DE2359402A1 - 7-AMINO-DELTA 3-CEPHEM-4-CARBONIC ACID ESTER AND THE PROCESS FOR THEIR PRODUCTION - Google Patents

Description

; FARBWVJiKK HOECHST AÖ-formerly Meister.Lueiüo ■ "& Brü-nirig: '.".

File number: ■ ' ■; / '_; / ^; : λ ^: - ": ^ QE ί? 3 / Ρ 363 ■".,. ί

Date: 2υ. November. 1973 Dr, Ka / stl

7-Amino- ^ j 3-cephem- ^ carboxylic acid esters and .Process for their-

The subject matter of the present "invention" is 7-amiO- ^ i 3-cephern-4-carboxylic acid esters and "a" process for their preparation. These esters have the advantage that, in contrast to the free acids, in organic, sc; hen solvents: are easily soluble and thus as fourth-full Zvri. cheii products for further reactions - in anhydrous. milieu Meaning _: they have. ■■ They allow on the one hand - a new ■. ■■. ■ acylation ¹ with moisture-sensitive carboxylic acid derivatives. the ... at. the right choice. the ester component can easily be split into the 'T-Äcylairiinocephemsäurenj which are valuable as antibiotic importance _} . On the other hand ^ put some "-". Aeyllei'-th .- f-AininO- ^ 3- .ce ph em ^ -carboxylic acid esters important therapeutics da.r _y after oral administration and ■ Res or-p tion by unspecific before fis It teras en - again "in. The free acids can be split. '. -; Vi _;

It was therefore desirable to have a Vei'fahren that the readily soluble in organic Löfiäungsmitteln ester of 7-A: Minoe - \ // 3. cephem- k ~ carboxylic acids make them easily accessible.

It is known (b <il ^ ische patents 717- lAl and 7 ^ 9 712), that by treating .7-Acylamino- ^ J-cephem-il-carboxylic acid esters with phosphorpentachxoride, a base, an alcohol and anhydrous

509823/0907

Hydrolysis-the corresponding amino acid esters with free amino group can be obtained. However, this known implementation proceeds in particular in terms of yields - unsatisfactory.

In the cited patents are also no examples of Ceph'em compounds described, the CHp group of which is linked to cyclic compounds in the 3-position via sulfur.

If you now apply the procedures described there as being optimal If such cephem compounds are used, the desired end products are obtained only in hardly detectable quantities

Surprisingly, it has now been found that cephem compounds of the general formula II _{bind one mole of PCI 1} - 'in a complex manner, so that the Airdd group is not attacked.

The present invention relates to 7 ~ amino ~ ^ / 3-cephem dicarboxylic acid esters of the general formula I.

HLN ^

N, J CH ₂ -SR ₁ (I)

COOR
and salts of these esters in which

R. for an optionally substituted five- or six-membered Ring, which can also be connected to a fused ring system and

R _{2 represents} optionally substituted straight-chain or branched alkyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, acyloxyalkyl, aroylalkyl or a heterocyclic radical.

The present invention is also a method for Preparation of the esters of the general formula Ϊ by adding 7-acylainido - ^ / j 3-cephem-ii-carboxylic acid ester of the general formula II

50 9823/0907

CU>

COOR ₂

in the

R_ for optionally substituted alkyl ^ aryl ·, aralkylY aryloxy ~ ^; alkyl, alkoxyalkyl or a heterocyclic radical and

R ₁ and R "have the meanings given above, in an inert solvent with a silylating agent in: Degonwart"

a base and with PCl ₁ - in a complex-like compound '

transferred, "the activated by the SiIylierung / unidgruppe by '. Addition of a halogenating agent to the iminohalpgeny converts y. this reacts with an alcohol to the imino ether hydrohalide and this hydrolyzes. ·

Since the acyl cleavage of esters without the SiIylation step carried out according to the invention brought only unsatisfactory yields, it must be regarded as surprising that the yield increases significantly in the process according to the invention. It was not expected that the inventive silicon rank of the amide group would increase its reactivity to such an extent that the subsequent reactions could be increased to over 90 % at low temperatures. It must also be regarded as surprising that the amide group according to the invention - could be silylated at all. . ' . -. - ' ';. '

In the "compounds" used as starting materials, R 1 can represent an optionally substituted alkyl radical, in particular one "having 1 to 8, preferably 1 to 5 carbon atoms, preferably an amino or carboxyl group as a substitute. 'as the optionally substituted aryl in particular phenyl may be mentioned, for example, by halogen, preferably chlorine or bromine, lower alkoxy,' may be substituted preferably methoxy or hydroxy _v, R ₇ represents an aralkyl group, it may be mentioned insbesondere'der benzyl DER in Aroinates can be substituted, for example, by halogen

BO 9 8-23 / 09 0.7 -. ".

preferably chlorine, low molecular weight alkoxy or hydroxy and ir; Alkyl part, for example, by non-triolecular alkyl, preferably methyl, ethyl, propyl, the arrdno group, halogen, preferably chlorine, an azide group, low molecular weight alkoxy, preferably methoxy, low molecular weight acyloxy, preferably acetoxy. If R., is an aryloxyalkyl group, a phenyloxyalkyl radical is particularly suitable, the alkyl moiety being an optionally branched, low molecular weight alkyl group of preferably 1 to 5 carbon atoms and the branches possibly present having 1 to 2 carbon atoms pollen. The aromatic part can be substituted, for example, by halogen, preferably chlorine, low molecular weight alkoxy or hydroxy. A low molecular weight Hezt is preferably used as the alkoxyalkyl radical. If a compound of the formula II with a heterocyclic radical R- is used, this can be bonded to the carbonyl group either directly or through a low-molecular-weight alkyl or oxyalkyl, preferably a methyl or oxymethyl group. For example, a thienyloxymethyl, thienylmethyl, pyridymethyl or isoxazoly3 group comes into consideration.

