DE2700178A1 - PROCESS FOR THE PREPARATION OF 1,3-DISUBSTITUTED-2-ACETIDINONE - Google Patents

Description

* 7ü) j 78

50 706 - Dr.T

Applicant: Fujikawa Pharmaceuticn] Co., Ltd., Wo. 3, 4-chome, Doshomachi, Higashi-ku, Osaka / Japan

• V

Process for the preparation of 1,3-disubstituted-2-acetidinone

The invention relates to a new and unique process for the preparation of 1,3-disubstituted-2-acetidinone; she particularly relates to a process for the preparation of 1,3-disubstituted-2-acetidinone of formula (III) given below, which consists in using a methylenamine compound of the formula (I) given below with a substituted acetic acid of the formula given below (II) or its reactive derivative at the carboxy function in the presence of a Lewis acid and a base. The invention particularly relates to a new method of manufacture of 1,3-disubstituted-2-acetidinone in higher yield by a 1-step synthesis. The subject of the invention is in particular a new and simple process for large-scale engineering Preparation of 1,3-disubstituted-2-acetidinone, which is obtained in high yield.

The compounds obtainable by the process according to the invention (III) encompass both new compounds and

7 O 9 R? S / 1 O 3? ORIGINAL INSPECTED

2 / ϋ Ο ι 7 8

knew compounds in the literature, for example in German Offenlegungsschrift 25 29 94-1 are.

After extensive studies on a synthesis process for the large-scale production of these compounds has now become a new, unique, and large-scale process for the preparation of 1, J-disubstituted - ^ - acetidinone (III) found.

The method according to the invention can be simplified by the the following scheme can be shown:

ti)

21

+ R ² -CH _o -C00H (II) or its reactive derivative on the carboxy function in the presence of a Lewis _R ² -CH-CH acid and a base

I I ι

C-N-R

where mean:

R is an organic radical bearing a carboxy group or a derivative thereof,

η is an integer from 1 to 3 and

709R? 8/1

2
K Asido, substituted amino, halogen, acyloxy, alkoxy, aryloxy or aralkoxy.

The mettryleneamine compound (I) ₁ used as the starting material in which η is the integer 3 can also be represented by the following formula:

CH ₀

• N.

CH _{0 R} l_jj NR *

CH ₂
v / orin R has the meanings given above.

The reaction of the present invention is carried out by reaction the methylenamine compound (I) with substituted acetic acid (II) or its derivative at the carboxy function in the presence a Lewis acid and a base.

The methylenamine compounds used as starting material

(I) are new and can be produced, for example, by a process as shown schematically below:

η- R ^ NH ₂ + n-HCHO * NR ¹ J η ^(I)

wherein H and η have the meanings given above.

The term "organic radical which carries a garboxy group or a derivative thereof" as used herein is defined for the symbol R of the compounds (I) and (III) includes:

709828/1 03?

an aromatic hydrocarbon _radical which always carries a carboxyl group or a derivative thereof, an aliphatic hydrocarbon radical which always carries a carboxy group or a derivative thereof, and an aromatic-aliphatic carbon radical which always carries a carboxy group or a derivative thereof, the aliphatic Hydrocarbon portion of the aliphatic and the aromatic-aliphatic carbon radical can be substituted by one or more suitable substituents and any aliphatic hydrocarbon atom of the abovementioned aliphatic and aromatic-aliphatic hydrocarbon radicals can be replaced by a heteroatom, and the aromatic portion of the aromatic and aromatic-aliphatic hydrocarbon radicals can be substituted by one or more suitable substituents. Suitable radicals, as given above, are explained in more concrete and more detail below as follows:

1.) With regard to the aromatic hydrocarbon radical, the always carries a carboxy group or a derivative thereof, the aromatic hydrocarbon component comprises an aryl group, such as phenyl, tolyl, xylyl, mecityl, naphthyl and the like, and the aromatic carbon part can be replaced by one or more suitable substituents, as indicated below, be substituted.

2.) With regard to the aliphatic hydrocarbon radical, the always carries a carboxy group or a derivative thereof, any carbon atom can be replaced by a heteroatom, e.g. Oxygen, sulfur and the like. Be replaced. The o '^ en defined aliphatic carbons include alkyl (such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, heopentyl and the like),

709829/103?

Alkenyl (such as vinyl, 1-propenyl, allyl, isopropenyl, butenyl, 1- or 2-methylpropenyl, pcntenyl and the like), alkynyl (such as Ethynyl, propynyl, butynyl, 1- or 2-methylpropynyl, pentynyl and the like), alkoxyalkyl (such as methoxymethyl, ethoxymethyl, Methoxyethyl and the like), alkoxyalkenyl (such as methoxyvinyl, Methoxypropenyl and the like) »alkoxyalkynyl (such as methoxyethinyl, Ethoxypropinyl and the like), alkylthioalkyl (such as methylthiomethyl, Ethylthiomethyl, ethylthioethyl and the like), alkylthioalkenyl (such as methylthiovinyl, mefchylthiopropenyl, ethylthiopropenyl and the like) and alkylthioalkynyl (such as methylthioäthinyl, methylthiopropynyl and the like). The aliphatic hydrocarbon content may be substituted by one or more suitable substituents as indicated below, and a suitable aliphatic hydrocarbon fraction can have up to 8 carbon atoms, preferably 1 to 6, in particular 1 to 5 carbon atoms.

3.) With regard to the aromatic-aliphatic carbon residue, which always carries a carboxy group or a derivative thereof includes the aromatic-aliphatic hydrocarbon portion an aromatic-carbocyclic-substituted aliphatic hydrocarbon component and an aromatic-heterocyclic-substituted one aliphatic hydrocarbon content. Any aliphatic carbon atom of the aromatic aliphatic Hydrocarbon content can be a hetero atom, e.g. oxygen, sulfur and the like, and the aliphatic carbon part is the same as it indicated above (i.e. alkyl, alkenyl and alkynyl). Details of this remainder are given below:

i) the aromatic carbocyclic-substituted aliphatic Hydrocarbon moiety includes an aryl-aliphatic hydrocarbon proportion, v / obei examples of its aryl and aliphatic hydrocarbon radicals are those like them

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~ ^ ' 27OuΪ78

for don the appropriate proportion in the sections above

(i) and (2) have been given, respectively.

A suitable aryl-aliphatic hydrocarbon fraction includes: aralkyl (such as benzyl, phenethyl, 1-phenylethyl, phenylpropyl, Phenylbutyl, phonylpentyl, tolylmethyl, tolylethyl, Tolylpropyl, xylylmethyl, xylylethyl, xylylpropyl, mesitylmethyl, Mesitylethyl, mesitylpropyl, naphthylmethyl, naphthylethyl, Naphthylpropyl, naphthylbutyl, diphenylmethyl, diphenylethyl, Diphcnylpropyl and the like), aralkenyl (such as styryl, Cinnamyl, phenylbutenyl, fhenylpentenyl, tolylvinyl, tolylpropenyl, Tolylbutenyl, xylylvinyl, xylylpropenyl, mesitylvinyl, Naphthylvinyl, naphthylpropenyl and the like.) And the like.

In the aryl-aliphatic hydrocarbon fraction indicated above can be any aliphatic carbon atom a hetero atom such as oxygen, sulfur and the like may be replaced, and examples thereof are as follows:

Aryloxyalkyl (such as phenoxymethyl, phenoxyethyl, tolyloxymethyl, Naphthoxyethyl and the like),

Aryl-substituted alkoxyalkyl (such as cx-methoxybenzyl, α- or ß-methoxyphenethyl, α- or ß-ethoxyphenethyl, α- or ß-propoxyphenethyl, α-, ß- or ^ -methoxyphenylpropyl, α-, ß- or τ- ethoxyphenylpropyl and the like), aryloxyalkenyl (such as phenoxyvinyl, phenoxypropenyl, naphthoxypropenyl and the like),

Aryl-substituted alkoxyalkenyl (such as α- or ß-methoxystyryl, α-, ß- or γ-methoxycinnamyl, α-, ß- or ^ -ethoxycinnamyl and the like),

Arylthioalkyl (such Phonylthiomethyl, PhenylthioHthyl, phenylthiopropyl, Phenylthiobutyl, Tolylthioniethyl, Tolylthioüthyl, Xylylthioäthyl, Xylylthiopropyl, Mesitylthiobu t; yl, naphthylthiomethyl, Naphthylthioäthyl, Naplibhylthiopropyl and the like.), Arylthioalkenyl (such Phonylthiovinyl, Phenylthiopropenyl, Phenylthiobutenyl, tolylthio \ ^r ynyl, Xylylthiopropeny 1 , Naphthy 1-thiovinyl, naphthylthioj ^ ropenyl and the like), aralkyloxyalkyl

709878/1 01?

such as benzyloxymethyl, benzyloxyethyl, phenäthyloxyäthyl, Tolylmefchoxyäthyl, Benz.yloxypropyl and the like.), Aralkylthioalkyl (such as benzylthioethyl, phenethylthiopropyl and the like),

Aralkyloxyalkenyl (such as benzyloxypropenyl, phenethyloxyvinyl and dpi.),

Aralkylthioalkenyl (such as benzylthiovinyl, benzylthiopropenyl and the like) and the like.

ii) the aromatic-heterocyclic-substituted aliphatic The hydrocarbon fraction comprises 5 to 10-membered aromatic heterocyclically substituted aliphatic hydrocarbon radicals, in which the heterocyclic portion is in particular a 5- to 6-membered monocyclic heterocycle or a 9 to 10 membered, fused heterocycle containing at least one heteroatom selected from nitrogen, oxygen and sulfur. In the case of the aliphatic hydrocarbon share is the one stated above in section (2). Any aliphatioches Carbon atom can be replaced by a hetero atom, e.g. oxygen, Sulfur and the like., Be replaced. Suitable examples of the aromatic - heterocyclic-substituted aliphatic Hydrocarbon residues are the following:

heterocyclic alkyl, eg thienylalkyl (!. as Thieny methyl, Thienyläthyl, thienylpropyl, Thienylbutyl, Dithienylpropyl and the like), furylalkyl (such as furylmethyl, Furyläth ^r l, Purylpropyl, Difurylbutyl and the like.), pyridylalkyl (such as P; / ridylmethyl, Pyridyläthyl, Pyridylpropyl and the like), pyrrolylalkyl (v / ie pyrrolylmethyl, pyrrolylethyl and the like),

Imidazolylalkyl (such as

Imidazolyl methyl, imidazolyl ethyi and the like), pyrimidinyl alkyl (v / ie pyrimidinylmethyl, pyrimidinylethyl and the like), thiazolylalkyl (such as thiazolylmethyl, thiazolylethyl and the like.), oxazolylalkyl (such as oxazolylmethyl, oxazolylethyl, etc.), thiadiazolylalkyl (like Thiadiazolylmethyl, Thiadiazolyläthvl and the like,

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27 0 υ ϊ 7 8

Oxadiazolylalkyl (such as oxadiazolylmethyl, oxadiasolylethyl and the like), isoxazolylalkyl (such as isoxazolylmethyl, isoxazolylethyl and dpi.) »Isothiazolylalkyl (such as isothiazolylmethyl, Isothiazolylethyl and the like), triazolylalkyl (such as triazolylethyl, Triazolylethyl and the like), tetrazolylalkyl (such as tetrazolylmethyl, Tetrazolylethyl and the like), indolylalkyl (such as indolylmethyl, indolylÜth.yl and the like), purinylalkyl (such as Purinylmethyl, parinylethyl and the like), benzymyclazolylalkyl (such as BenzimidazoLylmebhyl, Benzimidzolyläth. 1 and the like.), Benzotriazol.ylalkyl (such as benzotriazolylmethyl, benzotriazolylethyl and the like), ^ hinolylalkyl (such as quinolylmethyl, quinolylethyl and the like), benzofurylalkyl (such as benzofurylmethyl, Benzofurylethyl and the like), benzothienylalkyl (such as benzothienylmethyl, Benz-thienylethyl and the like), benzoxazolylalkyl (v / ie BenzoxazolyLraethyl, Benzoxazol; Läthy 1 and the like.); heterocyclic alkenyl, ζ.3. Thienylalkenyl (such as thieaylvinyl, Thienylproponyl, thienylbuteriyl and the like), furylalknyl (such as puryl vinyl, furyl propenyl, and the like), pyridyl alkenyl (such as pyridyl vinyl, pyridyl propenyl, and the like), isoxazolyl alkenyl (such as isoxazolylvinyl, inoxazolylpropenyl, and the like), isothiazolylalkenyl (such as isothiazolylvinyl, isothiazolylpropenyl and the like), oxazolylalkenyl (v / ie oxazolylvinyl, Oxazolylpropenyl and the like), Oxadiazolylalkenyl (v / ie Oxadiazol.ylvin.yl, Oxadiazolylpropenyl and the like), thiazolylalkenyl (such as thiazolylvinyl, thiazolylbutenyl and the like), thiadiazolylalkenyl (such as thiadiazolylpropene, yl, thiadiazolylbutenyl and the like);

heterocyclic oxyalkyl (such as thienyloxyiithyl, furyloxymethyl, Pyridyloxyethyl and the like);

heterocyclic thioalk.yl (v / ie thienylthiometh ;; l, furyl_ thioethyl, pyridylthioethyl, thiazolylthiomethyl, thiadiazolylthioraethyl, Triazolylthiomethyl, Tefcrai'olylthiomethyl, Benzothiazolylthioraethyl, oxazolylthioethyl, thiadiazolylthio-

709828 /

propyl and the like);

heterocyclic-substituted alkoxy alkyl (such as thenyloxymethyl, Furfuryloxymethyl and the like);

heterocyclic fhioalkenyl (such as thienylthiovinyl, furylthioallyl and the like.) and the like.

