CS692A3 - Process for preparing 3-exomethylenecephamsulfoxide ester - Google Patents

Description

1

Method of preparation

C-TL.

Technical field

The present invention relates to a process for the preparation of intermediates for β-lactam antibiotics. In particular, the invention relates to an improved process for the preparation of 7-substituted amino-3-exome thylene derivatives with thiosulfoxides.

BACKGROUND OF THE INVENTION 3-Ex, methylene-sulfamsulfoxide esters are prepared by a known two-step process which involves converting a penicillin sulfoxidarter to chlorosulfinylazetidinone and then cyclizing it to the 3-exomethylencephamsulfoxide ester. The ilinsulfoxide ester is converted to the intermediate by the chlorosulfinylazetidinone N-chloro halogenating agent as described in U.S. Pat. No. 4 165315 / Kukolja.RTM. 4-Chlorosulfinylase-tidinone intermediates are disclosed in U.S. Pat. No. 4 081440 / Kukolja / " No. 4,075,203 (Ohou) describes a process for preparing 3-exo-methylencephamsulfoxide ester by converting penicillin sulfoxide in step 1 to 4-chlorosulfinylazetidinone with an N-chloroacid reagent in the presence of alkylene oxide and calcium oxide. U.S. Pat. No. 4,289,695 (Chou) discloses an improved process for the preparation of 3-exomethylenecepham sulfoxide ester by the use of an acid-treated cross-linked polyvinylpyridine polymer in Step 1. U.S. Pat. No. 4,052,387 (Kuklja) describes the cyclization of 4-chlorosulfinylazetidinones using Friedel- A Lewis acid type Crafts catalyst, a Friedel-Crafts catalyst of the Bronsted acid type or a metathetic cation former. U.S. Pat. No. 4 190724 (Chou) discloses an improved process which includes the Kukoly cyclization with a Friedel-Craftscatalyst of 4-chlorosulfinylazetidinone in the presence of oxo compounds such as ethers, ketones or phosphine oxides. Oopp et al., U.S. Pat. No. 4,950,753, discloses a longer improvement in the Kukol method of preparation, which involves carrying out Friedel-Grafts cyclization in the presence of an oxo compound according to the invention (and an unsaturated compound, e.g. 1-hexene or 2-hexene, unconjugated alkadiene such as 1,4-hexadiene, cycloalkene such as cyclohexene, allene, or non-conjugated cycloalkadiene such as 1,4-cyclohexadiene. is performing a Friedel-Crafts cyclization in the presence of a nitro compound such as nitromethane, nitrobenzene, nitroethane and nitrobenzene.

SUMMARY OF THE INVENTION

By the method of the preparation of 3-exomethylenecepham sulfoxide ester of formula I

(1) wherein A is an amino protecting group or a general formula R - C-

cde represents R the carboxylic acid residue and Rj represents a carboxylic acid protecting group according to the invention, that the chlorosulfinylazetidinone of the general formula XI 0 → 1 S - Cl.

COOR / 11/1 - 3 - in an inert solvent under substantially anhydrous conditions with a leucis kayselinae type catalyst and a nitro compound at a sufficient temperature to produce a compound of formula I. The following description is illustrated by the accompanying drawings: FIG. a diagram illustrating the reaction rates of cyclization of 4-chlorosulfinylazetidinones under various conditions, and Fig. 2 is a diagram for comparing the reaction rates of Fig. 1. In the process of the invention, the chlorosulfinylazetidinone is reacted in an inert solvent with a Lewis acid type Friedel-Craft catalyst to form a complex with chlorosulfinylazetidinone, in the presence of a nitro compound. In a preferred embodiment, the forward-Craftscatalyst is tin tetrachloride and the nitro compound is nitro-methane, the reaction being carried out in the presence of an oxo compound, for example an ether, a ketone or a phosphine oxide and an alkene, cycloalkene, allene or cyclodiene. 3 - Exomethylenesulfamsulfoxide ester product; is obtained in improved yields, generally in the range of 2 to <% of the isolated product and at improved reaction rates.

According to the process of the present invention, a 3-exomethylenecephamoxide ester (I) of the above general formula (I) is prepared, wherein the symbols are as defined above. The term " carboxylic acid residue &quot; refers to the 7-position of the side chains in the cephalosporin and carbocephalosporin chemistry and the chemiipenicillin in the 6-position side chain. Generally, the side chains are C 1 -C 20 radicals, wherein R in these carboxyl radicals is hydrogen, C 1-6 alkyl, C 1-6 alkyl substituted with cyano, carboxy, halogen, amino, C 1-4 alkoxy, C 1-4 alkylthio, trifluoromethyl or a trifluoromethylthio group, a phenyl group or a substituted phenyl group of the formula

where it means a; and * independently of one another hydrogen, halogen, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkanoyloxy, C 1 -C 4 alkylthio, amino, C 1 -C 4 alkanoylamino; (C až-C uhlíku alkyl) alkylsulfones, carboxy, carbamoyl, hydroxymethyl, aminomethyl, carboxymethyl, (C až-C halogen) haloalkyl or (C až-C per) perhaloalkyl; wherein - aaa * is as defined above and wherein Z is an oxygen atom or a sulfur atom and 0 or 1, an arylmethyl group of the formula H 3 - CH 3 - wherein R 1 is naphthyl, thienyl, furyl, benzothienyl, benzoaminothiazyl, benzofuryl, pyridyl, 4-pyridylthio, pyrimidyl, piridazinyl, indolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl u, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl and such aryl groups substituted by amino, hydroxy, halogen, C1-4 alkyl, C1-4 alkoxy, phenyl, substituted phenyl or C1-4 alkylsulfonylamino carbon; or is a substituted methyl group of the general - 5 - formula

R 1 - CH -4 I

Q wherein R 1 is cyclohex-1,4-dienyl, phenyl or substituted phenyl

where a and a are as defined above, or R 1 is as defined for R 6 and Q is hydroxy, C 1 -C 4 alkanoxy, carboxy, sulpho, amino, sulphamo or substituted amino R x O

It is -NH-C-N-C-Ry where R x represents a hydrogen atom or a C1-C3 alkyl group, a C1-C4 alkyl group, a furyl group, a thienyl group, a phenyl group, a haloalkyl group , a nitrophenyl, a styrene, a halostyryl, a nitryryl, or a group of the formula

Rx i

- N - SS where Rx has. is as defined above and R 2 is hydrogen, C 1 -C 3 alkylsulfonyl, C 1 -C 3 alkyl or C 1 -C 4 alkanoyl, or Q is an amino group of the general formula 0

wherein R 1 is as defined above, and q is 2 or 3, or Q is a residual amino group of the formula

- (C 1 -C 4) alkyl or Q represents a benzamido group of the formula

wherein x is 1-3 or Q is pyridone or hydroxy substituted by pyridonylcarbonylamino

wherein Rx is as defined above, or Q is pyridylcarbonylamino

wherein the group is optionally substituted with an alkyl group having 1 to 4 carbon atoms, an amino group, a carboxy group, a hydroxy group or a halogen atom; or Q is imidazolyl or pyrazolyl - 7 -

or

N wherein such groups are optionally substituted by C 1 -C 4 alkyl, carboxy, amino or halogen, or Q is a benzpyridazin-4-one or tautomer of the formula or

wherein R x is as defined above and t is a benzpyranone group of formula

to 3; or Q

wherein H5 has the same meaning as defined above, R represents a hydrogen atom or a halogen atom such as R 1 or R 6 and R 8 represents a hydrogen atom, a C 1-8 alkyl group having 1 to 4 carbon atoms, a halogen substituted alkyl group, a carboxy-substituted cycloalkyl group of formula (b) / (c) where n is independently hydrogen or an alkyl group having from 1 to 3 carbon atoms, n is zero, 1, 2 or 3, where, together with the carbon atom they are bound to, they also form a three-membered to six-membered carbocyclic ring and R? is hydroxy, amino, C 1 -C 4 alkylamino or C 1 -C 4 dialkylamino or R 8 is C 1 -C 4 alkyl substituted by phenyl or phenyl substituted by one or two or more groups from the group; C 1 -C 4 alkyl, hydroxy, halo, carboxy or protected carboxy, or R is C 1 -C 4 alkyl substituted by amino or amino protected, or R 8 is C 1 -C 4 alkenyl, or R 8 is a cyclic lactam group of formula