R _p has the meaning of straight or branched alkyl, in particular alkyl se is from 1 to 10 carbon atoms, preferably from 1 to 5 carbon atoms are suitable, in particular methyl and tert. Butyl. Halogen atoms, preferably chlorine and iodine, may be mentioned as examples. Corresponding substituents would be, for example, 2,2,2-trichlorethylene or 2-iodoethyl. Particularly suitable cyeloalkyl radicals are those with 5 to 10 carbon atoms, such as, for example, cyclohexyl, especially isobornyl or adamantyl. Phenyl may be mentioned as the aryl radical, and those with low molecular weight alkyl, such as in particular benzyl or benzhydryl, which may be substituted, for example, by low molecular weight alkoxy, halogen, preferably chlorine or bromine or nitro groups, may be mentioned as aralkyl radical. Examples include p-methoxybenzyl, ρ-chlorobenzyl and p-nitrobenzyl. Particularly suitable aryloxyalkyl and alkyloxyalkyl groups are those with low molecular weight alkyl groups, such as preferably phenoxymethyl or methoxymethyl. There are also those of the acyloxyalky! Groups with

509823/0907

low molecular weight acyl and alkyl of interest such as Acetoxymethyl, pivaloyloxymethyl or phthalyl .. "From the aroylalkyl- · Examples of groups with low molecular weight alkyl are benzoyl methyl, as an example of a heterocyclic radical Thienyl.

Those esters which can be chemically or enzymatically cleaved back into the free acids are preferred. This cleavage can, among other things, take place reductively, e.g. hydrogenolytically as for example with p-nitrobenzyl ester, with, zinc and Acetic acid, e.g. "in the case of trichloroethyester, it can be in an acidic medium take place, such as at tert. Butyl ester, the p-methoxybenzyl ester or the benzhydryl ester. The p-methoxybenzy 1 and benzhydryl esters, which are in organic solvents, have proven particularly useful with trifluoroacetic acid in the presence of anisole into the corresponding Let carboxylic acids transfer.

Examples of enzymatically cleavable esters are the acetoxymethyl ester, the pivaloyloxymethyl ester and the phthalide ester.

R ₁ stands for an optionally substituted five- or six-membered, preferably five-membered ring which has carbon atoms and one to four heteroatoms, such as oxygen, sulfur and / or nitrogen, as ring atoms

The radical R. can also be connected to a fused-on ring system, for example a pyridine or triaxol ring, preferably with a benzene ring, although the radical R ₁ which is not condensed into a ring system is preferred. Then, forming the "radical TL," the ring system can also be completely or partially, preferably jc-nlooh nichu, hydrogenated.

For the radical R ₁ , the following basic ring systems may be mentioned, for example: thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriasolyl, pyrididazinyl, -Thiazinyl, oxazinyl, triazinyl, thiadiazinyl, oxydiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, tetrazinyl, thiatriazinyl. Oxatriazinyl, dithiadiazinyl, imidazolinyl and tetrahydropyrimidyl.

'50 9823/09 0 7

Of the ring systems listed above by way of example, 5-membered ring systems with 1 to 2 nitrogen atoms and optionally one oxygen atom, such as oxazolyl, preferably oxazol-2-yl, oxadiazolyl, imidazolinyl, etc. are preferred. Imidazolin ~ 2-yl and 6-glie'drige ring systems with 1 to 3 nitrogen atoms and optionally a sulfur atom such as pyridyl, such as pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimidyl vzw. Pyrimid-2-yl and pyrimid-4-yl, tetrahydropyrimidyl vzw. 1,4,5,6-tetrahydro-pyrimid-2-yl, thiadiazinyl, in particular 4H-1,3 ₅ 4-thiadiazine-2-yl _s triazinyl, vzw. l _> 3,4 ~ triazin ~ 2-yl and 1,3,5-triazin-4-yl and pyridazinyl, especially pyridazin-3-yl.

5-membered ring systems with one sulfur atom and 1 to 2 nitrogen atoms, such as thiazolyl, in particular thiazol-2-yl, thiadiazolyl, in particular 1,3, ^ - thiadiazol-S-yl and 1,2,4-thu.ridiazole, are particularly preferred -5-yl / 5-membered ring systems with 3 to 4 nitrogen atoms, such as triazolyl, preferably 4H-1 , 2 , M-triazol-jJ-yl and tfctrazolyl, preferably 1H-tetrazol-'5-yl, as well as 153J ^ -OXadiazol-5-y3. System.

The radical R ₁ can be substituted one or more times, the following substituents, for example, being embossed:

Alkyl groups with, for example, 1 to 15 carbon atoms, e.g. Methyl, ethyl, n-propyl, i-propyl, η-butyl, t-butyl, n-hexyl, ündecyl and pentadecyl, preferably those with 1 to 4 carbon atoms, especially methyl.

Cycloalkyl groups such as cyclopentyl and cyclohexyl, low molecular weight alkyl groups with 1 to 4 carbon atoms, preferably Methyl substituted, e.g. by aryl, e.g. Phenyl or thienyl, through aryloxy, for example phenoxy, through low molecular weight alkoxy, such as methoxy and ethoxy low molecular weight alkoxycarbonyl such as methoxy- or ethoxycarbonyl or by halogen, low molecular weight alkoxy groups such as methoxy and ethoxy, low molecular weight alkenyl groups. vde e.g. Allyl, low molecular weight alkyl and alkenyl mercapto groups, e.g.

5 0 9 8:? V 0

Me thy! Mercapto and Ally!. Mercapto, nickligmolecular alkoxy carbony 'J, such as methoxy carbonyl, low molecular weight alkoxy carbony lamino ₄ v.'ic a, B. A "thoxy carbony! Amino, low molecular weight carboxyalkylthio, such as carboxymethylthioj amino, low molecular weight mono- and dialkylamino, such as methylamines, dimethylamines, sthylamino, diethy lamino j Oxi do,, hydroxy, nitro, cyano, halogen _Λ preferably chlorine, mercapto, Carboxy, aryl radicals, such as phenyl, substituted phenyl, such as, for example, low molecular weight alkoxypbenyl vjie methoxy phenyl _a etho.xyijhenyly halophenyl, such as, for example, chlorophenyl, hydroxyphenyl, aminophenyl, alleylphenyl, especially low molecular weight aiky! Phenyl j as t -Butylpbenyl, ToIy1, cetylphenyl, nitrophenyl, biphenylyl or pyridyl, methylpyridyl, puryl, naphthyl, quinolyl, laocbinolyl, thienyl, 2-thiaolyl, 2-pyrrolyl, ij-imidazolyl, 5-pyrazolyl and ii-isoxazolyl.