In the aromatic-aliphatic hydrocarbon radical specified above (including the aromatic-carbocyclic and aromatic-heterocyclic-aliphatic hydrocarbon radical), both the aromatic component and the aliphatic hydrocarbon component can be substituted by one or more suitable substituents, as explained below, and ssir. suitable aliphatic hydrocarbon content int the same as it has been explained above and it contains up to 8 carbon atoms, preferably 1 to 6, in particular 1 to -V carbon atoms.

A suitable substituent as described in the explanation of the Residues in the above sections (Ό, (2) and (3) have been given, can e.g. be a substituent such as amino, azido, Cyano, halogen (such as chlorine, bromine and the like.), Hydroxy, mercapto, nitro, suIfο, alkoxy (such as methoxy, ethoxy, propoxy, isopropoxy, Butoxy, isobutoxy, sec-butoxy and the like), alkanesulfonylamino (such as mesylamino, athenesulfonylamino, propanesulfonylamino, 1-methylethanesulfonylamino, butanesulfonylamino, 1- or 2-methylpropanesulfonylamino and the like.) and the like. Of course, these substituents must not be disadvantageous participate in the reaction according to the invention.

With regard to the above-mentioned substituents are particular preferred substituents for each of the radicals are given below, i.e .:

a substituent for the aliphatic carbon / hydrogen part in de Host specified and explained in sections (2) and (3) above can be halogen, hydroxy, amino, alkanesulfonamido,

709828/103?

- ye -

Mcrcanto and del .;

a substituent for the aromatic hydrocarbon portion in the radical indicated and explained in the above sections (1) and (3) can be halogen, alkoxy, hydroxy, amino, nlkansulfonamido, Mercapto, Azido, Cyano, Nitro, OuIfο and like; and

a substituent for the aromatic-heterocyclic portion in the radical indicated and explained in the above section (3) can be alkyl (such as methyl, ethyl, propyl, butyl and Like.), halogen, amino, hydroxy, alkanesulfonamido, nitro and

Of the substituents given above, the hydroxy, Amino, alkanesulfonamido and mercapto groups if desired be protected in each case by a suitable protective group.

On suitable protecting groups for the amino and alkanesulfonamido groups include conventional protecting groups, i.e., acyl, e.g., substituted or unsubstituted alkoxycarbonyl (like Methoxycarbon.vl, Athoxycarbonyl, Propoxycarbonyl, Butoxycarbonyl, tert-butoxycarbonyl, chlorine thoxycarbonyl, Bromoethoxycarbonyl, tribromothoxycarbonyl, trichloroethoxycarbonyl and the like.), substituted or unsubstituted aralkoxycarbonyl (such as benzyloxycarbonyl, phenäthyloxycarbonyl, D iphe ny lir et ho xy carbonyl, nitrobenzyloxycarbonyl, bromobenzy] oxycarbonyl, Methoxybenzyloxycarbonyl and the like), substituted or unsubstituted alkanoyl (such as formyl, acetyl, propionyl, Butyryl, valeryl, dichloroacetyl, trifluoroacetyl, N-phthaloylglycyl and the like) and the like;

substituted or unsubstituted aralkyl (such as benzyl, Diphenymethyl, trityl, bromobenzyl, nitrobenzyl, methoxybenzyl and the like);

substituted or unsubstituted aralkylidene (such as benzylidene, salicylidene and the like);

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MV

substituted or unsubstituted alkylidene or the corresponding alkenyl, such as isopropylidene, 1-alkyl-2- _a lkoxycarbonylvinyl or 1-alkoxycarbon? ^r linothylalk, ylidene (such as i-methyl-2-ethoxycarbonylvinyl or 1-ethoxycarbonylmethylethyllderi and the like) or 1-alkyl-2-alkanoylvinyl or 1- (2-oxoalkyl) alkylidene (such as i-methyl-2-acelylvinyl or 1- Acetonyläthy] iüen and the like.) And the like.

Suitable protecting groups for the hydroxy and mercapto groups include essentially the same acyl and aralkyl as it does explained above for the protecting group for amino and alkanesulfonamido and in addition acyl, e.g. or unsubstituted aroyl (such as benzoyl, toluoyl, 4-bromobenzoyl, Salicyloyl and the like) and the like.

As used herein, the term "its derivative" means "an organic radical which is a carboxy group or a derivative of which "for R, the term" derivative "is to be understood as meaning the derivative of the carboxy function and this includes Acid amide, the ester, the nitrile and the like, as follows explained in more detail.

Suitable acid amides include: the acid amide, N-alkyl acid amide (such as N-methyl acid amide, N-ethy1 acid amide and the like), N, N-Dialkylsäureamid (such as Ν, Ν-dimethyl acid amide, N, N-diethyl acid amide, N-ethyl-N-methyl acid amide and the like), N-phenyl acid amide, the acid amide with pyrazole, imidazole or 4-alkylimidazole (such as 4-methylimidazole, 4-ethylimidazole and the like) and the like.

Suitable esters include an allyl ester, an aliphatic one Ester, an ester containing an aromatic or a heterocyclic group, and an ester with an N-hydroxy compound. Suitable silyl esters include the trialkylsilyl esters (such as trimethylsilyl, triethylsilyl esters, and the like) and The like. Suitable aliphatic esters include the saturated one

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270 μ 78

or unsaturated acyclic or cyclic aliphatic esters, v / whether the acyclic aliphatic ester can be branched, such as, for example, the alkyl ester (such as methyl, ethyl, propyl, isopropyl, butyl, tort.-butyl, octyl, nonyl -, undecyl ester and the like), the alkenyl ester (e.g. the vinyl, 1-propenyl, allyl, 3-butenyl ester and the like), the alkynyl ester (such as the 3-butynyl, 4-pentynyl ester and the like), a cycloalkyl ester (such as cyclopentyl, C ^ 'clohexyl, cycloheptyl ester and the like.) and the like. In the above-mentioned aliphatic ester, the aliphatic portion can optionally have one or more substituents, for example cycloalkyl (v / iο cyclopropyl, cyclohexyl and the like. ), Alkoxy (such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy and the like), alkanoyloxy (v / ie acetoxy, propionyloxy, pivaloyloxy and the like), alkylthio (v / ie methylthio, ethylthio, propylthio and the like), alkanesulfinyl (such as methanesulfinyl, atanesulfinyl, propanesulfinyl and the like), alkanesulfonyl (v / ie mesyl, atanesulfonyl and the like) the like), phenylazo, halogen (v / ie chlorine, bromine, fluorine and the like), cyano, nitro, dialkylamino (v / ie dimethhy 1 ami no, diethylainino and the like) and the like. Preferred examples of one such esters are explained in more detail below: Mono (di- or tri) haloalkyl esters (such as chloromethyl, bromoethyl, dichloromethyl, 2,2,2-trichloroethyl, 2,:. ⁾ , 2-tribromoethyl, 2,2,2-trifluoroethyl ester and the like), cyanoalkyl esters (v / ie cyanomethyl, cyanoethyl esters and the like), cycloalkyl-substituted alkyl esters (such as 1-cyclopropylethyl ester and the like), - ^ ialkylaminoalkyl esters (such as Dinethylaminoäthyl-, Dimethylaminopropylester and the like.) And the like.

For suitable esters that contain an aromatic ring, include, for example, aryl esters (such as Phonyl-, ToIy1-, XyIyI-, Naphthyl-, Indanyl, dihydroanthryl esters and the like); Aralkyl esters (v / ie benzyl, phenethyl esters and the like); Aralkenyl ester (such as cinnamyl ester and the like), aryloxyalkyl esters (such as phenoxymethyl,

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, 27 0 '! i78

Phenoxyethyl, phenoxypropyl esters and the like); Arylthioalkyl esters (such as phenylthiomethyl, phenylthioethyl, phenylthiopropyl esters and the like); Arenesulfynyl] alkyl ester (such as benzenesulfynylmethy.1-, benzenesulfinylethyl ester and the like); Aroy.1-ulkylester (v / ie bensoylmethyl-, toluoylethylester and the like.); and the like. The aromatic ring may optionally have one or more suitable substituents, for example those given above for the aliphatic ester, and in addition alkyl, hydroxy or the like. Preferred examples of one Such substituted esters are halophenyl esters (such as ^ -chlorophenyl, "t> , 5-dibromophenyl, pentachlorophenyl esters and the like.); Halogonphenylalkylesters (such as " j , 4-diculobenzyl esters and the like.); Alkoxyphenyl esters (such as ^ -Methoxyjihenyl esters and the like) .); Alkoxyphonylalkylester (such as ^L v- methoxybenzyl-, 3 / (-, 5-trimethoxybenzyl-, 3, '' (-, ^ -trimethoxyphenylpropylester and the like); ··: - hydroxy-3, 5-di-tert - "butylbenzyl ester, and the like. Suitable heterocyclic ring-containing esters include a heterocyclic ester, a heterocyclic alkyl ester, and the like.

A suitable heterocyclic ester contains a saturated or unsaturated, monocyclic or fused 3 to 10 membered heterocyclic group which has 1 to M heteroatoms such as oxygen, sulfur and nitrogen, and the heterocycle can have one or more suitable substituents have, which are selected from the same group v / ie it has been specified as a substituent for the aliphatic radical and the aromatic ring of the oils mentioned esters. Preferred heterocyclic esters, as defined above, can be a pyridyl ester, picolyl ester, tetrahydropyranyl ester, tetrahydrofuryl ester, quinolyl ester, pyrazolyl ester and the like, and a preferred heterocyclic alkyl ester includes, for example, the above-mentioned alkyl ester substituted by a heterocyclic group (v / ie methyl, ethyl, propyl and the like.), such as pyridylmethyl, furfuryl, 1, 4- Dioxanylmethylester, Pyrrolidinyläthylester, -4- Methylpiperazinyläthylester and the like _o

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27 η ο i 7 8

A suitable ester with an N-hydroxy compound is, for example, an ester with N, N-dialkylhydroxylamine (such as N, N-dimethylhydroxylamine, K, N-diethylhydroxylamine, N, N-dipropylhydroxylamine and the like) and the like the ester with an aldoxime or a cctoxime (v / ie propanalo>: im, butana, oxime, acetoxine, benzophenone oxime, p-bromoacetophenone oxime and the like), the ester with N-hydroxyimide (such as N-hydroxyphthalimide, N-hydroxysuccinimide. and the like), the ester with N-hydroxybenzotriazole (such as 6-chloro-1-h, 7droxotria: ^r , ol and the like) and the like.

The definitions for R '"of the compound (II) and (III) are explained ^{below near] 1,}

a) Substituted ;; Amino includes acylamino, aralkylamines, and the like and is further explained as follows: i) acylamino includes, for example; an aliphatic acylamino aromatic acylamino, an araliphatic acylamino, a heterocyclic acylamino and a heterocyclic-aliphatic Acylamino and acylamino of the formula

wherein Q is O: ry or arylmethylene, X is carbonyl or imino and Z Signify oxo or methylene substituted by aryl or by a heterocycle, or

wherein R is aryl.

