DE2950898A1 - NEW PENEM COMPOUNDS, METHOD FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS - Google Patents

Description

PATENT LAWYERS

J. REITSTÖTTER

PHOF. DR. DR. DIPL .. INO.

W. BUNTE 11958-1876) DR. ING.

W. KINZEBAC

DR. FHIL. DIFL CHBM.

K. P. HÖLLBR

DR. RKR. NAT. IjIPIj. CHBM.

TEXEPOKi (OSS) 37 SJ TELEX »Β2ΪΒ2Ο8 ISAR D

BAt) T ¹ ASSB 22, SOOO MUNICH 4O

Hünchen, December 14, 1979

M / 20 359

SY-1599A

BRISTOL-MYERS COMPANY 345, Park Avenue New York, N.Y. 10022 United States

New penem compounds, processes for their manufacture and drugs

POBTANBOHHUTf POSTFACH 780, D-SOOO MUNICH 43

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M / 20 359 SY-1599A

The invention relates to new and substituted in the 2-position in 2,6-position disubstituted penem compounds, the one have strong antibiotic activity. Various new intermediates are also created which are useful for the preparation of the biologically active penem derivatives, and various procedures for preparing the intermediates and the active compounds.

The Penem ring system has the following formula:

and can be systematically referred to as J-hept-2-en. For the sake of simplicity, it is referred to in the present application as ¹ % I ¹ S "2-penem". The numbering system is as follows:

According to the invention, new penem compounds of the general formula I are created:

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wherein Z is hydrogen or an easily removable ester protecting group;

X can stand for the following groups: (a) a residue of the formula:

{i) = OR_, where R _{3 is} hydrogen

α α

(ii) -CORj ₁ , in which R _{b can} denote hydrogen, hydroxy, desired-j if substituted (lower) alkyl or, if desired, ring-substituted phenyl or a "heterocyclic radical, the substituents on the alkyl group being one or more of the following radicals: halogen, hydroxy, oxo, carboxy, carb (lower) aTk6xy, carbamoyl, (lower) alkoxy, amino, (lower) alkylaniino, di (lower) alkylamine, (lower) alkanoylamino or optionally substituted phenyl or a heterocyclic The radical ynrf wobpf «cirh in the substituents on the phenyl group or the heterocyclic rings around one or more

(preferably 1 or 2) of the following group

030027/0777

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pen is: Hydroxy »(low) alkoxy, halogen,! (lower) alkyl, halogen (lower) alkyl, methane ί sulfonyl, oxo, (lower) alkylthio, amino, (lower?) alkylamino, di (lower) alkylamino, (lower) alkane / ^ mino, (lower) alkanoyloxy, carboxy, CarboAy (lower) alkyl, sulfo or Suifo (lower) -i'kyl; or

"(iii) -OCOR, Wherein R_" represents amino, (lower ^ alkylamino, di (niedi ig) alkylamino or gewiinschtentalls subst tuiertes (lower) alkyl wherein the substituents are as defined under dea point (ii); or

(Ib-) substituted (ηlow) aliphatic, (low) cycloaliphatic or (low) cyelosliphatic low} = aliphatic radicals or a ring-substituted phenyl radical, phenyl (lower) alkyl radical, a heterocyclic radical, a heterocyclic (lower) alkyl radical or a heterocyclylthio (lower) alkyl radical, where the substituents of said aliphatic groups, cycloaliphatic groups, Phenyl groups or heterocyclyl groups are the following:

NR ₁ (i) -CNR ₅ R, or -N = C-NR-R- where R- is hydrogen,

(lower) alkyl or phenyl and R _? and R _{3 is} (lower) alkyl, phenyl or benzyl;

(ii) -OR _d , where R _{d is} amino, (lower / alkylamino, bi (lower) alkylamino, substituted (lower) alkyl, (lower) aikenyl, or if desired

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(iv) -OCOR ₁ /, wherein

for amino, (lower) alkyl

amino, di (lower) alkylamino or R _r , where R _r 'cannot stand for unsubstituted (lower) alkyl;

(v) -OSO ₃ H;

(vi) -OP (OH) ₂ ;

(vii) -0S0 ₂ R _r »where R _{r is} as defined under point (b) (iii) above;

(viii) -OP (ORgJ (OK _r K where R _{6 stands} for tlow / Älkyi

and R _{r is} as defined under point (b) Cüi) above;

030027/0777

ring-substituted phenyl, phenyl (lower) alkyl, see a heterocyclic group or a heterocyeli (lower) alkyl group, with the Substituents on the alkyl groups, phenyl groups and heterocyclic groups are those as defined under (a) (ii);

(iii) -0 (CH ₂ ) _n OR _r , where η is an integer from 1 to 6 and R _{r is} optionally substituted (lower) alkyl or, if desired, ring-substituted phenyl or an optionally ring-substituted heterocyclic group, where the substituents on the alkyl groups, phenyl groups or heterocyclic groups are as defined by ynter (a) (ii);

C '

Μ / 20 359 SY-1599A

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(ix) -S (O) _n R _d , in which η stands for 0, 1 or 2 and R ^ is as defined under point (b) (ii) above

Ü ^R 4 or in the case that n = 0, is -C-NR ₅ R ₅ ,

wherein R ^ is hydrogen or (lower) alkyl and R ₅ and R _{ß are} each independently hydrogen or (lower) alkyl, where R ^ must not be unsubstituted phenyl;

(x) -COR _f , where R _{f stands} for amino (lower) alkyl, (lower) alkylamino (lower) alkyl, di (lower) alkylamino- (lower) alkyl, -NHNH ₂ , -NR ₁₇ NR ₁₈ , -NHOR ₁₉ , -SR -0 (GH ^ -A-Rg or -NR _e R, in which R ₁₇ , R ₁₈ and R _{e are} (lower) alkyl, R _{19 is} hydrogen or (lower) alkyl, A is 0 , S, NH or NCH ₃ and η and R are as defined under (b) (iii) and (b) (viii) above;

(xi) -P0 (OR _w ) ₂ , where R _{w is} hydrogen or (lower) alkyl;

(xii) -NHR _h , in which R _{h has} the following meanings: if desired substituted phenyl, if desired - "" * '"if necessary substituted heterocyclic group,

-CH = NH, -SO ₃ H, -OH, (lower) alkoxy, amino, (lower-

rig) Älkylamino, di (lower) alkylamino, -NHCOCH- ,,

S ^ά

-CS ₂ CH ₃ , -SO ₂ CH ₃ , -SG ₂ / \ -SO ₂ NH ₂ , -

SS _j _ ^. NH -CNHCH ₃ , -C-NH- / V -C-NR ₇ R ₈ , wherein R ₇ and R _ß

each independently for (lower) alkyl,

NH

Phenyl or phenyl (lower) älkyl, -C-Rg wherein R _g is (lower) alkyl, phenyl or phenyl (lower) .-

0300277077?

Μ / 20 359 -29 -

^SY " ^1599A 2950898

Il

alkyl stands * or -CR. stands * where R | for amino (lower) alkyl, -NH ₂ , (lower) alkyl-

amino, di (lower) alkylamino, -NH- ^ y _t

Ii

-NH-CR ₁₀ , in which R _{10 is} (lower) alkyl or optionally substituted phenyl or an optionally substituted heterocyclic group, the phenyl substituents and heterocyclic substituents as below

are defined in item (a) (ii) above, or NH

for -NH-C-NH ₂ , (lower) alkoxy, -

-0CH ₂ - ^ \ - N0 ₂ or -0 (CHg) ₂ Si (CH ₃ J ₃ ;

(xiii) -SCR ₁₁ , wherein R _{11 is} (lower) alkyl which is substituted by amino, (lower) alkylamino or di (lower) alkylamino;

(xiv) -NRjR _k , where R. is (lower) alkyl and R _{k is} (lower) alkyl, (lower) alkoxy, a

heterocyclic group, amino or 0

Il

-CR.J, in which R ₅ - is as defined under point (b) (xii) above, or in which, together with the nitrogen, the radicals R. and R ,. stand for the following group:

where when R _{fc is} amino or -CH ₂ CH ₂ NH ₂ , R. is methyl and where R. and R ^ are not (lower) alkyl at the same time;

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2850838

(xv) -NO.'R _1. ', where R.' stands for (lower) alkoxy

and R _k 'for (lower) alkyl, a heterocyclic group, amino (lower) aTkyl »(lower) alkylamino- |

(lower) alkyl, di (lower) alkylamino (lower) -0

stands in which R. as under the

alkyl or -C-

point (b) (xii) above is defined, or wherein

together with the nitrogen, the radicals R- ¹ and

j R-! stand for the following group:

(xvi) - ^ R ₁ R _m R "» where R ₁ , R ι m η im

and R are each independent

from each other for. (-lower) alkyl or together with the nitrogen atom represent the following group:

W = /

(xvii) -N = CH-R _V , where R _{v is} (lower) alkyl or, if desired, substituted phenyl or, if desired, a ring-substituted heterocyclic group, the substituents on the phenyl ring or on the heterocyclic ring being so-called as defined in item (a) (ii) above;

(xviii) -N = CR _x R, where R is (lower) alkyl or, if desired, ring-substituted phenyl or an optionally ring-substituted heterocyclic group, where the

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Substituents on the phenyl group and the heterocyclic group Group of trades as defined under point (a) (ii) above, and wherein R is as defined under point (b) (xvii) above;

(xix) = NR _s where R is hydroxy, (lower) alkoxy, amino, di (lower) alkylamino or

-NH-

stands; or NOH

(xx) -C- (CH ₂ ) _n NR ₁₅ R, j ₆ , in which η represents an integer from 1 to 6 and R ^ ₅ and R. _g each independently represent hydrogen or (lower) alkyl; and

Y stands for hydrogen or a radical which is selected from the following group: · ·

(a) If desired substituted {low) aliphatic Groups, (low cycloaliphatic groups or (low) cyeloaliphatic (low) aliphatic groups, where the substituents are one or more of the following: hydroxy, (lower) alkoxy, desired ^ if substituted phenyloxy, if desired substituted heterocyclyloxy, if desired unsubstituted (lower) alkylthio, if desired substituted Phenylthio, optionally substituted heterocyclyl thio; Mercapto. Amino. (lower) alkylamino, di (lower) alkylamino,. (lower) alkanoyloxy, (lower) alkanoylamino optionally substituted phenyl, if desired substituted heterocyclic radicals, carboxy, carb (lower

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M / 20 359 SY-1599A

rig) alkoxy, carbamoyl, N- (lower) alkylcarbamoyl, N, N-di (lower) alkylcarbamoyl, halogen, cyano, oxo, thioxo, -SO ₃ H, -OSO3H, -S0 ₂ - (lower) alkyl, (lower ) -

Alkylsulfinyl, nitro, phosphono or -OP (OR _g ) (OR _r ), in which R _ß and R _{r are} as defined above, the substituents on the (lower) alkylthio group being one or more of the following radicals: halogen , Hydroxy, (lower) alkoxy, amino, (lower) alkanoylamino or optionally substituted phenyl or an optionally substituted heterocyclic group ₉ and where the above phenyl substituents or heterocyclo substituents are one or more of the following groups: hydrox, ( lower) alkoxy, halogen, (lower) alkyl, halogen (lower) alkyl, hethanesulfonyl, (lower) alkylthio, amino, (lower) alkanoylamino, (lower) alkanoyloxy, carboxy, carboxy (lower) alkyl, sulfo or sulfo (lower) alkyl;

(b) -OR ₅ , in which R represents, if desired, substituted (lower) alkyl or (lower) alkanoyl or a ~ if desired, if desired substituted phenyl group or if desired substituted hete Ό cyclic group, the substituents on the alkyl radicals and alkanoyl radicals being one or more of the the following groups are: halogen, hydroxy (lower) alkpxy, (lower) alkylamino, di (lower) alkylamino, amino, oxo, (lower alkanoylaniino or a substituted phsnyl group if desired or if substituted heterocyclic group if desired, and where d; n substituents on the phenyl group or heterocyclic group are one or more of the following groups: hydroxy, (lower) alkoxy, halogen, (lower) alkyl, halogen (lower) alkyl, methanesulfonyl, (lower) alkylthio, (lower) alkylamino ₉ di (lower) alkylamino, amino, (niadrig) alkanoylamino, (lower) alkanoyloxy,

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Carboxy (n1edrig) alkyl Siilfo _s SuTfo (lower) alkyl, carboxy, or;

(c) -S (O) _n R ₅₅ where η is 0, 1 or 2 and R _{g is} as defined above;

fd) halogen: and

(e) an if desired substituted phenyl group or if desired substituted heterocyclic group; which is the substituent is one or more of the following groups: hydroxy, (lower) alkoxy, halogen, (lower) alkyl, Halogen (lower) alkyl, methanesulfonyl, (lower) alkylthio, Amino, (lower) alkylamino, di (lower) alkylamino, (low) alkanoylamino, (low) alkanoyloxy, Carboxy. CarLöxy (lower) alkyl, sulfo or sulfo (lower) alkyl ;

as well as their pharmaceutically acceptable salts and physiologically hydrolyzable ester;

where in the case that Y stands for hydrogen, X must not stand for -CH ₂ OCH ₂ CH ₂ OCH ₃ .

The compounds of the general formula I in which Z is hydrogen stands (as well as their pharmaceutically acceptable salts and physiologically hydrolyzable esters) are effective antibacterial agents. The remaining compounds are useful Intermediate products for the production of the biologically active PanomuorhinHnnnon.

The previously disclosed substituent groups for the 2- or 6-position of the penem ring cups are defined in more detail as follows:

0 3 00 2 7/0777

Μ / 20 359 SY-1599A

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(a) Halogen comprises chlorine, bromine, fluorine and iodine _s = HaIogensubstituenten Preferred are chlorine and fluorine;

(b) (Lower) alkyl includes straight-chain and branched saturated aliphatic R _ :. hydrogen radicals having 1 to 6 carbon atoms including, for example, methyl, ethyl, n-propyl, I. "propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, r-pentyl, isopentyl, n-hexyl, and the like. Preferred (lower) alkyl substituents have 1 bi, 4 carbon atoms , most preferably 1 to 2 carbon atoms;

(c) (Lower) aliphatic includes acyclic straight chain and branched, saturated and unsaturated hydrocarbon radicals with 1 to 6 carbon atoms inclusive. The unsaturated radicals can have one or more double bonds or triple terminations, but preferably contain either a double bond or a triple bond. Examples of (lower) aliphatic radicals are Methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, n-pentyl, isobutyl, vinyl, 1-propenyl, 2-propenyl, isopropenyl, 2-methyl-2-propenyl, ethynyl and 2-propynyl The most preferred aliphatic radicals are (lower) alkyl, as defined under point (b) above;

(d) (Low) cycloaliphatic stands for alicyclic saturated and unsaturated hydrocarbon radicals having 3 to 8 ring carbon atoms, preferably 3 to 6 ring carbon atoms. The unsaturated ring can comprise one or more (preferably one) double bonds. Examples of this group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclcaropenyl, cyclopentenyl 1 , 3 "CyclGhexsdiariy 7 and cyclohexenyl;

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••• J. ··.

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(e) (low) cycloaliphatic (low) aliphatic stands flit cycloaliphatic-aliphatic radicals with 3 to 8 carbon atoms (preferably 3 to 6 carbon atoms) in the cycloaliphatic ring and 1 to 6 carbon atoms (preferably 1 to 4, most preferably 1 to 2 carbon atoms in the aliphatic part. Examples include cyclopropylmethyl, cyclopropylethyl, cyclopropylpentyl, cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropenylmethyl, cyclopentenylethyl, cyclopropylethenyl, cyclopropylethinyl, and the like. The most preferred radicals of this type are cycloalkylalkyl radicals in which the cycloalkyl part has 3 to 6 carbon atoms and the alkyl part 1 to Contain 2 carbon atoms;

(f) (Lower) alkoxy comprises C 1 -C 6 alkoxy radicals, the alkyl part of which is as defined under point (b) above. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, n-pentyloxy, and the like. Preferred are C ₁ -C ₄ alkoxy and most preferred are C ₁ -C ₂ alkoxy;

(g) (Lower) alkylthio embraces C 1 -C 6 alkylthio radicals in which the alkyl part is as defined in item (b) above Examples include methylthio, ethylthio and n-butylthio;

(h) (f-lower) ATkylamino includes C 1 -C 6 -alkylamino radicals in which the alkyl part is as defined under point (b) above Examples include methylamino, xthylamino, n-propyl

(i) Di (lower) alkylamino represents di-C ₁ -C 6 -alkylamino, in which each alkyl radical is as defined under point (b) above. Examples are dimethylamine and diethylamino

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• ·

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(j) (Lower) Aikanoyloxy stands for radicals of the formula (lower) -0

Il

Alkyl-C-O-, in which alkyl as under point (b) above is defined;

(k) (Lower) alkanoylamino comprises radicals of the formula (lower) -O

Il

Alkyl-C-NH-, in which alkyl as under point (b) above is defined.

(1) Carb (lower) alkoxy includes -C- (lower) alkoxy, wherein (lower) alkoxy is as defined under point (f) above;

(M) Halogen (lower) alkyl represents alkyl radicals in which a or several hydrogen atoms have been replaced by a halogen atom;

(n) sulfo (lower) alkyl is - (CH ₂ J _n SO ₃ H, where η is 1 to 6;

(0) Carboxy (lower) alkyl is - (CH ₂ J _n COOH, where η is 1 to 6;

(p) Phenyl (lower) alkyl represents ~ represents 1 to 6;

* ^{where n}

(q) (Lower) alkylamino (lower) alkyl is - (CH ₂ ) _n NH- (nie | j rig) alkyl, in which η is 1 to 6 and alkyl is as defined under point (b) above;

(r) Di (lower) alkylamino (lower) alkyl represents (lower) alkyl

» ^{Where n stands for ] to 6 and} (lower) alkyl

each ATkyl radical is as defined under point (b) above;

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Il

(s) {Lower alkylcarroyl represents (lower) alkyl-C-, in which Alkyl is as defined under point (b) above;

(t) N- (lower) Alky1carbamoyl stands for (lower) alkyl-HN-C-, wherein alkyl is as defined under point (b) above;

(u) N, N-Di (lower) carbamoyl represents

(lower) alkyl _v O

χ "

N-C-, in which each alkyl radical as below

(lower) alkyl ^

is defined by item (b) above;

(v) Amino (lower) alkyl is - (CH ₂ J _n NH ₂ , where η is 1 to 6;

(w) Hydroxyamino (lower) alkyl is - (CH ₂ J _n NHOH, wherein

η is 1 to 6;

O (x) (lower) alkylsulfinyl represents -S- (lower) alkyl, wherein (lower) alkyl as defined under point (b) above

is; and

(y) (Lower) Alkenyl represents straight or branched chain unsaturated aliphatic hydrocarbon radicals with one double bond and 2 to 6 carbon atoms inclusive, for example vinyl, allyl, isopropenyl, 2- or 3-methallyl or 3-ßutenyl.

The term "heterocyclic", f'heterocyclyl "or" heterocyc 1Ische group "innfa & t hetsromonocyclic and hstercbicyclische Residues with an aromatic character, as well as corresponding partially or fully saturated radicals, the heterocyclic Radicals contain at least one heteroatom, selected from oxygen, sulfur and nitrogen and a carbon

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atom are connected to the penem ring carbon atom * In the Preferred heterocyclic groups are either 5- or 6-membered monocyclic radicals or fused 6,6 or 5,6-bicyclic radicals. To explain more suitable heterocyclic radicals are referred to as follows;

KJ KJ- U

r +,

LJ

^V NH

030Q27 / O777

M / 20 359 SY-1599A

Ν — ϊϊ ff

Γ "

Il

N-H

Τί

and-

In the same way, the terms heterocyclyl (lower) alkyl, heterocyclylthio (lower) alkyl, heterocyclyloxy or heterocyclylthio stand for - (CH ^ -heterocyclyl, - (CH ₂ ) _n -S-heterocyclyl, -O-heterocyclyl and -iS- Heterocyclyl, where η is 1 to 6 (preferably 1 or 2).

Since there is an asymmetric carbon atom in the two substituted compounds of general formula I, these compounds can be present either in the form of racemic mixtures (R, S form) or in the form of the individual dextrorotatory and levorotatory (R and S forms) optical isomers. The compounds in which the configuration on the 5-carbon atom corresponds to that of natural penicillin (5R configuration) are preferred. The substituents in the 5- or 6-positions of the 2,6-disubstituted penem compounds can be one-

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others are in the cis or trans position. If the 6-substituent in the penem compound has an asymmetric carbon atom, the resulting isomers are referred to in the present application as isomers A, B, C and D, respectively (cf. Example 58 for stereochemistry). The preferred isomers in the compounds of this type are the isomers B. The various optical and geometric isomers can be separated using customary separation methods known to the person skilled in the art.

The invention includes the compounds of general formula I in the form of the isomeric mixtures and also in the form of the individual separated isomers.

The aforementioned pharmaceutically acceptable salts include non-toxic carboxylic acid salts, for example non-toxic metal salts, for example salts with sodium, potassium, Calcium, aluminum and magnesium, the ammonium salt and salts with non-toxic amines, for example with trialkylamines (Triethylamine), procaine, dibenzylamine, N-benzyl-ß-phenethylamine, 1-ephenamine, Ν, Ν'-dibenzylethylenediamine, N-alkylpiperidine and other amines previously used to form salts with penicillins and cephalosporins. When a basic group is present, the present invention also includes the pharmaceutically acceptable acid addition salts, for example salts with mineral acids (inorganic acids), e.g., hydrochloric acid, hydrobromic acid, hydriodic acid, phosphoric acid, sulfuric acid, or with suitable λ ** π α η ί e / »Ko η

aHav * Cn! ^ To

Trifluoroacetic acid, p-toluenesulfonic acid, maleic acid, acetic acid, citric acid, oxalic acid, succinic acid, benzoic acid, Tartaric acid, fumaric acid, mandelic acid, ascorbic acid and malic acid. Compounds with an acidic group and a basic one Groups can also be in the form of internal salts, i.e. in

Ö3Ö027 / 0777

, .ρ φ m

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Form of zwitterions. The preparation of the salts described above can, according to customary procedures for the preparation of Salts unit ß-lactam antibiotics, for example penicillins and cephalosporins.

The term "easily removable ester protecting group" has acquired a clearly defined meaning in the field of β-lactam and peptide chemistry. Many such groups are known, the "zura" SVnutz the Carboxylgrc ⁿ oe during subsequent chemical reactions used and then can be removed by standard methods to give the free carboxylic acid. Known ester protecting groups include 2,2,2-trichloroethyl, tertiary "alkyl with 4 to 6 carbon atoms, tertiary alkenyl with δ to 7 carbon atoms, tertiary alkir-yl with 5 to 7 carbon atoms, alkoxymethyl, alkanoylmethyl with 2 to 7 carbon atoms, N- Phthalimidomethyl , benzoylmethyl,! 'Alogenbenzoylmethyl, benzyl, p-nitrobenzyl, o-nitrobenzyl, benzhydryl, trityl, trimethylsilyl, triethylsilyl, β-trimethylsilylethyl, and the like.

The choice of an ester protecting group depends on the subsequent reaction conditions which the group has to withstand and the conditions desired for removing the group. The choice of a suitable group is given to the person skilled in the art. For use as a chemical intermediate, the preferred ester is the p-nitrobenzyl ester, which can be easily cleaved by catalytic hydrogenation. For the preparation of compounds with functional groups which are reducible under such conditions, "represents a preferred alternative of the ß-trimethylsilylethyl ester, which can be cleaved by treatment with fluoride ions. Easily removable ester protecting groups also include physiologically cleavable esters, ie those esters of which is known in ^the! field of penicillin and cephalosporin chemistry, that they can be readily cleaved in the body to the acid base. examples

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such physiologically cleavable esters include indanyl. Phthalidyl, methoxymethyl, glycyloxymethyl, phenylglycyloxymethyl, thienylglycyloxymethyl or Äcyloxymethyl of the formula:

wherein Y ¹ is C 1 -C 4 alkyl or phenyl. Particularly preferred Este, this type are methoxymethyl, acetoxymethyl _s pivaloyloxymethyl, phthalidyl and indanyl.

It can be seen that the compounds of the formula I can be present in various degrees of stability, and that the water free form as well as the solvated forms (including of hydrates) fall within the scope of the invention.

In the case of the compounds of the general formula I, the preferred compounds are those in which Y is hydrogen or (lower) alkyl, which if desired (preferably on the »carbon atom) is substituted by hydroxy. More preferred compounds within the above group are those in which Y is hydroxy, ethyl or-hydroxyethyl stands. Even more preferred compounds of the formula I are those in which Y is hydrogen or oC-hydroxyethyl. The most preferred compounds are those in which Y is o ^ -hydroxyethyl.

A preferred embodiment of the present invention consists of the compounds of formula I in which the 5ubstituent X is a substituted (lower) aliphatic radical, (lower cycloaliphatic radical or (lower) cycloaliphatic (lower) aliphatic radical or a ring-substituted one Phenyl radical, - PhenyK low alkyl radical, heterocyclic radical,

Heterocyclyl (lower) alkyl radical or Heterocyclylthi'M low) -

111 4. · χ u. _L L. -.Substituenten der,. ,, .. alkyl radical, whereby it is in denyiuvor mentioned aliphatic

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see remnants, cycloaliphatic)! Radicals, cycloaliphatic-raliphatic radicals, phenyl radicals, phenylalkyl radicals, heterocycli see residues, Heterocyclylalkylireste and Heterocyclylthioalkylreste concern the following:

NR ₁ -CNR ₂ R ₃

or

-N = C-NR ₂ R ₃ «1

where R _{1 represents} hydrogen »(lower) alkyl or phenyl and R ₂ and R ₃ each independently represent hydrogen, (lower) alkyl, phenyl or benzyl. Within this class, the preferred compounds are those in which Y is hydrogen, ethyl or tert-hydroxyethyl, in particular those compounds in which Y is hydrogen or ci-hydroxyethyl, very particularly those compounds in which Y is c / -hydroxyethyl .

Another preferred embodiment of the invention consists of the compounds of the formula I in which X is a substitute te (lower) aliphatic group, one (lower) cycloatiphatic Group or a (low) cycloaliphatic (low) aliphatic Group or represents a ring-substituted phenyl radical, a phenyl (lower) alkyl radical, a heterocyclic radical, a heterocyclyl (lower) alkyl radical or a huterocyclylthio (lower) alkyl radical, the substituents of the above aliphatic radicals, cycloaliphatic radicals, cycloaliphatic-aliphatic radicals, phenyl radicals, phenylalkyl radicals, heterocyclic radicals, heterocyclylalkyl radicals or Heterocyclylthio'alkyl radicals around those of the formula

-COR,

is where R _f for amino (lower) alkyl, (lower) alkylamino (lower) alkyl, di (lower) alkylamino (lower) alkyl,

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-NHNH

₂ ,

-NR ₁₇ NR ₁₈ , -NHOR ₁₉ , -SR ₁₇ , "0 (CHg) _n -AR ₆ or -NR _e R _g

is where R

₁₇ , R ₁₈ , R ₆ and R are (lower) alkyl, R _{19 is} hydrogen or (lower) alkyl, A is 0, S, NH or NCHo and η is an integer from 1 to 6. Within this class, the preferred compounds are those in which Y is hydrogen, ethyl or -hydroxyethyl, especially those compounds in which Y is hydrogen or -hydroxyethyl, especially those in which Y is oi-hydroxyethyl, stands.

Another preferred embodiment of the invention comprises the compounds of the formula I in which X has the following meanings: 0

(a)

, where η is an integer from 1 to 6,

preferably represents from 1 to 4;

(b) - (CH ₂ J _n NHOH, where η is an integer from 1 to 6, preferably from 1 to 4;

(c) - (CHg) _n PO (OC ₁ -C ₆ -AUyI) ₂ , in which η is an integer from 1 to 6, preferably from 1 to 4, and alkyl is preferably methyl, ethyl or isopropyl;

NH

(d) - (CH,) NH-C, where η is an integer of

^{& n} ^ C ₁ -C ₆ alkyl

1 to 6, preferably from 1 to 4, and alkyl is preferably methyl or ethyl;

v "NHn

(e) - (CH ₉ ) N = C ^, where η is an integer from 1 to 6,

ά η \

preferably from 1 to 4;

030027/0777

M / 20 359 SY-1599A

, A _n B

(f) - (CH ₉ V OC (CH ₉ ) _m NR ^rt R, where η and m are each independently

AR

stand for 1 or 2 and R and R each independently stand for hydrogen or (lower) alkyl stand; or

(g) - (CH ₉ VNHC-R ⁰ , where η is an integer from 1 to 6, preference

NH

from 1 to 4, and R ^{c is} C ₁ -C ₄ -AlkYl (preferably methyl or ethyl), phenyl or

/) , in which m has the meanings 1 or 2 be

sits.

Within this class of compounds, the preferred members are those in which Y is hydrogen, ethyl or o ^ -Hydroxyäthyl, preferably those in which Y is Is hydrogen or tf-hydroxyethyl, most preferably those in which Y is -hydroxyethyl.

Other preferred embodiments of the present invention include the intermediates of the following formulas:

III

wherein Y is hydrogen or has the same definition as in the case of the compounds of the formula I, Q is

030027 / G777

M / 20 359 SY-1599A

- 46 -

2Ί60898

Phenyl or (lower) alkyl, R "represents an easily removable ester protecting group, χ stands for 1 or 2 and M stands for Cu (II) ₉ Pb (II) or Hg (II), when χ stands for Z or for Ag ( I) if χ has the meaning 1;

(B)

-N

SHgCOOCH.

P (Q)

CO ₂ R '

IHa

wherein Y, Q and R "are as previously defined under item (A) are; and

(C)

-T

PCQ)

IV

wherein Y as above in connection with the compounds of Formula I is defined, Q is phenyl or (lower) A] kyί represents, R "represents an easily removable ester protecting group and T represents

ι D D n

-CC ₆ H ₅ or -CX

^έ 6 ^Η 5

is in which X is as defined above for the compounds of formula I.

G3GQ27 / Q777

M / 20 359 - 47 -

SY-1599A 2SSQ898

For the intermediate products of the formulas III »IHa and IV stands Q preferably represents phenyl, R ″ preferably represents p-nitrobenzyl and X and Y are preferably those substituent groups which are preferred in the compounds of the formula I mentioned. Reactive functional groups, for example mercapto, amino and hydroxyl in the Y and X substituents, can during the conversion of the intermediate products into the biological effective end products are protected by common blocking groups.

Compound I can be prepared by one or more of the pathways discussed below. The various synthetic routes can be divided into three main processes depending on the stage at which the 6-substituent, ie the group Y, is introduced. Thus, in process I, the 6-substituent is introduced into the starting material; in method II the group Y is introduced at the end of the synthesis and in method III the substituent Y is introduced in the middle of the synthesis. Each of the three main processes can in turn vary with regard to the procedure for introducing the desired 2-substituent, ie the radical X. In general, it is preferred to introduce substituent Y in the middle of the synthesis and to introduce substituent X by acylation of hercaptide intermediate III or IHa, as shown below, since these procedures have been found to be the most generally applicable methods .

The steps of method I can be traced to the following Take the scheme:

030027/0777

Y N.
0 -> h * 2850898
ge introduction of the CHO- I
CO ₂ R " ^?
J ^ - ^ O
Il
XC-SNa ^ Base ^
0 ^y
Y pH 7.5 '
0
H deprotect I SOCl ₂
CO ₂ R "
γτ ^Χχ ί ^ - ^ώ \ ^ ^Ρ0 3
CO ₂ R " H / 20 359 - 48 - *
SY-1599A
Procedure I (Variation 1): Early O ^ I
CO_H! 2-substituents
Y-CH = CH-OAc CSI ^ ■ 7th
if ■
^υ "» λ- ^ SC-X v J
O
^γ , 1 sy "
O ^ H
0
Il
^ SC-X CO ₂ R "
-rV ^ <
CO ₂ K " O
i!
Ac = CH ₃ C-
0 = C ₆ H ₅ -

030027/0777

M / 20 359 - 49 -. '.' »*

SY-1599A

Procedure I (Variation 2): Late introduction of the 2-

Y
Y-CH = CH-OAc CSI.

PH 7.5

CHO II _socl

R " ^ KJXL

γ
P0 ^ η f SAC

^ Ci Base _{o <} J_N_.P0 ₃ Base

CO ₂ R '

SM H ^Y * ^ N SC-X

_{en ts} . _{c hutiin}

Ί Γ

^CO 2 ^H

XC- © = acylating agent
NA = SchwermetaTlsal2

030027/0777

to

M / 20 SY-1599Ä

- 50 *

Method I (Variation 3): Late introduction of the 2-substituent

th

Y-CH = CH-OAc CSI

Y ^N \

O ^

- ^0Ac

N,

CHO

F0

base

G
xc- ©

0 ₃ CSNa pH

CO ₂ R "

SC0,

O ₂

CO ₂ R "

SOd

deprotect

030027/0 7 77

SY-1599A * -vv_ ν

In process I, a vinyl ester (Y = H or a radical as defined in compounds I) which has the desired 6-substituent is, if desired, by a cycloaddition reaction with chlorosulfonyl isocyanate (CSI) followed by reduction with an organic reducing agent, for example sodium sulfite 4-acetoxy-2-azetidinone substituted in the 1-position is converted. The CSI reaction is expediently carried out in an inert organic solvent, for example diethyl ether, at a temperature of 0 ^° C. or below. Can be the reduction step in an aqueous or aqueous-organic reaction mixture at a temperature of 0 ⁰ C or below, and perform a slightly basic pH.

After the formation of 4-acetoxy-2-azetidinone can be Divide method I into three different ways. At a

Way (variation ·!) Is the azetidinone with a thiol acid

XC-SH, in which X is as defined above for the compounds I, or a salt thereof in a suitable solvent (for example aqueous or aqueous-organic). Displacement of the acetoxy group leads to the introduction of the desired 2-substituent into the azetidinone at this stage. The displacement reaction is preferably carried out at room temperature or below and a slightly basic pH (r- ¹ 7.5). When Y ^ H, the cis and trans isomers of the resulting azetidinone are preferably separated (e.g. by chromatography) at this point in the process. The variations 2 and 3 presented above serve the 4-acetoxy-2-azetidinone in the 4-acetylthio-2-azetidinone or 4-tritylthio-2-azetidinonprodukte to convert namely by nucleophilic displacement with thiolacetic acid or by triphenylmethyl mercaptan ( or a salt thereof, e.g. sodium salt).

030027/0777

Μ / 20 359 SY-1599A

- 52 -

2850898

Next is the 4-thioazetidinone with a glyoxylate-0

ti

ester HC-CO ₂ R "* where R" is a readily removable ester protective group, for example p-nitrobenzyl or trimethylsilylethyl, or a reactive oxo derivative of this compound, for example a hydrate, in an inert organic solvent (for example benzene, toluene, xylene and the like) , preferably implemented at elevated temperature (for example 50 ⁰ C up to the most preferred reflux temperature). If a hydrate of the ester is used, the water obtained can be removed azeotropically or with the aid of a molecular sieve. The hydroxy ester product is formed as a mixture of epimeric compounds which, if desired, can be purified, for example by chromatography, or can be used directly in the subsequent step.

The conversion of the hydroxy ester into the corresponding chloro ester is by reaction with a chlorinating agent (for example SOCl ₂ , POCl ₃ , PCl ₅ and the like) in an inert organic solvent (for example tetrahydrofuran., Diethyl ether, methylene chloride, dioxane and the like) in the presence or absence of a Base, preferably an aliphatic tertiary amine (e.g. triethylamine) or a heterocyclic tertiary amine (e.g. pyridine or collidine) achieved. The reaction is advantageously carried out at about -10 ⁰ C to room temperature. The chloroester product is obtained in the form of a mixture of epimeric compounds which, if desired, can be purified before use in the subsequent step.

The phosphorane intermediate can be prepared by reacting the chloro ester with a suitable phosphine (preferably triphenylphosphine or a tri (m'edrigialkylphosphine, e.g. triethylphosphine or tri-n-butylphosphine) in an inert organic

0300 27/0777

Μ / 20 359 SY-1599A

- 53 -

see solvents, for example dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dimethoxyethane, or dioxane an aliphatic, cycloaliphatic or aromatic hydrocarbon (e.g. hexane, cyclohexane, benzene, Toluene and the like) in the presence of a base, preferably a tertiary organic amine, for example triethylamine, pyridine or 2,6-lutidine. The reaction is preferably carried out at temperatures in the range from room temperature to the reflux temperature of the solvent system.

At this stage, the process again splits into two ways. In variation 1 (in which the 2-substituent has already been introduced), the phosphorane intermediate is obtained by thermal cyclization in an inert organic solvent at a temperature of just above room temperature to the reflux temperature of the solvent system in the desired Convicted penem connection. Most advantageously, the cyclization is carried out under reflux conditions. Suitable inert organic solvents include aliphatic, cycloaliphatic or aromatic hydrocarbons (for example benzene, toluene, hexane, cyclohexane), halogenated hydrocarbons (for example methylene chloride, chloroform, Carbon tetrachloride), ether (diethyl ether, dioxane, tetrahydrofuran, dimethoxyethane), carboxamides (for example Dimethylformamide), di-Cj-Cg-alkyl sulfoxides (for example Dimethyl sulfoxide) or a C ^ -Cg alkanol (for example Methanol, ethanol, tert-butanol) or a mixture of these solvents.

In Variations 2 and 3, the phosphorane is converted into a heavy metal mercaptide of the general formulas III or IHa:

030027 / a777

M / 20 359 SY-1599A

N. P (Q),

III

ode ν

(Q)

CO ₂ R '

Ilia

in which Q is preferably phenyl or (lower alkyl, χ stands for 1 or 2 and M stands for Cu (II), Pb (II) or Hg (II), if χ has the meaning 2 or stands for Ag (I), if χ has the meaning 1. The mercaptid formation is by reaction of the phosphorane with a salt of Hg (II), Pb (II), Cu (II) or Ag (I) or with (methoxycarbonyl) mercury (II) acetate in a methanol-containing solvent and in the presence of an organic or inorganic pass, for example aniline, pyridine, collidine, 2,6-lutidine, an alkali metal carbonate, and the like. A preferred base is pyridine. The reaction can be carried out at room temperature or, if desired, with mild cooling or heating be performed. With the anion (A) of the heavy metal salt it can be any anion which results in a soluble salt in the selected solvent, for example

030027 / & 777

M / 20 359 SY-1599A

- 55 -

2350898

CHoCOO ", BF.

CIO

CNO

3, ^ π ₃ ~ υ «, BF ₄ , F, CIO ₄ , NO ₂ , CNO, and the like. Then the mercaptide intermediate is treated with an acylation

means implemented that is capable of unity 0

X-C- to introduce, where X is for the desired penem-2 substituent

It

ten stands. The acylating agent (X-C- ©) can be 0

the acid XC-OH or a reactive functional derivative thereof is, for example, an acid halide (preferably an acid chloride), acid azide, acid anhydride, mixed acid anhydride, an active ester, an active thioester, and the like. The acylation is carried out in an inert solvent (for example a halogenated hydrocarbon, for example methylene chloride or an ether, for example dioxane, tetrahydrofuran or diethyl ether) and, if an acid derivative is used, in the presence of an acid acceptor, for example a tri (lower) alkylamine (for example triethylamine) or a tertiary organic base, for example pyridine, collidine or 2,6-lutidine. If the free acid is used, the acylation is carried out in the presence of a suitable condensing agent, for example a carbodiimide, for example NjN'-dicyclohexylcarbodiimide. The acylation of the mercaptide may be carried out over a wide temperature range, but it is preferably carried out at temperatures of about -20 ⁰ C to +25 ⁰ C. After the acylation, the phosphorane obtained is cyclized as described above. to result in the desired pen semester.

c 4- na.

i 1 Jmhi Αλ 0 *

the mercaptide intermediate (Variations 2 and 3) leads to a product that has a much better purity, than that obtained by the more usual route according to Variation 1 Product.

030027/0777

M / 20 359 SY-1599A

- 56 -

2950888

Once the carboxyl-protected penem is formed * you can remove the protecting group by standard deblocking procedures (e.g. hydrolysis, hydrogenation, or photolysis) to yield the deblocked penem. The distance of the p-nitrobenzyl ester, for example, by catalytic Hydrogenation in the presence of a noble metal catalyst, for example palladium or rhodium, including their derivatives, for example oxides, hydroxides or halides, take place, these catalysts, if desired, on a conventional carriers are worn, for example on activated carbon or on diatomaceous earth. One uses an irreducible one aqueous or non-aqueous inert solvent, for example water, ethanol, methanol, ethyl acetate, tetrahydrofuran, Diethyl ether or dioxane. The hydrogenation can be carried out at atmospheric pressure or elevated pressure; it is expedient at room temperature for a period of about 1 to 5 hours, depending on the solvent and the catalyst used. If you have an equivalent weight a base, for example an alkali metal hydroxide or Erdal kaiimetallhydroxids or an amine is used during the hydrogenation ^ one can win the product in the form of a carbonic acid salt. The removal of the ß-trimethylsilylethyl ester another useful protecting group is conveniently achieved by treatment with a source of fluoride ions. Other Ester protecting groups can be removed in the same way by methods known to those skilled in the art.

In a second main process (process II) the reaction sequence is shown below- *

030027/0777

M / 20 359 SY-1599A

2960888

Method II (Variation 1): Early introduction of the 2-substituent

CH ₂ = CH-OAc CSI

OAc

O U

XC-SNa

pH

.-SC-X ϊί
.SC-X

S - * k

CHO SOCl.

N OH

^Ν -γ ^

base

CO ₂ R "

base

CC ₂ R "

■ deprotect

030027/0777

S. / TO " ¹
Υ-15 I. I.
CO ₂ R " I. CO ₂ R " (Variation 2): J ο Λ
^C0 2 J N ^ - 58 - · · »Γ. ·
• Γ. ',,' ■% -. · \ ■ v ° eo ₂ R » 'Vx - ·
for β
• · SOCl ₂ t CSI ^ I. O Late introduction of the 2-sub N ^OH - / tftüefiter I. 99Α I. "* if
O > -X Y sniper protection ^ ^ .OAc
»AcSNa> ^ . ^CO 2 ^H Procedure II base pH 7.5
H CO-R " 030027/0777 CH —CR — OAC ^ SAC rr ^SAC "V, J N. ^ = P0, CHO CO _V R ^M CO ₂ R " O
.si-x
I-C ο ⁴ " ^P0 3 ^ 2 base s? ^^^ 3
T
CO ₂ R " ο ί
MA ^ O
ΪΙ
xc- φ Base ' Δ O

M / 20 359 SY-1599A

Method Π (Variation 3): Late introduction of the 2-substituent

CH ₂ = CH-OAc CSI

¹ —Γ *

0 ₃ CSNa

pH

• SC0-

-N.

CHO I

SC0,

base

-SM

O XC- ©

base

SC0-

soci.

.OH

MA

: P0,

base

rT

SC-X

l _o]

deprotect

030027/0777

M / 20 359 SY-1599A

It can be seen that Method II is essentially the same as Method I (except that Y is for H must stand) up to the thermal cyclization stage, which leads to the 2-substituted penem. However, a 6-substituent is then introduced at this point, if desired by reacting the 2-penem compound with a suitable electrophile in an inert solvent (e.g. tetrahydrofuran, diethyl ether, dimethoxyethane and the like) and in the presence of a strong base. At this The 2-penem can work in the form of the free acid (obtained by deblocking as described above) in the presence of about two equivalents of base, or, alternatively, in the form of a suitable 2-penemester in the presence of about one Equivalent base, 'are implemented. One can use any ester that is inert to anion chemistry (the Reaction comprises the formation of an anion with the aid of base, followed by reaction of the electrophile with the penemanion), for example (lower) alkyl esters, for example methyl, ethyl, n-propyl or tert-butyl, phenyl, trichloroethyl, methoxymethyl Silyl, e.g. trimethylsilyl or tert-butyldimethylsilyl, and the same. Penemesters with activated methylene groups, for example with p-nitrobenzyl groups, are not suitable and if the 2-pen semester is of this kind, it must first be unblocked and either in the form of the free acid used or converted into a suitable ester. The particular base is not critical, and the usual stronger ones Bases such as sodium hydride, phenyllithium or butyl lithium are suitable. However, it is more preferable to use a Lithium disilylamide or a lithium dialkylamide, for example Liiniumdicyclonexytänna (LDCA), Lithlümdiäthy! Ämid, Lithiufidimethylamid or Lithiumdiisopropylamid (LDA).

The electrophile is chosen so that it gives the desired Y substituent on reaction with the anion. It can

G3QQ27 / Q777

M / 20 359 SY-1599A

- 61 -

here, for example, a halogen (for example Br ₉ , I ₉ ), an alkyl halide (for example CH ₃ J) or a similar halide, for example an aliphatic halide, a cycloaliphatic halide, a cycloaliphatic-aliphatic halide, a phenyl (lower) alkyl halide, a heterocyclic Halide, a heterocyclylthiohalide, a heterocyclylthio (lower) alkyl halide or a heterocyclyl (lower) alkyl halide, a tosylate or mesylate (e.g.

CH ₃ CH ₂ OSO ₂ -Z ^ -CH ₃ , CH ₃ CH ₂ OSO ₂ CH ₃₁

Vso.

ise Δ).

0CH ₂ CH ₂ CH ₂ OSO ₂ CH ₃ , etc.), an epoxy (e.g.

S.
an episulfide (e.g. / \ ), an aldehyde (e.g.

e.g. CH ₃ CHO, C ₅ H ₅ CH ₂ CHO), a ketone (e.g. _{CH 3 COCH 3} , IJ) or an ester (e.g. _{CH 3} CH _{2 COOCH 3} or

CgH ₅ COOCH ₃ ) act. Representative examples of other suitable electrophiles are shown below:

CH ₂ = CH-CH ₂ Br

Cu

HCHO

O II CH ₃ CCH = CH ₂

Br
I.
CH., CH-CH-

0CH ₂ Br 0CHCCH ₂ Br

030027 / Q777

λ ₉ m

T7

M / 20 359 SY-1599A

- 62 -

295Q89 &

CH ₂ SCH ₂ Cl

00CH ₂ Cl

0CH = CHCHO

0 It CH ₃ CCH ₂ Cl

A most preferred electrophile is acetaldehyde. This gives the 6-hydroxyethyl substituent. The introduction of the 6-substituent according to this procedure is preferably carried out with cooling (for example -8O ⁰ C to 0 ^C ) according to the general procedure according to the Canadian Journal of Chemistry, 50 (19) 3196-3201 (1972).

After the formation of the desired 2,6-penem compound, you can any ester protecting groups present are removed as discussed above in order to ergeoen the deprotected product.

The third main reaction process (process III) can be found in the following scheme:

030Q-27 / 0-777

H / 20 359 SY-1599A

Procedure III {Variations 1 and 2):

SC0-

-N

base

SG0,

deprotect MA / ßäse

Il _Λ

x-c- Θ

030027/0777

M / 20 359
SY-1599A

2350888

SOCl-, Nj / 2

C0,

CO ₂ R "

base

SC0,

CO ₂ R "

MA / Base

. , -eTitschutzan ⁷ , ν

CHO I CO ^ R "

Y "

^ _n ^ SC-X

OH

CO ₂ R "

SOCl

030027 / C777

m m *

M / 20 359 SY-1599A

- 65 -

2350898

"ττ"

CO ₂ R '

Ii

SC-X

Cl

CO ₂ R "

deprotect

defend

B = blocking group for the ring nitrogen

0 300 27/07 77

.1 1 ··

H / 20 359 - 66 - 235Q898

SY-1599A

The 4-tritylthio-2-azetidinone according to Method III is as as described in procedure II (variation 3). The ring nitrogen of the azetidinone is then easily removable blocking group protected, for example by THorgane-MyI (e.g. trimethylsilyl or tert Butyldimethylsilyl), methoxymethyl, methoxyethoxymethyl, Tetrahydropyra ~ -'i, and the like. The introduction of the desired Y-5 substituent in the 1-position of the azetidinone is then made by reacting an appropriate electrophile with the N-protected azetidinone in the presence of a strong base (reaction conditions as above in connection with the Method II described) achieved. At this point the process splits into two routes depending on the deblocking time of the azetidinone.

In one way, the N-protected intermediate product is unblocked by conventional procedures (for example acid hydrolysis) and then via ester formation, chlorination of the hydroxyester, conversion of the chloroester into a phosphorane, conversion of the phosphorane into a heavy metal mercaptide, / cy-

lation of the mercaptide with X-C- ©, thermal cyclization of the phosphorane obtained is converted into the 2,6-penem compound with formation of the 2,6-penemester and removal of the carboxyl protective group. The reaction conditions for this stage are as previously disclosed in connection with Method II (Variation 3).

An alternative approach involves the steps of converting the N-protected azetidinone in a Schwennetai'imereaptid, Acy-

lation of the mercaptide with the unit X-C- Θ, distance the N-protective group, conversion of the deprotected fi «cetidinone with the glyoxylate ester, chlorination, reacting the chlorine ester with the phosphine to form the phosphorane, cyclization

030027/0777

a »♦ ·

Yy

HI

M / 20 359 SY-1599A

- 67 -

of phosphorane to form the penemester and removal of the carboxy protective group to form the 2,6-penem compound. The reaction conditions for these steps are as disclosed above.

To prepare the 2-penem compounds or 2,6-penem compounds according to the above procedures, the free functional groups in the substituents X and Y attached to the Do not take part in the reaction, protect temporarily in a manner known per se, for example in the case of free amino groups by acylation, tritylation or silylation, in the case of free ones Hydroxyl groups, for example by etherification or esterification tion, in the case of mercapto groups by / ch esterification, in the case of free carboxyl groups or sulfo groups, for example Esterification, including silylation. After the reaction has occurred, these groups can be used individually, if desired or be released again together in a manner known per se.

In addition, it is possible in the compounds of the formula I to functionally modify the 2-substituents and / or 2,6-substituents during or at the end of the reaction processes according to known procedures in order to obtain other substituents which fall within the scope of the present invention . For example, carbonyl groups can be reduced to alcohol groups, unsaturated aliphatic groups can be halogenated, amino groups can be alkylated or acylated, nitro groups can be converted into hydroxyl amino groups or amino groups, hydroxyl groups can be etherified or esterified, and the like *

The penem compounds in the form of the free acid can be used in pharmaceutically acceptable salts or easily cleavable esters (in particular physiologically cleavable esters) are transferred. The salts can by reaction of the free acid with a

030027/0777

t »

Μ / 20 359 SY-1599A

- 68 -

i.toichiometric amount of a suitable non-toxic acid or base in an inert solvent system, followed by recovery of the desired salt, for example by lyophilization or precipitation. The esters (in particular physiologically cleavable esters) can in analogous Way to produce the corresponding esters of penicillins and cephalosporins. Obtained isomers Mixtures can be separated into the individual isomers according to known procedures. Mixtures of diastereomeric Isomers can be separated, for example, by fractional crystallization, by adsorption chromatography (column chromatography or thin-layer chromatography) or by other suitable separation methods. Preserved Racemates can be separated into the antipodes in the usual way, for example by forming a mixture of diastereomers Salts with optically active salt-forming reagents, separation of the diastereomeric salts and conversion of the salts into the free compounds, or by fractional crystallization from optically active solvents.

The invention thus also provides a process for the preparation of the compounds of the general formula I, which is characterized in that a compound of the formula:

B- —CX

F (Q)

wherein Q is phenyl or (lower) alkyl, R "is a light represents removable ester group and X and Y as before de-

030027/0777

Μ / 20 359 - 69 - 2950898

SY-1599A

in an inert organic solvent at a temperature just above room temperature to cyclized to the reflux temperature of the solvent, in an in a known manner, the removable ester group and, if desired, other protective groups are removed and in the event that

Y stands for hydrogen, if desired the product through Treatment with an appropriate electrophile in an inert solvent in the presence of a strong base converts into another desired product in which Y is not hydrogen.

The invention also includes those embodiments in which compounds used as intermediates are used as starting material ieq and the remaining process steps are carried out with these, or in which the procedure is interrupted at any stage. In addition, the starting materials can be in the form of derivatives used or only formed during the reaction.

The penem compounds created by the invention in the form of the free acid and their pharmaceutically acceptable ones Salts and physiologically cleavable esters of these acids have proven to be effective broad spectrum antibacterial agents proven to be useful in the treatment of infectious diseases in humans and animals caused by gram-negative and gram-positive organisms have been found to be of value. The compounds are also valuable as a feed supplement in animal feed and as a means of treating mastitis in cattle,

The 2-penemic acids created by the invention (and their physiologically cleavable esters and pharmaceutically acceptable ones Salts) (i.e. compounds of general formula I, in which

Y = H) have an antibacterial activity per se and are also useful intermediate products (preferably in their

0 30027/077 7

M / 20 359 - 70 -

SY-1599A

Carboxyl-protected form) for the production of the 2,6-disubstituted ten penem compounds of the formula I via the formation of an anion and reacting with an electrophile.

The active compounds provided by the present invention can be formulated as pharmaceutical agents which, in addition to the active ingredient, comprise a pharmaceutically acceptable carrier or diluent. The compounds can be administered orally and parenterally. The pharmaceutical preparations can be in solid form, for example as capsules, tablets or dragees, they can also be in liquid form, for example as solutions, suspensions or emulsions. In the treatment of bacterial infections in humans, the active compounds according to the invention can be used orally or parenterally in one Amount of about 5 to 200 mg / kg / day, preferably about 5 to 20 mg / kg / day in a divided dose, for example 3 or 4 times a day. They are administered in dosage units, for example 125, 250 or 500 mg active ingredient along with physiologically compatible Contain carriers or diluents.

The invention enables the control of bacterial infections in humans and mammals in general, using a Acid of the formula I or a physiologically cleavable ester or a pharmaceutically acceptable salt of this compound, or a pharmaceutical preparation of this compound administered to a patient in an amount sufficient to combat aer Infection is sufficient.

The following are illustrative examples for preparing the starting materials and final products of the invention. All temperatures are in ⁰ C. For the sake of simplicity, certain abbreviations are used in the examples. the

030027/0777

M / 20 SY-1599Ä

2950838

Definitions of the less obvious abbreviations are as follows:

Pet ether

Ether Celite

n-BuLi MIBK

PNBG

HMPT

(or HMPA) EtOAc

Chlorosulfony isocyanate Petroleum ether nuclear magnetic resonance

hour

Diethyl ether (unless otherwise stated)

Trademarks of Oohns-Manyille Products. Corporation for Diatomaceous Earth

pounds per square inch (converted to bar)

Room temperature

p-nitrobenzyl

Lithium aluminum hydride

n-butyllithium

Methyl isobutyl ketone

C ₂ H ₅ -

CH ₃ -

Tetrahydrofuran

Phenyl

Di methy1formami d

Triethylamine

p-nitrobenzyl glyoxylate

Tetrahydropyranyl

Tri-fluorous acid

Hexamethylphosphoric triamide

Ethyl acetate

Dimethyl sulfoxide

OH-CO-

CH ₃ SO ₂ -

4-dimethylaminopyridine

PyH din

Lithium diisopropylamide

030027/0777

Η / 20 359 SY-1599A

2350898

Example ΐ 2 '- (2'-Diethylphosphono-r-ethyl) penem-3-carboxylic acid

2'2

(EtO) -P-

■ + (EtO)

J- [CKJ

η (EtO) P- (CH) COCl

Λτ £ -dm

■ + (EtO) ₂ - ^ - CH ₂ ) ₂ COSH

A mixture of 1 (11.2 g, 50 mmol) and 5N NaOH (10 ml) is stirred for 15 minutes and cooled (ice bath) and then stirred for 15 minutes at room temperature. The mixture is extracted with ether and the extract is discarded. The aqueous solution is acidified with 5N HCl and extracted _{with CH 2} Cl _2. After drying and evaporation of the solvent, 10.0 g (95 %) of compound 2 are obtained in the form of an UI.

NMR S (CDCl ₃ ); 4.1 (4H, m), 1.8-2.9 (4H, m), 1.2 (6H, t).

Oxalyl chloride (2.74: g, 1.88 ml, 21.5 mmol) is added dropwise to a cooled (ice bath) solution of compound 2 (2 * 26 g, 10.76 mmol). The mixture is kept at room temperature for 6 hours and then evaporated to dryness. The traces

0 30027/0777

M / 20 359
SY-1599A

• η

2350898

of (COCl) ₂ are removed azeotropically with benzene, 2.4 g (quantitative yield) of crude 3 being obtained.

IR v> Z " : 1800, 1735 cm " ¹ .

^X C1

NMRcT: 4.3 (4H, m), 3.0-3.7 (2H, m), 2.0-3.0 (2H, m), 1.4 (6H, m).

The product H ₂ S / TEA is treated according to a standard process, 1.9 g (80 %) of compound 4 being obtained in the form of an oil which is 80 % pure.

NMR <T: 4.1 (4H, q), 2.7-3.5 (2H, m), 1.7-2.5 (2H, m), t, 33 (6H, t).

OAc

(EtO) ₂ P-

An IM solution of NaHCO ₃ (10 ml) is added to compound 4 (1.9 g, 8.4 mmol) under N ₂ , followed by compound 5 (0.813 g, 6.3 mmol) in H ₂ O (3 ml). The pH is adjusted to 7 to 8 _{by adding more NaHCO 3.} After standing for 4 hours, the mixture is extracted with CHCl ₃ , 1.05 g (yield 56.4 %, based on compound 5) of a solid 6 having a melting point of 64 to 67 ° C. being obtained after drying and concentration.

NMRJ: 7.7 (NH), 5.3 (1H, q), 4.2 (4H), 3.8 (1H, q), 3.5 (1H, q), 2.6-3.2 (2H, m), 1.7-2.4 (2H, m), 1.3 (6H).

030027/0777

Η / 20 359 SY-1599A

2350838

(OEt)

-P- (OEt).

i o

A mixture of compound 6 (260 mg, 0.88 mmol) and p-nitro benzyl glyoxalate (198 mg, 0.88 mmol) is taken for 16 hours refluxed on a Dean-Stark device in benzene (6 ml). After evaporation of the solvent, 453 mg of a heavy oil 7 is obtained.

NMR (T: 8.3 (2H, d), 7.6 (2H, d), 5.3-5.7 (4H), 4.9 (OH),

4.2 (4H), 3.55 (IH, g), 3.4 (1H, g) _s 2.5-3.2 (2H, m), 1.7-2.5 (2H, m) , 1.3 (6H).

Zl

Crude compound 7 (504 mg, 0.88 mmol) is dissolved in a 1M solution of pyridine in THF (0.9 ml). _{A TM solution of SOCl 2} in THF (0.9 ml) is added dropwise with stirring and cooling (ice bath solution) and the mixture is stirred for 15 minutes in the cold and 40 minutes at room temperature. One gives

0 3 00 27/07 77

Μ / 20 3D9 SY-1599A

- 75 -

Benzene (10 ml) was added and the solid was filtered off. The filtrate Concentrate in vacuo to give 463 mg (quantitative yield) of crude compound 8.

NMR *: 8.3 (2H, d), 7.6 (2H, d), 6.1 (IH, s), 5.7 (1H, m), 5.3 (2H, d), 4.2 (4H), 1.8-3.6 (6H, m), 1 * 3 (6H).

O PNB

(CH) P- (OEtI * * 2

rrV "

-Poet).

CO PNB

To a solution of crude compound 8 (463 mg, 0.88 mmol) in THF (4 ml) are added triphenylphosphine (236 mg, 0.9 mmol) and 2,6-lithium (96 mg, 0.9 mmol X and The mixture is left to stand for 65 hours at room temperature, the filtrate is filtered and the remaining UI is chromatographed on a silica gel column with ethyl acetate / 2 % EtOH as the eluent to give 203 mg (30.6 %) of I9 which is left to stand solidifies, melting point 126 to 128 ° C.

V- (CH ₂ ) ₂ P (OEt) ₂

¹ ^ T _

to PSB

10

A solution of compound 9 (470 mg, 0.635 mmol) in toluene

030O-27 / O777

.mi · T · ·

Μ / 20 359 SY-1599A

- 76 -

235Ρ898

(30 ml) is refluxed for 5 hours and then concentrated and chromatographed on silica gel-ethyl acetate to give 167 mg (56 %) of compound 10 as an oil.

IR _y : 1795, 1710 cm " ¹ .

NMRi: 8.3 (2H, d), 7.7 (2H, d), 5.7 (IH, m), 5.38 (2H, d) 4.1 (4H), 1.8-3.8 (6H), 1.35 (6H).

h- N ^

(CH ₂ ) ₂ -P- (OEt) ₂

CO PNB

'11

_{NaHCO 3} (9 mg, 0.107 mmol), water (1 ml) and 10 % Pd / Celite (60%) are added to a solution of compound 10 (59 mg, 0.126 mmol) in THF (3 ml) and ether (1 ml) mg) and the mixture hydrogenated for 2 hours at 2.07 bar (30 psi). The product is isolated as usual, 36 mg (86 %) of compound 11 being obtained in the form of an UI.

IRiT (CHCl ₃ ): 1798, 1730, 1710

cm

NMRi: 9.0 (CO ₂ H), 5.6 (1H, m), 4.4 (4H), 3.6 (1H, q), 3.15 (TH, q), 1.7-3 , 0 (4H, m), 1.3 (6H).

030027/0777

M / 20 359 SY-1599A

- 77 -

B eis ρ i e T

6-Ace t ό xy me thy T - 2 ^ me thyTperieiri-S-caY bon acid

Production of 1, 3-Diacetoxyproperi J_ (see L.W.McTeer U.S. Patent 2,866,813, CA 53 ^, 9063)

CH ₀ = CH-CHO AcOCH ₉ CH = CH-CH OAc + ₉ = CH-CH (OAc) ₂ ² Cat. ^Ά

Preparation of the catalyst: a solution of boric acid (6.2 g) and oxalic acid (12.6 g) in water (44 ml) is evaporated to dryness to give the solid catalyst.

Procedure: Acrolein (140 g, 2.5 mol) is mixed with acetic anhydride (256 g, 2.5 mol) at RT. A 5 ml portion of this mixture is transferred to a 1 liter Erlenmeyer flask and treated with a few drops of catalyst prepared by dissolving 1.0 g of solid catalyst in 5 ml of acetic anhydride. A vigorous exothermic reaction ensues, and the reaction mixture is kept at a temperature of 40 to 60 ^° C. (regulated by cooling with an ice bath). The remainder of the acrolein-acetic anhydride mixture is added to the flask in 10-15 ml portions, followed by a few drops of catalyst. The resulting mixture is distilled to remove unreacted starting materials followed by 1,1-diacetoxypropene. Next you get the product in

030027/0777

: · '- · ":! T *
Μ / 20 359 - 78 - 2950838 NH SY-1599A 1 2a 2b an amount of 51.6 g (13.06 %) with boiling point 54 bis Working method: 57 ° C / 1.2 mm. You give CSI. (16.92 g, 0.12 mol) dropwise to chilled NMR S (ppm., CDCl ₃ ): 7.4 (H, d, J = 12), 5.3-5.8 (H, m), 4.5 (Ice-saline bath, -15 ° C) Compound 1 (18.96 g, 0 _s 12 mol). Man (2H, d, J = 7), 2.16 (3H, s), 2.05 (3H, s). holds the pale yellow mixture for 5 hours at 5 ⁰ C ₉ during it IR : ^. _n 1770, 1750, Λ_ _η 1680. turns dark yellow. It is diluted with ethyl acetate (20 ml), cools to -30 ⁰ C and adds in portions to one ) csi ^A Ί 1 ^AcO
AcOCH., CH = CH-OAc> j ' ⁺
2 d ^ J chilled (ice-saline bath) mixture of water (3.4 ml ;, Ice (17.0 g), NaHCO ₃ (0.3 g) and Na ₂ SO ₃ (3.4 g). After The resulting mixture is added vigorously for 20 minutes stir and add some additional NaHCO ₃ to adjust the pH hold at 7 through 8. The layers are separated, and the aqueous layer is extracted with ethyl acetate (2 × 50 ml). The combined organic phase is dried (Na ₂ SOaCNaHCO ₃ = 1: 1). It is filtered and evaporated, 17.4 g of a O Receives oil. This is under high vacuum (0.01 to 0.00 mm) distilled in a hot air bath (temperature 55 ° to 85 ° C) Remove connection 1. The undistilled, light brown one Oil is cooled, absorbed in ether and celite active filtered charcoal, after evaporation to dryness 030027/0777

• · ϊ

Η / 20 359 SY-1599A

- 79 -

5.28 g (22 %) of a 4: 1 mixture of compounds 2a and 2b (determined by NMR) in the form of a colorless oil.

NMR £ 7.25 (H, NH) ₉ 6.0 (0.25H, d, 0 = 4.3), 5.8 (0.75H, d, J = 15), 4.5 (0 _s 5H, d, 0 = 6.5), 4.4 (1.5H, d, 0 = 4.5), 3.8 (0.25H, m), 3.5 (0.75H, m), 2.13 (3H, s), 2.1

/ 11t _ \

From, s /.

: 0 _{c = 0} 1780, 1740.

aci / V-f

OAc

CH ₃ COSNa

AcO '

NH

"HH

SAC

AcS

.NH

3a

3b

3c

Working method:

Sodium thioacetate is prepared by adding thioacetic acid (2.22 ml, 2.363 g) to a solution of 1M NaHCO ₃ (31.0 ml) under nitrogen. This mixture is added to a cooled (ice bath) solution of compound 2 (5.2 g, 25.9 mmol) in water (ml) and stirred for 4 hours at room temperature. A little acetone (20 ml) is added to make the reaction mixture homogeneous. The mixture is concentrated in vacuo to remove acetone and then extracted with methylene chloride. The extract is dried and evaporated * to obtain 5.6 g of a mixture of isomers of 3a and 3b (83.14 %) . The NMR spectrum of the crude oil shows that only one

030027/0777

M / 20 359 SY-1599A

- 80 -

295Q8S8

trans compound and two cis compounds are present in the mixture. A sample (550 mg) is chromatographed on silica gel (30 g, 10% H ₂ O) and eluted with benzene-ether-methanol to give 200 mg of a mixture of compounds 3a and 3b in a ratio of 7: 1. This is followed by 150 mg of an unknown cis compound (ί 5.55, d, J = 4.3) which is initially assigned the structure 3c.

: 6.78 (N, NH), 5.52 (0.17H, d, J = 4.3), $ 5.1 (0.83H, d,

J = 1.5), 4.37 (2H, d, J = 4 _S 5), 3.45 (H, m), [2.35 (3H, s) 2.05 (3H _S s). j

¹ , ._ "1765, 1740, 1600 cm" ^1. J

AcO '

SAc

ACO

NH

CO PNB

Working method: {

A mixture of crude compound 3 (2.17 g, 10 | ΠΐΜο1) and p-nitrobenzyl glyoxylate (2.5 g, 11 mmol) in benzene (200 ml) is refluxed under a Dean-Stark water collector for 20 hours and then concentrated in vacuo. 3.4 g of crude compound 4 are obtained in the form of an oil. This is used without further purification. \

NMR: ο 7.5-8.5 (4H), 5.2-5.8 (4H), 3.4-5.1 (4H), | 2-2.4 (6H)

IR: v> _n 1665, 1740, 1740, 1730, 1700.

C -

030027/3777

Μ / 20 359 SY-I599Α

2850888

.SAc

SOCl.

Ν — CH-OH CO PNB

SAc

-N-CH-Cl CO PNB

Working method:

Thionyl chloride (1.01 g 8.5 mmol in benzene (10 ml) and stir the mixture at the above temperature for 15 minutes and then 15 minutes at RT. The benzene solution is decanted and the semi-solid that remains is washed 3 times with 15 ml portions of benzene. The combined benzene solution evaporated vrii-c to give 1.90 g of crude compound 5 (55 %) .

NMR: <f 7.5-8.5 (4H), 5.12 and 6.2 (1H), 5.66 (1H, m), 5.4 (2H, d, J = 6), 4.3-4.7 (2H, m), 3.63 (H, m), 2.4 (3H, d), 2.1 (3H, s).

_ _ft 1765, 1740, 1730, 1700.

■ "O

AcO

SAc

• Ν — CHCl CO PNB

Dioxane

_N— C = P (φ)

Working method;

A mixture of crude compound 5 (1.90 g, 4.27 mmol), tri-

030027/0777

M / 20 359 SY-1599A

- 82 -

phenylphosphine (1.572 g, 6 mmol) and 2,6-lutidine (0.642 g, 6 mmol) in dioxane (20 ml) is heated to 55 ° C for 18 hours. Cool, filter and evaporate to give 3.8 g of a crude, dark oil. This is chromatographed on silica gel to give 1.2 g (42 %) of compound 6.

AgO

<f

CO PNB

O FNB

Working method:

A solution of crude compound 6 (1.20 g, 1.79 mmol) in toluene (15 ml) is refluxed for 5 hours. It is cooled and evaporated to give an oil which is _{chromatographed on SiO 2} (3Π g) and eluted with benzene to give 0.4 g of compound 7 (57 %) .

Analysis door and .. 7 ^H 16 ^N 2 H 7th η C. 4.11 7th , 14 ber. : 52 , 04 4.08 , 30 found : 51 , 77

The separation of the eis and trains isomers is ensured by careful, Fold chromatography on silica gel (60 g) to elute achieved with benzene. Cis isomers

cis isomer: NMRi (ppm, CDCl ₃ ): 7.5-8.5 (4H, aromatic), 5.67 (1H, d, J = 5, H-5), 5.28 (2H, AB quartet ,

030027/0777

M / 20 359 SY-1599A

- 83 -

Benzyl), 4.33 (2Η, d, AcOCH ₂ ), 4.20 (1Η, dt, Η-6), 2.31 (3Η, S, CHg), 2.0 (3Η, s, CH ₃ CO ).

IR: J 1770, 1740, 1730 cm " ¹ .

