DE2166022A1 - Chemical compounds. Elimination from: 2138323 - Google Patents

Description

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95 / Ma CASE 25.99 - 182

(Relay Compounds Part 2/4)

GIAXO LABOEATOEIES LIMITED, Middlesex / Great Britain

"Chemical compounds"

The present invention relates to new semi-synthetic Intermediate products or key links for manufacture of cephalosporins, penicillins and relatives antibiotic ß-lactam compounds that are self-physiologically active.

The first total synthesis of a cephalosporin antibiotic was created by R.B. Woodward (J.A.C.S., 1966, 88 (4), 852)

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is enough, which started from L (+) - cysteine and reaches a ß-lactam (i) via about eight synthesis steps ^ that then was converted into a cephem (iii) according to the following reaction sequence.

O.GOIi

(i)

CO.

CH,

(CH ₃ J ₃ CO. CON

CH

(ii)

CO.

H H

00.OCH ₂ CCl ₅

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The compound (i) is thus a valuable intermediate for the production of cephalosporins and others ß-lactam antibiotics. By reacting with an analogous aldehyde reagent, it is also possible to use the compound (i) to convert into a penicillin, and it is understood that in this way penicillins with different Substitution on the 5-membered ring can be made. Similar can be done by replacing the 2,2,2-trichloroethyl-3,3-diformyl acrylate reagent A number of cephalosporin analogs can be produced by suitable substituted alternative compounds.

R.B. Woodward started from L (+) - cysteine to be a total synthesis to enable. However, this material is relatively expensive and, more importantly, requires conversion into a ß-lactam with the appropriate stereochemical configuration requires extremely careful control of stereochemistry and that in several places. It has now been found that intermediates analogous to that Woodward's see compound (i) are very similar, from penicillins can be produced, this conversion is easier and takes place in fewer stages and has the advantage of that one starts from a ß-lactam of the required steric configuration.

Furthermore, penicillins, especially penicillins G and penicillin V, are generally cheaper to produce than L (+) - cysteine, e.g. by fermentation.

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The present synthesis is based on the fact that the Reaction of a penicillin sulfoxide with a trivalent one Phosphorus compound to cleavage of the 1,2 bond with subsequent trapping of the sulfur atoms by the carbonyl group of the 6-acylamido group, so that a thiazoline is obtained. However, this cleavage leaves the remainder of the thiazolidine ring of the original penicillin on the nitrogen atom in the ß-lactam ring and to obtain intermediates that are closely analogous to the Woodv / ards compound (i) which require a further functionalization on the nitrogen atom and a subsequent formation of another If the ring is allowed, this hest must be thrown away. Such a cleavage to a penicillanic acid ester-1-oxide is in the patent specification

(Patent application (CASE No. 37186/70 and

52289/70)) of the same applicant on the same day \. <- ~ , whereby the separation of the nitrogen to the nitrogen! oin bound side chain by an oxidative process. · _ · - follows.

It has now been found that penicillin-1-oxides, which are in the 3-position carry a hydroxyl or amino group in which Cleavage with a trivalent phosphorus compound spontaneously eliminates the N-linked side chain »Yfenn continues k the hydroxyl or amino group in protected form, i.e. in the form of a derivative that selectively converts to a hydroxy or amino group can be converted, the side chain attached to the nitrogen atom in the ß-lactam if not spontaneously eliminated, bound is easily removed by subsequent cleavage of the protected groups will. The term "protected hydroxyl and amino groups" means groups that can easily be converted into free hydroxyl or amino groups can be converted, for example by hydrolysis, by reduction or by hydrogenolysis.

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Penicillin-1-oxides which have such groupings in the 3-position therefore are valuable intermediates for converting penicillins into new ring structures and according to the present invention, compounds of formula I

R ¹ COlIH, <T \ ^ (i)

created, wherein R CO is an acyl group with 1 to 21 carbon atoms, e.g. one of the many acyl groups that occur in the 6-acylamido groups of known penicillins,

ρ
R is a hydroxyl or amino group or a protected hydroxyl or araino group and X SO in the a ~ or ß-Kon-

2
figuration mean. The group R can be in the α or β configuration, but the α configuration is preferred.

In addition to their use as intermediates, as will be described hereinafter, the compounds of general formula I, as defined above, have activity against parasites such as _e worms and particularly showing the connection 'tS, 3S, 5R »6R -2,2-Dimethyl-3 £ -hydroxy-6-phenylacetylamidopenam «1-oxide activity against Nippostongylus muris and Asoaridia galli.

1 ? The new compounds of the formula I ₃ in which R, R and X have the meanings given above can be prepared according to the reaction sequences shown in Reaction Scheme _{9 below}

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which also explains the preparation of the compound of formula I, are converted into reactive intermediates, which are analogous to the compound I given above.

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21Ü6022

R ¹ CONl

R ¹ CONH

COOH

R ¹ CONH

H'

, - N

.2

χ = so X = SO

R ² = blocking \ ^rZ = ^ ⁷ OH or ~~ * NH te hyciroxy-
or amino group

III

R ^J

N "S

LJ.

^H "J

R '

R ¹ H

HN

N "S

ν

IV

O'

- H.

R ¹ H

HN

η - Ί r Ji

i NH

C. CO. N

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1 2

In the above reaction scheme, R and E are as given above Meaning and X represents an S atom or an SO group in the α or ß configuration. The compound of the formula I can be converted into a thiazoline of the formula II or IV by reacting with a trivalent phosphorus compound The thiazoline IV can be converted into the thiazolidine V e.g. by using aluminum amalgam be as it is in the patent specification

(Patent application (CASE HR. 37187/70 (Part 3))

by the same applicant on the same day. The thiazoline II can be obtained by separating the chain

as will be described below, can be converted into the thiazoline IV or can be reduced to a thiazolidine III before the side chain is separated to form the desired thiazolidine V. The latter can then protected e.g. with the tert-butoxycarbonyl grouping on the nitrogen atom used by Woodward, see above that one closely analogies with Woodward's compound (i) Compound is given (where R has the meaning given above possesses), which differ only with regard to the gem-dimethyl groups differs and those with reagents such as 2,2,2-trichloroethyl-3,3-diformyl acrylate can be reacted to form cephalosporin ring compounds (iii) identical to those of Woodward.

It should also be noted that the method according to the invention has the advantage that one can use easily accessible starting material

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materials, especially penicillins produced by fermentation, and that the steric configuration of the ß-lactanirring is retained throughout. In certain semi-synthetic processes that lead to conversion of natural penicillins into new analogous compounds of both the penicillin and the cephalosporin series it was necessary to remove the acyl group in the 6-acylamido group. However, such methods are difficult to perform in certain cases. An advantage of the method according to the invention is that this acyl group is eliminated in the course of the cyclization without the aid of these known methods.

To the Woordward * see compound of formula (iii) in a To convert an active antibiotic, it can involve acylation of the 7-amino group, for example using an acyl halide , whereby many different 7-acylamido substituents can be introduced, e.g. Phenyl, phenoxy or thienylacetamido groups. The esterified The 4-carboxyl group can be deesterified, for example, by hydrolysis v / earth. Cephems that have a 3-^ orinyl group, show antibiotic activity. You can also use a variety of active cephem antibiotics are converted, e.g. by reducing the formyl group of the group CHpOH or by reactions of the Wittig type, so that one 3-vinyl cephemes. With such transformations it is desirable to convert the Z ^ compounds into their Δ isomers to convert.

