DE2126277A1 - Method for protecting amino groups - Google Patents

Description

CIBA-GEIGY Άϋ -BkSKL (SCHWKIZ)

'I-7352 / 7GC6

Method for estimating amino groups.

The discovery of the valuable properties of the α-Am in benzyl-penicillin, the ampicillin. ¹ ", has led-to-an intensive suoiie after other ataino-iicylderlvaten of the penicillin and Ceph * - l'dsporin-series (FP Doyle pt al", J, Chcr.i. Soc. 14 * 10). In the synthesis of these compounds it is often ti} .clcrlieh, functional groups that protect the ^ n xu. The splitting off dor ßchut z & rxippet: n'tch runr; ytoi'on dor "T.:ibiJ.itUi.

109852/1031

Penain and Cephatn frameworks only under very mild conditions take place. Although some reasonably useful protecting groups for Are available, none of the known groups can fully satisfy, either because it is difficult to split off, requires relatively harsh conditions or long periods of Heactlon, or but so easily goes on that the groups become an undesirable one Point in time, e.g. when carrying out a course the reaction necessary for the synthesis.

It has now been found that the 2-iodo-thoxycarbonyl group does not have these disadvantages. This group can be at can be split off under very mild conditions and a short reaction time, with only a small amount of by-products being formed and hone

Yields can be obtained. The cleavage of the related 2 ^, 2,2-trichloroethoxycarbonyl group on the other hand, requires significantly longer reaction times, which is reflected in the formation of side pro-

*
In addition, the more labile ß'-iodoethoxy carbonyl group has the great advantage that it does not have to be present during the synthesis process, but only in the last step from a more stable, analogous protecting group ρ, for example the 2-bromoethoxycarbonyl group can be formed. This fact makes it possible to work with the synthesis at best under relatively sharp conditions, without therefore the disadvantages of a not easily split off.

1139852/1331

: ■ · BAD ORIGINAL

The invention accordingly provides a process for the preparation of o-aoylamino-penam-J-carboxylic acid and 7-acyiamino-eephem-M-carboxylic acid compounds in which the acyl radical is derived from a carboxylic acid and substituted by a free amino group, characterized in that that one treats the corresponding 64 ( S-iodoethoxycarbonylamino) -acylaminoJ-pena »-> - carboxylic acid * compounds« »(Ia) and 7-i (ö-Jodäthoxyearbonylamino) -acylamino] -cephero-A-carboxylic acid compounds (Ib) with chemical reducing agents .

When the 2-Jodäthoxycarbonylgruppe from the o-aoylaniino-penanj-carboxylic acid or 7-acylamino-cephem-4-cabonic acid compounds mentioned treatment with a chemical reducing agent becomes primarily reducing Metals, or metal compounds such as metal alloys or amalgams, advantageously in the presence of hydrogen-releasing agents which, together with the metals, Metal alloys or amalgams generate nasal hydrogen. Sole agents are in particular zinc, as well as zinc alloy processes, e.g. zinc copper, or zinc algaro, the acids advantageously in the presence of acidic agents, in particular optionally water, such as organic carboxylic acids, e.g. lower alkanoic acids, such as Acetic acid, e.g. 90% aqueous acetic acid, and also atonium chloride or pyridine hydrochloride, or from AlkQliolon, viie Niederalkanolosn, z.D. Muthanoi or Aethunol ", if necessary; In the presence of acid, has been used

109852/1931

BATH ORIGINAL

Magnesium, furthermore alkali metal amalgarn yarn, "e.g. sodium or Potassium amalgam, or aluminum amalgam, the preferred in the presence of a moist solvent such as Aether or Lower alkanols, as well as strongly reducing metal salts, such as Chrcm-II connections, si, B. Chroni-JI-chlorici odor Chrora-Ilaeetat, which especially in the presence of aqueous media «Will end. If the reduction is carried out in an aqueous medium through, it is preferred to use water-miscible organic solvents, such as lower alkanols, lower alkanecarboxylic acids or ethers, e.g. methanol, Aethanl, acetic acid, tetrahydrofuran, Dioxane, ethylene glycol dimethyl ether, ethylene glycol dimethyl ether, Dimethylformamide or acetone, too.

Hit the phrase "down" here as well as in the following such aliphatic compounds and iost; 2, e.g. Alkanols, alkanaic acid, alkyl radicals and derived from these Oruppeni such as alkoxy radicals, which contain up to 7 and preferably 1-4 carbon atoms.

The preferred embodiment of the new method uses zinc, zinc-copper or zinc amalgam in the presence of Methanol or aqueous, e.g. 90% acetic acid.

The reaction is usually conducted in the presence of at least one mole of water, and under mild conditions, for example at room temperature or even under refrigeration, for example bej temperatures of about -10 C to about +) ÖC, if desired, in eiuF-r Inert Gun, like. ", lickstoffatmoephüre, Dlfe Erlindufi /? Ci;« 2mU5s used 6- /

- or y-

109862/1931

BATH

Genes in which the Aoyirert is derived from a carboxylic acid and substituted by a 2-iodo-thoxycarbonylaininogruppe (Ia III Ib), can be obtained by converting the corresponding 6-i (2-X-Ae thoxycarbony! amino) ».acylamino j- penam-5-carbonsäVreverbindungen (Ila) or T-fi ^ - 'X-AethoxyearbonylatrinQ) - »cylemlnol-cephem - ^ - cmrboniJiur" compounds (XIb) -, wherein X is an iodine vertohleden "reactively esterified hydroxyl group" TEHT t X exchanged for a Jodatoe.

A reactive esterified hydroxyl group X let as a precaution a "hydroxyl group" esterified with a strong inorganic or organic acid gegebenenfalls'substituierte benzenesulfonic acids such as m-NAtrobenzolsulfonsäuro, p-örombenzolsulfonsäuren p-nitrobenzene sulfonic acid or p-toluenesulfonic acid, "The _# preferred meaning of X is a bromine atom _r

The exchange of the radical X to an iodine atom in the compounds Ha and Hb can be carried out in conventional manner, vB *, a suitable Uisungßetlttels by reacting with a suitable iodine salt, in particular an alkali metal iodide such as lithium iodide or Katrium-, in (leßVTwnri, insbenondere ei nee Orßaniuchen solvent in which the iodine salt, zH Nntriumode? r lithium iodld, c «t soluble and dos ciiLuteliondo iittla doa l«? ofccß X _t z, \ U Mati'iumhromid, only echw.rl "»: sUc! i iiu .. Mv.

BAD OBiGtNM.

Solvent ' αΧηά ε.Β. Acetone, ethyl-methylkeVon, Icopropyl-nie & hyl-keton - .. and dimethylformamide should be mentioned.

In accordance with what has been said above, the subject matter of the invention is also a process for the production of 6-Aeylajnlno-penam-J-carboric acid or T-aylamino-cephßm - ^ - carbonic acid compounds in which the ayl radical is removed from a carboxylic acid ur.d is substituted by an aminogrop ", characterized in that in the corresponding 6-f (2-X-Aethoxycar- 'bonylaroi.no) -acyla! ainoj - pönam-5 *'<!arbon3iurev" irbinduncsn (JIa ) or 7- { (2-X-Aethoxycarbonyla «ino) -acyljuriine | ~ c'fcp} iem ~ 4-carboxylic acid compounds (XIb), where X has meaning given above and is in particular for a BrosÄtoe, X exchanged for an iodine atom and the obtained 6 "l (2" iodine ethoxy carbonylamino) -aoylayninol-penam - ^ - carbonelureverbindungen (Ia) or 7- [(2-Jcdäthoxycftrbonylamino) -acylainino] -cephem-> 4-carbonaMureverbindungen (Xb) after or treated with chemical reducing agents without isolation.

