DD216936A5 - PROCESS FOR THE PREPARATION OF 7-AMINO-CEPHALOSPORANIC ACID DERIVATIVES - Google Patents

Abstract

Process for the preparation of 7-amino-cephalosporanic acid derivatives of the formula. formula

Description

AP C 07 D / 262 708 3 63 799/11

Process for the preparation of 7-amino-cephalosporanic acid derivatives

Field of application of the invention . ^

The invention relates to a process for the preparation of cephem compounds, in particular of 7-amino-cephalosporanic acid derivatives.

The compounds prepared according to the invention are used as starting materials for the preparation of numerous highly effective antibiotics.

Characteristic of the known technical solutions

There is no information available about processes for the preparation of 7-amino-cephalosporanic acid derivatives.

Object of the invention

The aim of the invention is to provide a simple and economical process for the preparation of cephem compounds, in particular of 7-amino-cephalosporanic acid derivatives.

Presentation of the invention of the invention

The invention has for A _U fg _a se of finding suitable starting materials and appropriate process steps for the preparation of cephem compounds, in particular of 7-aminocephalosporanic acid derivatives.

i O Ό. ι .

According to the invention, Y-amino-cepheiusporanic acid derivatives of general formula I

(D

wherein R is hydrogen or methoxy, A is a

Pyridi.niumrest ~ il '__ / »which may be monosubstituted or polysubstituted, identically or differently substituted by optionally substituted O ₁ -Og-alkyl, where two ortho-branched alkyl groups may also be zueihejn optionally substituted JDi bis Becamethylen- ing ing, in which a ring atom may be replaced by a hetero atom, and further also one or two double bonds can be contained, ^ by optionally substituted Cp Og-, alkenyl, through C ₉ -O / - alkynyl, by C_- C _{7 is} i-cycloalkyl or C 1 -C 4 -alkyl-yolino, where in both substituents the ring may also be substituted; by C 1-10 -cyclo-alkenyl, by optionally substituted C ₁ -O-AlkOZy, by C 9 -C 9 -alkenyloxy or G ₂ -Cg -alkynyloxy, by halogen, irifluoromethyl or hydroxy, by optionally substituted phenyl, benzyl or Heteroaryl, wherein furthermore

A quinolinium or isoquinolinium

in each case also mono- or polysubstituted, identical or differently substituted by given- if substituted Cj-Cg-alkyl, C ₁ -Cg-AIkOXy, halogen, trifluoromethyl or hydroxy.

, '. ι> ·

The present invention is particularly directed to compounds in which A is a pyridinium radical

-w ^ V means one or more times, the same or

can be variously substituted by CrC _g alkyl, which may be mono- or polysubstituted by hydroxyl or sulfo; by C.-Cg-alkyloxy, hydroxy-Cj-Cg-alkylöxy and wherein two alkyl groups can also be closed to an optionally substituted di- to decamethylene ring by a ring carbon atom may be replaced by a hetero atom and furthermore, one or two double bonds may also be present,

-. , ^V -. ''.

by C 1 -C 6 -alkenyl which may be substituted by hydroxy,

by C ₂ -C ₆ -alkynyl 25

by C ₃ -C ₇ -cycloalkyl or C ₃ -C ₇ -cycloalkyl-methyl, where in both substituents the ring may also be substituted by hydroxyl or halogen,

by C ^ Cy-cycloalkenyl,. ^

by C ₁ -C ₆ -alkoxy which may be substituted by hydroxy,.

by C ₂ -Cg alkenyloxy or C ₂ -Cg alkynyloxy,

by halogen, trifluoromethyl or hydroxy, by phenyl, benzyl or heteroaryl, which may also be substituted by halogen,

or in which A is a quinolinium or an isoquinolinium radical, which may each be monosubstituted or polysubstituted by identical or different substituents by C ₁ -C,

Alkyl t which may be substituted by hydroxy, by Cj-Cg-alkoxy, by halogen, tri fluorine thy I or hydroxy.

As optionally possible substituents of the under A

mentioned di- to decamethylene ring, in which a ring C atom may be replaced by a hetero atom and still contain one or two double bonds'sein. körinen, in particular the following substituents come into consideration, which may occur one or more times, but preferably simply:

C ₁ -C ₄ -alkoxy, hydroxymethyl, halogen, hydroxy, oxo, exomethylene.

These substituents can occur on the abovementioned rings fused to the pyrxdinium radical, regardless of whether the respective ring is saturated, unsaturated or interrupted by a heteroatom. '

The fused to the pyridinium 'ring may contain two to ten ring members (di- to decamethylene), but preferably contain three to five ring members and thus represent, for example, a cyclopenteno, cyclohexeno or cyclohepteno ring; Does such an anonymous

For example, when the ring is a double bond, examples include a dehydrocyclopentadieno, dehydrocyclohexadierip, or dehydrocycloheptadieno ring. If a C atom in such rings is replaced by a heteroatom, the preferred hetero atoms are oxygen or sulfur. As an oxygen atom. fused rings containing two or one double bond may be mentioned, for example, furo, pyrano, dihydrofuro and dihydropyrans; as fused rings with a sulfur atom containing two or one double bond, thieno, thiopyrano, dihydrothi'eno and dihydropyrano. Of the heteroatom-containing, fused rings come for a substitution, in particular by the abovementioned substituents, in particular those rings into consideration, which contain only one double bond.

Particularly preferred are, for example, the following substituents:

A is a quinolinium or an isoquinolinium est. each of which may also be monosubstituted or polysubstituted by identical or different substituents by C 1 -C 6 -alkyl such as, for example, methyl, ethyl, propyl, preferably methyl, by methoxy, hydroxy, by halogen or trifluoromethyl, a pyridinium radical _{r of} the on or multiply, preferably 1 to 3 times, in particular 1 to 2. , , ·. may be substituted, for example by Cj-C ₄ alkyl, in particular methyl, ethyl, propyl, isopropyl, η-butyl, sec-butyl, tert-butyl, di- .. '; methyl, trimethyl, methyl and ethyl, methyl and propyl, methyl and isopropyl, ethyl and ethyl; Hydroxy-C, jC ₄ -alkyl! in particular. Hydroxymethyl., Hydroxyethyl, hydroxypropyl, hydroxyisopropyl, hydroxybutyl, hydroxy-sec-butyl or hydroxy-tert, -

butyl, and v / obei example, two or three hydroxy ¹ groups may be on the alkyl group; C ^ -C.-alkenyl,

-sr

such as in particular allyl, 2 ~ methylallyl and ßufctsiv ^^ yl, which may also be substituted by hydroxy, 'in particular hydroxyallyl and hydroxybutenyl; CU-alkynyl, in particular propargyl; CU-Cg-cycloalkyl and C ^ -Cg-cyclic

.5. alkyl-methyl, wherein the carbon number refers to the cycloalkyl part, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclopentylmethyl, where the

_/ Rings can also be substiuiert, for example by hydroxy, in particular l-hydroxy-l-cyclopentyl and 1-hydroxy-lcyclohexyl or by halogen, preferably chlorine; Cn -Cg cycloalkenyl, in particular cyclopentene-1-yl and cyclohexene-1-y1;