In the cleavage of a compound of the formula I in which X is SO with formation of a thiazoline der.Formel II or IV, the trivalent phosphorus reagent can be represented, for example, by the formula PR ⁵ RR ⁷ , in which R ⁵ and R ⁶ are identical or different can be hydrocarbon · =

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groups, hydrocarbonoxy groups or hydrocarbonamino groups, e.g. alkyl groups, alkoxy groups or dialkylamino groups, preferably with 1 to 6 carbon atoms, such as methyl groups, ethyl groups, tert-butyl groups, Methoxy groups or ethoxy groups, aralkyl groups, aralkoxy groups or diaralkylamino groups, preferably monocyclic Groups with 1 to 6 carbon atoms in the alkyl part, such as benzyl groups, phenethyl groups, or benzyloxy groups Phenethoxy groups or aromatic groups, preferably monocyclic groups such as phenyl groups, tolyl groups, Phenoxy groups or tolyloxy groups or diary / amino groups

5 6
mean or R and R can together with the phosphorus

7th
atom form a ring and R means another group,

5 6

as defined for R and R or a hydroxyl group.

Examples of reagents of this type are di- and trialkyl phosphites, preferably the latter and trisubstituted phosphines, especially trimethyl and triethyl phosphite are suitable means.

The phosphorus compound is preferably in an inert solvent such as an ester, e.g. a medrigalkylacetate, e.g. ethyl acetate or an aromatic hydrocarbon solvent, e.g. benzene or (toluene). Yields can be improved by adding an alkaline earth metal carbonate, e.g. potassium carbonate, to the reaction medium brings in.

In addition to the conversions of the compounds of formula II and IV as they. above, these compounds can also / other useful intermediates are converted, which are capable of cyclization To form pename, cephame and cephemes. In the patent specification

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(Patent applications

(CASE HR. 52288/70 (Part 5), 52286/70 (Part 6) and 52290/70 (Part 9)) of the same applicant from the same day are such Conversions and new bicyclic ring compounds obtained thereby and the antibiotic activity have described.

The compounds of the formula I can be prepared from corresponding penicillins which have a 3-isocyanate group v / ground, which in turn is easily obtained from penicillanic acids by any known method for converting a Carboxyl group can be obtained into an isocyanate group can. The isocyanate can be urethane with either aqueous acid to form a 3-hydroxypenicillin in the 3-position, be implemented; the ^ -hydroxy compounds can, if desired, subsequently by reacting with a suitable esterifying or etherifying agent to be protected; the urethanes can, if desired, by cleavage of the esterified carboxyl part, which leads to spontaneous decarboxylation, converted into the corresponding free amines; the 3-Amino compound can then, if desired, be converted into another protected derivative, e.g. by acylation.

The conversion of penicillanic acid VI or its sulfoxide into the corresponding isocyanate VII is preferably brought about by prior conversion into a mixed anhydride. Such mixed anhydrides and their preparation are described in Belgian Patent No. 750 558 described.

The Curtius process for isocyanate formation is

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preferred, ie conversion to an acid azide followed by rearrangement. The azide can be easily prepared by reaction of the anhydride with an azide salt such as an alkali metal azide, for example sodium or potassium, or a quaternary ammonium azide, be suitably formed in an aqueous medium, wherein it is advantageous to keep the temperature below ⁰ ° C, preferably below -10 ⁰ C. holds. The azide can be isolated to remove impurities or can be rearranged in situ.

The Curtius rearrangement can be accomplished under neutral or basic conditions, e.g. by weak Erfc heat or can occur spontaneously and the isocyanate thus formed can then form the 3-hydroxy compound hydrolyzed under acidic conditions. However, it is preferred to rapidly decompose the isocyanate in order to Avoid level reactions and the azide is preferred for this in an aqueous acidic medium directly into the 3-hydroxy compound, for example by treatment with an aqueous Acid, for example a mineral acid such as hydrochloric acid or preferably sulfuric acid, where suitably in a cyclic ether solvent such as dioxane or tetrahydrofuran or a nitrile solvent, like acetonitrile, works.

"To form a urethane, the isocyanate is preferred formed in the presence of the appropriate alkanol or phenol, so that the desired reaction occurs directly and side reactions be avoided. To avoid ureid formation or carbinolamide formation, water should not be used to be available. An inert solvent, e.g. a cyclic ether solvent such as dioxane or tetrahydrofuran, a nitrile solvent such as acetonitrile or an aromatic hydrocarbon such as benzene or toluene can be present be.

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The esterification or etherification of carbinolamine (Compound of the formula 1, E = OH) can, for example, by customary Procedures are accomplished. For example, a tetrahydropyranyl group be introduced by reacting the carbinolamine with 2,3-dihydropyran, while a di- (2-chloroethoxy) ~ methyl group by reaction with 2-chloroethyl orthoformate is introduced.

The urethane can be de-esterified, followed by spontaneous decarboxylation, depending on the nature of the one present Ester groups depend in the corresponding amine

(Connection of the lormel 1, R = KEI ₂ ). Mild acidic or basic hydrolysis, enzymatic hydrolysis, reduction or hydrogenolysis can suitably be used for this purpose. When the esterifying group is a haloalkyl group, reductive cleavage, for example using zinc and an alkanecarboxylic acid such as acetic acid, suitably in the presence of an inert solvent, e.g.

a cyclic ether, such as dioxane or tetrahydrofuran,

2
be effected. If R is to be an acylamido group, the amino compound can be acylated, for example acetylated, using conventional methods.

As stated above, the S-atom of the penicillin must either before one of the above-mentioned transformations or after, e.g. after the formation of the mixed anhydride or

ρ
after the introduction of the group R to be oxidized to the sulfoxide. The sulfoxides can be in the cc or beta configuration, or a mixture of these compounds may be suitable.

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Oxidation can, as is the case with Chow, Hall, and Hoover (J. Org., Chem., 1962, 27, 1381), under Use of peracids such as peracetic acid, monoperphthalic acid, m ~ chlorop # gbenzoic acid or metaperiodic acid are accomplished./should at least one active oxygen atom per atom of thiazolidine sulfur however, excess oxidizing agent can result in undesirable 1,1-dioxide. Other suitable oxidizing agents include: tert-butyl hypochlorite, Phenyl iodine dichloride, molecular chlorine or bromine or N-chlorosuccinimide, these agents preferably in Presence of a weak base such as pyridine can be used. Water should be present in the medium or the initial products should be treated with water afterwards. Oxidation solvents include, for example, ether solvents such as tetrahydrofuran and dioxane, hydrocarbon solvents such as Benzene and toluene and halogenated hydrocarbon solvents, such as chloroform or methylene chloride.

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Bn general and the following main classes for that Aoyl group R CO particularly suitable «

(I) E ¹² C _n H _2n -CO, where R ^{11 is} an aryl group (carbocyclic or heterocyclic.), A cycloalkyl group, a substituted aryl group, a substituted cycloalkyl group, a cyclohexadienyl group or a non-aromatic or raesoionic heterocyclic group and η a whole Number from 1 to 4 mean. Examples of this group include phenylacetyl, substituted phenylacetyl, e.g. aminophenylacetyl, acetojyphenylacetyl, methoxyphenylacetyl, pluophenylacetyl, uitrophenylacetyl, methylphynylacetyl or hydroxyphenylacetyl, B ", IT-bis- (2-chloroaminophenyl) - »Thienyl-2- and -3-acetyl, 4-isoxazolyl and substituted 4-isoxazolylacetyl, pyridylacetyl, letrazolylacetyl or sydnonacetyl groups. The substituted 4-isoxazolyl group can be a 3-aryl-5-methylisoxazole-4 -yl group, v / whether the aryl group is, for example, a phenyl group or an ealogenphenyl group, for example a chlorine or bromophenyl group.

