HU194870B - Process for preparing 1-sulfo-2-oxo-azetidine derivatives and pharmaceuticals comprising such compounds - Google Patents

Abstract

The present invention relates to novel antibiotic-1-sulfo-2-oxo-azetidine derivatives of formula (I) wherein R1 is (F), (G), (U), (E), (J) or \ t A group of formula (V '), an amino group, an amino group or an azido group, R is a pipe powder of the formula (O), (A) or (C), an alkylcarbonyl group, a phenyl alkenyl group, or 4-halophenyl and X are hydrogen and pharmaceutically acceptable salts thereof. R-NH-CH-CO-WH R '(G)' γ5Ί ti —Lch-CO-NH - o = p-oc2h5 1 oc2h5 (V1) - C0Q5 (D188-ch2-co-n- (J) R2 I, - C- (CH2) n-R4 R3 (A) • CON (C) -1-

Description

The present invention relates to novel 1-sulfo-2-oxoazetidine derivatives. The compounds of the present invention have excellent antimicrobial and β-lactamase inhibitory activity.

To date, many different 2-oxoazetidine derivatives have been prepared and described in the literature, for example, Tetrahedron, 34, 1731-1967, Chemical Reviews, 76, 113-346 (1976) or Synthesis, 1973, 327-346. . However, no 2-oxoazetidine derivatives having a sulfo group at the 1-position and substituted at the 4-position have become known in the art.

We have now discovered that the novel 1-sulfo-2-oxoazetidine derivatives of formula (I)

R 'is (1) a group of formula (F) wherein R' and R * are the same or different alkyl groups having 1 to 4 carbon atoms, (2) a group of formula (G) wherein

R ⁶ is hydrogen or alkylcarbonyl containing from 1 to 4 carbon atoms in the alkyl moiety, carbamoyl, alkylsulfonyl having from 1 to 4 carbon atoms in the alkyl moiety, alkylbenzylsulphonyl in the alkyl moiety, from 1 to 4 carbon atoms in the alkyl moiety, methoxyethylacetyl; , alkoxy carbonyl, 1-methyl-1- (carboxyethyl) carbonyl, carboxyethylcarbonyl, carboxyethenylcarbonyl or a group of the formula (L) in the alkoxy moiety, and in the latter R ⁸ is (R) group of formula - alkyl group of the formula: wherein R ^c is from 1 to 10 carbon atoms - ^v w (S) is a group of formulas - in which R is a furyl or thienyl group, and

R ⁷ is phenyl, thienyl or a group of formula (I) and in the latter formula R ^e is an amino group, (3) a group of formula (U) wherein

R 'is amino, halo (1-4C) alkylcarbonylamino, (1-4C) alkyl or hydroxy,

R ^g is hydrogen or halogen; and

R ¹² is C 1 -C 4 alkyl, C 2 -C 5 alkenyl or -R ^{13 3} -R ¹⁴ and in the latter formula R ¹³ is C 1 -C 3 alkylene and R ¹⁴ is phenyl, carboxyl, C 1-4 alkoxycarbonyl, tri (C 1-4 carbon azo), 1-isosilyl (C 1-4) alkoxycarbonyl, benzhydryloxycarbonyl or 4-nitrobenzyloxy; carbonyl group, (4) a group of the formula I in which

R ¹⁶ is hydroxy, sulfo, carboxyl or benzyloxycarbonyl, (5) a group of formula (J) wherein:

R ¹⁸ is cyano, triethylsilylmethyl, thienyl, tetrazolyl, or in the latter case R ^e is as previously defined, (6) a group of formula V wherein

R ^e is as previously defined, (7) amino, (8) phenyl (1-4C) alkoxycarbonyl-amino optionally substituted with nitro, or (9) azido, and R is (1) '. A group of formula (D) wherein Q ⁵ is C 1-4 alkoxy, 4-nitrobenzyloxy, hydroxy or alkoxycarbonylalkoxy containing 1-4 carbon atoms in the alkyl moiety; A) wherein n is 0, 1, 2 or 3,

R ² and R ³ each independently represent hydrogen or C 1-4 alkyl, and

R ⁴ represents a halogen atom or an alkoxycarbonyl group containing 1 to 4 carbon atoms in the alkyl, phenyl, cyano, hydroxy, carbamoyloxy, alkylsulfonyloxy, hydroxysulfonyloxy, amino, azido, 1 to 4 carbon atoms in the alkyl moiety; -C4 alkylthio, pyridinium, alkylcarbonyloxy having from 1 to 4 carbon atoms, haloalkylcarbonyloxy having from 1 to 4 carbon atoms in the alkyl moiety, (1-4C) alkyltetrazolylthio, benzoyloxy, alkylcarbonylamino, benzoylamino, trifluoroacetylamino having 1 to 4 carbon atoms in the alkyl moiety, (alkylsulfonyl) (alkoxycarbonyl) amino, 4-nitro having 1 to 4 carbon atoms in the alkyl moiety benzyloxycarbonylamino or a group of the formula (R ') wherein X' is methylene, methylene thio or the group (S '), Q' is thienyl, 1- (1-4) carbon atoms containing al-2194870 kil) -tetrazolyl or 2- (amino-v brain is a halo (C 1 -C 4) alkylcarbonylamino) thiazolyl group and Q ^{2 is} a C 1 -C 4 alkoxy group, (3) 'is a group of formula C wherein Q ³ and Q ^{4 are the} same or having different meanings for hydrogen or C 1-4 alkyl,

C1-C4 alkoxy, phenyl, phenyl (C1-C4) alkoxycarbonyl (C1-C4) alkyl, carboxy (C1-C4) alkyl or sulfo, ( 4) 'alkyl has 1 to 4 carbon atoms in the alkyl moiety, (5)' is phenyl (C 2 to 4) alkenyl or (6) '4-halophenyl and X is hydrogen. - and their pharmaceutically acceptable salts possess excellent antimicrobial activity and β-lactamase inhibitory activity.

According to the present invention, compounds of formula (I) are prepared by sulfonating a compound of formula (II) wherein R, R ¹ and X are as defined in formula (I) or a salt of (III). acylating the compound of formula (I) wherein R and X are as defined in formula (I).

For example, the alkyl groups of the above-mentioned compounds of formulas I, II and III include methyl, ethyl, η-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl. group.

The 1-sulfo group of the compounds of formula (I) according to the invention and the carboxyl group or groups in the meaning of R and / or R ¹ may be present in the free compound R ¹ (formula a). Alternatively, these groups may have non-toxic cations such as sodium or potassium or basic amino acids (such as arginine, ornithine, lysine or histidine) or polyhydroxyalkylamines (such as N-methylglucamirine, diethanolamine). , triethanolamine or tris (hydroxymethyl) aminomethane). When R and / or R ¹ contains a basic group, a compound of formula I may be present with organic acids (e.g., acetic acid, tartaric acid or methanesulfonic acid), inorganic acids (e.g., hydrochloric, hydrobromic, sulfuric or phosphoric acid) or acidic amino acids. (e.g., aspartic or glutamic acid) may form an acid addition salt.

The compounds of formula (I) obtained by the process of the present invention may exist in the form of various isomers such as cis, trans, color, anti- and optically active isomers, as well as the starting compounds of formula (II). One skilled in the art will appreciate that any isomer or mixture of isomers is contemplated to be within the scope of the present invention, and that pure isomers or isomer mixtures may be used as active ingredients in pharmaceutical compositions.

For example, one type of stereoisomer of the compounds of formula (I) may be represented by the formula (Ia). In formula (Ia) wherein R, in the β-configuration, R 'and the α-configuration, X is as defined in formula (I) and the wavy line represents that with respect to the 3-position of R ¹ substituent of R is trans- or cis configuration.

The following are specific examples of compounds of formula (I).

XR (Number of Formula) (LXXV) (LXXVI) (LXXV) (LXXVI) (LXXVII) (LXXVa) (LXXVIa) (LXXVII) (LXXVII) (LXXIX) (LXXIX) (LXXIX) (LXXIX) ) (LXXXV) (LXXXVI) (LXXV)

H -COOCH ₃

H -C00CH ₃

H -CH ₂ OCOCH ₃

H -CH ₂ OCOCH ₃

H (LXXVII!)

H -C00CH ₃

H -C00CH ₃

H -C00CH ₃

H _-CH2 NHCOCHj

H -COOCH ₃

H -COOC ₂ H ₅

H - C 0 0-n- C i | H 9

H-COOH

H (LXXXIII)

H -C00CH ₃

H -C00CH ₃

H -C00CH ₃

H -C00C ₂ H ₅

-3194870

Compound R ¹ (Number of Formula) (LXXV) (LXXV) (LXXXVII) (LXXXVIII) (LXXXIX) (LXXVI) (XCI) (LXXVI) (LXXVI) (LXXVI) (LXXVI) (LXXVI)

NH ₂ 33 (LXXVI) (LXXVI) (LXXVI) (LXXVI) (LXXVI) (XCV) (LXXXVI) (LXXXVI) (LXXXVI) (LXXXVI) (LXXXVI) (XCV) (LXXXVI) (LXXXVI) (LXXVI) ) (XCVII) (XCVIII) (LXXXVI)

A preferred narrow group of compounds of formula (I) are compounds of formula (Ib), wherein Q ³ , Q ⁴ , Q ⁷ , Q ⁸ and the wavy line are as previously defined, and salts thereof. ⁷ When Q is amino, the compound of formula (Ib) may form an inner salt as a result of interaction between an amino group and a sulfo group in the 1-position in Q ⁷ is appropriate.

The compounds of formula I and their pharmaceutically acceptable salts possess valuable antibiotic activity against a variety of Gram-positive or Gram-negative bacteria. Thus, they can be used as active ingredients in pharmaceutical compositions for the treatment of human or domestic animals, or for pharmaceutical compositions having antimicrobial activity for the treatment of infections caused by Gram-negative or Gram-positive bacteria. In addition, the compounds of the present invention may be used as disinfectants for the preservation of animal feed. Further, 0.1 to 100 p.p.m. 4

X R (number of formula)

H -C00-nC ₄ H ₉

H (LXXXIII)

H -COOCH ₃

H -C00CH ₃

H -COOCH ₃

H (XC)

H -C00CH ₃

H (XCII)

H -CH ₃

H (XCIII)

H (XCV)

H -COCH ₃

H -CH ₂ C00CH ₃

H -C00CH ₃

H-COOH

H -CH ₂ NH ₂

H -CH ₂ OH

H -CH ₂ OCH ₃

H-CONH ₂

H -C00CH ₃

H-CO ₂ NH ₂

H -CH ₂ N ₃

H -CH ₂ OCH ₃

H -CH ₂ (CH ₂ ) ₃ COOH.

H -CH ₂ OH

H -CH (CH ₃ ) ₂

H -CH ₂ OCOCH ₃

H -CH ₂ NHCOCH ₃

H -CH ₂ CONHCH ₃

H -COOCH ₃

H -COOCH ₃

H-CO ₂ NH ₂

H-CH ₂ CO ₂ NH ₂ (i.e., 0.1 to 100 parts by weight antibiotic in 1 000 000 parts by weight) in aqueous formulations for killing harmful bacteria and stopping their growth on general medical or dental equipment or killing bacterial life in industrial aqueous media such as aqueous based paints or paper mills.

The compounds of the formula I and their salts may be used alone or in combination with one or more other active ingredients in the form of conventional pharmaceutical preparations such as capsules, tablets, powders, solutions, suspensions or elixirs. These compositions may be administered orally, intravenously or intramuscularly.

The oral tablets may contain conventional excipients such as binding agents (e.g. syrup, acacia, gelatin, sorbitol, tragacanth or pollvinilpirrolidon) töltőanyagoβ ₅ MOT (e.g. lactose and other sugars, corn starch, calcium phosphate, sorbitol

-4Ί or glycine), lubricants (e.g., magnesium stearate, talc, polyethylene glycol or silica), disintegrants (e.g., potato starch) or a suitable wetting agent, such as sodium lauryl sulfate. The tablets may be coated in a manner well known to those skilled in the art. Oral liquid preparations may be formulated, for example, in the form of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or in the form of lyophilisates, which may be dissolved in water or other suitable solvent when used. These liquid preparations may contain a suspending agent (such as sorbitol syrup, methylcellulose, glucose syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose or aluminum stearate gel); hydrogenated digestible oil (e.g. bitter almond oil, coconut oil fractions, oily esters, propylene glycol), ethanol or preservatives (such as methyl 4-hydroxybenzoic acid and / or propyl ester or sorbic acid). Suppositories may contain conventional suppository bases such as theobromo oil or other glyceride.

Injectable formulations may be marketed in ampoules or other dosage unit containers with the addition of a preservative. These injectable formulations may be in the form of suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain suitable additives such as suspending agents, stabilizers and / or dispersing agents. Alternatively, the active component may be in powder form for constitution with a suitable vehicle, for example sterilized anti-fever water, before use.

The active ingredient may also be formulated into a pharmaceutical composition which is capable of being absorbed through the mucous membranes of the nose, throat or lungs. Such compositions may be in the form of a powder, a liquid spray or an inhaler, a lozenge or a throat brush. Capsules or drops of liquid or semi-solid active ingredient are suitable for ophthalmic and aural use. In addition to the compositions described herein, pharmaceutical compositions such as ointments, creams, lotions, brushes or powders for external use may be prepared with hydrophobic or hydrophilic pharmaceutical ingredients.

In addition to carriers, these compositions contain other ingredients such as stabilizers, binders, antioxidants, preservatives, lubricants, suspending agents, rheological modifiers, and / or flavoring agents. However, to provide a broader antimicrobial spectrum, the pharmaceutical composition may contain one or more other active ingredients.

For use in domestic animals, the compounds of the present invention may be formulated with sustained release additives for intramuscular use.

The compounds of formula (I) of the present invention are thus useful in the treatment of microbial infections in mammals, such as infections of the respiratory tract, urinary tract, epetract and intestinal tract, purulent diseases, and in obstetrics, gynecology and wound healing. . The daily dose of the compounds of Formula I will depend, among other things, on the condition of the patient being treated, the weight of the host, the mode and frequency of administration, and the particular parenteral route for general infections or the oral route for intestinal infections. In general, the daily dose is about 15 to 600 mg per kilogram body weight of the patient in single or multiple administrations. In adult humans, the daily dose is about 10 to 200 mg / kg body weight of the active ingredient, which can be administered by 2-4 administrations a day, at doses ranging from 2.5 to 100 mg / kg body weight, by a different route than oral administration.

Thus, a pharmaceutical composition comprising an active ingredient of formula (I) may be administered in various solid or liquid dosage units for oral administration. The liquid or solid composition may contain from 0.5 to 99% by weight of the active ingredient. Preferred concentrations of the active ingredient are about 10-60%. The compositions will generally contain from about 15 mg to about 1500 mg, preferably from about 250 mg to about 1000 mg, per unit dose.

In addition to the uses described above, the compounds of formula (I) and their pharmaceutically acceptable salts and esters prepared by the process of the present invention can be used in combination with a β-lactam antibiotic because of their β-lactamase inhibitory activity. Examples of such β-lactam antibiotics include penam carboxylic acid derivatives such as benzyl penicillin, phenoxymethyl penicillin, carbenicillin, ampicillin, amoxicillin or sulbenicillin, as well as cephem-carboxylic acid, cephalic, , cefalexin, cefoxitin, cefacetril, cefainandol, cefmenoxime, cefsulodin, cefo5

-5194870 thiam, cefotaxime, cepharin, ceftizoxime, cefradine or cephaloglycine.

The 1-sulfo-2-oxoazetidine derivatives of formula (I) can be prepared, as mentioned, by sulfonation of a compound of formula (II).

The compounds of formula (II) used as starting materials in the process of the invention may be used in the form of their salts with various acids or bases, and also in the form of their esters or silyl derivatives. Since the compounds of formula II contain substituents at the 3- and 4-positions, they may be in the form of a cis or trans isomer or a mixture thereof. In addition, due to the asymmetry of the 3 and 4 carbon atoms, there are theoretically at least four stereoisomers in total. These stereoisomers may be used singly or in the form of mixtures thereof. The same is the case when R or R ¹ substituent contains asymmetric carbon atoms. Here again, the corresponding stereoisomers may be used singly or in the form of mixtures thereof.

Salts and esters of compounds of formula (II) include, for example, salts or esters of compounds of formula (I). However, the compounds of formula (II) may also be silylated with a suitable silylating agent. For example, a silylating agent is a compound of formula C, wherein Ρ ¹ , P ² and P ³ are each alkyl, such as methyl, ethyl, η-propyl, isopropyl, or a hydrocarbon derivative such as 1 to 4 carbon atoms. n-butyl) or aryl (such as phenyl or tolyl) and Hal represents a halogen atom, preferably a chlorine or bromine atom, and one or two of Ρ ¹ , P ² and P ³ may also represent a halogen atom, preferably a chlorine or bromine atom and one of Ρ ¹ , P ² and P ³ is hydrogen. The silylating agent can also be hexa (1-4C) alkylcyclo triosilanes, octa (1-4C) alkylcyclotetrasilazanes or bis [tri (1-4C) alkylsilyl] acetamides. Preferred silylating agents are those of formula (C1) wherein Y is a reactive silyl group, Y ¹ and Y ^{2 are C} 1-4 alkyl, C 1-4 alkoxy, phenyl or benzyl and Y ³ is tert-butyl or isopropyl.

In Y ¹ and Y ² , alkyl may be, for example, methyl, ethyl, η-propyl, isopropyl, n-butyl or tert-butyl, while alkoxy may be exemplified by methoxy, ethoxy, η-propoxy, for example, isopropoxy, n-butoxy or tert-butoxy.

A reactive group capable of releasing the silyl compound is, for example, a halogen atom (such as chlorine or bromine); N- (tri-1 kilo-11) -trifluoroacetimidoyloxy; N- (trialkylsilyl) acetimidoyloxy; acylamino (such as formylamino, acetylamino, propionylamino, butyrylamino or trifluoroacetylamino); a trialkylsilylamino group (such as tert-butyldimethylsilylamino, isopropyldimethylsilylamino or chloromethyldimethylsilylamino); amino; alkylamino (such as methylamino, ethylamino, or propylamino); An N, N-dialkylamino group (such as Ν, Ν-dimethylamino, N-chloromethyl-N-methylamino, N, N-diethylamino, Ν, Ν-dipropylamino, N-methyl-N-ethylamino, N-methyl-N-propylamino or N-ethyl-N-propylamino) or a heterocyclic group (such as imidazolyl). As for the alkyl moiety of this reactive group, it preferably contains from 1 to 4 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl.

Examples of the above-mentioned silyl compounds include, but are not limited to, Ν, Ο-bis (tert-butyldimethylsilyl) trifluoroacetamide, Ν, Ο-bis (isopropyldimethylsilyl) acetamide, bis (dimethylisopropylsilyl) acetamide, isopropyldimethylsilylacetamide, bis (dimethyl tert-butylsilyl) acetamide, N-methyl-N-tert-butyldimethylsilylacetamide, N- methyl N-isopropyldimethylsilyl 1-trifluoroacetamide, N-tert-butyldimethylsilyl diethylamine, 1,3-bis (chloromethyl) -1,1,3, 3-Tetra-tert-butyldimethyldisilazane, N-isopropyldimethylsilylimidazole, tert-butyldiphenylchlorosilane, isopropyldiethylchlorosilane, isopropyldimethyldichloro silane, tert-butyldimethylchlorosilane, isopropyldimethylchlorosilane or tert-butyl diethylchlorosilane. Of these, t-butyldimethylchlorosilane or isopropyldimethylchlorosilane are preferred. The silylation reaction is carried out in a manner known per se. The silylation temperature is from about 0 ° C to about 50 ° C, preferably not more than 38 ° C, usually room temperature (about 20 ° C). The reaction time may vary from a few minutes (about 10 minutes) to about 24 hours. The reaction is conveniently carried out in a solvent such as ethyl acetate, dioxane, tetrahydrofuran, Ν, Ν-dimethylacetamide, N, N-dimethylformamide, dichloromethane, chloroform, benzene, toluene, acetone, methyl ethyl ketone or acetonitrile. or in a mixture thereof or in any other solvent which is a reactant shock ^. is chemically inert. The reaction may be carried out with an inorganic base such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate or potassium carbonate; a trialkylamine such as triethylamine or tributylamine; a triarylalkylamine such as benzylamine; an organic tertiary amine such as N-methylmorpholine, N-methylpiperidine, an Ν, Ν-dialkinaniline, an N, N-6194870

-dialkylbenzylamine, pyridine, picoline or lutidine; or an organic base such as 1,5-diazabicyclo [2.2.2] octane or

In the presence of 1,8-diazabicyclo [5.4,4] undec-7-ene. If the base is in liquid form, it may also serve as a solvent.

The silyl derivative of the compounds of formula (II) prepared as described above can be used in the sulfonation reaction of the invention without isolation or after isolation and purification in a known manner.

The sulfonation reaction is a reaction suitable for introducing a sulfo group. In the process, a compound of formula II is treated with sulfur trioxide or a reactive derivative thereof.

As the reactive derivative of sulfur trioxide, it is possible to use, for example, the sulfur trioxide adduct with N, N-dimethylformamide, pyridine, dioxane, trimethylamine or chlorosulfonic acid.

In the reaction, sulfur trioxide or one of its reactive derivatives is used in an amount of about 1 to 10 moles, preferably 1 to 5 moles, per mole of the compound of formula (II).

The reaction temperature is about -78 to 80 ° C, preferably -20 to 60 ° C. The reaction may be carried out with a solvent. Suitable solvents for this purpose include water, ethers such as dioxane, tetrahydrofuran or diethyl ether; esters such as ethyl acetate or ethyl formic acid; halogenated hydrocarbons such as chloroform or methylene chloride; hydrocarbons such as benzene, toluene or n-hexane; amides, such as Ν, Ν-dimethylformamide or N, N-dimethylacetamide, or mixtures of these solvents. The reaction is usually complete within a few minutes to a few hours, depending on the nature of the starting compound (II) and the sizing agent used, the reaction temperature and the solvent, but in some cases it may take days to complete the reaction. After completion of the reaction, the reaction mixture is subjected to purification and isolation steps known per se, such as solvent extraction, recrystallization or chromatography, to give the target compound of formula (I) of any purity.

Alternatively, a portion of the compound of formula (I) may be prepared by acylating a compound of formula (III) wherein R and X are as defined above.

The acylation is carried out by reacting a compound of formula (III) or a salt, ester or silyl derivative thereof with an acylating agent using at least 1 mole, preferably 1.2 to 4 moles, of acylating agent per mole of compound (III). The acylating agent used in this reaction is an organic carboxylic acid or a reactive derivative thereof which contains an acyl group represented by R ¹ . Thus, the carboxylic acid is represented by the general formula R 0 COOH, wherein R 0 CO is an acyl group having the same meaning as previously defined for the acyl moiety of the acylated amino group mentioned in R ¹ .

Suitable reactive derivatives of organic acids include, but are not limited to, acid anhydrides, reactive amides, and reactive esters. Examples of such reactive derivatives of organic acids include:

1) Anhydrides:

Acid anhydrides include those disclosed, for example, with halogen hydrogens (such as hydrochloric or hydrobromic acid), monoalkylcarboxylic acids, aliphatic carboxylic acids (such as acetic acid, pivalic acid, valeric acid, isovaleric acid or trichloroacetic acid) such as aromatic carboxylic acids (e.g. benzoic acid!) and anhydrides. metric acid anhydrides.

2) Reactive amides:

Reactive amides include, for example, amides with pyrazole, imidazole, 4-substituted imidazoles, dimethylpyrazole or benzotriazole.

3) Reactive esters:

Reactive esters include, but are not limited to, esters such as methyl, ethyl, methoxymethyl, propargyl,

4-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl, pentachlorophenyl and mesylphenyl esters as well as esters with alcohols such as 1-hydroxy-1H-2-pyridone, N-hydroxysuccinimide or N-hydroxyphthalimide.

Depending on the nature of the acid used in the particular case, one of the reactive derivatives listed above is selected for the particular case. If, however, the free acid is used as the acylating agent, the acylation is preferably carried out in the presence of a condensing agent. Examples of suitable condensing agents are N, N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N'- (4-diethylaminocyclohexyl) carbodiimide or N- ethyl N ', 3-dimethylaminopropyl) carbodiimide.

The acylation is usually carried out in a solvent. Suitable solvents for this purpose include water, acetone, dioxane, acetonitrile, methylene chloride, chloroform dichloroethane, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, Ν, Ν-dimethylacetamide, pyridine and the like. , a known organic solvent which is inert to storage compartments. Of these, hydrophilic solvents, for example mixtures with water, may be used.

-7194870

The acylation may be carried out in the presence of an inorganic base (such as sodium hydroxide, sodium carbonate, potassium carbonate or sodium bicarbonate) or an organic base. The latter may be trialkylamines such as trimethylamine, triethylamine, tributylamine, N-methylmorpholine or N-methylpiperidine; organic tertiary amines such as N, N-dialkylanilines, Ν, Ν-dialkylbenzamines, pyridine, picoline or lutidine; tetra (n-butyl-ammonium) hydroxide; 1,5-diazabicyclo [4.3.0] non-5-ene; 1,4-diazabicyclo [2.2.2] octane or 1,8-diazabicyclo [5.4.4] undec-7-ene. When the base or the aforementioned condensing agent is in liquid form, it may also serve as a solvent. The reaction temperature is not a critical parameter, however, the reaction is usually carried out under cooling or at room temperature. The resulting compound of formula (I) can then be isolated and purified in a manner known per se, for example by concentration, acidification of the reaction mixture to an acidic or basic acid, solvent exchange, solvent extraction, crystallization, recrystallization, fractional distillation.

When a starting compound of formula (III), a reactive derivative thereof at an amino group, a salt thereof, or an acylating agent, contains at least one asymmetric carbon atom, the corresponding stereoisomers may be acylated alone or as mixtures thereof. If the acylation product is a mixture of the corresponding isomers, the individual isomers may be separated, if desired, by conventional means such as column chromatography. or by recrystallization.

In one of the target compounds of formula (I), the R group can be converted to another R group without loss of the 1-sulfo group.

If the resulting compound of formula (I) contains a protecting group, it can be removed by selective methods well known in the art. Such methods include the acid, base or hydrazine methods, the reduction method, or an imino halogenating agent followed by an imino etherification method. Following the latter method, bridge lysis is performed if necessary. The choice of these methods depends on the type of protecting group to be removed. In the acid-based method, depending on the type of protecting group and other conditions for the deprotection, you acidify the acids. For example, hydrochloric acid, sulfuric acid or phosphoric acid, and organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, benzene sulfonic acid or p-toluenesulfonic acid, and acidic ion-exchange resins can be used. depending on other conditions for the cleavage, inorganic bases such as hydroxides or carbonates of alkali metals (such as sodium or potassium) or alkaline earth metals (such as calcium or magnesium), and organic bases such as metal alcoholates, organic amines or quaternary ammonium salts and basic ionic salts.

When the method based on the use of an acid or a base is carried out in the presence of a solvent, the solvent is usually a hydrophilic organic solvent, water or a mixture thereof.

Depending on the type of protecting group and other conditions for deprotection, metals (such as tin or zinc), phenolic compounds (such as chromium (II) chloride or chromium (II) acetate) with an acid such as an organic or inorganic acid (e.g. with propionic acid or hydrochloric acid) or metal catalysts suitable for catalytic reduction. The catalyst used for such catalytic reduction is, for example, a platinum catalyst (such as platinum wire, platinum sponge, platinum carbon black, platinum oxide or colloidal platinum), a palladium catalyst (such as palladium sponge, palladium carbon black, palladium oxide, colloidal palladium or barium sulfate, supported palladium catalyst containing carbon or silica gel), reduced nickel, nickel oxide, Raney nickel or Urushihara nickel.

As mentioned, another reduction method is based on the combination of a metal compound and an acid. For this purpose, a mixture of a metal compound (e.g. an iron or chromium compound) and an organic acid (formic acid, acetic acid or propionic acid) or an inorganic acid (e.g. hydrochloric acid) is utilized. This reduction method is also usually employed in a solvent. For example, in the catalytic reduction method, the reaction is usually carried out in the presence of an alcohol (such as methanol, ethanol, propanol or isopropanol) or ethyl acetate. For the reduction method using metal and acid, for example, water or acetone are used as the solvent, but if the acid is in liquid form, it can also be used as a solvent.

When an acid, a base or a reduction is used, the deprotection can be carried out over a wide temperature range, by cooling or by heating.

When the deprotection is carried out by reaction with an iminohalogenating agent followed by hydrolysis with an iminoether ether, if necessary, the phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus tribromide, phosphorus tribromide, - 5 genes. The reaction temperature is not critical, however, the reaction is usually carried out at room temperature or under cooling. The resulting reaction product is then reacted with an iminoetherizer such as an alcohol 10 or metal alcoholate. Suitable alcohols include, for example, methanol, ethanol, propanol, isopropanol, n-butanol or tert-butanol, as well as compounds wherein the alkyl moiety of said alcohols has an alkoxy group such as methoxy, ethoxy, propoxy, , isopropoxy or butoxy substituted. Metal alcoholates include alkali metal alcoholates (e.g., sodium or potassium alcoholates) and alkaline earth metal alcoholates (e.g., calcium or barium alcoholates), which may be derived from the above-mentioned alcohols.

If the protecting group is derived from an organic carboxylic acid residue and has a substituent such as a free amino, hydroxyl, mercapto, carboxyl or sulfo group attached to the carbon atom adjacent to the carbonyl group, it may be advantageous to carry out a preliminary reaction of such a substituent to the carboxyl group. and then remove the protecting group. For example, when said substituent group is a free amino group, this free amino group is first converted to a thioureido group prior to the deacylation reaction. Thus, the protecting group can be removed by standard procedures for peptide bond abdominal pouch ^40. The reaction temperature is not a critical parameter, however, it may be selected depending on the type of protecting group, the method of cleavage of the protecting group, although the reaction is preferably carried out under mild conditions such as poor cooling or weak heating.

When R and / or ^one carboxyl-containing radical R 50 in some cases, the features may be derived from carboxyl derivatives then converted into a free carboxyl group in the carrier for reaction. These cases are also considered to be within the scope of the invention. 55

The resulting unprotected product of formula (I) may, if desired, be converted into the corresponding salt.

Compounds of general formula (I) containing the sulfo group (I) are generally capable of reacting with a base to form a salt. Thus, the compounds of formula (I) may be isolated in the form of a salt and, if desired, the free base may be liberated from the resulting salt or the salt may be converted to another salt θ ⁵ . The compounds of formula (1) obtained in the form of the free base can also, of course, be converted into their salts. For example, the free base can be liberated from the compounds of formula (I) in salt form by treatment with an acid. Suitable acids for this purpose are, for example, inorganic acids (such as hydrochloric, sulfuric or phosphoric acid) or organic acids (such as formic acid, acetic acid or p-toluenesulfonic acid), depending on the particular salt and other conditions. Alternatively, an acidic ion exchange resin may be used for this purpose. The solvent may be a hydrophilic organic solvent, such as acetone, tetrahydrofuran, methanol, ethanol or dioxane, and water or a mixture of any of said hydrophilic organic solvents. The reaction is usually carried out at room temperature, although it may be carried out under cooling or heating. The reaction time depends on the particular acid, solvent and reaction temperature used. It is preferred that the reaction is completed as soon as possible. The resulting free-form compound of formula (I) can be isolated by methods known per se, as described above.

The starting compounds of formula II are illustrated in the accompanying drawings 1 to 17. can be prepared by analogous methods to those described in Methods.

1 through 17. procedures Ac is acetyl, Et is ethyl, Me is methyl, isopropyl, is isopropyl, Ar is aryl, R ¹ 'is an acylated or protected amino group, the DBH

I-3-diazabicyclo [5.4.0] undec-7-ene and DCC for dicyclohexylcarbodiimide.

1 through 17. The starting materials used in the processes include, for example, the cis-3-amino-1- (2,4-dimethoxybenzyl) -2- (IV) compound of formula (IV) as described in J. Am. Chem. Soc. 99, 2352 (1977). azetidinone-4-carboxylic acid methyl ester; No. 136694/1976; methyl cis-1- (2,4-dimethoxybenzyl) -3-phthalimido-2-oxo-azetidine-4-carboxylic acid methyl ester (XIV) disclosed in Japanese Patent Application Laid-Open; the

J. Org. Chem., 34, 1977 (1969) cis-3-azido-4-phenyl-2-oxoazetidine (XXI); J. Am. Chem. Soc., 101. 4730 (1979), cis-3-azido-1- (2,4-dimethoxybenzyl) -4- (2,2-dimethoxy) ethyl) -2-oxoazetidine; Synthesis, 1979, 543, cis-1- (3,4-dimethoxybenzyl) -3- (phenoxyacetamido) -4-phenyl-2-oxoazetidine (XXXI) and J. Am. Chem., Soc., 100, 313 (1978), 2,2-dimethyl-1-aza-3-oxabicyclo [4.2.0] octan-8-one (LXXI). Of course, these examples are not intended to limit the scope of the starting materials to the specific compounds mentioned, and although

-9194870 which is a compound useful for the purposes of the present invention. Examples of such starting materials will be given in the reference examples.

The following experimental example, embodiments, and reference examples are intended to illustrate the invention.

In the Examples and Reference Examples, column chromatography on the eluate shows the presence of the product by thin layer chromatography. For these assays, the finished plates 60F ₂₅₄ supplied by Merck and Co. are used. The eluent used was column chromatography. We detect it with ultraviolet light. The fractions containing the desired product which, after spraying with 48% hydrobromic acid, contain spots which give a purple color with ninhydrin are considered to contain the desired product.

In the case where two types of solvents are mentioned in the elution, the first serves to wash the column and remove by-products from the column, and the second serves to elute the product unless otherwise noted. The products are dried over anhydrous sodium sulfate, unless otherwise noted. For column chromatography on Amberlite or Sephadex ion exchange resins, water is used first, unless otherwise noted, with a gradually increasing concentration of aqueous ethanol.

The Amberlite branded resin is from Rohm and Haas in the US, the Dowex brand from The Dow Chemical Co. in the US and the Sephadex brand from Swedish Pharmacia Fine Chemicals. All specified temperatures are uncorrected. Percentages are by weight, except in the case of solvents, which refer to volume percentages.

NMR spectra were recorded on Varian EM 390 (90 MHz) and T 60 (60 MHz) instruments, tetramethylsilane was used as the external or internal reference material, and delta values were reported in ppm. The following abbreviations are used when specifying chemical shifts: s = = singlet; d = doublet; dd - double doublet; t, triplet; q - quartet; m = multiplet; ABq = quartet AB, J = coupling constant; THF = tetrahydrofuran; DMF = dimethylformamide; DMSO - dimethyl sulfoxide; br. = wide, aroma = aromatic and sh = = shoulder.

In the embodiments, the following abbreviations are also used: Ph = phenyl; Me - methyl; Et = ethyl, DMSO = dimethyl sulfoxide and D ₂ O = heavy water.

Experimental example

In the following table, the minimum inhibitory concentration (MI) of some typical compounds of formula I prepared according to the embodiments is given.

The MIC of the test compounds is determined by agar-agar dilution. An aqueous solution of the test compound (obtained by serial dilution) was poured into an experimental petri dish (1.0 mL), and another 9.0 mL of Trypticase Soy (agar) agar solution was added to the dish and the two materials were mixed. To the resulting agar-agar plate is added a spoonful of bacterial suspension of the test microorganism at a concentration of about 10 ⁸ CFU / ml. After incubation at 37 ° C overnight, the lowest concentration of test compound that is apparent to cause complete inhibition of the growth of the test microorganism is determined. This will be the MIC value.

Enterobacter cloacae IFO-12937 (1) and Klebsiella pneumonia TN-1711 (2) are used as experimental microorganisms.

The results are given in the following table, in mcg / ml. The test compound is a microorganism

(the example serial number) (1) (2) 63 6.25 0.2 66 3.13 0.78 70 1.56 - 130 1.56 0.39 133 - 1.56 135 - 6.25 141 6.25 3.13 144 3.13 0.39 152 3.13 6.25

Example I

201.9 mg of methyl qis-3- [2- (2-chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido) -2-oxoazetidine-4-carboxylic acid (color) (Isomer) To a solution of 3.5 ml of Ν, Ν-dimethylformamide (15 ml) was added 159.2 mg of pyridine-sulfur trioxide complex and the mixture was stirred at room temperature for 5 days. A further 80 mg of pyridine-sulfur trioxide complex was then added and stirring continued for a further two days. Diethyl ether (50 mL) was added to the reaction mixture, resulting in the precipitation of insoluble materials. The upper ether phase is decanted off and the precipitate is washed again with ether. The ether layer was added again with decan-10194870 and the solid residue was dissolved in water (5 mL). The resulting solution is filtered and the filtrate is passed through a Dowex 50 W Na ⁺ resin column. The eluate was freeze-dried, then taken up in a minimum amount of water and purified by column chromatography on Amberlite XAD-II. The eluate was freeze-dried to give cis-3- (2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido) -4- (methoxycarbonyl) -2-oxoazetidine-1 sodium sulfonic acid (color isomer) is obtained.

IR (λ max): 3400, 3225, 1780, 1735, 1670, 1055.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.6 (s, - COOCH ₃ ), 3.84 (s, = N - OCH ₃ ), 4.29 (s, Cl - CH ₂ -), 4 , 45 (d, J = 6Hz, C ₄ -H), 5.38 (dd, J = 6Hz, 8Hz, C ₃ -H), 7.23 (s, CV), 9.41 ( d, J == = 8 Hz, CVI)

Example 2

Under ice-cooling and stirring, 23.85 mg of sodium monomethyldithiocarbamate is added with 85 mg of cis-3- (2- {2- (chloroacetamido) -4-thiazolyl) -2- (methoxyimino) acetamido} -4 - (methoxycarboxyl) -2-oxo-azetidin-1-yl fatty acid π atrium salt (color isomer) in a 2 ml aqueous solution, stirred at room temperature for 40 minutes, followed by another 7 mg of sodium monomethyl Stirring was continued for a further 30 minutes, the reaction mixture was filtered and the filtrate was washed with diethyl ether and the aqueous phase was purified by column chromatography on Amberlite XAD-II to freeze-dry the eluate to give cis-3- [2- (2-amino-). 4-Thiazolyl) -2- (methoxyimino) acetamido] -4- (methoxycarbonyl) -2-oxoazetidine-1-sulfonic acid (color isomer) is obtained.

IR (νmax ^M ) 3350, 1775, 1055.

NMR _(D6 -DMSO, ppm): 3.61 (s, -COOCHj), 3.81 (s, N == _-OCH3), 4.45 (d, J = 6Hz, C ₄ - H), 5.35 (dd, J = 6Hz, 8Hz, _C3 -H), 6.56 (s, a group of formula CV), 7.1 (br, _-NH2), 9.33 (d , J = 8Hz, CVI).

Example 3

418 mg of cis-4- (acetoxymethyl) -3- (2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido) -2-oxoazetidine (colorless). To a solution of isomeric solution in 3 ml of Ν, Ν-dimethylformamide was added 318 mg of pyridine sulfur trioxide complex and the mixture was stirred at room temperature for 24 hours, then another 159 mg of pyridine sulfur trioxide complex was added and mg of the complex was added and stirred for an additional 70 hours, then diethyl ether was added to the reaction mixture, resulting in the precipitation of insoluble materials.

The ether was decanted off, and the precipitate was washed again with ether and filtered. The resulting crystals were dissolved in water (5 mL) and the solution filtered. The filtrate was passed through a Dowex 50 W Na ⁺ resin column. The eluate was freeze-dried, taken up in 5 ml of water and purified by column chromatography on Amberlite XAD-II. Freeze drying of the eluate gave cis-4- (acetoxymethyl) -3- (2- [2- (chloroacetamido-4-thiazolyl) -2- (methoxyimino) acetamido] -2-oxoazetidin-1- The sodium salt of the sulfonic acid (color isomer) is obtained.

IR (ν max): 3400.3250, 1760, 1665, 1045.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.95 (s, - OCOCH 3), 3.83 (s, = N - OCH ₃ ), 3.8 - 4.4 (m, C ₄ --H) & - _CH2 OCO), 4.3 (s, C1CH ₂ -), 5.15 (dd, J = 4.5 Hz, 8Hz, _C3 -H), 7.3 (s, a group of formula CV ), 9.3 (d, J = 8Hz CVI).

Example 4

Under ice-cooling and stirring, 41 mg of sodium monomethyl dithiocarbamate are added, and 150 mg of cis-4- (acetoxymethyl) -3- (2- (2- (chloroacetamido) -4-thiazolyl) -2- (methoxyimino) are added. -acetamido) -2-oxo-azetidine-1-sulfonic acid, sodium salt (color isomer), in a volume of 4 ml, was stirred at room temperature for 30 minutes, and an additional 10 mg of sodium monomethyl dithiocarbamate was added. The filtrate was washed with diethyl ether and the aqueous phase was purified by column chromatography on Amberlite XAD-II, freeze-drying the cis-4- (acetoxymethyl) -3- [2- (2-amino-4) thiazolyl) -2- (methoxyimino) acetamido] -2-oxoazetidine-1-sulfonic acid sodium salt (color isomer) is obtained.

IR (ν, cm-1): 3425, 3300, 1760, 1660, 1050.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.94 (s, - OCOCH ₃ ), 3.78 (s, = N - OCH ₃ ), 3.9-4.4 (m, C ₄ H). <& - CH ₂ OCO), 5.15 (dd, J = 4.5 Hz, 8Hz, _C3 -H), 6.66 (s, a group of formula CV), 7.1 (br s, - NH ₂ ), 9.2 (d, J = 8Hz, CVI).

Example 5

To a solution of 150 mg of cis-3- (benzyloxycarboxamido (-4-) 1-methyl-5-tetrazolylthiomethyl) -2-oxoazetidine in 2 ml of Ν, Ν-dimethylformamide was added 137 mg of pyridine sulfur trioxide complex and at room temperature for 24 hours. stir. Then another 70 mg of pyridine-sulfur trioxide complex was added and stirring was continued for two hours. Diethyl ether was added to the reaction mixture, resulting in the precipitation of insoluble materials. The ether is decanted off, the precipitate is washed once more with ether and then filtered. The obtained crystals were dissolved in 15 ml of water and the residue was dried in vacuo

-11194870 solution was filtered. The filtrate was passed through a Dowex 50W Na ⁺ resin column and the eluate was freeze dried. The material was dissolved in water (5 mL) and purified by column chromatography on Amberlite XAD-II. Freeze-drying of the eluate gives the sodium salt of cis-3- (benzyloxycarboxamido) -4- (1-methyl-5-tetrazolylthiomethyl) -2-oxoazetidine-1-sulfonic acid.

IR (ν max cm ^-1 ): 3300, 1775, 1690, 1055

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 8.87 (s, -NCH ₃ ), 3.8-4.3 (m, C ₄ -H & CH ₂ S-), 4.96 (dd, J = 5Hz, 10Hz, C ₃ -H), 5.1 (s, -CH ₂ O-), 7.35 (s, -C ₆ H ₅ ), 8.16 (d, J = 10Hz, - NH).

Example 6

202 mg of cis-3- [2- [2- (chloroacetamido) -4-thiazolyl] -2-methoxyimino) acetamido} -2-oxoazetidine-4-carboxylic acid methyl ester (anti-isomer) 159 mg of pyridine-sulfur trioxide complex was added to a solution of 3.5 ml of Ν, Ν-dimethylformamide and the mixture was stirred at room temperature for 4 days. A further 80 mg of pyridine-sulfur trioxide complex was then added and stirring continued for a further 1 day. Diethyl ether (50 mL) was added to the reaction mixture, which resulted in the formation of an oily precipitate. The upper ether phase is decanted off and the oily precipitate is washed again with ether. The ether was decanted again and the remaining oily precipitate was dissolved in water (6 mL). After filtration, the filtrate was passed through a Dowex 50 W Na ⁺ resin column and the eluate was freeze-dried. The resulting material was taken up in a minimum amount of water and purified by column chromatography on Amberlite XAD-II. Freeze drying of the eluate gave cis-3- (2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetyl) -4- (methoxycarbonyl) -2-oxo. azetidine -1-sulfonic acid sodium salt (anti-isomer) is obtained.

IR (λ max ¹ ): 1760, 1670, 1040.

NMR spectrum (D _e -DMSO, ppm): 3.69 (s, -COOCH _3), 3.98 (s, NOCH _3);

4.35 (s, Cl-CH ₂ -), 4.49 (d, J = 6Hz, C ₄ -H), 5.41 (dd, J = 6Hz, C ₃ -H), 7.99 (s, CV), 9.14 (d, J = 8 Hz, CVI).

Example 7

Under ice-cooling and stirring, 21 mg of sodium monomethyldithiocarbamate are added with 85 mg of cis-3-12- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyiminoacetamido) -4- (methoxy) carbonyl) -2-oxo-azetidine-1-sulfonic acid sodium salt (anti-isomer) in 2 mL aqueous solution, stirred for 1 hour at room temperature, then added another 7 mg of sodium monomethyl dithiocarbamate and stirred for another hour. The reaction mixture was filtered and the filtrate washed with diethyl ether, the aqueous phase was purified by column chromatography on Amberlite XAD-II and freeze-dried on cis-3-12- [2-amino-4-thiazolyl] -2-methoxy. -imino) -acetamido] -4- (methoxycarbonyl) -2-oxo-azetidine-1-sulfonic acid sodium salt (anti-isomer) is obtained.

IR (λmax) 1760, 1050.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.68 (s, -COOCH ₃ ), 3.92 (s, = NOCH ₃ ),

4.46 (d, J = 6Hz, C ₄ -H), 5.36 (dd, J = 6Hz, 8Hz, C ₃ -H), 7.03 (br.s, -NH ₂ ), 7.38 (s, CV) 9.04 (d, J = 8Hz, CVI).

Example 8

To a solution of 112 mg of cis-3- (phenylacetamido) -2-oxoazetidine-4-carboxylic acid methyl ester in 3.5 ml of Ν, Ν-dimethylformamide is added 159 mg of pyridine-sulfur trioxide complex and the mixture is stirred at room temperature for 5 hours. stir for days. A further 80 mg of pyridine-sulfur trioxide complex was added and stirring continued for another day. 50 ml of diethyl ether are then added to the reaction mixture, which causes an oily precipitate to form. The ether was decanted off and the oily precipitate was washed once more with ether. The ether was decanted again and the oily precipitate was dissolved in water (5 mL). The solution is filtered, the filtrate is passed through a Dowex 50W Na ⁺ resin column and the eluate is freeze dried. The material was purified by column chromatography on Amberlite XAD-II resin in a minimum amount of water. Freeze-drying of the eluate affords the sodium salt of cis -4-methoxycarbonyl-3- (phenylacetamido) -2-oxoazetidin-1-yl fumaric acid.

IR (λ max): 1770, 1740, 1650, 1255, 1055.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.46 (CH ₂ CO & OCH ₃ ), 4.39 (d, J = 6Hz),

5.25 (dd, J = 6Hz, 8Hz), 7.24 (s, C ₆ H ₅ ), 8.82 (d, CONH).

Example 9 To a solution of cis-4- (acetamidomethyl) -3- (phenylacetamido) -2-oxoazetidine (mg) in 0.7 ml dimethylacetamide was added 52 mg of pyridine sulfur trioxide complex and the mixture was stirred at room temperature for 69 hours. stirred. 35 ml of diethyl ether were then added to the reaction mixture, resulting in the formation of an oily precipitate. The ether is decanted off and the precipitate is again washed with ether. The ether was decanted again and the residual oily precipitate was dissolved in 1 mL of water. The solution is filtered, the filtrate is passed through a Dowex 50W Na ⁺ resin column and the eluate is freeze dried. The resulting material was taken up in a minimum amount of water, purified by column chromatography on Amberlite XAD-II Resin 12194870 and freeze-dried on cis-4- (acetamidomethyl) -3- (phenylacetamido) -2-oxoazetidine-1 - yielding the sodium salt of sulfonic acid.

IR 3400 (br), 1760,

1640, 1515, 1255, 1050.

Nuclear Magnetic Resonance Spectrum (D ₂ O, ppm): 1.91 (s,

CH ₂ CO), 4.37 (dd, J = 5.5 Hz, 6 Hz, C ₄ H), 5.19 (d, J = 5.5 Hz, C ₃ H),

7.38 (m, C ₈ H ₅ ),

Example 10

250 mg of methyl Cis-3- [2-12- (chloroacetamido) -4-thiazolyl] -2- (ethoxyimino) acetamido-2-oxoazetidine-4-carboxylic acid (color isomer) 2 ml To a solution of Ν, Ν-dimethylformamide was added 190.4 mg of pyridine-sulfur trioxide complex and the mixture was stirred for 24 hours. Then another 95 mg of pyridine-sulfur trioxide complex was added and stirring was continued for another 24 hours. Addition of 20 ml of diethyl ether precipitates from the mixture. The upper ether phase is discarded and 20 ml of fresh ether are added to the residue to wash the precipitate. This operation is repeated once more, the ether phase is discarded and the precipitate is suspended in 20 ml of water. To the suspension was added 12 ml of Dowex 50W Na ⁺ resin and the mixture was stirred at room temperature for 2 hours. The resin was removed by filtration and the filtrate was freeze-dried. The resulting powder was dissolved in water (20 mL), purified by column chromatography on Amberlite XAD-II and freeze-dried on the eluate to give cis-3- (2- [2- (chloroacetamido) -4-thiazolyl] -2- (ethoxyimino) acetamido). ) The sodium salt of 4-methoxycarbonyl-2-oxo-azetidine-1-sulfonic acid (color isomer) is obtained.

IR (ν max): 3600-3200,1790-1750, 1700-1670, 1055.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.23 (3H, t, J = 6Hz, CH ₂ CH ₃ ), 3.62 (3H, s, COOCH 2) 4.12 (2H, q, J = 6Hz, CH ₂ CH _3), 4.34 (2H, s, C1CH _2), 4.49 (1H, d, J = 6Hz, C ₄ -H), 5.43 (1H, dd, J = 6Hz, 9Hz, _C3 -H), 7.29 (1H, s, a group of formula CV), 9.40 (1H, d, J = 9Hz, _C3 -NH), 12.92 (1H, br, C1CH ₂ CONH).

Analytical results for C ₁₄ H ₁₅ ClN ₅ NaO ₉ S ₂ . For ₂ H ₂ O:

Calculated: C, 30.25; H, 3.45; N, 12.60.

Found: C, 30.01; H, 3.46; N, 12.46.

Example 11

110 mg of cis-3-12- [2- (chloroacetamido) -4-thiazolyl] -2- (ethoxyimino) acetamido} -4- (methoxycarbonyl) -2-oxoazetidine-1 - To a solution of the sulfonic acid sodium salt (color isomer) in 8 ml of water was added 30 mg of sodium monomethyl dithiocarbamate under ice-cooling and stirring. The mixture was stirred at room temperature for one hour. The reaction mixture was then filtered and the filtrate washed with diethyl ether. The aqueous phase was purified by column chromatography on Amberlite XAD-II and freeze-dried the eluate to give cis-3- [2- (2-amino-4-thiazolyl) -2- (ethoxyimino) - cetam time] -4- (methoxy). -carbonyl) -2-oxo-azetidin-1-yl fatty acid sodium salt (color isomer) is obtained.

IR (λmax): 3500-3300,

1790-1750, 1680, 1625, 1055.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.21 (3H, t, J = 7Hz, CH ₂ -CH ₃ ) 3.61 (3H, s,? OCH ₃ ), 4.07 (2H, q , J = 7Hz, CH ₂ -CH ₃ ), 4.47 (1H, d, J = 6Hz, C ₄ -H), 5.39 (1H, dd, J = 6Hz, 9Hz, C ₃ - H), 6.56 (1H, s, a group of formula CV), 7.15 (2H, br, NH ₂ 9.30 (IH, d, J = 9Hz, _C3 -NH).

Analytical results for C ₁₂ H ₁₄ N ₅ NaO ₈ S ₂ .2H ₂ O:

Found: C, 30.33; H, 3.53; N, 14.76 Found: C, 30.06; H, 3J8; N, 14.61.

Example 12

In the same manner as in Example 10, cis-3- {2- [2- (chloroacetamido) -4-thiazolyl] -2- (n-propoxyimino) acetamido} -4-methoxycarbonyl). The color isomer of -2-oxo-azetidine-1-yl fonic acid is prepared.

IR (λmax *): 3250, 2970, 1780, 1750, 1680, 1055.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 0.89 (3H, t, J = 7Hz-CH ₂ -CH ₂ -CH ₃ ),

1.65 (2H, sextet, J = 7Hz, CH ₂ - CH ₂ -CH _3), 3.60 (3H 's,

COOCH ₃ ) 4.01 (2H, t, J = 7Hz,

CHO-CH ₂ -CH _3), 4.32 (2H, s,

C1CH _2), 4.48 (1H, d, J = 6Hz, C ₄ - H)

5.45 (1H, dd, J = 6 Hz, 9H, C ₃ -H),

7.25 (1H, s, CV),

09.04 (1H, s, J = 9Hz, _C3 -NH);

12.9 (1H, br. S, C1CH CONH _2].

Analysis results for C 1 _C H, ₇ ClN \ NaO _q S. For 1 / 2H ₂ O:

Found: C, 33.18; H, 3.34; N, 12.90 Found: C, 33.19; H, 3.51; N, 12.93.

Example 13

All. In the same manner as in Example 1, cis-3- [2- (2-amino-4-thiazolyl) -2- (n-propoxyimino) acetamido] -4- (methoxycarbonyl) -2-oxoazetidine-1- sodium sulfonic acid (color isomer) was prepared.

IR (λ max ') 3424, 1780, 1750, 1680, 1620, 1055.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): δ 88 (3H, i, J = 7Hz, CH ₂ -CH ₂ -CH ₃ ), 1.62 (2H, sextet, J = 7Hz, CH ₂ -Cl CH a), 3.61 (3H, s, COOCH ₃ ),

3.98 (2H, t, J = 7Hz, CH ₂ -CH ₂ - CH _3), 4.48 (1H, d, J = 6Hz, C ₄ -H);

5.4 (1H, dd, J = 6Hz, 9Hz, _C3 -H),

-13194870

6.52 (1Η, s, CV),

7.14 (2H, br.s, NH ₂ ), 9.31 (1H, d, J = 9Hz, C ₃ -NH).

Analysis for C ₁₃ H ₁₆ N ₅ NaO ₈ S ₂ .2H ₂ O:

Calculated: C, 31.64; H, 4.09; N, 14.19; Found: C, 31.70; H, 3.81; N, 14.43.

Example 14

In the same manner as in Example 10, cis-3- (2- [2- (chloroacetamido) -4-thiazolyl (-2- (isopropoxyimino) acetamido} -4-methoxycarbonyl) -2-oxo -azetidine-1-sulfonic acid sodium salt (color isomer ').

IR (λmax * ⁴ ). 3600-3300,

1780-1750, 1700-1670, 1055.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.23 (6H, d, J = 6Hz, CH (CH ₃ ) ₂ ), 3.62 (3H, s, COOCH ₃ ), 4.31 (1H, m, E (H (CH ₃ ) ₂ ), 4.33 (2H, s, C ₁ CH ₂ ),

4.50 (1H, d, J = 6Hz, C ₄ -H), 5.45 (1H, dd, J = 6Hz, 9Hz, _C3 -H), 7.24 (1H, s, a group of formula CV ), 9.32 (1H, d, J = 9Hz, _C3 -NH), 12.90 (1H, br, CICHjCONH).

Analysis results for C | ₅ H, ₇ ClN ₅ NaO ₉ S ₂ . For ₂ H ₂ O:

Calculated: C, 31.61; H, 3.71; N, 12.29. Found: C, 31.58; H, 3.65; N, 12.28.

Example 15

All. cis-3- [2- (2-amino-4-thiazolyl) -2- (isopropoxyimino) acetamido] -4- (methoxycarbonyl) -2-oxoazetidine-1-sulfonic acid sodium salt (color isomer) was prepared.

IR spectrum (vmax cw ^4): 3600-3200,

1780-1750, 1680, 1620, 1055.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.20 (6H, d, J = 6Hz, CH (CH ₃ ) ₂ ), 3.62 (3H, s, COOCH ₃ ), 4.27 (1H) , septet, CH (CH ₃ ) ₂ ), 4.47 (1H, d, J = 6Hz, C ₄ -H), 5.41 (1H, dd, J = 6Hz, 9Hz, C ₃ -H) 6.53 (1Ή, s, a group of formula CV), 7.12 (2H, br, _NH2), 9.18 (1H, d, J = 9Hz, _C3 -NH)

Analysis for C ₁₃ H, ₆ N ₅ NaO ₈ S ₂ .2H ₂ O:

H, 4.09; N, 14.19. Found: C, 31.92; H, 3.85; N, 14.37.

Example 16

In the same manner as in Example 10, cis-3- (2- [2- (chloroacetamido) -4-thiazolyl] 2- (n-butoxyimino) acetamido} -4- (methoxycarbonyl) -2- The oxo-azetidine-1-sulfonic acid sodium salt (color isomer) is prepared.

IR (λmax cm- ¹ ): 2960, 1780, 1750, 1680, 1055.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 0.89 (3H, t, J = 6Hz, CH ₂ CH ₂ CH ₂ CH ₃ ),

1.1-1.8 (4H, m, _{CH2 CH2} CH, CHO,

3.60 (3H, s, COOCH ₃ ), 4.04 (2H, t, J = 6Hz, CH ₂ CH ₂ CH ₂ CH ₃ ), 4.30 (2H, s, C ₁ CH ₂ ), 4.49 ( 1H, d, J = 6Hz, C ₄ -H), 5.42 (1H, dd, J = 6Hz, 9Hz, _C3 -H), 7.20 (1H, s, a group of formula CV), 9.37 (1H, d, J = 9Hz, _C3 -NH)

Analytical results for C, ₆ H ₁₉ ClN ₅ NaO ₉ S ₂ . For the formula .2H.0:

Found: C, 32.91; H, 3.97; N, 11.99. Found: C, 32.58; H, 3.80; N, 11.83.

Example 17

All. cis-3- [2- (2-amino-4-thiazolyl) -2- (n-butoxyimino) acetamido] -4- (methoxycarbonyl) -2-oxoazetidine-1-sulfonic acid, following the procedure of Example 1 sodium salt (color isomer) was prepared.