C 1-4 alkoxy, in particular methyl- and yyloxy; Halogen / in particular 3-fluoro, 3-chloro, 3-bromo, 3-iodo; Hydroxy, especially 3-hydroxy; Trifluoromethyl, especially 3-trifluoromethyl; Phenyl and benzyl which may also be substituted by,, for example by halogen, in particular chlorine, e.g. 4-chlorobenzyl, 2'-thienyl and 3'-thienyl;

A _{1 represents} a pyridinium residue, which by two to one

  t

Di- to Decaniethylen ring substituted alkyl groups is closed, which in turn may be monosubstituted or polysubstituted, preferably monosubstituted and may contain one or two double bonds> for this purpose, very particularly the following fused-on ring systems come into consideration:

Cyclobuteno, cyclopenteno, hydroxycyclopenteno, oxocyclopenteno, hydroxymethylcyclopenteno, exomethylenecyclopenteno, carboxycyclopenteno and carbamoylcyclopenteno, ι , · '

Cyclohexeno, hydroxycyclohexeno, oxocyclohexeno, hydroxymethylcyclohexeno, exomethylene-cyclohexeno, carboxycyclohexeno and carboamoylcyclohexeno, · '· ·

. ' ·. , ·. - ·. ' '.-;

Cycloheptenes, hydroxy, oxo, hydroxymethyl, exomethylene, carboxycyclohepteno and carbaoylcyclohepteno; Dehydro-.

- 6 - ','

cyclopentenes dehydrocyclohexeno and diohydrocyclohepteno.

If a ring C atom is replaced by a heteroatom, in particular oxygen, in the abovementioned fused ring systems, furo / 2, S-b_7pyridine _/ furo / ~ 3,2-b_7pyridine, furo / ~ are particularly suitable 2,3-c_7pyridin; Furo / 3,2-c_7pyridine; ihieno / ~ 2,3-b_7pyridine, 1hiend / ~ 3,2-b_ / pyridine, ilieno / 2,3-c_7pyridine, thieno / ~ 3,2-c_7pyridine, thieno / ~ 3,4-b_7pyridine, thieno / ~ 3,4-c_7pyridin.

The process according to the invention for the preparation of compounds of the formula I is characterized in that a compound of the general formula II or salts thereof

3 5 ¹

R CONH- =

(II)

-H ~ R COOH

wherein R is hydrogen or methoxy,

one by the base which corresponds to the radicals A of the formula I.

represents an interchangeable group and wherein R CO represents an acyl radical, for example a formyl radical or an acyl radical generally known from cephalosporin and penicillin chemistry, with the base which is the radical A defined above in formula I, reacting to form the compound of general formula III, R ¹

f e

CO ₂

, in which A, R and R have the abovementioned meaning and then cleave off the acyl radical according to general chemical or enzymatic methods known from cephalosporin and penicillin chemistry with the formation of compound I.

' ^: ' .... '- ⁷ -'.

Particularly suitable radicals R are acyloxy radicals of lower aliphatic carboxylic acids, preferably having 1 to 4 C atoms, such as, for example, Acetoxy or propionyloxy, especially acetoxy, which may optionally be substituted, e.g. Chloroacetoxy or acetylacetoxy. For R, other groups may also be considered, such as carbamoyloxy. . "

In the Äcylresten R CO- R is hydrogen or the

4 4

Group R - (CH ₂ ) -, wherein η = 0 or 1 and R is a C ₁ -C ₁₀ ", preferably C.-C ₄ ~ alkyl radical which may be mono- or polysubstituted by identical or different substituents by optionally substituted Carbocyclic or heterocyclic aryl, such as phenyl or thienyl, by optionally substituted aryl or heteroaryloxy, such as phenyloxy, by optionally substituted aryl or heteroarylthio, such as phenylthio or imidazolylthio by C ₃ -C> cycloalkyl or C ^ -Cg-Cycloalkenyl, by optionally substituted C ₁ -Cg -alkyloxy, by optionally substituted C.-Cg-alkylthio, by cyano, halogen, trifluoromethyl, sulfo, hydroxy, amino or carboxy, wherein hydroxy, amino and carboxy also protected or may be blocked, for example the group Z-NH-CH (CH ₂ ) ₃ -, ^Λ

COOH ^;

wherein Z is optionally substituted arylcarbonyl, such as phenylcarbonyl or heteroarylcarbonyl, such as thien-2-ylcarbonyl ^ optionally substituted C ^ C. alkyloxycarbonyl or the group -CH = C (CO ₂ C ₂ Hc) ₂ * optionally substituted C ₁ -Cg -Alkyl-sulforiyl or optionally substituted phenylsulfonyl, "such as 4-methyl-phenylsulfonyl

or 4-chloro-phenylsulfonyl, or R is an optionally substituted carbocyclic or _t- heterocyclic aryl radical * such as phenyl, thienyl or furyl. , '/.'

3 4 5

R furthermore denotes the group R-C- ', where R is hydrogen

or R _{1 is as} defined above, or R is the radical R CO-C-, in which R 2 -C denotes -CG. ¹ I _c

^0R are particularly preferred starting compounds in which the acyl radicals R CO-- represent a thienylacetyl or a Pheriylacetylrest which can be split off enzymatically by penicillin G amidohydrolase. "Further preferred are preparatively easily accessible and inexpensive starting compounds in which R CO The radicals of the natural product cephalosporin G, as well as their blocked and protected derivatives of the formula Z-NH-CH (CH ₂ ) 3 C0- _r in the Z, may also be especially preferably COOH

has. The starting compounds are therefore known from the literature or can be easily prepared by literature methods.

"...""^V; The reaction of compounds of the general formula II with the bases corresponding to the radicals A of the general formula I can be carried out in water or in a mixture of water and a water-miscible organic solvent, such as acetone, dioxane , ^{acetonitrile,;.} dimethylformamide, dimethylsulfoxide or ethanol can be carried out, the reaction temperature is generally in the range of about 10 to about 100 ⁰ C, preferably see be- ;: 20 and 80 ⁰ C. the base component trains enter in amounts between about The replacement of the radical R is facilitated by the presence of neutral salt ions, preferably iodide or thiocyanate ions, in the reaction medium, more particularly from about 10 to about 30 equivalents of potassium iodide, sodium iodide The reaction is advantageously carried out in the vicinity of the neutral point, preferably at a pH i m range of about 5 to about 8 performed.

'''''''' - ⁹ -. · '·

The reaction may also preferably be carried out in non-aqueous solution in the presence of tri-C.C.-alkyl iodosilane, such as trimethyl- or triethyl-iodosilane. The reaction of compounds of general formula II with pyridine bases is known. For example, in the literature (EP 60 144), it is described that 3-iodomethyl-cephalosporin derivatives, for example compounds corresponding to those of the formula I where A = J, react with pyridine bases to give the corresponding pyridinium compounds. Such Jodalkylverbindung'en can generally of esters, such as acetates, with Triir.ethyljodsilan ^f prepared (J. Amer Chem 9_9, 968, 1977;... Angew.