The unsubstituted radicals R ₁ are preferred according to the invention, as well as the radicals R., which are represented by straight-chain or branched alkyl having 1 to 8 carbon atoms, in particular low molecular weight alkyl, preferably methyl, and by aryl, in particular phenyl, optionally by low molecular weight alkoxy -, nitro groups or halogen may be substituted.j are substituted,

As specific examples of the radical R ^ are in particular below called:

lH-l, 2,3-triazol-5-yl,
l, 2, i} -triazol-3-yl _s: ''

5-methyl-1,2, iJ-tria55Ol-3-yl, · ■

l-phenyl-3-methyl-lH-l, 2,4 ~ triazol-5-yl,
^, 5-D.imethyl-'IH-1,2, il-triazol-3-yl _; . ■ ■

i »-Phenyl-MH- _{1,2 y} i» -triazol ~ 3-yl ,. . .

5-ethy 1-1,2, * {~ tria55Ol-3-y 1,
i »-amino-4H-1,2, ⁱ <- triazol-3-yl _J
5-ithyl-4-andno- '4H-1,2,' t ~ triazol-3-yl,

5-phenyl-1 _s 2, A-triazol-3 ~ yl _}
5- (M ~ methoxyphenyl) -l, 2, i | -triasol-3-yl>

509823/09 07

5- (ij-chloropheny 1) -1,2, 4-triazol ~ 3-yI ₁ 5- ( ⁱ l-pyridyl) -l, 2 _> 4-tria / .ol-3-yl, 5- / i- (2-Methyl-pyridyl) 7-l, 2 _J i) -triazol-3-yl, 5-phenoxymethyl-l., 2 ₃ '! -Triaxol-3-yl ₃ 5-methoxymethyl-l, 2 ₃ 4- triazol-3-yl. i 5-ethoxymethyl-1,2, il- _{triazol-3-yl) 5-ethoxycarbonylmethy 1-1,2, i} -triazol-3-yl s} 5- (2-ethoxyethyl) -l , 2, i | -triazol-3-y 1 j 5- (2-aminoethyl) -l, 2, Jl-tri asol-3-yl, l | -methyl-5-phenyl-4H-l, 2, ⁱ »-Triazol ~ 3-yl, i | - (il-ethoxyphenyl) -5- ( ^J! » -Pyridyl) -ilH-l, 2, 'f-triazol-3-yl * ί | ~ (ίι-methoxyphenyl) --5 "(Ί-pyridyI) - ¹ Ul-I ₅ 2 J} -tria.zol-3 ~ yl ₅ l \ ~ (il-ethoxypheny 1) -5- (3-pyridy 1) - ¹ IH- 1,2, 'i-tri azol ~ 3-y 1, k ~ ( H- 'A thoxypheny 1) -5-pheny 1- ¹ ^ H-1,2, il-triaaol-3-y 1, lJ- (4-Ethoxyphenyl) -5- ( ¹ * -aminophenyl) -4H-1,2,4-triazol-3 ~ yl, i |, 5-diphenyl- ¹ »Hl, 2, i | -triazole - 3- yl _i

4-Ally l ~ 5-phenyl- ¹ ^ H-1,2, ¹ l-triazol-3 ~ yl

i-methyl-5-phenyl-l, 2 ^ ₅ triazol-3 ~ yl ₃ 1-Phenyl-il-ally 1-5- (m-nitrophenyl I) - ^ IH-1,2, Ί-triazol-3 -y 1, l-phenyl-4-allyl-5-t-butyl-4H-l, 2 _s' l-triazol-3-yl _i lH-tetrazol-5-yl,

l-methyl-lH-tetrazol-5-yl, l-ethyl-lH-tetraz-ol-5-yl, l-n-propyl-lH-tetrazol-5-yl, l-i-propyl-lH-tfttrazol - ^ - ylj l-n-butyl-lH-tetrazol-5-yl, l-Cyclopentyl-lH-tetrazol-S-yl, l-phenyl-lH-tetrazol-5-yl, l-p-chlorophenyl-lK-tetrazol-S-yl, l-Cyolchexyl-lH-tetrazol-5-yl, l-benzyl-lH-tetrazol-5-yl, l-allyl-lH-tetrazol-5-yl,

1,2,3-Thiadii »:; ol-5-yl, 1,3,4 - Thi adi a ζ ο 1- 2 -y 1,

509823/0907

23594Q2

1,2,5-Thiadiaaol-3-yl, "3-Methyl-1,2, ii-thiadiazol-5-yl, 3-Phenyl-1,2 _J i | ~ thiadiazol-5 ~ yl _J 2" Methyl- l, 3 ^ - thiadiazol-5-yl, 2-Methylmercapfco-l, 3, ⁱ '-fchiadiazol-5-yl, _2-fithyl-i> 3, ^l l-thiad5.azol-5-yl, 2- _n-propyl-l> 3, ⁱ l-thiadiazol-5-yl ₅ 2-i-propyl-l, 3 ₃ ^ -thiadiazol - 5-yl, 2-Phc-nyl-l _J 3, ¹ "thiadiazol! -5-yl, '2- ( ^] l-MDthoxyphGnyl) -l _J 3 _i ¹ »-thiadiazol-5-yl ₉

2- (3-pyridyl) -1, 3 -, ^ - fchiadi "azQl-5-yl, 2-n-butyl-1,3,4-thiadiazol-5-yi_ 2- (2-pyridyl) -1 ₅ 3 ₃ ² i-thiadiazol-5-yl ₃ 2- (4-pyrddyl) - l _J 3 _J "} -thiadiazol-5-yl _J 2- (l" naphthyl) - l _i 3 ₃ ⁱ l ~ _{thiadiazol-5-yl}} 2- (2 'Chiiioiyl) -l, 3 ₃ ¹ f-thiadiazol-5-yl _J 2- (1-isoquinolyl) -1,3, Ί-thiadiazol ~ 5 ~ y1, 2- ^ thoxycarbonylmefchyl ~ 1,3 _J ^| l-thiad.5.azol "5-ylj 2-Phenjrl-3-mefchyl-1,3, ^J l-fchiadiazol-5-ylj 2 ~ ai: hoxycarbonylar [iino-'l- methyl- ^{1,3, <} lt-hiadiaaöl-i5 -: / 1,3-methylr. ^T .ei-'capto-1,2, 'f-thiadiazol-'i-yl,