C ~ "O

trans isomer: NMRi (ppm, CDCl ₃ ): 7.5-8.5 (4H, aromatic), 5.53 (1H, d, J-2, H-5), 5.30 (2H, AB quartet , Benzyl), 4.32 (2H, d, AcOCH ₂ ), 4.27 (1H, dt, J = 5, J-2, H-6), 2.31 (3H, s, CH ^ ₃ ), 2.0 (3H, s, CH ₃ CO).

^IR: ^ c = O ^{1770i 1740) 173} ° ^cm " ¹ *

NaHCO.

CO PNB

Working method:

NaHCO ₃ (25.2 mg, 0.3 mmol) and Pd / C (110 mg ) and hydrogenated at 2.07 bar (30 psi) for 4.5 hours. The mixture is filtered and the layers are separated. The aqueous layer is washed with ether and then lyophilized to give 40 mg of solid compound S (48 %).

IR: ^ _{c = 0} 1765, 1740, 1600

-1

030027/0777

M / 20 359 SY-1599A

- 84 -

NMR 6 (ppm, D ₂ O):

5.52 (1H, H-5), 4.85 (2H, AcOCH ₂ ), 4.0 (1H, H-6), 2.65 (3H, CHg) _9, 2.40 (3H, CJi

-N

CO ₃ H

11

Working method:

A solution of crude trans compound 8 (100 mg) in cold water (2 ml) is acidified with cold IN HCl and extracted _{with CHCl 3.} The extract is dried (Na ₂ SO ₄ ) and evaporated, 30 mg of a pale yellow solid having a melting point of 111 to 113 ° C. (decomp.) Being obtained.

IR: v> _ft 1780, 1750 »1680 (clear). IR: (KBr) v ^ _{c = o} 1775 (strong), 1745, 1670

Treatment of cis-p-nitrobenzyl-e-acetoxymethyl - ^ - methylpenem-3-carboxylate according to the above procedure gives this cis-sodium salt and the free acid.

C30027 / a777

M / 20 359 - 85 -

SY-1599A

' B eis ρ ie T' 3

Kai i urn-6- (2'-hydroxyisopropyl) -2-mettiyTperiem-3-carboxy1 at (anion method)

LDA

4a

A solution of acid 1 (116 mg, 0.627 mmol) in anhydrous THF (4 ecm, freshly distilled over LAH) is added dropwise at -78 ° C to a THF (2 ccm) solution of LDA (from diisopropylamine 70.7 mg, 98 μΐ, 0.699 mmol and η BuLi 1.6 M, 0.440 ecm, 0.704 mmol, stirred for 30 minutes at -78 ° C). The mixture is stirred for 5 minutes and then diisopropylamine (70.7 mg, 98 μΐ, 0.699 mmol) and 1.6Mn BuLi (0.440 ecm, 0.704 mmol) at -78 ° C. are added in sequence. The mixture is then stirred for 10 minutes at -78 ° C. and quickly treated with acetone (5 ecm). The mixture is allowed to react with acetone for 10 minutes. It is acidified with 1 % HCl (pH = 2), diluted with ethyl acetate (40 ecm) and washed with saline solution (3 × 20 ecm). Then it is dried over Na ₂ SO ₄ . Evaporation of the solvent gives a crude residue 3a, which is taken up in CHgC ^ (crude yield 90 mg). The crude acid is dissolved in cold

030027/0777

Μ / 20 SY-1599A

- 86 -

MIBK (2 ecm) and treated dropwise with potassium 2-ethylhexanoate. Two fractions of a potassium salt (36.4 mg, 26 %) are obtained in the form of a cis and trans mixture, the trans isomer predominating.

_{-6 cis} = 4, H-5), 5.55 (1H,

NMRd (ppm, DMSOd ₆ ): 5.60 (1H, d, _{56 cis}

d, J _{5-6 trans} = 2, H-5), 3.93 (1H, d, ^J 6-5 ^{cis = 4i Η} " ^{6) ϊ 3 '62 (1H) d> J} 6-5 trans ^{= 2} ' ^H " ⁶⁾ » ³ ' ⁵⁰ i ^b - ^s · » ^0H )> 2.34 (3H, s, CH ₃ ), 1.47, 1.40 (6H, 2s, 2CH ₃ ), 1.35, 1.32 (6H, 2s, 2CH ₃ ).

IR

: V ³ C = O (Nujol trituration) 1765, 1582, \? _QH 3600 - 3100.

UV

Max

(£ = 3920), 300 (6 = 4020)

At s ρ i el

Kaliuni-6-Hydroxyberizyl-2-niethylperiem-3-CarboxyTat (Ariionen process)

IX) A

φαίό

4b

Q30G27 / G777

Μ / 20 359 SY-1599A

- 87 -

2S50898

A solution of acid 1 (100 mg, 0.540 mmol) (ecm 6, distilled over LAH) in anhydrous THF is added dropwise μΐ to a cold (-78 ⁰ C) THF (2 ccmJ solution of LDA from diisopropylamine (84, 60, 6 mg, 0.599 mmol) and 1.6 M n-BuLi (0.380 ecm, 0.608 mmol). The mixture is stirred for 5 minutes and then visopropylamine (84 µ, 60.6 mg, 0.599 in mol) and 1.6 H n-BuLi (0.380 ecm, 0.608 mmol) are added. The mixture is then stirred for 7 minutes at -78 ° C. and quickly treated with benzaldehyde (300 μ!). The mixture is allowed to react for 20 minutes at -78 ° it is acidified with 1 % HCl (pH ¹ ^), diluted with ethyl acetate (40 ecm), washed with 1: 1 HgO saline solution (3 χ 20 ecm) and saline solution (1 χ 20 ecm) and then dried over NagSO «, Evaporation of the solvent gives a residue which is dissolved in MIBK (2 ecm). It is treated dropwise with potassium 2-ethylhexanoate to give compound 4b (35 mg) in a yield of 20 % in the form of a diastereomeric mixture schung.

NMR <f (ppm, DMSOd ₆ ): 7.95 (5H, s, H-aromatic), 5.57 (d,

5-6 trans

= 1.5, H-5), 5.45 (d,

5-6 trans

= 1.5, H-5), 5.35 (d, J ₅ _ _{6 cis} = 4, H-5), 5.0 (m, CH hydroxybenzyl), 4.25 (dd,

^J 6-5 cis ^{= 4> J} 6-CH hydroxybenzyl ^{= 10} 'H-6), 3.90 (m, -H-6), 3.65 (bs, OH),

2.35 (3H, 2s, CH ₃ ). IR: v> _{c = 0} (Nujol trituration) 1760, 1590, v> _QH 3600-3100.

uv

252 \ £ = δίαο), 256 \ e = 33Gu).

030027/0777

M / 20 359 SY-1599A

2S50898

example

Kaiium-6 -ttn timethyT-2-methyΊpenem-3-carboxyla t (anion process )

SHe

LDÄ

CH ₃ SSO ₂ CH ₃

fi - K ^

4c

A solution of acid 1 (100 mg; 0.540 mmol) (ecm 5 via LAH distilled) in anhydrous THF is added dropwise to a cold (-78 ⁰ C) THF (2 cc) solution of LDA, prepared from di isöpröpyl ämin ( 84 μΙ, 60.6 mg, 0.599 πίΜο!) And 1.6 H n-Büty! -J lithium (0.380 ecm, 0.608 mmol) were given. The mixture is stirred for 7 to 8 minutes and then diisopropylamine (84 μΐ, 60.6 mg, 0.599 mmol) and 1.6 M n-butyl ithiunj (0.380 ecm, 0.608 mmol) are added in sequence. Then stirred for 7 minutes at -78 ° C and treated quickly with methylthiomethylsulfonate (300 μΐ, excess). The mixture is allowed to react at -78 ° C. for 5 minutes. It is then acidified with 1 % HCl .an (pH ^ 2), diluted with ethyl acetate (40 ecm), washed with 1: 1 H ₂ 0 saline solution (3 χ 20 ecm) and then with saline solution (20 ecm). The organic solution is _{dried over Na 2} SO ^. Evaporation of the solvent leaves a residue which is dissolved in cold MIBK (2 ecm). The cold solution is added dropwise with

030027/07 77

Μ / 20 359
SY-1599A

- 89 -

Treated potassium 2-ethylhexanoate. Compound 4c (40 mg) is obtained in a yield of 28 % as an 8: 3 mixture of cis and trans isomers. Melting point 115 to 120 ⁰ C (dec.).

NMR <n _P pm ₉ DMSOd ₆ ): 5.85 (1H _S d,

_5-6 J _cis = 4, H-5), 5.57 (1H, d, J ₅ _ _{6 trans} = 1.5, H-5), 4.87 (1H, d, ^J 6-5 = eis ⁴ ^ ^H - ⁶ > - ⁴ x ^{72 (1H} ' ^d ' ^J 6-5 trans; = 1.5, H-6), 3.42 (bS, OH), 2.37 (s,

SCH ₃ ), 2.33 (s, CH ₃ ), 2.25 (s, SCH ₃ ).

IR: v ^? _{c = 0} (Nujpl trituration) 1770, 1600.

UV (H ₉ O) λ _ 252 (£ = 4200), 297 (ε = 3700)

C. Max

e i game 6

i-tp-NitroberizyTöxycarbpriyTmethyltripheriyTphosphöra (silbermer'cap'tidyT) ^ 2-azetidirion

CO ₂ PNB

, OAc

STr

TrSH

NaOMe

tr

^N H

300 27/0777

M / 20 359 SY-1599A

- 90 -

2350898

A methanol suspension (90 ecm) of triphenylmethyl mercaptan (13.8 g, 0.05 mmol) is degassed with a stream of nitrogen for 0.5 hour. The mixture is ^{cooled to 0 °} C. and sodium hydride (2.4 g, 0.05 mol, 50% dispersion in oil) is added in portions. The solution obtained is stirred for 5 minutes and 4-acetoxyazetidinone (7.7 g, 0.059 mol) in water (5 Stirred for hours at room temperature. The solid is filtered off, washed with water and dissolved in methylene chloride. The methylene chloride solution is washed with dilute HCl, water, aqueous sodium bicaronate, water and brine and dried over MgSO (yield 89.8 %). ) Melting point 146.5 to 147.5 ° C.

Analysis for ^C 22 "19 ^N

'C H N S

calc .: 76.49 5.54 4.05 9.28 %

found: 76.54 5.60 4.00 9.36 %

NMRi (ppm, CDCl ₃ ): 7.60-7.10 (15H, m, H-trityl), 4.62 (1H,

bs, NH), 4.40 (IH, dd _ä -J _{4-3 trans} = 3 _; 0 ₅

^J 4-3 cis = ⁵ ' ^H " ⁴⁾ > ³ ' ^{24 {1H} > ^ddd '° gem = ¹⁵ ' ^J 3-4.cis = ⁵ ' ^J 3-NH = ¹ ^ ⁸ * ^H " ³⁾ ' ² » ^{81 (1H} '

UuU, U ⁼ 10, On ρ. nc ~ ^ »^» " ¹ JM) -l ~ *» ^

H-3).

1760,

3340.

030027/0 7 77

_{# 9} tr ■ - ·

M / 20 359 SY-1599A

- 91 "

STr

CHO
CO PNB

ITr

-N _n

^k H

CO PNB

-STx ¹

Hyd ^ atized p-nitrobenzyl glyoxylate (4.54 g, 0.02 hol) and azetidinone 2 (6.90 g, 0.02 mol) are over a Dean-Stark condenser, which is filled with 38-hollow cell sieve, 24 hours refluxed in benzene. Further glyoxylate (2 × 454 mg, 2 mmol) is added, with each addition being kept under reflux (18 hours). The mixture is diluted with ether, washed with 5% aqueous HCl, water, 5% aqueous NaHCO ₃ , water and sodium chloride solution. It is dried over MgSO ₄ (yield 12 g, quantitative). A small fraction of the epimeric mixture is separated on a silica gel plate (CH ₂ C1 ₂ ether 6: 4).

Isomer A:

R _f = 0.87, melting point = 170.5 to 171.5 ⁰ C. NMR / (ppm, CDCl ₃ ): 8.07 (2H, d, J = 9, Hm aromatic), 7.45

(Part of d, Ho aromatic), 7.40-7.00 (15H, m, trityl), 5.25 (2H, s, CH ₂ -PNB), 4.75 (1H, s, HCO), 4 , 37 (1H, dd, * 3-4 trans '' ³ · ^J 3-4 cis = ⁴ * ^H " ³⁾ > ² * ⁸³ ( ^1H » ^dd »v» "' ¹⁶ ' Y ^{3 c} , ^{is =} * ''

2.10 (IH, dd, J _gem = 16, J _{4 -3 trans} -3, H-4), 1.42 (bs, OH).

IR: v> _{= o} (CHCl ₃ ) 1770, 1760 (shoulder), V ^ ₀ 1525, ^ 3475,

030027/0777

.... ί ■ Μ / 20 359 - 92 - R _f = 0.75, melting point = 152 to 153 ° C. S. SY-1599A 2950898 NMR / (ppm, CDCl ₃ ): 8.13 (2H, d, J = 9, Hm aromatic), 7.47 (2H Isomer B: d, J = 9, Ho aromatic), 7.40-7.00 (15H, m, Trityl), 5.30 (3H, s, CH ₂ -PNB, HCO), 4.45 (1H, t, J = 3.5, H-4), 2.90-2.70 (2H, S. AB part of ABX, H-4), 1.55 (b.s., OH). IR: v> _ (CHCU) 1767, 1755 (shoulder), v> _Mn 1525, <Λ _Η 3500.
CO 3 &quot; «* o Un .STr · ^ .STr γτ · ^soc1 2, I. j 1 - % A cold (-15 ⁰ C) THF solution (150 ecm, over molecular sieve \ dried) of azetidinone 3 (12 g, 21.7 mmol) is din (1.9 g, 24.1 mMoT, 1.94 ecm) and dropwise with thionyl I. chloride (2.86 g, 24 mmol, 1.88 ecm) under a nitrogen I. treated atmosphere. The mixture is stirred for 45 minutes 1 -15 ° C. The precipitate is filtered off and washed with benzene '*, to wash. Evaporation of the solvent gives a residue, \ which is absorbed in benzene and treated with activated carbon (11.7 g, 94 % yield, crystallized from chloroform). i NMR cf (ppm, CDCl ₃ ): 8.17 (2H, d, J = 8, Hm aromatic), 7.67-7.01 ■ 1 (17H, m, Ho aromatic, Tr-H), 5.80 (s, 1 HC-Cl), 5.37, 5.33 (2s, HC-Cl, CH ₂ -PNB), ι 4.81 (1H, m, H-4), 3.27-2.40 (2H, "m, H-3) I. IRv> _{c = 0} (KBr film) 1785, 1770, ^ _NOn 1525. 1 I.
3
'ti 030027/0777 ι
I.

M / 20 359 SY-1599A

or

STr

r ^cl

2,6-lutidine

Ρφ.

CO PNB

A THF solution (100 ecm, distilled over LAH) of chlorazetidinone 4 (11.6 g, 20.2 mmol) is treated with triphenylphosphine (7.86 g, 30.0 mmol) and 2,6-lutidine (2.36 g, 2.56 ecm, 22.0 mmol). The mixture is refluxed for 72 hours. The precipitate is filtered off and washed with ether. The organic solution is washed with 2 liter aqueous HCl and 5% aqueous bicarbonate and dried over MgS (K. Evaporation of the solvent gives a residue which is purified through a bed of silica gel (200 g) , 40 or 50% ether-benzene eluted (11.4 g product, 70.4 %, melting point 201 to 202 ⁰ C).

Analysis for C ₄₉ H ₄₀ N ₂ O ₅ SP:

73 C. H 3 N 4th S. ber .: 73 .57 5.04 3 , 50 3 .01 found: , 58 4.91 .44 .87

^ -A (CHCl,) 1740, v> phosphorane (1620, 1610), »Λ _η 1525,

Tr

AgNO.

- 2

Ρφ.

PNB

Pyridine

Say

CO PNB

030027 / α777

Dissolve 4-Trityimercaptoazetidinon 5 (1.6 g, 2 jiiMol) in CH ₂ CI ₂ (20 cc) and the solvent distilled off at 55 to 60 ⁰ C. At 55 to 6NC ° C to 5 solves phosphorane in prewarmed (55 to 60 ⁰ C) methanol (32 cc). Immediately after obtaining a methanolic solution of Compound 6, treating these with a pre-warmed (55 to 60 ⁰ C) mixture methancjlischer 0.15 M silver nitrate solution (16 cc, 1.2 Kq) and pyridine (174 mg, 178 μ! , 2.2 mmol, 1.1 eq). Then immediately remove the heat bath. The mixture is stirred for 2 hours at room temperature and 1 hour at ⁰ ° C. The silver mercaptide 6 is filtered off, ^{washed twice with cold (0} ° C.) methanol and three times with ether (1.12 g, 84.5 %). , Melting point 130 to 135 ° C (decomp.)).

IRv? (CHCl,) 1795, 1725 (Schulter), O phosphorane (1620, 1605] |

CO ο

B e i s ρ i e T 7

! - (p-NitrobenzyToxycarbonyTmethyTtriphenyTphösphoranyl) -4- (s i1bermercapti dyi) -2-azetidirion

MeOH -,

he

C = PPh

I COOK-'ΐ

COOPNB

O ^ C = PPh ^ T 3

030027/0777

H / 20 359 SY-1599A

2350888

A solution of the phosphorane 7 (1.796 g, 3.0 mmol) in chloroform (3 ml) is diluted with methanol (90 ml), ^{cooled to 0 °} C. under a nitrogen atmosphere and successively with silver nitrate (0.51 g, 3.0 mHöl) and potassium carbonate (0.33 g, 2.4 mmol). The reaction mixture is (protected from light) stirred at 0 ⁰ C for 15 minutes, then the Kühlfaad is removed and stirring is continued for 3 hours. The reaction mixture is cooled to -10 ⁰ C, stirred for 1 hour and filtered. The silver mercaptide is washed successively with cold methanol and with ether. 1.91 g of product with melting point 138 to 145 ° C (decomp.); Yield 96 %.

IR (Nujol) cm " ¹ : 1748, 1620 and 1605.

An analytical sample was determined by preparative TLC (ethyl acetate) obtain. Melting point 140 to 145 ° C (decomp.).

analysis for 54 ₀ H ₂₄ N _; 7O ₅ SPAg: 4th N 4th S. 54 C. H 3 , 22 4th , 83 ber .: , 31 3.65 , 92 , 62 found: , 11 3.48

' B e τ s ρ τ e T 8

1- (p-WitrobenzyloxycarbonylmethyTtripheriylpr:) sphorariy l (silver mercaptidyl) -2-azetidino n

Al use of aniline as a base

030027/0777

M / 20 359 SY-1599A

- 96 -

SCOCH-

Aniline,, AgNO.
HeOH

COOPNB

: oopnb

A solution of phosphorane 7 (1.8 g, 3.0 mmol) in chloroform (4 ml) is diluted with methanol (90 ml), cooled to -15 ° C. under a nitrogen atmosphere and treated successively with silver nitrate (0.56 g , 3.3 mmol) and aniline (1.5 ml, 16.5 mmol). The reaction mixture (protected from light) is stirred for 0.5 hours at -15 ° C., then the cooling bath is removed and the mixture is stirred for a further 24 hours. The reaction mixture is then cooled to -10 ⁰ C and stirred for 1 hour before filtration. The silver mercaptide is washed successively with cold methanol and ether. 1.55 g of product with a melting point of 114 to 115 ° C (dec.h yield 77.9 %.

IR (Nujol) cm "; identical to the compound of Example 7. STlber-1- (p-nitr6bsrizyT ^ 2" triphenylph <>sphGrariyliden-2'-acetate) -

2-azetidino-4-thioTat

B. Use of 4-DimethyTaminopyridiri (DMAP) as a base

.SCOCH.

AgNOVDMAP

PH C \ / CH OH
—2 - Z- 3

rf

CO PNB

CO PNB

A solution of the above S-acetylphosphorane (17.96 g, 30 mmol) in methanol and dichloromethane (1: 2, 450 ml) is flushed with nitrogen (5 to 10 minutes), cooled to 5 ° C. and one after the other

030027/0777

M / 20 359 SY-1599A

- 97 -

2950838

treated with silver nitrate (5.35 g _s 31.5 mmol) and 4-dimethylaminopyridine (3.85 g, 31.5 mmol). The ice bath is removed and the solution is vigorously refluxed for 2 hours and then stirred for a further hour at room temperature. The colored reaction mixture is treated with activated charcoal, filtered and evaporated. The residue is redissolved in the minimum amount of dichloromethane and added dropwise to cold methanol (300 ml) with stirring. The precipitated silver salt is collected by filtration, washed with ether and dried. 18.1 g (91 % yield).

^IR

1745 (C = O of β-lactam) and 1607 cm (C = O of ester).

SfTbet-1- (p-riitröberizyl-2'-tripheriyTphösphorariyliden-2 "-acetat)

■ 2-a \ zetidinori-4-t molate

C. Use of ufazabicycTouridecen (DBU) as a base

SCOCH

AgKO.

DBU, MeOH

Si »g

H-.

CO PNB

Dissolve the above S-acetylphosphorane (36.0 g, 0.060 mol) in methylene chloride (120 ml). The solvent is evaporated to obtain an oil. The oily residue obtained is redissolved in warm (35 ° C) methanol (240 ml) and rapidly with a methanolic solution (420 ml) of. Silver nitrate (10.68 g, 0.0628 mole). The resulting solution (or suspension) is 5 minutes at room temperature stirred, cooled (ice bath) and a solution of DBU (8.96 ml, 0.060 mol) in methanol (20 ml) is added over the course of Added 5 minutes. The mixture is stirred for 5 minutes.

030027/0777

Μ / 20 359
SY-1599A

- 98 -

2850898

The solid is filtered off, ^{washed once with cold (0 °} C.) methanol and with ether and dried under vacuum. 37 ₅ 0 g (93%).

IR (Nujol-Verre-E ^^ ng) ^ (C = O) and 1600 cm (Phosphorane)

ΠΙαΧ

D. Use of pyrrolidine as a base

Silver-V - (p-nitrobenzyl-2'-trfpheriyTphösphoranyliden-2 "- aeetät) -2-azetidinori-4-thietat

JX

SCOCH.

Pyrrolidine *

AegNO.

'C = PPh ΌΟΡΝΒ

Say

^ C = PPh I 3 COQPNB

To a cold (0 ⁰ C) solution of 4-acetylthio-1- (p-nitrobenzyl-2 "-triphenylphosphoranyliden-2" -acetate) -2-azetidinone (0.60 g, 1.0 mmol) in CH ₂ Cl ₂ (2 ml) are added to MeOH (ml), a solution of AgNO ₃ in MeOH (0.14N, 7.86 ml, 1.1 mmol) and a solution of pyrrolidine (0.92 ml, 1.1 mmol) in MeOH (2 ml). Removing the cooling bath and stir the reaction mixture 1.75 hours, cooled to -10 ⁰ C., stirred for 0.25 hours and then filtered. The solid is washed with cold MeOH and dried in vacuo. 0.548 g, melting point 115 ° C, 82.4 %.

TR (Nujol) J: 1755 (C = O) and 1600 cm " ¹ (aromatic).

III α λ

030027/0777

• * Λ • • · • «« # ♦ • *

M / 20 359 SY-1599A

- 99 -

B e i spin 9

Mercury ^ II) - / 2'-triphenylphosphoranylidene-2'-acetate7-2- azetidinone-4-thiolate

STr

Hg (OAc).

CO PMB

II

A solution of compound I (2.4 g, 3 mmol) in dichloromethane (15 ml) is cooled to 5 ° C. and treated with a solution of mercury acetate (0.525 g, 1.65 mmol) dissolved in methanol (15 ml) . After stirring for 2 hours at 5 ° C., the solvent is evaporated and the residue is redissolved in dichloromethane and washed with cold water. After the organic solution has been dried (MgSO ^) and treated with activated charcoal, it is evaporated, whereby a foam is obtained which crystallizes on trituration in ether. Yield 1.73 g (91 %) , melting point 123-127 ° C.

IR (CHCIo) 1745 cm ^"1 {0 _ _ft ß-lactam) 1608 cm

" ¹

(Phenyl)

030027 / & 777

M / 20 359 SY-1599A

- 100 -

' B eis ρ ie T "10

2-methylperiem-3-p-n-itrobenzyl-carboxylate (from the mercaptide intermediate)

2CH ₃ COCl

N E

PPh.

jpyridine

CO PNB

SCCXHi.

PPh.

CO PNB

II

III

A solution of compound II (262 mg, 0.2 mmol), Acetylchlo-Hd (35 mg, 0.44 mmol) and 2 drops of pyridine in 10 ml of dichloromethane is stirred at 5 ° C. for 1 hour. The precipitated mercury chloride is then filtered off and the filtrate is washed successively with cold dilute hydrochloric acid, sodium hydroxide and finally with brine. the organic solution is exposed to a stream of hydrogen sulfide for 2 hours at 5 ° C. and a further 10 minutes at this Stirred temperature to precipitate the last traces of mercury salts. Add some activated charcoal to the black mixture which is then filtered through a bed of celite. Evaporation of the clear filtrate leaves 193 mg (80.7 55) of compound III in the form of a foamy material.

IR (CHCl ₃ ) 1755 (%> _{c = o} 0 -lactam) 1692 (\? _SCOCH ) 1620 (phenyl).

030027/0777

■% —ίΟ »" ■■ - ■ · - · - · - - - · - · · -

M / 20 359 - 101 -

^SY - ^1599S 2950898

CO PNB CO PNB ²

2 III 3 IV

Phosphorane III (75 mg, 0.126 mmol) in toluene (10 ecm) is refluxed for 2.5 hours under a nitrogen atmosphere. Evaporation of the solvent and purification of the residue gives a crystalline derivative (25 mg, 63 %) whose physical and spectral data are in complete agreement with those of the title product.

If desired, the product IV can be catalytically hydrogenated (30 % Pd on Celite) to produce the corresponding 3-carboxylic acid product.

B e i s ρ i el 11

^ -AmfricimetHyTperiem-S-c'arboric acid (from the mercaptid-ZWfsehenprodukt)

ClCOCH_N Z-J

N ^ - - -w ν— * · * "" a

C = PPh ₃

COOPNB COOPNB

030027/0777

Μ / 20 359 SY-1599A

- »Ι J.0 ...- ^ -, .. - _β g _β _. . _# "-" -

A solution of silver mercaptide 1 (1.25 g, 1.99 mmol) in dichloromethane (15 ml), maintained under a nitrogen atmosphere is cooled to 0 ⁰ C and treated dropwise with a 2M solution of Azidoacetylchlorid in dichloromethane (1.13 ml _s 2.26 mmol). Stir the reaction mixture for 1 hour at 0 ⁰ C. The cooling bath is removed and stirring is continued for another 5 hours. The reaction mixture is filtered through a bed of celite and the solids are washed with dichloromethane (35 ml). The step and the washing liquids are combined, washed with sodium bicarbonate solution and with water, dried over anhydrous sodium sulfate and concentrated in vacuo to an orange-colored syrup, which can be obtained by column chromatography (30 g of silica gel 60, eluate of ether-2 % ethyl acetate (200 ml ), Ether-6 % ethyl acetate (200 ml) and ether-20 % ethyl acetate (500 ml), fraction size: 10 ml). A yellow powder is obtained by combining and evaporating fractions 49 to 80. Yield 0.73 g (60.8 %) with melting point 61 to 70 ° C.

5C0CH N

ToIuO T-2 = -

COOPNB

A solution of the phosphorane 2 (0.593 g, 0.93 mmol) in toluene (20 mL) for 1 hour at 105 ⁰ C is heated at 23 ° C cooled and concentrated to sinsr semi-crystalline compound, purified by column chromatography (12 g silica gel 60 Eluate: benzene (100 ml), benzene-2 % ether (100 ml) and benzene-4 % ether; fraction size: 10 ml) is purified. Combining and evaporating fractions 18 to 26 gives a yellow syrup which crystallizes on standing. 0.18 g of product

030027/0777

• * · ♦ «■

H / 20 359 SY-I599A

- 103 -

295Q8S8

(Yield 53 ₅ 7 %) with melting point 127 to 128 ° C.

NMR (CDCI ₃ ) S: 8.22 (2H _S d, J _{Ho Hm} = 8.8 Hz, Ho of p-nitro-

) (H H

benzyl), 7.60 (2H, d, p -nitrobenzyl), 5.71 (IH, 'dd,

_Ho

5.6

^Hz ' ^H " ⁵⁾ » ^{5> 33}

= 8.8 Hz, Hm from

_cis = 3.6 Hz,

^{Middle of}

ABq, J _ah = 14.0 Hz, CH ₂ of p-nitrobenzyl), 4.58 (2H ~ middle of ABq, J _{3 b} = 15.0 Hz, CH ₂ on C-2), 3.88 (IH , dd, J _{65 ci} s ⁼ 3 _S 6 Hz,

Hz, H-6 ds) and 3.55 (1H, dd, J ₅ ^ _{5 trans} = 2.1 Hz, J _gen , = 16.5 Hz, H-6 trans).

IR (Nujol) cm " ¹ : 2115 and 2090 (N ₃ ), 1780 (c = o of ß-lactam)

and 1685 (c = o of p-nitrobenzyl ester).

An analytical sample was obtained by preparative TLC. Melting point 127 to 128 ° C.

analysis for *
• 46 4 ^H 11 ^N i 5 ° 5 ^S. * 1 N 8th S. 46 C. H 1 9.37 8th .87 ber. , 54 3 .07 9.37 , 90 .43 3 .08

COOPNB

30t Pd / Ceiite. j f ' \ _CH_NH, ί ' ^H 2 ° J - * - /

COOH

THF, ether,

To a solution of the penem compound 3 (0.18 g, 0.5 mmol) in tetrahydrofuran (6 ml) are successively added ether (6 ml), water (6 ml) and 30 % palladium on Celite (0.18 g). The reaction mixture is at 23 ° C for 2.5 hours at 2.07 bar

030027/0777

M / 20 359 SY-1599A

- 104 -

Hydrogenated (30 psi) and filtered through a bed of CeTite. The bed is washed with water and the filtrate and washings are combined, washed with an ether-THF mixture and lyophilized. 30 mg (30%) of compound 4 are obtained. / The compound, which is insoluble in water and ether, is dissolved in chloroform, and the organic solution is washed with water and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gives 75 mg (42.8 %) of starting material 3J .

NMR (DMSO d-6) <f: 5.7 (dd, J _{5-6 cis} = 3.5 Hz, J _{5-6 tPans} ^B 1.5

Hz, H-5).

IR (Nujol) cm " ¹ : 1775 (c = o yon β-lactam) and 1615, 1585.

UV2 ^H 2 ° _mu: (£ = 2320) and 307 (£ = 2685).

Max

The title product 4 is also obtained from the intermediate 3 via get the following way:

H, Pd / D.E-

COOPNB

H ₂ O

Ϊ ₂ ΝΗ ₂

COOK

To a solution of the penem compound 3 (2.4 g, 6.89 mmol) in a tetrahydrofuran-ether-water mixture (1: 1: 1, 165 ml) is added 3D % palladium on üiatomeenerde (4, S g) . The reaction mixture is hydrisr for 2.5 hours at 23 ° C. under a pressure of 3.10 bar (45 psi) and filtered through a bed of celite. The filtrate and washing liquids are combined, washed twice with ether, centrifuged several times and filtered to give a clear solution which lyophilizes

030027/0777

SSSS 3 β

M / 20 359 SY-1599A

- 105 -

ft · ■

will. Han receives 0.622 g of product (45 %) . Crystallization of the compound is induced by adding water (0.8 ml). The suspension is centrifuged and the water is removed leaving an orange solid. This solid is washed twice with water and, after drying, a slightly yellowish solid is obtained in an amount of 0.273 mg (19.8 %).

^UV

^Η 2 ° max

307 (£ = 4318) and 257 (£ = 2650).

Some crude starting material (1.2 g, 50 "%.) Is recovered.

The compound (50 mg) can also be purified by column chromatography / Sephadex G10, column size: 1.6 χ 100 cm, flow rate: 10 ml / hour, eluent: distilled water, fraction volume: 1.5 ml _c detector: refractive index7-purified.

H ₂ O

307 (£ = 3597) and £ 255 = 2424).

The stability of the compound in aqueous solution was checked by UV:

UV: 6 h 307 (ε = 3545) and 255 (ε = 2773)

21 h 307 (e = 3467) and 255 (e = 2411)

28 5i 307 (ε = 3337) and 254 (ε = 2393)

46 h 307 (£ = 3259) and 254 (£ = 2338)

70 h 307 (ε = 3076)

94 h 307 (e = 2842)

170 h 307 (e = 1900)

A sample of compound 4 is kept at 23 ° C. for 3 days and a UV is recorded:

_m ² ": 307 (£ = 3055) and 255 (£ = 2008).

03002 7/0777

M / 20 359 SY-1599A

- 106 -

Compound 4 is divided into two additional as described below 2-penem derivatives transferred.

, HO

f CH ^ C-OEt

A suspension of compound 4 (30 mg, 0.25 mmol) in distilled Water (0.5 ml) is treated with one equivalent of sodium bicarbonate (21 mg) followed by the addition of ethyl acetimidate (21.8 mg, 0.024 ml). The reaction mixture is stirred 20 minutes at 23 ° C and then lyophilized, whereby 52 mg of a yellow solid are obtained.

NMR (D ₂ O) (T: 5.7 (m, H-5) and 2.23 (bs, CH ₃ of amides). IR (KBr) cm " ¹ : 1772 (c = o of βr lactam).

^UV ^ max ^{m | j: 305} ^ = ³¹¹⁶ ) ^{and 253} (^ = 2525).

Compound 5 is applied to a column (Sephadex G10, column _{size: 1 * β 100 cm s,} eluant: H ₂ O. Detector: IR, fraction size: 1.6 ml). By lyophilizing the appropriate fractions, 23 mg (yield 45 %) are easily obtained

Γ U I VCI.

UV λ * mp: 303 (ε = 2960) and 248 (i = 2t, 85).

UIu X

030027/0 7 77

9 9 9

H / 20 359 SY-1599A

- 107 -

2.

H NH

NH-HCl
HC-OEt

6NaCl

A suspension of compound 4 (50 mg, 0.25 mmol) in distilled water (0.5 ml) is treated with sodium bicarbonate (21 mg, 0.25 mmol) and stirred for 1.5 minutes before mixing of sodium bicarbonate (126 mg, 1.5 mmol) and ethyl formimidate hydrochloride (164 mg, ί _t B mmol) is added (2 minutes) The reaction mixture is stirred for 10 minutes at 23 ° C. and lyophilized, an orange powder being obtained .

H ₇ O

304 (£ = 2300)

B e s pie! 12th

Sodium-2-hydroxyamino-propylpenem-3-c'arböxyTat

OH

1) BaOH 5 *

2) HCl cone

030027/0777

M / 20 359 SY-1599A

- 108 -

2350898

Ester 1 (21.6 g, 0.134 mol) is added to a cold 35% aqueous solution of sodium hydroxide (320 ml). The resulting mixture is stirred for 2 hours at room temperature and then concentrated to 250 ml and acidified with concentrated HCl. The mixture is extracted with ethyl acetate (4 × 200 ml) and the organic extracts are dried over sodium sulfate. Concentration on a rotary evaporator results in an oil. Yield 13.2g (75 %).

SOCl.

A solution of acid 2 (13.2 g, 0.1 mol) in SOCl ₂ (25 ml) is stirred for 2 hours at 30 ⁰ C. After evaporation of the thionyl chloride, the residue is distilled under vacuum, boiling point 76 to 78 ° C. (P = O, 2 mm Hg). The yield is 8.8 g (58.3 %) of a colorless liquid.

NMR (CDClgJiTppm: 2.40 (2H, m, B-CH ₂ ), 3.15 (2H, t, ^ -CH ₂ )

4.50 (2H, t, T-CH _2).

IR (clear): 1550 cm
chloride)

-1

), 1790 cm " ¹ (^ _{c = 0} , Sa

Acid030027 / 0777

M / 20 359 SY-1599A

- 109 -

-OGl

2) NaHCO ₃ / Γ ~ Γ OH

A solution of compound 3 (19.46 g, 0.128 mol) in methylene chloride (200 ml) is quickly stirred into a cold (0 to 10 ⁰ C) solution of triethylamine (36 ml, 0.256 mol) in methylene chloride (500 ml) which was saturated _{with H 2} S at 0 to 5 ° C. The mixture is stirred 1 hour at -10 ⁰ C and then directs a stream of nitrogen through the solution to the excess ge H ₂ S to be removed. The mixture is washed with 10% HCl, the organic extract is concentrated to approximately 150 ml and then sodium bicarbonate (10.9 g) and water (500 ml) are added. The pH is adjusted to approximately 7.5 _{with NaHCO 3 or HCl.} The resulting mixture is cooled to 0 ⁰ C, and (16.8 g 0.13 mol) are added 4-acetoxy-2-azetidinone with vigorous stirring in water (20 mL). After 4 hours, the mixture is extracted with ethyl acetate. The extracts are washed with 10% HCl, saturated NaHCO ₃ and with brine, dried (Na ₂ SO ^) and evaporated. The residue is purified by column chromatography (SiO ₂ , eluent: ether, then ether-ethyl acetate 5 %) , whereby an UI is obtained which crystallizes in ethyl acetate-hexane, whereby compound 4 (3.5 g, 12.5 %) obtained in the form of a white powder with a melting point of 45 to 47 ° C.

"NCL

CH (OH) _ CO PNB

030027/0777

M / 20 359 SY-1599A

A mixture of azetidinone 4 (1.09 g, 5 mmol) and p-nitrobenzyl glyoxylate hydrate (1.2 g, 5.25 mmol) in benzene (100 ml> is done with a Dean-Stark trap that is fitted with a 4A molecular sieve. is filled, heated to reflux for 18 hours. Evaporation of the solvent gives the glyoxylate adduct 5 (2.1 g) 'in the form of an oil.

-N.

SOCl

Py

O PNB

"N,

CH-Cl

CO PNB

Azetidinone glyoxylate 5 (2.1 g) is dissolved in tetrahydrofuran (50 ml) and pyridine (0.57 ml, 7 mmol) is added to the solution. The mixture is cooled to 0 ⁰ C and SOCl ₂ (0.5 ml, 7 mmol) is added slowly. The mixture is stirred for 1 hour at 0 ^° C. and then filtered before it is evaporated to dryness. Filtering the material through a bed of silica gel using CH ₂ Cl ₂ gives a foam. Yield 1.9g (85 %).

CO PNB

ΡΦ,

2,6-lutidine

COJPNB

To a solution of chlorazetidinone (6.2 g, 14 mmol) in THF (300 ml) are triphenylphosphine (5.5 g, 0.02 mol) and

M / 20 359 SY-1599A

2350898

2,6-lutidine (2.4 ml, 0.02 mol). The mixture is then 20 hours heated to 45 ° C. Lutidine hydrochloride is filtered off and washed with ether. The filtrate is then evaporated. The The residue is purified by chrome graphing on a silica gel column while eluting with dichloromethane and dichloromethane-ethyl acetate (1: 1). Evaporation of the eluant gives one ν, 'είδεη solid (2.9 g, 30%).

toluene

Phosphorane 7 (2 »0 g, 3 mmol) in toluene (150 ml) is refluxed for 2.5 hours. Evaporation of the solvent gives an oil which is purified by chromatography on a silica gel column and eluting with dichloromethane and dichloromethane-ethyl acetate (9: 1). Evaporation of the solvent gives a syrup ₅ which crystallizes in thylacetate-hexane as a white solid (0.82 g, 40.7 %) .

30 * Pd / DE

THF-THER-H ₂ O-NaHCO ₃

PNB

030027/0777

M / 20 359 SY-1599A

• ·· 9

To a solution of the ester 8 (50 mg, 0.127 mmol) in a tetrahydrofuran etching mixture (2: 3, 25 ml) are added water (10 ml), sodium bicarbonate (10 mg, 0.127 mmol) and 30 % palladium on diatomaceous earth (50%) mg). The reaction mixture is hydrogenated for 3 hours at 25 ° C. under a pressure of 3.45 bar (50 psi), filtered through a bed of celite and washed with ether. The aqueous solution is lyophilized to give a yellow powder (30 mg) which is hygroscopic.

Example 13

6-ethyl-2-aminomethylpenem-3-carboxylic acid (cis and trans isomers )

and

Y > ^B

a. Silver cis- and trans-3-ethyl-1- (p-nitrobenzyl-2'-triphenylphösphorariylidenT2'-acetate) -2-azetidinone-4-thiolate

A solution of cis = and trans-3-ethyl-1- (p-nitrobenzyl-2'-phosphoranylidene-2 ^f -acetate) -4-acetylthio-2-azetidinones (1.88 g, 3.0 mmol, Example 1 , Structure 7) in chloroform (4 ml) is diluted with methanol (SG ml), shijeked 5uf G ⁰ C and successively with finely powdered silver nitrate (0.51 g, 3.0 mmol) and potassium carbonate (0.33 g, 2 , 4 mmol). The mixture is stirred vigorously for 15 minutes at 0 ⁰ C, 3 hours at room temperature and 1 hour at -10 ⁰ C. The precipitated silver mercaptide is overall by filtration

030027/0777

M / 20 359 SY-1599A

~ 113 -

collects, washed with methanol and with ether and dried in vacuo. The title product is in the form of a greyish Solid with melting point 112 to 135 ° C (decomp.) Obtained.

IR: v> _{c =} 0.1750, 1620, 1605.

b. eis- and traris-S-ÄthyT-T-Cp-rtitr'öbenzyi -2 '-phosphoranylidene 2 ' -acetate) -4-azTdoacetyTthio-2-azetidirione

A solution of the above crude mercaptide (1.31 g, 2 niHol) in dichloromethane (15 ml) is cooled to 0 ⁰ C and under a nitrogen atmosphere with a 2M solution of Azidoacetylchlorid in dichloromethane (1.13 ml, 2.26 mHol) treated. The mixture is stirred for 1 hour at 0 ^° C. and for 5 hours at room temperature. The insoluble silver salts are removed by filtration over CeIite and washed with dichloromethane. The combined filtrates are washed with dilute sodium bicarbonate solution and with water, dried and concentrated. The oily residue is purified by chromatography on silica gel (35 g), eluting with ether-ethyl acetate. The appropriate fractions are concentrated to give a mixture of cisacylated and transacylated compounds in the form of a semi-solid. 0.62 mg.

IR: Ο (CDCl ₃ ):

2105, 1760, 1690, 1621 cm

-1

c. eis- and traris-p-nitrobericyl-2-azidomethyl-e-a- carboxylates

A solution of the above crude phosphorane (0.60 g) in toluene (30 ml) is ^{kept at 105 °} C. for 1 hour, cooled and concentrated, leaving an oily residue which can be ascertained by column chromatography over silica gel (20 g) while evolving with increasing Proportions of ether purified in benzene

030027/0777

M / 20 359 SY-1599A

will. The appropriate groups are concentrated, whereby the cis and trans isomers are obtained.

ice isomer:
NMRi (ppm, CDCl ₃ );

3.25 (2H, d, J = 8.8, Ho of p-nitrobenzyl), 7.65 (2H, d, Hm), 5.93 (1H, d, J = 4.1, H-5), 5.38 (2H, AB quartet,

4.68 (2H, AB quartet 3.4 (1H, ir ,, H-6), 2.0 1.1 (3H, t, J-7.4 »

J = 14.0, benzyl) J = 15.0, CH ~ -N ")

(2H, m, CH_ ₂ CH ₃ ),

trans isomer:
NMR <f (ppm, CDCl ₃ ):

CH ₂ CH ₃ ).

8.18 (2H, d, J = S, 8, Ho), 7.59 (2H, d, Hm), 5.52 (1H, d, J = I, 4, H-5), 5.33 (2H AB quartet, J = 14 _- 0 _- benzyl). 4 _S 58 (2H AB quartet, .1 = 15.0, C ^ ₂ -N ₃ ), 3.7 (1H, dt, J = 1.4, J = 7.4, H-6), 1, 9 (2H, m, CJi ₂ CH ₃ ), 1.1 (3H, t, J = 7 _S 4, CH ₂ CH ₃ ).

d. traris-2-aminomethyl-6-ethylpenem-3-carboxylic acid

A mixture of the above trans-p-nitrobenzyl esters (0.20 g, 0.5 nmol), THF (6 ml), ether (6 ml), water (12 ml) and 30 % palladium on activated carbon (0.20 g ) is reduced for 2.5 hours at 23 ° C with an initial hydrogen pressure of 2.07 bar (30 psi). The catalyst is removed by filtration through CeIite and washed with water. The combined filtrates are washed with ether-THF and lyophilized to give the crude trans acid (12 mg). Chromatography over a column with Sephadex G-10 and quenching with water gives the pure trans-acid (6 mg in the form of a hygoscopic powder.

IR

1775, 1615 cm

-1

030027/0777

-J ■. "Ff - ι .. ψ,.

ι »· ι *

Μ / 20 359 SY-1599A

^UV ^ max ⁼

NMRJ (ppm, D ₂ O-DHSO)

- 115 -

5.40 (1H, d, J = 2.0, H-5), 2.0 (2H, m, CH ₂ CH ₃ ), 1.1 {3H, t, J = 7.4, CH ₂ CH ₃ ).

e. cis-Z-Aminomethyl-e-athyipenem-S-carboxylic acid

Reduction of the cis-p-nitrobency ester as described above for the transEster results in the cis-acid in the form of a yellowish, hygroscopic powder (13 %).

IR ι / 1775, 1615 cm

Πιο Χ

= 304 (£ = 3563).

D ₂ O-DMSo): 5.75 (IH, d, J = 4.0, H-5), 2.0 (2H, m, CH ^ ₂ CH ₃ ), 1.1 (3H, t, J = 7.4, CH ₂ CH ₃ ).

B ice ρ i e 1

14th

The following connections can be made according to the general
Procedure of Example 13 can be prepared.

030 027/0777

Μ / 20 359
SY-1599A

Acyiierürtcjsniittei

CH ₃ COCl

Ac ₂ O

CH ₃ CO ₂ SO ₂ CH ₃ C ₂ H ₅ COCl 0CH ₂ COCl 00CH ₂ COCl

D-

COCl

(CF ₃ CO) ₂ 0 C ₂ H ₅ O ₂ C-COCl

COCl

-TCH ₂ COCl

COC1

COC1

NC (CH ₂ ) ₂ COC1 O ₂ N (CH ₂ ) ₃ COC1

N ₃ (CH ₂ ) ₂ OCH ₂ COC1 N ₃ (CH ₂ ) ₂ SCH ₂ COC1

- 116 -

-CH. -CH, -CH, -CH, -CH. -CK. -CK. -CH. -CH. -CH.

-CH.

-CH.

-CH.

-CH.

-CH.

-CH.

-CH.

-CH.

-CH.

-CH

-CH- ₃

-CH

-C ₂ H ₅

-CH ₂ 0

-CH ₂ O0

JH

-CH-

NHOH

-CH ₂ S (CH ₂ )

Among other things, H N / A, H N / A, H N / A, H N / A, H N / A, H N / A, H N / A' H N / A N / A

Close

Close

Well, H H H H

030027/0777

can - 117 - Y * · T · ♦♦ ♦ # · · * ·
• ♦ · Z M / 20 359
SY-1599A U ■; -CH ₃ t · · »·« ·· «
• · · · · · *
2950898 Close. Acylation agents U -C ₂ H ₅ X Close AcNH (CH ₂ ) ₂ CO ₂ CO ₂ Et 0CH ₂ COCl - ^C 2 ^H 5 - (CH ₂ J ₂ NHAc Close CH ₃ COCl N ^ CH ₂ COCl - ^C 2 ^H 5 -CH ₃ Close C ₂ H ₅ COCl N ₃ (CH -) - GQGl -C ₂ H ₅ -C ₂ H ₅ Close 0CH ₂ COCl N ₃ (CH ₂ J ₃ COCl - ^C 2 ^H 5 -CH ₂ 0 Close 00CH ₂ COCl O ₂ N (CH ₂ J ₃ COCl -C ₂ H ₅ -CH ₂ O0 H . k-coci - ^C 2 ^H 5 H N ₃ (CH ₂ J ₂ COCl -C ₂ H ₅ - (CH ₂ J ₂ NH ₂ . Close N ₃ (CH ₂ J ₃ COCl -C ₂ H ₅ - (CH ₂ J ₃ NH ₂ H O ₂ N (CH ₂ J ₃ COCl XSO-C ₃ H ₇ - (CH ₂ J ₃ NHOH Close, N ₃ (CH ₂ J ₄ COCl XEO-C ₃ H ₇ - (Oi ₂ J ₄ NH ₂ Close ' CH ₃ COCl XSO-C ₃ H ₇ -CH ₃ Close C ₂ H ₅ COCl XSO-C ₃ H ₇ -C ₂ H ₅ Close b ^ coci XSo-C ₃ H ₇ - <! Close XSO-C ₅ H ₇ Close. XSo-C ₃ H H • 5 e-y-i-r · H
3 ~ 7 IJ H XSO-C ₃ H ₇ . I.
-CH ₂ 0 H XSO-C ₃ H ₇ -CH ₂ NH ₂ Close
Ϊ - - «= 2> 2» 2 . - (CH ₂ J ₃ NH ₂ j - (CH ₂ J ₃ NHOH!

030027/0777

M / 20 359 SY-1599A

· ♦ ■ # #

- 118 -

At game 15

cis and trans-S-acetoxymethyl ^ -aminotnethylpenem-Srcarbpn acid

AcO

S //

CO ₂ H

a) 3-acetoxymethyl-4-tritylthio-2-azetidinone (cis and trans iscmere)

A solution of a mixture of cis and trans-4-acetoxy-3-acetoxymethyl-2-azetidinone (4.7 g, 25 mmol) (Example 2, Structure 26) in water (200 ml) is quickly added to a vigorously stirred solution of sodium triphenylmethyl mercaptide (made from triphenylmethyl mercaptan, 55.2 g and sodium hydride, 9.6 g, in methanol, 300 ml). The mixture is stirred for 4 hours at room temperature and the solids are collected by filtration, washed with water and dissolved in dichloromethane. You wash them Solution with dilute hydrochloric acid, water, aqueous sodium bicarbonate and water, dry and concentrated, leaving 85% of a solid which is used as such in the subsequent experiment.

b) z \ z- and trans-S-acetoxymethyl-i-Cp-nitrobenzyl-2'-hydroxy 2'-acetate) -4-ttritylthio-2-azetidironen

A solution of the above azetidinone (8.0 g, 20 mmol) and p-nitrobenzyl glyoxylate (4.54 g, 20 mmol) is in Benzene (100 ml) via a Dean-Stark water separator

03Q027 / 0777

I ■ »

H / 20 359 SY-159SA

- 119 -

direction, which is filled with 3A-Mo1ekularsieb- held at reflux. After 24 hours a second amount of p-nitrobenzyl glyoxylate (4.54 g) is added and the mixture is refluxed for a further 24 hours. The mixture is diluted with ether, washed with 5% aqueous hydrochloric acid, water, aqueous 5% sodium bicarbonate and again with water. Drying and concentration gives 100 % of the crude isomeric mixture in the form of an 01s.

c) cis- and trans-S-acetoxymethyl-ip-nitrobenzyl ^ ¹ -chlor-2'- a acetate) -4-tritylthio-2-azetidinone

A solution of azetidinones from part b) above (12.2 g, 20 mmol and PyHdin (1.9 g, 24 mmol) in dried THF (150 ml) is cooled to -15 ° C and mixed with thionyl chloride (2 * 86 g _s 24 mmol) under a nitrogen atmosphere. the mixture is stirred 45 minutes at -15 ° C, removing the precipitate by filtration and washed with benzene. the filtrates are concentrated to give a semi-solid remaining (95%).

d) cis- and trans-3-acetoxymethyl-1- (p-nitrobenzyl-2'-triphenyTphosphoränyTiden-2-acetate) -4-tritylthio-2-azetidium

A mixture of azetidinones from step c) (12.6 g, 20 mmol), triphenylphosphine (7.8 g, 30 mmol) and 2,6-lutidine (2.6 ecm, 2.2 mmol) in THF (100 ml) is Heated to reflux for 50 hours. The insoluble material is removed by filtration and washed with ether. The filtrates are washed with 2 2 strength aqueous hydrochloric acid, 5 s strength aqueous sodium bicarbonate and water, dried and concentrated. The residue is dissolved in benzene, filtered slowly through a bed of silica gel (250 g) and the bed is eluted with increasing proportions of ether in benzene. Concentration of the appropriate fractions gives a mixture of the title compounds (65 %) *

030027/0777

M / 20 359 SY-1599A

1525 cm

-1

IR: ^ _Λ 1740, v ^ _Dn 1620, 161O _S ^ _wn

C = O C = rj0- PiUrt

Silver cis- and trans-3-acetoxymethyT-1- (p-nitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate) -2-azetidinone-4-thio1ate

The crude azetidinones of step d) (8.5 g, 10 mmol) are dissolved in hot methanol (55 to 60 ⁰ C). A hot solution is added (55 to 60 ⁰ C) of silver nitrate (2.04 g, 12 mmol) and pyridine (0.87 g, 11 mmol) in methanol (80 mL). The mixture is allowed to cool to room temperature over the course of 2 hours and is stirred at 0 ° C. for a further hour. The silver mercaptide is collected by filtration, washed with ice-cold methanol and then with ether (5.7 g 82 %, product melts with decomposition).

C -

1745 _S 174O ₅ 1625 cm

" ¹

f) eis- and traris-S-acetoxymethyl- ^ - azidoacetylthio-i-tpnitrobericyl-2'-triphenyTphosphoräriyTiden-2'-acetate) -2-azetidironen

The above silver mercaptide (from step e), 1.4 g, 2 mmol) in dichloromethane (15 ml) is treated as described in Example 13 with azidoacetyl chloride (2.3 mmol), whereby 0.78 g of a yellow powder is obtained.

g) eis- und tr ans-6-Aeetöxyme thy l ^ -azi dome thy I penem-3-carboxylic acid-p-nitrobenzyl ester

The lasting of the above crude phosphorus (0.70 mg) in toluene (35 ml) is ^{kept at 105 °} C. for 1 hour, cooled and concentrated, leaving an oil which is purified by chromatography over silica (25 g), whereby eluted with increasing proportions of ether in benzene. The appropriate fractions are concentrated, using the cis and trans isomers of the title compound

030027/07 77

H / 20 359 SY-1599A

receives.

cis isomer: NHRi (ppm, CDCl ₃ )

- 121 -

trans isomer: NMR S (ppm, CDCl-):

8.5-7.5 (4H, aromatic), 5.67 (1H, d, J = 5, K-5), 5.31 (2H ₅ AB quartet, CH ₂ -benzyl), 4.50 (2H , AB quartet, CIH ₂ N ₃ ) 4.33 (2H, d, AcO £ H ₂ ), 4.26 (1H, dt,
H-6), 2.0 (3H, s, CH ₃ ).

8.5-7.5 (4H; aromatic), 5.62 (IH, d, J = 2, H-5), 5.33 (2H, AB quartet,
CH ₂ -benzyl), 4.40 (1H, dt, H-6) _s 4.50
(2H, AB quartet, ^ H ₂ N ₃ ), 4.27 (2H, d, AcO £ H ₂ ), 2.0 (3H, s, CH ₃ ).

h) trans-6-acetoxymethyl-2-aminomethylpenem-3-carboxylic acid

Hydrogenate the above trans isomer according to that in Example 13 The procedure described results in the title compound.

^IRvJ _{c = 0} 1775, 1740, 1616 cm " ¹ .
UV 3. _v 304 (e = 3192).

Πια Α

i) c is-e-Acetoxymethyl ^ -ämiriomethylperiem-S-car bon acid

By hydrogenating the corresponding cis isomer as in As described in Example 13, the title compound is obtained in the form of an unstable, hygroscopic, semi-solid substance

030027/0777

Μ / 20 359 SY-1599A

- 122 -

2B50S98

Example 16

Following the general procedure of Example 15, the following compounds can be prepared.

Acylation agent1

CH ₃ COCl -CII ₂ OAc -CH ₃ H C ₂ H ₅ COCI - r · H
~ 2 "5 H L ^ -COCl -CH ₂ OAc H ' fT ^C0C1 -CH ₂ OAc H ' ^ o ^ ^ o ^ -CH ₂ OAc η Ii \ V ^COC1 - -CH ₂ OAc - (CH ₂ J ₂ NH ₂ H N ₃ (CH ₂ J ₂ COCl -CH-OAc - (CH ₂ J ₃ NH ₂ Hi N ₃ (CH ₂ J ₃ COCl -CH ₂ OAc - (CH ₂ J ₄ NH ₂ H N ₃ (CH ₂ J ₄ COCl -CK-CAc _ / J-IlS \ XTUY-tU
- \ ^ - * «2 ' ₃ " - "' - H O ₂ N (CH ₂ ) ₃ COCX. - (CH ₂ J ₂ OAc -CH ₃ H CH ₃ COCl - (CKT ₂ J ₂ OAc ■ < H t ^ -coci - (CH ₂ J ₂ OAc -CH ₂ NH ₂ η N ₃ CH ₂ COCl ' H

030027/0 7 77

M / 20 359 SY-1599A

Acylating agents

- 123 -

N ₃ (CH ₂ J ₂ COCl - (CH ₂ J ₂ OAc - (CH ₂ J ₂ IIH ₂ H N ₃ (CH ₂ ) ₃ COC1 - (CH ₂ J ₂ OAC - (CH ₂ J ₃ NH ₂ H CH ₃ COCl -CH-OAc -CH ₃ H N CH ₂ COCl -CIi-OAc -CH ₂ NH ₂ H

Example 17

eis- and traris-6- (1 '-hydroxy-ί' -ethyl) - * 2-ffiethylpenem-3-carbon acid, sodium salt

OH
. (V = -CH-CH ₃ ; X = -CH ₃ )

^{Diisopropylamine (0.08 ml, 0.57 mmol) at 0} ° C. and n-butyllithium (0 ° C.) are added to a solution of Z-methylpenem-S-carboxylic acid (100 mg, 0.54 mmol) in THF (8 ml) , 75 ml, 1.20 mmol) at -78 C. After 2 ^f minutes of stirring at -78 ° C is one freshly distilled acetaldehyde (0.5 ml) added and stirred for another 10 minutes. The reaction mixture is quenched with saturated ammonium chloride solution (10 ml) and washed with ethyl acetate. The aqueous layer is acidified with 0.1N hydrochloric acid (18 ml) and extracted with ethyl acetate (3 × 20 ml). Concentration of the dried ethyl acetate phases gives one oil (49 mg). The oil is dissolved in methyl isobutyl ketone and treated with an excess of sodium methyl] hexanoate in the same solvent. Addition of ether leads to the precipitation of the title compound in the form of a white »amorphous solid mg). . -.

030027/0777

I »» I 4 f

M / 20 359 SY-1599A

- 124 -

NMR S (ppm, D ₂ O): 5.6-5.83 (IH, m, H-5, cis and trans), 2.27

(3H, s, CH ₃ ), 1.22 and 0.90 (3H ₁ 2d, CHg).

example

18th

cis-6- (1 '-Hydroxy-1'-'ethyl) -2-methyTpenetri-3-carboxylic acid, sodium salt (isomer "D")

2-Methylpenem-3-carboxylic acid (100 mg) is with LDCA and with Treated acetaldehyde as described in Example 17. The residue (58 mg), which was obtained after concentrating the dried ethyl acetate phases, is extracted with ether and the ethereal solution is concentrated to one UI (48 mg). This oil is converted into a sodium salt using sodium methylhexanoate as described in Example 17. 29 mg of a white one are obtained Solid identified as cis-6- (1'-Hydroxy-1'-ethyl) -2-methylpenem-3-carboxylic acid, sodium salt, which with something Sodium 5-methyl-1,3-thiazole-4-carboxylate is contaminated.

NMRi (ppm, DMSO-d ₆ ): 5.5 (1H, d, J = 4.1, H-5), 2.22 (3H, S,

CH ₃ ), 1.02 (3H, d, J = 5.5, CH ₃ ).

Be i s ρ i e T

19th

cis- and trans-6-C2'-Hydroxy-2'-propyT) -2-ethyTpenem-3-carbon acids , Potassium salts

OH

If, in the general procedure of Example 3, the 2-methylpenem-3-carboxylic acid used there is replaced by a an equimolar amount of 2-ethylpenem-3'-carboxylic acid is obtained

030027/0777

»I.

• a

M / 20 359 SY-1599A

- 125 -

Mixture of potassium salts.

(ppm, DMSO-dg):

5.60 and 5.56 (IH, 2d, 0 = 4 and ΰ = 2, Η-5) 3.92 and 3.60 (1H, 2d, J = 4 and J = 2, H-6) 2, 88 and 2.86 (2H, 2q, CJi ₂ -CH ₃ ), 1.47, 1.41, 1.36 and 1.32 (6H, 4s, CH ₃ ), 1.2 and 1.4 (3H , 2t, CH ₂ CH ₃ ).

Max

257 Ce = 3705) and 302 (£ = 3815).

Be i s ρ i e T 20

cis- and traris-6- (1'-hydroxy-1'-ethyl) -2-n-1-ethoxymethylpenem-3 · carboxylic acids , sodium salts

To a solution of 2-methoxymethylpenem-3-carboxylic acid (see FIG. Preparation No. 6, 116 mg, 0.55 mmol) in THF (10 ml), diisopropylamine (0.08 ml, 0.57 mmol) at 0 ⁰ C and n-butyllithium (0.75 ml, 1.20 mmol) at -78 ° C. After stirring for 2 minutes at -78 ° C., freshly distilled acetaldehyde (0.5 ml) is added and the mixture is then stirred for a further 10 minutes. The reaction mixture is quenched with saturated ammonium chloride solution (10 ml) and washed with ethyl acetate. The aqueous layer is acidified with hydrochloric acid (0.1N, 18 ml) and extracted with ethyl acetate (3 × 20 ml). Concentration of the dried ethyl acetate phases gives an oil (53 mg) which, as described in Example 17, is converted into a mixture of the sodium salts of the title compounds. A white, arsorpheSi hygroscopic tulver (21 mg) is obtained.

NMR (T (ppm, D ₂ O):

5.7-5.85 (1H, m, H-5, cis and trans), 3.38 (3H, 2s, OCH ₃ ), 1.22 and 0.92 (3H, 2d, CH ₃ )

1770, 1600 cm

■ 0 30 027 / 0-7 77

359 SY-1599A

Example 1 21

ice and drink-e-Acetyi-E-methylpenem-S-carboxylic acid, sodium salts

0 (Y = -C-CH ₃ ; X = -CH ₃ )

(Mg 100, 0.54 mmol) to a solution of 2-methylpenem-3-carboxylic acid in THF (10 ml), diisopropylamine (0.08 ml, 0.57 mmol) at 0 ⁰ C and n-butyllithium (0 , 75 ml, 1.20 mmol) at -78 ° C. After stirring for 2 minutes at -78 ° C., ethyl acetate (1 ml) is added and the mixture is then stirred for a further 10 minutes. The reaction mixture is quenched with saturated ammonium chloride solution (10 ml) and washed with ethyl acetate. Acidify the aqueous layer was carefully at 0 ⁰ C with 0.1N hydrochloric acid and extracted quickly with ethyl acetate (3 χ 20 ml) concentrating the dried extracts gave an oil (36 mg), which is converted to the title compounds as described in Example 17 .

NMRo "(ppm, D ₂ O):

5.90-6.10 (1H, 2d, J = 4, J = 2, H-5), 3.8 (1H, m, H-6 cis and trans), 2.34 and 2.27 (3H , 2s, CH ₃ ), 2.12 and 2.0 (3H, 2s, CH ₃ ).

example

22nd

The following compounds can be prepared according to the general procedures of Examples 3 to 5- and 17 to 21.

0 30027/0777

i M / 20 359
SY-1599A Y
V X . .. - 127 - • · · * m · » ζ - L.
0 -CH ₃ • β ** ϊ K N / A 2950898 -CH ₃ co ₂ z N / A Y N / A -CH ₃ OH
T
-CH-CgH ₄ -OCH ₃ • N / A -CH ₃ OH
1 K -CH ₃ -CH-n3u -C ₂ H ₅ . 0
ir N / A Il
-C-0 " ^C 2 ^K 5 -CH ₂ OH N / A OH
I.
-CHCF ₃ ι
Well f -C ₂ K ₅ -SCH ₃ OH
i K -C-CH ₃ - ^C 6 ^H 5 0
Il Il
-t-cn ₃ OH
I.
-CH-CH ₃ OH
■ -C (CIi ₃ J ₂

030 0 2 7/0777

M / 20 359
SY-1599A

- ^C 6 ^H 5

-CH ₂ OCH ₃

-CH ₂ OCH ₃

CH ₂ OCH ₃

CH ₂ OCH ₃

-CH ₀ SCH,

- 128 -

O Il -C-CH.

OH -CH-CH.

OH I -C (CH)

OH i -C-0

-C-CH.

H -C-0

OH I

-CHCH.

OH -C-

2950098

N / A

N / A

N / A

N / A

N / A

Example 23

The following compounds can be used according to the general Procedure of Example 3 can be prepared.

030027/0 7 77

M / 20 359 SY-1599A

i)

-H

-H

-H

-H

-H

-H

-H

-H

_H

- 129 - 2850898 ο """""λ
co ₂ z Y Z OH -CHCH ₃ N / A OH
■ -CH-0 K OH
I.
-CH-C-.H.OCH-
6 4 3 N / A OH
I.
-CH-II-C ₃ H ₇ N / A OH
1
-CH-CF ₃ N / A -CH ₂ OH N / A O
Il
-C-CH ₃ N / A O
If Il
-C-0 N / A -SCH ₃ K OH
I.
-CHCH ₃ N / A

030027/0 7 77

• "■ ·

M / 20 359 - 130 -

SY-1599A

OH
-CH-0 K

Ο
" ^C ~ ^CH 3 ^Na

- OH
JZJ -CH-CH ₃ Na

OH
-CH-CH ₃ Na

OH
CH ₂ Op5 -CH-p K

OH
I.
GH ₂ Op -Ql (CH) ₂ K

030027/0777

■ i j

I * · « t

.- • ι- »« ι.

M / 20 359 SY-1599A

- 131 -

B is ρ ie 1 24 2- (4'-Phthaiimidu-1 "-butyl) periem-3-carboric acid

TEA-H S

A methylene chloride solution (75 ml) of the compound is added dropwise to a solution of triethylamine hydrosulfide, which had previously been prepared by bubbling H ₂ S-GaS through a methylene chloride solution (200 ml) of triethylamine (8.8 ml, 63.7 inHol) 1 (Gabriel Ber. A \ _, 2010) (10.65 g, 40.2 mmol) at 0 ⁰ C over 30 minutes. The mixture is stirred for 15 minutes at 0 ^° C. and for 2 hours at room temperature. The organic solution is diluted with methylene chloride (125 ml) and washed with IN HCl (2 × 15 ml), water (2 × 15 ml) and brine. It is dried over MgSO ₄ and the solvent is distilled off, 10.5 g (100 %) of compound 2 being obtained as a white solid with a melting point of 93 to 94.degree.

NMR (CDCl ₃ ) S :

7.5-8 (4H, m), 4.47 (IH, broad s), 3.5-3.9 (2H, m), 2.5-2.9 (2H, m), 1.4-1.9 (4H, m).

030027/0777

H / 20 359 SY-1599A

Analysis for

DAc

.NH

- 132 -

NaHCO.

59 C. 4th H N 12th S. ber .: 58 , 29 4th , 97 5.32 12th , 17th found: , 92 , 91 5.42 , 31

A suspension of compound 2 (3.04 g, 11.6 mmol) in a Solution of 1M sodium bicarbonate (11.6 ml) is stirred at room temperature for 15 minutes under nitrogen. One gives compound 3 (1.5 g, 11.6 mmol) and the mixture obtained is stirred for 1.5 hours those at room temperature. The reaction mixture is diluted with water and extracted with methylene chloride. The organic Phase is dried and evaporated in vacuo, 3.82 g of solid 4 having a melting point of 95 to 96 ° C. being obtained.

IR (CHCl ₃ ) 1775, 1710 cm " ^1. _Β . ^ ^ ₇ _ __

NMRi: 7.8 (4H, d, J = 2Hz), 7.05 (IH, broad s), 5.25 (1H, dd, J,.,. = 5Hz, J _{+ v} ,, ", = 3Hz), 3.5-3.0 (2H, m), 1.5-2.0 (4H, m)

Q3QQ27 / G777

Μ / 20 359 SY-1599A

Analyzes for C ₁₆ H _1e

calc .: 57.62

found: 57.43

- 133 -

4.85 4.82

8.43 8.44

9.64 9.71

CH-CO CH

A benzene solution (30 ml) of compound (3.0 g, 9.04 and p-nitrobenzyl glyoxalate (2.22 g, 9.8 mmol) is placed under a Dean-Stark condenser device filled with 3A molecular sieve, 21 Held at reflux for hours, evaporation of the solvent gives 5.4 g of compound 5 in the form of an oil (100 %).

IR (clear) 3200-3600, 1770, 1710, 1525 cm " ¹ .

NMR (CDCl ₃ ) c5:

8.21 (2H, d, J = 9Hz, 7.75 (4H, d, J = 2Hz), 7.52 (2H, d, J = 9Hz) 5.52 (1H, broad s), 5.32 (3H, 2s 4.55 (1H, broad s), 3.5-3.7 (2H, m), 3 .45 (1H,

^dd · ^J gem ^{= 15Hz} ' ^J cis ^{= 5Hz)} » ³ » ^{02 (1H} » ^dd · ^J gem ⁼ 15Hz, J _trans = 3Hz), 2.4-2.9 (2H, m), 1.4-2 , 0

(4H, m).

Ö30Q27 / 0777

M / 20 359 SY-1599A

t

• ·

SOCl.

