HRP940734A2 - Process for the preparation of cephalosporines - Google Patents

Description

The subject of the invention is a process for the preparation of cephem compounds of the general formula I

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where means

R is a thiazolyl residue

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or a 1,2,4-thiadiazolyl residue

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in which R 3 is hydrogen or halogen and B is in the given example a substituted amino group, and where

R1 hydrogen or methoxy,

R2 hydrogen, in the given example substituted C1-C6-alkyl, in the given example substituted C2-C6-alkenyl, C2-C6-alkynyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C6-alkyl, C4-C7 -cycloalkenyl,

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is m and n each time 0 or 1,

R4 and R5 can be the same or different and mean hydrogen, aryl or a C1-C4-alkyl group, or together with the carbon to which they are attached form a methylene or C3-C7-cycloalkylidene group, whereby C1-C4-alkyl and C3- The C7-cycloalkylidene group can be further substituted one or more times,

R6 group COOH, CN or CONH2, whereby the last one can be substituted on nitrogen once or twice,

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which can be one or more times, equally or differently substituted with in the given example substituted C1-C6 alkyl, C1-C6 - alkoxy, halogen, trifluoromethane or hydroxy, or a phenanthridinium residue or a pyridinium residue

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which can be one or more times, equally or differently substituted with in the given example substituted C1-C6-alkyl, whereby there can be 2 alkaline groups, standing in the ortho position, and closed in a di- to decamethylene ring, in the given example substituted, in which one carbon atom of the ring may be replaced by a heteroatom and further one or two double bonds may be present; with in the given example substituted C2-C6-alkenyl, with C2-C6-alkenyl, C3-C7-cycloalkyl or C3-C7-cycloalkylmethyl, whereby the ring may also be substituted in both substituted; with C4-C7-cycloalkenyl, with in a given example substituted C1-C6-alkoxy, with C2-C6-alkenyloxy or C2-C6-alkynyloxy, with halogen, trifluoromethyl or hydroxy, with in a given example substituted phenyl, benzyl, or heteroaryl, with formyl or ketalized formyl, with in the given example substituted C1 - C6 - alkylcarbonyl, which can also be found in ketalized form, with arylcarbonyl, with carbonyl, and in which the R2O group is in the syn position.

This invention is directed particularly to compounds, in which R and R1 have the aforementioned meaning and represents the B amino group, which can be substituted with protective groups for amino,

R2 hydrogen, C1-C6-alkyl, which may be one or more substituted with halogen, C1-C6-alkylthio, C1-C6-alkyloxy, aryl or heteroaryl, C2-C6-alkenyl, which may be one or more substituted with halogen; C2-C3-alkenyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-C1-C6-alkyl, C4-C7-cycloalkenyl and where

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A quinolinium or isoquinolinium residue, which can each be one or more times, equally or differently substituted with C1-C6-alkyl, which can be substituted with hydroxy;

with C1-C6-Alkoxy;

with halogen,

with trifluoromethyl,

with hydroxy, or means

[image] -alkyl, which may be substituted one or more times by hydroxy; formyl or C1-C6-alkylcarbonyl, whose carbonyl groups can also be found in ketalized form; sulfo, carbonyl, C1-C6-alkyloxy, hydroxy-C1-C6 alkyloxy and wherein 2 alkyl groups can be closed in and in the given example a substituted di-do decamethylene ring, in which one carbon atom of the ring can be replaced by a hetero atom and in which further may also contain one or two more double bonds,

with C2-C6-alkenyl, which may be substituted with hydroxy,

with C2-C6-alkynyl,

with C3-C7-cycloalkyl or C3-C7-cycloalkyl-methyl,

where both substituents may have a ring substituted with hydroxy or halogen,

with C4-C7-cycloalkenyl,

with C1-C6-Alkoxy, which may be substituted with hydroxy,

with C2-C6-alkenyloxy or C2-C6-alkynyloxy,

with halogen, trifluoromethyl or hydroxy,

with phenyl, benzyl or heteroaryl, which may be substituted with halogen, formyl or ketalized formyl,

with C1-C6-alkylcarbonyl, which may be substituted with hydroxy and may also be present in ketalized form,

with arylcarbonyl,

with carbamoyl,

whereby the R2O group can be found primarily in these compounds in the syn position, and they belong to the general formula I.

