Method and ester derivatives used to obtain cephalosporins

 

(57) Abstract:

The invention relates to a new method for the preparation of 3-substituted cephalosporins of the formula (I):

where R1is a para-nitrobenzyl or allyl, X is a halogen; comprising the stage of: a) cyclization trimethylphosphine the compounds of formula (IIIA):

where R1is a para-nitrobenzyl or allyl, R2selected from the group comprising FROM1-6alkyl, C6-10aryl, C6-10arils1-6alkyl and dithienyl; in a solvent to form compounds of the formula (II):

where R1is a para-nitrobenzyl or allyl; R2selected from the group comprising FROM1-6alkyl, C6-10aryl, C6-10arils1-6alkyl and dithienyl; and (b) interaction of the compounds of the formula (II) with the acid. The invention also relates to compounds of formula (I), formula (II), formula (III), formula (V) and formula (VI) used in the described way. The technical result - the compounds obtained have such favorable properties as crystalline form and high enantiomeric excess (E. E.). 6 N. and 11 C. p. F.-ly, 1 table.

Background of invention

This is s esters, used to obtain cephalosporins, substituted cyclic ether at the 3-position. The present invention also relates to new methods of producing the above-mentioned para-nitrobenzyl esters and allyl esters using trimethylphosphine. The present invention also relates to cephalosporins, substituted cyclic ether at the 3-position. These compounds possess some primary properties such as crystal shape and high enantiomeric excess (E. I.).

3-substituted cyclic ether cephalosporins, obtained by the methods of the present invention have a prolonged and high antibacterial activity and good absorption of parenteral administration to humans and animals. 3-substituted cyclic ether cephalosporins, obtained by the methods of the present invention contain a cyclic ether substituent in the 3-position of the cephalosporin nucleus.

In GB 1405758 described alternative ways to get some 3-substituted cyclic ether cephalosporins.

In the work of J. Antibiotics (1994), vol.47(2), page 253 and in WO 92/01696 also describes alternative methods for obtaining compounds of formula (I) defined below, and with the Lee, polymorph, solvate and hydrate cephalosporins, substituted cyclic ether at the 3-position.

In U.S. patent No. 6001997 described alternative ways of getting cephalosporins, substituted cyclic ether at the 3-position.

In the provisional application for U.S. patent entitled “Coupling Process And Intermediates Useful For Preparing Cephalosporins” and filed November 30, 2000, described intermediate compounds and methods for producing cephalosporins, substituted cyclic ether at the 3-position.

All of the foregoing publications, patents and patent applications in their entirety are included in the present description by reference.

The authors of the present invention has been described new compound of the formula (IIIA) as defined below and used to obtain the compounds of formula (I) defined below. The authors of the present invention has also been described a method of obtaining the compounds of formula (I) in high yields.

Brief description of the invention

The present invention relates to a method for obtaining compounds of formula (I):

where R1is para-nitrobenzyl or allyl, preferably, para-nitrobenzyl; X represents a halogen selected from the group consisting of bromine, chlorine, ASS="ptx2">

where R1is para-nitrobenzyl or allyl, preferably, para-nitrobenzyl; and R2selected from the group consisting of C1-6of alkyl, C6-10aryl, C6-10arils1-6the alkyl and ditional preferably represents C6-10arils1-6alkyl, such as benzyl; in a solvent to form compounds of the formula (II)

where R1is para-nitrobenzyl or allyl, preferably, para-nitrobenzyl; and

R2selected from the group consisting of C1-6of alkyl, C6-10aryl, C6-10arils1-6the alkyl and ditional preferably represents C6-10arils1-6alkyl, such as benzyl;

and, if necessary, then

b) interaction of the compounds of the formula (II) with an acid to obtain the compounds of formula (I).

Used herein, the term “alkyl” means, unless otherwise specified particularly, saturated monovalent hydrocarbon radicals having straight or branched fragments molecule or combinations thereof. Alkyl groups, if present, may be optional substituted with a suitable substituent.

Used herein, the term “cycloalkyl” if it's not slander is pentyl, cyclohexyl, cycloheptyl, cyclooctyl, cycloneii, cyclopentenyl, cyclohexenyl, bicyclo[2.2.1]heptenyl, bicyclo[3.2.1]octenyl and bicyclo[5.2.0]nonanal and so on), optionally containing 1 or 2 double bonds and optionally substituted by 1-3 suitable substituents as defined below such as fluoro, chloro, trifluoromethyl, (C1-4)alkoxy, (C6-10)aryloxy, triptoreline, deformedarse or (C1-4)alkyl, and more preferably, fluorine, chlorine, methyl, ethyl and methoxy.

Used herein, the term “alkoxy” means an O-alkyl group, where “alkyl” is defined above.

Used herein, the term “halogen”, if it is not specifically mentioned, means fluorine, chlorine, bromine or iodine, preferably bromine or chlorine.

Used herein, the term “aryl,” unless it is specified otherwise, means an organic radical derived from an aromatic hydrocarbon after removing one or more hydrogen atoms, such as phenyl or naphthyl, optionally substituted by 1-3 suitable substituents, such as fluorine, chlorine, cyano, nitro, trifluoromethyl, (C1-6)alkoxy, (C6-10)aryloxy, (C3-8)cycloalkane, triptoreline, deformedarse or (C1-6)alkyl.

Used herein, the term “cyclicism connection after removing one or more hydrogen atoms, such as benzimidazolyl, benzofuranyl, benzofurazanyl 2N-1-benzopyranyl, benzothiadiazin, benzothiazines, benzothiazolyl, benzothiophene, benzoxazole, bromanil, cinnoline, furutani, properidine, furyl, imidazolyl, indazoles, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolyl, ethenolysis, isothiazolin, isoxazolyl, naphthyridine, oxadiazole, oxazole, phthalazine, pteridine, purinol, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl, hintline, chinoline, honokalani, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl and triazolyl, where specified (C1-10)heteroaryl optionally substituted on any ring carbon atoms capable of forming an additional bond by one or two substituents, independently selected from F, Cl, Br, SP, HE, (C1-4)alkyl, (C1-4)perfluoroalkyl, (C1-4)perforamce, (C1-4)alkoxy and (C3-8)cycloalkane. The above group derived from the above compounds may be C - or N-attached, if possible. So, for example, a group derived from pyrrole, can be a pyrrol-1-yl (N-connection) or pyrrol-3-yl (C-accession).

Used herein, the term “heterocyclyl is who join after removing one or more hydrogen atoms, such as 3-azabicyclo[3.1.0]hexenyl, 3-azabicyclo[4.1.0]heptanes, azetidine, dihydrofurane, dihydropyran, dehydration, dioxanes, 1,3-DIOXOLANYL, 1,4-ditional, hexahydroazepin, hexahydropirimidine series, imidazolidinyl, imidazolyl, isoxazolidine, morpholine, oxazolidine, piperazinil, piperidinyl, 2H-pyranyl, 4H-pyranyl, pyrazolidine, pyrazoline, pyrrolidine, 2-pyrroline, 3-pyrroline, hemolysins, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridine, tetrahydrothieno, tetrahydrothiopyran, thiomorpholine, dioxane and tritional. The above group derived from the above compounds may be C-attached or N-attached, if possible. So, for example, piperidine, can represent piperidine-1-yl (N-attached) or piperidine-4-yl (C-attached). The above group derived from the above compounds may be optional substituted, if possible, a suitable substitute, such as oxo, F, Cl, Br, SP, HE, (C1-4)alkyl, (C1-4)perfluoroalkyl, (C1-4)perforamce, (C1-4)alkoxy or (C3-8)cycloalkane.

The term “suitable Deputy” means chemically and pharmaceutically reception is his invention. Suitable substituents can be selected routine manner known in the art. Illustrative examples of suitable substituents include, but are not limited to, halogen, performanceline group, performancebuy, alkyl groups, hydroxy-group, carbonyl group, mercaptopropyl, allylthiourea, alkoxygroup, aryl or heteroaryl group, aryloxy or heterokaryosis, kalkilya or heteroalkyl group, Alcoxy or heteroaromatic, carboxypropyl, amino groups, alkyl - and dialkylamino, carbamoyl group,alkylcarboxylic group, alkoxycarbonyl group, alkylaminocarbonyl group, dialkylaminoalkyl group, arylcarbamoyl group, aryloxyalkyl group, alkylsulfonyl group, arylsulfonyl group, etc.

The term “salt” means a pharmaceutically acceptable acid or basic additive salts of compounds of formula (I).

Acids, which are used to produce pharmaceutically acceptable acid additive salts of these basic compounds of the present invention are acids which form non-toxic acid additive salts, i.e. salts containing pharmaceutical preparations, only phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saharat, benzoate, methanesulfonate, aconsultant, bansilalpet, para-toluensulfonate, pamoate [i.e., 1,1’-Methylenebis(2-hydroxy-3-aftout)].