Since the 2-X-ethoxycarbonyl radical, apart from the reducing agents mentioned, must be inert towards the reagents commonly used in 6-aminopencim-jj-carboxylic acid and T-amino-cephem- ^ - carboxylic acid chemistry, the compounds can be used ha and Hb the various "dcn-nrtigsten reactions performed warden without si the _IAE! .1 aogruppe affected bent or cohtltzende vf-X Aothoxyc.arbonylrcot is cleaved U?" bil "herwolco iUJirt now ßowUnüChten \) Ui? .Al2un ~>

BUILDING

g-en nut don connections 11a and lib through urfd blldot the connections Ia and Ib through exchange of X ge ^ cn iodine only immediately before treatment with reducing agents.

The invention also relates to "those" embodiments of the process, according to which one obtainable as an intermediate product at any stage of the process Connection goes out and the missing procedure 3 steps are carried out, or aas process is terminated at any stage, or in which a starting material under the reaction conditions forms, or in which a reaction component where appropriate is in the form of their salts.

The output used in the process according to the invention compounds Ia and Ib or Ha and Hb are preferred 6- [(2-X '-Aethoxycarbonylamina) -acylaminoJ-penam -> - Cftrt> on acid compounds the formula

(O) _n

R ₁ -HN

j N ^ "5

⁰ COOR.

(HIa),

ßiturc compound of the formula

(Uli.)

10S852 / 1931

BATH ORIGINAL

and 7- [(2-X ¹ -Aethoxycarbonylarnino) -acylamino] -ceph - ^ - em - ^ - carboxylic acid compounds of the formula

(I lic),

COOR
ο

wherein η is 0 or 1, R is hydrogen, together with the -C (= 0) -0 grouping an easily cleavable, esterified carboxyl group or together with R ^ a methylene group, R denotes the acyl radical is a cyclically substituted Niederallcansäur-e, those on a non-aromatic carbon atom are as follows 2-X'-ethoxycarbonylamino group, denoted by R, of the formula -

-NH - CO - OCH ₂ - CH ₂ X '(IV)

j Rp and R independently represent hydrogen or methyl groups, R ^ represents hydrogen or an optionally substituted hydrocarbon radical and, together with R, can represent a methylene group and X ^{1 represents} the radical X defined above or an iodine atom.

The lower alkanoic acid of the radical R is e.g. cyclically substituted butyric or propionic acid, especially but acetic or formic acid.

109852/193 1

The cyclic substituent of the lower alkanoic acids

can be saturated or unsaturated and more cycloaliphatic or of an aromatic nature coin. KingkohlenstctfTatoiiie of such cyclic substituents can be replaced by heteroatoms, such as Sulfur, oxygen or nitrogen atoms.

Cyclic substituents of cycloaliphatic nature are in particular optionally by lower alkyl radicals, Substituted Cyeloaltey residues with 5-8 and <3, preferably 5, 6 or 7 ring carbon atoms, such as cyclopentyl, cyclohexyl, Cyclohexadienyl or cycloheptatrienyl radicals.

Lower alkyl radicals are, in particular methyl, ethyl, n-propyl or isopropyl, or straight or branched, bound in any position butyl, pentyl, hexyl heptyl odez ^1, for example, n- or tert. Butyl residues.

Cyclic substituents of an aromatic nature are optionally substituted, carbo- or heterocyclic, preferably monoeyclic radicals, such as pyridyl, puryl and especially phenyl and thiehyl radicals.

Substituents of the cyclic aromatic radicals mentioned are, for example, lower alkyl radicals, such as those given above, lower alkoxy radicals, especially methoxy, ethoxy, n-propoxy or isopropoxy radicals, halogen atoms, e.g. fluorine, chlorine or Bromate atoms, triflucromethyl groups, nitro groups, cyano groups or hydroxyl groups. The substitution can be one, two or more, Preferred substituents of the cyclic aroma

10 9852/1931

■ table radicals are hydroxy, methoxy, nitro and lower alkyl, e.g. tert. Butylp; rupperi, as well as chlorine atoms.

The 2-X'-ethoxycarbonylamino group R is preferred

wise in the α-position of the acyl radical R * but it can also alternatively

titer positions and x »B- are on a phenyl group, especially in the para position, or on a methyl group which substitutes a phenyl radical and is preferably in the para position.

_{^ The acyl radicals R 7} contained in the compounds of the formulas Illa-c are preferably aR thienylacetyl radicals, optionally substituted aR phenylacetyl radicals as indicated above, optionally lower alkylated, e.g. methylated 1-R ^ cyclohexyl or 1-R cyclopentylcarbonyl radicals or p- (R -

X X X

Methyl) phenylacetyl radicals.

Particularly noteworthy here are those a- R -phenylacetyl _{radicals 3} in which the phenyl radical is unsubstituted or a rn-chlorophenyl , m-hydroxyphenyl, para-hydroxyphenyl, "p-nitrophenyl, p-tert. Butylphenyl, p-methoxyphenyl" -j ^ -Chlor- ^ - hydroxyphenyl-, p-cyanophenyl-, o-butylphenyl- or ^ is.

The radical R is preferably one of the known ^

: "uiii protection of Cixi'uoyijlgrnppen usable, hydrolytically, reductively or photolytically cleavable groups represent» The remainder P. kap.ii rj.B »be a SiIy 1- and ßannylrest, which preferably by aliphatic carbon / hydrogen residues, especially lower ylgroupsn, sB »the obsn mentioned ^ is substituted before

109852/1931

BATH ORIGINAL

especially the trimethylsilyl radical, and by treatment with agents containing hydroxyl groups, for example. Water or lower alkanols, such as methanol, are split off.

R can also stand for a radical which can be split off by acid hydrolysis, for example with formic or trifluoroacetic acid, such as a tert. Lower alkyl, for example t-butyl or t-pentyl radical, the 1-adamantyl radical, or a suitably substituted "benzyl radical, for example the benzhydryl or 2- (4-biphenylyl) -2-propyl radical or one in the phenyl ring by lower alkoxy groups, eg Methoxy groups substituted Behzylrest, such as the 4-Methoxybenzyl- or the j>, 4-Dimethoxybenzylrest. Furthermore, the 2-Tetrahydropyranyl- and the 2 _i } -dihydro-2-pyranylrest and corresponding Sehwefei analogs should be mentioned initially also in acid-stable, unsaturated form, such as 5-methyl-5-buten-(1) -yl or 5-methyl-> butyn- (1) -yl radical Acids can be converted into a saturated form.

R can also be used for a weakly basic Be o

conditions that can be split off, in particular one through electron-withdrawing groups substituted hydrocarbons of irrest, such as a nitrophenyl, e.g. 4-nitrophonyl or 2,4-DinJtrophenyl, lHtrophenylniodoralicyl-, e.g. 4-Ni.trobr-riKyl-, or polyhalophenyl, e.g. 2,4,6-trichlorophenyl or 2,5, 4,5,6-Pentachlorphonyl-, or a Cyanrnothylrost .., odor oii.cn Acylaminomethyl, e.g. phthaliminomethyl or uuecinylirnlno-

10 9 8 5 2/1931

methyl radical.

The group R _Q can also represent a radical which can be split off under physiological conditions, primarily a methyl radical substituted by an acyloxy group , in which the acyl radical is e.g. the remainder of an organic carboxylic acid or a carbonic acid half derivative, in particular a lower alkanoyl, e.g. acetyl, propenyl, pivaloyi or 2-ethylhexoyl, or an optionally substituted benzoyl, phenylacetyl or 4-1soxazolyl carbonyl, e.g. 3, 5-dimethyl-4-isoxazolylcarbonyl radical.

A radical R which can be split off by reduction is, for example, a 2-haloalkyl, in particular 2-haloethyl group, especially the 2,2,2-trichloroethyl or 2-iodoethyl group, which can be split off as described above. The 2-iodoethyl group can also be formed first, for example from the 2-bromoethyl group, preferably at the same time as X is exchanged for iodine in the amino protective group. The cleavage of the 2-iodoethoxycarbonyl group expediently takes place simultaneously with the cleavage according to the invention of the amino protective group.