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A suitable acyl radical in the acylaniino groups given above are e.g. aliphatic acyl, aromatic acyl, araliphatic acyl, heterocyclic Acyl and heterocyclic aliphatic acyl radicals, which like explained in more detail below:

aliphatic acyl, e.g. alkanoyl (such as formyl, acetyl, propionyl, Butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, lauroyl, palmitoyl, succinyl and the like); Alkenoyl (such as acryloyl, methacryloyl, crotonoyl, isocrotonoyl, Maleoyl and the like);

Alkanesulfonyl (such as mes; v'l, ethanesulfonyl, propanesulfonyl, Butanesulfonyl and the like);

Alkenesulfonyl (w: .e ethylene sulfonyl, propensulfonyl and the like.); Alkoxycarbonyl (such as methoxycarbonyl, ethoxycarbonyl / Ί, propoxycarbonyl, Isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, Pentyloxycarbonyl and the like); Dialkylphosphoryl (v / ie dimethylphosphoryl, diethylphosphoryl, Diisopropylphosphoryl and the like.) And the like.

Aromatic acyl, ζ.Β «, aroyl (such as benzoyl, toluoyl, xyloyl, Naphthoyl, phthaloyl and the like);

Arenesulfonyl (such as benzenesulfonyl, toluenesulfonyl, xylenesulfonyl, Naphthalenesulfonyl and the like); Diarylphosphoryl (such as diphenylphosphoryl and the like) and the like.

Araliphatic acyl, e.g. aralkanoyl (such as phenylacetyl, Tolylacetyl, Xylylacetyl, ITaphthylacetyl, Biphenylylacetyl, Phenylpropionyl, Tolylpro]) ioiiyl, Nuphthylpropionyl, 2-Methyl-3-Phenylpropionyl, 2-methyl - ^ - phenylpropionyl, 2-Mei; hyl-3-naphthylpropionyl, Phenylbutyryl, naphthylbutyryl, phenylvaleryl, tolylvaleryl, naphthylvaleryl, diphenylacetyl, liphenylpropionyl and the like);

Aralkanesulfonyl (such as phenylmesyl, tolylmesyl, naphthylmesyl, Phenylathansulfonyl, Haphthyläthansulfony1, Phonylprop-msulfonyl, Phenylbutanesulfonyl and the like);

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Aralkene sulfonyl (such as phenylabhylenesulfonyl, tolylethylene sulfonyl, Naphthylethylene sulfonyl, phenylpropenesulfonyl, Naphthylpropenesulfonyl, phenylbutensulfonyl and the like); Aralkoxycarbonyl (such as Benz.yloxycarbonyl, Phenüthyloxycarbonyl, Phenylpronoxycarbonyl, benzhydryloxycarbonyl and the like); Diaralkylphosphoryl (such as dibenzylphosphoryl and the like) and the like.

Heterocyclic acyl, e.g. heterocyclic carbonyl, then contains a 'j> - bin 10-membered monocyclic or condensed heterocyclic group with 1 to 4 heteroatoms, consisting of nitrogen, oxygen and sulfur (such as asiridine carbonyl, acetidine carbonyl, pyrrole carbonyl, 2H -P, pyrrolecarbonyl, imidazolecarbonyl, pyrazolecarbonyl, nicotinoyl, isonicotinoyl, pyraziricarbonyl, piperidine carbonyl, piperazincarbonyl, pyrimidinearbonyL, pyridazincarbcnyl, triazolecarbonyl, thiazoline carbonyl, furazirocarbonyl, pyrazoline carbonyl, pyrazoline carbonyl, pyrazyl carbonyl carbonyl, pyrazolyl carbonyl, pyrazolyl carbonyl, pyrazolyl carbonyl, pyrazolyl carbonyl, pyrazine carbonyl, pyrazine carbonyl, then Furazane carbonyl, oxazole carbonyl, isoxazole carbonyl, thiazole carbonyl, thiadiazole carbonyl, oxadiazole carbonyl, indole carbonyl, jj ^ -indole carbonyl, isoindole carbonyl, indolizine carbonyl, IH-indazole carbonyl, ririne carbonyl, benzarbonimidincolecarbonyl, quinine cofonyl carbonyl, isoindole carbonyl, benzoxyline carbonyl, yl, chromene carbonyl, isobenzofuran carbonyl, benzothiphene carbonyl, xanthene carbon;. "- !, benzoxazole carbonyl, benzisoxazole carbonyl, benzothiazole carbonyl and the like);

heterocyclic-aliphatic acyl, e.g., heterocyclinic alkanoyl (such as thienylacetyl, furylacetyl, pyridylacetyl, (i'yridyl-1-oxide) acetyl, pyrrοIyIacetyl, imidazoIylacetyl, Pyrazolylacetyl, Triazolylacetyl, Tebrazol.vlacetyl, Oxazolyl-

acetyl, oxadiazolylacetyl, thiazolylacetyl, thiazolinylacetyl, Thiadiazolylacetyl, Morpholin.ylacetyl, Pyrany Iac etyl, Pyrrolidinylacetyl, pyrrolinylacetyl, benzothieny! Acetyl,

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2 7 Π Π I 7

Benzoxadiazolylacetyl, Benzothiazolylacetyl, Benzoxazolylacetyl, Benzisoxasolylacetyl, Benzotriazolylacetyl, Indolylacetyl, Purinylacetyl, Thionylpropionyl, Furylpropionyl, Pyrid.ylpropionyl, Imidazolylpropionyl, OXaZoIyIPrOPiOnVl ₁ Oxadiazolylpropionyl, Thiazolylpropionyl, thiadiazolylpropionyl, Purinylpropionyl, Indolylpropionyl and the like.).

In the acylamino of formulas (IV) and (V), the suitable aryl for the symbol R and the aryl radical in the definition of the symbols <1 and Z include phenyl, ToIy1, XyIyI, mesityl, naphthyl and del. And to the suitable heterocyclic .chen group in the definition of the symbol Z includes the same heterocyclic radicals as have been given in the explanation of the heterocyclic carbonyl in the acylamino given above.

ii) Suitable aralkylamines include benzylamino, l'henäthylamino, Phenylpropylamino, Diphenylme-hylamino, Tritylamino, Tolylmethylamino, Tolyläthylamino, XyIylmethylamino, Naphthylmethylamino and the like.

b) Suitable halogen includes chlorine, bromine, iodine and the like.

c) A suitable acyl radical in the acyloxy is practically the the same as given above for the acyl radical of the abovementioned acylamino, except for those of the formulas (IV) and (V).

d) Suitable alkoxy include methoxy, ethoxy, propoxy, Isopropoxy, butoxy, isobutoxy, tert-butoxy and the like.

e) Suitable aryloxy includes phenoxy, tolyloxy, xylyloxy, Naphthoxy and the like.

f) Suitable aralkoxy include benzyloxy, phenethyloxy, Phenylpropoxy, phenylbutoxy, diphenylmethoyy, trityloxy, Naphthylmethoxy, tolylmethoxy, tolylethoxy, xylylethoxy and the like

709828/1032

270.178

In addition, the alinatic hydrocarbon radical, the aromatic hydrocarbon radical and the heterocyclic Radical in the substituted amino, acyloxy, alkoxy ·, ·

2 aryloxy, aralkoxy, as indicated above for R, a or have a plurality of suitable substituents selected from those as are more suitable in the description Examples of the substituents in the radical bearing a carboxy group or a derivative thereof for R der Compound (I) and (Hl) are indicated. Additionally can the ali "hatic hydrocarbon radical in that given above Substituted amino green pe have Oxo, Hydroxyiinino or substituted imino, e.g. alkoxyimino (such as methoxyimino, Ethoxyimino, propoxyimino and the like), aryloxyimino (such as phenoxyimino and the like), aralkoxyimino (such as benzyloxyimino, Phenoxyloxyimino and the like), alkoxycarbonylalkoxyimino (such as Athoxycarbonvlmethoxyimino and the like.) and the like.

In these substituents, as stated above, amino, Alkanesulfonamido, hydroxy and carboxy protected, preferably by suitable protecting groups selected from such are as they are given in each of the above-mentioned substituents of the organic radical for R, and Hydroxyimino can also be protected by the same protecting group as given above for hydroxy.

With regard to the reactive derivatives on the carboxy group of compound (II), the following applies:

the "reactive derivative" on the carboxy group includes an acid anhydride, an ester, an acid halide Acid amide, an acid azide, a salt with a base and the like.

Suitable acid anhydrides include a mixed acid anhydride with an acid such as dialkyl phosphoric acid, phenyl phosphoric acid, Dipheny! Phosphoric acid, dibenzyl phosphoric acid,

709828/1032

halogenated phosphoric acid, dialkylphosphorous acid, Sulphurous acid, thiosulphuric acid, hydrohalic acid (such as hydrochloric acid, hydrobromic acid and like), sulfuric acid, monoalkyl carbonate (such as methyl carbonate, ethyl carbonate, propyl carbonate and the like.), an aliphatic Carboxylic acid (such as acetic acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-Ethy! Butyric acid, trichloroacetic acid, trifluoroacetic acid and the like), an aromatic carboxylic acid (such as benzoic acid and the like), or a symmetrical acid anhydride and like

Suitable esters preferably include conventional activated esters, e.g., a substituted alkyl ester (such as Cyanomethyl ester, methoxymethyl ester and the like), alkenyl ester (such as vinyl ester and the like), alkynyl ester (such as propargyl ester and the like), a substituted aryl ester (such as 4- nitrophenyl ester, 2,4-Dinitrophenylester, Trichlorornhenylester etc.), a heterocyclic ester (such as tetrahydropyranyl ester) and others as given for the "derivative of the carboxy group", e.g., an ester with an N-hydroxy compound (such as Ν, Ν-dialkylhydroxylamine, ketoxime, N-hydroxyimide, N-hydroxybenzotriazole and the like.) and the like.

Suitable acid amides preferably include conventional activated amides such as an acid amide with pyrazole, imidazole or 4-substituted m imidazole (such as 4-methylimidazole and the like), and the like

Suitable acid halides include an acid chloride,! ■ acid bromide, Acid iodide and the like.

Suitable salts include a salt with an organic base such as those given below, and a salt with an inorganic base such as an alkali metal salt (such as sodium salt, potassium salt and the like), an alkaline earth metal

709828/1032

Ί ι> :. ', ! 78

metal salt (v; ie calcium salt, magnesium salt and the like) and the like »

Suitable Lewis acids which can be used in the reaction include a halogenated metal or ¹ IU, chtr.otall compound, for example boron trihalide (such as bread trifluoride, boron trichloride, boron tribromide and the like), a complex of the boron trihalide with a solvent an ether compound (e.g., diithyl ether, tetrahydrofuran and the like), an alcohol (such as methanol and the like), a carboxylic acid (such as acetic acid and the like) or the like; an aluminum halide (v / ie aluminum chloride, aluminum chloride: ronide and the like); a zinc halide (such as zinc chloride and the like); a tin (IV) halide (such as tin (IV) chloride and the like); an Eir _J en (III) halide (such as iron (III) chloride and the like); a titanium halide (such as titanium chloride and the like); a silicon tetrarial ogenide (v / ie silicon tetrachloride and the like); a / Uitimonhalo ~ enid (such as antimony chloride and the like.) and the like.

Among the Lewis acids mentioned above is boron trifluoride diethyl etherate the Lewis acid customarily and preferably used according to the invention.

Suitable bases that can be used in the reaction include an organic base such as a trialkylamine (v / ie trimethyla ^ in, triethylamine, tributylamine, and the like) \ an N, N-dialkylaniline (v / ie Ν, Ν -Dimethylaniline, N, N-diethylaniline and the like.); a Ν, Ν-dialkylaralkylamine (such as N, N-Diin ^ thylbenzylamine and the like.); an N-sub :: tituiorte or unsubstituted heterocyclic compound (such as N-methylinorpholine, N-methylpiperidine, pyridine, dinethylaminopyridine, picoline, luthidine, quinoline, 1,5-diazabicyclo [4-.3 .0] -S-nonene, 1 , ^/ <- Diazabic, yclo [2.2.2] octane, 1, 5 -diazabicyclo [5. ^. 0] -5 -undecene and the like) and the like.

