DE2145946A1 - Process for the preparation of 7-AcyIamido-3-acyloxymethyl-Delta hoch 3 -cephalosporinsulfoxidestern - Google Patents

Description

DR. I. MAAS

DR. W. PFEIFFER

DR. F. VOITHENLEITNER

8 MUNICH 23

UNGERErtSl R. 25 - TEL 39 02 $ 3

OL 85 429
X - 3350

Eli Lilly and Company, Indianapolis , Indiana, V.St.A.

Process for the preparation of 7-acylamido-3-acyloxymethyl-delta-cephalosporin sulfoxide esters

The invention relates to the acylation of deacetylcephalosporins and relates to a new and improved process for the preparation of 3-alkanoyloxymethyl or 3-cycloalkanoyloxymethyl derivatives of cephalosporins.

The invention relates to a method for the production

3 development of 7-acylamido-3-acyloxymethyl-Delta -cephalospo-

3 rinsulfoxidestern, in which a 7-acylamido-delta-desacetylcephalosporinsulfoxidester reacted with the anhydride of a saturated carboxylic acid under acidic conditions will.

Recently, the semi-synthetic production of 7-acylamidodesacetoxycephalosporin antibiotics has started Penicillins gained importance as starting materials after Morin and Jackson (US-PS 3,275,626) a

209822/1039 «™ ^INSPECTED

Processes for converting penicillin sulfoxide esters into desacetoxycephalosporanic acid esters have found and since it has been found / that some esters of the penicillins used and the desacetoxycephalosporin esters produced are more advantageous in the process than those used by Morin and Jackson because they are easier to split. The Morin-Jackson method could be further improved by finding that the application of certain Solvent the thermal rearrangement of the penicillin sulfoxide esters specifically directs towards the formation of the corresponding desacetoxycephalosporin esters and the application lower temperatures allowed.

Some 7-acylamidodeacetoxycephalosporanic acid compounds have been shown to be have unique properties as antibiotics of a special kind. For example, are Cephalexin (7- ^ t) -2'-phenyl-2'-aminoacetamidcy-desacetoxycephalosporanic acid zwitterion) and pharmaceutically acceptable anionic and cationic salts thereof useful as oral antibiotics for combating infections, which, for example, by penicillin-resistant strains of Staphylococcus aureus and many other gram-positive and gram-negative microorganisms.

The products made according to the Morin and Jackson penicillin ring expansion process and / or its improvement " Serungen as described above, obtained are Delta -Desacetoxycephalosporins of the formula

(D

CGOR ₁

209822/1039

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wherein R is the remainder of the acylamido group in position 7 and R is a hydrogen atom, a salt-forming cation, a Ester group or an anionic charge means when the group C00 ~ a salt with a cation within or forms outside the molecule.

It is known that compounds of this type are good antibiotics or have antibacterial properties when the methyl group in position 3 is replaced by an alkanoyloxy group is substituted. For example, in U.S. Patent 3,218, the compound is

O- ^cH ^ - ^NH -fr ^ i

. ν J

// S ^ - CH ₂ - O - C - CH ₃

COOH (II)

described, which is known under the name cephalothin as a recognized and commercially available antibiotic.

However, there are currently only limited methods available for introducing an alkanoyloxy group into the 3-position of the cephalosporin system. As a result, most S-alkanoyloxymethyl cephalosporin compounds are generated from compounds which already contain a 3-alkanoyloxymethyl group. Example catfish is produced according to the information in US Pat. No. 3,218,318 already mentioned, cephalothin by acylation of 7-aminocephalosporanic acid

ir

-CH ₀ -OC-CH.

COOH obtained, 209822/1039

-A-

2U5946

which in turn is obtained from cephalosporin c, which is now known to have the following formula:

HOOC - CH - (CH) -C-NH NH "

Il

COOH

In addition, in the production of cephalosporin C by fermentation according to known methods, as described in the U.S. Patent 3,093,638, the reaction mixture generally desacetylcephalosporin C

Il

- C-NH

HOOC - CH

NH,

COOH

in quantities of 10 to 18 t that are not fully recycled will.

The invention also aims at a new and improved method for the production of 3-acyloxymethylcephalosporins.

In particular, the invention is intended to provide a new and improved one Process for the preparation of 3-acyloxymethylcephalosporin compounds from 3-hydroxymethylcephalosporin compounds.

209822/1039

The invention relates to a process for the preparation of 3-acyloxymethylcephalosporins, in which a T-acylamidodesacetylcephalosporin sulfoxide ester of the formula

-CH ₂ OH (VI)

COOR ₁

where R is the remainder of the 7-acylamido group and R. is an ester protecting group means with an aliphatic acid anhydride under acidic or basic conditions to the corresponding 3-Alkanoyloxymethy! Compound

It

C-CH "-O-C-R" (VII)

COOR ₁

is reacted, wherein R _{2 is} an aliphatic group derived from the acid anhydride. The invention thus creates the previously unavailable possibility of functionalizing the exocyclic hydroxymethyl group in position 3 of T-acylamidodesacetylcephalosporin sulfoxides without causing isomerization of the double bond from the 3-cephem compounds to the 2-cephem compounds in the production of known cephalosporin antibiotics.

