HU186303B - Process for preparing beta-lactam derivatives - Google Patents

Abstract

The present invention relates to a process for the preparation of the cefem and penam carboxylic acid derivatives of formula XXIV, wherein Rg is sulfur or oxygen, R, hydrogen or methoxy, R is hydrogen, optionally substituted with halogen, or one or two, optionally nitro- Lower alkyl substituted with C 1-4 alkoxy substituted with phenyl or lower alkanoyloxy or halogen substituted phenacyl, preferably benzyl, 4-nitrobenzyl, benzhydryl or 2,2,2-trichloroethyl, R 9 (t) or (u) wherein R7 is phenyl, phenoxymethyl, thienylmethyl or benzyl, X is chloro or bromo, and -NR2R3 is formamide, acetamido-, heptanoylamino, benzamide. amino, phenylacetamido, phenoxyacetamido, phenylthioacetamido, thienylacetamide or hydrochloride, Y is selected from the group consisting of (a), (b), (c) or (f). rt, wherein A is chloro or bromo, methyl, C1 -C4 alkoxy, hydroxy or C1-4 alkanoyloxy, and B is C2-4 alkanoyloxy. 186 303

Description

Extensive research in the field of cephalosporin backbone antibiotics has led to the discovery of several clinically relevant cephalosporin derivatives. Recent results of these studies include the discovery of cephem derivatives containing halogen as a substitute for the 3-position carbon atom. Chauvette, U.S. Patent Nos. 3,925,372, 4,064,343 and 3,962,227, disclose numerous 3-halo-3-cephem derivatives. These potent antibiotics are prepared by halogenating the corresponding 3-hydroxy-3-cephem derivatives. The 3-hydroxy-3-cephem derivatives are generally halogenated to the corresponding 3-chloro or 3-bromo-3-cephem derivatives by reacting the former, usually in the presence of dimethylformamide, with a chlorinating or brominating agent such as phosgene, oxalic acid. dichloride, thionyl chloride, thionyl bromide or phosphorus halides such as phosphorus trichloride or phosphorus tribromide.

Most chemical transformations in the preparation of semisynthetic penicillin and cephalosporin backbone antibiotics are carried out on β-lactams which have stable acyl groups at the 6 and 7 position of their amino groups, but these acyl groups have the highest antibiotic activity. not the most advantageous. Therefore, one or more steps in the preparation of most, if not all, clinically relevant penicillin and cephalosporin derivatives are the removal of the acyl group at the 6 and 7 position of the amino group when the corresponding 6-amino and 7-amino- and then acylated as desired. Undoubtedly the most commonly used method for such cleavage of the acylamino side chain is to convert the acylamino derivative first to the corresponding imino halide and then to the imino ether, and the resulting product is hydrolyzed or alcoholized to give the free 6-amino or It is converted to a 7-amino derivative. This general method and improved versions thereof are described in U.S. Patent Nos. 3,549,628, 3,575,970, 3,697,515, 3,845,043, and 3,868,368.

A number of acid halides, and in particular acid chlorides, which can be derived from the oxyacids of phosphorus, carbon and sulfur, have been described as reagents useful in the preparation of imino halide intermediates of the three-step amide cleavage process outlined above. Thus, in particular, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, phosgene, oxalyl chloride and catechyl phosphorus trichloride have been described as suitable for the preparation of imino halides. Laboratory experience has shown that phosphorus pentachloride can advantageously be used in the preparation of iminohalides.

Cephalosporin sulfoxides are also widely used intermediates in the synthesis of cephalosporin backbone antibiotics. Each step of the synthesis pathway is carried out on the sulfoxide form of the cephalosporin derivative, and then the sulfoxide group is reduced to give the reduced cephalosporin derivative, i.e. the sulfide group.

Prior to the development of the method of the present invention, the reduction of cephalosporin sulfoxides was preferably carried out according to the method of Murphy et al., U.S. Patent No. 3,641,014, namely

1. using hydrogen and a hydrogenation catalyst,

2. with the aid of tin (II), iron (II), copper (I) or manganese (II) cations,

3. dithionites, iodides or ferrocyanides,

4. derivatives of trivalent phosphorus,

5. halogen silanes or

6. Chloromethylene iminium chlorides.

Some of the reducing agents listed here also required the use of an activator such as acetyl chloride or phosphorus trichloride. For example, sodium dithionate can be activated with acetyl chloride. Another method for the reduction of cephalosporin sulfoxides is described by Hatfeld in U.S. Patent 4,044,002; this method uses acyl bromides in the presence of a bromine binding agent. Most recently, Kukolja and Spry described the reduction and concomitant chlorination of 3-hydroxycephem sulfoxides using phosphorus trichloride, phosphorus pentachloride or phosgene in the presence of dimethylformamide.

Recently, we have discovered a family of compounds that can be derived from aryl esters of phosphorus rather than from one of its oxyacids. More specifically, it has been discovered that when certain triaryl phosphites are reacted with an equivalent amount of chlorine or bromine, first kinetically controlled products are formed which, although thermodynamically unstable, are advantageously used for the preparation of β-lactam derivatives.

The present invention relates to a process for the use of the recently discovered triaryl phosphite halide compounds for the following purposes:

(a) halogenation of a 6-acylaminopenicillin or 7-acylaminoscephalosporin derivative;

b) halogenation of a 3-hydroxy-3-cephem derivative;

c) halogenating a 7-acylamino-3-hydroxycephem derivative in a single step;

d) reduction of a cephalosporin sulfoxide;

e) one step reduction and halogenation of a 3-hydroxycephalosporin sulfoxide;

f) reduction and halogenation of a 7-acylaminocephalosporin sulfoxide in one step;

g) one step reduction and halogenation of a 7-acylamino-3-hydroxycephalosporin sulfoxide.

Until now, no halogenating agent was known which was capable of carrying out reactions other than halogenation.

The present invention provides compounds of formula (XXIV) wherein R _{g is} sulfur or oxygen,

Rj is hydrogen or methoxy,

R is hydrogen, lower alkyl optionally substituted by halogen, or substituted by one or two phenyl optionally substituted by nitro, C 1-4 alkoxy or lower alkanoyloxy, or phenyl substituted by halogen, preferably benzyl, 4-nitrobenzyl, - or 2,2,2-trichloroethyl,

R ₉ is a group of formula (I) or (u) wherein R _{7 is} phenyl, phenoxymethyl, thienylmethyl or benzyl, X is chlorine or bromine, and -NR ₂ R _{3 is} formamido, acetamido, heptanoylamido; , benzamido, phenylacetamido, phenoxyacetamido, Fe3

-2186303 amino groups in the form of nylthioacetamido, thienylacetamido or hydrochloride,

Y is a group of formula (a), (b), (c) or (f), wherein

Chlorine or bromine, methyl, C 1-4 alkoxy, hydroxy or C 1-4 alkanoyloxy, and

B is a C 2-4 alkanoyloxy group.

We process a compound of the general formula (XXV) penam, cefam or cephem carboxylic acid, wherein

Rj, R and —NR ₂ R ₃ are as defined above,

R ' _{g is a} sulfur atom, an oxygen atom or a sulfoxide group,

Y is a group of formula (a), (b), (c) or (f) wherein A 'is chloro or bromo, methyl, C 1-4 alkoxy, optionally protected hydroxy or C 1-4 alkanoyloxy, and

B is a C 2 -C 4 alkanoyloxy group with a triaryl phosphite halide complex of formula XIII at or below

X is chlorine or bromine, and

Z is hydrogen or halogen, C 1-4 alkyl or C 1-4 alkoxy, which is a molar equivalent of a triaryl phosphite derivative of formula XII and chlorine or bromine in an aromatic hydrocarbon or halogenated hydrocarbon solvent of -70 and 0; Kinetically controlled product of the reaction at 0 ° C.

The present invention relates in particular

A process for the preparation of penicillin or cephalosporinimino halides by reacting a compound of formula I wherein:

R, Rj and Y are above and

R _{7 is} hydrogen, methyl, hexyl, phenylmethyl, phenoxymethyl, phenothiomethyl -

Reacting a 6-acylaminopenicillin or 7-acylaminocephalosporin derivative in a substantially anhydrous, inert solvent at about 30 ° C or less with about 1.0 equivalent to about 2.0 equivalents of the triaryl phosphite halide complex. from about 1.0 to about 1.2 equivalents per halogenating agent in the presence of a tertiary amine base;

Process 2 is a compound of formula (II) wherein R is as defined above but other than hydrogen,

R 1 and R ₇ are as defined above, and

M is hydrogen, chlorine or bromine, protected hydroxy, alkoxy containing up to 4 carbon atoms,

Reacting a 7-acylaminocephalosporin derivative with a triaryl phosphite halide complex;

Process 3 is of formula (III) wherein

X is chlorine or bromine,

R is defined as above but other than hydrogen, R₁ is hydrogen or methoxy, and R ₂ R ₃ N- group in the preparation of the above compounds in such a way that a (IV) wherein R, R, R ₂ and R ₃ are as defined above, reacting said compound in a substantially anhydrous, inert organic solvent at a temperature below about 30 ° C with about 1.0 equivalent to about 1.3 equivalent of a triaryl phosphite halide complex;

Process 4 is of formula (V) wherein

X is chlorine or bromine;

R is as defined above but other than hydrogen,

R 1 is hydrogen or methoxy, and R ₇ is for the preparation of a compound of formula VI wherein R, R, and R ₇ are as defined above, in a substantially anhydrous, inert organic solvent at about 30 ° C. At a temperature below about C, about 2.0 equivalents to about 3.0 equivalents in the presence of about 1.0 equivalents to about 1.2 equivalents of tertiary amine base per halogenating agent;

Process 5 is a compound of formula VII wherein

R is as defined above,

R 1 is hydrogen or methoxy; R ₂ R ₃ N - are as defined above, and

Y is a divalent radical of formula (b) or (f) wherein

A is as defined above for the reduction of a cephalosporin sulfoxide, or a compound of formula VIII wherein R, R 1 and -NR ₂ R ₃ and Y are as defined above, to a corresponding cephalosporin derivative such that reacting said cephalosporin sulfoxide of formula (VII) in a substantially anhydrous, inert organic solvent at a temperature of about 30 ° C or less with about 1.0 equivalent to about 1.3 equivalent of a triaryl phosphite halide complex with a halogen scavenger. in the presence of at least one equivalent;

Process 6 is of formula (III) wherein

R 1 is hydrogen or methoxy, and R, R 1, X and R ₂ R ₃ N- are used to prepare compounds of the above meaning by reacting a compound of formula VIII wherein

R 1 and -NR ₂ R ₃ are as defined above, in a substantially anhydrous, inert organic solvent, at a temperature of about 30 ° C or less, in an amount of about 2 equivalents to about 3 equivalents of a triaryl phosphite halogen complex. in the presence of an equivalent amount of a halogen scavenger;

Process 7 is of formula IX wherein

X is chlorine or bromine,

R, R, R _{7 are} as defined above, and

Y is a divalent radical, represented by the general formula (b ') or (f), substituted with an alkyl group, a protected carboxyl group or an alkyl group containing up to 4 carbon atoms substituted with a protected carboxyl group, with 1-4 heteroatoms, oxygen, a group derived from a heterocycle containing sulfur and / or nitrogen, for the preparation of cephalosporinimino halides by the preparation of a compound of formula X wherein R, R 1, R ₇ and Y are as defined above, 7-acylaminocephalosporin sulfoxide; in an essentially anhydrous, inert organic solvent, reacting with at least one equivalent of a halogen scavenger and from about 1 equivalent to about 3186303 to about 2 equivalent of a tertiary amine base in an amount of from about 2 to about 3 equivalents of a triaryl phosphite-halogen complex k and further

Process 8 is a compound of formula V wherein R is as defined above, but other than hydrogen, R1 is hydrogen or methoxy;

X is chlorine or bromine, and

R ₇ is as defined above,

For the preparation of 3-halo-cephalosporinimino-halides by reacting a 7-acylamino-3-hydroxy-cephalosporin sulfoxide of the formula XI in which R, R 1 and R ₇ are as defined above in a substantially anhydrous, inert organic solvent. at a temperature of about 30 ° C or lower, in the presence of at least one equivalent of a halogen scavenger and from about 2.0 to about 5.0 equivalents of a tertiary amine base in an amount of about 3 to about 5 equivalents of a triaryl phosphite halide complex. reacted.

The triaryl phosphite halide complexes used in the processes of the present invention are compounds which have been recently discovered and are formed by the reaction of certain triaryl phosphites with chlorine or bromine.

The compound of formula XII wherein Z is hydrogen or halogen, alkyl having up to 4 carbon atoms or alkoxy having up to 4 carbon atoms, triaryl phosphites is reacted with an equivalent amount of chlorine or bromine in a substantially anhydrous organic solvent, and under the control of general formula XIII, wherein

Z is as defined above, and

X is chlorine or bromine, compounds are formed.

In the above definition Z, the term "halogen" refers to chlorine, bromine or iodine. The term "alkyl having up to 4 carbon atoms" refers to methyl, ethyl, isopropyl, n-propyl, η-butyl, secondary butyl, tert-butyl or isobutyl. Typical "alkoxy groups having up to 4 carbon atoms" are, for example, methoxy, ethoxy, isopropoxy, tert-butoxy and n-butoxy.

In the general formula of the products resulting from the kinetically controlled reaction used in the processes of the present invention, the hyphen between the phosphorus atom and the X ₂ symbol is simply intended to chemically combine an equivalent amount of halogen and phosphorus reagent so that the products can be distinguished. previously described compounds of similar structure but thermodynamically stable, the formula of which is generally written without a hyphen (for example (PhO ₃ PCl ₂ )). The exact molecular structure of the triaryl phosphite-halogen kinetic complexes mentioned herein is not yet known; however, the physicochemical data of these compounds indicate that the phosphorus atom has a certain cationic character. As used herein, the terms "kinetic compound", "kinetic complex", "triaryl phosphite-halogen complex (compound)", "kinetically-controlled reaction product" and "kinetic-controlled halogenating agent" are used interchangeably.

Triaryl phosphites, tris (p-methoxyphenyl) phosphite, tris- (o-chlorophenyl) phosphite, tris (p-methoxyphenyl) -phosphite, tris- (o-chlorophenyl) -phosphite, tris- (o-chlorophenyl) -phosphite, tris- (p-chlorophenyl) phosphite, tris- (p-tolyl) -phosphite, tris- (o-tolyl) -phosphite, tris- (m-bromophenyl) -phosphite, tris- (p-bromophenyl) ) phosphite, tris (p-iodophenyl) phosphite, tris (p-propylphenyl) phosphite, tris (p-tert-butylphenyl) phosphite, tris (m-tolyl) - phosphite, tris (p-isopropoxyphenyl) phosphite and the like. Triphenyl phosphite is preferably used, mainly because it is commercially available.

A large number and a wide variety of neutral organic solvents are available for the preparation of the kinetically controlled halogenating agents and the halogenation processes described herein. The term "inorganic organic solvent" means an organic solvent which, under the reaction conditions used in the preparation of said halogenating agents, does not react with the reactants or the products to the smallest extent. Because said halogenating agents react with proton-containing compounds, the reaction medium must not contain such compounds as water, alcohols, non-tertiary amines, mercaptans, organic acids, and other phthalate-containing compounds.

Preferably, an aprotic organic solvent is used which is substantially anhydrous and does not contain a proton. The term "substantially anhydrous" indicates that while it is generally advantageous to use an anhydrous organic solvent, the reaction is not interfered with by the presence of traces of water, which are often found in commercial solvents. Although these kinetic products react with the small amount of water present in the reaction mixture, the resulting loss can be easily compensated by adding additional reagent amounts. Preferably, the solvents are dried by conventional laboratory techniques to eliminate moisture in the reaction mixture.

Solvents for use in the present processes include aliphatic or aromatic hydrocarbons such as pentane, hexane, heptane, octane, cyclohexane, cyclopentane, benzene, toluene, ο-, m- or p-xylene, mesitylene and the like; ethereal solvents such as diethyl ether, ethyl butyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and the like; carboxylic acid esters such as ethyl acetate, methyl formate, methyl acetate, amyl acetate, n-butyl acetate, secondary butyl acetate, methyl propionate, retryl butyrate and the like; nitriles such as acetonitrile, propionitrile and the like; halogenated aliphatic or aromatic hydrocarbons such as chloroform, dichloromethane, carbon tetrachloride, 1,2-dichloroethane, 1,1,2-trichloroethane, 1,1-dibromo-2-chloroethane, 2- chloropropane, 1-chlorobutane, chlorobenzene, fluorobenzene, ο-, m- or p-chlorotoluene, ο-, m- or p-bromotoluene, dichlorobenzene and the like; and nitro compounds such as nitromethane, nitroethane, 1- or 2-nitropropane, nitrobenzene and the like.

The material quality of the neutral organic solvent used in the preparation of the triaryl phosphite-halogen complexes resulting from the kinetically controlled reaction and the reactions of the present invention is not critical, however, the particular solvent properties such as polarity, melting point and boiling point, and the ease with which the final product can be isolated.

Hydrocarbons, in particular aromatic hydrocarbons and halogenated hydrocarbons, are preferably used as solvents for the preparation of the products formed under kinetic control and for the processes of the present invention. More preferably halogenated hydrocarbons other than chloroform, and most preferably dichloromethane. 10

Leaving the halogenating agent formed in the reaction of a triaryl phosphite with a chlorine or bromine in an organic solvent under kinetic control will convert this kinetic product into the appropriate thermodynamically stable form described above and the rate of depends on triaryl phosphite, the halogen, the solvent and the temperature of the solution. Experimental data show that the presence of an acid of formula HX or excess triaryl phosphite accelerates the conversion of a kinetic product to a thermodynamically stable product.

Half life resulting from the reaction of triphenyl phosphite and conducted to chlorine in methylene chloride at room temperature under kinetic control of product 25 ^3l P / nuclear magnetic resonance spectroscopy according to the ⁽³¹ P-NMR) measurements approximately 8 hours. Under the same conditions, the kinetic complex of triphenyl phosphite and bromine has a half-life of about 39 hours. As mentioned above, the half-life (conversion rate) of any of the kinetic complexes mentioned herein is influenced by the presence of halohydrogen acid or excess triaryl phosphite, which may be present in the system. For example, if the solvent used to prepare the kinetic complex is not completely dried, a shorter half-life is measured; the reaction of the kinetic complex and the reaction of the hydrohalic acid with water in the solvent accelerates the conversion to a thermodynamically stable form.

Table I summarizes some of the properties of the product formed by the reaction of triphenylphosphite with the chloro kinetically controlled product 40 and the product formed with the same reaction under thermodynamic control.

Table I ⁴⁵

Kinetic product

1. ³¹ P-NMR (dichloromethane); —3.7 ppm *

2. Half-life: approx. 8 hours at room temperature in dichloromethane

3. IR (dichloromethane): 1120-1190 (no), 1070 (no), 1035 (e), 1010 (no), 990 640 (k), 625 (k), 580 (gy), 510 (e) ), 465 (gy) **

4. Hydrolysis leads to triphenylphosphate and hydrochloric acid.

Thermodynamically stable product

1. ^31- P-NMR (dichloromethane): + 22.7 ppm *

2. A compound stable at room temperature

3. IR (dichloromethane):

1130-1210 (no), 1065 (no), 1035 (e), 1010 (no),

980 (no), 625 (ngy), 590 (k), 505 (e), 460 (e) ** 60

4. Its hydrolysis yields, inter alia, hydrochloric acid, phenol and phosphorous acid diphenyl ester dichloride. 65

Continuation of Table I

Kinetic would do Thermodynamically stable product 5. Reaction with n-butanol produces hydrochloric acid, n-butyl chloride and triphenylphosphate. 5. Reaction with n-butanol to form hydrochloric acid, phenol, n-butyl chloride and (PhO) _a (BuO) _b POCl _c where Ph is phenyl, Bu is n-butyl, a, b and c is 0, 1, 2 or 3 with the proviso that a + b + c = 3.

* Compared to the ^3l P-NMR signal of phosphoric acid, the (+) signal indicates a shift towards a higher field strength and the (-) signal indicates a shift towards a lower field strength.

* * no: very strong; e: strong; k: medium; gy; weak; ngy: very weak.

The term "product under kinetic control" is a term used when two or more products are formed in a chemical reaction and the term is applied to a product which is formed faster and does not consider the thermodynamic stability of that product. If such a reaction is frozen long before the products reach a thermodynamic equilibrium, then the reaction is said to be kinetically controlled because more of the faster product is present in the system. In some cases, such as the reaction of triaryl phosphites with chlorine or bromine in neutral organic solvents, the rate of formation of kinetic products and rate of thermodynamic equilibrium are such that the product formed under kinetic control can be isolated and used before this product a significant amount would isomerize to a thermodynamically stable product.

In order to maximize the production and stability of the product under kinetic control, the reaction conditions are selected so that the products formed at the beginning of the reaction achieve as little thermodynamic equilibrium as possible. Simply put, kinetic control is best achieved when the reaction is carried out at a low temperature, if the kinetic product is kept at a low temperature, and if no time is allowed for thermodynamic equilibration to occur, for example by using the kinetic product immediately after preparation.