Wherein R 2 is hydrogen or C 1 -C 3 alkyl or R 8 is an arylmethyl group of the general formula R 3 - CH 2 - wherein R 4 is as defined above. As used herein, the term "carboxy protecting group" is intended to mean one of the ester derivatives of the carboxylic acid group used regularly to block or protect the carboxylic acid group in reactions to other functional groups of the compound. for example, 4-nitrobenzyl, 4-methylbenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3; 4-methylenedioxybenzyl, benzhydryl, 4,4'-dimethoxybenzhydryl, 2,2 ', 4,4'-tetramethoxybenzhydryl, tert-butyl, tert-amyl, trityl, 4-methoxy trityl, 4,4'-dimethoxytrityl , 4,4 &apos;, 4 &apos; -trimethoxytrityl, 2-phenylprop-2-yl, trimethylsilyl, tert-butyldimethylsilyl, phenacyl, 2,2,2-tri-chloroethyl, di (n-butyl) methylsilyl. ethyl, p-toluenesulfonylethyl, 4-nitrobene zylsulfonylethyl, allyl, cinnamyl, 1- (trimethylsilylmethyl) prop-1-en-3-yl, and the like »A carboxy-protecting group is not critical so long as the derivatized group carboxylic acid is stable under the following reactions or reactions at other. in the ring system and if it can be removed at an appropriate stage without disrupting the other molecule. A preferred group protecting group carboxylic acids is an allyl group. Similar groups can also be used as used in chemistry of cephalosporins, penicillins and peptides to protect the carboxy group as an azetidinone substituent. Further examples of such groups are exemplified in E. Haslam, "Protective Groups in Organic Chemistry", J.G.W. McOmie Ed., Plenum Press, New York, N.Y. 1973, Chapter 5 and T.W. Greene, " Protective Groups in Organic Synthesis " / Organic System Protection (John Wiley &amp; Cons, New York, N.Y.). 1981, Chapter 5. The term "protected carboxy" is likewise equivalent to carboxy substituted with one of the above-mentioned carboxy protecting groups. The term " amino protecting group &quot; refers to amino substituents commonly used to protect and block the functional amino group upon reacting other functional groups of the compound. Examples of such protecting groups include the formyl, trityl and phthalimido groups. The term also includes amino protecting groups commonly used in the chemistry of cephalosporins, penicillins and peptides. Other examples of such groups are given, for example, in J.W. Bartoň "Protective Groups in Organic Chemistry", J.G.W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 2 and T.W. Greene "Protein in Groups in Organic Synthesis" (John Wiley &amp; Sons, New York, NY, 1981, chapter 7) &quot; Protected amino group &quot; In the context of the meanings of the symbols in formula I, the C1 -C6 alkyl group is a straight or branched chain alkyl group such as methyl, ethyl, n-propyl, isopropyl, n -butyl, tert-butyl, n-pentyl, n-hexyl, 3-methylpentyl, and like cyanomethyl, cyanoethyl, 4-cyanobutyl, as cyanomethyl, cyanoethyl, 4-cyanobutyl; C 1-6 alkyl substituted with carboxy means carboxymethyl, 2-carboxyethyl, 2-carboxypropyl, 4-carboxybutyl Halogen-substituted 5-carboxypentyl means chloromethyl, bromomethyl, 2-chloroethyl, 1-bromoethyl, 4-chlorobutyl, 4-bromopentyl, 6-chlorohexyl, 6-chloroethyl, 4-bromo-pentyl, 6-chloroethyl, 4-fluorobutyl, 3-fluoropropyl, fluoromethyl and the like; C 1-6 alkyl substituted by amino means 2-aminoethyl, aminomethyl, 3-aminopropyl and 4-aminobutyl; C1-C6alkyl substituted by C1-C4alkoxy means, for example, methoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, ethoxymethyl, 3-propoxy-propyl, 3-ethoxybutyl, 4-tert-butyloxybutyl, 3-methoxypentyl and 6-methoxyhexyl; C1 -C6 alkyl substituted with C1 -C4 alkylthio means, for example, methyl thiomethyl, 2-methylthioethyl, 2-ethylthiopropyl, 4-methylthiobutyl, 5-ethylthiohexyl, 3-tert-butylthio-propyl ; C1-6 alkyl substituted by trifluoromethyl means, for example, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl and 4,4,4-trifluorobutyl and alkyl of 1-6 trifluoromethylthio-substituted carbon atoms include, but are not limited to, trifluoromethylthiomethyl, 2-trifluoromethylthioethyl, 2-trifluoromethylthiopropyl, 4-trifluoromethylthiobutyl, 5-trifluoromethylthiohexyl, and the like.

When in formula (I) A represents a group of formula (O) 99 s - c - and R represents a substituted phenyl group, wherein the substituent is a substituent or is characterized by a and / or *, haloalphenyl for example 4-chlorophenyl, 3-bromophenyl, 2-fluorophenyl, 2,4-dichlorophenyl and 3,5-dichlorophenyl; further hydroxyphenyl, for example 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2,4-dihydroxyphenyl, 3,4-dihydroxyphenyl; further alkoxyphenyl, for example 2,6-dimethoxyphenyl, 4-methoxyphenyl, 3-ethoxyphenyl, 3,4-dimethoxyphenyl, 4-tert-butyloxyphenyl, 4-methoxy-3-ethoxyphenyl and 4-n-propoxyphenyl; furthermore alkanoyloxyphenyl, for example 2-acetoxyphenyl, 4-propionoxyphenyl, 4-formyloxyphenyl, 4-acetoxyphenyl, 3-butyryloxyphenyl and 3-acetoxyphenyl; in addition, the alkylphenyl group, for example, 4-methylphenyl, 2-methylphenyl, 2,4-dimethylphenyl, 3-tert-butylphenyl, 4-ethylphenyl, 4-ethyl-3-methylphenyl and 3,5-dimethylphenyl, pina; in addition, alkylthiophenyl, for example, 4-methylthiophenyl, 3-n-butylthiophenyl, 2-ethylthiophenyl, 3,4-dimethylthiophenyl, and 3-n-propylthiophenyl; 12 furthermore, an aminophenyl group such as 2-aminophenyl, 4-aminophenyl, 3,5-diaminophenyl and 3-aminophenyl; furthermore alkanoyl amino groups such as 2-acetylamino, 4-acetylamino, 3-propionylamino and 4-butyrylamino; in addition, alkylsulfonylamino, for example 3-methylsulfonylamino, 4-methylsulfonylamino, 3,5- (dimethylsulfonylamino) phenyl, 4-n-butylsulfonylaminophenyl and 3-ethylsulfonylaminophenyl; carboxyphenyl, for example 2-, 3-, or 4-carboxyphenyl, 3,4-dicarboxyphenyl and 2,4-dicarboxyphenyl; furthermore, carbamoylphenyl groups include 2-carbamoylphenyl, 2,4-dicarbamoylphenyl and 4-carbamoylphenyl; hydroxymethylphenyl, for example, 4-hydroxymethylphenyl and 2-hydroxymethylphenyl; aminomethylphenyl, for example 2-aminomethylphenyl and 3-aminomethylphenyl; and carboxymethylphenyl, for example 2-carboxymethylphenyl, 4-carboxymethylphenyl and 3,4-dicarboxymethylphenyl; furthermore, substituted phenyl groups having various substituents such as, for example, 4-chloro-3-methylphenyl, 4-fluoro-3-hydroxyphenyl, 3,5-dichloro-4-hydroxyphenyl, 4-hydroxy-3 -chlorophenyl, 4-hydroxy-3-methylphenyl, 4-ethyl-3-hydroxyphenyl, 4-methoxy-3-hydroxyphenyl, 4-tert-butyloxy-2-hydroxyphenyl, 4-acetylamino-3-methoxyphenyl , 3-amino-4-ethylphenyl, 2-aminomethyl-4-chlorophenyl, 2-hydroxymethyl-3-methoxyphenyl, 2-hydroxymethyl-4-fluorophenyl, 2-acetoxy-4-aminophenyl, 4-acetoxy-3 -methoxyphenyl, 3-isopropylthio-4-chlorophenyl, 2-methylthio-4-hydroxymethylphenyl, 4-carboxy-3-hydroxyphenyl, 4-ethoxy-3-hydroxyphenyl, 4-methylsulfonyl-amino-2-carboxyphenyl, 4-amino -3-chlorophenyl and 2-kax-methyl-4-hydroxyphenyl.

When E is a substituted phenyl group and a 'or a C 1 -C 4 haloalkyl or C 1 -C 4 perhaloalkyl group, chloromethyl, iodomethyl, trichloromethyl, trichloroethyl, 2- bromo-2-methylpropyl, chloropropyl and fluoromethyl. - 13

Examples of groups where R is a general formula group

where m is zero, phenylacetyl, 4-hydroxyphenylacetyl, 4-chlorophenylacetyl, 3,4-dichlorophenylacetyl, 4-methoxyphenylacetyl, 3-ethoxyphenylacetyl, 2-aminomethylphenylacetyl, 3-carboxyphenylacetyl, 4-acetoxyphenyl- acetyl, 3-aminophenylacetyl and 4-acetylamino-phenylacetyl; and, if m is 1 and Z is oxygen, the group is phenoxyacetyl, 4-chlorophenoxyacetyl, 4-fluoro-phenoxyacetyl, 3-aminophenoxyacetyl, 3-hydroxyphenoxyacetyl, 2-methoxyphenoxyacetyl, 2-methylthiophenoxyacetyl, 4-aceto- tylaminophenoxylation of tyl, 3,4-dimethylphenoxyacetyl and 3-hydroxymethylphenoxyacetyl; and in case m is 1 and Z is sulfur, for example, phenylthioacetyl, 4-chlorophenylthioacetyl, 3,4-dichlorophenylthioacetyl, 2-fluorophenylthioacetyl, 3-hydroxyphenylthioacetyl and 4-ethoxyphenylthioacetyl are mentioned.

