CS253736B2 - Process for the stereospecific controlled preparation of derivatives of penicillanic acid - Google Patents

Description

The present invention relates to a novel stereospecifically controlled process for the production of pencilin derivatives useful for the production of a key intermediate used in the synthesis of carbapenem and penem antibiotics.

The intermediate is an azetidinone of formula I

in which

R represents a conventional hydroxyl function protecting group as defined below and wherein the absolute configurations on the 1 ', 3 and 4-position carbons are R, R and R. The intermediates of formula I known per se are key intermediates in the synthesis of carbapenem and penem antibiotics containing a (R) -hydroxyethyl substituent at the 6-position of the carbapenem or penem nucleus and having at the 5 and 5-positions respectively; 6 absolute configuration R resp.

S (trans), a wide variety of these compounds, including the natural fermentation product known as thienamycin, has already been described in the patent and scientific literature as having excellent antibacterial activity.

Several total syntheses have already been described for the preparation of the above-mentioned penem and carbapenem antibiotics, but to date these processes have been unsatisfactory from a commercial point of view due to the large number of reaction steps required and the need to separate diastereomeric mixtures resulting from these processes.

One suitable way to synthesize carbapenems and penems of the type described above was to use 6-aminopenicillanic acid (6-APA) as a starting material. 6-APA is a readily available substance readily obtained by fermentation procedures. Hirai et al. describe in Heterocycles 17, 201-207 (1982) a method for converting 6-APA to an optically active 4-acetoxy-3-azetidinone of the formula

which can be converted into biologically active penems and carbapenems by known methods. In this process, the 6-APA · converts to the above azetidinone according to the following reaction scheme: ^H 2

Br

at about ₂ h

6-APA

CH ₃ MgBr

CH ₃ CHO

-60 ° C

-r

->

silylace

CO ₂ CH ₃

CO ₂ CH ₃

Hg (OCOCH _{3) 2} / CH ₃ COOH

OSi

JJ -OCOCH,

Wj

OSi - | II xOCOCH ₃ Co ₂ ch ₃

The above procedure is carried out by esterifying 6-APA to the methyl ester, which is then converted to the 6,6-dibromopenicillanic acid methyl ester by known methods, for example those described in British Patent Application No. 2,045,755. This ester is hydroxyethylated by the metal-halogen exchange method described in J. Org. Chem.

42, 2960-2985 (1977), to give a mixture of cis- and trans-diastereomers which can be separated at least on a laboratory scale to give the desired (R) -hydroxyethyl-cis-isomer. This isomer is silylated with tert-butyldimethylchlorosilane to the corresponding hydroxyl-protected intermediate, which is then subjected to reductive debromination with zinc of a mixture of cis- and trans- (R) -hydroxyethyl derivatives from which the desired trans-isomer can be separated. The hydroxyethylated penicillanic acid ester is then treated with diacetoxymercury in acetic acid to cleave the thiazolidine ring to form the intermediate 4-acetoxyazetidinone, from which the beta-methyl crotonate residue is cleaved off by oxidation with potassium permanganate to give the desired intermediate 4-acetoxyazetidinone.

Tetrahedron Letters 23 (39), 4,021-4,024 (1982) provides the following reaction scheme:

SeCcH

6 ⁿ 5 (c6B ₅ se) ₂

CgHgSe ·

CH ₃ MgBr ₂ ch ₂ c ₆ h ₅

_CO2 CH3 CHO CH ₂ C ₆ H ₅ ^C ~ eo

OH oc ₂ ch ₂ c ₆ h ₅

The starting esterified diazopenicillin is converted to benzyl 6,6-bis (phenylselenyl) penicillinate, which is hydroxyethylated with methylmagnesium bromide and acetaldehyde at -60 ° C to give a mixture of diastereomers from which the desired cis-isomer can be isolated.

The optically active 4-acetoxyazetidinone can be used in known procedures for the synthesis of carbapenem and penem antibiotics. For example, Tetrahedron Letters 23 (22), 2293-2282 (1982) describes the conversion of this intermediate to thienamycin and Chem. Pharm. Bull. 29 (11), 3,158-3,172 (1981) discloses the use of this intermediate to prepare penem antibiotics.