As in the given example, possible substituents under A of the mentioned di-do decamethylene ring, in which one carbon atom can be replaced by a heteroatom and in which there can also be one or two more double bonds, in particular the following substituents come into consideration, which can be represented one or more times, preferably once: C1-C6-alkyl, C1-C4-alkoxy, hydroxymethyl, halogen, hydroxy, oxo, exomethylene.

These substituents do not have to be represented on the mentioned rings, which are condensed on the pyridinium residue, regardless of that, but each time the ring is saturated, unsaturated or even interrupted with a heteroatom.

The ring fused to the pyridinium residue may contain 2 to 10 ring members (di-do decamethylene), preferably 3 to 5 ring members and may represent, for example, a cyclopentane, cyclohexane or cyclopentane ring. If this post-condensed ring contains a double bond, we will mention a dihydrocyclopentadieno, dehydrocyclohexadieno or dehydrocycloheptadieno ring as an example. If in rings of this type one carbon atom is replaced by a heteroatom, oxygen and sulfur are particularly suitable as heteroatoms. As post-condensed rings, which contain two or one double bond, and which contain an oxygen atom, we mention, for example, furo, pyrano, dihydrofuro and dihydropyrano; as post-condensed rings with a sulfur atom, containing two or one double bond, such as thieno, thiopyrano, dihydrothieno and dihydrothiopyrano. Of the post-condensed rings, which contain a heteroatom, those rings which contain only one double bond are suitable for substitution, especially with the above-mentioned substituents.

Substitutes that are particularly preferred and come into consideration are for example the following:

B: NH2, HCONH, CF3CONH, CCl3CONH, C6H5CH2CONH, (C6H5)3CNH, HSO3NH, (CH3)2CH=N,

R:

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R1: hydrogen, OCH3

R2: hydrogen, C1-C6-alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, preferably methyl, ethyl;

C1-C2-haloalkyl, for example alkyl substituted with chlorine, bromine, iodine or fluorine, preferably trifluoroethyl, difluoromethyl, 2,2,3,3-tetrafluoropropyl, with aryl, for example phenyl, tolyl, chlorophenyl substituted alkyl, especially benzyl ,

heteroaryl-substituted alkyl, such as 1,3-thiazol-4-yl-substituted alkyl, especially 1,3-thiazol-4-yl-methyl,

C2-C6-alkenyl, such as vinyl, allyl, isopropenyl, methallyl, especially allyl, methallyl,

with halogen, for example C2-C6-alkenyl substituted with chlorine or bromine, especially as 3-chloro-propen-2-yl, 2-bromo-propen-2-yl, 2-chloropropen-2-yl;

C2-C3- alkynyl, especially as propargyl,

C3-C7- cycloalkyl, especially as cyclopropyl, cyclobutyl, cyclopentyl,

C3-C7-cycloalkyl-C1-C6-alkyl, especially as cyclopropyl-methyl, cyclobutylmethyl,

C4-C7-cycloalkenyl, especially as cyclopenten-1-yl,

[image] preferably phenyl, C1-C4-alkyl, such as for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, preferably methyl, ethyl, especially methyl, or wherein

R4 and R5 together with the carbon atom to which they are attached can form a methylene group or a C3-C7-cycloalkyldiene group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, whereby cycloalkylene can group be substituted, for example with C1-C4-alkyl, preferably methyl, with halogen, preferably fluorine or chlorine, or may also be substituted with alkylene with 3 to 6 carbon atoms,

m = 0 or 1

n = 0 or 1, where the sum of m and n represents 1 or 2.

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In the example, if n = 0 and m = 1:

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in the example, if m = 0 and n = 1: -CH2- and, if n and m = 1: CH2-C(=CH2)-.