Any aliphatic carboxylic acid anhydrides can be used as the acid anhydride with 4 to 20 carbon atoms used

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will. Preferred anhydrides are those of the general formula

0 0

Il Il

wherein R _{2 is} a hydrogen atom, an alkyl radical having 1 to 7 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl and the like, or a cycloalkyl radical of the formula

R ₃ CH- (CH ₂ ) _n -

means in which R _{3 is} a C.-C ₃ -Al] Cflen group (ie methylene, dimethylene, trimethylene) and η is 0 or an integer from 1 to 4. Examples of such cycloalkyl radicals are cyclobutyl, cyclobutylmethyl, cyclobutylethyl, cyclopentyl, cyclopentylethyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl and the like.

Examples of the carboxylic acid anhydrides which can be used to carry out the process according to the invention, are acetic anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride, pentanoic anhydride, Hexanoic anhydride, heptanoic anhydride, cyclobutanecarboxylic anhydride, Cyclopentanecarboxylic anhydride, cyclohexanecarboxylic anhydride, cyclobutane acetic anhydride, cyclobutane propionic anhydride, Cyclopentane acetic anhydride, cyclohexane acetic anhydride, cycloheptane acetic anhydride, cyclohexane propionic anhydride and the same.

209822/1039

As indicated above, the inventive method is preferably in the presence of an acidic or basic catalyst carried out. An inorganic non-oxidizing catalyst is preferably used as the acidic catalyst Acid, for example perchloric acid, sulfuric acid or phosphoric acid, is used. As a basic catalyst Any of a variety of organic bases, and preferably tertiary bases, can be used. Exemplary for such suitable basic catalysts are pyridine, piperidine, morpholine, triethylamine and a considerable number of other bases known to those skilled in the art.

The reaction is preferably carried out in the presence of an inert organic solvent, especially if one of the acidic catalysts mentioned is used. In the case of the basic catalysts, however, it can expediently the use of a solvent can be dispensed with, and the reaction is carried out in the presence of the basic Catalyst carried out as a solvent. For best results, a solvent is used that is inert to the reactants and products. Many such solvents are suitable for those skilled in the art, including for example ethylene dichloride, chloroform, dioxane, dimethylformamide, aliphatic ethers such as diethyl ether, aliphatic ketones such as acetone or methyl ethyl ketone, aliphatic carboxylic acid esters such as ethyl acetate, isopropyl acetate and methyl isoamyl acetate and many others. The reaction temperature is not critical and can be within further limits can be changed. In general, room temperatures are sufficient, but higher ones can be used if desired or lower temperatures can be used. To achieve the best results, a reaction temperature should be im Range from -10 to ICX) degrees C and preferably 0 to 30 degrees C can be used.

209822/1039

The 7-acylamido group and the remainder of the ester protecting group in the 4-position are not involved in the reaction, and therefore the course of the reaction is not influenced by the nature of these groups. For this reason, the 7-acylamido group can have any. ^{One of} the numerous groups now familiar to those skilled in the PeniciHin and Cephalosporin fields.

Exemplary of suitable acyl groups in the starting materials which can be used to carry out the process according to the invention are acyl groups the formula

Il

R ₂ - (CH ₂ ) _n - C - (X),

wherein η is 0 or an integer from 1 to 6 and R _{2 is} an organic group, for example an aryl group or a substituted aryl group having 6 to 14 carbon atoms.

Preferred aryl groups are those derived from benzene or naphthalene,

or

(XI) (XII)

where Q is hydrogen or one or more substituents, for example C.-C-j-alkyl radicals (for example Methyl, ethyl, propyl, isopropyl), C- ^ Cg-alkoxy radicals

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(for example methoxy, ethoxy, propoxy), cyano groups, nitro groups, hydroxyl groups, halogen atoms (chlorine, fluorine, bromine and iodine), tri fluorine thyroid, carboxy groups, amino groups, C -C.-carboxyalkyl groups (e.g. carboxymethyl, Carboxyethyl, carboxypropyl) or C.-C.-carboxamidoalkyl groups / H ₉ NC (O) -alkyl / (for example carboxamidomethyl, carboxamidoethyl).

Representative examples for the AcyL groups mentioned are among many other BenzoyL, phenylacetyl, beta- (phenyl) propionyl, NaphthoyL, NaphthyLacetyl, gamma-PhenyLbutyryl, p-ilethylbenzoyl, 2,4-DLmethylphenylacetyl, 5-methoxynaphthylacetyl, p-Cyanphmiylacetyl, 4-üIitronaphthoyl, 3-Nitrobenzoyl, SjS-DicyiinnaphthylacetyL, beta- (3-NLtrophenyl) propionyl, p-IIydroscybenzoyL, 4-Hydroxyphenylacetyl, p-Chlorophenylacetyl, m- [Jforaben:; oyl, 3-Trifluonuethylphenylace ty 1, o-Carboxypheny L ace ty L, rn-Carboxy: ae thy lpheny Lace ty I, m-Carboxamidomethylpheiiy Lace ty L, beta (5-Carboxamidomethyl L-naphthyl) propiony L, Aminobenzoy L and AniLnopheny LticetyL.