IR (vLuCl ³ ) 3450-3350, 1790-1750, 1680, 1620, 1050.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 0.89 (3H, t, J = 6Hz, CH ₂ CH ₂ CH ₂ CH ₃ ),

1.1-1.8 (4H, m, CH, CH ₂ CH, CH ₃ ).

3.61 (3H, s, COOCH 3), 4.01 (2H, t, J = 6Hz, CH ₂ CH ₂ CH ₂ CH ₃ ), 4.47 (1H, d, J = 6Hz, C ₄ H). 5.39 (1H, dd, J = 6Hz, 9Hz, _C3 -H), 6.54 (1H, s, a group of formula CV), 7.13 (2H, br, NH _2), 9, 3 (1H, d, J = 9Hz, _C3 -NH).

Analysis for C ₁₄ H ₁₈ N ₅ NaO _g S ₂ .2H ₂ O:

Found: C, 33.13; H, 4.37; N, 13.80 Found: C, 33.01; H, 4.10; N, 13.85.

Example 18

In the same manner as in Example 10, cis-3- (2- [2- (chloroacetamido) -4-thiazolyl] -2- (benzyloxyimino) acetamido] -4- (methoxycarbonyl) -2-oxo- azetide in-1-sulfonic acid sodium salt (color isomer) is prepared.

IR (λmax ⁴ ) 3550-3250, 1780, 1750, 1680, 1055.

NMR spectrum (D _g -DMSO, ppm): 3.52 (3H, s, COOCH3), 4.33 (2H, s, C1CH _2), 4.51 (1H, d, J = 6Hz, C ₄ - H)

5.16 (2H, s, PhCH ₂ ), 5.49 (1H, dd, J = 6Hz, 9Hz, C ₃ -H), 7.27 (1H, s, CV), 7.38 (5H , s, Ph), 9.59 (1H, d, J = 9Hz, C ₃ - NH), 12.9 (1H, br, C1CH, CONH).

Analytical results for C ₁₉ H ₁₇ ClN ₅ NaO ₉ S ₂ . For H ₂ O:

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

Example 19

In the same manner as in Example 11, cis-3- [2- (2-amino-4-thiazolyl) -2- (benzyloxyimino) acetamido] -4- (methoxycarbonyl) -2-oxoazetidin-1-one. sodium sulfonic acid (color isomer) was prepared.

IR spectrum (vmax cw ^4): 3450-3325, 1780, 1750, 1675, 1620, 1055th

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.54 3H, s, COOCH 3), 4.49 (1H, d, J = 6Hz, C ₄ -H), 5.12 (2H, s, PhCH ₂ )

-14194870

5.42 (IH, dd, J = 6, 9Hz, _C3 -H), 6.57 (lH, s, a group of formula CV), 7.16 (2H, br, _NH2), 7 37 (5H, s, Ph), 9.48 (IH, d, J = 9Hz, _C3 -NH).

Analysis: Calculated for C ₁₇ H ₁₆ N ₅ NaO ₈ S ₂ .2H ₂ O: C, 37.70; H, 3.72; N, 12.93. Found: C, 37.26. H, 3.37; N, 12.93.

Example 20

In the same manner as in Example 10, cis-3- {2- [5-chloro-2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido) -4- (methoxycarbonyl). ) -2-oxo-azetidine-1-sulfonic acid sodium salt (color isomer was prepared).

IR (λmax *): 1790, 1740, 1680, 1550, 1060.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.63 (3H, s, COOCH ₃ ), 3.89 (3H, s, NOCH ₃ ), 4.37 (2H, s, ClCH ₂ ),

4.46 (1H, d, J = 6Hz, C ₄ -H), 5.40 (1H, dd, J = 6Hz, 9Hz, C ₃ -H), 9.48 (1H, d, J = 9Hz, C ₃ -NH), 13.1 (1H, br.s, ClCHOCONH1).

Analytical results for C ₁₃ Hi ₂ Cl ₂ N ₅ O ₉ S ₂ Na. 2H ₂ O:

Calculated: C, 27.09; H, 2.80; N, 12.15 Found: C, 27.42; H, 2.80; N, 12.39.

Example 21

In the same manner as in Example 11, cis-3- [2- (2-amino-5-chloro-4-thiazolyl) -2- (methoxyimino) acetamido] -4- (methoxycarbonyl) -2-oxo- azetidine-1-sulfonic acid sodium salt (color isomer) is prepared.

IR (ν ^c 3400, 1780, 1750, 1680, 1620, 1540, 1060).

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.64 (3H, s, COOCH ₃ ), 3.83 (3H, s, NOCH ₃ ), 4.44 (1H; d, J = 6Hz, C ₄ - H), 5.36 (1H, dd, J = 6Hz, 9Hz, C ₃ --H), 7.30 (2H, s, NH ₂ ), 9.32 (1H, d, J = 9 Hz, C ₃ -NH).

Calcd for _C], H ₁₁ CLN ₅ NaO ₈ S _2nd For ₂ H ₂ O:

Found: C, 26.43; H, 3.02; N, 14.01; Found: C, 26.11; H, 3.15; N, 14.13.

Example 22

In the same manner as in Example 10, cis-3- {2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido} -4- (n-butoxycarbonyl) -2-oxo sodium salt of azetidine-1-sulfonic acid-n (color isomer).

IR: 3250, 1780, 1740, 1680, 1060.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 0.731.73 (7H, m, CH ₉ CH, CH ₂ CH ₃ ), 3.86 (3H, s, NOCH ₃ ), 4.43 (2H, s, C1CH ₂ )

4.46 (lH, d, J = 5Hz, _C4 -H), 5.04 (IH, dd, J = 5Hz, 9Hz, _C3 -H),

7.30 (1H, s, CV),

9.41 (1H, d, J = 9Hz, C-NH),

11.93 (IH, br, CONH ₂ C1CH).

Analysis for C ₁₆ H ₉ NaO ₅ S _t9 CLN _second For H ₂ O:

Found: C, 33.95; H, 3.74; N, 12.37. Found: C, 33.79; H, 3.79; N, 12.39.

Example 23

In the same manner as in Example 11, cis-3- [2- (2-amino-4-thiazolyl) -2-methoxyimino) acetamido-4- (n-butoxycarbonyl) -2-oxoazetidin-1-one. sodium salt of sulfonic acid (color isomer is prepared.

IR spectrum (vmax ^cm-4); 3450, 3320, 1790, 1750, 1670, 1050.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 0.71.76 (7H, m, CH ₂ CH ₂ CH ₂ CH ₃ ), 3.80 (3H, s, NOCH ₃ ), 4.00 (2H, t,

CH, CH ₂ CH _? CH), 4.43 (IH, d, J = 5 Hz, C ₄ -H), 5.33 (IH, dd, J = 5, 9Hz, _C3 -H), 6.56 ( 1H, s, CV), 7.13 (2H, br.s. NH ₂ ), 9.41 (1H, d, J = 9Hz, C ₃ -NH).

Analysis for C ₁₄ H ₁₈ N ₅ NaO ₈ S ₂ .H ₂ O;

H, 4.11; N, 14.30 Found: C, 34.51; H, 4.07; N, 14.42.

Example 24

180 mg of trans-3- {2- [2- (chloroacetamidot-4-thiazolyl) -2- (methoxyimino) acetamido} -2-oxoazetidine-4-carboxylic acid methyl ester (syn isomeric) to a solution of ml, Ν-dimethylformamide (1.8 mL) was added 142 mg of pyridine sulfur trioxide complex and stirred at room temperature After two and four days another 142 to 142 mg of pyridine sulfur trioxide complex was added and the mixture was stirred for a total of six days. To the reaction mixture was added diethyl ether (50 mL) and the ether phase was decanted three times, the resulting ether-insoluble oily precipitate was taken up in a little water and passed through a Dowex 50W Na + resin column. The resulting powder was purified by column chromatography on Amberlite XAD-II resin, freeze-dried to give trans-3-12- [2- (chloroacetamido) -4-thiazolyl] -2 (methoxyimino) acetamido} -4 (methoxy) -carbonyl) -2-oxo-azetidine-1-sulfonic acid-n triumsót (Elemental Analysis-isomer) are obtained.

IR (λ max cm ^-1 ): 1780, 1670, 1550.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.7 (3H, s, COOCH ₃ ), 3.9 (3H, s,

NOCH _3), 4.1 (IH, d, J = 2Hz, C ₄ - H), 4.35 (2H, s, C1CH _2), 4.8 1 / H, dd, J = 2 Hz, 9Hz, _C3 -H), 7.4 (lH, s, a group of formula CV), 9.6 (IH, d, J = 9Hz, _C3 -NH).

Example 25

320 mg of cis-3-12- [2- (chloroacetamido) -4-thiazolyl] acetamido} -2-oxoazetidine-4-carbonyl

To a solution of the acid methyl ester -15194870 in 2 ml of Ν, Ν-dimethylformamide, 282.3 mg of pyridine-sulfur trioxide complex was added and the mixture was stirred at room temperature for 48 hours. An additional 141 mg of pyridine-sulfur trioxide complex was then added and stirring continued for another 24 hours. Diethyl ether (30 ml) was added and the ether phase was decanted. Perform this operation twice. The resulting ether-insoluble oily precipitate was dissolved in water (10 mL) and passed through a Dowex 50W Na ⁺ resin column. The eluate was evaporated in vacuo to a volume of 10 mL and purified by column chromatography on Amberlite XAD-II. Freeze drying of the eluate affords the sodium salt of cis-3- {2- [2- (chloroacetamido) -4-thiazolyl] acetamido) -4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid.

IR (λ max cm ^-1 ): 3600-3200,

1790-1760, 1680, 1060.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.26 (2H, s, CVII), 3.56 (3H, s, COOCH ₃ ), 4.32 (2H, s, ClCH ₂ ), δ , 43 (IH, d, J = 6Hz, C ₄ -H), 5.29 (lH, dd, J = 6, 9Hz, _C3 -Η), 6.92 (lH, s, CV formula group), 8.70 (IH, d, J = 9Hz, _C3 -NH)

12.56 (IH, br, CONH ₂ C1CH).

Analysis results for Ci ₂ Hi ₂ ClN ₄ NaO ₈ S ₂ . For H ₂ O:

Calculated: C, 29.97; H, 2.93; N, 11.65. Found: C, 30.13; H, 3.29; N, 12.02.

Example 26

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

IR (ν max): 3330, 1790,

1680, 1625, 1060.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.32 (2H, s, CH ₂ ), 3.59 (3H, s, COOCH ₃ ),

4.42 (IH, d, J = 6Hz, C ₄ -H), 5.29 (IH, dd, J = 6, 9Hz, _C3 -H),

6.28 (1H, s, CV,)

7.20 (2H, br.s, NH ₂ ), 8.59 (1H, d, J = 9 Hz, C ₃ -NH).

Analysis: Calculated for C ₁₀ H ₁₁ N ₄ NaO ₇ S ₂ .H ₂ O: C, 29.70; H, 3.24; N, 13.85 Found: C, 29.98; H, 3.49; N, 13.53

Example 27

169 mg of cis-3-D-2- [4- (n-butyl) -2,3-dioxo-1-piperazinecarboxamido] -2-phenylacetamido} -2-oxoazetidine-beta-structure Carboxylic acid methyl ester (Reference Example 39) To a solution of N, N-dimethylformamide (1) in 1 ml was added 114 mg of pyridine-sulfur trioxide complex and the mixture was stirred at room temperature. After ten days, and one day later, an additional 57-57 mg of pyridine-sulfur trioxide complex was added and stirring was continued for a total of 12 days. 20 ml of diethyl ether are then added and the ether phase is decanted. Perform this operation twice. The resulting precipitate was suspended in water (25 mL) and Dowex 50W Na ⁺ resin was added to the suspension and the mixture was stirred at room temperature for 1.5 hours. The resin is then removed by filtration and the powder obtained by freeze-drying the filtrate is dissolved in a little water. The aqueous solution was purified by column chromatography on Amberlite XAD-II and freeze-dried the eluate to give cis-3- {D-2- [4- (n-butyl) -2,3-dioxo-1-pyrerazine-carboxamido] -2-phenyl- acetamido} -4-meloxycarbonyl) -2-oxoazetidine-1-sulfonic acid, sodium salt (beta structure) is obtained.

IR spectrum (ν £ 1 → ⁴ ): 3410, 1775, 1720, 1685, 1290, 1055.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.09 (3H, s, COOCH ₃ ), 4.37 (1H, d, J = 6Hz, C ₄ -H), 5.20 (1H, dd, J = 6, 9Hz, _C3 -H), 5.54 (IH, d, J = 7.5 Hz, PhCH).

Analytical results for C ₂₂ H ₂₆ N ₅ NaO ₁₀ S ₂ H ₂ O:

Calculated: C, 43.21; H, 4.94; N, 11.45 Found: C, 43.10; H, 5.08; N, 11.41 [a] ²²⁰ = - 12.9 ° (c = 0.155, H ₂ O)

The corresponding alpha-structured compound is prepared in the same manner as above.

IR spectrum ^bwcw-1): 3450, 1780, 1720, 1680, 1270, 1055th

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.60 (3H, s, COOCH ₃ ), 4.47 (1H, d, J = 6, Hz, C ₄ -H), 5.13 (1H , dd, J = 6, 9Hz, _C3 -H), 5.48 (IH, d, J = 7.5 Hz, PhCH).

Analytical results for C ₂₂ H ₂₆ N ₅ NaO ₁₀ S ₂ H ₂ O:

Calculated: C, 43.21; H, 4.94; N, 11.45 Found: C, 43.66; H, 4.85; N, 11.54 [a] ²² - 43.7 ° (c = 0.135, H ₂ O).

Example 28

In the same manner as in Example 27, the cis-3- (D-2- [4- (n-butyl) -2,3-dioxo-1-piperazinecarboxamido) -2- (2-thienyl) alpha and beta structure is Acetamido-4- (methoxycarbonyl) -2-oxoazetidine-1-sulfonic acid sodium salt is prepared.

IR (λmax) 3300, 1775, 1710, 1675, 1520, 1370, 1185.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.26 (3H, s, COOCH ₃ ), 4.40 (1H, d, J = 6Hz, C ₄ -H), 5.31 (1H, dd, J = 6, 9Hz, _C3 -H), 9.82 (IH, d, J = 7.5 Hz, group of formula CVIII).

Analytical results for C ₂₀ H ₂₄ N ₅ NaO ₁₀ S ₂ . For ₂ H ₂ O:

Found: C, 38.89; H, 4.56; N, 11.34 Found: C, 38.50; H, 4.56; N, 11.30.

Alpha-form

IR (cm ^-1 ): 3300, 1780, 1720, 1680, 1520, 1370, 1185.

-16194870

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.61 (3H, s, COOCH 2), 4.46 (1H, d, J = 6Hz, C ₄ -H), 5.17 (1H, dd) , J = 6, 9Hz, _C3 -H), 5.73 (IH, d, J = 7.5 Hz, group of formula CVIII).

Analytical results for C ₂₀ H ₂₄ N ₅ NaO ₁₀ S ₂ .H ₂ O:

Calculated: C, 40.06; H, 4.37; N, 11.68 Found: C, 39.64; H, 4.53; N, 11.54.

Example 29

261 mg of cis-3-iD-2-14- (n-octyl) -2,3-dioxo-1-piperazinecarboxamido] -2- (2-thienyl) acetamido-beta-structure} -2-oxo To a solution of azetidine-4-carboxylic acid methyl ester (Reference Example 39) in 2 ml of Ν, Ν-dimethylformamide was added 155 mg of pyridine sulfur trioxide complex and the mixture was stirred at room temperature for 5 days. Diethyl ether (20 mL) was added to the reaction mixture and the ether phase was removed by decantation. Perform this operation three times. The ether-insoluble precipitate was suspended in water (50 mL), Dowex 50W Na ⁺ resin was added to the suspension and the mixture was stirred at room temperature for 2 hours. The resin was removed by filtration, the powder dried by freeze-drying the filtrate, dissolved in a little water and purified by column chromatography on Amberlite XAD-II. Freeze drying of the eluate gave cis-3-D-2- [4- (n-octyl) -2,3-dioxo-1-piperazinecarboxamido] -2- (2-thienyl) acetamido-4-methoxycarbonyl. ) -2-oxoazetidine-1-sulfonic acid sodium salt (beta structure) is obtained.

IR 3400, 1760, 1670.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.62 (3H, s, COOCH 3), 4.48 (1H, d, J = 6Hz, C ₄ -H), 5.77 (1H, d, , J = 7.5 Hz, CVIII).

Analytical results for C ₂₄ H ₃₂ N ₅ NaO | ₀ S ₂ . For 2H ₂ O:

Found: C, 42.79; H, 5.39; N, 10.40 Found: C, 42.98; H, 5.64; N, 10.64.

The corresponding alpha-structured compound is prepared in the same manner as above.

IR 3400, 1765, 1675.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.22 (3H, s, COOCH ₃ ), 4.42 (1H, d, J = 6Hz, C ₄ -H), 5.35 (1H, dd, J = 6, 9Hz, _C3 -H), 5.88 (lH, s, a group formula CVIII).

Analytical results for C ₂₄ H ₃₂ N ₅ NaO ₁₀ S ₂ . For 2H ₂ O:

Calculated: C, 42.79; H, 5.39; N, 10.40 Found: C, 42.64; H, 5.51; N, 10.62.

Example 30

300 mg of trans-3-D-2- [4- (n-octyl) -2,3-dioxo-1-piperazinecarboxamido] -2- (2-thienyl) acetamido] -2-oxo-beta structure To a solution of azetidine-4-carboxylic acid methyl ester (Reference Example 39) in 2 ml of Ν, Ν-dimethylformamide was added 196 mg of pyridine sulfur trioxide complex and the mixture was stirred at room temperature. On the third and fourth days, an additional 98-98 mg of pyridine sulfur trioxide complex was added, which was stirred for a total of 4 days. Diethyl ether (20 mL) was added to the reaction mixture and the ether phase was removed by decantation. Perform this operation twice. To the resulting sticky, ether-insoluble material was added 15 mL of water and 15 mL of Dowex 50W Na ⁺ resin and the mixture was stirred at room temperature for 1.5 hours. The resin was removed by filtration, the filtrate was freeze-dried and the resulting powder was dissolved in a little water. The aqueous solution was purified by column chromatography on Amberlite XAD-II and freeze-dried the eluate to trans-3-D-2- [4- (n-octyl) -2,3-dioxo-1-piperazinecarboxamido] -2- (2- thienylacetamido} -4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt (beta structure) is obtained.

IR (λ max cm -1): 3420, 2930, 1780, 1720, 1680, 1515, 1255, 1050.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.68 (3H, s, COOCH 2), 3.98 (1H, d, J = 3Hz, C ₄ -H), 4.70 (1H, dd) , J = 3Hz, 9Hz, _C3 -H), 5.69 (IH, d, J = 8 Hz, groups of formula CVIII).

The corresponding alpha-structured compound is prepared in the same manner as above.

IR spectrum (ν ^ «^ ^{Η ε):} 3450, 2925, 1780, 1710, 1680, 1510, 1470, 1365, 1260, 1050th

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.66 (3H, s, COOCH 2), 4.02 (1H, d, J = 3Hz, C ₄ -H), 4.72 (1H, dd) , J = 3Hz, 9Hz, _C3 -H), 5.71 (IH, d, J = 7Hz, a group of formula CVIII).

Example 31

625 mg cis-4- (acetamidomethyl) -3- (2-12- (chloroacetamido) -4-thiazolyl] -2-methoxyimino) acetamido} -2-oxoazetidine (color isomer) To a solution of 6 ml of Ν, Ν-dimethylformamide was added 477 mg of pyridine-sulfur trioxide complex and the mixture was stirred at 27-28 ° C for 28 hours. Diethyl ether (90 mL) was added and the ether phase was removed by decantation. Perform this operation twice. The oily residue was dissolved in 90 ml of water. To the solution was added 70 ml of Dowex 50 W Na ⁺ resin and the mixture was stirred at room temperature for 3 hours. The resin was removed by filtration and the filtrate was concentrated in vacuo, and the resulting concentrate was purified by column chromatography on Amberlite XAD-II and freeze-dried the cis-4- (acetamidomethyl) -3- {2- [2- (chloroacetamido) - Sodium salt of 4-thiaroyl] -2- (methoxyimino) acetamido) -2-oxoazetidine-1-sulfonic acid was obtained (color isomer).

IR spectrum (v ^ ^r cw ^'4): 3340, 1770, 1660, 1650, 1275, 1050th

-17194870

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.84 (3H, s, COCH ₃ ), 3.1-3.4 (2H, m, CH ₂ NH), 3.84 (3H, s, NOCH). ₃ ),

3.9-4.2 (1H, m, C ₄ -H), 4.40 (2H, s, ClCH ₂ ), 5.19 (1H, dd, J = 5Hz, 9Hz, C ₃ -H ), 7.51 (lH, s, a group of formula CV), 9.40 (IH, d, J = 9Hz, _C3 -NH), 12.65 (IH, br, CONH ₂ C1CH).

Analytical results for Ci ₄ H ₁₆ ClN ₆ NaO ₈ S ₂ . .2 1 / 2H ₂ O:

H, 3.75; N, 14.90 Found: C, 29.83; H, 3.69; N, 15.01.

Example 32

In the same manner as in Example 11, cis-4- (acetamidomethyl) -3- [2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -2-oxoazetidine The 1-sulfonic acid sodium salt (color isomer) was prepared.

IR spectrum (vmax CMI ^1): 3400, 1765, 1660, 1540, 1280, 1250, 1050th

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.77 (3H, s, COCH ₃ ), 3.20-3.60 (2H, m, CH ₂ NH), 3.86 (3H, s, NOCH). ₃ ),

3.8-4.1 (lH, m, C ₄ -H), 5.12 (IH, dd, J = 5Hz, 9Hz, _C3 -Η), 6.81 (IH, s, CV formula group), 7.15 (2H, br.s, NH ₂ ), 9.33 (1H, d, J = 9 Hz, C ₃ -NH).

Analysis results for C | ₂ H ₁₅ N ₆ NaO ₇ S ₂ .2H ₂ O Calcd * Calculated: C% = 30.13, H% = 4.00, N% = 17.56 found: C% = 30.43, H% = 4 , 12, N% = 17.34

Example 33

In the same manner as in Example 31, cis-4- (benzamidomethyl) -3- {2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido} -2-oxo The sodium salt of azetidine-1-sulfonic acid (color isomer) is prepared.

IR (ν max 1770, 1645, 1550, 1280, 1050).

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.33,6 (2H, m, CH ₂ NH), 3.92 (3H, s, NOCH ₃ ), 4.0-4.3 (1H, m , C ₄ -H),

4.45 (2H, s, C1CH _2), 5.28 (IH, dd, J = 5, 9Hz, _C3 -H), 7.54 (lH, s, a group of formula CV), 7.4 -7.9 (5H, m, Ph), 9.49 (1H, d, J = 9Hz, C ₃ -NH).

Analytical results for C ₁₉ H ₁₈ ClN ₆ NaO ₈ S ₂ . For 2H ₂ O:

Calculated: C, 36.99; H, 3.49; N, 13.62. Found: C, 36.94; H, 3.59; N, 13.29.

Example 34

In the same manner as in Example 11, cis-3-) 2- (2-amino-4-thiazolyl) -2-methoxyimino) acetamido] -4- (benzamidomethyl-2-oxoazetidine-1-sulfonic acid). sodium salt (color isomer) was prepared.

IR spectrum (vmax, ^cw-1): 1765, 1645, 1280, 1050th

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.33,7 (2H, m,? H ₂ NH), 3.86 (3H, s, NOCH ₃ ), 3.9-4.3 (1H, m, C ₄ -H),

5.23 (IH, dd, J = 5Hz, 9Hz, _C3 -H),

6.82 (1H, s, CV),

7.17 (2H, br.s, NH ₂ ), 7.4-7.9 (5H, m, Ph), 9.36 (1H, d, J = 9Hz, C ₃ -NH)

Analysis for C ₁₇ H ₁₇ N ₆ NaO ₇ S ₂ .2H ₂ O:

Found: C, 37.78; H, 3.92; N, 15.55. Found: C, 37.51; H, 3.73; N, 15.67.

Example 35

In the same manner as in Example 31, cis-3- {2- [2- (chloroacetamido) -4-thiazolyl] - (Z) -2- (methoxyimino) -acetaldehyde} -4- {2- [2- (Chloroacetamido) -4-thiazolyl] - (Z) -2- (methoxyimino) acetoxymethyl) -2-oxoazetidine-1-sulfonic acid sodium salt is prepared.

IR (ν cm ^-1 ): 1770, 1765, 1670, 1560, 1275, 1050.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.83

3.89 (2x3H, 2.times.s, 2XNOCH _3), 4.31 (4H, s, 2XC1CH _2), 4.1-4.4 (2H, m, _CH2 OC = O), from 4.80 to 5.10 (IH, m, C ₄ -H), 5.31 (IH, dd, J = 5Hz, 9Hz, _C3 -H), 7.19, 7.53 (2x1 H, 2.times.s, a group of formula 2XCV) 9.34 (IH, d, J = 9Hz, _C3 -NH).

Analytical results for C ₂₀ H ₁₉ Cl ₂ N ₈ NaOnS ₃ . , For 4H ₂ O:

Calculated: C, 29.67; H, 3.36; N, 13.84 Found: C, 29.53; H, 3.11; N, 13.83.

Example 36

221 mg cis-3-12- [2- (chloroacetamido) -4-thiazolyl] (Z) -2- (methoxyimino) acetamido} -4- {2- (2-chloroacetamido) -4 To a solution of the sodium salt of thiazolyl (Z) -2- (methoxyimino) acetoxymethyl] -2-oxoazetidine-1-sulfonic acid in 10 ml of water was added 85 mg of sodium monomethyl dithiocarbamate under ice-cooling. After stirring at room temperature for 1 hour, 40 mg of sodium monomethyldithiocarbamate is added. The mixture was stirred for an additional hour. The reaction mixture was washed with ethyl acetate and then with diethyl ether and then concentrated in vacuo. The concentrate was purified by column chromatography on Amberlite XAD-II and freeze-dried the eluate to give cis -3- [2- (2-amino-4-thiazolyl) - (Z) -2- (methoxyimino) acetamido] -4- [2- ( 2-Amino-4-thiazolyl) (Z) -2- (methoxyimino) acetoxymethyl] -2-oxoazetidine-1-sulfonic acid sodium salt is obtained.

IR (ν max): 1760, 1670, 1540, 1275, 1050.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.80,

3.86 (2X3H, 2Xs, 2XNOCH ₃ ),

4.1-4.4 (2H, m, CH ₂ OC = O), 4.85.05 (1H, m, C ₄ -H), 5.25 (1H, dd, J = 5Hz, 9Hz) , C ₃ -H), 6.63, 6.94 (2χΐΗ, 2Xs, 2XCV port -18194870 port), 7.10 (2H, br.s, NH ₂ ), 9.22 (1H, d, J -9 Hz, C ₃ -NH).

Analytical results for C ₁₆ H ₇ N ₈ NaO ₉ S ₃ .3H ₂ O:

date; C, 30.09; H, 3.63; N, 17.55 Found: C, 30.18; H, 3.51; N, 17.68.

Example 37

In the same manner as in Example 30, cis-3- {2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido) -4 - [(2-thienyl) acetoxy] methyl] -2-oxoazetidine-1-sulfonic acid sodium salt (color isomer) was prepared.

IR 3410, 1765, 1670,

1550, 1270, 1050.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.72 (2H, br.s, C ₁ -CX), 3.95-4.52 (1H, m, C ₄ -H), 4.30 (2H , s, CICH ₂ ), 5.25 (1H, dd, J = 6Hz, 9Hz, C ₃ -H), 7.41 (1H, s, CV).

Example 38

All. In the same manner as in Example 1, cis-3- [2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -4 - [(2-thienyl) acetoxymethyl] -2-oxo azetidine-1-sulfonic acid sodium salt (color isomer) was prepared.

IR (λ max): 3400, 1770, 1740, 1670, 1615, 1535, 1270, 1250, 1050.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.75 (3H, s, NOCH 2), 5.20 (1H, dd, J = 6Hz, 9Hz, C ₃ -H), 6.71 ( 1H, s, CV), 7.14 (2H, br.s, NH ₂ ), 9.22 (1H, d, J = 9Hz, C ₃ -NH).

Analytical results for C ₁₆ H ₁₈ N ₅ NaO ₈ Sg.2H ₂ O:

Calculated: C, 34.22; H, 3.59; N, 12.47 Found: C, 34.42; H, 3.23; N, 12.30.

Example 39

In the same manner as in Example 30, cis-3- (2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido} -4- (1-methyl-1H-tetrazole) -5-ylthiomethyl) -2-oxoazetidine-1-sulfonic acid sodium salt (color isomer) was prepared live.

IR (vi, &quot; c &quot;) 3420, 1765, 1660, 1560, 1050.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.91 (3H, s, NCH 2), 3.94 (3H, s, OCH ₃ ),

4.34 (2H, s, CICH ₂ ), 5.29 (1H, dd, J = 6Hz, 9Hz, C 8 H), 7.48 (1H, s, CV), 9.46 (1H , d, J = 9 Hz, C ₃ -NH).

Example 40

All. Example cis-3- [2- (2-Amino-4-thiazolyl) -2- (methoxyimino) acetamido] -4- (1-methyl-1H-tetrazol-5-ylthiomethyl) - The 2-oxo-azetidine-1-sulfonic acid sodium salt (color isomer ') is prepared:

IR (ν max (cw '): 3410, 1770, 1660, 1610, 1535, 1280, 1050).

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.88 (3H, s, NCH 2), 3.92 (3H, s, OCH ₃ ),

5.22 (IH, dd, J = 6, 9Hz, _C3 -H),

6.75 (1H, s, CV),

7.13 (2H, br.s, NH ₂ ) 9.31 (1H, d, J = 9 Hz, C 8 -NH).

Analytical results for Ci ₂ H ₁₄ N ₉ NaO ₆ S ₃ . .2 1 / 2H ₂ O:

Calculated: C, 26.46; H, 3.52; N, 23.15 Found: C, 26.46; H, 3.59; N, 22.70.

Example 41

In the same manner as in Example 10, cis-3- {2-12- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) -acetoyl-4- (methylthiomethyl) -2-oxo The azetidine-1-sulfonic acid sodium salt (color isomer) is prepared.

IR (λmax- ¹ ): 3420, 1760, 1660, 1550, 1270, 1240, 1050.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 2.08 (3H, s, SCH ₃ ), 2.68-3.06 2H, m, CH ₂ S), 3.89 (3H, s, NOCH 2). , 4.32 (2H, s, C ₁ CH ₂ ), 7.42 (1H, s, CV).

Example 42

Following the procedure of Example 11, cis-3- [2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -4- (methylthiomethyl) -2-oxoazetidin-1-one. sodium sulphonic acid (color isomer) is prepared.

IR (λmax * ¹ ): 3400, 1760, 1660, 1605, 1535, 1380, 1245, 1050;

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 2.08 (3H, s, SCH 8), 2.70-3.12 (2H, m, CH ₂ S), 3.71 (3H, s, NOCH _3). ), 6.74 (1H, s, CV), 7.14 (2H, br.s, NH ₂ ).

Example 43

500 mg of Cis-3- [2- (2-chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido) -4- (4-chlorophenyl) -2-oxoazetidine (colorless) isomer) To a solution of 12, Ν-dimethylformamide (12 ml) was added 353 mg of pyridine-sulfur trioxide complex and the mixture was allowed to stand at room temperature for 18 days. To the reaction mixture was added 150 ml of diethyl ether and the upper ether layer was discarded. To the residue was added water (30 ml), ethyl acetate (30 ml) and tetrahydrofuran (10 ml) and the mixture was shaken. The organic phase is extracted with another 30 ml of water. To the combined aqueous phases was added 20 ml of Dowex 50W NaOH and the mixture was stirred at room temperature for 30 minutes. The resin was removed by filtration and the filtrate was concentrated in vacuo in a water bath not warmer than 30 ° C. The concentrate was purified by column chromatography on Amberlite XAD-II and freeze-dried the eluate to give cis-3-12- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido} -4- (4- Chlorophenyl) -2-oxoazetidine-1-sulfonic acid sodium salt (color isomer) is obtained.

-19194870

IR spectrum (vmwCnP); 3450, 1760, 1665, 1550, 1270, 1045.

Nuclear Magnetic Resonance Spectrum (D ₅ -DMSO, ppm): 3.73 (3H, s, NOCH 3), 4.30 (2H, s, Cl

5.11 (1H, d, J = 5Hz, _C4 -H), 5.32 (1H, dd, J = 5, 8Hz, _C3 -H), 5.75 (1H, s, CV a group of formula), 9.23 (1H, d, J = 8 Hz, _C3 -NH).

Example 44

In the same manner as in Example 11, cis-3- [2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -4- (4-chlorophenyl) -2-oxoazetidine Sodium salt of -1-sulfonic acid (color isomer) was prepared.

IR (λ max cm ^-1 ) _: 3420, 1758, 1660, 1525, 1270, 1050.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO + D ₂ O, ppm): 3.88 (3H, s, NOCH ₃ ), 5.11 (1H, s, CV), 5.33 (1H, d, J = 5 Hz, C ₄ -H), 5.45 (1H, d, J = 5 Hz, C ₃ -H).

Analysis for C ₁₅ H _l3 CLN ₅ NaO ₆ S _2nd , For 3H ₂ O:

Found: C, 33.61; H, 3.57; N, 13.07 Found: C, 33.57; H, 3.28; N, 12.77.

Example 45

In the same manner as in Example 10, cis-3- {2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) _; Acetamido} -4- (.beta., .beta.-dimethylcarbamoyl) -2-oxoazetidine-1-sulfonic acid sodium salt (color isomer) was prepared.

IR (ν £ α »ωή ¹ ): 1770, 1660, 1550.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 2.8, 3.0 (2 × 3Η, 2X 5, N (CH ₃ ) ₂ ), 3.86 (3H, s, NOCH ₃ ), 4.2 (2H, s, CH 2 Cl 2, 5.0 (1H, d, J = 6Hz, C ₄ -H), 5.53 (1H, dd, J = 6Hz, 9Hz, C ₃ -H).

Example 46

The ll. In the same manner as in Example 1, cis-3- [2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -4- (N, N-dimethylcarbamol) -2-oxoazetidine- The 1-sulfonic acid sodium salt (color isomer) was prepared.

IR (λmax ¹ ) 3350, 1780, 1660.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 2.8, 3.0 (2X ₃ H, ₂ X 5, N (CH ₃ ) ₂ ), 3.83 (3 H, s, NOCH ₃ ), 4.93 (1H, d, J = 6Hz, C ₄ -H), 5.3 (IH, dd, J = 6Hz 9Hz, _C3 -H), 6.6 (lH, s, a group of formula CV) 8.96 ( H, d, J = 9Hz, C ₃ - NH).

Example 47

To a solution of 278 mg of cis-3- (benzyloxycarboxamido) -2-oxoazetidine-4-carboxylic acid methyl ester in 2.8 ml of Ν, Ν-dimethylformamide is added 320 mg of pyridine-sulfur trioxide complex and the mixture is stirred at room temperature for 2 hours. stir for days. A further 120 mg of pyridine sulfur trioxide complex is then added and stirring is continued for another day. Detyl ether (50 mL) was added to the reaction mixture and the resulting powdery precipitate was collected by filtration and washed with ether. The powdered product was dissolved in water (5 mL) and passed through a Dowex 50W Na ⁺ resin column. The freeze-dried eluate was dissolved in a little water and purified by column chromatography on Amberlite XAD-II. Freeze drying of the eluate gives the sodium salt of cis-3- (benzyloxycarboxamido) -4- (methoxycarbonyl) -2-oxoazelidine-1-sulfonic acid.

IR (vISV) 3300, 1750;

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.56 (3H, s, CH ₃ ), 4.43 (1H, d, J = 5Hz, C ₄ -H), 7.36 (5H, s) , Ph), 8.13 (1H, d, J = 9Hz, NH).

Analysis results for C | ₃ H ₁₃ N ₂ NaO for _g SH ₂ O:

H, 3.79; N, 7.03 Found: C, 39.19; Found: C, 39.04; H, 3.99; N, 7.26.

Example 48

To a solution of 190 mg of cis-3- (benzyloxycarboxamido) -4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt (monohydrate) in 10 ml of water was added 190 mg of 10% palladium-on-carbon catalyst. catalytic reduction is carried out at room temperature under normal pressure for one hour. The reaction mixture was passed through a pad of celite and the catalyst was filtered off. Freeze drying of the filtrate yields the cis-3-amino-4- (methoxycarbonyl) -2-oxoazetidine-1-sulfonic acid sodium salt.

IR (ν max ¹ ) 3450, 1770, 1740, 1060.

NMR spectrum (D _e -DMSO, ppm): 2,73,5 (2H, br, NH, 3.67 (3H, s, CHJ, 4.33 (2H, s, C ₃ -H and C ₄ —H).

Analytical results for C ₅ H ₇ N ₂ NaO ₆ S., 1 / 2H ₂ O:

Found: C, 21.98; H, 3.68; N, 10.25. Found: C, 22.10; H, 3.69; N, 10.48.

Example 49

In the same manner as in Example 30, the sodium salt of cis-3 - [(2-thienyl) acetamido] -4-methoxycarbonyl-2-oxoacetate din-1-sulfonic acid was prepared.

IR spectrum (\ + β "" ^1): 3350, 1770, 1680, 1540, 1440, 1260, 1060th

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.53 (3H, s, CH 3), 3.68 (2H, s, CH 3)

4.43 (IH, d, J = 6Hz, C ₄ -H), 5.26 (IH, dd, J = 6, 9Hz, _C3 -H), 8.85 (IH, d, J = 9 Hz, NH).

Example 50

To a solution of 380 mg of cis-3- (1H-tetrazol-1-yl-acetamido) -2-oxo-azetidine-4-carboxylic acid ester in 3 ml of Ν, Ν-dimethylacetamide is added 807 mg of pyridine sulfur trioxide complex. After stirring at 70 ° C for 4 hours, diethyl ether (50 mL) was added. The

Discard the -20194870 ether phase and add another 50 mL ether. Perform this operation twice. The insoluble material is dissolved in 5 ml of water and the aqueous solution is passed through a column packed with 40 ml of Amberlite IR-120 SO ₃ Na resin and purified by column chromatography on Amberlite XAD-II. The desired fractions were freeze-dried and purified by column chromatography on a Sephadex LH-20 gel. Freeze-drying of the eluate gives the sodium salt of cis-3- (1H-tetrazol-1-yl-acetamido) -4- (methoxycarbonyl) -2-oxo-azetidine-1-sulfonic acid.

IR 3400, 1770, 1700,

1630, 1550, 1440, 1280, 1260, 1180, 1100, 1060.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.68 (3H, s, CH ₃ ), 4.48 (1H, d, J = 6Hz, C ₄ -H), 5.26 (2H, s) , CH ₂ ), 5.29 (1H, dd, J = 6Hz, 9Hz, C ₃ -H), 9.30 (1H, s, CX), 9.31 (1H, d, J = 9 Hz, NH).

Analytical results for C ₈ H ₉ N ₆ NaO ₇ S. 1 / 2H ₂ O:

Calculated: C, 26.01; H, 3.28; N, 22.76 Found: C, 25.89; H, 3.25; N, 22.72.

Example 51

Following the procedure of Example 50 but reducing the reaction time to one hour, cis-ethyl-1,4-dihydro-7-methyl-4-oxo-8-naphthyridin-3-ylcarbonylamino) -4 - (Methoxycarbonyl) -2-oxoazetidine-1-sulfonic acid sodium salt was prepared.

IR spectrum (νXon '): 3450, 1770, 1660, 1615, 1540, 1500, 1450, 1370, 1260, 1060.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.40 (3H, t, J = 7Hz, CH ₂ E B ₃ ) 2.63 (3H, s, CXI) 3.66 (3H, s , COOCH ₃ ), 4.57 (1H, d, J = 6Hz, C ₄ H), 4.58 (2H, q, J = 7Hz, CH ₂ CH ₃ ), 5.68 (1H, dd , J = 6, 9Hz, _C3 -H), 7.49, 8.58 (2x1 H, 2xd, J = 8Hz, a group of formula CXII), 8.97 (lH, s, a group of formula CXIII) 10.45 (1H, d, J = 9Hz, NH)

Analytical results for C ₁₇ H ₁₇ N ₄ NaO ₈ SH ₂ O:

Found: C, 42.68; H, 4.00; N, 11.71 Found: C, 42.62; H, 4.28; N, 11.57.

Example 52

To a solution of 409 mg of methyl cis-3- (2- (chloroacetyloxy) -2-phenylacetamido] -2-oxoazetidine-4-carboxylic acid in 2 ml of N, N-dimethylacetamide was 549 mg of pyridine. Sulfur trioxide complex was added and the mixture was stirred at 70 ° C for 1 hour, 50 ml of diethyl ether were added, the mixture was stirred and the ether phase was discarded twice, and the resulting precipitate was washed with 15 ml of 1 M aqueous sodium hydroxide. solution of bicarbonate.

The solution was stirred at room temperature for one hour and passed through a column packed with 40 ml of Amberlite IR-120 SO ₃ N resin. The desired fractions were purified twice by column chromatography on Amberlite XAD-II, followed by further purification on a Sephadex LH-20 gel by column chromatography. The resulting eluate was freeze-dried to give a diastereomeric mixture of the sodium salt of cis-3- (2-hydroxy-2-phenylacetamido) -4-methoxycarbonyl-2-oxoazetidine sulfonic acid.

IR (λ max): 3400, 1770, 1680, 1520, 1445, 1380, 1260, 1100, 1060.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.44,

3.56 (3H, 2.times.s, _COOCH3), 4.43, 4.44 (IH, 2 x d, J = 6Hz, C ₄ -H), 4.98, 5.01 (IH, 2.times.s, PhCH). 5.31 (1H, dd, J = 6Hz, 9Hz, C ₃ -H), 7.32 (5H, s, Ph), 8.00, 8.33 (1H, 2Xd, NH).

Analysis for C ,, H ₉ NaO _n N _R S .1 / 2H ₂ O Calcd:

H, 3.62; N, 7.02. Found: C, 39.93; H, 3.94; N, 7.19.

Example 53

109 mg of cis-3- (D-2-sulfo-2-phenylacetamido) -2-oxoazetidine-4-carboxylate, v-methyl 1-ester sodium salt, was prepared with 1.5 ml of N, N-dimethylformamide. To the solution was added 1.2 ml of sulfur trioxide N, N-dimethylformamide complex (1.2 M) under ice-cooling and stirring and the mixture was allowed to stand at 5 ° C for 24 hours. To the reaction mixture was added pyridine (0.5 mL), the mixture was stirred for 5 minutes, and then diethyl ether (30 mL) was added. The ether phase was discarded, another 30 mL of ether was added and the ether layer was discarded again. The residual precipitate was dissolved in 2 mL of a 1M aqueous sodium bicarbonate solution and passed through a column of Amberlite IR-120 SO ₃ Na resin. The eluate was then purified by column chromatography on Amberlite XAD-II resin and Sephadex LH-20 gel, followed by freeze-drying of cis-3- (D-2-sulfo-2-phenylacetamido) -4-methoxycarbonyl-1-sulfo-2. a diastereomeric mixture of the oxo-azetidine disodium salt is obtained.

IR (λ max): 3450, 1770, 1680, 1535, 1440, 1290, 1250, 1100, 1055.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.42

3.66 (3H, 2.times.s, COOCH ₃₎ 4.39 4.42 (IH, 2 x d, J = 6Hz, C ₄ -H), 4.50,

4.54 (1H, 2Xs, Ph-CH), 5.2-5.5 (1H, m, C ₃ -H), 7.1-7.6 (5H, m, Ph-), 8.87 , 8.96 (1H, 2yd, J = 9Hz, NH).

Analysis results for C | ₃ H _l2 N ₂ Na ₂ O _{l ()} S ₂ . For 4 1 / 2H ₂ O:

Found: C, 28.52; H, 3.87; N, 5.12; Found: C, 28.64; H, 3.61; N, 5.00.

-21194870

Example 54

Following the procedure of Example 51, a diastereomeric mixture of the sodium salt of cis-3- [2- (benzyloxycarbonyl) -2-phenylacetamido] -4- (methoxycarbonyl) -2-oxoazetidine-1-sulfonic acid was prepared. live.

IR spectrum (λmax * '); 3400, 1780, 1750, 1536, 1450, 1260, 1060.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.02,

3.42 (3H, 2.times.s, _COOCH3), 4.36, 4.45 (1H, 2 x d, J = 6Hz, C ₄ -H), 4.86;

4.89 (1H, 2Xs, Ph-CH). 5.12, 5.15 (2H, 2.times.s, PhCH _2), 5,1-5-4 (1H, m, C ₃ -H), 7.34 (10H, s, 2xPh);

9.11 (1H, d, J = 9Hz, NH).

Analytical results for C ₂ | H, ₉ N ₂ NaO ₉ SH ₂ O:

Found: C, 48.84; H, 4.10; N, 5.42. Found: C, 48.60; H, 4.25; N, 5.62.

Example 55 To 80 ml of ethanol 106 mg of cis-3- [2- (benzyloxycarbonyl) -2-phenylacetamido] -4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt, 106 mg of 5% palladium on carbon and 16.8 mg of sodium bicarbonate are added and the mixture is stirred vigorously at room temperature under hydrogen at atmospheric pressure for 3.5 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on Amberlite XAD-II resin and freeze-dried the cis-3- (2-carboxy-2-phenylacetamido) -4- (methoxycarbonyl) -1-sulfo-2-oxoazetidine disodium salt. a diastereomeric mixture is obtained.

IR (λ max): 3420, 1770, 1670, 1620, 1530, 1380, 1290, 1250, 1060.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.45,

3.46 (3H, 2.times.s, _COOCH3), 4.40 4.48 (1H, 2 x d, J = 6Hz, C ₄ -H), 5.1 -

5.4 (1H, m, C ₃ -H), 5.59, 5.26 (1H, 2Xs, Ph-CH), 7.23 (5H, s, Ph-),

8.83 (1H, d, J = 9Hz, NH).

Analysis results for C | ₄ Hi ;, N ₉ Na, OoS. .3 1 / 2H ₂ O:

Found: C, 34.08; H, 3.88; N, 5.68. Found: C, 34.40; H, 4.13; N, 5.97.

Example 56

To a solution of 360 mg of cis-3- (cyanomethylcarboxamido) -2-oxoazetidine-4-carboxylic acid methyl ester in 3 ml of Ν, Ν-dimethylformamide is added 480 mg of pyridine sulfur trioxide complex and the mixture is stirred. and allowed to stand at room temperature for 6 days. To the reaction mixture was added diethyl ether (20 ml), the mixture was stirred and the ether layer was discarded. An additional 10 mL of ether was added to the residue, stirred and the ether phase was discarded. The oily residue was dissolved in water (10 mL). To the aqueous solution was added 10 ml of Dowex 50W Na2 resin and the mixture was stirred at room temperature for 30 minutes. The resin was removed by filtration and washed with water (4 x 10 mL). The filtrate and wash were combined and freeze-dried. The product thus obtained was dissolved in a little water and purified by column chromatography on Amberlite XAD-II resin followed by Sephadex LH-20 gel. Freeze drying of the eluate affords the cis-3- (cyanomethylcarboxamido) -4- (methoxycarbonyl) -2-oxoazetidine-1-sulfonic acid sodium salt.

IR ( ⁴ ); 2250, 1780, 1740,

1675, 1570, 1048.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.64 (2H, s, CH ₂ ), 3.67 (3H, s, CH ₃ ), 4.48 (1H, d, J = 6Hz, C _4-H), 5.27 (1H, dd, J = 6Hz, 9Hz, _C3 -H), 9.12 (1H, d, J = 9Hz, NH).

Example 57

341 mg of cis-3- (2-12- (chloroacetamido) -4-thiazolyl] -2- (methoxyamino) acetamido) -2-oxoazetidine-4-carboxylic acid p-nitrobenzyl To a solution of 3-ester in 3 ml of Ν, Ν-dimethylformamide is added 258 mg of pyridine-sulfur trioxide complex and the mixture is stirred at room temperature for 63 hours. Another 103 mg of pyridine-sulfur trioxide complex was added and stirring was continued for a further 38 hours. Diethyl ether (45 mL) was added to the reaction mixture and the ether phase was removed by decantation. Perform this operation twice. The oily residue was suspended in 45 ml of water. To the suspension was added 20 ml of Dowex 50W Na ⁺ resin and the mixture was stirred at room temperature for 1.5 hours. The resin was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on Amberlite XAD-II and freeze-dried to give a colorless powder. The powder was dissolved in water (16 mL) and δδ mg sodium monomethyl dithiocarbamate was added with stirring and ice-cooling. After stirring at room temperature for one hour, another 68 mg of sodium monomethyl dithiocarbamate was added. The mixture was stirred for an additional hour and then washed with ethyl acetate. The aqueous phase was purified by column chromatography on Amberlite XAD-II and freeze-dried the eluate to give cis-3- [2- (2-amino-4-thiazolyl) -2- (methoxy-amino) -acetamido] -4- ( 4-Nitrobenzyloxy-carbonyl) -2-oxoazetidine-1-sulfonic acid sodium salt (s2N isomer) is obtained.

IR spectrum (vmax, ^cw-1): 1770, 1750, 1670, 1610, 1280, 1050th

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.81 (3H, s, NOCH ₃ ), 4.60 (1H, d, J = 6Hz, C ₄ -H), 5.26 (2H, AB quartet, J = 14 Hz, _OCH2 Ar), 5.44 (1H, dd, J = 6, 9Hz, _C3 -H), 6.60 (1H, s, a group of formula CV), 7.13 (2H, br.s. NH ₂ ), 7.73 (2H, d, J = 9Hz, ArH),

-2219487 ()

8.17 (2Η, d, J = 9Hz, Ar H), 9.48 (IH, d, J = 9Hz, _C3 -NH).

Analytical results for C ₁₇ H ₁₅ N ₆ NaO ₁₀ S ₂ . For 2H ₂ O:

Calculated: C, 34.82; H, 3.27; N, 14.33. Found: C, 34.74; H, 3.26; N, 14.28.

Example 58 In a mixture of ml of tetrahydrofuran and 10 ml of water, 155 mg of cis-3- [2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -4- (4-nitrobenzyloxycarbonyl) were obtained. ) -2-Oxoazetidine-1-sulfonic acid sodium salt (color isomer) is dissolved. To the solution was added 145 mg of 10% palladium on carbon and the mixture was subjected to catalytic reduction at room temperature under normal pressure with stirring. After 3 hours, a solution of sodium bicarbonate (25 mg) in water (10 mL) was added. The catalyst was removed by filtration, and the filtrate was washed with ethyl acetate and concentrated in vacuo. The concentrate was purified by column chromatography on Amberlite XAD-II and freeze-dried the eluate to give cis-3- [2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -4-carboxyl-1-sulfo. The 2-oxo-azetidine disodium salt (color isomer) is obtained.

IR (λ max): 1760, 1660, 1605, 1270, 1050.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.82 (3H, s, NOCH ₃ ), 4.17 (1H, d, J = 6Hz, C ₄ -H), 5.12 (1H , dd, J = 6, 9Hz, _C3 -H), 7.10 (lH, s, a group of formula CV), 7.13 (2H, br, _NH2), 8.62 (IH , d, J = 9 Hz, C ₃ -NH).

Analysis results for C ₁₀ H ₉ N ₅ Na ₂ O ₈ S ₂ . .3 for 1/2 HjO:

Found: C, 24.00; H, 3.22; N, 14.00. Found: C, 24.00; H, 3.14; N, 13.86.

Example 59 Dissolve 462 mg of Cis-3- 2 - (12-chloroacetamido) -4-thiazolyl] -2-methoxycarbonyl-1-methyloxyiminoacetamido in Ν, Ν-dimethylformamide. The methyl 2-oxo-azetidine-4-carboxylic acid (color isomer) was cooled to -78 ° C and a solution of sulfur trioxide N, N-dimethylformamide complex (3 mmol) was added. After stirring at 4 ° C for 18 hours, pyridine (3 mmol) was added and stirred for an additional hour. A crystalline precipitate formed upon addition of 100 ml of diethyl ether. The mother liquor was discarded, the crystals were washed with ether (2 x 30 mL) and dissolved in water (10 mL). To the solution was added 23 ml of Dowex 50W Na ⁺ resin and the mixture was stirred at room temperature for 2 hours. The resin is filtered off and 300 ml of water are added to the filtrate. The resulting suspension was loaded on an Amberlite XAD-II column. The column was washed with water (350 mL) and eluted with 15% ethanol. The eluate (200 ml) was evaporated in vacuo and then dried (freeze dried) to give 420 mg of a colorless powder. This powder was rechromatographed on an Amberlite XAD-II column. The column was washed with 1 L of water and eluted with 100 mL of 15% ethanol. After freeze-drying of the eluate in vacuo, cis-3- [2- (2-chloroacetamido) -4-thiazolyl] -2- (methoxycarbonylmethyloxyimino) acetamido] -4 - (methoxy) a colorless powder of the sodium salt of 2-oxo-azetidine-1-sulfonic acid (color isomer) is obtained.

IR (λ max cm ^-1 ): 1790-1730, 1680-1550, 1055.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm):

3.6 (3H, s, COOCH ₃ ), 3.7 (3H, s, COOCH ₃ ), 4.4 (2H, s, ClCH ₂ ), 4.5 (1H, d, J = 6Hz, C _4- H), 4.68 (2H, s, NOCH ₂ ), 5.45 (1H, dd, J = 6Hz, 9Hz, C ₃ -H), 7.3 (1H, s, CV) ), 9.37 (IH, d, J = 9Hz, C ₃ - NH).

Analysis for C ₁₅ H _l5 CLN ₅ NaOnS _second .2 l / 2H ₂ O:

Calculated: C, 29.58; H, 3.3l; N, 11.50; Found: C, 29.49; 3,%, 3.30; N, 11.56.

Example 60

The ll. In the same manner as in Example 1, cis-3- [2- (2-amino-4-thiazolyl) -2- (methoxycarbonylmethyloxyimino) acetamido] -4- (methoxycarbonyl) -2-oxo- sodium salt of azetidin-1-yl fonic acid (color isomer) was prepared.

IR (ν ^ βκ ⁰ · ¹ ): 3300, 1790—

1730, 1670, 1610, 1530, 1055.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.60 (3H, s, COOCH ₃ ), 3.69 (3H, s, COOCH ₃ ), 4.49 (1H, d, J = 6Hz, C _4-H), 4.64 (2H, s, NOCH _2), 5.41 (IH, dd, J = 6, 9Hz, _C3 -H),

6.64 (1H, s, CV)

7.18 (2H, br.s, NH ₂ ) 9.29 (1H, d, J = 9 Hz, C ₃ -NH).

Analysis for C _l3 H ₁₄ N ₅ NaO | ₀ S ₂ . For 2H ₂ O:

Calculated: C, 29.83; H, 3.47; N, 13.38. Found: C, 30.14; H, 3.52; N, 13.48.

Example 61 in ml of dry Ν, Ν-dimethylformamide

1.35 g of Cis-3- [2- (2- (chloroacetamido) -4-thiazolyl) -2- (p-nitrobenzyloxycarbonylmethyl-oxyimino) -acetamido] -4- ( methoxycarbonyl) -2-oxoazetidine (color isomer) was added and 4.11 ml of a solution of sulfur trioxide-Ν, Ν-dimethylformamide complex (1.69 mol) was added with cooling at -78 ° C. After stirring at 4 ° C for 72 hours, 0.57 ml of pyridine was added and stirring was continued for another hour. After adding 500 ml of diethyl ether, the mixture was allowed to stand in the refrigerator overnight. The upper ether layer was discarded and the residue was washed twice with 50 mL of ether. To add 50 ml of water, add 23 ml

-23194870 The oily precipitate is partially soluble and becomes a sticky substance. To this product was added 50 ml of Dowex 50W Na ⁺ resin and the mixture was stirred at room temperature for 2 hours. After removal of the resin, the mother liquor (about 200 mL) was chromatographed on an Amberlite XAD-II column and eluted with 200 mL of 30% ethanol after washing with 1 L of water. Freeze drying of the eluate after evaporation in vacuo gave CIS-3-2- [2- (chloroacetamido) -4-thiazolyl] -2- (p-nitrobenzyloxycarbonylmethyloxyimino) acetamido} The sodium salt of 4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid (color isomer) is obtained.

IR (ν max / ⁰ * ¹ ): 3250, 1790—

1730, 1670, 1520, 1050.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.61 3H, s, COOCH ₃ ), 4.36 (2H, s, ClCH ₂ ), 4.53 (1 H, d, J = 6Hz, C ₄ H, 4.82 (2H, s, NOCH ₂ ), 5.37 (2H, s, CO ₂ CH ₂ ), 5.48 (1H, dd, J = 6Hz, 9Hz, C _3- H), 7.36 (1H, s, CV), 9.49 (1H, d, J = 9Hz, C ₃ -NH), 12.95 (1H, s, br.s, CICH 8 CONH). ).

Analysis results for C ₂ iH | ₈ ClN ₆ NaO ₁₃ S ₂ . .3H ₂ O Calculated Found:% C 35.22% H 3.38% N 11.74% Found: C = 34.86,% H 3.22,% N, 11.48

Example 62

A il. In the same manner as in Example 3, cis-3- [2- (2-amino-4-thiazolyl) -2- (p-nitrobenzyloxycarbonylmethyloxyimino) - cet amido] -4- (methoxy) -carbonyl) -2-oxo-azetidine-1-sulfonic acid, sodium salt (color isomer).

IR (¹³CM): 3450, 3330, 17901730, 1680, 1610, 1050.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.6 (3H, s, COOCH 3, 4.5 (1H, d, J = 6Hz, C ₄ -H), 4.77 (2H, s,

NOCH ₂ ), 5.35 (2H, s, COOCH ₂ ),

5.43 (IH, dd, J = 6Hz, 9Hz, _C3 -H),

6.66 (1H, s, CV),

7.2 (2H, br.s, NH ₂ ), 9.39 (1H, d, J = 9 Hz, C ₃ -NH).

Analytical results for C ₁₉ H ₁₇ N ₆ NaO ₁₂ S ₂ . For 2H ₂ O:

Found: C, 35.40; H, 3.28; N, 13.04. Found: C, 35.43; H, 3.22; N, 12.83.