A radical which can be split off by reduction is also an arylcarbonylmethyl group, in particular an optionally substituted phenacyl group, which can be split off, for example when treating with chemical reducing agents under neutral or weakly acidic conditions, for example when treating with zinc in the presence of aqueous acetic acid.

10 9 8 5 2/1931

A radical R which can be split off reductively is in particular also a radical which can be split off by hydrogenolysis, in particular a at most lower alkoxylated a-aryl-lower alkyl radical, e.g. the benzyl, 4-methoxybenzyl, benzhydryl or 4,4'-methoxybonzhydryl radical.

The radical R can also represent an aryl methyl group, in particular a preferably substituted benzyl radical,

which can be split off on irradiation, preferably with ultraviolet light, under neutral or acidic conditions. Such a Reet B «nthSlt all substituents dös aryl, preferably phenyl, in particular lower alkoxy groups, e.g. methoxy, and / or especially nitro groups and is, for example, 3- or 4-methoxybenzyl, 3'5-dimethoxy-benzyl, 2- Nitrobenzyl or 4,5-dimethoxy-2-nitro-benzyl or 4-nitrobenzyl radical. An optionally substituted hydrocarbon radical Rk is above all an optionally substituted methyl group, for example a formyl group or a methyl group substituted by a radical Hl , a radical R /. is, for example, an optionally functionally modified, such as etherified or esterified hydroxyl or mercapto group. But the rest of Ri can also be an azido or cyano group, an optionally esterified carboxyl group, a suitable, in particular, aromatic-substituted amino group, an-optionally substituted Pyridinlurngruppe or V.'fiKserstofi ^1-tasting, via a carbon atom bound residue of a

109852/1931

organic C-nucleophilic compound.

An etherified hydroxy or "mercapto" group is x.B. one with an aliphatic, optionally substituted, or in particular a fully or partially saturated or preferably aromatic, carbo- or especially heterocyclic radical etherified hydroxyl or mercapto group.

An esterified hydroxyl or mercapto group is, for example, a hydroxyl or mercapto group esterified with a carboxylic acid, such as an aliphatic, cycloaliphatic, araliphatic, aromatic, heterocyclischaliphatic or heterocyclic carboxylic acid, or with a carbonic acid derivative . In these acids, the oxo group can also be replaced by an imino or thioxo group. The hydroxyl group substituting for the methyl group can also be one by inorganic acids, for example mineral acids, for example phosphoric acid or, preferably, hydrohalic acids, Ä.B. Hydrochloric or hydrobromic acid-esterified hydroxyl group.

An aromatically substituted amino group is in particular one by a carbocyclic, e.g. di- or preferably monocyclic ^ aromatic radical substituted amino group.

The acid component of the esterified hydroxyl groups (acyloxy groups) and mercapto groups R ^ is preferably a carboxylic acid of the formula Rc-COOH, in which R ₁ . has one of the following meanings:

109852/1931

Hydrogen, alkyl radicals, preferably lower alkyl radicals, for example the stated alkenyl, in particular lower alkenyl radicals, e.g. vinyl, allyl or methallyl radicals, preferably lower alkynyl radicals, such as propargyl radicals, if appropriate by lower alkyl radicals substituted cycloalkyl radicals with in particular 5-8 ring members, especially cyclopentyl, Cyclohexyl or cycloheptyl radicals, corresponding cycloalkenyl radicals, especially 1-cyclohexenyl radicals, cycloalkyl-alkyl, cycloalkyl-alkenyl, Cycloalkenyl-alkyl and cycloalkenyl-alkenyl radicals, which above all contain the residues listed above, Arylalkyl and arylalkenyl radicals, in particular l'henylnio-

deralkyl and phenyl lower alkenyl radicals, poly-, bi- and monocyclic Aryl residues, primarily phenyl residues, heterocyclylalkyl - and alkenyl radicals in which the heterocycle has a bi- or, preferably, monocyclic, saturated, partially unsaturated or an aromatic radical with preferably 5 or 6 members, the one, two, three or more heteroatoms, such as Oxygen, nitrogen or sulfur atoms, as well as heterocyclic radicals, e.g. those just described.

The radicals mentioned can be further substituted on carbon atoms of an aliphatic character - i.e. non-aromatic carbon atoms - e.g. by halogen atoms, such as fluorine, chlorine, bromine or iodine atoms, hydroxyl groups, etherified hydroxyl or mercapto groups, acyloxy groups, Amino groups, acyl, such as lower alkanoyl or benzoyl groups, Carbamoyl-sulfamoyl and cyano groups.

109 852/1931

. - ιβ -

Aromatic, cartto- or heterocyclic rings in the radical R ₁ . can also be substituted, for example by lower alkyl groups, halogen atoms, lower alkoxy groups, trifluoromethyl, acyloxy, acylamino, amino, sulfamoyl or cyano groups.

Carbonic acid derivatives are, for example, carbonic acid halide derivatives, in which the alcoholic component is preferably aliphatic in nature, e.g. a lower alkyl radical, or nitrogen-containing carbonic acid derivatives, such as carbamic acid derivatives and thiocarbamic acid derivatives, and also urea and thiourea derivatives, which are via the oxygen or. Sulfur atom are bound. In the hydroxyl groups esterified with these carbonic acid derivatives, the nitrogen atoms can carry substituents, for example the radicals given as the meaning of R, - and in particular those of these radicals which are aliphatic in character and, as further substituents, halogen atoms, hydroxy groups, lower alkoxy, lower alkyl, thio, lower alkoxycarbonyl, Carbamoyl or cyano groups.

Contains an etherified hydroxy or mercapto group preferably one of those described above under Rp., -von.Wasserstoff various leftovers.

Preferred meanings of these radicals are nitrogen-containing, preferably 5-membered, heterocyclic radicals, such as, for example, optionally substituted triazolyl, tetrazolyl, thiadiazolyl or oxadiazolyl radicals. · Aromatically substituted amino groups R ^ contain

109852/1931

preferably substituted phenyl radicals as indicated under R _1. In substituted pyridinium radicals, substitutes are preferably lower alkyl groups, for example the hydroxyl groups mentioned, halogen atoms such as fluorine, chlorine, iodine and, above all, fluorine atoms, trifluoromethyl groups, sulfo groups, optionally substituted, in particular carbarnoyl groups substituted by lower alkyl radicals or hydroxyalkyl radicals, optionally esterified, e.g. carboxyl groups, cyano groups, lower alkanoyl groups and carboxymethyl groups esterified with lower alkanols.

Hydrogen-containing residues of C-nucleophilic organic compounds bonded via carbon atoms } \! are corresponding C radicals (ie radicals connected to the methyl group by a carbon atom) of organic, preferably unsaturated or enolizable compounds which have at least one carbon atom capable of electron enrichment and are connected to the methyl group via this carbon atom. In the first place, these are groups which contain at least one double bond activated by one or more oxygen, sulfur or nitrogen atoms, or groups which are then converted into such groups by tautomerism.

Radicals] \ l of this type are preferably naphthyl or especially phenyl that deralkoxy- a hydroxy, Nie in at least one of the ortho and para positions, or in equivalent to these positions, lower alkylthio, amino and /

109852/193 1

or di-lower alkylamino group and still further substituted can be, furthermore preferably mononuclear monooxaoyclisc'.he, rnonoazacyclic and monothiacycli sc ^ o hoste with an odd number of ring members, which in particular can be substituted as indicated above, as well as by ß-diketo compounds, in particular / 3-keto acid compounds, or radicals derived from ß-cyaric acid compounds, e.g. from malonic ester or residues derived from acetoacetic ester.

