AT413382B - Preparation of beta-lactam derivatives used as antibacterial agents by reacting cephalosporanic acid derivative with imine compound, then thiourea compound - Google Patents

Abstract

Preparation of beta -lactam derivatives (I) comprises: (1) reacting a cephalosporanic acid derivative (IV) with an imine derivative (III) and (2) reacting the obtained compound (II) with a thioether compound (V) to give a compound (VI) which is then desilylated to give (I) or (3) desilylating (II) and reacting with thiourea in a solvent system containing organic solvent and water to give (I). Preparation of beta -lactam derivatives of formula (I) comprises: (1) reacting a cephalosporanic acid derivative of formula (IV) with an imine derivative of formula (III) and (2) reacting the obtained compound of formula (II) with a thioether compound of formula (V) to give a compound (VI) which is then desilylated to give (I) or (3) desilylating (II) and reacting with thiourea in a solvent system containing organic solvent and water to give (I). [Image] [Image] X, R1substituents useful in cephalosporin chemistry; REa negative charge or COOREan ester; R : H or silyl; RE'silyl or COORE'an ester; Y : halo; Y' : a group forming a reactive compound (III); R' : H or silyl and R'' : silyl. An independent claim is included for new compounds of formula (VIa). [Image] R'a>, RE'a, R'''a>tri-1-4C alkylsilyl. ACTIVITY : Antibacterial. No biological data is given. MECHANISM OF ACTION : None given.

Description

5 5 2

AT 413 382 B 10

The invention relates to a process for the preparation of a compound of the formula

Via: R = H Vlb: R = Na where R is hydrogen, a monovalent metal atom or a pharmaceutically acceptable salt. 15

Numerous processes for the preparation of 3'-sulfur-substituted cephalosporin antibiotics are described. The introduction of the 2- (2-aminothiazol-4-yl) -2 (Z) - (methoxyimino) acetyl radical in position 7 can be carried out, for example, by reaction of an activated derivative of 2- (2-aminothiazol-4-yl) -2 (Z ) -methoxyiminoacetic acid with the corresponding 3'-sulfur-substituted β-lactam nucleus. Another possibility is a disclosed in USP 4,266,049 technology. Here, a 7-acyl-3-acetoxymethylcephalosporinderivat with the aid of a Jodtrialkylsilans converted into the corresponding (persilylated) 3-iodomethyl compound and then substituted nucleophilic in the i'-position. However, in these processes, for example, there may be problems in separating the activating component from the product after the acylation reaction, and in the case of using iodine or iodine compounds, stained compounds which are also difficult to separate and / or unfavorably deteriorate due to poor stability affect the products. 30

These possible disadvantages can be circumvented by proceeding according to the process of the invention for the preparation of compounds of the formula IVa or VIb, which is characterized in that 7- [2- (aminothiazol-4-yl) -2 (Z) - ( methoxyimino) acetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid or an alkali or ammonium salt of the formula

35 40 wherein R 'is hydrogen or an alkali or ammonium ion, in a compound of formula 45 50

CH,

III where R " represents hydrogen or a trialkylsilyl group, this compound of the formula III is reacted with a sulfur nucleophile of the formula IVa or IVb or a mixture of the two compounds IVa and IVb 5 3

AT 413 382 B

IVa: Re = H. R, = Si (CH 3), IVb: R 6, R 7 = Si (CH 3) 3 in the presence of an activated trialkylsilane of the formula 10 15 o

II R2R3R4S * os ι? V V wherein R2i R3 and R4 are the same or different and are each an aryl or Ci-C4-alkyl radical and R5 is an alkyl, perfluoroalkyl or optionally substituted aryl radical, and reacted from the Reaction mixture isolated the compound of formula I. The replacement of the acetoxy group in the starting compound of the formula II is accomplished here by means of an activated trialkylsilane of the formula V. In the conversion of cefo-taxim of the formula II into a silylated, reactive derivative of the formula III and in the preparation of the nucleophile of the formula IV, the choice of silylating is crucial. Since activated trialkylsilanes of the formula V themselves are strong silylating agents, it is desirable to achieve a high degree of silylation in the preparation of the reactants of the formulas III and IV so as to minimize the amount of compound of formula V to be employed. However, the reaction proceeds even without high degree of silylation of the reactants of the formulas III and IV, if one uses a correspondingly larger amount of compound of formula V 30.