1/3 j'l-OxaclIaKol-5-y 1 ,

2-ethyl-l, 3, No: radiazol-5-yl, 2-phenyl-l, 3, ^J 'oxadiazol-5-yl, 2 - (* J-nitrophenyl) -1,3, ^ - 2 oxad - (2-thienyl) ~ l, 3, ¹ * -oxadiaaol ~ 5-yX,

2- (Jl-chlorophenyD-1,3,4-oxadiazol-5-yl · »

5098237090?

2- (2-Thiaaolyl) -l, 3, * l-oxadiazoI-5-yl, 2- ^ -FuryD-l ^^ - oxadiazol-g-yl, 2- (4-pyridyl) -i _J 3, ^| J-oxadiazol-5-yl, 2- (3-nitropheny1) -1,3,4-oxadizaol-5-y1, 2- (2-methoxyphenyl) -l, 3,4-oxadiazol-5 ~ y1, 2- (2-Toly 1) -1,3, ^ »- oxadiazol-5-y 1, 2- (3-ToIyI) -I, 5, ^ - oxadiazol-S-yl, 2- (2-Hydroxy pheny 1) -1,3, ^i- i-oxadiazol-5 ~ y 1 ,? .- (Ί-Hydroxy pheny 1) -l, 3 _s ^ -oxadiazol-5-y 1 , 2-n-butyl- ^{1,3, i} l-oxadiazpl-5-yl, 2-n-propyl-l _J 3i ⁱ ) -oxadiazol-5-ylj 2 ~ benzyl-1,3, ^ - oxadiazol-5-yl, 2- (l-naphthyl) -l , 3, ¹ "-oxadiazol-5-yl, 2- (2-pyrrolyl) -1,3, 'l-oxadiazol-Sy 1, 2- (i" -imidazolyl) -1, 3,4-oxadiazol-5 -yl> 2- (5 ~ py _raz oiyl) _-l} 3, Jl-oxadiazol-5 ~ yl, 2- (3,5-dimethyl ^J J "1 isoxazoly) -1,3, ^ -oxadi azole 5-y

Thiazol-2-yl,
4-methyl-fchiazol-2-yl ₅
i | -Phenyl-thiazol-2-yl,
'I-pentyl-thiazol-2-yl,
ii-hexyl-thiazol-2-yl,
Jl-Unde cy 1-1 hi az ol- ■ 2 -y 1,

i | -Tridecyl-thiazol-2-yl,
^; ! -Pentadecyl-thiazol-2-yl, i ^ -pt-Butylphenyl-thiazol-2-yl, ^ tp-Cety! Phenyl-thiazol-2-yl, h ~ p ~ Phony! Phenyl-thiazol-2-yl, 'I-ethyl-thiazol-2-yl,
4,5-dimethyl-thiazol-2-yl, benzthiazol-2-yl,

4,5-dimethyl-oxazol-2-y1, ¹ J-Phenyl-oxazol-2-yl,
Benzoxazol-2-y1,
Oxazolin-2-yl,

Imidazol-2-yl, Iniidazolin-2-ylj, Benzimidazolin-2-y1, l ~ methyl-imidazolin ~ 2 ~ y1,

2-furyl, 2-thiophenyl, 2-pyrrolyl, 2-thiazolinyl ₃ 3-isoxasolyl, 3-pyrazolyl, thiatriazol-5-YLJ ■ Purinylj

Pyrid-2-yl, pyrid-3-yl, pyrid-1-yl, 5-nitr-o-pyrid-2-yl _} l-oxidopyrid-2-yl

Pyrimid-2-ylj

1, "Jj, 5 ₉ 6-Tetrahydropyrimid-2-yl, iJ-Hydr-oxy-pyrimid-2-yl, ⁱ 4-Hydroxy-6- ~ methyl-pyr3.m5vd-2-yl, 2-Hydroxy -pyriraid-iJ-yl, 2-phenyl-5-ethoxycarbonyl-6-methyl "pyrimide ~ ² Jy, 1 _J 2-phenyl-5-ethoxycarbonyl-6-ethoxy-pyrdmid-iJ-yl _J ii-phenyl-S -ethoxycarbonyl-ö-amino-pyrimid-ii-yl, 2 ~ hydroxy-5 ~ cyano-6-ynethyl-pyr'imid- ⁱ l-yl,

2, G-Diniethyl-S-acetyl-pyrimid-iJ-yl ₅ 2-Undecyl "5-acetyl-6-methyl-pyrimid- ⁱ ] -yl, 2, 6-Dimethyl-S-ethoxycarbonyl-pyrimid - ^ - ylj Triazolopyridylj pyridazinyl, pyrazinyl, 2-methylmercapto ~ 6-phenyl-l ^^ St

B09823 / 0907

"tt ·

5-Methy1-6-hydroxy-1,3,4-triazin-2-y1,

5-phenyl-4H-1,3,4-thiadiazin-2-yl,

5-Hydroxy- ^ Hl, 3 _J ⁱ "-thiadiazin-2-yl.

The 7-acylamino- ^ 3-cephem-dicarboxylic acids used as starting materials of the general formula II can easily be prepared from the corresponding acids known from the literature (US patents 3,516,997 and 3,530,123 and Dutch patent 7,005,519) by esterification represent.

As esterification methods are z. B. named:

a. Conversion of carboxylic acids with aliphatic diazo compounds, such as diazomethane and dipheny! diazomethane,

b. Reacting the carboxylic acids with alcohols R ₂ ^0H ~ ^ ⁿ presence ^of condensing agents such as Dicyclohexy! Carbodiimides

c. Activation of the carboxylic acids by the formation of mixed ones Anhydrides and subsequent reaction with alcohols Rp-OH and

d. Implementation halides of salts of carboxylic acids having alky!, Such as methyl iodide, benzyl bromide _s p-Methoxybenzylchlordd, pivalate, Essigsäurechlormethylester, J-Br omphthalid and chloromethyl methyl ether.