Chemie, 9J, 648, 1979 ), a reaction which has been subsequently transferred to cephalosporins (EP 34924, US 4266-049, Tetrahedron Letters 1981 , 3915, EP 70 706). , '. ''''.^;'· ^{:. ":} ''.. * ->'- · Following the procedure described in EP 60 144 two-stage process, for example the corresponding acetates of the formula II

2;:! · '

(R -OCOCH ₃ ) first converted into the 3-iodomethyl compounds, this isolated and then with the desired; Pyridine bases reacted. For the isolation of the final products, a chromatographic purification is necessary, the maximum yield of pure end product is less than 10% d.Th .. Also according to a variant described in EP 70 706, Example 5, wherein the 3-iodomethyl compounds are not isolated, after Reaction with pyridine the Titelverbinduhg next to several components only identified by chromatography. y

It is surprising that the yields of the end products of the formula I are increased more than tenfold,

when the nucleophilic exchange reaction starts in. Presence of an excess of the corresponding bases underlying the radical A in formula I is carried out, i.

TrI-C ₁ -C.-alkyl iodosilane, preferably trimethyl iodosilane is added to the reaction mixture after addition of the base.

I; ,.

The process is carried out in such a way that to a solution or suspension of the compound II in a suitable

Solvent, the base corresponding to the rest A is added, followed by trimethyliodosilane. Instead of trimethyliodosilane, for example, a reaction mixture of iodine and hexamethyldisilane, which were previously reacted at temperatures between about 60 and 120 ⁰ C in literaturbekarinter manner to form trimethyliodosilane, can be used. Instead of trimethyliodosilane, with the same good result, it is also possible to use triethyliodosilane, which has been prepared in the manner known from the literature. The reaction is carried out at temperatures between about '-5 ° to +100 ⁰ C, preferably between + 10 ° and + 8O ⁰ C.

Suitable inert aprotic solvents are e.g. chlorinated hydrocarbons, such as methylene chloride, chloroform, dichloroethane, trichloroethane, carbon tetrachloride, or lower alkyl nitriles, such as acetonitrile or propionitrile, or Frigene; in particular, methylene chloride is an excellent solvent.

The base corresponding to -A rest is added in at least a stoichiometric amount up to a twenty-fold excess, is preferably carried out with such amounts that the liberated amount of hydrogen iodide is bound and at least 1 mole, preferably 2-5 moles of the base for the substitution available stand.

Since, in addition to the group R to be exchanged in the starting compound II, other functional groups present, such as amino, carboxy or amide, react with trimethyliodosilane, the latter is added in at least four times to about twenty times, preferably five to ten times, excess.

Carboxyl and N-amino functional groups in compound II can also be obtained by addition of a silylating agent, such as e.g.

Bistrimethylsil.ylacetamid, Bistrimethylsilyltrifluoroacot- j amide, trimethylchlorosilane, hexamethyldisilazane, Bistri- 'methylsilylharnstaff be vorsilyliert, either without

or in the presence of a base, preferably the desired base of the group A in the amounts described above. Subsequently, trimethyliodosilane is added in at least stoichiometric amount or in excess, preferably in a double to a tenfold excess.

When in the base underlying the radical A of the formula I, functional groups, such as e.g. Hydroxy groups and the like, they are preferably pre-silylated with one of the abovementioned silylating agents and then used in the reaction.

The reaction products of the formula III can be isolated by adding ι of water or aqueous mineral acids, for example dilute HCl, HBr, HJ or H ₃ SO ₄ , from the aqueous phase in a customary manner, for example by freeze-drying the water phase, chromatography and the like. Preferably, the polar reaction products are precipitated from the aqueous solution in the form of a sparingly soluble salt, for example, a hydroiodide salt. <

In the resulting compounds of general formula III is then the acyl group R CO by well-known chemical - eg by hydrolysis with dilute mineral acids, such as hydrochloric acid or sulfuric acid or imide chlorides - or enzymatic processes, such as "in DE-OS 30 19838 describes split. _e>.

When using the imido chloride cleavage, the compound III is reacted with, for example, phosphorus pentachloride, the resulting imide chloride converted by the addition of an alcohol in the imino ether and this then cleaved by hydrolysis or alcoholysis. The reaction is advantageously carried out in the presence of a silylating agent such as trimethylchlorosilane. The resulting compound of the general formula I, after hydrolysis of the reaction mixture by adding water from the aqueous

Phase as usual, e.g. by lyophilization or chromatography on silica gel or the like. Preferably, the reaction products are isolated from the reaction solution directly as sparingly soluble salts, for example a hydrochloride or hydroiodide.

When d-he enzymatic cleavage is used, for example, in compounds of formula III, in which R CO =

C ₁ -H ₁ -CH ₉ CO- and Π Π, with fixed ^D * ^ S ^ CHCO-

Penicillin G-amidohydrolase cleaved off the acyl residue. The reaction is carried out in aqueous solution at a temperature of about 25-40 ⁰ C, preferably 35-37 ° C and a pH of about 6.5-8.0, preferably from 7.2-7.8. By adding 1N NaOH, the pH is kept constant. After completion of the reaction is separated from the fixed enzyme by filtration.

The reaction products of the formula I thus obtained are prepared from the aqueous phase in the usual manner, e.g. through freezing

ν ·. "

drying, chromatography or precipitation in the form of a sparingly soluble salt.

The compounds according to the invention of formula I are starting materials for the preparation of numerous highly effective antibiotics of general formula III ¹ ,

R ³ 'CO-NH \' ^ CH _n A (III ¹⁾

1 3 '

^; in which, for example, R = hydrogen or methoxy and R CO is in particular a 2- (aminoheterocyclyl) -2-oxyiminoacetyl radical , for example the 2- (2-aminothiazolyl) -2-oxyimino-acetyl radical, which is described in German patent applications DE-OS 31 18 732, P 32 07 840.4, P 32 47 614.0 and

-13-,, j? 'Describes Au af iiiir un s from ei s p e I' 32 47 6ΐ3ο2, '.' ,

The following AuBfühfUngsbeispiele to be prepared by the ER £ indungsgemäßerrVerfahren compounds serve aar: explain the invention further, but do not achränken it, a, y

- Prod RECOVERY the output smat erialien Example 1 ₍

3-L (2f 3-cyclopenteno-1-pyridinyl) met hy l] -7-t 2 -y ) acetamido) -qeph-3-em-4-carboxylate,.

• '' .. ''

Option A

• -: - _v ..

A mixture of 150 g (0.36 mol) of 7 - (2-thienylacetamido) -. , cephalosporanic acid sodium salt (cephalothin), 68Og (7 mol) Kaliuir.thiocyanat, 66.5 g (65 ml, 0.56 mol) of 2,3-cyclo-pentenopyridin, 150 ml of water and 30 g 85 percent. Phosphoric acid is stirred for 4 hours at 66-68 ° G. During this time, the pH drops to 6.6 ^! to pH 6.0. The yellow-colored viscous solution is diluted with 3 1 of water and extracted four times with 400 ml of methylene chloride. With cooling ^: and stirring are then at 5-10 ° C 110 ml 18 percent. Sodium acid added dropwise within 30 minutes, forming a voluminous precipitate. It is left for 2 hours in an ice bath, filtered off with suction, washed three times with 500 ml of water and dried in vacuo. <

Yield: 130 g (0.245 mol) of pale yellow colored crystals

(68% of Th,) from the decomposition point 156-158 ° C.