It is particularly preferable to carry out the process using compounds of the formulas IHb and especially IHa and IHc, in which X is primarily bromine, η is 0, Rp and R are hydrogen, R is an acyloxymethyl radical, for example one of the abovementioned acyloxymethyl radicals, especially a lower alkanoyloxymethyl radical, such as the acetyl, propionyl, isobutyryl or especially the pivaloyloxymethyl radical, or a benzoyl or phenylacetyloxymethyl radical, or a p-nitrobenzyl, bis (p-methoxyphenyl) methyl, 2-iodoethyl or 2,2,2-trichloroethyl radical or very particularly a hydrogen atom, R. stands for the radical -CHp-RJ, R ^ a pyridinium radical optionally substituted by lower alkyl radicals, especially methyl radicals, an optionally lower alkylated, especially methyl i. erten 1, 5, ^ -thiadiazolyl-thio or 1,2,4-triazolyl-thio radical, a hydroxyl group, but above all a lower alkoxy group, for example methoxy group _s and very special ones

109 8 5 2/19 3T

represents an acetoxy group or a hydrogen atom and the Amtnoacylrest of the radical R. differs from a 1-aminocycloalkanecarboxylic acid with 4-8 ring members, e.g. the 1-aminocyclohexanodcr l-aminocyclopentanecarboxylic acid, a 1-amino-cycloalkenecarboxylic acid, e.g. the l-aminocyclopentene CS) - or (>) - carboxylic acid, an a-amino-a-thienyl / acetic acid, e.g., a-amino-a- (2-thienyl) acetic acid or α-amino-α- (5-thienyl) -acetic acid, α-amino-α- (1,4-cyclohexadienyl) -acetic acid, one by halogen, especially chlorine or fluorine, lower alkoxy such as methoxy, hydroxy, trifluoromethyl or lower alkyl, e.g. the above-mentioned lower alkyl radicals, substituted a-amino-phenylacetic acid, like the p-hydroxy, m-hydroxy, p-chlorine, meta-chlorine, o-Chlpr-> m-fluorine, o-fluorine, p-methoxy, m-methoxy, o-methoxy, 2,4-dichloro, m-trifluoromethyl, m-chloro-o-hydroxy, 5 # 5-dichloro-4-hydroxy. Or 3-chloro-4-hydroxyphenyl-a-aminoacetic acid, but mainly derived from the unsubstituted a-aminoohenylacetic acid. As one in performing of the process in this preferred form, as is apparent to any person skilled in the art, the corresponding 6-acylamino-penam-5-carboxylic acid and Y-acylamino-cephem - ^ - carboxylic acid compounds obtained with analogous substituents, a detailed description of the preferred compounds to be prepared is superfluous. .

109852/1931

The compounds Ha and Hb can be obtained by adding 6-amino-penam-carboxylic acid or 7-amino-cephem-4-carboxylic acid compounds which are substituted, known or prepared by known methods at the amino group at most by easily cleavable radicals, for example silyl radicals introduces a 2-X-ethoxycarbonylaminoacyl radical on the amino group.

The introduction can take place according to methods known per se, in particular known in peptide chemistry, e.g. by treatment with 2-X-ethoxycarbonyl-aminocarboxylic acids or Halides, mixed anhydrides or activated esters thereof.

The compounds Ha and Hb can also be obtained

by introducing the 2-X-ethoxycarbonyl groups into corresponding compounds which are not protected on the amino group. The compounds of this type are also known or can be prepared by methods known per se. The introduction can take place in a manner known per se, in particular by the successive action of phosgene and a 2-X ethanol.

The o-acylamino-pfcr ^ mcarbonsäure- which can be prepared according to the invention or 7-acylamino-cephem-4-carboxylic acid compounds are partly known, partly new, valuable antibiotics or Starting materials for the production of such.

The invention is described in more detail in the following examples. The temperatures are given in degrees Celsius.

10 9 8 5 2/1931

For thin layer chromatography on silica gel were the following systems are used:

System 45 = sec. Butanol - aqueous ammonia 2% (70:30). System 52A = n-butanol - glacial acetic acid - water (67: 10 ..; 25). System 67 = n-butanol - ethanol - water (40: 10; 50). System 100 = ethyl acetate-pyridine - glacial acetic acid - water (62: 21: 6: 11)

System 110 = ethyl acetate - n-butanol - pyridine - glacial acetic acid water (42: 21: 21: 6: 10).

IRH. = Reindel-Hoppe reagent.

109852/1931

example 1

11.0 g (^ J .nr-iol) 3-acetoxyrr, ethyl-7j8- [N '- (2-br-omät: .oxy) -carbonyl-JD- (α) -phenyl ^ Ινανί ^ ηίαοj -ceph -J-em - ^ - carboxylic acid (Ro:, - 'crystallizate, m.p. 15 ^ ™ 55 "C with decomposition) were dissolved in 180N, 1 acetone. 12.0 g of sodium iodide in 120 ml of acetone were added to the filtrate and the mixture was left to stand at 35 ° C. for 15 hours, a thick white precipitate forming.

Almost all of the acetone was evaporated from the reaction solution in a water jet vacuum. The residue was digested with about 20 ml of dimethylformamide. After adding 200 inl. Water and 500 ml of ethyl acetate resulted in complete dissolution of the residue. The organic phase was separated off and washed four times with 100 ml of water each time. By adding a few sodium thiosulphate crystals to the first wash solution, the brown-yellow color of the solution was largely removed. The aqueous phases were extracted twice with fresh IL-ethyl acetate and discarded. The organic phases were dried over magnesium sulfate and evaporated to dryness together with-et v / a 50 u purified silica gel.

The residue was applied to a column of 350 g silica gel purified with concentrated hydrochloric acid (slurried in methylone chloride). With methylene chloride / i-ethyl acetate

'109852/1931

Jm ^ i :-) o _am BAD ORIGINAL;.

(4: 1 v / v) became practically colorless 5-acetoxymethyl-7 / 3- [N ¹ (2-iodoethoxy) carbonyl-D- (α) -phenylglycylamido] carboxylic acid [Jac- (D) -cephaloglycine] of the formula

1-CIl ₂ -O-COCH ₇

G-CH ₂ -CH ₂ J

COOH

eluted (11.6L g, 96.5 # d.Th). The product crystallized from acetone / ethyl acetate / cyclohexane in the form of very fine colorless needles, which decompose at 162-65.5 C melted (8.85 g) · The mother liquors contained almost pure Product which was only contaminated by small amounts of a very poorly soluble material.

The analysis sample was recrystallized twice more from acetone / ethyl acetate / cyclohexane and dried in a high vacuum at 55 ° C. for 18 hours. It melted at 166-67 ⁰ C (dec.) When heated at l60 °. Analysis: Ber. C 41.80 %, H 5.68 #, N 6.96 %, S. 5.5I %, J 21.05 % i found . C 41.62 %, H 5.8Ο < N 7.Ο6 %, S 5.45 %, ₃ J 21.18 %.

The 5-acetoxy-ethyl-7 / Ϊ- [N '- (2-broir: ethoxy) ^ carbonyl-D- (α) -phenylr.lycylamiuo] -cepri-5-em-'l-carbonnUure can v; as follows hcrgostcllt werdon:

¹ 109852/1931

22.7 g (0.15 mol) of D- (a) -phenylglycine (FLUKA pure); were suspended in 200 ml v / water and made 1 η solution by adding 80 nil 2N sodium hydroxide solution. The clear solution was mixed with 150 ml of ether and cooled to 0 to -5 ° C. At this temperature and with vigorous stirring, 21.8 ml (57 * 5 g, 0.20 mol) of 2-bromoethoxycarbonyl chloride in 200 ml of dioxane and 100 ml of 2N matron lye were simultaneously added dropwise over the course of one hour stirred further at 0 ° C and treated with 1 liter of ether. After stirring briefly, the layers were separated. The ether phase was washed with 50 ml of water and discarded. The aqueous components were covered with a layer of 500 ml of ethyl acetate, acidified to pH 2.5 with concentrated phosphoric acid and saturated with sodium chloride. The aqueous layers were extracted twice with 150 ml of ethyl acetate each time and discarded. The organic extracts were washed with 4 portions of saturated sodium chloride solution (50 ml each), dried over anhydrous magnesium sulfate and freed from the solvent in vacuo.

