alkenyl, aryl, aralkyl, mercapto, alkylthio, arylthio, aralkylthio, alkylsulfone aryl, arylsulfonyl, aralkylsulfonyl, trihaloalkyl, hydroxy, oxo, thiooxy, halogen, nitro, amino, cyano, carbamoyl, carboxyl, acyl, acyloxy, hydroxy, acylamino, carboxy, acylamino, and a dialkylaminoalkyl group, wherein the above-mentioned amino, carboxyl and hydroxyl groups may be protected, each of the above-mentioned alkyl and alkoxy groups having 1 to 6 carbon atoms, alkenyl and 2 to 6 carbon alkynyl groups, cycloalkyl and cycloalkenyl 3-8 carbon atoms, the amino group may be substituted with an acyl group, an alkyl group, a hydroxyalkyl group, an aralkyl group with an optionally substituted alkyl moiety, an optionally substituted aryl group another optionally substituted heterocyclic group, sulfo group, alkylsulfonyl group, aralkylsulfonyl group with optionally substituted alkyl group, arylsulfonyl group with optionally substituted aryl group, alkoxycarbonyl group, aralkyloxycarbonyl group with optionally substituted alkyl group, aryloxycarbonyl group with optionally substituted aryl group, wherein the optional substituents are as defined above, aralkyl is always benzyl, phenethyl, phenylpropyl or naphthylmethyl, aryl is phenyl, alpha-naphthyl, beta-naphthyl, biphenyl or anthryl, heterocyclic is a 5- to 8-membered heterocyclic radical with one to four heteroatoms selected from the group consisting of nitrogen, including N-oxide, oxygen, and sulfur; in each case a formyl group, an alkylcarbonyl group having 1 to 6 carbon atoms, a benzoyl group optionally substituted by a hydroxyl group or an alkyl group having 1 to 6 carbon atoms, an aralkylcarbonyl group having 7 to 9 carbon atoms optionally substituted by a hydroxyl group or an alkyl group having 1 to 6 carbon atoms or a five-membered heterocyclic carbonyl or acetyl group containing at least one oxygen, nitrogen and sulfur atom, optionally substituted by an amino, amino or acylated amino group, the acyl moiety having the general formula

R ⁵ - CO 253565 where is

R is an alkyl group or an optionally substituted heterocyclic group, or a general formula

R ⁶ -NH-CH-CO

Where R is

R ^G is vodíb with ^the nominal UPIN ^^, ^ ala nominal, nominal ^Ly va ^l ^ ^y EUC; LoVo isoleuc ^y salicylic, seryl, threonyl, cysteinyl, cystylovou, meehionylovou, alpha or beta-aspartyl-aspartyl, alpha -gunaarnylovou or gamaaglutamYlovou, lysyl, arginyl, phenylalanyl, phenylglycyl, tynsylovou, histidylovlt, tryptofanylovlu or propyluvou group, or an amino protecting group or a group of the formula ^{R8 - (CH2>} nJ ^- g ^CO wherein R is a heterocyclic group optionally substiuuovanou and 'n ₁ Integer 0 to 2

R ^{7 is} an alkyl group, an optionally substituted phenyl group, a heterocyclic carbonylamino group with an optionally substituted heterocyclic moiety, or an optionally substituted heterocyclic group, or has an acyl moiety of the formula wherein R ^{9 is} R ¹⁰

CO group of formula

OR where is

R ¹¹ optionally substituted alkyl, optionally substituted heterocyclic or phenyl; and

2

R is hydrogen, alkyl or a group of formula

-R ¹³ - ^{r 14} where is

R is an antenna or alkenyl group; and

R ^U substiuuovanou or phenyl group, or a karboxklooot alkylesUer or mooooakylvminoskupint or íialkyVaainoskupinu

R ^{10 is a} direct bond or a group of formula

-CO-NH-CH

L15 where is

R is an alkyl group, an optionally substituted phenyl group or an optionally substituted thiazolyl group, or has an acyl moiety of the general formula

where it means

R ( ^{16) is} hydroxy, hydroxy sulfonyloxy, carboxy, optionally substituted ureido, optionally substituted sulfamoyl, sulfo, optionally substituted phenoxycarbonyl or formyloxy, and R < ¹⁶ > a hydrogen atom, an alkyl group, an alkoxy group, a halogen atom, a nitro group or a hydroxy group, or has an acyl moiety of the general formula

R ¹⁸ - R ¹⁹ - CH ₂ - CO where

R is cyano, optionally substituted phenyl, optionally substituted phenoxy, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted heterocyclic, and

R is a direct bond or a sulfur atom, wherein

19 in the case of the symbols R to R, a heterocyclic group always means a 5- to 8-membered heterocyclic ring having 1 to 4 heteroatoms selected from the group consisting of nitrogen (including N-oxide), oxygen and sulfur, pyrido- [2,3-d] pyrimidyl, benzopyranyl, 1,6-naphthyridyl, 1,7-naphthyridyl, 2,7-naphthyridyl, 2,6-naphthyridyl, quinolyl or thieno- [2,3, b] pyridyl, optionally substituted heterocyclic, phenyl, thiazolyl, phenoxycarbonyl and phenoxy are in each case substituted with one to two groups selected from the group consisting of alkyl, alkoxy, alkenyl, aryl, aralkyl, mercapto, alkylthio, alkylthio, aralkylthio, aralkylthio, aralkylthio, aralkylthio, aralkylthio, aralkylthio, aralkylthio, aralkylthio, aralkylthio, aralkylthio arylsulfonyl, aralkylsulfonyl, trihaloalkyl, hydr oxy, oxo, thioxo, halogen, nitro, amino, cyano, carbamoyl, carboxy, acyl, acyloxy, acylamino, hydroxyalkyl, carboxyalkyl, haloalkyl and monoalkylaminoalkyl, the above-mentioned alkyl, monoalkylaminoalkyl and the alkoxy moiety each has 1 to 6 carbon atoms, the alkenyl group always has 2 to 6 carbon atoms, and the aralkyl and aryl moieties are as defined above, in the case of a substituted alkyl group the substituents are selected from halogen, hydroxy, cyano and trifluoromethyl , in the case of a substituted ureido group, the substituents are selected from the group consisting of a sulfo group in the form of a cation, a carbamoyl group, a sulfamoyl group, an amidino group or an alkyl group having 1 to 6 carbon atoms, optionally substituted the famoyl group has 1 to 6 carbon alkyl or amino groups as substituents, the amino group, the carboxyl group and / or the hydroxyl group may be protected, the amino group may be substituted as described above in the case of sylmL · R, or ^{r 1} represents an amino group hindered aioyiovou ^ s ^ ^p ^^ well -ni ^r oo ^{y e} enzo lovop group, and t-bptylbenziyloviu group, and t-butylbenzensulfonylovop group, a further group benzeessufonylovou, tilpessulfňisylivip, formyl moonoClooacceylovou, dichloroacetyl, trCchiofacetyioviP, mmehaassPfisyliViu, ethansulfisylovip, triPliOfCceУyioviP, mmacylovou, spkcisylivip, methoxycarbonyl, ethixykfrbisylivip, tert-Puioxykfrbisylovip, isopropoxycarbonyl, 2-kyanethoxykarbonylovou, beta, beta, beta-trClhireelixxykarbisylovip, trimetlylsilellihoxyfarionyiovip beta, beta-meehylsplfosyeehioxykfrbonylovou, benzyloxycarbonyl, and siriobeszyloxykfrbosyliviu-p-methoxybensyloxykfrbosylovou, diphenyl enylmetlyioxykarbosylovop, miehoxymeehlloxykarbonylovou, aceeylmeehyloxykarbinylivip, isiOirnylixykfrOinylovou, fenyloxykfrbisylivou, trityl, 2-sitroeesyllhisskuiSniP, a benzylidene group, a 4-sitiobeszylidesivou, trfalkylsiУyiovip, benzyl, I'-sitiobeszylovop or protons, přieemž share alkynyl, cycloalkyl, By, podlil cycloalkenyl, aralkyl and aryl and poddl poddl mmj shall always have the meaning given for R,

X is a hydrogen atom or a mitoxy group, or their or their esters, characterized in that the compound of formula III is sulfispersed

wherein the monovalent symbols are as defined above, or a salt or ester thereof, and optionally a protecting group is removed. .

In formulas (I) and (III) above, R is an organic group attached to the 4-position in the 4-position by a carbon atom, the above-mentioned organic group, that is, a group derived from an organic compound by removing one hydrogen atom from the corresponding carbon atom.

Such organic groups may be, for example, alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, aryl, heteroaryl, and the like, which may optionally be substituted with one or more sub-titers.

Any group that may optionally be spp. Is hereinafter referred to by the cross + as superscript. Naapíklad alkyl group which may optionally yl substipuov ^{b and} SF, everywhere oznatavfoa ^b ^ 1 ^ 1 ^^ group '.

In such cases, the number of sub-sites is not limited to a single sub-substituent. Some substituted groups may have two or more suboSpPests, either the same or different. Alkyl is preferably lower straight or branched chain C 1 -C 6 asylum, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl , isopentyl, hexyl, isohexyl and the like.

Cycloalkyl is preferably C 3 -C 8 cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, cycl hexyl, cycl-heptyl, adammanyl, and the like.

Alkenyl is preferably a lower straight or branched chain alkenyl group such as vinyl, allyo, 2-methallyl, 2-butenyl, 3-butenyl or the like.

up to 6 isopropenyl,

Alkynyl is preferably lower straight or branched chain alkynyl of up to 6 carbon atoms, such as, for example, ethynyl, 1-propyl, C1-6 alkynyl or lower alkynyl. β-propynyl or similar groups.

Metered cyclic groups include, for example, C 3 -C 8 cycloalkyl groups such as 1-cyclopropenyl, 1-cyclobutyl, 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyl, 2-hexenyl, 1-cyclopentenyl, 1-cyclopentenyl, 1-cyclopentenyl -cyclchexyl, 3-cyclhexyl, 1-cycloheptenyl, 1,4-cyclohexadienyl, etc.

Among the aryl groups anthryl and the like

A preferred cycloalkyl group is a (C 4 -C 6) cycloalkenyl group. Ponyl, alphthalphthyl, beta-naphthyl, biphenyl groups.

Of these, phenyl and naphthyl are usually preferred. Heterocyclic groups include 5- to 8-membered heterocyclic rings with one to several heteroatoms such as an atom (nitrogen (including N-oxide), oxygen and sulfur).

Corresponding condensed rings having an available binding site on the carbon atom are also steamed. Meei; examples of such a heterocyclic group, which is usually preferred, are 2- or 1-propyl, 2- or 3-furyl, 2- or 3-thienyl, 2- or 1-pyrrolidinyl,

2-, 3- or 4-pyridyl, N-ooido-2-, N-oxido-2-, N-ooido-4-pyridyl, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-prrtiyl, 2-, 3- or 4-thiopyrtirl, pyrazyl, 2-, 4- or 5-thitzolyl, 2-, 4- or 5-xazolyl, 3-, 4- or 5 'isothitzolryl, 3-, 4- or 5-isoxazolyl 2-, 4- or 5-imidazolyl, 3-, 4- or 5-pyrazolyl, 3- or 4-pyridazinyl, N-oxido-3- or N-oxido 4-pyridazinyl, 2-, 4- or 5-pyridinyl, N-oxido-2-, N-oxido-4- or N-ooido-5-pyridyl, oiperazinyl, 4- or SQ4; N-thiadiazolyl,

3- or 5- (1,2,4-thiadiazdyl), 1,3,4-thiadiazolyl, 1,2,5-thitdiazolyl, 4- or 5- (1,2,3-octathiazolyl) -, 3- or 5- (1,2,4-oxaiaziazCyl) -, 1,3,4-oxadiazolyl, 1,2,5,4-diaz (III, 1,2,3) or 1,2,4-triazolyl, 1H- or 2H-tertzolyl, pyrido-2,3-d-pyrimidinyl, benzoporanyl, 1,8-, 1,5-, 1,6- 1,7-, 2,7- or 2,6-naphthyl, quinolylcyclopropyl, 2,3-b pyridyl and the like.

Preferred groups include, but are not limited to, five- or six-membered heterocyclic rings with one to four heteroatoms which may be nitrogen or sulfur, such as thienyl, thiazllyl, thiadadiazolyl, triazollyl, tetrazolyl or the like.

Of these groups may be alkyl network, alkenyl-l-oic aa washed Hi alkyl group substituted by one to three subbsttuenty as nappíklad cycloalkyl, cyllltkenylová, aryl, tlкlx кtrblnyllv ^{Y and} Ac; ^yl OC ^{and, oxo,} halo · ^{1 yanoskupina,} hydroxy-carboxylic acid and aLкlxylcvá group, tryl -lx ^{+ Y к upiit,} acyllxys oup ^{1, 1} tr Tic ^{b) a} lox ^{y group} hydrcxysulfli ^{y y} LCX sku ^when it ^, alк lsullin ^{y y y} LXX with u ^{p to} IIT and aryl -suHony ^l OXYS upiia ^1, i ^{i 1} up Tlos ^Ia, amino, carboxy, aminocarbonyl · a.alkylthlltabboiylcvá group mmekaptoskupi ^{i and, y} lth tlк oskupiit ^C, ai ^and nil to ^{t 1} lthics ^{1 upiia,} acylam ^even nil KLL ^{t t} u ^p HICS ^{к INA} arallcyl ^- th axis ^{L 1} at ^{p IIa} tryl ^{+ l} -TH ass ^{p IIa} hetero cykl- -TH ^{+ -} os ¹ u ^{oi it, k} <^) ^ ^{ry RTE} amcmiov ^not the ^b o ^p ODD ^b n ^and s ^{to P} at INA.

Substituted alkyl groups include, for example, the group of formula (A)

I ²

- C - (CH ²⁾ _ - R ⁴ (A),

R3 wherein n is 0 to 3,

3. +

R @ 1 and R @ 2 may each independently be hydrogen, alkyl, cycloalkyl, aralkyl ⁺ , aryl ⁴ , heterocyclic ⁺ , alkoxycarbonyl or acyl; or

R and R taken together are oxo and + ++

R is hydrogen, alkyl, cycloalkyl, aryl, heterocyclic group, halogen, cyano, hydroxyl, alkoxy, tryl -OX ^{+ y} with ^{the tpiyu,} tralkyl ^{+ -} ox · ^{y acyloxy} ^^ ^ karbaee pin ^of oxyskupiyt, ^{y t} h droxysu ^by n ^yl ox ^y with u ^{p to aniline,} TLK ^y lstl ^by those ^of OXYS int ^k t ^p, t r ^{y +} L ^y lox ^y -sulOon SKU ^{P well,} a sulfoxy nitooskupinu, amino and azido. carboxy, alkoxycarbonyl, alkoxycarbonyloxy ^ i ^^ ^ loxyskui íinu, aminocarbonyl, aLkylhT ókkab ^ ^ C ^ N ^ ^ x ^ y OC ou AA ^^ yl, enrkaptoskupinu, TLK ^y lhhόosktpinu, amine N ^t k t ^y l · ^h. osk.u ^{of aniline,} c ^{y t} k ^k lte.inno lt ^h iosku ^s nu, tralk ^{y +} l "th ^of oskt ^{pi nt} aryl -thwskujnu ^{+ H} eteroc cloned ^{y + p} -TH ^of the axle or quaternary yne and The group is substituted.

The substituents on the alkyl, alkenyl and alkynyl SKU ^p Ina SKU ^p Ina general formula R ^2, R ³ or R ⁴ alkoxy group is preferably lower alkoxy SKU ^P inu straight or branched chain having 1 to 6 carbon atoms, such as nappíklad methoxy, ethoxy, propoxy, isopropoxy, butoxy, isoSutoxyL, sec.-butoxy, tert-butoxy, pentyloxy, i-sopene boxes, hexyloxy, isohexyloxy or the like.

Methyl alkyl groups include, for example, benzyl, phenethyl, phenylpropyl, naylmethyl, etc. Halogens include fluorine, chlorine, bromine and iodine. Quaternary ammonium groups include a group of the formula wherein W is hydrogen, alkyl, carbamoyl and carboxyl, sulfo or alkoxy, which may be derived from pyridine derivatives such as pyridine, carbamoyl-substituted pyridine (eg, nicotinamide, isonicotinone, etc.), carboxylic acid-substituted pyridine (eg, nicotinic acid, onicotonicin acid, etc.), sulfo-substituted pyridine (eg. other acid, etc.), etc.

These quaternary ammonium groups can form an internal salt of sulfosuccinic at the 1- or 2-position of the oxoazeeidine core. MEEI acyl groups steamed nappíklad formyl, alkylk phenyl ^and Rb ^{of the IP} and, YZ-^ + ^ brbonylová araltyl artonylová teterocyklo-acetyl-group and ATI ^{also be} acylated ^E) Cupin ^s age is specified for R ^3rd

Of these nappíklad preferred alkylcarbonyl group having 1-6 carbon atoms (e.g. acetyl, řropionyloiá, butyryl, pe ^nt anoylová, hexanoyl group etc.), benzoyl which may be substiuuována (e.g. benzoyl,? Hydroxybenzoolová, 4- (4-methoxyphenyl), etc.), (C7 -C9) aralkylcarbonyl which may be substituted (e.g., phenylacetyl, 4-hydroxyphenylacetyl, 4-mehooyphenylacetyl, etc.), five-membered Oeterocyclo-carboxyonyl or 5-acetyl; ^a group with at least one oxygen, nitrogen and / or sulfur atom which may be substituted (eg, 2-thienylcarbonyl, 2-trimethylcarbonyl, 2-, 4- or 5-thiazolylacetyl, 2- or 3-thienylacetyl, 2- or 3-frylacetyl, 2-amino-4 'or 2-amino-thiazolyl acetyl, etc.).

The alkyl group in alkylS ^ ffonyloxyskupině, ·· alkylhhiokarbonylové, alkylthio, ^p aninnflkklthioskt others acylaminnolkylthioskupině and llkfxykarrofnУalOyli> xytOtpině, alkoxyl group and in alkoxykarronylové l10oxy0arronnlalkyloxys0upině and acyl group in the acyloxy portion and means acylaiuinnolkylthioskupině ^ i as described above.

Among the sub-substituents which may be present in the cycloalkyl, cycloalkenyl, arylalkyl, aryl, heterocyclic and quaternary uno group are, for example, alkyl, alkoxy, alkenyl, aryl and aralkyl, mercapto, 10-ylthioalkylthio, lrylthio (III) thienylthio (III) thienylthio (III), lrylthio (III), lrylthio (III). haloalkyl, hydroxyl, hydroxyl, oxo, thioxosulfonyl, halogen, nitiostopine, amino, cyano, Oarbamoyl, carboxyl and acyl, acyloxy, acylamino, carboxyalkyl, hydroxyalkyl haloalkyl, mono- or (di-alkylamino) alkyl and the like (wherein the alkyl, alkoxy, alkenyl, aryl, aralkyl and acyl groups and the halogen atom are as defined above).

If the organic group R, which is attached to the azetidine ring by a carbon atom, contains an amino group, the above-mentioned amino group may be substituted or protected; if it contains a carboxyl and hydroxyl group, such a group may also be protected.

Meei^exeventually^E sub-ituenamine amine stopin^ypand^andř acy] .ov^and stopina s^hora listed in R¹and also alkyl, alkoxy, hydroxyalkyl, aralkyl⁺ , aryl⁺ , hetrr <cyclic⁺ , sulfide II^Oylst^ifonyli)^, lral^kyli> vá^+, lral^Oyl^{+ t}tulfc) n^yli> v^and, lryl^{+ t}st^ifonyli> va^, altox ^ arto nylová, miniature sheets!⁺tocycarronyl, aryl, γ-4-oxycarbonyl, and the like (wherein the alkyl, cyclohexyl,^kylfv^{á +,} ar^yhunting^{á +} and the whole c ^ 11th stop is ^! I^to ston indicated¹ .

Optionally, the amino group together with such substiuueneem quick match to create the cyclic amino such as NEP example ^ ^y p rn lidnnivá, piperidine, noffolinová, piperazino or the like.

MEEI amino protecting group Paar nappíklad those groups · are given below with R as c ^{h n} to healing StopIN amine StopIN ". CHH ⁿ to StopIN ^of HAr ^b oxides by ^Star StopIN jlOákoiiv may be a carboxylate protecting group used in the field konvenině betatlakaanů and other organic chemistry, such nappíklad an ester (e.g., methyl, ethyl, propyl, ntfpropylová, tert-utylová, Teri .amylová, tonzylová p-nitcobenzylcvá, ρtmethoxy-renzylová, tonzhhyldylová, fenylacylová, fenylivá, t nitroeenyli> acid, по ох ^ ^ уГ ^^! ^ ,, ethoxyyerh lfvá ^{y, y} rrnz loxyyeeh Nominal ^{y, y} Nominal acrtoxyyeeh, n-methyl-oxyethyl, r-trichloromethylethyl, r-trichloromethyl ethyl, r-triethylethyl, r-triethylethyl, triethylethyl, triethyl, triethyl, triethyl, triethyl, triethyl, triethyl, triethylethyl, triethylethyl, triethylethyl, triethylethyl, triethylethyl, triethylethyl, triethylethyl, triethyl, triethyl ^, ,, diyeethlltlylfvá, acetylyethylfvá p-nirfobenzfylyeth lfvá ^{y, y} ptyys lbrrnooУyyrhhlová, ftaliydf © methyl, propionyl onyl ^ ^ C ^ x ^ y ^ T ^ T ^ l ^^^^ Nominal, '1,1-diyerh ^y lpropylová, 3-yerhhУ-3trutrnyl, stkciniyndoynrh ^y l, 3,5- ^ 1 ^ гп.Г ^ у1-4thydroxyrrnz ^y l , YyesУmeehylová, renzeenttffnylyethylová, phenyl lthf «methyl, dimethylaminoethyl, pyridin-xxif © ^ methyl, yerhhУsulfinylyrthylová, RNS (p yrthfx ^y frnyl) yethylová 2-kyarlnft 1-diyethylrthylová group etc.), SH-Yro ^ v and similar groups.

The hydroxyl-protecting group may be any hydroxyl-protecting group, which is generally used in the β-retatlakaites and in other organic chemistry, such as the ester moieties, e.g. acetyl, etc., substituted carboxyl groups, e.g., retl, retl, rttrihirrehfoyocarbonyl, rerinerhnyl ethoxycarbonyl, etc., ether moieties, e.g. tert-butyl. benzyl, p-nitribenzyl, trityl, yerhethioyl, reta-yetoxyrthoxymethyl, etc., silyl ether radicals, e.g. triethyltilyl, tertiaryldimerhehsilyl, etc., acetal radicals, e.g. 4-tetrahydropyranyl, 4-tetrahydropyranyl, 4-tetrahydropyranyl, 4-tetrahydropyranyl, 4-tetrahydropyranyl, 4-tetrahydropyranyl, 4-tetrahydropyranyl. group etc. and similar groups. The choice of the above protecting group for the hydroyyl group is not critical in the present invention, as is the choice of the above protecting groups for the amino and carboyyl groups.

Preferred examples of organic R groups are those of formula (A) provided that when both R and R are both hydrogen, then R is not hydrogen. especially straight chain alkyl or, if one of R or R is hydrogen, the other is particularly straight chain alkyl and n is zero, then R is not hydrogen.

Of the groups of formula (A), a group of formula (B ') is generally used.

- J3: Wn - R <B 'in which n is as above, * 3' · 2 *

R and R independently of one another denote a hydrogen atom or an alkyl group or R a *

R together we mean ^! oxo and

4+

R represents a hydrogen atom, an alkyl group, an aryl group, a halogen atom, a cyano group, a hydroyyl group and an alkoxy group, an arylalkyl * -yloxy group, an acyloy group, a carbamoyloxy group, an alkylsulfonyloxy group, an sulfonyl group, amino ^, amide, azide, carboxy and R 4 is a carbonyl group, an alkoxycarbonylalkyl group, an alkylthio group, a heterocyclothio group or a quaternary ammonium group.

Of these, the amino group is optionally substituted or 23 is optionally protected as described above for R, R and protected and carboxyl r 4.

group

Of the groups of formulas A and B, they are more preferred

3 those groups of the general formulas A and B in which R and R, respectively. 4. 4 '' - · -ί ..л П ⁴ '3'

R @ 1 and R @ 2 taken together are oxo and r @ 1 and r @ 4 respectively represent an amine group which may be substituted or protected, i.e., a group of formula C1-4;

- CON ( _Q 4) wherein _q 3 and _q 4 can each independently be hydrogen, alkyl, alkoxy, aralkyl, aryl, and heterocyclic, sulfo, aralkyl, sulfomyl, alkylsulfonyl, amino, aryl-sulfonyl, alpha-cycloalkyl, aralkyl -yloxycarbonyl and aryl * -yloxycarbonyl, acyl or protecting group R ¹ , preferably R ¹ ,

1.

(E),

in which q3

independently of one another may be hydrogen, C1-C6alkyl, C1-C6alkoxy, amino, C1-6alkyl, wherein the alkyl is C1-C6alkyl, alkyl (C1-C6); carbon atoms) a carbonyl group which may be substituted by a halogen atom, a sulfo group, a phenyl group, a benzoyl group, a carbamino-C 1-6 alkylcarbonyl group, a p-nitro-benzyloyyclohexyl group or a beta-C 1-6 alkyl group) -alkoxy (C1-C6) -carbonyl and especially catamoyl, mono- or di-allyl (C1-C6-carbonobamoyl, phenylcarbamoyl, sullokaobamlyl-C1-4-alkoxy), alkoxy (C1-C6-alkoxy) (C-Cja-Cak-Cak-Cak-Cak-Cak-Cak-Cak-Cak-Cak-Cak-Cak-Cak-Cak-Cak-Cak-Cak-Cak-Cak-Cak-Cak-Cak-Cak-Cak-Cak-Cak-Cak-Cak-C

3 2 *

The second group ooecnéhr vzotce A and B in which R and R tespektive R · and R 4 together finish 4 'Mady meant an oxo group and R, R is OH tespektive Groups, klklxylovlu sl ^ ^ aryl pin -OX ^{+ y} StopIN ^ and ^ <^]. ¹ J ^]. ^{+ -} lX ^{l l} u s ^P LNT Neto kl ^l lX ^o Cr ^O on ^{nl ly} lox kl ^l with u ^{p to aniline,} i.e. Groups ooecného vzotce D

- COQ ⁵ (D ^wherein Q is ^5-hydroxy ou group may oyl chtáněna To this, ^ k ^ yl group aryloxlsltpinu, To this may oyl suOstiuuována, ^^ 1110X1 group may oyl To this suOoSitj lvan neoo ^ ^ ^ ι Ι ^ τ ^ οπγlalkiloxyslupinu preferably groups roecnéhr vzotce ^"5 COQ in which Q ⁵ is neoo ^ al ^ xy 1 to alkoxy having 1 to 6 carbon atoms, p-nitrobenzyloxycarbonyl atoms 13111 ^ X ^^ 0 ^ 11 ^ 10 ^ 1 up to 6 carbon atoms) oxy,

3. those groups

3'2 * 3 * yearly formulas of A and B in which R, R, R and R are hydrogen atoms, for example the yearly formula of E · ^{(CH 2)} _m ^- X ^{1 - q6} (E) ^, wherein m is 1 up to 4,

X ^1, A quick match -NH ^ - ^ ^{-, -} 0-, and weigh Neto

Q® · · represents hydrogen ^and atoms carboxy ^{about AM-l} /; LVLT StopIN ^L and y ^L .lVot sl ^ ^ ^kt UPIN The ETA ^by Yt • substituted, an alkyl group, a heterocyclic group may oyl subosituiována To this, neoo Kato ^ verifies the group To this may chtáněna oyl group, preferably roecného vzotce ^(CH2 _'m ^{- χ1 -} ° ^6' therein ^z has a mean X ¹ I, and ^the above uveteno

Q® from ^N and ^me on altylIs 1 ^of 6 atoms, and ^{Y is} carbon), carbon-ETA groups may be ^of Yt subositui ^- bath halogen atom, an alkyl group having 1 to 6 carbon atoms, oenzoylovru, 5- neor 6člennru heterrcylklickou group Łtětí oosahuje a nitrogen atom (e.g., pyrrole, thikz (III, thikdiazlll, dikzllllovl, (aza-L-rv, lxadiczolyl, tracolyl and tettazoyl, etc.)), itet may be substituted by an alkyl group having 1 to 6 tons of carbon or the neo 5člennlt 6 membered heterocyclic <L · thiokce tllovlt obssahjjcí nitrogen group whose heterocyclic ^y lliclý ktuh may suOotituován alkylovru oyl group having 1 to 6 carbon atoms, ·.

Specific examples of a group of formula C include catamorphyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N, N-dimethylcarbamoyl, N, N-dimethylcarbamoyl, N, N-carbamoyl, N-methylcarbamoyl, N-methylcarbamoyl, N-methylcarbamoyl, N et hoxykar ^ ^ o ^ am ^ i ^ l.ová, ptrpoxykatOamorlová N, N-isoproprxykktOkmoylová, N Nominal hydroxykktOamo ^L, N Kmin <lkar ^O AMO ^by Nominal _/ ^{[L 1} (I ^) - ^! ^ i ^ i ^ zyl (3 ^ ^ ^x ^ ^y ^ e ^ and ^ l ^ C ^ RNL <^ t ^] ^^^; L] aminocarbonyl ^V, and ^[1- (L) ~ ^^ ΟιχγθΙΗγΐ] aminocarbonyl N, N-phenylcarbamoyl, N, N-diphenylcarbamoyl, N- (p-chlorophenyl) kaobamoyl, N-Oenzylcarbamoyl, N, Nd, N, N, N, N, N, N, N, N, N, N, N, N, N, N and N; N-hydroxyethylcarbonyloyl, N-chloromethylcarbonyloyl, N-ketylcarbonyloyl, N-propynylcarbocoyl, N-alpha-oxycarbonyl-ammonium, N-ethoxycarbonyl-octyl-carboxylic acid, N-ethoxycarbonyl-cycloalkyloxycarbolylcarboloylcarboloylcarbonylcarboloylcarboloylcarboloylcarbonylcarboloylcarboloylcarbonylcarboloylcarbonylcarboloylcarbonylcarboloylcarboloyl.

Specific examples of groups of formula D are carboxyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoyyktrbonylová, butyloyykrrbonylová, isobuUyloxykarbonylová, sek.butyloyykrrboyylová, pentoyykarbonylová, benzyloxycarbonyl, fznethyloyykarbonylová, methoxχУkabolιnlmethhloxykarbonylová, ethoyykrrbonylmeehyloyykrrbonylová, fenyloyykarbonylová p-chlorZenyloxykarbonylová, hydroxymeZhhloxykarbonylová, sulfomethyloxykarbonylová and the like.

Among konkréaní examples of groups of formula E Paar rcylaeiyoatkylová (e.g. acetylrminomethalová, propionylaminomethylová, butyrylaaeinoeethylová, isobuhyrytemУnoeethylová, rcetylreinoethylová _/ propionylamiyoethylová _/ acebyltmiylprlpyllvá, acetyl · aeiyobutylová, btnzoylrminoInethhlová, benzoolrminoothylová, benzcylaminopropylová, formylamiyomethyllvá, ftnylrcthytamiyomethylová 4-aydroxyftyylacthytamiУlmethyllvá 2-haieyyaaarbonytamiylmethylová 2- furyaramonylaminomethyl, heterocyclylmethyl, 2-aminyl-4-thaazazoleacetyl-amino, etc., a pyrrolidinylmethyl group (e.g., carbamoolaminomethyl, carbaminolamenamethyl, carbromolamenamethylaminomethyl, carbaminolamenamethyl). 2- (2-chloroacetanidyl-4-thiitolyl) - (Z) -2-methoxyimidoylcethoxymethyl, 2- (2-aminomethyl-4-thiitzlyl) - (Z) 12-methoxyethoxy ethyl, 2-lhhieyytaceloxymethyllvá _/ 2: furytctelχyymthhylov.á, hhitzolytatelxxymtthylová 2 · lamenyll-taiazo0ytaceloxymebayllvá, beyzoyloxymeehylová benzoyl oyyehhyl ^ ^ oic acid, 4-hydroxybtnzoyloxymethylová 4-methoxybeeyooУoxymethhlová, mmonocaooacetoxyi methyl, hria0loteallУУkarrlonylyχymtaayllvá, acetacthoxymeehylová (11methal-lH-tetrazole (1-N, N-dimethylamino-thal-1H-atartzol-5-yl) -tethoxyl-tert-butyl, (O-N-dimethylaminomethyl-1H-indazol-5-yl) -hexyl-thiazol-1-yl-methyl-5-yl) -acetamide; , (2-methalol-triazol-5-yl) ahlaacelzoxymethyll, (O-ethoxy-1H-lritzzl'-5-yl) tailaceaoxymethyl group, etc.), an arrbrmooloocylacyl group (e.g. karbrmeollxymethylová, krrbamooloxχythylová _/ krrbamzolzxyprzpylová, karbtIiУoloxχisopropylová group etc.), HE-ncykll-haiotlallová group e.g. haityylahlomthal0lvá, haίtУl0aalztaallová, haityχlhaill propyl, furyiahiomthayiová, ftrlOtaizttayllvá, haitzl0l1aaloethay0lvá, haitzollOaail) thal0ll acid, 2laniynlhaχzoly0thlomttay0lvá 2-tmiyylhaitzloltailthay0lvá 2-tmiyylhaatzlχlthilisll propyl, ( 2-methalothiadiol-11-ahloettall-1, (2-methalol-thiol-15-χl) ahlomthyl, (1-methyl-1'-methyl-1H-lritzzl-5-yl) haismethyll-1'-t-5'-5'-5'-5'-5'-thi-5'-5'-thi-5'-5 (1, N _from N-dimethalorieoylthalH-ahtrazzl-5-yl) aalomthyl, (1'-pyrrole-methyl-5-χl) ^ 1tthrtzzl (5-χl) hail> propyl group, etc., tlltalztlkχlvl group (e.g., metaalhaiomethyl, methaltailtaalOl, methhltailprlpyOlv, methaltailislprlpyO, ttayltalzmthayll, e thylhailthall, propylthismethyl, proplhailthayl, isopropylpropyl, methyl, isobutylthiomethyl, sec-butyl-isopropylthio, etc., carboxy-alkyl or carboxy-alkyl. krrboxymeeaylová, karboxχeaaχllvá _of jcarbzxypropylová, aarboxyisopropylová, karboxybutxlová, krrbzxyislbutylová, karazKy-see.butylová, methoxχl.aabzllnlmethhlová, tthoyykarbonylmetaylová, meehaoχlarbbonlethylová, propoxykarbonylmethylová, isopropoxyaarbonylmetaylová, ftyoyykarbonylmetaylová, ftУlxykarbznnletaylová, benzyloxycarbonylmethyl, benzyloxykarbzonlethylová p-hydroxybtnzyloxykrrboyylmeahylová, plmeaazxybetyylzxykarbznnlmetaylová, karboxymeeayloxykarbonylmetaχll> weighing group ^ d .)! similar groups.

In the general formulas I, II and III above, R 'represents an' amino group which may optionally be acetylated or protected. The acyl groups of the asylated and substituted amino groups are those which are the conventional acyl groups of the 6- or N-amino groups of known penile derivatives or of the corresponding phaloxy derivatives. Examples of the acyl group are

i) a group of formula F. R ⁵ -CO- (F) ^, wherein R ⁵ represents a lower alkyl or aettrocyclic ⁺ group,

(ii) a group of formula G

(G) in which R6 is hydrogen, an amino acid residue, an amino protecting group or 8 + 8 group of the formula R - (CH ₉₎ -C0-, wherein R is a heterocyclic group AZN ₂ is 0 to 2, and R ⁷ represents a lower alkyl, phenyl, heterocyclo-carbonylamino or heterocyclic group, iii) a group of the general formula H

11 wherein R is a group of the formula RC-, wherein II

N £ r ¹²

R is alkyl, heterocyclic or phenyl and R is hydrogen,

14 is a lower alkyl and lower alkenyl group or a group of the formula -R-R, wherein. R ¹³ represents a lower alkylene or lower alkenylene group and R ¹⁴ represents a phenyl group, a carboxyl group, an ester of a carboxyl group or a mono- or di- (lower alkyl) amino group, and

R ¹⁰ represents a bond or a group of formula -CO-NH-CH-, wherein R represents alkyl, L ¹⁵ is phenyl * or thiazolyl * group, iv) a group of the general formula I

wherein R ¹⁶ represents a hydroxyl group, a hydroxysulfonyloxy group, a carboxy group, an ureido * group, a sulfamoyl group, a sulfo group; phenoxy- ^T- carbonyl or formyloxy and R ¹⁷ represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group or a hydroxyl group,

(v) a group of formula J

R ¹⁸ - R ¹⁹ - CH ₂ - CO - (J) wherein R ⁸ represents cyano, phenyl *, phenoxy * -group, a lower alkyl * + +19, alkenylene or heterocyclic group and R represents a bond or a "S" group, and the like.

Alkyl, heterocyclic, alkoxy and halogen in the symbols

519

R @ 1 to R @ 2 denote the respective R groups above. The amino acid residues include, for example, glycyl, alanyl, valyl, leucyl, isoleucyl, seryl, threonyl, cysteinyl, cystyl, methionyl, alpha- or beta-asparagyl, alpha- or gamma- glutamyl, lysyl, arginyl, phenylalanyl, phenylglycyl, tyrosyl, histidyl, tryptophanyl, prolyl and the like groups.

Among the amino-protecting group include those groups which are listed below as an amine with a protecting group ^Y in ^the UPIN R. Alkylene quick match with the above ^h Oda ^Y alk represents lower alkylene group having 1-3 carbon atoms, straight chain or branched ·, ^y alkylene meth example, ethylene, prop ^y alkylene, isopropylene and the like ^y.

The alkenylene group is preferably a lower alkenylene group having 2 to 4 carbon atoms in the carbon or branched chain, such as vinylene, propenylene or the like. Carboxylic acid esters include lower alkyl esters of 1 to 6 carbon atoms in the above-mentioned alkyl moiety, such as, for example, methyl, ethyl, propyl, butyl, isobutyl, t-butyl butter, etc.

The substituents on the heterocyclic-phenyl *, thiazolyl ⁺ , phenoxy * -carbonyl and phenoxy * groups refer to those substituents on the heterocyclic * and aryl group as described above for R.

Naa! ^ ^ Substituent on the thiazolyl * nominal group ^E can be for example yt ^{b, p and} SKU acllaíinov ina 2 to 4 carbon atoms substituted by alkyl, alkoxy, halogen, hydroxy, amino or the like.

The substituent on the heterocyclic * group ^E can be e.g. yl ^{kl b} and d ^ n ^ alkyl group substituted by alkyl, alkoxy, halogen, nitro, amino etc. Among the substituents on the ureido ⁺ -group include sulpho group in the salt form with a suitable cation such as sodium or potassium cation, carbamoyl, sulfamoyl, amidine, C 1 -C 3 alkyl and the like.

Subbtituent to sulfamoyl groups napiríkáad * is lower alk ^{y k} u with nominal ^P inu having ¹ to 3 carbon atoms, amidino and the like. A substituent on a lower alkyl ⁺ group is, for example, a halogen atom, a hydroxyl group, a cyano group, a trifluoromethyl group and the like.

Subbtituent to alk * ^^ enoic group ^E represents ^a carbonyl ^plated napříkJad nominal ox ^y, k ^{y p} ANOVA and ODD ^B No SKUs in ^{p and y.}

911

The general formula R-C- for R is either the syn isomer of R-N

O 12

OR ^1Z or anti- ^soot

0-R

or their network.

A preferred group of SKUs ^p in formula G is the sku ina ^p of formula

- 8 wherein R ° is amino-protecting group ^P ins SKU or group obedného formula R - (CH ^) _n -L · 8 4 * L ^clay

-CO-, wherein R · represents a heterocyclic group, and n. Is 0 to 2, and ¹ + 4

R represents a phenyl or heterocyclic group.

Advantageous a radical of formula H is a group of formula R ¹¹ - C - CO - N 3 - ^R12

R ¹¹ represents a heterocyclic ⁺ or phenyl ⁺ group and wherein

R is hydrogen, loweralkyl or a group of formula -R 13 -R 14 _f 'wherein R is as defined above and R is a carboxyl group or esterffikvaanou kvrboxylovou.

A preferred group of groups of formula J is a group of formula

in which

R ^xo

R ¹⁹ is a heterocyclic ⁺ group and is as defined above, and the like.

As an acyl radical acyP ovvné-amine with ^the UPIN ^yp ro R separately from HL-EDIS ^ účinnooti is useful group of formula in which

Q is an amino or protected amine group and. . _v . .

Q 0 represents a lower alkyl group, a lower alkenyl group, a group of the formula -CHCOOQ ⁹ or CH _Q ² I ³ 9

- C - COOQ, ^CH 3 wherein COOQ represents a free or esterified carboxyl group.

Examples of the aforementioned R 5 -CO- acyl groups include 3- (2,6-dichlorophenyl) -methyl-methoxy-4-yl-carbonyl, 4-ethyl-2,3-diclohexyl-1-piperazicarbonyl in similar groups . ·

MEEI ^{EXAMPLE l} sliora ⁱⁱ LVD. Uve enýc ^{d h-voltage-acyl} groups ^generally formula R-NH-CH-CO- ^ ^p ^ t ^s i?

D-alanyl, benzyl-N-carbonylbenzzoxy-gamma-D-glutaayl-D-arynyl, D-phenylglycyl-D-allynyl, N-carbobenzoxi-D-alanyl, N-carbonylbenzyl-D-phenyglycyl, D-alynyl , gamma] D-glutamyl-D-aanynyl, 2- (4-ethoxy-2,3,3-dikXk-1-pPerazine-carbonylamino-2-phenylacetyl), 2- (4-ethyl-2,3-dicxo-1- N - (4-Ethyl-2,3-dicxo-1-β-azazicocarbonyl) -D-oxylic acid, N- (4-Zthyl-2,3-dithicoxyl) -2- (4-zincyl-2,3-dithioxy) -1-zPz ^e 2,2-bis- (4-ethyl-22, 2-amino-4-thiazolyl) -2- (4-β-1-yl) -2- (2-amino-4-thiazolyl) -2,2-bis- (4-chloro-2-carboxylic acid) 2- (4-Hydroxy-6-methylcyclohexylamino) -2-phenylcyclohexanedioic acid, 2- (4-hydroxy-6-methyl) -cyclohexanedioic acid; zetyl i ^ '^ i ^ i.kot: ^ r ^ v ^ md ^) -2- (4-hydrxxxfzknl) aceto hunting ^{and y, (3 and} krzχ l- ^{l p} i ^p zrvzin ^l l) -S ^ x ^ yr ^ o ^{[2, 3} '^"d J ^ r ^ ii ^ n - ^^ rboxamddk" fznχlacetylkvá 2-2 (3,5-dioxkkI 2,4-trvzzin6-iaidkxaémidk) -2- (4IУyddXkχliznl) 2- (3-furfurzznazinx-2-ox) 2-Imidazzidine-1-carboxylic acid-2-phenylactyl, 2- (kuzmaine-4-carbonyl) -12-zylacetyl-2- (4-hydroxy-1-methyl-1,8-naphthylidin-2-acyl-zinc) -2-phenylactylsulfonyl-2-zinc-2-ylzzinyl-2-carboxylic acid (4-OyldOkχ-11-tdifluoroZZl2cУinklikozziaarbkxazidk) -2-phenyllcyclyl, N-Q2- (2-aziknk44tOvcyl) acztyl] -D-phenynylgylcyl, 2- (6-bdkizk-4'kizk-4-kiz-4'k) _2,3-b ^y p rkdkn 3-kaibkx <amdd) "22fzkylacztllkvá, 2- (4-ethyl-2,3-L-IdikXk pPzeaziikkaadbxaazidk) -2

-thienylacetyl, 2- (4-pentyl-2,3-dioxo-1-piperazinocarboxanido) -22thienylacetyl _/ 2- (4-octyl-2,3-dioxo-1-piperazinocarboxamido) -2-thienylacetyl, 2- (42cyclohexxy- 2- [4- (2-phenylethyl) -2,3-dioxo-1-pipeaazioocarboximido] -2-thienylacetyl] -2- (3-methylsulphonyl) -2- (3-methylsulphonyl) -2- (3-methylsulphonyl) -2,3-dioxo-12-piperazinylcarbonyl) 22-Oxoimidazoidin-2-trifluoromethyl) 22-phenylacetyl / 2- (3-furfuraminamino-2-oxoimidoroline-1-carboxmino) -2-N-hydroxy-phenol-acetyl) 24 (4-ethyl-2,3,3-ynyl-11-piperazinocarbamoyl) -2- 2- (Methyl-2,3-dioxo212-piperazinecarboxamido) 12- (4-methoxyphenyl) acetyl] -2- (8-hydroxydiphenyl-72-carboxamide) -phenylacetyl] -2- (4-methoxyl) acetyl] -2- (4-methoxysyl) acetamide; 2-Isopropylphenyl / 2 '- (- 2-amino-42-tetrahydro-1'-pyrrolidin-4-yl) -diphenyl and the like.

Examples of the aforementioned acyl groups of the formula R ⁹ -R ¹⁰ -CO- include N- (2 (- (4-isopropylphenyl) thiazolyl) -1-meth (methoxydopolyacetyl) -Da-4-yl) - N- (2- (2-amisylphenyl) thienyl) -1 4-Methoxyiminooactyl] -D-phenylglycyl- [2- (2-imidazol-4-ylthiazolyl)] - [2- (2-amino-4-tetrazolyl) -1-methoxyethoxy] imidazole-acetoxy] - (2-nitro-acptothiazole-4-thiazole) -) - 1-Methyl-amino-acyl / 2- (2-pyrimidinyl-4-thiazolyl) -1-2-methoxy-amino-acetynyl / 2- (2-pyrimidinyl-thiazolyl) -2-ethoxyiminoacetyl /

2- (2-Amino-4-thiophenol) -2-propynyliminoacetyl / 2- (2-piperidio-thiazolyl) -2-butoyylminoacetyl / 2- (2-amipno-4-thiaanlyl) -2-bedzyloxyiminoacetyl / 2- (2-aminoimido) -4- (2-Amino-4-thiazolyl) -2-l (1-methyl-1-carboxyphthyl) oxyimino] acetyl

2- (2-Amino-4-thiaanil-2- (11-methyl-1-methoxycarbonylettyl) oxyimino] acetyl) - 2- (1-amino-24-thiophenyl) -22carbophthyloxyimineacetyl, 2- (2-amipno-2-haloalinyl) -2-carboxycinyl [2- (2-Amino-12-ctoo-4-thiazololyl-1-methoximinoactyl), 2- (1-amino-5-bromo-24-yl) -2-methoxyimidyl] ethyl] -2- (2-aisilyl) -4-thiaminoolyl (2-10-acetyl) -2-oxo (2-oxo) amino 2-thienyl-2-thienyl-2-methoxy (2-thienyl-2-methoxyl) (2-thienyl-2-methoxyphenyl) -2-thienyl-2-thienyl (2-thienyl-2-methoxyl) - 2- (1,2,4-triazolol-5-yl) -1-methoxyimininoacetyl / 2- (13,4-thiazolyl) -2-methoxyethoxyacetyl / 2- (4-hydroxyphenyl) thiadiazole-33-yl-2-methoxyiminoacetyl (2-Methoxyiminoacetyl) - (phenyl-2-methoxyfimidoacetyl) - (2-phenyl-oxyiminoacetyl) -2- (4-amino-3-aminoiminoacetyl) -2- (4- (3-amino-3-carboxyyionin)) -enf] 222O2y2iminoactyl and similar groups.

They have examples of the above acyl groups of the general formula

CH — CO - belongs

alpha-sulfophenylphenyl (alpha-hydroxyphenylacetyl) (alpha-phenylacetyl (alpha-phenylamino) phenyloxy (phenylamino) phenylamino) phenylamino (phenyloxy) phenylamino (phenyloxy) phenylamino (phenyloxy) phenylamino (phenyloxy) phenylamino (phenyloxy) phenyloxy (phenyloxy) phenylamino (phenyloxy) phenylamino (phenyloxy) phenylamino (phenyloxy) phenyl)

19 Dec

Examples of the above-mentioned acyl groups of the general formula R-R-CH 2 CO- include Oyanonactyl (phenylacetyl) phenoxyaactyl, trifluoromethylthiomethylpentyl (1 H -tetraolyl-acetylphenyl) thiophenyl (thiophenyl) thiophenyl (thiophenyl) thiophenyl] thiophenyl (thiophenyl) thiophenyl (thienyl) thiophenyl (thiophenyl) thiophenyl (thiophenyl) thiophenyl] 2- (2-aminonithylphenyl) acetyl and the like groups (3-5-dihydro-4-oxo-pyridin-1-acetyl) -tetraacetyl (2- (2-aminonithylphenyl) acetyl) and the like.

The amino / carboxyl and / or thynyl group in the above examples of acyl groups may be protected with a protecting group. The amino protecting groups are those protecting groups (which are described below as amino protecting groups).

The carboxyl or hydroxyl protecting groups are tf protecting groups (as described above for R).

Like protecting! sku ^PP n ^y amine of ^the u ^p in u · R @ ¹ дорНдо ^ may be c ^h EAN ^{currency /} lae suitably be any protecting group of amine groups / that for this purpose, P ^ T ^ u ^ i ^ i ^ They are useful in the field of beta-rakrames or in peptide synthesis.

Examples of such amine protecting groups include, for example, acyl groups such as phthaloyl, p-nitrile-enzoyl, p-nitrile, p-nitro, p-nitro, p-tert. benzenesulfonyl, oenzesulfonyl, toluzsulfonyl, etc., aliphatic acyl groups, such as, for example, formyl, acetyl, propionyl, mono-chloro-aryl, dichloroacetyl, trichroraintyl, menhatsulfonyl, n-sulfenesulfinyl, n-sulfenesulfonyl, n-sulfenesulfonyl, n-sulfenesulfonyl, n-sulfenesulfonyl, n-sulfenesulfonyl, n-sulfenesulfonyl, n-sulfenesulfonyl, n _- sulfenesulfonyl; , nstnriiirvvasé carboxyl groups, nes nappíklad meZhoxykarbonylová, nthoxykarbonylová, tnrc.butoxykarbonylová, isořrr> řoxykarobnylová 2-kytnoethrxykarbonylová, beta, beta-Oett trίchrrnttrχyykarbrnylrvá, Oeta-trienhУ1lti1yletr © 1ytarbonylrvá, beta-mentylsulfosylnthoxyktrbrnylová, Onnzyloxyktrbonylrvá p-nitrobenzyroxykaroOn1lová, p- eethoxybonsyloxycarbonyl, di.nenylenethylmethylcarbonyl, eenhoxymethyloxycarbonyl, acetylmethyloxycarbonyl, i a silynyloxycarbonyl, phenylcarbonyl, etc., naphthyl amino protecting groups, such as, for example, triethylamino, benzylidene, 4-sitobenzylidene, trityl nitrosyl, benzylsilyl, benzylsilyl, benzylsilyl, benzylsilyl, benzylsilyl, benzylsilyl, benzylsilyl, benzylsilyl, benzylsilyl, benzylsilyl, benzylsilyl, benzylsilyl, benzylsilyl, benzylsilyl, benzylsilyl, benzylsilyl, benzylsilyl, benzylsilyl, benzylsilyl, benzylsilyl, benzylsilyl, benzyl. etc. The choice of an amino protecting group is not critical for the present invention.

Syrnl ^ L and R / ^R JTA Muto vn ^ SJ-ou Nina otecnéto vzorcn I ^h oto podln it in álnzu ^ o ^ l-Aho Sult group nnbo carboxyl group or carboxyl groups MV free state. Such a group may nnbo groups n ^ ^ sLst ovata also salt with a nontoxic cation microns, nappíklad sodium drasnlným etc., basic tminorkluninou, 'nappíklad arginine ornithnnem, lysine his.tdinnem etc., of ^the lyhldroxltlkytamSnem, e.g. N methylguucosamine, dinthanotamine, tritonotine, trSdroxyroxynehlylInSoomehtane, etc., or the like.

If R 1 and / or R ¹ contain a basic group, the compound of general formula I may also be a salt with an organic acid such as acetic, tartaric, methanesulfonic, etc., with an inorganic acid, e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc., with an acidic amino acid such as paraffinic acid, gluaamic acid, etc., or the like.

Jesslie R and / or R1 contain a carboxyl group, then it can be transferred to a corresponding biologically active nursery denivative which contributes to blood concentration enhancement and prolongation of efficacy in vivo.

Mineral groups which are effective in this manner are, for example, N, N-xyl-1-thienyl-thiomethyl groups (e.g., alRoxymethyl or alpha-alroxynthyl, such as, for example, mennaphenyl, n-oxenethyl, alpha-propoxymethoxy). ehlioxinthylová group etc.) tlkylУhroentУllové groups such manufacture nappíklad eentΊyltУireetУylrvá, nthylthroenhhylrvá, itopprpylУhroentУ1lová group etc., acyloximethylové nnbo tlft-ti1lrx1-altasjuOsУtΛrvvané menhylové groups such manufacture nappíklad pivalr1loxyeenhy1rvá, -tlfa-acnУrx1Out1lová group etc., tlft-tlkrx1ktpOonn1ory1atft-tubotituované menhylové groups, such as, for example, n-methoxycarbnyl-trimethyl, alpha-methoxycarbonyl-1-alkoxyethyl, etc., and the like.

The compound of the formula I according to the invention may be present as various atomic isomers (e.g. cis, trans, syn, anni and optically active compounds) as in the case of the above-mentioned starting compound of formula II.

This is to be understood as meaning that it covers the individual isomers and their vision. These isomers can be used as a drug either as a drug or as a drug.

The spherical isomer of the formula I according to the invention can be described, for example, by the formula:

wherein R, R ¹ (beta-configuration) and X (alpha-configuration) are as previously defined and the wavy line represents the trans or cis configuration of the R group to the RR group at the 3-position.

Compounds of Formula I of this invention include Compounds No. 1 to 58 below:

Compound

CICHjCONH

-COOCH3

CONH—

-COOCH3

CICH2CONH

CONH -

-CH ₂ OCOCH _h

OCH3

C Tj_ | l / -CONH- II ^N \ _OCH3 H -CH ₂ OCOCH ₃ —CH2OCONH- H N — N ^CH 2 ^S ЛД I

CH3 continued table

Compound ^R 1 X R cich ₂ conh ₄ 6 N — 1L / CONH- c II N CHjO '' '' H -cooch ₃

—Ch ₂ conh-

ch ₂ conh-

n_c, H _Q _N NCONHCHCONH - N NCONHCHCONH.n ó

H -COOCH2

H -COOCH ₃

H -CH ₂ NHCOCH ₃

H -COOCH ₃

H -COOCH ₃

H -COOCH ₃

H -COOCH ₃

X R table continuation

Compound

-och ₃

-COOCH ₃ . -COOC ₂ H ₅ c ₂ h ₅ -n nconhchconhH oo

-COOC ₄ H ₉ (n) ^c 2H ₅ -n "nCONHCHCONHH oo

H -COOH

H -COOCH ₃

CONH -

H -COOCH ₃

Compound

X

R continued table

21 nl | CONH-II N CHo \ I 3 ^ oc — CO2H OH ₃ H -COOCH3

22nd Ύ1 ^ CONH- H - ^ ₅ CJOC2H Íí N \ qch ₃

CONH -

H -COOC ^ H ^ o)

II ^ OCH ₃

24 ^H 2 * _with N__Q CONH - H N-N-CH ₂ S- ^ _N x ^N II N 1 CH ₃ ^ OCHj

25 ^H2N ^ s Ύ-Χ ^ C ^ CONH- H 26 ^h * ⁿ в> N__Π CONH I H -COOCH3 1 NHCONH2

continued table

Compound

CONHOCH ₃

H -COOCH ₃ ' ^CH 3

X

R continued table

Compound

-CH ₂ CH

H-boy ₃

CONH-

H-CH ₂ COOCH ₃ ^NH 2

H -COOCH ₃

CONHOCH ₃

H -COOH

H-CH ₂ NH ₂

H -CH ₂ OH continued table

Compound

h ₂ n

H -CH ₂ OCH ₃

^H 2 ^N \ S Yn ii Νχ ^х оен ₃ H: -CONH2

h ₂ n ^ Й-JL / ^CONH II N ^ OC ^ COOH H -COOCH3

/ CONHC <!! ^V 3 ^X OC-COOH

H -CONH ₂

CH3

N - O - C - COOH I CH3

-OCH 3 -CONH 2

CONH-

H CH2N3

O-C-COOH I CH3 continued table

Compound ^R 1 X R ^H 2 ^N ₄ S ₄ y 1 / CONH- 47 n γ ^Η 3 \ о ^- с-соон 1 H -CH2OCH ₃ ^сн з XL ^ C ^ -C ONH- Ά _C-OC ^H 3-COOH 48 H -C ^ CC ^ ^ OCON ^ | CH3 Her _from COI ^ l · ^ - r * 49 3 Ac ch ₃ ScCcOOOH I H -ch ₂ oh 1 CH3 50 ^H 2 ” _S Y ^with i ^ CONH- H -CH (CH 3) ₂ C N

XOCHjCOOH

Ύ1 _Z CONH- 51 in II \ CH ^{3 x} c> ³ ° C — COOH | H -CH2OCOCH3 CH3

continued table

Compound ^R 1 i

^H2N ^ s Ύ 11 _/ CONH— 52 C Л CH ₃ \ ¹³ OC-COOH H -CH ₂ NHCOCH ₃ | CH ₃ N --- 0-- CONH— / • c 53 II \ ₀ CH ₃ H -CH ₂ CONHCH ₃ ^OO С — COOH <:: h ₃ 'vs AT_ CONH- ^Ν \ _Λ 0 1 CH ₃ COOCH ₃ C 54 H -COOCH ₃ CH ₃ 55 «2 ^ 5. Xl_ CONH - c ^x II \ CH ₃ OJ C - COOC ₂ H _S H -COOCH ₃ CH ₃ 56 ^H 2 ^N ϊζ / ⁰ · 1 H -CONH ₂ NHCOCH3 57 XL C CONHII H -conh ₂

continued table

Compound

C-CONHII

CH N \ I ^J-COOH, OC

-CH ₂ CONH ₂

AND

CH3

Among other things, a preferred compound of the compounds of formula (I) of this invention may be a compound of formula (I)

in which

Q ^3, Q ^4, Q? Q ⁸ -a waves ^k and denote ^as above, or a salt or ester thereof. If Q in the above formula is an amino group, then this compound may form an inner salt with an amino group QQ and a sulfo group at the 1-position.

The compound of the formula I according to the invention and its salts or esters are valuable annibiotics effective for various gram-positive or gram-negative bacteria. They are used in the form of medicaments in humans or dommy animals as safe antipicrobial agents in the treatment of infections caused by grapho-positive or grappling bacteria.

In addition, the agents of the invention are used to add to the daily rations of animals as a diluent and protective food. Annibiotics can also be used in the form of aqueous compositions with a concentration of 0.1-100 ppm (i.e. 0.1-100 parts annibiotics per million parts of solution) as annipicrobial agents that kill harmful bacteria or prevent their growth, for example on medical or dental devices or in industrial aqueous media such as aqueous paints or white water passed through a paper mill.

The compounds of formula (I) and salts or esters thereof may be viewed alone or in combination with one or more other active ingredients in a variety of pharmacopoeia compositions such as capsules, tablets, powders, solutions, suspensions and elixirs. These compositions may be administered orally, italy, or ittraputculature.

Tablets for oral administration may contain conventional excipients such as binding agents such as syrup, gum arabic, gelatin, soobitol, tragacanth or o- ^{o in} itylOУJrroHon, foaming agents such as lactose and other sugars, corn starch, calcium phosphate, soobitol, or glycine, such as magnesium stearate, talc, ooyl ethyl glycol or quartz oxide, desitigating agents such as potato starch, or available buffering agents such as sodium larylsulphate.

The tablets may be coated in a manner well known to those skilled in the art. Liquid compositions which are intended for oral administration may exist in such dosage forms as aqueous or oily suspensions, solutions, emulsions, syrups, elixirs, etc., or as lyophilisates for possible dissolution in water or in a suitable solvent.

Such liquid compositions may contain suspending agents such as sorbitol syrup, methylcellulose, glucose / sugar syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose or aluminum stearate gel, hydrogenated edible oil such as almond oil, coconut oil fractions, oily esters, propylene glycol or ethyl alcohol, or preservatives such as methyl or propyl p-hydroxybenzoic acid or sorbovoy acid.

Suppositories may contain a conventional suppository base such as cocoa butter or other glycerides.

Formulations in the form of injectables may be prepared in ampoules or other unit dose containers, with the addition of preservatives. Such compositions may exist in such dosage forms as, for example, suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain a suitable adjuvant or adjuvants, such as a suspending agent, a stabilizer and / or a dispersing agent.

The active ingredient may also be in powder form, which may be formulated with a suitable solvent or sterile pyrogen-free water prior to use.

The active ingredient can also be formulated in suitable dosage forms absorbable by the mucous membranes of the nose and throat or bronchial tissues, e.g., powders, liquid nebulizers or inhalants, lozenges, compositions used to wipe the mucous membranes of the throat, etc. For ophthalmological or otological applications, administered as liquids or semi-solids or as drip drops.

In addition, they may be formulated together with hydrophobic pharmaceutical bases in such dosage forms as ointments, creams, lotions, lotions, powders, etc., which are pharmaceutical compositions for external application.

In addition to carriers, these compositions may contain other ingredients, such as stabilizers, binders, antioxidants, preservatives, lubricants, suspending agents, rheological agents, or fragrance delivery agents. In addition, other active ingredient (s) may be included in the composition to provide a broader antimicrobial spectrum.

For administration to domestic animals, the active ingredient of the invention may be formulated with an agent that causes slow release of the active ingredient. This provides slow release agents (i.e., agents that slowly release the active ingredient).

The compounds of formula (I) of this invention can be applied to mammals as therapeutic agents useful against microbial infection in the treatment of, for example, airway, urinary tract, purulent infections, bile duct infections, intestinal infections, gynecological infections, surgical infections, etc.

The daily dose depends on the condition of the patient to be treated, the weight of the patient, the route of administration and the frequency of administration, and in particular whether it is a parenteral route of administration which is generally suitable for infection or an oral route of administration. infections.

The oral daily dose is generally an amount of about 15 to 600 mg of active ingredient per kg body weight of the patient administered in one or more doses. A suitable daily dosage for neoral administration to adult patients is about 10 to about 200 mg of active ingredient per kg body weight. This amount is preferably administered in 2 to 4 doses of about 2.5 to 100 mg / kg.

9

A pharmaceutical composition comprising a compound of Formula I may be administered, for example, in various solid or liquid orally administered unit doses. The liquid or solid composition may contain 0.5 to 99% of the active ingredient. A preferred concentration of active ingredient is about 10 to about 60%.

Usually, it is preferred to use unit doses containing about a component

250 and each unit dose. 000 mg of active ingredient.

In addition to the above uses, the compounds of formula (I), salts and esters thereof may be used in combination with beta-1-acarnate antibiotics because of their efficacy in inhibiting beta-lactase. Examples of beta-aa aamových ^to antibiotics include penicillin antibiotics such as bennylpeencčlin, fenoxyyethhlpeeňcciin, karbbencciin and ^ mpici .in ^ and ^ oxiici.in, sulbenicčlin etc., cephalosporin antibiotics such as cephaloridine, cephalothin, cefazolin, cefalexin, cefoxitin, cefaaceril, cefamandole, cefmenoxin, cefsulodin, cefotiam, cefotaxio, cefapprin, ceftizoxime, cefradine, etc., etc.

The cephalogycin 1-sulfo-2-oxoazrtidine derivatives of formula I, which are compounds of the invention, can be prepared, for example, by sulfonation of a compound of formula II.

by tohotc

II can be used as the starting material with various acids or bases, in the form of esters or a silyl compound of the invention in the form of a salt with its derivatives. The compound of formula (II) includes cis and trans isomers because it has substituents at the 3- and 4- positions. Furthermore, since carbon atoms 3 and 4 are asymmetric, at least four stereoisomers exist.

method according to

These may be stereoioomery pužívány Buo samootatně or smsi .. This is where the group ^R or ^{R1 is H,} U is contained as methyl ^y ric ^{e to} y carbon in ^the coal; results obtained by ^{n e} ^ = OMe stereo also used either alone or in smsi ,.

Also the case may ^b YT

The salts and esters of the compound of formula II are used. such salts and esters, examples of which are given above for formula I, etc. A compound of formula II may also stylish forces ^y aačním agent. The silylating agent may be a compound of formula

3 p- ^ pp ^ Si.Hal

3 wherein P, P and P are a hydrocarbon group such as a lower alkyl group having 1 to 4 carbon atoms (for example methyl, ethyl, propyl, isopropyl, butyl, etc.), an aryl group (for example phenyl, tolyl, etc.) .) or groups and

Hal represents a halogen atom, preferably a chlorine or bromine atom, wherein one

3 of P, P and P can be halogen, preferably chlorine

3 and one of the substituents P, P and P 1 may be hexa-alkyl (C 1 -C 4 -cyclotetrasilazane, trialkyls C 1 -C 4) of slylaceo-azide.

like or two or bromine may be hydrogen. As Sipi reagent ^R-CUC atoms) ccllPOtisPl-Zn oktaalkyl (having 1 to 4 carbon atoms) carbon atoms, l) sllyaace ^AOI-d and bis-tri-alkyl having 1 to

A preferred compound is a compound of the formula wherein Y is a reactive group that is released from the silyl compound,

2

Y and Y respectively represent a lower alkyl group having 1 to 4 carbon atoms, a phenyl, benzyl or lower alkoxy group having 1 to 4 carbon atoms, and

Y stands for tert-butylated roboisopir <pj-y l ^ ovct group ...

2

Lower alkyl groups Y and Y may be methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like. As examples lower alkoxy

The 2 groups Y and Y may be mentioned as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy and the like.

As examples of a reactive group which is formed from a silyl group. The compound releases, for example, a halogen atom (e.g., chlorine, bromine), N- (triethylsilyl) trillactaacetadiolioxy groups. N- (tricycylsilyl) ecimimiltyl oxyl, acylamino, such as formylamino, acetylamino, propionylamino, butylylamino or trifluoroacetyl amino, (alkylsilyldimino) such as tertiaryl dimethylthiomethyl amide; or a (chloromethyldimethylyl) amino group, an amino group, an alkylamino group such as a methylamine, an ethylamine or a propylamine group, an N _/ N-diazolyl-amino group such as a Ν, Ν-dimethylamine, N-chloromethyl-N-methimide; a laminy, N, N-diththamine, N, N-dipropylaein, N-mehht-N-ethylamine, N-meheh-N-pcopylaein or N-ethene-1-propilinine, or heterocyclic group such as, for example, imidazolyl group.

The alkyl group in the aforementioned reactive group is preferably a C 1 -C 4 alkyl group, such as methyl, ethyl, propyl, isopropyl, butyl, and the like. tec.butyl group. Specific examples of the compounds described above are

Ν, Ο-bis (ttr.-butyldimethllsSltl) thiifluoactelamide, Ν, Ο-bis (itoproppldieeehpliSitl) acetamide, bis (di ^- teethplisopropil) cceaamide, ltlprlppldieeehplsilylacetleid, bis (dime) ily, bis (dime. methp1-N-ttbutylbutylplaceaamide, N-methpliN-sooPoopliimeehpl1S is triflooacteaamide, N-tert-butyldeplPlPl-1,3-bis (εΙΙΙι θθ ^θ)! -1,1,3,3-tet! atcc.buttldimttlyldisilazane, N - isoproopdimethylmethylsilylimidolzole, tecc.bu ttififenticpllrsillr, isopaoopliiethllchlolsilane, itpropplmethpldicClolcSlln, tecc.buu isoprlppldimethyltlcllflldl, or tlclflldlflcdl, or tlcpllflldlfllflcdlllflcdlflflflfldlflflflflflflflflflflflflflflflflflflflflflflflflflflfllflfllflfllflfllflfllflfllflfllflfllflfllfllflfllflfllfllflflflfll from.

Preferred compounds are tert-butyl-dimethyl-chlorosilane or isopropylcopyldimethyl-chlorosilane. The siltlation reaction is carried out in a conventional manner. Jt silpkce reaction temperature of about 0 ^{to 5} with 0 above ou ^h o ^{d y} SSI nt ^nt usually ³ θ t ^ e ^pl ^ ot ^ i and místnoo ^{(about 20} ° C). ^R eakční time from JT minutes (about 10 minutes) until about 24 hours. The treatment is preferably carried out, for example, in ethyl acetate, dioxane, tetrahydrofuran, N, N-dimethylacetamide, N, N-dimethptiormamide, dichloromethane, chloroform, benzene, toluene, acetone, methylthylketine or methyl ether, in any of their solvents or mixtures thereof. inert to this treatment.

The treatment can also be carried out in the presence of inorganic bases such as sodium hydroxide, potassium hydroxide, sodium pyrogen carbonate, sodium carbonate or potassium carbonate, trothylamines, such as tephylamine or trumpet, e.g. trbtenzylamin, an organic tertiary amine, such as N-meetihlmolfi> lin methplpPpptCdin-N, N, N-dbaliоlaailii, N, N-dialOtlbenztiaebn, pyridine, picoline or N-di-lub or or anic ^{g о} Yc ^p. Base Jato JT napi ítoad ^ ^^^ ^ to ^ ic lo β ^2,2, 2, ² of ^the tan or ^{1, 8-lb'diaza} cyt ^о ol, 5, ^4.4].

If the base is capaine, it can also be used as a solvent. The resulting derivative of the compound of formula (II) can be used as the starting material in the sulfonation reaction, either as a reaction mixture or as a solution. or purification in a conventional manner as follows.

Sulfonation is a treatment in which a sulfo group is introduced into position 1 of the compound of formula II. The sulfonation is carried out by treating a compound of formula II with, for example, sulfur trioxide or a reactive derivative thereof. The editorial sulfur trioxide derivative is, for example, its adducts, such as sulfur trioxide-base adduct (e.g. sulfur trioxide-pyrine, sulfur trioxide triethylamine, sulfur trioxide, sulfur trioxide). lutidine, etc.), sulfur trioxide, ethy-ethylene chloride, sulfur trioxide, sulfur trioxide, sulfuric acid and the like.

In this reaction, about 1 to 10 moles, preferably about 1 to 5 moles, of sulfur trioxide or a reactive derivative thereof are used per mole of the compound of formula (II). The reaction temperature is about -78 to ⁸⁰ ° C, preferably about -20 to ⁶⁰ ° C. ^R ESPONDING i.ze Rovai ^{p d p} ive out of five for říoomnooti rozpouStádia. In this case, conventional organic solvents including water, ethers such as dioxane, tetrahydrofuran, diethyl ether, etc., esters such as ethyl acetate, ethyl formate etc., halogenated hydrocarbons such as chloroform, chloroethane etc., hydrocarbons such as is, for example, benzene, toluene, hexane, etc., amides such as N 2 N -dimethyloormamide, Ν, lay-diethylayetaid, and the like, either alone or as a mixture. .

The treatment is usually completed in a few minutes to hours, which depends on the type of starting compound (II) used, the suloonating agent, the reaction temperature and the solvent; in some cases, however, it takes days to complete the reaction.

Upon completion of the work-up, the reaction mixture is subjected to suitable purification and separation methods which are generally known, such as solvent extraction, revitalization, chromatography or the like.

Thus, the desired compound of formula I is produced in any purity.

The compound of the formula I according to the invention can also be produced by acylation of the compound of the formula III

From ₀ to ₃ ^N h in which R and X ^ ZNV menj.í as above.

The acylation according to this procedure is carried out by adding 1 mol of the compound of the general formula

III (its various salts, esters or silyo derivatives) is treated with at least 1 mole, preferably 1 to 2 to 4 moles of acylating agent. Acylvčním agent that PPI used in this reaction may be ud ^b or ^g ^ anicka Vrtoxy weighing к. ^y se ^l ina ^, Vera. a ^b svhuje acyl sVpinu in ^{R1 [R} c ^COO H, wherein R ° CO is an acyl sJcupinu mentioned above as acyl slcupina ayylooan ^{é amines} for ^at pin ^Y u R J / ^thereof, or a reactive ^d Eriva ^s t n ^to r ^b ox ^y nominal group

Among the reactive derivatives of organic carboxylic acids. include, but are not limited to, acidic acid anhydrides, active amides, active esters, etc. Examples of such reactive derivatives are given below:

1. Acid anhhydes:

Methic acid anhydrides include, for example, mixed anhydrides with acid halide (e.g., hydrochloric acid, hydrobromic acid, etc.), carboxylic acid, carboxylic acid (e.g., acetic acid, pivalic acid). with aromatic carboxylic acid (e.g. benzoic acid, etc.) as well as synmeric acid anhydrides.

2. Active amides:

Active amides include, for example, amides with pyrazole, iodazole, 4-substituted iidazole, dimethylpyrazole, benzooriazoe, and the like.

3. Active esters:

Other active esters include, for example, such esters as methyl, ethyl, methoxymethyl, propagyl, 4-nitroethyl, 2,4-detrolines, trichlorophenyl, pennaadoophenyl, and ethyl etherol-tsttr as well as the esters of the aforementioned carboxylic acids. thyseine with 1-hydroxy-1H-2 H -pyridone, 1-hydroxysuccinimide and 1-hydroxyphthalimium or the like. |

The selection of the reactive organic carboxylic acid derivative depends on the acid used. If the acylating agent used is free carboxylic acid, the treatment is preferably carried out at a condensation level. The condensation reagent is used

i is I, N ' -actylxyltjriodiimii.

1-Cyclohetyl-N'-Inododiphethylethylbromodiamine, 1-Cytodetyl-N '- (4-riththylamino-cyclohexylcarbonyl), 1-ethyl-1' - (3-di-thiomethylpropyl) carbonyl and the like.

The acylation is usually carried out in a solvent. The solvent may be water, acetone, dioxane, iodine, sodium chloride, chloroform, rich diethane, tetrahydrofuran, ethyl acetate, N, N-dimethyldormamir, N-N, N-pyrimidine or other suitable organic solvents. Of these solvents, the hydrophilic solvents may be used in combination with water.

The alkali metal carbonate, triethylamine (e.g. triethylamine, triethylamine, triethylamine, triethylamine), e.g. rniUthylmrfooin, 11Пп111У1 ^ 11 ^ 6 ^ 12.Г:. ^ о etc.), I, N-dialiphanyl, N, N-octylberlzylamio, pyridine, picoline, lutim,¹, S-diazabicy ^ o [4,3, o] nonane '^{5 d}tn^{, 1}, ^^ zabic ^ klo [2-2-²] d^ttao^{, 1}, 8-diazabicylo β⁵, 4,4j шпГ1О1п-7 - etc. ’

The liquid bases and liquid condensation agents mentioned above may also serve as solvents. The reaction temperature is not critical. The treatment is carried out with cooling to room temperature. Processing is complete within minutes to hours. The resulting compound of formula (I) may be isolated and prepared in a manner known per se, such as thickening, deposition of an acidic liquid medium or naphtha, solvent change, solvent extraction, crystallization, recrystallization, fractional fractionation, chroimtool, and the like.

If the starting compound of formula (III) or a salt thereof and / or the acylating agent used in the acylation contains asymmetric carbon, either the self-rotating stereoisomers or a mixture thereof may be used.

If two or more redisomeric products are formed during acylation, then the individual isomers can be isolated, if necessary, in a conventional manner, such as by column chromatography, crystallization or the like.