Example 63 In a mixture of water (ml) and tetrahydrofuran (25 ml), cis-3- [2- (2-amino-4-thiazolyl) -2- (p-nitrobenzyloxycarbonylmethyl-oxyimino) -acetamido (500 mg) was obtained. The sodium salt of 4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid (color isomer) was dissolved and 500 mg of 10% palladium on carbon was added. The mixture was stirred under an atmosphere of hydrogen for 1 hour and then 25 ml of aqueous sodium bicarbonate solution (66 mg) were added. The catalyst was removed by filtration, and the filtrate was washed with ethyl acetate (30 mL) and evaporated in vacuo to 10 mL. This concentrate was chromatographed on an Amberlite XAD-II column, eluting with water. The first fraction (130 ml) was discarded, and the immediately subsequent 40 ml eluate was freeze-dried to give cis-3- [2- (2-amino-4-thiazolyl) -2- (carboxy-1-methyloxyimino) - Acetamido] -4- (methoxycarbonyl) -2-oxoazetidine-1-sulfonic acid disodium salt (color isomer) is obtained.

IR (cm- ¹ ): 3350, 1780, 1750, 1670, 1600, 1055.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.58 (3H, s, COOCH ₃ ), 4.27 (2H, s, NOCH ₂ ), 4.5 (1H, d, J = 6Hz, C _4-H), 5.37 (IH, dd, J = 6, 9Hz, _C3 -H), 6.72 (lH, s, a group of formula CV), 7.11 (2H, br, NH ₂ ),

11.3 (lH, d, J = 9Hz, _C3 -NH).

Analysis results for C ₁₂ HnN ₅ Na ₂ O ₁₀ S ₂ . .2 1 / 2H ₂ O:

Calculated: C, 26.67; H, 2.98; N, 12.96. Found: C, 26.63; H, 3.02; N, 12.93.

Example 64 In a mixture of water (ml) and tetrahydrofuran (20 ml), 950 mg of cis-3- (benzyloxycarboxamethyl) -4- (methoxycarbonyl) -2-oxoazetine din-1-sulfonic acid obtained in Example 49 was obtained. The sodium salt was dissolved and 950 mg of 10% palladium on carbon was added. The mixture was stirred under a hydrogen atmosphere at room temperature for one hour. The catalyst was filtered off and washed with 40 ml of water-tetrahydrofuran (1: 1). The filtrate and the washings were combined with 504 mg of sodium bicarbonate and 1.55 g of 2- [2- (chloroacetamido) -4-thiazolyl] - (Z) -2- [4 - methyl 1- (p-nitrobenzyloxycarbonyl) ethyl-oxyimino] -acetyl chloride hydrochloride. The mixture was stirred under ice-cooling for 40 minutes and then concentrated in vacuo. The residue was chromatographed on an Amberlite XAD-II column and freeze-dried the eluate to give cis-3- [2- (chloroacetamido) -4-thiazolyl] -2- [1-methyl-1- (p-nitrobenzyloxy) -carbonyl) -ethyloxyimino] -acetamido} -4- (methoxycarbonyl) -2-oxoazetidine-1-sulfonic acid, sodium salt (color isomer) was obtained as a colorless powder.

IR spectrum (v ™ c * ¹ ); 1775, 1740, 1680, 1550, 1525, 1280, 1055.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.50 (6H, s, 2XCH ₃ ), 3.62 (3H, s,

_COOCH3), 4.33 (2H, s, C1CH _2);

4.51 (IH, d, J = 6Hz, C ₄ -H), 5.31 (2H, s, COOCH _2), 5.52 (IH, dd, J = 6, 9Hz, _C3 - H), 7.25 (1H, s, CV) 7.62, 8.07 2X2H, 2Xd, aromatic protons).

-24194870

Analytical results for C ₂₃ H ₂₂ ClN ₆ NaO _{) 3} S ₂ . , For 3H ₂ O:

N, 10.96 Found: C, 36.09; H, 3.36; N, 11.06. Found: C, 36.01; H, 3.68; N, 10.96.

Example 65 1.158 g of cis-3- (2- (2- (chloroacetamido) -4-thiazolyl) -2- [1-methyl-1- (p-nitrobenzyloxycarbonyl) ethyl] in ml of water -Oximino] -acetamido} -4- (methoxycarbonyl) -2-oxoazetidine-1-sulfonic acid (color isomer) was dissolved and 241 mg of sodium monomethyl dithiocarbamate was added under ice-cooling and stirring. After stirring at room temperature for one hour, another 241 mg of sodium monomethyl dithiocarbamate was added and the mixture was stirred for an additional hour, then the reaction mixture was washed with diethyl ether and concentrated in vacuo. freeze-drying of the eluate cis-3-12- [2-amino-4-thiazolyl] -2- [1-methyl-1- (p-nitrobenzyloxycarbonyl) -ethyloxyimino] -acetamido} - The sodium salt of 4 - (methoxycarbonyl) -2-oxoazetidin-1-yl (color isomer) is obtained in the form of a colorless powder.

IR (λ max cm ^-1 ): 1775, 1740, 1680, 1615, 1520, 1280, 1055.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.48 (6H, s, 2XCH ₃ ), 3.63 (3H, s,

COOCH ₃ ), 4.50 (1H, d, J = 6Hz, C ₄ H), 5.33 (2H, s, COOCH

5.47 (1H, dd, J = 6, 9Hz, _C3 -H),

6.59 (1H, 's, CV),

7.24 (2H, br.s, NH ₂ ), 7.65, 8.14 (2X2H, 2Xd, aromatic protons),

9.18 (IH, d, J = 9Hz, _C3 -NH).

Analysis for C ₂ H _{2, ft} N NaO ₂ S _second .2 1 / 2H ₂ O:

Found: C, 36.99; H, 3.87; N, 12.34 Found: C, 36.99; H, 3.84; N, 12.33.

Example 66 In a mixture of ml of water and 25 ml of tetrahydrofuran, 500 mg of cis-3-12- (2-amino-4-thiazolyl) -2- [1-methyl-1- (p-nitrobenzyl) oxycarbonyl ) -ethyloxyimino] -acetamido} -4- (methoxycarbonyl) -2-oxoazetidin-1-ylsonic acid sodium salt (color isomer) and then 500 mg of 10% palladium on carbon we add. The mixture was stirred under a hydrogen atmosphere at room temperature for one hour. Aqueous sodium hydrogencarbonate solution (62 mg) (25 ml) was added, the catalyst was filtered off, and the filtrate was washed with ethyl acetate and concentrated in vacuo. The residue was chromatographed on an Amberlite XAD-II column and freeze-dried the cis-3-12- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido]. 4- (Methoxycarbonyl) -2-oxoazetidine-1-sulfone is obtained as the sodium disodium salt (color isomer).

IR 1775, 1740, 1660,

1630, 1580, 1280, 1055.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.36 (3H, s, CH 3), 1.45 (3H, s, CH ₃ ), 3.61 (s, CO ₂ CH ₃ , 4.53 (1H, d) , J = 6Hz, C ₄ -H), 6.60 (lH, s, a group of formula CV), 7.13 (2H, br, _NH2).

Analytical results for C, ₄ H, ₅ N ₅ Na ₂ O ₁₀ S ₂ . , For 4H ₂ O:

Found: C, 28.26; H, 3.89; N, 11.76 Found: C, 28.26; H, 3.68; N, 11.62.

Example 67 Cis-3- [2- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4- (methoxycarbonyl) in cold water. The 2-oxo-azetidin-1-yl fona v-disodium salt (color isomer) is dissolved and chromatographed on a column of 10 ml of Dowex 50W H ⁺ resin. Elution is carried out with water, the UV-absorbed fractions are collected and evaporated in vacuo. The residue was chromatographed on a Sephadex LH-20 column and freeze-dried on the eluate to give cis-3- [2- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino). ) -acetamido] -4- (methoxycarbonyl) -2-oxoazetidine-1-sulfonic acid (color isomer) is obtained in the form of a colorless powder.

IR (λ max. Δ): 1775, 1730, 1670, 1630, 1280, 1050.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.50 (6H, s, 2XCH ₃ ), 3.63 (3H, s,

COOCH ₃ ), 4.53 (1H, d, J = 6Hz, C ₄ -H), 5.45 (1H, dd, J = 6Hz, 9Hz, C ₃ -H), 6.87 (1H and a group of formula CV), 9.29 (IH, d, J = 9Hz, _C3 -NH).

Analysis results for C ₁₄ H ₁₇ N ₅ O ₁₀ S ₂ . For 2,3 H ₂ O:

Found: C, 32.28; H, 4.18; N, 13.45; Found: C, 32.28; H, 4.11; N, 13.20.

Example 68 In ml N, N-dimethylformamide, 550 mg of cis-3- (2-] 2- (chloroacetamido) -4-thiazolyl] -2- [1-methyl- (p-nitrobenzyl) -oxycarbonyl) -ethyloxyimino] -acetamido} -4-methoxycarbonyl-2-oxoazetidine (color isomer) was dissolved in 1.6 ml of sulfur trioxide with cooling at -78 ° C. A solution of -Ν, Ν-dimethylform mid complex (1.69 mol) was added.

After stirring at 3-5 ° C for 24 hours, pyridine (0.22 mL) was added. An oil precipitate was then poured into 75 ml of diethyl ether. The ether layer was discarded and the ether-insoluble oily precipitate was washed with ether (2 x 50 mL) and suspended in water (25 mL). To the suspension 20 ml of Dowex _z 5Q Na ⁺ W-shaped resin is added and stirred at room temperature for one and a half hours. The resin was filtered off and the filtrate was concentrated in vacuo. The residue was chromatographed on an Amberlite XAD-II column and freeze-dried the eluate to give cis-3-12- [2-chloro

-25194870

-acetamido) -4-thiazolyl] -2- [1-methyl-1- (p-nitro-benzyloxycarbonyl) -ethyloxyimino] -acetamido} -4- (methoxycarbonyl) - The sodium salt of 2-oxoacetin din-1-sulfonic acid (color isomer) was obtained as a colorless powder. This product had the same IR and NMR spectra as in Example 64.

Analytical results for C ₂₃ H ₂₂ ClN ₆ NaO ₁₃ S ₂ . For H ₂ O:

Calculated: C, 37.79; H, 3.31; N, 11.50. Found: C, 37.50; H, 3.42; N, 11.69.

The amino and carboxy protecting groups in the compound can be removed by the procedures described in Examples 65 and 66, respectively.

Example 69

In the same manner as in Example 10, cis-3- {2- [2- (chloroacetamido) -4-thiazolyl] -2- (allyloxyimino) acetamido} -4- (methoxycarbonyl) -2 The oxo-azetidine -1-sulfonic acid sodium salt (color isomer) is prepared.

IR 3250, 1780, 1750,

1680, 1055.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.60 (3H, s, COOCH ₃ ), 4.32 (2H, s, ClCH ₂ ), 4.49 (1H, d, J = 6Hz, C ₄ -H), 7.27 (1H, s, CV), 9.49 (1H, d, J = 9Hz, c ₃ -NH).

Analytical results for C ₁₅ H ₁₅ ClN ₅ NaO ₉ S ₂ . .1 1 / 2H ₂ O:

Calculated: C, 32.23; H, 3.25; N, 12.53 Found: C, 32.42; H, 3.30; N, 12.59.

Example 70

In the same manner as in Example 11, cis-3- [2- (2-amino-4-thiazolyl) -2- (allyloxyimino) acetamido] -4-methoxycarbonyl) -2-oxo azetidine-1-sulfonic acid sodium salt (color isomer) is prepared.

IR spectrum (vmax, ^r 'cm'): 3325, 1790- 1740, 1670, 1050th

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.60 (3H, s, COOCH ₃ ), 4.4-4.7 3H, m, CH ₂ CH = E H ₂ and C ₄ -H), δ , 0-5.5 (3H, m, CH ₂ CH = CH ₂ and C ₃ H), 5.7-6.2 (1H, m, CH ₂ CH = CH ₂ ),

6.56 (1H, s, CV),

7.12 (2H, br.s, NH ₂ ), 9.39 (1H, d, J = 9 Hz, C ₃ -NH).

Analytical results for C ₁₃ H ₁₄ N ₅ NaO ₈ S ₂ . .1 1 / 2H ₂ O:

Calculated: C, 32.36; H, 3.55; N, 14.52. Found: C, 32.47; H, 3.75; N, 14.46.

EXAMPLE 71 Trans-3- 3- [2- (Chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamidoyl-4-methoxycarbonyl-2-oxoazetidine in ml water The sulfonic acid sodium salt (color isomer) (prepared according to Example 24) was dissolved and 15 mg of sodium monomethyl dithiocarbamate (26) was added under ice-cooling and stirring. After stirring at room temperature for 30 minutes, another 15 mg of sodium monomethyl dithiocarbamate was added and stirred for an additional 30 minutes. The reaction mixture was filtered and the filtrate was washed with diethyl ether. The aqueous layer was chromatographed on an Amberlite XAD-II column and freeze-dried the eluate to trans-3- [2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -4- (methoxycarbonyl) - The sodium salt of 2-oxoazetidine-1-sulfonic acid (color isomer) is obtained.

IR (ν max cm ^-1 ) _: 3400, 1780 NMR (D ₆ -DMSO, ppm): 3.70 (3H, s, COOCH 3), 3.85 (3H, s, NOCH ₃ ), δ 10 (lH, s, d, J = 2Hz, C ₄ -H), 4.77 (IH, dd, J = 2Hz, 9Hz, _C3 -H), 6.70 (lH, s, CV), 7.20 (2H, br.s, NH ₂ ), 9.47 (1H, d, J = 9Hz, C ₃ -NH).

Example 72

In the same manner as in Example 10, cis-3- {2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido} -4- (chloromethyl) -2-oxo- azetidine-1-sulfonic acid sodium salt (color isomer) is prepared.

IR (ν ^max cm- ¹ ) 1770, 1670, 1550, 1270, 1055.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.89 (3H, s, NOCH ₃ ), 4.34 (2H, s, ClCH ₂ )

5.28 (IH, dd, J = 6, 9Hz, _C3 II)

7.38 (1H, s, CV),

9.37 (lH, d, J = 9Hz, _C3 -NH), 12.90 (IH, br, CICHoCONH).

Example 73

In the same manner as in Example 11, cis-3- [2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -4- (chloromethyl) -2-oxoazetidine sodium sulfonic acid (color isomer) was prepared.

IR (λ max): 1770, 1660, 1610, 1530, 1270, 1050.

Analysis for C _l0 H _u (i. IN ₅ NaO ₆ S ₂ .2H ₂ O Calcd:

Found: C, 26.35; H, 3.32; N, 15.36 Found: C, 26.31; H, 3.18; N, 15.33.

Example 74

In the same manner as in Example 10, cis-3- {2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido} -4- (methylsulfonyloxymethyl) The 2-oxo-azetidine-1-sulfonic acid sodium salt (color isomer) was prepared.

IR (ν max cm ^-1 ): 1770, 1670, 1560, 1350, 1275, 1175, 1050.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm) 3.10 (3H, s, SO ₂ CH ₃ ), 3.90 (3H, s,

NOCH _3), 4.35 (2H, s, C1CH _2), 5.33 (IH, dd, J = 5Hz, 9Hz, _C3 -H),

7.41 (1H, s, CV),

-26194870

9.42 (IH, d, J = 9Hz, _C3 -NH);

12.91 (1H, br.s, ClCHoCONH) ·

Analytical results for C ₁₃ H ₁₅ ClN ₅ NaO ₁₀ S ₃ . For 2H ₂ O:

Found: C, 26.28; H, 3.24; N, 11.83 Found: C, 26.54; H, 3.26; N, 11.72.

Example 75

In the same manner as in Example 11, cis-3- 3- [2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -4- (methylsulfonyloxymethyl) -2 The oxo-azetidine-1-sulfonic acid sodium salt (color isomer) is prepared.

IR spectrum (vmax, cm ^{r 4):} 1770, 1670, 1620, ¹⁵

1535, 1350, 1280, 1175, 1055.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.10 (3H, s, SO ₂ CH ₃ ), 3.86 (3H, s, NOCH ₃ ), 5.28 (1H, dd, J = 5Hz) .

Hz, C ₃ -H), 6.74 (lH, s, a group of formula CV), 9.30 (IH, d, J = 9Hz,

C ₃ -NH).

Analytical results for C,, H ₁₄ N ₅ NaO ₉ S ₃ . For 2H ₂ O:

Calculated: C% = 25.63, H% = 3.52, N% = 13.59 ^ö% Found: C = 25.64,% H 3.41,% N, 13.56

Example 76

Following the procedure of Example 10 cis-3- {2- [2- (chloroacetamido) -4-thiazolyl] -2- (Meth ³⁰ oxyimino) acetamido] -4- (azidomethyl) - The 2-oxo-azetidine-1-sulfonic acid sodium salt (color isomer) was prepared.

IR (λmax '): 2110, 1765, 1650, 35

1550, 1260, 1045.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.653.80 (2H, m, CH ₂ N ₃ ), 3.92 (3H, s, NOCH ₃ ), 4.25 (2H, s, ClCH ₂ ), 5.24 (1H, dd, J = 5 Hz, 9 Hz, C ₃ -H), ⁴⁰

7.44 (1H, s, CV),

9.33 (IH, d, J = 9Hz, _C3 -NH).

Analytical results for C ₁₂ H ₁₂ ClN _g NaO ₇ S ₂ . For 2H ₂ O:

Calculated: C, 26.75; H, 2.99; N, 20.79 45 Found: C, 26.59; H, 2.90; N, 20.80.

Example 77

Following the procedure of Example 11, cis-3- [2- (2-amino-4-thiazolyl) -2- (methoxyimino) -50

-acetamido] -4- (azidomethyl) -2-oxoazetidine-1-sulfonic acid sodium salt (color isomer) was prepared.

IR spectrum (λmax * ¹ ) _; 2110, 1765, 1660, 55

1530, 1270, 1050.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.603.85 (2H, m, CH ₂ N ₃ ), 3.87 (3H, s, NOCH ₃ ), 5.20 (1H, dd, J = 5Hz) .

Hz, C ₃ -H), 6.75 (lH, d, CV θθ their existence image group), 7.16 (2H, br, NH _2);

9.22 (IH, d, J = 9Hz, _C3 -NH).

Analytical results for C ₁₀ H ₁₁ N ₈ NaO ₆ S ₂ .2H ₂ O:

Calculated: C, 25.98; H, 3.27; N, 24.23 Found: C, 26.11; H, 3.41; N, 24.34 ⁶⁵

Example 78

In the same manner as in Example 3, cis-3- (2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido} -4- (benzoyloxymethyl) -2 The oxo-azetididine-1-sulfonic acid sodium salt (syn isomer) is prepared.

IR (νΐΐ Ί) 3250, 1770, 1720-1660, 1545, 1050.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.69 (3H, s, NOCH ₃ ), 4.35 (2H, s, ClCH ₂ ).

5.32 (IH, dd, J = 6, 9Hz, _C3 -H),

7.35 (1H, s, CV).

Analytical results for C ₁₉ H ₁₇ ClN ₅ NaO ₈ S ₂ . .3H ₂ O:

Calculated: C, 36.81; H, 3.74; N, 11.50 Found: C, 36.92; H, 3.63; N, 11.38.

Example 79

In the same manner as in Example 4, cis-3- [2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -4-benzoyloxymethyl) -2-oxoazetidine Sodium salt of 1-sulfonic acid (color isomer).

IR (λ max cm ^-1 ): 3300, 1770, 1710, 1665, 1050.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.67 (3H, s, NOCH ₃ ), 5.28 (1H, dd, J = 6Hz, 9Hz, C ₃ -H), 6.62 (1H, s, CV), 7.12 (2H, br.s, NH ₂ ), 9.38 (1H, d, J = 9Hz, C ₃ -NH).

Analytical results for C ₁₇ H ₁₆ N ₅ NaO ₈ S ₂ . .1 1 / 2H ₂ O:

Calculated: C, 38.34; H, 3.60; N, 13.15 Found: C, 38.23; H, 3.53; N, 13.15.

Example 80

In the same manner as in Example 1, cis-3- {2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido} -4-acetyl -2-oxoazetidin-1-one. sodium sulfonic acid (color isomer) was prepared.

IR (λmax ₈ cm ^-1 ): 3420, 1760, 1650, 1540, 1265.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 2.30 (3H, s, COCH ₃ ), 3.85 (3H, s,

NOCH _3), 4.34 (2H, s, ₂ C1CH), 4.40 IH, d, J = 5Hz, _C4 -H), 5.18 (IH, dd, J = 5 Hz, 10 Hz, C ₃ -H), 7.40 (lH, s, a group of formula CV).

Example 81

In the same manner as in Example 11, cis-3- [2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -4-acetyl-2-oxoazetidine-1-sulfonic acid sodium salt was obtained. (color isomer is prepared.

IR spectrum (\ ÜV ^{c t-1):} 3400, 1760, 1660, 1535, 1260, 1050th

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm), 2.30 (3H, s, COCH ₃ ), 3.81 (3H, s,

NOCH ₃ ), 4.40 (1H, d, J = 5Hz, C ₄ -H), 5.26 (1H, t, C ₃ -H), 6.64 (1H, s, CV).

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Example 82 In ml N, N-dimethylformamide, 172 mg cis-3-12- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido) -4- (hydroxymethyl) -2-Oxoazetidine (color isomer) was dissolved and 318 mg of pyridine-sulfur trioxide complex was added. After stirring at room temperature for 24 hours, another 159 mg of pyridine-sulfur trioxide complex was added and stirring was continued for another 106 hours. Addition of diethyl ether gives an oily precipitate from the reaction mixture. The ether phase was discarded and the precipitate was washed with ether. This operation was repeated and the precipitate was dissolved in water (20 mL). Dowex 50W Na ⁺ resin (40 ml) was added to the solution and the mixture was stirred at room temperature for 2 hours and then filtered. The filtrate was evaporated in vacuo, the residue chromatographed on an Amberlite XAD-II column and freeze-dried the eluate to give cis-3- {2- [2-chloroacetam time) -4-thiazolyl] -2- (methoxyimino) acetone. ) The sodium disodium salt (color isomer) of 4- (parenterified tooxymethyl) -2-oxoazetidine-1-sulfonic acid is obtained.

IR spectrum (v * ® _^): 1765, 1665, 1545, 1275, 1240, 1055, 1030th

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.90 (3H, s, NOCH ₃ ), 4.35 (2H, s,

C1CH _2), 5.34 (IH, dd, J = 4.5 Hz, 9Hz, _C3 -H), 7.66 (lH, s, CV formula group), 9.38 (IH, d, J = 9 Hz, C ₃ -NH).

Analysis results for C ₁₂ H | ₂ ClN ₅ Na ₂ O,, S. , For 4H ₂ O:

Found: C, 22.11; H, 3.09; N, 10.74. Found: C, 22.25; H, 2.92; N, 10.47.

Example 83

In the same manner as in Example 1, cis-3- {2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido} -4- (chloroacetoxymethyl) -2 The oxo-azetidine-1-sulfonic acid sodium salt (color isomer) is prepared.

IR (λ max cm ^-1 ): 3400, 1760, 1670, 1050.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.80 (3H, s, NOCH ₃ ), 5.23 (1H, dd, J = 5Hz, 9Hz, C ₃ -H), 7.43 (1H, s, CV), 9.34 (1H, d, J = 9Hz, C ₃ -NH).

Analysis for _{C) 4} Cl ₂ F ₅ H _l4 NaOgS _second For ₂ H ₂ O:

Found: C, 28.48; H, 2.73; N, 111.86 Found: C, 28.49; H, 2.77; N, 11.84.

Example 84 Cis-3- {2- [2-chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido} -4-chloroacetoxymethyl-70 mg in ml water The oxo-azetidine -1-sulfonic acid sodium salt (color isomer) was dissolved and 39 mg of sodium monomethyl dithiocarbamate was added under ice-cooling and stirring was continued for 30 minutes. 28

The reaction mixture was then filtered and the filtrate washed with diethyl ether. The aqueous phase was chromatographed on an Amberlite XAD-II column and freeze-dried the eluate to give cis-3- [2- (2-amino-4-thiazolyl) -2- (methoxyimino) -acetamido] -4- (hydroxymethyl) - The 2-oxo-azetidinylsulfonic acid sodium salt (color isomer) was prepared.

IR (ν [α] D 25) _: 3400, 1760, 1660, 1050.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 5.15 (1H, dd, J = 5Hz, 9Hz, C ₃ -H),

6.90 (1H, s, CV),

7.60 (2H, br.s, NH ₂ ), 9.07 (1H, d, J = 9 Hz, C ₃ -NH).

Analysis for C ₁₀ H, ₂ N ₅ NaO ₇ S ₂ .2H ₂ O:

Found: C, 27.33; H, 3.21; N, 15.94. Found: C, 27.16; H, 3.44; N, 15.70.

Example 85

In the same manner as in Example 31, cis-3- [2- (2-chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido} -4- [2- (methylsulfonyl) ethoxy] -carbonyl-a-minomethyl] -2-oxoazetidine-1-sulfonic acid (color isomer) is prepared.

IR spectrum (νΧΧ) _; 1770, 1690, 1550, 1275, 1050.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.97 (3H, s, SO ₂ CH ₃ ), 3.44 (2H, t, J = 6Hz, CH ₂ SO ₂ ), 3.93 ( 3H, s, NOCH _3), 4.34 (2H, t, J = 6Hz, _COOCH2), 4.37 (2H, s, C1CH _2), 5.21 (IH, dd, J = 6Hz, 9 Hz, C ₃ -H),

7.51 (1H, s, CV),

9:48 (lH, d, J = 9Hz, _C3 -NH). Analytical results for C ₁₆ H ₂₀ ClN ₆ NaOnS ₃ . .3H ₂ O:

Calculated: C, 28.22; H, 3.85; N, 12.34. Found: C, 28.34; H, 3.63; N, 12.10.

Example 86

In the same manner as in Example 10, cis-3- {2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido} -4- (trifluoroacetylamino) methyl ) -2-Oxoazetidine -1-sulfonic acid sodium salt (color isomer) was prepared.

IR (λ max ¹ ): 1770, 1710, 1670, 1550, 1270, 1050.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.91 (3H, s, NOCH ₃ ), 4.36 (2H, s, ClCH ₂ )

5.28 (IH, dd, J = 6Hz, 9Hz, _C3 -H),

7.49 (1H, s, CV),

9.46 (IH, d, J = 9Hz, _C3 -NH).

Analysis for C ₁₄ H ₁₃ ClF ₃ N ₆ NaO ₈ S ₂ . 3H ₂ O Calcd Calculated: C% = 26.82, H% = 3.05, N% = 13.41 found: C% = 26.63, H% = 2.85, N = 13.22%

Example 87

All. Following the procedure of example cis-3- [2- _v i 2-Amino-4-thiazolyl) -2- (methoxyimino) -28,194,870

-acetamido] -4-trifluoroacetylaminomethyl-2-oxoazetidine-1-sulfonic acid sodium salt (color isomer) was prepared:

IR spectrum (ν «« ο ^«4): 1770, 1720, 1670, 1530, 1050th

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.85 (3H, s, NOCH ₃ ), 5.17 (1H, dd, J = 6Hz, 9Hz, C ₃ -H), 6.80 (lH, s, a group of formula CV), 7.12 (2H, br, _NH2), 9.35 (1Ή, d, J = 9Hz, C ₃ - H).

Analysis results for C ₁₂ H ₁₂ F ₃ N ₆ NaO ₇ S ₂ . .3H ₂ O:

Calculated: C, 26.19; H, 3.30; N, 15.27. Found: C, 26.30; H, 3.07; N, 15.0588. Example

In 3.5 mL of N, N-dimethylformamide, 416 mg of CIS-3-N- [2-chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido} -4- (p-nitro) Benzyloxycarbonylaminomethyl) -2-oxoazetidine (color isomer) was dissolved and 239 mg of pyridine-sulfur trioxide complex was added. After stirring at room temperature for 48 'hours, another 119 mg of pyridine-sulfur trioxide complex was added and stirring continued for 72 hours. Addition of 55 ml of diethyl ether gave an oily precipitate from the reaction mixture. The upper ether phase was discarded and the precipitate was washed with ether. This operation is repeated and the oily precipitate is suspended in 50 ml of water. To the suspension was added 25 ml of Dowex 50W Na ⁺ resin and the mixture was stirred at room temperature for 2 hours. The resin was removed by filtration and the filtrate was concentrated in vacuo. The residue was chromatographed on an Amberlite XAD-II column to freeze-dry the eluate to give 404 mg of a colorless powder. The powder was dissolved in 15 ml of water and 87 mg of sodium monomethyl dithiocarbamate was added under ice-cooling and stirring. After stirring at room temperature for 1 hour, water (5 ml), tetrahydrofuran (5 ml) and sodium monomethyl dithiocarbamate (87 mg) were added. After stirring for an additional hour, the mixture was washed with ethyl acetate and chromatographed on an Amberlite XAD-II column. Freeze drying of the eluate gave cis-3- [2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -4- (p-nitrobenzyloxycarbonylaminomethyl) The sodium salt of -2-oxoazetidine-1-sulfonic acid (color isomer) is obtained.

IR (λ max): 1765, 1710, 1660, 1615, 1260, 1050.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.87 (3H, s, NOCH ₃ ), 5.20 (2H, s,

COOCH,). 6.83 (1H, s, CV).

Analysis for C ₁₈ H _l8 N ₇ NaO ₁₀ S _2nd .2 1 / 2H ₂ O:

Found: C, 34.62; H, 3.72; N, 15.70 Found: C, 34.53; H, 3.52; N, 15.70.

Example 89 In a mixture of ml of water and 15 ml of tetrahydrofuran, 203 mg of cis-3- [2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -4- (p-nitrobenzoyloxy) -carbonylaminomethyl) -2-oxo-azetidine-1-sulfonic acid sodium salt (color isomer) was added and 190 mg of 10% palladium on carbon was added. The mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. The catalyst was filtered off, the filtrate was washed with ethyl acetate and evaporated in vacuo. The residue was chromatographed on an Amberlite XAD-II column and freeze-dried the eluate to give a colorless powder. The powder was rechromatographed on a Sephadex LH-20 column and freeze-dried the eluate to give cis-3-12- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -4- (aminomethyl) -2 oxo-azetidine-1-sulfonic acid (color isomer) is obtained.

IR spectrum (v ^ c _^'i-1): 1770, 1660, 1620, 1530, 1275, 1050th

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.88 (3H, s, NOCH ₃ ), 6.84 (1H, s, CV).

Analysis for C _l4 H ₀ N ₆ O ₆ S ₂ .2H ₂ O Calcd:

Calculated: C, 28.98; H, 4.38; N, 20.28. Found: C, 29.29; H, 4.3 L; N, 20.19.

Example 90

Following the procedure of Example 27, cis-3- [D-2- [4-ethyl-2,3-dioxo-1-piperazinecarboxamido] -2-phenylacetamido] -4-methoxycarbonyl-beta- 2-Oxoazetidine -1-sulfonic acid sodium salt was prepared.

Beta-form

IR spectrum (vmax, ^cw-1): 1770, 1710, 1675, 1510, 1280, 1055th

NMR _(D6 -DMSO, ppm): 1.10 (3H, t, J = Hz, N-CH, _CH?). 3.10 (3H, s, _COOCH3), 4.37 (IH, d, J = 6Hz, C ₄ -H), 5.31 (IH, dd, J = 6 Hz, 9 Hz, C _3- (Η), 5.55 (1H, d, J = 7Hz, PhCH), 7.38 (5H, s, Ph),

9.28 (IH, d, J = 9Hz, _C3 -NH);

9.82 (1H, d, J = 7Hz, PhCHNH).

Analytical results for C ₂₀ H ₂₈ N ₅ NaO ₁₃ S ₃ H ₂ O:

Calculated: C, 39.94; H, 4.69; N, 11.74 Found: C, 40.08; H, 4.53; N, 11.53.

Alpha-form

IR (νν ^ ^: 1780, 1710, 1675, 1510, 1270, 1055).

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.10 (3H, t, J = 6Hz, N-CH 2 CH ₃ ), 3.59 (3H, s, COOCH ₃ ), 4.47 (1H, d, J = 6 Hz, C ₄ -H), 5.15 (1H, dd, J = 6 Hz, 9 Hz, C ₃ -Η), 5.48 (1H, d, J = 7 Hz, PhCH) , 7.40 (5H, br.s, Ph),

9.38 (IH, d, J = 9Hz, _C3 -NH), 9.74 (IH, d, J = 7Hz, PhCHNH).

-29194870

Analytical results for C _'20 H ₂₈ N ₅ NaO _{3 3} S ₃ H ₂ O:

Calculated: C, 39.94; H, 4.96; N, 11.74 Found: C, 40.21; H, 4.42; N, 11.61.

Example 91

Following the procedure of Example 27, cis-3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido] -4- (acetoxy) -beta and alpha methyl) -2-oxoazetidine -1-sulfonic acid sodium salt was prepared.

Beta-form

IR (ν max cm ^-1 ): 1770, 1705, 1665, 1500, 1240, 1045.

NMR spectrum (D _g -DMSO, ppm): 1.10 (3H, t, J = 8 Hz, _{CH2 CH3),} 1.58 (3H, s, _COCH3), 5.14 (IH, dd , J = 5Hz, 9Hz, C ₃ -H), 5.50 (1H, d, J = 7Hz, PhCH), 9.28 (1H, d, J = 9Hz, C ₃ -NH).

Alpha-form

IR spectrum (νmax »c> ¹¹ ): 1770, 1710, 1670, 1505, 1240, 1050.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.11 (3H, t, J = 7Hz, CH ₂ CH ₃ ), 1.86 (3H, s, COCH ₃ ), 4.98 (1H, dd). , J = 5Hz, 9Hz, C ₃ -H), 5.40 (1H, d, J = 7Hz, PhCH), 9.22 (1H, d, J = 9Hz, C ₃ -NH).

Example 92

Following the procedure of Example 27, the cis-3-D-2- [3- (furan-2-aldimino) -2-oxo-1-imidazolidinecarboxamido] -2-phenylacetamido-beta and alpha-structure} Sodium salt of 4- (methoxycarbonyl) -2-oxoazetidine-1-sulfonic acid is prepared.

The beta form has an IR spectrum of 1770, 1725, 1665,

1415, 1275, 1240.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.10 (3H, s, COOCH ₃ ), 3.76 (4H, s, NCH ₂ CH ₂ N), 4.35 (1H, d, J = 6 Hz, C ₄ - H), 5.32 (1H, dd, J = 6Hz, 9Hz, C ₃ --H), 5.55 (1H, d, J = 6Hz, PHCH), 9.05 ( H, d, J = 6Hz, PhCHNH), 9.25 (IH, d, J = 9Hz, _C3 -NH).

Alpha-form

IR (λ max = ¹ ): 1770, 1725, 1415, 1275, 1240.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.61 (3H, s, COOCH ₃ ), 3.78 (4H, s, NCH ₂ CH ₂ N), 4.46 (1H, d, J = 6 Hz, C ₄ -H), 5.12 (1H, dd, J = 6Hz, 9Hz, C ₃ -H), 5.47 (1H, d, J = 7Hz, PhCH), 8.97 (1H , d, J = 7Hz, PhCHNH), 9.32 (IH, d, J = 9Hz, _C3 -NH).

Example 93

Following the procedure of Example 27, the cis-3- (D-2- [3- (thiophene-230)

-aidimino) -2-oxo-1-imidazolidinecarboxamido] -2-phenylacetamido} -4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid, sodium salt.

Beta-form

IR (C 17 H 1770, 1735, 1666, 1530, 1405, 1270, 1235).

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.11 (3H, s, COOCH ₃ ), 3.80 (4H, s, NCH ₂ CH ₂ N), 4.33 (1H, d, J = 6 Hz, C ₄ H), 5.30 (1H, dd, J = 6 Hz, 9 Hz, C ₃ -H), 5.55 (1H, d, J = 7 Hz, PhCH). 8.11 (1H, s, N = CH), 9.07 (1H, d, J = 7Hz, PhCHNH). 9.22 (IH, d, J = 9Hz, _C3 -NH1.

Alpha-form

IR spectrum (vmax ICM ^'4): 1765, 1740, 1680, 1535, 1405, 1270, 1240th

NMRrSpektruma (D _g -DMSO, ppm): 3.62 (3H, s, _COOCH3), 3.80 (4H, s, _{NCH2 CH2} N), 4.45 (IH, d, J = 6Hz, C ₄ -H), 5, ll (IH, dd, J = 6, 9Hz, _C3 -H), 5.47 (IH, d, J = 7 Hz, PhCH). 8.10 (1H, s, N = CH).

Example 94

Following the procedure of Reference Example 3, 0.8 g of methyl 3-cis-3- (benzoyloxycarboxamido) -2-oxoazetidine-4-carboxylic acid was prepared and dissolved in 10 ml of methylene chloride. and, under ice-cooling and stirring, 0.4 ml of triethylamine followed by dropwise addition of 0.6 g of a solution of 2- (2-methyl-4-thiazolyl) -2- (methoxyimino) acetyl chloride in methylene chloride. added. The mixture was stirred under ice-cooling for 20 minutes and then at room temperature for 1.5 hours. Water was added to the reaction mixture, and the methylene chloride layer was separated, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was cooled to -10 ° C and

1.75 ml of a solution of sulfur trioxide N, N-dimethylformamide complex (1.58 mol) were added. The mixture was allowed to stand in a closed flask at 5 ° C for 3 days. To the reaction mixture was added pyridine (0.29 mL), poured into diethyl ether (100 mL) and stirred. Discard the supernatant and dissolve the residue in 2 mL of water. To the solution was added 30 ml of Dowex 50W Na ⁺ resin and the mixture was stirred at room temperature for 30 minutes. The resin was filtered off and the filtrate was concentrated to 20 ml. The concentrate was chromatographed on an Amberlite XAD-II column and freeze-dried the eluate to give cis-3- [2- (2-methyl-4-thiazolyl) -2- (methoxyimino) acetamido] -4- (methoxycarbonyl) -2-. The oxoazetidine-1-sulfonic acid sodium salt (color isomer) is obtained.

IR (ν cm -1 ^H ) 3425, 1770, 1750, 1275, 1050.

Nuclear Magnetic Resonance Spectrum (D ₂ O, ppm): 2.72 (3H, s, CXIV), 3.81 (3H, s, COOCH ₃ ), 4.05 (3H, s, NOCH ₃ ), δ, 04 (IH, d, J = 6Hz, C ₄ -H), 5.75 (IH, d, J = 6Hz, C ₃ -H), 7.68 (lH, s, a group of formula CV).

-30194870

Elemental analysis C H _{I 2 3} N ₄ NaO ₈ S ₂ .2H ₂ O Calcd:

Found: C, 31.03, H, 3.69, N, 12.06 Found: C, 31.10, H, 3.48, N, 11.94.

Example 95

499 mg of cis-3- (2- {2- (chloroacetamido) -4-thiazolyl) -2- (diethylphosphono) acetamido) -2-oxoazetidine-4-carboxylic acid methyl ester A solution of sulfur trioxide-N, N-dimethylformamide complex (1.58 moles) was added at 1.9 ° C and the mixture was allowed to stand in a closed flask at 5 ° C for 3 days. Pyridine (0.32 mL) was added to the reaction mixture, which was poured into diethyl ether (100 mL) and stirred. The supernatant was discarded and the residue was dissolved in 20 ml of water. To the solution was added 15 ml of Dowex 50W Na ⁺ resin and the mixture was stirred at room temperature for 30 minutes. The resin is filtered off and the filtrate is concentrated to 20 ml. The concentrate was chromatographed on an Amberlite XAD-II column and freeze-dried the eluate to give cis-3- [2- (2-chloroacetamido) -4-thiazolyl] -2- (diethylphosphono) acetamido} -4- (methoxycarbonyl) The sodium salt of 2-oxo-azetidine-1-sulfonic acid is obtained.

IR spectra (ν max cm -1): 3450, 1770, 1750. 1670, 1540, 1260, 1230, 1050.

Analytical results for C ₁₆ H ₂₁ ClN ₄ NaO ₁₁ PS ₂ . For 2H ₂ O:

H, 3.34; N, 8.82 Found: C, 30.26; Found: C, 30.19; H, 3.64; N, 8.72.

Example 96

In the same manner as in Example 11, cis-3- [2- (2-amino-4-thiazolyl) -2- (diethylphosphono) acetamido] -4- (methoxycarbonyl) -2-oxoazetidin-1-one. sodium sulphonic acid is prepared.

IR 3400, 1775, 1750,

1670, 1510, 1270, 1230, 1045.

Analytical results for C ₁₄ H ₂₀ N ₄ NaO ₁₀ PS ₂ . For 2H ₂ O:

Calculated: C, 30.11; H, 4.33; N, 10.03 Found: C, 30.39; H, 4.14; N, 10.20.

Example 97

Following the procedure of Example 95, the cis-3- (2- (triethylsilyl) ethylcarboxamido) -4- (methoxycarbonyl) -2-oxoazetidin-1-sulfone acid sodium salt was prepared.

IR (ν max): 3450, 1775, 1745, 1660, 1540, 1260, 1250, 1055.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.61 (3H, s, COOCH _a ), 4.41 (1H, d, J = 6Hz, C ₄ -H), 5.24 (1H, dd, J = 6Hz, 9Hz, C ₃ -H), 8.59 (1H, d, J = 9Hz, C ₃ -NH).

Analytical results for C, ₄ H ₂₈ N, NaO ₇ SSi. , For H ₂ O:

Found: C, 38.69; H, 6.26; N, 6.45. Found: C, 38.71; H, 6.18; N, 6.36.

Example 98

Following the procedure of Example 95, cis-3-] 2- (2-chloroacetamido-4-thiazolyl) -2- (methoxy)

-imino) -acetamido] -4- (2-phenylethyl) -2-oxoazetidine-1-sulfonic acid sodium salt (color isomer) was prepared.

IR spectrum (v '^ ^cw-1): 3450, 1750, 1660, 1540, 1260, 1045th

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO -) - D ₂ O, ppm):

3.82 (1H, s, NOCHj), 4.38 (2H, s, C1CH _2), 5.32 (1H, d, J = 6Hz, C ₃ -H), 7.34 (5H, s, Ph), 7.42 (1H, s, CV).

Analytical results for C ₁₉ H ₉ ClN ₅ NaO ₇ S ₂ . 3 1 / 2H ₂ O:

H, 4.26; N, 11.39. Found: C, 37.00; H, 3.97; N, 11.64.

Example 99

In the same manner as in Example 11, cis-3- [2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -4- (2-phenylethyl) -2-oxoazetidine The -1-sulfonic acid sodium salt (color isomer) was prepared.

IR (ν max 3425, 1750, 1660, 1610, 1520, 1240, 1050).

NMR _(D6 -DMSO, ppm): 3.64 (3H, s, NOCH _3), 5.15 (1H, dd, J = 6, 9Hz, _C3 -H), 6.66 (1H, s, a group of formula CV), 7.10 (2H, br, _NH2), 9.34 (1H, d, J = 9Hz, C ₃ - NH).

Analysis results for C ₁₇ H ₁₈ NaO ₆ S ₂ . .2 1 / 2H ₂ O:

Calculated: C, 39.22; H, 4.45; N, 13.46 Found: C, 39.55; H, 4.21; N, 13.47.

Example 100

Following the procedure of Example 95, cis-3- [2- (2-hydroxy-4-thiazolyl) -2- (methoxyimino) acetamido] -4- (methoxycarbonyl) -2-oxoazetidin-1-one. sodium sulfonic acid (color isomer) was prepared.

IR (ν max ¹ ) 3450, 1770, 1750, 1660, 1530, 1440, 1250, 1050.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.61 (3H, s, COOCH ₃ ). 3.87 (3H, s, NOCH _3), 4.50 (1H, d, C ₄ -H), 5.38 (1H, _S, C? -H), 6.33 (1H, s, a group of formula CV) , 9.60 (1H, C ₃ -NH).

Analytical results for C ₁ , H ₁ , N ₄ NaO ₉ S ₂ .2H ₂ O:

Found: C, 28.32; H, 3.24; N, 12.01. Found: C, 28.55; H, 3.25; N, 12.40.

Example 101

In the same manner as in Example 10, cis-3- (2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido} -4- (ethoxycarbonyl) -2-oxo the color and anti-isomers of the sodium salt of azetidine-1-sulfonic acid are prepared.

Syn isomer

IR (ν max cm ^-1 ): 3350, 1770, 1670, 1610, 1050.

NMR spectrum (D ₈ -DMSO, ppm): 1.19 (3H, t, J = 7Hz, CH, CHG), 3.86 (3H,

-31194870 s, NOCH _3), 4.07 (2H, q, J = 7Hz, _{CH2 CH3),} 4.36 (2H, s, C1CH _2), 4.46 (IH, d, J = 5 Hz, C ₄ -H), 5.40 (IH, dd, J = 5Hz, 9Hz, _C3 -H), 7.28 (lH, s, a group of formula CV), 9.44 (IH, d, J = 9 Hz, C ₃ -NH).

Analytical results for C ₁₄ H ₁₅ CIN ₅ NaO ₉ S ₂ . For ₂ H ₂ O:

Calculated: C, 30.24; H, 3.44; N, 12.59. Found: C, 30.40; H, 3.49; N, 12.42.

Anti-isomer

IR (µcuwwi ¹ ) 3300, 1760, 1660, 1050.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.20 (3H, t, J = 7Hz, CH ₂ CH ₃ ), 3.96 (3H, s, NOCH ₃ ), 4.16 (2H, q, J = 7 Hz, CH ₂ CH ₃ ), 4.33 (2H, s, C ₁ -C ₂ ), 4.47 (1H, d, J = 5Hz, C ₄ -H), 5.42 (1H, dd, J = 5 Hz, 9 Hz, C ₃ -H), 8.00 (1H, s, CV), 9.12 (1H, d, J = 9 Hz, C ₃ -NH).

Analytical results for C ₁₄ H ₁₅ ClN ₅ NaO _g S ₂ . , For 3H ₂ O:

Found: C, 29.06; H, 3.68; N, 12.20 Found: C, 29.06; H, 3.48; N, 11.87.

Example 102

Following the procedure of Example 11, cis-3- [2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -4- (ethoxycarbonyl) -2-oxoazetidin-1-one. the color and anti-isomers of the sodium salt of sulfonic acid.

Syn isomer

IR 3450, 3250, 1780,

1730, 1670.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.18 (3H, t, J = 7Hz, CH ₂ CH ₃ ), 3.80 (3H, s, NOCH ₃ ), 4.04 (2H, q, J = 7 Hz, CH ₂ CH ₃ ), 4.43 (1H, d, J = 5 Hz, C ₄ - H), 5.36 (1H, dd, J = 5 Hz, 9 Hz, C ₃ --H) , 6.57 (1H, s, CV), 7.12 (2H, br.s, NH ₂ ), 9.32 (1H, d, J = 9Hz, C ₃ -NH).

Analysis for C ,, H _l4 NcNaOoS _9th 2 1 / 2H ₂ O Calcd: 'Calculated: C% = 29.50, H% = 3.92, N% = 14.33% Found: C = 29.39% H = 3.71% N 14.09

Anti-isomer

IR (cm- ¹ ) _: 3300, 1770, 1720, 1660.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.18 (3H, t, J = 7Hz, CH, CH 2). 3.90 (3H, s, NOCH ₃ ), 4.15 (2H, q, J = 7Hz, CH ₂ CH ₃ ), 4.43 (1H, d, J = 5Hz, C ₄ -H), 5.36 (1H, dd, J = 5 Hz, 9 Hz, C ₃ -H), 7.06 (2H, br.s, NH ₂ ), 7.36 1H, s, CV), 9, O 2 (1H, d, J = 9Hz, C ₃ -NH).

Analysis. for C _l2 H ₁₄ N ₅ NaO ₈ S _2nd For the formula 2 1 / 2H ₂ O:

Found: C, 29.50; H, 3.92; N, 14.33 _; Found: C, 29.84; H, 3.88; N, 14.17.

Example 103

In the same manner as in Example 1, cis-3- {2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido} -4-phenylcarbamoyl) -2-oxoazetidine Sodium salt of -1-sulfonic acid (color isomer) was prepared.

IR (ν c = ¹ ): 3450, 3250, 1770, 1680, 1050.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.67 (3H, s, NOCH ₃ ), 4.30 (2H, s, ClCH ₂ )

4.60 (1H, d, J = 5Hz, C ₄ -H), 5.40 (1H, dd, J = 5Hz, 9Hz, C ₃ -H).

Example 104

In the same manner as in Example 11, cis-3- [2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -4- (phenylcarbamoyl) -2-oxoazetidin-1-one. sodium sulfonic acid (color isomer) was prepared.

IR spectrum (hydrogen, λmax 3300, 1770, 1680, 1050).

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.66 (3H, s, NOCH ₃ ), 4.55 (1H, d, J = 5Hz, C ₄ -H), 5.36 (1H, dd, J = 5, 9Hz, _C3 -H), 6.64 (lH, s, a group of formula CV), 6.9-7.7 (5H, m, Ph), 9.23 ( H, d, J = 9Hz, _C3 -NH), 9.95 (IH, br, CONHPh).

Example 105

In the same manner as in Example 10, cis-3- (2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido) -4- (ethoxycarbonylmethyloxy) Carbonyl) -2-oxo-azetidin-1-yl-fonic acid (color isomer) is prepared.

IR (νΧ, λΎ 1780, 1765, 1740, 1670, 1550, 1280, 1055).

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.19 (3H, t, J = 7Hz, CH ₉ CH ₃ ), 3.85 (3H, s, NOCH ₃ ), 4.11 (2H, q , J = 7Hz, CH ₂ CH ₃ ), 4.36 * (2H, s, C ₁ CH ₂ ), 4.63 1H, d, J = 6Hz, C ₄ -H), 4.64 (2H, q , J = 15 Hz, _OCH2 CO), 5.52 (IH, dd, J = 6, 9Hz, _C3 -H), 7.31 (lH, s, a group of formula CV), 9.23 ( H, d, J = 9Hz, _C3 -NH).

Analytical results for C ₁₆ H ₁₇ ClN ₅ NaO ₁₁ S ₂ . For 2H ₂ O:

Found: C, 31.30; H, 3.45; N, 11.41; Found: C, 31.18; H, 3.22; N, 11.44.

Example 106

In the same manner as in Example 11, cis-3- [2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -4- (ethoxycarbonylmethyloxycarbonyl) -2 (oxo-azetidine-1-sulfonic acid, sodium salt, color isomer).

IR (ν ^c ) ¹ : 1770, 1750, 1670, 1535, 1285, 1055.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.20 (3H, t, J = 7Hz, CH ₂ CH ₃ ), 3.80 (3H, s, NOCH ₃ ), 4.12 (2H, q , J = 7 Hz,

-32194870

CH ₂ CH ₃ ), 4.60 (1H, d, J = 6Hz, C ₄ -H), 4.64 (2H, q, J = 15Hz,

OCH ₂ CO), 5.48 (IH, dd, J = 6, 9Hz, _C3 -H), 6.59 (1H, s, a group of formula CV), 7.12 (2H, br, NH ₂ ).

Analysis results for C | ₄ H ₁₆ N ₅ NaO ₁₀ S ₂ . For 2H ₂ O:

Found: C, 31.29; H, 3.75; N, 13.03 _; Found: C, 31.38; H, 3.65; N, 12.95.

Example 107 Trans-3- {2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido} -4- (acetoxy) (630 mg) in dry N, N -dimethylformamide methyl) -2-oxoazetidine (color isomer) was dissolved. The solution was cooled to -78 ° C and

A solution of 2.69 ml of sulfur trioxide N, N-dimethylformamide complex (1.69 mol) was added. After standing at 4 ° C for 12 hours, 358 mg of pyridine and then 40 ml of diethyl ether are added under cooling at 0 ° C. The supernatant was discarded and the precipitate was washed with ether (3 x 30 mL). After removal of the ether, 10 ml of water and 20 ml of Dowex 50W Na ⁺ resin were added to the residue and the mixture was stirred for two hours. The resin was filtered off, the filtrate was evaporated and chromatographed on an Amberlite XAD-II column. Freeze-drying of the eluate gave trans-3- (2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido} -4- (acetoxymethyl) -2-oxoazetidine. The sodium salt of 1-sulphonic acid (color isomer) is obtained.

IR (λ max cm -1): 3450, 1765, 1730, 1640, 1540, 1250, 1040.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 2.04 (3H, s, COCH ₃ ), 3.90 (3H, s,

NOCH _3), 4.35 (2H, s, C1CH _2);

4.77 (1H, dd, J = 3, 8Hz, _C3 -H),

7.39 (1H, s, CV),

9.45 (1H, d, J = Hz, C ₃ -NH).

Analysis for C _l4 Hi CLN ₅ NaO ₅ S _{9 2nd} , For H ₂ O:

Found: C, 31.26; H, 3.19; N, 13.02 _; Found: C, 31.60; H, 3.41; N, 12.91.

Example 108

In the same manner as in Example 11, trans-3- [2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -4- (acetoxymethyl) -2-oxoazetidine sodium sulfonic acid (color isomer) was prepared.

IR (3420, 1765, 1730, 1660, 1530, 1245, 1050).

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 2.01 (3H, s, COCH ₃ ), 3.83 (3H, s,

NOCH _3), 4.76 (IH, dd, J = 3, 8Hz, _C3 -H), 6.70 (lH, s, a group of formula CV), 7.16 (IH, br, NH ₂ ),

9.30 (IH, d, J = 8 Hz, _C3 -NH).

Analytical results for C ₁₂ Hi ₄ N ₅ NaO ₈ S ₂ .

. I 1/2 H ₂ O:

Found: C, 30.64; H, 3.64; N, 14.89 _; Found: C, 30.66; H, 3.65; N, 14.94.

Example 109

Freeze-dried cis-3- [2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -4- (methoxycarbonyl) -2-oxo obtained by the procedure of Example 2. 300 mg of the azetidine-1-sulfonic acid sodium salt (color isomer) are dissolved in 3 ml of water and the mixture is stirred until whitish clouding is observed. The mixture was allowed to cool overnight, and after 10 ml of ethanol was added, the mixture was cooled for an additional three hours. The resulting crystalline precipitate was collected by filtration and dried to give 241 mg of a colorless crystal, the monohydrate of the above compound.

Melting point: 235-245 ° C (dec.).

IR (ν cm -1) _: 1785, 1750, 1690.

Analytical results for _C11 Hi ₂ N ₅ NaO ₈ S ₂ .H ₂ O:

Calculated: C, 29.53; H, 3.15; N, 15.66 Found: C, 29.48; H, 3.13; N, 15.54.

Example 110 Cis-3- [2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -4- (methoxycarbonyl) -2-oxoazetidine (86 mg) in 1N hydrochloric acid (ml) The -1-sulfonic acid sodium salt (color isomer) was dissolved and the solution was stirred under ice-cooling, and 500 mg of zinc powder was added in one portion. The mixture was stirred for 5 minutes then filtered. The filtrate was chromatographed on an Amberlite XAD-II column using water as eluent. The fractions containing the desired product were collected and freeze-dried to give cis-3- [DL-2- (2-amino-4-thiazolyl) -2-ammonioacetamido] -4-methoxycarbonyl-2-oxoazetidine. 1-sulfonate is obtained.

IR (λ max cm -1): 3400, 1775, 1750, 1690.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.44 and 3.66 (3H, both s, COOCH ₃ ), 4.44 and 4.47 (1H, both d, J = 5Hz, C _4). -H), 4.67 and 4.77 (1H, both s, -CHCO), 5.40 and 5.26 (1H, both dd, J = 5 Hz and 9 Hz, C ₃ -H), 6, 54 and 6.60 (1H, both s, CV), 7.10 and 7.15 (2H, both br.s, NH ₂ ), 8.7-

9.4 (1H, br.s, CONH).

Example 111

The procedure described in Example 110 is followed up to filtration after reduction of the zinc powder. To the filtrate was added 500 mg of sodium cyanate and the mixture was stirred at 45 ° C for 30 minutes. The reaction mixture was cooled with ice, acidified to pH 1 with 1N hydrochloric acid, and then quenched with 1N sodium bicarbonate solution (pH 7). The mixture was chromatographed first on an Amberlite XAD-II column and then on a Sephadex LH-20 column using water as eluent. Fractions containing the desired product were collected and freeze-dried with cis-3- [DL-2- (2-amino-4-thiazolyl) -2- (carbamoylamino) acet33

-33194870 amido] -4- (methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt is obtained.

IR (ν max _; 3350, 1770, 1670,

1620th

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.48 and 3.62 (3H, both s, COOCH ₃ ),

4.36 and 4.40 (1H, both d, J = 5Hz, C ₄ -H), 5.0-5.5 (2H, m, -CHCON and C ₃ -H), 5.66 ( 2H, br.s, CONH3), 6.32 and 6.34 (1H, both s, CV),

6.86 (2H, br.s, NHJ.

Example 112 mg cis-3- [DL-2- (2-amino-4-thiazolyl) -2-ammonioacetamido] -4-methoxycarbonyl-2-oxoazetidine-1-sulfonate, 45 mg A mixture of diisopropylethylamine, 1 mL of dichloromethane and 3 mL of acetone was stirred under ice-cooling, and 77 μϊ of 1- (chloroformyl) -2,3-dioxo-4-ethyl-1,4-piperazine was added. of water. After vigorous stirring for 30 minutes, the organic solvent was evaporated in vacuo. The residue was chromatographed first on an Amberlite IR-120 (Na ^{+ form} ), then on an Amberlite XAD-II column and finally on a Sephadex LH-20 column using water as eluent. Fractions containing the desired product were collected and freeze-dried to give cis-3- [DL-2- (2-amino-4-thiazolyl) -2- (2,3-dioxo-4-ethyl-1,4-piperazin-1-yl) -carbonyl 1-amino) -acetamido] -4- (methoxycarbonyl) -2-oxo-azetidine-1-sulfonic acid sodium salt is obtained.