The reagents, i.e. triaryl phosphite and chlorine or bromine are generally mixed in a substantially anhydrous, inert organic solvent at a temperature below about 30 ° C. Although the products formed in the kinetically controlled reaction are formed at higher temperatures, rapid conversion to a thermodynamically stable form is favored at higher temperatures. Therefore, the halogenating agent is preferably prepared at a temperature of about 30 ° C or less. The lowest temperature applicable

-5186303

II is, of course, determined by the freezing point of the solvent to be used. Most preferably, the reaction is carried out at a temperature of about -70 ° C to about 0 ° C.

It has also been found that the triaryl phosphite itself reacts slightly with the chlorine or bromine-formed kinetic complex and accelerates the conversion of the complex to the corresponding thermodynamically stable product. Therefore, it is preferred, although not necessary, for the halogen present to be present in the reaction mixture during the preparation of the halogenating agents. In practice, this can be achieved by adding the triaryl phosphite to a solution of an equivalent amount of halogen, or by adding the halogen and the triaryl phosphite in parallel to the desired organic solvent at the desired temperature. Such parallel addition of reagents is performed with the halogen color predominating in the reaction mixture, with only the last drop of triaryl phosphite eliminating this color. Alternatively, excess halogen may be removed by known halogen scavengers such as acetylene derivatives or olefins such as alkenes, dienes, cycloalkenes or bicycloalkenes. Examples of such preferred halogen scavengers are alkenes containing from 2 to 6 carbon atoms, such as ethylene, propane, butene and pentene.

The solution of halogenating agents used in the processes of the present invention can be stabilized by adding to the solution from about 10 mol% to about 100 mol% of the halogenating agent, having a pK _b (dissociation constant) of about 6 to about 10. For example, if in addition to the triphenyl phosphite and chlorine kinetic dichloromethane as solvent control by reactions of the product were added to about 50 mole% of pyridine, then ^3I P NMR analysis of the thermodynamically stable products can be detected only in traces, even after prolonged storage at room temperature. The tertiary amine base may be added to a solution of the freshly prepared chlorinating agent or, if desired, added to a solution of the triaryl phosphite or halogen to give a stabilized solution of the halogenating agent used in the processes of the present invention.

The halogen scavenger

As the reduction reaction of the present invention proceeds, chlorine or bromine will be formed as a byproduct of the reaction (depending on the triarylphosphite-halogen complex used). A halogen scavenger is added to the reaction mixture to react with or deactivate the halogen as soon as the halogen is formed in the reaction mixture to avoid any undesirable side reaction between the halogen formed as a by-product and the cephalosporin derivative formed in the reaction. As used herein, the term "halogen scavenger" refers to organic compounds that readily react with chlorine or bromine but do not react with the triaryl phosphite halide complexes used as reducing agents in the processes of the present invention. The halogen scavengers used in the processes of the present invention include, for example, alkenes, cycloalkenes, bicycloalkenes, dienes, cyclodeenes, bicyclodeenes, alkines, or substituted aromatic hydrocarbons that are readily electrophilic in substitution reactions such as monovalent phenols and monovalent phenols. ethers and esters of polyhydric phenols. Examples of such halogen scavengers are alkenes having from 2 to 10 carbon atoms, such as acetylene, propene, 1-butene, 2-butene, isobutene, 1-pentene, 2-pentene, 2-methyl-1-butene, 3-methyl-1 butene, 1-hexene, 1-heptene, 1-octene, the isomer would grow and the like; 5-8 membered cyclic alkenes (cycloalkenes) such as cyclopentene, cyclohexene, cycloheptene, cyclooctene; dienes having 4 to 8 carbon atoms and cyclic dienes having 5 to 8 members (cyclodeenes) such as pentadiene, hexadiene, heptadiene, cyclopentadiene, cyclohexadiene, cyclooctadiene, 2,3-dimethylbutadiene, 1,3-isoprene and the like ; alkenes containing from 2 to 6 carbon atoms, such as acetylene, methylacetylene, ethylacetylene, dimethylacetylene, 1-pentine, 2-pentine, isomeric hexins, 3-methyl-1-butine, 3,3-dimethyl -1-Butine and the like, acetylene derivatives whose acetylene bond is fast to add chlorine or bromine (phenylacetylene is not a suitable halogen binder); bicyclic (bicyclic) unsaturated hydrocarbons such as camphene and pinene; and in the general formula XIV, wherein

R ₄ is alkyl of up to 4 carbon atoms or alkanoyl of 2 to 5 carbon atoms, and

R 1 and R 8 are independently selected from hydrogen, alkoxy of up to 4 carbon atoms, alkanoyl of 2 to 5 carbon atoms, or alkyl of up to 4 carbon atoms, characterized phenol ethers, substituted phenol ethers and lower alkanoyl phenol esters. Examples of compounds of formula XIV are hydroquinone monomethyl ether, hydroquinone dimethyl ether, anisole, phenethol, m-dimethoxybenzene, veratrol, phenylpropionic acid, phenylacetic acid, 0.0-diacetyl resorcinol. and other phenolic esters and phenol ethers which readily react with bromine or chlorine.

Preferred halogen scavengers are alkenes containing from 2 to 6 carbon atoms, such as ethylene, propene, butene, peitene, cyclopentene and cyclohexene.

Since the reduction of each equivalent amount of sulfoxide according to the present invention theoretically yields at least one equivalent amount of halogen, at least one equivalent amount of halogen scavenger based on the starting cephalosporin sulfoxide is used to reduce the cephalosporin sulfoxide. Generally, the starting material is ca. 1 equivalent and approx. 3 equivalents of a halogen scavenger; however, more halogen scavengers can be used without altering the result of the reduction.

the starting 7-acylaminocephalosporin and 6-acylaminopenicillin derivatives used in the halogenation process of the present invention are all known compounds or can be prepared from known such derivatives by methods known per se. Both patents and publications provide many guidelines on how to prepare the starting penicillin and cephalosporin derivatives used in the present process. For example, U.S. Patent Nos. 3,932,393, 4,060,688 and 4,052,387 disclose 3-exomethylene cepham derivatives. 2-Methyl-3-cephem7 is also known

-6186303 derivatives [J. Chem. Soc., 97, 5020 (1975) and 98, 2342 (1976)]. ₅₎ Penicillins and Cephalosporins (Penicillin and Cephalosporin Derivatives) (Ed. H. Flynn, Academic Press, New York, 1972) also describes various penicillin and cephalosporin derivatives and describes their preparation.

The starting materials of the process of the present invention can be characterized by the general formula I wherein R, R ¹ , R ⁷ and Y are as defined above. When the substituents of these starting compounds do not contain free amino-hydroxyl or carboxyl groups or other proton-containing groups, the nature of R, R ¹ , Y and R ^{7 is} not critical to the methods of the present invention. In the processes of the present invention, the 6- and 7-acylamido groups are converted, the -CONH group to XC = N, where X is chlorine or bromine, while R, R _p R ₇ and Y are generally unchanged . However, as with other chemical transformations, the production of imino halide-like products or esters derived therefrom will vary depending on the meaning of each substituent.

In a preferred embodiment of the process of the present invention, one of the compounds of formula II wherein R, R ¹ and R ⁷ are as defined above, and M is as defined above, is derived from a 1-oxadetacephem derivative as 7-acylamino-. cephalosporin. They are also known compounds or can be prepared from known compounds by methods known per se. Such compounds, as well as the corresponding 1-carbadiazepephem derivatives and 1-azadiazepephem derivatives, which may also be used as starting materials for the process of the present invention, are described in U.S. Patent 4,123,528.

All of the above-described embodiments of the present invention are carried out in the presence of a tertiary amine base. Generally, about 1.0 equivalent to about 1.2 equivalent, and preferably about 1.0 equivalent, of tertiary amine base is used per halogenating agent employed. Preferred tertiary amine bases having a pK _b value of from about 1 to about 10 are preferably used in the halogenation process and enol halogenation concurrently with imine halogenation as described herein. More preferably, tertiary amine bases having a pK _b of from about 6 to about 10 are used. Suitable tertiary amine bases for use in the methods of the invention include trialkylamines such as irimethylamine, triethylamine, tri-n-propylamine, ethyldimethylamine, benzyldimethylamine and the like; dialkyl arylamines such as Ν, Ν-dimethylaniline, N, N-diethylaniline, N, N-diethyl-4-methylaniline, N-methyl-N-ethylaniline, Ν, Α-dimethyl toluidine and the like; mono- and bicyclic tertiary amines such as pyridine, collidine, quinoline, isoquinoline, 2,6-lutidine, 2,4-lutidine, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1 , 5-diazabicyclo [5.4.0] undec-5-ene (DBU), triethylene diamine and the like; and polymeric tertiary amine bases such as those derived from divinylbenzene and vinylpyridine, described by Hallensleben and Wurm, Angew. Chem. Inti. Ed. Engl., 75, 163 (1976)]. Preferably, the tertiary amine base is pyridine.

Cephalosporin sulfoxide

The process of the present invention can generally be used to reduce any of a variety of cephalosporin sulfoxides. Representative cephalosporin sulfoxides that can be reduced to the corresponding cephalosporin derivatives include, for example, the cephalosporin sulfoxides of formula VII wherein R *, R ² , R ³ , R 'and Y are as defined above. If the substituents of these starting materials do not contain a free amino or non-enolic hydroxyl group, the nature of R ¹ , R ² , R ³ and Y is not critical. In carrying out the process of the present invention, the groups R ¹ , R ² , R ³ and Y generally remain unchanged. However, as with other chemical transformations, the production of the cephalosporin derivatives obtained by the process of the present invention will vary with each substituent.

The preparation of sulfoxides as starting materials for the process of the present invention is well known in the patent literature. For example, the preparation of compounds of formula VII wherein A is (C4-alkyl) carbonyl or (C2-C6) halogenated alkoxy) carbonyl is described in Spry, U.S. Patent 3,953,436. 3-Hydroxy-3-cephem sulfoxides are described in Chauvette, U.S. Patent No. 3,917,587, and Kukolja in U.S. Patent 4,052,387. Sulfoxides wherein A is an alkanesulfonyloxy group having up to 4 carbon atoms, a phenyl group or a substituted benzenesulfonyloxy group can be prepared according to the method of U.S. Patent 3,985,737. 2-Methyl-3-cephem derivatives are described in J. Am. Chem. Soc., 97, 5020 (1975) and 98, 2342 (1976). In addition, Cooper discloses a generally applicable method for preparing cephalosporin sulfoxides in U.S. Patent 3,647,786.

Starting from the free carboxylic acid form of the cephalosporin derivatives in the process of the present invention generally results in a lower yield because the kinetic complex reacts not only with the sulfoxide group but also with the carboxyl group and converts the latter to the corresponding acid halide. The latter is re-hydrolyzed to the free acid under standard conditions for product isolation. The 4-position carboxyl group of the starting cephalosporin sulfoxide is preferably protected before reduction. If the starting cephalosporin sulfoxide is to be used as the free carboxylic acid, an additional equivalent amount of kinetic complex is used to increase the yield of the reduction. Aqueous work-up of the reaction mixture allows the isolation of the appropriate carboxylic acid cephalosporin derivative.

In the above definitions, it is not fully specified which groups may be used to protect the amino, hydroxy and carboxyl groups. The role of such protecting groups is to protect the reactive groups during the process of the present invention, and after the reaction, these groups are cleaved so that the rest of the molecule is not damaged. Many protecting groups are known in the literature, and protecting groups not specifically mentioned above can also be used in the process of the invention.

The halogenating agent 7186303 for the halogenation of the present invention is preferably triphenylphosphite-halogen complexes of the formula XIII wherein Z is hydrogen, and most preferably the triphenylphosphite-chlorine kinetic complex. The best results of the enol halogenation process are achieved when about 1.1 equivalents to about 1.2 equivalents of halogenating agent are used, based on the enol to be converted. For the enol halogenation concurrently with the imine halogenation, preferably about 2.2 equivalents to about 2.4 equivalents relative to the starting enol, and most preferably about 2.3 equivalents are used.

Reaction conditions

The halogenation process of the present invention is preferably carried out at a temperature of about 0 ° C or lower. Preferably, temperatures of about -10 ° C or lower are employed. The process of the invention is generally not carried out at temperatures below -70 ° C. It will be appreciated that, although not advantageously, the chlorination of the present invention may be carried out at temperatures below -70 ° C or above 30 ° C. The reduction of the reaction temperature is limited by the freezing point of the reaction mixture and the solubility of the substance to be converted, while it must be taken into account that too high a temperature can be converted to a thermodynamically unstable halogenating agent. Of course, if the halogenating agent solution is stabilized as described above by the addition of a tertiary amine base, it is possible to carry out the conversion at a higher temperature without converting a significant amount of the halogenating agent into its undesired thermodynamically stable form without suffering any harm to the halogenation process. .

The imine halogenation of the invention is generally carried out at a temperature of about 30 ° C or lower. Preferably, the reaction is carried out at a temperature of about 0 ° C or lower, and more preferably at a temperature of about -10 ° C or lower. We usually do not work at temperatures below -70 ° C. Most preferably, the reaction is carried out at a temperature of about -10 ° C to about -70 ° C.

It will be appreciated that the imine halogenation of the present invention may be carried out at temperatures below -70 ° C or above 30 ° C. The reduction of the reaction temperature is limited by the freezing point of the reaction mixture and the solubility of the compound to be converted, whereas a higher reaction temperature is not chosen because the halogenating agent is not thermodynamically stable at higher temperatures. Of course, if the halogenating agent solution is stabilized as described above by addition of a tertiary amine base, it is possible to carry out the conversion at a higher temperature without converting a significant amount of halogenating agent into the undesired, thermodynamically stable form and without damaging the halogen itself. .

The reduction process of the present invention is carried out in a substantially anhydrous, inert organic solvent. Such solvents are exemplified by the above description of the triaryl phosphite-halogen complexes. Preferred solvents for the process of the present invention are hydrocarbons, in particular aromatic hydrocarbons and halogenated hydrocarbons. Halogenated hydrocarbons other than chloroform are preferably used. The most preferred solvent for carrying out the process of the invention is dichloromethane.

The reduction of the present invention is generally carried out at a temperature of about 30 ° C or lower. Preferably, temperatures of about 10 ° C or lower are employed. The reduction is generally not carried out at temperatures below -50 ° C. Most preferably, the reaction is carried out at a temperature of about 0 ° C to about -30 ° C.

It is noted that the reduction according to the invention can also be carried out at temperatures above 30 ° C or below -50 ° C. The reduction of the reaction temperature is limited by the freezing point of the reaction mixture, the solubility of the compound to be converted and the reaction rate, while too high a reaction temperature is not chosen because the thermodynamically unstable triaryl phosphite halide complex and the resulting cephalosporin derivative . Of course, if the solution of the triaryl phosphite-halide complex is stabilized as described above by the addition of a tertiary amine base, the reaction can be carried out at elevated temperatures without losing a significant amount of reducing agent and without reducing the reduction itself.

In a preferred embodiment of the reduction process of the invention, the reaction is carried out by simply adding cephalosporin sulfoxide in solid form or as a solution in an amount of from about 1 equivalent to about 1.3 equivalents of the triaryl phosphite halide complex and from about 1 equivalent to about 3 equivalents of sulfoxide in an inert organic solvent at the desired temperature. The progress of the reaction can be monitored, for example, by comparative thin-layer chromatography. Under preferred reaction conditions, the reaction generally takes from about half an hour to about 2 hours. The resulting cephalosporin derivatives can be isolated by conventional laboratory techniques such as extraction, crystallization and recrystallization, filtration, or trituration with a solvent. The resulting cephalosporin compounds are known compounds that can be used (after deprotection) as antibiotics or used to prepare other cephalosporin derivatives.

The triaryl phosphite halide complexes used as reducing agents in the process of the invention are also active halogenating agents. They can be used to convert enolic hydroxyl groups to the corresponding vinyl chlorides and the amide groups to the corresponding imino halides in the presence of a base. The multidirectional reactivity of the triaryl phosphate halide kinetic complexes is exploited in some of the methods of the present invention. Thus, halogenated reduction of cephalosporin sulfoxides is also within the scope of the invention. According to the invention, this process is illustrated by the reaction equations Α, B and C. In the formulas ΠΙ, V, VIII, IX, X and XI, R is a carboxyl protecting group, and R 1, R ₂ , R ₃ , R ₇ , X and Y are as defined above.

-8186303 with the proviso that when Y is a group of formula b, then A is not a hydroxy group. The imino halides obtained according to reaction equations B and C can be isolated and converted into the corresponding esters of general formula XV and XVI via the known imino ether by alcoholysis.

In a preferred embodiment of the process of the present invention illustrated by the reaction equation A, enol halogenation-reduced reduction, a 3-halogenated cephalosporin derivative is prepared by reacting a 3-hydroxy cephalosporin sulfoxide in a substantially anhydrous, inert organic at a temperature of about 30 ° C or less in the presence of at least one equivalent of a halogen scavenger with about 2 to about 3 equivalents of a triaryl phosphite halogen kinetic complex.

In a preferred embodiment of another embodiment of the process of the invention illustrated by Reaction B, cephalosporinimino halides are prepared by reacting a 7-acylamino-cephylcosporin sulfoxide in a substantially anhydrous, inert organic solvent at or about 30 ° C. at a lower temperature, in the presence of at least one equivalent of a halogen scavenger and from about 1.0 to about 2.0 equivalents of a tertiary amine base, reacting with about 2 equivalents to about 3 equivalents of a triaryl phosphite halogen kinetic complex,

In a preferred embodiment of the third embodiment of the process of the invention illustrated by the C-reaction equation, the 3-halo-cephalosporinimino halide is prepared by reacting a 7-acylamino-3-hydroxy-cephalosporin sulfoxide with a substantially anhydrous, inorganic organic in a solvent at a temperature of about 30 ° C or less, with about 3 equivalents to about 5 equivalents of triaryl phosphite-halogen complex in the presence of at least 1 equivalent of a halogen scavenger and about 2 equivalents to about 5 equivalents of a tertiary amine base. In the variant illustrated by Reaction C, the best results are obtained when the reaction is carried out in methylene chloride as a solvent in the presence of about 3.8 equivalents of pyridine to about 7 equivalents of the starting 7-acylamino-3-hydroxycephalosporin sulfoxide. amount of triphenylphosphite-chlorine complex.

The various chemical transformations of the present invention illustrated by the Α, B and C reaction equations in a further preferred embodiment of the process of the invention are carried out under substantially the same conditions as the triaryl phosphite halide of cephalosporin sulfoxides. complex reduction as described above. All the reaction parameters of the multidirectional conversion illustrated by the reaction equations Α, B and C are the same as those described for the basic process of the present invention, except that the structural properties of the particular starting cephalosporin sulfoxide can result. In each of the process variants, the B and C reaction equations are carried out in the presence of a tertiary amine base, and the molar ratios of starting materials, auxiliaries, and reagents are typically different in each embodiment. However, apart from the latter differences, each variant may be carried out in the same temperature range, in the same solvent, with the same triaryl phosphite-balogen complex, in the presence of the same halogen scavenger.

The cephalosporin derivatives obtained by the process of the present invention can be isolated by conventional laboratory techniques such as shaking, crystallization and recrystallization, or by trituration with a solvent.

Because imino halide-type products are sensitive to acid-catalyzed hydrolysis and alcoholysis, and generally to nucleophilic attacks, care should be taken in isolating such products to avoid exposing the product to conditions under which the imino-halides undergo this type of conversion. . For example, under neutral conditions, which may be provided with a non-nucleophilic acid acceptor such as propylene oxide, the imino halides may be washed with water and brine and the solvent removed under reduced pressure to give the product in substantially pure form.

Since the imino halides obtained in the above manner can be used primarily as intermediates of the corresponding 7-aminocephalosporin derivatives, the imino halides of the present invention produced by the halogenation reduction reaction are preferably without isolation with up to 15 carbon atoms. or more preferably, by reacting with an excess of a beta-disubstituted primary aliphatic alcohol, a 1,2- or 1,3-diol, to give the corresponding amino esters,

An improved method for the alcoholysis of cephemimino halides via imino ether intermediates using beta disubstituted aliphatic alcohols, 1,2- or 1,3-diols, is described in U.S. Patent No. 3,845,043.

For the conversion of the imino halides to the imino ether and subsequent alcoholysis, it is preferable to use a beta-disubstituted primary aliphatic alcohol having from 4 to 12 carbon atoms and an aliphatic having from 3 to 15 carbon atoms.

1.3-diol or an aliphatic 1,2-diol containing from 2 to 12 carbon atoms is used.

Beta-substituted primary aliphatic alcohols for use in the process of the present invention are compounds of formula XVII wherein both R _x and R _y are alkyl and the beta disubstituted primary aliphatic alcohol has from 4 to 12 carbon atoms or R _x and R _y together represent , together with the carbon atom to which they are attached, is a cyclic alkyl group having from 5 to 8 carbon atoms. Examples of such alcohols are isobutanol, 2-methylbutanol, 2-ethylbutanol, 2-ethylhexanol, hydroxymethylcyclopentane, hydroxymethylcyclohexane, 2-n-butyloctanol, 2-n-propyl hexanol and the like.