The R group of a compound of formula (I) of the present invention can be converted to another group, wherein the compound of formula (I) retains the 1-sulfo group. This leads to the production of another compound of the invention. ,

If oappitlar R is acetoxymethyl, meehaansШldoyldxymethyl, iodomethyl or the like, it can be converted by reaction with an oukleophaticioio into the desired^withkupi^nu. Like nužtetdllo^and ^ niTlo can be used^žt strained^d jl^tyl^{+ d}t^hΠO^lč, aryl^{+ d}t^hidly^, ^ tero cycle ^ th ^! ' ^ r ^ in 'and after^rref^and ^ n ^ l ^

There is thus obtained compounds of the formula I according to the invention in which R represents a substituted thiomethyl, quaternary ammonium ⁺ -methyl or the like. Alkyl ^+, aryl ^{and +, +} and heterocykli.cká kvaa ^ rnzí AMC> piperidinium ^{A +} S ^for oup in -the following-on-nucleophilic nírh čzLniXl-all means as above.

The treatment is preferably carried out in an aqueous solution or in a water-miscible solvent, such as acetone, acetonitrile, N, N-dimethylaminamide or the like, or in a mixture of water and a water-miscible solvent.

In some cases, it is beneficial to add a base such as an alkali metal carbonate, an alkali metal phosphate or the like. The processing is conducted usually at te ^{pl rt H} c ranging from ² 0 to 100 ° C. The resulting compound of formula (I) may be cycled and purified in a manner known per se, as in the case of compounds prepared by drying or acetylation.

If the compound of formula (I) thus produced carries a protecting group, then, if desired, the group may be removed. Such a protecting group may be removed by conventional means, such as by using an acid, base or hydrazine, reduction, a method employing an irinhalogenating agent, followed by an imine contaminating agent and, if necessary, hydrolysis.

Whether or not this method is used depends on the type of protecting group to be removed. If the protecting group is removed by the action of an acid, then inorganic acids such as. for example, hydrochloric acid, sulfuric acid, phosphoric acid, etc., and organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, benzene sulphonic acid, pentene sulphonic acid, etc., as well as acidic inverters.

The choice of acid depends on the type of protecting group and other conditions. If the protecting group is removed by treatment with a base, inorganic bases such as alkali metals (e.g., sodium, potassium, etc.), caustic earth metals (e.g., calcium, magnesium, etc.), hydroxides, carbonates, etc. are offered as bases. and organic bases such as metal alkoxide, organic amine, quaternary ammonium salt, etc., as well as basic ion exchangers.

The choice of base depends on the type of protecting group and other conditions.

When the protecting group is removed by treatment with an acid or a base in a solvent, the solvent is generally an organic solvent, water or a mixture of solvents.

If the protecting group is removed by reduction, for example, reduction by metals such as tin and zinc or by metal compounds such as chromate chloride or stannous acetate and by an organic or inorganic acid such as acetic acid, propionic acid or hydrochloric acid is used. , catalytic reduction in the presence of metal hydrogenation catalysts or the like, depending on the type of protecting group and other conditions.

Catalysts offered in the catalytic reduction include, for example, platinum catalysts such as platinum wire, sponge platinum, platinum black, platinum oxide, colloidal platinum, etc., palladium catalysts such as sponge palladium, palladium black, palladium oxide, palladium on cuprous sulfur, palladium on cuprous palladium on carbon, palladium on silica gel, colloidal palladium etc., nickel catalysts such as reduced nickel, nickel oxide, Raney nickel, Urushihar nickel, etc., and the like catalysts.

In metal and acid reduction, metals such as iron, chromium or potassium, and inorganic acids such as formic, acetic or porpionic acid are used as metal compounds. Removal of the protecting group by reduction is usually carried out in a solvent. Solvents commonly used in catalytic reduction include, for example, alcohols such as methanol, ethanol, isopropanol, propanol, etc., ethyl acetate and the like.

The metal and acid reduction is preferably carried out in water, acetone or the like; if the acid is liquid, it can itself serve as a solvent.

Depending on the processes in which the acid, base or reduction is used, the treatment is usually carried out with cooling and with heating.

Jessieie is deprotected by treatment with amino halogenating reagent, then with an anti-diphtheria reagent, and, if necessary, the following hyaluronating agents, such as, for example, sodium chloride, e.g. phosphorus pentachloride, phosphorus tribromide, phosphorus oxychloride, thilyl chloride, phosgene etc.

The reaction temperature is not ηΣί ^^ Ιοί; the reaction is usually carried out at temperatures ranging from room temperature to temperatures obtained by cooling. The resulting reaction product is then treated with an iminoetheziftant, alcohols and metal altoxides. The alcohols are steamed with alkanols, such as methanol, ethanol, propyl alcohol, butyl alcohol, methyl alcohol, methyl alcohol, ethanol, ethanol, ethyl alcohol, ethyl alcohol, ethyl alcohol, ethyl alcohol, ethyl alcohol, ethyl alcohol, ethyl alcohol, ethyl alcohol, ethanol, ethanol, ethyl alcohol. etc., as well as those compounds in which the alkyl group of said alcohols is substituted with alkoxy groups, such as, for example, methoxy, ethoxy, propoxy, isopropyl, butoxy or the like.

Metallic altoxides are steam metal alkoxides, such as sodium alkoxide, potassium alkoxide, etc., and alkaline earth metal alkoxides, such as calcium altoxide, basal alkoxide and the like, which are derived from the aforementioned alcohols.

The protecting group is a residual organic acid, and if a free amino, hydroxyl, mercapto, carboxyl or sulfo group is attached to the carbon atom adjacent to the carboxyl group of the carboxyl residue, it is preferred to carry out the pretreatment which results in As the substituents on the carbon atom adjacent to the carbonyl of the carboxyl are increased, the reactants and carbonyl groups are increased before the reaction is carried out to remove the protecting group.

This will, for example, be the case where the substituent on the carbon atom adjacent to the carbonyl group is a free amine group. In such a case, the protecting group may be modified by converting the amine group into a trisdicocin followed by deacylation, or in any case by any known method of cleavage of the peptide chain. The temperature at which the processing is carried out is not ^^ гокА;

The appropriate temperature is selected according to the type of protecting group and the manner in which the protecting group is used. The treatment is preferably carried out under mild reaction conditions, such as, for example, with cooling or even with heating.

Jessiiie R and / or R ³ in the previously listed NYCHA REA ^ ^k c ^s c ^h denotes a radical comprising a bore formed terboxylovou ^ group can then dee-AS to the carboxyl group converted to a deduction ^ ídaící tarboxylovlt free compound. Such a case is naturally included in the present invention.

The free compound of formula (I) thus produced can be converted to the ice salt by the conventional method described above.

The compound of formula (I), which contains a sulfosuccinate, is usually treated with a base to form a sulfur. The compound of formula (I) may thus be prepared in the form of a salt. The salt thus produced may be further converted to the free compound or its salt.

The compound of formula (I) which is produced as the free compound can be converted to a salt. The compound of formula I, which exists in the form of soM, can be converted to the free compound of formula I by treatment with acid. According to the type of salt and other conditions, the acid is preferably an inorganic acid such as hydrochloric acid, acid sulfuric or phosphoric acid, or an organic acid, such as formic acid, acetic acid, or β-bisulfosulfonic acid.

An acidic ion exchanger or the like can also be used. As the solvent, a conventional organic solvent, such as acetone, tetroflyl diphosphates, methanol, ethanol, ethanol or the like, water or a solvent mixture, is conventionally used. The processing is usually carried out at room temperature, cooling or heating can be used.

The reaction time depends on the acid, solvent and temperature. It is usually advantageous if the processing is completed within a short time. The resulting compound of general formula (I) in the free state can be isolated by the above known method.

The starting compound of general formula (II) used in the present invention can be prepared, for example, by the following or similar processes.

OCH3

ArC ^ OCOC ^

^K 2 ^N 2 ° 8 --->

^H 2

Pd — C

CO2CH3 acylation or introduction of a protecting group

Procedure 2

(IX)

CH ₃ COCI

^K 2 ^N 2 ° 8

(XI) acylating or introducing a protecting group

Procedure 3

O

acylation or introduction of a protecting group

R ^{ť HH} rn гм H =, CO2 ^CH 3

OCH ₃

NaBH ₄

-

(XVI)

Procedure 4

(XXI)

H ₂

Pd-С

acylation or introduction of a protecting group

У У Ar

Procedure 5

N ₃ 5 = CH ₂ CH (OCH ₃ ) _{2 0} ^ ~~ \: h ₂ - <O> - ^осн з (XXIV) 0CH 3 ^H 2

Pd — C

acylation or introduction of a protecting group

CH ₂ CH (OCH ₃ ) ₂

(XXVI)

K _2S2 O ₈ --->

с ₂ (осн ₃ ) ₂

AcOH

Jones oxidation

---------- (XXVIII)

(XXIX)

(XXX)

осн

Η Η

ArOCH ₃ CONH = Ar

X (XXXII)

Procedure 7

K ₂ s ₂ o ₈ --->

what ₂ ch ₃ (XXXIIl)

Procedure 8

^h 2 Pd-C

K ₂ S ₂ O ₈ --->

ťxxxiX)

Procedure 9

acylation or introduction of a protecting group

3,4-trans isomer ^K 2 ^S 2 ° 8.

СО / ° Из

3,4-trans isomer

Procedure 10

(XXXV) OCH ₃

NaBH ₃ CN

K ₂ ^with 2 ° 8

(XLV)

Procedure 11

Procedure 12

OHC

CHnCOCI (XLVII)

ArCH ₂ OCONH

Ce (NO ₃ ) ₄ · 2NH ₄ NO ₃

OCH ₃ (XLIX) and ₃ (XLViil)

1) ch ₃ nh ₂

2) ArCH ₂ OCOCI o ·

2) Me ₂ S

OCH ₃

1) H ₂ , Pd-C

2) acylation or introduction of a protecting group

Procedure 13

1) (coci) ₂

2) EtOH

1) k ₂ s ₂ o ₈

2 H ₂ , Pd-C

(LVII) acylating or introducing a protecting group

(LVII!)

Procedure 14

(VI)

CO ₂ CH ₃

K ₂ C ₃ ArCH ₂ OCONH У У CO ₂ H | сн ₃ ; _л г

DCC

NH ο · (LIX)

ArCH ₂ OCONH-H С01М (СНз) ₂

1) H ₂ , PP - C

2) acylation or introduction of a protecting group

Procedure 15

OHC

OCH ₃ (LX)

1)

CH3NHNH2

2)

3)

4)

ArCH ₂ OCOCi K ₂ 2 ₂ O ₈ H ₂ , Pd-C

(LXVIII) acylation or deprotection

CH ² CH ² Ar

Procedure 16

ΑιΌΗ ₂ ΟΟΟΝΗ ^ M ^{CO 2CH} 3

X (VI)

NH4OH

ArCHiOCONH s = X ° (LXIX)

CONH2

1) H 2 PP-C

2) acylation or introduction of a protecting group я ¹ 'conh ₂

X (LXX)

Procedure 17

1) LiN (isoPr) ₂

(LXXI)

1) Jones oxidation

2) CH2N2

SO ₂ Nj

trans isomer (LXXII)

CH2CO2CH3 trans isomer (LXXHI)

H2 / Pd-C

-

2) acylation or introduction of a protecting group

In the above formulas

Ac represents an acetyl group,

Et represents an ethyl group,

Me represents a methyl group, isoPr means an isopropyl group, ^r1 \ ^ _{% ч} \ СН2СО2СНз i!

trans is.omcr

Ar represents aryl.ovou, ^R ^ n z.nam ^and acylating ^L or hindered amine alkylated with u ^{p to} i.nu,

Ing ^ n DBU ^{l, 3} - ^{di aza-bi} c ^YKL of [5,4,0-7 ^d-un and revaluation

DCC means dicyclohexylcarbodiimide.

The starting materials used in the above procedures 1 to 17 are, for example, the methyl 3-α-amino-2,4-dimethoxy-2-oxothzeidine-4-carboxylic acid (IV) described in J. Armr. Chem. Soc. 9_9, 2352 (1977) merУy'Sertrr cis -1- (2--dimethoxybbenyy) -3-o-ftaiimi ^d 2 ^d oxotzrti ή- "4-carboxylic acid (XIV) described in Japanese Patent Laid Open Pat. 136694 (1976), cis-3-azide-4-trans-2-tetraazetidine (XXI) described in J. Org. Chem. 34, 1477 (1969), cis 3-azido-1- (2,4-diethoxybenzyl) -4- (2,2-dimethoxyyeethyl) -2-oxoazetidine (XXIV) described in J. Arnmr. Chem. Soc. 11, 4730 (1979), cis -1- (3,4-dimethoxybbenzS) -3-frntxyаcettmi ^d Ot44fenyS 2-txoаaztidin (XXXI) described in Synthesis 197 * 9 543 and 2,2-dimethyl-l-aza-3 -oxtb ⁱ c ^with klt ^f 4, ² , 0 ~ | octan-8-one (L ^X XI) described in ^J. Anmr. Chem. ^S oc. ¹⁰⁰ , ³¹³ ( ^197-8 ).

These examples are not listed here as ermining the default eaterials. Any compound that meets the purpose of the present invention may be used as the starting compound. Examples of batch starting materials will be set forth in the following Reference Examples. It is to be understood, however, that the examples are given solely for the purpose of illustration and not for the purpose of referring to the invention.

There are many variations that do not depart from the spirit and scope of the invention.

In the following Reference Examples and Examples, the effluent elution of cУromaotrafie on the column is controlled. by thin-layer metering (TLC). Merek TLC plates are used for TLC Elution of plates is performed with the same solvent as the elution of croma and trot on the wheel:

No. An ultraviolet detector is used for detection.

By isolation, the fraction with the desired compound, stained with ninhydrin, sprayed with 48% hydrobromic acid and heated to cause hydrolysis, turns red-purple.

If two kinds of solvents are used for elution, the by-product is eluted from the column with the first solvent described. The second solvent elutes the desired product, except where specifically described otherwise.

The compound was dried over anhydrous sodium sulfate unless otherwise noted. Unless otherwise indicated in the Examples and Reference Examples, water is first used for elution in purification by Amberlite or Sephadex column chromatography, then sequentially an aqueous ethanol solution with a gradually increasing ethanol concentration.

Amberlit resin is a product manufactured by Rohn and Haas Co., USA. ”Bowex” is a product of Dow Chemical Co., Sephadex is a product of Pharmacia Fine Chemicals. All temperatures are uncorrected. All percentages are percent by weight except for percentages used with solvents.

Solvents are always used in percent by volume. The NMR spectra were measured on a Varian Model EM 390 (90 MHz) or T60 (60 MHz) spectrometer with tetramethylsilane as an internal or external standard. All delta values are given in ppm. S is singlet, d is doublet, q is quartet, ABq is AB quartet, t is triplet, dd is doublet, m is multiplet, sh is shoulder, br is wide (eg brs is wide singlet) and J means the interaction constant. The symbols in the examples and reference examples have the following meanings:

mg = milligram g = gram ml = milliliter = liter dec. = decomposition ppm = part per million mmol = millimol

M = molar (concentration)

HZ = Herz

Me = methyl

Et = ethyl group ° C = degrees Celsius max = maximum

NMR = nuclear magnetic resonance absorption

IR = infrared absorption

DMSO = dimethylsulfoxide

D ^ O = heavy water.

Try

The table below shows the minimum inhibitory concentrations (MICs) of some typical compounds of Formula I of the present invention produced in the Examples.

Method:

Minimum inhibitory concentrations of test compounds were determined by the agar dilution method. Specifically, 1.0 ml of an aqueous solution of test compounds diluted with serial dilutions is poured into a test petri dish. Then 9.0 ml of Trypticase Soy agar is added to the dish and mixed.

One loop of the suspension (about ^{10 8} CFU / ml) tested ^for riorgasism is applied to the agar plate. ^B U is incubated with ^{straight overnight} s ³⁷ ° C. Minimum İshleme ^a i ⁱ N ^s concentration is the lowest concentration of test compound causing distinct inlibici (total) growth of the test microorganism.

Tested microorganism:

(1) Enterobacter cloacae IFO 12937 (2) Cleansers TN 1711

Result:

(g / ml)

Compound MikriorgasSstus (1) (2) Example 65 6.25 0.2 Example 68 3.13 0.78 Example 72 1.56 - Example 133 1.56 0.39 Example 136 - 1.56 Example 138 - - 6.25 Example 144 6.25 3.13 Example 147 3.13 0.39 Example No. 158 3.13 6.25

Example 1

To a solution of 201.9 mg of cis-3- [2- (2-chlorophenylthio-4-thiilyl) -methyloxy-acetylphosphin-2-oxo-aza-thiis-4-potassium oxyl ester (syn isomer) in 3.5 ml of N _from N-dimethylformamide 159.2 mg of pyridine-sulfur trioxide complex are added. The mixture was stirred at room temperature for 5 days. An additional 80 mg of pyridine-sulfur trioxide complex was then added.

Stirring was continued for another two days. To the reaction mixture was added 50 mL of ether. Solidly insoluble matter is separated from the reaction mixture. The succinate ether layer is.

The insoluble matter was washed with additional ether.

The ether layer was decaned again. The remaining undissolved material is slurried in 5 ml of water. The resulting solution was filtered. The filtrate was not passed through a Dowex 50W (Na-form) column. The flow-through was lyophilized. The lysate was dissolved in a minimum amount of water and then purified by chromatography on an Ambrlite XAD-II column. By re-lyophilization, cis-3- [2- (2-chloro-thiamido-4-thiazolyl) -2-trifluoromethyl] -aminoacetamide-4-methyl-carboxylic acid-2-iodo-phenoidin-1-spionic acid sodium salt (syn · ^^^) was prepared.

IR ^sp ektru ^m cm ^"1): 3400, ^3225, 1780, 1735, 1670 and 055. 1 H-NMR ^ with trimethylsilyldiazomethane (DMSS-d _6, ppm): 3.6 (s, -COOCC ₃ J, 3.84 (s, = N-OCH ₂ ), 4.29 (s, C 1 -C 4 -), 4.45 (d, J = 6 Hz, C4-H), 5.38 (dd, J = 6 Hz (J = 8 Hz, CH3), 7.23 (s, S, -H), 9.41 (d, J = 8 Hz, NH-1-1).

j - ^N Example 2

To 2 ml vodnělo solution containing 85 mg sodium sooi cis-3- [2- (2-ch0rfctefamido-4-azo th ^{f y} y ^-) -2-methyl lχyyim ^{i n f} im IACT ^{into -} -4-MTT ^l oxykar Onn ^{0 y} 2 ^{- t} i ⁱ cxoifz is - L-su ^t0 to sndvé ^{y y} n ^y (syn isomer) under cooling iedem with stirring 23.85 mg sodium Sou moonrnmtetiyithiokarbamově acid. Stirring was continued for 40 minutes at ambient temperature. ►

An additional 7 mg of sodium monomethyldithiocarbamic acid was added. Stirring was continued for another 30 minutes. The reaction mixture was then filtered. The filtrate was washed with ether. The aqueous layer was purified by chromatography on an Anbrreit Ш-Π column and then lyophilized.

VyroW SO ^d n ^and the salt of cis ² 3 ² £ 2 ^{2 (-} Bamin "4 ² УУ ^and alolyl) ^2B2 mynhoxyin ^on> crebbm ^{amino] 2} 4 ² mrthox ^yl CSC - 1 kbrronnl-2-nxolbetidin L-suiinnové cyseeins (syn isme. IC spectrum (V / cm 3 350,

775 and 1055. NMR-ipptrpm (DMSO-d6) ppm): 3.61 (s, -COOCH ₃ , 3.81 (s, = N-OCH ₃ ), 4.45 (i, J = 6 Hz) Δ41З), 5.35 (dd, J = 6Hz> J = 8Hz, 03-3) ^ - 6.56 (s, S), 7.1 (broad s, -N32), 9.33 ( d, J = 8Hz, NH

Example 3

К solution ⁴ 1 ⁸ mg of ^{cis-4 2} bcr Ox ^{e l} h ^r BE ² -3 ^{hl [2 2 (2} -chlnraceta ^{m i di-2} thibzol ^yl) 22 ² MRE ox ^{y y} imioobc: ctbmidol 2 -oxolLbetiiin (syn isomer) in 3 ml of Ν, Ν-dimethylformamide is added 319 mg of pyridine-sulfur trioxide complex. The mixture was stirred at room temperature for 24 hours.

An additional 159 mg of pYridine-sulfur trioxide complex was added and stirring was continued for an additional hour. A second portion of 159 mg of the complex is then added and stirring is continued for an additional hour. Ether was then added to the reaction mixture. The insoluble maaeral precipitates from the smmsi reactions. The ether is decaned.

The insoluble material was washed with additional ether and then filtered. . The crystals obtained are dissolved in 5 ml of water. The solution was filtered. The filtrate was passed through a Dowex 50W (NN-form) column. The filtrate was dissolved in 5 ml of water. It is purified on an Anbereit XAD-II column.

After lllϋlZzaci give sodium 4-cis-3- bcreoxlmerthl £ 2- (2-cУloraLcrebmíio ^{tУibzo-4-l)) l 2-} -mrУhox ^b Zminobcetbm di ^lj-2 -> oxnzet ^r d n ^{d n} l ^- su ⁱⁱ sulfonic tyseH ^ ^(Y ^ ni ^ £ ^ r nm). IR Spectrum (νmax cm ^-1 ): 3400, 3250, 1760, 1665 and 1045. NMR Spectrum (DMSO-D6, ppm): 1.95 (s,

-OCOCHHj, 3 ₍ 83 (with, = N- (OH) ₃ ), 3.8 to 4.4 (m, C4-H and -H2H2O4O), 4.3 (s, C1CH2— 5.15 (dd J = 4 Hz J = 8 Hz, C _q H), 7.3 (s, S ₄ = H), 9.3 (d, J =. 8Hz, NH --- - | ) X 1 J P Píkl and d 4

Under ice-cooling and stirring, 41 mg of sodium salt; The mono-methyldithiocarabine acid is added to 4 ml of an aqueous solution containing 150 mg of sodium cis-4 ^2- butoxymerhhl-3 [2- (2-chlorobenzylbenzidyl) 2-methyloxybinoabeeaaidd] -2dxχizetedin-1-isomeric acid.

The mixture was stirred at room temperature for 30 minutes. An additional 10 mg of sodium monohydroxymethyldiocarboxylic acid was added. Stirring is continued for another 30 min. The reaction mixture was filtered. The filtrate was then washed with ether, and the aqueous layer was purified on a Dmerlite XAD-I column.

425, 3300, 1760, 1660, 1050. NMR Spectrum (DMSOd6, (s, = N-O-HH ₃ ), 3.9-4.4 (m, H 4 -H and ² H ₃ OCO) ), 5.15 (dd, J 6.66 (s, 1H, 7.1 (broad s, -NH 2)), 9.2 (d, J = 8 Hz, -NH)

IC spectrum ppm): 1.94 (s = 4.5 Hz, J &lt; - &gt;

After lyoHizzaci is prepared a sodium salt of cis 4 ^{2 2} bcrtoxybertyl ² 3 ² 2- ^{(2-шninnn4-beУaazOll)} -2-methoxyiminobcrtbmido -2-oxobaeetdin ² l - suilonl) as acid (syn isome) < »ms. ^"-1 -OCOOCHj 3.78 = 8 Hz, ₃ H), Example

К solution of 150 mg of cis-3 brnzyloxykbrrnxbmidco ² - (L-beeУyl25 tetrbzollltУlobebУyl) -2-oxnazetidinu in 2 ml of Ν, Ν-dimrthlfnrrbbmidu was added 137 mg kommlexu sulfur trioxide-pyridine. The mixture was stirred at room temperature for 24 hours. An additional 70 mg of pyridine-dioxide complex was added. Stirring was continued for a further 2 hours.

Ether was added to the reaction mixture. An insoluble solid is obtained. The ether is decanted. An additional portion of ether was added to insoluble matter. This is then filtered off. The filtered crystals are dissolved in 15 ml of water and the solution is filtered. .

The filtrate was passed through a Dowex 50W (Na-form) column. The eluent is lyophilized. The lyophilisate is dissolved in 5 ml of water, purified by chromatography on an Amber li column and lyophilized again. The sodium salt of cis-3-benzoxycyclboxamide O- (1-methyl-5-ethoxy-1H-methyl) -2-oxoazeeidine-1-sulfonic acid was prepared.

iC s ^p ectruil · ( ⁱⁿ cm ¹ ) · ^{3 300, 1 775, 1 690, 1 0} 5 ⁵ . With ^p ektrum NMR ^(D MSO d ^{for g} ppb

8.87 (s, -NCH ₃ ), 3.8-4.3 (m, C ₄ -H and CH 2 -), 4.96 (dd, J = 5 Hz, J = 10 Hz, C 4 H) δ J (s, -C ₁ H ₄ O-), 7.35 (s, J C ₆ H ₅ ), 8.16 (d, J = 10 Hz, -NH).

Example 6

To a solution of methyl ^ h ^ ester ²⁰² mg of C ³ S ^and - N 2- ^{(2-c hl} frtcetamidf- ^4-0h Thiazolyl) ²² Mee ^h0 ox ^y im noaceOtшl ⁱ ^ (^ ^f ^ 2-FW ^ t ^ г e ^ ^e oi ^{di-nx 4} - ^ ^k ^ t ^ l ^ ^b ^ f ^ x sel ^yl Όvé ^{alkyl and} n ^y (anti-Omer) in ^3.5 ml of N, ^N-dimethyl formamide was added ^hyl 159 mg The pyridine-sulfur trioxide complex was stirred at room temperature for 4 days.

An additional 80 mg of pyridine-sulfur trioxide complex was added. Stirring was continued the next day. 50 ml of ether are then added. An insoluble syrupy substance precipitates from the reaction mixture. The ether layer was decanted. Insoluble materials were washed with ether. The ether layer was decanted again.

Dissolve the remaining undissolved syrups in 6 ml of water. After solution, the solution is passed through a Dowex 50W column (Ν - ^^). The eluent is eluted with a minimum of water, then purified by chromatography on a Merrill XADd-1 column and lyophilized.

Prepared siil ^and sodium ^{cis-3- 2} 2 () ^- -t oaametam ^{IF io} ~ of 4-th ^and zfí ^{NO |} 1) ^-2-f mot oyyiminoacmtami ^and a ^J-4-yl meehofχУaarbf ---- fxfzetiidn L-suifonfvé acid (anti isome).

IR spectrum ^(K B) 'cm ^-1) · 1 760, 1 670, 1 040. The nmr spectrum (D-ends to be connected ^^ ,, ppm): 3.69 2.98 (s, NOCH 3), 4.35 ( s, C 1 -CH 2), 4.49 (d, J = 6-Hz, C 1 H -H), 5.41 (ϋ, J

Hz, C3-H), 7.99 (s, S, H), 9.14 (d, J = 8 Hz, NH)

Ex (s, = 6

-CO ^ I ^ HJ, Hz, J = 9 í k l ad Ke 2 me

of an aqueous solution that o^bsthuje⁸⁵ m^G sodium salt¹ cL · -³- ^^2-^ -cMor ^ ceUmno -4-thaazocyl) -4-methoxyiminoacetamido-⁴-me^Ehoo^χyktbbo^yl-^---fxazeti^andin- · l-su^ffhe^Oin^E acid^andn^y21 mg of the sodium salt of mono-monomethyldi-thiocarbamic acid was added under ice-cooling and stirring.

The mixture was stirred for one hour from room temperature. An additional 7 mg of monophthalic sodium carbamic acid sodium salt was added. Stirring was continued for an additional 1 hour. The reaction mixture was filtered. The filtrate was washed with ether. The aqueous layer was purified by column chromatography / Alerllt XADd-1 and lysed.

Prepared sodium ^and srnl ^C1-3- [2-) ⁴ taπino- ^J - ^T h ^and AFI) ^No. Y ^-) -2-methyl ^{t 0} χyyimiooace -amide] ⁴ 4 "MMT ^H FX karbonyč ^{y-2-oxxfazmidin} 1-sulfonic acid (anti-isornee).

IC ^s spectrum ⁽ in Kb) cm ^-1) ; 1,760 ^1,050 . ^{The nmr} spectrum MS ^ ⁰⁰ ^ pp ^{m) 3.68} · ^ ^-C ^ ^000), 3.92 (s, = N003), 4.46 (d, J = 6Hz, C ₄ -H), 5, 36 (dd, J = 6Hz, _C3-H, 7.03 (br s, NH))

7.38 (s, 0 J1, 9.04 (d, J = 8 Hz, NH)

X

Peak a d 8

To a solution of 112 mg of 3-phenylphosphoric acid-2-phosphorylphosphine-4-carboxylic acid in 3.5 ml of Ν, ib-dimethylsorbabide is added a mixture of 159 mg of pyridine with sulfur trioxide. The mixture was stirred for 5 days at P 2. An additional 80 mg of pyridine-sulfur trioxide complex was added.

Stirring is continued for one more day. 50 ml is then added to the reaction. A syrup-like precipitate is formed from the solution. The ether was decanted. Add another to wash the syrup precipitate. The ether is again resuspended in 5 ml of water.

of ether. ether,

The solution was filtered. The filtrate was passed through a Dowex 50W (Na-form) column. I. C c oiiiiii.. The eluent from the column is swollen in minimal water. Then, it is purified by chromosurgery on a Dmereit XAD-II column. The sodium salt of cit-4-benzyloxycarbonyl-3-ifnyl-thiophenylphosphine-1-sulfonic acid is obtained.

^Ic ^ Hrum (cm ^3): 1 ⁷⁷⁰ -1 ⁷⁴⁰ 1 ^{650 1 and 255. NMR} sweaters (DMSO-d6):

3.46 (CH 2 CO and CCH 3), 4.39 (d, J = 6 Hz), 5.25 (dd, J = 6 Hz, J = 8 Hz), 7.24 (s, C 6), 82 (d, CON HH.

Example 9

To a solution of 30 mg of cis-4-aclaabidombphtho-3-iloyl-octabifo-2-oxoafelifine in 0.7 ml of H, H-tibibylthilacphthabide was added 52 mg of pyridine-sulfur trioxide complex. The mixture was stirred at room temperature for 69 hours. 35 ml of ether are then added. This yields a syrupy tragedy.

decant and add another. ether. Ether is up! in 1 ml of water. The solution was filtered.

decant and the remaining syrup-like filtrate was washed with a Dowex column

Ether prewet 50W (Nc ^ atform ^). The lyophilizate of the column is dissolved in a minimum of water and purified by chromatography on a Dmerlite XAD-II column. After lysing, the sodium salt or the .alpha.

IC spekUum (

NMR (D2C (dd, J = 5.5 Hz, J ^ χ ν ^'c m ^-1): 3400 (broad ^p AS) ^{1760, 1640,} 1 ppin): 1.91 (s, COCC ^, 3.52 (d, J = 6Hz, _CH2 N = 6Hz, C4-H), 5.19 (d, J = 5.5 Hz, C ₃ -H), 7.38

515, 1 255 ^and 1 050.

3.68 (s, C ^HCO), 4.37 (m, CgH ₅ ).

Example 10

To a solution of 250 mg of cis-3- [2- (chloro-amide-4-thiazolyl) -tethoxy-thio [beta] 2-oxo-phosphine-4-carboxylic acid (sysomeyl) in 2 ml of Ν, ib-tibiphenylSobbabide was added 190.4. The mixture was stirred at room temperature for 24 hours.

An additional 95 mg of trisulfide oxide complex was added to the mixture. Stirring was continued for an additional 24 hours. Ether (20 ml) was added to the reaction. Insoluble solids precipitate from the mixture. The supernatant ether layer was triturated with EtOAc. After the solid was washed, 20 ml of fresh ether was added to the residue.

A similar procedure is repeated. The ether layer was discarded. The insoluble solid was suspended in 20 ml of water. 12 ml of Dowex 50W (Naatyp) was added to the suspension. The mixture was stirred at room temperature for 2 hours. The resin was filtered off. The filtrate was lyophilized. The resultant powder was dissolved in 20 ml of water and purified by anoraphoraphia on an Anberlite XAD-II column.

The product thus purified is lyophilized. The sodium salt of cis-3 - [[2- (2-chlorophenylbiphenyl-4'-thaazoyyl) -1,2-ethoxybimisaccephabiphenyl] -4-methoxy] -arosol-1-t-tsosphetedinol-sulfonic acid (syn isomer) was prepared.

IC ektrup (i- .. cm ^-1): 3 600 to 3 ²⁰⁰ 1 ⁷⁹⁰ 1 750 1 700 ^and 1 670 ^and 1 055. NMR @ serectin (DMSSOdg ppi): 1.23 (3H t, J = 6 Hz, C 1 -C 4), 3.62 (3H, s, COOCH 3), 4.12 (2H, q, J = 6 Hz

CJHCCj), 4.34 (2H, s, C1CH _2), 4.49 (1H, d, J = 6Hz, C ₄ -H), 5.43 (1H, d, d, J = 6 Hz, J = 9 Hz, C, -H), 7.29 (1H, s, S, H), 9.40 (1H, d, J = .9 Hz, C, - NH), 12.92 (1H, broad s, (CH ₂ CONH).

For C ₁₄ H ₁ 5ClN5NaOgS ₂ .2H? O: calculated: 30.25% C, 3.45% H, 12.60% N? .Nalezeno: 30.01% C, 3.46% H, 12.46% 'N.

Example 11

К solution ¹¹⁰ m ^g of ^a sodium and cis-3- ^ 2- (2-chloro-4- ^j ojacetamido ^ih Thiazolyl) 22get ^{j n} lOyyim oojcgtř APID ^about -4-PE ^gi Hoy ^y kjbioyl 220oooaetidit-L-SZL ^about -ones уеЫ ^ ^e ^ ^{(s y} n isomer) in 8 ml in ^soil under ^{refrigeration;} 30 mg of sodium phosphinic acid are added thereto in ice. The mixture was stirred at the slurry temperature for one hour.

Then, an additional 10 mg of sodium salt of polythiocarbonic acid was added to the reaction mixture. The reaction mixture was stirred for an additional hour. The resulting reaction mixture was filtered and the filtrate was washed with ether. The aqueous layer is clarified by chromatography on a perlite XAA-I column and then lyophilized. The sodium salt of cis-3- [2- (2-piperidin-4-riazolyl) -2-ethoxyipitoacetamido-4-peghonylbenzoyl-2-oxo-indole-1-tufonic acid (synisomer) is prepared,

IC ektn »(in ^KBI / ^CP-1): 3 500-3 ³⁰⁰ 1 790-1 ⁷⁰⁰ 1 ⁶⁸⁰ 1 ⁶²⁰ 1 055th

max

NMR Spectrum (DMSO-d6 ppi): 1.21 (3H, t, J = 7 H2, O ^ 3), 3.61 (3Hy s, COOCH2), 4.07 (2H, q, J = 7) Hz, CH 2 CH 3), 4.47 (1H, d, J = 6Hz, C ₄ -H), 5.39 (1H, dd, J = 6Hz, J = 9Hz, C ₃ -H), 6, 56 (1H, s, O 2 H),. 7.15 (2H, br s, N +), 9.30 (1H, d, J = 9 Hz, C ₃ -NH).

For ^C i2H14 ^N 5 ^N aO8O ₂ .2H ₂ O Calculated: 30.06% C, 3.78% H, 14.61% N; Found: C, 30.33; H, 3.53; N, 14.76.

Example 12

In the same manner as in Example 10: cis-3-2 2 ((- (chloro-β-thioyl-thiazooyl)) -2- (oroooxyipinoyacetridine)] - 4-methoxy-carbonocarbon-2-oxo-ortho-tufonic acid sodium salt (syn-topg).

IC ^SPE ktru ^{p (μ-CP-1); 3200, 2970,} 1780, ^1750, 1680 and 055. 1 H NMR (DMSO-d ₆ ppi): 0.89 (3H, t, J = 7Hz, C ^ CH ^ j ^) 1.65 (2Hy sextet, J = 7Hz, C ^ C ^ C ^), 3.60 (3H, s, COOCH3), 4.01 (2H, t, J = 7Hz, CH3 C ^); , 4.32 (2H, s, C1CH2), 4.48 (1H, d, J = 6Hz, C ₄ -H), 5.43 (1H, dd, J = 6 Hz, J = 9 Hz, C -H), 7.25 (1H, s, S, J), 9.4 (1H, s, J = 9 Hz, Cl-NH), 12.9 (1H, br s, ClCH3 CONH). AND

For C15H17ClN5Na GO ₂ '.'122H2O calculated: 33.18% C, 3.34% H, 12.90% N; found:. H, 3.51; N, 12.93.

Example 13

The sodium salt of ait-3- [2- (2-rminio-hájojlУ) -2- (linkage: yipiniOaraginidod | -4-methoxycartaobo-2-oxo-iodoedithiol sulphonic acid (isopropyl) is produced in the same manner as in step 11). . IC. (VP r ^ ^{CP-1): 3420, 1780, 1700,} 1680, 1620 and 055. 1 H NMR setrům (DMSOoppi): 0.88 (3H, t, J = 7 Hz, CH ^ H 2 O), 1.62 (2H, sextet, J = 7 Hz, CH 2 CH 2 CH 3), 3.61 (3H, s, COOCH 3), 3.98 (2H, t, J = 7 Hz, CH 2 CH 2 CH 3), 4 48 (1H, d, J = 6 Hz, C? H), 5.4 (1H, dd, J = 6 Hz, J = 9 Hz, _C3 -H), 6.52 (1H, s, O H, 7.14 (2H, broad s, N @ +), 9.31 (1H, d,

J. = 9 Hz, C3-NHH.

For _{C 1} 3 H 6N5tJaO8S2.3H2 ° off <lčtei-: 31.64% C, 4.09% H, 14.19% N; Found: C, 31.70; H, 3.81; N, 14.43.

Example 14

In the same manner as in case 10, cis-3- [2- (2-chloroacetamide-4-thiazolyl) -2-chloro-oilyl-piperazin-4-yl] -4-ethoxy-2-oxotetidine-L-sulfonic acid sodium salt (synisol) is produced. .

IR ( ^KBr , cm ^-1 ): 3600-3,300, 1780-170, 1700-1705, 1055.

max '

Sp ^ trum NMR (DMSO-d _6, ppm): 1.23 (6H, d, J = 6Hz, CH ^ H ^), 3.62 (3H, s, COOCH3), 4.31 (1H, m C ^^^), 4.33 (2H, s, dCty, 4.50 (1H, d, J = 6Hz, C-H), 5.45 (1H, dd, J =. 6Hz _Z J = 9 Hz, C3-H), 7.24 (1H, s. SH), 9.32 (1H, d, J = 9Hz, _C3-NH), 12.90 (1H, brs, ClCHjCONlH .

For C ₁ 5 H ₁ 7ClN5NaO _g S2-2H2O calculated: 31.61% C, 3.71% H, 12.29% N; Found: C, 31.58; H, 3.65; N, 12.28.

Example 15

The sodium salt of cis-3- [2- (2-anin-4-thialzlyr) acid (syn.

-2-S-Opoylmethylcetyl-C-4-ethoxylpyrrole-220-x-tetidine-1-sulO (Daily Isole).

IC with ^p ektrum (VCM ^-1): 3600 and 3 ^200, 1 780 to 1 750 1 680 1 NMR ^(DMSO-dg, ppm): 1.20 (6H, d, J = 6Hz, CH 3 R 3 b 3.62 (3H, (1H, septet, 4.47 (1H, d, J = 6Hz, C ₄ -H)), 5.41 (1H, dd, J = C-H), 6.53 (1H, s, 5xH), 7.12 (2H, br s, NH4, 9 ^, 18 (1H, d ^, J = 9 Hz),

AND

620 to 1,055.

s, COOOC ₃ ), 4.27

Hz, J = 9 Hz,

C ³ ™) ·

For C13H3gNgNaO S2.2H ₂ O ₈ calculated: 31.64% C, 4.09% H, 14.19% N; Found: 31.92:% C, 3.85% H, 14.37% N.

Example 16

In the same manner as in Example 10, cis-3- [2- (2-chloroacetamide-4-thiazolyl) -2- (butyloxy) -1-acetyl] -4-methyl-4-thiophen-2-y-2-yl ethedinil-suf-ynoic acid (syn).

^IR (ppm): 0.89 (3H, ts, COOOCh), 4.04 (2H, t, J = 6 Hz, C4-H, 5.42 (1H, dd, J d, J = 9 Hz, C3-NH3).

cm ^-1): 2960, 1780, 1750, 1680 and 055. 1 H NMR (DMSO-J ^g 6th Hz, CH2CH2CH2CH3), 1.1 to 1.8 (4H, m, C ^ 3.60 (3H, Hz, CH 2 CH 2 CH 2 CH 3), 4.30 (2H, s, dClH), 4.49 (1H, d, J = 6 Hz, J = 9 Hz, C ₃ -) H), 7.20 (1H, s, 5H, H), 9.37 (1H,

X

For C ^ gHH gClClNNNOOSSSH HO

H, 3.80; N, 11.83.

calculated: 32.91% C, 3.97% H, 11.99% N; found: C, 32.58;

Example 17

The sodium salt of cis-3-22- (2'-amino-4-hydroxy-2-yl) -2- (butylamino) -4-methyl-4-iodo-4-carboxylic acid was prepared in the same manner as in Example 11. ylr-2 - χ-zeZědinil-on-8ul acids (syn i ^ £ ^ M ^ e) ^ · IC with KTR ™ ^{(in cm "3)} 3450 3350 F ^{and 1} 790-1 750 , ^1680, 1620, 050. 1 H NMR ktrum s ^ _(DMSO-d6, ppm): 0.89 (t, 3H, J = 6Hz, C ^ C ^ C ^ C ^), 1.1 to 1.8 (4H, m, C CCH CCH ^), 3.61 (3H, s, COOCCH), 4.01 (2H, t, J = 6 Hz, C ^CH CH ^^CH CH, 4) , 47 (1H, d, J = 6Hz, C, -H),

5.39 (1H, dd, J = 6Hz, J = 9Hz, C, -H), 6.54 (1H, s, S, H), 7.13 (2H, br s, NH-) , 9.3

12 (1H, d, J = 9Hz, C 3 -NH).

For C ₁₄ H ₃₈ N ₅ NaO ₂ S ₂ O ₂ S ₂ O ₃ : C, 33.13; H, 4.37; N, 13.80. Found:% C, 33.01;% H, 4.10;% N, 13.85.

Example 18

In the same manner as in Example 10, cis-3- [2- (2-fluoroaceaamido-4-thaoolyl) -2-benzyloyylaminoacetaamido] -4,4-methoxycarbonyl-2-oxoazeeidine-1-suioonic acid sodium salt (syn isomer) was prepared.

iC s ^p e ^k trum (v ^ 0 ^{'cm for 3 550-3 250} 1 ⁷⁸ °, ^{1750, 1680, 1055} NMR · s ^ ktrum (DMSSod ppm): 3.52 (3H, s, 'COOCC _3), 4.33 (2H, s, C1CH (), 4.51 (1H, d, J = 6 Hz, C? H), 5.16 (2H, s, lenyl- ^ C ^ ₂₎ 5.49 (1H, dd, J = 6Hz, J = 9Hz, J = -H), 7.27 (1H, s, S,

7.38 (5H, s, lenyl protons), 9.59 (1H, d, J = 9Hz, C-NH), 12.9 (1H, broad s, d-COCN).

H, 3.19; N, 11.67. Found: C, 38.03; H, 3.19; Found: C 38.07, H 3.27, N 11.72.

Example 19

In the same manner as in Example 11, the sodium salt of cis-3- [2- (2-amino-4-thiazolyl) -2-beneylooyiminooactamido] -4-nitrocarbonyl-11-oxoazetidine-1-sulfonic acid (syn isomer) was prepared.

Ir _(ax * 'spectrum (DlSSc-d₆, ppm): s ^ enyl-CH), 5.42 (1H,

cm) : 3450 ^and 3 325, 1,780, 1,750, 1 675, 1,620, 1,055. . NMR 3.54 (3H, s, CCCCH 3 ⁾⁾ 4.49 (1 H, d, J) = 6 Hz, C ₄ -H, 5.12 (2H, dd, J = 6 HZ, , J = 9 Hz , C3-H, 6.57 (1H, p. S (H), 7.16 (2H, X

br s, NH 2), 7.37 (5H, s. lenyl protons, 9.48 (1H, d, J = 9 Hz, C 8 NH).

For C1 ₇ Ilona NaOgSz.2 ₅ ^ 20: calculated: 37.70% C, 3.37% H, 12.93% N.

H, 3.72; N, 12.93; found: 37.26% 0,

Example 20

Zpsůobem same as in Example 10 was prepared the sodium salt of cis-3- [2- (5-chloro-2-chloracetamiddo4 "th ^{t the} azo ^yl) - ² ~) methoxyiminoocetamidcj - methyl ^ ^ ^ ny oykra ^^ ^ in oooazeti -l.-sulfonamide-sulfonic yseli.n ^{to y} (with ^y n j.sommr). ^ir (cm4: ¹ 7 ^{90 1} 74 ^{0 1 68 0, 1} 550 and ¹ 060th NMR (DMSS-d ppm: 3.63 (3H, s, _COOCH3), 3.89 (3H, s, NOCH _3), 4.37 (2H, s, C ^), 4.46 (1H, d, J = 6Hz, C ₄ -H), 5.410 (1H, dd, J = 6 Hz, Cg- H), 9.418 (1H, d, J = 9 Hz, C8-NH), 13.1 (1H, broad singlet, H1 H32 HCNH).

For H1 2N5 _{3-H_2C} 9S2Na.232O ^O: calculated: 27.09% C, 2.80% H, 12.15% N; Found: C, 27.42; H, 2.80; N, 12.39.

Example 21

Similarly caused ^b em I ^to 11 s ^{an example, a} swarm ^and sodium salt cjts ^ -f ^ - ^ - amino-S-chloro ^-4 -thiazoyyl) -i-rthOolyiminoaceaaiidO>] -4-ierhooolkrr2oyl - 2-1-ooozetidin -suioonic acid (syn isomer). I ^{C P} ektrum ⁽ⁱⁿ cm ^-1): 3 ^{40 0, 1780, 1} 7 ^{50 1 68} 0 ^{1 62} 0 ^{1 540} ° ^{1 60th}

Nuclear Magnetic Resonance Spectrum (DMSO-d), ppm): 3.64 (3H, s, COCCl 3), 3.83 (3H, s, NCCH 3), 4.44 (1H, d, J = 6 Hz, C4-H) 5.36 (1H, dd, J = 6Hz, J = 9Hz, Cg-1, 7.30 (2H, s, NHg)), 9.32 (1H, d, J = 9Hz, 1H-NH) ).

14.13% N.

% C, 26.43;% H, 3.02;% N, 14.01; found: 26.22% C,

3.15 «H,

In the same manner as in Example 10, cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyimioacetamide] -4- (butooyltrbooyl) -2,2-oxo-alzetdin-1-sullonic acid sodium salt (isome) was prepared.

^iC ^^ ги ^{2 _(max} ppm): 0.73 to 1.73 (7H, (1H, d, J = 5 Hz, C42H), 5.40 9.41 (1H, d, J = 9Hz, C32H,

KBr /

m, CH 2 CH ₂ CH ₂ CH 3), (1H, dd, J 11.93 (1H, cm ^{h: 3 25 ^ 1 78 0 1 7} 4 0 1 6 8 1 ° and ^060th NMR with ^p e ^k trum (DMSO- -d ^g

3.86 (3H, s, NOCH _3), 4.43 (2H, s, C1CH2), 4.46 = 5 Hz, J = 9 Hz, C32H), 7.30 (1H, s, Si H, br s, ClCH ₂ COCNH X

For C ^ H ^ d ^ N-O ^^ O '

% C, 33.79;% H, 3.79;% N, 12.39

% H, 3.74;% N, 12.37; found:

calculated

he said

cis- ^3- (2- (2-Amino-4-terthoxyl)) 12-methoxycarbonyl tert-imidol β 4 - (η 4 -) - (2-amino) -4- (2-amino) ethyl] pyridine-1-sulfonic acid (syn. ^ c). IC spectrum (in KD, ppm): 0.7 to 1.76 (7H,

4.43

7 ^, 13

In the same manner as in Example 11 cm &^lt; -1 ^&gt; ): 3450, 3320, 1790, 1750, 1670, 1050. NMR Spectrum (DMSOd6, m, C32CH2C32CH3), 3.80 (3H, s, NOCC3), 4 00 (2H, t, CH 2 C 32 C 32 C 33), (1H, d, J = 5 Hz, C 4 H), 5.33 (1H, dd, J = 5 Hz, J = 9 Hz, C 8 H), 6.56 ( 1 H, s, S), (2 H + ^s NH 2b 9 ^, 41 (1 H d ^, J = 9 Hz ^, (1 H -N 2)).

4.07

For C ₁₄ H ₈ N ₅ NaO ₈ S ₂ .H ₂ O calculated: 34.35% C, 4.11% H,% H, 14.42% N.

14.30% N; found: 34.51% C,

Example 24

To a solution of 180 mg of 2611-115-trans-3--2- (2-chloro-2-chloro-2-chloro-2-yl) -2-chloro-4-trifluoromethyl-4-trifluoromethyl-4-trifluoromethyl-4-trifluoromethyl-acid (synomer) in 1.8 ml of N, N- 142 mg of pyridine-sulfur trioxide complex was added to the mixture and the mixture was added to the mixture at room temperature for 14 days and then after four days. Two each pyridine-sulfur trioxide.

The mixture was stirred for a total of six days. To the reaction mixture was added 50 mL of ether. The ether layer is decanted. This procedure is repeated three times. The resulting syrupy substance, which is not soluble in ether, is dissolved in a small amount of water. . Pass the solution through a Dowex 50W (Na-form) column. The duyl lyllizate dissolves in a small water anciosity. The solution was purified by Dnierllt XAD-H Chromatography.

After 1ioí ^ L] .Z ^ Measuring give sodium trtnt-3 - [. 2- (2-chllrtccttaidco24thitzolχl) 2-mctCl0liminlaceeamidol - _{4-O-maehcoykartonlnl2} loaztZedin-lltjl0onlvé acid (syn isomec). Ir ^{(CIO). 1} 7 ^80, 1 ^{670-1 550th} NMR SPE ^to trua ^(DMSO-gp pm): ^3, 7 (3 R

3.9 (3H, s, NOCC ₃ 8 4.1 (1H, d, J = 2Hz, C ₄ -H), 4.35 (2H, s, C1CH2), 4.8 (1H, dd, 3z J = 9, C ₃ -2), 7.4 (12, s, s ^^ 3), 9.6 (12, d, J = 9Hz, C3-NH).

cooch ₃ ), J = 2Hz,

Example 25

To a solution of 320 mg of 2- [2- (2-chloro-tertimidio-24-holitholyl) -acetamido] -2-l-triethyin-4-clobloylic acid in 2 ml of act, act act yl yl orm O O ia ia ia u 282 282 was added 282.3 mg of pyridine sulfuric acid complex. The mixture was stirred at room temperature for 48 hours. It will be added. an additional 141 mg of pyridine sulfur trioxide.

Stirring was continued for another 24 hours. 30 ml of ether are then added and the ether layer is decanted off. This procedure is repeated twice. The resulting syrupy substance, which is n-soluble in ether, was triturated in 10 ml of water.

The insoluble material was filtered off. Pass the filtrate through a Dowex 50W (Na-form) column. The eluent is concentrated to a volume of about 10 ml under reduced pressure and purified by chromatography on an Amberlite XALdii column. After freeze-drying, the sodium salt of cis-3 - [(2- (2-chloroaceaamido-4-thiazolyl) -acetamido] -4- (1-thiocarbamoyl) -20-oxo-ethyl] -2-sulfonic acid is obtained.

^{IR (? max 'cm 3): 3 600-3 2} ° 0, 1 ⁷⁹⁰ to 1 760 1 680 1 ⁶ 0 ° NMR spectrum (DMSSOdg ppm) 3 26 (2H, s, S γ) 3.56 (3H, s, COOCH 3), 4.32 (2H, s, C 1 CH-), 4.43 (1H, 2 H -2 C ^H ₂ D, J -Z 6 Η, H · 9 Hz, C3 -H), 6.92 (1H, s, OH), 8.70 (1H, d, J = 9Hz, C3-NH), 12.56

A (1 H, br s, C 1 CH (CONN)).

For C ^ _2H ^H -Cl,6NOOSSSH,9 requires: C, 29.97; H, 2.93; N, 11.65. Found: C, 30.13; H, 3.29; N, 12.02.

Example 26

In the same manner as in Example 11 was prepared the sodium salt of 3- £ CII-2- (22abinog442hh ^and zg0yč) ACEO 2 ^m. (^ T: 0- ⁴ 2mClh) oy ^y aa] abOJ ^ ^t ^ - ² ^ j ^ 22om and ^ t ^ ^c . ^If I ^tZl2 Sul ^ ^ i ^ ^ oic JTR IcyseHn ^ 1 ^{C p} ektrum (cm ^l):

330, 1 790-1 750 and 1 680, 1 625 and 1 060. NMR (DMSSOdg ppm): 3.32 (2H, s, CH>, 3.32 (2H, s, CH ₂₎ 3, 59 (3H, s, COOCCH), 4.42 (1H, d, J = 6 Hz, C4-H), 5.29 (1H, dd, J = 6 Hz, J = 9 Hz, rH) , 6.28 (1H, s, H .___ O) 7-2 ^ 0 (2H, br s, NH ₀₎ 81 - - 59 (1H, d, J = 9 Hz, C ₃ - _N11). X

For C ₁₀ H ₁₁ N ₄ NaO ₂ H ₂ S ₂ · H ₂ O calculated: 29.70% C, 3.24% H, 13.85% N; Found:% C, 29.98;% H, 3.49%.

Example 27

To the solution¹⁶⁹ mg of the beta-isomer of the mm @ 2 ester c^ands- ^ 2 ^ '{D²2² [4- (Bu-1,1'-dioxo-1-piperazin) carboxandido - ^ - den ^ acetam ^ o | -²- ^ oxoazc^o1^^F: ^ r ^^⁴^^^to^ a ^ rl ^ o ^ x^yi^ ové^toysel^andn^{y (}re^Feren^Cn^and ex^land^{d 39)}114 mg of p-complex are added in 1 ml of Ν, Ν-dibasulforbabide^ysulfur trioxide.

The suspension is stirred at the temperature of the miter. After ten days, and then after a further one day, added 57 mg of p ^y kommlexu rifin2oxid trioxide. The reaction mixture was stirred for a total of 12 days. 20 ml of ether are added. The ether layer was decanted.

This procedure is repeated twice. The remaining undissolved material was suspended in 25 ml of water. Dowex 50W (Naaformaa) was added and the mixture was stirred at room temperature for 1.5 hours to give a powdery product which was dissolved in a small amount of water and the aqueous solution was purified on an Amerllt XADd2I chrommaograaii column.

After l ^y ^ i ^ il ^{i i} .zac eluate from ^{ISK and} sodium ^{C 2} S 3 ² | D ² 2 ^{2 [4} - (BuLi ^{0C) 22} 3 ^{2 g} l ^-pi digxo piperazinyl ^I O ² karboxaimddg ²² 2 ^- ene ^nt acetamiId0-- ⁴² BE ^C hog ^χč krbogyl- ²² -gχazeti ^If n ^o l ² Sulfongv Yssel ^{e k and y} n ^{(beta 2} 2i ^ £ ^ o> m ^ e ^).

IR ^spc Koru ^{m (C} ^ ^{m_1): 3410, 1775, 1720,} 1685, 1290 ^and 055. 1 H NMR ^ ktiriOT (DMSO-d ^pp m): 3.09 (3H, s, COOOCh) 4.37 (1H, d, J = 6Hz, C 4 H), 5.20 (1H, dd, J = 6Hz, J = 9Hz, C 4 H), 5.54 (1H, d, J = 7.5 Hz, bitches.

For c22H26 5NaO10S.2H2O vyjDočteno ^N: 5.08% H, 11.41% N. [t] = ²¹² 9 ^O (C

% C, 43.21;% H, 4.94;

0 ^{155: j} H O).

11.45% N;

43.10% C,

In the same manner as above, the corresponding IR (cm): 3450, ^{1 780/1 7 2 0/} 1 6 80/1 2 70 1 The ^55th With ^p ektrum NMR (DMSO-d₆, ^pp m):

3.60 (3H, s, _COOCH3) / 4/47 (1H, d, J = 6Hz, C4-H), 5.13 (1H, dd, J = 6 Hz, J = 9 Hz, Cj- U), 5.48 (1H, d, J = 7.5Hz, phenyl-1H).

For C 22 ^H 26 ^N 5 ^N aO10S. H, 4.94; N, 11.45. found: 43.66% C., 4.85% H, 11.54% N. ²² = -43.7 ° (c = 0.135, 1H).

Example 28

In the same manner as in Example 27, the alpha- and beta-isomer of sodium salt of cis-3 {d-²- [4- (^butyl)^-^²! з^--d^iVovc-^l-^ -ⁱ⁰^^E) (^ j ^ an^-k ^^j^_l^ l ^ⁱⁿoamií^andvΊ -2- (2-^thien^yl) acetates^dN, N -methoxycarbonyl -2-oxoaealidine-1-suioonic acids.

Beta-isomer: 1 H-NMR spectrum (DMSO-d6, 5.31 (1H, dd, J = 6 Hz, J = 9)

KBr max (cm ppm): 3.26

Hz, C.--H), ¹ ): 3,300, 1,775, 1,710, 1,675, 1 at 520, 1,370, (3H, s, COOCHh),

5.82 (1 H, d, J =

4.40 (1H, d, J = 6Hz, C ₄ -1I), 7.5Hz, Π P).

^s ^ c н

For H ₂ oH ₂₄ N ₅ O ₂ NaO1oO2.23 calculated: 38.89% C, 4.56% H, 11.30% N.

H, 4.56; N, 11.34;

found:

38.50% C,

Alla-ivomer: 1C spectrum 1185. NMR Spectrum (DMSO-d6 5.17 (1H, dd, J = 6Hz, J = 9, KBr · (v, cm max ppm)): 3.61

Hz, C ₃ -H,

Λ ^{1 :} 3 300 ^, 1780, 1720, 1 (3H, s, COOCl 3), 4.46 (1H, 5.73 (1H, d, J = 7.5 Hz),

680

520, 1370 and d, J

= 6 Hz, C ₄ H).

CH

For C 20 ^H 24 NaO 10 S 2 · ^Η 2 ° calculated: 40.06% C, 4.37% H, 11.68% N; Found:% C, 39.64;% H, 4.53;% N, 11.54.

Example 29

K roeto^toat²⁶¹ mg metal smear^beta-^withoomer cii^-3^{- {}D-²-^-[4- (vkt^ll) -², 3-^Fivxv-1-p^Operai^andO karboxamidoo-²- (²--and^hieo^ylj aceaamiavJ-²-vxvazeti^andin-4-^toarbvx^ylvv^{é ky}se^tio^y (referential^pExample 39) 155 mg of pyridine-sulfur trioxide code are added in 2 ml of Ν, Ν-diethylvrimide. The mixture was stirred for 5 days at an isinium temperature.

To the reaction network was added 20 mL of ether. The ether layer is decanted. This procedure is repeated three times. The solids insoluble in ether are suspended in 50 ml of water. Dowex 50W (Na-form) was added to the suspension, and the mixture was stirred at room temperature for 2 hours. The resin was filtered off. The filtrate was lysed.

The resulting powdery product spans in a small volume of water. The solution is purified by chromatography on an Anmbrlite XAD-I column and the eluate is filtered. Prepared sodium salt of cis-3- ^[D-2- [4- (oKLky].) - ^{2, 3-AI} vxo- ^- eaez ^{0 t} op ^{of the} kkab xxaii ^and vj ^{-2- (2} - ^T Hien ^s)) ctetaii ^d o ^}

-2-oxoajeti ^{d io-l-yl} sulVonvvé to seeioy (isomef beta]. IR (vcm ^1. 3400, 1760, 1v 670. NMR ^(DMSO-d _6, ppm) 3.62 ( 3H, s, COCCl 3), 4.48 (1H, d, J = 6Hz, C 4 -H), 5.77 (1H, d, nn ⁾ .

For H2 ₄ H ₃ 2N5NaO10O2.2H2D calculated:

H, 5.64; N, 10.64.

% C, 42.79;% H, 5.39;% N, 10.40.

In the same manner as above with ^iC ^ ktrum cm ^{-1): 3400, 1765,} was prepared socme alpha] vdaooídající compound.

⁶ 75. NMR ktrum s ^ (DMSS) - ^{and _б,} ppm): ^{3.22 (3H,} s

СООСНр ,. 4.42 (1H, d, J = 6Hz, C ₄ -H), 5.35 (1H, dd, J = 6Hz, J = 9Hz, C 1 H), 5.88 '(1H,

For ^C 24 ^H 32 ^Na 10 ° 2.2HjC ^S: calculated: 42.79% C, 5.39% H, 10.40% N; Found: C, 42.64; H, 5.51; N, 10.62.

Example 30

К, a solution of ³³⁰ mg menhjnstnru ^b ett- roenru t.rtss- ^{N 3} - [| D ^- 2 · ^{- (4-rktyl-2, 3} -dirxo "L ^{p r} i ^to r ^b nrtzis oxtmidoj2- (2 ^{- hy} INS ¹ la ^r acntaeido rxrtzeti ^--2-d-4-one karbrx hunting SZI ^e ^ ^ ¹ (R ^f nrnn her ^c. example 39) in 2 mL of Ν, Ν-dient.hylromnaeidu was added 196 mg of KRE- The pyridine-sulfur trioxide mixture was stirred at room temperature.

On the third and fourth days, 98 mg of pyridine sulfur trioxide are added to the reaction mixture. The reaction mixture was then stirred for a total of four days. Add sn with 20 ml nthnru. The ether layer is decanated. This procedure was repeated twice. The resulting gum, which is insoluble elsewhere, is mixed with 15 ml of water and 15 ml of Dowex 50W (Na-foroaa).

The mixture was stirred at room temperature for 1.5 hours. The resin resin is filtered off. Filtrát sn

This yields a powdered product which dissolves in a small amount of water. The aqueous solution sn vyččstí iУromotorratfí DnOerlitu column of XAD-II náslndujn Prepared SN sodium -Trans-3-FD-2- ^(4-ethyl-r of ^{2, 3-LP} -dirxr etai ^{pn and n} and ^d of ^the oxaoi) -2- (2- iso ^{those 1L) and} d tccetao ^rj -4-ooZУyry1atboryS- 22orortetndin · L-suironové acid (Oett-isroez).

IC ^with pekhru ^m _(C ^m-1): 3 42 (^ 2930, 1780, ^1720, 1680, 1515 NMR spectrum (DMSOc-d₆, ppm): 3.68 (3H, s, COCC δ J, 3.98 (1H, d, J = 3 Hz, dd, J = 3 Hz, J = 9 Hz, C 1 H), 5.69 (1H, d, J = 8 Hz,)

255 and 1050.

44-Ю, 4.70 (1H,

CH

Jessližz sn proceeds in the same manner as the above-mentioned, producing a sniper-iroozr. IR (νmax cm ^-1 ): 3450, 2925 ^, 1780, 1710, 1680, 1510, 1470, 1465, 1260 and 1050. NMR Spectrum. (DMSOdd ppm): 3.66 (3H, s, COOCCl 3, 4.02 (1H, d, J = 3Hz, C ₄ -H), 4.72 (1H, dd, J = 3Hz, J = 9) Hz, C-H), 5.71 (1H, d, J = 7Hz, [lambda]).

S ^ CH

EXAMPLE 31

К 625 m ^{g of} a solution of ^IIS-4-y l- aczttoidomoth ³ - ^- N2- ^(2-t -chlrrtcztamidco4 thiazol ^{y 1} l) ^{2 2-yl} πιzt ^y rx mlinracettmidir- -oxoateZi ^II ou ² (i ^ s ^ s ^ ir ^ om) in ⁶ ml N, ^N-II ^ OEt ^y ^ 1 ^lira oπ AML ^and when u sn ^give 477 mg of p ^y komplnxu riiis R XII-sulfur. The mixture is stirred for 28 hours at a temperature of 27 to 28 ^° C.

90 ml of nitrile are added to the maceration mixture. Ethnic layer with decaine. Repeat this procedure twice. Dissolve the remaining syrup substance in 90 ml of water. К sn solution was added 70 ml Dówžxu 50W (NN-ioroaa. The mixture stirred at sn oístaoosi 3 hours. Pr ^{y y} sk Rice oddilt-rujna.

The filtrate was concentrated under reduced pressure. Coancnnrát se v^ypartially by chirography on a DOerlih XA-II column. after 1 ^¹O ^:^andlb ^ tc^and salt C is obtained^ands-4-aczttoi^andrmz^Ztl^y1-³-^{£ 2}- (²-ch^ysteed aceZa^tmdd-4 “th^yate^ry1) -²-ooZhon^y1m^OnortcZami^OO^ir2-oooara^eZd^andn^Ol^-su^lronrv^E ^ 3-1: 1^Ο1 jyn i (srmz).

IR spectrum (cm 3 340, 1770, 1660, 1650, 1275 and 1050). NMR spectrum (DMSO-d ₆ , ppm): 1.84 (3H, s, COCH 2), 3.1 to 3.4 (2H, m, CH 2 NH), 3.84 (3H, s, NOCH ₃ ), 3.9 to 3

4.2 (1H, m, C ₄ -U), 4.40 (2H, s, C ₁ CH ₂ ), 5.19 (1H, dd, J = 5 Hz, C ₃ H), 7.51 (1H , s, S. H)

9.40 (1H, d, J = 9 Hz, C ₃ -NH), 12.65 (1H, broad s, C 1 H 3 CONH).

For C ₁₄ U ₁₆ ClN ₆ KaO ₈ S ₂ .21 / 2H ₂ O calculated: 29.82% C, 3.75% H, 14.90% N; found: '·.

% H, 3.69;% N, 15.01.

Example 32

In the same manner as in Example 11, cis-4-acetamidomethyl-3- [2- (2-amino-4-thiazolo) -2-methoxyiminoacetamido-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

KRr - 1

IR spectrum (? _Max, cm): 3400, 1765, 1660, 1540, 1280, 1250 and 050. 1 H NMR (DMSO-d _6, ppm): 1.77 (3H, s, COCH ₃ ), 3.20-3.60 (2H, m, CH 2 NH), 3.86 (3H, s, NOCH ₃ ),

3.8 to 4.1 (1H, m, C ₄ -h), 5.12 (1H, dd, J = 5 Hz, J = 9 Hz, C ₃ -H), 6.81 (1H, s, SH),

7.15 (2H, br s, NH ₂ ), 9.33 (1H, d, J = 9 Hz, C 1 H -H).

For ^C j2 ^H 15 ^N 6 ^NaO 7 ^S 2 • ^2H 2 ° Calculated: 30.13% C, 4.00% H, 17.56% N; calculated: 30.43% C,

H, 4.12; N, 17.34.

Example 33

In the same manner as in Example 31, cis-4-benzamidomethyl-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared. Ir _(CIN lj. J 770, 1645, 1550, 1280 and 050. 1 H NMR (DMSO-d₆, ppm): 3.3 to 3.6 (2H, m, CH ₂ NH) 3 92 (3H, s, NOCH ₃ ), 4.0-4.3 (1H, m, C ₄ H),

4.45 (2H, s, C1CH _2), 5.28 (1H, dd, J = 5 Hz, J = 9 Hz, _C3-H), 7.54 (1H, s, H-Sx) 7 , 4 to

7.9 (5H, m, phenyl protons), 9.49 (1H, d, J = 9 Hz, C8-NH).

For _Ig C H ₁₈ ClN ₆ NaOgS ₂ .2H ₂ O Calculated: C 36.99%, H 3.59 0 13.62% N; found:

% C, 36.94;% H, 3.49;% N, 13.29.

Example 34

In the same manner as in Example 11, cis-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -4-benzamidomethyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared. IR spectrum ^(* max / cm ^-1): 1765, 1645, 1280, 050. 1 H NMR (DMSO-d6, ppm): 3.3 to

3.7 (2H, m, CH ₂ NH), 3.86 (3H, s, NOCHg), 3.9 to 4.3 (1H, m, _С д -Н), 5.23 (1H, dd, J = 5 Hz, J = 9 Hz, c ₃ -H), 6.82 (1H, s, S, H), 7.17 (2H, br s, NH ₂ ), 7.4-7.9 ( 5H, m, phenyl protons), 9.36 (1H, d, J = 9 Hz, C ₃ -NH).

For C ₁₇ H ₁₇ N ₆ S ₂ to 0 ₇ .2H ₂ 0: calculated: 37.78% C, 3.92% H, 15.55% N; found: 37.51% C,

H, 3.73; N, 15.67.

Example 35

In the same manner as in Example 31, sodium cis-3- [2- (2-chloroacetamido-4'-thiazolyl) - (Z) -2-methoxyiminoacetamido] -4- [2- (2-chloroacetamido-4'-thiazolyl)] was prepared. - (Z) -2-methoxyiminoacetoxymethyl] -2-oxoazetidine-1-sulfonic acid.

IR (vm, cm ^-1 ): 1770, 1765, 1670, 1560, 1275, 1050. NMR Spectrum (DMSO-d6, ppm): 3.83 and 3.89 (2 x 3) H, 2 xs, 2 x NOCl ₂ ), 4.31 (4H, 2 x C ₁ CH ₂ ), 4.1 to 4.4 (2H, m, CH ₂ OC-), 4.80 to 5.10 (1H , m, C ^ H), 5.31 (1H, dd, J = 5 Hz, J = 9 Hz, _C3-H), 7.19

For C ₂₀ H ₁₉ Cl ₂ N ₆ NaO ₃ S ₃ · 4H ₂ O calculated: 29.67% C, 3.36% H? 13.84% N; Found:% C, 29.53;% H, 3.11;% N, 13.83.

Example 36

To a solution of ²²¹ mg of ^{n e} SOU - ^ - S ^^^ - ^^ h ^ chloracetamiťžlo zz ^^ - Z) - ^{2-meth yl} minoacetami ^C ox ^d oo £-4- 2- (--chloracetamiiooC4 h ^C azo ^l-yl) - (Z) ^ ^ -mettoxy inoace-thioxo ^ et ^ l] -2 ^- lxoazz ^t i ^on in-1-sulfonic acid in 10 ml of water was added under ice cooling 85 mg of sodium monnometClOithiokabtamové acid stirring. The mixture was stirred with one Codin at milli temperature, then 40 mg of sodium mono-thiocioctrbamic acid sodium was added and the reaction mixture was stirred for another one Codin at a temperature of one minute.

The reaction mixture was washed with ethyl acetate and ethyl acetate, respectively. The reaction mixture was then concentrated under reduced pressure. The conjugate is purified by cromaZoogrz1 on a Aberlite XAD-II column. After following L ^ Dfiliza-i zí.s ^kA, with ^d n ^and salt -it-3-12 ^- (2 ^- imino-44 ^{- No} hiazo ^l y) ~ (Z) -2-metCoxyiminoacetamido1-4- (2- amino-4-trifluoromethyl-(Z) -methoxyiminotceoxymethyl] -2-oxo-azidine-1-sulfonic acid.

iC ktrum ^SPE (v ^, cm ^-1): 1760, ^1670, 1540, 1275 ^and 1 ppm): 3.80 <and 3.86 (2 x 3H, 2 x s, 2 x NOCH _3), 4 1 to 4.4 (2H,

050. ^NMR with ^p e ^k m trum, CH90C) 4.8 to ² if O (2 x 1H, 2 x s, 2

(NH 2).

(DMSSocdg,

5.05 (1H, X m, C4-H, 5.25 (1H, dd, J = 5 Hz, J = 9 Hz, _C3 -H), 6.63 and 6.94

S / H), 7.10 (2H, broad single, NH), 9.22 (1H, d, J = 9 Hz,

AND

For C ₁₆ H ₁₇ N ₈ NaO ₃ O ₃ .3H-O calculated: 30.09% C, 3.63% H, 17.55% N; Found:% C, 30.18;% H, 3.51;% N, 17.68.

Example 37

Úsobí same from ^{p to} s ^p I of manufacture of ice ^{to 30} were prepared in the salt of ^{d, cis-3-} [2- (2-chloracetam ^id o-4-thi azolyl) -2-metCoxy inoacetam ^ ^ ol - ⁴ - (З-г е ^е а ^е ^ t х 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 ^ in) ox oxoazet in in su suHono yš acid (syn isomee)

iC s ^p e ^k um (in ^KBr cm ^-) : max (DMSC) - ^d ₆ , ^p pm): 3.72 (2H, br s,

CICH2), 5.25 (1H, dd, J = 6Hz,

410, 1765, 1670, 1550, 1270, 1050. NMR Spectrum), 3.95 to 4.52 (1H, m, C4-H), 4.30 (2H, s,

CH

J = 9 Hz, C 3 H), 7.41 (1H, s, SH).

Ϊ

Example 38

In the same manner ^PU I ^to 11 s treasure swarm ^b i n ^{a d} with ^UL-cis-3- [2- ^(- -am ^m Ino azz ^{C4-HC l No} y) --- mehCox ^yl minotcetam ^I Oo ^{J -4-} (2- ^{t C} and ^TN-yl ttox ^No. mm ^ThCC) -2-ZL ^(D0 zozz i ^th AD ^- here again ^{10 e (syn Somm} i r). (C ^spec tru ^m (^ Z cm ^-1 ): 3400 ^, 1770, 1740, 1670, 1615, 1535, 1270, 1250 and 1050. NMR Spectrum (DMSOd6, ppm): 3.75 (3H, s, NOCH2); 5.20 (1H, dd, J = 6 Hz, J = 9 Hz, C-H), 6.71 (1H, s, s ₄ H), 7.14 (2H, br s, NH 2 9 22 (1H, d, C-NH).

X

For _lб Hз C ₆ N ₅ NaO ₃ O ₈ ^P tho ye octene: 34.22% C, 3.59% H, 12 ^47% N; found: 3 ^{4 4} 2% C, 3.32% H, 12.30% N.

Example 39

Zpteobem same as in pMkladu ³⁰ swarm ^b i n ^{a d} with ^UL ci.f ^ - ^ - ^ - ^ -tCiazo cWoracetamHo- ⁴ l) --- mehCoxy minoαcetamiOo ^i] - ⁴ - ^{{l t} hc -mm ^Article tetrazolčl ^H l ^{(~5) -1-Star} suioonov ^acid; n ^y (syn-ommr). iC Spec microns ⁽ⁱⁿ crn ^: ^{3420, 1765, 1660, 1560} and 050. 1 H NMR (DMSSodg, ppm): 3.91 (3H, s, NCH3), 3.94 (3H, s , OCH 3, 4.34 (2H, s, C1CH _2), 5.29 (1H, dd, J = 6Hz, C3-H)

7.48 (1 H, s,

9.46 (1H, d, J = 9Hz, Cl-NH).

Example 40

The same. z ^ manner Jato v ^ i ^ range of ¹¹ v.roM croscarmellose c ⁱ t ³ t · ^[2 - ⁽² -lninni ^{t h} -TH aa! ^iyt O) ^t2 -yet ^h ox ^{y O} iyinoacetam ⁱ dc - 4- t ² tphoaleeidin-1-su ^fi (new

KRr —1 tyselto. (s ^y n ⁱ ^ soy ^ r). IC ektrum (Vmax / cm): 4 ° ^{3 1} 7 ^{70 1 660 1 61 1535} 0 ¹ 2 ⁸ 0 · 1 and 050. NMR (DMSS-d6, ppm): 3.88 (3H δ, NCI δ, 3.92 (3H, s, OCH ₃ ), 5.22 (1H, dd, J = 6Hz, J = 9Hz, C ₃ -H), 6.75 (1H, s, SVH), 7.13 (2H, br s, NH 2, 9.31 (1H, d, J = 9 Hz, C ₃ -NH).

