CS244105B2 - Method of beta-lactams production - Google Patents

Abstract

.beta.-Lactams having a sulfonic acid substituent in the 1-position and an amine function in the 3-position and having the formula: (see fig. I) wherein R1 is H or acyl derived from a carboxylic acid; R2 is H or alkoxy; R3 and R4, the same or different, are H, alkyl, cycloalkyl, phenyl or substituted phenyl, or one of R3 and R4 is H and the other is alkoxycarbonyl, alken-1-yl, alkyn-1-yl, 2-phenylethenyl or 2-phenylethynyl; and X is H or SO3X is SO3-M+ wherein M+ is a cation, and the use of said .beta.-lactams as antibiotics.

Description

The present invention provides a process for the preparation of compounds of formula (I)

(AND)

in which

R1 represents a hydrogen atom or an acyl group as defined below,

R ₂ represents the hydrogen atom or an alkoxy group. having 1 to 4 carbon atoms,

R1 and R1, which may be the same or different, are each hydrogen, C1-C10alkyl, C3-C7alkylalkyl or phenyl optionally substituted by one, two or three substituents independently of one another selected from the group consisting of amino stopin, halogen atoms, hydroxy, trifluoromethyl, C 1 -C 4 alkyl and C 1 -C 4 alkoxy, or one of the ebmols R 1 and R 3 is hydrogen and the other is an alkenylcarboxylic acid; C1-C10 alkoxy, 1-alkenyl of up to 10 carbon atoms, 1-alkenyl of up to 10 carbon atoms, 2-phenylethyl or 2-phenylethyl and

M ⁺ represents hydrogen or a cation of the siphonic acid residue.

These records have the above general symbols throughout the text.

In addition to the abovementioned beta-pharmacies containing a sulfonic acid residue at the 1-position and an acyl amine substituent at the 3-position, the invention thus also includes beta-1 (s) reducing the sulfonic acid residue at the 1-position. ) and at position 3, the amine s ^ 1 ^ b ^ s ^ tluei ^ t ·

Preferred compounds of this type are of formula (Ia)

Cla)

These compounds are intermediates used for the preparation of the corresponding 1-acyl amino derivatives.

The term acyl group in the meaning of the symbol R1 it includes all organic residues derived from an organic acid (i.e., a carboxylic acid) by cleavage of the hydroxyl group. Certain acyl groups are preferred, but the scope of the invention is not limited to these preferred clues. Examples of acyl groups include the acyl stoppers that have been used to date to acylate beta-1 scouts including 6-amiaoponacilimic acid and derivatives thereof and 7-amlaocephalotporic acid and derivatives thereof - see e.g. ^{F lyaa,} Academic Press DOS ^No. 2 · 7 ¹⁶⁶⁷⁷ published October 10, 1978, Belgian Pat. No. 867,994 published December 11, 1978, US Pat. No. 4,152,432 issued May 1, 1979, US patent no. No. 3,971,778, issued July 27, 1976, U.S. Pat. No. 4,172,199, issued October 23, 1979, and British Patent, issued March 27, 1974. Parts of these disclosing various acyl traces are incorporated herein by reference. .

Suitable acyl traces in the meaning of the symbol R were:

Ca) aliphatic traces of formula θ! »

R5-C244105 represents alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, cyclohexadienyl or alkyl or alkenyl substituted with one or more substituents selected from the group consisting of halogen atoms, cyano, nitro, amino, alkyl, mercapto;

(b) carbocyclic aromatic groups corresponding to formulas d; I ³ · »4 ° C

«7

or having a value of 0, 12 or 3, R? and R 6 independently represent a hydrogen atom, a halogen atom, or a hydroxyl atom;

group οδ ^ ^^ ^ ρΐ, skip inu amino, cyano, triflooiπιetlyrioviu skipinu, alkylϋϋ group having 1 to 4 carbon atoms, tlkoxytkupiuu having 1 to 4 carbon atoms or aiinometth Liviu group and ^R

represents an amino group, a hydroxy group, an oxy group, a carboxy-protected group, a carboxyl group, a firium group, a sulfonium group, a sulfonium group in the αϋϋ form, an azide group, a halogen atom, a hydrogen atom, a hydrogen atom or a hydrogen atom; alkyl and ^L ^ ^y drtzinitk: u ^p IUU ^f euylhy rtzinit ^{d to} u uu ^pi ILkУ ^ylthio or ^R i) - ^ ^^ ходеНЬт ЗД1 the group.

Preferred corbocyclic aromatic acyl groups include radicals corresponding to the formula

CH2NH2

wherein R 8 is preferably a carboxyl group in a salt, and in the form of a salt or sulfo group in the form

wherein R8 is preferably a carboxyl group in the salt form or an azo group in the salt form;

(c) acetylene acetylation 0 n 10 ^((CH 2 ⁾ n ^{C C-}

* 10 '

O

It

R | _{0 -S-CH2} -Cnebo

0 Π II Rkj-c-cj in which n is 0, 1, 2 or 3,

Rg is as defined above and

R 10 represents optionally substituted 5-, 6-or 6-substituted heteroaryl to the ring of 1, 2, 3 'or 4 (preferably 1 or 2) nitrogen atoms, rabbit Mbo, and

Examples of heterocyclic rings include the thienyl, the yl, the phenyl, the pylidinyl, the pyrazinyl, the thiazolyl, the morrooinyl, the pyrinidinyl and the tetrazolyl. Examples of substituents lae include halogen atoms, hydroxyl group, nitro group, amino group, cyanostapine, trifluoroethyl, C 1 -C 4 alkyl or C 1 -C 4 alkoxystapine.

Preferred heteroaromatic acyl groups include those groups of the above formulas wherein R 1q represents a 2-aminoo4-thiazolyl radical, a 2-aminoo-5-haloβee-4-thiazulyl radical, a 4-amino-pyrimidin-2-yl, a 5-amino-1,2,4- thltditzol-5-yl, 2-thleoyl or 2-Olooyl residue;

(d) ^{C (P} i ^P /4-tlStt.-2.3-dioχu-1- ertzioyl / ^s who u! ^MFL) йш! ™] ωoyltce ^t yluvé generally causes ^the dough ^ o

formulas 0 0 n Λ / ~~ C-CH-NH-CN NR ₁₂ * 11 Л

in which

R 1 represents an aromatic group, including aromatic carbocyclic radicals, such as those of the formula

and heteooarumatic residues as defined in the definition of the symbol a

RL2 represents an alkyl hundred ^P inu optionally substiuuověrnou эдЬо one or more substituent groups selected from-the group includes! halogen atoms, cyano, nitro, amino, and further represents trylmethylenamioostapine, i.e. a group of the formula -N = CH-R, wherein R R is as defined above;

a group of the formula -NH-C-R 3, wherein R 1 is as defined above, or ethylcarbonyl. plnu.

^M is preferably ^{the E} Ezi ^Q / TL-4 ^with зt. ^diuxo--2,3-1 - ^pi peotzioyl / kasboo ^yl) ξmio ^{u] l} toy tcetylové groups náležeeí those in which R? represents ethyl, phenylethylenethoxy or 2-furylaethyleneaminostapine;

(e) a (tert-butyl) imidyl group of the general formula

O

II

-CC = NOS ₁ wherein:

R 3 is as defined above and

Rjj represents a hydrogen atom, a stylish group, a cyclostyl group, a styrene group, a trifluoromethyl group or a group (i.e. a group of the formula -C-NH-R 1, wherein · O)

R 1 is as hereinbefore defined) or a substituted Style group comprising one or more tubstitueotes selected from the group consisting of halogen atoms, these groups, a nitro group, an amino group, a mercapto group, an alkylthio group, an aromatic group (as defined for R 1), carbosxy (including salts thereof), amldosloipinu, alkoxykarbonplovou group fenylenthoxykarbonylovou group difenylmethojykarbonylovou group hУ <l ^ ^{'0 эχ} г alkooyfo8finyllvé group dihydroлyfolfinylovou group hyd ^r ° 5Qyfenylmeehhxy) fosfinylovoe group and groups dialklχyfl8finyllvé ·

Preferred (substituted oximino) arylacetyl groups are those wherein R 1 is 2-amino-14-thiazllyl. Preference is also given to those groups in which R 3 represents a methyl group, an ethyl group, a carboxymethyl group or a 2-carboxyisopropyl group;

(f) the (acylamino) -4-acyl groups of the general formula

O O

H II

-c-ch-nhc-r ^ in which

R 1 is as defined above and R 4 is a radical of formula

where n is 0, 1, 2 or 3 and R 8, R 8 and R 8 are as defined above, amino, alkylamino, (cyanalkyl) amino, amido, alkylthimido, (kyaialtyl) amido 810-4 ™, the remainder of the formula * - ²⁰

I I

-CH-C 1 -C-NH-CHp r

- CH ₂ - NH - C

OH

Preferred (acylamino) acyl groups of the above formula are those in which R 14 is amino or amido. Also preferred are those in which R 1 is phenyl or 2-thienyl;

(g) E (3-Substituted-10-oxo-1 _- imidazolidinoyl) (amino) amino (allyl) _and cetyl groups of the general formula

O. 11 -C-CH-NH-C-n '

II

I ^R 11 in which

R1 is as defined above and

R 1 represents a hydrogen atom, an alkylphenyl group, an arylethyleneamino group (i.e., a group -N = CH-R 1, wherein R 1 is as defined above, a group -C-R 1 g (where R 1 g represents an atom)

(Hydrogen, alkyl or halogen substituted alkyl), an aromatic group (as defined above for R 6)> an alkyl group or an alkyl group substituted by one or more substituents selected from the group consisting of halogen atoms, cyanostaupine, nitro, amino or may be substituted;

Preferred [(3-methyl-2-oxo-1-imidazolyl-carbonyl) carbonyl] amino] aryl groups of the above general formula include those wherein R 1 is phenyl or 2- (1-methyl). Also preferred are those in which R 5 represents a hydrogen atom, a methylsulfonyl group, a phenylmethyleneamino group or a 2-furylmethyleneaminosuccinine.

Unless expressly stated otherwise, the terms "alkyl" and "alkoxy" as used herein are intended to mean both straight and branched chain. Preferred are those groups having 1 to 10 carbon atoms.

The terms cycloalkyl and cycloalktnyl group mean cycloalkyl and cycloalkenyl groups containing 3, 4, 5, 6 or 7 carbon atoms.

The term alkenyl group refers to both straight and branched chain groups. Preferred are those groups having from 2 to 10 carbon atoms.

By halogen is meant fluorine, chlorine, bromine and iodine.

As used herein, cation refers to any positively charged atom or group of atoms.

The &lt; RTI ID = 0.0 &gt; -SO2M * &lt; / RTI &gt; Of course, pharmaceutically acceptable salts are preferred, although other salts are useful for the purification of the products of the invention or as intermediates for the preparation of pharmaceutically acceptable salts. The cationic moiety of the sulfonic acid salt of the present invention can be obtained from any organic or inorganic base. This cationic moiety includes, but is not limited to, the following ions:

ammonium ion, tubstituted ammonium ions such as alkylammonium ions (for example, tetra-n-butylammonium ion, hereinafter referred to as tetaabutyammonium ion), alkali metal ions such as lithium, sodium and potassium, pyridine ion, dicycloyl γ-lithium ion, The LD 3 is an ionic ion.

alkaline earth metals such as calcium and magnesium, hydrabarninyl ion, benzathinium ion and N, as mentioned above, the symbol

M + is hydrogen.

As described below, the beta-lakaams of the invention may be prepared synthetically. Non-alkoxylated, 4-unsubstituted beta-lakes of formula I, i.e., those compounds of formula I wherein R 8, R 8 and R 8 are hydrogen atoms, can be prepared using β

6-aminopenicillanic acid or 6-acylaminopenilcianoic acid as starting material. The beta-lactams of formula I in which they are alkoxy may be prepared from the corresponding non-alkoxylated beta-lactams.

Some of the compounds of the invention may be crystallized or recrystallized from water-containing solvents. The invention encompasses both stoichiometric hydrates and compounds containing varying amounts of water which may be formed by processes such as lyophilization.

The beta-lactams containing at position 1 an eubstistuent consisting of a sulfonic acid salt residue and an amino or acylamine substituent at position 3 contain at least one chiral center,. namely, the carbon atom (at the 3-position of the beta-lakiam nucleus) to which an amino or acylamine substituent is attached. The invention relates to those beta-lactases described above wherein the stereochemistry at the chirality center at the 3-position of the beta-lactam nucleus is the same as the configuration at the carbon atom at the 6-position of the natural penicillins (e.g. penicillin G) and cefamycin (e.g., cefamycin C).

With respect to the preferred beta-lactams of formulas I and Ia, their structural formulas have been drawn to show the stereochemistry of the nacetra chirality at the 3-position. Because of nomenclature convention, those compounds of formulas I and Ia in which Rg is hydrogen are S and those compounds of formulas I and Ia wherein R? represents an alkoxy group, R configuration.

Racemic mixtures containing the above-described beta-lactams are also within the scope of the invention.

The beta-lactams containing the 1-position substituent of the sulfonic acid salt moiety and the amino or acylamine substituent at the 3-position of the beta-lactam core exhibit activity against a wide variety of gram-negative and gram-positive organisms. The substituent of the sulfonic acid salt residue plays a decisive role in the activity of the compounds of the invention. Particularly useful activity is shown by those compounds in which R @ 1 and / or R @ 2 is hydrogen or alkyl, especially methyl.

The compounds of the invention can be used to combat batkerial infections (including urinary tract infections and respiratory tract infections) in various mammalian species, such as domestic animals (e.g., dogs, cats, cows, horses, etc.) and humans.

To combat bacterial infections in mammals, the compound of the invention may be administered to a mammal in need of such treatment in an amount of from about 1.4 mg / kg / day to about 350 mg / kg / day and preferably from about 14 mg / kg / day to about 100 mg / kg / day. mg / kg / day. All the routes of administration that have hitherto been used to bring penicillins and cephalosporins to the site of infection can also be used for the novel class of beta-lactams of the invention. These delivery methods include oral administration, intravenous administration, intramuscular administration, and suppository administration.

The beta-lactam derivatives are prepared in accordance with the invention by introducing a sulfonic acid (sulfo -SO4-) residue on the nitrogen atom at the 1-position of the beta-lactam core. This sulfonation reaction is readily accomplished by reacting the beta-lactam with a complex containing sulfur trioxide or an equivalent sulfonating agent such as chlorosufonate.

The most commonly used complexes containing sulfur trioxide are pyridine - sulfur trioxide, lutidine - sulfur trioxide, dimethylformamide - sulfur trioxide and picoline - sulfur trioxide. Instead of using a previously prepared complex, it can be prepared in situ, for example using chlorosulfonyltrimethylsilyester and pyridine as reagents. Alternatively, the sulfonation may be accomplished via a suitable intermediate, such as by first silylating the nitrogen atom of the beta-lactam core and then silylating the silyl compound by reaction with trimethylsilylchlorosulfonate or the like. Examples of suitable silylating agents include monosilyltrifluoroacetamide, trimethyl-244105 silyl chloride-triethylamine and bis (trimethylsilyl) trifluoroacetamide.

Generally, the sulfonation reaction is carried out in the presence of an organic solvent such as pyridine or a mixture of organic solvents, preferably a mixture of a polar solvent such as dimethylformamide and a halogenated hydrocarbon such as dichloromethane.

The product primarily formed in the sulphonation reaction is a sulphonated beta-lactam salt. When pyridine and sulfur trioxide are used as the sulfonation complex, the primary product is the pyridine salt of the sulfonated betarlactam below wherein M ⁺ is the pyridinium ion of the formula,

These complexes can be converted to other sulfonic acid salts by conventional methods, for example by ion exchange, crystallization or ion pair extraction. It is particularly suitable. conversion of the pyridinium salt to the potassium salt with potassium phosphate or potassium ethylhexanoate, to the tetrabutylammonium salt with tetrabutylammonium hydrogen sulfate, or to the zwitterionic (M ⁺ = hydrogen) using formic acid.

It will be appreciated that the sulfonation reaction to introduce the sulfo group on the nitrogen atom of the beta-lactam nucleus can be carried out at various stages of the synthesis, including introduction prior to the formation of the beta-lactam nucleus, as described below. The sulfonation reaction is carried out in the presence of the solvents described above, usually at room temperature. In the presence of an amine function, it is preferred to work to protect the amine function.

For example, using a benzyloxycarbonyl protecting group, the sulfonation reaction may be illustrated by the following reaction scheme:

sulfonation (II)

removal of the Protective Group

(III)

Other protecting groups may be used to protect the amine function, for example tert-butyloxycarbonyl, simple acyl groups such as acetyl, benzoyl or phenylacetyl, triphenylmethyl, or the amine function may be protected as an azide group, the desired acyl group (R 6). it can then be introduced by a conventional acylation reaction.

An example of an acylation technique useful for converting a compound of formula III to a product of formula I is by reaction with a carboxylic acid corresponding to R 1 -OH, or with a halide or anhydride of the corresponding carboxylic acid. When R2 is alkoxy, it is best to perform acylation using an acid chloride or bromide.

The carboxylic acid reaction is most easily carried out in the presence of a carbodiimide, such as dicycleexylcarbodiimide, and a substance capable of forming an in situ activated ester, such as an N-hydroxybenzotri group or groups (such as amino or carboxyl groups). finally, cleave off the resulting protecting group product.

Alternatively, it is already in place, i.e., the sulfonation reaction can be stored if the following reaction scheme;

the acyl group is

->

sulfonation

(IV)

An excellent source of the starting beta-lectic compounds are 6-aminopropicilanic acids and 7-aminoacetic acid, which may optionally be substituted at the 6-position or the 7-position by an alkoxy group. These compounds correspond to the general formulas XXVa and XXVa, respectively. XXVb

(XXVa) (XXVb) in which:

Ib> represents a hydrogen atom or an alkoxy group and

R 1 represents a hydrogen atom or an acyl group. group.

By the literature procedure, 3-thio-2-azetidinones can be prepared [cf. Soc. Speeitl Pittsburgh No. 28, 288 (1977), The Chernistry of Pee-Hins, Princeton Univ. Press, p. 257, and Synthheis, 494 (1977)].

6-Amisipinisilanoic acid or 7-aminocephthalosporanic acid is first desulfurized by reduction using Raniennicl. The reaction can be carried out in refluxing water. The resultant compound corresponds to the general formula XXVI

24410>

(XXVI)

Substitution of the carboxyl group in the compound of formula XXVI with an acetate group and subsequent hydrolysis affords the 3-amino-3-alkoxy-2-azetidinone of formula I wherein a is hydrogen, R 1 is hydrogen or acyl and R 2 is hydrogen or lower alkoxy. Reaction of a compound of formula XXVI with copper (II) acetate and lead (II) acetate in an organic solvent (e.g. acetonitrile) replaces the carboxyl group with an acetate group. Hydrolysis of the resulting compound can be accomplished using potassium carbonate in the presence of sodium borohydride.

The starting 3-azido-2-azetidinone can be prepared by starting from an olefin of formula XXVII

(XXVII) is reacted with 3 halosulfonylisocyanate (preferably chlorosulfonylisocyanate) of formula XXVIII

O ⁼ ON-SC &gt; 2-halogen (XXVIII) to give the azetidinone of formula XXIX

^R 3 (XXIX)

N-SO4-halogen

Reductive hydrolysis of the azetidinone of formula XXIX yields the unsubstituted beta-lactam of formula XXX

(XXX)

A more detailed description of the above reaction sequence can be found in the literature (see, for example, Chem. Soc. Rev., Ц, 181 (1976) and J. Org. Chem. 2,043 (1970)].

The azido group can be introduced at the 3-position of the azetidinone of formula XXX (or the corresponding sulfonated analog) by reaction with an arylsulfonylazide (such as toluenesulfonylazide) to give the starting azetidinone of formula XXXI ^N J

(XXXI)

Preferably, the reaction is effected by first protecting the azetidinone residue nitrogen with a silyl residue (e.g., a tert-butyldimethylsilyl residue or a tert-butyldiphenylsilyl residue), then producing an anion at the 3-position of the core at low temperature with a strong organic base (e.g. lithium diisopropylamine). this anion is then treated with toluene sulfonylazide. The resulting intermediate is treated with trimethylsilyl chloride, followed by acid hydrolysis or fluoride solvolysis to remove the nitrogen protecting group to give compounds of formula XXXI.

Alternatively, the compound of formula XXXI can be obtained by first reacting the primary amine of formula

H ₂ N - CH ₂

O-Alk ^H , N ° - ^Alk

wherein Alk is an alkyl group, with an aldehyde of formula

R ₃ CH = O to form Schiff base · (2 + 2) cycloaddition with activated form of azidoacetic acid to give 3-azido-2-azetidinone of formula

in which

Q is a radical of formula

O-Alk

Subsequent cleavage of the substituent Q yields a compound of formula XXCI.

3-Acylasino-2-azetidinones can be obtained by first reducing the 3-azido-2-thiazetidinone of formula XX &apos; to give the corresponding 3-thmino-2-thiazetidinone, and then tert-butyl 3-thmino-2-azide.

When Rg is lower alkoxy, the product may be prepared from the corresponding analogue in which Rg is hydrogen.

Chlorination of the amide nitrogen of the alumina compound yields an intermediate of formula ΧΏΧΙ

1 --------------------- j 1 I-SO.

(XXII) The reagents and procedures used to chloro the amides on nitrogen are known in the art.

Examples of suitable agents include sodium hypochlorite and chlorine.

The reaction may be carried out in an organic solvent (e.g., a lower alkanol such as methanol) or biphasic solvents of the system (e.g., water-methylene chloride) in the presence of a base such as sodium borate decalhydrate. The reaction is preferably carried out at a snow-topped temperature. '

Reaction of the intermediate of formula XXX with an alkoxylating agent, for example an alkali metal alkoxide, yields the product of formula I in which R8 is alkoxy, in combination with its enantiomer. This reaction can be carried out in an organic solvent, for example in an organic solvent, such as in dimethylformamide, at reduced temperature.

An alternative synthesis suitable for the preparation of compounds of formula (I) in which R8 is an alkoxy group consists first of an alkoxy product of formula (V) wherein the RNH moiety is a carbamate residue (e.g. and R 8 is a hydrogen atom enriched in the introduction of the sulfo group at the 1-position of the resulting compound. The compounds of formula (VI) are treated using the procedure described above (used to convert a non-carbocyclic compound of formula (I) to a compound of formula (XXXI)) to yield a meel product corresponding to formula (XXXII).

Cl l

C ₆ H ₅ -CHg-Q-CQ-N --- 1-

0 * ^

(mni)

Using the alkoxylation process described above (to convert a compound of formula XXXI to a product of formula I) followed by the addition of a reducing agent such as trimerthifosite, the compound of formula XXIII can be converted to the intermediate of formula XXXIV

in combination with its enantiomer.

The above processes yield those products of formula (I) wherein R 1 is alkoxy, such as racemic salt. If desired, the corresponding R-configuration enantiomer can be isolated from the racemic mixture using conventional solutions, such as fractional crystallization of a suitable salt with an optically active organic amine, or aromatic pairs ^, or pairs using optically active cations.

The invention is illustrated by the following. however, the scope of the invention is in no way intended

Example 1

(S) -N- (2-t-1-S-t-3-azrtidenyl) -f-phenyla-potassium potassium salt

Method I

A) 1- ^r Ϊ 1 ^R ) -carb 5 ^χ r-2-methyl ⁽ 1-pryl) ^J -2- ^ 0- (33) - ^f -n ^- 1 (ac-tl ^a ml.nl/)Jazrt ^iíie

Ranne-nkl was purged by decanting water for several hours until the pH of the water was 7.6 (5 to 6 times the volume of water, based on ЖЖ г гш-пPПП ^: 1) was used.

To a solution of ⁹ 0 ^g penncilinu ^G (Na **) in ⁵⁰⁰ ml of water přUá 5 ⁴ g ^{(9 0} mL) ^ non-nickel and reaction ^flask, chilled reflux opatřerá ičeo ^{s is p} onnří to l ^and Zn ^with the ¹⁵⁵ ° C. ^p o are ^and TKU boiling in zadívání boiled under way ^ ^ what Nym chilled poraduje Ješ ^{ts 15} minutes NACE bank okamžžtě ^z is cooled in ice water and the Realee-Nekl ldíiltruj- through Ořroorinc (οβ - ^ -). The pH is diluted. The solution is concentrated to about 150 ml and cooled. The oil layer crystallizes after trituration. After three hours PROBYT water and drying under vacuum ^at s temperature of 5 ⁰ C ^ ka of ^{3.83 g} of compound UV-ene HV ^and invite.

^{B) 1 -} Γaírt ^- LRX - 2-yl ^th mr. (propyl-2-oxo): 3S.5 - [phenyl (acetyl) acetyl;

A suspension of 608 mg (2 M) of the above compound in 20 mL of dry ace-o-o-gilc was stirred with nitrogen for 15 minutes. To dissolve all of the acid from pouužje někcOikaminutového hřevu ^plated on a ^water-la destruction of te ^ OTE ^{40 and 4} 5 ° C. Water-l-Zen paragraph Raji, ^e mixture was added 182 mg (IOOO) powder moneOy-rátc ažánatého acetate and after stirring jednominctrvém then 886 mg (2 mnoD lead acetate itého ^. The resulting mixture was stirred for 20 minutes at an ACE The solution was decanted from the precipitate and the solid was washed with ethyl acetate, and the combined solutions in acetonitrile and rth-lacrtate were removed by evaporation and the residue was taken up in a mixture of rth-lacrtate and water.

The ethyl acetate layer was washed successively three times with water, aqueous sodium bicarbonate solution (pH 7) and again with water. The ethyl acetate layer was dried with sodium sulfate and washed to a residue of 515 mg, which was used in the next reaction without further purification.

C) 2-oxoo (3S) -fluoro (acetyl (amino)) Jaztidin

To a solution of 911 mg (2.86 mamo) of the above compound in 21 mL of methanol was added first S, 5 mL of water and then S8S (&^gt; 86 mol) of potassium carbonate. The mixture was stirred under nitrogen for 1 hour and 160 mg (4.0 mmol) of sodium borohydride was added. The reaction mixture was stirred at Ostnoot for 20 minutes, the methanol was removed in vacuo and the residue was taken up in ethyl acetate and a little water at pH 2.5. The ethyl acetate layer was washed at pH 7.0 with aqueous sodium hydrogencarbonate solution and then with a small amount of water, dried over sodium sulfate and finally evaporated to give 493 mg of crude product which, after addition of a small amount of ethyl acetate, yielded 250 g. mg (yield 43%) of the desired crystalline product. Further amounts of product may be obtained by crystallization or by chr / mol / era.

(D) Potassium salt of (S) -N- (2-oxo / 11SuUf) -S-1-azididioyl) -2-chloro-octyl amide

To a solution of 251 mg (1.23 oaol) of the above product in 2 ml of dry diethethoamide and 2 ml of dry MeOH is added in a nitrogen atooopher at room temperature with stirring, with pyridine-ooid sulfuric acid 215 mg (1.5 ml). . The resulting mixture was stirred for 3 hours, the solvents were removed in vacuo, the residue was taken up in a mixture of methanol and water.

The pH was adjusted to 6.5 with 2N sodium hydroxide. The aqueous layer was washed three times with methylene chloride, filtered and evaporated. The residue was stirred with 20 ml of oethuool and sulfate. The potassium is filtered off. The filtrate was evaporated and the residue was stirred with 10-15 liters of ethanol. The solid product was collected to give 49 mg of the title compound, melting at 189 ° C with decomposition.

Auaysis ^: calculated C 40.99% HS, 44% N 8.69% S 9.9S% i found S 45.99 »HS, 8S» N 9.86 »S 8.99 ».

This compound has the same spectral characteristics as the product obtained by Mot II.

Method II

A solution of 660 mg of potassium salt of (S) -2- / oo £-3- (/ feolloethoэolkаrЬo / oll ^N O ^T A O [11- ^ 1 ^ 111fonové acid (Example S) in В ml water in hydrogen at ^ · The mixture was stirred with 200 mg of 10% palladium and charcoal for 2 hours.

The catalyst was filtered off, the filtrate was diluted with acetone and cooled in ice. During S0 min add ftoyllcetylcl 8 doses / reef 40ц1 after the pH by addition of 10 »solution of hyphae ^г / eenoSličitaos udžuje solution between 5.2 and 5.8. After 40 minutes, the acetone removal solution is bent under vacuum and the residue is applied to a column of 200 µL of orbР-20 adsorbent. Boys with water and then a mixture of water and acetone (9: 1) afforded 160 mg of crude product (after analysis of Rg1020-β / Thin layer chromato / eryl fractions, pooling of the appropriate fractions and pad). Crystallization from methanol / ether gave 101 mg of the title compound, melting at 210 ° C with decomposition.

Anolysis: for C ,, ^ ^ ^ ^OCO: H, O; N, 8.45; S, 9.68% K, 11.80;

found 0 40.01 »H S, S7» N 8.59 »S 9.59% K 11, Я8».

NMR (deuterium oxide) δ 3.66 (singlet, ZN), 3.67 (doublet of doublets, J = 6.4), 3.90 (triplet), 4.90 (doublet of doublets, J = 6.4), 7 .36 ppm (multiplet, 5H).

Method XII

To a solution of 121 mg of (S) -3-amino-2-oxo-1-azetidine sulfonic acid tetrabutylammonium salt (see Example 6A) in 3 ml of dry methylene chloride, 40 mg of phenylacetic acid and 61 mg of dicyclohexylcarbodiimide are added. The dicyclohexylurea is filtered off, the solvent is evaporated off under vacuum and the residue is taken up in acetone. The solution is filtered and the title compound is precipitated by the addition of 5 ml of potassium iodide saturated with acetic acid. The supernatant is decanted off, the residue is washed three times with acetone and dried. 46 mg of the desired product are obtained, the spectral characteristics of which correspond to those of the product prepared according to methods X and XX.

Method IV

A solution of 2.83 g of (S) -2-oxo-3-Q ((phenylmethoxy) carbonyl) amino] -1-azetidine sulfonic acid pyridinium salt (see Example 2) in 36 ml of water was stirred with 707.5 mg under a hydrogen atmosphere. 10% palladium on carbon, absorbing 175 ml hydrogen · After 2 hours, the suspension is filtered, the filtrate is cooled to 0 ° C and diluted with 46 ml acetone (initial pH 4.25 adjusted to 6 with cold 10% potassium bicarbonate solution). 7) · The solution is added dropwise within 15 minutes

2.4 ml of phenylacetyl chloride in 10 ml of acetone while maintaining the pH between 5.2 and 5.8 by the simultaneous addition of cold 10% potassium bicarbonate solution. After 45 minutes, the resulting suspension was diluted with 93 mL 0.5M potassium phosphate (pH 4.2) and evaporated to remove acetone. The residue is filtered, washed with water, the filtrate combined with the screening liquids and applied to a column of 450 ml of HP-20 adsorbent. The column is eluted first with 1 liter of 0.5 M potassium phosphate solution (pH 4.2), then with 1 liter of water. and finally 2.5 liters of a 9: 1 mixture of water and acetone. From fractions 14 to 19 (fractions 1 to 15 are taken in 200 ml portions, fractions # 16 to 1 .pb 100 ml), 1.285 g of the title compound is obtained. · Spectrum data are consistent with spectral data compounds prepared according to the foregoing methods.

Example 2

(S) -2-Oxo-3-f ((phenylmethoxy) carbonyl) amino] -1-azetidine sulfonic acid salt of 8 with pyridine (1: 1)

Method I

A) 1-Q (1 R) -carboxy-2-methyl (propyl)] -2-oxo- (3 S) -Q ((phenylmethoxy) carbonyl) amino] azetidine

To the Raney-nickel suspension (washed with water to pH 8.0; 260 ml suspension «130 g) 8 · add 12.98 g (0.06 mmol) of 6-amino foam in a single portion of the suspension with vigorous mechanical stirring. of acid in 140 ml of water containing 5.18 g of sodium bicarbonate (stirred for about 10 minutes without complete dissolution). The addition of DC was carried out with heating in an oil bath at 70 ° C. After 15 minutes the resulting suspension was cooled, filtered, and 5.16 g of sodium bicarbonate solution of 11.94 g (0.07 mol) of benzyl chloroformate in 12 ml of acetone was added to the filtrate. After 30 minutes, the reaction solution was acidified to pH 2.5 and extracted with methylene chloride. The organic layer was dried, evaporated and the residue triturated with ether / hexane. A total of 6.83 g of the title compound is obtained.

B) 1- [(acetyloxy) -2-methyl (for polyl)] -2-oxo- (3S) - (phenylmethoxy / carbonyl) amind] azetidine

To a solution of 6.83 g (0.0213 mol) of the above acid in 213 ml of acetonitrile was added 1.95 g (0.0107 mol) of copper acetate monohydrate and 9.5 g (0.0213 mol) of lead acetate. The flask and supernatant were placed in a 65 ° C oil bath and the slurry was stirred until the starting material was consumed under nitrogen flow. The resulting slurry was filtered and the solid was washed with ethyl acetate. The filtrate was combined with the washes, evaporated in vacuo. vacuum, the residue is taken up in 100 mL EtOAc and 100 mL of water, and its pH is adjusted to 7 · EtlnlbCíetátnvá layer n <ičliě) _i> dried and evaporated, yielding 6,235 g of the title compound.

C) Fenylmetthl ^ester (S) - (2-oxo-3-azetidinyl) karbemové acid

A solution of 3.12 g (0.0093 mol) of the above-prepared acetic acid in 70 ml of ice, ethanol and 7 ml of water was cooled to -15 ° C. 1.33 g of potassium carbonate and 349 mg of sodium nitrile driil were added. the reaction mixture is stirred at a temperature from -15 ° C to 0 ° C. After completion of the reaction (about 2 hours), the mixture was neutralized with 2N hydrochloric acid to pH 7 and stirred in vacuo. The pH of the residue was adjusted to 5.8, the residue was saturated with sodium chloride, and extracted three times with ethyl acetate. The organic layer was dried and dried in vacuo. The residue was combined with the material obtained in an analogous experiment and triturated with ether to give 3.30 g of the title compound.

D) (S) -2-Oxo-3-L ((phenylphenyl) carbamino) -1-azetidine sulfonic acid salt with pyridine

Method X

A solution of 440 mg (0.002 mol) of the above prepared keetidinone in 2 ml of dry methylene chloride and 2 ml of dry dimethyl ether was stirred under nitrogen for 2 hours with 350 mg (0.0022 mol) of pyridine complex. - sulfur trioxide. Most of the solvent was then evaporated in vacuo and ethyl acetate was triturated with ethyl acetate to give 758 mg of a solid which was predominantly composed of the title compound.

NMR (CDCl3): 3.63 (1H, doublet of doublets, J = 6.4), 3.90 (1H, triplet, J = 6), 4.85 (1H, doublet of doublets, J = 6.4) ), 5.10 (2H, singlet), 7.27 (5H, [omega] H), 8.0-9.0 ppm (muleiplets, 5H).

Method II of stirring under nitrogen atmosphere After the addition was complete, the mixture was evaporated in vacuo to stir the trleethylchlorosiebne.

To 7.9 g of anhydrous pyridine at -20 DEG C. with 18.87 g of triethylformic acid is added for 30 minutes at room temperature, and a solution of 20 g of the above prepared benzothiazole is added (see Method I). , part C) in 120 ml of dimethylformibeide and 120 ml of ietthenenchloride, and stirring at room temperature was continued.

3.5 hours. The solvent was removed in vacuo and ethyl acetate was added to the oily product and the oil was incinerated. 31 g of the title compound are obtained. The NMR spectra of this compound are the same as the NMR spectra of the product prepared according to Method I.

Example 3

(S) '- 2-Oxo-3-L (1-methoxylcarbonyl) -amino-1-azethanesulfonic acid potassium salt

Method 1 ml per ml no.

435 mg of (S) -2-o-o-3-E ((phenoxyithoxycarbonyl) amino) - (1-benzothiophenone) 0.5M solution (diphenylphenol-3-phosphate) were applied to a column of 25 ml of water adsorbent and 100 ml of water. equal parts of acetone 14 to 15 are highly Ryonone-donated (see Example 2) and dissolved in 2 h (pH of the solution adjusted with 2N sodium hydroxide HP-20AG. The column is washed with 100 ml of water, 200 ml and water). The fraction was eluted to give 80 mg of acetyl, which is predominantly composed of the title compound, the spectral data of which is identical to that of the product prepared below.

AND"

Method II

600 mg of piperidine salt (S1-oxo-1- (phenylethoxyl) keabooyan-Danix-K1-1-azstidinone sulfonic acid) (see Example 2) was dissolved in 2 mL of water and the solution was mixed with 15 ml. The supernatant is cooled to 0 ° C, filtered, the residue on the filter is washed with a cold illumination solution, cold 50% ethanol, ethanol and ether to thereby remove the solids. A solution of 280 mg of the salt obtained in 10 ml of water is added to a 100 ml adsorption column (-20) and the column is washed with 200 ml of water and then with a mixture of the following: A 50 ml fraction was collected by fractionation of fraction 7 to give a solid material which, upon irituration with acetone, filtration and drying in vacuo, yielded 164 mg of the title compounds starting at 90 ° C. 193-196 ° C.

Analysis: for CjH ^ ^NgOOSK. 1/2 HjO in / calculated C 38,02% H 3,48% N85,06% N 9,23% К 11,25%, found C 38,19% H 3.24% N8J5% S9J2% К 11,53% .

NMR (Euterolmoid): 3.69 (1H, doublet of doublets, J = 6.2), 3.91 (1H, iriplele, J = 6), 2.76 (1H, muutippet), 5.16. (2H, singlet), 7.23 ppm (5H, singlet).

Method III

20.0 g of (S) - (2-oxo-3-azeididyltyl canine / methine) methyl ester (see Example 2C) was suspended in 200 ml of ecetoortril, and 21.6 ml of moonmethylmethylsilyl trifluoromethyl ether (25.3 g) was added. The mixture was heated to 50 DEG C. with stirring for 1 hour. After cooling to 0 DEG C. in ice, 17.2 g of trimethyl / silo / 1-chloro-chloro-phthalate were added dropwise, and the resulting solution was stirred at room temperature for 6 hours. 24.2 g of potassium eih / hexanoate in 100 ml of butanol are added thereto, and stirring is continued for another hour, the suspension is poured into 1 liter of dry ethyl ether / ether, the precipitate formed is separated and dried in vacuo. 500 ml of water were added, the pH was adjusted to 5.0 with potassium carbonate, the aerosoluble material was filtered off and the caustic liquor was filtered off (yield 19.4 g). The product obtained contained a small amount of potassium chloride which was removed. chromategraafi, and its speciaal daia are ieaeatic s dai / product prepared according to methods / II.

Peak d 4

(S) -2-Oxo-3-n (phenyyl-ethoxy (taerone)) emino-1-azetieiatilizole (selin) (1: 1)

Method I '

34.3 g (1: 1; see Example 2) of (S) -2-oxo-3-fluoro-3-oxo-1-azetidiazole-oic acid (S: 2; see Example 2) are dissolved in 800 ml of water, the solution is clarified with carbon 30.7 g of tetrobromide (γ-ammonia) in 80 ml of water are added and the pH is adjusted to 5.5 with 1N h / potassium hydroxide. The resulting solution is concentrated by evaporation of the solvent under vacuum to a volume of about 200 g. The ml of tetrazoate / ammonium salt was separated and dried under vacuum. The product can be recrystallized from water or dissolved in methanol, filtered and the product precipitated by addition of ether. The yield of the desired compound (m.p. 108 DEG-110 DEG C.) was 34.3 g.

Method II

20.2 g of (S) -2-oxo-3- [j (phenynylmethoxy) keroayl] emine (2-1-azeilinsulfonic acid) / (1: 1; see Example 3) potassium salt were dissolved in 500 ml. The solution was filtered and treated with 20.3 g of tetrobromide / ammonium fluoride in 100 ml of water, adjusted to pH 5.5 with 1N potassium hydroxide and the solution turned to vacuum in vacuo. A volume of about 100 ml and the precipitated 19% butylimmonium salt was filtered off, the product was dissolved in 30 ml of methylene chloride, filtered and the product precipitated again with ether to give 21 g of the title compound, melting at 109-111 ° C.

Example 5

(3: 1) Phecylmethyl (1S) -alpha-Q ((2-oxo-1-sulfo-3-azetidinyl) amino) carbonyl] benzeneacetic acid potassium salt

A) (S) -3-Amino-2-azetidinone g of (S) - (2-oxo-3-azetedecyl) L-lactic acid phenyl ester (see Example 2C) was lydrogenated in 100 ml of methanol in the presence of 1 g of palladium on carbon as of the catalyst. After uptake of the theoretical hydrogen, the catalyst was filtered off and the filtrate was evaporated to the salt. On standing, 1.1 g of the title compound crystallized from the residue.

B) (3S) -alpha - [(((-) - o -oo-3-azetide CrLpa / miCo)) cabanyl] eceneneacetic acid phenyl phenyl ester

3.0 g of the olefin of said azetidinone are dissolved in 100 ml of dimethylformamide, the solution is cooled to 0 DEG C. and 4.5 g of β-methyl-2-methyl ester are added dropwise with stirring, followed by 10.8 g of alpha-methyl ester. (Chlorocarbooutyl) benzeneacetic acid in 50 ml acetorntril. The reaction mixture is stirred at 5 ° C for about 16 hours, then the solvent is distilled off in vacuo and 100 ml of water are added to the residue. The aqueous suspension is extracted twice with 100 ml of methylene chloride each time, the organic layers are combined, washed with sodium bicarbonate solution, 2N phosphoric acid and water, dried over sodium sulphate and evaporated to dryness after filtration. The residue was crystallized from ethyl acetate and control ether to give 8.7 g of the title compound, m.p. 164-166 ° C.

C) Potassium salt (1: 1) of (3S) -alpha - [(1,2-oxo-1-tuflo-3-azenynyl) amino] carbonyl] benzeneacetic acid

6.9 g of the above compound are suspended in 150 ml of accSonCtril, 5.7 g of monotrimethylsilyl-trifluoroacstadiene are added, the solution is heated to 50 ° C with stirring for 30 minutes, then cooled to 0 ° C and added dropwise thereto 3, 9 g. After the addition was complete, the mixture was looked at 50 ° C for 5 hours, then cooled to 20 ° C, treated with 7.6 g of potassium ethylhexanoate in 10 ml of butanol and stirring was continued for 30 minutes. Addition of 300 mL of ether precipitates the title compound, which is filtered off. The crude product was stirred with 100 ml of dry acetointril for 30 minutes and then filtered off to give 4.5 g of the title compound, melting at 118-120 ° C. Further purification of the crude product by chromatography on HP20 adsorbent followed by purification afforded pure material, m.p. 188-190 ° C.

Example 6

(S) -3-Π (2-Amino-4-thienyl) acetylamino] -2-oxo-1-estidinsuindonic acid potassium salt

A) (S) -3-Lorino-2-oxo-1-azetieintuinone-tonic acid tetrabutylnonium salt g of the (S) -2-nitro-3 - [([tert-butyl] retirin) carbonyl] amino-β-lysidine sulfonic acid tetrabutylmionium salt (see Example 4) in 100 ml of dimethylformamide and in the presence of 1 g of 10% palladium per catalyst as catalyst were hydrogenated for about 30 minutes. The dimethylformamide was also filtered off to afford the title compound as an oil. .

NMR (dsutsoclnroforr): 3.82 (1H, triplet, J = 5.5), 4.05 (doublet, 1H, doublet of doublets, J = 5.5);

5.5, 2.5 Hz).

B ¹ (S) -3- E ((2-amino-4-thiazolyl) acetyl) miinone potassium salt | -2-oxo-1-azetidine sulfonic acid

To the mixture (g of the above compound), 0.5 g (minohi) zole acetic acid (0.4 g hydroxybesophosphol) was stirred at 0 ° C in 100 ml of dry dimethylformamide / solution of 0.7. g of dicyclohexyl / t -bodliride in 10. After the addition was complete, stirring was continued for 1 hour at 0 [deg.] C., insoluble urea was removed (filtered) and the solvent was evaporated in vacuo. The oily residue is left at room temperature for 15 minutes. .

is treated with a solution of oerlluorobutrosullooate dr / sel in (0.1 ml) cetoou. After addition of (00 ml of dimethyl ether), the title compound (v / v) was filtered off. The product was dried (clarified) using a column (300 ml) of HP-adsorbent (eluent). 850 µg of the title compound is obtained, m.p. at 300 ° C. /

Swallowed 7.

Potassium salt of [33 (+ 1) -3- [1 (/ foriyloxy) ethylacetyl / mino] -2-oxo-1-roetidine sulfonic acid

A mixture of 1.5 g of tetrachloro-ronium salt of (S1-1-amino-o-o-1-azetidine sulfonic acid (see Example 6A) in 100 ml of methyl 4-methyl-propylene oxide) was cooled. The mixture was stirred at 0 [deg.] C. for 10 hours with a solution of O-formylmidyl chloride in 10 ml of cetooitrile and maintained at this temperature for 1 hour while the solvent was refluxed in water. The oily residue is treated with a solution (g of perchlorobutane) of sulfuric acid in 15 ml of (cetone) and added to the mixture (100 ml of ether), and the title compound is recrystallized. Yield 1.5 g. After purification of the chromium (III) ions, the product was decomposed at 180 [deg.] C. at 180 [deg.] C.

Example 8

Potassium salt of [3S (+) 1 -3-Q ([formyl] ethyl] amino-2-oxo-1- / zetidine-8Ulphonic acid

The process is carried out in the manner described in Example 7, except that D-O-Lorrylic acid chloride is used in place of the chloidide of the O-form. The title compound is obtained after freeze-drying at a temperature of 1/0 / 1/5 ° C.

Example 9

[3S (-1) -3- [· ((Fluoro-oxy) -phenyl-ethylamino] -ethylamino] -2-oxo-1-ro-trimet8-sulfonic acid potassium salt

The procedure was carried out in the manner described in Example 7b by substituting L-O-lorryl-trichloroic acid chloride for O-chloro-butyric acid chloride. The title compound was obtained, containing 1 part of water at a temperature of (03) / 05 ° C. After careful drying, t / the product is at / 8 / i / 30 ° C.

Ex / d 10 ^D raseln siil ^á / ^S f- ^ oxo ^ Ij / L-oxooktty ^MiinoII-1 - / zetidinsulfonové. tyseli. ^

Mix 3 1.5 g of tetrambu / monium salt of 1,3-tetrahydro-1-azonidine sulfonic acid (see Example 6A) in 100 ml of dimethylformin / ml of propylene oxide was cooled to 0 ° C. , at this temperature, a solution of 0.8 g of k (prylic acid chloride) in (0 ml of dry) cetoou was added dropwise thereto, stirring was continued for 30 minutes. The solvent was removed in o / o (oily residue). Acetoo is removed by evaporation in water, the remainder is dissolved in 5 ml of water (Chromium / Tor) and washed with (300 ml of resin). (0: 1) using a water / cetoou mixture (9: 11: 1 as eluent). After some 10 Hz (ci), 0.9 g of the title compound was obtained, m.p.

Example 11

(3S / Z) - 3 - ((/ 2-1rinio4-thiaae / ytl) (((hydro: o / lenylrrtholo / losinyl) rsthooy) irino) ethyl) amino) -2-oxo / 1-isetidinone acid

A mixture of 0.8 g of tetiabutylmmonium salt of (3) -3-methyl-2- (0-1) -aldehyde sulfonic acid (see Example 6A) in 30 ml of dimethylformamide, 0.9 g of (Z) -2-amino / all- ((((R) pyrrolidinoyl) phenylamino) -4-thiazolecarboxylic acid, 0.3 g of Oriazole hydroxyethyl and 0.7 g of dicyclohexylcarodiimide were stirred at rt for 24 h. The precipitated product is filtered off and the solvent is evaporated off under vacuum, treated with an equivalent amount of potassium perlluoroutine sulfonate in 10 ml of acetone, and the title compound is filtered off and thickened on a HP-20 resin using water as 500 mg of the desired product melting with decomposition at 210 to 215 ° C is obtained.

EXAMPLE 12 (3S / Z) -3 (((2-Amino-4-thiazolyl) eth (o) Qrimino (1-ethyl) amino) -2-oxo-1-isetidiilsulfoic acid)

A mixture of 1.5 g of tetaabutyryltrium salt of tetaabuyyimmonium disodium (S) -3-chloro-4-carboxylic acid (see Example 6A) in 100 ml of dimethylformamide. 6 g of hydroxybenzoriazole, 1 g of dicyclic / hysoylacare / diiride and 0.8 g of (Z) -2-arinioalla- (ethooyirinoC-4-thiazoleacetic acid) were stirred at rt / Si for 24 hours. 30 ml of acetone, the urea is filtered off and the mother liquor is treated with a solution of 2 g of potassium perl / reuthanesulphate in 20 ml of acetone, after addition of 200 ml of ether, the title compound precipitates and is filtered / dried. By using HP-20 resin and water as the eluent, 1.1 g of the title compound melting at 180-185 ° C was obtained.

Example 13

(3S / E) -3 '(((2-Mino-4-thiisoltol // ethoxtimino / aceeyt) amino) -2-ooo-1-azetidine sulfonic acid potassium salt)

The analogy of Example 11 was carried out as in Example 12 except that (E) -2-iodo-α- (-) (4-thiazoleacetyl) was used in place of (2) -2-8- (1-alpha) -4-thiazoleacetyl. Ethyl-4- (4-thiol) acetic acid After lyophilization, the title compound is obtained, m.p. 160-170 ° C.

Example 14

Potassium salt of (3S (Z)) - 3- (((2-1-trinothiazolyl) - (2,2,2-trifluoroethoxy (imino) ethyl) amino) -2-oxo-1-azetidine) onc) acids

The procedure is analogous to that of Example 12 except that (Z) -2-iraxyl) -alkyl- (1 '- (1') - (1'-amino) -1- (1'-oxyimino) -4-thiazoleacetic acid is used instead 2,2,2-trifluoro-thoxy (imine) -4-thiaeole / ct acid. After filtration, the title compound melting at 160-170 ° C is obtained.

Example 1 15

(S) -2-Oxo-3 - ((1-X-propyl) -amino) -1-azetidine-sulfonic acid potassium salt

Method I

1.5 g of tetrabutylmonium salt of (S) -3-amino-2-oxoo-1. _aZe thidinsulfo) new acids (see pi ·

Example 6A) in 100 µl of dry dimethylformamide and 4 ml of propylene oxide are cooled to 0 ° C with stirring, at which temperature 0 * 5 g of propionic acid chloride in 10 ml of acetooitrile are added dropwise and the resulting mixture is stirred for 2 hours. The solvent was distilled off in vacuo and an equivalent amount of potassium perfluorobutan sulfonate in 5 ml of acetone was added to the oily residue. Upon addition of ether, the title compound eluted out and filtered. After freeze-drying, 0.8 g of product is obtained, m.p. 135-140 ° C.