IR 3400, 1780, 1720,

1680, 1620.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.10 (3H, t, J = 7Hz, CH ₃ CH ₂ -), 3.45-3.62 (3H, both s, COOCH 3), 3.2 -

4.2 (4H, m, _{-CH2 CH2} -), 4.37 and 4.43 (lH, each d, J = 5 Hz, C ₄ -H), 5.0-5.5 (lH, m, C ₃ -H), 5.38 (1H, d, J = 8Hz, -CHCON), 6.50 and 6.52 (1H, both s, CV), 8.72 and 8.92 (1H, both d, J = 8Hz, -CONH-CJ, 9.52 & 9.56 (1H, both d, J = 8Hz, NCONH)

Example 113 Cis-3- [DL-2- (2-amino-4-thiazolyl) -2-ammonioacetamido] -4-methoxycarbonyl-2-oxoazetidine-1-sulfonate (40 mg) in acetonitrile (ml) slurry, stir the suspension under ice-cooling and add 150 μΐ acetic anhydride. After stirring for 5 minutes, a solution of sodium bicarbonate (20 mg) in water (2 mL) was added. The mixture is stirred for 30 minutes and then concentrated to one third of its original volume. To the residue was added 1 M sodium bicarbonate solution (1 mL) and the resulting mixture was chromatographed on an Amberlite XAD-II column followed by a Sephadex LH-20 column, eluting with water. The two fractions containing the desired product were collected and freeze-dried to give cis-3- fDL-2- (2-amino-4-thiazolyl) -2-formamidoacetamido] -4- (methoxycarbonyl) -2-oxoazetidine. The sodium salt of 1-sulfonic acid is obtained.

IR (? X?): 3400, 1780, 1670, 1620.

Nuclear Magnetic Resonance Spectrum (D ₂ O, ppm): 3.63 and

3.74 (3H, both singlet,

COOCHJ, 4.89 and 4.93 (lH, each d, J = 6Hz, C ₄ -H), 5.38 and

5.56 (1H, both d, J = 6Hz, C ₃ -H), 5.44 (1H, s, -CH =). 6.70 and 6.72 (1H, both s, CV), 8.17 and 8.19 (1H, both s, NCHO).

Example 114 In a mixture of acetonitrile (mL) and dimethylacetamide (0.5 mL), cis-3-DL-2- (2-amino-4-thiazolyl) -2-ammonioacetamido] -4-methoxycarbonyl-40 mg After suspending the oxo-azetidin-1-yl phonethane, add 50 μόΐ methanesulfonyl chloride and 100 μϊ diisopropylethylamine with stirring at −20 ° C. The mixture was stirred at this temperature for 10 minutes and then at 0 ° C for 20 minutes. The reaction mixture was then cooled to -50 ° C, diethyl ether (3 x 30 mL) was added and the mixture was shaken. The resulting oily precipitate was collected and water (5 mL) was added. The solution is chromatographed first on an Amberlite IR-120 (Na ^{+ form} ) and then on an Amberlite XAD-II column using water as eluent. The fractions containing the desired product were collected and freeze-dried to give cis-3- [DL-2- (2-amino-4-thiazolyl) -2- (methanesulfonylamino) acetamido] -4- (methoxycarbonyl) -2 The sodium salt of -oxoazetidine-1-sulfonic acid is obtained.

IR (ν max 3400, 1780, 1690, 1630).

Nuclear Magnetic Resonance Spectrum (D ₂ O, ppm): 3.03 and 3.06 (3H, both s, CH ₃ SO ₃ , 3.76 and 3.65 (3H, both s, COOCH 3)

4.91 and 4.94 (lH, each d, J = 6Hz, C ₄ -H), 5.12 (IH, br, CHCON), 5.41 and 5.56 (lH, each d , J = 6Hz, C ₃ -H), 6.80 (IH, br.s, a group of formula CV).

Example 115 Cis-3- [DL-2- (2-amino-4-thiazolyl) -2-ammonioacetamido] -4-methoxycarbonyl-2-oxoazetidine-1-sulfonate (80 mg) in acetonitrile (ml) slurry, add 38 μϊ benzoyl chloride with ice-cooling and stirring, followed by 1 ml of 1 N sodium bicarbonate solution. After stirring for 30 minutes, water (10 mL) and ethyl acetate (15 mL) were added. The mixture was shaken, the aqueous layer separated and chromatographed on an Amberlite XAD-II column using water as eluent. Fractions containing the desired product were collected and freeze-dried on c-3- [DL-2- (2-amino-4-thiazolyl) -2- (benzoylamino) acetamido] -4-methoxycarbonyl-2 The sodium salt of -oxoazetidine-1-sulfonic acid is obtained.

IR spectrum (v £ ^r * c * · ^'4): 3300, 1770.1750 (sh), 1640th

NMR spectrum (D ₂ O, ppm): 3.60 and 3.73 (3H, each s, _COOCH3), 4.89 and 4.93 (1H, each d, J = 6Hz, C ₄ -H ), 5.43 and 5.58 (1H, each d, J = 6Hz, C ₃ -H), 5.58 (1H, s, CHCON), 6.73 and 6.74 (1H, each s, CV), 7.4-8.0 (5H, m, aromatic protons).

Example 116 80 ml of cis-3- [DL-2- (2-amino-4-thiazolyl) -2-ammonioacetamido] -4- (methoxycarbonyl) -2-oxoazetidine-1 in dimethylacetamide sulfonate was suspended and 50 mg of p-toluenesulfonyl chloride was added under ice-cooling and stirring followed by 120 μΐ of diisopropylethylamine. The mixture was stirred for 30 minutes under these conditions and then for 2 hours at room temperature. To the reaction mixture was added diethyl ether (3 x 30 mL) and shaken. The resulting oily precipitate was chromatographed first on an Amberlite IR-120 (Na ^{+ form} ), then on an Amberlite XAD-II column, finally on a Sephadex LH-20 column using water as eluent. The fractions containing the desired product were collected and freeze-dried to obtain cis-3- [DL-2- (2-amino-4-thiazolyl) -2- (ptoluenesulfonylamino) acetamido] -4- (methoxycarbonyl) -2 The sodium salt of -oxoazetidine-1-sulfonic acid is obtained.

IR spectrum (νmax): 3400, 1770, 1690, 1620.

Nuclear Magnetic Resonance Spectrum (D ₂ O, ppm): 2.40 (3H, s, CH ₃ ), 3.56 and 3.72 (3H, both s, COOCH ₃ ), 4.82 and 4.88 (1H, both d, J = 6 Hz, C ₄ -H), 4.92 (1H, s, NCHCON), 5.30 and 5.35 (1H, both d, J = 6 Hz, C ₃ -H), 6 , 40 and 6.42 (1H, both s, CV), 7.36 and 7.62 (4H, both d, J = 8 Hz, aromatic protons).

Example 117 Cis-3- [DL-2- (2-amino-4-thiazolyl) -2-ammonioacetamido] -4- (methoxycarbonyl) -2-oxoazetidin-1 (80 mg) in dimethylacetamide sulfonate was suspended and 20 μΐ methoxyacetyl chloride was added under ice-cooling and stirring. After stirring at room temperature for 2 hours, the mixture was cooled with ice and 300 mg of sodium bicarbonate was added. After stirring for a further 20 minutes, diethyl ether (3 x 30 mL) was added and shaken. The resulting oily precipitate was chromatographed on an Amberlite XAD-II then Sephadex LH-20 column using water as eluent. The fractions containing the desired product were collected and freeze-dried to give cis-3- [DL-2- (2-amino-4-thiazolyl) -2- (2-methoxyacetamido) acetamido] -4- (methoxycarbonyl). The sodium salt of -2-oxoazetidine-1-sulfonic acid is obtained.

IR: 3400, 1770, 1670, 1630;

Nuclear Magnetic Resonance Spectrum (D ₂ O, ppm): 3.46 (3H, s, CH ₃ O), 3.66 and 3.76 (3H, both s, COOCH ₃ ), 4.10 (2H, s, OCH). ₂ C),

4.91 and 4.94 (1H, each d, J = 6Hz, C ₄ -H), 5.41 and 5.55 (1H, each d, J = 6Hz, C ₃ -H), 5 , 49 (1H, s, -CHCO), 6.76 (1H, s, CV).

Example 118 80 ml of cis-3- [DL-2- (2-amino-4-thiazolyl) -2-ammonioacetamido] -4-methoxycarbonyl-2-oxoazetidine-1-sulfonate in acetonitrile suspended. The suspension was cooled with ice, stirred and 200 μΐ acetic anhydride, 60 mg sodium acetate and 2 ml water were added and the mixture was stirred for 10 minutes. Stirring is continued at room temperature for an additional hour and 3.6 ml of 1M sodium bicarbonate solution are added. The resulting mixture was chromatographed first on an Amberlite XAD-II column and then on a Sephadex LH-20 column using water as eluent. Fractions containing the desired product were collected and freeze-dried to give cis-3- [DL-2- (2-amino-4-thiazolyl) -2-acetamidoacetamido] -4- (methoxycarbonyl) -2-oxoazetidine-1. yielding the sodium salt of sulphonic acid.

IR spectra (cm-viral ^ _^4): 3400, 1770, 1660, 1520th

Nuclear Magnetic Resonance Spectrum (D ₂ O, ppm) 1.93 and 2.08 (3H, both s, COCH ₃ ), 3.63 and 3.74 (3H, both s, COOCH ₃ ),

4.89 and 4.92 (1H, each d, J = 6Hz, C ₄ -H), 5.34 (1H, s,

-CHCl), 5.40 and 5.56 (1H, each d, J = 6Hz, C ₃ -H), 6.67 and

6.69 (1H, both s, CV).

Example 119 Cis-3- {2- [2- (chloroacetamido) -4-thiaroyl] -2- (methoxyimino) acetamido} -4- (methyl) in dry N, N-dimethylformamide (402 mg). -carbamoyl) -2-oxoazetide int (color isomer) was added and 320 mg of pyridine-sulfur trioxide complex was added. After stirring for 24 hours, dry N, N-dimethylformamide (40 ml) and pyridine-sulfur trioxide complex (320 mg) were added and stirring continued for 72 hours. The reaction mixture was poured into 500 ml of diethyl ether, the resulting precipitate was filtered off, washed with ether and suspended in 500 ml of water. To the suspension was added 30 ml of Dowex 50W Na ⁺ resin and the mixture was stirred for 3 hours.

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The resin was filtered off and the filtrate was freeze-dried to give a colorless powder. This powder was dissolved in water and chromatographed on an Amberlite XAD-II column. Freeze drying of the eluate gave cis-3- (2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido} -4- (methylcarbamoyl) -2-oxo- yielding the sodium salt of azetidine-1-sulfonic acid (color isomer).

IR (ν max cm ^-1 ) _: 3250, 1770, 1650, 1050.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 2.68 (3H, d, J = 5Hz, NHCH ₃ ), 3.85 (3H, s, NOCH ₃ ), 5.35 (1H, dd, J = 5 Hz, 9 Hz, C ₃ H), 7.50 (1H, s, CV).

Example 120

Following the procedure of Example 11, cis-3- [2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -4- (methylcarbamoyl) -2-oxoazetidin-1-one. sodium sulfonic acid (color isomer) was prepared.

IR (microscopy ¹ ) 3350, 1770, 1670, 1050.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 2.60 (3H, d, J = 5Hz, NHCH ₃ ), 3.80 (3H, s, NOCH ₃ ), 4.35 (1H, d, J = 5 Hz, C ₄ -H), 5.28 (lH, dd, J = 5Hz, 9Hz, _C3 -H), 6.86 (lH, s, a group of formula CV), 7.13 (2H , br.s, NH ₂ ), 7.65 (1H, d, J = 5Hz, NHCH ₃ ), 9.01 (1H, d, J = 9Hz, C ₃ -NH).

Example 121

Following the procedure of Example 68, trans-3- (2- {2- (chloroacetamido) -4-thiazolyl] -2- (1-methyl-1- (p-nitrobenzyloxycarbonyl) ethyloxy) - write no] - The sodium salt of mido} -4- (methoxycarbonyl) -2-oxoazetidine-1-sulfonic acid is prepared.

IR (λmax) 3400-3200, 2980, 1780, 1740, 1680, 1050.

Analytical results for C ₂₃ H ₂₂ ClN ₆ NaO ₁₃ S ₂ . For 2H ₂ O:

Calculated: C, 36.88; H, 3.50; N, 11.22. Found: C, 37.02; H, 3.41; N, 1.54.

Example 122

Following the procedure of Example 65, trans-3- {2- (2-amino-4-thiazolyl) -2- [1-methyl-1- (p-nitrobenzyloxycarbonyl) -ethyloxyimino] ] -acetamido} -4- (methoxycarbonyl) -2-oxoazetidine-1-sulfonic acid sodium salt (color isomer) was prepared.

IR (λ max ¹ ) _; 3325, 1780, 1740, 1670, 1600, 1520, 1050.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 4.15 6H, s, 2XCH ₃ ), 3.69 (3H, s,

COOCH ₃ ), 4.15 (1H, d, J = 3Hz, C ₄ -H), 4.82 (1H, dd, J = 3Hz, 9Hz, C ₃ -H), 5.33 (2H , s, COOCH _2), 6.7 (lH, s, a group of formula CV), 7.25 (2H, br, _NH2), 7.65, 8.15 (2x2H, 2xd, aromatic protons); 9.37 (IH, d, J = 9Hz, _C3 -NH).

Calcd for _{C] 2} H _2l N ₆ NaO S _{l2 second} For 2 l / 2H ₂ O:

Calculated: C, 37.0; H, 3.84; N, 12.33 _; Found: C, 36.90; H, 3.78; N, 1.22.

Example 123

Trans-3- [2- (2-amino-4-thiazolyl) -2- (1-carboxy-1-methyl-ethoxyimino) -acetamido] -4- (methoxycarbonyl) was prepared as described in Example 66. The disodium salt (color isomer) of -2-oxoazetidin-1-yl fonic acid is prepared.

IR (ν max cm ^-1 ): 3375, 1780, 1745, 1580, 1050.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.40,

1.43 (2x3H, 2.times.s, 2 x CH _3), 3.7 (3H, s, _COOCH3), 4.17 (IH, d, J = 3 Hz, C ₄ -H), 4.85 (IH, dd , J = 3Hz, 9Hz, _C3 -H), 6.73 (lH, s, a group of formula CV) 7.12 (2H, s, _NH2), 11.7 (lH, d, J = 9 Hz, C ₃ -NH).

Analysis results for C ₁₄ H ₁₅ N ₅ Na ₂ O ₁₀ S ₂ . VpnIptrp 'calculated: C, 27.41; H, 4.11; N, 11.42; Found: C, 27.10; H, 3.90; N, 11.46.

Example 124

In the same manner as in Example 59, cis-3- {2- [2- (chloroacetamido) -4-thiazolyl] -2- [1- (methoxycarbonyl) -1m-ethyl-ethoxyimino] -acetamido) - Sodium 4- (methoxycarbonyl) -2-oxoazetidine-1-sulfonic acid (color isomer) was prepared.

IR: 3250, 2950, 1780, 1740, 1680.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.46 (6H, s, NOCMe ₂ ), 3.63, 3.66 (2X X ₃ H, 2X 5, 2XCOOCH ₃ ), 4.33 (2H, s, C ₂ ), 4.5 (1H, d, J = 6Hz, C ₄ --H), 5.49 (1H, dd, J = 6Hz, 9Hz, C ₃ --H), 7.27 (1H , s, CV), 9.22 (1H, d, J = 9Hz, C ₃ -NH), 12.93 (1H, br.s, ClCH 2 CONH).

Elemental analysis for C _l9 H ₇ NaO _{5 II} S CLN _second .1 1 / 2H _for O:

Found: C, 32.99; H, 3.58; N, 11.32 _; Found: C, 33.26; H, 3.64; N, 11.14125. Example

In the same manner as in Example 60, cis-3- (2- (2-amino-4-thiazolyl) -2- [1- (methoxycarbonyl) -1-methylethoxyimino] acetamido} -4- (methoxycarbonyl) -2-oxoazetidine-1-sulfonic acid sodium salt (color isomer) is prepared.

IR (λ c '') 3400, 1780, 1735, 1670.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.43 6H, s, NOCMe ₂ ), 3.62 3.64 (2X ₃ H, 2 X ₅ , 2 X COCH ₃ ), 4.48 (1H, d, J = 6 Hz) , C ₄ -H), 5.43 (1H, dd, J = 6 Hz, 9 Hz, C ₃ -H), 6.58 (1H, s,

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(CV), 7.2 (2H, s, NH ₂ ), 9.05 (1H, d, J = 9Hz, C ₃ -NH).

Analytical results for C, ₅ H ₁₈ N ₅ NaO _{) 0} S ₂ . C, 32.67; H, 4.02; N, 12.70 Found: C, 32.63; H, 3.96; N, 12.43.

Example 126

In the same manner as in Example 59, cis-3- {2- [2- (chloroacetamido) -4-thiazolyl] -2- [1-methyl-1- [2- (trimethylsilyl) ethoxycarbonyl]. -ethoxyimino] -acetamido} -4- (methoxycarbonyl) -2-oxoazetidine-1-sulfonic acid sodium salt (color isomer) was prepared.

IR (ν ^{B 20} T): 3400, 1775, 1740.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 0.92 (2H, CH 3 Si), 1.45 (6H, s, NOCMe ₂ ),

3.64 (3H, s, COOCH ₃ ), 4.16 (2H, COOCH ₂ ), 4.35 (2H, s, C ₁ CH ₂ ),

4.50 (IH, d, J = 6Hz, C ₄ -H), 5.50 (IH, dd, J = 6, 9Hz, _C3 -H), 7.24 (lH, s, CV a group of formula), 9.11 (IH, d, J = 9Hz, _C3 -NH), 12.89 (IH, br, CONH ₂ C1CH).

Example 127

In the same manner as in Example 60, cis-3- (2- (2-amino-4-thiazolyl) -2- [1-methyl-1- [2- (trimethylsilyl) ethoxycarbonyl] ethoxyimino]. -acetamido) -4- (methoxycarbonyl) -2-oxoazetidine-1-sulfonic acid sodium salt (color isomer) was prepared.

IR (λmax) _: 3410, 1780, 1740, 1675.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 0.95 (2H, CH ₂ Si), 1.48 (6H, s, NOCMe ₂ ),

3.66 (3H, s, COOCH ₃ ), 4.18 (2H, COOCH ₂ ), 4.50 (1H, d, J = 6Hz, C ₄ -H), 5.47 (1H, dd, J = 6, 9Hz, _C3 -Η), 6.60 (lH, s, a group of formula CV), 7.19 (2H, br, _NH2), 8.98 (IH, d, J = 9 Hz, C ₃ -NH).

Example 128 Cis-3-12- [2- (chloroacetamido) -4-thiazolyl] -2- [1-methyl] (630 mg) in dry Ν, dimet-dimethylformamide (ml). -1- (p-Nitrobenzyloxycarbonyl) -ethyloxyimino] -acetamido} -4-carbamoyl-2-oxoazetidine (color isomer) was dissolved. Then, at -78 ° C, 1.69 ml of a 1.56 molar solution of sulfur trioxide-NN-dimethylformamide is added. The mixture was allowed to stand in a refrigerator at 4 ° C overnight. To the reaction mixture was added pyridine (208 mg), followed by diethyl ether (30 ml), under ice-cooling. The resulting oily precipitate was washed by decantation with 3 x 20 mL of diethyl ether. The precipitate was dissolved in water (15 ml), Dowex 50W Na ⁺ resin (15 ml) was added and the mixture was stirred at room temperature. Stir for 2 hours. The resin was then filtered off and the filtrate was concentrated in vacuo. The rest is Amberlite

Chromatography on an XAD-II column eluted with water and 10-20% ethanol until dissolution of the disulfo compound followed by 40% ethanol. Freeze-drying the 40% ethanol fraction containing the desired product gave cis-3- {2- [2- (chloroacetamido) -4-thiazolyl] -2- [1-methyl-1- (p-nitrobenzyl) oxycarbonyl-ethyl-oxyimino] -acetamido) -4-carbamoyl-2-oxo-azetidine-1-sulfonic acid sodium salt (color isomer) is obtained.

IR (νK ^K ^) 3420, 1770, 1730, 1690, 1520, 1350, 1280, 1055.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.50 (6H, s, 2XCH ₃ ), 4.34 (2H, s, ClCH ₂ ).

4.38 (1H, d, J = 6Hz, C ₄ -H), 5.31 (2H, s, COOCH ₂ ), 5.34 (1H, dd, J = 6Hz, 9Hz, C ₃ - H), 7.54 (1H, s, CV), 7.62, 8.07 (2χ2Η, 2Xd, aroyl protons).

Example 129 In cis-3-12- [2- (chloroacetamido) -4-thiazolyl] -2- [1-methyl-1- (p-nitro) Benzyloxycarbonyl) -ethyloxyimino] -acetamido} -4-carbamoyl-2-oxoazetidine-1-sulfonic acid, sodium salt (color isomer) was dissolved and 104 mg of sodium monomethyl was added under ice-cooling and stirring. -dithiocarbamate is added. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was washed twice with diethyl ether and purified by Amberlite XAD-II column chromatography. Elution was performed with water followed by 20% ethanol. The fractions containing the desired product were combined and freeze-dried to give cis-3-12- (2-amino-4-thiazolyl) -2- [1-methyl-1- (p-nitrobenzyloxycarbonyl) -ethyloxy Sodium salt of the imino] -acetamido} -4-carbamoyl-2-oxoazetidine-1-sulfonic acid (color isomer) is obtained.

IR (λ max cm ^-1 ): 3410, 1770, 1730, 1685, 1525, 1350, 1280, 1055.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.48 (6H, s, 2XCH ₃ ), 4.37 (1H, d, J = 6Hz, C ₄ -H), 5.33 (2H, and,

COOCH ₂ ), 6.92 (1H, s, CV), 7.21 (2H, br.s, NH ₂ ), 7.40 (2H, br.s, NH ₂ ), 7.68, 8 , 16 (2H, both d, J = 9 Hz, aromatic protons), 8.82 (1H, d, J = 9 Hz, C ₃ -NH)

Example 130 200 mg of cis-3- (2- (2-amino-4-thiazolyl) -2- [1-methyl-1- (p-nitrobenzyloxy) -carbonyl) -ethyloxyimino] -acetamido) -4-carbamoyl-2-oxoazetidine-1-sulfonic acid sodium salt (color isomer) was added and 200 mg of 10% palladium on carbon was added. The mixture was stirred under a hydrogen atmosphere at room temperature for one hour. The catalyst was filtered off and 27 mg of sodium bicarbonate was added to the filtrate under ice-cooling. The mixture was stirred for 5 minutes and then washed with ethyl acetate. 30 ml Do37 for the aqueous phase

-37194870 wex 50W H ⁺ resin was added and the mixture was stirred for 1.5 hours. The resin was filtered off and the filtrate was concentrated in vacuo to half volume. The residue was chromatographed on an Amberlite XAD-II column (40 g); elution with water followed by 15% ethanol. The fractions containing the desired product were combined and freeze-dried to give cis-3- [2- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] - 4-Carbamoyl-2-oxo-azetidine-1-sulfonic acid (color isomer) is obtained.

IR (λ max): 3250, 1770, 1690, 1625, 1280, 1230, 1045.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.51 (6H, s, 2XCH ₃ ), 4.36 (1H, d, J = -6Hz, C ₄ -H), 5.33 (1H , dd, J = 6, 9Hz, _C3 -H), 7.18 (lH, s, a group of formula CV), 9.18 (IH, d, J = 9Hz, _C3 -NH).

Analysis results for C ₁₃ H ₁₆ N ₆ O ₉ S ₂ . .1 1 / 2H ₂ O:

Calculated: C, 31.77; H, 3.90; N, 17.10. Found: C, 31.69; H, 3.90; N, 17.00.

Example 131

In Example 128, freeze-drying of the 10-20% ethanol fractions obtained by chromatography on an Amberlit XAD-II column gave 174 mg of cis-3-12-β-chloroacetamido-4-thiazolyl] -2- [1-methyl -1- (p-Nitrobenzyloxycarbonyl) -ethyloxyimino) -acetamido} -4- (benzo-aminocarbonyl) -2-oxo-azetidine-1-sulfonic acid, disodium salt (color isomer) in the form of a colorless powder. Removal of the amino-protecting group followed by the carboxyl-protecting group as described in Examples 129 and 130, respectively, resulted in the removal of cis-3-12- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxylic acid). Ethyl oxyimino) acetamido] -4- (sulfoaminocarbonyl) -2-oxoazetidine-1-sulfonic acid trisodium salt (color isomer) is obtained.

IR spectrum (v ^ ^r, tw '): 3400, 1770, 1630th

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO + D ₂ O, ppm): 1.34 (3H, s, CH ₃ ), 1.50 (3H, s, CH ₃ ), 4.49 (1H, d, J = 6 Hz,

C ₄ -H), 5.45 (IH, d, J = 6Hz, C ₃ - H), 6.77 (lH, s, a group of formula CV).

Example 132

The cis-4- (acetoxymethyl) -3-benzyloxycarboxamido-2-oxoazetidine prepared according to Reference Example 7 was treated according to Reference Example 91 with cis-3- {2- [2 - (chloroacetamido) -4-thiazolyl] -2- [1-methyl-1- (p-nitrobenzyloxycarbonyl) -ethyloxyimino] -acetamide j-4- (acetoxy- Methyl) -2-oxo-azetidine (color isomer) is obtained as colorless crystals, m.p. 120-123 ° C.

IR: 3250, 1740, 1670.

This compound was first sulfonated as in Example 68 and then removed in accordance with Example 65 to remove amino38.

N- protecting group. Thus, cis-3-12- (2-amino-4-thiazolyl) -2- [1-methyl-1- (p-nitrobenzyloxycarbonyl) -ethyloxyimino] -acetamido} -4- (Acetoxymethyl) -2-oxoazetidine-1-sulfonic acid (color isomer) is obtained.

IR (ν cm -1); 3400, 1770, 1740, 1670.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.47 (6H, s, 2XCH ₃ ), 1.95 (3H, s,

COCH ₃ ), 6.66 (1H, s, CV), 7.13 (2H, br.s, NH ₂ ).

Analytical results for C ₂₂ H ₂₃ N ₆ O ₁₂ S ₂ Na. 2H ₂ O:

H, 3.96; N, 12.24. Found: C, 38.46; H, 4.09; N, 12.18.

Example 133

In the same manner as in Example 66, cis-3- [2- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4- (acetoxy) methyl) -2-oxo-azetidine-1-sulfonic acid dinium (color isomer) is prepared.

IR (vi. Cw, ' ¹ ); 3350, 1760, 1650.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.36 (3H, s, CH ₃ ), 1.43 (3H, s, CH ₃ ),

1.93 (3H, s, COCH ₃ ), 5.25 (1H, dd, J = 5Hz, 9Hz, C ₃ -H), 6.70 (1H, s, CV), 7.10 (2H, br.s, NH ₂ ).

Example 134

Referring to Reference Example 3, the 3-amino protecting group was removed from cis-3- (benzyloxycarboxamido) -4- (carbamoyloxymethyl) -2-oxoazetidine, a compound of Reference 167. Prepared according to the method of Example 1 to give colorless crystals of the corresponding 3-amino compound.

IR (νΧΧ40): 3430, 1740, 1695. This compound was acylated according to Reference Example 4 to cis-3- {2- [2- (chloroacetamido) -4-thiazolyl] -2. Colorless crystals of (methoxyimino) acetamido} -4-carbamoyloxymethyl-2-oxoazetidine (color isomer) are obtained.

IR (λ C ° C) 3250, 1750, 1680, 1660.

This compound was sulfonated as in Example 1 to give cis-3- {2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido] -4- (carbamoyloxymethyl). ) -2-oxo-azetidine-1-sulfonic acid sodium salt (color isomer) is obtained.

IR (λ max cm -1): 1770, 1700, 1690, 1650.

NMR spectrum (D _s -DMSO, ppm): 3.87 (3H, s, NOCH _3), 4.33 (2H, s, C1CH _2), 5.27 (IH, dd, J = 5 Hz, 9 Hz, C ₃ -H), 6.38 (2H, br.s, NH ₂ ), 7.39 (1H, s, CV), 9.16 (1H, d, J = 9Hz, C ₃ -NH).

Elementary analysis for C, H ₁₄ CLN ₃ O ₉ S ₂ Na ₆ .2,5H ₂ O Calcd.:

Found: C, 27.59; H, 3.38; N, 14.85 _; Found: C, 27.86; H, 3.32; N, 14.73.

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Example 135

Following the procedure of Example 2, cis-3- [2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -4- (carbamoyloxymethyl) -2-oxoazetidine Preparation of the sodium salt of 1-sulfonic acid (color isomer).

IR 3400, 1780, 1690,

1645th

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.83 (3H, s, NOCH ₃ ), 5.24 (1H, dd, J = 5Hz, 9Hz, C ₃ -H), 6.36 (2H, br.s, NH ₂ ), 6.70 (1H, s, CV), 7.10 (2H, br.s, NH ₂ ), 9.10 (1H, d, J = 9Hz) , C ₃ -NH).

Analytical results for C ₁₁ H ₁₃ N ₆ O ₈ S ₂ Na ₃ H ₂ O:

H, 3.84; N, 16.86 Found: C, 26.50; Found: C, 26.51; H, 3.49; N, 16.42.

Example 136 In cis-3- (benzyloxycarboxamido) -4- (iodomethyl) -2-oxo (1.08 g) prepared in Reference Example 12, in dry?,? -Dimethylformamide. azetidine was added and 5.8 mL of a 1.56M solution of sulfur trioxide-Ν, dimet-dimethylformamide complex was added at -78 ° C. After stirring at 3-5 ° C for 17 hours, pyridine (0.73 mL) and diethyl ether (95 mL) were added. The solid precipitate is filtered off, washed with diethyl ether and suspended in 50 ml of water. To the suspension was added 30 ml of Dowex 50W Na resin and the mixture was stirred at room temperature for 2 hours. The resin was filtered off and the filtrate was concentrated in vacuo. The residue was purified by Amberlite XAD-II column chromatography; elution with 10-20% ethanol. The eluate was evaporated and freeze-dried to give the cis-3- (benzyloxycarboxamido) -4- (iodomethyl) -2-oxoazetidine-1-sulfonic acid sodium salt as a colorless powder.

IR (λ max ¹ ): 1770, 1690.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.23.7 (2H, m, CH ₂ I), 4.0-4.3 (1H, m, C ₄ -H), 4.94 (1H , dd, J = 5 Hz, 10 Hz C ₃ -H), 5.08 (2H, s, COOCH ₃ ), 8.13 (1H, d, J = 10 Hz, C ₃ -NH).

Calcd for C ₁₂ H _l2 IN ₂ NaO ₆ S, H ₂ O Calcd:

Calculated: C, 30.01; H, 2.94; N, 5.83. Found: C, 30.08; H, 2.73; N, 6.06.

Example 137 320 mg of cis-3- (benzyloxycarboxamido) -4- (iodomethyl) -2-oxoazetidine-1-sulfonic acid sodium salt in pyridine are suspended and the suspension is refluxed for 9 hours. The pyridine was evaporated in vacuo and diethyl ether (50 mL) was added to the residue to give an oily precipitate. The ether layer was discarded and the precipitate was washed twice with diethyl ether. Water (50 mL) was added, the insoluble material was filtered off and the filtrate was concentrated in vacuo. The residue was purified on an Amberlite XAD-II column by chromatography on chromato; elution with 20% ethanol. The eluate was evaporated and freeze-dried to give cis-3- (benzyloxycarboxamido) -4- (pyridinomethyl) -2-oxo-azetidine-1-sulfonate as a colorless powder.

IR (ν max cm ^-1 ): 1770, 1710. NMR (D ₆ -DMSO, ppm): 4.54.7 (1H, m, C ₄ -H), 4.87 (2H, d) , J = 6Hz, C ₄ -CH ₂ ), 5.06 (2ft, s, COOCH ₂ ), 5.08 (1H, dd, J = 6Hz, 10Hz, C ₃ -H) 7.37 ( 5H, s, C ₆ H ₅ ), 7.96-8.26, 8.4-8.7 8.9-9.2 (m, protons of C ₃ -NH, pyridine ring).

Analysis: Calculated for C ₁₇ H ₁₇ N ₃ O ₆ S: C, 49.87; H, 4.67; N, 10.26 _; Found: C, 49.66; H, 4.50; N, 10.20.

Example 138 Cis-3- (benzyloxycarboxamido) -4-carbamoyl-2-oxoazetidine (1.537 g) prepared in Reference Example 165 was suspended in dry Ν, Ν-dimethylformamide and A solution of sulfur trioxide-Ν, Ν-dimethylformamide complex (10.51 mmol) was added at 0 ° C. The mixture was allowed to stand in the refrigerator for 3 hours and then 0.85 ml of pyridine was added under ice-cooling followed by 40 ml of diethyl ether. The precipitate was washed with diethyl ether (3 x 50 mL) and the ether was evaporated in vacuo. To the residue were added 10 ml of water and 40 ml of Dowex 50W Na ⁺ resin and the mixture was stirred at room temperature for 2 hours. The resin was filtered off and the filtrate was purified by Amberlite XAD-II chromatography; water is used as eluent. Freeze drying of the eluate affords the sodium salt of cis-3- (benzyloxycarboxamido) -4-carbamoyl-2-oxoacetidine-1-sulfonic acid.

IR (λmax cm- ⁴ ): 3410, 3250, 1780, 1680.

NMR _(D6 -DMSO, ppm): 4.26 (1H, d, J = 6Hz, C ₄ -H), 4.98 (1H, dd, J = 6, 9Hz, _C3 - H), 5.02 (2H, s, C ₆ H ₅ CH ₂ ), 7.32 (5H, s, C ₆ H ₅ ), 7.67 (1H, d, J = 9Hz, C ₃ - NH).

The trans-3- (benzyloxycarboxamido) -4-carbamoyl-2-oxoazetidine prepared according to Reference Example 168 is converted to the trans-3- (benzyloxycarboxamido) -4-carbamoyl-2-like compound by the same method. -oxoazetidine-1-sulfonic acid, sodium salt. This product is a highly absorbent powder and was used directly in the next reaction step.

Example 139 From the sodium salt of cis-3- (benzyloxycarboxamido) -4-carbamoyl-2-oxoazetidin-1-yl-fonic acid, cis-3- {2- [2-chloroacetamido] was prepared as in Example 66. ) -4-Thiazolyl] -2- [1-methyl-1- (p-nitrobenzyloxycarbonyl) -ethyloxyimino] -acetamido} -4-carbamoyl-2-oxo-azetidine -1- sodium salt of sulfonic acid (color isomer)

-39194870. The product was eluted from the Amberlite XAD-II column with 40% ethanol. The IR and NMR spectra of the product were identical to those of Example 131.

Example 140 The trans-3- (benzyloxycarboxamido) -4-carbamoyl-2-oxoazetidine-1-sulfonic acid sodium salt was first reduced and then acylated as in Example 64. The chloroacetyl group is then removed as in Example 65 to give trans-3- {2- (2-amino-4-thiazolyl) -2- [1-methyl-1- (p-nitrobenzyl) oxycarbonyl) -ethyloxyimino] -acetamido} -4-carbamoyl-2-oxoazetidine-1-sulfonic acid (color isomer) is obtained.

IR (ν max cm ^-1 ): 3400, 1765, 1730, 1690, 1670.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.50 (6H, s, 2XCH ₃ ), 5.32 (2H, s,

CO ₂ CH ₂ ), 6.85 (1H, s, CV).

Example 141

Trans-3- [2- (2-Amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4-carbamoyl-2, following the procedure of Example 130. oxo-azetidine-1-sulfonic acid (color isomer) was prepared.

IR (λmax cm- ¹ ): 3280, 17.60, 1660.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO-d ₂ O, ppm):

1.61 (6H, s, 2XCH ₃ ), 4.17 (1H, d, J = 3Hz, C ₄ -H), 4.84 (1H, d, J = 3Hz, C ₃ -H), 7.11 (1H, s, CV).

Example 142

From cis -4-acetamidomethyl-3- (benzyloxycarboxamido) -2-oxoazetidine prepared according to Reference Example 50, cis-3-J2- [2 - (chloroacetamido) -4-thiazolyl] -2- [1-methyl-1- (p-nitrobenzyloxycarbonyl) -ethyloxyimino] -acetamido} -4- (acetamidomethyl) -2-oxoazetidine (color isomer) was prepared.

IR (ν max W ¹ ): 3300, 1780-1730, 1650.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.49 (3H, s, CH ₃ ), 1.51 (3H, s, CH ₃ ),

1.81 (3H, s, COCH ₃ ), 4.35 (2H, s, ClCH ₂ ), 5.20 (1H, dd, J = 6Hz, 9Hz, C ₃ -H), 5.32 ( 2H, s, CO ₂ CH ₂ ), 7.39 (1H, s, CV).

This compound was sulfonated as in Example 68 to give cis-3- (2- [2-chloroacetamido) -4-thiazolyl] -2- [1-methyl-1- (p-nitrobenzyloxycarbonyl). -ethyloxyimino] -acetamido} -4- (acetamidomethyl) -2-oxoazetidine-1-sulfonic acid sodium salt (color isomer).

IR (ν max cm-1): 3350, 1780-1730, 1690-1630.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.52 (6H, s, 2XCH ₃ ), 1.81 (3H, s,

_COCH3), 4.35 (2H, s, C1CH _2), 5.2 (IH, dd, J = 6, 9Hz, _C3 -H),

5.31 (2H, s, CO ₂ CH ₂ ), 7.37 (1H, s, CV).

Analysis for C ₂₄ H ₂₅ CLN NaO ₇ S _{I 2 second} For ₂ H ₂ O:

Found: C, 37.82; H, 3.84; N, 12.87. Found: C, 38.04; H, 3.71; N, 12.87.

Example 143

In the same manner as in Example 65, cis-3- {2- [2-amino-4-thiazolyl] -2- [b-methyl-1- (p-nitrobenzyloxycarbonyl) -ethyloxyimino] - Acetamido} -4- (acetamidomethyl) -2-oxoazetidine-1-sulfonic acid (color isomer) is prepared.

IR: 3350, 1780-1730,

1680-1600.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.5 (6H, s, 2XCH ₃ ), 1.74 (3H, s,

COCH ₃ ), 5.13 (1H, dd, J = 6Hz, 9Hz C ₃ -H), 5.31 (2H, s, CO ₂ CH ₂ ), 6.677 (1H, s, CV), 9 29 (IH, d, J = 9Hz, _C3 -NH).

Analytical results for C ₂₂ H ₂₄ N ₇ OnS ₂ .3H ₂ O:

Found: C, 37.55; H, 4.29; N, 13.94. C, 37.56; H, 4.12; N, 14.03. '

Example 144

In the same manner as in Example 130, cis-3- [2- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4- (acetamido- methyl) -2-oxoazetidine-1-sulfonic acid (color isomer) was prepared.

IR 3325, 1770, 1720,

1670, 1635.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.49 (3H, s, CH ₃ ), 1.51 (3H, s, CH ₃ ),

1.8 (3H, s, COCH ₃ ), 5.17 (1H, dd, J = 6Hz, 9Hz, C ₃ -H), 7.0 (1H, s, CV), 9.35 (IH, d, J = 9Hz, _C3 -NH).

Analytical results * C ₁₅ H ₂₀ N ₆ O ₉ S ₂ . For the formula 2 1 / 2H ₂ O:

Found: C, 33.51; H, 4.69; N, 15.64 _. Found: C, 33.70; H, 4.75; N, 15.33.

Example 145

In the same manner as in Example 64, cis-3- [2- (2-chloroacetamido) -4-thiazolyl] -2- [1-methyl-1- (p-nitrobenzyloxycarbonyl) ethyl] oxyimino] -acetamido} -4- (methylcarbamoyl) -2-oxoazetidine-1-sulfonic acid sodium salt (color isomer) was prepared.

IR spectrum (v ^KBr ); 3350, 1780, 1670.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.52 (6H, s, 2XCH ₃ ), 2.63 (3H, d, J = 5Hz, NHCH ₃ ), 4.33 (2H, s, C ₁ -C ₂ ), 4.43 (1H, d, J = 5Hz, C ₄ -H), 5.33 (2H, s, CO ₂ CH ₂ ), 7.53 (1H, s, CV) .

Analysis results for C ^ H ^ ClNjNaOuSj. For 2H ₂ O:

Calculated: C, 36.92. H, 3.64; N, 13.10; Found: C, 36.80; H, 3.53; N, 13.15.

-40194870

146. · Example

In the same manner as in Example 65, cis-3- {2- (2-amino-4-thiazolyl) -2- [1-methyl-1- (p-nitrobenzyloxycarbonyl) -ethyloxyimino] ] -acetamido} -4-methylcarbamoyl-2-oxoazetidine-1-sulfonic acid sodium salt (color isomer) was prepared.

IR (λ max cm ^-1 ): 3330. 1770, 1760.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.49 (6H, s, 2XCH ₃ ), 2.60 (3H, d, J = 4Hz, NHCH ₃ ), 4.38 (1H, d, J = 5 Hz, C ₄ -H), 6.86 (lH, s, a group of formula CV), 7.21 (2H, br, _NH2).

Analytical results for C ₂ , H ₂₂ N ₇ NaO ₂ , S ₂ . For 2H ₂ O:

Calculated: C, 37.55; H, 3.90; N, 14.59; Found: C, 37.54; H, 3.80; N, 14.63.

Example 147

In the same manner as in Example 130, cis-3- [2- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4- (methyl- carbamoyl) -2-oxoazetidine-1-sulfonic acid (color isomer) was prepared.

IR spectrum (vmax * ^ct-1): 1800, 1650th

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.50 (6H, s, 2XCH ₃ ), 2.62 (3H, d, J = 4Hz, NHCHH) 4.40 (1H, d, J = = 5 Hz, C ₄ -H), 5.33 (1H, dd, J = 5 Hz, 9 Hz, C ₃ -H), 7.16 (1H, s, CV), 7.83 ( 1H, q, J = 4Hz, NHCH3).

Analysis results for _C14 H _lg N ₆ O ₉ S ₂ . .2 l / 2H ₂ O:

Calculated: C, 32.11 _; H, 4.42; N, 16.05 _; Found: C, 32.39; H, 4.30; N, 15.87.

Example 148 240 ml of CIS-3-2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido} -4- (E) in Ν, Ν-dimethylformamide Dissolve styryl-1- (tert-butyldimethylsilyl) -2-oxoazetidine (color isomer) in 0.83 ml at -10 ° C.

Sulfur trioxide N, N-dimethylformamide complex solution (1.58 mol) was added. The reaction mixture was allowed to stand well at 2 ° C for 2 days. To this solution was added 0.136 mL of pyridine, followed by 100 mL of diethyl ether. The ether layer was discarded and the precipitate was dissolved in a mixture of water (20 mL) and ethanol (10 mL). To the solution was added 10 ml of Dowex 50W Na ⁺ resin and stirred for 20 minutes. The resin was then filtered off and the filtrate was concentrated to 20 mL and purified by Amberlite XAD-II column chromatography; elution with 10% ethanol. Freeze drying of the eluate gave cis-3- {2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido} -4- (E) -styryl-2-oxo-azetidine. The sodium salt of l-sulfonic acid (color isomer) is obtained,

IR 3450, 1760, 1660.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.64 (3H, s, OCH ₃ ), 4.27 (2H, s, ClCH ₂ ),

4.65 (1H, dd, J = 6Hz, 7Hz, C ₄ -H), 5.30 (1H, dd, J = 6Hz, 9Hz, C ₃ -H), 7.11 (1H, s, CV).

Analysis results for 'C, _q H ₁₇ ClN _and NaO ₇ S,'. Calcd. For C 37 /H 1 1N 1O ₂ : C, 37.22; H, 3.95; N, 11.43 _. Found: C, 37.09; H, 3.82; N, 11.44.

Example 149

All. In the same manner as in Example 1, cis-3- [2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -4- (E) -styryl-2-oxoazetidine-1-sulfonic acid sodium salt (color isomer) was prepared.

IR spectrum (v ^ W ^1); 3400, 1755, 1660.

NMR spectrum (D _e -DMSO, ppm): 3.62 (3H, s, _OCH3), 4.62 (IH, dd, J = 6Hz, 7Hz, C ₄ - H), 5.25 (IH, dd, J = 6, 9Hz, _C3 -H), 6.43 (lH, s a group of formula CV).

Analytical results for C ₁₇ H, ₆ N ₅ NaO ₆ S ₂ . .2 l / 2 H ₂ O Calcd:

Found: C, 39.38; H, 4.08; N, 13.5 _; Found: C, 39.29; H, 4.03; N, 13.54.

Example 150 145 mg of 3-azido-4- (methoxycarbonyl) methyl) -2-oxoazetidine (1: 4 cis-trans mixture) are suspended in 100 ml of methanol followed by 100 mg of 10% palladium on carbon catalyst. we add. The suspension was stirred at room temperature under a hydrogen atmosphere for 30 minutes. The catalyst was then filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in tetrahydrofuran (20 mL) and, with ice-cooling and stirring, 0.35 mL of triethylamine and 332 mg

2- [2- (Chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetyl chloride hydrochloride salt was added. The mixture was stirred under ice-cooling for 15 minutes and then at room temperature for 1.5 hours. The tetrahydrofuran was evaporated in vacuo and the residue was shaken with ethyl acetate and water. The organic layer was separated, washed with water and dried over anhydrous sodium sulfate. The solution was then evaporated to dryness in vacuo to give 3- {2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) -acetamido) -4- (methoxycarbonylmethyl) -2-oxo a 1: 4 mixture of cis-trans azetidine (color isomer) was obtained as a powder.

IR (λ max. ¹ ): 3350, 1750, 1730, 1670.

This product was sulfonated as in Example 107 to give 3- {2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido} -4- (methoxycarbonylmethyl) -2-. a 1: 4 cis-trans mixture of the oxo-azetidine-1-sulfonic acid sodium salt (color isomer) is obtained.

IR spectrum (v ^ i CWI ^'4): 3455, 1760, 1730, 1660th

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO-d ₂ O, ppm): 4.88 (d, J = 2 Hz, trans-C ₃ -H),

5.35 (d, J = 5 Hz, cis-C ₃ -H).

-41194870

This product was treated as in Example 11 to remove the amino protecting group. Thus, sodium salt of 3- [2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -4-methoxycarbonylmethyl-2-oxoazetidine-1-sulfonic acid (colorless) isomer) in a 1: 4 mixture of cis-trans.

IR spectrum (vmax, ^cw-1): 3400, 1762, 1730, 1665th

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO -) - D ₂ O, ppm), 4.88 (d, J = 2 Hz, trans-C ₃ -H),

5.32 (d, J = 5Hz, C ₁ -C ₃ -H), 6.88 (1H, s, CV).

Analysis for C _l2 H _l4 N ₅ NaO ₈ S ₂ .2H ₂ O Calcd:

Calculated: C, 30.06; H, 3.78; N, 16.6 _; Found: C, 30.13; H, 3.7l; N, 14.63.

Example 151

The trans-3-azido-4- (methoxycarbonylmethyl) -2-oxoazetidine prepared according to Reference Example 177 was sulfonated in the same manner as the trans-3-azido-4- (methoxycarbonylmethyl) - The sodium salt of 2-oxo-azetidine-1-sulfonic acid is obtained.

IR spectrum (v ** ^r cw ^4): 3425, 2125, 1762, 1730th

Example 152 In 26 ml of mg, Ν-dimethylformamide, 266 mg of the sodium salt of trans-3-azido-4- (methoxycarbonylmethyl) -2-oxoazetidine-1-sulfonic acid was dissolved in 150 mg of 10% palladium. carbon is added. The mixture was stirred under a hydrogen atmosphere at room temperature for 45 minutes. The catalyst is then filtered off and washed with 5 ml of N, N-dimethylformamide. The filtrate and the washings were combined and 284 mg of 2- [2- (chloroacetamido) -4-thiazolyl] -2- [1-methyl-1- (tert-butoxycarbonyl) ethyloxyimino] was added. acetic acid, 110 mg of N-hydroxybenzotriazole monohydrate and 150 mg of dicyclohexylcarbodiimide are added. The mixture was stirred at room temperature for 4 hours and then allowed to stand at 5 ° C overnight. Water (20 mL) was added, and the resulting precipitate was filtered and washed with water (5 mL). The filtrate and wash were combined and sodium monomethyl dithiocarbamate was added. This mixture was reacted as in Example 11 for trans-3-] 2- (2-amino-4-thiazolyl) -2- [1-methyl-1- (tert-butoxycarbonyl) ethyloxyimino]. Acetamido} -4- (methoxycarbonylmethyl) -2-oxoazetidine-1-sulfonic acid sodium salt (color isomer) is obtained.

IR (ν max cm ^-1 ): 3425, 1760, 1725, 1660.

Under ice-cooling and stirring, 84 ml of the above product are added with 2 ml of trifluoroacetic acid and the mixture is stirred for 3 hours. The reaction mixture was evaporated to dryness in vacuo. The residue was dissolved in 5 ml of water and Amberlite XAD-II (eluent: water then 10% ethanol), followed by Sephadex 42

It was purified by column chromatography on LH-20 (eluent: water).

The eluate was freeze-dried, taken up in 5 ml of water and stirred with 2 g of Dowex 50W H ⁺ resin for 10 minutes. The resin was filtered off and the filtrate was freeze-dried to trans-3- [2- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4- ( methoxycarbonylmethyl) -2-oxoazetidine-1-sulfonic acid (color isomer) is obtained.

IR (λmax) 3375, 1760, 1725

Nuclear Magnetic Resonance Spectrum (D ₂ O, ppm): 1.72 (6H, s, 2XCH ₃ ), 3.24 (2H, m, C ₄ -CH 3), 3.86 (3H, s, <O ₂ CH _3). ), 4.60 (1H, m, C ₄ -H), 5.08 (1H, d, J = 2Hz, C ₃ -H), 7.30 (1H, s, CV).

Example 153

The cis-3- (benzyloxycarboxamido) -4-methoxyaminocarbonyl-2-oxoazetidine prepared according to Reference Example 178 was

Sulfonation as in Example 141 afforded the sodium salt of cis-3- (benzyloxycarboxamido) -4-methoxyaminocarbonyl-2-oxoazetidin-1-yl.

IR (δ = 1 H): 3270, 1760, 1680.

Analysis for C ₁₃ H ₄ N, S. NaO _g .11 / 2 _H2 O Calcd:

Found: C, 36.97; H, 4.06; N, 9.95; Found: C, 36.99; H, 4.06; N, 9.97.

Example 154

In the same manner as in Example 140, cis-3- (2- (2-amino-4-thiazolyl) -2- [1-methyl-1- (p-nitrobenzyloxycarbonyl) -ethyloxyimino] ] -acetamido} -4-methoxyaminocarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt (color isomer) is prepared.

IR (ν max 3400, 1775, 1730, 1680).

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.51 (6H, s, 2XCH ₃ ), 3.57 (3H, s, OCH ₃ ),

4.33 (1H, d, J = 6Hz, C ₄ H), 5.36 (2H, s, CO ₂ CH ₂ ), 6.83 (1H, s, CV).

Analytical results for C ₂₁ H ₂₂ N ₇ NaO ₁₂ S ₂ . 2H ₂ O Calcd calculated: C ==% 36.68, H% = 3.81, N% = _14.26; Found: C, 36.68; H, 4.11; N, 14.28.

Example 155

In the same manner as in Example 130, cis-3- [2- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4- (methoxy) aminocarbonyl) -2-oxoazetidine-1-sulfonic acid (color isomer) was prepared.

IR (see "c"): 3280, 1770, 1730, 1670.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.52 (6H, s, 2XCH ₃ ), 3.60 (3H, s, OCH ₃ ),

4:34 (1H, d, J = 6Hz, C ₄ -H);

5.38 (1H, dd, J = 6 Hz, 9 Hz, C ₃ H),

-42194870

7.14 (lH, s, a group of formula CV), 9.02 (IH, d, J = 9Hz, _C3 -NH).

Analytical results for C ₂₁ H ₂₂ N ₇ NaO, ₂ S ₂ . Calcd for C20H20N: C, 31.23; H, 4.12; N, 15.61; Found: C, 31.06; H, 3.96; N, 15.40.

Example 156

Cis-3-12- [2- (chloroacetamido) -4-thiazolyl] -2- [1-methyl-1- (p-nitrobenzyloxycarbonyl) ethyl] prepared according to Reference Example 181. -oximino] -acetamido} -4- (cyanomethyl) -2-oxoazetidine (syn isomer) was sulfonated as in Example 68. By removal of the amino protecting groups as in Example 65, cis-3- [2- (2-amino-4-thiazolyl) -2- [1-methyl-1- (p-nitrobenzyloxycarbonyl) ethyl] oxyimino] -acetamido} -4- (cyanomethyl) -2-oxoazetidin-1-yl-fonic acid is obtained as the sodium salt (color isomer).

IR (λ max): 3420, 2250, 1765, 1670, 1620, 1520, 1345, 1280, 1050.

Example 157

In the same manner as in Example 129, cis-3- [2- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4- (cyano) methyl) -2-oxoazetidine-1-sulfonic acid (color isomer) was prepared.

IR (λmax) ⁴ : 3290, 2250, 1775, 1635

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.56 (6H, s, 2XCH;), 5.29 (1H, dd, J = 6Hz, 9Hz, C ₃ -H), 7.07 (lH, s, a group of formula CV), 9.42 (lH, d, J = 9Hz, _C3 -NH).

Analysis results for C ₁₄ H ₁₄ N ₆ O _g S ₂ . .2 1 / 2H ₂ O:

Found: C, 33.27; H, 4.18; N, 16.63 _. Found: C, 33.57; H, 4.01; N, 16.28.

Example 158 In methylene chloride (708 mg), (1-methyl-1H-tetrazol-5-yl) -thioacetic acid prepared in Reference Example 183, was dissolved and thionyl chloride (806 mg) was added under ice-cooling. The mixture was refluxed for one hour, then concentrated in vacuo and the residue dissolved in methylene chloride (10 mL). In a mixture of 50 ml of tetrahydrofuran, 50 ml of methylene chloride and 0.5 ml of pyridine was added 1 g of cis-3- (p-nitrobenzyloxycarboxamido) -4- (hydroxymethyl) prepared according to Reference Example 182. -2-oxoazetidine was dissolved and the acid chloride solution prepared above was added dropwise at room temperature. After stirring at room temperature for 4 hours, the mixture was extracted with ethyl acetate: tetrahydrofuran (3: 1). The extract was washed with 3N hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine, then dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (140 g silica gel; eluent; ethyl acetate then ethyl acetate: methanol = 8: 1 then 4: 1). There was thus obtained 1.52 g of cis-3- (p-nitrobenzyloxy-carbamido) -4 - [(1-methyl-1H-tetrazol-5-yl) thioacetoxymethyl] -2 sulfonated -oxoazetidine as in Example 138 to cis-3- (p-nitrobenzyloxycarboxamethyl) -4 '- ((1-methyl-1H-tetrazol-5-yl) thioacetoxymethyl ] -2-oxoazetidine-1-sulfonic acid sodium salt is obtained.

IR (Oarf ⁴ ); 3400, 3320, 1760, 1730, 1685.

NMR spectrum (D _e -DMSO, ppm): 3.98 (3H, s, _N-CH3), 4.90 (IH, dd, J = 6, 9Hz, _C3 -H).

Calcd for C ₆ H _l6 N ₇ NaO ₁₀ S ₂ .h ₂ O Calcd:

Found: C, 33.63; H, 3.17; N, 17.16 _; Found: C, 33.42; H, 3.05; N, 17.17.

Example 159 In a mixture of ml of tetrahydrofuran and 20 ml of water, 1.02 g of cis-3- (p-nitrobenzyloxycarboxamido) -4 - ((1-methyl-1H-tetrazol-5-yl) -thio Acetoxymethyl] -2-oxo-azetidin-1-yl fatty acid sodium salt was dissolved and 1 g of 10% palladium-on-carbon catalyst was added and the mixture was stirred under hydrogen for 5 hours. neutralized with hydrogen bicarbonate solution and washed twice with ethyl acetate, 30 ml of tetrahydrofuran were added to the aqueous phase, followed by 356 mg of sodium bicarbonate under ice-cooling and 1.16 g of 2- [2- (chloroacetamido) -4- Thiazolyl] -2- [1-methyl-1- (benzhydryloxycarbonyl) -ethyloxyimino] -acetyl chloride hydrochloride salt was added, followed by cooling with ice (476 mg) for one hour, After addition of dithiocarbamate, the mixture was stirred at room temperature for an additional hour, and the reaction mixture was washed twice with diethyl ether and evaporated. lite is purified by column chromatography on XAD-II (eluent: water, 20% then 3% ethanol) and the eluate is freeze-dried to cis-3- {2- (2-amino-4-thiazolyl) -2- [ 1-Methyl-1- (benzhydryloxycarbonyl) -ethyloxyimino] -acetamido] -4 - [(1-methyl-1H-tetrazol-5-yl) -thioacetoxymethyl] -2- The oxo-azetidine-1-sulfonic acid sodium salt (color isomer) is obtained.

IR (λmax) 3420, 1760, 1740, 1670.

545 mg of this product are suspended in 2.5 ml of anisole and after cooling to -12 ° C, 12 ml of trifluoroacetic acid are added.

After stirring at -10 to -12 ° C, diethyl ether (20 ml) and hexane (20 ml) were added. The resulting precipitate was washed with diethyl ether (3 x 60 mL) and dissolved in water (40 mL). After addition of sodium bicarbonate, the mixture was filtered. The filtrate was evaporated and chromatographed on an Amberlite XAD-II column43

-43194870 by purification by filtration (eluent: water). Freeze drying of the eluate gave cis-3- [2- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4 - [(1-methyl- 1H-Tetrazol-5-yl) -thioacetoxymethyl] -2-oxoazetidine-1-sulfonic acid disodium salt (color isomer) is obtained.

IR (λ max): 3400, 1760, 1680.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.38 (3H, s, CH ₃ ), 1.43 (3H, s, CH ₃ ), 3.97 (3H, s, N-CH ₃ ). , 5.27 (IH, dd, J = 6, 9Hz, _C3 -H), 6.77 (lH, s, a group of formula CV).