For C3 H34NgNaOgS3.21 ₂ / 2H ₂ O · Calculated: 26.46% C, 3.52% H, 23.15% N; found: 26.46%, 3.59% H, 22.70% N.

Example 41

Similarly zptoobem Jato 10 in the ^y ro ^B i ^^ siil ^and sodium - 3 ^- £ ² - ^{(2 t h} i loaace ^and Уyido- ^4- tt ^ ^h · l ^ц ^: ^ o ^{T1) T (m-r} (^ t ^ ⁱ ^ ^O oУ ^y n ^ ^N ^ OAc (2 ^l y ^ ci ^f] -4tyn ^{e t} t ^h hh ifye ^rtht 1 ² -oxofle id ^{r d n-1 fi} nNew ^alkyl sulphonyl Selin ^y ( s ^y n ^ ⁿ ^ e toy). Jktaum ic ^ (^ У ах 'cm ^{3): 3} 4 ^{2 0} 1 76 ^0, 1660, 1550, 1270, 1240 and 050. 1 H NMR coming ^ µm (DMSS-dg ppm): 2.08 (3H, s, SCH ₃ ), 2.68-3.06 (2H, m, CH 3 S), 3.89 (3H, s, NOCH ₃ ), 4 32 (2H, s, C ₁ H ₃ ), 7.42 (1H, s, S 1 H).

Example 42

The sodium salt i was prepared in the same manner as in Example 11^andt^t3^t[^2t(^2tlyinn^it4tthalo^i1t) t²-yethofy^yminc) flctamino^di4-^ynt^ry^hУh^hoont^ry^hy^-2tfOfzet^rd^dn-l-tu^finew toselii-n. (with^yn^and(e). IC ^ ectr ^ (v [1^x»^cm^¹1300, 1760, 1660, 1 605, 1 535, 1 380, 1 245 and 1 050. NMR Spectrum (DMSO-d6 ppm): 2.08 (3H, s, SC3, 2.70) up to 3.12 (2H, m, C ^ SS), 3.71 (3H, s, ΜΟΜΟ),

6.74 (1H, s, S H), 7.14 (2H, br s, NH ₀ ).

X

Example 43

055. NMR Spectrum (DMSO-d6, (2H, s, ClCH2)): 5.10 (1H, J = 9 Hz, C3-NH).

In the same manner Jato ^ Jítoadu 1 ° in ^y ro ^b i c ⁱ sodium t-3- ^[22 - ^{(CH 2 c i l} oaace ayidf ^T4T haaz ^ ^ y ^ -N-rehfoxyi inflcrtlmi ^{y i} to ⁱ -4- tmrh ^hy l220oxflet ^{e (id} NNL TTL sulfonic k.selto ^{f. (Y} n ^ оууг). IC ^sp e ^to tau ^s (in ^{cm -1):} 3420, 1760, 1670, ^1560, 1275 and 1 ppm): 1.26 (3H, d, J = 6Hz, C4-CH3), 3.98% 3H, s, NOCl4), 4.32dd, J = 6Hz, J = 9Hz C ₃ -H), 7.38 (1H, s, 5H, H), 9.33 (1H, d,

Ex. o cm ^): ^{3 41} 0, · ^{1 76} 0, ¹ 60 60, 1 5 ³ 5, South and South. NMK spexrrum ψηου-α-d, 4-CH3), 3.82 (3H, s, ₃ NOCC), 5.08 (1H, dd, J = 6 Hz, J = 9 Hz, C-H,

H, 7.16 (2H, br s, NH2), 9.24 (1H, d, J = 9Hz, C, NH).

Zptootom same as VP ≤ k ≤ 11, the range of ^y in the RF ^bi sodium IIT ^{-3 t [2 tons (2} lyinn ^it4tth allo ^iyy) 2- ^t ethox ^y i ^{y y n} to inoaietay) - ^{4 th} TYER ² t - ixoiLle ^e idin- ¹ -su ^fi nNew ^0у 5 «^ ¹ ^ _ ^{п п} у ^(syn TOMRA ^ ^n). IC ^SPRK tau ^s (V c ^{m -1):} 3410 · 1760, 1660, 1535, 1245 and 060. 1 H NMR ^ ektrum (DMSO-d _(ppm): 1.22 (3H

6.72 (1H, s, S peaks and d

500 mg cii. with 3 - ^ - 2 CCH ² rlcre ^{i l l} th ayidf ^{T4T the} azo ^{- (- n} -rt ^hf oy ^{n yn} m cOlcrtlyido ⁰ 4- ^(4-

To a solution of trifluoromethyl-22-oxylzetidine (syn isomer) in 12 ml of N, N-diethyl Ooynayide was added 353 mg of sulfur trioxide pfridine foxide. The mixture was allowed to stand for 18 days at room temperature. Ether (150 ml) was added to the reaction mixture.

The supernatant ether layer was removed. To the residue was added 30 mL of water, 30 mL of ethyl.

acetate and 10 ml tttralyrrdfuraou. The sites shake. The organic layer was extracted again with 30 mL of water. The aqueous layers were passed through, 20 mL of Dowex 50W (Ia-form) was added thereto, and the mixture was stirred at room temperature for 30 minutes. The resin was filtered off. The filtrate was zahuiusí n for ^eh at the L ^ That it, it does not rise ^above-30 ° C

eats

Ionate is purified by chroimaooyaafi on an Ambrite XAA-II column. After lyofiUzaci z ^{i KA and} sodium salt of ^cis-3 - ^{[2- (2-r} c ^h ldract aii ^{i o} 4- ^-TH iazd ^No yl) - ^{i i} -trl ^d xxy rπ ^of doactaam ^and R ^{4 d} Jd - ^{(4-ChI d} r phenyl) -2-L-dXdajeerdlo sufdonooé acid (syn isdme).

IR _(, cm ^-1): 3.73 (3H, s, KCCCh ,, 4.30 (2H, s, C H H _2). 5; 11 (1Η, Ti, J = 5 Hz, C ₄ -H) 5.32 (1H, dd, J = 5Hz, J = 8Hz, C3-H), 5.75 (1H, s, S ' H), 9.23 (1H, d, J = 8Hz) , C ₃ -IH)

Example 46 (c) (c).

^S 5.45 tejným ^PU manner ^j ATO in pii ^ ACLU ¹¹ weeks ^{and 3} d_2- cπs- salt ^{(2 d} amiIπo- ⁴ -TH Alz ^{l d} y ^{y) and} d2 manoacteгmir0j-methoxy-4 ^d (C 4 ^{d ( d} ) 2-dxdaletrrio-1-suldonic acid (syn IC spectrum (V cm - 2 420, 1 758, 1 660, 1 525, 1 270 and 1 050). UR spectrum + D ₂ K, ppm): 3.88 (3H, sH, J), 5.11 (1H, s, SyH), 5.33 (1H, d, J = 5Hz, JH), (1H, d, J = 5Hz, C3) ^d H)

For CззHззIlN ₅ NaKyS ₂ .3H2O: calculated: 33.61% C, 3.57% H, 13.07% I Found: 33.61% C 3.28% H 12.77% I

Example 47

In the same manner as in Example 10 was prepared the sodium salt of cis-3- ^ 2- (2-c ^{and d} 0olacelaiidOd4d -TH a2O ^y yl) methyl-d2 χyy ^{LD i} m ⁿ d ^{j ir doacetam]} -4- ^(N, N ^Dr. IMET ^Hylke arblmo ^oyl) -2-dxoalz d ^{sr o -} l-su ^fo -ones tyseHo ^{s' (y} n ^and s ^ e SDM). With IC ^ trum (V ^ ax 'cm: ^{1 77 0,} 1 ⁶⁶⁰ and ^{1 550th} N ^MR ^ Torum (dd-DlSO ^ and 3.0 (2 x 3H, 2 x s, N (IHз) ₂₎ 3.86 (3H, s, ^ IJC), 4.2 (2H, s, C1CH _2), 5.0 = 6Hz, C4-H), 5.53 (1H, dd, J = 6 Hz, J = 9 Hz, ppm): 2.8 (1H, d, J)

Example 48

Same way Jato vp ^^ du ^{11 characterized} in weeks ^and makes salt of cis ^-3- £ · ^d 2 ^(d 2 lm ^m πo ^{4 4} t ^rl Alz ^dyy) d2dmethoxyiminoacetn ^m to ^about - ^{4- (N,} Nd ^r IMET ^hyl0 lrbamo ^dУ ) d2ddxoalz ^tr dio-l-su ^fd onoo ^é IcyseMo '

KRr-1 (with ^y n ^Π ^ som ^ t). ^iC setrům (in cm ^{-1): 3 35 0, 1 780} and ¹ 660. N ^{MR p} ektržm ^{(DMSO-d c, pp} m):

δ (N (CH ₃ ) ₂ ), 3.83 (3H, s, IKCl 3), 4.93 (1H, d, J = 6Hz, C 4 -H), Hz, J = 9Hz, H), 6.6 (1H, s, SKH), 8.96 (1H, d, J = 9Hz, C 2 H 4 NH).

χ 3

2.8

5.3 and 3.0 (2x (1H, dd, J)

3H, = 6

To a solution of the acid in 2.8 mL

The mixture was stirred for 2 days at sulfur trioxide temperature.

278 mg of cas-3 ^d beozyloxycarbodexamido [1,2- ^d] -dex-4-carboxylic acid N, N-dimethylacetamide are added 320 mg of pyridine-sulfur trioxide complex.

an additional 120 mg of the bowl complex. To the reaction mixture was added

The mixture was stirred for an additional 1 hour and the mixture was separated and the solution was allowed to stir with water and ether. The resulting powder was dissolved in 5 ml of water.

day. To the reaction mixture was added 50 mL washed with ether. Powder-like product

The Dowex 50W (IIaformca.) The lychilisate of the enzyme was dissolved in a small column and purified by chromatography on an Ambrlite XAA-I column.

the product thus purified yields the sodium salt of cas-3-benzyloxycarboxamido-4 ^cm -1: 3 300 d, J = 5 Hz, ₁₄ -H),

LyOH-zát _ _ _ _ _

-mithl) d ^χ Уtrbinyn ^yd -doxdze ^of d n ^{r n} L ^d are ^f0 enov ^{s ky and} the ^y sel. .C spectrum and 1 IIR 750. NMR (DMSO-d _6, ppm): 3.56 (3H, s, CH3), 4.43 (1H,

7.36 (5H, s, phenyl protons), 8.13 (1H, d, J = 9 Hz, D).

For C ₁₃ H ₁₃ N ₂ NaO ₅ S · H ₂ O calculated: 39.19% C, 3.79% H, 7.03% N; Found: C, 39.04; H, 3.99; N, 7.26.

Example 50

To a solution of 190 mg of cis-3-benzyloxycarboxamido-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid monohydrate in 10 ml of water was added 190 mg of 10% palladium on carbon. It was then catalytically reduced for one hour at room temperature and normal pressure. The reaction mixture was passed through a pad of celite to filter out the catalyst. The filtrate was lyophilized. Produces: ο cis-3-amino-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt. IR max ^{IV 'cro-1)} * ^3450, 1770, 1740 and 060. 1 H NMR (DMSO-d₆, ppm): 2.7 to 3.5 (2H, broad singlet, NH ₂₎ 3, 67 (3H, s, CH ₃ ), 4.33 (2H, s, and C 1 H -H).

For C ₅ H _? N ₂ NaO ₆ S.1 1/2 of H₂O Calculated: 21.98% C, 3.68% H, 10.35% N; found: 22.10% C,

H, 3.69; N, 10.48.

Example 51

In the same manner as in Example 30, cis-3- (2-thienylacetamido) -4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt was prepared. IR (cm -1): 3550,

770, 1680, 1540, 1440, 1260 and 060. 1 H NMR (DMSO-d₆, ppm): 3.53 (3H, s, _CH3), 3.68 (2H> s, CH ₂₎ , 4.43 (1H, d, J = 6 Hz, Сд-Н), 5.26 (1H, dd, J = 6 Hz, J = 9 Hz, _C3-H)

8.85 (1H, doublet, J = 9Hz, NH).

Example 52

To a solution of 380 mg of cis-3- (1H-tetrazol-1-ylacetamido) -2-oxoazetidine-4-carboxylic acid methyl ester in 3 ml of N, N-dimethylacetamide was added 807 mg of pyridine-sulfur trioxide complex. The mixture was stirred at 70 ° C for 4 hours. 50 ml of ether are then added. The ether layer was decanted. To the residue was added 50 ml of ether again. The procedure is repeated two more times. Dissolve the undissolved material in 5 ml of water. The aqueous solution is passed through a column packed with 40 ml of Amberlite IR-120 (SOgNa-form) and then purified by chromatography on an Amberlite XAD-II column. the desired fractions are lyophilized. This is followed by purification on a Sephadex LH-20 column. The eluate from the chromatography is again lyophilized. The sodium salt of cis-3- (1H-tetrazol-1-ylacetamido) -4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid was prepared.

IR spectrum (ν max / cm ^-1 ): 3400, 1770, 1700, 1630, 1550, 1440, 1280, 1260,

180, 1100 and 060. 1 H NMR (DMSO-d₆, ppm): 3.68 (3H, s, _CH3), 4.48 (1H, d, J = 6Hz, C ₄ -H), 5 26 (2H, s, CH ₂ ), 5.29 (1H, dd, J = 6Hz, J = 9Hz, Cg-H), 9.30 (1H, s, Ν = Ν _χ ),

9.31 (1H, d, J = 9Hz, NH). | N—

N = C ^Z H

For C ₈ H ₉ NgNaO _? H, 3.28; N, 22.76. found:

% C, 25.89;% H, 3.25;% N, 22.72.

Example 53

In the same manner as in Example 52, cis-3- (1-ethyl-1,4-dihydro-7-methyl-4-chloro-1,8-naphthylidin-3-ylcarbonylamino) -4-methoxycarbonyl- 2-oxoazetidine-1-sulfonic acid, the reaction time being reduced to one hour.

IC spectrum (V cm ^-1 ); 3,450, 1,770, 1,660, 1,615, 1,540, 1,500, 1,450, 1,370,

260, 1060. NMR Spectrum (DMSO-d6, ppm): 1.40 (3H, t, J = 7Hz, CH3CHp, 2.63 (3H, s,)), 3.66 (3H, s, COOCH3 ₎ ), 4.57 (1H, d, J = 6Hz, C ₄ H), 4.58 (2H, quartet, J =

CH ₃

= Ί Hz, CH ₂ CH ₃ ), 5.68 (1H, dd, J)

В

= 6 Hz, J =

O

Hz, C3-H), 7.49 (a), 10.45 (1H, d, J)

8.58 (2 × 1H, 2 × d, = 9 Hz, NH).

CH ₃

Et

For C _1? H ₁₇ N ₄ to 0 ₈ SH ₂ 0: calculated: 42.68% C, 4.00% Ή 11.71 4.28% H, 11.57% N.

% N; found: 42.62% C,

Example 54

To a solution of 409 mg of cis -3- (2-chloroacetyloxy-2-ieniaca-yeido) -2-oxo-alpha-pyridine-4-carboxylic acid meehhlestec in 2 ml of N, N-diethylpolyacid was added 549 mg of pyridine-sulfur trioxide complex. ^R ^ <^! To ^to ^ i ^: ^{s with} a mixture with one mícM Todina ^p s ⁷⁰ ° C. We ctatóní solder ^on a ^m mixture add ⁵⁰ ml ether, stirring was continued, and finally the ether layer dekaanuje. This procedure is repeated twice more. Addition of 15 ml of a 1M aqueous solution of sodium pyrophosphate to the remaining insoluble drugs will cause these substances to dissolve. The solution was stirred at room temperature for one hour. The reaction solution was then passed through a column packed with 40 ml of Ambrtit IR-120 (Na ₃ S -form). The desired fractions were twenty times overrun with cPromeaolithia on an Ameritite XAD-I column and then further purified on a SepPadex LH-20 column. Takao purified produka st ^ НИг ^ е. It produces the sodium salt of cis-3- (4-hydroxy-4-hydroxy-phenylamino) -4-methyl-oxoyl-2-ol: xoleaidin-1-suilonic acid.

KBr - 1 as a mixture of diltterelisomers. IC spectrum V V _max cm: 3,400, 1,770, 1,680, 1,520, 1,445, 1,380, 1,260, 1,100 and 1,060. NMR Spectrum (DMSO-d6, ppm): 3.44 and 3 56 (3H, 2 xs, COOCH 3), 4.43 and 4.44 (1H, 2 xd, -J = 6 Hz, C4-H), 4.98 and 5.01 (1H, 2 xs, ienyl- CH, 5.31 (1H, dd, J = 6Hz, J = 9Hz, C3-H, 7.32 (5H, s, itnyl protons), 8.00 and 8.33 (1H, 2xd, NH) ).

For C ₁₃ H ₁₃ N ₂ NaO ₅ S · 1 / 2H ₂ O calculated: 40.11% C, 3.62% H, 7.02% N; found: 39.93% C,

H, 3.94; N, 7.19.

Example 55

To a solution of 109 mg of ethyl-3- (D-2-phenyl-4-enyl-acetamide) -2-oxoazeaidin-4-oxoxoic acid in the form of sodium salt in 1.5 ml of N, N-dimethyioorramide is added with cooling and stirring. 2 ml of sulfur trioxide-N, N-diethhyormormide complex (1,2M). After addition the reaction was allowed st ^and STAs 24 Todina te ^p s ^p] rt ^{of 5} ° C. ^To a otatoní ei ^ st Add, ^{and 0.5} ml of pyridine. ^MES st ^p and ^k stirred for 5 minutes. 30 ml of ether are then added. The ether layer was removed and 30 ml of ether was again added to the mixture and the ether layer was removed again. The remaining undissolved material was dissolved in 2 ml of a 1M aqueous solution of sodium pydrogate. The solution is passed through an Amerlite IR-120 ((NiSO 3 - ^ Foo 4) column) and then purified by chromatography on an Ambrlite XAO - I column and Sephadex LH - 20 column to obtain cis - 3- ( D-2-Suio-2-effloroacetyl-4-methoxybenzyl-4-methyl-2-oxo-azetidine as a mixture of diasaereomers.

IC ^sp ektru ^m (Vax ^{'cm-1): 3450, 1770, 1680, 1535, 1440, 1290, 1250,} 1100 and 055. 1 H NMR (DMSO-d₆, ppm): 3 , 42 and 3.66 (3H, 2 xs, O 3 O 3), 4.39 and 4.42 (1H, 2 x d, J = 6 Hz, C4-H), 4.50 and 4.54 (1H, 2 xs, phenyl-CH), ^5, 2 to 5.5 (1H, m, C H), 7.1 to 7.6 (5H, m, ienylové protons), 8.87 and 8.96 (1 H , 2 xd, J = 9 Hz, NH). '

For C13H1 ₂ N ₂ N) ₂ - _1o S2.4 1 / 2H ₂ O Calculated: 28.52% C, 3.87% H, 5.12% N; Found: C, 28.64; H, 3.61; N, 5.00.

Example 56

In the same manner as in Example 53, the sodium salt of cit-3- (2-ethynyloxycarboline-20-phenyl-LC-thiocido) -4-teethPl-4-phenylbutyl02Oxoxyl-zincine-tullonic acid was prepared as a mixture of the .alpha.-isomers.

IC speet) ·· u (. K ^ / c ^J1) J ^{400, 1780, 1750,} 1535, 1450, 1260 and 060. 1 H NMR (DMSO-FDG, ppm): 2.0 2 _and .., 4 2 (3H, 2 xs, HOOOHh), 4.36 and 4.4 5 (1H, 2 xd, J = sixth Hz, C ₄ -H), 4.86 and 4.89 (IIi Phenyl, CH, 5.12 and 5.15 (2H, 2 * s, phenyl-CH2), 5.1-5.4 (1H, m, C3-H); 34 (10H, s, 2 x phenyl), 9.11 (1H, d, J = 9Hz, NH).

For C 21 H 21 N ₂ O 9 S ₂ O ₂ requires: C, 48.84; H, 4.10; N, 5.42. Found: 48.60% C,

4.25% H, 5.6? N.

Example 57

Κ Cl 6-80% ethanol was added 106 mg of sodium SOU cis-3- (2-beizyl iylarborlir-2-feiylacetamídc - 4-Meeth irlrbbnyir22 - _χ-L-e ticlČIil sullonové kseH-ny, 106 mg of 5 The mixture was stirred under an atmosphere of hydrogen at room temperature and at atmospheric pressure for 3.5 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. Purified by clumato-gaaffi on an Anerlitite column After freeze-drying, the disodium salt of cis-3- (2-carboxyr-2-phenylcetyl) -4-phenyl-hexylbenzyl-1-sulpho-2-oxoazetidine is obtained as a diastyl mixture. They are dried.

IC (? /? Cm? ¹ ) ^: 3,420 ^, 1,770 ^, 1,670 ^, 1,620, 1,530, 1,380, 1,290, 1,250, and 1,060. NMR Spectrum (DMSO-d6, ppm): 3.45 and 3.46 (3H, 2 xs, HOOOHH3, 4.40 and 4.48 '(1H, 2 xd, J = 6 Hz, C ₄ -H), 5.1-5.4 (1H, m, - 5.59 and 5.62 (1H, 2 xs, phenyl-CH), 7.23 5H, s, phenyl pr-t-i), 8.83 (1H, d, J = 9) Hz, NH).

For C1 ₄ 1/2 H12N2Na2OgO.3 HJO calculated: 34.08% C, 3.88% H, 5.68% N; found:

H, 4.13; N, 5.97.

Example 58

To a solution of 360 mg of cis-3-cyarethylethylcarbamido-220-x-isoltdine-4-carboxylic acid ethyl ester. of the acid in 3 ml of N, N-diethyltrifluoride was added 480 mg of pyridine-sulfur trioxide complex. The mixture is stirred. The mixture was then allowed to stand for 6 days at the temperature of the flask. Ether (20 ml) was added to the mixture. The mixture was then stirred again. The ether layer is decanted. 10 ml of ether are again added to the residue, the mixture is stirred again and the ether is removed again. The resulting oily product was r-dissolved in 10 ml of water. To the aqueous solution was added 10 ml of Dowex 50W (N-pharma), the mixture was stirred for 30 minutes at ambient temperature, the resin was filtered, and the filtrate was washed with 4 x 10 ml portions of water. The product thus obtained was dissolved in a small volume of water and purified by chromatography on an Anmerlite XAA-II column, then on a Sephadex LH-20 column, and finally the eluent of Lrlfilzil. Thus, cis-31-arylthiocarbonyl-4-fido-4-fel-4-yl-phenyl-2-ε-letedinilililic acid sodium salt was prepared.

IR (cm V ^_ 1): 2250, 1780, 1740, 1675, 1570, 048. 1 H NMR (DMSO-d ppm): 3.64 (2H, s, CH2), 3.67 (3H, s, CH3), 4.48 (1H, d, J = 6Hz, C4-H), 5.27 (1H, J = 6 Hz, J = 9 Hz, dd, C ₃ -H) 9.12 (1H, d, J = 9Hz, NH).

Example 59

To a solution of 341 m ^g p · nitKDbenz ^^ ^^ ⁱ c S ³ - ^L 2 ^(- -lH ^- olcce ^{and AI-Id} --4 Iaz t ^{l-yl) -2-m} av MLT ^{l i} i ⁱ notcltt ^mI d ^0] 2 - x ^f azzli-in- -кlrb ^{4-hunting s} x ^y ^ tyseli in ³ mL of the ^p řičlá

8 mg of pyridine sulfur trioxide. The mixture was stirred at 63 ° C for 63 hours. An additional portion of 103 mg of pyridine-sulfur trioxide complex was added to the mixture. The reaction mixture was stirred for an additional 38 hours. To the mixture was added 45 d. Of ether. The ether layer is filtered. This procedure is repeated twice. The remaining syrupy substance is suspended in 45 ml of water. 20 µl was added to the suspension. Dowex (Na-form). The mixture was stirred at room temperature for 1.5 hours. The resin was filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by chromatho-gaaffin on the clericite of XAA-II. No colorless powder was obtained. The powder is dissolved in 16 ml of water. To the solution was added mg of sodium monohydrate-ocrdimic acid under ice-cooling and stirring. The mixture was stirred for an additional hour at RT. A further portion of 68 mg of sodium monomethyldithiocarbamic acid is then added. The reaction mixture was stirred for an additional hour. The reaction mixture was then washed with ethyl acetate. The aqueous layer was purified on an AmbrHU XAD-II column. After l ^y ofilizaci the ZIS ^kA, with salt cit ^ -_ ^{3 2} - ⁽² -laino-4-t ^{h iai.oly))} -2-oxyl Meh ^{i 0} nolCltlaido] -4- (4-nirirbenzyioxykkrrioy1) -2 -ixoacelidio-1-sulionic acid (syn isomee).

IR with ^p ektrum cm ^-1): 1770, 1 7 ⁵ 0, 1 ⁶ 70 (DMSO-d _6, ppm: 3.81 (3H, s, NOCH3), 4.60 (1H, d, J 'J = 14 Hz, OCHnDr), 5.44 (1H, dd, J = 6Hz, J = 9Hz (2H, brs, NH2)), 7.73 (2H, d, J = 9Hz, D-protoc) 9/48 - (1H, d, J = 9Hz, C 3 -NH).

6Ж 1280 ^{to 1050,} with ^P NMR ektru ^m

Hz, C4-H)

Cq-H, 6.60

5.26 (2H, AB quartet, (1H, s,

_V O H), 7.13

X

8.17 (2H, d, J = 9Hz, D-protons),

For C3 ₇ H 3 N ₅ O ₆ NkO3 _{Q 2} .2H ₂ O Calculated: 34.82% C, 3.27% H, 14.33% N; Found:% C, 34.74;% H, 3.26;% N, 14.28.

Example 60

In a 10 ml-EI tetrkhydrofuranu and 10 ml of water, 155 mg sodium rozpuusí sooi cis-3-72 (2-km ^and nOi4 kiilyl ^hi-t) - ^{0 and} eth oyy ooace ^and m is ^{0, and the} AAID] ^- 4- M-yloxy nitroleozy ^y ^ and us!) - 2 - ooiae ^IL-dirol suioonové acid (syn i ^ s ^ e ^ om). 145 mg of 10% palladium on charcoal are added to the solution. The mixture is catalytically reduced at room temperature, under normal pressure and with stirring. After three hours, 10 ml of an aqueous solution of 25 mg of sodium hydrogen carbonate were added to the reaction mixture. The catalyst was filtered off. The filtrate was washed with ethyl acetate and ground under reduced pressure. The concentrate is purified by chromatography on an Amrrlit XAD-II column. The eluate was lyifilized. Cis-3- (2- (2H-methyl-4-hicolyl) 22-aethioxyacetyl ⁾ -44-carbonyl-1-sio-2-oxoalzeidiosodium (syn isomer) disodium salt was prepared. 760, 1660, 1 605, 1270 and 1050. NMR Spectrum (DMSO-dg ppm) δ 3.82 (3H / 8 / NOOO / 4.17 (1H, d, J = 6 Hz, C4-H) ), 5.12 (1H, dd, J = 6Hz, J = 9Hz,

CyHb 7/10

7.13 (2H, br s, NH, 8.62 (1H, d, C ₃ -NH)

For £ 10 ^^^ 20 ^ 2 ^ 3 1/2 H ₂ O Calculated: 24.00% C, 3.22% H, 14.00% N; Found: C, 24.00; H, 3.14; N, 13.86.

Example 61

In 7 ml of Ν, Ν-dialthyliramaaids rozpuutí with 462 mg aalhhllstlru cit-3- [2- (2-chliracltaaidi · - ⁴ -TH ^and Zioła ^{Y) -, and} Ar ^{0 kk} -mhthox nyylme ^h hy ⁱ _O yyim esterification ^c · AAI ^{d l} o] -2 ^- iXiazi! If ^d io ⁴ -klr iX ^{r y y} ester to Selice ^y (syn. for οΙγΙ Ι ^! ⁰ o and ⁷⁸ ° C ^{can be} extended when tomplexu oxi ^d ^ t ⁱ aový N, N ^{-di i} aethyl oaaamid ^(about 3 mm). OMES the mícM ^18h Odin ^p s ⁴ ° C. Otom ^p is ^{p p} s ^can Yai ^d ic (3 mnml) and the mixture stirred another hour. After addition of 100 ml of ether and ^y Cr ^y j; Salusan insoluble compound. the mother liquor was removed and the crystals were washed with two 30 ml portions of ether. the crystals are dissolved in 10 ml of water. to the solution was added 23 ml of Dowex 50W (Na yield as) and the mixture After stirring at room temperature for 2 hours, the resin was filtered off, 300 ml of water was added to the tetrate, and the resulting suspension as such was chrialable and filtered on an Anmerlite XAD-II column, washed with 350 ml of water and eluted with 158 etcoils. decay at reduced The residue was lyophilized to give 420 mg of a colorless powder. This powdered product was chromatographed on an Amrrit XAD-II column. The column is washed with 1 L of water and eluted with 100 ml of 158 ethanol. The eluate ^is ^ i ^ Reho tlat zahuusí. Skis ^ ^í Iízicí of ^{Ka b} izbarvý PR ^and that ^the sodium ^é SOJ and ^cis-3 - (2- (2-chloro ^{CET <to} add 4-thhalziy j) -2-aethoxy ^the Cr ^b onylaet ^{h yl} .oxyiainokCltaai ^d o] ^- 4 ^- aethoiχ ^y when ^{r ron-y} --2 oxxilz ^lt ltsuiionoié-diol to t ^ i ^ ^ where ^ Oy (syn itoml).

SpeJctrum ^IR (cm ^{-1): 1790} and ^{F 1} 7 ³ 0 ¹ 6 ⁸ 0, ^{1 550} and ^{1 05} 5. snoops ^{NMR (DMSO-d,} r, max ppm): 3.6 (3H, s COO-H ₃ ), 3.7 (3H, s, COOOC ₃ ), 4.4 '(2H, s, ClCHp, 4.5 (1H, d, J = 6 Hz _t C 4 -H), 4 68 (2H, s, NOCH _2), 5.45 (1H, dd, J = 6 Hz, J = 9 Hz, _C3 -H), 7.3 (1H, s, OH);

^9, 37 ^{(1H, d,} J = 9Hz), _C3 NH). J

For C15H ₁ 5ClN5NkO ₁₁ O2.2 1 / 2Η., 0 Calculated: 29.58% C 3.31 8 H, 11.50% N; hledino:

H, 3.30; N, 11.56.

Example 62

Same method as in Example 11 was prepared the sodium salt of cis-3- £ 2- (2-amino-4-thiazolyl) -metbox ^ ^ a ^ m ^ ^ onylmethylox oacetcm ^ ^0] 4 ^- m ^ ^e ^ l ^ cjxy ^y kabbn ^^] ^ -; ^- -OOO ^and ZT ^ '^ Li ^d r ^ - ^-l - ^ £ ^ nc ^ ul.o Vé

KRR -i acid (syn OMe ^ ^. IR (V _x *, ^{X cm)} 3 ³ 00 1 7 790-1 ° ^3, 1670, 1610, 1530 and 055. 1 H NMR (DMSSHdg, ppm): 3.60 (3H, s, COOCH 3), 3.69 (3 #, s, COOCH 3), 4.49 (1H, d, J = 6Hz, H 4 -H), 4.64 (2H δ, δ Η-Η), 5.41 (1H, dd, J = 6Hz, J = 9Hz, _β-β ), 6.64 (1H, S, S ^ z Η), 7.18 ( 2H, bs, NH4), 9.29 (1H, d, J = 9Hz, 1H-NH).

For C ₁₃ H _{10 1} 4N5NaO S2.2H2O calculated: 29.83% Н, 3.47% H, 1Э, 38% N; found: 30.14% Н,

H, 3.52; N, 13.48.

Example 63

Dissolve 1.35 g of cis-3-) -2- (2-bromoacryoidx-4-tazolazol-1H-p-n) in 20 ml of dry Ν, Ν-dimethylX-bromamide.^andtro^benz^ylox^ykab^bxn^ylmet^hylχyy^andminx⁾acetam^d<^χ -4-met^hox^ykab^bheⁿl-²-oooaze ^ clinu (son of homee). With cooling to ~⁷8 ° C Ex^idand the extent of the complex^d sulfuric-N, N-ethyl formamide (4.11 mL; 1.69S).

The mixture was stirred at 4 ° C for 72 hours. 0.57 ml of pyridine is then added and the mixture is stirred for an additional hour. After addition of 500 ml of ether, the mixture was allowed to stand overnight in the refrigerator. Remove the upper ether layer. The residue was washed with two 50 ml portions of ether.

50 ml of water are added. The syrupy insoluble fraction is partially dissolved to give a gummy product. To this product was added 50 µl. Dowex 50W (Naaforma). The mixture was stirred at room temperature for 2 hours. The resin was filtered off.

The mother suspension (about 200 mL) was chromatographed on an Amberit XAD-II column. The column is washed with one cup of water and eluted with 200 ml of 30% ethanol. The eluate is flooded under reduced pressure and the concentrate is lyophilized. Prepared sodium zol ^yl) -2- (p-nitbobrnzylox kabboo ^{y y} L · oethylxoyioino) -acetaoidX] ^-4-yl oethxx ^{karrbxol-2-one} xxoxzzeidio- -ss ^{l. o} ^ I ^ not kysežny (s ^y n: 1.5oooг). ^IR spectrum (? Max ^cm-3) · ^{3 2 50 1 790} to ^{1 730, 1} · ^{67 0,} 1 520 and 1 050. NMR (DMSScd ^, ppm): 3.61 (3H, s, HOOOCh.), 4.36 (2H, s, ClCH2),

4.53 (1H, d, J = 6Hz, H ₄ -H), 4.82 (2H, s, NOCH ₂ ), 5.37 (2H, s, COOCH ₂ ), 5.48 (1H, dd) J = 6 Hz, J = 9 Hz, H ₃ -H), 7.36 (1H, s, SyH), 9.49 (1H, d, J = 9 Hz, H 3 -NH), 12.95 ( 1H, singlet and broad sinter, H (CH ₂ HONH). Д

For Н2 ₁ HrgC1N6aaO .3H2O ₁₃ S ₂ Calculated: 35.22% Н, 3.38% H, 11.74% and, narezrox: 34.86% Н

H, 3.22; N, 1.48%;

Example 64 cis- ³ '[2- (2-aninoa-44-thiazolyl) Sodium salt was prepared in the same manner as in Example 11

-2- ^(p-rn of nitrcb lxoykarbon ^{y y h} lτnerh iminn ^about loo) ACC AA ^{of e} to ^{C "4} amothoxykar ^b> No ^o - ^l -oxoacetate ^r d ^f n ^o la -suioonové acid (syn úomjrb ^IR spežrim (V ^ ax '

680, ^H ₄ ^-h >

6.66 cm Ь. · ^{3450, 3330,} 1790 ^and 1 ^730,

610, 1050. NMR Spectrum (DMSO-d6, ppm): 3.6 (3H, s, [delta]): 4.5 (1H, d, J = 6 Hz, 4.7; 77 (2H, s, NOCl 3), 5.35 (2H, s, HOOOHh), 5.43 (1H, dd, J = 6Hz, J = 9Hz, N 3 -NO), (1H, s, S / H), 7.2 (2H, br s, NHJ), 9.39 (1H, d, J = 9Hz, H, -NH).

X

3.22

Example 65

Dissolve 500 mg of cis-3- [2- (2-amino-4-thiazolyl) -2- (p-nitrobenzyloxycarbonylmethyloxyimino) acetamido] -4-methoxycarbonyl-2-oxoazetidine-1 sodium salt in 25 ml of water and 25 ml of tetrahydrofuran. -sulfonic acids (syn isomer).

500 mg of 10% palladium on carbon was added to the solution. The mixture was stirred under an atmosphere of hydrogen for one hour. Add 25 mL of aqueous sodium bicarbonate solution (66 mg). The catalyst was filtered off. The filtrate is washed with 30 ml of ethyl acetate and concentrated to 10 ml under reduced pressure. The concentrate was chromatographed on an Amberlite XAD-II column, eluting with water. The first 130 ml fractions were discarded.

-sulfonic acids (syn isomer).

IR (cm ý ^ # 3350, 1780, 1750, 1670, 1600 and 055. 1 H NMR (DMSO-d₆, ppm): 3.58 (3H, s, _COOCH3), 4.27 (2H, s, NOCH ₂ ), 4.5 (1H, d, J = 6Hz, C 1 H -H),

5.37 (1H, dd, J = 6 Hz, J = 9 Hz, _C3-H), 6.72 (1H, s, Sy H), 7.11 (2H, br s, _NH?), 11 3 (1H, d, J = 9Hz, _C3 -NH). Д

For C ₁₂ H ₁₁ N ₅ NaO ₂ S _1Q .2 1 / 2H ₂ O Calculated: C, 26.67% _F 2.98% H, 12.96% N; found:

% C, 26.63;% H, 3.02;% N, 12.93.

Example 66

950 mg of cis-3-benzyloxycarboxamido-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt produced in Example 49 are dissolved in a mixture of 20 ml of water and 20 ml of tetrahydrofuran and treated with 950 mg of 10% palladium on carbon. The mixture was stirred at room temperature under hydrogen atmosphere for one hour.

The catalyst was then filtered off and washed with a 1: 1 mixture of water and tetrahydrofuran (40 ml). The filtrate was combined with the washed liquid. 504 mg of sodium bicarbonate and 1.55 g of 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2- [1-methyl-1- (p-nitrobenzyloxycarbonyl) hydrochloride are added thereto under ice-cooling and stirring. ethyloxyiminoacetyl chloride. The mixture was stirred under ice-cooling for 40 minutes.

It is then concentrated under reduced pressure. The residue is chromatographed on an Amberlite XAD-II column. The eluate was lyophilized. The sodium salt of cis-3- [2- (2-chloroacetamido-4-thiazolyl) -1'-2-] 1-methyl-1- (p-nitrobenzyloxycarbonyl) ethyloxyiminoacetamido-4-methoxycarbonyl-2-oxoazetidine-1 was prepared. -sulfonic acids (syn isomer) as a colorless powder.

IC spectrum (γ max, ^{cm -1)} * ¹⁷⁷⁵ ' ¹⁷⁴⁰ ' ¹⁶⁸⁰ ' ¹⁵⁵⁰ ' ^{1525/1280 and 1055 NMR} spectrum (DMSO-d6, ppm); 1.50 (6H, s, 2 x _CH3), 3.62 (3H, s, _COOCH3), 4.33 (2H, s, C1CH £)

4.51 (1H, d, J = 6Hz, C ₄ -H), 5.31 (2H, s, COOCH _2), 5.52 (1H, dd, J = 6 Hz, J - 9Hz, C ₃ ~ H),

7.25 (1H, s, SyH), 7.62 and 8.07 (2 x 2H, 2 x d, aromatic protons).

C ₂₃ H ₂₂ ClN ₆ NaO ₁₃ S ₂ .3H ₂ O requires C, 36.01; H, 3.68; N, 10.96. Found: C 36.09, H 3.36, N 11.06.

Example 67

Dissolve 1,158 g of cis-3- [6- (2-chloroacetamido-4-thiazolyl) -2- (1-methyl-1- (p-nitrobenzyloxycarbonyl) ethoxyimino) acetamido-4-methoxycarbonyl-2- (2-chloroacetamido-4-thiazolyl) sodium salt in 30 ml of water. oxoazetidine-1-sulfonic acid (syn isomer).

To this. of the solution was added 241 mg of sodium monobutyl dicarboxylic acid while cooling with ice and stirring. The mixture was stirred at room temperature for one hour. Thereafter, 241 mg of sodium monohydrate is added ^to araamic acid. The mixture was stirred for an additional hour.

The reaction mixture was then washed with ether and concentrated under reduced pressure. EndContaminated with Ambrl-tu XAD-II. The eluate is liophilized. Prepared sodium cis-3- ^{[2- (2} -aa-Иlc ^{about 4} l; c ^ ^ey AOL · ^{II) -} 2- ^[l-yl mbeh l- ^{(p-n t r} ir ^r enz ^{l lk} br lox ^r nn ^NL) et ^yyl nx IBIN ^l (^ acetamido. -4-mer LKA ^y yo ^yl] rrn ^y l - 2-L-ooozeZedin tsfionl) as ky ^ E ^ l ^ i ^ cy (syn isomer) as colorless powder.

IR (V ^{^^,} cm ^-1): 1 trum (DSSO-d ppm): 1.48 (63, s, C ₄ -H), 5.33 (23, s, COOCH 2), 5.47

775, 1740, 1680, 1615, 1520, 1280 and 1055. NMR Spect 2 x Cl 2 -, 3.63 (3H, s, (13, dd, J = 6 Hz, J =

СООСН ₃ 3> 4.50 (1H, d, 9Hz, H ₃ -H), 6.59 (13

J = 6 Hh

7.24 (23, br s, NH ₂ ), 7.65 and 8.14 (2 x 23, 2 xd, Brno protons), 9.18 (13, d, J = 9 Hz, C3-NH) .

For ^C 21321N6NaO12S _2- S

H, 36.99; 3.87%; 12.34

1/23 ₂ O calculated:% N.

37.01% H, 3.84% 3,

12.33% N; found:

Example 68

Smměi in 25 ml of water and ²⁵ mL of ^t rtra ^Yli rofsrbnu r ^ pnusí 500 ml Sodium ^{To L} and ^cis-3 - £ ² - (2-Amino --- tУaazlyl) -2- £ ^1-yl bee-l hl - (p-ciroobocc 'l · ^b oxy.kar onyl) ^-yl ll ee> ^xyiminc) -acetamide <-4 °-merhonylkbbrnyCl --- noizeteddncl-sslionové capable of associating Jacy TSyn У ^ тег).

500 mg of 10% palladium on carbon was added to the solution. The mixture was stirred under a hydrogen atmosphere at room temperature for one hour. 25 ml of aqueous sodium hydrogencarbonate solution (62 mm) was added. The calibrator is iddiltrsjr. The filtrate was washed with ethyl acetate and quenched under reduced pressure.

The residue is concentrated on an AMerlk XAD-II column. The eluate was 10: 1: 1 to 5: 1. Prepared with ^{disodium-L-cit} 3- £ 2- ^(2-Amino-b ncl4 te alzly ^{y l} - ² - (i-i- JMR ^{ey l} r ^l -carboxamide ^eУl benzyloxy Bino ^b) bcreami ^{D0 -}

-4-mbrhynylkbbrnyClI - ooozet ^bd incl-silicic acid (syn isoM ^ rr.

tbum d, J

IR ^{(cm -1} (DSSS _CD-6, ppm). 1.36 (33-6 Hz, H4-3), 6.60 (13): ^{1775, 1740,} 1660, 1630 , ^1580, with, Ο _3), 1.45 (33, s, h, j,. 3.61 s

Sv3), 7.13 (23, br s,

AND

NH ₂ ).

(with,

280 and 1055. NMR (CDCl3), 4.53 (13,

3.68

For H ₁₄ 3 ₁₅ N5Na ₂ O _{1 ()} .43 ₂ S ₂ O Calculated: 28.24% H, 3.89% H, 11.76% N; found: 28.26% H,% 3, 11.62% N.

Example 69

In 4 ml of cold water with 85 mg of disodium rnzpuutí Srni cis-3- [2- (2-lminoi44I Уalzlll ^yl) -2- (1- ^{m ert-yl} lkbarboxyrt yioyy ^{b y} m ^c oo) areaamid ^{n] I} 4- Me hУo ^{r y} l- ^yl kbbro ^-2 -ooolet ^e d ^o n ^c l ts ⁱⁱ onl> Mo Selice to ^y (i ^ TOMRA son).

The solution was flashbrafted on a Dowex 50W (3-form) column (10 mL), eluting with water. The fractions which are not absorbed in the UV range are filtered and then suffocated under reduced pressure. Concentrate with Hhromaengraisjr on Sep column^yadexu L3-20. The eluate was lyophilized. IN^ycis-3-22 is made²(-amino-4-t^dlzol^yl) -2²(1^2mere^yl²l-carbox^lre^yllox^ydm^andno) acr^Ebm^dto⁰-4-be^ryyn^χlkabln^yCl2²Oooazat^Ed^dn^Cl - suonic acid (syn isomer) as a colorless powder.

^IR Spec microns (v * _x r (DMSSOd ^, ppm): 1.50 (63 5.45 (13, dd, J = 6 3Z ^{CB "1): 1775, 1730, 1670,} 1630 ^, 1280 and 050. 1 H NMR spektnm, s, 2 x _3-H), 3.63 (33, s, COOCHj), 4.53 (13, d, J = 6 Hz,? -3), J 9 Hz, .delta. -3), 6.87 (13, s, S ^ 3), 9.29 (13, d, J = 9 Hz, H ₃ -N ₃ )

Why

4.11% H,

14 ^ ₅ j7N O1 ₀ S2-2.3H2O calculated; % C, 32.28;% H, 4.18;% N, 13.45; Found:% C, 32.38;% N, 13.20.

-í 70

In 3 ml of ^N, N-- ^s ielt ^lyfo ormaei ^d will burst at the ⁵⁵⁰ m ^{g of} cis ^{- J2} 3- (2-У llnrayetamidío4 ^l - h ^l Atzl к ^{yl) -} 2 ^- £ ¹² ee ^e h .- ^{lk2k -} P ^{2 of} ni ro ^{l -yl} IIK mesh abbni ^{k y} l) e ^ y ^ ^ ^j yyim) yee- ^<i m inj - ⁴ -ietl (lx ^{y k-n} to the bon-2-oxnazeeiíinu (syn isniel). vol CII Zuii to -78 ° C was added 1.6 mL of a solution of the complex oxide of Si AC ^ ² N, ^-t ielt ^lyfO rrmaii ^{i (1,} 69M). ^MES was stirred for ^{24 h n p} s Odin ^к temperature 3 ^and 5 ° C.

Then, 0.22 ml of pyridine is added. Addition of 75 ml of ether precipitated a syrupy product. The ether layer was discarded. The ether-insoluble syrup is washed with two portions of ether (50 ml each) and suspended in 25 ml of water. 20 ml of Dowex 50W (Na-form) are added. The mixture was stirred at room temperature for 1.5 hours. The resin was filtered off. The filtrate was concentrated under reduced pressure.

The residue was collected on an AmerUtu X ^ c ^ DEi column. The eluate was ΙΗΜι Ι ^ ^b · Prepared ez ^b arvý pr ^{to as} E-to-E SOL and cis-lj 2 - ^(2-L 4-yhlnracetamidí t ^t i i ^l-yl) -2- ^£ l-mettiyl -II (ρ- · -! ^ - ^ · ^b eni ^also oxy Arbon ^{to nk) y} lox ^y lth ^Iain] acetyl ^ ^- 4-ee ^l hlny ^to aabbn -2 ^{yk 2} -nontet ^{l I} N d ^alkyls are ^fo nNew ^s carbamic acid (syn i ^ snml).

IR and NMR tnlntn product is identical with the IR spectrum and NMR spectrum of the compound produced will seize 66 Atmospheres. For ^C C23H22 1N6 aO13S2.H23 ^N calculated: 37.79% C, 3.31% H, 11.50% N; found; % C, 37.50;% H, 3.42;% N, 11.69.

The amino and carboxyl protecting groups can be removed by the procedures described in Example 67 and Example 68, respectively.

EXAMPLE ⁷¹ tejným manner příkřLačlu ^{10 ANNUAL bi} sodium cis Sj ^{2 '2} 2 ^y s ^l oaace ^{and AAI-pyrimidin-4-th t} aiolyl) 22-A ^to L ⁿ lkX ⁱ in ^L noyet ^{- d} im ^DOJ-4-L hunts ii aabbnylk22 ^y _O N _O ^L d ^I nzei NL-sulfonic acid trihydrate ^f0 (syn ί ^ snmr).

IC ektrum with ^{p (v,} cm ^{b): 3 25} 0 ¹ 7 ^{8 0, 1} 6 ^{8 1} 0 ¹ 0 ^55th Spec ^trum-NMR (DMSO-d₆) delta: 3.60 (3H, s, COOCH3), 4.32 (2H, s, C1CH _2), 4.49 (1H, d, J »6Hz, C ₄ -H 7.27 (1H, s, Sx / H), 9.49 (1H, d, J = 9Hz, C-NH).

X

For C ₁ GH- _L 5ClN..NvOgS2 Α · 1 / 2HjO calculated: 32.23% C 3.25% H 12.53% N; Found:% C, 32.42;% H, 3.30;% N, 12.59.

Example 72

Similarly z ^ solja spring in příkhráu ^{11 ANNUAL b} i биЫ salt y ^{y 2 [I} 2 ² (2 ² Aninn ^{4 4} th ^l atz ^{lyk) -} 2 ² and ^the ky0oy ^y im ⁱ n aceaaiií ⁿ l ⁴ 4 "ILT ^{l y} nx k.aabbn ^{2-yl yl 2} ononteti n ^{2k. 2 Sulfuric} acids ⁽ synomeome). IC spectrum (ν max cm -1): 3,325, 1,790 to 1,740, 1,670 and 1,050-NMR spectrum (DMSO-d6, ppm: 3.60 (3H, s, COCK, J 4.4) to 4.7 (3H, m, CH 2 CH 4 H and C ⁴ H), 5.0 to 5.5 (3H, m, CH ₂ CH = CH ₂ and C ₃ -H), 5.7 to 6.2 (1H, m, CH ₂ CH = CH 2) / 6.56 (1H, s, SH), 7.12 (2H, br s, N 4), 9.39 (1H, d, J = 9 Hz _f C) -NH).

For C43 · ₁ 4NjNaO S2-1 ₀ 1 / 2H2O Calculated: 32.36% C, 3.55% H, 14.52% N; H, 3.75; N, 14.46.

Example 1 and d 73

Dissolve 50 mg of trans-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-methoxycarbonyl-2-ocazetidine-1-sulfonic acid sodium salt (syn isomer) in 2 ml of water. in Example 24.

To the solution was added 15 mg of sodium salt of zococtyl dicotric acid while cooling with ice-water and stirring. The mixture was stirred at a temperature of 30 minutes. An additional 15 mg of sodium sono mono-ethyldic acid is added and the mixture is stirred for 30 minutes.

The reaction mixture was filtered. The filtrate was washed with ether. The water layer crays the XAD-II Dráerlite. Elution ^and T ^ ofildzuje. Prepared ^and sodium salt of trans-l ^- ^^ - ^ 100- ^4-

(thiazolyl) -Z-2-cyclohexylaminocarbonyl-4-zzalkylcarbonyl-1,2-cyclohexyl-1-sulfonic acid (synisozz). - Ί

IR ektrum with ^P (V _max / cm ³ 78 ^{400 1 0th} with ^p ektrum NMR ^{(DMSOodg, pp} m): ^3, 70 ( ") ^s

_COOCH3), 3.85 (3H, s, NOOHg), 4.10 (1H, s, d, J = 2 Hz, Сд-H), 4.77 (1H, dd, J = 2 Hz,

J = 9 Hz, C 1 -), 6.70 (1H, s, 7.20 (2H, br s, N 4), 9.47 (1H, d, J = 9 Hz, C 8 -NH)

Example 74

In the same manner as in Example 10, the sodium salt of cis-3- [2- (2-chlorocycloidyl-4-thlazolyl) -2-cyclohexylamino] -zazidyl] -4-chloro (Z-11-yl-2-oxylcidin-1-sulfonic acid isolamine) (syn isome) ).

IR ^sp ektru ^{m (fc KB-1):} 1770, ^{1670, 1550,} 1270 and 1 055th @ 1 H NMR (CDCl3, .delta. Ppm): 3.89 (3H, s, NOCH3), 4.34 (2H, s, ClCH-J), 5.28 (1H, dd, J = 6Hz, J = 9 Hz, Cg-H),

H), 9 '? 7 (1H, d, J = 9Hz, Cy-NH) 12.90 (1H, br s, α, ΟΗ ^ ΟΝΗ).

7.38 (1 H, s

Example 75

In the same manner as in Example 11, cis-31 [21 [2- (2-liazin-4-yl) -cyl] -2-zinc-zinc-zinc-4-chloro-zinc-2-oxo-sodium salt was prepared (syn igorne).

VDу ._I

IR ^sp ektru ^{m (X} in ^{cm): 1770, 1660,} 1 6 ^ 1 ^530, 1 270 and 1 050. V'5;

For C ₁₀ H _{5 1} 1ClN NaOgS2.2H ₂ O: calculated: 26.35% C, 3.32% H, 15.36% N; Found:% C, 26.31;% H, 3.18;% N, 15.33.

He said ad6

In the same manner as in Example 10, cis-3-22 '(1'-cyclohexyl azide-4'-thiazolyl) -1,2-dimethyl-4'-methylsulfonyl-2'-octyl-2'-sulfonic acid sodium salt was prepared. '

IR ^spt. Kt: ru ^m ( ^γ ,) ^, ™ ^-1 ) ^{; 1770, 1670) 1560, 1350, 1275,} 1175 and 050. NMR 1 with ^p ektrum (DMSS-d ppm) .: 3.10 (3H, s, Soocha '), 3.90 (3H , s, NOCl 3), 4.35 (2H, s, C 1 H 3, 5.33 (1H, dd, J = 5 Hz, J = 9 Hz, C 1 - 1)), 7.41 (1H, s, Sy) 9.42 (1H, d, J = 9Hz, C 1 - 4 NH),

12.91 (1H, br s, ClCl ₂ CONH). D

For CззH _{1 0} 5ClN5NaOз Sg.2H ₂ O: calculated: 26.28% C, 3.24% H, 11.83% N; Found:% C, 26.54;% H, 3.26;% N, 11.72.

Example 77

In the same manner as in Example 11, cis-3,122- (2-lmino-1-haloalkyl) -1,2-cyclohexylcarbonylcycloalkylsilyl-oxyl ^and oatodine-1-sulphonic acid (sodium) isosine was prepared.

IR (ν, cm -1): 1770, 1670, 1620

Nuclear Magnetic Resonance Spectrum (DMSOd6, - ppm): 3J10 (3H, s, SO2CH3),. = 5 Hz, J = 9 Hz, C, -H), 6.74 (1H, s, Sv H), 9.30

AND

For C ₁₁ H ₁₄ N 3 NaCl _Q 2 C ₂ H ₂ O requires C, 25.63; 1Li56 1 H.

535, (3 H, d, J)

3.86 (1 H,

3.52

350, 1280, 1175 a s, NOCH 3), 5.28 (1H, = 9 Hz, C3-NH).

055.

dd, J% H

13.59% N; found:

Example '78 sodium salt

In the same manner as in Example 10, 3- [2- [2- (2-chloro-ethoxy) -ethoxy] -2-methoxyimino [eta] &lt; 4 &gt; KRr _- 1-isomer). IR (.delta., Cm @ -1): 2110, 1765, 1650, 1550, 1460. NMR spectrum (DMSO-d6, ppm): 3.65 to 3.80 (2H, m, CH2N3) 3.92 (3H, s, NOCH3) 4.25 (2H, s, CICHh),

5.24 (1H, dd, J '= 5Hz, J = 9Hi, Ci-H), 7.44 (1H, s, βχH), 9-, 33 (1H, d, J = 9Hz) (C ₃ -NH).

For C ₁ 2? 12C1NpNaO7O2.2H20 calculated: 26.75% C, 2.99% H, 20.79% N; Found: C, 26.59; H, 2.90; N, 80% N

Example 79

In the same manner as in Example 11, cis -3- [2- (2-amino-4-thiazolyl) -2-methoxy-naphthaleneamidod-4-azidimethyl] -1-oxazetidine-3-sulfonic acid sodium salt (syn isomer) was prepared.

For C10H1 ₁ N8NaO6S2.2H2O calculated: 25.98% C, 3.27% H, 24.23% N; Found: C, 26.11; H, 3.41; N, 24.34.

(DMSO-d6,

J = 9 Hz

IC spectrum ( ^γ cm ^-1 ): 2110, 1765, 1660, 1530 ^, 1270 ppm): 3.60-3.85 (2H, m, CH 2), 3.87 (3H, s, NOCl 3, C 3 -NH), 6.75 (1H, s, SiH), 7.16 (2H, br s, NX), 9.22 A

Ad 80 Ex ^{1 05} 0 NM ^R spektrrnn 5.20 (1H, dd, J = 5 Hz, (1H, d, J = 9Hz, C3-NH).

In the same manner as in Example 3, the sodium salt of cis-3--2- (2-cillracetamide-4'-thiazdyl) -2-methoxyethoxy-4-actamido-4-triazoloxomethyl-2-thaloolithino-4-sulphonic acid KRr _- 1 (syn isomer) was prepared _. . IR (ν ^, ^{cm -1):} 3250, 1770, 1 720 to 1 660 and 1 545 050. 1 H NMR (DMSOdg, ppm): 3.69 (3H, s, NOCC ₃₎ 4, 35 (2H, s, dCl2), 5.32 (1H, dd, J = 6Hz, 3 = 9Hz, dH), 7.35 (1H, ss in H).

X

For C ₁₉ H ₁ 7C] ^ N ₅ NaO ₈ S2.3H2O calculated: 36.81% C, 3.74% H, 11.50% N; Found: 36.92% C

H, 3.63; N, 11.38.

Example d 81

In the same manner as in Example 4, the sodium salt of cis-3- [2- (2-amino-4-thiazolyl) -2-metholyimino [eta] &lt; 3 &gt; -dimethyl-4-beeooyloxylmethyl-2-oxoalaloidino-4-sulfonyl acid (syn [beta]) is prepared. . ^IR spectra rum ^(MAJ 'cm ^{-1): 3300, 1770,} 1 7 ^{1 0, 1 665} and 1 050. ^NMR Spectrum ^(D M ^S °-d6, ppm): 3.67 (3H, s, NOCH ₃ ), 5.28 (1H, dd, J = 6 Hh, J = 9 H ^, Gy-H), 6.62 (1H, s, SV / H), 7.12 (2H, b ^r s, NH ^ ^9, 38 (1H, d, J = 9Hz, C ^t NH). Д

For ^C 17 ^H 16N5 ^On OgS2.1 1 / 2H2O Calculated: 38.34% C, 3.60% H,% N 123.15; found:

% C, 38.23;% H, 3.53; 11.15% N.

Example 82

Sodium was produced in the same manner as in Example 1. cis-3- [2- (2-cyanoaceamidin-4-thiazolyl) -2-methoxyethoxyminoacetamide] -4-methyl-2-oxoacetamide-1-sulfonic acid salt (syn isomir). IC spectrum (ν. Cm -1): 3420, 1760, 1650, 1440 and 1265. NMR spectrum (DMMSO-ψ ppm): δ, COCH ₃ ), 3.85 (3H, s, NO) ^ j, 4.34 (28, s, ClCH ₂ i, 4.40 (1H, d, J »5 Hz, C H), s, H.

2.30 (38,

7.40 (1 H,

Example 83

In the same manner as in Example 11 ee, cis-3- [2- (2-amino-4-thiazonyl) -2-methoxyminocetamirodo-4-acytytyr-4-oxoanatidine dinilofluoronic acid sodium salt (syn bomBe) was prepared.

IC ektr ^ (V * ®X cm ^"1): 3400, 1760, 1660, 1535, 1260 and 050. 1 H NMR (DMMO-and _6: ppm 2.30 (3H, s , COCH, 3.81 (3H, s, NOCH 3), 4.40 (1H, d, J = 5 Hz, C ₄ -H), 5.26 (1H, t, C3-H, 6.64 (1H , s, S (H).

Example 84

In 2 mL of Ν, Ν-dimethylnorramidu the rozpuntí in 172 mg of cis-3- | .2- (2-chlocacttaridb ·-4-thiazolyl) 22-methoxyirinoacetjmid ^{(LN-4-2-hydroXJУmthyУ} ooooaetidini (syn -SO ^ R The mixture was stirred at room temperature for 24 hours, then 159 mg of sulfur trioxide-pyridine complex was added and the mixture was stirred for another 106 hours.

After adding ether to the reaction mixture, the syrupy product is separated off. The ether layer was discarded. Insoluble matter was triturated with ether. The same procedure is repeated once more. After removal of the ether layer, the insoluble matter was dissolved in 20 ml of water. 40 ml of Dowex @ 50 W (NN-form) were added and the mixture was stirred for 2 hours at m.p.

The resin was added. The filtrate was concentrated under reduced pressure. The conjugate is chromatographed on an ATerlite X ^ AD-1 column. The eluate was lyophilized. They are made disodium. cis - [2- (2-Chloroacetamido-4-thiazollyl) 22-methoxyoxyinoacetaride (14-tulfonatooxyreeethyl-2-oxoa-6-pyridine-1-brothonic acid (syn isomer)) IC spectrum (ν H, m ^-1 ) 1 1765 1,665, 1,545, 1,275, 1,240, 1,055, and 1,030. NMR Spectrum (DMSO d6, ppm): 3.90 (3H, s, J), 4.35 (2H, s, C1CH2), 5.34 (1H, dd, J = 4.5Hz, J = 9Hz, CJ = 9Hz, C3-NH).

For C28H12ClN5Na2O11S.422 ° calculated: 22.11% C, 3.09% H, 10.74% N; Found: C, 22.25; H, 2.92; N, 10.47. ·

NH), 7.66 (1H, δ, S \ yH), 9.38 (1H, d,

Λ

Example 85

In the same manner as in Example 1, the sodium salt of cit-3- [2- (2-chloro-imidido-4-thiazolyl) -2-methoxy-amino-naphthalene] -1,4-chloroacetone-hexyl-120-oxozetidine-1-sulfonic acid (syn itoree).

IC spectrum 7.43 (1H, s, Sw

X ( ^V m / ^cm -1 ^{cm 3} '- 80 (3H, s, NOCH ₃ ), H, 9.34 (1H, d, J = 9 Hz, C 1 -NH).

5.23 (1H, dd, J = 5Hz, J = 9Hz, 3-y,

For C ₁₄ H ₁₄ C ₉ ^ 2N5NaO O2.222O calculated: 28.48 HC 2.73% H, 11.86% N; Found:% C, 28.49;% H, 2.77;% N, 11.84.

Example 86

Dissolve 70 mg of cis-3 - [[2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-chloroacetoxymethyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) in 2 ml of water. .

39 mg of meaomethoidocarboxylic acid sodium salt are added under ice-cooling and stirring.

The mixture was stirred for one hour at room temperature. After the addition of 10 mg of the monomethyl-octrocarbamic acid sodium salt, the mixture was stirred for 30 minutes. The RoalkKnX mixture is then filtered. The filtrate was washed with water. The aqueous layer was eluted with a column of Amerllt XAD-tl.

The eluate is lilfiliosje. Prepared sodium eήs ^{3-22-_ (2} caeinat4thOicoaiyl) -t-eéhiaУiieinoacetamidol4t-hoУoraymitthli2 · -oxoaletedOnot-of sulphonic acid (syn nsamet). iC spectrum

KRR ^J -1 (VmaCč ^{'cm' 3400 '1760' 1660} and 050. 1 H NMR (DMSO-d _6, ppm): 5.15. (1H, dd,

J = 5 Ho, J = 9 Ho, C 1 H, 6.90 (1H, s, OX 2 H), 7.60 (2H, br s, NH ₂ ), 9.07 (1H, d, J = 9 Ho, C ₃ -NH). AND

H, 3.21;% N, 15.94. Found: C, 27.16; H, 3.44; N, 15.70.

Example a d 87

Using the same method as in Example 31, 3- [2- [(2-chloro-chloro-4-thiazolyl) -2-ethoxy] -inacetic acid -4- (2-methoisulfonylethoyloxycarboxyoyl-amino-methanoic acid-2-thienoic acid-1-thioate-1-thioic acid) was obtained. nsamet).

IC ^P k O ^e ^ ^r ^ ^{m (in} cm ^-1) :. 1770 ^, 1690 ^, 1550 ^, 1275 and 1050. NMR Spectrum (DMOOdg

ppm: 3.97 (3H, s, OO ^ CH), 3.44 (2H, q, J = 6 Ho, CH2OO3), 3.93 (3H, s, NOCH _3), 4.34 '(2H

o, J = 6 (Ho, COOCH2), 4.27 (2H, s, C1CH2), 5.21 (1H, dd, J = 6Hz, J = 9Hz, Cg-H), 7.51 (1H, s, Sx / H), 9.48 (1H, d, J = 9Hz, C 1 H -H). AND

For Cn6H26N1ClNN0OOOlllHHHtemO: C, 28.22; H, 3.85; N, 12.34; % H, 12.10%;

Example 88

Flexible opůsobem as in Example 10 was prepared SUI sodium cis-3- [2 ((2eihloceteCmiOat4tthiazoiyl) -i-L4-eeiayyyim0aaaceeamida4 trifluaraethilceinamethol-T-L-tayacetOnOn sullanavé acid (syn nsae ^ I ^). IR ^(R ^ m γ, cm ^-1 ): 1770, 1710, 1670, 1550, 1270 and 1050. NMR Spectrum (DMSO-d6, ppm): 3.91 (3H, s, NOCHh), 4.36 · ( 2H, s, C1CH2), 5.28 (1H, dd, J ⁼ 6 Hz, J = 9 Ho, C3-H), 7.49 (1H, s, OH), 9.46 (1H, d, J = 9Hz, _C3-NH).

For C1 ₄ H1 ₃ CLF ₃ N ₆ NaO _Q S2.3H2O calculated: 26.82% C, 3.05% H, 13.41% N; nálevno:

% C, 26.63;% H, 2.85; *

Ex. and d 89

In the same manner as in Example 11, cis-3- [2- (2-amino-1,44-thinolyl) -1,2-methoxymethyl-amino] -4-trifluoromethyl-amino-2-o-pyrrolidino-11-sullooic acid sodium salt (synisolated) was prepared.

IC ^SPE ktru ^m (in cm ^-1): 1 7 ^ ^{1720, 1670,} 1530, 1050 '. NMR Spectrum (DMSO-d6, ppm): 3.85 (3H, s, NOCHg), 5.17 (1H, dd, J = 6Hz, J = 9Hz, C8-H), 6.80 (1H, s, Oy 4 H), 7.12 (2H, br s, NH ₂ ), 9.35 (1H, d, J = 9 Hz, C 1 -NH). AND

For C ₁₂ H ₂ F ₃ N ₆ NaO ₇ S ₂ .2H ₂ O requires C, 26.19; H, 3.30; N, 15.27 _. Found _e NO: 26.30% C, 3.07% H, 15.05% N.

Example 90

416 mg of cis-3- [2- (2-chloroacetamido-4-thiazolyl) 22-methoxyiminoacetamido] -4- (p-nitphobenzyloxycarbonylaminomethyl) -2-oxoazetidine (syn isomee) was dissolved in 3.5 ml of Ν, Ν-dimethylphomiamide. . 239 mg of sulfur trioxide-pyridine complex was added to the solution.

The mixture was stirred at methanol temperature for 48 hours. 119 mg of sulfur trioxide-pyridine complex was added and the mixture was stirred for another 72 hours. After addition of 55 ml of ether to the reaction mixture, the syrup-like product is collected. The upper ether layer was removed.

The insolubles were washed with ether. The same procedure is repeated once more. The ether layer was removed again. The syrupy insoluble product is suspended in 50 ml of water. To the solution was added 25 mL of Dowex 50W (Naalorma). The mixture was stirred at room temperature for 2 hours. The resin was filtered off.

The filtrate was bent under reduced pressure. The conjugate is chromaaooralized on an Anberlite XAD-I column. The eluate was lyophilized. This gives -04 mg of a colorless powder. Dissolve the powder in 15 ml of water. For cooling! 87 mg of boonobthyldiethif2 carbamic acid sodium salt was added to the solution with ice and stirring. The mixture was stirred at Ь1зЬпо ^ 1 for 1 hour.

Then 5 ml of water, 5 ml of tetrahydrolurane and 87 mg of sodium monoethyl dibasic acid are added. The reaction mixture was stirred for an additional hour, then washed with ethyl acetate and chromatographed on a Aberllt XADdII column. The eluate was lyophilized. The sodium salt of cis -3- [2- (2-amino-2-thiazolyl) -2-methoxyethoxyiminoacetamido-4- (p-n-benzobenzyloxycarbonyl) amino] methyl-6-oxo-eeeidine-1-suioonic acid is prepared.

Ir (c) X ^{1 to} C® ~ ^{1: 1765,} 1710, 1660, 1615, (DMSSOdg ppm: 3.87 (3H, s, NOCH ^, 5.20 (2H, s, COOCHp,

260 and 1050. NMR Spectrum

6.83 (1 H, s,

H, 3.72; N, 15.70. Calculated: C, 34.62; H, 3.72; found:

H, 34.53; H, 3.52; N, 15.70.

Example 91

In a mixture of 15 ml water and 15 ml of tetrahydrofuran was burst the 203 mg of sodium cis-32Č2- (22 amlnOf2-thiazoyУ 2) 2-2 _m ethoxyiminoacetamiěo] -4- (p-nitoobenzyloxykarbonyl <minomethtУ) 2-2oχo2 aeetiěin21-julfonf) as acid. (son isomer). To the solution was added 190 mg of 10% palladium on carbon. The mixture was stirred at room temperature in a hydrogen atmosphere for 3 hours.

The catalyst is filtered off. The filtrate was washed with ethyl acetate and concentrated under reduced pressure. The residue is chromatographed on a Dnberlite XA-II column. By lyophilizing the eluate, a colorless powder is obtained. The powder is recovered on a Sephadex LH-20 column. The eluate was lyophilized. Cis-3-2- (2-amino-4-thiophen-2-yl) 2b-methoxyimiooaceabmido] -2-2-amino-benzoic-2-oxo-ethanedi-1-suioonic acid (syn isfbet) was prepared.

, 1530, X ”.

IC spekarim (V ^cm-1): 1770, 1660, 1620 (DMSQod ₆ ppm: 3.88 (3H, s, NOCH _3), 6.84 (1H, s, S

275 and 1050. NMR spectra

For C? H _{1 1} -Nr0 ₆ S-H -.- 0 vypočaeno 28.98% C, 4.38% H, 20.28% N; Found: C, 29.29; H, 4.31; N, 20.19.

Example 92

In the same manner as in Example 27, the beta and alpha isomers of the cis-3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido] -4-methoxycarbonyl-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) salt are prepared. oxoazetidine-1-sulfonic acid.

Beta-isomer

IR cm ^"1): 1770, 1710, 1675, 1510, 1280 and 055. 1 H NMR (DMSO-d₆, ppm): 1.10 (3H, t, J = 7Hz, N CH ₂ CH ₃ ), 3.10 (3H, s, COOCH ₃ ), 4.37 (1H, d, J = 6Hz, C ₄ -H), 5.31 (1H, dd, J = 6Hz, J = 9 Hz, C ₃ -H), 5.55 (1H, d, J = 7 Hz, phenyl-CH),

7.38 (5H, s, phenyl protons), 9.28 (1H, d, J = 9Hz, _C3 -NH), 9.82 (1H, d, J = 7 Hz, Ph-CH-NH) .

For C ₂₀ H N ₅ NaO _{2 g 13} s, 3H ₂ O Calculated: 39.94% C 4.69% H 11.74 I Nj Found: 40.08% C, 4.53% H, 11.53 % N.

Alpha-isomer:

IR spectrum cm ^-1 ): 1780, (DMSO-d6, ppm): 1.10 (3H, t, J = 6 Hz, = 6 Hz, C ₄ -H), 5.15 (1H, dd, J = 6 Hz, 7.40 (5H, broad s, phenyl protons) (phenyl-CHNH).

710, 1675, 1510, 1270 and 1055. NMR Spectrum

N-CH ₂ -CH _3), 3.59 (3H, s, _COOCH3), 4.47 (1H, d, J = J = 9 Hz, _C3 -H), 5.48 (1H, d, J = 7Hz, phenyl-CH),

9.38 (1H, d, J = 9Hz, _C3 -NH), 9.74 (1H, d, J = 7 Hz,

For C ₂₀ H N ₅ NaO _{2 g 13} s, 3H ₂ O Calculated: 39.94% C, 4.42% H, 11.61% N.

H, 4.69; N, 11.74. Found: C, 40.21;

Example 93

In the same manner as in Example 27, the beta and alpha isomers of the sodium salt of cis-3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido] -4-acetoxymethyl-2- are prepared. oxoazetidine-1-sulfonic acid.

Beta-isomer: IC spectrum (cm ^-1 ): 1,770, 1,705, 1,665, 1,500, 1,240, and 1,045,

NMR (DMSO-d₆, ppm): 1.10 (3H, t, J = 8Hz, CH ₂ CH _3), 1.58 (3H, s, _COCH3), 5.14 (1H, dd, J = 5 Hz, J = 9 Hz, C ₃ -H), 5.50 (1H, d, J = 7 Hz, phenyl-CH), 9.28 (1H, d, J = 9 Hz, C ₃ -NH) ).

Alpha-isomer:

IR (* ϊχ ^{'cm -1): 1770' 1710 '1670' 1505} '1 240 and 1 050. NMR (DMSO-d₆, ppm): 1.11 (3H, t, J = 7Hz, CH ₂ CH ₃ ), 1.86 (3H, s, COCH ₃ ), 4.98 (1H, dd, J = 5Hz, J = 9Hz, C ₃ -H), 5.40 (1H, d, J = 7 Hz, Ph-CH), 9.22 (1H, d, J = 9Hz, _C3-NH).

Example 94

In the same manner as in Example 27, the beta and alpha-isomers of the sodium salt of cis-3- [D-2- [3- (furan-2-aldimino) -2-oxo-1-imidazolidinecarboxamido] -2-phenylacetamide] -4-methoxycarbonyl-2 were prepared. -oxoazetidine-1-sulfonic acid.

Beta-isomer:

IC spectrum (ν max, cm ^-1 ): 1770, 1725, 1665, 1415, 1275 and 1240. NMR Spectrum (DMSO-d6, ppm): 3.10 (3H, s, COOCH ₃ ) 3.76 (4H, s, NCH ₂ CH ₂ N), 4.35 (1H, d, J = 6Hz, C ₄ -H), 5.32 (1H, dd, J = 6Hz, J = 9 Hz, C-H-H), 5.55 (1H, d, J = 6Hz, phenyl-CH), 9.05 (1H, d, J = 6Hz, phenyl-CHNH), 9.25 (1H, d, J = 9Hz, C 1 -NH).

Alpha ^- isomer: ^IR spp ^ rum ^{(cm: 1? 77} ° ^{1772 »1 1 415 4 2} 2 7 1 ² and 40. NMR (DMSO-Ig, ppm): 3.61 (33, s, COOCHp, 3? 8 (4H, s, NC? O? NC, 4.46 (1H, d, J%. 6Hz, C4-H), 5.12 (1H, dd, JC C 2, J = 9Hz) 5.47 (1H, C, (J = 7 H2, phenyl-CH), 8.97 (1H, d, J = 7Hz, phenylCl2NH), 9z32 (1H, d, J = 9) Hz, C ^-NH).

Example 95

In the same manner as in Example 27, the beta and alpha isomers of the cis-3-β-D-2- [3- (thiophene-1-aminoimino) -2-oxo-1-ylidazolinyl] amino] -2-phenylethylmethylamino-4-erthethoxycarbonyl salt were prepared. 2-oxo-pyridine-1-sulfonic acid.