The reaction according to the invention can, as a rule, be carried out in one conventional solvents such as dichloromethar, chloroform,

709828/1032

ORIGINAL INSPECTED

Carbon tetrachloride, diethyl ether, tetrahydrofuran, Dioxane, pyridine, Ν, Ν-dinuothylformamide or any Mixture thereof or in any other solvent which does not adversely affect the reaction, be performed.

The reaction temperature is not subject to any restrictions and the reaction is preferably carried out with cooling to ambient temperature.

In the reaction according to the invention, the side reaction indicated below can occasionally occur in the course of the reaction or occur in the aftertreatment, i.e. the carboxy group of the compound (I) or (III) can be converted into the corresponding functional derivatives can be converted or, conversely, the functional derivatives of the carboxyl group of the compound (I) or (10) converted into the carboxyl group or a salt thereof v / earth.

The amino, monosubstituted amino, mercapto and / or hydroxyl group (s) can be acylated with the compound (II) in the above-mentioned substituent in which the radical for R of the compound (I) carries the carboxy group or a derivative thereof corresponding acylamino, N-monosubstituted-N-acylainino, acylthio and / or acyloxy group; or the amino group can be converted into its salt with an acid such as an organic acid (such as formic acid, acetic acid, fumaric acid, maleic acid, p-toluenesulfonic acid and the like) or an inorganic acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like) ; and in addition, all or some of the protected functional groups in R ^ and R _p of Verijfadungen (I) j (II) u. φΐ) are occasionally partially or completely converted into the corresponding unprotected functional group (s) and also the substituted amino, acyloxy, alkoxy, aryloxy and aralkoxy groups of R "of the compound (II) or (III) in

709828/1032

-14 -

the corresponding amino or hydroxyl group (s) are converted will. Of course, the above-mentioned side reaction also falls into the Ra! men of the present invention.

The compound produced by the process of the invention (III) may exist in the form of a mixture of two epimeric stereoisomers because of the asymmetric carbon atom in the:? 3-position of the acetidinone ring and this Mixture can optionally, if necessary, applying conventional separation process into the corresponding Stereoisomers are separated.

The compound (III) is a valuable antibiotic for the treatment of microbial infections in animals and humans and a valuable intermediate for the production of useful antibiotics. That is, the 3-acylamino-2-acetidinone compounds (III) have antimicrobial activities (Efficacies) against various pathogenic microorganisms, such as Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and the like. Furthermore, the 3-phthalimido, 3-azido, 3- (3> ^{/ l} ~ diphenyl-2-oxo-4-oxazolin-3-yl) -2-acetidinone compounds (III) are important intermediates for the preparation of the represent the above-mentioned 3-acylamino-2-acetidinone compounds. That is, the compound (III) can be converted into the 3-amino-2-acetidinone compound and this 3-amino-2-acetidinone compound by a conventional method can then be acylated to form the 3-acylanino-2-acetidinone compound, which has antimicrobial activity (effectiveness) against various pathogenic microorganisms.

The compounds (III) according to the invention can be used for administration be formulated in any suitable way analogous to other antibiotics «,

709828/1032

21 ΰ ·) 178

The pharmaceutical which forms a further subject of the invention Means (preparation) can be in the form of a pharmaceutical preparation, for example in solid, semi-solid or liquid form, used v / earth, which the invention would active compound (s) (III) mixed with a pharmaceutically acceptable organic or inorganic Contains carrier or excipient for external or parenteral use Applications is suitable. The active ingredient (drug) can, for example, with conventional carriers too Tablets, pellets, capsules, suppositories, solutions, emulsions, aqueous suspensions and other forms suitable for therapeutic administration.

Examples of suitable carriers are glucose, lactose, acacia gum, Gelatine, mannitol, starch paste, magncsium trisilicate, Talc, corn starch, keratin, colloidal silicon dioxide, potato starch, Urea and other carriers, such as those for use in the manufacture of preparations in solid, semi-solid or liquid form are suitable, and also auxiliaries, stabilizers, thickeners, colorants and perfumes. The preparations according to the invention can also Preservatives or bacteriostatic agents included, thereby turning the active ingredient (ingredient) into the desired To keep preparations stable with regard to its activity.

The active compound (III) of the present invention is in that of the present invention pharmaceutical agent (preparation) contained in an amount sufficient to affect the bacterial Infection process or state of infection the desired therapeutic To exert an effect. Although the dosage or the therapeutically effective amount of the compound of the invention (III) will generally vary and also depend on the age and condition of the particular individual patient being treated a daily dose of from about 0.5 to about 5, preferably from 1 to 2 g (per day) of the active ingredient (drug) administered.

The invention wildly illustrated by the following examples, but without being limited to it.

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270 ^; i 178

a) Creation of the result ( 1)

Production example 1

A solution of 25.0 g of D-2- (2-thienyl) glycine methyl ester hydrochloride 130 ml of water were mixed with 250 ml of benzene. 120 ml of an aqueous 1N sodium hydroxide solution were added dropwise to this mixture with stirring and while cooling with ice, then 9.9 ml of a 37% strength aqueous formaldehyde solution were added added dropwise. After stirring was continued for a further 2 hours at the same temperature; p; e; -. Et: ', t v / orden, van * de die The benzene layer was separated and the aqueous layer was extracted with ethyl acetate. The extract and the separated benzene layer were combined with each other, washed with water, dried over magnesium sulfate and under reduced pressure evaporated to dryness. The remaining oil was crystallized from diisopropyl ether, 16.5 g of 1,3 »5-tris- [D-1-methoxycarbonyl-1- (2-thienyl) meth.yl] -perhydro-1 , 3,5-triazine.

IR V ^ H ¹ : 1739 cm " ¹

WE 6ppm ^GDC1 3: 3.69 (9Π, s), 3.78 (6H, s), 4-, 89 (3H ₁ s),

6.80 - 7, ^ - J (9H, m)

The compounds given below (preparation examples 2 to 18) were prepared by reacting the corresponding compounds Amino acid derivatives with formaldehyde in practically the same way as in Preparation Example 1 above specified.

Production example 2

1,3, 5-'l RIS ¹ (D-ß-methoxycarbonyl-3-mesylaminobenzyl) -perhydro-1,3,5-triazine.

709828/103?

IR _v liquid film. _{y? r? 0 (wide) j} 3 ^ _{1? 30 cm} -1

Max

KMβ £ ppm ^CDC1 3: 5.08 (3H, s), 3.61 (SH, broad s),

, c), 7.0-7, ^r ; (4H, m), 7.71 (1H, broad s)

Production example 5

1, p ^ - 'J'risCcll-i-nethoxyc-irbonyl-i-Ci-naphLhyDmethyl] -perh.vdro-1, J>, 5-triazine, F. 1-Ί-8 - 1 ^r ; 1 ° C .

Manufacturing example 4-

^{1,3,5-1 1} ^ iSCdI-I -riethoxycarbonyl-2-phenylthioethyl) -perhydro 1,3, S-triazine.

6 ppiir ¹ ^ - ¹ -? : ^; 3.10 - 3, ^ 0 (1SH, m), 3.68 (9H, s),

7.1 - 7.5 (15H, m) production example 5

1,3,5-tris ('4 - benzyloxy-a-methoxycarbonylphenethyl) -perhydro-1,3,5-triazine, 106-109 ° G.

Production example 6

1,3,5-tris (dl-erythro-a-methoxycarbonyl-ß-methoxy-phenethyl) -perhydro-1,3,5-triazine.

Production example 7

1,3,5-Tris [dl-1- (2-furyl) -1-methoxycarbonylmethyl] -perhydro-1,3,5- ^ ri

70982Θ /

-is -

NMR £] <pm ^CDC1 5: 3.5-3.8 (12H, m), 4.74- (!) H, s),

6.28 ceil, m), 7.32 (3H, m)

Herst; ol. "Uin {'; sexample 8

1,3,5-TriG (methoxycarbonylmethyl) -perhydro-1,3,5-triazine. IR v liquid film. ^ ₀ _ ^ _{55 cm} -1

NMR £ ppm ^COC13 3: 3, ^ 8 (6H, s), 3.73 (1 ^ H, s)

Production example 9

1,3,5-tris (ethoxycarbonylmethyl) perhydro-1,3,5-triazine.

^IR ^ ^fl max ^{iger film: 173} ° - " ¹

mfflSppm ^CDG1 3: 1.25 (9H, t, J = 6Hz), 3Λ5 (6H, s),

3.73 (6H, s), 4.17 (6H, q, J = 6Hz)

Production example 10

1,3,5-Tris (benzyloxycarbony! Methyl) -perhydro-1,3,5- briazine.

NMR & ppm ^{GI) G1} 3: 5, ^ (6H, s), 3.69 (6H, s),

5.10 (6H, s), 7.40 (15H, s)

Production example 11

1,3,5-tris (D-a-methoxycarbonylbenzyl) -perhydro-1 »3,5-triazine, 148-155 ° C

709828/1033

270U

^IR> - max

m <IR £ ppm ^{Cr) G1} 3: 3.49 (9H ₁ s), 3.51 (6H ₁ s),

4.50 (1H ₁ s), 7.42 - 6.90 (15H ₁ m)

Production example 12

1,3,5-Tris (D-4-benzyloxy-a-metho: cycarbonylbenzyl) -perhydro-1,3,5-triazine, M.p. 141-145 ° C.

: 1725 cm " ¹

5.04 (6H, s), 6.80 (6H, d, J = 9Hz),

7.29 (6H, d, J = 9Hz), 7, ^ 0 (15H, s) manufacturing example 13

1,3, 5-tris _{(D-4-benzyloxycarbonyloxy-a-i} mothoxycarbon yl-benzyl) -perhydro-1,3,5-triazine.

_{IR v} , liquid film. ^ _Q ^ _{1? 1Q cm} -1 max

LMWH «S ppm ^CDC1 3: 3.50 (15H, s), 4.42 (5H, s),

5.23 (6H, s), 6.99 (6II, d, J = 9Hz), 7.23 (6H, d, J = 9Hz), 7.27 (15H ₁ s)

Manufacturing example 14

1,3,5-tris (dl-2-methoxycarbon, yl-1-phenylethyl) -perhydro-1,3,5-triazine, F. 92-96 ⁰ G

Nujol Max

709828/1032

2 7 ü: j i 7

Production example 15

1,3,5-Tris (4-m ^o thoxycarbon; / l-phenyl) -perhydro-1,3,5-triazine, mp 208-209,5 ° 0 (dec.)

_IR ^ Nujöl. _{1710 cm} -1 max

Production example 16

1,3,5-Tris (Da-benzyloxycarbonylbenzyl) -perhydro-1,3,5-triazine,?. 118 - 119 ⁰ C.

_IR ^ Nu, jol. ₁₇ 3ο, 1740 (shoulder) cm " ¹ max

measured 8ppm ^CDC1 3: 3.57, (6H, s), 4, S2 (3H, s),

4.95 (GH, s), 6.95 - 7.4-5 CoOK ₁ m)

Production example 17

1,3,5-tris (L-α-methoxycarbonyl-3-nitrobenzyl) -perhydro-1,3,5-triazine.

IR ν ^{liquid film} : 1740 cm " ¹ max

KMRSppm ^CDC1 3: 3.65 (15H, broad s), 4.65 (3H, s),

7, ^ 5 - 8.2 (12H, m)

Production example 18

1,3,5-Tris (Da-benzyloxycarb (^ n: ^r l-4-benzyloxybenzyl) -perhydro-1,3,5-triazine, F. 108 - 110 ⁰ G.

709828 /

27ÜUI78

IR \) ^im ^ ^Ui : 1745, 1735, 1720 cm " ¹
Max

ITIvIR S ppm ^CDC1 3: 3.55 (6II, s), 4.47 (3H, s), 4.92 (12H, s),

6.76 (6Ii, d, J-BHz), 7.00 - 7.44 (36H, m)

Preparation example 19

A solution of 9.18 g of N-tert-butoxycarbonyl-2- (4-hydroxyphenyl) g3ycin, 6.86 g of phenacylbroniid and 1.37 g of sodium hydroxide in 100 ml of N, H-dimethylform; :: id was for 4 hours at ambient temperature touched. The roaction mix was made in Pour 500 ml of water and 3 times with SO ml portions each time Ethyl acetate extracted. The combined extract was washed with water, dried over magnesium sulfate and taken under evaporated to dryness under reduced pressure, giving 13.19 g of an oily N-tert-butoxycarbonyl-2- (4-hydroxyphenyl) -glycine phenacyl ester received.