ΌΗ

Azetidinone glyoxalate 5 (4.9 g, 9.05 nmol) is treated at ⁰ ° C. with thionyl chloride (15 ml) for 0.5 hours and 1 hour at room temperature. The excess of the thionyl chloride is distilled off together with benzene in vacuo, compound 6 being obtained in the form of a yellow syrup (5.0 g, 100 %).

NMR (CDCl ₃ )

8.2 (2H, d, J = 9Hz), 7.72 (4H, broad s), 7.60 (2H, d, J = QHz), 6.1 (1H, broad s), 5.50- 5.85 (1H, m), 5.32 (2H, 2s), 3.4-4.0 (2H, m), 3.1-3.3 (1H, m), 2.8-3, 05 (1H, m), 2.50 to 2.85 (2H _t m), 1.5-1.9 (4H, m).

'N.

A solution of compound 6 (21.6 g, 38.8 mmol) in tetrahydrofuran (85 ml, distilled over LAH) is treated with triphenylphosphine (10.2 g, 38.8 mmol) and 2,6-lutidine (5.0 ml, 42.9 mmol) ^{treated at 40 0} C hours. The mixture is diluted with benzene-ether 1: 1 (30 ml), washed with water, 1N HCl, saturated

030027/0777

M / 20 359 SY-1599A

- 135 -

2850838

NaHCO ₃₈ saline and dry over MgSO ₄ . Evaporation of the solvent gives a dark brown oil. One gives e? over a silica gel column (700 g) (benzene ether), 16.0 g (53 %) of compound 7 being obtained in the form of a thick oil.

NMR (CDCl ₃ ) (T:

8.2 (2H, d, J = 9Hz), 7.8 (8H, d, J = 2Hz), 7.52 (16H, broad s), 5.2 (1H _S broad s), 4.78 ( IH, 2s 4.30-4.52 {1H, m), 3.5-3.8 (2H, m), 2.8-3.5 (2H, m), 2.1-2.9 ( 4H, m), 1.5-1 _ä 9 (4H, m).

A solution of phosphorane 7 (5.0 g, 6.4 mmol) in toluene (35 ml) is refluxed for 3 hours. Evaporation of the solvent gives a residue, which over a silica gel column (100 g) is given. Eluting with benzene followed by ether gives 600 mg of ester 8 as an oil.

IR (clear) 1790, 1710, 1520 cm

-1

τ ο / ν

D OO lOU

A _v J = QUz) ₁ 7 ^ 82 (4H ₁ ά. J = 2Hz). 7.65 (2Η, d, J = 9Hz), 5.69 (1H, dd, J _cis = 4Hz, J _trans = 2Hz), 5.35 (2H, 2s), 4.12 (IH, dd,

^J gem ^{= t6Hz} » ^J cis ^{= 4Hz)} > ^{3 '50 (fH} ' ^dd > ^J gem ^{= ieHz} » ', 3.1-3.8 (2H, m), 2.5-3.0 (2H, m ),

1.4-2.0 (4H, m).

030027/0777

• · C

M / 20 359 SY-1599A

- 136 -

A two-phase mixture of ester 8 (196 mg, 0.39 mmol) in ether (2 ml), tetrahydrofuran (4 ml) and sodium bicarbonate (32 mg, 0.39 mmol) in water (2 ml) is mixed on a Parr shaker 30 % palladium on diatomaceous earth (190 mg) hydrogenated _{at 2.76 bar (40 psi) H 2.} After 4.5 hours, a celite bed is filtered usable and the bed is washed with water and tetrahydrofuran. The filtrate and the washing liquid are combined and the organic phase is separated off. The aqueous solution is washed with ether, washed with 1N hydrochloric acid (3 × 0.4 ml) and extracted with ethyl acetate (4 × 2 ml) (after each part of the acid has been added). The organic extracts are washed with brine, dried over MgSQi and the solvent is removed by evaporation to give 67 mg of acid 9 (47 %) as a yellow solid.

IR (Nujol) 1775, 1705, 1690 cm

" ¹

NMR (DMSO) (T:

7.92 (4H, s), 5.71 (1H, dd, J _cis = 4Hz, J _trans = 2Hz 3.90 (1H, dd, J _gem = 16Hz, J _cis = 4Hz), 3.47 (1H ,

^dd ' ^J gem ^{= 16Hz} ' ^J trans ^{= 2Hz)} ' ³ ' ³ " ⁴ » ³ 2.7-3.05 2H, m), 1.5-2.0 (4H, m).

03GÖ27 / Q777

IO

M / 20 359 SY-1599A

- 137 -

28SQ898

B is ρ ie T 25

Sodium 2- (acetony-methyl oxime) periem-3-carboxy1ate

N-

CO PNB

CO PNB

Ketal 1 (2.0 g, 4.54 mHol) is treated at ⁰ ° C. with 95 % TFA (20 ecm) for 15 minutes. The mixture is diluted with saline solution and extracted with methylene chloride (4 × 30 ecm). The methylene chloride extracts are washed with water-sodium chloride solution (3 times) and with sodium chloride solution and _{dried over MgSO 4} (1.44 g ₅ 80 %).

NMR <T (ppm, CDCIo):

8.27 (2H, d, J = 9, Hm aromatic), 8.60 (2H, d, .1 = 9, Ho aromatic). 5.70-5.25 (m,

CH ₂ -PNB, HCO, H-4, _H ^ C = C _{S () H} ), 4.75 (IH, bs, OH), 3.76 (middle of ABq, CHo-CO), 3.47 ( Part of a dd, J _{3-4 cis} = 5, H-3), 3.05 (2H ₁ 2dd, J _gem = 15, 0 _{3. 4} " _rans = 3, H-3), 2.30, 2 , £ 2 (1.67H, 2s, CH ₃ ), 1.98 (1.33H, s, CH ₃ ).

030027/0777

^{M / 20 359} " ¹³⁸ '

SY-1599A

IR v ⁾ _{c = o} (CHCI ₃ ) 1780, 1755, v> _NQ 1525.

COCH ₂ CCH ₃ ^ ^ "- '2' 3

SCOCH ^ -C-CU.

CO PNB

A methylene chloride solution gives (50 CCNO to ketone 2 (1.44 g, 3.63 mmol) is treated at 0 ⁰ C under a nitrogen atmosphere with methoxylamine hydrochloride (334mg, 1.1 eq).

Triethylamine (367 mg, O ₃ SI ecm, 1 eq) is then added dropwise to the mixture. The mixture is then stirred for 18 hours at room temperature. The reaction mixture is diluted with methylene chloride, washed with sodium chloride solution (twice) and with sodium chloride solution and _{dried over MgSO 4} (1.52 g, 98%).

, _CDCl3): 8.12 (2H, d, J = 8, Hm aromatic), 8.40 (2H d _s -J ^ 8, Ho aromatic) _ä 5.50 to 5.05 (4H m _{s 5} CH ₂ -PNB ₉ H-4, HCO), 3.80-3.60 (m, OCH ₃ , part of H-3 cis, part of OH), 3.55-2.70 (m, part of H- 3 cis, H-3 trans, CH ₂ CO, part of OH), 1.97, 1.90, 1.88 (3H, 3s, CH ₃ ).

(CHCl ₃ ) 1770, 1750, 1690.

030027/0777

· 9

.- # - # —- ι

M / 20 359 SY-1599A

- 139 -

HIGH.

SCOCH

.4-CH.

SOCI2

OH

P * yridine

_ ^ SCOCH -C-CH.

N. "Cl

CO PNB

A cold (-15 ⁰ C) THF solution (20 ecm, distilled over LAH) of the azetidinone 3 (1.52 g, 3.57 mmol) is added dropwise with pyridine (325 mg, 0.332 ecm, 4.10 mmol, 1 , 15 eq) and treated with thionyl chloride (488 mg, 0.299 ecm, 4.10 mmol, 1.15 eq) under a nitrogen atmosphere. The mixture is stirred at -15 ° C. for 15 minutes. The solid is filtered off and washed with benzene. The solution obtained is evaporated. The residue is taken up in benzene and treated with activated charcoal (1.2 g, 76 %).

NMRi (ppm, CDCl ₃ ): 8.23 (2H, d, Hm aromatic), 7.80 (2H, d,

Ho aromatic), 6.12, 6.08 (1H, 2s, HC-Cl 5.75-5.55 (1H, m, H-4), 5.40, 5.30 (2H, 2s CH ₂ - PNB), 3.95-3.80 (3H, 3s, OCH ₃ ), 3.80-2.95 (4H, m, 2H-3, CH ₂ -CO), 2.00-1.85 (3H , 4s, CH ₃ ).

IRP _{C = O} (CHCl ₃ ) 1790, 1765 (shoulder), 1700, J _m 1530.

STILL.

B ³
SCOCH ..- C-CH,

r '

"V ^C1

.scoai.-c-CH.

CO PNB

030027/0777

Μ / 20 359 SY-1599A

- 140 -

A THF solution (20 ecm, distilled over LAH) of chloroacetidine 4 (1.2 g, 2.70 ml. Mol) is treated with triphenylphosphine (1.06 g, 4.05 ml. Oil, 1.5 kg.) And 2.6 -Lutidine (318 mg, 0.346 ecm, 2.97 mmol, 1.1 eq). The mixture is stirred for 4 days at room temperature under a nitrogen atmosphere. Then it is diluted with ethyl acetate, washed with 2 SS aqueous HCl, H ₂ O, 2 # aqueous NaHCO ₃ , water and sodium chloride solution. The solution is then _{dried over MgSO 4} and the solvent is evaporated. Crude compound 5 is purified on a silica gel column (10 times the weight) (ethyl acetate). 770 mg of product (45 %) are obtained.

IRt? _{c = 0} (CHCl ₃ ) 1755, 1695, ^ 1630-1610, v> _NQ 1525.

N- ^ OCH.

.SCOCH ₂ -C-CH ₃

TolucV "

CO ₂ PNB

N-OCI.

Ii CH ₂ -C-CH ₃

Phosphoran 5 (700 mg, 1.05 mmol) is refluxed in toluene for 4.5 hours. Evaporation of the toluene gives a residue which is passed through a silica gel column (1:15 ratio (4 % ether-benzene). Compound 6 is obtained in the form of a crystalline material (251 mg, yield 62 %) with melting point 116-125 ° C.

analysis for • ^C 1 7 ^H. 17 ^N. 3 ° 6 S: 1 0 N •
• C. H 1 0 .74 ber. 52 ,1 7th 4th , 38 , 33 found 51 ,1 5 4th .18

030027/0777

M / 20 359 SY-1599A

- 141 -

NMR cf (ppm, CDCl ₃ ); 7.70 (2H, d, Hm aromatic), 7.12 (2H, d,

Ho aromatic), 5.00 (2H, s, CH ₂ PNB),. 4.85 (1H, m, H-5), 3.75 - 2.70 (7H, m, CH ₃ O, CH ₂ , H-6), 1.77, 1.72, 1.65 (3H, S, CH ₃ ).

IR y> _{c = 0} (CHCI ₃ ) 1787, 1742, 1705,

1530.

UV (EtOH) ^ l _mav 318 fe = 8420), 262 (£ = 12 539).

UlO. Λ

A mixture of the ester 6 (151 mg. 0.386 mmol) in THF (20 ecm) ether (40 ecm) and NaHCO ₃ (32 mg, 0.381 mmol) in water (20 ccn is 3 hours at a pressure of 2.41 bar ( 35 psi) H ₂ using 30 % Pd on CeIite (200 mg) as catalyst. The catalyst is filtered off and washed with water and ether. The aqueous mixture obtained is washed with ether (3 × 60 ecm) and lyophilized ( 32 mg, 30 %) ♦

NMR & (ppm, DMSO): 5.50 (m, H-5), 3.75 (s, OCH ₃ ), 0.77 (s, CH ₃ IRv? ₌ (Nujol mull) 1770, 1600, 1400 UV (H ₉ O) λ _av 300 (£ = 2800), 255 (e = 2400). * In a Parr hydrogenator

030027/0777

Μ / 20 359 SY-1599A

- 142 -

B e i s ρ i e T

The following 2-penem compounds can be prepared by acylation of 1 - (p-nitrobenzyloxycarbonylmethyl triphenylphosphoranyl) -4- (silver mercaptidyl) -2-azetidinone with the appropriate acylating agent, followed by cyclization and deblocking steps, getting produced. The general reaction scheme is shown below:

^ SAg 1. 0 0
II Il
RC-0-CO-iBu ^^ SCOR I. CO ₂ PNB j? —— "v ^ ^ P0 or CO ₂ PNB 2. RCOCl Q

CO ₂ PNB

H_ / 30% Pd / Siatomaceous earth

Variation 1: RCO ₂ H + iBuCOCl is used. Variation 2: HCl + PCl ₅ + RCO ₂ H is used

03QG27 / 0777

H / 20 359 SY-I599A

Acylating agents

OCH ₂ OCONH- (CH ₂ ) ₄ -CO ₂ H

- 143 -

Method product

CH ₂ CH ₂ SCH ₃ 0CH ₂ OCONh-CH-CO ₂ H (η and L)

₂₄

0CH ₂ OCONh-CH-CO ₂ H (D and L)

2- (4-aminobutyl) penem-3-carboxylic acid

CH ₃
0CH ₂ OCONH-Ch-CO ₂ H CH ₃
CH-CH ₃ CH ₂ CO ₂ CH ₂ ^ -NO ₂ -P CH ₂ CONH ₂ 1 2- (1-aminoethy1) penem-3- - (D and L) 0CH ₂ OCONh-CH-CO ₂ H 0CH ₂ OCONh-CH-CO ₂ H 0CH ₂ OCONh-CH-CO ₂ H carboxylic acid 2- (1-amino-2-methylpro- 0CH ₂ OCONH-CH-Co ₂ H (D and L) (D and L) (D and L) 1 2- (1-aminopropyl) penem-3 pyl) penem-3-carboxylic acid (D and L) 0CH ₂ OCONh-CH-CO ₂ H carboxylic acid 2- (1-aminobenzyl) penem-3 (D and L) carboxylic acid CH ₂ 0
0CH ₂ OCONh-CH-CO ₂ H 1 2- (1-amino-2-phenylethyl (D and L) penem-3-carboxylic acid CH ₂ OCH ₂ 0-NO ₂ -p
0CH ₂ OCONh-CH-CO ₂ H 1 2- (1-amino-2-hydroxy- (D and L) S-J-Ki / T ^ no7iom-3-i ^ airhon <tälJr 1 2- (1-amino-2-carboxy- 1 ethyl> penem-3-carboxylic acid (2- (1-amino-2-carbamoyl- 1 ethyl) penem-3-carbonic acid 1

2- (1-Αππηο-3-methyithio propyl) penem-3-carboxylic acid

2- (1,5-diaminopentyi) penetn-3-carboxylic acid

030027/0777

M / 20 359
SY-1599A - 144 2350898 Acyl ierurigsirn ttel method product CH ₃ 0Ch ₂ OCONCH ₂ CO ₂ H 1 2 - / (methylamino) methyl / - penem-3-carboxylic acid CH ₃ 0CH ₂ OCONCH ₂ CH ₂ Co ₂ H 1 2- / 2- (methyl amino} ethyU penem-3-carbonStIure ? ^H 3 0CH ₂ OCONCH ₂ Ch ₂ CH ₂ CO ₂ H 1 2- / 3- (methylamino) pro-! pyUpenem-3-carboxylic acid ? ^H 3 OCH ₂ OCONCH ₂ CH ₂ CH ₂ Ch ₂ CO ₂ H 1 2- / 4- (methylamino) butyU penem-3-carboxylic acid C ₂ H ₅
0Ch ₉ OCONCH ₉ CO ₉ H 1 2 - / (Ethy1amino) methyU- penem-3-carboxylic acid ? 2 ^H 5
0CH ₂ OCONCH ₂ CH ₂ Co ₂ H 1 2- / 2- (ethylamino) ethy 17- penem-3-carboxylic acid C ₂ H ₅
OCH ₂ OCONCH ₂ CH ₂ CH ₂ Co ₂ H 1 2- / 3- {ethylamine) propyU- penem-3-carboxylic acid OCH ₂ OCONCH ₂ CH ₂ CH ₂ CH ₂ Co ₂ H 1 2- / 4- (ethylamino) buty 17- fl penem-3-carboxylic acid V
0CH ₉ OCONCH ₉ Co ₉ H 1 2 - / (phenylamino) methyl7 * penem-4-carboxylic acid W.
0CH ₉ OCoNCH ₉ CH ₉ CO ₉ H
L * Cm C * t- 1 2- / 2- (phenylamino) ethylJ ρenem-3-carboxylic acid V
OCH ₂ OCONCH ₂ CH ₂ CH ₂ Co ₂ H 1 2- / 3- (Phenyl ami no) pro- • pyl7penem-3-carboxylic acid

030027/0777

• SS · · *

H / 20 359 SY-1599A

Acylating agents

0 0CH ₂ OCONCH ₂ CH ₂ CH ₂ CH ₂ Co ₂ H

ch _q conhch ₂ co ₂ h CH ₃ CGNHCH ₂ CH ₂ Co ₂ H CH ₃ CONHCH ₂ CH ₂ CH ₉ Co ₂ H CH ₃ CONKCH ₂ CH ₂ CH ₂ Ch ₂ CO ₂ H

C _C H _C CONHCH ₉ CO ₉ H ob cc

C ₆ H ₅ CONHCH ₂ CH ₂ CO ₂ H CgH ₅ CONHCH ₂ CH ₂ CH ₂ CO ₂ H

- 145 -

0CH ₂ OCONHCH ₂ CONHCH ₂ Co ₂ H 0CH ₂ OCONHCH ₂ CONHCH ₂ CH ₂ Co ₂ H

method

product

2- / 4- (Phenyl amino) butyl / penem-3-carboxylic acid

2 - / "(Acetylamino) methyl 7-penem-3-carboxylic acid

2- / T2- (acetylamino) ethyl 7 penem-3-carboxylic acid

2- / 3- (Acetyl ami no) propyl / peneni-3-carboxylic acid

2- £ 4-acetylamino) butyl7-penesi-S-carboxylic acid

2 - / "(Benzoyl amino) methy penem-3-carboxylic acid

2- / 2- (benzoylamino) ethyl. penem-3-carboxylic acid

2- / 3- (Benzoylamino) propyl-penem-3-carboxylic acid

2 - / "4- (Benzoyl amino) butyU penem-3-carboxylic acid

2 - / "(Glycinamido) methyl 7-penem-3-carboxylic acid

2- / 2- (glycinamido) ethyl 7 penem-3-carboxylic acid

030027/0777

β r ψ * * * ro

Μ / 20 359
SY-1599A
* - 146 2950898 Acylating agents method product 0CH ₂ OCONHCH ₂ CONHCH ₂ CH ₂ CH ₂ Co ₂ H 1 2- ^ 3- (Glycinamido) pro-
pyl / penem-3-carboic acid 0CH ₂ OCONHCH ₂ CONHCH ₂ CH ₂ Ch ₂ CH ₂ CO ₂ H 1 2-A- (Glycinamido) butyU-
penem-3-carboxylic acid H ₂ NCONHCH ₂ CQ ₂ H 1 2- (Ureidorc2 * hyl) penem-3-
carboxylic acid H ₂ NCONHCH ₂ CH ₂ Co ₂ H 1 2- (2-ureidoethy1) penem-
3-carboxylic acid H ₂ NCONHCh ₂ CH ₂ CH ₂ CO ₂ H 1 2- (3-ureidopropyl) permanent
3-carboxylic acid H ₂ NCONHCH ₂ CH ₂ CH ₂ CH ₂ Co ₂ H 1 2- (4-ureidobutyl) penem-
3-carboxylic acid CH ₃ NHCONHCH ₂ Co ₂ H 1 2 - / "(methylcarbamoyl amino!
methyUpenem-3-carboxylic acid CH ₃ NHCONHCH ₂ CH ₂ Co ₂ H 1 2- ^ 2- (methylcarbamoyl-
amino) methyUpenem-3-
carboxylic acid CH ₃ NHCONHCH ₂ CH ₂ CH ₂ Co ₂ H 1 2- / 3- (methylcarbamoyl ami
no) propyl7peneii-3-carbon
acid λμι now ma un u r> ur * u cn rn u
υΠΛ «Γ! 1-1 / ΙΙΠΟΠΛΐ / Ι1η (/ ΙΐΛΐ / ΙΙΑΙ / υΛΐι 1 2 - / "4-methyl carbamoyl ami
no) buty17penem-3-carbon-
acid

030027/0777

M / 20 359
SY-1599A - 147 - «· * · · ♦ #
• i · # · ·
e <| t ♦ * · «··· · ··
2950898 Acylating agents method product 0NHCONHCH ₂ Co ₂ H 1 2 - / (Phenylcarbamoylami no) -
methyUp6nem-3-carboxylic acid 0NHcONHCH ₂ CH ₂ CO ₂ H 1 2- / 2- (phenylcarbamoyl amino]
äthyUpenem-3 -carbon acid 0NHCONHCH ₂ CH ₂ CH ₂ Co ₂ H 1 2- / 3- (phenyl carbamoyl ami nc]
propyl_7penem-3-carboxylic acid ( OHCONHCH ₂ CH ₂ CH ₂ CH ₂ Co ₂ H 1 2- / 4- (phenyl carbamoyl amino]
butyl_7penem-3-carboxylic acid CH ₃ CONHCONHCh ₂ CO ₂ H 1 2 - / (acetylcarbamoylami no) -
methyl jpenem-3-carboxylic acid CH ₃ CONHCONHCH ₂ CH ₂ Co ₂ H I. 2- / 2- (acetyl carbamoyl amino] -
ethyl / penem-3-carboxylic acid CH ₃ CONHCONHCH ₂ CH ₂ CH ₂ Co ₂ H 1 2- / 3- (acetyl carbamoyl amino] -
propyl ^ penem-3-carboxylic acid " CH ₃ CONHCONHCH ₂ CH ₂ CH ₂ CH ₂ Co H 1 2- / 4- (acetyl carbamoyl ami ncj-
bu ty l_7penem-3 -car bon acid 0CONHCONHCH ₂ Co ₂ H 1 2 - / (Benzoylcarbamoylanino] ■
me thy Upenem-3 carbonic acid 0CONHCONHCH ₂ CH ₂ Co ₂ H 1 2- / 2- (benzoyl carbamoylami
no) ä thy l_7ppne! n-3-carbon
acid 0CONHCONHCh ₂ CH ₂ CH ₂ CO ₂ H 1 2- / 3- (benzoylcarbamoylamino) -
propyl / penem-3-carboxylic acid

- 1 ···· ·· * · * · M / 20 359
SY-1599A Acy'h'erüncjsnnttel method 1 • ·· <α · · ···
·· ■ · β ···
14-8 *** "* ** ··« «··· *» ·
2950898 0CONHCONHCH ₂ CH ₂ CH ₂ CH ₂ Co ₂ H 1 product CH ₃ OCONHCONHCH ₂ Co ₂ H 1 2 - / "4- (Benzoylcarbamoylamino) -
butyl / penem-3-carboxylic acid CH ₃ OCONHCONHCH ₂ CH ₂ Co ₂ H 1 2-ZTCarbomethoxycarbamoyl -
amino) methyl / penem-3-car-
boric acid CH ₃ OCONHCONHCH ₂ CH ₂ CH ₂ Co ₂ H 1 2- / 2- (Carbornethoxycarb-
amoylamino) ethyl7penem-3-
carboxylic acid CH ₃ OCONHCONHCH ₂ CH ₂ CH ₂ Ch ₂ CO ₂ H 1 2- / 3- (carbomethoxycarb-
amoylamino) propyl7penem-3-
carboxylic acid (CH ₃ J ₃ Si (CH ₂ J ₂ OCONHCONHCh ₂ CO ₂ H 1 2- / 4- (carbomethoxycarb
amoyl ami no J butyl_7penem-3-
carboxylic acid (CH ₃ J ₃ Si (CH2) 20C0NHC0NHCH2-
CH ₂ CO ₂ H 1 2 - / (2-trimethylsilylethyl
oxycarbonylcarbamoylami no)
methylUpenem-3-carboxylic acid (CHg) ₃ Si (CHg) ₂ OCONHCONHCH ₂ -
CH ₂ CH ₂ CO ₂ H 2- / 2- (trimethylsilylethyl-
oxycarbonylcarbamoylamino)
ethyl / penem-3-carboxylic acid (CHg) ₃ Si (CH ₂ ) ₂ 0C0NHC0NHCH ₂ -
CH ₂ CH ₂ CH ₂ CO ₂ H 2- / 3- (Trimethylsi IyIäthyl-
oxyearbonylcarbainoyl amino;
propy IJpenem-3-carboxylic acid 2- / 4- (2-trimethylsilylethyl
oxycarbonylcarbamoylamino]
buty17penem-3-carboxylic acid

- 149 * · · · * · * · 0 M / 20 359
SY-1599A method 2950898 Acylating agents 1 product CH ₃ S ₂ CNHCH ₂ CO ₂ H 1 2 - ^ (methylthiothiocarbo-
nylamino) methyl7penem-3-
carboxylic acid CH ₃ S ₂ CNHCH ₂ CH ₂ Co ₂ H 1 2 - / "2- (methylthiothiocarbo
nylamino) ethyl7penem-3-
carboxylic acid CH ₃ S ₂ CNHCH ₂ CH ₂ CH ₂ Co ₂ H 1 2- / 5- (methylthiothiocar-
bonylamino) propyl7penem-
3-carboxylic acid CH ₃ S ₂ CNHCH ₂ CH ₂ CH ₂ CH ₂ Co ₂ H 1 2- / 4- (methylthiothiocar-
bonylamino) butyl_7penem-
3-carboxylic acid CH ₃ SO ₂ NHCH ₂ CO ₂ H 1 2 - / (methanesulfonylamino) -
methyiypenem-S-carboxylic acid " CH ₃ So ₂ NHCK ₂ CH ₂ CO ₂ H 1 2- / 2-methanesulfonyl amino) ■
ethy17penem-3-carboxylic acid CH ₃ SO ₂ NHCH ₂ CH ₂ CH ₂ Co ₂ H 1 2- / 3- (methanesulfonyl amino]
propylJpenem-S-carboxylic acid CH ₃ SO ₂ NHCH ₂ CH ₂ CH ₂ CH ₂ Co ₂ H 1 2- / 4- (methanesulfonyl ami no)
butyl_7penein-: 3 -carbon acid JJSO ₂ NHCH ₂ CO ₂ H 2 - / * (benzene sulfonyl ami no) -
methyl_7penem-3-carboxylic acid

M / 2ü 359 SY-1599A

l_ * .A -

■ ·

- 150 -

I 9tf4 «f

• · β · i

Acyl grounding agent

S.
H ₃ CNHCNHCH ₂ CH ₂ Co ₂ H

Method product

2 - / '2- (N-MethyUhiocarb-

amoylamino) ethyUpenem-3-carboxylic acid

H ₃ CNHCNHCH ₂ CH ₂ CH ₂ Co ₂ H

S.
H ₃ CNHC ¹ NHCH ₂ CH ₂ CH ₂ CH ₂ Co ₂ H 2- / 3- (N-methylthiocarb-

amoylamino) propy17penem-3

carboxylic acid

2- / 4- (N-methylthiocarb-

amoylamino) buty1Jpenem-3-

carboxylic acid

(3NHCNHCH ₂ CO ₂ H

2 - / (N-henylthiocarbamoyl amino) methyl 17penem-3-carboxylic acid

JJNHCNHCH ₂ CH ₂ Co ₂ H

2 - / "2- (N-Pheny1thiocarbamoy! Amino) ethy / penem-3-carboxylic acid

0NHCNHCH ₂ CH ₂ Ch ₂ CO ₂ H 2- / 3- (N-phenylthiocarb-

amoy1amino) propyl / penein-3-

carboxylic acid

JJNHCNHCH ₂ CH ₂ CH ₂ Ck ₂ CO ₂ H

η rj - NHCH_CO ₂ H

HO

II "

2- / 4- (N-Phenylthiocarbamoyl ami no) butyl _7p <? Nem-3-carboxylic acid

2- / Ϊ Guanyl ami no) methy17-penem-3-carboxylic acid

N Π "

2- / 2- (Guanyl ami no) ethy 17 ■ penem-3-carboxylic acid

»· Β β · 4

- 151 • · · · * * · ■■ · H / 20 359
SY-1599A method 2950898 Acylating agents i product 1 2- / 3- (guanyl amino) propyl7-
penem-3-carboxylic acid Jf M ^ aI ₂ CII ₂ CiI ₂ CO ₂ II
HO 1 2- / 4- (guanyl amino) buty 17-
penem-3-carboxylic acid
2 - / "(acetimidoylamino) -
methyl7peflem-3-carboxylic acid Jj _N 2 2 ^ 22
HO ^υ
^ ■ 0> ^ O
Jl N-CH-CO-H
H ₃ C 1 2- / 2- (acetimidoylamino) -
ethyl-7penem-3-carboxylic acid -CH ₂ CH ₂ CO ₂ H H 1. 2- / 3- (acetimidoylamino) -
propyl7penem-3-carboxylic acid - -CH ₂ CH ₂ CH ₂ CO ₂ H 1 2- / 4- (acetimidoylamino) -
butyl7penem-3-carboxylic acid ■ -CH ₂ CH ₂ CH ₂ CH ₂ CO ₂ 1 2r / (Formimidoylainino) -
methyl7penem-3-carboxylic acid 2 2 1 2- / 2- (formimidoylamino) -
ethyl-7penem-3-carboxylic acid * 2- / 3- (formimidoylamino) -
propy \ J penem-3-carboxylic acid -CH ₀ CH ₀ CH ₀ CO ₀ H 2- / 4- {Forirnnn doy 1 ami no) -
butyl7penem-3-carboxylic acid ⁹ -CK_CK_CH_CK_CO_H

030027/07 77

ces »* ·

H / 20 359
SY-1599A - 152 1 • 9 »9 · * · * · €
• · · · · · «· · ·
2950898 and unblocked with F ". Acylating agent method product O ₂ NCH ₂ CO ₂ H 1 2 - / (hydroxyamino) methyl7- penera-3-carboxylic acid O ₂ NCH ₂ CH ₂ CO ₂ H 1 2- ^ 2- (HydroxyaminoJäthyy penem-3-carbon acid: O ₂ NCH ₂ CH ₂ CH ₂ CH ₂ CO ₂ H 2-CA- (Hydroxyamine Jbuty 17 *1 penem-3-carboxylic acid OCHg (CHg) ₃ Si (CH _{2) 2} 0C0N-CH ₂ C0 ₂ H *1 2 - / "(methoxyamino) methyl7- penem-3-carboxylic acid OCHg
(CHg) ₃ Si (CH ^) ₂ OCON-CH ₂ Ch ₂ CO ₂ H 2- / 2- (methoxyamino) ethyl7 * penem-3-carboxylic acid OCHg (CHg) ₃ Si (CH ₂ J ₂ OCONCH ₂ CH ₂ Ch ₂ CO ₂ H *1 2- / 3- (methoxyamino) propylJ penem-3-carboxylic acid OCHg
(CHg) ₃ Si (CH ₂ J ₂ OCONCH ₂ CH ₂ CH ₂ CH ₂ CO ₂ H * 2 2- / 4- (Methoxyami no Jbuty17- penem-3-carboxylic acid NH ₂
(CHg) ₃ Si (CH ₂ J ₂ OCONCH ₂ CO ₂ H * 2 2-Z "(hydrazine ο J methyl7- penem-3-carboxylic acid NH ₂
(CHg) ₃ Si (CH ₂ J ₂ OCONCH ₂ CH ₂ Co ₂ H * 2 2- / 2- (hydrazino ethyl 7- penfem-3-carboxylic acid NH _?
(CHg) gS i (CH ₂ J ₂ 0C0NCH ₂ CH ₂ CH ₂ C0 ₂ H 2- / 3- (hydrazino) propyl7- penem-3-carboxylic acid * Use in place of azetidinone intermediate from PNB trimethylsilylethyl

030027/0777

- 153 * 2 g ta τ * ■ * * * *
11 «· · * ^e * * M / 20 359
SY-1599A Acylating agent method 2950898 NH,
I L- product (CH ₃ J ₃ Si (CH ₂ J ₂ OCONCH ₂ CH ₂ CH ₂ CH ₂ CO ₂ H * 2 2 - / ^ - (hydrazino) butyl7- N (CH ₃ J ₂ penem-3-carboxylic acid (CH ₃ J ₃ Si (CH ₂ J ₂ OCONCH ₂ Co ₂ H * 2 2 - / (2,2-dimethyl hydrazine N (CH ₃ J ₂ methyl7penem-3-carboxylic acid (CH ₃ J ₃ Si (CH ₂ J ₂ OCONCH ₂ Ch ₂ CO ₂ H * 2 2- / 2- (2,2-dimethylhydra- zino) ethyl 7penem-3-car N (CH ₃ J ₂ boric acid _(CH3 J ₃ Si (CH _{2) 2} 0C0NCM ₂ CH ₂ CH ₂ C0 ₂ H * 2 2- / 3- (2,2-dimethylhydra- zino) propy17penem-3-car N (CH ₃ J ₂ boric acid (CH ₃ J ₃ Si (CH ^) ₂ OCONCH ₂ CH ₂ CH ₂ CH ₉ CO ₂ H * 2 2- / 4- (2,2-dimethylhydra- * 2 zino) butyl7penem-3-car- CH ₃ CONHNHCH ₂ Co ₂ H boric acid * 2 2 - / (2-acetylhydrazino) - CH ₃ CONHNHCH ₂ CH ₂ Co ₂ H methyl7penem-3-carbon acid * Z 2- / 2- (2-acetylhydrazino) - CH ₃ CONHNHCH ₂ CH ₂ CH ₂ Co ₂ H St hy! ./ penem-3-carbon acid 2 2- / 3- (2-acetylhydrazine) - CH ₃ CONHNHCH ₂ CH ₂ CH ₂ Ch ₂ CO ₂ H propy 17penem-3-carboxylic acid Z- / 4- (z-acetylhydrazino) - (CHg) ₂ NCH ₂ CO ₂ H buty 17penem-3-carboxylic acid 2 - / (dimethylamino) methyl7 penem-3-carboxylic acid

030027/0777

W ι -

M / 20 359 SY-1599A

- 154 -

Acylating agent

method

product

(CH ₃ J ₂ NCH ₂ CH ₂ CO ₂ H 2- / 2- (Dimethy1 ami no) ethy17-ρenem-3-carboxylic acid

2- / 3- (dimethyl amino) propyl. penem-3-carboxylic acid

CH ₃ CH ₃ CONCH ₂ CO ₂ H

CH ₃ CH ₃ CONCH ₂ CH ₂ Co ₂ H

CH ₃ CH ₃ CONCH ₂ CH ₂ CH ₂ Co ₂ H

CH ₃ CH ₃ CONCh ₂ CH ₂ CH ₂ CH ₂ CO ₂ H

I-CH CO H 2

[-CH CH CO H 2 2

1.

2- / 4- (dimethyl amino) buty 17 ■ ρenem-3-carboxylic acid

2 - / (N-Methylacetamido) -methyUpenem-3-carboxylic acid

2- / 2- (N-Methylacetamido) -äthyUperiem-3-carboxylic acid

2- / 3- (N-methyl acetamido) -propyUpenem-3-carboxylic acid

2- / 4- (N-methylacetamide) -butyUpenem-3-car bon acid

2 - / (phthalimido) methyl7 ~ penem-3-carboxylic acid

2- / 2- (Phthalimido) ethyypenem-3-carboxylic acid

2- / 3- (Phthalimido) propyl7-pe: <em-3-carboxylic acid

2- / 4- (Phthalimidü) butyl / -penem-3-carboxylic acid

030027/0777

M / 20 359
SY-1599A

Acy deepening agent

0CH ₂ OCONHCH ₂ CH ₂ OCH ₂ Co ₂ H

0CH ₂ OCONHCH ₂ CH ₂ SCH ₂ Co ₂ H

₂₂ 0CH ₂ OCONHCH ₂ CH ₂ NCH ₂ Co ₂ H

CH ₃ -0CH ₂ OCONHCH ₂ CH ₂ NCH ₂ Co ₂ H

0CH ₂ OCONH

0CH ₂ OCONH

CO ₂ H

0CH ₂ OCONH

CO ₂ H

0CH ₂ OCONH

0CH ₂ OCONHCH ₂ - // y-COjH - 155 -

Method product

2-f (2-aminoethoxy) methyl 7

penem-3-carbonic acid

2 - / "(2-annnoethylthio) -

methyl7penem-3-carboxylic acid

2- / ~ (2-Aminoethylanrino) -me thy 17penem-3-carboxylic acid

2- / N- (2-aminoethyl) -N-methylamineq7methylpenem-3 carboxylic acid

2- (p-Aminobenzy1) penem-3-carboxylic acid

ΐ 2- (o-aminobenzyl) penem-3-carboxylic acid

1 x 2- (p-aminophenyl) penem-3-carboxylic acid

1 '2- (m-aminophenyl) penem-3-carboxylic acid

2- (o-aminophenyl) penem-3- carhonic acid

2- / p- (aminomethyl) phenyV penem-3-carboxylic acid

030027 / & 777

M / 20 359
SY-1599A

Acylating agents

0CH ₂ OCONHCH ₂

CO

0CH OCONHCH

- 156 -

method

product

2- / m- (aminomethyl) phenyU penem-3-carboxylic acid

2- / o- (aminomethyl) phenyV penem-3-carboxylic acid

example

27

The 2-penem products listed below in the form of the triethylamine salts are treated with (CH _{3 I 3} N-SO ₃ in CH ₂ Cl ₂ solution at ⁰ ° C. Addition of sodium 2-ethylhexanoate in 1-butanol to the reaction solution leads to precipitation of the specified products in the form of the disodium salts.

Source material

-N / Γ ^^

product

^ - (CH ₂ ) _n -NHS0 ₃ Na

Ex. A. η = 1 Ex. B. η = 2 Ex. C. η = 3 Ex. D. η = 4

A. B. C.

π η η

D. η =

3 4

030 027/07 77

Μ / 20 359
SY-1599A

- 157 -

B e i s ρ i e T 28

The following 2-penem products can be made from the specified Starting materials prepared by the following procedure will:

₂ ) ₂ Ν (CH ₃ ) ₃ Ι

H ₂ / Pd

Aüsgarigsniaterial

product

CO ₂ PNB

θ (CH ₂ J _n N (CH ₃ )

Example * A

Example B

Ex. C

Ex. D

η =

η =

π =

η =

A. η = 1 B. η = 2 C. η = 3 D. η = 4

030 0 2 7/077 7

1 a II i *

M / 20 359
SY-1599A

- 158 -

29508S8

At s ρ i e 1 29

The following 2-penem products can be made from the specified Starting materials can be produced by the following process:

SAg

+ Cl (CH ₂ ) _n COCl

SCO (CH.,) Cl

CO ₂ PNB

CO ₂ PNB

(CH ₂ J _n Cl

CO ₂ PNB

Unblock

CO ₂ PNB

Unblock

(CH ₂ J _n -N / \

030027 / & 777

M / 20 359 SY-1599A

Starting material

product

S. ₂ PNB ) _n C] CO η = 1 Ex. A. η = 2 Ex. B. η = 3 Ex. C. η = 4th Ex. D.

A. η = 1 ε. η = 2 C. η = 3 D. η = 4

030027/0777

M / 20 359 SY-1599A

example

The following 2-penem products can be used according to the following Process prepared from the specified starting materials will:

Il

SC-

-N

eo ₂ z

Η, ΝΒ

O I

TFA

2 m

N II -C-R

OH

CO ₂ Z

OH

SOCl

2 ^

NB Il
SC- (CH ₂ ) -CR

CO ₂ Z

030027/0777

2. Δ

M / 20 35S SY-1599A

OH

m = 0-2 R = E, CH

Source material iäl

) 2Si (CH ₃ ) 3
-O (CH ₂ I ₂ Si (CH ₃ )

product

-C-R

• N

V * iL /

OH I

V N

^N Il

(CH-) _- C-R

2'm

Ex. A Ex. B Ex. C Ex. D Ex. E Ex. F

CO ₂ PNB

R = H, m = R = H, m = R = H, m = R = CH ₃ , m = R = CH-, nr = R ■ CH ₃ , m =

A. R

B. R

C. R
-D. R.

E.
F.

R.
R.

CO ₂ K

H, m = 0 H, m = 1 H, m = 2 CH ₃ , m = 0 CH ₃ , m = 1 CH ₃ , m = 2.

030027/0777

M / 20 359 SY-1599A

2350898

_{If the H 2} NO (CH ₂ J ₂ Si (CH ₃ ) ₃ used in the above expiry is replaced by H _{2 NOCH 3} , the following products are obtained:

STILL, ti (CH ₂ ) _m -CR

Ex. A
Example B
Example c
Example = D
Ex. E
Ex. F

m m m

m m

0, R

1, R

2, R Q, - R

1, R

2, R

■ H = H = H = GH. = CH. = CH.

_{If the H 2} NO (CH ₂ J ₂ Si (CH ₃ ) 3 used in the above process is replaced by (CH ₃ J ₃ Si (CH ₂ J ₂ OCONHNH ₂₎ , the following products are obtained:

030027/0 7

Μ / 20 359 SY-1599A

- 163 -

• «· 4

295089a

NNH-It 2

A. CO ₂ H R = H Ex. B. m: = 0, R = H Example. C. in i = 1, R = H Ex. D. m: = 2, R = CH Example ε m · ■ = 0, R = CH Ex. F. VX ■ " 1, R = CH Ex. m: = 2,

_{If the H 2} NO (CH ₂ J ₂ Si (CH ₃ ) ₃ <the following products are used in the above process:

ι (CH ₂ J ₂ Si (CH ₃ ) ₃ by (CH ₃ J ₂ NNH ₂₎ so one obtains the

I.
N ^ 7th Or R = H O Co ₂ 1, R - H A. m => 2, R = H B. m » Or R = CK ₃ C. -m = Ir R = CH ₃ Ex. D. j «= 2, R = «CH, Ex. E. πι = Ex. F. m = » Ex. - (CB Ex. a Example,

030027/0777

M / 20 359 SY-1599A

- 164 -

Replace the one used in the above procedure

0 H ₂ NO (CH ₂ ) ₂ Si (CH ₃ ) ₃ through (CH ₃ ) ₃ Si (CH ₂ ) ₂ OCON-NH ₂ so one obtains the following products:

Ex. A Ex. B Ex. C Ex. D Ex. E Ex. F

NNH0 C

m m m m m m

9, R 1 / R 2, R

0, R

1, R

2, R

CH,

CH.

GH »

030027/0777

M / 20 359
SY-1599A

• · i

Example 31

r ι-

<3Ag

Φ.

CO-PNB

+ ClCOCH CH Cl

II

, Cl

-N

CO PNB

III

A solution of compound I (1.1 g, 1.6 mmol) and compound II (0.16 ml, 1.6 mmol} in methylene chloride (30 ml) is cooled in an ice bath and treat them dropwise with a 1M solution of pyridine in methylene chloride (1.7 ml, 1.7 mmol). The resulting reaction mixture is stirred for 1 hour at room temperature, then filtered through Celite and washed with methylene chloride. The filtrate and wash liquids are combined and washed successively with 1N HCl (5ml), water (5ml), 1M NaHCO (5ml) and brine, then dried (MgSO-) and concentrated in vacuo to give 900 mg (87%) Compound III is obtained in the form of an amorphous solid. The compound is used in the next step without further purification used.

IR (CHCl ₃ ) 1755, 1690 cm

-1

030027/0777

- # # - <· »fr - ·

M / 20 359 ■ SY-1599A

- 166 -

2950598

NMR (CDCl ₃ ) δ 8.22 (2H ₇ d, J = 9 Hz), 7.55 (15H, m), 6.72 (2H, d, J = 9 Hz), 5.7 (1H, m ), 5.0 (2H, 2s), 3.55 (2H, 2s), 2.8 (4H, m).

h "ci

CO PNB

III

IV

A mixture of compound III (1.3 g, 2 mmol) and compound IV (0.65 ml, 3 nölol} heated to 4 hrs. At 80 ⁰ C. Dilute the reaction mixture with 10 ml methylene chloride and washed with 2 χ 5 The organic layer is dried (MgSO ₄ ) and concentrated in vacuo to give 1.4 g (90%) of compound V as an amorphous solid, which is used in the next step without further purification.

IR (CHCl ₃ ) 1755, 1690 cm " ¹ .

NMR (CDCl ₃ ) 6: 8.25 (2H, d, J = 9 Hz), 7.55 (15H, m), 6.8 (2H, d, J = 9 Hz), 5.7 (1H, m), 5.1 (2H, 2s), 4.72 (2H, dq J = 12 Hz, J = 6 Hz), 2 _r 6 (4H, m) , 1.4 (6H, s) , 1, 28 (6H, s).

0 300 27/07 77

M / 20 359 SY-I599A

^ ^s

- 167 -

• • ■ mmm • * ■ · · •

O ^ - ^N \ ^? Φ

V ^s

-N

CO PNB

VI

A solution of compound V (1.6 g, 2.06 mmol) in toluene (60 ml was heated for 5 hours at reflux.

The solvent is evaporated in vacuo and the remaining residual oil is eluted on a silica gel column (30 g). Eluting with benzene and then with ether removed first niehu-pölares material, further Eiuieren with ethyl acetate then gave compound VI, 620 mg (62%} as a white solid, mp = 83-84 ⁰ C from ether.

IR (CHCl ₃ ) 1790, 1710 cm " ¹ .

NMR: (CDCl ₃ ) δ 8.2 (2H, d, J = 9 Hz), 7.6 (2H, d, J = 9 Hz), 7.5

(2H, s} 5.65 (1H, dd, J _trans = 4 Hz, J _cis = 2 Hz), 5.22 (2H, 2s), 4.75 (2H, dq J = 12 Hz, J = 6 Hz), 3.85 (1H, dd, J _gem = 15 Hz, J _trans = 4 Hz), 3.5 (1H, dd, J _gem = 15 Hz, J _cis = 2 Hz), 2.8-3 , 3 (2H, m), 1.4 (6H, s), 1.28 (6H, s).

-N

- «■

COH

VI

VII

030027/0777

M / 20 359 SY-I599A

2350898

To a solution of compound VI (200 mg, 0.4 mmol) in tetrahydrofuran (8 ml) and fither (4 ml) are added sodium bicarbonate (34 mg, 0.4 mmol), water (4 ml) and 30% Pd / Celite (200 mg) and then hydrogenated for 2 hours at 2.75 bar (40 p.s.i.). The mixture is filtered and the layers are separated. After washing with methylene chloride (2-5 ml), the aqueous solution is cooled Phase with ice, acidified with IN HCl (1 ml) and extracted with 5 × 5 ml of chloroform. The organic extracts are dried (HgSO.) And evaporated in vacuo, compound VII, 76 mg (52%) is obtained in the form of an oil.

IR (CHCl ₃ )

1790, 1710 cm

-1

NMR (CDCl-) 6 9.6 (TH, ws), 5.65 (1H, dd, J.,. _{= T} , = 4Hz, J. = 2Hz) 4.72 (2H, dq J = 12 Hz _r J = 6 Hz), 4.2-5.1 (2H, m), 3.4-4.1 (2H, m), 2.7-3.4 (2H, m), 1.35 (6H , s), 1.25 (6H, s).

example

32

• N

COS

,Say

φ.

₂ > ₃ P (OC ₂ H ₅ ) ₂

CO PNB

0 30 027/0 777

β · β

Μ / 20 359 SY-1599A

- 169 -

(G 1/324, 2 mmol) to a cooled mixture (ice bath) of Compound 1 and Compound 2 _(f 0 54 g, 2, -2 mmol, crude) are ₃ Cl ₂ (15 ml) in CH dropwise a 1M Solution of pyridine / CH, C1 (2.2 ml, 2.2 mmol). The mixture is stirred for 1 hour at room temperature and filtered through Celite. The filtrate is washed successively with 0.5N HCl, H ₂ O, 0.5M NaHCO ₃ and brine. It is dried (MgSO ₄ ) and filtered through Celite / activated charcoal, 0.9 g of an oil being obtained after evaporation to dryness. The oil is _{chromatographed on SiO 3} (10 SH ₃ O) and eluted with stylacetate, woi. 0.5 g of compound 3 is obtained. (32 _f 8%).

NMR δ (ppm, CDCl ₃ ) 7.0-8.4 (m, 19H), 4.8-5.8 (3H, m), 4.1 (4H, g), 3.3-4.2 (2H, m), 2.7 (2H, m), 1.9 (2H, m), 1.3 (6H, t).

Compound 3 (0.4 g, 0.52 mmol) in toluene (35 ml) is refluxed for 4 hours and evaporated to dryness, an oil which contains compounds 3, 4 and _{O 3} P = O This is chromatographed on SiO “(10% H ₉ O) and eluted with EtOAc, 0.1 g of pure compound 4, then 0.15 g of compounds 3 and 4 being obtained.

030027/0 7 77

M / 20 359 SY-1599A

»♦ a

r »- ■ ■ * ■ - - «

- 170 -

2910898

NMR δ (ppm, CDCl ₃ ) 8.3 (2H, d), 7.67 (2H, d), 5.7 (H, q),

5.33 (2H, d), 4.2 (4H, g), 3, -83 (H, q), 3.4 (H, q), 2.9 (2H, m), 1.9 (2H, m), 1.3 (6H, t).

IR (clear) 1790 cm

* ί.ί-

Lactam) 1710 cm (ester).

(OEt).

-N

(OEt)

A mixture of compound 4 (0.1 g, 0.207 mmol), 30% Pd / Ceiite (0.1 g) and NaHCO- (17 mg, 0.207 ffiMoi) in THF (10 ml), Xther (5 ml) and water ( 5 ml) is hydrogenated at an initial pressure of 2.75 bar (40 psi) for 2 hours. Filter through Ceiite and separate the layers. The basic aqueous layer is washed thoroughly with stylacetate and acidified with 1N HCl. Extract with CH ₃ CL ₂ and dry (MgSO ₄ ). The CH ₂ Cl ₂ solution is concentrated to give 48 mg of compound 5 (66.5%).

O IR spectrum δ 1790 (β-lactam) and δ 1700 (-C-OH).

Example 33

030 0 2 7/0777

Μ / 20 359 SY-1599A

171 -

+ (MeO) ϊ

(OMe)

CO PNB '

CO PNB

A mixture of compounds 1 (1.07 g, 1.66 mmol) and 2 (0.42 g, 3 mmol) in CH ₂ Cl ₂ (3 ml) is heated for 5 hours at 80 ⁰ C. Chromatograph the crude oil of SiO ₂ (3% H ₂ O) mid eluted with ether, ether-ethyl acetate (1: 1) and ethyl acetate: 5% EtOH, 1.0 g of compound 3 (82%) being obtained. The oil crystallizes on standing, mp. (Ether) 138-140 ⁰ C.

NMR δ (ppm, CDCl ₃ ) 8.2 (2H, d) 7.0-8.0 (17H, m), 4.6-5.5

(3H, m), 3.8 (3H, s), 3.6 (3H, s), 1.5-3.5 (6H, m).

COMe).

CO PNB

Compound 3 (0.5 g, 0.69 mmol) in toluene (30 ml) is refluxed for 4 hours. It is evaporated to dryness, chromatographed on SiO ₂ (3% H ₃ O) and eluted with Et ₂ OiEtOAc (1: 1) then with EtOAc: 10% EtOH, 0.18 g of compound (58%) being obtained.

030027/0777

Μ / 20 359 SY-1599A

- 172 -

■ * t

NMR δ (ppm, CDCl ₃ ), 8.25 (2H, d), 7.6 (2H, d), 5.65 (H, q),

5.3 (2H, d), 3.8 (3H, s), 3.6 (3H, s), 2.7-3.6 (2H, m), 1.5-2.5 (4H, m).

ti.

(OMe).

30% Pd / celite NaHC0_

(OMe),

A mixture of compound 4 (50 mg, 0.112 mol), NaHCO ₃ (9.125 mg) and 30% Pd / Celite (50 mg) in THF (5 ml), Et ₂ O (2 ₇ 5 ml) and water (2, 5 ml) is hydrogenated at an outlet pressure of 2.75 bar (40 psi) (for 2 hours). Filter through gelite and separate the layers. The basic aqueous layer is washed thoroughly with EtOAc and lyophilized under high vacuum to give 28 mg of compound 5 (75.9%) '(hygroscopic)

IR (KBr) 1770 cm (β-lactam), aö10 cm " ¹ {-COO ~).

030027 / a777

Μ / 20 359 SY-1599A

Example 34

(1'R, 5R, 6r) and (1'S, 5S, 6S) 6- (1'-Hydroxy-1'-ethyl-2-methylpenem-3-carboxylic acid (Isomer D) (illustrates the most preferred method of introducing the 6-substituent in the middle of the synthesis)

OH

A. Preparation of 4-tritylthio-2-azetidinone intermediates

1. 1- (Trimethylsilyl) -4-tritylthio-2-azetidinone

sc4> _

-N.

■ Si (Me)

A solution of 4-tritylthio-2-azetidinone (345 mg, 1 mmol), 1/1 t 1 ^ 3,3,3-hexamethyldisilazane (80 mg _f 0.5 mmol) and chlorotrimethylsilane (55 mg, 0.5 mmol ) in dichloromethane (20 ml) is refluxed for 19 hours. Concentration of the seafood mixture gives the practically pure title compound.

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SY-1599A

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δ (ppm, CDCl ₃ ): 7.32 (15H, m, aromatic), 4.22 (1H, dd, H-4), 2.67 (1H, dd, J = 4.1, J = 16, H-3), 2.22 (1H, dd, J = 2.2, J = 16, H-3), 0.3 (9H, S / CH ₃ ).

2. 1- (tert -Butyldimethylsilyl) -4-tritylthio-2-azetidinone

-N

C (CH ₃ )

Triethylamine (1.62 ml, 11.6 mmol) is added dropwise over 5 minutes to a cooled (0 ⁰ C) and stirred solution of 4-tritylthio-2-azetidinone (3.5 g, 10.1 mmol) and chlorine -Tert-butyldimethylsilane (1.68 g, 12.7 mmol) in DMF (35 ml). The reaction mixture is stirred for 18 hours at room temperature, diluted with water (250 ml) and ether (200 ml). The organic phase is washed with water (3 × 50 ml), dried and concentrated, leaving an oil (4.33 g). Crystallization from pentane gives a total of 4.1 g (89%) of the title compound as a white solid, mp. 113-114 ⁰ C.

6 (ppm, CDCl): 7.45 (15H ₇ m, aromatic), 4.2 (1H, dd, -H-4)

2.63 (1H, dd, J = 4, J = 16, H-3), 2.13 (1H, dd, J = 2, J = 16, H-3), 1.0 (9H, s, t-Bu), 0.35 (6H, s, Me).

-1

ν 1735 cm

Analysis C ₂₈ H ₃₃ NOSSi:

calculated: found:

C. , 15 H 24 N _r 05 S. 97 73 , 27 7, 32 3 .97 6, 94 73 7, 2 6,

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3. 1 -Me ^ hj3xym ethyl-4-trityltlii Q-2-azetidinone

εοφ.

ί-r

• Ν,

A solution of 4-tritylthio-2-azetidinone (1.38 g, 4.0 mmol) in THF (10 ml) is added to a well-stirred suspension of sodium hydride (200 mg commercial, 50% purity, 4.1 mmol, washed with pentane ml) in THF (10) and holding at a temperature of -15 ⁰ C. It is methanol (12 drops) and the mixture stirred for 0.5 hours at -15 ⁰ C. Methoxymethylbroiüid {0.58 g, 4.6 sMol} is added and the mixture is stirred for 2 hours, diluted with ether, washed with water and brine, dried and concentrated to leave an oil (1.72 g). Crystallization from petan gives a white solid (1.41 g), mp 72-76 ° C

δ (ppm, DCCl ₃ ): 7.3 (15H, m, aromatic), 4.4 (3H, m,

and H-4), 3.22 <3H, s, CH ₃ J, 2.76 (2H, m, H-

4. 1- (Methoxyethoxymethyl) -4-tritylthio-2-azet i dinone

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To a suspension of tetrabucylammonium bromide (322 mg, 1 mmol) and potassium hydroxide (85%, 70 mg, 1.1 mmol) in Pichloromethane (10 ml), cooled to 5 ° C, is added vigorous stirring 4-tritylthio-2-azetidinone (345 mg, 1 mmol) and methoxyethoxymethyl chloride (187 mg, 1.5 mmol). Man stir the mixture for 2 hours at room temperature, evaporate the solvent and partition the residue between Water and ethyl acetate. The dried organic phases are concentrated, a viscous oil remaining (415 mg]) Purification by column chromatography, eluting with ether (5%) - dichloromethane gives the title compound (246 mg, 48%) in the form of an oil.

6 (ppm, CDCl ₃ ) I 7.30 (15H, m, aromatic), 4.57 (2E, AB quartet, N-CH ₂ O), 4.46 (1H, dd, H-4), 3, 50 (4H, s, OCH-CH ^ O), 3.30 (3H, s, CH-J, 2.75 (2H, m, H-3).

5. 1- (2'-Tetrahydropyranyl) -4-tritylthio-2-azetidinone

N.

■ Η

n-Butyllithium (1.6M, 1.6 ml, 2.56 mmol) is added dropwise to a solution of 4-tritylthio-2-azetidinone (863 mg, 2.5 mmol) in THF, which is kept at -78.degree. After one Has stirred for 15 minutes, 2-chlorotetrahydropyran is added (560 mg, 4.7 mmol) and let the mixture warm to room temperature over 1.5 hours. The reaction solution is diluted with ethyl acetate with brine

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washed, dried and concentrated, leaving an oil (635 mg) remains behind. Column chromatography over silica gel and eluting with dichloromethane filter gives a mixture of the isomeric title compounds, which is contaminated with some starting material.

δ (ppm, CDCl ₃ ): 7.28 (15H, m, aromatic), 4.4 (H, dd, H-4),

2.9-2.2 (2H, m, H-3), 4.1-3.2 and 2.2-0.7 (tetrahydropyranyl).

B. Preparation of 3- (1'-Hydroxy-1'-ethyl) -1-methoxymethyl-4-tritylthio-2-azetidinones

O. 3

a) (1'S, 3S, 4R and 1 ^I R, 3R, 4S) isomer (isomer C)

A solution of lithium diisopropylamide in THF provides (5 ml) (0.25 mL, 1.84 mmol) at -78 ⁰ C n-butyl lithium (1.6M, 1.0 mL 1.6 mmol) and diisopropylamine forth. After 30 minutes, a solution of 1-methoxymethyl-4-tritylthio-2-azetidinone (491 mg, ",, 42 ΐτ, ΜσΙΪ in THF {6 ™ 1> is added dropwise and the solution is stirred for 15 minutes. Acetaldehyde (3 , 0 ml) is added dropwise, then after 20 minutes water (30 ml). The mixture is acidified to pH 3 with 2% HCl and extracted with ethyl acetate (5 20 ml). The combined organic phases are washed with brine,

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• * ♦

Μ / 29 359 - 178 -

SY-1599A

dried and concentrated to give an oil remains which crystallizes by trituration with ether. 440 mg, 80%, mp 188.5 to 189 ⁰ C;

¹ Hmr (CDCl ₃ ? 6: /, 3- (15H, m, aromatic), 4.37 (2H, ABq, N-CH ₂ O), 4.32 (1H, d, J = 2, H-4 ), 3, -17 (3H, - s _r OCH ₃ ), 3.32-2.70 (2H, m, H-3 and H-5), and 1.12 ppm (3H, d, J = 7, CH ₃ );

Analysis C_ _i .H _o ^ N0_S:

C. 02 H 28 N 23 S. / 39 calculated: 72, 99 6, 02 3, 21 7th / 40 found: 71 6, 3, 7th

b) (1'S, 3S, 4R and VR, 3k, 4S) and (1'R, 3S, 4R and VS, 3R, 4S) Isomers C and B

A solution of lithium diisopropyamide. "" ¹ . (0.482 mmol) at -78 ⁰ C in dry ether (3 ml) prepared from 1 Buti "lithium (0.191 ml of a 2.52 M solution in hexane, 0.482 mmol) and diisopropylamine (0-067 mL, 0.482 mmol). After A solution of (4R and 4S) 1-methoxymethyl-4-tritylthio-2-azetidinone (0.171 g, 0.439 mmol) in a mixture of dry ether (1 ml) and dry THF (1 ml) is added dropwise for 20 minutes Stir the resulting clear solution for 15 minutes at -78 ⁰ C. Then, a solution of tetrabutylammonium fluoride (0.96 ijal of a 0.5M solution in THF, 0.48 mmol) zu.Es forms a precipitate wobai a slight Rosafärtnmg results. After 5 minutes at -78 ⁰ C, the reaction mixture is quenched with freshly distilled acetaldehyde (0.2 mL excess) and the mixture is stirred an additional 15 minutes the treatment is carried out by adding to a saturated ammonium chloride solution and wit ethyl acetate (2 χ. 25m

030027/0 7 77

• «

I a>

Μ / 20 359 SY-1599A

- 179 -

extracted. The combined organic phases are washed with brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent in vacuo gives an oil (0.228 g) which is chromatographed over 10 g of silica gel. A mixture of benzene and ethyl acetate (6: 4) gave 0.106 g (62% yield) of a substrate and a mixture of the two isomeric alcohols, which were separated by chromatography on thick-layer plates (same solvent system. The alcohol with the high Rf value (0 / 033 g, 17%) is identical to the above isomers (isomers C) r m.p. 188.5-189 ° C (ether-dichloromethane); the alcohol with the low Rf value (0.030 g, 16%) (isomer B) is obtained as an oil, which crystallized with difficulty from hexane: mp 94-95 ⁰ C..

IR

v _m ι 3600 (OH), 1760 cm

-1

(C = O);

Hmr (CDCl ₃ ) 6: 6.9-7.5 (15H, m, aromatic), 4.2 (2H, center of ABg, J = 11.5, CH ₂ -O-CH-), 4.28 (1H, d, J = 2.0, 4-H), 3.65 (1H, center of a broad sextet, H-1 '),

3.3 (1H, dd, J,

. = 2.5,

'3.4 trans "'""" 3.1 _r s, O-CH ₃

s, OH-1 '), 1.05 (3H, d, J = 6.5, H2 ³ );

, = 4.5,

H ₃ ), 3.15 (3H, s, 0-CH ₃ ), 1.55 (1H, broad

Analysis C_

calculated: found:

C. 02 H 28 N 23 S. 39 72, 77 6, 36 3, 15th 7, 43 71 6, 3, 7,

030027 / O777

»Mm

U / 20 359 SY-1599A

- 180 -

2850898

C. Manufacture of

trans-3-acetyl-1-methoxyinethyl-4-tritylthio-2-azetidinone

LDA

EtOAc

Lithium diisopropylamide is prepared under a nitrogen atmosphere at -78 ° C. in the usual way from diisopropylamine (0.34 ml, 2.4 mmol) and n-butylithium (1.1 ml of a 2.2M solution in hexane, 2.4 mmol) in THF (3 ml). A solution of 1-methoxymethyl-4-tritylthio-2-azetidinone (0.78 g, 2 mmol) in THF (3 ml) is added dropwise and after 20 Minuten'bei has stirred at -78 ⁰ C, is added at once 0.53 g, 6 mmol of ethyl acetate are added and stirred a further 0.75 hours at -78 ⁰ C. dilute the reaction mixture with ether and washed with a Ananoniumchloridlösung, water and brine, dried and concentrated to give an oil is obtained (0, 7 g). Purification is carried out by chromatography over silica gel (20 g), eluting with increasing amounts of ether in benzene. The appropriate fractions are concentrated to give the title compound as a colorless oil (0.32 g, 37%);

Hmr (CDCl ₃ ) 5: 7.7-6.8 (15H, aromatic) _r 4.85 (1H _r d, J = 2, H-4), 4.5 (2H, s, N-CH ₂ - O), 3.9 (1H, d, J = 2, fi-3), 3.22 (3H, s, CH ₃ ) and 2 ₇ G ppm (3H, Ξ,

CH ₃ );

IR v _max : 1770, 1710 cm

-1

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Μ / 29 359 - 181 -

SY-1599A 2950898

D. Manufacture of

trans -3-acetyl-1- (tert. "-butyldimethylsilyl) -4-tritylthio-2-azetidinone

Diisopropyl-lithium amide is prepared in the usual way from diisopropylamine (0.18 ml, 1.24 mmol) and n-butyllithiura (0.78 ml of a 1.6M solution in hexane, 1.24 mmol) in THF (8 ml) » A solution of i- (tert-butyldimethyl-silyl) -4-tritylthio-2-azetidinone (0.46 g, 1 mmol) in THF (8 ml)
is added dropwise at -78 ⁰ C. After stirring for 5 minutes, 1 ml of ethyl acetate is added all at once and
the mixture is stirred for 3 hours at -78 ⁰ C. The mixture is acidified, the
Mix the kit with cold hydrochloric acid (0.5N) to pH 6 and extract with ethyl acetate (2 × 20ml) · The combined organic phases are dried and concentrated to give an oil (0.5 g) which is crystallized from pentane! Siert: 200 mg total, 40%, mp 122-124 ⁰ C..

^{IR v} rr, ^ ^z 1750, 1710 cm "¹;

¹ Hmr (CDCl ₃ ) 5: 8-7.1 (15H, m, aromatic), 4.83 (1H, d,

J = 2, H-4) _r 3.38 iiH, d, J = 2, H = 3j, 7.80 f3H, s, CH ₃ ), 0.92 (9H, s, Bu and 0.3 ppm ( 6H, s, CH ₃ ).

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1 ■ · ·

E. Manufacture of

trans-1- (tert-butyldimethylsilyl) -3-formyl ~ 4-trltylthio ~ 2-azetidinone

t-bu

"Si (CH ₃ ) t-Bu

To a cooled (-78 C) solution of diisopropylamine (0/34 ml / 2> 4 mmol) in tetrahydrofuran (5 ml) is added dropwise under N ₂ a solution of 1 ₇ 5 M n-BuLi (1.6 mL, 2.4 mmol). After stirring for 30 minutes, a solution of 1- {tert-butyldimethylsilyl) -4-tritylthio-2-azetidinone (1.0 g, 2.18 mmol) in tetrahydrofuran (5 ml) is added dropwise and the mixture is stirred for 30 minutes Further. Ethyl formate (0.8 ml, 9.9 mmol) is added and the cooled solution is stirred for a further 10 minutes. The reaction mixture is washed successively with cold 1N hydrochloric acid (5 ml), 1.Μ sodium bicarbonate (6 ml), water (10 ml) and brine. The organic layer is dried (MgSO.), Evaporated and crystallized from pentane to give 810 mg (76%) of formate as a white solid; . Mp 132-133 ⁰ C;

-1

IR (CHCl ₀ ) ν: 1760, 1715cm

O ΤΠ3.Χ

'Hmr (CDCl ₃ ) δ: 9.0 (1H, d, J = 1.25 Hz), 7.30 (15H, m),

4.7 (1H, d, J = 1.5Hz) and 3.5 ppm (1H, t, J = 1.5Hz).

030027/0777

• * · ■■ «· · ■.» · - · -_ ■ -. μ m λ

Μ / 20 359 SY-1599A

- 183 -

29S0898

Note: a) Diisopropylamine is distilled over CaH and stored on KOH,

b) Tetrahydrofuran is available from L.A.H. distilled and stored on molecular sieves 3 8 /

c) Fithylformate is stirred at room temperature with ^ C, then _{distilled over Ρ 2} ° ς,

d) n-BuLi is ver with 1N hydrochloric acid rubbed.

F. Manufacture of.

1- {t-butyldimethylsilyl) -3- (1'-hydroxy-1 ^r ethyl) -4-tritylthio-2-azetidinones (4 isomers)

OH

a)

.t-Bu

Cf

■ Ν ΛΒιι

(Me).

(n-butyllithium (1.6M, 3.4 mL, 5.44 mmol) are over 5 minutes to a solution of diisopropylamine (0.847 ml, 6.23 mmol) in THF (30 ml) which at -78 ⁰ C. After 0.5 hours a solution of 1- (tert-butyl-dimethylsilyl) -4-tritylthio-2-azetidinone (2.0 g, 4.4 mmol) in THF (20 ml) is added; after 15 minutes acetaldehyde (10 ml) is added all at once; after a further 15 minutes water (100 ml) is added. The mixture is acidified with dilute hydrochloric acid at {pK 5-5} and extracted with ethyl acetate (3 χ 30 ml) The organic phases are washed with saline solution, dried and concentrated, leaving an oil that is due to thin layer

030027/0777

M / 20 359 SY-1599A

Chromatography turns out to be a mixture of 4 isomers (corresponding to the decrease in polarity with isomers A, B, D, C).

Crystallization of the oily residue in ethyl acetate-pentane gives isomers B and C in the form of a white solid, with isomers A and D remaining in the mother liquors. The four pure compounds are obtained by preparative chromatography (Waters, 500) of the above solid and the mother liquors. The corresponding proportions are; A, 17 % 7 B, 32%; C, 39%; D, 12%. By replacing in the above reaction, the THF by ether and deters the reaction after 1 minute at -78 ⁰ C., so are the respective proportions of A, B, C and D: 12.9; 30.5; 38.2 and 18.4%. If the reaction mixture is allowed to warm to 20 ° C. in ether for 2 hours before quenching, the proportions are as follows: 13.4; 24.6; 44 and 18%. If 1 mol equivalent of magnesium bromide is added to the reaction mixture, the proportions change as follows: 19.2; 19.7; 30.1 and 31%.