Beta-isomer:

IC spectrum (γ ^K OX, cm -1): 1770, 1735, 1660, 1530, 1440, 1270 and 1235. NMR Specimum trum (D 2 SO 4 -dg, ppm): 3.11 (3H, s, 000 ([delta], 3.80 (4H, s, NCH3CH3N)), 4.33 (1H, d, J = 6Hz, [beta] -H), 5.30 (1H, dd, J = 6Hz) J = 9 Hz, C-H), 5.55 (1H, d, J = 7Hz, phenyl-CH) (8.11 (1H, s, N = CH), 9.07 (1H, d) J = 7 Hz, pheny-CHINH), 9.22 (1H, d, J 9 Hz, Cl-NH).

Alpha-isomer:

IC spectrum (in cm -1): 1765, 1740, 1680, 1535, 1240, 1270, 1240. NMR Spectrum (DMMO ₆ , ppm: 3.62 (3H, S, COOCH 3), 3.80 (4H, s, NCH 2 CH 2 N), 4.45 (1H, d, J = 6 Hz,

C4-H, 5.11 (1H, dd, J = 6Hz, J = 9Hz, C, 1H, 5.47 (1H, d, J = 7Hz, phenyl-CH3), 8.10 (1H , s, N = CH).

Example 96

Dissolve the 3-amino compound, which was made from 0.8 g of ethyl 3-benzylcarbonyl-2-oxyl-2-oxylthyidine-4-carboxylic acid in 10 ml of methylene chloride, in the same manner as described in Reference Example 3, while cooling with ice and stirring. 4 ml of treithylamine.

Then a solution of 0.6 g of 2- (2-methyl-4-thiolyl) -2-carboethoxyolyl chloride is added dropwise. The mixture was stirred under ice-cooling for 20 minutes and then at room temperature for 1.5 hours. Water was added to the reaction mixture. The methyl layer was separated. This layer is dried over anhydrous magnesium sulfate.

The rotary filter is separated. The residue was cooled to -10 ° ^C and added 'thereto 1.75 ml solution of sulfur py-N, N-dierPУyftomtaeid (1.58 «mixture was allowed to stand for 3 days at 5 ° C in a sealed flask. To this reaction SMMS 0.29 ml of pyridine was added and the mixture was poured into 100 ml of ether and then stirred.

The supeenatant is removed. Dissolve the residue in 2 ml of water. After addition of 30 ml of Dowex 50W (Na-form), the mixture was stirred for 30 minutes at temperature. The resin was then filtered off and the filtrate was concentrated to 20 ml. The cooneenate is cotermotrafuted on an AmerllPu XAD-I column. Elution with cis-3-22 - (- (methyl-4-hexyl) ethyl) -2-methoxy-4-methoxy-4-methylcyclohexonyl-oxoacryldiine-sulfonic acid sodium salt (syn isomme).

IC specimen (δ P cm @ -1): 3,425, 1,770, 1,750, 1,275, and 1,050. NMR Spectrum (D 1 O, ppm): 2.72 (3H, s, -H 3 O), 3 Δ 81 (3H, s, COOCH ₃ ), 4.05 (3H, s, NOCH 3), 5.04 (1H, d, J = 6 Hz, 1 H 2 -H), 5.75 (1H, d J = 6 Hz, C3-H), 7-, 68 (1H, s, Sy H)

For ci2H1 N4NaOgS2 ₃ * 2H2O vypoCyeno: 31.03% C, 3.69% H, 12.06% Ni, found: 31.10% H, 3.48% H, 11.94% N.

Example 97

To 499 mg of cis-3- [2- (2-chlorotrimido-4-thiolyl) -2-dihydroxyphosphinacetic acid dol-2-1-lazztidyl-4-carboxylic acid methyl ester was added 1.9 ml of sulfur trioxide-N complex solution. N ^ld: L ^ m ^{thhy0 l} om-am ^{id (1,} 58 ^m) at ¹ 0 ° C. After NTCA ^and STAT 3 ^d b ^y at 5 ° C uzrvřtn ^é flask.

To this reaction mixture was added 0.32 ml of pyridine and the mixture was poured into 100 ml of ether. The resulting mixture was stirred. The supeenatant is removed and the residue is dissolved in 20 ml of water. After addition of 15 ml of Dowex 50W (Na-form), the mixture was stirred at room temperature for 30 minutes. The resin was filtered and the filtrate was concentrated to 20 ml. ,

The concentrate zcaromarhlrrfuje-on a column of Dnmerlite XAD-II. The eluate was lyophilized. The sodium salt of cis-1- 2- (2-chlorotetimidol-4-thitiolyl) -2-dimethylyl-tololaathtemido] -4-methylthiocarbonyl-11-oxo-thiidine-O-thiophene was prepared.

XRr - 1

Ir ^(cm): 3450, 1770, 1750, ^1670, 1540, 1260, 1230 ^and 1 050th

For C ₆ H ₂₁ C 3 _{N 4} NaO ₂ PS ₂ .2H ₂ O requires C, 30.27; H, 3.34; N, 8.82. Found: C, 30.19; H, 3.64; N, 8.72.

Example 98

In the same manner as in Example 11, the sodium salt of cit13l- [2- (2-teinyl-14haatzlol) -2-diethyphospholylactividyl] -4-methoxylcarbonyl-12-oxylthetidine-1-stearic acid was prepared.

IC spectrum ⁽ m ^-1 ): 3400, 1775, 1750, 1670 ^, 1550 ^, 1230 ^, 1 230 ^and 1 045.

For C 14 H 20 N 4 N ^and O ₁₀ PS ₂ .2H ₂ O requires C, 30.11; H, 4.33; N, 10.03. Found:% C, 30.39;% H, 4.14;% N, 10.20.

Example 99 5.

In the same manner as in case 97, is prepared a sodium salt citl3- (2 "· trittayltilylttalll KBr - 3 ^ d ^^ Oxea) - ^L4 llethaxy ^y y ^t) the ONL in ^yl0 -yχoylt ^{ZTH yl} -tul oylvé ^l ^ J Selin ^{-. iC} spektirum (^ _тах, cm): 3450, 1775, 1745, 1660, 1540, 1260, 1250 and 055. 1 H NMR (DMSC, d, ppm): 3.61 (3H, s COOCCl 3, 4.41 (1H, d, J = 6Hz, C ₄ -H), 5.24 (1H, dd, J = 6Hz, J '= 9Hz, C ₃ -H), 8.59 (1H, d, J = 9Hz, C 1 -NH).

For C 6HH25NNNNSSOSSSS3O ^ requires C, 38.69; H, 6.26; N, 6.45. % C, 38.71; H, 6.18; N, 6.36.

Example 100

In the same manner as in Example 97, the sodium salt of cit13- [2- (2-teinyl-14-haazzlyl) -1-2-meth- (1-methoxyiminyl acetyl) -1- (2-phthylthayl) -2-l-azalithiyl-thiylsulfoline was prepared. γ- (syn).

IC ektrum (\), cm ^{-1): 3450, 1750,} 1660, ^{1540, X,} 260 and 045. 1 H NMR (DMSO-d ₆ + D? O, ppm): 3.82 (1H, s NOCH 3), 4.38 (2H, s, C H 2), 5.32 (1H, d, J = 6 Hz, C ₃ -H), 7.34 (5H, s, phenol protons), 7 42 (1H, s, SyH).

For C19H19ClN5NaO3S2.31 / 2H2O calculated: 37.10% C, 4.26% H, 11.39% N; Found:% C, 37.00;% H, 3.97;% N, 11.64.

Example 101

In the same manner as in Example 11, the sodium salt of cis-3-] 2- (2-methyl-2-carboxylic acid) is prepared.

-2-methoxyiminoacetamide <o] -4- (2-phenylethyl) -2-oxoazetidine-1-sulfonic acid (syn

^Ic pektru ^m (KB *, cm ^-1): 3425, 1750, 1660, 1610, 1520, 1240, 050. 1 H NMR (DMSO-d _6, ppm) 3.64 ( 3H, s, NOCHp, 5.15 (1H, dd, J = 6Hz, J = 9Hz, C3-H), 6.66 (1H, s, OvH), 7.10 (2H, brs, N @ +, 9.34 (1H, d, J = 9 Hz, Hg - NH).

For C ₁₇ H ₅ N _lg NaC6O2.2 1 / 2HgC calculated: 39.22% H, 4.45% H, 13.46% N; found:

% H, 4.21;% N, 13.47.

Example 102

In the same manner as in Example 97, cis-3-22- (2-hydroxy-44-thiazolyl) -2-methoxyimino-trimethyl-4-methyl-4-carbonyl-20-oxo-azido-1-suffonic acid sodium salt (syn isomer) was prepared. IR ektru with ^{p m} (in cm ^-1): 3450, 1770, 1750, 1660, 1530, 1440, 1250 and 050. 1 H NMR (DMSO-d₆, ppm): 3.61 ( 3H, s, (CCCCH3), 3.87 (3H, s, NOCHH), 4.50 (1H, d, [delta]),

5.38 (1H, C3-H), 6.33 (1H, s, J / H), 9.60 (1H, C1-NH).

For C ₁₁ H ₁₁ N ₄ NaO ₉ S ₂ .2H ₂ O calculated: 28.32% H, 3.24% H, 12.01% N; found: 28.55% H,

H, 3.25; N, 12.40.

Example 103

The following compounds were prepared in the same manner as in Example 10. The cis-3- (2- (2-chloroacetamido-4-thiazolyl) -2-methoxyphenyl) acetamido-4-ethoxycarbonyl-2-oxoxazolidine-1-sulfonic acid sodium salt and an isomer of sodium salt. .

Oyn-isomer:

IR .delta. ([Nu] C ^{-m &lt; -1 &gt;} ): 3,350, 1,770, 1,670, 1,610, and 1,050. ^[ 0193] NMR spectrum (DMSO-d6, ppm) (: 1.19 (3H, t, J) = 7 Hz, J 3, 3.86 (3 H, s, NO 2), 4.07 (2H, q, J = 7 Hz, CH 3 CH 3), 4.36 (2H, s, J 2), 4 46 (1H, d, J = 5Hz, 1H-H), 5.40 (1H, d, J = 5Hz, J = 9Hz, Hg-H),

7.28 (1H, s, OxzH), 9.44 (1H, d, J = 9Hz, Hg-NH).

For H1 ₄ H15HlN5NaO ₉ S2.2H2O calculated: 30.24% H, 3.44% H, 12.59% N; found: 30.40% H, 3.49% H, 12.42% N.

Anti-isomer:

^IR ektrum with ^{P (V} m ^ X 'cm ^{-1): 3300} out of ^1760, 1660 and 050. 1 H NMR (DMSO-d₆, ppm): 1.20 (3H, t, J - 7 Hz, ( ¾ ¾) 3.96 (3H, s, NOO 3), 4.16 (2H, q, J = 7Hz, δ 2 ^ 3), 4.33 (2H, s, d 6), 4.47 (1H, d, J = 5 Hz, 1 H, 5.42 (1H, dd, J = 5 Hz, J = 9 Hz, 1 H), 8.00 (1H, s, SyH), 9.12 ( 1 H, d, J = 9 Hz, C 3 -NH).

For H1 H1 _{5 4 HL-5} to 0 ₉ O2.3H20 calculated: 29.29% H, 3.68% H, 12.20% N; found: 29.06% H, 3.48% H, 11.87% N.

Example 104

In the same manner as in Example 11, the following compounds were prepared: the syn and the isoforms of the sodium salt of cis- ^3- [22- (2-amine-4-hafthyl) - (- 2-methoxyphenyl) -phaaceae] -4-ethoxycarbonyl-2-oxoazethiol-1 -uuffonic acids.

N-isomer; ^ir spetorum ^(у cm ^-1): 3 4 ⁵ 0, ^3250, 1 ⁷⁸ 0 ^{1 73} ° 1 ⁶⁷ 0. ^NMR (DMSO-d _6, ppm · 1.18 (3H, t, J = 7 Hz CH-CH2), 3.80 (3H, s, NOCl2), 4.04 (2H, q, J = 7 Hz)

CH-CH3), 4.43 (1ii, d, J = 5Hz, C ₄ -IL), 5.36 (1H, dd, J = 5 Hz, J = 9 Hz, C? H), 6.57 (1H, s, S (1H), 7.12 (2H, br s, NH)), 9.32 (1H, d, J = 9Hz, C-NH).

For C ^ 2HH74NN^^^^ ^{í , ,} ^^^S.2.2.1 / 2H-O calculated; 29.50% C, 3.92% H, 14.33% N; Found: C, 29.39; H, 3.71; N, 14.09.

ΑΑ-0 ~ 1 £ ™

1 H spectrum (γ ^{cm -1} 3,388, 3,770, 1,720, and 1,660. NMR spectrum, ppm):

1.18 (3H, t, J = 7Hz, CH2CH3), 3.90 (3H, s, NOCH3), 4.15 (2H, q, J = 7Hz, CH-CH3), 4.43 1H, d, J = 5 Hz, C ₄ -H), 5.36 (1H, dd, J = 5 Hz, J = 9 Hz, C ₃ -H), 7.06 (2H, br s, NH)),

9.02 (1 H, d, J = 9 Hz)

C ₃ -NH.

For ^C ₁₂ ^H 14 ^N 5 ^NaO 8 ^S 2 * ^{2 1} / ^2H 2 ° ⁱⁿ YP ^: C, 29.50; H, 3.92; N, 14.33. Found: C, 29.84; H, 3.88; N, 14.17.

Example 105

In the same manner as in Example 1, the sodium salt of cis-3- [2- (2-chlorotetamido-4-thiazolyl) -2-methoxyethoxyacetamino] -4-aminocarbamophenyl-2-phenylamino-1-suffonic acid (syn. ej.

1C spectrum (V · cm ¹⁾ ; ^{3 -5 -5} 0 3, ^{1770, 1} 6 1 ⁸ 0 and 050. NMR (D ^ S ^ o- ^ dg, ppm): 3.67 (3H, s, NOCH 3), 4.30 ( 2H, s, CÍCH3), 4.60 (1H, d, J = 5Hz, C - H), 5.4 (1H, dd, J = 5 Hz, J = 9 Hz, _C3 -H).

Example 106

In the same manner as in Example 11, cis-3 - [- (2'-amino-4'-thiazolyl) -2-methoxysophthalemide-1'-amino-2-oxoaphthalene-4'-sulfonic acid sodium (syn isomer) was used. IC with ^p EKT) rum (ν '^ tx' ³ cm: ^{3300, 1770, 1680} and 1 O ^{50th P NMR} with ektrum foMSCOdg, ^pp m): ^3.66 (3H, s, NOCH ₃₎ 4.55 (1H, d, J = 5 Hz, J - 9Hz, _C3 -H), 6.64 (1H, s, Sx / H, 6.9 to 7.7 (5H, m, protons ienylové 9.23 (1H, d, J = 9Hz, C 3 -NH), 9.95 (1H, br s, COONphenyyl).

Example 107

In the same manner as in Example 10, the sodium salt of cis (4- (4-chlorotetamido-thiazocyl) -2'-methoxyimino) octamido-4-ethoxyl-4-ethoxy-tetrahydro-2-oxo-ethoxy-6-sulfonic acid (syn isome) was prepared. .

1C ^spe ctrum (V ^c rn ^-1 ); 1,780, 1,765, 1,740 ^, 1,670, 1,550, 1,280, and 1,055. NMR Spectrum (DMSOd ₆ , ppm; 1.19 (3H, t, - = 7 Hz, CH-CH 3), 3.85 (3H, s, NOCCl 3.11 (2H, q, J = 7Hz, CH 2 CH 3), 4.36 (-H, s, ClCH-1, 4.63 (1H, d, J = 6Hz, C- -H), 4.64 (-H, q, J = 15Hz, OCH-CO), 5.52 (1H, dd, J = 6Hz, J = 9Hz, C 1 H), 7.31 ( 1H, s, CyH), 9.23 (1H, d, J = 9Hz, C3-NH)

For ₁ H ₁₇ RF HlNrNaOo- .2f _L S ₂ O Calculated; C, 31.30; H, 3.45; N, 11.41. Found: C, 31.38; H, 3.22; N, 11.44.

Example 108

In the same manner as in Example 11, the sodium salt of cis-3- [] 2- (2-amino-4-thiophenyl) -2-tethoxyitinoacetate-4-trifluoromethylimethylsulfonyl-1,2-difluorin-1-sulfonic acid (syn.

^{Ic-to-trum (max} 'cm ^{-1): 1 77} 0 1 ^{75 0} 1 ^{67 0,} 1 ^535, 1 ²⁸⁵ and 1 O ^{55th P} NMR with ektrum (DMSS-d _6, ppm): 1.20 (3H, t, J = 7Hz, C ^ C ^), 3.80 (3H, s, NOC ^ j, 4.12 (2H, q, J = 7 Hz, CH ₂ CH 3), 4.60 (1H, d, J = 6 Hz, C 1 H), 4.64 (2H, q, J = 15 Hz, OCH 2 Cl 2), 5.48 (1H, dd, J = 6 Hz, J = 9 Hz, _C3 -H), 6.59 (1H, s, Ss = H), 7.12 (2H, br s, (NH _2).

For Cз ^ HзgN ₅ nF-зQS ₂ .2H2O: calculated: 31.29% C, 3.75% H, 13.03% N; Found: 31.38% C, ^{3, 6} H 5% ¹² 5% ⁹ children.

Example 109

630 mg of trans -3- [2- (2-chlorophenyl-4-thaolin-4-thienylimino) pyrimidine] -beta-4-oxo-azidine was dissolved in 3 ml. t). The solution was ochlacK at -7 ⁸ ° C. Then ^some к he ^ ICA ^2.68 ml solution com ^ ^í EXU oxide with Riva ^- N, ^N - ^I imi ^t h ^lУ -ioπ ^^ ^ and d ^{(1, 69} M. mixture. NEC ^la st ^carboxylate 12 ^h Odin ^p s ^{4 DEG} C Otom was cooled to 0 ° C.

358 mg of pyridine and 40 ml of ether are added. The supernatant is discarded.

The dried substance was washed three times with 30 ml girls of ether. Ether was added with 10 ml of water and 20 ml of Dowex 50W (Na-form) was stirred for 2 hours. The resin was filtered. The filtrate is concentrated and is collected by filtration. to.·.·. banad Amerit.itu XAD-II.

Prepared trfns sodium salt 3- [2 - ((clhlofaeet. <· Ml of di-4-lhfzooly -) - m-methχyyimiofccefamiii] ^-4-yl fCttiX mithll · --2-ixifetedirnl - iionové acid (syn ISIM ' .t).

trtm (1 H,

IC spectrum cm ^-1 : 3450, (DMSO-d ₆ , ppm): 2.04 (33, s, COOC) ν d, J = 3 Hz, J = 8 Hz, C ₃ -H), 7.39

765, 1730,.

3.90 (3H, s (1H, S, Sy / 3),

AND

640, 1540, 1250 and 040. 1 H NMR Sieja ^, NOCH3), 4.35 (2H, s, C1CH _2), 4.77

9.45 (1H, d, J = 8Hz, C-NH).

3.41

For C _: 4H %зClNNNfOgS ₂ · H ₂ O calculated:% H, 12.91% N.

H, 31.26; N, 13.02; Found: 31.60% C,

Example 110 was made sodium

-2-methoo: χУminoifctaaiioii4-afctoiymeityly2-oxoaofZtdίnn --- ulOonivé acid (syn sot ^ i ^ t) with ^{p iC} ektrum ⁽⁷ cm): ^{3420, 1 76 5 1 7 3 ^ 1} ( DMMS-d₆, ppm 2.01 (3H, s, 000 [delta], 3.83 (3H, s,

C ₃ -H), 6.70 (1H, s, J 3 H), 7.16 (1H, br s, NH ₂ ), in the same manner as in Example 11, the trans-3 - [] 2- (2- (NMR (1H-zzyl) 660, 1530, 1245 and 1050. NOCH 3 NMR spectrum), 4.76 (1H, dd, J = 3Hz, J = 8Hz, 9.30 (1H, d, J = 8 Hz, C3-NH3).

For 'NaO ^^^ ^ 1 / 2H ₂ O Calculated: 30.64

% C, 30.66;% H, 3.65;% N, 14.94.

% C, 3.64% H, 14.89% N; found:

Example 111

Using the same procedure as in Example 109, the sodium salt of trans-3- [2- (2-chlorophenyl-4-thiazolyl) -2-melioxyimino] trifluoromethyl-4-methyl-2-oxo-phosphinin-1-one isionic acid (syn). . IC ^sp ektru ^{m (rn c -1): 3420, 1760, 1660, 1560, 1270,} 1050 and 030. 1 H NMR ^ with trimethylsilyldiazomethane (DMSS-d _6, ppm): 1.44 ( 3H, d, J = 6Hz, C4-CH3), 3.90 (3Hy s, NOOH)), 4.33 (2H, s, d6), 4.41 (1H, dd, J = 3Hz, J = 8 Hz, C1-3), 7.40 (1H, s, Sy3), 9.38 (1H, d, J = 8 Hz, C1-NH).

For ^C Π2HyзI1N5NaO2 ^ '^ · ^2H 2 ° Calculated: 28.94% · C, 3.44% H, 14.07% I found:

H, 3.48; H, 14.06

Example 1 and d 112

Dissolve in 3 ml of water! 300 mg of sodium lyofllidolaoé sdoí CAS-3- [2- (2-cminood4dhlazodlč) d2 ~ ^{methoxyπLminolC,} tramidod] I4InethhdχУtlbinynyI2IdXdzeZedrn "L-sufdondoé acid (syn isomer) produced in příOlaru second

The mixture is stirred. First, the solution then develops crystals. The mixture was allowed to stand overnight with cooling. Ethanol (10 ml) was added and the mixture was cooled for an additional 3 hours. The resulting / crystalline precipitate was decanted and dried. Manufactures Tzu Stora Uve ^ ^ ciated with sausage 'Jato btzbaro ^é ^ it Tal' tt ²³⁵ and ^{24 5} and 241 mg monodhdrá 'C ^ J ^ oz.

Trum ^^ IR ^(KBr, cm ^"1): 1785, 1 750 and 1 690. max

For H12NsNaJ8O2.H I ₁₁ O _2: calculated: 29.53% C, 3.15% H, 15.66% I Found: 29.48% C,

H, 3.13; I, 15.45

Example 113

86 mg of sodium salt of cis-3- [2- (2-aminodihild tallow-4-yl) d-2-ethoxy-4-iodo-d-dethoxide-2-oxo-2,4-dihydroxybenzoic acid was added to 3 ml of hydrochloric acid. acid (syn isdmt).

The solution was stirred under ice-cooling. Then 500 mg of zinc dust is added in one go.

The mixture was stirred for 5 minutes. The reaction mixture was filtered. The filtrate was collected on an Amereit ™ W-Ad-I column _; e] .uce · · water. The fractions containing the desired product are collected and lyophilized.

Cis-3- (DL-2 '(2-Amino-azol-4-yl)) - 22-indole-o-ocanan-4-non-cyclohexylbenzoate was prepared.

^Ic ^ Hruw ⁽ⁱⁿ cm ^{L): 3 40, 1 775,} 1 ⁷⁵⁰ and ¹ · ⁶⁹ 0. ^IMR spectrum (DMSOdg, ppm):

3.44 and 3.66 (3H, two sioglets, CJOCH 3), 4.44 and 4.47 (1H, two d, J = 5 Hz, 4.67 and

4.77 (1H, two s, -CHCO), 5.40 and 5.26 (1H, two doublet, doublet, J = 5 Hz, J = 9 Hz, 1H-H), 6.54 and 6.60 (1H, two s, O --- H), 7.10 and · 7.15 (2H, two broad sioglety, Harom), 8.7 to 9.4 (1 H>. ^Fr broad ^s, C-H ). AND.

Example 114

The procedure of Example 113 is repeated until the reduction with zinc dust and filtration. To the filse at ^{500 500} m ^{g of} thyanatene is added. ^ nes ball ^{IIa 't} howl minutes ld ^t t ^{t p} of ⁴⁵ ° C.

The mixture was then cooled with ice. The pH of the reaction mixture was adjusted to 1 by the addition of H hydrochloric acid. Thereafter, the pH of the reaction mixture was simulated by the addition of II to a pH of 1. 7.

The mixture was subsequently flushed onto an Amerlite XAA-II column and a Seplhadex LH-20 column. Water is used as the drying solvent. The fractions containing the desired compound are pooled and lyophilized. Prepared sodium ci.S "3-DDL-2- (2-jmioothillol-4-yl) 2Itl _{il n O} YiLi aninodaetrmid <rj" I4Iethhxy ^to aoaoio Oy22alztidioon ^r - dISulOonové kyi ^ e ^ enoyl. · Γ

IR (in cm- ¹ ): 3550, 1770, 1670 and 1620. UR spectrum (DMSO-d6, ppm): 3.48 and 3.62 (3H, two s, COOCH3), 4, 36 and 4.40 (1H, two d, J = 5 Hz, C 1 H), 5.0 to 5.5 (2H, m, -CHCl 3 and C 1 H), 5.66 (2H, br s) , CONH ₂ ), 6.32 and 6.34 (1H, two s, SyrH), 6.86 (2H, br s, nh ₂ ). AND

Example 1 a d 115

A mixture of 60 mg of cis-3-DL-2- (2-thiazolidin-4-yl) -thiaminotinamido] 44-oethoxycarbonyl-2-thiazolidine-1-sulfroate, 45 mg of diisopropyltin-thiazine, 1 ml of dichloromethane and 3 ml of ice is stirred with cooling. 77 µl of 1-chloroformyl-2,3-dihydro-4-ethyl-1,4-piperazines was added to the mixture, followed by 1 mL of water.

The mixture was stirred vigorously for 30 minutes. The organic solvent was distilled under reduced pressure. The evaporation residue is sequentially on a DnOllert IR-120 column (Nn-form α, DObrlits XAD-II and S i 1) hadex LH-20, eluting with water.

The fractions which contained the desired product were saved and produced with cis-3- [DL-2 (2-amino-2-chloro-44I) -2- (2,3-dihydro-ethyl-1,4-furanin-1-yl). rorbona ^y omnraacea [oido] -4-oeZhУoχ1aabonyS1-2ItzZidinone-salonic acid. <

IC sintered cm 3): 3400,. 1780, 1720, 1680 and 1620. NMR Spectrum (DMSO-d6 ppm): 1.10 (3H, t, J = 7Hz, C ^ j ^ - -), 3.45 and 3.62 (3H) 3.2 s, 3.2-4.2 (4H, m, -CH2H4), 4.37 and 4.43 (1H, two d, J = 5 Hz, 4-H); 0-5.5 (1H, m, 3-H), 5.38 (1H, d, J = 8Hz, CHCCN), 6.50 and 6.52 (1H, two s, S _xy H), 8.72 and 8.92 (1H, two i, J = 8 Hz,

CONH-C3), 9.52 and 9.56 (1H, two i, J = 8 Hz, NCONH).

He said 116

In 2 ml of tCl2-rs2-ls is suspended 40 mg. D.LL2- (2-tninnoI ^aУianr-yl · 2fooniotcentmiddÓ 4-mettyoykarbonoS12-ateZi <iinors - sl ^ 'ioná-. .. sn suspension stirred under ice-ch tuning. Add sn 150/11 mixed anhydride K15 <^ The mixture was stirred for 5 minutes, then a solution of 20% sodium bisulfite in 20% water was added. The reaction mixture is then quenched to one minute of its original volume.

To the residue was added 1 ml (1M) sodium hydroxide solution. The resulting mixture sn chromium · ^g oato RAFS SW POS ZupoS Column DObrli XAD-u - I and Sephadex LH-20, nluce water. The fractions which contain the desired product are pooled and lyophilized. It produced the sodium salt of 3- [3- (2-amino-zoo-4-yl) -1-2-formotrimido] -cetido] -1-4-oxo-oxo-trans-2-azeoisidine-1-sulfonic acid.

IR ^u p l ^{k e j} JL hз ^m (^ r ^c o ^{-1): 3400, 1780,} 1680 and 620. 1 H NMR ektnm with ^p (D ^ ^pp m): ^3, 63 and 3.74 (3H, two s, COOOC ₃ , 4.89 and 4.93 (1H, two d, J = 6 Hz, C ₄ -H), 5.38 and 5.56 (1H, two d, J-6) Hz, C 3 H, 5.44 (1H, s, -CH =), 6.70 and 6.72 (1H, s, s, Sy ^H ), 8.17 and 8.19 (1H, two s) , NI1COJ ^X

He said 117

40 ml of cis-3-DL-2- (2-amino-pyrrolidin-4-yl) -1-nitro-quinone-4-oxo-octylcarbonyl-12-acetone-dinosulfosate was suspended in a mixture of 1 ml of tin-ethyl-0.5 ml of ethyl acetate. For ^m s ^c s ^p Hani ^sn -20 ^DEG C RID ^{and 50} microns oeZhyasulfon ^{n1 y} c ^Cy ori ^d u 1 ^d ^ Ш iiso ^p ropylethy ^t Aoin. ^{After m} s ^{c s} tejn IIa ^with t ^ LO ¹ 10 ^p minuj Otom ²⁰ minutes it ^ o ^{-1 0} ° ^{C. R} eakční mixture of ^ l ^ Ia ^: s at -50 ° ^C.

Add 3 x 30 ml of ether (shake). The resulting syrupy insoluble matter was separated and 5 ml of water was added thereto. The resulting solution was chromatographed on a DOerlite IR-120 (Na-form) and DOerlite XDD ^ I column. ; 'by evil.

The fractions which contain the desired product are combined and lyophilized. The sodium salt of cis-3- [D-12- (2-trifluoromethyl-4- ^yl ) -12-oethanesulfonyl-amino-acetic acid-4-mono-carbonyl-11-nitro-1-morpholin-1-sulfonic acid was prepared.

^IR spetorum ^(V m ^{ax 'cm - -: 3400, 1780, 1690} and ¹ 6 ^{30th NMR pp} m): ^3, 03, and 3.06 (3H, two s, CH3SO0) · 3, 76 and 3.65 (3H, two s, COOCH3), 4.91 and 4.94 (1H, two d, J = 6 Hz, C4-H, 5.12 (1H, bs s, CHCOO)), 5.41 and 5.56 (1H, two d, J = 6 Hz, 6.80 (1H, br s, S in H) ·

Example 118

80 mg of cis-3- [DL-2- (2-amino-palpol-4-yl) -20-amino] -cetamide-1-O-methoxyl-2-ol-zedinone-1-phthalate are suspended in 3 ml of aceetlitriif. While cooling with ice and stirring, 38 µl of bon-poridine and 1 ml of 1 N sodium pyrophosphate are added. The mixture was stirred for 30 minutes. Then 10 ml of water and 15 ml of ethyl acetate are added.

After shaking, the aqueous layer was separated and chromatographically eluted with water on an Ambrill column. The fractions containing the desired product were combined and concentrated. It produces sodium salt of β-3- ω-2- (2-aminohialzl-4-yl) o -benzoyleainoacetyloidol-4-teethPolylphenyl-O-oltidinone-sulfonate.

^{Ic p} ektrum (KBr, cm ^{3): 3300, 1770, 1750 (P} s) and ^{1 640th NMR} spectrum (D .. ^ ^pp m): 3.60 and 3.73 (3H, two s, C-CH3), 4.89 and 4.93 (1H, two d, J = 6Hz, C4-H ), 5.43 and 5.58 (1H, two d, J = 6Hz, C ₃ -H), 5.58 (1H, s, CHCO), 6.73 and 6.74 (1H, two s, Sy H), 7.4 and 8.0 ^(5H rubbing-i ^ EE Acom ^{and i} c s ^о protons). ^AND

Example 119

In 1 ml of diethylpyetamide, 80 mg of cit-3- [DLL- (2-amino-pyrazol-4-yl) -2-aminocapidol-4-yl] -pentylcarbonite is suspended in letridine-one-amino acid. Under ice-cooling and with stirring, 50 mg of p-tolftutulionylplloid are added, followed by 120 µl of ditsopropthylthiamine. The mixture was stirred for 30 minutes. The reaction mixture was stirred at room temperature for a further two hours. Then shake three times with 30 ml of ether.

The resulting syrup-like insoluble material was deprotected sequentially on a column of Amertit IR-120 (NH4-Foc), Ambritte XAO-I and Sepbadex LH-20, with water, and the fractions containing the desired product were combined. Produces cis-3-DDL-2- (2-amino-piperazin-4-yl) -O-p-thiophenesulfonylamino-cet-eidol-4-methyl-4-methyl-polysidinol-1-tullone acid sodium salt,

IR (у Г ^ ^C] m ^{- 3):} 3400, 1770, 1 (09 0 620. 1 NMRspeOumim (D ₂ O, ppm): 2.40 (3H, s, CH)) -, 56 a -, 72 -3H, -, s, COOCCH 3, 4 _Z 82 - δδδ - 1H, two d, J = 6 Hh, C4-H), 4.92 (1H, s, NHCCOO), 5.30 and 5.35 (two d-CH- group J - -h С Н ~ _3)), 6.40 and 6 ^ 2 (1H, two s _f s <yH), 7. 36 and 7.62 -4 , two d, J = 8 Hz). prltonyl)

P Pikl a d 120

80 mg of cit-3 - [[DL-20 (2-L-nitro-piperazin-4-yl) -2-fluoro-acetol-4-yl] -carbonyl-2-aaetidinol-1-losullpine acid is suspended in 1 ml of dieethethyl chloride. While cooling with ice and stirring, 20 µL of 2-ethyl-ethyl-ethyl chloride is added.

The mixture was stirred at room temperature for two hours, then cooled with ice and 300 mg of 1 N sodium pyrosulphite were added. The mixture was stirred for an additional 20 minutes and shaken three times with 30 ml of ether. The resulting insoluble syrup-like syrup-oleaph gradually sequentially on the columns

Amerlite XAA-I and Sepbadex LH-20, eluting with water.

The fractions containing the desired product are pooled and isolated. Prepared sodium cis-3- [DL-2- (2-ainnlhρizzl-0-ol) O2- (2-eetPoxyacet midolacetaeido ^{2-O4-eetPoxykarbollnl} ~ 2o-Zeo tidinouoltfuilnoové-hundredth.

1 H NMR spectrum (δ, /, cm -1): 3400, 1770, 1670 and 1630. NMR spectrum O0 ppm (ppm): 3.46 (3H, s, CH ₃ O), 3.66 and 3.76 (3H, s, s, COO-CH), 4.10 (2H, s, OCH ₂ C), 4.91 and 4.94 (1H, two d, J = 6 Hz) C ₄ -H), 5.41 and 5.55 (1H, two d, J = 6 Hz, C-H), 5.49 (1H, s, -CHCO), 6.76 (1H, s, s, SvH).

And.

Example · 121

In 2 ml of ethyl acetate, 80 mg of (2-chloro-4-yl) -acetamide-4-ylcarbonyl-22aleridinone-thionic acid are suspended. The suspension is cooled with ice and stirred. To this suspension was added 200 µl of acetic anhydride, 60 mg of sodium acetate and 2 ml of water. The mixture was stirred for 10 minutes. The mixture was stirred for one hour, then 3.6 ml of 1M sodium hydrogen carbonate solution was added.

The resultant mixture is chromatographed sequentially on aluminum columns XAD-II and Sephadex LH-20, eluting with water. The fractions which contain the desired product are combined. and lyolize. The sodium salt of 3 ', 3', [2- [2- (2-amino) -hizol-4-yl) 22-methylpyridin-4-yl] -4,4-cyclohexanecarboxylic acid [1,2-a] ethanone-1'-sufinic acid was prepared.

IC ^ ktny with (in KB * ⁴ cm *): ^3400, 1770 ^and 1660 and 520. 1 H NMR ktrum s ^ (^ D ppně: ¹ for max 93 2.08 (3H, two s, lentils ^ ), 3.63 and 3.74 (3H, two s, C-OH), 4.89 and 4.92 (1H, two d, J = 6 Hz, C ₄ H), 5.34 ( 13, s, -CHCON), 5.40 and 5.56 (13, two d, J = 6 Hz, C H H), 6.67 and 6.69 (1H, s, s, Sy H).

and

Example 122

In 20 ml of dry Ν, Ν-diylmethylfoyyl amide there are suspended 402 mg of cis-1- (4H-2-quioacetylphenyl-4-thiazolyl) -1,2-methoxyiynnoacrtayido-1,4-methylcarboyoyl-2-phenyafetidine (syn isoyer). To this solution was added 320 mg of sulfur trioxide-pochidine complex.

The mixture was stirred for 24 hours. After addition of 40 ml of dry Ν, y-di-ethylphenylformamide and 320 mg of tris-tertiary oxide complex, the reaction mixture is stirred for 72 hours. It is then poured into 500 µl of ether and the insoluble material is filtered off, washed with ether and suspended in 500 µl of water. Add 30 ml of Dowex 50W (Nniformaa).

The suspension was stirred for 3 hours. The resin was filtered. Lyophilization yielded a colorless powder. This powder was dissolved in water. The aqueous solution was chromatographed on a column of XAD-II. The eluate was 1tifilZzhje. ·

Cit-3- [2- (2-chloro-chloro-4-thiazolyl) -n-ethyl-yimino-oaceamido-14-ethyl-ethylcarramyl-11,21-phospholefin-11-insulinulin acid (syn isomer) was prepared.

IC with karum ^ (V, 2.68 (3H · 7.50 (1H, rnax 'θη ^{-1>: 3250, 1} J d · - · · NHCH.- 5Hz) · 3.85 (3H · s, SyHH).

AND

770 ^and 1 650, 1 050. NMR @ ektrim (DMSO-d _6, ^p pm): a · N-CH3) · 5.35 (1H ^ dl · d · J · · 5 Hz, J = 9 Hz · CJH) ,

He said a d 123 is v.rfloí todn^and salt οί ^^-3-E2- (²·^ANDand^mnn^i-4ah^halo^i1t) 12-yeahoxylthiophthyridof-4-methylcoabryoyl-2-oxoaillo-quinone acid (syn i-sonee).^iC with^pectruy (V KBr, cm¹⁾:^{3 350}, 1⁷⁷⁰ (3 H, d, J dd, J = 5)

In the same embodiment as in Annex ¹¹

KBr y and x * = 5Hz, NHCH 3), 3.80 Hz, J = 9 Hz, C3-H), 1670 and 050. 1 H NMR bakers (DMSO-d ₆ · ^pp m): 2.60 (3H with, Nocchi), 4.35 (1H, d, J = 5Hz, _C4-H), 5.28 (1H, 6.86 (1H, s, _s Η), 7.13 (2H, br s, NH 2), 7.65 (1H, d,

Λ

J = 5 Hz

NHCH 3), - 9.01 (13, d,

J = 9 Hz, C ₃ -N ₃ ).

In the same manner as in Example 70, traost3- {2- (2cchSrfCcefabiCst) sodium salt was prepared.

-4-thienylsilyl-2-t-l-tert-1-yl (o-nStrl) oxazoxoxycarbonyl) ethoxycarbonyl] acetabidyl-4-bethoxycarbonyl-2-oxo-ethoxy-1-sulphonic acid. .

Example 124

IR spektrim (V ^^, cm ^-1) · 3 400-3 200 ', 2980' 1780 '1740, 1680, 050. 1 -¾

For C2 _{3 6} H22C1N Hao ₁₃ S ^ J ₂ .ŽH calculated: 36.88% C, 3.50% H, 11.22% H; Found:% C, 37.02;% H, 3.41;% H, 11.54.

Example 125 tejným of spots ^ s ^^ j and ^k Hel 67 Preparation of the sodium salt of ³ trfos · t · t (2 t ^{(m 2} TFI nose ^t 4ttiafoSyУ) -2 t [1-belhylt--) p. ^ ^O-to nStrfnenlsXxxa arbonyl 4-Ethylcarbonyl-4-ethoxycarbonyl-2-oxo-azylfluorone-sulfonic acid (syrup).

KRv · * 1

Ic ^ ktrum (in cm ^-1): 3325, 1780, 1770, 1670 '1600, 1520 ^and 050. 1 H NMR _(DMSS-d6, ppm): 1.5 (HH, s, 2 x CH3), 33.69 (3HH s, COCCO3, 4.15 (1H, d, J = Hz),

C4-H), 4.82 (1H, dd, J = 3 Hz, J = 9 Hz, C 3 H, 5.33 (2H, s, 000), 6.7 (1 H, s, SyH 2) ,

7.25 (2H, br s, NH 4), 7.65 ^and 8 _Z 15 (22 x 2H, 2 xd, aromatic protons), 9.3 7 (1H, d, J = 9 Hz, C ₃₎ -N ^).

For c2 _1H N6NaO _{21 12} S2.2 1/2 ^ 0 Calculated: C 37.01, H 3.84%, N 12.33%; oalezeoo:

% C, 36.90;% H, 3.78;

^EXAMPLE 1 ad 126

In the same manner as in příkaadu 68 was prepared disodium trfost3- [2- (2-fbino- · 4-thift zooyy) -2- (1-carboxy-1-blthylethoxyib0no) acetabiCs] t0tbelhooy ^ka rbons0y1 oxoxsftldif-L-ester A suSist kyseHoy (with ^y o itsber ⁾ . ^{IR cm)} З 3 ^375, 1 ^780, 1 Μ ⁵ '1 ⁵⁸⁰ and 1 ^050th

Nuclear Magnetic Resonance Spectrum (DMSO-d6 ppm): 1.40 and 1.43 (2 x 3H, two s, 2 x CH3), 3.7 (3H, s, COOCl 3, 4.17 (1H, d, J) = 3 Hz, C4-H, 4.85 (1H, dd, J = 3 Hz, J = 9 Hz, _C3 -H), 6.73 (1H, s, SyH), 7.12 (2 s ^ 11.7 (1H, d, J = 9Hz, C.-NH)

For Cχ4H ₁ 5N5NaO ₂ O ₁ s ₂ .5H2O: calculated: 27.41% C, 4.11% H, 11.42% N; Found: C, 27.10; H, 3.90; N, 11.46.

Peak d 127

In the same manner as in Example 61, the sodium salt of cit-3-Q2z (- (chlorofluoramido-4-thiazolyl) -2- (1-bephenoxycarbonyl) -1-benzyloxyimonoaceaabido] α-methoxycarbooyl-2-oxophosphorosulfonic acid) is obtained. .

IR (cm @ ^-1 ): 3250, 2950, 1780, 1740 and 1680. NMR (CDCl3): 1.46 (6H, s, NOCMe2), 3 63 and 3.66 (2 x 3H, two s, 2 x COO-C ₃ , 4.33 (2H, s);

4.15 (1H, d, J = 6 Hz, C 4 H 3)) 5.49 (1H, dd, J = 6 Hz, C 1 H), 7.27 (1H, s, Sy Η), 9.22 ( 1H, d 1 J = 9 Hz, C ₃ -NH 1 '93 (1H' br ^with C ₁ CH ₂ CONH).

For C ₁ 731rClN5HaC1 ₁ S2.l 1/3320 calculated: 33'69% C, 3.58% H, 11.32% N; Found: C, 33.26; H, 3.64; N, 11.14.

Example 128

In the same manner as in příkaadu 62 blancmange was prepared SUA cis-3 t [2- (2-fminos4 ttiafoSyУ ~) t -2- (1-b _e lhooyУkabos У ^{n-l "Thy} MBF et oxyibino ^{h) of} fcetamidc - ⁴ -be ^ft Hoy ^y 2 ² carbonyloxy ^0y OCcasftidid L-suafooové kyseHoy (SYO itsbef).

KBr-1

IR spectrum (ν _max , cm): 3400, 1780, 1735 and 1670. NMR Spectrum (DMSO-d6, ppm):

1.43 (6H, s, NOCMe ₂ ), 3.62 and 3.64 (2 x 3H, two s, 2 x COOCH ₃ ), 4.48 (1H, d, J = 6 Hz, Cd-N),

5.43 (1H, dd, J = 6 Hz, J = 9 Hz, _C3 'H), 6.58 (1H, s, MW H), 7.2 (2H, s, _NH2), 9.05 ( 1 H, d, J = 9 Hz, C ₃ -NH). Д

For ^C 15 ^H 18 ^N 5 ^NaO 10 ^S 2 * ^2H 2 ° ⁱⁿ YP ° ^: 32.67% C, 4.02% H, 12.70% N; found: 32.64% C,

H, 3.96; N, 12.43.

Example 1 a d 129

In the same manner as in Example 61, cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2- [1-methyl-1- (2- (trimethylsilylethoxycarbonyl) ethoxyimin] acetamido-4-methoxycarbonyl) sodium salt was prepared. -2-oxoazetidine-1-sulfonic acid (syn isomer).

Ir _(χ ^, cm ^-1): 3400, 1775 and 1 740. ⁴ NMR (DMSO-d₆, ppm): 0.92 (2H, CH ₂ Si), 1.45 (6H, s, NOCMe ₂ ), 3.64 (3H, s, COOCH ₃ ), 4.16 (2H, COOCH ₂ ), 4.35 (2H, s, C ₁ CH ₂ ), 4.50 (1H, d, J = 6 Hz) C ₄ -H), 5.50 (1H, dd, J = 6Hz, J = 9Hz, C ₃ -NH), 7.24 (1H, s, 5H), 9.11 (1H, d , J = 9 Hz, C ₃ -NH), 1 ё 89 (1H, br s, C ₁ CH ₂ CONH).

Example 130

In the same manner as in Example 62, the sodium salt of cis-3- [2- (2-amino-4-thiazolyl) -2-i-methyl-1- (2-trimethylsilylethoxycarbonyl) methoxyiminol acetamido} -4-methoxycarbonyl-2KBr &lt; -1 &gt; oxoazetidine-1-sulfonic acid (isome spectrum and spectrum (in _max , cm)): 3,410, 1,780,

740 and 675. 1 H NMR (DMSO-d₆, ppm): 0.95 (2H, CH ₂ Si), 1.48 (6H, s, ₂ NOCMe), 3.66 (3H, s, COOCH ₃₎ 4.18 (2H, COOCH ₂ ), 4.50 (1Π, d, J = 6Hz, Cd-N), 5.47 (1H, dd, J = 6Hz, J = 9Hz, C ₃ -H ), 6.60 (1H, s, SyH), 7.19 (2H, br s NH), 8.98 (1H, d, J = 9 Hz, C ₃ NH).

Example 131

630 mg of cis-3- {2- (2-chloroacetamido-4-thiazolyl) -2- [1-methyl-1- (p-nitrobenzyloxycarbonyl) ethyloxyimino] acetamido} -4- is dissolved in 2 ml of dry Ν, dimethyl-dimethylformamide. carbamoyl-2-oxoazetidine (syn isomer) produced in Reference Example 166. Then, at -78 ° C, add

1.69 ml (1.56M) of sulfur trioxide-N, N-dimethylformamide complex solution was left in the refrigerator at 4 ° C overnight. To this mixture was added 208 mg of pyridine under ice-cooling.

30 ml of ether are then added. The resulting syrupy precipitate was decanted with ether (3 x 20 mL). Dissolve the precipitate in 15 ml of water. 15 ml of Dowex 50W (Na-form) was added to the solution, and the mixture was stirred at room temperature for 2 hours.

The resin was filtered off. The filtrate was concentrated under reduced pressure. The concentrate is chromatographed on an Amberlite XAD-II column, eluting first with water, then with a gradient of 10 to 20% ethanol. The disuflo compound (Example 134) was obtained.

Elution was continued with 40% ethanol. The fraction containing the desired compound is lyophilized. Cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-C1-methyl-1- (p-nitrobenzyloxycarbonyl) ethyloxyimino] acetamido} -4-carbamoyl-2-oxoazetidine-1-sulfonic acid sodium salt is produced. acid (syn isomer).

IR spectrum (* _ax ^{cm -1> J} 3420, 1770, 1730, 1690, 1520, 1350, 1280 а 1 055. NMR (DMSO-d₆, ppm): 1.50 (6H, s, 2 x CH ^, 4.34 (2H, s, C1CH _2), 4.38 (1H, d, J = 6Hz, C ₄ -H), 5.31 (2H, s, COOCH ₂₎ , 5.34 (1H, dd, J = 6 Hz, J = 9 Hz, _C3-H), 7.54 (1H, s, SyH), 7.62 and 8.07 (2 x 2И, 2 xd , aromatic protons).

E ^{In 20} ml of water was rczρuu ^I I ²⁸⁰ mg sod sodium ^{2 l} ll c> rlClta: íidd- ^- 4-t ^l alzlyr) -2 ^{'- [1-} IE ^LT L ^r -L- (p-nitro ^L inzy ixykar ^{b l y} l -i) LT ^l ly ^- oxyiíii-] - ⁴ -karblmíyl · ^ -2-oχ-ztZedfni - suHonové acid (syn Isoí ^ i), which was produced in Example 131st

Example 132

During ice cooling and stirring was added 104 mg of sodium-íorюoíthyrdith Okar ^B im-acid methyl ester. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was washed twice with ether and then purified by column chromatography on an ACebdt XAA-I column (40 g), eluting with water, eluting with 20% ethanol. Fractions containing the desired product were pooled and lyolized.

Prepared sodium salt of ^C i ^- 3 ^{- {2} - ^{(C 2} -ai amino-4 thiazz ⁴ · ^l-yl) - ² - ^[- -cιe ^TLR ll- (pin ^r- ro ^{l l} izry ixylarbo "оУ ^ о ^ ^ у хухсхоо] αceta ^{Mi d-C} -4 r ^{0 -2} karbaaíy --I-flight ^e Article ^F n-l-Iu ONL ^i> V ^e ^ ι θΙ ¹ ^ (n s ^y ^^ ι) . IC with ^p ektrum Ы ϋ cm ^-1): 3410, 1770, 1730, 1685, 1 52S, 1350, 1280 and 1055 · NMR (DMSCOí ^, ppm): 1.48 (6H, s, 2.times.1 (1H), 4.37 (1H, d, J = 6 Hz, -4), 5.33 (2H, br s, NH2), 7.40 (2H, br s, NH2) ), 7.68 and 8.16 s, COOCH ₂ ),

6 · “

6.92 (1 H, s, s

O-j 2 H, 7.21 (2H, (2 x 2H, d,

J = 9 Hz, aromatic proto ^] ^)

8.82 (1H, d, J = 9Hz, C ₃ NH).

d 133 ^{In 10} ml of water was ^y rczjpuutí ²⁰⁰ m ^{g s} IDDM SOD cisзЗ- ² 2- ⁽² 'tmiIi ^l 4 "th alzly ^{L r} L ^-2 - ^ -ceUi ^1-1 - ^(p ^ -il · a l ^ l ^ Izy: ^l c ^ i trbo ^yl ^ i ^ ^rL) о ^^ - ^ жухсго αcl ^t αmi oJ- ^f ~ 4 - carboxylic αnc ^b> L ^{of 2} '- X-azeidii · - L · ⁱ sul -ones 1Г ^é ^ ^ ё 1-1пУ (syn-is · IEL), which was produced in Example 132nd

To the solution was added 200 mg of 10% palladium on carbon. The mixture was stirred for one hour in a hydrogen atmosphere at room temperature. The catalyst was filtered. Under ice-cooling, 27 mg of sodium (sodium citrate) was added and the mixture was stirred for 5 minutes, washed with ethyl acetate and ethyl acetate. Dowex 50W (H-form) was added to the aqueous layer and the mixture was stirred for 1.5 hours.

The resin is ιΐϋΐ · u) i. The filtrate was concentrated under reduced pressure. tsi half of its original volume. The residue was chromatographed on 1-1-phosphate XAA-I (40 g), eluting with water, after 15% ethanol. Fractions which were the desired product were collected and lyophilized. Prepared е ^ -3- [2- (2-acinco4 "-hUaizCir) -2- (1-íelhhr llkabboiyltUy-oxyimino) aclt € CIF -] - 4-karblmD Ί 2-L ^{four-oioaleltdii} SuiConová acid (^ η-ί ^ -ίθ).

IC spectrum (γ ... cm -1): 3250, 1770, 1690, 1625, 1280, 1230 and 1045. NMR Spectrum (DMSO-d6, ppim: 1.51 (6H, s, 2 x _CH3), 4.36 (1H, d, J =. 6Hz, -4), 5.33 (1H, dd, J = 6 Hz, J = 9 Hz, С -) 7, 18 (1H, s, J 2 H), 9.18 (1H, d, J = 9 Hz, C 1 -NH).

³ A

For C ₁₃ H ₁₆ N ₆ O ₆ Cl 2: 1 / 2H ₂ O calculated: 31.77% C, 3.90% H, 17.10% N; found:

% C, 31.69;% H, 3.90; 17.00% N.

Example 134

The elution fractions (10 to 20% ethanol) obtained by urigamatography on an ACerlite XAD-I column in column 131 were thyonded. Ne ^ a i ⁷⁴ m ^gd iso ^{n e} sod ο ^ ^-3 '· ^ · ^ - ^^^^ ¹ · - ⁴ - • UIizo ^ I) ^ - [ΐ-ίβ ^^ - Ι ^{- ( p} -iit ^lick-yl lc> ^yk i tr -nyl ^b) et ^{Ur loxyiíiilo].} acetamido) ^-44 IU ^I0 ICAO-4 ktbbo-IR-2 - L-xoolzlidio sufConové acid (syn isccer). as a colorless powder.

The amine group and the protecting group of the kibbexyl group were removed from the product by the wall method as in Example 132 and Example 133, respectively. prepared tbícodná οί salt; 3- [2- (2 - 01 --- ^^ ^ 1 ^ 2 ^ 1 ^) -2- (1- íelhur ^ 41kkabboxylthyCoxyímnno) aeetaíidl] 444ijlCoaíiiO ^к Labbe-IR-2-oc: iOletiifn SulConC ⁴ l ⁴⁾ as acid (syn Isocee).

I ^ ^C ektruc (in cm ^{3400, 1770.} And.. ^1630. ^ Ektbum ^NMR (DMSO + ^{D i, 0, pp} m):

Itiax o z '

1.34 (3H, s, CH 3), 1.50 (3H, s, CH 3), 4.49 (1H, d, J = 6.Hz, C4-H), 5.45 (1H, d, J) = 6 Hz,

1.34 (ЗН, s, СН ₃ ), 1.50 (ЗН, with CHg), 4.49 (1Н, d, J = 6 Hz, C ₄ -H), 5.45 (1H, d, J = 6 Hz,

C ₃ -II), 6.77 (1H, s, S γ H).

Example 135

In the same manner as in Reference Example 91, cis-4-acetoxymethyl-3-benzyloxycarboxamido-2-oxoazetidine, which was produced in Reference Example 7, was treated. Cis-3- [2- (2-chloroacetamido-4-thiazolyl) - 2 '] 1-Methyl-1- (p-nitrobenzyloxycarbonyl) ethyloxyiminojacetamido] -4-acetoxymethyl-2-oxoazetidine (syn isomer) as colorless crystals, melting at 120-123 ° C. IR spectrum (γ cm ^-1 ): 3250, 1740 and 1670.

The above product was sulfonated in the same manner as in Example 70. The amino protecting group was removed by the procedure of Example 67. The sodium salt of cis-3- [2- (2-amino-4-thiazolyl) -2- N -methyl-1- (p-nitrobenzyloxycarbonyl) ethyloxyiminojacetamido] -4-acetoxymethyl-2-oxoazetidine-1-sulfonic acid was prepared. (son isomer).

IR (cm ^-1 ): 3400, 1770, 1740 and 1670. NMR Spectrum (DMSO-dg ppm):

1.47 (6H, s, 2 X CH ₃ ), 1.95 (3H, s, COCH ₃ ), 6.66 (1H, s

H), 7.13 (2H, br s, NH ₂ ).

For C ₂₂ H ₂₃ N ₆ O ₁₂ S ₂ Na ₂ H ₂ O calculated: 38.48% C, 3.96% H, 12.24% N; Found:% C, 38.46;% H, 4.09;% N, 12.18.

Example 136

In the same manner as in Example 68, cis-3- [2- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4-acetoxymethyl-2-oxoazole disodium salt was prepared. idine-1-sulfonic acid (syn isomer). IR (У ах * ^ ^cm ^ ³ 0, 1 760 and 1 650. NMR (DMSO-d ^, ppm): 1.36 (3H, s, _CH3), 1.43 (3H, s, CH ₃ ), 1.93 (3H, s, COCH ₃ ), 5.25 (1H, dd, J = 5 Hz, J = 9 Hz, C ₃ -H), 6.70 (1H, s, SVH), 7.10 (2H, br s, NH ₂ ).

Example 137

Following the procedure of Reference Example 3, the 3-amino protecting group of cis-3-benzyloxycarboxamido-4-carbamoyloxymethyl-2-oxoazetidine, which was produced according to Reference Example 167, was removed. The corresponding 3-amino compound was prepared as colorless crystals.

IR spectrum (cm ^-1 ): 3430, 1740 and 1695.

The above product was acylated in the same manner as described in Reference ² One example 4. Production du cis-3- [2- (2-chloroacetamide-4-thiazolyl) -2-methoxyiminoacetamidq] -4-carbamoyloxymethyl-2-oxo-azetidine ( son isomer) as colorless crystals. IR spectrum ( ^cm):

250, 1750, 1680 and 1660.

The above product was sulfonated in the same manner as in Example 1. The sodium salt of cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamide] -4-carbamoyloxymethyl-2-oxoazetidin-1-sulfonic acid was prepared. acid (syn isomer).

IR (W₁, cm ^-1): 1770, 1700, 1690 and 650. 1 H NMR (DMSO-d ppm): 3.87 (3H, s, NOCH _3), 4.33 (2H, s , C1CH _2), 5.27 (1H, dd, J = 5 Hz, J = 9 Hz, C-H), 6.38 (2H, br s, NH _2), 7.39 (1H, s, SH), 9.16 (1H, d, J = 9Hz, _C3-NH).

Pro. C1з314ClN ₆ 0gS Na.2.53 ₂ O ₂ Calculated: 27.59% H, 3.38% 3 14.85% N; found:

% H, 3.86;% N, 13.73.

P Pikl a d 138

In the same manner as in Example 2, the sodium salt of cis-3--2- (2-amino-1- (9-azazolyl) -2-methoximinoiminomethylbenzoyl) -brombonyl-mononylbutyl-zincincethionic acid (syn) isomer.

IH spectrum (v · cm ¹ ): 3400, 1780, 1690 and 1645. NMR spectrum (DMSO-d6> PPJnH)

3.83 (33, s, NOHH ₃ ), 5.24 (13, dd, J = 5 Hz, J = 9 Hz, H 3-3), 6.36 (23, br s, N 4 J, 6, 70 (1H, s bp, 7.10 (23, br s, NH2 ₎ ), 9.10 (13, d, J = 9 Hz, H3-N3).

For ₁ H 13 ₁₃ N _{6 2} O8S Na.332O calculated: 26.50% H 3.84% 3 16.86% N; found: 26.51% H

3.49% 3, 16.42% N.

Example 139

In 3 mL of Ν, Ν-dimrehlfir> rIlamids rozpuutí with 1.08 g of 3-cit-bčnzyloxykbrbnxamido-4-jnimerhyl- ^-2- nxnalz i ^{r II E, kt} ^ Rota RRY the case of L by reížrrecáníto ^second When - ⁷ H 8 ° to this solution was added 5.8 ml (1.56 M) solution of sulfur trioxide-N, N-dimeehllirmamid. The mixture was stirred. ¹⁷ din ^ ^{p 3} s ^{and 5} ° ^H. After the ^p ^ m řiclá ^0.73 ml of pyridine and 95 ml of ether.

The solid precipitate was washed with ether and suspended in 50 ml of water. Ml D <owex 50W (NN-form) is added. The slurry was stirred for 2 hours at RT. The filtrate is thickened under reduced pressure. The residue is triturated on an Anbrrles XAD-II column, eluting with 10-20% ethanol, and the eluate is concentrated.

Prepared sodium cit-3-benzylnxlkbrrnx <- [bdio4-joOmbthyl "-2) Noo-L-etiddn sufinnové ^to YSE ^ei c ^y j and ^{k b} of ^the race ezbbrvý ^p. I ^H spectrum (((r cm ^{"1): 1 770} and 1 ^690th NMR (DMSSOdg, ppm): 3.2 to 3.7 (23, m, o ^) 4.0 to 4.3 (13, m, C-H)

J = 10 Hz, H3-3), 5.08 (23, s, COOCH2), 8.13 (1Hh 6, J 1 Hz, γΝΗ <.

For H,) 3 _{ί 9} JN _? N'íVOi-S.3 ₂ O calculated: 30.01 1 J _? 2.34 J (5.33% N; found: 30.08% H,

2.73% 3. (33 l N.

Fig. 140

In 30 ml. pyridine was suspended 320 mg of sodium SOU cis-3-benzyloxy-9- ^to arboxamidn) lidmreУl 12th · ol. oazazeddn · L-sulionové acid. The suspension was refluxed for 9 hours. Pyiidic .se odifstilsjr at a reduced rate.

50 ml is added to the residue. The ether layer was washed twice with ether, then 50 ml of water were added. The insoluble immateral was filtered and the filtrate was concentrated under reduced pressure. Purify on a AMAD column ^, for XAD-II, 20% CHCl3.

The eluate is concentrated and lyophilized. Prepared cit-3-brnzyli> xlkar · RNX ^mdco-4-2- pridininmerhyl of Ilz ^ C ^ ^ i ^ ⁽ⁱ ^ di ^ '^ l ^- ^ ^lΐ the IN ^and e Jato ^b čzbarvý ^{PRA to} r . Spec ^H ^ m ((^ ^{j r} x cm⁻¹: ¹⁷⁷⁰ and ^1710. NMR (-MSS-d ppm): 4.5 to 4.7 (13, m, H4-3), 4.87 (23, d, J = 6 Hz, C 9 -CH 2), 5.06 (23, s, COOCH 2), 5.08 (13, dd, J = 6 Hz, J = 10 Hz, J -3), 7 37 (53, s, HgHg), 7.96-8/26, 8.4-8.7 and 8.9-9.2 (m, 1H-protons of the pyridine ring).

For H3i3 0gS ^^ N ₃ calculated: 49.87% H, 4.67% H, 10.26% N; % H, 49.66; H, 4.50; N, 10.20.

Peak d 141

1.537 g of cis-3-benzyloxycarboxoxime-1,4-trimethylol-12-oxyl-hexane ₍ produced according to Reference Example G15) is suspended in 12 ml of dry. Under cooling NR -7 ⁸ ° ^{C there} was added a solution of the complex Oxie síroivý iaet ^^^ ^ l ^ raimid.í ^{10, 5!} . ^It is allowed to stand for 3 hours at room temperature.

0.85 [mu] l of pyridine for 40 [mu] l of ether was added under CH 2 Cl 2. The insoluble material was washed three times with 50 ml portions of ether. Ether under reduced pressure To the residue were added 10 ml of water and 40 ml of Dowex (50W (Na-form)).

The mixture was stirred at room temperature for two hours. The resin was filtered off. The filtrate was purified by column chromatography on an Aierlite XDD-2 column (elution with water) and filtered. The sodium salt of cit-3-benzyl-1-cyclohexanedilene-4-bromo-bromo-12-oxo-azededinone-tonic acid was prepared.

IR (KR ^ r V cm ^"1): 3410, 3250, 1780 and 680. 1 H NMR (DMSO-d ppi:

4.26 (12, d, J = 6 2z, _C4-2), 4.98 (1H, dd, J = 6 2z, 2z J = 9, C ₃ -H), 5.02 (2H, s C, 8 (CH3) # 7.23 (52, s, C8H4), 7.67 (12, d, J = 92z, C ^ -NH).

According to Reference Example 168, the trint-3-benzyloxycarboorai-4-crrbraoll-2-olol rzeeidine produced was treated in the same manner as described above. Sodium trichloro-3-carboxylic acid 4-cyano-2-oxo-azido-2-oxazolone acid is produced. This product is a hygroscopic powder. Therefore, okia2StS was used for subsequent processing.

Example 142

The sodium salt of 3-cit-bcnzylz) oykrrbooraidco2-kkibbmoaO-2 "2XZ) OOitldinnlltulOonové kyselinχ treated in the same ^PU EA j with ^b-a is shown in the case 66. ^In ýroba sodium salt of ^cis-3 - ^{- 2} - ⁽² lcCllrtcettmiddo4 -TT ^c alo ^about yl) ^ - ^ Ι ^ ^ βΟΙ -Ι- (ρ ^l-oitlobeo2 Loo ^yk -R ^b onyl) CT ^Cχ0 ooyimin ^0] acetamido} "4 krrbtInaol-222) L-oolletldin tU10onl> In the · kyelioy ·· (tyo isomeer.

The product was eluted with a Dnierlite XAD-I 40% ctanolea column. IR and NMR spectra of the product were identical to those of the product produced in Example 131.

Example 143

Croscarmellose tr-NT-3 "bcnzylloyk-rblx ^<b anidiol4lk- brmy0l ² 2 ₀ loazl! Teddn" 12tuf0onové acid is first reduced and naatceyluje j, as in Example 66. Thereafter, the same způsobea j, as in Example 67 removed cCllr- Cctll group. Sodium salt Prepared trlLot 3 - { '2- ⁽² -taiol-4-2- [1-MECT ^cl - ^l - (p-ni n ^{l e>} nnly oxyk ^{l-r b} lo ^ll) oxyimino ^{l of} ethyl | - ^ (^ ta ^ ^ iT as ^L 4 -R ^{b lk} -ac) ^ol - ^{2 2} -oooalzltdin L-sui0onové acid (syn isomer).

IR (.delta., Cm @ -1: 3400, ppa): 1.50 (6H, s, 20 DEG CH), 5.32 (2H,

765, 1730, 1690 and 1670. NMR Spectrum (DMSO-d6, s, COOCCX, 6.85 (12, S, 1H)).

AND

He said 144

In the same manner as in Example 133, tris-O- (2-amino-4-ololoyl) -2- (1-cyclohexyl) cyclohexylamino] -c4-to-bimoll122-olollethylenedi-l-tolylic acid was prepared in the same manner. - (son i ^ tlmc).

^{SPE and} ktru IR (cm ^{-1): 3280,} 1 7 ^ 1 660. NMR (DMIS Cl · * PPA)

max o

1.61 (62, s, 2 of _CH3), 4.17 (1H, d, J = 3 2z, C4-H), 4.84 (1H, d, J = 3 Hz, CGH) 7 11 · (1 H, s, SD / H) *

According ггУггг ^ пУУг vynoený Example 50 cis-3-4kccekamidomethyl benzyloxykarboxαmidl lxoakУtidin-2-treated in the same manner as in Example 91. The teferenčním Prepared cis ^-3- ®2- ^(2-e chlorkce aaido- -thiikУ ^{l l} y ^l ) ^{-2- [mzeh} ^ ^ -l- (p-nirrobnzlyloxykkrOlnyl) eth ^y l) x ^l i ⁱ i ^NLL kcetkmidcl 4-kcetkI ^m dolmthyl- ^L 2-din olXlkzt ^{t (Y} ^ ni Somr).

IR spekttrum ppm (1.49 (3H, s (1H, dd, J = 6 Hz ⁽ⁱⁿ cm ^{-1): 3} of ^{30 1780} and ^Z-1730 and the ^{1 650th} spelktrum NMR (CH DMSCHdg, 1.51 (3H, s, _CH3), 1.81 (3H, s, CO ^, 4.52 (2H, s, C1CH '), J = 9 Hz, C3-H), 5.32 (2H, s, COOCH3), 7.39 (1H, s, SyH).

The 5.20 product is sulfonated in the same manner as in Example 70.

^-3) -2- ^{(2-c y l} llrkcetkInidd ^4-yl th IKZ ^Ly1)) · ² - [lmet ^yl-y Li ^{(- r} NNZ nnilro ¹ lxx ¹ · S · ^Y XRA said

The ^y makes Stone salt of cis-rton ^ ^ -eto oxyiminc)] acetkmidol- ^4- kcrtkmidolet ^ryУ1-2 -lOlZLZ ^e d ^d nl ^STL-L onlV acids ^{y s} (syn sjoektLrum ^IR (cm ^{H s): 3 35} 0 ^1,780 to ^1,70 · ^{1,690 to 1,630} . NMR ppm): 1.52 (6H, s, 2 × 4), 1.81 (3H, s, HOCHh), 4.35 (2H, s) ΔШШ, 5.2 = 6 Hz, J = 9 Hz, H ₃ -H), 5.31 (2H, s, COOCH 3) ', 7.37 (1H, s, S 5 of H).

s ^p e ^to trum (1H, dd, (DMSOdc ^g

Pto H ₂ N ⊕ 4H2gd ^ ^ NkCз2S2.2H2O calculated: 37.82% C 38.04% C, 3.71% H, 12.87% N.

H, 3.84; N, 12.87.

found:

Example 146

In the same manner Jato přtaladu ⁶⁷ in ^{the y} or s Stone salt of cis-3- ⁽² - ⁽² -kminn) l ^- 4th AKZ ^{y l} y ¹⁾ - ² - [L-Mey ^ -l ^{- (p} -n ^ITT ^ r ^ lx ^1L lэrnz ^yl αr ^O Ln; ^ ^l) et ^yy] ^ ^y Ix ^I ^ amino] ^-4- acdamido- acrtkml ^d omi ^y h ^h1LI lXlkzze ^2-yl di-lstul·lnlové lyseeini (syn (slmr).

^IR spectrum (cm ^{-1): 3 35 0, 1 780} to ^{1 730, 1 680th} up to ¹ бМ. ¹ H ^NMR (d 6 -SO-d ppm): 1.5 (6H, s, 2 × 0 ^), 1.74 (3H, s, COCCH-), 5.13 (1H, dd, J = 6 Hz) J = 0 Hz (Cg-H), 5.31 (2H, s, COOCH-), 6.67 (1H, s, S, 1H), 9.29 (1H, d, J = 9 Hz, C). --NH).

J 3

For H ₂₂ H. _,,) M. ₇ Cз1S®. 3H ₂ O Calculated: 37.55% C, 4.29% H, 4.12% H? 14.03% N.

13.94% N; found:

37.56% C a l d 147

In the same manner in Example 133, the invention is improved. cis-3- £ 2- ^{(2-kIlmnn-l-yl} 4 Уkkolll) -2 - (UltУ1lI ^{llkroloxyrthyloxy-y} M ^y no) kcztamidol - aceramid0liir ^4-yl-У12 oloar: kУeddnna-sullonová acid (syn islmr) .

IC ktrurn (in ^KB \ ^J 1 ^{cm: 3325,} 1770 ^c m x ppm): 1.49 (3H, s, 1.51 (3H, s, CH

J = 9 Hz, C 3 H), 7-0 (1H, s, S ® H), 9.35 ³ A

720, 1.8 (3H (1H, d,

67. 1 635. NMR ektrum with ^p (DMSO-d ₆ (1 H, dd, J = 6 Hz, s, COCH3), 5.17 J = 9Hz, C - NH).

Pn C ^ i ^ o ^ O ^ S ^ 2 1 / 2H ₂ O Calculated: 4.75% H, 15.33% N.

33,51%

H, 4.69; N, 15.64; found: 33.70% C,

Example 148 se

-2-lxoascidin. Under cooling and stirring ledzm to thličikant solution and 1.0 g У сНУ ^^ ^:! ^ · 2- (2-L-chllrkcerkaddo ^{tУУaayl-y1)} -2- (Z) - 1-IκrУy1-2- (pn ^y tlobrnУ1llX1lkrOonn1) rtУ1lox1iminl kceeylcУllridt.

In addition to 15 ml of tetrahydrofuran and 15 ml of water cis-3-amino-4-isopropylamine ^, 216 mg of this add 438 mg of hydramine.

The mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure. The residue is shaken with 30 ml of water and 50 ml of ethyl acetate. The ethyl acetate layer was separated, washed with aqueous sodium hydrogen carbonate, water, and dried over anhydrous sodium sulfate.

The RooppoUtentil is removed under reduced pressure. The residue is dissolved in 2 ml of N, N-dimethylohylamine and sulfonated as follows.^podle^psay^andaclu⁷0. Sodium cit^-3-)²-⁽²-chlsr acenaaeda-4-th^laaz^withy^y) -2^-[l-mnt^lyl · - '(^Amn^rsroⁿnzyy^withoУ^tocarbsnyl) e^lhy^withoxyimins] acetamidoo '⁴~ -issprsp^y1- (2-oxazoline-1-sulfonic acid) (cornea).

YYr - 1

IR Spec microns ^{(> ý} # _max cm): ³⁴⁰⁰ and ^{3250 M 1 770} to ^{1 730, 1 680} and ^{1 050th} NMR ^for spectrum (DMSO-d6, ppm): 0.92 (3H, d, J = 6Hz, CH3), 1.04 (3H, d, J = 6Hz, CH3), 1.49 (3H, s) , CH3), 1.52 (3H, s, CH3), 3.73 (1H, dd, J = 6 Hz, J = ⁷ Hz, C4-H), 4.33 (2H, s, d ^) 5.15 (1H, dd, J = 6 Hz, J = 9 Hz, C.H), 7.32 (1H, s, S2 of H).

For C24H28ClNgNaO13S2.2H10 requires: C, 39.32; H, 4.12; N, 11.46. Found: C, 39.57; H, 3.82; N, 11.54.

Example 149

In the same way as in^pŘ^íkReferring to Example 67, the sodium salt c^andt-^3-22- (2-Amino-4-thiazole)^withyl⁾~ -2-^tl-mnt^ly1- (p-niSro)ⁿnnyy^withoУ^kaarbsn^yl) e ^ y ^ xyiminc:] ace ^ aido}^{with -}4^-Sat^withpr^spy-2 “OSOsaet^Ed^Enⁿl Acetic acid (syntmine).

¹ H- ^NMR (DMSO-d 6 ^pp m): (3H, s, CH 3), 5.31 (2H, s, ^{IR (} ν _max ) cm -1: ^{30 30 1770 to 1730 and 1670} 0.89 (3H, d, CH 3), 1.03 (3H, d, CH 3), 1.49 (3H, s, CH 3, 1.52 COOCH 2), 6.64 (1H, s, S) > yH).

² A

12.80% N; Found: C 40.10, H 4.22, N 12.69.

For ^C 2 ^H 25N6N ^{and -10S2,} 2H2 ° Calculated: 40.24% C, 4.45% H,

Example 150

In the same manner as in Example 133 was prepared cit-3- [2- ^(2-4-4 aiini- hlaazSlУ) -2- (1-1-menhyl karbsxyntlyloxyimins) acntamiěs] -4-2-itsprspyl sxoaaeetdin-l- SULSA (insvá acid (syn ίtsmee). NMR (DMSSOddj, ppm): 3.71 (1H, dd, J = 6 Hz, J = 9 Hz, _C3 -H), 6.90 (1H, s (1 H , dd, J = 6 Hz, J = 9 Hz, _C4-H, 5.13

9.27 (1H, d, J = 9Hz, C ₃ -NH).

For C ₅ H 2 N ₅ O ₁ S 2 _g; 3H2O Calculated: 34.81% C, 5.26% H, 13.53% N; Found:% C, 34.51;% H, 4.96;% N, 13.25.

Example 151

The same way I do^too v^pŘ^íkaIn step 148, the sodium salt of cis-s-³- £²-⁽(2-ch^withoaace^andamids -4- · tlaizsl^ya) 22 - i-eelУy^and- (p (ⁿ-n^withtbnⁿenz^withloУ^kaarboiy^lAcetinido^WITH(4-Methyl-artiamino) -2-oxosenidine-1-sulfonic acid (synsimide).

. IR ^{(cm "1):} 3350, 1780 and 1 670th

TtlaX (6H, s, 2 x CHh) -, 2.63 (3H, d, J = 5 Hz, NHCHp, 4.33)

C ₄ -H), 5.33 (2H, s, COOCH 2), 7.53 (1H,

Nuclear Magnetic Resonance Spectrum (DSSO-d 6, ppm): 1.52 (2H, s ClCH 2), 4.43 (1H, d, J = 5 Hz,

For C2 H2 _{3 3} C1N7NaOLLO2.2H ₂ O: calculated: 36.92% C, 3.64% H, 13.10% N; Found: C, 36.80, H, 3.53, N, 13.15.