Examples of R @ 1 R @ 6 R @ 4 where R @ 4 is aryl are naphthyl, 2-thienylacetyl, 3-thienylacetyl, 2-furylacetyl, 2-benzothienyl-acetyl. 2-benzofurylacetyl, indol-2-ylacetyl, 1H-tetrazol-1-ylacetyl, oxazol-2-ylacetyl, oxazol-4-ylacetyl, thiazol-4-ylacetyl, 2-amino-thiazol-4-ylacetyl, 1, 3,4-oxadiazol-2-ylacetyl, 1,3,4-thiadiazol-2-ylacetyl, 5-ethyl-1,3,4-thiadiazol-2-ylacetyl and benzoaminothiazolyl and similar aralkyl groups optionally substituted. C 1 -C 4 alkylsulfonylamino, hydroxy, halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy.

By way of example, R represents a substituted methyl group of the formula R 4 -CH (Q)! 14 and Q are amino, carboxy, hydroxy or sulfo are 2-carboxy-2-phenylacetyl, 2-carboxy-2- (4-hydroxyphenyl) acetyl, 2-amino-2-phenylacetyl, 2-amino-2 - (4-hydroxyphenyl) acetyl, 2-amino-2- (3-chloro-4-hydroxyphenyl) acetyl, 2-amino-2- (cyclohex-1,4-dien-1-yl) acethyl 2-hydroxy-2-enylacetyl, 2-formyloxy-2-phenylacetyl, 2-sulfo-2-phenylacetyl, 2-sulfo-2- (4-methylphenyl) acetyl and 2-a-cetoxy -2- (3-hydroxyphenyl) acetyl, 2-amino-2- (2-thienyl) acetyl, 2-amino-2- (3-benzothienyl) acetyl, 2-amino-2- (1H-tetra) -zol-1-yl / acetyl, 2-hydroxy-2- (1,3,4-thiadiazol-2-yl) acetyl, 2-amino-2- (2-aminothiazol-4-yl) acetyl, 2 carboxy-2- (2-thienyl) acetyl, 2-carboxy-2- (benzothien-2-yl) acetyl and 2-hydroxy-2- (benzofur-2-yl) acetyl; and when Q represents a substituted amino group of the formula

HxvvNH-C (O) - N - C (O) - are exemplified as such acyl groups - 2 - [N-methyl-N-benzoylcarbamoylamino] -2-phenylacetyl, 2- (N-methyl-N-benzoylcarbamoylamino) [(2-N-methyl-N-cinnamoylcarbamoylamino) -2- (4'-chlorophenyl) acetyl] 2- (N-methyl-N- (2-chlorocinnamoyl) carbemoylamino-7-2- (2)). -thienyl / -acetyl and 2- (N-ethyl-N-acetylcarbamoylamino) -2- (4-hydroxy-phenyl) acetoethyl; and when Q represents a substituted amino group of formula 0

- NH - C - R2 N - R 2 / ¾ v are given as examples of such 2 - [(3-methylimidazolidine) 2-on-1-yl] carbonylamino-7-2-phenylacyl-ethyl, 2- / 73-scetylimidazolidin-2-one-1-yl / carboxymethylcarbonylacetic acid, 2- (3-methylsulfonylamidazolidin-2-on-1-yl) -2- (2-thienyl) acetyl and 2- 73-acetylhexahydropyrimidin-2-one-15-1-yl / carbonylamino-2-phenylacetyl; and when Q represents a hydroxy-substituted benzamido group of the formula

Examples of such groups include 2- (2,4-dihydroxybenzamido) -2-phenylacetyl, 2- (4-hydroxybenzamido) -2- (4-hydroxyphenyl) acetyl, 2- (3,4-dihydrobenzamido) - 2- (2-Aminothiazol-4-yl) acetyl, 2- [3,5-dihydroxybenzamido] -2- (3-thienyl) acetyl and 2- (2-hydroxybenzamido) -2- (2-benzfuryl) / acetyl group ·

When Q is a hydroxy-substituted pyridine-carbonylamino group, for example, 2-hydroxypyridin-4-on-6-ylcarbonylamino and 3-hydroxypyridin-4-on-6-ylcarbonylamino are exemplified. When Q is a pyridylcarbonylamino group, pyridin-3-ylcarbonylamino, 4-aminopyridin-3-ylcarhonylamino, 5-chloropyridin-2-ylcarbonylamino, 3-carboxypyridin-4-ylcarbonylamino and 4-aminopyridine-2 are examples of such groups. ylcarbonylamino If Q is an imidazole or acarazole group as defined in the above examples, 2-aminoimidazol-4-ylcarbonylamino, 5-carboxy-2-methylimidazol-4-ylcarbonylamino, 5-carboxy-2-methylimidazol-4-ylcarbonylamino; -carboxypyrazol-3-ylcarbonylamino, 3-aminopyrazol-4-ylcarbonylamino and 4-hydroxypyrazol-5-yl-carbonylamino. When Q is benzpyridazin-4-one-3-ylcarbonylamino, the examples have the formula Q

0 -16-

- NH

When R is a keto group or an oximino-substituted group of the formula

Re - C - and Re - C - 5 »5

0 N

As examples of keto groups, 2-oxo-2-phenylacetyl, 2-oxo-2- (2-thienyl) acetyl, 2-oxo-2- (2-aminothiazol-4-yl) acetyl; and as examples of oximino-substituted groups, 2-phenyl-2-methoxyiminoacetyl, 2- (2-thienyl) -2-ethoxyiminoacetyl, 2- (2-furyl) -2-methoxyiminoacetyl, 2- (2-benzothienyl) -2- carboxymethoxyiminoacetyl, 2- (2-thienyl) -2- (2-carboxyethoxy) iminoacetyl, 2- (2-amino-1,2,4-thiadiazol-4-yl) -2-methyloxyiminoacetyl 2- (2-aminothiazole-4) 2-methoxyiminoacetyl, 2- (2-chlorothiazol-4-yl) -2-methoxyiminoacetyl, 2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-yl) oxyiminoacetates - 2-, 2- (2-aminothiazol-4-yl) -2- (2-carbamoylprop-2-yl) oxyiminoacetyl, 2- (5-emino-1,3,4-thiadiazol-2-yl) - 2-methoxyiminoacetyl, 2- (2-aminothiazol-4-yl) -2- (pyrrolidin-2-one-yl) oxy-iminoacetyl, 2- (2-aminothiazol-4-yl) -2- (1-) methylpyrrolidin-2-on-3-yl / oxyiminoacetyl, 2-phenyl-2- (pyrrolidin-2-on-3-yl) oxyiminoacetyl, 2- (2-aminooxazol-4-yl) -2- 1-ethylpyrrolidin-2-on-3-yl / oxyiminoacetyl, 2- (2-aminothiazol-4-yl) -2- (1-ethylpiperidin-2-on-3-yl) -2-oxyiminoacetyl; / 2-furyl / - The 2- (pyrrolidin-2-on-3-yl) oxyiminoacetyl group may be found in U.S. Pat. No. 4,634,617 / Ha-17-mashima. Examples of substituents for R1 are hydrogen and phenyl, furyl, thienyl, oxazolyl, isoxazolyl, optionally protected aminoisoxazolyl, thiazolyl, optionally protected aminothiazolyl, thiadiazolyl, and aminothiazolyl, and alkenyl groups for Rg; carbon atoms, especially methylene. When R 8 is a C 1 -C 4 alkyl-substituted phenyl or substituted phenyl group, examples of such groups are benzyl, 4-hydroxybenzyl, 4-chlorobenzyl, 3-carboxybenzyl, 3-chloro-4-hydroxybenzyl, 2- phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-hydroxy-2-phenylpropyl, 3-phenylbutyl and the like phenylalkyl groups.

When R is an alkyl group having from 1 to 4 carbon atoms substituted with an amino group or an amino group, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 2-aminopropyl and the like are exemplified as examples of such groups. a group wherein the amino part is protected by an amino protecting group.

When R 8 is an alkenyl group having 2 to 6 carbon atoms, examples of such groups are the allyl-butene-2 group, butene-3 group and the like. "Lewis acid catalysts are characterized by the presence of free orbit, which can accept an available e-lectton pair either shared on, for example, an oxygen, sulfur, or halide atom, or in an orbital Lewis backbone compound to form a covalent bond. Examples of suitable uewis acid catalysts include aluminum chloride, tin tetrachloride, tin bromide, zinc chloride, zinc bromide, antimony trichloride, titanium tetrachloride, ferric chloride, gallium chloride, zirconium chloride, mercuric chloride, chromium chloride. and a similar metal halide by the activity of a Friedel-Crafts type catalyst. Such preferred catalysts are tin tetrachloride, zirconium chloride and titanium tetrachloride. Particularly preferred is tin (IV) chloride. The catalyst is preferably used in an amount of about 1.0 to 3 moles per mole of sulfinyl chloride of formula II.