^C 22 ^H 21 ^N 3 ° 4 ^S 2 ^{X HSCN XH} 2 ° '

Ber. G 51 ^ 86 H 4.54 N 10.52 S 18.06 H ₃ O 3.38% Gef. C 51.8 H 4.3 N 10.2 S 18.0 H "0 -2.9"%

IR (KBr): 1775 (lactam-CO); 2040 era ¹ (SCN) ¹ H-NMR (CF ₃ CO ₂ D): β = 2.3-2.8 (in, 2H, cyclopentene-H);

3.15-3.95 (m, 6H, 4 cyclopentene-H and SCH,); 4:06 (s, 2H, CH ₀ CO); 5.2-6.2 (m, 4H, CH ₀ Py and 2 ''

... lactam-H) ;; ¹ 6.8-7-> Cm, 3H, thiophene),

, '7.65-8.70 ppm (m, 3H ₁ PY).

Variant b

3.96 g (10 mmol) of 7- (2-thienylacetamido) -cephalosporanic acid are dissolved in 90 ml of methylene chloride and 10.2 g (10 ml, 86 mmol) of 2,3-cyclopentenopyridine are added. With stirring and cooling then 14 g (10 ml, 70 mmol) of trimethyl-1-iodosilane are added dropwise and the solution is heated under reflux for 2 hours. It is cooled to -15 ⁰ C, added 25 ml of 2N hydrochloric acid and separated from the organic phase. The aqueous phase is adjusted to pH 6.0 by addition of sodium bicarbonate and chromatographed on silica gel (Grace, 0.1 mm) with acetone: water (3: 1). After freeze-drying of the product fractions, the title compound is obtained in the form of a pale yellow amorphous solid.

Yield: 3.2 g (70.5% of theory)

IR (KBr): 1775 cm ^-1 (lactam-CO)

¹ H-NMR (CF ₃ CO ₂ D): 5-2.3-2.8 (m, 2H, cyclopentene-H);

3.1-3.95 (m, 6H, 4 cyclopentene-H and 'SCH ₂ ); 4.09 (s, 2H, CH ₂ CO); 5.2-6.25

(m, 4H, CH ₂ Py and 2 lactam H); , 6.8.-7.4 (m, .311, thiophene); 7.65- - '..''.8.85; ppm (m, 3H, Py)

Example 2

3-L (2,3-cyclopenteno-1-pyridinio) methyl-7-phenylacetamido ceph-3-em-4-carboxylate ^!

Variant a ^v .

From 14.4 g of 7-PJienylacetamido-cephalosporanic acid "= sodium salt, 68 g of potassium thiocyanate, 6.5 ml of 2,3-cyclopentenopyridine, 15 ml of water and. 3.4 g 85 percent. Phosphoric acid in, analogous to Example / 1 a. The reaction mixture is diluted with 120 ml of acetone and over 500 g of silica gel (Grace,

0.1 mm) with acetone: water (8: 1) and then with acetone: water (2: 1). Chromatograph. After freeze-drying, the product fractions give 7.5 g (48% of theory) of light-colored

i gray colored amorphous solid.

IR (KBr): 1770 cm ^-1 (lactam-CO)

¹ H-NMR (CF ₃ CO ₂ D): g = 2.25-2.85 (m, 2H, cyclopentene-H);

- .3.1-3.75 (m, 6H, 4 cyclopentene-H and SCH ₂ ); 3.87 (s, 2H, CH ₂ CO); 3.2-6.25 (m, 4H, CH ₂ Py and 2 lactam-H); 7.38, (s, 5H, phenyl); 7.6-8.7 ppm (m, 3H, · Py).

Variant b . ,

From 3.9 g of T-phenylacetamido-cephalosporanic acid, 10 ml of 2,3-cyclopentopyridine and 1.0 ml of trimethyliodosilane in 90 ml of methylene chloride in analogy to Example 1b. After the hydrolysis is chromatographed as above on silica gel and acetone: water (3: 1).

Yield:. 2.4 g (53.5%) of amorphous solid,

The compound is identical in all properties with that of Example 2 a.

Be ir. P_i_o'l; 3

3 ~ L (2, 3-cyclopenteno-r l-pyrid inioJ methyl.j- ^ -p ^ henoxyacet amido-ceph -eiri- 4-carboxylate

Option A

From 21.4 g of? -Phenoxyacetamido-cephalosporanic acid sodium salt, 95 g of potassium thiocyanate, 9 ml of 2, 3-cyclopentenopyridine and 1.5 g of 85 percent strength. HoPO ₄ in 21 ml of water in analogy to Example 1a. To; After dilution with acetone, it is chromatographed over 600 g of silica gel with acetone: water (8: 1) and then with acetone: water (2: 1). The product fractions are freeze-dried. This gives 11.9 g

, - (51% of theory) of a colorless amorphous solid.

IR (KBr): 1770 cm.sup.- ¹ (lactam-CO)

¹ H-NMR (CF ₃ CO ₂ D): £ = 2.25-2.85 (m, 2H, cyclopentene-H);

3.15-3.9 (m, 6H, cyclopentene-H and SCH ₂ ); 4.81 (s, 2H, CH ₂ CO); 5.25-

-20 6.20 (m, 4H, CH ₃ Py and 2 lactam-H)

) 6.8-7.5 (m, 5-phenyl-H); 7.65-

8.7 ppm (m, 3H, Py). '

 v. ,

Var ian te b

25 '. ' ^: .-. , , ·

From 2.5 g of 7-phenoxyacetamido-cephalosporanic acid, 5 ml of 2/3-cyclopentenopyridine and 5 ml of trimethyliodosilane in. 45 ml of methylene chloride in analogy to Example 1 b. After hydrolysis, the aqueous phase is chromatographed on silica gel with acetone-water (3: 1). After freeze-drying, the product fractions give 1.8 g (61.5% of theory) of a brownish-colored amorphous solid. The compound is identical in all properties with that of Example 3a.

Example 4

7- (D-5-benzamido-5 - carboxypentanairiido) -3- L (2, _3-f cyclo- penteno-1-pyridinio) methyl} -ceph-3-em-4-carboxyla t - '

Option A

A solution of 5.2 g (10 mmol) of 7- (DSB.enzamido-S-carboxy- pentanamido) -cephalosporanic acid, 11.9 g (11.7 ml, 0.1 mol) of 2,3-cyclopentenopyridine, 66 g (0.4 mol) of potassium iodide and 30 mg of ascorbic acid in 75 ml of water and 25 ml of acetone is heated to 66-68 ° C for 4 hours. After cooling, it is diluted with 500 ml of acetone and chromatographed over 300 g of silica gel. With acetone: water (7: 1), the salts are eluted, with acetone: Wassex (2: 1) the title compound. After freeze-drying the product fractions, 3.2 g (55% of theory) of a colorless amorphous solid are obtained.

IR (KBr): 1770 cm ^-1 (lactam-CO)

¹ H-NMR (CF ₇ CO ₀ D): Γ = 1.8-3.9 (m, 15H, 6 cyclopentene-H, SCH _{2 and} pentane-H); 4.8-6.2 (m ', 4H,

₂ Py and 2 lactam Hj; 7.3-8.7 ppm (m, 8H, Py and phenyl).