Example 160 A mixture of cis-3- (benzyloxycarboxamido) -2-oxoazetidine-4-carboxylic acid (prepared in Reference Example 68) (2.56 g) in tetrahydrofuran (15 mL) and water (895 mg) bicarbonate,

2.23 g of 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide hydrochloride salt and 3.62 g of tosylalanine benzyl ester are added. The mixture was stirred at room temperature for 12 hours. The reaction mixture was extracted with ethyl acetate: tetrahydrofuran (2: 1), and the extract was washed with water, twice with 3N hydrochloric acid, then with saturated aqueous sodium bicarbonate, and then with anhydrous magnesium sulfate. The solvent was evaporated and the residue was chromatographed on a silica gel column (450 g silica gel; eluent: chloroform: ethyl acetate = 1: 1, then chloroform: ethyl acetate: methanol = 20: 20: 1, then 10: 10: 1). ). Thus, diastereomers of the cis-3- (benzyloxycarboxamido) -4 - {[1- (L) -benzyloxycarbonyl) ethyl] aminocarbonyl] -2-oxoazetidine (beta and alpha forms) were obtained. (cf. Reference Example 39).

These products were sulfonated as in Example 138 to give cis-3- (benzyloxycarboxamido) -4 - {[1- (L) - (benzyloxycarbonyl) ethyl] aminocarbonyl] -2-. the beta and alpha forms of the oxo-azetidine-1-sulfonic acid sodium salt are obtained. Beta Shape ''

IR spectrum (vmax ^cm-4): 3300, 1770, 1735, 1690, 1660th

Lamination results for C ₂₂ H ₉ N, NaO _Q S. 1/1/21 + 0:

Calculated: C, 47.65; H, 4.54; N, 7.58; % C, 47.55; H, 4.53; N, 7.44.

Alpha-form

IR (cm ^-1 ) 3300, 1770, 1695, 1660.

Analytical results for C ₂₂ H ₂₂ N ₃ NaO ₉ S. 1.1 / 2H ₂ O:

Found: C, 47.65; H, 4.54; N, 7.58; Found: C, 47.51; H, 4.45; N, 7.47.

Example 161 Sodium salt of cis-3- (benzyloxycarboxamido) -4 - {[1- (L) -benzyloxycarbonyl) ethyl] aminocarbonyl] -2-oxoazetidine-1-sulfonic acid beta - and the alpha form of the cis-3-amino-4- [1- (L) -carboxyethyl) aminocarbonyl] -2-oxo-azetidine-1-sulfonic acid sodium salt of the beta and alpha were reduced as in Example 64. - we get the men. These products were acylated as in Example 64, followed by removal of the chloroacetyl group as in Example 65, using cis-3- {2- (2-amino-4-thiazolyl) -2- [1-methyl-1 - (p-nitro-benzyloxycarbonyl) -ethyloxyimino] -acetamido) -4- {1- (L) -carboxy-ethyl) -aminocarbonyl] -2-oxo-azetidin-1 the beta (alpha) and alpha forms of the sodium (color isomer) of the parent fatty acid.

Beta-form

IR (λmax) ⁴ = 3400, 1775, 1730, 1665.

Alpha-form

IR (ν ^, αχΟκι ⁴ ): 3400, 1780, 1730, 1670.

Example 162

In the same manner as in Example 130, cis-3- [2- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4- [1- The beta and alpha forms of (L) -carboxyethyl) aminocarbonyl] -2-oxoazetidine-1-sulfonic acid (color isomer) are prepared.

Beta-form

IR (λmax) ⁴ . 3300, 1770, 1720, 1665.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.27 (3H, d, J = 7Hz, CH ₃ ), 1.51 (6H, s, 2XCH ₃ ), 4.48 (1H, d, J = 6 Hz, C ₄ -H), 5.45 (1H, dd, J = 6Hz, 10Hz C ₃ -H), 7.14 (1H, s, CV).

Alpha-form

IR (λ max ⁴ ): 3300, 1775, 1720, 1670.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.25 (3H, d, J = 7Hz, CH ₃ ), 1.51 (6H, s, 2XCH ₃ ), 4.48 (1H, d, J = 6 Hz, C ₄ -H), 5.34 (1H, dd, J = 6 Hz, 9 Hz, C ₃ -H), 7.23 (1H, s, CV).

163-167. EXAMPLES Reaction of cis-3- [DL-2- (2-Amino-4-thiazolyl) -2-ammonioacetamido] -4- (methoxycarbonyl) -2-oxoazetidine-1-sulfonate with the following acylating agents the corresponding cis-3- [DL-2- (acylamido) -2- (2-amino-4-thiazolyl) acetamido] -4- (methoxycarbonyl) -2-oxo- azetidine-1-sulfonic acid sodium salts are prepared.

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Example Acilezoser

163. CjHsCOCl

164. Compounds of general formula CH2OCOCl (Ib)

reaction conditions for Product IR NMR notices ... picture . OKBr -j. (1 / cm) ^v rrax. (D ₂ O ppm) Same, 340C, 1775, 1760, 1.13 4 1.15 (3H, both t, sample 1740, 1620, 1515, J = 7Hz, CH ₃ CH ₂ CH), 2.37 4 115th 1380, 1340, 1280, 2.41 (2H, both q, J = 7H, but 1250, 1050. CH ₃ CH ₂ CO ₃ , 3.65 4 3.77. (3H, acetone is used instead of acetonitrile. rc ₂ h ₅ - 3400, 1780, 1730, 1630, 1520, 1450, both s, C00CH ₃₎ 4.91 4 4.95 (1H, each d, J = 6 Hz Cu-H), 5.40 (1H, s, CH (F) -CO) 4 5.49 5 59 (1H, both d, J = 6Hz, C ₃ -H), 6.73 (1H, s, thiazol-5-Η). 4 3.66 3.75 (3H, each s, C00CH _3), 3.72 (3H, s, as in Fig. 163. r = ch ₃ O 1350, 1280, 1250, NHCOOCH3), 4.90 4 4.93 (1H, Example 1060 both d, J = 6Hz, Ci, H),

5.22 (1H, s, = CHCO), 5.41 & 5.54 (1H, both d, J = 6Hz,

C ₃ -H), 6.72 (1H, s, thiazol-5-Η)

as in Fig. 163. 3400, 1770, 1660, 1.41 (6H, s, --CHCl3) -, 3.63 example, 1620, 1510, 1400, 4 3.74 (3H, both s, 165th (ch ₃ ) _a C (C 0 Cl) ₂ but double R = NaOCOC / CH _3/3 1350, 1280, 1255, C00CH _a ), 4.88 δ 4.92 (1H, d, amounts J = 6Hz, C 1 -H), 5.38, 4.53 (1H, NaHCO ₃ bowl 3400, 1770, 1660, d, J = 6Hz, C 1 -H), 5.40 (1H, s, = CHCON), 6.72 (1H, s, thiazole -5-H). 2.54 / 4H, t, J = 5Hz, -CH ₂ CH ₂ -), amber- as in Fig. 117. 1570, 1520, 1405, 3.64 4 3.76 (3H, both s, 166th stone acid-an- Example. R = NaOCOCH ₂ CH ₂ 1280, 1055, 815. C00CH ₃₎ 4.81 4 4.94 (1H, hydride both d, J = 6Hz, C 1 -H), 5.16 4 5.40 (1H, both d, J = 6Hz, C ₃ -H), 6.69 (1H, s, thiazol-5-Η) . 3400, 3410, 1765, 3.63 4 3.75 / 3H, both s, 1580, 1520, 1440, C00CH ₃₎ 4.90 4 4.93 (1H, 167th maleic as in Fig. 117. NaOCOCH R = CH 1340, 1280, 1250, both d, J = 6Hz, Ci, -H), anhydride Example 1055th 5.38 4 5.54 (1H, both d,

J = 6Hz, C ₃ -H), 5.40 (1H, s, -CHCON), 6.00 (1H, d, J = 12Hz, -CH-), 5.44 (1H, d, J = 12Hz) , -CH =), 6.70 4 6.72 (1H, both s, thiazole-5-H).

Example 168

In the same manner as in Example 142, cis-3- {2- [2- (chloroacetamido) -4-thiazolyl] -2- [1-methyl-1- (benzhydryloxycarbonyl) -ethyloxyimino] ] -acetamido} -4-carbamoyloxymethyl-2-oxoazetidine-1-sulfonic acid sodium salt (color isomer) is prepared.

IR (λ max ¹⁶ ): 3400, 1750, 1720.

Example 169

In the same manner as in Example 65, cis-3- {2- (2-amino-4-thiazolyl) -2- [1-methyl-1- (benzhydryloxycarbonyl) -ethyloxyimino] -acetamido} Sodium salt of 4-carbamoyloxymethyl-2-oxoazetidine-1-sulfonic acid (color isomer) was prepared. 55

IR (λmax * ¹ ): 1760, 1720, 1670.

Example 170 Anisole ml ml cis-3- (2- (2-amino-θθ -4-thiazolyl) -2- [1-methyl-1- (benzhydryloxycarbonyl) ethyloxyimino] 250 mg) - Acetamido} -4- (carbamoyloxymethyl) -2-oxoazetidine -1-sulfonic acid (color isomer) was added and 5 ml of trifluoroacetic acid was added dropwise with stirring at -20 ° C. At 15 ° C ⁶⁵

After stirring for 30 minutes, diethyl ether (10 ml) and petroleum ether (10 ml) were added. The resulting powder is recovered by centrifugation and dissolved in water. To the solution was added Dowex 50W H ⁺ resin and stirred. The resin was then filtered off, the filtrate evaporated and purified by Amberlite XAD-II column chromatography (eluent: 100 mL water, 100 mL 10% ethanol, 100 mL 30% ethanol, then 50 mL 40% ethanol). The 30 and 40%

Freeze-drying of 5θ ethanol fractions cis-3- [2- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4-carbamoyloxymethyl) -2-oxoazetidine-1-sulfonic acid (color isomer) is obtained.

IR spectrum (v ^ e ^'1): 1760, 1710, 1630. NMR spectrum _(D6 -DMSO, ppm): 1.51 (6H, s, 2 x CH _3), 7.01 (IH, s, group of formula CV), 9.23 (IH, d, J = 9Hz, _C3 -NH).

I. Reference Example

To a solution of 2.94 g of methyl cis-3-amino-1- (2,4-dimethoxybenzyl) -2-oxoazetidine-4-carboxylic acid in 12 ml of methylene chloride was added under ice-cooling and stirring 6.7 g. ml of propi45

-45194870 lene oxide was added followed by 3.24 g of benzyloxycarbonyl chloride and the mixture was stirred at room temperature for 30 minutes. The solvent is then evaporated in vacuo, diethyl ether is added to the residue and the precipitated crystals are filtered off with cis-3- (benzyloxycarboxamido) -1- (2,4-dimethoxybenzyl) -2-oxoazetidine-4- Carboxylic acid methyl ester - op: 115-

116 ° C.

Analysis for C ₂₂ H ₂₄ N ₂ O _7: Calcd: C% = 61.67, H% = 5.65, N% = 6.54; Found: C, 61.64; H, 5.67; N, 6.49.

2. Reference Example

A solution of cis-3- (benzyloxycarboxamido) -1- (2,4-dimethoxybenzyl) -2-oxoazetidine-4-carboxylic acid methyl ester (2.7 g) in acetonitrile (150 mL) under nitrogen with stirring Heat to 90-95 ° C and add a solution of 2.73 g of potassium persulphate and 1.65 g of dipotassium phosphate in 55 ml of water. After the addition, the mixture was stirred at this temperature for 3 hours. After cooling, the pH was adjusted to 6-7 by addition of dipotassium phosphate, and the acetonitrile and water were evaporated in vacuo. The residue is dissolved in chloroform and the solution is washed first with water and then with aqueous sodium chloride solution. The chloroform solution was dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was chromatographed on a silica gel column. Elution with ethyl acetate gave methyl cis-3- (benzyloxycarboxamido) -2-oxoazetidine-4-carboxylic acid, m.p. 127-128 ° C.

Analysis: Calculated for C ₁₃ H ₁₄ N ₂ O ₅ : C, 56.11; H, 5.07; N, 10.07 Found: C, 56.03; H, 5.01. , N% = 9.99.

3. Reference Example

To a slurry of 0.8 g of cis-3- (benzyloxycarboxamido) -2-oxoazetidine-4-carboxylic acid methyl ester in 20 ml of ethanol was added 0.8 g of 5% palladium on carbon and catalytic reduction at atmospheric pressure with stirring. After hydrogen uptake ceased, the catalyst was filtered off and the filtrate was concentrated in vacuo. The oily residue was allowed to stand under cooling. Precipitated crystals were collected by filtration to give 0.38 g (92%) of methyl cis-3-amino-2-oxoazetidine-4-carboxylic acid, m.p. 59-61 ° C. Analysis: Calculated for C ₅ H ₈ N ₂ O ₃ : C, 41.66; H, 5.59; N, 19.44; Found: C, 41.54; H, 5.59; N, 19.67.

4. Reference Example

To a suspension of 1.18 g of 2- [2- (chloroacetamido) -4-thiazolyl) -2- (methoxyimino) acetyl chloride (color isomer) in 10 ml of tetrahydrofuran under ice-cooling and stirring was added 288 mg of cis- A solution of 3-amino-2-oxo-azetidine-4-carboxylic acid methyl ester and 561 mg of sodium bicarbonate in water (6 ml) was added and the mixture was stirred at room temperature for 2 hours and the solvent was evaporated in vacuo.

Water was added to the solidified residue, and the crystals were filtered off and washed first with water and then with ethanol. Thus, methyl cis-3-12- [2- (chloroacetamido) -4-thiazolyl] -2-methoxyiminacetamido-2-oxoazetidine-4-carboxylic acid (color isomer) m.p. 270-275 ° C (dec.);

Analysis C H _{I3 I4} C1N ₅ O ₆ S Calcd:

Found: C, 38.66; H, 3.49; N, 17.35; Found: C, 38.50; H, 3.78; N, 17.25.

Reference Example 5 A solution of cis-3- (benzyloxycarboxamido) -1- (2,4-dimethoxybenzyl) -2-oxoazetidine-4-carboxylic acid methyl ester g in 500 ml of tetrahydrofuran was cooled with ice and while stirring, a solution of sodium borohydride (2.65 g) in water (250 ml) was added. The reaction mixture was stirred at room temperature for 5 hours. The tetrahydrofuran was then evaporated in vacuo, water was added to the residue and the precipitated crystals were filtered off and dried to give 9.8 g (87%) of cis-3- (benzyloxycarboxamido) -1- (2,4-dimethoxybenzyl) - 4-hydroxymethyl) -2-oxoazetidine is obtained, m.p. 129-131 ° C.

Analysis for C ₂₁ H ₂₄ N ₂ O _6: Calcd: C% = 62.99, H% = 6.04, N% = 7.00; Found: C, 62.78; H, 5.91; N, 7.05.

6. Reference Example

To a solution of 5.1 g of cis-3- (benzyloxycarboxamido) -1- (2,4-dimethoxybenzyl) -4- (hydroxymethyl) -2-cxoazetidine in 50 ml of methylene chloride is 0 °. At C, 3.8 ml of pyridine was added with stirring, followed by dropwise addition of 2.04 ml of acetyl chloride. After stirring for 30 minutes, the solvent was evaporated in vacuo. The residue was chromatographed on a silica gel column eluting with ethyl acetate to give cis-4- (acetoxymethyl) -3- (benzyloxycarboxamido) -1- (2,4-dimethoxybenzyl) (5.45 g, 96%). ) -2-oxoazetidine is obtained, m.p. 110-111 ° C.

Calcd for C ₂₃ H ₂₆ N ₂ O _7: Calcd: C% = 62.43, H% 5.92, N% = 6.33; Found: C, 62.26; H, 5.68; N, 6.07.

Reference example

Cis-4- (acetoxymethyl) -3- (benzyloxycarboxamido) -1- (2,4-dimethoxybenzyl) -2-oxoazetidine (4.862 g) in acetonitrile (275 mL) was stirred under a stream of nitrogen 80 Heat to -83 ° C. A solution of potassium persulfate (4.752 g) and dipotassium phosphate (2.871 g) in water (110 ml) was added dropwise. After the addition was complete, the mixture was stirred at 9 ° C for 2.5 hours. After cooling, the pH was adjusted to 6-7 by addition of dipotassium phosphate, and the acetonitrile and water were evaporated in vacuo. Chloroform was added to the residue, the precipitate was filtered off and washed with water, then with chloroform, and dried. Thus, cis-4- (acetoxymethyl) -3- (benzyloxycarboxamido) -2-oxoazetidine, m.p. 137-138 ° C.

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Analysis for C ₁₄ H _I6 N ₂ O _5: Calcd: C% = 57.53, H% = 5.52, N% = 9.59; Found: C, 57.38; H, 5.43; N, 9.58.

8. Reference Example

To a suspension of 1.46 g of cis-4- (acetoxymethyl) -3- (benzyloxycarboxamido) -2-oxoazetidine in 50 ml of ethanol is added 1.5 g of 5% palladium on carbon and the mixture is subjected to catalytic reduction with stirring at atmospheric pressure. The reaction was completed in 30 minutes. The catalyst was filtered off and the filtrate evaporated in vacuo to give 750 mg (95%) of cis-4- (acetoxymethyl) -3-amino-2-oxoazetidine as a colorless oil.

IR (ν max): 3300, 1770-1710. Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 1.83 (br.s, -NH ₂ ), 2.1 (s, -CH ₃ ), 3.6-4.1 (m, -CH ₂ -), 4.1-4.8 (m, C ₃ -H and

C ₄ H), 6.0-6.3 (br.s, NH).

9. Reference Example

To a suspension of 2.36 g of 2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetyl chloride (color isomer) in 20 ml of tetrahydrofuran was added, under ice-cooling and stirring, 632 mg of cis- A solution of 4- (acetoxymethyl) -3-amino-2-oxoazetidine and 1.122 g of sodium bicarbonate in 12 ml of water was added. After stirring for 2 hours at room temperature, the solvent was evaporated in vacuo. The residue was allowed to solidify and then water was added and filtered. The crystals obtained were washed first with an aqueous solution of sodium bicarbonate, then with water and finally with diethyl ether, and dried over cis-4- (acetoxymethyl) -3- {2- [2- (chloroacetamido) -4-thiazolyl]. ] For -2- (methoxyimino) acetamido} -2-oxoazetidine (color isomer) - op 180-190 ° C (dec.);

Elementary analysis for C ₄ H ₆ O ₆ C1N ₅ S

Found: C, 40.24; H, 3.86; N, 16.76. Found: C, 39.89; H, 3.67; N, 16.60.

10. Reference Example

To a solution of 4.5 g of cis-3- (benzyloxycarboxamido) -1- (2,4-dimethoxybenzyl) -4- (hydroxymethyl) -2-oxoazetidine in 30 ml of pyridine was added ice-cooling and stirring. while methanesulfonyl chloride (1.94 g) was added. After stirring for 30 minutes at room temperature, ethyl acetate (100 mL) and water (50 mL) were added and finally acidified with dilute hydrochloric acid. The precipitated crystals were filtered off and the filtrate separated the organic layer and concentrated in vacuo. Water was added to the residue and the crystals formed were filtered off and combined with the crystals obtained above. The crystals were washed with aqueous sodium bicarbonate solution, then with water and then with diethyl ether, and dried to give 5.0 g (93%) of cis-3- (benzyloxycarboxamido) -1 (2,4-dimethoxybenzyl). -4- (methane gives birth to 1-oxymethyl) -2-oxo92

of azetidine, m.p. 140-141 ° C. Analysis: Calculated for C ₂₂ H ₂₆ N ₂ O ₈ S: C, 55.22; H, 5.48; N, 5.85. Found: C, 55.16; H, 5.40; N, 5.61.

11. Reference Example

A solution of 3.83 g of cis-3- (benzyloxycarboxamido) -1- (2,4-dimethoxybenzyl) -4- (methanesulfonyloxymethyl) -2-oxoazetidine in 200 ml of acetonitrile, while stirring it was heated to 80-83 ° C and a solution of 3.46 g of potassium persulfate and 2.09 g of dipotassium phosphate in 80 ml of water was added dropwise. After the addition was complete, the mixture was stirred at 85-90 ° C for 3 hours. The solvent was evaporated in vacuo and water (200 mL) was added. The resulting crystals are filtered off, washed with water and then with diethyl ether and dried. M.p. 132-133 ° C. Cis-3- (benzyloxycarboxamido) -4- (methanesulfonyloxymethyl) -2-oxoazetidino.

IR (λ max): 3325, 1770, 1690.

Reference Example 12 Methyl ethyl ketone (1.4 ml) was treated with 1.4 g of cis-3- (benzyloxycarboxamido) -4- (methanesulfonyloxymethyl) -2-oxoazetidine and 4.2 g of sodium iodide. and the mixture was stirred for 2 hours at 90 ° C and then for 12 hours at 60 ° C. The solvent was evaporated in vacuo and the residue was shaken thoroughly with water (100 mL) and chloroform (50 mL). The precipitate is filtered off, washed with water and then with chloroform and dried. The product was cis-3- (benzyloxycarboxamido) -4- (iodomethyl) -2-oxoazetidine, m.p. 160-162 ° C.

Analysis: Calculated for C ₁₂ H ₁₃ IN ₂ O ₃ : C, 40.02; H, 3.64; N, 7.78. Found: C, 40.26; H, 3.64; N, 7.93.

13. Reference Example

To a solution of 103.5 mg of sodium in 9 ml of methanol was added 522 mg of (1-methyl-5-tetrazolyl) -thiol and the mixture was stirred at room temperature for 15 minutes. The methanol was evaporated in vacuo and 12 ml of N, N-dimethylformamide was added to the residue. To the resulting solution was added 900 mg of cis-3- (benzyloxycarboxamido) -4- (iodomethyl) -2-oxoazetidine and the mixture was stirred at room temperature for 19 hours. Water (100 mL) was added to the reaction mixture, and the resulting crystals were filtered and washed with water and diethyl ether. The crystals were then dissolved in ethyl acetate and passed through a small silica gel column. The eluate was collected and the solvent was evaporated in vacuo. The resulting colorless crystals were cis-3- (benzyloxycarboxamido) -4 - [(1-methyl-5-tetrazolyl) thiomethyl] -2-oxoazetidine (780 mg, 90%): 151-152 ° C.

Analysis results for C _I4 H | ₆ N ₆ O ₃ S: Calcd: C% = 48.26, H% = 4.63, N% = 24.13 Found:% C 48.38% H 4.65% N 23.89.

-47194870

14. Reference Example

To a suspension of 1.18 g of 2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetylchloride (anti-isomer) in 10 ml of tetrahydrofuran under ice-cooling and stirring, 288 mg A solution of cis-3-amino-2-oxo-azetidine-4-carboxylic acid methyl ester and 561 mg of sodium bicarbonate in water (6 ml) was added. After stirring at room temperature for 2 hours, the solvent was evaporated in vacuo. The residue was allowed to solidify, then water was added and filtered. The filtrate was neutralized with aqueous sodium bicarbonate solution and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and concentrated in vacuo. The product was cis-3- {2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido] -2-oxoazetidine-4-carboxylic acid methyl ester (anti -isomer) - op:

119-129 ° C.

Analysis results for C _I3 H | _{4 for the} formula C1N ₅ O ₆ S:

Found: C, 38.66; H, 3.49; N, 17.34 _; Found: C, 38.56; H, 3.60; N, 17.05.

15. Reference Example

To a solution of 2.94 g of cis-3-amino-1- (2,4-dimethoxybenzyl) -2-oxoazetidine-4-carboxylic acid methyl ester in 40 ml of methylene chloride was added 2.10 ml of triethyl under ice-cooling and stirring. A solution of 2.31 g of phenylacetyl chloride in 15 ml of methylene chloride is added dropwise over 1 hour. After stirring for one hour under ice-cooling, the mixture was washed first with dilute hydrochloric acid, then with 5% aqueous sodium bicarbonate solution, and finally with aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was then evaporated in vacuo and diethyl ether was added to the residue. The resulting crystals were filtered off with methyl cis-1- (2,4-dimethoxybenzyl) -3- (phenylacetamido) -2-oxoazetidine-4-carboxylic acid, m.p. 124-

126 ° C.

Analysis for C ₂₂ H ₂₄ N ₂ O _6: Calcd: C% = 64.07, H% = 5.86, N% = 6.79; Found: C, 63.98; H, 5.98; N, 6.70.

16. Reference Example

A mixture of 412 mg of methyl cis-1- (2,4-dimethoxybenzyl) -3- (phenylacetamido) -2-oxoazetidine-4-carboxylic acid, 810 mg of potassium persulfate and 261 mg of dipotassium phosphate was added. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate and washed with 5% aqueous sodium bicarbonate solution and then with aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was evaporated in vacuo and ethyl acetate was added to the residue and the resulting crystals were filtered off with cis-3- (phenylacetamido) -2-oxoazetidine-4-carboxylic acid methyl ester, m.p. 176-180 ° C. 48

IR (λmax ') 1790, 1740, 1655. Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.47 (s,

CH ₂ CO & OCH ₃ ), 4.20 (d, J = 6Hz, C ₄ -H), 5.35 (dd, J = 6Hz, 8Hz, C ₃ -H), 7.32 (s , C ₆ H ₅ ), 8.44 (s, NH)

8.62 (d, J = 8 Hz, CONH).

17. Reference Example

A solution of 2.06 g of cis-1- (2,4-dimethoxybenzyl) -3- (phenylacetamido) -2-oxoazetidine-4-carboxylate in a solution of v-methyl ester in 24 ml of tetrahydrofuran was cooled under ice-cooling and A solution of sodium borohydride (570 mg) in water (12 ml) was added with stirring, and the reaction mixture was stirred under ice-cooling for 30 minutes and then at room temperature for 1.5 hours, the tetrahydrofuran was evaporated in vacuo and the aqueous sodium chloride solution The organic layer was separated and washed with aqueous sodium bicarbonate solution, brine, and dried over magnesium sulfate. 1.75 g (91%) of cis-1- (2,4-dimethoxy; benzyl) -4- (hydroxymethyl) -3- (phenylacetamethyl) -2-oxoazetidine - m.p. 154 ° C.

Analysis for C ₂ H ₂₄ N ₂ O _5: Calcd: C% = 65.61, H% = 6.29, N% = 7.29; Found: C, 65.37; H, 6.47; N, 7.55.

18. Reference Example

To a solution of 1.12 g of tosyl chloride in 6 ml of pyridine at 0 ° C with stirring was 1.73 g of cis-1- (2,4-dimethoxybenzyl) -4- (hydroxymethyl) -3- (phenyl) -acetamido) -2-oxoazetidine was added and the mixture was stirred for 2 hours and then allowed to stand overnight in a refrigerator. The reaction mixture was then treated with 0.68 ml of lactic acid and stirred for one hour. The reaction mixture was diluted with ethyl acetate (45 mL) and tetrahydrofuran (15 mL), washed with dilute hydrochloric acid, then with aqueous sodium chloride solution, then with aqueous sodium bicarbonate, and again with brine. The organic layer was dried over magnesium sulfate and evaporated. To the residue was added a 5: 1 mixture of diethyl ether and ethyl acetate and the crystals formed were filtered off with 2.21 g (91%) of cis-1- (2,4-dimethoxybenzyl) -3- (phenylacetam time). 4- (p-toluenesulfonyloxymethyl) -2-oxoazetidine is obtained, m.p. 109-110 ° C.

Analysis: Calculated for C ₂₈ H ₃₀ N ₂ O ₇ S: C, 62.43; H, 5.63; N, 5.20; Found: C, 62.18; H, 5.72; N, 5.07.

Reference Example 19 to ml of acetone 2.27 g of cis-1- (2,4-dimethoxybenzyl) -3- (phenylacetamido) -4- (p-toluenesulfonyloxymethyl) -2-oxoazetidine and 4.95 g of sodium iodide are added and the mixture is refluxed for 6 hours and then concentrated in vacuo. The residue was dissolved by the addition of methylene chloride and water, the aqueous phase was separated and washed with aqueous sodium thiosulfate solution and then with sodium chloride solution. The methylene chloride solution was dried over magnesium sulfate and evaporated. Ethyl acetate was added to the residue and the crystals formed were filtered off with cis-1- (2,4-dimethoxybenzyl) -4- (iodomethyl) -3- (phenylacetamido) -2-oxoazetidine, m.p. 181-182 ° C. - we get.

Analysis for C ₂ | H ₂₃ IN ₂ O _4: Calcd: C% = 51.03, H% = 4.69, N% = 5.67; Found: C, 51.14; H, 4.64; N, 5.81.

Reference Example 20 for N, N-Dimethylformamide mL 740 mg cis-1- (2,4-dimethoxybenzyl) -4- (iodomethyl) -3- (phenylacetamido) -2-oxoazetidine and 146 mg of sodium azide were added and the mixture was stirred for 4 days at room temperature. The solvent was evaporated in vacuo and ethyl acetate and water were added to the residue. The ethyl acetate layer was separated, washed with brine, then dried over magnesium sulfate and concentrated in vacuo. Diethyl ether was added to the residue and the crystals formed were filtered off with cis-4- (azidomethyl) -1- (2,4-dimethoxybenzyl) -3- (phenylacetamido) -2-oxoazetidine - m.p. -111 ° C.

IR spectrum (FTW Vx ^'f): 3270, 2210, 1755, 1650th

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 3.32 (m, -CH ₂ N ₃ ), 3.63 (s, CH ₂ CO), 3.83 (s, OCH ₃ X 2), 4.36 (dd) , J = 14 Hz, CH 2 Ar), 5.28 (q, J = 5 Hz, C ₃ -H),

6.40-6.80 (m, ArH and CONH), 7.16 (m, ArH), 7.15 (s, C ₆ H ₅ ).

21. Reference Example

To a solution of cis-4- (azidomethyl-1-12.4-dimethoxybenzyl) -3- (phenylacetamido) -2-oxoazetidine (449 mg) in ethanol (80 mL) was added 10% palladium on carbon (200 mg) and the mixture was hydrogenated at room temperature and atmospheric pressure for 1.5 hours. The catalyst was filtered off and the filtrate was evaporated to dryness in vacuo. The residue was taken up in methylene chloride (30 ml) and triethylamine (0.2 ml) was added with stirring at 0 ° C. A solution of acetyl chloride (0.1 mL) in methylene chloride was added dropwise over 10 minutes. After stirring for 40 minutes, the reaction mixture was washed with dilute hydrochloric acid, then water, followed by aqueous sodium bicarbonate solution and finally aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was then evaporated in vacuo, ethyl acetate was added to the residue and the resulting crystals were filtered off with cis-4- (acetamidomethyl-1- (2,4-dimethoxybenzyl) -3- (phenylacetamido) -2-oxoazetidine. m.p. 205-207 DEG C. - IR (λmax): 3270, 1750, 1640.

22. Reference Example

A mixture of 298 mg of cis-4-facetamidomethyl) -1- (2,4-dimethoxybenzyl) -3- (phenylacetamido) -2-oxoazetidine, 576 mg of potassium persulfate and 183 mg of dipotassium phosphate. of water and 15 ml of acetonitrile was refluxed for 1.5 hours. The reaction mixture was concentrated in vacuo and the residue was taken up in ethyl acetate and the resulting solution was washed with aqueous sodium bicarbonate solution and then with aqueous sodium chloride solution. The ethyl acetate solution was dried over magnesium sulfate and concentrated in vacuo. Ethyl acetate was added to the residue and the resulting crystals were collected by filtration to give cis -4- (acetamidomethyl) -3- (phenylacetamido) -2-oxoazetidine, m.p. 200-202 ° C.

IR spectrum (v ^> ^M): 3250, 1750, 1640, 1520th

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.77 (s, COCH ₃ ), 3.11 (m, CH ₂ N), 3.69 (d, t, J = 5Hz, 6Hz, C _4- H), 5.00 (dd, J = 5 Hz, 8 Hz), 7.26 (s, C ₆ H ₅ ),

7.59 (m, NH), 8.20 (br, CXV), 8.75 (d, CONH, J = 8Hz).

23. Reference Example

8.5 g of methyl cis - (2,4-dimethoxybenzyl) -3-phthalimido-2-oxoazetidine-4-carboxylic acid and 3.1 g of 1,8-diazabicyclo [5.4. The mixture of O] -7-undecene was heated in 200 ml of benzene for 72 hours. After cooling, ethyl acetate (100 mL) was added to the reaction mixture, which was washed with water (100 mL), 1N hydrochloric acid (50 mL), and water (100 mL) again. To the resulting mixture was added chloroform (100 mL), dried over anhydrous sodium sulfate, and evaporated in vacuo. Ethyl acetate (50 mL) was added to the residue and the resulting precipitate was filtered off and washed with ethyl acetate (30 mL). The resulting crude product (6.4 g) was recrystallized from ethyl acetate (220 ml) to give methyl trans-1- (2,4-dimethoxybenzyl) -3-imido-2-oxoazetidine-4-carboxylic acid, m.p.

186-188 ° C.

Analytical results for C ₂₂ H ₂₀ N ₂ O ₇ :

Calculated: C, 62.26; H, 4.75; N, 6.60. Found: C, 62.13; H, 4.64; N, 6.43.

Reference Example 24 To methylene chloride was added 8.3 g of 2,4-dimethoxybenzylamine and 6.0 g of anhydrous magnesium sulfate and 6.5 g of n-butylglyoxylate in 65 ml of ice-water with stirring. of methylene chloride is added dropwise. The mixture was stirred for two hours and then filtered. To the filtrate was added 5 g of triethylamine, followed by a solution of 11 g of phthalimidoacetyl chloride in 110 ml of methylene chloride. After stirring overnight, the mixture was washed with dilute hydrochloric acid, followed by aqueous sodium chloride solution, followed by aqueous sodium bicarbonate solution, and again with brine, and dried over anhydrous sodium sulfate. The solution was filtered and the filtrate was evaporated. Diethyl ether was added to the residue and the resultant 49 was obtained

-49194870 precipitate was filtered off. The filtrate was evaporated in vacuo to give 20.1 g (86%) of n-butyl ester of? 2 -2- (2,4-dimethoxybenzyl) -3-phthalimido-2-oxoazetidine-4-carboxylic acid as an orange oil. . A portion of the product was purified by silica gel column chromatography to give a colorless, foamy product. However, in the reactions described below, the compound is used crude.

IR spectrum (v ^ _w ^c-1): 1770, 1720th

NMR (CDC1 _3, ppm): 4.26 (1H, d, J = 5Hz, _C4 -H), 5.63 (1H, d, J = 5Hz, _C3 -H).

Reference Example 25 A solution of g cis-1- (2,4-dimethoxybenzyl) -3-phthalimido-2-oxoazetidine-4-carboxylic acid n-butyl ester in 190 ml of methylene chloride

Methylhydrazine (3.7 g) was added and the mixture was stirred overnight at room temperature. The reaction mixture was then filtered and the filtrate was concentrated in vacuo. Ethyl acetate was added to the residue and the resulting precipitate was filtered off. The filtrate was extracted twice with 100 mL of 1N hydrochloric acid. The extracts were neutralized with sodium bicarbonate and then extracted with ethyl acetate. This extract was washed with aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Concentration of the solution afforded 12 g (87.5%) of the n-butyl ester of cis-3-amino-1- (2,4-dimethoxybenzyl) -2-oxoacetidine-4-carboxylic acid as an oil.

IR (ν max cm ^-1 ): 3400, 1750.

NMR spectrum _(CDCl3, ppm): 3.83, 3.93 (2x3H, 2.times.s, ₂ x OCH3)

In a similar manner, methyl methyl ester of trans-3-amino-1- (2,4-dimethoxybenzyl) -2-oxoazetine-4-carboxylic acid was prepared as an oily product.

IR spectrum (v, cm ^4): 3400, 3330, 1760th

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 3.70 ( ₁ H, d, J = 2 Hz, C ₃ H), 3.79, 3.80, 3.81 ( ₃ X ₃ H, ₃ X S, ₃ X CH ₃ ), 4 21 (1H, d, J = 2Hz, C ₄ -H), 4.45 (2H, q, J = 14 Hz, _CH2).

Reference Example 26: To a solution of cis-3-amino-1- (2,4-dimethoxybenzyl) -2-oxoazetidine-4-carboxylic acid n-butyl ester g in 40 ml of methylene chloride under ice-cooling and stirring 1 g. Propylene oxide (8 g) and benzyloxycarbonyl chloride (5.5 g) were added and the mixture was warmed to room temperature and stirred for one hour. The solvent was evaporated in vacuo and diisopropyl ether was added to the residue. The resulting crystals were filtered off with 11.7 g (83.5%) of cis-3- (benzyloxycarboxamido) -1- (2,4-dimethoxybenzyl) -2-oxoazetidine-4-carboxylic acid n- Colorless crystals of butyl ester, m.p. 97-98 ° C. Analysis for C ₂₅ H ₃₀ N ₂ O _7: Calcd: C% = 63.81, H% = 6.42, N% = 5.95; Found: C, 63.51; H, 6.26; N, 6.09.

In a similar manner, trans-3- (benzyloxycarboxamido) -1- (2,4-dimethoxy)

benzyl) -2-oxo-azetidine-4-carboxylic acid methyl ester. Since this product did not crystallize from the above treatment, it was purified by column chromatography (silica gel; eluent: hexane-ethyl acetate 1: 1). 89% of a colorless oily product are obtained.

IR spectrum (v '^ CWF ^1); 3340, 1770,

1740-1720.

NMR (CDC1 _3, ppm): 3.93 (1H, d, J = 3 Hz, C ₄ -H), 5.07 (2H, s, _CH2 Ph).

27. Reference Example for a mixture of ml of acetonitrile and 60 ml of water

2.35 g of cis-3- (benzyloxycarboxamido) -2- (2,4-dimethoxybenzyl) -2-oxoazetidine-4-carboxylic acid n-butyl ester, 4.05 g of potassium persulfate and 1.74 g of dipotassium hydrogen phosphate were added and the resulting mixture was refluxed for one hour under argon. The acetonitrile was evaporated in vacuo, ethyl acetate and water were added to the residue and the mixture was shaken. The organic layer was separated, washed with aqueous sodium bicarbonate solution, then with brine and dried over anhydrous sodium sulfate. The solution was concentrated in vacuo and the residue was chromatographed on a silica gel column using ethyl acetate: hexane (1: 1) as eluent. Crystals of cis-3- (benzyloxycarboxamido) -2-oxoazetidine-4-carboxylic acid n-butyl ester are thus obtained, m.p. 112-113 ° C. Analysis for C ₁₆ H ₂₀ N ₂ O _5: Calcd: C% = 59.98, H% = 6.29, N% = 8.74; Found: C, 69.25; H, 6.33; N, 8.53.

In a similar manner, methyl 3- (benzyloxycarboxamido) -2-oxoazetidine-4-carboxylic acid methyl ester, m.p. 139-140 ° C, was prepared.

28. Reference Example

To a suspension of cis-3- (benzyloxycarboxamido) 2-oxoazetidine-4-carboxylic acid n-butyl ester (640 mg) in ethanol (23 ml) was added 640 mg of 10% palladium on carbon and the mixture was pressed at hydrogenation with stirring. After the hydrogen condition had ceased, the catalyst was filtered off and the filtrate was concentrated in vacuo. Crystallization of the residue afforded 330 mg (87.1%) of cis-3-amino-2-oxoazetidine-4-carboxylic acid n-butyl ester. A portion of the product was recrystallized from ethyl acetate-hexane to give orange-scaled crystals, m.p. 87-89 ° C.

Analysis for C _g H ₁₄ N ₂ O _3: Calcd: C% = 51.60, H% = 7.57, N% = 15.04% Found: C = 51.35% H = 7.58 N, 14.80

The trans-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester, m.p. 135-136 ° C, was prepared in a similar manner.

29. Reference Example

To a solution of 13.6 g of methyl 2- (hydroxyimino) acetic acid in 70 ml of acetone was added, under ice-cooling, 20.8 g of potassium carbonate 50194870. 17.0 g of n-propyl iodide are added dropwise over 30 minutes. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The acetone was evaporated in vacuo, water (250 mL) was added to the residue and the resulting mixture was extracted with methylene chloride. The extract was washed twice with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The product was a pale yellow oily product, methyl 2- (n-propoxyimino) -acetic acid.

IR (294, 1750, 1695, 1600).

NMR (CDC1 _3, ppm): 0.95 (3H, t, J = 7Hz, CH ₂ CH ₂ CH _3), 1.75 (2H, sextet, J = 7Hz, CH, CH, CH.

2.38 (3H, s, CH ₃ CO), 3.86 (3H, s, COOCH ₃ ).

Similarly, 2- (n-butoxyimino) -acetic acid methyl ester (80%) was obtained as a pale yellow oil.

IR (λ max, - '): 2975, 1755, 1700, 1600.

NMR (CDC1 _3, ppm): 0.94 (3H, t, J = 6Hz, CH ₂ CH ₂ CH ₂ C H, 1,2-, 2.0 (4H, m, CH ₂ CH ₂ CH ₂ CH? , 2.36 (3H, s, CH ₃ CO), 3.85 (3H, s,

COOCH 3, 4.29 (2H, t, J = 6Hz, CH ₉ CH ₉ CH ₉ CH 3).

and 2- (benzyloxyimino) -acetic acid methyl ester, also as a pale yellow oil, in 98% yield.

IR (ν, ^z , 'ci') 1750, 1690.

NMR (CDC1 ₃ ppm): 2.36 (3H, s, _CH3 CO), 3.83 (3H, s, COOCHJ,

5.28 (2H, s, CH 3), 7.27 (5H, s, -Ph).

30. Reference Example

To a solution of 7.4 g of methyl 2- (n-propoxyimino) acetic acid in 7.4 ml of acetic acid was added 5.5 g of sulfuryl chloride and the mixture was heated at 40 ° C for 10 minutes and then at room temperature for 6 hours. stir. The reaction mixture was poured into 100 ml of ice water and extracted twice with chloroform. The extract was washed with aqueous sodium chloride solution and then with aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. Evaporation of the solvent in vacuo 8.2 g (94%)

Methyl 4-chloro-2- (n-propoxyimino) -acetic acid is obtained as a pale yellow oil.

IR (λ max): 2980, 1750, 1720, 1595.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 0.97 (3H, t, J = 7Hz, CH ₂ CH ₂ CH 3), 1.77 (2H, sextet, J = 7Hz, CH ₂

3.89 (3H, s, COOCHJ, 4.30 (2H, t, J = 7Hz, CH CH _{9 9} CHJ, 4.56 (2H, s, CICHJ.

100

Similarly, 4-chloro-2- (n-butoxyimino) acetic acid) methyl ester (92%) was obtained as a pale yellow oil.

IR spectrum (vS »» ^1): 2975, 1750, 1720, 1595

NMR (CDC1 ₃ ppm): 0.97 (3H, t, J = 6Hz, CH ₂ CH ₂ CH ₂ C H, 1,2-, 2.0 (4H, m, CH ₂ CH ₂ CH ₂ CH? 3.88 (3H, s, COOCHJ ^- 4.33 (2H, t, J = 6Hz, CH ₂ CH _{9 9} CH CH J, 4.56 (2H, s, CICHJ and also a pale yellow oily product 4 methyl chloro-2- (benzyloxyimino) -acetic acid in 97% yield.

IR spectrum (v cm ^ ^t): 1755, 1720th

NMR (CDC1 _3, ppm): 3.87 (3H, s, COOCHJ, 4.50 (2H, s, CICHJ, 5.29 (2H, s, _CH2 Ph), 7.28 (5H, s, -Ph).

31. Reference Example

To a solution of 7.0 g of methyl 4-chloro-2- (n-propoxyimino) -acetic acid in 20 ml of water and 25 ml of ethanol was added 2.4 g of thiourea and

Sodium acetate water (1: 3) (4.3 g) was added and the mixture was stirred at 40 ° C for 1 hour. The reaction mixture was adjusted to pH 6.5 with cooling with a saturated aqueous solution of potassium carbonate and stirred for 30 minutes. The resulting crystals are filtered off, washed with water and then with diisopropyl ether and dried. Crystalline 2- (2-amino-4-thiazolyl) - (Z) -2- (n-propoxyimino) -acetic acid methyl ester, m.p. 115-116 ° C.

Analysis: Calculated for C ₉ H ₁₃ N ₃ O ₃ S: C, 44.43; H, 5.39; N, 17.27 _; Found: C, 44.20; H, 5.38; N, 17.11.

Similarly prepared 2- (2-amino-4-thiazolyl) - (Z) -2- (n-butoxyimino) -acetic acid methyl ester, m.p. 118 DEG C., and 2- (2-amino- 4-Thiazolyl) - (Z) -2- (benzyloxyimino) -acetic acid methyl ester, m.p. 148-149 ° C.

32. Reference Example

To a solution of 5.0 g of 2- (2-amino-4-thiazolyl) - (Z) -2- (n-propoxyimino) -acetacetic acid methyl ester in 35 ml of Ν, Ν-dimethylacetamide was added ice-cooling and stirring. during 10 minutes

3.25 g of chloroacetic acid are added dropwise. After stirring at room temperature for 1 hour, the mixture was poured into 200 ml of ice-water, whereupon an oily precipitate formed which was allowed to crystallize. The crystals were filtered off, washed with water and dried to give 6.35 g (96.7%) of 2- [2- (chloroacetamido) -4-thiazolyl] - (Z) -2- (n-propoxyimino) -acetic acid. methyl ester, m.p. 100 ° C.

Analytical results for C 1, H ₁₄ C ₁ N ₃ O ₄ S:

Calculated: C, 41.31; H, 4.41; N, 13.14. Found: C, 41.35; H, 4.34; N, 13.14.

In a similar manner, 2- [2- (chloroacetamido) -4-thiazolyl] - (Z) -2- (n-butoxylamine) was prepared.

-51194870

101- (N) -acetacetic acid methyl ester - m.p. 86-87 ° C - 85%; and 2- [2- (chloroacetamido) -4-thiazolyl] - (Z) -2- (benzite). oxyimino) -acetic acid methyl ester, m.p. 110-115 ° C in 96% yield.

33. Reference Example

A solution of 3.2 g of 2- [2- (chloroacetamido) -4-thiazolyl] - (Z) -2- (n-propoxyimino) acetic acid in 50 ml of ethanol was added under ice-cooling and stirring. A solution of 85% potassium hydroxide (2.23 g) in water (20 ml) was added and the mixture was stirred at room temperature for 5 hours and then concentrated in vacuo. The residue was dissolved in water (30 mL) and the solution was washed with ethyl acetate (2 x 30 mL) and charcoal was added. The activated carbon was filtered off and the filtrate was adjusted to pH 2 with 1N hydrochloric acid. The resulting crystals are filtered off, washed with water, then with hexane and then with diethyl ether. There was thus obtained 2- [2- (chloroacetamido) -4-thiazolyl] - (Z) -2- (n-propoxyimino) -acetic acid, m.p. 170-171 ° C (dec.).

Analytical results for C ₁₀ H ₁₂ ClN ₃ O ₄ S:

Found: C, 39.28; H, 3.96; N, 13.74 _. Found: C, 39.34; H, 3.84; N, 13.41.

Similarly prepared 2- [2- (chloroacetamido) -4-thiazolyl] - (Z) -2- (n-butoxyimino) acetic acid, m.p. 167-168 ° C (dec.) And [2- (Chloroacetamido) -4-thiazolyl] - (Z) -2- (benzyloxyimino) -acetic acid, m.p. 160-161 ° C (dec.).

34. Reference Example

To a suspension of 583 mg of 2- [2- (chloroacetamido) -4-thiazolyl] - (Z) -2- (ethoxyimino) acetic acid in 5 ml of methylene chloride was added ice-cooling with 243 mg of triethylamine, followed by

416.5 mg of phosphorus pentachloride were added and stirred for 30 minutes at room temperature. The methylene chloride is evaporated in vacuo and the residue is washed three times with hexane and then suspended in 7 ml of tetrahydrofuran. A solution of 216 mg of cis-3-amino-2-oxo-azetidine-4-carboxylic acid methyl ester and 308 mg of sodium bicarbonate in 4.2 ml of water is added dropwise to the suspension. The mixture was stirred at room temperature for 2 hours and then concentrated. To the residue was added water (20 mL) and the mixture was made slightly basic by addition of sodium bicarbonate. The resulting precipitate is filtered off, washed with aqueous sodium bicarbonate solution, then with water, then with hexane and finally with diethyl ether, and dried to give cis-3- {2- [2- (chloroacetamido) -4-thiazolyl]. 2- (Ethoxyimino) acetamido] -2-oxo azide in-4-carboxylic acid methyl ester (color isomer) is obtained. Mp 270-280 ° C (dec.).

Analytical results for C ₁₄ H ₁₆ ClN ₅ O ₆ S:

Found: C, 40.24; H, 3.86; N, 16.76 _. Found: C, 39.98; H, 3.80; N, 16.91.

102

We produce in a similar way:

CIS-3-2- [2- (chloroacetamido) -4-thiazolyl] -2- (n-propoxyimino) acetamido] -2-oxoazetidine-4-carboxylic acid methyl ester (color isomer) M.p. 260-270 ° C (dec.), Cis-3- {2- [2- (chloroacetamido) -4-thiazolyl] -2- (isopropoxyimino) acetamido] -2-oxoazetidine -4-Carboxylic acid methyl ester (color isomer) - m.p. 215-225 ° C (decomposed), cis-3-12- [2- (chloroacetamido) -4-thiazolyl] -2- (n- butoxyimino) acetamido] -2-oxoazetidine-4-carboxylic acid methyl ester (color isomer) - m.p. 275-280 ° C (dec.), cis-3- (2- [2- (chloro) -acetamido) -4-thiazolyl] -2- (benzyloxyimino) acetamido] -2-oxoazetidine-4-carboxylic acid methyl ester (color isomer) - m.p. 275-285 ° C (dec.) ), cis-3-12- [5- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido] -2-oxoazetidine-4-carboxylic acid methyl ester (color isomer) 215-220 ° C (dec.), Cis-3-12- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido] -2-oxoazetidine 4-Carboxylic acid n-butyl ester (color isomer) - m.p. 239 ° C (dec.) And trans-3-12- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido] -2-oxoazetidine-4-carboxylic acid; methyl ester (color isomer) m.p. 137-139 ° C

Analysis for C ₃ H ₁₄ C1N ₅ O ₆ S, CH ₃ OH Calcd:

Found: C, 38.57; H, 4.16; N, 16.07 _; Found: C, 38.93; H, 4.15; N, 16.04.

35. Reference Example

To a solution of 9.3 g of ethyl 2-amino-4-thiazolylacetic acid in 50 ml of Ν, Ν-dimethylacetamide was added under ice-cooling and stirring.

7.91 g of chloroacetyl chloride are added. After stirring at room temperature for 1 hour, water (300 ml) was added. The resulting crystals are filtered off and washed with water and then with diethyl ether. The crystals were dried over phosphorus pentachloride to give 12.1 g (92%) of [2- (dichloroacetamido) -4-thiazolyl] -acetic acid ethyl ester, m.p. 145-146 ° C.

Analysis results for CgHuCir ^ OjS:

Found: C, 41.14; H, 4.22; N, 10.66 _. Found: C, 41.16; H, 4.14; N, 10.86.

36. Reference Example

To a solution of potassium hydroxide (2.5 g) in water (10 ml) and ethanol (100 ml) was added 3.0 g of [2- (chloroacetamido) -4-thiazolyl] -acetic acid, [ester] and the mixture was stirred at room temperature for one hour. and evaporated in vacuo. Water (10 mL) was added to the residue, and the resulting solution was washed with ethyl acetate and adjusted to pH 2 with 10% hydrochloric acid. The resulting crystals were filtered off, washed with water and dried to give 2.2 g (84%) of [2- (chloroacetamido) -4-thiazolyl] acetic acid, m.p. 193-195 ° C.

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Analysis: Calculated for C ₇ H ₇ ClN ₂ O ₃ S: C, 35.83; H, 3.01; N, 11.94. Found: C, 36.00; H, 3.15; N, 12.24.

37. Reference Example

To a suspension of 1.41 g of [2- (chloroacetamido) -4-thiazolyl] acetic acid in 30 ml of methylene chloride under ice-cooling and stirring

1.5 g of phosphorus pentachloride are added. The mixture was stirred at room temperature for 40 minutes and then filtered. This gave 1.7 g (98%) of a colorless crystal, m.p. 123-125 ° C (dec.), which was the hydrochloride salt of the corresponding acid chloride.

IR (λmax,% cm '): 1780, 1712.

At the same time, a solution of cis, 3-amino-2-oxoazetidine-4-carboxylic acid methyl ester in 4 ml of water and 4 ml of tetrahydrofuran was stirred under ice-cooling and stirring with 840 mg of sodium hydrogencarbonate and 864 mg. The mixture was stirred at room temperature for 2 hours and evaporated to dryness in vacuo. To the residue was added water (5 mL), the precipitate was filtered off and washed with aqueous sodium bicarbonate solution, then water, hexane and finally diethyl ether. The product was dried to give cis-3- (2- [2- (chloroacetamido) -4-thiazolyl] acetamido} -2-oxoazetidine-4-carboxylic acid methyl ester, m.p.

120-122 ° C.

Analytical results for (CH.TINAS. 1 / 2H ₂ O:

Found: C, 38.97; H, 3.82; N, 15.15 _; Found: C, 39.01; H, 4.23; N, 15.40.

Reference Example 38 To a solution of 1- (n-butyl) -2,3-dioxopiperazine (g) in dry methylene chloride (10 mL) was added trimethyl chlorosilane (0.766 g). To the mixture was added 0.712 g of triethylamine under a stream of nitrogen at room temperature and stirred for one hour. The reaction mixture was then cooled to -30 ° C and 0.39 ml of trichloromethyl ester of chloroformate was added dropwise. The temperature of the mixture was gradually increased, stirred at room temperature for 30 minutes and then evaporated to dryness in vacuo.

To a suspension of 0.924 g of D- (2-thienyl) glycine in 20 ml of dry methylene chloride at the same time was added 1.28 g of trimethyl chlorosilane, followed by

Triethylamine (1.19 g) was added at room temperature and the mixture was stirred for one hour.

The reaction mixture was cooled to 0 ° C and the evaporation residue from the first reaction was added. The mixture was stirred at room temperature for 2 hours and dissolved in ethyl acetate. The solution was washed with water followed by aqueous sodium chloride and dried over anhydrous magnesium sulfate. The dried solution was concentrated in vacuo to give D-2- [4- (n-butyl) -2,3-dioxo-1-piperazinecarboxamidol] -2- (2-thienyl) -acetic acid as a solid.

104

IR 1715, 1510, 1180.

NMR spectrum _(CDCl3, ppm): 5.72 (1H, d, J = 6Hz, CHCOOH), 9.70 (1H, d, NH).

We produce in a similar way:

D-2- [4- (n-octyl) -2,3-dioxo-1-piperazinecarboxamido] -2 (2-thienyl) -acetic acid.

IR spectrum (vmax Xcní ^4): 3250, 1720; NMR spectrum (CDC1 _3, ppm): 5.72 (1H, d, J = 6Hz, CHCOOH), 9.75 (1H, d, J = 6 Hz, NH).

and D-2- [4- (n-butyl) -2,3-dioxo-1-piperazinecarboxamido] -2-phenylacetic acid.

IR spectrum (vmax cni'l: 1715. NMR spectrum (CDC1 _3, ppm): 5.40 (1H, d, J = 7Hz, CHCOOH), 7.22 (5H, s, Ph); 9.73 (1H, d, NH).

39. Reference Example

362 mg D-2- [4- (n-butyl) -2,3-dioxo-1-piperazinecarboxamido] -2-phenylacetic acid and 150 mg cis-3-amino-2-oxoazetidine-4 dicyclohexylcarbodiimide (236 mg) was added to a solution of methyl acid carbonate in dry N, N-dimethylformamide (3 ml) under ice-cooling. After stirring under nitrogen for 5 hours at room temperature, tetrahydrofuran was added and the resulting precipitate was filtered off. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica gel, 200 g; eluent: ethyl acetate: chloroform = 1: 1 followed by ethyl acetate: chloroform: methanol = 15: 15: 1) to give cis-3- as a diastereomeric mixture. D-2- [4- (n-butyl) -2,3-dioxo-1-piperazinecarboxamido] -2-phenylacetamido} -2-oxoazetidine-4-carboxylic acid methyl ester is obtained. In column chromatography, the first material to come down is arbitrarily called the beta form, and the subsequent material is called the alpha form.

1680th

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 3.12 (3H, s, COOCH ₃ ), 7.24 (5H, br.s, -Ph).

AI f 3.13 k

IR (λ max): 3295, 1780, 1720, 1680.

NMR spectrum _(CDCl3, ppm): 3.44 (3H, br, COOCHJ, 7.27 (5H, br.s, Ph).

We produce in a similar way:

Cis-3-1D-2- [4- (n-butyl) -2,3-dioxo-1-piperazinecarboxamido] -2- (2-thienyl) acetamido} -2-oxoazetidine-4-carboxylic acid methyl ester, beta form

IR (λmax * ¹ ): 3300, 1775, 1710, 1675.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 3.30 (3H, s, COOCH 3).

Alpha-form

IR 3300, 1780, 1720,

1680th

CIS-3-1D-2- [4- (n-octyl) -2,3-dioxo-1-piperazinecarboxamido] -2- (2-thienyl) acetamido} -2-oxoazetidine-4-carboxylic acid methyl ester,

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Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 3.31 (3H, s, COOCH ₃ ), 4.42 (1H, d, J = 5Hz, C ₄ -H).

Alpha-form

NMR (CDC1 _3, ppm): 3.45 (3H, s, COOCHJ, 4.40 (IH, d, J = 5Hz, _C4 -H).

and trans-3-D-2- [4- (n-octyl) -2,3-dioxo-1-piperazinecarboxamido] -2- (2-thienyl) acetamido} -2-oxoazetidine-4 carboxylic acid methyl ester.

Beta-form

IR (λ max): 3280, 2920, 1780, 1710, 1670.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 3.68 (3H, s, COOCH ₃ ), 4.15 (1H, d, J = 2Hz, C ₄ -H).

Alpha-form

The IR and NMR data are the same as the beta.