The nitro compounds used include nitroalkanes having from 1 to 6 carbon atoms and nitro substituted aryls, and nitromethane, nitroethane, 1-nitropro-pan, 2-nitropropane, p-nitrotoluene, -nitrotoluene, and nitro-benzene are representative examples. Nitromethane, 1-nitroprocane, nitroethane and nitro-benzene are preferred, nitromethane being particularly preferred. The nitro compound is preferably used in an amount of about 1 to about 4 moles of namole sulfinyl chloride of formula II. The 4-chlorosulfinylazetidinones of formula (II) used in the process of the present invention are known compounds described in U.S. Pat. No. 4 081440 (Kukolja). Examples of starting materials used in the process of the present invention are tert-butyl 3-methyl-2- (4-chlorosulfonyl-2-ω-3-phenylacetylamino-1-azetidinyl). 3-butenoate, tert-butyl-3-methyl-2- [4-chlorosulfinyl-2-oxo-3-phenyoxyacetylamino-ΐ-α-zetidinyl] -3-butenoate, diphenylmethyl-3-methyl-2- [4-chlorosulfinyl-2-oxo-3-phenoxyacetylamino-1-azetidinyl] -3-butenoate, p-methoxybenzyl-3-methyl-2- (4-chlorosulfinyl-2-oxo-3-phenylacetylamino-thiazetidinyl) -3- butenoate, p-nitrobenzyl-3-methyl-2- (4-chlorosulfonyl-2-oxo-3-phenoxyacetylamine) 1-azetidinyl (3-butenoate, difluoromethyl) -3-methyl-2- [4-chlorosulfinyl-2-oxo-3-bzoylamino-1-azetidinyl] -3-butenoate, p-nitrobenzyl-1-methyl-O, 4-chlorosulfinyl-2-oxo-3-aU-ester .beta.-butyloxycarbonylamino-phenylacetyl-amino-.beta.-azetidinyl-.beta.-butenoate, benzyl-3-methyl-2- [4-chlorosulfinyl-2-oxo-3-phenylacetylamino-1-azetidinyl] -3-butenoate abenzhydryl-3 -methyl 2- (4-chlorosulfinyl-2-oxo-3-acetylamino-1-azetidinyl) -3-butenoate. Preferred azetidinones have the general formula II wherein A is a group of the formula

Q R - C - wherein R is benzyl, phenoxymethyl or thienylmethyl. A preferred ester group R 1 in the compound of formula II is benzyl or substituted benzyl, especially p-nitrobenzyl. - 19 -

The process of the invention is carried out at a temperature of about -15 ° C to about +60 ° C, and preferably at a temperature of about -10 ° C to about 0 ° C, and in an inert organic solvent. Preferred are aprotic solvents which include aromatic hydrocarbons such as benzene, toluene, xylene and chlorobenzene, and halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetrachloride, 1; 2-dichloroethane, 1,1,2-trichloroethane, with benzene and toluene being particularly preferred solvents

As mentioned above, the process is carried out under substantially anhydrous conditions. Traces of water are acceptable, but the reaction mixture should be kept as dry as possible during the preparation process.

According to a preferred embodiment of the process according to the invention, the oxo compound is also present during the cyclization. The oxo compounds used in the process of the invention are described in U.S. Pat. No. 4 190724 (Gou) and are selected from the group consisting of Λ

from - K

R - - O - R 2 '"_ ?, E 2 - S" R 2, Z ^ C = O and / κ' / βΡO 0 where each R 2 is independently C 1 -C 4 alkyl, each R 2 independently of one another C 1 -C 4 alkyl, C 5 -C 6 cycloalkyl, C 1 -C 4 alkyl or C 1 -C 4 alkyl, C 1 -C 4 alkoxy or halogen, Z is C of formula -CE2-CH2-C-CH2-C6H2- or -CH8-O-CHCHCH2CH2; 4 or 5 and Z * are a group of the formula R 0 wherein each R 2 is hydrogen or an alkyl group having 1 to 20 carbon atoms and 3 to 6. Preferred oxo compounds are diethyl ether, di-n-propyl ether, acetone and methyl ethyl ether . Diethyl ether is particularly preferred. The oxo compounds are preferably used in the process according to the invention in an amount corresponding to about 0.75 to about 2 moles per mole of the sulfonyl chloride of general formula II.

In another preferred embodiment of the process of the invention, an unsaturated compound is present during the cyclization. The unsaturated compound of the present invention is selected from the group consisting of C 2 -C 10 olefins, C 5 -C 10 cycloolefins, C 5 -C 10 diolefins, C 3 -C 10 allenes, and unconjugated C 6 -C 10 cyclodiolefins. Examples of such alkenes, alkadienes, cycloalkenes, allenes and cyclodienes include ethylene, propylene, 1-butene, 2-butene, 1-pentene, 2-pentene, 1-hexene, 3-hexene, 1-heptene, from alkenes, 3-heptene, 1-octene, 2-n-nn, 3-nonene, 1-decene, 5-decene and similar terminal or non-terminal alkenes; unconjugated alkadienes such as 1,4-pentadiene, 1,4-hexadiene, 3-methyl-1,4-hexadiene, 1,5-hexadiene, 1,5-heptadiene, 1,6-hepatadiene and the like dienes; unconjugated cyclohexenes, for example, 1,4-cyclohexadiene, 1,4-cyclopentadiene; alleny for example allene, methylallene (1,2-butadiene), dimethylallene (2,3-pentadiene); cycloalkenes such as cyclopentene, 1-methylcyclopentr-2-ene, cyclohexene, cycloheptene, cyclooctene. The alkene, alkadiene or alkene may be straight-chain or branched and may be substituted by an inert group, preferably on a saturated alkene carbon atom. For example, the unsaturated compound may be substituted by an alkyl group such as methyl, ethyl or iso-propyl; a halogen atom (preferably in a non-allyl position) esterified with a carboxy group; an aromatic group such as a phenyl or a tolyl group; nitro; cyano, alk-alkyl such as methoxy or ethoxy; and similar aprotic substituents which are inert under the conditions of the reaction in the preparation process.

Non-terminal alkenes 3e can be used either in cis or trans form. Preferred unsaturated compounds of the invention - 21 are alkenes, for example 1-pentene, 2-pentene, 1-hexene, 2-hexene, 1-heptene, 1-octene and 1-decene; and cycloalkanes cyclopentene and cyclohexene. Particularly preferred is 1-hexene »

The unsaturated compounds are preferably used in the process according to the invention in an amount corresponding to about 1 mole to about 2 moles per mole of sulfinyl chloride of the formula II. Particularly preferred is an amount of about 1 mole to about 1.5 mole of the non-saturated compound per mole of sulfinyl chloride of formula II. Best results are obtained with 1 mole of unsaturated compound, especially 1-hexene, per mole of compound of formula II.

In a particularly preferred embodiment of the process according to the invention, the compound of formula I is prepared by reacting a 4-chlorosulfinyl-azetidin-2-one of formula II with about 1.5 to about 3 mM tin tetrachloride per mole of azetidinone, with about 0.75 to about 2 moles of ethyl ether per mole azetidinine with about 1-2 moles of 1-hexane per mole of azetidinone and with about 1 to 4 moles of nitromethane per mole of azetidinone in an inert solvent under substantially anhydrous conditions at -10 to 0 ° C. Best results are obtained using 2.5 molar equivalents of nitrate and 1.0 molar equivalents of 1-hexene with ethyl ether and tin tetrachloride.

The process of the invention is generally carried out as follows: 4-Chlorosulfinylazetidinone (II) is dissolved in an anhydrous inert organic solvent and the solution is cooled to about 0 ° C to about 15 ° C. Nitro compound was added to the solution, cooled to -10 ° C and stirred. the catalyst and optionally the oxo compound and the unsaturated compound are cooled to about 10 ° C in the solvent and the sulfinyl chloride solution is added. The solution was then stirred under nitrogen and the temperature allowed to rise to room temperature. The complex is separated from the reaction mixture, for example by filtration or centrifugation, and washed with an inert solvent and quenched with a lower alcohol such as methanol. 3 “Ex> omethylencephamsulfoxidesters form in the form of a solid precipitate, is filtered off and washed with sea dried for subsequent use.

As noted above, the use of the aforementioned nitro compounds 22 in a known method of cyclization results in improved reaction rates and yields of 3-exomethylene glyphosulfoxide ester. The sulphoxide yields generally obtained are (2 to 4% higher than in the control), the increase in yields and the improved reaction rates have substantial economic value in the production of large amounts of 3-exomethylenecepham sulfoxide ester. The 3-methoxymethylcell sulfoxide of formula (I) is used as a prodrug in the preparation of cephalosporin antibiotics, for example, cephalosporin, β-phenylglycylamino-3-chloro-3-cefam-4-carboxylic acid by methods known per se. The intermediate of formula I can also be used to prepare cephalexin, 7-phenyl-glycylamino-3-methyl-3-cephem-4-carboxylic acid. The increased yields of the process according to the invention therefore also lead to an increase in the yields of these valuable antibiotic compounds.

The way in which the nitro compounds are involved in increasing the yields of the compounds of formula (I) with improved reaction rates are known. It is possible that the nitro compounds allow a higher degree of absence of insoluble metal sulfinyl chloride complex to precipitate in ring-closure reactions and affect the formation of by-products. However, it is not yet known that the nitro compound acts to select the desired reaction to suppress unwanted reactions or in some minor way.