Variant b

5.1 g (4 m)., 28 mmol) of trimethyliodosilane are added, while cooling, all at once to a mixture of 2 * 1 g (4 mmol) of 7- (D-5-benzainide-5-carboxypentanilo-mido) -cephalosporanic acid, 4.06 g ( 4 ml, 34 mmol) of 2,3-cyclopentenopyridine and 40 ml of methylene chloride. There v; ith heated for 2 hours under reflux, / cooled and hydrolyzed by the addition of S ml 2nHCl. The aqueous phase is separated, adjusted to pH = 6 with sodium bicarbonate and chromatographed over 150 g of silica gel with acetone: water (5: 1), then with acetone: water (2: 1). The product fractions give after

- • 19 -

Freeze-dried 1.9 g (47.5%) of a light yellow amorphous solid. The connection is in all properties with

, identical to those described above. Example 5

7- (D-5- (4-chlorobenzamido) -S-carboxypentanarnido) -3-L (2, 3- cyclic-penteno-T-pyridinio) -ethyl-ceph-S-em ^ -carboxylate

Variant a '

In analogy to Example 4 a from 5.5 g (10 mmol) of 7-fb-5- (4-chloro-benzamido) -S-carboxypentanamidcT] -cephalosporanic acid, 11.9 g (0.1 mol) of 2,3-cyclopentenopyridine, 66 g (0.4 mol) of potassium iodide, 30 mg of ascorbic acid in 100 ml of water: acetone (3: 1) as an amorphous solid obtained in 48% yield.

IR (KBR): 1770 cm ^-1 (lactam CO)

¹ H-NMR (CF ₃ CO ₂ D): / = 1.9-2.9 (m, 8H, (CH ₂ ) ₃ and 2 cyclo

pentene-H); 3.1-3.8 (in, 7H, 4 cyclopentene-H, SCH ₃ and CH); 4.9-6.3 (m, AU, CH ₂ Py and 2 lactam H); 7.3-8.7 ppm Cm, 7H, phenyl and Py).

Variant b 1

In analogy to Example 4 b from 7-CD-5- (4-chlorobenzamido) -S-carboxypentenanamido-cephalosporanic acid (2.2 g), 2,3-cyclopentenopyridine (4.06 g) and trimethyliodosilane (5.1 g) in methylene chloride (40 ml). obtained as an amorphous solid after chromatography. Yield: 51% d. Th.

The compound is identical in all respects to those described above. ·

In analogy to Example 4, variant a (exchange in water), or 4, variant b (Trimethyljodsilanverfahren), v / earth the compounds of the following examples 6-12 obtained from the corresponding cephalosporin derivatives and 2,3-cycloperttenopyridine.

Example 6

7- (D-5-benzenesulfonamido) -5-carboxypentane on ido) -3-jj2, 3-cyclopenteno-1-pyr-idinio) methyl 3-ceph-3-em-4-carboxylate

I '

Yield according to variant a: 45%, according to variant b 52%.

¹ H-NMR (CF ₃ CO ₂ D): ^ = 1.6-4.4 (m, 15 "H, 6 cyclopentene-H, 7 pentane-H and SCH ₂ ); 5.15-6.2

'*.' (m, 4H, CH ₂ Py and 2 lactam H); _f

7.4-8.65 ppm (m, 8H, phenyl and Py)

Example 7

7- [D-5- (4-Methylbenzenesulfonamido) -5-carboxy-pentanamido3-3-D2,3-cyclopenteno-1-pyridinio] -methyl-ceph-3-em-4-carboxylate

Yield according to variant a: 38%

(D _C -DMSO): /1.2-4.1 (m, 18H mi t ^ s at 2.36-CH _o , - 6 cyclopentene-H, 7 pentane-H and CH

4.8-5.7 (4H, CH ₂ Py and 2Lactam-H); 7.2-9.4 ppm (9H, 3Py-H, 4-phenyl-H and 2NH).

-.21 -

Example 8 '.

7- [DS- (4-chlorobenzenesulfonamido) -5-carboxypentanamido] - _i 3- (2,3-cyclopenteno-1-pyridinio) methyl-ceph-3-em-4-carboxy- Ia,

Yield variant a: 48%, according to variant b 55%

₁ H NMR (CF ₃ CO ₂ D): ν / = 1.6-4.4 (ra, 15II, 6 cyclopentene-H,

7-pentane-H and SCH ₂ ); 5.1-6.25 (m, 4H, CH ₃ Py and 2 lactara H); ¹ P 7.4-8.7 ppm (m, -7H, phenyl and Py)

Example 9

7- (D-S-amino-S-carboxy-pentanamido-B- (2,3-cyclopenteno 1-pyridinium ^; thyl ~ ceph-3-em-4-carboxylate

Yield (variant a): 19%

¹ H-NMR (D ₂ O): J = 1.6-2.7 (m ', 8H / (CH ₃ J ₃ and 2 cyclopentene-H); 2.9-3.9 (m, 7H, 4 cyclopentene-H; SCH ₂ and CH N); 5.9-5.95 (m, 4H _f CH ₃ Py ' ^and 2 lactam H); 7.6-8.7 ppm (m, 3H, Py)

Example 10

, 7- (D-5-tert-Butyloxycarbonylamino-S-carboxypentanamido) -3- (2S-cyclopene- 10- pyridinyl) -methyl-ceph-3-em-4-ca rboxylate,

Yield according to variant a: 15 % of theory

1 H NMR (D ₆ -DMSO) 1.2-1.9 (m,] 5H, (CII ₇ ), and C (XMI) _$ ) 1.9-2.4 (m, 2 cyclopentene-II); 2.7-4.Q (m, 7H ₇ CHN, SCH ₂ and 4 cyclopentene-H) 4.8-5.7 (m, 4H, CH ₃ Py and 2 lactam H); 6.0-6.3 (NH); 7.7-8.9 (m, 3H, Py); 9.1-9.4 ppm (NH)

example

7-tj ( D-5-carboxy-5- (2,2-diethoxycarbonyl) -vinyl-amino-pentane-amido3-3- (2,3-cyclopenteno-1-pyridinio) methyl-ceph-3-em-4-carboxylate )

Yield according to variant a: 14% of theory ι

H-NMR

(D ₆ -DMSO): ^ = 1.0-1.4 (t, 611, ethyl); 1.4-1.8

(m, 6H, (CH ₂ J ₃ ); 1.9-2.4 (m / 2 cyclopenten-H); 2.8-4.3 (m _f HH, 4 cyclopentene-H, CHNH, SCH _3, and 4 ethyl); 5.7 (4H, CH ₃ Py and 2 lactam-H); 7.6-9.8 ppm (6H, 3Py-H, vinyl-H, 2NH)

example

7- (2-Acetyl-2-syn-methoxyimino-acetamido) -3- (2,3-cyclopentenes-1-pyridini) methyl-ceph-3 "-em-4-carboxylate

Yield according to variant a: 18% of theory .-_ ^, ¹

H NMR (CF ₃ CO ₂ D) £ = 2.3-2.9 (m with s at 2.49, 5H, CH ₃ CO and 2 cyclopentene-H); 3.1-3.9 (m, 6H, SCH ₂ and 4 cyclopentene-H) 4.26 (s, 3H, NOCH ₃ ); 5.1-6.2 (m, 4 ¹ II, 'CH ₃ Py and 2 lactam-H); 7.6-8.7 ppm (m, 3H, Py)

10

Analogously to Example 4b (Trimethyljodsilanverfahren) are>> the compounds listed below, the general formula

C, H _C CONH-CH (GH "), CONH-COOH

and in which A is the substituent indicated in the second column of Table 1.