The Foundation, which can be used as reagents to obtain pharmaceutically acceptable basic salts of the above compounds of formula I that are acidic in nature, are bases which form non-toxic basic salts with the abovementioned compounds. Such main non-toxic salts include, but are not limited to, salts formed by these pharmacologically acceptable cations, such as cations of alkali metals (e.g. potassium and sodium), alkaline earth metal cations (e.g. calcium and magnesium), and ammonium or salt attaching a water-soluble amines, such as N-methylglucamine (meglumine), the lowest alkanolammonium and other basic salts of pharmaceutically acceptable organic amines.

Some compounds of formula I contain chiral centers and therefore exist in different enantiomeric forms. The present invention relates to all optical out what about the inventions are also present in various tautomeric forms. The present invention relates to all tautomers of the formula (I). Each specialist is well known that cephalosporin nucleus exists as a mixture of tautomers in solution. Different ratios of tautomers in the solid and liquid form depend on various substituents on the molecule, and the specific crystallization method used to allocate the connection.

In one of the embodiments the present invention relates to a method for the transformation of compounds of the present invention of the formula (IIIA) in the compounds of formula (II) where the specified R1is allyl.

In another embodiment, the above transformation of the present invention specified R2is1-6alkyl, such as methyl or ethyl. In yet another embodiment, the specified R2is6-10aryl, such as phenyl. In another embodiment, the specified R2is6-10arils1-6alkyl.

In a preferred embodiment, the above transformation R1if present, represents the pair-nitrobenzyl; and R2if present, represents benzyl.

Suitable solvents for the above transformations are toluene, xylene, tetrahed EUcasino the transformation of compounds of formula (IIIA) in the compounds of formula (II) can be carried out at a temperature of from about 40C to 160S, preferably, about 65S. The above transformation can be carried out within a time period of about 1-24 hours, preferably for about 16 hours.

In a preferred embodiment, the above-mentioned stage b) of the method of the present invention R1if present, represents the pair-nitrobenzyl; and R2if present, represents benzyl.

In accordance with the present invention suitable acid in a specified way transformation of compounds of formula (II) into compounds of formula (I) are of a Lewis acid such as pentachloride phosphorus or pentabromide phosphorus, preferably, pentachloride phosphorus.

In accordance with the present invention the transformation of compounds of formula (II) into compounds of formula (I) is carried out at a temperature from about-40C to +40C, preferably from approximately-40C to +30C. The above transformation can be carried out during the period of time from about 1 hour to 24 hours, preferably for about 1 hour.

Suitable solvents for the above transformations are toluene, xylene, tetrahydrofuran, methylene chloride or acetonitrile. Preferred RA is inane formula (IIIA), defined above, including interaction of the compounds of formula (IIIb)

where R1is para-nitrobenzyl or allyl, preferably, para-nitrobenzyl; R2selected from the group consisting of C1-6of alkyl, C6-10aryl, C6-10arils1-6the alkyl and ditional preferably represents C6-10arils1-6alkyl, such as benzyl; and X is halogen, preferably chlorine, with trimethylphosphine in a solvent and optionally in the presence of a base.

Suitable solvents are tetrahydrofuran, acetonitrile, methylene chloride or mixtures thereof, preferably tetrahydrofuran.

Appropriate grounds for processing are imidazole, 2,6-lutidine, pyridine, N-methylmorpholine or sodium bicarbonate. In one embodiment of the present invention the specified base is 2,6-lutidine or N-methylmorpholine. In another embodiment of the present invention the specified base is pyridine. In a preferred embodiment of the present invention the specified base is sodium bicarbonate. The above transformation is preferably carried out in the presence of a suitable base in the process.

In line to be carried out at a temperature of from about-40C to-20C, preferably, at about-40C. The above transformation can be carried out during the period of time from about 30 minutes to 1 hour, preferably for about 1 hour.

The present invention also relates to a method for obtaining compounds of formula (IIIb) by reaction of compounds of formula (S)

where R1is para-nitrobenzyl or allyl, preferably, para-nitrobenzyl; and R2selected from the group consisting of C1-6of alkyl, C6-10aryl, C6-10arils1-6the alkyl and ditional preferably represents C6-10arils1-6alkyl, such as benzyl; with a halogenation agent in a solvent and in the presence of a base.

Suitable halogenation agents for the implementation of the above method of converting compounds of formula (S) in the compounds of formula (IIIb) of the present invention are thionyl chloride, thienylboronic, trichloride phosphorus or tribromide phosphorus. The preferred halogenation agent is thionyl chloride.

Suitable solvents for the implementation of the above method of transformation of the present invention are methylene chloride or tetrahydrofuran. Preferably the method of transformation of the present invention are pyridine, 2,6-lutidine, N-methylmorpholine or imidazole. In one embodiment of the present invention the specified base is 2,6-lutidine or N-methylmorpholine. In another embodiment of the present invention the specified base is pyridine. In another embodiment of the present invention the specified base is imidazole. In a preferred embodiment of the present invention the specified base is 2,6-lutidine.

In accordance with the present invention the specified transformation is carried out at a temperature from about-40C to-20C, preferably at about-20C. The above transformation can be carried out during the period of time from about 15 minutes to 1 hour, preferably for about 1 hour.

The present invention also relates to a method for obtaining compounds of formula (S), as defined above, by reaction of compounds of formula (V)

where R1is para-nitrobenzyl or allyl, preferably, para-nitrobenzyl; R2selected from the group consisting of C1-6of alkyl, C6-10aryl, C6-10arils1-6the alkyl and ditional preferably represents C6-10arils1-6alkyl, such as benzyl; with the connection foreststhe Foundation.

Suitable leaving groups of the above compounds of formula (IV) are bromine, chlorine, fluorine, iodine and toilet, preferably bromine or chlorine, most preferably bromine.

Suitable solvents for the implementation of the above method of converting compounds of formula (V) into compounds of formula (S) of the present invention are alcohols selected from the group consisting of methanol, ethanol and propanol; methylene chloride; acetone; dimethylformamide; or mixtures thereof. In another embodiment of the present invention the specified solvent is methylene chloride. In another embodiment of the present invention the specified solvent is a mixture of acetone and alcohol, such as methanol. The preferred solvent is acetone.

The transformation of compounds of formula (V) into compounds of formula (C) can be carried out at a temperature of from about 10C to 25C, preferably, at about 20C. The above transformation can be carried out during the period of time from about 2 hours to 24 hours, preferably for about 4 hours.

In one embodiment, the above transformation of this interaction is carried out in the presence of a base, such as flax, carried out in the absence of a base.

In accordance with the present invention in another embodiment, the above method of converting compounds of formula (V) into compounds of formula (C) compound of formula (IV) can be obtained in situ by reaction between the compounds of formula (V) with the compound of the formula (IV)

in aqueous solution or alcohol solution of bromine, chlorine or iodine; and processing the specified aqueous or alcoholic solution of the acid. Suitable acids are pair-toluensulfonate acid, Perlina acid or dilute phosphoric acid, preferably, para-toluensulfonate acid. In the specified method of obtaining in situ is the preferred solvent is an alcohol, such as methanol. The above may be made within 2 hours at 60C.

The present invention also relates to a method for obtaining compounds of formula (V) by reaction of compounds of formula (VI)

where R1is para-nitrobenzyl or allyl, preferably, para-nitrobenzyl; and R2selected from the group consisting of C1-6of alkyl, C6-10aryl, C6-10arils1-6the alkyl and dithienyl, predpochtitelnei with the present invention the above method of converting compounds of formula (VI) in the compounds of formula (V) is carried out at a temperature of from about 20C to 25C, preferably, at about 20C. The above transformation can be carried out during the period of time from about 2 hours to 24 hours, preferably for about 2 hours.

Suitable acids used in the above method, are pair-toluensulfonate acid or methansulfonate acid. The preferred acid is para-toluensulfonate acid.

Suitable solvents for the implementation of the above method are methylene chloride, tetrahydrofuran, acetone or mixtures thereof. The preferred solvent is acetone.

The present invention also relates to a method for obtaining compounds of formula (VI) by reaction of compounds of formula (VIb)

where R1is para-nitrobenzyl or allyl, preferably, para-nitrobenzyl; and R2selected from the group consisting of C1-6of alkyl, C6-10aryl, C6-10arils1-6the alkyl and ditional preferably represents C6-10arils1-6alkyl, such as benzyl; with a reducing agent in a solvent.

In accordance with the present invention suitable reducing agents used in the above method, prepr the Oran or triacetoxyborohydride sodium. In one embodiment of the present invention the specified reducing agent is borohydride sodium. The preferred reducing agent is triacetoxyborohydride sodium or borohydride sodium. The preferred reducing agent is triacetoxyborohydride sodium.