In the 7-acylamino- ^? 3-cephem-4-carboxylic acid ester of the general formula II must have functional groups that could interfere with the subsequent reaction steps. $ be appropriately protected.

For example, hydroxyl, amino and carboxy groups are recommended to block using well-known methods.

The esters of the general formula II are according to the invention in one inert solvents with silylating reagents in the presence of Bases implemented.

5 09823/0907

Halogenated solvents, for example, are suitable as inert solvents Hydrocarbons, ethers, ketones and esters.

As Silylierungsrnittel are preferably strong silylating called ₅ such as trimethylchlorosilane., Dimethyldichlorosilane. Methyltrichlorosilane, triethylchlorosilane, trimethylbromosilane, phenyltrichlorosilane, methoxytrichlorosilane, Ν, Ο-bist-rimethylsilylaeetamid. And trimethylsilyltrifluoroacetamide. Trimethylchlorosilane and dimethyldichlorosilane are preferably used.

Particularly high yields are obtained if one'mit'molar amounts especially with an excess such as the 1.5 to * s 2 ~ times the amount of silylating agents works, but also with less than molar amounts, an increase in the yields can be achieved.

The bases used in accordance with the invention are preferably organic Bases into consideration, especially tertiary amines, which are the same or can be substituted differently, such as triethylamine, Ν, Ν-dimethylaniline, Ν, Ν-diethylaniline, N-methy! Piperidine and ethylmorpholine, but also aromatic amines such as pyridine and its substitution products with inert Substituenfcen-, such as picolines or also quinoline and its inert substitution products .. According to the invention, N, N-dimethyl aniline is particularly suitable.

The bases are used in at least an equimolar amount, based on the silylating agent. The reaction is carried out at Temperatures between about 0 and about 100 ° C., preferably between 10 and 60 ° C. If the reaction is particularly preferred at If carried out at room temperature, it will end after a short time.

These silylated products are preferably mixed _{with one mole of VCl 1} in the same inert solvent, whereby a complex-like compound is formed. From spectroscopic data and model reactions it can be demonstrated that the complex formation

. 509823/0307

takes place on the heterocyclic group in the 3-position. For example, a shift in the signal for the proton in the thiadiazole from 538 Hz to 565 Hz against TMS (measured in CDCl ^) can be observed in the NMR spectrum. The stability of the complexes depends primarily on the Reaktionsternperatur. The complexes are stable at low temperatures (-3Ö to -70 C), but decomposition can be observed at room temperature. It is therefore advantageous not to isolate the complexes formed, but to react them further, namely the acylamino group activated by the silylation according to the invention is reacted with halogenating agents in opposition to bases to form the imino halide at low temperatures. Acid halides can be used for this, such as 2.B. Phosphorus oxychloride5 Phosphorus pentachloride, phosphorus trichloride, thionyl chloride, phosgene or oxyalkyl chloride. Phosphorus pentachloride is particularly suitable according to the invention.

The halogenation reaction succeeds in at least equimolar amounts Halogenating agent based on the cephem compound. In order to obtain particularly high yields, it is advisable to use an excess ivie for example, to use 1.5 to 3 times the amount.

The conversion into the iminohalide group also takes place in an inert solvent. With a view to simplifying the experimental conditions, it is advisable to use the same solvents as in the silylation reaction and the complex formation and to enter the iminohalide-forming agent in substance or in solution.

For this implementation, too, the counterwai't of bases is required. Suitable bases are the organic bases already mentioned, in particular tertiary amines. One is also expedient here use the same ones that were used in the silylation. The base can be used in two portions, i.e. during the silylation added to the amide group and the conversion into the iminohalide will. However, it is more expedient to use the entire amount of base required for both steps during the preceding silylation to add.

982 3/08

The Iminohalogenidbildung can be in a wide temperature range from -100 to +100 ⁰ C perform. To achieve high yields, however, it is advisable to work in the range from 0 to -80 C, preferably between -30 to -50 C,

The imino halide is converted into an imino ether in a manner known per se — by adding alcohols to the reaction mixture. It is expedient to use an excess of about 5 to ¹ JO mole of alcohol per mole of imino halide. Suitable alcohols here- in particular, the award ^ ierten lower aliphatic alcohols such as methanol, ethanol ₃ isopropanol or n-butanol into consideration. To avoid undesirable side reactions must with anhydrous alcohols as possible and at low temperatures of about +30 "to -80 ° C, in particular about. Be worked -30 to -50 ⁰ C. The subsequent hydrolysis of the iminoether is carried out in a known manner, in particular so that the frozen reaction mixture is poured into 2 to 3 times the amount of water, stirred for some time and then the ester of general formula I formed is isolated.

Isolation can be done in different ways by j it is filtered off, for example, in the form of a sparingly soluble salt formed during the reaction, such as, for example, the hydrochloride by setting the ester free from such a salt by adding inorganic bases, whereby it is mixed with the organic Phase separated and can be isolated directly or in the form of salts. The sulfonates, for example, are used as salts for this purpose such as p-Töluenesulfonate or ß-Naphthalinsulfonate 'or salts of organic Acids such as Acetates into consideration.

The salts of the 7-amino / j 3-cephem * t - carbonsäureester of the general formula I are particularly dsr for cleaning products of the invention, for example by recrystallization _s suitable. In addition, a stable storage form stellen.sie the erfindungsgemäs- sen compounds. For example, it can be considered salts with inorganic acids such as hydrochloric acid, hydrobromic ~ ^ äure, sulfuric acid and Phorphorsäure or with organic acids, for example ν.-ίί-- with acetic acid and arysulfonic acids, such as, for example, p-toluenesulfonic acid, β-haphthalenesulfonic acid, and alley isulfonic acid, such as, for example, methanesulfonic acid.

509B23 / 09.0.7._, "...

The production can take place in the usual V / one by merging of equimolar amounts of base and acid component in a « suitable solvent.