Isomer A :

This isomer has a cis stereochemistry _{at C 3} -C _4. It is a racial mixture consisting of the (1'3.3R-4R) and the (1 ¹ R, 3S, 4S) enantiomers. Compounds which are later derived from Compound A are referred to as "Isomer A". They consist of an enantiomeric mixture and have the same configuration _{at C 1} , C ₃ and C _4. Compounds which are derived from compound A by a reaction causing configuration inversion are referred to as "isomer D" when the inversion occurs at C ₁ and "isomer C" when the inversion occurs at C_. . Mp 152-153 ⁰ C;

0 3002 7/07 77

ι (■

M / 20 359
SY-1599A

- 185 -

Hmr (CDCl _-3 ) δ: 8.0-6.8 (15H, m, aromatic), 4.30 (1H, d, J = 5.5, H-4), 3.78 (1H, ra, HT), 3.10 (1H, dd, J = 5.5, J = 10, H-3), 1.22 (3H, d, J = 6.5, CH ₃ ), 0.95 (9H, s, Bu), 0.27 (6H, 2s, CH ₃ )

Analysis C ^ _n ]

calculated: found:

Isomer B:

C. 52 H 40 N 78 S. , 36 71 28 7, 41 2, 48 6th , 19th "Ί, 7, 2, 6th

This isomer has a trans stereochemistry _{at C 3} -C _4. It is a racemic mixture consisting of the (1'R, 3S, 4R) and the (TS, 3R, 4S) enantiomers. Compounds which have _{the same configuration at C 1} , C ₃ and C ₄ are referred to as "isomer B";

IR (CHCl-) v

ί 1745 cm " ¹ (C = O); mp. 158-159 ⁰ C.

¹ Hmr (CDCl ₃ ) δ: 7.60-7.10 (15H, m, aromatic /, 4.02 (1H, d,

J = 0.8 H-4), 3.32 (1H, dd, J = 3.0, J = 0.8, H-3), 3.55-3.15 (1H, m, HT), 0.88 (12H, CH ₃ and t -Bu), 0.16 (6H, s, CH ₃ );

Isomer C:

This isomer has a trans stereochemistry at C_-C-. It is a racemic mixture consisting of the i [Ts, 3S, 4R) and the (TR, 3R, 4S) enantiomers. Compounds which have _{the same configuration at C 1} , C _3, and C ₄ are referred to as "isomer C". . Mp 134-136 ⁰ C;

'' Hmr: (CDCl ₃ ) ö: 7.60-7.10 (15H, m, aromatic), 4.32 (1H, d,

J = 1.8, H-4) 3.02 (1H, dd, J = 2.7, J = 1.8, H-3), 3.0-2.5 (1H, dq, J = 2 , 7, J = 6, HT), 1.02

0 27 / a77

L ± »- β

Μ / 20 359
SY-1599A

- 186 -

2350898

(3H, d, J = 6,

, 0.95 (9H, s, t-Bu),

0.27 (6H, s, CH _3);

IR (CHCl-) V _7n : 1735 cm " ¹ (C = O).

Isomer D;

This isome.-w has a cis stereochemistry _{at C, -C s.}

3 *

It is eii-y racemate, consisting of the (1 ^e R, 3R, 4R) and the (1'8,33,4S) enantiomers. Compounds which l ~ ai C ₁ ,, C-. and C. have the same configuration are referred to as "isomer D". . Mp 171-172 ⁰ C;

Hmr (CDCl ₃ )

: 7.80-6.90 (15H, m, aromatic), 4.70 (1H, d, J = 4.5, H-4), 3.02 (1H, dd, J = 4.5,. 1 = 0.5, H-3), 2.39 (1H, Uq, J = 0.5, J = 6.5, HV), 1.0 (3H, d, J = 6.5, CH ₃ ), 0.97 (SK, 5, t = Bu), 0.32 (6H, s, CH ₃ ).

Analysis C ₃₀ H ₃₇ NO ₂ SSi:

calculated:
found:

71.52 71.27

H 40 N 78 S. , 36 7, 43 2, 51 6th , 31 7, 2, 6th

b)

bra

Me_

2 trans isomers

A solution of trans -3-acetyl-l- (tert -butyldimethylsilyl) 4-tritylthio-2-azetidinone (1.0 g, 2 mmol) in THF 830 ml) is added dropwise under a nitrogen atmosphere

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If Λ .._ * _

M / 20 359 Si-1599A

- 187 -

a cooled (OC) and stirred suspension of sodium bromide (0.38 g, 10 mmol) in THF (120 ml). Remove the ice bath and stir for 4 hours at room temperature. It is poured into ice-cold hydrochloric acid (1N, pH6), stirred for 15 minutes and extracted with ether (3x). The combined ether extracts are dried and concentrated / leaving an oil (1.04 g) which is crystallized from pentane to give the title compound as a 70:30 mixture of the C and B isomers. Mp. 119-121 ⁰ C, 84%.

c)

I _x SOiL

V;

Bu

Isomer B

A suspension of copper (I) iodide (4.78 g, 15 mmol) in ether (50 ml) is cooled to 0 ⁰ C and treated un € er 'N ₂ with a 1.9 M solution of methyl lithium (26 ml , 50 mmol). Stirring the brown solution for 10 minutes at 0 ⁰ C, then cooled to -60 ⁰ C and treated dropwise with a trans-: 1-1 (tert-butyl-dijnethylsilyl) -3-f ormyl-4-trithylthio I-azetidinone (2 _r 43 g, 5.0 mmol) in a mixture of tetrahydrofuran (10 ml) / ether (40 ml). Stirring is continued for 3 hours. The solution was warmed to -40 ⁰ C and treated cautiously with IM solution of -Ämnioniumchiorid = The mixture is filtered over Celite, the organic phase is washed with a 1M solution of ammonium chloride (2x5 ml) and then with brine and dried over sodium sulphate . Filtration and evaporation gives an alcohol, isomer B, which crystallizes from warm pentane to give 1.6 g

03 0027/0777

M / 20 359 SY-I599A

β ·· · mw * Φ

(65%) yield; . Mp 160-161 ⁰ C;

IR (CHCl ₃ ) V _103x : 1730 cm

-1

Hmr (CDCl ₃ ) ß: 7.32 (15H, in), 4.05 (1H, s), 3.4 (1H, d,

J = 3Hz, 3.25-3.55 (1H, rn), 1.6 (1H, s), 0.9 (12H, s) and 0.1 ppm (6H, s).

Note: a) Tetrahydrofuran and ether are available from L.A.H. distilled;

b) Methyl lithium became with 1N hydrochloric acid rubbed in,

c) Copper (I) iodide was purified by continuous extraction with anhydrous tetrahydrofuran in a Soxhlet extractor for 18 hours, then dried in vacuo in a desiccator for 18 hours (P ₂ O).

-N

«■ tBu

Methyl magnesium iodide (0.1 ml, 0.1 mmol) is added dropwise to a cooled (0 ³ C) and stirred solution of trans-1- (tert-butyl-dimethylsilyl) -S-formyl-'i-tritylthio ^ - azetidinone (25 mg, 0.05 mmol) in THF (2 ml). The solution is stirred for 1.5 hours at 0 C _#, poured onto an ammonium chloride solution, acidified with a hydrochloric acid solution (1N) and extracted with ether. Drying and concentrating the organic extracts gives an oil which consists of the starting material and a small amount of a mixture of the two trans-title compounds, the B-isomer predominating. .

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29S0598

Production of

(1'8,38,4R and 1'R, 3R, 4S) 1- (tert -butyldimethylsilyl) -3- (1'-trimethylsilyloxy-i'-ethyl) -4-tritylthio-2-azetidinone (Isomer C)

OH

A solution of (1'S, 3S, 4R and 1'S, 3R, 4S) 1- (tert-butyldimethylsilyl) -3- (1'-hydroxy-1-ethyl) -4-tritylthio-2-azetidinone (15 mg, 0.3 mmol) and azidotrimethylsilane (35 mg, 0.30 mmol) in dry THF (6 ml) are stirred at room temperature until the starting material has disappeared. Purification of the reaction mixture by column chromatography (silica gel, CH ₂ Cl ₂₎ gives the desired compound as a white solid (128 mg, 74%), mp. 144-146 ⁰ C.

¹ HmT (CDCl ₃ ) δ: 7.10-7.60 (15H, m, aromatic), 4.30 (1H, d, J = 1.5, H-4), 2.25-2.89 (2H, m, H-3, H-1 ^f ), 0.82-1.07 (12H, m, t-Bu, H-2 '), 0.27 (6H, s, CH ₃ ), - 0.10 (9H, S, -O-Si (CH ₃ J ₃ );

IR (CHCl-) ν: 1736cm

-1

(C = O).

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M / 20 359 SY-1599A

G. Manufacture of

(1'S, 3R, 4R and 1'R, 3S, 4S) 1 '(tert-butyldimethylsilyl) -3- (1 '-methoxy-methoxyether-1' -ethyl) -4-tritylthio-2-azetidinone (Isomer A)

OH

Si (Me).

t-bu

n-Butyllithiuni (approx. 12.5 ml of a 1.6M solution in hexane, 20 mmol; just enough to achieve a lasting pink color) is added dropwise to a solution of (1'S, 3R, 4R and 1'R, 3S, 4S) 1- (tert-butyldimethylsilyl) -3- (1'-hydroxyl '-ethyl) -4-tritylthio-2-azetidinone (isomer A) (10.1 g, 20 mmol) in THF (100 ml), which one keeps ^{at -78 0 C.} After stirring for 15 minutes, a solution of bromomethoxymethyl ether (2 ml, 24 mmol) in THF (30 ml) is added dropwise. The mixture is stirred 1 hour at -78 ⁰ C and 2 hours at room temperature and then poured into an ammonium chloride solution (200 ml) ♦ extraction with ethyl acetate (3 χ 200 ml), washing with brine, drying with sodium sulfate and concentration gives the crude title compound which is purified by chromatography on silica gel, eluting with increasing amounts of ether in benzene (10.4 g 95%).

(CDCl ₃ ) 6: 7.1-7.5 U5H, mn, aromatic) _f 4 ^ 47 (IH ₇ d _? H-4), 4.23 (2H, ABq, J = 7, = -CH ₂ O ), 3.1-3.4 (2H, m, H-3 and HV), 3.23 (3H, s, 0-CH ₃ ), 1.37 (3H, d, J = 6.5, CH ₃ ), 0.97 (9H, s, Bu) and 0.25 ppm (6H, 2s, CH ₃ ).

030027/0777

M / 20 359 - 191 -. [

H. Manufacture of

{1'S, 3S, 4R and 1 'R, - 3R, 4S> 1- (tert-butyldimethylsilyl) -3- (1 '-formyloxy-1' -ethyl) ^ -tritylthio ^ -azetidinone (isomeric C

A solution of (1'5,35,4R and 1'R, 3R, 4S) 1- {tert -butyldimethylsilyl) -3- (1'-hydroxy-1. -Ethyl) ^ -tritylthio ^ -azetidinone (Isomeres C) C50 mg, 0.1 mmol) p-bromobenzenesulfonyl chloride (100 mg, 0.4 mmol) and dimethyl aminopyridine (24 mg _r Q _f 2 mmol) in DMF (3 ml) are stirred at room temperature until the starting material has disappeared ( 0.5 hours). The reaction mixture is then diluted with water and extracted with ether. The organic extracts are washed with brine, dried (MgSO.) And evaporated. The title compound is purified by column chromatography.

¹ Hmr (CDC1-) 5: 7.80 (1H, s, CHO), 7.20-7.66 (15H, m, aromatic), 3.90-4.36 (1H, m, HT), 4 , 07 (1H, d, J = 2, H-4), 3.22 (1H, broad s, H-3), 1.18 (3H, d, J = 6.5, H-2 '), 1.0 (9H, s, t-Bu), 0.31 (6H, s, di-CH ₃ ).

030027/0777

M / 20 359
SY-1599A

28SQ898

I. Her collar of

(1'E, 3S, 4E and 1 ¹ S, 3R, 4S> 1 (tert-butyldimethyisilyl} -3-1 ·· acetoxy-1'-ethyl / -4-trifcylthio-2-azetidinone (isomer B)

"rf

OAc

Pyridines

rf <f

Si

A solution of (1'11,38,4S and 1 'S, 3R, 4S) 1- (tert-butyl-dimethylsilyl) -3- ^(1-hydroxy-r 1 · ethyl) -4-tritylthio-2 -azetidinor (13/85 g _f 27/5 mmol) in pyridine (75 ml) acetic anhydride (50 ml) (prepared at 0 ⁰ C) one stirred for 40 hours at room temperature-The reagents are evaporated (with the last sensations Szeotiröpisch 3 χ removed with xoiliöi) leaving an almost white solid. The crude derivative is crystallized from an ether-petroleum ether mixture, resulting in the pure compound (£ 97/5%).

¹ Hmr (CDCl ₃ ) ö: 7.64-7.03 (15H, m, H aromatic), 4.60 (1H, m,

J = 6, HT) / 3.92 (1H, d, J = 2, H-4), 3.55 (1H, dd, J = 2, J = 6, H-3), 1.79 (3H , s, CH ₃ CO), 0.98 <3H, d, J = 6, CH ₃ ), 0.88 (9H, s, t-butyl), 0.12 (6H, s, CH ₃ );

IR (CHCl ₃ ) v _max : 1775, 1740 cm

(C = O)

J. Manufacture of

1- (tert-ButyldimethyIsilyl) -3- (1 ^l -p-nitrobenzyldioxycarbonyl) -! -Ethyl) -4-tritylthio-2-azetidinone (4 isomers)

030027/0777

M / 20 359
SY-1599A

2350898

"Isomer C":

n-butyllithium (8 _r 8 ml of a 1.6 M solution in hexane, 14 mmol, just sufficient to provide sustained pink color to achieve) is added dropwise to a solution of "C isomer of 1- (t-butyldimethylsilyl) -3 - (1'-hydroxy-1'-ethyl) -A- tritylthio-2-azetidinone (6.55 g, 13 mmol) in THF (70 ml) which is maintained at -78 ⁰ C. After being stirred for 15 minutes. has, is added dropwise a solution of p-nitrobenzyl chiorformirt (3.2 g, (14.8 mmoles \ in THF 830 mL). the mixture is stirred 1 hour at -78 ⁰ C and poured into a .Ammoniumchloridlösung ( 100 ml), extraction with ethyl acetate (3 × 100 m washing with saline solution, drying and concentration gives 11 g of raw material. The pure title compound is obtained by chromatography over silica gel (220 g), eluting with increasing amounts of ether in benzene. 93%, melting point. 118-119 ⁰ C (ether);

¹ HMR (CDCl ₃ ) 6: 8.35-7 (19H, m, aromatic, 5.12 (2H, s, benzyl), 4.08 (1H, d, J = 1.8, H-4), 4.35

(IH, dq, J = 6.5, J = 2, HT), 3.10 (IH, dd, J = 2 J = 1.8, H-3), 1.2 (3H, d, J = 6.5, CH ₃ ), 1.0

(9H, s, Bu) and 0.30 ppm (6H, 2s, CH ₃ );

Ir (CHC1_) V _n ,: 1745 cm " ¹ (C = O);

Analysis of C-QH

calculated: found:

"Isomer B"

C. 83 H 20th N 10 S. , 69 66 90 6, 26th 4, 11 4th , 59 66 6, 4, 4th

Treating the "isomer B" of 1- {tert »-Butyldimethylsilyl) -3- (1 '-hydroxy-1' -ethyl) ^ -tritylthio ^ -azetidinone as described above, the pure "isomer B" is obtained

030027/0777

M / 20 359

of 1- (tert-butyldimethylsilyl) -3- (1 '-p-nitrobenzyldioxycarbonyl-1 ^f -ethyl) -4-tritylthio-2-azetidinone in the form of a foam, 95%.

Mr

>: 3.32-6.90 (19H, m, aromatic), 5.1 (2H, s, Ben / 1 "f.), 4.65-4.20 (1H, m, H-1 ¹ ) , 3.97 (1H, d, J = 1.5, H-4), 3.58 (1H, dd, J = 1.5, J = 5.8, Hb), 1.1 (3H, d , CH.,), 0.7 (9H, s, Bu) and 0.22 ppm (6H, s, CH ₃ );

-1

IR (film) V _7n : 1755 "1740 cm" ¹ C = O. Max

Isomer

If the "isomer A" of 1- (tert-butyIdimethylsilyl-3- (1'-hydroxy-1'-ethyl ) -4-tritylthio-2-azetidinone as described above, the pure "isomer A" is obtained of 1- (tert-Buty! dimethylsilyl-3- (1 * -p-nitrobenzyidioxycarbony1-1'-ethyl) -4-tritylthio-2-azetidinone in the form of an oil; 95%.

¹ Hmr (CDCl ₃ ) 6: 8.3-6.7 (19H, m, aromatic), 4.95 (2H, ABq, benzyl), 4.53 (1H, ρ, J = 7.5, J = 7.5, H-1 ¹ ) / 4.31 (1H, d, J = 6, H-4), 3.32 (1H, dd, J = 6, J = 7.5, H-3), 1.44 (3H, d, J = 6.5), 0.95 i9H, s tBu) and 0.2 ppm (6H, 2s, CH ₃ ).

"Isomer D"

In the same way, the "isomer D" of 1- (tert-buty1-dimethylsilyl-3- (1 '-hydroxy-1' -ethyl) -4-tritylthio-i azetidinone the pure "isomer D" of 1- (tert-butyldinethylsilyl) -3- (1 & -p-nitrobenzy ldioxy carbonyl-1'-ethyl) -4-tritylthio-2-azetidinone, 90%.

030027/0777

Μ / 20 359
SY-1599A

- 195 -

¹ Hmr (CDCl ₃ ) 6i 8.3-6.7 (19H, m, aromatic, 5.20 (2H, ABq,

Benzyl), 4.72 (1H, d, J = S, H-4), 3.50 (1H, dq J = 6.5, J = 0.5, H-1 ·) / 2/85 (1H , dd, J = 0.5, J = 5, H-3), 1.03 (3H, d, J = 6.5, CH ₃ ), 1.0 (9H, s, t-Bu) and 0 , 35 ppm (6H, s, CH ₃ );

Mp. 130-132 ⁰ C-

analysis
calculated
found:

66.83
66.56

6.20 6.28

4.10

3.96

4.70% 4.89%

K- manufacture of

(1'S, 3S, 4R and 1'S, 3R, 4S) 1- (tert-Uutyldimethylsilyl) -3- (1 '-methanesulfonyloxy-1' -ethyl) ^ -tritylthio ^ -azetidinone (Isomer C)

OMs

.N

t-bu

t-bu

A solution of (1'5,354R and 1'R, 3R, 4S) 1- (tert -butyldimethylsilyl) -3- (1'-hydroxy-1. -Ethyl) -4-tritylthio-2-azetidinone (Isoermes C ) (2 _r 0 g, 4 mmol) in dichloromethane (80 ml) is treated at 5 ⁰ C and methanesulfonyl chloride (0,99g, 8.6 mmol) and triethylamine (0.87 g, 8.6 mmol). After stirring for 1 hour under N ₀ at this temperature, to the solution is washed with brine, dried (MgSO.) And evaporated to dryness. After crystallization from ether-petroleum ether, 1.9 g (81.9%) of mesylate are obtained. Mp. 120-122 ⁰ C

030027/0777

M / 20 359 SY-1599A

- 196 -

Hmr (CDCl ₃ ) 6: 7.13-7.61 (15H, m, aromatic, 4.50 (1H, d, J = 2, H-4), 3.62 (1H, dq, J = 6, 5, 2, HT), 2.96 (1H, dd, J = 2, 2, H-3), 2.84 (3H, s, methanesulfonyl), 1.22 (3H, d, J = 6.5 , H-2 ¹ ) / 0.99 (9H, s, Si-t-Bu) and 0.30 ppm (6H, s,

Si (CH ₃ J ₂ );

" ¹

Irv "(CHCl,): 1746 (C = O), 1343 and 1180 cm" ¹ (SO ").

L- manufacture of

(1'R, 2S, 4R and 1'S, 3R, 4S) 1- (tert -butyldimethylsilyl) -3- (1'-methanesulfonyloxy-1'-ethyl) -4-tritylthio-2-azetidinone (Isomer B)

OH

so

A solution of (1'R, 33,4R and 1'3,3R ₇ ^ S) 1- (tert-butyldimethylsilyl) -3- {1'-hydroxy-1. -Ethyl) -4-tritylthio-2- azetidinone (Isoermes B) (5.03 g, 10 mmol), methanesulfonyl chloride

(2.52 g, 22.0 mmol) and in CH triethylamine (2.23 g, 22.0 mmol) ₂ Cl ₂ (200 ml) is stirred 1 hour at 5 ⁰ C. Then, the solution is washed with brine, dries (MgSO-) and evaporates, leaving a residue which crystallizes as a white solid when it is triturated with ether (5.40 g, 93%). FP. 127-131 ⁰ C.

¹ HMT _(CDCl3) δ: 7.20 to 7> 63 (15H, m, aromatic), 4.51 (IM, dg, J = 5.0 to 6.2, H-1 ^1), 4.10 (1H, d, J = 2.0, H-4), 3.60 (1H, dd, J = 5.0-2.0, H-3), 2.03 (3H, s, -CH ₃ ), 1.01 (3H, d, J = 6.2, H-2 ¹ ), 0.90 (9H, s,

IR (CHCl

t-Bu), 0.12 (6H, s, -CH ₃ ); : 1745cm ^-1 (C = O).

030027/0777

M / 20 359 SY-1599A

2350898

M. Manufacture of

(1 ^for r:, 3S, 4R and 1'R, 3R, 4S) 3- (1 «-p-bromobenzenesulfonyloxy-i'-ethyl) -1- (tert-butyldimethylöilyl) -4-tritylthio-2-azetidinone (Isomer C)

OH

OSO φΒΓ

51-

Χ »-

A solution of (1'S, 3S, 4R and 1'R, 3R, 4SJ 1- (tert-butyldimethylsilyl) -3- (1'-hydroxy-1'-ethyl) -4-tritylthio-2-azetidono] i ( isomer C) (2.5 g, 5 mmol) in dry THF (100 ml) is cooled to -78 ⁰ C and treated with 2.38 ml 2,52M butyllithium / hexane (6 mmol). After 3-4 Minutes, p-bromobenzenesulfonyl chloride (1.53 g, 6 mmol) dissolved in THF is added dropwise. The solution is stirred for 3 hours at -78 ^° C. and then allowed to warm up to room temperature again. The solvent is then concentrated and purified, the desired product purified by column chromatography (silica gel, CH ₂ Cl ₂₎ (g 3.36, 94.6%), mp. 142-144 ⁰ C.

¹ Hmr (CDCl ₃ ) δ 7.68 (4H, s, benzenesulfonyl), 7.28-7.60

(15H, m, aromatic), 4.59 (1H, d, J = 1.8, H-4) 3.68 (1H, dq, J = 6.2, H-1 ^1), 2.99 ( 1H, dd, J = 1.8, 2.0, H-3), 1.18 (3H, d, J = 6.2, H-2 ¹ ), 1.08 (9H ₇ s, t-Bu ), 0.40 and 0.38 (6H, 2S, -CH ₃ );

IR (CHCl ₃ ) _V

1 / 4y cm

(UU)

030027/0777

M / 20 359
SY-1599A

- 1 DQ _

N. Manufacture of

(1'S, 3R, 4R and 1'R, 3S, 4S) 3- (1'-methoxymethyl-1'-ethyl) -4-tritylthio-2-azetidinone (Isomer A)

OCH ₂ OCH ₃

OCH ₂ OCH ₃

Si t-Bu

A cold (OC) HMPA-H ₃ O (116 ml-13 ml) solution of the isomer A of 1- (tert-butyldimethylsilyl) -3- (1'-methoxymethyl-1'-ethyl) -4-tritylthio-2- Azetidinone (11 g, 20 mmol) is treated with sodium azide (2 _r 7 g, 42 mmol). Remove the cold bath and stir for 30 minutes. Then pour into cold water (1.3 l) and dry. The title compound is recrystallized from ethyl acetate-hexane (7.2 g, 83%} white solid, mp. 173-174 ⁰ C.

Hmr (CDCl ₃ ) δ: 7.10-7,

(15H, m, aromatic), 4.85 (2H,

ABq, J = 7.4, 0-Ch ₂ -O), 4.53 (1H, d, J = 5.2, H-4), 4.42 (1H, s, NH), 4.15 ( 1H, m, HV), 3.5 (1H, m, H-3), 3.47 (3H, s, O-CH ₃ ), 1.5 (3H, d, J = 6, CH ₃ ).

IR (KBr) ν: 3400-3500 (NH) and 1760 cm " ¹ (C = O). Max

○: Manufacture of

(VS, 3S, 4R and 1 ^f R, 3R, 4S) 3- {V-methoxymethyloxy-V-ethyl) 4-tritylthio-2-azetidinone (isomer C)

OCH ₂ OCH

STr

BrCH ₂ OCH ₃

OCH OCH

NaN.

030027/0777

M / 20 359 - 199 - - _Λ _ _ _{Λ Α Α}

A cold (dry ice-acetone bath) solution of (1'S, 3S, 4R and 1'R ₇ 3R ₇ 4S) 1- (tert-butyldimethylsyl) -3- (1 * -hydroxy-1. -Ethyl) -4 Tritylthio-2-azetidinone (5.03 g, 10 mmol) in THF (50 ml, distilled over LAH) is treated dropwise with a 1.6M solution of n-butyllithium in hexane (13.0 ml) until a pink color persists . A THF (20 ml) solution of bromomethyl methyl ether (1.49 g, 0.97 ml, 1119 mmol) is added dropwise. The mixture is stirred 30 minutes at -78 ⁰ C and then for 3 hours at 0 ⁰ C. They were poured into an ice-cold ammonium chloride solution and extracted with ether. The ether extracts are combined, washed with water, dried (MgSO-) and concentrated, whereby the crude (1 ^T S, 3S ₇ 4R and 1'R ₇ 3R, 4S) 1- (tert-butyldimethylsiiyl) -3- ( 1'-methoxymethyloxy-1'-ethyl) -4-tritylthio-2-azetidiinone. '. (5 ₇ 83 g ₇ 100%), which is deprotected as described below:

A cold (ice bath) solution of the derivative described above (5 ₇ 83 g ₇ 10 mmol) in HMEA-HO (90 ml-10 ml) is treated with sodium azide (1.365 g ₇ ^ 21 mmol). The cooling bath is removed and the mixture is stirred for 2 hours at room temperature. It is then poured slowly into ice-cold water (900 ml) and stirred for 30 minutes. The precipitate is collected by filtration and redissolved in methylene chloride. The solution is washed with water and brine and dried (MgSO-) to obtain the 'title compound (3.0 g, 69.3%), mp 172 to 172.5 ⁰ C iÄthylaeetat-hexane).

IR (CHCl-) v ^: 3400 (NH) and 1760 cm " ¹ .

¹ HmT (CDCl ₃ ) 5: 7.67-7.12 (15H, m, H aromatic), 4.63 (2H, center of ABq, J = 6, = -ch ₂ ~ O), 4.49 ( 1H ₇ s, NH), -4, -40 (IH, - A. J = 3. H-4), 4.25-3.80 (1H ₇ m, HT), 3.35-3.15 and 3.26 (4H, s + m, CH ₃ and H-3) and 1.30 ppm (3H, d, J = 6, CH ₃ ).

030027/0777

Μ / 20 359 SY-1599A

P. Manufacture of

1'R, 3S, 4R and 1 ^T S, 3R, 4S) 3- {1 ■
thio-2-azetidinone (isomer B)

OSO "<i> Br

OCHO

A solution of (1'S, 3S, 4R and 1'R> 3R, 4S) 3- (1'-p-bromobenzenesulfonyloxy-1'-ethyl) -1 - (terfc.-butyldimetnyIsilyl) -4-tritylthio-2- then it is diluted azetidinone (Isoermes C) ind DMF (3 ml) is heated for 48 hours at 50 ⁰ C and then 4 hours at 100 ⁰ C., the reaction mixture with K "0 and extracted with ether. The ethereal extracts are washed with brine, dried (MgSO.) And evaporated. The title compound is obtained in the form of white crystals after purification by column chromatography (silica gel, 5% GH

₃ CN-CH ₂ C1 ₂₎ (2 mg, 4.8%), mp 131-132 ⁰ C.

Hmr (CDCl,) δ: 8.07 (1H, s, CHO), 7.24-7.-56 (15H, m, aromatic), 5.23 (1H, dq, J = 6.4, 7, H-T), 4.38 (1H, dm J = 2.4, H-4), 4.25 (1H, s, NH), 3.20 (1H, dd, J = 7, 2.4, H-3), 1.43 (3H, d,

" ¹

IR (CHCl-) ν: 3400 (NH), 1765 (C = O), 1725 cm " ¹ (C = O).

030027Ό777

M / 20 359 SY-1599A

Q. Manufacture of

(1 ¹ R ₁ -SS ^ R and 1'S, 3R, 4S) 3- (1'-Acetoxy-1 '-ethyl) -4-tritylthio-2-azetidinone (isomer B)

OAc

J -STr

OAc

NaN-;

A.

STr

HMPT

.NH

'tBDMS

The pure derivative (1'R, 3S, 4R and 1'S, 3R, 4S) 1- (tert-butyldimethylsilyl) -3- (1 · -acetoxy-1'-ethyl) -4-tritylthio-2-azetidinone (5 , 77 g, 1057 mmol) is dissolved in warm HMPT water (60 ml, 10 ml). The solution is cooled to room temperature and NaN ₃ (1.2 g) is added. Stir for 45 minutes (the progress of the reaction is monitored by TLC and pour slowly into stirred cold water (800 ml). Stir the mixture for an additional 20 minutes. Collect the crystalline material and wash with water. Repeat in CH ₃ Cl ₂ dissolved, washed with water (twice) and with sodium chloride solution and _{dried over MgSO 4.} After evaporation of the solvent, a foam is obtained which crystallizes from ether-petroleum ether (4.90 g, 9S, 5%, melting point 143-144.5 ° C).

IR (CH "C1, J ν: 3395 (NH), 1772, 1738 cm" ¹ (C = O).

ZZ ΙΙΙΟ.Λ.

¹ Hmr (CDCl ₃ ) 5: 7.9-6.8 (15H, m, H aromatic), 5.12 (1H,

7.eT> -hT-um from Λα). J = 6.5. 7.5, HV) / 4.33 (1H, d, J = 2.8, H-4), 4.20 (1H, bs, NH), 3.17 (1H, ddd, J _3-1 , = 7 , 5, J ₃ _ ₄ = 2.8, J ₃ _ _NH = 1 , H-3), 2.1 (3H, Sf CH ₃ Co ;, 1.35 (3H, d, J-6.5, CH ₃ ).

030027/0777

C ··

fc »- -Λ

• β

- ²⁰² -

2950893

R. Manufacture of

3- (V-Hyaroxy-1 · ethyl) -4-tritylthio-2-azetidinone. Mixture of four isomers

OH

OAc

CH CHO

themselves_). 3 y

0 ί

Si-Cl

l Si-t ~

A solution of lithium diisopropylamide (0.74 mmol) to set at -78 ⁰ C in dry tetrahydrofuran (5 ml) of diisopropylamine (0.103 ml, 0.74 mmol) and BuLi (0.29 ml of a 2.52 M solution in hexane) here. After 30 minutes at -78 ⁰ C is added a solution of (R and S) 1-trimethylsilyl-4-tritylthio-2-azetidinone (0.292 g, 6.99 mmol) in dry tetrahydrofuran (2ml) added dropwise. After 5 minutes, an excess of freshly distilled acetaldehyde (0.2 ml) is added all at once. After 20 minutes at -78 ⁰ C dis TLC analysis reveals the complete Concealed © !! Remove the raw material and quench the reaction mixture by adding it to a saturated solution of ammonium chloride. Extraction with ethyl acetate (2 × 25 ml) and subsequent washing of the combined organic phases with saturated NH.Cl, sodium chloride solution and drying over anhydrous magnesium sulfate gives a yellow oil after evaporation of the solvent. If this oil is filtered through silica gel (10 g, eluting with CH, -: EtOAc, 6: 4), one obtains a

O D

Mixture of alcohols (0.215 g. 80%). This mixture

Hmr) cannot be separated by either HPLC or TLC.

030027/0777

M / 20 359 SY-1599A

a: acetylating

Acetylating an aliquot of the mixture (0.065 g) with an excess of acetic anhydride (1.0 ml) and pyridine (1.4 ml) gives a mixture of adetates. HPSL analysis gives four components ² : a) 34.6%, b) 17.4%, c) 30.1% d) 17.9%. In direct comparison (HPLC), compound a) is identical to isomer B.

b) tert-butyldimethyl-silyl derivatives

The mixture of alcohols (0.121 g, 0.34 mmol) is treated one with tert-butyldimethylchlorosilane (0.117 g, 0.776 mmol) and triethylamine (0.10 ml, 7.14 mmol) in dry dimethylformamide (1 ml) for 36 hours at room temperature. To Dilute with ethyl acetate and wash the 7 ^ ~ "ng with saturated Ammonium chloride and dry over anhydrous magnesium sulfate. Evaporation gives an oil (0.716 g) which has 4 components according to HPLC, a. = 3.7%, b = 60.6%, σ = 31.1% d = 4.6% (the identity of each individual was

4th
not yet established).

Annotation:

Butyllithium and lithium hexamethyldisilazane were ineffective

2
Order of increasing polarity

3
Acetylation of i-tert-butyldimethylsilyl-4-trityl-

thio-2-azetidinone derived product gives the following ratio:

d = 29.5%, c = 24.1 %, _r b = 33.8%, a = 12.6%.

4th
conversion of a mixture of alcohols derived from (4 and S) 1- (tert-butyldimethylsilyl) -4-tritylthio-2-acetidinone gives the following proportions: a = 5.2%, b = 41.3%, c = 48 %, d = 4.6%.

030027 / G777

M / 20 359 SY-1599A

S. Manufacture of

(1'R, 3S, 4R and 1'S, 3R, 4S) 3- (1 '-Benzoxy-1' - ethyl) -4-tritylthio-2-azetidinone (Isomer B)

MsO

OCO <f>

rf

Y N

^S H

A solution of (1'S, 3S, 4R and 1'R, 3R, 4S) 3- (1'-Methanesulfony 1 · -ethyl) -4-tritylthio-2-azetidinone (Isomer C) (035mg, 2mmol) and sodium benzoate (432 mg, 3 mmol) in 10% H ₂ O-DMF i10 ml) is heated for 7.5 hours at 90 ⁰ C. Then it is diluted with the reaction mixture H_O and extracted with ethyl acetate. The organic extracts are washed with brine, dried (MgSO.) And evaporated. The residue, purified by column chromatography (silica gel, 5% CH_ CN-CH ₂ Cl ₂ ) gives the title compound as a white solid (108 mg, 23.2%) mp 158 ^° C.

¹ Hmr (CDCl ₃ ) 6: 7.03-8.25 (20H, m, aromatic), 5.32 (1H, dq, J = 6.1, 9, HT), 4.40 (1H, d, J = 2.5, H-4), 4.30 (1H, s, NH), 3.40 (1H, dd, J = 9, 2.5, H-3), 1.50 (3H, d , 3 = 6, Λ, H-2 ¹ );

IR (CHCl) v _m : 3400 (NH), 1765 CC-), 1715 cm " ¹ (C = O). 3 iucix

030027/0777

M / 20 359
SY-1599A

- 205 -

T. Manufacture of

3- (1'-p -nitrobenzyldioxycarbonyl-1. -Ethyl) -4-tritylthio-2-azetidinone (4 isomers)

pc ° 2 ^PIi

SC (J).

JZ

.PNB

'Ν,

tBu

"Isomer C"

a) A solution of the "isomer C" of 1- (tert-butyldimethylsilyl) -3- (1'-p-nitrobenzyldioxycarbonyl-1'-ethyl) -4-tritylthio-2-azetidinone (1.3 g) in a Mixture of TEA (5 ml), water 85 ml), dichloromethane (20 ml) and methanol (30 ml) is stirred for 2 days at room temperature. The solution is diluted with water and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with sodium bicarbonate and water, dry, s2t and concentrated, an oil remaining. Crystallization from ether gave the pure title compound (902 mg), mp 78-80 ⁰ C.

¹ Hmr (CDCl-) 6: 8.25-6.75 (19H, m, aromatic), 5.21

(2H, s, benzyl), 5.05 (1H, m, H-1 ·), 4.40 (1H, s, NH), 4.27 (1H, d, J = 2.8, H-4 ), 3.37 (IH, dd, J = 5.3, 2.8, Ή-3) and 1.37 ppm (3H, d, J = 6.5, CH ₃ );

IR (CHCl ₁₁ ) ν: 3390 (NH), 1765 and 1745 (shoulder),

HIcLX

and 1525 cm

( ^N0 ₂ > -

030027/0777

M / 20 359 SY-1599A

- 206 -

b) A cold (0 ⁰ C) HMPT-H ₂ O (90ml - 19 ml) solution of the "isomer C" of 1- (tert-butyldimethylsilyl) -3- (1'-p-nitrobenZyldioxy-carboxyl-1 ' ethyl) - ⁱ 4-tfitylthio-2-azetidinone (9.11 g, 13.3 mmol) is treated with sodium azide (1.82 g, 27.9 mmol). The cold bath is removed and the mixture is stirred for 30 minutes. Then it is poured into water (1 liter) and extracted with ether (5 × 200 ml). The ether fractions are combined and washed with water (5 200 wt%) and sodium chloride solution and dried over MgSO. dried. Since the title compound precipitated on dilution with water / it was alternatively filtered off and recrystallized from ether; 7.22 g, 89%, m.p. 78-80 ° C.

"Isomer B"

The "B isomer" of 3- (1'-p-Nitrobenzyldioxycarbonyl-i'-ethyl 4-tritylthio-2-azetidinone is prepared as described above under "isomer C"; 92%, mp 155,5- 156 ⁰ C. (Ether).

¹ Hmr (CDCl ₃ ) 5: 8.25-6.80 (19H, si, aromatic), 5.20 (2H, s, benzyl), 4.95 (1H, m, HT), 4.35 (1H , d, J = 2.9, H-4), 4.17 (1H, S, NH), 3.20 (1H, dd, J = 10.8, J = 2.9, H-3) and 1.40 ppm (3H, d, J = 7.5, CH ₃ );

IR (CHCl ₀ ) ν ί 3480, 3390 (NH), 1772, 1750 (C = O) and

j ΙΠ3.Χ _ - »

1525 cm '

Analysis C ₃ .

calculated: found:

C. , 59 K , 96 N 93 S. 64 67 , 48 4th , 38 4, 92 5, 67 67 4th 4, 5,

030 0 27/0777

M / 20 359
SY-1599A

"Isomer A"

The "isomer A" of 3- (1'-p-nitrobenzyldioxycarbonyl-i-ethyl) 4-tritylthio-2-azetidinone is prepared as described above for "Isomer C"; Mp 205-106 ° C.

¹ Hmr (CDCl ₃ ) 5: 8.2-6.7 (19H, m, aromatic), 5.22 (2H, ABq, benzyl), 5.57-4.85 (IH, m, HT), 4 , 65 (1H, NH), 4.50 (1H, d, J = 6.5, H-4), 3.65 (IH, dd, J = 6.5, 12, J _N _ _H = 1, H-1) and 1.52 ppm (3H, d, J = 7.5).

"Isomer D"

The "isomer D" of 3- (1'-p-nitrobenzylclioxycarbonyl-1'-ethyl) -4-tritylthio-2-azetidinone is prepared as described above for "Isomer C";

¹ Hmr (CDCl) 6: 8.15-6.70 (19H * m, aromatic), 5.23 (2H,

ABq, benzyl), 5.20 (1H, si, ¹ H-1), 4.75 (TH, NH), 4.52 (1H, d, J = 5.5, H-4), 3.42 (1H, J = 5.5, 3, H-3 and 1.5 ppm (3H, d, J = 6.5, CH-). (The J value for H-3 was determined after DO exchange) .

U. Manufacture of

(1'R, 3S, 4R and 1'S _f 3R, 4S) 3- (1-methanesulfonyloxy-1'-ethyl) -4-tritylthio-2-azetidinone (isomer B)

030027/0777

M / 20 359
SY-1599A

A solution of (1 '! 1,33,4R and l'S, 3R, 4S) 1- (tert-butyldimethylsilyl) -3- (1 ^f -methanesulfonyloxy-1 ^f -ethyl) -4-tritylthio-2-azetidinone ( Isomer B) (4.95 g, 8.5 mmol) and sodium azide (1.11 g, 17.0 mmol) in 10% HO-HMPA (50 ml) are stirred for 30 minutes at room temperature. The solution is then diluted with water (250 ml) and extracted with ether. The organic extracts are washed with brine, dried (MgSO ₄ ) and evaporated. Crystallization of the residue (fither petroleum ether) gives the title compound (3.33 g, 83.8%). M.p. 130-131 ° C.

¹ Hmr (CDCl ₂ ) 5: 7.20-7.62 (15H, m> aromatic), 4.97 (1H, dq, J-6.4, 6.1, HT), 4.56 (1H, d, J = 2.8, H-4), 4.22 (1H, m, NH), 3.27 (IH, dd, J = 6.1, 2.8, H-3), 3.0 (3H, s, -CH ₃ ), 1.63 (3H, d,

J = 6.4, H-

IR (Nujol) ν: 3195 (n-H), 1768 cm

luäX

-1

(C = O).

V. Manufacture of

(1 ^l S, 3S, 4R and 1'R, 3R, 4S) 3- (1'-Methanesulfonyloxy-1'-ethyl) -4-tritylthio-2-azetidinone (isomer C)

OMs

-N.

A solution of (1'S, 3S, 4R and 1'R, 3R, 4S) 1- (tert-butyldimethylsilyl) = 3 = {1'-methanesulfonyloxy-1'-ethyl) -4-tritylthio-2-azetidinone (Isomer C) (2.85 g, 4.9 mmol) in 10% aqueous HMPA (25 ml) is treated with sodium azide (0.65 g,

0 300 27/0777

M / 20 359 - 209 - ^: · ·· '«· ·! .. Γ ** ^; I.

SY-1599A

10 mmol) and stirred for 0.5 hours at 25 ⁰ C. By diluting the solution with water (250 ml), the reaction product is forced to crystallize. The crude mesylate is redissolved in dichloromethane, washed with brine, dried (MgSO.) And evaporated. Trituration with ether gave the title compound in the form of white crystals, mp 155- 160 ⁰ C. 1.80 g; 78.6%;

¹ Hmr (CDCl ₃ ) δ: 7.43 (15E, m, aromatic), 5.02 (TH, dg, J = 6.5, 4.9, H-1 ¹ )., 4.55 (.. H, s, NH), 4.95 (1-H, d, J = 3, H-4), 3.33 (1H, dd, J = 4.9, 3, H-3), 1.51 (3H, d, J = 6.9, H-2 ¹ )?

^{IR v} ™ = ^ ^{: 3395} (NH), 1768 cm " ¹ (C = O);

C. 22nd H , 39 N OO % 64, 93 5 , 39 3, 24 % 63, 5 3,

Analysis C

calculated:
found

W. Manufacture of

(1'S, 3S, 4R and 1'R, 3R, 4S) 3- (1'-p-bromobenzenesulfonyloxy-1 ethyl) -4-tritylthio-2-azetidinone (isomer C)

OSO <f> Br OSO φ Br

^ "" "Si-f- ~ Ή

A solution of (1'S, 3S, 4R and 1 ¹ R ^ R, 4S) -3- (1'-p-Brombenzolsulfoxyloxy-1'-ethyl) -1- (tert-butyldimethylsilyl) -A- tritylthio-2-azetidinone (Isomer C) (1.42 g, 2 mmol) and sodium benzoate (0.865 g, 6 mmol) in 1 =% H_O-HMPA (40 ml)

0 30027/0777

»*« ■ a LJ 1 »»,

SY-1599A

is stirred for 1 hour at room temperature. Then the solution is diluted with H_O (100 ml) and extracted with ether. The jither extracts are washed with brine, dried (MgSO ₄ ) and evaporated. The crude crystalline title compound is triturated in a small volume of ether and collected by nitration (0.92 g, 77 %) _r .

¹ Hmr (CDCl ₃ ) Z: 7.80 (4H, s, benzenesulfonyl), 7.30-7.65 (15H, m, aromatic), 5.13 (1H, dg, J = 6.5, 4, 0, HT), 4.50 (1H, d, J = 2.9, H-4), £, 40 (1H, s, Nh :, 3.40 (1H, dd, J = 4.0, 2 , 9, H-3), 1.50 (3H, d, J = 6.5, H-2 ^1);

IR (CHCl-) ν: 3400 cm " ¹ (NH), 1770 cm" ¹ (C = O).

O 1Ώ3.Χ

X. Manufacture of

(1'R, 3S, 4R and 1'S, 3R, 4S) 3- (1x -hydroxy-1'-ethyl) -4-tritylthio-2-azetidinone (Isomer B)

OSO ΦΒγ

Su a warm solution of (1 ^f S, 3S, 4R and 1Ή, 3Η 3- (1'-p-bromobenzenesulfonyloxy-1'-ethyl) -1 - (tert-butyldimethylsilyl) -4-tritylthio-2-azet; Ldinon (isomer C) in HMPA (5 mi) is added dropwise 1 ml H ^ G. one häl-c aie React-IOE mixture for 20 hours at 90 ⁰ C, then diluted with ether and washed 4 times with brine. The The organic solution is dried (MgSO.) evaporated and the crude title compound is purified by column chromatography (silica gel, 15% CH ₃ CN-CH ₂ Cl ₂ ) to give a white solid (122 mg,

0 3 00 27/0777

M / 20 359 SY-1599A

2350898

44/5 %), m.p. 187-189 C, which was found to be identical to a sample of the title compound prepared in a different manner.

Y. Manufacture of

3- (1'-Hydroxy-1-ethyl) -4-tritylthio-2-azetidinone

-N,

Both isomers, (1'8,38,4R and 1'R, 3R, 4S) 3- (1'-hydroxy-1'-ethyl) -4-tritylthio-2-azetidinone (isomer C) and (1'R , 3S, 4R and 1 '8,3R ^ S) 3- (1' -Hydroxy-1 '-ethyl) -4-tritylthio-2-azetidinone (isomer B) are prepared by the same procedure. For example, a solution of (1'S, 3S, 4R and 1'R, 3R ₇ 4S) 1- (tert-butyldimethylsilyl) -3- (1'-hydroxy-1'-ethyl) -4-tritylthio-2-azetidinone (Isomer C) (1.0 g, 2 mmol) and sodium benzoate (0.865 g, 6 mmol) in 10% H ₂ O-DMF (40 ml) stirred for 18 hours at room temperature. The reaction mixture is then diluted with H ₃ O and extracted with ether. The organic extracts are washed with brine, dried (MgSO.) And evaporated. The crude title compound is crystallized from cold ether (0.47 g, 61%), mp 134-135 ° C.

¹ Hmr (CDCl ₃ ) δ: 7.12-7.56 (15H, m. Aromatic, 4.48 (1H, s,

N-H), 4.28 (1H, d, J = 2.8, H-4), 2.94 (1H,

dg, J = 6.5, 6.2, HV) ₁ . 3.06 (1H, dd, J = 6 _r 2,

2.8 ₇ H-3), 2.18 (1H, s, -OH), 1.30 (3H, d, J = 6.5, H-2 ');

IR (CHCl-) ν r 3400 (nH), 1760 cm " ¹ (C = O).

030027 / O777

Μ / 20 359 SY-1599A

- 212 -

Analogously one obtains

(1'R, 3S, 4R and 1'S _/ 3R, 4S) 1- (tert-butyldimethyl-silyl) -3- (1'-hydroxy-1'-ethyl) -4-tritylthio-2-azetidinone (isomer B ), M.p. 190-192 ⁰ C.

HMR (CDCl ₃ ) 6: 7.10-7.55 (15H, m, aromatic), 4.45 (1H, d, J = 2.5, H-4), 4.28 (1H, s, NH ), 4.10 (1H, dq, J = 6.4, 5.3, H-1 '), 3.08 (1H, dd, J = 5.3, 2.5, H-3), 1 , 50 (1H, s, -OH), 1.30 (3H, d, J = 6.4, H-2 ');

IR (CHCl-) ν: 3400 (NH), 1760 cm " ¹ (C = O).

Z. Manufacture of

(1'S, 3R, 4R and 1'R, 3S, 4S) 3- (1'-methoxymethyl-1. -Ethyl) -1- (p-nitrobenzyl-2 "-hydroxy-2" -acetate) -4-tritylthio -2-azetidinones (Isomer. A)

OCH ₂ OCH ₃

<f

-N

OCH ₂ OCH ₃

χ.

CO PNB

030027/0777

M / 20 359 SY-1599A

28SQ898

A mixture of the isomer A of 3- (1'-methyl-methyl-1-ethyl 4-tritylthio-2-azetidinone (7.5 g, 7.3 mmol), p-nitrobenzyl glyoxylate hydrate (4.7 g, 20.8 mmol) and toluene (300 ml) are heated for 1 hour in a Dean Stark device which is filled with 3 8 molecular sieves, at reflux. Cool the solution in ice and use triethylamine (0.24 ml, 1.7 mmol) added dropwise. The mixture is stirred for 1 hour, washed with dilute hydrochloric acid, sodium bicarbonate and brine, dry and concentrate to give the title compound as a foam (10.5 g, 94%).

¹ Hmr (CDCl ₃ ) δ: 8.25-6.84 (1.9H, m, aromatic), 5.24 (2H, s, benzyl), 4.67-4.83 (3H, m, 0-CH ₂ and H-4), 4.34-4.55 (1H, m, H-2 ¹ ), 4.02 (1H, m, H-1 ·), 3.54 (1H, m, H-3 ), 3.40 (3H, s, 0-CH _3), 1.38 (3H, d, J = 6.5, CH _3);

IR (KBr) ν: 3360 (OH), 1770 (C = O of ß-lactam), 1735 max _ *

(C- = from the ester) and 1605 cm (aromatic).

AA. Production of

(1'S, 3S, 4R and 1'R, 3R, 4S) 3- (1'-methoxymethoxy-1'-ethyl) -1- (p-nitrobenzyl 2 "-hydroxy-2" -acetate) -4-tritylthio-2-azetidinone (isomer C)

OCB ₂ OCIi ₃

OCBJXS,

Mh

CHO CO PNB

X.

STr

r ^0H

CO "PNB

A solution of hydrated p-nitrobenzyl glyoxylate (1.73 g, 7.11 mmol) is refluxed for 2 hours in toluene (90 ml) using a Dean Stark device filled with 3 ft. Molecular sieves. (1'S, 3S, 4R and 1'R _r 3R, 4S) 3- (1'-methoxymethyloxy-1'-

030027 / Q77?

• -J- *

• « t

M / 20 359
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- 214 -

ethyl) -4-tritylthio-2-acetldinone (3.0 g, 6.93 mttol) and reflux the mixture for a further 2 hours. The mixture is cooled to room temperature and triethylamine is added (70 mg, 97 μΐ, 0.69 mmol) and stir for 2 hours. Man dilute the reaction mixture with ether, wash with 1% strength [r aqueous HCl, water, 1% aqueous NaHCO-, water and Saline solution, dry (MgSO.) And concentrate, whereby one the title compound is obtained (4.60 g, 100%);

IR (CHCl-.) Υ _a : 3550-3100 (OH), 1765, 1750 (C = O) and

j ΓΠ3.Χ μ

1525 cm "'(NO ₂ );

(CDCl ₃ ) 6: 8.22, 8.18 (2H, 2d, J = 8, Hm aromatic), 7.67-7.0 (17H, m, H-aromatic), 5.3 (2H, bs , CH ₂ -PNB), 5.30-5.02 (m, H-2 "), 4.89-4.52 (m, HT and OH), 4.63, 4.59 (1H, 2d, J = 2, H-4), 4.33, 4.30 (2H, 2 centers of 2 ABq, J = 7, J = 7, 0-CH ₂ -O), 4 / 1-3.67 (1H , m _r H-1 ·), 3.2 (1H, H-3), 3.1, 3.6 (3H, 2s, CH ₃ -O) and 1.15 ppm (3H, d, J = 6 , 5, CH ₃ ).

BB. Production of

(1'R, 3S, 4R and 1 ¹ S, 3R, 4S) 3- (1'-acetoxy-1'-ethyl) -1- (p-nitrobenzyl-2 "-hydroxy-2" -acetate) -4 -tritylthio-2-azetidinone

OAc

: ho

'Isomer B "

TEA

-N

OH

CO PNB

A solution of hydrated p-nitrobenzyl glyoxylate (triturated with ether) 1.82 g, 30 mmol) is heated in benzene in a Dean-STark device filled with 3§ molecular

Q30027 / 0777

M / 20 359 - 215 -

^SY " ^1599Ä 2S50S98

seven 2 hours at reflux. Auetidinone (1 · -R, 3S, 4R and I ¹ S, 3R, 4S) 3- (1'-acefcoxy-1 ^s -ethyl) -4-tritylthio-2-azetidinone (10.88 g, 25 , 2 mmol) and the mixture is refluxed for a further hour. The solution is cooled to room temperature and triethylamine (0.35 ml, 2.5 mmol) is added. The intestine is stirred for 2 hours. The progress of the reaction is monitored by thin layer chromatography. Evaporation of the solvent gives a white foam in quantitative yield (100%, mixture of epimers) aging;
getting washed.

Epimers) Alternatively, the solution can be acidic and basic

IR (CH_C1_) ν: 3520 (OH), 1775, 1745 cm ¹ (C = O);

¹ Ητητ- (CDCl-) 6: 8.2, 8.18 (2H, 2d, J = 8, Ho aromatic), 7.80-6.90 (17H, m, Η-aromatic), 5.28, 5.17 (2H, 24, CH ₂ -PNB), 4.59 (0.67H, d, J = 7.2, CHO), 4.80 (center of m, HI ¹ ), 4.38 (0 , 33H, 2d, J = 8.8, CHO), 4.22 (D.33H, d, J ₄ _3 = 2.5, H-4), 4, -09 (0.67H, d, J ₄ _ ₃ = 2.1, H-4), 3.65 (D.67H, dd, J _3-1 = 5.8, J ₃ _ ₄ = 2.1, H-3), 3.47 (0.33H, dd, J ₃ .- ,, = 2.5, H-3), 3.33 (0.33H, d, J = 8.8, OH), 3.23 (0.67H, d, J = 7.5, OH), 1.88, 1.86 (3H, 2s, CH ₃ CD), 1.10, 1.06 (3H, 2d, J = 5.8, 6.3, CH ₃ ).

CC. Production of

3- (1 * -p-nitrobenzyldioxycarbonyl-1'-ethyl) -1- (p-nitrobenzyl) 2 "-hydroxy-2" acetate) -4-tritylthio-2-azetidinone (4 isomers)

OCO-PNB - OCO_PNB

^{2 2}

J— *

Cr \ H

Cf

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SY-I599A

- 216 -

"Isomer C"

A mixture of the "isomer C" of 3- (1'-p-nitrobenzyldioxycarbonyl-1 ^f -ethyl) -4-tritylthio-2-azetidinone (1.70 g, 0.3 mmol), p-nitrobenzyl glyoxylate hydrate (815 mg, 3.6 mmol) and toluene (50 ml) are refluxed for 7 days in a Dean Stark device filled with 3 l molecular sieves. The cooled solution is washed with dilute hydrochloric acid, sodium bicarbonate and brine, dried and concentrated to give the title compound (2.1 g) in the form of an epimeric mixture on the 2 "carbon atom. Purification is carried out by chromatography over silica gel. Alternatively, the The title compound can be prepared using a catalytic amount of triethylamine.

Less polar epimer at 2 "position:

¹ HmT (CDCl ₃ ) 6: 8.25-6.80 (23H, m, aromatic /, 5.30 and 3.12 (4H, 2s, benzyls), 4.65 (IH, d, J = 9, H-2 "), 4.45 (1H, d, J = 2.5, H-4), 4.45 to 4.10 (1H, m, H-1 ^1), 3.50 (1H, d , J = 9.2 "-0H), 3.28 (1H, dd, J = 2.5, J = 2.5, H-3) and 1.23 ppm (3H, d, J = 6.5 , CH ₃ );

IR (CHCl3,) ν: 3520 to 3200 (D-H), 1765, 1750 (C = O) and

1525 cm "'(NO ₂ ).

More polar isomer at C-2 "position:

¹ Hmr (CDCl ₃ ) δ: 8.25-6.85 (23H, m, aromatic), 5.25 and

5, OS <4H, 2s, BensyIe), 5; 05 (1H _r & _: J = 7. H-2 "), 4.35 (1H, d, J = 2.5, H-4), 4, 40-4.05 (1H, m, HV), 3.42 (1H, J = 7.2 "-0H), 3.33 (1H, dd, J = 2.5, 2.5, H-3 ), ΐ, 23 (3H, d J = 6.5, CH ₃ );

IR (CHCl-) V: 3520 to 3200 (0-H), 1755 (C = O) and

1525 cm " ¹

030027Ό777

M / 20 359 - 217 -

"Isomer B"

A mixture of hydrated p-nitrobenzyl glyoxylate (1.74 g, 7.66 mol) and (1'R, 3S, 4R and TS, 3R, 4S) 3- (1'-p-nitrobenzyldioxycarbonyl-1'-ethyl) - 4-tritylthio-2-azetidinone (3.63 g, 6.38 mmol) is refluxed in toluene (70 ml) in a Dean Stark device filled with 38 molecular sieves for 3 hours. The solution is cooled to room temperature and triethylamine (64.5 mg, S 9 ml, 0.539 mmol) is added. The mixture is then diluted with ether for 4 hours and washed with 2% strength aqueous HCl, water, 2% strength aqueous NaHCO, water and saline solution. It is dried and concentrated to give the pure title compound (5, 02 g, 100 %) Separation of the 2 epimers took place on a preparative silica gel plate.

Less polar epimer in the 2 "position:

IR (CHCl ₀ ) v_ ": 3500 (= -H), 1772, 1750 (C = O) 1525 cm" ¹ (NO ₂ )

Hmr (CDCl ₃ ) δ: 8.30-8.0 and 7.65-6.80, (23H, m, aromatic) 5.27 and 5.13 (4H, 2s, benzyls), 4.71 (1H , m, J = 6.5, 6.5, HT), 4.28 (1H, d, J = 2.2, H-4), 4 _r 23 (1H, d, J = 8.7, H -2 ") , 3.50 (1H, dd, J = 2.2, 6.5, H-3), 3.28 (1H, d, J = 8.7, 0-H) and 1.18 ppm (3H, d, J = 6.5 _/ CH ₃ ).

More polar epimer:

IR (CHCl,) V ₁₁ : 3480 (0-H), 1772, 1750 (C = O) and j max "

¹ Hmr (CDCl ₃ ) 5: 8.35-6.90 (23H, m, aromatic), 5.15 (4H, benzyls). 4.72 (1H, d. J = 7.5 _f H-2 "0), 4.90-4.50 (1H, m, J = 6.5, HV), 4.10 (1H, d, J = 2, H-4), 3.68 (1H, dd, J = 2, 6.5, H-3),

030027/0777

Μ / 20 359 - 218 -

SY-1599A

3.28 (1H, d, J = 6.5, OH) and 1.15 ppm (3H, d, J = 6.5, CH ₃ ).

"Isomer A"

The "isomer A" of 3- (1'-p-Nitrobensyldioxycarbonyl-1'-ethyl) -4-tritylthio-2-azetidinone yielded in the same way a mixing ¹ .IG of "isomer A" of 3- (1'- p-Nitrobenzyldioxycar. * - ionyl-1 '-ethyl) -1 - (p-nitrobenzyl-2 "-hydroxy-2" -acetate} -4-tri-lylthio -2-azetidinones.

¹ Hmr (CDCl ₃₎ δ: 8.3 to 6.7 (23H, m, aromatic), 5.17 (2H, benzyls), 5.0 OH, m, H-1 ^1), 4.9 and 4 ,8th

(1H _f 2a, J = 6, H-4, two epimers), 4.32 and 3.96 (1H, 2s, H-2 ", two epimers>, 3.68

(1H, ddt, J = 6, 6, H-3) and 1.47 ppm (3H, 2d J = 6.5, CH_, two spimers) -

"Isomer D"

The "isomer D" of 3- (1'-p-nitrobenzyldioxycarbonyl -1'-ethyl) -4-tritylthio-2-azetidinone similarly gave a mixture of "isomers D" of 3- (1'-p-nitrobenzyldioxycarbonyl-1-ethyl) -1-i-p-nitrobenzyl 2 "-hydroxy-2" acetate) -4-tritylthio-2-azetidinones.

¹ Hmr (CDCl ₃ ) ö: 8.30-6.60 (23H, m, aromatic), 5.20 (4H, m benzyls), 4.83 (1H, 2d, J = 5, H = 4), 5.50-4.30 (2H, m, H-1 • and H-2 "}, 3.48 (1H, m, H-3), 3.15 (1H, m, OH), 1.37 and 1.30 ppm (3H, 2d, CH ₀ ).

030027/0777

■ # ■ - * ■■ »- - * -— ττ '- · ♦ --- # - · - · -

M / 20 359 - 219 - * '

SY-1599A 2950896

DD. Production of

(1'S, 3S, 4R and 1'11,311,4S) 3- (1'-Methanesulfonyloxy-1'-ethyl) 1 ~ p-nitrobenzyl-2 "-hydroxy - 2" -acetate) -4-tritylthio-2 · - azetidinone (isomeric C)
(Epimers in C_ ,, position)

OMs OMs

.N OH CO "PNB

A solution of p-nitrobenzyl glyoxylate hydrate (9.72 g, 42.6 mmol) in Bezol (350 ml) is refluxed for 2 hours while the water is in a Dean STark device azeotropically removed. The (1'S, 3S, 4R and 1'R, 3R, 4S) 3- (T-methanesulfonyloxy-T-ethyl) -4-tritylthio-2-azetidinone are added to this solution (16.62 g, 35.5 mmol) and reflux for an additional 0.5 hour. Then you cool them Reaction mixture to room temperature, treated with triethylamine (0.5 ml, 3.5 mmol) and stirred for 3 hours to the Complete reaction. Evaporation of the solvent gives a white foam that remains unchanged in used in the next stage.

¹ Hmr (CDCl ₃ ) 6: 8.12 (2H, d, J = 9, Hm aromatic), 7.28 C7H, part of d, Ho aromatic, trityl), 5.28 (2H, S, -CH ₂ _, PNB), 4.88 (0.5H, s, H-1 "), 4.62 (1.5H, m, H-2" and H-4), 4.00 (2H, m, HT , -OH), 3.15 (1H, m, H-3), 2.73 i3H. see mesylate and 1.30 ppm (3H, d, J = 6 Hz, H-2 ^f );

IR ν: 3520 (0-H), 1775 (C = O) and 1765 cm " ¹ (C = O).

Q30027 / 0777

M / 20 359
SY-1599A

EE. Production of

(1'8,311,4R and 1'R, 3S, 4S) 3- (1-methoxymethyl-1'-ethyl) -1- (p-nitrobenzyl-2 "-chlor-2" ~ acetate) -4-tritylthio- 2-azetidonone (Isomer A)

OCH ₂ OCH ₃

OCH ₂ OCH ₃

3 OH

"Lf" ³

CO PNB

CO PNB

Pyridine (1.1 ml, 14.2 mmol) is added dropwise to a solution of the isomer A of 3 (1'-methoxymethyl-1'-ethyl) -1- (p-nitrobenzyl-2 "-hydroxy-2" - acetate) -4-tritylthio-2-azetidinone (7 g, 10.9 mmol) in THF (350 ml), cooled to -15 ⁰ C. immediately thereafter gibt.man thionyl chloride (1.0 ml, 14.0 mmol) dropwise and the mixture is stirred at -15 ° C. for 0.5 hours. The precipitate is removed by filtration and washed with benzene. The combined filtrates are concentrated, the residue is redissolved in fresh benzene and the solution is treated with activated charcoal, filtered and concentrated, the title compound remaining in the form of an oil (6.5 g, 90%),

¹ Hmr (CDCl ₃ ) 5: 6.65-8.35 i19H, m, aromatic), 5.24 (2H, s, benzyl), 3.43 (3H, s, OCH ₃ ) and 1.42 ppm ( 3H, d, J = 6, CH ₃ ).

030027/0777

M / 20 359 - -221- ...: ":

SY-1599A

2880-898

FF. Production of

(1'S, 3S, 4R and 1'R, 3R, 4S) 3- (1'-ethoxymethy1oxy-1-ethyl) 1-ip-nitrobenzyl-2 "-chlor-2" -acetate) -4-tritylthio ~ 2-azetidinone (Isomer C)

^ STr SOCl ₂

JCJ

v ^cl

CO PNB

A cold (ice-MeOH bath) THF (60 ml, distilled over LAH) solution of (1'3,35,4R and 1'R _/ 3R _/ 4S) 3- (1'-methoxymethyloxy-1'-ethyl ) -1-panitrobenzyl-2 "-hydroxy-2" -acetate) -A- tritylthio-2-azetidinone (4.25 g, 6.62 mmol) is treated dropwise with pyridine (0.696 ml, 8.61 mmol) and Thionyl chloride (0.530 ml, 8.61 mmol). The mixture is stirred 30 minutes at -15 ⁰ C. The precipitate is collected by filtration and washed with benzene. The THF-benzene solution is concentrated and the residue is redissolved in benzene. The solution obtained is treated with activated charcoal. Removal of the activated charcoal on a bed of celite followed by evaporation of the benzene gives the title compound (4.86 g, 100%);

IR (CHCl-) ν: 1770 (C = O) and 1525 cm " ¹ (NO_). ■ i max £

¹ Hmr (CDCl ₃ ) 6: 8.15, 8.12 (2H, 2d, H-aromatic), 7.70-7.00

(17H, m, H-aromatic), 5.62, 5.02 (1H, .2s, H-2 "), 5.27 (2H, s _r CH ^ -PNB), 4.7 (1H, d , H-4), 4.7-3.7 (m, O-CH ₃ -O, HV), 3.5-2.8 (m, H-3), 3.12, 3.08 (3H _r 2s, 0-CH ₃ ) and 1.30-0.96 ppm (3H, i, CH ₃ ).

030027/0777

M / 2Ü 359
■ 3Y-1599A

2850898

GG. Production of

(1'R, 3S, 4R and 1'S, 3R, 4S) 3- (1'-acetoxy-1'-ethyl) -1- (p-nitrobenzyl-2 ¹¹ -chloro-2 "-acetate) -4-tritylthio -2-

azetidinone

Äc

OAc

SOCl.

OH

Pyridine

STr

CO PNB

CO PNB

"Isomer B"

A THF (distilled over LAH) solution of (1'R, 3S, 4R and 1 '3,3R ^ S) 3- (1' -Acetoxy-1 · -ethyl) -1- (p-nitrobenzyl-2 " -hydroxy-2 "-acetate) -4-tritylthio-2-azetidinone (10.88 g of NH) g is at -15 ⁰ C (ice-methanol bath) under Sticksotffatmosphäre with pyridine (2.19, 2.24 ml, 27.7 mmol), thionyl chloride (3.3 g, 2.02 ml, 27.7 mmol), and thionyl chloride (3.3 g, 2.02 ml, 27.7 mmol) * The mixture is stirred 20 minutes at -15 ⁰ C. The salt is washed abfiltrieri and benzene. Evaporation of the solvent (THF + benzene) gives a residue which is taken up in warm benzene and treated with activated charcoal. The suspension is filtered through a pad of Celite and, after evaporation of the solvent, a foam is obtained;

IR (CH-Cl ₀ )

: 1780, 1740 cm " ¹ (C = O)

(CDCl ₃ ) δ: S, 17, S _? 21 (2H, - 2d _F J = S, - Hq aromatic) .-

7.76-6.88 (17H, m, H-aromatic), 5.31, 5.16, 5.12, 4.73 (3H, 4s, CH ₂ PNB, CHCl), 5.12-4, 55 (1H, m, H-1 ¹⁾ / 4.35-4.25 (1H, m, H-4), 3.80 to 3.45 (1H, m, H-3) 1.90 (3H , s, CH ₃ CO), 1.12, 1.07 (3H, J = 6.5, CH ₃ ).

03ÖQ27 / 0777

M / 20 359 - 223 - "*"

SY-1599A 2850898

HH. 3- (T -p-Nitrobenzyldioxycarbonyl-1'-ethyl) -1 - (p-nitrobenz y i- 2 "-chloro-2" -acetate) -4-tr itylthio-2-azefcidinone (Mixture of epimers in C2 "position)

OCO PNB OCO "PNB

CO PNB

"Isomer C"

Pyridine (58 mg, 0.73 mmol) is added dropwise to a solution of "isomers C" of 3- {1'-p-nitrobenzyldioxycarbonyl-1'-ethyl) -1- (p-nitrobenzyl-2 "-hydroxy- 2 "-acetate) -3-tritylthio-2-azetidinones (470 mg, 0.6 mmol; mixture of epimers in C-2 'position) in THF (15 mi), which is cooled to -15 ⁰ C immediately. thionyl chloride (86.5 mg, 0.73 mmol) is then added dropwise to the mixture and it is stirred for 0.5 hours at -15 ° C. The precipitate is removed by filtration and washed with benzene is dissolved in fresh benzene and the solution is treated with activated charcoal, filtered and concentrated to leave the title compound as an oil, 530 mg, 100%.

Hmr (CDCl-) δ: 8.7-6.8 (23H, m, aromatic), 5.53 (IH, s, H-2 "), 5.30 and 5.17 (4H, 2s, benzyls), 4.52 (1H, d, J = 2, H-4), 4.20-370 (1H, m, HT) , 3.31 (1H, dd, H-3), 1.27 and 1.21 ppm (3H, 2d, J = 6.5);

IR (CHCl.,) V: 1780, 1750 (C = O) and 1525 cm " ¹ (NO.,).

030027/0777

»C » Λ *

Μ / 20 359 SY-1599A

- 224 -

2810898

"Isomer B"

The "isomer B" of 3- (1-p-Nitrobenzyldioxycarbonyl-T-ethyl) -1- (p-nitrobenzyl-2 "-chlor-2" -acetate) -4-tritylthio-2-azetidinones (mixture of C-2 "spinners) is as above for "Isomer C described in quantitative yield.