The invention is further illustrated by the following non-limiting Examples. EXAMPLES OF THE INVENTION

Nitro Compounds / Nitromethane, Nitroethane,. 1-nitropropane anitrobenzene (dried with alumina 3 / activity 1). Toluene is dried by a 4A molecular sieve. All reactions described in the examples are carried out in a dry nitrogen atmosphere. The 3-methylene-cefem products of general formula (I) were tested by HPLC (4.5 mm x 5.0 cm, octyl, 3 micron column, wavelength 254 nm, 1.7 ml / min flow rate and 32% tet- hydrofuran, 0.5 g phosphoric acid in water as mobile phase or NI R spectrum in CDG1 and recorded on a QE-300/300 MWH / spectrometer. Abbreviations have the following meanings: s-sin-glst, d-doublet, t-tripiet, ω-quartet, m-multipiet. Preparation 1 (3) methyl-2- (2-chloro-sulfonyl) -4-oxo-3-imid-1-azetidinyl (3-butenoate), referred to herein as sulfinyl chloride

The procedure is as follows: A 1-liter round neck flask is equipped with a mechanical stirrer, a Dean-Stark stirrer, a condenser with a nitrogen inlet and a thermometer. Then, 29.48 g of wet poly / 4-vinylpyridine / divinylbenzene copolymer (KE = 44.9% water) was introduced into the reaction flask (a796). ml of toluene. The suspension is refluxed (110 to 1-2 ° C) under nitrogen until 160 ml of toluene-azotrope is collected by means of a Dean-Stark apparatus. The suspension is cooled to 60 ° C with an ice bath before 49.28 is added to the reaction flask. g / 97.8% purity, 96.1 mmol of 1 H, 6H-N-phenoxyacetyl / amino-7-penicillanic acid, 4-nitro-phenyl / methyl ester 1-oxide and 21.86 g / 12, 1 mmol, 1.26 equivalents of N-chlorophthalimide. Toluene is used to flush the reactants into the flask. The mixture is refluxed for 120 minutes / time at 109 DEG C. and a further 59 ml of toluene azeotrope is collected. The reaction mixture was then immediately cooled to 15 ° C and filtered, and the solid cake-polymer / flimide was washed with 104 mL of toluene and discarded. The yellow sulfinyl chloride solution is then used immediately or stored in argon at 0 to 5 ° C for use. 1 H NMR: CDCl 3 300 MHz, ppm (1.92) s, 3H, CH 2, 4.50: 4.56 / AB, 2H ,. J = 15.1 Hz, side chain CH 3, 4.99 / s, 1H, olefinic CH 2, 5.06 / s, 1H, -CHCOOpNB /, 5.22 / d, 1H, J = 1.6 Hz , olefinic CH 3 / 5.25: 5.33 / AB, 2H, J = 4.6 Hz, azetidinone H 2, 6.27 / dd, 1H, J = 4.6 Hz and 10.8 Hz, azetidinohe H 6.90 / dd, 2H, J = 7.4 Hz and 8.5 Hz, ArH side chain, 7.01 / t, 1H, J = 7.4, side chain ArH /, 7.30 / dd, 2H, J = 7.4 Hz and 8.5 Hz, side chain ArH /, 7.50 / AA BB, 2H, J = 8.9-24 - ha, pNB ArH /, 7.98 / d, 1H , J = 10.8 Hz, NH 4, 8.23 (ΑΑ'βε ', 2H, J = 8.9 Hz, pNB ArH). Examples

In the following examples, 3-methylene-7- (phenoxyacetyl) amino-amino-4-carboxylic acid, 4-nitro-phenyl / methyl ester, 1-oxide (general formula 1) is prepared. The results according to the individual examples are summarized in Table I. Example 1 A 500 ml round necked round neck flask with a mechanical stirrer, a nitrogen inlet and a thermometer. It is charged with 220 ml of a toluene solution of sulfinyl chloride, (25.5 mmol, based on 1 H) -6- (phenoxyacetyl) amino-penicillanic acid, (4-nitrophenyl) methyl ester-1-oxide. To a separate 50 mL flask was added 10 mL of toluene and diethyl ether (ml2.5 mL / 1.76 g / 23.9 mmol-7) and the solution was cooled to 0-5 ° C. Stannic chloride (5.1 ml, 11.36 g, 43.6 mmol) was added to a toluene diethyl ether solution and the resulting suspension was immediately cooled to 0 ° C in an acetone / dry ice bath. The toluene solution of the sulfinyl chloride is cooled to 15 ° C and the tin tetrafluoride suspension in the diethyl ether / toluene system is introduced with enough AlFinyl chloride over 5 to 10 seconds to rinse with 5 ml of toluene. The resulting suspension temperature was increased to 21-23 ° C and stirred under nitrogen for 18 hours.

The suspension is filtered, washed with 25 ml of toluene and returned to the bottom reaction flask with 70 ml of methanol. The suspension was stirred and allowed to crystallize at 21-23 ° C for 15 minutes. The suspension was then cooled to 0-5 ° C and stirred for an additional three hours and 45 minutes. Two hours later, 15 ml of deionized water was added to this methanol medium.

The suspension is filtered and the product is washed with 30 ml of methanol. The light colored solid is dried in a vacuum oven at 45-60 ° C for 15-16 hours. Yield of product: 25-3-methylene-7H-phenoxyacetyl / amino-7-carboxy-4-carboxylic acid, 4-nitrophenyl / methyl ester, 1-oxide. (formula 1) is 68.1% (9.21 g), theoretically should be 12.74 g / and the purity determined by HPCL is 94.2%. 1 H-NxMR: CDCl 3 + 300 MHz, ppm / 3.75: 3.74 (AR, 2H, J = 14.1 Hz, CH 3), 4.55 / s, 2H, side chain CH 3 /, 4.89 / d, 1H, J = 4.80 Hz, azetidinone H, 5.28 (s, 2H, pNB CH2), 5.31 (s, 1H, -CHCOOpNB), 5.48 / d, 1H, J = 1 , 50 Hz, exo CH 3 /, 5.78 / s, 1H, exo CH 3 /, 6.03 / dd, 1H, J = 4.80 Hza 10.70 Hz, azetidinone H /, 6.93 / dd, 2H , J = 8.30Hz and 7.40Hz, ArH side chain, 7.0 / t, 1H, J = Hz, ArH side chain, 7.29 / dd, 2H, J = 8.30 Hza 7, 40 Hz, ArH side chain, 7.49 / AA * BBZ, 2H, J = 8.90 Hz, pNB ArH /, 8.11 / d, 1H, J = 10.70 Hz, NH /, 8.25 / ΑΑ'ββ, 2H, J = 8.90 Hz, pNB ArH /. Example 2

The procedure of Example 1 was repeated with the following variations: The toluene solution of sulfinyl chloride was cooled to -50 ° C before addition of a slurry of tin tetrachloride and diethyl ether / toluene cooled to 0 ° C. No water is added while stirring the methanolic medium. The yield of general formula I was 65.3% (8.5 g instead of theoretical 12.33 g) and the purity determined by HPLC was 94.7%. Example 3

The procedure of Example 1 was repeated with the following variations: The toluene solution of sulfinyl chloride was cooled to-10 ° C before addition of a slurry of tin tetrachloride in diethyl ether / toluene cooled to 0 ° C. No water is added while stirring the methylalcohol medium. The yield of the product of formula I was 66.3% (8.45 g instead of 12.33 g) and the purity of the product determined by HPLC was 97.3%. - 26 Example 4

The procedure of Example 1 was repeated with the following variations: no diethyl ether was used in the reaction. No water is added to the stirring of the alcoholic medium. The yield of the product of formula I is 50.5% (10.15 g instead of the theoretical 19.58 g) and the purity of the product determined by HPLC is 97.3%.

The round-bottomed flask, three-necked and 500-ml capacity, features a mechanical stirrer, a nitrogen inlet and a thermometer. To the reaction flask was added 192 ml of a toluene solution of sulfinyl chloride (25.5 mmol), based on 1 B (-6-) phenoxyacetyl (amino) pentanillanic acid, 4-nitrophenyl (methyl ester-1-oxide). 50 ml of the separated flask was charged with 10 ml of toluene. This to luen. is cooled to 0-5 ° C prior to the addition of tin tetrachloride (5.1 mL / 11.36 g / 43.6 mmol). The solution obtained is immediately cooled to -10 ° C in an acetone bath and dried. Nitromethane / 7 * 3.5 ml (3.94 g, 64.6 mmol) was added to the sulfonyl chloride solution and the resulting solution was cooled to -10 ° C in an acetone / dry ice bath. The toluene solution of tin tetrachloride is added to the sulfinyl chloride solution at a temperature of -10 ° C over a period of 5 to 10 seconds, rinsing with 5 ml of toluene. The resulting suspension was allowed to exotherm to 21-23 ° C and stirred for 4 hours under nitrogen.

The suspension was filtered, washed with 25 ml of toluene and returned to the reaction flask with 70 ml of methanol. The resulting suspension was stirred and allowed to crystallize at 21-23 ° C for 15 minutes. The suspension is then cooled to 0-5 ° C and stirred for an additional three hours and 45 minutes. After two hours of this methanol treatment, 15 ml of deionized water was added.