R ₉ can also mean a CycLoaLkyLrest with 4 to 8 carbon atoms, beispLels ^ / a CyclobutyL, CycLoptint / l., Cyclohexyl, CycloheptyL and the like. These CycloaLkyL radicals can also be substituted by eLrirm or more of the substituents Q described above.

Examples of such acyl groups are cyclopentanoy, Cyclohexanoyl, 3-MetliyLcycLohüKanoyl, Cyclobutylcarboiiyl, 2-MethoxycyclohexanoyL, J-Chlorcyclohexylacetyl, CycLopentylacetyl, beta-CycLopentyipropionyl, J-HethoxycycLohexylacetyl, 2-CyancycLoprrityLactityl, 3-iIitrocycLohexunoyL, 3-carboxycyclohexyLacetyL and 3-carboxamidomethylcycLohexyL-acetyl.

20982 2/1039 & * & ORIGINAL

R ₂ can also mean a heberocyclic radical which contains as heteroatom 0, S, N or any combination thereof, for example dioxanyl, 2-furyl, 3-furyl, imidazolyl, isoxazolyl, morpholinyl, oxazolyl, pyranyl, pyrazinyl, pyrazolyl, N- Pyridyl, 2-pyridyl, 3-pyridyl, pyrimidyl, N-pyrryl, 2-pyrryl, 3-pyrryl, thiazolyl, 2-thienyl, 3-thienyl, 2-benzothienyl, 3-benzothienyl, triazinyl, triazolyl and the like, the partial and fully hydrogenated derivatives of these resins, for example. Tebrahydrofuryl, imidazolinyl, imidazolidyl, piperidyl, tebrahydropyrimidyl, pyrrolidyl and the like, as well as all the aforementioned radicals substituted by one or more of the groups Q described above, for example the picolyl radicals, methyl fury ir es te, flethylthienylresbe, nibrofuryl Cyanfuryl, nitrobenzothienyl, mitropyridyl, cyanpyridyl, mebhoxypyrimidyl, bromopyridyl, trifluoromebhyLpyridyl and other such quantities as described in US Pat. No. 3,218,318.

Examples of acyl groups in which R is a heterocyclic residue are dioxanyl acetyl, 2-furylcarbonyl, beta-pyrazinylpropony1, 2-pyridylacetyl, 3-pyridyl carbonyl, 2-thienyl acetyl, J-benzobhienylcarbony1, piperidroyl 1 idy Lcarbony 1, Hi brobenzοbhieny Liiceby 1, ψ beta- (MLtrofuryL) -propionyL, Cyanpy ridy lcarbonyl etc.

Further suitable AcyLreste are those of the general Form1

Il

R ₃ -C- (XIII),

wherein R- is an alk /! radical having 1 to 8 carbon atoms (for example methyl, ethyl, isopropyl, η-butyl, tert-butyi, Hexyl, Isooctyl) or an AlkenyLre ^ t with

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2U5946

2 to 8 carbon atoms (for example vinyl, allyl, 2-butenyl, 3-hexenyl). The mentioned alkyl or alkenyl radicals can furthermore be substituted by one or more substituents, including, for example by an amino group, a cyano group, a nitro group, a hydroxyl group, a halogen atom, chlorine, fluorine, bromine and iodine), a carboxy group or a carboxyamide group

(H ₂ NC-).

Examples of these acyl radicals are the acetyl, propionyl, Acrylyl, crotoyl, 2-aminoacetyl, 3-chloropropionyl, 6-heptenoyl, adipoyl, 3-hydroxypropionyl and 5-nitrohexanoyl radical.

For the method according to the invention, there are also those Desacetylcephalosporinsulfoxidester into consideration, in which the Äcylrest of the 7-acylamido group of the formula

II

R ₄ - (CH ₂ ) _m - X - (CH ₂ J _n - C - (XIV),

where η is as defined above, m is 0 or an integer from 1 to 5, X is 0 or S and R _{4 has} the same meaning as the radical R ₂ defined above (ie aryl radicals, cycloalkyl radicals or heterocyclic radicals) including substituted derivatives thereof or like the radical R defined above (ie C -C -alkyl radicals or C _o -C _o -alkenyl radicals) including substituted ones

Δ O

Has derivatives thereof.