R6 group COOH, CN, CONH2, with C1-C6-alkyl, preferably methyl or ethyl-substituted carbamoyl, A quinolinium or isoquinolinium residue, which can also be each one or more times, equally or differently substituted with C1-C6-alkyl, such as for example methyl, ethyl, propyl, isopropyl, preferably methyl, with methoxy, with hydroxy, with halogen or trifluoromethyl, a pyridinium residue, which can be one or more times, preferably 1 - to 3 - times, especially 1 - to 2 - times substituted, for example with C1-C4-alkyl, and especially with methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, dimethyl, trimethyl, methyl and ethyl, methyl and propyl, methyl and isopropyl , ethyl and ethyl: with hydroxy-C1-C4-alkyl, and especially with hydroxy-methyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, hydroxybutyl, hydroxy-sec-butyl or hydroxy-tert-butyl, and in addition to the alkyl residue, there may be two or three hydroxy groups; formyl-C1-C4-alkyl, and especially with formylmethyl, C1-C4-alkyl-carbonyl-C1-C4-alkyl, especially with methylcarbonylmethyl, ethylcarbonylmethyl, methylcarbonylethyl and ethylcarbonylethyl; C3-C4-alkenyl, especially with allyl, 2-methylallyl and buten-3-yl, which can be further substituted with hydroxy, especially hydroxyallyl and hydroxybutenyl; with C3-alkynyl, and especially with propargyl; C3-C6-cycloalkyl and C3-C6-cycloalkyl-methyl, whereby the number of carbon atoms refers to the cycloalkyl part, and especially with cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclopentyl-methyl, whereby the rings may be substituted for example with hydroxy , and especially with 1-hydroxy-1-cyclopentyl and 1-hydroxy-1-cyclohexyl or halogen, preferably chromium; with C5-C6-cycloalkenyl, and especially as cyclopenten-1-yl and cyclohexen-1-yl, with C1-C6-alkoxy, and especially with methyl- and ethoxy, halogen, and especially with 3-fluoro, 3-chloro, 3-bromo, 3-iodo; hydroxy; especially 3-hydroxy; trifluoromethyl, especially 3-trifluoromethyl; phenyl and benzyl, which may be substituted, for example with halogen, especially chlorine, such as for example 4-chlorobenzyl; 2'-thienyl and 3'-thienyl; C1-C4-alkylcarbonyl, especially acetyl and propionyl, preferably acetyl; formyl, benzoyl, carbamoyl.

If A represents a pyridinium residue, which is substituted by two alkyl groups closed in the di-do decamethylene ring, which again can be one or more times, preferably monosubstituted and, can contain one or two double bonds, and therefore come into consideration especially the following post-condensed ring systems: cyclobutene, cyclopentane, hydroxycyclopentane, oxocyclopentane, hydroxymethylcyclopentane, exoethylene-cyclopentane, carboxycyclopentene and carbamoyl-cyclopentane, cyclohexane, hydroxycyclohexene, oxocyclohexene, hydroxymethylcyclohexane, exo-methylenecyclohexene, carboxycyclohexene and carbamoyl-cyclohexene, cycloheptene, hydroxy-, oxo -, hydroxy-methyl, exomethylene, carboxycycloheptene and carbamoyl-cyloheptene, dehydrocyclopentene, dehydrocyclohexene and dehydrocyclohepteno.

If in the above-mentioned post-condensed ring systems one carbon atom of the ring is replaced by a heteroatom, especially oxygen or sulfur, the following ring systems come into consideration in particular:

furo[2,3,-b]pyridine, furo[3,2,-b]pyridine, furo[2,3,-c]pyridine, furo[3,2,-c]pyridine, thieno[3,2, -b]pyridine, thieno[2,3,-c]pyridine, thieno[3,2,-c],pyridine, thieno[3,4,-b]pyridine, thieno[3,4,-c]pyridine.

The process according to the invention for the preparation of compounds of formula I is characterized by the fact that the compound of general formula II

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or its salts, in which R, R1, R2 have the meaning specified in formula I, and R7 means a group that can be replaced with that base, which corresponds to the residues A of formula I, chemically converted with that base and in the presence of tri-C1-C4 alkyliodosilane , preferably trimethyl- or triethyliodosilane, and

a) in the given example, we cleave off the present protecting group i

b) if necessary, we translate the obtained product into a physiologically tolerable acid addition salt.