While the above processes are potentially useful for large-scale synthesis of (8R) -hydroxyethylpenem and -carbapenem antibiotics, they do not occur stereospecifically in aldol condensation and in the reduction step. That is, the hydroxyethylation of the esterified dibrompenicillin or bis (phenylselenyl) penicillin and subsequent reduction of the hydroxyethylated intermediates obtained to remove the bromo or phenylselene group results in a mixture of diastereomers which must be separated to give the desired optically active product.

This division, especially when working on a larger scale, results in the aforementioned procedures being much less effective than they might otherwise be.

These disadvantages are solved by the improved process of the invention, which describes a stereospecifiocylated process for the preparation of penicillanic acid derivatives of formula III

(III) wherein

R 'represents a hydrogen atom or a hydroxyl-protecting group selected from the group consisting of: acyl radicals of not more than 20 carbon atoms, aralkyl radicals of not more than 20 carbon atoms and triorganosilyl radicals of not more than 21 carbon atoms, characterized in that (a) 6,6-disubstituted anhydropenicillin of the general formula V

(V) in which

X and Y are each independently chlorine, bromine or iodine or phenylsulfonyl, reacted with a reagent selected from the group consisting of Grignard reagents of the formula R 1 MgX and organolithium compounds of the formula R 1 L 1 in which R 1 is lower alkyl; aryl group and X is as defined above, in an anhydrous inert organic solvent at a temperature ranging from 0 to -78 ° C, followed by the addition of acetaldehyde to form exclusively the cis-isomer of formula IIa

(Ha) in which

X is as defined above, (b) the intermediate of formula (IIa) is subjected to reduction in an inert solvent, and the 5,6-trans-isomer of formula (III) thus formed is isolated, wherein R 'is hydrogen, which is optionally the corresponding protecting groups are converted to the corresponding product of formula III, wherein R 'is a hydroxyl function protecting group as defined above.

The resulting compounds of formula (III) wherein R 'is a hydroxyl-protecting group as defined above and thus correspond to formula (IIIb)

(Illb) in which

R is a hydroxyl protecting group selected from the group consisting of acyl radicals of at most 20 carbon atoms, aralkyl radicals of at most 20 carbon atoms and triorganosilyl groups of at most 21 carbon atoms, then can be converted to the desired optically active intermediates of formula I by the thiazolidine ring in the compound of formula IIIb cleaves to form the intermediate acetoxyazetidinone of formula IV

and the intermediate of formula (IV) is oxidized to cleave the beta-methylcrotonate residue and produce the desired optically active intermediate of formula (I).

The present invention provides a significant improvement in the known method of converting 6-aminopenicillanic acid to the key optically active intermediate acetoxyazetidinone of formula I which is used to synthesize various carbapenem and penem antibiotics, including the broad-spectrum carbapenem antibiotic thienamycin, corresponding to the formula sch ₂ ch ₂ nh ₂

COOH

OH

As mentioned above, the prior art methods known for the preparation of (8R) -hydroxyethylpenemic and -carbapenem compounds via an 6-aminopenicillanic acid include an aldolic condensation reaction to introduce the desired 6-hydroxyethyl substituent. One method reported in the literature involves the conversion of 6-aminopenicillanic acid to the 6-acetylderivative and subsequent reduction of this derivative to the desired hydroxyethylpenicillin (J. Am. Chem. Soc. 103: 6 765-6677 (1981)). However, this reduction step is not stereospecific and the desired optical isomer must be separated from the resulting mixture of diastereomers. Direct hydroxyethylation of 6-halopenicillin, 6,6-dihalopenicillin or 6,6-bis (phenylselenyl) penicillin is described, for example, in Chem. Pharm. Bull. 29 (10), 2899-2909 (1981), J. Org. Chem. 42, 2960-2985 (1977), Heteroxycles 22, 201-207 (1982) and Tetrahedron Letters 23 (39), 4,021-4,024 (1982), but this has the disadvantage that the aldol reaction taking place on the interraedial The penicillin is not stereospecific and the desired (8R) -hydroxyethyl isomer must be separated before performing the remaining steps of the synthesis.

The present invention is based on the unexpected discovery that an aldol condensation reaction on certain 6,6-disubstituted anhydropenicillins results in the exclusive formation of only a single stereoisomer, i.e., an isomer of formula Ha (Ha)

O in which

X represents a chlorine, bromine or iodine atom or a phenyl-silane group having the desired stereo-1 chemical configuration of 5R, 6R, 8R.

