AT393839B - Stereocontrolled process for the preparation of novel penem compounds - Google Patents

Abstract

The invention relates to a stereocontrolled process for the preparation of penem compounds of the general formula IIa in which X is bromine. These compounds are valuable intermediates for preparing stereospecific azetidinones, from which in turn carbapenem or penem compounds of required stereospecificity are obtained. <IMAGE>

Description

AT 393 839 B

The present invention relates to a process for the preparation of new penem compounds of the general formula:

in which X stands for bromine.

The penem compounds are intermediate compounds for the preparation of compounds of the formula

m, wherein R1 is hydrogen or a conventional hydroxy protecting group.

From these compounds (ΙΠ), in turn, the optically active azetidinone intermediate compounds of the general formula

in which R 'is a conventional hydroxy protecting group and in which the absolute configuration for the carbon atoms Γ, 3 and 4 is R, R and R These azetidinones are used to prepare stereospecific carbapenem and penem antibiotics which have a (R ) -Hydroxyethyl substituents in the 6-position of the carbapenem or penemkeme and the absolute configuration R and S (trans) in the 5-or. 6 position. A variety of such compounds, including the natural fermentation product thienamycin, have been reported in the patent and technical literature to have exceptional antibacterial activity.

Several total synthesis processes for the preparation of the above-mentioned penem and carbapenem antibiotics have been reported, but these processes have so far remained unsatisfactory from an economic point of view, including: between the large number of stages required and the need to separate the mixtures of diastereomers formed in such processes.

One method of synthesizing carbapenems and penems of the type described above uses 6-aminopenicillanic acid (6-APA) as a starting material, an readily available substance that can be easily obtained by fermentation methods.

Hirai, et al. in Heterocycles 17: 201-207 (1982) report a process for converting 6-APA into the optically active 4-acetoxy-3-azetidinone of the general formula

-2-

AT 393 839 B which can be converted into biologically active penems and carbapenems by known processes. In this process, 6-APA is converted into the azetidinone given above according to the following scheme:

6-APA

CKj &gt; i $ 3r

CHjCHO -6 0 * C ^ OSi-r l! ? r s

2 »: o2cb3 CH3oB / c» 3cooa

Eg (CAEC) 2 / CH3COOH osi-f-A ·. U v · XMnO. —1- co2ch3

OAc 0 NH

For a detailed explanation: 6-APA is esterified to form the methyl ester and then by known methods, e.g. B. those described in British Pat. No. 2,045,755 A, converted into the methyl ester of 6,6-dibromophenicillin. This ester is then hydroxyethylated by the metal-halogen exchange process described in J. Org. Chem. 42, 2960-2965 (1977) to form a mixture of cis and trans diastereomers which, at least on a small scale, are separated chromatographically can be produced by producing the desired (R) -hydroxyethyl-cis-isomer. This isomer is tert. Butyldimethylchlorosilane silylates to produce the corresponding hydroxy-protected intermediate, which is then subjected to reductive bromination with zinc to produce a mixture of the cis- and trans- (R) -hydroxyethyl products, from which the

treated in acetic acid to cleave the thiazolidine ring to form a 4-acetoxyazetidinone intermediate which is oxidized with KMn04 to remove the β-methylcrotonate portion to give the desired optically active 4-acetoxyazetidinone intermediate. -3-

AT 393 839 B

Tetrahedron Letters 23 (29), 4021-4024 (1982) describe the following reaction scheme:

(C ^ Se, co2ch2c6h5

Nc} * “Λ'Λ

Me * lyBr CBjCHO -60 * C

The diazopenicillin ester starting material is converted into benzyl-6,6-bis (phenylselenyl) penicillinate, which is hydroxyethylated with MeMgBr and CH3CHO at -60 ° C to form a mixture of diastereomers from which the desired cis isomer can be isolated .

The optically active 4-acetoxyazetidinone can be used according to known methods for the synthesis of carbapenem and penem antibiotics. For example, tetrahedron Letters23 (22): 2293-2296 (1982) describes the conversion of this intermediate into Ihienamycin, and Chon. Pharm. Bull, 29 (11): 3158-3172 (1981) describes the use of this intermediate for the production of penem antibiotics.