40. Reference Example

To a solution of 1.18 g of cis-3-amino-1- (2,4-dimethoxybenzyl) -2-oxoazetidine-4-carboxylic acid methyl ester in 5 ml of methylene chloride was added 2.7 ml of ice-cooling with stirring. propylene oxide was added and a solution of 0.83 ml of chloroformate 2,2,2-trichloroethyl ester in 1 ml of methylene chloride was added dropwise over 10 minutes. After stirring at room temperature for 30 minutes, the solvent was evaporated in vacuo to give a residue which crystallized. The crystals were washed with diethyl ether and dried to give 1.67 g (89%) of cis-1- (2,4-dimethoxybenzyl) -3- (2,2,2-trichloroethoxycarboxamide) -2 m.p. 135-136 ° C is obtained. m.p. 135-136 ° C. Analytical results for C, ₇ H ₁₉ CI ₃ N ₇ O:

Found: C, 43.51; H, 4.34; N, 6.34; Found: C, 43.64; H, 4.42; N, 6.16.

41. Reference Example

939 mg of methyl cis-1- (2,4-dimethoxybenzyl) -3- (2,2,2-trichloroethoxycarboxamide) -2-oxoazetidine-4-carboxylic acid. A solution of sodium borohydride (228 mg) in water (10 ml) was added to a solution of tetrahydrofuran (ml) in ice-cooling and stirring. The mixture was stirred under ice-cooling for 10 minutes and then at room temperature for 4.5 hours. Excess sodium borohydride was decomposed with acetic acid under ice-cooling and the solvent was evaporated in vacuo. A saturated aqueous solution of sodium chloride was added to the residue, followed by extraction with ethyl acetate. The extract was washed with 5% sodium bicarbonate, then with a saturated aqueous solution of sodium chloride, then with dilute hydrochloric acid, and then again with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography (30 g silica gel; eluent: ethyl acetate: chloroform = 2: 1). The eluate was evaporated

106 and diethyl ether was added to the residue. The resulting crystals were filtered off with cis -1,2,4-dimethoxybenzyl) -4- (hydroxymethyl) -3- (2,2,2-trichloroethoxycarboxamido) -2-oxoazetidine, m.p.

112-114 ° C.

Analytical results for C ₁₆ H ₁₉ Cl ₃ N ₂ O ₆ :

Found: C, 43.51; H, 4.34; N, 6.34; Found: C, 43.64; H, 4.42; N, 6.16.

42. Reference Example

To a solution of 340 mg cis-1- (2,4-dimethoxybenzyl) -4- (hydroxymethyl) -3- (2,2,2-trichloroethoxycarboxamido) -2-oxoazetidine in 3 ml pyridine under ice-cooling and stirring, 132 mg of methanesulfonyl chloride were added. After stirring for 50 minutes at room temperature, water and ethyl acetate were added and the pH was adjusted with dilute hydrochloric acid.

Set to 2. The organic layer was separated, washed with saturated aqueous sodium chloride solution, then with aqueous sodium bicarbonate solution, and finally again with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo; the residue crystallizes. Diethyl ether was added to the crystals and filtered. 375 mg (94%) of cis-1- (2,4-dimethoxybenzyl) -4- (methanesulfonyloxymethyl) -3- (2,2,2-trichloroethoxycarboxamido) -2-oxo Colorless crystals of azetidine, m.p. 139-140 ° C.

Analysis C H _{I7 2I} C1 ₃ N ₂ O ₈ S Found:

H, 4.07; N, 5.39 Found: C, 39.28 _; Found: C, 39.21; H, 4.16; N, 5.48.

43. Reference Example

8.32 g of cis-1- (2,4-dimethoxybenzyl) -4- (methanesulfonyloxymethyl) -3- (2,2,2-trichloroethoxycarboxamido) -2-oxoazetidine 450 ml of acetonitrile while stirring

A solution of 7.79 g of potassium persulfate and 4.70 g of dipotassium hydrogen phosphate in 180 ml of water is added dropwise under a stream of nitrogen at 85-90 ° C for a total of 20 minutes. The mixture was stirred at this temperature for a further 2.5 hours, then cooled and adjusted to pH 6-7 with dipotassium hydrogen phosphate. The reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography (270 g silica gel; eluent: 2: 1 ethyl acetate: hexane followed by ethyl acetate) to give cis-4- (methanesulfonyloxymethyl) -3- (2,2,2-trichloro colorless crystals of ethoxycarboxamido) -2-oxoazetidine, m.p. 85-86 ° C.

Analysis results for CgH ^ ClgNjOgS:

Calc'd: C, 26.00; H, 3.00; N, 7.58; Found: C, 26.15; H, 3.04; N, 7.62.

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44. Reference Example

For 130 ml of methyl ethyl ketone, 3.7 g of cis-4- (methanesulfonyloxymethyl) -3- (2,2,2-trichloroethoxycarboxamido) -2-oxoazetidine and 8.85 g of sodium are added. iodide was added and the mixture was heated under a stream of nitrogen for 3 hours. The reaction mixture was concentrated in vacuo, water and ethyl acetate were added to the residue and the mixture was shaken. The ethyl acetate layer was separated, washed with sodium sulfite and then with an aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo and the residue crystallized. The crystals were added with diethyl ether and filtered off with 3.56 g (88.6%) of cis-3- (2,2,2-trichloroethoxycarboxamido) -4- (iodomethyl) -2-oxo. colorless crystals of azetidine - op 152-154 ° C.

Analysis results for formula C ₇ H ₈ C _{1 3} IN ₂ O ₃ :

Found: C, 20.95; H, 2.01; N, 6.98; Found: C, 21.19; H, 2.06; N, 7.21.

45. Reference Example

To a solution of 3.21 g of cis-3- (2,2,2-trichloroethoxycarboxamido) -4- (iodomethyl) -2-oxoazetidine in 40 ml of Ν, Ν-dimethylformamide is added 0.78 g sodium azide was added and the mixture was stirred at room temperature for 43 hours, followed by another 260 mg of sodium azide. The mixture was stirred for another 12 hours at 35 ° C and then concentrated in vacuo. Ethyl acetate and water were added to the residue and the mixture was shaken. The ethyl acetate layer was separated, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography (150 g silica gel; eluent: ethyl acetate: hexane = 1: 1) to give cis-4- (azidomethyl) -3- (2,2,2-trichloroethoxy). colorless crystals of the carboxamido) -2-oxoazetidine, m.p. 93-95 ° C.

46. Reference Example

To a solution of 1.12 g of cis-4- (azidomethyl) -3- (2,2,2-trichloroethoxycarboxamido) -2-oxoazetidine in 35 ml of ethanol was added 560 mg of 5% palladium on carbon catalyst. and the mixture was stirred under a stream of hydrogen at room temperature and atmospheric pressure for 2 hours. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in a mixture of 10 ml of methylene chloride and 10 ml of N, N-dimethylacetamide and 2.45 ml of propylene oxide and 0.5 ml of acetyl chloride were added under ice-cooling and stirring. The mixture was stirred at room temperature for two hours and then concentrated in vacuo. To the residue was added 50 ml of a saturated aqueous solution of sodium chloride and the mixture was extracted with ethyl acetate: tetrahydrofuran (4: 1). The extract was washed with dilute hydrochloric acid, then with a saturated aqueous solution of sodium chloride, then with aqueous sodium bicarbonate solution, and finally with a saturated sodium chloride solution, and

Dry over 108 anhydrous magnesium sulfate. The solvent was evaporated in vacuo, hexane (40 mL) was added to the residue and the mixture was allowed to stand under cooling overnight. The resulting crystals were filtered off and washed with diethyl ether to give cis -4- (acetamidomethyl) -3- (2,2,2-trichloroethoxycarboxamido) -2-oxoazetidine, m.p. 178-180 ° C. . Analytical results for C ₉ H _{] 2} Cl ₃ N ₃ O ₄ :

Found: C, 32.50; H, 3.64; N, 12.63 _; Found: C, 32.83; H, 3.60; N, 12.79.

47. Reference Example

To a solution of 372 mg of cis-4- (acetamidomethyl) -3- (2,2,2-trichloroethoxycarboxamido) -2-oxoazetidine in 30 ml of tetrahydrofuran was added 3.0 g of activated zinc, followed by phosphoric acid. and potassium dihydrogen phosphate

Add 6 ml of a 1 N / L aqueous solution. After stirring for 8 hours at room temperature, tetrahydrofuran (30 ml) was added and the zinc filtered. The filtrate was concentrated in vacuo and to the residue was added water (15 mL) and ethyl acetate (20 mL). The mixture is shaken, and the aqueous phase is separated off under vacuum

Evaporate to a volume of II ml. To the residue was added tetrahydrofuran (11 mL), and with cooling with ice, 282 mg of sodium bicarbonate, followed by 559 mg of

2- [2- (Chloroacetamido) -4-thiazolyl] - (Z) -2- (methoxyimino) acetyl chloride is added. After stirring for 1 hour under ice-cooling, 2 g of sodium bicarbonate and a saturated aqueous solution of sodium chloride are added and the mixture is extracted with ethyl acetate and tetrahydrofuran. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvents were evaporated in vacuo and the residue crystallized. The crystals were added to a mixture of ethyl acetate and diethyl ether and filtered to give cis-4- (acetamidomethyl) -3- {2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxy) colorless crystals of imino) -acetamido} -2-oxo-azetidine (color isomer), which do not have a definite melting point but decompose in the color range between 140 and 165 ° C.

IR (cm -1): 3380, 3250, 1760, 1660.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.73 (3H, s, COCH ₃ ), 3.6-4.0 (1H, m, C ₄ -H), 3.90 (3H, s, OCH ₃ ), 4.33 (2H, s, C ₁ H ₂ ), 5.16 (1H, q, J = 5Hz, 9Hz C ₃ -H), 7.46 (1H, s, CV).

Reference Example 48 Cis-3- (benzyloxycarboxamido) -1- (2,4-dimethoxybenzyl) -4- (hydroxymethyl) -2-oxoazetidine (1.0 g) was dissolved in tetrahydrofuran (ml). mg of triphenylphosphine and 441 mg of phthalimide. To the solution was added 0.471 ml of azodicarboxylic acid 55

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diethyl ester was added and the mixture was stirred at room temperature for one hour and then concentrated in vacuo. The residue crystallizes. To the crystalline residue was added ethyl acetate (30 mL) and the precipitate was filtered off and washed with ethyl acetate. Colorless crystals of cis-3- (benzyloxycarboxamido) -1- (2,4-dimethoxybenzyl) -4- (phthalimidomethyl) -2-oxoazetidine (882 mg) were obtained. The mother liquor and the washings were combined and purified by silica gel column chromatography to give an additional 280 mg of colorless crystals. Total yield 1.16 g (87.8%), m.p. 182-184 ° C.

Analysis: Calculated for C ₂₉ H ₂₇ N ₃ O ₇ : C, 65.11; H, 5.20; N, 7.85; Found: C, 65.05; H, 5.17; N, 7.80.

49. Reference Example

To a suspension of 1.059 g of cis-3- (benzyloxycarboxamido) -1- (2,4-dimethoxybenzyl) -4- (phthalimidomethyl) -2-oxoazetidine in 80 ml of ethanol was added 0.39 ml of hydrazine. hydrate was added and the mixture was refluxed for 3.5 hours. The reaction mixture was cooled and the resulting crystals were filtered off. The filtrate was concentrated in vacuo, methylene chloride (30 mL) was added to the residue and the precipitate was filtered off. The filtrate was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo and the residue was dissolved in a mixture of methylene chloride (10 ml) and N, N-dimethylacetamide (5 ml). The solution was cooled with ice

Propylene oxide (1.4 ml) was added followed by acetyl chloride (0.28 ml). After stirring for one hour at room temperature, methylene chloride (10 ml) and aqueous sodium bicarbonate (50 ml) were added and the mixture was shaken. The methylene chloride layer was separated, washed with water, dilute hydrochloric acid, and finally with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography (100 g silica gel, eluent: chloroform: acetonitrile 4: 1 then 3: 2). The eluate was concentrated in vacuo and the residue was treated with ethyl acetate / diethyl ether (1: 3). The resulting crystals were filtered off with cis-4- (acetamidomethyl) -3- (benzyloxycarboxamido) -1- (2,4-dimethoxybenzyl) -2-oxoazetidine, m.p. 195-196 ° C. - we get. Analysis: Calculated for C ₂₃ H ₂₇ N ₃ O ₆ : C, 62.57; H, 6.16; N, 5.92; Found: C, 62.20; H, 6.08; N, 9.41.

Similar preparation of cis-3- (benzyloxycarboxamido) -4- (benzamidomethyl) -1- (2,4-dimethoxybenzyl) -2-oxoazetidine, m.p. 112-115 ° C. too.

50. Reference Example

To a suspension of 1.104 g of cis -4-acetamidomethyl-3- (benzyloxycarboxamido) -1- (2,4-dimethoxybenzyl) -2-oxoazetidine in 65 ml of acetonitrile was added 1.081 g of potassium persulphate and 56

110

A solution of dipotassium hydrogen phosphate (653 mg) in water (25 mL) was added dropwise over 15 minutes under a stream of nitrogen while boiling. The reaction mixture was refluxed for one and a half hours, then neutralized by the addition of aqueous sodium bicarbonate and evaporated in vacuo. The residue was extracted with a 1: 1 mixture of ethyl acetate and tetrahydrofuran. The extract was washed with aqueous sodium bicarbonate followed by saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was evaporated and ethyl acetate was added to the residue. The resulting crystals were filtered off with cis-4- (acetamidomethyl) -3- (benzyloxycarboxamido) -2-oxoazetidine, m.p.

226-228 ° C. Similarly, cis-3- (benzyloxycarboxamido) -4- (benzamidomethyl) -2-oxoazetidine was also prepared, m.p. 209-21 ° C.

51. Reference Example

To a suspension of 364 mg of cis-4- (acetamidomethyl) -3- (benzyloxycarboxamido) -2-oxoazetidine in 80 ml of ethanol and 20 ml of methanol is added 364 mg of 5% palladium on carbon catalyst. The mixture is hydrogenated with stirring at ambient pressure and room temperature. The catalyst was then filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in 12 ml water and 12 ml of tetrahydrofuran a mixture of uranium ^r. Under ice-cooling and stirring, 315 mg of sodium hydrogencarbonate was added followed by 624 mg of the 2- [2- (chloroacetamido) -4-thiazolyl] - (Z) -2- (methoxyimino) acetyl chloride hydrochloride salt. After stirring for 1 hour under ice-cooling, aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution and a 2: 1 mixture of ethyl acetate and tetrahydrofuran were added. The mixture is shaken and the organic phase is separated. The aqueous phase was extracted four times with 2: 1 ethyl acetate: tetrahydrofuran. The organic phases are combined, washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvents were evaporated in vacuo and the residue crystallized. A 1: 2 mixture of ethyl acetate and diethyl ether was added to the crystals and the crystals were filtered off with cis -4-acetamidomethyl-3- {2- (2- (chloroacetamido) 4-thiazolyl) -2- (methoxy) Colorless crystals of -imino) -acetamido} -2-oxo-azetidine (color isomer) are obtained, which do not have a definite melting point, but decompose gradually during coloring in the temperature range 140 ° C to 165 ° C. Spectrum was identical with that of Reference Example 47. Prepared in a similar manner, cis -4- (benzamidomethyl) -3- {2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) -. acetamido} 2-oxoazetidine (color isomer), which does not have a definite melting point, but decomposes gradually during coloring in the temperature range of 130 ° C to 150 ° C.

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IR (λmax * δ): 3420, 3260, 1755, 1660.

Analysis results for Formula C, ₉ Hi ₉ C1N ₆ O ₅ S:

Found: C, 47.65; H, 4.00; N, 17.55 _; Found: C, 47.48; H, 3.86; N, 17.26.

52. Reference Example

557 mg of methyl cis-3- (benzyloxycarboxamido) -2-oxo-azetidine-4-carboxylic acid

To a solution of 2.6 ml of tetrahydrofuran is added, under ice-cooling and stirring, a solution of 189 mg of sodium borohydride in a volume of 1.3 ml. After stirring for 80 minutes under ice-cooling, the excess sodium borohydride was quenched with acetic acid and the tetrahydrofuran was evaporated in vacuo. A saturated aqueous solution of sodium chloride was added to the residue, followed by extraction with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (30 g silica gel, eluent: ethyl acetate: acetonitrile 4: 1) to give colorless crystals of cis-3- (benzyloxycarboxamido) -4- (hydroxymethyl) -2-oxoazetidine. Mp: 103-104 ° C.

Analysis C H _{I2 I4} N ₂ O _4: Calcd: C% = 57.59, H% = 5.64, N% = 11.19; Found: C, 57.32; H, 5.41; N, 11.12.

53. Reference Example

To a solution of cis-3- (benzyloxycarboxamido) -4- (hydroxymethyl) -2-oxoazetidine (250 mg) in ethanol (5 ml) was added palladium on carbon (5%, 250 mg) at room temperature and pressure. hydrogenate with stirring. The catalyst is then filtered off, the filtrate is concentrated in vacuo and the residue is allowed to crystallize under cooling. The crystals were collected by filtration to give 108 mg (93%) of cis-3-amino-4- (hydroxymethyl) -2-oxoazetidine, m.p. 105-407 ° C.

Calcd for C ₄ H ₈ N ₂ O _2: Calcd: C% = 41.37, H% = 6.94, N% = 24.12; Found: C, 41.40; H, 6.84; N, 23.86.

Reference Example 54. A solution of cis-3-amino-4- (hydroxymethyl) -2-oxoazetidine (mg) in methylene chloride (5 ml) and Ν, Ν-dimethylacetamide (1 ml) under ice-cooling and stirring (0.4 ml) triethylamine followed by 498 mg of 2- [2- (chloroacetamido) -4-thiazolyl] - (Z) -2- (methoxyimino) acetyl chloride hydrochloride salt. After stirring for 1 hour under ice-cooling, water (20 ml) was added and the pH adjusted to 7-8 by addition of sodium bicarbonate. The reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate / tetrahydrofuran (2: 1). The extract was saturated with aqueous sodium chloride

The solution was washed with a solution of 112, dried over anhydrous magnesium sulfate and evaporated in vacuo. To the crystallization residue is added a 1: 2 mixture of ethyl acetate and diethyl ether and the crystals are filtered off with cis-3- (2-12- (chloroacetamido) -4-thiazolyl) - (Z) -2- (methoxyimino). ) -acetamido} -4- {2- [2- (chloroacetamido) -4-thiazolyl] - (Z) -2- (methoxyimino) acetoxymethyl} -2-oxoazetidine - yellow crystals 157-159 ° C.

Analytical results for C ₂₀ H ₂₀ Cl ₂ N ₈ O ₈ S ₂ :

Found: C, 37.80; H, 3.17; N, 17.63 _; Found: C, 37.85; H, 3.27; N, 17.22.

Reference Example 55 Methyl Cis-1- (2,4-Dimethoxybenzyl) -3- (2,2,2-trichloroethoxycarboxamido) -2-oxoazetidine-4-carboxylic acid 20 ml A solution of 1.08 g of potassium persulphate and 716 mg of crystalline disodium hydrogen phosphate in 20 ml of water is added dropwise over 10 minutes to a solution of acetonitrile in acetonitrile. The mixture was refluxed for another 30 minutes, cooled and the acetonitrile evaporated in vacuo. The residue was extracted with ethyl acetate, and the extract was washed with 5% aqueous sodium bicarbonate solution and then with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (20 g silica gel; eluent: chloroform: ethyl acetate = 1: 2) to give cis-3- (2,2,2-trichloroethoxycarboxamido) -2-oxoazetidine-4-carboxylic acid. colorless crystals of methyl ester, m.p. 140-141 ° C. Analysis: Calculated for C ₈ H _g Cl ₃ N ₂ O ₅ : C, 30.07; H, 2.84; N, 8.77; Found: C, 30.30; H, 2.82; N, 8.87.

56. Reference Example

To a solution of 1.41 g of cis-3- (2,2,2-trichloroethoxycarboxamido) -2-oxoazetidine-4-carboxylic acid methyl ester in 40 ml of tetrahydrofuran was added 417 mg of sodium boron with ice-cooling and stirring. hydride is added in 20 ml of water. The mixture was stirred for 30 minutes under ice-cooling and then for one hour at room temperature and the tetrahydrofuran was evaporated in vacuo. The residue was dissolved in ethyl acetate and the solution was washed twice with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate and concentrated in vacuo. To the crystallization residue is added diethyl ether and the crystals are filtered off with cis-4- (hydroxymethyl) -3- (2,2,2-trichloroethoxycarboxamido) -2-oxoazetidine - m.p. 162-164 ° C. - we get.

IR (λ max cm -1): 3450, 3300. 1720, 1700.

57. Reference Example

To a solution of 2-thienylacetic acid (468 mg) in dry methylene chloride (7 mL) was added 424 mg of thionyl chloride and the mixture was stirred for two hours.

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113 boil. The reaction mixture was concentrated in vacuo and the residue was dissolved in dry methylene chloride (5 mL). At the same time, to a solution of cis-4- (hydroxymethyl) -3- (2,2,2-trichloroethoxycarboxamido) -2-oxoazetidine in 30 ml of dry methylene chloride was added 416 mg of triethylamine.

To this solution is added dropwise a solution of 2-thienylacetyl chloride in methylene chloride prepared under ice-cooling and stirring. The resulting mixture was stirred for 20 minutes under ice-cooling and then overnight at room temperature. Ethyl acetate was added to the reaction mixture, which was washed with 3N hydrochloric acid, then with aqueous sodium bicarbonate solution, and finally with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. Finally, the residue was purified by column chromatography (60 g silica gel; eluent: hexane: ethyl acetate = 1: 1 then 2: 3) to give cis-4 - [(2-thienyl) acetoxymethyl] -3- (2,2). (2-trichloroethoxycarboxamido) -2-oxoazetidine is obtained.

NMR spectrum _(CDCl3, ppm): 3.92 (2H, s, -CH ₂ COO-), 4.71 (2H, s,

CCl ₃ CH ₂ ), 5.14 (1H, dd, J = 5Hz, 9Hz, C ₃ -H), 6.10 (1H, d, J = 9Hz, -CH ₂ COO).

58. Reference Example

600 mg of cis -4-1 (2-thienyl) acetoxymethyl -3- (2,2,2-trichloroethoxycarboxamido) -2-oxoazetidine in 25 ml of tetrahydrofuran and 5 ml of 1N aqueous ammonium acetate 2.16 g of activated zinc are added to a solution of the mixture, and the resulting mixture is stirred at room temperature for 5 hours and then filtered over celite. Methylene chloride was added to the filtrate, dried over anhydrous magnesium sulfate, and then concentrated in vacuo. The residue was dissolved in a mixture of tetrahydrofuran (2 mL) and water (2 mL), and sodium bicarbonate (850 mg) was added under ice-cooling. To this mixture was added 720 mg of 2- [2- (chloroacetamido) -4-thiazolyl] - (Z) -2- (methoxyimino) acetyl chloride hydrochloride salt and vigorously stirred under ice-cooling for 15 minutes. . The reaction mixture was stirred at room temperature for an additional hour and then the solvent was evaporated in vacuo. Water was added to the residue, and the resulting crystals were filtered off, washed with water and then with aqueous sodium bicarbonate solution, then with diethyl ether and finally with hexane to give cis-3-12- [2- (chloroacetamido) -4-thiazolyl]. 2- (methoxyimino) acetamido-4 - [(2-thienyl) acetoxymethyl] -2-oxoazetidine (color isomer, m.p. 201-204 ° C) is obtained.

IR: 3280, 1760, 1660.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.86 (3H, s, OCH ₃ ), 3.90 (2H, s,

-CHjCOO), 4.32 (2H, s, C1CH _2);

7.48 (1H, s, CV).

114

59. Reference Example

To a solution of 1-methyl-1H-tetrazol-5-yl-mercaptan (314 mg) in dry Ν, Ν-dimethylformamide (ml) was added 65 mg of sodium hydride under ice-cooling and the mixture was ice-cooled for 10 minutes and then for 10 minutes. stirring at room temperature. A solution of cis-3- (2,2,2-trichloroethoxy carboxamido) -4- (iodomethyl) -2-oxoazetidine (724 mg) in készült, Ν-dimethylformamide (724 mg) was then added. The resulting mixture was stirred at room temperature for 2 days, then dissolved in ethyl acetate, washed 5 times with water, then with aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (60 g silica gel; eluent: hexane: ethyl acetate = 1: 2 then 1: 4) to give cis-4- (1-methyl-1H-tetazol-5-yl) 610 mg (86.8%). Crystals of 1-thiomethyl) -3- (2,2,2-trichloroethoxycarboxamido) -2-oxoazetidine, m.p. 67-69 ° C.

IR (ν ^K X cm -1): 3300, 1740.

Reference Example 50 To tetrahydrofuran (ml) was added 1.49 ml of a 4N solution of methylthiol in tetrahydrofuran, followed by dropwise addition of 1.37 ml of a 1.6 N solution of n-butyllithium in hexane under ice-cooling. The mixture was stirred under a stream of nitrogen under ice-cooling for 10 minutes, then cooled to -45 ° C and 800 mg of cis-3- (2,2,2-trichloroethoxycarboxamido) -4- (iodine). methyl) -2-oxoazetidine in 5 ml of tetrahydrofuran was added dropwise. The temperature of the reaction mixture was gradually raised to -3 ° C to -20 ° C with stirring for 4 hours. The mixture was dissolved in ethyl acetate and a saturated aqueous solution of ammonium chloride was added and stirred. The organic layer was separated, washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (100 g silica gel; eluent: hexane: ethyl acetate = 2: 1 then 1: 1) to give cis-4-methylthiomethyl) -3- (2,2,2-tetrichloride). crystals of ethoxycarboxamido) -2-oxoazetidine, m.p. 114-115 ° C.

IR (3350, 1780, 1715).

61. Reference example

Cis-4- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3- (2,2,2-trichloroethoxycarboxamido) -2-oxoazetidine (674 mg) was prepared in tetrahydrofuran (10 ml). To this solution was added 2 ml of 1N aqueous ammonium acetate solution, then 1 g of activated zinc and stirred for 3 hours at room temperature and filtered. Methylene chloride was added to the filtrate, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was dissolved in a mixture of tetrahydrofuran (3 mL) and water (3 mL) and treated with sodium bicarbonate (1.02 g) under ice-cooling.

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115 to it. To the resulting mixture was added 863 mg of 2- [2- (chloroacetamido) -4-thiazolyl] - (Z) -2- (methoxyimino) acetyl chloride hydrochloride salt, followed by ice-cooling for 15 minutes, and then stirred at room temperature for one hour. The solvent was evaporated in vacuo and water was added to the residue. The resulting crystals were filtered off, washed with water followed by aqueous sodium bicarbonate, then with diethyl ether and finally with hexane to give cis-3- (2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) Crystals of -acetamido} -4- (1-methyl-1H-tetrazol-5-ylthiomethyl) -2-oxoazetidine (color isomer), m.p. 195-198 ° C (dec.).

IR spectrum (vmax, ^cw-1): 3270, 1760, 1660th

In a similar manner, cis-3- (2-12- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido} -4- (methylthiomethyl) -2-oxoazetidine (colorless) was prepared. -isomer) - mp 172-176 ° C (dec.).

62. Reference example

1.0 g of cis-3- (benzyloxycarboxamido) -1- (2,4-dimethoxybenzyl) -4- (methanesulfonyloxymethyl) -2-oxoazetidine, 50 ml of methyl ethyl 1.88 g of sodium iodide are added to a suspension of ketone. The mixture was heated at 90 ° C for 6 hours and the solvent was evaporated in vacuo. Ethyl acetate (150 mL) and water (100 mL) were added to the residue, followed by shaking. The ethyl acetate layer was separated, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting solid residue was recrystallized from 50 mL of a 1: 1 mixture of hexane and ethyl acetate to give 850 mg (80%) of cis-3- (benzyloxycarboxamido) -1- (2,4-dimethoxy) as colorless needles. benzyl) -4- (iodomethyl) -2-oxoazetidine, m.p. 165-166 ° C.

Analysis: Calculated for C ₂₁ H ₂₃ IN ₂ O ₅ : C, 49.43; H, 4.54; N, 5.49. Found: C, 49.55; H, 4.56; N, 5.67

63. Reference Example

3.29 g of cis-3- (benzyloxycarboxamido) -1- (2,4-dimethoxybenzyl) -4- (iodomethyl) -2-oxoazetidine in 10 ml of hexamethylphosphoric triamide 1.62 g of sodium cyanoborohydride are added and the mixture is stirred under a stream of nitrogen at 90-100 ° C for 5 hours. To the reaction mixture was added diethyl ether (250 mL), washed once with water (6 x 20 mL), brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Diethyl ether and hexane were added to the solid residue after filtration

2.15 g (86.7%) of cis-3- (benzyloxycarboxamido) -1- (2,4-dimethoxybenzyl) -4-methyl-2-oxoazetidine - m.p. 130-132 ° C - we get.

Analysis: Calculated for C ₂₁ H ₂₄ N ₂ O ₅ : C, 65.61; H, 6.29; N, 7.29; Found: C, 65.23; H, 6.49; N, 7.53.

116

64. Reference Example

5.10 g of 2,4-dimethoxybenzylamine hydrochloric acid salt are added to an aqueous solution of potassium carbonate and the resulting oily product is extracted with 120 ml of benzene. The extract was washed with water and dried over anhydrous sodium sulfate, followed by addition of 3.50 g of p-chlorobenzaldehyde. The mixture is heated to reflux for one hour. The solvent was evaporated and the crystals which crystallized out were dissolved in methylene chloride (68 ml). To the resulting solution is added 3.8 ml of a solution of triethylamine in 20 ml of methylene chloride with stirring at -5 to -10 ° C, and a solution of 6.15 g of phthalimidoacetyl chloride in 25 ml of methylene chloride is added dropwise. into it. After 20 minutes, a solution of triethylamine (1.9 ml) in methylene chloride (10 ml) was added, followed by a solution of phthalimidoacetyl chloride (3.1 g) in methylene chloride (13 ml). The resulting mixture was stirred under ice-cooling for 7 hours, allowed to stand overnight under cooling, and then washed with water followed by aqueous sodium bicarbonate solution, 5% hydrochloric acid, water, dried over anhydrous sodium sulfate and dried over anhydrous sodium sulfate. evaporate in vacuo. The residue was purified by column chromatography (60 g silica gel; eluent: chloroform: methanol = 20: 1) to give 9.4 g (84%) of cis -4- (4-chlorophenyl) -1- (2,4-dimethoxybenzyl). ) - 3-phthalimido-2-oxoazetidine is obtained in the form of colorless crystals. Recrystallization from a mixture of acetone and hexane yields 1 colorless prismic crystals, m.p. 178-180 ° C.

Analysis for C ₂₆ H _2I C1N ₂ O ₅ Calcd:

Found: C, 65.46; H, 4.44; N, 5.87. Found: C, 65.42; H, 4.42; N, 5.90.

Reference Example 65: To a solution of cis-4- (4-chlorophenyl) -1- (2,4-dimethoxybenzyl) -3-phthalimido-2-oxoazetidine g in 50 ml of methylene chloride, 0.89 ml of methylhydrazine are obtained. We are added. The mixture was stirred at 35-40 ° C for 17 hours, then filtered and the filtrate was concentrated in vacuo. Ethyl acetate was added to the residue and the resulting precipitate was filtered off. The approx. The filtrate (100 ml) was extracted with a mixture of 30 ml of water and 10 ml of 10% hydrochloric acid. The extract was neutralized with aqueous sodium bicarbonate solution and extracted twice with methylene chloride. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue (2.6 g) was dissolved in methylene chloride (30 mL), and propylene oxide (5.5 mL) and benzyloxycarbonyl chloride (5.5 g) were added dropwise under ice-cooling and stirring. The mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. Hexane was added to the residue and the resulting crystals were filtered off. The crystals were washed with diisopropyl ether to give 3.31 g (81%) of cis-3- (benzyloxycarboxamido) -4- (4-chloroph

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117 Nyl) -1- (2,4-dimethoxybenzyl) -2-oxoazetidine was obtained.

IR (λ max) 3325, 1759, 1688.

NMR (CDC1 ₃ ppm): 3,59-

3.77 (2x3H, 2.times.s, ₂ x OCH3), 4.70 (IH, d, J = 5Hz, _C4 -H), 5.20 (lH, d, J = 5Hz, 9Hz, _C3 - H), 5.82 (1H, d, J = 9Hz, NH).

66. Reference example

2.15 g of cis-3- (benzyloxycarboxamido) -1- (2,4-dimethoxybenzyl) -4-methyl-2-oxoazetidine

To a solution of 150 ml of acetonitrile was added dropwise a solution of 2.42 g of potassium persulfate and 1.46 g of dipotassium hydrogen phosphate in 75 ml of water at 90-100 ° C. The mixture was refluxed at this temperature for 1.5 hours and the acetonitrile was evaporated in vacuo. Ethyl acetate and water were added to the residue, followed by shaking. The ethyl acetate layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (200 g silica gel; eluent: hexane: ethyl acetate = 1: 2) to give crystals of cis-3- (benzyloxycarboxamido) -4-methyl-2-oxoazetidine, m.p.

169 ° C.

Analysis: Calculated for C ₁₂ H ₁₄ N ₂ O ₃ : C, 61.53; H, 6.02; N, 11.96 Found: C, 61.36; H, 6.05. N, 11.65

Similarly, cis-3- (benzyloxycarboxamido) -4- (4-chlorophenyl) -2-oxoazetidine was prepared.

IR (<*> + '): 3310, 3225, 1772, 1722, 1684.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 4.85 (2H, s, CH ₂ ), 7.74 (1H, d, J = 9Hz, -OOCNH-), 8.55 (1H, br, .s, N, -H), 6.90-7.50 (9H, aromatic protons).

67. Reference Example

To a suspension of 210 mg of cis-3- (benzyloxycarboxamido) -4-methyl-2-oxoazetidine in 10 ml of ethanol was added 210 mg of 5% palladium on carbon and the mixture was stirred under a stream of hydrogen for 1 hour. The catalyst was filtered off and the filtrate was evaporated. The residue crystallizes (p. 111 -

112 ° C). To the crystals were added 1 ml of water and 1 ml of tetrahydrofuran, followed by 382 mg of sodium bicarbonate under ice-cooling. 2- [2- (Chloroacetamido) -4-thiazolyl] - (Z) -2- (methoxyimino) acetyl chloride (453 mg) was added with vigorous stirring. The reaction mixture was stirred under ice-cooling for 15 minutes and then at room temperature for one hour and then concentrated in vacuo. Water was added to the residue, and the resulting precipitate was filtered, washed with water, aqueous sodium bicarbonate, then with diethyl ether, and finally with hexane to give cis-3-12- [2- (chloro) (276 mg, 84%). -acetamido) -4-thiazolyl] -2- (methoxyimino) acetamido} -4-methyl-1-2-oxo60

118

azetidine (color isomer) is obtained in the form of crystals. Mp 212-215 ° C (dec.).

IR spectrum (λmax *); 3260, 1745, 1670.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.16 (3H, d, J = 6Hz, C ₄ -CH ₃ ), 3.90 (3H, s, OCH ₃ ), 4.36 (2H, s, C1CH _2), 5.15 (IH, dd, J = 5Hz, 9Hz, _C3 -H),

7.40 (1H, s, CV).

In a similar manner, cis-3- {2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido} -4- (4-chlorophenyl) -2-oxo- azetidine (also color isomer).

IR (λ max): 3250, 1740, 1652.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.66 (3H, s, OCH ₃ ), 4.30 (2H, s, ClCH ₂ ),

4.96 (IH, d, J = 5Hz, _C4 -H), 5.39 (IH, dd, J = 5Hz, 9Hz), 5.82 (lH, s, a group of formula CV), 9 , 24 (1H, d, J = 9Hz, C ₃ -NH).

68. Reference Example

To a solution of 1.4 g of cis-3- (benzyloxycarboxamido) -2-oxoazetidine-4-carboxylic acid methyl ester in 14 ml of methanol is added dropwise a solution of 0.9 g of potassium carbonate in 9 ml of water under ice-cooling. . The mixture was stirred at room temperature for one hour and then methanol was evaporated. The remaining aqueous solution was washed with ethyl acetate and neutralized with dilute hydrochloric acid. This solution was extracted with ethyl acetate, and the extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue crystallizes. Addition of ethyl acetate to the crystals followed by filtration gave 1.1 g (84.6%) of cis-3- (benzyloxycarboxamido) -2-oxo-azetide in-4-carboxylic acid, the crystals of which were crystallized from acetonitrile. . 156-157 ° C. Analysis for C ₁₂ H ₁₂ N ₂ O _5: Calc:% C 54.54% H 4.57% N 10.60% Found: C = 54.55% H = 4.45 N, 10.77

69. Reference Example

To a dry solution of cis-3- (benzyloxycarboxamido) -2-oxoazetidine-4-carboxylic acid (1.32 g) in dry tetrahydrofuran is added 4 g of dicyclohexylcarbodiimide. After 10 minutes, 0.5 ml of a 40% aqueous solution of dimethylamine is added. After stirring for 2 hours at room temperature, the reaction mixture was filtered and the filtrate was concentrated in vacuo. Ethyl acetate and aqueous sodium bicarbonate solution were added to the residue and the resulting mixture was shaken. The ethyl acetate layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give crystals of cis-3- (benzyloxycarboxamido) -4- (N, N-dimethylcarbanoyl) -2-oxoazetidine.

IR (λmax) 3280, 1785, 1770, 1730, 1690, 1640.

-60194870

119

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 2.77,

2.80 (2x3H, 2.times.s, 2 x CH _3), 4.53 (1H, d, J = 5Hz, _C4 -H), 5.36 (1H, dd, J = 5Hz, 9Hz, _C3 -H ).

70. Reference Example

To a solution of cis-3- (benzyloxycarboxamido) -4- (-, Ν-dimethylcarbamoyl) -2-oxoazetidine (291 mg) in methanol (10 mL) was added 5% palladium on carbon (291 mg) and the the mixture was hydrogenated under normal pressure at room temperature for two hours. The catalyst was filtered off and the filtrate evaporated to give cis-3-amino-4- (N, N-dimethylcarbamoyl) -2-oxoazetidine (141 mg, 90%) as colorless crystals. This product is reacted with cis-3- {2- [2- [2- (chloroacetamido) -4-thiazolyl] - (Z) -2- (methoxyimino) acetyl chloride as in Reference Example 34. Crystals of 2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido) -4- (Ν, Ν-dimethylcarbamoyl) -2-oxoazetidine, m.p.

160-165 ° C - Rap.

IR spectrum (vmax ^cm-4): 3200, 1760, 1640th

71. Reference example

A mixture of 288 mg of methyl cis-3-amino-2-oxoazetidine-4-carboxylic acid, 10 ml of tetrahydrofuran and 5 ml of 1 N sodium bicarbonate solution was stirred under ice-cooling and 0.32 ml of 2-thienyl Acetyl chloride solution in tetrahydrofuran (10 ml) was added dropwise. The resulting mixture was stirred for 10 minutes, then ethyl acetate (100 mL) and saturated sodium chloride solution (20 mL) were added and the mixture was stirred and the organic layer was separated. The aqueous phase is extracted with 30 ml of ethyl acetate and the extract is combined with the former organic phase. The resulting ethyl acetate extract was washed with saturated aqueous sodium chloride solution (3 x 20 mL), dried and concentrated in vacuo. To the residue was added 4 mL of a 1: 2 mixture of ethyl acetate and hexane, and the resulting crystals were filtered and dried to give 430 mg (80%) of cis-3- (2-thienylacetpmido) -2-oxoazetidine. Methyl 4-carboxylic acid, m.p. 133-136 ° C.

Analysis for C ,, H ₁₂ N ₂ O ₄ S: Calcd: C% = 49.43, H% = 4.15, N = 10.48%, found: C% = 49.00, H% = 4.37, N% = 10.20.

72. Reference example

288 mg cis ^; A mixture of 3-amino-2-oxo-azetidine-4-carboxylic acid methyl ester, 4 ml of propylene oxide and 3 ml of Ν, Ν-dimethylacetamide was stirred under ice-cooling and 400 mg of 1H-tetrazol-1-yl acetyl chloride is added dropwise. After stirring for 30 minutes, diethyl ether (50 ml) was added, the mixture was stirred at -30 ° C and the upper layer was decanted. With the lower phase, the same procedure is repeated twice, and then 10 ml of acetone are added. The resulting solution was purified by column chromatography (40 g silica gel; 3 x 10 cm)

120 columns; eluent: 1: 1 acetone / methylene chloride) and evaporating the eluate to give cis-3- (1H-tetrazol-1-yl-acetamido) -2-oxo-azetidine-4-carboxylic acid (403 mg, 84%). methyl ester.

Analysis results for C ₈ H ₁₀ N ₆ O ₄ . 2/3 CH ₃ COCH _3: Calcd: C% = 41.00, H% = 4.82, N% = 28.69; Found: C, 41.16; H, 5.08; N, 28.65.

73. Reference Example

A mixture of 696.7 mg of nalidixic acid and 10 ml of methylene chloride was stirred at room temperature and then 2 ml of thionyl chloride was added. The reaction mixture was stirred for one hour, then evaporated to dryness in vacuo and the residue dissolved in 5 ml of N, N-dimethylacetamide. A mixture of 288 mg of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester, 6 ml of propylene oxide and 3 ml of Ν, Ν-dimethylacetamide was stirred under ice-cooling, and the Ν 5 ml of a solution in Ν-dimethylacetamide. The resulting mixture was stirred at room temperature for two hours, the resulting precipitate was removed by vacuum filtration and the filtrate was shaken with a mixture of ethyl acetate (100 mL) and water (200 mL). The organic layer was separated, washed with brine (3 x 50 mL), dried and evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography to give cis-3- (1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridin-3-ylcarbonylamino) 2-oxoazetidine-4-carboxylic acid. methyl ester -

mp 223-224 ° C.

IR (w ·?): 3400, 1780, 1765, 1745.

74. Reference Example

To a solution of 288 mg of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester in 2 ml of N, N-dimethylacetamide was added 534 mg of mandelic anhydride after stirring under ice-cooling, and and stirred at room temperature for 30 minutes. After stirring under ice-cooling, 1.05 ml of chloroacetyl chloride was added dropwise and stirring was continued at room temperature for 3 hours. The reaction mixture was shaken with 100 mL of ethyl acetate and 20 mL of 1N hydrochloric acid. The organic layer was separated, washed with brine (3 x 30 mL), 1N aqueous sodium bicarbonate (20 mL), and brine (3 x 30 mL), then dried and concentrated in vacuo. The residue was purified by silica gel column chromatography to give cis-3- [2- (chloroacetoxy) -2-phenylacetamido] -2-oxoazetidine-4-carboxylic acid methyl ester.

IR spectrum (ν "α" οί ^1): 3300, 1760, 1695, 1530, 1220, 1160, 740, 700th

75. Reference Example

288 mg methyl cis-3-amino-2-oxoazetidine-4-carboxylic acid, 1 ml tetrahydrofuran, 61

-61194870

A mixture of 121 ml of water and 15 ml of 1N aqueous sodium bicarbonate solution was stirred under ice-cooling, followed by the dropwise addition of 469 mg of Da-sulfophenylacetyl chloride, followed by ice-cooling for 10 minutes, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residue was dissolved in water (5 mL). The aqueous solution was purified by column chromatography on Amberlite XAD-Ιζ followed by Sephadex LH-20 and freeze-dried the eluate to give cis-3- (D-2-sulfo-2-phenylacetamido) -2-oxo-azetidine-4-carboxylic acid methyl. yields the sodium salt of the ester.

Analysis for C, _3H ,, NnNaO ₇ S, 3 / 2H ₂ O:

Found: C, 39.90; H, 4.12; N, 7.16; Found: C, 39.78; H, 4.48; N, 7.29.

76. Reference example

After stirring for 16 hours at room temperature, 2.7 g of phenyl malonic acid monobenzyl ester and 5 ml of thionyl chloride are added, and the residue is made up to 10 ml with methylene chloride. A mixture of methyl cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester (288 mg), triethylamine (0.42 ml) and methylene chloride (10 ml) was stirred under ice-cooling and added dropwise to a mixture of methylene chloride prepared previously. 3 ml. The reaction mixture was stirred for 3 hours, then concentrated in vacuo. The residue is shaken with a mixture of 200 ml of ethyl acetate and 30 ml of water. The organic layer was separated, washed with brine (3 x 30 mL), 1N hydrochloric acid (20 mL), brine (2 x 20 mL), then dried and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent: ethyl acetate: methylene chloride = 1: 1) to give cis-3- [2- (benzyloxycarbonyl) -2-phenylacetamido] -2-oxoazetidine-4. methyl carboxylic acid is obtained.

IR: 3300, 1780, 1740, 1690, 1530, 1270, 1210, 1160.

77. Reference Example

400 mg of cis-3- (benzyloxycarboxamide-2-oxo-azetidine-4-carboxylic acid methyl ester) were prepared in a similar manner as in Reference Example 3 and dissolved in 15 ml of tetrahydrofuran. To the solution was added 120 mg of cyanoacetic acid and stirred under ice-cooling, 290 mg of dicyclohexylcarbodiimide were added, followed by stirring at room temperature for 2 hours, the reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (20 g silica gel; eluent: ethyl acetate) to give methyl cis-3- (2-cyanoacetamido-2-oxoazetidine-4-carboxylic acid).

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IR (ν max): 3300, 2250, 1758, 1680.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm) 3.60 (2H, s, CH ₂ ), 3.67 (3H, s, CH ₃ ),

4.39 (1H, d, J = 6Hz, C ₄ -H), 5.28 (1H, dd, J = 6Hz, 9Hz, C ₃ -H).

78. Reference Example

808 mg of methyl cis-3-12-12- (chloroacetamido) -4-thiazolyl] -2-methoxyiminoacetamido-2-oxoazetidine-4-carboxylic acid (color isomer). A solution of 552 mg of potassium carbonate in 12 ml of water is added dropwise to a suspension of methanol in methanol under ice-cooling. After stirring at room temperature for 1 hour, 6 ml of 1N hydrochloric acid was added and the methanol was evaporated. The remaining aqueous mixture was washed with ethyl acetate, adjusted to pH 2 with dilute hydrochloric acid, and extracted with ethyl acetate: tetrahydrofuran (1: 2). The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was suspended in a mixture of methylene chloride (40 mL) and tetrahydrofuran (10 mL). Pyridine (1.0 mL) was added to the suspension with stirring at room temperature and a solution of p-nitrobenzyl (864 mg) in methylene chloride (4 mL) was added dropwise over 30 min. After stirring for 30 minutes at room temperature, the mixture was washed with water, dilute hydrochloric acid, water, water, sodium bicarbonate, and brine, then dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (100 g silica gel; eluent: ethyl acetate) to give cis-3- (2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido) -2-oxo. crystals of azetidine-4-carboxylic acid p-nitrobenzyl ester (color isomer) - op:

231-236 ° C (dec.) - obtained.

IR (λ max cm ^-1 ): 3250, 1760, 1750, 1670, 1550, 1510.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.83 (3H, sNOCH ₃ ), 4.33 (2H, s, CICH ₂ ),

4.58 (1H, d, J = 6Hz, C ₄ -H), 5.25 (2H, s, OCH ₂ Ar), 5.48 (1H, dd, J = 6Hz, 9Hz, C _3- H), 7.31 (1H, s, CV), 7.66 (2H, d, J = 9Hz, ArH), 8.17 (2H, d, J = 9Hz, ArH), 8.77 (1H, br.s, N, -H), 9.56 (1H, d, J = 9 Hz, C ₃ -NH), 12.87 (1H, br.s, CICH ₂ CONH).

79. Reference Example

In a mixture of 510 ml of dioxane and 42.6 ml of acetic acid, 53.2 g of [2- (chloroacetamido) -4-thiazolyl] acetic acid ethyl ester are dissolved, 28.3 g of selenium dioxide are added and the mixture is stirred for 4 hours. Stir at 110-115 ° C. After cooling, the resulting black precipitate was removed and the resulting solution was concentrated in vacuo. The residue was dissolved in 3 liters of ethyl acetate,

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This solution was washed twice with aqueous sodium bicarbonate solution, twice with water, then dried over anhydrous sodium sulfate and evaporated to a volume of 1 liter. This residue was heated to reflux until 800 mL of hexane was added and cooled. Ethyl 2- (chloroacetamido) -4-thiazolyl] -glyoxylic acid ethyl ester is obtained as yellow needles, m.p. 178-180 ° C after recrystallization from ethyl acetate-hexane.

IR (λmax * ¹ ): 3220, 3000, 1740, ^P 1710, 1680, 1550.

NMR spectrum (D ₆ -DMS0, ppm): 1.31 (3H, t, _{CH2 CH3),} 4.35 (2H, q, CH ₉ CH _3), 4.40 (2H, s, ₂ C1CH ), 8.49 (1H, s, CV).

Analytical results for C ₉ H ₉ C ₁ N ₂ O ₄ S:

Found: C, 39.07; H, 3.28; N, 10.12. Found: Q, 39.16; H, 3.21; N, 10.13.

80. Reference Example

35 g of [2- (chloroacetamido) -4-thiazolyl] -glyoxylic acid ethyl ester are suspended in 646 ml of ethanol and 250 ml of 1N aqueous sodium hydroxide solution are added dropwise under ice-cooling. The mixture was stirred at room temperature for one hour and then concentrated in vacuo to 200 ml. Water (200 mL) was added and the mixture was washed with ethyl acetate (400 mL). After clarification with activated charcoal, light yellow crystals are precipitated by adjusting the pH of the mixture to 1.5 with 10% hydrochloric acid. The crystals were filtered off, washed with water and then hexane and dried to give [2- (chloroacetamido) -4-thiazolyl] glyoxylic acid. Recrystallization from a mixture of ethyl acetate and hexane yields light yellow prismic crystals, m.p. 205-210 ° C (dec.).

IR (ν max ⁴ ) 3450, 3200,

1730-1690, 1680, 1560.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 4.29 (2H, s, CICH ₂ ), 8.30 (1H, s, CV).

Analysis: Calculated for C ₇ H ₅ ClN ₂ O ₄ S: C, 33.81; H, 2.03; N, 11.27. Found: C, 33.94; H, 2 , 04, N% = 11.23.

Reference Example 81 To 10 ml of dry N, N-dimethylformamide was added 10 g of N-hydroxyphthalimide, 9.38 g of methyl bromoacetate and 8.5 g of potassium carbonate. This mixture was stirred at room temperature for 2 days, then poured into 400 mL of water. The resulting crystalline precipitate was filtered off, washed with water, hexane and finally diethyl ether. Colorless needle crystals of N-methoxycarbonylmethyloxy-phthalimide, m.p. 137-142 ° C.

IR (λ max ¹ ): 1790, 1760, 1730.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm) 3.71 (3H, s, COOCH ₃ ), 4.8 (2H, s,

NOCH ₂ ), 7.77 (4H, s, aromatic protons).

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N- (p-nitrobenzyloxycarbonylmethyloxy) phthalimide, m.p. 158-160 ° C, was prepared in the same manner.

IR spectrum (vSXcwl ⁴ ): 1785, 1760, 1730.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 4.94 (2H, s, NOCH ₂ ), 5.32 (2H, s,

COOCH ₂ ),

Analysis results for C | Calculated for C ₇ H ₁₂ N ₂ O ₇ : C, 57.31; H, 3.40; N, 7.86; Found: C, 57.22; H, 3.32; N, 7.93.

82. Reference example

3.5 g of N-methoxycarbonylmethyloxy-phthalimide are dissolved in 60 ml of methylene chloride and 745 mg of hydrazine hydrate are added under ice-cooling and stirring. After stirring for two hours at room temperature, an additional 149 mg of hydrazine hydrate was added. The mixture was stirred for two hours and the resulting crystalline precipitate was filtered off. The filtrate was washed with dilute aqueous ammonia, then with 15 mL of water, dried over anhydrous sodium sulfate and evaporated. To the residue was added diethyl ether (10 mL) and the precipitate was filtered off. The filtrate was evaporated to give O-methoxycarbonylmethylhydroxylamine as a light yellow oil.

IR (β &gt;) ³³ 3320, 2950, 1740.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ + D ₆ -DMSO, ppm)

3.73 (3H, s, CH ₃ ), 4.2 (2H, s, CH ₂ ), 6.07 (2H, br.s, NH ₂ ).

O-p-nitrobenzyloxycarbonylmethylhydroxylamine is prepared in the same manner.

IR (CM: 3325, 1760, 1720, 1600).

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 4.33 (2H, s, NOCH ₂ ).

83. Reference Example

1.0 g of [2- (chloroacetamido) -4-thiazolyl] glyoxylic acid prepared in Reference Example 80 is dissolved in a mixture of 20 ml of water and 12 ml of tetrahydrofuran and then, under ice-cooling, 465 mg of 0- (methoxy) carbonylmethyl) hydroxylamine is added. The pH of the mixture was adjusted to 5 with 1 N aqueous sodium hydroxide solution. After stirring at room temperature for 20 hours, the reaction mixture was adjusted to pH 7 with aqueous sodium bicarbonate solution and then washed with ethyl acetate (2 x 15 mL). The aqueous phase was separated and adjusted to pH 2 with 2N hydrochloric acid. The resulting crystalline precipitate is filtered off, washed first with water, then with hexane and finally with diethyl ether. Colorless crystals of 2- [2- (chloroacetamido) -4-thiazolyl] - (Z) -2- (methoxycarbonylmethyloxyimino) acetic acid, m.p. 177-179 ° C (dec.) is obtained.

IR (viCcw ¹ ): 3200, 1750, 1725, 1690.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.69 (3H, sCOOCH ₃ ), 4.39, (2H, s, ClCH ₂ ), 4.71 (2H, s, NOCH ₂ ), 7.41

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125 (1H, s, CV), 12.7 (1H, br.s, NH).

2- [2- (Chloroacetamido-4-thiazolyl) - (Z) -2- (p-nitrobenzyloxycarbonylmethyl-oxyimino) -acetic acid, m.p. 168-170, was prepared in the same manner. ° C (dec.).

IR (λ max): 3200, 1760, 1710-1680, 1520.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 4.34 (2H, s, ClCH ₂ ), 4.84 (2H, s, NOCH ₂ )

5.33 (2H, s, COOCH _2), 7.48 (lH, s, a group of formula CV).

Analytical results for C, ₆ H ₁₃ ClN ₄ O ₈ S:

Found: C, 42.06; H, 2.87; N, 12.27 _; Found: C, 41.95; Η, 2.8β; N, 12.30.

84. Reference Example

810 mg of 2- [2- (chloroacetamido) -4-thiazolyl] - (Z) -2-methoxycarbonylmethyloxyimino) acetic acid was suspended in 20 ml of methylene chloride and stirred under ice-cooling and stirring. Phosphorus pentachloride (602 mg) was added. The mixture was stirred for 1 hour under ice-cooling and then for 30 minutes at room temperature, and then 30 ml of hexane were added under ice-cooling. The resulting crystals were filtered off and washed with hexane to give 910 mg of the 2- [2- (chloroacetamido) -4-thiazolyl] - (Z) -2- (methoxycarbonylmethyl-oxyimino) -acetyl chloride hydrochloride salt. m.p. 77-80 ° C.

IR (? X T): 3000, 1775, 1740, 1695.

Analytical results for C ₁₀ H ₉ Cl ₂ N ₃ O ₅ S.HCl:

Calculated: C, 30.74; H, 2.58; N, 10.76. Found: C, 30.69; H, 2.46; N, 10.89.

2- [2- (Chloroacetamido) -4-thiazolyl] - (Z) -2- (p-nitrobenzyloxy-carbonylmethyl-oxyimino) -acetyl-chloro-id was prepared in the same manner. hydrochloric acid salt, m.p. 158-16 ° C.

IR: 2940, 1780, 1740, 1680.

Analytical results for C ₁₆ H ₁₂ Cl ₂ N ₄ O ₇ S.HCl:

Calculated: C, 37.55; H, 2.56; N, 10.59 Found: C, 37.61; H, 2.65; N, 10.87.

85. Reference Example

Dissolve 280 mg of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester in a mixture of 5 ml of tetrahydrofuran and 5 ml of water and 773 mg of sodium bicarbonate, followed by ice-cooling and stirring with 910 mg of [2- (Chloroacetamido) -4-thiazolyl] - (Z) -2- (methoxycarbonylmethyl-oxyimino) -acetyl chloride hydrochloride salt is added. The mixture was stirred at room temperature for 2 hours and then water was added. The resulting crystals are filtered off, washed first with water, then with hexane and finally with diethyl ether to give cis-3- [2-] 2- (chloroacetamido) -4-thiazolyl] -2-methoxycarbonylmethyloxy. -imino) -acetamido-2-oxoazetidine-4-carboxylic acid methyl ester (color isomer, m.p. 260-265 ° C (dec)).

126

IR (ν ^KBr ) 3290, 2950, 1780-1730, 1685, 1660.

Analysis results for C ₁₅ H | ₆ C1N ₅ O ₈ S Found:

Found: C, 39.01; H, 3.49; N, 15.17 _; Found: C, 39.00; H, 3.58; N, 15.06.

In a similar manner, cis-3- {2- [2- (chloroacetamido) -4-thiazolyl] -2- (p-nitrobenzyloxycarbonylmethyl-oxyimino) -acetamido} -4- (methoxycarbonyl) -2-oxoazetidine (color isomer), m.p. 270-275 ° C (dec.).

IR spectrum (O> ^f-1): 3250, 1760, 1740, 1700, 1675th

Analysis for C ₂ H ₁₉ C1N Oi _{0 6} S Calcd:

Found: C, 43.27; H, 3.29; N, 14.42 _; Found: C, 42.85; H, 3.38; N, 14.27.

86. Reference example

15.3 g of p-nitrobenzyl alcohol are dissolved in 250 ml of dry diethyl ether and 8.90 ml of pyridine are added under ice-cooling and stirring, followed by the dropwise addition of 25.3 g of? -Bromo-isobutyl bromide over 50 minutes. After stirring for 5 hours at room temperature, the resulting crystalline precipitate was filtered off and washed with diethyl ether. The filtrate and the washings were combined and 150 ml of ethyl acetate were added. The mixture was washed with dilute hydrochloric acid, water, followed by aqueous sodium bicarbonate solution and finally aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel column (600 g silica gel; eluent: chloroform: hexane = 1: 1).

29.6 g of p-nitrobenzyl a-bromoisobutyrate are obtained. The product is a yellow oil which solidifies on cooling when solidified.

IR (λ max ⁴ ): 1735, 1520, 1345, 1150.

NMR (CDjC1 _3, ppm): 1.96 (6H, s, 2 x CH _3), 5.27 (2H, s, _COOCH2), 7.49, 8.13 (2χ2Η, 2 x d, aromatic protons).