Representative examples of the acyl groups defined by formula XIV are, among many others, tert-butoxycarbonyl, tert-butoxyacetyl, ethoxyacetyl, tert-butyl

209822/1033

mercaptocarbonyl, tert. -Butylmercaptoacetyl, vinyloxy-. - acetyl, allyl mercaptoacetyl, 3-bromopropoxyacetyl, 3-hydroxypropylcarbonyl, 2-thienyloxyacetyl, piperidyl mercaptoacetyl, 2-pyridyloxycarbonyl, phenoxyacetyl, naphthoxyacetyl, Phenoxycarbonyl, aminophenoxyacetyl, beta- (phenoxy) propionyl, cyclohexyloxyacetyl, chlorcyclopentyloxyacety1, Benzyloxyacetyl, phenylmercaptoacetyl, Phenylbutoxyacetyl, Phenylathy liner cap topropionyl and Phenylmercaptoacetyl.

Further suitable 7-acyl groups are those of the general types formula

R ₅ - CH - C - (XV),

wherein Y is an amino group, a protected amino group, a hydroxy group, a C1 "C ₃ alkoxy group (for example methoxy, ethoxy etc.), a carboxyl group or a C 1 -C 6 alkanoyloxy group (for example acetoxy, propionyloxy etc.) and R _{5 means} one of the groups defined above by R "(ie an aryl radical, heterocyclic radical or cycloalkyl radical, as described in detail above). Examples of such acyl groups are, among many others, 2-phenyl-2-aminoacetyl, 2- (p-meihoxyphenyl) - 2-aminoacetyl, 2-cyclohexyl-2-methoxy7, §gftyl, 2-phenyl-2-acetoxyacetyl, 2- (2'-pyridyl) -2-hydroxyacetyl, 2-piperidyl-2-aminoacetyl, 2- (2'- Thienyl) -2-acetoxyacetyl.

In addition to the radicals mentioned above, many other acyl groups are suitable, including, for example, pheny l-alpha, alpha-dimethylacetyl radical and Q-substituted derivatives thereof. Various other suitable acyl groups

209822/1039

are described in U.S. Patents 2,479,295, 2,479,297, 2,562,407, and 2,623,876.

The implementation is also not significantly influenced by the type of ester protection group R _1. In general, it is preferred that R is an ester radical which can easily be cleaved off by known measures, for example with dilute aqueous base, with trifluoroacetic acid or by hydrogenation in the presence of a palladium or rhodium catalyst on a suitable support such as carbon, barium sulfate or aluminum oxide so that the cephalosporin is not damaged since the end product is generally used in the form of the acid.

Representative groups R. are, for example, C.-Cgtert-alkyl radicals (for example tert-butyl, tert-pentyl, etc.), C ₅ -C _? -tert-alkenyl radicals (for example tert-pentenyl, tert-hexenyl, etc.), Cc-C ₇ -tert-alkynyl radicals (for example l, l-dimethyl-2-pentinyl and the like), benzyl, methoxybenzyl, Nitrobenzyl, phenacyl, trichloroethyl, benzhydryl, phthalimidomethyl, succinimidomethyl and numerous other radicals which are obvious to the person skilled in the art.

A suitable starting material for use in the invention Process is for example the compound tert-butyl ^ -phenoxyacetamido-S-hydroxymethyl-S-cepheml-oxide-4-carboxylate of the formula q

0 - CH ₂ - C - IJIfr

[ 1

N \ ^ C-CH ^ OH (XVII)

CH ,, t · *

COO-C-CH, » ■>

CH ₃

Other S-deacetylcephalosporin sulfoxide esters available as Starting materials that can be used for the process according to the invention are, for example, the following:

p-Nitrobenzyl-T-phenoxyacetamido-S-hydroxymethyl-3-cephem ~ 1-oxide-4-carboxylate /

Benzyl-T-phenylacetamido-S-hydroxymethyl-S-cepheml-oxide-4-carboxylate,

beta, beta, beta-trichloroethyl-V-phenylmercaptoacetamido-3-hydroxymethyl-3-cephem-1-oxide-4-carboxylate,

Phthalimidomethyl-V-benzyloxyacetamido-S-hydroxymethyl-3-cephem-1-oxide-4-carboxylate,

tert-butyl 7- (4'-methylphenylbutyrylamido) -3-hydroxymethyl-3-cephem-1-oxide-4-carboxylate,

1,1-dimethyl-2-pentinyl-7- (4'-propylbenzyliuercaptoacetamido) -3-hydroxymethyl-3-cepheIn-1-oxide-4-carboxylate,

Succinimidomethyl-T-benzylmercaptopropionamido-S-hydroxymethyl-3-cephem-1-oxide-4-carboxylate,

beta, beta, beta-trichloroethyl-T-phenylpropionamido-S-hydroxymethyl-3-cephem-l-oxide-4-carboxylate,

Benzhydryl-T-phenyläthylinercaptopropionamido-S-hydroxy- · methyl 3-cephem-1-oxide-4-carboxylate,

Benzyl-T-phenylbutoxybutyrylamido-S-hydroxymethyl-S-cepheml-oxide-4-carboxylate ,

Benzyl-T-phenylbutoxybutyrylamido-S-hydroxy-diethyl-S-cepheial-oxide-4-carboxylate *