Suitable solvents for the implementation of the above method are acetic acid, methylene chloride, tetrahydrofuran or mixtures thereof. The preferred solvent is methylene chloride. If a reducing agent is borohydride sodium, the preferred solvent is acetic acid.

The above transformation can be carried out at a temperature of from about 20C to S. The above transformation can be carried out during the period of time from about 4 hours to 24 hours.

The present invention also relates to an alternative method of obtaining the compounds of formula (VI) by reaction of compounds of formula (XI)

where R2selected from the group consisting of C1-6of alkyl, C6-10aryl, C6-10arils1-6the alkyl and ditional preferably represents C6-10arils1-6alkyl, such as benzyl; with the connection is tramentel; in a solvent, in the presence of a base, preferably, a catalytic amount of base.

In accordance with the present invention suitable solvents for the implementation of the above method of converting compounds of formula (XI) in the compounds of formula (VI) are methylene chloride, tetrahydrofuran or mixtures thereof. In one of the preferred variants of the present invention the specified solvent is a mixture of methylene chloride and tetrahydrofuran, 1:1. The preferred solvent is methylene chloride.

Suitable bases for the implementation of the above transformations are Diisopropylamine, triethylamine, pyridine or 2,6-lutidine. The preferred base is triethylamine. The preferred base is a catalytic amount of triethylamine.

The above transformation can be carried out at a temperature of from about 20C to 25C. The above transformation can be carried out during the period of time from about 30 minutes to 2 hours, more preferably for about 1 hour.

The present invention also relates to a method for obtaining compounds of formula (VIb) via interaction connection is UB>6-10arils1-6the alkyl and ditional preferably represents C6-10arils1-6alkyl, such as benzyl; and L2represents a leaving group, with a compound of formula (VII)

where R1is para-nitrobenzyl or allyl, preferably, para-nitrobenzyl, in a solvent, in the presence of a base.

Suitable leaving groups L2the compounds of formula (VII) are halogen, azide or1-6alkoxy, preferably halogen, such as chlorine or bromine.

Suitable solvents for the implementation of the above transformation of compounds of formula (VIII) in the compounds of formula (VIb) of the present invention are methylene chloride, tetrahydrofuran or mixtures thereof, preferably methylene chloride.

Suitable bases for the implementation of the above transformations are Diisopropylamine, triethylamine, pyridine, 2,6-lutidine, preferably triethylamine.

The above transformation can be carried out at a temperature of from about-S to 25 ° C, preferably at about-S. The above transformation can be carried out during the period of time from about 5 minutes to 10 minutes, preferably within about 5 mine is gaining the compounds of formula (VIII) can be obtained by reaction of compounds of formula (XI)

where R2selected from the group consisting of C1-6of alkyl, C6-10aryl, C6-10arils1-6the alkyl and ditional preferably represents C6-10arils1-6alkyl, such as benzyl; with the compound of the formula (IX)

where each of these L1and L2represents a leaving group, in a solvent and in the presence of a base.

Suitable leaving groups L1and L2the compounds of formula (IX) are halogen, azide or1-6alkoxy, preferably halogen, such as bromine and chlorine.

Suitable solvents for the implementation of the above transformation of compounds of formula (XI) in the compounds of formula (VIII) are methylene chloride, tetrahydrofuran or mixtures thereof, and, preferably, methylene chloride.

Suitable bases for the implementation of the above transformations are Diisopropylamine, triethylamine, pyridine, 2,6-lutidine, preferably triethylamine.

The above process is carried out at a temperature of from about-S to 25 ° C, preferably at about-S. The above transformation can be carried out during the period of time from about 5 minutes to 10 minutes, preferably for about his invention, the aforementioned compounds of formula (VIII) can be selected, or they can be directly converted into the compounds of formula (VIb) in the same reaction vessel as described above. Preferably, the compounds of formula (VIII) were selected prior to their conversion into compounds of the formula (VIb).

The present invention also relates to an alternative method of obtaining the compounds of formula (VIb) through interaction of the compounds of formula (VI)

where R1is para-nitrobenzyl or allyl; R2selected from the group consisting of C1-6of alkyl, C6-10aryl, C6-10arils1-6the alkyl and ditional preferably represents C6-10arils1-6alkyl, such as benzyl; R3represents hydrogen or C1-6alkyl, preferably WITH1-6alkyl, such as methyl; and R4represents hydrogen or C1-6alkyl, preferably WITH1-6alkyl, such as methyl; with the oxidant in a solvent.

A suitable oxidizing agent used for the above transformation of compounds of formula (VI) in the compounds of formula (VIb) is ozone.

Suitable solvents for the above transformations are methylene chloride, tetrahydrofuran, an alcohol (such as isopropanol), or a mixture thereof. Predpologat to be carried out at a temperature of-70C. The above transformation can be carried out during the period of time from about 1 hour to 24 hours, preferably for about 6 hours.

The present invention also relates to another alternative method of obtaining the compounds of formula (VIb), as defined above, by reaction of compounds of formula (XI)

where R2selected from the group consisting of C1-6of alkyl, C6-10aryl, C6-10arils1-6the alkyl and ditional preferably represents C6-10arils1-6alkyl, such as benzyl; with the compound of the formula (XII)

where L3represents halogen, such as chlorine or bromine, and R1is para-nitrobenzyl or allyl, preferably, para-nitrobenzyl; in a solvent and in the presence of a base.

Suitable solvents for the implementation of the above transformation of compounds of formula (XI) in the compounds of formula (VIb) are methylene chloride, tetrahydrofuran or mixtures thereof, and, preferably, methylene chloride.

Suitable bases for the implementation of the above transformations are Diisopropylamine, triethylamine, pyridine or 2,6-lutidine. The preferred base is treatedpatients, from about 20C to 25C. The above transformation can be carried out during the period of time from about 5 minutes to 15 minutes, preferably for about 10 minutes.

The present invention also relates to the compound of formula (I)

where R1is para-nitrobenzyl or allyl, and X is halogen.

The compounds of formula (I) can be used to produce cephalosporins, substituted cyclic ether at the 3-position. These compounds possess some primary properties such as crystal shape and high enantiomeric excess (E. I.).

In one embodiment, the compounds of formula (I) of the present invention R1is allyl. In another embodiment of the present invention R1represents allyl, and X is halogen, such as chlorine or bromine, preferably chlorine.

In a preferred embodiment, the compounds of formula (I) of the present invention R1is para-nitrobenzyl. In the most preferred embodiment of the present invention R1is para-nitrobenzyl, and X is chlorine.

The present invention also relates to the compound of formula (II)

6-10arils1-6alkyl or ditional, preferably, WITH6-10arils1-6alkyl, such as benzyl.

In one embodiment, the compounds of formula (II) of the present invention R1is allyl. In another embodiment of the present invention R1represents allyl, and R2is1-6alkyl, such as methyl.

In a preferred embodiment, the compounds of formula (II) of the present invention R1is para-nitrobenzyl. In the most preferred embodiment of the present invention R2represents benzyl.

The present invention also relates to the compound of formula (III)

where R1is para-nitrobenzyl or allyl; R2is1-6alkyl, C6-10aryl, C6-10arils1-6alkyl or ditional; It represents hydroxy, halogen, or-R-(CH3)3where the relationship With-It is a simple link, if It represents hydroxy or halogen, and a double bond, if It is R-(CH3)3.

In accordance with the compounds of the formula (III) are compounds of the formulas (IIIA), (IIIb) and (S)

In one embodiment, the compounds of formula (III) of the present invention, the connection form is, WITH6-10aryl, C6-10arils1-6alkyl or ditional. In another embodiment, the compounds of formula (IIIA) R1represents allyl, and R2is1-6alkyl, C6-10aryl, C6-10arils1-6alkyl or ditional, preferably, WITH6-10arils1-6alkyl, such as benzyl. In a preferred embodiment, the compounds of formula (IIIA) R1is para-nitrobenzyl, and R2is6-10arils1-6alkyl, such as benzyl.

In one embodiment, the compounds of formula (III) of the present invention the compound of formula (III) has the formula (IIIb), where R1is para-nitrobenzyl, and R2is1-6alkyl, C6-10aryl, C6-10arils1-6alkyl or ditional. In one embodiment, the compounds of formula (IIIb) R1represents allyl, and R2is1-6alkyl, C6-10aryl, C6-10arils1-6alkyl or ditional, preferably, WITH6-10arils1-6alkyl, such as benzyl. In a preferred embodiment, the compounds of formula (IIIb) R1is para-nitrobenzyl, and R2is6-10arils1-6alkyl, such as benzyl.