_IRv liquid film. ^ ₀₀ ^^^ I75O, 1710, 1690 cm " ¹ max

A mixture of 3.56 g of the above-prepared N-tert-butoxycarbonyl-2- (4-hydro: <yphenyl) glycine phenylacyl ester, 1.84 g of phenacyl bromide and 1.28 g of potassium carbonate in 71 ml of v / anhydrous acetone was used for 7 hours heated under reflux for a long time. The insoluble substances were filtered off and the filtrate was evaporated to dryness under reduced pressure. The remaining oil was dissolved in chloroform, washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was triturated with diisopropyl ether, 4.12 g of crystalline N-tert-butoxycarbonyl-2- (4-phenacyloxyphenyl) glycinepher) ylacyl ester, which was recrystallized from ethanol to give the pure compound, mp 125 - 126.5 ⁰ G.

709828/103?

"^" 270U178

■ II '

To a solution of 1.0 g of N-tert-butoxycarbonyl-2- (4-phenacyloxyphenyl) glycine pheny] .acy] .ester in 10 ml of ethyl acetate, 2 ml of a mixture of hydrobromic acid and acetic acid (volume ratio 4: 1) were added and then the mixture was stirred for 1/2 hour at ambient temperature. The precipitates were collected by filtration and washed with ethyl acetate to give 830 mg of 2- (4-phenacyloxyphenyl) glycine phenylacyl ester hydrobromide, which was recrystallized from an ethanol / methanol / diethyl ether mixture to give 550 mg of pure crystals, mp 176 177 ⁰ C

9.5 g of 2- (4-Phenacyloxyphenyl) glycinphenacylesterhydrobromids was mixed with 6 ml of a 57 ^r - aqueous formaldehyde solution in substantially the same \ 7eise implemented as indicated in the Preparation Example 1 to obtain 7.25 S ^ »3.5 -Tris- (4-phenacyloxy-a-phenacyloxycarbonylbenzyl) perhydro-1,3,5-triazine received, F. 80 to 90 ⁰ C.

HMR <$ ppm ^GDC1 3: 3.70 (6H, s), 4.65 (3H, s),

5.19 (6H, s), 5.23 (6H, s), 6.86-8.04 (M2H, m).

709828/1032

27 0 ο] 78

■ b) Preparation of the compound (III) according to the invention example 1

To a solution of 1,3 ^ 6 2-phthalimidoacetyl chloride in 20 ml of dichloromethane, a solution of 4-80 mg of pyridine in 2 ml of dichloromethane was added dropwise over the course of 6 minutes with stirring at -35 to -30 ° C. and stirring was continued for a further 15 minutes continued for a long time at the same temperature. After cooling down to about -60 to -55 C, a mixture of 4-30 mg boron trifluoride diethyl etherate and ^m S 1,315-tris (D-tl-methoxycarbonylbenzyl) perhydro-1,3,5-triazine in 10 was added to this mixture ml of dichloromethane were added dropwise over the course of 14 minutes. Stirring was continued for further 3 hours at the same temperature and stirring was continued for 20 minutes under ice-cooling, then the reaction mixture was evaporated to dryness under reduced pressure. The residue was treated with a mixture of 30 ml of ethyl acetate and 30 ml of water and the insoluble materials were filtered off. The ethyl acetate layer was separated, washed successively with dilute hydrochloric acid, an aqueous sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The oily residue (1.3 ^ g) was subjected to column chromatography on silica gel (15 g) and eluted with chloroform to give 850 mg of oily methyl-D-2- (2-oxo-3-phthalimido-1-acetidinyl) - 2-phenyl acetate was obtained, which was identified as a mixture of the two epimeric isomers (a) and (b) (mixing ratio 8: 1) in the 3-position of the acetidinone ring by determination by NMR spectrometry.

NMR j ppm ^CDC1 3:

709828/1032

ί_ι. 2 7 G O i 7 8

• V \ '

Isomeres_ (_a) isomeres _ (b_)

3.46 (1H, q, J = 3Hz, 5Hz) 3.60 (1H, t, J = 5Hz)

3.83 (3H, s) 3.83 (3H, s)

3.94 (1H, t, J = 5Hz) 4.10 (1H, q, J = 3Hz,

5.48 (1H, q, J = 3Hz, 5Hz) 5.3 ^ (1H, q, J = 3Hz,

5.78 (1H ₁ s) 5.72 (1H, s)

7.38 (5H, s) 7.36 (5H, s)

7.57-7.96 (4H, m) 7.57-7.96 (4H, m)

Example 2

To a cold solution of 0.53 ^ g 1,3,5-tris (benzyloxycarbonylmethyl) perhydro-1,3,5-triazine in 15 ml of dichloromethane 0.430 g Bortrifluoriddiäthylätherat were added dropwise at -40 ⁰ C and the mixture was half Stirred for hour at the same temperature. Separated it became one
cold solution of 1.34 g of 2-phthalimidoacetyl chloride in 15 ml of dichloromethane a solution of 0.480 g of pyridine in 5 ml of dichloromethane was added dropwise with stirring at -35 to -30 ° G, and
stirring was continued for 15 minutes at the same temperature and then this mixture was increased with stirring
-60 ⁰ C cooled down. To the latter solution, the mixture at -60 ⁰ C prepared above, first mentioned was added dropwise. After stirring for 1 hour at the same
Temperature was continued, the reaction temperature was gradually increased to -5 to 0 C over 2 hours with stirring. The reaction mixture was washed successively with dilute hydrochloric acid, water, a 5% aqueous solution of sodium bicarbonate and water, dried over magnesium sulfate and reduced under reduced pressure

709828/1032

Evaporated to dryness to give an oily residue (1.4 g). The oil was subjected to column chromatography on silica gel (30 g), eluted with chloroform and crystallized in diethyl ether, a mixture of the two epimeric isomers in the 3-position of the acetidine ring of benzyl-2- (2-oxo-3-phthalimido- 1-acetidinyl) acetate (190 mg), P. 120 to 122 ⁰ C, received.

IR yNujol. _178Oi 1750, 1730, 1710 cm " ¹ NMR 6ppm ^{CI) C1} 3: 3.81-3.94 (2H, m)

5.08, 5.36 (2H, AB-q, J = 18Hz)

5.19 (2H, s)

5.50, 5.54 (1H, d, d, J = 2Hz, 4Hz)

7.37 (5H, s)

7.68 - 7.92 (4H, m)

Example 3

2.53 g of 1,3 »5-tris- (D-cX-methoxycarbonyl-3-mesylaminobenzyl) -perhydro-1,3,5-triazine were dissolved in 30 ml of dichloromethane and 1.36 g of boron trifluoride diethyl etherate were added dropwise to the solution and the mixture was allowed to stand for 15 minutes at ambient temperature. Separately, a mixture of 1.48 g of pyridine in 8 ml of dichloromethane was added dropwise to a solution of 8.38 g of 2-Fhthalimidoacetylchlorid in 55 ml of dichloromethane in about 7 minutes with stirring at -35 to -30 ⁰ C and the mixture was further Stirred for 13 minutes at the same temperature. After cooling down to -60 ° C., the above-prepared, first-mentioned solution was added dropwise to this solution over the course of 15 minutes. The mixture was stirred for 2 hours at -67 to -60 ^{0 C and}

709828/103?

- > - 2 7 OO! 7 3

then it was stirred for another half hour while cooling with ice. The reaction mixture was evaporated to dryness under reduced pressure and the oily residue was chromatographed on silica gel in the same manner as in Example 2, yielding 0.99 g of crystals of methyl-D-2- £ 3- (N-mesyl-2 -phthalimidoacetamido) phenyl] -2- (2-oxo-3-phthalimido-1-azetidinyl) -acetate, m.p. 127-132 ⁰ C were obtained. IR y ^Nu Ö ^o1 : 1? 80 (shoulder), 1770, 1730, 1720 cm " ¹

Max

NMR OPpm ^CDC1 3: 3.57 (3H, s)

3.74 (1H, m)

3.85 (3H, s)

4.03 (1H, t, J = 6Hz)

4.22 (2H, s)

5.5 ^ (IH, d, d, J = 6Hz,

5.93 (1H, s)

7.60 (12H, m)

Example 4

To a cold solution of 0.67 6 2-phthalimidoacetyl chloride in 10 ml of dichloromethane, a mixture of 0.24 g of pyridine and 1 ml of dichloromethane was ^{added dropwise at -35 to -3O 0} C within 6 minutes and the mixture was for 14 minutes at stirred at the same temperature. After cooling down to -60 ⁰ C. To this solution, a mixture of 0.425 g of 1,3,5-tris (D-4-benzyloxy-.alpha.-methoxycarbonylbenzyl) perhydro-1,3,5-triazine and 0.22 g Bortrifluoriddiäthylätherat in 5 ml of dichloromethane was added dropwise over 15 minutes and the mixture was kept at the same temperature for 2 hours

709828/103?

stirred, then it was stirred for another half hour while cooling with ice. The reaction mixture was evaporated to dryness under reduced pressure and the residue was treated with a mixture of 20 ml of ethyl acetate and 20 ml of v / water. The ethyl acetate layer was separated and the remaining aqueous solution was extracted with 20 ml of ethyl acetate. The ethyl acetate layer and the ethyl acetate extract were combined, washed three times with dilute hydrochloric acid, three times with an aqueous sodium bicarbonate solution and then once with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure to give an oily residue (0.80 g) . The oil was subjected to column chromatography on silica gel (20 g) and eluted with chloroform, an oily mixture of the two epimeric isomers (a) and (b) (mixing ratio 5: 1) in the 3-position of the acetidine ring of methyl-D -2- (4-benzyloxyphenyl) -2- (2-oxo-3-phthalimido-1-acetidinyl) acetate (550 mg). IR vilÜ ^{SSisser Film} : 1780, 1760, 1740, 1720 cm " ¹

Ul 9th X

NMR appm ^CDC1 3:

Isomere_s (j &) Isomeres (b)

3.42 (1H, d, d, J = 2.5Hz, 6Hz) 3.66 (1H, t, J = 6Hz)

3.78 (3H, s) 3.78 (3H ₁ s)

3.90 (1H, t, J = 6Hz) 4.06 (1H, d, d, J = 2.5Hz, 6Hz)

5.01 (2H, s) 4.97 (2H, s)

5.06 (1H, d, d, J = 2.5Hz, 6Hz) 5.32 (1H, d, d, J = 2.5Hz, 6Hz)

5.72 (1H, s) 5.65 (IH, s)

7.00 (2H, d, J = 9Hz) 6.98 (2H, d, J = 9Hz)

7.33 (2H, d, J = 9Hz) 7.35 (2H ₁ d, J = 9Hz)

709828/1032

7.37 (5H, s) 7.37 (5H, s)

7.70 (4H, m) 7.70 (4H, m)

Example 5

To a cold solution of 0.67 g of 2-phthalimidoacetyl chloride in 10 ml of dichloromethane, a solution of 0.24 g of pyridine in 1 ml of dichloromethane was added dropwise at -35 to -30 ° C. over the course of 4 minutes and the mixture was stirred for 15 minutes stirred at the same temperature. To this solution a mixture of 480 mg of 1,3,5-tris (D-4-benzyloxycarbonyIoxy- OL-methoxycarbonylbenzyl) perhydro-1,3,5-triazine and 0.22 was after cooling to -60 ⁰ C g Boron trifluoride diethyl etherate in 5 ml dichloromethane was added dropwise over the course of 15 minutes, after which the mixture was stirred for a further 3 hours at the same temperature and then for half an hour while cooling with ice. The reaction mixture was evaporated to dryness under reduced pressure and the residue was treated with a mixture of 20 ml of ethyl acetate and 20 ml of water. The ethyl acetate layer was separated and the remaining aqueous solution was extracted with 10 ml of ethyl acetate. The extract and the ethyl acetate layer were combined, washed three times with dilute hydrochloric acid, three times with an aqueous sodium bicarbonate solution and once with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was subjected to column chromatography on silica gel (20 g) and eluted with chloroform, an oily mixture of the two epimeric isomers (a) and (b) (mixing ratio 3: 1) in the 3-position of the acetidine ring of methyl-D -2- (4-benzyloxycarbonyloxyphenyl) -2- (2-oxo-3-phthalimido-1-acetidinyl) acetate (290 mg) received

709828/1032

27 0-.J 1 7 8

IR ν liquid film.