15

example

20

13

Table I

Yield% d. Th.

38 '

TI NMR (CF ₃ CO ₂ D): (ppm)

1.7-3.9 (m, 9H, SCH ₂ , 7 pentane-H) 4.8-6.4 (m, 4H, CH ₂ Py, and 2Lactam-H); 7.4-9.2 (m, lOH, Py and phenyl)

14

22

1.7-3.9 (m, 9H, SCH ₂ and 7 pentane-H); 4.8-6.3 (m, 4H _# CH ₂ Py and 2Lactam-H) 7.3-8.6 (m, 1H, phenyl and quinoline) 8.9-9.4 (m, 2 quinoline-H)

15

26

1.8-3.1 (m, 7H, pentane); 3.39 and 3.82 (AB, J = 19 Hz, SQL ·); 4.8-6.3 (m, 4H, CH-Py and 2 Lactanv-H); 7.3-8.7 (mf IIH, phenyl and isoquinoline); 9.5-9.85 '(m, 1 isoquinoline-H)

example

, 5

16

17

20

18

Yield% d. Th.

62

H-NMR

1.6-4.1 (in, 17H, 8-cyclohexene-H, 7-pentane-H and SCH), 4.9-6.4 (m, 4H, CH Py and 2 lactam-H); 7.3- \ 9.0 (m, 8H, phenyl and P, y)

1.7-3.0 (m, 7H _/ pentane); 2.76 (s, 311, CHO; 3.65 and 3.73 (AB, J = 19 Hz, SCH ₉ ); 4.7-6.3 (m, 4H, CH ₉ Py and 2 lactam H 7.3-879 (m / 9H, phenyl and Py)

1.8-2.9 (m, 7 pentane-H); 3.4 2 and Λ. 76 (AB, J = 19 Hz, SCH ₉ ); 4.9-6.4 (m, 4H, CH ₉ Py and 2 lactam H); 7.3-9.25 (m, 14H, phenyl and Py)

In analogy to Example 1 b (Trimethyljodsilanverfahren), the compounds listed below, the general. Formula -

CONH-

and in which A represents the substituent given in the second column of Table 2.

Table 2

example A / CH .V Yield% d. Th. ¹ H-NMR (CF ₃ CO ₂ D): ζ (ppm) 19 84 2.66 (s _t 311, CH ₃ ); 3.40 and 3.72 (AB, J = 19 Hzt 2H, SCH ₂ ); 4.06 (s, 2H, CH ₂ CO); 5.05-6.40 (m, 4H,     '' CH ₂ Py and 2 lactam H); g .8- 7.4 (m, 3H, thiophene); ^C 6 ^H 5 7.95-9.20 (m, 4H, Py) 20 65 3.38 and 3.72 (AB, J = 19Hz SCH ₂ J; 4.10 (s, 2H, CH ₂ CO) 4.9-6.3 (m, 4H, CH ₃ Py and 2 lactam-H); 6.9-7.3 (m, 3H, thiophene); 7.'66 (s,   5H-, 'phenyl); 8.0-9.4 (m, 4H, Py) · '.

Beispj 5 15 A Yield% d. , Th. - - H NMR (CF ₃ CO ₂ D): J "(ppm) 21 O 35 1.7-2.4 (m, 4H, cyclohexene-H); 28 2.8-3.8 (m, 6H, 4 cyclohexene-H, on ²³ SCH ₂ ); 4.05 (s, 2H, CH ₂ CO); ¹⁰ 22 20 5:15 to 6:25 (m, 4H, CH ₃ Py and 2 lactam-H); 6.8-7.5 (m, 3Ή, Thiophene); 7.6-8.8 (m, 3H / Py) 25 / 38 3.40 and 3.78 (AB, J = 19 Hz, -. · 2H, SCH »); 4.08 (s, 2H, CH ₉ CO); 5:15 to 6:35 (m, 4H, CH ₃ Py and 2 lactam-H); 6.8-7.4 (m, 3H Thiophene); 7.9-8.8 (m, 6H, Isoquinoline-H); 9.5-9.8 (m, 1 isoquinoline-H). 3.42 and 3.75 (AB, J = 19Hz, SCH_); 4:06 (s, 2H, CH ₀ CO); 5.26-6.42 (m, 4H, CH ₃ Py and 2 Laetam H); 6.8-7.4 (m, 3H, _ Thiophene); 8.0-9.2 (m, 5H, Py) '' ·. ' "ί r. : '-'

In analogy to Example Ib (Trimethyljodsilanverfahren), the compounds listed below are obtained; that of the general formula

and in which R and R are the substituents shown in Table 3.

T a b e 11 e 3 -

example R ¹ R ³ Yield% d. Th. ¹ H-NMR (CF ₃ CO ₂ D): < '24 H r-- ^N y 28 2.1-2.9 Cm, 5H, CH ₃ - sing _s at 2.33 and 2 cyclopenten-H); 3.1- 3.9 (m, 6H, SCtI ₂ and 4Cyclopenten-H); 4.03 (s, 2H ₇ CH ₂ CO); 5.15-6.25 (m, -4H, QI ₃ Py and 2 lactam W); 7.3-8.7 (m, 5H, Py and imidazole)

example

25

CNCH ₀ -

26

STILL.

20 25

27

OCH.

) C0

Yield% d. Th.

32

68

65

N-NMR (CF ₃ CO D) / (ppm)

2.1-2.9 (m, 2Cyciopentene-H); 3.1-3.8 (m, 6H, SCH ₂ and 4 cyclopentene-H); 3.88 (s, 2H, CH ₉ CO); 5.2-6.25 (m, 4H, CH-Py and 2Lac, tam-H); 7.65-8.7 (m, 3H, Py)

2.2-2.9 (m, 2 cyclopentene-H); 3.15- '3.85 (m, 6H, SCH ₂ and 4 cyclopentene-H ¹ ); 5. ^ - 6.25 (m, 4H, CH ₉ Py and, 2 lactam H); 6.60; 6.98 and 7.57 (one furan H each); 7.6-8.7 (m, 3H, Py)

2.2- ^ 2.9 (^ / 2 cyclopentene-H); 2.9-3.8 (m, 6H, SCH ₂ and 4 cyclopentene-H); 3.70 (s, 311, OCH ₃ ); 4.10 (s, 2H, CHpCO); 5.25-6720 (m, 4H, CH ₂ Py, and 2Lactam-H); 6.7-7.45 (ra, 3Thiophen-H); 7.65-8.7 (m, 3H, Py)

E ndprod ukte

example 1

7-Amino-3 - [(2,3-cyclopenteno-1-pyridinio) methyl ] -cep h- 3-em-4-carboxylate

a) Chemical cleavage . '. .. .. '/''' \ '' · '''To the stirred suspension of 5.6 g (10.5 mmol) of 3 - [(2,3-cyclopenteno-1-pyridinio) methyl] -7- (2. -thie.nylacetämido) ceplv ^ -em ^ -carboxylate-IIydrothiocyanatsalz (Example 1) in 40 ml of dry methylene chloride are added 5.6 ml (44 mmol) of Ν, Ν-dimethylaniline and 2.8 ml (22.2 mmol) of trimethylchlorosilane with slight increase in temperature to 27 After stirring for 1 hour at room temperature, the mixture is cooled to -40 ° C. and all of one and the same is added to 4.6 g (22.2 mmol) of PCI5, the temperature rising to -25 ° C. The dark brown solution is stirred for 1 hour Stirred at -30 ° C and then poured into a cooled to -40 ° C solution of 9 ml of isobutanol in 18 ml of methylene chloride .There is a precipitate After standing overnight in the refrigerator is filtered off and washed with methylene chloride The wet crude product immediately Dissolved in 15 ml of methanol from -5 ° C and 80 ml of methylene chloride: üther (1: 1) was added dropwise after stirring for 2 hours at -1 ° C., the mixture is distilled off over P ₂ ⁰ C i. Vak. dried.