This stereospecific hydroxyethylation eliminates the need for separation of stereoisomers after this reaction step and, in conjunction with the stereoselective reductive cleavage of X, under the preferred conditions of the invention greatly improves the usability of the pathway taking place. via 6-aminopenioilanoic acid to synthesize penemic and carbapenem antibiotics.

In general, the reaction scheme of the process of the invention, including the preparation of the starting material and the subsequent treatment of the resulting compounds into no compounds of Formula I, is illustrated by the following procedure using 6,6-dibrompenicillin as starting material:

6- A PA

(6)

Hg (OCOCH _{3) 2}

The CH 3 COOH reduction is>

N-ethoxycarbonyl -

-2-ethoxy-1,2 ¹¹ '''-

-dihydroquinoline

(8) CO 2 CO 2 C 2 H 5 oxidation

0 '

Ί

The above process is carried out by first converting 6-aminopenicillanic acid to the intermediate 6,6-dihalogenanhydropenicillin or 6,6-bis (phenylselenyl) anhydropenicillin of the general formula V in a known manner

X

(V) in which

X and Y are each independently chloro, bromo, iodo or phenyl.

The intermediates of formula (V) which are the starting materials for the novel process of the invention are known or are prepared by known methods. These intermediates can be prepared by converting 6-APA to the corresponding 6,6-dihaloprenicillinic acid or 6,6-bis (phenyl selenyl) penicillinic acid, converting it into an acid halide or mixed anhydride, and reacting the halide or anhydride with a tertiary amine to form a formation of anhydropenicillin. British Patent Application No. 2,405,755A describes the preparation of various 6,6-dihaloprenicillanic acids, such as 6,6-dibrompenicillanic acid, 6-chloro-6-iodopenicillanic acid, 6-bromo-6-iodopenicillanic acid, and 6,6- dijodpenicillanic acid. Tetrahedron Letters 23 (39), 4,021-4,024 (1982) describes the preparation of 6,6-bis (phenylselenyl) penicillins. Conversion of 6,6-dihalo-penicillanic acids to the corresponding anhydropenicillins is discussed, for example, in J. Chem. Soc. (C), 2,123-2,127 (1969), which specifically describes the preparation of 6,6-dibromanhydropenicillin.

U.S. Pat. No. 3,311,638 describes general procedures for converting penicillins to anhydropenicillins. The most preferred starting anhydropenicillins for use in the process of the invention are 6,6-dihalogenanhydropenicillins, preferably 6,6-dibromanhydropenicillin and 6-bromo-6-iodoanhydropenicillin, and most preferably 6,6-dibromanhydropenicillin.

The starting anhydropenicillins are subjected to an aldol condensation reaction to give the desired hydroxyethylated intermediates of formula IIa.

X is chlorine, bromine, iodine or phenylsulfonyl, most preferably bromine, and in which the absolute configuration is 5R, 6R, 8R.

This reaction represents a key step in the process of the invention, since the aldol condensation of the intermediate anhydropenicillin produces exclusively the optically active isomer, i.e. the stereoisomer with the cis arrangement at the 5 and 6 positions and the (8R) -hydroxyethyl substituent at the 6 position. condensation eliminates the need for separation of diastereomers that was required in prior art processes and therefore greatly increases the practical applicability of the 6-APA process for the synthesis of carbapenem and penem end products.

This aldol condensation can be carried out in substantially the same manner as the prior art reactions with penicillins - see, for example, J. Org. Chem. 42 (19),

960-2,965 (1977). From 6,6-dihalogenanhydropenicillin with a metal-halogen exchange process carried out at temperatures below about 0 ° C, for example from 0 ° C to -78 ° C using an organolithium reagent or a Grignard reagent, the enolate is first prepared, which is it is then reacted in situ with an excess of acetoaldehyde to form a hydroxyethylated product.

This aldol condensation reaction is carried out in an inert anhydrous organic solvent, for example methylene chloride, chloroform, tetrahydrofuran, diethyl ether, toluene, dioxane, dimethoxyethane or mixtures thereof, at a temperature below 0 ° C, preferably below -20 ° C. The enolate is prepared using about a mole equivalent of an organolithium reagent or a Grignard reagent.