According to the invention, in addition to those described in the exemplary embodiments 7-Amino-3-cephem - ^ - carboxylic acid esters, for example also the compounds of general formula I compiled in the table below

HN i ^/ S ^v ~ "i

J IK-J— CH ₀ -SR ₁ (I)

0 COOR ₂

will be obtained:

R ₁ R ₂

^u e ^A 5'2

-CH ₀ -O-CO-C (CH -.) -,

N "Jf -CH ₂ -O-CO-CH,

509823/0907

R.

- Vh-

-CH ₂ -O-CO-CCCH

ΐ ί

~ Ng / ' -CH ₂ -O-CO-CH ₃

6 -CH-

-CH.

-CK ₂ -O-CO-CH ₃

-CF /

■ ^C 6 ^H 5.

N,

-CH ₂ -O-CH ₃

CH-

SÖ3823: / 0-357

N / A

-U J

CH.

-CIU-O-CO-CH

"CH.

CH ₂ -O-CO-C (CH)

N π C _r H

-CH ₀ -O-CO-C (CH ₇ ). . d 3

3 "T" ⁿ " ^C 3 ^H 7

N N '

Ii N ~ \ '

N ■ H -nn-A Vs-

-CH _o -C0- <;

^C 6 ^H 5

N N

Jf ■ N

CH, -CH ₂ -O-CO-C (CH ) ₇

N N

Il N

-CH ₂ -O-CO-CH ₃

R.

N N

¹ A

N N

CH

Il

¹ A -CH

HIGH.

N N

-CH ₂ -O-CO-C (CH ^) ₃

CH.,

The following exemplary embodiments are intended to address the present Explain the invention without restricting it to them.

Examples

The new compounds were determined by spectroscopic data and characterized by thin layer chromatography.

In the infrared spectrum (liBr pressed) they show the ß— Ivaeta.m—

- 1

absorption at 1700-1775 cm and the ester absorption at

1710-17 ² IO cm " ¹ .

In the NMR spectrum (60 MHk, CDC! «) The proton of C-7 appears at e" - 4.7 and the NH ₀ proton at J = 1.8 ppm (Merck) and ethyl acetate used as a flowing liquid. The plates were developed by the action of iodine bowl. The purified products gave correct elemental analyzes and easily interpretable mass spectra.

example 1

To 1.86 g of 3- (i _> 3,4-thiadia3ol-2-yl) -tiiiomethy: L-7- (thieri-2-yl-acetamidb) - ΑΛ "-cephent-'t-carboxylic acid benzhydryl ester in 20 ml of absolute methylene chloride are added to 1.56 ml of N, N-dimethylaniline and 0.6 ml of tri-methylene chloride and the mixture is stirred for one hour at room temperature.

After cooling to -70, 0.63 g of phosphorus pentachloride is first added added and stirred for 30 minutes at -50. After this Time has formed the coraplex-like connection. Kim cool again to -70 C and add another 0.68 g of phosphorus « pentachloride added, stir for two hours at - ^ O, cool again to -70 C, add 20 ml of methanol and stir again two Hours at -'- OK C. Then the solution is in 100 ml of water poured, stirred for half an hour, with sodium bicarbonate neutralized j the organic phase separated off, the aqueous Phase still extracted twice with methylene chloride and the

509823/0907

combined organisclieji Phasoii over sodium: i.urasulfat ^ eti-ocknet. After filtering, the solution is concentrated in vacuo and through. Adding petroleum ether 1.40 g (9-4 f _a d. Th.) '3 ~ (1j 3,4-thiadiazol-2 ~ yl) -. Thiomethyl-7 ~ aniino- ^ 3- ~ cephem-4 ~ carboxylic acid byizhydryl ester precipitated. For purification, this product is dissolved in warm methylene chloride and a solution of p-toluene sulfonic acid hydrate in ethyl acetate is added. After adding a little methanol and diethyl ether, 1.48 g- (74 # d. Th.)

3 ™ (1} 3,4-thiadiazol-2-yl) -thiomethyl-7-a! Jiino-Zj - -cephem-4-carboxylic acid benzhydryl ester-p-toluenesulfonate, colorless crystals with a melting point of 151-152 ° C. (with decomposition).

This p-toluenesulfonate is suspended in aqueous sodium bicarbonate solution, mixed with methyl chloride and stirred at room temperature. After separating off the methylene chloride phase and distilling off the solvent in vacuo, the 3- (i, 3, 4-th.iadiazol ~ 2-yl) -tbJLomethy 1-7-amino- ^ i ^ - cep] iem is obtained again -carbonsäui: e »bensliydrylestr as pale yellowish crystals of m.p. 1.86-187 C (uiitoi decomposition). 'DCi R _f 0.59

IR spectrum ; ß-lactam at 1770 and ester at 1715 cm

Similarly to Example 1, from 1.90 g of 3- (5-methyl-l, 3 ₅ 4 ~ thiadiazol-2 ~ 3-l) -thioniethyl-7 "(thien-2-yl-acetamido) -O cephem ^-4-cai> bonsäure "benzli3 ^r drylester 1.11 g (73 ° ^c f ^ · Th.) 3_ (5-methyl-1, 3,4-thiadiazol-2 ~ yl) thiomethyl" 7-amino-A ^ "Cepheni- ^ l-carboxylic acid benzhydryl esters as pale yellowish crystals of melting point 145-147 (with decomposition). TLC; R_ 0.43

IR Spectrum; ß-lactam at 1 j60 and ester at 1715 cm "".

509823/0907

Hei sp iel 3

If 1.93 S '3- (5-methyl-1 j 3,4 »thiadiazol-2 ~ yl) -thioiTiethyl-7-phenoxyacetaiüido- -Δ-cephera - ^ - carboxylic acid beeuzhydryl ester is used in the manner indicated in Example 1. one gets 1.19 g (? 8 $ d. Th.) 3- (5-Meth.yl-i, 3, ² <-thiadiazol ~ 2-yl) thd.ometh.yl-7-amino- ^ i-cepheni-4-carboxylic acid benzhydryl ester of m.p. 144-146 ° C (with decomposition).