In one embodiment, the compounds of formula (III) of this izobrajaet1-6alkyl, C6-10aryl, C6-10arils1-6alkyl or ditional. In one embodiment, the compounds of formula (C) R1represents allyl, and R2is1-6alkyl, C6-10aryl, C6-10arils1-6alkyl or ditional, preferably, WITH6-10arils1-6alkyl, such as benzyl. In a preferred embodiment, the compounds of formula (C) R1is para-nitrobenzyl, and R2is6-10arils1-6alkyl, such as benzyl.

The present invention also relates to the compound of formula (V)

where R1is para-nitrobenzyl or allyl; and R2is1-6alkyl, C6-10aryl, C6-10arils1-6alkyl or ditional, preferably, WITH6-10arils1-6alkyl, such as benzyl.

In one embodiment, the compounds of formula (V) of the present invention R1is allyl. In another embodiment, compounds of the present invention R1represents allyl, and R2is1-6alkyl, C6-10aryl, C6-10arils1-6alkyl or ditional. In a preferred embodiment of the present invention R1is para-nitrobenzyl, and R2is6-10

where R1is para-nitrobenzyl or allyl; R2is1-6alkyl, C6-10aryl, C6-10arils1-6alkyl or ditional; T represents hydroxy or >O, where the-T is a simple relationship, if T is hydroxy, and a double bond when T is >o

In accordance with this, the compound of formula (VI) selected from the group consisting of compounds of formulas (VI) and (VIb)

In one embodiment, the compounds of formula (VI) of the present invention the compound of formula (VI) has the formula (VI), where R1represents allyl, and R2is1-6alkyl, C6-10aryl, C6-10arils1-6alkyl or ditional, preferably, WITH6-10arils1-6alkyl, such as benzyl. In a preferred embodiment, the compounds of formula (VI) of the present invention R1is para-nitrobenzyl, and R2is6-10arils1-6alkyl, such as benzyl.

In another embodiment, the compounds of formula (VI) of the present invention the compound of formula (VI) has the formula (VIb), where R1represents allyl, and R2is1-6alkyl, C6-10aryl, C6-10arils1-6alkyl or ditional, preferably, WITH6-1 is to place a pair-nitrobenzyl, and R2is6-10arils1-6alkyl, such as benzyl.

Specific compounds of the present invention are:

the compounds of formula (I):

4-nitrobenzyloxy ester of 7-amino-8-oxo-3-(tetrahydrofuran-2-yl)-5-thia-1-azabicyclo[4.2.0]Oct-2-ene-2-carboxylic acid;

allyl ester of 7-amino-8-oxo-3-(tetrahydrofuran-2-yl)-5-thia-1-azabicyclo[4.2.0]Oct-2-ene-2-carboxylic acid;

and their salts;

the compounds of formula (II):

4-nitrobenzyloxy ether 8-oxo-7-phenylacetylamino-3-(tetrahydrofuran-2-yl)-5-thia-1-azabicyclo[4.2.0]Oct-2-ene-2-carboxylic acid;

allyl ether of 8-oxo-7-phenylacetylamino-3-(tetrahydrofuran-2-yl)-5-thia-1-azabicyclo[4.2.0]Oct-2-ene-2-carboxylic acid;

and their salts;

the compounds of formula (III):

4-nitrobenzyloxy ether {2-oxo-4-[2-oxo-2-(tetrahydrofuran-2-yl)ethylsulfanyl]-3-phenylacetylamino-1-yl}(trimethyl--postenligaen)acetic acid;

allyl ether {2-oxo-4-[2-oxo-2-(tetrahydrofuran-2-yl)ethylsulfanyl]-3-phenylacetylamino-1-yl}(trimethyl--postenligaen)acetic acid;

4-nitrobenzyloxy the chlorine ether{2-oxo-4-[2-oxo-2-(tetrahydrofuran-2-yl)ethylsulfanyl]-3-phenylacetylamino-1-yl}acetic acid;

4-nitrobenzyloxy the hydroxy ether{2-oxo-4-[2-oxo-2-(tetrahydrofuran-2-yl)ethylsulfanyl]-3-phenylacetylamino-1-yl}acetic acid;

allyl ether hydroxy{2-oxo-4-[2-oxo-2-(tetrahydrofuran-2-yl)ethylsulfanyl]-3-phenylacetylamino-1-yl}acetic acid;

and their salts;

the compounds of formula (V):

4-nitrobenzyloxy ether hydroxy(2-mercapto-4-oxo-3-phenylacetylamino-1-yl)acetic acid;

allyl ether hydroxy(2-mercapto-4-oxo-3-phenylacetylamino-1-yl)acetic acid;

and their salts;

the compounds of formula (VI):

4-nitrobenzyloxy ether (3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3.2.0]hept-2-EN-6-yl)hydroxyoctanoic acid;

allyl ether (3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3.2.0]hept-2-EN-6-yl)hydroxyoctanoic acid;

4-nitrobenzyloxy ether (3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3.2.0]hept-2-EN-6-yl)octoxynol acid;

allyl ether (3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3.2.0]hept-2-EN-6-yl)octoxynol acid;

and their salts.

The above new compounds of the present invention can be used to produce cephalosporins, substituted cyclic ether at the 3-position.

A detailed description is recorded in the following reaction schemes. If it is not specifically mentioned in these reaction schemes and in the following discussion of the substituents R1, R2, R3, R4, X, L1, L2and L3are the same as defined above.

SCHEME 1

SCHEME 2

SCHEME 3

Scheme 1 illustrates obtaining the compounds of formula (I). In scheme 1, the compound of formula (I), where R1is para-nitrobenzyl can be obtained by reaction of compounds of formula (II), where R1preferably represents para-nitrobenzyl, and R2preferably represents C6-10arils1-6alkyl, such as benzyl, with an acid in a solvent. Suitable acids are Lewis acid, such as

pentachloride phosphorus or pentabromide phosphorus, preferably, pentachloride phosphorus. Suitable solvents for the above transformations are toluene, xylene, tetrahydrofuran, methylene chloride or acetonitrile, preferably methylene chloride. The above method can be carried out at a temperature of from about-40C to +40C. The above method is carried out for from about 1 hour to 24 hours.

The compound of formula (II), where B>arils1-6alkyl, such as benzyl, can be obtained by cyclization of compounds of formula (IIIA), where R1preferably represents para-nitrobenzyl, and R2preferably represents C6-10arils1-6alkyl, such as benzyl, by heating the compounds of formula (IIIA) in a solvent.

The above method of converting compounds of formula (IIIA) in the compounds of formula (II) represents a so-called intramolecular reaction type of reaction, Wittig, and this reaction is usually carried out by heating the above compounds of formula (IIIA). Suitable solvents are toluene, xylene, tetrahydrofuran, methylene chloride and acetonitrile, preferably methylene chloride. The above process is carried out at a temperature of from about 40C to 160S. The above method is carried out in the period of time from about 1 hour to 24 hours, preferably about 16 hours.

The above conversion of the compounds of formula (IIIA) in the compound of formula (I) can be carried out by two-stage method in which the compound of formula (II) can be selected, but preferably, this transformation is realized by means of single-stage R is rirovanie in scheme 2.

Figure 2 shows the formation of compounds of the formula (IIIA), where R1preferably represents para-nitrobenzyl, and R2preferably represents C6-10arils1-6alkyl, such as benzyl, methods of the present invention. Compounds of the formula (IIIA) are intermediate compounds used to obtain the compounds of formula (I), as shown in figure 1.

In scheme 2 above, the compound of formula (IIIA) can be obtained by reaction of compounds of formula (IIIb), where R1preferably represents para-nitrobenzyl, and R2preferably represents C6-10arils1-6alkyl, such as benzyl, and X preferably represents chlorine, trimethylphosphine, in a solvent and optionally in the presence of a suitable base.

Suitable solvents are tetrahydrofuran, acetonitrile and methylene chloride, preferably, tetrahydrofuran. Suitable bases are imidazole, 2,6-lutidine, pyridine, N-methylmorpholine or sodium bicarbonate, preferably sodium bicarbonate. This reaction is preferably carried out in the presence of a suitable base during processing. The above process is carried out at those who chickpeas to 1 hour.

The compound of formula (IIIb), where R1preferably represents para-nitrobenzyl; and R2preferably represents C6-10arils1-6alkyl, such as benzyl, can be obtained by reaction of compounds of formula (S), where R1preferably represents para-nitrobenzyl; and R2preferably represents C6-10arils1-6alkyl, such as benzyl, with a halogenation agent in the presence of a base in a solvent. Suitable halogenation agents are thionyl chloride, thienylboronic, tribromide phosphorus or trichloride phosphorus, preferably thionyl chloride. Suitable bases are pyridine, 2,6-lutidine, N-methylmorpholine or imidazole, preferably 2,6-lutidine. Suitable solvents are tetrahydrofuran or methylene chloride, preferably methylene chloride. The above process is carried out at a temperature of from about-40C to-20C, preferably at about-20C. The above method is carried out in the period of time from about 15 minutes to 1 hour, preferably for about 1 hour.