Method II g (E) - (1-azetidine) sulfonic acid (S) -2-oxo-3-H- (1-azylidene-ethoxy) -carbonyl) -ethoxybutyric acid salt (see Example 4) was hydrogenated in 100 ml of diethyl ether of ethylene glycol to 1 g of palladium on carbon. The catalyst is filtered off, 2 ml of propylene oxide are added to the filtrate and, after cooling to 0 DEG C., 0.5 g of propionic acid chloride in 10 ml of dry dimethyl ether of diethylene glycol is added to the filtrate with stirring. The residue is treated with an equivalent amount of potassium perfluurbutaitulufoleate in 20 ml of acetone and added to ether to elute the title compound which, after filtering and re-filtering from a mixture of water and acetone, yields 0.9 g of the melting product at 156 to 160 ° C.

Example 16

(3S) -1- (3-Indoxyderneacetyl) -2lium) -2-oxo-1-aletidinazufuonic acid potassium salt

1.5 ml of tert-butylamine (S) -amino-2-oxo-1-azeiedinone (according to Example 6A) in 100 ml of dry dimethyl was stirred for about 16 hours with stirring. 5 g of dicyclohexylcarbodiimide, 0.5 g of cyclohexenizriazole and 0.6 g of mandelic acid. The solvent was removed in vacuo and the residue was dissolved in 20 ml of acetone. The precipitated urea is filtered off and the mother liquor is treated with an equivalent bridge of potassium difluorobutane sulphate. Upon addition of ether, the title compound is isolated by filtration. 1.4 g of crude product are obtained. After reinstallation from water, the product melts at 138-140 ° C.

Example 17

/ S / -3 - ((((nairetin / thuo) acynyl) trans) -2-oxo-1-azetldinsufluonic acid potassium salt

1,5-ethoxybutyrate (SS salts) - amino-2-oxo-1-azetylisuldioic acid in the case of Example 6A) and 0.72 g (/ ketiaethyl) / thiol (acetic acid is dissolved in 70 ml of acetominyl) and the solution is added dropwise. 1.04 g of dicyclolexylcarbodiuride in acetonntril is stirred for about 16 hours at 0 ° C, then the precipitated decyclohexylurea is filtered off, the filtrate is evaporated and the oily residue is dissolved in acetone After addition of a saturated solution of potassium iodide in acetone, the title compound precipitates. This gives 1.1 g of the desired product, m.p. 150-155 ° C.

Example 18 '

(S) -2-uxo-3 - ((1-tetralul-1-ylacetyl) aluminum) -1-azetedinuoniconic acid potassium salt

AND

To a solution of 0.005 mol of tetrabutylammonium salt of (S, N-amino-4-oxo-1-azetidine diphosphonic acid (see Example 6A) in 70 ml of diethyl-digestamide) was added 0.77 g of 1H-etrazole-1-acetic acid and a solution of 1.13 The mixture is stirred at room temperature for 16 hours, the solvent is removed in vacuo, the oil is dissolved in 20 ml of acetone and treated with a solution of 0.006 mol of potassium difluorobutanitulphonate from potassium acetate in acetone. g of the title compound melting at 170-175 ° C with decomposition.

and

Example 19

(S) -2-Oxo-3 - ((2H-tetrazol-2-ylacetyl) amino) -1-azetidine sulfonic acid potassium salt

The procedure is analogous to Example 18 except that 2H-tetrazole-2-acetic acid is used instead of 1H-tetrazole-1-acetic acid. The title compound melts at 175-177 ° C with decomposition.

Example 20

(S) -2-Oxo-3 - ((2-thienylacetyl) amino) -1-azetidine sulfonic acid potassium salt

The procedure is analogous to Example 18 except that 2-thiopheneacetic acid is used instead of 1H-tetrazole-1-acetic acid. The title compound melts at 180-190 ° C with decomposition.

Example 21

(3S / Z) - 3 - (((2-Amino-4-thiazblyl) methoxyimino / acetyl) amino) -2-oxo-1-azetidine sulfonic acid potassium salt

(S) -3-Amino-2-oxo-1-azetidine sulfonic acid tetrabutylammonium salt {prepared as described in Example 6A from 7.9 g of tetrabutylammonium salt of (S) -2-oxo-3 - ((/ phenylmethoxycarbonyl) amino) - Of 1-azetidine sulfonic acid} was cooled to 0 ° C and then 3 533 g of (Z) -2-amino-alpha (methoxyimino) -4-thiazoleacetic acid was added followed by a solution of 3.27 g of dicyclohexylcarbodiimide in 10 ml dimethylformamide. The mixture was stirred at 5 ° C for 16 h, then filtered and the solvent was evaporated in vacuo. The residue was dissolved in acetone and the solution was filtered. After addition of 60 ml of a 10% solution of potassium perfluorobutanesulfonate in acetone, 4.7 g of crude product crystallized. After purification of the crude product by chromatography on an HP-20 adsorbent (100-200 mesh), 3 * 0 g of the title compound melting at 235 ° C was obtained.

Example 22

(3S) -alpha- ([2-Oxo-1-sulfo-3-azetidinyl] amino) carbonyl benzeneacetic acid dipotassium salt

100 mg of (3S) - .alpha .- [(2-oxo-1-sulfo-3-azetidinyl) amino] carbonyl benzeneacetic acid phenylmethyl ester potassium salt (see Example 5) was dissolved in 20 ml of anhydrous methanol. After addition of 10 mg of 10% palladium on carbon, the mixture was treated with hydrogen for 15 minutes, then the catalyst was filtered off and the methanol was evaporated in vacuo. The residue was dissolved in 5 ml of water and adjusted to pH 6 with 1N potassium hydroxide. After lyophilization, a crude product was obtained, which was chromatographed on ЯР-2О resin with water as eluent to give 60 mg of the title compound, m.p. 85 ° C.

Example 23

(S) -3- (Acetylamino) -2-oxo-1-azetidine sulfonic acid potassium salt

Method I

A) (S) -3-Amino-2-oxo-1-azetidine sulfonic acid potassium salt

169 mg of (S) -3- (benzyloxycarbonylamino) -2-oxo-1-azetidine-sulphonic acid potassium salt (see Example 3) were dissolved in 4.0 ml of water and added with 37 mg of 10% palladium on carbon for 1 hour and 40 minutes. minutes. The catalyst was filtered off and washed with 1 ml 50% aqueous acetone.

B) (S) -3- (Acetylmino) -2-oxo-1-azetidine sulfonic acid potassium salt

The free amine solution obtained above was diluted with 3.5 ml of acetone and added in small portions of 320/11 acetyl chloride over about 15 minutes with stirring while stirring in ice, maintaining the pH by occasional addition of solid potassium bicarbonate.

6.5 to 7.2. After 30 minutes, thin-layer chrominatoeaealate (acetone-acetic acid 19: 1) and the Rydon test indicated virtually complete completion of the reaction. 6 ml of 0.5 M potassium dihydroeenloschlorate (pH 5.5) was added and the solution was acidified to pH 4.8 with 2N hydrochloric acid.

The acetone is evaporated in vacuo and the aqueous solution thus obtained is passed through a column of 50 ml of Hj-20 AG adsorbent to give 2.197 e of a solid which, by punching with methanol, affords 282 m of extractable material. which still contains a certain amount of salt. The product is further purified by passing it through an IRC-50 adsorbent column, then olysed to pH 6.8 followed by evaporation of the solvent to dryness in vacuo. T-ituration with acetone yields 64 me of the desired product enveloping about 0.5 equivalents of potassium theoretically salts. Final pouring through a column of 200 ml of HP-20 AG adsorbent followed by lyolization from 0.5 ml of water yields 22 me product in lorum amorphous powder, which melts after vacuum drying at 50 ° C for two hours (after melting at 100 ° C) at mp 170-180 ° C.

Anaalysis: calculated C 24.38% H 2.87% N 11.37% K 15.9% found C 26.06% H3.14% N9.96% К 18.04 %.

Meeoda II

A solution of 2.0 e of (S) -2-o-pyridine salt of ((phenylmethoxy) -carbonyl) -amino-1,1-tetrahydro-sulfonic acid (see Example 2) in 25 ml of water is hydrogenated in the presence of 500 me 10% palladium / ml. After 2 hours, the solution is filtered, cooled to 0 ° C and 40 ml of acetone are added, maintaining the pH of the solution between 5.2-5.8 by concurrent addition of acetyl chloride and cold 10% potassium lydrogen solution. The pH of the solution was then adjusted to 4.2 with ethyl chloride and acetone was removed from the solution on a rotary evaporator.

Chloromethylphosphate on a 300 ml column of HP-20 AG adsorbent (water elution, 25 ml fraction) yielded 900 me of the title compound in fractions 13 and 14, contaminated with some acetate potassium. An analytical sample of the product, m.p. ‘

H, 2.89; N, 11.38. S, 13.02.%, K, 15.88. Found: C, 24.23; H, 2.81%. N, 11.25%. N 12.89% K 15.74%

Example 24

(S) -2-Jo-3 - ((Phenylacetyl) -mino-1-azetidine sulfonic acid potassium salt)

A solution of 1.5 e of (S) -3-amino-2-fluoro-azetidine sulfonic acid tetra-butyl-ammonium salt (see Example 6A) in 100 ml of dry dimethylformamide is cooled to 0 DEG C. and 2 ml of propylene oxide are first added with stirring. then 1 e-leoo: erythylyl chloride is added dropwise thereto. The reaction is complete in 1 hour. The solvent was evaporated in vacuo and the residue treated with an equivalent of potassium pyrobutyrate-oxoate in 20 ml of acetone. After addition of the ether, the title compound crystallized out. The product is filtered off, dried and filtered with boiling water. The title compound obtained has a melting point of 176-180 ° C.

Example 25

Potassium salt of ⁽³ R / ^{/ R /)} -3- ⁽⁽⁽⁽⁽³ - (/ 2f ^c uaιn ^'- Llorthylre / ^fmieř) -2-RXO-1-ioi ^{thiazolidinone} IIIn ^{R y)} carbonyl řny1 ^b) amino) (N-Laccyl) amino) -2- (0-1) -azolidinedioic acid

3 ^{g i} b ^s tr1rratcttylmOe SOH ^(S) n · 2-oxo-3- ^{j /} / fe-y ^o r ^ thřχ ^- / ^{0 ares b} l ^e m) rcin (e-1L-IIIE is ucfonové ^t k- Mlin- '(see example 4) with HY (UTR ^g ene in 100 OL j íimethylformaдаidc aříuoonouti in 1.5 g of palladium to DI. After 0.5 hours, catalyst 1díi ^y Truji to the filtrate was added 1.8 g íicykluhrχylkrгbudiioiíc 2 g (R) -alpha - (((- ((- (- (-) -) -) -) - 1 - (1 - (- (1 - (-) -) -) -) -) -) - amino) benzoic acid and 0.9 g of hydrobromic acid. After the reaction mixture was added to dryness, the residue was dissolved in 50 ml of dry acetone, and the precipitated urea was filtered and the title compound precipitated after addition of an amount of potassium tetrafluorobetaetulfate in 20 ml of acetone. mL of ether. After ldíiltrlvreí ρгuU ^] ^^ tc and re crystallized from water to give 2 g tlucčrniey listed in the Razvi ^ JCI decomposition at ²²⁰ and ²²⁵ ° C.

Example 26

Potassium salt ^(3S / ^{R /)} -2-oxo-3- ^{((((1-oxo-and>} ioi azoles ^{í ß} ey ^l / ^b o ^{e carbonyl) amino)} e ^ ^f lacets ^yl) amino ) -Naze tidinscfřonuvé acid g tetrabutyaMoniové Sou S) -2-uxua ³ -Q (frn-yгme.thuχy / krtЫřnl) Aminei-1-N zeidietulfunové acid ester (see. example 4) hy <Uto Enej 100 ^g OL of dry dimethyl bromide in a water content of 1.5 g / ml. After 30 minutes, the catalyst was added 1.8 g of (R) -alpha (η 2 -oxidazol-10-yl) -benzene acetic acid, 1.3 g of bicyclocarbonylcarbonyl. and 0.9 g of hydrobromotriazole, and the solution was stirred for 2.5 hours. Unwanted under vacuum, the residue was pulverized in 50% acetone, the precipitated seaweed was added and the mother liquor was added with an amount of aerofluoromethanesulfate in ethanol in 20% acetone. After addition of 200 µl of ether, the precipitated title compound is filtered off, yielding 1.8 g of product melting from crystalline water / acetone at 210-215 ° C.

Example 27

Potassium salt £ 33 ^{(2)] -} 3- ^{[(/ R} orthřxyioine frnyl acetyl) -2-amine ^R-L řxř- azetidUisu NNC ^ ^ Ο ^-8 ©! ^ ^{- A) (S} j ^{(2 J} -3 -Q / ®e ^h > x ^- i ^oi eo / ^f re ^- lacrt ^-l ) aιoie (q'- ² -azrtid ^e nue

3.58 g of (2) -afaa- (relomer) Merenz. acid dissolved in EA 06-1 1-0 ^ ^^ ^^ 0, ⁰ Mzu ee ocM.adí ^N and ⁵ ° ^C and p-tert ^to ntau г ^^ ^{0 4.53} g ^{of di cyclo-} luhrxy 0rг ^{y b} u ^{i i id id} 5 ⁰ OL oa ^ lencttorita. SMEA to 3 ⁰ minutes at tejo? 5 at the ^C e ^F was added ³ A solution of 1.72 g of 2--aoiieř · azetidenřec (see Example 5a) in 100 ml of mixture ¹ Realkční Todina c ^ ranks at 5 ° C and allowed ^to PA Jea ^ h ^ 2 ^y reacting in a ^P s ^ s ^ oístno-book. The cyclohexyl ether is separated and the filtrate is collected to give 6.6 g of crude product. This oat is purified by trituration to 750 g of sieve using a mixture of mixtures. oo The mixture was treated with chloride and .beta.-.beta. (7: 3) as eluent to give 2.9 g of product.

B) Potassium salt ^£ ЗS (from ^FL -3- ^[(/ / mrthřx ^- ioino ^Of rl ^e- Lacet ^-l) -2-εmieoř RXL-1 and t ^{n i} D NSU ^FD ENC) in ^E k ^- eeliny . Add 0.5 L of addition to 5 L of absolute solution and cool to

-30 ° ^C and p ^ has ^{to some} degrees at mites ⁰ 0 ⁹³ ml tri-n-thylsilylchloraul ^UV-5-ol oeUwlencM.orita. The mixture was stirred at room temperature for 30 minutes and then evaporated to dryness in vacuo. The residue was dissolved in 10 [mu] l dimethyl Ooooaoid and treated at room temperature with a solution of 1.23 g of the above prepared in 10 l of dimethylfooiaoid. After stirring at room temperature for two hours, the solution was evaporated to dryness to give 2.1 g of crude pyridinium. SOK £ js (Z) -J 3-Fc / aemino] -Z-oxo -l ^^ 1 ^«é stidinвuffoIaí acid.

Reaction of the pyridinium salt with tetratatyl / formyl-hydrogen sulphate yields a corresponding tetratnitylmonium salt which is extracted as a oily residue after removal.

Reaction of equimolar tetrabutyimoniové SOH UK-ATIII / peIflufrbutlOaulffnátu dřisolného in acetone by evaporation and treating the residue with ether gave 1.6 g of potassium shock title which vytlatí ^CH omilofralfí ni idsorbantu HP-20TM. Elution with i voty icetonu (9 ^{0 1 (0)} from the ^d ^^ typist to sell or acquire PTT gonna hit ²²⁰ ° C.

Ex. 28

Potassium salt of (3H / Z) -3- (( ^α2- amino-4-methylphenyl) -2 (2-trifluoromethyl-1,1'-dimethoxy) -1-oxo-phenethoxy) imino) -cetyl) amino) - 2-chloro-1-methyl-1-sulfonyl (1: 1)

To a solution of 0.005 mol tetrabutyimoniové salt of (S) -3-) 2-mLnf fx (f (1-lzstidin8ulfonfvé acidly ^ ^(see p ^ kl ^ ^6A) and 0 ° ⁰⁶ moles ^{(/) -2-m} l nof- ^la a- ^{([(2- aa} i ^f e ^ot] Loothí ^f s ^and - ^{(J-2-djmBthrl} fxfsthfзQr) imlnof 4-thiaífloctoíé acid in 60 ml dimethyffomMidu 0.7 g and 1.13 g hydroxybenzzfrilzflu The mixture was stirred at room temperature for 16 hours, filtered and evaporated, the residue was dissolved in 30 ml of acetone, filtered and 20 ml of a 10% solution of potassium perfluorobutine sulphonate in icetone was added. petraletheru addition precipitated the title compound which, after heehaw get stuck ^ ^ i from her ettisrem Rovte ^^! ^p ostytne 3 ^{8 g} ^ ^ odiuictu jícího rozklidu zi at 19 ° C.

Example 29

Dipotassium salt (3S / Z /) - 3 - ((/) - miinO (· 4-hilzphotyl / (/ klrbfboty- (mastietylethfxy / i / ino) accSyt) irino) - ^2- o xo-1 -lz · thiainsul0onfíé ktesliny g potassium sH (3S / Z) (3 - (((2'Mlinf-4-thiazflyl) / ((α-fSOotylmethyl) -1,1-diethyl-2-f (fStStí))) (1 о п) alcyl) liino) -2-oxo -1-lZStiainsulfonoíé acid (see příklid 28) suspended ^ taught in ⁵ ml of suspension к niaolu and ss at pL ^ -I ^ of ⁰ ° C ²⁵ ml přmá tr ^Flu fooocfoíé to ^y ^ sel. A mixture of DC ¹⁰ minutes mícM ^p s MPTA ^ -1 ⁰ C ss niěež ^thereto mmlu ^ ^ BC and ¹⁰⁰ ml of ^t hsru on that lot ^{of p} -I ⁰ ° ^C and ^p i ^{to 50} ml troletaeru ^. ^ tert iltoováním ^{characterized} Lou ^No en ^Star aražeoio ^y ss zmká ^1.6 g of tri ^ ^ ^ ktsel ooroctové, Sr, ^{and kt. P} ss mplo s ^ ⁰ ° ^C suspended in ²⁰ ml voty after pH adjustment with dilute hydroxide driseliým ni ni 5,5 IE vytiasí HP column idsorbantu -20. Merged ini Uve ^d Measured DC HV ^and invite you ^ js ^ ui ^t in ije zi ECR-sulfide ^p s ²²⁵ ° C.

PPíklid 30

(3S / Z) - 3 - (((2-) minof4- (thia)) ethyl) ((2- / af-methyl-2-methylphenyl) amino) amino-2-oxo-potassium 1-thiophenoic acid

Pricuje ss inilogickým procedure Jiko leisurely 28 tm, IB nimísto ss' (/) - 2-Amino-i ^ a-jj ² - ^AD IFO ^{ylmethyl five} fз ^χy · ^{(1 1} - ¹ IMET ^and ht. 2 -oxfe hf ^{χt t,)} iiinof- ^- -thillo ^l octfí ^s kysβl ^{and yp} of ije ou ^{u (/)} -2-) mioo ^ll-f I- ^{[(2- aa} otylmethfX i ^{and T / 2-d} oxfet The ^{compound of} formula (4-trifluoromethylphosphine) is hydrogenated. / ^ka IS SS title compound, tijdcí rfzkl zi) and at 180 ° C.

He said i 31

Potassium salt (3 / ^a - ^and (- (l · ·) Ziaffo ^and ethylccetyl ^and imooo (-2-ofo- (lazetadnunuuffooo kaolins)

Metodi I

A) (- ₍ 1) -) - [alpha] - [alpha] - [1- (2-oxo-3-l-zididine)] beozenyl acetyl

2.15 g of (R) -3-methyl-2-trisolidinol (see Example 5A) and 2.1 g of sodium hydrogen carbonate are suspended in 50 ml of a 2: 1 mixture of acetone and water, maintaining the temperature in the range of A solution of 5 g of ^{(-) -} tert -butyl-acetyl-ethyl acetate in 10 ml of acetone is added dropwise to a ^{pH of} 6.8 to 5 [deg.] ^{C. to} bring the ^{pH of the} sodium bicarbonate to 6.8. After stirring for one hour, the acetone is stripped off, the remaining aqueous solution is adjusted to pH 8 with sodium hydroxide solution, extracted three times with 50 ml of carbon tetrachloride each time. The organic layer is dried over sodium sulfate and stripped to give 3.6 g. the title compound in the form of an oil which is triturated with β ether after trituration. After recrystallization from TMBS beetцrУrnchhortdu ether gave the compound in Devel uvMená melting ^p s ⁷ t 9 ^ž '1ДО ° C.

В) Dratelró salt ^{(3 /} / ^d) /) - 3- ^{(TD 0i} rfeyylietty ^t / BT ⁿ oo) -2-ouo-1tzre ^titl EAA ⁱ⁰ Inova tyse ^t ^ n ¹

A solution of 2.45 g of the above azetidione, 3 g of bilyltrifluoroacetate, in 20 ml of water was heated at 40 ° C for ¹ hour. After cooling to ⁰ ° C, the solution к instance ^IDs and ^1.88 g eribrthyltilylohlurtžlfcnáež mixture was stirred for 5 hours in an argon tObooféře then EE was added 6.12 ml of 2-2H rthylhrxanoátu potassium n-butanol and stirring te continues for 45 minutes. The reaction solution is poured into 300 ml of ether and the precipitate formed is decomposed. Zfiltrovtný solution of 1.2 g of the precipitate in phosphate buffer pH 5.5 ^{ihrumbáegrεt,} ujr 100 ml ad Erben with the H? -20. The loop is carried out with the following solvents:

1) 2)

3)

4) ml ppfru

200 ri of water,

200 ml mixture

200 ml of a mixture of water and acetone (9: 1), water and acetone (3: 1).

It follows a thin layer (Rydon ' s assay at &lt; RTI ID = 0.0 &gt; 8111) &lt; / RTI &gt; Fractions Nos. 15 and 16 yielded 280 mg of the title compound. After a second column of this material, 120 mg of the title compound is obtained, which is sampled at ¹⁴⁸ ° C.

Method II Tetrabutylthioic acid salt of (R) -3-abilo-2-oxo-1-trisidinylsulfonic acid (see 0.9 g of (-) tertiaryl-dibasic acid) is dissolved in 30 µl. 10 ml of water · Mix with

2.03 g Example 6A) tk solution is first reacted ¹ hour s of 0 ° C and then 1 ° p5i hours to ^p lotto bístrno ^8!. After filtering off the precipitate formed, the solvent is removed in vacuo, the oily residue is dissolved in 20 µl. acetone t. to the solution was added 1.70 g of potassium perfluoroaleauleate in acetone. After adding 10. vytarystaluje ml of ether the title compound of melting point ^P s of 149 ° C. ·

Method III

K. To a solution of 4.06 g of 3-thino-2-oxo-1-tertine di-sulfonic acid salt (see Example 6A) 5 g of propylene oxide in 30 ml of 2.5 ml of t-azidofrlyltronic acid are added. ^ о ^^. After two hours. . After stirring with the solvent, 1 equivalent of potassium p-trifluoroutal sulpholate in acetone is added to the oily residue. Upon addition of the ether, the title compound crystallizes out and is recovered. Etje product decomposition from 149 ^and 148 ° C.

P ř ‘. Example 32

(3S / D) Potassium Salt - (- (((((4-ae-tert-phenyl) -methoxy) -tronic acid) -tinoyl) -2-uxo-1-azrtidine-8-tonic acid)

To a solution of 2.03 g of 3-aaino-22oxo-1-azetidine-8-sulfonic acid tetrabutylimmonium salt (see Example 6A) and 1.58 g of Dalfa - ((((4-aethooyphenyl / aathooy) carbonyl) emino) benzoacetic acid) A solution of 1.03 g of dicyclohoylcarbodiimide in 10 µl of acetonitrile was added dropwise. The mixture is allowed to react for 1 hour at 5 ° C and then for 6 hours at room temperature, then the precipitated dicyclohoylthaurea is removed and the solvent is distilled off. On· . The oily residue of the title compound was treated with acetonitrile-potassium sulfonate potassium ether and ether to give 2.4 g of product, m.p. 108-111 ° C (dec.).

Examples 3-7

The procedure is analogous to that in Example 32 except that the corresponding compound listed in column I of the following table is used instead of (D) -alpha - (((4-methoxyphenyl / methoxy) carboinyl) emino) benenoacetate. . The compounds of column II of this table are thus obtained.

Example

Number I

II / D] -alpha - ((((4-methoxyphenyl / methooyl) carbonyl) aBino) -22 thiopheneacetic acid / ♦ / -amino-alpha-((((4-methoxyphenyl / mm thojoy) carbinyl)) amino (4-thiazolinyl) -H-alpha-((((4-methylphenyl / methyl) cyclohexyl) amino) -2-1-ureacetic acid / L) -alpha- (((4 (methylphosphorylcarbonyl) amino (ino) benzenoic acid [alpha] - ((([eta] -ethozylenyl) (thyloxycarbonyl) amino) -2-thiolenium potassium salt [(0)] - 3 - (((((4- (1 H, 4-oxo-1-ethyl) -ethioyl-carton) amino-acetyl) -amino) -2-io-1-azetidine-sulfonic acid * melting at dec 144-146 ° C) (3- (4 - [(4-methyl-thiazolyl) ((((4-ethoxyphenyl) (ethoxyl) amino) (amino) amino)) amino-1-ol-1 -ase ιβυΚοί ^^! ^ N; mp 232-234 ° C ůraselná salt Ο ^ ^ -Ό ΗΟ ^{Αιγιι-011-4} -methyl tho2oyreny1 / Me tHNX) kartannrl) and / Lno) acetyl) and / inon2-oxo- 1-azetidinesLonic acid melting at 124-126 ° C potassium salt (3S / L / (- (- (((( (methanoprenyl / methooylcarbonyl) amino) phenylation of thyl-amino-10-onone-1-asetidine sulfonic acid, melting at 172-175 ° C, potassium salt of (3 & (V) -3 - <((((( Methylphenylcarbonyl-2-methyl-2-methyl-2-methyl-1-methyl-1-acetyl-4-carboxylic acid having a melting point of 146 DEG-148 DEG C. Example 38

[3S] -3 - ((((((Methyl) thio / t] Lloxo-ethyl) thi> tMn) phenyl-4-ethyl) siol) --- lol-1-azetidine sulfonyl acid, tetrabutylammonium salt

To a solution of 1.03 g of (-) - alpha - ((netlyltl (o / ll-ometlyl) 1l) o) tannanoic acid and

0.66 g of tetrabutylammonium and 3-amino-2 oxo-1-azetide of insulin acid (see Example 6A) in 30 ml of acetonitrile are added at -5 ° C to 0.8 g of dicyclohexylcarbodiimide dissolved in 10 ml of acetonitrile. The reaction mixture is stirred for about 16 hours, then the resulting dicyclohexylurea is filtered off and the mother liquor is filtered off. The oily residue is chromatographed on a column of 400 g of silica gel, eluting with ethyl acetate / methanol / water (8.5: 1: 0.5). 1.3 g of the title compound are obtained.

Example 39

3 / S / -3 - (((((methylthio / thioxomethyl) thio) phenylacetyl) amino) -2-oxo-1-azetidine sulfonic acid potassium salt)

1.3 g of tetrabutylammonium salt of [3S] -3 - (((((methylthio / thioxomethyl) thio) phenylacetyl) amino-2-oxo-1-azetidine sulfonic acid) (see Example 38) is dissolved in acetone and an equivalent is added to the solution amount of potassium perfluorobutanesulfonate · After addition of ether, the title compound crystallizes and is filtered off. 0.18 g of product melting with decomposition at 157 ° C is obtained.

Example 40

(3S / D) - 3 - ((((4-Ethyl-2,3-dioxo-1-piperazinyl / carbonyl) amino) -2-thienylacetyl) amino-2-oxo-1-azetidine sulfonic acid potassium salt

Dissolve 3.25 g of (D) - (- ((4-ethyl-2,3-dioxo-1-piperazinyl) carbonyl) amino) -2-thiopheneacetic acid, 4.20 g of tetrabutylammonium salt in 25 ml of acetonitrile. amino-2-oxo-1-azetidine sulfonic acid (see Example 6A) and 1.3 g of N-hydroxybenzotriazole. A solution of 2.06 g of dicyclohexylcarbodiimide in 10 ml of acetonitrile was added dropwise at -10 ° C over 20 minutes and the reaction mixture was stirred for 16 hours. The resulting urea was filtered off and the solvent was evaporated in vacuo. The oily residue is dissolved in 50 ml of acetone and an equivalent amount of potassium perfluorobutanesulfonate is added to the solution to crystallize the title compound, melting with decomposition at 185-187 ° C.

Example 41

(3S / -) - 3 - ((Bromophenylacetyl / amino) -2-oxo-1-azetidine sulfonic acid potassium salt

To a solution of 5 mM 3-amino-2-oxo-1-azetidine sulfonic acid tetrabutylammonium salt and 3 g propylene oxide in acetonitrile, 1.4 g alpha-bromophenylacetyl chloride in 10 ml acetonitrile was added dropwise at 0 ° C. After stirring for 3 hours, the solvent was distilled off and the oily residue was dissolved in 30 ml of acetone. An equivalent amount of potassium perfluorobutanesulfonate in acetone was added to the solution. After addition of ether, the title compound crystallizes, melting at 135-137 ° C.

Example 42

(3S / -) - 3 - ((((Aminocarbonyl / amino) -2-thienylsulfanyl) amino) -2-oxo-1-azetidinoneulonic acid potassium salt)

Method I

To a solution of 2 g of tetrabutylammonium salt of (S) -3-amino-2-oxo-1-azetidine sulfonic acid and 1.5 g of propylene oxide in acetonitrile is added 1.1 g of (-) - 2-amino-4- (2-thienyl) -5 (4H) -oxazolone hydrochloride. After stirring at 0 ° C for 3 hours and stirring at room temperature for 1 hour, the solvent was distilled off and the oily residue was dissolved in acetone (30 ml).

Upon addition of an equivalent amount of potassium perfluorobutanesulfonate in acetone, the title compound crystallizes. After purification by chromatography on an HP-20 adsorbent column

using water as eluent to give the title compound, melting at 218-222 ° C with decomposition.

Method II

To a suspension of 2 g / / / a of if / «l« «« rio rio ny ny l l l l l l l l l l M M) ino)))))))) 10 3-Amino (2-oxo) -1-azetidine-8-sulfonic acid and 10 oeol of N-hydroxybenzoyl trisole in 50 µl of o-onethanol were added at 0 ° C with stirring to 10 µl of dicyclohexylcarbodiimide dissolved in 15 µl of acetone. stirring is continued for 1 hour at -15 DEG C. and then for about 16 hours at room temperature After filtering off the dicyclohexylurea, the solvent is evaporated off and the oily residue is dissolved in 50 [mu] l of acetone and treated with an equivalent amount of potassium perfluorobutenesulfonate in acetone. a crystalline product which, after purification by chromatography on a column of adeorbent №-20, with water as eluent, affords the title compound, melting at 220-223 ° C.

Example 43

(3S / -) - 3 - (((((Methylamino / carbornyl) amino) / 2 / thienylacetyl) amino) / 2) oxo-1-azetidine sulfone thyeelines

0.54 g of .alpha .- (((methaloquinocarbon)) amino-2-thiophenoic acid and 1.00 g of tetrabutylammonium salt of (3) / 3-amino-2-oxo-1-azetidine sulfone basin (see Example 6A) so 0.5 g of dicyclohexylcarbodiimide is added at 0 [deg.] C. After stirring for 8 hours, the dicyclohexylurea is filtered off, the solvent is removed by distillation, the oily residue is dissolved in 20 ml of ethyl acetate. 50 mL of acetone was added and an equal amount of potassium perfluorobutane sulfonate was added to the solution, and the resulting product was filtered off and then chromatographed on an HP / 20 adsorbent using water as the eluent to give the desired compound melting at 205 ° C.

EXAMPLE 44

Potassium salt (3S ///) - 3 - (((/ amino oxoaceeyl / thainl) - / - thiervla-eeyl) kmnlr - / - / xoo / 1a-eeid insulin acid

A similar procedure as described in Method II of Example 42 and that instead of / - / - 111 FA - (/ aminkkrblo) phenyl / imino) / 2 / TH ^{i ofenoc-byte} Kyai ^ ny used (/ 'eidno exotics e ^e y ^y / amiilr-2-thiopheneacetic acid. -e give the title compound, t-limiting at 218-222 ° C.

Example 45 ^{D and} the salt raseln ^ S / H ^ / ^ - UU / E / ethyl 1- / ^2,3-di-oxo-1 / ^p and ^{p er-ynyl} from / ^to ARBO ^{n LL)} -min) ^{phenylpropan y-} 1-cetyl ^{) /} amino) (2) - (0-1) -zetidine sulfonic acid **

The procedure was carried out in the same manner as in Example 40 except that instead of (D) -kLla-2 (((4) / βthll-2, 2-hydroxy-1-piperazyl-1-piperazinyl) carbonyl) -in (2) thiopheneacetyl acid. The salts of (R) -1H- (- ((4-ethyl-3 H -dioxo-l-pylilylcyclopropyl) amino) aminoacetic acid gave the title compound. , decomposing at 155 to 157 ° C.

Example 46

3- (Acetyl-amino) -3- (ethyl) -silal-2-oxo-1-azetifinsulfonic acid potassium salt

Mtod— I

A) Sodium-potassium salt mixture of 3 / ((N / acetylN / -chloro) amino) -2 (oxo-1) ketidine bisuffonic acid

To a solution of 172 mg of 3- (acetylthio) ^-2 -oxo-1-arytidic acid (see Example 23) in a 17% solution containing 4%. solution, under cooling at - ^{15 °, and} 110 ° ^C -ΊΟ ^ 1 t. ^The mixture was stirred well for ¹ hour and passed for 45 hours, then poured into 50 ml of 0.5 M potassium hydrogen sulphate and the pH was precipitated to 5.5. The solvent was removed in vacuo, the residue was dissolved in a minimum amount of water and chromatographed on 140 L of HP-20AG (100-200 mesh), eluting with water, to give 63 mg of liquid which, on standing; After trituration with a mixture of methanol and ether, 53 mg of a solid melting at 124 DEG C. is obtained.

B) 3- (Acetyloieu) -3-ortho-2-oxo-1-azo-1-azetidenesulfonic acid potassium salt 37 and a mixture of 3 - ((N-acetyl-N-chloro / oieu)) - ^2- oxo-1-azenidenesulfonic acid / E ^ acid ester is extended in Ussi ^{1.5 01} dry ⁱⁱ ltth ^{y1. Mn} RMJ ^ ⁱⁱ ca give гuztu ⁰ at -78 ° C ma ^ ruztukc 50mg Mlhného methoxide in 1 O ethancHu. After fifteen minutes at oíchárá trpl ^thee -76 ° C přlto ol ^{10 0 5 M} solution of ⁱ y ⁱ i ^{h g} г1 refotfore ^No naeu ^s ratrleé ^{H u,} resulting in гuz ^{t k} IN Oytelinuc chluгovuíí0u / uc 1lk ^r yttrium pH 4, 70% of tetabas ^, ethylhydrogen and ethyl acetate were added thereto ^, and the sOSs were extracted four times with lithium chloride. The combined extracts were dried over sodium sulphate and dried in vacuo. 55. The residue was concentrated to 5.5 g of 4-methyl-2-ol (a mixture of 8% methanol and 92% of sodium-2-ol was used as the eluent) to give 41 g / ml of trisulfonyl chloride. 31 mg of the solids of the product were dissolved in water and the mixture was passed through a column of 5 OL iontosir ^AG 50 ⁰ -X2 in K ⁺ -tyW.u ⁽⁰ ° 74 - ^0.0 38 0 ° ^0.6 oo-o). / mIL. odpí of ^P ^ ERA water in and out of ^the ec ^ tO ulejřvitý residue krystaluj- from methanol and ether. After being twice with ether gave 11 at 182-183 ° C.

tritration with decomposition

Og of the desired product in the form of a colorless powder melting

Method II

A) Tetra-3-methyl-3-oxo-α-ethyl-α-ethanesulfonic acid 10% palladium on carbon in 2% methanol was added 100µl 4%

To a suspension of 30 mg of sodium borohydride in methanol and the mixture was stirred for 15 minutes in hydrogen, then 60 mg of 3-ololithium salt was added and the mixture was stirred for 15 minutes. Fer-L0rthu:) _χ) y / carbonization · nL and aoinn) -1-azeУiíintclOonu / E ester (see example 49) in 2 oethonolu ol and the resulting mixture was ¹ 5 oinut Oichi hydrogen ι6ο ^ 0 £ -. The beta-lactate is saturated with H 2 O. The solids were passed through an oily-lime (0.5%) solution and the filtrate was run in vacuo for 10 ^minutes . yl- ^ ⁰ ^ is the extra olУH ^-1 rechlorideo to Extra ^ u for TN: ^Iz rn ^eh ^ o ^ and rozaouUtědlu. 35 mg of the title compound in oil form are added.

E) Potassium salt of 3- (acetyloieu) -3-oxo-2-oxo-azetidenesulfonic acid yields

OL z ^^

The ruztu0c 35mg irУrabuУy1olueiuvé SOU 3aeoieo ^{3'aoethooy--2--ořoo1} azzУiíietclfonuvé acids ^{- 10} oe OL ^-tн lrnch ^h rt ^and Ic pulse ^P s ^^ ⁰ aruaylrn () xi ^{i (2 °).} And acetyl chloride (74/1). After 2 hours, the solvent was evaporated under reduced pressure and the oily residue was chromatographed on 4 g of silica gel. Elution with 6% to 8% in oeyhanoleo oeeih-1rnchloridc 18 mg ulrjuviéélo οη * - ^^ that гuzau8Sí гuztu0 water and with 3 column prooij- iuetoo ^of ni ^and r AG 5 ^0W - ^{X2 +} K ^to -CY lu ^(0, 6 o ^ ^- k ^ l // ^L. After measurement in pM ^ e ^ ^d yz herein in vacuo, the axes 10 of the desired product.

Example 47

The salt of N- (3-aeroxy-2-methyl-1-methyl-azz-phenyl) -2-re-

A) Potassium sUL N-chloro-N- (2auχo-1-tufl-3aazetirirlala-2-phenylacetamide)

To a solution of 50 mg of potassium (N) - N- (2-oxo-1-sulfo-3-trididyllyl) -2-allyl tetrachloride (see Example 1) in lithium containing 4% of sodium boron (5 iD) cooled in a bath at -5 [deg.] C., 20 .mu.l of butyl butyl chloride are added. The mixture is stirred for 32 minutes and then poured into a pH 5.5 separation of 0.5M potassium phosphate. , 'odtlaгод о ^ nt ⁰ ° C. the resulting extended ° o ^to 5.9 with ^H op otyseH nt ^pH 4, ^{5 / k} udprfení methuolu concentrated in vtkuu T residue ctarubltoogatujr nt 100 ml of HP-20? gE adeorbentu (0.147 - After washing the column with 100 ml of 0.5 M buffer pH 5.5 t with water and water / acetone (9: 1), the desired product is eluted and concentrated in vacuo to give 50 mg of the title compound.

B) Tetrabutylmuniuvé EUL N- (3-bethooyy2-OO ~ 8ulfioЗ OO1-atzridilyl) -2ieny | tcretmidu ruztuta ^{to 160} m ^g bbthoxi Httaěho ^d in 5 ml mithimolu, ocOtozentoo nt -7 ⁸ ° C with stirring, a solution of 149 mg of potassium soOi CLH-N, omega-N- (2-oxoo1-8SŽiooЗ atzeidinУ.) - 2-fenyltirttmidu in 10 ml dry dtbzthylforatbidu · After the addition was allowed to stirred for 15 minutes at toploto -7 ⁸ ° ^{C for} the PA poured into 1 ⁰⁰ ml 0.5N tytougentoetorečíntnu fraeetaéhu ^ · t thrice iztltyLenchloridOT graduate. 213 mg of tetrahydrofuran were added to the aqueous layer, and the aqueous layer was extracted three times. The combined extracts were dried over sodium sulfate and the solvent was removed in vacuo to give a yellow oil. 271 mg of an oily material are obtained which, after chromatography with 25 g of e-ckagel, elutes with 4% methanol in 96% by weight of ethylene htoride and provides 145 mg of the desired product as an oil.

Example 4β

N- (3-Bromo-2-ooo1-slphio-azeeidilyl) -2-phenyl tiretmide potassium salt of ertrabutyl methoxide salt of N- (3-Marhtuo-2-ooo-1-sff (> oZ-azerkdilyl) -2iely | tcretmkdu '( see example 47) was dissolved in water solution t proOije column of 10 ml οι ^ ^^ ^ ι ο AQ 50W-X2 ^{k +} -c ^ lu. eluate zthuu also in ^the swab in oil flow from ^Tory ^ ^p s flow The solid was then solidified with acetone / ether to give 53 mg of solid product twice.

^H 1 762 ^, 1 665 cm · ¹ ;

max:

NMR (.delta., 8): 3.4 .mu.l (s, 3H, OC4), 3.59 (s, 2H, QHg, 3.84 (AB-quwtet, J = 6.3 Hz, 2H); R), 7.30 (m, 5H, aromatic α-protons).

In the previous and following text, the signal shapes in NMR spectra are ο ^ ίζΙ ^ ί with the usual abbreviations, namely: s = Singlet, d - dubbet, О = triplet, m = bedlet ·

Aiatýza: for CjgR / NGQ .mu.l / HHgQ Calculated: C 39.88% H 3.62% N 7.75% found C i _ч 39.62% H 3.65% N 7.60 #.

Example 49

^Tetra u ^{t e} У ιmoniov ^é salt of 3-Both: ^{χ y2-Oxo-3'-C (Cf} enylbithooy / kιtrboon ^yl) alanine ^n] - ¹ -azrt d ^{i | n} ru ^fO oιové acid

Method I

A) Tetrabutylmonium salt of 2-oxo-3- [N-chloro-N- (felnyl-ethoxy) -carbonyl] amino-1-acetylsulfonyl acid

The emission of 3.17 g Deki ^ t ^ i ^ i ^ t the boritcnu solution 11.8 ml of 5.25 » 'sodium hypochlorite' sodium 7 ⁰ ml in ^ cooled to ⁰ t ^≥ 5 ° C ^{EXAMPLE ID,} and roe ^e o ^k 0. " g totratuityalboni.ové EOM ^(/) -2-qxo33 ^(Q 3 / ^f m · en ^tl oo ^{third χУ /} kl * Ьbf ^OTL шino | -1 Iz · Ti ^and Ios ^ff onfv tyseli ^s ^ (^ see MIId 4 ) in ⁸⁰ ml nitthrt ·! about Ch.oridu. the reaction mixture Zi ss ochlizsní on ice 55 minutes vigorously stirred ničež diluted with 0.5M aihyarogeafOsforrδn) ιau potassium and the product was extracted three times with 150 i metthУ.enoCí.oriau. Combine the individual extracts, dry with sodium sulfate and evaporate the solvents in vacuo to give 0.94 g of the title compound as an oil. *

В) salt of 3- ^{i s} e hífyt2 - fOfЗ- ^- '(/ FSO LMST ^{s s s} oзq kalbof ^about l) 8l1innJ - ^ - ^ iz diosulfomové _kteslioy%

To a solution of 667 mg methoxide in 10 ml of anhydrous methanol is stirred at zi TSPL ^thee -78 ° C and expanded ^T ^ of ^the ^ mtrabuy moaiové sol. and 2-oxo-3- [J · ^N c · ^Ch patterning (N- ^(phenyl ethoxy 01yL ^m / klrbfatl) liioof 1-lZStid0nзulfonoíé kt * S.ioy ⁸ (0.94 g) in 10 mL of dry, aimθthylformamidu The mixture was stirred at -78 ° C for 1 hour, poured into 0.5M potassium dihydrogenphosphoric solution, extracted three times with 150 ml each time and the combined extracts were dried over sodium sulphate and the solvent was evaporated in vacuo. 0.83 g of an oily residue which was chromatographed with 100 g of silica gel containing from 4 to 5% of methiool in methylsilyl as a light source for an amount of 513 mg of product as an oil.

Ί “(subas ^^): ^1,767 , ^1,720 cm” ¹ nax *

NMR (deuterocnLfrfform, δ values): 3.40 (s, OH ≠ j, 3.03 (AB-kvitet, J = 6.5 Hz, H *), 5.08 (s, _CH2), 6.00 (s, NH, 7.27 (s, Irish proton).

Method II

To a solution of 400 mg of potassium 3-benzoyl-cyclohexyl-oxo-1-aletidansulfonate in water was added 10.9 ml of 0.1M potassium hydroxide-treated potassium hydroxide solution at pH 4.3. . The mixture was extracted three times with 100 ml of sodium chloride, the extracts were combined, dried over sodium sulphate and the solvent was evaporated in vacuo. 625 mg of a masterlike maitral is obtained, the characteristics of which are close to the characteristics of the preparation / product prepared according to Method I.

TR í.k 1 ID 50 ^D a peat ^and salt ^to hífχy ³ -MK ^- -OOO ^- з ^{[(/ e} kl ^ym orthophosphates ^{χy /} klrboIa ^y). If ^{M 1} nof- -lZktiainaul onoíé ^f k ^{y y} ^ Selim Tods I ^A) potassium salt of 2-oχo- ³ - ^[N -chlfr-N- ^{(Fe y} Llmkt ol oxy ^d / ^b fnyl KLT) imino ^o - ^{1 t} id -lzk ^of nзul0onoíé oy

To a solution of 1.00 g of potassium SOH (/) - 2-fχf-3-p // fonyleeíhoJy7karbfoyl)) mio (D- (1alekiaiosulffnfíé acid (see příklid 3) in 90 L of 4% methwoolu obзalnιUjícdho arkllhylrátu boritiau sodium ^p ss s tapioca -I ^^ ^{0 4} 2 ^{0 s) at} mrc.fcjutylty l ^ chloro ^ u. ^C o dvouhotH new ^stirring mplf ^ s - ¹⁰ ° ^C ss přMá ¹⁰⁰ ml ^{0 5M} stretched ^ the ^ ^ ogeofosfor Nin arlar ^l oi them ^and iN hydrochloric acid adjusted to pH value of 6. AI solvent evaporated ss lid and the aqueous volume of about 1.30 odpirek chrfmalofrrlfuje DC ai 200 ml of HP-20? gE laaorbrntu (.147 to .074 m /. After Proi / three columns with 50 g of potassium dihydroxyphosphate in 1000 ml of water and 2,000 ml of water / sec. is eluted with a mixture of 10% icstone and 90% water, the solvent is evaporated off in vacuo and the residue is crystallized from water to give 530 mg of the title compound. in the form of a solid having a melting point of 173 _to 175 ° C.

в) Potassium salt of ^{1 to 3} -mi hoo ^χ y ^- -of; oo ^- з ^{([(/ r} ei em ^y L ^to about ^{three χy / b} fn ^{oУ KLR)} L] ^{m of} n - ^{1 t} id ^of -lZk nsul onoíé ^about the ^y aklУ 67 ^to a solution of ⁴ mg mmthoxidu littaiého in ¹⁰ ml of dry mettamolu at -78 ° C was added ⁸⁵⁷ ms potassium salt of 2-TxO - ^ - H-chloro-K-, polyesters ^ e ^ oxy) carbonyl bonyl) amino] -1-azstine disulfonic acid in 13 mL of dry dimethylformamide. After a fifteen-minute reaction at heat ^TE - ⁷⁶ ° ^C, the mixture was poured into ^{200 m 0,} 5M roztota ^d i ^hyd rlsenfosforeδnanu raselné ^{d h} o and the ^y bismethylenesalicylic IN hydrochloric him & iota pH adjusted to 5.5. The aqueous mixture is treated three times with 100 ml of meethylene chloride each time and 1.169 g of tracutylsulfate is added. The product is extracted three times with 200 ml each. ml of meethrlenchhoride, the combined extracts are dried over sodium sulphate and, after filtration, concentrated in vacuo. The oily residue is chromatographed on 150 g of silica gel, the product being eluted with 2% to 4% meet methanol in acetonitrile. 701 mg of oily tetra-4-lamonium salt are obtained. Part of this llejlvitéhl maateiálu. hmolnnlti 51 mg in water and burst the HRD ^t l ^to the PROM 3 ml column of ion exchangers AG 50W-X2 in K ⁺ form ⁽⁰ ° ^74-0, 03β mm, 0.6 meltkvml). Concentration of the eluate in vacuo afforded 30 mg of an oily product which crystallized after trituration with acetone.

ν _Μχ (KBr-UchdlkOi 1776 (°. 1 725 cm-1)

NMR (CDCl3) δ: 3.48 (s, 3H, OOH), 3.92 (s, 2H, H, 5.20 (s, 2H, CH2 ₎ ),

7.42 (s, 5H, aromatic protons) The product melts at 196-198 ° C.

Method II ^{A) 1} -cMor- fN ^ c ^ or N-phenyl re ^t -methoxy ^m / ^ktrblmУ)) Aninn ^about -2-tгrtidnon

Solution ⁴ 40 m ^{g of 3} - [1 ^] . ^{(/ R} nI ^yl Lart oχy ^h / ^b of ⁿ KTR ^УL) tminnl-2-financing by third ⁿ dinln (vl.z case ^2C) in ⁴⁰ ml of ^{a 4%} solution methaoHcktóto ^b oraxu octiadí to ⁰ ° C before carefully quenching with a thereto к O , ^5ml rc.butylh ^y ^ pol OLiDATA ^{ct. p} o tMceiiidnutové reaction at IPL S ^ ⁰ ° C was extended ^to a ^T-howling ije into ²⁰⁰ ml of cold water and extracted ^Star dvatarát with 100 mL each of ethyl state · combined ethyl ^^ e ^ in the layer were washed with water and dried, is under vacuum. This afforded 546 mg of the title compound as an oil.