(II) ° n ^H 2n + 1 ^C0 "' ^{where n is an} integer from 1 to 7. The alkyl group can be straight-chain or branched, if desired be interrupted by an oxygen or sulfur atom or, for example, by one or more halogen atoms, a cyano group, a carboxy group, an alkoxycarbonyl group, a

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Hydrosy group or a carboxycarbonyl group (-CO.COOH) Examples of such groups include: cyanoacetyl, hexanoyl, Heptanoyl, octanoyl, butylthioacetyl, chloroacetyl and trichloroacetyl groups,

(III) CH ₉ -CO-, where η is an integer from 2 to 7

Il CL * - 'fmr *

· The alkenyl group can be straight-chain or branched and, if desired, be interrupted by an oxygen or sulfur atom. An example one such group is the allylthioacetyl group.

(IV) R ^U OC ~ CO-, where R ^{u is} the above under (I)

has meaning and also denotes the benzyl group and E ^v and R ^w , which can be identical or different, can denote hydrogen, phenyl, Benayl, phenethyl or medrigalkyl groups «. Examples of such groups include phenoxyacetyl, 2-phenoxy-2-phenylacetyl, 2-phenoxypropionyl, 2-phenoxybutyryl, 2-methyl-2-phenoxypropionyl, p-cresoxyacetyl, and p-methylthiophenoxyacetyl groups.

(Y) E ¹¹ SC-CO-, where R ^{u is the Be-E v} given under (i) above

has meaning and can also mean a benzyl group and R ^v and R ^{w have} the meaning given above under (HT). Examples of such groups include: S-phenylthioacetyl, S-chlorophenylthioacetyl, S-fluorophenylthioacetyl, pyridylthioacetyl and S-benzylthioacetyl groups.

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(VI) R ¹³ Z (CH ₉ ) CO-, in which R ^{u has} the meaning given above under (I) and can also mean the benzyl group, Z is an oxygen or sulfur atom and m is an integer from 2 to 5. An example of such a group is the S-benzylthiopropionyl group.

(VII) R ¹¹ CO-, before R ^{13 has} the meaning given above under (I). Examples of such groups include: benzoyl, substituted benzoyl (e.g. aminobenzoyl), 4-isoxazolylcarbonyl and substituted 4-isoxazolylcarbonyl, cyclopentanecarbonyl, sydnoncarbonyl, liaphthoyl and substituted eaphthoyl (sB _e 2-a'thoxynaphthoyl ), Quinoxalinylcarbonyl and substituted quinoxalinylcarbonyl groups (e.g. 3-carboxy-2-oxalinyl carbonyl group) · Other possible substituents for the benzoyl group include alkyl, alkoxy, phenyl, phenyl, alkylamido, cycloalkylamido substituted by carboxy - ^ Allylaaido, phenyl (lower) - »alkylamido- ₉ horpholinocarbonyl, pyrrolidinocarbonyl =» ^ piperidino carbonyl, tetrahydropyridine, Eurfurylainido or H-alkyl-H-anilino groups or derivatives thereof and such substituents can be used in the 2- or 2- and 6-positions. Examples of such substituted benzoyl groups are 2,6-dimethoxybenzoyl group, 2-methylamidobenzoyl group and 2-carboxybenzoyl group. If the group R ^{u represents} a substituted 4-isoxazolyl group, the substituents can have the meaning given above under (I). Examples of such 4-isoxazolyl groups are: 3-phenyl-5-methylisoxazol-4-yl-carbonyl-, 3-o-chlorophenyl-5-methyl-8-oxazol-4-yl-carbonyl- and 3- (2,6-dichlorophenyl) -5 methylisoxazol-4-yl-carbonyl groups.

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(VIII) H ^U -CH-CO-, in which Ε ^υ those given above under (i)

Has meaning and Σ an amino group has a substituted amino group (ζ · Β · an acyl arido group or a group obtained by reacting the ou-alainoacyl arido group of the 6-side chain with an aldehyde or ketone, eg acetone, methyl ethyl ketone or ethyl aeeto aetate), a hydroxy group , a carboxy group, an esterified carboxyl group, a Triaaolylgruppe, a l'etrazoly! group, cyano group, halogen atoms, a Acylo30 ^r group (eg the IPorrnyloxygruppe or liiedrigalkanoyl- "oxy group) or an etherified hydroxy group, examples of such acyl groups are a- Aminophenylacetyl groups and α-carbozyphenylacetyl groups.

(IX) R ^y -C-CO-, wherein E ^x , E ^y and R ^z , which are identical or

R ^z
can be different, I-lower alkyl groups, phenyl groups or substituted phenyl groups and R ^{x can be} a hydrogen atom. An example of such an acyl group is the 2? Riphenyliae thylcar bonyl group.

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² "
(X) (CH ₀ ) ,, C-CO-, where X is the one indicated under (VIII)

CH ₂ 'X

has given meaning and η represents an integer from 1 to 4. An example of such an acyl group is the I-aminocyclohexanecarbonyl group.

(XI) Aminoacyl groups, for example of the formula E ^W CH (M ₂ ). (CH ₂ ) _n C0, where η is an integer from 1 to 10 or of the formula IiII ₂ .C _n H _2n Ar (CH ₂ ) _m C0 where m is zero or an integer from 1 to 10 and η is Hull, 1 or 2, R ^{w is} a hydrogen atom or an alkyl, aralkyl or carboxy group or a group as defined above under R ^u and Ar is an arylene group , for example a p-phenylene or 1,4-iaphthylene group. Examples of such groups are described in British Patent Specification No. 1,054,806. One group of this type is the p-aminophenylacetyl group. Other acyl groups of this type include those derived from naturally occurring amino acids, for example the ef-aminoadipoyl group or its derivatives, for example the IT-benzoyl-cf-aminoadeipoyl group or the N-chloroacetyl-cf-aminoadipoyl group.

The group II is a hydroxyl or amino group or a Protected hydroxyl or amino group, i.e. a group that can be formed without undesired degradation of other parts of the molecule, e.g. by mild acidic or basic hydrolysis, by enzymatic hydrolysis, by reduction or by hydrogenolysis can be converted into a hydroxyl or amino group. Suitable protected hydroxyl groups include, for example, easily cleavable ether and ester groups, such as the tetra-

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hydropyranyloxy or 4-methoxytetrahydropyranyloxy or the di- (2-chloroethoxy) methoxy groups, which can be removed by mild acidic hydrolysis, and the diphenylmethoxy groups, which can easily be split off by hydrogenolysis and the carbobenzoxy and trifluoroacetoxy groups, which can easily be removed by hydrolysis. With some of these groups, e.g. with the letrahydropyranyloxy group, another asymmetrical center can be introduced. However, avoids the 4-methoxytetrahydropyranyloxy group the introduction of such an asymmetrical center "

W Suitable protected amino groups include in particular urethane groups, ie esterified carboxylamino groups. As indicated above, urethanes can be made from the corresponding 3-isocyanates and are key intermediates for the preparation of the free amino compounds and other protected derivatives thereof, such as for the acylates can be split off from the urethane, for example by mild acidic or basic hydrolysis, by enzymatic hydrolysis, by reduction or by hydrogenolysis. Such groupings include, for example, 2-halo-lower alkyl groups, which preferably have more than one halogen atom, e.g.

the 2,2,2-! Erichloräthyl- or 2,2,2-Trichlor-1-Raethyläthylgruppe or the 2,2,2-tribromoethyl group or a 2-bromoethyl or 2-iodoethyl group. In general, the halogen atoms are preferably chlorine atoms. These haloxy groups can easily be assisted by treatment with a chemical reducing agent under mild conditions in general Room temperature or with cooling, such Agents are essentially nascent hydrogen, such as it can be found e.g. through the reaction of a metal, a metal

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receives alloy or a metal amalgam to a hydrogen donor, and can be, for example, zinc, zinc alloys, _c as an acid such as an organic carboxylic acid, for example, for a zinc-copper alloy or zinc amalgam in the presence of a lower alkanoic carboxylic acid such as formic acid or preferably acetic acid or an alcohol , such as a lower alkanol such as methanol or ethanol, or an alkali metal amalgam such as sodium or potassium amalgam or aluminum amalgam in the presence of a solvent containing water such as ether or a lower alkanol. Zinc can also be used in aprotic solvents such as pyridine and dimethylformamide. It converts the halogen ester into a complex zinc salt of the corresponding acid. The acid can then be formed by the action of protic solvents, such as water, preferably under acidic conditions on v / eist, such as with a compound of divalent chromium * such as ghrom-II chloride or acetate, preferably in an aqueous medium that contains a water-miscible organic solvent, such as a lower alkanol, a lower alkanecarboxylic acid or an ester, such as methanol, ethanol, acetic acid, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether

2
holds, split v / earth. R can also be an arylmethylamino group, the separation in this Pall being effected by hydrogenolysis, for example using a platinum or palladium catalyst.