Example 4

The reaction stirred up in Example 1 is treated with 2.85 S dibenzhydryl ester of 3- (5-methyl-1,3> ^ - thiadiazol-2-yl) -thiometky] -7 (D-oc ~ phthaloylarnino-adipoylaraido) - Zj - cephem-'l -carboxylic acid repeated. 1.1Og (? 2 fj ö. Th.) 3- (S-methyl-1,3 »'^ -thiadiazol-2-yl) -thioinetuyl-7-arriino- ^"' - cepliem - ^ - carboxylic acid are formed -benzhydryl ester of m.p. ihh-lh ^ C (under decomp.) »

Example 5

Places i «on 1.85 S 3- (1, 3, - ^; i- ~ thiadiazol-2 ~ yl) .- thioniethyl-7-phenyl" acetami.do-Δ-cephern - ^ - carboxylic acid benzhydryl ester in which it = i Example 1 given in order to obtain 1.22 g (82 $ · d. TIi.) 3 ~ (1, 3 j ' ¹ -thiadiazol-2-yl) -tliiomethyl "7-aini" o-ii - cepheiii-4-carboxylic acid benzhydryl ester ΛΌ'η m.p. 185-186 C (with decomposition).

Be ispiel 6

The execution sequence given in example 2 is repeated with the difference that instead of the 0.6i nil Triniethylchlorosilane 0.62 g Diineth.yldich.lorsd.lan as a silylating agent can be used.

1.90 g of 3- (5-methyl-1,3, U-thiadiazol-2-yl) -thiomethyl-7 ~ (thien-2-yl -acetamido) - - ^ - J- "-cepheni- are obtained. 4 -carboxylic acid "benzhydryl ester 1.24g (81 % of theory ) 3- (5-methyl-1,3,4-thiadiazol-2-yl) -thiomethyl 1-7-amino-zi-cephem -'-l -carboxylic acid benzhydi ^ lester of m.p. 145-146 C (under decomposition) ..

509823/0907

game 7

The reaction sequence given in Example 1 is repeated with the change that instead of the 1.56 ml Ν, Ν-diraetliylaniline 1.63 in 1 Ν, ίί-dietliylaiiiliii are added as a base.
1.86 g of 3- (1, 3, 4-thiadiazol ~ 2-yl) -thiornethyi-7- (thien-2-yl-acetaemido) -Δ-ceph.em - ^ - carboxylic acid benzhydr ^ lester 1 are obtained, 18 g (79.5 $ of theory) 3- (1, 3, 4-thiadia ^ .ol-2-yl) -thiomet] iyl-7-arnino-Ζλ-cepiem-i | -ca-rbönsäurebenzliydr3 ^r lester in front of Sciirnp. 185 ~ 186 ° C (with decomposition)

] j example 8

Analogously to Example 1, 1.88 g of 3 ~ (5-methyl-1, 3 »^ ^- t] iiadiazol ~ 2-yl) -thioineth3''l-7- (thien-2-yl-acetamido) - - ^ ->
cepliera- ⁱ i-carboxylic acid - 3-pli'tiialidester 0.89 S (62 ° fi d. Th,)
3- (5-Methyi-1, 3, 4-th.iadiazol-2 ~ yl) -thioraetb.yl-7-amino-Z \ ^ - cepheni ~ 4-ca .: rboxylic acid 3-phthalide ester as an amorphous solid, which decomposes at 175.

DC: R_ 0.38

IR spectrum: ß-lactam at 1770 and ester at 1750 cra ~ ¹ .

Example 9; · ..-.-

Analog Beisi ^ iel 1 to eirhält from 1.90 g of 3- ^{(1-methyl-thiazol-2} ^ 3 ^r ~ l) thio "~ ethyl 7- (thien-2-3 ^r 'l-acetamido) - Δ ~ eephera-4-carboxylic acid - benzhydr) 4ester 1,0- ·! g (68 ° C of theory) 3- (4-Piethylthiazol-2-yl) -thiome.thyl-7-aniino- - I-cephein-4-carboxylic acid benzhydryl ester as an amorphous solid, which settles at 145 ° C decomposed.

D_C: R _f 0.69

lit ~ S ρ eic ti-am ; β - lactam at 1775 and ester at 1715 cm ".

509823/0907

rrisniel 10

Analogously to Example 1, 1.80 g of J ~ (h- 2-yl) -thiomethyl-7- (thien-2-yl-ac et amido) --O -cephent - ^ - carboxylic acid 3-phthalide ester '0 are obtained , 90 g · (63 ^ d. Th,) 3 - (^ »methyl · thiazol-2-yl) -thiomethyl-7 ~ amino- / i-cGphem - ^ - carboxylic acid ~ 3" phthalide ester as a pale yellow powder, which is decomposed at 165-170 C.

TLC: R _f 0.55

- 1

XR ~ Spektirum: ß-lactam at 1775 and ester at 1750 cm

At game 11

Analogously to Example 1, 1 , h'j g 3 - (5-? Ie thy1-1, 3 ^ - th.iadiazol-2-yl) ~ thioinethyl-7- (thien-2-yl ~ ac et amido ) - ^ - cephem-'t-carboxylic acid methyl ester 0., 90 g (83 ^c / ° d. Th.) 3 ~ (5 ·· JHethyl-T, 3 »'t-thiadiazol-2-yl) -thio ! nethyl · ■ 7-c ^ · π ^ illo-- ii "-cepheir; - • i-carboxylic acid methyl ester as a cream-colored solid which decomposes at 1 '(0.

DC: R_ 0.26
XR spectrum; ß-Lactani at 1770 tirid ester at 1715 cm "'.