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1 , l-Dimethyl - ^ - pentenyl -? - (3 '-f luophenoxy-acetamido) S-hydroxymethyl-S-cephem-l-oxide-4-carboxylate,

p-Nitrobenzyl-7-pheny 1-alpha, alpha-dimethylacetamido-3-hydroxymethyl-3-cephem-1-oxide-4-carboxylate,

p-methoxybenzyl-7- (2'-chlorobenzyloxypropionamido) -3-hydroxymethyl-3-cephem-1-oxide-4-carboxylate,

tert-butyl-T-benzamido-S-hydroxymethyl-S-cephem-1-oxide-4-carboxylate ,

p-nitrobenzyl-7- (2'-phenyl-2'-aminoacetamido) -3-hydroxymethyl-3-cephem-1-oxide-4-carboxylate,

tert-butyl-7- (4'-nitrophenylmercaptoacetamido) -3-hydroxyme thy 1- 3 -cephem-l -oxide- 4 -carboxy lat ,

Benzyl 7- (3'-cyanophenylpropionamido) -3-hydroxymethyl-3-cephem-1-oxide-4-carboxylate,

p-methoxybenzyl-7- (3'-trifluoromethylphenoxyacetamido) -S-hydroxymethyl-S-cephem-1-oxide-4-carboxylate,

1 , l-Dimethyl ^ -pentynyl ^ -butyrylamido-S-hydroxymethyl-3-cephem-1-oxide-4-carboxylate ,

tert-butyl-7-cyclohexylacetamido-3-hydroxymethyl-3-cepheml-oxide-4-carboxylate ,

Succinimidomethyl 7- (beta-aminopropionamido) -3-hydroxymethyl-3-cephem-1-oxide-4-carboxylate _f

p-Nitrobenzy 1-7-allylmercaptoacetamido-3-hydroxymethy 1 · ^ '3-cephem-1-oxide-4-carboxylate ,

p-Methoxybenzyl-7- (gamma-chlorocrotylmercapta-acetamido:> e? v \> 3-hydroxymethyl-3-cephem-l-oxide-4-carboxylate _/

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tert-butyl 7- (5'-amino-5'-carboxyvaleramido) -3-hydroxymethyl-3-cephem-1-oxide-4-carboxylate,

beta, beta, beta-trichloroethyl-7 "(2 ^l -thienylacetamido) -3-hydroxymethyl-S-cephem-1-oxide-1-carboxylate,

p-nitrobenzyl-7- (n-butylmercaptoacetamido) -3-hydroxymethyl-3-cephera-1-oxide-4-carboxylate,

p-methoxybenzyl-7- (tert-butoxyacetamido) -3-hydroxymethyl-3-cephem-1-oxide-4-carboxylate,

Benzyl 7- (2'-benzothienylacetamido) -S-hydroxymethyl-S-cephem ~ 1-oxide-4-carboxylate,

Benzhydryl-7- (3'-pyridy! Acetamido) -S-hydroxymethyl-S-cephem- * l-oxide-4-carboxylate,

tert-butyl-7- (2'-pyranylacetamido) -S-hydroxyraethyl-S-cepheml-oxide-4-carboxylate,

p-nitrobenzyl-7- (5'-oxazolylacetamido) -S-hydroxymethyl-S-cephem-1-oxide-4-carboxylate,

1, l-Dimethyl ^ -pentenyl -? - (2'-pyrazinylacetamido) -3-hydroxymethyl-3-cephem-1-oxide-4-carboxylate,

p-Nitrobenzyl-7- (5'-fluoro-2'-pyridyIpropionamido) -3-hydroxymethy1-3-cephem-1-oxide-4-carboxylate,

Benzyl-7- (2'-furoylamido) -S-hydroxymethyl-S-cephem-l- ^ oxide-4-carboxylate,

Benzhydryl-7- (2'-furylacetamido) -S-hydroxymethyl-S-cepheml-oxide-4-carboxylate,

tert-butyl 7- (5'-nitro-2'-thienylpropionamido) -3-hydroxymethyl-3-cephem-1-oxide-4-carboxylate,

beta, beta, beta-trichloroethyl-7- (5'-methoxy-3 ¹ -pyridy1-acetamido) -3-hydroxy-methyl-3-cephem-1-oxide-4-carboxylate.

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The 3-deacetylcephalosporin sulfoxide esters, which are available as Starting materials used for the process according to the invention can be made in a number of ways. For example, 7-acylamino-3-deacetylcephalosporanic acid esterified and then by treatment with an organic peroxy compound, for example peracetic acid, meta-chloroperbenzoic acid or organic peroxides, are oxidized in a known manner to the corresponding sulfoxide. Alternatively can the acid is first oxidized and then esterified v / earth to the as starting material for the invention Methods used 7-acylamido-3-deacetylcephalosporin sulfoxide ester to create.