^B) ^ Me ^ ooy- ^- - [(/ ^e eι ^{s) ш} r ^ih oχy / ktrbony ^yl) amino ^^ - ^ azetidin IMN ^R in its capacity ^{to 730 mg (0, 025} ° mol) of ¹ -chllr- ³ - [ ^N c ^hl LR-N- ^(phen nylart ^{χy h} l / ^k tr ^b oo ^{NY) ш} ш nol- ^{- di} --az ^et ethylcarbonylhydrazone in ⁵ ml ^ tratydrof uranium algorithm as -78 ° C and add ^to ntau ⁴ ml шс ^ Ноо ^ o ^b containing 285 mg methoxide Ι ^ Ιο ^! After twenty minutes the reaction at -78 ° C was added 0.6 ml of acetic acid and 0.6 ml triaetlhУfoзfitu resulting rozthk was stirred 5 minutes at ^thee warm -78 ° C ^for the PA to Necmi oltfát ^ PII room and mícM ae ³⁰ minutes. ^The reaction solution was diluted with ethyl acetate, washed with 5% sodium hydrogencarbonate solution, water, 5% potassium bisulfate solution, water and saturated sodium chloride solution, and dried. After evaporation of the solvent, an oily residue is obtained, which is applied to four thin glass plates (20 x 20 cm χ 1 mm).

The plates are charged in a 1: 1 benzene-ethyl acacia solvent system and the main band detected by UV radiation is isolated, with Rf = 0.25. 91 mg of an oily material was obtained, which was crystallized from ether to give a solid. After reinstalling from ether gave the title compound HV ^and invite taj ^ Π ² and at ^{from 114} ° C.

^C) Potassium salt of ³ -mi Hol ^{r χ} y ^- 20lχo ^- - ^E / ^L frny ^meth 02χr / k1M'boo ^{NY) ш} ш ^Nol-1-t TZR idin8U ^f0 nNew ^s of ^R in its capacity ^{to 25} mg of ³ -m ^e hto yЗ- ^{χ -} (/ ^f rx ^of alcohol ylmm ^{r χ} / carboline amino ^ny ^ '] - ^ - azetidinone in 75 ml of dichloromethane ^0.1 and 0.175 ml dimethyioormamidu hour and stripped stirred for 24' with 55.4 mg of pyridine - sulfur The resulting suspension was diluted with 5 mL of cold 0.5M potassium dihydrogen phosphate (adjusted to pH 4.5) and extracted with ethyl acetate. The aqueous layer was applied to a column of 40 µl of HP-20 AG adsorbent, eluting the column with additional buffer, water and mixture. water and acetone (9: 1) gave 32 mg of the title compound as an oil which solidified slowly, crystallizing from acetone to give the title compound, melting at 196-198 ° C.

Example 1 a'.d 51

3 - [(1,3-dioxo-2-phenyl-3- (phenylmethoxy) propyl) amino] -3-methoxy-2-oxo-1-azetidine sulfonic acid potassium salt

A) 3 - [(1,3-Dioxo-2-phenyl-3- (phenylmethoxy) propyl) amino] -3-methoxy-2-oxo-1-azetidine sulfonic acid tetrabutylammonium salt

431 Dg of crude tetrabutylammonium salt of 3-amino-3-methoxy-2-oxo-1-azetidine sulfonic acid (see Example 74) containing borax is dissolved in 30 ml of dry acetonitrile, 317 µl of dry pyridine is added, stirred vigorously in dry nitrogen atmosphere. 568 g of alpha (benzyloxycarbonyl) phenylacetyl chloride in 3 ml of dry acetonitrile was added dropwise. Thin layer chromatography indicated complete reaction in 15 minutes. 17 ml of potassium phosphate buffer (0.5 M, pH = 5.5) was added and most of the acetonitrile was evaporated in vacuo. The residue was diluted with water and extracted three times with an equal volume of methylene chloride. The extracts were dried over anhydrous sodium sulfate and evaporated in vacuo to give 1.032 g of crude product which was dissolved in 3 mL of methylene chloride and chromatographed on a silica gel column using methylene chloride / methanol as eluent. 470 mg of the title compound are obtained.

B) 3-Q1,3-dioxo-2-phenyl-3- (phenylmethoxy / propyl) amino] -3-ipethoxy-2-oxo-1-azetidine sulfonic acid potassium salt

470 mg of 3- [(1,3-dioxo-2-phenyl-3- (phenylmethoxy) propyl) amino] -3-methoxy-2-oxo-1-azetidine sulfonic acid tetrabutylammonium salt are dissolved in 15 ml of 30% aqueous acetone and Pour through a column of Dowex 50WX2 ion exchange resin in a K * -cycle using the same solvent as the eluent. The entire eluate was evaporated in vacuo to give 345 mg of an amorphous solid which, after lyophilization, gave an amorphous powdered product, mp 100-120 ° C.

H, 3.94; N, 5.76; S, 6.59. Found: C, 49.08; H, 4.00; N, 5.56;%, S, 6.29.

Example 52

/ - / - 3 - ((((cyanomethyl / thio) acetyl) amino) -3-methoxy-2-oxo-1-azetidine sulfonic acid potassium salt)

To a solution of 414 mg of 3-amino-3-methoxy-2-oxo-1-azetidine sulfonic acid tetrabutylammonium salt (see Example 74) in 50 ml of dry acetonitrile at -20 ° C was added 210 µl of diethylaniline and 169 mg of cyanomethylthioacetyl chloride. After 10 minutes, the solvent was evaporated under reduced pressure, 22.8 ml of a 0.1 M solution of tetrabutylammonium sulfate adjusted to pH 4.3 were added and the product was extracted three times with 50 ml of methylene chloride each time. The extract was dried, filtered, and concentrated under reduced pressure. The oily residue is purified by chromatography on 60 g of silica gel. 294 mg of product are eluted with 4% methanol in methylene chloride. This purified product was passed through a column of 16 ml AG 50W-X2 ion exchange resin (K * -cycle, 0 > 6 meq (ml, (0.074-0.038 mm)) to remove 164 mg of partially purified product which was further purified to 100 ml of Diaion AG HP 20 adsorbent using water as the eluent, after evaporation of the solvent, 126 mg of the product were obtained, which by trituration with ether gave 76 mg of the title compound, melting at 110-125 ° C.

H, 2.88; N, 12.10%. S, 18.44%.

Found C 27.25% H 3.00% N 10.84% S 17.53%.

Example 1 a d y. 53 - 56

For ^{p beta} oožití process ccording meto ^{soil 11} pŠkladLu oátaadou ⁴² / - / - C-alpha / aiBlookarbo ul / amino) -2-thlofenoctové modes odppoíddjící acid compound shown in Column I of Table následuUící compounds shown in column II of the table. *

Table

Example No. II II - [- alpha - ((aninooxoacetyl) a] ino-2-furanacetic acid ⁵⁴ H - / - and ^{1f a} - ((.alpha.-oxo (4-oxo-4-ooycetyl) aaino) -2-thiopheneacetic acid) s / -hдlfa) OaloOnnoxolcetylУlton) benzeneacetic acid / R / -a l- (all in ^the arbooy1 / адion) benzeooctová draselnásůl acid (3S / -) - 3 - (((/ адinnnxnac etylalмion) -2-furenylaceeyУ) amion) - 2-non-1-acetylidonic acid, melting with decomposition at 212 DEG-215 DEG C. (3S ///) - 3 - (((((cyanoethyl) amino) oxoacetyl) ylamino) -2-thiaminobutyric acid potassium salt (amino) -2-nitro-1-azetidone sulfonic acid, melting with decomposition at 195 ° C to 197 ° C.

toaselná (3S / Я * /) - 3 - ^((l // a0nooooyce tulle / nino) f enylace butyl) and / amino) -2-OOO-1 -azetdd0n8Ufnonoíé acid, the temperature t ° £ ^{207, and} even 209 ° C (potassium salt) (3 ^/ / R * ^/ O-3 - (( ^{) /} (- ⁾ - (- ⁾ - (- ⁾ - ⁾ -) -) - di-phenylacsyl) alno o-2-oxo-1-azetidine-monfonic acid, decomposing at 225 Deň: 32 ° C

Example 57.

Potassium salt of (1 H) - 3 - [(2- / methylthi-1-one) -polyoyl) -noyl] -2-non-1-azetidine-trifluoronic acid

The procedure was carried out according to Method II of Example 31, wherein (-) - 2 - ((ethyl) -diphthoic acid) was replaced with (-) - alpha-adiobiotonic acid to give the title compounds which decomposed on decomposition at Mp ⁷³ ° C.

Example 58

Potassium salt ^(3S / R ^/) -3- _^(((((-) 3-d ⁱ ooo-4- ^{(/ l} rl FEI / eth ^ll EO /) ^muon) '- ¹ - ^p t ^p erlzi ^of U yr ^to nnyl ^b) yion) phenyl thirty ^ ^) f / ion) --- non-1 -azetdd0n8ufnonoíé acid

Dissolve 0.7 g of (R) - ((((2) d-0000)) 4 - ((1-glycoletlyeone) -1-piperazin-4-yl) aminolyl] -nonic acid and 0.8 g in 20 ml of acetonitrile. tetrabutll (зynnioíé sooi /// - 3-and / ^{ioo-2-oxo-1-azetidineacetic d} in8u ^fn onni tysel ^ ^ ds la lecture ^{Cart d6 a)} Zy lícbfc ⁰ BC temperature ⁰ ° C was added dropwise 0.4 The mixture was stirred for 18 hours. After filtration, the solvent is de-distilled, the oily residue is dissolved in acetone, and potassium peralunbutyl sulfonate is added to the solution to precipitate the title compound. The title compound melting at 193-194 ° C afforded the title compound after purification of the HP-20 adsorbent column using water as the eluent.

Example 59

(3S / Z) -3- (((2-Amino-4-thiazolyl) / (2-methoxy-2-oxoethoxy / imino) acetyl) amino) -2-oxo-1-azetidine sulfonic acid potassium salt

1.3 g of (Z) -2-amino-alpha - ([2-methoxy-2-oxoethoxy] imino) -4-thiazoleacetic acid and 2.03 g of tetrabutylammonium salt of (S) -3-aaino-2-oxo- 1-azetidine sulfonic acid (see Example 6A) is dissolved in 50 ml of acetonitrile, and 1.03 g of dicyclohexylcarbodiimide dissolved in 5 ml of acetonitrile is added dropwise at 0 ° C. The mixture is stirred for 15 hours, then the dicyclohexylurea is filtered from the solvent. distills off. The oily residue is dissolved in acetone and an equivalent amount of potassium perluorobutane sulfonate is added to the solution. The title compound is isolated and purified by chromatography on an HP-20 adsorbent column eluting with water. The product obtained melts at 195-196 ° C.

Example 60

(3S (R *)) - 3 - ((((((3 - ((4-chlorophenyl / methylene) amino) -2-oxo-1-imidazolidinyl) carbonyl) amino) phenyl) methyl) amino) - 1-azide sulfonic acid

A mixture of 1.5 g of tetrabutylammonium salt of (S; -3-amino-2-oxo-1-azetidine sulfonic acid (see Example 6A) in 100 ml of absolute dimethyl ether of diethylene glycol, 1.5 g of (R) -alpha - (((/ - (((4-chlorophenyl) -thylene) amino) -2-oxo-1-imidazolidinyl) tarbonyl) amino) benzeneacetic acid, an equivalent amount of dicyclohexylcarbodiide and 0.5 g of hydroxybenzotriazole was heated for 12 hours, then the solvent was evaporated in vacuo The residue is dissolved in 200 ml of methylene chloride, the solution is washed with aqueous sodium bicarbonate solution and aqueous sodium chloride solution, the methylene chloride layer is dried over sodium sulfate and evaporated to dryness. The product is recrystallized from a mixture of acetone and ether, the resulting white crystalline powder is dissolved in acetone and an equivalent amount of potassium perfluorobutanesulfonate in acetone is added to the solution. filtration of the precipitated title compound affords 1.4 g of the desired product, m.p. 217-222 ° C.

Example 61.

(3S (R *)) - 3 - ((((((2-oxo-3- (/ phenylmethylene / amino) -1-imidazolidinyl) carbonyl) amino) phenyl) methyl) amino) -1-azetidine sulfonic acid potassium salt

Seal 2.25 g of (S) -3-amino-2-oxo-1-azetidine sulfonic acid tetrabutylammonium salt (see Example 6A) in 100 ml of dry di-methylformsmide, 2.5 g of (R) -alpha - (((2-oxo) -3- ((phenylmethylene / amino) -1-imidazolidinyl) carbonyl) amino] benzeneacetic acid and 0.85 g of hydroxybenzotriazole were stirred at room temperature for 12 hours, then dimethylformamide was evaporated in vacuo and the residue was dissolved in 50 ml of acetone. An equivalent amount of potassium perfluorobutanesulfonate in 20 ml of acetone was added to the filtrate, and after addition of 100 ml of ether, the title compound precipitated, which was filtered off and purified by dissolving in a mixture of dimethylformamide and acetone and precipitating with water. 5 g of product melting at 224 DEG-226 DEG C. with decomposition.

Example 62

(3S (R *)) -3 - ((((((3- (Methylsulfonyl / -2-oxo-1-imidazolidnyl) carbonyl) amino) phenylacptyl) amino) -2-oxo-1-azetidine sulfonic acid potassium salt)

2.25 g of the (S) -3-amino-2-oxo-1-azetidine sulfonic acid tetrabutylanonium salt (see Example 6A) in 60 ml of diaethylformamide was stirred with 1.9 g of (R) -alpha - (((3) - (methylsulfonyl) 244105

2-oxo-1-imidazolidinyl) carbonyl) amino) benzeneacetic acid, 0.75 g of hydro-benzotriazole and 2.3 g of cyclohexylcarbodidium. The solvent is removed in vacuo, the residue is taken up in 20 ml of acetone and the solution is filtered. To the filtrate was added 1.87 g of potassium perfluorobutanesulfate in 20 ml of acetone, and then the ether compound precipitated out by addition of ether. 2.0 g of ialtbital are obtained which, after purification by recrystallization from water, melts and decomposes at 240-245 ° C.

Example 63

Draselró salt ⁽³ S / R ^ж /) - 3- ^(hУir nχ} ^y f er ^{s e l} rlacbtyl адlion) -2noxn- ¹ -a ^^ bt ⁱ d ^{n 0} 8uul sulfonic acidified ^

1.5 g of tetrabutyl adenine salt of (S) -3-amino-2-nitro-1-isetidine acid (in Example 6A) in 100 ml of dry dimethylformamide are stirred for about 16 hours with 1.5 g of idycyclohexylcarbodidium, 0.5 g of hydrogen bromide, and 0.5 g of hydrogen bromide. 0.6 g of R-llaa-Uydnxacylbenzoic acid. The solvent was removed in vacuo, the residue was taken up in 20 ml of acetone, the precipitated molar oil was decanted, and an equivalent amount of potassium perfluorobutyl sulfoate was added to the filtrate. Upon addition of ether, the title compound precipitates and is filtered. 1.3 g of crude product are obtained which, after purification by chromatography on an HP-20 adsorbent and the use of mixtures in ^beige and acetone (9: 1) as eluent, melts and melts at a temperature of ¹⁵⁰ ° C.

Example 64

Potassium salt ^{(S 3} / S * /) зЗ - (/ ^r hy ox: ^l мlien ^yfb diphenylacetyl) ^azetidin-1 -2noχn- ^and dinsul -ones ^{of Star} tyseHny

The procedure was carried out as in Example 63, substituting (R) -alpha-hydroxybenzene ester of (S) - (1) - (alpha) -benzene acid for the acid. Give S ^ u ^ oIui Uve ^and BE ^and v ^ o ^ melting at ¹⁹ 5 and ¹¹⁹⁷ ° C.

Example 65

Potassium salt (3S / - /) - 2nχχo-3 - (/ finy3uulOaaceУyllmninn) -1l0zeifdisuulOinnvt acid (1: 2)

A mixture of 2.25 g of tert-butylamine in (S) -3-amino-2-oxo-1-azetidine-8-ynonic acid (see Example 6A) in 100 ml of ethylene glycol ethyl ether, 2.4 g of treetlyllaile and 0.3 g of ]mitolylpyrrolide was cooled to room temperature. 0 ° C, and adhered ^thereto 1.3 g of ^(R) -llfa ^n-ch trlabbnoyl) beeoeemithenзulfoenvé - acid in 20 ml iiethyleoglyknlu. The above temperature is maintained for 2 hours, then the solvent is removed under vacuum and the residue is mopaused in acetone. The non-permeable precipitate is then freeze-dried and an equivalent of potassium perchlorbutyl sulfate is added to the filtrate. Upon addition of ether, the title compound precipitates and is compressed. 1.4 g of crude product which after přektystllnvání with a mixture of water and an ACE nu ^ oa ťooW.adu melts at ⁴⁰ 2 and ²⁴⁵ ° C.

Example -66

(3S / Z) -3- (((2-amino-4-thaonolyl) ((d / dienaphosphinomethylmethyloxyimino) 1-ethyl)) styrene) -2-naphthalen-1-lzetidinone sulphonic acid potassium salt

To 2.25 g of tetrabutylammonium ^4- sool (S) -3-) adn-2-nitro-1-loetdinidinulonic acid (vio Example 6A) in 100 ml of dry dimethylmethylenemide is added 1.87 g of (Z) -2-liinonalfl ( (/ deethnxyfosfdnyl / iethnχy) people) - ⁴ -thaazoloctové 0.75 g hУ <ftoзχfbbnooOtilzolu ϋcyklnheχylkarbndiliidu and 2.29 g and the resulting mixture stirred for 12 hours e. The precipitated solid was dissolved in vacuo. To the oily residue was added equivalent potassium perfluorobutenesulfneate in 20 mL acetone. Ether was added and the title compound precipitated, which was filtered to give 2.77 g of crude product. The crude product was purified by column chromatography on HP-20 adsorbent and eluted with 9: 1 water / acetone (9: 1) as eluent to give the title compound (9: 1) as eluent. of the reagent yields the title compound, melting at 155-160 ° C.

Example 67

Potassium salt (3S / Z / (- 3 - ((// - aainno4-thia / olyl) / ([2- / 1,1-dimethylethylhexyl-oxo-1-phenylethoxy) imino) acetyl) / oino) - The (2-oxo-1-azetidine-1-azoic acid ² , 5-tetrahydroanone) salt of (3-arino-2-oxo) (3-azine-indinsulfonic acid (see Example 6A)) in 60 ml of dimethylformamide was stirred at room temperature for 1 hour. ² , 4 r ///-/- amino-amino-((/-/1,1-dirβeOh1.βthoэvУ- ^2- oxχo(/fany1ethoxy)iminn)1--thiazoleacetic acid and 1,5 r dicycohexylcarbodilride. Evaporate in vacuo, dissolve the residue in 50 ml of acetone, filter the precipitated urea and add an equivalent amount of potassium peroxybutane sulphate After addition of ether, the title compound melts and is filtered off with water and melting with decomposition.

This compound was purified by chromatography on a H-20 o / acetone (7: 3) adsorbent column as eluent. 1 g of the desired product is obtained above / 50 ° C.

Example 68

(3S (Z)) -3 - ((22-Mino-4-thiazolyl) ((1 H-eotraool-1-electroloylaminoimidino acely) amino) -2-oxo-1-azetidine-sulfonic acid potassium salt

The (R) -3-azetidine sulfonic acid (1.9 R) tetrobutyl-ammonium salt (see Example 6A) in dimethylformamide (60 ml) was treated with 1.4 R ((R) -amino-allyl- (1 H -tetrazol-55-ylmethoxy) / imino) for 4 hours with stirring. 4-Thiazoleacetic acid, 0.7% of hydroxybenzoicazole and 1.4% of dicyclohexylcarbodiimide After evaporation of the solvent in vacuo, the residue is dissolved and the precipitated urea is filtered off. The title compound is precipitated by the addition of 0000 ml of ether and is eluted by chromatography on a column of HP- / 0 resin using water as the eluent to give 1.05 g of product melting with decomposition at / 50 ° C.

Example 69

(3S / Z) -3- (((2-Amino-4-thiazolyl) -enenyleol-1-yl) -amino) acetyl) -2-oxo-1-azetidine sulfonic acid potassium salt

A mixture of (R) -3-amino-2-oxo-1-azetidine sulfonic acid 1,5-tetrbutyl-ammonium salt (see Example 6A), 1, 3R-2-arino-alpha - ((Eilylmethoxy) nrino) -4 Thiazoleacetic acid, 0.57% hydroxyphenol azole and 1.14% dicyclohexylcarbodiiride were stirred at room temperature in 60 ml of dimethyl amine amine. The precipitated moiety is filtered off, the solvent is added to the residue and an equivalent amount of potassium perlorbtansulphonate in 10 ml is added. After addition of / 00 ml of ether, the title compound precipitates which is filtered off by chromatography on a HP- / 0 resin column. a mixture of water and acetone (9: 1) as eluent. The desired product melts with decomposition at / 00 ° C.

/ 4 acetone hood.

and vylčstí

Example 70

Potassium salt (3 ////) - 3- ((/ 2-ад) 1по-4-1Ь1аоо1у1 / (/ каоЬоктпеЪОопог / 1т1по) асеУ ^у 1) ад | .1по) -2-ω-1-azetidine-sulphonic acid / 1 ^: 11

1,3 r of potassium salt of (3S / Z) - 3 - ((22-mino-4-thiazolyl) (((2-diphenylthiazolyl) -2-oxoethoxyl) amino) acetyl) mino-2-oxo-aetidine sulfonic acid (1) 1) (see Example 30) is mixed with 5 ml of anisole, 5 ml of trifluoroacetic acid is added at -15 DEG C. and the mixture is stirred for 10 minutes. ml of petroleum ether, the precipitate formed is suspended in 0 ml of water with cooling and with dilute potassium hydroxide solution at pH

to 5.0. Purification of the product 410 c ^ ^ 0 ^ Affi on a column of HP-20 of i ^ tion ^3.0 g of the branched, melting at ²³⁰ rozHadu ^{and 2} 35 ° C.

Example 71

(3S (Z)) - 3 - ((( ² -Amino-4-1H-thiazolyl) ((1-oxo-1-methyl-methylsulfonyl) -hexyl) amino) amino) -2-eye-1- tzetidunsulfonic acids

In a similar manner as in Example 28 except that instead / ^ / - 2 - ^^ ^ 0 ^ 1 - ⁽⁽² -ddifuylliethilχ / -1,1-diiitřh1 · 2-ixiβthoiχг) iilnui 4-thiazilictivé acid used / Z / - 2-ailnoialft - ((- iOχo- ² - / fu1yimθthiχy / ethixy) iiiuo) -4-thiaziliCtiiá acid. give t ^l iučentnt Uve en ^{d and} the title product: mp rozHadu at about ¹⁷⁰ ° C .

Example 72

(3S ///) Potassium salt of 3 - ((([2- (4-amino-2-iodo-hexyl) -amino-1-tetrazolyl] -tetyl) -thio) -2-eye-1-azetidine-unionic acid *

Works with analogictým manner as in Example 28 by the nemísto -tlfa - ⁽⁽² -dfife1lliethiзц1' ^{1,1-dimethyl-2} ety1- -ixiet it iχr) being iminated-4-acetic acid was used thitZil / Z / -2tмlui -tlfa - (/ 2 шnioo- ² iOxiethiK1 / iiiuo) -4-thiazilictiiá acid. yield compound ntov ^ detuning melting at ^{205 F} and ²¹⁰ ° C.

Example 73

(3S / Z) - 3 - ((( ² -nitro-4-hlazolyl) -thyloxy-aminoacetyl) potassium) amino ( ^2- oxi-1-tetetidiusiphonic acid) potassium salt

A solution of 0.6 g of 90% tydriзκ7benuziritzolu in 100 ml of dimethyl amide thylfomi stirred for 1 hour with ¹⁰ g múehilárního sieves ⁽⁴ x ^f of the mixture and the filtrate iltruje ^{EXAMPLE ID,} and ^a solution of

0.004 mol of the tetrabutyrium salt of (S) -3-amino-2-iodo-1-azetidine-phosphonic acid (see Example 6A) in dimethylforiamide. After addition of 0.89 g of (Z-amino-alpha - ((those riχyiíinu ^d) - 4-thit2ilicti- acid are added 0.91 g Jeet dicyklihexylktrbidiiíidu _f resulting mixture was stirred for about 16 hours, then the dep ^ i in vacuo, EA rispu8tí in 20 ml of acetone and the solution zfiltuje. the title compound is precipitated by adding a solution perfluirbuttutulfiuátu potassium · ^P o ctarimíto ^and raαfl to ^ ystyrtici HP-20 to give ^{0 44 g} ^ jícího over ² 4 ⁰ Deň: 32 ° C.

Example 74

3-Ethyl-2-oxo-3 - (( ^2- thieuyl) ethyl) -1-thiazetidin-8-bionic acid potassium salt

A) 3-Eiino-3-ethoxy-2-oxo-azetidine-tintonic acid tetra-butylmont salt

143 g tet ^ l ^ 1 ^ t ^ u ^ ^^^ ytnoni OIE ^ o ^ if (-) - 3-methOJχ * ³ - (/ eeryrlíethiχy / ktrboц1Lltíino) - ^2-1--ixo azstidUnзufioniié acid (see example 49) was dissolved in 15 ml of dry methanol, to which 12 mg (0.1 equivalents) of sodium tetrachloride decahydrate was added first, followed by 72 mg of 10% palladium to Н1 N. The mixture was hydrogenated under ethereal pressure for 15 minutes, then the catalyst was filtered off and the filtrate was evaporated in vacuo to give 114 mg of the title compound.

B) 3-Ethyl-2-oio-1 - ((2-thieuyl-tetylethylamino) -1-aaminotin-1-enoic acid) -tetrabutylinium salt ^{102 * *}

102 mg of tetrabutyl tertiary salt of 3-oxo-3-oxo-2-oxo-azetidine sulfonic acid in 10 ml of dry aceetoittil are added, 56.5 ml of dry pyridine are added and the resulting solution is stirred vigorously at -10 ° C under a dry nitrogen atmosphere. To 44 ml (100 ml of 1 ml of dry glycerol) is added. According to the thin layer, the rectum is terminated after 15 ml. To the mixture is added 4.2 ml of potassium phosphate buffer (0.5 M, pH = 5.5) and 8.5 mg (0.1 equivalents) of Oetrabutyl monoisulphate, and most of the tert-butanol is removed in vacuo. Dilute with water and extract three times with 20 ml portions. Dry the extract with anhydrous sodium sulphate and evaporate in vacuo. This yields 107 mg of a resinous product, which is obtained after purification by purification with ethylene chloride / titanium (III) as the eluent. 66 mg of the title compound.

C) 3-Ethyl-20-oxo-potassium - (/ 2-thtelecyl / tlino) -1-trisulphonic acid potassium salt

154 mg of 3-chloro-2-oxo-O - ((2-thiopheneacetyl) -amilo) -11-azerieile sulfonic acid is dissolved in 3 - 30% aqueous acetone, the solution is passed through the column in a column. The Dowex ⁵⁰ W-X2 ⁽ K @ ⁺ - @ ⁺ @ ¹¹ @ ¹¹ ) column is eluted with a clear solution. All of the eluate is discharged under vacuum to give 95 mg ^{of p} amofní R ^{A S} O ^ ek ture of point ^120, and ^from 135 ° C.

the product it provides after lyophilization

H, 3.09%. Found: C, 33.46; H, 3.08.

N 7.82%

N 7.92%

17.89% J

17.64%.

Example 1 ad

(3S / Z) -3- (((t-imo) 4-thiazolyl / baobymveetho [theta] (imino) airtylamidol) -2-oxo-1-azrtidine-8-ynoic acid potassium salt

0.1 g of potassium (3 (Z)) - 3 - () - (4-thiazolyl) (((0-oxo-2-yl) methoxy (methylthio) phenyl) acetyl) 8-amino) · 2-oxo- 1-tetridizoleic acid (see Example 71) was dissolved in 5 ml of 5 ml of water and 5 ml of water, which was thyrogenated at room temperature in the presence of 0.2 g.

10% palladium per run. After 2 h, the catalyst t endlessly to beat the remaining solution -.ionizuje ^objectives shall zítfó composite uvtoená title Tojice for rozWLadu ^p s ²³⁵ ° C.

3- (R) (S) - (tert-butyloxybenzyl) amyl] -2-methyl-methyl-imino) -3-methyl-2-oxo-1-thiazolidinedulonic acid (isoier A)

To a solution of 277 mg of 3-ertrabuУytЮltové soOi Tiina-3-ie ^ 100 ^ ^ 6 12-00001- tidinsufOnnové acid (see Example 46, Method II, Catty) in dry i-15 tcctoonteilu at - ²⁰ ° ⁰ p ^Rida 71 / L ^(0.8 ni ^of 8S) p ^ R ^ and ^ nu ^{(6 mg /)} - ² -tlinjo44 ^(2-ll l ^{OH lr)} -5- ^(4H) ~ -oxtzoljn mixture tydroihloriiu · 10 ilinut odd, then treated with additional 71/11 pyridine t (166 mg zasolinu. After a further 10 minutes the solvent fires at níženého pressure, the residue rozpuu ^with even in Sitos as ^dy t acetone and ^{p ro} ije to column ²⁰ ml tontoběntoe ^AG 5 ^0W -X2 ^{(K +} -cyklut, from 0.074 to 0.038 megabytes). After odpplení water from fractions 2-3 yielded 248 mg of a mixture dittOeaeoierů.

The product is purified and Ι £ μι0ιγθοιθγ! are separated by dithromitoorption on a column of 130 µl of the adtorbent / AG AG 20 mixture, using water as the reagent.

Medium and 59 mg

Analysis for melting point 158 DEG-165 DEG C .; C _n t / ₃ M ₄ O / S ₂ K. 1/2 H / O Off C '- 31,05% H 3,29% Halaseno C 30,95%' H 2,97%

N 13.18 N 12.98%.

Fractions 23-28 yield 30 mg of A isomer A, fractions 35-45 yield 30 mg i.soier B.

a fraction (10 mg) was combined with a total of 11 experiments. A total of 35 mg was isolated.

i.eomer B.

Analysis for isomer V, m.p. 160-170 ° C (dec.); C 1 H ₂ N ₂ O ₂ S ₂ K. 1/2 H ₂ 0 calculated C 31.05% found C 31.17%

H, 3.29;% N, 13.18;% S, 15.05%;

H, 3.09% .P 13.13%, S 15.09%.

3-Methoxy-2-oxo-3- ((phenylsulfoacetyl) amino) -1-azetidine sulfonic acid dipotassium salt

To a solution of 366 mg of crude tetrabutylammonium salt of 3-amino-3-methoxy-2-oxo-1-azetidine sulfonic acid (see Example 74A) and 38 mg of borax in 35 ml of dry acetonitrile is first added under nitrogen at -10 ° C. 53 ml of dry pyridine and then within 2 minutes a solution of 348 mg of alpha-sulfophenylacetyl chloride monoetherate in 8 ml of acetonitrile. After 20 minutes, the solvent was evaporated in vacuo and 39 ml of potassium phosphate buffer (0.5 M, pH = 5.5) was added to the residue. After addition of 383 mg of tetrabutylammonium hydrogen sulfate, the mixture was extracted three times with methylene chloride, the extract was dried over sodium sulfate and evaporated to give 685 mg of crude product.

This crude product was combined with 115 mg of the crude product obtained in the second experiment and the material was purified by SiliCAR CC-4 adsorbent column chromatography using methylene chloride followed by 2%, 4%, 6%, 8% and 10% methanol in methylene chloride as eluent. reagents. The product, which is a mixture (about 6; 1), of the racemic diaethereomers in the form of tetrabutylammonium salts, is converted to the potassium salt by Dowex 50W-X2 ion exchange chromatography (K * -cycle) using 20% aqueous acetone as solvent. Lyophilization to give 171 mg of the title compound, melting at 205-210 ° C with decomposition.

Analysis ^H 2 ^W 12 2 ° 9 ^S 2 ^{K 2 H} 2 ° Calculated C 29.51% H 2.89% N 5.74% S 13.10%; Found C 29.45% H 2.74% N 5.51% S 12.82%.

Example 78

3 - ((carboxyphenylacetyl / amino) -3-methoxy-2-oxo-1-azetidine sulfonic acid, dipotassium salt mg of 3 - [(1,3-dioxo-2-phenyl-3- (phenylmethoxy) propyl) amino] potassium salt - 3-methoxy-2-oxo-1-azetidine sulfonic acid (see Example 51) was dissolved in 5 ml of methanol, 3.9 mg of anhydrous potassium carbonate and 19 mg of 10% palladium on carbon were added, and the mixture was hydrogenated under atmospheric pressure for 20 minutes. The catalyst was filtered off and the filtrate was evaporated in vacuo to give 34 mg of a glassy residue which, after lyophilization, gave an amorphous powder melting at 178-190 ° C with decomposition.

For ^C 13 ^H 12 ° 8 ^N 2 ^SK - 0.5 H ₂ O calculated C 35.20% H 3.18% N 6.32% S 7.23%;

found C 35.51% H 2.96% N6.29% S 6.92%.

Example 79

(3S / Z) - 3 - (((2-Amino-4-thiazolyl) - ((2- (1,1-dimethylethoxy) -1- (methylthio) -2-oxoethoxy) imino) acetyl) amino) potassium salt -2-oxo-1-azetidine sulfonic acid

The procedure is analogous to Example 73 except that (Z) -amino-alpha- (hydroxyimino) -4-thiazoleacetic acid is used instead of (Z) -2-amino-alpha- (hydroxyimino) -4-thiazoleacetic acid. (Z) -2-Amino-alpha - ((2- (1,1-dimethylethoxy) -1- (methylthio) -2-oxoethoxy) imino) -4-thiazoleacetic acid. The title compound melted with decomposition at 130 ° C.

Example 80

(-) - Potassium salt

A solution of 185 mg of the tetrabutylammonium salt of 2-oxo-3- [N-chloro-N - ([ferylmethooyl] carboin-1) iminoo-1-azetidine sulfonic acid (see Example 49A) was cooled to -78 ° C in 1 mL of diaethylforaimide at this temperature. To this is added 3.8 ml of 0.73N alcohol-n-butooide in n-buanol After 15 minutes, 0.5 M potassium dihydrogen phosphate base buffer is added and the product is extracted three times with 40 ml of dichloromethane each time. The mixture was filtered and concentrated in vacuo to give 179 mg of the tetiabutyimmonium salt of the title compound.

To a solution of 109 mg of the tert-butyl ester salt prepared above in icetone was added 60 mg of perfluorobutine sulfonic acid disodium salt in icetone. The solvent was evaporated in vacuo and ethyl acetate was added to the residue. The resultant product was collected and dried. 66 mg of the title compound were obtained, mp at 186.5-187.5 ° C.

They said d 81

(Α + - / E) Potassium salt of α-aethooy-3 - ((/ aethooyiaino) ((2 - ((phthyllaethooy / clbonyl) amino) -4-thiisolyl) icyl) imine) -2-oxo-1-isetidinsuioonic acid

To a suspension of 0.175 M tetrabutyl methyl ester salt of 3-amino-3-amino-10-oxo-o-azidine sulfonic acid (see Apparatus 46, Method II, Part A, 0.0175 maol) to dissolve the sodium salt in dichloromethane at 0 ° C. C was added pyridine -8yul and 0.175 mmol of (E) -il ^ am ^ i ^^ l ^ ¹ ^ o ^ ^ oyl mln (o) - ^- - ^C (/ FEL У.matho ^{n -} ^ 1 ^ n ° 01 ) ^1-r liaq o4- hialz ^{4 0} s ^t u 1lcelychlori ^{i. p 1} 'clock ^{é í} reikčn the mixture was diluted dtchlormethшlea, shaken with water, orginická layers are washed with water and īje ^ nisyceným brine, dried and Purification of the residue with -00 g of Mailinckrodt Silic® R CC-4 gave 43 mg of the tetrabutylmonium salt of the title compound.

mg of this tetrbutyl-ammonium salt is dissolved in 0.5 ml of icetone and to the solution is added -0 mg of perfluorobutine sulphonate. 0.5 ml icetone. After addition of 3 ml of ether, the precipitated solid material is filtered off and dried, under vacuum. This afforded -8 mg of the title compound, mp 144-146 ° C.

EXAMPLE 8Potassium salt -з + - (Z) - 3-aethooy-3 - ((/ aethooyiaini0 (2 - ((lfinylaethoot / carbon)) amino) -44thilzolyl) ethyl) lmino) -2- ooo-1-azetidine8ulonic acid

The procedure was followed by an analogous procedure to that described in Example 81, substituting (Z) -I1Lfa- (aethooytino) -2-f (1-phenylaminoethoxy) -4-thiophenol / carbonylphenyl] -4-thiazolyl-4-thiolyl (1-alpha) - (aethooylamino) -2-f. -ern tlDatho ^r o) to ^r boron). amiaoj ^ j 4htazol) 1Lalceetchlorii. The title compound is obtained, m.p. 168 DEG-17 DEG.

He also said 83

3 - (((R) - (- (4-Ethyl-2,1-oxo-1-piperazinyl-1-propanol) -1-phenylcarbonyl) mino) phenylcetyl-llaino) -3-methyl-2-oxo-1-azetidine-sulfonic acid potassium salt

To a solution of 0.69 mmol of 3-laino-3-methyl-2-oo-1-alzeidinesulfonic acid ethylbutyl-ammonium salt (see Example 46, Method II, Part A) in 30 ml of dry iceto-lithium at -30 ° C. -0 ° C under nitrogen firstly add -4- [mu] l of dry pyridine, a solution of 35 mg (R) -alpha - (([4-ethyl-2,3'-oxo-1-piperidinylcarbonyl) laino) phenylacetyl chloride] in 4 ml

After 1 hour 84/11 pyridine was added followed by an additional 117 mg of the above acid chloride in 1 mL acetonitrile. The reaction mixture was stirred for 20 minutes, then diluted with 24 ml of 0.5M potassium dihydrogen phosphate buffer, pH 5.5, and concentrated in vacuo to remove acetonitrile. The aqueous residue was extracted three times with methylene chloride, the combined extracts were dried over sodium sulfate and evaporated to give 546 mg of residue. This residue gave silica gel column chromatography using first methylene chloride and then 2%, 4% and 6% methanol in methylene chloride as eluent to give two fractions (285 mg and 173 mg) of the corresponding tetrabutylammonium salt of the title compound.

Chromatography of the 173 mg fraction and 4.5 g of Dowex 50-X2 ion exchange resin (K * -cycle) using aqueous acetone as eluent gave 119 mg of the title compound. 104 mg of this material was applied to a column of HP 20-AG resin in water. Gradual elution with water, 5% aqueous acetone and 10% aqueous acetone gave 60 mg of the product as a mixture. (about 1: 1) diastereomers. Lyophilization of this 60 mg fraction gave a solid melting at 171-172 ° C.

Example 84

N- (3-butoxy-2-oxo-1-sulfo-3-azetidinyl) -2-phenylacetamide tetrabutylammonium salt

The procedure is analogous to Example 80, but substituting tetrabutylammonium salt of N-chloro-N in place of the tetrabutylammonium salt of 2-oxo-3- (N-chloro-N - ((phenylmethoxy / carbonyl) amino) -1-azotidinaulfonic acid). - (2-oxo-1-sulfo-3-azetidinyl) -2-phenylacetsamide (see Example 47A for the preparation of the corresponding potassium salt). The title compound is obtained as an oil.

NMR (CDCl 3): 3.62 (s, 2H, C ₆ H ₅ CH ₂ ), 4.03 (AB-quartet, 2H, η ₇ H ₅ , C ₄ -CH ₂ ), 6.98 (s, 1H, NH) and 7.30 ppm (s, 5H, CH3).

Example 85

(R) -3-Methoxy-2-oxo-3- (phenylacetyl) amino} -1-azetidine sulfonic acid potassium salt

Slowly adding trimethylsilyl chlorosulfonate to dimethylformamide at 0 ° C followed by 30 min evacuation at 0 to 25 ° C to prepare a 1M solution of dimethylformamide-sulfur trioxide complex. 50 mg of (R) -N- (3-methoxy-2-oxo-1-azetidinyl) phenylacetamide are dissolved in 0.2 ml of anhydrous dimethylformamide under argon, the solution is cooled to 0 ° C and 0.428 ml of cold are added. The solution was stirred for 2 hours and then poured into 15 ml of a 0.5 M potassium dihydrogen phosphate solution. The resulting solution was extracted twice with dichloroethane (the extracts were discarded) and 73 mg of tetrabutylammonium bisulfate was added thereto. Extraction three times with 10 ml of dichloromethane each time and evaporation in vacuo gave a viscous oil which was chromatographed on 50 times silica gel (Mallincrodt CC-4) using 2% methanol in dichloromethane to give 34 mg of tetrabutylammonium salt of (R) -3-methoxy-2. -oxo-3- ((phenylacetyl) amino) -1-azetidine sulfonic acid. After chromatography on Dowex 50W-X2 (K + -cyklus, 10 equivalents) was obtained after lyophilization of the aqueous eluate potassium salt of the above title compound melting at 130 DEG C., .alpha _D «* 52 ⁰ (c = 0, 5, water).

Example 86

(S) -3 - ((((1-Ethyl-4-hydroxy-3-methyl-1H-pyrazolo (3,4-b) pyridin-5-yl / carbanyl) amino) phenylacetyl) amino) potassium salt - Of 2-oxo-1-azetidine sulfonic acid

Using the procedure described in Example 73, substituting (Z) -2-amino-alpha- (hydroxyimino) -4-thiazolylacetic acid alpha ((1-ethyl-4-hydroxy-3-methyl-1H-pyrrole) ( 4-b) pyridin-5-yl (carbonyl) amino) benzeneacetic acid gives the title compound, melting at 233-236 ° C.

Example 87

(R) -3-Acetylamino-3-methoxy-2-oxo-1-azetidine sulfonic acid potassium salt

A) 3-Acetylamino-1- (1-carbocyc-2-methyl / propyl) - (3R) -3-methoxy-2-oxoazetidine

650 mg of (6R-cis) -7-acetylamino-7-methoxy-3-methyl-8-oxo-5-thia-1-azabicyclo (4.2.0) oct-2-ene-2-carboxylic acid and 191 mg of sodium bicarbonate in water are added 11 ml of a slurry of technically pure Raney-nickel (0.6 g / ml) washed to neutrality with water. The mixture was placed in an oil bath preheated to 170 ° C and refluxed for 2-3 minutes while maintaining a bath temperature of 150-170 ° C. After boiling for 15 minutes, the reaction is quenched by cooling in ice, the catalyst is filtered through a pad of diatomaceous earth and the filtrate is acidified to pH 2 with 1N hydrochloric acid. The aqueous solution is extracted five times with ethyl acetate, the combined extracts are dried over sodium sulphate and solvent. . 487 mg of an oily residue are obtained which, after chromatography on silica gel with chloroform as eluent, affords 381 mg of the desired product as an oil.

B) 3-Acetylamino-1- (1- (acetyloxy) -2-methyl-propyl) - (3H) -3-methoxy-2-oxoazetidine

464 mg of the above azetidinone is dissolved in 15 ml of dry acetonitrile, the solution is purged with argon for 15 minutes, then copper (I) acetate (359 mg) is added, and the mixture is stirred for 1 minute to dissolve the salt. While the argon is continuously introduced into the reaction mixture, its temperature is raised by immersing the reaction flask in an oil bath preheated to 55-65 ° C and held at that temperature for 15 minutes. The mixture was allowed to cool to room temperature, filtered through a pad of diatomaceous earth, and the filter aid was washed thoroughly with acetonitrile. The filtrate was combined with the washings, the solvent was evaporated in vacuo. The residue was taken up in water and the solution was extracted four times with ethyl acetate. The combined extracts were dried over sodium sulfate and the solvent was evaporated in vacuo to give 382 mg of the desired product as an oil.

C) (R) -N- (3-Methoxy-2-oxo-1-azetidinyl) acetamide

The oily material obtained above was dissolved in a mixture of 10 ml of methanol and 1 ml of water, cooled to -10 to -15 DEG ^{C. in an} ice / methanol bath, and then 194 mg of potassium carbonate and then 53 mg of sodium borohydride were added. The mixture was stirred at -15 to -8 ° C for 110 minutes, then the solvent was removed in vacuo, the residue was taken up in water and acidified to pH 6 with 1N hydrochloric acid. thorough extraction with ethyl acetate, drying of the extract with sodium sulfate and evaporation of the solvent in vacuo gave 224 mg of an oily product which, after chromatography on silica gel with 5% methanol / 95% methylene chloride, yielded 169 mg of oily material. From the ether / pentane mixture, 131 mg of the title compound crystallized, m.p. 106-112 ° C (sintered at 103.5 ° C).

D) (R) -3-Acetylamino-3-methoxy-2-oxo-1-azetidine sulfonic acid potassium salt

50 mg of (R) -3-acetylamino-3-methoxy-2-oxo-1-azetidine were charged to the reaction flask under argon, the flask was cooled to 0 ° C, and 0.95 ml of 1M dimethylformamide complex solution was added. dimethylformamide sulfur trioxide and the resulting solution were stirred for 15 minutes. The contents of the flask are added to 40 ml of 0.5 N potassium monohydrogen phosphate solution and the mixture is extracted twice with 10 ml of methylene chloride each time. 1.2 equivalents of tetrabutylammonium sulfate are added to the aqueous solution and the resulting mixture is extracted four times with 10 ml of methylene chloride each time. The extracts were dried over sodium sulfate and concentrated to give 39 mg of product. The tetrabutylammonium salt is converted to the title potassium salt by passing through a Dowex 50-X2 ion exchange column (K * -cycle). Concentration of the aqueous fraction gave 19 mg of the desired potassium salt, the NMR spectrum of which was identical to that of the compound prepared in Part IB) of Example 46 and the substance isolated from natural material (see Example 165).

Example 88.

(R) -3- ((Azictophenylacetyl) amino) -3-iodo-2-oxo-1-azetidine sulfonic acid potassium salt

A) Tetrabutylmoniová salt // - 3- (laziOifeyylaceyyl // iino) ^-3-methyl, 2-methoxy-oxoo) -azeeidiisuLlonové kyseliey

202 [mu] g of tetrburtylmonium salt of 3-laino-3-methoxy-2-n-n-l-1-pyridinesulfonic acid (see Example 74A) is dissolved in 20 ml of dry lcetooitrile and decanted with vigorous stirring at -20 [deg.] C. adds 167yu! of dry pyridine 96 mg / ml of 11-azidolenylcetyl chloride. After 20 minutes, 12 ml of 0.5 M potassium dihydrogen chloride chlorate (pH 5.5) was added to the solution, which was absorbed in a wolf. The aqueous residue is extracted three times with methylene chloride, and the extract is dried over anhydrous sodium sulphate and it is flashed. 281 mg of crude product are obtained in the form of a gum. Purification of the product by chromatography on a column of 30 g of silica gel using first of the chlorine chloride with a mixture of ethyl chloride and methylthymol containing up to 6% methanol yielded 231 mg of the title compounds.

B) Potassium salt of [beta] -3- (lzZ0leeyytacttyl // name) --- methoxyl-2-oxo-1-isolizudonic acid

A solution of 231 mg of tetrabuylmmonium salt of [beta] - ((azenylphenyl) (C) amino) -3-methyl-2-oxo-1-isetidinsuloonic acid in 15 ml of a 30% aqueous solution was passed through a column of 3 ml Dowex 50W-X2 ion exchanger ( The K-cycle column is washed with water. Evaporation of all the eluate in a wolf yielded 168 mg of a first glassy compound consisting of a 1: 1 dilsteeooer mixture. This mixture was partitioned nl with a 60 ml column of HP 20-AG adsorbent using first 1 l of water with 10% lcetone as eluents. 71 mg of a 1: 1 mixture of racemic dilutions / es were obtained. 70 mg of a 1: 3 mixture of racemic mixtures / mixtures. The 1: 1 mixture was freeze dried at 40 ° C to give a pure product as a herniyl heptide-quenching product. decomposition at 130 ° C.

Annlýza: for D | 2H | 2 N ^ ^{<^} o * ^K O »5 H ₂ O Calculated C 35.90% H 3.26% N 17.45% S 7.98%; Found: C 35.94% H 3.07% N 17.24% S 8.02%.

Example 89

3 - (/ azzofofytocytes / lleno) -3-actothi-2-oxo-1-azisizine sulfonic acid potassium salt, isomer A

The 1: 3 mixture of the diastereoisomeric salts obtained in Example 88B was allowed to stand at room temperature in deuterium oxide to precipitate isomer A. After cooling, the mother liquor separated also from the crystalline maleate. in a wolf at 40 ° C. There were obtained 28 mg of the ice compound in lorm aonendejerate, m.p. 130 DEG C. (dec.).

Example 90

(3- (H)) - 3 - (((((4-Ethyl-2,3-dioxo-1-piperazinylcarbonyl) (mie) lc] e) (l) ethylcetyl) lmino) -3-methyl-t-potassium salt The compound of formula (II): 1-oxo-1-azetidenesulonic acid

To a solution of 0.69 mmol of the tetrbutylmmonium salt of 3-l / ino-3-methyl-22-oxo-1-alzcedenesulfonic acid (see Example 74A) in 30 ml of dry 1-acetonitrile at -20 ° C under nitrogen is first added 242 µl of dry pyridine and plk solution of 352 mg of (4'-ethyl) - ((4-ethyl-2,3-zioxo-1-p-propynyl / carbonyl) lano) phenylacetyl acetyl in 4 ml of acetonitrile. After 1 hour, a further 117 mg of p-addine and pl of an additional 117 mg of the above acid chloride in 1 ml of acetone were added first. The reaction mixture is stirred for 20 minutes, the plk is diluted with 24 ml of a 0.5 M pulse nl of ZHHiZ ™ 47 based potassium diphosphate (ρ Η 5.5) and concentrated in vacuo to remove acetonitrile. The aqueous residue is extracted three times with methylene chloride, the combined methylene chloride extracts are dried over sodium sulphate and the residue is recycled to a residue of 546 mg. This material is chromatographed on a column of SilCcAR CC-4 adsorbent using firstly the mixture. C 1 H 2 O 3 and then 2%, 4%, and finally 6% mothanol in C 2 H 3 O 2 O 3 as eluents. Two fractions (285 mg and 173 mg) of the purified product are obtained in the form of the t-butyryl salt.

The 173 mg product was passed through a column of 4.5 g of Dowex 50-X2 ion exchange resin (K @ 1 cycle) using aqueous acetone as eluent to give 119 mg of potassium salt. 104 mg of this material was applied to a column of HP20-AG adsorbent in water and the column was successively washed with water, 5% aqueous acetone and finally 10% aqueous acetone. 60 mg of product are obtained in the form of a mixture of dittteteomers (ca. 1: 1) and 21 mg of the product are in the form of a mixture of dittteeoooters (ca. 9: 1). Lyophilization of the 60 mg fraction gave the title compound, melting with decomposition at 171-172 ° C.