The residue (50.9 β) was dissolved in methylene chloride while warm dissolved and treated with cyclohexane. When left standing in the refrigerator, a thick paste of needles formed Crystals sucked off in the cold. The colorless precipitate was washed with methylene chloride / cyclohexane (1: 9 v / v) and washed with pentane and weighed in a vacuum oxiccator s constancy dried. Co j> 5.5 g of S-brornäUioxy-

109852/1931

carbonyl-D- (a) -phenylglycine (74 % of theory, melting point 99-100 ° C uncorr.) Further 5> O5 g of yellowish crystals with a melting point of 85-88 were obtained from the filtrate v / earth. The mother liquors (4.75 g yellow oil) were discarded. After another crystallization, the 2nd crystal fraction gave 4.52 g of colorless material which melted at 96-98 ° C. (total yield: 58.02 g, 84 % of theory).

After recrystallization from methylene chloride / cyclohexane, the product of analysis melted unchanged at 99-100 ° C (uncorrected). In a replicate approach, the same was used Conditions obtained a waxy colorless product which had a melting point of 110-111 ° C, but otherwise in none Way different from the product of the 1st approach.

A solution of 50.2 g (0.1 mol) of 2-bromoethoxycarbonyl-D- (a) -phenylglycine in 500 ml of absolute tetrahydrofuran, 15.2 ml (0.1 mol) of absolute triethylamine were added and the mixture was added -10 ° C cooled. With the exclusion of moisture. And good 15.5 ml (0.1 mol) of isobutyl chloroformate were added dropwise with stirring. The white suspension was stirred for a further 15 minutes at -10.degree. In the meantime, 52.6 g (0.12 mol) about 9 ($ iger ^ -aminocephalosporanic acid is suspended in 400 ml of 50% aqueous tetrahydrofuran and by adding 15 * 8 ml (0.12 mol) of triethylamine brought into solution. After cooling down 0 C one called this solution to the mixed anhydride zuTlionaon. The reactionary sound was during an ötundc at 0-lo C

• ■

and stirred for a further hour at room temperature (20-25 0) . ·

The tetrahydrofuran was then reduced at a reduced rate :) Pressure: evaporated. The residue was diluted with 500 ml v / a and shaken out with 200 ml of ethyl acetate. The organic phase was separated and washed with 100 ml of 0.5% Dikaliu.-hydrogen phosphate solution post-extracted. Some undissolved material was removed by filtration. The ethyl acetate extracts were over Magnesium sulfate dried and evaporated. According to the thin-layer chromatogram, the residue (about 17 g) contained not only non-polar ones By-products made little of the desired material and was discarded. The aqueous extracts were mixed with 40 ml of ice-cold Layered ethyl acetate and adjusted to pH with about 5M phosphoric acid 2.5 acidified. The resulting precipitate was filtered off, washed with water and ethyl acetate and dried: 5 * 2 g (according to the chromatogram on silica gel plates in the systems 52Λ and 67 practically pure 7-aminocephalosporanic acid, 19 mmol). The aqueous phase of the filtrate was separated off, extracted twice with 500 ml of ethyl acetate each time and discarded. The organic extracts were each saturated with 200 ml of water and Washed brine, dried over anhydrous magnesium sulfate and freed from the solvent in vacuo. Do drying 44.58 g of thin-layer chromatography remained in the high vacuum uniform material in the form of a slightly yellow-colored «» o'haüms zurück '. "'

109E62 / 1931

Filtration of the crude product dissolved in ethyl acetate with the addition of acetone through a column of 800 g of silica gel and subsequent elution of the substance residues with ethyl acetate / methanol (90% v / v) removed 1.76 g of non-polar by-product and the yellow coloration. Thin-layer chromatography-pure iJ-acetoxymethyl- ^ ß- [N ¹ - (2-bromoethoxy) -carbonyl-D- (α) -phenylglycylamido] -ceph-5-em-4 ~ carboxylic acid (Bac-D-cephaloglycine) (57 * 5 s) crystallized from ethyl acetate. The analysis product was recrystallized from acetone / methyl acetate / cyclohexane and, after drying in a high vacuum, melted at room temperature at 159.5-116 ° C. with decomposition (uncorrupted).

The optical rotation in methanol was + 21 °

(c = o, 989

109852/1931

Example 2

5-acetoxymethyl-73- [N '- (2-iodoethoxy) -carbonyl-D- (α) phenylglycylamidoj-ceph-5-em-4-carboxylic acid (6θΟ mg, 1 mmol) was dissolved in 50 ml of dimethylformamide degassed under high vacuum. After adding 20 ml of 90% aqueous acetic acid, the clear solution was mixed with 1.0 g of zinc dust (Riedel-DeHaen puriss.) added and for 20 minutes at room temperature with a

W Ultrasonic stirrer stirred.

The unreacted zinc dust was removed by filtration and in several portions with a total of 40 ml of dimethylformamide rewashed. The filtrate became for a few minutes mixed with JjO ml exchange resin (Dowex-50X16, 20-50 mesh) in the H form. The exchange resin was filtered off and 'Washed off with several servings of water. The filtrate was evaporated to dryness in a high vacuum at a bath temperature of less than 50 ° C. on a rotary evaporator. The raw pro -

™ product (0.75 g) which still contained little solvent 5-acetoxymethyl-7β- [D- (α) -phenylglycylamidoj-ceph-5-em-4-carboxylic acid which is uniform according to thin-layer chromatography (D-cephaloglycine) of the formula

CH — CO — NH

NH

CH ₂ -O-COCH ..-

, 109852/1931

In a diluted sample, the content of cephaloglycine was determined microbiologically, which corresponded to 0 * 56 g.

The crude product was dissolved in 15 ml of acetonitrile / methanol / Water (1: 1: 1: v / v) dissolved and filtered clear. The weak The yellowish colored solution was by dropwise addition of concentrated ammonia / water (1: 1) to a pH-V / ert of 4.5 set, whereupon a slight cloudiness appeared immediately. It was left to stand in the refrigerator overnight, whereby colorless crystal needles excreted. These were filtered off with an ice-cold solution of acetonitrile / methanol / water (1: 1: 1) and washed with methanol and ether and dried in a high vacuum for 5 hours at JO C. The thus obtained Cephaloglycine (205 mg) was noted for microbiological activity and the physicochemical properties indistinguishable from authentic cephaloglycine.

In the thin layer chromatogram on silica gel G plates failed to develop with either iodine vapor or the ninhydrin collidine reagent (NC) after development with systems 52A, 67 and 110 Impurities can be detected:

System: 52 A Rf value: 0.25 NC coloring: ocher

67 0.19 purple

110 '0.27 purple

After the addition of acetone and more, the filtrate became Keep another fraction of cephaloglycine in the refrigerator isolated (75 mg) * which is different from the main amount only differed by a very faint yellow color. -Au «the Mother liquor ^ can be isolated further Cephalon.ycin wc-r.don with the help of the procedure described.