The compound of formula (S), where R1preferably represents para-nitrobenzyl; and R2, predpochtitelnye the compounds of formula (V), where R1preferably represents para-nitrobenzyl; and R2preferably represents C6-10arils1-6alkyl, such as benzyl, with a compound of formula (IV)

where Y represents a leaving group such as bromine, chlorine, fluorine, iodine or tosylate, preferably bromine, in a solvent.

Suitable solvents are alcohol, such as methanol, ethanol and propanol; methylene chloride; acetone; dimethylformamide; or mixtures thereof. The above process is carried out at a temperature of from about 10C to 25C. The above method is carried out in the period of time from about 2 hours to 24 hours.

The compounds of formula (IV) are known and can be obtained in accordance with the standard method. For example, the compounds of formula (IV), where Y is chlorine or bromine, can be obtained from compounds of formula (IV)

through the interaction of the compounds of formula (IV) with a halogenation agent such as thionyl chloride or tribromide phosphorus, to obtain the corresponding gelegenheid (such as harborinternational or bromorestricted). The specified gelegenheid subjected to interaction with diazomethane with Abim hydrogen to obtain the corresponding compounds of formula (IV).

The compounds of formula (IV), the corresponding halides and diazomethane are commercially available compounds.

Alternatively, the compound of formula (IV) can be obtained in situ by reaction between the corresponding carboxylic acid of formula (IVb)

with a halogenation agent in methanol or aqueous solution, and subsequent treatment of the acid solution, preferably, para-toluensulfonate acid. Suitable halogenation agents are bromine, chlorine or iodine, preferably bromine.

For every person it is obvious that the method of the present invention the compound of formula (IV) obtained in situ, then subjected to interaction with compounds of the formula (V) and obtain the compounds of formula (S) in the manner described above.

The compounds of formula (V) can be obtained by methods illustrated in scheme 3.

Figure 3 illustrates the formation of compounds of the formula (V), where R1preferably represents para-nitrobenzyl, and R2preferably represents C6-10arils1-6alkyl, such as benzyl; with the methods of the present invention. The compounds of formula (V) represent intermediate soiduradade compounds of the formula (V) into compounds of formula (I) are illustrated in schemes 1 and 2. In accordance with scheme 3, the compound of formula (V) can be obtained by reaction of compounds of formula (VI), where R1preferably represents para-nitrobenzyl; and R2preferably represents C6-10arils1-6alkyl, such as benzyl; with the acid in the solvent. Suitable acids are pair-toluensulfonate acid and methanesulfonamide acid, preferably, para-toluensulfonate acid. Suitable solvents are methylene chloride, tetrahydrofuran, acetone or mixtures thereof, preferably methylene chloride. The above process is carried out at a temperature of from about 20C to 25C. The above method is carried out in the period of time from about 2 hours to 24 hours.

The compounds of formula (VI), where R1preferably represents para-nitrobenzyl; and R2preferably represents C6-10arils1-6alkyl, such as benzyl; can be obtained by reaction of compounds of formula (VIb), where R1preferably represents para-nitrobenzyl; and R2preferably represents C6-10arils1-6alkyl, such as benzyl; with a reducing agent in a solvent. Appropriate restore the tion, triacetoxyborohydride sodium or borohydride sodium. Suitable solvents are acetic acid, methylene chloride, tetrahydrofuran, an alcohol (such as isopropanol), or a mixture thereof. If a reducing agent is triacetoxyborohydride sodium, the preferred solvent is methylene chloride. If a reducing agent is borohydride sodium, the preferred solvent is acetic acid. The above process is carried out at a temperature of from about 20C to S. The above method is carried out in the period of time from about 4 hours to 24 hours.

Alternatively, the compound of formula (VI), where R1preferably represents para-nitrobenzyl; and R2preferably represents C6-10arils1-6alkyl, such as benzyl; can be obtained by reaction of compounds of formula (XI), where R2preferably represents C6-10arils1-6alkyl, such as benzyl, with a compound of formula (X)

where R1preferably represents para-nitrobenzyl; in the presence of base and solvent. Suitable bases are Diisopropylamine, triethylamine, pyridine, 2,6-lutidine, preferably, Auda methylene chloride, tetrahydrofuran or mixtures thereof. The above process is carried out at a temperature of from about 20C to 25C. The above method is carried out in the period of time from about 30 minutes to 2 hours, preferably for about 1 hour.

Compounds of formula (X) and (XI) are known and commercially available compounds.

The compound of formula (VIb), where R1preferably represents para-nitrobenzyl; R2preferably represents C6-10arils1-6alkyl, such as benzyl, can be obtained by reaction of compounds of formula (VIII), where R2preferably represents C6-10arils1-6alkyl, such as benzyl, and the L2represents halogen, such as bromine or chlorine, with a compound of formula (VII)

where R1preferably represents para-nitrobenzyl; in a solvent and in the presence of a base.

The specified compound of formula (VIII) are obtained by reaction of compounds of formula (XI) with the compound of the formula (IX)

where each of these L1and L2represents a leaving group such as halogen, preferably chlorine; in a solvent, optionally in the presence of the Sabbath.) methylene chloride. Suitable bases are Diisopropylamine, triethylamine, pyridine, 2,6-lutidine, preferably triethylamine. The above process is carried out at a temperature of from about-S to 25 ° C, preferably at about-S. The above method is carried out in the period of time from about 5 minutes to 10 minutes, preferably within about 5 minutes.

The compound of formula (VIII) may be isolated, or it can be used in the next stage without selection. Preferably, the compound of formula (VIII) was selected.

Compounds of formulas (VII) and (IX) are commercially available.

Alternatively, the compound of formula (VIb), where R1preferably represents para-nitrobenzyl; and R2preferably represents C6-10arils1-6alkyl, such as benzyl; can be obtained by reaction of compounds of formula (VI), where R1preferably represents para-nitrobenzyl; R2preferably represents C6-10arils1-6alkyl, such as benzyl; R3preferably represents C1-6alkyl, such as methyl; and R4is1-6alkyl, such as methyl; with the oxidant in retroporn or mixtures thereof, preferably, methylene chloride. The above process is carried out at a temperature of-70C. The above method is carried out in the period of time from about 1 hour to 24 hours.

The compound of formula (VI) is commercially available.

Alternatively, the compound of formula (VIb), where R1preferably represents para-nitrobenzyl, and R2preferably represents C6-10arils1-6alkyl, such as benzyl; can be obtained by reaction of compounds of formula (XI), where R2preferably represents C6-10arils1-6alkyl, such as benzyl; with the compound of the formula (XII)

where R1preferably represents para-nitrobenzyl, and L3represents a leaving group such as halogen, preferably chlorine; in a solvent and in the presence of a base. Suitable solvents are methylene chloride, tetrahydrofuran or mixtures thereof. Suitable bases are Diisopropylamine, triethylamine, pyridine or 2,6-lutidine. The above process is carried out at a temperature of from about-40C to 25C. The above method is carried out in the period of time from about 5 minutes to 15 minutes.

Connections form the cephalosporins, substituted cyclic ether at the 3-position, that is, the active compounds of formula (Ia)

(Ia)

where

group CO2R5represents a carboxylic acid or salt of carboxylic acid; and

R6has the formula:

where

A1is6-10aryl, C1-10heteroaryl or1-10heterocyclyl;

A2represents hydrogen, C1-6alkyl, C3-10cycloalkyl,6-10aryl, C1-6alkyl(CO) (1-6)alkyl-O-, BUT(WITH)(C1-6)alkyl, mono(C6-10aryl)(C1-6alkyl), di(C6-10aryl)(C1-6alkyl) or three(C6-10aryl)(C1-6alkyl).

A way of turning the above compounds of formula (I) in the above compound of formula (Ia) described in the provisional application for U.S. patent entitled “Coupling Process And Intermediates Useful For Preparing Cephalosporins”, and filed on 30 November 2000 the Specified active compound has activity against gram-positive and gram-negative bacteria. Methods of analysis for the specified activity and methods of producing the compositions and the introduction of the active compounds described in U.S. patent No. 6020329, issued February 1, 2000, Methods of treatment are also described in the above patent, which lead may be crystallized or recrystallized from solvents, such as organic solvents. In such cases, may form a solvate. In the scope of the present invention includes a stoichiometric solvate, including hydrates, as well as compounds that contain different amounts of water and which can be obtained through methods such as lyophilization.