2 hours stirring at -10 C filtered off with suction, washed with acetone

'.' , , , '. '·. Yield: 3.3 g (78% of theory) light brown, crystalline.

_1C C H ^ N, O ^ S χ 2 HCl "

Calc .: C 47.41 H 4.97 Cl 17.49 N 10.37%

Found: C 46.2 H 5.6 Cl 16.6 N 9.8%

IR (KBr): 1785 cm (lactam CO) _s

, ¹ H-NMR (CF ₃ CO ₂ D): C. = 2.55-2.95 (m, 2H, cyclopentene-II); · 3.15-3.95 (m, 6H, 4 cyclopentene-H nv.iä

Lind S-CM ₉ ); 5.53 (s, 2H, Lcictam-It); 5.55 and 6.03 (AB, J = 15 ¹ Hz, 2H, CH ₂ Py); 7.65-8.70. ppm (m, 3H, Py).

b) Enzymatic splitting

106 g (0.2 mol) of 3- (2,3-cyclopenteno-1-pyridinio) methyl-7- (2-thienyl-acetamido), ceph.-3-one-4-carboxylate-hydrothiocyanate salt (Example 1) suspended in 600 ml of water, a solution of 150 ml of Amberlite LA-2 (Rohm and Haas) in 8ÖO ml of ethyl acetate and the mixture gerülirt 1/2 hour in an ice bath. The phases are separated and the aqueous solution is extracted twice with 50 ml of LA-2 (acetate form) in 150 ml of methyl isobutyl ketone and washed four more times with 100 ml of methylene chloride. The Viasser phase is supplemented to a volume of 500 ml and adjusted to pH 7 with NaHCO3 (0.2 g). 100 g of fixed penicillin G amidohydrolase enzyme are added and stirred at 37 ° C. and pH 7.1. The pH is kept constant by adding 1N NaOH. After 2 hours is e, in 90 percent. Sales reached (TLC system: acetone / H 2 O = 5: 1, silica gel plates). The fix. Enzyme is filtered off, three times with 100 ml,. 'Water gev ash, the aqueous phases with 2N HGl adjusted to pH and freeze-dried. The amorphous lyophilisate is stirred with 250 ml of methanol, a little undissolved is filtered and the filtrate 300 ml 15 percent. alcoholic hydrochloric acid and then added 1 1 ether. After 2 hours at ⁰ ° C., the precipitate is filtered off with suction, with ether: methanol

(4: 1) and i.Vak. dried. 30

Yield: 61 g of colorless product (75% of theory). The compound is identical in all properties with that described in Example 1a above. , ·

In analogy to .Example 1 (method -a: chemical cleavage) method b: enzymatic cleavage), the compounds of the general formula I listed below in Tab. 4 are obtained from the corresponding 2-thienylacetamido-cephalosporin derivatives.

-!

CH ₂ CON Η-τ - <"/

Part e

example A * Method yield TI NMR (CF ₃ CO ₂ D): % d. Th. 2 Q a (b) 72 1.7-2.4 (m, 4H, cyc Θ V \ lohexen-H); 2.7-3.95 (69) (m, 6H, 4 cyclohexene H and SCH ₂ ); 5.35- 6.25 (m, 4H, CH ₃ Py and 2 lactam-H); 7.75-8.65 (m, 311, Py) ff a (b) 81 2.69 (s, 311, _CH3); 3 I = J 3.66 (s, 2H, SCH ₂ ); (73) 5.25-6.39 (m, 4H, CH ₂ Py ^ and 2Lactam-II); 7.83-9.03 (m, 4Py-M)

example

5th

-N

method

a (b)

a (b)

Auslaute% ά. th

77

(75)

80

(74)

³ H-NMR (CF ₃ CO ₂ D) ί (ppm)

3.4-3.9 (AB, 211 / SCH ₂ ); 5.2-6.4 OMHfCTI ₂ Py and 2 lactam H); 7.9-8.8 (in, 5 Cliinplin-H) -; 8.85-9.2 (m, 2 quinoline-H) ^Λ

3.5-4.0 (AB, 2H, SCIL ·);

, 1 . Z

5.1-6.6 (m, 4H, CiI ₂ Py is 2 lactam-H); 7.9-8.8 (m, 6 isoquinoline-H); 9.8-9.95 (bs, 1 isoquinoline-H)

Example 6

? -Amino-3- (2,3-cyclicpenteno-1-pyridinio) methylceph-3-em-4? Earboxylate

3 g (5.2 mmol) of 7- (DS-benzamido-S-carboxypentanamido) -3- (2,3-cyclopenteno-1-pyridinio) methyl-ceph-3-em-4-carboxylate (starting example 4) are dissolved in 20 ml Suspended methylene chloride. After addition of 3.9 ml (31.2 mmol) of Ν, Ν-dimethylaniline and 3.9 ml (31.2 mmol) of trimethylchlorosilane is stirred for 1 hour at room temperature.

The clear solution is cooled to -40 ° C. and 6.2 g (30 mmol) of PCl _{5 are} added. The solution is stirred for 1 hour at -30 and then poured all at once into a cooled to -40 ° C solution of 4.1 ml of isobutanol in 10 ml of methylene chloride. The mixture is left at 0 for 1 hour and then the solvent is removed on a rotary vacuum evaporator. The residue is dissolved in 5 g of ice-water and prepared by addition of NaHCO ₃ to pH 6. It is chromatographed on a silica gel column with acetone: water (2: 1).

The product fractions are freeze-dried.

Yield: Ό.83 g (48% of theory)

¹ H-NMR (CF ₃ CO ₂ D) : J- 2.2-2.9 (m _f 2H _# cyclopentene-H); 3.15-3.93 (m, 6H, 4 cyclopentene-H

and SCH ₂ ); 5.25-6.35 (m, 4H, CH ₃ Py and 2 lactam H); 7.65-8.0 (m _# 'lH, Py); 8.23-8.7 ppm (m, 2H, Py)

Example 7

The compound of Example 6 is obtained analogously to the manner described there from the benzenesulfonamido compounds of the starting examples 6, 7 and 8.