87. Reference Example

14.7 g of N-hydroxyphthalimide and 27.2 g of p-nitrobenzyl a-bromoisobutyrate are dissolved in 75 ml of dry Ν, Ν-dimethylformamide and 12.4 g of potassium carbonate are added. After stirring for one hour at room temperature, 75 ml of dry Ν, Ν-dimethylformamide are added, when stirring becomes difficult due to the formation of an orange precipitate. The reaction mixture was stirred at room temperature for 24 hours and then concentrated in vacuo to half. The residue was poured into 700 ml of water with ice-cooling and stirring. After stirring for 30 minutes, the resulting crystalline precipitate was filtered off and washed with water. The crystals were dissolved in methylene chloride (500 mL), washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo.

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The solid residue was washed with diethyl ether / petroleum ether (1: 1) followed by a little diethyl ether to give 27.0 g of N- [1-methyl-1- (p-nitrobenzyloxycarbonyl) ethyloxy]. colorless crystals of phthalimide, m.p. 145-146 ° C.

IR (Cch ⁴ ): 1790, 1740, 1725. 1520, 1345.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.61 (6H, s, 2XCH ₃ ), 5.28 (2H, s,

NOCH ₂ ), 7.59, 8.10 (2X2H, 2Xd, CXVI), 7.75 (4H, s, CXVII).

88. Reference Example

7.68 g of N- [1-methyl-1- (p-nitrobenzyloxycarbonyl) ethyloxy] phthalimide are dissolved in 80 ml of methylene chloride and 0.97 ml of hydrazine are added under ice-cooling and stirring. hydrate is added. After stirring for two hours at room temperature, hydrazine hydrate (0.97 ml) was added again. After stirring for 3 hours, the resulting crystalline precipitate was filtered off and washed with methylene chloride. The filtrate and washings were combined, washed with dilute aqueous ammonia, then with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel column (300 g silica gel; eluent: ethyl acetate: hexane = 1: 1) 4.58 g of O- [1-methyl-1- (p-nitrobenzyloxycarbonyl) ethyl]. -hydroxylamine is obtained. The product is a yellow oil which solidifies on cooling.

IR spectrum (ν ^ οΓ ¹ ); 3310, 3250, 2980, 2930, 1740, 1535, 1350.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 1.46 (6H, s, 2XCH ₃ ), 5.26 (2H, s, COOCH ₂ ),

5.33 (2H, br.s, NH ₂ ), 7.48, 8.17 (2X X 2 H, 2 X d, aromatic protons).

89. Reference Example

1.49 g of [2- (Chloroacetamido) -4-thiazolyl] glyoxylic acid are dissolved in a mixture of 30 ml of water and 18 ml of tetrahydrofuran and, under ice-cooling and stirring, 1.83 g of 0- [1-methyl-1- (p -nitrobenzyloxycarbonyl) ethyl] -hydroxylamine is added. The pH of the mixture was adjusted to 5 with 1N aqueous sodium hydroxide solution. After stirring for 12 hours at room temperature, the reaction mixture was adjusted to pH 7.0 with aqueous sodium bicarbonate solution and the tetrahydrofuran was evaporated in vacuo. The remaining aqueous solution was washed with diethyl ether and extracted with ethyl acetate after adjusting the pH to 2 with dilute hydrochloric acid. The extract was washed with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was dissolved in diethyl ether and poured into 2 volumes of light petroleum. The resulting powdery precipitate was filtered off with 2- [2- (chloroacetamido) -4-thiazolyl] - (Z) -2- [1-methyl-1- (p-nitro-enzyloxycarbonyl) -ethyloxy] imino] -acetic acid is obtained.

128

IR (ν max, λ ⁴ ): 1740, 1695, 1540, 1520, 1345.

NMR spectrum _(CDCl3, ppm): 1.61 (6H, s, 2 x CH _3), 4.29 (2H, s, C1CH _2);

5.23 (2H, s, NOCH _2), 7.26 (lH, s, a group of formula CV), 7.43, 8.05 (2X X2H, 2 x d, aromatic protons).

90. Reference Example

1.445 g of 2- [2- (chloroacetamido) -4-thiazolyl] - (Z) -2- [1-methyl-1- (p-nitrobenzyloxycarbonyl) -ethyloxyimino] - Acetic acid was dissolved in methylene chloride (15 mL) and phosphorus pentachloride (686 mg) was added under ice-cooling and stirring. After stirring for 30 minutes under ice-cooling, hexane (4.5 mL) was added. The resulting crystalline precipitate was filtered off and washed with hexane to give 2- [2- (chloroacetamido) -4-thiazolyl] - (Z) -2- [1-methyl-1 - (p-nitrobenzyloxycarbonyl) - ethyl oxyimino] acetyl chloride - op: 79-82 ^? C - we get.

IR (λmax * ⁴ ): 2998, 1775, 1735, 1715, 1565, 1520, 1340, 1140.

Elemental analysis for _{C] 8} H ₁₇ Cl ₃ N ₄ O ₇ S:

Calculated: C, 40.05; H, 3.17; N, 10.38; Found: C, 39.80; H, 3.31; N, 10.30.

91. Reference example

417 mg of the cis-3- (benzyloxycarboxamido) -2-oxoazetidine-4-carboxylic acid methyl ester prepared according to Reference Example 2 are suspended in 20 ml of ethanol and 200 mg of 5% palladium carbon catalyst is added. After stirring for 30 minutes at room temperature under a hydrogen atmosphere, the catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in a mixture of water (15 mL) and tetrahydrofuran (15 mL) and 2- [2- (chloroacetamido) -4-thiazolyl] - (Z) -2- [1-methyl-1- (p-nitro) benzyloxycarbonyl) ethyloxyimino] acetyl chloride is added. The reaction mixture was stirred for 30 minutes and then extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was washed with an aqueous solution of sodium bicarbonate followed by sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. The solid residue was washed with 5: 1 diethyl ether / ethyl acetate then diethyl ether to give cis-3-12- [2- (chloroacetamido) -4-thiazolyl] -2- [1-methyl-1 Colorless crystals of (p-nitrobenzyloxycarbonyl) -ethyloxyimino] -acetamido) -4- (methoxycarbonyl) -2-oxo-azetidine (color isomer), m.p. 198-202 ° C. (decomposes) - we get.

IR (ν max): 3360, 1770, 1745, 1690, 1525, 1350.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm) 1.52 (6H, s, 2XCH ₃ ), 3.63 (3H, s,

COOCH ₃ ), 4.34 (2H, s, C

4.47 (IH, d, J = 6Hz, C ₄ EH, 5.29 (2H, s, COOCH _2), 5.48 (HI, dd,

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129

J = 6 Hz, 9 Hz, C ₃ -H), 7.23 (1H, s, CV).

Reference Example 92. Methyl 2- (hydroxyimino) -acetic acid methyl ester (g) was dissolved in methylene chloride (50 ml) and sulfuryl chloride (19.6 g) was added dropwise with ice-cooling and stirring. The mixture was stirred at room temperature for 3 days and then concentrated in vacuo. The residue was dissolved in diethyl ether (200 mL) and this solution was washed with water (2 x 100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. 20.2 g of methyl 4-chloro-2- (hydroxyimino) -acetic acid are obtained in the form of a light yellow oil.

NMR (CDC1 _3, ppm): 2.65 (IH, brs, N-OH), 3.90 (3H, s, COOCH _3);

4.57 (2H, s, C ₁ H ₂ ).

This product was dissolved in 200 mL of a 1: 1 mixture of water and tetrahydrofuran and 16.96 g of thiourea and 49.27 g of sodium acetate-water (1: 3) were added under ice-cooling. After stirring at room temperature overnight, the mixture was adjusted to pH 7.0 with sodium bicarbonate. Upon saturation with sodium chloride, the organic phase is separated. The aqueous phase is extracted with tetrahydrofuran, the organic phases are combined, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated in vacuo. The oily residue was crystallized from 100 ml of diethyl ether. After standing overnight, the crystals are filtered off and washed thoroughly with water. The crystals thus obtained were dissolved in ethyl acetate / methanol (5: 1) and evaporated until crystals precipitated. The mixture was allowed to stand overnight, and the crystalline precipitate was filtered off and dried to give light yellow granules of 2- (2-amino-4-thiazolyl) - (Z) -2- (hydroxyimino) -acetic acid, m.p. -192 ° C (dec.) - obtained.

IR (δ): 3430, 3300, 3220, 3130, 1730, 1620.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.80 (3H, s, COOCH ₃ ), 6.87 (1H, s, CV), 7.17 (2H, br.s, NH ₂ ). , 11.76 (1H, s, N-OH).

Analysis: Calculated for C ₆ H ₇ N ₃ O ₃ S: C, 35.81; H, 3.51; N, 20.89; Found: C, 36.05; H, 3.52, N, 20.96.

93. Reference Example

4.62 g of 2- (2-amino-4-thiazolyl) - (Z) -2- (hydroxyimino) -acetic acid methyl ester are dissolved in 10 ml of Ν, Ν-dimethylformamide and 3 ml of triethylamine and 6.42 g of trityl chloride are added with stirring at -30 ° C for one hour. The mixture was stirred at this temperature for an additional hour and then at 15 ° C for an additional two hours. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (200 mL). Extract the extract with twice 200 ml water 66

The mixture was washed with 130, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (100 g silica gel; eluent: hexane: ethyl acetate = 1: 1) and the resulting crystals were recrystallized from ethyl acetate to give 2- [2- (tritylamino) -4-thiazolyl] - (Z). ) Colorless granules of methyl 2- (hydroxyimino) acetic acid, m.p. 204-205 ° C.

IR (ν max, ^r , cw ¹ ): 3375, 1740.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.45 (3H, s, COOCH ₃ ), 6.70 (1H, s, CV), 7.18 (15H, s, 3XPh), δ , 47 (1H, br.s, NH), 11.27 (1H, s, N-OH).

Analytical results for C ₂₅ H _2] N ₃ O ₃ S:

Found: C, 67.70; H, 4.77; N, 9.48. Found: C, 67.55; H, 4.67; N, 9.14.

94. Reference Example

To 0.5 ml of N, N-dimethylformamide, 7.05 g of methyl 2- [2- (tritylamino) -4-thiazolyl] - (Z) -2- (hydroxyimino) -acetic acid and 3 3 g of potassium carbonate are added. Allyl bromide (2.12 g) was added dropwise over 5 minutes with ice-cooling and stirring. After stirring for 4 hours under ice-cooling, 1.65 g of potassium carbonate and 1.06 g of allyl bromide are added. The reaction mixture was stirred for an additional 4 hours, then diluted with water (150 mL) and extracted with diethyl ether (3 x 100 mL). The extract was washed twice with 100 ml of aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (300 g silica gel; eluent: hexane: ethyl acetate = 1: 1) and the resulting product was crystallized from diethyl ether / hexane to give 7.0 g of 2- [2- (tritylamino) -4 -thiazolyl] - (Z) -2- (allyloxyimino) acetic acid methyl ester, m.p. 115-116 ° C.

IR (ν max): 3360, 1740.

NMR (CDC1 _3, ppm): 3.88 (3H, s, _COOCH3), 6.53 (lH, s, a group of formula CV), 6.93 (IH, br.s. NH);

7.30 (15H, s, 3XPh).

Analysis for C _2g H ₂₅ N ₃ O ₃ S: Calcd: C% = 69.54, H% = 5.21, N% = 8.69; Found: C, 69.57; H, 5.18; N, 8.51.

95. Reference Example

6.45 g of methyl 2- [2- (tritylamino) -4-thiazolyl] - (Z) -2- (allyloxyimino) acetic acid are dissolved in 32 ml of tetrahydrofuran and 32 ml of 50% os formic acid. The mixture was stirred at 60 ° C for 40 minutes and then concentrated in vacuo. The residue was dissolved in ethyl acetate and the solution was washed with aqueous sodium bicarbonate followed by aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was subjected to column chromatography on 150 g of silica gel; eluent: hexane: ethyl acetate = 1: 1). By evaporation of the eluate

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131 was obtained by washing the residue with hexane and then with a little diethyl ether and drying with methyl 2- (2-amino-4-thiazolyl) - (Z) -2- (allyloxyimino) acetic acid, m.p. 133 134 ° C.

IR (ν max): 3430, 3230, 1720, 1610, 1540.

NMR (CDC1 _3, ppm): 3.90 (3H, s, _COOCH3), 5.98 (2H, br, NH,

6.67 (1H, s, CV).

96. Reference Example

Using the procedure of Reference Example 32, methyl 2- [2- (chloroacetamido) -4-thiazolyl] - (Z) -2- (allyloxyimino) acetic acid, m.p. 114-115 ° C. C - we produce.

IR (? X?): 3150, 3060, 2950, 1740, 1710, 1680, 1565.

NMR (CDC1 _3, ppm): 3.93 (3H, s, COOCHJ, 4.28 (2H, s, CICHJ,

7.25 (1H, s, CV),

10.12 (1H, br.s, CONH).

97. Reference Example

Referring to Reference Example 33, 2- [2- (chloroacetamido) -4-thiazolyl] - (Z) -2- (allyloxyimino) acetic acid, m.p. 162 DEG C. (dec.). live.

IR (λ max) _: 3180, 2950, 1715-1680.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 4.33 (2H, s, ClCH 3, 7.42 (1H, s, CV)).

Analytical results for C ₁₀ H ₁₀ ClN ₃ O ₄ S:

Calculated: C% = 39.54, H% = 3.32, N = 13.84% _i% Found: C = 39.41, H% = 3.55, N% = 13.71.

98. Reference Example

2- [2- (Chloroacetamido) -4-thiazoloyl] - (Z) -2- (allyloxyimino) acetic acid (610 mg) was suspended in methylene chloride (13 ml) and 502.4 mg of phosphorus in ice-cooling and stirring. pentachloride is added. After stirring at room temperature for 30 minutes, hexane (100 mL) was added. The resulting crystals were filtered off and washed with hexane to give 2- [2- (chloroacetamido) -4-thiazolyl] - (Z) -2- (ayloxyimino) acetyl chloride hydrochloride salt, op: 67- 70 ° C.

Analytical results for C, ₀ H ₉ Cl ₂ N ₃ O ₃ S.HCl:

Found: C, 33.49; H, 2.81; N, 11.72 _. Found: C, 33.87; H, 2.76; N, 11.79.

99. Reference Example

185.5 mg of methyl cis-3-amino-2-oxoazetidine-4-carboxylic acid are dissolved in a mixture of 2 ml of tetrahydrofuran and 2 ml of water and 469.6 mg of sodium bicarbonate are added under ice-cooling and stirring. 600 mg of 2- [2- (chloroacetamido) -4-thiazolyl] - (Z) -2- (allyloxyimino) acetyl chloride hydrochloride salt are added. The mixture was stirred at room temperature for two hours

The reaction mixture was stirred and then concentrated in vacuo. Water (20 mL) was added to the residue and the resulting crystals were filtered off. The crystals were washed first with an aqueous solution of sodium bicarbonate, then with water, then with hexane and finally with diethyl ether, and dried over cis-3-12- [2-chloroacetamido) -4-thiazolyl] -2- (a) Light yellow granules of I-oxyimino) -acetamido] -2-oxo-azetidine-4-carboxylic acid, m.p. 270-280 ° C (dec.).

IR: 3260, 1770, 1745, 1720, 1680;

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.60 (3H, s, COOCH 3, 4.33 (2H, s, C ₁ H 2), 4.45 (1H, d, J = 6Hz, C ₄ -H) .

7.29 (1H, s, CV),

9.49 (IH, d, J = 9Hz, _C3 -NH).

Analysis: Calculated for C ₁₅ H ₁₆ ClN ₅ O ₆ S: C, 41.91; H, 3.75; N, 16.29 _; Found: C, 41.83; H, 3.85; N, 16.37

100. Reference Example

657 mg of cis-3- (benzyloxycarboxamido) -4- (methylsulfonyloxymethyl) -2-oxoazetidine, prepared as in Reference Example 11, are dissolved.

7.8 ml of Ν, Ν-dimethylformamide and this solution is poured into a solution of 861 mg of lithium chloride in 7.8 ml of N, N-dimethylformamide. The mixture was stirred under argon at 73 ° C for 3 hours, then cooled, poured into aqueous sodium chloride solution (60 mL) and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride; dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (50 g silica gel; eluent: hexane: ethyl acetate = 1: 2). The resulting crystals were washed with diethyl ether to give cis-3- (benzyloxycarboxamido) -4- (chloromethyl) -2-oxoazetidine, m.p. 147-149 ° C. Analytical results for C, ₂ H ₁₃ ClN ₂ O ₃ :

Found: C, 53.64; H, 4.88; N, 10.43 _; Found: C, 53.49; H, 4.81; N, 10.35.

101. Reference Example

Cis-3- (benzyloxycarboxamido) -4-chloromethyl-2-oxoazetidine (376 mg) was suspended in methanol (20 ml) and 5% palladium on carbon (376 mg) was added. After stirring at room temperature under a hydrogen atmosphere for 20 minutes, the catalyst was filtered off and the filtrate was evaporated. The solid residue was dissolved in 28 mL of a 1: 1 mixture of tetrahydrofuran and water and, under ice-cooling and stirring, first, 470 mg of sodium bicarbonate followed by 698 mg of 2- [2- (chloroacetamido) -4-thiazolyl]. The 2- (methoxyimino) acetyl chloride hydrochloride salt (color isomer) was added. The mixture was stirred for 30 minutes under ice-cooling and then extracted with ethyl acetate. The aqueous phase was re-extracted with ethyl acetate and tetrahydrofuran

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The organic layers were combined, washed with aqueous sodium bicarbonate and then with sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. The solid residue was washed with a 1: 3 mixture of ethyl acetate and diethyl ether in CIS-3-2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido} -4- ( Colorless crystals of chloromethyl) -2-oxoazetidine (color isomer), m.p. 212-217 ° C (dec.).

IR spectrum (v &^lt; ^Crt &gt;): 3420, 3260, 1755, 1660, 1560.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.90 (3H, s, NOCH 3), 4.34 (2H, s, ClCH ₂ ).

5.28 (1H, dd, J = 5Hz) 9Hz, C ₃ -H),

7.46 (1H, s, CV),

8.72 (1H, br.s, N, -H), 9.33 (1H, d, J = 9Hz, C ₃ -NH), 12.57 (1H, br.s, C 1 H 2 CONH).

102. Reference example

From cis-3- (benzyloxycarboxamido) -4- (methylsulphonyloxymethyl) -2-oxo-azetine prepared according to Reference Example 11, cis -3- {2- [2- (Chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido} -4- (methylsulfonyloxymethyl) -2-oxoazetidine (Syn. m.p. 186-189 ° C (dec.).

Analytical results for C, ₃ H ₁₆ CIN ₅ O ₇ S:

Found: C, 34.40; H, 3.55; N, 15.43. Found: C, 34.27; H, 3.63; N, 15.28.

103. Reference Example

All. cis-3- (benzyloxycarboxamido) -4- (methylsulphonyloxymethyl) -2-oxoazetidine prepared according to Reference Example

3.28 g was suspended in 100 ml of ethanol and 3.28 g of 5% palladium on carbon catalyst was added. After stirring at room temperature under a hydrogen atmosphere for 50 minutes, the catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in a mixture of 100 ml of methylene chloride and 15 ml of Ν, Ν-dimethylacetamide, and, under ice-cooling and stirring, first, 6.99 ml of propylene oxide, followed by 2.79 g of chloroformate-2-methylsulphonyl a solution of ethyl ester in 25 mL of methylene chloride was added. After stirring for 2 hours at room temperature, the methylene chloride was evaporated. Water and a 1: 1 mixture of ethyl acetate and tetrahydrofuran were added to the residue and the mixture was shaken. The organic phase is separated off and the aqueous phase is evaporated to dryness in vacuo. The residue was dissolved in tetrahydrofuran, dried over anhydrous magnesium sulfate and combined with the former organic phase. The combined mixture was again dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was subjected to column chromatography (150 g

134 lycagel; eluent: ethyl acetate followed by ethyl acetate / ethanol 9: 1). The crystals thus obtained were washed with a 1: 1 mixture of ethyl acetate and diethyl ether to give cis-3- [2- (methylsulfonylethoxy) carboxamido] -4- (methylsulfonyl-1-oxymethyl) -2- Colorless crystals of oxoazetidine, m.p. 141-142 ° C.

Analytical results for C ₉ H ₁₆ N ₂ O ₈ S ₂ :

Found: C, 31.39; H, 4.68; N, 8.14; Found: C, 31.34; H, 4.76; N, 8.34

104. Reference Example

1.894 g of cis-3- [2- (methylsulphonylethoxy) carboxamido] -4- (methylsulphonyloxymethyl) -2-oxoazetidine and 4.884 g of sodium iodide in 75 ml of methyl ethyl ketone slurry and reflux under nitrogen for 3 hours. The reaction mixture was concentrated in vacuo and water, ethyl acetate and aqueous sodium thiosulfate were added to the residue. The resulting crystalline precipitate was filtered off, washed with water, ethyl acetate and diethyl ether to give 382 mg of cis-3- [2- (methylsulfonylethoxy) -carbamido] -4- (iodomethyl) -2-. colorless crystals of oxoazetidine are obtained. The filtrate and washings were combined and the organic phase was separated. The aqueous phase was saturated with sodium chloride and extracted with a 4: 1 mixture of tetrahydrofuran and ethyl acetate. The extract and the organic phase were combined, dried over anhydrous magnesium sulfate and concentrated in vacuo. The crystalline residue was washed with ethyl acetate to give 1.367 g of the above 4- (iodomethyl) compound, m.p. 186-190 ° C (dec.).

Analysis results for C ₈ H ₁₃ IN ₂ O ₅ S:

Found: C, 25.54; H, 3.48; N, 7.45. Found: C, 25.64; H, 3.53; N, 7.34.

Reference Example 105 for N, N-Dimethylformamide ml 1.504 g of cis-3- [2- (methylsulfonylethoxy) carboxamido] -4- (iodomethyl) -2-oxoazetidine and 390 mg of sodium azide were added and stirred at room temperature and then stirred at 40 ^DEG C for 24 hours and 66 hours. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (100 g silica gel; eluent: ethyl acetate followed by ethyl acetate: ethanol 9: 1). The eluate was evaporated and the residue was crystallized from ethyl acetate and the colorless crystals were filtered off with cis-3- [2- (methylsulfonylethoxy) carboxamido] -4- (azidomethyl) -2-oxoazetidine - m.p. - 160 ° C.

IR (λ max): 3200, 2110, 1780, 1700, 1550.

106. Reference Example

757 mg of cis-3-12- (methylsulfonyl-ethoxy) -carboxamido] -4- (azidomethyl) -2-oxo-azet -68194870

135 din was dissolved in a mixture of 60 ml of ethanol and 6 ml of N, N-dimethylformamide and 11.4 ml of 0.5 N sodium hydroxide solution in ethanol was added under ice-cooling and stirring. After 40 min, 5.7 mL of 1N hydrochloric acid was added and the mixture was concentrated in vacuo. To the residue were added 15 ml of water and 15 ml of tetrahydrofuran, followed by ice-cooling and stirring with 874 mg of sodium hydrogencarbonate, followed by 1.297 g of 2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxy) imino) -acetite-hydrochloric acid salt was added and stirred for 40 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, then with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. The crystalline precipitate was washed with ethyl acetate and then with diethyl ether. CIS-3-12- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyiminoacetamido) -4- (azidomethyl) Colorless crystals of -2-oxoazetidine (color isomer), m.p. 223-230 ° C (dec.).

IR (λ max cm ^-1 ): 3420, 3250, 2110, 1760, 1660, 1550 '.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm) 3.4-

3.6 (2H, m, _{CH2 N3),} 3.90 (3H, s, NOCH _3), 4.34 (2H, s, C1CH _2), 5.22 (IH, dd, J = 5 Hz , 9Hz, _C3 -H), 7.37 (lH, s, a group of formula CV), 8.49 (IH, br, N-H), 9.20 (IH, d, J = 9 Hz, C ₃ -NH).

107. Reference Example

The cis-3- (benzyloxycarboxylic acid) -1- (2,4-dimethoxybenzyl) -4- (hydroxymethyl) -2-oxoazetidine 5 prepared according to Reference Example 5, Dissolve 0 g in 50 ml of methylene chloride and add 3.75 ml of pyridine at 0 ° C with stirring. 3.94 g of benzoyl chloride are added dropwise and the mixture is stirred at room temperature for 1.5 hours. Ice water (100 mL) was added to the reaction mixture, and the organic layer was separated, washed with aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo. The residue was purified by column chromatography (325 g silica gel; hexane: ethyl acetate = 1: 2) and the eluate was evaporated. Hexane was added to the residue and the crystalline residue was filtered off with colorless crystals of cis-3- (benzyloxycarboxamido) -4- (benzoyloxymethyl) -1- (2,4-dimethoxybenzyl) -2-oxoazetidine M.p .: 133-134 ° C.

Analytical results for C ₂₈ H ₂₈ N ₂ O ₇ :

Found: C, 66.65; H, 5.59; N, 5.55; Found: C, 66.48; H, 5.49; N, 5.36.

108. Reference Example

Following the procedure of Reference Example 7, cis-3- (benzyloxycarboxamido) -4- (benzoyloxymethyl) -2-oxoazetidine, m.p. 188-189 ° C, was prepared.

136

IR (cm- ¹ ): 3300, 1770, 1725, 1690.

Analysis: Calculated for C ₁₉ H ₁₈ N ₂ O ₅ : C, 64.40; H, 5.12; N, 7.9; Found: C, 64.42; H, 4.96; N, 7.86.

109. Reference Example

550 mg of cis-3- (benzyloxycarboxamido) -4-benzoyloxymethyl-2-oxoazetidine are suspended in 20 ml of ethanol and 550 mg of 5% palladium on carbon are added. The suspension was stirred for 2.5 hours under an atmosphere of hydrogen and the catalyst was filtered off and the filtrate was evaporated in vacuo to colorless crystals of cis-3-amino-4- (benzyloxymethyl) -2-oxoazetidine - m.p. 150-151 ° C - obtained.

IR spectrum (* O i '): 3200, 1735, 1710. Analysis for C ,, Hi ₂ N ₂ O _3: Calcd: C% = 59.99, H% = 5.49, N = 12% , 72 _; Found: C, 60.06; H, 5.66; N, 12.84.

110. Reference Example

Following the procedure of Reference Example 9, cis-3- [2- (2-chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido} -4- (benzoyloxymethyl) -2 oxoazetidine (color isomer) - m.p. 210-220 ° C (dec.).

IR (λ max): 3250, 1760, 1715, 1660 Analysis for C ₁₉ H ₁₈ ClN ₅ O ₆ S:

Found: C, 47.55; H, 3.78; N, 14.59 _; Found: C, 47.06; H, 3.63; N, 14.53.

111. Reference example

To 250 ml of benzene was added 35 g of α-methyl cinnamic aldehyde and 29.5 g of p-anisidine and the mixture was refluxed for one hour and then concentrated in vacuo. The residue was dissolved in 1 L of methylene chloride and 29 g of triethylamine was added under ice-cooling and stirring followed by the dropwise addition of a solution of 53.5 g of phthalimidoacetyl chloride in 250 ml of methylene chloride over 45 minutes. After stirring for 24 hours at room temperature, the mixture was washed with water, dried over anhydrous magnesium sulfate and evaporated. The solid residue was recrystallized from ethyl acetate-hexane to give cis-3-phthalimido-4- (α-methylstyryl) -1- (4-methoxyphenyl) -2-oxoazetidine, m.p. 105-107 ° C. - we get.

IR (λ max) 1760, 1725, 1515, 1385, 1250.

NMR spectrum _(CDCl3, ppm): 1.70 (3H, br,? C-CHJ, 3.74 (3H, s, NOCHJ

4.77 (1H, d, J = 6Hz, C ₄ -H), 5.52 (1H, d, J = 6Hz, C ₃ -H), 6.50 (1H, br.s, = CH Ph).

Reference Example 112 Cis-3-phthalimido-4- (α-methyl-styryl-1- (4-methoxyphenyl) -2-oxoazetidine g) is dissolved in 200 ml of dimethoxyethane and 10.2 g of methylhyd

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We add 137 pounds. After stirring for 12 hours at room temperature, the resulting crystals were filtered off and the filtrate was evaporated. The residue was dissolved in methylene chloride (200 mL) and propylene oxide (14.8 g)

10.62 g of benzyloxycarbonyl are added. The mixture was stirred for one hour and then concentrated in vacuo. The residue was purified by column chromatography (300 g silica gel; eluent: hexane: ethyl acetate = 1: 1, then 1: 2) to give cis-3- (benzyloxycarboxartido) -4- (α-methylstyryl) -1. - (4-Methoxyphenyl) -2-oxoazetidine is obtained.

IR (O &lt; + &gt;) _: 1750, 1720, 1680.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 1.85 (3H, br.s, = C-CH ₃ ), 3.75 (3H, s, OCH ₃ ), 5.08 (2H, s, PhCH ₉ ). , 5.50 (1H, dd, J = 6Hz, 9Hz, C ₃ -H), 6.43 (1H, br.s, = CH = Ph), 7.84 (1H, d, J = 9 Hz, C ₃ -NH).

Reference Example 113 g cis-3- (benzyloxycarboxamido) -4- (α-methylstyryl) -1- (4-methoxyphenyl) -2-oxoazetidine was dissolved in 750 ml of methylene chloride, and excess ozone is passed through the solution at -78 ° C. The excess ozone is then expelled by bubbling nitrogen and 11.6 g of dimethylsulfide are added. The reaction mixture was stirred for 30 minutes at room temperature and then concentrated in vacuo. The residue was purified by column chromatography (400 g silica gel; eluent: hexane: ethyl acetate = 1: 2 then 1: 4) to give cis-3- (benzyloxycarboxamido) -4-acetyl-1- (4-methoxyphenyl). ) -2-oxoazetidine - op: 188-

191 ° C.

IR spectrum (v ^ ^{r cm-1):} 1760, 1720, 1700 ,. 1655th

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 2.20 (3H, s, COCH ₃ ), 3.74 (3H, s, OCH ₃ ),

5.15 (2H, s, PhCH 3, 5.20 (1H, d, J = 6Hz, C ₄ -H)), 5.64 (1H, dd, J = 6Hz, 9Hz, C ₃ - H), 9.48 (1H, d, J = 9Hz, C ₃ -NH).

Reference Example 114 g of cis-3- (benzyloxycarboxamido) -4-acetyl-1- (4-methoxyphenyl) -2-oxoazetidine was dissolved in a mixture of 50 ml of acetonitrile and 25 ml of water. To the solution while cooling with ice,

- At 15 ° C, 3 g of ammonium cerium (IV) nitrate was added and the resulting mixture was stirred for 10 minutes, then quenched by the addition of a saturated aqueous solution of sodium sulfite and its pH adjusted with sodium bicarbonate.

Set it to 5-6. The acetonitrile was evaporated in vacuo and the residue acidified with 3N hydrochloric acid and extracted with chloroform. The aqueous phase was extracted twice with chloroform / ethanol (4: 1). The extracts were combined, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was subjected to column chromatography (80 g silica gel, eluting with hexane and 70 g silica gel)

Ethyl acetate (1: 2) followed by ethyl acetate followed by ethyl acetate: methanol (9: 1) to give cis-3- (benzyloxycarboxamido) -4-acetyl-2-oxoazetidine.

IR (ν «θ / ο« ¹ ): 3240, 1770, 1705, 1635, 1540, 1450, 1380, 1305, 1180.

NMR (CDC1 ₃ ppm): 2.20 (3H, s, _COCH3), 4.58 (IH, d, J = 6Hz, C ₄ -H) 5.20 (2H, s, ₂ PhQÜ ), 8.18 (1H, d, J = 9Hz, C ₃ -NH).

115. Reference Example

Following the procedure of Reference Example 67, cis-3- {2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido} -4-acetyl-2-oxoazetidine (colorless) -isomer).

IR (λmax cm ^-1 ): 3350. 1760, 1650, 1545.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 2.12 (3H, s, COCH ₃ ), 3.73 (3H, br. S, NOCH ₃ ), 4.35 (2H, s, CICH ₂ ), 7.90 (1H, s, CV).

116. Reference example

75 mg of cis-3-amino-4- (hydroxymethyl) -2-oxoazetidine prepared in Reference Example 53 are dissolved in a mixture of 2 ml of tetrahydrofuran and 2 ml of water and 168 mg of sodium under ice-cooling and stirring. hydrocarbonate followed by addition of 332 mg of 2- [2- (chloroacetamido) -4-thiazolyl] - (Z) -2- (methoxyimino) acetyl chloride hydrochloride salt. After stirring for 1 hour under ice-cooling, the mixture was neutralized with aqueous sodium bicarbonate and extracted with ethyl acetate: tetrahydrofuran (2: 1). The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. To the residue was added a 1: 2 mixture of ethyl acetate and diethyl ether and the resulting crystals were filtered off with cis-3- (2- [2- (chloroacetamido) -4-thiazolyl] -2-methoxyimino) acetamido} -4 - Colorless crystals of (hydroxymethyl) -2-oxoazetidine (color isomer) - op: 238-

241 ° C) dec.

IR (ν max cw ⁴ ): 3400 (br.), 1750, 1660, 1045.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 2.07 (1H, s, OH), 3.89 (3H, s, NOCH ₃ ),

4.34 (2Hs, C1CH _2), 5.20 (IH, dd, J = 5Hz, 9Hz, _C3 -H), 7.50 (lH, s, a group of formula CV), 9.15 (IH , d, J = 9 Hz, C ₃ -NH).

117. Reference example

172 mg of cis-3-12- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido) -4 (hydroxymethyl) -2-oxoazetidine (color isomer) are dissolved in of methylene chloride (6 ml) and N, N-dimethylformamide (6 ml) and pyridine (0.2 ml) were added. Chloroacetyl chloride (0.12 ml) was added dropwise to the resulting mixture under cooling with brine and stirred for 30 minutes.

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The solvent was evaporated.

Aqueous sodium chloride and ethyl acetate were added to the residue and the mixture was shaken well. The organic layer was separated, washed with an aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and evaporated. The residue was crystallized from diethyl ether and then recrystallized from a mixture of chloroform and methanol to give cis-3-12- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido) -4- ( colorless crystals of chloroacetoxymethyl) - 2-oxoazetidine (color isomer) - op:

225-227 ° C (dec.) - obtained.

Analysis C H _{I4 I5} C1 ₂ N ₅ O ₆ S Calcd: 15 calculated: C% = 37.17, H% = 3.34, N% = _15.48; Found: C, 36.79; H, 3.37; N, 15.44.

118. Reference Example

The cis-3- (benzyloxycarboxamido) -1- (2,4-dimethoxybenzyl) -4- (phthalimidomethyl) -2-oxoazetidine 4 prepared according to Reference Example 48, 45 g are suspended in 320 ml of ethanol and 2.03 ml of hydrazine hydrate are added. The mixture was refluxed for 2 hours, then cooled, filtered and the filtrate evaporated in vacuo. Methylene chloride (200 mL) was added to the residue and the precipitate was filtered off. The filtrate was washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was dissolved in a mixture of methylene chloride (84 ml) and N, N-dimethylacetamide (11 ml) and propylene oxide (5.88 ml) under ice-cooling and stirring, followed by dropwise addition of 2.35 g of p-methylsulphog A solution of the nyl ethyl ester in 20 ml of methylene chloride was added. The mixture was stirred for one hour at room temperature, washed with water and then washed with sodium bicarbonate aqueous solution and then with water, dilute hydrochloric acid and finally nátri- ₄ θ um chloride saturated aqueous solution and dried over anhydrous magnesium sulfate and concentrated in vacuo. The crystalline residue was washed with ethyl acetate to give 2.94 g of cis (3-benzyloxycarboxamido) -1- (2,4-dimethoxybenzyl) -4- (2-methylsulfonyl-ethoxycarbonylamino-45-). methyl) -2-oxoazetidine, m.p. 172-174 ° C.

IR (ν cm3, 3400, 1755, 1690,

1610, 1535, 1125. ' 50

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 2.97 (3H, s, SO ₂ CH ₃ ), 3.38 (2H, t, J = 6Hz, CH ₂ SO ₂ ), 3.75, 3.77 (2X XCH ₃ , 2XS, 2XOCH ₃ ), 4.24 (2H, q, J = 15 Hz, N, -CH ₂ ), 4.28 (2H, t, 55 J = 6 Hz, COOCH ₂ ), 4.82 (1H, d,

J = 5 Hz, 9 Hz, C ₃ -H), 5.05 PhCH 2). 7.37 (5H, s, Ph (1H, d, J = 9Hz, C ₃ -NH).

119. Reference Example

According to Reference Example 50, cis-3- (Benzyloxycarboxamido) -4- (2-methylsulfonylethoxycarbonylaminomethyl) -2-oxoazetidine - m.p. 149-150 ° C. - we produce it.

(2H, s,), 8.05

140

Analysis for C ₁₆ H _2I N ₃ O ₇ S: Calcd: C% = 48.11, H% = 5.30, N% = _10.52; Found: C, 47.99; H, 5.22; N, 10.37.

120. Reference Example

Following the procedure of Reference Example 51, cis-3-12- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido} -4- (2-methylsulfonylethoxy) carbonylaminomethyl) -2-oxoazetidine (color isomer) was prepared. This product gradually decolorises at 150-170 ° C and decomposes at 195-199 ° C.

IR (3250, 1760, 1690, 1550).

Analytical results for C ₁₆ H ₂₁ CIN ₆ O ₈ S ₂ :

Found: C, 36.61; H, 4.03; N, 16.01 _; Found: C, 36.48; H, 4.08; N, 15.92.

121. Reference example

457 mg of dimethyl tert-butylsilyl chloride and cis-3- (benzyloxycarboxamido) -4- (2-methylsulfonylethoxycarbonylaminomethyl) prepared according to Reference Example 119 - 1.197 g of 2-oxoazetidine are dissolved in 3 ml of N, N-dimethylformamide and 0.46 ml of triethylamine are added dropwise to the solution under ice-cooling at 0 ° C. After stirring for 30 minutes under ice-cooling, water and ethyl acetate were added. The organic layer was washed with dilute hydrochloric acid, then with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was subjected to column chromatography (100 g silica gel; eluent: hexane: ethyl acetate = 1: 2, then 1: 3) to give cis-3- (benzyloxycarboxamido) -4- (2-methylsulfonylethoxy). carbonylaminomethyl) -1- (dimethyl-tert-butylsilyl) -2-oxoazetidine was obtained as a foam.

IR (ν ^κθΓ ): 3330, 1750, 1720, 1695.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 0.26 (3H, s, SiCH ₃ ), 0.28 (3H, s, SiCH ₃ ), 0.96 (9H, s, tert-Bu), 2, 93 (3H, s, SO ₂ CH ₃ ), 3.28 (2H, t, J = 6Hz, CH ₂ SO ₂ )

4.50 (2H, t, J = 6Hz, COOCH ₂ ), 5.03 (1H, dd, J = 5Hz, 9Hz, C ₃ -H), 5.15 (2H, s, PhCH ₂ ). , 6.18 (1H, d, J = 9Hz C ₃ -NH), 7.38 (5H, s, Ph).

122. Reference example

514 mg of cis-3- (benzyloxycarboxamido) -4- (2-methylsulfonylethoxycarbonylaminomethyl) -1- (dimethyl-tert-butylsilyl) -2-oxoazetidine were dissolved. In 20 ml of ethanol, 4.4 ml of 0.5 N sodium hydroxide solution in ethanol are added under ice-cooling and stirring. After stirring for 15 minutes under ice-cooling, 2.2 ml of 1N hydrochloric acid were added. The solvent was evaporated in vacuo and the residue was extracted with a mixture of methylene chloride and tetrahydrofuran. The extract was washed with an aqueous solution of sodium chloride, anhydrous

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It was dried over magnesium sulfate (141) and concentrated in vacuo. 4 ml of dry trifluoroacetic acid and 2 ml of trifluoroacetic anhydride are added to the residue under ice-cooling. The mixture was stirred for 30 minutes and concentrated in vacuo. The residue was purified by column chromatography (40 g of silica gel; eluent: hexane: ethyl acetate = 1: 1, then 1: 2) to give cis-3- (benzyloxycarboxamido) -4- (trifluoroacetylaminomethyl). ) -2-oxoazetidine, m.p. 197-201 ° C.

IR spectrum (v ^> _^'1): 3280, 1760, 1705, 1690th

Analysis results for Formula C, ₄ H _I4 F ₃ N ₃ O ₄ :

Found: C, 48.70; H, 4.09; N, 12.17 _; Found: C, 48.31; H, 4.05; N, 12.01.

Yellow crystals of cis-3- (benzyloxycarboxamido) -4- (trifluoroacetylaminomethyl) -1- (dimethyl-tert-butylsilyl) -2-oxoazetidine as a by-product in the above reaction, m.p. 130-135 ° C.

IR (ν max, ^Br tcw ¹ ): 3300, 1765, 1700, 1685.

123. Reference Example

In the same manner as Reference Example 67, cis-3-12- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido} -4-trifluoroacetylaminomethyl). 2-oxoazetidine (color isomer) m.p. 220-225 ° C (dec.).

IR (νmax): 3270, 1760, 1705, 1660.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.89 (3H, s, NOCH ₃ ), 4.31 (2H, s, ClCH ₂ )

5.22 (1H, dd, J = 5 Hz, 9 Hz, C ₃ -H),

7.43 (1H, s, CV).

124. Reference Example

525 mg of cis-3-12- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido} -4- (2-methylsulfonyl) prepared according to Reference Example 119. 1-Phenyl-ethoxy-carbonylaminomethyl) -2-oxo-azetidine (color isomer) was suspended in a mixture of 25 ml of ethanol and 5 ml of Ν, Ν-dimethylformamide and 5 ml of 0.5 N sodium hydroxide. solution. After stirring for 20 minutes at room temperature, 1N hydrochloric acid (2.5 mL) was added and the ethanol was evaporated in vacuo. The residue was dissolved in a mixture of water (8 ml) and tetrahydrofuran (10 ml) and with ice-cooling and stirring, 185 mg of sodium bicarbonate followed by dropwise addition of 432 mg of p-nitrobenzyl chloroformate in 10 ml of tetrahydrofuran over 50 minutes. . After stirring for 20 minutes under ice-cooling, water (10 ml) and ethyl acetate (20 ml) were added and shaken well. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The extract and the organic phase were combined, washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was taken up in ethyl acetate

The crystals are crystallized from 142 and the cis-3-12- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido} -4- (p-nitrobenzyloxy) is isolated by filtration. m.p. 235-245 DEG C. (decomposition), m.p. 235-245 ° C (dec.).

IR IR 3380, 3230, 1760, 1690, 1660, 1550, 1520.

125. Reference Example

Following the procedure of Reference Example 39, the following compounds were prepared.

methyl cis-3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido] -2-oxoazetidine-4-carboxylic acid,

Beta-form

IR spectra ([nu] <^r> o): 1770, 1740, 1710, 1675.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.11 (3H, t, J = 7Hz, N-CH 2 -CHD.) 3.08 (3H, s, COOCH ₃ ), 4.30 (1H, d, , J = 6Hz, C ₄ -H), 5.38 (1H, dd, J = 6Hz, 9Hz, C ₃ -H), 5.52 (1H, d, J = 7Hz, PhCH -), 8.68 (1H, s, N, -H),

9.26 (1H, d, J = 9Hz, C ₃ -NH), 9.86 (1H, d, J = 7Hz, PhCHNH).

Alpha-form

IR (λ max = 1770, 1740, 1710, 1670;

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.10 (3H, t, J = 7Hz, N-CH, CH 2), 3.55 (3H, s, COOCH ₃ ), 4.40 (1H _; d, J = 6Hz, C ₄ -H), 5.20 (1H, dd, J = 6Hz, 9Hz, C ₃ -H), 5.47 (1H, d, J = 7Hz, PhCH). 8.70 (1H, s, N, -H), 9.25 (1H, d, J = 9Hz, C ₃ -NH), 9.80 (1H, d, J = 7Hz, PhCHNH).

cis-3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido] -4-methyl-2-oxoazetidine,

Beta-form

IR (λ max ⁴ ): 1750, 1710, 1670.

NMR (CDC1 _3, ppm): 1.15 (3H, d, J = 4 Hz, C ₄ -CH _3).

Alpha-form

IR spectrum (νmax ¹ ): 1760, 1715 ', 1690.

NMR (CDC1 _3, ppm): 1.39 (3H, d, J = 4 Hz, C ₄ -CH _3).

cis-3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido] -4- (acetoxymethyl) -2-oxoazetidine,

B-form ¹H-spectrum (ν max ⁴ ): 1770, 1710, 1670.

NMR (CDC1 _3, ppm): 1.85 (3H, s, OCOCHj).

Alpha-form

IR (m.p. 1780, 1720, 1670).

NMR (CDC1 _3, ppm): 1.90 (3H, s, OCOCH _3).

126. Reference example

300 mg of D-2- [3- (furan-2-aldimino) -2-oxo-1-imidazolidinecarboxamido] -2-phenylacetic acid-72194870

143 watts of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester (110 mg) in the same manner as in Reference Example 39 to give cis-3- {D-2- [3- (furan-2-aldimino) - Methyl 2-oxo-1-imidazolidinecarboxamido-2-phenylacetamido} -2-oxoazetidine-4-carboxylic acid is prepared. Beta-form

IR (α d6): 1760, 1720, 1660. Alpha form

IR: 1770, 1720, 1660

In the same manner, N, N- {D-2- [3- (phiophene-2-aldimino) -2-oxo-1-imidazolidinecarboxamido] -2-phenylacetamido} -2-oxoazolidine-4-carboxylic acid is prepared. methyl ester.

Beta-form

IR spectrum (O * ^'first): 1765, 1725, 1660th

Alpha-form

IR (δ &lt; &gt;): 1770, 1720, 1660.

127, Reference Example

0.8 g of cis-3-benzyloxycarboxamido-1-2-oxo-azetidine-4-carboxylic acid methyl ester) is dissolved in tetrahydrofuran and treated with under cooling and stirring, 1.2 ml of triethylamine followed by dropwise addition of a solution of 2- [2- (chloroacetamido) -4-thiazolyl] -2- (diethylphosphono) acetyl chloride (1.2 g) in tetrahydrofuran (10 ml) add it. The mixture was stirred at room temperature for 2.5 hours and then concentrated. Ethyl acetate and water were added to the residue, and the resulting mixture was shaken well. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (eluent: chloroform: methanol = 95: 5) to give cis-3- {2- [2- (chloroacetamido) -4-thiazolyl] -2- (diethylphosphono) acetamido} -2-. yields oxo-azetidine-4-carboxylic acid methyl ester.

IR (ν max): 3250, 1770, 1750, 1685, 1540, 1230, 1050, 1025.

128. Reference example

Starting from 0.8 g of cis-3- (benzyloxycarboxamido) -2-oxoazetidine-4-carbonate v-methyl ester, the 3-amino compound prepared according to Reference Example 3 is dissolved in tetrahydrofuran and ice-cooling. 0.42 ml of triethylamine and 0.56 g of 3- (triethylsilyl) propionyl chloride are added with stirring. The mixture was stirred for 3 hours at room temperature and then concentrated. Water and ethyl acetate were added to the residue. The phases were separated, the organic phase was washed with water and then with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was crystallized from a mixture of chloroform and diethyl ether and the crystals were filtered off with methyl cis-3- (2- (triethylsilylethyl) carboxamido) -2-oxoacetidine-4-carboxylic acid, m.p. 143 -

145 ° C.

144

IR spectrum (ν max pn * '): 3260, 1790, 1750, 1640, 1540.

Analysis calculated for C ₁₄ H ₂₆ N ₂ O ₄ Si: C, 53.47; H, 8.33; N, 8.91. Found: C, 53.54; H, 8.40; N, 8.73.

129. Reference Example

Dissolve 5.01 g of 2,4-dimethoxybenzylamine in 100 ml of methylene chloride, then add 4.2 g of trans cinnamic aldehyde and 30 g of anhydrous magnesium sulfate. The mixture was stirred at room temperature for 3.5 hours, then filtered. To the filtrate was added, under ice-cooling and stirring, triethylamine (8.4 mL), and a solution of phthalimidoacetyl chloride (7.0 g) in methylene chloride (50 mL) was added dropwise over 30 minutes. The mixture was stirred at room temperature for 2.5 hours, then washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. To the residue was added 50 ml of chloroform ¹ and the precipitate was filtered off. The filtrate was evaporated and the residue passed through a silica gel (30 g) column. The eluate was evaporated and the solid residue was recrystallized from ethyl acetate to give cis-3-phthalimido-4- (E) -styryl-1- (2,4-dimethoxybenzyl) -2-oxoazetidine, m.p. 173-177 ° C. - we get.

IR (Ο * ϊ '): 1750, 1720, 1390; Analysis: Calculated for C ₂₈ H ₂₄ N ₂ O ₅ : C, 71.78; H, 5.16; N, 5.98. Found: C, 72.14; H, 5.01; N, 5.85.

Reference Example 130 g cis-3-phthalimido-4- (E) -styryl-1- (2,4-dimethoxybenzyl) -2-oxoazetidine was dissolved in 150 ml tetrahydrofuran and 2.5 g 10% palladium. carbon is added. After stirring for 30 minutes under hydrogen, the catalyst was filtered off and the filtrate was concentrated in vacuo. Crystallization of the residue from diethyl ether and filtration of the crystals gave 4.8 g of cis-3-phthalimido4- (2-phenylethyl) -1- (2,4-dimethoxybenzyl) -2-oxoazetidine, m.p. 148-150 ° C. C - we get.

IR spectrum (v c ^ ^«f-1): 1750, 1720, 1390. Analysis for C ₂₈ H ₂₆ N ₂ O _5: Calcd: C% = 71.47, H% = 5.57, N% = 5.69; Found: C, 71.55; H, 5.45; N, 5.75.

131. Reference example

4.1 g of cis-3-phthalimido-4- (2-phenylethyl) -1- (2,4-dimethoxybenzyl) -2-oxoazetidine are suspended in 35 ml of dimethoxyethane and 1.4 ml of methyl hydrazine is added. After 3 days at room temperature, the resulting precipitate was filtered off and the filtrate was evaporated. The residue was dissolved in ethyl acetate and extracted three times with dilute hydrochloric acid. The extract was adjusted to pH 7-8 with sodium bicarbonate and then extracted three times with chloroform. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate.

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The mixture was dried and concentrated in vacuo. The residue was dissolved in methylene chloride (50 ml) and propylene oxide (20 ml), followed by dropwise addition of benzyloxycarbonyl chloride (3 ml). The mixture was stirred at room temperature for two hours and then concentrated in vacuo. The residue was subjected to silica gel column chromatography (eluent: chloroform: ethyl acetate = 1: 1). The eluate was evaporated and the residue was crystallized from diethyl ether. The crystals were filtered off with cis-3- (benzyloxycarboxamido) -4- (2-phenylethyl) -1- (2,4-dimethoxybenzyl) -2-oxoazetidine, m.p. 150-152 ° C. we get.

IR: 3300, 1760, 1680, 1535, 1265.

Analysis: Calculated for C ₂₈ H ₃₀ N ₂ O ₅ : C, 70.86; H, 6.37; N, 5.90. Found: C, 70.68; H, 6.44; N, 6.09.

132. Reference example

Following the procedure of Reference Example 2, cis-3- (benzyloxycarboxamido) -4- (2-phenylethyl) -2-oxoazetidine was obtained, m.p. 173-175 ° C.

IR (ν max cm ^-1 ): 3300, 1770, 1685, 1540, 1260.

Analysis: Calculated for C ₁₉ H ₂₀ N ₂ O ₃ : C, 70.35; H, 6.22; N, 8.64. Found: C, 70.13; H, 6.05; N, 8.48.

133. Reference Example

Following the procedure of Reference Example 67, cis-3- (2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido} -4- (2-phenylethyl) - 2-Oxoazetidine (color isomer) was prepared.

IR spectrum (v cw ^ ^1?); 3260, 1740, 1700, 1650, 1540.

134. Reference Example

9.6 g of methyl 2- (methoxyimino) -acetic acid are dissolved in 40 ml of chloroform and a solution of 9.1 g of bromine in 10 ml of chloroform is added dropwise with stirring at 40 ° C. The mixture was stirred for 20 minutes and then poured into ice water. The organic layer was separated, washed with a saturated aqueous solution of sodium bicarbonate, then with water, dried over anhydrous sodium sulfate and concentrated in vacuo. 13.12 g as an oil

Methyl 4-bromo-2- (methoxyimino) -acetic acid is obtained. 10.74 g of this oil and 4.4 g of methylthiocarbamate are added to 40 ml of ethanol and the mixture is refluxed for 1.5 hours and then concentrated. The residue was dissolved in chloroform, washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The crystals of 2- (2-hydroxy-4-thiazolyl) - (Z) -2- (methoxyimino) -acetic acid methyl ester are obtained, m.p. 97-98 ° C.

IR (λ, '): 1720, 1670, 1440, 1260, 1150, 1040.

146

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 4.02 (3H, s, NOCH ₃ ), 6.79 (1H, s, CV), 11.76 (1H, s, COOH);

136. Reference example

Referring to Reference Example 34, cis-3- [2- (2-hydroxy-4-thiazolyl) -2- (methoxyimino) acetamido] -4- (methoxycarbonyl) -2-oxoazetidine m.p. 202-204 ° C (dec.).

IR: 3260, 1775, 1735, 1685, 1660, 1520, 1440, 1220, 1040.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.50 (3H, s, COOCH ₃ ), 3.86 (3H, s, NOCH ₃ ), 4.33 (ΓΗ, d, J = 5Hz, C). _4- H), 5.25 (1H, dd, J = 5 Hz, 8 Hz);

6.23 (1H, s, CV);

8.53 (1H, br.s, N, -H), 9.33 (1H, d, J = 8 Hz, C ₃ -NH).

137. Reference example

2.14 g of cis-3- (benzyloxycarboxamido) -1- (2,4-dimethoxybenzyl) -2-oxoazetidine-4-carboxylic acid methyl ester prepared according to Reference Example 1 Dissolve in 150 ml of methanol and add, under ice-cooling and stirring, a solution of 0.83 g of potassium carbonate in 25 ml of water. After stirring for 6.5 hours at room temperature, the methanol was evaporated in vacuo. Water was added to the residue and the resulting mixture was washed with ethyl acetate / diethyl ether and then acidified with 1N hydrochloric acid. The resulting precipitate was filtered off and washed with water, 1.95 g of cis-3- (benzyloxycarboxamido) -1- (2,4-dimethoxybenzyl) -2-oxoazetidine-4-carboxylic acid, m.p.

189-191 ° C.

IR (λ max ⁶ ): 3300, 1760, 1705.

1690th

138. Reference Example

Dissolve 4.1 g of cis-3- (benzyloxycarboxamido) -1- (2,4-dimethoxybenzyl) -2-oxoazetidine-4-carboxylic acid in 80 ml of dry tetrahydrofuran and 4 ml of oxalyl chloride. we add. The mixture was stirred for 30 minutes and then concentrated. The residue was washed with hexane, dissolved in 80 ml of methylene chloride and 4 ml of ethanol were added under ice-cooling. The mixture was stirred for 20 minutes and then concentrated. The residue was crystallized from diethyl ether and filtered to give colorless crystals of cis-3- (benzyloxycarboxamido) -1- (2,4-dimethoxybenzyl) -2-oxoacetate din-4-carboxylic acid ethyl ester. The product has a melting point of 117-118 ° C after recrystallization from ethanol.

IR (?): 3250, 1770, 1735, 1680.

Calcd for C ₂₃ H ₂₆ N ₂ O _7: Calcd: C% = 62.43, H% 5.92, N% = 6.93; Found: C, 62.43; H, 5.91; N, 6.05.

139. Reference Example

Referring to Reference Example 2, cis-3- (benzyloxycarboxamido) -2-oxo-74194870

147

-azetidine-4-carboxylic acid ethyl ester, m.p. 134-135 ° C.

IR spectrum (v ^ ^j "c ** t ^<): 3300, 1800, 1740, 1720th

Analysis: Calculated for C ₁₄ H ₆ N ₂ O ₅ : C, 57.52; H, 5.51; N, 9.58; Found: C, 57.58; H, 5.44; N, 9.60.

140. Reference Example

Following the procedure of Reference Example 3, ethyl cis-3-amino-2-oxoazetidine-4-carboxylate, m.p. 105-106 ° C (dec.), Is prepared.

IR spectrum (v ^^ 'CWI ^4): 3400, 3200, 1745, 1720, 1700th

Analysis: Calculated for C ₆ H ₁₀ N ₂ O ₃ : C, 45.56; H, 6.37; N, 17.71 _; Found: C, 45.66; H, 6.20; N, 17.70.

141. Reference example

Referring to Reference Example 4, cis-3- (2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido] -2-oxoazetidine-4-carboxylic acid ethyl ester isomers.

Color isomer m.p. 280-283 ° C (dec.).

IR (ν cm -1): 3230, 1750, 1730, 1670.

NMR _(D6 -DMSO, ppm): 1.20 (3H, t, J = 7Hz, _{CH2 CH3),} 5.73 (1H, dd, J = 5Hz, 9Hz, _C3 - H), 7.42 (1H, s, CV).

M.p. 108-110 ° C.

IR spectrum (v Chi ^ ° ^1): 3250, 1760, 1720, 1650th

NMR _(D6 -DMSO, ppm): l, 20 (3H, t, J = 7Hz, _{CH2 CH3),} 5.50 (lH, dd, J = 5Hz, 9Hz, _C3 - H), 8.00 (1H, s, CV),

142. Reference example

2 g of cis-3- (benzyloxycarboxamido) -1- (2,4-dimethoxybenzyl) -2-oxoazetidine-4-carboxylic acid prepared according to Reference Example 137 are dissolved in 60 ml of dry tetrahydrofuran. and 2 ml of oxalyl chloride was added. The mixture was refluxed for 30 minutes and evaporated. The residue was washed with hexane and dissolved in 40 mL of tetrahydrofuran. To the solution was added 1 ml of aniline while cooling with ice-water and the mixture was stirred for 30 minutes. The resulting crystalline precipitate was filtered off and washed with diethyl ether followed by methanol to give cis-3- (benzyloxycarboxamido) -1- (2,4-dimethoxybenzyl) -4- (phenylcarbamoyl) -2-oxoazetidine. we get. The compound, after recrystallization from chloroform / methanol, m.p. 255-257 ° C.