The use of trimethyliodosilane is particularly preferred.

As residues R7 come into consideration especially acyloxy residues of lower aliphatic carboxylic acids, preferably with 1 to 4 carbon atoms, such as for example acetoxy or propoynyloxy, especially acetoxy, which may be substituted in the given example, such as for example chloroacetoxy or acetylacetoxy. For R7, other groups are also possible, such as carbamoyloxy.

The starting compounds are known from the literature or can be prepared according to procedures known from the literature (for example DE-OS 27 16 707, DE-OS 31 18 732, German patent applications P 32 07 840, P 32 47 613, P 32 47 614) .

From EP 64 740 as well as P 32 07 840. 4 it is known that compounds of the general formula I, in which R means a 2-aminothiazol-4-yl residue, and their physiologically tolerable salts have excellent antibacterial activity against both Gram-positive and Gram negative germs. These compounds can, for example, be prepared from compounds of the general formula II by direct chemical conversion with suitable bases, preferably in water or a mixture with water as a solvent. Furthermore, it is described in the literature (EP 60 144) that 3-iodomethyl-cephalosporin derivatives, for example compounds corresponding to those of formula I with A = I, react with pyridine bases to form the corresponding pyridinium compounds. These types of iodoalkyl compounds can generally be prepared from esters, for example acetates, with trimethyliodosilane (J. Amer. Chem. Soc. 99, 968, 1977; Angew. Chem. 92, 648, 1979), a reaction which was later transferred to cephalosporins (cf. EP 34 924, US 4 266 049, Tetrahedron Letters 1981, 3915, EP 70 706 (example 5).

According to the two-step procedure, described in EP 60 144, they convert for example acetates, which correspond to formula II (R7=OCOCH3), first into the compound 3-iodomethyl, only this is isolated and then chemically converted with the desired pyridine bases. Isolation of the final products requires chromatographic purification. The maximum utilization of the pure final product is less than 10% theoretically.

Suddenly, we have now established that according to the process according to the invention, the yield of the product with formula I is decisively increased up to more than ten times after the addition of a base to the reaction mixture, if we perform the nucleophilic replacement reaction from the beginning in the presence of an excess of the corresponding bases, which are the basis of the residue A in of formula I, i.e. tri-C1-C4-alkyliodosilane, preferably trimethyliodosilane.

The procedure is carried out by adding to the solution or suspension of compound II a base dissolved in a suitable solvent, which corresponds to residue A, and then trimethyliodosilane. Instead of trimethyliodosilane, we can use, for example, a reaction mixture of iodine and hexamethyldisilane, which we previously chemically converted at a temperature between about 60 and 120°C in a manner known from the literature, whereby trimethyliodosilane is formed. Instead of trimethyliodosilane, we can use triethyliodosilane, which is prepared in a way known from the literature, with equally good results.

The reaction is carried out at temperatures between about -5 and +100°C, preferably between +10 and +80°C.

Suitable inert aprotic solvents are, for example, chlorinated hydrocarbons, such as methylene chloride, chloroform, dichloroethane, trichloroethane, carbon tetrachloride or lower alkylnitriles, such as acetonitrile, or propionitrile, or freegenes or toluene; methylene chloride is a particularly excellent solvent.

The base, which corresponds to the residue A, is added in at least a stoichiometric amount up to twenty times the excess, we preferably work with such quantities, that the released amount of hydrogen iodide binds and at least 1 mol, preferably 2 to 5 mol of the base remains available for the substance.

Since, in addition to the R7 group, which needs to be changed, other functional groups present in the starting compound II, such as amino, carboxy or amide groups, react with trimethyliodosilane, we add the latter in at least four to about twenty times, preferably in five to ten times, excess .