P scheming ad 152 ^S tejným cr ^ OBEM Jato in příHadu 67 was prepared sodium cit-8- £ 2- (2- ^{r y} NEN ll4thaa ^tz l ^{yl) -} L2- [lmethal-II (beta-yitlobtyiyll) yykarboy ^yl ) ttayllxyieiyo] acetaeidoll4-lnethh ^{aarbrme-y-oxo760} --2. NMR Spectrum (DMSO-d6, ppm): 1.49

4.38 (1H, d, J = 5 Hz, C ₄ -H), 6.86 (1H, trans-tert-tert-tonic acid) (syn islmt).

Ir ^(c m ^{-1); 3330,} 1770, and 1 (6Η, 1, 2 x CC3), 2.60 (3H, d, J = 4 Hz, NHCH3), with, SVH, 7.21 (2H, br s, NH ") .

AND

For C, 1C22N7NrO ₁₁ S, .2C2 ° calculated: 37.55%

N, 14.59; Found: C, 37.54; N, 3.80.

Example 153

In the same manner as in Example 133 cit-3- [2- (2-methyl-4'-thtaatzlol) 12- (1-methyl-1-methylcarbamyl) -tayloyyimide] -tethamidol [4-methylcarbamyl] -2- (4-methylcarbamyl-11-yl) -tin-1-yl-tert-butylamine is prepared; i ^ somt).

XRr - 1

IR (cm: 1 80- 1 and 650th spekturnn NMR ^(DMSO-dg, pp ^m): 1 ^ 0 (HH, s, x CCH), 1.62, 3H, d, J = 1 HHZ 11 (4), ^{1H (d} , J = 5 Hz, CH3). , 5.33 (1H, dd, J "= 5, J = 9 HHZ HHZ CCH) 1 7116 1 11 H 1 S << H) 1 7.83 11 H 1 Q _t J = 1Hz NCCCj 1).

For C1 ₄ C _{6 g of} N O9S ₂ .2 1 / 2H2O Calculated: 32.11% C, 4.42% H, 16.05% N; H, 4.30; N, 15.87.

Example 154

In 2 mL of Ν, Ν-diethayflormaeidu were dissolved 240 mg of feeling "3 ~ [pl (2-lchll.rtcetrnidOll4-hi« '<- l, 1 ^·, 1 ··) -2-methoxyiminoacthrmidl] -4- (E) -ST-R-1-1- (t, butyldieettal·lS-llУ.) -2 l ^ l ^ x ^ oai¾ч; t.dinn syn ⁱ ^ the ^ t). ^{At -10} DEG ^C. , ^0.83 ml of sulfur trioxide-NN-amine solution was added.

The reaction mixture was sealed and allowed to ^s t ^{st, and 2} days ^- at ⁵ ° C. To this is added. 0.136 ml of pyridine and 100 ml of ether. The ether layer was discarded. Insoluble ethers were dissolved in a mixture of 20 ml of water + 10 ml of ethanol. To the solution was added 10 ml of Dowey 5OW (Na-form a).

The mixture was stirred for 20 minutes. The resin was filtered. Zabnusí filtrate to about 20 ml and purified ^y caromet0l6atfí column Dmerlitu XDD-2 (10% zOucz thaanolem). The eluate was lyophilized. 1 Preparation of the sodium salt citl3 '- [2 · ^{(2-caloracthamido-4-yl} taiaiol 12 "to mhaOχyyemnooacet <midlle] l L4 · -СE) lttyryl 2-o.xltietidinlltuullnюvé acid' (the son i ^ ^ t).

ICso ektruni ^IV ·· max cm ^{No. 1): 3450,} 1760 and 660. 1 H NMR ^with peatrum (DMSO-d ^ ^pp m): ^3, 64 (3Η, s, OCH), 4.77 (2H , s, CH 2), 4.65 (1H, dd, J = 6Hz, J = 7Hz, C4-H), 5.30 (1H, dd, J = 6Hz, J = 9Hz, C-, 7.11 (1H, S, Sv H).

³ .. X

For ^C 0) C17ClN5NrC7S2.3 1 / 2H2O Calculated: 37.22% C, 3.95% H, 11.43% N; Found: C 37.09, H 3.82, N 11.44.

Example 155

Cit-3- [2- (2-Amino-4-thiololyl) -1,2-methoxylamino] acetyl-4 - ((E) -tyryl-2-olaiethyidyl) -succinic acid, 1-sodium salt, was prepared in the same manner as in Example 11.

vrv _- 1 *

IR spectrum (in max ^cm ) ^: 3400, 1755 and 1660. NMR spectrum (DMSO-d6, ppm): 3.62 (3H, s, OCH3), 4.62 (1H, dd, J = 6) Hz, J = 7Hz, C4-H), 5.25 (1H, dd, J = 6 Hz, J = 9 Hz, C H _a), 6.43 (1H, s, O in H).

³ A

For C ₁₇ H gNgNaOgO ₁ .2 ₂ 1 / 2H ₂ O Calculated: 39.38% C, 4.08% H, 13.51% N; found:

% C, 39.29;% H, 13.54;

Example 156

145 mg of cis- and tris-5-sooer (1: 4) of 3-azido-4-ethoxycarbonyl-phinone-2-oxo-oetidine are suspended in 10 ml of methanol. To the solution was added 100 mg of 10% palladium on carbon. The suspension was stirred under an atmosphere of hydrogen at 30 ° C for 30 minutes. The catalyst is then filtered off. The filtrate was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20m).

To the solution, 0.35 ml of tree oilyl and 332 hydrochloride of 2- (2-chloroacetamide-44-thiazol-2-yl) -2-ethoxyoxy-ethyl-ethyl-L-chloride were added under ice-cooling and stirring. The mixture was stirred under ice-cooling for 15 minutes and then at room temperature for 1.5 hours.

The tetrahydroiurts are de-distilled under reduced conditions. The residue is shaken with ethyl acetate and water. The ethyl acetate layer was separated, washed with water and dried over anhydrous sodium sulfate. Under reduced conditions, it is separated to dryness. A mixture of cis- and triethylether (1: 4) 3- (2- (2-cyclotethoido-4-thiazolyl) -1-methylamino) nitroaceae-4-ethoxycarboforpheethof-2-oloatztidiyu (syn isomer) was prepared as a powder.

IC ^ CTE (<- cm ^-1): 3350 '1750' 1 730 and 1 670th

The above product was isolated in the same manner as in Example 109. A mixture of cis- and triethyl-sodium (1: 4) 3- [2- (2-chlorotetylidol-tetraitzol) -ethoxy] yoleacetate was prepared. .amiddO-4-mihoxχkarboyonyeetyOf2-oxoarlaZeddyy - tuiOoyoié kfseeiyf (syn

IR ^SRE ktru ^{e (y КВГ 'cm-1)} 3455' 1760, 1730 and 660. 1 H NMR ktrum s ^ (d-DMMO _O + O D _o max oz ppm): 4.88 (d, J = 2 Hz, trans-C 1 H), 5.35 (d, J = 5 Hz, cis-C 1 H -H).

The above product is treated in the same manner as described above in Case 11. This removes the amino protecting group. This process produces a mixture of cis-traytyl ether (1: 4) of 3- [2- (2-hydroxy-tolylolyl) -2-methoxy] -olylthio [0-4-ethoxy] -capryl acrylic acid salt (syntoomtic acid). ).

IC ^ CTE (in ^{cm -1):} 3400, 1762 '1 730 and 1 665. NMR (DMSO-D + D ₂ ppm): 4.84 (d, J = 2 Hz, ^ ^ ш ед- Δ, 5.32 (d, J = 5 Hz, cis-C 1 H 4 H), 6.88 (1h, s, S 1 H).

For C ₁₁ H ₁₄ N ₅ NaO ₅ S ₂ · 2H ₂ O calculated: 30.06% C, 3.78% H, 14.61% N; Found: C, 30.13; H, 3.71; N, 14.43.

Example 157

According to the procedure of Example 141, trans-3-azo-4-ethoxycarboyl-soyl-ethyl-2-oxo-azide was prepared according to Reference Case 177. This produced the sodium salt of trans-3-zido-4-ethoxycarbamoylmethyloxysoyl-denoic acid.

IR (kt) (V ^{: cm -1} ): 3425, 2125, 1762 and 1730.

Example 158

266 mg of sodium salt of 3-azdol 4 - zztУkxyklrbkl is dissolved in 5 ml of izldizztУyikorzczid.

·-yl zeZtyll2 okOkц _e ziddn L-suf0onové acid. To the solution was added 150 mg of 10% palladium on carbon. The mixture was stirred for 45 minutes under a hydrogen atmosphere at room temperature. The catalyst is then filtered off and washed with 5 ml of N, N-idetetethorcazazide.

The filtrate s for the washed (Ν) diz-dizztУyf kkz] and amdd solution is swirled. To the mixture was added 284 mg of 2- (2-chloro-cyclohexylmethyl) -2- [11-methyl-tert-butyl-tert-butyloxy-acetic acid, 110 mg of N-hydrohydroxybenzoic acid mixture and 150 mg of dibasic acid (150 mg). 4 hours at room temperature and then allowed to stand overnight at 5 [deg.] C. 20 ml of water were added.

Insoluble materials are filtered off and washed with 5 ml of water. The filtrate and the washed aqueous solution were mixed. To this is added the sodium salt of mono-ththylcarbonic acid. The mixture was treated STZ manner to a) of the above Example 11. Preparation of the sodium salt of trans .-- "3- [2- (2 · ^! - o · 4-thiazolyl ^{pounds) l2} - ^ I- zz ¹¹¹¹ -! - ^) ^ ^^ oiykarbon ^{11) of} ethylene ^from oxy zin ^k] acetazi ^dk} l I ^4-yk zztУko ar ^e kKBi? 3 ⁰ ^; ¹ ^ e ^ ^{ZT yl1I2} ^ o} ^ i ^ ^t oklet ^I1I in- ^ S ^ u: ^1o 0I ^ o \ Re (s ^y n ^ ⁱ ^ from ACS). ^IR with ^p ektrum IV _a ³ cm ^ r)

425, 1,760, 1,725 and 1,660.

With ice-cooling and stirring, 84 mg of the above product was added to 2 ml of thi &lt; 1 &gt; The mixture was stirred for three hours. The reaction mixture was evaporated under reduced pressure. The residue is taken up in 5 ml of water and cleaned using a DDrnerlite XAD-I column (slurry; water, then 10% color) and then on a Sephadex LH-20 column (slurry: water). Eluát sz lyoUizujz. It was dissolved in 5 ml of water and the solution was stirred for 10 minutes with 2 g of Dowex 50W (H-form).

The resin is filtered off. Filtrát sz liofilizujz. Manufactures sz ~ .3-22 trans (2-amino-4ltУlizolll) -2- ^(1-to-1 zeZhy.l arbkOlztУllkoyizink) vcztvzidoj] l4- ^ m ^ tlhk] ^; ^ l ^^^^ XE ( I I--1.xz.Zlyly] 12lll synkazkazkazkazzt synidin syn syn syn syn syn syn syn syn syn syn (syn ^ som somz).

IC екЬггш (in ^{cm "1): 3375,} 1760 ^and 725. 1 H NMR (.- 0 0 ^-? 1 .. 72 <

s, 2 x C)), 3.24 (2H, m, C4-CH2), 3.86 (3H, s, COOCF.,) _f TV, m, C4-H), 5.08 (1H, d, J = 2 Hz, C-H), 7.30 (1H, s, S &gt; H).

P P1) 159

Rocedure according to Example 141 sz sulfonujz ^CDS-3-yl BZNZ kxlyVae0xxazido · zetУkOlvzin -4- (0i ''; - Bonk-l220ookzetίddn ktzrý-SS prepared in Reference Example 178. Prepared • longitude and sodium L-cis-3-bzndyloxykvrekoazido ⁴ - mzZhУkoazizo-krvoleol · 2-ol: oooazidine-sulfonic acids.

. IR spectra (VK® * rn ^{c -1): 3270),} 1 760 and 1 680th

For C13H1sNgNaOgS.1 1 / 2H ₂ O Calculated: 36.97% C, 4.06% H, 9.95% N; H, 4.06; N, 9.97.

Example 160

Same method as in Example 143 sz prepared sodium salt of cis-3 -Y 2 (2-vzin hhalz01l-OL4) -2- ^ 1J ^{l i0} eobnzly ⁰ -n ⁱ oУ kaebo- ^yl) θ ^ υ ^ χ ^ ζϊ -χ] acetvzidx ^j) l ^{4 l} methyl oo ^{y y} шz nx ^{from about} kvbeo ^NL1 -2 l - ^^ ^ xd nl-di-o-sui nxvé acid (syn i ^ somz). .

I ^C spectrum (V). cm ^{-1): 3400) 1775,} 1730 and 680. 1 H NMR ^(DMSO-dg, ppm):

1.51 (6H, s, 2X CH3), 3.57 (3H, s, OCH3), 4.33 (1H, d, J = 6Hz, C4-H), 5.36 (2H, s) , COOCH ₂ ),

6.83 (1 H, s, S., H)

For ^C 2 ^H 22 ^N ^ ^N ^ 7 12 ^ 2 ^'2H 2 ° Calculated: 36.68% C, 3.81% H, 14.26% N; Found:% C, 36.68;% H, 4.11;% N, 14.28.

Example 161

In the same manner as in Example 133 cis-3- [2-r (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4-methoxyaminocarbonyl-2-oxoazetidine-1- was prepared. sulfonic acid (syn isomer).

IR (cm ^-1): 3280, 1770, 1730 and 1670 1.52 (6H, s, 2 x _CH3), 3.60 (3H, s, _OCH3), 4.34 ( 1H, d, J = J = 6 Hz, J = 9 Hz, _C3 -H), 7.14 (1H, s, s-H), 9.02 (1H, d

Nuclear Magnetic Resonance Spectrum (DMSO-d 6, ppm): 6 Hz, C ₄ -H), 5.38 (1H, dd,

J = 9 Hz, C ₃ -NH).

For ^C 14 ^H 17 ^N 6 ^O 2 ^S 2 · ² 1 / ^2H 2 O Calculated: C 31.23, H 4.12, N 15.61; Found: C, 31.06; H, 3.96; N, 15.40.

Example 162

Following the procedure of Example 70, cis -3- [2- (2-chloroacetamido-4-thiazolyl) -2- (1-methyl-1- (p-nitrobenzyloxycarbonyl) ethyloxyimino) acetamido] -4-cyanomethyl-2-oxoazetidine (syn. isomer) which was prepared in reference Example 181 in the same manner as in Example 67 ¹ are removed; amino protecting group of the product obtained above.

Cis-3- {2- (2-amino-4-thiazolyl) -2-C1-methyl-1- (p-nitrobenzyloxycarbonyl) ethyloxyimino] acetamido-4-cyanomethyl-2-oxoazetidine-1-sulfonic acid sodium salt was prepared acid (syn isomer). IC spectrum (cm &^lt; -1 ^&gt; ): 3420, 2250, 1765, 1670, 1620, 1420, 1345, 1280 and 1050.

Example 163

In the same manner as in Example 133, cis-3- [2- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4-cyanomethyl-2-oxoazetidine-1-sulfonic acid was prepared. acid (syn isomer).

IR spectrum (cm ^-1 ): 3290, 2250, 1775 and 1635. NMR spectrum (DMSO-d6, ppm):

1.56 (6H, s, 2 x _CH3), 5.29 (1H, dd, J = 6 Hz, J = 9 Hz, C ₃ "H), 7.07 (1H, s, H Sy) 9 42 (1H, d, J = 9Hz, C ₃ -NH). Λ

^C 14 ^H 14 ^N 6 ^O 8 ^S 2 ' ² 1 / ^2H 2 O requires C, 33.27; H, 8.8%; N, 16.62; Found: C, 33.57, C, 33.57, H, 4.01, N, 16.28.

Example 164

708 mg of 1-methyl-1H-tetrazol-5-yl-thioacetic acid prepared according to Reference Example 183 are dissolved in 20 ml of methylene chloride. 806 mg of thionyl chloride are added under ice-cooling, and the mixture is refluxed for an hour. The reaction mixture was then evaporated under reduced pressure. The residue is dissolved in 10 ml of methylene chloride.

Ve; g of cis-3- (p-nitrobenzyloxycarboxamido) -4-hydroxymethyl-2-oxoazetidine, prepared according to example (reference) 182., is added dropwise at 50 DEG C. to a mixture of 50 ml of tetrahydrofuran, 50 ml of methylene chloride and 0.5 ml of pyridine. acyl chloride solution prepared above. The mixture was stirred at room temperature for 4 hours.

The product was extracted with ethyl acetate / tetrahdyrofuran (3: 1). The extract was washed with 3N hydrochloric acid, saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.

The residue was purified by chromatography on a silica gel column (140 g, eluting with a mixture of ethyl acetate and methanol in a ratio of 8: 1 and even 4: 1 using initially pure ethyl acetate).

1.52 g of cis-3- (piperidin-1-oxazol-4-yl) -4- (1-methyl-1H-tetrazol-5-yl) trifluoroacetyl-2- (1-oxo) -zolidine are obtained.

This product is sulfonated in the same manner as described above in the drip tray 141. Produce cis · -3 "(p-nitroZyylχУkaabloxtmido)" 4 "(1'-methyl-1H-tetrazzl-5-yl) tliotcetoxyxetyl sodium - 2-> ooojetedSn- of 1-trifluoronic acid.

KBr ~ 1

IR spectrum (in _mA * · cm: 3400, 3320, 1760, 1730 and 685. 1 H NMR speatrum (DMSO-d₆, ppm): 3.98 (3H, s, N-CH), 4 90 (1H, dd, J = 6Hz, J = 9Hz).

For C ₆ H 7 ₆ N7NaO _1Q .H2O ₂ S Calculated: 33.63% H, 3.17% H, 17.16% N; found: 33.42% H, 3.05% H, 17.17% N.

Example 165

In SIMIS tztralydflfurant · 20 ml and 20 ml of water is dissolved 1.02 g of sodium SOU cis-3- (p ^J nčtrobzčzyloxχktrboxaeido) -4- (L-methll teerazol-lH-5 - yl) tlil) tcztlxymeZltll 2- olooaeZedSnčl acids.

1 g of 10% Pd / char is added to the solution. The mixture was stirred under a hydrogen atmosphere for 5 hours. The catalyst was &quot; И ^г ^ е. The filtrate was diluted with aqueous sodium bicarbonate and washed twice with ethyl acetate. The aqueous layer was mixed with 30 ml of water.

Under ice-cooling, to this solution was added 356 mg of sodium pyrogens and then

1.16 g of 2- (2-chloro-acetyl-4-thiazolyl) -2- (1-methyl-1-benzyl) (methylcyclohexyl) aminoethyl chloride hydrochloride.

The mixture was stirred under ice-cooling for one hour. 476 mg of sodium monohydrochloride are added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was washed twice with ether and evaporated. The residue is purified by Chromite on a column

XXD-II (Cells: water, 20% ethanol and then 30% ethanol). sin? - sylyl (2-zinc). The sodium salt of cis-3- [2- (2-trifluoromethyl) -2- (1-} ζΖΡ% .- ··· ·; e, r.hl · УsyУloχУttrbnlyZZlУoxyimino) acetamido ”] is produced. -4- (3-aa.thxl-1H-teZrazzl-5-χΙ) Zinc-2-ω-1-stoic acid Sn-1-stearonic acid (syn is> mee) ..

IR (in cm @ ^-1 , .delta. 9,420, 1,760, 1,740 and 1,670).

^In e ^2.5 ml. jnisolt the sus ^{p g} End ⁵⁴⁵ m ^ o sliora given for uktu ^d. For dlazzní ^-12 ° ss ^ l ² ml ICLA tr ^ ^f ^ oroodové Sélune ^ mixture was stirred at ^-1 ° and ⁱ - ¹² ° C for ³⁰ minutes. 40 ml of ether and 20 ml of hexane are then added. The resulting solid precipitate was washed three times with 60 ml of ether and then dissolved in 40 ml of water.

Sodium hydrogen chloride was added and the mixture was filtered. The filtrate was bent and purified by column chromatography on a DmerliZ Ш-Π column (water pool). The eluate is lylfilzztjz. Cis-3- [2- (2-Amino-4-thiazolyl) -2- (1-ethyl-1-carboxymethyl) oxy-acetylazo-4- (1-ethyl-H-tetrazol-5-ylthio) oxo-ethyl-2- disodium salt was prepared. oxoate 2-sulfonic acid (syn isomer).

IR spectrum (ν max ^{cm -1} ) ^{: 34} ° C, 1760 ^, (3H, s, HH 3), 1.43 (3H, s, CH ₃ ), 3.97 (3H, s,

H ₃ -H), 6.77 (1H,

680. NMR Spectrum (DMSO-d6, ppm): 1.38 N-CH3), 5.27 (1H, dd, J = 6Hz, J = 9Hz, s,

Example 166

2.56 g of cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid prepared according to Reference Example 68 are dissolved in a mixture of 30 ml of tetrahydrofuran and 15 ml of water. 895 mg of sodium bicarbonate, 2.23, are added to the solution. g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 3.62 g of alanine benzyl ester p-toluenesulfonate. The mixture was stirred at room temperature for 12 hours. The reaction mixture was extracted with ethyl acetate / tetrahydrofuran (2: 1), washed with water, twice with 3N hydrochloric acid, saturated aqueous sodium bicarbonate solution, brine. and dried over anhydrous magnesium sulfate.

The solvent is then distilled off. The residue is chromatographed on a silica gel column (450 g, 1: 1 chloroform-ethyl acetate, then 20: 20: 1 chloroform-ethyl acetate-methanol and finally 10:10 chloroform-ethyl acetate-methanol). : 1).

Diastereoisomers (beta and alpha isomers; see Reference Example 39) of cis-3-benzyloxycarboxamido-4- [4- (L) -benzyloxycarbonylethyl] aminocarbonyl-2-oxoazetidine were prepared.

These products are sulfonated in the same manner as described in Example 141. The beta and alpha isomers of cis-3-benzyloxycarboxamido-4- [1- (L) -benzyloxycarbonylethyl] aminocarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt are prepared.

Beta-Isomer: IR ( ^vmax , cm ^-1 ): 3,300, 1,770, 1,735, 1,690 and 1,660.

IuaX

For ^C 22 ^H 22 ^N 3 ^NaO 9 ^S * ¹ calculated: 47.65% C, 4.54% H, 7.58% N; Found: C, 47.55;

4.53% II, 7.44% N.

Alpha isomer: IR <Vmax ^{'3300 cm' 1770 '1695' 1 66} ° *

For C ₂₂ H ₂₂ N ₃ NaO 1 _g S.1 / 2H ₂ O Calculated: 47.65% C, 4.54% H, 7.58% N; found: 47.51% C,

H, 4.45; N, 7.47.

Example 167

In the same manner as in Example 66, the beta and alpha isomers of cis-3-benzyloxycarboxamido-4- [1- (L) -benzyloxycarbonylethyl] aminocarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt were reduced. The beta and alpha isomers of cis-3-amino-4- [1- (L) -carboxyethyl] aminocarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt were prepared.

These products are acetylated as in Example 66. Thereafter, the chloroacetyl group is removed as in Example 67. The beta and alpha isomers of the sodium salt of cis-3- [2- (2-amino-4-thiazolyl) -2- [1-] are prepared. methyl 1- (p-nitrobenzyloxycarbonyl) ethyloxyimino] acetamido} -4- 1- (L) -carboxyethylaminocarbonyl-2-oxoazetidine-1-sulfonic acid (syn isomer).

КВт Beta-isomer: IR spectrum (s), cm ¹ ): 3 400, 1,775, 1,730, and 1,665. Alpha isomer: IR spectrum (V HlCLA cm ¹ ): 3 400, 1,780, 1,730 and 1,670. Example 168 In the same way as in the example 133 se manufactures The beta and alpha isomers of cis-3- [2- (2-amino)

-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4- 1- (L) -carboxyethyl aminocarbonyl-2-oxoazetidine-1-sulfonic acid (syn isomer).

Beta-isomer: IR spectrum (cm ^-1 ): 3,300, 1,770, 1,720 and 1,665. NMR spectrum (DHMSodθ, ppm): 1.27 C4-H), 5.45 (1H, dd, ( 3H, d, J 'J = 6Hz, J

Alpha-isomer: IC ppm) i: 1.25 (3H, d, J spectrum (V = 7 Hz, CH ₃ ),

Hz, CH _3), 1.51 (6H, s, 2 x CH ^, 4.48 = 10 Hz, dH), 7.14 (1H, s, _S H).

A ^ m zc * ^{CIN 1) and} 3300 '1775, 1720' 1 670th

1.51 (6H, s, 2 × CHh >), 4.48 (1H, d, J (1H, O, J '6 Hz),

Nuclear Magnetic Resonance Spectrum (DMSOd 6, - 6 Hz, C 1 H -),

5.34 (1H, dd, J = 6 Hz, J = 9 Hz, _C3-H), 7.23 (1H, s, H-S

P ricings 169 to 173

Cis 3- (DL-2 - (- aminoOhitzol-4-ylC-thiol) nitrocetimidin-4-methoxymethoxycarbonyl) -azoline-1-inonone was treated with the acylating agents listed in the table below. Prepared PM VID ^ ^ ICI sodium cI8-3-DDL-2-acylzmi0o --- ^(x -caminnOhCazol 4cyl) acetmiOo] -4-metCoxykarbonnč azeti0inon-2-L-su10nnovýcC compounds which are also listed in the same table .

G гЧ 1 6 no ϋ -μ 34 φ X ÍX сб ω Ε ο > Η -

-μ

О гЧ Ό • Н • н ю

> υ

* m « N 41 « II ко со д см СП ш N N г- ок д ч ок д ω Ю ю ω ш II > 1 ω тГ Ю ко к г- -μ О * ю Д гЧ Гз сП φ no сб сб II д II т-Ч • μ OI > гЧ <б д rtí к сч μ Д | Ό гЧ • “3 »-D 1 > 1 d no ок ок СП ш СО 4J ъ > СП О чг г- гЧ Ф А 44 Д Д τι хг ь Ό ъ γι к I — 1 О no сп Ш КО > гЧ Л no Ρ - · л ш сб 0 • н ΟΙ > > -ч > ·. > * гЧ ·· μ Д τι N г- сп лЗ ч τι - · 0 • μ О д > Я л О Д N О - * no * д no * 1 сб см CD сп Д г- СП о д 1 no д СП • н Q > д 04 / о гЧ и — д гЧ д Ό no II (б о о 1 no • μ о о о Ο о о о KD СМ 00 00 Ш Г— KD СП сч о СП гЧ гЧ гЧ г — С гЧ _ч л ιη О ιη о О μ гЧ м · ιη Г ~~ г- ιη СП 04 / гЧ гЧ гЧ гЧ

ш д см и

о μ 0 гЧ 34 Р • μ • Η <б Ό сб сл μ • ГЧ сб β Μ 4-> гЧ а • Η чб > Ф 34 > Ν α > Ρ а Ή Сб φ 0 Ή 0 Ό > μ (Л • μ > Ν -μ 0 а оо Φ Ρ φ Д гЧ φ υ 0 υ ω > г-Ч > Ν сб Οι (Π

no СП ОК СП д м · СП см <б ш γ- О γ- οπ О \ όη - сб СП Д А— КС υ СП ко О д О no СП no § .. no no « о й OJ <б Ω > ЛК * - * Ό no

ο * *

ООО тг m μ г-щ m гЧ тЧ

II о + J Ψ> Ό

О СП ко

* Ιη в * ιη

450, 1350, (1N, two d, J =

280, 1,250 С ₄ -Н), 5.22 (1Н

060 -CHCON), 5.41 and net

М ⁴ Ч N Ч II М ⁴ СП 1 * d • г | ч ч ч ко II ч Я Г- чг К Я к ко я чз КО Λ я d ко Я г-ч _х и N ι-Ч л G ч гЧ кл СМ > Э ч no ко -Р со гЧ я ч / \ Я '-г я со ч КО СО о d гЧ о II 1 Я 1 ч ч ч ч О > ч ч (Т сп 1 Я см СМ ' КЛ г- · No. d СП II со КО Р ч no Ό КЛ h> ω кл ч м ⁴ no О ч гЧ г- - ч Я кл я я ^ ч Г- М ⁴ КЛ no N ч > 1 л_ ч со О »-Э ч 1 ч 1 ч 1 ч ч ч Ч я Я II ко > о к КО О кл СО ^ ч кл я ..см СП Я ^ ч Ό Я со ч та кл N ο- О ч ^ ко ч о ч о Я я гЧ я Я ι СМ (h) d гЧ * - * со no d О > 1 - · no d 1 d d со d d гЧ 0 л no > см > М ¹ > Я > КО о N а гЧ ч ч ч со N я 0 Я Ό ' no Ό <У> / -Ч со υ Ό 00 II ω II Ό d μι ** <~ ч ω я СО Я ο- гЧ кл О σκ ко Я ко о со Ч • rl 4J | ι О 1 1 о Гэ ко Λ > -ч СМ d —Г кл КО N см Я М ⁴ N Я КО кл со no Я КЛ • э я Я • Р ф > d со я «- < гЧ гЧ гЧ ч - ’Р < »· СО Ό СМ ч II ω • «Ч • I N · - · d > - ч > 1 ·· ч · ч Ч Ό - · ч (0 Я (Л ^ -ч А Λ Я ко > ^ ч no Ό II (0 О О ч ч Я • Р О ко гЧ о Я 0 О со я о Ч Ό СМ Я 1 я см 1 кл г * 00 II 1 гЧ см d <Т1 1 d Я d Q о со «- < Q II со 0 Q > ’З’ > г-Ч > Я 'd d no ЧЭ ω со • м · ti кл О N М ⁴ О Ό КЛ 1Л Я

и /

no

II

S4> Ю XD Д 0) л • го 0 W СО мП О д 0 > N no • го Р 0 Я 0 • Р д d > Ό ЗЕ Я Ό

о

Д4 XD «о па • го d гЧ

XD Д4

-Р TJ

(М Г ° ЧУ °

100 ALIGN!

Example 174

In the same manner as in Example 145, the cis-3-E2- (2-chloraceaamido-4-th-C-zolII) -2- (1-methyl-1-benzene-hydroxyryloxycarbonylethyloxyimino) acetomethyl] -4-carbamoyoxyoxyethyl group-1 sodium salt was prepared.

-2- (3-xylamino) -in-1-yl-oxoic acid (syn isomee). IR (ν _ma x ^{cm -1} ) ^: 3400, 1750 and 1720.

Example 175

In the same manner as in Example 67, cC8-3- [2- (2'-amino-4-thiazolly) -2- (1-methyl-1-benzene-1-benzene-oxycarbonylethylPoxy-amino) -acetamido-4-carbamoyloxy-ethyl-22-oxo-zetiCinKBr · '* - I

-? - sufoonic acid (syn isomer). IR ( _{.delta. Cm @} -1): ₁₇₆₀ , 1720 and ₁₆₇₀ .

Example 176

Ml 1 ml of anisole is added 250 mg of cls-3- [2- (2-aminoo-4'-hazolazolyl) -2- (1-methylbenzhydryloxycarbonylethyloxyimino) acetyl] -4-carbamxolx-4-ylethyl-22-oxoacetate sodium salt. sulfoxic acid (syn isomee). While stirring, 5 ml of trifluoroacetic acid is added dropwise at -20 ° C.

The mixture was stirred at -15 ° C for 30 minutes. Then 10 ml ether and 10 ml petroleum ether were added. The resulting powder is centrifuged, dissolved in water, and Dowex 50 µ W (H-form) is added. The mixture was stirred. The resin was filtered off. ,

The filtrate was concentrated and VP! Chromatograií purified on a column of A ^ <^ l ^^ l · p ^TU XDřžjíeluce 100 ml water, 100 ml of 10% ethanol, 100 ml of 30% ethanol and finally with 100 ml of 40% ethanol). Fractions with 30% ethanol were lyophilized. Cis-3 - [[2- (2-Amino-4- [4- (4-carbonyl) -yl] -2- (1-methyl-1k-1b)} was prepared; x ^ yrthyPoxylmino) -acetamide <0 ^_ 4 "karbamoylPoχletethyp-oxoaoaeeddcnl-sůPfonová acid (syn l ^ s ^ a ^ e ^ · m).

Ic ^sp ektru ^m W? _Max cm ^-1): 1760, 1710 and 630. NMR 1 with ^p ektrim (DMSCHdg, ^pp m): 1.51 (6H, s. 2 x CH3), 7 Δ (1H, s, S Η), 9.23 (1H, d, J = 9 Hz, C ^-NH).

In the same manner as in the above examples, the following can be produced by the following:

cis-3- [2- (2-Amino-4-thiazol-2-yl-methyl-oxo-oxo-oxo-oxo-oxo-1-oxo-1-sulfonone) disodium salt (4syloxy) ^ om ^ jr), DCS-to-CCS-salt of 3- [2- (2 - oino-4-thia-zo01y) 4 2- ^(1-to-l- meehyl arboxyethyloxyioino) acetaoido- t4tactaoidomerhyl-424> o-o-acetillin-1-isonic acid (synsosoee), cis-3-22- (4-mono-4-heopoyl) - (2-bromo-methyl) -oxoacetamido-4'-acetylidazole-4-mono-4-aceto-4-amino-4-mono-4-amino cis-3- [2- (2-oino-4-thiazolly) -42- (1-methyl-1-carboxyethyloxyloino) acetoacetate-4-ls- ^p -iodo-salt - polyl-2-oxo-eidin-1-sulfonic acid (synsome), dls-> d-salt of cis-3- [2- (2-minx-4-thiazxyl)] - 42- (1- methyl-1-carboxyethyloxylmloo) acetamido-4-methoxycarbolomethyl-1,220-α-α-acetic acid (syn isomer) and cis-3- [2- (2-anilino-44-thiazoxyl) carbonyl] 42- (1-mercaptoxy) ethyl-1- (1-mercaptoxy) ethyl Acetamido] -4-methylcarbamx-1,2-oxo-eetdinic acid (syn isomer).

Reference Example 1

Under ice-cooling and stirring, 6,94 g of methyl-cis-3-oino-4- (2,4-dimethoxybenzoyl) -2-oxo-oxo-4-carboxyPoic acid methyl ester in 12 ml of methylene chloride are added to the mixture. , 7 ml

101 propylene oxide and 3.24 g carbobenzoxy chloride. The reaction mixture was stirred at room temperature for 30 minutes. The solvent was distilled off in vacuo. Ether was added to the residue. The precipitated crystals are aspirated. Cis-3-Benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -2-oxoazetidine-4-carboxylic acid methyl ester, m.p. Mp 115-116 ° C.

For ^C 22 ^H 24 ^N 2 ° ^to 7 ° C yp ^theory: 61.67% C, 5.65% H, 6.54% N; Found:% C, 61.64;% H, 5.67;% N, 6.49.

Reference Example 2

A solution of 2.7 g of cis-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -2-oxoazetidine-4-carboxylic acid methyl ester in 150 ml of acetonitrile was heated under a stream of nitrogen and stirred at 90-95 ° C. . To this solution is added dropwise 55 ml of an aqueous solution containing 2.73 g of potassium persulfate and 1.65 g of potassium hydrogen phosphate.

After completion of the dropwise addition, the mixture was stirred at the same temperature for 3 hours. The reaction mixture was cooled.

The pH of the reaction mixture was adjusted to 6-7 by the addition of potassium hydrogen phosphate. The acetonitrile and water were distilled off in vacuo. The residue was dissolved in chloroform. The solution was washed with water and brine.

The chloroform solution was dried over anhydrous sodium sulfate. The solvent is then distilled off in vacuo. The residue is chromatographed on a silica gel column. Elution with ethyl acetate gave cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid methyl ester, m.p. 127-128 ° C.

For C ₁₃ H ₁₄ N ₂ O ₅ Calculated: C 56.11, H 5.07, N 10.07; Found: C 56.03, H 5.01, N 9.99.

Reference Example 3

To a suspension of 0.8 g of cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid methyl ester in 20 ml of ethanol was added 0.8 g of 5% palladium on carbon. Catalytic hdyrogenation is carried out at atmospheric pressure with stirring. When the uptake of hydrogen ceased, the catalyst was filtered off. The filtrate was concentrated in vacuo.

The remaining oil was allowed to stand while cooling. The precipitated crystals are filtered off. Produced

0.38 g of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester (92%), m.p. 59 ° C.

For C ₅ H ₈ N ₂ O ₃ calculated: 41.66% C, 5.59% H, 19.44% N; Found:% C, 41.54;% H, 5.59;% N, 19.67.

Reference Example 4

Under ice-cooling and stirring, 6 ml of an aqueous solution containing 288 mg of cis-3- methyl ester are added to a suspension of 1.18 g of 2- (2-chloroacetamido-4-thiazolyl) -2-methoxyethoxyacetyl chloride (syn isomer) in 10 ml of tetrahydrofuran. amino-2-oxoazetidine-4-carboxylic acid and 561 mg sodium bicarbonate.

The mixture was stirred at room temperature for two hours. The solvent was distilled off in vacuo.

The remaining residue solidified. Water is added to the solidified residue, the mixture is filtered and the crystals obtained are washed first with water, then with ethanol. Cis-3- [2- (2-Chloroacetamido-4-thiazolyl) -1H-methoxyiminoacetamide [eta] &lt; 2 &gt; -2-oxoazetidine-4-carboxylic acid methyl ester (syn isomer) was prepared.

m.p. 270 DEG-275 DEG C. (dec.).

For C ₁₃ H ₁₄ ClN ₅ O ₆ S calculated: 38.66% C, 3.49% H, 17.35% N; Found: 38.50% C

H, 3.78; N, 17.25.

102

Reference Example 5

While cooling with ice and stirring, a solution of 12 g of cis-3-benzyloxycarboxamido-1- (2,4-dimethoxoleezyl) -2-oooiseeidine-4-carboxamiidil- (2,4-dimethoxoleezyl) -2-oooisetidine-4- of carbooilic acid in 500 ml of tetrahydrofuran add 250 ml of the aqueous solution it contains

2.65 g of sodium borohydride. The reaction mixture was stirred at room temperature for five hours.

Tetrahydrofuran was added in vacuo Water was added to the reaction mixture. The decrystallized crystals are filtered off. After drying, 9.8 g (87%) of C8-3-beoloxylcareloxananilide (2,4-diethylbenzyl) -4-oxalzeeidine, mp 129-131 ° C, were obtained.

For ^C 21 ^H 24 ^N 2 ^O 6 calculated; % C, 62.99;% H, 6.04;% N, 7.00; Found:% C, 62.78;% H, 5.91;% N, 7.05.

Reference Example 6

To a solution of 5.1 g of cis-3-beneyloolcarboxylic acid (2,4-dimethyl-benzoyl) -1,4-hydroxyethyl-1-oxoazetidiz in 50 ml of ethylene chloride is added dropwise, at 0 ° C, first with 3.8 ml of pyridine and then with 2 ml. 04 ml of acetic acid. The reaction mixture was stirred for 30 minutes. The solvent was distilled off in vacuo.

The residue is chromatographed on a silica gel column, eluting with ethyl acetate. 5.45 g (96%) of cis-4-aceloxlietyl-13-eneoyl-oocarboxylic acid-11 (2,4-dimethyl-oxo-azel) -220xolzeeidine, m.p. Mp 110-111 ° C.

For C ₂₃ H 26 N ₂ O 7 calculated: 62.43% C, 5.92% H, 6.33% N; Found:% C, 62.26;% H, 5.68;% N, 6.07.

Reference Example 7

A solution of 4.862 g of cis-4-aceloxyl-3-benzoyloxycaroxoxide (11,4-diethoxybenzyl) -121-oxoacetate in 275 ml of acetone is heated to 80-83 ° C under a stream of nitrogen at room temperature. stirring.

110 ml of an aqueous solution containing 4.752 g of potassium persulfate and 2.871 g of potassium hydrogen phosphate are added to this solution.

After the addition, the mixture was stirred for an additional 2.5 hours at 90 ° C. While cooling, the pH is adjusted to up to 77 by the addition of potassium hydrogen phosphate. Aceto-4H and water were removed in vacuo.

Chloroform was added to the residue. The insoluble materials were filtered off, washed with water and chloroform and dried.

Cis-4-aceloxyl-ethyl-leezzyl-1-oxylaabeoxa-O-22-oxetetdin-m.p. Mp 137-138 ° C.

For ^c 14 H 11 ₆ N2 vyPOČtenoi ₅ 57.53% C, 5.52% H, 9.59% N; Found:% C, 57.38;% H, 5.43.

9.58% N.

Reference Example 8

To a suspension of 1.46 g of cis-4-methyl-3-benzyloxycarboxootiido-2-oxolaetidine in 50 IU of ethanol was added 1.5 g of 5% palladium on charcoal. The mixture is catalytically reduced under stirring at atmospheric pressure. The reaction is complete in 30 minutes. The catalyst is filtered off. The filtrate was evaporated to dryness in vacuo.

750 mg (95%) of cis-4-acetyl-methyl-3-amino-2-oxoazetidizu (colorless oil) are obtained.

IR ^cm-1): 3 · 300, 1 770-1 710. NMR CDC13, ppm) :. 1.83 (br s,

-NH 2), 2.1 (s, -CH 3), 3.6 to 4.1 (m, -CH 1, 4.1 to 4.8 (m, C 1 -C ₁₁ -C ₄ -H), 6, 0-6.3 (br s, NH).

103

Reference Example 9

To a suspension of 2.36 g of 2- (2-chloro-4-trifluoromethyl-4-trifluoromethyl) -methoxyiminoxyl-5-chloro (this contains 632 mg of sodium.

isomer) in 20 ml of tetrahydrofuran is then added 12 ml of an aqueous solution containing citrate-4-acetoxylmethyl-4-amino-4-oxoazetin and 1.122 g of hydrogeenilicate.

The mixture was stirred at room temperature for two hours

The remaining residue solidified. Water was added to the solidified residue and the mixture was filtered. The crystals were washed successively with an aqueous solution of sodium lyodate, water, ether and dried. Produce cit-4-acetoxymestlyl-3- [2- (2-trifluoromethyl-4-thaatolyl-32-m-methyymimidaceaadido) -2-thiazapidine (syn isomme), mp 180-190 ° C (dist.).

distilled off in vacuo.

For ^C 14 ^H 16 ^C W calculated: 40) 24% c, 3.86% H, 3.67% H, 16.60% N.

N, 16.76; found: 39.89% C,

Reference Example 10

While stirring and cooling with ice, heat to the solution 4.5 g

dimethoxybenzenesulfonyl-1,2-oxothiazine in 30 nyl chloride. The mixture was stirred at room temperature for 30 min at room temperature (2.4 ml of pyridine was added 1.94 g of methanesulfonate), and 100 ml of stearic acid and 50 ml of dilute hydrochloric acid were added to the reaction mixture.

ml with water. Then the reaction mixture is acidified by filtration. The filtrate was partitioned to water and the resulting residue was added

The organic layer is dried to dryness in a vacuum, distilled off the crystals and mixed with the crystals obtained above. The combined crystals were washed sequentially with aqueous sodium hydrogen carbonate solution, water and ether and dried. There was obtained 5.0 g (93%) of cis- ³ -benzyl-oxy-benzimidazole-1- (2,4-dimethoxy-benzenes) -4-methanesulfonyl-methyl-2-oxo-azetine, mp 140-141 ° C.

N, 61% N.

For ^C 22 ^H 26 ^N 2 ^ 8 ^: calculated: 55.22% C, 5.48% H, 5.85% N; Found: C 55.16, H 5.40,

Reference Example 11

A solution of 3.83 g of cis- ³ -benzylthoxycarbonylthioidethoxy (2,4-dimethoxyphenyl) -4-methanesulfonylthiomethyl-2-tetraazetidine in 200 ml of acetonntril is heated to 80 DEG-83 DEG C. with stirring in an aqueous solution containing 3, 46 g potassium potassium persulfate. ác · / ku. To the solution is added dropwise 80 ml. And 2.09 g of hydrogen phosphate are stirred at 85-90 ° C for 3 hours. The solvent is then distilled off under vacuum. 200 ml of water are added to the residue and the resulting crystals are removed by suction. The crystals obtained are washed with water, then with ether and dried. Manufactures te ^{cis-3-benzyloxy-4-yl-txxykarboxгmίet} methannu ^Ui} tnyltX snmth ^1SL 2 ² Otxtae ^{e pyrrolidine; tt} . ¹³² DEG- ¹³³ DEG. IR number (cm ³⁾ : ^{3 325}

770 and 1,690.

After the addition is complete, heat the mixture

Reference Example 12

To 55 ml of methyl ethyl glycol was added 1.4 g of cis- ^3- benzyloxycarbonyloxy-4-methanesulfonylmethyl-SH-2-thiazolesetine and 4.2 g of sodium iodide. The mixture was stirred at 90 ° C for 2 hours and then at -60 ° C for 12 hours. ?C.

and 50 ml

Unleash tddestilšjs in vacuum. Shake the residue thoroughly with 100 ml of water. Remove insoluble material by rinsing with water and chlorine by flame.

Mon ¹

Mp 162 ° C. ]

3.64% H, dried to give cis-3-bβnzsloxykarbtxaInidet - JT (dnmShlSl22oxxtaeSiein7 mp 160 DEG ^C for 3 12H13IN2 ° vypxčteno: 40.02% C, 3.64% · H 7.78% N Found: · 40.26% C,

7.93% N. '

104

Reference Example 13

To a solution of 103.5 mg of sodium dissolved in 9 ml of methanol is added 522 mg of 1-methyl-5-tetrazolyl-mercaptan. The mixture was stirred at room temperature for 15 minutes. The methanol was distilled off in vacuo. The residue is dissolved in 12 ml of Ν, Ν-dimethylformamide. 900 mg of cis-3-benzyloxycarboxboxridof4-indolyl-2-oxoffetidium were added to the resulting solution, and the mixture was stirred at room temperature for 19 hours. 100 ml of water are added to the reaction mixture.

The separated crystals are filtered off and washed successively with water and ether. The crystals are then passed through in ethyl acetate. The solution is passed through a small silica gel column. The solvent was removed from the eluate in vacuo. 780 mg (90%) of cis-3-benzyloxycyclobenzofloxido-4- (1-methyl-5-tetphezolytifluoromethyl) -2-oxofeetidase were obtained as colorless crystals, m.p. Mp 151-152 ° C.

For C 14 H 16 N 6 O 3 S: calculated: 48.26% C, 4.63% H, 24.13% N; Found:% C, 48.38;% H, 4.65;% N, 23.89.

Reference Example 14

Under ice-cooling and stirring, an aqueous solution containing 288 mg of cis-3-miao-2-oxoazetinine methyl ester (288 mg) is added to a suspension of 1.18 g of 2- (2-trifluoromethylphosphoryl) -2-methooylminoacetyl chloride (anti isomer) in 10 ml of tetrahydrofuran. Of 4-carboxylic acid and 561 mg of sodium hydrogen carbonate, and the mixture was stirred at room temperature for two hours.

The fabric was then vacuum fddesStlsjs. The remaining residue solidified. Water was added to the solidified residue and the mixture was eluted. The filtrate was extracted with aqueous sodium hydrogen carbonate solution and the product was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate.

Roopbuckle under vacuum fddesSilsjs. Prepared reShyl ster-cis-3-Q2- ^(C fc 2cchf ^of efmief 4-thfafolyl) -2-tgУOχyyiminofcet mieO ¢] -2-4-oxffeetidan aabfoxyfoJ | é acid (anti isomer), mp 119-129 ° C. ;

For C33H3 ^ Nj.OgS ₄ Cl calculated: 38.66% C, 3.49% H, 17.34% N; Found:% C, 38.56;% H, 3.60;% N, 17.05.

Reference Example 15

While ice-cooling and stirring, to a solution of 2.94 g of cis-3-quinolinyl (2,4-trans-oxyl) -2-oxo-phenyl-4-carbonyl-acid in 40 ml of methylene chloride is added 2.10 ml of trimethylsilyl. Then, 2.31 g of methyl ethyl acetate in 15 ml of methylene chloride was added dropwise over one hour.

The reaction mixture was stirred for an additional hour with ice cooling. Then it is washed. successively with dilute hydrochloric acid, 5% aqueous sodium hydride, aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was removed in vacuo.

Ether was added to the residue. The precipitated crystals are filtered off. Cis-1- (2,4-Eethoxyethoxy) -3-phenylacetophrido-2-oxoazetin-4-arboxylic acid methyl ester, m.p. Mp 124-126 ° C.

For C22 ^H 24N2 vypPČteno ° 6: 64.07% C, 5.86% H, 6.79% N; Found:% C, 63.98;% H, 5.98;% N, 6.70.

Reference Example 16

Mixture of 412 mg of cis-1- (2,4-ethylsulfonyl) -Ззphenylacetfridef2-ooxffeeidin105

Of 4-carboxylic acid, 810 mg of potassium persulfate and 261 mg of potassium hydrogen phosphate in 20 ml of acetonitrile and 20 ml of water are refluxed for one hour. The reaction mixture was evaporated to dryness in vacuo. The residue was dissolved in ethyl acetate, washed successively with aqueous 5% sodium hydrogen carbonate solution, aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was distilled off in vacuo.

Ethyl acetate was added to the residue. The precipitated crystals are filtered off. Cis-3-Phenylacetamido-2-oxoazetidine-4-carboxylic acid methyl ester, mp 176-180 ° C, was prepared. IR KRR - 1 (M cm): 1790, 1740 and 655. 1 H NMR (DMSO-d ,, ppm): 3.47 (s, CH _-CO and OCH,

Iuo.X O Z J

4.20 (d, J = 6Hz, C ₄ -H), 5.35 (d, d, J = 6 Hz, J = 8 Hz, _C3-H), 7.32 (s, C ^) 8.44 (s, NH); 8.62 (d, J = 8Hz, CONH).

Reference Example 17

Under ice-cooling and stirring, 12 ml of an aqueous solution containing 570 ml of cis-1- (2,4-dimethoxybenzyl-3-phenylacetamido-2-oxoazetidine-4-carboxylic acid methyl ester in 24 ml of tetrahydrofuran) are added to a solution of 2.06 g. mg sodium borohydride.

The reaction mixture was stirred under ice-cooling for 30 minutes and at room temperature for 1.5 hours. Tetrahydrofuran was distilled off in vacuo. Aqueous sodium chloride solution and ethyl acetate were added to the residue. The resulting ethyl acetate layer was separated and washed successively with aqueous sodium bicarbonate and brine, dried over magnesium sulfate, and the solvent was distilled off in vacuo.

Ether was added to the residue. The precipitated crystals are filtered off. 1.75 g (91%) of cis-1- (2,4-dimethoxybenzyl) -4-hydroxymethyl-3-phenylacetamido-2-oxoazetidine are obtained, m.p. Mp 152-154 ° C.

For ^C 21 ^H 24 ^N 2 ^O 5 ⁱⁿ YP ^calculated: 65.61% C, 6.29% H, 7.29% N; Found:% C, 65.37;% H, 6.47;% N, 7.55.

Reference Example 18

To a solution of 1.12 g of p-toluenesulfonyl chloride in 6 ml of pyridine, 1.73 g of (2,4-dimethoxybenzyl) -4-hydroxymethyl-3- Lacetamido-2-oxoazetidine. The reaction mixture was stirred for 2 hours and then allowed to stand overnight in the refrigerator. 0.68 liters was added to the reaction mixture. of lactic acid and the mixture was stirred for one hour.

The reaction mixture is then diluted with 45 ml of ethyl acetate and 15 ml of tetrahydrofuran, and washed successively with hydrochloric acid, aqueous sodium chloride solution, aqueous sodium hydrogencarbonate solution and aqueous sodium chloride solution.

The organic phase is dried over magnesium sulphate and the solvent is distilled off in vacuo. A mixture of ether and ethyl acetate (5: 1) was added to the residue. The resulting crystals were filtered off. Thus, 2.21 g of cis-1- (2,4-dimethoxybenzyl) -3-phenylacetamido-4- (p-toluenesulfonyloxymethyl) -2-oxoazo [eta] &lt; 5 &gt;, m.p. Mp 109-110 ° C.

For C2gH ,, N ₃₀ O ₇ S Calculated: 62.43% C, 5.63% H, 5.20% N; Found:% C, 62.18;% H, 5.72;% N, 5.07.

Reference Example 19

2.27 g of cis-1- (2,4-dimethoxybenzyl) -3-phenylacetamido-4- (p-toluenesulfonyloxymethyl) -2-oxoazetidine and 4.95 g of sodium iodide are added to 70 ml of acetone. The mixture was refluxed under stirring for 6 hours. The reaction mixture was evaporated in vacuo. Methylene chloride and water were added to the residue.

106

After dissolution of the residue, the methylene chloride layer was separated and washed with an aqueous solution of sodium sulfate and an aqueous solution of sodium chloride. The solvent layer was then dried over magnesium sulfate and the solvent was removed in vacuo. To the evaporators was added tert-butyl acetate.

The separated crystals were collected by filtration. -1,4- (2,4-Methoxycarbonyl) c4-iodomethylc6- was prepared,

Oxoozetidine, m.p. Mp 181-182 ° C. '·

For C _z ^ 23 23 ((C 04 04 04O 04: C, 51.03; H, 4.69; N, 5.67. Found: C, 51.14; H, 4.64.

5.81% N.

Reference Example 20

To 6 ml of Ν, Ν-dimethylamino-amide was added 740 mg of α- (- (4-dimethyloxybenzyl) -4-iodomethyl-3-thienyl) acetamido-oxoazytoline and 146 mg of sodium azide. The mixture was stirred at room temperature for 4 days. RooppuStёdlf is removed in vacuum by Shlsjt. To the residue was added tert-butyl acetate and water. The ethyl acetate layer was separated, washed with an aqueous solution of sodium chloride and dried over magnesium sulfate.

The roo was removed in vacuo. EtCer was added to the residue. Dropped crystals are filtered off. It was prepared from 4-methyl-methyl-C- (2,4-dimethoxy-phenyl) -3-phenyl-acehamido-2-oxol-2-yoline, m.p. Mp 110-111 ° C.

IR spectrum (V cm -1): 3270, 2110, 1755 and 1650. NMR spectrum (CDDC? ppM):

3.32 (m, -CH ₂ N ₃ ), 21.63 (s, CH ₂ CO), 3.83, ( _s , 2 x OCH 3), 4.36 (dd, J = 14 Hz, CH ₂ Dr) Δ, δ 8 (q, J = 5 Hz, C ₃ -H), 6.40 to 6.80 (m, D H and CONN), 7.16 (s, C 6 H 9).

Reference Example 21 '

To a solution of 449 mg of α-3-methyl-methyl-Cl (2,4-methylmethoxybenzyl) -phenylacetylaminomethyl-2-o-oeyeidine in 80 ml of ethyl acetate was added 200 mg of addition per carbon. The mixture was cydrogenated with 1.5 Codins at ambient temperature and at atmospheric pressure.

The catalyst is separated off. The filtrate was separated in vacuo. The residue is taken up in 30 ml of methylene chloride. To the methylene chloride solution was added 0.20 ml of hemi-amines under stirring at 0 ° C. To this solution was added dropwise 0.10 ml of tetrachloride in methylene chloride over 10 minutes.

The reaction mixture was stirred for 40 minutes. Then, the reaction mixture was washed successively with dilute hydrochloric acid, water, aqueous sodium cyanoborohydride solution, aqueous sodium carbonate aqueous solution, dried over sodium sulfate and the solvent was removed in vacuo.

To the residue was added tert-acetate. The resulting crystals are filtered off. Ethyl-4-acetimidimidyl-1 - (-, 4-dimethoxybenzyl) -cyclohexene acetic acid (mp 205-207 ° C) was obtained (C spectrum (и ^КВГ , cm -1): 3270, 1750, 1640.

in max

REFERENCE EXAMPLE 22 A mixture of 193 mg of eit-4-aeetamethylammonium chloride (-, 4-hydroxymethyl-phenyl)) - phenylacettmidoo-2-oxoxayeidine, 576 mg of potassium perborate and 183 mg of Orasel sodium phosphate in 15 ml of water and 15 ml of acetic acid. ... 5 Codins under RefluxCooler.

The reaction mixture was concentrated in vacuo. The conjugate is dissolved in tert-butyl acetate. The solution was washed successively with an aqueous solution of sodium cydrogen chloride and an aqueous solution of sodium chloride. The ethyl acetate solution was dried over magnesium sulfate and the solvent was removed in vacuo. To the residue The precipitated crystals are filtered off.

107

Cis-4-acetamidomethyl-3-phenylacetamido-2-oxoazetidine, m.p. 200 DEG-202 DEG.

KBr-1

IR spectrum (v _max, cm): 3250, 1750, 1640 and 520. 1 H NMR (DMSO-d ppm): 1.77 (s, _COCH3), 3.11 (m, CH ₂ N) , 3.69 (dt, J = 5 Hz, J = 6Hz, C ₄ -H), 5.00 (dd, J = 5 Hz, J = 8 Hz), 7.26 (s, ₆ H, C ₅ ), 7.59 (m, NH), 8.20 (wide band, [α], 8.75 (d, CONH,

J = 8Hz). 1— | J

Reference Example 23

To 200 ml of benzene was added 8.5 g of cis-1- (2,4-dimethoxybenzyl) -3-phthalimido-2-oxoazetidine-4-carboxylic acid methyl ester and 3.1 g of 1,8-diazabicyclo [beta], 4.0 -7-undecene. The mixture was refluxed for 72 hours. Ethyl acetate (100 ml) was added to the reaction mixture with cooling. The solution was washed successively with 100 ml and 50 ml of 1N hydrochloric acid and 100 ml of water.

To the resulting mixture was added 100 mL of chloroform, and the solution was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. 50 ml of ethyl acetate were added to the residue. The resulting insoluble material was filtered off and washed with 30 mL of ethyl acetate. 6.4 g of crude product are obtained, which is recrystallized from 220 ml of ethyl acetate to give trans-1- (2,4-dimethoxybenzyl) -3-phthalimido-2-oxoazetidine-4-carboxylic acid methyl ester, m.p. Mp 186-188 ° C.

For ^C 22 ^H 20 ^N 2 ° ^to 7 ° yP ^čtGnoí 62.25% C, 4.75% H, 6.60% N; Found:% C, 62.13;% H, 4.64.

6.43% N.

Reference Example 24

To 83 ml of methylene chloride was added 8.3 g of 2,4-dimethoxybenzylamine and 6.0 g of anhydrous magnesium sulfate. A solution of 6.5 g of glyoxylic acid butyl ester in 65 ml of methylene chloride is added dropwise with ice-cooling and stirring. The mixture was stirred for an additional two hours.

The reaction mixture was filtered. To the filtrate was added 5 g of triethylamine and a solution of 11 g of phthalimidoacetyl chloride in 110 ml of methylene chloride. The mixture was stirred overnight. It is then washed successively with dilute hydrochloric acid, aqueous sodium chloride solution, aqueous sodium hydrogen carbonate solution, aqueous sodium chloride solution and dried over anhydrous sodium sulphate.

The mixture was filtered and the filtrate was concentrated. Ether was added to the concentrate. The insoluble material was filtered off. The filtrate was evaporated under reduced pressure. 20.1 g (86%) of cis-1- (2,4-dimethoxybenzyl) -3-phthalimethyl-2-oxoazethanine-4-carboxylic acid butyl ester (orange-colored oily product) are obtained.

A portion of the product was purified by silica gel column chromatography. The product is obtained in the form of a colorless foam. However, the above product was used in the crude product in the crude IR spectrum (cm ^-1 ): 1770 and 1720. NMR Spectrum (CDCl 3 ppm): 4.26 (1H, d, J = 5 Hz, α-H), 5.63 (1H, d, J = 5Hz, _C3 -H).

Reference Example 25

To a solution of 19 g of cis-1- (2,4-dimethoxybenzyl) -3-phthalimido-2-oxoazetidine-4-carboxylic acid butyl ester in 190 ml of methylene chloride was added 3.7 g of methylhydrazine. The mixture was stirred overnight at room temperature. The reaction mixture was filtered. The filtrate was distilled off under reduced pressure.

Ethyl acetate was added to the residue. Insoluble material was removed by filtration. The filtrate is extracted in two portions of 100 ml of 1N hydrochloric acid. The extracts were neutralized with sodium bicarbonate and the resulting solution was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.

108

They make it. 12 g (87.5%) of cis-3 butyllitlrš-imirncli (2,4-dIcelho-iУbliyl) -2-осос ^ ^^ 1101о market-xylc у ^ ¹ ^ (^ ^1-1 ^ о ^у (o ^C EI ). ^ic ^ ktrn (cm ^-1): 3 ⁴ ° 0. ¹ and 750. the nmr ^ ktric (HDCI3, ppm): 3.83 and 3.95 (2 x 3H, 2 x s, 2 x -CH )).

In a similar manner, the amino acid (2,4-di-methoxybenzyl-2-oxo-methyl-4-carbonyl) is prepared (olbj). IR spectrum (cm ^-1 ): 3400, 3330 and 1760. NMR spectrum (CD- ₃ , ppm): 3.70 (1H, d, J = 2 Hz, C-H), 3.79, 3, 80 and 3.81 (3 x 3H, 3 xs, 3 X CH 3), 4.21 (1H, d, J = 2 Hz, C 1 H), 4.45 (2H, q, J = 14 Hz, CH ₂ ).

Reference Example 26

To a solution of 10 g of cis-3-methyl-2,4-dimethyl-2,4-difluorobutyl-2-oxyl-4-oxyl-2,4-butylester, first add 1.8 g of temperature.

Acid in 40 ml of cellular chloride was added under ice-cooling (5.5 ml and then 5.5 ml) and the mixture was heated under reduced pressure.

Stir at this temperature for one hour. It spread

The resulting crystals were filtered. Produced 11.7 g (83.5%) butyllitlrš CII-3-blizyloiyktrboxaaidf-l- (2,4-dicβthoxiУbliyl) -2 - xoa1glifio-'4-sel ktrbciylové ^ ¹ ^ Cr ^ how- anyway tal tt ^ 97 and ^from 9 ^{to 8} ° ^C.

For C ₂₅ H 3 _{O 7} N ₂ 0: calculated: 63.81% C, 6.42% H, 5.95% N; .nalezeno: 63.51% C, 6.26% H, 6.09% N.

Similarly prepared: celhuУestlr ^{TRTO-3-yl-blog} iykаrУo-imidf-C- (2,4 · 4dicetUoxχУblliχrL424 ioazelifio-4-kαrb-iylc) as carbamic acid. Since this product was recrystallized in the same manner as above, the product was purified by purification of O-SiO2 (1: 1) with hexane / ethyl acetate (1: 1). A colorless shiny product is produced. Yield 89%.

^Ic ektruc ^P (V ^th ^ cm ^{3): 3340, 1740} and ^{1 1 720th} N ^MR ^ etoruc ( ^- D ^- .L ^{, pp} m):

3.93 (1H, d, J = 3 Hz, C ₄ -H), 5.07 (2H, s, CH-Fenny..

Reference Example 27

The mixture 60. 1cellitrile and 60 µ. 2.35 g of cis-3-blozyloxycarbonylamide- (2,4-acetoxy-biphenyl) -2-oxo-pyrimidin-4-carboxylic acid; potassium sulphate and 1.75 g of potassium uyarogenitricate.

The resulting mixture was refluxed under argon for one hour. Acelooiirrl will detonate at reduced! pressure. Ethyl acetate and water were added to the residue and the mixture was stirred at room temperature. shy-pe. The ethyl acetate layer was washed with aqueous sodium chloride solution, and dried over anhydrous sodium sulfate.

sodium,

The solvent was evaporated under reduced pressure. The residue was treated with silica gel, eluting with ethyl acetate / hexane (1: 1). Crystals are produced; ^Cίi-3-y lox ^y bliz kαrbcia ^s to 2-oxocL1elidio- ⁴ - ^to αrb ^{iylov-E k ei} YSE ^iy, mp 112-113 on kclcně ester and bullae ° C.

H, 6.29; N, 8.74. Found:% C, 60.25;% H, 6.33;% N, 8.53.

In a similar manner, the carboxylic acid was prepared by trituration of 3- (3-blizyloxy-trichloramide-2-thio-biphenyl-4), mp 139-140 ° C.

Reference Example 28 Butyl-3-blozyloxycarbonyl-2-ocxyl-lelt (trans-44-carbonyl)

To a suspension of 640 mg

In 1 ml of ethanol was added 640 mg of 10% paltdit on carbon. The mixture was catalytically (Uyarogen) with stirring at normal pressure.

109

When hydrogen uptake is complete, the catalyst is filtered off from the reaction mixture. The filtrate was concentrated under reduced pressure. The residue crystallized. 330 mg (87.1%) of cis-3-amino-2-oxoazetidine-4-carboxylic acid butyl ester are obtained. A portion of the product was recrystallized from ethyl acetate and hexane.

Orange colored flaky crystals, m.p. Mp 87-89 ° C.

For C ₉ H ₁₄ N ₂ O ₃ Calculated: C 51.60, H 7.57, N 15.04; Found: C 51.33, H 7.58, N 14.80.

Similarly prepared trans-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester, m.p. Mp 135-136 ° C.

Reference Example 29

To a solution of 2-hydroxyiminoacetacetic acid methyl ester (13.6 g) in acetone (70 ml) was added potassium carbonate (20.8 g) under ice-cooling. 17.0 g of propyl iodide are added dropwise over 30 minutes. After the dropwise addition, the mixture was stirred at room temperature for 2 hours. Acetone was evaporated under reduced pressure.

250 ml of water are added to the residue. The mixture was extracted with methylene chloride. The extract was washed twice with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. 2- (Propoxyimino) acetic acid methyl ester was prepared as a pale yellow oily product.

IC spectrum (λmax) ^cm: 2,975, 1,750, 1,695, and 1,600. NMR spectrum (CDCl ₃ , ppm): δ, 95 (3H, t, J = 7 Hz, CH ₂ CH ₂ CH ₃ ) , 1.75 (2H, sextet, J = 7Hz, CH ₂ CH ₂ CH _3), 2.38 (3H, s, CH ₃ CO), 3.86 (3H, s, _COOCH3).

The following compounds were prepared in a similar manner: 2- (butoxyimino) acetacetic acid methyl ester, light yellow oily product, yield 80%. iC spectrum cm ¹ ):

975, 1755, 1700 and 600. 1 H NMR (CDC1 _3, ppm): 0.94 (3H, t, J == 6 Hz, _CH? CH ₂ CH \. J ·,

1.2 to 2.0 (4H, m, CH ₂ CH ₂ CH ₂ CH ₃ ), 2.36 (3H, s, CH-jCO), 3.85 (Z 2, s, COOCH 3, 4.29 (2H) , t, J = 6 Hz, CH ₂ CH ₂ CH ₂ CH ₃ ) and 2-benzyloxyiminoacetacetic acid methyl ester, pale yellow oily product, 98% yield. IC spectrum cm ^-1 ): 1,750 and 1,690. NMR spectrum (CDCl _3). (ppm): 2.36 (3H, s,

CH ₃ CO), 3.84 (3H, s, COOCH ₃ ), 5.28 (2H, s, CH ₂ ), 7.27 (5H, 5H, s, phenyl protons).

Retirement Example 30

5.5 g of sulfuryl chloride are added to a solution of 7.4 g of methyl 2- (propoxyimino) acetic acid methyl ester in 7.4 ml of acetic acid. The mixture was stirred at 40 ° C for 10 minutes and then at room temperature for 6 hours. The reaction mixture was poured into 100 mL of ice-water. The product was extracted twice with chloroform.

The extract was washed with aqueous sodium chloride solution, aqueous sodium bicarbonate solution, water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. 8.2 g (94%) of 4-chloro-2- (propoxyimino) acetacetic acid methyl ester (pale yellow oily product) were obtained.

IR cm ^{^):} 2980, 1750, 1720 and 595. 1 H NMR (CDC1 _3, ppm):

0.97 (3H, t, J = 7Hz, CH ₂ CH ₂ CH _3), 1.77 (2H, sextet, J = 7Hz, CH ₂ CH ₂ CH ₃₎ 3> 89- (3H, s COOCH ₃ ), 4.30 (2H, t, J = 7 Hz, CH ₂ CH ₂ CH ₃ ), 4.56 (2H, s, C ₁ CH ₂ ).

The following compounds were prepared in a similar manner:

110 4-Chloro-2- (butoxyimino) acetic acid methyl ester, pale yellow oily product, 92% yield. iC s ^p e ^Truro (in cm ^-1): 2975, 1 ⁷⁵ 0 1 ⁷² 0 1 595 s ^ ktrum NMR (CDCC. ,,

Ppm (ppm): 0.97 (3H, t, J = 6 Hz, CH 2 CH 2 CH 2 CH 3), 1.2 to 1.2 (4H, m, ΟΟΟ, ΟΟΟΟ), 2.88 (3H, s, COOCH ₃ ), 4.33 (2H, t, J = 6 Hz, CH ₂ CH ₂ CH ₂ CH ₃ ), 4.56 (2H, s, CICH 2) and 4-chloro-2-benzyloxyiminoacetacetic acid methyl ester, pale yellow oil, yield 97%. IC spectrum (γ cm ^{-1 with} 1 and 1,720) NMR spectrum (CDCl 3 ppm): 3.87 (3H, s, COOCH 3), 4.50 '(2H, s, ClCH ₂ ), 5.29. ( 2H, s, (4-phenyl), 7.28 (5H, s, phenyl protons).

Reference Example 31

7.0 g of 4-chloro-2- (propoxyimino) acetic acid meenhyester, 2.4 g of thiourea and 4.3 g of sodium acetate trihydrate are added to a mixture of 20 ml of water and 25 ml of ethanol. The mixture was stirred at 40 ° C for one hour. While cooling, the pH of the reaction mixture was adjusted to 6.5 by addition of saturated aqueous potassium carbonate solution. The reaction mixture was then stirred for 30 minutes.

The resulting crystals were filtered, washed with water, isopropyl ether and dried. Thus crystals of 2- (2-amino-4-thiazolyl) - (Z) 42- (propoxyiyino) acetic acid yethhlestter are produced:

mp 115-116 ° C.

H, 5.39; N, 17.27. Found: C, 44.20; H, 5.38; N, 17.11.

In a similar manner, 2- (2-ayne-4-thiazolyl) - (z-24 (bisthoxy) acetic acid) ethyl ester, mp 118 ° C and 2- (2-amino-4-thinzolyl) - (Z) were prepared in a similar manner. M.p. 148-149 ° C.

Reference Example 32

To a solution of 5.0 g of 2- (2-ayinoo-4-thinzooyl) - (Z) 42- (propoxyamino) acetic acid yethlester in 35 ml of Ν, di-diethyl acetayide was added dropwise over ten minutes while cooling with ice and stirring.

3.25 g of chloroacetyl chloride. The mixture was stirred at room temperature for one hour, then poured into 200 ml of ice-water.

The oily product is separated. This product is allowed to stand to crystallize. Crystals (Χΐϋ ^ υΰί, wash with water and eject. Prepared 6.35 g (96.7%) íethhlesteru 2- (2-chlorlcetaInidf ^{4-th and the} allo У ^l) - ^{(Z) 42} - (propoxyiíino) vinegars ^é acidulous, ^{m. p. 100} ° ^C.

For C 4,4 HH ^ ClNNO C requires: C, 41.31; H, 4.41; N, 13.14. Found: C, 41.35; H, 4.34; N, 13.14.

Similarly prepared 2- (2-chloroacetayidophenyl) thiazolyl) - (Z) 42- (butoxy-4-chloro) acetic acid, m.p. 86-87 ° C, yield 85%, and 2- (2,4-chloroacetyl-44- (4-chloroacetamide) -44 thiol). - (Z) 42- (benzyloxyiíino) acetic acid 361 ^^ ^e ^ ^{t. t} . ПО II to ⁵ ° ^C in ^YT Eze ^to 96

Reference Example 33

To a solution of 3.2 g of 2- (2-chloroacetamido-44-triazolyl) - (Z) 42- (propoxyyino) acetic acid ethyl ester in 50 ml of ethanol is added a solution of 2.23 g of potassium hydroxide (85%) while cooling with ice and stirring. in 20 ml of water. The mixture was stirred at room temperature for 5 hours.

Thereafter, the reaction mixture was evaporated under reduced pressure. Dissolve conoenate in 30 ml of water. The solution was washed twice with 30 ml portions of ethyl acetate, then treated with charcoal. The mixture was charcoal filtered, adjusted to pH 2 by addition of 1N hydrochloric acid, the resulting crystals were separated by filtration, washed with water, hexane and ether and dried.

111

2- (2-Chloroacetamido-4-thiazolyl) - (Z) -2- (propoxyimino) acetic acid was obtained, m.p. 170-171 ° C (dec.).

For ^C iq ^H 12 ^C1N 3 ° 4 ^S Calculated: 39.28% C, 3.96% H, 13.74% N; found: 39.34% C,

H, 3.84; N, 13.41.

Similarly prepared 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2- (butoxyimino) acetic acid, m.p. 167-168 ° C (dec.) And 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-benzyloxyiminoacetic acid, m.p. 160-161 ° C (dec.).

Reference Example 34

To a suspension of 583 mg of 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-ethoxyimino-acetic acid in 5 ml of methylene chloride, 243 mg of triethylamine are added under ice-cooling. To the mixture was added

416.5 mg of phosphorus pentachloride. The mixture was stirred for 30 minutes at room temperature.

The methylene chloride was distilled off under reduced pressure. The residue is washed three times with hexane and suspended in 7 ml of tetrahydrofuran. A solution of 216 mg of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester and 308 mg of sodium bicarbonate in 4.2 ml of water is added dropwise to the suspension. The mixture was stirred at room temperature for two hours. The solvent was evaporated.

20 ml of water are added to the residue. The solution was made slightly alkaline by addition of sodium bicarbonate. The undissolved material was filtered off, washed successively with aqueous sodium bicarbonate solution, water, hexane and ether and dried. There was thus obtained cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-ethoxyiminoacetamido] -2-oxoazetidine-4-carboxylic acid methyl ester (syn isomer), m.p. 270 DEG-280 DEG C. (decomposition).

For C ₁₄ H ₁₆ ClN ₅ O ₆ S calculated: 40.24% C, 3.86% H, 16.76% N; Found:% C, 39.98;% H, 3.80;% N, 16.91.

The following compounds were prepared in a similar manner:

cis-3- [2- (2-chloroacetamido-4-thaisolyl) -2- (propoxyimino) acetamido] -2-oxoazetidine-4-carboxylic acid methyl ester (syn isomer), mp 260-270 ° C (dec.), methyl ester cis-3- [2- (2-chloroacetamide-4-thiazolyl) -2-isopropoxyiminoacetamido] -2-oxoazetidine-4-carboxylic acid (syn isomer), mp 215-225 ° C (dec.), cis-3 methyl ester - [2- (2-chloroacetamido-4-thiazolyl) -2- (propoxyimino) acetamido] -2-oxoazetidine-4-carboxylic acid (syn isomer), mp 275-280 ° C (dec.), Cis-3 methyl ester - [2- (2-Chloroacetamido-4-thiazolyl) -2-benzyloxyiminoacetamido] -2-oxoazetidine-4-carboxylic acid (syn isomer), mp 275-285 ° C (dec.), Cis-3- [2- (methyl ester) 5-chloro-2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido-2-oxoazetidine-4-carboxylic acid (syn isomer), mp 215-220 ° C (dec.), Cis-3- [2- (butyl) ester 2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -2-oxoazetidine-4-carboxylic acid (syn isomer), mp 235-239 ° C (dec.) And trans-3- [2- (2-chloroacetate) methyl ester amido-4-thiazolyl) -2-methoxyiminoacetamido] -2-oxoazetidine-4-carboxylic acid (syn isomer), mp 137 to 139 ° C for .CH3OH computed ^f i theory: 38.57% C, 4.16 % H, 16.07% N; Found:% C, 38.93;% H, 4.15;% N, 16.04.