The products of the process according to the invention, which have the following formula:

0 0

Il
Il

R-C-NII

COOR

Il

, -0-CR ₂ (XVIII)

where R is the remainder of the 7-acylamino group described above, R is the remainder of an ester protecting group as explained above and R is an alkyl or cycloalycl radical derived from the acid anhydride, are advantageous as intermediates for the preparation of active cephalosporin antibiotics. For example, if the 7-acylamido group is a heterocyclic group, for example the 2-thienylacetamido group, the product of the formula XVIII given above can be prepared by using a suitable reducing agent, for example sodium dithionate, in the presence of an activator,

209822/1039

for example acetyl chloride, to the compound

) -C-CH ₃ (XIX)

which is a well known antibiotic described in U.S. Patent 3,218,318 is. In addition, according to the information provided by. U.S. Patent 3,218,318 products of Formula XVIII by refluxing in aqueous solution with an excess of a tertiary amine, for example pyridine, in cephalosporin C antibiotics are transferred, for example

A.

wise in the connection

.CH ^ - C - NH

Il I // v \

ψ It is intended within the scope of the invention to later remove the 7-acylamino group in compounds obtainable according to the invention. For example, deacetylcephalosporin C, which is produced as a by-product in the production of cephalosporin C by fermentation, can be acylated according to the invention after oxidation and esterification as follows:

209822/1039

Il

HOOC - CH - (CH ₀ J ₀ -C -NH

2'3

NH,

Il

(R ₂ CO) ₂ O

(XXI)

HOOC - CH -

R ₂ -C- NH

It

■ ι

- C - NH

-N

Il

COOR,

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The product of reaction XXI can be used to remove the 7-acylamido group to form the corresponding 7-Aminocephalosporins can be deacylated, which in turn can be reacylated to produce an antibiotic des to generate the type explained above by Formula XVIII. Alternatively, the deacety! Cephalosporin, which is found in of the above reaction XXI is used as the starting material, before the reaction with a carboxylic acid anhydride desacylated and then reacylated. In any case, the method according to the invention offers a simple and effective way to utilize the by-product of the cephalosporin C fermentation process formed deacetylcephalosporins C.

The method according to the invention also provides an advantageous link in the method path to the upper guide of desacetoxycephalosporins produced by the Morin-Jackson penicillin ring expansion method described above be obtained in compounds of the type of cephalosporin C. For example, can

2
Delta -S-Desacetoxycephalosporins through the following stages

into the corresponding 3-bromomethyl-Delta-Ccphalosporinsulfoxidester be transferred, which in turn is in

2
the delta -3-hydroxymethyl compound can be converted

209822/1039

R-C-NH.

/ λ

COOR ₁

Base R 0-1O ⁰ C.

(XXII)

N-Bfcomide succimide

R-C-NH

(f

(XXIII)

/ C-CH ₂ Br

COOR,

hydrolysis

R-C-NH

(XXIV)

COOR,

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The 3-hydroxymethyl-delta cephalosporin obtained as product (XXIV) can then be oxidized and rearranged as shown below:

Il

R-C-NH.

Υ: Γ) ι

L. 0_ / R - 0
Il
C - WITH 0
Il ■ Q , 0H (XXV) Ö I.
COOR ₁ CH,

tet, can then to the corresponding 3-alkanoyloxy or

3-Cy ₁ den.

3-Cycloalkanoyloxymethyl-Delta compound be acylated

The invention is further illustrated by the following examples explained.

example 1

0.220 g of tert-butyl V-phenoxyacetamido-S-hydroxymethyl-3-cephem-1-oxide-4-carboxylate are dissolved in 3 ml of ethyl acetate, and the mixture obtained is brought to a temperature chilled by about 18 degrees C. Then 0.5 ml of acetic anhydride and 1 drop of perchloric acid are added to the reaction mixture added. By thin-layer chromatography found that implementation in less than one Minute has ended.

The reaction mixture is then diluted with 20 ml of ethyl acetate with a 5 percent sodium bicarbonate solution washed, dried over sodium sulfate and evaporated to dryness to give 0.215 g of product

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and the product of the above reaction XXV, derived from the product of the Morin-Jackson process

will. It is demonstrated by NMR spectroscopy that the product of tert-butyl ^ -phenoxyacetamido-S-acetoxymethyl-3-cephem-1-oxide-4-carboxylate consists.

Example 2

0.25 g beta, beta, beta-trichloroethyl-7-phenylacetamido-3-hydroxymethyl-3-cephem-1-oxide-4-carboxylate are dissolved in ethyl acetate and cooled to a temperature of about 20 degrees C. Then the reaction mixture is with about 0.6 ml of acetic anhydride and a drop of concentrated Sulfuric acid added.

The product is isolated according to the procedure of Example 1 and as beta, beta, beta-Trichloräthy1-7-pheny1-acetamido-3-acetoxymethyl-3-cephem-1-oxide-4-carboxylate identified.

Example 3

0.25 g of p-nitrobenzy 1-7-phenylmercaptoacetamido-3-hydroxymethyl-3-cephem-1-oxide-4-carboxylate are dissolved in ethyl acetate, and the resulting mixture is cooled to about 20 degrees C. Then about 0.5 ml Propionic anhydride and 1 drop of perchloric acid were added.