It is likewise advantageous that in the preparation of the compounds of the formulas III and IV only those silylating agents are used whose by-products do not or only to a small extent react with the trialkylsilane of the formula V. 35

In the preparation of the reactant of formula III, the choice of the silylating agent further depends on whether one starts from cefotaxime acid in which R is a hydrogen atom, or from a salt, for example from the sodium salt in which R is sodium. For example, 1,1,1,3,3,3-hexamethyldisilazane (HMDS), N, 0-bis-40 (trimethylsilyl) trifluoroacetamide (BSTFA), N-methyl-N-trimethylsilyl trifluoroacetamide (MSTFA) are suitable for cefotaxime acid. or a combination of said silylating agents. For cefotaxime sodium, for example, bis (trimethylsilyl) sulfate (BSS) or else BSTFA or HMDS can be used in the presence of a halotrialkylsilane, for example trimethylchlorosilane (TMCS). If one has the choice of using either cefotaxime acid or the sodium salt, the sodium salt is clearly to be preferred. Cefotaxime acid is a highly solvating molecule. For example, an ethanol solvate and the acetone solvate are described in the literature. In addition, it can contain considerable amounts of water. Cefotaxime sodium, on the other hand, is low in residual solvent and relatively low in water, thus consuming less silylating agent, which can be a significant cost factor. 50

BSTFA is preferably suitable for the preparation of the reactant of the formula IV, with which complete silylation of the thiol function and other silylatable groups present in the molecule is generally achieved, but inexpensive silylating agents, for example HMDS, bis (trimethylsilyl) - may also be used. urea (BSU), 2-trimethylsilyl-1-oxazolidinone (TMSO) or 55 TMCS in the presence of a base or else a combination of one of the last-mentioned silyl-4

AT 413 382 B, for complete S-silylation, preferably with BSTFA. Also with bis (trimethylsilyl) acetamide (BSA), the S-silylated compound of formula IV is usually obtained. 5 If one chooses potent and universal silylating agents, for example BSTFA, a one-pot variant is also suitable. Thus, for example, cefotaxime acid can be silylated together with the selected sulfur nucleophile and finally mixed in the same vessel with the activated silane of formula V and reacted. Depending on the achieved degree of silylation of the 7-amide function of the compound of formula III and the thiol function (and optionally other silylatable functional groups) in the radical X of the compound of formula IV is then after combining the reactants of the formulas III and IV with a corresponding excess of the activated Silylsulfonsäureesters the formula V added. 15

The choice of the activated silane of the formula V depends on its reactivity but also on its availability. There are e.g. the commercially available trialkylsilyl-sulfonic acid esters trimethylsilyl-trifluoromethanesulfonate (TMSTf), t-butyl-dimethylsilyl-trifluoro-methanesulfonate, trimethylsilyl-heptafluoropropanesulfonate, trimethylsilyl-methanesulfonate or trimethylsilyl-benzenesulfonate. Particularly suitable here are compounds of the formula V in which R 2, R 3 and R 4 have the above meaning and R 5 is a strongly electron-withdrawing substituent, for example a perfluorinated alkyl group or an aryl group with electron-withdrawing substituents. The solvent should be inert to all reagents used during the synthesis, but should also be compatible with the reaction conditions (temperature, concentration, silylating agent). Here are, for example, chlorinated hydrocarbons such as dichloromethane, aliphatic and aromatic hydrocarbons such as cyclohexane or toluene, nitriles such as acetonitrile, ethers such as tetrahydrofuran, but also mixtures of the solvents mentioned. Typically, the same solvent is used in both the silylations to prepare the compounds of formulas III and IV as well as in the reaction with the compound of formula V to ensure ease of solvent regeneration. Dichloromethane, but also cyclohexane or toluene, are preferably used in order to be able to filter off any sparingly soluble by-products resulting from the silylations, for example urea from BSU, before the reaction with a compound of the formula V.