In the following examples describe the formation of compounds of the present invention. The melting temperature is not adjusted. Data of NMR are expressed in ppm (M. D.) and measured with respect to a clock signal deuterium, obtained from solvent-to-sample (deuterochloroform, if it is not specifically mentioned). Commercial reagents were used without additional purification. Room temperature or ambient temperature is the temperature from 20C to 25C. For convenience and to maximize outputs all anhydrous reactions were carried out in nitrogen atmosphere. Concentration under reduced pressure means that was used rotary evaporator. TLC means thin layer liquid chromatography. HPLC means liquid chromatography high pressure. GC means of gas chromatography. ITSELF means cerium molybdate-ammonium. UV means ultraviolet light.

oil acids

Thionyl chloride (45 ml) of 0.615 mol) was added dropwise to a solution of 4-nitrobenzylamine of hydroxy ether{2-oxo-4-[2-oxo-2-(tetrahydrofuran-2-yl)ethylsulfanyl]-3-phenylacetylamino-1-yl}acetic acid (202 g, 0,362 mol) and 2,6-lutidine (58 ml, 0,500 mol) in dichloromethane (4 l) at-20C. After stirring for 1 hour, the solution was twice washed with saturated sodium chloride (1 l) and concentrated to obtain 4-nitrobenzylamine of chlorine ether{2-oxo-4-[2-oxo-2-(tetrahydrofuran-2-yl)ethylsulfanyl]-3-phenylacetylamino-1-yl}acetic acid, which was used in the next stage without selection. To the concentrated solution was added a solution of trimethylphosphine in tetrahydrofuran (110 l, 3M, 330 mmol), and then the solution was stirred for 1 hour, washed with dilute sodium bicarbonate and saturated sodium chloride to obtain 4-nitrobenzyl ether {2-oxo-4-[2-oxo-2-(tetrahydrofuran-2-yl)ethylsulfanyl]-3-phenylacetylamino-1-yl}(trimethyl--postenligaen)acetic acid which was used in the next stage without selection. After stirring while boiling under reflux for 16 hours, the solution was washed with water and saturated sodium chloride to obtain 4-nitrobenzyl ether 8-oxo-7-Fenn next stage without selection. The solution was concentrated and cooled to-40C, and then was added dropwise pentachloride phosphorus (104 g, 0.5 mol). Then was added a solution of picoline (92 ml) in dichloromethane (60 ml) while maintaining the temperature ranges from-40C to-30C. The mixture was stirred for 1 hour and then was added isopropanol (660 ml). The reaction mixture was heated to 22 ° C, was granulated, filtered and dried to obtain specified in the connection header (250 g, 45%).

Example 2

4-nitrobenzyloxy ether 8-oxo-7-phenylacetylamino-3-(tetrahydrofuran-2-yl)-5-thia-1-azabicyclo[4.2.0]Oct-2-ene-2-carboxylic acid

Specified in the title compound was obtained as described in Example 1 and used in the next stage without highlighting.

Example 3

4-nitrobenzyloxy ether {2-oxo-4-[2-oxo-2-(tetrahydrofuran-2-yl)ethylsulfanyl]-3-phenylacetylamino-1-yl)(trimethyl--postenligaen)acetic acid

Specified in the title compound was obtained as described in Example 1 and used in the next stage without highlighting.

Example 4

4-nitrobenzyloxy the chlorine ether{2-oxo-4-[2-oxo-2-(tetrahydrofuran-2-yl)ethylsulfanyl]-3-phenylacetylamino-1-yl}acetic acid

Specified in the header connection poluchilosy the hydroxy ether{2-oxo-4-[2-oxo-2-(tetrahydrofuran-2-yl)ethylsulfanyl]-3-phenylacetylamino-1-yl}acetic acid

Bromine (51 g) and methanol (270 ml) were combined, and then was added dropwise a solution of (S)-1-(tetrahydro-2-furanyl)ethanol (30 g) in methanol (30 ml) at 30C. After this was added an aqueous solution of sodium thiosulfate, and then methylene chloride (300 ml). The layers were separated and the organic layer was twice washed with an aqueous solution of sodium bicarbonate (300 ml). The obtained organic layer was concentrated, and then acetone was added (600 ml) and para-toluensulfonate acid (6 g). After boiling under reflux for 2 hours, the reaction mixture was cooled and was added 4-nitrobenzyloxy ether (3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3.2.0]hept-2-EN-6-yl)hydroxyoctanoic acid (100 g) and an additional amount of steam-toluensulfonate acid (6 g). Formed 4-nitrobenzyloxy ether hydroxy(2-mercapto-4-oxo-3-phenylacetylamino-1-yl)acetic acid was used in the next stage without selection. The resulting solution was stirred for 2 hours and then the pH is brought up to 3-4 using pyridine. The reaction mixture was concentrated, and then added water (180 ml), methylene chloride (600 ml) and hydrochloric acid (9 ml, 15%) to bring the pH to a value of 1-2. The layers were separated and the methylene chloride was replaced with methanol (600 ml). Then to complete the deposition and isopropanol. The product was dried in vacuum to obtain specified in the connection header.

Example 6

4-nitrobenzyloxy ether hydroxy(2-mercapto-4-oxo-3-phenylacetylamino-1-yl)acetic acid

Specified in the title compound was obtained as described in Example 5 and used in the next stage without highlighting.

Example 7

4-nitrobenzyloxy ether (3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3.2.0]hept-2-EN-6-yl)octoxynol acid

Method AND

In a 250 ml round-bottom flask equipped with a magnetic stirrer, under nitrogen atmosphere was added 5.0 g (to 22.9 mmol, 1.0 EQ.) 3-benzyl-4-thia-2,6-diazabicyclo[3.2.0]hept-2-EN-7-she 5,98 g (26,3 mmol, 1.15 EQ.) monohydrate para-nitrobenzothiazole and 75 ml of methylene chloride. To the stirred suspension was added to 0.22 ml (1.6 mmol, 0.7 EQ.) of triethylamine. After adding triethylamine solids began to slowly dissolve in the solution. Stirring is carried out for approximately 1 hour. Usually all solids were dissolved in the solution, and elution with ethyl acetate (ethyl acetate staining HIMSELF) did not reveal residual 3-benzyl-4-thia-2,6-diazabicyclo[3.2.0]hept-2-EN-7-it.

To bring the pH to 4-5, the solution was acidified with 0.1 M hydrochloric acid. Layers besieged and otdalennyi salt solution). The solution was dried with anhydrous magnesium sulfate and concentrated in vacuum. The result has been 9,37 g specified in the title compound as an oily foam with a yield of 96%.

Method IN

Isopropanol (500 ml), methylene chloride (1800 ml) and (1R)-(4-nitrophenyl)methyl ester-1-methylethylidene)-7-oxo-(3-phenylmethyl)-4-thia-2,6-diazabicyclo[3.2.0]hept-2-ene-6-acetic acid (250 g) were combined and the reaction mixture was cooled at-70C. To the cooled reaction mixture was barbotirovany ozone until the completion of ozonolysis and received 4-nitrobenzyloxy ether (3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3.2.0]hept-2-EN-6-yl)hydroxyoctanoic acid, which was used in the next stage without selection. To the resulting solution was added a mixture of glacial acetic acid (625 ml) and isopropanol (750 ml), and then a mixture of isopropanol (100 ml), water (100 Il) and sodium borohydride (22 g). After the recovery solution was added sodium metabisulfite in water and the pH brought up to 1.5 to 2.5 by the addition of hydrochloric acid (15%). The layers were separated and the organic layer twice washed with an aqueous solution of sodium chloride (1000 ml). The organic layer was concentrated in vacuum, the resulting slurry was granulated and filtered and the filter cake was washed with isopropanol. Provy ether (3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3.2.0]hept-2-EN-6-yl)-3-methylbut-2-Noynoy acid

Method AND

In a round bottom flask, equipped with a magnetic stirrer, under nitrogen atmosphere was added 3-benzyl-4-thia-2,6-diazabicyclo[3.2.0]hept-2-EN-7-he (0,76 g, 3.5 mmol, 1.0 EQ.), methylene chloride (8.0 ml) and triethylamine (of 0.64 ml, 4.6 mmol, 1.3 EQ.). The suspension was cooled to-S, and then was added a 2M solution of oxalicacid (of 1.85 ml, 3.7 mmol, of 1.05 equiv.) in methylene chloride for 1 minute. The color of the solution became dark red/brown. Thin-layer chromatography (ethyl acetate, UV, staining HIMSELF) showed that the reaction was completed after 5 minutes. Then one portion was added a solution of (4-nitrophenyl)methanol (0.54 g, 3.5 mmol, 1.0 EQ.) triethylamine (of 0.64 ml, 4.6 mmol, 1.3 EQ.) in methylene chloride (5.0 ml). Thin-layer chromatography (ethyl acetate, UV, staining HIMSELF) showed that the reaction was completed after 5 minutes. The reaction extinguished with water (15 ml). Then the organic layer was sequentially washed with saturated aqueous sodium bicarbonate (15 ml) and saturated aqueous sodium chloride (15 ml). After drying with magnesium sulfate and processing of coal organic solution was concentrated in vacuum to obtain specified in the title compound (1.0 g, 2,35 mmol, yield 67%) as a dark brown solid.