The product is isolated as described in Example 1 and as p-nitrobenzyl-7-phenylmercaptoacetamido-3-propionoxymethyl-3-cephem-1-oxide-4-carboxylate identified.

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Example 4

tert. -Butyl ^ -benzyloxyacetamido-S-hydroxymethyl-S-cephem-1-oxide-4-carboxylate is dissolved in 5 ml of pyridine, and the resulting mixture is cooled to a temperature of about 20 degrees C. About 0.5 ml of acetic anhydride are then added.

The product is made from the reaction mixture in the usual way Way isolated and identified as tert-butyl-7-benzyloxyacetamido-3-acetoxymethyl-3-cephem-1-oxide-4-carboxylate.

Example 5

p-Methoxy-7- (4 * -cyanphenoxyacetamido) -3-hydroxymethyl-3-cephem-1-oxide-4-carboxylate is dissolved in ethyl acetate, and 1 ml of triethylamine is added to the mixture. The mixture obtained is cooled and then cyclohexanecarboxylic anhydride is added.

p-Methoxybenzy 1-7- <4 * -cyanphenoxyacetamido) -3-cyclohexap-methloybenzyl-7- (4'-cyanophenoxyacetamido) -3-cyclohexanoyloxymethyl-3-cephem-1-oxide-4-carboxylate identified.

Example 6

Following the procedure of Example 1, 1,1-dimethyl-2-pentinyl-7- (3 '-f luorbenzylmercaptoacetamido) -3-hydroxyraethyl-3- * cephem-1-oxide-4-carboxylate is reacted with butyric anhydride in the presence of perchloric acid .

The product is identified as 1,1-dimethyl-2-pentynyl-7- (2 · - fluorobenzylmercaptoacetamido) -S-butyryloxymethyl-S-cephera-1-oxide-4-carboxylate identified.

Example 7

Following the procedure of Example 1, succinimidomethyl ^ -phenylpropionacetamido-S-hydroxymethyl-S-cephem-1-oxide-4-carboxylate is obtained reacted with cyclobutanecarboxylic anhydride in the presence of concentrated phosphoric acid.

The product is called succinimidomethyl-7-phenylpropionacetamido-3-cyclobutanoyl-3-cephem-1-oxide-4-carboxylate identified.

Example 8

Following the procedure of Example 4, benzyl 7-allylmercaptoacetamido-S-hydroxymethyl-S-cephem-1-oxide ^ -carboxylate with cyclopentanecarboxylic acid in the presence of a pyridine catalyst implemented.

The product is called benzyl 7-allyl mercaptoacetamido-3-cyclopentanoyloxymethyl-3-cephem-1-oxide-4-carboxylate identified.

Example 9

Benzhydryl 7-cyclohexyl acetamido-3-hydroxymethyl-3-cepheml oxide-4-carboxylate is with propionic anhydride in the presence of triethylamine according to the procedure of Example 4 implemented.

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The product is called Benzhydryl ^ -cyclohexylacetamido-3-propionoxymethyl-3-cephem-1-oxide-4-carboxylate identified.

Example 10

Following the procedure of Example 1, benzyl 7- (5'-amino-5'-carboxyvaleracetamido) -3-hydroxymethyl-3-cephem-1-oxide-4-carboxylate is obtained reacted with acetic anhydride in the presence of perchloric acid.

The product is identified as benzyl-7- (5'-amino-5 • -carboxyvaleracetamido) -3-acetoxyme thy 1-3-cephem- 1-oxide-4-carboxy lat .

Example 11

tert-butyl 7- (2'-thienylacetamido) -3-hydroxymethyl-3-cephem-1-oxide-4-carboxylate is with propionic anhydride in the presence of perchloric acid according to the procedure of Example 1 implemented.

The product is found to be tert-butyl 7- (2'-thienylacetamido) -3-propionoxymethyl-3-cephem-1-oxide-4-carboxylate identified.

Example 12

Following the procedure of Example 4, tert-butyl-7- (2 -thienylacetamido) -S-hydroxymethyl-S-cephem-1-oxide ^ - carboxylate reacted with cyclohexaneacetic anhydride in the presence of pyridine.

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The product is isolated from the reaction mixture and identified as tert-butyl 7- (2 ^l -thienylacetamido) -3-cyclohexyl acetoxymethyl-3-cephem-1-oxide-4-carboxylate.

Example 13

Following the procedure of Example 4, p-nitrobenzyl-7- (2'-benzothienylacetamido) -S-hydroxymethyl-S-cepheml-oxide-4-carboxylate is reacted with propionic anhydride in the presence of pyridine.

After isolation from the reaction mixture, the product is identified as p-nitrobenzyl-7- (2'-benzothienylacetamido) -3-propionoxymethyl-3-cephem-1-oxide-4-carboxylate.