In addition to the compounds of general formula I defined above, the azides of the formula

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R ¹ CONH / ^X

_ h 1 CON ₃

where R has the meaning given above, new compounds.

Other new compounds are the thiazolines of the formula II, in which R has a meaning other than hydrogen and R has the meaning given above.

The following examples are intended to explain the present invention further without, however, restricting it.

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example

2,2-Dimethyl-6ß-phenylacetamidopenam-3ct-carbonylazid-1ß oxide

A solution of 75 g (0.214 mol) of 2,2-dimethyl-6ß-phenylacetamidopenam-3cc-carboxylic acid-1ß-oxide in 750 ml of dry tetrahydrofuran was at r-20 ° C successively with 30 ml (0.214 mol) of triethylamine and 21 ml (0.22 mol) ethyl chloroformate treated _c After 45 minutes of stirring at -2O ⁰ C, the temperature was lowered to -35 ° C and there was a solution of 21.3 g (0.328 mol) of sodium azide in 200 ml of water with such Speed added that the temperature did not rise above -20 ⁰ C. The mixture was then poured into 1000 ml v / ater and extracted with 4 × 300 ml ethyl acetate. The combined extracts were washed with 1 300 ml aqueous sodium hydrogen carbonate and 1 300 ml water and then dried and then the volume was reduced to 150 ml. Upon addition of petroleum ether (boiling point 60 to 80 ⁰ C) to the concentrate, the acid azide was eliminated in the form of colorless prisms (48.2 g). The mother liquors were evaporated under reduced pressure to dryness and the residue was crystallized from ethyl acetate with petroleum ether (boiling point 60 to 80 ⁰ C), so that a second batch of acid azide obtained (10 g). The two batches were combined (58.2 g, 73 ⁰ Zo) _1, the material decomposes before melting.

[ccj-p + 240 ° (£ 1.05, tetrahydrofuran),

IR spectrum ^ _max> (CHBr ₃ ) 3390 (NH), 21βθ (N ₃ ), 18OO (β-lactam), 17IO (CON ₃ ) and 1680 and 1510 cm -1 (CONH).

Nuclear Magnetic Resonance Spectrum (100 MHz., CDCl ₃ ,?) 2.70 (CgH ₅ ), 4.02 (double doublet, J = 4.5 Hz and 10 Hz, Hg), 5.08 (doublet, J = 4 , 5 Hz, H ₅ ), 5.47 (H ₃ ), 6.45 (PhCH ₂ ) and 8.31 and 8.74 (< ^CH 3).

^C 16 ^H 17 ^N 5 ° 4 ^S: CHN ^- S

calc .: 51.2 4.6 18.7 8.5 % found : 51.3 4.6 17.3 8.8 %

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example

2,2 ~ Dimethyl-3f-hydroxy-6ß-phenylacetamide openam-1ß-oxide

A solution of 115 g (0.307 mol) of 2,2-dimethyl-3-azidocarbonyl-6β-phenylacetamidopenam-1β-oxide in 1150 ml of dioxane was "a refluxed mixture of 2070 ml of dioxane and 1035 ml of water, the 154 ml (0.308 mol) of 2N sulfuric acid, after 10 minutes under reflux, the mixture was rapidly cooled by stirring in an ice bath, then about 2500 ml of dioxane were removed under reduced pressure (<2 mm Hg). The residue was saturated with sodium chloride and extracted with 4 × 500 ml of ethyl acetate. The combined extracts were washed with 2 × 500 ml of sodium hydrogen carbonate and the wash washes were back-extracted with 2 × 200 ml of ethyl acetate. The combined extracts were dried over magnesium sulfate and evaporated under reduced pressure to give a white foam A solution of this foam in methanol gave the title compound in the form of colorless prisms (74 g, 68 #), F = 126 ^° C.

[aj ^ ° + 160 ° (£ 0.75, tetrahydrofuran), IR spectrum ^ _mair (CHBr _x ) 3590 (OH), 3480 (NH), 1780

(β-lactam) and 1675 and 15IO cm " ¹ (CONH).

Nuclear Magnetic Resonance Spectrum (100 MHz, dg-DMS0, Tf) 2.20 (doublet, J = 9.5 Hz, NH), 2.70 (C ₆ II ₅ ), 3.18 (doublet, J = 5.5 Hz, OH), 4.28 (double doublet; J = 4.5, 9.5 Hz; kg), 4.66 (doublet, J = 4.5 Hz, H ₅ ), 4.71 (doublet, J. = 9.5 Hz, H ₃ ), 5.93 (OH.), 6.39 (PhCH ₂ ), 6.80 (CH ₇ OH) and 8.57 and 8.78 (^ CK _x ).

^ CH ₃

C ₁₅ ILoN ₂ OhS. CH ^ OH:

^ CHNS

calc .: 54.3, 6.3 7.9 9.1 % found : 54.2 6.0 8.2 9.4 %

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This compound could also be crystallized from Benaol, so that a solvent-free material was obtained in the form of colorless prisms, F = 111 to 115 ^° C.

Example 3

2,2-dimethyl-3; - (2 (-tetrahydropyranyloxy) ~ 6β-phenylacetamidopenam-1β-oxide

A solution of 1.5 g (4.7 mmoles) of 2,2-dimethyl-3'-hydroxy-6ß-phenylacetamidopenam-1ß-oxide (crystallized from benzene) in 75 ml of fresh, distilled dihydropyran was 3 hours held at reflux. The solvent was removed under reduced pressure and the resulting resin was absorbed Merck chromatographed 0.05 to 0.2 mm silica gel (5 x 10 cm) with benzene / ethyl acetate (4/1) as solvent. the zv / ei reaction products, the two isomers (A and B) of the title compound were obtained from the column in three fractions:

Isomer A (0.47 g, 25 ° / o)

Isomer B (0.36 g, 19% )

Isomer A and / _{A κο on} c ₀ / \

Isomer B ⁽⁰ > ^{52 g} » ²⁷ ' ^{6 / o)}

Overall yield (1.35 g _r 71.6 ^).

2098A0 / 1 176

^The isomer A crystallized as colorless needles from ether, m.p. = l40 to L4L ° C,

Hp ³ + 33 ° (c 1, tetrahydrofuran).

IR spectrum ^ _maY (CHBr,) 3385 (MH), 1800 (β-lactam) and 1680 and 2510 cm " ¹ (CONH).

Nuclear Magnetic Resonance Spectrum (100 MHz, CDCl ,, X) 2.76 (C ₆ H ₅ ), 2.82 (doublet, NH), 4.11 (double doublet, J = 4.5 and 10 Hz, Hg), 4.52 (H ₃ ), 5.07 (doublet, J = 4.5 Hz, H ₅ ), 5.22 (1-proton multiplet, OCH < ₀ ) 6.1 to 6.6 (OCH ₂ ), 6.45 (PhCH ₂ ), 8.1 to 8.6 (tetrahydropyran) and 8.43 and 8.72

7.9 % 7.9 %

S: ber .: 59 C. 6th H 6th N ^ CH ₃ found: 59 , 2 6th , 5 6th , 9 Π Vi TJ Π
20 2ο 2 5 , 0 , 6 , 9

Isomer B crystallized out of ether in the form of colorless prisms, F = 151 to 153 ° C,

^ ⁷ + Ι6θ ° (c_ 0.75, tetrahydrofuran)

IR spectrum ^ _av (CHBr ₇ ) 3 ^ 50 (NH), 1790 (β-lactam) and 1680 and 1510 cm " ¹ (CONH).