1 Q9 8 5 2/193 1

Example 5

6.0 g sodium iodide (MERCK p.a.) and 5.0 g 6-N '- [2-bromoethoxycarbonyl-D- (α) -phenylglycylamidoJ-penieillanic acid (released in the usual way from the sodium salt) are dissolved in 50 ml of purified acetone with stirring. The clear one The solution is kept in the refrigerator at 0 for 28 hours, a thick precipitate of sodium bromide separating out. The reaction mixture is gently evaporated to dryness in vacuo. The residue is taken up in ethyl acetate and washed several times with water, a drop of dilute sodium thiosulphate solution being added to the first washing fraction. The organic phase is dried over magnesium sulfate and freed from the solvent under reduced pressure. The weak yellow, foamy residue of 6-N '- [2-iodoethoxycarbonyl-D- (a) -phenylglycylamido] -penieillanic acid the formula

(D)

0, H-GH-CO-HN 6 5 ι

NH

i
GO

ti "

COOH

is almost uniform in terms of thin-film chromatography (systems of ethyl acetate / ice-cream 9: 1 * 100), but differs in the Rf value not from the source material. The structure of the connection

1 QI8 5 2/1 9 3 1

is confirmed by determining the specific iodine content. The crude product is used for the next without further purification Reaction step used.

The product from the above approach is in 150 ml Tetrahydrofuran and dissolved with 150 ml of 90 # aqueous acetic acid diluted. The solution is cooled in an ice bath and stirred in portions with an ultrasound stirrer (Tornado) nifc a total of 10 g zinc dust (size 525 »Zoeo, Canada) added. The reaction mixture is cooled with ice for 30 minutes touched. The excess zinc dust is removed with the help of diatomaceous earth (Hyflo filter aid) filtered off and treated with tetrahydrofuran washed. The filtrate is in a high vacuum on a rotary evaporator Gently evaporated to dryness. The residue is taken up in 50 ml of methyl isobutyl ketone and 20 ml of water, adjusted to pH 1.5 with 1N hydrochloric acid while cooling with ice and immediately saturated with sodium chloride. The aqueous phase is separated off, washed with 10 ml of methyl isobutyl ketone and discarded. The organic extracts are used twice each Washed 10 ml of saturated sodium chloride solution and adjusted to pH 5 * 0 with triethylamine while cooling with ice. One preserves over Night in the refrigerator, whereupon the crystals are filtered off, washed and dried. The obtained practically colorless 6- [D- (a) -phenylglycylamido] -penicillanic acid of the formula

10 9 8 5 2/1931

C ^ H-CH-CO-NH 6 5 ι

COOH

is in the thin-layer chromatogram on silica gel plates (systems 45, 100, acetone / Eisesslg 95i5i detection with IRH reagent or

\ Iodine vapor) cannot be distinguished from authentic ampicillin and shows the same microbiological activities against selected test germs. According to thin-layer chromatography, the mother liquors still contain small amounts of unreacted starting material;

In the analogous reduction reaction using excess chromium (11) acetate [manufactured according to G. Rosenkranz, 0. Mancera, J. Gatica and C. Djerassi, J. Amer. Chem. Soc. 72, 4077 (1950)] -in dimethylformamide can already after I5

P minutes reaction time at 0 ° no more starting material detected will.

The 6-N ^T - [2-bromoethoxycarbonyl-D- (α) -phenylglycylamido] -penicillanic acid used as starting material can be prepared as follows:

36.24 g of 2-bromoethoxycarbonyl-D- (a) -phenylglycine will be dissolved in 600 ml of absolute tetrahydrofuran, cooled to -10 and treated with 15.84 ml of absolute triethylamine.

10 9 8 5 2/1931

16.4 ml of isobutyl chloroformate are added to this solution and stir for 15 minutes at -10. The suspension obtained in this way is then mixed with a suspension cooled to zero Solution of 28.5 g of 6-aminopenicillanic acid and 17.4 ml Triethylamine in 480 ml of 50% aqueous tetrahydrofuran.

After a reaction time of one hour at 0 ■ and for one hour at room temperature, the tetrahydrofuran is evaporated off under reduced pressure. The aqueous residue is mixed with 500 ml of water and 500 ml of ethyl acetate and under Ice cooling by adding about 5 M phosphoric acid to pH 2.5 acidified. The aqueous phase is separated, twice extracted with 200 ml of ethyl acetate and discarded. The organic extracts are mixed with 200 ml of water and twice 300 ml of saturated saline solution extracted over anhydrous Magnesium sulfate dried and freed from the solvent in vacuo. The residue (71.98 g) shows on chromatography on silica gel plates in systems 52A, 67, 100 and ethyl acetate / glacial acetic acid (9: 1) almost uniform substance spots. . .

A sample of this crude product is purified by a Sehnellchrom at ogram on about 20 times the amount of silica gel .. MERCK (puriss., Addition of 1 % glacial acetic acid). The obtained 6-N '- [2-bromoethoxycarbonyl-D- (a) -phenylglycylamido] -penicillan ^ acid, which in the form of a colorless foam with toluene / Es-

10985271931

sigester (2: 1) is eluted shows the following absorption bands in the IR spectrum (in methylene chloride): 2.92 (m); 2.98 (wm); 3.28 (wm) ;. 3.93 (W ^ r.); 5.59 (s) j 5.78 (s) i 5.9O (s); 6.02 (s); 6.23 (W); 6.67 (s); 7.27 (wm) V 8.15 (s); 8.69 (m) _} 8.85 (m) x 9.25 (m); 9.62 (wm) µ.

The main amount (70.0 g) is dissolved in 500 ml of ether and 6θ ml of 3 M methanolic sodium α-P äthyIhexanoatlösung added dropwise. The suspension is left to stand in the refrigerator for 2 hours and the white crystals are filtered off. The precipitate is washed several times with dry ether and dried under high vacuum overnight (48.89 g). The mother liquors, which, according to thin-layer chromatograms on silica gel plates, contain further material * are discarded. The crystals of the sodium salt decompose when heated at approx. 190. The IR spectrum (in Nujöl) shows the following absorption bands: 2.99 (ms, br. ) ' ₃ sh3.65 (w); 5.65 (s) j 5.83 (s); 5.93 (β) s 6.21 (s); 6.55 (s, br.) _; 7, ll (s); 7.48 (ms); 8 _s 02 (ms, br.); 8.87 (wm); 9.24 (m) f 12.98 (m, br. ) '% 14'

109852/1931

Example 4

In a manner analogous to the previous examples The following compounds, for the most part known from the literature, can also be prepared, for example: 5-methyl-7 / 3- (a-aminophenylaeetylamiho) -ceph-3-em-4-carboxylic acid -p-nitrobenzyl ester, p-töluenesulfonate, m.p. 211-216 (decomp.), 5-methyl-7j3- (a-aminophenylacetylamino) -ceph-3-em-4-carboxylic acid,

J-methyl ^ jS-tD-a-amino-o-il ^ -cyclohexadienylJ-acetylaminoJ-ceph-2-em-4-carboxylic acid. .

7- [D-a-Äminö-a- (1,4-cyclohexadienyl) -acetylarnino] -cephalosporanic acid, Hydrate, m.p. 265-270 ° (decomp.),

7- [D - (-) - a-j ^ mino-a- (2-thienyl) -acetylamino] -cephalosporanic acid, Na-SaIz, dec. 188

7- (a-amino-p-chlorophenylacetylamino) -cephalosporanic acid, 7- (ot-amino-m-chlorophenylacetylamino) -cephalosporanic acid, 7- (a-amino-m-bromo-phenylacetylamino) -cephalosporanic acid, 7- (a-Amino-m-fluoro-phenylacetylamino) -cephalosporanic acid, 7- (a-Amino-m-methoxy-phenylacetylamino) -cephalosporanic acid, 7- (a-Amino-m-hydroxy-phenylacetylamino) -cephalosporanic acid, 3-methoxymethyl- 7ß- (Da-amino-phenylacetamino) -ceph-3-em-4-carboxylic acid, mp 248-260 ° (dec.),
2,2-dimethyl-7 / 3- (Da-aminophenylacetamino) -ceph-3-em-4-carbon-

109852/1931

acid, IR spectrum: 5.6l / z, 5> 8 <? μ, 6.12μ, 6.52μ, 6.85μ, 7.10μ ,. 2,2-Dimethyl-7iS- [ot-amino-a- (2-thienyl) -acetylamino] -ceph-5-em-4-carboxylic acid, Rf = 0.47, (silica gel; ethyl acetate: methyl ethyl ketone: formic acid: water = 5: 3: l! L) i