Although the methods described above are principally suitable for the large-scale synthesis of (8R) -hydroxyethylpenem and carbapenem antibiotics, they suffer from the lack of stereospecificity in the aldol condensation step and in the reduction step, i. i. hydroxyethylation of the dibromophenicillin or bis (phenylselenyl) penicillin ester, and reduction of such hydroxyethylated intermediates to remove the bromine or phenylseleno group results in a mixture of diastereomers which must be separated to provide the desired optically active product. Such separation, particularly on an economic scale, leads to processes which are significantly less effective than in other cases.

However, when the penem compounds of the general formula (Ha &gt;) prepared in accordance with the invention are used in the course of the process for the preparation of the desired azetidinones, these are immediately obtained in the required stereoconfiguration.

The process according to the invention for the preparation of the penem compounds of the general formula (Ha) is characterized in that a compound of the general formula:

X

-4-

AT 393 839 B in which X and Y represent bromine, with a Grignard reagent of the general formula RjMgX 'or an organolithium compound of the general formula RjLi, in which Rj represents lower alkyl or aryl and X1 represents chlorine or bromine, in an anhydrous inert organic solvents and at a temperature in the range of about 0 ° to -78 ° C and then acetaldehyde with (exclusive) preparation of the desired new (8R) -hydroxyethyl-cis-isomer of the general formula (Ha)

The process for the preparation of the desired azetidinones of the formula (I) from the penem compounds (Ila) prepared according to the invention is that they are either a) in an inert organic solvent in the presence of a base at from -40 ° C. to room temperature a bulky triorganosilyl halide or triorganosilyl triflate for the preparation of the corresponding new intermediate compound of the general formula

in which R &quot; is a bulky triorganosilyl group and X has the meaning given above, and b) the new intermediate compound of the general formula (ü) a reduction in an inert solvent with a chemical reducing agent such as a zinc-silver pair, a zinc-copper pair , Sri ^, tin hydride, tin amalgam, zinc or zinc activated with acid (e.g. HCl or CH ^ COOH) or by means of a catalytic hydrogenation ring, the new 5,6-trans isomer of the general formula OR * thus prepared

(IHb ·), in which R &quot; has the abovementioned meaning, isolated or, instead of a) and b) a ’), the new intermediate of the general formula (Ha) is subjected to a reduction as under b) and the new 5,6-trans isomer of the general formula thus prepared

IF

isolated and -5- if desired

AT 393 839 B b1) the intermediate compound of the general formula (Dia) is converted in a manner known per se into the corresponding new compound of the general formula (Illb), in which c) the thiazolidine ring is then cleaved to produce an acetoxyazetidinone intermediate compound of the general formula

and d) the intermediate compound of the general formula (TV) is oxidized to remove the β-methylcrotonate component and the desired optically active azetidinone of the general formula (I) is prepared. In a variant of the method described above, the new intermediate compound of general formula (IIa) can be reduced before the protection of the functional hydroxy group.

The connections of the general formulas:

O (Π)

in which X is bromine and R1 is hydrogen or a conventional hydroxyl protective group are new compounds.

The process according to the invention leads to a «considerable improvement of the already known process for converting 6-aminopenicillanic acid into the optically active acetoxyazetidinone intermediate compound of the general formula (I) which is used for the synthesis of various carbapenem and penem antibiotics, including thienamycin, which is present in the broad spectrum of carbapenem general formula:

2 is used.

As mentioned above, the known processes following the 6-APA for the preparation of (8R) -hydroxyethyl-carbapenem and penem compounds include an aldol condensation reaction to introduce the desired 6-hydroxyl substituent. A method of the literature comprises converting 6-APA into the 6-acetyl derivative and then reducing this derivative to produce the hydroxyethyl penicillin product (JACS 103: 6765-6767, 1981). However, the reduction stage is not stereospecific and the desired optical isome must be separated from the mixture of the diastereomers. Direct hydroxy- -6-

AT 393 839 B ethylation of a 6-halogenopenicillin, 6,6-dihalogenpenicillin or 6,6-bis (phenylselenyl) penicillin is described, for example, in Chem. Pharm. Bull. 29 (10): 2899-2909 (1981), J. Org Chem. 42: 2960-2965 (1977), Heterocycles 17: 201-207 (1982) and Tetrahedron Letters23 (39): 4021-4024 (1982), but this method suffers from the fact that the aldol reaction does not occur on the penicillin intermediate is stereospecific and it is necessary to separate the desired (8R) -hydroxyethyl isomer before proceeding with the remaining stages of the synthesis.