Method IN

In a round bottom to the (161 mg, to 0.74 mmol, 1.0 EQ.), methylene chloride (10 ml) and triethylamine (0,22 ml, 1.55 mmol, 2.1 EQ.). The solution was stirred at 20-25C and one portion was added 4-nitrobenzyloxy ether Chlorococcales acid (198 mg, 0.81 mmol, 1.1 EQ.). After about 10 minutes initial light yellow solution had acquired a light orange color. Then the reaction mixture is then washed with water, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic layer was dried with magnesium sulfate and concentrated in vacuum to obtain specified in the title compound (250 mg, 0.55 mmol, yield 79%) as a pale orange solid.

Getting 1: 4-nitrobenzyloxy ether Chlorococcales acid

In a round bottom flask, equipped with a magnetic stirrer, under nitrogen atmosphere was added methylene chloride (60 ml) and then 2M solution oxalicacid in methylene chloride (15.0 ml, 30 mmol, 1.0 EQ.). The solution was cooled in ice water to 0-5C. To oxalylamino the solution in one portion was added (4-nitrophenyl)methanol (4.59 g, 30 mmol, 1.0 EQ.). After adding a pair of nitrobenzyl alcohol, the reaction mixture was left for 24 hours at 20-25C for mixing. The resulting solution was concentrated in vacuo and was titrated hot Huck is on the matter.

Example 9

4-nitrobenzyloxy ether (3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3.2.0]hept-2-EN-6-yl)hydroxyoctanoic acid

Specified in the title compound was obtained as described in Example 8, Method, and used in the next stage without highlighting.

Example 10

Allyl ester of 7-amino-8-oxo-3-(tetrahydrofuran-2-yl)-5-thia-1-azabicyclo[4.2.0]Oct-2-ene-2-carboxylic acid

In a 10 l glass vessel was added methylene chloride (4,50 l), and then pentachloride phosphorus (277,0 g of 1.33 mol). The vessel was purged with nitrogen was added pyridine (350,4 g, 4,43 mol) with a maximum temperature of 25C. The solution was again cooled to-20C. Allyl ether of 8-oxo-7-phenylacetylamino-3-(tetrahydrofuran-2-yl)-5-thia-1-

azabicyclo[4.2.0]Oct-2-ene-2-carboxylic acid (190,0 g, 0,443 mol) was dissolved in methylene chloride (350 ml), was added to the vessel top, and was introduced in methylenechloride solution for approximately 20 minutes at-20C. Chemical glass used for dissolution, and the vessel top, washed with methylene chloride. The solution was left to warm to 0 C and stirred at this temperature for one hour.

Then took a sample solution for analysis. After adding methanol (3,70 l) at-20C, the usual took 90 minutes then the temperature was raised to 0C and the solution was stirred for 30 minutes. To a methanol solution was added 7% sodium carbonate solution (10 l) at a maximum temperature of 5 ° C to bring the pH to 7-7,5. While there was slight foaming. Then the solution was transferred into a 20 l separating funnel and the two phases were separated. The aqueous phase was extracted with methylene chloride (1.5 l). United metilenhloride phase was washed with 20% saturated sodium chloride (1.5 kg) and dried over sodium sulfate (50 g) obtaining specified in the connection header.

Example 11

Allyl ether of 8-oxo-7-phenylacetylamino-3-(tetrahydrofuran-2-yl)-5-thia-1-azabicyclo[4.2.0]Oct-2-ene-2-carboxylic acid

In a 100 l glass vessel was added toluene (47 l) and allyl ether {2-oxo-4-[2-oxo-2-(tetrahydrofuran-2-yl)ethylsulfanyl]-3-phenylacetylamino-1-yl}(trimethyl--postenligaen)acetic acid, (1990). The solution was purged with nitrogen and brought to the temperature of reflux distilled. All present water was collected and the solution boiled under reflux for 20 hours. After taking samples for TLC/HPLC analysis of the solution was again cooled to room temperature. This solution was passed through silica gel 60 (4.5 kg) and then given a temperature of 60C. Then added ethyl acetate, after which it is evaporated in vacuo at a maximum temperature of 60C. To semi-solid oil was added tert-butyl methyl ether (2.5 l) and the solution was stirred over night. The crystalline product was filtered and washed another 0.3 l of tert-butyl methyl ether. The mother solution was concentrated and again subjected to chromatography on silica (dissolved in 5 l of toluene was added to the silica, was suirable 15 l of toluene) and was led in the same way to obtain a second collection of product. This product was isolated as a white crystalline solid. Outputs ranged from 70% to 80%.

Example 12

Allyl ether {2-oxo-4-[2-oxo-2-(tetrahydrofuran-2-yl)ethylsulfanyl]-3-phenylacetylamino-1-yl)(trimethyl--postenligaen)acetic acid

A solution of allyl ether hydroxy{2-oxo-4-[2-oxo-2-(tetrahydrofuran-2-yl)ethylsulfanyl]-3-phenylacetylamino-1-yl}acetic acid in tetrahydrofuran obtained as described in Example 14, was diluted with additional tetrahydrofuran (12 l of tetrahydrofuran). The solution was again cooled to-20 ° C in nitrogen atmosphere, was added 2,6-lutein (654,0 g 6,09 mol), and then was added dropwise tioner was left to warm up to-10C and samples were taken for TLC. TLC showed that the transformation of the source material in the allyl ether chlorine{2-oxo-4-[2-oxo-2-(tetrahydrofuran-2-yl)ethylsulfanyl]-3-phenylacetylamino-1-yl}acetic acid was completed. Then the precipitated compound was filtered and again washed with tetrahydrofuran. Tertrahydrofuran ring solution was concentrated in vacuo at a maximum temperature of 30C was again dissolved in fresh tetrahydrofuran (6 l) and was again cooled to-10C. After stirring overnight at room temperature, samples were taken of the solution for analysis at the completion of the reaction was diluted with ethyl acetate (35 l) and washed with 5% sodium bicarbonate (20 l) and 20% saturated sodium chloride (20 l). Then the ethyl acetate evaporated in vacuo at maximum temperature of 40 ° C to obtain a thick dark oil. The outputs were in the range of 88% to 90%.

Example 13

Allyl ether chlorine{2-oxo-4-[2-oxo-2-(tetrahydrofuran-2-yl)ethylsulfanyl]-3-phenylacetylamino-1-yl}acetic acid

Specified in the title compound was obtained as described in Example 12, and used in the next stage without highlighting.

Example 14

Allyl ether hydroxy{2-oxo-4-[2-oxo-2-(tetrahydrofuran-2-yl)ethylsulfanyl]-3-phenylacetophenone (1.0 l) and allyl ether (3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3.2.0]hept-2-EN-6-yl)hydroxyoctanoic acid (2016, 6.05 mol), obtained as described in Example 15. To this solution was added 45% aqueous solution of para-toluensulfonate acid (500.0 g). After stirring for 3 hours, samples were taken of the solution for TLC analysis on completion of the reaction. The solution was transferred into a 50 l glass separating vessel, was added methylene chloride (5 l) and then water (2 l). Then the separated organic phase was washed with water (4 l). Metilenhloride phase was dried over sodium sulfate to obtain a dry solution of allyl ether hydroxy(2-mercapto-4-oxo-3-phenylacetylamino-1-yl)acetic acid in methylene chloride, which was used immediately. To the above solution was added 86% solution of 2-bromoacetophenone in methylene chloride (6.3 mol). The resulting solution was evaporated in vacuum at a maximum temperature of 30 ° C to a final volume of 50% of its original volume. Then was added pyridine (503,1 g, 6,36 mol) with a maximum temperature of 10C. The solution was stirred overnight, diluted with methylene chloride (10 l), twice washed with water (10 l) and once with saturated sodium chloride (10%, 10 l). After drying over sodium sulfate, the solution was concentrated to dryness in vacuo at a maximum temperature of 40C. The solution again is should be saved, it was first placed into storage, and then, before use, dried.