The procedure for the preparation of celafosporin of formula I can also be performed by adding a mixture of the base, which corresponds to residue A, and trimethyliodosilane to a suspension of compound II in a suitable solvent, such as methylene chloride, or vice versa, and then the reaction occurs. A further variant consists in the fact that the reaction can be carried out after combining the reaction components in the manner described above in a closed system, such as in an autoclave, at a temperature between 10 and 100°C. After cooling to 0 to 20°C and venting the closed system, process in the usual way.

The carboxyl and N-amino functions in compound II can also be previously silylated with the addition of a silylated agent, such as bistrimethylsilylacetamide, bistrimethylsilyltrifluoroacetamide, trimethylchlorosilane, hexamethylsilazane, bistrimethylsilylurea, either without or in the presence of a base, preferably the desired base, which is the basic group A, in the forward described quantities. Then we add trimethyliodsilane in at least a stoichiometric amount or also in excess, preferably in an excess of two to ten times.

If functional groups, such as hydroxy groups and the like, are present in the base, which is the base of residue A in formula I, only these are first silylated with one of the aforementioned silylating agents and then used in the reaction.

The reaction products of formula I are for example isolated with the addition of water or mineral acids in water, for example diluted HCl, HBr, HI or H2SO4, from the aqueous phase in the usual way, for example with lyophilization of the aqueous phase, chromatography and the like. First of all, polar reaction products are precipitated from the reaction solution as poorly soluble salts with the addition of mineral acids in water, such as HCl, HBr, HI or H2SO4, dissolved in alcohol such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol or acetano or their mixtures.

These are then translated according to procedures known from the literature, for example according to patent application P 32 48 828.7 (patent) into physiologically tolerable acid addition salts.

The following exemplary embodiments for the compounds, which are prepared according to the methods of the invention, are necessary for further explanation of the invention, however they do not limit the invention.

Example 1

7-[2-(aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-[(2,3-cyclopentano-1-pyridino)methyl]-cef-3-em-4-carboxylate dihydroiodide

Variant a:

To a mixture of 45.5 g (0.1 mol) of 7-[2-(2aminothiazol-4-yl)-syn-methoxyimino-acetamido]-cephalosporanic acid and 900 ml of methylene dichloride, add 100 ml (0.85 mol) of 2, of 3-cyclopentanopyridine and then 140 g (100 ml, 0.7 mol) of trimethyliodosilane. Reflux the red-brown colored solution for 2 hours, then cool it to -15°C and, while shaking, add a solution of 60 g of potassium iodide in 250 ml of 2n HCl. A precipitate forms, which, with occasional shaking, is left in an ice bath for 2 hours and then overnight in the refrigerator. Drain, mix the yellow precipitate in a glass three times with 100 ml of ice water and drain each time. The wet product is then mixed with 500 ml of acetone, sucked off and washed three times with 100 ml of acetone each. After drying in a vacuum over H2SO4, we obtain 54.5 g (69 % of theory) of light yellow colored crystals with a decomposition point of 179 to 181°C.

C22H22N6O5S2 x 2HI x H2O (788.43)

Calc. C 33.51 H 3.32 I 32.19 N 10.66 S 8.13 H2O 2.3%

Mouth. C 33.6 H 3.6 I 31.3 N 10.7 S 7.1 H2O 2.5 %

IR (KBr): 1785 cm-1 (lactam CO)

1H-NMR (CF3CO2D): δ = 2.3 - 2.85 (m, 2H, cyclopentene H); 3.10 - 4.05 (m, 6H, 4 cyclopentene H and SCH2); 4.41 (s, 3H, OCH3); 5.25 - 6.23 (m, 4H, CH2Py and 2 lactam H); 8.11 (s, 1H, thiazole; 7.65 - 8.70 ppm (m, 3H, Py).

Option b

Heat 58.5 g (82 ml, 0.4 mol) of hexamethyldisilane to 70 to 75°C and add 88.8 g (0.7 mol) of iodine in portions over 20 minutes. After the addition of iodine, reflux for 30 minutes, cool to 10°C and dilute with 900 ml of methylene dichloride. Then we add 100 ml (0.85 mol) of 2,3-cyclopentenopyridine, then 45.5 g (0.1 mol) of 7-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido] cephalosporanic acid. The mixture is heated under reflux for 2 hours and then hydrolyzed with KI/2n HCl, as stated above. The resulting precipitate is isolated, as described for variant a. The yield is 57.5 g (73 % of theory) of the light yellow dihydroiodide salt. The compound is identical in all its properties to the one described above.