NMR Spectrum (100 MKz, CDCl ₃₉ O 2.78 (CgH ₅ ), 2.86 (NH), 4.10 (double doublet, J = 4.5 and 10 Hz, H ₆ ), 4.70 (H. ₃ ), 5.05 (doublet, J = 4.5 Hz, H ₅ ), 6.20 (1-proton multiplet / OCH < ₀ ), 6.0 to 6.6 (OCH ₂ ), 6.45 ( PhCH ₂ ), 8.1 to 8.6 (tetrahydropyran) and 8.46 and 8.72

C ₂₀ H ₂₆ N ₂ O ₅ S: ber .: 59 C. 6th H 6th N 7th S. found: 59 , 2 6th , 5 6th , 9 7th , 9 ,1 > 3 , 9 , 9

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2166Q22

B e i s ρ i e 1 4

3-Benzyl-4,7-aiaza-6-oxo-2-thia-i (R), 5 (R) -bicyclo- [3.2.0J- h ept- 3- en ______ ^ ______ «.

(a) A solution of 20.8 g (64.5 mmol) of 2,2-dimethyl-3 ^ί . -hydroxy-6β-phenylacetainidopenam-1β-oxide in freshly distilled 2,3-dihydropyran was refluxed for 6 hours and then the solvent was removed under reduced pressure so that a yellow foam was obtained (see Example 3) · A solution of the foam in 300 ml of ethyl acetate which contained 11.1 ml (94 mmol) of trimethylphosphorus and 8 g of potassium carbonate, was refluxed for 24 hours. The suspension was filtered off and evaporated to dryness under reduced pressure to give a resin. A solution of this resin in 400 ml of benzene was vigorously stirred with a mixture of 40 ml of trifluoroacetic acid and 15 ml water for 5 minutes, after which was added the mixture into a vigorously stirred mixture of ice and aqueous you Hatriumhydrogencarbonat (100 ml). The organic layer was separated and the aqueous layer with 2 χ 100 ml of ethyl acetate extracted _β The combined extracts were dried and evaporated under reduced pressure. The resulting resin was chromatographed on Merck 0.05 to 0.2 mm silica gel (10 χ 7 cm) with benzene / ethyl acetate (3/1) as the solvent. The fractions containing the main product were combined and evaporated. The white foam was dissolved in ether. The title compound separated out in the form of colorless prisms (4.93 g, 35 10) . 1 = 182 to 184 ° C (decomp.), + 83 ° (£ 1, tetrahydrofuran),

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UV spectrum λ ",""(ethanol), 243 nm. (8 1,920),

IR spectrum S>"_ _ν (Fujol) 3190 (IiH), 1735 and 1710 cnf ¹

IDcAX »

(ß-lactam),

MR spectrum (100 MHz, dg-DMSO, Ό 1.10 (HH), 2.73. (C ₆ H ₅ ), 4.06 (1-proton multiplet, H ₅ ), 4.45 (doublet, J. = 4 Hz, H ₁ ), 6.10 (PhCH ₂ ),

H N S

calc .: 60.5 4.6 12.8 14.7

get,: 60.5 4.5 13.1 14.5

(b) A solution of 5 g (15.5 mmol) of 2,2-dimethyl-3 ^! '-hydroxy 6ß-phenylacetamidopenam-1ß-oxide in 200 ml of dry ethyl acetate containing 2.9 ml (24.6 mmol) of trimethylphosphite and 1 g of potassium carbonate was refluxed for 18 hours. Thin-layer chromatography (Merck silica gel 1 * 254 » ^BenZ0 VÄ" fcky ^ac etat (2/1)) gave the title ^{compound (0.567 g, 17 c} / 0, which crystallized from ether in the form of colorless prisms. The structure of this material was confirmed by ITPIR and IR spectra.

209840/1176

example

3? - [Di- (2-chloroethoxy) -] -methoxy-2,2-dimethyl-6ß-phenylacetainido-penam-1ß-oxide

A solution of 1 g (3 »1 mmol) of 2,2'-dim ethyl-3 '' - hydroxy-6ß-phenylaeetamidopenam-1ß-oxide in 3 ml of 2-chloroethyl-orthoforraiat for 30 minutes at 100 ⁰ C. The heated. The cooled reaction mixture was then applied directly to a Merck silica gel column (0.05-0.2 mm, 8x5 cm) and chromatographed using benzene / ethyl acetate (4/1) as the solvent, and the fractions containing the desired product were chromatographed combined and evaporated that one £ 3 - [di- (2 ^r -chloroethoxy) -] - methoxy-2,2-Äimethyl-6ß-phenylacetamidopenam-1ß-oxide (0.53 g, 35 ^ΰ / °) in the form of a brown resin received.

IR spectrum S _ (bromoform) 3 ^ 50 (NH), 18O7 (β-lactam) _s max · ^

1688 and 1510 (CONH), 1032 (S - »0) cm".

NMR spectrum (CDCl ₃ , 100 MHz t ), 2.71 (CgH ₅ ), 2.82 (doublet, NH), 4.08 (double doublet, J = 10 Hz and 4.5 Hz, 6H), 4 , 52 (2-proton singlet, 3-H and OCH (OCH ₂ CH ₂ Cl) ₂ ), 5.03 doublet, J = 4.5 Hz, 5-H) 6.1 to 6.5 (8 protons Multiplet (OCII ₂ CH ₂ Cl) ₂ ), 6.41 (PhCH ₂ ), 8.4l and 8.72 (2-CH,).

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example

[3-Benzyl-4,7-diaza-6-oxo-2-thia-1 (R), 5 (R) -bicyclo- [3.2.0] -hept-3-enyl] - [bis- (2- ehlorethoxy) ~ methoxy] - [isopropenyl] ~ raethan

A solution of 0.53 g (1JO7 mHol) 3 - [Di- (2 ^f ~ chloroethoxy) -J-methoxy-2,2 ~ dimethyl-6ß-phenylacetamidopenam-1ß-o: x: id in 10 ml of ethyl acetate was with 0.16 ml (1.4 ml-Iol) of trimethyl phosphite and 50 mg of finely divided potassium carbonate (Calofort II) were kept under reflux for 16 hours. The potassium carbonate was removed by filtration and the 3? Filtrate was evaporated under reduced pressure to give a brown resin which was deposited on Merck 0.05-0.2 mm silica gel (2 x 6 cm) with benzene / ethyl acetate (5%). 1) was chromatographed as a solvent. Those fractions containing the desired product were collected and evaporated to give the desired compound [3-benzyl-4,7 ~ diaza-6-oxo - 2-thia-1 (R), 5 (R) -bicyclo- [3.2.0] -hepi; -3-enyl] - [bis- (2-chloroethoxy) -methoxyJ- [isopropenyl] -methane (0.38 g, 78 ^c / o) in the form of a pale yellow resin.

UV spectrum λ 244 ran E * ^ 1.700. nicix · χ cm

NMR spectrum (CDCl ₃ , 100 MHz, t) 2.76 (C ₆ H ₅ ), '1.12 and 4.43 (5-H and 6-H, quartet J = 4.5 Hz),

4.54 A ^) » ¹¹ ^ O (OCK (OCH ₂ CH ₂ Cl) ₂ ), 4.76 and 5.04

CHp
(2 broad singlets, / ^ -) 6.12 to 6.47 (8 protons

Multiplet ((OCH ₂ CH ₂ Cl) ₂ ), 6.18 (PhCH ₂ ) and 8.42 (CH ₃ ).