The invention is based on the unexpected discovery that an aldol condensation reaction on certain 6,6-disubstituted anhydropenicillins for the exclusive formation of only one stereomer, namely the isomer of the general formula:

X = bromine, which has the desired 5R, 6R, 8R stereochemistry. This stereospecific hydroxyethylation eliminates the need to separate the stereoisomers subsequent to this step and, coupled with the stereo-selective reductive removal of X, greatly improves the usefulness of the 6-APA pathway for the synthesis of penem and Carbapenem antibiotics.

The general reaction scheme for the preparation of the azetidinone from 6-APA is illustrated below with the 6,6-dibromophenicillin intermediate used according to the invention:

CHjMg &amp; r

CHjCHO

-7-

AT393 839 B

In order to illustrate the above process in more detail, 6-APA is first converted into a 6,6-dibromanhydropenicillin intermediate compound of the general formula by known processes

X

in which X and Y stand for bromine, transferred L The interconnection »! of the general formula (V) - the starting compounds of the process according to the invention - are known compounds »! or can be prepared by known methods. They can be prepared by converting 6-APA to the corresponding 6,6-dibromophenicillanic acid, an acid halide or a mixed anhydride thereof, and then reacting it with a tertiary amine to produce the anhydropenicillin. GB-PS 2 405 755A describes the preparation of various 6,6-dihalogenpenicillanic acid, such as 6,6-dibromophenicillanic acid, 6-chloro-6-iodpenicillanic acid, 6-bromo-6-iodpenicillanic acid and 6,6-diiodopenicillanic acid. Tetrahedron Letters 23 (39): 4021-4024 (1982) describes the preparation of 6,6-bis (phenylselenyl) penicillins. The conversion of 6,6-dihalogenpenicillanic acids into the corresponding anhydropenicillin is described, for example, in J. Chem. Soc. (C), 2123-2117 (1968), where the preparation of 6,6-dibromanhydropicicin is specifically described. U.S. Patent 3311638 teaches general methods for converting penicillins to anhydropenicillins.

The reaction step of the present invention is the key step in the process for the preparation of the stereospecific azetidinones by the aldol condensation and anhydropicillin intermediate for the exclusive formation of the desired optically active isomer, i. i. which carries stereoisomers with a cis configuration at carbon atoms 5 and 6 and an (8R) -hydroxyl substituent at position 6. This unexpected stereospecific aldol condensation eliminates the need to separate the diastereomers as required in the known processes and therefore largely increases the practicality of the 6-APA route for the synthesis of carbapenem and penem end products. -8th-

AT 393 839 B

The aldol condensation can be carried out essentially in the same way as in the known reactions with penicillins, see for example J. Org. Chem. 42 (18): 2960-2965, (1977). First, the 6,6-dibromanhydropenicillin is converted to a metal-halogen exchange process at temperatures below about 0 ° C e.g. B. 0 ° C to 78 ° C, using an organolithium reagent or a Grignaid reagent, an enolate is generated, the enolate thus produced is then reacted in situ with excess acetaldehyde to form the hydroxyethylated product.

The aldol reaction stage is carried out in an inert anhydrous organic solvent, e.g. B. methylene chloride, chloroform, tetrahydrofuran, diethyl ether, toluene, dioxane, dimethoxyethane or mixtures thereof at temperatures below 0 ° C and preferably below about -20 ° C. The enolate is generated using about one molar equivalent of organolithium reagent or Grignard reagent

Preferred organolithium reagents are those of the type RjLi in which Rj is for lower alkyl, i.e. Cj-Cg-alkyl, or aryl, i.e. i. Cg-CjQ-aryl such as phenyl, is an example of a suitable Chrganolithium reagent is n-butyl-lithium. The Grignard reagent is preferably a reagent of the type RjMgX, where Rj is Cj-Cg-alkyl or Cg-CiQ-aryl and X is chlorine or bromine. Preferred Grignard reagents are CH ^ MgBr and CH ^ MgCl. A preferred embodiment involves the use of CHgMgCl at a temperature of about -40 ° to -45 ° C. Another preferred embodiment involves the use of CH3MgBr at a temperature of about -20 ° C. After the enolate is formed, a molar excess of acetaldehyde is added to produce the desired hydroxyethylated isomer.

In the further processing of the compound (Ha) by direct reduction thereof, the hydroxyl group of the compound of the general formula (purple) is protected to form the intermediate compound of the general formula (IDb) before the subsequent cleavage step of the thiazolidine ring is carried out.