JB game 12

Analogously to Example 1, 1.68 g are obtained from; 3- (5-Phe3iyl-1, 3, - ¹ I-oxadiazol-2-yl) -thiomethyl "7- (thien-2-yl-ace fcamido) ~ -Zj -'-ceplieni-4-carboxylic acid methoxymethyl ester 1 .01 g (78 4> of theory ) 3- (5 ~ phenyl-1,3 '^ - oxadiazol ~ 2' ~ yl) - tlii ome thy 1-7 - amino - Zl ^J -cepiiem-4-carboxylic acid -niethoxymethylester as an amorphous powder, which is in

DC: R _r 0.52

190 C decomposes.

IR spectrum; ß-lactam at 1770 and ester at 1720 crn ™ ¹

$ 09823/0907

_ 25 -

Example 1 3

Analogously to Example 1 is obtained from 1.4i g of 3- (1,3> ^ - thiadiazol-2-yl) ~ thiomethyl-7- (th.ien-2-yl-acetaraido) - ιΛ ~ ceplaem-4- " carboiisäure-niethylestex '· 0.91 g (. 88 fo of theory). 3 ~ (1, 3 ^ -Thiaclia.zol-2 ~ yl.) -fclaiomethyl-T- amino - Δ "-cephem - ^ - carboxylic acid niethyl ester as a viscous oil.

TLC: R- 0.34

IR octrum: ß-lactam at 177 * 0 and Eiitex "x at 1715 cm ' _c

Example 1 h

Analogously to Example 1 is obtained from 1.50 g of 3 ~ (1.3,4 «thiadiazol-2-yl) -thiorriethyl-7- (tliien-2-3'-l-acetainido) -A ^ -ceplxem- ^ lcarbonääure- metho.tymetliylester 0.8 ^; 1- g (75 i ° of theory ) 3 ~ (1 _S 3> ^ ~ Thiadiazol-2-yl) -thiometh3-1-7-amino-Δ-cephem-4-carboxylic acid methoxy methyl ester as an amorphous solid ".

B £: R 0.58

- XR spectrum: ß-lactam at 1770 and ester at 1720 cm

Example 15

Analogously to Example 1, 1.71 S 3- (1 »3» 4-thiadiazo.l-2-yl) -thiomethyl-7- (thien-2-yl-acetamido) - Δ ■ -cephem-ίί-carboxylic acid is obtained -pivaloyloxymethylester 0.93 8 ". (70 ' ⁰ Jo d. Th.) 3 ~ (1 j 3 j ^ -Thiad.iazol-2-yl) -thiomethyl-7-amirio- Δ ^ -cephein - ^ - carboxylic acid -pivaloyloxymethyl ester as an amoarphic solid.

DC: R _f 0.50

IR spectrum: ß-lactam at 1775 and. Ester at 17 ^ 0 cm "

509823/0907

Claims (1)

jlj 7-amino- / I 3-cephem-A-carboxylic acid ester of the general formula I. (D in the R _{1 stands} for an optionally substituted five- or six-membered ring which can also be connected to a fused ring system and Rp for optionally substituted straight-chain or branched one Alkyl, cycloalkyl j aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, acyl- ' is oxyalkyl, aroylalkyl or a heterocyclic radical, and salts of these esters. 2. 7 ~ amino / 7 3-cephem - ^ - carboxylic acid ester according to claim I ₅ in which R _{1 is} the remainder stands in which Rj, the meaning of hydrogen, straight-chain or branched alkyl having 1 to 8 carbon atoms, or optionally has phenyl substituted by low molecular weight alkoxy, nitro groups or halogen. 3. l ~ km.no - / \ 3-cephem- ⁱ -carboxylic acid ester according to claim 1, in which R _{1 is} the remainder stands in which Ru has the above meaning 509823/0907 k * 7-amino ~ <-i y-cephem-ij-carboxylic acid ester according to claim 1. in * which R. for the rest is where R ₁ . has the above meaning. 5. 7-Amino-4 3-cephem-4-carboxylic acid ester "according to claim 1, in which R. for the rest Ν — in. . - puts in what. Ru has the above meaning, 6. 7 ~ a'mino - \ /] 3 ~ cephem-4-carboxylic acid ester according to claim 1, in which R., for the rest N Ti Ii Λ is in which R _{1 has} the above meaning. 7. 7-Amino -: ^ 3 ~ cephem- ⁱ } -carboxylic acid ester according to claim 1, in which R _{1 stands} for the remainder ". stands in which Ru has the above meaning. 8. "7-Amino -. ^ 3 ~ eephem-J) -carboxylic acid ester according to claim 1, in which 50 9823/09 07 -2G- for the rest
-CH ₂ -OC-A stands in which A is straight-chain or branched Has alkyl of 1 to 8 carbon atoms. 9. Process for the preparation of 7-amino-vd 3-cephem-i | ~ carboxylic acid ester of the general formula I. S. COOR "CH ₂ -SR ₁ (I) characterized in that 7-acylamino- ^ 3-cephem-4-carboxylic acid ester of the general formula II R -CO - NH_. CH ₂ -SR ₃ (II) COOR ₂ in the R. for an optionally substituted five- or six-membered Ring, which is also connected to a condensed ring ^ system can be and Rp for optionally substituted straight-chain or branched one Alkyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, acyl- ■ oxyalkyl, aroylalkyl or a heterocyclic radical and R., for optionally substituted alkyl, aryl, aralkyl, aryloxy- alkyl, alkoxyalkyl or a heterocyclic radical means in an inert solvent with a silylating agent in the presence a base and converted with phosphorus pentachloride into a complex-like compound, the amide group activated by the silylation 509823/0907 by adding a halogenating agent to the imino halide transferred, this is reacted with an alcohol to form the imino ether hydrohalide and hydrolyzed and optionally converted into salts. 10. The method according to claim 9, characterized in that the Silylation reaction at a temperature between 0 and 100 C, preferably between +10 and +60 C. 11. The method according to claims 9 to 10, characterized in that the silylating agent is trimethylchlorosilane, dimethyl dichlorosilane, Methyltrichlorosilane, trietbylchlorosilane, trimethylbromosilane, NjO-bistrimethylsilylacetamide and trimethylsilyltrifluoroacetamide used. 12. Process according to · Claim 9, characterized in that the Complex formation with phosphorus pentachloride makes. 13. A method according to claims 9 and 12, characterized in that one carries out the complex formation in inert solvents at 0 to -80 ° C, preferably at -10 to ⁰ C --50. lh. Process according to Claim 9, characterized in that the reaction with iminohalide-forming agents and the reaction of the iminohalide with alcohol are carried out at temperatures of +30 to -80 C, preferably -30 to -50 C. 5098-23 / 0907