The suspension is filtered and the product is washed with 30 ml of methanol. The light colored solid is dried in a vacuum oven at 45-60 ° C for 15-16 hours. The yield of the product of formula I was 60.9% (7.96 g instead of the theoretical 12.74 g) and the purity of the product determined by HPLC was 97.4%. Example 6

The procedure of Example 5 was repeated with the following variations. 1-Hexene (3.2 mL, 2.17 g, 25.8 mmol) of the toluene solution of sulfinyl chloride was added before the addition of C chloridu chloriduCl chloridu. The yield of the Formula I product was 65.2% (8.47 g instead of 12). 74 g (98.0%). Example 7 A 500 ml three-necked round-bottomed flask with a mechanical stirrer, a nitrogen inlet and a thermometer. 179 ml of a toluene solution of sulfinyl chloride (24.7 mmol), based on (1B) - (-) - * / 6-phenoxyacetyl-1-oxo-acetic acid, (4-nitrophenyl / methyl ester-1-oxide) was added to the reaction flask. . 10 ml of toluene and diethyl ether (2.4 ml, 1.70 g, 22.9 mmol) are added to a separate 50 ml flask and the solution is cooled to 0-5 ° C. Chloridcinium (4.9 mL, 10.91 g, 41.9 mmol) was added to the toluene / diethyl ether solution and the resulting suspension was immediately cooled and kept at 0 ° C in an acetone bath and dried. Add 1-hexane (3.1 mL, 2.10 g, 25.0 mmol) to the sulfonyl chloride solution and cool the resulting solution to 10 ° C. A slurry of tin tetrachloride in diethyl ether / toluene cooled to 0 ° C was added to the sulfinyl chloride over a period of 5 to 10 seconds using a rinse of 5 mL of toluene. The resulting suspension was allowed to exotherm to 21-23 ° C and stirred for 4 hours under nitrogen.

The suspension was filtered, washed with 25 ml of toluene and returned to the reaction flask with 80 ml of methanol. The suspension obtained is stirred and crystallized at 21-23 ° C for 15 minutes. The suspension is then cooled to 0-5 ° C and stirred for a further 3 hours and 45 minutes. No water is added to the methanol during stirring.

The suspension is filtered and the product is washed with 30 ml of methanol. The light colored solid was dried in a vacuum oven at a temperature of 45-60 ° C for 15-16 hours. The yield of the product of formula (I) is 70.0% / 8.9 g instead of 12.34 g / &amp;amp; purity of the product, determined by HPLC is 97.1%. Example 8

The procedure of Example 5 was repeated with the following variations: Diethyl ether (2.5 ml, 1.76 g, 23.9 mmol, as described in Example 1, yield 71.1%) was used. (9.60 g instead of theoretical 12.74 g) and the purity of the product determined by HPLC is 94.3%.

A mechanical stirrer, a thermometer and a nitrogen inlet were introduced into a 500 ml round bottom three-necked flask. The reaction flask was charged with 179 ml of a toluene solution of sulfinyl chloride (24.7 mmoles, based on 1 H) -6- [(phenoxyacetyl) amino] penicillanic acid, (4-nitrophenyl) methyl ester-1-oxide). of 50 ml, 10 ml of toluene and diethyl ether (2.4 ml / 1.70 g / 22.9 mmol / 7) are added and the solution is cooled to 0 to -5 ° C. 91 g (41.9 mmol) were introduced into toluene diethyl ether solution and the resulting suspension was cooled immediately and maintained at 0 ° C using an acetone / dry ice bath. 1-Hexane (3.1 ml, 2.10 g, 25.0 mmol) is added to the sulfinyl chloride solution and the resulting solution is cooled to 0 DEG C. in an acetone / dry ice bath.

At 0 ° C, the cooled tin tetrachloride suspension and the diethyl ether / toluene system are added to 0 ° C of cooled sulfinyl chloride over 5-10 seconds, using 5 ml of toluene, rinsed using. The resulting suspension was allowed to exotherm at 21-23 ° C and stirred for 4 hours under nitrogen.

The suspension is filtered, washed with 25 ml of toluene and returned to the reaction flask with 30 ml of methanol. The resulting suspension was stirred and allowed to crystallize at 21-23 ° C for 15 minutes. The suspension is then cooled to 0-5 ° C and stirred for a further three hours and 45 minutes. No water is added while stirring the methanol-29 environment.

The suspension is filtered and the product washed with 30 ml of methanol. The light colored solid is dried in a vacuum oven at 45-60 ° C for 15-16 hours. The yield of the product of general formula (X) was 72.2% (9.16 g instead of 12.34 g) and the purity of the product determined by HPLC was 97.3%. Example 10

The procedure of Example 5 was repeated with the following variations: Diethyl ether (2.5 ml; 1.76 g; 23.9 mmol, as in Example 1) and nitrobenzene (6.6 ml) were used; 21 g (64.1 mmole) instead of nitromethane. The sulfinyl chloride / chloride / diethyl ether / toluene / nitrobenzene suspension is also only stirred for 90 minutes at 21-23 ° C instead of 7 hours for 4 hours. The yield of the product of formula (I) is 70.5% (9.50 g). 74 g (94.6%). Example 11

The procedure of Example 5 was repeated with the following variations. A 2.5 ml diethyl ether (1.76 g), 23.9 mmol, as in Example 1, and 1-nitropropane (5.7 ml, 5.68 g, 63.8 mmole, 7 instead of nitromethane) was used. The sulfinyl chloride / chloride / diethyl ether / toluene / 1-nitropropane suspension is allowed to stir for 90 minutes at 21-23 ° C instead of 4 hours. The yield of the product of formula I is 69.7% (9.13 g instead of the theoretical 12.74 g) and the purity of the product determined by HPLC is 97.2%. Example 12

The procedure of the example is repeated. 5 with the following variations: Diethyl ether (2.5 ml, 1.76 g, 23.9 mmol, as in Example 1 and nitroethane 4.6 ml, 4.80 g, 64.0 mmol instead of nitromethane) was used. The sulfinyl chloride / chloride / diethyl ether / toluene / nitroethane suspension is stirred for 30 minutes at 30 ° C to 21 ° C to 23 ° C instead of 4 hours, yielding 69.5% (9.18 g instead of 12.74 g) and purity of the product. EXAMPLE 13 A 500 mL round neck round bottom flask equipped with a mechanical stirrer, a nitrogen inlet, and a thermometer, was charged with 220 mL of a toluene solution of sulfinyl chloride (25.5 mmol) into a reaction flask. based on (1E) -6- (phenoxyacetyl) amino-7-acetillanic acid, (4-nitrophenyl) methyl ester (1-oxide) The tososulfinyl chloride solution is cooled to 15 ° C prior to addition of titanium tetrachloride (5.6). ml (9.69 g), 51.1 mmol / min with a graduated scale, the suspension obtained is immediately heated to 6 ° C. 0 ° C under nitrogen for a total reaction time of 4 hours.

The suspension is filtered, washed with 25 ml of toluene and returned to the seven reaction flask with 70 ml of methanol. The resulting suspension is stirred and allowed to crystallize at 21-23 ° C for 15 minutes. The suspension is then cooled to 0-5 ° C and stirred. after 3 hours and 45 minutes. No water is added to the methanol during mixing.

The suspension is filtered and the product is washed with 30 ml of methanol. The light-colored solid is dried in a vacuum oven at a temperature of 45-60 ° C for 15-16 hours. The yield of the product of formula I is 65.4% (8.82 g instead of the theoretical 12.74 g) and is 94.4% determined by HPLC. Example 14

The procedure of Example 13 was repeated with the following variations: Nitromethane / 2.8 mL (3.16 g), 51.7 mmol / 7 was added to the toluene solution of sulfinyl chloride before cooling to 15 ° C and titanium tetrachloride was added. The yield of the product was 68.8% (9.45 g instead of the theoretical 12.74 g) and the product purity, determined by HPLC, was 92.7%. 31 Example 15

The procedure of Example 13 was repeated with the following variations: Nitromethane / 3.5 ml (3.94 g), 64.6 mmol / 7 and 1-hexene / 3.2 ml / 2.17 g / 25.8 mmol / 7 is introduced into the toluene solution of sulfinyl chloride prior to cooling to 15 ° C and titanium tetrachloride is added. The suspension of sulfinyl chloride / titanium tetrachloride / nitromethane / 1-hexene is stirred for 3 hours instead of 4 hours at 60 ° C. The yield of the product of general formula (I) is 68.2% (8.99 g instead of the theoretical 12.74 g / .mu.m &amp;amp; tota of product, determined by HPLC to be 96.7%). mechanical stirrer, nitrogen inlet and thermometer. The reaction flasks were charged with 216 ml of a toluene solution of sulfinyl chloride (25.5 mmol) based on (1B) -6- (phenoxyacetyl) -aminoJ-foilillanic acid, 4-nitrophenyl / methyl ester-1-oxide. zirconium chloride (20.3 g / 99.6% purity), 86.8 mmol) was weighed into a 50 ml round bottom flask in a nitrogen-filled glove bag. Close the 50 ml flask and add 25 ml of toluene by syringe. The chloride-toluene suspension was added to a solution of sulfinyl chloride in toluene at 5 ° C using another 25 mL of toluene flushing. The suspension was allowed to exotherm to 21-23 ° C and stirred for 48 hours under nitrogen. HPLC showed that the reaction was not complete, so that the suspension was heated and maintained at 60 ° C for hours.