112

Reference Example 35

To a solution of 9.3 g of 2-amino-4-thiazolylacetic acid ethyl ester in 50 ml of N, N-dimethylacetamide was added, with ice-cooling and stirring, 7.91 g of chloroacetyl chloride. The mixture was stirred for one hour at room temperature. Water (300 ml) was added to the reaction mixture.

The resulting crystals are filtered off. The crystals were washed with water, ether and dried over phosphorus pentachloride. 12.1 g (92%) of 2-chloroacetamido-thiazazolyl-acetic acid ethyl ester, m.p. Mp 145-146 ° C. .

Calculated: C 41.14%, H 4.22%, N 10.66%. Found:% C, 41.16;% H, 4.14;% N, 10.86.

Reference Example 36

To a solution of 2.5 potassium hydroxide in 10 ml of water and 100 ml of ethanol is added 3 g of 2-chloroacetamido-4-thiazolyl-ethyl ester. The mixture was stirred at room temperature for one hour. The solvent was distilled off under reduced pressure.

Water (10 ml) was added to the residue. The resulting aqueous solution was washed with n-acetic acid. The pH of the solution was adjusted to 2 by adding 10% hydrochloric acid. The crystals are rejected, washed with water and dried.

2.2 g (84%) of 2-chloro-stamides-4-thiazazolyl tic acid were obtained, mp 193-195 ° C. For C ₇ H ₇ ClN ₂ O ₃ S calculated: 35.83% C, 3.01% H, 11.94% N; Found: C 36.00, H 3.15,

12.24% N.

Reference Example 37

To a suspension of 1.41 g of 2-acetyl-4-thiazolyl-acetic acid in 30 ml of methylene chloride was added 1.5 g of phosphorus pentachloride under ice-cooling and stirring. The mixture was stirred at room temperature for 40 minutes. After filtration, 1.7 g (98%) sdppoídeaícíУs chloride hydrochloride (colorless crystals), mp 123-125 ^o C (^ C ^ z ^ kl.). iC spectrum (V ^KR _X · ccm: 1780 and 1712.

To a solution of cis-3-amino-2-thiazoazetin-4-carboxylic acid methyl ester in a mixture of 4 ml of water and 4 ml of trisulphurane was added 840 mg of sodium bicarbonate followed by 864 mg of the above hydrochloride acid. The mixture was stirred at room temperature for two hours, then evaporated to dryness under reduced pressure.

Water (5 ml) was added to the residue. The insoluble material is filtered, washed sequentially with aqueous sodium hydroxide solution, water, hexane and ether and dried. Produced. cis -3- [2- (4-cyanoSoacsiaamies-4-thiazolyl) astaamedo] 22-oxsaoctetin-4-carboxylic acid methyl ester, mp 120-122 ° C. For C _X 2H ₁₃ ClN ₄ O ₅ S.1 / 2H ₂ O calculated: 38.97% C, 3.82% H, 15.15% N; Found:% C, 39.01;% H, 4.23;% N, 15.40.

Reference Example 38

To a solution of 1 g of 1-butII-2,3-dSxxopipnrakin in 10 ml of dry menhhlenchlorine is added

0.766 g of trimethylchloride is added to the mixture in a stream of nitrogen at room temperature. The mixture was then stirred for one hour. Reaction. The mixture was cooled to 430 ° C. To the cooled reaction mixture was added dropwise 0.39 ml of irichloromethyl tertiuromethane.

The temperature of the mixture gradually increased. The mixture was stirred at room temperature for 30 minutes. Subsequently, dosages were evaporated under reduced pressure.

113

To a suspension of 0.924 g of D- (2-t. Selyl) glycine in 20 ml of dry methylene chloride is added

1.28 g of trimethylchlorosilane, then 1.19 g of trielhylamine. The mixture was stirred at room temperature for one hour. The reaction mixture was cooled to 0 ° C. ^To the reaction Smee ^at d ^and solid matte! ^z i ^with the above ^Aný evaporation.

The mixture was stirred for two hours at room temperature, washed with ethyl acetate, washed with water and aqueous sodium chloride solution, dried over anhydrous magnesium sulfate. and evaporated under reduced pressure. pressure. D-2- is produced 4-butyl-1,2,3-dioxo-1-piperazocyclooxamido] -2I (2H) -acetic acid as a solid compound in quantitative yield.

IR s ^p e ^k trum (in cm ^{-1): 1715, 1510} and ¹¹⁸⁰ with ^P-NMR · e ^k trum (CDDL ^, ^pp m): 5.72 (1H, d, J = 6Hz, CHCOOH) 9.70 (1H, d, NH).

Two compounds are prepared in a similar manner.

D-2- (4-o-l- tylI2,3Idinxo ^{to P} and ^{P to} erazlk arboxamidn) 2- (2-tlSelll) nctnaá acid spektnm IC ^(V χ m ^ ^O1, 3250 and 720. NMR 1 with ^p ektrim (CDC1 _3, ppm). 5.72 (1H, d, J = 6 Hz, C.HCOOH)

9.75 (1H, d, J = 6Hz, NH) and D-2- (4-butyl-2,3-L-Dinx piperazlk asboxari ^to (into) I2Ilenllnctoaá acid.

IR ektrum with ^{p (X} in cm): 1715, nmr ektrum ^p '(CDCC _3, ^pp m): 5.40 (1H, d, J = 7 Hz,

C.HCOOH), 7.22 (5H, s, phenyl protons), 9.73 (1H, d, NH).

Reference Example 39

To a solution of 362 mg of D "- ⁴ -bsiyl Dinx-2,3-L-2-piperazinkarboxamidon fenylnctnaé acid and 150 mg of cis-3 methllesteci - amilnI2-nxnazetidin 4- ^to arboxyloaé acid in 3 ml of dry N, N-dimethylnormamide was added with 236 mg of dicyclohexylcarbodiimide under ice-cooling. The mixture was stirred under a stream of nitrogen at the bowl temperature for 5 hours.

To the reaction mixture was added tetrahydrofuran and the insoluble material was separated by filtration. The filtrate was decanted under reduced pressure. The residue was purified by column chromatography on silica gel (200 g, eluting with 1: 1 ethyl acetate / chloroform and then ethyl acetate / chloroform / methanol 15: 15: 1).

3- (2-Di2- (4Si-tl-2,3'-dinxo-1-piptrazinecarboxarido)) -2-lenylacetamidone-2-nitro-azetidine-4-carboxylic acid intermediate ester was prepared as a mixture of dietherteromers. Experimentally, the first eluted compound in the above column chromatography is called the beta-isomer, and the second eluted compound is allannorer.

Beta-isomer: IR spectrum (cm ^-1 ): 3280, 1780, 1715 and 1680. NMR spectrum (CDCl3, ppm: 3.12 (3H, s, COOCH3)), 7.24 (5H, br s. phenyl protons).

VD _{r -} 1

Alpha isomer: IR _(x, ^{cm-1): 3 29} 5 ^{1 780 1 720 1} 6 ⁸⁰ · ^NMR spe trum ^to (C ^D C1 _3, ppm: 3.44 (br, s, COOCH3) 7.27 (5H, broad single phenyl phenyl protons).

The following two isomers were produced in a similar way:

мet^ll^ltt ^ (^ c cls-3-Qd-2- (⁴-but^y1-2, ^ Cwxo-¹- pipeaai^lto^toasⁿoxami^dn) I²- ^ - • ^ m ^ nacetamMo] I2Inxoazetidine-4-carboxylic acids:

BBta-isomer: ^IR s ^p e ^k trum cm ^{-1): 3300, 1775, 1710} and ¹ 6 ⁷ 5th ^NMR spe ^ RTM ^(CDCl3 ppm: 3.30 (3H, s, COOCH3).

Al and ^{F-isomer: IR} speHrum max ^{-1): 3300, 1 78} 0 ^{1 720 and 1 680th}

114

Melhhlestir cis-3- [D-2- (4-octyl-2,3-diXi-1-piperidyltaarioxaaidi) -2- (2-thecyl) acitlaido] -2-oxoazzlidine-4-carrixylic acid:

Betk-isoaer: NMR spectrum (CDCC.7, ppm): 3.31 (3H, s, COOOHp, 4.42 (1H, d, J = 5 Hz),

C ₄ -H).

Al @ 1 H-So @ .alpha.: NMR spectrum (CDCl3, ppm): 3.45 (3H, s, C-O-Cp, 4.40 (1H, d, J = 5 Hz);

C4-H).

Melhhlestir tract-3- [D-2- (4-methyl-2, -dixio-1-piperidinyltrioxaaido) -2- (2-thioyl) acetamido] -2-xxxylidic-4-carboxylic acid.

Beta isomer: ^IR cm ^{3): 3280, 2920, 1780,} 1 ⁷ 10 1 ⁶⁷ 0. NMR with ^p i ^to trum (CDCCj ppm): 3.68 (3H, s, COO Cp, 4.14 (1H, d, J = 2Hz, [delta] -).

Alpha-thioalr: the IC spectrum and the NMR spectrum are identical to those of the retk-tooalrs IC and NMR spectra.

Reference Example 40

To a solution of 1.18 g of cis-3 meltihlistiru-lainOil- (2,4-diaelhooχУrloyl)) 2-xxeolzltdio-4-karroxylové acid in 5 ml MLT ^ h ^ l ^{<^ 1} ^ ^{<^} C ^ H <^ ri ^ 2.7 ml of propyl oxide are added under ice-cooling and stirring. Then, a solution of 0.83 ml of 2,2,2-trichloro-thiol chloride in 1 ml of methanol was added dropwise over 10 minutes.

The mixture is stirred for 30 minutes at aístnoiti temperature. The crystals were taken up in ether and dried to give 1.67 g (89%) of the iso-1-methyl ester (2.15 g, 89%). 4-diaethoxybrlOzУ) -3- (2.2 _/ 2-trChdioletOχУkkrrioxaaid) -2-oxokZlt ^{d of} d n44t ^to arbox Loie ^y ^ ¹ ^ ^1, mp 1 ^{35-1 3} 6 ° ^C.

C, 43.51; H, 4.34; N, 6.34. Found: C 43.64, H 4.42,

6.16% N.

Reference Example 41

To a solution of 939 mg mlt ^. ^ ^I Tiru cit-1- (2,4 · -diaethox brlcz1 ^Y) 73- (2,2,2-trCchirithixx kkdrixkmidd ^y)) 2 oxxolzlidin-4-karrixyloié acid in 10 ml titakhydrofuraou for chlazicí ice and stirring a solution of 228 mg of sodium hydridobritac in 10 ml of water is added. The mixture was stirred for 10 minutes at room temperature and then for 4.5 hours at room temperature.

Excess sodium borohydride was quenched by the addition of acetic acid under ice-cooling.

It was flaring at a reduced rate. A saturated aqueous sodium chloride solution was added to the residue, and the mixture was then extracted with ethyl acetate. The extract was washed successively with 5% aqueous sodium chloride solution, dilute hydrochloric acid, saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate.

RoippoStёdli under reduced pressure idddltilsjl. The residue was purified by silica gel column chromatography (30 g, eluting with ethyl acetate / chloroiramine 2: 1). The illusion spreader is distilled off. The ithium was added to the evaporator. The resulting crystals are removed by centrifugation.

Preparation of cis-1- (24-dimethylaminobutyl) -4-hydroxy-4-hydroxy-3- (2,2,2-cycloalkoxycarbamide). · 2- ^ 032 ^ 11 (^ tt 112 ° ^- from 114 ° C. For C ^ e ^ eC ^ ^ype in Octin: 43.51% C ^4, 34% H ⁶ 34% 'N found H, 4.42; N, 6.16.

Reference Example 42

To a solution of 340 mg of cit-1- (2,4-diaeco-hexyl) -4-hydroxy-oxyl-(2,2,2-carboxylic acid)

115 ktrb (1-amido) ^y- 2-oxolylthiazole. in 3 ml of pyridine, 132 mg of eethanesulfol-o-chloride are added under ice-cooling and stirring. The mixture was stirred at 50 ° C for 50 minutes. Water and ethyl acetate were added to the mixture, and the pH was adjusted to 2 by addition of dilute hydrochloric acid. The ethyl acetate layer was separated and washed successively with aqueous sodium chloride solution (saturated solution), aqueous sodium hydrogencarbonate solution, aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate.

The residue is reduced under reduced conditions. In this case, the residue is crystallized. Ether was added to the crystals and filtered. Prepared 375 mg (94%) of colorless -г - ^ - И cit-one l - (2 4ldimethoxybetlnzl) -4-metaansulfoyyIoxymethy1-3- (2,2,2-hrCa0loeet0y-karr0oxгeidI) L2 oyotzztid Уt ^{i, t. t} . ^{Mp 139-140} ° ^C.

For C 17 C 21 C 8 N 2 O 6 S calculated: 39.28% C, 4.07% H, 5.39% N; found: 39.21% C,

H, 4.16; N, 5.48.

Reference Example 43

To a solution of 8.32 g of cit-1- (2,4-diethylethyl) -4-methanesulfolyol-methyl-1- (2,2,2-trichloroethyl-4-carboxylate) -2-oxoethyl ester in 450 ml of toluene was stirred for 20 minutes. in choke flow at ⁸⁵ - ^{from 90} ° ^{C P P} e tells extended ^ ^gp eroxosíranu ^7.79 and ^{4.70 g} potassium-dr ^ enfostorečnanu potassium in 180 ml of water.

The mixture was stirred for another 2.5 hours at the same temperature. After cooling, the pH of the solution is adjusted to 6-7 by addition of potassium hydrogen phosphate. The product is concentrated under reduced pressure. The concentrate is extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent is filtered off under reduced pressure.

The residue was purified by chromatography on a silica gel column (270 g, eluted with ethyl acetate: hexane 2: 1, with neat ethyl acetate). Colorless arsenic cis-4-methoxylphenylmethoxy-3- (2,2,2-trichloroethylcarbamido) -122-isoalztidint, m.p. Mp 85-86 ° C.

For (^ Η ^ ^^ Ι Ο) ^8: calculated: 26.00% C, 3.00% H, 7.58% N; Found: C, 26.15; C, 3.04; N, 7.62.

Reference Example 44

To a 130 ml-meehaleta lkttont was added 3.7 g of CIT - 4 eetaanstUf (lnyloy-ethal ^_3_ (2,2,2-tricalIrttal) xyкarbIУreidcO-2- (lxoatztidiuu and iodides 8.85 g of sodium methoxide. The mixture was The reaction mixture was refluxed for three hours under a stream of nitrogen and the solvent was removed under reduced ttaat ^ (^, ^ ϊΙ ^ ζ).

Water and ethyl acetate were added to the residue and the mixture was shaken. The ethyl acetate layer was separated, washed sequentially with aqueous sodium chloride solution, brine and dried over anhydrous sodium sulfate.

Upon evaporation of the solvent under reduced pressure, the residue in the crystal is. Ether was added to the crystals. The crystals are old-filtered. 3.56 g (88.6%) of colorless .alpha .- (4-chloroethylcarbonyl) oxo-1,4-diethalide-2- (oxatheidyl), m.p.

For _the C13-C7 H 203 calculated: 20.95% C, 2.01% H, 6.98% N; found: C, 21.19; H, 2.06

7.21% N.

Rereference example 45.

To a solution of 3.21 g of cit-3- (2,2,2-hrCaOlOeetOχУkacaroxoxide) 1,4-iodomethal·l2-oУ (lazzeidiyt

116 ml of 40 ml of sodium bromide add 0.78 g of sodium tide. The mixture was stirred at room temperature for 43 hours and an additional 260 g of sodium is added. Sm-Sn stirred for further 12 ho.ís ^p s 35 ° ^C.

Under reduced conditions, the amino acids were reduced. Water and ethyl acetate were added to the residue, and the mixture was shaken. The ethyl ether layer was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate.

Roopbundle under reduced pressure rddinUils3z. The residue was purified by silica gel column chromatography (150 g, 1: 1 ethyl acetate / hexane). Colorless crystals of isis-4-triazol-2-yl- (2,2,2-trichloro-octa-octooxoxyl) -2-oxazazilate were prepared, m.p. 93-95 ° C.

Reference Example 46

To a solution of 1.12 g of cis-4-trifluoromethyl-3- (2,2,2-trimethylsilyl-oxo-oxyl) -2-nitro-acetic acid in 35 ml of ethanol is added 560 g and 5% palladium on carbon. The mixture was stirred in a stream of hydrogen at room temperature for two hours. The catalyst is filtered off. The filtrate was evaporated to reduce the yield.

The residue was dissolved in a mixture of 10 ml of methylene chloride and 10 ml of N, N-diethyl acetate.

2.45 ml of prrpylnooxis and 0.50 ml of tertiary iron are added successively to the solution under ice-cooling and stirring. The mixture was stirred at room temperature for 2 hours. Roopweave with a reduced pressure of rdiinUil · s3z.

50 [mu] l of saturated aqueous sodium chloride solution was added to the residue. The reaction mixture was extracted with ethyl acetate / tetrahydrofuran (4: 1). The extract was washed successively with dilute hydrochloric acid, a saturated aqueous solution of sodium chloride, an aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride.

The extract was then dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. 40 ml of hexane are added to the residue. The mixture was allowed to stand overnight under cooling. The resulting crystals were filtered and washed with ether. Manufactures sn IIu-4-aczttoidrюZhh1-3- (2,2,2 -ti ^and Уhroretro1y ^t aoboxtmiio) -2 ^- rxoatz in ^Zhi, tt 1 ⁷ 8 ^{and 180} ° ^C.

H, 3.64; N, 12.63. found: 32.83% C,

H, 3.60; N, 12.79.

Reference Example 47

In a solution of 372 ogacyl-4-acetamidomethyl-3- (2,2,2-trichloro-oxyl-oxoximide) -2-oxazolidine vn. 30 ml of zinc precipitate were added to 3.0 g of aquisated zinc. 6 ml of an aqueous solution of phosphoric acid-potassium phosphate-phosphate (by 1 molar concretion) are added to the mixture. The mixture was stirred at room temperature for 8 hours.

To the reaction mixture was added 30 mL of tetrahydrofuran. Zinc sn rčliilhrsjn. The filtrate was evaporated under reduced pressure. Water (15 ml) and ethyl acetate (20 ml) were added to the residue and the mixture was shaken. The aqueous layer separates and the reduced pressure is reduced to a volume of 11 ml. To the concentrate was added 11 ml of trisodium.

The mixture was added under cooling with Indium 282 and hydrogen chloride and 559 &lt; 3 &gt; and 3- (2-chlorobutyl-4-carboxylic acid) (Z) 12-oethorylminortyl chloride, while stirring the reaction mixtures. The mixture was stirred under ice-cooling for one hour.

The solution was stirred for 2 g of sodium hydroxide and a saturated aqueous solution of sodium hydroxide. The mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was washed with a saturated aqueous sodium hydroxide solution and dried over anhydrous magnesium sulfate.

117

Removal of the solvent under reduced pressure crystallizes the residue. The crystals were mixed with n-ethylacanethane and ether, and the mixture was filtered. Colorless crystals of cis-4-acetamido [3- (2-) 2- (2-chloro-4- (2'-thiazolyl) -1- (4'-thiazolyl) -1- (5'-thiazolyl) -1'-ocosyl) amino] syn (syn)

Ísonier) that no nevykaazjí s ^ p ^ EIFI ^ C ^ cal tt, přčeemž is gradually decomposes ^even zabarvováním ^p te ^ s ^ MEEI speed 14 ⁰ and ¹⁶⁵ ° C.

k) j- m · ^iC s ^p e ^k trum ⁽ Vmax * cm ⁾ : 3 380 3 ²⁵ 0 ^{1 760} and ^{1 660} . ^ ^ Elctrum ^NMR MSO-d ^ ^pp m) j. 73 (3H, s, COCH3), 3.6 to · 4.0 (1H, m, C4-H), 3.90 (3H, s, OCH 3), 4.33 (2H, s, C 1 H 3),

5.16 (1H, q · J = 5Hz, J = 9Hz, C ^H), 7.46 (1H, s, SyH)

Reference Example 48

In 20 ml tntřalydrsfurřnu was dissolved 1.0 g of iis_3-bnnzylsxykřrboxaaido-1J2,4-dimetlsx benizУ ^yl) -4-lydrsxymenhlУ- -oxoszzntdinu ^2, 787 mg and 441 mg trineiylSstfiiu phthalimide. To the solution was added 0.471 ml of diethylneter azodicarboxylic acid. The mixture was stirred at room temperature for one hour.

The oil is synthesized under reduced pressure. The residue crystallizes. To the solid, crystallized residue was added 30 ml of ethyl acetate. The insoluble material was filtered off, washed with ethyl acetate to give 882 mg of colorless crystals of isis-3-benzoyloxycarboxaaidos-1- (2,4-phenoxy-benzyl) -44-trimethylidene-2-oxazazidine.

The mother liquors and washings were rinsed and purified on a Haagel column.

This gave an additional 280 mg of colorless crystals. The overall yield is 1.16 g (87.8%), m.p.

Mp 182-184 ° C. For ^^^ ^ ye Ο ⁷ Readings: ^65, 11% C ⁵ H 7 ^20%, 85% ^N; Found: ^65, 05% C

H, 5.17; N, 7.80.

Re-example example 49

0.39 ml of hydrazine hydrate is added to a suspension of 1.059 g of isis-3-benzyloxycarboxaaido-1- (2,4-dimethylsilyl-44-trifluoromethyl-2-sulfoxide in 80 ml of ethanol) and the mixture is refluxed for 3.5 hours. The precipitated crystals are filtered off and the filtrate is concentrated under reduced pressure.

To the residue was added 30 µL of mentholililorif. The insoluble material was filtered off. The filtrate was washed with water and dried over anhydrous magnesium sulfate. RooppoutědZo is shared under reduced · tacu. The residue is dissolved in a mixture of 10 ml of carbon tetrachloride and 5 ml of N, N-dimethylyl chloride. 1.4 ml of propylene oxide and then 0.28 ml of aceeyl hydride are added to the solution under ice-cooling. The mixture was stirred at room temperature for 1 hour.

To the mixture was added 10 ml of carbon tetrachloride and 50 ml of aqueous sodium hydrogen carbonate solution. Shake the mixture. The supernatant layer was drained, washed successively with water, dilute hydrochloric acid, saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate.

Rooppěedlo depiilil behind tnížnnoho taaku. The residue is purified by column chromatography (100 g, eluting with 4: 1, a 3: 2 mixture of acetone / aceeositrin). The solvents are separated from the eluate under reduced pressure. Ethyl acetate / ether (1: 3) was added to the residue. The precipitated crystals are filtered. Prepared ^{cit-4-acntamidsmenhhУ-3-yl} carboxylic bnnzylsx ^b oxca ^m doolL- ^{(2, 4-f l} limnt sx Beni ^{y y} y ^ ^ din -oxooae, ^{m. P.} 1 ^95, and ^{from 196} ° C.

For ^C 23 ^H 27 ^N 3 ° 6: calculated: 62.57% C, 6.16% H, 9.52% N; %: 62.20% C, 6.08% H, 9.41% N.

In a similar manner was prepared 3-IIT ^{bnneyloxykřrbsxřmido-4-yl} bgnieaidoagmn lyll ^(2,4-b dimgthoxy ENI ^zy -sxoazz ² L ⁿ i ^d in ^{t. T.} И И5 to ² ° C.

118

Reference Example 50

To a suspension of 1.104 g of cis-4-aceabmidobethyl-232-benzylphenylcarboxamido- (2, 6-bethoxycarbonyl) -

A solution of potassium persulfate (1.081 g) and potassium hydrogen phosphate (653 mg) in 25 ml of water was added dropwise over 15 minutes under a stream of nitrogen while the reaction mixture was boiling, dropping a solution of potassium perphosphate (1.081 g) in 25 ml of acetonitrile. under reflux. The reaction mixture was refluxed for 1.5 hours.

It is then misused with an aqueous solution of hydrogen chloride. sodium and bent under reduced pressure. The residue was extracted with ethyl acetate / ethyl acetate (1: 1). The extract was washed with an aqueous sodium methoxide solution, a saturated aqueous sodium chloride solution, and dried over magnesium sulfate. Rozpooutědlo se fdděesiljje.

Ethyl acetate was added to the residue. The precipitated crystals were separated by 1H-trituration. 24-Acetabidoobthium-Z-benzene oxyloxy-α-box-22-oxoeetdin _/ mp 226-228 ° C was prepared.

In a similar manner, cis-3-benzyloxycarboxabido-2-iso-methyl-22-oxo-acetyl ₍ mp 209-211 ° C) was prepared.

Reference Example 51

To a suspension of 364 mg of cis-4-aminomethyl-3-benzyloxycarboxamide-2-oxoethyl ether in a mixture of methanol and 20 ml of Meithanol was added 364 mg of 5% carbon on carbon. The mixture was catalytically reduced under stirring, temperature < 5 &gt;

The catalyst is separated off. The solvent was removed from the filtrate under reduced pressure. The residue is dissolved in a mixture of 12 ml of tetrahydrolurane and 12 ml of water. To the mixture, 315 mg of sodium hydrogencarbonate and then 624 mg of 2- (2-chloroacetamido-2-2-naphthyl) - (Z) - 2-butymino-succinic acid hydrochloride were added with stirring and ice-cooling.

The mixture was stirred under ice-cooling for one hour. Then the reaction mixture of ^R utřeoe successively with saturated aqueous sodium chloride solution, aqueous sodium bicarbonate and a hdyrogrtilUtlčitanu ^ tttathydrojuanneb network ethyl acetate (2: 1). The organic layer was separated. The aqueous layer was extracted four times with ethyl acetate / tetrahydrolurane (2: 1).

Combine the organic layers, wash! saturated aqueous sodium chloride solution and dried over sodium sulfate. The filtrate was evaporated under reduced pressure and the residue crystallized. Ethyl acetate / ether (1: 2) was added to the crystalline residue. The crystals were filtered off.

Colorless 1 crystals of (2- (2-acetyl) midin-2-η 22 - (2-chloroacetamio-2-2H-aza-phyl) -2,222-ethoxyimineactamioC-222-oxuaeeidine (syn i-somee) are obtained, which do not have a distinct melting point but gradually decompose; in the range of 140 to 165 ° C. 1 H and NMR spectra. of this product are identical to the IC and NMR spectra of the product produced in Example 47.

In a similar manner, the product is produced - {- 2--2-2CtlOractamidou442hta jefyУ) -22bbthoxχУmbínuaeetalbdod] - 20u ₀ ujpeidii (syn ί ^^ Γ). This product does not have a high melting point, but decomposes gradually with coloration in the range of 130 to 150 ° C.

Ir (^ *, cm ^-1): 3420, 3260, 1755 and 1 660. For C ^ H ^ S ^ ClN Calculated:

H, 47.65; H, 4.00; N, 17.55. found: 47.48 »C, 3.86% H, 17.26% N.

Reference Example 52

To a solution of 557 mg of cis-32-benzyloxycarbuxabid-2-oxoxujetidine-2-carboxylic acid

Of acid in 2.6 ml of tert-alkali acid was added with stirring and under ice-cooling, 1.3 ml of an aqueous solution of 189 mg of sodium borohydride was added. The mixture was stirred under ice-cooling for 80 minutes. The excess sodium borohydride is then decomposed with acetic acid. To the residue was added a saturated aqueous sodium chloride solution, and the mixture was extracted with ethyl acetate.

The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The undercoat was under reduced pressure. The residue was purified by silica gel column chromatography (30 g, eluting with 4: 1 acetonitrile / acetonitrile). Prepared colorless crystals polyphenyl-3-4- blnzylotkkarbntamido hydroxkeilhhl "2 nxontieidinu, mp 103 ^and 104 ° C. For C1 ² H 4 N ^{2 1} ₄ ° reproach: ^57, 59% C ⁵ H 64% ¹¹ 19% ^{N; t-Iizií-57,} 32% C, 5.41% H, 11.12% N.

Rereference example 53

To a solution of 250 mg of 3-benzyloxycarbonyl-4-hydroxy-22-oxoalithium in 5 ml of ethanol was added 250 mg of 5% palladium on charcoal. The mixture is catalytically reduced at room temperature and at room temperature under stirring. The catalyst was filtered off. The filtrate was destroyed from the reduced vacuum and allowed to stand from cooling. The rest raises. The crystals were filtered off.

It produced 108 mg (93%) of [eta] < 3 &gt; -3-amino-4-lylamino-4-oxo-aluminum, mp 105-107 [deg.] C. For C ₄ H ₈ N ₂ O ₂ calculated; % H, 6.94;% N, 24.12; Found:% C, 41.40;% H, 6.84;% 23.85

23.85% N.

Reference Example 54

To a solution of 58 mg of 3-amino-4-lysyldimethyl-2- (1-oxoate) in a mixture of 5 ml of methylene chloride and 1 ml of Ν, ilt-diiltlyllillate was ice-cooled and 0.4 ml of trichloride was added with stirring. 498 mg of 2- (2-pyrrolidinyl-4-thiolyl) - (Z) -2-methoxyimino-cetylchloride hydrochloride was added to the mixture.

The mixture was stirred under ice-cooling for one hour. 20 ml of water are then added to the mixture, and the pH is adjusted to 7 to 8 with sodium dihydrogen chloride. The reaction mixture was included under reduced pressure. The residue was extracted with a mixture of tert-alkalilan (2: 1). The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate.

The residue is crystallized under reduced pressure. A ethyl acetate / ether mixture (1: 2) was added to the fixed evaporator. The crystals were filtered. Vkrobí Yellow crystals (2-chlnrlClt Imdío4-thlalilyl) - (Z) -2-ietloxyiiinoacetaiidp-4- ^ -U-chlortcelaaido- ^{l l} -TH alolk ^{k)) (Z)} - ² -iet oxkiiinoaaelon ^{l t l} kit ylk- ^-2 · 0oonti ^pyrrolidine, mp ^{157 159} ° C tower.

For ^C 20 ^H 20 Cl 2 ^N 8 ^O 8 ^S 2 calculated: 37.80% C, 3.17% H, 17.63% N; Found: C 37.85, H 3.27, N 17.22.

Reference Example 55

To a solution of isopropyl-1- (2,4-trimethoxybenzyl-3- (2,2,2-trifluoromethylbenzoic acid) -2-nitro (lazididyl-4-carbonyl) acid in 20 ml of celite was added dropwise over 10 minutes at the boiling point. The solution was refluxed with 716 mg of crystalline sodium phosphate and 1.08 g of potassium persulfate in 20 ml of water.

The reaction mixture was refluxed for an additional 30 minutes. After the reaction reaction simulation, the distillation is distilled off. The residue is extracted with ethyl acetate. The resulting solution was rubs 5% aqueous solution of sodium lydrogelnUhičitanu, ^e nvtkc nm, brine and dried over anhydrous magnesium sulfate NVD. Rooppattёdlo with z reduced pressure <^^ 1Ъ11 ^ 1. The residue is purified by column chromatography (20 g, 1: 2 by mixing mixtures of ethyl acetate and ethyl acetate).

120

Prepared ϋΙΗ Γ ^ ^ θβ cis-3- (2,2,2-t.rCch0ocetlolkiarbox-miil) L2-ool zetidin-4 "karbz> oχlové Ιο θΗο ^ ^{1 (colorless} mp ¹⁴⁰ - 1 ^{from 14} ° C. ^P rz ^CgHgC 13 ^N 2 ^{0 g} ^ in očtcno: ^30, 0 ^7% C

H, 2.84; N, 8.77; Found: 30.30% C, 2.82% H, 8.87% N.

Reference Example 56

To a solution of 1.41 g aeehhlesteru cis-3- (2,2,2-trCch0oteCloУkkarbюtaido) -2- (lXOlleCidij- ⁴ l ^ - ^ ^ 00x11 acid in 40 ml tctraClirlfuranu Zr CD-R zcní ice was added a solution of Zr 417 mg of sodium hydride in 20 ml of water was added and the mixture was stirred for 30 minutes at room temperature for one hour.

Tetr-Cy (Urlfur-o 01 (1)) was removed under reduced pressure, and the residue was dissolved in ethyl acetate (1 *). The solution was washed twice with brine and dried over anhydrous magnesium sulfate. The residue was crystallized and ether was added to the residue to give the crystals.

Cis-4-CyclolylChCl13- (2,2,2-trichlorocyclolyclohexyl )midul-2-oxollelidium, mp 162 DEG-164 DEG C., was prepared. IC ektrurn (V ^c m ^-1): 3450, 3300 1 ^720-1 700th

Reference Example 57

To a solution of 468 mg of 2-chlorobutyric acid in 7 ml of dry methanol was added 424 mg of chloroform. The mixture was refluxed for 2 hours. The reaction mixture was evaporated under reduced pressure. The residue was dissolved in 5% dry 2211 .mu.l.

In addition, to a solution of cit-4-hydroxymethyl-3- (2,2,2-trichloroethoxy-pyrrole-amino) -2-oxyl-zincidine in 30 ml of dry methylenediorium was added 416 mg of γ-amine. To this alone! In the process of stirring and cooling, the alcohol-containing solution of burnt produced 2-1C1-chloro-cetyl chloride is added dropwise. The resulting mixture was stirred for 20 minutes from ice-cold and then over room temperature.

To the reaction mixture was added ctCl 3 -acetate. The mixture was washed successively with 3N hydrochloric acid, aqueous sodium bicarbonate, aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by chromatography on a silica gel column (60 g, 1: 1 and 2: 3 hexane / ethyl citrate). Produces St cis-4- (2-Chlorolaceloolmeehcl) -3- (2,2,2-trCdoteCloУkkabbzotmddo) -2-lXOllztdddo. NMR Spectrum (CDCC ₃ , ppm): 3.92 (22 s, OCCH ₂ ), 4.71 (2H, s, CCl ₃ CH ₂ ), 5.14 (1H, d, d, J = 5 Hz,

O

J = 9 Hz, _C3 -H), 6.10 (1H, d, J = 9Hz, OCNH2.

O

Reference Example 58

To a solution of 600 mg of cis- ^4- (2-chloro-chloro-cyclohexyl) -2- (2,2,2) trichloro-abloxyl) -2100oazzinc in a mixture of 25 ml of triphenylphosphine and 5 ml of 1N aqueous ammonium stearate solution add 2.16 g of activated zinc. . The mixture was stirred for 5 hours at room temperature.

The mixture was filtered through celite. To the st add 2β11ι ^ βη nchoz-íd. · · RO st is dried with anhydrous magnesium sulfate. The filtrate was evaporated under reduced pressure. The residue was dissolved in 2 ml of triturate and 2 ml of water. To the solution under stirring was added 850 mg of sodium bicarbonate.

To the mixture was added 720 mg of C [2- (2-chloroacetyl-4-thal-2-yl) - (Z) -2-methylcyclohexyl] -2- (2-chloroacetyl) -chloride. The reaction mixture was stirred vigorously for 15 min. After stirring vigorously for one hour at room temperature, the solvent was removed under reduced pressure. Water was added to the residue. The collected crystals were washed with water, an aqueous solution of Cχdrlgenι on on-onuslodonCl, ether and hexane sequentially.

121

acetoxymethyl) -2-oxoazetidine (syn isomer), m.p. Mp 201-204 ° C (dec.). IR spectrum (ν max max): 3280, 1760 and 1660. NMR spectrum (DMSO-d6, ppm): 3.86 (3H, s, OCHy), 3.90 (2H,

Reference Example 59

To a solution of 314 mg of 1-methyl-1H-tetrazol-5-yl-mercaptene in 2 ml of dry N, N-dimethylformamide was added 65 mg of sodium hydride under ice-cooling. The mixture was stirred under ice-cooling for 10 minutes and at room temperature for 10 minutes. A solution of 724 mg of cis-3- (2,2,2-trichloroethoxycarboxamido) -4-iodomethyl-2-oxoazetidine in 3 ml of N, N-dimethylformamide was added to the mixture. The reaction mixture was stirred at room temperature for two days.

The reaction mixture was dissolved in ethyl acetate, washed five times with water, then brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (60 g, eluting with 1: 2 and 1: 4 hexane: ethyl acetate).

610 mg (86.8%) of cis-4- (1-methyl-1H-tetrazol-5-yl-thiomethyl) -3- (2,2,2-trichloroethoxycarboxamido) -2-oxoazetidine crystals, m.p. 68 ° C. IC spectrum (νmax cm ^-1 ): 3,300 and 1,740.

Reference Example 60

To 10 ml of tetrahydrofuran was added 1.49 ml of a solution of methyl mercaptan in 4N tetrahydrofuran. Under ice-cooling, a solution (1.37 ml) of butyllithium in 1.6N hexane was added dropwise. The mixture was stirred for 10 minutes under a stream of nitrogen while cooling with ice. The mixture was then cooled to -45 ° C. A solution of 800 mg of cis-3- (2,2,2-trichloroethoxycarboxamido) -4-iodomethyl-2-oxoazetidine in 5 ml of tetrahydrofuran was added to the cooled mixture.

The temperature of the reaction mixture gradually increases to -20 to -30 ° C. The reaction mixture was stirred at this temperature for 4 hours. The reaction mixture was dissolved in ethyl acetate, saturated aqueous ammonium chloride solution was added and the mixture was stirred. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.

The residue was purified by silica gel column chromatography (100 g, eluting with 2: 1 and 1: 1 hexane: ethyl acetate). Crystals of cis-4-methylthiomethyl-3- (2,2,2-trichloro KBr-1 ethoxycarboxamido) -2-oxoazetidine, mp 114-115 ° C, were obtained. IC spectrum (V _max / ^cm ) with 3 350, 1780 and 1 715.

Reference Example 61

To a solution of 674 mg of cis-4- (1-methyl-1H-tetrazol-5-yl-thiomethyl) -3- (2,2,2-trichloroethoxycarboxamido) -2-oxoazetidine in 10 mL of tetrahydrofuran was added 2 mL of 1N aqueous solution ammonium acetate. To the mixture was added 1 g of activated zinc. The mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered. Methylene chloride is added to the filtrate.

The solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is dissolved in a mixture of 3 ml of tetrahydrofuran and 3 ml of water. To the solution was added 1.02 g of sodium bicarbonate under ice-cooling. 863 mg of 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-methoxyiminoacetyl chloride hydrochloride was added.

The mixture was then stirred under ice-cooling for 15 minutes and 1 hour at room temperature. The solvent was distilled off under reduced pressure. Water was added to the residue. The precipitated crystals are filtered off, washed successively with water, aqueous sodium bicarbonate solution, ether and hexane.

122 and dried. Prepared crystals of cis-3- [2- (2 'Ollortcztteido-4tthtazoXy-) TE-methoyyimčntozetamSdH] ⁴ - ^{- (l -} h ee ^{of lχ} tztrtzo ^{-lH-L-5-yl-l- 1} l · ^{l of} OEE h ^{1X) -2-} lXlazz ^of i ^with int ^(Y n ⁱ ^ the ^ ^Z), mp ¹ 95 and ¹ 98 ^and H (rozkk.). H spectrum ^(R ^ _x ·· r cm: 3270, 1760, and 1 660th

In a similar manner was prepared CIF-3- [2- (2-4-ollortcztteids tlitkolχl ·) - "mzlhoxχieičЮtoett tIг dd ^{e l} -4-Im ^from H ^1XL hioee ^zZlχ -2-oxclatz> e ^ts in ^(Y n ⁱ ^ ^toe-out), mp ^{172 AI 176} H (understands.).

Reference Example 62

1.88 g of sodium iodide are added to a suspension of 1.0 g of ois-3-benzyloxy-triethyl-1- (2,4-dimethoxybenzyl) -4-ethanesulfonyloxymethyl-2-oxoaldehyde in 50 ml of sodium iodide. The mixture ball ^{hook 6} din ^ ^p s 90 ° ^H. The solvent was removed from the solution. X from ^{p to} r in 150 mi ethyl-sacrificing and 100 ml of water and the mixture proZřzpz.

E ^z l ^y ltozZátová oddděí layer was washed with water and dried over anhydrous sodium sulfate. D The distress gets stronger under pressure. The resulting solid was arzk from ^{p-crystallized} from 50 ml of hexane and seee ztlχltoztάtt (1: 1). Prepared 850 mg (80%) of colorless needles cist3-bznzyllx karboxaaieo ^yl-l- (2,4-Sieetlox bbZčzX ^yl) L4-jldeeZZhX- -lXoalzZidičt ^2, TT 165 and even 166 ° H. For H21H ₂₃ IN ₂ O ₅ Calculated: 49.43% H, 4.54% H, 5.49% N; Found: H, 49.55; H, 4.56; N, 5.67.

Reference Example 63

To a solution of 3.29 g of ois-3-bis-oxo-trboxamides-11 (2,4'-di-oxybenzoyl) -14-oxo-benzothiazole-2-oxothiazide in 10 ml of hexamethylphosphoric acid was added 1.62 g of sodium tetrachloride. The mixture MIC? 5 ^h Odin rou ^{p d d} u u ^{p ears 90} s ¹⁰⁰ ° ^ι ζ ^{H. R} eakční mixture ^of with the rungs to ²⁵⁰ ml of t-canceled washed heavier 20m1 · portions of water, once with brine, dried over · anhydrous magnesium sulfate and the solvent is s ^: íizn ^ l ^ C ^ '^ а ^ odSsztiltje.

Ether and hexane were added to the final solid residue. The mixture was filtered. 2.15 g (8 (6.7%)) of 3-benzyloxycarboxa-1-l- (2,4-dibenzoxybenzyl) -4-methyl-2-oxo-azidine are obtained, m.p. 130 DEG-132 DEG.

H, 6.29; N, 7.29. Found: H, 65.23, H, 6.49,

7.53% N.

Reference Example 64

5.10 g 2,4-diethyloxybenzene-2-amine lydrochloride was added to the aqueous potassium potassium solution. The resulting oily product was extracted with 120 ml of benzene. The extract was washed with water and dried over anhydrous sodium sulfate. To the extract was added 3.50 g of chlorobenzyl chloride. The mixture is refluxed for one hour with a device that removes moisture from the reaction mixture (separator v / v).

After evaporation of the solvent, the residue crystallized out. The crystals were rotated in 68 ml of m.p. To výsadnému solution under ^stirring at ^-5 ° C s ^ι ζ · ^-10 BC ro ^ a ^^ t ^ ^3.8 ml) IETT tei ^ y ^ ^ C ^ T in 20 ml eeZhlXenn01oridt. To this was added dropwise a solution of 6.15 g of phthalidothecyl chloride in 25 ml of carbon monoxide.

After 20 minutes, a solution of 1.9 ml ZrZelУtaintin in 10 ml eeZhXen01oridor and a solution of 3.1 g of otoSSSotootootootootootoZZZStSt ve in 13 ml eeZZlУ01enn0101oriStStSt přidá přidá přidá přidá are added. The resulting mixture was stirred under ice-cooling for 7 hours and then allowed to stand overnight with cooling. The mixture was washed successively with water, aqueous sodium bicarbonate solution, 5% hydrochloric acid, water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.

The residue was purified by chromatography on silica gel (60 g, 20: 1 chloroform / methanol). 9.4 g (84%) of colorless crystals were obtained

123

3-phthalimiel-2-oxo-zeeinfiner. Retolysis from acetone-hexane yields tartarose ^and ra- ^l- y ^{, t} . ^t . ¹⁷⁸ DEG- ¹⁸⁰ DEG. For C ^{2 H} 6 2 ^{1 5} ° C ^1N2 you read ^ ^{6 5 4} 6% C ^{4, 4} 4%) 5.87 »Nj Found: 65.42% C, 4.42% H, 5.90% N.

Reference example 65

To a solution of 4 g of cis-4- (4-fluorophenyl) -1- (2,4-dimethylpentyl) -2-methyl-2-ololysis in 50 ml of methylene chloride was added 0.89 ml of methyl tert-butyl ester. hours at 35-40 ° ^ ^{p f} Otom of iltruje and etbylacetát added. the resulting OOZ uštóďlo ^ for ^ ^^ етё t ^l and f ^о odéldetiluje. Arto K o ^ st, ·. insoluble ^ - ^ € .ΟΑ; 1 is filtered off.

The filtrate - (about 100 ml) was extracted with a mixture of water (30 ml) and 10% hydrochloric acid (10 ml). The extract was neutralized with an aqueous solution of sodium chloride, extracted twice with ethyl acetate and a saturated aqueous solution of sodium chloride. The washed extract was dried over anhydrous sodium sulfate.

The solvent was removed under reduced pressure. The residue (2.6 g) was dissolved in 30 ml of eetpteneCPoride. 5.5 ml of propyltulxide are added to the solution with stirring and ice-cooling. Subsequently, 2.3 g of K-solvate CPCP was added. The mixture was stirred at room temperature for 2 hours.

The solution was distilled off under a reduced rate. Hexane was added to the residue. The resulting Ootstalt was filtered off and washed. itopoopylePheree. 3.31 g (81%) of cit-3-benzyloxy-oxalate-1- (44cCPolCekul) -1- (2,4-diethoxyphenyl) -2- (1-oxo-ethanol) were obtained.

KRv - 1

IC ektrum (V ^ _and X 'cm ^х - ^3- З ^{25, 1759} and 688. ^{1 H NMR} ktirum s ^ (^ ^gr ^ CDCl) ³ 59 and 3.77 (2 x 3H, 2 x s 2 x OCH 3), 4.70 (1H, d, J 5 = 5 Hz, J = 9 Hz, C 1 H), 5.82 (1H, d, J = 9 Hz, NH).

Reference Example 66

To a solution of 2.15 g of cit-3-ethoxy-oxo-4-methoxyl-4-methyl-2-oxo-ethoxy-4-methyl-2-oxo-oxo is heated dropwise in 150 ml of solution 2 dropwise. , 42 g peroxide ¹ ^^ anus doatk Joint phosphate and 1.46 to ¹ tk no ^h s in ⁷⁵ mi ^{dy - p} s t ep ^ ot ^ ^l in the range ^of about 9 ° ^{d d} about ¹⁰⁰ ° C. The mixture was refluxed for 1.5 hours at the same temperature.

Λ ^ μΒιΟΙ is repelled under reduced pressure. Ethyl acetate and water were added to the residue. The ethyl acetate layer was separated, washed with brine and dried over anhydrous sodium sulfate. The surfactant was removed under reduced pressure. The residue was purified by column chromatography (200 g, 1: 2 hexane / ethyl acetate).

and mixture

It was prepared as methyl-3-butyloxy- ⁴ -cycloxamideo ^4- imidibi-2-oxolazeidine, mp 168-169 ° C. For. ^H14N2 ° ^{C 1} 2 ^{3 P} about you ^No theory: ^{61.53 -%} C, ^6.02% H, ^{11.96% N;} Found:% C, ^61.36 ;% H, ^5.05 ;% N, 11.65.

Similarly prepared cit-3-euzyloxycarboxoxo-1- (4-chloro-phthal) -2-oxoalzodium. ^ MSO-d ^ ^pp ):

6.90 to 7: 50

IC KTR ^ ^{(V c} rn ^-1): 3 3 ^ ^{3225, 1772,} 1722 and 684. NMR 1 s ^ ktrumi

4.85 (2H, s, CH3), 7 _t 74 (1H, d, J = 9 Hz, OCNH), 8.55 (1H, broad s, N.-H), ^] ^ '

Reference Example 67

To a suspension of 210 mg of cit-3-beuzyloxy-oxxide-4-methpt-2-oxolazeidine in ml of ethanol was added 210 mg of 5% palladium carbon. The mixture was stirred under a stream of hydrogen for one hour. The mixture is filtered and the solvent is separated from the solvent. The mpc crystallizes (mp 111-1 ^{) 2} ° C).

To the crystals was added 1 ml of water and 1 ml of tert-pyrimidine.

124

382 mg of sodium hydrogencarbonate were added to the solution under ice-cooling. 453 mg of 2- (2-chloroacetimidoyl-44-benzyl) - (Z) -2-methooyiminoacetyl chloride were added to the network under vigorous stirring. The resulting mixture was stirred under cooling. ice 15 minutes and one hour at missnoosi temperature.

Then, the solvent was removed under reduced pressure. Water was added to the residue. The insoluble material was separated and washed successively with water, aqueous sodium cyanoborohydride solution, ether and hexane.

276 mg (84%) of cit-3- [2- (2-chloroacetamido-4-thiesolyl) -2-methylsulfonylamino] -4-methyl-2-zooazetidine crystals (syn. ° C (dec), 1C spectrum, νϋχ 3 3,260, 1,755 and 1,670. NMR Spectrum (DMSO δ ^g , ppm) δ 1.16 (3H, d, J = 6 Hz);

H 4 -H 3 d), 3.90 (3H, s, OCH 3), 4.36 (2H, s, Cl 3), 5.15 (1H, dd, J = 5 Hz, J-9 Hz, C 4 H) )

7.40 (1 H, s

H)

Similarly prepared cis -3- [2- (2-chloroacetamido-4-thiazolyl-22-methooyliminoacetKBr) amino-4- (- (- (4-chlorophenyl)) -2-oxoaieridine (syn isomia). IR spectrum (V _max *) cm): 3,250, 1,740 and 1,652. NMR Spectrum (DMMS-d6, ppm: 3.66 (3H, s, δα 4), 4.30 (2H, s, δ 0½), 4.96 (1H, d) J = 5 Hz, C 4 H, 5.39 (1H, dd, J = 5 Hz, J = 9 Hz), 5.82 (1H, s, Sy H), 9.24 (1H, d) , J = 9 Hz, -C-NH). ^Д

Reference Example 68

A solution of 0.9 g of potassium carbonate in 9 ml of water is added dropwise to a solution of 1.4 g of cis-3-benzylooylcarboamido-2-oxo-ylamine-4-carbooylic acid methyl ester in 14 ml of methanol. The mixture was stirred at room temperature for one hour. Seritaol is inherited. The remaining aqueous solution was washed with ethyl acetate and diluted with hydrochloric acid. The neutralized solution was extracted with ethyl acetate. The extract was washed with aqueous sodium chloride solution and then dried over anhydrous sodium sulfate.

The solvent was removed under reduced pressure. The residue evaporates. To the crystals was added titanium acetate and the mixture was eluted. · It is prepared by 1.1 g (84.6%) of cis-3-benzylooykarbzoamidds2- ₀ χozizeidIn 4-karbzoylzvé acid. Crystallization from icetozetrietry gave crystals of mp 156-157 ° C. For C 2 H _{1 1} 2N2 ° 5: calculated: 54.54% C, 4.57% H, 10.60% N; found:

H, 4.45; N, 10.77.

RRferential example 69

To a solution of 1.32 g of cis-3'-benzyloxycarbzoamidos-2-oxosizine-4-carbonyl in dry trtrahydrolurin was added 4 g of dicyclo-hydroxylkirbidimide. After 10 minutes, 0.5 ml of a 40% aqueous dlmR-Thylamine solution was added to the mixture. The mixture was stirred at room temperature for two hours.

NNrozpustný maateiál filtered and Hltrát will be killed under reduced ^even .tlaku. To the residue was added titanium acetate and an aqueous solution of sodium hydrogencarbonate and the mixture was shaken. The ethyl acetate layer was separated, washed with brine and dried over anhydrous sodium sulfate.

The detergent was removed under reduced pressure. The residue is chromatographed on a silica gel column. Crystals of cis-32benzyloxycarbamido-4- (N, N-dimethycarbamool) -2-sooazeridine were prepared. ·

IR (.delta., ¹ cm @ -1): 3280, 1785, 1770, 1730, 1690 and 1640. NMR spectrum .delta. (D1 .alpha.), Ppm: 2.77 and 2.80. (2 o 3H, 2 axis, 2 o ^), 4.53 (1H, d, J = 5Hz, C4-H, 5.36 (1H, dd, J = 5Hz, J = 9Hz, H) ₃ -3).

125

Reference Example 70

To a solution of 291 mg of cis-3-benzyloxycarboxamido-4- (Ν, Ν-dimethylcarboamoyl) -2-oxoazetidine in 10 ml of methanol was added 291 mg of 5% palladium on carbon. The mixture is catalytically reduced at room temperature and normal pressure. After two hours, the reaction mixture was filtered and the solvent was evaporated from the filtrate.

141 mg (90%) of colorless crystals of cis-3-amino-4- (Ν, Ν-dimethylcarbamoyl) -2-oxoazetidine are obtained. This product was treated with 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-methoxyiminoacetyl chloride in the same manner as in Reference Example 34. Crystals of cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4- (Ν, Ν-dimethylcarbamoyl) -2-oxoazetidine, mp 160-165 ° C, were prepared. IR (cm ^-1 ): 3200, 1760 and 1640.

Reference Example 71

To a mixture of 288 mg of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester, 10 ml of tetrahydrofuran and 5 ml of 1N sodium bicarbonate, which is stirred under ice-cooling, a solution of 0.32 ml of 2-thienyl-acetyl- chloride in 10 mL of tetrahydrofuran. After stirring for 10 minutes, 100 mL of ethyl acetate and 20 mL of saturated aqueous sodium chloride solution were added to the mixture.

The mixture is then stirred further. The organic layer was separated. The aqueous layer was extracted with 30 mL of ethyl acetate. The extract was combined with the organic layer. The combined organic layers were washed with 3 x 20 mL of saturated aqueous sodium chloride solution, dried and the solvent was distilled off under reduced pressure. 4 ml of a solvent mixture (ethyl acetate / hexane 1: 2) was added to the residue.

The precipitated crystals are filtered off and dried. 430 mg (80%) of cis-3- (2-thienylacetamido) -2-oxoazetidine-4-carboxylic acid methyl ester are obtained, m.p. Mp 133-136 ° C.

For ^{C 11 H 12 N} 2 ^O 4 ^{S :} C, 49.43; H, 4.15; N, 10.48. Found:% C, 49.00;% H, 4.37;% N, 10.20.

Reference Example 72

To a mixture of 288 mg of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester, 4 ml of propylene oxide and 3 ml of Ν, Ν-dimethylacetamide, stirred under ice-cooling, 400 mg of 1-H-tetrazole-1 are added dropwise. -yl-acetyl chloride. The reaction mixture was stirred for thirty minutes. Ethyl ether (50 ml) was added. Stirring was continued with cooling to -30 ° C.

The upper layer was removed by decantation. The lower layer was treated twice as above. To the mixture was added 10 mL of acetone. The resulting solution was purified by silica gel column chromatography (40 g, 3 x 10 cm), eluting with acetone-methylene chloride (1: 1). After drying, cis-3- (1H-tetrazol-1-yl-acetamido) -2-oxoazetidine-4-carboxylic acid methyl ester (403 mg, 84%) was obtained.

For C _g H ₁₀ N ₆ O ₄ .2 / 3 CH ₃ COCH _3: calculated: 41.00% C, 4.82% H, 28.69% N; Found: C, 41.16; H, 5.08; N, 28.65.

Reference Example 73

To a mixture of 697.6 mg of nalidixic acid and 10 ml of methylene chloride, which was stirred at room temperature, 2 ml of thionyl chloride were added and stirring was continued for two hours. The reaction mixture was evaporated to dryness under reduced pressure. The residue is dissolved in 5 ml of Ν, Ν-dimethylacetamide.

In addition, a mixture of 299 mg of cis-3-amino-2-oxoazetidine methyl ester was stirred with ice-cooling

6 ml of erythrocylsulphate, 6 ml of erythrocyte and 3 ml of Νtociblyl phylactyl. To this solution is added 5 ml of the above-prepared tanning solution. The mixture was stirred at room temperature for two hours. Insoluble bafteials are discarded. The filtrate was filtered with a mixture of 100 ml ethyl acetate and 200 water. The organic layer was washed with a saturated aqueous sodium chloride solution (3 x 50 mL), and then dried to dryness under reduced pressure.

The residue is purified by chrsbiphosrafia and a siliaage column. Prepared П у ^ ^ Угster Cis-3-C1-ethyl-1,0-7-CiУydro mefhyУ14 ^osost-8-yl oaítУyriC0nзЗy LIF) rSon fabins ^yl) -2-4-oxsfzetiCin kfrboxylové žseeio ^ mp 223 DEG 224 ° C. I ^C S ^ ktrum (V ^ J. Cm ^-1): 3400 '1780' 1765 ^'and 1745.

Reference example 74

To a solution of 288 mg of citric-3-fbios-2-oxo-alpha-cine-0-carbonyl acid in 2 ml of tert-butyl acetate was stirred under ice-cooling, 534 mg of mixed mandelic anhydride was added. The mixture was stirred at room temperature for 30 minutes. The mixture was then stirred under ice-cooling. The mixture thus stirred. 1.05 µl of chlorine is added dropwise and the mixture is stirred for 3 hours at room temperature.

The reaction mixture is shaken with 100 ml of ethyl acetate and 20 ml of 1N hydrochloric acid. The organic layer was then purified. The organic layer was washed successively with a saturated aqueous sodium chloride solution (3 x 30 ml, 20 ml of a 1N aqueous sodium hydrogencarbonate solution), a saturated aqueous sodium chloride solution (3 x 30 ml), dried and the solvent was removed under reduced pressure.

The residue is purified using a phosphorous column and a ειΠΙ ^ ι ^ column. Vyroyí the mnetyyester ^ ί-3- (2 ^t C ^{y y1} srfClt lsxy-2- ^yl acltflbi EOL ^{e c} o) t ^{2 t} sxsazzfi ^d io ⁰ -kfr sx ^{b y} ^ IR lsvé tyseHo setrům,, I®)) cm ¹ ): 3 300, 1 760, 1 695, 1 530, 1 220, 1 160, 740 and 700.

Referendum Example 75

To 288 mg of non-hydroxy ester of cis-3-Amino-2tsxsaaeeidio-4-kfrboxylové acid, 1 ml tltraУyCrsfurfoU '2 ml of water and 15 ml of 1N aqueous ^1N sodium УydrogrloUУičitfou solution, which was stirred for chУazloí January, the comm ^ e 469 mg --afif-sulisieo ^y lfcel ^y ltcУlsriCu. The mixture was stirred for 10 minutes under ice-cooling and then for one hour at room temperature.

The reaction mixture was bent under reduced vacuum. The residue is dissolved in 5 L of water. The aqueous solution was transferred to an Anbritite XAD ™ column and then to a Sepnadex LH-20 column. The eluate was lyophilized. Sodium salt or cis-3 - (- ~ 2SulSo22feonyfacefabiCs) t2-oxa α-α-4-carbonyl oxide salt is produced.

For C ,зHз %N2NOзS.3 / 232O calculated: 39.90% C, 4.12%, H, 7.16% N; Found:% C, 39.78;% H, 4.48;

Reference Example 76

A mixture of 2.7 g BC) onOelO ^y УilSeru ienyma-sulfonic acid and 5 tУisoylcУlsriCs was stirred 1 h at bístnooti. The mixture was bent under reduced pressure. To the rest, add as much as needed to make a total volume of 10

In addition, a mixture of 288 mg of cis-3-benzothiazolylsulfonyl-4-carboxylic acid iyselioyl) (0.42 ml) of tree hyfabine and 10 ml of beltylene chloride was prepared and stirred under ice-cooling. To this mixture was added dropwise 3 ml of the above-made ььУУуnnncycyiorioriorifififové, rnběběS. The reaction mixture was stirred for 3 hours. The decomposition was increased under reduced pressure.

200 ml of phthalate and 30 ml of water are added to the residue and the mixture is shaken. The organic layer was washed with a saturated aqueous sodium chloride solution (3 x 30 L), 20 Λ 1 N acid.

The solution was then concentrated in vacuo and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography using a mixture of ethyl acetate and methylene chloride (III).

Cis-3- (2-Benzyloxycarbonyl-2-phenylacetamido-2-oxoazetidine-4-carboxylic acid methyl ester) was prepared, IR spectrum (cm ^-1 ): 3 300, 1780, 1740, 1690, 1530, 1270 , 1 210 and 1 160.

Reference Example

The 3-amino compound prepared from 400 mg of cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid methyl ester in a similar manner to Reference Example 3 was dissolved in 15 ml of tetrahydrofuran. 120 mg of cyanoacetic acid are added to the solution and the mixture is stirred under ice-cooling. 290 mg of dicyclohexylcarbodiimide was added and the mixture was stirred for two hours. The reaction mixture was filtered and the filtrate was concentrated.

Ethyl acetate (30 ml) was added to the residue, the solution was filtered again and the filtrate was concentrated. The concentrate was purified by silica gel column chromatography (20 g, eluting with ethyl acetate). Cis-3- (2-Cyanoacetamido) -2-oxoazetidine-4-carboxylic acid methyl ester was prepared.

KRr —1

IR spectrum (y cm): 3200, 2250, 1758 and 1680. NMR spectrum (DMSO-d6, ppm):

3.60 (2H, s, _CH2), 3.67 (3H, s, _CH3), 4.39 (1H, d, J = 6Hz, C ₄ -H), 5.28 (1H, dd , J = 6 Hz, J = 9 Hz, _C3 -H).

Reference Example

К suspension of 808 mg of methyl cis-3- [2 ^2- (2-chloroacetamido-4-thiazolly) -2-methoxyiminoacetamido] -2-oxoazetidine-4-carboxylic acid (syn isomer) in 40 ml of methanol was added dropwise under ice cooling a solution of 552 mg of potassium carbonate in 12 ml of water. The mixture was stirred at room temperature for one hour. 6 ml of 1N hydrochloric acid are added to the reaction mixture. The methanol is distilled off. The remaining aqueous solution was washed with ethyl acetate. The pH was adjusted to 2 by addition of dilute hydrochloric acid. The product was extracted with ethyl acetate / tetrahydrofuran (1: 2).

The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue is suspended in a mixture of 40 ml of methylene chloride and 10 ml of tetrahydrofuran. 1.0 ml of pyridine was added to the suspension with stirring at room temperature.

A solution of 864 mg of p-nitrobenzyl chloroformate in 4 ml of methylene chloride is then added dropwise over 30 minutes. The mixture was stirred at room temperature for 30 minutes, washed sequentially with water, dilute hydrochloric acid, water, aqueous sodium bicarbonate solution and aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate.

The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (100 g, eluting with ethyl acetate). Crystals of cis -3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -2-oxoazetidine-4-carboxylic acid p-nitrobenzyl ester (syn isomer), m.p. Mp 231-236 ° C (dec.).

IR (y "and x 'θ ^™: 3250, 1760, 1750, 1670, 1550 and 510. 1 H NMR (DMSO-d₆, ppm): 3.83 (3H, s NOCH _3), 4 33 (2H, s, C1CH _2), 4.58 (1H, d, J = 6Hz, C ₄ -H), 5.25 (2H, s, O-Ar), 5.48 (1H, dd , J = 6 Hz, J = 9 Hz, C ² H _3), 7.31 (1H, s, SH), 7.66 (2H, d, J = 9 Hz, Ar- H), 8.17 (2H, d, J = 9 Hz, Ar- H), 8.77 (1H, br s, Nj-H), 9.56 (1H, d, J = 9Hz, _C3 -NH), 12.87 (1H, br s, C (CH ₂ CONH).

128

Reference Example

In a mixture of 510 mg of dioxane and 42.6 ml of acetic acid, 53.2 g of ethyl 2-chloro-trimido-4-tritolyl-acetic acid are dissolved. 28.3 g of telmonium oxide are added to the mixture. The mixture is stirred with 4 Codines at 110-115 [deg.] C. After cooling, the resulting black precipitate is removed and the solution is bent under reduced pressure.

The residue was dissolved in 3 liters of —C thCyl acetate. The solution was washed twice with aqueous sodium hydrogen carbonate and then twice with water, dried over anhydrous sodium sulfate and brought to a volume of 1 liter. The conjugate is boiled under reflux to dissolve the precipitate. 800 ml of Cexane are added and the solution is cooled. Yellow spheres of tert-butyl trichloroacetamide amide of 4-thiazolgygyloxyoxylic acid are obtained, which, after recrystallization from (ethyl acetate) with Cexane, melt at 178-180 ° C.

(C spectrum ([nu] C--1): 3220, 3000, 1740, 1 ppm): 1.31 (3H, t, CH-CH6), 4.35 (2H, q, [beta]), 4 , 40

710, 1680 and 1550. NMR (DMO-Og, (2H, s, dCH3), 8.49 (1H, s,

H, 3.28; N, 10.13.

N, 10.12; Found: C, 39.16; H, 3.21.

Reference Example 80

In 646 ml, 35 g of t-Cyclohexyl-4-chloro-4-chloro-4-cycloxylic acid was suspended. A 1N aqueous solution of potassium cyoxide (250 ml) was added dropwise to the suspension while cooling with ice and stirring. The mixture is mixed with one Codin at a temperature of about one minute. Then it bends behind. reduced Co, pressure to 200 ml. Water (200 mL) was added and the mixture was washed with 400 mL of ethyl acetate. After decolourisation with active HCl, the pH of the solution was adjusted to a value of 1.5 by the addition of 10% hydrochloric acid, whereby pale yellow crystals were formed.

The crystals are filtered off, washed first with water, then with Cexane and dried. The product is produced from tert-butylolyl-oxyoxylic acid. Recrystallization from Cexane-ethyl acetate yields pale yellow Cranberries, mp 205-210 ° C (m / z).

C spectrum (V

KBr max; cm ^{-1): 3450,} 3200, 1730 and ^{1 690} '1 680 and 1 560. NMR ektrum ^ (^ DMMSOd ppm): 4.29 12H, s, DHCP, and 8.30 (1H, s,

For C ₇ H ₅ ClN ₂ O ₄ S calculated: 33.81% C, 2.03% H, 11.27% N; Found: C, 33.94; H, 2.04;

11.23% N.

Reference Example 81

To 50 ml of N, N-O-methyl-methyl-methacrylate was added 10 g of N-hydroxybutyric acid and 9.38 g of methyl bromoate. Then 8.5 g of potassium carbonate are added. The mixture was stirred at ground temperature for 2 days, then poured into 400 rt of water. The resulting crystalline precipitate was filtered off, washed with water, then with Cexane and finally with EtCer. Colorless spheres of N-methoxycarbonyl-methyloxy-oxalimide were prepared, m.p. Mp 137-142 ° C.

(C spectrum (he "b: 1 790, 1 760 and 1 730. NMR spectrum (DMSOod _б, ppm):" 3.71 (3H, s, COOOChI, 4.8 (2H, s, Nocchi 7 , 77 (4H, s, armatmatic protons).

In the same manner as described above, the following compound was prepared: N- (p-nitro-KBr-1 benzylphenyl-cyclobenzylmethylene) -phenyl], mp 158-160 ° C (spectrum, (ν _max ) - cm): 1785 NMR spectrum (DMMSOdg, ppm): 4.94 (2H, s, NOOChI, 5.32 (2H, s, COOCH2)).

129

For Ci _? H, 3.40; N, 7.86. Found: C, 57.22; H, 3.32; N, 7.93.

Reference Example 82

In 60 Κι merУy1rncCУoriUt rlzputSÍ with 3.5 g of N-mertУl 1lkbol ^{y y y} lmiteyУol 1fakimidt under ice-cooling and stirring was added 745 g of hydrazine hydrate. The mixture was stirred at room temperature for 2 hours. Then an additional 149 mg of hydrazine hydrate was added. The mixture was stirred for 2 hours, the resulting crystalline precipitate was filtered off. The filtrate was 15 Kb of dilute aqueous ammonia and then 15 ml of water. The solution is dried over anhydrous sodium sulphate and the solvent is evaporated.

To the residue was added 10 ml of ethyl acetate and an insoluble solid. se e. Concentrate iittáátt to wash out! pale yellow oil C-mirthyl-hexyl-1-hydroxy-hydroxylamine.

IR Spectrum cm 3 320, 2950 and 1740. NMR Spectrum (CDCl 3 + DMSO d 6 ppm):

3.73 (3H, s, CH 3), 4.2 (2H, s, CH 3) and 6.07 (2H, or s, NHh). ‘

In the same way jalr shota mentioned sr vytrO! nááseduuící compound O- (p-nitroOrnzyllxy ^to Cr ^{y O} onyl h ^{h1) yyd} TLX Kmin ^{1 l, l-p} C lectin: RCoA ^{(V K} A ^{× C /} cm ·· 3 ^{32 5 1 76} 0 ^{1 720} and 1600. NMR spectrum (HDDH 2 O, ppm): 4.33 (2H, s, NOCH 8).

Reference Example 83

Vr mixing 20 ml of water and 12 ΚΙ trtraУ1Urlftrknt SR rlziutsí 1.0 g of 2-cУllrkcrtkmi ^d Ol - tУikzolilglyrxilrvé lyseeini, Heta to replace sweated · ^ p ^ KAA 80 Under ice cooling, 465 mg C-mirtУ) ^y Hydroxy lχУlαroon1mirhy1h ^y laminu. The pH was adjusted to 5 by addition of 1N aqueous sodium hydroxide. The mixture was stirred at room temperature for 20 hours.

Adding aqueous У ^y drogerntУičitknu solution adjusted to pH 7. The solution is swill two milliamperes portions 15k1 with ethyl ac-carboxylate. The aqueous was separated vtstva ^ i and the pH was adjusted with 2M hydrochloric acid to 2. ^Y fallen crystalline precipitate was ΙΗΙΙγ) and pt-washed successively with water, hexane and ether. Produced. tal OezOarvé crystals of 2- (2-chllrkcerajκdU "4 thУiazryl) I (Z) ^-2-yl metУnxykαrOonnlmerhyΊrx iminooct.ové selřn ¹ ^ tt I ^{77 and} 1 ⁷⁹ ° ^C kozlúj.

vn · .. - 1

IC spectrum (v max ') ^: 3200, 1750, 1725, 1690. NMR Spectrum (DMSO-d6, ppm):

3.69 (3H, s, HOOCH3), 4.39 (2H, s, CICE)), 4.71 (2H, s, N (CH3)), 7.41 (1H, s, S); from H), 12.7 (1H, or s, NH).

In the same manner as described above, it was washed. nááSedující compound 2 ^{'(2-chllrkcetkmidu-4-yl} thУakyl 1) - (Z), 22- ^(i-y nitlobenzylox lkr0ln1lmetУ llxyiminl ^y) lCtlvá acid, mp 168-170 ° C (Rozzi ·).

VRr _- 1

IR (Vmax ^'X cm): 3200, 1760, 1 710 to 1 680 520. 1 H NMR (DMSSOdg, ppm): 4.34 (2H, s, C1CH ₂ -, 4.84 (2H s, NO2; 5.33 (2H, s, HOOCH3), 7.48 (1H, s, Sy1).

For C, čHH čClNOgS · calculated: 42.06% C, 2.87% · H, 12.27% N; found: 41.95% C,,

H, 2.86; N, 12.30.

Reference Example 84

In 20 ml merУy'1encCУoriUt was suspended 810 mg of 2 '· (2-chllrkcerakmdUl4 thУakzly1) I (Z) ^-2-yl κethox karbonn1merhyΊ (Lx ^y iminloctlvé liseeini. Under ice cooling and stirring, 602 mg of phosphorus pentachloride. The mixture The mixture was stirred under ice-cooling for one hour and at room temperature for 30 minutes, 30 ml of hexane were added under ice-cooling, and the resulting solution was washed with hexane to give 910 mg of yydrochyoride 2- (2-chloro-4-tetrakec-4-yl). ) - (Z) -2-kα mirУoly ^{y n r} Ol LMIT ^hole lol ^{y Cr} iminnack l-- ^cy or ^id u, ^{m. p. 77 and 8} 0C.

130

IC with ^p ektrum (VK ^R r, cm Ь: 3000 ^and 1775 ^and 1740 and 1 695 for C ^ HgCl ^ N ^ S.HCl in feeling ⁰ 30.74% C 2.58 "H N, 10.76; Found: C, 30.69; H, 3.46; N, 10.89.

In the same manner as above, the following are produced: sulfuric material: hydrochloride

2- (2-4-hhlorlceeaaidu thUIlziyt) - (Z) -2- (p-iitoorrnzyloxykarbooitmithylooyimiío) ocaCratcChooid ^u, UCT. Mp 158-161 ° C.

^IC ektruy with ^{p (y [1} * ⁵ cm: ^{2940, 1 7} 80, ¹⁷⁴⁰ and ^{1680. P} ro C ^ H ^ C. ^ O ^ ^S-HCl-1 očte- NO: 37.55% Found:% C, 37.61;% H, 2.65;% N, 10.87.

Reference Example 85

In a mixture of 5 [mu] l of hydrofluoric acid and 5 [mu] l of water, 280 mg of α-ω-3-α-α-oxazoline-4-carboxylic acid was dissolved. 73 mg of sodium hydrogen carbonate are added to the solution. Under ice-cooling and stirring, 910 mg of 2- (2-chloromethyl-4-methyl-Z-2-yl-ethyl) - (Z) -2-methylethyl-bromo-imino-imino-amino-crotin-hydrochloride hydrochloride was added and the mixture was stirred at room temperature for two hours.

Water was added to the wash reactions. The resulting crystals were stripped off and washed sequentially with water, hexane and ether. 3- [2- (2-Chloro-hexyl-4-thiazolyl) -1H-yloxy] -carbonylalkylamin-4-yl] -oleridine-14-carboxylic acid (syn. KgOg), m.p. Mp 260-265 ° C (dec.).

IC 50 (cm 3 cm ^-1 ): 3290, 2950, 1780 and 6 ^; 1 730 ^and 1 685 and 1 660 respectively. H, 3.49; N, 15.17. Found:% C, 39.00;% H, 3.58;% N, 15.06.

In the same manner as above, the following is prepared: cis-4- (2-hydroxy-4-thiolyl) -2- (p-nitro-benzyloxycarbonylyl-oxy-yloxy) -acrylaminocarbonyl- ² -oxo-oxo- ² -oxo-oxo (s ^y n ⁱ somr), 2 ° to ²⁷⁵ ° C (m.).

IR ( ^KBr , cm “ ¹ ): 3,250, 1,760, 1,700 and 1,675. -S found:

max 21 20 6 10

% C, 43.27;% H, 3.38;% N, 1-4.42; Found: C, 42.85; H, 3.38; N, 14.27.

Reference Example 86

In 250 µl of dry ether, 15.3 g of p-nitrobenzylbenzoic acid are dissolved. The solution was diluted with solvents

8.90 mi ppyiUint under ice-cooling and stirring. 25.3 g of 31'Irroyisobutyl-iodine are then added dropwise over 5 minutes (3 min) and the mixture is stirred for 5 hours at RT. The resulting crystalline precipitate is filtered off and washed with ether.

The combined ether filtrate was combined and 150 ml of ethyl acetate was added to the solution. The mixture was washed successively with dilute hydrochloric acid, water, aqueous sodium hydrogen carbonate, aqueous sodium hydroxide, and dried over water-thick magnesium sulfate.

The dissolving agent was then reduced at a reduced rate. The residue was chromatographed on silica gel (600 g column, 1: 1 chloroform-hexane). 29.6 g of a yellow oil of .alpha.-isorrisylteretrol alaarto-o-olonate acid are obtained. This product solidifies upon cooling.

IC ektru ^{1 (ν-311 3 'cy_1):} 1735 ^and 1520 ^and 1345 ^and 150. 1 H NMR ^ ιΟΙγπι (СОСЦ ^PP n);

1.96 (6H, s, 2.times.C.sub.2), 5.27 (2H, s, COOCl.sub.4), 7.49 and 8.13 (2.times.2H, 2.times.d, aronaonic protons).

Reference Example 87

14.7 g of (11%) and 27.2 g of (10%) -trifluoromethyl-trisulphonic acid are added in 75. The mixture was stirred at room temperature for one hour.