Protection of the hydroxyl group is accomplished according to known methods using conventional hydroxy protecting groups known to those skilled in the art. Protection of the hydroxyl functional group of the new intermediate of general formula (Ila) or (IHa) is desirable to avoid side reactions and reduced yields in later stages of the reaction sequence, e.g. B. to prevent the ring degradation with Mercuri salt. Suitable hydroxy protecting groups can be, for example, acyl groups such as benzyloxycarbonyl, benzhydryloxycarbon, trityloxycarbonyl, p-nitrobenzyloxycarbonyl and 2,2,2-trichloroethoxycarbonyl, aralkyl groups, such as benzyl, benzhydryl, trityl or p-nitrobenzyl or triorganosilyl groups ) -Alsylsilyl (e.g. trimethylsilyl, triethylsilyl, triisopropylsilyl, isopropyldimethylsilyl, teit-butyldimethylsilyl, methyldiisopropylsilyl or methyldi-tert.-butylsilyl), triarylsilyl (e.g. triphenylsilylylilyllysilyl, tri-pylsilyl . Tribenzylsüyl). Examples of these and other suitable hydroxy protecting groups and methods of making and removing them are known, see for example Piotective Groups in Organic Synthesis, T. W. Greene, John Wüey &amp; Sons, New York, 1981, chap. 2nd

Although any hydroxyl protecting group can be used in the reductive removal of the substituent X, it has been unexpectedly found that the use of bulky trioiganosquyl-hydroxyl protecting groups such as tert-butyldimethylsilyl, tert-butyldiphenylsilyl or triisopropylsilyl for essentially exclusive formation (e.g. about 95%) of the desired new trans-isomer of the general formula (mb) leads, while the use of other hydroxyl protective groups or the unprotected intermediate compound of the general formula (Ha) leads to the coproduction of the undesired cis isomer in an amount which is sufficient, to require a separation stage. Therefore, the compound (Ha) is preferred in the corresponding hydroxyl-protected intermediate compound of the general formula (ü), wherein R &quot; a bulky, bulky triorganosilyl group, preferably the L-butyldimethylsilyl.tert-butyldiphenylsilyl or triisopropylsilyl group, is transferred to then subject this intermediate to reduction, followed by substantially stereospecific formation of the trans compound of general formula (IHb)

The invention is explained in more detail by the following examples, to which, however, it is not restricted. All temperature data relate to ° C. unless otherwise stated.

PÄspisLU

Preparation of anhydro-6a-bromo-6ß - [(IR) -hydroxyethyl] penicülin A. Preparation of the starting material anhydro-6,6-dibromophenicillin

Br Br

-9-

AT 393 839 B

A cold (ice-methanol bath) solution of 20.00 g (55.56 mmol) of 6,6-dibromophenicillanic acid in 200 ml of CH2Cl2 is treated dropwise with 8.00 ml (58.4 mmol) of triethylamine and stirred for 15 min. 8.40 ml (61.2 mmol) of trifluoroacetic anhydride are added dropwise to the solution. The mixture is stirred for 30 min and then treated dropwise with 4.8 ml (61.2 mmol) of pyridine. The mixture is stirred for 30 min at -10 ° C and then 8h at 5 ° C. The mixture is washed successively with ΙΝ aqueous HCl, water, 1M aqueous NaHCO ^ and brine and dried over MgSC ^. The residue obtained after evaporation of the solvent is redissolved in ethyl acetate (EtO Ac) and treated with activated carbon to give the title compound.

Tp 102-103 ° C (CH3OH), (16.1 g, 47.2 mmol, yield 85%): 1Hmr (CDCI3.80 MHz) δ: 5.80 (1H, s, H-5), 2.21 (3H, s, CH3) , and 2.15 ppm (3H, s, CH3); ir (CH2CI2) v max: 1800 (s, β-lactam C = 0), 1708 (s, lactone C = 0) and 1640 cm'1 (w, olefin); [a] D22 + 88.9 ° (£ 0.144, CH3OH);

Anal. Ber. for C8H7N02SBr2: C 28.17, H 2.07, N 4.10; Found: C 28.08, H 1.98, N 4.06. B. Anhydro-6a-bromo-6ß - [(rR) -hydroxyethyl] penicillin