The suspension was filtered and returned to the reaction flask with 70 mL of methanol. In the methenol treatment, no product crystallizes, so that the compound of formula I is not obtained. 32 Example 17

A 500 ml round necked round-bottomed flask is equipped with a mechanical stirrer, a nitrogen inlet and a thermometer. The reaction flask was charged with 136 ml of a toluene solution of sulfinylchloride (19.3 mmol) based on (1B) -6- (phenoxyacetyl) amino-7-piperidinilic acid (4-nitrophenyl / methyl ester-1). -oxide. The sulfinyl chloride solution was cooled to 15 ° C. Zirconium chloride (7.7 g, 99.6% pure, 32.9 mmol) was weighed into a 50 ml round bottom flask in a nitrogen-filled glove bag. The 50 ml flask was sealed and 25 syringes added. ml of toluene and diethyl ether (.1.9 ml (1.34 g), 18.1 mmoles). The zirconium chloride / diethyl ether / toluene suspension is cooled to 0 DEG C. in an acetone bath and dry ice by adding 15 DEG to a toluene solution of sulfinyl chloride. C. Toluene (5 ml) was used to rinse and the resulting suspension was exothermically heated to 21-23 ° C and stirred for 18 hours under nitrogen. HPLC analysis indicated that the reaction was not complete so that the suspension was heated and maintained at 60 ° C for one hour.

The suspension is filtered and returned to the reaction flask with 55 ml of methanol. The resulting suspension was stirred and allowed to crystallize at 21 and 23 ° C for 15 minutes. Water (10 ml) was added to the suspension and the resulting suspension was then cooled to 0-5 ° C and stirred for an additional hour.

The suspension is filtered and the product is washed with 20 ml of methanol. The light colored solid is dried in a vacuum oven at 45-60 ° C for 15-16 hours. The yield of the product of formula I was 32.1% (3.36 g) compared to the theoretical 9.64 g and the purity of the product was 92.0% by HPLC. EXAMPLE 18 A 500 ml round necked round-bottomed flask was equipped with a mechanical stirrer, nitrogen inlet and thermometer. The reaction flask was charged with 216 mL of a toluene solution of sulfinyl chloride (25.5 mmol, relative to 1 B) -6-phenoxyacetyl amino amino-33-penicillanic acid, 4-nitrophenyl / methyl ester 1-oxide. Nitromethane (80 ml (90.16 g), 1.48 mol) was added to the sulfinyl chloride solution and the resulting solution was cooled to 15 ° C, zirconium chloride / 10.1 g / 99.6% The purity of the 50 mL round bottom flask in a nitrogen-filled glove bag was 50 mL and the 50 mL flask was sealed with toluene (25 mL) and injected with a syringe. The toluene solution is cooled to 0 DEG C. in an acetone / dry ice bath and then added to a toluene solution of sulfinyl chloride and nitromethane at 15 DEG C. The precipitate is precipitated from the starting solution after 6 minutes. 23 ° C and the reaction mixture was stirred for 105 minutes more nitromethane (3535 ml (39.45 g), 646.2 mmol7 was added while maintaining the reaction mass in a homogeneous state. The reaction solution was transferred to round-bottomed vacuum vapors (using further nitromethane (35 mL, 39.45 g, 646.2 mmol) to facilitate transfer.

The reaction solution was evaporated in vacuo to an oil and 70 ml of methanol was added. The resulting suspension was cooled and stirred at 0-5 ° C for 100 minutes. Deionized water (15 ml) was added 50 minutes after methanol treatment.

The suspension is filtered and the product washed with 30 ml of methanol. The light colored solid is dried in a vacuum oven at 45-60 ° C for 15-16 hours. The yield of the product of formula I is 66.2% (8.76 g instead of 12.74 g) and the purity determined by HPCL is 96.4%. 34 24 1, Φ 24 1> N 2> Q Ό a ^ a * S * a * a * a ^ oo O O o fH • wmm «« te 0 • 'C C CX 1 «o PO> s P 2 > UP CO 0 0 oo 0 o V0 0 0 m 0 0 r * '> 3'> 5 '> s ·'> »>> cc Γ * C q -M 24 Ό Ό Ό 0) CO 'CO OJ * <0 XO 'CO> N> N> N> N> N p

Table ΙΑ acid = tin tetrachloride / 1,7 eq • HXJZ 3o <Pw »P p> <25 JSP PM i)

Oj XO XO q c q TJ 3 OJ XO OJ N> N> N

OJ c (0 2 = p ** Φ> ε 24 c (0 P * 4-i oj r ε 0 34 Φ XO 0 í t P 10 p 0 q P> P Ό xo • p CX • H cx XO> N cc "« * N 5 φ 5 Φ> 24 Φ q cn cn n σ> σι σ XSJ * x · »» N o Ό o

C Ό

OJ

> N c

xO> tsi> 24 Φ σι σι

CO t>

O • rl Φ -5 and M P q o Ό i — 1 24 and Q, and λ Φ Φ o P «O m cn cn CX 'cx - CX, cx Cx cx cx Z 1 Λ 1 25 1 25 1 1 1. 125 p P p p 25 P 25 P CO CN CO CX 00 CM CO cx cx cx p · ** p ip ** P rjt - * n * n ·

Φ S (0> P CO P'CO H O> O.rH p and o,

> with O ΦΛ4 P

I 24 Ό f f-t an. - <

U 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 P P C C *) pl 0 0 f *

Table IA / continued /

Lewisc acid = tin tetrachloride / 1.7 eq. - 35 -

1 1 CM}} o o o o 3 3 3 O * d d d d d d d d d d d ι ι ι 0,4 0,4

X 4> p

I 'c. '03

> N>

Ad Φ '> 5 c Ό Ό3

> N Ό Ό3

> N

CO o c Φ + J> o • H 3 z o, -t ra i d i-4> • u -u

M 4J Μ CO d Ο Ο <-Γ Ad C0 ο. CO X) <DΦ O -t-> PS O φ x coΦ -p '(S H O1 c <0 c c c 0. and IU 4) 0 c C OS N u <0 u * J * w &amp; "5. £ ε ε> Ad ε ε> Λ4 Φ 0 £ 0 Ad Jj® xJ í Ai 0 í 0 Φ 0 φ 0 Φ mu in U m • k in u ΙΟ • u ·«. -1 - C - 4J d CM • H CM • H CM 1 04 • H CM c Se * cc r4 c ► * £> Ad £> Ad Φ φ Φ dnddd σ »tn σ φ σι * · · * * * , U U U U CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM d d d CM CM O CM O CM o CM σ> · - CM O Ch> - σ -> -> CXrH • pgo, uo O 9 u 0> 5 O Φ 0 o 0 OO> Ad + - »CO and what pH d I 1 O 1 1 1 What about pM CM Ad Μ T3 >> - 4 CO Pt r-1 d Ή d {1 36

Table IB

Lewis acid = titanium tetrachloride / 2.0 eq. 24 Iω 24> n

> <u ie + -> o '>> 1 H 3> O. + J

NO. 1)

X o

CO a

• H o c

M CDM> and h 32 O co »r- (C4

> »4) Λ NU -μ) Cd <U Ή

C

XI

24 CO CO ΛCO O T3

WHAT

O

H

Cl

CD

• P c a

(D x m> Fh <D + j'CO r — I O + - »S Q |> s O φ> 24 + j

I 24

Ή Ό> C-COO. H ^ 5 o O o «4» <3 cx ** tn 3 3 3 3 3 Ό

XO

> N

XO c Ό xa> «S1 '> p

C τ x x

> N> 24

CD c C 2 z * »· 3> 3 ø * 1) 24 <u 5 4 5 CD Ξ 0 0 O u Uf) U • + J • H cx • H c c

> 'S C f f f f f f f f O O O O O O O O O O O O OΌ

O O 0 0 0 m tn m M π π m 37. 37

Table IG acid = zirconium chloride / 3,4eq. and 1.7 eq. what> o 03

• H Φ -q 34 IΦ 34> S 3> O Ό

P O, '5 P 3> α, -ρ

C Φ

X υ X: i CO £ H £ ΦΌ1

31 »O < - I03 1

O

P 4J ,; »P P> 4) J3 JZP PCd 4)

WHAT

Ή P

£ O

34 H 34 CO CXCO JO ΦΦ O P05 Ό Ή £ Φ

> p Φ -P 3

X CO

OJ>

-P

oQ, P and -x

I 34 Ό Ό> P ai r ~ 4 Ή S '? O

CM p

S-S o

CM • x, <o M3 c

"O

XO> IS3 '> 1 c T3' «3

MSI -> s £ Ό

xO> 53 c ta

JZ 4-1 φ 5 <d £ O O £ p p p p p p p p p p p p p p p p p £

XO

> N> 34 Φ p σ> c? Ό

XO

U u C C ι 0 0 0 j 0 0 0 0 j j j j j j j j j j j j j j j j j j CC, O u Φ u 0 0 P 0 ΙΛ m tn r-4 r-4 ω! —4 - 38 -

FIG. 1 illustrates the isothermal reaction of nitromethane supporting ring closure in the presence of tin tetrachloride. Individual symbols have the following meanings: Q - 15 ° C, nitromethane (Al) 15 - 15 ° C (A2) 9 - 0 ° C, nitromethane (B1) - OeC (B2) - 15 ° c, nitromethane. (Cl) □ - -15 ° C (C2) The individual tests are carried out according to the procedure of Example 1, with or without addition of nitromethane (2.5 equivalents / setpoints of sulfinyl chloride). It can be seen from FIG. 1 that in the presence of nitromethane, the ring closes faster than in the absence of nitrate. In addition, the yields of exomethylene in the presence of nitro-methane are higher than in its absence.