Suitable 1,2- and 2-hydroxyethylpyrrolidone for the process of the invention

1.3-diols are compounds of Formulas XVIII and XIX wherein R _c and R _d are hydrogen or alkyl and 1,2-diols of Formula XVIII contain 2 to 12 carbon atoms and R _w and R _z are hydrogen, methyl or ethyl, or a hydrocarbon group such that 1,3-9186303 of formula XIX

nuts contain from 3 to 15 carbon atoms. This is typical

Examples of 1,2-diols are 1,2-propylene glycol, 2,3-butanediol,

1,2-butanediol, 3,4-pentanediol and 3,4-hexanediol. Typical such 1,3-diolocaz 1,3-propanediol, 1,3-butanediol, 1,3-pentanediol, 2,2-dimethyl-1,3-propanediol, 2,2-diethyl -1,3-propanediol, 2,4-pentanediol and 2,2-diphenyl-1,3-propanediol. Most preferably for the cleavage of the imino halide products of the present invention, the alcohol or the nuts are preferably isobutanol, 1,2-propanediol or

1,3-propanediol is used.

An excess of alcohol is used to cleave the imino halide product of the present invention. The amount of excess alcohol or nuts is not critical. It is sufficient to use the 1,2- or

Use 2-3 times the excess of 1,3-diols. When a beta-disubstituted primary aliphatic alcohol is used, a 3- to 6-fold excess is generally preferred. Naturally, more alcohol or nuts can be consumed without affecting the course of the reaction. Often a 10 to 15-fold excess of the preferred alcohol or nuts is used. Generally, 3 to 15 times the excess of alcohol or nuts is used. When aliphatic alcohols other than those mentioned above are preferably used for the cleavage of the iminohalide-type products of the present invention, an excess of about 10 to 100 times the excess is generally used.

The halogenation reaction mixture containing the iminohalide obtained by the process of the present invention is usually simply added to the alcohol or nuts.

Alcoholization of the imino halide (via imino ether formation) is an acid-catalyzed process. The reaction mixture itself is usually sufficiently acidic, and thus alcoholysis is carried out without the addition of a separate acid to add alcohol or nuts. However, in order to increase the rate of alcoholysis and thus the rate of formation of the desired ester, the reaction mixture is preferably acidified, for example with hydrochloric acid, after the addition of alcohol or nuts. This can simply be accomplished by briefly introducing hydrogen chloride gas into the reaction mixture. However, other acids, such as organic or inorganic acids, may be used. Generally, at least one equivalent of hydrochloric acid is added to the reaction mixture to facilitate the formation of the desired ester.

The product esters are often isolated from the reaction mixture by simple filtration in the form of their crystalline hydrochloric acid salts. The non-crystalline esters obtained by the process of the invention are isolated from the reaction mixture by conventional laboratory methods. Alternatively, the esters obtained may be further reacted (acylated) in solution without isolation. Acylation of the esters in a manner known per se yields 7-acylaminocephalosporin esters, the ester group of which can be hydrolyzed to give known antibiotic compounds, or further chemical conversion of the hydrolyzed products.

The reduction of enol and imine halogenation, illustrated by the C reaction equation described above, which is carried out with a triaryl phosphite-chlorine complex followed by subsequent alcoholysis of the iminochloride thus obtained is in fact an improved method of 3-chloro-3-cephem. For the preparation of 4-carboxylic acid esters from the corresponding 7-acylamino-3-hydroxy-3-cephem-4-carboxylic acid ester sulfoxides. In the methods prior to the present invention, these three types of conversion were either carried out in three separate operations (reduction, chlorination, and side chain cleavage), or in two steps, either by reduction and chlorination in one operation (see U.S. Patent No. 3,115,643). followed by cleavage of the oxy chain as a separate operation, or by first reducing the sulfoxide group followed by chlorination and side-chain cleavage in one operation (see, for example, U.S. Patent 4,044,002). According to the present disclosure, the reduction, chlorination and cleavage can be carried out in one operation in the same reaction vessel, with excellent production without isolation of the individual intermediates.

The 3-halo-cephem-4-carboxylic acid esters are known compounds. They can be acylated by methods known per se and then hydrolyzed by their ester groups to yield known antibiotic compounds.

Such ester-type intermediates are of particular interest in the preparation of 7- (D-2'-phenyl-2'-amino) -acetamido-3-chloro-3-cephem-4-carboxylic acid, a relatively new and clinically relevant antibiotic. point of view.

According to a preferred embodiment of the process of the invention, 7-amino-3-chloro-3-cephem-4-carboxylic acid ester hydrochloride of general formula XX is prepared by:

a) 7-Acylamino-3-hydroxy-3-cephem-4-carboxylic acid ester sulfoxide in a substantially anhydrous, inert organic solvent at a temperature of about -10 ° C to about -30 ° C, about 3.5 equivalents and about 4.0 equivalents of pyridine and from about 1 equivalent to about 3 equivalents of alkene containing from 2 to 6 carbon atoms, the equivalent amount of triphenylphosphite and chlorine in a substantially anhydrous, inert organic solvent under kinetic control. Reacting with about 4.0 equivalents to about 5.0 equivalents of the product;

b) after the formation of 3-chloro-3-cephemimino chloride is complete, isobutanol, 1,3-propanediol or 1,2-propanediol is added in an amount of about 3 equivalents to about 15 equivalents; then

c) acidifying the reaction mixture with hydrochloric acid.

Dichloromethane is most preferably used as the neutral organic solvent.

Preferably, starting materials are 3-hydroxy-3-cephem sulfoxides which have a carboxamido group at the 7-position of the penicillin and cephalosporin derivatives. Particularly preferred are the 3-hydroxy-3-cephem sulfoxides wherein the 7-position is an acylamino group of the formula R 0 - (Q) _m -CO, Q ₂ -CO-NH-, wherein

R ³ is 2-thienyl, phenyl or substituted phenyl, Q is oxygen, m is 1 or 0, and Q ₁ and Q ₂ are hydrogen; even more preferred, especially for economic and not necessarily reactive reasons, such compounds having the 7-position of the phenylacetamido, phenoxyacetamido and 2-thienylacetamido groups.

-10186303

Furthermore, in another preferred embodiment of the process according to the invention, the p-nitrobenzyl ester group is preferably used to protect the carboxyl group because the hydrochloride of the resulting p-nitrobenzyl ester is crystalline and thus obtains the desired ester easily and in a very pure state. .

The invention is further illustrated by the following non-limiting examples.

In the examples, nuclear magnetic resonance spectroscopy measurements are referred to as NMR. NMR measurements were performed on a Varian Associates Τ-60 spectrometer using tetramethylsilane as the internal standard. Chemical shift values are reported on the-scale in ppm and coupling constants (J) in Hz (cycles per second).

Example 1

7- (1'-Chloro-2'-phenylethylidene) imino-3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester was charged with chlorine gas at -15 ° C in dichloromethane. and at the same time drip it

3.2 ml (12.3 mmol) of triphenylphosphite. The chlorine and triphenylphosphite are added at a rate such that the pale yellow color of the chlorine is continuously detectable in the mixture during the parallel addition. Immediately before the end of the triphenylphosphite addition, the chlorine gas supply is stopped and the triphenylphosphite addition is continued until the color of the chlorine disappears. Additional chlorine and triphenylphosphite are then added so that the last drop of the latter eliminates the color of the chlorine.

To a solution of the triphenylphosphite chlorine complex thus prepared at -15 ° C is added 4.68 g (10 mmol) of 7-phenylacetamido-3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl). ), and a solution of pyridine (1.01 mL, 12.5 mmol) in dichloromethane (4.01 mL) was added dropwise over 12 min. The mixture was stirred for an additional quarter hour at -10 to -15 ° C and then propylene oxide (2.1 ml) was added. The cooling bath was then removed and the mixture heated to 0 ° C for an additional quarter hour. The mixture was washed with water (25 ml), dried over calcium chloride dihydrate and the solvent was distilled off under reduced pressure. The residue was triturated with diethyl ether (25 mL) containing 6 drops of propylene oxide, filtered, washed with diethyl ether and dried under reduced pressure. This gave 4.58 g (94.2%) of the title compound as snow-white crystals, mp 132-133 ° C.

Nuclear Magnetic Resonance Spectrum (deuterochloroform, pentadeuteropyridine) = 2.18 (s, 3H), 3.37 ABq, 5.5 (d, 1H, J = 5 Hz), 7.3 (s, 5H , ArH) and 7.4-8.4 (m, 4H, ArH).

Analysis calculated for C ₂₃ H ₂₀ N ₃ O ₅ SCl: C, 56.35; H, 4.15; N, 8.65; S, 6.60; Cl, 7.30 Found: C, 56.60; H, 4.25; N, 8.83; S, 6.49. Cl, 7.07.

Example 2

6- (1 'Chloro-2'-phenylethylidene) iminopenicillanic acid (2', 2 ', 2'-trichloroethyl) ester

In a similar manner to Example 1, a solution of about 12.3 mmol of triphenylphosphite-chlorine complex in 45 mL of dichloromethane was added and 4.66 g (10 mmol) of 6-phenylacetamido was added at -30 ° C. (2 ', 2', 2'-trichloroethyl) -penicillanic acid and washed with dichloromethane (5 ml). A solution of pyridine (1.01 mL, 12.5 mmol) in dichloromethane (4 mL) was added dropwise over 20 minutes and stirred at -20 to -30 ° C for an additional quarter hour. Propylene oxide (2.1 ml) was then added to decompose any chlorinating agent and hydrochloric acid present in the reaction mixture, and the mixture was allowed to warm to about 0 ° C over a quarter hour. The mixture was washed with ice water (25 ml) and dried over calcium chloride dihydrate. The solvent was distilled off under reduced pressure, and to the residue (11 g), 1 ml of diethyl ether was added, and the product crystallized. To the crystallized product is added 25 ml of diethyl ether containing 4 drops of propylene oxide, the suspension is stirred for 5 minutes at room temperature, and the white crystalline product is filtered off, washed with diethyl ether and dried under reduced pressure at room temperature. 2.52 g of the title compound are obtained, m.p. 84-85.5 ° C. The filtrate was distilled off under reduced pressure and to a slurry (12 g) of the residue was added 10 ml of diethyl ether and 10 ml of hexane. An additional 1.06 g of the title compound is obtained. Total yield: 74%.

Nuclear Magnetic Resonance Spectrum (carbon tetrachloride) = 1.56 (s, 3H), 1.68 (s, 3H), 3.96 (s, 2H), 4.57 (s, 1H), 4.8 ( s, 2H), 5.3 (d, 1H, J = 4Hz), 3.93 (d, 1H, J = 4Hz), and 7.3 (s, 5H).

Analysis calculated for C ₁₈ H ₁₈ N ₂ O ₃ SCl ₄ : C, 44.65; H, 3.75; N, 5.78; S, 6.62; Cl, 29.29. Found: C, 44.76; H, 3.84; N, 5.90; S, 6.71; Cl, 29.06.

Example 3

7- (l-Chloro-2'-phenoxy- ethylidene) imino-3-chloro-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester

A solution of about 12.3 mmol of triphenylphosphite chlorine complex in 45 mL of dichloromethane was prepared as described in Example 1, followed by the addition of 5.04 g (10 mmol) of 7-phenoxyacetamido at -15 ° C. The 3-chloro-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester was washed with dichloromethane (5 mL). Immediately thereafter, a solution of 1.01 ml (12.5 mmol) of pyridine in 4 ml of dichloromethane was added dropwise over a quarter hour, and the mixture was stirred for an additional quarter hour at -10 to -15 ° C. Then, propylene oxide (2.1 mL) was added, the cooling bath was removed and the mixture was allowed to warm to about 0 ° C over about a quarter hour. The mixture was washed with ice water (25 ml), dried over calcium chloride dihydrate and the solvent was distilled off under reduced pressure. Addition of diethyl ether (50 ml) to the resulting syrup did not crystallize. Diethyl ether was poured from the syrup and the residual solvent was removed under reduced pressure. 11 g of a thick oil are obtained, which is washed three times with 25 ml of diethyl ether and 25 ml of hexane, and the residue is triturated with 25 ml of diethyl ether. The crystallized product is filtered off,

-11186303, washed with diethyl ether and dried under reduced pressure at room temperature. This gave 3.58 g (68.6%) of the title compound as slightly colored crystals, m.p. 94-97 ° C.

Nuclear Magnetic Resonance Spectrum (deuterochloroform, pentadeuteropyridine): 3.56 (ABq, 2H, J = 18Hz), 4.8 (s, 2H), 5.13 (d, 1H, J = 5Hz). , 5.3 (s, 2H), 5.53 (broad d, 1H, J = 5Hz), and 6.8-8.3 (m, 9H),

Analysis calculated for C ₂₂ H ₁₇ N ₃ O ₆ SCl ₂ : C, 50.59; H, 3.28; N, 8.04; S, 6.14; Cl, 13.57. Found: C, 50.32; H, 3.36; N, 8.20; S, 5.92; Cl, 13.57.

Example 4

6- (1'-Chloro-2'-phenoxyethylidene) iminopenicillanic acid (p-nitrobenzyl) ester

A solution of 9.71 g (20 mmol) of 6-phenoxyacetamido-penicillanic acid (p-nitrobenzyl) ester in 75 ml of dichloromethane is dried over calcium chloride dihydrate for about a quarter hour, and the desiccant is filtered off and the solution is filtered. concentrated to about 40 ml.

In the same manner as in Example 1, a solution of about 24.3 mmol of triphenylphosphite-chlorine complex in about 50 ml of dichloromethane was prepared at -15 to -20 ° C, cooled to -40 ° C, and a solution of penicillanic acid ester prepared as above. During the addition, the temperature of the mixture rises to about -22 ° C. A solution of pyridine (2.02 ml, 25 mmol) in dichloromethane (8 ml) was added dropwise over a quarter hour at -20 to -30 ° C, and the mixture was stirred for about a quarter hour and then added.

4.2 ml (60 millimoles) of propylene oxide. The mixture was then allowed to warm to 0 ° C over about a quarter hour, washed quickly with 50 mL of ice water, and dried over calcium chloride dihydrate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure to a total weight of about 27 g. Diethyl ether (50 mL) was added and the solvent was distilled off under reduced pressure. Then, 20 ml of carbon tetrachloride are added to the residual oil and the solvent is distilled off under reduced pressure. NMR analysis of this crude product showed the title compound to be contaminated with triphenyl phosphate.

Nuclear Magnetic Resonance Spectrum (deuterochloroform) = 1.33 (s, 3H), 1.46 (s, 3H), 4.46 (s, 1H), 4.8 (s, 2H), 5.2 ( s, 2H), 5.3 (d, 1H, J = 4Hz), 5.57 (d, 1H, J = 4Hz), and 6.7-8.3 (m, 9H).

Example 5

7- (1'-Chloro-2'-phenoxyethylidene) imino-3-acetoxy-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester in ml of dichloromethane cooled to -10 ° C chlorine gas was added, and 3.16 ml (12 millimole) triphenylphosphite was added dropwise at such a rate that the yellow color of the excess chlorine predominated throughout the addition, and that yellow color was removed by the last drop of phosphite. To the resulting solution was added 5.28 g (10 mmol) of 7-phenoxyacetamido-3-acetoxy-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester and washed with dichloromethane (ml). A solution of 1.01 ml (12.5 mmol) of pyridine in 5 ml of dichloromethane is added dropwise at -10 ° C and the mixture is stirred at this temperature for a quarter hour.

Propylene oxide (2.1 ml, 30 mmol) was added, the mixture was stirred at 0 ° C for 10 min, then washed with ice water (50 ml) and dried over calcium chloride dihydrate. The solvent was distilled off under reduced pressure and the residual oil could not be crystallized. Traces of solvents were also removed from the product under reduced pressure, carbon tetrachloride (25 ml) was added and the solvent was distilled off under reduced pressure. This crude product was identified by NMR to be the title compound.

Nuclear Magnetic Resonance Spectrum (deuterochlorochloroform): 2.06 (s, 3H), 3.41 (ABq, 2H, J = 18Hz), 4.83 (s, 2H), 5.05 (d, 1H, J = 5Hz), 5.28 (s, 2H-, 5.56), (broad d, 1H, J = 5Hz), and 6.8-8.3 (m, ArH).

Example 6

7- [1'-Chloro-2 '- (2-thienyl) ethylidene] imino-3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester

Following the procedure described in Example 1, a solution of about 12 millimoles of triphenylphosphite-chlorine complex in 45 ml of dichloromethane was prepared and 4.74 g (10 millimoles) of 7- (2'-thienyl) were added at -10 ° C. Acetamido-3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester and washed with dichloromethane (5 mL). After 5 minutes, a solution of 1.01 ml (12.5 mmol) of pyridine in 5 ml of dichloromethane is added dropwise over 20-30 minutes. The reaction mixture was stirred at -10 ° C for about half an hour, then allowed to warm to room temperature and stirred for about 2 hours. Propylene oxide (2.1 mL, 30 mmol) was added, the mixture was washed with ice water (50 mL), dried over calcium chloride dihydrate (10 mL), and evaporated under reduced pressure. Addition of a 1: 1 mixture of dichloromethane and diethyl ether to the residual oil crystallizes. The product was filtered off to give 2.02 g (41.3%) of the title compound, mp 129-132 ° C. Concentration of the filtrate afforded an additional 1.95 g (39.6%) of the title compound, overall yield 80.9%.

Nuclear Magnetic Resonance Spectrum (deuterochloroform) = 2.16 (s, 3H), 3.33 (ABq, 2H, J = 18Hz), 4.16 (s, 2H), 5.03 (d, 1H, J = 4Hz), 5.33 (s, 2H), 5.5 (broad d, 1H, J = 4Hz), and 6.8-8.4 (m, ArH).

Analysis calculated for C ₂₁ H ₈ N ₃ O ₅ S ₂ Cl: C, 51.27; H, 3.69; N, 8.54; S, 13.03. Found: C, 51.30; H, 3.72; N, 8.31; S, 12.91.

Example 7

7- (a-chlorobenzylidene) imino-3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester

Following the procedure described in Example 1, a triphenylphosphite / hour complex was prepared in 45 mL of dichloromethane, 3.16.

Starting from -12186303 ml (12 mmol) of triphenylphosphite, 4.14 g (10 mmol) of 7-benzamido-3-methyl-3-cephem-4-carboxylic acid (p-nitro) are added at -10 ° C. benzyl) ester and 1.01 mL (12.5 mmol) of pyridine. Removing the cooling bath immediately raises the temperature to 0 ° C. After stirring for about 3 minutes, the iminochloride begins to crystallize. After stirring for 1 hour at room temperature, the precipitate was filtered off, washed with diethyl ether and dried. 2.28 g (48.3%) of the title compound are obtained, m.p. 175 ° C.

The filtrate was diluted with dichloromethane, washed with dilute hydrochloric acid and then brine, dried over calcium chloride dihydrate, and the solvent was distilled off under reduced pressure. The residue was triturated with diethyl ether, and a new generation of the title compound crystallized out, which was filtered off, washed with diethyl ether and dried. Weight: 1.72 g (36.4%), total yield: 84.7%.

Nuclear Magnetic Resonance Spectrum (deuterochloroform) = 2.20 (s, 3H), 3.43 (ABq, 2H, J = 18Hz), 5.15 (d, 1H, J = 5Hz), 5.37 (s, 2H), 5.75 (d, 1H, J = 5Hz), and 7.2-8.4 (m, ArH) Analysis calculated for C ₂₂ H ₁₈ N ₃ O ₅ SCl: Calculated: C 55 99; H, 3.84; N, 8.90; S, 6.79; Cl, 7.51. Found: C, 56.16; H, 4.06; N, 9.00; S, 6.54; Cl, 7.67.

Example 8

7- (l-Chloro-2'-phenoxy- ethylidene) imino-3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester

In the same manner as in Example 1, a triphenylphosphite-chlorine complex is prepared in 45 mL of dichloromethane starting from 3.95 mL (15 mmol) of triphenylphosphite and 4.84 g (10 mmol) of 7-phenoxy is added to the solution. acetamido-3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester and washed with dichloromethane (5 mL). The mixture was then added dropwise at -10 ° C

A solution of pyridine (1.3 mL, 15.6 mmol) in dichloromethane (8 mL) was added. The cooling bath was then removed and, after stirring for half an hour, 2.1 ml (30 mmol) of propylene oxide was added. After stirring for 10 minutes, the mixture is washed with 50 ml of ice water, dried over calcium chloride dihydrate and the solvent is distilled off under reduced pressure. Diethyl ether (50 ml) was added to the residual oil, whereupon the product crystallized. The crude material was filtered off to give 3.44 g (68.6%) of the title compound, mp 110-111 ° C.

Nuclear Magnetic Resonance Spectrum (deuterochloroform, pentadeuteropyridine) = 2.16 (s, 3H), 3.26 (ABq, J = 18 Hz), 4.83 (s, 2H), 5.01 (d, 1H, J = 5Hz), 5.28 (s, 2H), 5.52 (broad d, 1H, J = 5Hz), and 6.7-8.2 (m, ArH).