15.02 g (44 mmol) of anhydro-6,6-dibromophenicillin are dissolved in 450 ml of cold (-78 ° C) THF, treated dropwise with a 2.85 M solution of 18.0 ml (513 mmol) of MeMgBrin ether and 20 min stirred at -78 ° C. The magnesium enolate obtained is trapped in excess acetaldehyde (25 ml, 0.45 mmol) and stirred for 20 min. The cooling bath is removed and 70 ml of ΙΝ aqueous HCl and 300 ml of ether are added to the reaction mixture. The aqueous phase is removed and extracted twice with 200 ml ether each time. The organic phases are combined, washed in succession with ΙΝ-aqueous HCl, water, ΙΜ-aqueous NaHC03 and brine and dried over MgSO4. The solvent is removed, the title compound (13.8 g; 42.7 mmol; yield 97%) in the form of an oil: 1Hmr (CDCI3) δ: 5.61 (1H, s, H-5), 4.28 (1H, q, 1 = 6.0, Η-Γ), 2.21 ( 3H, s, CH3), 2.16 (3H, s, CH3), 1.64 (1H, bs, OH), and 1.31 ppm (3H, d, 1 = 6.0 Hz, CH3); ir (CH2C12) v, ^: 3560 (m, OH), 1785 (s, β-lactam C = 0), 1710 (s, lactone 0 = 0) and 1635 cm'1 (m, olefin); [a] D22 + 83.8 ° (ς 0.128, MeOH);

Anal. Ber. For. C10H12NO3SBr C 39.23, Η 3.95.N4.57; Found: 38.31, H4.63, N4.61.

Example 2:

Preparation of anhydro-6a-bromo-6ß - [(l'R) -hydroxyethyl] penicillin, the aldol condensation taking place at a relatively high temperature (-20 ° C.):

To a »solution of 10.23 g of anhydro-6,6-dibromophenicillin 150 ml of dry THF cooled to -20 ° C is added dropwise 12.21 ml of methyl magnesium bromide within 10 min, while the temperature is kept at -10-

Claims (1)

AT 393 839 B holds -15 ° to -20 ° C. The solution obtained is stirred at -20 ° for 10 min, whereupon 8.4 ml of acetaldehyde, initially dropwise, are added over the course of 5 min, the temperature being kept at -15 ° to -20 ° C. The solution is stirred for 15 min at -20 ° C. 10 ml of saturated ammonium chloride and then 80 ml of water are added to the reaction mixture. The mixture is then extracted with ethyl acetate (150 ml. 50 ml). The ethyl acetate extract is washed twice with 100 ml of brine each time, dried over anhydrous sodium sulfate and concentrated to give 8.9 g (97%) of an oil. HPLCX 92% cis, no trans isomer, 8% impurities. xcolumn: solvent: stream: detection: dilution: pPorasil (water) 3% CHoCN / CH9C19 90ml / li and 275 nm 0.2 Example 3: preparation of anhydro-6a-bromo-6ß - [(l, R) -hydroxyethyl] penicillin, CH ^ MgCl being used as the Grignard reagent. A solution of 34.1 g of anhydro-6,6-dibromophenicillin in 350 ml of dry THF is cooled to -45 ° C and 39.6 ml of methyl magnesium chloride are added dropwise within 20 minutes, the temperature being below -40 ° C is held. The resulting solution is stirred at -45 ° to -40 ° C for 10 minutes and 28 ml of acetaldehyde are initially added dropwise over 5 minutes, keeping the temperature below -30 ° C. The solution is stirred at -40 ° C for 15 min. 35 ml of saturated ammonium chloride and then 400 ml of water are added to the reaction mixture. The mixture is extracted with toluene (350 ml and 150 ml). The toluene extract is washed twice with 300 ml of brine, dried over anhydrous magnesium sulfate and concentrated to a volume of about 100 ml. 300 ml of toluene are added to the concentrated solution and the mixture is then concentrated to about 300 ml. This toluene solution is used for further processing without further processing. PATENT CLAIM Process for the production of new penem compounds of the general «! Formula: (Ha), in which X represents bromine, characterized in that a compound of the general formula: -11- (V) 5 X (V) 5 X 10 AT 393 839 B ^ -rsv r in which X and Y represent bromine, with a Grignard reagent of the general formula RjMgX 'or an organolithium compound of the general formula RjLi, in which Rj represents lower alkyl or aryl and X' represents chlorine or bromine, in an anhydrous inert organic solvent and at a temperature in the range from about 0 ° to -78 ° C. and then acetaldehyde is added with (exclusive) preparation of the desired new (8R) -hydroxyethyl-cis-isomer of the general formula (Ha). 20 25 30 35 40 45 50 -12- 55