After complete reaction of the reactants of the formulas III and IV in the presence of a compound of formula V, the reaction mixture in an aqueous or alcoholic system, optionally in the presence of an organic solvent, neutralized with a base neutralized and 40 by known methods in the compound of formula Via or Vlb transferred.

The reaction product is first extracted from the reaction mixture in the pH-neutral range with a suitable organic solvent, preferably dichloromethane, with water. This is preferably done after a desilylation step with an alcoholic solution of sodium acetate or another alkali salt of a weak acid in the presence of a little water and then adding organic solvent and water.

Optionally, after extraction with charcoal or adsorbent resin, decolorizing and subsequently precipitating and isolating the compound of formula Via in the appropriate pH range, usually between 2.0 and 3.5. Subsequently, if appropriate, a conversion of the acid of the formula Via into the desired, pharmaceutically acceptable form. Likewise, isolation of the pharmaceutically acceptable or used form without intermediate isolation of the acid is also possible. 55 5 5 5

AT 413 382 B 10

According to the subject process, the preparation of ceftriaxone disodium of the formula

Via: R = H Vlb: R = Na therefore preferably proceeded as follows: 15

A suspension of cefotaxime sodium of formula II in which R 'is sodium is suspended in dichloromethane, cooled and treated with 2 to 4 molar equivalents of BSS. At the same time, a suspension of 3-mercapto-2-methyl- (2,5-dihydro-6-hydroxy-5-oxo-as) -triazine in dichloromethane is admixed with 1 to 5 molar equivalents of BSTFA. After silylation, the two components of the formulas III and IVa or IVb

IVa: Re = H, R7 = Si (CH3) 3 IVb: Re, R7 = Si (CH3) 3 30 then combined, cooled and mixed with 1 to 10 molar equivalents TMSTf. In the case of the reaction in the same vessel (one-pot variant), preference is given to cefotaxime acid of the formula II in which R is hydrogen and 3-mercapto-2-methyl- (2,5-dihydro-6-hydroxy-5- oxo-as) -triazine was suspended together with dichloromethane and reacted with an excess of silylating agent. To the solution thus obtained, TMSTf is then added as described above.

After completion of the reaction, the reaction mixture is desilylated in an aqueous or aqueous-methanolic solution of sodium acetate, the water content is preferably kept small, and preferably about 5%. 40

By further addition of water and a water-immiscible organic solvent (for ease of regeneration, preferably dichloromethane), the extraction of the product is made possible as the sodium salt of formula VIb in the aqueous phase. The pH is usually between 5 and 7, preferably between 6 and 6.5, and is optionally adjusted by addition of a base, preferably sodium bicarbonate or sodium acetate.

After separation of the organic phase may now optionally be a decolorization with activated carbon or adsorber, preferably by stirring with activated carbon, take place. 50

For the separation of water-soluble constituents, if appropriate, the pH is set to a range between 1.0 and 3.5, preferably 3.0, the product precipitating as the acid of the formula Via. After filtration, ceftriaxone acid of the formula Via can then be converted into the target compound of the formula VIb by known methods by reacting with the sodium salt of a weak acid, for example sodium hydroxide, sodium carbonate, sodium 6

AT 413 382 B hydrogen carbonate or sodium acetate, at a pH of 4 to 8, preferably from 5.8, ceftriaxone disodium of formula VIb produced and crystallized from water / acetone.

Optionally, at the stage of ceftriaxone acid of the formula Via, a cleaning-5 operation is performed. For this purpose, the compound of formula Via is dissolved in an alcohol, preferably methanol, treated the alcoholic solution with activated carbon or adsorbent and after evaporation of most of the alcohol, the compound of formula Vlb as described above and, optionally in the presence of a little alcohol, from Water / acetone crystallized. Ceftriaxone disodium of the formula VIb is obtained in excellent quality.