Example 9

Preparation of 7-Amino-3-methylene-cepham-4-carboxylic acid (p-nitrobenzyl) ester hydrochloride 7- (1'-chloro-2'-phenoxyethylidene) imino-3-methylene-cepham. Via 4-carboxylic acid (p-nitrobenzyl) ester

By proceeding as described in Example 1, about 12.3 mmol of triphenylphosphite-chlorine complex is prepared. To the solution was added 4.84 g (10 mmol) of 7-phenoxyacetamido-3-methylene-cepham-4-carboxylic acid (p-nitrobenzyl) ester, followed by dropwise addition of 1.01 mL (12.5 mL) over a quarter hour. millimoles) of pyridine in 4 ml of dichloromethane. After stirring for about a quarter hour at -10 to -15 ° C, propylene oxide (2.1 ml, 30 mmol) was added and the mixture was washed rapidly with ice water (25 ml), dried over calcium chloride dihydrate (5 minutes) and distilling off the solvent under reduced pressure. The resulting thick oil (11 g) was dissolved in 25 ml of carbon tetrachloride and the solvent was distilled off. The residual oil was found to be the only iminochloride contaminated with triphenyl phosphate by NMR.

Nuclear Magnetic Resonance Spectrum (carbon tetrachloride) = 3.4 (ABq, 2H), 4.87 (s, 2H), 5.30 (m, 3H), 5.45 (s, 2H) and 6.7-. 8.4 (m, ArH).

The above crude iminochloride is dissolved in 50 ml of dichloromethane and 5.1 ml (55 mmol) of isobutanol are added and hydrogen chloride gas is introduced. The reaction temperature rises from about 20 ° C to about 30 ° C. After stirring for 2 hours in a cooling bath, the precipitated crystalline material was filtered off, washed and dried; This gave 3.58 g (92.7%) of nearly colorless, crystalline 7-amino-3-methylene-cepham-4-carboxylic acid (p-nitrobenzyl) ester hydrochloride, m.p. 181 ° C.

Nuclear Magnetic Resonance Spectrum (hexadeutero-dimethylsulfoxide) δ = 3.67 (bs, 2H), 5.0 (d, 1H, J = 5Hz), 5.35-5.53 (m, 6H). and 7.6-8.4 (m, ArH).

Example 10

7-Amino-3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester hydrochloride

To a solution of isobutanol (4.1 mL, 44 mmol) in dichloromethane (40 mL) was added 7- (1'-chloro-2'-phenylethylidene) imino (2.89 g, 8 mmol) obtained in Example 1. -3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester. Hydrochloric acid gas is introduced into the solution at medium speed for one and a quarter minutes, at which time the title ester hydrochloride begins to precipitate in the form of a gelatinous precipitate. Since the mixture is not stirred, 40 ml of dichloromethane are added. After stirring at room temperature for 2 hours, the product was filtered off to give 2.52 g (81.6%) of the title compound, m.p. 183.5 ° C. The filtrate was treated with HCl gas to give an additional 0.47 g of the title compound, m.p. 183.5 ° C. Total yield of alcoholysis: 96.8%.

Nuclear Magnetic Resonance Spectrum (hexadeutero-dimethylsulfoxide) δ = 2.21 (s, 3H), 3.65 (ABq, 2H, J = 16 Hz), 5.18 (q, 2H, J = 4 Hz, β lactam-H), 5.41 (s, 2H), and 7.6-8.4 (m, ArH).

Example 11

7-Amino-3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester hydrochloride

A) Starting from 7-Phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester

-13186303

A triphenylphosphite-chlorine complex was prepared by adding chlorine gas to a solution of triphenylphosphite (2.89 mL, 11 mmol) in dichloromethane (50 mL) at -15 ° C, followed by the addition of 5.02 g (10 mmol). 7-Phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester and 0.85 mL (11.5 mmol) of pyridine. The mixture was stirred at -10 to -15 ° C for 1 hour, then 6.0 mL (64.8 mmol) of isobutanol was added. The cooling bath was removed and the reaction was allowed to warm to room temperature over about 2 hours. The title ester hydrochloride begins to crystallize in the first quarter hour. The precipitated product is filtered off, washed with dichloromethane and dried. This gave 3.55 g (92%) of the title compound as a white crystalline solid, m.p. 189 ° C.

B) Starting from 7-Heptanoylamido-3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester

In the same manner as in (A) above, but starting from 4,61 g (10 mmol) of 7-heptanoylamido-3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester 6.32 g (93.8%) of the ester hydrochloride are obtained in the form of crystals, m.p. 188.5 ° C (dec.),

Starting from C 7-Phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester in tetrahydrofuran as solvent

A triphenylphosphite-chlorine complex is prepared by introducing chlorine gas into a solution of 11 milliliters of triphenylphosphite in tetrahydrofuran at -10 ° C. To the solution thus obtained is added 4.84 g (10 mmol) of 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester, followed by 0.95 ml (11 mmol). ) pyridine. The reaction mixture was stirred at -10 ° C for 1 hour, then allowed to warm to room temperature and stirred for a further 2 hours. Isobutanol (6.0 mL, 65 mmol) was added and the mixture was stirred for an additional 2 hours. The precipitated product is filtered off, washed with tetrahydrofuran and dried. A total of 3.03 g (78.5% yield) of the title ester hydrochloride are obtained, m.p. 151-153 ° C (dec.).

D) Starting from 7-Phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester in acetonitrile as solvent

A triphenylphosphite-chlorine complex is prepared by introducing chlorine gas into a solution of about 11 millimeters of triphenylphosphite in 45 mL of acetonitrile at -10 ° C. To the solution thus obtained at -10 ° C was added 4.84 g (10 mmol) of 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester, followed by 0 95 ml (11 millimoles) of pyridine. After stirring at -10 ° C for 2 hours, the cooling bath was removed and after stirring for a further 2 hours, 6.0 mL (65 mmol) of isobutanol was added. The product crystallizes upon inoculation. After stirring for 1 hour, the product is filtered off, washed with acetonitrile and dried. A total of 2.55 g (66.1%) of the title compound are obtained, m.p.

E) Starting from 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester in ethyl acetate as a solvent, proceed as described in D above, except that the preparation of triphenylphosphite-chlorine complex and amide cleavage in ethyl acetate as solvent. Total yield: 2.48 g (64.2% yield), m.p. 177-179 ° C (dec).

E) Starting from 7-Phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester with the aid of tris (o-tolyl) phosphite-chlorine complex

The tris (o-tolyl) phosphite-chlorine complex is prepared as follows:

Trichloromethane (3.91 g, 11 mmol) was added to dichloromethane (mL) and the solution was cooled to -45 ° C under a nitrogen atmosphere. Chlorine gas is then introduced into the solution until a permanent yellow color is obtained, and this yellow color is removed by the addition of about 0.5 mmol of tris- (o-tolyl) phosphite. Then, 4.84 g (10 mmol) of 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester and 1.0 ml (12.5 mmol) are added to the solution. pyridine. The heat bath was removed, and the mixture was stirred for 1.5 hours and then wasobutanol (5.1 mL, 55 mmol) was added. Anhydrous hydrochloric acid gas was introduced into the mixture, and 5 minutes later, the product began to crystallize from the mixture. After 1.5 hours, the precipitate was filtered off, washed with dichloromethane (25 mL) and dried under reduced pressure. Total yield: 3.46 g (89.6%), m.p. 184 ° C (dec.).

G) Starting from 7-Phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester using a copolymer of divinylbenzene and vinylpyridine as the base in dichloromethane as solvent, -10 At <RTI ID = 0.0> C, </RTI> the triphenylphosphite-chlorine complex is prepared by first introducing chlorine gas into the solvent and then adding the triphenylphosphite at the same rate as the gas addition, while maintaining the yellow color of the solution. When almost all triphenyl phosphite has been added, it is discontinued by introducing chlorine gas and additional triphenyl phosphite is added until the solution becomes colorless. A total of 3.0 mL (11.4 mmol) triphenyl phosphite was used. To the resulting solution was added 5.0 g (10.3 mmol) of 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester, followed immediately by 5.0 g. g copolymer of divinylbenzene and vinylpyridine. The cooling bath was then removed and the mixture was stirred at room temperature for 2 hours. The polymer was then filtered off and washed with dichloromethane (about 20 mL). Isobutanol (6.0 mL, 64.8 mmol) was added to the filtrate and hydrogen chloride gas was added for about 2 minutes. About 3 minutes later, the expected ester hydrochloride begins to crystallize. After 1 hour, the product is filtered off, washed with dichloromethane and dried. This gave a total of 2.98 g (75%) of the title compound, m.p. 183 ° C (dec.).

-14186303

H) Starting from 7-Phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester with the help of tris-p-methoxyphenylphosphite-chlorine complex

The tris (p-methoxyphenyl) phosphite-chlorine complex is prepared as follows:

Chlorine gas was added to 10 ml of dichloromethane at -10 to -20 ° C and a solution of 4.6 g (11.5 mmol) of tris- (p-methoxyphenyl) phosphite in about 5 ml of dichloromethane was added dropwise. to obtain a colorless solution at the end of the addition. After the addition of all the phosphite, additional chlorine gas was added to a pale yellow color; this yellowish color of chlorine disappears quickly without the addition of additional phosphite. To the solution obtained above was added 4.84 g (10 mmol) of 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester and washed with 5 ml of dichloromethane. A solution of 1.01 ml (12.5 mmol) of pyridine in 4 ml of dichloromethane is then added dropwise over a quarter hour. The mixture was stirred for an additional quarter hour at -10 ° C, 5.1 ml (55 millimole) of isobutanol was added, hydrogen chloride gas was added and the cooling bath was removed shortly thereafter. The mixture was stirred for 2 hours at room temperature and the precipitate was filtered off; 0.89 g (23%) of the desired ester hydrochloride is obtained, m.p. 173-174 ° C.

I) starting from 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester using triethylamine as the base

The triphenylphosphite-chlorine complex is prepared by adding chlorine gas to 45 ml of dichloromethane at -10 ° C and simultaneously adding 3.16 ml (12 mmol) of triphenylphosphite while maintaining the yellow color of the chlorine in the mixture. . The color of the excess chlorine was removed by the addition of 0.5 millimole triphenylphosphite. To the solution thus obtained is added 4.84 g (10 mmol) of 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester and washed with 5 ml of dichloromethane. After stirring for 5 minutes, a solution of triethylamine (1.8 ml, 13 mmol) in dichloromethane (8 ml) was added dropwise over a quarter hour. After stirring for an additional quarter hour at -10 ° C, the cooling bath was removed and 5.1 mL (55 mmol) of isobutanol was added. Hydrogen chloride gas was then added for 3 minutes, inoculated and allowed to warm to room temperature. After 2 hours, the precipitated product was filtered off to give 1.28 g (33.2%) of the ester hydrochloride, m.p. 180.5 ° C (dec.).

J) Starting from 7-Phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester using 1,5-diazabicyclo [5.4.0] undec-5-ene (DBU) as base

All of the procedures described in (I) above were repeated except that 1.95 mL (13 mmol) of 1.5 diazabicyclo [5.4.0] undec-5-ene (DBU) was used in place of triethylamine. Yield: 0.59 g (15.3%) of ester hydrochloride, m.p. 181 ° C (dec.).

K) Starting from 6-Phenoxyacetamido-penicillanilic acid (p-nitrobenzyl) ester 1-oxide

5.02 g (10 mmol) of 6-phenoxyacetamido-penicillanic acid (p-nitrobenzyl) ester and 0.25 g (1 mmol) of pyridinium dichloromethane phosphonate in 88 ml of 1,1,2-trichloroethane The solution was stirred at reflux for 4 hours and then concentrated under reduced pressure to a volume of about 44 ml.

Prepare 12 millimoles of triphenylphosphite-chlorine reagent by adding chlorine gas to a solution of 3.15 ml of triphenylphosphite in 44 ml of 1,1,2-trichloroethane at -10 ° C, followed by a drop of triphenylphosphite. by adding the yellow color is removed.

Then, to the triphenylphosphite-chlorine complex solution, the solution obtained as described in the first paragraph is added at -10 [deg.] C., and then 0.89 ml (11 mmol) of pyridine is added at the same temperature. After half an hour, the cooling bath was removed and the mixture was allowed to warm to room temperature. After another half hour, 0.42 mL (5 mmol) of pyridine was added and after stirring for 10 minutes, 9.25 mL (100 mmol) of isobutanol was added. After stirring overnight, the precipitated crystalline product was filtered off to give 2.67 g (69.2%) of the ester hydrochloride, m.p. 183 ° C (dec.).

L) Starting from 6-Phenoxyacetamido-penicillanic acid (p-nitrobenzyl) ester 1-oxide using 2,6-lutidine as base

Proceed as in K above, except that 1.25 mL (11 mmol) of 2,6-lutidine is used in place of pyridine and hydrochloric acid gas is added to the mixture for about 1 minute after the addition of isobutanol. Two to three minutes after the addition of hydrochloric acid, the product begins to crystallize to give a total of 2.47 g (64%) of the title ester hydrochloride, m.p. 173 ° C (dec.).

Example 12

7-amino-3-methoxy-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester hydrochloride

To a solution of triphenylphosphite (0.4 mL, 1.5 mmol) in dichloromethane (10 mL) was added chlorine gas at -10 ° C until a pale yellow color of excess chlorine appeared. This color is removed by adding a small drop of triphenylphosphite. To the solution thus obtained was added 0.5 g (1 mmol) of 7-phenoxyacetamido-3-methoxy-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester, followed by 0.12 ml (1), 5 millimol) pyridine. The cooling bath was removed and the mixture was stirred at room temperature for 1.5 hours. Isobutanol (0.6 mL, 6.4 mmol) was added and the title ester hydrochloride crystallized 5 minutes later. After 1.5 hours, the product was filtered off to give 0.3 g (75%) of the title compound as almost colorless crystals, m.p. 185 ° C (dec.).

N NMR (hexadeutero-dimethylsulfoxide): δ 3.92 (br s, 2H), 4.0 (s, 3H), 5.02 (d, 1H, J = 5 Hz), 5.32 (d, 1H, J = 5Hz), 5.45 (s, 2H) and 7.6-8.4 (m, ArH).

Analysis calculated for C ₁₅ H ₁₆ N ₃ O ₆ SCl: C, 44.84; H, 4.01; N, 10.46; Cl, 8.82; S, 7.98. Found: C, 44.69; H, 4.17; N, 10.34; Cl, 9.05; S, 7.77.

-15186303

Example 13

7-Amino-3-methylenecepham-4-carboxylic acid (p-nitrobenzyl) ester hydrochloride

5.02 g (10 mmol) of 7-phenoxyacetamido-3-methylene-cepham-4-carboxylic acid (p-nitrobenzyl) ester 1-oxide and 2.4 ml (22.5 mmol) of pentene 50 1.15 ml (22.5 mmol) of acetyl bromide are added dropwise to a solution of dichloromethane (15 ml) at 15 ° C over 10 minutes. The mixture was cooled to 0 ° C, 25 ml of ice water was added and the mixture was stirred for half an hour. The dichloromethane solution was separated, washed with water (25 mL) followed by dilute sodium chloride solution (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to about 25 mL.

The triphenylphosphite-chlorine complex was prepared by introducing chlorine gas into a solution of triphenylphosphite (2.89 mL, 11 mmol) in dichloromethane (25 mL) at -10 ° C until a yellow color was obtained. To remove this yellow color, an additional 0.12 ml (0.46 mmol) of triphenylphosphite is added to the solution, followed by the addition of the solution obtained in the first paragraph at -10 ° C, followed by 0.93 ml ( 11.5 mmol) pyridine. The cooling bath was removed and the mixture was allowed to warm to room temperature. After one hour, 5.1 ml (55 mmol) of isobutanol are added, and after about 10 minutes the product begins to crystallize. The product was filtered to give 3.17 g (82.1%) of the title ester hydrochloride, m.p. 182 ° C (dec.).

Nuclear Magnetic Resonance Spectrum (hexadeutero-dimethylsulfoxide): = 3.6 (bs, 2H), 4.95 (d, 2H, J = 5Hz), 5.33-5.7 (m, 6H) and 7.6-8.4 (m, ArH).

Example 14

7-amino-3-acetoxy-methyl-3-cephem-4-carboxylic acid benzhydryl ester

To a solution of the dibenzhydryl ester of 2,4-dichlorobenzoyl-cephalosporin C (1.39 g, 1.5 mmol) in dichloromethane (10 mL) was added pyridine (0.484 mL, 6 mmol) at -35 ° C and then 1.57 mL. (6 mmol) of triphenylphosphite-chlorine solution of triphenylphosphite and chlorine at -10 ° C in 10 mL of dichloromethane. The mixture was stirred at about 18 ° C for two and a half hours, then cooled to -5 ° C and 3.0 ml of isobutanol was added. The mixture was allowed to warm to about 20 ° C and the solvent was distilled off. The resulting dark brown syrupy material was dissolved in a mixture of dichloromethane (20 mL) and water (10 mL), adjusted to pH 0.9 with hydrochloric acid, and the dichloromethane solution was separated and extracted with water (pH 7.5). After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue, weighing approximately 3.5 g, very dark brown in color, was dissolved in 2.5 ml of ethyl acetate-toluene 3: 7 and applied to a column 9 mm in diameter filled with 40 g of silica gel. The column was eluted with ethyl acetate-toluene (3: 7) and ethyl acetate-toluene (1: 1) to give the title compound (0.24 g, 36%).

J5. example

7-Amino-3-acetoxymethyl-3-cephem-4-carboxylic acid (7-ACA)

2.94 g (5 mmol) of 2,4-dichlorobenzoyl-cephalosporin C, 0.16 mL (1.34 mmol) of quinoline and 2.39 mL (15 mmol) of N, N-diethylaniline in 30 mL of dichloro- 2.45 ml (34.5 mmol) of acetyl chloride are added to a suspension of methane in methanol at room temperature with stirring. The mixture was then cooled to -25 ° C and diethylaniline (0.6 mL, 3.75 mmol) and triphenylphosphite-chlorine complex (3.68 mL, 14 mmol) were added. The cooling bath was then removed and the mixture was allowed to warm to room temperature over 2 hours. Then, with cooling to -15 ° C, 8.5 ml (116 mmol) of propylene glycol are added, stirred for about half an hour at 20 ° C, then cooled to -15 ° C and 25 ml of ice are added. water. The aqueous solution was separated to pH 3.5 with 3.3 ml of ammonium hydroxide solution and stirred for 1.5 hours in an ice bath. The precipitate was collected by filtration to give 0.4 g (29%) of 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid.

Example 16

7-Amino-3-methyl-3-cephem-4-carboxylic acid (7-ADCA)

3.40 g (10 mmol) of 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid, 0.158 mL (1.34 mmol) of quinoline and 2.38 mL (15 mmol) of N, N-diethyl- To a suspension of aniline in 30 ml of dichloromethane was added 2.46 ml (34.5 mmol) of acetyl chloride at room temperature and the mixture was stirred at 18-22 ° C for 6 hours, then cooled to -15 ° C and 6 ml (3.75 mmol) of Ν, Ν-diethylaniline followed by triphenylphosphite-chlorophenyl complex of 3.68 ml (14 mmol) of triphenylphosphite in 15 ml of dichloromethane. The mixture was stirred for 7 minutes without external cooling, cooled to -20 ° C, and 10.7 mL (116 mmol) of isobutanol was added. The cooling bath was removed, and after about 45 minutes, a significant amount of crystalline material precipitated out of the mixture. After another half hour, the mixture was cooled to 0 ° C and the precipitate was filtered off. This gave 1.95 (73% yield) of 7-a-mino-3-methyl-3-cephem-4-carboxylic acid, which showed a slight impurity NMR spectrum.

'Example 7

7-Amino-3-acetoxymethyl-3-cephem-4-carboxylic acid (7-ACA)

4.18 g (9.76 mmol) of 7-phenoxyacetamido-3-acetoxymethyl-3-cephem-4-carboxylic acid sodium salt, 0.154 mL (1.31 mL mol) of quinoline and 2.91 mL (18 mL). To a suspension of N, N-diethyl arylline (2 mmol) in dichloromethane (29 mL) at room temperature was added acetyl chloride (2.40 mL, 33.6 mmol) and the mixture was stirred for one and a quarter hours. It is then cooled to -35 ° C and triphenylphosphite chlorine from 3.6 ml (13 mmol) of triphenylphosphite in 15 ml of dichloromethane is added.

-16186303 messy complex. The mixture is stirred at -20 to -25 ° C for about 1 hour and isobutanol (10.5 ml) is added. The mixture was allowed to warm to room temperature and stirred for 2 hours. It was then poured into 50 g of ice water, the aqueous solution was separated, the pH was adjusted to 3.5 and stirred for 1 hour in an ice bath under a stream of nitrogen. The precipitate was collected by filtration to give 2.7 g (78%) of 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid.

Example 18

7-Amino-3-acetoxymethyl-3-cephem-4-carboxylic acid (7-ACA)

4.55 g of cephalosporin C sodium salt are suspended in 142 ml of chloroform containing pentene and the solution is concentrated to 67 ml. A suspension of cephalosporir sodium salt C in chloroform was then cooled to 26 ° C, quinoline (0.464 mL, 3.94 mmol), N, N-diethylamine (6.95 mL, 43.5 mmol) and 131 mmol) of acetyl chloride. The mixture is then heated to 35 [deg.] C. with stirring for about 7 minutes and then quenched. After stirring for 2 hours, the mixture was filtered.

Triphenylphosphite-chlorine reagent was prepared by introducing chlorine gas into 35 ml of chloroform at -20 ° C and simultaneously adding 8.9 ml (34 mmole) of triphenylphosphite. The reagent solution thus obtained is added to a mixture of the solution obtained as described in the first paragraph and 3.2 ml (20 millimoles) of N, N-diethylaniline at -30 ° C.