-1

Max

NMR 4ppm ^CDC13 :

I_sqmeres_ (a_2_ Isojneres (b)

3.49 (1H, d, d, J = 2.5Hz, 6Hz) 3.75 (1H, t, J = 2.5Hz, 6Hz) 3.94 (1H, t, J = 6Hz) 3.88 (3H, s)

5.28 (2H, s) 5.28 (2H, s)

5.50 (1H, d, d, J-2.5Hz, 6Hz) 5.35 (IH, d, d, J = 2.5Hz, 6Hz) 5.80 (1H, s) -5.75 (1H, s)

7.10 - 8.05 (13H, m) 7.10 - 8.05 O3H, m)

Example 6

10.72 g of 2-phthalimidoacetyl chloride were dissolved in 160 ml of dichloromethane and cooled to -35 to -30 ° C. To this cold solution, a mixture of 3.84 g of pyridine in 24 ml of dichloromethane was added dropwise over 7 minutes, and then the mixture was stirred for 15 minutes at the same temperature. To this solution, after cooling to -60 ⁰ C a mixture of 4.60 g of 1,3,5-TΓis- (D, L-2-metho: xycarbonyl-1-phenylethyl) perhydro-1, 3,5- triazine and 3.44 g of boron trifluoride diethyl etherate in AO ml of dichloromethane were added dropwise over the course of 20 minutes and the mixture was stirred for a further 2 hours at the same temperature and then stirred for a further half an hour while cooling with ice. The reaction mixture was evaporated to dryness under reduced pressure and the residue was treated with a mixture of 100 ml of ethyl acetate and 100 ml of water. The ethyl acetate layer was separated, successively with dilute hydrochloric acid, an aqueous sodium bicarbonate solution and

709828/1032

Washed with water, dried over magnesium sulphate and evaporated to dryness under reduced pressure. The residue was subjected to column chromatography on silica gel (200 g) and eluted with chloroform to give an oily mixture of the two epimeric isomers (a) and (b) (mixing ratio about 1: 1) in the 3-position of the acetidine ring of Methyl D, L-3- (2-oxo-3-phthalimido-1-acetidinyl) -3-phenylpropionate (5.06 g) was obtained. This product (100 mg) was triturated with ethanol to give a crystalline mixture of two epimeric isomers (a) and (b) (mixing ratio about 2: 1) in the 3-position of the acetidine ring (60 mg), F. to 153 ° C.

^IR V? "J ^o1 : 1760, 1745, 1715 cm" ¹

Example 7

To a cold solution of 7 ^ 0-N Benzyloxycarbonylglycylchlorid mg in 20 ml dichloromethane was added dropwise to -30 ⁰ C a solution of 480 mg of pyridine in 2 ml dichloromethane within 4 minutes at -35 and the mixture was I5 minutes at the same Temperature stirred. A solution of 530 mg of 1,3,5-TΓis- (D-ol.-metho: xycaΓbonylbenzyl) perhydro-1,3,5-triazine and 430 mg of boron trifluoride diethyl etherate in 10 ml of dichloromethane was added to this solution within minutes at -65 to -6O ⁰ C was added dropwise, then the mixture was stirred for 3 hours at the same temperature and then for 15 minutes while cooling with ice. The reaction mixture was evaporated to dryness under reduced pressure and the residue was dissolved in ethyl acetate. The solution was washed successively with dilute hydrochloric acid, an aqueous sodium bicarbonate solution and water, dried over magnesium sulfate and then under reduced pressure

709828/1032

Pressure evaporated to dryness. The residue (0.42 g) was subjected to column chromatography on silica gel (10 g), and eluted with chloroform. The eluate was evaporated under reduced pressure, leaving an oily mixture of the two epimeric isomers in the 3-position of the acetidine ring of methyl-D-2- (3-benzylocycarbonylamino-2-oxo-1-acetidinyl) -2-phenyl acetate (I30 mg) received.

-1

^{IR v} ^ Ü ^{SSiSer Film} : 3300, 1740, 1720, 1710 cm

Example 8

720 mg of 2-azidoacetyl chloride were dissolved in 22 ml of dichloromethane. To the solution, a solution of 480 mg of pyridine in ml of dichloromethane was added dropwise over 3 minutes at -35 to -30 ⁰ C and the mixture was stirred I7 minutes at the same temperature. A solution of 530 mg of 1,3,5-tris (D-oL-methoxycarbonylbenzyl) perhydro-1,3 »5-triazine and 430 mg of boron trifluoride diethyl etherate in 10 ml of dichloromethane was added to this solution within 16 minutes at -35 to - 30 ° C added dropwise. The mixture was stirred for 1 hour at the same temperature and then for half an hour under ice-cooling. The reaction mixture was evaporated to dryness under reduced pressure. To the residue thus obtained, 30 ml of diethyl ether and 30 ml of water were added, and the mixture was stirred for a while. The diethyl ether layer was separated, washed successively with a dilute hydrochloric acid, an aqueous bicarbonate solution and water, dried over magnesium sulfate and then evaporated to dryness under reduced pressure. The residue (0.64 g) was subjected to column chromatography on silica gel (20 g) and eluted with chloroform, and the eluate was evaporated under reduced pressure to give an oily

709828/1032

Mixture of the two epimeric isomers (a) and (b) (mixing ratio about 3: 1) in the 3-position of the acetidine ring of methyl-D-2- (3-azido-2-oxo-1-acetidinyl) -2-phenyl acetate (313 mg) received.

IR liquid film. _{2080i Λ? 60} ^ _{730 cm} -1

NMR «ippm ^{CI) C1} 3:

Isojneres_ £ a_) Isomei'es (b)

2.93 (IH, q, J = 2Hz, 6Hz) 3.26 - 3.76 (2H, m)

3.73 (3H, s) 3.80 (3H, s)

3.86 (1H, t, J = 6Hz) 4.50 (IH, q, J = 2Hz,

4.63 (IH, q, J = 2Hz, 6Hz) 5.60 (1H, s)

5.56 (1H, s) 7.33 (5H, s)

7.28 (5H, s)

Example 9

65Ο mg of ethyl chloroformate were added at -5 ° C to a suspension of 1.23 g of 2-phthalimidoacetic acid, 606 mg of triethylamine and 2 drops of Ν, Ν-dimethylbenzylamine in 20 ml of dichloromethane. The mixture was stirred at the same temperature for 25 minutes, then 480 mg of pyridine were added at -6O ⁰ C to the mixture. A solution of 53Ο mg of 1,3,5-tris (D- CL- methoxycarbonylbenzyl) perhydro-1,3,5-triazine and 430 mg of boron trifluoride diethyl etherate in 10 ml of dichloromethane was added to this solution over the course of 10 minutes at the same temperature . The mixture was stirred for 20 minutes at -60 ° C. and then for a further 3 hours with ice-cooling. The reaction mixture was evaporated to dryness under reduced pressure to give the residue thereby obtained

709828/1032

ethyl acetate and water were added. The insoluble materials were filtered off from the solution and the filtrate was stirred for a while. The ethyl acetate layer was separated, washed successively with dilute hydrochloric acid, an aqueous sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue (85O mg) became one Was subjected to column chromatography on silica gel (15 g), eluted with chloroform, and the eluate was reduced under reduced pressure Evaporated pressure, leaving an oily mixture of the two epimeric isomers (a) and (b) in the 3-position of the acetidine ring from methyl D-2- (2-oxo-3-phthalimido-1-acetidinyl) -2-phenyl acetate (20 rag).

NME <ippm ^CDG1 3:

Isomeres_ (a) _ Isomeres, (JpJ

3.46 (1H, q, J = 3Hz, 5Hz) 3.60 (1H, t, J = 5Hz) 3.83 (3H, s) 3.83 (3H, s)

3.94 (1H, t, J = 5Hz) 4.10 (1H, q, J = 3Hz, 5Hz)

5.48 (1H, q, J = 3Hz, 5Hz) 5.34 (1H, q, J = 3Hz, 5Hz) 5.78 (1H, s) 5.72 (1H, s)

7.38 (5H, s) 7.36 (5H, s)

7.57-7.96 (4H, m) 7.57-7.96 (4H, m)

Example 10

1.23 g of 2-phthalimidoacetic acid were dissolved in 10 ml of dichloromethane suspended, and 1.26 g of 2,2,2-trifluoroacetic anhydride were added to the suspension was added dropwise, and then the mixture was allowed to stand for 10 minutes. Became the solution

709828/1032

27-Γ: 173

600 mg of triethylamine were added and the mixture was stirred for 20 minutes at ambient temperature. Pyridine and a solution of 530 mg of 1,3,5-TΓis- (D- '■ iL-metho:} cycarbonylbenzyl) perhydro-1,3,5-triazine and 4-30 mg of boron trifluoride diethyl etherate in 10 ml of dichloromethane were added to this solution added dropwise ^{at -60 0} C within 10 minutes. The mixture was stirred for 1.5 hours at the same temperature and for another half hour at 5 ° C. The reaction mixture was evaporated to dryness under reduced pressure, and 50 ml of ethyl acetate and 30 ml of water were added to the residue thus obtained. The insoluble materials were filtered off and the filtrate was stirred for a while. The ethyl acetate layer was separated, washed successively with dilute hydrochloric acid, an aqueous sodium bicarbonate solution and water, dried over magnesium sulfate and then evaporated to dryness under reduced pressure. The residue (700 mg) was subjected to column chromatography on silica gel (30 g) and eluted in chloroform. The eluate was evaporated under reduced pressure, leaving an oily mixture of the two epimeric isomers (a) and (b) in the 3-position of the acetidine ring of methyl-D-2- (2-oxo-3-phthalimido-1-acetidinyl ) -2-phenyl acetate (80! Img) was obtained.

NMR 4ppm ^CDC13 :

Isomeres_ (a_) Isomeres_Cb)

3.46 (1H, q, J = 3Hz, 5Hz) 3.60 (IH, t, J = 5Hz)

3.83 (3H, s) 3.83 (3H, s)

3.9 ^ (1H, t, J = 5Hz) 4.10 (1H, q, J = 3Hz, 5Hz)

5.48 (1H, q, J = 3Hz, 5Hz) 5.34 (IH, q, J = 3Hz,

5.78 (1H, s) 5.72 (1H, s)

709828/1032

²⁷ ° ^{u '78}

7.38 (5H, s) 7.36 (5H, s)

ΊΪΊ - 7.96 (4H, m) 7.5 7 - 7.96 (411, m)

Example 11

5.38 g of 2-Phthalimidoacet: / lchlorid were dissolved in 80 ml of dichloromethane and to the solution 1.92 g of pyridine in 8 ml of dichloromethane were added dropwise within 16 minutes at -35 to -30 ⁰ C. The mixture was stirred for 4 minutes at the same temperature. To the above prepared solution was within 40 fdnuten at -60 ⁰ C a solution of 3.04 g of 1,3 '5-tris (D oi. -Benzyloxycarbonylbenzyl) perhydro-1,3,5-triazine and 1, 72 g of boron trifluoride diethyl etherate in 40 ml of dichloromethane were added dropwise. The mixture was stirred for 2 hours at the same temperature and then for half an hour under ice-cooling. The reaction mixture was evaporated to dryness under reduced pressure, and water and ethyl acetate were added to the residue thereby obtained. The insoluble materials in the mixture were filtered off. The ethyl acetate layer was separated from the filtrate, washed with dilute hydrochloric acid and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then evaporated under reduced pressure. The residue (7.55 g) was subjected to column chromatography on silica gel (250 g), eluted with chloroform and the eluate was evaporated under reduced pressure to give an oily mixture of the two epimeric isomers (a) and (b) (mixing ratio about 3: 1) in the 3-position of the acetidine ring of benzyl-D-2- (2-oxo-3-phthalitrido-1-acetidinyl) -2-pyryl acetate (3.46 g).