IR (ν max): 3250, 1760, 1690, 1670.

Analysis: Calculated for C ₂₇ H ₂₇ N ₃ O ₆ : C, 66.24; H, 5.55; N, 8.58. Found: C, 65.80; H, 5.34; N, 8.43.

148

143. Reference Example

Following the procedure of Reference Example 2, cis-3- (benzyloxycarboxamido) -4- (phenylcarbamoyl) -2-oxoazetidine, m.p. 235-238 ° C (dec.), Was prepared.

IR (ν ^, ^) 3270, 1760, 1690, 1670.

NMR _(D6 -DMSO, ppm): 4.4 (lH, d, J = 5Hz, _C4 -H), 5.02 (2H, s, _PhCH?) .5.15 (lH, dd, J = 5 Hz, 9 Hz, C ₃ -H).

144. Reference Example

In the same manner as in Reference Example 3, cis-3-amino-4- (phenylcarbamoyl) -2-oxoazetidine, m.p. 152-154 ° C (dec.), Is prepared.

IR spectrum (vm ct · ^ » ^'4): 3300, 1740, 1690th

145. Reference Example

Referring to Reference Example 4, cis-3- (2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido] -4- (phenylcarbamoyl) -2 oxoazetidine (color isomer) was prepared.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.53 (3H, s, NOCH ₃ ), 4.3 (2H, s, ClCH ₂ ),

4.48 (lH, d, J = 5Hz, _C4 -H), 5.57 (lH, dd, J = 5Hz, 9Hz, _C3 -H).

146. Reference example

Dissolve 2.502 g of cis-3- (benzyloxycarboxamido) -2-oxoacetyldin-4-carboxylic acid methyl ester prepared according to Reference Example 2 in 160 ml of methanol and ice-cooling and stirring. while adding an aqueous solution of 1.242 g of potassium carbonate in 50 ml. After stirring for 70 minutes at room temperature, 9 ml of 1N hydrochloric acid was added under ice-cooling and stirring. The methanol was then evaporated in vacuo, the residual aqueous solution was washed with ethyl acetate and evaporated in vacuo. The residue was chromatographed on an Amberlite XAD-II column and freeze-dried the eluate to give a colorless powder of the cis-3- (benzyloxycarboxamido) -2-oxoazetidine-4-carboxylic acid potassium salt.

IR spectrum (v £ ® ^r <^ *) 1770, 1755, 1705, 1675, 1590, 1410, 1320th

NMR _(D6 -DMSO, ppm): 3.82 (lH, d, J = 5Hz, _C4 -H), 4.78 (lH, dd, J = 5 Hz, 9 Hz, C _r H ), 5.01 (2H, s, CH ₂ ), 7.29 (5H, s, Ph-), 7.31 (1 H, d, d = 9Hz, C ₃ -NH), 8.26 (1 H , br.s, N, -H).

147. Reference example

717 mg of the potassium salt of cis-3- (benzyloxycarboxamido) -2-oxoazetidine-4-carboxylic acid are dissolved in 5 ml of Ν, Ν-dimethylformamide and 0.25 ml of bromoacetic acid ethyl are added under ice-cooling and stirring. -ester is added. The mixture was stirred for one hour at room temperature and then 75

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Water (149 mL) was added and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. Diethyl ether was added to the residue and the precipitate was filtered off with colorless crystals of cis-3- (benzyloxycarboxamido) -4- (ethoxycarbonylmethyloxycarbonyl) -2-oxoazetidine, m.p. 109-111. ° C - obtained.

IR spectrum (v ^, ^r ^ c _'): 3350, 3260, 1775, 1765, 1750, 1710, 1675th

Analysis for C ₁₆ H ₁₈ N ₂ O _7: Calcd: C% = 54.86, H% = 5.18, N% = 8.00; Found: C, 54.90; H, 5.24; N, 7.79.

148. Reference example

Following the procedure of Reference Example 67, cis-3-12- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido) -4- (ethoxycarbonylmethyloxy). carbonyl) -2-oxoazetidine (color isomer) m.p. 226-231 ° C (dec.).

IR (ν ^KBr ): 3270, 1765, 1750, 1690, 1670.

Analytical results for C ₁₆ H _lg ClN ₅ O _g S:

Calculated: C, 40.38; H, 3.81; N, 14.72 _. Found: C, 40.08; H, 3.97; N, 14.51.

149. Reference Example

Diethyl ester for trans-3- (benzyloxycarboxamido) -1- (2,4-dimethoxybenzyl) -2-oxoazetidine-4-carboxylic acid prepared according to Reference Example 26. and allow the mixture to cool. On standing, crystals precipitate out which are filtered off and washed with diethyl ether to give colorless crystals, m.p. 65-68 ° C.

Analysis for C ₂₂ H ₂₄ N ₂ O _7: Calcd: C% = 61.67, H% = 5.65, N% = 6.54; Found: C, 61.84; H, 5.48; N, 6.36.

This product was reduced with sodium borohydride as in Reference Example 5 and purified by column chromatography on silica gel (eluent: hexane: ethyl acetate = 1: 4). Trans-3- (benzyloxycarboxamido) -1- (2,4-dimethoxybenzyl) -4- (hydroxymethyl) -2-oxoazetidine was obtained as a colorless oil.

IR (λ max cm ^-1 ): 3400, 3325, 1740 (br), 1030.

150. Reference Example

Trans-3- (benzyloxycarboxamido) -1- (2,4-dimethoxybenzyl) -4- (hydroxymethyl) -2-oxoazetidine (5.8 g) was dissolved in methylene chloride (50 mL) and ice-cooled. and while stirring

Pyridine (2.29 g) was added followed by acetyl chloride (1.54 ml). The mixture was stirred at room temperature for one hour and then concentrated. The residue was dissolved in ethyl acetate, washed with 3N hydrochloric acid, then with aqueous sodium bicarbonate and finally with sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. 76

150

The residue was dissolved in 300 ml of acetonitrile and a solution of 5.87 g of potassium persulfate and 3.78 g of dipotassium hydrogen phosphate in water was added dropwise to the solution under reflux. Upon completion of addition the mixture was refluxed for an additional hour, the acetonitrile removed in vacuo and the remaining aqueous solution was extracted with ethyl acetate _r. The extract was washed with a saturated aqueous solution of sodium bicarbonate and then with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (140 g silica gel; eluent: hexane: ethyl acetate = 1: 2) to give trans-3- (benzyloxycarboxamido) -4- (acetoxymethyl) -2-oxoazetidine - m.p. 121 ° C.

IR (λ cm -1): 3245, 1750, 1725, 1705, 1550, 1270, 1250, 1035.

151. Reference example

Following the procedure of Reference Example 67, trans-3- (2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido} -4- (acetoxymethyl) -2- oxoazetidine (color isomer), m.p. 177-190 ° C (dec.).

IR spectrum (vmax, ^cw-1): 3180, 1760, 1735, 1710, 1640, 1565, 1040th

152. Reference example

Trans-3- (benzyloxycarboxamido) -1- (2,4-dimethoxybenzyl) -4- (hydroxymethyl) -2-oxoazetidine (18.3 g) was dissolved in pyridine (50 mL) under ice-cooling. 76 g of methanesulfonyl chloride are added. After stirring for one hour at room temperature, the reaction mixture was poured into ethyl acetate and washed with 6N hydrochloric acid, aqueous sodium bicarbonate and sodium chloride, and dried under anhydrous magnesium sulfate. The residue was dissolved in 400 mL of methyl ethyl ketone and 34.25 g of sodium iodide was added. The mixture was refluxed for 2.5 hours and then concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with a saturated solution of sodium bisulfite and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting oily residue is trans-3- (benzyloxycarboxamido) -4- (iodomethyl) -1- (2,4-dimethoxybenzyl) -2-oxoazetidine.

IR (OV ¹ ): 3300, 1760, 1710, 1605, 1510, 1285, 1260, 1210.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 3.78 (6H, s, 2XOCH ₃ ), 5.00 (2H, s, Ph-CH ₂ ),

7.28 (5H, s, Ph-).

153. Reference example

Following the procedure of Reference Example 63, trans-3- (benzyloxycarboxamido) -1- (2,4-dimethoxybenzyl) -4-methyl-2-oxoazetidine was prepared. The product does not crystallize,

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Therefore, it was purified by column chromatography (350 g silica gel; eluent: hexane: ethyl acetate = 2: 1 then 1: 2).

IR spectrum (vmax * cw ^4): 3280, 2950, - 1750, 1710, 1605, 1505, 1260, 1210th

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 1.20 (3H, d, J = 6Hz, C ₄ -CH ₃ ), 3.75 (6H, s, 2XQCH ₃ ), 5.02 (2H, s, ph-CHO).

5.55 (IH, dd, J = 6Hz, 8Hz, _C3 -H), 7.21 (5H, s, Ph).

154. Reference Example

By using the procedure of Reference Example 66, trans-3- (benzyloxycarboxamido) -4-methyl-2-oxoazetidine, m.p. 109-111 ° C, was prepared.

IR (λ max ¹ ): 3320, 3220, 1780, 1690, 1535, 1450, 1265, 1045, 730.

155. Reference example

Using the procedure of Reference Example 67, trans-3- (2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetamido} -4-methyl-2-oxoazetidine ( color isomer) m.p. 240-248 ° C (dec.).

IR (λ max): 3330, 1740, 1680, 1665, 1575, 1540, 1355, .1045.

156. Reference example

140 mg of cis-3- (benzyloxycarboxamido) -4-methoxycarbonyl-2-oxoazetidine are dissolved in

1.4 ml of dry tetrahydrofuran and 0.1 ml of 40% methylamine solution and a drop of acetic acid are added. The mixture was allowed to stand for 4 hours in a cool place (5 ° C) and the resulting precipitate was filtered off and washed with diethyl ether to give cis-3- (benzyloxycarboxamido) -4- (triethylcarbamoyl) -2-oxoazetidine. m.p. 207-208 ° C after recrystallization from ethyl acetate / methanol.

IR 3270, 1770, 1700,

1660th

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 2.56 (3H, d, J = 5Hz, NHCH ₃ ), 4.13 (1H, d, J = 5Hz, C ₄ -H), 7, 33 (5H, s, Ph), 8.33 (1H, d, J = 5Hz, NHCH ₃ )

Analysis for C _I3 H ₁₅ N ₃ O _4: Calcd: C% = 56.30, H% = 5.45, N% = 15.15% Found: C = 56.17% H = 5.31 N, 15.23

157. Reference example

Cis-3- (benzyloxycarboxamido) -4-methylcarbamoyl-2-oxoazetidine (831 mg) was dissolved in a mixture of tetrahydrofuran (50 ml) and methanol (50 ml) and 5% palladium on carbon (830 mg) was added. After stirring for 1 hour under a hydrogen atmosphere, the catalyst was filtered off and the filtrate was concentrated in vacuo to give 410 mg of cis-3-amino-4-methylcarbamoyl) -2-oxoazetidine as a colorless powder.

152

IR (λ max): 3300, 1750, 1650.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 2.70 (3H, d, J = 5Hz, NHCH ₃ ), 3.96 (4.23) 2X1H, 2Xd, J = 5Hz, C ₃ -H .

C ₄ -H).

320 mg of this material are dissolved in a mixture of 6 ml of water and 6 ml of tetrahydrofuran and 500 mg of sodium bicarbonate are added. Under ice-cooling and stirring, 2- [2- (chloroacetamido) -4-thiazolyl] -2- (Z) -methoxyiminoacetyl chloride hydrochloride salt (960 mg) was added and stirred for one hour, then the tetrahydrofuran was evaporated and the remaining aqueous phase was filtered. The resulting powder was washed first with an aqueous solution of sodium bicarbonate, then with water, then with ethanol and then with diethyl ether to give cis-3- {2- (2- (chloroacetamido) -4-thiazolyl) -2- (methoxy) imirto) -acetamido} -4- (methylcarbamoyl) -2-oxoazetidine (color isomer) is obtained.

IR (λ max ¹ ): 3220, 1750, 1700, 1660.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 2.50 (3H, d, J = 5Hz, NHCH ₃ ), 3.76 (3H, s, NOCH _S ), 5.3 (1H, dd, J = 5 Hz, 9 Hz, C ₃ H), 7.28 (1H, s, CV), 7.8 (1H, d, J = 5 Hz, NHCH ₃ ), 8.3 (1H, br. s, N, -H).

158. Reference Example

By using the procedure of Reference Example 91, but trans-3- (benzyloxycarboxamido) -2-oxoazetidine-4-carboxylic acid methyl ester instead of the cis isomer. using trans-3-] 2- [2- (chloroacetamido) -4-thiazolyl] -2- [1-methyl-1- (p-nitrobenzyloxycarbonyl) ethyl-oxyimino] - acetamido) -4- (methoxycarbonyl) -2-oxoazetidine (color isomer) crystals) m.p. 110-120 ° C (dec.).

IR (v ^{Br ( 4} )); 3280, 2980, 1790-1740, 1680, 1525.

Analytical results for C ₂₃ H ₂₃ ClN ₆ O _{1 ()} S:

Calculated: C, 45.21; H, 3.79; N, 13.76 Found: C, 45.60; H, 4%; N, 13.14.

159. Reference Example

Following the procedure of Reference Example 81, the following compounds were prepared:

N- [1- (methoxycarbonyl) -1-methylethoxy] phthalimide

Mp 106-107 ° C

IR spectrum (vmax, ^»1): 2990, 2960, 1790, 1740th

Analysis: Calculated for C ₁₃ H ₁₃ NO ₅ : C, 59.31; H, 4.98; N, 5.32. Found: C, 59.60; H, 4.98; N, 5.22.

N- {1-methyl-1- [2- (trimethylsilyl) ethoxycarbonyl] ethoxy] phthalimide

IR (λmax c = ⁴ ): 2940, 1790, 1735.

NMR (CDC1 _3, ppm): 0.10 (9H, s, _SiMe3), 0.92 (2H, t, J = 9Hz,

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CH ₂ Si), 1.62 (6H, s, NOCMe), 4.31 (2H, 1H, J = 9Hz, COOCH3), 7.73 (4H, s, aromatic protons).

160. Reference Example

Following the procedure of Reference Example 82, the following compounds were prepared: 0- [1- (methoxycarbonyl) -1-methylethyl] hydroxylamine

IR (νmax 1) ⁴ : 3325, 2980, 2950, 1735.

NMR (CDC1 ₃ ppm): 1.43 (6H, s, CMeJ, 3.75 (3H, s, COOCHJ, 5.33 (2H, br, NH.

O- {1-Methyl-1- [2- (trimethylsilyl) ethoxycarbonyl] ethyl} -hydroxylamine

IR 3320, 2950, 1730.

NMR (CDC1 _3, ppm): 0.10 (9H, s, SiMeJ, 1.12 (2H, t, CH ₂ Si), 1.45 (6H, s, NOCMej, 4.25 (2H, t, J = 9Hz, COOCH3, 5.12-5.43 (2H, br., NH3).

161. Reference example

Following the procedure of Reference Example 83, the following compounds were prepared: 2- [2- (Chloroacetamido) -4-thiazolyl] -2- [1- (methoxycarbonyl) -1-methylethoxyimino]. acetic acid.

IR: 3200, 2980, 1750—

1680th

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 1.58 (6H, s, CMeJ, 3.72 (3H, s, COOCH

4.3 (2H, s, CH 2 Cl 2, 7.33 (1H, s, thiazole-5-H)).

2- [2- (chloroacetamido) -4-thiazolyl] -2- (1-methyl-1- [2- (trimethylsilyl) ethoxycarbonyl] ethoxyimino] acetic acid.

IR (ν max cw ⁴ ): 3420, 3200, 2960, 1740, 1730.

162. Reference example

Using the procedure of Reference Example 84, 2- [2- (Chloroacetamido) -4-thiazolyl] -2- [1- (methoxycarbonyl) -1-methylethoxyimino] acetyl chloride hydrochloride salt. Mp 105-115 ° C.

IR spectrum (v, cm ^4): 2980, 1790, 1745, 1700th

Analysis for C | _I3 C1 2 H ₂ N ₃ O ₆ S.HC1 formula:

Found: C, 34.42; H, 3.37; N, 10.03 _; Found: C, 34.94; H, 3.46; N, 10.21.

163. Reference Example

In a similar manner to Reference Example 85, cis-3-12- [2- (chloroacetamido) -4-thiazolyl] -2- [1-methoxycarbonyl) -1-methylethoxyimino] acetamido} - 4- (methoxycarbonyl) -2-oxoazetidine (color isomer), m.p. 212-214 ° C (dec.).

IR spectrum (v ^ ¹ CWI); 3300, 3080, 2975, 1780-1750, 1720, 1660.

154

Analytical results for C ₁₇ H ₂₀ C ₁ N ₅ O ₈ S:

Found: C, 41.68; H, 4.12; N, 14.30 _; Found: C, 41.47; H, 4.14; N, 14.06.

164. Reference Example

820 mg of 2- [2- (chloroacetamido) -4-thiazolyl] -2- [1-methyl-1- [2- (trimethylsilyl) ethoxycarbonyl] ethoxyimino] acetic acid are dissolved in 25 ml. of methylene chloride and ice-cooling, 221 mg of triethylamine and 380 mg of phosphorus pentachloride were added. The mixture was stirred for 15 minutes under ice-cooling and then for 2 hours at room temperature. The reaction mixture was concentrated in vacuo and the residue dissolved in tetrahydrofuran (5 mL) to give an acid chloride solution.

On the other hand, 219 mg of cis-3-amino-4- (methoxycarbonyl) -2-oxoazetidine was dissolved in a mixture of 5 ml of tetrahydrofuran and 10 ml of water and 638 mg of sodium bicarbonate was added under ice-cooling. To this mixture is added dropwise a stirred solution of the acid chloride solution just prepared. The reaction mixture was stirred for 15 minutes under ice-cooling and then for one hour at room temperature and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and evaporated to give cis -3-12- [2- (chloroacetamido) -4-thiazolyl] -2- [1-methyl-1- [2- (trimethylsilyl) ethoxycarbonyl]. 1-ethoxyimino] -acetamido} -4- (methoxycarbonyl) -2-oxoazetidine (color isomer) is obtained.

IR spectra (ν ± c * nj: 3280, 2950, 1760, 1730, 1685).

Nuclear Magnetic Resonance Spectrum (CDCl ₃ - (- D ₆ -DMSO, ppm): 1.18 (2H, CH ₂ Si), 1.81 (6H, NOCMe, 4.40 (2H, CO

4.44 (2H, s, CH 2 OH, 4.67 (1H, d, J = 6Hz, C ₄ -H), 5.88 (1H, dd, J = 6Hz, 9Hz, C ₃ -H) 7.57 (lH, s, a group of formula CV), 8.03 (1H, br, N-H), 8.29 (1H, d, J = 9Hz, _C3 -NH).

165. Reference example

Methyl cis-3- (benzyloxycarboxamido) -2-oxoazetidine-4-carboxylate prepared according to Reference Example 2.

1.5 g is dissolved in 20 ml of tetrahydrofuran and 10 ml of a 1M aqueous ammonium chloride solution are added. At room temperature, while stirring, 0.5 ml of aqueous ammonia solution (25-28%) was added and the mixture was stirred for 3 hours. A further 2 mL of aqueous ammonia was added and stirring continued for an additional 16 hours. The tetrahydrofuran was evaporated in vacuo and the resulting crystalline precipitate was filtered off. The crystals were washed with water and then with diethyl ether and dried over cis-3- (benzyloxycarboxamido) -4-carbamoyl-2-oxoazetidine - m.p.

237 DEG C. (decomposition).

. IR spectrum (v *> t ^4, _3400, 3300, 3200, 1760, 1670.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 4.14 (1H, d, J = 6Hz, C ₄ -H), 5.05 (2H, s,

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155

PhCH ₂ ), 5.08 (1H, dd, J = 6Hz, 10Hz, Cl-H), 7.36 (5H, s, aromatic protons).

Analysis _I2 C H ₃ N ₃ O _4: Calcd: C% = 54.57, H% = 4.98, N% = 15.96% Found: C = 54.93% H = 4, 90, N% = 15.65.

By the same method, the corresponding trans compound is also prepared.

166. Reference Example

Cis-3- (benzyloxycarboxamido) -4-carbamoyl-2-oxoazetidine (304 mg) was suspended in ethanol (15 mL) and 5% palladium on carbon (304 mg) was added. After stirring at room temperature under a hydrogen atmosphere for 1.5 hours, the catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in a mixture of 6 ml of tetrahydrofuran and 6 ml of water and 534 mg of sodium bicarbonate was added under ice-cooling. To the solution thus obtained was added 2- [2- (chloroacetamido) -4-thiazolyl] - (Z) -2- [1-methyl-1- (p-nitrobenzyl) 2- (2- (chloroacetamido) -4-thiazolyl) prepared as in Example 90. 686 mg of the oxycarbonyl) -ethyloxyimino] -acetyl chloride hydrochloride salt and the mixture was stirred for 15 minutes under ice-cooling and then for one hour at room temperature. The reaction mixture was extracted with ethyl acetate (200 mL), and the extract was washed twice with 0.1 N aqueous sodium hydroxide solution and once with aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. Cis-3- {2- [2- (chloroacetamido) -4-thiazolyl] -2- [1-methyl-1- (p-nitrobenzyloxycarbonyl) -ethyloxyimino] in the form of a foam. ] -acetamido] -4-carbamoyl-2-oxoazetidine (color isomer), m.p. 144-147 ° C.

IR spectrum (v ^ w, ^4); 3380, 1760, 1750, 1680.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.52 (6H, s, 2XCH ₃ ), 4.27 (1H, d, J = 6Hz, C ₄ -H), 4.34 (2H, s, ClCH ₂ ), 5.32 (2H, s, COOCH ₂ ), 5.46 (1H, dd, J = 6Hz, 9Hz, C ₃ -H), 7.41 (1H, s, CV) group).

By the same method, the corresponding trans compound is also prepared.

167. Reference example

Dissolve 4 g of cis-3- (benzyloxycarboxamido) -1- (2,4-dimethoxybenzyl) -4- (hydroxymethyl) -2-oxoazetidine prepared in Reference Example 5. In methylene chloride (80 ml) and chlorosulfonyl isocyanate (0.9 ml) was added under ice-water cooling. After stirring for 30 minutes, chlorosulfonyl zocyanate (0.9 ml) was added once more and stirred for an additional 10 minutes. The reaction mixture was added dropwise to a stirred solution of 2.8 g of sodium sulfite in 60 ml of water while cooling with ice-water. The mixture was stirred for 1 hour at room temperature and the resulting crystals were added to methylene chloride

156. The methylene chloride layer was separated, washed with an aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, evaporated and diethyl ether was added to the residue. The resulting crystals were collected by filtration to give 3.3 g of cis-3- (benzyloxycarboxamido) -1- (2,4-dimethoxybenzyl) -4- (carbamoyloxymethyl) -2-oxoazetidine.

IR (λ max) 3400, 3300, 3200, 1760, 1690.

This product was added to a mixture of 75 mL of acetonitrile and 37.5 mL of water, followed by addition of 6.5 g of potassium persulfate and 3.9 g of dipotassium hydrogen phosphate. The mixture was stirred under argon for 1 hour at 95 ° C, then cooled and ethyl acetate was added. The organic phase was separated, washed with aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated. Diethyl ether was added to the residue, and the resulting precipitate was filtered off and purified by column chromatography on silica gel (90 g silica gel; eluent: chloroform: methanol: ethyl acetate = 85: 10: 5) to give 4-ethyl-4-benzyloxycarboxamido. Colorless crystals of - (carbamoyloxymethyl) -2-oxoazetidine, m.p. 205-207 ° C.

IR: 3430, 3300, 1760,

1700th

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm), 6.33 (2H, br.s, NH ₂ ), 7.30 (5H, s, C ₆ H ₅ ),

7.8 (1H, d, J = 9Hz, C ₃ -NH), 8.16 (1H, br.s, N, -H).

Analysis: Calculated for C ₁₃ H ₁₅ N ₃ O ₅ : C, 53.23; H, 5.15; N, 14.32 _; Found: C, 53.33; H, 4.90; N, 14.09.

168. Reference Example

3 g of the trans-3- (benzyloxycarboxamido) -2-oxoazetine in-4-carboxylic acid methyl ester prepared according to Reference Example 27 are dissolved in a mixture of 30 ml of tetrahydrofuran and 30 ml of water and while cooling, 6 ml of a 1M aqueous ammonium chloride solution were added, followed by 4 ml of a 25-28% aqueous ammonia solution. After stirring for 3 hours at room temperature, the tetrahydrofuran was evaporated in vacuo. To the remaining aqueous solution was added sodium chloride and extracted twice with chloroform / ethanol (3: 1). The extracts were combined, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (180 g silica gel, eluent: ethyl acetate followed by ethyl acetate: methanol = 8: 1) to give trans-3- (benzyloxycarboxamido) -4-carbamoyl-2-oxoazetidine. mp: 179-184 ° C.

IR 3280, 1760, 1695,

1660th

NMR _(D6 -DMSO, ppm): 3.90 (IH, d, J = 3 Hz, C ₄ -H), 4.42 (IH, d, • J = 3 Hz, 9 Hz, _C3 -H), 8.04 (1H, d, J = 9Hz, C 1 -NH);

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169. Reference Example

31.0 g of freshly distilled methacrolein are dissolved in 300 ml of methylene chloride and 36.9 g

2,4-Dimethoxybenzylamine is added. Anhydrous sodium sulfate (100 g) and p-toluenesulfonic acid monohydrate (440 mg) were added and the mixture was stirred at room temperature for three hours. The reaction mixture was filtered and the filtrate was evaporated. The residue was dissolved in methylene chloride (300 mL) and a solution of triethylamine (24.5 g) in methylene chloride (100 mL) was added dropwise with ice-cooling and stirring. A solution of 49.4 g of phthalimidoacetyl chloride in 300 ml of methylene chloride is then added dropwise over 1 hour. The reaction mixture was stirred overnight at room temperature, then filtered and the precipitate was washed with methylene chloride. The filtrate and the washings were combined and concentrated in vacuo to a volume of 0.5 L. This residue was washed first with 200 ml of 1N hydrochloric acid, then with 200 ml of water, twice with 300 ml of 2% aqueous sodium bicarbonate solution, and again with 200 ml of water, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel column (400 g silica gel; hexane: ethyl acetate = 1: 1) to give 55.8 g of crude cis-3-phthalimido-4-isoprenyl-1- (2,4-dimethoxybenzyl) -2 -oxo-azetidine is obtained. This product was dissolved in methanol (500 mL) and 5% palladium on carbon (25 g) was added. The mixture was stirred for 7 hours under a hydrogen atmosphere to bind 870 cm ^{3 of} hydrogen. The catalyst was then filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate and the solution was washed three times with 100 ml of 1N hydrochloric acid and once with aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue (47 g) was dissolved in ethanol (700 ml) and 5% palladium on carbon (47 g) was added. The mixture was stirred for 24 hours under an atmosphere of hydrogen to bind 1900 cm ^{3 of} hydrogen. The reaction mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography (400 g silica gel; eluent: hexane: ethyl acetate = 1: 1), the eluate was evaporated and ethanol was added to the residue. The resulting crystalline precipitate was collected by filtration to give 8.6 g of cis-3-phthalimido-4-isopropyl-1- (2,4-dimethoxybenzyl) -2-oxoazetidine. The mother liquor is evaporated and the residue is redissolved in 450 ml of ethanol using 15 g of 5% palladium on carbon to yield 700 cm ^{3 of} hydrogen. The catalyst was filtered off and the filtrate was evaporated. The resulting crystalline precipitate was filtered off and washed with ethanol to give another 5.3 g of 4-isopropyl compound. Recrystallization from ethanol gave colorless crystals melting at 151-152 ° C.

158

Mass Spectrum m / e 408 (M ⁺ )

IR spectrum (vmax Jetman * ^4): 1760, 1715 Elementary analysis for C ₂₃ H ₂₄ N ₂ O _5: Calcd: C% = 67.63, H% = 5.92, N% = 6 "86 Found: C, 67.53; H, 5.89; N, 6.79.

170. Reference Example

8.5 g of cis-3-phthalimido-4-isopropyl-1- (2,4-dimethoxybenzyl) -2-oxoazetidine are dissolved in 170 ml of dimethoxyethane and 2.1 ml of methylhydrazine under ice-cooling and stirring. drip it. The mixture was stirred at room temperature for 4 hours, then at 35-40 ° C for 2 hours, then filtered and the filtrate evaporated in vacuo. The previously filtered crystals are added to the residue and 120 ml of dichloroethane are added. The mixture was stirred at 60-70 ° C for 3 hours, then cooled, filtered and the filtrate evaporated in vacuo. The residue was dissolved in ethyl acetate and the resulting solution was extracted with 50 ml, then 20 ml of 1N hydrochloric acid. The extract was washed with diethyl ether and then 8.4 g of sodium bicarbonate was added. The resulting oil was extracted with chloroform, the extract was washed with an aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was dissolved in methylene chloride (10 mL) and propylene oxide (30 mL) was added. A solution of 3.55 g of benzyloxycarbonyl chloride in 10 ml of methylene chloride is added dropwise with ice-cooling and stirring, thereby precipitating crystals. After adding 70 ml of propylene oxide and 30 ml of methylene chloride, the mixture is stirred at room temperature, whereupon the crystals are gradually dissolved and a clear solution is obtained within 4 hours. The solution was evaporated and the residue was purified by column chromatography (250 g silica gel; eluent: hexane: ethyl acetate = 1: 1) followed by crystallization from diethyl ether (4.7 g of cis-3-benzyloxycarboxamido) -4-isopropyl- 1- (2,4-Dimethoxybenzyl) -2-oxoazetidine - op: 123-

125 ° C.

IR spectrum (vmax ° <L · ^4): calcd 3300, 1760, 1690. Analysis for C ₂₃ H ₂₈ N ₂ O _S: Calculated: C% = 66.97, H% = 6.84 N% 6.79; Found: C, 66.96; H, 6.83; N, 6.81.

Reference Example 171 A solution of cis-3- (benzyloxycarboxamido) -4-isopropyl-1- (2,4-dimethoxybenzyl) -2-oxoazetidine (2.06 g) in acetonitrile (ml) and water (25 ml) was added. Potassium persulfate (1.89 g) and dipotassium hydrogen phosphate (1.13 g) were added and the mixture was stirred at 95 ° C for 2 hours and then cooled. The acetonitrile was evaporated in vacuo, water (50 mL) was added to the remaining aqueous solution, and the mixture was extracted with ethyl acetate (200 mL). The extract was washed twice with 100 ml of 2% aqueous sodium bicarbonate solution and then with sodium bicarbonate solution.

159

chloride, washed once with an aqueous solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was heated briefly with 50 ml of benzene and allowed to cool. The resulting precipitate was filtered off and washed with benzene and then with a little diethyl ether,

1,1 S cis-3- (benzyloxycarboxamido) -4-isopropyl-2-oxoazetidine, m.p. 184-185 ° C.

IR spectrum (vmax ° c> »i ^'4): 3340, 1760, 1690. Analysis for C ₄ H ₁₈ N ₂ O _3: Calcd: C% = 64, I0,% H = 6.92 N, 10.68 Found: C, 63.85, H, 6.75, N, 10.47.

172. Reference example

1.0 g of cis-3- (benzyloxycarboxamido) -4-isopropyl-2-oxoazetidine is suspended in 30 ml of ethanol and 1.0 g of 5% palladium on carbon catalyst is added. After stirring for 30 minutes under a hydrogen atmosphere, the catalyst was filtered off and the filtrate was concentrated in vacuo to give 430 mg of crystalline cis-3-amino-4-isopropyl-2-oxoazetidine, m.p. 91-93 ° C.

IR (O): 3350-3150, 1735.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 0.95 (6H, d, J = 6Hz, 2XCH ₃ ), 1.59 (2H, br.s, NH ₂ ), 3.2 (1H, dd, J = 5 Hz, 9 Hz, C ₄ -H), 4.17 (1H, d, J = C ₃ -H).

Analysis: Calculated for C ₆ H ₁₂ N ₂ O: C, 56.22; H, 9.44; N, 21.86. Found: C, 56.35; H, 9; 45, N% = 21.38.

173. Reference Example

3.7 g of p-anisidine are dissolved in 100 ml of methylene chloride and 4.2 g of trans cinnamic aldehyde and 30 mg of anhydrous magnesium sulfate are added. After stirring for 2 hours at room temperature, the mixture was filtered and the precipitate was washed with methylene chloride (60 mL). The filtrate and the washings were combined and 8.4 g of triethylamine were added under ice-cooling and stirring, followed by the dropwise addition of a solution of 7 g of phthalimidoacetyl chloride in 50 ml of methylene chloride. After stirring for 1.5 hours at room temperature, the mixture was washed with water, aqueous sodium chloride and concentrated in vacuo. To the residue was added chloroform (50 mL), the precipitate was filtered off and the filtrate was concentrated in vacuo. The residue was crystallized from 25 ml of ethyl acetate and the crystals were filtered off with cis-3-phthalimido-4- (E) -styryl-1- (p-methoxyphenyl) -2-oxoazetidine - mp 202-203 ° C. we get.

IR spectrum (v, cm ^4): 1740, 1720th

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 3.74 (3H, s, OCH ₃ ); 5.00 (1H, dd, J = 5Hz, 7Hz, C ₄ -H), 5.65 (1H, d, J = 5Hz, C ₃ -H), 6.24 (1H, dd, J = 7 Hz, 16 Hz, -CH =), 6.78 (1H, d, J = 16 Hz = G-Ph).

Calcd for C ₆ H ₂₀ N ₂ O _4: Calcd: C% = 73.57, H% = 4.75, N% = 6.60; Found: C, 73.56; H, 4.58; N, 6.87.

160

Reference Example 174 g of cis-3-phthalimido-4- (E) -styryl-1- (p-methoxyphenyl) -2-oxoazetidine was dissolved in 25 ml of tetrahydrofuran and at -5 to -10 ° C with stirring. a solution of 3 g of ammonium cerium (IV) nitrate in 10 ml of water is added dropwise over 5 minutes. After stirring at -5 to 0 ° C for 20 minutes, the tetrahydrofuran was removed in vacuo and the residue was shaken with ethyl acetate and water. The ethyl acetate layer was separated, washed with an aqueous solution of sodium sulfate, then with sodium chloride, dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel (eluent: chloroform: ethyl acetate = 7: 3) and crystallized from ethyl acetate: diethyl ether to give cis-3-phthalimido-4- (E) -styryl-2-oxoazetidine, m.p. : 168—

170 ° C.

IR (OM) 3250, 1750, 1720.

NMR (CDC1 _3, ppm): 4.68 (IH, dd, J = 5 Hz, 8 Hz, C ₄ -H), 5.57 (IH, d, J = 5Hz, _C3 -H) , 6.66 (1H, s, N, -H).

Analysis: Calculated for C ₁₉ H ₁₄ N ₂ O ₃ : C, 71.69; H, 4.43; N, 8.80; Found: C, 71.61; H, 4.37; N, 8.55.

175. Reference example

546 mg of cis-3-phthalimido-4- (E) -styryl-2-oxoazetidine are dissolved in 6 ml of N, N-dimethylformamide and 0.36 ml of triethylamine and 323 mg of tert- butyldimethylsilylchloride is added. The mixture was stirred for 30 minutes under cooling and then for 4 hours at room temperature, then shaken with ethyl acetate and water. The ethyl acetate layer was separated, washed twice with water and once with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: chloroform) and crystallized from diethyl ether to give cis-3-phthalimido-4- (E) -styryl-1- (tert-butyldimethylsilyl) -2-oxoazetidine - m.p. -168 ° C.

IR (ν max X) 1750, 1715.

NMR (CDC1 _3, ppm): 4.58 (IH, m, C ₄ -H), 5.62 (IH, d, J = 6Hz, C ₃ -H).

Analytical results for C ₂₅ H ₂₈ N ₂ O ₃ Si:

Found: C, 69.41; H, 6.52; N, 6.48. Found: C, 69.22; H, 6.46; N, 6.48.

176. Reference example

Cis-3-phthalimido-4- (E) -styryl-1- (tert-butyldimethylsilyl) -2-oxoazetidine (440 mg) was suspended in dimethoxyethane (5 mL) and methylhydrazine (0.26 mL) was added. The mixture was stirred at room temperature for 30 minutes and then concentrated in vacuo. The residue was dissolved in methylene chloride (5 mL) and allowed to stand overnight. The resulting csa81

-81194870

161 beds were filtered off and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent: chloroform: ethyl acetate = 6: 4) to give cis-3-amino-4- (E) -styryl-1- (tert-butyldimethylsilyl) -2-oxo as an oil. -azetidine is obtained. This oil was dissolved in tetrahydrofuran (10 mL) and triethylamine (0.2 mL) under ice-cooling and stirring, followed by 2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino) acetyl (0.212 g). hydrochloric acid salt is added. The mixture was stirred for 10 minutes under ice-cooling and then for 30 minutes at room temperature, then shaken with ethyl acetate and water. The ethyl acetate layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: chloroform: ethyl acetate = 7: 3) and crystallized from diethyl ether to give cis (2- [2- (chloroacetamido) -4-thiazolyl] -2- (methoxyimino)). -acetamido} -4- (E) -styryl-1- (tert-butyldimethylsilyl) -2-oxoazetidine (color isomer), m.p. 228-231 ° C (dec.).

IR 1725, 1670.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 3.15 (3H, s, OCH ₃ ), 4.20 (2H, s, ClCH ₂ ), 4.63 (1H, m, C ₄ -H), δ 50 (1H, dd, J = 6Hz, 6Hz, C ₃ -H), 7.20 (1H, s, a group of formula CV), 8.50 (1H, d, J = 6Hz, C ₃ - NH).

Analytical results for C ₂₅ H _{3 2} CIN ₅ O ₄ SSi:

Found: C, 53.41; H, 5.74; N, 12.46 _. Found: C, 53.09; H, 5.7; N, 12.47

Reference Example 177 Dry tetrahydrofuran (ml) was cooled to -78 ° C with stirring under nitrogen and 20 ml of a 15% solution of n-butyllithium in n-hexane were added. Diisopropylamine (3.66 ml) was added dropwise and the mixture was stirred at -78 ° C for 15 minutes. Then 3.1 g

A solution of 2,2-dimethyl-1-aza-3-oxabicyclo [4.2.0] octane-8-one in 15 ml of dry tetrahydrofuran is added dropwise and the mixture is stirred at -78 ° C for one hour. Then

A solution of p-toluenesulfonyl azide (4.34 g) in dry tetrahydrofuran (15 mL) was added dropwise and the resulting mixture was stirred at -50 ° C to -60 ° C for 1.5 hours. To this mixture, trimethylsilyl chloride (5.1 mL) was added dropwise and refluxed for 5 hours and then cooled. The precipitate was filtered off and the filtrate was concentrated in vacuo. The residue is shaken with water and ethyl acetate, the organic phase is separated off, washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography to give a 1: 4 mixture of 2,2-dimethyl-7-azido-1-aza-3-oxobicyclo [4.2.0] octane-8-one.

162

IR spectrum (λmax cw ⁴ ); 2100, 1750.

NMR (CDCl 3, ppm): 4.20 (d, J = 1.5 Hz, trans-Ca-H). 4.68 (d. J = 5 Hz. Cis-C ₃ -H).

This mixture is selectively crystallized from diisopropyl ether to give crystals of the trans-film, m.p. 78-80 ° C.

178. Reference example

Trans-2,2-dimethyl-7-azido-1-aza-3-oxabicyclo [4.2.0] octane-8-one (330 mg) was dissolved in acetone (30 mL) with ice-cooling and stirring.

Jones reagent (3.3 mL, 8N solution) was added. After stirring for 2.5 hours, isopropanol (5 ml) was added and the mixture was stirred for an additional 10 minutes. The precipitate was filtered off with Celite and the filtrate was concentrated in vacuo. The residue was shaken with tetrahydrofuran and a little saturated aqueous sodium chloride solution. The organic layer was separated and the aqueous layer was extracted three times with tetrahydrofuran. The tetrahydrofuran layers were combined, dried over anhydrous sodium sulfate, treated with a solution of diazomethane in diethyl ether and allowed to stand. The solvent was evaporated and the residue was shaken with water and ethyl acetate. The ethyl acetate layer was separated, washed with an aqueous solution of sodium bicarbonate and water, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography to give trans-3-azido-4- (methoxycarbonylmethyl) -2-oxoazetidine.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 2.76 (2H, d, J = 6Hz, C ₄ -CH ₂ ), 3.70 (3H, s, CO ₂ CH ₃ ), 382 (1H, m, C ₄ -H), 4.36 (1H, C ₃ -H), 6.75 (1H, s, N, -H).

By the same method, but starting from a 1: 4 cis / trans mixture, a 1: 4 cis / trans mixture of 2-oxoazetide in is obtained.

NMR (CDC1 _3, ppm): 4.83 (cis-C H _3).

179. Reference example

800 mg of cis-3- (benzyloxycarboxamido) -2-oxoazetidine-4-carboxylic acid prepared according to Reference Example 68 are dissolved in a mixture of 20 ml of tetrahydrofuran and 10 ml of water and 280 mg of sodium hydrogen carbonate followed by 303 mg of 0-methylhydroxylamine hydrochloride salt and 638 mg of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride salt. The mixture was stirred at room temperature for 3 hours and then extracted with ethyl acetate / ethanol (10: 1). The extract was washed first with 3N hydrochloric acid, then with a saturated aqueous solution of sodium bicarbonate, and finally with an aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The extract was then concentrated in vacuo to give cis-3-benzyloxycarboxamido) -4- (methoxyaminocarbonyl) -2-82194870

163

m.p. 212-216 ° C (dec.).

IR: 3290, 1760, 1680.

Reference Example 180 For ⁵ ml of dry dimethylsulfoxide, cis-3- (benzyloxycarboxamido) -1- (2,4-dimethoxybenzyl) -4- (iodomethyl) prepared as in Reference Example 62, 5.1 g of 2-oxoazetidine and 2.6 g of potassium cyanide and 50 mg of 18-CROWN-6 are added. The mixture was stirred at room temperature for 2 days, then at 50 ° C for 3 hours, then poured into 250 ml of ethyl acetate.

The reaction mixture three times with water and once with sodium chloride aqueous solution and then dried over ¹⁵ anhydrous magnesium sulphate and evaporated. The residue was purified by column chromatography on silica gel (400 g of silica gel; eluent: ethyl acetate: hexane = 1: 2, 2 _x 2: 1 then 2: 1) to give cis-3- (benzyloxycarboxamido) -4- (cyanomethyl) -1 - (2,4-Dimethoxybenzyl) -2-oxoazetidine is obtained.

IR (λmax): 3290, 2920, 2240, 25

1770, 1690.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 2.48 (2H, d, J = 6Hz, CH ₂ CN), 3.78 (3H, s, OCH ₃ ), 380 (3H, s, OCH ₃ ), 4.82 (1H, dd, J = 5Hz, 8Hz, C ₃ -H). _3θ

181. Reference example

1.7 g of cis-3- (benzyloxycarboxamido) -4- (cyanomethyl) -1- (2,4-dimethoxybenzyl) -2-oxoazetidine are dissolved in 210 ml of acetonitrile and ₃₅ ml of water. 1.68 g of potassium persulfate and 1.085 g of dipotassium hydrogen phosphate are then added. The mixture was heated to 85-90 ° C for 2.5 hours, the acetonitrile was removed in vacuo and the remainder the _four θ derivative was extracted with ethyl acetate. The extract was washed with a saturated sodium bicarbonate solution and then with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (140 g silica gel; eluent: ethyl acetate: hexane = 1: 2 then 3: 1) to give cis-3- (benzyloxycarboxamido) -4- (cyanomethyl). -2-oxoazetidine, m.p. 113-115 ° C, is obtained.

IR (ν cm ^-1 ): 3300, 2250, 1760,

1685th

185. Reference example

In the same manner as Reference Example 166, cis-3- (2- [2- (chloroacetamido) -4-thiazolyl] -2- [1-methyl-1- (p-nitrobenzyloxycarbonyl)]. -ethyloxyimino] -acetamido-4- (cyanomethyl) -2-oxoazetidine (color isomer) was prepared.

IR (λmax ^H ): 3360, 2980, 2250,

1740, 1680, 1600, 1520, 1345, 1140.

Reference Example 183 c, cis-3- (benzyloxycarboxamido) -2164 prepared according to Reference Example 2.

The oxo-azetazidine-4-carboxylic acid methyl ester was dissolved in a mixture of tetrahydrofuran (100 mL) and water (100 mL), and sodium borohydride (1.359 g) was added under ice-cooling. The mixture was stirred for one hour under ice-cooling and then for two hours at room temperature. The tetrahydrofuran is then evaporated in vacuo and the residue is extracted three times with chloroform. The extract was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was dissolved in ethanol (30 mL), 5% palladium on carbon (1 g) was added and the mixture was stirred under an atmosphere of hydrogen for 4 hours. The catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in a mixture of 20 ml of water and 20 ml of tetrahydrofuran and 3.62 g of sodium bicarbonate was added under ice-cooling. 3.41 g of p-nitrobenzyloxycarbonyl chloride are then added and the mixture is stirred at room temperature for two hours. This reaction mixture was extracted three times with chloroform, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (160 g silica gel; eluent: ethyl acetate followed by ethyl acetate: methanol = 4: 1) to give cis-3- (p-nitrobenzyloxycarboxamido) -4- (hydroxymethyl). Mp 166-167 ° C.

IR spectrum (νΧ ^ <) _; 3280, 1770, 1700. Analysis results for C _I2 H | ₃ N ₃ O _6: Calcd: C% = 48.82, H% = 4.44, N% = 14.23 found: C% = 48.58, H% = 4.53, N = 13%, 87

184. Reference Example

Sodium hydride (2.28 g) was suspended in dry tetrahydrofuran (40 ml) and a solution of 1-methyl-1H-tetrazol-5-yl-thiol (3 g) in tetrahydrofuran (40 ml) was added under ice-cooling. A solution of bromoacetic acid (3.59 g) in dry ethanol (80 ml) was added and the mixture was stirred under ice-cooling for 30 minutes and then at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residue was shaken with water (100 mL) and diethyl ether (100 mL). The aqueous layer was separated, acidified with 3N hydrochloric acid and extracted twice with chloroform / ethanol (3: 1). The extract was dried over anhydrous magnesium sulfate and evaporated to give 1-methyl-1H-tetrazol-5-yl-thioacetic acid.

IR spectra 2990, 1700.

NMR (CDC1 ₃ + D ₆ - -DMSO, ppm): 3.82 (3H, s, _CH3);

3.98 (2H, s, CH ₂ ), 4.10 (1H, s, COOH).

Claims (21)

PATENT CLAIMS A process for the preparation of 1-sulfo-2-oxoazetidine derivatives of the formula I -83194870 165 ^R1 is (1) a group of formula (F) wherein R ^U and R ⁶ are the same or different and each represents an alkyl group having 1 to 4 carbon atoms, (2) a (G) a group of formula in which R ⁶ is hydrogen or alkylcarbonyl containing from 1 to 4 carbon atoms in the alkyl moiety, carbamoyl, alkylsulfonyl, from 1 to 4 carbon atoms in the alkyl moiety, alkylbenzylsulfonyl, methoxy having from 1 to 4 carbon atoms in the alkyl moiety; acetyl, alkoxycarbonyl containing 1 to 4 carbon atoms in the alkoxy moiety, 1-methyl-1- (carboxyethyl) carbonyl, carboxyethylcarbonyl, carboxyethenylcarbonyl or the group L ^R8 is (R) group of general formula: - wherein ^Rc is an alkyl group having 1 to 10 carbon atoms - or (S) a group of formula - in which R ^d represents a furyl or thienyl group, and R ⁷ is phenyl, thienyl or a group of formula (I) and in the latter formula R ^e is an amino group, (3) a group of formula (U) wherein R 'is amino, halo (C 1-4) alkylcarbonylamino, C 1-4 alkyl or hydroxy, R ^g is hydrogen or halogen; and R ¹² is C 1 -C 4 alkyl, C 2 -C 5 alkenyl or -R ¹³ -R ¹⁴ and in the latter formula R ¹³ is C 1 -C 3 alkylene and R ¹⁴ is phenyl, carboxyl -, (1-4C) alkoxycarbonyl, tri (1-4C) alkylsilyl (1-4C) alkoxycarbonyl, benzhydryloxycarbonyl or 4-nitrobenzyloxycarbonyl (4) a group of formula (Γ) wherein R ^{1 S} is hydroxy, sulfo, carboxyl or benzyloxycarbonyl; (5) a group of formula (J) wherein R ¹⁸ is cyano; , triethylsilylmethyl, thienyl, tetrazolyl, or a group of formula (I), where R ^e is as previously defined, 166 (6) a group of formula (V ') in which R ^e is as defined above, (7) amino, (8) phenyl (1-4C) alkoxycarbonylamino optionally substituted with nitro; or (9) azido, and R is (1) 'is a group of Formula D wherein Q ⁵ is C 1-4 -alkoxy, 4-nitrobenzyloxy, hydroxy or C 1-4 -alkoxy; -carbonylalkoxy, (2) 'is a group of formula A wherein n is 0, 1, 2 or 3, R ² and R ³ each independently represent hydrogen or C 1-4 alkyl, and R ⁴ is halo, phenyl, cyano, hydroxy, carbamoyloxy, 1-4 carbon atoms in the alkyl sulfonyloxy, hydroxy-sulfonyloxy, amino, azido, alkoxycarbonyl, one containing 1-4 carbon atoms in the —C4 alkylthio, pyridinium, alkylcarbonyloxy having from 1 to 4 carbon atoms, haloalkylcarbonyloxy having from 1 to 4 carbon atoms in the alkyl portion, tetrazolylthio (1-4C) alkyl, benzoyloxy, alkylcarbonylamino containing 1 to 4 carbon atoms in the alkyl moiety, benzoylamino, trifluoroacetyl trifluoroacetylamino, alkylsulfonyl (alkoxycarbonyl) amino having 1 to 4 carbon atoms in the alkyl moiety, , 4-nitrobenzyloxycarbonylamino or a group of the formula (R '), wherein X' is methylene, methylene-thio or (S '), Q ¹ is thienyl, 1- (1-), Alkyl having 4 carbon atoms, tetrazolyl or 2- (am yno or halogeno thiazolyl group, and Q ² (1-4C) alkyl-carbonylamino) is 1 - alkoxy group having 4 carbon atoms, (3) 'a group (C), wherein Q ³ and Q ^{4 have the} same or different meanings of hydrogen or C 1-4 alkyl, C 1-4 alkoxy, phenyl, phenyl (C 1-4) alkoxycarbonyl (C 1-4) containing) alkyl, -84194870 167 carboxy (1-4C) alkyl or sulfo groups, (4) 'alkylcarbonyl containing 1-4 carbon atoms, (5)' phenyl (2-4C) alkenyl or (6) '4-halophenyl, and X is hydrogen; and pharmaceutically acceptable salts thereof, wherein: a) sulfonating a compound of formula II, wherein X, R and R ¹ are as defined herein, with the proviso that the amino, hydroxy and / or carboxyl groups may be protected with conventional protecting groups; in which case the protecting group (s) is (are) removed, or b) the formula A compound being a narrower group of the compounds of formula (I), (Γ) - wherein R and X are as defined above and ^R1 'acylamino group jelent- and salts thereof (III) of the formula or a salt thereof, wherein R and X are as defined herein, with the proviso that the amino, hydroxy and / or carboxyl groups may be protected with conventional protecting groups, optionally deprotecting and optionally removing the protecting group (s). we do one or more of the following: (i) removing any sequence occurring in R ¹ and R substitutes protective group or groups, compounds having an alkoxyimino group at R ¹ is reduced to the amino derivative is converted to compounds having an amino group at R ¹ is a suitable carboxylic acid or sulfonic acid is acylated with an alkali metal cyanate, ureido derivative reacted with and / or reacting a derivative containing a haloalkyl group with R with pyridine, (ii) converting a compound of formula (I) into a pharmaceutically acceptable salt, and (iii) releasing a compound of formula (I) from its salt. 2. Process according to claim 1, wherein the starting material is R is a group of the general formula (A), in which R * and R ^{3 are a} hydrogen atom and R ⁴ is an alkyl radical of 1 to 4 carbon atoms. starting material containing alkylcarbonyloxy or optionally (1-4C) alkylcarbonyl protected amino group having n = 0. 3 according to Claim 1 a) or b) A process, wherein as a starting material in which R (C) of the formula or the same or different in the group consisting of hydrogen and 1-4 carbon atoms Q ³ and Q ⁴ is alkyl -, alkoxy having 1 to 4 carbon atoms, Starting material containing 168 phenyl or parent groups was used. 4 according to Claim 1 a) or b) A process, wherein as a starting material in which R (C) of the formula or the same or different in the group consisting of hydrogen and 1-4 carbon atoms Q ³ and Q ⁴ is alkyl Starting material containing 1 to 4 carbon atoms of alkoxy, carboxyalkyl, sulfo, phenyl or 4-nitrobenzyloxycarbonyl of 1 to 4 carbon atoms in the alkyl moiety. 5 according to Claim 1 a) or b) A process, wherein as a starting material in which R (C) of the formula or the same or different in the group consisting of hydrogen and 1-4 carbon atoms Q ³ and Q ⁴ is alkyl The starting compound having 1 to 4 carbon atoms of alkoxy, phenyl, sulfo or carboxyalkyl group having 1 to 4 carbon atoms is used. 6 according to claim 1, a) or b) a process wherein the starting compound having (D) a group of formula, and Q ⁵ is appropriate hydroxy, alkoxy of 1-4 carbon atoms, 4-nitrobenzyloxy or a starting compound having from one to four carbon atoms containing an alkoxycarbonylalkoxy group in the alkyl moieties. 7. Process according to claim 1, characterized in that the starting material is selected from the group consisting of R in alkoxy, 4-nitrobenzyloxy and alkyl in the formula (D) and Q ⁵ in the range of 1 to 4 carbon atoms. Starting compounds containing from 1 to 4 alkoxycarbonylalkoxy groups are used. A process according to claim 1, wherein the starting material is R ¹ is selected from the group consisting of the formula (0) and Q ⁷ is selected from the group consisting of amino or halo (C 1-4) alkylcarbonylamino-. ^8, Q is alkyl of 1-4 carbon atoms, alkenyl of 2-5 carbon atoms, -CH ₂ COOQ ⁹ or (P) a group of formula - in the last two -COOQ ⁹ is carboxy, the alkyl portion. The starting compound or the acylating agent containing a C 1-4 alkoxycarbonyl or 4-nitrobenzyloxycarbonyl group is used. 9. Figures 1-8. The method of any preceding claim used with respect to the azetidine ring ^R1 is beta-configuration and X is the preparation of compounds of formula I wherein the alpha-configuration group (I), characterized in that substituted starting compounds accordingly. 10. The method according to claim 9 relative to the R ¹ group to prepare the compounds of formula the radical R is in the trans position (I), characterized in that using appropriately substituted starting materials. -85194870 169 11. A process according to claim 9 for the preparation of compounds of formula (I) carrying the R group in a cis position, wherein the starting materials are suitably substituted. 12. The according to Claim 1 a) or b) A process, wherein R ¹ is (0), a group of formula and Q 'is amino or halogenated alkyl-carbonyl-amino- (1-4C) alkyl group, and Q ⁸ represents 1-4 carbon atoms, alkenyl of 2-5 carbon atoms, -CH ₂ COOQ ⁹ or (P) a group of formula - in the last two -COOQ ⁹ is carboxy, the alkyl part has from 1 to 4 carbon atoms starting materials containing an alkoxycarbonyl or 4-nitrobenzyloxycarbonyl group, and R is a group of the formula C 'wherein Q ³ and Q ^{4 are the} same or different and each represents a hydrogen atom or a C 1-4 alkyl group. or an acylating agent. 13. A process according to claim 12 wherein the Q ³ 'and Q ⁴ ' are hydrogen starting materials and Q ⁷ is amino starting materials or acylating agents. 14. The method of claim 13 with respect to the R ¹ group, R is trans to support the preparation of compounds of formula I, characterized in that using appropriately substituted starting materials. 15. The method of claim 13, characterized in that correspondingly substituted starting materials are used in the preparation of compounds of formula 1 R a group comprising cis position relative to ^one of the R group. 16. A 13-15. Process according to any one of claims 1 to 4, characterized in that the starting materials in racemic form are used. Process b) according to claim 1, characterized in that 3-amino-4- (methoxycarbonyl) -2-oxoazetidine-1-sulfonic acid, 3-amino-4- (ethoxycarbonyl) -2 -oxoazetidine -1 170 sulfonic acid, 3-amino-4-carbamoyl-2-oxoazetidine-1-sulfonic acid, 3-amino-4- (carbamoyloxymethyl) -2-oxoazetidine-1-sulfonic acid, or 3-amino-4- ( acetamidomethyl) -2-oxoazetidine-1-sulfonic acid or a salt thereof. 18. The process of claim 1, a) or b), wherein R is a compound of formula (A) The starting compound containing 10 groups or the carbamoyl group in which R ⁴ is substituted is used. A process according to claim 1 a) or b) or a process according to claim 18, 15, characterized in that, instead of (A) a group of formula, and a starting compound containing a group bearing a hydrogen atom or 1 ^{to 4} carbon atoms the same or different R ² and R ³ represents alkilcso20 place in this group as a starting material in which R. A process according to claim 1, wherein the starting material is R in formula (A). The starting compound containing 25 groups or R ² and R ³ is hydrogen and R ⁴ is carbamoyloxy is used in this group. A) or b) according to claim 1 Process 30 or a process according to claim 20, wherein the starting material is a compound of formula (A) wherein R is n = 0. 22. A process for the preparation of a pharmaceutical composition which is predominantly antimicrobial or beta-lactamase inhibiting, wherein a compound of formula (I), wherein the substituents are as defined in claim 1, or a pharmaceutically acceptable salt thereof, optionally without one or more synergistic effects with the compound of formula (I) 45-beta-lactam in combination with excipients and / or excipients conventionally used in the manufacture of pharmaceuticals to form a pharmaceutical composition.