The mixture was stirred at -20 to -15 ° C for 1 hour, then cooled to -35 ° C and 15 ml of propylene glycol was added. The mixture was stirred for 2 hours at 0 ° C and then poured onto 51 g of ice. The chloroform solution was separated and extracted once more with 5 ml of ice water. The combined aqueous solution was adjusted to pH 3.5 with about 7.5 mL of ammonium hydroxide solution and stirred for one hour in an ice bath while a stream of air was passed over the solution to remove residual chloroform. The precipitate was filtered off, washed with water (6 ml), methanol (15 ml) and acetone (5 ml). A total of 1.87 g (73%) of air-dry 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid were obtained.

Example 19

7-Amino-3-acetoxymethyl-3-cephem-4-carboxylic acid (7-ACA)

A) 4.8 g (10 mmol) of cephalosporin C sodium salt dihydrate are suspended in 80 ml of dichloromethane (cyclohexane stabilized and dried on a 4 Å molecular sieve), add 7.4 g (8 ml, 50 mmol) of potassium hydroxide, Ν Α-diethylaniline and 4.7 g (4.3 mL, 60 mmol) of acetyl chloride were added and the mixture was stirred at 30-40 ° C for 1 hour and then at room temperature for 2 hours. The insoluble precipitate (1.65 g) was filtered off, the filtrate was cooled in an ice-alcohol cooling bath, and a solution of triphenylphosphate chlorine kinetic complex prepared as described below was added:

To a solution of 6.8 g (5.8 mL, 22 mmol) of triphenylphosphite in 100 mL of anhydrous dichloromethane was added chlorine gas to a permanent yellow color in an ice-alcohol cooling mixture, and the yellow color of excess chlorine was removed by adding a few drops of triphenylphosphite.

After the solution of the triphenylphosphite-chlorine complex is added to the solution obtained as described in the first paragraph, the mixture is also added dropwise to the ice-alcohol cooling bath for 10 minutes.

A solution of N, N-diethylaniline (3.3 g, 3.5 mL, 22 mmol) in dichloromethane (20 mL) was added. After stirring for 2 hours at the same temperature, 6.0 g (7.4 mL, 80 mmol) of isobutanol, dried on a 3 A molecular weight sieve, are added, cooled to -35 ° C. Anhydrous hydrochloric acid gas was then added for about half a minute and kept in the refrigerator overnight. The next day, 20 mL of water was added and the biphasic mixture was vigorously stirred for 5 minutes. The dichloromethane solution was separated and washed with water (20 mL). The combined aqueous solutions were shaken with ethyl acetate, adjusted to pH 3.8 with saturated ammonium bicarbonate solution and stirred for half an hour in an ice bath. The precipitate is filtered off and the solid product is dried under reduced pressure. 1.5 g (83%) of 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid are obtained.

B) 4.8 g (10 mmol) of cephalosporin C sodium salt dihydrate is suspended in 80 ml of 5 Å molecular weight filter dried tetrahydrofuran, 7.4 g (8.0 ml, 50 mmol) of potassium hydroxide is added. ,? -Diethylaniline and 4.7 g (4.3 mL, 60 mmol) of acetyl chloride and the mixture was stirred at about 30-40 ° C for 1 hour and then at room temperature for a further two and a half hours. The insoluble solid in the mixture (5.7 g) was filtered off. The filtrate was cooled in an ice-alcohol cooling bath, and a solution of triphenylphosphite-chlorine complex in tetrahydrofuran instead of dichloromethane as in (A) above was added dropwise and 3.3 g (22 mmol) was added dropwise over 10 minutes. N-diethylaniline in 20 ml of anhydrous tetrahydrofuran. After stirring for 2 hours at the same temperature, the mixture is cooled to about -35 ° C, 16 ml of propylene glycol is added, and hydrochloric acid gas is introduced for about 15 seconds. It is kept in the refrigerator overnight and processed the next day as described in A above in this example. 1.2 g (45%) of 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid are obtained.

C) 3.3 g (5 mmol) of cephalosporin C quinoline salt monohydrate are suspended in 40 ml (cyclohexane-stabilized, 4A molecular weight filter) dichloromethane, add 3.0 g (20 mmol), potassium hydroxide Ν, Α-Diethylaniline and 1.9 g (1.8 ml, 25 mmol) of acetyl chloride were added and the mixture was stirred at room temperature for 1 hour. After cooling in an ice-alcohol cooling bath, a solution of triphenylphosphite-chlorine complex (3.4 g, 11 mmol) in triphenylphosphite complex (3.4 g, 11 mmol) was added dropwise over 10 minutes. 11 mmol) of Ν, Ν-diethylaniline in 10 ml of anhydrous dichloromethane. The mixture was stirred for 2 hours in a cooling bath, then cooled to -35 ° C, treated with -17186303 (3.7 mL, 3A pore size molecular sieve) and then hydrochloric acid gas introduced for about 15 seconds. Store overnight in the refrigerator and process as described in A above in this example. 730 mg (54%) of 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid are obtained.

Example 20

Preparation of 7-Amino-3-methyl-3-cephem-4-carboxylic acid (2 ', 2', 2'-trichloroethyl) ester hydrochloride in benzene as a solvent

A) Chlorine gas is introduced into 45 ml of benzene at 10-15 ° C and 3.16 ml (12 mmol) of triphenylphosphite is added at a rate such that the pale yellow color of chlorine predominates throughout the addition, and remove the last drop of phosphite. To the solution thus obtained was added 4.64 g (10 mmol) of 7-phenylacetamido-3-methyl-3-cephem-4-carboxylic acid (2 ', 2', 2'-trichloroethyl) ester and then A solution of 1.1 ml (12.5 mmol) of pyridine in 8 ml of benzene is added dropwise at 10-15 ° C over a period of 10 minutes. After stirring for 45 minutes, isobutanol (5.1 mL, 55 mmol) was added and hydrochloric acid gas was added for about 1.5 minutes. The mixture was stirred for an additional 2 hours, during which time the product crystallized. The product was filtered off to give 3.5 g (91.6%) of the title ester hydrochloride, m.p. 179 ° C (dec.).

Nuclear Magnetic Resonance Spectrum (hexadeuterodimethylsulfoxide) δ = 2.27 (s, 3H), 3.6 (ABq, 2H, J = 16 Hz), 5.00 (s, 2H) and 5.12 (q , 2H, J = 4Hz, β-lactam-H).

B) By proceeding as described in A above above, but working at room temperature (20-25 ° C) instead of 10-15 ° C, a total of 3.26 g (85.4%) of the title ester hydrochloride is obtained. mp 179 ° C (dec.).

Example 21

7-Amino-3-chloro-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester

To a solution of triphenylphosphite (2.63 mL, 10 mmol) in dichloromethane (50 mL) was added chlorine gas at 0-5 ° C and the yellow color of excess chlorine was removed by dropwise addition of triphenyl phosphite. In addition to the amount originally measured, 0.47 ml (1.8 mmol) of triphenylphosphite is required to give 11.8 mmol of triphenylphosphite-chlorine kinetic complex. To this solution was added 5.04 g of 7-phenoxyacetamido-3-chloro-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester followed by 1.01 mL (12.5 mmol) of pyridine in 2 mL dichloromethane. Addition of pyridine causes the temperature of the mixture to rise from 5 ° C to 12 ° C. After stirring for 2 hours at room temperature, isobutanol (5.1 mL, 55 mmol) was added. After 10 minutes, the title ester hydrochloride begins to crystallize. After 1.5 hours, the product was filtered off and dried, yielding 3.71 g (91.4%) of the title compound as an off-white crystalline solid, m.p. 180-181 ° C (dec.).

Nuclear Magnetic Resonance Spectrum (hexadeutero-dimethylsulfoxide) = -3.7 (bs, 2H), 5.33 (q, 2H, β-lactam-H), 5.46 (s, 2H) and 7.5 -8.4 (ArH).

Example 22

7-Amino-3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester hydrochloride

To a solution of 2.89 ml (11 mmol) of triphenylphosphite in 50 ml of dichloromethane was added chlorine gas at 0-5 ° C until a residual yellow color was added, followed by additional 0.17 ml (0.65 mmol) of triphenyl to remove the yellow color of excess chlorine. phosphite is added to the solution. To the solution thus obtained is added 4.84 g (10 mmol) of 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester and washed with 5 ml of dichloromethane. . Pyridine (1.01 mL, 2.5 mmol) was then added, causing the reaction temperature to rise from 5 ° C to 12 ° C. The mixture is then stirred for 2 hours at room temperature, isobutanol (5.1 ml, 55 mmol) is added and traces of hydrochloric acid gas are added after 20 minutes. The product begins to crystallize immediately. After two and a half hours, the product was filtered off and dried; 3.29 g (85.3%) of the title ester hydrochloride are obtained, m.p. 177 DEG C. (dec.).

The filtrate of the above product was treated with additional hydrochloric acid gas to give an additional 0.32 g of product. Total yield: 93%.

Example 23

7-Amino-3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester hydrochloride

To a solution of 2.89 ml (11.8 mmol) of triphenylphosphite in 50 ml of dichloromethane at 0-5 ° C is added chlorine gas to a persistent yellow color indicating excess chlorine, and the yellow color is removed by adding two more drops of triphenylphosphite. To the solution thus obtained was added 4.67 g (10 mmol) of 7-phenylacetamido-3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester, followed by 0.85 ml (10 ml). 5 millimol) pyridine. The mixture was allowed to warm to room temperature, stirred for 2 hours, and then cooled to 15 ° C with 5.1 ml (55 mmol) of isobutanol. The mixture was stirred for an additional 2 h at room temperature and the precipitated product was filtered off. Thus, 3.5 g (90.6%) of the title ester hydrochloride are obtained in three generations, m.p. 188 DEG C. (dec.).

Example 24

7-Amino-3-methyl-2-cephem-4-carboxylic acid (p-nitrobenzyl) ester hydrochloride

All of the procedures described in Example 23 above were followed except that starting material was 4.84 g (10 mmol) of 7-phenoxyacetamido-3-methyl-2-cephem-4-carboxylic acid (p-nitrobenzyl). ) -ester. 3.27 g (84.7%) of the title ester hydrochloride are obtained, m.p. 184 DEG C. (dec.).

-18Í863O3

Nuclear Magnetic Resonance Spectrum (hexadeutero-dimethylsulfoxide) δ = 1.96 (s), 5.12 (bs, 2H), 5.4 (m), 6.34 (bs, 1H) and 7.6 -8.4 (ArH).

Example 25

7-Amino-3-methylene-cepham-4-carboxylic acid (p-nitrobenzyl) ester hydrochloride

Each was prepared as in Example 23 above, except that starting material was 4.83 g (10 mmol) of 7-phenoxyacetamido-3-methylenecepham-4-carboxylic acid (p-nitrobenzyl). ester. This gives 3.58 g (92.8%) of the title ester hydrochloride, m.p. 176.5-177 ° C (dec.). The product has the same NMR spectrum as the product obtained in Example 9.

Example 26

7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester hydrochloride

To a solution of 2.89 ml (11 mmol) of triphenylphosphite in 50 ml of dichloromethane is added chlorine gas at a temperature of 5-10 ° C until a persistent yellow color is obtained, and the excess chlorine is removed by adding an additional 3 drops of triphenylphosphite. The cooling bath was removed and 5.28 g (10 mmol) of 7-phenoxyacetamido-3-acetoxy-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester was added, followed by 0.85 mL (10.5 mmol) of pyridine. The mixture was stirred at room temperature for 2 hours and then wasobutanol (6.0 mL, 64.8 mmol) was added. After 8 minutes the product begins to crystallize from the mixture. After 2 hours, the product is filtered off to give 2.57 g (59.9% yield) of the title ester hydrochloride as a bright white crystalline solid, m.p. 160 DEG C. (dec.). An additional amount of product is still present in the filtrate of the above product, which is not isolated.

Nuclear Magnetic Resonance Spectrum (hexadeutero-dimethylsulfoxide) δ = 2.2 (s, 3H), 3.93 (bs, 2H), 5.45 (m) and 7.6-

8.4 (ArH-).

Example 27

Preparation of 7-Amino-3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester hydrochloride using the tris (p-chlorophenyl) phosphite-chlorine kinetic complex

A solution of 5.17 g (12.5 mmol) of tris- (p-chlorophenyl) phosphite and 0.27 mL (3.28 mmol) of pyridine in 25 mL of dichloromethane was introduced at -70 ° C and To remove excess chlorine, add 0.40 mL of pentene. To this solution was added 2.42 g (5 mmol) of 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester followed by 0.79 mL of pyridine (9 mL). (22 mmol) in dichloromethane (4 mL) was added dropwise over 11 minutes. After stirring for 3 hours, the cooling bath is removed, 6.94 ml of isobutanol are added and the mixture is allowed to warm to -10 ° C. Subsequently, salt gas 20 is added for about 1 minute and the precipitated product is filtered off after a quarter. This gave 1.86 g (96%) of the title compound as a white solid, mp 184-185 ° C (dec.).

Example 28

7- (1'-Chloro-2'-phenylethylidene) imino-7-methoxy-3-acetoxymethyl-3-cephem-4-carboxylic acid benzyl ester

To a solution of triphenylphosphite-chlorine complex (12.3 mmol) from triphenylphosphite in 45 mL of dichloromethane at -15 ° C in the presence of 0.1 mL of pyridine is added 5.11 g (11 mmol) of 7-phenylacetamido-7- methoxy-3-acetoxy-3-cephem-4-carboxylic acid benzyl ester and a solution of 1.01 ml (12.5 mmol) pyridine in 4 ml dichloromethane was added dropwise over 10 minutes. After stirring for 1 minute at -15 to -10 ° C, propylene oxide (2.1 ml, 30 mmol) was added, and after a further 10 minutes (at 0 ° C), the mixture was washed with water (25 ml). dried in chloride and the solvent was distilled off under reduced pressure. The syrup-like material thus obtained (11 g) was triturated three times with carbon tetrachloride and then dissolved in 50 ml of diethyl ether. The ethereal solution was decanted from the insoluble precipitate (about 0.5 g) and concentrated to about 25 ml. To the concentrated solution was added 25 mL of hexane to give an oily product. This oily product was washed twice with hexane: diethyl ether (1: 1) and then twice with carbon tetrachloride, and the solvent was distilled off under reduced pressure. This gave 2.5 g of the title compound as a foam. Infrared spectrum (chloroform): 1780 and 1730 cmA

Nuclear Magnetic Resonance Spectrum (deuterochloroform, pentadeuteropyridine) δ = 1.96 (s, 3H), 3.3 (ABq), 3.43 (s, 2H), 3.93 (s, 2H), 4.86 (ABq), 4.93 (s, 1H), 5.25 (s, 1H) and 7.3 (ArH).

Example 29

-Amino-3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester hydrobromide

To a solution of 25.4 millimoles of triphenylphosphite-bromine complex [prepared as 6.67 ml (25.4 millimoles) of triphenylphosphite and 1.30 ml (25.4 millimoles) of bromine in the presence of 2.10 ml (26 millimoles) of pyridine 100 (dichloromethane, 10-15 ° C), 9.67 g (20 mmol) of 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester are added. and the mixture was stirred at -10 to -15 ° C for 1 hour. The cooling bath was removed and 13.88 mL (150 mmol) of isobutanol was added and the mixture was stirred at room temperature for 2 hours. The precipitated product was filtered off to obtain 4.76 g (55.3%) of the title compound, m.p. 179-181 ° C (dec.).

Analysis calculated for C ₁₅ H ₁₆ N ₁₀ O ₅ SBr: C, 41.87; H, 3.75; N, 9.77; S, 7.45; Br, 18.57. Found: C, 42.04; H, 3.57; N, 9.54. S, 7.54; Br, 18.37.

Nuclear Magnetic Resonance Spectrum (hexadeutero-dimethylsulfoxide) δ = 2.2 (s, 3H), 3.65 (broad s, 2H), 5.27 (m, 2H, β-lactam-H), 5.42 ( s, 2H) and 7.6-8.4 (m, 4H, ArH).

-19186303

Example 30

7- (α-Chloro-p-methylbenzylidene) imino-7-methoxy-3- (1)

benzhydryl of methyl-tetrazol-5'-yl-mercapto) -methyl-1-de-thia-1-oxa-3-cephem-4-carboxylic acid

200 mg of 7- (p-methyl-benzamido) -7-methoxy-3- (1'-methyl-tetrazol-5'-yl) -methyl-methyl-1-de-thia-1-oxa-3-cephem-4 To a solution of the benzhydryl carboxylic acid ester in 10 ml of deuterochloroform is added, in a few hours, 4 equivalents of triphenylphosphite-chlorine complex (prepared in the usual manner) and 4 equivalents of pyridine. Large amounts of the complex and pyridine are probably due to impurities in the parent oxacephem derivative. The salts and impurities are precipitated with carbon tetrachloride and then with diethyl ether, and the solvent is distilled off to give an oily product. The NMR spectrum of the oil obtained from the diethyl ether extract shows that the title compound is contaminated with triphenyl phosphate.

Nuclear Magnetic Resonance Spectrum (deuterochloroform): δ = 2.25 (s,

3H), 3.53 (s, 3H), 3.65 (s, 3H), 4.16 (s, 2H), 4.53 (broad s, 2H), and 5.16 (s, 1H, C). -6-one).

Example 31

7-phenylacetamido-3-chloromethyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester

To a solution of triphenylphosphite (2.89 mL, 11 mmol) in dichloromethane (50 mL) was added chlorine gas at -15 ° C until a yellow color indicating excess chlorine appeared, and this yellow color was removed by the addition of 2 drops of triphenylphosphite. To the triphenylphosphite-chlorine reagent solution thus obtained is added 4.54 g (10 mmol) of 7-phenylacetamido-3-hydroxy-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester and A solution of 0.89 ml (11 mmol) of pyridine in 8 ml of dichloromethane was added dropwise over 40 minutes. During the addition of the pyridine solution, the temperature of the mixture was maintained at -15 to -10 ° C, stirred at this temperature for an additional hour, and the cooling bath was removed. The resulting small amount of iminochloride was quenched by the addition of 1 mL of concentrated hydrochloric acid, and the mixture was stirred for half an hour and the precipitated crystalline product was filtered off. This gave 2.67 g (54.7%) of the title compound as a white crystalline solid, m.p. 214 ° C (dec.). The filtrate was concentrated under reduced pressure to a volume of about 50 mL to give a second generation of the title compound, 1.52 g (31.1% yield). Total yield: 85.8%.

Nuclear Magnetic Resonance Spectrum (hexadeuterosulfoxide) δ = 3.62 (s, 2H), 3.94 (ABq, 2H, J = 18 Hz), 5.3 (d, 1H, J = 5 Hz), δ, 52 (s, 2H), 5.82 (q, 1H, J = 5 Hz and 8 Hz), and 7.2-8.4 (ArH).

Analysis calculated for C ₂₂ H ₁₈ N ₃ O ₆ SCI: C, 54.16; H, 3.72; N, 8.61; Cl, 7.27; S, 6.57. Found: C, 53.91; H, 3.92; N, 8.44; Cl, 7.27; S, 6.55.

Example 32

Phenoxyacetamido-3-chloro-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester

From 6.31 ml of triphenylphosphite and chlorine in 45 ml of dichloromethane at -15 ° C, the kinetic product of triphenylphosphite-chlorine is prepared as described in Example 31 and added at -15 to 10 ° C. 24 g (10 mmol) of 7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester are washed with 5 ml of dichloromethane. A solution of pyridine (1.01 ml, 12.5 mmol) in dichloromethane (8 ml) was added dropwise over half an hour. After stirring for 2 hours at -10 ° C, 1 ml of concentrated hydrochloric acid was added. After stirring for a further half hour, the mixture was washed with water (3 x 100 ml), dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The resulting oil was crystallized from ethanol (100 mL) to give 4.19 g (83.2%) of the title compound, mp 142.5-146 ° C.

Nuclear Magnetic Resonance Spectrum (deuterochloroform) δ = 3.7 (ABq, 2H, J = 18Hz), 4.60 (s, 2H), 5.12 (d, 1H, J = 5Hz), δ 4 (s, 2H), 5.93 (q, 1H, J = 5Hz and 9Hz), and 6.8-8.4 (ArH).

Analysis calculated for C ₂₂ H ₁₈ N ₃ O ₇ SCl: C, 52.44; H, 3.60; N, 8.34; S, 6.36. Cl, 7.04. Found: C, 52.67; H, 3.73; N, 8.12; S, 6.15; Cl, 6.95.

Example 33 Preparation of ^7- Phenoxyacetamido-3-chloro-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester using tris-o-tolylphosphite-chlorine complex

To a solution of 3.91 g (10 mmol) of tris (o-tolyl) phosphite in 45 ml of dichloromethane was introduced chlorine gas at a temperature of -10 ° C until the yellow vein was removed by the addition of about 0.5 mmol of phosphite. . To the resulting solution at -10 ° C was added 5.4 g (10 mmol) of 7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester and 5 ml. was washed with dichloromethane and 1.01 mL (12.5 mmol) of pyridine was added. The reaction mixture was stirred at -10 ° C for 1.5 hours and then concentrated hydrochloric acid (1 ml) was added. After stirring for a further half hour, it was washed with water (2 x 25 ml), diluted with 25 ml of dilute sodium chloride solution, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting oil was crystallized from 50 ml of ethanol to give 3.35 g (66.5%) of the title compound. The NMR spectrum of the product was identical to that obtained in Example 32.