131

As mixing becomes increasingly difficult due to the loss of the orange-colored solid, 75 ml of Ν, Ν-diethylphosphorus are added to the mixture. The mixture was stirred at room temperature for 24 hours. The volume of the reaction mixture was reduced to about one half of the original volume by separating the solvent and the coccetate was poured into 700 ml of water while cooling with ice and stirring. The mixture was stirred for 30 minutes.

The resulting crystalline precipitate was filtered off and washed with water. The crystals were dissolved in 500 µl. eethofenyC0oridt. The solution was washed with water and dried over anhydrous magnesium sulfate. The looped fabric was then detached under reduced taak. The solid residue was washed with a 1: 1 mixture of ether ^, ethyl acetate and a small amount of ether.

Prepared colorless crystals of N- [L-methyl-l- (p-nitrstnnzfΊoУfktrSozyfLethyfoyyfftllieiit ° C. ^IR ^ ektrum ·· ^<V (6H, s, s (27'0 ^g) and

345. NMR (2 × 2H, 2

).

mp 145-146 (DMSO-d 6, ppm): 1.61 xd, NO ₂ , 7.75 (4H,

cm ^-1 ) -L 790 '1 740' 1 725, x CH ₃ ), 5.28 (2H, s, NO 2),

520 a

7.59 and 8.10

For ^C 19 ^H 16 ^N 2 ° 7 calculated: 59.38% C, 7.26% N.

4,20%

H, 7.29% N; found: 59.14%

C, 4.27% H,

7.68 g

N- [l ~ ee ^t h · ^{L OFL} .- (p-Loy nitrsbьyz ^{f f LR} on ^NF) in 80 ml ethyl eethofenyCOoridt the rozkutí ^ y] ittlieidt. 0.97 hydrazine hydrate is added under ice-cooling and stirring.

The mixture was stirred at room temperature for 2 hours. An additional 0.97 hydrazine hydrate was then added. OMES was stirred for three hours and the resulting crystalline r ^R eipřtát and washed with oOfiltrtje eethyltnchloridem.

Combine the filtrate with washed ethyl ether. The combined solutions were further ^tr zeyfí with dilute aqueous ammonia, water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was chromatographed on a silica gel column (300 g, eluting with 1: 1 hexane / hexane / hexane).

Prepared 4.58 g of a yellow oil - [ll menthol-L1 · (p-nitrzStУzy lzyykaabsznfLetOyl] hydroyyla ^ in. This odukt ^ ^p ^ ztiu by cooling e. ^Ic ^ ktrum

930, 1740, 1535 and 350. 1 H NMR (ppm CDDCij- · · '1.46 s, COOCH2), 5.33 (2H, br s, NH _2), 7.48 and 8.17 ( 2 x 2H, 2 xd, cm ^"1) 3310 '3250' 2980 '(6H, s, 2 x CH3), 5.26 (2H, aroeaaicкé protons).

Rereference example 89

1.49 g of 2-chlorobenzoyl-4-hitol-glycoloyoyl acid. While cooling with ice and stirring, 1.83 g of O- [1- (4-oxo-1- (4-nitro-benzoyl) cyclohexanone) -thiophthalic acid is added. The pH was adjusted to pH 1 by addition of aqueous 1N sodium hydroyide

In a batch of 30 ml of water and 18 ml of tttraOf’irzfurlУt will burst

5.0.

The mixture was stirred for 12 hours at 150 ° C. The aqueous sodium hydrogen carbonate was then at 7.0. The tetrahydrofuran was removed under reduced pressure. The remaining aqueous solution

The mixture was adjusted to pH with ether, the pH was adjusted to 2 with dilute hydrochloric acid, and the product was filtered.

Eytrakt r ^ro ^ m is an aqueous у01сг.1 (п ^ bicarbonate and dried over anhydrous magnesium sulfate. Rozpcoiutědlo under reduced Bag odddetiltjt. To burst the residue in ether and poured into twice the volume of t ^{e r} zletOert. The resultant powdery precipitate was odfiltrtje .

132

2- (2-Chloroacteamido-4-thiazolyl) - (Z) -2- [1-methyl-1- (p-nitrobenzyloxycarbonyl) ethyloxyimino] acetic acid was prepared. IR spectrum (in KB *, cm ^-1 ): 1740, 1695, 1540, 1520 and 1345.

NMR (CDC1 _3, ppm): 1.61 (6H, s, 2 x _CH3), 4.29 (2H, s, C1CH _2), 5.23 (2H, s, NOCH _2), 7.26 (1H, s, S1H), 7.43 and 8.05 (2 * 2H, 2 * d, aromatic protons).

Reference Example 90

1,445 g of 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-1-methyl-2- (p-nitrobenzyloxycarbonyl) ethyloxyimino] acetic acid are dissolved in 15 ml of methylene chloride. 686 g of phosphorus pentachloride are added under ice-cooling and stirring. The mixture was stirred under ice-cooling for 30 minutes. 4.5 ml of hexane are then added. The resulting crystalline precipitate was filtered off and washed with hexane.

2- (2-Chloroacetamido-4-thiazolyl) - (Z) -2- [1-methyl-1- (p-nitrobenzyloxycarbonyl) ethyloxyimino] acetyl chloride hydrochloride, m.p. Mp 79-82 ° C.

IC spectrum (cm ^-1 ): 2,998, 1,775, 1,735, 1,715, 1,565, 1,520, 1,340 and 1,140.

For C _g H ₁₇ Cl ₃ N ₄ O ₇ S Calculated: 40.05% C, 3.16% H, 10.38% N; Found:% C, 39.80;% H, 3.31;% N, 10.30.

Reference Example 91

417 mg of cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid methyl ester prepared according to Reference Example 2 and 200 mg of 5% palladium on carbon are suspended in 20 ml of ethanol. The mixture was stirred under a hydrogen atmosphere for 30 minutes. The catalyst is then filtered off. The filtrate was concentrated under reduced pressure. The residue is dissolved in 15 ml of water and 15 ml of tetrahydrofuran.

336 mg of sodium bicarbonate and 972 mg of 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2- [1-methyl-1- (p-nitrobenzyloxycarbonyl) ethyloxyimino] acetyl- chloride.

After stirring for 30 minutes, the reaction mixture was extracted with ethyl acetate / tetrahydrofuran. The extract was washed successively with aqueous sodium bicarbonate, brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The solid residue was washed first with ether: ethyl acetate (5: 1) then ether. Colorless crystals of cis-3- {2- (2-chloroacetamido-4-thiazolyl) -2- [1-methyl-1- (p-nitrobenzyloxycarbonyl) ethyloxyimino] acetamidoyl-4-methoxycarbonyl-2-oxoazetidine (syn isomer) were prepared. , tt Mp 198-202 ° C (dec.).

IC spectrum (ν **, cm ^-1 ): 3,360, 1,770, 1,745, 1,690, 1,525, and 1,350. NMR Spectrum (DMSO-d6, ppm): 1.52 (6H, s, 2 x CH ₃ ), 3.63 (3H, s, COOCH ₃ ), 4.34 (2H, s, C ₁ CH ₂ ), 4.47 (1H, d, J = 6 Hz, C ₄ -H), 5.29 (2H, s, SO 3, 5.48 (1H, dd, J = 6Hz, J = 9Hz, C ₃ H), 7.23 (1H, S, S / H).

Reference Example 92

19 g of 2-hydroxyiminoacetacetic acid methyl ester are dissolved in 50 ml of methylene chloride.

While cooling with ice and stirring, 19.6 g of sulfuryl chloride are added dropwise. The mixture was stirred at room temperature for 3 days. The methylene chloride was then distilled off under reduced pressure. The residue was dissolved in 200 ml of ether and washed seven times with 100 ml portions of water. The ether layer was dried over anhydrous sodium sulfate.

The solvent was distilled off under reduced pressure. 20.2 g of a pale yellow oil of 4-chloro-2-hydroxyimino-acetic acid methyl ester are obtained. NMR (CDC1 _3, ppm) 2.65 (1H, br s, N-OH), 3.90 (3H, s, _COOCH3), 4.57 (2H, s, ₂ C1CH).

¹³³ 253565

This product was dissolved in 200 mL of a 1: 1 mixture of water and tetrahydrofuran. Under ice-cooling, 16.96 g of thiourea and 49.27 g of sodium acetate trihydrate are added to this solution.

The mixture was stirred overnight at room temperature. The pH of the reaction mixture was adjusted to 7.0 by the addition of sodium bicarbonate. The solution was saturated with sodium chloride while separating the organic layer.

The aqueous layer was extracted with tetrahydrofuran. The tetrahydrofuran extract and the above organic layer were combined, the combined solution was washed twice with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate.

The solvent is then distilled off. The oily residue was crystallized from 100 ml of ether. The crystal solution was allowed to stand overnight, then the crystals were filtered off and washed well with water. The resulting crystals were dissolved in a mixture of ethyl acetate and methanol (5: 1).

The product is concentrated until crystals precipitate out of solution. The concentrate is then allowed to stand overnight. The resulting crystalline precipitate was filtered off and dried. Light yellow granules of 2- (2-amino-4-thiazollyl) - (Z) -2-hydroxyiminoacetic acid methyl ester, m.p. Mp 191-192 ° C (dec.).

IR? Max IV ^{'cm⁻¹: 3430,} 3300, 3220, 3130, 1730 and 620. 1 H NMR (DMSO-d₆, ppm): 3.80 (3H, s, COOCH _3), 6, 87 (1H, s, SO 2), 7.17 (2H, br s, NH ₂ , 11.67 (1H, s, N-OH)).

For C ₆ H _? N ₃ O ₃ S: calculated: 35.81% C, 3.51% H, 20.89% N; Found: C 36.05, H 3.52,

20.96% N.

Reference Example 93

4.62 g of 2- (2-amino-4-thiazolyl) - (Z) -2-hydroxyiminoacetic acid methyl ester are dissolved in 10 ml of Ν, Ν-dimethylformamide. 3 ml of triethylamine are added to the solution. 6.42 g of trityl chloride are then added with stirring at -30 ° C over one hour.

The mixture was further stirred at this temperature for one hour and then at 15 ° C for a further two hours. Water (200 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 ml). The ethyl acetate extract was washed with two 200 ml portions of water and dried over anhydrous sodium sulfate. The solvent is then distilled off.

The residue was purified by silica gel chromatography (100 g, eluting with hexane / ethyl acetate = 1: 1). The resulting crystals were recrystallized from ethyl acetate. Colorless granules of 2- (2-tritylamino-4-thiazollyl) - (Z) -2-hydroxyiminoacetic acid methyl ester, m.p. Mp 204-205 ° C.

IR (VK® * cm *): 3375 and 1 740. NMR (DMSO-d₆, ppm): 3.45 (3H, s, COOCH ^), 6.70 (1H, s, _S H ), 7.18 (15H, s, 3 phenyl groups), 8.47 (1H, br s, NH), 11.27

I (1 H, s, N-OH).

For ^C 25 ^H 21 ^N 3 ^S ° 3 ° yP ^reading: _l ^{67 »70%} C, ^{4.77% H, '9.48% N?} Found:% C, 67.55;% H, 4.67;

9.14% N.

Reference Example

7.05 g of 2- (2-tritylamino-4-thiazolyl) - (Z) -2-hydroxyiminoacetic acid methyl ester and 3.3 g of potassium carbonate are added to 70.5 ml of Ν, Ν-dimethylformamide. 2.12 g of allyl bromide are then added dropwise over 5 minutes with ice-cooling and stirring. The mixture was further stirred under ice-cooling for four hours.

134

To this reaction mixture was added 1.65 g of potassium carbonate and 1.06 g of allyl bromide. Mix the mix four more heroes. The reaction mixture was diluted with 150 mL of water and extracted with three (100 mL) portions of ether. The ether extract was washed with two (100 mL) portions of brine and dried over anhydrous sodium sulfate.

Then the rooster is distilled off. The residue is purified by column chromatography on silica gel

(F) (300 g) eluting with hexane / ethyl acetate (1: 1). The product was crystallized from ether with hexane. 7.0 g of 2-C1-4-methyl-2-methyl ester were obtained, m.p. (z) (Z) - (Z). -2- (4-allyl) -cyclohexylamino-acetic acid, m.p. Mp 115-116 ° C.

IR (V ^C ™ ^{1 1} 1 ³³⁶⁰ and 740. NMR CDCC ₃ ppm · 3.88 (3H, s, C ^ O ^ j,

6.52 (1 H, s

Δ), 6.93 (1H, bris, NH), 7.30 (15H, s, three phenyl groups).

For C2 ₈ H25N3 O3 S: calculated: 69.54% C 5.21% H 8.69% N> Found: 69.57% C, 5.18% H, 8.51% N.

Reference Example

6.45 g of 2- (2-tritylamino-4-thiazolyl) - (Z) -2-allyroxyiminoic acid methyl ester are dissolved in 32 ml of tetrahydrofuran. To the solution was added 32 ml of 50% formic acid. The mixture was stirred at 60 ° C for 40 minutes. The reaction mixture was recovered under reduced pressure. The solid residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate, brine and dried over anhydrous sodium sulfate.

The fabric was then reassigned under reduced pressure. The residue was purified by TLC column chromatography (150 g, eluting with hexane / ethyl acetate 1: 1). Rooppostedlo rdeetSilujt. The solid residue is washed first with hexane, then with a small amount of ether and dried. 2- (2-Allyl-4-hiazolyl-2-yl) -2-allyliminimineate acetic acid, m.p. Mp 133-134 ° C. .

IR spectrum (V cm ^-1 ): 3430, 3230, 1720, 1610 and 1440. NMR spectrum (CDCl 3, ppm: 3.90 (3H, s, COOOCH)), 5.98 (2H, br s, NH ₂ ), 6.67 (1H, s, SyH).

Reference Example 96

2- (2-chloroacetyl-4-triazollyl) - (Z) -2-allyroxyiminoic acid, mp 114-115 ° C, was prepared in the same manner as in Reference Example 32. IR spectrum (ν max) cm ^-1 : 3,150, 3,060, 2950, 1740, 1710, 1680 and 1565. NMR Spectrum · (CDCl 3 ppm): 3.93 (3H, s, COOCH 3) 4.28 (2H, s, CH2), 7.25 (1H, s, SyH), 10.12 (1H, br s, CONH).

Reference Example 97

2- (2-Clractactamide-4-thiazrlyl) - (Z) -2-allyroxyiminoic acid, mp 162 ^° C (dec), was prepared in the same manner as in Reference Example 33 '. Ir (ах ^ 'cm ^L) 1 3180, 2950, 1 715 to 1 680. NMR (DMSOodg, PP ^: 4.33 (2H, s, kitty ^), 7.42 (1H, s , SyH).

For C ₁₀ H ₁₁ ClN ₃ O ₄ S calculated: 39.54% C, 3.32% H, 13.84% N; found: 39.41% C,

H, 3.55; N, 13.71.

Reference Example 98

610 mg of 2- (2-chloroacetyl-4-hlazoryl) - (Z) -2-hydroxyiminoacetic acid are suspended in 13 ml of methylene chloride. To this solution was added under ice-cooling and stirring

502.4 mg of phosphorus pentachloride.

135 DEG C. The mixture is stirred at room temperature for 30 minutes, then 100 ml of hexane are added to the reaction mixture. The resulting crystals were filtered and washed with hexane. Prepared lydrooClorid 2- (2-S-chlorřceeaamdo 4hlaaolyУ)) (Z) -2-řllySoxyiminsřietγl · _l + ihlsridu mp 67-70 ° C.

For C ₁ gHgCCmNjOjS.HICl calculated: _# 33 · 49% C 2.11% H 11.22% N _r · ^ on eeno: 33.77% C,

H, 2.76; N, 11.79.

Renernational example 99

185.5 mg of cis-3-amino-2-oxo-pyridine-4-quartzylsulfonic acid are dissolved in 2 ml of tetrahydrofuran and 2 ml of water. To the solution, 469.6 mg of sodium lydrogensulfonic acid was added first with ice-cooling and stirring, followed by 600 mg of 2- (2-pyrrolidino-4-thiazolyl) - (Z) -flyl-oxylminosacceyl-R-sulfide. The mixture was stirred at room temperature for 2 hours.

The solvent was removed under reduced pressure. Water (20 ml) was added to the residue. The insoluble material is filtered, washed successively with aqueous sodium bicarbonate, water, hexane and ether and dried. Prepared pale yellow granules mgthy letter of the IIS-3-22 ~ (4-2ilh0rlceeaamids thaazslyl) 22-ljlylyxminSloanelmnddo] 2-soχoleetidin44ikarbsxylsvé acid (syn isomer) _f

mp 270 · 280 ° C (dec.). IC ektn with ^p '(in cm ^-1): 3260, 1770, 1745, 1720 and 1 680th

NMR Spectrum (DMSO-d 6 ppm): 3.60 (3H, s, COOCH 3), 4.33 (2H, s, C H 3), 4.45 (1H, d, J = 6 Hz, C ₄ -H 7.29 (1H, s, SyH), 9.49 (1H, d, J = 9 Hz, C 1 H -H).

For C 15 H ₁₆ ClN50gS calculated: 41.91% C, 3.75% H, 16.29% N; Found: 41.83% C

H, 3.85; N, 16.37.

Reference Example 100

657 mg of ith-3-benoxyoxycarboxoxamido-4- "ethylsulfsnylsxy" -eh-2-sxoalenidine, prepared as described in Example 11, are dissolved in 7.8 ml of Ν, Ν-imlylphosphoramide, prepared as described in Example 11. Add this solution to the solution. 861 mg of U-di-methylsulfate in 7.8 ml of Ν, “-di-ethylsulfide. The mixture was stirred from t ^{s h!} N ^y ltmoo ERN Ar ^{1 g of} one ^{of p p} fm n ^{t, thickness} ls ^{of 73} ° C.

The reaction mixture was cooled, poured into 60 ml of aqueous sodium chloride solution and extracted with ethyl acetate. The extract was washed with aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The solvent was then removed under reduced pressure. The residue is purified by column chromatography on hexane / methylene chloride (1: 2) (the column contains 50 g of silica).

The obtained crystals were washed with ether. Prepared IHT-3-bnneyloxyklrbsxřΐdes ⁴ - _C hlsr "enhll- ^2" in sxoalzna ^e, mp 1 ^47-149 ° C. ^P ro ^<3 i2 ^H 13 ^C1N 2 ^{T '>} 3 ^ ye Readings: ^53.64% C, ^4.88% H, ^10.43% N; Found: C 53.49, H 4.81, N 10.35.

Reference Example 101

In 20 ml of methanol is suspended (376 mg) _IIS-3-C-4 bnneylsxyklrboxlmdes duty mgntlУ _{r-2-sxoaazeidin.} 376 mg of 5% palatine per µM was added to the suspension. The mixture was stirred at room temperature under a hydrogen atmosphere for 20 minutes. The catalyst was then filtered and the filtrate was evaporated.

The solid residue was dissolved in 28 mL of 1: 1 toluene-furfurene water. 470 mg of sodium bisulfite are added under ice-cooling and stirring. Then 698 mg of 2- (2-methylsulfonyl- ^4- methylsulfonyl) -2-methylsulfonyl] hydrochloride (syn) was added.

The mixture was stirred under ice-cooling for 30 minutes. The reaction mixture was then extracted with ethyl acetate. The aqueous layer was extracted again, which was a mixture of n-lyllintate and uranium. The extracts are

The resulting solution was washed successively with aqueous sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate, and the solvents were distilled off under reduced pressure. The solid residue was washed with ethyl acetate / ether (1: 3). Colorless crystals of cis-3- [2- (2-chloroacetamide-thiazinyl) + 2-methoximino-10-acetamido] -14-chloromethyl-12-oxo-aletidinium (syn isomme), m.p. Mp 212-217 ° C (dec).

IC spectrum (γ max X cm ^-1 ): 3420, 3260, 1755, 1660 and 1560. NMR spectrum (DMMO-d6, ppm: 3.90 (3H, s, NOCCl 3), 4.34 ( 2H, s, C1CH2), 5.28 (1H, dd, J = 5Hz, J = 9Hz, C1-H), 7.46 (1H, s, OyH1), 8.72 (1H, br s, N 3 -H), 9.33 (1H, d, J = 9 Hz, C 1 -NH), 12.57 (1H, br s, C 1 CH 2 CONH).

Reference Example 102

According to Reference Example 11, his-β-benzyloxycarbamoyl-4-methylsulphonylmethyl-4-oxonaeeidine was prepared, which was further processed by the screening method as described in Reference Example 88 above, to produce β-3- [2- (2-chloroacetamidine) -4-thiazonyl. () - (Methoxyiminoacetamido) -4-retinylsulfinyl] oxymethyl-2-oxxoazeidine (syn isomer), m.p. Mp 186-189 ° C (low).

C ₁₃ H ₁₆ ClN ₅ O ₇ S ₂ calculated: 34.40% C, 3.55% H, 15.43% N; Found: 34.27% C, ·,

H, 3.63; N, 15.28.

RRferential Example 103

3.28 g of his-3-benzyloxycarbamido-4-renylsulfstylsulfonyl-2-oxone] eidini, prepared according to Reference Example 11, are suspended in 100 ml of ethanol. 3.28 g of 5% palladium on carbon are added to the suspension. The mixture was stirred under hydrogen atmosphere for 50 minutes at room temperature.

The catalyst was then filtered off and the filtrate was bent under reduced pressure. The concentrate was swelled in a mixture of 100 ml of methylene chloride and 15 ml of Ν, dir-direthllacttide. While cooling with ice and stirring, firstly add 6.99 ml of propilene oxide and then a solution of 2.79 g of 2-rethalosulfonylethyl chloroformic acid in 25 ml of methylene chloride. The mixture was stirred at room temperature for two hours. .

Methylene chloride is separated. . Water and ethyl acetate / tetrahydrofuran (1: 1) were added to the residue. Shake the mixture well. The organic layer was separated. The aqueous layer was evaporated to dryness under reduced pressure. The residue is taken up in tetrahydrofuran, dried over anhydrous magnesium sulfate and combined with the above organic layer.

The combined mixture was dried again over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was chromatographed on a tilica gel column (150 g, eluting with ethyl acetate, with ethyl acetate: ethanol: 9: 1). The resulting rats were washed with ethyl acetate with ether (1: 1).

Colorless crystals of his-3-2-meShlLSilfStyyleShol: iarrSoamids) -4m ^ eSУllsulntlyl; oxymethyl-I20oxaaetidine, m.p. M.p. 141-142 ° C.

For ^C 9 ^H 36 ^{N 2} O ₈ S 2 calculated: 31.39% C, 4.68% H, 8.14% N; Found:% C, 31.34;% H, 4.76;% N, 34%.

Reference Example 104

In 75 ml of methyl ethyl ketone, 1.894 g of 3-methyl-2-methylsulfonyl-4-methylsulphonylaminoxymethyl-2-oxazazidine and 4.864 g of sodium iodide are suspended. The suspension was boiled under a foamed condenser for 3 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. To the concentrate was added water, ethyl acetate, and sodium salt. The resulting crystalline precipitate was added and washed sequentially with water, ethyl acetate and ether. .

137

382 mg of colorless crystals of cit-3 - ((2-ethylsulphonylcarbonylcarboxylic acid) -4-iodide) are obtained. The filtrate is combined with the washings. odddlí.

The aqueous layer was treated with sodium chloride and extracted with tetrahydrofuran / ethyl acetate (4: 1). This extract was combined with the organic layer and the combined phases were dried over anhydrous magnesium sulfate. ‘

The solvent was removed under reduced pressure. The crystalline residue was washed with ethyl acetate. Prepared ^{1,367 g} ^ ora said ⁴ - ^{- No} crimps jidaaihyl-Enio ^y, mp 186 and ^from 190 ° C (rozzk.). H, 3.48; N, 7.45. Found: C, 25.64; H, 3.53;

7.34% N.

Reference Example 105

1.504 g of cit-3- (2-aithylsulficylethylcyclohexylcarbonyl) -4-pyridyl] -2-oxalziidine and 390 mg of sodium azide are added to 20 ml of. The mixture was stirred at 40 ° C for 66 hours and then at 40 ° C for 24 hours. The solvent was removed from the reaction mixture under reduced pressure. The residue is purified by chromatography on a silica gel column (100 g, illusion 1: 12101), followed by a 9: 1 mixture of ithylacitate and thiol.

Then iddd1tilsj1 settled. The residue was fe ^y stalsji of ithχlkc1tátu. The crystals were filtered. Prepared colorless crystals cit-3- (2-a1thylsufinyy1ehiχУkkar0oxaaido) -4-ki ⁱ diaait 1 ^{H) -2-one} and ^di iXoali Cu, LL ¹⁵⁸ and ^{Z '160} ° ^{C. IR} ( ^cm @ ^{-1): 3 20} 0 2110 ^,

780, 1700 and 1550.

Rederin Example 106

To 60 ml of ithanol and 6 ml of N, N diaethyloleaidide was added 757 mg of cis-3- (2-methylsulfonylphenylcarbonyl) -4-pyridinyl-2-piperidinyl. While cooling with ice and stirring, 5.7 ml of 1N hydrochloric acid are added and the mixture is concentrated under reduced pressure. To the concentrate were added 15 ml of water and 15 ml of titration hydrosulfate.

874 mg of sodium hydrogen carbonate are added under ice-cooling and stirring. Then, 1,297 g of 2- (2-chloroacetamide di-4-hazziyl) -2-aithoxylmino-1-yl-chloride (syn isomer) hydrochloride is added and the mixture is stirred for 40 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, brine and dried over anhydrous magnesium sulfate.

Roi: pStaned under reduced pressure iddd1tilsji. The crystalline product is washed first with ethyl lithium, then with ether and dried. Prepared colorless crystals cit-3- [2- (2-chlirlCitlaido- ⁴ -TH azΌjχl ^l) - ^{and also} -deh χyχim ioacetaa ^{id c} i ^J - ^4- IAE If ^{ID 1} H ^H1 -2-oxoa ^l i ⁱ i ^d inu ⁽ son де ^ е ^, ^{L. L.} 22 ^{3 to} 230 ° C (тг ^.)).

Ir (71χ 'c ^m ~': ^3420, 3250, 2110, 1760, 1660 and 550. 1 H NMR (DMSO-d _6, ppm): 3.4 to 3.6 (2H , m, CH ^), 3.90 (3H, s, NOCH _3, 4.34 (2H, s, ClCIi ^, 5.22 (1H, dd, J = 5 Hz, J = 9 Hz, C-H ), 7.37 (1H, s, ^ 7 «) / ^8, 49 (1H, br s, N-H), 9.20 (1H, ^d, J = 9 C ^ NH). ^d

Reference Example 107

In 50 ml of Mel-ihlencchoridu rizpustí with 5.0 g of 3-cit-riCiylixykarroxxlado-l- (2,4-dia1thoxyrenoz1) -4-hydroxyae1th1-2-ixoalziidios which is produced the proportion of the reference case, the fifth ^{tetrabutylammonium} Rida ^{3 75} ml of ^p yr ^ID iciu ^p lo ^ s ^{-1 0} ° ^C under stirring. The SMI-IEI ^{sd BC-ik-1}

3.94 g of chloride and the mixture was stirred at room temperature for 1.5 hours.

To the reaction mixture was added 100 ml of popular water. The organic layer was separated, washed with aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The contractor then iddd1tilsj1. The residue was purified by chromatography on a silica gel column (325 g, 1: 2 hexane / ithylacitic acid).

138

The solvent was distilled off, hexane was added and the crystalline residue was filtered off. Prepared colorless crystals AIT-3-bgtzyloxykrrboxrmidfo bgioylooχleigyhyhl-4- (2,4-dipethoxybbeiyl) -2-oxoaage ^ d ^ nu, mp ϋ33 ¹ to 34 ^o C.

For gH2 _B C ₂ N ₂ O7: calculated: 66.65% C-59% H, 0.00% N; Found:% C, 66.48;% H, 5.49;% N, 5.36.

Rgfgrence example 108

In the same manner as in Reference 7 was prepared příkaadu AIS "3 betzy0oxyкarboxrpido-4-bgnzo loxympthy ^{of l} -2-dit oxXjagg ^i, mp ^{188-189 o} C. with IC ^ Kiz-rum <V ^ ax cp ^{_1): 3300, 1770,} 1725 and 1 690. For Ig ^{C H} 2 i8 ^N ° 5: calculated: 64.40% C, 5.12% H, 7.91% N; found: 64.42% C,

H, 4.96; N, 7.86.

Reference Example 109

In 20 ^ il ethanol was suspended 550 pg aIt- -beilzy0oxyкarboxrpido ^{3-4-2-igtzoyloxypigeul} oxoaaggiditž. 550 µg of 5% palladium on charcoal is then added to the suspension. The suspension was injected for 2.5 hours under a hydrogen atmosphere. The catalyst is filtered off and the filtrate is concentrated under reduced pressure.

Colorless crystals of .alpha.-3-piperazo-4-benzoyloxymphoxyl-oxaaegidite were obtained, mp 150-15. I ^O C ^C ^ ktřrup ^(V max; cm ^{-1): 3200, 1 735th} and 1 ⁷ 1 ⁰ . ^P ro ^c u i2 ^H 2 ^N ° 3 vroočteno: ^59.99% C,

H, 5.49; N, 12.72; H, 5.66; N, 12.84.

Reference Example 110

In the same manner as in Reference příkaadu ⁹ was prepared cit 3- £ 2- (2-4-ch0oracerapido thrazoУy - (- i-geUOχyyimnoraceramidoJ-4-igtzoyaox; ypghulh2-oxojaegtdit (son of the isomers), mp 210 ^and from 220 ^o C (rozzL ·).

VRy _ 1

IC spectrum (χμ χ ' ^cm ): 3 250, 1 760, 1 715 and 1 660. For ^c ₁ gH ₁ gClN ₅ -aS calculated: 47.55% C, 3.78% H, 14.59% N; Found: C 47.06, H 3.63, N 14.53.

Reference Example 111

To 250 ml of benzene were added 35 g of R-α-p-methylcaptayl-lactide and 29.5 g. The mixture was heated under reflux for one hour, after which the water was distilled off. The Sepak solvent under reduced vacuum is removed. The residue is dissolved in 1 liter of methylene chloride. For ice cooling and. 29 g of water are added with the addition. A solution of 53.5 g of trimethylethyl chloride in 250 ml of pegiulentCorrhea is then commanded within 45 minutes.

The mixture was stirred at room temperature for 24 hours, washed with water, dried over magnesium sulfate and the solvent was removed by distillation. The solid residue was crystallized from a mixture of hexylacetate and hexane. Prepared cit-3-ftaIpido-4- (rhfa-meehhlhtylyl) -1- (4-peghoxχlegtl) -2-oxoaakgidit ^IT · ¹⁰⁵ and ^{from 107 o} C.

IC ktnrn ^{(V c} m ^{-1): 1760,} 1725, 1515, 1385 and 250. 1 H NMR (CDCC., Ppm): 1.70 (3H, br s, = CC ^) 3 74 (3H, s, NOC ^ j, 4.77 (1H, d, J = 6Hz, C4-H), 5.52 (1H, d, J = 6Hz, C ₃ -H), 6 50 (1H, br s, C 1 H 4 phenO).

Rigidity Example 112

Dissolve 28 g of alpha-3-phthalimino-4- (alpha-heterocyclyl) -1- (4-methoxyphenyl) -2-oxo-kgieit in 200 µl of di-ethoxyethate. 10.2 g of p-methylhydrrzite are added to the solution. Stir the mixture for 12 hours at room temperature. The resulting crystalline precipitate is collected. The filtrate is concentrated. The cognate is broken up in 200 µl peghulentaUorIeu.

139

Subsequently, 14.8 g of polyoxyoxide and 10.62 g of carbobenzoyl oxide are added. The mixture was stirred for one hour, then concentrated under reduced pressure. The residue is purified by chromatography on a silica gel column (300 g, 1: 2 hexane / ethyl acetate: 1: 2, hexane / ethyl acetate).

Cit-3-benzzloxy-octroxyl-1- (11-methyl-ethylsilyl) -1- (4-methoxy-phenyl) -2-oxo-iodine was prepared by ^{IR (in} cm ^-1) : ^{1750, 1720} and ¹⁶⁸⁰ . ^NMR speJatnm DC ^ ¹ ^ ppm): ^1.85 (3Η, br s = 0 to 013), 3.75 (3H, s, 00) 3), 5.08 (2H, s, phenyl ^) 5.50 (1H, dd, J = 9Hz, O3-1, 6.43 (1H, br s, C5-enn1)), 7.84 (1H, d, J = 9Hz, O3-); .

Reference Example 113

In 750 ml eeeha1enyCaoridt rozpiutí with 75 g of 8-cit-beni-0IУ-ktrboχynido-44-ater-eeehalstyr ¹ l) l ¹ - ^{(4 h} -leee et aI ^{y1 n1)} · l ² lOxoatzeidint. Solution at ^t t ^{l p0} It -7 ⁸ ° C to keep ^{and P} roc ^h AZET nadbxtz ^to ozone. The excess ozone was then purged with nitrogen, and 11.6 g of die-sulfide was added to the solution. The mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure.

The residue was purified by column chromatography (400 g, 1: 2 hexane / ethyl acetate: 1: 4).

Manufactures CITL st-3-btУiylIУ karboIУrieo 4caCtt1l--L- (4-eeehaIy1etn1) - ² lIxOItzttdin, mp 188 ^- from 191 ° C. IC ektrurn (* ^ ν cm ^-1): 1760, 1720, 1700 and 655. 1 H NMR ^(CMSO-dg, ppm): 2.20 (3Η, s, COCH.-), 3.74 (3H, s, OCH 8, 5.15 (2H, s, phenyl-CC ₂ ), 5.20 (1H, d, J = 6Hz, C ₄ -H), 5.64 (1H, dd, J = 6 Hz, J = 9 Hz, C-H), 9.48 (1H, d, J = 9 Hz, C-NH).

Retention Example 114

In 50 ml boldly tcctolitti] u st 25 ml water, 1 g of cis-3-t-L4 benzyIxxykarboxteidOl et ^{1 c} II (- 1) - ^{t 2} -IУItze idint. ^R in its capacity ^and medium cooled to ^-15 ° ^{C. To} this was added trisodium nitrate (3 g) and the mixture was stirred for 10 minutes. The reaction was quenched by addition of a saturated aqueous sodium solution. The pH of the solution of st is adjusted to 5 to 6 with sodium hydrogencarbonate.

The mixture was separated under reduced pressure. The residue is acidified with 3N hydrochloric acid and extracted with chloroform. The aqueous layer was extracted with ca0 (loloreu) with ethryol (4: 1) (dvaraate), and the extracts were dried, dried over anhydrous magnesium sulphate and evaporated under reduced pressure. beat hexanes with ethyl acetate (1: 2), ethyl acetate and finally ethyl acetate (9: 1).

• KBr _- 3

Manufactures st cit-8 l ^ t ^ eni ^yl .Ix ^{yk b} lr ^ l ^ ^ol írklo 4LA ^tt ^^^ l · ^ol ^ - ^ ^ Oxx Itz ^{ZT (dd} .y. Spelatrum ^{IR (r} _max ^cm)

240, 1770, 1 705, 1 635, 1 540, 1 450, 1 380, 1 305 and 1 180. NMR spectrum ppm):

2.20 (3H, s, OOCC 3), 4.58 (1H, d, J = 6Hz, O 4 -H), 5.20 (2H, s, phenyl-CC ₂ ), 8.18 (1H, d , J = 9 Hz, C1-NH3).

Reference Annex 115

Stance of ^m ^ manner as in referetoním ^^^ du ⁶⁷ ST ^- makes sense ^{l 8 l} ^ ^C ^ ^l 2 ⁽² L ^c (L ^ ^and R ^ ^a (^ t! ^T ^ No mί ^d l ^L4L KBr lthtazI1yl ( ~ e-eeaIoxyieinItcettmidcO- -acceyl ^{4-2-IXIazzeidiy} (syn ί ^ tim ^ z). IR (V _x * m ^c m ^-1): 3350, ^1760, 1650 and 545. 1 H NMR ^ ektrum φΜβΟ -ά ^ ^pp m): 2 ^, 12 Ο) ^with COOCp ^, 3 ^{, 7} 3

7.90 (1 H, s

C).

(3Η, br s, NOCC 3), 4.35 (2H, s, CHCl 3),

Reference Annex 116

In a mixture of 2 ml of water and 2 ml of water it dissolves 75 mg of cis-3-methyl-4-hydroxymethyl-2-iodatase, which is produced according to Reference Example 53. Cooling on ice! and, with stirring, 168 mg of sodium ahydrogen monosodium salt and then 332 mg of 2-methyl- (2-trifluoromethyl) -thaatolyl) - (Z) -2-ethylhexylmethyl-carboxylate are added. The mixture was stirred under ice-cooling for one hour.

140

The reaction mixture was treated with aqueous sodium hydroxide solution and extracted with ethyl acetate / ethyl acetate (2: 1).

A mixture of ryhil c-tate and ether (1: 2) was added. The crystalline product was prepared, colorless crystals of cis-3-2 ² 2 (--Уhioaareaamidc> -9-Уhizloly -) - b-eeУOolyimCoo ^{crtlmiiol-4-yl -Уyi} УnxyImrh l- ² - ⁽ⁱ lxoalzri ICS ^{(s y} n isomer ) ^ t. ² 38 - ²⁴¹ ° ^F H (· dec).

^{Ir (ίθ} * CN ^{1): 3,400 Pa} s), ^{1 750, 1} 660 and ^{1 04} 5th ^NMR (d ^ -MSO iuclx ppm): 2.07 (13, s, OHJ, 3.89 (33, s, NOCH 2), 4.34 (23, s, J 2), 5.20 (13, dd, J = 5 Hz, J = 9 Hz, H ₃ -3), 7, 50 (13, s, Sv, 3), 9.15 (13, d, J = 9Hz, 1H-NH).

Ref-a-does Example 117

Inc ^ MSI 17 ml mbr ^{y y} ylrnc Уoridu and 6 ml of Ν, Ν-IIM-eУlfOrbmbmiiu were dissolved 172 mg of cis-3- [2- ^(2-cy loracetamido "Thiazolyl ⁴ -t ^{y)" 2-methyl-oxyiminoacetamido2} | ^y ydboxymet -4- yl ² 2 ^y "oxoazetidine (syn tnм ί ^ ^ r). 0.2 ml of pyridine was added to the solution. 0.12 ml of ^γ -eryl-ceryl-cililis was added to the mixture with ice-cooling with sodium chloride and stirring. The mixture was stirred for 30 min with cooling. UncompleteCondition is oddidtilsjd.

Aqueous sodium chloride and ethyl acetate were added to the residue and the mixture was shaken well. The organic layer was washed with aqueous sodium bicarbonate and dried over sodium bisulfate. RlopooSedel then odifdtil · sje. The residue was crystallized from ether. Recrystallization from a mixture of chlorine and methanol gives colorless crystals of cit-3I [2- ( ^2- chloro-pyrimidin-9-ylolyl) -2-methoxyiminone-e-eaidyl] -9-fluorobethoxy-b-yl-2-n-ololizine. son, tt 225 to

227 ° H (m ^/ z);

For C, 4H, ₂ g of L-N .0gO calculated: 37.17% H, 3.34% 3 15.48% N; Clz-no: 36.79% H, 3.37% 3, 15.44% H.

Reference is made to Example 118

4.45 g of cit-3-nitro-oxylbenzyl-2- (2,9-dimethoxy-benzyl) -9-phthalimino-brtilyl-2-oxoazerieics, which is prepared according to pyrrolidine, are suspended in 320 ml of potassium carbonate. Example 48 2.03 ml of hydrous hydrate are added. The Smbs were refluxed for 2 hours. After stirring, the mixture was filtered. The filtrate was concentrated under reduced pressure.

200 ml of carbon tetrachloride are then added to the filtrate. Mberrál, who remains undissolved, with ИШег ^ -. The filtrate was washed with water, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue is dissolved in a mixture of 84 ml of methylene chloride and 11 ml of N, N-dimethyl-b-thiimide.

Under ice-cooling and stirring, 5.88 ml of panpiperidine are added first, followed by dropwise addition of a solution of 2.35 g of methylbenzylsulfonic acid in 20 ml of mereylcloloid. The reaction mixture is stirred for one hour at ambient temperature, washed successively with water, aqueous sodium bicarbonate, dilute hydrochloric acid and saturated aqueous sodium chloride, and dried over sodium sulphate. The solvent and solvent are removed under reduced pressure.

The basic residue was taken up in ethyl acetate. Produced 2.94 g of the cit-3-b-czyll> xyk-rrnχr ambdco-i (2,9-iimethoxybrncyl) -9- (2-merehlsulfncylrthoxlk rrocylbminombthhl) -2-nxoolzriiic, mp 172 ^- 174 ° F H.

IC ktru ^"(in cm ^{-1): 3900, 755, 690,} 6 ^ 535 and 125. NMR (-MSCJ-d ppm): 2.97 (33, s, OO CHз _2), 3.38 (2H, t, J = 6 Hz, .delta., 3.75 and 3.77 (2 * 0 ^ 3, 2 * s, 2 * OHH ₃ ), 4.24 (23, quaternary, J = 15 3z, N ₁ -HH 3), 4.28 (23, t, J = 6 Hz, ωοα ^),

141

4.82 (1Н, dd, J = 5 Hz, J = 9 Hz, _C3-H), 5.05 (2H, s, _Ph-CH2), 7.37 (5H, s, phenyl), 8.05 (1H, d, J = 9Hz, C ₃ -NH).

Reference Example 119

In the same manner as in Reference Example 50 cis-3-benzyloxycarboxamido-4- (2-methylsulfonylethoxycarbonylaminomethyl) -2-oxoazetidine, mp 149-150 ° C, was prepared. For ^c i (j ^H 21 ^N 3 ° 7 ^S Calculated: 48.11% C 5.30% H 10.52% N Found: 47.99% C, 5.22% H, 10.37% N.

Reference Example 120

In the same manner as in Reference Example 51 cis-3 - [[2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4- (2-methylsulfenylethoxycarbonylaminomethyl) -2-oxoazetidine (syn isomer) was prepared. This product decolorizes gradually at 150-170 ° C and decomposes at 195-199 ° C.

IR _(χ y ^ cm ^): 3250, 1760, 1690, 1650 and 1 550. Analysis - for ^C i6 ^H 21 ^C1N 6 ° 8 ^S 2 Calculated: 36.61% C, 4.03 % H, 16.01% N; Found:% C, 36.48;% H, 4.08;% N, 15.92.

Reference Example 121

1.197 g of cis-3-benzyloxycarboxamido-4- (2-methylsulfonylethoxycarbonylaminomethyl) -2-oxoazetidine, prepared according to Reference Example 119, are dissolved in 3 ml of Ν, Ν-dimethylformamide, which is prepared according to Reference Example 119. 475 mg of dimethyl tert-butylsilyl- of chloride and, while cooling to 0 ° C, 0.46 ml of triethylamine is added dropwise. The mixture was stirred under ice-cooling for 30 minutes.

Ethyl acetate and water were added. The ethyl acetate layer was separated, washed with dilute hydrochloric acid, brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue is chromatographed on a silica gel column (100 g, eluting with hexane / ethyl acetate 1: 2 then 1: 3).

Cis-3-Benzyloxycarboxamido-4- (2-methylsulfonylethoxycarbonylaminomethyl) -1-dimethyl-tert-butylsilyl-2-oxoazetidine was prepared as a foamy product. IR spectrum (γ ^{cm 3} ) ^:

330, 1750, 1720 and 695. 1 H NMR (CDCl ppm): 0.26 (3H, s, SiCHg), 0.28 (3H, s, SiCH _3), 0.96 (9H, s, t butyl group), 2.93 (3H, s, SO ₂ CH ₃ ), 3.28 (2H, t, J = 6Hz, CH ₂ SO ₂ ), 4.50 (2H, t, J = 6Hz , COOCH _2), 5.03 (1H, dd, J = 5 Hz, J = 9 Hz, _C3-H), 5.15 (2H, s, _Ph-CH2), 6.18 (1H, d , J = 9Hz, _C3-NH), 7.38 (5H, s, Ph).

Reference Example 122

514 mg of cis-3-benzyloxycarboxamido-4- (2-methylsulfonylethoxycarbonylaminomethyl) -1-dimethyl-tert-butylsilyl-2-oxoazetidine are dissolved in 20 ml of ethanol. 4.4 ml of ethanolic sodium hydroxide (0.5N) are added under ice-cooling and stirring. The mixture was stirred under ice-cooling for 15 minutes.

2.2 ml of 1N hydrochloric acid were added to the reaction mixture. The solvent was distilled off under reduced pressure. The residue was extracted with methylene chloride / tetrahydrofuran. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure.

4 ml of dry trifluoroacetic acid and 2 ml of trifluoroacetic acid are added under ice-cooling. The mixture was stirred for 30 minutes, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (40 g, eluting with hexane / ethyl acetate 1: 1, then 1: 2).

Cis-3-Benzyloxycarboxamido-4-trifluoroacetylaminomethyl-2-oxoazetidine, m.p.

Mp 197-201 ° C.

142

KBr —I

IR (y _max »cm): 3,280, 1,760, 1,705, and 1,690. Analysis - for ^C 14 ^H 14 ^F 3 ^N 3 ^O 4 requires C, 48.70; H, 4.09; 17% N? Found:% C, 48.31;% H, 4.00;% N, 12.01.

Yellow crystals of by-product cis-3-benzyloxycarboxamido-4-trifluoroacetylaminomethyl-1-dimethyl-tert-butylsilyl-2-oxoazetidine are also prepared by the above reaction, m.p. Mp 130-135 ° C. IR (in cm &^lt; -1 & gt ^; ): 3,300, 1,765, 1,700 and 1,685.

Reference Example 123

In the same manner as in Reference Example 67, cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-trifluoroacetylaminomethyl-2-oxoazetidine (syn isomer) was prepared, m.p. Mp 220-225 ° C (dec.).

IR spectrum (ν max ^{cm 3} 270, 1760, 1 705 and 1660). NMR spectrum (DMSO-dd, ppm): 3.89 (3H, δ, NOCHg), 4.31 (2H, s, CICHg), δ 22 (1H, dd, J = 5Hz, J = 9Hz, Cg-H), 7.43

H).

Reference Example 124

525 mg of cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4- (2-methylsulfonylethoxycarbonylaminomethyl) -2-oxoazetidine are suspended in a mixture of 25 ml of ethanol and 5 ml of N, N-dimethylformamide. (syn isomer), which was produced according to Reference Example 119.

5 ml of ethanolic sodium hydroxide (0.5N) was added to the suspension. The mixture was stirred at room temperature for 20 minutes. Then 2.5 ml of 1N hydrochloric acid are added. Ethanol was distilled off under reduced pressure. The residue is dissolved in a mixture of 8 ml of water and 10 ml of tetrahydrofuran. Under ice-cooling and stirring, 185 mg of sodium bicarbonate are added, then a solution of 432 mg of p-nitrobenzyl chloroformate in 10 ml of tetrahydrofuran is added dropwise over 50 minutes.

The mixture was stirred under ice-cooling for 20 minutes. Water (10 ml) and ethyl acetate (20 ml) were added to the reaction mixture. Shake the mixture well. The organic layer was separated. The aqueous layer was extracted with ethyl acetate. The ethyl acetate extract and the above organic layer were combined. The combined portions were washed with brine and dried over anhydrous magnesium sulfate.

The solvent was distilled off under reduced pressure. Evaporate. recrystallized from ethyl acetate. The crystals were filtered off. Cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4- (p-nitrobenzyloxycarbonylaminomethyl) -2-oxoazetidine (syn isomer), mp 235-245 ° C (dec.) . IR spectrum (V cm ^-1 ); 3,380, 3,230, 1,760, 1,690, 1,660, 1,550 and 1,520.

Reference Example 125

In the same manner as in Reference Example 39, the following compounds were prepared.

cis-3- [D-2-44-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido] -2-oxoazetidine-4-carboxylic acid methyl ester:

KRR - 1 beta isomers ir (? _Max, cm)! 1770, 1740, 1710 and 675. 1 H NMR (DMSO-d₆, ppm): 1.11 (3H, t, J = 7 Hz, N-CH ₂ CH), 3.08 (3H, s, COOCHg), 4.30 (1H, d, J = 6Hz, C ₄ -H)

5.38 (1H, dd, J = 6Hz, J = 9Hz, Cg-H), 5.52 (1H, d, J = 7Hz, phenyl-CH-), 8.68 (1H, s,

.alpha.-isomer: IR (V ^ ax ^'cm⁻¹: 1770, 1740, 1710 and 1 670. * H NMR ^(DMSO-dg, ppm) d 1.10 (3H, t, J = 7Hz, N-CH ₂ CH ₃ ), 3.55 (3H, Sv C 0 OCH 3), 4.40 (1H, d, J = 6 Hz, C ₄ H), 5.20 (1H, dd, J = 6 Hz, J = 9 Hz, Cg-H), 9.25 (1H, d, J = 9Hz, Cg-NH), 9.80 (1H, d, J = 7Hz, phenyl-CH-NH).

143 cis-3- [D "2- (4" ELHY З- _L-22 (L-jixdo pepazattlkiobxlamrdo) 22feonylacelanaró] -4-methyl-2I -dxoalztidio:

1 H-1 beta-isomer: IR spectrum (ν max cm ^-1 : 1,750, 1,710 and 1,670). UR spectrum (DMSO-d6, ppm): 1.15 (3H, d, J = 4 Hz, 1 (C ^).

alfl- ^with oontr: ^IR spetorum (V ^ ax 'cm ^-1): 1 ^{76 0,} 1 ⁷¹⁵ and 1 690. ^I M ^R spetorum (IDC ^1,. ppm): 1.39 (3H, d, J = 4 Hz, C ₄ -.

cis-3i [D-2- (4-Ethyl-2,3-radox-1-piperidyllaxyl) -O] -2-sulfonylamino-1,4-ethoxymethyl

-2-dxoalzSarao:

^ taiisomer: I ^C spectrum cm ^{- -)} 1 0 ⁷⁷ 1 ⁷ 10 1 ⁷ 6 °. IMR with ^p ektrum (IDCI ^3, ppm) .: 1.8 5 (3H, s, JCJCH3).

alfl.-πSdontr: IR spectrum .mu.m / cm @ -1 1770, 1720 and 1767. @ ₁ H-NMR (CDCl3, ppm): 1.90 (3H, s, KCO3).

Reference Example 126

300 mg of D-2 - [- 3 - [(furo-2-allyl) -2-dihydro-1-amido] di-1-amido] -dibenzoyl] -oxifluoroacetic acid were treated with 110 mg of methyl tert-butyl-3-carboxylic acid according to the method of Example 39. jmiodI - ^{2 and} O- -dXoalztir ⁴ -kl.r ⁱ⁾ dx ^y Loo ťsel.o ^é '. Prepared ^^ methyl ester of cis-2- ^i3-- D ^-3 - ^(f shitting · I ² -II ^{R 2} nioo ^about I idx (d - ^d Laim imidazole dan ^l ai ^{r d r} d xlana] ^-2H FTO ^yd lcttlni ^r d ^dI2I dXda'ie ^{ra t} i on -karbdxy ^-4 dv ^{d é} Ο ^ ι ^ (^ ^{1π .ο} '.

Beta-isomer: ^IR (tm) (cm ^-1 ): 1760, 1720 and 1660.

IUclX

VDv _ Ί

Alpha-and-lOC ^ m ^ r: ^IR spektirum ⁽ _'χ -1 * cm) 1 770, 1 720 and 1 660th

In the same manner as described above compound was prepared náileddUíci: neehhčester clsi3- | d-2- [3- ⁽² tliddtn- -l dim ^{r 0 2} O- -oxd- ^{I m} m ^{r 0 t} lzdoli nkar xlanl ^{d y} d] ^I2 Ifet ^yl acetanilides ^{d r} o - ² IdXoazztarao 4-klLri) dxylooi acid.

Beta-Isomers: ^IR spectrum (? Max 'cm ^{-): 1 765,} 1 ⁷²⁵ and 1 ^{66 of} the 0th

Alfι ^^^ γ: spektrim IR (cm ^-1): 1770, 1720 and 1 660th

Reference Example 127

The 3-amino compound (which was prepared from 0.8 g of cas-3-benzyloxycarboxamado-2-dioxazetarao-4-pyridoxylic acid nehltster by the same method as in Reference Example 3) was dissolved in 10 ml of tetrahydrofuran. While cooling with ice and stirring, 1.2 ml of treelone is added. To this was added dropwise a solution of 1.2 g of 2- (2-chloro-acetamide-4-haloxy-2-ritrlyl-10-o-o-oodoacetyl) chloride in 10 ml of rttralyrfurlou.

The mixture was stirred at ambient temperature for 2.5 hours. Tetrlhyrrofuran is diverted. Water was added to the residue, and the mixture was well washed. The organic layer was separated, washed with saturated aqueous sodium chlorine, and dried over anhydrous sodium sulfate. The solvent then dissipated.

The residue is purified by column chromatography on a siltaacel column (95: 5 mixture of chilled water and methaool). Produces п ^ И ^ 1 ^ У | ^ £ ^ 111: cis cis-3i [2- (2-chloro-stamdro-4-thyloyl) - 2-Dithlylphosphonacetamidine] 12-dioxidetirin-4'-carbonyloxy acid.

IR ^with p ^{<t] tr) zum} (£ * in cm ^{"1): 3250, 1770, 1750,} 1685, 1540, ^1230, 1 050 and 1 025th

144

Reference Example 128

The 3-amino compound (prepared from 0.8 g of cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid methyl ester in the same manner as in Reference Example 3) was dissolved in 20 ml of tetrahydrofuran. 0.42 ml of triethylamine and 0.56 g of 3-triethylluilyl chloride were added successively with ice-cooling and stirring.

The mixture was stirred at room temperature for 3 hours. The tetri-hydride is distilled off. Water and ethyl acetate are added to the evaporator. The phase is stolen. The organic layer was washed with water, saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.

The residue was recrystallized from ether / ether. The crystals are not filtered. Methyl-3- (2-trans-methyl-llyl-3-ylbenzyl) -oxo-20-oxoazstedine-O-diabenzylic acid was prepared, m.p. Mp 143-145 ° C.

IC spectrum (ν max cm -1) 3,260, 1,790, 1,750, 1,640, and 1,540. Calc'd for ^C 14 ^H 26 ^N 2 ^O 4 ^S 1: C 53.47, H 8.33, 91% N; Found: C 53.54, H 8.40, N 8.73.

Reference Example 129

5.01 g of 2,4-dimethoxybenzylimine are dissolved in 100 ml of carbon black. To the solution was added 4.2 g of trans-tin-mylaedehyei and 30 g of anhydrous magnesium sulfate. The mixture was stirred at room temperature for 3.5 hours. The reaction mixture was then filtered. 8.4 ml of triethylimil are added to the filtrate under ice-cooling and stirring.

A solution of 7.0 g of dimethyliminoacetylcelline in 50 ml of carbon black was added dropwise over 30 minutes. The mixture was stirred at room temperature for 2.5 hours, washed with water, dried over anhydrous sodium sulfate, and the mixture was concentrated under reduced pressure. To the concentrate was added 50 ml of chloroform. The precipitate was ldeilirljs.

The filtrate was evaporated and the residue was passed through a silica gel column (30 g). The eluate was evaporated and the solid residue was recrystallized from silica. Prepared cis- _and t ^ of lmiel-4- (E) -styrrl-l- (2,4o ^e imethon ^χy beíyl) -2-dii onxniěS ^i, tot. 1 ⁷³ and ^from 177 ° C.

vn *. - 1

IC spektrxm (V ^ ax '· cm)' 1750, 1720 and 1 390. For ^C 2 g ^H 24 ^N 2 ° 5: calculated: 71.78% C 5.16% H 5.88% N Found % H, 5.11;% N, 5.85.

Reference Example 130

5 g of cit-3-phthalimiel-4- (E) -styryl-1- (2,4-dimethoxyphenyl) -2-nitroacetyl is dissolved in 150 ml of tstrahyerofuriil. 2.5 g of 10% palladium per needle was added to the solution. The mixture was stirred for 30 minutes in a hydrogen atom. The catalyst was separated. The filtrate was rotten under reduced pressure. The concentrate was crystallized from ether.

The crystals are not filtered. Prepared cit 4.8 g · 3-ftalimielo3o (2ofsillsiУylj1- (2,4-dimytho nxybbeíyl)) · 2 · onxoaizSieiii, mp 148-150 ^o C. ir (m ^Ry, · cm) 1 750 1720 and 1 390. For C 28 ^H 26 ^N 2 ° 5: calculated: 71.47% C, 5.57% H, 5.96% N; found: C, 71.55;

H, 5.45; N, 5.75.

Reference Example 131

4.1 g of cis-3-phthalimido [4- (2-sulfonyl) -1- (2,4-dimethoxybenzyl) -1-o-o-sidinidine] are dispersed in 35 ml of dimethoxyethyl, and 1.4 ml of methylhydrazine is added and the mixture is allowed to stand for 3 days. The resulting precipitate was separated, the filtrate was evaporated (evaporate with ricotta in ethyl acetate) and the solution was extracted three times with dilute hydrochloric acid.

The pH of the solution was adjusted to 7-8 by the addition of sodium bicarbonate. The solution was extracted three times with chloroform. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue is dissolved in 50 ml of methylene chloride. Propylene oxide (20 ml) was added to the solution, and carbobenzoxy chloride (3 ml) was added dropwise.

The mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure. The residue was chromatographed on a silica gel column, eluting with a 1: 1 mixture of chloroform and ethyl acetate. The solvent was then distilled off and the residue was crystallized from ether. The crystals were filtered off. Cis-3-Benzyloxycarboxamido-4- (2-phenylethyl) -1- (2,4-dimethoxyberisyl) -2-oxoazetidine, m.p. Mp 150-152 ° C.

IR spectrum ^(KBr, cm ^-1): 3300, 1760, 1680, 1535 and 1 265. For C _oo H N ₉ 0 _{0A C.} Calculated: JU IUciX from about £ D

% C, 70.86;% H, 6.37;% N, 5.90; Found:% C, 70.68;% H, 6.44;% N, 6.09.

Reference Example 132

In the same manner as in Reference Example 2, cis-3-benzyloxycarboxamido-4- (2-phenylethyl) -2-oxoazetidine, m.p. Mp 173-175 ° C. IR spectrum .nu.max ^cm: 300, 1770,

685, 1540 and 1 260. For C _g H _{2 ()} N ₂ O ₃ Calculated: 70.35% C, 6.22% H, 8.64% N; Found: C 70.13, H 6.05, N 8.48.

Reference Example 133

In the same manner as in Reference Example 67 cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4- (2-phenylethyl) -2-oxoazetidine (syn isomer) was prepared.

IR (in cm &^lt; -1 ^&gt; ): 3260, 1740, 1700, 1650 and 1440.

Reference Example 134

9.6 g of 2-methoxyiminoacetacetic acid methyl ester are dissolved in 40 ml of chloroform. While stirring at 40 ° C, a solution of 9.1 g of bromine in 10 ml of chloroform was added dropwise. The mixture was stirred for 20 minutes. It is then poured into ice-water. The organic layer was separated, washed successively with saturated aqueous sodium bicarbonate, water, and dried over anhydrous sodium sulfate.

The solvent was distilled off under reduced pressure. 13.12 g of methyl ester oil are obtained

4-bromo-2-methoxyiminoacetacetic acid.

To 40 ml of ethanol was added 10.74 g of this oil and 4.4 g of thiocarbamic acid methyl ester. The mixture was refluxed for 1.5 hours. Ethanol was distilled off. The residue was dissolved in chloroform, washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Crystals of 2- (2-hydroxy-4-thiazolyl) - (Z) -2-methoxyiminoacetic acid methyl ester, m.p. Mp 97-98 ° C. IR spectrum (cm -1 720),

670, 1440, 1260, 1150 and 040. 1 H NMR (CDC1 _3, ppm): 3.93 and 4.03 (2 x 3H, 2 x s, _COOCH3 and _NOCH3), 6.35 (1 H , s, S (H).

Reference Example 135

1.0 g of 2- (2-hydroxy-4-thiazolyl) - (Z) -2-methoxyiminoacetic acid methyl ester is dissolved in 3 ml of ethanol. 5 ml of aqueous potassium hydroxide solution (1.3 g) are added dropwise under ice-cooling. The mixture was allowed to stand for 4 hours, the pH was adjusted to 2-3 with 1N hydrochloric acid, and the solution was extracted three times with butanol. The extracts were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.

146

This i> st ostupcm vtoobí tan i ^ rá.šeO 2- (2-t-PydeolχtO] li-thiazolyl) '(Z) 2 - ^and metPoxyo einooctov tyskl.n ^{s 1,} t. t. ¹⁴³ to ¹⁴⁵ ° ^C (ιόζΚΙ.). ^IC ektrum

620, 1450, 1170 and 1040. NMR .alpha.-NMR (DMSOd6, [delta]): 4.02 s, S-11), 11.76 (1H, s, COOH).

Λ (λ max, cm ^-1 -: 1740 1690 (3H, s, NOCC)), 6.79 (1H,

Reference Example 136

In the same manner as in Reference příkCiddu 34 cis-3- [2- ^(2-y Р drouχl4-tРi Zuo-diyl) 22-meРloxyimnnolckt-eΐdo] ^"4 omethoз: χtо-relul'l2-oxolLlzktdin (syn i.tlr ^ k), mp 202-204 ° C ^- (Rozzi.). 1C ^SOE khru ^{m (cm-1):} 3 26 ^ ^{1775, 1735, 1685, 1660,} 1 52 ^ ^1440,

220 and 1040. NMR Spectrum (DMSOd6 ppin): 3.50 (3H, s, C-CH3), 3.86 (3H, s, NOCH.-), 4.33 (1H, d, J = 5 Hz) C4-D, 5.25 (1H, dd, J = 5Hz, J = 8 Hz, 6.23 (1H, s, S), 8.53 (1H, bs s, J = ^{9) ,} 33 (1) ^e, J = 8 C ^ N). 'i

Recreation example 137

In 150 ml of methanol, 2.14 g of cis-3-ethoxyquoxycyclohexane-2,4-methyl-2,4-methyl-4-ketone Otsecins are obtained according to the reference Olaf 1. 25 ml of an aqueous solution of potassium carbonate (0.83 g) was added with stirring and stirred for 6.5 hours at room temperature.

The MetPanoi was removed under reduced pressure. Water was added to the residue, and the mixture was poxed with ether-ether. The solution was treated with 1N hydrochloric acid. The sc-Z (^ i ^ U 'St ocdfltruje, poo ^^^ is water and dried. 1.95 g Manufactures st cit-3-etuzyluxyO reoxxaide-1- (2,4-eimetРoxy ekiyl ^yl) - -2-oxoo ^ztiein--4 - ^{k e} -o oχ hunting ^{t e} ^ Sehn ^'t .t. 191 ° C.

IC ektourn (V ™ I ^{O1 (cm -1):} 3 3 ° ⁰ 1 760 1 705 1 690th

Reference Example 138 '

4.1 g of cit-3-ecuzyluxycaroxcaide-11 (2,4-ethoxy-oxyethyl)) - 2-oxo-oxyl- ⁴ -κ-reloxyl octecins are dissolved in 80 ml of dry tetrabydrofuran. To the solution of st add 4 ml of Oysecint chloride. The mixture was refluxed for 30 minutes. The solvent st odedetilfje. The residue is washed with bexantine and dissolved in 80 ml of methylene chloride.

While cooling with ice-water, 4 ml of methanol are added and the mixture is stirred for 20 minutes. Rozppuftёdlu se paO ldeeetilfjk. The residue was crystallized from ether. The crystals were separated. Prepared colorless Ootstalt the ethyl-3-cit-etnztluxyk reoxxaide if (2,4-dieethooχlekiyl'-2- ⁽⁴ lxollztio eiu- -OR ^e · ux ^those UVE ^о χse ^ei u ^{y O} TTR ^{s p} o cekrysUHzaci kt from anol ^{p p} s II melts ⁷ and ¹¹⁸ ° C.

^{1C (} etorum cm ^-1 ): ^{3 25} 0 1 ^{1 735} and ¹ 68 ⁰ . ^P ro ^C2 3 ^H 26 ^N 2 ° ⁷ read:

% C, 62.43;% H, 5.92;% N, 6.33; N, 62.43; H, 5.91; N, 6.05.

Reference Example 139

In the same manner as in Reference Example 2 We prepared etbyltster cit-3-bkuzyloxyO oeuχo and ^ ^e ^ e ^ i u ^o 2 ^ (^ ^ LCC uazk ^t (j ^ ⁱ ^ ^o ^ no4- -l: ^e ^ ^y ux l ^ v ^ e ^ Sehne 'tt ¹³⁴ and ^{1 35} ° C. with ^iC ^ ktrum (V CE3 ^O1, cm ^{- 1):} 3300, 1800, 1740 and 1 720. For Ci4H1 _{5 6} N2 calculated % C, 57.52;% H, 5.51;% N, 9.58;% C, 57.58;% H, 5.44;

Reference Example 140

In the same manner as in Reference ORIO AEF-3 was prepared etbyltstec cit-3-aeiuo-2 · L) XU-Zeo ^t id ⁱ n4 ^- о ^- aebux hunting ^{t é Oy ki} n ^y, mp ¹⁰⁵ and ¹⁰⁶ ° ^{C. (} OC ^Ol) . ^iC - ^- ^ ectrum ^(V аа ° ° ^m):

400, 3200, 1745, 1720, 700. 1 ^H 1o for CE 2-3 ^N calculated: 45.56% C, 6.37% H, 17.71% N;

Found:% C, 45.66;% H, 6.20;% N, 17.70.

147

Reference Example 141

In the same manner as in Reference Example 4 ce, the following compounds were prepared:

Cis-3- [2- (2-Chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -2-oxoazetidine-4-carboxylic acid ethyl ester:

syn-isomer: mp 280-283 ° C (dec.). IR spectrum (cm ¹ ): 3230, 1750,

Шал

730 and 670. 1 H NMR (DMSO-d₆, ppm): 1.20 (3H, t, J = 7Hz, CH ₂ CH _3), 5.73 (1H, dd,

Hz, J = 9 Hz, Cg-H), 7.42 (1H, s, SyH).

anti-isomer: mp 108-110 ° C. IR ([nu] D- ⁰¹ , cm &^lt; -1 ^&gt; ): 3,250, 1,760, 1,720 and

650. NMR (DMSO-d₆, ppm): 1.20 (3H, t, J = 7Hz, CH ₂ CH _3), 5.50 (1H, dd, J = 5 Hz,

J = 9 Hz, Cg-H), 8.00 (1H, s, S)

Reference Example 142

2 g of cis-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -2-oxoazetidine-4-carboxylic acid, prepared according to Reference Example 137, are dissolved in 60 ml of dry tetrahydrofuran, and 2 ml of acid chloride are added to the solution. šřavelové. The mixture was refluxed for 30 minutes.

The solvent is then distilled off. The residue is washed with hexane and dissolved in 40 ml of dry tetrahydrofuran. Aniline (1 mL) was added to the mixture under ice-water cooling, and the mixture was stirred for 30 minutes. The resulting crystalline precipitate was filtered off and washed first with ether and then with methanol. Cis-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -4-phenylcarbamoyl-2-oxoazetidine is obtained, which melts at 255-257 ° C after recrystallization from chloroform-methanol.

IR spectrum (cm ^-1): 3250, 1760, 1690 and 1 670. For _the C ^ H ^ _o ^ N 0 Calculated _C:

% C, 66.24;% H, 5.55; Found:% C, 65.80;% H, 5.34;% N, 8.43.

Reference Example 143

In the same manner as in Reference Example 2, cis -3-benzyloxycarboxamido-4-phenylcarbamoyl-2-oxoazetidine, mp 235-238 ° C (dec.), Was prepared. IR spectrum (cm ^-1 ): 3270,

760, 1690 and 670. 1 H NMR (DMSO-d₆, ppm): 4.4 (1H, d, J = 5 Hz, Сд-Н), 5.0 (2H, s, _Ph-CH2) 5.15 (1H, dd, J = 5Hz, J = 9Hz, Cg-H).

Reference Example 144

In the same manner as in Reference Example 3 cis-3-amino-4-phenylcarbamoyl-2-oxoazetidine, mp 152-154 ° C (dec.), Was prepared. IR spectrum (cm ^-1 ): 3300, 1740 a

690.

Reference Example 145

In the same manner as in Reference Example 4 cis-3- [2- (2-chloroacetamide-4-thiazolyl) ^{-2-methoxyimino:]} -4-phenylcarbamoyl-2-oxo-azetidine (syn isomer). Nuclear Magnetic Resonance Spectrum (DMSO-d6, ppm): 3.53 (3H, s, NOCHg), 4.3 (2H, s, CHCl3), 4.48 (1H, d, J = 5 Hz, Cd-N) , 5.57 (1H, dd, J = 5 Hz, J = 9 Hz, _C3 -H).

Reference Example 146

2.502 g of cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid methyl ester, prepared according to Reference Example 2, are dissolved in 160 ml of methanol.

148 ml of aqueous potassium carbonate solution (1.242 g) was added with ice and stirring. The mixture was stirred at room temperature for 70 minutes,

9 ml of 1N hydrochloric acid are added under ice-cooling and stirring. Meeiianol se. desalcates under reduced pressure. The remaining aqueous solution was washed with ethyl acetate and the solvent was distilled off under reduced pressure. The residue is chromatographed on a Drtoerll WkD-II column. The eluate is lyophilized.

A colorless powder of cis- ^3- benzyloxy-cyclohexanone between 1-oxazoline-4-triethoxylate is prepared. ^No. 1 with ^p ekt.rim (V ^cml1): 1770, 1755, 1705, 1675, 1590 and 1410, one 320th

NMR (DMMSoI _6, ppm): 3.82 (1H, d, J = 5 Hz, C ₄ -H), 4.78 (1H, dd, J = 5 Hz, J = 9 Hz, CjiH · 5 Δ (2H, s, CH 2), 7.29 (5H, s, phenyl protons, 7.31 (1H, d, J = 9 Hz, C 1 H -H), 8.26 (1H, broad singlet, Ν) --Η).

Reference Example 147

In 5 ml of N, N-dimethylformamide was dissolved 717 mg of cis- ^3- benzyl-zinc-cycloboxamido-2-z-tertaridine-4-carboxylic acid (as potassium salt). 0.25 ml of ethyl bromoate are added under ice-cooling and stirring. The mixture was stirred at room temperature for one hour.

Water (50 ml) was added and the solution was extracted with water. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure with oddertils. Ether was added to the solid residue. Filtration gave colorless crystals. C 18-3 -benzyloxycarboxamoyl-4-methoxycarbonylmethylamino-2-oxoxateine, m.p. · 109 to. 111 ° C.

&Lt; 1 &gt; C spectrum (cm &lt; -1 &gt;): 3,350, 3,260, 1,775, 1,765, 1,750, 1,710 and 1,675. -.

For C ^ H ^^ O? calculated: 54.86% C, 5 (18% H, 8.00%; found: 54.90% C, 5.24% H,

7.79% N.

Reference Example 148

In the same manner as in Reference Example 67, cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methylpyrimidine-cetido] -4-ethoxycyclobonylmethyloxylcarbonyl-12-oxoateine (syn isomee) was prepared, m.p. Mp 226-231 ° C (dec.). @ 1 C spectrum (.delta., Cm @ -1): 3270, 1765, 1750, 1690 and 1670. Calcd for C18H18ClNgOgS: 40.38% C, 3.81% H, 14.72 % N; Found: 40.08% C, 3.97% H, 14.51% N.

Reference Example 149

Ether was added to the trans-3-benzyloxy-cyclohexanediyl- (2,4-ethoxy-ethyl) -2-oxo-triazine-4 H -carboxylic acid mercapto-3-benzyloxy-cyclo-box prepared by Reference Example 26. The mixture was allowed to cool. On standing, crystals precipitated which were aspirated and washed with water. Colorless crystals were obtained, m.p. Mp 65-68 ° C.

For ^С 22 ^ 24 ^ 7 2 ^{М у УР о епо ^:} 61.67% C, 5.65% H, 6.54% N; Found:% C, 61.84;% H, 5.48;% N, 6.36.

The above product was reduced by treatment with sodium borohydride in the same manner as in Reference Example 5. The product was obtained and was obtained by column chromatography (eluting with 1: 4 hexane / hexane). . A colorless oil of trans- (1,3-benzyl) oxycarboxetide-1- (2,4-dimethoxy-β-β) -4-hydroxymethyl-12-oxo-oxidine is prepared.

1C ektrxm ^{p (in} cm ^{-1): 3 0} ° ^{4, 3325, 1} 740 * ^(Si y P ^{with mesh) and 1 030th}

149

2535.65

Reference Example 150

5.8 g of trans-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -4-hydroxymethyl-2-oxoazetidine are dissolved in 50 ml of methylene chloride. 2.29 g of pyridine and then 1.54 ml of acetyl chloride are added to this solution under ice-cooling and stirring. The mixture was stirred at room temperature for one hour.

The solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with 3N hydrochloric acid, aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.

The residue is dissolved in 300 ml of acetonitrile. The mixture is refluxed. An aqueous solution containing 5.87 g of potassium persulfate and 3.78 g of potassium hydrogen phosphate is added dropwise. After the dropwise addition, the mixture was refluxed for one hour. The acetonitrile was distilled off under reduced pressure. The remaining aqueous solution was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate and then brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (140 g, eluting with hexane / ethyl acetate 1: 2).

Trans-3-benzyloxycarboxamido-4-acetoxymethyl-2-oxoazetidine, mp 119-121 ° C, was prepared. IC spectrum (ν max * ^cm -1 ^{): 3 245} ' ^{1 750} ' ^{1 725} ' ^{1 705} ' ^{1 550} ' ^{1 270} ' ^{1 250 and 1} ° ^35,

Reference Example 151

In the same manner as in Reference Example 67, trans-3-L2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido-4-acetoxymethyl-2-oxoazetidine (syn isomer) was prepared, mp 177-190 ° C (dec. ). IR spectrum (νmax ^cm): 3160, 1735, 1710, 1640, 1565 and

040.

Reference Example 152

18.3 g of trans-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -4-hydroxymethyl-2-oxoazetidine are dissolved in 50 ml of pyridine and 5.76 g of methanesulfonyl chloride are added under ice-cooling. The reaction mixture was added to ethyl acetate and the mixture was washed with 6N hydrochloric acid, then with aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.

This residue was dissolved in 400 ml of methyl ethyl ketone. Sodium iodide (34.25 g) was added to the solution. The mixture was heated at reflux for 2.5 hours. Then, the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate. The solution was washed with saturated aqueous sodium sulfite, brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. By this procedure trans-3-benzyloxycarboxamido-4-iodomethyl-1- (2,4-dimethoxybenzyl) -2-oxoazetidine oil is obtained, IR spectrum <V cm ^-1 ): 3 300, 1 760, 1 710, 1 605, 1 510, 1285, 1260 and 1210.

NMR (CDC1 _3, ppm): 3.78 (6H, s, 2 x _OCH3), 5.00 (2H, s, Ph-CH), 7.28 (5H, s, Ph).

Reference Example 153

In the same manner as in Reference Example 63, trans-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -4-methyl-2-oxoazetidine was prepared. This compound does not crystallize. It was therefore purified by silica gel column chromatography (350 g, eluting with hexane / ethyl acetate 2: 1, then 1: 2).

150

IR (cm ^-1 ): 3280, 2950, 1750, 1710, 1 605, 1 505, 1 260, 1 210.