Option c:

To a solution of 4.6 g (36 mmol) of iodine and 35 ml of methylene dichloride, add 3.2 ml (20 mmol) of triethylsilane and heat the solution under reflux for 30 minutes. Cool, add 1.45 ml (12 mmol) of 2,3-cyclopentenopyridine and then 0.91 g (2 mmol) of 7-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]- cephalosporanic acid. The red-brown colored solution is heated under reflux for 2 hours, cooled to -20°C and hydrolyzed with the addition of a solution of 2 g of potassium iodide in 10 ml of 2n HCl. The mixture is stirred for 4 hours in an ice bath and left overnight in the refrigerator, the precipitate is sucked off and washed 3 times with 5 ml of ice water and 3 times with 10 ml of acetone. After drying, we get 1.1 g (70 % of theory) of light yellow crystals.

The compound is identical in all its properties to the compound described in variant a.

Example 2

3-[(2,3-cyclopenteno-1-pyridino)methyl]-7-[2-syn-methoxyimino-2-(2-phenylacetamido-thiazol-4-yl)acetamido]-cef-3-em-4- carboxylate hydroiodide

From 0.86 g (1.5 mmol) of 7-[(2-syn-methoxyimino-2-(2-phenylacetamidothiazol-4-yl)acetamido]-cephalosporanic acid 1.1 ml (9 mmol) of 2,3-cyclopentenopyridine and 1.1 ml (7.5 mmol) of trimethyliodosilane in 35 ml of methylene dichloride analogously to example 1a.After hydrolysis with 40 ml of 2n HCl at 5°C, the separated yellow precipitate is dried, washed with a little cold water and dried over P2O5.

The yield is 1.0 g (88 % of theory) of a light yellow solid.

IR (KBr): 1785 cm-1 (lactam CO)

1H-NMR(D6-DMSO): δ = 1.8 - 2.4 (m, 2H, cyclopentene H); 2.8 - 3.5 (m, 6H, 4 cyclopentene H and SCH2); 3.72 (s, 2H, CH2 - CO); 3.83 (s, 3H, OCH3); 5.17 (d, 1H, lactam H); 7.27 (s, 5H, C6H5); 7.5 - 8.8 (m, 4H, Py and thiazole); 9.67 (d, 1H, NH); 12.70 ppm (s, 1H, NH).

Example 3

3-[(2,3-cyclopenteno-1-pyridino)methyl]-7-[(2-syn-methoxyimino-2-(2-tritylamino-thiazol-4-yl)acetamido]-cef-3-em-4 -carboxylate hydroiodide

From 1.16 g (1.5 mmol) of 7-[(2-syn-methoxyimino-2-(2-tritylamino-thiazol-4-yl)acetamido]-cephalosporanic acid, 1.1 ml (9 mmol) 2, 3-cyclopentenopyridine and 1.1 ml (7.5 mmol) of trimethyliodosiline in 35 ml of methylene dichloride analogously to example 1a. After hydrolysis with 40 ml of 2n HCl at 5°C, the methylene chloride is removed with a rotary vacuum evaporator, the aqueous phase is decanted from the oily residue and the rest is mixed for 2 hours with 40 ml of water at 0 to 5° C. The resulting precipitate is filtered off with suction, washed with ice water and dried over P2O5.

The yield is 1.24 g (93 % of theory) of a light yellow solid.

IR (KBr) : 1785 cm-1 (lactam CO)

1H-NMR(D6-DMSO): δ = 1.8 - 2.4 (m, 2H, cyclopenthemic H); 2.9 - 3.5 (m, 6H, 4 cyclopentene H and SCH2); 3.80 (s, 3H, OCH3); 5.16 (d, 1H, lactam H); 5.50 (broad s, 2H, CH2Py); 5.74 (q, 1H, lactam H); 6.70 (s, 1H, thiazole); 7.30 (s, 15H, C6H5); 7.7 - 8.8 (m, 3H, Py); 9.0 (broad s, 1H, NH); 9.58 ppm (d, 1H, NH).