Example 54

7-phenoxy-acetamido-3-chloro-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester

4) Chlorination without the use of a base.

From triphenylphosphite (2.89 mL) in dichloromethane at -10 ° C, a triphenylphosphite-chloro reagent was prepared as described in Example 31. To this solution was added 4.86 g (10 mmol) of 7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester and the mixture was stirred for 10 hours at -10 ° C. Stirring is carried out at 0 ° C. Comparative TLC21

-20186303 indicates that the chlorination was carried out at about 50% during these 2 hours and that a small amount of iminochloride was present.

B) Using 2,6-lutidine as the base.

To the reaction mixture obtained in (A) above is added 1.2 ml (10.5 mmol) of 2,6-lutidine. The mixture was stirred at -10 ° C for 1 hour and then concentrated hydrochloric acid (1 ml) was added. The cooling bath was removed, and after stirring for another half hour, the mixture was washed with water (2 x 100 mL), diluted with sodium chloride (100 mL), dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting oil was crystallized from ethanol (75 mL). 3.83 g (76%) of the title compound are obtained, m.p. 124-126 ° C.

Example 35

7-Amino-3-chloro-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester hydrochloride

A) In dichloromethane all in a solvent using pyridine as the base

To a solution of triphenylphosphite (6.31 mL, 25 mmol) in dichloromethane (45 mL) was added chlorine gas to a persistent yellow color at -10 ° C and the yellow color was removed by addition of a few drops of triphenylphosphite. To a solution of the triphenylphosphite chlorine reagent thus obtained at -15 ° C was added 4.86 g (10 mmol) of 7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid (p-nitrobenzyl). ester and a solution of pyridine (2.02 mL, 12.5 mmol) in dichloromethane (8 mL) was added dropwise over 40 min. The mixture was stirred for half an hour at -10 ° C and 9.25 ml (100 mmol) of isobutanol were added. The cooling bath was then removed and hydrogen chloride gas was added to the mixture for about half a minute. After about 5 minutes the product begins to crystallize. The mixture is stirred for 2 hours at about 20 ° C and the product is filtered off. Yield: 3.33 g (82%) of the title ester hydrochloride, m.p. 181 DEG C. (dec.).

Nuclear Magnetic Resonance Spectrum (hexadeutero-dimethylsulfoxide) δ = 4.06 (bs, 2H), 5.33 (q, 2H, J = 4.5 Hz, β-lactam-H), 5.5 (s) , 2H), 7.8-8.3 (ArH) and 8.6 (very broad s, -NH2).

B) In 1,2-dichloroethane as the solvent, using pyridine as the base

All were carried out as in Example A above, except that 1,2-dichloroethane was used as solvent instead of dichloromethane. A total of 3.10 (yield: 76.4%) of the title ester hydrochloride was obtained.

C) In dichloromethane as a solvent using quinoline as base

All were carried out as described in A above, except that quinoline was used as the base instead of pyridine. This gives a total of 3.2 g (79.8% yield) of the title compound, m.p. 181 C (dec).

D) Dichloromethane as solvent using isoquinoline as base

All were carried out as described in A above, except that isoquinoline was used as the base instead of pyridine. This reaction mixture is noticeably darker in color than the above. This gave 2.29 g (56.4%) of the title compound, m.p. 181 DEG C. (dec.).

E) Dichloromethane as solvent using Ν, Ν-dimethylaniline as base

All of the procedures described in part A) of this example were repeated except that Ν, Ν-dimethylaniline was used as the base instead of pyridine. 0.91 g (22.4%) of the title compound are obtained, m.p. 182 DEG C. (dec.).

F) In acetonitrile as the solvent using pyridine as base

To a solution of triphenylphosphite (7.9 mL, 30 mmol) in acetonitrile (45 mL) was added chlorine gas at -10 ° C. As the mixture solidifies, allow to warm to 10 ° C and add more chlorine gas to the yellow color remaining in the thawed mixture. The yellow color of the solution was removed by addition of triphenylphosphite (0.1 mL); In this way, about 30.4 mmol of triphenylphosphite-chlorine kinetic complex is formed. To this solution was added 5.4 g (10 mmol) of 7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester and then at 0 to 10 ° C for half an hour. a solution of 2.42 ml (30 mmol) of pyridine in 8 ml of acetonitrile was added dropwise. After stirring for an additional hour, the cooling bath was removed and the mixture was stirred for an additional 1.5 hours. 9.25 ml (100 mmol) of isobutanol are then added and after 1.5 hours the precipitated crystalline material is filtered off. 0.95 g (23.4%) of the title ester hydrochloride is obtained, m.p. 186 ° C (dec.).

G) Starting from 7-Phenylacetamido-3-hydroxy-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester

From triphenyl phosphite and chlorine (2.89 ml, 11 mmol) in 45 ml of dichloromethane, a kinetic complex of triphenylphosphite-chlorine is prepared as described in (A) above. To the solution of the complex was added 2.3 g (5 mmol) of 7-phenylacetamido-3-hydroxy-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester and at -15 to -10 ° C, A solution of 0.89 ml (11 mmol) of pyridine in 5 ml of dichloromethane is added dropwise over a quarter hour. The mixture was stirred at -15 to -10 ° C for 1.5 hours, then the cooling bath was removed and isobutanol (6 mL, 64.8 mmol) was added. Further stirring for one hour while the temperature of the mixture rises to 23 ° C, the product crystallizes. The precipitate was filtered off to give 1.59 g (78.3%) of the ester hydrochloride as a white crystalline solid, m.p. 188 DEG C. (dec.).

-21186303

H) with the help of tris (o-tolyl) phosphite-chlorine kinetic complex

To a solution of 9.24 g (26 mmol) of tris (o-tolyl) phosphite in 45 ml of dichloromethane is added chlorine gas at -10 DEG C. to a yellow solid which is then reacted with additional 0.5 mmol of phosphite. To the resulting solution was added 5.44 g (10 mmol) of 7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester and washed with 5 ml of dichloromethane. Subsequently, a solution of 2.58 ml (32 mmol) of pyridine in 8 ml of dichloromethane was added dropwise at -10 ° C over half an hour. After stirring for half an hour at -10 ° C, isobutanol (9.25 mL, 100 mmol) was added. The cooling bath was removed and hydrogen chloride gas was added to the reaction mixture for about 1 minute. After stirring at room temperature for 1.5 hours, the precipitated product is filtered off. Yield: 3.31 g (81.5%) of the title ester hydrochloride, m.p. 183 ° C (dec.).

Example 36

7- (1'-Chloro-2'-phenoxyethylidene) imino-3-chloro-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester

The procedure described in Example 35 (A) was followed except that propylene oxide (4.2 ml) was added to the reaction mixture instead of isobutanol and stirred at 0 ° C for a quarter hour. The mixture was then washed with 50 ml of ice water, dried over calcium chloride dihydrate and the solvent was distilled off under reduced pressure. Adding diethyl ether (a few drops of propylene oxide) to a dark colored syrup-like substance (21 g) gave a small amount of tar. After adding 5 ml of dichloromethane, the solution is decanted from the precipitated black tar weighing about 1 g.

The solvent was distilled off under reduced pressure, the residue was triturated three times with 25 ml of diethyl ether and 25 ml of hexane, the solvent mixture was discarded and the resulting semi-solid product was stored in a refrigerator for several days. Triturate with diethyl ether; 1.08 g of a solid is obtained, which according to NMR analysis is 7-phenoxyacetamido-3-chloro-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester. The solvent was removed from the diethyl ether filtrate by evaporation under reduced pressure, the resulting foam was dissolved in dichloromethane (a few ml), diluted with a little diethyl ether, and alcohol (a few drops of propylene oxide) added. The title iminochloride crystallizes out of solution. Weight: 0.24 g, m.p. 97-98 ° C.

The structure of the product is confirmed by its NMR spectrum.

Nuclear Magnetic Resonance Spectrum (deuterochloroform, pentadeuteropyridine) δ = 3.56 (ABq, 2H, J = 18 Hz), 4.8 (s, 2H), 5.03 (d, 1H, J = 5 Hz) ), 5.3 (s, 2H), 5.53 (d, 1H, J = 5Hz), and 6.9-8.3 (ArH).

Example 37

7-Amino-3-chloro-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester hydrochloride

A) Prepare about 25.5 mmol of triphenylphosphite chlorine reagent by adding excess chlorine gas to a solution of 6.31 mL (24 millinol) triphenylphosphite in 45 mL of dichloromethane at -10 ° C and the color was removed by the addition of about 1.5 µmol triphenylphosphite. To this solution was added 5.24 g (10 mmol) of 7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester and washed with 5 ml of dichloromethane. A solution of pyridine (2.02 mL, 25 mmol) in dichloromethane (8 mL) was added dropwise at -10 to -15 ° C for 25 min, and isobutanol (9.25 mL, 100 mmol) was added. Immediately thereafter, the cooling bath was removed and hydrogen chloride gas was added to the reaction mixture for about half a minute. The mixture was inoculated and stirred at 20 ° C for about 2 hours. The precipitated product is filtered off to give 3.49 g (yield, 86%) of the title ester hydrochloride as a white crystalline solid, m.p. 179-180 ° C (dec.).

B. All the procedures described in A above in this example are followed except that 3.61 ml of 1,3-propanediol are used instead of isobutanol. This gave a total of 3.25 g (80% yield) of the title compound, m.p. 182 ° C (dec.).

38-50. example

Following the general procedure described in Example 31, using the following starting compounds and the specified phosphite-halogen complexes, the following compounds were prepared:

Example 38

Starting material: 7-Phenylacetamido-3-hydroxy-3-cephe: n-4-carboxylic acid (2 ', 2', 2'-trichloroethyl) ester.

Product: 7-Phenylacetamido-3-chloro-3-cephem-4-carboxylic acid (2 ', 2', 2'-trichloroethyl) ester.

Reagent: triphenylphosphite-chlorine complex.

Example 39

Starting material: Benzhydryl of 7-formamido-3-hydroxy-3-cephem-4-carboxylic acid.

Product: Benzhydryl of 7-formamido-3-bromo-3-cephem-4-carboxylic acid.

Reagent: triphenylphosphite-bromine complex.

Example 40

Starting material: 7-acetamido-3-hydroxy-3-cephem-4-carboxylic acid (tert-butyl) ester,

Product: 7-Acetamido-3-chloro-3-cephem-4-carboxylic acid (tert-butyl) ester.

Reagent: tris (p-methoxyphenyl) phosphite-chlorine complex.

Example 41

Starting material: 7-Benzamido-3-hydroxy-3-cephem-4-carboxylic acid (p-methoxybenzyl) ester.

-22186303

Product: 7-Benzamido-3-chloro-3-cephem-4-carboxylic acid (p-methoxybenzyl) ester.

Reagent: Tris (o-tolyl) phosphite-chlorine complex.

Example 42

Starting material: 7-Phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid (2'-iodoethyl) ester.

Product: 7-Phenoxyacetamido-3-chloro-3-cephem-4-carboxylic acid (2'-iodoethyl) ester.

Reagent: triphenylphosphite-chlorine complex.

Example 43

Starting material: 7-methoxy-7-phenylacetamido-3-hydroxy-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester.

Product: 7-Methoxy-7-phenylacetamido-3-bromo-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester.

Reagent: triphenylphosphite-bromine complex.

Example 44

Starting material: 2-Phenylpropionamido-3-hydroxy-3-cephem-4-carboxylic acid (p-chlorophenacyl) ester.

Product: 2-Phenylpropionamido-3-chloro-3-cephem-4-carboxylic acid (p-chlorophenacyl) ester.

Reagent: Tris (p-ethylphenyl) phosphite-chlorine complex.

Example 45

Starting material: 7-Methoxy-7- (2'-thienyl) -acetamido-34-hydroxy-3-cephem-4-carboxylic acid benzyl ester.

Product: 7-Methoxy-7- (2'-thienyl) -acetamido-3-chloro-3-cephem-4-carboxylic acid benzyl ester.

Reagent: triphenylphosphite-chlorine complex.

Example 46

Starting material: 7- (tetrazol-5'-yl) -acetamido-3-hydroxy-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester.

Product: 7- (Tetrazol-5'-yl) -acetamido-3-chloro-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester.

Reagent: Tris (2-ethoxyphenyl) phosphite-chlorine complex.

Example 47

Starting material: 7- [2 '- (tert-butoxycarbonylamino) -2'-phenyl] -acetamido-3-hydroxy-3-cephem-4-carboxylic acid (pivaloyloxymethyl) ester.

Product: 7- [2 '- (tert-butoxycarbonylamino) -2'-phenyl] -acetamido-3-bromo-3-cephem-4-carboxylic acid (pivaloyloxymethyl) ester.

Reagent: tris (p-propylphenyl) phosphite-bromine complex.

Example 48

Starting material: 7- [2 '- (p-nitrobenzyloxycarbonylamino) -2'-phenyl] -acetamido-3-hydroxy-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester .

Product: 7- [2 '- (p-nitrobenzyloxycarbonylamino) -2'-phenyl] -acetamido-3-chloro-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester.

Reagent: triphenylphosphite-chlorine complex.

Example 49

Starting material: 7- (2'-chloroacetamido-thiazol-5'-yl) -acetamido-3-hydroxy-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester.

Product: 7- (2'-Chloroacetamido-thiazol-5'-yl) -acetamido-3-chloro-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester.

Reagent: Tris (o-tolyl) phosphite-chlorine complex.

Example 50

Starting material: 7-Chloroacetamido-3-hydroxy-3-cephem-4-carboxylic acid (2 ', 2', 2'-trichloroethyl) ester.

Product: 7-Chloroacetamido-3-bromo-3-cephem-4-carboxylic acid (2 ', 2', 2'-trichloroethyl) ester.

Reagent: triphenylphosphite-bromine complex.

51-59. example

By following the procedure described in Example 35 (A), 7-amino-3-chloro-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester hydrochloride is prepared from the corresponding 3-hydroxycephem derivatives as shown below. , with the aid of the triaryl phosphite-chlorine complex prepared from the indicated triaryl phosphite and chlorine.

Example 51

7-Formamido-3-hydroxy-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester, triphenylphosphite.

Example 52

7-Phenylacetamido-3-hydroxy-3-cephem-4-carboxylic acid (p'-nitrobenzyl) ester, tris (o-tolyl) phosphite.

Example 53

7- (2'-Thienyl) acetamido-3-hydroxy-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester, triphenylphosphite.

Example 54

7-Phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester, triphenylphosphite.

Example 55

7-Benzamido-3-hydroxy-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester, triphenylphosphite.

Example 56

7-Phenylmercaptoacetamido-3-hydroxy-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester, tris (o-tolyl) phosphite.

-23186303

Example 57

7- [2 '- (tert-Butoxycarbonyl-amino) -2'-phenyl] -acetamido-3-hydroxy-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester, triphenylphosphite.

Example 58

7-Phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester, tris (p-methoxyphenyl) phosphite.

Example 59

7-Phenylacetamido-3-hydroxy-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester, tris (p-tolyl) phosphite.

60-67. example

By following the procedure described in Example 35 (A), the following starting materials are converted to the corresponding products using a kinetic complex of the following triaryl phosphite and chlorine or bromine.

Example 60

Starting material: 7-phenylacetamido-3-hydroxy-3-cephem-4-carboxylic acid (tert-butyl) ester,

Product: 7-amino-3-chloro-3-cephem-4-carboxylic acid (tert-butyl) ester,

Phosphite: triphenylphosphite.

Example 61

Starting material: 7-methoxy-7-phenoxyacetamidno-3-hydroxy-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester.

Product: 7-Methoxy-7-amino-3-chloro-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester.

Phosphite: triphenylphosphite.

Example 62

Starting material: 7-Acetamido-3-hydroxy-3-cephem-4-carboxylic acid (2 ', 2', 2'-trichloroethyl) ester.

Product: 7-Amino-3-bromo-3-cephem-4-carboxylic acid (2 ', 2', 2 '-trichloroethyl) ester.

Phosphite: tris (o-tolyl) phosphite.

Example 63

Starting material: 7- (p-chlorophenoxy) acetamido-3-hydroxy-3-cephem-4-carboxylic acid benzyl ester.

Product: 7-Amino-3-chloro-3-cephem-4-carboxylic acid benzyl ester.

Phosphite: tris (p-ethoxyphenyl) phosphite.

Example 64

Starting material: 7-methoxy-7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid benzhydryl ester.

Product: 7-Methoxy-7-amino-3-chloro-3-cephem-4-carboxylic acid benzhydryl ester.

Phosphite: triphenylphosphite.

Example 65

Starting material: 7- (m-nitrobenzamido) -3-hydroxy-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester.

Product: 7-amino-3-bromo-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester.

Phosphite: triphenylphosphite.

Example 66

Starting material: 7- (2'-Formyloxy-2'-phenyl) -acetamido-3-hydroxy-3-cephem-4-carboxylic acid (p-methoxybenzyl) ester.

Product: 7-amino-3-chloro-3-cephem-4-carboxylic acid (p-m; toxic-benzyl) ester.

Phosphite: tris (m-tolyl) phosphite.

Example 67

Starting material: 7- (2'-Thienyl) acetamido-3-hydroxy-3-eephem-4-carboxylic acid (p-nitrobenzyl) ester.

Product: 7-amino-3-bromo-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester.

Phosphite: triphenylphosphite.

68-75. example

Using the general method described in Example 36, the following starting materials are converted to the corresponding products using a kinetic complex of the following triaryl phosphites and chlorine or bromine.

Example 68

Starting material: 7-methoxy-7-benzamido-3-hydroxy-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester.

Product: 7-Methoxy-7- (alpha-chlorobenzylidene) amino-3-chloro-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester.

Phosphite: triphenylphosphite.

Example 69

Starting material: 7-Phenylacetamido-3-hydroxy-3-cephem-4-carboxylic acid benzyl ester.

Product: 7- (1'-Chloro-2'-phenylethylidene) imino-3-chloro-3-cephem-carboxylic acid benzyl ester.

Phosphite: tris (o-tolyl) phosphite.

Example 70

Starting material: 7- (2'-Thienyl) acetamido-3-hydroxy-3-eephem-4-carboxylic acid (2 ', 2', 2'-trichloroethyl) ester.

-24186303

Product: 7- [1'-Chloro-2 '- (2-thienyl) ethylidene] imino-3-chloro-3-cephem-4-carboxylic acid (2', 2 ', 2'-trichloroethyl) -ester.

Phosphite: triphenylphosphite.

Example 71

Starting material. 7-acetamido-3-hydroxy-3-cephem-4- (p-methoxybenzyl) ester.

Product: 7- (1'-Chloroethylidene) imino-3-chloro-3-cephem-4-carboxylic acid (p-methoxybenzyl) ester.

Phosphite: triphenylphosphite.

Example 72

Starting material: 7-Phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester.

Product: 7- (1'-Bromo-2'-phenoxyethylidene) imino-3-bromo-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester.

Phosphite: triphenylphosphite.

Example 73

Starting material: 7- (2'-chloroacetoxy-2'-phenyl) -acetamido-3-hydroxy-3-cephem-4-carboxylic acid (tert-butyl) ester.

Product: 7- (1'-Chloro-2'-chloroacetoxy-2'-phenylethylidene) imino-3-chloro-3-cephem-4-carboxylic acid (tert-butyl) ester.

Phosphite: tris (o-methoxyphenyl) phosphite.

Example 74

Starting material: 7- (p-chlorobenzamido) -3-hydroxy-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester.

Product: 7- (p, α-dichlorobenzylidene) imino-3-chloro-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester.

Phosphite: triphenylphosphite.

Example 75

Starting material: 7-Phenylacetamido-3-hydroxy-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester.

Product: 7- (1'-Bromo-2'-phenylethylidene) imino-3-bromo-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester.

Example 76

Preparation of 7-Phenoxyacetamido-3-bromo-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester using triphenylphosphite-bromine complex

To a solution of bromine (2.30 mL, 4.5 mmol) in anhydrous dichloromethane (90 mL) was added triphenylphosphite (12.22 mL, 46.6 mmol) at -70 ° C. After the addition of phosphite, the color of bromine disappears. To the resulting solution was added 10.6 g (20 mmol) of 7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester and washed with 10 ml of dichloromethane.

The reaction mixture was then warmed to -35 to -30 ° C and a solution of 3.64 mL (45 mmol) of pyridine in 16 mL of dichloromethane was added dropwise over 35 minutes; and the mixture was stirred for an additional 4 hours. Then 50 ml of ice water was added and stirred for half an hour. Three layers of liquid are formed. The middle dichloromethane layer was washed with water (50 mL), brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residual oily product (29.7 g) was treated with 150 ml of methanol to crystallize. After drying, 3.78 g of the title compound are obtained, m.p. 138-139 ° C.