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example

3-Benzyl-4,7-diaza-6-oxo-2-thia-1 (R), 5 (H) -bicyclo- [3.2.0] -hept-3-ene

0.38 g (0.83 mmol) [3-Benzyl-4-, 7-diaza-6-oxo-2-thia-1 (R), 5 (R) -bicyclo- [3.2.0] -hept- 3-enyl] - [bis- (2-chloroethoxy) methoxy] - [isopropenyl] metal was stirred with 10 ml of 80% acetic acid for 3 hours, whereupon thin-layer chromatography indicated a complete reaction. The disfiguring solution was poured into excess aqueous sodium hydrogen carbonate solution and extracted with 350 ml of ethyl acetate. The combined organic phases were washed with saturated lithium hydrogen carbonate solution (2 × 50 ml), dried and evaporated under reduced pressure to give a resin. The resin was chromatography on Merck 0.05 to 0.2 mm silica gel (2 × 10 cm) with benzene / ethyl acetate (4/1) as the solvent. The fractions containing the desired product were combined and evaporated to give a crystalline solid of 3-bensyl-4,7-diaza-6-oxo-2-thia-1 (R), 5 (R) -bicyclo - [3 _e 2.0] -hept-3-ene (0.11 g, 60% ) was obtained. The ITIiR and IR spectra were consistent with the product of Example 4 (b).

B is ρ ie 1 8

2,2-dimethyl-6β-phenylacetamido-3ct- (li-2 ^!, 2 ", 2 ^! -Trichloroethoxycarbonylamino) -penam

A solution of 46 g (0.137 mol) of 2,2-dimethyl-6ß-phenylacetamidopenam-3ö.-carboxylic acid in 300 ml of anhydrous tetrahydrofuran was cooled to -15 ⁰ C. Then 19 ml

209840/1176

(0.137 mol) of triethylamine followed by 12 ml (0.148 mol) of ethyl chloroformate was added and the mixture was kept for 2 hours at -10 ⁰ C. After further cooling to -2O ⁰ C, a solution of sodium azide (7.0 g, 0.108 mol) in 50 ml of water to obtain the temperature at <-20 ⁰ C. Then allowed the reaction to proceed for 30 minutes at -1O ⁰ C. Pouring into 1000 ml v / ater, extraction with 2 χ 300 ml ethyl acetate, v / ashing with v / ater, drying and evaporation of the organic phase gave 2,2-dimethyl ~ 6ß-phenylacetamido-penam-3 - carboxylic acid azide in the form of a foam (45 g, 91 ^c / o).

IR spectrum> i _nnv (CHBr,) 3400 (NH), 2150 (N,), 1790

ID CA X · JJ

(β-lactam), 1710 (COH ₃ ), 1680 and 1510 cm " ¹ (COOlffi).

A solution of the acid azide (5.0 g, 0.0139 mol) in 30 ml of dry benzene containing 4.05 ml (3 equivalents) of 2,2,2-trichloroethanol was refluxed for 1 hour. On evaporation to a small volume, the title compound crystallized out in the form of prisms (3 »7 g, 55.5 ^c ß>) , = 19O ⁰ C,

[tt] <p + 162.5 ° "'(c. 1, tetrahydrofuran).

IR spectrum \? _max ^ (Nujol) 3333 (NH), 3200 (NH), 1789 (β-lactam), 1724 and 1566 cm " ¹ (NH CO ₂ R).

NMR Spectrum (CDCl ₃ , t) 2.72 (Ph), 2.91 (NH), 4.6 (6-H, 5-H and 3-H, 3-proton multiplet), 5.31 and 5 , 40 (AB-quartet, J 13 Hz CH ₂ CCl ₃ ), 6.40 (CH ₂ Ph), 8.58 (CH ₃ ) and 8.66 (CH).

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example

2,2-Diroethyl-6β-phenylacetamido-3a- (N-2 ^!, 2 ', ^2f -trichlorathoxycarbonylamino) -penara-1 -oxides

A solution of 1.0 g (2.6 mmol) of 2,2-dimethyl-6ß-phenyl- ^ 3oc- (N ~ 2 ^t , 2 ·, 2 ^l -trichloroethoxycarbonylamido) -

penam in 10 ml of anhydrous tetrahydrofuran was cooled to ^{0 ° C.} Then 0.58 ml (1 equivalent) of 35 % B ^e peracetic acid was added dropwise and the reaction was allowed to proceed for 1/2 hour. Evaporation under reduced pressure gave a solid. Thin layer chromatography indicated the presence of three products including two major products (L 0.23 and 0.13). Chromatography on Merck 0.05-0.2 mm silica gel (10 g) with benzene / ethyl acetate (1/1) as solvent gave two main components (0.46 g). One of these components 2,2-dimethyl-6ß-phenylacetamido-3cr- (LT-2 ^1, 2 ', 2'-trichloräthoxycarbonylamino) -penam-1a-oxide crystallized from chloroform / petroleum ether from (boiling point 60 to 8O ⁰ C). S ¹ = 159 to 163 ⁰ C,

[OL] ^ ² + 113 ° (c.1. Tetrahydrofuran).

IR spectrum ^. (Nuj oil) 3330 (NH), 3240 (NH), 178Ο (β-lactam), 1740 and 12 * 10 (NHCO ₂ R), 1665 and 1525 (CONH) and IO35 cm " ¹ (SO).

NMR spectrum (CDCl ₃ , * c) 1.30 (NH), 270 (Ph), 4, Ml (3-H, doublet, J 9 Hz), 4.61 and 5.22 (6ll or 5- H, AB-quartet, J 4 Hz), 5.15 and 5.33 (AB-quartet, J 13 Hz, CH ₂ CCl ₃ ), 6.40 (CH ₂ Ph), 8.57 (CH ₃ ) and 8.62 (CH ₃ ).

C oH _pn Cl, N, O, .S:
^{18 20 3 3 5} CH Cl 'NS

calc .: 43.5 4.0 21.5 8.5 6.5 % found : 43.2 4.1 21.5 8.7 6.5 %

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It was found that the mother liquor from the above crystallization contained the non-crystalline 2,2-dimethyl-6β-phenylacetamido-3cX- (N-2 ^I , 2 », 2'-trichloroethoxycarbonylamino) -penam-1a-oxide.

IR spectrum V _{m & x} (iTujol) 3300 (ITH), 1800 (β-lactam, 1736 and 1518 (MCO ₂ R), 1670 and 1530 cm " ¹ (COIIH).

IMR spectrum (CDCl ₃ ,?) 2.70 (Ph), 4.1 (6-H, 5-H and IiH, multiplet), 6.45 (CH ₂ Ph) ^{>> 8} > ⁴⁶ ( ^CH 3) ^{and 8} » ⁷⁹ ( ^cn ₃ )

Example 1 £

N-2,2,2-Trichlorethoxycarbonyl-a-isopropenyl-a- (3 ^f -benzyl-4 ^f , 7'-diaza ~ 6 '~ oxo ~ 2 «-thia-1 · (R), 5 ¹ (R ) -bicyclo- [3'.2 ".0"] -hept-3-en-7'-yl) -m ethylamine

A solution of the 2,2-dimethyl-6ß-phenylacetamido-3 <x ~ (N-2 ¹ , 2 ', 2'-trichloroethoxycarbonylamino) -penam-1a-oxide and -iss-oxide mixture (approx. 1: 1) (1 g, 2.02 mmol) (see Example 9) in 10 ml of anhydrous ethyl acetate containing 0.375 ml (1.5 equivalents) of trimethylphosphite was refluxed for 36 hours. The solvent was removed under comparable ψ reduced pressure, so that to obtain a Peststoff. Thin layer chromatography indicated a new product (R ^ 0.54) which was isolated by chromatography on Merck 0.05-0.2 mm silica gel (10 g) with benzene / ethyl acetate (2/1) as solvent. The title compound crystallized from ether (0.25 g, 27 ^C I °) , P = 141 to 142 ⁰ C,

^ ² - 81.5 ° (c. 1, tetrahydrofuran).