¹ HaIT (CDCl ₃ ) 5: 8.25-6.90 (23H, m, aromatic), -5 _? 40-5, -C

(4H, m, benzyls), 5.40-4.45 (1H, m, HT), 4.82 and 4.57 (1H, 2s, H-2 "), 4.36 and 4.31 (1H , 2d, J = 2.5 ₇ H-4), 3.63 (1H, m, J = 2.5, J = 6.5, H-3), 1.25 and 1.18 ppm (1H, 2d,

IR (CHCl,) v: 1780, 1750 (C = O) and 1525 cm " ¹ (NO,).

ό ID 3.X £

"Isomer A"

"Isomer A" of 3- (T-p-nitrobenzyldioxycarbonyi-1'-ethyl) 1 '- (p-nitrobenzyl-2 "-chlor-2" -acetate) -4-tritylthio-2-azetidinones (Mixture of C-2 "epimers).

Hmr (CDCl ₃ ) 6: 8.30-6.80 (23H, m, aromatic), 5.45-4.80

(Him

HT); 5; 18 and 5.21 (4H, 2s, benzyl 4.87 (1H, 2d, H-4), 4.22 and 3.87 (1H _r 2s, H-2 "), 4.05-3, 40 (1H, m, H-3), 1.57 and 1.50 ppm (3H, 2d, CH ₃ ).

"Isomer D"

"Isomer D" of 3- (1'-p-Nitrobenzyldioxycarbonyl-1'-ethyl) -1 '- (p-nitrobenzyl-2 "-chlor-2" -acetate) -4-tritylthio-2-azetidinones (Mixture of C-2 "epimers).

Hmr (CDCl ₃ ) δ: 8.30-6.70 (23H, m, aromatic), 5.32-5.10 (4H, m, benzyls), 5.48 and 5.30 (1H, 2s, H. -2 "), 4.82 (1H, d, J = 5, H-4), 5.30-5.20

030027/0777

se »a

Μ / 20 359
SY-1599A

- 225 -

2910838

(1Η, m, H-1 ¹⁾ / 3.15 (1H, m, H-3), 1.40 and 1.30 ppm (3H, 2d, J = 6.5, CH _3);

IR (CHCl-) ν.: 1780, 1750 (C = O) and 1525 cm " ¹ (NO_). Ο max £

II. Manufacture of

(1'S, 3S, 4R and 1'R, 3R, 4S) 3- (1'- ^{Methanesulfonyloxy-1 1} -ethyl) 1- (p-nitrobenzyl-2 "-chior-2" -acetate) -4-tritylthio- 2-azetidinone (isomer C>

(C ₂ ,, - epimers)

OMs

OMs

-N

3 OH

> · Ρ ^Γ 3

PNB

To a cold solution (5 C) of (1'S, 3S, 4R and 1 'R, 3R, 4S) 3- (T-methanesulfonyloxy-1'-ethyl) - (p-nitrobenzyl-2 "-hydroxy-2" - acetate) -4-tritylthio-2-azetidinone (24.0 g, 35.5 mmol) in dry tetrahydrofuran {350 ml) are added dropwise pyridine (3.65 g, 46.2 mmol) and thionyl chloride (5.5 g, 46.2 mmol). After stirring for 45 minutes, add ioman ether (100 ml) to precipitate the hydrochloride salt, which is then filtered off. The filtrate is evaporated and the residue is redissolved in benzene (200 ml) and treated with. Activated carbon. Evaporation of the solvent gives an almost white foam which is used unchanged in the next stage.

¹ HnVr (CDCl ₃ ) 6: 8.18 (2H, d, J = 9, Hm aromatic), 7.72

(17H, m, part of d, Ho aromatic), trityl) 5.57 and 5.12 (1H, s, H-2 "), 5.28 (2H, s,

030027/0777

-CH ₂ PNB), 4.73 (1H, 2d, H-4), 3.21 (1H,

2dq, H-3), 2.78 (3H, 2s, mesylate and 1.21 ppjK

(3H, 2d, H-6H ₂ ; H-2 ¹ );

IR ν: 1779 cm "'(C = O).

ΙΩ32 £

JJ. Production of

(1'S, 3R, 4R l: J 1'R, 2S, 4S) 3- (1'-methoxymethoxy-1'-ethyl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -4 -tritylthio-2-azetidinone (Isomer A)

OCH2OCH3 - OCH ₂ OCH ₃

Df

Cl

-PNB

A mixture of the isomer A of 3- (1'-methoxymethoxy-1'-ethyl) -1- (p-nitrobenzyl-2 "-chlor-2" -acetate) -4-trityl: Λο- 2-azetidinone (6, 6 g, 10 mmol ^, tripehynphosphine (3.3 g,
12.5 HiMoI), 2,6-lutidine (1.3 ml, 11 μmol) and dioxane (140 ml are heated under reflux for 2 days. The solution is diluted with ether, washed with dilute acid (5% HCl) and water , dilute sodium bicarbonate solution and saline solution, dry and concentrate The residue is purified by chromatography
on silica gel and eluted with 10% ether in benzene
cleaned. Concentration of the desired fractions results
the title compound as a foam (1.4 g, 13.7%)

IR (KBr) ν: 1750 (C = O) and 1660-1650 cm " ¹ (C = C, aroma-

HIaX

table).

030027/0777

• I · ·

M / 20 359 SY-1599A

- 227 -

2350838

KK * production of

(1'S, 3S, 4R and 1'11,311,4S) 3- (1'-methoxymethyloxy-1'-ethy 1) 1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" acetate) -4-tritylthio-2-azetidinone (Isomer C)

OCH ₂ OCH ₃

STr

η ..

OCH ₂ OCH ₃

"Λ

STr

.PNB

CO PNB

A dioxane solution (100 ml, distilled over for XiAH) of (1 ^f S, 3S, 4R and 1'R, 3R, 4S) 3- (1'-methoxymethyloxy-1'-ethyl) 1- (p-nitrobenzyl ~ 2 "-chlor-2" -acetate) ^ -tritylthio ^ - azetidinone (4.86 g, 6.62 inMol), triphenylpho sphin (2.60 g, 9.93mmol) and 2,6-lutidine ( 770 mg, 0.837 ml, 7.20 mmol) was heated to reflux for 4 hours and then keeping them 16 hours in a hot bath (100 ⁰ C) - the mixture is diluted with ether, washed with 1% aqueous HCl, water , 10% aqueous NaHCO, water and saline solution and dry (MgSO.). The solution is concentrated and the residue is filtered through a silica gel column (65 g) (5%, 10% and 20% ether-benzene), whereby the title compound is obtained (2.8 g, 48%).

IR (CHCl ^) ν

: 1795 (C = O), 1620 and 1605 (phosphorane) and 1515 cm

030027/0777

M / 20 359
SY-1599A

- 228 -

2850898

LL. (TR, 3S, 4r and 1'S, 3R, 4S) 3- (1 ^f -acetoxy-1 · -ethyl) -1- (pnitrobenzy1-2 "-triphenylphosphoranylidene-2" -acetate) -4-tritylthio-2-azetidinone (Isomer B)

OAc

OÄC

.STr

STr

Cl

PNB

2,6-lutidine

CO PNB

A dioxane solution (100 ml, freshly distilled over LAH) of crude (1'R, 3S, 4R and 1'S, 3R _/ 4S) 3- (1'-acetoxy-I'-ethyl) -1- (p-nitrobenzyl -2 "-chlor-2" -acetate) -4-tritylthio-2-azetidinone is treated with 2.6 lutidine (2.97 g, 3.23 ml, 27.72 μmol) and triphenylphosphine (9.91 g, 37.8 mmol). The mixture is refluxed for 18 hours (oil bath, 130 °). The solvent is evaporated and the residue is redissolved in methylene chloride. The solution obtained is washed successively with dilute HCl, H0, dilute aqueous NaHCO, RJD and saline solution. After drying and evaporation of the solvent, the title compound remains as a solid which is triturated with ether and collected by filtration (14.6 g, 65.9%);

IR (CH ₂ Cl ₂ )

Max

1750 (C = O) and 1620, 1610 cm ¹ (phosphorane)

MM. 3- (T-p-Nitrobenzyldioxycarbonyl-1'-ethyl) -1- (p-nitrobenzyl-2 "~ triphenylphosphoranylidene-2" acetate) -4-trityl-

^ ■ 1 ^ 1? TTQTf

OCO ₂ PNB

OCO

J-A ei

CO

PNB

CO ₂ PNB

030027/0777

M / 20 359 - 229 -

^SY " ^1599A 2950898

Isomer B

A mixture of (1 ¹ R, 3S, 4R and 1'S, 3R, 4S) 3- (1 · -p-Nltrobenzyl-dioxycarbonyl-1'-ethyl) -1 ~ (p-nitrobenzyl-2 "-chlor-2" acetate) -4-tritylthio-azetidinone (isomer B) (4.96 g, 6.22 mmol, mixture of C-2 "epimers), trxphenylphosphine (2.47 g, 9.42 mmol) and 2.6 -Lutidine (740 mg, 0.80 ml, 6.91 mmol) is heated for 30 hours in dioxane (freshly distilled over LAH) .The solution is diluted with ether and ethyl acetate, washed with 5% aqueous HCl, water, 10% % aqueous NaHCO, water and saline solution and dried (MgSO.). Evaporation of the solvent gives a residue which is passed through a silica gel column (10 times its weight) (10% ether-benzene, ether and ethyl acetate) . This gives the title compound as a crystalline solid (3.1 g, 49%), mp. 189-190 ⁰ C (ether)

IR (CHCl ₃ ) v _max : 1750 (C = O), 1620, 1605 (phosphorane) and

1522 cm " ¹ (NO ₂ ).

Isomer C

The isomer C of 3- (1'-p-nitrobenzyldioxycarbonyl-1 * - ethyl) -1- (p-nitrobenzyl-2 "-trxphenylphosphoranylidene-2" acetate) -4-tritylthio-2-azetidinone is prepared as described above for isomer B.

IR (CHCl-.) Ν: 1750 (C = O), 1610, 1620 (phosphorane) and

j BaX _ ".

1520 cm (NE-);

¹ Hmr (CDCl ₃ ) S: 8.6-6.7 (7H, aromatic), 5.22 and 4.95

(Benzyl egg, 4.70 (H-4 /, 2.6 {H-3 /, 1.15 µfiu 1 _r 07 ppm (CH-).

030Q27 / 0777

M / 20 359 - 230 -

SY-1599A 2950898

Isomer D

A mixture of isomer D of 3- (1'-p-nitrobenzyldioxy carbonyl-1'-ethyl) -1- (p-nitrobenzyl-2 "-chlor-2" -acetate) -4-tritylthio-2-azetidinone (4.598 g, 4.45 mmol, purity 77%, mixture of C-2 "epimers), triphenylphosphine (1.425 g, 5.44 mmol), Aldrich) and 2.6 lutidine (0.63 ml, 580 mg, 5, 40 mmol; anachemia) in dioxane (65 ml, distilled from LAH) is _{gently refluxed for 41 hours under an N 2} atmosphere, the reaction being monitored using TLC (benzene: ether = 3: 1) The dark reaction mixture is cooled, diluted with EtOAc and washed successively with 0.1 N HCl, water, 2% NaHCO and then with brine. Drying (Na “SO.) and evaporation of the solvents gives 4.18 g of a dark colored oil, which is purified by column chromatography (SiO-, 88 g; eluent 10-25% ether in benzene) to give 1.108 g (1.08 mmol, yield 24.3%) of the title compound as a yellowish foam.

¹ Hmr (CDCl ₃ ) 6: 1.08 (d, J = 6Hz, V-CH ₃ ); IR (neat) ν: 1745 cm " ¹ (s, C = O).

NN. Production of (1'S, 3S, 4R and 1'R, 3R, 4S) 3- (1 • -methanesulf onyloxy-1'-ethyl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" acetate) -4-tritylthio-2-azetidinone (Isomer C)

030027/0777

M / 20 359 SY-1599A

- 231 -

2850838

A solution of (l'S, 3S, 4R and 1'R, 3R, 4S) 3- (1'-methane sulf onyloxy-1 * -ethyl) -1 - (p-nitrobenzyl) -2 "-chlor-2" -acetate) -4-tritylthio-2-azetidinone (24.7 g, 35.5 mmol), triphenyl phosphine (11.2 g, 42.7 mmol) and 2,6-lutidine (4.2 g, 39.1 mmol) in dry dioxane (350 ml) is refluxed under nitrogen for 19 hours. The solvent is evaporated and the crude product is redissolved in ethyl acetate and washed successively with dilute HCl, NaHCO., And brine. The cleaning will completed by chromatography on a silica gel column (8.5 χ cm). E3.uition with 10% ether-dichloromethane (1.5 1) and then with ether (1.5 1) gives the purified phosphorane; 12.36 g (40%).

¹ HmT (CDCl ₃ ) δ: 2.53 and 2.93 ppm (3H, 2s, mesylate); IR ν: 1749 and 1620 cm " ¹ (C = O).

OO. Production of

{1'R, 3S, 4Rund V3,3R, 4S) 3- (1'-hydroxy-1'-ethyl) -1- (p-nitrobenzy1-2 "-triphenylphosphoranylidene-2" -acetate) -4-tritylthio- 2-azetidinone (Isomer B)

OAc A "^ ^STr

OH

NaOS

CO PNB

A solution of phosphorane (1 ^r R / 3S, 4R and 1 * S, 3R _y 4S) 3- (1 '-Acetoxy-1' -ethyl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" - acetate) -4-tritylthio-2-azetidinone (4.43 g, 5.00 mmol) in methanol (10 ml) THF (60 ml is treated at room temperature with 1% aqueous NaOH (1 eq., 200 mg in 20 ml of H-)

030027/0777

SY-1599A λ-. · »*.

is followed by TLC ⁺ . The mixture is diluted with fither stylacetate and washed with HCl, H ₂ O, aqueous NaHCO, H_0 and saline solution. Evaporation of the solvent gives a residue which is crystallized from benzene ether (3.7 g, 87.7%), melting point 169.5-170.5 ° C.

IR (CH ₀ Cl ₀ ) ν: 1745 (C = O) and 1620 cm " ¹ (Phosphoranl A £ max

Heating the mixture increases the reaction rate -,

PP. Production of

(I ¹ S, 3R, 4R, and 1'R, 3S, 4S) Silver 3- {1'-methoxymethyl-1 × - ethyl) -1- (p-nifcrobenzyl-2 "-triphenylphosphoranyliden 2-acetate ⁿ⁾ - 2-azetidinone-4-thiolate (isomer A)

OCH ₂ OCH ₃

OCH ₂ OCH ₃

Silver 3- (1'-methoxymethyl-1'-ethyl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -3-tritylthio-2-azetidinone (Isomer A) is as described for isomer C from the p-nitrobenzyldioxycarbonyl derivative manufactured. Yield: 50%.

IR (pure) ν

745 cm " ¹ (C = O).

030027/0 7 77

• ·· ♦.

M / 20 359 - 233 - · '

^SY - ^1599Ä 2950898

QQ. Production of

(1 'S _r 3S , 4R and 1' R, - 3R, 4S) Silver 2- (1 '-methoxymethyloxy-1' · ethyiy -1 - (p-nitrobenzyl-2 "-triphenylphosphoranyliden ™ 2" -acetate) -2-azetidinone-4-thiolate (isomer C)

OCH-OCH, OCH ₂ OCH ₃

I 2 3 ι

J .STr J SAg

^ N S AgNO ₃ "Λ T ^

Y N

AgNO ₃

CO PNB CO PNB

(1 'S, 3S, 4R and 1' R, 3R _r 4S) 3- (T -methoxymethyloxy-1 '-ethyl) 1- (p-nitrobenzyl-2 ^SI -triphenylphosphoranvlidene-2 "-acetate.) 4-tritylthio -2-azetidinone (887 mg, 1.0 mmol) is dissolved first in hot (40 ⁰ C) methanol (30 ml), treated with Pyridln (103 mg, 0.105 ml, 1.3 mmol) and treated after cooling, a 0.15 M methanol solution of silver nitrate (8.7 ml, 1.3 mmol)., the mixture was stirred for 1 hour at 23 ⁰ C, cooled (ice bath) and stirred for another 20 minutes. the salt is filtered and washed successively with cold Methanol and ether (3 times, 671 mg, 87%) washed.

IR (CHCl} y: 1745 (C = O); 1605 (phosphorane) and

1520 cm " ¹ (NO ₂ ).

RR. Production of

Silver 3- (1 * -p-nitrobenzyldioxycarbonyi-1 ^5- ethyi) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone-4-thiolate

OCO PNB

Say

► '1 — Γ

^Φ 3

Ό PNB,

2 CO PNE

030027/0 7 77

M / 20 359 - 234 - ·

^SY " ^1599A 2850888

"Isomer B"

(1 ⁵ R, 3S, 4R and 1 ^! S, 3R, 4S) 3- (Ισ-p-nitrobenzylcarbonyldioxy-

1 '-ethyl) -1- (p-nitrobenzyl-2 "-triphenylphosphornylidene-2" acetate) -4-tritylthio-2-azetidinone (1.02 g, 1 mmol) is first dissolved in CE ₂ Cl ,, ( 3 ml) and diluted with hot (55 ⁰ C) MeOH 820 ml) Dt ~ hot solution is treated first with 120 ml pyridine (117 mg, 1.48 mmol) and a hot (55 ° C) 0.15M met ^K Unolian silver nitrate solution (SmI ₇ "i _f 2 mmol). The mixture is stirred for 15 minutes at room temperature, then

2 hours at 0 ^° C. It is then concentrated on a rotary evaporator (no bath) to a 10% solution. The mercaptide is filtered off and washed twice with cold (-15 ⁰ C) methanol and three times with ether. (917 mg, 100%).

IR (Nujol, trituration) v _max : 1745 (C = O), 1600 (phosphorane)

and 1517 cm

"Isomer C"

Silver 3- (1 '-p-nitrobenzyldioxycarbonyl-1' -ethyl} -1 (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" acetate) 2-azetidinone-4-thiolate, "Isomer C" is prepared as described above for "Isomer B";

IR (Nujol) v_: 1745 (C = O) and 1600 cm " ¹ (phosphorane).

"Isomer D"

A solution of the isomer D of 3- (1'-p-nitrobenzylcarbonyldioxy-1'-ethyl) -1 - (p-nitrobenzyl-2 "-triphenylpho3phoranylidene-2" -acetate) -4-tritylthio-2-azetidinone (145 mg , 0,142mMol |) is prepared by first dissolving it in CH ₇ Cl ₇ (5 ml), the CH ^ Cl ^ are added and removed at 55 to 60 ⁰ C hot MeOH 84ml). _{A hot solution of AgNO 3} in MeOH (0.15M, 1.14 ml, 0.17 mmol, 1.2 Squ), and then pyridine <14 μΐ, 0.17 mmol, 1.2 equiv) are added to this solution.

030027/0777

M / 20 359 SY-1599A

The silver mercaptide begins to precipitate immediately. The mixture is stirred for 2 hours at room temperature and 1 hour at ⁰ ° C. The mercaptide is collected by filtration and washed with ice-cold MeOH and ether, 99 mg (0.11 mmol, 78%) of the title compound being obtained as a brownish solid:

IR (Nujol)

ΠΙαΧ

: 1750 cm " ¹ (s, C = O).

SS. Manufacture of

(1'R, 3S, 4R and 1'S, 3R, 4S) silver-3- (1'-hydroxy-1'-ethyl) 1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) 2-azetidinone-4-thiolate {isomer B)

OH

ΡΦ,

CO PNB

AgNO,

OH

X ^ ^SAg

CO PNB

A solution of (1 ^f R, 3S, 4R and 1 ^l S, 3R, 4S) -3- (1'-hydroxy-1 '-ethyl) -1- (p-nitrobenzyl 2-acetate ⁿ -triphenylphosphoranyliden-2 ") -4-tritylthio-2-azetidinone (1 g, 1.19 mmol) in MeOH (10 ml) is treated with pyridine (124 μΐ, 121.3 mg, 1.53 mmol) and at 10 ⁰ C with a 0, 15M solution of silver nitrate in MeOH (15 ml, 2.25 mmol - or until no further precipitation of the silver mercaptide takes place) - The mixture is stirred for 1 hour and concentrated on the rotary evaporator (no bath) to a concentration of about 10% The solvent is filtered off, the cake is washed once with MeOH and three times with ether and suctioned off under high vacuum (954 mg, 100%).

IR (Kujol Verr-) v: 3500-3400 (0-H) 1595 (phosphorane) and

"'(NO ₂ ).

1525 cm ₂ ⁺ The crystalline material is first in

solved.

030027/0777

_ 6 Λ

* C

M / 20 359 SY-1599A

- 236 -

TT. Production of

(1'11,311,4R and 1'3 / 33,4S) 4 <-Acetylthio-3- (1 '-p-nitrobenzyldioxycarbonyl-1'-ethyl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" acetate) -2-azetidinone (Isomer D)

OCO_PNB

XL,

Say

CHvCOCl-Pyr

OCO PNB

Φ.

CO PNB

To a stirred solution of silver 3- (1'-p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" acetate) -2-azetidinone-4-thiolate (isomer D) (85 mg, 0.095 mmol) in CH ₂ Cl ₂ (5 ml) which pyridine (30 μΐ = 0.37 mmol; Fischer) which are added at 0 - 5 ⁰ C CH ₃ COCl (20 μΐ, 0.28 mmol) and the mixture stirred for 30 minutes at 0-5 ⁰ C. The precipitate that has formed is filtered off and washed _{with CH 2} Cl _2. The filtrates and washing liquids are combined, washed successively with brine, dilute HCl, saturated NaHCO ₃ and then with brine, dried (Na ₃ SO ₄ ) and evaporated to give 75 mg (0.091 mmol, crude yield 95%) of the title compound as a syrup ;

'Hmr (CDCl ₃ ) 5: 2.33 (s, -30COCH ₃ );

IR (pure) ν

: 1750 (β-lactam, ester), 1696 (thioester), 1520 and 1350 cm (-NO ₂ ).

030027 / G777

Μ / 20 359 SY-1599A

-9 4 «

UU. Production of

(1'R, 5R, 6R and TS, 5S, 6S) cis-p-nitrobenzyl ~ 2-methyl-6- (1 ' -p-nitrobenzyl-dioxycarbonylmethyl-penem-S-carboxy lat (Isomer D)

OCO ₂ PNB

OCO PNB

SAc

toluene

-N

CO PNB

A solution of the above acetylthioazetidinone (74 mg / 0.09 mmol) in toluene (30 ml) is refluxed for 7 hours _{under an N 2 atmosphere.} After evaporation of the solvent, the residue is purified by HPLC (SiO_, eluent benzene: ether = 3: 1), 24 mg (0.044 mmol, yield 49%) of the penem ester being obtained as a syrup. (Note. This oil could be _{crystallized from THF ether or CH 2} Cl ₂ ether.)
₁ Hmr (CDCl ₃ ) 6: 1.40 (3H, d, J = 6.5 Hz, T-CH ₃ ), 2.38

(3H, s, 2-CH ₃ ), 4.07 (1H, dd, J _{5 6} = 4 Hz,

J,. = 9 Hz, 6-H), 5.05-3.30-5.34-5.59 0.1

(2H, AB Tpy, 3-CO ₀ CH ₀ -Ar), 5.30 (2H, S, 1'-OCO ₂ -CH ₂ -Ar), 5.1-5.6 (1H, m, TH) , 5.68 (1H, d, J _{5 6} = 4Hz, 5-H), 7.49-7.64-8.18-8.33 (4H, A ₂ ¹ B ₃ ¹ , T-aromatic Hs) , 7.53-7.68-8.18-8.33 (4H, A ₃ ¹ B _3- , 3-aromatic Hs);

XR irein) ν

Max

1780 (ß-lactam), 1750 (-OCO ^ -), 1710

(Ester), 1520 and 1350 cm

-V

03 00 27/0777

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• ♦ ι

2950888

VV. Production of

(1'R, 5R, 6R and 1'S, 5S, 6S) Potassium and Sodium 6- (1'-hydroxy ethyl) -2-methylpenem-3-carboxylate (isomer D)

OK

DCO ₂ PNB S. H "/ Pd-Celite I. λ o ^ ^I3 ^ ^ -CH ₃ CO PNB

⁰ \ i = iff)

CO ₂ Mf- ^ Na

A solution of the above penem ester (24 mg, 0.044 mmol) in THF (5 ml) is mixed with ether (10 ml), H ₂ O '(5 ml), phosphate buffer (1.00 ml, 0.05 molar pH 7.00, Fisher) and 30% Pd-Celite (50 mg, Engelhard). This mixture is hydrogenated at 2.27 bar (35 psi) for 21.5 hours at room temperature. After the catalyst has been removed (via Celite), the aqueous layer is separated off, washed with ether and lyophilized, whereby 12 mg of the mixture of sodium and potassium salts indicated in the title are obtained as a white powder:

Hmr (D ₂ ) 5: 1.23 (3H, d, J = 6Hz, T-CH ₃ ), 2.27 (3H, s, 2-CH ₃ ), 3.85 (1H, dd, J- _c = 4Hz, J _c . = 9Hz, 6-H), 4.3 (1H, m, 1'-H) and 5.65 ppm (1H, d, J _{5 6} = 4Hz, 5-H);

-1

IR (Nujol) ν: 1755 (-lactam) and 1570 cm

ICIcLjC jL

UV (LOA ' 297 (£ 2300, calculated as K-SaIz), 258% tl900 2. max.

ber. as K-SaIz).

This material was identical to a sample of the title compound which was prepared by aldol condensation of acetaldehyde with the dianion of 2-methylpenem-3-carboxylic acid ( ¹ Hmr, IR, UV) -

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M / 20 359 SY-1599A

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35

(1 ¹ S, 5R, 6S and TR, 5S, 6R) 6- (1'-hydroxy-1'-ethyl) -2-methylpenem-3-carboxylic acid (isomer C)

OH

H.

O ₂ H

Method A:

OCO-PNB

OCO BNB

Al ^.

CO PNB

CO PNB

OH

CO PNB

Method B:

, PNB

OC0 "PNB

iAg

-Κ,

030027/0 7

S ti
■ * S ·

m it ·.

M / 20359 SY-1599A

- 240 -

OCO ₂ PNB

OCO PNB

-SAc

PNB

OH

Method A:

1) (1'S, 3S, 4R and 1'R, 3R, 4S) 4-acetylthio-3- (1 · -p-nitrobenzyldioxycarfaonyl-1'-ethyl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2 "-acetate) -2-azetidinone (Isomer C)

0CO ₀ PNB

Say

OCO ₂ PNB

CH ₃ COCl

C ₅ H ₅ N

CO PNB

A cold (ice-MeOH bath) solution of (1'3,3S, 4R and 1'R, 3R, 4S) silver-3- (1-p-nitrobenzyl-dioxycarbonyl-1'-ethyl) -1 ( p-Nitrobenzyl-2 "-triphenylphosphoranylidene-2" acetate) -2-azetidinone-4-thiolate (isomer C) (1.14 g, 1.30 mmol) in CH ₃ Cl ₂ (60 ml) is treated with pyridine (0.6 ml, 0.74 mmol) and dropwise with acetyl chloride (236 mg, 0.213 ml, 3.0OmMoJL)

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The reaction mixture is stirred for 1 hour at -15 ° C. The precipitate is filtered off and washed with ether. The filtrate is washed with 2% aqueous. HCl, water, 2% aqueous NaHCO ₃ , water and brine and dry (MgSO.). The residue remaining after evaporation of the solvent residue is triturated uit ether (895 mg, 83.7%, mp 184-185 ⁰ C (decomp.).);

IR (CHCl ₃ ) v _max :

1755, 1695 (C = O), 1620 and 1605 cm (phosphorane).

-1

Analysis C ₄₂ H ₃ N ₃ O ₁

C. 38 H 42 N 11 S. , 90 61, 26th 4, 49 5, 88 3 , 26 61, 4, 4, 4th

calculated: found:

2) (1 ¹ S, 5R, 6S and 1'R, 5S, 6R) p-Nitrobenzyl-2-methyl-6- (1'-pnitrobenzyldi'oxyearbonyl-1'-ethyl) -penem-3-carboxylate (Isomeres C)

OCO PNB

co

Ρφ

CO PNB

A solution of (1'S, 3S, 4R and 1'R, 3R, 4S) 4-acetylthio-3- (1 · -p-nitrobenzyldioxycarbonyl-1'-ethyl) -1- (p-nitrobenzyl-2 "-triphenyiphosphoranyIiden- 2 ⁼ -acetai; -2-ά26ΐ ± ά ± ποη (Isomer C) (855 mg, 1.04 mmol) in toluene (60 ml) is refluxed for 4.5 hours a column of silica gel (10 g) (1% ether in benzene) to give the pure title compound (393 mg, 69.6%); m.p. 157-158 ether);

C (CHCl ₃ -

030027/0 7 77

• β · * «». _β

Μ / 20 359 - 242 -.:. ',,' ~,.: ..

SY-1599A

2S50898

IR (CHCl-) ν: 1785, 1745, 1710 (C = O) and 1525 cm " ¹ (NO);

• 5 IUcLX ■ £ ·

Hmr (CDCl ₃ ) 6: 8.30-7.2 (8H, m, Η-aromatic), 5.46 (1H, d,

J = 1.8, H-5), 5.40-5.0 (5H, m, ζ ₂ and HT) / 3.95 (1H ₇ dd, J = 1.8, J = 5.4, H -6), 2-jJ (3H, s, CH-) and 1.43 ppm (3H, d, u = 5.4, CH ₃ );

Analysis C ₁ H ₂₁ N ₃ O ₁₀ S:

calculated:
- found:

3) (1 ¹ S, 5R, 6S and 1 R, 5S, 6R) 6- (1 -hydroxy-1'-ethyl) -2-methyl penem-3-carboxylic acid (isomer C)

C. 04 H 89 N / 73 % 53 76 3, 86 7th / 69 % 52, 3, 7th

* - ■

A mixture prepared from (1'S, 5R, 6S and 1'R, 5S, 6R) p-nitrobenzyl-2-methyl-6- (1'-p-nitrobenzyldioxycarbonyl-1'-ethyl) -penem-3-carboxylate (206 mg, 0.379 mmol), THF-ether-H ₂ = (30 ml, 40 ml, 20 ml), a 0.05 M buffer solution (7.64 ml 0.382 mmol) and 30% Pd hydrogenated on Celite (500 mg) at 2.89 bar (42 psi) H ^ in a Parr shaker for 16 hours. The catalyst is filtered off and washed with water. The aqueous phase is washed with ether (3 times), acidified in portions with cold 1% aqueous HCl to pH 2.5 and extracted with ethyl acetate (15-20 ml) after each addition of HCl. The ethyl acetate extracts are combined and washed with saline solution (3 × 30 ml).

030027/0777

Μ / 20 359 SY-1599A

- 243 -

2950888

Evaporation of the solvent and trituration of the residue with ether gives the title compound (57 mg, 65/6%).

IR (KBr) ν: 3580-3300 (OH), 1755 and 1660 cm " ¹ (C = O);

UV (EtOH) Λ _max : 311 (C 6538), 262 (£ 3672);

_Max

¹ Hmr (DMSO-d ₆ ) 6: 5.57 (1H, d, J = -1.7, H-5), 4.02 (1H, m,

H-1 ¹ ) / 3.75 (1H, dd, J = 1.7, J = 3.5, H-6), 2.23 (3H, s, CH ₃ ) and 1.23 ppm (3H, d,

CH ₃ )

Method B:

1) Silver- (1'S, 3S, 4R and 1 ¹ R, 3R, 4S) 1- (tert-butyldimethylsilyl) "- 3- (1 '-p-nitrobenzyldioxycarbonyl-1' -ethyl) -2-azetidinone-4 -fchiolate (isomer C)

OCO ₂ PNB

OCO PNB

The iscmere C of 1 '- (tert-butyldimethylsilyl) -3- (1'-pnitrobenzyldioxycarbonyl-1' -ethyl) -4-tritylthio-2-azetidinone (1 g, 143 mol) is dissolved by stirring in hot (40 ⁰ C) methanol. (12 ml). A solution of silver nitrate (0.59 g) in methanol (12 ml) is added followed by pyridine (0.13 ml). The mixture is stirred vigorously for 1 hour at room temperature and 2 hours at ± 0 ° C. The solid silver mercaptide is collected by filtration and washed with ether, 352 mg (46%).

030027/0777

Μ / 20 359 SY-1599A

^IR

- 244 -

1735 cm " ¹ (C = O).

2) (1'S, 3S, 4R and 1 ^f R, 3R, 4S) 4-acetylthio-1- (tert-butyldimethylsily 1-3- (1 '-p-nitrobenzyldioxycarbonyl-1'-ethyl) -2-azetidinone (Isomer C)

OCO ₂ PNB

OCO ₂ PNB

tBu

tBu

To a solution of the isomer C of silver 1- (tert-butyldimethylsilyl) -3- (1'-p-nitrobenzyldioxycarbonyl-1'-ethyl) -2-azetidinone-4-thiolate (880 mg) in dichloromethane (40 ml ), which is ^{stirred at 0 °} C., pyridine (0.57 ml) and then acetyl chloride (0.49 ml) are added dropwise. The mixture is stirred for 0.5 hours at 0 ⁰ C, remove the solids by filtration and dilute the filtrate with ether, washed with aqueous hydrochloric acid (2%), water, sodium bicarbonate (2%) and brine, dried and concentrated, wherein the title compound remains as an oil. (610 mg).

Hmr (CDCl ₃ ) 6: 8.2 and 7.48 (4H, 2d, aromatic), 5.40

(1H, d, J = 2.2, H-4), 5.2 (2H, s, benzyl), 5.3 to 4.9 (IH, m, H-1 ^1), 3.42 (IH , dd, J = 2, H-3), 2.32 (3H, s, CH ₃ ), 1.40 (3H, d, J = 6.5, CH_), 0.95 {9a, 3, t -Bu) üu 0.2 ppi (6H, CH ₃ ).

030027/0777

M / 20 359 - 245 -

3) (1'S, 3S, 4R and 1 ^f R, 3R, 4S) 4-Acetylthio ~ 3- (1 -p-nitrobenzyldioxycarbony1-1-ethyl) -2-azetidinone (isomer C)

tBu

Isomer C of the above S-acetyl-N-tert-butylmethylsilylazetidinone derivative (1.4 g) is dissolved in a mixture of TFA (0.5 ml), water (0.5 ml), methanol (3 ml) and dichloromethane (2 ml) and stir for 48 hours at room temperature. The solution is diluted with water (100 ml) and extracted with dichloromethane (4 × 20 ml). The combined organic extracts are made with sodium bicarbonate (2%) and sodium chloride solution washed, dried and concentrated to leave the crude title compound as an oil. The cleaning done by chromatography over silica gel (30 g) eluting with 5% ether in benzene (650 mg). Crystallization from Benzene gives a white solid.

¹ Hmr (CDCl ₃ ) δ: 8.15 and 7.45 (4H, d, aromatic), 6.18 (1H, NH), 5.19 (2H, s. Benzyl), 5.05 (2H, m , H-4 and H-1 ') 3.35 (1H, dd, J = 2.5, 4.5 H-3), 2.34 (3H, s, CH ₃ ) and 1.42 ppm (3H , d, J = 6.5, CH ₃ );

IRv: 1780, 1750, 1695 cm " ¹ (C = O). Max

030027/0777

M / 2U 359

4) (1 «S, 3S, 4R and 1'R, 3a, 4S) 4-acetylthio-3- (1 · -p-nitrobenzyldioxycarbonyl-1'-ethyl) -1- (p-nitrobenzyl-2" -hydroxy -2 "-acetate) -2-azetidinone (C-2 "Epitize) (Isomer C)

OCO ₉ PNB

OCO ₂ PNB

SAc

A mixture of isomer C of 4-acetylthio-3- (1'-p-nitrobenzyldioxycarbonyl-1'-ethyl) -2-azetidinone (750 mg), p-nitrobenzyl glyoxylate hydrate (525 mg) and benzene (50 ml) it is refluxed for 3 days over a Dean Stark device which is filled with 3 S molecular sieves. Man add a second portion of glyoxylate (52 mg) and reflux for a further 2 days. The mixture is diluted with Ether, washes with hydrochloric acid (2%), water, Sodium carbonate (2%) and water, dried and concentrated, leaving an oily residue (975 mc?). Chromatography from silica gel while eluting with benzene ether (85 = 15) gives the pure title compounds.

¹ Hmr (CDCl ₃ ) 6: 8.25-6.75 (8H, m, aromatic), 5.30 and 5.12

(4H, 2s, benzyls), 5.05-4.70 (1H, H-2 "), 4.45-4.35 (1H, 2d, H-4), 4.50-4.10 (1H , ia, H-1 ¹ ), 3.30 (1H, m, H-2 and 1.25 ppm (3H, 2d,

030027/0777

• C *

• »ι ·

Μ / 20 359
SY-1599A

- 247 -

5} (1'8,35,4R and 1 ^f R, 3R, 4S) 4-acetylthio-3- (1'-p-nitrobenzyldioxycarbonyl-1 ^l -ethyl) -1- (p-nitrobenzyl) -2 ^K - triphenyl-phosphoranylidene-2 ⁿ -acetate) -2-azetidinone (isomer C)

OCO ₂ PNB

Säc

OCO PNB

SOCl.

ff

CO PNB

SAc

ei CO ₂ PNB

O PNB

- ¹ V

Φ.

CO PNB

The isomers C of 4-acetylthio-3- (1'-p-nitrobenzyl-dioxycarbonyl-i '-ethyl) -1- (p-nitrobenzyl ^2-M -hydroxy-2 "-acetate) -2-azetidinone (577 mg , 1 mmol) is dissolved in anhydrous THF (10 ml) and pyridine (95 mg _r 1.2 mmol) of the solution is added. the solution is cooled to 0 ⁰ C and slowly add thionyl chloride <143ing, 1,2 mKol) to - the mixture is stirred at 0 ⁰ C for 30 minutes, diluted with a little ether, removes the unlsölichen salts by filtration and washed with ether the combined filtrates are concentrated to give the crude mixture of epimers cer C-2 "-chloro. Connection received. Dissolve in THF (20 ml), triphenylphosphine (314 mg, 1.2 mmol) and 2,6-lutidine (129 mg, 1.2 mmol) are added and the solution is stirred for 4 days at 45 ° C. The solids become removed by filtration, washed with benzene and the combined filtrates concentrated to leave an oil whose spectral data and TLC values are identical to those of a sample of the title compound which had been prepared by acylation of the corresponding silver thiolate. i

M / 20 359 SY-1599A

- 248 -

The desired Penem products can be made, by reacting the title compound according to the procedures of Steps 2 and 3 of Example 35 (Method A).

example

U'R, 5R, 6S and 1 * S, bS, 6R) 6- (T-Hydroxy-1 * -ethyl) -2-methylpenem-3-carboxylic acid (Isomer B)

OH

CK.

Method Ä:

OCO ₂ PNB

Say

CO PNB

OCO PNB

030027/0777

a t «♦ ·

M / 20 359 SY-1599A

- 249 -

Method B:

OH

.1

T

CO PNB

DIMS / TEA

2) AcCl pyridine

3) H ₃ O ⁺ -

OH

, SAc

GO ₂ PNB

Method a

T) (1 '11, 33,4R and 1'S, 3R, 4S) 4-acetylthio-3- (1 '-p-nitrobenzyldioxycarbonyl-1'-ethyl) -1- (p-nitrobenzyl-2 "-tr! Phenyl = phosphoranylidene-2 "acetate) -2-azetidinone (isomer B)

OCO-PNB

J ² say

CO PNB

AcCl ^C 5 ^H 5 ^N

CCO-PNB I ² SAc

CO PNB

030027/0777

• · «a

M / 20 359 - 250 -

sY-i 599A

A solution of (1'R, 3S, 4R and 1'S, 3R, 4S silver 3- (1 '-pnitrobenzyldioxycarbonyl-1'-ethyl) -1' -p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone-4-thiolate (isomer B) (917 mg, 1.03 mmol) in CH ₂ Cl ₂ (20 ml is treated at -15 ° C (rlis-MeOH bath) with pyridine (242 μl, 247 mg , 3.31 mmol) and tror-i ^ nweise with acetyl chloride (142 μΐ, 157 mg 2.0 mmol). The mixture is stirred for 15 minutes at -10 ° C, the plastic is filtered off and washed with ether. The organic The solution is washed with 2% aqueous HCl, water, 2% aqueous NaHCO, water and sodium chloride solution and dried over MgSO .. After evaporation of the solvent, the residue crystallizes from ether (710 mg, 80%, melting point 183-185 ° C;)

IR (CHCl-) ν: 1755, 1695 (C = O), 1620, 1605 (phosphorane) and 1625 cm

2lcL

2) (V R, 5R, 6S and 1 x S, 5R, 6R) p -nitrobenzyl-2-methyl-6- (1'-p nitrobenzyldioxycarbonyl-1'-ethyl) penem-3-carboxylate (Isomer B)

OCO PNB OCO_PNB

A solution of (1'-R, 3S, 4R and 1'S, 3R, 4S) 4-acetylthio-3- (1 ι -r ^ -n ± inrr \ y \ ar \ rrvl ri-i r> wc-ar- t \ r \ nvl -1 '-äthvl) -1- (D-nitrobenzyl-2 ¹¹ - triphenylphosphoranylidene-2 "acetate)" 2-azetidinone (650 mg, 0.791 mmol) is refluxed in toluene for 7 hours. The solution, which has been concentrated after evaporation of the solvent, is passed through a silica gel column (10 times its weight) and the title compound (0.5% ether-benzene to 2% ether-benzene) is obtained as a white solid; 329 mg, 77% ,

030027/0777

• ··

M / 20 359
SY-1599A

- 251 -

Pp. 134-135 ⁰ C, (CH ₂ C1 ₂ -Xther);

IR (CHCl ₃ )

1785, 1745, 1705 (C = O) and 1525 cm

-1

¹ Hmr (CDCl ₃ ) 6: 8.20 (2H, d, Ho aromatic), 7.60 (2H, d, Hm aromatic), 5.55 (1H, d, J = 1.5, Hs), 5 , 5-4.75 (5H, m, 2CH ₂ -PNB, HV) / 3.86 (1H, dd, J = 7.8, J = 1/5, H-6), 2.38 (3H, s, CH ₃ ) and 1.50 ppm (3H, ά, J = 6.3, CH ₃ );

Analysis C ₃₄ H ₂₁ N ₃ O ₁₀ S:

calculated: found:

3) (1 ^f -R, 5R, 6S and 1'3,53,6R) 6- (1'-Hydroxy-1'-ethyl) -2-methylpenem-3-carboxylic acid (isomer B)

C. 04 H 89 N 73 S. 90 53 05 3, 98 7, 63 5, 02 53 3, 7th 6,

OCO PNB

A mixture of (1'S, 5R, 6S and 1'3,53,6R) p-nitrobenzj1-2-methyl-6- (1'-p-nitrobenzyldioxycarbonyl-1'-ethyl) -penem-3-carboxylate (isomer B ) (65 mg, 0.12 mmol), 0.05 M pH buffer solution (1.06 egu), H ₂ O-THF-ether (10 ml, 10 ml, 25 ml) are shaken on a Parr hydrogenator using 30% Pd on Celite (200 mg) 16 hours at 3.45 bar (50 psi) H ₃ . The catalyst is filtered off and washed with small amounts of water. The aqueous layer is washed with ether (3 times) and acidified in portions

030027/0777

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2350898

with 1% cold aqueous HCl, extracted with ethyl acetate after each acidification with HCl and saturated with sodium chloride solution and extracted thoroughly with ethyl acetate. The ethyl acetate extracts are combined, washed with brine (5 times) and dried (MgSO.) - Evaporation of the Solvent gives a solid residue which is triturated with methylene chloride (19.4 mg, 71%).

IR (Nujol) v _m : 3500 (OH), 1785, 1672 cm

Iu el X.

-1

(C = O);

UV (EtOH) Λ: 260 (£ 3450), 309 (t 6400);

Iu el X

¹ Hmr (DMSO d) 6: 5.54 (1H, d, J = 1.5, H-5), 3.88 (1H, m, H-1 '

4.2-3.5 (2H, bs, 0-H), 3.65 (1H, dd, J = 6.5,

J = 1.5, H-6), 2.28 (3H, s, CH ₃ ) and 1.1.5 ppm

(3H, d, J = 6, CH ₃ ).

Method B:

1) (1'R, 3S, 4R and 1'S, 3R, 4S) 4-acetylthio-3- (1'-trimethylsilyloxy-1'-ethyl) -1- (p-nltrobenzyl-2 "-triphenylphosphoranylidene-2" - acetate) -2-azetidinone (Isomer B)

OH

OTMS

TMSCl

TEA

AcCl

C ₅ H ₅ N

Φ.

CO PNB

CO PNB

A suspension of (1'R, 3S, 4R and 1 ^I S, 3R, 4S) silver 3- (1'-hydroxy-1'-ethyl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" acetate) -2-azetidinone-4-thiolate (505 mg, 0.715 mmol) in THF (25 ml) is cooled to - 15 ⁰ C (ice-MeOH

030027/0777

M / 20 359 " ^J.

SY-1599A 2850898

Bath), treated dropwise with triethylamine (289 mg, 398 μΐ, 2.86 mmol), trimethylchlorosilane (310 mg, 362 μΐ, 2.85 mmol) and finally with imidazole (50 mg, 0.734 mmol) and stirred for 3 hours at - 15 ⁰ C and 16 hours at room temperature. (The IR of an aliquot shows the absence of a hydroxyl group). The mixture is cooled to -15 ⁰ C, diluted with CH ₂ Cl ₂ (20 ml), treated with pyridine (226 mg, 231 VI, 2.86 mmol) and acetyl chloride (168 mg, 152 μΐ, 2.14 mmol) , stir for 0.5 hours, dilute with ether, wash with dilute aqueous HCl, water, 5% aqueous NaHCO ₃ , water and brine and dry. The solvent is removed on a rotary evaporator and the residue is filtered through a silica gel column (1:10 ratio, 3% to 10% ether in benzene) to give the title compound (360 mg, 84.2%) mixed with a little desilylated derivative (30 mg, 7.8%).

IR (liquid film) v _max : 1750, 1790 (C = O), 1620 (phosphorane)

and 1518 cm (NO ₂ ).

2) (1'R, 3S, 4R and 1'S, 3R, 4S) 4-acetylthio-3- (1'-hydroxy-1'-ethyl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" - acetate) -2-azetidinone (Isomer B)

OTMS

^SAc

JL

A solution of (1'R ₇ SS ^ R and 1 * S, 3R, 4s) «-Acetylthio-S-1 '-trimethylsilyloxy-1' -ethyl) -1 - (p-nitrobenzyl-2" -triphenylphosphoranylidene-2 Acetate) -2-azetidinone (360 mg, 0.504 mmol) is treated with TFA (3 drops) and stirred for 18 hours at room temperature. The mixture is diluted with ethyl

030027/0777

M / 2C 359

^SY " ^1599A

254 -

acetate, washed with water, dilute aqueous NaHCO, water and brine and dried (MgSO ₄ ). Evaporation of the solvent gives the title compound (334 mg, 100

IR (CHCl ₃ ) v _max : 1755, 1690 (C = O), 1620, 1605 (phosphorane)

and 1520 cnT ¹

3) (1 'R, 5R, 6S and 1' S, 5S, 6R) p-nitrobenzyl-a-methyl-Ö- (V hydroxy-1'-ethyD-penem-3-carboxylate (isomer B)

SAc

OH

A solution of (1'R, 3S, 4R and 1'S, 3R, 4S) 4-acetylthio-3- (1 '-hydroxy-1' -ethyl) -1- (p-nitrobenz.yl-2 "-triphenylphosphoranylidene- 2 "acetate) -2-azetidinone (41G mg, 0.638 mmol) in toluene (40 ml) is refluxed for 7 hours. The toluene is partially evaporated. The residue is passed through a silica gel column (ratio 1:10) (3%, 4% and 5% ether in benzene) to give the title compound (151 mg, 65 %) as a white solid, m.p. 161- 161.5 ⁰ C;

IR (CDCl-) ν: 3600, 3500-3400 (OH), 1780, 1608 (C = O) and

" ¹

1525 cm " ¹ (NO ₂ );

Hmr (CDCl-J 5: 8.20 (2H, J = 7, Ho aromatic), 7.60 (2H, i

aromatic), 5.57 (1H, d, J = 2, H-5), 5.29 (2H center of ABg, J = 15, CH ₂ -PNB), 4.2 (1H, dq, J = 7 , J = 6, HT), 3.67 (1H, dd, J = 7, J = 2, H-6) 2.33 (3H, s, CH ₃ ) and 1.33 ppm (3H, d, J = 6, CH ₃ );

030027/0777

H / 20 359 SY-1599A

Analysis C, H., _N _o 0, S

calculated: found:

C. 74 M. 43 N 69 S. , 80 52, 67 4, 41 7, 71 8th , 96 52, 4, 7, 8th

4) (T-R, 5R, 6S and 1 ■ S, 5S, 6R) 6- (1'-hydroxy-1 ■ -ethyl) -2-methylpenem-3-carboxylic acid {Isomer B}

OH

A.

CO PNB

OH

Y- N

A mixture of (1 ¹ R ₇ SRrOS and TS, 5S, 6R) p-nitrobenzyl-6- (T-hydroxy-1'-ethyl) -2-methylpenem-3-carboxylate (89 mg, 0.0244 iriMol), THF-H ₂ O ether (15 ml, 10 ml, 30 ml), a 0.05M pH 7 buffer solution (5.06 ml, 0.253 mmol) and 30% Pd on Celite (250 mg) are shaken in a Parr hydrogenator 3.5 hours at 3.10 bar (45 psi) H. A work-up identical to that described above gave the title compound (32 mg, 57%) ,

Example 37

(TS, 5R, 6R and TR, 5S, 6S) 6- (T-Hydroxy-T-ethyl) -2-methylpenem-3-carboxylic acid (Isomer A)

030027/0777

M / 20 359 SY-1599A

1) (1'S, 3R, 4R and 1'R, 3S _r 4S) 4-Acetylthio-3- (1'-methoxymethoxy-1'-ethyl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" - acetate) -2-azetidinone (isomer A)

CXTH ₂ OCH ₃

₂ CXH ₃

CO PNB

CO PNB

The isomer A of 4-acetylthio-3- (1'-raethoxymethoxy-i'-ethyl) 1- (p-nitrobenzy1-2 "-triphenylphosphoranylidene- ^" -acetate) -2-azetidinone is prepared as described elsewhere for isomer C of the p-nitrobenzyl-dioxycarbonyl derivative, yield 85%:

IR (neat) ν: 1750 and 1690 cm

IuäX

-1

(C = O).

2) (1'S, 3R, 4S and 1'R, 3S, 4S) 4-acetylthio-3- (1'-hydroxy-1 · ■ ethyl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" acetate) -2-azetidinone (isomer Äj

OH

CO PNB

Isomer A of 4-acetylthio-3- (1'-methoxymethoxy-i'-ethyl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone (500 mg, 0.68 mmol ) are added to a cooled solution (0 ^° C.) of trifluoroacetic acid (50 ml) and water (10 ml) and the mixture is stirred in ice for 15 minutes and for 3 hours

030027/0777

Μ / 20 359 SY-1599A

- 257 -

Room temperature. The reaction mixture is concentrated, dichloromethane is added and the solution is washed with sodium bicarbonate _f water and brine, dried and concentrated to give the title compound (450 mg, 96%);

IR (neat) v _m : 3400 (OH), »745 and 1690 cm" ¹ (C = O).

3) (1'S, 5R, 6R and 1'R, 5S, 6S) p -nitrobenzyl 6- (1'-hydroxy-1'-ethyl) -2-methyl-penem-3-carboxylate (Isomer A)

OH

OH

. Λ

CO PNB

The preparation takes place as above for the isomer C des p-nitrobenzyl-dioxycarbonyl-derivative, yield 45%,

Hmr (CDCl ₃ ) ö: 7.93 (4H, ABq, aromatic), 5.58 (IH, d, J = 4.0, H-5), 5.33 (2H, ABq, benzyl), 4, 3 (1H, m, HI ¹ ), 3.8 (1H, dd, J = 4.0, H-6), 2.41 (3H, s, CH ₃ ), 2.31 (1H, s, OH ), and

1.42 ppm (3H, d, J = 6, CH ₃ );

-1

IR (CHCl3, v _m : 3100-3600 (OH), 1780 and 1710 cm (C = O).

4) (1'S, 5R, 6R and 1 ⁵ R, 5S, 6S) 6- (1'-Hydroxy-1'-ethyl) -2-methyl penem-3-carboxylic acid (isomer A)

OH

OH

"HL /" ™ '

nJ— M ^ -

CO PNB

CO _- H

030027/0777

M / 20 359 SY-1599A

- 258 -

A mixture of isomer A of p-nitrobenzyl-6- (1'-hydroxy 1'-ethyl) -2-methyl-penem-3-carboxylate (82mg, 0.2 mmol), Palladium on Celite (30%, 400 mg). THF (10 ml), ether (25 ml). Water (10 ml) and buffer (0.05 M, pH = 7, Fisher SO-B-108) (4 ml) is hydrogenated on a Parr shaker at an ~ starting hydrogen pressure of 3.10 bar (45 psi) for 4 hours. The catalyst is removed by filtration over Celite and washed with water, man Wash the filtrates with ether and acidify the aqueous layer in cold hydrochloric acid (0.25 M) and extracted with ethyl acetate (5 10 ml). The United organic extracts are washed with sodium chloride solution, dried and concentrated. The foamy solid is in Triturated ether to give a white solid (20 mg, 44%);

IR (Nujol) v UV (EtOH) λ

IUC1.X.

3500 (OH), 1765 and 1665 cm " ¹ (C = O);

301 (£ 5922), 260 (£ 4280).

example

(1'R, 5R, 6S and 1'S, 5S, 6R) 2-aminomethyl-6- (1'-hydroxy-1'-ethyl) penem-3-carboxylic acid (isomer B)

CH
O ³

(1 'R, 3S, 4R and 1 · S, 3R, 4S) 4-Azidoacetylthio-3- (1'-hydroxy-1 ethyl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2J'-acetate) -2-azetidinone (Isomer B)

030027/0 7 77

M / 20 359 SY-1599A

- 259 -

OH

TMSCl
TEA

CO PNB

CO ₂ PNB

A cold (ice-MeOH bath) suspension of (1'R, 3S, 4R and 1'S, 3R, 4S) silver-3- (1'-hydroxy-1 '-ethyl) -1- (p-nitrobenzyl-2 "Triphenylphosphoranylidene-2" acetate) -2-azetidinone-4-thiolate (970 mg, 1.37 mmol, from 1 g of the corresponding trityl) in THF (40 ml) is treated dropwise with trimethylchlorosilane (0.695 ml, 595 mg , 5.48 mmol), triethylamine (0.765 ml, 555 mg, 5.49 mmol) and imidazole (50 mg, 0.734 mmol). The mixture is stirred for 17 hours N ", then cooled to -15 ⁰ C (ice-MeOH bath) and outputs Azidoacetylchlorid (406 mg, 3.40 mmol). The mixture is stirred for 30 minutes (the reaction being followed by TLC). The filtrate is diluted with more ether, washed with 1% aqueous HCl, water, 1% aqueous NaHCO ₃ , water and brine and dried (MgSO ₄ ). After evaporation of the solvent, the residue is taken up in moist CHCl (50 ml) and treated with TFA (3 drops, the cleavage of TMS-ether being followed by TLC). The methylene chloride solution is then washed with 1% aqueous NaHCO, water and sodium chloride solution and dried (MgSO.). The residue is passed through a silica gel column (8 times its weight) (benzene-ether 1: 1 / ether and ethyl acetate-ether 1: 1) whereby the title compound is obtained (565 mg, 69.8%)

IR (film) υ

·. 3500-3200 (OH), 2100 (NJ, 1755, 1609 (C = O), 1620-1605 iPhosphorane) and 1518 es " ¹ (NO),

030027/0777

-i ft - «

Μ / 20359 SY-1599a

- 260 -

(1'R, 5R, 6S and 1'S, 5S, 6R) p -nitrobenzyl ^ -azidomethyl-δ- (1'-hydroxy-1'-ethyl) -penem-3-carboxylate (Isomer B)

OH

SCOCH ₂ K ₃

: O PNB

toluene

PNB

A solution of (1 ^f R, 3S / 4R and 1'S / 3R, 4S) 4-azidoacetylthio-3- (1'-hydroxy-1 "-ethyl) -1- (p-nitrobenzyl-2" -triphenyl-phosphoranylidene- 2 "-acetate) -2-azetidinone (500 rag ^ 0.731 mmol) in toluene (100 ml) is refluxed under nitrogen for 30 minutes. The solution is concentrated in vacuo and the residue is passed through a silica gel column (5 g) (3.5-4γ ether benzene), the title compound (193 mg, 65.1%) being obtained as a yellowish solid.

¹ Hmr (CDCl ₃ ) 6: 8.13 (2H, d, Ho aromatic), 7.52 (2H, d, Hm aromatic), 5.59 (1H, d, J = 1.8, H-5) , 5.27 (2H, center of ABq, J = 13.5, CH ₂ -PNB), 4.50

(2H, center of ABq, J = 16, CH ₃ -N,), 4.15 (1H, m, H-1 ^1), 3.73 (1H, dd, J = 6.3, J = 1 , 8, H-6), 1.92 (1H, d, J = 4, OH) and 1.33 ppm (3H, d,

J = 6.3 CH ₃ );

IR (CHCl3,) ν _o : 2110 (N-), 1785, 1705 (C = O) and 1520 cm

O IucLX ~>

(NO ₂ ).

-1

030027/0777

™ »· · · ■ ^ 9 P φ ff

M / 20 359 - 261 -

SY-1599A 2950898

(1'R / 5R / 6S and 1'S, 5S, 6R) 2-aminomethyl-6- (1'-hydroxyl '-ethyl) penem-3-carboxylic acid (Isomer B)

_s CO PNB TI • OH —Τ 1 U.N A- Ι 'τ— Γ -N. J- ¹ J- Ό 7 ^z ^ CO ₂ H

A solution of (1'R, 5R, 6S and 1'S, 5S, 6R) p-nitrobenzyl-2-azidomethyl-6- (1'-hydroxy-1'-ethyl) -penem-3-carboxylate (25 mg, 0.062 mmol) in THF-ether-water (6 ml, 6 ml, 15 ml) shake one for 2.5 hours on a Parr hydrogenator at 2.75 bar (40 psi) using 10% Pd on charcoal (100 mg). The catalyst is filtered off and washed with small volumes of water. The aqueous layer is washed with ether (3 times) and lyophilized to give the title compound (11 mg, 73%).

1 _a ^ (D ₀ O) 5: 5.75 (1H, d, J = 2, H-5), 4.30 (1H, center of m, J = 6.5, H- ¹¹ ), 4 , 02 (1H, dd, J = 6.5, J = 2, H-6) and 1.37 ppm (3H, d, J = 6.5, CH ₃ );

IR (Nujol, trituration) ν ζ 3550-2450 (OH, NH), 1765 (C = O)

and 1600 cm ~ ^l (CO ₂ ")?

DV (H_0) λ _m z 309 (£. 3650), 255 (£ 2ST5).

030 0 27/0777

M / 20 359 SY-1599A

- 262 -

Example 39

(1'R / 5R, 63 and 1'S, 5S, 6R) 2- (4-aminobutyl) -6- (1'-hydroxy-ethyl) penem-3-carboxylic acid (isomer B)

OH

COOH

(1 'R, 3S, 5R and 1 ^r S _/ 3R, 4S) 4 - ffi-Azidobutanoylthio) -3- (1' -hydroxyethyl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate ) -2-azetidinone

Say

THSCl

TEA, Im-

C ₅ H ₅ N

COOPNB

H ₂ O

A solution of {1 'R, 3S, 4R and TS, 3R, 4S) silver 3- (1 · -hydroxyethyl) -1- (p-nitrobenzy 1-2 "-triphenylphosphoranylidene - ?," - acetate) 2- azetidinone-4-thiolate (3.03 mg, 4.28 mmol) in dry THF (55 ml) s which is maintained under a nitrogen atmosphere, cooled to -25 ⁰ C and treated successively with triethylamine (2.39 ml, 1712 mmol), trimethylchlorosilane (2.18 ml, 17.12 mmol) and imidazole (0.10 g, 1.47 mmol). Stir the reaction mixture at 0.25 hours - 25 ⁰ C, remove the cooling bath and stirred for a further 16 hours. One cools the reaction

03Ö027 / Ö777

M / 20 359 - 263 -.:

SY-1599A

mix to O ⁰ C and dilute with CH-Cl ₂ (55 ml); they are then treated successively with pyridine (0.73 ml, 3.0 mmol) and with a solution of 4-aminobutanoyl chloride (1.36 g, 8.56 mmol) in CH-Cl- (10 ml). The reaction mixture is stirred for 1 hour at 0 ^° C. and filtered through a bed of Celite. Wash the bed with CH Cl, (25 mL), combine the filtrate washes and dilute with EtOAc (300 mL). The organic solution is washed with 1N HCl solution _F H „Q _f saturated NaHCO .., solution and HO, dried over anhydrous MgSO and concentrated on a rotary evaporator to give an orange-colored syrup (3.83 g). The syrup is dissolved in CH-Cl- (75 ml) and water (4 ml) and TFA (0.2 ml) is added; stirring the reaction mixture for 1.5 hours at 23 ⁰ C, washed with NaHCO and H_0, dried over anhydrous Na ₃ SO ₄ and concentrated to an orange syrup (3.4 g) Purification of the syrup is carried out by Säulenchromatographxe (silica gel G60, 80 g; eluent: EtOAc in CH-Cl ^ 10 % to 75%). Evaporation of the appropriate fractions gives: an oil, 2.14 g, 67.7%

Analysis C ₃₇ H ₃₆ N ₅ SP:

calculated: found:

(1'R, 5R, 6S and 1'S, 5S, 6R) p-nitrobenzyl-2-tS-azidobutyl) -6- (1'-hydroxy-ethyl) -penem-3-carboxylate

OH

C. 23 H OO N 65 S. 42 61, 17th 5, 10 9, 02 4, 71 61, 5, 10, 3,

Toluene _ο ^ _ν ^ ^{2 4 3}

₃ ^ ööPNB

COOPNB

0300 27/0777

M / 20 359 SY-1599A

- 264 -

C. OO H 73 N 65 S. Λ *?
B / α.
Ό 51, 05 4, 86 15, 86 7, 19th % 51, 4, 15, 7,

A solution of (1'R, 3S, 4R and 1'5,311,4S) 4- (S-azidobutanoylthio) -3- {1 ^e -hydroxy-1 ■ -ethyl) -1- (p-nitrobenzyl-2 "- triphenylphosphoranylidene-2 "-acetate) -2-azetidinone (2.04 g, 2.81 mmol) in a toluene-CH ^^ - mixture (30: 1, 310 ml) is refluxed under a nitrogen atmosphere for 9 hours (at the beginning The CH Cl, is removed under reflux). The reaction mixture is cooled to 23 ^° C. and the toluene is removed in vacuo, an orange-colored residue remaining _? which is purified by column chromatography (silica gel 60, 45g; eluent: ether in petroleum ether, 1: 1 to 9: 1). The appropriate fractions are combined and concentrated to a syrup-petroleum ether mixture wixd crystallized from a, 0,44i g, mp 85 ⁰ C, 35.2%.

Analysis C ₁₀ H ₀₁ N ^ S:

calculated: found:

The fractions which would correspond to the unreacted material ^ were cyclized as described above to give an additional amount of the title compound (0.276 mg, 21.9%).

ν: 2100 (N,), 1770 (C = O, β-lactam) and 1705 cnT ¹ (C = O, PnB max -j

Ester);

UV (H ^ O 23 ° C) λ s 268 (C 13757), 316 (C 9826).

¹ Hmr (CDCl ₃ ) 6: 1.36 (d, J _R _ ₂ "_ _U _ ^ , = 6.3 Hz, 3H, methyl),

1.52-1.77 (m, 4H, H-2 ¹ , H-3 '), 2.57-3.00 (m _; 2H, H-4 ¹ ), 3.00-3.42 (m , 2H, HT), 3.72 (dd,

Jh-6-HS = ¹ ' ^{6 Hz} ' ^j _H -6-H-1 " ^{= 6} ' ^{4 Hz} ' ^H " ⁶⁾ '4.02-4.42 (m, IH, KV), 5.32 ( AEg, - J _a _ _b = 13, -6Hz ,.

2H, CH _{2 of} the PNB ester), 5.60 (d, J _{H- 5- H- 6} = 1.6 Hz, 1H, H-5), 7.61 (d, J " _m " = 8.8 Hz, 2H, Hm of PNB ester), and 8.21 ppm (d, ^{J = 8} H _O -Hm ^'8Hz'

030027/0777

M / 20 359 SY-1599Ä

2050898

(1 R5R, 6S and 1 S, 5S, 6R) 2- (4-aminobutyl) -6- (1'-hydroxyethyl) penem-3-carboxylic acid

OH

«VA

10% Pd / C

DME: Ei: 0, HO

OOPNB

OOH

To a solution of (1 ¹ R, 5 6S and 1'S, 5S, 6R) p-nitrobenzyl 2- (5-azidobutyl) -6- (1'-hydroxyethyl) penem-3-carboxylate (0.54 g _r 1.21 mmol) in dimethoxyethane (50 ml) are added to ether (50 ml), water (50 ml) and 1G% Pd on activated charcoal (0.54 g). The reaction mixture is hydrogenated for 3 hours under a pressure of 3.10 bar (45 psi) hydrogen. The reaction mixture is filtered through a bed of Celite and the filtrate is diluted with Xther. The aqueous phase is separated off, washed with ether and lyophilized. The crude title product is identified by HPLC

cleaned.

IR (KBr) ν: 1760 (C = O, ß-lactam) and 1565 cm " ¹ (C- =,

ITIcLjC

Carboxylate);

¹ Hmr (D ₂ O) δ: 1.32 (d, J _CH ^ _-1 "= 6.4 Hz, 3H, CH ₃ ), 1.45-1.85

im, 4H, KI ¹ ^ HS *), 2.50-3.20 (m, 4H, HI ¹ , H-4 ■), 3.84 (dd, J _E _ ₆ _ _H _ ^ "= 6, 1 Hz, J _{H- 6- R- 5} = 1.4 Hz, 1-H, H-6), 4.00-4.45 (m, 1H, H-1 ") and 5.62 ppm (i.e. , J _{H- 5- H- 6} = 1.4 Hz, 1H, H-5);

UV

: 260 (£ 4240), 302 (£ 5480).

030027/0777

M / 20 359 SY-1599A

Example 40

(1'R, 5R, 6S and 1'S, 5S, 6R) 2- (trans-3'-amino-1'-cyclobutyl) -6- (1 "-hydroxy-1" -ethyl) -penem-3-carboxylic acid (Isomer B)

OOH

(1 ^:! R, 3S, 4R and 1 "S _r 3R, 4S) 4- (trans-3 '-Az idocy clobutanoy Ithio) 3- (1" -hydroxy-1 "-ethyl) -1- (p- nitrobenzyl-2 ^m -triphenylphosphoranylidene-2 '"acetate} -2-azetidinone

OH
X I. _ _N TEA, Htt
^> ^ C = PPh
COOPNB C ₅ H ₅ ^N 3 H ⁺ OH
Λ. ■ - H ₂ O N
C = PPh
COOPNB Cf

A solution of (1'R, 3S, 4R and 1'S »3R, 4S) silver 3- (1'-hydroxyethylj -1- (p-nitrobenzyl-2" -triphenylphosphoranylidene ^ 2 "^ acetate) = 2-azetidinone -4-thiolate (1.01 g, 1.43 mmol) in dry THF (25 ml) which is maintained under a nitrogen atmosphere, cooled to -40 ⁰ C and treated successively with triethylamine (0.80 ml, 5 , 74 mmoles), trimethylchlorosilane (0.726 ml, 5.72 mmol) and imidazole (0.1C Cj, 1.47 mmol). it is the ReaktJonsmischung warmed to -15 ⁰ C, stirred for 3 hours, 'the cooling bath removed and stirred an additional 18 The reaction mixture is cooled to -15 ° C. and diluted with CH Cl, (25 ml); then it is treated with pyridine (0.15 ml, 1.5 mmol) and trans-3-azidocyclobutanoyl chloride (0.274 g, 1 The cooling bath is removed and the solution is stirred and treated for 1 hour

030 0 27/0777

M / 20 359 SY-IS99A

with pyridine (0.15 ml, 1.85 mmol) and trans-S-azidocyclobutanoyl chloride (0.274 q, 1.72 mmol). Stir the P.eaktionsmischung 1 hour at 23 ⁰ C and filtered through a bed of Celite. The filtrate is diluted with EtOAc (100 ml) and washed with 1N HCl, HO, saturated NaHCO 3 solution and HO, and dried over anhydrous MgSO. and concentrated on a rotary evaporator to an orange syrup (1.47 g). To a solution of the syrup in CH ₂ Cl ₂ (50 ml), add H ₃ O (2 ml) and TFA (0.2 ml). The reaction mixture is stirred for 2 hours at 23 ° C., washed with saturated NaHCO 3 solution and HO, dried over anhydrous Na SO and concentrated to give an orange-colored syrup (1.1 g). The syrup is purified by column chromatography (silica gel 60, 20 g, eluent EtOAc-ether 35% to 70%). Evaporation of the appropriate fractions gives the title compound as an oil, 0.77 g, 74.4%.