Nuclear Magnetic Resonance Spectrum (hexadeutero-dimethylsulfoxide) δ = 4.0 (AB _q , C ₂ -H), 4.65 (s, 2H, methylene group of the side chain), 5.28 (d, 1H, J = 5 Hz) ), 5.47 (s, 2H, methylene group of the ester), 5.8 (q, 1H, J = 5 Hz) and 6.9-8.4 (ArH),

Example 77

7- (1'-Chloro-2'-phenylethylidene) imino-7-methoxy-3-acetoxymethyl-3-cephem-4-carboxylic acid benzyl ester

To a solution of triphenylphosphite-chlorine complex (12.3 mmol) from triphenylphosphite and chlorine in 45 mL of dichloromethane at -15 ° C in the presence of 0.1 mL of pyridine is added 5.11 g (10 mmol) of 7-phenylacetamido- 7-Methoxy-3-acetoxymethyl-3-cephem-4-carboxylic acid benzyl ester is added dropwise over a period of 10 minutes in a solution of 1.01 ml (12.5 mmol) pyridine in 4 ml dichloromethane. The mixture was stirred at -15 to -10 ° C for 50 min, then propylene oxide (2.1 mL, 30 mmol) was added and stirred at 0 ° C for a further 10 min. The mixture was washed with ice water (25 ml), dried over calcium chloride and the solvent was distilled off under reduced pressure. The resulting syrup-like material (11 g) was triturated three times with carbon tetrachloride and dissolved in diethyl ether (50 mL). The diethyl ether solution was decanted from the insoluble precipitate (about 0.5 g) and concentrated under reduced pressure to about 25 ml. To the concentrated solution was added 25 mL of hexane to give an oily product. This oily product was washed twice with hexane: diethyl ether (1: 1), twice with carbon tetrachloride and the carbon tetrachloride was distilled off under reduced pressure. This gave 2.5 g of the title compound as a foam.

Infrared spectrum (chloroform): 1780 and 1730 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (deuterochloroform, pentadeuteropyridine) δ = 1.96 (s, 3H), 3.3 (ABq), 3.43 (s, 2H), 3.93 (s, 2H), δ , 86 (ABq), 4.93 (s, 1H), 5.25 (s, 1H) and 7.3 (ArH).

Example 78

Preparation of 7-Amino-3-chloro-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester hydrochloride using the kinetic complex of tris (p-chlorophenyl) · phosphite-chlorine

To a solution of 10.34 g of tris (p-chlorophenyl) phosphite and 0.53 ml (6.5 mmol) of pyridine in 50 ml of dichloromethane are added 15 ml of dichloromethane solution at -70 ° C, and 0.52 ml of pentene for binding excess chlorine. To a solution of the tris (p-chlorophenyl) phosphite-chlorine complex obtained above was added 5.28 g of 7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid (p-nitro-25186303).

benzyl) ester and then washed with dichloromethane (10 mL). A solution of pyridine (1.57 mL, 19.5 mmol) in dichloromethane (9 mL) was added dropwise over 35 min and the mixture was stirred for a further 2 h. The mixture was allowed to warm to 2 ° C, 6.94 ml of isobutanol was added and hydrogen chloride gas was added for 2 minutes. The solvent was evaporated under reduced pressure, ethyl acetate (50 mL) was added to the resulting syrup and the resulting sticky material was triturated with methanol (100 mL). Tris (p-chlorophenyl) phosphate precipitated as a white solid was filtered off and the filtrate was evaporated under reduced pressure. To the residue were added 7.5 mL of toluene, 7.5 mL of ethyl acetate, and the minimum amount of methanol needed to dissolve the sticky insolubles. After about 5 minutes, the title compound begins to precipitate out of solution as a white crystalline solid. 0.97 g of the title compound is obtained, m.p. 184-186 ° C (dec.).

Example 79

7-Phenylacetamido-3-methylene-cepham-4-carboxylic acid (p-nitrobenzyl) ester is introduced into dichloromethane at -20 [deg.] C. and 10 ml of triphenylphosphite is added at a rate such that during the addition, the mixture is constantly dominated by the yellow color of excess chlorine and the temperature of the mixture is -20 to 25 ° C. After addition, 3 ml of pentene is added and the resulting solution of triphenylphosphite-chlorine complex is stored at -30 ° C.

To a 5 ml portion of the solution of the complex obtained as described above was added 0.5 ml of pentene and 500 mg of 7-phenylacetamido-3-methylene-cepham-4-carboxylic acid (p-nitrobenzyl) ester 1-oxide, and the mixture was stirred at 10 ° C for 45 minutes. Methanol (2 ml) was added and the solvent was distilled off under reduced pressure. The residue was triturated with diethyl ether and the solid was filtered off. 410 mg of the title compound are obtained.

In this example and in paragraphs 80-86 below. The NMR data for the products obtained as described in Examples 1 to 8 are shown in Example II after Example 86. table.

Example 80

7-phenoxyacetamido-3-methylenecepham-4-carboxylic acid (p-nitrobenzyl) ester

The reduction was carried out in the same manner as in Example 79 and starting from 500 mg of 7-phenoxyacetamido-3-methylene-cepham-4-carboxylic acid (p-nitrobenzyl) ester 1-oxide, 370 mg of the title compound were obtained. .

Example 81

7-Phenoxyacetamido-3-chloro-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester

The reduction was carried out in the same manner as in Example 79, and starting from 500 mg of 7-phenoxyacetamido-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester 1-oxide, 310 mg of the title compound were obtained.

Example 82. (2'-Thienyl) acetamido-3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester

The reduction was carried out in the same manner as in Example 79 and 500 mg of 7- (2'-thienyl) acetamido-3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester 1-oxide. 260 ml of the title compound are obtained.

Example 83

7-heptanoyl-amino-3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester

The reduction was carried out in all the manner described in Example 79 and starting from 500 mg of the title compound of 500 mg of 7-heptanoylamino-3-methyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester 1-oxide. compound was obtained.

Example 84

7- (2'-Thienyl) acetamido-3-methyl-3-cephem-4-carboxylic acid (p-methoxy-benzyl) ester

The reduction was carried out in the same manner as in Example 79 and 500 mg of 7- (2'-thienyl) acetamido-3-methyl-3-eephem-4-carboxylic acid (p-methoxybenzyl) ester 1-oxide. Starting with 470 mg of the title compound.

Example 85

7- (2'-Thienyl) acetamido-3-methyl-3-cephem-4-carboxylic acid benzyl ester

Using the general reduction method described in Example 79 and 300 mg of 7- (2'-thiethyl) acetamido-3-methyl-3-cephem-4-carboxylic acid benzyl ester 1-oxide as described in Example 79. A solution of the resulting triphenylphosphite-chlorine complex in 3 mL of volume was reduced with 0.3 mL of pentene to give 240 mL of the title compound.

Example 86

7-phenoxyacetamido-3-methylenecepham-4-carboxylic acid (2 ', 2', 2'-trichloroethyl) ester

Following the general reduction method described in Example 79, 300 mg of 7-phenoxyacetamido-3-methylene-cepham-4-carboxylic acid (2 ', 2', 2'-trichloroethyl) ester 1-oxide were obtained. Reduction of a solution of triphenylphosphite-chlorine complex obtained in the same manner as in Example 79 in a volume of 3 ml with 0.3 ml of pentene afforded 80 mg of the title compound.

-26186303

II. spreadsheet

79-86. NMR (S-values) of the products obtained as described in Examples 1 to 4 in deuterochloroform

Example number C 2 H C 6 H C-7 NH ester CH2 side chain-CH 79th 3.60 5.27 5.50 9.13 5.45 3.60 80th 3.53 -5.3 - 5.35 9.07 -5.4 4.63 81st 3.93 5.30 5.83 9.18 5.26 3.78 82nd 3.60 5.15 5.73 9.05 5.45 3.83 83rd 3.55 5.12 5.68 8.67 5.45 84th 5.50 5.07 5.63 9.05 5.18 3.78 85th 3.50 5.07 5.63 9.13 5.26 3.78 86th 3.63 -5.3 -5.5 9.13 5.02 4.63

Example 87

Preparation of 7-Phenoxyacetamido-3-methylene-cepham-4-carboxylic acid (p-nitrobenzyl) ester using a stabilized triphenylphosphite-chlorine complex

Nuclear Magnetic Resonance Spectrum (deuterochlorochloroform): δ = 2.05 (s, 3H, CH2 COOH), 3.67 (bs, 2H), 4.53 (s, 2H), 5.01 (d, 1H, J = 4 Hz), 5.31 (ABq, 2H), 5.65 (q, 1H, J = 4 Hz and 9 Hz), and 6.8-8.4 (ArH).

To a solution of pyridine (0.8 ml, 10 mmol) in dichloromethane (150 ml) was added chlorine gas at -20 ° C, and a dropwise addition of triphenylphosphite (20 ml) at a rate such that the pale yellow color of the excess chlorine prevailed. maintaining the temperature of the mixture at -20 ° C. To this stabilized solution of the triphenylphosphite-chlor complex is added 8 ml of pentane and 19.13 g of 7-phenoxyacelamido-3-methylene-cepham-4-carboxylic acid (p-nitrobenzyl) ester-1 oxide, and the mixture was stirred at -15 to -20 ° C for about 1 hour. After allowing to warm to room temperature, the solvent was distilled off under reduced pressure and the resulting syrupy material was crystallized by addition of 40 ml of methanol. The methanol mixture was stirred for half an hour and then the product was filtered off. 11.58 g of the title compound of structure are obtained

This is confirmed by a comparison of its NMR spectrum with that of an authentic sample.

Example 88

7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester

The triphenylphosphite-chlorine complex is prepared by adding chlorine gas and 6.1 ml triphenylphosphite simultaneously to 45 ml of methylene chloride at -15 ° C and adding further triphenylphosphite until the iodine starch reaction is negative. . 3 ml of pentene and 10.6 g of 7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester 1-oxide are added to the final reagent solution and the mixture is stirred for 40 minutes. and stirred for 15 minutes at -15 ° C. The reaction mixture was allowed to warm to room temperature and the unreacted starting material was filtered off (5.08 g). The filtrate was concentrated under reduced pressure to a volume of about 35 ml, cooled to 0 ° C, and acetic acid (10 ml) was added. The product was filtered off to give 1.81 g of the title compound in two generations in the form of its acetic acid solvate.

Example 89

7-phenoxy-acetamido-3-chloro-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester

Starting from 17.1 ml of triphenylphosphite and following the procedure described in Example 88, 70 ml of dichloromethane at -20 ° C are used to prepare triphenylphosphite-chlorine complex. To the final solution was added pentene (2.2 mL) followed by 10.6 g of 7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester 1-oxide. The temperature of the reaction mixture rises to -8 ° C. After stirring for 45 minutes, a solution of pyridine (3 ml) in dichloromethane (15 ml) was added dropwise over 70 minutes, followed by stirring at -10 to -15 ° C for an additional 45 minutes. The mixture was then concentrated to a volume of about 35 mL and 10 mL of ethanol was added. Further concentration and addition of a few ml of acetic acid causes the product to crystallize. The precipitate was filtered off to give a total of 3.2 g of the title compound in two generations. The structure of the product is confirmed by comparing its NMR spectrum with that of an authentic sample.

Example 90

7-Amino-3-chloro-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester hydrochloride

A triphenylphosphite-chlorine kinetic complex is prepared by introducing chlorine gas into 150 ml of dichloromethane at a temperature of about -10 ° C to about -20 [deg.] C. and simultaneously dropping 36.8 ml (based on 22.3 g of starting cefem sulfoxide). (5 equivalents) of triphenylphosphite, the addition is carried out while the mixture is constantly dominated by excess yellow chlorine. After the addition of the last drops of triphenylphosphite, the test gives a negative result when tested with chlorine for iodine. The mixture was cooled to -25 ° C, 5.1 pen-27186303 was added, followed by 22.3 g of 7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid (p-nitrobenzyl). ester-l-oxide. After stirring at -15 to -10 ° C for 1 minute, a solution of 11 ml (3.4 equivalents of starting cephem sulphoxide) in pyridine (30 ml) in dichloromethane was added dropwise over 53 minutes, and the mixture was stirred for an additional quarter hour. 37 ml (10 equivalents) of isobutanol are then added and hydrogen chloride gas is added for 6 minutes. The product which crystallizes out of the solution is filtered off, washed with 100 ml of dichloromethane and dried under reduced pressure. 6.4 g (37%) of the title compound are obtained.

Nuclear Magnetic Resonance Spectrum (hexadeutero-dimethylsulfoxide): δ = 4.06 (bs, 2H), 5.33 (q, 2H, J = 4.5 Hz, beta-lac10 support-H), 5.5 (s, 2H), 7.8-8.3 (ArH) and 8.6 (very broad s, -NH ₃ +).

91-134. example

In order to optimize the conditions of the reaction described in Example 90, the reaction described therein was extensively studied, the results of which are shown in Example III. is shown in Table. In these experiments, the general procedure described in Example 90 was followed, starting from the same cephem sulphoxide in each case, the amount of starting material (22.3 g), the amount of dichloromethane used to dissolve the pyridine (30 ml) and the amount of isobutanol used. 37 ml) was the same in each experiment.

III. spreadsheet

91-134. example data

Example number triphenyl phosphite-chlorine complex The amount, equivalent * Reagent- solution volume, ml Start of addition of pyridine solution, minute*· Pentene, ml, equivalent * Initial amount of dichloromethane, ml Duration of administration of the pyridine solution, minute Volume of pyridine, ml, equivalent Adjusted yield, gram,% 90th 3.5 36.8 25 5.1; 1.2 150 53 11.0; 3.4 6.40; 37.0 91st 4.5 47.3 55 5.1; 1.2 150 99 13.6; 4.2 12.42; 71.6 92nd 4.0 42.1 40 5.1; 1.2 150 76 12.3; 3.8 13.06; 76.4 93rd 4.5 47.3 25 5.1; 1.2 150 53 13.6; 4.2 12.94; 75.7 94th 3.5 36.8 55 5.1; 1.2 150 99 13.6; 4.2 9.48; 55.9 95th 4.5 47.3 55 5.1; 1.2 150 99 11.0; 3.4 12.13; 70.6 96th 3.5 36.8 55 5.1; 1.2 150 53 13.6; 4.2 7.73; 44.8 97th 4.0 42.1 40 5.1; 1.2 150 122 12.3; 3.8 13.32; 78.3 98th 3.5 36.8 25 5.1; 1.2 150 53 13.6; 4.2 9.52; 55.1 99th 4.0 42.1 40 5.1; 1.2 150 76 9.7; 3.0 5.43; 31.7 100th 4.0 42.1 10 5.1; 1.2 150 76 12.3; 3.8 13.58; 79.2 One hundred and first 4.5 47.3 55 5.1; 1.2 150 53 11.0; 3.4 11.65; 68.6 102nd 3.5 36.8 55 5.1; 1.2 150 53 11.0; 3.4 10.37; 61.2 103rd 4.0 42.1 40 5.1; 1.2 150 76 12.3; 3.8 12.24; 70.8 104th 4.5 47.3 25 5.1; 1.2 150 99 13.6; 4.2 12.35; 73.3 105th 4.0 42.1 40 5.1; 1.2 150 76 12.3; 3.8 12.85; 75.5 106th 4.0 42.1 40 5.1; 1.2 150 76 14.9; 4.6 12.36; 71.4 107th 3.0 31.6 40 5.1; 1.2 150 76 12.3; 3.8 -; 5 ~ 108th 3.5 36.8 55 5.1; 1.2 150 99 11.0; 3.4 9.15; 54.2 109th 3.5 36.8 21 5.1; 1.2 150 99 13.6; 4.2 7.69; 44.7 110th 4.0 42.1 40 5.1; 1.2 150 76 12.3; 3.8 12.18; 72.1 111th 5.0 52.7 40 5.1; 1.2 150 76 12.3; 3.8 13.48; 78.8 112th 4.0 42.1 70 5.1; 1.2 150 76 12.3; 3.8 12.93; 75.6 113th 4.5 47.3 55 5.1; 1.2 150 53 13.6; 4.2 13.25; 77.2 114th 4.5 47.3 25 5.1; 1.2 150 53 11.0; 3.4 12.66; 73.6 115th 4.5 47.3 25 5.1; 1.2 150 99 11.0; 3.4 11.45; 66.3 116th 3.5 36.8 25 5.1; 1.2 150 99 11.0; 3.4 10.70; 61.8 117th 4.0 42.1 40 5.1; 1.2 150 30 12.3; 3.8 12.42; 72.2 118th 4.0 42.1 0 5.1; 1.2 150 76 12.3; 3.8 13.16; 76.5 119th 4.0 42.1 40 0 150 76 12.3; 3.8 0; 0 120th 4.0 42.1 10 5.1; 1.2 150 76 9.0; 2.8 3.32; 18.3 121st 4.0 42.1 40 5.1; 1.2 100 76 12.3; 3.8 12.68; 72.3 122nd 4.0 42.1 10 5.1; 1.2 150 76 12.3; 3.8 8.2; 48.4 123rd 4.0 42.1 10 6.4; 1.5 150 76 12.3; 3.8 13.33; 78.6 124th 4.0 42.1 10 6.4; 1.5 150 76 12.3; 3.8 13.90; 81.0 125th 4.0 42.1 10 8.5; 2.0 200 76 12.3; 3.8 13.19; 75.4 126th 4.0 42.1 10 5.1; 1.2 150 76 12.3; 3.8 14.4; 83.1 127th 4.0 42.1 10 6.4; 1.5 150 40 12.3; 3.8 13.16; 75.7 128th 4.2 44.5 10 6.4; 1.5 150 76 12.3; 3.8 13.54; 81.6 129th 4.2 44.5 10 6.4; 1.5 200 40 12.3; 3.8 11.05; 65.0 130th 4.2 44.5 10 6.4; 1.5 200 60 12.3; 3.8 14.09; 82.8

-28186303

III. Continue Table

Example number triphenyl phosphite-chlorine complex The amount, equivalent * Reagent- solution volume, ml Start of addition of pyridine solution, minute** Amount of pentane, ml, equivalent * Initial amount of dichloromethane, ml Duration of administration of the pyridine solution, minute Volume of pyridine, ml, equivalent Adjusted yield in grams,% 131st 4.2 44.5 10 6.4; 1.5 200 60 12.3; 3.8 14.00; 81.7 132nd 4.4 46.3 10 6.4; 1.5 200 60 12.3; 3.8 14,16 133rd 4.4 46.3 10 6.4; 1.5 200 60 12.3; 3.8 14.35 134th 4.2 44.5 10 6.4; 1.5 200 60 12.3; 3.8 13.77

* Number of equivalents calculated for the starting cephem sulfoxide. * * From the addition of cefem sulfoxide.

Example 135

7-Amino-3-chloro-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester from triphenylphosphite and chlorine in 100 mL of dichloromethane was prepared as described in Example 90, triphenylphosphite-chloro complex, 5.28 ml of cyclopentene (3.0 equivalents relative to the starting cephem sulphoxide) are added to the final reagent solution at -10 to -15 ° C, followed by 11.15 g of 7-phenoxyacetamido-3-hydroxy-3 cephem-4-carboxylic acid (p-nitrobenzyl) ester-1-oxide. Thereafter, a solution of pyridine (6.2 ml) in dichloroethane (6.2 ml) was added dropwise over 1 hour at -10 to -15 ° C, and 18.5 ml of isobutanol were added and hydrogen chloride gas was added thereto for about 3 minutes. The mixture was allowed to warm to room temperature and after stirring for 2 hours the precipitated product was filtered off. This gave the title compound in 80.4% yield.

136-139. example

All of the procedures described in Example 135 were followed except that different halogen scavengers were used in each example.

The results are shown in Table IV. Table.

ARC. spreadsheet

135-139. example data

Example number The halogen scavenger Yield, % name The amount, ml 135 cyclopentene 5.28 80.4 136 cyclohexene 6.08 72.8 137 cycloheptene 7.1 78.2 138 1,5-cyclooctadiene 7.4 73.4 139 m-dimethoxybenzene 7.9 60.5

* 3.0 equivalents based on starting cephem sulfoxide

Example 140

Preparation of 7-Amino-3-chloro-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester hydrochloride in acetonitrile as solvent

A) Following the general procedure of Example 90, triphenylphosphite-chlorine complex is prepared from 23 ml of triphenylphosphite in 100 ml of acetonitrile as a solvent. To the resulting solution was added 11.15 g of 7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester 1-oxide, and 6.2 ml of pyridine acetonitrile was added dropwise thereto. solution. 18.5 ml of isobutanol are then added, and hydrochloric acid gas is added while the temperature of the mixture rises to 40 ° C. The mixture is cooled to about 25 ° C in an ice bath and the product begins to crystallize out of the mixture when cooled to below 28 ° C. In this way, the title compound was obtained in a yield of 46.5%.

B) In the same manner as in Example A above, except that 100 ml of tetrahydrofuran is used as solvent, about 25 ml of dichloromethane are added to the final reaction mixture after the addition of isobutanol and hydrogen chloride gas. The title compound was obtained in 35.1% yield.

Example 141

Preparation of 7-Amino-3-chloro-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester at room temperature

To a solution of pyridine (0.93 ml) in dichloromethane (100 ml) was added chlorine gas at 21-25 ° C, and at the same time 22.9 ml of triphenylphosphite was added at such a rate that a greenish-yellow color of chlorine was observed throughout the addition. To this solution of triphenyl-55-phosphite-chlorine complex was added 4.2 ml of pentane followed by 11.2 g of 7-phenoxyacetamido-3-chloro-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester. l oxide. The temperature of the mixture then rises to about 30 ° C. After cooling to 22 ° C, a solution of 5.3 ml of pyridine in 15 ml of dichloromethane is added dropwise over an hour. One quarter hour after completion of the pyridine addition, 18.5 ml of isobutanol are added and then 5 minutes of hydrochloric acid gas are added. After 2 hours, the precipitated product is filtered off to give 5.69 g of the title compound.