H, 4.37; N, 12.65. S, 5.78.

found N 41.39% H 4.12% N 12.58% S 5.63%.

Lyophilization of the 21 mg fraction gives the title compound, melting at 171-172 ° C with decomposition.

Anaalysis: C 41.23% H 4 → 7% N 12.65 calculated for C 18 H 18 NO 2 SK 3 · H 2 O;

found: 041.43% H4J1% N 12.28%.

Treatment of the fraction of 285 mg of tetra-butanoic salt to ion exchange with only 50-X2 (K-cycle) yielded 145 mg of potassium salt which was combined with the remaining 15 mg of the potassium salt of the above 119 mg, obtained after ω-chromium chromatography. . This was chromatographed on the HP20-AG absorbent as described above to give an additional 31 mg of the product as a mixture of diastetooers (about 1: 1) and an additional 42 mg of the product as a mixture of diastetomers (ca. 1: 1). 9: 1). The overall ratio of the 1: 1 mixture of diastereomers is 91 mg and the total ratio of the 9: 1 mixture of ieto-stereoisomers is 63 mg.

EXAMPLE 91 (33/2) -3 - (((^ ^хххх! О опппп / / / ((f f f f kat kat kat kat kat a a a a a a a a a a a a a a a a a a a a a a a a a a a)) a))) )L))))))))))) )ylylylylylylylylylylylylylylylylylylylylylyl)

To a solution of 0.170 molar tert-butylamine salt of (S) -3-ainoino-2-oxo-1-azetidine sulfonic acid (see Example 6A) and 0.170 molar sodium boronate in 2 ml of ethyl chloride are added at 0 ° C 62. 51 oool (ZZ-tfa) oShoxylimino-2 - ((phthylotthoxy / carboayl) thiazol-44-thiazolyl) acetyl chloride. After 40 minutes, the reaction mixture was diluted with water and dichloromethane, and 5.1 ml of 0.1 M sodium phosphate buffered saline buffered to pH 4 was added. The organic layer was separated, washed with acidified water to pH 2, adjusted to pH 7 and saturated water. sodium chloride, dried with sodium sulfate and, after filtration, concentrated in vacuo. The residue was purified by chromatography on 10 g of silica gel with SilCcAR CC-4 using 10% methanol in methyl chloride to elute the product.

The tetrabutylmonium salt is dissolved in aqueous acetone and poured over an ion exchange column

AG 50W-X2, (8 mL, K-cycle, 0.147-0.074 mm). Evaporation of water from fractions 1 and 2 in vacuo gave 40 mg of the title compound, melting at 172-174 ° C with decomposition.

Analysis: for HgO calculated C 37.04% H 3.33 «N 12.99% S 11.87«;

found C 37.95 «H 3.30% N 12.73« S 11.53 «.

Example 92

Potassium salt of () - 3-Uunoxy-2-oxo-3 - ((folylaetlyl) (10) -) can besusuidone acid

A) Tetrabutylimoniová are: 3- (illnrfforyrlaiety / aмlinn) - ^2-1-noxn azetdd0ssuf0onníé acid

To a suspension of 1.27 with sodium bordtaate in a mixture of 4.72 ml of a 5.25% sodium hypochlorite solution and ²⁰ ml of water at ⁰ ° ^C is ^{added a} solution of ^{0 350} mg of sodium hypochlorite. / ^/ / -2-non-3 - ((efenylettno5y / 0karbťJOll) llLoo) -1-azetid0n8ufnonoíé ester (see example 4) in 3 mL of m / ethylene enchloridu. After one hour, 25 ml of a 0.5 M solution of potassium diphosphinate is added and the mixture is extracted three times with 50 ml of water. The organic extracts are dried over sodium sulphate and, after filtration, concentrated in vacuo to give 344 mg. the title compounds.

B) Tetrabutylιmoniníá salt / --- 3-UtOo5l-- noxn ^2-J - ((/ eolyaaeelyl / Mton) -) ^d lzeetd OsulfLOonové acid

To a mixture of 6 ml of 0.73N lithium butoxide in n-butanol and 1 ml of di-phosphoralide are stirred at room temperature. Fences ^of 78 ° ^C under inert pl ^ u pM mites ^{give 0344} mg of ^t etrabuty ^and mιnoioí ^s SOH 3- (ilhnor / folylmelhooy / karbnoyl) lmioo) -1-azetidOnuufnonoíé acid in 5 ml of di methyl ^ m ^ ^ i ^ om ^ i ^ idu. After 10 minutes, the mixture was diluted with 175 ml of a 0.5 M solution of dilydrogenphosphate ^, extracted with potassium ether (3.times.). The organic extracts were dried over sodium sulphate, filtered and the solvent was evaporated in vacuo. The residue is purified with 80 g of silica gel. cAR CC-4. 130 mg of the title compound are eluted with 4-8-methanol in ethylene chloride.

C) ^and potassium salt of ^(-) зЗ ^Ulnox-l - ^- -non-3- (f ^e o] -acetate ^{IIa and /} NINN) -1aazθt ^d d ^{0 f0} Suu onni ^ i ^ (^ 1 ^{even if} a SOM mg tetгabutylетюniníá Insulin acid ^(- / -) - Ununo}φ---non-3-(phenol ^and acetyl ^and / ^or dool-1-yzeeid) was dissolved in a mixture of water and acetone (9: 1) and an oy column was added. 5 g cation exchanger ⁽ Dowex AOM ^{P 50W-} X ^{2, 0.1 47-0.0} 74 mm, K 2 -cell). Frodukt in ¹¹ ^ y eluáfc with water zahuusí in vacuo with ^no injection by IM ^{or 20} mg zístt merged Uve ^d ^ ^é eo title .mu.Ci @ ²² pH I 1 ^{y 25} ° C.

H, 4.96; N, 6.95; S, 7.94. Found C, 44.77, H, 4.76, N, 6.76, S, 7.75.

Example 93

The potassium salt / --- 3-θlOoxy- noxn ^2-3 - (/ eolyaaeeУyl / Mton) -1lzeetddOsuufOonoíé acid ^{to 12,} 20 ml of 0.5N ettoxidu Шпё ^ ^ ю in ethanol ^p ^ s ^ plo -7 ⁸ ° C in taertaí yl ^ <^ i ^ l ^ <^ ^Rf: 200 mg tetrabutya / lootníé SOH 3- (illnrfeoryLlacety / aDOnn) -2ooχn azetddOsaufnonníé 1-ester (see example 92a) in 4 ml of dimethylformamide / ethylfon / chloride. After 10 minutes, the mixture was diluted with 15 mL of a 0.5 M potassium dihydrogenphosphine solution and extracted three times with 1 / ethylcyclide. The organic layer was dried over sodium sulphate, filtered and the solvent was evaporated in vacuo. The residue was passed through a column of 20 g of Silic / R CC-4 silica gel. 2 «methyoolem in ebony. The amide was washed with 40 mg of tetrabutylamine salt of the above acid.

Tetrabutylmoniová salt is dissolved in a mixture of water y acetone (9: 1) and applied to a column Oy 5 ^g of Dowex cation exchange resin ^and GMP 5 ⁰ W-X2 ^(0, 140 to ^{0, 0} 74 mm, K ^ -cyklus). The product is in ^{y /} ^, is water and the eluate was zahuusí vacuum Ci / well to give 25 mg of the title compound, tyjící, 94 and even 96 ° C.

disconnected C ^42,62 %

111Г1Г1О c ⁴⁰ 3 ⁶ «

H 4.10% N 7.65%

H 3.66% N 6.77%

S 8.74 «

S, 8.44

(3- / Z / 1 -3- (2- / 2-t10n4-Tutololyllyl) methyl (1'-amino) ethyl) -methoxy-2-oxo-1-azrtidine-naphthyric acid

Dissolve 3-iiineo3-1010110X1220000 1-828- (4-acetic acid) salt (see Method A-IX - Example 46) sr in 20 ml of Cronton t 1 l of pyridine, add t solution to the vigorously stirred suspension (Z) - ala-- ^and lothoχyilino !!) - ² -lminno4-2htazoOyllcstyliUloriiu vr ²⁰ ml of ¹ icotooKtHu, cooled nt ⁰ t ^≥ 5 ° C. The reaction mixture was etodrna 1 hour odd ^to PT was diluted with 100 ml of 0.5M potassium dthyirogenfoslOreU1t1u (pH of the mixture is 4.8) and of a solvent sr odpelí VR vacuum residue · sr vyjir οΐ ιά ^ ^ ΐ obseauujcí volume of water, a small amount of acetone . CluoomtografjÍ.í ^ ii ²⁰⁰ ml toátoiěntoe ^0W AG 5 -X ^{2 (0,} 147 - ^0.074 mm, C ^ -C ^ ⁰ lui after elution with water, the crude yolk sell the phoneme potassium icOi. Additional purification on 200 ml of HP-20 pryelkyřice We poožití water as eL-učního reagent and Oaiiuatci sr Sibe iGores ^^ l ^ t ether PTK Oaiuirici twice with ether gave 59 mg of the powder product. the aiooftií prášfový ^p and ^d i ^ l ^ ^'0 Oije slowly triturated with t ^P rl temperature above 150 ° C

Analysis: for C 10 H 10 Cl 2 O 3 / SK calculated

28.77%

27.77 »

H 2,90%

H 2,82%

N 16.78%

N 15.87%

N 15,, 36% N 13663%

К% 37 К 10.11%.

d 95

Potassium TDL ^(3R) R / t 3 ^^ /) 33 - ((but ^{at al O and} R b L · ^{O] y |} l / mt ^l oo ^ir phenyl cee ^{y l} y ^l) itι ^j n>) - 3 -LR .hoxy ^t-2-oxo-1-1 ^ 010 ^ tulOonové kyselily

A) External Ed. (-) - 3-l (alinofluorylmethyl) mono-3-nitrophenyl-2-oxo-l-1-nitrosulfonic acid ²⁰⁹ mg of potassium tert-butylacetyl / arine-1-methanoic acid. Dissulfuric acid N-oxo-isetide is dissolved in 60 ml of dry ethyl acetate, 0.6 ml of anhydrous Oifluoroacetic acid is added and 105 mg of 10 palladium nitr is added and the mixture is hydrogenated for 1 hour. The catalyst was filtered off and the filtrate was evaporated in vacuo to give 271 mg of crude product.

B) Potassium EDL (3R / R / T 3 S // * /) - 3 - (((/ ami1b ^to araoonУ / lminnOOiмnrУacetyl) amino) -3-iethoxy-2-ooo 1-izeei ^ dn ^ i The acid is 10-10%

271 mg of potassium [3- (3-methyl-methyl) methyl] methyl-22-oxo-1-isothioic acid If swelling in 6.5 ml of water, 87 mg of potassium tetraacetate are added and the mixture is stirred at room temperature for 3 hours. . The reaction solution was reduced in volume to about 2 ml in vacuo, and 100 ml of HP20-AG absorbent was used on the column using water as the eluent. After tyofllizaci the ZIE and 2 ^{to 9} mg Toomer ^A tojído ECR ZT ^ u ^p s 16 ⁰ Q.

AnO ^Sa: for Cj /H H NN / O / SK-R calculated C 36.44 «found C 36.35

H 3,99 »

H 3,79 «

N - 13.07 «N 12.81«

S 7.48%;

S, 7.32

Example 96

Potassium salt OR ^ / S ^ ⁸ / and 3S / ^R5ý) 3S / ^R /) - 3- ^(((/ ARBO aшlno ^{to about} У and / ^{ш amino)} phenyl ^N ATC ^r-yl) tuioo) - ^{3 ih} -MR ooy-2-100-1-thiazidium with N, N, N-hexanoic acid

Along with ďrasetaou ^(3S / ^R / and ЗЭ / б -ЗЧ ^ ^{((/ n} was aшinlkιи * l / Ti ^ш in frnylt ¢ ^l ethyl) aшinl aRthoxyy2 3-oxo-1 -azi ^ I ^ d: The acid produced in Example 95 gave 25 mg of the potassium salt of (3R / S) -3 - ((((aminocarbon) / shine)). Phenylacetyl) trioxo-3-methyl-3,030-1,8-oxo-1-azetide sulphonic acid in a film of melting point with decomposition at 160 ° C.

For ^C 13 ^{H 11} N 3 O 2 S 2: Sequihydrate calculated C 35.69 H 4.14 N 12.81% S 7.33; Found C 35.98% H 3.87% N 12.50% S 7.32%.

Example 97

Potassium salt (3- / S * /) зЗ-mritlχy-3 - ^ (((((2cOlpзЗ- (r.te) lШШrθthyrene / ιøinc) -1-itidaaolidil'nУ) carbon ^) оШпо))) amino) -2-oxo-1-trididine-amino acid

To a solution of 3-thieno-3-blackholodazole sulfonic acid trtrabutylsulphonium salt (306 mg crude containing probably 274 mg of the organic substance prepared by sub ^-process according to Example 74) in ²⁰ ml of ^water at 0 ° C to 100 ° C was added at ²⁰ ° ^{C. 20} ° C under nitrogen first add 0.30 ml (3.72 maml) of dry pumidium and then 484 mg / S / - (((2-oxo33 ((phenolmethyl / cis-1-imidazolidinyl) carbon)) ·) оШпо 2-Trifluoromethyl chloride partially dissolved and suspended in 10 ml of dry accetoacetate and allowed to warm to 0 ° C with stirring over 1 hour.

The reaction mixture was diluted with a large volume of methyl chloride and added to 22 ml of 0.5M potassium dihydrogen phosphate buffer (pH 5.5). The aqueous layer was washed with 1: 1-pyridine, the combined methyl ethyl chloride extracts were combined. water, dried over sodium sulphate and evaporated to a residue of 508 mg which was taken up in 50 g of silicagel Silic CC-4 using methylchloride and then with 258 and 496 of methanol in the eluent of eluent. 251 mg of the tributyltinium salt of the title acid are obtained.

To 251 mg of this salt in acetone was added a solution of 107 mg of perfluorobutyrsulfonic acid potassium salt in a few millimeters of acetone. After addition of N, N ethylc the precipitate ^ i ^ r washed with ^{41 nl t} h ^e em TCR and ^ODS diluted to ^{c o u 2 h} Odin ^y ^ plo dried at? ⁴⁰ ° C cotton

¹³³ Pa. 95 ^mg Mda drttr ^ ^{l s} n ^f Orme SOM in a direction ^m of diastereomers ^{(ca. 1} dec ²⁰⁰ ° ^C. : 2) melting Analysis: for ^C 21 ^ 21 ^ 6 ° 8 ^ 2 ^K knitted C 42.85% H 3.60% found C 43.02% H 3.74% N 14.28% K 13.94% WITH WITH 10.87 10.71

Example 98

Dr ^ Elne salt / ^L cis) ^-4-n l- ² mrth -oo1- ³ - ^{(((l e} fβr Шrtthoo ⁿ // ^to arbcn ^AD) aшin1) - ¹ -tzrtl ^de nιэul ^of enov ^é acid

A) Ν ^ π ^ Ιιο, ·) · ^ · ^^ -θΙΟι ^ ο ^ οπΟπιπι ^

To a solution of 6.9 g of 1-t-tert-toluene and the free amine liberated in ethyl carbonate was dissolved therein. z ^r , J. Ir-drh of the class of λ-bromotyridine (about 0.033 * 11) in all of tetrahydrofuran is added 4.0 g of N-hydroxybenzotrebolitzitol and 6.5 g of dicycltrotrophodide in ml of tetrahydrofuran. The resulting suspension was stirred at room temperature for about 16 hours, then filtered, the filtrate was concentrated in vacuo and the residue was chromatographed on a 400 µl silica gel column. Elution with 5-10% ethyl acetate in chloroform gave 6.8 g of the title compound from fractions No. 7-22 (200 mL fraction).

(i) boc and butoxycarbones1

N- (-cis) -N-benzyloxy-3-tert-butoxycarbonylamino-4-methylazetidinone

A solution of 6.8 g of N-benzyloxy-tert-butoxycarbonylallothreonine amide in 200 ml of tetrahydrofuran was stirred with 5.24 g of triphenylphosphine and 3.2 ml of diethyl azodicarboxylate for about 16 hours. The solvents were evaporated in vacuo and the residue was chromatographed on a 500 ml silica gel column. Elution with methylene chloride followed by crystallization from ether gave a total of 2.65 g of azetidinone. Rechromatography of the mother liquors and mixed fractions gave an additional 0.6 g of product. Recrystallizing twice a portion of the product from ether (-20 ° C) gave an analytical pure sample of the title compound, melting at 140-142 ° C.

C) (- (cis) -3-tert-butoxycarbonylamino-1-hydroxy-4-methylazetidinone

A solution of 3.2 g of cis-N-benzyloxy-3-tert-butoxycarbonylamino-4-methylazetidinone in 200 ml of 95% ethanol was stirred with 0.7 g of 10% palladium on carbon in a hydrogen atmosphere. After 40 minutes (hydrogen consumption 249 ml), the suspension is filtered, the filtrate is evaporated and the residue is triturated with ether. 2.05 g of solid are obtained in 2 fractions, m.p. 134-136 ° C.

D) (- (cis) -3-tert-butoxycarbonylamino-4-methylazetidinone)

To a solution of 2.05 g of cis-3-tert-butoxycarbonylamino-1-hydroxy-4-methyl-azetidinone in 60 ml of methanol add a total of 90 ml of a 4.5 M ammonium acetate solution (40, 20 and 30 ml portions) and 45 ml of 1, 5M titanium tetrachloride (20, 10 and 15 ml portions), the second and third portions of both reactants being added after 15 and 120 minutes. After 135 minutes, the reaction solution was diluted with an equal volume of 8% sodium chloride solution and extracted three times with 300 ml of ethyl acetate each time. The combined organic layers were washed with 100 ml of 5% sodium bicarbonate and 100 ml of saturated sodium chloride solution, dried and evaporated. Trituration of the residue with ether gave 1.65 g of solid material in 2 portions. Part of the first portion of this material was recrystallized from ether analytical sample, mp ^176-1 DEG C. 78.5.

E) (- (cis) -3-Benzyloxycarbonylamino-4-methyl-azetidinone)

A solution of 1.55 g of cis-3-tert-butoxycarbonylamino-4-methyl-azetidinone in a mixture of 4 ml of methylene chloride and 4 ml of anisole was cooled to 0 ° C and 50 ml of cold trifluoroacetic acid was added. After 90 minutes the solvents were removed in vacuo, benzene was added to the residue and the mixture was evaporated three times, the residue was dissolved in 25 ml of acetone, the initial pH (2.5) was raised to 7 with 5% sodium bicarbonate and 2 g of benzyl chloroformate are added. The reaction solution was cooled at pH 7 to 0 ° C for 4 hours, then the acetone was evaporated in vacuo and the remaining suspension was filtered. The filtrate was saturated with sodium chloride and extracted with methylene chloride. The solid material was dissolved in methylene chloride and dried. The organic layers were combined, concentrated and the residue chromatographed on a 200 ml silica gel column. Elution with a 3: 1 mixture of chloroform and ethyl acetate gave 850 mg of the title compound from fractions # 4-11 (100 ml fraction). Crystallization of a small amount of the product from ether gave an analytical sample, mp 165-166 ° C.

F) .beta.-cis-4-Methyl-2-oxo-3 - (((phenylmethoxy) carbonyl) amino) -1-azetidine sulfonic acid potassium salt

To a suspension of 0.75 g of cis-3-benzyloxycarbonylamino-4-methylazetidinone in a mixture of 7 ml of dimethylformamide (dried at 4.10 µm molecular sieve, activated for 15 hours at 320 ° C under argon) and 7 ml of methylene chloride (dried over basic alumina) 1.66 g of pyridine-sulfur trioxide complex are added. After stirring at room temperature for 3 hours under a nitrogen atmosphere, an additional 1.66 g of pyridine-sulfur trioxide complex was added. The reaction mixture was stirred under nitrogen at room temperature for about 16 hours, after which dimethylformamide was evaporated in vacuo. 4.6 g of residue are obtained, which is dissolved in 300 ml of a 0.5 M potassium dihydrogen phosphate solution (dissolution is carried out at 40 DEG C. and takes 10 to 15 minutes). The resulting solution was cooled, applied to a column (3 cm x 60 cm) of HP-20 resin and eluted with 400 mL of a 0.5 M potassium dihydrogen phosphate solution (dissolving at 40 ° C for 10-15 minutes). The resulting solution was cooled, applied to a column (3 cm x 60 cm) of HP-20 resin and eluted with 400 mL of a 0.5 M potassium dihydrogen phosphate solution, 1 liter of distilled water and water / acetone (14: 1). collecting 100 ml fractions. Fractions 13-26 yield 280 mg of product. An analytical sample obtained after crystallization from a mixture of methanol and petroleum ether melts at 214-215.5 ° C with decomposition.

Analysis: ^H 13 ^N 2 ^SO 2 requires C 6 ^to 40.90% H 3.72% N7,95% S9,10% К 11.10%; found C 40.43% H 3.60% h 7.89% S 8.69% К 10.82%.

Example 99

3S-trans / -4-Methyl-2-oxo-3 - (((phenylmethoxy) carbonyl) amino) -1-azetidine sulfonic acid potassium salt

Following the procedure of Example 98 using 1-tert-butoxycarbonylthreonine instead of d, 1-tert-butoxycarbonylallothereonine, the title compound melting at 133-135 ° C was obtained.

For ^C 12 ^H 13 ^N 2 ^O 6 ^SK calculated C 40.90% H 3.12% N7.95% S9.10% K 11.10%; Found C 40.72% H 3.60% N 7.99% S 8.80% К 10.82%.

Example 100

(3S-trans) -4-Methyl-2-oxo * 3 - ((phenylalethyl) amino) -1-azetidine sulfonic acid potassium salt

A) (3S) -3-Amino-4-methyl-2-oxo-1-azetidine sulfonic acid tetrabutylammonium salt

352.4 mg of (4S-Trana) -4-methyl-2-oxo-3 - (((phenylmethoxy) carbonyl) amino) -1-azetidine sulfonic acid potassium salt (see Example 99) are dissolved in 20 ml of distilled water and 373.5 mg (1 mmol) of tetrabutylammonium hydrogen sulfate were added to the solution. After stirring at room temperature for 10 minutes, the solution was extracted three times with 10 ml of methylene chloride each time after saturation with sodium chloride. The methylene chloride solution was dried over sodium sulfate and evaporated in vacuo to give 536 mg of tetrabutylammonium salt which was hydrogenated in 25 ml of dimethylformamide in the presence of 270 mg of 10% palladium on carbon. The reaction mixture is filtered through diatomaceous earth, which is washed twice with 2.5 ml of dimethylformamide each time. A solution of the title compound is obtained.

B) (3S-trans) -4-Methyl-2-oxo-3 - ((phenylacetyl) aneaino-1-azetidine sulfonic acid) potassium salt

To a solution of the crude (3S) -3-amino-4-methyl-2-oxo-1-azetidine sulfonic acid tetrabutylammonium salt of Part A (filtrate associated with the washings) was added 206 mg dicyclohexylcarbodiimide, 153 mg N- hydroxybenzotriazole and 138 mg phenylacetic tysteine. The reaction mixture is stirred for 1 hour at 0 ° C and then for 2 hours at room temperature. The precipitate formed is filtered off, the filtrate is evaporated in vacuo, the residue is dissolved in 10 ml of acetone and the solution is filtered. 25 ml of acetone saturated with potassium iodide and 200 ml of ether are added to the filtrate. The precipitated solid material, weighing 752.7 mg, consists of a mixture of potassium and tetraternary salt of the title acid. This solid mineral is dissolved in 50 [mu] l

0.5 M potassium dihydrogen peroxide solution and the solution was applied to a resin column

HP-20. Elution with water and then with water and acetone yields several fractions which are spoox and evaporated. The above tetrabutylammonium salt is dissolved in water and the solution is passed through a column of ion / Dowex 5OT-X2 ^(K- cycle) ^, with the remaining 1213 mg of potassium salt given in the water. ^names .

Trituration with acetone / hexane gave 104.6 mg of the title compound melting at 211-113 ° C.

Analysis: for ^ Ο ^ Κ. 2.1 H ₂ 0 requires C 41.72% H 4.09% N8,11 "9.28% K 113i>«;

found C 41.70 «H 4.01« N 8.07 «S 9.01« K 1100 «.

Example 101

(Ii8) -4-lletlyl-2-ooo-3- (pholylccelylaacin) -1lZzetddsulphonic acid

Prepare a solution of 320 mg of potassium sooi / - -iit / 4- / etlll --- non-3 - ((feolyl / etlnχ _I l / karboroУ.) Y / amino) -1-azetidnsulOonníé acid / see example 8Э / in 20 ml of water containing 483 mg of trisodium cyanobutyrate and the pH was adjusted to 5.5. Six times the extraction of 25 ml of ethyl ether to give 517.3 mg of oily aaltrial, which is dissolved in 15 ml of dihydroxybenzene, and the solution is stirred under 400 ml of carbon black for 90 minutes under a hydrogen atmosphere. . The calibrator was decanted, and the filtrate was stirred with 150 mg of phenoxyacetic acid, 169 mg of N-nitro-carbonyl chloride and 247 mg of di-carbonyl chloride for 7.5 hours. The residue was evaporated in vacuo, the residue was dissolved in 20 ml of acetone and the solution was filtered. 25 ml of a 0.044M solution of potassium iodide in acetone was added to the hate and diluted with volume / ether to give 330 mg of solid which was loaded onto a 50 ml column of HP-20 in 20 µl of 0.05M potassium dihydrogen phosphorate. Elution of a 200 ml column of water with a 1: 9 mixture of acetone and water (Fractions 6 and 10, v / v / v) yields Rydon.RTM. (V / v). 7 if 9 to afford 81 mg of solid which after recrystallization from sa / sd s aCietn0ttilu water gives 46 mg of the title compound, dec) ICI is ^p s t ^ ture nid ²⁰ 5 ° ^C. The second ^p oo ^d l ^p roducts of ^l l / onnonti ^{6 / g} ^ and evaporation of fractions 6 y 10 y ojřrOrystaloíání / residue.

Analysis: ^ 2 ^ 3 ^ 0 ° 5 requires C 42.84 ^SM «H, 3.89% N, 8.33" 9.53 "K.

Found: C, 42.75; H, 3.82; N, 8.32; N, 9.26; K, 11.63.

Examples 102 and 102

Potassium salt (3S-3alfa / Z /, 4beea)) -3- ((/2-lmico-4-tllaznlll//metlno;yl/inonalcryl)aminc)-4-/ertlУ.---noo-1-azrtidOn8ufOonnít acid

A) Tetraethyl salt of ( ^4- methyl- ^2- oxo-a) - ((rfel / relhooylcartin) lm.n) -1-azrtidone sulfonic acid

352.4 mg of potassium salt of ^4- methyl- ^2- oxo-3 - ((E / C / Letolocybococb) 8/10) -1-) 2-imidonic acid mononite (see Example 99) is dissolved in 20 liters of water were added to the solution. 373 (g of tetratyl chloride) was added and the aqueous solution was extracted three times with brine. The combined extracts were dried over sodium sulphate. After evaporation of the solvents 534.6 mg of the title compound was obtained. .

B) Potassium salt (a / (aalfa ^{1 /} Z /, 4te: ta)) aЗ - ((/) aacdno-4ltainzylyl / rtιlnholyitOo / lcrtllaaic) v · 4- / rtlll --- oon-1-azeiddifCuf0onnít OiséliLoi

A solution of 534.6 mg of the tetrabutylammonium salt of (3S-trans) -4-methyl-2-oxo-3 - (((phenylmethoxy) carbonyl) amino) -1-azetidine sulfonic acid in 20 ml of dimethylformamide in the presence of 220 mg of 10% palladium on The coal is hydrogenated at atmospheric pressure for 2.75 hours. The hydrogen consumption was 26.3 ml. The mixture was filtered and the filter residue was washed twice with 2.5 ml dimethylformamide each time. The filtrate was combined with the washings (total volume approx. 25 ml) and stirred with 161 mg of (Z) -alpha- (methoxyimino) -2-amino-4-thiazoleacetic acid, 136 mg of N-hydroxybenzotriazole and 164.8 mg under nitrogen. dicyclohexylcarbodiimide. The mixture is stirred under nitrogen for about 16 hours, then dimethylformamide is evaporated in vacuo, the gummy residue is dissolved in acetone and the urea is filtered off. A solution of 272 mg ( _0-8 mmol) of perfluorobutanesulfonic acid potassium salt in 0.8 ml of acetone was added to the filtrate, the resulting suspension was diluted with an equal volume of ether and filtered. 325.5 mg of crude product is obtained, which is purified by chromatography on 75 ml of HP-20AG resin using first 400 ml of water and then 400 ml of a 9: 1 mixture of water and acetone as eluents. Fractions of 50 [mu] l are collected. Fractions 3-10 contained 335 mg of product. 97.3 mg of analytical material was obtained from fractions 3 to 5 after trituration with acetone / hexane. A similar trituration of fractions # 6-10 gave an additional 90.4 mg of solid product.

Analysis: q ^u | 2 ^N 5 ° ^K 6 ^S 2 requires C 29.92% H 3.01% N 17.45% S 15.97% К 9.74%;

Found C 30.32% H 3.49% N 15.82% S 13.95% К 10.45%.

NMR Spectrum (Deuterium Oxide): 1.57 (3H, d, J = 7 Hz), 3.97 (3H, e), 4.30 (1H, doublet of quartets, J = 7.3 Hz), 4.70 (1H , d, J = 7 Hz), 6.95 ppm (1H, a).

Example 103

Dipotassium salt (3S (3alpha / Z /, 4beta)) -3 - (((2-amino-4-thiazoles) / ((1-carboxy-1-methylthoxy / imino) acetyl) amino) -4- methyl 2-oxo-1-azetidine sulfonic acid

A) N-Benzyloxy-tert-butoxycarbonylthreonine amide

To a solution of 8.76 g of tert-butoxycarbonylthreonine and free amine released by sodium bicarbonate in ethyl acetate from 6.4 g of C-benzylhydroxylamine hydrochloride, in 100 ml of tetrahydrofuran was added 6.12 g of N-hydroxybenzotriazole and 8.24 g of dicyclohexylcarbodiimide in 20 ml of tetrahydrofuran. . The mixture was stirred under nitrogen for 26 hours, then filtered and evaporated in vacuo. The residue is chromatographed on 300 g of silica gel using chloroform and a 3: 1 mixture of chloroform and ethyl acetate as eluents to give 7.2 g of the desired product. Crystallization from ether / hexane gave 4.18 g of the title compound.

B) (3S-trans) -N-Benzyl-xy-3-tert-butyloxycarbony lamino-4-methyl azetidinone

A solution of 12.67 g of N-benzyloxy-tert-butoxycarbonylthreonine amide, 11.5 g of triphenylphosphine and 6.23 ml of diethyl azodicarboxylate in 380 ml of tetrahydrofuran is stirred for 16 hours under nitrogen, then evaporated and the residue is chromatographed on a 900 g silica gel column. . Combined with chloroform / ethyl acetate (3 ^: 1) to give 13.69 g of material which was crystallized from ether / hexane to give 9.18 g of the title compound.

C) (3S-trans) -3-tert-butoxycarbonylamino-1-hydroxy-4-methylazetidinone

A solution of 9.18 g of (3S-trans) -N-benzyloxy-3-tert-butoxycarbonylamino-4-methylazetidinone in 300 ml of 95% ethanol was stirred under a hydrogen atmosphere in the presence of 1.85 g of 10% palladium on carbon. After 141 minutes, the resulting suspension was filtered and the filtrate was evaporated in vacuo. The residue was recrystallized from ether / hexane to give 5.12 g of the title compound.

D) (3S-trans) -3-tert-Butoxycarbonylamino-4-Tnhylazotidinone

To a solution of 4.98 g of (3S-trans) -3-tert-butoxycarbonylamino-1-hydroxy-4-methylanetidinone in 200 l of methanol is added first 132 ml of 4.5 M ammonium acetate solution and then 66 ml of 1.5 M titanium tetrachloride, After stirring for 4.5 hours, the resulting aqueous solution was diluted with an equal volume of 8% sodium chloride solution and extracted with ethyl acetate. The ethyl acetate extract yielded 3.48 g of crude product which, after recrystallization from ether / hexane, yielded 3.3 g of the title compound.

E) (3S-trans) -3-Benzyloxycarbonylamino-4-methyl-azetidinone

A solution of 3.3 g of (3S-trans) -3-tert-butoxycarbonylamino-4-methyl-azetidinone in a mixture of 10 ml of dichloromethane and 10 ml of anisole is cooled to 0 DEG C. and 112 ml of trifluoroacetic acid are added. The resulting solution was stirred for 50 minutes, then evaporated in vacuo and the residue evaporated with benzene three more times. The residue is dissolved in 70 ml of acetone and the pH of the solution is adjusted to 7 with 5% sodium bicarbonate solution. At pH 6.5 to 7.5 a total of 5.33 g of benzyl chloroformate is added over 1 hour, the mixture is stirred for 33 minutes at pH 7, then diluted with 100 ml of saturated sodium chloride solution and extracted three times with 400 ml of ethyl acetate each time. The evaporation residue is chromatographed on a 1 liter silica gel column. Elution with chloroform / ethyl acetate (4: 1) gave 2.19 g of product which, after crystallization from ether / hexane, gave 1.125 g of the title compound.

(F) (3S-trans) -4-Methyl-2-oxo-3 - (((phenylmethoxy) carbopropyl) amino) -1-azetidine sulfonic acid tetrabutylammonium salt

A solution of 600 mg of (3S-trans) -3-benzyloxycarbonylamino-4-methyl-azetidinone in 2 ml of dimethylformamide was cooled to 0 ° C and 4 ml of 0.8 M sulfuric oxide in dimethylformamide was added thereto. The reaction mixture is poured into 80 ml of cold 0.5 M potassium dihydrogen phosphate solution, adjusted to pH 5.5, extracted three times with 50 ml of methylene chloride each time (the extracts are discarded), 868 mg of tetrabutylammonium bisulfate are added thereto, and the resulting the solution is extracted four times with 75 ml of methylene chloride each time. The organic layers were combined, washed with 8% aqueous sodium chloride solution, dried and evaporated in vacuo. 1.54 g of the title compound is obtained.

O) 3S- (3alpha / Z /, 4beta) Potassium Salt - 3 - (((2-amino-4-thiazolyl) ((1-diphenylmethoxycarbonyl-1-methylethoxy) imino) amino) amino) -4- methyl-2-oxo-1-azeidine sulfonic acid

A solution of 1.54 g of tetx * abutylammonium salt of (3S-trans) -4-methyl-2-oxo-3 - (((phenylmethoxy) carbonyl) amino) -1-azetidine sulfonic acid in 45 ml of dimethylformamide in the presence of 800 mg 10% Pd / C was stirred under a hydrogen atmosphere for 2 hours. The catalyst is filtered off and the filtrate is stirred for about 16 hours with 1.24 g of (Z) -2-amino-alpha - ([1-diphenylmethoxycarbonyl-1-methylethoxy) imino) -4-thiazoleacetic acid, 0.4 g of N-hydroxybenzotriazole. and 580 mg of dicyclohexylcarbodiimide. The suspension is evaporated in vacuo, the residue is triturated with 20 ml of acetone, the mixture is filtered and the residue on the filter is washed. 868 mg of potassium perfluorobutanesulfonate in 3 ml of acetone are added to the filtrate, together with 2 ml of the washing liquid, and the mixture is diluted with ether. The precipitated solid material is isolated by decantation of the mother liquors, trituration with ether and filtration. 0.91 g of the title compound is obtained. A second crop of 0.45 g of the title compound was obtained from the mother liquors by diluting with an additional 100 mL of ether.

H) Dipotassium salt (3S (3alpha / Z /, 4beta)) - 3 - (((2-amino-4-thiazolyl) ((1-carboxy-1-methylenethoxy) imino) amino) -4-methyl -2-oxo-1-azeidine sulfonic acid

For a suspension of 140 mg of potassium salt of (3S- (3alpha / Z /, 4beta)) - 3 - (((2-amino-4-thiazolyl)) ((1-diphenylmethoxycarbonyl-1-methylthoxy) imino) imino (a) methyl) amino) -4-methyl-2-oxo-1-azide insulfonic acid (first crop) in 0.5 ml of anisole is stirred under nitrogen at -12 ° C with 2.5 ml of trifluoroacetic acid , cooled to -10 ° C. After 10 minutes, ether (10 ml) and hexane (5 ml) were added, and the resulting suspension was stirred at -12 ° C for 5 minutes, then allowed to warm to room temperature. The solid material was collected by centrifugation and washed twice with ether.

A solution of this first material in 5 ml of cold water is immediately basified with 0.4N drapelar hydroxide at pH 5.5. A column of 80 ml of HP-20AG adeorbent is collected by elution with water in fractions 7 to 11 (fractions of 10/1). 72 mg of the title compound, which is isolated by denial of these fractions, is evaporated by evaporation of the residue with icetointrilei t. Ether ei Protokt ^O ije for nozUadu ztaruta ^p s ²⁵⁰ ° C

Analysis: pao C (JHL / 5 ^Μ οθ8 ^{3 4 * *} 2 ^Κ 2 calculated C 30.5% H 2.95% N 13.69% S 12.53% X 15.28 found C 29.63% H 3 % 20% N 12.96% S 11.94% K 12.78%.

NMR Spectrum (CDCl3): 1.46 (i, 6H), 1.58 (1H, d, J = 7 Hz), 4.28 (1H, doublet of quartets, J = 7 Hz, 2.5) Hz), 4.67 (1H, d, J = 2 Hz), 6.95 ppm (i, 1H).

1,2 ^ ааНи 1,22 g 4ιιιι1ι4 α4i (3S (3aa '/ L-aett)) -3 - ((Z2-thiinjo44te (iazlyl /// dilenyl1e οίοχ ^ α ^ οηΐι 1-methyl otoxi / ibtio) ace tyl) .) Tiina-4-IE-оиу1-2 ооо-1 -izi OidjnsufOznové acid (poddly 1 t 2) SR will process described způdobrm Thor (4.2 mL inisolu, 16 mL Ort ^ fu ^ oaoctové kysali ^{11 1} 3 ^p linut s te ^ OOS -15 ° C). Cluroimtz afil.í ^ 3 ⁰⁰ ml of HP-20A adeorbentu ^G (fractions 60 .mu.l) SR yolk 694 mg of the title compound (in fractions Nos. 6 to 9 days after ehort described zpricooán1 ).

Examples 104-133

From the procedure described in Example 11 with the replacement of / ^ 2 / ^ <^ 1 ^ '^ 1 ^: 11о-1 ^ 11 ^ 1 - ((((У ^ с ^) ^ о ^ оу / ГепуИиоиоэкИоз ШпуЦ ^ и- The acids listed in column I of the table below gave the compounds listed in column II of this table.

Example number

I starting material

II product potassium salt of (3R / 4R) -3 - ((2-1R 11R - ^ 1R - ^ 11R 1 - azzolyl)) (2- / 1,1-diurotyric acid) -1 - / 1íOUyl0Uío / -2ozxoitUoxy) Imiimi) c © butyl) and / i1o) -2-oxz 1-1ZltidntulOznová-acids, see example 79) drněná Cane (3S ^ J ^ * /) 2 220 ⁰ <alpha ^ _ ^ (((( G ^ - ^<0 ^ 02 ^ -3 - ((/ phenylimide OUoxy / karboiny.) amino) -1 -iiid ^ s ^ oxadiazol ^ t ^ l ^ i ^ J ^ y) carbanion) ш / пп-ОагпУаШо! ) imino) 2121Zltidjn8uf0jnové acid (see example 128) drieeliá (3S / 2 /) 23 - (/ '2 (imino-4tUiizolyl / ((kabOoiy / iM] UyLOthOz / mejUooy) Tiina ¹⁾ aceeyl) Tiina) -2 <- oozo1 Aze 0П11пeulfonové kyselily (1: 2) melting decomposition of t ^p s 165 ° ⁰ potassium salt X / NW XU (/ t mtinz-2-OOO-1 -Ι / ϋιζοΟϋηιιΙ ^ ^ ιη οιίτΙ) amino) butyl f iiIаи ) amine 10-oxo-1-iodoic acid, m.p.

Potassium salt (3tlf1 / Z), ialia (-3- (¢1,11-11-iano-etiaZol lolyl / loιtol) | yilt1oo1icetyOa1l0o) --- / et] UУ. The acids were acidified

A solution of 51.8 mg of potassium (zinc) (1- (1-methyl-2-oxo-2-carboxylic acid) amino) -121X1- (8-amino-8-amino) -121X1- (8-amino) -acid (51 mg) (Dioxide in 5 µl of water from the extract is 4 times with 10 ml / ml each), yielding 81 mg of olefin material which is odd for 2 hours in a hydrogen atmosphere at 40 µg 10 palladium per liter in the catalyst. The filtrate was charged with the foaming liquids and the product was stirred for 31 minutes (ZO-4-amino-η 11 - (εικα) (ω 6). (ino) -4-OH-azole of its acid, 27 mg of N-Uydro 30-4x10: 0010-131.5 g of cyclohexylcarbonyl diimide The reaction solution was evaporated in vacuo and the residue triturated with 3 ml of acetone. The mixture was centrifuged and the liquid was mixed with 51 mg of potassium perfluorobutane sulphonate, diluted with 5 ml of ether and filtered to give a solid which was chromatographed on HP additive. -20 AG (40 mL) using water as the eluent yielded Rydon-positive material in fractions 3-5 (fractions of 20 µl). After evaporation of the ether and trituration, 23 mg of product are obtained as a hygroscopic solid.

Analysis: for R ^ ₀ RGN OgSgK Calculated C 29.91% H 3.01% N 17.44% found C 29.30% H 3.31% N 16.66%.

NMR (CDCl3): 1.40 (d, 3H, J = 7 Hz), 3.97 (a, 3H), 4.46 (apparent pentet, 1H, J = 7 Hz), 5.37 (d, 1H, J = 7 Hz), 6.97 ppa (a, 1H).

Example 137 (33-cis) -3-Amino-4-methyl-2-oxo-1-azetidine sulfonic acid

▲) tert-butoxycarbonyl-1-allothreonine

To a suspension of 6.72 g of 1-allothreonine in 70 [mu] l of 50% aqueous dioxane was added 9.45 [mu] l of triethylaine and 18.1 g of tert-butyl pyrocarbonate. The resulting mixture was stirred at room temperature for 4 hours, then diluted with 70 L of water and 140 L of ethyl acetate. After vigorous shaking, the gates were separated and the organic gates were washed with 30 L of a mixture of water and brine (2: 1). The combined aqueous fractions were extracted with 70 [mu] l of ethyl acetate, the aqueous phase was cooled in ice, and a pH of 10% potassium bisulfite was added to pH 2.3. The acidified solution was extracted four times with 150 l of ethyl acetate each time, the combined layers were dried over anhydrous sodium sulfate, and the solvent was evaporated. 9.13 g of the title compound are obtained.

B) N-Mothoxy-tert-butoxycarbonyl-1-allothreoninamide * 9.13 g of tert-butoxycarbonyl-1-allothreonine are dissolved in 85 ml of water, to which 41 ml of 1 N potassium hydroxide solution are added first, followed by 5.22 g of methoxyamine. hydrochloride and 8.67 g of 1-ethyl-3,3- (dimothylaminopropyl) carbodiimide hydrochloride. The mixture was stirred at room temperature for 4 hours, then saturated with sodium potassium tartrate and extracted four times with 150 ml of ethyl acetate each time. The organic phase is dried over anhydrous sodium sulfate and the solvent is evaporated. 7.38 g of the title compound are obtained as a solid.

C) O-Aothanaulfones 1-N-methoxy-tert-butoxycarbonyl-1-allothreoninamide

7.32 g of N-methoxy-tert-butoxycarbonyl-1-allothreoninamide were dissolved in 40 [mu] l pyridine, the solution was cooled to -20 [deg.] C. under nitrogen and 3 ml of methanesulfonyl chloride was added dropwise via syringe over 5 minutes. The resulting mixture was slowly warmed to 0 ° C, stirred at this temperature for 3 hours, then 500 mL of ethyl acetate was added and the solution was washed first with 250 mL of ice-cold 3N HCl and then with 100 mL of 5% sodium bicarbonate. The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent was evaporated. 8.64 g of the title compound is obtained as a white solid.

D) (3S-Cia) -3-tert-butoxycarbonylamino-1-methoxy-4-methylazetidinone

8.64 g of O-methanesulfonyl-N-methoxy-tert-butoxycarbonyl-1-allothreoninamide are dissolved in 530 ml of acetone and to the solution and 11 g of solid potassium carbonate are added. The mixture was slowly heated to 65 ° C under nitrogen and stirred at this temperature for 1 hour. The reaction mixture was filtered through diatomaceous earth and the filter cake was washed with ethyl acetate. The filtrate is concentrated and the residue is taken up in 250 ml of ethyl acetate. The ethyl acetate solution was washed with 100 ml of 1N hydrochloric acid solution and 100 ml of 5% sodium hydrogen carbonate solution, the ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent was removed by filtration.

E) (3 &apos; -cis) -3-tert-Butoxycarbosyrmino-4-Behya-4-etidinone

1.35 e of sodium is dissolved in about 300 ml of liquid ammonia at -50 DEG C. and 5.87 e of (3S-chloro) 33-tert-butyloxy-carbonyl-1-methoxyl-methhyazetidinone in 35 ml is added dropwise via syringe. tetrahydrofuran. A further 10 ml of tetrahydrofuran was used to rinse the solution. At the end of the addition of the above solution, an additional about 100 moles are added. The mixture was stirred for 5 minutes and 3.35 e of solid ammonium chloride was added in one portion. Ammonia was blown out with a stream of nitrogen and 250 ml of Ι / Ι ^ ^ Ζ přidá was added to the residue. The solid was filtered off and the ethyl acetate was crushed, the filtrate was combined with the wash liquid and the solvent was evaporated. This gives 4.82 e of the title compound.

F) (3 &lt; 3 &gt; C) -1-3-tert-butoxyltrbonylamino-4-methyl-3-oxo-allyl-sulfonic acid tetrabutylammonium salt.

4.98 e of (3S, 4R) α3-erc.Uutoxycyclinino-4-methyl-azetinone are dissolved in 30 ml of dimethylformamide, ee of 11.9 e of pyridine-sulfur trioxide complex is added and the mixture is stirred at room temperature under nitrogen. ^ i. After 14 days of stirring, an additional 1.8 e of pyrrole-sulfur trioxide complex was added and stirring was continued for 80 hours. The reaction mixture is poured into 700 ml of 0.5M sodium dihydrogen phosphate solution and 100 ml of methanol are added three times each. To the aqueous solution was added 8.45 g of tetra-biphenyl-dihydrogen-phosphate and the mixture was extracted four times with 300 ml of methylene chloride each time. The combined Detthlene chloride layers were dried over anhydrous sodium sulfate and the solvent was removed to give 10.76 e of the title compound as a resin.

G) (3S-cis) -Lino-4-methyl-2-oxo-l-1-thiazolin-8-enoic acid

10.76 e of (3S-C18) -butyl-tert-butoxy-4-methyl-4-methyl-2-oxo-1-1H-sulfulfonic acid tetrabutylmonium salt was dissolved in 50 ml of 95% to 97% formic acid and the solution was stirred under nitrogen for 4 hours. To the inoculation is added a small mooss product of the previous! The mixture was stirred for an additional hour, then left in the refrigerator for about 16 hours, allowed to warm to room temperature for 3 hours and stirred for an additional hour. The precipitated solid was filtered and washed with methyl chloride to give 982% of the title compound. The filtrate was diluted with 1 L of meetylene chloride and cooled at -20 ° C for 4 hours. Overlapping the precipitate formed from the mixture of water, methanol and acetone gave an additional 167 me of the title compound.

NMR (CDCl 3): 1.63 (d, 3H, J = 6.5 Hz).

ΐδ (found ¹⁷⁷⁵ ca '.

Example 138

(3S) Jaafn (Z) (6-methylphenyl) -3- (((2-chloro-4-triazolyl) methyl) acetyl) thio-4-methyl-2-oxo-4-thiazine sulfonic acid

To a solution of 201 [mu] l-thiazoleacetic acid and 153 [mu] l N-hydroxybenzotriazo-3-monoleate in 3 ml of dimethylformamide was added 206 [mu] l-cyclopentylcarbododimide. The mixture was stirred under nitrogen at room temperature for 20 minutes, then a solution of 180 me (3Szci8) -halo-4-methyl-2-oxo-1-zolidine acid and 0.14 ml of trimethylsilyl in 2 ml of dimethylformamide (daU) was added. 1 ml of trimethylamide was used to flush this solution) and the resulting mixture was stirred for about 16 hours. The reaction slurry was vacuum filtered, the residue was triturated with 12 ml of acetone, centrifuged and 338 mg of potassium perfluorobutanesulfonate was added to the liquid. Dilution with 10 ml of ether and filtration afforded a solid which, after flashing onto 200 ml of HP-20 adsorbent, eluting with water as the eluent, afforded 274 mg of the title compound from pooled fractions 18-30 as title compound. The product was isolated (20 ml fraction) calculated C 29.91% found C 30.03%

H 3> 01

H, 3.21

N 17.44%;

N 17 * 06%.

NMR (deu teriumooid d):

1.40 (-, 3H, J = 6.5 Ha), 3.98 (s, 3И), 4.48 (doublet of triplets, IH, J = 6.4, 5.5 Hz), 5.36 ( 1 H, J = 5.5 Hz), 6.97 (s, 1H).