IR (pure) ν

_M : 3440 (OH) ₇ 2100 (N-), 1755 (C = O β-lactam),

1735 (C = O), 1680 (C = O) and 1625 cm (aromatic)

(1 "R, 5R, 6S and 1" S, 5S, 6R) p-Nitrobenzyl-2- (trans-3'-azidocyclobutyl) -6- (1 "-hydroxy-1" -ethyl) -penem-3- carboxylate

OH

Y N

Toluene-

COOPNB

A solution of (1 "R, 3S, 4R and 1" S, 3R, 4S) 4- (trans-3'-azidocyclobutanoyl thio) -3- (1 "-hydroxy-1" -ethyl) -1- (p -nitrobenzyl-2 ^M '-triphenylphosphoranylidene = 2 " ^t = acstat) -2-3zetiäinon (2 # 27 %, 3.14 mmol) in CHCl ₃ <40 ml) is diluted with toluene (300 ml) and heated under a stream of nitrogen 6 hours at reflux The first 60 ml of the solution (CHCl + toluene) are removed with a Dean-Stark trap and the reaction mixture is cooled

030027/0777

-t - «s— t

M / 20 359 SY-1599A

- 268 -

C. 24 H 30th N 73 S. , 20 51, 98 4, 20th 15, 83 7th , 10 50, 4, 15, 7th

23 C and evaporates the solvent under reduced pressure, leaving an orange syrup, which over a Silica gel column is purified (silica gel 60, 35 g, eluent Ether-benzene 0 to 6%). Evaporation of the appropriate fractions gives the title compound, 0.38 g, m.p. 134-135 ° C, 27.3%.

Analysis C ₁₉ H ₁₉ N ₅ OgS:

calculated: found:

IR (KBr) ν: 2110 (Nj, 1765 (C = Oβ-lactam), 1690 (C = OPNB

ΠΙα. X J *

Ester), 1510 (NO ₂ ) and 1355 cm (NO ₂ );

¹ Hmr (CDCl-) 1.36 6s (d, J__ "." = 6.3 Hz, 3H, CH,), 2.0-2.75 ο ^ χΐ ~ —π.— ι j

(m, 4H, H-2 ¹ , H-4 ¹ ), 3.67 (dd, J _H _ ₆ _ _H _ ₅ ^e 1 »5 Hz, J" f.. "= 6.5 Hz, 1H, H-6), 3.8-4.55 (m, 3H,

Xl-O-Xl-I

1 ^H-1, H-3 ¹ and H-1 "), 5.30 (ÄBq, J _ _{a b} = 13.6 Hz, 2H, CH ₂ -Ph-NO _2), 5.60 (d, ^J _H _ ₅ _ _H _ ₆ ^{= 1} ' ^{5 Hz} ' ^ΐΗ '

H-5), 7.59 (d, J_ _ = 8.8 Hz, 2H, H-m of PNB) Ho-lim

and 8.20 (d, J ₀₀ = 8.8 Hz, 2H, HO of PNB). Hm — Ho

UV (CHCl ,, 23 ° C) λ: 266 (£ 13050) and 322 ppm (C 10008). 0 max

The unreacted phosphorane was mixed with Ph ₃ PO recovered and cyclized as described above before majn received an additional amount of the title compound: 0.145 g, 10.4% for an overall yield of 37.7%.

030027/0777

M / 20 359 SY-1599A

a # # ♦

• · ♦

• k · ft

(1 "R, 5R, 6S and 1" S, 5S, 6R) 2- (trans-3 ¹ -amino-1'-cyclobutyl) -6- (1 "-hydroxyethyl) -penem-3-carboxylic acid

10% Pd / C

DME, ether, H ₂ O

OOPNB

COOH

To a solution of (1 "RrSR ₇ OS and 1" S, 5S, 6R) p-nitrobenzyl-2- (trans-3'-azidocyclobutyl) -6- (1 "-hydroxyethyl) ~ penem-3-carboxylate (0 , 33 g, 0.74 mmol) in dimethoxyethane (40 ml) are added ether (40 ml and 10% palladium on activated carbon (0.33 g). The reaction mixture is hydrogenated for 3 hours at a pressure of 3.10 bar ( 45 psi) H ₂ and filtered through a bed of Celite. The bed is washed with water, the filtrates and washings are combined and diluted with ether. The aqueous phase is separated off, washed with ether and lyophilized, 0.20 g, 95%;

(H ₀ O, 23 ⁰ C) λ : 258 (£ 2725) and 306 (Γ 3613).

UV

The crude material is triturated with water, the white solid is filtered off and 5 hours in a high vacuum over ^ ₂ ⁰ S ~ ^ge dried, 84 mg, 40%;

¹ Hmr (D_O) 6: 1.34 (d, J "_ ,,." = 6.3 Hz, 3H, H-2 "), 2.3-2.7 (m,

Δ Π. — Ζ —rl— I

4H, H-2 ¹ , Η-4 ·), 3.90 (dd, J _H _ ₆ _ _H _ ₅ = 1/5 Hz,

^J H-6-H-1 ' ^{l == 6 / l Hz} ' ^1H ' ^H ~ ^{6) and 5} ' ^{68 (d / J} H-5-H-6 ⁼ 1.5 Hz, 1H, H-5) ;

UV (H ₀ O, 23 ° C) X: -. : 258 (£ 4738) and 306 (f 6318).

The filtrate is purified by HPLC, 58 mg; UV (H ₂ O, 23 ° C) ^: 257 (t 3580) and 306 (£ 5033).

030027/0777

M / 2C 359 M / 1599A

example

Following the general procedure of Example 34, the following 2, 6-disubstituted penem compounds can, using the specified electrophiles are used.

Eiectrophil

CH «CH-CH 2 ~ ^B

HC = C-CH Br

Br

product

CH ₃ -CH ₃ CH ₂ -

CH ₃ CH ₂ CH ₂ -

HCHCCH.

030027/0777

M / 20 359 SY-1599A Electrophil

0CH = CHCH Br 0C = CCH ₂ Br O-

Br
1
CH ₃ CH-CH ₃ CH ₃ OCH ₂ Cl CH ₃ SCH ₂ Cl ex CH ₃ OCH ₂ CH ₂ Cl

3
HCHO

- 271 -

Φ can be oxidized too

0C = CCH_-

CH ₃ OCH ₂ -CH ₃ SCH ₂ -

CH ₃ OCH ₂ CH ₂

CH, SCH_CH_

■ 3 4 pounds.

HIGH-

CH ₃ SCH ₂ - and CH ₃ SCH-

O *

φ can be oxidized to

O H

© OH protected by -c-OPNB CH ₃ SCH ₂ CH - and. CH ₃ SO ₂ CH CH -

30027/0777

M / 20 359
SY-1599A

Electrophil l

CH ₃ CH ₂ CHO

Cr

0OCH Cl

0CH

0SCH ₂ Cl

OSCH ₂ CH ₂ Cl
ÖCH-SCH-CH-Cl

I!

@ SH protected -C-O-PNB (^ can be oxidized to Φ can be oxidized to

© can be oxidized to (£> can be oxidized to - 272 -

HO ₃ SCH ₂ CH ₂ -

SO H

R =

2850898

CH ₃ CH ₂ CH-

OH

HIGH ₂ CH ₂ -

OH
I.
CH CH-CK

HSCH ₂ CH ₂ -SH

CH ₃ CH-CH ₂ -

0OCH ₂ -

0CH SCH -

OH

CH, and 0SO, CH, - ScH - and

0SCH ₂ CH - and

ι ■ - 0Ch-OWiI-Un, -

O 3 O O 2 7 / CF7 77

can be oxidized too

can be oxidized to - - 0CH-SCH-CH, - and 0CH, SO_CH_CH,

0 27 / CF7T7

i

M / 20 SY-1599A

Electrophilic

0CH = CH-CHO

CH ₃ CH ₂ CO ₂ CH ₃

5 II CH ₃ C-SC ₂ H ₅

JL

- 273 -

can be oxidized, whereby SO ₃ H

R =

2930898

SH

CH CH ₃ C-

S ü

results.

030027/0777

· * ■ · - ■

M / 20 359 SY-1599A

Electrophilic

- 274 -

R =

0CH = CHCO CH

0C = C-CHO

0CHS

CHO

CO-CH-

Cl

Il Π

Br

030027/0 7 77

M / 20 259
ElectropHil

- 275 -

fY "

II ■

-N

Br

C ₂ H ₅ OC-Cl

C ₂ E ₅ OCCH ₂ Br cx ^;

C ₂ H ₅ OC-

O Il

C ₂ H ₅ OC -

NC

030027/0777

M / 20 359 SY-1599A

- 276 -

; —— -

ti t ··

2850898

Electrophile R =

FCH ₂ CH ₂ CO ₂ CH ₃ '

O ₂ N-CH ₂ Cl HCNH

'V- OCH ₂ Cl

(PNB-O)

CH ₃ CHO NH.

030027/0777

M / 20 359 SY-1599A

- 2 77 -

2950888

(D via

OMS

as in example

58

.3

NHCO ₂ PNB

Even

NH.

NHCH ₃

or <f ^H 3

N-CO ₂ PNB

NHCH.

CH.

030027/0777

M / 20 359
SV-1599A

- 278 -

• 4 -4 *

NH.

or

NHCOCH.

or NHCOCH,

0.

NH-

NHCONHR NHCONHR

CH.

or R * H, CH ,, CH ₃ CO-

NH.

030027/0777

M / 20 359

Even

STr

OH

STr

OH

STr

- 279 • ■ t

OCOCH. 2950638

OCOCH,

or

OCONHCH. OCONHCH.

or

OMS

CO.

SH

JO

030027/0777

M / 20 359
SY-I599A

Electrophilic

0CH ₂ CHO

- 280 -

R =

NRR ¹

CH ₃ G-

030027/0777

R, R ¹ = H, CH.

M / 20 359 SY-1599A

- 281 -

• ·

2950838

Example 42

(1'S, 5R, 6S and 1'R, 5S, 6R) β-trimethylsilylethyl 6- (1'-acetoxy-1'-ethyl) -2-methylpenem-3-carboxylate (Isomer C)

3- (1'-Hydroxy-1 · ethyl) -1- (β-trimethylsilylethyl-2 "-triphenylpho sphorany liden-2 "-acetate) -4-trityltliio-2-az et idinon

ITr

1) IDA

iMe-

2) CH CHO

(Mg 185, 1,84mMol) To a solution of diisopropylamine in tetrahydrofuran (5 ml) at -78 ⁰ C is one n-butyl-lithium (1.3 ml, 2.0 mmol) with stirring. After 5 minutes, a solution of 1- (ß-trimethylsilylethyl-2 "-triphenylphosphoranyiiden-2 ^I -acetat) -4-trityithio-2-azetidinone (1.27 g, 167 mmol) in tetrahydrofuran (15 ml) is added dropwise. during 20 minutes under stirring. After 2 minutes, add freshly distilled acetaldehyde (1 ml) was added and the solution stirred for 5 minutes. they are hydrochloric acid (12.6 ml of 0.3M) was added and the mixture is allowed to 23 ⁰ C. Then water and ethyl acetate (20 ml each) are added, shaken and separated off. The organic phase is washed with water and saturated sodium chloride solution (20 ml each), dried and the solvent

030Q27 / 0777

M / 20 359 SY-1599A

2350898

is evaporated in vacuo to give the crude product, 1.37 g. The product is absorbed from methylene chloride onto 7 g silica gel and applied (dry) to a 28 g silica gel column. The column is eluted with ether (100 ml) and then with ether / ethyl acetate 1: 1 (^ O ml). The first 20 ml of the column fractions will evaporate. The residue is combined and the solvent is evaporated in vacuo to give a product, 1.03 g. This product is absorbed from ether onto a 50 g silica gel Siiale (moist) = the column is eluted with ether (680 ml) and that eluted with ethyl acetate (200 ml. Later fractions are combined (mainly low Rf spot on TLC) and the Solvent is evaporated in vacuo, giving a partially purified title product, 440 mg (33%);

IR ν: 3400 (OH) and 175C cm (β-lactam and ester); Max

Hmr (CHCl ₃ ) δ: Too weakly dissolved to show peaks other than aromatic and trimethylsilyl.

Silver 3- (1'-hydroxy-1'-ethyl) -1- (B-trimethylsilylethyl-2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone-4-thiolate

OH

STr

AgNO ₃ / pyridine <

iMe.

A solution of silver nitrate (425 mg, 2.5 mmol), pyridine (79 mg, 1.0 mmol) and water (10 ml) are added to a solution of the above compound (403 mg, 0.50 mmol) in ether (10 ml) The mixture is stirred vigorously for 1 hour. The precipitate is collected by filtration and washed with water and ether, resulting in the mercaptide given in the title, 267 mg (80%)

030027/0777

M / 20 359 SY-1599A

- 283 -

IR V: 3400 (OH) and 1750 cm (β-lactam and ester). Max

4 ~ Acstylthio-3- (1 '~ acetoxy-1 ■ -ethyl) -1- (β-trimethylsilylethyl-2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone

AcCl / fyridine.

OAc

I SAc

Me - ^^ Γ

A solution of acetyl chloride (70 mg, 0.88 mmol) in methylene chloride (1 ml) is added dropwise to a solution of the above silver mercaptide (267 mg, 0.40 mmol) and pyridine (70 mg, 0.88 mmol) in methylene chloride (5 ml) at 0 ^° C. The mixture is stirred for 1.5 hours at 0 ^° C. and then for 15 minutes at 23 ^° C. The precipitate is filtered off and the solution is acidified with 0.1 M hydrochloric acid and 0.1 M Washed sodium bicarbonate (10 ml each). The solvent is evaporated in vacuo to give the title compound, 153 mg (59%);

IR v _max : 3450 (OH), 1750 (β-lactam and ester) and 1690 cm " ¹ (thioester;

¹ Hmr (CDCl ₃ ) 6: 7.5-8.2 (m, 15H, Ph), 5.85 (br, 1H, H-4), 3..0-5.0. (Not resolved, 4H , OCH, OCH ₂ , H-3), 2.0-2.6 (3 singlets; 6H, OAc, SAc), 0.9-1.7 (m, 5H, CH ₃ , CH ₂ Si) and 0 , 20 ppm (s, 9H, SiMe ₃ ).

M / 20 359 M / 1599A

- 284 -

1 u *

J '_i. _ · ♦ • ..j.

(1'S, 5R, 6S and 1'R, 5S, 6R) β-trimethylsilylethyl 6- (1'-acetoxy -] '- athyD - ^ - methylpenem-S-carboxylate (Isomer C)

Qhc

SAc

SiMe.

SiMe.

A solution of the above phosphorane (150 mg, 0/23 inMOl) in toluene (15 ml) is refluxed for 2 hours. The solution is mixed with 1 g of silica gel and the solvent is evaporated off Vacuum. The silica is placed on a 4 g column of silica gel (dry) and eluted with ether. The first 5 ml fraction (only high Rf spot on TLC) gives after evaporation of the Solvent the title compound, 65 mg (76%) as a waxy Solid.

IR ν: 1790 (β-lactam), 1740 (ester) and 1700 cm

HIgLX

-1

iOAc);

Hmr (CDCl ₃ ) 6:

(d, J = 2Hz, 1H, H-5), 5.4 (m, 1H ₇ HI ¹ Jr 4.3 (m, 2H, OCH ₂ ), 3.90 (q, J = 2Hz, 4Hz, 1H , H-7) 2.37 (s _f 3H, 2-CH ₃ ), 2.11 (s, 3H, OAc), 1.42 (d, J = 6.5, Hz, 3H, 2'-CH ₃ ), 1.1 (m, 2H, CH and 0.05 ppm (s, 9H, SiMe ₃ ).

The product turned out to be the only isomer.

Example 43

(1'R, 5R, 6S and 1'S, 5S, 6R) 6- (T-amino-1'-ethyl) -2-methylpenem-3-carboxylic acid

Μ / 20 359 - 285 -

Μ / 1599Α

2,5,898

Procedure A

(1'Fv, 3S, 4R and 1'S, 3R, 4S) 3- (1'-Azido-1'-ethyl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -4-tritylthio -2-azetidinone (Isomer B)

Ρφ.

CO PNB

CO _- PNB

A solution of (1'S, 3S, 4R and 1'R, 3R, 4S) 3- (1-methanesulfonyloxy-1'-ethyli-i- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -4- Tritylthio-2-azetidinone (isomer C) (12.36 g, 13.4 mmol) in 10% H ₂ O-HMPA (135 ml) is heated for 7 hours
(g 1.75, 27.0 mmol) in presence of sodium azide to 85 ⁰ C. Then the solution is poured into cold water (1 L) and collect the reaction product, which crystallized by Filtrate: redissolution in dichloromethane, wash with brine un <drying (MgSO ₄ ) gives the azidophosphorane as yellow
Foam after evaporation of the solvent; 11.5 g (98.9%). It is used unchanged in the next stage.

IRv _v (CHCl,): 2100 (N-), 1740 and 1610 cm " ¹ (C = O).

(1'-R, 3S, 4R and 1'S, 3R, 4S) 4-Acetylthio-3- (1 · -azido-1 · -ethyl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate ) -2-azetidinone (Isomer B)

N_

■ Φ,

CO PNB

CO PNB

SCOCH.

O PNB

—R ·· -

M / 20 359 SY-1599A

- 286 -

i " O,

A cooled solution (3 "C) of (1'R, 3S, 4R and 1'S, 3R, 4S) 3- (1 · -Azido-1 · -ethyl) -1- (p-nitrobericyl-2" -triphenylphosphoranylidine- 2 "acetate) ~ 4-tritylthio-2-azetidinone (8.9 g, 10.25 mmol) in dichloroethane (30 ml) is treated with a solution of mercury (II) acetate (2.12 g, 6, 66 mmol) in methanol) 30 ml). After stirring for 0.5 hours at 5 ⁰ C and 1.5 hours at room temperature, the solvent is evaporated and the crude mercury salt redissolved in dichloromethane and washed dilute mic NaHCO-, and brine . cools the solution to 5 ⁰ C, and treated directly with pyridine (1.66 g, 21 mmol) After drying '(MgSO ₄₎ and treated dropwise (1.65 g, 21 mmol) with acetyl chloride. Stir the reaction mixture 1 5 hour at ⁰ C. the precipitated mercury (II) chloride is abfiltrieztund the filtrate is washed successively with dilute HCl, NaHCO-, and brine. the organic solution at 5 ⁰ C is saturated with hydrogen sulfide remaining um_ precipitate the mercury impurities as mercury (II) sulfide. The crude thioester obtained after evaporation of the solvent is purified on a silica gel column (8.5 × 9 cm), eluting with dichloromethane (500 ml) and 15% acetonitrile dichloromethaii : 5.1 g / 74.6%);

¹ Hmr (CDCl ₃ ) 6: 3.70 (1H, m, H-1 ·), 2.98 (1H, m, H-3), 2-33 and 2.20 (3H, 2s, acetyl), 1.28 (3H, d, J = 6.2 Ha, H-2 ");

IR ν: (CHCl-) 2115 (N-), 1758, 1693 and 1620 cm " ¹ (C = O).

lUclX ö j

(1'R, 5R, 6S and 1'S, 5S, 6R) p -nitrobenzyl-6- (1 '-azido-1' - ^ 2-methyl-penem-3-carboxylate (isomer B)

O ^

COPNB

ϊ ·

Μ / 20 359 SY-1599A

- 287 -

2950838

A solution of (TR, 5R, 6S and TS, 5S, 6R) 4-acetylthio-2-C1 ^e -az ido-1 ^! -äthy 1} -1 -p-nitrobenzy 1-2 "-tripheny Iphosphorany liden 2" -acetat) -2-azetidinone (5.1 g, 13.1 mmol) in toluene (100 ml) is heated for 2 hours on Reflux. The solvent is evaporated and the mixture is purified by chromatography on a silica gel column (7x5 cm). The azido-penem is eluted with dichloromethane (further elution with 10% ether-dichloromethane results in the recovery of a further 1.82 g unreacted phosphorane) 1.21 g (40.6%) PP. 132-134 ⁰ C;

¹ Hmr (CDCl ₃ ) δ: 8.21 (2Η _Γ d, Hm aromatic), 7, SO (2H, d, Ho

aromatic), 5.51 (1H, d, J = 1.6 Hz, H-5), 5.33 (2H, ABq, H-benzyl), 3.92 (1H, dq, J = 8, 6, 4 Hz, HT), 3.67 (1H, dd, J = 1, £, 8 Hz, H-6), 2.37 (3H, s, CH ₃ ), 1.46 (3H, d, J = 6.4 Hz, H-2 ');

XR ν (CDCi j: 2123 (N-), 178S and 1712 cm "(C = G).

ZQL2C j O

(1'R, 5R, 6S and 1'S, 5S, 6R) 6- (1 · -amino-1'-ethy1) -2-methyl-penem-3-carboxylic acid (Isomer B)

CO PNB

A solution of (TR, 5R, 6S and 1 ^! S, 5S, 6R) p-nitrobenzyl-6-azido- {1 ^r azido-1'-ethyl) -2-methyl-penem-3-carboxylate (440 mg, 1.13 mmol) in THF-ether-water (120 ml) is hydrogenated for 1 hour at 3.45 bar (50 psi) in the presence of 10% Pd-C (440 mg). The catalyst is filtered off, the filtrate is extracted with ether and the aqueous phase is lyophilized. The crude amino acid (100 mg) is purified by HPLC: 19.5 mg.

Mr

(D ₂ O) 6: 5.69 (1H, d, J = Q, 9 Hz, H-5), 3.94 (2H, m, H-6,

HT), 2.28 <3H, s, CH ₃ ), 1.50 (3H, d, J = 6.4 Ha,

030027/0777

C »■

M / 20 359 SY-1599A

- 288 -

2350888

H-2'J;

-1

IR v _m (Nujol): 1767, 1576 cm (C = O);

UV (H "0) λ: 300 ίαμ (£ 5326).

£. OtaX

Procedure B

(1'R, 3S, 4S and 1 ^f S, 3R, 4S) 3- (1 '-azido-1' -ethyl) -4-tritylthio-2-azetidinone (isomer B)

"Si. (C

t-B

A solution of (1'3,33,4R and 1'R, 3R, 4S) 1- (tert-butyldimethyl silyl) -3- (1'-methanesulfonyloxy-1'-ethyl) -4-tritylthio-2- Azeti ~ dinone (isomer C) - (1.75 g, 3 mmol) and sodium azide (0.39 g, 6 mmol) in 10% H2 OrHMPA (15 ml) are heated to 75 to 80 ° C. for 3 hours under K " The reaction mixture is then diluted with ethyl acetate and washed several times with sodium chloride solution. The organic phase is dried (MgSO.) And evaporated, leaving an oil which crystallizes spontaneously. Trituration in ether and filtration gives 951 mg (76.5%) of the azido compound as a white solid, mp. 185-190 ⁰ C (dec.).

'Hmr (CDCl ₃ ) 6:

7.23-7.78 (15H, m, aromatic), 4.43 (IH, d, J = 3, H-4), 4.37 (1H, s, NH), 3.89 (1H, dq , J = 7, 6.5, H-1 ¹ ), 3.16 (1H, dd, J = 7, 3, H-3), 1.50 (3H, d, J = 6.5, H- 2 ·);

-1

IR V _1n . ' (CHCl-): 3410 (nH), 2123 (N ₀ ) and 1765 cm

(C = O).

030027/0777

M / 20 359 SY-1599A

- 289 -

(1'R, 3S, 4R and 1 ¹ S, 3R, 4S) 3- (1'-Amino-1'-ethyl) -4-tritylthio-2-azetidinone (isomer B}

H.

A suspension of (1'R ₇ SS, R and 1'S, 3R, 4S) 3- (1'-azido-1-ethyl) -4-tritylthio-2-azetidinone (isomer B) (1.0 g, 2, 41 mmol) and platinum oxide (100 mg) in ethyl acetate (1.00 ml) are hydrogenated for 1 hour at a pressure of 3.45 bar (50 psi). Since the reaction is incomplete, 200 mg of platinum oxide are added and the mixture is hydrogenated for a further hour. Finally, another 200 mg of platinum oxide are added and the reaction is continued for 2.5 hours. Total catalyst: 500 mg. Total time: 4.5 hours. The catalyst is then filtered off and the solvent is evaporated. The crude amine crystallizes from ether: 700 mg (80%). Mp 128-130 ⁰ C.

¹ Hmr (CDCl ₃ ) 6: 7.13-7.63 (15H, m, aromatic), 4.40 (1H, d,

J = 2.5, H-4), 4.30 (1H, broad, H-1), 3.30 (1H, dq, -J = 5.1, 6.3, HV), - 3, - 03 (IH, - dd _r - J = 5.1, 2 ₇ 5 _? H-3), 1.20 (3H, d, J = 6.3, H-2 ¹ ) and 1.0-1.80 ppm (2H, broad, NH ₃ ).

(1'R, 3S, 4R and 1'S, 3R, 4S) 3- (1'-p -nitrobenzyloxycarbonylamino-1'-ethyl) -4-tritylthio-2-azetidinone (Isomer B)

NH-

, sc <t>.

HNCOPNß

030027/0777

M / 20 359 SY-1599A

A solution of (1'R, 3S, 4R and 1'S, 3R, 4S) 3- (1'-amino-1'-ethyl) -4-tritylthio-2-azetidinone {isomer B) (1.00 g, 2 57 mmol in dichloromethane (100 ml) are cooled to 5 ° C. and treated with p-nitrobenzyl chloroformate (0.61 g, 2.83 mmol) and pyridine (0.22 g, 2.3 mmol}. After 45 minutes has stirred at 5 ° C and 2.25 hours at room temperature, the reaction mixture is washed with dilute HCl, sodium chloride solution, dried (MgSO ₄ ) and finally evaporated to dryness. The crude carbamate is crystallized from ether: 1 .03 g (70.5%), m.p. 147-150 ° C.

¹ Hmr (CDCl ₃ ) δ: 7.10-8.33 (19H, m, aromatic), 5.23 (2H, s,

Benzyl), 5.08 (1H, N-H), 4.40 (1H, s, N-H), 4.29

(1H, d, J = 2.2, H-4), 4.10 (1H, dq, J = 8, 6, ¹ H-1) 3.18 (1H, dd, J = 2.2, 8 , H-3) and 1.23 ppm

(3H, d, J = 6, H-2 ^1);

IR V

-1

(CHCl ₀ ): 33S5 (NH), 1765 and 1724 cm

(1 ¹ R, 5R, 6S and 1'S, 5S, 6R) p-Nitrobenzyl-2-methyl-6- (1'-p-nitrobenzyloxycarbonylamino-1'-ethyl) -penem-3-carboxylate (Ison eres B)

NHCO-PNB

NHCO ₂ PNB

COPNB

The title compound is obtained from (1'R> 5R, 6S and 1'S, 5S, 6R) 3- (1 ¹ ^ p-nitrobenzyloxycarbonylamino-1 '-ethyl) -4-tritylthio-2-azetidinone (isomer B) after standard stirring ; Mp 108 -110 ⁰ C.

¹ 'Hmr (CDCl ₃ ) 6: 7.50-8.40 (8H, m, aromatic), S, SS (IH, d, J = 1.20, H-5), 5.35 (2H, ABq , Benzyl ester) * 5.20 (2H, s, benzyl carbamate), 4.90 (1H, broad

0 300 27/07 77

• f • i • ι ι ι

M / 20 359 SY-1599A

- 291 -

♦ J ι · <>

2350898

^{: 3435}

NH), 4.20 (1H, dq, J = 6, 8, HT), 3.80 (1H, dd, J = 1.2, 8.0, H-6), 2.40 (3H, s , CH ₃ ), 1.40 (3H, d, J = 6, CH ₃ );

iH), 1777 and 1717 cm " ¹ (C = O).

The p-nitrobenzyl ester can be catalytically hydrogenated, such as described in Example 43 (method A), the corresponding Carboxylic acid gives.

Example 44

6-Dimethylaminomethyl-2-raethylpeneni-3-carboxylic acid * '' ^e ?

1 - (tert -Butyldimethylsilyl) -S-dimethylaminomethylM-tritylthio-2-azetidinone (ice and trans).

Me ₃ NH

NaBH CN

CH.

CH.

Me.

SiT

t-Bü

To a solution of dimethylamine (18.5 ml of a 2N solution in Methanol, 36 * 9 mmol) in methanol (80 ml) is added to a solution. of hydrochloric acid in methanol (2.5 ml of a 5N solution in methanol), then trans-1- (tert-butyl-dimethylsilyl) -3-formyl-4-tritylthio-2-azetidinone (3.0 g, 6.16 mmol) and after

030027/0777

M / 20 359 SY-1599A

292 -

Cyanoborohydride (0/27 g, 4.31 mmol). 'You stir the mixture 3.5 hours at room temperature, let go on ice-hydrogen chloride acid (pH = 2) and makes it basic with sodium hydroxide (1N NaOH, pH = 9). The mixture is extracted with ether and washed the ether phase with saline solution, dried and evaporated, whereby the title compound is obtained as an eäh.rohes oil (3.0 g).

ice and trans-3-dimethylaminomethyl-4-tritylthio-2-azetidinone

Me '

ι sc4> ._

Si

NaN.

HMPT

-Bu

A solution of the above crude compound (3.0 g, 6 mmol) in Hexamethylenphosphortriamid (HMPT, 16 ml) which contains water (10%), the mixture is cooled (5 ⁰ C) and treated with sodium azide (0.78 g 12 mmol). The mixture is stirred for 1.5 hours at room temperature, poured onto ice-water and extracted with ether (5 × 30 ml). The organic phases are extracted with hydrochloric acid (1N) and the acidic extracts are washed thoroughly with ether in order to remove HMPT. The acidic phase is made basic (1N, NaOH) and extracted with dichloromethane. Wash the organic layer with brine, dry, and concentrate to give the title compound as an amorphous white solid (1.5 g, 62.5% total). The isonation mixture is separated on a Waters Prep 500 device, eluted with methanol (5%), ammonium hydroxide (0.2%) and ethyl acetate (95%. Trans isomer 1.0 g, melting point 129-131 ° C (pentane)) ;

ö (ppm, CDCl ₃ ): 6.8-7.8 (15H, m, aromatic), 4.5 (1H ₇ NH), 4.28 (1H, d, J = 2.5, H-4) , 3.35 (1H, m, H-3), 2.75-2.1 (2H, m, HV), 2.3 (6H, s, CH ₃ ).

030027/0777

M / 20 259 - 293 - 9QKnGaQ

SY-1599A £ ον> υο # 0

. Cis isomer: 0.5 g, mp 132-133 ⁰ C (ether-pentane);

5 (ppm, CDCl ₃ ): 7.7-6.7 (15H, m, aromatic) " 4.72 (1H, NH), 4.5 (1H, d, J = 5.3, H-4) , 3.5 (1H, m, H-3), 2.85-2.35 (2H, m, HV), 2.31 (6H, s, CH ₃ ).

The ratio of cis to trans compounds can be changed by changing the process conditions can be changed.

cis- and trans-e-Dimethylaminoinethyl ^ -methylpenem-S-carboxylic acid

The tits connection is made according to the procedure of Example 34 from cis- and trans-S-dimethylaminomethyl ^ -tritylthio ^ - azetidinone produced.

ö (ppm, CDCl ₃ ): 5.5 (1H, d, J = 1.3), 3.7 (1H, dt, J = I, 3, J = 8), 2.8 (2H, d, J = 8, 2.35 (6H, s), 2.3 (3H, s).

Example 45

2-Aminoacetoxymethyl-penem-3-carboxylic acid (via mercaptide intermediate)

4-Azidoacetoxyacetylthio-1- (p-nitrobenzyl-2 · triphenylphosphoranylidene-2'-acetate) -2-azetidinone

^{6 5}

CO ₂ PNB

030027 / a777

M / 20 359 5Y-1599A

2950698

A cold (ice-MeOH bath) solution of 4-hydroxyacetylthio-i- (p-nitrobenzyl-2 —Triphenylphosphoranylidene-2'-acetate) -2-azetidinone (586 * mg, 0.954 niMol) in methylene chloride (15 ml) are treated successively with azido-acetyl chloride (240 mg, 2.01 mmol) and dropwise with pyridine (226 mg, 231 ml, 3.0 mmol) in methylene chloride (10 ml); shows after the addition TLC the disappearance of the starting material. The mixture is diluted with ether, washed successively with dilute HCl, Water, dilute aqueous sodium bicarbonate, water and saline solution. It is dried over sodium sulfate. The cleaning the ■ residue is carried out through a silica gel column (10 g), Elute with 20% ether in benzene, ether and 30% ethyl acetate in ether. Concentration of the appropriate fractions gives the title compound as a foam; 533 mg, 80.1%;

IRv (CHCl,): 1763, 1702 (C = O), 1625 (C = P0-J, 1522 max ο ₁ i

and 2110 cm " ¹ (N ₃ ). p -nitrobenzyl ^ -azidoacetoxymethylpenem-S-carboxylate

rf '

A solution of phosphorane (533 mg, 0.764 mmol) is heated Using reflux for 0.5 hours in toluene (90 ml) a catalytic amount of hydroquinone. The solvent is concentrated on the evaporator and the concentrated solution is given through a silica gel column (10 g). (Benzene: ether 48: 2 "). Man receives the title compound as an oil. It turns out that this oil is unstable at room temperature. You keep it up -78 ° C until you need it.

Q30Ö27 / 0777

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SY-1599A

2850898

Hmr (CDCl-) δ: 8.21 (2Η _# ά, Hm aromatic), 7.57 (2Η, d, Ho

aromatic) _Γ 5.68 (IH, dd

_g _c is

^{= 4}

^J 5-6 trans ^{= 2 / E} ~ ⁵⁾ ' ⁵ ' ^{43 (2H} ' ^{center of}

J = 16, CH ₂ -PNB), 5.39 (2H,

, 3.93 (2H, s.

CH-N-), 372 (part of dd, J, -. = 4, K-6),

and 3.50 ppm (1H, dd, J = 17, J ^ <- ^ = 2,

according to ο — 5 trans

H-6);

IR v _mav (CHCl-): 1795, 1755, 1710 (C = 0.1525 INO ₀ ), 2110 cm

Z-aminoacetoxymethyl-penem-S-carboxylic acid

N.

-N

CO H

A mixture of the above ester (219 mg, 0.522 mmol) in THF (16 ml) ether (30 ml) and water (16 ml) is shaken on a Parr hydrogenator for 2.25 hours at 3.45 bar (50 psi) H ₉ using 10% Pd / C (240 mg) as a catalyst. The catalyst is filtered off and washed with water and ether. The aqueous phase is washed with ether (3 × 30 ml) and lyophilized. The crude powder is purified on a reverse phase HPLC column to give the title compound (8 mg, 6.7%) as a white powder.

Hmr (D ₀ O) 6: 5.72 (1H, dd, J,

. = 3.5 J _t

. = 2, H-5),

'5-6 cis ""'"'5-6 trans 5.37 (2H, center of ABq, J = 13.5, CH ₂ -O), 3.96

(2H, s, (CH ₂ -NH ₂ J, 3.87 (IH, dd, J _gem = 16.5, ^J 6-5 cis ^{= 3} ' ^{5 # H} " ^{6) and 3} ' ^{49 Nmr (1H / dd} '

according to

= 16.5, J

6-5 trans

= 2, H-6)?

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M / 20 359 SY-1599A

2350888

_1

IR ν (Nujol): 1775, 1755 and 1600 cm "(C = O);

DV (H "0) λ" 306 (£ 4900), 256 (£ 3000).

Example 46

Silver 1- (ß-trimethylsilylethyl-2-triphenylphosphoranylidene-2'-acetate) -2-azetidinone-4-thiolate

CH ₃

: o ₂ CH CH si -CH ₃

XH-

Di-ß-trimethylsilylethyl fumarate

Cl

Cl

Pyxidine

(CH ₃ J ₃ Si

To a cold (-10 "C) ether (20 ml solution of 2-triraethylsilyl-ethanol (4.73 g, 0.04 mmol) [H. Gerlach HeIv. Chim. Acta 60, 3039 (1977)] and Pyridine (5.66 ml, 0.07 mol) is added dropwise (over 15 minutes) under nitrogen, fumaric chloride (3.78 ml, 0.035 mol), dissolved in ether (10 ml), and the black mixture is stirred for 5 minutes . -10 ⁰ C and then 10 min at room temperature, active carbon were added and the reaction mixture filtered through a bed of Celite the filtrate is washed with sodium bicarbonate 1% - brine (1:.. 1, 15Ö mi / washed the aqueous phase is extracted with Ether (30 ml) back-extracted. The ether solutions are combined, washed with sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a brown

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2350898

Solid obtained. This compound is purified over a bed of silica gel (30 g, 4 × 5 cm} with benzene {300 ml) as the eluent, an oil (4.855 g, 77%) being obtained which solidifies on standing: mp 33- 34 ⁰ C.

Analysis C ₁₄ H ₂₈ O ₄ Si ₃ :

calculated: found:

C. 12th H , 91 53 35 8th , 91 53 8th

Hmr (CDCl ₃ ) δ: 6.78 (2H, s, C = CH), 4.26 (4H, m, CH ₂ -O),

1.03 (4H, m, CH ₂ -Si) and 0.06 ppm (18H, s, (CH ₃ J ₃ Si);

IR (CHCl-) ν: 1710 (C = O from the ester), 1643 (C = C), 1267, 1258,

ό KlclX ^

862 and 840 cm " ¹ (Si-C).

Trimethylsilylethyl glyoxylate hydrate

(GH.

Si CCH ₃ )

1)

2) (CH ₃ )

A solution of di-ß-Trimethylsilyläthyl fumarate (37 g, 0.117 mmol) in methylene chloride (1.1 1) was ozonized at -78 ⁰ C. until a blue color persists. The excess ozone is purged with nitrogen and dimethyl sulfide (2.57 ml, 0.351 mol) is added. The solution is allowed to warm up ^{gradually to 23 ° C.} The reaction mixture is diluted with. Carbon tetrachloride to 2 liters and washed with 1% aqueous sodium carbonate solution (500 ml). The organic phase was trocJient over sodium sulfate / filtered through Gelite and evaporated (- ~ 25 ⁰ C) to dryness to obtain 43.9 g of the title compound (97%) of:

IR (neat) ν: 3450 (-0H), 1740 (ester) 1255, 860 and 840 cm " ^raax (SI-C).

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1 - (β-trimethylsilylethyl> -2'-hydroxy-2'-acetate) -4-tritylthio-2-azetidinone

STr

ΓΤ

CH (OH) T O

co.

Si (CH ₃ )

Trimethylsilylethyl glyoxylate hydrate (4.000 g, 11.5 inMol) and the 4-tritylthio-2-azetidinone (4.8 g, 24.96 mmol) reflux in benzene (25 ml) in a Dean Stark device for 24 hours. The solvent is in vacuo evaporates. The product is chromatographed on a silica gel column (450 g, 8.5 χ 14.5 cm) and eluted with stylacetate: Methylene chloride (1:19) until the title compound begins to emerge {^! ^ 1.5 1) and then with ethyl acetate methylene chloride (1; 9-2 1). The fractions containing the title compound are combined and evaporated to dryness, giving 5.415 g (89%) the title compound receives.

¹ Hmr (CDCl ₃ ) δ: 7.80 to 6.70 (15H, m, trityl), 5.23 and 4.90

(1H, 2s, HCO), 4.50-4.10 (3H, m _} H-3 and O-CH_) f, 2.60 (2H, m, H-2), 0.95 (2H, m , CH_-Si)

and 0.1 ppm (9H, s, Si-CH-);

IR (CHCl ₀ ) v ": 3520 (-0H), 1765 (C = O of β-lactam), 1740

(C = O from the ester), 1595 (CH, aromatic), 1257, 860 and 840 cm " ¹ (C-Si).

1- (β-Trimethylsilylethyl-2'-chloro-2 ■ -acetate) -4-tritylthio-2-azetidinone

scci.

-STr

Pyridines

030027/0777

SY-1599A - 299 - 2950898

• A solution of thionyl chloride (0/74 ml / 10/37 mmol) in dry THF (9 ml) is added dropwise with stirring to a solution of 1- (ß-trimethylsilylethyl-2 ¹ -hydroxyl'-acetate) -4- trityithio-2-azetidinone (4.9 g, 9.37 mmol), pyridine (0.84 ml, 10.38 mmol) and dry THF (40 ml) at -15 ⁰ C under nitrogen atmosphere. The mixture is stirred for 2 hours at -15 ⁰ C. The precipitate is washed away by filtration through a bed of Celite and with benzene (50 ml). The filtrate is evaporated ^{at 30 ° C. in vacuo.} The residue is dissolved in benzene (100 ml), treated with activated charcoal and filtered through a bed of Celite. Evaporation of the solvent gives a residue which is purified over a silica gel bed (100 g, 4.7 x 11 cm): hexane-benzene (1: 1, 400 ml), ether-benzene (1:19, 1: 1) . Evaporation of the appropriate fractions gives 4.64 g of the title compound (92%).

¹ Hmr (CDCl ₃ ) δ: 7.30 (15H, m, aromatic H), 5.77 and 5.43 (1H, 2s, CH-Cl), 4.7-4.2 (3H, m, H -4 and CH ₂ -O) 2.85 to 2.50 (2H _r m, H-3), 1.15 (2H, m, CH ₂ -Si) and 0.06 ppm (9H, s, Si- CH ₃ );

Ir (neat) ν: 1760 (C = O), 860 and 840 cm " ¹ (C-Si).

fflclX

1 - {ß-Trimethylsilylethyl ~ 2 '-triphenylphosphoranylidene-2' -acetate) 4-tritylthio-2-azetidinone

STr

A dioxane (20 ml) solution of the above chloroazetidinone (4.12 g, 7.568) is treated with triphenylphosphine (2.209 g, 8.424 mmol) and 2,6-lutidine (0.98 ml, 8.424 mmol). The mixture is refluxed for 3 hours. The cooled solution is filtered and

030027/0777

• · • ·

M / 20 359 SY-1599A

- 300 -

and the white solid is washed with THF. The filtrate is evaporated to dryness * the residue on a silica gel column is purified (200 g, 4 χ 31 cm) using ethyl acetate-hexane (3r, 7, 1 1; 7: 3, 1: 1) to give the in Phosphorane listed in the title is obtained (4.836 g, 83%).

IR (film): 1755 (C = O), 1615 (phosphorane), 850 and 830 cm

IUclX

(Si-C).

Analysis C ₄₇ H ₄₆ NO ₃ PSSi;

C. 89 H 07 N 81 73, 18th 6, 08 1, 83 72, 6, 1,

calculated: found:

Silver 1- (ß-trimethylsilylethyl-2 ^t -triphenylphosphoranylidene-2 ¹ -acetate) -2-azetidinone-4-thiolate

STr

+ AgKO ₃ + CnBu) ₃ N + CF ₃ CO ₂ H

5i (CH ₃ ) ₃

1- (ß-trimethylsilylethyl-2-triphenylphosphoranylidene-2'-acetate) 2-azetidinone (7.64 g, 10 mmol) is dissolved in ether (60 ml). An aqueous solution of silver nitrate (0.5M, 80 ml, 40 mMOl) is added and then quickly (1 minute) a solution of Tributylamine (3 ml, 12.58 mmol) and trifluoroacetic acid (0.154 ml

030027/0777

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SY-1955A

0.2 mmol) in ether (20 ml). The mixture is stirred mechanically For 19 minutes, filter off the precipitate, rinse with Ether (200 ml), triturated in water (70 ml), filtered again and rinsed with ether (100 ml). The light brown solid is dried in vacuo (water aspirator 10 minutes and pump 65 minutes), v / obei one the title compound (6.42 g) receives.

IR (CHcI-) υ: 1862 (COO), 1630 (phosphorane), 860 and

j 1Ώ3.Χ μ

840 cm " ¹ (Si-C).

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2350898

Example 47

6-Formamidoinethyl-2-raethylpenem-3 "carboxylic acid sodium; ain and Potassium salts

H η

and

trans -1- (tert -butyldimethylsilyl) -3-methanesulfonyloxymethyl-4-tritylthio-2-azetidinone

OH

H H

J-K

H H

MsO ι ι · 3

Si (

• t-

YES

Bu

t-bu

A solution of trans-1- (t-butyldimethylsilyl) -3-hydroxymethyl-4-tritylthio-2-azetidinone (8, og, 16.36 mmol) in dichloromethane (50 ml) is treated with llfonyl Methane at 5 ⁰ C Chloride (1.4 ml, 18 mmol) in dichloromethane (10 ml) and triethylamine (2.5 ml, 18 mmol) - Stirring is continued for 1 hour under an N ₂ atmosphere - The solution is then washed successively with cold 1N hydrochloric acid , 1M sodium bicarbonate and brine, dry (MgSCK) and evaporate in vacuo. The residue (mixture of hydroxy and mesylate cpd) is treated a second time as described above, giving the mesylate (90 g, 97%) as an amorphous solid. It is used unchanged in the next stage without further purification. The analytical sample is recrystallized from methylene chloride, mp 167-168 ⁰ C;

030027/0777

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IR (pure) v _max r 1755 cm

- 303 -

2350898

Hmr (CDCl ₃ ) 5: 7.3 (15H, m), 4.4 (1H _r d, J = 2Hz), 3.9 (1H, dd, J = 8Hz, 4 Hz), 3.2 (2H bs), 2.8 (3H, s), 0.95 (9H, s) and 0.3 ppm (6H, s).

trans-S-Methanesulfonyloxymethyl ^ -tritylthio - ^ - azetidinone and trans -3-azidomethyl-4-tritylthio-2-azetidinone

H H

H H

" ³

Si (CH ₃ ) ₂

t-bu

A solution of trans-i- (tert-butyldimethylsilyl) -3-methanesulfonylmethyl ^ 4 ^ tritylthio = 2 = azfetiäinon {21.0 g, 37.0 mmol) in HMPA (90 ml) is cooled in an ice bath and treated with sodium azide (2-7 g, 41.2 mmol) in H ₃ O (10 ml). The reaction mixture is stirred for 1 hour at room temperature, diluted with ethyl acetate, washed with H ₂ O (5 100 ml), dry (MgSO ₄ ) and evaporated in vacuo. The trans-3-methanesulfaonyloxymethyl-4-tritylthio-2-azetidinone is diluted with HMPA (90 ml), treated at room temperature with sodium azide (2.7 g, 41.2 mmol / l in H ₃ O (10 ml), heated for 2 hours at 60 ⁰ C and triturated with cold water the crude azide is diluted with benzene-ether. (5: 1) and washed with water (5 χ 20 ml) evaporating the solvent by means of and subsequent crystallization from ether gave 18.0 g (. 77%) of the azide as a white solid. The analytical sample is recrystallized from CH Cl .- / ether * mp 174-175 ° C;

Analysis C ₉ -H _0n N ₁ OS:

calculated: found:

C. 97 H 03 H 99 68, 78 5, 00 13, 16 68, 5, 14,

030027/0777

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«" T

M / 20 359 SY-1599A

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IR (Nujol) ν: 2100, 1765 cm '

-1

Hmr (CDCl ₃ ) δ: 7.35 (15H, m), 4.75 (1E, bs), 4.4 (1Η, d, J = 2Hz and 3.1-3.7 ppm (3H, m) .

trans -3-aminomethyl 1-4-tritylthio-2-azetidinone

H H

To a solution of trans-3-azidomethyl-4-tritylthio-2-azetidinone (10.0 g, 47.5 mmol) in dry methanol (500 ml) are added ammonium chloride (19.0 g) and zinc powder (1.0 g) and stir the suspension for 5 hours at room temperature. The reaction mixture is filtered and concentrated. The residue is partitioned between 1N hydrochloric acid and benzene. The aqueous layer is basified with 1M sodium bicarbonate and extracted with methylene chloride. The extracts are washed with brine, dried (MgSO.) And evaporated in vacuo. The crude amine crystallizes from ether (14.05 g, 79% melting point 139 ^° C.

Analysis C ₂₃ H ₂₂ N

calculated: found:

IR (CHCl-) ν

C. 56 H , 73 N 08 70 68 5 , 94 7, 27 7C, 5 7,

: 3400 and 1760 cm

Hnr (CDCl ₃ ) δ: 7.35 (15H, m), 5.15 (1H, m), 4.3 (1H, bs), 2.7-3.5 (3H, m) and 1.3 ppm (2H, m).

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trans-S-phthalimidomethyl ^ -tritylthio ^ -azetidinone

H H

»/" ■■■

A solution of 3-aminomethyl-4-tritylthio-2-azetidinone (13.9 g, 37.2 mmol) and N-carbethoxyphthalimide (8.3 g, 37.9 mmol) in benzene (200 ml) is heated for 15 hours on . reflux the solvent is evaporated off under vacuum and the residue is crystallized from ether to give 17.4 g (95%) of the title compound, mp 172-173 ⁰ C.

Analysis C-.H-.N ₀ CL ₁ S:

calculated: found:

C. 78 H 79 N 55 73, 92 4, 87 5, 49 73, 4, 5,

IR (CHCl-) v _m : 1770 and 1715 cm "¹;

¹ Hmr (CDCl ₃ ) 5: 7.8 (4H, m), 7.3 (15H, m), 4.45 (1H, d, J = 2Hz),

3.3-4.1 (3H, m) and 3.3-4.6 ppm (1H, m).

trans -3-phthalimidomethyl-1- (p-nitrobenzyl-2'-hydroxy-2'-acetate) -4-tritylthio-2-azetidinone

CO_]

A mixture of trans-3-phthalimidomethyl-4-tritylthio-2-azetidinone (17.4 g, 34.52 mmol) p-nitrobenzyl glyoxylate hydrate (9.4 g, 41.4 mmol) and triethylamine (4.8 ml, 34.5 mmol) in Tetrahydrofuran (250 ml) is stirred for 20 hours at room temperature

030027/0777

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SY-1599A 2350898

The reaction mixture is evaporated in vacuo and treated with activated charcoal in benzene. Evaporation of the solvent gives the crude hydroxyglyoxylate (25 g, quantitative) as an amorphous solid. It will be without in the next stage further purification used.

IR (CHCl-) ν: 1770 and (715 cm "¹;
j niax

* Hmr (CDCl,) 6: 8.1 (2H _x d, J = 9Hz), 7.55 (3H, d, J = 9Ha),

7.3 (19H, m), 5.0-5.4 (2H, bs), 4, ^ - 5.0 (2H, m) UD-I 2.8-3.8 ppm (4H, m).

trans -3-phthalimidomethyl-i- (p-nitrobenzyl-2'-chloro-2'-acetate) -4-tritylthio-2-azetidinone

⁰ 2 ^PNB

To a cooled (ice bath, 0 ⁰ C) solution of trans-3-Phthalimidomethyl-1- (p-nitrobenzyl-2'-hydroxy-2'-acetate) -4-tritylthio-2-acetiuinön {25 g, 35 inMoi) in tetrahydrofuran {150 sal) are added dropwise a 1M solution of thionyl chloride in tetrahydrofuran (46 ml, 46 mmol) and then a 1M solution of pyridine in tetrahydrofuran (46 ml, 46 mmol). The reaction mixture is stirred for 20 minutes at room temperature, diluted with petroleum ether (50 ml) and filtered through a bed of Celite activated carbon. The solvent is evaporated in vacuo to give the chloroazetidinone (26 g, quantitative) as an amorphous solid. It is used in the next stage without further purification.

030027/0 7 77

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IR (CHCl-) ν: 1775 and 1720 cm " ¹ .

O ΙΠ3.Χ

Hmr (CDCl ₃ ) 6: 8.12 (2H, d, J = 9Hz), 7.60 (2HV d, J = 9Hz),

7.3 (19H, m), 5.25 (2H, m), 4.7-5.4 (1H, m), 4.55 (1H, bs) and 3.3-4.0 ppm (3H, m ).

trans -3-phthalimidomethyl-i- (p-nitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate) -4-tritylthio-2-azetidinone

H H

CO PUB

CO PNB

A mixture of trans -3-phthalimidomethyl-i- (p-nitrobenzyl-2 ^f -chloro-2'-acetate) -4-tritylthio-2-azetidinone (26 g, 35.5 mmol) , triphenylphosphine (10.25 g , 39.1 mmol) and 2,6-lutidine (4.6 ml, 39.1 mmol) in dioxane (200 ml) are heated to 100 ° C. for 20 hours. The reaction mixture is filtered through Celite and evaporated. The residue is chromatographed on a silica gel column i350 g) and eluted with benzene to benzene / ether (1: 1) giving the phosphorane (21 g, 62%), white solid.

-1

IR (CHCl-J ν: 1750 and 1710 cm
ό max

Hmr (CDCl ₃ ) 6: 7.4 (38H, m), 4.8-5.4 (3H, m), 4.6 (2H, τη) and 3.7 ppm (1H bs).

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trans -3-Phthalamidomethyl ~ 1- (p-nitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate) -4-tritylthio-2 ^ azetidinone

HH t

H H

CO PNB

A cold (ice bath) suspension of trans -3-phthalimidomethyl-1- (p-nitrobenzyl-2 · triphenylphosphoranylidene-2'-acetate) -4-tritylthio-2-azetidinone (18.02 g, 18.83 mmol) in tetrahydrofuran (30 ml), water (30 ml) and acetone (30 ml) are treated dropwise with sodium sulfide (4.97 g, 20.7 mmol) in acetone / Water 1: 1 (30 ml) and refluxed for 8 hours. The reaction mixture is diluted with water and acidified with 1N hydrogen chloride acid and extracted with dichloromethane, the organic extracts are washed with brine and evaporated in vacuo, 17.1 g (88%) of the title compound being obtained as an amorphous pale yellow solid. He will used in the next stage without further purification.

IR (neat) ν: 3150-3600, 1750 and 1700 cm

Hll2 £

" ¹

¹ Hmr (CDCl ₃ ) δ: 7.4 (38H, m) and 3.3-5.5 ppm (8H, m).

trans-3-phthalisoimidomethyl-i- (p-nitrobenzyl-2'-triphenylphosphoranylidene-2 ' acetate) ^ -tritylthio ^ -azetidinone

B B

CO PNE

CO PNB

030027/0777

M / 20 359 SY-1599A

A solution of trans -3-phthalimidomethyl-i- (p-nitrobenzyl-2 ¹ -triphenylphosphoranylidene-2'-acetate) -4-fcritylthio-2-azetidinone (17.1 g, 17.54 mmol) in dichloromethane (125 ml ) is treated dropwise at room temperature with Ν, Ν'-dicyclohexylcarbodiimide (3.62 g, 17.54 mmol) in dichloromethane (30 ml). The solution is filtered through Celite and evaporated to give the title compound (18.23 g, quantitative) as an oil. It is used in the next stage without further purification.

IR (neat) ν: 2110, 1755 and 1710 cm "¹; max

¹ Hmr (CDCl ₃ ) δ: 7.5 (38H, m), 4.6-5.3 (4H, m) and 3.9 ppm

(2H, bs).

trans -3-aminomethyl-i- (p-nitrobenzyl-2'-triphenylphosphoranylidene-2 -Acetate) ^ -tritylthio ^ -azetidinone

CO ₂ PFB

A solution of trans -3-phthalisoimidomethyl-i- (p-nitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate) -4-tritylthio-2-azetidinone (5.9 g, 6.16 mmol) in tetrahydrofuran (40 ml ) cooled to -20 ⁰ C, is treated dropwise with N with hydrazine (0.2 mL, 6.16 mmol) and stirred for 30 minutes further. The reaction mixture is acidified with 1N hydrochloric acid and washed with fither; the aqueous phase is made basic with 1M sodium bicarbonate and extracted with methylene chloride. The organic extracts are washed with brine, dried (MgSO ₄ ) and evaporated. The residue is purified on a silica gel column (60 g) while eluting with ether to give ethyl acetate, giving 3.38 g (66%) of the aminophosphorane as an amorphous solid.

0 3 0027/0777

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SY-1599A

IR (CHCl-) ν: 1730, 1710 cm "¹;

»5 IUclX

Hmr (CDCl ₃ ) δ: 6.5-8.1 (34H, m), 3.8-5.3 (6H, m) and 0.9-1.9 ppm (2H, m).

trans -3-formamidomethyl-i - (p-nitrobenzyl-2 · triphenylphosphoranylidene-2 '-acetate) -4-tritylthio-2-azetidinone

H H

"CN 'H

CO PNB

O PNB

To a cooled (ice bath) solution of trans-3- (Arainomethyl-1- (p-nitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate) -A- tritylthio-2-azetidinone (5.0 g, 6.04 mmol ) in dichloromethane (50 ml) are added dropwise under N _? a solution of acetic acid-formic acid anhydride (600 mg, 6/8 mmol) in dichloromethane (5 ml) and then a solution of triethylamine (1 ml, 7 mmol) in dichloromethane (2 ml). Stirring is continued for 30 minutes. The solution is washed successively with 1N hydrochloric acid, water, 1M sodium bicarbonate and brine. The organic layer is dried (MgSO.), Evaporated and the residue is chromatographed on a silica gel column (50 mg Eluting with ether to give ethyl acetate gives 2.0 g (39%) of the formamide as an amorphous solid.

IR (CHCl ₃ ) v _max :

1740, 1685 and 1620 cm

l * / 6i 6.6-8.2 {35H, iü> -and 2.5 = 5.3 ppm {7H, Ht)

0 3 0027/0777

M / 20 359 - 311 - '· ··' -iri- · · ·· ι

SY-1599A

trans-silver-3-formamidomethyl-1 - (p-nitrobenzyl-2'-triphenylphosphoranylidene-2 '-acetate) -2-azetidinone-4-thiolate

PNB "CO ^ PNB

A solution of trans -3-formainidomethyl-i- (p-nitrobenzyl-2 '-triphenylphosphoranylidene-2'-acetate) -4-tritylchio-2-azetidinone (550 mg, 0.64 mmol) in dichloromethane (10 ml) evaporated one to dryness and diluted with hot methanol (20 ml). The solution is stirred at 60 ⁰ C and treated with a pre-warmed (60 ⁰ C) solution of 0.15 M silver nitrate in methanol (5.7 ml, 0.86 mmol) followed by a solution of 1.5 M pyridine in Methanol (0.57 ml, 0.86 mmol). The creamy solution is stirred for 30 minutes at room temperature and then in an ice bath for 2 hours. The solid is filtered off, washed with cold methanol and ether and dried, 300 mg (65%) of the silver salt being obtained as a beige solid. It is used in the next stage without further purification.

trans -4-acetylthio-3-formamidomethyl-1- (p-nitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate) -2-azetidinone

CO ₂ FBB "V

To a cold (ice bath) solution of trans-silver-3 * -formamidomethyl-1 - (p-nitrobenzyl-2 ^f -triphenylphosphoranylidene-2'-acetate) -2-azetidinone-4-thiolate (800 mg, 1.11 mmol ) in

030027/0777

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SY-1599A

Dichloromethane (10 ml) is added dropwise under N "a solution of 1M acetyl chloride in dichlorosiethane (1 _r 33 ml- 1.33 mol) and then a solution of 1M pyridine in dichloromethane (1.33 ml, 1.33 mol) - The solution is stirred in a cold bath for 1 hour and then filtered through Celite. The filtrate is washed successively with 1N hydrochloric acid. Water, 1M sodium bicarbonate and brine, dry the organic layer (MgSO.) And evaporate. The residue is purified on a silica gel column (5.0 g) and eluted with ethyl acetate to 10% methanol in ethyl acetate to give 450 mg (62%) of the title compound.

-1

IR (CHCl-.) Ν: 1755, 1685 and 1620 cm .3 max

Hmr (CDCl ₃ ) 6: 8.18 (2H, d, J? 9Hz), 7.0-8.0 (2OH, m), 6.75

(2H, d, J = 9 Hz), 6.3 (1H, nt), 5.5 (1H, m), 5.2 (2H, bsj, 4.9 (IH, bs) / 3.6 ( IH, m) ^ 3.0 (IH, m) and 2.2 ppm (3H. Two s).

p-Nitrobenzyl-e-formamidomethyl ^ -methylpenem-S-carboxylate

JL

ntH

SAc

CO PNB

A solution of trans-4-acetylthio-3-formamidomethyl-1- (pnitrobenzyl-2'-triphenylphosphoranylidene-2 ^f -acetate) -2-incri {450 215 _r Q _r SS6 siMol) in toluene (10 ml)

{450 215

man

12 hours at reflux. Concentration and purification on a silica gel column, eluting with ether to 10% methanol in ether, yields 100 mg (39 %) of the penem compound as an amorphous solid,

IR (CHCl-) ν; 3 max

1780 and 1690 cm

-1

030027/0777

M / 20 359 SY-1599A

• α ·

Hmr (CDCl ₃ ) 5: 8.2 (2H, d, J = 9Hz) , 8.2 ("IH, s), 7.6 (2H, d, J = 9Hz), -6.9 (1H, m), 5.55 (1H, s), 5.35 (2H, 2s), 3.3-4.1 (3H, m) and 2.33 ppm (3H, s).

Sodium 6-formamidomethyl-2-penem-3-carboxylic acid and potassium salts

H H

CO PNB

and

A mixture of p-nitrobenzyl-6-fo: mamidomethyl-2-methylpenem-3-carboxylate (80 mg, 0.21 mmol), palladium on gelite (30%, 100 mg), tetrahydrofuran (10 ml), ether (25 ml) and 0.05 M buffer solution pH 7 (4.46 ml, 0.223 mmol) is hydrogenated on a Parr shaker for 3 hours at a Exit hydrogen pressure of 3.1O bar (45 psi. Remove filter the catalyst over CeIite and wash with Water. The filtrate and the washing liquids are combined and the phases are separated. The aqueous phase is washed with ether (3x15 ml) and lyophilized. The raw solid is purified by HPLC, giving 18 mg of a mixture of the sodium and potassium salts.

^(H 2 ⁰⁾

max ^:

299 (£ 4933), 259 (£ 4094);

¹ Hmr (D ₂ O) 5: 8.15 (1H, s), 5.53 (1H, d, J = 1.4Hz), 4.0 (1H, m), 3.74 (2H, d, J = 5, Hz, 3.25-4.25 (1H, m) and 2.27 ppm (3H, s).

030027 / a777

M / 20 359 SY-I599A

- 314 -

example

(1'S, 5R, 6S and 1'R, 5S, 6R) 6- (1'-Hydroxy-1'-propyl) -2-methylpenem-3-carboxylic acid, sodium salt (Isomer C)

\ o ₂ Na

trans-1 tert. -Butyidimethylsilyl-S-propionyl ^ -tritylthio-Z-azetidinone

STi

H CK C = C

+ LDA + CK CK C = OCH SiMe.

STr

j-ύ

Procedure:

n-BüIii £ 37 _r 50 ml- 1 -6M / hexane, 60 mmol) is added dropwise under N _n to a cooled (dry ice-acetone bath) and stirred solution of diisopropylamine (8.50 ml, 60 mmol) in dry THF (200 ml). The mixture is stirred in the cold and i-tert-butyidimethyisiiyi-4-trit.yithio-2-azetidinone (22.9 g, 50 mmol) in dry TIIF (100 ml) is added. After 15 minutes, methyl propionate (40 excess ml,) is added and the reaction mixture kept for 4 hours at -78 "C. then removed the cooling bath and allowing the inner temperature to 0 ⁰ C (^ 4O minutes) increase. The mixture is poured over ice Hcl (pH ~ 6) and extracted with ether * Separate the layers and extract the aqueous layer with ether. The combined ethereal solutions are washed with water and brine and dried (Na ₂ SO-).

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2950888

Evaporation in vacuo gives an oil in quantitative yield. This contains a mixture of starting materials and the title compound. It is used unchanged and in the cleaned in the next stage.

IR (neat) ν: 1710 (-C-), 1750 cm " ¹ (ß-lactam). In 3.x

i-tert -Butyldimethylsilyl-S- (1'-hydroxy-1'-propyl) -4-tritylthio 2-azetidinone

if

NaBH,

OH

N.

.STr

SiWe

Procedure:

A solution of 1-tert-butyldimethylsilyl-3-propionyl-4-tritylthio-2-azetidinone (26 g, 50 mmol) and sodium borohydride (7.6 g, 200 mmol) in THF (400 ml) is stirred for 18 hours Room temperature. It is poured onto ice-HCl (1N) (pH 6) and extracted with ether. The acidic phase is extracted several times with ether and the combined ethereal solutions are washed with saline solution, dried (Na SO.) And evaporated to give an amorphous solid, 25.0 g. The crude product is tographed over SiO chromium ^ - and _{eluted first with CH 3} Cl ₂ , 10.8 g of 1-tert-butyldimethylsilyl-4-tritylthio-2-azetidinone being obtained. Eluting with 20% ether in CH ₂ Cl ₂ gives 10.3 g of the title compound as a mixture of two isomeric trans alcohols. This is determined by HPLC (Water Associates, System 500) using 10% EtOAC in CH ₂ Cl ₂ separated as eluent. Isomer C, white solid, FP (petroleum ether)

134-136 ⁰ C.

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2850898

'Hmr (CDCl ₃ ) 6: 7.1-7.8 (15H, m, STr), 4.35 (H, d), 3.1 (H, dd), 2.5 (H, m), 0.7-1.7 (5H, m), 0.97 (9H, s) and 0.25 ppm (6H, s).

Analysis C_

calculated: found:

71.91 71.51

7.59 7.60

2.71% 2.96%

Isomer B, white solid, 5.4 mg mp (pental-Petrolätfrer) 97-99 ⁰ C.

(CDCl ₃ ) 5: 7.1-7.8 (15H, m, STr), 4.15 (H, d), 3.4 (H, dd), 3.2 (H, m), 0, 7-1.7 (5H, m), 0.85 (9H, s) and 0.1 ppm (6H, s).

The total yield of these two alcohols (based on re recovered starting material) is 67.5%.

(1'Si3S, 4R and 1'R, 3R, 4S) i-tert-Butyldimethylsilyl ^ - (1 '-p-nitrobenzyl-dioxycarbonyl-1'-propyl) -4 ~ tritylthio-2-azetidinone (Isomer C)

OCC

Ό.ΡΝΒ 2

SiMe.

Procedure:

To a cooled (dry ice-acetone bath) solution of {Λ 'S, 3S, 4R and 1'R, 3R, 4S) 1-tert-butyldimethylsily1-3- (1'-hydroxy-1'-propyl) - 4-tritylthio-2-azetidinone (isomer C) (3.1 g, 6 mmol) in dry THF (20 ml) is added dropwise under N _{2 to} a solution of 1.6M n-BuLi / hexane (4.88 ml, 7.8 mmol) and stirred for 25 minutes at -78 ⁰ C. Then it is p-nitrobenzyl chloro-

030027/0777

M / 20 359 SY-1599A

• l · ·

formiät (1.56 g, 7.2 mmol) in dry TKF (10 mL) and added dropwise to the resulting mixture is stirred for 4 hours at -78 ⁰ C. The mixture is diluted with ether and washed with NH.Cl solution and brine. The organic phase is dried (Na ₃ S and evaporated to dryness, giving 4.2 g of the title compound (quantitative yield).

¹ Hmr (CDCl ₃ ) 6: 8.2 (2H, d), 7.0-7.7 (17H, m), 5.13 (2H, s),

4.05 (H, d), 3.75 (H, dt), 3.25 (dd), 0.55-1.8 (5H, m), 0.9 (OH, s) and 0.25 ppm (6H, d).

(1'S, 3S, 4R and 1'R, 3R, 4S) 3- (1'-p-nitrobenzyldioxycarbonyl-1'-propyl) ^ -tritylthio ^ -azetidinone (isomer C)

OCO ₂ PNB

he

QCO PNB

-N.

"SiMe.

+ HMPT
(10% K

+ NaN.

Procedure:

To a cooled (ice bath) solution of (1'S, 3S, 4R and 1'R, 3R, 4S) 1 -tert. -Buti'ldimethylsilyl-3- (1 '-p-nitrobenzyldioxycarbonyl-1'-propyl) -4-tritylthio-2-azetidinone (isomer C) (4.2 g, 6 mmol) in HMPT (40 ml) which 10% Contains H ₃ O, add sodium azide (0.78 g, 12 mmol). The mixture is stirred for 1 hour at room temperature. Then it is diluted with water (100 ml) and extracted with benzene: petroleum ether (1: 1 (4 15 ml). The organic phase is washed several times with water (6 χ 30 ml) and sodium chloride solution. It is dried (^ 2SO ₄ ) and evaporated to dryness whereby 3.5 g of a solid (quantitative yield) is treated with pentane and filtered to obtain 3.4 g of a pale yellow solid is obtained (m.p. 84-86 ⁰ C;.. ¹ Hmr _(CDCl3) δ: 8.2 (2H, d), 7-7.7 (17H, n), 5.2 (2H, s), 4.95

(H, dt), 4.4 (NH), 4.25 (H, d), 3.4 (H, dd), 1.7 (2H, m) and 0.95 ppm (3H, t).

030027/0777

M / 20 359 SY-1599A

(1 * S, 3S, 4R and 1'R, 3R, 4S) 3- (1'-p-nitrobenzyldioxycarbonyl-1'-propyl) -1- (p-nitrobenzyl) -2 "-hydroxy-2" -acetate ) -4-tritylthio-2-azetidinone (Isomer C)

OCO ₂ PNB

THF

+ PNB glyoxalate.

I,> STr

TEA

CO PMB

Procedure:

To a solution of (1'S, 3S, 4R and I'R / SR ^ S) 3- (1 ' -p-Witrobenzyldioxycarbonyl-1'-propyl) -4-tritylthio-2-azetidinone (isomer C) (3.2 g, 5.5 mmol) and p-nitrobenzyl glyoxylate hydrate (1.362 g 6 mmol) in dry THF (50 ml) are added a catalytic amount of TEA (4 drops) and Na SO. (to absorb the formed H_0). The mixture obtained is stirred for 6 hours at room temperature. It is filtered and evaporated to dryness to give 4.35 g of an amorphous solid (quantitative yield).

¹ Hmr (CDCl ₃ ) 6: 8.25 (4H, dd), 7-7.9 (19H, m), 5 _r 28 (2H, s),

5.1 (2H, s), 4.8 (H, d), 4.4 (H, dd), 4.1 (H, dt), 3.4 (H, m), 1.1-1.8 (2H, m) and 0.8 ppm (3H, t).