Example 4

7-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-(-1-pyridiniomethyl)-cef-3-em-4-carboxyl dihydroiodide

From 4.55 g (10 mmol) of 7-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamino]-cephalosporanic acid, 6.8 ml (8.5 mmol) of pyridine and 10 ml (70 mmol) of trimethyliodosilane in 100 ml of methylene dichloride analogously to example 1a. After cooling, the red-brown solution is hydrolyzed with a solution of 10 g of KI in 50 ml of 2n HCl, the mixture is stirred for 4 hours in an ice bath and left overnight in the refrigerator. The precipitate is filtered and washed four times with a little ice water. After drying over P205, we obtain 4.5 g (61 % of theory) of the title compound in the form of a yellow solid.

IR (KBr) : 1783 cm-1 (lactam CO)

1H-NMR(CF3CO2D): δ = 3.53 and 3.95 (AB,J = 19Hz 2H, SCH2); 4.40 (s, 3H, OCH3); 5.2 - 6.4 (m, 4H, CH2Py and 2 lactam H); 7.9 - 9.3 ppm (m, 6H, Py and thiazole).

Example 5

7-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-(-5-phenentridinomethyl)-cef-3-em-4-carboxylate dihydroiodide

A mixture of 0.91 g (2 mmol) 7-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamindo]-cephalosporanic acid, 2.87 g (16 mmol) phenanthridine and 2 ml ( 14 mmol) of trimethyliodosilane in 20 ml of methylene dichloride is heated under reflux for 2 hours. The mixture is cooled, the yellow crystalline precipitate of phenanthridine hydroiodide is sucked off and the filtrate is evaporated in a vacuum. This creates a precipitate, which is sucked off and washed successively with methylene dichloride, water and ether. After drying over P2O5, we obtain 930 mg (81 % of theory) of the title compound in the form of light yellow crystals.

IR (KBr) : 1785 cm-1 lactam CO)

1H-NMR(CF3CO2D): δ = 3.47 and 3.73 (AB,J = 18Hz, 2H, SCH2); 4.48 (s, 3H, OCH3); 5.25 and 6.4 (AB,J = 7Hz, 2H, CH2-phenanthridine); 5.40 and 6.03 (AB,J = 5Hz, 2H, 2 lactam H); 7.90 - 8.70 (m, 7H, phenanthridine and thiazole); 8.80 - 9.30 (m, 2H, 1-H and 10-H of phenanthridine); 9.88 ppm (s, 1H, 6-H of phenanthridine).

Analogously to example 1, variant a, we obtain the following compounds in the form of free bases, which correspond to the general formula I'

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After hydrolysis of the reaction solution and addition of sodium bicarbonate, the obtained crude hydroiodide salt is stored and chromatographed over silica gel (Merck 0.063 - 0.2 mm) with acetate/water (3:1). After lyophilization of product fractions, compounds from examples 6 to 20 are obtained in amorphous form.

Table 1: Compounds

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[image] [image]

Example 21

7-[(2-(2-amino-5-chlorothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-[(2,3-cyclopenteno-1-pyridinio)methyl]-cef-3- em-4-carboxylate

Obtained analogously to example 1a from 7-[(2-(2-amino-5-chlorothiazol-4-yl)-2-syn-methoxyimino-acetamido]-cephalosporanic acid and 2,3-cyclopentenopyridine with 66% yield.

1H-NMR (CF3CO2D): δ = 2.2-2.8 (m, 2H, cyclopentene H); 3.1-4.2 (m, 6H, 4 cyclopentene H); and SCH2); 4.21 (s, 3H, OCH3); 5.2-6.2 (m, 4H, CH2Py and 2 lactam H); 7.6-8.6 (m, 3H, Py).