Fig. 2 shows a mathematical representation of the speed and evidence that during the first 30 minutes of the reaction, the ring-closing rate (# exomethylene formation) is 85%, 191%, and 41% at 15 ° C, 0 ° C, and -15, respectively. ° C. Mathematically, AI is represented by the equation Y = 3.6467X and A2 by the equation Y -1,9667X. B1 is mathematically represented by the equation Y = 0.6800X and B2 Y = 0.23333X, C1 is represented by the equation Y → Q, 1Q333X and C2 by the equation Y = 7,3333Χ1θ “2.

Industrial usability

Process for the preparation of 1-exomethylenecepham sulfoxide esters resulting in a higher reaction rate to increased yields.

Claims (32)

- 39 CLAIMS λΛ3Γ90 V 'λΣ.3 l'? The process for the preparation of the 3-methoxymethylenecepham sulfoxide ester of formula I) CH, (I) wherein A is an amino-protecting group or a group of formula (R) - C - wherein R is a carboxylic acid moiety and R1 is a carboxy protecting group, characterized in that chlorosulfinylazetidinone of formula (II) is reacted (11) COOR1 in an inert medium under substantially anhydrous conditions with a Friedel-Crafts type Lewis acid catalyst and in the presence of a nitro compound at a temperature and for a time sufficient to form a compound of formula (I); 2. The process of claim 1 wherein the nitro compounds are selected from the group consisting of nitromethane, nitroethane, nitrobenzene, and nitropropane. 3. A process according to claim 1, wherein the Lewis acid Friedel-Crafts catalyst is selected from the group consisting of titanium tetrachloride, 40 zirconium chloride and tin tetrachloride. 4. The process of claim 1 wherein the reaction is carried out in the presence of an unsaturated compound. 5. The process of claim 4 wherein the unsaturated compound is unconjugated alkadiene 5 to 5. 10 carbon atoms » 6. The process of claim 4 wherein the unsaturated compound is allen of from 3 to 10 carbon atoms. 7. The process of claim 4 wherein the unsaturated compound is a cycloalkene of 5 to 10 carbon atoms. A method according to claim 7, characterized in that. cycloalkene is cyclopentene or cyclohexene. 9. The process of claim 4 wherein the unsaturated compound is an alkene of 2 to 10 carbon atoms. 10. The process of claim 1 wherein the alkene is alkene and 5 to 8 carbon atoms. 11. The method of claim 10, wherein the alkene is straight-chain or branched. 12. The process of claim 11 wherein the alkene is 1-pentene, 1-hexene, 2-hexene, 1-heptene or 1-octane. carried out in the presence of an oxo compound. 14. A process according to claim 13, wherein the oxo compound of formula (41) is R2-Q-R2, Z0, R2-C-R2, Z * C = O / r '/ (O) where each R2 is independently of one another an alkyl group of 1 to 1; 4 carbon atoms, each R 2 independently of one another an alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 5 to 6 carbon atoms, a phenyl group or a phenyl group substituted with an alkyl group having 1 to 4 carbon atoms, alkoxy group 1 or a halogen atom, Z is CH 2 CH 2 -CH 2 CH 2 -O-CH 2 CH 2 - or 4 or 5 and Z * is a group of formula -ch 2 -a-ch 2 -c-R 0 where each R 2 is hydrogen or C1-4 alkyl and an 3-6. A process according to claim 14, wherein A represents a group of the general formula R - C - wherein R represents a benzyl, phenoxymethyl or 2-thienyl group and R 4 represents a benzyl or substituted benzyl group. 16. The process of claim 15 wherein R is phenoxymethyl and R5 is p-nitrobenzyl. 17. A process according to claim 16 wherein the oxo compound is R2-O-R2 or R2-C-R20 18. The compound of Claim 17 wherein the oxo compound is diethyl ether. or acetone. 19. The method of claim 1, wherein the reaction is carried out in a compound. characterized in that the unsaturated compound is present in an amount of about 1 to about 2 moles and the osmoxy compound is present in an amount of about 0.75 to about 2 moles, in each case per mole of 4-chlorosulfinylazetidinone. 21. A process according to claim 20 wherein A is a group of formula R-C-II wherein R is phenoxymethyl, R5 is 4-nitrobenzyl, oxo is diethyl ether and unsaturated is alkene of 5 up to 8 carbon atoms » 22. The method of claim 21 wherein the alkene has a straight chain. The method of claim 1 wherein the temperature is about -15 to about 60 ° C. 24. The method of claim 23, wherein the temperature is about -10 to about CC. 25 »Process for the preparation of 3-exomethylene sulfoxide ester of general formula I 0 wherein A is an amino protecting group or a general formula - 43 R - C - wherein R is a carboxylic acid radical and R @ 1 is a carboxy protecting group, wherein chlorosulfinylazedininone of general formula II is not reacted. (11) in an inert solvent of substantially anhydrous conditions in the presence of a Friedel-Crafts Lewis acid catalyst of the group consisting of titanium tetrachloride, zirconium chloride and tin tetrachloride and nitro compounds of nitromethane, nitroethane, nitrobenzene and nitropropane at about -15 to about 15 ° C. about 60 QC for a sufficient period of time to form a compound of Formula I. 26. The process of claim 25 wherein the reaction is carried out in the presence of an unsaturated compound comprising from 2 to 10 carbon atoms, 5 to 10 carbon cycloefin, 5 to 10 carbon unconjugated diolefins, allen. with from 3 to 10 carbon atoms and unconjugated cyclodienes having from 6 to 10 carbon atoms. 27. The process of claim 25 wherein the reaction is carried out in the presence of an oxo compound. 28. The method of claim 25, wherein the reaction is carried out in the presence of an unsaturated compound and an acid. 29. The process of claim 28 wherein the nitro compound is nitromethane and the catalyst is a tin-crafts type Lewis acid catalyst. The method of claim 29, wherein the nitromethane is present in an amount of about 1 to about 4 moles per mole of azetidinone, the Friedel-Crafts catalyst is present in an amount of about 1 to 3 moles per mole of azetidone, the oxo compound is it is present in an amount of about 0.75 to 2 moles per mole of azetidinone and the unsaturated compound is present in an amount of about 1 to 2 moles per mole of azetidinone. 31. The process of claim 30 wherein the unsaturated compound is 1-hexene and the oxo compound is diethyl ether. 32. A process according to claim 31 wherein A represents a radical of formula R (R) - C - wherein R is benzyl, phenoxymethyl or 2-thienyl and benzyl or substituted benzyl. 33. A process for the preparation of the 3-exomethylenecepham sulfoxide ester of formula (I) wherein A is an amino-protecting group or a group of formula (0) R-C-wherein R is a carboxylic acid moiety and R 1 is a carboxy-protecting group, characterized in that. the chlorosulfinylazetidinone of formula XI-45 A-N S-Cl O is reacted COOR C-CH. (11) in an inert solvent under substantially anhydrous conditions in the presence of about 1 to about 3 moles relative to 1 mole of azeotidinone, a Friedel-Crafts Lewis acid catalyst of titanium tetrachloride, zirconium chloride and tin tetrachloride, about 0, 75 to about 2 moles, based on 1 mole of azetidinone, of an oxo compound, about 1 to about 2 moles, based on mol of azetidinone, of an unsaturated compound; and in the presence of about 1 to about 4 moles, based on molazetidinone, of nitro compounds of nitro-methane, nitroethane, nitrobenzene and nitropropane, at a temperature of about -15 to about 60 ° C and for a time sufficient to form the compound of Formula I. 34. The process of claim 33 wherein the unsaturated compound is 1-hexene. 35. The process of claim 33 wherein the oxo compound is diethyl ether or acetone. 36. The process of claim 33 wherein the reaction is carried out at a temperature of about -10 ° C to about 0 ° C. 37. The process of claim 33 wherein the Lewis acid catalyst is tin tetrachloride. 38. The process of claim 37 wherein the nitro compound is nitromethane in an amount of about 2.5 moles per mole of azetidinone. - 46 39. The method of claim 33 wherein A is a generic group. In R - C - wherein R is benzyl, phenoxymethyl or 2-thienyl and R 1 is benzyl or substituted benzyl.