Preferred ¹ organolithium reagents are those corresponding to the general formula R @ 1 Li, wherein R @ 1 represents a lower alkyl group, i.e. a C1 -C6 alkyl group, or an aryl group, i.e. a C6 -C10 aryl group, such as fennel.

An example of a suitable organolithium reagent is n-butyllithium. Suitable Grignard reagents are preferably those corresponding to the formula R 1 MgX, wherein R 1 represents an alkyl group having 1 to 6 carbon atoms or an aryl group having 6 to 10 carbon atoms and X is chlorine, bromine or iodine. A preferred Grignard reagent is methylmagnesium bromide or methylmagnesium chloride. According to a preferred embodiment, methylmagnosium chloride is used and is operated at a temperature of about -40 ° C to -45 ° C. Another preferred embodiment consists of using methylmagnesium bromide and operating at about -20 ° C. After formation of the enolate, a molar excess of acetaldehyde is added to give the desired hydroxyethylated isomer.

The intermediate of formula IIa is then subjected to reduction to give the compound of formula IIIa

wherein the hydroxyl group is optionally protected to provide a compound of formula (IIb) above.

Protection of the hydroxyl function is accomplished by known methods using conventional hydroxyl protecting groups known in the art. Protection of the hydroxyl functionality in the intermediate of formula IIIa is desirable in order to avoid side reactions and lower yields in later reaction steps, for example, by ring cleavage with a mercury salt. Suitable hydroxyl protecting groups may be, for example, acyl groups such as benzyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, p-nitrobenzyloxycarbonyl, and 2,2,2-trichloroethoxycarbonyl, aralkyl groups such as benzyl, benzhydryl, nitrobenzyl, trityl or trityl groups. as trialkylsilyl groups containing from 1 to 6 carbon atoms in each alkyl moiety (for example, trimethylsilyl, triethylsilyl, triisopropylsilyl, isopropyldimethylsilyl, tert-butyldimethylsilyl, methyldiisopropylsilyl or methyldi-tert-butylsilyl) or triarylsilyl-silyl) or triarylsilyl triaralkylsilyl groups (e.g., tribenzylsilyl group).

Examples of these and other suitable hydroxyl protecting groups and methods for their introduction and cleavage are known in the art - see, for example, Protective Groups in Organic Synthesis, T.W. Greene, John Wiley and Sons, New York, 1982, Chapter 2.

It is necessary to choose a hydroxyl-protecting group which can be easily removed at a later stage of the process. Preference is given to using triorganosilyl protecting groups (in addition to certain of these groups which are advantageous for a stereospecifically controlled reduction step, i.e. bulky triorganosilyl groups such as triisopropylsilyl, tert-butyldiphenylsilyl or tert-butyldimethylsilyl groups), since these groups can be readily cleaved off mild conditions, for example by treatment with methanolic hydrogen chloride or fluoride ions (for example, by treatment with tetra-n-butylamine fluoride in tetrahydrofuran), without damaging the susceptible beta-lactam core. Silylation may be accomplished with a suitable silylating agent (e.g., silyl chloride or silyl trifluoromethanesulfonate) in an inert organic solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethoxyethane, chloroform or diethyl ether, and in the presence of a base such as an organic base such as pyridine, 2,6- lutidine, imidazole or triethylamine. Although silylation can be performed over a wide temperature range, it is nevertheless preferred to operate at temperatures of about -40 ° C to + 5 ° C. According to a preferred embodiment, the hydroxyl group of the intermediate of formula IIIa silyl is by treatment with triisopropylsilyl trifluoromethanesulfonate, tert-butylphenylsilyl trifluoromethanesulfonate or tert-butyldimethylsilyl trifluoromethanesulfonate in methylene chloride, tetrahydrofuran, tetrahydrofuran, chloroform.