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IR spectrum ^ _n (CHBr,) 3 ^ 40 (NH), 1760 (ß-Laetam),

ΙΠ3.Χ. j.

1745 (NHCO ₂ R), 1610 (C = N) and 910 cm (C = CH ₂ ).

- NMR spectrum (CDCl ₃ X ) 2.7 (Ph), 4.1 (5-H and NH, multiplet), 4.45 (1-H and CH-NCO ₂ R, multiplet), 4.90 ( = CH ₂ ), 5.22 (-CH ₂ CCl ₃ ), 6.1 (CH ₂ Ph) and 8.3 (CH ₃ ).

^C 18 ^H 18 ^C1 3 ^N 3 ° 3 ^S:

H Cl N S

ber .: 46 ,8th 3 , 9 23 , 0 9 A. 6th , 9 found: 46 ,8th 4th A. 22nd , 7 9 , 2 6th , 2

Example 11

3-Benzyl-4,7-diaza-6-oxo-2-thia-1 (R), 5 (E) -bicyclo- [3.2.0] -hept-3-ene

A solution of 0.5 g (1.17 mHol) of H-2,2,2-trichloroethoxycarbonyl-cc-isopropenyl-a ~ (3 "-benzyl-4 ^!, 7'-diasa-6 ^f -oxo-2 ' -thia-1 «(R), 5 ¹ (R) -bicyclo- [3 ^f .2 '.o'] - liept-3-cn-7-yl) -iaethylamine in 10 ml of anhydrous tetrahydrofuran, the 0.2 ml (3 »3 mmol) of glacial acetic acid was treated with 0.5 g of zinc dust. The reaction mixture was stored ^{at 20 ° C. for 2 1/2 hours.} After filtration, the piltrate was evaporated to give a foam which was treated with 20 ml of ethyl acetate and 20 ml of water. The organic phase was separated, washed with water, dried and evaporated to a small volume. On addition of ether, the title compound crystallized out (0.175 g, 60 fo), P = 181 to 183 ^° C. This material had physical constants similar to those of the product described in Example 4- (a).

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B is ρ i θ 1 12

(1S, 3S, 5R, 6R) -2,2-I) iiiietliyl-3-hydroxy-6-phenoxyacetainidopenam-1-oxide

To a solution of 50 g (0.137 mole) of cis, 3S, 5R, 6R) -2,2-dimethyl ~ 6-phenoxyacetainidopenara-3-carboxylic acid 1-oxide in 500 ml of anhydrous tetrahydrofuran was added at -20 ⁰ C 20 ml of , (1.1 equivalents) triethylamine followed by 14 ml (1 equivalent) of ethyl chloroformate. The mixture was then held for 1 hour at -15 ^0C. After cooling to -4O ⁰ C, a solution of 14 g (1 equivalent) of sodium azide ^ in 150 ml of water was added, the temperature being kept at "5 to 20 ⁰ C. Then 500 ml of water and 500 ml of ethyl acetate were added and The organic phase was separated off. Back-extraction with 250 ml of ethyl acetate, washing of the organic layers with water and with dilute sodium hydrogen carbonate solution, drying and evaporation gave (iS, 3S, 5R _f 6R) -2,2-diinethyl-6-pheii03yacetamido- penam-3-carboxylic acid-azide-i-oxide in the form of a foam (17.3 g, 32.5 #).

IR spectrum>? _mov (CHBr,) 3328 (NH), 21 * 10 (CN,), 1786 (β-lactam), 1700 (CON ₃ ), I678 and 15IO (CONH) and 751 cni

(Ph).

NMR spectrum (60MHz, CDCl ₃₃ ^) 1.71 (NH), 2, ^ 0 to 3.10 (Ph), 3.88 (multiplet, J5 and 10 Hz, 6-H), 4.9 ^ ( Doublet, J 5 Hz, 5-H), 5.35 (singlet, 3-H), 5, l | i | (-CH ₂ OPh) and 8.28 and 8.71 (two methyl groups).

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A solution of the acid azide (15 g, 0.038 mol) in 150 ml of dioxane was added to a refluxed mixture of 270 ml of dioxane and 130 ml of water containing 20 ml of 2N sulfuric acid. After 10 hours of reflux, the reaction was stopped with ice cooled and the excess solvent removed in vacuo. Extraction with 2 × 250 ml of ethyl acetate, washing with Yfasser and with saturated sodium bicarbonate solution, drying and evaporation gave an oil. The title compound was obtained by crystallization from benzene / petroleum ether (boiling point 60 to 80 ⁰ C) mixture in the form of white crystals (5.3 g, 41 ^c / o), P = 127 to 129 ° C,

[α]]} ¹ + 55.5 ° (£, 1.3, tetrahydrofuran).

IR spectrum ^ _mpir (CHBr,) 3530 (OH), 338 (NH), 1781 (β-lactam), I676 and 1511 (CONH) and 750 cm " ¹ (Ph).

NMR spectrum (6OMHz, CDCl ₃ , ^) 1.64 (NH), 2.4l to 3.1 (Ph), 3.09 (doublet, J 5 Hz, OH), 4.08 (multiplet, J 5 and 10 Hz, 6-H), 4.58 (doublet, J 5 Hz, 3-H), 4.60 (doublet, J 5 Hz, 5-H), 5.37 (-CH ₂ OPh), 8 , 57 and 8.79 (two methyl groups).

⁵ C HN S

calc .: 53.3 5.3 8.4 9.5 %

found: 53.2 5.4 8.2 9.2 %

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Example 13

(iR, 5R) -4.7 ~ Diaaa-6-oxo ~ 5-phenoxj ^{! r} methyl-2-tliiabicycla- [3.2.O] -liept-3-en

A solution of 0.5 g (1.48 mmol) of (1S, 3S, 5R, 6R) -2,2-dimethyl-3-hydroxy-6-phenoxyacetamidopenam - 1 - oxide with 15 ml of ethyl acetate containing 0, Containing 3 ml (2.5 ml) of trimethylphosphoric, it was refluxed for 16 hours. The excess solvent was removed under reduced pressure to give an oil "This oil was hydrogenated over 10 g of silica gel using benzene / £ thylb acetate (4/1) as solvent. The main component was isolated (R-0.3, benzene / ethyl acetate (1/1)) and crystallized in porrn of colorless prisms from ethyl acetate and it was found that this was the title compound (0.12 g, 34.5 <f ) , i ¹ = 155 to 157 ⁰ C,

107 ° (c, 1, tetrahydrofuran).

IR spectrum O _max> (CHBr ₃ ) 3386 (NH), 178O (β-lactam), 1619 (C = N) and 750 cm " ¹ (Ph).

NMR spectrum (βΟΜΗζ, CDCl ₃ ? ) 1.68 (NH), 2.5 to 3.2 (Ph), 3.95 (multiplet 5-H), 4.49 (doublet, J = 5Hz, 1- H) and 5.05 (O CH ₂ Ph).