NMR ippm ^CDC1 3:

709828/1032

27 ) j i 7 8

I ^ £ tneres_ (a_) isomer ej »(b)

3.42 (1H, d, d, J-3HZ, 6Hz) 3.59 (IH, t, J = 6Hz)

3.93 (IH, t, J * 6Hz) 4.11 (1H ₁ d, d, J = 3Hz, 6Hz)

5.27 (2H, s) 5.28 (2H, s)

5.53 (1H, d, d, J = 3Hz, 6Hz) 5.32 (1H, m)

5.90 (1H, s) 5.82 (1H, s)

7.38 (5H, s) 7.25 - 7.45 (1OH, m)

7.44 (5H, s) 7.65-7.90 (4H, m)

7.7 - 7.9 (4H, m)

Example 12

1.88 g of 2- (2-0xo-4,5-diphenyl-4-oxazolin-3-yl) acetyl chloride were dissolved in 20 ml of dichloromethane and to the solution was added a solution of 480 mg of pyridine in 2 ml dichloromethane within 4 Added dropwise at -35 to -30 ° C for minutes. The mixture was stirred for 15 minutes at the same temperature. To this solution, a solution of 530 mg of 1,3,5-tris (D- qlmethoxycarbonylbenzyl) perhydro-1,3,5-triazine and 430 mg Bortrifluoriddiäthylätherat in 10 ml dichloromethane was added within 15 minutes at -60 ⁰ C. The mixture was stirred for 2 hours at the same temperature and then for half an hour under ice-cooling. The reaction mixture was evaporated to dryness under reduced pressure. To the residue was added a mixture of 30 ml of ethyl acetate and water, and the mixture was stirred for a while. The ethyl acetate layer was separated, washed twice with 1% hydrochloric acid, twice with a 1% aqueous sodium bicarbonate solution and once with water, dried over magnesium sulfate and then under reduced pressure

709828/1032

- «- - 27Q-Ji 78

evaporated to dryness. The residue was subjected to column chromatography subjected to silica gel (25 g) and eluted with chloroform. The eluate was taken under reduced pressure evaporated to dryness, leaving an amorphous mixture of the two epimeric isomers (a) and (b) (mixing ratio about 5 to 4: 1) in the 3-position of the acetidine ring of Methyl-D-2- [2-oxo-3- (2-oxo-4,5-diphenyl-4-oxazolin-3-yl) -1-acetidinyl] -2-phenyl acetate (1.09 g) was obtained.

" ¹

^{IK v} max ^{: 1 - 6} ° ^cm

NMR <$ ppm ^{CI) C1} 3:

Isqmeres _ (_ a) Isomerej; _ (b)

3.47 (1H, d, d, J = 2.5Hz, 6Hz) 3.48 (1H, t, J = 6Hz)

3.72 (3H, s) 3.72 (3H, s)

3.76 (1H, t, J = 6Hz) 4.11 (1H, d, d, J = 2.5Hz, 6Hz)

4.91 (1H, d, d, J = 2.5Hz, 6Hz) 4.78 (1H, d, d, J = 2.5Hz, 6Hz)

5.56 (1H, s) 5.50 (1H, s)

6.88 - 7.60 (I5H, m) 6.88 - 7.60 (I5H, m)

Example I3

A mixture of the two epimeric isomers (a) and (b) (mixing ratio about 3: 2) of methyl D, L-2- (2-oxo-3-phthalimido-1-acetidinyl) -3-phenylthiopropionate (1.22 g) was prepared by reacting 5.40 g of 1,3,5-tris (D, L-1-methoxycarbonyl-2-phenylthioethyl) perhydro-1,3,5-triazine with 11 »56 g of 2-phthalimidoacetyl chloride in the presence of 7.32 g Boron trifluoride diethyl etherate and 8.18 g pyridine to practically in the same manner as in Example 10.

709828/103?

IR V ^ j ⁰¹ : 1785, 1770, 1735, 1715 cm " ¹

LU CiJt

NMR 6 ppm ^CDCl 3:

Isiomares _ (a) Isomeres, (b)

3.1 - 3.9 OH, m) 3.1 - 3.9 OH, m)

3.76 (3H, s) 3.76 (3H, s)

4.64 (1H, d, d, J = 8.5, 5 Hz) 4.64 (1H, d, d, J = 8.5, 5 Hz)

5.20 (1H, d, d, J = 6, 3Hz) 5OO (1H, t, J = 6Hz)

7.30 (5H, m) 7.30 (5H, m)

7.70 (4H, m) 7.70 (4H, m)

Example 14

A mixture of the two epimeric isomers of methyl-D, L-2- (1-naphthyl) -2- (2-oxo-3-phthalimido-1-acetidinyl) acetate (3.13 g) was prepared by reacting 4, 00 g of 1,3,5-TΓis [D, L-1-methoxycaΓbonyl-1- (1-naphthyl) methyl] perhydro-1,3,5-triazine with 2.50 g of 2-phthalimidoacetyl chloride in the presence of 2.50 g boron trifluoride diethyl etherate and 2.78 g pyridine in practically the same manner as indicated in Example 10. The compound thus obtained was pulverized with diethyl ether, and the powder thus obtained (2.10 g) was recrystallized from ethanol to give one of the two isomers of the desired compound, mp 200.5 to 201.5 ⁰ C.

" ¹

IR V max ^{: 1724} ', 1740, 1750, 1782 cm'

NMR 4ppm ^CDC13 : 3.16 (1H, d, d, J = 6.3Hz)

3.80 (3H, s)
3.89 (1H, t, J = 6Hz)

709828/103?

5.50 (1H, d, d, J = 6, 3Hz)

6.45 (1H, s)

7.3 - 8.3 (7H, m)

Example 15

A mixture of the two epimeric isomers (a) and (b) (mixing ratio about 3 = 2) of methyl-D, L-erythro-3-methoxy-3-phenyl-2- (2-oxo-3-phthalimido-1- acetidinyl) propionate (6.73 g) was obtained by reacting 6.66 g of 1,3,5-tris (D, L-erythro-cL-methoxycarbonyl- β- methoxyphenethyl) perhydro-1,3,5-triazine with 13.45 S 2-phthalimidoacetyl chloride in the presence of 4.25 g boron trifluoride diethyl etherate and 4.74 g pyridine in practically the same manner as in Example 10 indicated. The compound thus obtained was pulverized with diethyl ether to give 3.05 g of the isomer (a) received, F. I50 to 155 ⁰ C.

^{Ir V} max ^{O1: 1? 85} (shoulder), 1760, 1735, 1715 cm " ¹ NMR ippm ^{CI> C1} 3

Isomej? Es_ £ a) lsojneres_0))

3.24 (3H, s) 3.36 (3H, s)

3.86 (3H, s) 3.68 0H, s)

4.56 (1H, d, J = 8Hz) 4.71 (1H, d, J = 6Hz)

4.84 (1H, d, J = SHz) 4.95 (IH, d, J = 6Hz)

5.08 (1H, d, d, J = 3.6Hz) 5.38 (1H, d, d, J = 6.4Hz)

7.37 (5H, s) 7.40 (5H, s)

7.6 - 7.8 (4H, m) 7.60 - 7.9 (4H, m)

709828/10 ^ 2

-So-

Example 16

A mixture of the two epimeric isomers of methyl-D, L-3- (4-benzyloxy phenyl) -2- (2-oxo-3-phthalimido-1-acetidinyl) propionate (4.95 g) was obtained by reacting 9.0 g of 1,3,5-tris- (D, L-OL-methoxycarbony 1-4-benzyloxyphenethyl) perhydro-1,3,5-triazine and 13.5 g of 2-phthalimidoacetyl chloride in the presence of 4.3 g of boron trifluoride diethyl etherate and 4.7 g of pyridine actually the same way as indicated in Example 10.

: 1780, 1760, 1738, 1705 cm " ¹

Example 17

A solution of 480 mg of pyridine in 2 ml of dichloromethane was added to a solution of 1.34 g of 2-phthalimidoacetyl chloride in 20 ml of dichloromethane was added dropwise over the course of 15 minutes at -35 to -30.degree. A solution of 550 mg of 1,3,5-tris [b-1 - (2-thienyl) -1-methoxycarbonylmethyljperhydro-1,3,5-triazine was added to the solution and 430 mg of boron trifluoride diethyl etherate in 10 ml of dichloromethene added dropwise within 15 minutes at -60 ° C. The mixture was kept at the same temperature for 2 hours and then stirred for half an hour while cooling with ice. The reaction mixture became dry under reduced pressure evaporated. Into the residue thus obtained, 30 ml of ethyl acetate and 30 ml of water were poured, and the insoluble materials were poured were filtered off. The ethyl acetate layer was separated from the piltrate and the remaining aqueous Layer was extracted with ethyl acetate. The extract was combined with the ethyl acetate layer, three times with dilute Hydrochloric acid, three times with an aqueous sodium bicarbonate solution and washed once with water, dried over magnesium sulfate and then under reduced pressure

709828/1032

27 0 0) 78 -54 '

evaporated. The residue was subjected to column chromatography on silica gel (20 g) and eluted with chloroform. The eluate was evaporated under reduced pressure to give an oily mixture of the two isomers of methyl D-2- (2-oxo-3-phthalimido-1-acetidinyl) -2- (2-thienyl) acetate (720 mg) . The compound obtained in this way was recrystallized from ethanol, one of the two epimeric isomers (300 mg) being obtained, mp 167 "to 170 ^° C.

Example 18

A mixture of the two epimeric isomers (a) and (b) (mixing ratio about 1: 1) of methyl D-2- (3-azido-2-oxo-1-acetidinyl) -2- (2-thienyl) acetate (3 * 4-1 g) was prepared by reacting 7i8 g of 1,3,5-TrisLD-1-methoxycarbonyl-1- (2-thienyl) methyi3 perhydro-1,3,5-triazine with 10.1 g of 2-azidoacetyl chloride in the presence of 6.10 g of boron trifluoride diethyl etherate and 6.73 g of pyridine in much the same manner as reported in Example 17.

NMR ^ ppm ^{CI) C1} 3:

Isomeres_ (ja) Isgmeres_ (b)

3.17 (IH, d, d, J = 2.5, 6Hz) 3.60 (2H, m)

3.80 (3H, s) 3.82 (3H, s)

3.95 OH, t, J-6Hz) ^, 53 (IH, d, d, J = 2.5, 6Hz)

4.70 (1H, d, d, J = 2.5, 6Hz) 5.87 (IH, s)

5.88 (1H, s) 7.05 (2H, m)

7.05 (2H, m) 7.26 (1H, m)

7.26 (1H, m)

709828/1 032

"27GU 178

-5 λ-

Example 19

A mixture of the two epimeric isomers (a) and (b) (mixing ratio about 2: 1) of methyl-D-2-L2-oxo-3- (2-oxo-4,5-diphenyl-4-oxazolin-3-yl) -1-acetidinyr] -2- (2-thienyl) -acetate (1.86 g) was prepared by reacting 1.10 g of 1,3,5-Tris fD-1-methoxycarbonyl-1- (2-thienyl) methyl] perhydro-1,3,5-triazine with 3.96 g of 2- (2-0xo-4, 5-diphenyl-4-oxazolin-3-yl) acetyl chloride in the presence of 860 mg of boron trifluoride diethyl etherate and 960 mg of pyridine in practically the same manner as indicated in Example 17.

NMR ^ ppm ^CDC1 3:

Isomejres __ ( &) Isomeres_ (b)

3.67 (111, d, d, J = 2.5, 6Hz) 3.60 (1H, t, J = 6Hz)

3.76 (3H, s) 5.80 OH, s)

3.84 (1H, t, J = 6Hz) 4.08 (1H, d, d, J = 2.5, 6Hz)

4.92 (1H, d, d, J = 2.5, 6Hz) 4.80 (1H, d, d, J = 2.5, 6Hz)

5.82 (1H, s) 5.78 (1H, s)

6.88 - 7.62 (13H, m) 6.88 - 7.62 (13H, m)

Example 20

A mixture of the two epimeric isomers (a) and (b) (mixing ratio about 2: 1) of phenocyl -D-2- (2-oxo-3-phthaliraido-1-acetidinyl) -2- (4-phenacyloxyphenyl) acetate (830 mg) was obtained by reacting 1.24 g of 1,3,5-Tris- (oL phenacyloxycarbonyl-4-phcnacyloxybenzyl) perhydro-1,3,5-triazine with 1,3 ^ g of 2-phthalimidoacetyl chloride in the presence of 1.55 g of boron trifluoride diethyl etherate and 1.11 g of pyridine in a manner similar to that given in Example 10.