The preferred process according to the invention can be summarized as follows: a) silylation of cefotaxime sodium with bis (trimethylsilyl) sulfate and preparation of the sulfur felnucleophils of the formula IVb by silylation of the thiol function and the hydroxyl function with bis (trimethylsilyl) trifluoroacetamide or common silylation of cefotaxime acid and generation of the sulfur nucleophile of the formula IVb by silylation of the thiol function and the hydroxyl function with BSTFA in the solvent dichloromethane. b) Reaction of the compound of formula III where R " a trialkylsilyl group or hydrogen, with a sulfur nucleophile of formula IVa or IVb in the presence of tri-methylsilyl trifluoromethanesulfonate. c) isolation of ceftriaxone acid of formula Via after aqueous-alcoholic workup and 25 optionally treatment of the compound of formula Via with activated carbon in an alcohol or in a water-alcohol mixture. d) conversion of ceftriaxone acid of formula Via into ceftriaxone disodium of formula VIb and crystallization of the compound of formula I from acetone and water, optionally in the presence of a little alcohol. 30

In the following examples, which are intended to illustrate the invention, but without limiting the scope, all temperatures are given in degrees Celsius.

Example 1: 7- [2- (aminothiazol-4-yl) -2 (Z) - (methoximino) acetamido] -3 - {[(2,5-dihydro-6-hydroxy-35 2-methyl-5-oxo -as-triazin-3-yl) thio] methyl} -3-cephem-4-carboxylic acid. Disodium salt (ceftriaxone disodium) Solution A: 23.87 g of 7- [2- (aminothiazol-4-yl) -2 (Z) - (Methoxyimino) acetamido] -3- (acetyloxy) methyl-3-cephem-4-carboxylic acid.Sodium salt (cefotaxime sodium) are suspended in 100 ml of anhydrous 40 dichloromethane and 30.31 g BSS added under ice cooling, inert gas and light. The solution is clear after about 30 minutes and is stirred for a total of 3 hours in an ice bath. Solution B: 7.95 g of 3-mercapto-2-methyl- (2,5-dihydro-6-hydroxy-5-oxo-as) -triazine are suspended in 32 ml of 45% anhydrous dichloromethane and mixed under protective gas with 32.18 g of BSTFA. The resulting solution is refluxed for a total of 3 hours. Solution B is added all at once to solution A with stirring, and 38.90 g of TMSTf are added to the mixture under ice-cooling, protective gas and light exclusion. The reaction mixture 50 is stirred overnight at room temperature for 16 hours, and the reddish solution is subsequently introduced into an intensively stirred, ice-cold solution of 20.50 g of sodium acetate in 350 ml of methanol / water (95/5). After stirring for 30 minutes, 250 ml of water and 500 ml of dichloromethane are added and the pH of the clear, biphasic mixture is adjusted to 6.5 with saturated sodium bicarbonate solution. After 15 minutes, the organic phase is separated abge-55, washed the aqueous phase with 100 ml of dichloromethane and then with

Claims (5)