The reduction of the compound of formula (IIa) may be accomplished by treatment with a chemical reducing agent such as a combination of zinc-silver or zinc-copper, stannous iodide, tin hydride, amalgamated zinc, zinc or acid-activated zinc (e.g. hydrochloric or acetic acid) or catalytic hydrogenation. Generally, the reaction is carried out in an inert solvent such as tetrahydrofuran, diethyl ether, methanol, ethanol, isopropanol, acetic acid, mixtures of ether and alcoholic solvents and the like. According to a preferred embodiment, a zinc-silver combination is used and tetrahydrofuran / methanol is used as solvent system. Another preferred embodiment consists in the use of an acid-activated zinc, preferably hydrochloric or acetic acid. The reduction can be carried out over a wide temperature range, for example at -45 ° C to room temperature. The reduction generally yields the most desirable trans (5R, 6S) -isomer as the predominant product containing only a small amount of the less desirable cis-isomer.

After reduction, the resulting intermediate anhydropenicillin of formula IIIa, optionally after protection of the hydroxyl group, is converted in a manner known per se to the desired acetoxyazetidinone of formula I. In accordance with the most preferred embodiment, the hydroxyl-protected intermediate corresponding to formula IIIb having on the carbons at the 5, 6 and 8 positions, the desired chirality is subjected to cleavage of the thiazolidine ring, for example by treatment with mercuric acetate in acetic acid, to form the intermediate of formula IV

and the intermediate of formula IV is then oxidized to the desired optically active intermediate of formula I. The cleavage of the thiazolidine ring is described in the literature and can be accomplished, for example, by reacting the intermediate of formula IIIb in acetic acid or acetic acid with an inert organic solvent such as tetrahydrofuran or dioxane, with a mercuric salt such as mercuric acetate or mercuric chloride, at a temperature between about 0 ° C and 40 ° C.

The cleavage of the crotonate residue is carried out by oxidation of the intermediate of formula IV. The use of ozonolysis (e.g., ozone in methanol) allows direct oxidation of the acid of formula IV to the intermediate of formula I. When using chemical oxidizing agents such as potassium permanganate, potassium permanganate together with phase transfer catalysts, a combination of potassium permanganate with sodium periodate and ruthenium S sodium periodinate, it is generally desirable to protect the carboxyl function of a compound of formula IV from oxidation, for example by conversion to an ester or anhydride.

The reactions described above can be carried out sequentially without the isolation of one or more intermediates, with the appropriate choice of solvents. Alternatively, where possible, the intermediates can be isolated as crystalline materials and optionally purified by recrystallization prior to their processing in subsequent reaction steps.

It is to be understood that the process of the acetoxyazetidinones of formula I, of the intermediate azetidinones of the type of the invention, although only described in terms of manufacture, can easily be modified to produce other useful

Wherein L represents a conventional leaving group. For example, the intermediate of formula (IIb) above can be subjected to chlorolysis (chlorine gas, temperature -15 ° C) to give a compound of formula

which can be oxidized, after conversion to the corresponding acid or ester, as described above for the corresponding acetoxy derivative, to form the intermediate chloro derivative of the general formula

STEED.

Intermediate (R) -hydroxyethylazetidinones produced by the process of the invention, i.e., intermediates of formula (I) or analogues thereof, such as the above chloro derivative, are readily converted by known methods to thienamycin and other carbapenem and penem derivatives exhibiting useful antibacterial activity.

The invention is illustrated by the following non-limiting examples.

Example 1

Anhydro-6,6-dibrompenicillin

Br

Brco ₁ h

O: O

Κ a solution of 20.00 g (55.56 mmol) of 6,6-dibrompenicillanic acid in 200 ml of dichloromethane cooled in an ice / methanol cooling bath was added dropwise with 58.4 mmol (8.00 ml) of triethyl amine; After stirring for 15 minutes, trifluoroacetic anhydride (8.40 mL, 61.2 mmol) was added dropwise and pyridine (4.8 mL, 61.2 mmol) was added dropwise for 30 minutes. The reaction mixture was stirred at -10 ° C for 30 minutes and then at 5 ° C for 18 hours, then washed sequentially with 1N aqueous hydrochloric acid, 1M aqueous sodium bicarbonate, and brine, and dried over magnesium sulfate. The solvent was evaporated, the residue was dissolved in ethyl acetate, the solution was decolourised with charcoal and evaporated. 16.1 g (47.2 mmol; yield 85%) of the title compound are obtained, m.p. 102-103 ° C.