Example

Number

AND

Acid acid

II

Product

104

2-Amino-alpha - ((2- (1,1-dimethylethoxyl) -1-methyl-2-oxoethyl) -3ylamino] -44 thiazoleacetyl thiazolium potassium hydrate with sodium (3S / Z) - 3 - (( ((2-amino) -4-thiazolyl) (2- (1,1-dimethylethyl) -1-methyl-4-oxoethoxy) amino-2-oxo-4-azetide-monosulfonic acid (1: 1) m.p. with decomposition at 280 ° C

105 / RAsI1 α - ((/ 4ee Uyl-2,3- (Ηοχο-1-β-piperaziryl / cartonyl) amino) (4-hydroxysulfonic acid potassium salt (3S / (R / (- 3 - (( ((/ 4-ethУL-2,3-4-diiXi pipeгtzinyl / ktrbonД.) · amino) / Л-Ьу JFE-пK ^ l ^ and / ^ ce butyl) amino Aze tidiusulfOnové tyseUny detuning melting at 1 ⁹⁷ Noc: 2 ° C

106 / А ^ ^ '^ а-ССА- Ьу! - ³ L ^i-1 ioio pipert- -гttslná (3S / s /) - 3 - ((((/ 4-tthy1-2,3- Dioxidinyl (trifluoromethyl) -2-fluoroacetic acid-4-piperidinyl / cyclinyl) amino-4-pyridyl-α-ethyl-amino) -2-oxo-1-aze-1-intuphonic acid - of acid melting at 169-171 ° C

107 (R) —al fa - ((4 —-- 11,11-2 3 —- --ο «> - 1-piperidyl / kaolin) uyl) ιmdn - 1,4-ey / l · xadienietiiá tyMliaa ^d ratslu ^and the salt ⁽³ S / R / ⁽³ - ^((1, 4-ey ^/ lihsxt ^d ien- 1-yl ((/ ^4-ethyl-3 · »3 - ^ 1 χο- -pdpertsduyl / KTR vouchers. (amino) acetyl) amino) -2-oxo-1-azetidenesulfonic acid melting at ¹⁸ 5

108 / RAalpha-C ((2,3-diixo-4- (phenylmethylene / amino) -1-piperidinyl) / trbornyl) amino-4-hydroxybenzeneacetic acid potassium (33 H) -3- (((((2,3-iixo-44 (('phylme tl / amini) -1-pdpertzine ^r )) / ЬЬЬг ^!) Amino) / 4-1 ^^ xyf огп1 / ace tyl) amino) -2-oxo-1 -tzeti ^d nnsufOoniié acid of melting Riz / 1 ton-u at 194-197 ° C

109 / ZA-thiamino-4 - ((1-methylthiomethylsulfonyl) -4-thiazolietic acid potassium salt (3S / Z) - 3 - (((2-thiamino-4-thiazolyl) 11A (1-methyl-thiazol) (ino-inyl) amino) -1-azetinyltinic acid melting with decomposition pH 195 ° C

110 (Z) -2-thiophen-α- (in other N, N-thiazolethioic acid, potassium salt (3S / Z)) - 3 - (((2'Mlini-4-thiazol) // thiazolyl) amino) -2 —Oxo-1-tertidinidinofonic acid melting at risotto at 165 ° C

Example number

I acidic

II

Product

111 (R) -ilpha - (((3- (((4-Chlorophenol) ethyl) yno)) - noo-1-iididonidin (1) carbonyl) a (innen) benoenoic acid

112 (R) -alpha - (((--nxo- · 3 - ((4-oyτdd01yfl / rtlllrc / a / icn) -1-idazcoidinyl) kirbonyl) irnion) benzoacetic acid

113 (Z / --- 1 / inona1fa - ((1-methyl-n-oxon2- / phenyl) / halo / ethoxy) -4-1H-azoleacetic acid

114 / Z / -21mtcn-1fli- (Cloknoprntylnol / i / ico) -4-thiazoleacetyl tyseltoa

115 / R / - ^{and LF} - ((1-nxonг .- ((froiyi / RT ⁱ no ^l / ^k 1rbnoyl) and / ino) TTY e) y / i.no) benzo ^ -acetic kyselica

116

117 / R / -1lfa - ((- 2-ono-afrenll-1-i / tazonidioyl / kirbonyl) 1 / 10o)

118 / R / -alpha - (((- (nxonЗ- / frnyl / eetll / -1-i / idazooid ioyl) carboxol)) and / ino) potassium boronic acid (3SR /) - 3 ((((((( (3 - (([4- (N-chloro-thiol) amino) -2-oxo-1-d] dazododep (1) carbonyl) / inylphenyl] -ethyl. ) imioo) --- 1 ooo- -1zetddnnsufOnnoít kyselica ¹ .mu.Ci ^the detuning zi ^P s ²³⁶ ° C ^with drmU of (? s / R /) - · ^-> nЗa x ^o ((((--.- non- and - / 4p ^p yrdd0ly / meHy! EO / ιмicn) -1-i / idazcoidin) karborn) amino) butyl feoylac e) and / ico M-Aze tidnnsufOnnní t) alkyl Selin ¹ tyjící zi HAZ ⁰¹⁾ ^ ^p at ²³⁰ ° C, the potassium salt of [alpha] - (Z) - [alpha] - [((- [1 ml] -4- [1,2-a] zyl) ((1 - (ethyl-2-oxOn ² -)) Rhloro (ethoxyl) aileyl) imiool-ooo-1-azrtidone sulfonic acid melting at 110 ° C 115 ° C potassium salt (a // Z /) - a - ((/ 2-м>) ion-4-thiaonlyl / i / coknorentynoxl / MTON) aceeyl) amino) --- non-1 -1ortid0ntulf ooové kyselica m.P. p ^ and 200 ° C d ^^ ^feature a range of from SU. (R and // * /) ^ -0 ^ 3- ((f ^eo yl (((- / enrlllartloxy / carbonate) s / ioo) thirty) and / Ino) eeyl c) and / amino) -1 Aze ttdtosulfocové zi tyjící acid decomposition at 260 ° C potassium salt /// - and - (- 2fUur (nll1ieeyУ / imioo) --- Noo 1-1zrtdd0n8ufnonnít ^KYSE-l ^; ^ o ^y zi .mu.Ci ^the detuning ^p s ^110C potassium SU / a // - ooo-3 - <(((- 2noon-3-phenyl-1-i-indazolidyl / carbonyl) ω / phenoxy) a (io10) -1-aortidintULine -> new acids decomposing at 217 to 222 ° C potassium salt ^(and S / R * ^/ ) - ^- -nxone ³ and ^{(- (} ( ^--- .., -ooo- ³ - / fccL / · rtll) / -1 -i / id1zzn pyrrolidinylmethyl) karborn) imioo) phenyl) -1 -azedtotulfonovt kyselica melting at 195 to 200 ° C, potassium SU / aS / -a · ⁽⁽⁽⁽⁽³ - ((- <- furaoil / ertУlen / alino) -2 - non11ididololidinolcarbonyl) alino) / 4-Hloro (phenyl) -1-imino-2-oxo-1-oxo-1-oxo-1-oxo-1-olonoyl cyanide ⁰¹ melting from decomposition pM 244 ° C alpha- (((a) (1-glycol) (amino) -1-oxo-1-d (idazolidinyl) carbonyl / dool-4-ylpyrrolidinylbenzoic acid

119

Жк1а1

Number

I Starting acid

II

Product

120 (R 2 -alpha - (((3 - ((1 - (- (1-Phenyl) -1-propanol )iden) amino) -2-oxo-1-thiazolinyl) carbonyl) amino) benoeneacetic acid Potassium salt of (3 H) -3 - (((((3 - ((3- (2 H, 4-phenyl) -α-ro-peoylider)) amino) -2-oxo-1-thiazole-4-yl)) carboyryl) amino) phenyl-cetyl) amino) -2-oxo-1-azetidine sulfonic acid melting and decomposing at 195 ° C 121 N- (2-fimino-afa- ((((ethyl-imino / carbonyl) oxy) amino) a4-thlazoleacetic acid) Potassium salts of (3S / Z) -3 - (((2-amino-4-thialoyl )/(((/thylalamino) oxy) imino) acyl) amino) -2-oxo-1- - thiinsulfonic acid melting at about 230 ° C 122 N- (- (((2,3-dioxo-4- (phenylthio) -1 apiperazine) carbonyl) amino) benoenoic acid) druwlM ^with L (33 / // //) 3 - (((((2,3- 1 1 ° χo-4- / phenyliet ^ hl / -1-pi-trzinin.)) k'ffl · a bory! ) Aninn)) erylaa Weyl c) amino) -2-oxo -1 - zetidnisuf-sulfonic acid melting rozkladlu o and ^p s ¹⁵⁸ to 159 ° C 123 (R) -alpha - (((4- (1-methylphenyl) -2,3-dioxo-1-piperazinyl) carbonyl) amino) benzeneacetic acid [Α] η 3 (((((4- (1-methylhexyl) -2,3-dioxol-1-propynyl) carbamoyl) amino) phenyl-ethyl) amino) -2 -0x01-10 ^ 111 ^ ^ ™ 01-0 acids ot ^ep l ^of the 185 DEG-187 DEG C. 124 (R) - (Methoxy) -2-fluoro-acetic acid. potassium 'salt (35/2 // - 3- ((/2-furanl.//me tho ^ xlmimO / ac Weyl) amino-2-o xo-1-carboxylic acid melting zttidOnsufOonové oa extended ^kl - ^{p d} at ¹⁶⁰ s Noc: 2 ° C

125 / R-alpha - (((3 - (((diethylmino / ethylene amino) -2-0x01-ΙΙΙΙ -ζ-ΙΙΙΙΙΙο)) carboyryl) aminobenzeneacetic acid- (35 H) -4 ((((3 - (/ (11 - (1 - (1) - (1) - (meth) - amino) - amino) - amino) α-oxo-1-thiaziazole).) carbonyl) amino) phenyl) (amino) -2-oxo-1-azinesulfonic acid. m.p. at 195 ° C 126 [(4H) [H] thio-L-imidazol-4-yl] (1-carbonyl) amino] benzeneacetic acid- drweLná salt (S /) ^R /)) - ((((/ 3- ^t t ^hy l-diyl 2-0x0-1-011000010.) karboinl) amino) feyyl се-methyl) amino) -2-oxo- 1 - from thinsulfonic acid melting at 185-190 ° C 127 (R) aalpha-t (((((4-Ethoxyphenyl / ithoxyl) -carbonyl) amino) -cyclohexyl) amino) benoenoic acid dr-ael ⁽ 3 (V *) - (((((((4-methoxyphenyl) ethoxy) carbonyl) amino) acetyl) amino) -tinylacetyl) amino-2-oxo-1 -azetidine sulfonic acid melting and decomposing at 268 ° C

12 $ / R--alpha-CCCS-oxooS-CC (phenylmethoxy) -bromo potassium salt (3S / R) - 2-oxo 3 - ((((2-yl) ω1ηο) -1-1αϋαζζ01ϋη1,) carboryl.) Ami - -oxo-3- (((phenylmethyl) carbonyl) amino) no) baneneacetic acid -1-imidazooidinyl) carbonyl) amino)

Example I II number Starting acid Product

128

129 / Z) -2-Amino-alpha - ([2-amino-1,1-dimethyl-2-oxoethoxy] imino) -4-thiazoleacetic acid

130 R-alpha - (((4- (1-methylethyl) -2,3-dioxo-1-piperazinyl) carbonyl) amino) -4-hydroxybenzeneacetic acid

131 R-alpha - (<(3- (1-methylethyl) -2-oxo-1-imidazolidinyl) carbonyl) amino) benzenoic acid

132 / Z) -2-Amino-alpha - ((2- (diphenylmethoxy) -1-methyl-2-oxoethoxy) imino) -4-thiazoleacetic acid

133 5-Methyl-3-phenyl-4-isoxazolecarboxylic acid phenylsulfonyl) amino) -1-azetidine sulfonic acid melting at 175 ° C with potassium salt (3S / Z) - 3 - (((/ 2-α-1-1, 1'-dimethyl-2-oxoethoxy (imino) (2-amino-4-thiazolyl) acetyl) amino) -2-oxo-1-azetidine sulfonic acid melting at 210 ° C with potassium sdl (3S (H *)) ) -3 - ((((((4- (1-Methylethyl) -2,3-dioxo-1-piperazinyl) carbonyl) amino) (4-hydroxyphenyl) aryl) amino) -2-oxo-1- azetidine sulfonic acid melting at 201-203 ° C with potassium sdl (3S / R *) - 3 - (((((3- (1-aethylethyl) -2-oxo-1-imidazolidinyl) carbonyl) amino) phenylacetyl (amino) -2-oxo-1-azetidine sulfonic acid melting with decomposition at 195-200 ° C potassium salt of (3S / Z) -3 - (((2-amino-4-thiazolyl)) ((2- / diphenylmethoxy) (1-Methyl-2-oxoethoxy) imino) amino) amino) -2-oxo-1-azetidine sulfonic acid, m.p. 145-150 ° C potassium salt / S / -3 - ((/ methyl-3-phenyl-4-isoxazolyl / carbonyl) amino) -2-oxo-1-azetidine sulfonic acid selins melting at 230-232 ° C with decomposition

Examples 134-135

The procedure described in Example 70 was repeated except that (3S / Z) -3- (((2-amino-4-thiazolyl) ((2- (diphenylmethoxy) -2-oxoethoxy) imino)) was substituted for the potassium salt) Acetyl) amino) -2-oxo-1-azetidine sulfonic acid is used in each case the corresponding compound shown in column I below. · The compounds listed in column II of this table are obtained.

Examples 139-142

The procedure is analogous to Example 139, using (3S-trans) -3-amino-4-methyl instead of (3S-cis) -3-amino-4-methyl-2-qxo-1-azetidine sulfonic acid. 2-oxo-1-azetidine sulfonic acid and, instead of (Z) -2-amino-alpha- (methoxyimino) -4-thiazole acetic acid, the corresponding acid listed in column I of the following overview.

Example I substance number

II

Product

139 / R'-yiah - (((3 - ^ - uraayy methyl eu / amino))

-Z-oxo-1-iididazolimidazol-1-carbonyl) emino) benzeneacetic acid

140 / R / -jft ^ ((/ 4eet] _YFL-2> 3-1-dVoxv oioerazi ·! * Phenyl / carbonyl) ami.no) benzeneacetic Call to tyseeina

141 (Z) -2-Amino-α- (trifluoromethyl) -4-thienoic acid

142 / ^ / - N and ^{J (in} -an nvovoacetyl) a- ⁱ nv) - ² -thVoeenvctvíá drwrtná acid salt (38-43 ^ /, ^ 41)) -3 - (((((3- (2 -allyl-amino-ethylene / amino-2-yl-1-imidazolidinyl) -carbonylamino-phenylation of ethylimino-4-methyl-2-yl-1-isoetidine-sulfonic acid, melting at 213 ° C with decomposition dramble salt (---- datahl / beta)) --- (((((4-ethyl-4-ethyl-1-piperazinyl / carbonylamino) amino) phenylamino) amino) -4-methyl -2-1-VXV jzetddnnsuaOnnvíé KYSE-NY, ^{the d} c j ^{d p} s gonna hit at ¹ 77 ° C, the potassium salt of (3S- (33afíťZ /, 4bbtt))) 3 - ((/ 2 jminnv44thijzolyl / htydrvχlimino / acceyl ) amino) 1 - jzttddinsuaVonvvé

For зeldn ^{l l} a t-EPLO mp ²³⁰ ° C dnitiná ^UL--Ζ ΛΑΛΖ / ^^)) ^- - (((/) minoooovcetyl / ¢ allinn) --- thleϊulacetyl-tmdno) -4-meth ^ hУ- -oxv ^2-1 hietidnnsuaOnnvíé Tajč ^d dec at ¹³ 5 ° ^C

Example 143 ‘

Potassium salt (38-3atta, 4beta) J-3 - (((2-amino-4-thiazole) / ((1,1-dimethoxy-22 ((4-nitrenylphenyl) methoxy) -2-methoxyethyl) amino) amino) amino (4-methyl) -2- (0-1) -hexanoic acid

To a suspension of 0.36 g of methyl-3-t-bottom-4-ethyl-2-oxo-1-hittidinaphthoic acid (see Example 139) in ³⁰ ml of dimethylformamide was added under nitrogen at room temperature. ²⁶ ° C, add, ^and -09 / ul after about 5 minutes the mixture was a clear solution to which was added first 0.816 g /// - 2tι-inv-hlft- (111 (ddimethll- ² - (/ 4-eiOatnlny- / my: l) (- vovoethvxy) J i-amino) -4-thiazvloctvíé acid, and then 0.334 g of N-hydrv: ιqfbbenzVritzvlp and 0.453 g diclULvhetyl- ^'with aг ^b VDL .mi ^{d and} p. the reaction was ¹² hours míctá ^p s tepmi * ²⁶ ° C, then extended ^ uštědlo evaporated in vacuo and the residue tritmuje with 30 ml of acetone. After oёtiminuVovém stirring solid poddly <3 <LDE-dak filtrate was added 3,680 g oerfluvrbpttnsulfvnátp potassium in 5 ml of After adding about 40 ml of ether, a precipitate formed, which was filtered off and dried in vacuo to give 1.073 g of product and 0.066 g of product in the second half, giving a total yield of 1.4 g.

Calcd for C 38 H ₂₃ N ₃ O 3 requires C 38.33 * H 3.70% N 13.41% 8 10.22% K 6.24%;

found C 38.30% H 3.63% N 13.41% 8 9.88% K 5.98%.

Example 144

Potassium salt of (3alpha ///, 4afta) -3- ((( ² -amino-4-thiazole-1H-cyclohexyl-1-methyl-ethyl) -7-imino) amino) -4-methyl-2-oxyl-1-aztidinosulfonic acid ( 1 2)

A) Potassium salt (-alpha / Z /, 4aaha) -3 - (([ ^{2- (} amino-4-hydroxy ⁾ -lyl] (1-methyl-1-trifluoromethyl-1-methylthioxy) amino) -4ms 0 ^ -2- [0-1] -Etidinidine acid

A solution of 201 mg of the tetratmtylmamonium salt of (C 18) -4-methyl-2-oxo-3 - (((phenylmethylmethoxy) carbornyl) aaino) -1-azetidine sulfonic acid (prepared from the corresponding potassium salt of Example 98 as described in Example 136). . ml of diemthyioonamide was stirred in a hydrogen atmosphere for 90 hours at 90 mg 1 (0 * on calcium tartrate). The resulting suspension was filtered and the filtrate was stirred with 146 mg / Z / -2-amino-4a-4a - (/ 1) under nitrogen for about 16 hours. -dieel'yrlletht] q <kkarbtyl-1-41etth lβthooylilino ^R) -4-thiaztltctové acid 73mg ЗДсуНпМэхг! carbodiimide and 51 mg of R-hldrotylbryztrrazolu. the reaction mixture was evaporated in vacuo and the residue is tritium with 4 ml of acetone. the suspension The filtrate was combined with the wash liquors and 113 mg of potassium iodide was added by dilution with 24 ml of ether to give a solid material which, after washing three times with ether, gave 186 mg of the title compound.

B) Potassium salt of (3.alpha / Z _/> Aalf /) 43 - (/ al-enltno / ttthitzlly1 / (1rbtι · BL / y / lleetУyeetto: YR) ilint) acetyl) 6min) -24> Lee) h <l / 4-txt4 14azetidine8ultonic acids (1: 2)

Suspension of 186 mg of potassium salt (3aall (Z), 4alpha) (3) ^, (([amino] - (Jhaaztyl) (() / diphenyl)) methoxide (1). -me thyl tht: ιχl / iliyt) aceeyl) amino) -4-methyl-Z / 1-oxo-azrtidУn8ulOontaé kyseiy ^ at 0.6 ^m fostltavintáto anis ^ u is cooled to -12 ° C and at -10 ° supposedly C was added 3.0. ml of distilled acid. The solution was stirred for 10 minutes, then ether (12 ml) was added followed by hexane (6 ml). After five minutes of reaction at - ¹⁰ ° ^C and mixing supposedly tatatimindovém ^ ^ tep U, ^P room evný pxiíl isolated odetře ^ga n ^m and washed four times with ether. 141 mg of maaerral are obtained, which are dried under vacuum, the spray is dissolved, dissolved in 5 ml of water and the solution is immediately treated with 0.4R sodium hydroxide to pH 5.6. The resulting solution was applied to an HP-20 AG adsorbent column and the column was eluted with water to remove water. 10 ml fraction. Fraction 8. The mixture is concentrated to dryness and the mixture is evaporated to dryness under vacuum. This procedure takes three times abbot's. The residue, after trituration with ether, gave 101.7 mg of the desired product as a hygroscopic solid.

Aialysis: for Cj 3 ^ 5 ^ 5% ¾. H, 2.95%; R, 13.69; S, 12.53;

ya) rzeno C 30.11 H 3.26 N 13.35 S 12.12 К 15.02.

Example 145 (3S- (3aafa (Z, 4butyl)) - 3 - (((2-amino-4-thiazolyl) -1 / 1-carboxy) -1-methylthioxy (phenyl) amino) amino) -4- trans-12-azetieintanoic acid

87.3 mg of diphosphate (3S (3aall / Z /, 4beta)) (3 - (((amino-4-ehiaztayl) - // (kaabboχy / 1-lttyarthtJχг / iliУo) acetyla) amiyo) -4 / ^ h ^г LLR L-2/1-tχt / azrtidУyзulOoУtvé acid (vis' on ^{kl d 1} and ⁰³⁾ are lighted at ^1.38 mA ^{water extensible} on ^to the OCM-ADI to ⁰ ° C, přMá it is к ⁰ 3 ^{4 m} IR hydrochloric acid and the precipitated crystals were .odsstředí. the wet solid was dissolved in maaterál nthmolu solution is filtered, zabussí to ca. 0.5 ml and mixed with 1 m of water. There were obtained 55 9 mg of the title compound.

Example 146

(3S- (3aafa / Z, 4beta)) -3 - (((2-ilyl-4-thiazollyl) 1 / k-carboxylate) - (naУкkу ^ июхх / Ут У У У У У У У У У У У -4 -4 -4 -4 -4 2 2 2) 2 2 2/2 2 2 2 -1-aminoedinsulfonic acids

99.7 mg (3S- (3aafa / Z /, 4be ea)) 43 - ((/ 2-amyly4444etaaotyl) ((1-carboyl) 14merlhloe ^ юtχ / Уlai4 yo) acetya) ali44) -44llrl'hУ- 24-tert-1-azreidonic acid was mixed with 0.207 ml of ¹ N sodium hydroxide and the resulting mixture was gently warmed to dissolve any remaining solids. The water was removed by azetropic depilation and the residue was crystallized from a mixture of 0.5 .mu.mol of ethanol (to dissolve the residue) and 1 ml of acetonitrile. 81.8 mg of solid product is obtained. After a second recrystallization from 0.8 ml of methanol, 47.9 mg is obtained, for the third time! recrystallization from 0.24 ml of methanol and 0.24 ml of absolute ethanol gave 44.8 mg of β after a fourth recrystallization from 0.225 ml of methanol and 0.225 ml of absolute ethanol to give 33.8 mg of product. The solid was dried at 20 DEG C. under a pressure of 1 mmHg for 18 hours and then subjected to atmospheric humidity for 24 hours. 40.9 mg of the title compound is obtained

They said d 147

Disodium salt (3S- (Zzlfa / Z /, / beta)) - 3 - (((2-ε-amino-4-thienyl) -1 H -carboxymethylmethoxy) imino) -4-methyl-2-oxo -4-azetidine sulfonic acid

3.00 g of (S-Oalfi (2-beta)) -3 - (((2-lminif4) thiylphenyl- (1-carboxy-1-methylthio (imino) acetyl) amino) - / - methanol The 2-oxo-1-azetidine sulfonic acid (see Example 146) was suspended in 30 mL of water and titrated with 1 N sodium hydroxide to give the title disodium salt (consumption 12.0 mL). The pH value was added by adding a small amount! The Dowex 50W-X2 (I *) ion exchangers are reduced to 6.5, the mixture is filtered, and the filtrate is diluted to 66.3 g with a defect. From this amount, a 6.63 g sample is taken for other purposes. The residual diluted filtrate was filtered to give 2.38 g of a solid which, by partial etavilibration (24 hours) with an absolute humidity, afforded 2.54 g of the title compound. title.

Examples

148-150 an analogous procedure to Example 138 by replacing (ZD-to-imino-llfa- (шtthfxyiшino) -4-kl thiazflfCtovt ^lazy using the appropriate compound in column I of the following table. To give the compounds listed in Column II of this table.

Working

Example Number

AND

Starting material

II, its ioxo-4- (((phenylii, xy) / carbonylamino) -1-piperazines, carbans, wa, U, benzeneacetic acid, naphthalene. (3S- (3alpha, 4'a)) - (4'-1- (4-methyl-2-oxo-1-sulfonyl) -1-) ester i. i. 1 DMY. / f-MENTAL amino) -2-oxo-1 -fenílei.Uyi. .ia »·. ·· - ylcarbonyl> -2 _F J-dioxo-1-piperazinyl. r. -и . .karbanové acid of melting zi · rozklai: yM ^U C

149 [h] -ilphi (((((7,7-furanylphenyl / amino) -2-oxoimidazolidinyl)) carbonyl) amino · oenzeneacetic acid butyrate (S-Al) / R (R) - (- (((((- ((2-luranylmethyl) amino) -2-fluoro-21-imidazophidinyl) carbsnyl) amino) trimethyl) imino) -4-methyl-2-ooOf-1-azide sulfide acid

50 (R) -alpha- ((4-ethyl-2, -ddSoxs-1-piperazinyl / carbonyl) amino) benzeneacetic acid potassium salt of (R) (R) (R) (i) (- ((( 4-Ethyl-4-methyl-1H-dioxo-1-piperidinyl (carbonyl) amino) phenylmethyl) amino) -4-methyl-2-oxo-1-azetidine sulfonic acid

and

151

Potassium salt (3S * (331: Tea / Z /,, fi l l ^ ^)) - 3 - (((2-linino-4-thiazflyl) - (1-methylthio) - 1-methylthio)) (ethyl) amino) -4-methyl-2-oxo-1-azetidine-18-sulfonic acid (1: 2)

A) Potassium salt of (3S- (3alla / Z /, / alpha)) з-з (((1-isoiso-4-thiazolyl) -1 / d-phenylethoxycarbonyl-1-Ш) thlethogs (lino) & cetyl) amino) - / 1-2-oxo-14-azetidiisulfonic acid / 44105

66 '

To a solution of 440 mg of (2-amino-1-methyl-1-methyl-1-ethyl-ethoxyl) -ino-4-trifluoro-acetic acid (153 mg of N-thydoxryenizori) zole in 3 ml of phenylamine. (mifu) was added (06 mg of dicyclohexylcrreodilide), the mixture was stirred at room temperature for 30 minutes in a nitrogen / thiolomer, and a solution of 180 mg of (3S-cis-3-amino-4-menthoxy-12-oxo-11s) zetdio8ullonic acid was added. (see Example 1371 / 0.14 ml of tri-fluoride in / ml of diretylformamide (another 1 ml of dimethylformamide was used to flush out the above solution)), and the resulting mixture was stirred for 16 hours. The residue was triturated with 1 ml / acetone, the suspension was filtered (the solid material was changed twice with 3 ml / cetone each time). 338 mg of potassium perlluorobutyrone sulphonate, diluted with 30 ml of ether, yielded a gummy solid which slowly solidified, which solid was filtered / rinsed with ether. C56 g of the title compound is obtained.

B1 Potassium salt (3S- (3allr / Z /, 4rlfa1) зЗ - ((/ 2-imino-4-triazole) / (/ 1-ketyl-1-methyl-1-mercuryl / imino) aceyl / mino) -4-ienlu-2 -oxofl-azetidine sulfonic acid

A suspension of 656 mg of drium salt (3S- (2-zinc-4-ol)) - 3 - (((2-amino-4-thiazolyl) ((1-dilinyl) methoxy) / benn-1-ethoxyethanol) (4-chloro-4-iodo) -2-oxo-1-rontidine sulphonic acid in (3 ml of n-nitrooxide) was cooled to (-1 / ° C) - 11.5 ml was added thereto trilluoroacetic acid, pre-chlorine at / -10 ° C. The resulting solution was stirred for 15 minutes, after which 46 ml of ether - (p) to 3 ml of Uexrine were first added. After stirring for 5 minutes at -10 ° C, stirring was continued at room temperature for one minute. filter / wash with ether. 457 mg of a very hygroscopic resin is obtained, which is dissolved in 6 ml of cold water. The solution was then treated with 0.4 N sodium hydroxide solution (pH 5.6), carried through a column (00 ml of HP- resin), and the column was eluted with water, combining from the roots. They are separated. (39 mg of compound 1r) is obtained with a volume of 50 g. Fractions 7/11 are indicated in the title, in the loro solid.

for C ₃ H, ₅ o ₈ n ₅ s ₂ to ₂ . _{i / 2} h ₂ % S 1 /, 32%;

% S 11.93 S.

Hz), 1.46 (s, 6H), 4.48 (doublet of triplets, 1H, J = 75, 5.5 dec), 5.34 (d, 1H, J = 5.5), 6.96 ppm (s, 1).

Example 1 / d 15 / (-) - 3- (mino-4,4-diienyl-2-ooo-1- (ontidin8ulone) cysey)

A) (-) - 4,4-diethyl-2-oxo-1-arrolidinitrile-ethylenediline calculated C / 9.99% n / found C / 9.94%

H 3.10% H 3.30%

N, 13.45

N, 13.30

NMR .44

3H. J = 75

A solution of 40.5 ml of tert-ethylchlorophenylsilane in 11 ml of ethylformilide was cooled to 0 DEG C., and then ml of triturate was added thereto and the solution was shaken from the solution for 10 minutes. 1, 87 8 4,4-Trifluoro-2-rontidinone in 5 ml of dimethylformamide. The resulting solution was stirred at 5 ° C for 18 hours. The reaction mixture was then poured into 400 ml of ice-water (150 ml of ether / ethyl acetate) (3 times). 1). The combined extracts are washed four times with 100 ml of 0.5N dihydrogen mono-phosphine-base each time, once with 150 ml of sodium bicarbonate solution, twice with 150 ml of water / once with 150 ml of o. sodium chloride solution. The resulting solution was dried with sodium sulphate (z) and inflated in vacuo to give 33.03 g of the title compound as a solid.

B) (-) - 3- [Zifo-4,4-trimethyl-2-oxo-1-roetifio-ter-butyldilnoylsilane

In a 100 ml flask, a solution of 4) 25 [mu] l of 1,6 M o-butyl lithium (in hexane) in 11 [mu] l of dry tetrahydrofuran is prepared in -gon at -50 [deg.] C. a solution of 0.083 g of tritrile / ethine in 1 ml of tetrahydrofuran was added. The resultant solution was cooled -60 ° C ni y ^ ij m / oi ^ .oje alpha stfíka ^ ⁰ is the command the thereto 1.0 ml iisopro ^{d pi} la№iou. After 15 linut / ¹ IC! ^{6, p} and ^o ny cooled - ⁷⁸ ° C. y @ zi Mooi .ojeWní STRIKE ^ These Oi ^ Malu solution of 2.3 g (-) - 4,4 ^<di / 2-eeiнl nM) of interest - aУУzetddn-ttri.butyldift0lltilan in 8 ml of tetrahydrofuran. The resulting solution was stirred for 20 minutes at -78 ° C, during which time the mixture was allowed to volatilize by uniform stirring and became difficult to stir. A solution of 1.33 g ρ-toluectulfncylazidu tetIyHidгnfuracu in 5 ml of the mixture was 20 linut stirred at ^ i - ^ ^ζ οι ^{78 0} alpha-AE ikajiou 2/1 Ι ^ / ^ οΉ ¹¹ !! ¹ ^ ¹¹ ^! ^1-mixture was seeded oi ^ fence / ísttnooH ¹ TODI was stirred pi ^o oc ^ ranks Oy ⁰ y you ^y ije to ¹ 5 ⁰ ml ettyace ^melt in her ^h lioen ^Elongated O OI ⁰ ° C. ^J i · orgunicloL ^to the aqueous layer ^to vyCeJM, add / přísTižnéHo / οΤ tli ^ νί 0.5M / ívého solution diHydoogtofnsforečn1nu potassium oddděí two layers, the organic layer / de three modes 150 ml of 0.5M tuu / thy a solution of potassium hydrogen phosphate, once with 150 ml of sodium chloride solution and once with 150 ml of saturated sodium hydroxide, and dried over sulfur / sodium. The organic solution was dried in vacuo to give 2.83 g of oily material which, after trituration with hexane, gave 1.67 g of the title compound as a solid.

C) (-) - α-1oidine-4,4-di / tHfl-noo-1-azetidine

In Ιο ^) ^ flask of 50 ml in 25 ml iceeooOtrilu rnoouutí 1.52 g (-) - 3-Izida _4-4'-di / eet1l-2p0oon) -a1zetddnottri.butyldifeniltillnш O and this solution was added with stirring zi 0.25 and 48% hydrofluoric acid. The mixture was flushed at room temperature, after which an additional 0.5 ml of 48% fluoride citric acid was added after 60 minutes. From 6.5 hours, total / 3.25 ml of 48% hydrofluoric acid was added. The reaction mixture was cooled ⁰ ° ^{C oi,} oeut RAL ^t oujt the OIS rates ^y / sodium tydrogeec ičitinu sodrého ^ i ^ ex Ittai ¹²⁰ ml Ιι ^^ ^ ^ ίά. The organic layer was passed through 100 [mu] l of water and 100 [mu] l of a saturated sodium chloride solution and dried (sodium sulphate). Concentration / dried solution in vacuo gave 1.34 g of oily / Byteral. This crude oil was chromatographed with 27 g of silica gel using hexane first at 33% hexane in hexane as the eluent. 0.358 g of the title compound is obtained as a solid.

D) Te trabutylmoniová siil (R) -3-azido-4,4-dimethyl-2-oxo-1-azetidinesulfonic acid ^{To a} 0-∞ ^{1 g of (-))} aЗyoti Q44 ^{_n) -} d ⁱ il] E: T ^{l! L-1} 2noxn- -aoetid ethylcarbonylhydrazone ⁰ to ^p s at ⁰ ° C Irgon ^ atmosphere is added 2.8 ml of 0.5M complex of di / etlifoo / II / id - trioxide. The mixture is allowed to warm to room temperature, stirred for 45 minutes and poured into 20 ml of a 0.5 M buffer solution of potassium dihydroxy-triphosphinate, pH 5.5. The resulting mixture was washed three times with 20 ml of ethyl ether (these organic phases were discarded) and 0.237 g of tetrabutylamide / hexonone acetate was added to the aqueous solution. The mixture was extracted four times with 20 .mu.l of methylene chloride and the combined extracts were poured through 20 ml of 8% sodium chloride solution. The solution was dried with sulfuric acid and dried in water. 0.31 g of an oil is obtained which, according to NMR, consists of 50% diethyl ethyl chloride and 50% of the title compound.

E) -) a31MtLnn-4,4-di / etH11-2-oon-1-aottddansulfonate tyelt

A solution of 0.155 g of tetrabutyl / modal salt (-) and 31 [deg.] To 3,4-diethiol-2-non-1'-1-ortho-sulfonic acid in 0.6 ml / ethanol was added in 10 ml of ethanol in 2 ml of ethanol. hydrogenates at a pressure of 1 bar. The catalyst was filtered off with ether (chloroform). Methyl chloride from the solution was mixed with the alcohol solution and the resulting solution and 0.123 l and 97% acidic acid was added to the clear solution. Upon addition of the acid, the solution became acidic. After jednnhndinové / space ^P s temperature 5 ° C, ^of evný ^P ro ^{duo 't} O (l ^df filtered ^if m ⁱ is ^{0, 0664} g slo ^ eoic ^one said vo ^and invite ^t yjíc ^s zi née ⁰⁾ ^ ^p and s ^{200 and 202} ° C.

NMR (CDCl3): 1.64 (s, 31H), 1.68 (s, 3H), 4.42 (s, 1H).

^iC -tec ¹⁰ . ⁰ ^: ^1,776 5 cm ·

Example 153

Potassium salt (3 ^ / 2 /) - 34 (/2-08^1044-160.80011/1 // ^ 6100 ^ 10 ^ 0/10013 ^ 3 ^ 1 ^ 10) -414 ^ 1 ^ 1 ^ 171-2 ^ O-O-1-azetyl-dicycrylic acid

To a solution of 50 g of N-H-triphenylbenzofrlazole hydrate and 0.323 m / ol of (Z) -2-α-ino-alla - ((ethooyl) ino) -4-thiazoleacetic acid in 0.5 l of dloethylphosphine was added in argon at / oofer at temperature. 67% ricyclohexyloxycarbonyl chloride was added. Deer and with 1 hour Oc1í | 57 mg of solid (R) -3-amino-4,4-methyl-2-oxo-1-azetirine sulfonic acid (see example 153) are added first and then added dropwise. The reaction mixture was stirred at ambient temperature for 16 hours, then the di-ethyl amide was evaporated under high / vacuum at -30 ° C, the residue was stirred in 4 L of acetone and the suspension was poured. The filter cake is additional 4 [mu] l of acetone and first 85 [mu] g of potassium perfluoroutaneULfonate a is added to the filtrate. potoo ether · Trituration of the resulting resin substance with ethereo yields 40 / g of a reddish-brown solid solid which is chromatographed on a 70 OL column of HP-20 AG resin. The column is eluted with water, collecting 5/1 fractions of 16 to 40 fractions after separating the residue with equal portions of acetone and hexane, and drying to give the desired product melting at 225 °. C·

Anaaýza: for CllHl4 5 ^N ° 6 ^S 2 requires C 31.80 ^K IH 3.40% N 15.86% S 15.43 «1 found C 29.47% H 3.48% N 14.98% S 13.35 »·

Example 154 '

Potassium salt (-A,, / rdimet ^ ψl- / f0xo-3-1lfβУotcctty / tminf) -1-α-αddin8ulonic acid

To a solution of 45 g of N-hydrophenoxyzazazole hydrate and 40 g of phenylacetic acid in 0.5 OL. 61% of the cyclohexyl amide was added in an argon atrnoopher at a temperature of 100 DEG C. The resulting mixture was stirred for 1 hour, and then 52 / g of solid (1) -methylamine was added. The reaction mixture was allowed to stir at room temperature for 24 hours, then the di-ethylphosphoric acid was evaporated under high vacuum at a temperature of 0.04 .mu.l. 30 ° C, the residue is suspended in acetone and the suspension is filtered. The potassium perfluoromethanesulfonate and then the ether were added first and the mixture was cooled. The precipitated solid product was washed with acetone and hexane and dried to give the title compound as a powder.

Anaalysis: calculated C 44.55 H 4.32 N 8.00% S 9.15% K 11.16 found C 43.83% H 4.16 # N 7, 96% N 8.76% K 11.43 ».

NMR (CDCl 3): 1.33 (s, 3H, 1.58 (s, 3H, 3.68 (s, 3H)), 4.70 (s, 1H, 7.56 ppo ( wide, 5H ·

Example 155

(3S-trans) -3- (((2-Aalno-4-thiazolyl / ootactyl) olino) -4-methyl-2-axo-1-acetyl) sulfonic acid

To a solution of 1.85 g of riphenylffsphilylchloride in 15 OL of dry ice in a cold bath of Ledern v / ethanol at -15 ° C to -20 ° C is added 2.14 g of salt 2 (aolno) The thiol salts of glycolic acids with thiocylamine were stirred for half an hour to cool the solution to be mixed. of anhydride is added a solution of 1.08 g of (3S-toan8) -3-andn- (o4-acetylthio) olanthalene sulfonic acid (see Example 139) and 1.92 O.triazine / b / in at 5. The reaction mixture was stirred at 5 [deg.] C. for 24 hours. The solution was dissolved in vacuo, the amber-colored oily residue was dissolved in water and chromatographed on a 200 ml column of Dowex 50 X 2-400 (K). The column is washed with water, collecting 15 m fractions. Fractions 13 to 27 yield 3.37 g of crude product which is chromatographed on a 200 ml column. The HP-20 was allowed to purify with water as eluent. (Fraction of about 1 mil. Yield was collected in fractions 18-26. Evaporation of the water in vacuo yielded a solid. reported as anase, in the form of an amorphous powder.

ANALYSIS: ° C for HGN ° K ₆ S ₂ (372.42) in / poCieno C-02% H ^ г О 0% N 15.04% S 17.22 10.50 1 10%;

Found C 08.87% H 2.62% N 14.85% S 15.09 1 К 11, 81%.

Example 156 *

Potassium salt triple trifluoroacetate (3S / R) - 3 - ((([alpha] -aacetyl / alino) phen (leceyl) allyl) -6-oxo-1-ezetidra8uloyl tyseline) (1: 1) ’

Removal of protecting groups from potassium salt (3S / RУ /) - 3 - ((((((((4-leihox / fen / l / lθihox /) carolo / l) amino) acdi / l) amino) phenylacet / 1) amino) -6-oxo-1-aza-sulfonic acid (see Example 127) using trifluoroacetic acid (a) and the anole yield the title compound, decomposing at 165 ° C.

Example 157

Potassium salt of (3S-tris) -3-letho [-2-letho] -6-oxo-3 - ((phenylene-ethoxy) -carbonyl) - (in) -isulfonyl sulfonic acid]

A) (3S-tran8 / 2-Lethyl-3-ethoxy-6-oxo-4 - ((phenylphenyl) carboxylic acid) thiazine

A solution of 2.5 g (0.0106 mo) of (3R-irialt) 24-lethyl-2-oxo-3 - (((fa) ω-ω-cyclo-coboayl) alia) thiazole (prepared in 12.6% yield from S-ihreoaiau using) of the procedure described in Example 98C for the preparation of racemic in 112 ml of 4% borax in methanol is cooled to 0 DEG C. and 3.5 ml of ierc.Oзt / lh / pochhooiiз are added thereto. After 20 minutes the solution is poured into 1 liter of cold The reaction mixture was extracted with water (750 ml cold ethyl acetate). The organic layers are washed twice with 750 ml of cold water, then with saturated sodium chloride solution, dried and evaporated. 3.05. Of crude NN-dichloromethane is obtained.

A solution of 426 mg of squid in 20 ml of dry methanol is cooled to -78 ° C and diluted with 40 ml of dry ietral / drofuran. Within 30 seconds, a syringe was added from the top of the syringe. of the prepared chloride amide in 20 ml of tetrahydrofuran, cooled to -78 ° C. After the Svaceilium reaction at -78 ° C, 2 ml of acetic acid and 2 ml of irileeth / photosensitizer were added. The reaction solution is poured into 500 ml of water and extracted in each case (300 ml of ethyl acetate). The organic layer is washed with water, dried and evaporated to an oily residue, eluting with chrome-fibrillation. on a 200 ml silica gel column using chloroform / ethyl acetate (3: 1) as the eluant, provided a total of 1.25 g of the title compounds.

B) Potassium salt of (3S-trans) -3-methyl-4-methyl-2-oxo-3 - (((ennylmethoxy) keroyl) eliao) -1- (2-oxo) -butyric acid]

A solution of 800 mg (0.00303 moo) [3S-triazine-24-leth] -1-3-lethox] -6-oxo-4 - ((phosphoryl-ethoxy) -9-oxazoline] in 2 ml of dimethylformamide was cooled to 0 ° C, and thereto was added a ml. .koi ^ f ^ p ^ <BXU dímethylformamiS - trioxide. the mixture was reacted for 1 hour at 0 ° C ieploiě then 4 hour / ieploiě _líítnaoti> reaction roziok TX / ije to 80 ml of 0.M dilydrogeilosl / potassium potassium (adjusted to pH 5.5) and extracted twice with 50 ml of methyl methacrylate / potassium salt each time. 1.04 g of tetrahydrofuran (II) -sulfate was added and the mixture was extracted with dichloromethane to give 1.42 g of dsj / vitel / material which was dissolved in acetone and 1.04 g of potassium perl / reutaisulfate in 10 ml was added. of acetone, the mixture was diluted with 250 mL of ether and the oily mixture was thoroughly triturated to give 584 mg of crude product, which product was chromatographed with 200 mL of HP-20 AG adsorption using 1L first. water and acetone (9: 1) mixture as a reagent. Fractions of about 100 ml were added. From fractions 13 to 16, 418 mg of purified product was obtained. Trituration of 114 mg of this material with ether gave 104 mg of analytical product.

Analysis calculated: C 39.06% H 4.44% Found: C 38.91% H 3.62%

N 7 ^ 1%

N 6.11% S 8.06%

К 9.78 К 9,, 11%.

NMR (CDCl3): 1.33 (d, 3H, J = 7Hz), 3.46 (s, 3H, 4.22 (doublet of doublets, 2H, J = 6Hz)), 5.18 (s, 2H) , 7.43 ppm s, 5H).

Example 158

Potassium salt of (3Srtrans) -Зmsel / o-4-retlyl-2-ooo-3 - ((ethylsilyl)) -1-azetidineSulfonyl acid

By catalytic hydrogenation potassium SDI-ZЗS tr1is / Reth} ^-3-t-Ø 4Πlrthhl-2 - / ooЗз ((/ leIiylrreho / a · / ^b KKA e / ytl) i: slope) aetidiisulforlOvé 1I-ester (see Example 157 After its conversion to the orthebutyrium salt, the tetrabutylimonium salt (3S-trams) of armino-3-methyl-4-methyl-2-ooo-1-azetidine-sulfonic acid was prepared according to the procedure of Example 88. using 3-tetrasolecular amino (3S-erans) for 4-carboxylic acid 4-carboxylic acid-4-oxo-azazididylsulfonate and phenylacetyl chloride yields the title compound.

Anal. Calcd for C 41 H 21 N 2 O 2 O 3 C 42.61% H 4.31% N 7.65%; Found C 39.67% H 4.09% N 7.30%.

NMR (deuteriurnoxid): 1.29 (d, 3H, J = 7Hz ^ 3.45 (s, 3H), 3.73 (s, 2H), 4.36 (doublet of soul, 2H, J = 6H _Z z, 7.38 ppm (s, 5H).

Example 159

Potassium salt of US- (a (Z) -ethyl) -3- (((2-1 / 4-methyl-4-methyl) -yl) -2-dilenylethoxy) -2-ooosehooylamino) acetyl) amino] -methylamine 4- (oo-1-azetidinosulfonic acid)

An analogy to the procedure of Example 138 is followed except that [Z] -2-arine / - is replaced with / Z / -2-mino- / reel). 1fa - ((2- (diphenylrsehl) -2-oxooShl) o) - (4-thiol) acetic acid to (3S-cis) α-αΠLinc-4-methyl-2-co--1-aestidinsui The tartaric acid is first treated with ethylamine. The title compound melted at 155-160 ° C with decomposition.

First calm 160

(3S- (Zz1f1 ^/ Z /, 4eΰta)) -3 - ((((kare / oymrSeloo / imini) // - (amino-0-thienyl) acyl) arie)) - 4-rethyl-2- (o-1-1-estidinsuf) onacetic acid

By deprotection of the potassium salt (3S- (3alla / Z /, 4bθ / a)) 43 - ((2-amino-4-yhiazolyl) ((2- (10-octenyl) -2-oxo / thioDt)) imioi) acθУtl) amio) -2-meУlhft44-O _X O 1-azetidinesulfonic acid (see example. 159) for pouuiyí acid and anisole yielded compound St uvtdtná title rozkládaaící st at a temperature above 250 ° C.

Example 161

Potassium salt of (S) -3- (1) (2d 6-dichloro-4-pyridinyl) thioacetyl) armino-oxo-1-azequinazioic acid

Acylation of the tetrabuyl ammonium salt of (S, N-amino-4-oxool) azetidine sulfonic acid (see Example 6A) with 4-oltrophthalothlose ([2,6-dichloro-4-ptridiol] thio) acetic acid, followed by treatment with potassium perluorobutosulfooate. the title compound, m.p. 212-214 ° C.

Example 162

Potassium salt (3S / R * / (- 34)) (14-amino-2,3-dio100-1-piperazioyl / carbinyl) amino) phenylacetyl) amino) -4-methyl-2-ooo- 1-acetic acid

(3S / R * / (o1)) - (((2 - ([4-Methoxy-2-oxo] / uSfo-3-azinyl) amino) -2-oxo-1- The (amino) carbonyl-2,3-diixo-1-piperazinecarboxylic acid (see Example 148) was hydrogenated with hydrogen gas using 10% palladium on carbon catalyst. The title compound melted with decomposition at 165 ° C.

Example 163

(3S / Z) 73 - (((2-Amino-44-thiazolyl)) ((1-aarooxy-1-methylethoxy) imino) acetyl) amino) -2-axo-1-azetidinesuioonic acid) 1: 2 ^)

(3-Ethyl ammonium salts of (3S / Z)) - 3 - (((2-aminoo-hhiazoyl))) 2- (diferylmethoxy) -1,1-dimethoxy-2-oxo-oxo ₍ 2-oxo-1-amino) -2-oxo-1-azeonidine sulfide After the conversion with aqueous sodium hydroxide to the diisidium salt and purification by ctrima / irr on the HP-20 adsorbent, the title compound melts with decomposition. at

185 ° C.

Examples 164-167

The procedure is analogous to that of Example 11 except that the amino acids listed in column (I) of the following table are those obtained in column (II) of this table.

Example Number

AND

Default láyka

II. The product is always used instead of the [Z] -2-amino acid

164 2,6-Dimethoxybenzoic acid potassium salt / S / -3- (22-di / thioybenzoyl) ammonium

165 (Z) -2-Amino-aa - ((4- (dlthiyl) methylthio) -4-oxo-oxo) o-thiazoleacetic acid) -2-iodo-1-azothiosulionic acid, with decomposition at 180 ° C potassium (3S / Z) - 2 - (((2-) thio-4-thiazol-1/1 (4-diphenylmethyl) -hexyl-4-oxibuoyloxy) imiool) acyl) amino) -2-oxo-salt Of 1-azididinulonic acid, melting with decomposition at 125 to 130 ° C

IX

Product

Example Number

I Starting substance

166 2- ((otphotylmeth (> yr / carbsotl) aios) * iittyl) btnzo thyelioa dyaselea salt / S / -2-sn> -3 - (((((/ (β-yLintttsχt / kaybsnt1) amino) me thrl) benzoyl) amino) -1 t) thi-dulfulfone tyselioy, melting and decomposition at 234.5 ^O C 167 alpha - (((5-cyano-2- / 44fsxntL-1 • piperazofi / pyrido (2,3-d) pyrimidio-6-ylcarbonyl)) benzeneate kysioa potassium ^ SŮL / 3S / -3 - (((((5-tertyl-2- / 44 (Ethyl-1-piperazioyl / pyrido (2,3-d) pyrimidine (46) (carbonyl) (1-amino) phenylacetyl) amino-AZ-14-azazolidinylphosphoric acid melting at 265-270 ° C with decomposition

Example 1 168 (Braio) -340-amino-4-ethyl) 24-oxo-14-azetide: U8 sulfone tyselioa

A) tert-ButoxycarbonylX-N.Ithiy-teta-threoethylseronide

1.33 g of threo-D, l4btaae; tjh1313tri at dissolved in 10 .mu.l of 2N potassium hydroxide and 5. After the addition of 2.46 g of di-tert-butyl pyro-bicarbonate, the resulting biphasic mixture was stirred for 4 hours at the same temperature, followed by the addition of 1 - 25 g of O-mittylhydroxyxysinium chloride and a pH of ¹ . XN is adjusted to pH 4 with 4.times.HCl, and 1.92 g of 1-methyl-4- (2-ethylthio) -butylhydrocyanide are added and the pH is adjusted to pH 4. After stirring for one hour, the reaction mixture is washed with sodium chloride. and extracted with 4 x 50 ml of ethyl acetate, 4 times 50 ml of ethyl acetate, combined and dried with magnesium sulphate. After removal of the solvent in vacuo, 1 g of compound is obtained.