Example 22

7-[(2-(5-amino-1,2,4-thiadiazol-3-yl)-2-syn-methoxyimino-acetamino]-3-[(2,3-cyclopenteno-1-pyridino)methyl]- cef-3-em-4-carboxylate

A mixture of 46 mg (0.1 mmol) of 7-[(2-(5-amino-1,2,4-thiadiazol-3-yl)-2-syn-methoxyimino-acetamido]-cefanosporanic acid, 0.1 ml (0.85 mmol) of 2,3-cyclopentenopyridine, 0.1 ml (0.7 mmol) of trimethyliodosilane and 1.5 ml of methylene dichloride are boiled under reflux for 1.5 hours. of water and the solution is chromatographed over a ready-made Lobar-B column (Merck, Darmstadt, art. 10401) with acetone/water (2:1). The product fractions are evaporated and lyophilized. Addition: 32 mg (61.6 %) of a colorless amorphous product.

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

1H-NMR (CF3CO2D): δ = 2.25-2.85 (m, 2H, cyclopentene H); 3.1-4.05 (m, 6H, 4 cyclopentene H); and SCH2); 4.30 (s, 3H, OCH3); 5.2-6.2 (m, 4H, CH2Py and 2 lactam H); 7.66-8.0 (m, 1Py-H); 8.16 - 8.7 ppm (m, 2H, Py).

Analogous to example 1, variant a, we obtain the following compounds in the form of free bases.

Table 2: Compounds

[image]

[image]

Claims (2)

1. Process for the preparation of cephem compounds of the general formula I [image] where means R is a thiazolyl residue [image] or a 1,2,4-thiadiazolyl residue [image] in which R3 is hydrogen or halogen and B is in the given example a substituted amino group, R1 hydrogen or methoxy, R2 hydrogen, in the given example substituted C1-C6-alkyl, in the given example substituted C2-C6-alkenyl, C2-C6-alkynyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C6-alkyl, C4-C7 -cycloalkenyl, or [image] is m and n each time 0 or 1, R4 and R5 can be the same or different and mean hydrogen, aryl or a C1-C4-alkyl group, or together with the carbon to which they are attached form a methylene or C3-C7-cycloalkylidene group, whereby C1-C4-alkyl and C3- The C7-cycloalkylidene group can be further substituted one or more times, R6 group COOH, CN or CONH2, where the latter can be substituted on nitrogen once or twice, [image] multiple times, equally or differently substituted in the given example by substituted C1-C6 alkyl, C1-C6-alkoxy, halogen, trifluoromethyl or hydroxy, or a phenanthridinium residue or a pyridinium residue [image] which can be one or more times, equally or differently substituted with in the given example substituted C1-C6-alkyl, whereby there can be 2 alkyl groups, standing in the ortho position, also closed in the given example a substituted di-do decamethylene ring, in which it can be one carbon atom of the ring replaced by a heteroatom and in which there can be one or two more double bonds; with in the given example substituted C2-C6-alkenyl, with C2-C6-alkynyl, with C3-C7-cycloalkyl or C3-C7-cycloalkylmethyl, whereby the ring of both substituents can also be substituted; with C4-C7-cycloalkenyl, with in a given example substituted C1-C6-alkoxy, with C2-C6-alkenyloxy or C2-C6-alkynyloxy, with halogen, trifluoromethyl or hydroxy, with in a given example substituted phenyl, benzyl, or heteroaryl, with formyl or ketalized formyl, with in the given example substituted C1-C6-alkylcarbonyl, which can also be found in ketalized form, with arylcarbonyl, with carbamoyl, and in which the R2O group is in the syn position, indicated by the fact that the compound of the general formula II [image] or its salts, in which R, R1 and R2 have the meaning given in formula I, and R7 means a group, which can be replaced by the base corresponding to the residues A of formula I, chemically converted with this base and in the presence of tri-C1-C4- alkyliodosilane, i a) in the given example, the present protecting group is cleaved off and b) if necessary, convert the obtained product into a physiologically tolerable acid addition salt. 2. The method according to claim 1, characterized in that tri-C1-C4-alkyliodosilane is trimethyl- or triethyl-iodosilane.