(1 ^f S, 3S, 4R and 1'R, 3R, 4S) 3- (1'-p-Nitrobenzyldioxycarbonyl-1'-propyl) -1- (p-nitrobenzyl-2 "-chlor-2" -acetate) -4-tritylthio-2-azetidinone (isomer C)

DCO. , PNB STr I. he CO PNB

Py / THF

OCO PNB

STr

SOCl / THP

CO ₂ PNB

030027/0777

M / 20 359 - 319 - "" *

SY-1599A 2950838

Procedure:

To a cooled (ice-salt bath) solution of the above glyoxylate (4.35 mg, 5.5 mmol} in dry THF (30 ml) are added 1M Py / THF (7 ml, 7 mmol) and then 1M SOC1 dropwise ₂ / THF 7 ml, 7 mmol). The mixture obtained is stirred for 1 hour at the temperature indicated above, then diluted with benzene (30 ml), stirred in the cold (ice-water bath) for 30 minutes and filtered through Celite activated carbon. The filtrate is evaporated to dryness to give 3.8 g of an amorphous solid (85.3%);

¹ HmT (CDCl ₃ ) 6: 8.15 (4H, d), 6.75-7.7 '(19H, m), 5.65. (H, s), 5.2 (2H, s), 5.1 (2H, s), 4.5 (H, m>, 3.85 (H, m), 3.4 (H, m) 1.25-2 _r 0 (2H, m) and 0, 9 ppm (3H, t).

{1'S, 3S, 4R and 1'R, 3R, 4S) 3- {1'-p-nitrobenzyldioxycarbonyl-1'-propyl) -1 - (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2 '-acetate) 4-tritylthio-2-azetidinone (isomer C)

OCO ^ PNB OCO ₂ PNB NL .Cl Lutidine «^ - ^;

Procedure:

To sins3T TJjQvmet Aar ol ^ i ^^ zi 0ίι1οΐΓνβχ1> ΐϊϊΛιιηα ί3-7 α. 4,568 mmol) in dioxane (35 ml) are added φ ^ Ρ (1.197 g, 5 mmol) and lutidine (0.54 g, 5 mmol). The mixture is heated to TOO ~ C in an oil bath for 3 days. It is then cooled, diluted with ether, and washed successively with 1N HCl, 1M NaHCO ₃ and saline solution. The filtrate is evaporated to dryness, 3.6 g of an oil being obtained. This is _{chromatographed over SiO 2} (120 g) and

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2850898

eluted with benzene _f benzene ether to give 1.45 g of the title compound as an amorphous solid (31%);

IR (neat) ν: 1750 cm " ¹ (wide).

lucuC

(1S, .3S, 4R and 1 * R, 3R, 4S) 4-Acetylthio-3- (1 '-p-nitrobenzyldioxyearbonyl-1 '-propyl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone (Isomer C)

OCO PNB

vA- ^{> STr}

AgNO,

Ό PNB

■ Φ.

Py / MeOH

Say

- O

CO PNB

CO PNB

CH.

OCO ₂ PNB

Py / MeOH

0 PNB

Procedure swe i s e:

A hot solution of AgNO- is added to a hot solution (60 ° C.) of the above phosphorane (1.4 g, 1.35 mmol) in MeOH (40 ml) while stirring. (0.3 g, 1.76 mmol) in MeOH (10 ml) followed by pyridine (0.107 g, 0.11 ml, 1.76 mmol). The silver mercaptide begins to precipitate immediately. The mixture is stirred for 15 minutes at room temperature uxiä 2 hours at 0 ⁰ C, filtered and the solid is washed thoroughly with cold MeOH and ether, 1.2 g, quantitative yield. Mp. 113-115 ⁰ C (d)

030027/0777

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SY-1599A 2950838

IR (Nujol) ν: 1740-1760 cm ^-1 (broad). This solid

TQcOC

will continue to be used unchanged

_{Acetyl chloride (0.118 g, 0.107 ml, 1.5 mmol) in CH 2} Cl _{2 is added} to a cooled (ice bath) solution of the above mercatpide (1.2 g, 1.35 mmol) in CH-Cl- (15 ml) (2 ml) then pyridine (0.119 g, 0.122 ml, 1.5 mmol) in CH ₂ Cl ₂ (2 ml). This mixture is stirred 30 minutes at 0 ⁰ C, filtered through Celite, remove the silver salt, and washed successively with HCl (0 _t 5N), H ₂ O, NaHCO ₃ (0, ^1, SM) and brine. The CH Cl ₂ solution (MgSO) is dried and evaporated to dryness, giving 0.94 g of the title compound as an amorphous solid. (83.4%)

IR (neat) ν: 1750 cm " ¹ (wide).
Max

(TS, 5R, 6S and 1 'R, 5S, 6R) p -nitrobenzyl 6- (1' -p-nitrobenzyldioxycarbonyl-1'-propyl) -2-methylpenem-3-carboxylate (Isomer C)

OCO ₂ PNB OCO ₂ PNB

CO PNB 2

Procedure:

A solution of the above phosphorane (0.4 g, 1.077 mmol) in toluene (35 ml) is heated to reflux and 5 ml of toluene is distilled off. The yellow solution is refluxed for a further 7.5 hours. It is evaporated to dryness giving 0.76 g of a thick oil. This is chromatographed over SiO ₀ (ACT 1.30 g) and eluted with benzene and benzene-ether to give the title compound as a solid, 0.32 g, (53.4%) mp (pentane) 160-162 ⁰ C.

030027/0777

e - ο

Μ / 20 359 SY-1599A

- 322 -

2350898

Hmr (CDCl ₃ ) δ: 7.3-8.4 (8Η _Γ m, aromatic), 5.4 (H, d), 5.3 (4H, benzyls, m), 5.0 (H, dt) , 4.0 (H, dd), 2.35 (6H, s), 0.8 (2H, dg) and 1.0 ppm (3H, t)

(1 · S, 5R, 6S and TR, -5-s . <, &) 6- (1 '-Hydroxy-1' -propyl) -2-raethylpenem-3-carboxylic acid (isomer C), sodium salt

OCO PNB

H / Pd-Celite

Phosphate. buffer

Procedure:

A mixture of the above ester (48 mg, 0.086 mmol) and 30% Pd-Celite {100 mg) in THF (10 ml, Et ₃ O (20 ml), H ₃ O (10 ml) and phosphate buffer (pH 7.2 ml) the mixture is hydrogenated at an initial pressure of 3.45 bar (50 psi) for 23 hours, filtered through Celite and the layers separated, the organic layer is faded with HO (2x5 ml) and the combined aqueous layers are washed with EtOAc (2 x 10 ml) The aqueous layer is then lyophilized to give the title compound as a white salt;

IR (KBr) ν: 1750 (ß-lactam) and 1600 - 1650 cm "'(broad, CO ~)

mci2c ^

KlcLSC

: 258 (£ 1105) and 305 (£ 1244).

030027/0777

Μ / 20 359 SY-1599A

- 323 -

Example 49

(1 ^f R, 5R, 6S and 1'S, 5S, 6R) 6- (1'-Hydroxy-1'-propyl) -2-methylpenem-3-carboxylic acid sodium and potassium salts (ISomers B)

CH.

(1'R, 3S, 4Rund 1'S, 3R, 4S) i-tert-Butyldimethylsilyl-S- (1'-formyloxy-1 '-propyl) -4-tritylthio-2-azetidinone (isomer B)

OH

HCO H, Et N DMAP, Ac O

OCHO

Tr

^sTr

SiMe,

4-Dimethylaminopyridine (DMAP) is prepared as a) by HC Brown et al-, Org. Synth-Collect. Vol. 5, 977 (1973) and b) Heimet Vorbruggen et al. Angew. Chem. Int- Ed-described 17, 569 r (1978).

Procedure:

To a cooled (0 ⁰ C) solution of (1'R, 3S, 4R and 1'S, 3R, 4S) 1-tert-butyldimethylsilyl-3- (1-hydroxy-1 * ^f -propylJ-4-tritylthio-2 -azetidinone (isomer B) (3.612 g, 7 mmol) in CH ₂ Cl ₂ (50 ml) add Et ₃ N (4.48 ml 35 mmol), HCO ₂ H (0.63 ml, 16.8 mmol ) and DMAP (0.854 g, 7 mmol) followed by acetic anhydride (7.14 g, 70 mmol) dropwise

clear yellow solution at -40 mixture.

C. A milky one is obtained

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2950888

Pour onto ice-1N HCl (pH 6) and separate the layers. The ^ H-Cl solution is washed with 1M NaHCO., And brine. Dry (Na ₂ SO ₄ ) and evaporate to dryness to give 3.8 g of a solid residue. This is treated with pentane and filtered to give 3.7 g of a white solid (96.8%); FP. 125-127 ° C;

IR (pure) ν

Max

Hmr (CDCl ₃ ) 6:

1720 (HC-) and 1750 cm " ¹ (β-lactam);

7.1 (H, s, HC-), 6.8-7.7 (15H, m), 4.8 (H, m), 4.05 (H, d, J = 1.5), 3 , 7 (H, m, J = 1.5, J = 7), 1.4 (2H, m), 0.95 (9H, s), 0.8 (3H, t) and 0.1 ppm (6H, s);

Analysis C ₃₂ H ₃₉ NO ₃ SSi:

calculated: found:

C. / 42 H 20th 70 , 20 7, 33 70 7,

2.57% 2.73%

(1'R, 3S, 4R and 1 · S, 3R, 4S) 3- (1'-Formyloxy-1'-propyl) -4-tritylthio-2-azetidinone (Isomer B)

OCHO

On. - ^STr

-N.

+ NaN.

HMPT

OCHO

O,

SiMe.

10%

Procedure:

To a cooled (ice bath) solution of (-3.7 g, 6.77 mmol) in HMPT (4Q ml) which contains 10% HO - give NaN_ ζθ.91 g, 14 mmol), the mixture is stirred for 1.5 hours at room temperature, pour it onto ice water (200 ml) and extract with ether (4 × 40 ml). The ether solution is diluted with petroleum ether and washes extensively with water and saline to remove HMPT. One dries (Na SO.) And evaporates to dryness,

030027/0777

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SY-1599A 2950898

where roan 2.92 g of a thick, colorless oil is obtained. (Quantitative Yield).

¹ Hmr (CDCl ₃ ) 5: 8.1 (H, HC-, S), 7.1-7.7 (15H, m, -STr), 5.23 (H, m, J = 7), 4 , 38 (H, d, J = 2.5), 4.3 (H, -NH), 3.35 (H, dd, J = 2.5, J = 7), 1.75 (2H, m ) and 1.0 ppm (3H, t).

(1'R, 3S, 4R and 1'S, 3R, 4S) 3- (1'-Formyloxy-1'-ethyl) -1- (p-nitrobenzyl-2 "-hydroxy-2" -acetate) -4-tritylthio -2-azetidinone (Isomer B)

OCHO OCHO

PNB GLYOXYLATE. T Γ

Λ - ^STr

_H Et ₃ NZTHF er-> y ^OH

CO PNB

Procedure:

A mixture of 3- (1'-formyloxy-1'-propyl) -4-tritylthio-2-azetidinone \ isomer B), (2.9 g, 6.77 mmol), PNB glyoxylate (1.59 g, 7 mmol), Et ₃ N (5 drops) and Na-SO ₄ (anhydrous, 5.0 g) in THF (50 ml) are stirred for 18 hours at room temperature. Filter and evaporate to dryness to give an amorphous solid in quantitative yield (4.33 g);

¹ Hmr (CDCl ₃ ) 6: 8.2 (2H, d), 7.1-7.8 (18H, m), 5.2 (2H, d), 4.9 (H, m), 4, 65 and 4.3 [H, 4.65 (1/2 H, s> 4.3 (1 / 2H, s)] _v 4.2-4.3 (H, d, 1 / 2H at 4.2 , 1/2 H at 4.3), 3.65 (H, m), 1.4 (2H, m), and 0.8 ppm (3H, t).

030027/0777

M / 20 359 SY-1599A

(1 '11, 33,4E and 1 ¹ S, 3R, * S) 3- (1'-Formyloxy-1'-propyl) -1- (pnitrobenzyl-2 "~ chloro ~ 2" -acetate) -4- tritylthio-2-azetidinone (isomer B)

OCHO

Py / THF

OCHO
k

OH

CO PNB

.Cl

CO PNB

Procedure:

To a cooled (ice-salt bath) solution of the above gyoxylate (4.3 g, 6.77 mmol) and 1M Py / THF (8 ml, 8 mmol) in dry THF (30 ml) is added, 1M SOCl / Py (8 ml, 8 mmol) is added dropwise The solid mixture obtained is stirred for 1 hour at the temperature indicated above. Then dilute with benzene (30 ml) and stir for another 20 minutes. It is filtered through Celite activated charcoal and the filtrate is evaporated to dryness, whereby 4.1 g of an amorphous solid are obtained (92%).

IR (pure) ν

Il

Max

1720 (H-C-), 1750 (-C-OPNB) and 1780 cm (β-lactam);

-1

Hmr (CDCl ₂ ) 6: 8.25 (2H, d), 7.8 (H, s, HC-), 7-7.75 (17H, m), 5.25 (2H, d), 5, 0 (H, m), 4.6 (H, s), 4.4 (H, d), 3.7 (H, m), 1.6 (2H, m) and 0.9 ppm (3H, t).

030027/0777

M / 20 359 SY-I599A

23508 ^ 8

(1 'R, 3S, 4R and 1'8,311,4S) 3- (1' -Formyloxy-1 '-propyl) -1- {p-nitrobenzy 1-2 ⁿ -triphenyiphPsphoigayliÖeB. _-2 "-aetate) -A- tritylthio-2-azetidinone (isomer B)

OCHO I

STr

Dioxane

OCHO A.

"rf _ _φ

CO ₂ VHB ■ _t CO ₂ PNB

Procedure:

A mixture of the above chlorine compound (4.0 g, 6.07 mmol) O ₃ P (1.834 g, 7 mmol) and lutidine (0.749 g, 7 mmol) in dioxane (40 ml) is heated to 100 in an oil bath for 2 days ⁰ C. It is cooled, diluted with ether and washed successively with a cold solution of 1N HCl, 1M NaHCO and sodium chloride solution. The organic solution is dried (Na SO.) And over Celite activated charcoal

2 ⁴
filtered. It is evaporated to dryness giving an oil,

which is _{chromatographed over SiO 2} (Act. 1, 200 g) and eluted with benzene and benzene-ether to give 2.60 g of the title compound as an amorphous solid (48 ^ 45%)

IR (neat) ν: 1720 (HCO-) and 1750-1760 cm " ¹ (-CO ₀ PnB and

ß-lactam).

(1'R, 3S, 4R and 1'S, 3R, 4S) 4-acetylthio-3- (1'-formyloxy-1'-propyl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone (Isomer B)

^ STr

OCHO

Tf

Say

CO-PNB

CO PNB

OCHO

rf

SAc

Ρφ.

CO PNB

030027/0777

M / 20 359 SY-I599A

Procedure:

- 328 -

A warm solution (60 ⁰ C) of 0.15 M AgWO ₃ -CH ₃ OH (8.7 ml, 1.3 mmol) is added to a mixture of the above phosphorane (0.88 g, 1 mmol) and pyridine ( 0.103 g, 1.3 mmol) in MeOH (5ml), which is heated to 60 ⁰ C. The mixture is stirred for 15 minutes at room temperature and 2 hours at 0 ^° C., then filtered and washed with cold MeOH, 0.53 g of the silver mercaptide being obtained as a yellow solid (71%), which is used as such. To a cooled (ice bath) mixture of the above mercaptide (ti, 53 g, 0.71 mmol) and pyridine (0.079 g, 1 mmol) in CH ₂ Cl ₂ (10 ml) are added dropwise CH ₃ COCl (0.079 g, 1 mmol) in CH-Cl ₂ 8 5 ml). After stirring for 1 hour at 0 C, it is filtered off. The filtrate is washed thoroughly with a cold solution of 0.5M HCl, 0.5M NaHCO ₃ and saline. Dry (Na SO,) and evaporate to dryness to give 0.43 g of an oil. (63%).

IR (pure)

ν: 1700-1760 cm max

(broad -C and ß-lactam).

(1'R, 3S, 4R and 1'S, 3R, 4S) 4- acetylthio-3- (1'-hydroxy-1'-propyl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" acetate) -2-azetidinone (Isomer B)

OCHO

SAc

HCl / MeOH

^ sS '* -

SAc

CO PNB

CO PNB

Procedure:

The above formate (1.0 g, 1.45 mmolJ in THF (To ml) is treated with HCl / MeOH at room temperature (10 ml, prepared from 2 ml conc. HCl and diluted with MeOH to a volume of 24 ml). The mixture is kept at room temperature for 0.5 hours,

03002 7/0777

M / 20 359 SY-I599A

- 329 -

2350898

make basic with 1M NaHCO ₃ , extract with EtOAc solution, wash with brine and dry (Na ₃ SO ₄ ). Evaporation gives 0.9 g of the crude title compound. This is _{chromatographed over SiO 3} and eluted with ether and ether: EtOAc (1: 1), 0.6 g of pure title compound being obtained as an amorphous solid (62.5%);

¹ Hmr (CDCl ₃ ) 6: 8.25 (2H, d), 7.3-8.1 (17H, m, aromatic), 5.6 (H, m), 5.2 (2H), 4, 9 (H), 4.4 (H, m), 2.3 (3H, Ξ '".), 1.5 (2H, m) and 0.9 ppm (3H, t)

(1'R, 5R, 6S and 1'S, 5S, 6R) p -nitrobenzyl 6- (1'-hydroxy-1'-propyl) -2-methylpenem-3-carboxylate (Isomer B)

Procedure:

The above phosphorane (0.2 g, 0.3 mmol) in toluene (45 ml) is heated under reflux and 5 ml of toluene are distilled off. The resulting mixture is then refluxed for 6 hours, then cooled, evaporated to dryness to give 0.2 g of an oil. This is chromatographed over SiO_ and eluted! with ether, 0.1 g of the title compound being obtained as a white | Solid obtained. (87%); Mp (pentane) 133-135 ⁰ C; j

¹ Hmr (CDCl ₃ ) 5: 8.3 (2K, d), 7.6 (2H, d), 5.6 (H, - d), 5.35 (2H, d), 4.15 (H. , m), 3.8 (H, m), 2.4 (3H, s, CH ₃ ), 2.2 (H, OH), 7.7 i'2H, Si) and 1.05 ppfii (3K , t).

030027/0777

M / 20 359

SY-1599A

- 330 -

2350898

(1 ¹ R, 5R ₇ 6S and 1 'S, 5S, 6R) 6- (T -hydroxy-1 · propyl) -2-methyl penem-3-carboxylic acid (isomer B) mixed K and Na salts

Ρ? "Γ

Procedure:

A mixture of the above ester (0.07 g, 0.185 mmol), 30% Pd-Celite (150 mg) and buffer solution (pH 7.4 ml) in THF (15 ml), Et “O (25 ml) and deionized water (15 ml) was _{hydrogenated at a starting H 2} pressure of 3.30 bar (48 psi) for 4 hours. Filter through Celite and separate the layers. The aqueous layer is washed with ethyl acetate and then lyophilized to give 92 mg of a solid;

IR (KBr) ν: 1780 (β-lactam) and 1650 cm " ¹ (broad, -CO ~) ; max 2.

UV H ₂ O λ _{m = v} : 255 (£ 983) and 300 (£ 1092).

example

(1'R, 5R, 6S and 1'5,53,6R) 6- (1'-Hydroxy-2 ¹ -phenylethy1) -2-methylpenem-3-carboxylic acid (isomer B)

030027/0777

• ■ ΐπιπίί-.ι-1 · .- ■ ir · - · -

M / 20 359 SY-1599A

- 331 -

trans -1 - (tert -butyldimethylsilyl) -S-phenylacetyl ^ -tritylthio-2-azefcidinone

/ -N-SiMe.

+ LDA -f <j> CH CO Et

STr -SiMe.

N- ^ i

i-tert-butyldimethylsilyl -tritylthio ^ ^ -azetidinon (18.32 g, 40 mmol) (100 ml) in dry THF is added dropwise under _N2 to a cooled (-78 ⁰ C) solution of LDA [prepared under N_ , at -78 ° C by dropwise addition of 1.6 M n-BuLi (101.25 ml, 162 mmol) to diisopropylamine (22.95 ml, 162 mmol) in dry THF (150 ml) and stirring for 30 minutes at - 78 ⁰ G]. The mixture is stirred 30 minutes at -78 ⁰ C., and ethyl phenylacetate (15.66 g, 15.12 ml, 93.6 mmol) in dry THF (50 ml) and the mixture is then stirred for 2 hours at - 78 ^° C. It is poured onto ice-1N HCl (pH 5-6), extracted several times with ether, the ether solutions are washed with sodium chloride solution and dried (Na_SO.). Evaporate to dryness to give 33.7 g of a crude solid. This is dissolved in ether (10 ml) and triturated with pentane (200 ml). The solid is filtered off and washed several times with pentane to give 18.3 g of a white solid (79.6%) is obtained, mp 141-113 ⁰ C.

¹ Hmr (CDCl ₃ ) 5: 7.0-7.6 (2OH, m), 4.8 (H, d), 3.7 (H, d), 3 _f 53

(H, s), 3.43 (H, s), 1.5 (9H, s) and 0.3 ppm (6H, s).

030027/0777

rr- - < * * β

M / 20 359 SY-1599A

- 332 -

2350898

1- (tert-butyldimethylsilyl-3- (1'-hydroxy-2'-phenylethyl) -4 *; ritylthio-2-azetidinone (2 trans diastereomers)

OH

_k STr

N-SiMe.

N-SiMe.

trans-1 - (tert-butyldimethylsilyl) -S-phenylacetyl ^ -tritylthio-2-azetidinone (28.8 g, 50 mmol) and NaBH ₄ (0.5 g, 0.25 mmol) in THF (200 ml) the mixture is stirred for 18 hours at room temperature. The mixture is poured onto ice-1N HCl and extracted with CH_Cl ₂ -The CH ₂ Cl ₂ solution is washed with brine and dried (Na ₃ SO ₄ ). An amorphous solid is obtained on evaporation (27.7 g). A portion of the solid (23.0 g) is _{chromatographed over SiO 2} and eluted with hexane-ether to give an off-white solid (14.4 g) which turns out to be a mixture of the (1'R, 3S, 4R and 1'S, 3R, 4S) and (1'S, 3S, 4R and 1'R, 3R, 4S) isomers in a ratio of 1: 1 (60%).

¹ Hmr (CDCl ₃ ) 6: 7-7.7 (2OH, m), 4.37 (1 / 2H, d), 4.18 (1 / 2H, d), 3.3-3.8 (H. , m), 3.45 (1 / 2H, dd), 3.1 (1/2 H, dd) 2.7 (2H, m), 0.87 (9H, d) and 0.25 ppm (6H , s).

1- (tert-butyldimethylsilyl) -3- (1'-formyloxy-2-phenylethyl) -4-tritylthio-2-azetidinone

"-1 S *

JL

—SiMe,

Isomer B

Isomer C

030027/0777

M / 20359-333 -, * ^':> -''*

To a cooled (-40 ⁰ C) solution of the above Älkoholmischung (14.4 g, 24.9 mmol) (ml 250) in CH ₂ Cl ₂ are one Et ₃ N (15.93 ml, 125 mmol), HCO ₂ H (2.24 ml, 59.76 mmol) and DMAP (3.04 g, 24.9 mmol). After stirring for 5 minutes, acetic anhydride (2.35 ml, 249 mmol) is added dropwise. The clear solution is stirred for 15 minutes at -40 ⁰ C, where it turns into a weiie, cloudy mixture. They are considered an additional 45 min. At -40 ⁰ C (total 1 hour), then is poured onto ice-1N HCl and separate the layers. The CH ₂ C1 ₂ solution is washed thoroughly with cold 1N HCl, H ₃ O, 1M NaHCO ₃ and saline solution, dried over MgSO ₄ and evaporated to give 14.0 g of an amorphous solid. This is separated by HPLC (Water Associates, System 500), "Isomer B" 6.0 g, melting point 172-173 ° C. and "Isomer C" 6.0 g, melting point 188-189 ° C. being obtained. The total yield of pure compound is 12.0 g (73.2 %) .
Isomer C:

¹ Hmr (CDCl ₃ ) 6: 6.8-7.7 (21H, m), 5.05 (H, dtj, 4.05 (CH, d),

3.65 and 3.75 (H, two doublets), 2.7-2.9 (2H, d), 0.88 (OH, s) and 0.2 ppm (6H, s).

3- (1 * -Formyloxy-2'-phenylethy1) -4-tritylthio-2-azetidinone (1'R, 3S, 4R and 1'S, 3R, 4S enantiomers)

, OCHO H Ο ⁰¹ * ⁰

1
he "- ^

Isomer B

_{NaN 3} (1.3 g, 20 mmol) is added to a cooled (ice bath) solution of the above formate (5.9 g, 9.375 mmol) in HMPT, which contains 10% water (50 ml). The mixture is stirred for 1.5 hours at room temperature, poured into fresh water (300 ml) and extracted

030027/0777

M / 20 359 SY-1599A

with ether (3 χ 100 ml). The ether solutions are washed - / round with water and saline solution. Dry (Na ₇ SO ₄ ) and evaporate to give a solid residue. This is treated with petroleum ether and filtered, whereby 4.4 g of a white solid (92

Analysis C ₃₁ H ₂₇ NO-S:

calculated: found:

%) Fp 169-171 "C receives. 84 C. H N 78 75 / 43 5, 51 2, 75 , 04 5, 64 2,

Hmr (CDCl ₃ ) 5: 7/9 (H, s), 7.1-7.6 (20H, m), 5.4 (H, m), 4.6 (H, NH), 4.2 iH, d), 3.3 (H, dd), 3.15 (H, s) and 3.0 (H, s).

3- (1'-Formyloxy-2'-phenylethyl) -1- (p-nitrobenzyl-2 "-hydroxy-2" -acetate) -4-tritylthio-2-azetidinone (1'R, 3S, 4R and 1'S, 3R, 4S enantiomers)

OCHO

STr

CO PNB

A suspension of PNB glyoxylate (2.37 g, 10.16 mmol) in dry benzene (100 ml) is refluxed in a Dean STark device (filled with 3A * molecular sieves) for 2 hours. The above NH compound is then added (4.2 g, 8.537 ϊπΜσΙ} and the mixture is refluxed for a further hour. It is cooled to room temperature, and Et ₃ N (0.12 ml, 0.85 mmol) is added and stir the mixture for 1.5 hours at room temperature.

030027/0777

M / 20 359 SY-1599A

- 335 -

29S08S8

It is evaporated to dryness, whereby the title compound in quantitative yield as a mixture of two isomeric alcohols.

¹ Emr (CDCl ₃ ) δ: 8.0-8.3 (2H, 2d), 7.5 and 7.6 (H, 2 singlets), 7.0-7.4 (2OH, m), 5.25 (2H, d), 4.9 (H, OH), 4.25 and 4.35 (H, 2 doublets), 3.5-4.5 (H, m, broad), - 3, -1- 3, -3 (H, - m) and 2-9 ppm (2H. M).

3- {1 * -Formyloxy-2 ^I -phenylethyl) -1- (p-nitrobenzyl) -2 "-chlor-2" -acetate) -4-tritylthio-2-azetidinone (1'R, 3S, 4H and 1'S , 3R, 4S enantiomers)

H OCHO

he

-r ^0H

CO PNB

CO PNB

To a cold (ice-salt bath) solution of the above glyoxylate (6.0 g, 8.537 mmol) in dry THF (30 ml) is added a IM solution of pyridine in TEF (10 ml, 10 mmol) and then drop by drop an IM solution of thionyl chloride in THF \ 1G ml, 10 mmol). After 1 hour at the above temperature has held, the mixture is diluted with benzene (30 ml) and stirred in the cold for a further 30 minutes. It is filtered through Celite Active charcoal and evaporated to dryness to give 6.0 g of an amorphous solid (98%);

* Hmr (CDCl ₃ ) 5: 8.2 (2H, m), 7-7.7 (23H, m) , 5.8 (H, s}, 5.25

(2H, s), '4.35 (H, d), 3.5-4, o (H, m) -3 ₇ 3 (H, m) and 2.9 ppm (2H, d).

030027/0777

M / 20 359 SY-1599A

3- {1 ¹ -Formyloxy-2 * -phenyläthyl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranyliäen-2 ⁿ -acetate) -4-tritylthio-2-azetidinone (1'R, 3S, 4R and 1S, 3R, 4S enantiomers)

OCHO

STr

COPNB

JPa

CO PKB

A mixture of the above chlorine compound (5.0 g, 8.333 mmol), O ₃ P (2.489 g, 0.5 mmol) and lutidine (1.0165 g, 1.1 ml, 9.5 mmol) in dioxane (50 ml ) is heated for 18 hours at 110 ⁰ C (bath temperature). It is cooled and filtered through Celite, the filtrate is diluted with ethyl acetate and washed with cold 1N HGl, H ₃ O, 1'M NaHCO ₃ and brine, dried (Na ₃ SO ₄ ) and evaporated, 8.0 g of a crude Product receives. This is chromatographed over SiO ₂ and eluted with ether: hexane (1: 1), 4.0 g of the title compound being obtained. Mp (needles from ether) 235-237 ⁰ C (d), (51%);

IR (film) ν

Max

1720, 1750 cm

-1

4-Acetylthio-3- (1 ^l -formyloxy-2'-phenylethyl) -1- (p-nitrobenzyl-2 ⁿ -triphenyiphosphoranylidene-2 ^!! -aoetate) -2-azetidinone (1'R, 3S, 4R and 1'S , 3R, 4S enantiomers)

OCHO

STr

CO PNB

O _-1 PNB

CO PNB

030027/0777

M / 20 359 SY-I599A

To a refluxed solution of the above phosphorane (3.6 g, 3.8 mmol) and fyridine (0.33 g, 4.2 mmol) in CH ₂ Cl ₂ (30 ml) and MeOH (30 ml) is added a 0.15M AgNO / MeOH solution (28 ml, 4.2 mmol) dropwise. The mixture is stirred at room temperature for 2.15 hours, concentrated to a small volume (- "10 ml), cooled and filtered to give the silver mercaptide as a yellow solid (2.3 g, 77%).

Put this mercaptide and pyridine (0.277 g, 3.5 mmol) in ice cold

CH_C1_ (5 ml) is treated dropwise with CH COCl (0.27 g, ZZ 3

3.5 mmol). The mixture is stirred for 3 hours at room temperature, filtered through Celite and the filtrate is washed with cold 1N HCl, H ₃ O, 1M NaHCO and sodium chloride solution. Dry (MgSO ₄ ) and evaporate to dryness to give 1.0 g of an amorphous solid (89.8%).

Hmr (CDCl ₃ ) 6: 8.2 (2H, d), 7.0-8.0 (23H, m), 4.5-5.7 (4H, m), -, 0-3.3 ( 3H, m) and 2.3 ppm (2H, ä, SAc).

4-acetylthio-3- (1'-hydroxy-2'-phenylethyl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone (1'R, 3S, 4R and 1'S, 3R, 4S enantiomers)

H -OCHO

-N

CO ^ PNB

CO PNB

A solution of the above phosphorane (1.8 g, 2.416 mmol) in THF {IC ml) is treated ir.an ip.it 15 HC 1 / MeOH ilO ml} and the mixture is stirred for 4 hours at room temperature. The mixture is concentrated to remove methanol, diluted with cold water, made _{basic with 1M NaHCO 3} and extracted with CHCl ₃ . The CHCl solution (MgSO.) Is dried and evaporated to give 1.65 g of an amorphous solid. This is chromium-containing _{via SiO 3}

030027/0777

M / 20 359 SY-1599A

2850898

graphed and eluted with ether: ethyl acetate, 1.30 g the title compound (75%) is obtained.

¹ Hmr (CDCl.,) 6: 8.2 (2H, d), 6.7-8.0 (22H, m), 4.0-6.0 (5H, m),

2-5-3.5 (3H, m) and 2.2 ppm (3H, SAc).

p-Nitrobenzyl-fi- (1'-hydroxy-2'-phenylethyl) -2- carboxylate Π-P, 5R, 6S and 1'S, 5S, 6R enantiomers)

H..

^H v. y- \ Φ \ Ρ <>, ¹ N.

SAc

-K

CO PNB

CO PNB

A solution of the above phosphorane (1.2 g, 1.67 mmol) in toluene (80 ml) is refluxed for 6 hours (10 ml are distilled off to remove moisture and low-boiling solvents which are present). It is evaporated to dryness and the crude product is chromatographed over SiO ₃ . The title compound is obtained by eluting the column with ether to give 0.65 g of an amorphous solid (89%).

(CDCl ₃ ) 5: &, 2 (2H, d), 7.6 (2H, d), 5.4 (H, d), 5.2-5.4 (2H, d), 4.0- 4.5 (H, m), 3.7-4.0 (H, dd), 3.0 (2H, d) and 2.3 ppm (3H, s).

6- (1 '-Hydroxy-2' -phenylethyl) -2-methylpenem-3-carboxylic acid (I ¹ R. 5P;. Ss-? And I ¹ S. 5S. 6R enantiomers)

CH.

CO PNB

030027/0 7 77

M / 20 359 SY-1599A

A mixture of the p-nitrobenzyl ester (0.33 g, 0.75 mmol), 0.05 M buffer solution (pH 7, 17.4 ml), THF (30 ml), Et ₂ O (30 ml), distilled H ₃ O (.60 ml) and 30% Pd / Celite (0.69 g) are hydrolyzed at an outlet pressure of 3.45 bar (50 psi) for 24 hours. It is filtered through Celite and the organic layer is washed with water. The combined water layers are washed several times with EtOAc and lyophilized for 18 hours, giving the title compound as a yellow solid salt. This is treated with a small amount of water, acidified with cold 1N HCl and extracted thoroughly with CHCl ₃ . The CHCl solution is dried (MgSO.) And evaporated to give a solid residue. This is treated with ether and filtered to obtain 30 mg of a white solid is obtained (13.2%), mp 165-167 ⁰ C?

IR (Nujol) ν: 3580 (OH, Sharp), 1660 and 1760 cm "¹;

UV (MeOH) X i 310 (C 5490) and 254 (£ 4880). inax

Example 51

(4 ^f R, 5R, 6S and 4 '$, 5S, 6R) 6- (2 *, 2 ^f -dimethyl-1, 3'-dioxolan-4'-yl) -2-methylpenem-3-carboxylic acid ( Isomer C)

A. Manufacture of:

030027/0777

• ♦. · * Ι

M / 20 359 SY-1599A

- 340 -

(4'R, 3S, 4R and 4'S, 3R, 4S) and (4'S, 3S, 4R and 4'R, 3R, 4S) 1- (tert -butyldimethylsilyl) -3- (2x, 2'-dimethyl-1 ', 3'-dioxolan-4'-yl) -4-tritylthio-2-azetidinone ("Isomer C" and "Isomer B")

Ethyl O- (2-methoxy-2-propyl) -glycolate '

OEt

POCl.

• Et

To a solution of ethyl glycolate (15.6 g, 0.150 mol; freshly distilled) and 2-methoxypropane (16.4 g, 0.216 mol; 95% pure) ² * in CH ₂ Cl ₃ (150 ml) are added at 0 to 5 ⁰ C phosphorus oxychloride (3 drops, 35 mg, 0.23 mmol) and stir the Mischutig 15 minutes at 0-5 ⁰ C and 1.5 hours at room temperature. Then quench with pyridine (30 drops), stir for 45 minutes and evaporate the solvent. The residue is diluted with pentane (150 ml) and dried over K ₂ CO ₃ . After filtering off, the solvent is evaporated to give 27.89 g (0.158 mol, 100%, 94.4% pure) of the title compound as a colorless oil;

¹ Hmr (CCl-) δ: 1.25 (3H, t, J = 7Hz -CH ₀ CH,), 1.28 (6H, s, Me,)

3.12 (3H, s, -OCH ₃ ), 3.88 (2H, s, -OCH ₂ CO-), 4.10 (2H, q, J = 7Hz, -CH ₂ CH ₃ );

IR (neat) V: 1760 and 1735 cm (ester).

1) J. Meinwald et al., Tet. Lett., 4327 (1978)

2) M.S. Newman and M.C. Vander Zwan, J. Chem., 38, 2910 (1973)

030027/0777

■ Τ · -. · ~ Ϊ́, rrT --- j

M / 20 359 - 341 -

SY-1599A 2-50898

(3S, 4R and 3R, 4S) 1- (tert -butyldimethylsilyl) -3-d-keto-2 '- (2 "-rcethoxy ~ 2" -isopropyloxy) -1 ^l -ethyl) -4-tritylthio-2 -azetidinone

J ^ -STr 1) LDA / THF

(18/5 ml, 0.134 mol) to a stirred solution of diisopropylamine in THF (400 mol, freshly distilled from LAH) at -78 ⁰ C is one n-Butyllithiura (1.6M in hexane, 90 ml, 0.144 mol) under N atmosphere. After 30 minutes, a solution of 1- (tert-butyldimethylsilyl) -4-tritylthio-2-azetidinone (50.0 g, 0.109 mol) in THF (100 ml) is added dropwise over 10 minutes and then stirred for 5 minutes . Ethyl - () - (2-methoxy-2-propyl) glycolate (23.94 g, 0.136 mol) is added to this pink solution and the mixture is stirred for 1 hour. After the dry ice bath has been removed, NH ₄ Cl-: solution (200 ml) and then brine (100 ml) are added. The aqueous phase is extracted with Et ₃ O (3 × 100 ml). The combined organic extracts are washed with saline solution, dried (Na ₃ SO ₄ ) and evaporated to give 60.95 g (0.103 mol, crude yield 94.6%) of the title compound as a crude, orange-colored oil. This raw material will be used in the next implementation. A pure sample is obtained by column chromatography (SiO_, eluent: 2% Et ₂ O in benzene);

¹ HmT (CDCl ₃ ) S: 0.30 (6H, s, Si-CH ₃ ), 0.95 (9H, s, tert-Bu),

1.12 (3H, s, CH ₃ ), 1.15 (3H, s, CH ₃ ), 3.15

(3H, s _r OCH ₃ ), 3.57 (1H, A of AB, J _em = 17Hz),

3.77 (1H, d, J = 1.6Hz, H-3), 3.97 (1H, b

J = 17Hz), 4.83 (1H, d, J = 1.6Hz, H-4), according to

7.1-7.6 (15H, m, aromatic Hs);

030027/0777

M / 20 359 SY-1599Ä

- CB « • • · '- ·
• · β - * - ^ - ' ι · - 342 -

IR ( _{neat) v m = jv} : 1750, 1725, 1710 cnf ¹ (C = O);

TLC, Rf 0.53 (benzene: Et ₂ O = 4: 1), Rf 0.61 (HexärtrEtOAc = 2--1)

(3S, 4R and 3R / 4S) 1- (tert ^ -butyldimethylsilyl) -3- (1'-hydroxy 2'-methoxy-isopropyloxyethyl) -4-tritylthio-2-azetidinone (Mixture of epimers at C-1 ')

STr

KaHH.

OH

OCH.

STr

A solution of crude 1- (tert-butyldimethylsilyl) -1- (1'-keto-2 '- (2 "-raethoxy-2" -isoproyloxy) -1'-ethyl) -4-tritylthio-2-azetidinone ( 60.95 g, 0.103 mol) in THF (100 ml) are diluted with abs. EtOH (350 ml) and to this solution at 0 ⁰ C, NaBH. (4.88 g, 0.156 mole). This mixture is stirred for 2 hours at room temperature and quenched by the slow addition of saline solution (280 ml). The mixture is extracted with Et “O (3 150 ml), the extracts are washed with brine, dried (Na_SO.) And evaporated to give a yellow residue which is redissolved in CH ₃ Cl ₂ (500 ml). It is dried (Na ₅ SO ₄ ) and evaporated again, giving 57.1 g (0.0966 mol, crude yield 93.8%) of the title compound as a crude, yellow foam:

¹ Hmr (CDCl ₄ ) 6: 0.17 (s, SiCH ₃ ), 0.80, 0.87 (2s, Si-tBu), 1.22,

IR (pure) ν

1.25 (2s, CH ₃ ), 3.03 is, OCH ₃ ), 4.32 (d, J-2 H-4), 7.0-7.7 (m, aromatic Hs);

: 3460 (OH), 1745 (C = O), 1595 (aromatic)

Rf = .47 and 0.42 (hexane: EtOAc = 2: 1).

This raw material is used in the next stage without further purification,

030027/0777

Μ / 20 359 - 343 -

SY / 1599A 2850898

(4'R, 3S.-4R and 4'3,311,4S) and (4 ¹ S, 3S, 4R and 4'R, 3R, 4S) 1 - (tert-butyldimethylsilyl) -3- (2 ·, 2 -Dimethyl-1 ', 3'-dioxolan-4'-yl) -4-tritylthio-2-azetidinone (isomer C and isomer B)

IF

A solution of (3S, 4R and 4R, 4S) 1 - (tert-butyldimethylsilyl) -3- (T -hydroxy-2 -methoxyisopropyloxyethyl) -4-tritΫ.lthio-2-azetidinone (mixture of diastereoisomersix at C- 1 ') (57.1 g, 0.0966 mol, crude) in CH ₂ Cl ₂ (500 ml) is treated at room temperature with p-toluenesulfonic acid monohydrate (200 mg) and 2,2-dimethoxypropane (20 ml) and then stir for 1 hour. Wash with saturated NaHCO 3 and then with brine, dry (Na ₂ SO ₄ ) and evaporate to give 49.64 g (0.0888 mol, crude yield 91.9%) of a mixture of the title compounds (isomers B and isomers C ) as a yellowish foam. This is purified by HPLC (Waters 500 silica gel; eluent hexane: EtOAc = 9: 1) and by crystallization, 14.28 g (25.5 mmol, 26.4%) of the title compound (isomer C) being obtained as white crystals ; Mp 146-147 ⁰ C (pentane).

¹ Hmr (CCl ₄ ) 5: 0.27 (6H, s, Si-CH ₀ ), 0.95 (OH, s, Si-tBu), 1.15 (6H, s, di-Mei, 2.5 -2.9 (1H, m, H-4 ') _r 2.97 (1H, t. J = 1.8 Hz, H-3), 3.25-3.9 (2H, m, H-5 ¹ } 4.27 ΠΗ, i.e. J = 1.8Hz, H-4), 7.1-7.6 (15H, m, aromatic Hs);

IR (Nujol) ν: 1750 (C = O) and 1595 cm " ¹ (aromatic);

Rf 0.45 (hexane: EtOAC = 4: 1) and 14.5 g (25.9 mmol, yield 25.9%) of the title compound (isomer B) as white crystals:

030027/0777

»» A

M / 20 359 SY-1599A

- 344 -

2150898

M.p. 144-145 C (Et ₂ O-pentane);

¹ Hmr (CCl ₄ ) 5: 0.02 (6H, s, SiMe), 0.833 (9H, s, Si-tBu),

1.13, 1.18 (6H, 2s, diMe), 2.5-2.8 (1H, m, H-4 ¹ 3.3-4.1 (2H, m, H-5 ^! ), 3 , 48 (1H, dd, J _{3 4} = 1/5 Hz, J _3-4 , = 5.0 Hz, H-3), 3.93 (1H, d, J _4-3 =

1.5 Hz, H-4), 7.1-7.1 (15H, m, aromatic Hs); Ir (Nujol) ν ϊ 1650 (C = O) and 1595 cm " ¹ (aromatic);

IUaX

Rf 0.37 (hexane: EtOAc = 4: 1).

analysis

C. C. , 80 H 38 W. 50 S. , 73 calculated: B. 70 , 23 7, 30th 2, 41 5 , 53 found: isomer 70 , 52 7, 31 2, 40 5 , 05 Isomer 7G 7, 2, 5

B. Preparation of Penem Product (Isomer C) (4'R, 3S, 4R and 4'S, 3R, 4S) 3- (2 ', 2'-dimethyl-1', 3'-dioxolan-4'-yl) -4-tritylthio-2-azetidinone (Isomer C)

, STr

NaN.

HMPT-H ₃ O

To a stirred solution of (4 "k, 3ö, 4k and 4 ^! Ξ, 3Κ, 43> 1- (tert-butyl-dimethylsilyl) -3- (2 ', 2'-dimethyl-1', 3'- Dioxolan-4'-yl) -4-tritylthio-2-azetidinone (isomer C) (14.3 g, 25.6 mmol) in hexamethylphosphorus thiamide (230.4 ml) is added slowly (over 20 minutes) at 0-5 ⁰ C a solution of sodium azide (2.50 g, 38.4 mmol; 1.5 equ.) In H_O (25.6 ml).

030027/0777

M / 20 359 SY-1599A

- 345 -

2850898

The mixture is stirred for 2 hours at room temperature and poured; them then in cold water (2 1). The white precipitate that forms is collected, _{washed with H 3} O and dried: to give 11.26 g (25.3 mmol, crude yield 98.8%) of the title compound as a white solid. Pure material is obtained by crystallization from CH ₃ Cl ₂ -EtO: mp 192-193 ⁰ C (dec.)..

¹ IMr (CDCl ₃ ) δ: 1.33, 1.37 (6H, 2s, di-Me), 3.27 (1H, t,

J = 3Hz, h-3), 3.8-4.4 (3H, m, H-4 ¹ and H-5 '), 4.40 (IH, d, J = 3Hz, H-4), 4 , 47 (1H, br, NH, D «O exchanged) and 7.1-7.7 ppm (15H, m, aromatic Hs);

IR (Nu j oil) ν

Max

3220 (NH), 1760 (C = O) and 1959 cm (aromatic);

-1

Rf 0.31 (hexane: -StOAc = 3: 2).

(4'R, 3S, 4R and 4'S, 3R, 4S) 3- (2 ', 2 · -dimethyl-1 ·, 3 · -dioxolane 4'-yl) -1- (p-nitrobenzyl-2 "-hydroxy-2" -acetate) -4-tritylthio 2-azetidinone (mixture of C-2 "epimers) (isomer C)

STr

PNB

fcs

Tr

Et N / THF

CO PNB

A suspension of p-nitrobenzyl giyoxylate hydrate (6.57 g, 28.95 mmol; 1.15 eq) in benzene (500 ml) is refluxed for 2 hours using a Dean-Stark trap. Evaporation of the solvent gives p = Ni-trohenzyl-glycxylate as an oil. A mixture of this oil and (4'R, 3S, 4R and 4'S, 3R, 4S) 3- (2 ', 2'-dimethyl-1 · _f 3'-dioxolan-4 ^l -yl) -4-tritylthio- 2-azetidinone (isomer C) (11.2 g, 25.2 mmol)

030027/0777

* "- 5Tf 3 · · · · C ι

^SY " ^15SSA 23508S8

in THF (350 ml, distilled from LAH) is treated at room temperature under N “18 hours (overnight) with triethylamine (289 mg, 2.86 mmol). After evaporation of the solvent, the residue is diluted with CH ₂ Cl ₃ (200 ml and washed successively with brine, which contains 1N HCl (2.9 ml), saturated NaHCO ₃ , brine, dried (Na ^ SO.) And evaporated after the addition of Et ₃ O (30 ml) whereupon 1/2 g (26.3 mmol, crude yield 100 % _f purity 95.8%) of the title compound is obtained as a white foam: Rf 0.40 and 0.30 (benzene: Et ₂ O = 3: 2).

Each isomer: is separated by HPLC (SiO ₂ , eluent Benzo Et “O = 3: 2) and purified _{by crystallization from CH 3} Cl ₂ -Et _{2 O.}

. Isomer I: Rf 0.40 (benzene: Et ₂ O = 3: 2), mp 153-154 ⁰ C;

¹ Hmr (CDCl ₃ ) 6: 1.20 (6H, s, di-Me), 3.1 (2H, m, H-3 and OH)

3.5-4.2 (3H, m, H-4 ¹ and h-5 ¹ ), 4.55 (1H, d, J = 2Hz, H-4), 5.12 (1H, br, H- 2 "), 5, ^ 0 (2H, s, OCH ₂ Ar) and 7.1-8.3 ppm (19H, m" aromatic Hs);

IR (Nujol) ν: 3370 (OH), 1775 (ß-lactam) and 1745 cm "

TCIcLX

(Ester);
Analysis C, _C H, ^ N ₀ O ₀ S:

calculated: aefundenι

Isomer II: Rf 0.30 (benzene: Et ₂ O = 3; 2); . Mp 164-165 ⁰ C;

C. , 04 H 23 N 28 % 66 .85 5, 64 4, 11 %. 65 5, 4,

030027/0777

9 Φ * ■ · Φ 0 i

Μ / 20 359
SV-1599A

- 347 -

Hmr (CDCl ₃ ) 6: 1.17 (6H, s, di-Me), ~ 3.2 (2H, nt, H-3 and OH 3.4-4.0 (3H, m, H-4 ¹ UridH-5 ¹ ), 4.57 (1H, d, J = 2Hz, H-4), 5.23 (1H, br, -2 "), 5.27 (2H, s, -OCH ₂ Ar) and 7.1-8.3 ppm (19H, m, aromatic Hs);

IR (Nujol) v _ra : 3340 (OH), 1765 (ß-lactam) and 1740 cm '

TO 3.x

(Ester); C. 04 H 23 N 28 S. 90 66 01 5, 34 4, 28 4, 75 66 5, 4, 4,

Analysis C ₃₆ H ₃₄ N ₂ O.

calculated: found:

- (4'R, 3S, 4R and 3'S, 3R, 4S) 3- (2 ', 2 * -Dimethyl-1', 3'-dioxolane 4'-yl) -1- (p-nitrobenzyl-2 "-chlor-2" -acetate) -4-tritylthio-2-azetidinone

(Mixture of C-2 "epimers) (isomer C)

SOCl -Pyr

THF

Ν— <* ο

CO PNB

CO PNB

To a stirred solution of (3'R, 3S, 4R and 4 ^f S, 3R, 4S) 3- (2 ', 2'-dimethyl-1 ·, 3 · -dioxolan-4'-yl) -1- ( p-nitrobenzyl-2 "-hydroxy-2" -acetate) -4-tritylthio-2-azetidinone (isomer C) (17.13 g, 25.07 μmol; mixture of C-2 "epimers) in THF (250 ml ) are added at -15 ⁰ C under N ₂ of pyridine (2.84 ml, 35.1 mmol) and then immediately thereafter thionyl chloride (2.20 ml, 30.1 mmol; Anachemia) the mixture is stirred for 20 minutes at -. 15 ^° C. and the white precipitate is then filtered off. After washing with benzene, the filtrates and washing liquids are combined and concentrated. The residue is dissolved in benzene (250 ml) and treated with active

030027/0777

M / 20 359 SY-1599A

—Τι * # ■ * -j— _{i #} - -j ---, - —J

fourth charcoal, filtered and evaporated to give 17.94 g (26.65 mmol, crude yield 100%, purity 94.1%) of the crude titan compound as a white foam: Rf 0.76 (benzene: Et ₂ O = 3 : 2);

¹ Hmr (CDCl ₃ ) δ: 1.20 (6H, s, diMe), 3.17 (1H, m, H-3), 3.4-3.9 (3H, m, H-4 ^{f and} H- 5 ¹ ), 4.67, 4.72 (1H, 2d, J = 2.5 Hz, H-4), 5.30 (2H, s, OCH ₂ Ar), 5.83 (s, H-2 ") and 7.1-8.3 ppm (19H, m, aromatic Hs);

IR (pure) ν

Max

1770 cm (P-lactam and ester).

This material is used in the next step without further purification.

(4'R, 3S, 4R and 4'S, 3R, 4S) 3- (2 ¹ , 2 ^r -Dimethyl-1 ·, 3'-dioxolan-4'-yl) -1- (p-nitrobenzyl) -2 " -triphenylphosphoranylidene-2 "acetate) -4-tritylthio-2-azetidinone (isomer C)

rJ®

Diox.

STr

CO PNB

1O ₂ PNB

A mixture of (4'R, 3S, 4R and 4'S, 3R, 4S) 3- (2 ', 2'-dimethyl- ^1r , 3'-dioxolan-4 · -yl) -1- (p-nitrobenzyl- 2 ⁿ -chlor-2 "acetate) -4-tritylthio-2-azetidinone (isomer C) (17.87 g, 25.0 mmol; purity 94.1% mixture of C-2" epimers), triphenylphosphine ( , 7.27 g, 27.5 mmol) and 2,6-lutidine (3.19 ml, 27.5 mmol) in dioxane (350 ml, distilled from LAH) are heated under reflux for 40 hours.

030027/0777

Μ / 20 359 - 349 -

SY-1599A 2950898

Evaporation of the solvent in vacuo gives 29.5 g of a dark oil, which is purified by column chromatography (SiO_ 330 g; eluent: 20-50% Et in benzene), 10.5 g of a yellowish solid being obtained. This solid is rinsed with Et_O, whereby one 7.49 g (8.33 mmol), yield 33.3%) of the title compound as slightly yellowish crystals:

Hmr (CDCl ₃ ) 6: 1.07 (s, di-Me) and 7.1-8.2 ppm (m, aromatic Hs);

IR (Nujol) V _1113,: 1760 cm " ¹ (C = O).

IiIaX

An analysis sample is made by crystallization from CH-Cl -.- Et,

2 2. ι

. prepared, mp 231-232 ⁰ C;
Analysis C ₅₄ H ₄₇ N ₃ O ₇ PSi

calculated: found:

Rf 0.37 (Benzo: Et ₂ 0 = 1: 1)

(4 »R, 3S, 4R and 4'S, 3R, 4S) silver 3- (2 ¹ , 2'-dimethyl-1 ·, 3 ¹ -dioxolan-4'-yl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylden-2" -acetate) -2-azetidinone-4-thiolate (isomer C)

C. 14th H 27 N 12th S. 57 72, 18th 5, 43 3, 98 3 _f 41 72, 5, 2 _f 3,

J ΡΦ ^Me0H

A solution of (4'S, 3S, 4R and 4'S, 3R, 4S) 3- (2 ¹ , 2 ¹ -dimethyl-1'3'-dioxolan-4'-yl) -1- (p-nitrobenzyl-2 "- triphenylphosphoranylidene-2 "acetate) -4-tritylthio-2-azetidinone (iso-

030027/0777

Μ / 20 359 SY-1599A

2850898

meres C) (319 mg, 0.355 mmol) in CH ₂ Cl ₃ (10 ml) is evaporated, whereby. an oily residue is obtained which is redissolved in hot methanol (8 ml / 60 °). To this solution at 60 ⁰ C is added a hot solution of AgNO in MeOH (0.15M, 4.0 ml, 0.60 mmol) followed by pyridine (29 μΐ, 0.36 mmol): The mixture is stirred 5 Hours at room temperature and 1 hour at 0 ^° C. The precipitate is collected, washed with ice-cold methanol and then with cold Et ₃ O, whereby 255 mg (0.334 mmol, yield 94.1%) of the title compound are obtained as a brownish solid:

IR (Nu j oil) ν

Max

1750 cm " ¹ (s, CO).

(4'R, 3S, 4lt and 4'S, 3R, 4S) 3- (2 ¹ , 2'-dimethyl-1 ·, 3'-dioxolan-4 '-yl) -1- (p-nitrobenzyl-2 "- triphenylphosphoranylidene-2 "acetate) -4-acetylthio-2-azetidinone (isomer C)

CH COCl / Pyr

. , SAc

ro

CO ₂ PNB

CO PNB

To a solution of (4'R, 3S, 4R and 4'S, 3R, 4S) silver-o- (2 ¹ , 2'-dimethy 1-1 ', 3Ä-a.ioxolan-4 ^f -yl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone-4-thiolate (isomer C) 254 mg, 0.333 mmol) in CH Cl. (15 ml} which μΐ pyridine (100, 1.24 mmol; containing 3.72 eq) are added at 0-5 ⁰ C acetyl chloride (71 μΐ, 1.0 mmol, 3.0 ÄquJ Han the mixture is stirred 40th minutes at 0-5 ⁰ C. After filtering the precipitate on Gelite wash the filtrate in succession with brine containing 1 N HCl (1.25 mL), saturated NaHCO ₃ and then with brine, dried (Na ₂ SO ₄₎ and evaporated to give 200 mg of an oil which _{crystallizes from Et 2} O to give 155 mg (0.222 mmol) of the title compound as white crystals.

030027/0777

M / 20 359
SY-15S9A

235089!

Hmr (CDCl ^) δ: 1.23 (s, di-Me), 2.20, 2.33 (2s, -SAc) and 7.2-8.3 ppm (m, aromatic Hs):

IR (Nujol) v _{ra = v} : 1750 (β-lactam and ester) and 1690 cm

(Thioester).

-1

An analysis sample is obtained by crystallization from CH-Cl «-

: M.p. 177-178 ° C;

Analysis C ₃ ^ H ₃₅ N

calculated: found:

Rf 0.62 (EtOAc)

(4'R, 5R, 6S and 4'S, 4S, 6R) p ^{-nitrobenzyl-6- (2 1} , 2'-dimethy1-1 ', 3'dicxolan-4'-yl) -2-methylpenem-3-carboxylate (Isomer C)

C. 60 H 05 N 01 S. 59 63, 34 5, 32 4, 83 4, 31 63, 5, 3, 4,

toluene

SAc

CO PNB

A suspension of (4'R, 3S, 4R and 4 ¹ S, 3R, 4S) 3- (2 ', 2'-dimethyl-1', 3 · -dioxolan-4 · -yl) -1- (p- nitrobenzyl-2 "-triphenylphosphoranylidene-2" acetate) -4-acetylthio-2-azetidinone (isomer C) (443 mg, 0.634 mmol) in toluene (70 ml) is _{refluxed under N 3 for} 6 hours. Evaporation of the solvent gives a white solid which is purified by column chromatography (BiO ₂ 10 g; solvent 10% Et ~ O in benzene) to give 247 mg (0.587 mmol), yield 92.7%) of the title compound as a white solid:

030027/0777

M / 20 359

- 352 -

¹ Hmr (CDCl ₃ ) 6: 1.42 (6Η, s, di-Me), 2.38 (3R, s, 2-CH ₃ ),

3.8-4.5 (4H, m, H-6, H-4 ¹ and H-5 ¹ ), 5.02-5.25-5.33-5.57 (2H, AB type, -OCH ₂ Ar), 5.57 (1H, d, J = 1.8 Hz, H-5), and 7.52-7.67-8.12-8.27 ppm (4H, A ₂ ¹ B ₂ ¹ , aromatic Hs);

IR (Nujol) ν: 1760 (β-lactam) and 1700 cm " ¹ (ester).

An analytical sample is obtained by crystallization from CH ₂ Cl ₂ -Et ₂ O: mp 167-168 ° C;

UV (EtOH) λ " ₌ : 265 (S 14,000) and 314 mn (C 10,000);

IQaX

Analysis C ₁

calculated: found:

Kf 0.62 (Benzene-Et ₂ 0 = 1: 1).

(4'R, 5R, 6S and 4 ^f S, 5S, 6R) 6- (2 ¹ 2 ^f -Dimethyl-1 ', 3'-dioxolan-4'-yl) -2-i-ethylpenem-3-carboxylic acid (Isomeres C)

C. 28 H 79 N 66 S. 63 % 54, 15, 4, 78 6, 54 7, 64 % / 54, 4, 6, 7,

CO PNB

A solution of (4'R, 5R, 6S and 4'S, 5S, 6R) p-nitrobenzyl-6- (2 ¹ , 2'-dimethyl-1, 3'-dioxolan-4-yl) -2-methylpenem- 3-carboxylate (isomer C) 195 mg, 0.464 mmol) in THF (20 ml) is mixed with Et ₂ O (20 ml), H ₃ O (20 ml) NaHCO ₃ (39 mg, 0.46 mmol) and

030027/0777

Μ / 20 359 SY-1599A

- 353 -

10% PD-C (200 mg, Engelhard). The mixture is hydrogenated for 4 hours at 2.27 bar (35 psi) at room temperature. After removing the catalyst (over Celite), the aqueous layer is washed with EtOA (x2), saturated NaCl, acidified with 1N HCl (0.47 ml) and extracted immediately with EtOAc (20 ml χ 3). The extracts are washed with brine, dried (Na_S0 ₄ ) and evaporated, giving 94 mg of a yellowish solid which, rinsed with pentane, gives 89 mg (0.31 mmol, yield 67%) of the title compound as a yellowish solid. Mp 132-133 ⁰ C;

Rf 0.60 (acetone: HOAc = 5: 0.7);

¹ Hmr (CDCl ₃ ) δ: 1.37, 1.43 (6H, 2s, di-Me), 2.36 (3H, s, 2-CH ₃ ), 3.9-4.6 (4H, m , H-6, H-4 ¹ and H-5 ¹ ) and 5.59 ppm (1H, d, J = 1.7 Hz, H-5);

IR (Nujol) ν: 1860 (ß-lactam) and 1660 cm " ¹ (CO-H); UV (EtOH) λ s 309 (£ 6300) and 263 ταμ. Kt 3800).

IuglX

example

(4'S, 5R, 6S and 4 «r, 5S, 6R) 6- (2 ', 2'-Dimethyl-1', 3'-dioxolan-4'-yl / -2-methylpenem-3-carboxylic acid (Isomer Bj

ι A- tv «.

XLTXO. fit,

t Λ ■ O

j.— ι _t j

4-tritylthio-2-azetidinone (isomer B)

STr

NaN.

HMPT-H 0

STr

030027/0 7 77

• ψ · · • · • · r - a »■ • *

M / 20 359 - 354 -

SY-1599A 2950898

The title compound ^ ejected as described in Example 51 for the "isomer C" (4 "S, 3S, 4R and 4'R, 3R, 4S) 1 - (tert-butyldimtthylsilyl) -3- (2 ·, 2 ■ -dimethyl-1 ', 3 · -dioxolan-3' -yl) -4-tritylthio-2-azetidinone (isomer B) (14.4 g, 25.8 mmol) prepared: Yield: 10.8 g 24.3 mmol, 94.1%, mp 155 ° C (CH ₂ Cl ₂ -Et ₂ O);

Rf 0.24 (hexane; EtüAc - 2: 1);

Hmr (CDCl ₇ ) ö: 1.37, 1.40 (6H, 2s, di-Me), 3.23 (1H, dd,

J ₃ _ ₄ = 2.5Hz, J _3-4 , = 5Hz, H-3), 3.7-4 _r 5 (4H, m, H-4 ¹ , H-5 ¹ , NH), 4.50 (1H, d, J = 2.5Hz, H-4) and 7.1-7.6 ppm (15H, m, aromatic Hs);

IR (Nujol) 3170 (NH) and 1745 cm " ¹ (C = O). Analysis C ₂₇ H ₂₇ NO ₃ S:

calculated:
found 2

(4'S, 3S, 4R and 4'R, 3R, 4S) 3- (2 ' , 2 ' -Dimethyl-1 ', 3'-dioxolan-4'-yl) -1- (p-nitrobenzyl-2 "- hydroxy-2 "acetate) -4-tritylthio-2-azetidinone (mixture of C-2" epimers) (isomer B)

C. 78 H 11 N 14th 5 , 20 72, 16 6, 11 3, 14th 7th , 17th 72, 6, 3, 7th

O PNB

The title compound is prepared as described in Example 51 for isomer C from (4'S, 3S, 4R and 4 ^; K, 3R, 4S; 3- (2 ^!, 2 ^! -Dimethyl-1, 3 ^l -dioxolane-4'- yl) -4-tritylthio-2-azetidinone (isomer B) (10.8 g, 24.3 mmol) prepared: Yield: 15.8 g, 24.1 mmol, 93.3 %, yellowish foam;

030027/0 7 77

M / 20 359 SY-1599A

Rf 0.29 and 0.22 (Benzene.-Et ₃ O = I: 1);

¹ Hmr (CDCl ₃ ) 6: 1.28, 1.34 (2s, di-Me), 3.4-4.4 (m, H-3, H-4,

H-5 ', H-2 ", OH), 4.39, 4.53 (2d, J = 2Hz, H-4),

5.15, 5.25 (2s, OCH ₂ Ar) and 7.1-8.3 ppm (m, aromatic Hs);

IR (clear) ν: 3440 (br, OH), 1760 (C = O), 1520, 1350 cm

ΙΠ α. Λ

(4'5,33,4R and 4'R, 3R, 4S) 3- (2 ⁽ , 2'-dimethyl-1 '-3'-dioxolan-4'yl) 1- (p-nitrobenzyl-2 "- chloro-2 "acetate)" 4-tritylthio-2-azetidinone (mixture of C-2 "epimers) (isomers B)

SOCl ₂ -PyT

THF

CO PNE

CO PNB

The title compound is obtained as described in Example 51 for isomer C from (4'S, 3S, 4R and 4'R, 3R, 4S) 3- (2 ¹ , 2'-dimethyl-1 · _r 3'-diQxolan-4'- yl) -1- (p-nitrobenzyl-2 "-hydroxy-2" -acetati -A- tritylthio-2-azetidinone (isomer B) (14.9 g, 22.8 mmol; from Mix C-2 "epimers ); Yield: 14.1 ς, 20.9 mmol, 91.9%; yellowish foam;

Rf (benzene: Et ₂ 0 = 3: 2);

¹ Hmr (CDCl ₃ ) 6: 1.30, 1.38 (6H, 2s, di-Me), 3.4-4.5 (4H, m,

H-3, H-4 ·, H-5 ¹ ), 4.57 (1H, d, J = 3Hz, H-4), 5.13 (s, H-2 "), 5.27 (s , OCH ₃ Ar) and 7.1-8.3 ppm (19H, ία. Aromatic Hs);

IR (clear ) ν : 1780 cm "(ß-lactam, ester).

030027/0777

M / 20 359 SY-1599A

- 356 -

• · * ■ I I I I Ii ·· · · · ■ ■

. 9. · —I— · 1— ι

•, · · I) I

I I

4'S, 3S, 4R and 4'R, 3R, 4S) 3- (2. ·, 2'-dimethyl-1 ', 3 ¹ -dioxolan-4 ' - yl) -1- (p-nitrobenzy1-2 "- triphenylphosphoranylidene-2 "acetate) -4-tritylthio-2-azetidinone (isomer B)

STr

ρφ ₃ -

Di ox.

CO PNB

Tr

CO PNB

The title compound is described as in Example 51 for the "isomer C" from (4'S, 3S, 4R and 3'R, 3R, 4S) 3- (2 ', 2'-dimethyl-1 ·, 3'-dioxolane-4 '-yl) -1- (p-nitrobenzyl-2 "-chloro-2" -acetate) -A- trltylthio-2-azetidinone (isomer B) (14.0 g, 20.8 mmol); Mixture of C-2 "epimers). The yield is 4.64 g, 5.16 in mol, 24-8%; mp. 190-195 ⁰ C (dec., CH ₂ Cl ₂ -Et ₂ O);

¹ Hmr (CDCl ₃ ) 6: 1.12, 1.2O ₇ 1.27, 1.35 (4s, di-Me) and 7.0-8.1

ppm (m, aromatic Hs);

IR (CH ₀ Cl ₀ ) ν: 1750 cm " ¹ (β-lactam ester);

Z, Z, ΙΏ3.Χ

Analysis C ₅₄ H ₄₇ N ₂ O ₇ PS:

calculated: found:

C. 14th H 27 N 12th S. 57 72, 90 5, 57 3, 07 3, 56 71 5, 3, 3,

Rf 0.21 (benzene: EtoQ = 1: 1)

030027/0777

■ · I I Il

• · ι ■■■

Μ / 20 359 - 357 - "· ··.: ... '.,

^SY " ^599A 2950898

(4 "3,33,4R and 4'R, 3S, 4R) silver-3- (2 ¹ , 2» -dimofchyl-i ', 3 · - dioxolan-4 · -yl) -1 (p-nitrobenzyl- 2 "-triphenylphosphoranylidene-2" -acetate) -2- ^j azetidinone-4-thlolate (isomer B)

STr

ν pyr.

HeOH

tf

'^ ^Ρφ 3

CO-PNB

The title compound is described as in Example 51 for "isomer C" from {4'8,33,4R and 4 ^e R, 3S, 4R) 3- (2 ¹ , 2'-dimethyl-1 ', 3 ^s -dioxolane -4'-yl) -1- (p-nitrobenzyl-2 "-triphenyl-phosphoranylidene-2" acetate) -4-tritylthio-2-azetidinone (isomer B) (1.00g, 1.12mmol) . Yield 580 mg, 0.760 mmol, 67.8%. Mp 129-135 ⁰ C (dec.).

IR (Nujol) ν: 1745 cm "(β-lactam, ester).

ΙΠ 33C

(4 ^f S, 3S, 4R and 4'R, 3R, 4S) 3- (2 *, 2'-dimethyl-1 ·, 3'-dioxolan-4 ^f yl) -1- (p-nitrobenzyl-2 " -triphenylphosphoranylidene-2 "-acetate) 4-acetylthio ~ 2-azetidinone (isomer B)

ti.

SAg ^ S- - * ^SAc

" _Λ j" · ^y CH COCl / Pyr.

J-I.

: O ₂ PN3 -. CO ₂ PNB

The title compound is obtained as described in Example 51 for isomer C from (4'S, 3S, 4R and 4'R, 3R, 4S) silver- (2 ', 2'-dimethyl-1 ·, 3 '-dioxolan-4' yl) -1 - (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone-4-thiolate (isomer B) (2.46 g, 3.22 mmol) prepared: yield after purification

030027/0777

M / 20 359 SY-1599A

♦ β

»E

by means of chromatography (SiO- / 32 g, eluent 10% -50% EtOAc in CH _{2 Cl 2} = IjI);

Hmr (CDCl ₃ ) 6: 1.23, 1.27, 1.30 (3s, di-Me), 2.22, 2.33 (2s, SAc) and 7.3-8.3 ppm (m, aromatic Hs);

-1

IR (clear) ν: 1755 (ß-lactam, ester) and 1695 cm '

ITl α. Χ

(Thioester).