B) tert-Butoxycarbonyl-O-ietal-8-sulfonyl-N-methoxt-btta-threopropionide

10.5 g of tert -butylcarbonyl-N-hexylbutyrate-ethyl ethyl serene are dissolved in 65 ml of pyridine and at 0 DEG C., 4.65 ml of isothylammonium chloride are added dropwise. ml of XN hydrochloric acid · pH with concentrated hydrochloric acid up to 4 a. the mixture was extracted three times with 85 ml of ethyl acetate each time. The combined extracts were dried with magnesium sulphate and bent under vacuum. The residue was stirred with tetrahydrofuran. and - the solution is evaporated off. After stirring with ether and filtration, 6.9 g of oily fat are obtained.

C) (tyan8) 43-tert-Sotykerbsoylaiinos4-ethyl-1-methyl-2-azetidinone

4.15 g of anhydrous potassium phosphate and 125 ml of dry acetone are brought to reflux under reflux, and 3.4 g of tert-butyl chloride-O-thi-18-sulfsnyl-Ni · thoχt4btta-thrθOpyyopSonetouou are added to the mixture under reflux. . After 1 hour, the reaction mixture was cooled and filtered, the filtrate was concentrated in vacuo and the oily residue stirred with hexane to give 2.2 g of the title compound as an oil. .

D) (thiant) -3-ethylsilylbonylamino-444-ethyl-2-aztidinone

3 - g (traoz) 434 was added to 170 ml of liquid ammonia at 478 ° C

1-methylbutylcarbonylthio-444-ethoxy-1-hydroxyethanone _l is added to the mixture in 5 portions of 1.68 g over 5 minutes. The mixture was stirred for 30 minutes. Ammonium chloride is slowly added to the mixture until the blue color disappears, until the amniac is evaporated under rain and the solid residue is extracted twice each time. 100 ml of ethyl acetate. Evaporation of the residue followed by drying in vacuo afforded 2.7 g of the title compound.

E) -Butylbutyl salt (tgame) -3-erccuoyoyloxycarboylmino-4-methyl-2-benzoyl-aidinidineullonic acid stirring at room temperature with sulfuric reacoxide. A clear solution was formed in the flask which was admixed with e (trian3) -3-trbutoylbutoylbjonylbutton for 15 minutes.

To 2 ml of absolute pyridine in 20 ml of dry dichloromethane is added 3.7 ml of triethylsilyl sulfide chloride in 5 ml of dry dichloride. The addition was carried out under nitrogen at -30 ° C and lasted for 10 minutes. After three minutes, the flask was evacuated to give the pyridine complex to an alley bath preheated to 90 ° C, 2.67 -4-ethyl-2-azetidine and 20 ml dry pyridine were added. Afterwards, it is poured into 200 ml of a 1M solution of potassium hydroxide. Addition of 27 .mu.-potassium non-sodium hydrogen chloride and 100 ml of water gives a clear solution which is extracted twice with 60 ml of ethyl acetate each time. To the aqueous layer was added tetrahydrofuran, filtered and extracted three times with 100 ml each of 100 ml of water, and the combined oreanic layers were dried over magnesium sulfate. Concentration in vacuo afforded 6.9 e of the title compound.

F) (tert) -3-Amino-4-ethyl-2-iodo-1-azide: Lysulphonic acid

9.75% (trtos) -3-methylbutylbutylbutylbenzoyl-4-methyl-2-iodo-1-thesulfonate salt (trtos) -3-methylbutyric acid salt in 40 ml of 98% formic acid was stirred at room temperature for 3 hours. 60 ml of dichloromethane and the mixture was cooled for about 16 hours. The precipitate formed is filtered off and dried in vacuo. 0.85 e of the title compound melting at 185 ° C with decomposition is obtained.

Example 169

Dibasic potassium salt (trans, Z) -3 - (((2-amino-4-thi azooyl) ((1-carbonyl-1-alylthiyl) amino) amino) -4-ethyl-2 -oxo-1-azetidine sulfonic acid

A) Dipotassium salt / tans, Z / s, - (((1'-tert-44-1-azoyl-1/1-dinynyl ⁾ -thoxycarbonyl-1-retlyl-1-yloxy) amino) -4-tlyl- 2-chloro-1-thiazolidinone acid

0.55 e (trt8) sЗ-mho-4-ethyl-2-iodo-1-thiazetidine-sulfonoyllylamine and 335 methyltrimlimine are dissolved in 50 ml of dry dimethylformamide and 450 ml of dry dimethylformamide are first added under stirring at 0 ° C. and then 0.69 .mu.l of cycliclexylcarbodiiride. After stirring for about six hours at 0 ° C, the flask was evacuated and 25 ml dry acetone was added to the solid residue. The mixture is filtered and 25 ml of dry acetone are added to the filtrate ee. The mixture was filtered, and potassium filtrate was first added to the filtrate, and then 100 ml of ether was added. After standing at 0 ° C for 1 hour, the solid product was filtered off, washed with ether and dried in vacuo. This gives 3e 1.58 e of the title compound.

B) Dipotassium salt (tris, Z) -3 - (((2-amino-1-thiazolyl) ((1-carboyl-1-retlylethoxyl) irio) tert-yl) amino) -4-ethyl-2- o-i-1-thiazolidinone sulfonic acid

To a suspension of 1,3,3-dibasic salt (trans, N-S - (((2-thiazol-4-thiazollyl)) - 1-accordingonylrethoxy) - (1-nitroethyl) (amino) acetyl) amino) -4- Ethyl 4-oxo-1-azidonic acid in 10 ml of anisole was added at -15 ° C over 5 minutes with 5 ml of trifluoroacetic acid. After stirring at -10 ° C for 2 hours, a clear solution is obtained, to which 80 ml of dry ether is added at -30 ° C. The precipitate formed is filtered off, stirred with 5 ml of water, and the pH is added at -30 DEG C. with 80 ml of dry ether. The precipitate formed is filtered off, stirred with 5 ml of water, the pH is adjusted to 5.5 at 0 [deg.] C. and the mixture is filtered to remove the undiluted starting material. The filtrate is chromatographed on HP adsorbent. -20 using water as a Beating Agent. LyGollizaci so

Example 170

(3S / Z) -Potassium salt (((-Mino-4-thiazolyl) // ((O-hydroxy-4-oxophutoxy) amino) acetylamino) -2-oxo-azetidine sulfonic acid

Removal of the protecting group from the potassium salt of (3S / Z) - 3 - (((2-Amino-4H-azulyl) ((4- (diphenyl-ethoxy) -4-oxo-butoxy) imino) acttyl) amino) -2-oxo-1- azetidine sulfonic acid (see Example 165) using trifluoroacetic acid and the title compound yielded the title compound, melting above 200 ° C.

Example 171 (S) -3 - ((- (amino) tert-butyl (amino)) amino) -2-oxo-1-auetidinobuffonic acid in the form of the inner salt

By deprotecting the potassium salt of (R) -2-oxo-3 - ((2 - (((((phenylphenyl) carbonyl) amino) methyl) benzo) (aainin) -1-aautidinsuffonic acid) using hydrogen gas, palladium on carbon and hydrochloric acid gave the title compound, m.p. 162-165 ° C.

Example 172

N- (3 - (((2- [4- (1-piperidin-1-yl) -5-hydroxyethyl) (2,3-piperidinyl) carbonylamino) -2-oxo-1-azeol) potassium salt; Гиз ^ Ого ^ acids

Tetrabutylmonium salt of (S) -3-amino-2-oxo-1-azetidine-tonic acid (see Example 6A) is reacted with 2- (4-phenyl-1-trifluoromethyl) -5-hydroxy-6- (4-nitrophinoxy) carbonyl It is then treated with potassium tert-butyrimidine and then treated with potassium tert-butylamine in acetone. The title compound melted with decomposition at 290 ° C.

Example 173

(3S-Trant) -aff - (((Methoxy-2-foxo-1-suffo-3-azeijdity / amino) carboyl) carbonyl) benzeneacetic acid (3S-trant) -3-amino-4-ethyl-2- The oxo-1-azetinine-phosphonic acid (see Example 139) was treated with alpha-tert-oxo-benzylactyllchloroformate and the resulting product was treated with triethylamine and potassium trifluorobutane sulfonate. The title compound melted at 147 ° C with decomposition.

Píka al 74.

O-trans-3-Amino-4-yl-phenyl-12-of-0-zinc-sulfonic acid

A) .alpha .- (chloro-tert-butoxycarbonylamino) -butta-cyclohexyl-bealoalypyridyl] -threo-propionic acid g. . 17.8 g are added and the mixture is heated to 60 ° C with stirring. At this temperature, the mixture becomes a clear solution, to which 21.0 g of di-tert-butylityocarbonate are added and stirring at 60 ° C is continued for 1.5 hours. The solvent was evaporated in vacuo and 50 ml of water was added to the residue. The aqueous layer was acidified to p-2 with 3N hydrochloric acid and extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate and evaporated to dryness. The remaining crystalline material was collected and washed with petroleum ethylene. 20.4 g of the title compound melting at 113-115 ° C is obtained

3) alpha-ttrc. butotk''aarfitylímino) -eeaa-tk'k0onetLΊ-BC-o-hj'drot N · ^τ ~ íetoxy- 'thefOprfip0inmid>

20.2 g of N-tert- (tert-butoxycarbonyl) -beta-cyclohexyl-C-thiophenol-threo-propionic acid and 7.6 g of O-methyl-hexyl chloride are suspended in 250 l of water and 175 l of ttrc. .bstlo / Γs. The pH of the mixture was adjusted to 4 with potassium carbonate, 16.4 g of 1-tert-butyl-3-carboxylic acid / propyl) carbofile was added and the reaction mixture was stirred for 1.5 hours while maintaining pH 4. The t-butanol was evaporated in The resulting aqueous solution was washed with sodium hydroxide and extracted twice with 100 l of ethyl acetate. The organic layers were combined and, after drying with sodium sulfate, evaporated to dryness. The acid residue was filtered and washed with petroleum ether to give 18.6 g of the title compound, melting at 125-127 ° C.

C) .alpha .- (4-tert-butoxycyclotonylamino) -beta-cyclohexyl-eeta-mmethaiS3-sulfoyl-yf) -N-methoxy-Un * eo-propionamide

18.5 g of alpha- (tert.b (tertb ^, aacOolyloin)) - beak-lkk (lhoxylceel-llddooxy-N-oetloxylthr) -pr) pionaoide are dissolved in 100 l of dry pyridine with stirring, the solution is cooled with stirring at 0 ° C and 9 .mu.g of oethanesulfonyl chloride is added dropwise thereto. After jtdo / h / din / VA reaction at 0 ° C for an additional S oethannuSjřonyУchl ³ g / reef and stirring was continued for another hour. The reaction solution is poured into 100 ml of ice-water, 200 ml of ethyl acetate are added and the pH is adjusted with dilute sulfuric acid and the layers are separated, dried over sodium sulphate and the solvent is evaporated in vacuo. The solid residue was filtered off in a five-hour run to give 19.0 g of the title compound, melting at 150 ° C.

D) (1S-trans) -} - ttrc.bu (oycaryc): oylloin] -4-Clk1 (1-yl-1-oe th) :) 11,22-azetifin / o

Dissolve 18.7 g of alpha-tert-butylbutylorpholin-1-btta-cyclohtoll-btta- (α-tertoloolool / 0.1) -N-oethooyl-threoApr / pionamide in 500 ml of dry acetone, 9.8 g of potassium carbonate are added and the suspension is added. with stirring for 5 hours at reflux. The insoluble inorganic oil was filtered off, the solvent was evaporated in vacuo and the oily residue was dissolved in SO 2 ethyl acetate. Upon addition of the petroleum filter, the title compound precipitated and was filtered. 12.9 g of the expected product are obtained, melting at 110-112 ° C.

E) (SS-Traos) -S- (errc.UutolylrrOonlliO) / - 4-Clk1 / heol-2-isetifin / o

Ol to 50 liquid ammonia is added with stirring 1 g ⁽³ --trlOs) - ³ - (terc.Uu0oзlkaιrC / nylaoino) -4-Clklohe: OLL-1-oethoJ0l2 azetifinons over 5 minutes at 5-6 was added portionwise 0.154 g of sodium. After this time an additional 0.025 g of sodium was added and stirring was continued for 5 minutes. After the addition of 0.89 g of ammonia, the ammonia was evaporated and the residue was extracted with warm ethyl acetate. The organic extract was blown to dryness and the residual crystals were removed by use of a 3: 1 ether. 0.5 g of the title compound is obtained, melting at 1S to 1S2 ° C.

F) Tyridioic salt (SS-trlns) -3 - ((trrc.Su/olkaar/ooylaoio/)-4-ilkl/he}ol-2-oxo/11azztifiosulf/o/ your acids

5.5 g of (3S-trifluoromethyl) -3- (tertbenzoylbenzyl) -4-cyclohexyl-12-azetifin / ns are dissolved in 20 .mu.l of ethylene chloride and 80 .mu.l of diethylphenol. After adding 60 ool of coinolex sulfur trioxide, the resulting solution was stirred at ambient temperature for 6 hours. Evaporation in vacuo provided 113 g of the title compound as an oil.

G) Tetrabutyltoonium salt (JS-traosyl-urr (b) tolyanronynyl) - 4-Clk 1-ol-2- (o) -1-

-lzttldnn8ul0onc) acids ·

Pyrifioi 113 g / VA salt (SS-traos) - ³ - (ttrc.buto2lk ARC / ollloino) -4-clkl / Ie:> OLL-2 / x / 1-lzttid0nsuiOontvá acid rozpuutí ol in 250 of water. With stirring, 9.0 g of tetrabutyl εoonium hydroxide is added and the pH is adjusted to 6.5 with 1N potassium hydroxide. The aqueous solution was extracted twice with 200 ml each of ethyl chloride. The organics were dried over sodium sulfate, filtered and the solvent was distilled to give 8 g of the title compound, melting at 1S5 to 1S8 ° C.

H) (3S-Traos) -Samino-4-cyclic-hexyl-2- [iso-1-isotidin-sulfonic acid]

3.8 g of tetrabutylammonium salt of (3S-trans) -3- (tert-butoxycarbonylamino) -4-cyclohexyl-2-oxo-1-aetidine sulfonic acid was stirred for 3 hours in 20 a. 20 ml of methlene chloride are added. The precipitated title compound st is filtered off. Obtained 1.0 ^g of the desired proctaktu te ^{p th} ture it 2I ^7-219 ° ^C *

Example 175

Potassium salt of (3S- (3alla / Z, 4reta)) -3 - (([2-] miot-4-thiazollyl / ethooylion / acetyl)) mio0-4-cyclotheyl ₎ -1,2-oxo-1-isidine sulfone acid

0.25 g of (3S-trans) -3-amino-4-cyclohexyl-2-oxo-1-azididine sulfonic acid was dissolved in 30 ml of dry dimethyl amide and 0.12 g of triethylaine. Once the mixture becomes a clear solution with stirring, 0.2 g of (Z) -2-γ-mint-alpha- (attoxyiaino) -4-thiazoleacetic acid, 0.16 g of hydroxylrtzoOriazole and 0.42 g of cyclopropylphosphoric acid are added. The reaction mixture was stirred at room temperature for 48 hours, then the precipitated urea was filtered off and the solvent was removed in vacuo. The residue was dissolved in 10 ml of acetone and 0.41 g of potassium perlluoro-butanone sulphonate was added. After addition of 50 ml of ether, the title compound precipitates, which is filtered off and subjected to chromatography on an HP-20 adsorbent column using a 9: 1 mixture of water and acetone as eluent. 0.36 g of product is obtained (m.p. 200 DEG-205 DEG C.).

Example 176

Dipotassium compound (3S- (3alpha / Z /, 4beta) -з - / ((1-amOf-4-thiatolyl) ((1-hexoxy-1-ethyl-ethyl) -olino) amino) -4 - cyclohexyl-2-oxo-1-zinc-2-enoic acid

A) Potassium salt (3S- (Зalla / Z /, 4reta)) - 3 - ((/ 2-aaino-4-thiazolium) / (/ d-nallnalettOooyУarronУ · ^ · -1-methyl / iaino) ace (4- (1-Amino) -4-cyclohetyl-2-oxo-1-azetidone) -suloonic acid

0.2 g of (3S-, tr10) -3-amino-4-cyclotheol-2-oxo-1-aztidone sulfonic acid (see Example 175) was dissolved in 30 ml of fimethyltyl amide and 0.09 g of ammonium (after the Add 0.30 g / Z / -2lamiоt-alfl - (/ ^r 1fdtOθnylettfoэlrkarbtlо L-1-AET (hl.θthotχrУimlnо) -4-thilZtloettvé acid and 0.33 g fielklthtχylkarbtdiiaifu _l and stirred at ^ i ^ d) at The oily residue is dissolved in 5 ml of acetone, 0.3 g of potassium perliuorobutosulfonate is added to the solution, and the mixture is poured into 100 ml of ether with stirring. Potassium salts of (3S- (3alla (Z), 4Xe and a) -3 - (([2- (1-chloro-4-thiazol)) - ((1-dimethylaminocarbonyl-1-methylthio)) imino-acetyl-amino-4-cyclomethyl-2-oxo-1-isopropylphosphonic acid, which was filtered. The yield was 0.61 g.

B) Dipotassium salt (3S- (3alla / Z /, 4retl)) -3- ([2-amint-4-thiazolyl] 11-arylo-1-oetlethylthiophthalicyl) amino-4-chloro-4-carboxylic acid 2-thio-1-azidonosloonic acid

0.61 g of potassium sooi (3S- (3alla / Z / _l 4retl)) - 3 - (2-βaint // 4-ttilZtlll // 11fdlfolylaettcxykarbofnll1-aetttllthtfol / minо) aletyl) aninо) -4-cyklohteχl-2- oxo-1-lZttidOn8ulfоnové acids with ^y ^ is resuspended in 6 ml ιπΙ ^ ^ Ι suspension was cooled to -Ί5 e ^{C with} stirring was added dropwise 5 ml eye trlfbfoooc0ové kysseioy. The above temperature was maintained for 1 hour, followed ^by sn? .I to -30 ° C and the mixture к eg N, ¹⁰⁰ mL of dry zhruta e ^ is discontinued such that the temperature oepřestoupla -I ⁰ ° C. VysráOná composite is from ^ ^ filtered and ctaroamta afuje to pr ^y skkyici HP-20 absorbs water and acetone mixture (9: 1) as eluent. ⁰ are ^obtained, 3 ^g of the combination of UV-eO title ^(p o ^ o ^ tion. ^ I ^ Tej decomposition at ¹¹⁰ and ¹²⁰ ° C.

Example 177

Potassium salt of (3S- / 3alpha, 4-methyl-4-chloro-thiol-3 - (((((3 - (/ 2-furaoyl-ethyl) -amino-3-oxo-1-carboxylic acid) carbooyl) amino) leoylation ethyl) amino) 2-oxo-1-azetide-monosloonic acid

0.1 g of (3-methyl-3-methoxy-4-cyclothiol) -2-tot-1-azetide-sulphonic acid (via Example 17 '5') was dissolved in 3 ml of 30 ml of dry dimethylformamide and stirred for 3 hours. , 05 g of trietiylamine add st 3,14 g (((((/2-lbronylaeettlleOalllno)-2-oxo-1-iaidlZolidioyl)lab1f)oy1)am.oo) leoylocoove. kyssliny 0.06 g hl ^<i f'ooOfЬrnootrilZolbL and 0.17 g dieyklot · o ^y lkarrodiiaidu, Vy

4 ¹ 05 sequent solution was stirred 5 days at room temperature the solvent was removed under vacuum ... The residue is dissolved in 10 ml of acetone and the precipitated urea is filtered off. The mother liquor is mixed with 0.15 g of potassium perfluorobutanesulfonate and diluted with 50 ml of ether. The precipitate was filtered off and chromatographed on HP-20 resin using water and acetone. 1) as eluent. After freeze-drying, 0.14 g of product melting at 195-200 ° C is obtained.

P. ex 1 and d 179

DRAs n ^{l and} the salt of (3S- ^(3-allyl and ^f / R / ^{4b eta))} - ⁴ c ^h a ^YKL exy ^l -3- ^{((3- /} 4-e ^thyl - ^{2, 3-d} ioxo- 1-piperazines ^{( 1} '- 1,3-dioxo-2-phenylpropyl) amino) -2-axo-1-azetidine sulfonic acid

0.1 g of (3S-trans) -3-emino-4-cyclohexyl-2-oxo-1-ezetidine sulfonic acid (see Example 175) was dissolved in 30 ml of dimethylformamide and 0.5 g of triethylamine under stirring. [alpha] - ((( ^4- ethyl-2,3-dioxo-1-trifluoroeinyl / carbonyl) emino) benzeneacetic acid, 0.06 g hydroxybenzotriazole and 0.17 g dicyclohexylcarbodiinide, and the reaction mixture is stirred for about 16 hours at room temperature. The solvent was distilled off in vacuo and the oily residue was dissolved in 10 ml of acetone. The precipitated urea is filtered off, the mother liquor is stirred with 0.15 g of potassium perfluorobutanesulfonate and diluted with 50 ml of ether. The precipitate was filtered off and chromatographed. After

160 ° C.

0.15 g of the title compound is obtained on a HP-20 resin eluting with a 9: 1 mixture of water and acetone as the eluent, m.p.

Example d 179

(Trans, Z) -3 - (((2-Amino-4-thiazolyl) trans (nethoxylroino) acetyl) amino) -4-ethyl-2-oxo-1-azetidine sulfonic acid potassium salt

The procedure was carried out in an analogous manner to that of part λ) in Example 169 except that (Z) -2-emino-efae (methoximino) ^-4- thiazoleacetic acid was used as the starting material instead of / Z / -2-emino-alpha-2-carboxylic acid. (1-Diphenylmethoxycarbonyl-1-methylethoxy) imino) -4-thiezoleacetic acid. The title compound melted with decomposition at 190 ° C.

Example 180 (-) - (trans) -3-Amino-2-oxo-4-phenyl-1-azetidine sulfonic acid

4) (-) - (trans) -2-oxo-4-phenyl-1-azetidine-tert-butyldiphenylsilane

A solution of t-butylchlorodiphenylsilane (20.56 g) in DMF (45 ml) was cooled to 0 ° C under argon and triethylamine (10.4 ml) was added followed by (-) - 2-oxo-4-phenyl-1-azetidine. After reaction at 0 ^° C for several hours, an additional 1 ml of triethylamine and 2.11 g of tert-butylchlorodiphenylsilane are added to the mixture, the mixture is stirred at 5 ° C and 65 ° C for 65 hours, poured into 300 ml of ice water and extracted. 125 ml of ethyl acetate (3: 1) were added each time. The organic extracts were washed three times with 50 ml of phosphate buffer pH 4.5 each, then with 50 ml of saturated sodium bicarbonate solution, twice with 50 ml of water each, finally with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The solid residue was washed with hexane and dried under high vacuum to give 15 g of the title compound as a solid.

B) (-) - (trans) -3-Azido-2-oxo-4-phenyl-1-azetidine-tert-butyldiphenylsilane

A 50 ml flask equipped with a mechanical stirrer, gas inlet and dropping funnel was dried over a flame under argon, charged with 0.65 ml of a 1.6 M n-butyllithium hexane solution which was cooled to -40 ° C and Dissolve in 2 ml of tetrahydrofuran. After the addition of 0.16 ml of diisopropylamine, the mixture was stirred for 30 minutes while cooling to -78 ° C, and a solution of (-) - (trans) -2-oxo-4-phenyl-1-azetidine was added dropwise over about 5 minutes. tert-butyldiphenylsilane (400 mg) in 1.5 mL of tetrahydrofuran. After stirring for a further 20 minutes, 204 mg of p-toluenesulfonylacide in 0.5 ml of tetrahydrofuran was added to the solution, and the resulting mixture was stirred at -78 ^° C for 10 minutes, then 0.4 ml of chlorotrimethylsilane was added dropwise. After further stirring for 10 minutes, the cooling bath was removed, the reaction mixture was stirred at room temperature for 2.5 hours, then 20 ml of ethyl acetate was added thereto, followed by 8 ml of phosphate buffer pH 4.5. The organic layer was washed twice with 8 ml of buffer each time; three times with 10 ml each of 5% sodium bicarbonate solution and 1 ml of saturated sodium chloride solution, and dried over sodium sulfate. Filtration and concentration of the organic phase in vacuo afforded 500 mg of an oily residue which, by percolation with 5% ethyl acetate in hexane, gave 253 mg of the title compound.

C) (-) -, - 1'-azo-2-oxo-4-phenyl-1-azetidine^Roz^flow 17^G raw^hO⁽-⁾-⁽trance-²-azido-2-oxo-44^-enyl-1-azetidine-tert.^bat^youl^dand^Fen^yl silane 240 ml of methanol are cooled to 0 DEG C. and 35 ml of hydrochloric acid concentrate are added dropwise thereto. Remove the cooling bath, stir the reaction mixture at room temperature for 1 hour, then re-cool to 0 ° C and add saturated sodium bicarbonate until neutral. The resulting mixture is extracted once with 300 ml and four times with 100 ml of ethyl acetate each time, the organic extracts are washed first with 3 portions of equal portions of p% sodium bicarbonate solution and 50% sodium chloride solution and then with saturated sodium chloride solution and finally dried over sodium sulfate. Filtration and concentration in vacuo afforded 15 g of a heavy oil which was chromatographed on 100 g of silica gel using 20¾ ethyl acetate in hexane to give 460 mg of the title compound.

D) Tetrabutylammonium salt of (-) - (trans) ^{-3-azido-4-phenyl-1-d} Atet insulfonooé acid

A solution of 300 m ^{g (i)} - ^(trans) -3-azido-2 in ^{i-oxo-4- phenyl- 1} azetidine in 3 ml ^d ime ^{thy f} l u ^id ORMA under argon was cooled to 0 ° C and dimethylformamide-sulfur trioxide complex (4.78 mL of a 0.5 M solution in dimethylformamide) was added dropwise. The cooling bath was removed, the reaction mixture was stirred at room temperature for 2 hours, then poured into 80 ml of a 0.5 M potassium dihydrogen phosphate solution (pH 5.5). The solution was extracted with dichloromethane (the extract was discarded), 541 mg of tetrabutylammonium hydrogen sulfate was added thereto, and the resulting mixture was extracted with dichloromethane. The organic extracts were washed with 10% sodium chloride solution and dried over sodium sulfate. Filtration and concentration in vacuo afforded 800 mg of an oily material containing about 40% of the desired product, the remainder being dimethylformamide. This mixture was used in the next step without further purification.

E1 (~) - (trans) -3-Amino-4-phenyl-1-azetidinesuleonic acid

A solution of tetra ^b ut ^yl amon ⁱ b ^s with ^{poly (I)} - (trans)), 3-4- aшino ^- enyll11 αteidinsul ^e-ONOO acid amide in 4 mL methanol at room temperature under a pressure of 0.1 MPa in the hydrogenated presence of 30 mg platinum oxide. After 15 minutes, the reaction system was evacuated and fresh hydrogen was introduced. After a further 4b minutes the reaction is complete and the reaction system is purged with nitrogen. After standing the reaction mixture at room temperature for several days in 200 ml of a mixture of dichloromethane and methanol (4: 1), the catalyst was clumped together to allow filtration. The filtrate is concentrated in vacuo to a volume of 18 ml and 0.2 ml of 97% formic acid is added to the residue. The mixture was cooled to 5 ° C for several hours, then the precipitated solid material was filtered off and washed with dichloromethane. After drying, 150 mg of the title compound is obtained.

Analysis calculated for: C H HH ^gO ^SgS: C, 44.62%; C, 43.36%.

H 4,17%

H 4,31%

N 11.57%

N 11.09% with 13.23%;

S 13.02%.

Example 181

(-) - (tran3) -2-oxo-4-phenyl-3- ((phenylacetyl) amino) -1-azetidine sulfonic acid potassium salt

A) Tetrabutylammonium salt of - (trans) -2-oxo-4-phenyl-3- ((phenylacetyl) amino) -1-azetidine sulfonic acid

To a solution of 52 mg of N-hydroxybenzotriazole monohydrate and 46 mg of phenylacetic acid in 0.3 ml of dimethylformamide was added 70 mg of solid dicyclohexylcarbodiimide under argon at 0 ° C. The cooling bath was removed and the resulting mixture was stirred at room temperature for 1 hour. After dilution with an additional 0.3 ml of dimethylformamide, 75 mg of solid (-) - (trans) -3-anino-2-oxo-4-phenyl-1-azeladolidesulfonic acid (see Example 180) are added first and then added dropwise to 0.05. ml of triethylamine. The reaction mixture was stirred at room temperature for 23 hours, then filtered and the filter cake was washed with dimethylforraamide. The filtrate was added to 20 ml of 0.5M potassium dihydrogen phosphate solution (pH 4.5), washed three times with 8 ml of ethyl acetate each time (the extract was discarded), and 105 mg (0.31 mmol) of tetrabutylammonium hydrogen sulfate were added. The resulting mixture is extracted three times with 15 ml of dichloromethane each time, the extracts are washed twice with 15 ml each of 10% sodium chloride solution and 10 ml of saturated sodium chloride solution, and dried over sodium sulfate. Filtration, concentration in vacuo and heating under high vacuum to 32 ° C afforded 165 mg of an oily material containing about 40% of the desired compound and 60% of dimethylformamide.

B) Potassium salt of / - / - / trans / -2-oxo-4-phenyl-3 - (/ phenylacetyl / amino) ^{-1-azetldinsulfonov,} benzenepropanoic acid

To a solution of tetrabutylammonium salt of - (-) - (trans) -2-oxo-4-phenoxy-3- ((phenoxyacetyl) amino) -1-azetidinesulfonic acid in 1.5 ml of acetone was added 41 mg (0.121 mmol) of perfluorobutanesulfonate potassium. Dilution with 12 ml of ether gives a glassy material which, after trituration with ether, yields 43 mg of a solid containing about 20% impurity containing tetrabutylammonium residue. This solid was dissolved in 50% aqueous acetone and passed through a column of 1 ml Dowex 50W-X2 (K +) ion exchanger. After washed with acetone and hexane and dried substituting Compound title makes the measurement ^{of DP sted} la solvent of ^{s and p} sk evný ^P ro ^d uct, ^kt er ^y in a high vacuum at 60 ° C. Yield 15 mg.

Analysis calculated for: C .HHjjNgO ^S

51,23%

50,44%

H, 3.80

H4.20

N, 7.03

N, 7.01

8.05%

7.59%

K 9.81%;

K 9.40%.

Example d 182

/ - / - / triois Potassium salt, Z / -3 '(((2-amino-4-thiazolyl // methoxyxino / acetyl) anino) -2-oxo-4-phenyl-1-azetidine sulfonic acid

To a solution of 52 ng of N-hydroxybenzotriazole hydrate and 69 mg of (Z) -2-aino-α-α-η 4 - ((R) -amino) -4-thiazoleacetic acid in 0.3 ml of dimethylformamide at room temperature under argon was added 70 mg of solid dicyclohexylcarbodiimide. the mixture was stirred for 1 hour then ^added was ⁷⁵ mg of ^p EVN ^{e (i)} - ^{(t trans) -.3-amino-2-oxo- 4-phenyl- 1} Aze ^t idinsul sulfonic ^f sel k ^y n ^{y i} (see example 180) and then added dropwise 0.05 ml of triethylamine. the reaction mixture was stirred for 23 hours at room temperature, then it The DMF was evaporated under high vacuum at 30 DEG C., the residue was triturated with 2 ml of acetone and the mixture was filtered, the filter cake was washed twice with 3 ml of acetone each, and 86 ml > of potassium perfluorobutanesulfonate was added. material which, after trituration, washing with acetone and hexane, and drying afforded 82 mg of the title compound.

Analysis: Calculated: C 40.26% -1.36% N 15.55% S 14.33% K 8.1, 74%;

Found C 38.60% -3.9% N 15,. 07% N 13.87% К 7.5% ·

Example 183

(Cis-2-Coo) -7-phenyl-3- (phenynyl-phenylalanine) -1-allylinsulfonic acid potassium salt

A) N-benzylidene-2,4-dimethylaminophenol

To 100 ml of 1N sodium hydroxide solution was added 12.0 g of 2,7-dimethoxybenzylamino-cycloduron.eu and the mixture was extracted with 125 ml of ethyl acetate. The organic layer was dried with sodium sulfate and the solvent was evaporated. to give 10.2 g of 2,7-dimethoxybenzoline as an oil. This amine is dissolved in 150 ml of benzene and 6.47 g of benzaldehyde and 0.6 g of p-tolueneitulonic acid are added to the solution. The mixture is refluxed, equipped with a Dean-Stark water separator and boiled 2 times. hours until the calculated amount of water (1.1 ml) was separated. The reaction mixture is cooled to room temperature. Upon further cooling, some precipitate is formed from the benzene fat. Benzene was evaporated under reduced pressure and the residue was added 60 mL of ^t ruletleru O®. The ultraviolet layer containing larger precipitates was separated. The mixture was stabilized by adding 10 ml of benzene and the remaining precipitate was pressed. Evaporation of the solvent from the filtrate gave 14.2 g of the title compound. · »

B) (N - (C 1 R 3 -phenyl) -1- (2,40-6-methoxy-enninyl-2-oxo-aaidoazztidine)

1.62 g of .alpha.-azidoacetic acid are dissolved in 25 ml of carbon tetrachloride under nitrogen, and 3.24 g. Of triethylllium and 1.02 g. (4.0 mmmo) of N-beeidan-2,7-diethethoxybenzyl are dissolved in 10 ml. ml of methylene chloride. 3.36 g of trifluoroacetic anhydride are slowly added to the mixture while cooling in ice, whereby the mixture turns dark. After stirring for 1 hour under ice-cooling, the reaction mixture was warmed to room temperature and stirred for an additional 15 minutes. The resulting solution was washed with 60 ml of water, twice with 50 ml of a 5% solution of dibasic lydrogel / llltate and 60 ml of 1N hydrochloric acid each. The organic layer was dried over sodium sulfate and the solvent was evaporated to give 1.72 g of crude product as a dark crystalline crystal. This material was decolorized several times with activated carbon and the resulting brown colored material was chromatographed on 40 g of silica gel using a mixture of equal parts of the cartridge and ethyl acetate as eluent. Pooled fractions after rapid intensive cooling in a bath of solid carbon dioxide in acetone to give crystal, which is used to inoculate reinstall the product from ethyl O® ^t ruletleru and ethyl scstátu. 817 mg of the title compound is obtained in the form of deer crystals melting on heating to revenge.

C) (-) - (Cts) 7-ynyl-oxo-3-allyl acetate

737 mg of (-) - (cis) 7-phinyl- (2- (7-chlorophenyl) -2-oxo-3-azieu azetiol are dissolved.

in 25 ml of acetoxniril, the solution is heated to 80-83 ° C under nitrogen, and a solution of 943 mg of potassium persulfate and 570 mg of potassium orthophosphorofuranate in 25 ml of water are added in one hour. After the addition was complete, the reaction mixture was heated at 80-83 ° C for 7 hours, then cooled and adjusted to pH 6-7 by addition of solid potassium pyrophosphate. The reaction mixture was evaporated under reduced pressure and the remaining mixture was extracted with 60 ml. chloroform. The chloroform layer was washed with 60 ml of water, dried over sodium sulfate and the solvent was evaporated. The crude product was chromatographed on 40 g of silica gel using equal portions of the extruder and ethyl acetate as eluent. From the combined fractions containing the desired product, a crystalline material was obtained, which after re-extraction from a mixture of octruletlers and ethyl acetate gave 267 mg of the title compound.

D) Tetrúbutylarununium salt (s) - (cts) 7-enyne - 2-oooзЗ-azedo-1-azeledinsulic acid

162 mg of (-) - (cis) -4-phenyl-2-oxo-3-azidoazetidine were cooled to 0 under nitrogen. and 3.5 ml of about 0.5 M dimethylformamide solution of direthylforraride-sulfur trioxide complex was added dropwise thereto. The resulting clear solution is stirred for 15 minutes at 0 ° C, the puck is poured into 50 ml of a 0.5 M potassium dihydrogen phosphate solution and washed three times with 50 ml of methanol each. . To the aqueous solution was added 292 mg of 3-methyl-4-methylsulfonate (sodium sulfate), and the mixture was extracted six times with 50 ml of MeOH. The combined chlorine layers were dried over anhydrous sodium sulfate and the solvent was evaporated to give 272 mg of the title compound as a gum. Substances.

E) Potassium salt of - (-) - [(4R) -oxo-4-ynyl-4 (2-) - ((phenylacetyl) amino) -1-azetephenesulfonate

293 mg of (4) - (cis) -2-phenyl-2-benzyl-1- (2-benzoyl) -9-methylbenzenesulfonic acid tetaabularimmonium salt are dissolved in 4 ml of ethanol and hydrogenated at 0.1 MPa in the presence of 80 mg of platinum (IV) oxide catalyst. After stirring for one hour, the catalyst was filtered through a porous silica pad. Catalyst particles that pass through the filter will cause the filtrate to turn black. The ethanol is evaporated off under reduced pressure, the residue is dissolved in 4 ml of dimethylformramif, 81 mg of N- (1-hydroxyidene) -oriso-iso-monohorofate, 78 mg of phenylacetic acid and 117 mg of phicylchexylcarbodirif are added, and the mixture is stirred under nitrogen for about 16 hours. The resulting suspension is evaporated in vacuo, the residue is triturated with 10 ml of acetone, filtered through a quartz porous filter, and 193 mg of potassium perflestanisulfate is added to the brown-colored filtrate. After addition of 20 ml of ether, the resinous material precipitated. The liquid fraction was separated, the resinous maacel was washed with ether and dissolved in 10 ml of methanol. A small amount of precipitate formed upon addition of ether. The mixture was filtered and longer ether was added to the colored filtrate. The precipitate formed is recovered and, after recrystallization twice from a mixture of ether and .beta., Yields 26 mg of the title compound.

H, 4.41; N, 6.45%. found 0 47.24% H4.19% Ji 6.34%.

Example 184

Potassium salt / cis, Z4з4 - ((/ memmeo4-2t1hiažoУχlr / methoyyimino / acetyS) rrieo) -2- (4-phenylethyl) 414 -zetidine-sulfonate acid

560 mg of / cis-4-oxo-4-feeyl-3- (trans-ethyl-amino) -1-azethoxydene-enoic acid potassium salt (see Example 184, part D) are dissolved in 5 ml of ethanol and hydrogenated under a pressure of 1 bar. mg of platinum oxide as catalyst. After stirring, the catalyst is filtered through a porous silica pad. The catalyst particles that pass through the film cause the filtrate to become black. The ethanol was evaporated under reduced pressure, the residue was dissolved in 4 ml of dimethylformamide, 168 mg of N-hydroxybenzotriazole-ronoyl dilate, 221 mg (Z) of β-β-pyrimidine with β-t, β-oleic acid and 227 mg were added. mg of ficyclohexylcarbofiriride, and the mixture was stirred in a nitrogen trap for about 16 hours. The resulting suspension was evaporated in vacuo and the residue triturated with 15 mL acetone. The resulting suspension is filtered through a porous filter with a crescent layer and 372 mg of potassium perfluorobutanesulfonate is added to the filtrate. After adding 15 ml of ether-precipitated resin macrrál ^e. The liquid podium is separated off, sputtering. The mixture was washed with ether, dissolved in 5 ml of water and applied to a column of 150 ml of HP-20 resin. The sc column is eluted with water, collecting 30 ml fractions. Fractions 16-34 were combined and lyophilized to afford 201 mg of the title compound as a solid.

H, 3.49;% N, 14.28;% S, 13.07;% K, 7.97%; found c 36.65% H 3.00% N 13.99% S 13.48% K 8.30%.

EXAMPLE ice 185 '(CSS) зЗt _θ isio oxo'4-2 - (2-phenyl ethenyl) -1-acid tzctíd0nsίulfooové

A) N- (3-Phenyl-2-iroicnylidene) -4-methylphenyl

12.32 g of titanium is dissolved in 160 ml of ethylene chloride, 20 g of anhydrous magnesium sulphate are added, and 13.22 g of trans-cintaitidine are added under cooling in ice.

The mixture was stirred under nitrogen for 2 hours and then filtered. The filtrate was evaporated and the solid crude product was recrystallized from a mixture of CH2Cl2 and triethyl acetate. 20.96 g of the title compound is obtained as a solid.

B) (-) - (cis-Iso-1- (4-Methoxyphenyl) -2-oxo-4- (2-phenylthenyl) thiazetidine)

24.26 g of 4-azidoacetic acid are dissolved in 100 ml of chloroform _{. The} solution is cooled in ice and a solution of 48.57 g of triethylamine and 14.24 g of N- (3-phenoxy-2) is added. 4-iodo-2-ol in 250 ml of carbon tetrachloride. 50.41 g of trifluoroacetic acid anthyride were added dropwise over 1 hour to the resulting network. After stirring for 1 hour under ice-cooling, the mixture is warmed to room temperature, stirred for about 16 hours, then diluted with 250 ml of methylene chloride and washed successively with 750 ml of water, twice with 750 ml of 5% NaHCO3 and 750 ml of 1N HCl. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The solid crude product afforded 11.39 g of the title compound as a solid after recrystallization from ethyl acetate.

C) (-) - (cis) -3-azido-2-oxo-4- (2-bromo-2-oxo-4-) azide

To a solution of 10.22 g of cerium (III) nitrate in 13 ml of water at 0 ° C was added a solution of 1.99 g (1%) of (4-methylphenyl) -2-o-o-4- ( 2-pholylcoyl) 126X (1) in 65 ml of teto-acetonitrile (another 10 ml is used to rinse the above solution. The mixture is stirred at 0 ° C for 15 minutes, then diluted with 750 ml of ethyl acetate, washed six times with 600 ml each. The crude oil was chromatographed on 90 g of tiliktecium, eluting first with 250 ml of 30% ethyl acetate in petroleum and then with 50% acetonitrile in triethylamine. Collect fractions of 50 mL Fractions 11-16 were pooled and stripped to give 802 mg of the title compound as an oil.

D) (-) - (cS) t-O-oxo-4- (2-methyl-ethyl) -1-azelate-tert-sulfonic acid tert-o-butythioic acid salt

334 mg of (R) - (CTS) зЗtzií0o-2-oxo-4- ^(2-f eillctlciyl) in tzctiíinutc rozpuutí. 3 ml of dimethylformamide was added and 868 mg of pyridine-sulfur trioxide coramlex was added to the solution. The mixture is stirred under nitrogen at room temperature for 40 hours, then poured into 200 ml of a 0.5 M solution of potassium phosphate dibasic and treated with 30 ml of hydrogen chloride. To the aqueous solution was added 530 mg of tert-o-butyl, mono-haloalkyloosulfate and the mixture was extracted four times with 50 ml of methylene chloride each time. The combined organic layers were washed twice with 100 ml of water each time, dried over anhydrous magnesium sulphate and evaporated. 824 mg of the title compound is obtained as a gum.

E) (-) - (cis) zZ-azido-2-oxo-4- (2- (trifluoromethyl)) -1-thiazidine sulfonic acid

300 mg of (1) - (ct) -benzidido-2-oxo-4- (2-phenoxy) -1-azetosulfonic acid tert-n-buitonium salt are dissolved in 4 ml of orthotrophilia and the solution is dissolved in With vigorous stirring, 600 mg of zinc dust was added first, followed by 0.8 ml of an iN potassium dilyl phosphate solution. The mixture is heated to 45 ° C for 3 hours, then filtered and the filtrate is taken up in 10 ml of water and 40 ml of methylene chloride. The aqueous layer was extracted three times with 40 ml of methylene chloride each time and the solvent was evaporated from the combined methylene chloride layers to give 256 mg of a pan-like residue. This crude product was dissolved in small amounts ^of 30% acetone in water and deposited on the ^p ou ^l ec ^7.5 ml tontoměn ^ e Dowex ^{(K +)} (0.7 meq / ml), which was eluted with 40 ml water. Evaporation of the eluate yielded 151 mg of the bovine residue which was dissolved in 2 ml of water and acidified to pH 2 with 1N HCl. To dissolve the precipitate, a small amount of acetonitrile was added and the resulting solution was applied to a 15 ml HP-20 resin. elute first with 150 ml of water and then with 10% acetone in water. Fractions of 15 ml are collected. Fractions 2 to 13 were combined and evaporated to give 101 mg of the title compound as a foam.

Example 186

(-7-) cis, Z] -3 - (((2-Amino-4-thiezolyl) methoxyimino / acetyl) amino) -2-oxo-4- (2-phenylethenyl) -1-ezetidine sulfonic potassium salt acid.

To a solution of 68 mg of (Z) -2-amino-.alpha .- (methoxyimino) -4-thienolacetic acid and 51 mg of N-hydroxybenzotriezole monohydrate in 2 ml of dimethylformamide was added 69 mg of dicyclohexylcarbodiimide. The resulting mixture was stirred under nitrogen at room temperature for 30 minutes. 90 mg of (CIG) -3-raisin-2-oxo-4- (2-fenylehtenyl) -1-azetidinesulfonic acid (see Example 185) and 34 mg of _{triethylamine>} and the mixture was stirred for 20 hours under nitrogen. The resulting suspension is evaporated in vacuo, the residue is triturated with 10 ml of acetone, filtered and 113 mg of potassium perfluorobutanesulfonate are added to the filtrate. After dilution with 30 ml of ether and filtration, 169 mg of solid product is obtained, which is dissolved in a small amount of about 10% acetone in water and applied to a column of 4 ml of HP-20 resin. The column is eluted first with 150 ml of water and then with a 15 ml fraction. Fractions 16-10 combine the title compounds as a solid

10% acetone in water was collected and the solvent was evaporated, yielding 110 substances.

mg

Analysis: for C ^ YHH gOONNS ^K. HgO calculated

40,23%

40,03%

H 3,50%

H 3,05%

N 13.80%

II 13.61%

12,63%

12,31%

K 7.70 K;

K 7.56%.

EXAMPLE d 187 (cis) -3-Amino-4- (methoxycarbonyl) -2-oxo-1-ezetidine sulfonic acid

A) (4-Methoxyphenyl) imino) acetic acid methyl ester

To a dried three-necked 1 liter flask equipped with nitrogen inlet and mechanical stirrer 3e was charged 56.88 g of magnesium sulfate and then a solution of 19.43 g of recrystallized anisidine in 250 mL of dichloromethane. After cooling to 0 ° C, a solution of 19.92 g of methyl glyoxylate hemiacetal in 250 ml of dichloromethane was added to the mixture over 1.5 hours. The reaction mixture is stirred at 0 ° C for 20 minutes, then filtered off with suction, the filtrate is dried over sodium sulphate, filtered and concentrated in vacuo to 1/4 of the original volume. Hexane (300 ml) was added and the solution was concentrated to an oily residue which solidified partially upon standing under high vacuum at 5 ° C. ’

B) (cis) -J- (1 ^ - ^ (^: ^ H ^ ^{t ^!} ^ ^C ^ '1, 3-dioxo-2H "isoindol-2-yl) -4-methoxypyrimidine-2 xykarboínyl Oxo-1- (4-methoxyphenyl) azetidine

A dry 500 ml three-necked flask equipped with a stirrer, dropping funnel, drying tube and nitrogen inlet was charged with a solution of 21.09 g of (4-methoxyphenyl) imino) acetic acid methyl ester in 150 ml of dichloromethane and cooled to 0. ° C over 1 hour, firstly 19 * 2 µl (0.14 mol) of trithylamime was added dropwise, followed by a solution of 28.4 g of (N-phthalido) acetic acid chloride in 150 µl of dichloromethane. The resulting mixture was stirred at 0 ° C for 1.5 hours, diluted with 2.5 L of dichloromethane, washed with 500 mL of potassium dihydrogen phosphate (pH 4.5) twice, 500 mL of 5% bicarbonate twice each. NaCl, and finally 500 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The solid residue was washed with ethyl acetate, cold acetone and hexane to give 18.65 g of the desired product.

C) (c is) -4- (Methoxycarbonyl) -1- (4-methoxyphenyl) -2-oxo-3- (((phenylmethoxy) carbonyl) amino) azetidine

18.65 g of (cia) -3- (1,3-dioxo-2H-ioindol-2-yl) -4-methoxycarbonyl-2 are charged to a dried 500 ml flask equipped with a nitrogen inlet, stirrer and drying tube. oxo-1- (4-methoxyphenyl) azetidine and 325 [mu] l dichloromethane. The resulting suspension was cooled to -30 ° C and 3.52 mL of methylhydrazine was added dropwise. The resulting mixture was heated to 0 [deg.] C., stirred for 1 hour, an additional 0.4 [mu] l of ethylhydrazine was added thereto, and stirring was continued for 10 minutes. This process was repeated until a total of 2.9 equivalents (7.7 mL) of ethylhydrazine was added. The solvent is removed in vacuo, 200 ml of fresh dichloromethane are added and the mixture is again concentrated. This procedure is repeated two more times. The resultant pan product was dried under high vacuum for 20 minutes, then redissolved in 225 mL of dichloromethane and allowed to stand at room temperature for about 16 hours, during which time an easy amount of solid material precipitated from the solution. The mixture is filtered under nitrogen / the filtrate is cooled to 0 ° C under a due atmosphere and 17 µl of diopropylethylamine are added dropwise thereto, followed by 7 ml of benzyl chloroformate. The reaction mixture is first stirred at 30 DEG C. for 30 minutes and then at room temperature for 1.5 hours, washed successively with 300 ml of potassium dihydrogen phosphate buffer pH 4.5, twice with 300 ml of 5% sodium bicarbonate solution and 300 ml each. ml of saturated sodium chloride solution, dried over sodium sulphate and filtered. Concentration in vacuo gave a panic residue which, after trituration and ether, afforded 9.9 g of the title compound as a solid.