IUaX

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 1.20 (3H, d, J = 6 Hz, C ₄ -CH ₃ ), 3.75 (6H, s, 2xO 2, 4), 5.02 (2H, s, Ph-CH =), 5.55 (1H, dd, J = 6 Hz, J = 8 Hz, C-H) _f 7.21 (5H, s, Ph) and

Reference Example 154

Trans-3-benzyloxycarboxamido-4-methyl-2-oxoazetidine, mp 109-111 ° C, was prepared in the same manner as in Reference Example 66. IR (cm ^-1 ): 3220, 3220, 1780,

690, 1 535, 1 450, 1 265, 1 045 and 730.

Reference Example 155

In the same manner as in Reference Example 67, trans -3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido-4-methyl-2-oxoazetidine (ethylene isomer) was prepared, mp 240-248 ° C (dec. ). IR (V, Cr, and ^1: 3330, 1740, 1680, 1665, 1575, 1540, 1355 and 1 045th

Reference Example 156

140 mg of cis-3-benzyloxycarboxamido-4-methoxycarbonyl-2-oxoazetidine are dissolved in 1.4 ml of dry tetrahydrofuran. 0.1 ml of a 40% methylamine solution and one drop of acetic acid are added to the solution. The mixture was allowed to stand in the cold (5 ° C) for four hours. The resulting crystalline precipitate was filtered off and washed with ether.

Cis-3-benzyloxycaroxamido-4-methylcarbamoyl-2-oxoazetidine is prepared which melts at 207-208 ° C after crystallization from ethyl acetate-methanol. IR (V ^ ^ Ηχθ "dm" ^1): 3270, 1770, 1700 and 660. 1 H NMR (DMSO-d₆, ppm): 2.56 (3H, s, J = 5Hz, NHCH ₃ ), 4.13 (1H, d, J = 5 Hz, C ₄ -H), 7.33 (5H, s, phenyl protons), 8.33 (1H, d, J = 5 Hz, s, Ph ), 8.33 (1H, d, J = 5Hz, NHCH3).

For ^C 13 H ₁₅ N ₃ O ₄ Calculated: C 56.30, H 5.45, N 15.15; Found: C 56.17, H 5.31, N 15.23.

Reference Example 157

831 mg of cis-3-benzyloxycarboxamido-4-methylcarbamoyl-2-oxoazetidine are dissolved in a mixture of 50 ml of tetrahydrofuran and 50 ml of methanol. 830 mg of 5% palladium on carbon was added to the solution. The mixture was stirred under an atmosphere of hydrogen for one hour. Catalyst sq. filtered.

The filtrate was evaporated under reduced pressure. 410 mg of a colorless powder of cis-3-amino-4-methylcarbamoyl-2-oxoazetidine are prepared. IR (in .nu.max. ^{01 cm} @ ^-1 ) ^: 3030, ^{1750 and} 1650. ' NMR (DMSO-d₆, ppm): 2.70 (3H, d, J = 5Hz, NHCH _3), 3.96 and 4.23 (2 x 1H, 2 xd, J = 5Hz, C ₃ - H and C ₄ -H).

This product (320 mg) was dissolved in a mixture of 6 mL of water and 6 mL of tetrahydrofuran. To this solution was added 500 mg of sodium bicarbonate. 960 mg of 2- (2-chloroacetamido-4-thiazolyl) -2- (Z) -methoxyiminoacetyl chloride hydrochloride are added under ice-cooling and stirring.

The mixture was stirred for one hour. Tetrahydrofuran was distilled off. The remaining mixture was filtered. The resulting powder was washed sequentially with aqueous sodium bicarbonate, water, ethanol, and ether. Cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-methylcarbamoyl-2-oxoazetidine (syn isomer) was prepared.

IR spectrum 2.50 (3H, d, J =

7.28 (1H, s, ^s x ^(V max ° ^{1f 3 220} ' ¹⁷⁵⁰ ' ^{1700 and 1660} ) ^NMR Spectrum (DMSO-d 6, ppm): 5 Hz, NHCH 3), 3.76 (3H, s) (NOCH 3), 5.3 (1H, dd, J = 5Hz, J = 9Hz, C ³ H), H), 7.8 (1H, d, J = 5Hz, NHCH 3), 8.3 ( 1 H, br s, _{χ χ} -Η).

151

Reference bow

The procedure of Reference přídaíu 91 that is used melhlкester trans-3-blniylotykarb (4-lXívπiíín22ontnteteíín karbonχkntu place níppnVííjící II -t0ouilniny. Prepared she became ^kk r ^{y y 3} trans - N- ^{(2 H} -CH oratietLliio- ^l- 4hilZl) i ⁿ l) -2 - lk - itl ^y hkk- · ppnitr ⁿ blnz ^y l <lx ^y carbon ^nk) lt ^lk lot ^y iein (^ acetamiic ⁿ -4-eilhh> n ^ty kaboo L'-K2 ^to ONC:) ntitiíinu (s ^y n ^y somite), mp 110-120 ° C ^IR spedrum (у cm ^{-1): 3} 2 ⁸ 0 'for H ₂ ² ₂ 3 H 3 Cl ^ NgO3gS calculated: 45.21 % H,

13.14% N.

980 '1 790 ^- ž 1 740' 1 680 ^and 1 525.

H, 3.79; N, 13.76. Found: 45.60% H, 4.14% H,

Reference bow 159

In the same manner as in reference case 81, the following icing is produced:

Ν- ⁽¹ -methyl ^l hh) · ^y n ^{t r} ca boil-l ^{- ly} -iet LLT lnty ^h) IT LIMITE TT ^{106 from 107 m_1 C)} 2 90 ^° 2996 ⁰ · H ^^% 40. Píro H ⁷ C ^ H ^ ^ype octene in NOG% 59.1% found: 59.60%, H, 98% H, 5.22% N.

° ^H , ^γH spectrum, C, 4.98%; 5.32% N% ·

IR spedrum (ν ^ _χ ^,

790% H, H75. HMM H ^ edum% CCCHg ^pp m):? 10 (% HH s, SiMe _3%, 0.92) 2H, t,

4.31% 2H, t% · J = 9Hz COOCH _2%) 7% 73 _R ((H, s% ARN-atУiN "[k-k ielhlk. · ((2-tiime · ^y hh: yklell0htkclarblnkl) ι ι ^ ^^ οχ!.! - chromatography. ^c m ^-1): 2940

J = 9 Hz, Cl 2 Si), 1.62 (6H, s, NOCMm ₂ ) (protons).

Reference bow 160

In the same manner as in Reference Additive 82, the compound compounds are produced:

0- ^(1-tk πielhho cabbn ^kik L - H ^LK et ^LKK) rnxk ^hyd ^ min. ^IR spedrum ^(V ^ ax ^ ^{'c-1): 3325,} 2980, 2950, 735. 1 H NMR (CDC ^, ppm): 1.43 (6H, s, CMe _2), 3.75 ( 3H, s, SO 2 N, 5.33 (2H, br s, NH ₂ ).

¹ - ^{K1 (2} '· ^tri ILT ^lyk those ^{alkyl ln} e ox ^{y C} ar ^b nn ^yk) LT ^LKK] ^ droxyladn. ^iC spedrum ^{iv u} ^ ^{tc m) cm -1):} 3 ° ^52, 2950 ^and 730. 1 H NMR ^{PE y} trum (CDC ^ ^pp m): ^0, 10 ^(9), SiMe ^{^,} 1.12 (2H, CH ₂ Si), 1.45 (6H, s, NHOH), 4.25 (2H, t, J = 9 Hz, HOCOC)), 5.12 to 5.43 (2H, broad band, nh ₂ ).

Reference bow

In the same manner as in Reference Example 83, the healing compounds are produced:

2- (2-chlnrlceealm ^di-4-yl thhУlil kk-2- (1-eeltlotkcabboil l · -ietl llthntyieУnn ^yl) acetic KYSE to ^{ki. Ir (χ} ^ c ^ m ^{1): 3 2} 00 2 ⁹⁸ 0 1 75 ° ⁶⁸ ° 1 tower. spedumi NMR (CDC13, ^p pm): 1.58 (6H, s, СМв)), 3.72 (3H, s, ^ dOKC, 4.3 (2H s, CILCH) -, 7.33 (1H, s, quinolin-5-H).

2- (2-Chloro-thienyl) -22Γ-1-methyl-1- (2-triethylthiocylthioxycarbonyl) ethine (1-amino) acetic acid. IC spectrum ( _{ν max} ) cm: 3420, 2960, 1740 and 1730.

Reference bow 162

In the same manner as in Reference 84 was prepared přídaíu ^кd ronihorií l 2- (2-il ^to nraiet шni ^d IN4 ^"to the tthalil) -2 · ^(1-a R ^b ieehlntk onniyl · k · mithl ^to elhlntkminn) ^to acetl - Chloride, mp 105 to 105 ° C

115 ° H. IR (cm ^-1): 2980, 1790, 1745 ^and 700. 1 H Pr ^{of 1} H _{2 13} H1 ₂ N ₃ O ₅ S.HH1 calculated: 34.42% H 5.59% H 10.03% N; Found: 34.94% H, 3.46% H, 10.21% N.

152

Reference Example 163

In the same manner as in Reference Example 85, chit-6- [2- (2-chloroacetamoyl-4-thiazolyl) -2- (1-mmShoxyl) -benzon-4-methoxy-4-methoxy-4-methoxycarbonyl-oxo-azetoline (syn. Form) was prepared. Mp 212-214 ° C (dec.). -1

VR Ί (C, cm cm): 3 300, 3 08 °, 2 975- 1 780 to 1 750, 1 720 and 1 660. ',

For C 11 H 16 ClN 6 O 6 O: calculated: 41.68% C, 4.12% H, 14.30% N; Found: C 41.47, H 4.14, N. 14.06%.

Reference Example 164

820 mg of (- (chloroacetamide) 44 - (2-chloromethyl) -1c (- (trimethylcyclohexyl) hexyl) ethyl acetate was dissolved in 25 ml of methylene chloride. 221 mg of triethylamine and 380 mg of photo-chloride were added to this solution under ice-washing. '

The mixture was stirred for 15 minutes while cooling with ice and 2 Codines at ambient temperature. The reaction mixture was stirred. Concentration under reduced pressure is thus obtained. The residue was dissolved in a 5% solution containing C ^ loíOri kyseliny kyseliny acid.

ml water dissolution 219 mg cis-3-eminaddition 638 mg sodium cdyrogeenCitrate ·

In addition, the mixture was stirred in a mixture of 5 ml of hydrogen chloride and 10 -4-methoxycarbonyl-2-oxylphosphine. Ice cooling followed by one Codine at room temperature, the solution was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate, and the solvent was removed.

1- [3- (chloro-ethanamide OC-hCazoO1) -1c [1-methyl-1- (2-methyl-4- (2-methylsulfonylcarbonyl) ethoxyimino] acetamido) -4-mmtCoxo-octro [alpha] 2-ofXfZoeidine (syn isomer) was prepared. (C spectrum ((KAX, cm -1): 3280, 2950, 1760, 1730 and 685. 1 H NMR (CDC1 ₃ + DHMScdg, ppm): 1.18 (2H, CH2.), 1 81 (6H, NaCl 4, 4.40 (2H, HOOCHH 3), 4.44 (2H, s, HIHHhI, 4.67 (1H, d, J = 6 Hz, C ₄ -H), 5.88 (1H, dd, J = 6 Hz, J = 9 Hz, C 1 H, 7.57 (1H, s, Sy H), 8.03 (1H, br s, N 4 H), 8.29 (1H, d , J = 9 Hz, (Cg-NH)

Reference Example 165

Dissolve 1.5 g of cis-3-benzoxy-oxoazetidine-4-carboxylic acid in 20 ml of tetrakrans. of the acid, which was prepared according to Reference Example 2.

To the solution was added 10 mL of 1M aqueous Co-Chlorosulfonate. While stirring at room temperature, 0.5 ml of aqueous ammonia (25-28%) was added and the mixture was stirred with 3 Codines. A further 2 ml of aqueous ammonia was added. The mixture was stirred with 16 Codin. TetraCydrofuran is considered. reduced pressure subtracted. The precipitated crystalline precipitate was filtered off, washed first with water, then with ether and dried.

Isis-3-benzyloxy-octboxamido-4-carboxylic acid-200X-Zydin is produced, mp 236-237 ° C (dec.). (C spectrum (in cm -1): 3400, 6600, 3200, 1760 and 1670. NMR spectrum (D 6 -D 6, ppm): 4.14 (1H, d, J = 6 Hz) C ₄ H, 5.05 (2H, s, phenyl-CH ₂ ), 5.08 (1H, dd, J = 6 Hz, J = 10 Hz, C ₃ -H), 7.36 ( 5H, s, aromatic protons).

For - 1 ^H 16 ^N 6 ° 4 calculated: 54.57% C, 4.98% H, 15.96% N; Found:% C, 54.93;% H, 4.90.

15.65% N.

The corresponding trans compound is prepared in the same manner as the thyroid indicated above.

153

Reference Example 166

304 mg of cis-3-bromo-alkoxycarbonyl-4-ylamino-222-hexylamine are suspended in 15 ΚΙ ethanol. To the suspension was added 304 Kg of 5% palliate per death. The mixture is stirred 1.5 heroes at room temperature under a hydrogen atmosphere. The catalyst was removed (Iggy) and the filtrate was smeared with reduced lacquer.

The remainder was dissolved in a 6 Kc. of triturate and 6 ml of water; 534 mg of sodium hydride are added under ice-cooling. To this solution was added 686 mg of hydrochyoridu 2- (2-4-chlnrkceraaidu thУakyly1) I (RU ² 2- [2 κrtУ1l ^{2 2} 2 ² (P ² niroobny1yro1lαaobonyl) eyhyloxyiiino] -acetyl-L-chloride, which was prepared according rrfrrrnčníУl of Example 90.

The mixture was. The mixture was stirred for 15 minutes under ice-cooling and for one hour at ambient temperature. Then, 200 ΚΙ ethyl acetate was added to the reaction mixture. The organic layer was washed twice with 0.1 N aqueous sodium hydroxide, once with aqueous sodium cyanide, dried over magnesium sulfate and concentrated.^poušt^Edlr is considered reduced^éyseparates by this.^INit is made^to cis^23-{^{22 (2-}C^ylrr^{2 k}cera^andidu²4²t^yУakУly1) -2-cell-mer^yy1-l²(p-nilrcbezyloxycarboxylic)¹!) eyhytoxyimtol] ketetididol^-4 -to^ktO^toκ^l1²2 - oxQiLayridine (p^yn isomer) such as^pěnnritý^prl^atukt^, t. ^ I⁴⁴ to I⁴⁷ Deň: 32 ° C.^IR with ^ ktoum cm "¹NMR sPectum (DMSO-d6, ppi: 1.52 (6H, s, 2.times.CH3-, 4.27 (1H, d, .delta. = 6 Hz, C4) -H), 4.3⁴ (2H, s, CCH 2), 532 (2H, s, COOCH 2), 5,6 (1H, dd,

J = 6 Hz, J = 9 Hz, _C3 -H, 7.41 (1H, s

By the same method as described above, it was obtained. odpovedaje! trans-compound.

Reference Example 167

In 80 ml K ^ et ^ y ^ l ^ l ^ r ^ N ^ C ^ yl ^ rozpuusí chloride with 4 g of cis-3-Ornz1llxykkrOoxékmdu ² l ² (2.4 1 ^ ^^^) Oenzyl) -4-hydtlxyIκrty1 ² 2- (lxokayriUinu which vitrOÍ according ггг гг ^ ^ ^ п г case 5. In chlazeyí mixed with ice water, the solution was added 0.9 ΚΙ chilrstilon1iSlkУyknktkLnt. the mixture was then stirred for 30 minutes.

Again, adding the same mnnrssví c and ^y lltsulronyiSrk1kanktant sKěs dklších stirred for 10 minutes. The reaction mixture was added dropwise to a 60 ΚΙ aqueous solution of sodium sulfite (2.8 g) while cooling the ice-water mixtures with stirring. The mixture was stirred at room temperature for one hour, with exclusive crystals. The crystals were suspended by the addition of merhylene chloride. Mer hlryc ^{y y} loričlliá layer of ^ C ^ U1 i, washed with Chli ^ een sodnýK O and dried over anhydrous-sodium sulfate.

Ror: ρpllttёdll se ldUuetiltjr. Ether was added to the residue. The resulting crystals were filtered. Prepared 3.3 g of cis ² 3 ² OrnzyllxykkrOoxxαmdu ^L-2 (2.4 Uimethlxyborny1 ²⁾ -4-karbkκoyllxyIκrth1 ^{2 2-u} lxoaayri Int. ^Ic ^ ktoum ⁽ⁱⁿ ΚΚ ^^ 'cm ^{3 4 00 3 3 00 3} 2 ^{0 1 760 and 1 690th}

The above product is added to 75 ml of Accecoitrile and 37.5 ml of water. 6.5 g of potassium persulfate and 3.9 g of potassium hydrogen phosphate are added to the mixture. The mixture ball ^Y and the outo ar ^ ^g per one Jeto Todina for iv ^{and y} it at 95 ° C. ^P o ^p řičlá cooling rtУylkcetát. The organic layer was separated, washed with brine and dried over sodium sulfate.

Rozpolιttёdll se ldUueSiltjr. Ether was added to the residue. Insoluble materials were filtered and purified by chromatography on a silica gel column (90 g, 85: 10: 5 chloroform-Kithanol 7 ethyl acetate). Prepared OezOarvé crystals of ^cis-3 -benzyloxykkrboxkmiUo 4-2 ² - ^{0 to} Cr KMO ^L1 Olχy ^[2- lithyl 2OЮlkУ ^rt were ^obtained, which, tai ^{s p} s 205 and ²⁰⁷ ° C.

^IR spektiruK ^(V) 33 ^{0 cm-1): 3 43} ^ ^{3 300 1 760 1 700th} N ^{MR p} ektrum ^{(DMSOcd6, pp} K: 6.33 (2H, Or NH2), 7.30 (5H, s, ^ Hh) 7m8 (1H, d, J = 9 Hz, --NH) 8.16 (1H, Or s, ^{N and} H.

154

For ^{C 13 H} 15 ^N 3 ^O ₅ calculated; % C, 53.23;% H, 5.15;% N-14.3; found; % C, 53.33;% H, 4.90;

Reference Example 168

In a mixture of 30 ml of Oetrahyiffurtn and 30 ml of water, 3 g of N, N-3-benzyloxycarboxamide-O, N-oxo-azine-4-carbonyl acid, methyl ester prepared according to Reference Example 27, are dissolved first. (1M) aqueous ammonium chloride solution and then 4 mL of -5-28% aqueous ammonia. The mixture was stirred for 3 hours at a temperature of 50 ° C.

The mixture was filtered under reduced pressure. Sodium chloride was added to the remaining aqueous solution, and the solution was extracted twice with a 3: 1 mixture of chloroform and mohayol. The extracts were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled in vacuo. The residue is run on silica gel (180 g, eluting with ethyl acetate, then mixed with ethyl acetate, then ethyl acetate / methanol 8: 1).

N- [3- (3-Benzyloxycarboxboximidophen-4-carbamuron) -22-oxoszetdin, mp 179-184 ° C, was prepared. vn _r —1

1C spectrum (V _max , cm); 3-80, 1760, 1695, and 1660. NMR Spectrum (DMMCOdg, ppm); 3.90 (1H, d, J = 3 Hz, C ₄ -HI, 4.42 (1H, dd, J = 3 Hz, J = 9 Hz, C3-H) Я 04 (1H, d, J = 9 Hz, C ₃ -NH).

Reference Example 169

A span of 31.0 freshly sprayed meeakrolein was added in 300 ml of methylene chloride.

To the solution was added 36.9 g of .alpha. To this solution was added 100 g of anhydrous sodium sulfate and 440 mg of p-tolumnsuffonic acid monynydiate. The mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered. The filtrate was bent under reduced pressure.

The residue is dissolved in 300 ml of methylene chloride. While cooling with ice and stirring, a solution of -4.5 g of methylmethyl in 100 ml of methylene chloride was added dropwise.

Then, a solution of 49.4 g of fealiminoacetyl chloride in 300 ml of methylene chloride is added dropwise over about one hour. The mixture was stirred overnight at room temperature. The reaction mixture was filtered. Insoluble materials are quenched with meehyienchlojide. The filtrate was combined with the washed dichloromethane solution and the combined portions were crimped under reduced pressure to 0.5 L.

The conjugate was washed sequentially with 200 mL of 1N hydrochloric acid, 0000 mL of water, 300 mL of 2% aqueous sodium bicarbonate (twice) and 200 mL of water, and dried over anhydrous sodium sulfate. The foam was then under reduced pressure. The residue was chromatographed on a silica gel column (400 g, eluting with hexane / ethyl acetate 1: 1).

55.8 g of crude product of cis-3-phthalimino-4-isoproplylyl-di (-, 4-dimethoxybenzyl) -dioxoaztinine are thus obtained. This product is spread in 500 ml of methanol and the solution is mixed with 25 g of 5% palladium y and the solution is stirred for 7 hours in a hydrogen monoxide while absorbing

870 ml of hydrogen.

The catalyst was removed by filtration and the filtrate was removed under reduced pressure. The conjugate is swollen in methyl acetate, washed first three times with 100 ml portions of 1N quinic acid and then once with brine. After drying over anhydrous sodium sulfate, the solvent is removed under reduced pressure.

47 g of residue are obtained. This residue is taken up in 700 ml of eehannl and 47 g of palladium are added to the solution. The mixture was stirred under an atmosphere of hydrogen for 24 hours while absorbing 1900 ml of hydrogen. The reaction mixture was filtered and the filtrate was concentrated. The residue was chromatographed on a silica gel column (400 g, eluting with hexane / hexane / silica gel (400 g, eluting with hexane / ethyl acetate 1: 1)).

155

The resulting crystalline ^ τιζιοιοι to give f, 6 g ^{cis-3-f1aliгifdo-4-yl} isootoo L4 14 (2,44fIm ^ l ^^ C ^ C ^ ^ iУblo] ^) -; ^^ (^) ^ oc1zli The mother liquor was concentrated and the remainder was reduced in volume

450 ml ltUtool. The product was catalytically reduced again with 5% palliate to carbon (15 g).

700 ml of hydrogen are absorbed. The catalyst is filtered off and the filtrate is concentrated.

A crystalline precipitate is obtained. The crystalline precipitate was filtered off with ethanol and dried. A further crop (5.3 g) of the above 4-isooropor-4-feriol was prepared. ^{R l} and KRR ^s ^ ¹ - ^ ^ί as: ^{U A} ^ ^lt; TM: ίu získají_ are colorless crystals which ^{e s p} s TIJI 151-152 ° C. spectrum: Wz ⁴⁰⁸ (M ⁺⁾ .

^Ic ^ kt ^ RUC cm ^{-): 1} 76 ^{0 1 71} and the fifth ^P ro -23) ^ 2 ^{4 5} ° in ^yP očtnnc: 67.63% ^-

H, 5.92; N, 6.86; Found:% C, 67.53;% H, 5.89;% N, 6.79.

Reference Example 170

8.5 g of cis-3-italyl-4-isopropanol (2,44-difluorobenzyl) -2-icazlidide were dissolved in 170 ml of diethyl ether. During ice cooling and stirring, is added dropwise 2.1 ml celhulU ^y draziou. After ^{4 h} mícM Odin ^y at t ^ lo ^ cístnoc ^with i ^p and ^{the second} Todi ^p ^ s ^ t lctó ^{35 and 40} ° C. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Pre-filtered crystals were added to the residue, 120 ml of ΙΙ-γ-γ-γ was added, and the mixture was stirred at 60-70 ° C for 3 hours. .

After cooling, the retention mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was tczouusí lacetátš ^y in the LTU. The solution is extracted first with a 50 ml peak with a 20 ml portion of 1N hydrochloric acid and the extract is washed with ether. After the addition of 8.4 g of sodium hydroxide, sodium oleate was added. This oil was extracted with chloroform, washed with aqueous sodium chloride and dried over anhydrous sodium sulfate.

The reaction was then carried out under reduced pressure. The residue was taken up in 10 ml of methylene chloride. chlor-riff. To the solution 30 ml intermarry prop llioxifš ^y · During ice cooling and stirring, then přikupe t ztck 3.55 g k1rb <cbeni o-χyhUoridu 10 cl celhuУeni! HUoridu, PRUEM N-crystals falls. 70 ml of ethyl acetate and 30 ml of urea were added and the mixture was stirred at room temperature.

At the same time, the above crystals were successively treated with a clear solution (over 4 hours). The solvent was then removed by filtration. The residue was purified by chromatography on a column (250 g; hexane / ethyl acetate). Crystallization from ether gave

4.7 g eίs blizyloiykaabbOiaiío-3-C-4ssprop Prl- (2,44fίíetho ^iУbli-yl) -2 'OXOO1zlidiiu which melts instance 123-125 ° C. ICso ^KTR-cm-1): 3300, 1760 and 690. 1 Pgo C ₂ ^H 3 ^O 2 5 ^{g of N} 2: calculated: 66.97% C, 6.84% H, 6.79% N; H, 6.83; N, 6.81.

Reference example -71

To a mixture of 50 ml of cellulose and 25 ml of water is added 2.06 g of cis-3-benzoyloxycarbonyl-44-isopropor-1- (2,4-methyl-4-oxo-4-oxo-4-olide), 1.89 g. pegoxosítanu potassium and 1.13 g ^^ огвСи ¹ ^ d ^^ l ^ h ^0th SMDS furiously at 95 ° C for ² cicaní ¹ ^ <^ ^(о у ^p o ^f a c ^^ ^pS tnýc ICEM -chlazení After the iceeocitrri odfdltilšjl under reduced pressure. Add 50 cl of water, into free resulting solution was extracted with 200 ml ethyl acetate.

The extract was swivels ^y jl two milliamperes Ccl-l portions of 2% aqueous U ^y droggliUUičitαiu solution and once with aqueous sodium sulfate. After drying the naphtha-free sodium sulfate, the solvent was separated under reduced pressure. -d ^p Arek slightly heated with 50 ounces of benzene and allowed to odhaiat. The insoluble material is filtered and washed first with benzene and then with a small amount of ether.

The ^y makes EII 1.1 g ^{of 4-3-blizyl} iyk1rboxaaiddc 4isoootoor ^{4-2-oxi-1eltdiou} which melts at from 185 ^and 184 ° C. IC ^ of the electrode ^- (in cm ^-1 ): 3 3 ⁴ 0, ¹ 760 and ¹ m. Fro ^^^ 2 ^{-3 v} У0 ⁰ ^ ^1le no ^:

% C, 64.10;% H, 6.92;% N, 10.68; Found:% C, 63.85;% H, 6.75;% N, 10.47.

156

Reference Example 172

1.0 g of cis-3-benzyloxycarboxamide-44-isopropyl-2-oxoazeeidine is suspended in 30 ml of ethanol. 1.0 g of 5% palladium on carbon was added to the suspension. The suspension was stirred under a hydrogen atmosphere for 30 minutes. The catalyst is then filtered off and the filtrate is evaporated to dryness under reduced pressure. This gave 430 mg of cis-3-amino-4-isopropyl-424-oxoazzidine crystals melting at 91-93 ° C.

IR spectrum <^ Х ^'Ù cm: ^{3350 and 3} I ^{50, 1 73 of} the fifth NMR spectrum ^(CDCl ₃ ^C, ppm): ^{0.95 (6H,} d, J = 6Hz, 2 x _CH3) , 1.59 (2H, br s, NH _2), 3.2 (1H, dd, J = 5 Hz, J = 9 Hz, C4-H), 4.17 (1H, d, J = 5 Hz, C ₃ -H).

For C 8 H 11 N 3 O: calculated: 56.22% C, 9.44% H, 21.86% N; Found:% C, 56.35;% H, 9.45;% N, 21.38.

Reference Example 173

3.7 g of p-anisidine are dissolved in 100 ml of methylene chloride. 4.2 g of trans-cinnamyl aldehyde and 30 mg of anhydrous magnesium sulfate are added to the solution. The mixture was stirred at room temperature for two hours. The reaction mixture is filtered and the filtered material is washed with 60 ml of dichloromethane. The filtrate and the washed dichloromethane are saved.

While cooling with ice and stirring, 8.4 ml of trielhynamine are first added, and then a solution of 7 g of phthalifoncetyl chloride is added dropwise in 50 ml of ICH. The mixture was stirred at room temperature for 1.5 hours. The editorial mixture was washed with water and aqueous sodium chloride.

The mixture was stirred under reduced pressure. To the residue was added 50 ml of chloroform. Insoluble ianeas are filtered off. The filtrate was bent under reduced pressure. The residue was crystallized from 25 ml of ethyl acetate. The crystals are filtered off. C18434-phthadiide-44- (E) -selrl4,41- (p4-Interhoxyl) -2-oxxoneeidine, which melts at 202-203 ° C, is thus obtained.

IR (V · cm ^-1): 1740 and 1 720. NMR spektrim (CCCI3, ppm): 3.74 (3H, s, _OCH3), 5.00 (1H, dd, J = 5 Hz, J = 7 Hz, C 1 H), 5.65 (1H, d, J = 5 Hz, C 1 H), 6.24 (1H, dd, J = 7 Hz, J = 16 Hz, H -) 6.78 (1H, d, J = 16Hz).

For C ₁₆ H ₂ N 2 _{O 4} calculated:. H, 4.75; N, 6.60. Found:% C, 73.56;% H, 4.58;% N, 6.87.

Reference Example 174

In 25 ml of ertrahydrofurnin, a span of 1 g of cis434 phthalimido-4- (E) -silyl414- (p-methoxyphenyl) -2-oxoazetidine was added. To this solution, with stirring at -5 ° C to -10 ° C, was added dropwise a solution of potassium nitrate nitrate (3 g) in 10 ml of water over five minutes. The mixture was stirred for 20 minutes at -5 ° C to 0 ° C. Tetrahydrofuran was distilled off under reduced pressure and the residue was shaken with ethyl acetate and water. The ethyl acetate layer was separated, washed with aqueous sodium sulfite, then brine, and dried over anhydrous sodium sulfate.

The solvent was distilled off. The residue was chromatographed on a silica gel column (eluting with 7: 3 chloroform: ethyl acetate). The product is crystallized from a mixture of ethyl acetate and ether. Cis-34ftadienyl-444 (E) 4-Str-2- (4-methyl) -ethanol was produced, which melted at 168-170 ° C.

KBr - 1 ^Ic ektrum ^p <V _max, cm ^3): 3250, 1750 and 720. NMR 1 01 ^ ^3, P ^{pm): 4,} 68 (1H ^ dd, J = 5 Hz, J = 8 Hz, C4-H, 5.57 (1H, d, J = 5Hz, C3-H), 6.66 (1H, s, [delta]).

For ^C 19 ^H 14 N 2 ° 2 ° 3 ⁱⁿ Poole: C 71.69, H 4.43, N 8.80; Found: C, 71.61; H, 4.37;

8.55% N.

157

Reference Example 175

Dissolve 546 mg of cis-3-phthadimido-4- (E) -styry-2-o-casselide in 6 ml of diz-disodium chloride. While cooling under stirring and with stirring, 0.36 ml of triethylamine and 323 mg of tert-butyl butylated silicide are added. The mixture was stirred for 30 minutes and then at room temperature for 4 hours.

The reaction mixture is then shaken with water and water. The ethyl acetate layer (washed) was washed twice with water, once with saturated aqueous sodium chloride, and dried over sodium bisulfate. Under reduced pressure, thickened and the rest of the cyrozzVoogafiLi is about a silica gel column (cuce1o ^ okomeZ).

The product is crystallized from ether. Manufactures SZ cisl3 itllizído-4- (E)) Styryll1- (teii.eutyl ^ of ^ ^ y ^ YLS ^-2- kOkaliti ^{d i) P} s RTII melts 167-168 ° C. I ^C. s ^p ectrum ( ^V cz ^-1 ) ^:

750 and 1715. NMR spectrum (CDCl 3, ppm): 4.58 (1H, z, C 4 -)), 5.62 (1H, d, J = 6 Hz, C 8 -H) ·. For ^C 25 ^H 28 ^N 2 ^{O 3} S 1 calculated: 69.41% C, 6.52% H, 6.48% N; nv11i1nk; % C, 69.22;% H, 6.46;% N / 6.48.

Reference Example 176

440 mg of cis-3-itylidene-4- (E) -syl-1- (methylthienylmethyl) -2-ooclzetide were suspended in 5 ml of diethyl ether. To the suspension was added 0.26 sz zl zeiyyiyydrvzinu longitude and the mixture stirred for 30 minutes at hexaneether ^ S ^ i ^ - ^ .. OSI Rooppoutědlo longitude peak under reduced pressure to ddzSilu ^d) z.

The residue is taken up in 5 ml of green-Chorddu and the solution is allowed to stand overnight. The precipitate is filtered off. The filtrate was dried under reduced pressure. The residue was purified by silica gel column chromatography (combining more chloroform with ithylacitate 6: 4). Manufactures SZ-oil cisl3 lmiíl-ol IE) -lStlil1I1 ^{^} (tzii.eutlldiaethylsily) - lkOXOlZztidiru.

This oil was dissolved in 10 .mu.l of titration. With cooling, 0.2 ml (0.212 g of 2- (2-chloroacetazidyl) thiazol-2-yl) -2-azzhocolmin-klethyl-chloro-chloride was added while stirring, while stirring with ice. 10 minutes, then 30 minutes at room temperature and then shaken with ethyl acetate and water. The ethyl acetate layer was drained, washed with saturated aqueous sodium bicarbonate, and dried over sodium sulfate.

The co-surfactant was dried under reduced pressure. The residue was purified by silica gel column and silica gel column chromatography (eluting with a mixture of cyclohexane and a 7: 3 ratio). The product is recrystallized from Zhiiu. Manufactures SZ cis- [2- (2-cУlkiaclZaaido-4-ZУiaiklylI22 azУhoxyiaink> acltaaidoO-4- (E) -. '· S Buzy ^No dizeZ ylsily ^h) - ^2lk OXOlieZid ^s n (a n ^{d s skzzl) to} tiiý 228 and melts at ^from 231 ° C (Rozi.).

s, OCH))

7.20 (1H,

IC spectrum (cm -1): 1725 and 1670. NMR spectrum

4.20 (2H, s, C 10 H 11), 4.63 (1H, z, s, ^{S 11} )

H) 8.50 (1 H, d,

J = 6 Hz

C4-H, 5.50 (1H, dd, C ₃ -NH).

(CDDCg, ppm)

J = 6Hz, J =

3.15 (3 H,

Hz, C "-)

For C 25 H 12 ClN 5 O 4 S · d. calculated: 53.41% C, 5.74% H, 12.46% N; Found: 5.71% H, 12.47% N.

53.09% C,

Reference Example 177

Under stirring and ^p ioudu ^d usíku longitude ochlvZ 50 ml suc ^yéy of TZTŘ ^{yl d} ikfuranu OA ^- 78 ° C. After ^TCD added thereto longitude "20 .mu.l solution of 15% buliHi-thia-hexane. 3.66 zl Přikvpz sz "diSoopropylazdnu and longitude ^of Zs MIC ^HA 15 minutes at ^-78 ° C. Přikv ^p NW ^3.1 g of ^2, 2- ^{DIZ outers} y ^l1I1I - ^lZll3-

-kxabicyclic [4.2. oo] kktanl8-KNU "in 15 .mu.l of dry 1ζ1Γ31ι ^) ΌίπΓΐ-π and longitude SZeŠ Zich one hour ^p s ^t a ^{pi I -7} to 8 ° C.

Then, sz přikapz solution of 4.34 g of ^p · Itkluz ^{sulfk--yl-lZidu} in 15 .mu.l of dry tztaaУy ^d rkfuranu ^longitude and ^longitude of ^the hook 1 ^c hexaneether ^{5 УосН} -у mzzi at temperatures -50 and - ⁶ ° C . ^To this sz ^z íi sz pri-kvp ^{1 5,} 1 zl

158 trimethylsilyl chloride and the reaction mixture was refluxed for 5 hours. After cooling, the insoluble materials were filtered. The filtrate was concentrated under reduced pressure.

The residue was treated with water and lithium chloride. The ethyl acetate layer was separated, washed with water, dried. cad blunted with sodium sulfate and exacerbated. under reduced pressure. RoipooStddlo was deleted. The residue is chromatographed on a tilklag1ls column. 2,2-Diahihl-7-azidi- ¹ -aza-3-oxalicyl [4.2.Cf-octane-S-one was prepared as a 1: 4 mixture of cis- and trans-SiOalers.

KRR s ^ -1 IR ktrum ⁽ⁱⁿ May ^'cm) ·· ³¹⁰⁰ and 750. 1 H NMR with ^ODT tl ^ sm (D ^{CC H 3-m), 4.20} J = ^1.5 Hz, trans-Cg - H), 4.68 (d, J = 5 Hz, cis-Cm-H).

Kryjsa-ISATIO above putty from diisopropyl) prioyl1th1ru selectively crystallized ^TRACS-No sliu ^{inink, kt} IRA secrets ^P 78 s and ⁸⁰ ° ^C.

A Rererative Example 178

330 mg of tract-2,2-di-ethyl-7-azido-1-azl-3-ixalbcy ^to [4.2.0] octan-B-one are added in 30 mL of acetone. While cooling in humans and stirring, add 3.3 ml (8n solution) of the Jinesiva reagent. The mixture was stirred for 2.5 hours. 5 ml of itiorooylalkihil are then added and the mixture is stirred for a further 10 minutes. The insoluble materials were filtered off by filtration. The filtrate is concentrated under reduced pressure.

The residue was shaken with titanium hydride and a small amount of aqueous sodium chloride. The tetrahydrofuran layer was separated and extracted three times with titanium hydroformate. Tetrahydro uranium nitrate is combined. and dried cad with sodium sulfate. A solution was added to the solution. dihydrochloride in ether. fímes to them. RozppoStёdli iddd1tilsji and the rest of the orotř1 ^e Oi with water and ithylkcitáiea.

The ethyl acetate layer was separated, washed successively with aqueous sodium bicarbonate, water, and dried over anhydrous sodium sulfate. The ethyl citrate solution was concentrated under reduced pressure. The remainder was chiral and reacted with silklag1ls. Trans-3-Amino-4-α-oxytarpine-methyl-2-oxilizine is produced.

Nuclear Magnetic Resonance Spectrum (CDCC), ppm): 2.76 (2H, d, J = 6Hz, C ^H ^ ^), 3.70 (3H, s, COOCHg), 3.82 (1H, m, C ₄ -) H), 4.36 (1H, C-H), 6.75 (1H, s, _Ν χ -Η).

The procedure was followed in a staged manner when it emerged from the cis- and trans-thiolar taels (in a ratio of 1: 4), then a 2-ixoazziidyl press was produced in addition to the cis- and trantio-thiol salts (in a ratio of 1: 4). ). Nuclear Magnetic Resonance Spectrum (CDCC), δ: 4.83 (cis-C 6).

Reference Example 179

800 mg of cis-3-binyloxycarbocarbonyl-4-carbonyl-4-carbonic acid was prepared in 20 ml of titration and 10 ml of water and prepared according to the example. 68. 280 mg of sodium hydrogen carbonate are added under ice-cooling. Towards the mixture. 303 mg of i-ethylhydrixyllaine hydrochloride and 638 mg of 1-lithium-β- ((- dimethylaminoethyl) propionyl) hydrochloride are added and the mixture is stirred at room temperature.

After three hours, sodium chloride was added and the reaction mixture was extracted with a 10: 1 mixture of ithylacitate and toluene. The extract was washed with 3N hydrochloric acid, aqueous sodium bicarbonate, aqueous sodium chloride and dried over anhydrous sodium sulfate. They were dissolved under reduced pressure. Prepared cis Зr1enzyiχУkαrr0xαamido 4miithoxyamiookarbo ^{c-yl- 2} -iXiаlzeidic, ^kt Irish secrets ^P s ²¹² and ^{from 216} ° ^{C IR} pektru ^{T m.} - ^{om, 7} ) or ^{3 290} ,

760 and 1680.

Reference Example 180 <

To 8 ml of dry diahenyl sulfixide was added 5.1 g of cit-3-binzylixycrrixabido-1- (2,4-di

To this solution was added 2.6 g of potassium cyanide and 50 mg of 18-coown-6. OMES was stirred for ^two days at t ^ ture IIS ^{i i} i new, ^3h Odin te ^ OTE at ^{50 o} C and poured into 250 ml of ethyl-E State.

The reaction mixture was washed first with water three times, once with brine, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (400 g, eluting with 1: 2 ethyl acetate: hexane, 2: 1).

Prepared -btneyloxykarbvxami ³ cis- (4-IAV klanietyl .mu.l (2,4-aiiethovχУetoyl)) 2-oxovzztidin. I ^{C P} ektrum (in cm ^{"1): 3290,. 2920,} 1770, 2240 and 690. NMR 1 s ^ ktrurn (CDCC rn ^ ^pp):

2.48 (2H, d, J = 6Hz, CH3), 3.78 (3H, s, C (CH3)), 3.80 (3H, s, QCl3), 4.82 (1H, dd, J = 5Hz, J = 8Hz, Oj-H).

Reference Example 181 *

1.7 g of cis- ^3- benzyloxycarboxamino-4-cyanomethyl-1,1-2,4-oxo-azetidine are dissolved in a network of 210 ml of acetonitrile and 70 ml of water. 1.68 g of potassium methoxysulphate and 1.085 g of potassium hydrogen phosphate are added to the solution. OMES 2.5 hxdiny is heated to a temperature of ^85-90 ° ^C from ^{P PE} sLex ^hl c and ^d ICEM. ^A cceooi ^a r ^r l per sn ^ Enco ACCOUNTS ^DD ft ^with ilujt. ^{The Cdp} arcs are extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium bicarbonate, aqueous sodium chlorate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. '

The residue was purified by column chromatography (140 g, eluting with 1: 2 ethyl acetate: hexane) then 3: 1). Prepared cίi beneyVoxykarЬvxliiao-3-4-2-kylnmithhl oxolzetiaio ^which melts ^p s ¹¹³ and ¹¹⁵ ° ^{C. iC} ektrum with ^{p (in} cm ^{-1): 3300, 2} 25 ^{0 1} 76 ⁰ .a

685.

Reference Example 182

It is me^toReference is made to JklaC 166^bcis-3- [2- (2^Cch^Ool^andce^andai^iain -4-t^lilevly⁾-^22nd- [- l-me^lbullfinch-^-(O-⁰ⁱnⁱⁿtrt^Oenzⁱⁿlox^kaabⁱⁿoo^(l)) e ^ y ^ xy ^ ino]^-lct^tl^m.^dO^IN^^-4^{- to}^^ylnm^E^^^hl-2-acetylthio (syn).

IC spectrum ( _ν max, cm -1): 3,360, 2,980, 2,250, 1,740, 1,680, 1,600, 1,520, 1,345 and 1,140.

Reference Example 183

4 g of methyl cis- ³ -benzylcarboxamido-4-carboxylic acid, which is produced according to Reference Example 2, are dissolved in a network of 100 ml of tetrahydrofuran and 100 ml of water. 1.595 g of sodium borohydride are added under ice-cooling. The Ornes was stirred for 1 hour with ice cooling and then 2 hours at room temperature.

Tetrahyarvfurao under reduced taaku vdaaeiilsjt. Caparek was extracted three times with chloroform. "The extract is dried over anhydrous magnesium sulfate and" bent under reduced tau. The residue is dissolved in 30 ml of ethanol. 1 g of 5% pH: 10 is added and the mixture is stirred for 4 hours under a hydrogen atmosphere. The catalyst is then filtered and the filtrate is thickened. the residue was dissolved in a mixture of 20 ml of water and 20 ml of tetrahydrofuran. .

Under ice-cooling, 3.62 g of sodium hydrogencarbonate are added. 3.41 g of p-iodobenzoic acid chloride was then added and the mixture was stirred for 2 hours at room temperature. This reaction mixture was extracted three times with chloro ol. The extract was dried over anhydrous magnesium sulfate. The solvent was then removed under reduced pressure. The residue was chromatographed on a column (160 g, eluting with 4: 1 ethyl acetate / methanol) when initially pure ethyl acetate was used as the reagent). '

160

Prepared cis-3- _(p-n itrobinyylyχkaarbóxamino 4-hydroyyImehyУl2 ooyazeeidii which melts at ^{166 to 167} ° ^e. Trvm IC ^ sp ^{(in RR} £, cm ^{"1): 3280,} 1770 and 1 700. For 4 ^ ³ ° ⁶ calculated 48.82% C, 4.44% H, 14.23% N found: 48.58% · C, 4.53% H, 13.87% N.

Reference Example 184

2.28 g of sodium hydride are suspended in 40 ml of dry tetrahydrofuran. Under ice-cooling, a solution of 3 g of 1-phenyl-12-triazol-5-ylthiol in 40 ml of tetrahydrofuran is added. A solution of 3.59 g of bromoacetic acid in 80 ml of dry ethanol is then added. The mixture was stirred for 30 minutes under ice-cooling and then for one hour at room temperature.

It is concentrated under reduced pressure and the residue is shaken with 100 ml of water and 100 ml of ether.

The aqueous layer was separated, acidified with 3N hydrochloric acid, and extracted twice with a 3: 1 mixture of chloroform and ethanol. The extract was dried over anhydrous magnesium sulfate. The solvent is removed. 1-Ethyl-12-nitrazul-5-ylthiourea acid was prepared.

^IR spektrim (£ V ^RR, cm ^{"1) 2} 1 0 and 700. NMR ektru with ^{p m (g} CDCl + DMSO-d pp ^{m): 3.8} 2 (3H, s, CH3), 3.98 (2H, s, CH ₂ ), 4.10 (1H, s, CO ₂ H).

Claims (45)

SUBJECT OF THE INVENTION A process for the preparation of 1-suffix-2-otazazine of the formula I (I) wherein is R is a group of formula R2 I ₄ “C” (CH) “R P wherein n is an integer from 0 to 3 r 2 and r 3 which are the same or different, hydrogen, alkyl, cycloalkyl optionally substituted, optionally substituted aryl or aryl, optionally substituted heterocyclic, alkyloxycarbonyl or acyl, or together they change the oyloxy group; is hydrogen, alkyl, optionally substituted cyclic alkyl, optionally substituted aryl, optionally substituted heterocyclic, halo, cyano, hydrotylutyl, alkyl, optionally substituted alkyl, alkyl, aryl, aryl, aryl, acylalkyl alkylstylthylotyl, arylstylthiothynyl, optionally with a substituent aryl moiety, sulfo, β, γ, γ, amino, azido, carbotyl, alkutycarbonyl, alkutycarbonylalkynyl, 161 aminocarbonyl, alkylthiocarbonyl, acyl, mercapto, alkylthio, aminoalkylthio, acylaminoalkylthio, aralkylthio with optionally substituted alkyl, arylthio with optionally substituted aryl, optionally substituted heterocyclic thio, or optionally substituted quaternary, or optionally substituted quaternary, an alkynyl group, a cycloalkenyl group, an aryl or heterocyclic group, which are optionally substituted by one or more substituents, wherein the substituents of the optionally substituted alkenyl and alkynyl groups are each selected from optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, an optionally substituted heterocyclic group, alkoxycarbonyl for a group, acyl, oxo, halogen, cyano, hydroxyl, alkoxy, aryloxy, optionally substituted aryl, aryloxy, carbamoyloxy, hydroxysulfonyloxy, alkylsulfonyloxy, amino, arylsulfonyloxy, arylsulfonyloxy, alkylthiocarbonyl, mercapto, alkylthio, aminoalkylthio, acylaminoalkylthio, aralkylthio with optionally substituted alkyl, arylthio with optionally substituted aryl, heterocyclic thio with optionally substituted heterocyclic, and optionally substituted quaternary one of the same, or various and optional substituents of a substituted cycloalkyl group, cycloacenyl, aryl, aralkyl, heterocyclic and quaternary ammonium groups are selected from the group consisting of alkyl, alkoxy, alkenyl, aryl, aralkyl, mercapto, alkylthio, arylthio, aralkylthio, alkylsulfonyl, aralkylsulfonyl, arylsulfonyl, and arylsulfonyl, , trihaloalkyl, hydroxy, oxo, thio, halogen, nitro, amino, cyano, carbamoyl, carboxyl, acyl, acyloxy, acylamino, hydroxyalkyl, carboxyalkyl, dialkylamino, haloalkyl and monoalkyl and the above-mentioned monoalkyl and monoalkyl; the amino, carboxyl and hydroxyl groups may be protected, each of the above alkyl and alkoxy groups having 1 to 6 carbon atoms, alkenyl and alkynes an alkyl group having 2 to 6 carbon atoms, a cycloalkyl and a cycloacenyl group of 3 to 8 carbon atoms, the amino group may be substituted by an acyl group, an alkyl group, a hydroxyalkyl group, an aralkyl group having an optionally substituted alkyl group, an optionally substituted aryl group, optionally substituted heterocyclic group; sulfo, alkylsulfonyl, aralkylsulfonyl, optionally substituted alkyl, arylsulfonyl with optionally substituted aryl, alkoxycarbonyl, aralkyloxycarbonyl with optionally substituted alkyl, aryloxycarbonyl with optionally substituted aryl, and optionally substituted with aminocarbonyl are defined above; , "aralkyl" means always benzyl phenethyl, phenylpropyl or naphthylmethyl, aryl means a phenyl, alpha-naphthyl, beta-naphthyl, biphenyl or anthryl group, a heterocyclic group means a 5- to 8-membered heterocyclic radical with one to four heteroatoms 253565. 162 from the group consisting of a nitrogen atom including N-oxide, oxygen and sulfur, an aryl group means a formyl group, an alkylcarbonyl group having 1 to 6 carbon atoms in the alkyl moiety, a benzoyl group optionally substituted by a hydroxyl group or an alkyl group having 1 to 6 carbon atoms a C7 -C9 aralkylcarbonyl group optionally substituted by a hydroxyl group or a C1-6 alkyl group or a five-membered heterocyclic carbonyl or acetyl group containing at least one oxygen, nitrogen and sulfur atom, optionally substituted by an amino group, R @ ^{1 is} amino or acylated amino, the acyl moiety having the general formula R ⁵ - CO where R 1 represents an alkyl or optionally substituted heterocyclic group, or an acyl ¹ , the moiety has the general formula R ⁶ - NH - CH WHAT R ⁷ wherein R ⁶ represents a hydrogen atom, a glycyl, alanyl, vallyl, leucyl, isoleucyl, seryl, threonyl, nyl, tulle, myyl, nyl, histidyl, tryptophenyl or pyrrolyl, or amino protecting group or a cysteinyl group, cystyl, methioalpha-aspartyl or beta-asparalpha-glutamyl or gamaglutalysyl, arginyl, phenylalaphenylglycyl, tyrosyl, ^r8 - ^(СН 2> _П1 θ where R is CO optionally substituted heterocyclic group and integer 0 to 2, R ^{7 is} an alkyl group, an optionally substituted phenyl group, a heterocyclic carbonylamino group with an optionally substituted heterocyclic moiety or an optionally substituted heterocyclic group, or has an acyl moiety of the general formula - CO where q is R is a group of formula R ¹¹ C II N £ R ¹² wherein R ¹¹ represents optionally substituted alkyl, optionally substituted heterocyclic group, or phenyl group, and 163 is a hydrogen atom, an alkyl group or a group of the formula EMI3.0 wherein is ^R13 or the alkylene group and ^R alkenslentvtu opřipa ^de Su ^p ^ ^^ t ^ n ^ alkylated verifies StopIN carboxy-s-TK ⁱⁿ the pin ^with I · or a allslsstsr or mooooakylaminoskupinu or eialkylamintskupinu, R 1 is a direct bond or a group of the general formula - CO - NH CH where is R15 alkyl or phenyl-substituovantu verifies or optionally substiuuovanou tliaztlylovtu group or an acyl group having the formula wherein r1® lsdrtxyskupinu, lydrtxysulitnyltxyskupinu, karbtxysкupinu optionally substituted ursietskúpinu _/ or suSstituovantu sulfamtyltvtu group, sulfo group, an optionally substituted group or isntxykarbtnyltvtu formyltxsskupinu and R is hydrogen, alkyl, alkoxy, atom. halogen, nitro, or hydroxyxy, or has an acyl moiety of the general formula - CH2 --CO where R @ 18 is cyano, optionally a sulfite of an alkenyl group, optionally a substituent of an alkoxy group, optionally a substituent of an alkyl group, an optionally substituted alkynyl group, or an optionally sulfite of an lethal radical and an alkyl group; R19 a direct bond or a sulfur atom, or wherein in ^and DE meanings with ^{R5 SM} sol ažFŘ ^{19 1} etsrtcy ^{kl KTU} ic pi ^^ S ^ ^ai y ^{m IR} INI five-membered ^to eight-membered letsrtcsllic! lysed ring having 1-4 heteroaoomy selected · Nitrogen (including N-oxide), oxygen and sulfur, pyrrolo [2,3-d] pyrimidyl, benzopyranyl, 1,8-naphthyl, 1,5-naphthyl, 1,6- a naphthyridyl group, 164 1,7-naphthyridyl, 2,7-naphthyridyl, 2,6-naphthyridyl, ahinolyl or thieno [2,3-6] pyridyl, optionally substituted with heterocyclic, phenyl, thiazolyl, phenoxycarbonyl and phenoxy; in each case it is intended that the groups are substituted by one to two groups selected from the group consisting of alkyl, alkoxy, alkenyl, aryl, aralkyl, mercapto, alkylthio, arylthio; aralkylthio, alkylsulfonyl, arylsuffonyl, aralkylsufoonyl, trihaocgenalkyl, hydroxy, oxo, thiphenyl, halogen, nitro, amino, cyano, carbamoyl, carboxy, halo, acyl, acyloxy, acyloxy, acyloxy, acyloxy, and a mono-acylaminoalkyl or dialkylamino-alkyl group wherein the acyl group is as defined above, the alkyl moiety and the alkoxy moiety each have from 1 to 6 carbon atoms, the alkenyl moiety each has from 2 to 6 carbon atoms and the aralkyl moiety and the aryl moiety thereof. as defined above, in the case of a substituted alkyl group, the substituents are selected from the group consisting of halogen, hydroxy, cyano and trifluoromethyl, in the case of substituted ureide groups, the substituents are selected from the group consisting of a cationic group, a carbamoyl group, a middle group , an amidione or an alkyl group having 1 to 6 carbon atoms, the optionally substituted sulfamyl group having as a substituent an alkyl group having 1 to 6, carbon atoms or an amino group, an amino group, a carboxyl group and / or a hydroxyl group may be protected; substituted as described above for R, or R @ 1 is phthaloyl-protected amino, p-tert -benzoyl, p-tert-tutyloneoyuffon, p-tert-butyloneensuffonyf, benzenesulfonyl, toluenesulfomyl, formyl, mono-chloroethyl. acid, ^ CH ^^ cetyl, trichloracetyfovfu, meehanoulfooylnvnt, ethαo8ulfnnylovou, trlfjnoaacetyfovft, maleyl, stkcioylnvou, methoxycarbonyl, ethoxykarbnnylnvou, tert-UunoxykarЬnnylovnu, isopropoxykarbonylnvnt 2-kyanethoxykarbnoylovnu, beta, beta, beta-trichfreetnoxykаrbonylfvnt, beta-trimethylsilyethnxxykаrbf) oylnvou beta -methylsulfonyeehOχyykarbonyfovou benzyloxykarbnnylovou :, p-nitnobenzyfoxykαrbnnylnvnu, P-methyl (fxybenzylnxykarbnnylovou, di-phenyl-methyloxy a carbonyl, methoxJη [neehyloxykarbnnylnvou, acetylmethylxxykarЬooylovou, isobnrnylf) xykarbnnylovou, leoyloxykαrbonylovou, trityfxvft 2-nitrfleoylthinskupinou, benzyliíenovnt group, 4-oitrobeozylidennvot, trialkylsllyovvcu , benzyl, p-oxobenzyl or proton, wherein the alkyl moiety, alkoxy moiety, alkenyl moiety, alkynyl moiety, acycloalkyl cycloalkenyl moiety, aralkyl moiety and aryl moiety are each as defined for R, X is hydrogen or methoxy, or a salt or ester thereof, characterized in that the compound of formula III'i (III) 165 wherein each symbol is as defined above, or a salt or ester thereof, and optionally a protecting group is cleaved. 2. Process according to claim 1, characterized in that the corresponding starting material is used A compound of formula III to form a compound of formula I wherein R and R are each hydrogen and R is not a hydrogen atom or a straight chain alkyl group having 1 to 6 carbon atoms, the other symbols being as defined in point 1 above. 3. A process according to claim 1, wherein the starting material is a corresponding compound of formula III to form a compound of formula I, wherein one of 2 3 R @ 1 and R @ 2 are hydrogen and a second C1 -C6 straight chain alkyl group and n is zero and R @ 2 is not hydrogen, the other symbols being as defined in 1. 4. The process of claim 1 wherein the corresponding compound of formula (III) is used as the starting material to form a compound of formula (I) wherein R is not a straight chain alkyl group and the other symbols are as defined in point 1. 5. A process as claimed in any one of claims 1 to 4, wherein the corresponding compound of formula III is used as the starting material to form a compound of formula I wherein the protecting group of the protected carboxyl group is an ester residue or a trialkylsilyl group having from 1 to 4. The C 6 alkyl atoms and the other symbols are as defined in 1-4. 6. A process according to any one of claims 1 to 4, wherein the corresponding compound of formula (III) is used as the starting material to form a compound of formula (I) wherein the hydroxy-protected group is an ether, silyl ether, acetal, ester or esterified carboxyl group. group and individual symbols have a point 1 to 4 meaning. · ’..... ·· к; 7. A process according to claim 1, wherein the corresponding compound of formula (III) is used as the starting material to form a compound of formula (I) wherein optionally substituted alkenyl, optionally substituted aryl: R ⁴ ' 2 '3'; 3, R and R, which are the same or different, in each case a hydrogen atom 2'3 '4 1 and R together represent an oxo group and R represents a halogen atom wherein n is an integer of 0 to or an alkyl group or R 'a hydrogen atom, an alkyl group, an optionally substituted aryl group, cyano, hydroxyl group, alkoxy group, optionally substituted aralkyloxy group, acyloxy group, carbamoyloxy, alkylsulfonyloxy, sulfooxy, amino, afcido, carboxyl, alkoxycarbonyl, alkoxycarbonylalkyloxy, alkylthio, optionally substituted heterocyclic thio or optionally substituted quaternary, optionally substituted amino, carboxy, amino, an acyl group, an optionally substituted group, an optionally substituted heterocyclic group, an alkyl group and an alkoxy group are further defined in Section 1. an acyl group, optionally a substiaralkyl group 2'3'4 ' 8. A process according to claim 7, wherein R, R, and R are subject to the proviso that in the case of the case where R and R are each hydrogen, R is not hydrogen or alkyl. A 3 's-straight chain group and when one of R and R is hydrogen, 4 'the other is a straight chain alkyl group and n is zero, not R is a hydrogen atom. 9. The process of claim 7, wherein the optionally substituted alkenyl group is a C2-6 alkenyl group optionally substituted by a phenyl group. 166 10. A process according to claim 7, wherein the optionally substituted spectacle group is a nitro group optionally substituted by a halogen atom. 11. A process according to claim 7, wherein the tuberculosic group is optionally substituted with a C 1-6 -alkyloxy group. 12. A process according to claim 7, wherein the -cyloxy moiety is an alkynyl group, an allyl-alkyloxycarbonyl group, an aryl group or a non-aryl group having the formula: -CO - X - Q ^1, X represents -02-, -HH2S- očIÍ - H 2 N i 2 0 2. to ^de marks ^-mčná MEMBER ^Q PC ^ ^ y ^ y ^ trrocyklic floe ^{h 4 from h} -teroatom of ^y. File zayrnui ^ 1Ую nitrogen atom nčbn síryppřllebž Уetrroc llický ^y ring is optionally substituted .. aminosku2 pico or -lklll) VNS, Q -lknxyskupicu wherein -Hylová skupin- -Hoxyskupin- and RN-micron to 6 carbon atoms and the spectacle group is specified in more detail in. 1. 13. The method of claim 7, vyznačiný that optionally ssbstiSuovbnou Уet-rncyklickns eУioskspinns is tetrizol ^y IOOA skupin-, KT-Ra can be substiSuovácb -Hýlovou having up to 6 carbon atoms. 14. A method podl- Claim 7 vyznačiný said quaternary group -mbninvnu jr ^y p rίiiclooá group. 15. The process of claim 7, wherein the protecting group or protecting group of the sublothed protected amino group is one of two groups of up to 4 carbon atoms in the blend. Yl ^, R (4b), R (4) -cycloalkyl, (C skupinu-Ciliili) alkyl, (C 4-Cili,), (Cili-Cili alkyl) alkyl, (Clak-C alkyliol) alkyl (Clak-Clak v), C vždy-Crrn (Cng-Ccyrn) having up to 4 -eo> mi atoms in -lk ^yl ester a poddlu, rstrrif 1ov Ana-to-rrnxyli ^ Vou group tulfl> tkspins, llknxy 'having up to 4 carbon atoms and к-г х ^ ^ ^^ НуХ group. The alkyl moiety having an aryl group or an aryl moiety has the meaning of the particulars specified in point 1. 16. A process according to claim 7, wherein the protecting group protected by the oxo group is an alkyl group having up to 6 carbon atoms. 17. A method podl- Claim 7 vyznačiný that R - R-Zn MMENU d πι hydrogen, ^{R2 - R3 nbaibicl} of: d-d dohrom nxoskupicu ^1, n of an n-Men ^A zero - ^r4 Zn-men ^N toxyHupi ^ s ^- f 4 carbon atoms, alkylcarbonyloxy groups having up to 4 carbon atoms in the alkoxy moiety, five- or six-membered nitrogen containing a cyclic group with one to four carbon atoms, and the nitrogen or sulfur atom which contains one or more of the nitrogen atoms which may be nitrogen. allylones having up to 4 carbon atoms or an amino group optionally protected by an iliphatic phenyl group. 18. The method of claim 1, wherein the starting material is a niponizing compound of formula III to form a compound of formula I, wherein R is a group of formula I. -CON 167 where Q ³ and · ⁴ measure the same or different meanings and let us denote ^! a water atom or a substituted alkyl group, a alkoxy group, an alkyl group, an optionally tubstituted aryl group, an optionally tubstituted aryl group, an optionally tubstituted aryl group, an alkyl group, an alkyl group, an alkyl group, an alkyl group, an alkyl group a rhkoxycririyl group, a rhoxycririyl group, a rhoxycririyl group, or a tubstituite, optionally a rryloxycriotyl group, a group of the general formula R ⁵ - R ⁶ CO - NH - CH - CO ^r10 7 CO R b ^{no of} R ¹⁸ - R ¹⁹ - CH ² - CO kd ^e. R ^{11 and} R ^{19 ρρ} f ^ ^t-u and ^I shown in him ^ 1 and ^ ípadnými s ^ i ^ i ^ .t ^SI tgni ^y are Sapina asylum rlkoxytkupitr as further defined in claim 1 and in the other raking PSAI 1. 19th FTS ^{with P} ob in ODL point ^e ^ Nacen ^{tip, F} e Q ³ and Q ⁴ are .erá stejiré vigorously or Zn ^ ^ MenA hydrogen stylish group having 1 to 6 carbon atoms, altoxylovou group having from 1 to 6 carbon atoms aninoskupinu, carbo ^^^ i ^ lkyl ^ c ^ v ^ ou group having 1 to 6 carbon atoms in ^. ^ ^ ^ ονέρ poddl Γ ^ ^ρογ1 ρ Lkylovou group having 1 to 6 carbon atoms and ^. ^ ονέρ ooddlt, г ^ у ^ ггЬлуlovou group having 1 to 6 carbon atoms in ^. ^ ονέρ after ^ DLU optionally substituovátr halogen, tulfotкtoItot, phenyl, benzyl, o ^_ titobbgtkyloxykrrionylovou group or Betr-rlkylsulOtyyj ^and lkoykr ^p i0otyjovou . C 1 -C 6 alkyl in the C 1 -C 6 alkyl moiety. 3 4 20. The method of claim 18 wherein Q and Q, which are the same or different, are: a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a phenyl group, a sulfosulfine or a C 1 -C 6 -crioxyalkyl group. 21. A process according to claim 1, wherein the starting material is a corresponding reagent of formula (III) to form a compound of formula (I) wherein R is a group of formula - COQ where Q ^{5 5} Known ^ ^ -hydroxy ^ verifies Toer The situations is ^ ^ ^^ and CTO, Aloxi ^ verifies Sapin ¹ and ^f C 1-6 carbon atoms, a rryloxy group optionally with a tubite, a alkyloxy group or an alkyl group having from 1 to 6 carbon atoms; The alkyl group having 6 to 6 carbon atoms in the alkoxy group and 1 to 6 carbon atoms in the alkyl group, the aryl and the alkyl group and the other syrups have the meaning given in point 1. ε 22. The method of claim 21, wherein Q is C1-C6alkoxy, C1-C6alkyloxycarbonyl or C1-C6alkoxycarbonyloxy having from 1 to 6 carbon atoms. ^ ί ^ ρ oojldlt. 168 23. The method of claim 1, wherein said AC as starting material pouU ^ t ^ PM Vid-ICI sloučenin- of formula III to give a compound of vzooce I From R represents a group of - vzooce ^{- (CH 2)} m ^{- χ1 - From Q6 brand} currencies ^and m-cel ^e, with ^{1 and 4 χ3} lupine ^{- NH -, Y} represents month, ^Oy atom sl ^Io at UEE ^{in Binding and Q8 at} ^^ m Vudi ^{о u о} and ^{e y} AEM nominal t ^{о upiuu, the} lean and ^{DE P} ^ s c ^s nominal shading group -lk ^y alkoxycarbonyl having 1 to 6 carbon atoms optionally substiuuovanou Рeteouc klickuf ^yl or optionally O-cРoáuSuuu rbuxylovuu group, p-KEMZ -cylová group and Pettroc ^y klic0á tubbtitukuty group and are further defined in claim 1 in the definition of R @ soouvisoos.is and other symmbly гз- ^ as defined in point 1. 24. The method of claim 23 wherein m is an integer from 2 to 4. ²⁵ . p ^ le ^{Claim 23} wherein the ^TIE ZT ^Q8 znameá - l.karbuu ^{plurality of projections y} Luvu tkupin ^No. 1 Cy v v pod-^ popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě popřípadě. C 1 -C 6 alkyl or pentenoic or hexagonal nitrogen containing a nitrogen-containing group which is optionally substituted by a cyclic group a C1 -C6 -cyclic group, wherein the nitrogen-depleting Peterocyclic group is as defined in point 17. 26. The method pudke claim 1 wherein Zt j st-ku starting material ponížjt PM ^ Vid-ICI vzooce compound of III to give a compound of vzooce I p ^ KEMZ -cyluvý poddl acyiované aгхпозЗоирхпу corresponds to the formula ^{R 6 - N} " WHAT Since Zn ^{e -} Me ⁿ and R ⁸ cPiánicí ntlto quick match quick match Oto-EtO ⁱⁿ a ^ooce R ⁸ - (CH 2) n - CO n _x Since ^{e lower} alkylene R ^{8, and} if tubstiUuov Nuu toterucyklictou quick match and _η χ ^c elé ^{CI io 0-2 and R7} ^ when ^ ga ^ ^f bstiuuovanou en ^yl ^^^ uu quick match ntto after ^{P at} pH and ^EC subst ^ UOV et ^{-nuu p to} r ^{u u} cyklicto group optionally přčkemž substiuuov-NE group, and other symbols are defined in detail bo? · du first 27. The process of claim 1, wherein the compound of formula III is used as the starting material to form a compound of formula I, wherein the acylated moiety of the -cylamino group is a group of formula R ¹¹ - C - ^- CO II • N l 12 ' 0 ~ R ^{'Ode knows} me ⁿ and R ^ when ^11-ga subst ^ ^p uovanuu eterocyklictou quick match n ^eb oo ^o PRIO ^-d ^ b ^ ito ¹ 12 - * ^ ^va Nou f ^{e i} ^ phenyl ^ ^uu pin in R is hydrogen - ^{plurality of projections} hunting quick match with ^{1-6 and we} at ^p sorry ^OR group of the formula ^{Ode knows} me ⁿ and ^{R33 and} ik ^y the ^{ovuu with} Oupia ^nu s is ^from 1 to ⁶ carbon uhlíto ntto and ^also knylen ^ovo at StopIN ^{1 to 6} . toms ^{and up} LIO ^{u R14} 0 ^- rb ^oxy L ^{ovuu not} bo tsttr ^f f ^O O to- ^and Niu rbuxy.ovuu quick match-p ^ l .enté ^{in nuvO-} in the formula means a group ZT son or anni 0onϋefr -C and, optionally, sulfonyl groups and other symols have the same meaning as described in item 1 above. 169 28. A process according to claim 1, wherein the starting material is a compound of formula (III) to give a compound of formula (I), wherein the acyl moiety of the formula (III) is a group of the general formula (I). of formula ^r18 ' ^{- r19} 0H2- CO ^- de znrmey ^{and R1} ® ^{P P} A ^de Lean tubsti ^t uovanIt ^and eterIcý ^and LIC they quick match ^to R ¹⁹ and p-direct bond or a sulfur atom přččemž after a ^{case-tubstituovtné} groups are further defined in point 1. 29. The process of claim 1, wherein said starting material is an additional quaternary formula (III) to form a compound of formula (I), wherein the acyl moiety and the amino group is a group of formula (I). Wherein Q is an amine or protected amino group and Q is an O (C 1 -C 6) alkyl group having from 1 to 6 carbon atoms, an (C 1 -C 6) alkenyl group having the formula: -ch ₂ -cooq ^{9 a} group of the general formula 0Co ^{I 3 9} - C - COOQ AND 0H ₃ and COOQ - (-) - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 30. A process according to any one of Claims 1 to 29, wherein the starting material is a corresponding compound of formula III to form a compound of formula I, wherein R @ ¹ has a beta configuration and the X group is alpha-alpha. circle. 31. The process of claim 30 wherein the starting material is an Idp IV addition compound of formula (III) to form a compound of formula (I), wherein the ^R group has a moiety. with respect to the trace with ^y mbol R ¹ . 32. The process of claim 30 wherein -žt - e Jato starting material used (ldpρIVdatící compound of formula III to give a compound of formula I wherein ^R has ^the cis ^and ^ I ^ ^I ^ i ^ ^6; rr ^ i with reference to the trace of R ¹ . 33. The process of claim 1, wherein the starting material is a compound of formula (III) to give a compound of formula (I) wherein X is hydrogen and the other symbols are as defined in (1). 34. The process of claim 30, wherein the starting material is a compound of formula III to form a compound of formula I wherein r1 is a group of formula C-CONHX 1 8 Q — Q ⁸ 170 Wherein Q is a C1-10 protecting group and a C1-C6-alkyl group having 1 to 6 carbon atoms; -CH ^g COOQ ⁹ otbz a group of general formula ¹ 3 9 - C - COOQ AND _CH3 and COOQ ⁹ is ^to -rboxylovou slkupiou NCbz cstcrif of ^KL-yl sometimes inappropriate ^to -rbzo Iva with ^the upiou and ^R zoamtoá vzorcc KDC group of Q ³ and 1 ¹ a as ^E has the same NCbz-ί different, Zn-amcn is a water atom of 1 to 6 carbon atoms. 35. A process ^{P b} odlc ZDU З ^{4, characterized} zoačen ^χ t ^2, Q ·· · means rmiogroup. from —material to ¹ hydrogen atom - 36. ^p úszb podlc item 34, wherein ^p zt SKU ior R has the trans configuration st '1 · ztotchm NR ^y group, with MboI ^r1. 37. The method podlc misery 34 wherein Zt skupin- R has a cis configuration from ^row st CTE ^c em NR ^y group with MboI ^r1. 38. A process according to claim 34, wherein the compound of formula (I) is prepared in racemic form. 39. The process of claim 35, wherein the starting material is a corresponding compound of formula II to form a compound of formula I in the form of an inert salt of formula II. kdt Q has the meaning given in paragraph 34. 40. The process according to claim 1, wherein the starting material is a corresponding compound of formula III to form trlos-3- [2- (12-chloro-1,2,3-aol) -12,212-quinolyl-12-cyclohexyl-ethylzoyl]. -cet-mideZ-4-methoxylcarbonyl-2-oxo-t-CddnnllSulOn-tonic acid (synisomer), cis-3,11- [lalaainzl4-tcitzzlyll-11alzol-1-oxinocreteine] -4-methoxylcarbonyl-3-cosulfonamide -2-4--21aaino th1azolyl - 2-ieCOooyimiool tcetamid ^and Z-4-Xk- ETCz ^{of R 2} boyl- 2looo1et ^e d ⁱ n L ⁿ ts ^f0 ONOO acid N, N-isomer, cis ^-3 - [ ^- - / ^- 4-ltmino tCiazzl 12lkarboOoxateCOoxyiInnooacctamido ^yl] -4-meChcooУkrbonojl2-zxzal-ZCdinnllSuUfOl new acid уи ^ ^ ^ отес, cis-32 [- / - 1min-l- · lhitzzlyl / -22 / L-aetCχl 4-Methyl-4-isomeric acid, cis-3,11- [2,2 / 2-methyl-4'-ZzZyl (---- / 11'-methyl-1-methyl-1'-methyl) ethyl] -1'-methyl-4-methyl-4-isomeric acid 4-chloro-4-carbonyl-2-oxazolecidyl -1-sulfontvé (SSN-istmeru) trans-3- [2-2-2aamlnt tliaztlsl 4 ^y / 2 2 / lmselhyllkarbtxsstlyltxsieino / acetaeidot 4-karSametl --- otxtzetidfn suitontvé-L-cis-3- (2 -22amino-4-lhaatoly-2-2-methylthiomethyl-amino] -4- ^to asbamtyltxysulfonyl-5-oxo-1-sulfonic acid cis-3- [2- / 2-amino-4-thiazolyl] -2- (1-mstlsl.-llsbsbtxsstlsloxyimine) iacetinidet--acteamidethmethyls-2-α-oxazetidine-1-sulfonic acid (syn-isxmer) or cis-3- [2- (2-amino-4-thiazolyl) -2171-methylthiazol (4-xyxyl) methyl] -; Methylmethylene-1,2-hexaetidine-1-sulfonic acid (syn-mesmes). 171 41. snlslujs 2. The process of claim 1 wherein the starting compound of formula (III) is a silylating agent. 42. The method of claim 41, wherein the silicating agent has a group of formula Y ¹ . - Si - Y ³ 12: wherein Y ¹ and a group, a group. 2 Y is C 1 -C 4 alkyl, phenyl, benzyl 3 C 1-4 alkyl and Y is tert -butyl or isopropyl 43. 1 2 3. The method of claim 42, wherein both Y and Y are each alkyl C 1 -C 4. 44. The process of claim 43, wherein the C1 -C4 alkyl group is a methyl group. A process for preparing a compound of formula -C-CONH CH CH ₃ II _{2. A process} according to claim 1, wherein the protecting group is removed from the compound of formula (I). CONH ₂ C-CONH ^SO 3 ^H 0-C-C00Q ³ p I CH3 ^wherein z ^e ^^ ° and ^Q7 Neno amino and ^{cooq9 CHR oěntu sкupnnu axis} b ^{t is} from her salt or ester thereof. 4 · 46. The method of claim 7, wherein R is carbaoyoyloxy. 47. The method of claim 7 or 46, wherein R and R, which are the same or different, are hydrogen or C1-C6alkyl. 172 2 * 3 * 4 48. The process of claim 7 wherein R and R are each hydrogen and R is carbamoyloxy. 49. The method of claim 7 or 48, wherein n is zero.