3- [4-Methyl-1,2,4-triazolyl- (3)] -thiomethyl-7β- (a-aminophenylacetylakino) -ceph-3-em-4-carboxylic acid, -A ^ 5- te-methyl -i ^^ - thindlazolyl- (5) J -thiomethyl ^ ß- fot-amino-phenylacetylamino) -ceph-J-em ^ -carboxylic acid, 3-pyridiniummethyl-7i8- [α-amino-a - ^ - thie nyl ) -acetylamino] -ceph-5-em-4-carboxylic acid, inner salt, 3-a-picoliniummethyl-7/3 - [«- amino-a- (2-thienyl) -acetylamino] -ceph-5-em- 4-carboxylic acid, inner salt, 5-7-picoliniummethyl-70- [a-amino-a- (2-thienyl) -acetylamino] -ceph-5-em-4-carboxylic acid, inner salt, 5- (2,4 -Lutidiniummethyl) -70- [a-amino-a- (2-thienyl) -acetylamino] -ceph - ^ - em ^ -carboxylic acid, inner salt,

k 5-hydroxymethyl-70- [a-amino-a- (2-thienyl) -acetylamino] -ceph-5-em-4-carboxylic acid, Sodium salt,

3-methyl-70- [a-amino-a- (2-thienyl) -acetylamino] -ceph - ^ - em - ^ - carboxylic acid,

7- (a-Amino-p-hydroxyphenylacetylamino) -cephalosporanic acid, d-7- [p- (l-Aminoethyl) -phenylacetylamIno] -cephalosporanic acid, inner salt, α = + 105 °,

5-methyl-70- (p-aminomethyl-phenylacetylamino) -ceph-5-em-4-carboxylic acid, A _οί - _η = 65ΟΟ,

109852/1931

7- (p-aminomethyl-phenylacetylamino) -cephalosporanic acid, A ₂ g_ = 69OO,

, 6- (p-aminophenylacetylamino) -penicillanic acid, 6- (l-aminocyclohexyl-carbonylamino) -penicillanic acid (cyclacillin). 6- (l-aminocyclopentyl-carbonylamino) -penicillanic acid, 6- (l-aminocyclobutyl-carbonylamino) -penicillanic acid, 6- (l-aminocycloheptyl-carbonylamino) -penicillanic acid ,. 6- (l-Amino-cyclopenten- (2) -yl-carbonylamino) -penicillanic acid, 6- (l-Amino-cyclopenten- (5) -yl-carbonylamino) -penicillanic acid, 6- (5-amino-2-pyridpyl -aminp) -penicillanic acid, (-) - 6- (/3-Amino-a-phenyl-p.ropipnylamino) -penicillanic acid-pivaloyloxymethyl ester, hydrochloride, IR spectrum 1785-178O cm ", 1760 cm" ¹ , 1675 cm " ¹ , ■

6- (a-Amino-phenylacetylamino) -penicillanic acid pivaloyloxymethyl ester,

6- [D-a-amino-a- (1,4-cyclohexadienyl) -acetylamiho] -penieillanic acid, Semihydrate, decomp. 202,

6- (ot-Amino-p-hydroxyphenylacetylamino) -penicillanic acid, 6- (a-Amino-p- _{hydroxyphenylacetylamino) -p:} enic ill ansäure-pivaloy1oxyme thyIe st er,

6- (a-Amino-p-hydroxyphenylacetylamino) - peiniGillanic Acetoxymethyl Ester,

6- (a-Amlno-p-hjrdroxy.-phenylacet ^ lamiRp) -penicillanic acid benzoylpxymethyl ester *

6- (a-Amino-p-hydroxyphenylacetylamino) penlcillanic acid propionyloxymethyl ester,

6 - '(a-Amino-p-hydroxyphenylacetylamino) penicillanic acid isobutyryloxymethyl ester,

6- (a-Amino-p-hydroxy <-phenylacetylamino) -penicillanic acid-2-ethyl hexanoyloxymethyl ester *

6- (a-Amino-p-hydroxyphenylacetylamino) -penieillanic acid-phenylacetoxymethylesterj,

6- (a ~ amino-p-hydroxyphenylacetylamino) - »penicillanic acid-3,5-diraethyl-4-isoxazolylcarbonyloxymethyl ester, 6- (D-a-Amino-phenylacetylamino) -penicillanic acid-bis- (p-methoxyphenyl) -methyl ester *

6- (a-Amino-p-chlorophenylacetylamino) -penicillanic acid-pivaloyloxymethyl ester,

6- (a-Amino-m-chlorophenylaGetylamino) -penicillanic acid pivaloyloxymethyl ester,

6- (a-Amino-o-chlorophenylacetylamino) -penicillanic acid-pivaloyloxyraethyleater,

6- (a-Amino-o-fluoro-phenyIacetylarnino) -penicillanic acid pivaloyloxymethyl ester,

o-Ccx-Amirio-rn-.tPifluoromethyl-phenylacetylaminoj-peniGillansäu-

6 - (α-amino · «p.-meth y 1 - phe ny 1 ae e t y 1 ami no) -p e-ni c i 11 anic acid - pi va -

o-ia-amino-p-bromo-phenylaGetylaminoJ-penicillanic acid-pivaloyl-

oxymethyl ester,

6- (a-Amino-2 ₎ 4-dichloro-phenylacetyIämino) -penicillanic acid pivaloyloxymethyl ester,

ö-Ca-amino-o-methoxy-phenylacetylaminoJ-penicillanic acid-pivaloyloxymethyl ester,

6- (a-Amino-p-methoxy-phenylacetylamino) -penicillanoic acid-pivaloyloxymethyl ester,

6- (a-Amino-o-nitro-phenylacetylamino) -penicillanic acid pivaloyloxymethyl ester,

6- (a-Amino-m-hydroxyphenylacetylamino) penicillanic acid pivaloyloxymethyl ester,

6- (a-Amino-o-hydroxy-m-chloro-phenylacetylamino) -penicillanic acid-pivaloyloxymethyl ester,

6- (a-Amino-m-amino-phenylacetylamino) -penicillanic acid pivaloyloxymethyl ester,

6- (a-Amino-a- (2-thienyl) -acetylamino) -penicillanic acid benzoyloxymethyl ester,

(-) - β- (a-Amino-α- (3-thienyl) -acetylamino) -penicillanic acid acetoxymethyl ester,

6- (a-Atnino-a- (3-thienyl) -acetylamino) -penicillanic acid-pivaloyl-

oxymethyl ester,

6- [a-Amino-a- (3-pyridyl) acetylamino] penicillanic acid pivaloyloxymethyl ester,

109852/1931

- 4o -

ö-ia-amino-a-C ^ -pyrldylJ-acetylaminoJ-penicillanic acid-pivaloyl-. oxymethyl ester, 6- {a-amino-a- (2-pyrrolyl) -acetylamlnoj-penieillanic acid pivaloyloxymethyl ester, ^ -Methyl-YÖ-ia-eLmino-p-chloro-phenylacetylamino) -ceph - ^ - em - ^ - carboxylic acid, ^ -Methyl-Tß-ia-amino-m-chlorr-phenylacetylaminoJ-ceph-J-em - ^ -

carboxylic acid, P- 5-methyl-73- (a-amino-m? -fluor-phenylacetylamino) -ceph-5-em-4-carboxylic acid, J-Methyl-TjS-Ca-amino-m-bromo-phenylacetylamino) -ceph-3-em-4-carboxylic acid, 3-Meth3rl-70- (a-arnino-m-hydroxy-phenylacetylarnino) -ceph-3-em-4-carboxylic acid, J-Methyl-TÖ-Ca-ä.mino-m-methoxy-phenylacetylaminoJ-ceph-J-em-4-carboxylic acid,