D) (cis) -4- (N-methoxycarbonyl) -2-oxo-3 - (((phenylmethoxy) carbonyllamino) -1-asetidine

To a solution of 8.59 g of cerium ammonium nitrate in an equal volume of acetonitrile and water (60 mL) was added a suspension of 2 g of (cis) -4- (methoxycarbonyl) -1- (4-methoxyphenyl) -2-oxo-3 over 10 minutes. - ((/ phenylmethoxy / carbonyl) amino) azetidine in 50 ml acetonitrile. Reaction. The mixture was stirred for 10 minutes at room temperature, then diluted with 100 [mu] l of ethyl acetate, the separated aqueous layer was washed three times with 40 ml of ethyl acetate and the combined organic extracts and washed three times with 70 ml of 50% sodium bicarbonate solution.

The basic wash liquors are shaken with 50 ml of ethyl acetate and the combined organic extracts are washed with aqueous sodium sulfite solution, 100 µl of 5% aqueous sodium carbonate solution, twice with 100 µl of 5% sodium chloride solution and twice with 50 µl of saturated sodium chloride solution each. minutes with activated carbon (Dareo G-60). Sodium sulfate was added, the mixture was filtered and the filtrate was concentrated in vacuo. The oily residue afforded 685 mg of the title compound as a solid after trituration with ether.

E) Tetrabutylanonium salt of -4- (methoxycarbonyl) -2-oxo-3 - (((phenylmethoxy) carbonyl) amino) -1-azetidine sulfonic acid

A mixture of 100 mg of (4 - [(4-methoxycarbonyl) -2-oxo-3 - (((phenylmethoxy) carbonyl) amino) -1-acetamide) 172 mg of pyridine-sulfur trioxide complex in 1 ml of pyridine and stirred under argon for 3 hours at 80 ° C. The reaction mixture was poured into 70 [mu] l of a 0.5 M potassium dihydrogen phosphate solution (pH 5.5) and extracted four times with 30 ml of dichloromethane each time. These extracts ее work. 122 mg of tetrabutylammonium hydrogen sulfate were added to the aqueous layer, and the mixture was extracted four times with 30 l of dichloromethane each. The organic extracts were washed with 8% sodium chloride solution, dried over sodium sulfate and filtered. Concentration in Khkuu ae gave 186 mg of the title compound as a viscous oil.

F) (cis) -ZH 3 -Ou-4-lOuO: yrktra-nL) -2 - () - 1-yellowfluoronic acid

A solution of 166 mg of eetrabutyric acid selenium (4-) - (methoxylbutyl-L-2-oxo-3-phenylphenyl) trans-trifluoromethyl-1'-trifluorophosphonic acid in 2 ml of methanol and dissolved in methanol ^. The catalyst was filtered off, rinsed with H2 O, to the filtrate and 97% formic acid was added and the mixture was stirred for 30 minutes. ^ l ^ la ^DI at -50 ° C ^(to induce crystallization at this point třdta solution inoculated toystalem authentic material). After crystallization commenced, the mixture was allowed to stand at ¹⁰ ° C for about 16 hours. Vfsle solid aateriál ^ ee ^ рто У ^ ^d ichlorrethenem and taxane off and dried in vacuo benzothiazepine ee gave 50 mg of the title compound.

He called himself d 168

(Cis) - 3- (C (2-Trincu-3-thiazol-yl) potassium) (C (4 - (phenylyl) - (-) - cyclohexyl) -1-methylthio (1-amino) ethyl) amino) -4- (trifluoromethyl) -4- (cyclohexyl) potassium N-2-oxo-1-azidanedulphonic acid

To a solution of 34 mg of N-Oydro-2-oxalazurothiazole hydrate and 101 mg of 2-aminobutyl-((1-phenoxy) oxo-4-cyclohexanediol) -4-oxo-4-azulacetic acid in 0.5 ml of dimethylsulfonate was added 45 mg of solids. under argon at 45 ° C for 45 minutes, then 45 mg of solid (> cit) -3-ω-4- (4-trifluorocarboxylic-2-uxu-1-azltidanediol) -fluonic acid (see Example 187) was added first and then The mixture is stirred at room temperature for about 16 hours, then the dimethylphosphate is evaporated.

high vacuum at temperatures of 3 ° ^C and ^T r is about ^to triuruje and acetone. ^{K? K} EP <n ^{j Eli} supernatant was added 67 mg of potassium ItfluurautaatULfuaátu *. Dilution with ether gave a solid rate which, after washing with ether and drying in vacuo, yielded mg of compound. - in title

Example 189

Trisodium salt of cis- ~ 3 - ((1'-amino-4'-thizisolyl) -1 H -oxox-1-oloyl 100-oxo) imidyl) amino] -4- (1'-amino) -4-oxo-2-carboxylic acid -1-tlltidin8ufuanoic acids

For potassium suspension Н / -38 / -3l ((/ t-wno-4-0hta-oУyl / 1 ((f / di0lLmleιe00oJlrktraocοl) -1' -reethylethoΐφΗ-Ιηο Catclyl) emino C-4- / re1U0ocχlarraual / -2- 1 -xo-Aze-tidin8uf0on ▼ ⁰ acid methyl ^ester, 4- ^(l aoisdu stirring under dog BC t ^ lo ^ - ¹² ° ^C Example 0 ^{gives 9} ml fuoro tr ^f <> coov ^E mixture of ¹ ^ lation to - ¹⁰ ° C. for ^{1.5 h p} Odia the straight-Aji 4 ml of ether and 2 ml of hexane sends ^f n e ^and the suspension stirred for ¹⁵ rinut BC pulse ^^ - ¹⁰ ° C, and ^{p 1} and 5 rinut BC TLPL t ^j to ^{c o u} a solid product was centrifuged and the pro-L is the ether. raaeerél This was suspended in 0.5 ml of cold water, the pH was adjusted with 1N draseliým aa = 6, and the mixture is applied to a column and and 30 ml of resin The column was eluted with water, the eluate was evaporated, the residue was treated with CH 2 Cl 2, and the mixture was re-evaporated to give the title compound (30mg) to give the title compound (30mg).

A ^ is an analysis for C ^

C 31.15 H 2.81 N 12.98;

found C 29.08 H 3.03 N 12.19.

Example 190 (S) - (trans) -4-Methyl-4-trans-2-ox-1-trans-monoanonic acid

Crimped 50 ml flasks, flame-dried and kept under flame

244105 ´86 of nitrogen, 20 ml of dry tetrahydrofuran, 2.20 ml of trimethyl-bilylacetylene and 5.05 ml of a 3.06 M solution of methylmagnesium bromide in ether are introduced. The title compound is obtained from the mixture after stirring for 140 minutes.

B) (S) - [(4- (2- (trimethylsilyl) ethyl)) 22-oxo-3 - ((triphenylsulfonyl) amino) azetidine

A 250 ml three-necked flask, dried over a flame, is charged with 6.00 g of (S / - / cls / -4-m-hexylphenyl) -2-oxo-3 - ((tinynylmethyl) / 6flo) azetide. The flask is purged with nitrogen and then kept under positive nitrogen pressure. under cooling in a bath of cardice oxdiem ulhLlčitm in isopropanol ^to a ^{b h} is at ^least ba alkyl vigorous stirring via a syringe Phka ^ St ^ KACT 4.65 ml of 3.06 solution of methylmagnesium bromide in ether. Teflon a solution of 2- (trimethylsilyl) ethyl amine prepared in paragraph A (a flask containing this reagent was rinsed with 7 mL of tetrahydrofuran) was added via a nitrogen overpressure tube, after which the cooling bath was removed and after 45 minutes a solution of 3.5 g of potassium hydrogen sulfate was added. The residue is taken up in a separatory funnel using ether and water, the aqueous layer is separated and extracted twice with ether. The combined ether layers were washed once with saturated aqueous sodium chloride and dried over sodium sulfate. The solution was evaporated and the foam residue was chromatographed on a silica gel column. Column elution with 2 liters of dichloroethane, 2 liters of 2 »ether in dichloromethane and 1.5 liters of 10» ether in dichloromethane (fraction 1 000 ml, fractions 2 and 3 500 ml), from fraction 4 ai to the end of the column. 250 ml fractions were collected, 1.30 g of the title compound were obtained in fractions 2 and 18 and 1.80 g of the trans-isomer fraction in fractions 12 and 19, respectively. Fractions 9 and 11 contained 1.19 g of cis-a mixture

C) (S) - / tmlз / 44ittliyill-2-ooo-3 ((/ triphenyl)} (/ mifu) azetidif

2.97 g of (S) - / tan / 44- (2-triethyll-3-ethyl-ethynyl) -U-ouo-3 (( triphenylmethyl) -ylamin-azazidine are dissolved in 30 ml of dichloromethane and 330 mg of titrabutylmunlumine are added to the solution. After 20 minutes, the solvent was removed in vacuo and the residue was taken up in ethyl acetate and water. The org. phase was separated, washed once with water and once with saturated aqueous sodium chloride solution, dried over sodium sulfate and filtered. The solvent was removed by evaporation and the oily residue was stirred with 60 ml of pentane for 15 minutes to give 2.35 g of the title compound as a powder after drying in vacuo.

D) (S- (trans) -3-Mino-4-ethynyl-2-fluoroazazoline-5-fluorophenoic acid

To a flask was charged with 25 ml 404 mg / S / - / raадi / ^-4-ithiiyl, -2-uxouЗ - ((trifinplmθthy1 / aminophenyl) aazeidinu and 560 mg of pyridine-sulfur trioxide complex. The flask was purged with nitrogen, add ^with e her ⁴ 0 ml of dry ^ ^ ridin mixture for 3 ^{h <y} ^ JLN zdtfívá ⁸⁰ to ⁸⁵ ° C and then added to a vigorously stirred mixture of 4.0 ml of concentrated hydrochloric acid, 50 ml water and 50 ml The pH was adjusted to 3.15 with sodium carbonate, the aqueous layer was separated and extracted once with ethyl acetate, the combined organic layers were washed once with saturated aqueous sodium chloride solution, dried over sodium sulfate and filtered, and the solvent was evaporated in vacuo, foamed. the residue is taken up in 10 ml of dichloromethane, 8 ml of 98% formic acid are added, after 15 minutes the mixture is concentrated to a volume of 4 ml and 10 ml of ethyl acetate are added to give a solid suspension in solution. listed in the title, in the form of pe An aqueous substance which, when determining the melting point, is noticeably discolored and melts above ¹⁸⁰ ° C.

Example 191

Potassium salt of (3S- (3eafa (Z), 4butyl)) - 3 - (([2- (2-amifo-4-thiazulyl) methyl] imino) -4-ethyl] -2-oxo-1-azeililizole acid

Weigh 100 mg of (Z) -2-emifo-alpha- (methoximino) -44-thiazole-87-acetic acid, 85 mg of N-hydroxybenzoforazole-1-nitrate and 113 / g of di-chloro-4-carbonyl chloride in a 10 ml flask. The flasks were flushed with nitrogen, treated with ice-water, 0.6 ml of diethyl ether were added, the mixture was stirred for 10 min. The reaction mixture was stirred for an additional 0.6 .mu.l of dioethylforoaoide. To the resulting mixture was added 95 µg of solid (R) - (0annt) α-1 H -indol-44-trifluoromethyl-1- (1-azetidiosulfonic acid) (see Example 191), along with 1.0 µL of diethylglyphthamine. / ul trtet1yL1otcu. The cooling bath was mixed with 22 ml of acetone for 22 hours, 3 ml of acetone was added thereto, and the solids were washed with another 4/1 of acetone. All solvents were removed in vacuo, the residue was taken up in 5 ml of lethool and 162 g of potassium perfluorobutyotulfnoate was dissolved in this solution. A solid product is separated from the standing and isolated by decanting. ZIS ^Ka is 68 ^{/ g} of the title composite tyjící NID ² 3 ⁰ ° ^C Example 192

Potassium salt /// - (((/ (3) dtCHc01phenylphenyl) thienyl) allyl) -n-ono-) 1zettddsusuOutonate

100 mg of aa / inoo2-oxo-1-azididine sulfonate acid are dissolved in a mixture of 2 / L of sucrose and 0.083 / L of treetlylimic acid. Was added 123 mg (0 _t 602 m / oo) -, 5-dicHlnrftn! TLI acetic Kyss-Ins, 81 / g of N-HldroJgrУetoo0r0azol-Hidrátu and 124 mg diclk1nHto1karbndii / sulfide, and the resulting S / EC Aichi first for 2 hours at Low: 14 ° ^C. Dissolution ^ / DLO is € ^ i ^ ^{1i: Even} in wadding, unnecessary diatomaceous ⁰ / ETIO of the filtrate / Ethyl acetate ije TEM 612 / g-tetrabutyloicoiuo Hydrogenosufátu i ni value of 3. So / S is extracted three times with dichloro (ethineo, the combined extracts were dried with sulfur) and the solvent was removed from ppi! under vacuum. The oily residue is taken up in acetone and this solution is added to an acetone solution of 612 / g potassium p-trifluorobutyl sulphate to precipitate the product. After addition of a small amount, acetone is dried and dried. Obtained at rístnossi and peak 2 days at room temperature is taken up in water onotn ^to from ^filtered through aqueous layer was treated with dichloro / ethaneo added pH IN potassium hydroxide solution adjusted ether, the solid dter ^ i ^ JL oddfltruje, cěkooi206 / g práškovatého product.

se

Alialysis: calculated for CHHgNgO ^CigClK

31,21%

27,90%

H 2,14%

H2.11%

.66.62 »N 5.84% cl cl

16.75%;

18.04%.

Example d 193

Potassium SU / and / -to1nt-3- (((/ ^2, 5-dic1loffeoyl / 1iOoaaceУ1laoιinn) -4- / etHУ .-- · • oxool diotulfonoít acid

250 / g of (3S-tr1nt) -Зa | LiCN-4 / Et] HУ1 --- non-1-azttid0nsufnnnoí ^t ester (see Example 138) was onzpuutí in 2 ml of di / etHylfomecidu obsehtuícílo 193 / U1 triethyl mine . 213 mg of N-Hdro2Qrietoonr Oazol-Hydrochloride 287 / g are added. The mixture was oddly stirred at room temperature for about 16 hours, filtered and the solvent was removed in vacuo. The residue is taken up in water, the solution is filtered, the filtrate is washed with ethyl lotate (4.2 ml of ethyl ether) and 4.2 ml of tetrrabuccinone / hydrogen sulphate are added. After a total of frictional extractions of dichloromethane and ethyl acetate, the combined extracts were dried over sodium sulphate and the solvent was removed in vacuo. 920 g of an oily residue are obtained, which is dissolved in acetone and 946 g of perfluorobutyl sulphate are added to the solution dissolved in acetone. The solid was precipitated (1: 1), which was filtered off, dried twice. 306 g of a powdered product is obtained which is chromatographed on a 100/1 column of HP-20. Elution with a mixture of 20% ethyl acetate in water yields a radiolabelled product which is stylized after stripping off the mixture with water. Tritution of the residue with acetone yielded 233 g of a powder melting from solution. ²¹² DEG- ²¹³ DEG.

Analysis calculated for CjNjN ^O ^CloSoK ββ: C, 32.95%; H, 2.54; N, 6.41; Cl, 16.21; N, 14.66. Found: C, 32.91; H, 2.60%; 50% S 13.77

Example 194 to 195

The procedure was analogous to that in Example 137 except that (3S-trans) -3-amino-3-amino-3-amino-4-nitro-2-oxo-1-azetidine sulfonic acid was used 4-methyl-> 2-oxo-1-azetidinesilic acid and in place of (Z) -2-amino-α- (non-pyrimidino) -4-thiazoleacetic acid, the corresponding acid listed in column I of the following table *. The compounds listed in column II of this table are obtained

I substance

II Product

194 (R) - (Amino-oxoacetyl / 8-quino) (4-hydroxyphenyl) -acetic acid

195 / R / (((io 10 -oxoacatyl / thmioo) phenylacetic acid potassium salt (3S- (3alpha / H * /, 4bete)) -3 - (((/ asino) A-hydroxy (methyl) amino) amino)) 4-Methyl-2-oxo-1-azetidine sulfonic acid draMLalato ((U, 4 ', 4'MbbtaO 4 -CU (aminooxoationyl) (imiool) toluyl) amino) -4-mehrl-2-oxo-1-azetidine sulfonic acid tyselioy, melting with decomposition at 187 ° C

Ex. 196

Potassium salt ^(3S / R /) - X ^((/ ^ aminooxxacc ^e y ^y / ^m ш NO) / 4 lhrddrxχfmyL / ^{methyl) amino) -2-oxo-1} -asetidineulfonové acid

The procedure is analogous to that in Example 28, but with the difference that, instead of (Z) -2-amino-alpha - ((2- (diphoyylmethoxy) -111- [imidium] -) - - - - - - - - - 4-thiazol-4-yl] -4-thiazoleacetic acid used (R) - ((mono-oxoactyl) amino) - (4-hydroxyphenyl) acetic acid. The title compound melted with decomposition at 128 ° C.

Example 197

Draaelrá (3S ^/ R ^{/ S)} -3 - ((/ 2 Éminoc44thiazal ^cyyL ((3 - (/ 2 ^- ^^ ^tt hl·lV'aиino ^.m) -2-cxo- UimidazoCldilor ^s) ka ^ av (1) amino) acetyl) amino) -2-oxo-1-azetidine-1-fluoro-acid

When the same procedure as in Example 6, ie instead alíinoCtЦazzCoctové acid pzužije / R✓ --- aminooaa and £ - (((- (/ 2lfurιnlyLлetlhr ^y O! N2aamαo) -220cx imadaaoCLdi-1] -yl) karbocylL ) aιino) -44tih.azzlocicvl tysalioa. This gives the title compound, melting above. 250 ° C.

Biological efficacy

Minimáání. The inhibitory concentration (MIC) of the beta-lactones of the invention is determined as follows.

The test organisms are grown in test tubes for about 15 to 20 ml of antibiotic test medium (AOtbiztic Assy broth; Difco). The soil is inoculated with the eye of the organism taken from it. . Dilute agar (BHI; Difco). The test tubes were 18 to 20 hours. iokubnijí. at 37 ° C. the ^'Z ^ s aahují cultures produced in miHll Tru-10® colony forming units (CFU).

Zdíslraoé bHtru ¹ zřetH SOLUTION ask ^ m ^ ¹⁰ ° K in a ratio of ^{1: 100} FILO OA & alpha tonccnOnci .ookul ¹ 10 ⁴ CFU.

Test compounds are dissolved in a suitable diluent and a solution of Πόο ^ ηΟΓβο. 1000 µg / ml. This stock) was serially diluted twice with K-10 medium and doubled to give a series of concentrations from 100 ° _/ µg / ml to 0.5 Ag / m 2. Each 1.5 ml - of each of these preparations was added to separate ^ tt ^ Vex Cove Fetriho shell ^{1 d} of the Oiz ^{p Class 13,} 5 mL of ³⁰ ^ clones Igar. Focal concentrations of the test substance in agar are coated from 100 µg / mL to 0.05 µL. Before and after the test plates, control plates containing only the agar medium are prepared and calibrated. On the surface of each plate to test for organisms ipUkijí poubžtí culator which dispenses approximately 0.001 ml agar limbs ^{p j} e ¹⁰⁴ CFU.

. ^ ΠΗ ^ οί ^ Establishment of Denley Muutipoiot Even if lioallo concentration iookULi on the surface

Floto ¹ .okububi ¹⁸ hours at ³⁷ ° C oa ^p e ^z is ťtanoví todnoty MIC is oejnižěí konccnOraci test compound at Oiz dodhází к organism ^M IC. io ^ ibLc :) growth value

o) The environment of K-10 has the following composition:

XX) K-10 agar has the following composition:

beef extract 1.5 G yeast extract 3.0 G pept ^ 6.0 G dextroai 1.0 G Distilled water d ^ o ^ pL ^ O.t. to 1 liter beef extract 1.5 G yeast extract 3.0 G pept ^ 6.0 G dextrose 1, o G agar 15,0 .. G Distilled water d ^ o ^ pL ^ O.t. to 1 liter efficiency tests beti-laklmiu according to

The results of the invention for various organisms are shown in the following tables. The number given by the name of each organism corresponds to that of the organism in the collection of ER Squibb & Sons, Ioc., Priocetoo, New Jersey. (-) indicates that the compound exhibits konccnOraci 100 _/ ug / ml against přísUuOuéámu organism no effect. The * NT symbol indicates that the test has been performed in the present case.

MIC values (/ µg / ml)

Organism

1 3 5 6 Staphylfefeeut aureus, 1 276 1.6 6.3 1.6 12.5 Staph1lfefcebt lureus, 2 399 1.6 6.3 0.8 6.3 Stalhylfefceut lureus, 2 400 3.1 3.1 1.6 2,5 Stalh1lt · eteeut lureus 10 165 12.5 3.1 6.3 25 Streltocfcebs laecalis, 9 011 - - - - Streltocfccus agalactiie, 9 287 3.1 25 0.8 6.3 Ero.eroefeebs luteus, 2 495 6.3 50 1.6 50 ExchteiehLl cooi, 8 294 50 - - - ΕιοίΜΓϋ ^ ι cooi 10 857 100 ALIGN! - 25 - XacehtichLa cooi, _L 10 896 25 - - 100 ALIGN! EscchriclhLa cooi, 10 909 25 - - 50 Oeteiella eerogenes, 10 440 100 ALIGN! - - -

Cont. tab.

Organism HIC values (/ µg / ml)

The product of Example 6.

J 3 5 6

Klebsiella pneumoniae, 9 527 100 ALIGN! - - - Próteus mirabilis, 3 855  - - - 100 ALIGN! Próteus rettgeri, 8 479 25 100 ALIGN! 12.5 Próteus vulgaris, 9 416 - - 25 - Salmonella typhoaa, 1 195 50 - - 100 ALIGN! Shigella sonnei, 8 449 50 - - - Enterobacter cloacae, β 236 - - - - Enterobacter aerogenes, 10 078 - - - - Citrobacter freundii, 9 518 - - - - Serratia marcescens, 9 783 100 ALIGN! - - 50 Pseudomonas _t aeruginosa, 9 545 100 ALIGN! - - - Pseudomonas aeruginosa, 8 329 - - - - Acinetobacter calcoaceticus, 8 333 - - 100 ALIGN! Organism 7 MIC values (/ µg / ml) Product of Example 8 9 10 Staphylococcus aureus, 1 276 3.1 6.3 3.1 3.1 Staphylococcus aureus, 2 399 3.1 3.1 6.3 3.1 Staphylococcus aureus, 2 400 6.3 6.3 6.3 6.3 Staphylococcus aureus, 10 165 12.5 12.5 25 12.5 Streptococcus faecalis, 9 011 - - 100 ALIGN! 100 ALIGN! Streptococcus agalactiae, 9 287 1.6 6.3 3.1 3.1 Micrococcus luteus, 2 495 6.3 12.5 3.1 6.3 Escherichia coli, 8 294 - - - - Escherichia coli, 10 857 100 ALIGN! 100 ALIGN! 100 ALIGN! - Escherichia coli ,; 10 896 100 ALIGN! 100 ALIGN! 100 ALIGN! - Escherichia coli, 10 909 100 ALIGN! 100 ALIGN! 50 - Klebsiella aerogenes, 10 440 - - 100 ALIGN! - Klebsiella pneumonae, 9 527 - 100 ALIGN! - Próteus mirabilis, 3 855 100 ALIGN! - 50 - Próteus rettgeri, 8 479 100 ALIGN! 50 50 - Proteus vulgaris. 9 416 100 ALIGN! - 100 ALIGN! 100 ALIGN! Salmonella typhosa, 1 195 100 ALIGN! - 50 - Shigella sonnei, 8 449 100 ALIGN! - 100 ALIGN! - Enterobacter cloacae, 8 236 - - - - Enterobacter aerogenes, 10 078 - - - - Citrobacter freundii, 9 518 - - - - Serratia marcescens, 9 783 100 ALIGN! 50 -. -

Organism 7 Values Product 8 MIC (uµg / ml) from Example n » 9 10 Pseudomonas aeruginosa, 9 545 25 100 ALIGN! 25 100 ALIGN! Pseudomonas aeruginosa, 8 329 - - - - Acinetobacter calcoaceticus, 8 333 - - - -

Organism HIC values (^ jg / ml)

The product of Example no.

12 13 14 15 Dec Staphylococcus aureus, 1 276 12.5 25 12.5 100 ALIGN! Staphylococcus aureus, 2 399 6.3 25 6.3 50 Staphylbcoccus aureus, 2 400 6.3 12.5 6.3 50 Staphylococcus aureus, 10 165 - - . - 50 Streptococcus faecalis, 9 011 100 ALIGN! - 100 ALIGN! - Streptococcus agalactiae, 9 287 1.6 12.5 1.6 12.5 Micrococcus luteus, 2 495 1.6 25 0.8 50 Escherichia coli, 8 294 0.4 25 0.4 - Escherichia coli, 10 857 0.8 50 0.8 - Escherichia coli, 10 896 ´, 6 50 3.1 - Eschirichia eoli, 10 909 0.4 25 0.2 - Klebsiella aerogenes, 10 440 0.4 25 0.4 - Klebsiella pneumoniae, 9 527 0.1 12.5 0.2 - Próteus mirabilis, 3 855 0.2 12.5 0.1 - Próteus rettgeri, 8 479 0.05 1.6 0.05 - Próteus vulgaris, 9 416 0.4 25 0.1 - Salmonella typhosa, 1 195 0.1 12.5 0.05 - Shigella sonnei, 8 449 0.4 25 0.8 - Enterobacter cloacae, 8 236 0.4 - 0.4 - Enterobacter aerogenes, 10 078 0.8 100 ALIGN! 0.8 - Citrobacter freundii, 9 518 3.1 - 3.1 - Serratis marcescens, 9 783 12.5 - 3.1 25 Pseudomonae aeruginosa, 9 545 0.8 50 0.4 50 Pseudomonas aeruginosa, 8 329 .12,5 - 12.5 - Acinetobacter calcoaceticus, 8 333 25 - 100 ALIGN! 50 Organism Values MIC (/ Ug / ml) Product from Example 6. 16 17 18 Staphylococcus aureus, 1 276 3.1 12.5 50 Staphylococcus aureus, 2 399 6.3 12.5 50 Staphylococcus aureus, 2 400 12.5 12.5 25 Staphylococcus aureus, 10 165 12.5 12.5 50 Streptococcus faecalis, 9 011 - - - Streptococcus agalactiae 9 287 6.3 6.3 50 Micrococcus luteus, 2 495 25 25 100 ALIGN! Escherichia coli, 8 294 - - - Escherichia coli, 10 857 - - - Escherichiaccoli, 10 896 100 ALIGN! 100 ALIGN! - Escherichia coli, 10 909 100 ⁴ 100 ALIGN! -

ΡοΜγ. teb.

Organism

MIC values (yu ^ ml) Example product δ ·

17 18

K.θtatθlle eerogenes, 10 440 - - - B.lbatelle p ^ <^ iu ^ oo0i ^ <i, 9 527 - - - Próteus miaeaiit, 3 855 100 ALIGN! - - Próteus rettgeri, 8 479 25 25 - Próteus vulgaris, 9 416 100 ALIGN! - - Slřmounelř eyahose, 1 195 100 ALIGN! - - ShOggHe s-Innnl 8 i 449 - -. - ' Ε ^ ιγ ^ ζο tsr cl-ecel 8 236 - - - Ει ^ ιγ ^ ο ^ γ alrogen · a, 10 078 - - ^ γ ^^ ιγ fnundi, 9 518 - - - S ^ i ^ r? R ^ l ^: ie marcesceae, 9 783 100 ALIGN! 6.3 100 ALIGN! eerugiaota, 9 545 25 50 50 Pslud-monas aeru ^: 8 329 - - 100 ALIGN! Αοϊοι ^^ αοίβΓ ticus, 8 333 - 6.3 -

Organism MIC values (C / UE / oI) Product from the example δ • 19 Dec 20 May • 21 22nd SeeaOlloοoccue eunus, 1 276 25 3.1 12.5 50 StaaOyloο-οcue sunut, 2 399 12.5 3.1 1’2,5 100 ALIGN! Seaahyl-c-οcue hureus 2 400 12.5 3.1 12.5 100 ALIGN! Seaa0lloc-ccue'hureus 10 165 12.5 6.3 100 ALIGN! 100 ALIGN! Sereat-coccue felcaeit 9 011 - . - 100 ALIGN! - Streatocoοcue адаеасим, 9 287 12.5 3.1 1.6 12.5 1ιΗ1sme, 2 495 50 6.3 6.3 50 EachoeicOie c ^ oi 8 294 - 25 0.8 - Eschoeichie coM, 10 857 - 25 0.8 100 ALIGN! Eschoerchie cooi, 10 896 - 12.5 1.6 100 ALIGN! EachoeicOie cooi, 10 909 - 6.3 0.8 100 ALIGN! Klebat · lle elrogenes, 10 440 - 50 0.8 - Klebatelle poauornlao, 9 527 - 25 0.8 - Próteus mraeaiit, 3 855 - 100 ALIGN! 0.8 -. Próteus rettgeri, 8 479 -. 12.5 <0.05 - Próteus vulgaris, 9 416 - 50 1.6 - SamoonHe typO ^ e, 1 195 - 50 0.8 100 ALIGN! ShOgeHe sonoel ', 8 449 - 12.5 0.8 100 ALIGN! ΕιοΙι ^ α ^ ιγ οl-eοel, 8 236 - ' 100 ALIGN! 1., 6 100 ALIGN!

PoJar. tab.

Organ MIC values (/ Ag / ml)

The product of Example 3.

19 Dec 20 May 21 22nd E ^ lte: rob ^ <^ 1Le ^ aerogeoes, 10 078 - - 0.8 - 01ЛгоЬ1С1гг freunedi, 9 - 518 - 50 6.3 100 ALIGN! marceacens, 9 783 25 50 50 100 ALIGN! ^^ ποίο ^ ο ^ arruginosl, 9 545 25 25 3.1 6.3 Pseudomonas lrrugino8l _l 8 329 50 - 25 100 ALIGN! Acioetobacter ca; lco ^ (^ 4 ^ 1 ^; icus ₎ 8 333 50 50 25 - Ograeism Hocdooty MIC (/ µg / ml) Product 2 of Example 8. 23 24 25 26 Staphylncnccu8 aureus, 1 276 50 6.3 1.6  1.6 Staphylococcus aureus, 2 399 50 6.3 1.6 1.6 Staphylococcus aureus, 2 400 50 3.1 1.6 3.1 Slap ^^^^ us aureus 10 165 100 ALIGN! 6.3 25 25 Streptococcua faecaa.is, 9 011 - - 50 50 Streptococcue ι ^ βΙθοΙΙι!) 9 287 50 3.1 0.1 0.8 Ute ^ τκ ^ ο ^ luteus · 2 495 - 12.5 0.8 3.1 Ε8ΟΗΟ! ^ №1 coU, 8 294 - - 0.4 6.3 Eacheelchla coU, 10 857 - - <0.05 3.1 Escchaichia coli 10 896 - 100 ALIGN! 0.2 25 Escchrichia coU 10 909 N.T. 100 ALIGN! <0.05 1.6 KlebbSella aerogeees, 10 440 - - 0.4 6.3 Ώ1 ^) 8ο11ι p ^ <^ 'u ^ íoíí ^ (», 9 527 - - _φ <0.05 0.4 Proteus) 1γ & 1) 118, 3 855 - - 0.2 0.4 Proteus rettg ^ i ^ r., 8 479 - 100 ALIGN! 0.4 0.4 Próteus vulgaris, 9 416 - - <0.05 0.2 Salmooorll typen8l, 1 195 - - <0.05 0.4 S ^ gen 8огшоГ, 8 449 - - 0.2 6.3 E ^ terobi ^ c ter clnaclr, 8 236 - - 0.4 6.3 ΕοίΜ ^ βοίθΓ arrogeees, 10 078 - - 0.8 25 ОИпЬю ^ г freundi, 9 518 - - 0.4 25 marco8cen8, 9 783 100 ALIGN! 100 ALIGN! 0.8 50 Pseudomonas arrugieosa, 9 545 - 50 0.4 0.4 Pseudomonas aerulieo8l, 8 329 - - 3.1 12.5 Acieetobactar ^^^ Ico ^ i ^^ ti ^ cus, 8 333 - - 25 50

Organism

MIC values (µg / ml).

27 Mar: 28 29 30 Slapky ^^^^ aureus, 1 276 6.3 12.5 - 12.5 Staphylococcus auгiUi _J 2 399 12.5 25 - 12.5 Staphyl.ococcui aureus, 2 400 25 25 - 25 Staphyl.ocuccui aureus, 10 165 100 ALIGN! 100 ALIGN! - 100 ' Streptococcus fa ^ aUs 9 011 - 25 - - Stript) ocuccui agalaciae 9 287 3.1 0.4 12.5 0.4 M ^ ciococcus luteus 2 495 12.5 3.1 25 12.5 Eachhiichia cool, β 294 100 ALIGN! 12.5 0.4 12.5 Escřheichia ΟΙ, 10 857 25 1.6 0.2 6.3 Eachhiichia cooi, 10 896 25 3.1 0.8 12.5 Eschaeichia cooi, 10 909 50 1.6 0.1 3.1 Klebaseila Be ^ genes, 10 440 - 25 0.4 1214 · 5 ^ ebaseila pneumoonae, 9 527 50 1.6 <0.05 6.3 Próteus miiamis, 3 855 12.5 1.6 <0.05 6.3 Próteus rettgerl, 8 479 6.3 0.2 <0.05 0.8 Proteus vulgato, 9 416 25 1.6 0.1 12.5 Salmoufllla typhosa, 1 195 25 0.8 <00) 5 3.1 Sh ^ gila sonni 8 449 100 ALIGN! 3.1 0.2 6.3 Entirobacter gIoscho, 8 236 - 6.3 0.8 6.3 Entirobac tor aerogenes 10 078 - 50 0.8 12.5 Citrobactir freuindi, 9 518 100 ALIGN! 25 1.6 - Sairatia m8a'cescens, 9 783 - 12.5 0.8 50 Pieudumonai arruginoia, 9 545 12.5 3.1 0.8 12.5 Piruduoonai aerugi.noia, 8 329 - 50 3.1 50 A ^ in ^ tob ^ e ^ l ^ i ^ r 0010006 ^ 0 ^, 8 333 - - 100 ALIGN! - Organism Values MIC (/ Ug / ml) Product from the example δ • 31 32 33 35 Staphyl ^^ occus aureus 1 276 1.6 1.6 1.6 3.1 Staphylooccus aureus, 2 399 3.1 0.8 1.6 3.1 Staphylphioccus ai ^ eus, 2 400 6.3 1.6 1.6 3.4 Staphylococcus amus, 10 165 6.3 12.5 3.1 12.5 Streptococoui r ^ caUs, 9 011 - 100 ALIGN! - - Streptococcus et al. 9 287 1.6 0.4 0.2 0.4 Μίσοούσ ^ luím, 2 495 6.3 1.6 0.8 1.6 Eschheichia cooi, 8 294 - - '- - Eschae-iciha cooi 10 857 50 3.1 3.1 12.5 Eschheichia c ^ oi 10 896 50 100 ALIGN! 50 - Eschheichia cooi, 10 909 50 50 50 100 ALIGN! Klebsshlla aerogenas, 10 440 - - - - K ^ besena pnaiunoonae, 9 527 100 ALIGN! 100 ALIGN! - - Proteus miiaHHs, 3 855 100 ALIGN! 100 ALIGN! 100 ALIGN! - Forteus rettgeri, 8 479 25 100 ALIGN! - - Próteus vulgUs, 9 416 100 ALIGN! 6.3 3.1 12.5 typhosa, 1 195 50 - - 100 ALIGN! Shigella опппГ 8 449 100 ALIGN! - - - - Entirobactor cloacar, 8 236 - - - - Enterobacter aerogenas, 10 078 - - - - Citrobactir freunidi, 9 518 - - - - Sarmatia 9 • 783 - - - -

Po tor. tab.

OrgttUcmus

HIC values (/ ug / ol)

The product of Example 6

31 32 33 34 Pseudoaonae aerujinosa, 9 545 25 »2.5 12.5 25 Pseusooonas aeruginosa, 8 329 - - - - Acinetobacter calcoaceticus, 8 333 - - - - Organism MXC values (/ ig / ol) Product from Example 5. 36 37 39 40 Staphylococcus aureus, 1 276 6.3 6.3 0.8 3.1 Staphylococcus aureus, 2 399 6.3 6.3 0.8 3.1 Staphylococcus aureus, 2 400 3.1 1.6 0.8 3.1 Staphylococcus aureus, 10 165 50 100 ALIGN! 3.1 6.3 Streptococcus faecslis, 9 011 - - 50 100 ALIGN! Streptococcus ogalactias, 9 287 0.4 0.4 0.4 0.8 Mcorococcus luteus, 2 495 6.3 1.6 0.8 1.6 ^ι ^ γΙ ^ ι coli 8 294 - - - 1.6 Bscheeichla coli, 10 857 - 50 12.5 0.2 EscherichLa coli, 10 896 - - 100 ALIGN! 1.6 Bscltaerichia cóli, 10 909 - - - 0.2 KebaleHa aerogenes 10 440 - - - 0.8 K-content of pneumoniae, 9 527 - - - 0.4 Próteus obraHlis, 3 855 - - - <00> 5 Próteus rettgeri, 8 479 - - 100 ALIGN! ^<0, 5 Proteus vulgiwis, 9 416 - 100 ALIGN! 25 <0.5 Salmonnlla typhosa, 1 195 - - - <0.5 Shigella somai, 8 449 - - - 0.4 Bntarobwter cIoicis, 8 236 - - ae 0.8 Bnterobacter aerogenes, 10078 - - - 1.6 Citrobacter freunddl, 9 518 - - - 1.6 Sercatia marcescens, 9 783 - - - 1.6 Pseudomonas aar ^ inosa, 9 545 - 100 ALIGN! 12.5 0.2 Pseudnmnnae aerugLnosa, 8 329 - - - 6.3 AciLnetobacter ^ 1 ^ ιοοΗ ^ 8, 8 333 - - - 25

у \\

IN

Organism 41 MIC values (.mu.g / ml). 42 43 44 Staphylococcus aw ^ i ^ i ^ e, 1 276 1.6 6.3 25 3.1 Staphylococcus aureus, 2 399 1.6 6.3 12.5 3.1 Staptylococcua aureus, 2 400 1.6 12.5 12.5 6.3 Staphylococcus aureua, 10 165 3.1 100 ALIGN! 100 ALIGN! 25 Streptococcus faecalis, 9 011 - - - 100 ALIGN! Streptococcus agalactiae, 9 287 1.6 1.6 3.1 1.6 Micrococcus luteus, 2 495 3.1 6.3 12.5 3.1 Escherichia coll, 8 294 - - 50 3.1 EscherichLa coH, 10 857 50 100 ALIGN! 25 3.1 Escherichia coli, 10 896 - 50 25 6.3 Eaahhrrchia coli, 10 909 100 ALIGN! 50 25 1.6 Kebasella aerogenes, 10 440 - - 50 6.3 Ksbsiella pneunoniae, 9 527 - - 25 3.1 Próteus oirraaiis, 3 855 50 100 ALIGN! 25 3.1 Próteus rettgeri, 8 479 6.3 50 25 1.6 Próteus viu.gaaÍ8, 9 416 50 - 50 3.1 Salooonlla typhosa, 1 195 100 ALIGN! 100 ALIGN! 25 1.6 Shigella snrnni, 8 449 100 ALIGN! 100 ALIGN! 25 3.1 Enterobaater cloacae, 8 236 - 100 ALIGN! 50 12.5 EiteroSaater aerogenes, 10 078 - - 50 6.3 CitroSacter freuniii, 9 518 - - 50 25 Serratia osarcscens, 9 783 50 100 ALIGN! 50 25 Ра ^ одопаа aeruginosa, 9 545 100 ALIGN! 50 12.5 3. ’ aeruginosa, 8 329 - - - 100 ALIGN! AcinetoSacter calcoaceticus, 8 333 - - 100 ALIGN! - Organism MIC values (/ Lg / ol) Product with the example δ • 45 46 48 50 Staphylococcus aiureua, 1 276 1.6 100 ALIGN! 12.5 12.5 StaphУlocnccuа aureus, 2 399 1.6 100 ALIGN! 12.5 25 Staphylococcus aureus, 2 400 1.6 100 ALIGN! 12.5 25 Staplhylococcus aureus, 10 165 25 100 ALIGN! 25 25 Streptococcus fuceUs, 9 011 - - - - Streptococcus agalactin, 9 287 1.6 50 6.3 12.5 Micrococcus luteus, 2 495 1.6 50 3.1 6.3 Escherichia coli, 8 294 0.8 - 50 - Escherichia coli, 10 857 0.4 - 50 100 ALIGN!

Cont. tab.

Organism 45 Values Product 46 The meter (/ Ug / ml) of Example no. 48 50 Eacherichia coli, 10 896 0.8 100 ALIGN! 25 - Eacherichia coli, 10 909 0.2 N.T. 12.5 100 ALIGN! Klebaiellla aerogaaes, 10 440 », 6 100 ALIGN! - Klebsiella pneumoniae, 9 527 <0.05 - 50 - Próteus nirabilia, 3 855 0.1 - 100 ALIGN! - Próteus rettgeri, 8 479 OJ - 50 100 ALIGN! Próteus vulgaris, 9 416 <0.05 - - - Salmonella typhosa, 1 195 0.1 - 50 - Shigella sonnei, 8 449 0.4 - 50 - Enterobacter cloacae, 8 236 0.8 100 ALIGN! - - Enterobacter aerogenes, 10 078 1.6 - - - Citrobacter freundii, 9 518 1.6 100 ALIGN! 100 ALIGN! - Serratia marceacens, 9 783 3.1 100 ALIGN! 100 ALIGN! - Pseudomonas aeruginosa, 9 545 0.4 12.5 - 50 Pseudomonas aeruginosa, 8 329 3.1 - - - Acinetobacter calcoaceticus, 8 333 12.5 100 ALIGN! - -

Organism 51 Values Product 52 The meter (/ Ug / ml) from Example δ. 53 54 Staphylococcus aureus, 1 276 12.5 50 »2,5 3, » Staphylococcus aureus, 2 399 25 50 »2,5 3.1 Staphylococcus aureua, 2 400 50 100 ALIGN! »2,5 6.3 Staphylococcus aureus, 10 165 50 100 ALIGN! 100 ALIGN! 100 ALIGN! Streptococcus faecalia, 9 011 - - - 100 ALIGN! Střeptococcua agalactiae, 9 287 6.3 25 3.1 1.6 Micrococcus luteuo, 2 495 1.6 12.5 6.3 1.6 Eacherichia coli, 8 294 - 100 ALIGN! »2,5 6.3 Eacherichia coli, 10 857, 100 ALIGN! 100 ALIGN! »2,5 6.3 Ěschekichia coli, 10 896 - 25 »2,5 6.3 Eacherichia coli, 10 909 - 25 »2,5 3.1 Klobaiolla aerogenes, 10 440 - 100 ALIGN! 25 6.3 Klobsiella pneumoniae, 9 527 - 50 »2,5 6.3 Próteus mirabilis, 3 855 - - »2,5 3. » Próteus rettgeri, 8 479 - 100 ALIGN! »2,5 3.1 Próteus vulgaris, 9 416 100 ALIGN! - 25 6.3

244105 98 Cont. tab. Organism HIC values (/ µg / ml) 51 52 53 54

Salmonella typhosa, 1 195 - 100 ALIGN! 6.3 1.6 Shigella sonnei, 8 449 - 100 ALIGN! 12.5 3.1 Enterobacter cloacae, 8 236 - 50 25 25 Enterobacter aerogenes, 10 078 - 100 ALIGN! 50 12.5 Citrobacter freundii, 9 518 - 50 50 25 Serr.atia marcescens, 9 783 - 50 25 25 Pseudomonas aeruginosa, 9 545 100 ALIGN! 50 12.5 6.3 Pseudomonas aeruginosa, 8 329 - - - 100 ALIGN! Acinetobacter calcoaceticus, 8 333 - 100 ALIGN! - -

Organism 55 Values Product 56 The meter (yug / ml) from Example δ 57 58 Staphylococcus aureus, 1 276 6.3 12.5 25 0.8 Staphylococcus aureus, 2 399 6.3 12.5 25 0.8 Staphylococcus aureus, 2 400 12.5 12.5 50 1.6 Staphylococcus aureus, 10 165 50 - 100 ALIGN! «2,5 Streptococcus faecalis, 9 011 - - 100 ALIGN! 50 Střeptococcus agalactiae, 9 287 3.1 12.5 6.3 ^0.8 Micrococcus luteus, 2 495 12.5 6.3 25 1.6 Escherichia coli, 8 294 50 - - 0.8 Escherichia coli, 10 857 25 - - <0.05 Escherichia coli, 10 896 100 ALIGN! 100 ALIGN! - 0.2 Escherichia coli, 10 909 25 100 ALIGN! - O," Klebsiella aerogenes, 10 440 100 ALIGN! - - 0.8 Klebsiella pneumoniae, 9 527 50 - - 0.1 Próteus mirabilis, 3 855 25 100 ALIGN! - O," Próteus rettgeri, 8 479 25 50 100 ALIGN! O," Próteus vulgaris, 9 416 25 - - <0.05 Salmonella typhosa, 1 195 12.5 100 ALIGN! - O," Shigella eonnei, 8 449 50 100 ALIGN! - 0.4 Enterobacter cloacae, 8 236 100 ALIGN! - - 0.8 Enterobacter aerogenes, 10 078 100 ALIGN! - - «, 6 Citrobacter freúndii, 9 518 - - - «, 6 Serratia marcescens, 9 783 50 - «, 6 Pseudomonas aeruginosa, 9 545 12.5 50 50 0.8 Pseudomonas aeruginosa, 8 329 - - - 12.5 Acinetobacter calcoaceticus, 8 333 - - 100 ALIGN! 25

Organism HIC values (µg / ml). 59 60 61 62

Staphylococcus aureus, 1 276 12.5 1.6 3.1 3.1 Staphylococcus aureus, 2 399 6.3 1.6 1.6 1.6 Staphylococcus aureus, 2 400 6.3 3.1 3.1 3.1 Staphylococcus aureus, 10 165 25 50 50 50 Streptococcue faecalis, 9 011 - 100 ALIGN! 100 ALIGN! 50 Streptococcus agalactiae, 9 387 1.6 0.2 0.2 0.4 Micrococcus luteus, 2 495 3, ι 0.4 0.8 1.6 Escherichia coli, 8 294 1.6 0.8 1.6 6.3 Escheribhia coli, 10 857 1.6 <0.05 <0.05 0.4 Escherichia coli, 10 696 6.3 0.2 0.2 3.1 Escherichia coli, 10 909 0.8 ο, ι 0.1 1.6 Klebsiella aerogenea, 10 440 3.1 0.8 1.6 12.5 Klebsiella pneumoniae, 9 527 0.8 0.2 0.2 1.6 Próteus mirabilis, 3 855 1.6 1.6 0.8 0.8 Próteus rettgeri, β 479 0.1 3.1 1.6 0.8 Próteus vulgaris, 9 416 3.1 0.2 <0.05 0.1 Salmonella typhosa, 1 195 0.8 0.8 0.4 1.6 Shigella sonnei, 8 449 1.6 0.4 0.4 3.1 Enterobacter cloacae, 8 236 3.1 1.6 0.8 6.3 £ nterobacter aerogenes, 10 078 3.1 3,1 ' 3.1 12.5 Citrobacter freundii, 9 518 25 0.4 0.4 6.3 Serratia marcescens, 9 783 25 1.6 1.6 25 Pseudombnas aeruginosa, 9 545 6.3 0.4 0.2 3.1 Pseúdomonas aeruginosa, 8 329 - 6.3 6.3 100 ALIGN! Acinetobacter celcoaceticus, β 333 100 ALIGN! 6.3 25 -

Organism 63 Values Product 64 MIC Qug / al) from example δ. 65 66 Staphylococcus aureus, 1 276 6.3 3.1 100 ALIGN! 25 Staphylococcus aureus, 2 399 6.3 6.3 - 25 Staphylococcus aureus, 2 400 12.5 12.5 - 25 Staphylococcus aureus, 10 165 12.5 12.3 - - Streptococcus faecalis, 9 011 - - - - Streptococcus agalactiae, 9 287 6.3 6.3 50 3.1 Micrococcus luteus, 2 495 50 12.5 - 0.8 Escherichia coli, 8 294 - - - 12.5 Escherichia coli, 10 857 - 100 ALIGN! - 1.6

244105 100 ALIGN! Cont. tab. Compound HIC Values ( _/ µg / nl) 63 64 65 66

£ scherichla coli 10 896 100 ALIGN! «2,5 Eecherichia coli, 10 909 - 100 ALIGN! - 3.1 Klebsiella aerogenee, 10 440 - - - 12.5 Klebsiella pneumoniae, 9 527 - - - 3, « Próteus mirabilis, 3 855 - - - 0.8 Próteus rettgeri, 8 479 -, 100 ALIGN! 100 ALIGN! 0.2 Proteus vulgaria, 9 416 - - - 0.1 Salmonella typhosa, 1 195 - 100 ALIGN! E - 3.1 Shigella eonnei, 8 449 - 100 ALIGN! - 12.5 Enterobacter cloacae, 8 236 - - - 12.5 Enterobacter aerogenee, 10 078 - - - 25 Citrobacter freundii, 9 518 - - - 12.5 Serratia marcescens, 9 783 100 ALIGN! 100 ALIGN! 100 ALIGN! 12.5 Pseudomonas aeruginoea, 9 545 100 ALIGN! 12.5 6.3 25 Pseudomonas aeruginosa, 8 329 - - - - Acinetobacter calcoaceticus, 8 333 - - - -

Organism 67 Values Product 68 HIC ( _from µg / ml) with Example No. 69 70 Staphylococcus aureus, 1 276 25 50 3.1 - Staphylococcus aureus, 2 399 12.5 50 3J 100 ALIGN! Staphylococcus aureus, 2 400 12.5 50 3.1 100 ALIGN! Staphylococcus aureus, 10 165 - - 50 - Střeptococcue faecalis, 9 011 25 - 25 - Streptococcus agalactiae, 9 287 1.6 12.5 0.1 25 Micrococcus luteus, 2 495 0.4 25 0.1 100 ALIGN! EacherichiS coli, 8 294 12.5 1.6 12.5 1.6 Eecherichia coli, 10 857 1.6 1.6 0.8 1.6 Eecherichia coli, 10 896 6.3 6.3 12.5 3.1 Eecherichia coli, 10 909 1.6 0.8 1.6 0.4 Klebsiella aerogenee, 10 440 6.3 1.6 25 1.6 Klebsiella pneumoniae, 9 527 1.6 0.4 6.3 0.8 Próteus mirabilis, 3 855 0.4 0.4 1.6 1.6 Próteus rettgeri, 8 479 0.2 <0.05 0.2 <0, W Proteus vulgaria, 9 416 0.2 0.8 0.4 •, 8 Salmonella typhosa, 1 195 0.2 0.2 3.1 4.4

101

Pote ?, tab. Organism MIC values (.mu.g / ml). 67 68 69 70 Shigella sonnei, 8 449 6.3 1.6 6.3 0.6 Enterobacter cloacae, 8 236 6.3 0.8 12.5 0.8 Enterobacter aerogenes, 10 078 12.5 1.6 25 1.6 Citrobacter freundii, 9 518 6.3 25 12.5 1.6 Serratia marcescens, 9 783 6.3 50 25 6.3 Pseudomonas aeruginosa. 9 545 6.3 3.1 ´, 6 1.6 Pseudomonas aeruginosa, 8 329 100 ALIGN! 50 100 ALIGN! 12.5 Acinetobacter calcoaceticus, 8 333 - - - -

Organism 71 Values Product 72 MIC ( _{/ U} g / ml) from Example δ. 73 74 Staphylococcus aureus, 1 276 3.1 12 ^ 5 6.3 12.5 Staphylococcus aureus, 2 399 3.1 2,5 6.3 25 Staphylococcus aureus, 2 400 3.1 12.5 12.5 25 Staphylococcus aureus, 10 165 50 50 12.5 50 Streptococcus faecalis, 9 011 50 100 ALIGN! - Streptococcus agalac i tae 9 287 1.6 3.1 3.1 12.5 Micrococcus luteus, 2 495 -3.1 6.3 6.3 3.1 Escherichia coli, 8 294 25 0.8 25 25 Escheriehla coli, 10 857 3.1 1.6 25 25 Escherichia coli, 10 896 25 3.1 * 12.5 25 Escherichia coli, 10 909 12.5 0.8 12.5 12.5 Klebaiella aerogenes, 10 440 50 1.6 25 50 Klebsiella pneumoniae, 9 527 12.5 0.8 25 25 Próteus mirabilis, 3 855 12.5 1.6 12.5 50 Próteus rettgeri, 8 479 1.6 0.1 1.6 50 Próteus vulgaris, 9 416 3.1 ´, 6 25 100 ALIGN! Salaonella typhosa, 1 195 12.5 0.8 25 25 Shigella sonnei, 8 449 25 0.8 12.5 25 Enterobacter cloacae, 8 236 50 0.8 25 100 ALIGN! Enterobacter aerogenes, 10 078 100 ALIGN! 1.6 25 100 ALIGN! Citrobacter freundii, 9 518 50 12.5 25 50 Seratia marceacens, 9 783 100 ALIGN! 25 25 50 Pseudomonas aeruginosa, 9 545 12.5 6.3 25 50 Pseudomonas aeruginosa, 8 329 - 50 100 ALIGN! -

102

NIC Values (-ug / ol)

The product of Example δ.