-29186303

Example 142

7-Amino-3-methylenecepham-4-carboxylic acid (p-nitrobenzyl) ester hydrochloride

31.6 ml of triphenylphosphite and chlorine were prepared as described in Example 90, followed by the addition of 5.1 ml of pentane and 19.13 g of 7-phenoxyacetamido-3-methylene-cepham-4-carboxylic acid. - (p-nitrobenzyl) ester-l-oxide. After stirring for half an hour, a solution of pyridine (6.3 ml) in dichloromethane (16 ml) was added dropwise (a further 1 hour), and a further solution of pyridine (3.1 ml) in dichloromethane (8 ml) was added. After stirring for a further quarter hour, 37 ml of isobutanol were added, and hydrochloric acid gas was added for 6 minutes. After 2 hours, the precipitated product was filtered off to give 10.5 g (69.5%) of the title compound.

Nuclear Magnetic Resonance Spectrum (hexadeuterodimethylsulfoxide) δ = 3.67 (bs, 2H), 5.0 (d, 1H, J = 5Hz), 5.35-5.53 (m, 6H) and 7.6-8.4 (m, ArH).

Example 143

Preparation of 7-Phenoxyacetamido-3-methylene-cepham-4-carboxylic acid (p-nitrobenzyl) ester using triphenylphosphite-bromo kinetic complex

A) The triphenylphosphite-bromine complex is prepared by adding 19.9 ml of triphenylphosphite to a solution of 3.9 ml of bromine in 150 ml of dichloromethane at -30 ° C. The mixture remains slightly colored even when it is no longer possible to detect bromine in the iodine-starch reaction. To this solution at -45 ° C was added 8 ml of pentene followed by 19.14 g of 7-phenoxyacetamido-3-methylene-cepham-4-carboxylic acid (p-nitrobenzyl) ester 1-oxide. TLC showed the reduction to occur within 20 minutes. The mixture was allowed to warm to room temperature and concentrated under reduced pressure to a volume of about 40 ml. Methanol (40 mL) was added to the concentrated solution, and the product began to crystallize within half a minute. The product was filtered off to give 14.06 g (76.8%) of the title compound, which confirmed its structure by NMR.

B. All of the procedures described in A above above are repeated except that the solution of triphenylphosphite-bromine complex is cooled to -60 ° C before the addition of pentene and 3-methylene cepham sulfoxide. The reaction is carried out at a temperature of -40 ° C to 45 ° C, at which time the reduction takes place within 1 hour. This gives a total of 14.06 g of the title compound.

144-153. example

Using the general procedure of Example 79 and using the triaryl phosphite halide complexes set forth below, the following cephalosporin sulfoxides are reduced.

Example 144

7-Formamido-3-acetoxymethyl-cephem-4-carboxylic acid benzhydryl ester 1-oxide; triphenylphosphite-chlorine complex

Example 145

7- [2 '- (2-thienyl) acetamido] -3-chloro-3-cephem-4-carboxylic acid (p-methoxy-benzyl) ester-l-oxide; triphenylphosphite-bromine complex.

Example 146

7-Chloro-acetamido-3-bromomethyl-3-cephem-4-carboxylic acid (2 ', 2', 2'-trichloroethyl) ester-l-oxide; tris (p-methoxyphenyl) phosphite-chlorine complex.

Example 147

7-Benzamido-3-methyl-3-cephem-4-carboxylic acid benzyl ether 1-oxide; triphenylphosphite-chlorine complex.

Example 148

7-phenoxyacetamido-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester-l-oxide; triphenylphosphite-chlorine complex.

Example 149 ⁷ - [2 '- (2-Furyl) -2'-methoxyimino] -acetamido-3- (1'-methyltetrazol-5'-yl) mercapto-methyl-3-cephem-4 carbonyl tert-butyl ester 1-oxide; triphenylphosphite-chlorine complex.

Example 150

7- (2'-Formyloxy-2'-phenyl) -acetamido-3- (1'-methyl-tetrazol-5'-yl) -mercapto-methyl-3-cephem-4-carboxylic acid benzhydryl ester-1- oxide; tris (p-chlorophenyl) phosphite-chlorine complex.

Example 151

7- (p-Nitrobenzyloxycarbonyl) amino-3-methoxymethyl-3-cephem-4-carboxylic acid (p-nitrobenzyl) ester 1-oxide; tris (o-tolyl) phosphite-chlorine complex or triphenylphosphite-bromine complex.

Example 152

7-phenylacetamido-3-acetyl-mercaptomethyl-3-cephem-4-carboxylic acid (p-methoxy-benzyl) ester-l-oxide; triphenylphosphite-chlorine complex.

-30186303

Example 153

7- [2 '- (2-Thienyl) acetamido] -3-methoxycarbonyl-3-cephem-4-carboxylic acid benzhydryl ester 1-oxide; tris (p-methoxyphenyl) phosphite-bromine complex.

154-163. example

144-153. In Example 1, the cephalosporin sulfoxides used as starting materials are first converted to the corresponding cephalosporinimino halides, then to the corresponding 7-aminocephalosporin esters, using the corresponding triaryl phosphite halide complexes and alcoholization of the imino halides with isobutanol, 1,2-propanediol or 1,3-propanediol.

163-172. example

Using the general procedure described in Example 90, the 7-acylamino-3-hydroxy-cephalosporin sulfoxide esters of the following table were converted to the corresponding 7-amino-3-chloro by using the reagents listed in the following table. cephalosporin esters.

Example number R r ₇ Triaryl-fi isphite Solvent Base Alcohol 163rd p-nitrobenzyl benzyl triphenylphosphite dichloromethane pyridine isobutanol 164th benzhydryl methyl tris (o-tolyl) - -phosphite 1,2-dichloroethane quinoline 1,2-propanediol 165th 2,2,2-trichloro- -ethyl hydrogen triphenylphosphite 1,2-dichloroethane triphenyl amine 1,3-propanediol 166th p-nitrobenzyl 2-thienylmethyl tris (p-Cl phenyl) phosphite dichloromethane N, N-diethyl- -aniline 2-methyl-n- butanol 167th benzyl benzyl tris (p-methoxy- phenyl) phosphite 1,2-dichloroethane pyridine 1,2-butanediol 168th pivalate methyl phenoxymethyl triphenylphosphite chlorobenzene isoquinoline isobutanol 169th t p-chlorophenyl mercaptomethyl tris (o-tolyl) - -phosphite dichloromethane DBU 1,2-propanediol 170th p-nitrobenzyl a-formyloxy benzyl triphenylphosphite 1,2-dichloroethane pyridine 1,3-butanediol 171st phenacyl phenoxymethyl tris (p-methoxy- phenyl) phosphite l, l-dibromo-2- chloro-ethane 2,6-lutidine isobutanol 172nd benzhydryl a-benzhidríloxi- benzyloxy carbonyl triphenylphosphite dichloromethane pyridine isobutanol

Example 173 Claims

Claims (34)

7- (2'-Thienylacetamido) -3-methyl-3-cephem-4-carboxylic acid In dichloromethane, as a solvent, a triphenylphosphite-chlorine complex is prepared by adding 10 ml of triphenylphosphite to 75 ml of dichloromethane containing excess chlorine at -20 to -35 ° C and binding the excess chlorine with 3 ml of pentene. To a 30 ml portion of the solution obtained above (12.9 mmol) triphenylphosphite-chlorine complex at 0 ° C was added 0.5 ml of pentene and 0.90 g (2.2 mmol) of 7- (2'-thienyl) acetamido) -3-methyl-3-cephem-4-carboxylic acid 1-oxide is added, which is dissolved after stirring for 5 minutes at 0-5 ° C. After stirring for a further 20 minutes, a precipitate formed, 0.1 ml of water was added, followed by 50 ml of diethyl ether after 5 minutes of stirring, the precipitate was filtered off and dried at 120 mmHg and 45 ° C for 2 days. 0.5 g of the title sulfide are obtained. Nuclear Magnetic Resonance Spectrum (hexadeutero-dimethylsulfoxide) δ = 8.21 (d, J = 8Hz, NH), 7.38 (m), 6.96 (d, J = 4Hz), 5.67 ( d, d, J = 5 Hz and 8 Hz, H ₇ ), 4.81 (d, J = 5 Hz, H _u ), 3.82 (s), 3.60 (AB, H ₂ ), 2, 03 (s, methyl). A process for the preparation of cephem and penam carboxylic acid derivatives of formula XXIV wherein R _{8 is} sulfur or oxygen, R, hydrogen or methoxy, R is hydrogen, lower alkyl optionally substituted by halogen, or substituted by one or two phenyl optionally substituted by nitro, C 1-4 alkoxy or lower alkanoyloxy, or phenacyl by halogen, preferably benzyl, 4 benzyl, benzhydryl or 2,2,2-trichloroethyl, R ₉ is a group of formula (t) or (u) wherein R _{7 is} phenyl, phenoxymethyl, thienylmethyl or benzyl, X is a chlorine or bromine atom, and an amino group in the form of -NR ₂ R 1 formamido, acetamido, heptanoylamido, benzamido, phenylacetamido, phenoxyacetamido, phenylthioacetamido, thienylacetamido or hydrochloride, Y is a group of formula (a), (b), (c) or (f), wherein -31186303 Chlorine or bromine, methyl, C 1-4 alkoxy, hydroxy or C 1-4 alkanoyloxy, and B is a C 2 -C 4 alkanoyloxy group characterized in that it is a penam, cefam or cephem carboxylic acid derivative of the formula XXV wherein R 1, R and -NR ₂ R ₃ are as defined above, Rg is sulfur, oxygen or sulfoxide, Y is a group of formula (a), (b ')> (c) or (f) wherein A' is chloro or bromo, methyl, C 1-4 alkoxy, optionally protected hydroxy or C 1-4 alkanoyloxy and B is a C 2-4 alkanoyloxy group, At a temperature of 30 ° C or less, optionally in the presence of a tertiary amine base, with a triaryl phosphite halide complex of formula (XIII): X is chlorine or bromine, and Z is hydrogen or halogen, C1-C4 alkyl or C1-C4 alkoxy, which is a molar equivalent of a triaryl phosphite derivative of formula XII and chlorine or bromine in an aromatic hydrocarbon or halogenated hydrocarbon solvent of -70 to 0; Kinetically controlled product of the reaction at 0 ° C. 2. The process of claim 1, wherein the acylamino-substituted penam derivative at position 6 or the cephem derivative at position 7 is reacted with a triphenylphosphite-chlorine complex. 3. A process according to claim 1 or 2 wherein the halogenating agent is present in an amount of from 1.1 equivalents to 1.2 equivalents relative to the starting 6-acylaminopenam derivative or 7-acylaminocephem derivative. 4. A process according to any one of claims 1 to 3, wherein the reaction is carried out in the presence of an equivalent amount of tertiary amine base calculated on the halogenating agent used. The process of claim 1, wherein the compound of formula (XXIV) is a narrow group of compounds of formula (III) wherein: X is chlorine or bromine, R is a group as defined in claim 1, but other than hydrogen, and R 1 and R ₂ R ₃ N- are as defined in claim 1 for the preparation of compounds of formula (IV) wherein R 1, R 1, R ₂ and -NR ₂ R ₃ are in the range of 1.0 to 1.3 equivalents of the above compound in a substantially anhydrous, inert organic solvent at a temperature of 30 ° C or less, wherein X is chlorine or bromine, and Z is a hydrogen or halogen atom, a C 1-4 alkyl group or a C 1-4 alkoxy group with a triaryl phosphite halogen complex, which is a triaryl phosphite halogen complex of the formula (XII) wherein Z is a triaryl phosphite and a reaction product of an equivalent chlorine or bromine in a substantially anhydrous, inert organic solvent under kinetic control. A process for the preparation of a compound according to claim 5, wherein: X is chlorine, and R, R 1 and —NR ₂ R ₃ are as defined in claim 5, which is? characterized in that a compound of formula IV wherein R, R 1 and -NR ₂ R ₃ are as defined in claim 5 is reacted with a triphenylphosphite-chlorine complex. 7. A process for the preparation of a process according to claim 5 for the preparation of imino halides of the general formula (XXIV) wherein: X is chlorine or bromine, R₁ is hydrogen or methoxy, and R ₇ represents phenyl, phenoxymethyl, 2-thienylmethyl or benzyl, wherein the formula (VI), where R, R and _R7 are as defined above, compound in the presence of 1.0 to 1.2 equivalents of the tertiary amine base calculated on the halogenating agent employed, in an essentially anhydrous, inert organic solvent at a temperature of 30 ° C or less, of 2.0 to 3.0 equivalents, wherein X is chlorine or bromine and Z is hydrogen or halogen, (C 1 -C 4) alkyl or (C 1 -C 4) alkoxy, with a triaryl phosphite-halogen complex which is of the general formula (XII) , where Z is the kinetic age of triaryl phosphite and equivalent chlorine or bromine in a substantially anhydrous, inert organic solvent reaction product. A process for the preparation of a process according to claim 7 for the preparation of imino halides of the general formula (XXIV), wherein X is chlorine, and R, R 1 and R ₇ are as defined in claim 7, wherein R 1, R 1 and R ₇ are as defined in claim 7, in an amount of 2.0 to 3.0 equivalents of triphenyl. reaction with a phosphite-chlorine complex. 9. A process according to claim 7 or claim 8 wherein 2.2 to 2.4 equivalents of halogenating agent are used. 10. A process according to any one of claims 1 to 4, wherein the reaction is carried out in the presence of 1.0 to 1.2 equivalents of tertiary amine base per halogenating agent. 11. A process according to claim 10 wherein the equivalent of tertiary amine base is 1.0 equivalent per halogenating agent. 12. A process according to any one of claims 1 to 4, wherein the tertiary amine base used has a pK _b (dissociation constant) of from 6 to 10. The process of claim 1, wherein the cephem is of formula (XXV) -32186303 for the conversion of cefam sulfoxide - wherein R _{8 is a} sulfoxide group and R 1, -NR ₂ R ₃ , R and Y are as defined in claim 1, with the corresponding cephem derivative of formula (XXIV) wherein R _{8 is} sulfur and R, R _t , R ₉ and Y as defined in claim 1, wherein the sulfoxide of formula (XXV) is present in an essentially anhydrous, inert organic solvent at a temperature of 30 ° C or lower in the presence of at least one equivalent of a halogen scavenger. 1.3 equivalents of the general formula (XIII) wherein X is chlorine or bromine, and Z is a hydrogen or halogen atom, a C 1-4 alkyl group or a C 1-4 alkoxy group with a triaryl phosphite-halogen complex, which is a triaryl phosphite-halogen complex of the general formula (XII) wherein Z is the above, triaryl phosphite and the reaction product of an equivalent chlorine or bromine in a substantially anhydrous, inert organic solvent under kinetic control. 14. The process of claim 13, wherein the cephem or cefam sulfoxide is reacted with 1.0 to 1.3 equivalents of triphenylphosphite-chlorine of formula XIII, wherein X is chlorine and Z is hydrogen. as defined in claim 13. 15th embodiment The method according to claim 13 and 14, characterized in that (VII) starting from the formula 3-cephem-szulfoxidbóI or 3-exomethylene-cepham sulfoxide, wherein -NR ₂ R _3, r and R 1 is as defined in claim 1 and Y is (b '), (c) or (f). 16. The process according to claim 1, wherein the compound of formula (XXIV) is a narrow group of compounds of formula (III), wherein X is chlorine or bromine, and R, R 1 and -NR ₂ R ₃ are as defined in claim 1 for the preparation of a compound of formula (VIII) wherein R, R 1 and -NR ₂ R ₃ are as defined above, in an amount of at least one equivalent. in the presence of a halogen scavenger, in a substantially anhydrous, inert organic solvent at a temperature of 30 ° C or less, in an amount of about 2 to 3 equivalents of the formula (XIII), wherein X is chlorine or bromine, and Z is hydrogen or halogen, C 1-4 alkyl or C 1-4 alkoxy, with a triaryl phosphite halogen complex, which is a triaryl phosphite halogen complex of formula (XII) wherein Z is as defined above, the reaction product of phosphite with an equivalent chlorine or bromine in a substantially anhydrous, inert organic solvent under kinetic control. The process of claim 16 for the preparation of compounds of formula (III) wherein: X is chlorine, and R, R 1 and -NR ₂ R ₃ are as defined in claim 16, characterized in that a compound of formula (VIII) wherein R, R 1 and -NR ₂ R ₃ are as defined in claim 16 34 is triphenylphosphite. reaction with a chlorine complex. 18. The process according to claim 16 or 17, wherein the reaction is carried out in the presence of 1-2 equivalents of tertiary amine base. 19. The process of claim 1 for the preparation of a cephemimino chloride of formula (IX), which is a narrower group of compounds of formula (XXIV), wherein: X is chlorine, and R, R 1, R ₇ and Y are as defined in claim 1, characterized in that one of the following general formula (X) wherein R, R 1, R ₇ and Y are as defined in claim 1, is 7-acylaminocepham or - cephem sulfoxide is reacted with triphenyl phosphite-chlorine complex. A process for the preparation of a process according to claim 1 for the preparation of a 3-chloro-cephem-iminochloride of the general formula (XXIV), which is a narrower class of compounds X is chlorine, and R 1, R 1 and R ₇ are as defined in claim 1, characterized in that one of the following general formula (XI): R, R 1 and R ₇ are as defined in claim 1, in the amount of 7-acylamino-3-hydroxy-cephem-sulfoxide in 3-5 equivalents of formula (XIII) - wherein Z is chlorine and X ₂ is reacted with a triphenylphosphite-chlorine complex as defined in claim 1. 21. A process according to claim 20 wherein the amount of triaryl phosphite halide complex is 4-5 equivalents and tertiary amine base 3.5 equivalents based on the starting cephem derivative. 22. The process of claim 21 wherein 4.4 equivalents of triphenylphosphite-chlorine complex and 3.8 equivalents of pyridine are used relative to the starting cephem derivative. 23, pp. 13-22. A process according to any one of claims 1 to 4, wherein the halogen scavenger is a pseudo- ring having 2 to 10 carbon atoms, a cycloalkene having 5 to 8 membered rings, a diene having 4 to 8 carbon atoms, a cyclodeene having 2 to 6 or a compound of general formula (XIV) wherein R ₄ is an alkyl group of up to 4 carbon atoms or an alkanoyl group of 2 to 5 carbon atoms, and R 1 and R _b are each independently hydrogen, an alkoxy group of up to 4 carbon atoms, an alkanoyl group of from 2 to 5 carbon atoms, or an alkyl group of up to 4 carbon atoms, a phenol derivative that is readily halogenated. 24. The process of claim 23 wherein the halogen scavenger is a pendant containing from 2 to 6 carbon atoms. 25. A process according to any one of claims 1 to 3, wherein the reaction is carried out at a temperature of -50 ° C to 30 ° C. The method of claim 20, which is an embodiment -33186303, characterized in that the reaction is carried out at a temperature of -30 ° C to 0 ° C. 27. A process according to any one of claims 1, 5, 7, 13 and 16 wherein the starting materials of formulas (III), (V), (IX) and (XIII) are used, where X is bromine, and R 1, -NR ₂ R ₃ and Y, and Z and X _{2 are} as defined in claim 1. 28. The process of claim 27 wherein the starting materials of formula XIII are used wherein Z is hydrogen and X _{2 is} as defined in claim 1. 29. A process according to any one of claims 1, 5, 7, 13 and 16 wherein the starting materials of formulas III, V, IX and XIII are used. , wherein X is chlorine and R 1, -NR ₂ R ₃ and Y, and Z and X _{2 are} as defined in claim 1. 30. A process according to any one of claims 1 to 3, characterized in that the triaryl phosphite-halogen complex is stabilized with a tertiary amine base. 31. Figures 1-4, 7-12, 18-20. A process according to any one of claims 1 to 3 and 30 wherein the tertiary amine base has a pK _b (dissociation constant) of from about 6 to about 10. 32. The process of claim 30 or 31 wherein the tertiary amine base is pyridine. 33. Process according to any one of claims 1 to 3, characterized in that the inert organic solvent is an aromatic hydrocarbon or a halogenated hydrocarbon. 34. The process according to claim 33, wherein the inert organic solvent is dichloromethane. 35. A process according to any one of claims 1 to 3, characterized in that the triphenylphosphite-chloro complex (XXIII) is used as a reagent, (a) has a ³¹ P NMR signal in dichloromethane, negative at -3.7 ppm with respect to phosphoric acid, (b) having an infrared spectrum in the dichloromethane solution having the following characteristic absorption bands: 1120-1190 (very strong), 1070 (very strong), 1010 (very strong), 990 (very strong), 640 (medium), 625 (medium), 580 (weak), 510 (strong), and 465 (weak) cm ' ¹ , (c) which, when reacted with water, gives hydrochloric acid and triphenyl phosphate; and d) reacting with n-butanol to give hydrochloric acid, n-butyl chloride and triphenylphosphate.