Example 14

p-Nitrobenzyl 7- (3'-pyridylacetamido) -3-hydroxymethyl-3-cephem-1-oxide-4-carboxylate is reacted in isobutyric anhydride in the presence of pyridine.

The product is identified as p-nitrobenzyl 7- (3'-pyridylacetamido) -3-ieobutyryloxymethyl-3-cephem-1-oxide-4-carboxylate.

Example 15

Following the procedure of Example 1, beta, beta, beta-trichloroethyl-7- (2'-furylacetamido) -S-hydroxymethyl-S-cephem-1-oxide-4-carboxylate with acetic anhydride in the presence implemented by perchloric acid.

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The product is made from the reaction mixture in the usual way Heise separated and as beta, beta, beta-trichloroethyl-7- (2 '-furylacetamido) -S-acetoxyinethyl-S-cephem-l-oxide - * - carboxylate identified.

Example 16

Following the procedure of Example 4, p-methoxybenzyl-7- (n-butylmercaptoacetamido) -S-hydroxymethyl-B-cephem-1oxide-4-carboxylate is obtained reacted with cyclohexane acetic anhydride in the presence of morpholine.

The product is called p-methoxybenzyl-7- (n-butylmercaptoacetamido) -S-cyclohexylacetoxymethyl-S-cephem-l-oxide ^ - carboxylate identified.

Example 17

Following the procedure of Example 1, benzyl 7- (tert-butoxyacetamido) -S-hydroxymethyl-S-cephem-1-oxide-4-carboxylate is obtained reacted with cyclopentane acetic anhydride in the presence of perchloric acid.

The product is found to be benzyl 7- (tert-butoxyacetamido) -3-cyclopentylacetoxymethyl-3-cephem-1-oxide-4-carboxylate identified.

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Claims (9)

'29 "2U59A6 claims 1. Process for the production of T- 3
Oxymethyl-delta-cephalosporinsulphoxide esters, characterized in that a 7-acylamido-delta-desacetylcephalosporinsulphoxide ester is reacted with the anhydride of a saturated carboxylic acid under acidic or basic conditions. 2. The method according to claim 1, characterized in that an anhydride having 4 to 20 carbon atoms is used . 3. The method according to claim 1 or 2, characterized in that a 7-acylamido-delta-desacetylcephalosporinsulfoxidester the formula Il R-C-NH , 0H Il ■■ COOR ₁ used, in which R is the remainder of the 7-acylamido group and R _{1 is} the remainder of an ester protecting group. 4. The method according to claim 1, 2 or 3, characterized characterized in that an anhydride of the formula 209822/1039 2U5946 R ₂ -COCR ₂ used, wherein R _{2 is} a hydrogen atom, a C -C_ -alkyl radical or a cycloalkyl radical of the formula -CH- R ₃ CH - means in which η 0 or an integer from 1 to 4 and R- is a C -C alkylene group. 5. The method according to claim 3, characterized in that that the group If- R-C- in position 7 (1) is an acyl group of the formula ^R 2 - " ² Vn" ^C ■ ' wori η 0 or an integer from 1 to 6 and R _{2 is} an aryl radical with 6 to 14 carbon atoms, a cycloalkyl radical with 4 to 8 carbon atoms or a heterocyclic radical which is the heteroatom 0, S * N or 209822/1039 2U5946 Combinations thereof, or substituted derivatives thereof, are (2) an acyl radical of the formula R ₃ - C - _f wherein R _{3 is} a Cj-Cg-alkyl radical, a C ₂ -Cg-alkenyl radical or substituted derivative thereof, (3) an acyl radical of the formula • I ^R 4 - ^(CH 2> m - ^X - ^(CH 2> n " ^C ~ ' where η is as defined above, m is 0 or an integer from 1 to 5 and X is 0 or S and R. is a radical R ₂ as defined above, a C 1 -C 6 alkenyl radical or a substituted C ₂ -C 6 alkenyl radical means (4) an acyl radical of the formula Il Ra "" CH "" C ™ ", wherein R _{2 is} as defined above and Y is an amino group, protected amino group, hydroxy group, C -C alkoxy group, carboxyl group or C -C alkanoyloxy group, or (5) a phenyl-alpha ^ lpha-dimethylacetyl radical or a substituted derivative of which is. 209822/1039 2U5946 6. The method according to claim 3, characterized in that a R. C.-Cg-tert-alkyl, C, - C ₇ -tert-alkenyl, C ₅ -C ₇ ~ tert-alkynyl, benzyl, methoxybenzyl , Nitrobenzylrest, Phenacylrest, Trichloräthylrest, Benzhydrylrest, Phthalimidomethylrest or Succinimidomethylrest means. 7. The method according to any one of the preceding claims, characterized in that the reaction at a temperature is carried out in the range of -10 to 100 degrees C. 8. The method according to any one of the preceding claims, characterized in that the reaction in the presence of Perchloric acid, sulfuric acid or phosphoric acid is carried out. 9. The method according to any one of claims 1 to 7, characterized in that the reaction is in the presence a base with a pK value of less than 8 is carried out. 209822/1039