Yield: 55% from the compound of the starting example

62% from the compound of the original example 58% from the compound of the original example

The compound obtained in each case is identical in all properties with that described in Example 6 above. ''

Example 8

a) 3 - [(2 3-C yclo penteno -. l-pyridinio) methylj-7-formyl aml.noceph-3-em-4-carboxylate-H did ydrojo

24 g (0.08 mol) of anhydrous 7-formylaminocephalosporanic acid are suspended in 400 ml of dried methylene chloride and 46.8 ml (0.4 mol) of cyclopentenopyridine are added at room temperature. To the clear solution is added dropwise with stirring and Feuchtigkeisausschluß 45.6 ml (0:32 moles) of trimethylsilyl iodide and the mixture heated for two hours under reflux ^v. Thereafter, the reaction mixture is cooled to 0 ° C., 200 ml of water are added and the mixture is neutralized with about 400 ml of saturated sodium bicarbonate solution (pH 6). The phases are separated and the organic phase is extracted by shaking with 80 ml of water Phase is extracted three times with 200 ml of methylene chloride, separated, removed in vacuo, residues of methylene chloride from the aqueous phase and clarified with 4 g of activated carbon.The filtered aqueous solution is adjusted with 200 ml In HJ to a pH word of about 1.5 'and The mixture is then concentrated in vacuo on a rotary evaporator to about 100 ml The precipitate is filtered off with suction, washed with acetone and washed in

Vacuum dried over P.O.

Yield: 24.1 g (59.6% of theory) C ₁₇ H ₁₇ N ₃ O ₄ S x H j x H ₂ O (505.3)

Ber. C 40.41 H 3.99 J 25.11 N 8.32 S 6.35 H ₂ O 3.56% vessel C 40.1 H 4.1 J 23.7 N 8.2 S 6.4 H ₃ O 4.2%

¹ H-NMR (CF ₃ CO ₂ D) :, J = 2.3-2.8 (m, 2H, cyclopentene-H); ¹ 3.15-3.95 (m, GH, 4 cyclopentene-H and SCH ₀ ); 5.25-6.30 (m, 411, CHPy and 2 lactam-H); 7.65-8.75 (m, 4H, HCO and 3Py-H) \. ; .. .. - · .. ';'·'

b) 7-amino-3-O, 3-cyclopenteno-1-pyridinio) inot} 1-yl-J-cep-l- 3-em-4-carboxylate

pihydrochlorid

: '.' · \ ' . - 20.2 g (0.04 mol) of the product of step a are suspended in 200 ml of 2N hydrochloric acid. Man, heated to 60 ° C, with a clear solution is formed and left for 5 minutes at this temperature. On rotation

2-> vacuum evaporator is concentrated to a volume of about 40 ml. After addition of 120 ml of acetone, the dihydrochloride of the title compound precipitates in crystalline form. It is suctioned off, washed with acetone and dried in vacuo over P ₉ 0_.

Yield: 15.4 g (86% of theory), dec. 167 ° C

H 2HCl x H ₃ O (422.4)

Ber. C 45.5 H 5.0 Cl 16.8 N 9.9 H ₀ O 4.3 ΐ _: vessel C 44.0 H 4.8 Cl 15.2 N 9.6 H ₂ O 3.3 %

The NMR spectrum is in full detail with that of Example 1a. identical.

Monohydroiodide and monohydrochloride , ^Λ .

0.422 g (lmmol) of the above dihydrochloride is dissolved in 2 ml of water at room temperature. Are added 84 mg of sodium bicarbonate and 0.05 ml (ca o.4 mmol) 57 percent. Added hydriodic acid. From the clear solution, the monohydroiodide precipitates in crystalline form. It is filtered off, washed with a little water and in vacuo over H ₀ SO. dried. -

Yield: 0.2 g _:

C TT NO ¹ ^ vr ¹ TT · χ'Vt OM 77 Ό JLo J. / ό JZ ,,

.BER. C 40.26 H 4.22 J 26.59 N 8.80%. Gef '·! C 40.7 H 4.2 J 25.0 N 8.9%

The monochloride is obtained from the mother liquor by the addition of acetone until the crystallization starts, and recrystallization from 200 mg of acetone: water (6: 1) gives 130 mg of pure monochloride monohydrate.

^c i6 ^H i7 ^N 3 ° ^ ^{S x HC1 x H} 2 ° ^ί385 · ⁹⁾

Ber. , C 49.80 H 5.22 Cl 9.18 N 10.89 S 8.31% Gef. C.50.1 H 5.6 Cl 8.8 N 10.9 S 8.9%

Claims (5)

':'. ' .-ν .. '.- .-. · -37- · '' Λ ·; '. '. 1 ' ' wherein R is hydrogen or hethoxy, A is a Pyridiniumreat ^ -il ⁷ ^^, of one or more identical or may be variously substituted by optionally substituted G.Cg-alkyl, wherein two ortho-stable alkyl groups may also be closed to an optionally substituted di- to becamethylene-ring in which a fting C-atota is replaced by a heteroatom can and further comprising one or two double bonds also may be present yet, by optionally substituted C ^ -CG-alkenyl, by C ₂ -Gg alkynyl, by Cv-G ₇ -Gyoloalkyl or C _i -C ₇ - ^ü ycloalkyl-methyl * .wobei in both ^ö ubstituenten the üing may also be substituted by C ^ .-} G "cycloalkenyl, optionally substituted by C .-- G / --- alkoxy, by Gp-G ^ alkenyloxy or Cp-Gr-Alkinyloxj , by halogen, ^ rifluormethyl or hydroxyl, by optionally subatituiertee phenyl, benzyl or iieteroaryl, wherein further a is an ühinolinium- f ~ \ or Isochinoliniumreat each one or more times, the same or different which may be substituted by optionally substituted C ₁ -O ₆ -alkyl, G ₁ -G ₆ -alkoxy, halogen, trifluoromethyl or hydroxy, characterized in that a
salts Compound of the general formula II or its R ³ GOKH (ID, COOH wherein R
_n 2 Hydrogen or methoxy, a group which is exchangeable by the base which corresponds to the radicals A of the formula I and in which R ^{3 is} CO-anane aoyl radical, is reacted with the base which is based on the formula A as defined in formula I, to give the compound of the general formula III, , S (III) in the A, R 'and Rr ^{7 have} the abovementioned meaning and then the acyl radical according to general, from the cephalo-spüfin- and penicillin chemistry known chemical or Enzymatisahen methods to form the compound 1 .ab / cleaves ·. - 1. A process for the preparation of 7-amino-cephalosporan acid derivatives of the general formula I. CD ι 2. Verfairiren according to item 1, characterized in that the radical R-CO- is a i'ormylrest or an aua cephalosporin and penicillin known acyl group. 3. The method according to item 2, characterized.dadurch that the radical R-CO- is a thienylacetyl, Ehenylaoetyl-, Phenoxyacetylrest or the radical NH ₀ -GH (GH ₀ ) -GO- COOH whose functional groups can be protected. Method according to items 1 to 3, characterized in that the conversion with the Baae corresponding to the substituent A is carried out in the presence of tri-C.-C.-alkyl iodine. ' 4 rfindunga addressed . 5 * process according to item 4 », characterized in that daa rri-G ₁ ~ G ₄ -'MXkyliodosilane trimethyl- or 'X'-ethyl-, iodosilane .Let,