56 C. 4th H N 13th S. ber .: 56 4th , 3 12.0 13th , 7 found : , 5 11.7 , 2

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2166Q22

Example 14

(3R, 5R, 6R) -2,2-dimethyl-6-pheno ^ acetainido-3-- (11-2 *, 2 ■, 2 ' trichloroethoxycarbonylamino ^ penam

A solution of 30 g (0.086 mol) of 6-plienoxyacetamidopennicillanic acid (penicillin V) in 300 ml of anhydrous tetrahydrofuran containing 18 ml (0.12 mol) of triethylamine was ^{cooled to -20 0} G and 8.4 ml (0.086 Hol ) Treated ethyl chloroformate. The reaction was continued for 1 hour at -20 ^0C. After cooling to about -50 ⁰ C a solution of sodium azide (5.4 g, 0.082 mol) was added (temperature <-20 ⁰ C). The mixture was then poured into excess water and extracted with 2 × 400 ml of ethyl acetate. The combined organic layers were then washed with saturated ITatriura hydrogen carbonate solution and with water, dried, and foam to give (3R, 5R, 6R) -2,2-dimethyl-6-phenoxyacetamidopenam-3-carboxylic acid aside (23.0 g , $ 72 6) evaporated.

IR spectrum>) ^^^ (CHBr ₃ ) 3386 (NH) ₉ 21 * 18 (N ₃ ), 1783 (ß-Laetam), 1695 (CON ₃ ), I685 and 1515 (CONH) and 746 cm " ¹ ( Ph) '.

NMR spectrum (60MKz, CDCl ₃ , X ) 2.4 to 3.1 (Ph and NH), 4.1 to 4.55 (multiplet, 6-H and 5-H), 5.40 (-CH ₂ Ph), 5.69 (3-H), 8.42 (CH ₃ ) and 8.58 (CH ₃ ).

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ORiQINAL INSPECTED

A solution of 5.0 g (0.0132 mol) of (3R, 5R, 6R) -2,2-dimethyl-6-phenoxyacetamidopenam-3-carboxylic acid azide in 30 ml of anhydrous benzene, which is 4.05 ml (3 equivalents) 2 , 2,2-trichloroethanol, was refluxed for 1 hour. Evaporation gave an oil which was chromatographed on silica gel (40 g) with benzene / ethyl acetate (3/1) as the solvent. The title compound was obtained on trituration with ether (2.2 g, 34 ^) in 3? Orm of white prisms, 3? = 161 to 163 ⁰ C,

[α] _Ώ + 106 ° (c 1, tetrahydrofuran).

IR spectrum N _max ^ (CHBr ₃ ) 3390 (NH), 178Ο (β-lactam), 1736 and 1510 (NCOpR), I689 and I510 (CONH), and 754 cm " ¹

(Ph)

NMR spectrum (6QMHs, CDCl ₃ , t) 2.4 to 3.2 (Ph and NH), 4.33 (doublet, J 5 Hz, 6-H), 4.40 (3-H and NH), 4.59 (doublet, J 5 Hz, 5-H), 5.20 (CH ₉ CCl,), 5.42 (CH ₀ Ph) and 8.50 (two methyl groups).

C ₁₈ H ₂₀ Cl ₃ N ₃ O ₅ S:

.ber .:
found:

43.5 43.5

4.1
4.2

Cl

21.4 8.5 6.5 % 20.8 8.4 6.4 %

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Example 15

(1 'R ₁ IE ₁ SR) -T- [T- (I ^l -2 ", 2", 2 "-Trichlorethoxycarbonylamino-2'-methylenepropyl) -] - 4 _f 7-diaza-6-oxo-3- phenoxymethyl-2- thiabicyclo- [3 «2.0] -hept-3-en " ____ _-______ "

A solution of 1.23 g (2.48 mol) (3R, 5R, 6R) -2,2-dimethyl-6-phenoxyacetamido-3- (H-2 ^I , 2 ·, 2'-trichloroethoxycarbonylaniino) -penaiD in 12.5 ml of anhydrous tetrahydrofuran was ^{treated at 0} ° C. with 1.5 ml (3 equivalents) of 37 Seiger peracetic acid in acetic acid. The reaction mixture was allowed to ^{warm to 22 °} C. over 1 hour. After evaporation, the resulting oil was dissolved in 50 ml of ethyl acetate and washed with sodium bicarbonate solution. Drying and evaporation of the organic layer gave a mixture of (3R> 5R, 6R) -2,2-dimethyl-6 ~ phenoxyacet ~ am id ο- 3- ( Ή- 2 ^l , 2 ', 2 * - ^: brichlorethoxycarbonylainino) -penam-1-oxide (1.23g, $ 96.5).

IR spectrum>? _mQV (CHBr,) 3 ^ 00 (NH), 1800 (β-lactam). nkO and 1510 (NCO ₂ R), 1689 and 1510 (NCOpR), 1689 and 1510 (CONH), 1040 (SO) and 750 cm " ¹ (Ph).

Nuclear Magnetic Resonance Spectrum (6 MHz, CDCl ₃ , t) 1.69 (NH), 2.4 to 3.2 (multiplet, Ph and NH), 3.82 and 4.91 (multiplet, J 5 Hz, 6 -H or 5-H, IS isomer), 4.49 and 5.12 (multiplets, J 5 Hz, 6-H or 5-H, 1R isomer), 3.81 and 4.01 (3 -H protons), 5.20 (CH _n CCl _x ), 5.43 (CH ₀ Ph), 8.52 and 8.60 "(two methyl groups, 1R isomer), 8.4l and 8.71 (two Methyl groups, IS isomer) "

209840/1176

A solution of 1.1 g (2.14 mol) of (3R, 5R, 6R) -2,2-dimethyl-6-ph.eno ^ acetaiaido-3- (H-2 ^l , 2 ', 2 ^l - trichlorethoxycarbonylamino) -penam-1-o: xide in 12 ml of ethyl acetate containing 0.4 ml (3.2 mmol) of trimethylphosphate was refluxed for 16 hours. The excess solvent was removed in vacuo and the crude product was chromatographed over 12 g of silica gel using benzene / ethyl acetate (4/1) as the solvent. The title compound was obtained in the form of a foam (0.425 g, $ 41.5).

IR spectrum ^ _mov (CHBr,) 3396 (NH), I767 (ß-lactam),

IU α. Λ ψ P j

1738 and 1500 (NHCO ₂ R) and 750 cm (Ph).

NMR spectrum (60 MHz, CDCl ₃ , ^) 2.70 to 3.2 (Ph),

4.00 (multiplet, J 4 Hz, 5-H), 4.44 (doublet, J 4 Hz, l-H),

4.08 and 4.40 (-CK ^ and NH), 4.75 and 4.96 (CH ₃ OPh,

Quartet, J 13 Hz), 5.04 (= CH ₂ ), 5.22 (-CH ₂ CCl ₃ ) and

8.21 (CH,).

209840/1176

Example 16

(1R, 5R) -4,7-Diaza-6-oxo-3-phenoxymethyl-2-thia-bicyclo- [3.2.O] -hept-3-en

A solution of 0.3 g (0.64 mmol) (1 »R, 1R, 5R) -7- [i '- (- | · _2", 2 ", 2"-Trichlorethoxycarbonylamino-2'-methylenepropyl) - ] -4,7-diaza-6-oxo-3-plienoxyi2ietliyl-2-thiabicyclo ~ [; 5.2.O] -hept-; 5-ene in 12 iqI anhydrous tetrahydrofuran, the 0.2 ml (3.1 mmol) zinc dust for 2 i / 4 hours at 22 ⁰ g was treated with glacial acetic acid containing 0.45 g (6.9 mmol). the reaction mixture was then filtered through diatomaceous earth and evaporated to a resin the Piltrat ". Partitioning between 70 ml of ethyl acetate and a dilute sodium hydrogen carbonate solution, drying and evaporation gave the crude product. Chromatography on silica (5 g) using benzene / ethyl acetate (4/1) as solvent gave the title compound in 3 µm of white crystals (0.09 g, 62 $ 6), i ¹ = 152-153 ° C. The other physical data were similar to those of the compound obtained in Example 13.

2098A0 / 1176

Claims (1)

Claim Compounds of the formula O- v / orin R is the remainder of an acyl group R'CO with 1 to 21 carbon atoms and R is a blocked hydroxyl or amino group. 209840/1176