Getting 1: 2-bromoacetylation

In 20 l glass vessel was added methylene chloride (10.0 l), and then acetylhydrolase (838,0 g, 7,34 mol). Then the solution was again cooled to-10 ° C was added triethylamine (854,0 g, 8,44 mol). The vessel was purged with nitrogen, and was added dropwise trimethylsilyltriflate (1713,0 g, 7,71 mol) with a maximum temperature of-8C. Add is usually completed in 45 minutes. After stirring for 15 minutes, samples were taken for TLC and GC analysis, which indicated that the reaction was complete. To the solution at a maximum temperature of-5C, for about 45 minutes six portions were added N-bromosuccinimide (1340, 7,53 mol). After stirring for 30 minutes, samples were taken of the solution for GC and TLC analysis indicated that the reaction was complete. Then the solution was transferred into a 50 l separating vessel, and carefully added 5% sodium bicarbonate (5 l). The solution was stirred and the phases were separated. The upper aqueous phase was discarded, and methylenchloride phase was washed with water, dried over sodium sulfate, filtered and kept in refrigerator until use in the subsequent stage.

Example 15

And lenny vessel was added methylene chloride (20,6 l), and then 3-benzyl-4-thia-2,6-diazabicyclo[3.2.0]hept-2-EN-7-he (1700, 7,79 mol). To this suspension was added monohydrate of allylglycine (1285 g, 9,74 mol), and then a sufficient amount of triethylamine (about 175 g) to bring the solution pH to 7.5 to 7.9. After stirring for 1 hour, samples were taken of the solution for TLC/HPLC analysis. After completion of the reaction the solution extinguished 0.1 M hydrochloric acid (2,75 l) to bring the pH up to 4,50-5,00. The upper aqueous phase was discarded, and methylenchloride phase was washed with water (8 l) and saturated sodium chloride (8 l). The solution was dried over sodium sulfate and concentrated to obtain a thick oil. This oil was dispersible in hexane (5 l), filtered and again suspended in tert-butylmethylether ether (5 l) and then filtered and again washed with tert-butylmethylamine ether. After drying by air received no white crystalline product. The outputs were in the range from 72 to 99%.

Although the present invention is described and illustrated certain specific embodiments, its implementation, however, it is clear that his methods and protocols may be made various improvements, changes, modifications, substitutions, bills, or add, is not beyond being and volume nosratinia and that said claims shall be if possible, widely interpreted. Table 1

Comparative data for the compounds with 4-nitrobenzyloxy group (PNB) and 4-methoxybenzyloxy group (RNG)

Spectroscopic data

Example 1

(CVG): 3420, 1780, 1719, 1521, 1348 cm-1

Example 5

(CVG): 3385,9, 3283, 1783, 1654, 1518, 1350 cm-1

Example 8

(CVG): 3412, 1943, 1738, 1609, 1532, 1349 cm-1

1. The method of obtaining the compounds of formula (I)

where R1is a para-nitrobenzyl or allyl;

X represents halogen,

which includes stages

a) cyclization trimethylphosphine the compounds of formula (IIIA)

where R1is a para-nitrobenzyl or allyl;

R2selected from the group comprising FROM1-6alkyl, C6-10aryl, C6-10arils1-6alkyl and dithienyl;

in a solvent to form compounds of the formula (II)

where R1is a para-nitrobenzyl or allyl;

R2selected from the group comprising FROM1-6alkyl, C6-10aryl, C6-10arils1-6alkyl and dithienyl;

b) interaction of the compounds of the formula (II) with acid.

2. The method by which the compounds of formula (IIIb)

where R1is a para-nitrobenzyl or allyl,

R2selected from the group comprising FROM1-6alkyl, C6-10aryl, C6-10arils1-6alkyl and dithienyl;

X represents halogen,

with trimethylphosphine in a solvent, where the specified solvent is tetrahydrofuran, acetonitrile, methylene chloride, in the presence of a base, where the specified base selected from the group consisting of imidazole, 2,6-lutidine, pyridine, N-methylmorpholine and sodium bicarbonate.

3. The method according to p. 2, which additionally includes the stage of receipt of the compounds of formula (IIIb) by reacting the compounds of formula (S)

where R1is a para-nitrobenzyl or allyl;

R2selected from the group comprising FROM1-6alkyl, C6-10aryl, C6-10arils1-6alkyl and dithienyl,

with a halogenation agent, where the specified halogenation agent are thionyl chloride, thienylboronic, trichloride phosphorus or tribromide phosphorus, and the specified halogen is chlorine or bromine, in a solvent and in the presence of a base, where the specified base selected from the group consisting of pyridine, 2,6-lutidine, N-methylmorpholin the formula I (S) by reacting the compounds of formula (V)

where R1is a para-nitrobenzyl or allyl;

R2selected from the group comprising FROM1-6alkyl, C6-10aryl, C6-10arils1-6alkyl and dithienyl,

with the compound of the formula (IV)

where Y is a leaving group selected from the group including bromine, chlorine, fluorine, iodine and toilet, in a solvent, where the specified solvent selected from the group consisting of alcohol (where specified alcohol selected from the group consisting of methanol, ethanol and propanol, methylene chloride, acetone, dimethylformamide and mixtures thereof.

5. The method according to p. 4, which additionally includes the stage of receipt of the compounds of formula (V) by reacting the compounds of formula (VI)

where R1is a para-nitrobenzyl or allyl;

R2selected from the group comprising FROM1-6alkyl, C6-10aryl, C6-10arils1-6alkyl and dithienyl,

acid, where the specified acid is para-toluensulfonate acid or methansulfonate acid, in the presence of a solvent, where the specified solvent are methylene chloride, tetrahydrofuran, acetone or mixtures thereof.

6. The method according to p. 5, which further on is 2">

where R1is a para-nitrobenzyl or allyl,

R2selected from the group comprising FROM1-6alkyl, C6-10aryl, C6-10arils1-6alkyl and dithienyl;

with a reducing agent in a solvent.

7. The method according to p. 5, which additionally includes the stage of receipt of the compounds of formula (VIa) by reacting the compounds of formula (XI)

where R2selected from the group comprising FROM1-6alkyl, C6-10aryl, C6-10arils1-6alkyl and dithienyl;

with the compound of the formula (X)

where R1is a para-nitrobenzyl or allyl;

in a solvent in the presence of a base.

8. The method according to p. 6, which additionally includes a step for obtaining compounds of formula (VIb) by reacting the compounds of formula (VIII)

where R2selected from the group comprising FROM1-6alkyl, C6-10aryl, C6-10arils1-6alkyl and dithienyl;

L2is a deleted group selected from the group consisting of halogen, azide and C1-6alkoxy,

with the compound of the formula (VII)

R1-OH, (VII)

where R1is a para-nitrobenzyl or and the II) by reacting the compounds of formula (XI)

where R2selected from the group comprising FROM1-6alkyl, C6-10aryl, C6-10arils1-6alkyl and dithienyl;

with the compound of the formula (IX)

where each of these L1and L2is a deleted group selected from the group consisting of halogen, azide and C1-6alkoxy,

in a solvent, optionally in the presence of a base.

9. The method according to p. 6, which also includes a step of obtaining the compounds of formula (VIb) by reacting the compounds of formula (VI)

where R1is a para-nitrobenzyl or allyl,

R2selected from the group comprising FROM1-6alkyl, C6-10aryl, C6-10arils1-6alkyl and dithienyl,

R3represents hydrogen or C1-6alkyl;

R4represents hydrogen or C1-6alkyl,

with ozone in a solvent.

10. The method according to p. 6, which additionally includes a step for obtaining compounds of formula (VIb) by reacting the compounds of formula (XI)

where R2selected from the group comprising FROM1-6alkyl, C6-10aryl, C6-10arils1-6alkyl and dithienyl;

with the compound of the formula (XII)

in a solvent in the presence of a base.

11. The method according to p. 1, where each of these R1if it is present, is a para-nitrobenzyl.

12. The method according to p. 1, where each of these R1if present, represents allyl.

13. The compound of formula (I)

where R1is a para-nitrobenzyl or allyl;

X represents halogen.

14. The compound of formula (II)

where R1is a para-nitrobenzyl or allyl;

R2is a (C6-10)aryl(C1-6)alkyl.

15. The compound of formula (III):

where R1is a para-nitrobenzyl or allyl;

R2is a (C6-10)aryl(C1-6)alkyl;

It represents hydroxy, halogen, or-R-(CH3)3,

where the connection To the-To is a simple relationship, if It represents a hydroxy or halogen, and a double bond, if It is a R-(CH3)3,

where the aforementioned compound of formula (III) selected from the group consisting of compounds of formulas (IIIA), (IIIb) and (S)

16. The compound of formula (V)

where R1<1-6)alkyl.

17. The compound of formula (VI):

where R1is a para-nitrobenzyl or allyl,

R2is a (C6-10)aryl(C1-6)alkyl,

T represents hydroxy or =O;

where the-T is a simple relationship, if T represents hydroxy, and a double bond when T is a =O;

where the aforementioned compound of formula (VI) selected from the group consisting of compounds of formulas (VI) and (VIb)



 

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