7 AT 413 382 B 10 g charcoal Norit CG-1 destained for 15 minutes. The activated carbon is filtered off and washed 3 times with 50 ml of water, after which the pH of the filtrate with 2N HCl within 15 minutes to 3.0. This precipitates a yellowish precipitate, the precipitation is completed by stirring for 15 minutes in an ice bath. The wet product can after filtration 5 and rinsing with ice water (5 x 50 ml each) are stored without decomposition at -20 ° until the conversion. The moist product (about 200 g) is dissolved in 3000 ml of methanol and the solution stirred for 15 minutes after addition of 2.5 g of activated carbon Norit CG-1. The activated carbon is filtered off, washed three times with in each case 50 ml of methanol and the filtrate is evaporated in vacuo at 30-35 °. The residue is then mixed with 300 ml of acetone and 150 ml of water and the pH of the suspension with 5 M aqueous sodium acetate solution to 5.8. The title compound is then crystallized by addition of a total of 1500 ml of acetone within 1 hour with exclusion of light, the precipitate was filtered off and washed three times with 100 ml of acetone. After drying of the precipitate at 50 mbar, the title compound is obtained as a hemiheptahydrate in a purity of 99.9% (HPLC, area). Example 2: 7- [2- (aminothiazol-4-yl) -2 (Z) - (methoximino) acetamido] -3 - {[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo) as-triazin-3-yl) thio] methyl} -3-cephem-4-carboxylic acid. Disodium salt 20 (one-pot variant) 23.87 g of 7- [2- (aminothiazol-4-yl) -2 (Z) - (methoxyimino ) acetamido] -3- (acetyloxy) methyl-3-cephem-4-carboxylic acid (cefotaxime acid) and 7.95 g of 3-mercapto-2-methyl- (2,5-dihydro-6-hydroxy-5-oxo-as ) -triazine are suspended in 150 ml of anhydrous dichloromethane and treated under protective gas 25 and light with 57.92 g of BSTFA. The resulting solution is refluxed for a total of 3 hours with exclusion of moisture and light and then cooled under inert gas in an ice bath. After addition of 33.34 g of TMSTf, the ice bath is removed and the solution is stirred for 5 hours with exclusion of light. For work-up, the reaction mixture is added to an intensely stirred, ice-cold solution of 20.50 g of sodium acetate in 350 ml of methanol / water (95/5) and then treated as in Example 1. The title compound is obtained as a hemiheptahydrate in a purity of 99.6% (HPLC, area). Claims: 1. A process for the preparation of a compound of the formula Via: R = H Vlb: R = Na where R is hydrogen or a monovalent metal ion, in particular a sodium ion, characterized in that 7- [2- (aminothiazol-4-yl) -2 (Z) - (methoxyimino) acetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid or an alkali or ammonium salt of formula 55 δ 5 ΟΗ wobei wobei wobei 413 382 Β 10 15 20 wherein R 'is hydrogen or an alkali or ammonium ion, by reacting with a silylating agent in a compound of formula where R " represents hydrogen or a trialkylsilyl group, this compound of the formula III is reacted with a sulfur nucleophile of the formula IVa or IVb or a mixture of the two compounds of the formula IVa and IVb IVa: R6 = H, R7 = Si {CH3) 3 IVb: R6, R7 = Si (CH3) 3 in the presence of an activated trialkylsilane of the formula II wherein R 2, R 3 and R 4 are identical or are different and are each an aryl or Ci-C4-alkyl radical and R5 is an alkyl, perfluoroalkyl or optionally substituted aryl radical, is reacted, desilylated and from the reaction mixture, optionally after conversion to the salt form wherein R is a monovalent metal ion is isolated, the compound of formula Via or Vlb. 2. The method according to claim 1, characterized in that one isolates ceftriaxone acid of the formula 45 Via and then converted into the disodium salt of formula VIb. 3. The method according to claim 1, characterized in that trimethylsilyl trifluoro-methanesulfonate as activated silane of the formula V, wherein R2, R3 and R4 are methyl groups and R5 is a trifluoromethyl group used. 50 4. The method according to claim 1, characterized in that the sulfur nucleophile with N, 0-bis (trimethylsilyl) trifluoroacetamide or with N, 0-bis (trimethylsilyl) acetamide in an S-silylated reactant of the formula IV, at R7 is a trimethylsilyl group converts. 55 9 AT 413 382 B 5. The method according to claim 1, characterized in that silylating the reactants of the formulas III and IV in the same reaction vessel and then reacted with the compound of formula V. 5 6. 3-Mercapto-2-methyl- [2,5-dihydro-5-oxo-6- (trimethylsilyl) oxy-as] -triazine of the formula IVa. Germs drawing 10 15 20 25 30 35 40 45 50