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IR _w ^fl üssiger film. ^ ₇₈₀ ( _sh ) <] ₇₆ ο ^ ^ ₇₂ O, 1700, 1680

(sh) cm "

NMR a _P pm ^CDCl 3

Isome re s __ (a ^ I_some re_s_ (b}

3.43 (1H ₁ d, d, J = 3Hz, 5Hz) 3.55 (IH, t, J = 5Hz)

3.82 (1H, t, J = 5Hz) 4.06 (1H, d, d, J = 3Hz, 5Hz)

5.30-5.5 ^ (5H, m) 5.30-5.5 ^ (5H, m)

Example 21

A mixture of the two epimeric isomers (a) and (b) (mixing ratio about 4: 1) of methyl-dl-2- (2-furyl) -2- (2-oxo-3-phthalimido-1-acetidinyl) acetate ( 1.44 g, mp 1? 6-178 ⁰ C) was obtained by reacting 4.05 g of 1,3,5-tris- (oL-methoxycarbonyl-2-furfuryl) perhydro-1,3,5-triazine with 10.8 g of 2-phthalimidoacetyl chloride in the presence of 3 * 44 g of boron trifluoride diethyl etherate and 3.81 g of pyridine in practically the same manner as in Example 10.

" ¹

^{IR V} üa ^ ^01: ^ 77O (sh), 1760, 1730, 1710 cm

QIoIjC

NMR jppm ^CDC1 3: Isomeres_ (a}

3.64 (1H, d, d, J = 3Hz, 6Hz)

3.80 (3H, s)

4.02 (1H, t, J = 6Hz)

5.52 (1H, d, d, J = 3Hz, 6Hz)

5.84 (1H, s)

6.44 (1H, m)

6.56 (1H, d, J = 4Hz)

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7.47 (1H, d, J = 3Hz)
7.77 (4H, ω)

Example 22

A mixture of the two epimeric isomers (a) and (b) of benzyl D-2- (3-azido-2-oxo-1-acetidinyl) -2- (4-benzyloxyphenyl) "acetate (1.10 g) was made obtained by reacting 1,35 1,3,5-tris (cx -benzyloxycarbonyl - ^ - benzyloxybenzyl) perhydro-1,3,5-triazine with 890 mg of 2-azidoacetyl chloride in the presence of 800 mg of boron trifluoride diethyl etherate and 750 mg of pyridine similar manner to that given in Example 10. IR ^ _a ^ ^{SSiser Film} : 2100, 1765, 1735 cm ^-1

NMR ^ ppm ^CDC13

Isomeres_ (j_) Isomeres (b)

2.94 (1H, d, d, J = 2Hz, 5Hz) 3.35 (1H, t, J = 5Hz)

3.84 (1H, t, J = 5Hz) 3.56 (1H, d, d, J = 2Hz, 5Hz)

4.62 (1H, d, d, J = 2Hz, 5Hz) 4.46 (1H, d, d, J = 2Hz, 5Hz)

5.03 (2H, s) 5.03 (2H, s)

5.13 (2H, s) 5.18 (2H, s)

5.61 (1H, s) 5.58 (1H, s)

7.09 (4H, AB-q, J = 8Hz) 7.09 (4H, AB-q, J = 8Hz)

7.12 - 7.56 (1OH, m) 7.12 - 7.56 (1OH, m)

Example 23

A mixture of the two epimeric isomers (a) and (b)

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(Mixing ratio about 5 = 2) of benzyl-dl-2- (3-benzyloxy-2-oxo-1-acetidinyl) -2-phenyl acetate (530 mg) was obtained by reacting 1.52 g of 1,3,5-triε- (D-o ^ .- benzyloxycarbonylbenzyl) perhydro-1,3,5-triazine with 2.21 g of benzyloxyacetyl chloride in the presence of 860 mg of boron trifluoride diethyl etherate and 960 mg of pyridine in a manner similar to that given in Example 10.

_IR liquid film. _{1? 60 1? 4 <) cm} -1 max ''

NMR oppm ^CDC1 3:

! Isomeres _ £ a) Isomeres (b)

3.18 (1H, d, d, J = 4Hz, 5Hz) 3.52 (1H, d, d, J = 4Hz, 5Hz)

4.02 (1H, d, d, J = 5Hz, 6Hz) 3.78 (1H, d, d, J = 2Hz, 4Hz)

5.17 (4H, s) 5.12 (1H, d, d, J = 2Hz, 6Hz)

5.27 (1H, d, d, J = 2Hz, 5Hz) 5.17 (^ H, s)

5.75 (IH, s) 5.72 (1H, s)

6.8 - 7.4 (15H, m) 6.8 - 7.4 (I5H, m)

Example 24

A mixture of the two epimeric isomers (a) and (b) (mixing ratio about 1: 1) of methyl D-2- (3-phenoxy-2-oxo-1-acetidinyl) -2-pheny] acetate (730 mg) was obtained by reacting 1.06 g of 1, 3, 5-1 ¹ ris- (o - methoxycarbonylbenzyl) -perhydro-1,3,5-triazine with 2.05 g of phenoxyecetyl chloride in the presence of 685 mg of boron trifluoride diethyl etherate and 950 mg Pyridine in practically the same manner as indicated in Example 10.

_IR liquid film. ^ _{17 Λ} ^ -Λ max

7Q9a? 8 / irn?

NMR 4ppm ^CDC13 :

Is qme re s __ (a) .1 s oni ere s_ (b)

3.15 (1H, d, d, J = 2Hz, 6Hz) 3.52 (1H, d, d, J = 5Hz, 6Hz)

3.70 (3H, s) 3.70 (3H, s)

5.28 (1H, d, d, J = 2Hz, 5Hz) 5.06 (1H, d, d, J = 2Hz, 5Hz)

5.67 CH, s) 5.63 (IH, s)

6.3-7.4 (1OH, m) 6.8-7.4 (1OH, m)

Example 25

A mixture of the two epimeric isomers (a) and (b) (mixing ratio about 1: 1) of methyl D-2- (3-chloro-2-oxo-1-acetidinyl) -2-phenyl acetate (200 mg) was obtained by reaction from 1.06 g of 1,3,5-tris- (D-ci-niethoxycarbonylbenzyl) -perhydro-1,3,5-triazine with 1.36 g of chloroacetyl chloride in the presence of 685 mg of boron trifluoride diethyl etherate and 950 mg Pyridine in practically the same way as given in Example.

IR v ^ ^üssi 6 ^{er Filffi} : 1770 (wide), 174O ctn " ¹ max

NMR ^ ppm ^CDC1 3:

Is_omere_s_ (a.)

3.14 (1H, d, d, J = 2Hz, 6Hz) 3.60 (1H, t, J = 6Hz)

3.75 (3H, s) 3.78 (3H, s)

4.81 (1H, d, d, J = 2Hz, 5Hz) 4.77 (1H, d, d, J = 2Hz, 6Hz)

5.64 (1H, s) 5.61 (1H, s)

7.2 - 7.5 (5H, m) 7.2 - 7.5 (5H, m)

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Example 26

A mixture of the two epimeric isomers of methyl D-2- (3-diethylphosphorylamino-2-oxo-1-acetidinyl) -2-phenyl acetate (60 mg) was obtained by reacting 530 mg of 1,3,5-Tris (a methoxycarbonylbenzyl) perhydro-1,3,5-triazine with diethylphosphorylaminoacetyl chloride, which had been prepared from 1.27 g of the corresponding acid, in the presence of 430 mg Boron trifluoride diethyl etherate and 480 mg of fyridine to practically the same procedure as given in Example 10.

-1

IR v5oii ^{SSieer film:} 3 ^ 5O, 1750, 1710, 1270 cm

NMR ei ppm ^CDC1 3: 1.28 (3H ₁ t, J = 7Hz)

3.75 (3H, s)

3.78 - 4.31 (6H, m)

4.98 (1H, m)

5.99 (1H, s) 7.32 (5H, m)

Example 27

A mixture of the two epimeric isomers (a) and (b) of benzyl-D-2- (4-benzy_oxyphenyl) -2- (2-oxo-3-phthalimido-1-acetidinyl) acetate (6.68 g) was obtained by reacting 5.40 g of 1 ^^ - tris-ioL-benzyloxycarbonyl - ^ - benzyloxybenzyl) -perhydro-1,3,5-triazine with 6.70 g of 2-phthalimidoacetyl chloride in the presence of 2.15 g of boron trifluoride diethyl etherate and 2.40 B Pyridine in practically the same manner as in Example 10 indicated. The resulting mixture became a mixture recrystallized from diethyl ether and ethanol and then

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was recrystallized from ethanol to give isomer (a), mp 127 to 128 ° E. The mother liquor former was concentrated under reduced pressure and the residue was recrystallized from a mixture of a small amount of ethanol and Diäthylather and then from ethanol to give the isomer (b), F. I05 to 107.5 ⁰ C.

Isomeres_ ^ a)

NMR (ippm ^CDC1 3: 3.40 (1H, d, d, J = 4.5Hz, 2.5Hz)

3.89 (1H, t, J = 4.5Hz)

5.02 (2H, s)

5.21 (2H, s)

5.47 (1H, d, d, J = 4.5Hz, 2.5Hz)

5.79 (1H, s)

6.92 - 7.52 (14H ₁ m)

7.56 - 7.90 (4H, m)

Isomers_s

NMR <sppm ^CDC1 3: 3.55 (1H, t, J = 4.5Hz)

4.05 (1H, d, d, J = 4.5Hz, 2.5Hz)

5.02 (2H, s)

5.24 (2H, s)

5.31 OH, d, d, J = 4.5Hz, 2.5Hz)

5.70 (1H, s)

6.89 - 7.50 (14H, m)

7.60 - 7.94 (4H, m)

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Example 28

A mixture of the two epimeric isomers (a) and (b) of benzyl D-2- (4-benzyloxycarbonyloxyphenyl) -2- (2-oxo-3-phthalimido-1-acetidinyl) acetate (1.41 g) was obtained by reacting 1.21 g of 1,3,5-Tx ¹ IS- (ol-benzyloxycarbonyl-4-benzyloxycarbonylcxybenzyl) perhydro-1,3,5-triazine with 1.34 g of 2-phthalimidoacetyl chloride in the presence of 850 mg of boron trifluoride diethyl ether and 720 mg of l'yridine in practically the same manner as indicated in Example 10.

TR. Liquid film. _{1? 80} ,.> _{1? 65} ^ ₇₅₀ , _h) max λ

cm"

NMR 6 ppm ^CDCl 3:

Isomer (a) Isomer Cb)

3.41 (1H, d, d, J = 2.5Hz, 3.63 (1H, t, J = 5.5Hz)

3.89 (1H, t, J = 5.5Hz) 4.14 (1H, d, d, J = 2.5Hz, 5.5Hz)

5.23 (2H, s) 5.31 (4H, s)

5.24 (2H, s) 5.42 (1H, d, d, J = 2.5Hz, 5.5Hz)

5.48 (1H, d, d, J = 2.5Hz, 5.90 (1H, s)

5.5Hz)

5.86 (1H, s) 7.06 - 7.52 (14H, m)

7.06 - 7.52 (14H, m) 7.72 (4H, m) 7.72 (4H, m)

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Claims (7)

Claims Process for the preparation of a 1, jj-disubstituted Acetidinonn of the general formula v ² - CH -CH ₀ where R is an organic radical which is a carbo :: y group or a derivative thereof, and R ^ "carries azido, substituted Mean amino, halogen, acyloxy, alkoxy, aryloxy or aralkoxy, characterized in that one uses a Meth.ylenamine compound the general formula ^CII 2 i
NR ¹ Jn 1
wherein R has the meanings given above and η is an integer from Λ to 3, with a compound of the general formula R ² - GH ₀ - COOK (II) C- 2
wherein R has the meanings given above, or a reactive derivative thereof reacts at the carboxy function in the presence of a Lewis acid and a base. 2. The method according to claim 1, characterized in that a compound of the formula (I) is used, v / orin η the Number 3 means. 709828/1032 'ORIGINAL INSPECTED 27 0 ·. "; Ϊ78 3. The method according to claim 1 or 2, characterized in that that the Lewis acid is a complex of boron trihalide with a solvent consisting of an ether compound bes t; eht, used. 4-O method according to claim ;;, characterized in that boron trifluoride diethyl etherate is used as the Lewis acid. 5. The method according to one of claims 1 to ^L \ , characterized in that an organic base is used as the base. 6. The method according to claim ^, characterized in that is used as the base PyrLdin. 7. Pharmaceutical agent, characterized in that it as an active ingredient (active ingredient) at least one compound of the formula (III) given in claim 1, if appropriate together with a pharmaceutically acceptable carrier and / or Thinner. 709828/1032 ORIGINAL INSPECTED