(4'S, 5R, 6S and 4'R, 5S, 6R) p-Nitrobenzyl-6- (2 ¹ , 2'-dimethyl-1 ·, 3 · ■ dioxolan-4 * -yl) -2-methylpenem-3- carboxylate (isomer B)

SAc

The title compound is obtained from (4'S, 3S, 4R and 4'R, 3R, 4S) 3- (2 ', 2'-dimethyl-1'-3'-dioxolane-4 · -Yl) -1- (p-nitrobenzyl) -2 "-triphenylphsphoranylidene 2" -acetate) -4-acetylthio-2-azetidinone (isomer B) (200 m.; 0.286 mmol) prepared: Yield 65 mg, 0 , 15 mmol, 53%; Mp 151-152 ⁰ C. (CH ₂ Cl ₂ / Et ₂ 0); Rf 0.67 (benzene: Et ₂ O = 1: 1) 7

¹ Hmr (CDCl ₃ ) 5: 1.29, 1.38 (6H, 2s, di-Me), 2.30 (3H, s, 2-CH ₃ ), 3.6-4.4 (4H, m , H-6, H-4 ⁸ , H-5 '), 5.00-5.18-5.28-5.46 (4H, ABq, -OCH ₂ Ar), 5.47 (1H, d, J = 1.5Hz, H-5) and 7.42-7.55-8.05-8.15 ppm (4H, A ₂ ¹ B ₂ ¹ , aromatic Hs);

IR (clear) ν: 1785 cm "(ß-lactam) and 1710 cm ~ (ester), Max

UV (EtOH) A: 266 (£ 13,300) and 314 mn (£ 9,700);

ntcL

030027/0777

- 359 -

M / 20 359 SY-1599A

Analysis C ₁ ,

calculated: found:

(4'S, 5R, 6S and 4'R, 5S, 6R) 6- (2 ¹ , 2'-Dimethyl-1 ·, 3'-dioxolan-4'-yl) 2-ntethylpenem-3-carboxylic acid (isomer B)

C. 28 H 79 N , 66 S. 63 54, OO 4, 75 6th , 68 7, 61 54, 4, 6th 7,

H_ / Pd-C

K ..

CO PNB

The title compound is described as in Example 51 for "isomer C" from (4'S, 5R, 6S and 4 ¹ _{RzSS 7} OR) p-nitrobenzyl-6- (2 ¹ , 2'-dimethyl-1 *, 3'-dioxolane -4 ¹ -yl) -2-methylpenem-3-carboxylate (Isomer B) (79 mg, 0.19 mmol). Yield after recrystallization from CH ₂ C1 ₂ -pentane 9 mg, 0.032 mmol, 17%.

Rf 0.54 (acetone: HOAc = 5: 0.5);

¹ Hmr (CDCl ₃ ) 6: 1.35, 1.44 (6H, 2s, di-Me), 2.37 (3H, s, 2-CH ₃ ),

3.6-4 _; 5 (4H ^ nu H-6, H-4 ¹ , H-5 ¹ ) and 5 ^ 56 ppm (1H, brs, H-5);

" ¹

IR (clear) V _11n : 1785 cm " ¹ (β-lactam);

ITIcLjC

DV (EtOH) % : 307 (£ 4300) and 262 ΐημ (£, 3700).

030027/0777

M / 20 359 SY-1599A

Example 53

(1'R, 5R, 6S and TS, 5S, 6R) 6- (T-hydroxy-2'-methoxymethoxy-2 '■
ethyl) -2-ethyl) -2-methylpenem-3-carboxylic acid (isomer C)

1'S, 3R, 4S) 3- (1x, 2'-dihydroxyethyl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -4-acetylthio-2-azetidinone (Isomer C)

: ac

Φ.

CO PKB

TFA-HO

OH

CO PNB

A solution of (4'R, 3S, 4R and 4'S, 3R, 4S) 3- (2 * ^ '- Dimethyl-I', 3 dioxolan-4'-yl) -1- (p-nitrobenzy1-2 "- triphenylphosphoranylidene-2 "acetate) -4-acetylthio-2-azetidinone (isomer C) (472 mg,
0.676 mmol) in trifluoroacetic acid (1.0 ml) and H _o 0 (0.1 ml)
allowed to stand for 30 minutes at room temperature. The mixture is then added dropwise to a cold solution of NaHCO- (2.5 g) in H ₂ O (50 ml) and extracted with CH ₂ Cl ₂ (20 ml x 3). Man
washes the extracts with saturated KaKCG ₃ , then ir.with saline solution and dried (Na ₂ SO.) and evaporated, whereby 458 mg,
(0.695ϋηΜο1), raw yield 100%, purity 97.3%) of the raw
Title product is obtained as a yellowish foam.

030027/0777

9 Μ— β

»Mm a · ·

So

Μ / 20 359 SY-1599A

- 361 -

29SQ898

Hmr (CDCl ₃ ) δ: 2.20, 2.32 (2s, SAc) and 7.2-8.3 ppm (m, aromatic Hs);

IR (clear) ν: 3420 (OH), 1745 (ß-lactam, ester) and

ΏΙαΧ.,

1690 cm "(thioester). Rf 0.16 (EtOAc).

(1'R, 3ü, 4R and 1'S, 3R, 4S). ' (1'-Hydroxy-2'-methoxymethoxy-1 "-ethyl) -1- (p-nitrobenzyl-2" -triphenylphosphoranylidene-2 "-acetate) -4-acetylthio-2-azetidinone (Isomer C)

CH

HO

OH

SAc

J-K

BrCHoOCH-j-dimethylaniline CHCl.

2 2

CO PNB

To a solution of (1'R, 3S, 4R and 1'S, 3R, 4S) 3- (1 ·, 2 * -dihydroxyethyl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" acetate) - 4-acetylthio-2-azetidinone (Isomer C) (291 mg, 0.430 mmol); Purity 97.3%) and Brommethylmethyläther (55.2 mg, 0.442 mmol; 4 droplets) in CH ₂ Cl ₂ (8 ml) are added at 0 ⁰ CN, N '' dimethylaniline (58.8 mg, 0.483 mmol; 5 Drops) and stir the mixture for 20 hours at room temperature. Then more bromomethyl methyl ether (2 drops) and N, N'-dimethylaniline (2 drops) are added and the mixture is _{stirred for a further 4 hours. The mixture is diluted with CH 0} Cl., Washed successively with 1N HCl, saturated NaHCO 3 and sodium chloride solution, dried (Na _o SO _A ) and evaporated. The crude residue is purified by HPLC (SiO, eluent EtOAc) to give (31 mg, 0.86 mmol, yield 42.2%) of the title product as an oil: Rf 0, 24 (EtQAc);

030027/0777

M / 20 359 - 362 -

SY-1599A 2980898

¹ Emr (CDCl ₃ ) δ: 2.20, 2.32 (2s, SAc), 3.30 (s, OCH ₃ J ₁ , 4.52

{s, -OCH ₂ O-) and 7.4-8.3 ppm (m, aromatic Hs):

IR (clear) ν: 3420 (OH), 1755 (br, ß-lactam and ester)

Max _"

and 1690 cm '(thioester).

£ 1'R, 5R, 6S and; 'S, 5S, 6R) p-nitrobenzyl-6- (1 · -hydroxy-2' -methoxy-t methoxy-2'-ethyl) -2-methylpenem-3-carboxylate

toluene

CO PNB

A solution of (1'R, 3S, 4R and 1'S, 3R, 4S) 3- {1'-hydroxy-2'-methoxymethoxy-1'-ethyl) -1- (p-nitrobenzyl-2 "~ triphenylphosphoranylidene-2 "-acetat) -4-acetylthio-2-azetidinone (isomer C) (" 67 mg, 0.238 mmol) in toluene (30 ml) is _{refluxed under N 3 for} 8 hours. Evaporation of the solvent in vacuo gives an oily residue, which is purified by HPLC (SiG _3, Eluierungsjüittel EtOAc) to give 68 mg (0.16 aimo-l, yield 67%) of T itelverbindung oil obtained as a:

Rf 0.61 (EtOAc), 0.15 (benzene: Et ₃ O = I: 1); ¹ HJIr (CDCl ₃ ) δ: 2.38 (3H, s, 2-CH ₃ ), 3.35 (IH, br, OH), 3.40

(3H, s, OCH _3), 3.6-3.8 (2H, m, 2 ^K-1), 3.90

(IH, dfl, ^J g_c ⁼ 2HZ, ^J g_-ji ~ 4HZ, H-6), 4 _r Tö

(1H, m, H-1 ^1), 4.67 (2H _r s, -OCH ₃ O-), 5,03-5,27-5, -38-5, -62 (2H, - ABq, - OCH ₂ Ar), -5, -65 (IH- d, J = 2Hz, H-5) and 7.55-7.70-8.15-8.30 ppm (4H, A ₃ · B ₂ ', aromatic Hs ;

030027/0 777

M / 20 359 SY-1599A

- 363 -

IR (clear) ν ·. 3450 (OH), 1785 (β-lactam), 1710 (ester) max λ

and 1520 cm

UV (EtOH) A: 266 (£ 13,000) and 313 ΐημ (£ 9,100);

ΙΏ3Χ

Analysis C ₁ ,

calculated: found:

C. 94 H 75 N 69 50, 13th 4, 77 6, 36 51, 4 / 6,

(1'R ₇ SR ₇ OS and 1'S, 5S, 6R) 6- (1'-Hydroxy-2'-methoxymethoxy-2 * ethyl) -2-ynethylpenem-3-carboxylic acid (isomer C)

pns

CO "H

A solution of (1'R, 5R _r 6S and 1'S, 5S, 6R) p-Nitrcbenzyl-6- (1'-hydroxy-2 ^r -methoxymethoxy-2'-ethyl) -2-methylpenem-3-carboxylate (Isomeres C) (51 mg, 0.12 mmol) in THF (10 ml

mix with Et O (10 ml) _r

(10 ml), NaHCO- (10 mg, 0 _r 12

mmol) and 10% Pd-C (50 mg, Engelhard). It is hydrogenated for 3 hours at room temperature at a pressure of 2.20 bar (32 psi). After filtering the catalyst through gelite, the separated aqueous layer is washed with Et_O (3 ×) and saturated NaCl. The aqueous phase is acidified at 0 ⁰ C with 0.1 N HCl (1.2 mL) and then extracted immediately with EtOAc (15ml χ 3). The extracts are washed with brine, dried (Na ₂ SO ₄ ) and evaporated to give 22 mg of a yellowish solid which, _{rinsed with a small amount of Et 2} O, 20 mg (0.069 mmol, yield 58%) of the title compound as a light yellow Solid gives:

030027/0 777

M / 20 359 SY-1599A

• ·> f

• * 9 t I

- 364 -

2850898

¹ Hmr (DMSO-dg) 5: 2.28 (3H, s, 2-CH _3), 3.27 (3H, s, OCH), 3.49

(2H, d, J = 6.2Hz, 2'-H), 3.87 (1H, dd, J ₆ _ ₅ = 1.7 Hz, Jg _-1 , = 3.3 Hz, 6-H), 4.58 (2H, s,

-OCH ₂ O-) and 5.55 ppm (1H, d, J = 1.7Hz, 6-H); IR (KBr) ν: 3410 (OH), 1755 (β-lactam) and 1655 cm " ¹ (CO ₀ H);

UV (EtOH) Λ _m - ' 308 (£ 6800) and 262 πιμ (£ 4200),

Mp. 137-138 ⁰ C (Zers-).

Example 54

(1'S, 5R, 6S and 1'R, 5S, 6R) 6- (1'-Hydroxy-2 · -methoxymethoxy-2 · - ethyl) -2-methylpenem-3-carboxylic acid (isomer B)

(1 'S, 3S, 4R and 1'R _r 3R, 4S) 3- (1', 2'-dihydroxyethyl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -4-acetylthio -2-azetidinone (isomer B)

THF-H -O

O PNB

OH

CO PNB

030027/0777

M / 20 359 - 365 -

SY-1599A 2950898

The title compound is obtained as described in Example 53 for isomer C from (4'S, 3S, 4R and 4'R, 3R, 4S) 3- (2 ¹ , 2 ' -Dimethyl-1', 3 · -dioxolane-4'- yl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -4-acetylthio-2-azetidinone (isomer B) (1.03 g, 1.47 mmol) prepared: Yield 970 mg, 1 , 47 mmol, 100%, yellowish foam.

¹ Hmr (CDCl ₃ ) δ: 2.20, 2.32 (2s, -SAc) and 7.3-8.2 ppm (m, aromatic Hs);

IR (clear) ν: 3410 (0-lactam, ester) and 1690 cm (Thiomax

ester); Rf 0.16 (EtOAc).

(1'-S, 3S, 4R and 1'R, 3R, 4S) 3- (V-Hydroxy-2'-methoxymethoxy-1'-ethyl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" ~ acetate) -4-acetylthio-2-azetidinone (Isomer B)

PH

^{HQ 7} SAc

BrCH_OCH, / pear thylaniline

The title compound is described as in Example 53 for the "isomer C" from (1 ^f S, 3S, 4R and 1'R, 3R _r 4S 3- (1 ', 2'-dihydroxyethyl) -1 - (p-nitrobenzyl- 2 "-triphenylphosphoranylidene-2" acetate). -4-acetalthio-2-azetidinone (Isomer B) (485 mg, 0.736 mmol prepared. Yield: 205 mg, 0.292 mmol, 39.6%; oil.

¹ Hmr (CDCl ₃ ) 5: 2.22, 2.33 (2s, SAc), 3.32 (s, OCH ₃ ), 4.57

(s, -CH ₂ O-) and 7.2-8.3 ppm (m, aromatic Hs);

030027/0777

._. C - Aft— —t

M / 20 359 SY-1599A

- 366 -

ι _t

IR (clear) ν: 3420 (OH), - 1755 (ß-lactam, ester) and max _λ

1690 thioesters) cm.

Rf 0.32 (EtOAc).

(1'S, 5R, 6S and 1'R, 5S, 6R) p-nitrobenzyl-6- (1 '-hydroxy-1' · methoxymethoxy-2'-ethyl) ^ -methylpenem-S-carboxylate

T-oluene -HQ

CO PNB

The title compound is described as in Example 53 for "isomer C" from (1 ^f S, 3S, 4R and 1'R, 3R, 45) 3- {1'-hydroxy-2'-methoxymethoxy-1'-ethyl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -4-acetylthio-2-azetidinone (Sisomeres B) (205 mg, 0.292 mmol) and hydroquinone (10 mg, 0.09 mmol). Yield: 38 mg, 0.090 mmol, 31%; Rf 0.23 (benzene: Et ₂ O = I: 1);

¹ Hmr (CDCl ₃ ) 5: 2.37 (3H, s, 2-CH ₃ ), 3.40 (3H, s, OCH ₃ ),

3.4-3.9 (3H, m, H-6, H-2 "), 4.15 (1H, m, HT), 4.67 (2H, s, -OCH ₂ O-), 5, 10-5.27-5.39-5.56 (2H, ABq, - -OCH ₂ Ar), 5.67 (1H ₇ d, J = 1.5 Hz, H-5) and 5.55-5 , 16-8.15-8.27 ppm (4H, A ₃ ¹ B ₃ ¹ , aromatic H_);

• IR (CH ₀ Cl ₀ , trituration) v _m : 3370 (OH), 1785 (ß-lactam) and

1700 cm (ester).

UV (THF-EtOH = I: 1) λ : 265 (£ 10400) and 314 ΐημ (£ 7800).

030027/0777

M / 20 359 SY-1599A

28 ^ 0898

(1'8,5R _x OS and 1'R, 5S, 6R) 6- (1 ¹ -hydroxy-2 ^I -methoxymethoxy-2 ^I -ethyI} -2-methylpenem-3-carboxylic acid (isomer B)

H / Pd-C

The title compound is described in Example 53 for the “isomer C) from {1 * S, 5R, 6S and 1'R, 5S, 6R) p-nitrobenzyl-6- (1 ^T -hydroxy-2'-methoxymethoxy-2 · Ethyl) -2-methylpenem-3-carboxylate (isomer B) (36 mg, 0.085 mmol) Yield: 7.5 mg, 0.026 mmol, 30%; yellowish crystals;

(CDCl ₃ ) & t 2.36 (3K, S ₇ 2-CH ₃ ), 3.39 (3K, s, OCH ₃ ),

3.6-3.9 (3H, m, H-6, H-2 '), 4.15 (1H, m, H-1'), 4.66 (2H, s, OCH ₂ O) and 5 , 67 ppm (1H, d, J = 1.4Hz H-5);

IR (CH ₉ Cl-) ν: 1785 (β-lactam) and 1675 cm " ¹ (CO"H);

UV (EtOH) Λ _max ^{: 308} (C 2900) and 263 mμ (6 2900).

030027/0777

M / 20 359 SY-1599A

2910898

Example 55

2-Benzimidoylaminomethylpenem-3-carboxylic acid

NH
Il
I- C- CH,

JT \

CD

in)

To a suspension of 0.38 g (0.0015 mol) of sodium 3-benzyl-1,2,4-oxadiazol-5-one-4-acetate (I) 0.13 ml is added to 10 ml of methyl chloride containing 2 drops of DMF at room temperature (0.0015 mol) oxalyl chloride, causing the mixture to foam. The reaction mixture is then stirred for 1 hour and the NaCi that has formed by filtering and washing the filter cake with several small portions of methylene chloride. The solution of the acid chloride (II) is used immediately.

1. K = Takacs and K. Harsanyi. Ber. 103, 2330 (1970).

(II)

^CH 2 ^C1 2 iyridine

CO PNB

(IV)

030027/0777

Μ / 20 359 SY-1599A

- 369 -

2350898

A solution of 1.0 g (0/0015 mol) of compound (III) and 0.12 ml (0.-015 mol) of pyridine in 10 ml of methylene chloride under a nitrogen atmosphere is cooled to 4 ^° C. and the acid chloride solution (II) is added all at once for solution (III), the reaction mixture is stirred for 5 minutes at 4 ^° C. and then for 1.5 hours at room temperature. A thick precipitate forms in the reaction mixture. The mixture is filtered and the filtrate is diluted with methylene chloride to a volume of 70-90 ml. The organic phase is then washed successively with 70 ml of 0.1N hydrochloric acid and 80 ml of 1% sodium *. jicarbonate and 80 ml of water. The methylene chloride phase is dried over magnesium sulphate, the solvent is removed under reduced pressure and the residual oil is ohromacographed over Mallineckrodt SilicAR CC-7 s silica gel using chloroform as the eluent, 0.4 g (30.5%) of the compound ( IV) obtained as an oil. The IR and NMR spectra are in agreement with those of Compound (IV).

(IV)

Toluene reflux "

A solution of 0.4 g (0.00045 mol) of compound IV in 50 nil Toluene is refluxed for 4 hours, the solvent is removed under reduced pressure and the chromatographed Residue over Mallinckrodt SilicAR CC-7 Silicagei under Use of 5% ethyl acetate in methylene chloride as eluant, using 0.15 g (66.6%) of compound V as a receives oil, which solidifies. The IR and NMR spectra are consistent with aenes for compound V.

030027/0777

M / 20 359 - 370 -

Analysis C_

calculated: found:

C. 86 H 67 N 33 % 55, 17th 3, 76 11 23 % 56, 3, 11

κ "2

Pd / C

A solution of 0.135 g (0.00027 mol) of compound V in 40 ml of tetrahydrofuran and 40 ml of anhydrous diethyl ether is added to a slurry of 10% Pd on carbon catalyst in 40 ml of water under a nitrogen atmosphere. The resulting mixture is hydrogenated in a Parr hydrogenator at room temperature with an initial hydrogen pressure of 3.58 bar (52 psi) for 3.5 hours. Hydrogen uptake ^ 0.31 bar (4.5 psi). The catalyst is removed by filtration and the filter bed is washed thoroughly with water.
Additional diethyl ether is added to the filtrate and the phases are separated. The aqueous phase is extracted 3 with diethyl ether.unc it is then concentrated to dryness under reduced pressure. The residue is chromatographed using a high pressure liquid chromatography method (HPLC) wherein one 0.050 g (58%) of the title penem acid, mp 156-173 ⁰ C (dec.). The IR and NMR spectra are in agreement with those of the ap> wiiri & ciht.em product.

Analysis C ₁₅ H ₁₅ N ₃ O ₃ SI ^ H ₂ O:

calculated: found:

C. , 31 K 27 12, 20th 52 , 64 5, 95 12, 31 51 4,

030027/077 7

• J « ( ..

K / 20 3Ö9 SY-1599A

- 371 -

2050898

Example 56

2-phenylimidoylarainomethylpenene-3-carboxylic acid

COOH

However, following the procedure of Example 55 using an equimolar amount of sodium 3-phenyl-1,2 * 4-oxadiazol-5-one-4-acetate as a starting material instead of the previously used sodium 3-benzyl-1 ^^ - oxadiazol-S-one ^ one obtains the title compound.

Biological values

Representative compounds of the present invention were subjected to in vitro antibiotic screening tests against a variety of microorganisms. Samples of the specified compounds showed the following minimal Henun concentrations (MIC) χη.γ / ml after dissolving with water and diluting with nutrient broth. against the listed microorganisms, determined by overnight incubation at 37 C using the serial dilution method.

030027/0777

M / 20 SY-1599A

organism

Streptococcus pneumoniae A9585 Streptococcus pyogenes A9604 Staphylococcus aureus A9537 Stäph aureus + 50% Serum A9537 Staphylococcus aureus A9606 Staphylococcus aureus • A15097 Streptococcus faecalis A20688 Escherichio coli A15119 Escherichia coli A20341-1 Klebsieila pneumoniae A15130 Klebsiella species A20468 Proteus mirabilis A9900 Proteus mirabilis A9716 Proteus morganii A15153 Proteus rettgeri A21203 Serratia marcescens A20019 Enterobacter cloacae A9659 Enterobacter cloacae A9656 Pseudomonas aeruginosa A9843A Pseudomonas aeruginosa A21213 Hemophilus influenzae A9833 Haemophilus influenzae A21522 Bacteroides fragilis A20931 Bacteroides fragilis A20929

MIC in γ / ml '"'"' «ϊ ·· ί ··

Connection (Pglsp ie.1; No.)

1
> 1 25th
25th 1 8th 32 4th 1 25th 8th 2 1 25th 4th 8th 63 63 32 63 16 16 1 25th > 1 25th

030027/0777

M / 20 SY-1599A

organism

Streptococcus pneumoniae

Streptococcus pvogenes

Staphylococcus aureus

Staph aureus + 50 % serum A9537 Staphylococcus aureus

Staphylococcus aureus A15097 Streptococcus faecalis A20688 Escherichia coli A15119 Escherichia coli A20 341-1 Klebsiella pneumoniae A15130 Klebsiella species A20468 Proteus mirabilis

Proteus yulgaris

Proteus morganii

Providencia stuartii

Serratia marcescens

Enterobacter cloacae

Enterobacter cloacae

Pseudomonas aeruginosa

Pseudomonas aeruginosa

Hemophilus influenzae

Haemophilias influenzae

Bacteröiaes fragilis

Bacteroides fragilis

• - · * * ψ ψ
If ■ te * • 111 4th 1 5 - 373 - * * · · • · t * »
• ■ · 4th 0.5 MIC in Y / ml Connection (example no.) 8th 4th 3 763 4th 2 1 4th > 63 1 4th 125 9 2 2 125 63 8th > 63 > 125 125 > 63 4th > 125 63 4th 32 > 125 '125 8th 125 Π 25 63 63 63 63 > 125 32 63 63 53 32 125 125 32 63 7125 125 125 ? 125 63 > 125 32 63 32 > 125 b3 63 125 ^ 125 125 63 63 - 125 32 63 _ > 125 125 125 > 125 > 125 125 > 125 > 125 > 125 > 125 > 125

030 0 2 7/0777

M / 20 SY-I599A

organism

Streptococcus pneumoniae A9585 Streptococcus pyogenes A9604 Staphylococcus aureus A9537 Staph aureus + 50% serum A9537 Staphylococcus aureus A9606 Staphylococcus aureus A15097 Streptococcus faecalis A20J88 Escherichia coil A15119 Escherichia coli A20 341-1 Klebsiella pneurnoniae A15130 Klebsiella species A20468 Proteus mirabilis A9900 Proteus vulgaris A21559 Proteus morganii A15153 Proteus rettgeri A21203

Serratia marcescens A20019 Enterobacter cloacae A9659 Enterobacter cloacae A9656 Pseudomonas aeruginosa A9843A Pseudomonas aeruginosa A21213 Hemophilus influenzae A9833 Haemophilus influenzae A21522 Bacteroides fragilis Ä20931 Bacteroides fragilis A20929

• · · V er Jb i η α un cj 2950898
• ♦ · # * * # * ·· - 374 -:. "· ' 1ί (5) • «·» - · MIC in γ / ml 1
2 (Example no.) 4th 11 (6) 32 2
4th 32 4th 63 63 ■> 63 125 16 63 ^ 63 125 63 16 > 63 125 8th 125 63 > 125 16 16 32 32 32 32 63 32 63 63 16 63 32 63 32 > 125

03 0 027/077

2950838

M / 20 359 SY-1599A

organism

- 375 MIC in γ / ml

Connection (example no.) 12

Streptococcus pneumoniae 0.016 A9585 Streptococcus pyogenes 0.06 A9604 Staphylococcus aureus 0.13 A9537 Staph aureus + 50% 4th Serum A9537 Staphylococcus aureus 8th A9606 Staphylococcus aureus 125 A15097 Streptococcus faecalis 63 A20688 Escherichia coli 0.5 A15119 Escherichia coli 63 A20 341-1 Klebsiella pneumoniae 8th A15130 Klebsiella species > 125 A20468 Proteus mirabilis 1 A9900 Proteus vulgar! S A9716 Proteus morganii 1 A15153 Proteus rettgeri 2 A21203 Serratia marcescens 1 A20019 Enterobacter cloacae 2 A9659 Enterobacter cloacae 1 A9656 Pseudomonas aeruginosa 1 A9843A Pseudomonas aeruginosa 125 A21213 Hemophilus influenzae 125 A9833
·· _ ..til JC "* _ Α21522 Bacteroides fragilis Α20931 Baeieroides fra.gil ± s A20929

030027/0777

M / 20 SY-159SA

MIC in γ / ml

organism

Streptococcus pneumoniae Streptococcus pyogenes A9585 A9604 A9537 Staphylococcus aureus Staph aureus + 50% serum A9537 Staphylococcus aureus A9606 Staphylococcus aureus Streptococcus faecalis A15097 A20688 Escherichia coli Escherichia coli Α15Π9 A20 341-1 Klebsiella pneumoniae A15130 Klebsiella species Λ20468 Proteus mirabilis A9900 Proteus vulgaris Proteus morganii A15153 A9 555 Proteus rettgeri A21203 Serratia marcescens A20019 Enterobacter cloacae A9659 Enterobacter cloacae A9656 Pseudornonas aeruginosa A9843A Pseudomonas aeruginosa A21213 Hemophilus influenzae A9833 Haemophilus influenzae

Bacteroides fragilis A20931 Bacteroides fragilis

• · * fc ■, f * -

Connection (example no.)

32 18

0.25 0 _r 25 0.016

8 2 0.25

8 4 0.03

32 63 63

16 4 16

63 16 VI2i

M25 125 16

63 4 63

> 125 16> 125

125 32 * 125

> 125 125> 125

63 16 32 125 16

125 32 32 63 32

63 32 16

125 32> 125

125 63 125 -

125 125> 125

125 125> ί25

030027/0777

M / 20 359
SY-1599A

organism

2800898

- 377 -

MIC

Connection (example no.) 32

18th

24

Pseudomonas aeruginosa A20 599

Pseudomonas aeruginosa A9925

Pseudomonas aeruginosa A20229

Proteus species A20543

Proteus mirabilis A9716

Providencia stuar-tii A21 205

16 63

030027/0777

M / 20 SY-1599A

- 378 -

• ■ · · β

MIC in γ / ml

organism

Streptococcus pneumoniae A9585 Streptococcus pyogenes A9604 Staphylococcus aureus A9537 Staph aureus + 50 %, serum A9537 Staphylococcus aureus A9606 Staphylococcus ε -eus Al 5097 Streptococcus ^ necila species A20688 Escherichia-eus A20688 Escherichia-eus A20688 A20688 Escherichia-colus A20688 Escherichia-colus A20688 Escherichia-colus A20688 A20688 Escherichia A9716 Proteus morganii A15152 Proteus rettgeri-A21203 Serratia marcescens A20019 Enterobacter cloacae A9659 Enterobacter cloacae A9656 Pseudomonas aeruginosa A9843A Pseudomonas aeruginosa A21213 Hemophilus Bacteraeides A9833 Haemophilus influenzae .21522 fragilis A20931 Bacteroides fragilis compound (Ex. No.) 25

> 63

Vl 25

> 125

125

> 125> 125> 125

125

125> 125> 125> 125

125

125

030 0 2 7/0777

• t f ♦ ♦

M / 20 359 SY-1599A

- 379 -

MIC γ / ml

organism

Pseudomonas aeruginosa A20599

Pseudomonas aeruginosa A9925

Pseudomonas aeruginosa A20229

Proteus species A20 543

Proteus mirabilis A9716

Proteus mirabilis A9555

Connection (example no.)

25th

63

Ö3ÖO27 / O777

M / 20 SY-1S99A

MIC in γ / ml

organism

Streptococcus pneumoniae ΑΓ585 Streptococcus pyogenes A9604 Staphylococcus aureus A9537 Staph aureus + 50% serum A9537 Staphylococcus aureus A9606 Staphylococcus aureus A15097 Streptococcus faecalis A20688 Escherichia coil A15119 Escherichia coli A20 341-1 Klebsiella pneuincniae A15130 Klebsiella species A20468 Proteus mirabilis A9900 Proteus vulgaris A9555 Proteus morganii \ 15153 Proteus rettgeri A21203 Serrafcia marcescens A20019 Enterobacter cloacae A9659 Enterobacter cloacae A9656 Pseudomonas aeruginosa A9843A Pseudomonas aeruginosa A21213 Hemophilus influenzae A9833 Haemophilus influenzae A21522 Bacteroides fragilis A20931 Bacteroides fragilis A20929 Connection (ex.

31

63 125 32 32

> 125 63 63 63 32

> 125 63

1.25

> 125 125 125 125 125 32 125 125

33

0.06 0.13

34

16

125

> 125

125

16

> 125

125

> 125

63 32 16 63

125 63

125

125

0.25 2

4 63

16 125

4 16

32

125

16

16

32

32

32

32

63

125

125

030027/0777

295P898

Μ / 20 SY-1599A - 381 -

MIC in γ / ml

organism

Streptococcus pneumoniae Α9585 Streptococcus pyogenes 96Ö4 Staphylococcus aureus A9537 Staph aureus + 50% serum A9537 Staphylococcus aureus A9606 Staphylococcus aureus A15097 Streptococcus faecalis A20688 Escherichia coli A15119 Escherichia coli A20 341-1 Klebsiella pneumoniae A15130 Klebsiella species A20468 Proteus mlrabilis A9900 Proteus vulgaris A21559 Proteus morganii A15153 Proteus rettgeri A21203 Serratia marcescens A20019 Enterobacter cloacae A9659 Enterobacter cloacae A9656 Pseudomcnas aeruginosa Ä.9843A Pseudomonas aeruginosa A21213 Hemophilus A9833 Haemophilus influenzae A21522 Bacteroides fragilis A20931 Bacteroides fragilis A20929

influenzae compound (Belsp. no.) 35 36 '

125

125

> 125> 63> 125

> 125> 125> 125 ? 125> 125 > 125> 125> 125 > 125> 125> 125> 125> 125 > 125> 125> 125 > 125> 125> 125> 125 > 125> 125> 125 > 125> 125 > 125> 125> 125 > 125

2 8

63 63 16 16 16 16 16 16 16 16 32 16 16 16 32 16 16 16 16

· '32

16> 125> 125

0.004

0.008

0.004

0.008

0.008

0.008

0.06

0.06

0.06

0.06

0.06

0.25

0.5

0.5

0.13

0.25

* 0.25 0.13

<0.25 0.5 0.5 0.5

«0.25 0.25

<0.25 0.25 1 1

0.5

0.5

0.5

0.5

0.5

16

16 125

63

030027/0777

M / 20 SY-1539A

- 382 -

MIC in γ / ml

organism

Streptococcus pneumontae A9585 Streptococcus pyogenes

A96Ö4 Staphylococcus aureus A9537 Staph aureus + 50% serum A9537 Staphylococcus aureus A9606 Staphylococcus aureus A15C97 Streptococcus faecalis

Escherichia coli A15119 Escherichia coli A20 341-1 Klebsiella pneumoniae A15130 Klebsiella species A20468 Proteus mirabilis A9900 Proteus vulgar! S A21559 Proteus morganii A15153 Proteus rettgeri A21203 Serratia marcescens A20019 Enterobacter cloacae A9659 Enterobacter cloacae A9656 Pseudomonas aeruginosa A9843A Pseudomonas aeruginosa A21213 Hemophilus influenzae A9S33 Haemophilus influenzae A21522 Eacteroides fragilis A20931 Bacteroides fragilis A20929

Connection (Belsp. No.)

0.03
0.06

0.5

38

0/03 0.5

0.03

0.25

0.25

0.5 32

16 32

16 32

39

0.016 0.03

0.06

0.13

0.13

0.25

16 16

030027/0 7 77

2850898

M / 20 SY-1599A

organism

Streptococcus pneumoniae Streptococcus pyogenes A9585 A9604 A9537 Staphylococcus aureus Staph aureus + 50% serum A9537 Staphylococcus aureus A9606 Staphylococcus aureus Streptococcus faecalis A15097 A20688 A15119 Escherichia coli Escherichia coli A20 341-1 Klebsiella pneumoniae A15130 A20468 Klebsiella species Proteus mirabilis Proteus morganii A99ÖÖ Proteus vulgaris A21559 A15153 Proteus rettgeri A21203 Serratia marcescens A20019 Enterobacter cloacae A9659 Enterobacter cloacae A9656 Pseudomonas aerugiiiosa A9843A Pseudoittonas aertiginosa A21213 Hemophilus influenzae A9833

- 3B3 -.;. ■ ■ · 45 47 HIC in γ / ml
Connection (example no.) 2
16 0.5
0.5 43 32 8th > 63
> 63 > 32 32 > 63 2 16 > 32 ft
O 32 * 63 63 > 63 > 63 2 32 > 63 32 32 > 63 8th 63 > 63 - > 63 63 > 63 4th 32 > 63 16 32 > 63 8th 63. > 63 8th 32 > 63 8th 63 yes 8th 63 > 63 8th 63 > 63 63 > 63 > 63 "> 63 * 63 > 63

A21522 Bacteroides fragilis A20931 Bacteroidss fragi A2G929 030027/0777

M / 20 SY-1599A

organism

Streptococcus pneumoniae A3535 Streptococcus pydgenes A9604 Staphylococcus aureus A9537 Staph aureus + 50% serum A9537 Staphylococcus aureus A9606 Staphylococcus aureus A15097 Streptococcus faecalis A20688 Escherichia coli A15119 Escherichia coli A20 341-1 Klebsiella pneumoniae A15130 Klebsiella species A20468 Proteus mirabilis AS900 Proteus vulgaris A21559 Proteus itnorganii A15153

Proteus rettgeri A21203 Serratia marcescens A20019 Enterobacter cloacae AS659 Enterobacter cloacae A9656 Pseudomonas aeruginosa A9843A Pseudoroonas aeruainosa A21213 Hemophilus influenzae A9S33 Haemophilus influenzae A21522 Bacteroides fragilis A20931 Bacteroides fragilis A20929

- 38 * - 49 (Example no.) 1 50 MIC in γ / ml
link 16 32 48 32 32 > 125 > 63 125 > 125 32 > 63 > 125 > 125 > 125 > 63 > 125 > 125 > 125 > 125 > 125 > 125 > 125 > 125 > 125 > '(25 > 125 > 125 > 125 > 125 > 125 > 125 > 125 > 125 > 125 > 125 > 125 > 125 > 125 > 125 > 125 > 125 > 125 > 125 > 125 > 125 > 125 7125 > 125 > 125 > 125 > 125 > 125 > 125 ;> 125 7125 > 125 > 125 Vi 25 > 125 > 125

030027/0777

2S5Q898

M / 20 SY-1599A

organism

Streptococcus pneumoniae

Streptococcus pyogenes

Staphylococcus aureus

Staph aureus + 50% serum A9537 Staphylococcus aureus

Staphylococcus aureus A15097 Streptococcus faecalis

A20688,

Escherichia coli A15119 Escherichia coli A20 341-1 Klebsiella pneumoniae A15130 Klebsiella species A20468 Proteus mirabilis

Proteus vulgaris A21559 Proteus morganii

Proteus rettgeri A21203 Serratia marcescens

Enterobacter cloacae

Enterobacter cloacae

Pseudomonas aeruginosa A9843A Pseudomonas aeruginosa

Hemophilus influenzae

Haemophilus influenzae

Bacteroides fragilis

Bacteroides fragilis

. ■ j-
- 385 - 52 • · ·
av
* * • · ·
• · ·
• ···
• · Z ä «
* we »
C *
• - · 16 (Ex. • · ·
No.) MIC in γ / ml
link 32 53 54 51 63 4th 32 ie 63 > 32 4th 32 63 63 78 63 > 63 63 > 32 > 32 > 32 63 63 > 63 > 63 > 63 > 63 > 63 > 63 > 63 > 63 > 63 > 63 > 63 63 63 > 63 > 63 63 63 > 63 > 63 63 > 63 > 63 > 63 > 63 > 63 > 63 > 63 > 63 63 63 63 > 63 > 63 > 63 > 63 > 63 > 63 _? 63 "> 63 32 63 > 63 > 63 763 63 > C3 63 63 -> 63 '> 53 63 63 63 > 63 63 63 o3 63 63 63

0300 27/0777

M / 20 359 - 386 - MIC in γ / rol organism * · · * · « · * M
• - · ■ * · * »> SY-1599A Streptococcus pneumoniae A9585
Streptococcus pyogenes A9604 link (Example no.) Staphylococcus aureus 55 56 A9537 0.5 0.25 Staph aureus + 50% 0.5 0.25 Serum A9537 Staphylococcus aureus 0.5 0.25 A96Ö6 Staphylococcus ^ areus 16 16 Al 5097 Streptococcus faecalis 32 16 Ä20688 Escherichia coli > 63 > 125 A15119 Escherichia coli > 63 125 A20 341-1 Klebsiella pneumoniae 63 s? - A15130 Klebsiella species > 63 > 125 A20468 Proteus mirabilis "> 63 125 A9900 Proteus vulgaris > 63 > 125 A21559
Proteus morganii AI5153 63 63 Proteas rsttgeri A2i203
Serratia marcescens 63 125 A20019 63 63 Enterobacter cloacae A9659 63 63 Enterobacter cloacae 63 125 A9656 > 63 125 63 1 25 63 63

A9843A Pseudomonas aeruginosa A21213 Heirophilus influenzae A9833

Haemophilus influenzae a2i522 Bacteroides fragllis

Ä20931 Bacteroides fragilis A20929

63

125

0300 27/0 7 77

M / 20359 SY-1599A

- 387 -

Representative compounds of the invention were also examined in vivo in mice and their PD ₅ values (dose of compound in mg / kg required to protect 50% of the treated mice against an otherwise fatal infection of a microorganism) were listed below Microorganisms detected.

link

S. aüreüs A9537

Number of infi-

AnzaJ-1

Appointment

H) ₁

ornamental organisms treatments rslrhnngs-S. aureus A 9537 art

50

gg

Treatment)

Connection according to
Example 36

Connection according to
Example 38

Connection according to
Example 56

Connection according to
Example 39

Connection according to
Example 40

6.6 χ 10 "

8.6 χ 10 "

8x10 '

8 χ 10 "

7.8 χ 10-

!,in,

in the.

in the.

in the.

in the.

7.7

1.0

0.04

0.12

M / 20 359 SY-1599A

- 388 -

Blood levels of mice were determined after intramuscular administration representative compounds according to the invention determined and are listed in the table below.

link

Connection according to the example

Mice blood levels in γ / ml after intramuscular administration of 40 mg / kg body weight

Minutes after administration

20th

45 60

90

44.7 34> 4 23.7 17.6 9.8 3.6

Mean of 6 mice

21 / Hch

Claims (10)

Claims X can stand for the following groups:
(a) a residue of the formula: (i) -OR ,, where R _{a is} hydrogen; (ii) - € 0R _b , where R _fa = hydrogen, hydroxy, optionally substituted (lower) alkyl or ge =
if desired, ring-substituted phenyl or
, .... "- ^. a ^ Ti can mean heterocyclic radical, the substituents on the alkyl group being one or more of the following radicals: halogen, hydroxy, oxo, carboxy,
CarbiniedrigjTil-koxy, carbamoyl, (lower) alkoxy _s amino, (lower) Alkylatnino, EDSR di (lower) alkylaminc (lower) alkanoylamino or gewünsehtenfalls substitui tes a phenyl substituted gemmschtenfälls heieroaycl see Re ^ tunfrwobä it the substituents
on the phenyl group or the heterocyclic ones
Wrestling for one or more of the following groups 030027/0777 pen is: hydroxy, (lower) alkoxy _s halogen, (lower) alkyl, halogen (lower) alkyl, methanesulfonyl, oxo, (lower) alkylthio, amino, (lower) alkylamino, di {lower) alkylamino, (lower) alkanoylamino , (lower jalkanoyloxy, carboxy, carboxy (lower) alkyl, sulfo or sulfo (lower) alkylj or (iiiJ-OCOR ^, where .._ for amino, (lower) alkylamino, C C- Di (lower) alkylamino or, if desired, subst tuted (lower) alkyl, in which the substituents are as defined under point (ii); or (b) Substituted (low) aliphatic, (low) cycloaliphatic or low) cyclic aliphatic radicals or a ring-substituted one Phenyl radical, phenyl (lower) alkyl radical, a heterocyclic radical, a heterocyclic (lower) alkyl rest or a heterocyclylthio (low) alücylrest, where the substituents of said aliphatic groups, cycloaliphatic groups, Phenyl groups or heterocyclyl groups are the following: NR ₁ (i) -CNRgR ₃ or -N = C-NR-R ₃ where R. is hydrogen, (lower) alkyl or phenyl and R ₂ and R ₃ ί λ a.j λ «ΐ 1 * · linskk'anAJn κληλ ·? n & n / la ^ ίΐΐϊ * Use COVCt / tf f J ^ .n »i ι ϊ J Miiui /» «rijj iy TWIIW fhviiivvi ■« · »- - - - - - - -., (lower) alkyl, phenyl or benzyl "; (ii) -OR _d , where R _{d is} amino, (lower) AUylamino, di (lower) alkylamino, substituted (lower) alkyl, (lower) alkenyl, or if desired 30027/0777 M / 20 359 - * ³ "- SY-1599A £ §50838 ring-substituted phenyl »phenyl (lower) alkyl. a heterocyclic group or a heterocyclic group see (low) ATkyl group, where the Substituents on the alkyl groups, phenyl groups and heLcf-ocyclic groups are those as defined under (a) (ii); (i-.v) -0 (CH ₂ ) _n OR _r , where η is an integer from 1 to 6; and R "represents, if desired, substituted (lower) alkyl or, if desired, ring-substituted phenyl or an, if desired, ring-substituted heterocyclic group, the substituents on the alkyl groups, phenyl groups or heterocyclic groups being those as described under (a ) (ii) are defined; (iv) -OCORp ¹ , where R 'is amino, (lower) alkyl- amino, di (lower) alkylamino or R _p stand ⁺ , if R _r 'not for
can stand; R · not for unsubstituted (lower) alkyl (v) -OSO ₃ H; 0
(vi) -OP (OH) ₂ ; (vii) -0S0 ₂ R _r , where R _r as under the point above (b) Ciii) is defined;
η (viii) -OP (OR _e ) (OR _r ), where R _{e is} (lower) alkyl and R _{r is} as defined under point (b) (iii) above; 030027/0777 M / 20 359 SY-1599A (ix) -S (O) _n Rj, in which η is 0, 1 or 2 and R _{d is} as defined under point (b) (ii) above 1n or the case where n = 0, is -C-NR ₅ R g, wherein R ^ is hydrogen or (lower) alkyl, and Rg and R _g are each independently hydrogen or (lower) alkyl, wherein R ^ must not stand for unsubstituted phenyl; (x) -C0R _f , where R _{f stands} for amino (lower) alkyl, (lower) alkylamino (lower) alkyl, di (lower) alkylamino- (lower) alkyl, -NHNH ₂ , -NR ₁₇ NR ₁₈ , -NHOR ₁₉ , -SR ₁₇ -O (CH,) - AR. or -NR ^ R "where R ₁₇ , R _1R and R _{e are} (lower) alkyl, K _{1g is} hydrogen or (lower) alkyl, A is O, S, NH or NCH ₃ and η and R are as defined under (b) (iii) and (b) (viii) above; (xi) -P0 (OR _w ) ₂ , where R _{w is} hydrogen or (lower) alkyl; (xii) -NHRj ₁ , in which R ^ has the following meanings: if desired substituted phenyl, if desired • * ■ * * ^r case scenario, substituted heterocyclic group, -CH = NH, -SO ₃ H, -OH, (lower) alkoxy, amino, (ni-drig) alkylaraino, di (lower) alkylamino, -NHCOCH ₃ , -CS ₂ CH ₃ , -SO ₂ CH ₃ , -S S. -CNHCH -SO ₂ NH ₂ , -CNH ₂ , NH , -C-NH-ζ V -C-NR ₇ R ₈ , wherein R ₇ and R _g each independently for (lower) alkyl, NH Phenyl or phenyl (lower) alkyl, -CR _g , where R _{g is} (lower) alkyl, phenyl or phenyl (lower) - 030027/0777 M / 20 359 SY-1599A 2850898 alkyl, or -CR ₁ . stands, wherein R ₁ -for amino (lower) a1kyl, -NH ₂ , (lower) alkyl- amino, di (lower) alkylamino, -NH- ^ 7, 0 N = / Il -NH-CR ₁₀ , in which R _{10 is} (lower) alkyl or optionally substituted phenyl or an optionally substituted heterocyclic group, the phenyl substituents and heterocyclo substituents as below are defined in item (a) (ii) above, or NH for -NH-C-NH ₂ , (lower) alkoxy, - -OCH ₂ - / ^ J ~ NO ₂ or -0 (CH ₂ ) ₂ Si (CH ₃ ) ₃ ; (xiii) -SCR ₁₁ , in which R _{11 is} (lower) alkyl which may be substituted by amino, (lower) alkylamino or di (lower) alkylamino; (xiv) - wherein R. is (lower) alkyl and ) R _k for (lower) alkyl, (lower) alkoxy, a heterocyclic group, amino or 0 Il -C-R. is where R ^ as under the above Point (b) (xii) is defined, or in which, together with the nitrogen, the radicals R. and R. for J κ stand in the following group: where if represents amino or -CH ₂ CH ₂ NK ₂ , R. stands for methyl and where R. and R _k do not simultaneously stand for (lower) alkyl; 030027/0777 M / 20 359 SY-1599A • • * • ■ · • • * * · 9 # • ■ · · * * · · • *
• · · • · (xv) —NR'R ,, ¹ , Wherein R. ' represents (lower) alkoxy. and R _k 'for (lower) alkyl, a heterocyclic group, amino (lower) alkyl, (lower) alkylamino (lower) alkyl, di (lower) alkylamino (lower) -0 Il alkyl or -C-R. stands in which R .. as under the above point (bj (xii) is defined, or wherein together with the nitrogen the radicals R. ¹ and ^R k stand for the following group: 0 (xvi) - where R and R _n each independently stand for- (lower) alkyl or together with the nitrogen atom represent the following group: (+3 -N N = / (xvii) -N = CH-R _x , wherein R for (lower) alkyl or If desired, ring-substituted phenyl or an optionally ring-substituted heterocyclic group, where it is in the Substituents on the phenyl ring or on the heterocyclic ring are unr those as they are under the (a) (ii) above are defined; (xviii) -N = CR _x R _y , where R _{y is} (lower) alkyl or optionally ring-substituted phenyl or an optionally ring-substituted heterocyclic group, which are 030027/0777 I i • • ·
• # * • *
• I ·
I · M / 20 359 - 7 - SY-1599A 29 ^ 0888 Substituents on the phenyl group and the heterocyclic group are as defined in item (a) (ii) above, and wherein R _{x is} as defined in item (b) (xvii) above; (xix) -N-R, where R is hydroxy, (lower) alkoxy, Amino, di (lower) alkylamino or -NH stands; or NOH I! (xx) "C ^- (C ^) NR, rR-iß» where η is an integer from 1 to 6 and R ₁₅ and Rg each independently represent hydrogen or (lower alkyl; and Y stands for hydrogen or a radical which is selected from the following group: - - - (a) optionally substituted (lower) aliphatic groups (low) cycloaliphatic groups or (lower) cycloaliphatic (lower) aliphatic groups, wherein the substituents are one or more of the following acts: hydroxy, (lower) alkoxy, desired · if substituted phenyloxy, if desired substituted heterocyclyloxy, if desired substituted (lower) alkylthio, if desired substituted phenythio, if desired substituted heterocyclyl thio, mercapto, amino, (lower) alkylamino, di (lower) alkylamino, (lower) alkanoyloxy, (lower) alkanoylamino If desired substituted phenyl, if desired substituted heterocyclic radicals, carboxy, carb (lower 030 02 7/077 7 H / 20 359 SY-I599A 2950888 rig) alkoxy, carbamoyl, N- (lower) ATky1carbamoyl, N ₅ N-di (lower) alkylcarbamoyl, halogen, cyano, oxo, Thioxo, -SO-H, -OSO-H, -SO, - (lower) alkyl, (lower) - iic 0 Alkylsulfinyl, nitro, phosphono or -0P (OR _e ) (OR _r ), in which R _g and R _{r are} as defined above, the substituents on the (lower) alkylithio group being one or more of the following radicals; Halogen, hydroxy, (lower) alkoxy, amino, (lower) alkanoylaniino or optionally substituted phenyl or an optionally substituted heterocyclic group, and where the above phenyl substituents or heterocyelo substituents are one or more of the following groups: Hydrox (lower) alkoxy, halogen, (lower) alkyl, halogen (lower) alkyl, hethanesulfonyl, (lower) alkylthio, amino, (lower) alkanoylamino, (lower) alkanoyloxy, carboxy, carboxy (lower) alkyl, sulfo or sulfo ( lower) alkyl; (b) -0R _s , wherein R _{5 is} optionally substituted (lower rig) alkyl or (lower) alkanoyl or a desired case substituted phenyl group or, if desired, substituted het means cyclic group, where the substituents are on the alkyl radicals and alkanoyl radicals by one or several of the following groups are: halogen, hydroxy (lower) alkoxy, (lower) alkylamino, di (lower) alkylamino, Amino, oxo, (lower) alkanoylaraino or an optionally substituted phenyl group or desired if substituted heterocyclic group, and where it is tendency vutr heterccycl "; see substituents on the phenyl group
is one or more of the following groups: hydroxy, (lower) alkoxy, halogen, (lower) alkyl, halogen (lower) alkyl, Hethanesulfonyl, (lower) AlkyT-thio, (lower) alkylamino, di (lower) alkylamino, amino , (low) alkanoylamino, (low) alkanoyloxy, 030027/0777 »» · A s M / 20 359 SY-1599A ■ *
t. ι ·· 2950Θ98 Carboxy * carboxy (lower) alkyl, sulfo or sulfo (lower) alkyl; (c) -S (O) _n R., where η is 0, 1 or 2 and R is as previously defined; (d) halogen; and (e) a optionally substituted phenyl group or heterocyclic group in which the substituents are one or more of the following groups: hydroxy, (lower) alkoxy, halogen, (lower) alkyl, halogen (lower) alkyl, methanesulfonyl, ( lower) alkylthio-, amino, (lower) alkylamino, di (lower) alkyl amino, (lower) alkanoylamino, (lower) alkanoyloxy, carboxy, carboxy (lower-alkyl , sulfo or sulfo-lower) alkyl; . and their pharmaceutically acceptable salts and physiologically hydrolyzable esters; where in the case that Y stands for hydrogen, X must not stand for -CH ₂ OCH ₂ CH ₂ OCH ₃ . 2. Compounds according to claim 1, wherein Y is hydrogen. 3. Compounds according to claim 1 ₉ wherein Y is Cj-Cg-alkyl which is optionally substituted by a hydroxyl group. 4. Compounds according to claim 1, wherein Y is rf-hydroxyethyl stands. 030027/0777 »See egg Μ / 20 359 SY-1599A - 10 - 5. Compounds according to any one of claims 1 to 4 _ä wherein X has the following meanings: 0 , where η is an integer from 1 to 6 represents; (isi ~ -ΐΌΗ ₂ ') ^ ΝΗ0Ή, where * represents an integer from 1 to 6; (c) - (CH ₂ ) _n P0 (0-C ₁ -Cg-alkyl) ₂ , wherein η is an integer from 1 to 6; (i) - (CH ₂ J _n NH-CC ₁ -Cg-Alkyl, where η is an integer from 1 to 6 ^ is NH ₉ (e) - (CH ₂ J _n N = CH, where η is an integer from 1 to 6; (f) - (CH ₉ ) OC (CHj _n NF ^ R ⁶ , where η and m are each independent c. η ά πι α ρ each other for 1 or 2 and R and R each independently of one another represent hydrogen or (lower) -alkyl; or (g) - (CH ")" NHC-R ^C , where η is an integer from 1 to 6 to ■■ NH and R ^{c is} C ₁ -C ₄ -AUyI, phenyl or - where m is 1 or 2. 6. Intermediate, selected from compounds of the general formula: 030027/0777 • a> I I 1 « 1 · I M / 20 359 SY-1599A CO-R "J wherein Y is hydrogen or a radical selected from the following: (A) a "substituted (lower) aliphatic, (lower) cycloaliphatic; lower) alkoxy _s desired tenfails substituted phenyloxy, if desired substituted heterocyclyloxy, if desired substituted (lower) alkylthio, if desired substituted phenylthio, if desired substituted heterocyclylthio, mercapto, amino, (lower ^ alkylamino, di (lower alkylansino, {lower alkyl) -alkanoyl roy <? mino, optionally substituted phenyl, an optionally substituted heterocyclic group, carboxy, carb (lower) alkoxy, carbamoyl; N- (lower) alkylcarbamoyl, N, N-di (lower) alkylcarbamoyl, halogen, cyano, oxo, thicxo, -SO ₃ H, -OSO ₃ H, -S0 ₂ - (lower) alkyl, (lower) alkylsulfinyl, Mitro, Phosphcno or υ -OP (OR _e ) (OR _r ), where R are as previously defined _s r the substituents on the (lower) alkylthio group being one or more of the following pen acts: halogen, hydroxy, (low) alkoxy, amino, 030027/0777 Μ / 20 359 SY-1599A (lower) alkanoylamino or optionally substituted phenyl or an optionally substituted heterocyclic group and where the obi gene substituents on the phenyl or on the heterocyclic Group is one or more of the following groups: hydroxy, (lower) alkoxy, halogen, (lower) alkyl Halogen (lower) alkyl, methanesulfonyl, (lower) alkylthio, amino, (lower) alkanoylamino, (lower) alkanoyloxy. Carboxy * carboxy (lower) alkyl, sulfo or sulfo (lower) alkyl; (b) -OR ₅ , wherein R _{g stands} for optionally substituted (lower) alkyl or (lower * alkanoyl or for an optionally substituted phenyl group or heterocyclic group, the substituents on the alkyl group and alkanoyl group being one or more of the the following is: halogen, hydroxy, (lower) alkoxy, (lower) alkylamino, di (lower) alkylamino, amino, oxo, (lower) alkanoylamino or an optionally substituted phenyl group or heterocyclic group, and where the substituents are at the Phenyigruppe or the heterocyclic group is one or more of the following: hydroxy, (lower) alkoxy, halogen, (lower) alkyl, halogen (lower alkyl, Hethanesulfonyl, (lower) alkylthio, (lower) alkylamino, di (lower) alkylamino, amino , (lower) alkanoylamino, (lower) alkanoyloxy, carboxy, carboxy (lower) alkyl, sulfo or sulfo (lower) alkyl; ic) -S (O) _R_. wherein η is "0.1 or 2 and R ^ is as previously defined; (d) halogen; and 030027/0777 .mi · « M / 20 359 SY-1599A - 13 - (e) a optionally substituted phenyl group or heterocyclic group, where the substituents are one or more of the following: Hydroxy, (lower) alkoxy, halogen, (lower) alkyl, Halo (lower) alkyl, methanesulfonyl, (lower) alkylthio, amino, (lower alkylamino, di (lower) alkylamino (low) alkanoylamino, (low) alkanoyloxy, carboxy, Carboxy (lower) alkyl, sulfo, or sulfo (lower) alkyl; Q is phenyl or (lower) alkyl; R "represents an easily removable ester group; X is 1 or -2; and M represents Cu (II), Pb (II) or Hg (II) when χ is 2, or Ag (I) when χ is 1; and Compounds of the general formula: SHgCOOCH, (Q) CO ₂ R " wherein Y, Q and R ^{K are} as previously defined. 030027/0777 M / 20 359 SY-1599A - 14 - 7. Intermediate products of the general formula: JS-I CO ₂ R " wherein Y is hydrogen or a radical selected from the following: (A) an optionally substituted (lower) aliphatic, (lower cycloaliphatic or (lower) cycloaliphatic (lower) aliphatic group, where the substituents are in one or more of the following groups: hydroxy, (lower) alkoxy, optionally substituted phenyloxy, if desired substituted heterocyclyloxy, if desired substi * ' tied (lower alkylamino, if desired stibsti- = tuie / tes phenylthio, if desired substituted heterocyclylthio, mercapto, amino, (lower alkylamino, di (lower) alkylamino, (lower) alkanoyloxy, (lower) - "' ATkanoylamino- if desired substituted phenyl, an optionally substituted heterocyclic group, carboxy, carb (lower) alkoxy, carbamoyl; N- (lower) alkylcarbamoyl, N, N-di (lower) alkylcarbamoyl, halogen, cyano, oxo, TMcrxo, -SO ₃ K, -OSO ₃ H, -S0 ₂ - (low Alkyl, (lower) alkylsulfinyl, nitro, phosphono or ö -OP (OR ₆ ) (OR _r ), where and R _{-1 are} as previously defined r where the substituents on the (lower) -alkylthio group are one or more of the following groups: halogen, hydroxy, (lower) alkoxy, amino, 030027/0777 M / 20 359 SY-1599A 2850898 (Lower) alkanoylamino or optionally substituted phenyl or an optionally substituted heterocyclic group and where the above substituents are on the phenyl or on the heterocyclic group Group is one or more of the following groups: hydroxy, (lower) alkoxy, halogen, (lower) alkyl Halogen (lower) alkyl, methanesulfonyl, (lower) alkylthio, amino, (lower) alkanoylamino, (> lower) alkanoyl- "'" oxy, carboxy; Carboxy (lower) alkyl, sulfo or sulfo (lower) alkyl; (b) -OR ₅ , wherein R _{g is} optionally substituted (lower) alkyl or (lower) alkanoyl or a desired unsubstituted phenyl group or heterocyclic group, the substituents on the alkyl group and alkanoyl group being one or more of the the following is: halogen, hydroxy, (lower) alkoxy, (lower) alkylamino, di (lower) alkylamino, amino _s oxo, (lower) alkanoylainino or an optionally substituted phenyl group or heterocyclic group, and the substituents on the phenyl group or the heterocyclic group is one or more of the following: hydroxy, (lower) alkoxy, halogen, (lower) alkyl, halogen (lower) alkyl, methanesulfonyl, (lower) alkylthio, (lower) alkylamino, di (lower) alkylamino, Amino, (lower) alkanoylamino, (lower) alkanoyloxy, carboxy, carboxy (lower) alkyl, sulfo or sulfo (lower) alkyl; Ce) -SiO) _n R, where η is _{0.1 or 2 and R 3 is} as defined above; (d) halogen; and 030027/0777 M / 20 359 SY-1599Ä (e) an optionally substituted phenyl group or heterocyclic group, where the substituents are one or more of the following: Hydroxy, (lower) alkoxy, halogen, (lower) alkyl, Halogen (lower) alkyl, methanesulfonyl, (lower) alkylthio, amino, (lower) alkylamino, di (lower) alkylamino (low) alkanoylamino, (low) alkanoyloxy, carboxy, Carboxy (lower) alkyl, sulfo, or sulfo (lower) alkyl; Q is phenyl or (lower) alkyl; R "represents an easily removable ester group; and C ₅ H ₅ 0 T stands for -CC ₅ H ₅ -or -CX, in which X stands for the following groups ^C 6 ^H 5 can be: (a) a residue of the formula: (i) -OR, where R _{3 is} hydrogen; (ii) -0R _b , where R _{fa is} hydrogen, hydroxy, desired ^ tat S3 3OL / JVffc> MftI U ^ & ^ n iw »· · 31 β" · ~ * ' ———- ZT * ~ " in the case of ring-substituted phenyl or, if desired, a heterocyclic radical where the substituents on the alkyl group are one or more of the following radicals: halogen, hydroxy, oxo, carboxy, carb (low alkoxy), carbamoyl (lower) alkoxy, amino, (lower) alkylamino, di (niedrigjalkylaminc (lower) alkanoylamino or, if desired ~ sübstituie pjjgrjyi _{D (i sr} "inen gewünscbtenfalls substituted heterocyclji - Vchen rest unä'Wobei Essich the substituents on the phenyl group or the heterocyclic ones . Wrestling for one or more "of the following group 030027/0777 M / 20 359 SY-I599A • fc Ci) (lower) alkyl or phenyl and R ₂ and il (lower) alkyl, phenyl or benzyl; Cii) -OR ₀ , where R _{rf stands} for amino, (lower alkylaraino, di (lower) alkylamino, substituted (lower) alkyl, (lower) alkenyl or if desired 030027/0777 pen acts: Hydroxy .. (low) alkoxy, halogen, (lower) alkyl, halogen (lower) alkyl, methanesulfonyl, oxo, (lower) alkylthio, amino, (lower) alkylamino, di (lower) alkylamino, (lower) alkanoylamino, (lower) alkanoyloxy, carboxy, Carboxy-lower) alkyl, sulfo or sulfo (lower) alkyl; or (iii) -OCOR ₀ , "where R ~ stands for amino, (lower) alkylamino, di (lower) alkylamino or, if desired, substituted (lower) alkyl, in which the substituents are as defined under point (ii); or (b) substituted (low) aliphatic, (low) cycloaliphatic or (low) cyclGaliphaticinisdrig) " aliphatic radicals or a ring-substituted phenyl radical, phenyl (lower) alkyl radical, a heterocyclic radical, a heterocyclic (lower) alkyl radical or a heterocyclylthio (lower) alkyl radical, where the substituents of said aliphatic groups, cycloaliphatic groups, Phenyl groups or heterocyclyl groups are the following: NO, -CNR ₂ R ₃ or -N = C-NR "R" where R _{4 is} hate substance, Lr -ϊ M / 20 359 SY-1599A ring-substituted phenyl, phenyl (lower) alkyl, a heterocyclic group or a heterocyclic group see (lower) alkyl group, the substituents on the alkyl groups being phenyl groups and heterocyclic groups are those as defined under (a) (ii); (ill) -0 (CH ₂ ) _n QR _r , where η is an integer from 1 to 6 represents ύη R _r if desired substituted represents (lower) alkyl or, if desired, ring-substituted phenyl or, if desired, a ring-substituted heterocyclic group, the substituents on the alkyl groups being phenyl groups or heterocyclic groups
Groups are those as defined under (a) (ii); ; iv) -OCOR _r ', where R 'is amino, (lower) alkylamino, di (lower) alkylamino or R _r , R _r ' would not be unsubstituted (niadMg) alkyl
can stand; (v) -OSO ₃ H; 0
(vi) -OP (OH) ₂ ; (vii) -0S0 ₂ R _r , where R _r as under the point above Cb) CIiD is defined; (viii) -OP (OR _e ) (OR _r ), where R _{e is} (lower) alkyl and R _{r is} as defined under point (b) (iii) above; 030027/0717 M / 20 359 SY-1599A (ix) -S (O) _n R _d , where η is 0, 1 or 2 and R _d as defined in item (b) (ii) above or in the case that n = 0, for -C-NR ₅ R ₅ »where R- is hydrogen or (lower) alkylj and P. ₅ » .. d R ₆ each independently of one another is hydrogen or (lower) Are alkyl, where R _{d must} not stand for unsubstituted phenyl; Cx) »COR _f , where R _{f stands} for amino (lower) alky ί , (lower) alkylamino (lower) alkyl, di (lower) alkylasino- (lower) alkyl, -NHNH ₂ , -NR ₁₇ NR ₁₈ , -NHOR ₁₉ , -SR ₁₇ or -NRgR-, in which R ₁₇ , R ₁₈ and .R _{e are} (lower) alkyl, R _{19 is} hydrogen or (lower) alkyl, A is 0, S, NH or NCH ₃ and η and R _{g are} as defined under (b) (iii) and (b) (viii) above; (xi) -PO (OR _W ) ₂ , where R _{w is} hydrogen or (r-lower) alkyl; fxii) -NHR. _; where R- has the following meanings: if desired substituted phenyl, if desired substituted heterocyclic group, -CH = NH, -SO ₃ H, -OH, (lower) alkoxy, amino, (lower alkylamino, di (lower alkylamino, -NHCOCH ₃ , / V -i -CS ₂ CK ₃ , -SO ₂ CH ₃ , -S0 ₂ - ^ __ ^ _i -SO ₂ NH ₂ , -CNH ₂ , f ·· «I Ii O i> ffn -CNHCH ₃ , -C-NH- ^ Λ, -C-NR ₇ R ₈ , in which R ₇ and R _g each independently represent (lower) alkyl, Phenyl or phenyl (lower) alkyl, -CR ₀ , where R _{g is} (lower) alkyl, phenyl or phenyl (lower) - 030027/0777 »Ί ι
- * - Jl Μ / 20 359 SY-1599A - 20 - Il alkyl, or -CR ^, where R .. is amino (lower) alkyl, -NH ₂ , (lower) alkyl- amino, di (lower) alkylamino, -NH- ^ y, -NH-CR ₁₀ , in which R _{10 is} (lower) alkyl or optionally substituted phenyl or an optionally substituted heterocyclic group »where the phenyl substituents and heterocyclic substituents - are as defined under point (a) (ii) above, or Ψ for -NH-C-NH ₂ , (lower) alkoxy, - -OCH ₂ - ^ VnO ₂ or -0 (CH ₂ ) ₂ Si (iH ₃ ) ₃ ; (xiii) -SCR ₁₁ , wherein R _{11 is} (lower) alkyl which is substituted by amino, (lower) alkylamino or di (lower) alkylamino; (xiv) -NRjR ^, where R. is (lower) alkyl and R _{k is} (lower) alkyl, (lower) alkoxy, a heterocyclic group, amino or 0 -CR ₁ -, in which Rj is as defined under point (b) (xii) above, or in which, together with the nitrogen, the radicals Rj and R _fc fl'r are the following group: where when R ^ is amino or -CHgCH ₂ NH ₂ , R ^ is methyl and where R. and R _{k are} not (lower) alkyl at the same time; 030027/0777 Μ / 20 359 SY-1599A -NR- ¹ R ^ ¹ , where K. * stands for (lower) alkoxy and R _k 'for (lower) alkyl, a heterocyclic group, amino (lower) alky1, (lower) alkylamino * (lower) alkyl, di (lower) alkylamino (lower) -0 It alkyl or -C-P ^, in which R ^ as under the point (b) (xii) above is defined, or in which, together with the nitrogen, the radicals R. ' and R ^ stand for the following group: (xvi) - ^NR -j ^R _m ^R _n »where and R are each independent each other for (lower) alkyl or to- together with the nitrogen atom represent the following group:> -N 8. Intermediate product according to claim 7, wherein Y stands for hydrogen, ethyl or oct-hydroxyethyl and T stands for _c_x _s . 9. The intermediate of claim 7 wherein Y is hydrogen 0
or * i-Hydroxyethyl and T is -CX, where X is a radical of the following formulas: 030027/0777 Μ / 20 359 SY-1599A (a) - (CH ₂ J _n -N , where η is an integer from 1 to 6 ₍ represents; (b) - (CH ₂ ) _n NHOH, where η is an integer from 1 to 6; (c) - (CH ₂ J _n PO (OC ₁ -C ₆ -AlKyI) ₂ , wherein η is an integer from 1 to 6; (d) - (CH ₂ J _n NH-CC ₁ -C ₆ -AllCyI ₈ wherein η is an integer from 1 to 6; NH ₂ (e) - (CH ₂ J _n N = CH, where η is an integer from 1 to 6; (f) - (CH ₂ ) _n OC (CH ₂ ) _m NR ^A R ^B , in which η and m each independently represent 1 or 2 and R and R each independently of one another represent hydrogen or (lower) -alkyl; or o) NHC-R ^C , where η is an integer from 1 to ζ η H NH and R ^{c is} C ₁ -C ₄ -AlkVl, phenyl or - * where m is 1 or 2. 10. A method for the preparation of the compounds according to any one of claims 1 to 5, characterized in that one Compound of the general formula: 030027/0777 H / 20 359 SY-1599A - 23 - Pl c P (Q) CO ₂ R ¹ v / orin Q is phenyl or (lower) alkyl, R "is a represents easily removable ester group and X and Y are as defined above, cyclized in an inert organic solvent at a temperature from just above room temperature to the reflux temperature of the solvent in a manner known per se, the removable ester group and optionally other protective groups removed and, for the case that Y is hydrogen, if desired convert the product to another desired product in which Y is not hydrogen by treating the product with an appropriate electrophile in an inert Solvent transferred in the presence of a strong base. Pharmaceutical agent containing as an active ingredient At least one connection according to one of Claims 1 to or a pharmaceutically acceptable salt or a physiologically cleavable ester thereof together with a pharmaceutically acceptable carrier or diluent. 030027/0777