5-hydroxymethyl-7J3 -. (A-iunino-phenylacetylamino) -ceph-3-eni-4- " carboxylic acid, 7- (a-amino oil-l-uiaphthylacetylaraino) -cephalosporanic acid, 7- (p-Amino-phenylacetylamino) -cephalQsporanic acid, 7- [L-p- (1-aminopropyl) -phenylacetylamino] -cephalosporanic acid, 7 - (^ - Amino-l-naphthylacetylamino) -cephalosporanic acid, 7- (jB-Amino-ß-phenylpropionylamino) -cephalosporanic acid, 7- (a-Ajnino-J ^ -dichloro-phenylacetylamino) -cephalosporanic acid,

109852/1931

ö-CD-a-amino-rn-chloro-p-hydroxy-phenylaeetylainino) -panicillanic acid /

5-methyl-73- (Da-aminophenylaeetylamino) -ceph-j5-em-4-carboxylic acid-2,5-di-tert-butyl-4-hydroxy-benzyl ester, P. IO6-IO8 , 7- (Da -Arnino-phenylacetylamino) -cephalosporanic acid- ^ j ^ -ditert.butyl-4-hydroxy-benzyl ester, F. 125-129, 7- (Da-amino-phenylacetylamino) -cephalosporanic acid-bis- (p- methoxyphenyl) -methyl ester, F. · 68- ^ 71 , 6- (l-Amino-lb.exahydrolndanyl-carbonylamino) -penicillanic acid _i 6- (l-Amino-l-decaliHyl-carbonylamino) -penicillanic acid ₄

109852/1931

Claims (1)

Claims 1. Process for the preparation of o-acylamino-penam-J-carboxylic acid and 7-acylamino-cephem-4-carboxylic acid compounds, in which the acyl radical is derived from a carboxylic acid and substituted by a free amino group, characterized in that that one corresponding 6 - [(2-Jodäthoxycarbonylamino) -acylaminol-penarn-5-carboxylic acid compounds (Ia) uncL 7 - [(2-Jodäthoxycarbonylamino) acylamino] -cephem-4-carboxylic acid compounds (Ib) treated with chemical reducing agents. 2. The method according to claim 1, characterized in that that one uses reducing metals or metal compounds as chemical reducing agents. _. "- ■ - ·
3. The method according to claim 2, characterized in that that you reduce with zinc or zinc alloys. 4. The method according to any one of claims 2 and 5, characterized characterized by working in the presence of acidic agents. 5. The method according to claim h, characterized in that one works in the presence of aqueous organic acids. 10 9 8 & 2/19 3 t 6. The method according to claim 5, characterized in that that one works in the presence of aqueous acetic acid * 7. The method according to claim 4, characterized in that one in the presence of Amm.oniumchlorld or pyridine hydrochloride is working. 8. The method according to any one of claims 2 and 5, characterized characterized in that one works in the presence of lower alkanols. 9. The method according to any one of claims 1 and 2, characterized characterized that one with magnesium, an.Alkalimetallamalgam or aluminum amalgam reduced. 10. The method according to claim 1, characterized in that that one reduces with strongly reducing metal salts. 11. The method according to claim 10, characterized in that that one reduces with chromium (II) salts. 12. The method according to any one of claims 1 to 11, characterized characterized in that in the presence of aqueous media containing water-miscible organic solvents is working. " 109852/1931 12. Modification of the method described in claim 1 _; rens for the production of e-Acylamino-penarn-J-carboxylic acid and "7-Aciylam: Lno-cephem-4-earbon3äure compounds in which the Acylruct is derived from a carboxylic acid and substituted by a free Alino group, characterized in that in 6- [(2-X-ethoxycarbonylamino) -acylamino] -penarn-3-carboxylic acid compounds (Ha) or 7 - [(2-X-ethoxycarbonylamino) acylamino} «cephem ^ 4-carboxylic acid compounds (lib), where X is a reactive esterified hydroxyl group different from iodine , X is exchanged for an iodine atom and the 6 - [(2-iodoethoxycarbonylamino) acylamino] penam-5-carboxylic acid compounds (Ia) or 7 - [(2-iodoethoxycarbonylamino) acylamino] ' -cephem-4-carboxylic acid compounds (Ib) treated with chemical reducing agents after or without isolation. 14. The method according to claim 15, characterized in that that X esterified for one with an organic sulfonic acid P is hydroxyl group. 15.. Method according to claim 15, characterized in that that X stands for a chlorine atom. 16. The method according to claim 1J5., Characterized in, • that X stands for a bromine atom. 10 9 8 5 2/1931 17. The method according to any one of claims 15-I6, characterized characterized in that the exchange of X for iodine is carried out in acetone as the solvent. 18. The method according to any one of claims 1-17 * characterized in that the starting materials are 6 - [(2-X'-ethoxycarbonylamino) acylaminoJ-penam-5-carboxylic acid compounds of formula (0) ί K (HTa) R-HN S ⁿ . ^M.
1 . -N - \ ^w "3. ⁰ COOR 7 - [(2-X'-ethoxycarbonylamino) acylamino] -ceph ^ -em - ^ - carboxylic acid compounds the formula R -MH- S ⁿ / NO -N (UIb) COOR 0 or 7-t (2-X'-ethoxycarbonylamino) acylaminoJ-ceph-5-em-4-carboxylic acid compounds the formula 3 ^a > _r (IHc) CuOIi 0 109852/193 1 is used in which η O or 1, R is hydrogen, together with the -C (-O) -O grouping an easily cleavable, esterified carboxyl group or together with R _; denotes a methylene group, H ₁ denotes the alkyl group of a cyclically substituted leatheralluic acid which, on a non-aromatic carbon atom, denotes the 2-X ¹ -ethoxycarbonylamino group of the formula - NH - CO --O- - CH ₀ -CHjT "(IV) carries} R ₂ and R, are independently hydrogen or methyl groups, R _1, hydrogen or a given substituted hydrocarbon radical and may also represent together with R is a methyl group and X ¹ is as defined in claim 15 X radical or an iodine atom stands. 19 · The method according to any one of claims 1-18, characterized in that one starts from a compound obtainable as an intermediate at any stage of the process and carries out the missing process steps, or ■ '■■■ -' the process is terminated at any stage, or forms a starting material under the reaction conditions, or a reaction component is optionally used in the form of its salts 20. The method according to any one of claims 1-17, characterized in that compounds of the formulas Ilia, HIb or IHc, where X 'is bromine or iodine, η is 0, 109852/1931 - 117 - Rp and R denote hydrogen, R denotes an acyloxymethyl radical, a p-nitrobenzyl, bis (p-methoxyphenyl) methyl, 2-iodoethyl or 2,2,2-trichloroethyl radical or a hydrogen atom, R ₂ ^ for the Radical -CHg-Rj !, R'.a pyridinium radical optionally substituted by lower alkyl, an optionally lower alkylated 1,3,4-thiadiazolyl-thlo- or 1,2,4-triazolyl-thio radical, a hydroxy group, a lower alkoxy, an acetoxy group or a hydrogen atom ^ and the. Aminoacyl radical of the radical R, differing from a 1-aminocycloalkanecarboxylic acid with 4-8 ring members, an l-amino-cycloalkenecarboxylic acid, an α-amino-a-tertiary acetic acid, the α-amino-α- (1,4-cyclohexadienyl) -acetic acid _i or an α-aminophenylacetic acid which is optionally substituted by halogen, lower alkoxy, hydroxy, trifluoromethyl or lower alkyl. 21. The method according to claim 20, characterized in that that one starts from a compound obtainable as an intermediate product at any stage of the process and the missing ones Performs process steps ^ or the process on any Cancels stage, or forms a starting material under the reaction conditions, or a reaction component, if appropriate uses in the form of their salts. 10 9 8 5 2/1931