76 77 78 79 Staah _< y1coccct aur-us 1 276 6.3 - - 25 Staahy1ococcut aur-us 2 399 6.3 - - 25 Staphy1ocřccct 2 400 6.3 - - 12.3 Siaahy1ococcct aur-us 10 165 12.5 - - - Stгrptocuccut fa-caHs 9 011 - - - 100 ALIGN! agaLactiae, 9 287 3.1 - - 3.1 ^ογό ^^ 1ct-en » 2 495 0.8 - 50 1.6 Escli-lchla coH 8 294 3.1 50 25 1.6 Escli-iclla coH 10 857 3.1 100 ALIGN! 12.5 0.4 Eachieichia coH, 10 896 1.6 25 6.3 '1,6 Eachieichia coH, 10 909 0.8 25 6.3 0.4 K-bsseeia argoseeet » 10 440 3.1 100 ALIGN! 25 3.1 K-bHo-la pne1cioioeae » 9 527 1.6 50 25 0.8 Proteus oiiabblis, 3 855 3, i 25 25 0.2 Proirct г-iigeri, 8 479 3.1 50 25 <0.05 Prot-us vulgaTIS, 9 416 3.1 50 50 0.2 Saloooerlb .iy plosa, 1 195 1.6 50 25 0.2 SHse-la ιοι ^ -, 8 449 0.8 25 2,5 1.6 Entrrubabter c1obcar, 8 236 12.5 25 12.5 1.6 Enterobacter beгogene8 ». 10 078 6.3 100 ALIGN! 25 6.3 9 518 25 25 12.5 3.1 Serratia marcescens, 9 783 6.3 50 25 3.1 Psrudřoonbs beгugiřta » 9 545 12.5 6.3 6.3 3.1 Psrudřoonbs brrueieu8a, & 8 329 100 ALIGN! 50 25 25 Acinetobacter οιΙοιοθ ^ μ, 8 333 12.5 - - -

Organism 88 MTC values (/ µg / ol) of the product of Example δ. 89 90 91 Staphy1ocuccct 1 276 12.5 25 2.5 3.1 Staply1ucoccut 2 399 12.5 25 25 3.1 Siaahylocuur aur-us, 2 400 12.5 50 25 6.3 Staphy1ocuccut 10 165 50 50 100 ALIGN! 25 fa-csais 9 011 - - - 100 ALIGN! Strratococcut ο ^ αοΗ-, 9 287 12v5 12.5 12.5 0.8 Μ ^ γόομ ^ 1ctrct » 2 495 0.8 0.4 12.5 1.6 Escli-iclla coH 8 294 - - 12.5 -

103

Polo »tab.

Organism

MIC values (ng / ol) The product of Example δ. 89 90

Escherichia coOi, 10 896 50 50 6.3 - Escherichia coli, 10 909 100 ALIGN! 50 1.6 - K.ebsSella arrogrnes, 10 440 - - 12.5 - Klebbiolla pneuooiae, 9 527 100 ALIGN! 100 ALIGN! 1.6 - Proteus oirabblii, 3 855 100 ALIGN! 100 ALIGN! 6.25 - Próteus rettgeei, 8 479 50 50 3.1 - Próteus vulgaris, 9 416 100 ALIGN! 50 0.1 100 ALIGN! Saloooneia typhosa, 1 195 100 ALIGN! 50 1.6 - Shhggeia soinme, 8 449 - - 3.1 - Eiterobacter cloacae, 8 236 - - 6.3 - Enterobacter aeroge ^ gs 10 078 - - 12.5 - Citrobacter frewndi, 9 518 - - 12.5 - Serratia οίΗΌ ^^ ηβ, 9 783 - - 6.3 - Pseudomonae aeroginosa,. '· 9 545 25 25 3.1 100 ALIGN! Pseudomonas aeruginosa, 8 329 - - 50 - Acingtobacter calcoaceticus, 8 333 - - - -

Organism Value of MIC (/ Ug / ol) Product from example no · 92 93 94 Staphylococcus aureus, 1 276 - 50 100 ALIGN! Staphylococcus aureus, 2 399 - 50 100 ALIGN! Staphylococcus aureus, 2 400 - 50 100 ALIGN! Staphylococcus aureus, 10 165 - 50 - Streptococcus faecaais, 9 01 1 - - - Streptococcus agaactiae :: 9 287 - 25 3.1 Micrococcus luteus, 2 495 100 ALIGN! 25 3.1 Esec ^ e ^^^ coH, 8 294 - - 100 ALIGN! Escl ^ ich ^ coH, 10 857 - - 25 Escheeichia di, 10 896 - - 25 EscheeicMLa coki, 10 909 - - 25 Rebe ^ eHa aerogenes 10 440 - - 100 ALIGN! Heb ^ eHa pnaweoonae, 9 527 - - 100 ALIGN! Próteus oiraaiiis, 3 855 - - 25 Próteus rettgeri, 8 479 - 100 ALIGN! 3.1 Próteus vulgaris, 9 416 - - 50 SalooonUa typhosa, ϊ 195 - - 50 Shiggeia soiune, 8 449 - - 50

104

MXC values (/ «g / ml)

The product of Example ft.

Cont. tab.

Organism

92 93 94 Enterobacter cloacae, 8 236 - - Enterobacter aerogenes, 10 076 - - - Citrobacter freundii, 9 518 - - - Serratia marcescens, 9 783 • - 100 ALIGN! Pseudomonas aeruginosa, 9 545 - 25 - Pseudomonas aeruginosa, 8 329 - - - Acinetobacter calcoaceticus, 8 333 - - - Organism 95 Values Product 96 MIC (µg / ml) of Example 6. 97 98 Staphylococcus aureus 1 276 50 - 6.3 100 ALIGN! Staphylococcus aureus, 2 399 • 50 - 6.3 50 Staphylococcus aureus, 2 400 50 - 12.5 50 Staphylococcus aureus, 10 165 100 ALIGN! - 25 100 ALIGN! Streptococcus faecalis. 9 011 - - - - Streptococcus agalactiae, 9 287 6.3 12.5 », 6 100 ALIGN! Micrococcus luteus, 2 496 6.3 6.3 1.6 - Escherichia coli, 8 294 25 - 6.3 - Escherichia coli, 10 857 25 100 ALIGN! 0.2 - Escherichia coli, 10 896 12.5 50 1.6 - Escherichia coli, 10 909 6.3 50 0.8 - Klebsiella aerogenes, 10 440 50 - 6.3 Klebsiella pneumoniae, 9 527 50 - 1.6 - Próteus mirabilis, 3 855 50 100 ALIGN! 3.1 - Próteus rettgeri, 8 479 25 100 ALIGN! 6.3 - Próteus vulgaris, 9 416 50 - <0.05 - Salmonella typhosa, 1 195 50 - 1.6 - Shigella sonnei, 8 449 12 ^ 5 50 3.1 - Enterobacter cloacae, 8 236 50 50 6.3 - Enterobacter aerogenes, 10 078 50 100 ALIGN! 12.5 - Citrobacter freundii, 9 518 50 50 3.1 - Serratia marcescens, 9 783 25 50 12.5 - Pseudomonas aerogino sa, 9 545 50 50 6.3 - Pseudomonas aeruginosa, 8 329 - - »00 - Acinetobacter calcoaceticus. 8 333 50 50 •

105

Organism

MIC values (ug / ml) Product from Example δ.

100 101

Staphylococcus aureus, 1 276 100 ALIGN! 50 25 Staphylococcus aureus, 2 399 100 ALIGN! 50 25 Staphylococcus aureus, 2 400 100 ALIGN! 50 50 Staphylococcus aureus, 10 165 - 100 ALIGN! 100 ALIGN! Streptococcus faecalia, 9 011 - - - Streptococcus agalactiae, 9 287 100 ALIGN! E 25 12.5 Micrococcus lutéus, 2 495 100 ALIGN! 25 50 Escherichia coli, 8 294 - 100 ALIGN! « 100 ALIGN! Escherichia coli, 10 857 - 50 50 Escherichia coli, 10 * 896 - 50 100 ALIGN! Escherichia coli, 10 909 - 25 50 Klebsiella aerogenes, 10 440 - 100 ALIGN! - Klebsiella penuomoniae, 9 527 - 100 ALIGN! 100 ALIGN! Próteus mirabilis, 3 855 - 100 ALIGN! - Próteus rettgeri, 8 479 - 50 100 ALIGN! Próteus vulgaris, 9 416 - 100 ALIGN! - Salmonella typhosa, 1 195 - 50 100 ALIGN! Shigella sonnei, 8 449 - 50 100 ALIGN! Enterobacter cloacae, 8 236 - - - Enterobacter aerogenes, 10 078 - - - Citrobacter freundii, 9 518 - 100 ALIGN! - Serratia marcescens, 9 783 - 50 - Pseudomonas aeruginosa, 9 545 - 50 - Pseudomonas aeruginosa, 8 329 - - - Acinetobacter calcoaceticus, 8 333 - - -

Organism 102 MIC (/ Ug / ml) Product of Example δ. юз 104 105 Staphylococcus aureus, 1 276 • 100 - 12.5 3.1 Staphylococcus aureus, 2 399 100 ALIGN! - 6.3 3.1 Staphylococcus aureus, 2 400 50 - 6.3 3.1 Staphylococcus aureus, 10 165 - - 50 50 Streptococcus faecalis, 9 011 - - 50 100 ALIGN! Streptococcus agalactiae, 9 287 3.1 50 1.6 1.6 Micrococcus luteus, 2 495 3.1 12.5 1.6 3.1 Escherichia coli, 8 294 0.1 0.4 6.3 0.4 Escherichia coli, 10 857 <0.05 <0.05 0.2 ο, ι

106

After ta *. tib.

Organism MIC values () g / ml

The product of Example δ.

102 103 104 105

Eachírichil coH) 10 896 0.1 0.2 6.3 0.8 Εθο ^ ο ^ Ιι!) Di, 10 909 <0.05 <0.05 1.6 0.1 Klebbsalli lktogrnka, 10 440 0.2 0.4 25 0.4 KLsbbselli pakum / onak, 9 527 0.1 <0.05 3.1 0.1 Próteus miralbiis, 3 855 0.1 <0.05 1.6 0.1 Próteus rettgari, 8 479 <0.05 <0.05 0.2 <0) 0) 5 Próteus vulgaris, 9 '416 <0.05 <0.05 0.8 <0.05 / almoriokli typhfal, 1 195 <0.05 <00) 5 0.8 0.1 / dgani sonoS «. 8 449 0.1 0.2 3.1 0.4 Entkrobactkr clncis, 8 236 0.2 0.4 6.3 . 0.8 Entkrobacter ^^ gross) 10 078 0.4 0.4 25 0.8 ΛΓίΛΓ ^ ηίηΓ ftawaldi, 9 518 0.1 0.4 ,12, 5 1.6 / arratii marcaacana, 9 783 0.8 0.2 12.5 3.1 Paeuafmonaa ikrugiaosi, 9 545 0.8 0.8 3.1 0.2 Pseuafmona8 lkruginfal, 8 329 100 ALIGN! 3.1 50 3.1 Acinktobactrr cllcflceticus, 8 333, 12.5 100 ALIGN! - 25

Organism MIC values (/ ig / ml) Product from the example δ. 106 107 108 Stlphy1ococcua iurkus, 1 276 12.5 3.1 1.6 Stlphy1oeoeeua lurrus, 2 399 6.3 1.6 3.1 Stlphy1ococcua lurrus, 2 400 12.5 1.6 3.1 / tlphy1ococcua iursus! 10 165 50 50 25 Streptoeoceua fiecalis, 9 011 - - 50 Strkptococcua ^ c ^) ^ i ^ (^ 1 ^: iis, 9 287 0.8 0.8 0.8 lutrus, 2 495 12.5 3.1 0.8 Ekol ^^ ch !.) dl 8 294 0.8 3.1 0.8 Esecho! ^!) CoH, 10 857 0.1 0.1 <0.05 E ^ c ^ ^ h ^ et.cl ^ ii coH, 10 896 1.6 1.6 0.2 E ^ c ^ la ^ ei.el ^ ii di, 10 909 0.2 0.4 0.1 Klsbbsalli ikrogenes 10 440 0.8 3.1 0.8 Ka ^ seHi pnkumonOak, 9 527 0.2 0.4 0.05 Próteus miralbiis, 3 855 0.1 0.4 0.2 Próteus rettgari, 8 479 <005 0.1 <005 Próteus vulgaris, 9 416 40.05 0.1 <0.05 Salmo gorge típlos), 1 195 0.1 0.4 0.1 S ^ hi ^ e ^ kli sormok, 8 449 0.4 0.8 0.4 Entrtobactkr clncis, 8 236 0.8 1.6 1.6 Entkrobactkr isrogrars, 10 078 1.6 6.3 1.6 Citrobictet fteunOdi, 9 518 6.3 3.1 0.8 / arnatii maгcθacena, 9 783 12.5 6.3 1.6 Paruafmonaa lkruginfal, 9 545 0.8 0.2 0.8 Paeuafmonaa lkruginfal, 8 329 12.5 12.5 12.5 Aciaktobactkr elleolcetieua, 8 333 50 25 50

107

Organism HIC values (/ µg / ml)

The product from Example #

109 110 111 112 Staphylococcus aureus, 1 276 12.5 1.6 1.6 1.6 Staphylococcus aureus, 2 399 12.5 1.6 1.6 1.6 Staphylococcus aureus, 2 400 6.3 1.6 3.1 1.6 Staphylococcus aureus, 10 165 100 ALIGN! 12.5 25 50 Streptococcus faecalis, 9 011 50 25 50 100 ALIGN! Streptococcus agalctiae, 9 287 1.6 0.4 0.2 0.1 Micrococcus luteus, 2 495 0.8 0.4 0.8 0.8 Escherichia coli, 8 294 0.8 12.5 6.3 0.8 Escherichia coli, 10 857 0.2 0.2 <0.05 <0.05 Escherichia coli, 10 896 0.8 6.3 1.6 0.2 Escherichia coli, 10 909 0.2 3.1 0.8 0.1 Klebsiella aerogenes, 10 440 1.6 25 6.3 1.6 Klebsiella pneumoniae, 9 527 0.2 6.3 1.6 0.2 Próteus mirabilis, 3 855 0.2 1.6 1.6 0.4 Próteus rettgeri, 8 479 <0.05 0.4 3.1 0.8 Próteus vulgaris, 9 416 0.2 0.4 0.4 <0.05 Salmonella typhosa, 1 195 0.1 6.3 3.1 0.4 Shigella sonnei, 8 449 0.8 12.5 3.1 0.4 Enterobacter cloacae, 8 236 1.6 25 6.3 1.6 Enterobacter aerogenes, 10 078 3.1 25 12.5. 3.1 Citrobacter freundii, 9 518 1.6 12.5 3.1 0.8 Serratia marcescens, 9 783 12.5 25 6.3 3.1 Pseudomonas aeruginosa, 9 545 0.4 0.8 0.8 0.8 Pseudomonas aeruginosa, 8 329 12.5 25 12.5 25 Acinetobacter calcoaceticus, 8 333 100 ALIGN! - 25 25

Organism MIC values (/ µg / ml) 113 114 115 Staphylococcus aureus, 1 276 3.1 12.5 1.6 Staphylococcus aureus, 2 399 3.1 12.5 0.8 Staphylococcus aureus, 2 400 3.1 6.3 0.8 Staphylococcus aureus, 10 165 6.3 25 3.1 Streptococcus faecalis, 9 011 50 50 100 ALIGN! Streptococcus agalactiae, 9 287 0.4 0.8 0.8 Micrococcus luteus, 2 495 0.8 0.2 3.1 Escherichia coli, 8 294 25 1.6 - Escherichia coli, 10 857 0.4 0.2 6.3 ’

108

Cont. tab.

Organism MIC values (^ µg / ml)

The product of Example δ.

113 114 115 Eacherichia coli, 10 896 12.5 0.8 - Eacherichia coli, 10 909 6.3 0.4 - Klebaiella aerogenes, 10 440 25 3.1 - Klebsiella pneumoniae, 9 527 6.3 1.6 100 ALIGN! Próteus mirabilis, 3 855 6.3 0.4 - Próteus rettgeri, 8 479 0.4 <0.05 100 ALIGN! Próteus vulgaris, 9 416 1.6 <0.05 6.3 Salmonella typhosa, 1 195 3.1 0.4 - Shigella sonnei, 8 449 12.5 1.6 - Enterobacter cloacae, 6 236 25 3.1 - Entегоbacter aerogenes, 10 078 25 6.3 - Citrobacter freundii, 9 518 25 6.3 4 Serratia marcescens, 9 783 25 6.3 - Pseudomonas aeruginosa, 9 545 3.1 0.8 12.5 Pseudomonas aeruginosa, 8 329 100 ALIGN! 25 - Acinetobacter calcoaceticua, 8 333 - - -

Organism8 MIC values (/ Ug / ml)

The product of Example δ.

116 117 118 119 Staphylococcus aureus, 1 276 6.3 3.1 1.6 6.3 Staphylococcus aureus, 2 399 6.3 3.1 1.6 6.3 Staphylococcus aureus, 2 400 6.3 6.3 3.1 3.1 Staphylococcus aureus, 10 165 12.5 25 12.5 100 ALIGN! Streptococcus faecalis, 9 011 - 50 100 ALIGN! 100 ALIGN! Streptococcus agalactiae, 9 287 3.1 0.2 0.4 <0.05 Micrococcus luteus, 2 495 12.5 1.6 3.1 0.8 Eacherichia coli, 8 294 100 ALIGN! 3.1 12.5 0.2 Eacherichia coli, 10 857 50 <0.05 0.1 <0.05 Eacherichia coli, 10 896 50 0.8 1.6 0.2 Escherichia coli, 10 909 50 0.2 0.8 <0.05 Klebaiella aerogenes, 10 440 100 ALIGN! 3.1 12.5 0.4 Klebsiella pneumoniae, 9 527 100 ALIGN! 1.6 6.3 0.1 Próteus mirabilis, 3 855 100 ALIGN! 0.8 3.1 0.4 Próteus rettgeri, 8 479 25 1.6 6.3 0.2 Próteus vulgaris, 9 416 100 ALIGN! <0.05 0.2 <0.05 Salmonella typhosa, 1 195 100 ALIGN! 1.6 6.3 0.2 Shigella sonnei, 8 449 100 ALIGN! 1.6 6.3 0.2 Enterobacter cloacae, 8 236 100 ALIGN! 3.1 6.3 0.8 Entero bac ter aerogene β, 10 078 6.3 25 0.8 Citrobacter freundii, 9 518 - 1.6 6.3 0.4 ’ SerratiE * marcescens 9 783 12.5 1.6 12.5 0.8 Pseudomonas aeruginosa, 9 545 12.5 6.3 1.6 0.4 Pseudomonas aeruginosa, 8 329 - 100 ALIGN! 50 6.3

109

2441 05

Potar. tab.

frgaeizous MIC values ( _from ug / ol)

The product of Example δ.

116 117 118 119 Acieetobacter calcoaceticus, β 333 50 100 ALIGN! 25 50

Organism Hotaoty MIC (yUg / riL) Product from Example δ. 120 121 122 Staphylococcus 1276 3.1 25 0.8 Staphylococcus aureue, 2 399 3.1 25 1.6 Staphylococcus awreus, 2 400 3.1 12.5 3.1 Staphylococcus 10 165 100 ALIGN! 100 ALIGN! 6.3 Streptococcus faecalis, 9 011 100 ALIGN! - - Streptococcus agalactiae, 9 287 <0.05 3.1 0.8 Mcrococcus luteus, 2 495 0.8 6.3 0.4 EscherichLa coli, β 294 3.1 3.1 6.3 EseheriehLa coli, 10 857 <0.05 1.6 <00> 5 EacherichLa coli, 10 896 0.8 3.1 1.6 Sscherichia coli, 10 909 0.2 1.6 0.4 ^ obsieUa aerogenes, 10 440 6.3 6.3 6.3 Kebsialla pneumoolae, 9 527 0.8 3.1 0.2 Próteus oiraHlis, 3 855 3.1 3.1 1.6 Próteus rettgeri, β 479 3.1 0.2 0/8 Próteus vuLgaris, 9 416 (M . 3.1 <0.05 Saloonella typhosa, 1 195 1.6 1.6 0.8 Shhgeeia sowiei, 8 449 1.6 3.1 1.6 Eeterobactlr ducae, 8 236 3.1 6.3 3.1 Eeterobaeter urosena s, 10 078 6.3 12.5 12.5 Citrobacter freunddi, 9 518 1.6 50 3.1 Serratia βι ^ ι ^ μΖ, 9 783 6.3 25 6.3 Pseudo ^ eds aerujinosa, 9 545 0.2 6.3 3.1 Psludneneas aerusieoea, 8 329 3.1 100 ALIGN! 25 Aieetobacter cllclacetdcui 8 333 6.3 100 ALIGN! 25

Organism 123 MIC Values (yug / ol) Product of Example δ. 126 125 126 StaphУLncnecus aureus, 1 276 3.1 12.5 6.3 3.1

110

Potar. ttb.

Organism

HIC values (^ 0) 1) Example product -.

12-12 124 125 126

8eaphylvcoccps hureus, 2 400 6.3 12.5 6.3 3.1 -taohylococcu8 hureus, 10 165 25 25 50 25 -treptocvccps ftecatiB, 9 011 - - 10 <v 100 ALIGN! -treptocvccua agatactite, 9 287 1.6 0.8 0.4 0.8 Micrvcvccps lpetps, 2 495 1.6 3.1 -, 1 -, 1 Eschheichie cdi, 8 294 '6 25 6.3 2,5 Eschheichie coU, 10 857 <0.05 6.3 0.1 0.4 Eschheichie cdi, 10 896 0.4 12.5 -, 1 6.3 Eschheichie coU, 10 909 0.1 12.5 0.8 1.6 KLebbielle eerogenes, 10 440 16 25 12.5 25 Klebbielle p ^ i ^ iu ^ oo ^ ni ^ ie, 9 527 0.2 25 0.8 6.3 Próteus miratblisj - 855 0.2 6.3 0.4 -, 1 Proteus re ^ ga ^, 8 479 <0.05 1.6 1.6 -, 1 Proteus vulg ^ tis, 9 416 <0.05 3.1 <0.05 0.2 -al-ovnelh typhosa 1 195 0.2 6.3 3.1 6.3 -hhgellt sormne, 8 449 0.4 12.5 -, 1 6.3 Enterobacter breastfeed, 8 2-6 0.8 100 ALIGN! 12.5 12.5 Enterobacter aerogenes, 10 078 -, 1 100 ALIGN! 50 50 Citrobader f ^ udnH 9 518 0.8 100 ALIGN! 12.5 25 -aeratit marcescens, 9 78- 1.6 25 12.5 25 Pseudomonae aerpginvah) 9 545 0.8 25 12.5 1.6 Pseudomonas herpginvah) 8 -29 6.3 - 12.5 25 Acinatobacter celcvhceticpt) 8 --- 50 - - 50

111

Organisms HIC values (yug / ml)

The product from Example #

127 128 129 StaptylococeuB aureus, 1 276 3.1 0.8 50 Staphylococcus aureus, 2 399 3.1 3, » 25 Staphylococcus aureus, 2 400 3.1 6.3 12.5 Staphylococcus aurens, 10 165 25 50 50 Streptococcus faecalis, 9 011 100 ALIGN! 50 50 Streptococcus едаЗ-аШее, 9 287 1.6 0.8 1.6 Mcrococcus luteus, 2 495 6.3 3.1 0.8 Ε801 NašιΤ ^ Μι coli 8 294 - 25 0.4 Εβ ^^ ι ^ Μι cell, 10 857 25 0.2 0.2 ΕβοΗογΙ ^ Ιι coli, 10 896 '- 6.3 0.8 Escherichia coli, 10 909 - 1.6 0.1 Kebssella aerogenes, 10 440 - 50 0.8 Kebsieeia pneunonnae, 9 527 -. 3.1 0.2 Próteus oiirSblis, 3 855 - 12.5 <0.05 Próteus rettgeri, 8 479 - 12.5 0.05 Próteus vdgnis, 9 416 25 0.8 0.2 SaloonHa typhosa, 1 195 - 12.5 <0.05 SMiseHa somni, 8 449 . - · 12.5 0.4 Enterobacter drncee, 8 236 - 12.5 0.4 Enterobacter aerogenes, 10 078 - 50 0.8 Citrobacter freudnni, 9 518 - 12.5 1.6 Е ^ 1г ^ | ^ 1 ^: 11 θΕθ ^ 8θβη8, 9 783 - 25 3.1 Pseudon ^ Ms leriglnnsl 9 545 25 3.1 0.4 Pseudom ^ i ^ as aeruginosa, 8 329 - 100 ALIGN! 12.5 Acinetobacter 8 333 - - -

toganiamus Values КС UuíSol) Product from the example δ 130 131 132 133 Staphyloenccus 1 276 25 6.3 12.5 6.3 Staphylncoccus aureus, 2 399 25 6.3 12.5 3.1 Staph ^ ococcue aureus. 2 400 25 6.3 6.3 12.5 Staphylnenecus aureus, 10 165 100 ALIGN! 50 50 12.5 Streñtncnccus f ^ ceHs, 9 011 - 100 ALIGN! 50 - Streptococcus υ · € 18 9 287 12.5 0.4 0.4 12.5 Mcrococcus luteus, 2 495 25 3.1 3.1 1.6 EsclwricWla coli, 8 294 1.6 25 3.1 - Eschezichia coli, 10 857 0.2 0.2 0.8 50

112

Tab.

Organism MIC Values (µg / ml) Product of Example δ. 130 131 132 133 Escherichia coli. 10 896 1.6 6.3 3.1 100 ALIGN! Escherichia coli, 10 909 0.4 1.6 0.8 - Klebsiella aerogenes 10 440 1.6 50 6.3 - Klebsiella pnemoniae, 9 527 0.2 1.6 - Proteus mirabilis » 3 855 0.8 b, 3 1.6 - Proteus rettgeri » 8 479 0.2 6.3 <0.05 100 ALIGN! Proteus vulgaris » 9 416 0.2 0.4 1.6 50 Salmonella typhosa » 1 195 0.4 12.5 0.4 - Shigella sonnei, 8 449 0.8 12.5 1.6 - Enterobacter cloacae, 8 236 3iíl 25 1.6 - Enterobacter aerogenes, 10 078 3.1 50 6.3 • Citrobacter freundii, 9 518 6.3 25 12.5 - Serratia marcescens, 9 783 6.3 25 12.5 - Pseudomonas aeruginosa, 9 545 0.8 25 3.1 100 ALIGN! Pseudomonas aeruginosa, 8 329 12.5 25 -  - Acinetobacter calcoaceticus, 8 333 - 50 100 ALIGN!

Organism MIC values (/ ig / ml) Example product δ · 134 135 136 Staphylococcus aureus, 1 276 - 3.1 100 ALIGN! Staphylococcus aureus, 2 399 - 3.1 100 ALIGN! Staphylococcus aureus, 2 400 - 3.1 50 Staphylococcus aureus, 10 165 - 50 - Streptococcus faecalis, 9 011 - 50 - Streptococcus agalactiae, 9 287 50 0.8 3.1 Micrococeus futsus, 2 495 100 ALIGN! 6.3 6.3 Escherichia coli, 8 294 3.1 6.3 0.2 Escherichia coli, 10 857 0.8 ο, β <0.05 Escherichia coli, 10 896 3.1 12.5 0.2 Escherichia coli, 10 909 0.8 0.8 ο, ι Klebsiella aerogenes, 10 440 3.1 3.1 0.4 Klebsiella pneumoniae. 9 527 0.8 0.8 ο, ι Próteus mirabilis, 3 855 0.4 0.4 <0.05 Próteus rettgeri, 8 479 <0.05 0.4 <0.05 Próteus vulgaris, 9 416 0.4 0.4 <0.05 Salmonella typhosa, 1 195 0.4 ο, β <0.05 Shigella sonnei, 8 449 1.6 3.1 0.2

113

Cont. tab

Organism

Hotaoty HIC (yUg / ml) Product from Example δ.

135 135 136

Enterobacter cloacae, 8 236 0.8 3.1 0.2 Enterobacter aerogenes, 10 078 3.1 6.3 0.4 Citrobacter freundii, 9 518 3.1 12.5 0.2 SitfraUa 9 783 6.3 25 0.4 Pseudomonas aeruginosa, 9 545 6.3 0.8 0.8 Pseudomonas οιγ ^ Ι ^ ο ^ 8 329 50 12.5 - ' Acinetobacter calcoaceticua, 8 333 - 25 50 Organism Values HIC (/ µg / ml) Product from the example δ. 138 139 140 141 Staphylococcus aureus, 1 276 100 ALIGN! 25 25 25 Staphylococcus aureus, 2 399 50 25 50 N.T. Staphylococcus aureus, 2 400 50 25 50 12.5 Staphylococcus aureus, 10 165 - - - 25 Streptococcus ГмсаШ, 9 011 - '- - - Streptococcus эда ^ сИм, 9 287 1.6 0.4 6.3 25 Micrococcus luteus, 2 495 6.3 6.3 6.3 3.1 Escherichia coli, 8 294 0.1 1.6 1.6 1.6 Escherichia cooi, 10 857 <0.05 <0.05 <0.05 1.6 Escherichia coli, 10 896 0.1 0.4 1.6 1.6 Escterichia coli, 10 909 <0.05 0.1 0.1 0.8 Keessella aerogenes, 10 440 0.2 0.8 1.6 1.6 Kebasella pneunooiae, 9 827 <0.05 0.1 0.1 1.6 Próteus oíícíHís, 3 855 <0.05 0.4 0.4 1.6 Próteus rettgeri, 8 479 <0.05 0.4 0.4 0.1 Próteus vuLgiaris, 9 416 <0.05 <00> 5 <0.05 0.8 Saloomilla typhosa, 1 195 <0.05 0.2 0.2 0.8 Shigella sownni, 8 449 0.1 0.4 0.8 1.6 Enterobacter cIoícíi, 8 236 0.1 0.8 1.6 1.6 Enterobacter aeroBene ^, 10 078 0.2 1.6 3.1 3.1 Citrobacter frmiiii, 9 518 0.1 0.8 1.6 0.8 Pseudomonas aerugiioea, 9 545 0.4 1.6 0.8 6.3 Pseudomonas aeruginosa, 8 329 100 ALIGN! 12.5 12.5 - AAinetobacter 8 333 25 2,5 12, .5 12.5 Organism Values MIC (/ µg / ml) Product from the example δ. 142 143 144 Staphylococcus aiureus, 1 276 50 6.3 - Staphylococcus aureus, 2 399 50 6.3 - Staphylococcus aureus, 2 400 100 ALIGN! 12.5 - Staphylococcus aureus, 10 165 -. 50 - Streptococcus faecaais, 9 011 - - - Streptococcus aga ^ tiM, 9 287 3.1 0.8 50 Micrococcus luteus, 2 495 12.5 1.6 25

114

Pbla ·. t * b.

О / аШши · MICE values (yug / ol)

The product of Example δ.

142 143 144 SacharichLa coli, 8 294 1.6 50 0.4 Sackhrichia coli, 10 857 0.4 0.4 0.2 Eacharichla coli, 10 896 1.6 6.3 0.2 SaclhmiclhLa coli, 10 909 0.8 6.3 <0.05 Kabblalla aeroganaa, 10 440 3. » -, 0.8 Kabalalla pnaumoiat, 9 527 1.6 12.5 0.1 Proteui oirrlblia, 3 855 0.8 6.3 <0.05 Proteua ratt / eri, 8 479 0.8 1.6 <0.05 Proteua vUigaTa, 9 416 0.8 1.6 <0.05 Salnocneia typhcaa, 1 195 0.8 6 ^ 3 <0.05 Sihgella iinne, 8 449 0.8 25 0.4 Eitarobacter cloacae, 8 236 3.1 25 0.8 Sn terobac ter aero / enei 10 078 3.1 100 ALIGN! 0.8 Citrobacter freuridi, 9 518 1.6 25 0.8 Serratia iareaacena, 9 783 3.1 50 0.4 Pae ^ udom ^ i ^ aa aeru / Lioaa, 9 545 3.1 12.5 0.8 Pae ^ u ^ do ^ m ^ i ^ i ^ ia aeru / Lioaa, 8 329 100 ALIGN! . - 3.1 Acinetobacter calcoacaticua, 8 333 100 ALIGN! - 50

Organiaoua 149 № »<tooty MIC (uu / mi) Product from example δ. 148 150 151 Staptylococcua 1 276 6.3 3.1 6.3 - Staph ^ lococcua awreua, 2 399 6.3 3.1 6.3 - Staptylococcua aureus, 2 400 25 6.3 25 - Staphyllcoccua aureus, 10 165  - 100 ALIGN! 100 ALIGN! - Streptococcua faecalis, 9 011 '- - - - Streptlclccuι agalaitiíe, 9 287 3.1 0.4 6.3 12.5 Mirrococcua luteua, 2 495 3.1 3.1 6.3 12.5 SacharichLa coli, 8 294 3.1 1.6 3.1 0.2 SacharichLa coli, 10 857 <0.05 <0.05 0.1 0.1 SacharichLa coH, 10 896 0.8 0.4 1.6 0.2 SadherlohLa coli, 10 909 • 0.4 0.2 0.4 N.T. nebaaella aerogenea, 10'440 12.5 1.6 12.5 0.4 Kebaaalla pneumoniae, 9 527 0.4 0.2 0.1 0.05 Proteua Orriaiie, '' 3 855 1.6 0.8 0.4 0.05 Proteua rett / ari 8 479 1.6 1.6 0.2 0.05

115

Po кг. tab. MIC values (µg / ml) Product of Example δ. Organism 148 149 150 151 Próteus vulgaris, 9 416 <0.05 <0.05 <0.05 0.05 ββίοοτ ^ ΐη typhosa, 1 195 1.6 0.4 0.4 0.05 Sl ^ gaHa soirnei, 8 449 1.6 . 0.8 1.6 0.1 Enterobaater cloacae, 8 236 1.6 1.6 0.8 0.1 Enterobacter aerogenes, 10 078 6.3 3.1 6.3 0.8 Citrobacter freunddi, 9 518 3.1 1.6 3.1 0.4 Seeratda oorcescens, 9 783 3.1 3.1 6.3 0.2 Pseudomonas aeruginosa, 9 545 . 3.1 12.5 6.3 0.4 Pseudomonas atrugdaosa, 8 329 100 ALIGN! 12.5 12.5 1.6 Accnetobacter ctlcotceticst, 8 333 50 50 12.5 25

Organism MIC values (^ tg / nl) Product from the example δ. 153 154 155 Staphylococcus aureus, 1 276 - - - Stap ^ lococcus aureus 2 399 - - - Staphylococcus aureus, 2 400 - - - Staphylococcus aureus, 10 165 - - - Streptococcus ftecaait, 9 011 - '- - Streptococcus 9 287 - - 12 ₄ : 5 Mdcrococcus lut ^ eus, 2 495 , - - 100 ALIGN! Escheeidiia coli, 8 294 50 - 6.3 EscharichLa cooi, 10 857 6.3 50 3.1 Eзcheeiceia cool, 10 896 25 - 3.1 Escherichia cool 10 909 25 - 1.6 K ^ beseHa aerogenes, 10 440 100 ALIGN! - 6.3 Klábosila patumooaae, 9 527 6.3 - 6.3 Próteus oiraailis, 3 855 12.5 - 3.1 Próteus rettgeri, 8 479 0.8 100 ALIGN! 0.4 Próteus vidgaris, 9 416 12.5 100 ALIGN! 6.3 Saloo ^ na typhosa, 1 195 12.5 - 3.1 Shigella sonnei, 8 449 25 - 3.1 Enterobacter cloacae, 8 236 100 ALIGN! - 3.1 Eiterobacter aerogenes, 10 078 100 ALIGN! - 6.3 Citrobacter freunddi, 9 518 25 - 3.1 oeacescens, 9 783 100 ALIGN! - 3.1 Pseudomonas aerugiaott, 9 545 - - 50

116

Cont. tab.

Organism

MIC (/ Ug / ml) Product of Example δ.

153 154 155

Pseudomonas aeruginosa, β 329 - - - Aclnetobacter calcoaceticus, β 333 - - -

Organism Values MIC (/ µg / ml) Product from the example δ. 156 158 160 Staphylococcua aureus, 1 276 12.5 - - Staphylococcus aureus, 2 399 12.5 - Staphylococcua aureus, 2 400 12.5 - - Staphylococcus aureus, 10 165 50 - - Streptococcus faecalis, 9 011 100 ALIGN! - - Streptococcus agalactiae, 9 287 6.3 - 100 ALIGN! Micrococcus luteus, 2 495 1.6 - - Eacherichia coli, 8 294 50 - 0.4 Escherichia coli, 10 857 25 - 0.2 Escherichia coli, 10 896 25 100 ALIGN! 0.1 Escherichia coli, 10 909 25 100 ALIGN! 0.1 Klebsiella aerogenes, 10 440 50 - 0.8 Klobsiélla pneumoniae, 9 527 50 100 ALIGN! 0.2 Próteus mirabilis, 3 855 50 ‘ 0.2 Próteus rettgeri, 8 479 50 0.05 Próteus vulgaris, 9 416 50 - 0.2 Salmonella typhosa, 1 195 50 - 0.2 Shlgella aonnei, 8 449 25 - 0.4 Enterobacter cloacae, 8 236 50 - 0.2 Enterobacter aerogenes, 10 078 100 ALIGN! - 0.4 Citrobacter freundii, 9 518 50 - 0.2 Serratia marceacens, 9 783 50 - 0.4 Pseudomonas aeruginosa, 9 545 12.5 - 0.8 Pseudomonas aeruginosa, 6 329 50 - 12.5 Acinetobacter calcoaceticus, 8 333 100 ALIGN! - 100 ALIGN!

1'7

Organi smus MiC values (y-ugZml) Product from Example no. 161 162 163 Staphylococcus aureus, 1 276 0.1 25 - Staphylococcus aureus, 2 399 0.1 12.5 - Staphylococcus aureus, 2 400 0.2 25 - Staphylococcus aureus, 10 165 0.4 - - Streptococcus faecalis, 9 011 50 - - Streptococcus agalactiae, 9 287 0.4 6.3 50 Micrococcus luteus, 2 495 0.4 6.3 25 Escherichia coli, 8 294 - 3.1 0.4 Escherichia coli, 10 857 25 0.4 0.1 Escherichia coli, 10 896 100 ALIGN! 12.5 0.8 Escherichia ¹ coli, 10 909 - 0.8 <0.05 Klebsiella aerpgenes, 10 440 - 1.6 0.2 Klebsiella pneumoniae, 9 527 - 0.2 <0.05 Próteus mirabilis, 3 855 50 0.4 <0.05 Próteus rettgeri, 8 479 - 0.4 <0.05 Próteus vulgaris, 9 416 25 0.2 <0.05 Salmonella typhosa, 1 195 100 ALIGN! 0.2 <0.05 Shigella 'sonnei, 6 449 - 6.3 0.1 Enterobacter cloacae, 8 236 - 6.3 0.1 Ento-obacter aerogenes, 10 078 - 6.3 0.8 Citrobacter freundii, 9 518 - 3.1 0.4 Serratia marcescens, 9 783 - 3.1 0.8 Pseudomonas aeruginosa, 9 545 25 6.3 0.4 Pseudomonas aeruginosa, 8 329 - 50 1.6 Acinetobacter calcoaceticus, 8 333 - 50 100 ALIGN! SUBJECT OF THE INVENTION

The present invention relates to a process for the preparation of beta-laternate antibiotics of the general formula

Claims (4)

The present invention relates to a process for the preparation of beta-laternate antibiotics of the general formula Rg R ₄ R, -NH-C ---- c -R ₃ in which R 1 represents a hydrogen atom or an acyl radical selected from the group consisting of -44105 118 (i) aliphatic residues of the formula wherein: R 8 represents an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, cyclohioidenyl or alkyl or alkenyl group substituted with one to five substituents selected from the group consisting of halogen atoms, cyano, nitro, amino, mercapto, mercapto; (b) carbocyclic aromatic radicals of formula O ¹ II CH-C- o about him 119 in them! n is 0, 1, 2 or 3, Rg, γγ and Rg * · independently of one another are hydrogen, halogen, hydroxyl, aryl, amino, aminostopine, cyano, trifluoromethyl stopin, (C 1 -C 4) alkyl, (C 1 -C 4) alkyl or amino · nth ^row lioou and ^R g is amino quick match, a hydroxyl group, a carboxyl group in forot salts, carboxy esterifkoovarnou farmakooogieky acceptable ester protecting StopIN, formyloxy, sulfo quick match in forot salts sulphoamino quick match in forot salt, azido, halogen, hydrazino, alkylhydrazinostorium, phenylhydrazino or (/ alkylthio / thioxomethyl) thio, (c) heteroaromatic radicals of formula o R. -CH-1'Ί ^Rg O R ₁₀ -O-CJH ₂ -1 o AND R ₁₀ -S-CH ₂ -Cor wherein 0, 1, 2 or 3 is an aminostopine, a hydroxyl group, a carboxyl group in the salt form, a carboxylic group of a pharmacologically acceptable esterified ester group, a formyllostopine, a sulfonate a halide in a forot salt, a sulfamino-stopopin in a forot salt, azido, halogen, hydrazino, allylhydrazino, phenylhydrazino or (/ alkyl) -thio and represents a 5-, test- or seven-membered heterocyclic aromatic ring containing two, , three or four nitrogen, oxygen and sulfur atoms and optionally 9 I * 10 The 120-substituted 1 to 5 substituents selected from the group consisting of haloeenes, hydroxyl, nitro, amino, cyano, trifluoromethyl, (C 1 -C 4) alkyl and (C 1 -C 4) alkyl groups (D) radicals of formula wherein: R @ 1 represents a moiety of the formula ## STR2 ## wherein R e, R e and R e are each independently hydrogen or holotene, heteroaryl, nitro, amimino, cyano, trifluoromethyl, C 1 -C 4 alkyl, alkoxy or alkoxy; Or a 5, 6 or 7-phenylene ring having one, two, three or four nitrogen, oxygen and sulfur atoms, optionally substituted as indicated for the radicals R, qa. R 12 represents an -NCH-R 6 -, -NH-R 6 -alkyl, C 1 -C 6 alkylcarbonyl group; Substituents or alkyl groups are substituted by one to five substituents selected from the group consisting of halogen, cyenockipine, nitro, amino, and mmr, (e) radicals of the formula JU ^and NOR I * 11 »3 in which R (represents the group of where 121 Rg, R? and Rg is not in each case hydrogen or halogen, hydroxy, nitro, amino, cyano or cyano. a (C 10 -C 10) -alkyloxy group, a (C 10 -C 10) -alkylene group and 1 to 4 carbon atoms, or a (C 1 -C 4) -alkylene group, or a (C 1 -C 4) -sulfonyl group -n-Η-Ι-η-γΉ. ^ a ring of two, three or four nitrogen, oxygen and sieve atoms, optionally substituted by the radical R @ 10, and R13 is hydrogen, alkyl stop, cycloalkyl, alkyl stoplo, stoplo-c-mh-R, or b10yl / uc tubule. one to five tuberculins selected from the trace include halogen atoms, cyanostopine, eitrottopine amino stopin, oercaptottopine, b10-thio group, residues of the symbol R-, arbutyl stophole v- photoS soH, amidostopine, and 10 x 10-b / t , f'rnylorihoχy0brbony1o / oC group difenylorthoxy0aгbonylř / ou group lydroзφab1olfutfieyluvé stopin-, dihydroxyfutfiI-nominal quick match, lydroзQr (freyloethoэχ) futfinylovuc íibl01χfo1Sfnylové StopIN quick match and, (f) radicals of the formula v- wherein ^R 11 represents a quick match formula The radicals R @ 1 and R @ 2 are in each case a hydrogen atom, a hydrogen atom, a hydroxyl atom, an amino stop atom, an amino stop atom, a keto-yesatopine. a tri-methylethyl group, a C až-C stopbutyl group, a C až-C b bbutyl, or Cinc-Cinc stoptin (C až-C st stop stop) or a C nebo st st st π π π π π π π jeden jeden jeden jeden jeden jeden jeden jeden jeden jeden jeden, two, three or four atoms choke, oxygen and sulfur, optionally substituted as above-o * the radical R _a, n 4 denotes the footprint of the formula 122 n is 0, 12 or - a Rg, Ry and Rg mm are as hereinbefore defined, further defined as aminostopine, alkyl (amino) cyanolyl). ) -IdostopinU) alkylamido quick match, -Uyhnhlkyl) lmidottopinU) a group of formula (β) radicals of the formula ^{0 0} s U I Λ C-CH-M-C-N-N-R In which CH represents - CH ₂ ^R n in which it represents a trace of the formula 123 R @ 8, R @ 87 and R @ 8 are each independently hydrogen, halogen, Uydruxy, aryloxy, amihostapine, cyanostaphy, trifluoromethyl, or the like. (C 1 -C 4) -alkyl, (C 1 -C 4) -alkyloxy or C 1 -C 4 -alkyloxy; where or - represents a five-, йее ^ - or seven-membered hotarocyclic ring ^ з ^ и ^ с! one, two, three or three nitrogen, oxygen and sulfur radicals optionally substituted as indicated for ^{R &lt;} ₁₅ ^& gt ^{; R &lt;} ₁₅ &gt; is hydrogen, alkylthiooyl, -N = CH-R &lt; 3 &gt; Rfg represents a hydrogen atom, a tlalkyl group or a Ι Ι ο ^ ^ ^ 1 Or is a radical Rf, an alkyl group or an alkyl group substituted by one to five tubers independently selected from the group consisting of halogen-reducing carbon atoms, cyanostaphy, oitro, αmioustapine and captostapine. and wherein, unless otherwise indicated, with all of the above alkyl and alkoxy groups, straight or branched-chain residues of 1 to 10 carbon atoms, cycloalkeoyl groups suitably 3 to 7 carbon atoms, and alkeoyl groups straight or branched (C 2 -C 10) alkanoyl, the radicals of ^{R 8} being hydrogen or (C 1 -C 4) alkoxy, R3 and R, which may be the same or different, are in each case hydrogen, C 1 -C 10 -stylic stapine, C 3 -C 7 -cyclostyl or O 50 / O, optionally substituted by one, two or three substituents independently selected from the group consisting of aminostapine, halogen atoms, hydrooxystapine, C 1 -C 4 alkyl, C 1 -C 4 alkyl, or C 1 -C 4 alkyl, or one of R 2 and R 2 is hydrogen and the other represents a Cχχ S Sapobunyobapapapapapapapapapapapapapapapapapapapapapapapapapapapapapapapapapapapapapapapapapapapapaxaxaxaxax představuje představuje představuje a salt of a sulfonic acid residue, characterized in that the compound of formula (2) is (4) R @ 1 --NH - C CC-R. I ³ -N-H 0 ' 124 in which it has the same meaning as R 1 or is an amine-function-group of cheating, R 8, R 8 and as defined above, by reacting the starting material with sulfur trioxide complex or equivalent sulfonation. an agent in the presence of an organic solvent, such as pyridine, or a mixture of organic solvents, preferably a mixture of a polar solvent. . such as dimethylformamide, and a halogenated hydrocarbon such as dichloromethane, whereupon optionally the present functional group is cleaved and the resulting product in which R @ 1 is hydrogen is converted to the corresponding product in which R @ 1 is acyl as defined above by acylation; the compound obtained is optionally converted into a salt. · I Severography, n. P., MOST Price 2,40 Kčs