@ 1 H NMR (CDCl3, 80 MHz, .delta. Ppm):

5.80 (1H, s, H-5), 2.21 (3H, s, _CH3) and 2.15 (3H, s, CH ^.

IR (dichloromethane): v ' _max 1θθ (thick band, beta-lactam carbonyl), 1 708 (strong band, lactone carbonyl) and 1 640 cm ¹ (weak band, olefin).

[α] D = + 88.9 ° (c = 0.144, methanol).

H, 2.07; N, 4.10. found: 28.08% C, 1.98% H, 4.06% N.

Example 2

Anhydro-6-alpha-bromo-6-beta - [(1'-R) -hydroxyethyl] penicillin

15.02 g (44 mmol) of anhydro-6,6-dibrompenicillin is dissolved in 450 ml of cold (-78 ° C) tetrahydrofuran, to which 18.0 ml of a 2.85 M methylmagnesium bromide solution (51.3 mmol) is added dropwise. in ether and the mixture was stirred at -78 ° C for 20 min. To the mixture containing the formed magnesium enolate was added excess (25 mL; 0.45 mol) acetaldehyde, the reaction mixture was stirred for 20 minutes, then the cooling bath was removed and 70 mL of 1N aqueous hydrochloric acid and 300 mL of ether were added.

The aqueous phase is separated, extracted twice with 200 ml of ether each time, the organic phases are combined, washed successively with 1N aqueous hydrochloric acid, water, 1M aqueous sodium hydrogen carbonate solution and brine, and dried over magnesium sulfate. Evaporation of the solvent gave 13.08 g (42.7 mmol; 97% yield) of the title compound as an oil.

HNMR (deuterochloroform, delta values in ppm):

5.61 (1H, singlet, H-5), 4.28 (1H, quartet,

J = 6.0, H-1 '), 2.21 (3H, singlet, CH2), 2.16 (3H, singlet, CH2), 1.64 (broad singlet, OH), 1.31 ( 3H, doublet, J = 6.0 Hz, CH3).

IR (dichloromethane): _max ^3,560 (medium band, OH), 1,785 (strong band, beta-lactam carbonyl), 1,710 (strong band, lactone carbonyl) and 1,635 cm (medium band, olefin).

[.alpha.] @ ²² = + 83.8 DEG (c = 0.128, methanol).

Analysis: for ^C 20 ^H I2 ^NO 3® ^Br 39.23 Calculated from C, 3.95% H, 4.57% N; Found: C, 38.31; H, 4.63; N, 4.61.

Example 3

6-alpha-bromo-6-beta - [(1'R) -hydroxyethyl] anhydropenicillin - this example illustrates an aldol condensation reaction at a relatively high temperature (-20 ° C)

Br

1) CK ₃ MgBr

2) CH 2 CHO -20 ° C

Reagents:

anhydropenicillin methylmagnesium bromide (CH3MgBr) acetaldehyde (CH3 CHO) tetrahydro furan

10.23 g (0.03 mol)

12.21 ml (0.0 348 mol, 16% excess, 2.85M ether solution, Aldrich) 6.6 g = 8.4 ml (0.15 mol, density 0.788, Aldrich) 150 ml (dried over molecular weight) sieve)

Method:

To a solution of 10.23 g of anhydro-6,6-dibrompenicillin in 150 ml of dry tetrahydrofuran cooled to -20 ° C was added dropwise 12.21 ml of methylmagnesium bromide over 10 minutes, maintaining the temperature of the mixture between -15 to -20 ° C. . The resulting solution was stirred at -20 ° C for 10 minutes, then 8.4 mL of acetaldehyde (initially dropwise) was added over 5 minutes, maintaining between -15 and -20 ° C. The reaction mixture was stirred at -20 ° C for 15 minutes, then 10 mL of saturated ammonium chloride solution and 80 mL of water were added, and the resulting mixture was extracted first with 150 mL and then 50 mL of ethyl acetate. The ethyl acetate extracts were washed with brine (2 x 100 ml), dried over anhydrous sodium sulfate and concentrated. 8.9 g (97%) of an oily product are obtained, which consists of 92% cis-isomer (no trans-isomer) and 8% impurities (high performance liquid chromatography; column: Porasil (Waters /, solvent: 3%) acetonitrile in dichloromethane, flow rate: 90 ml / h, detection: UV (275 nm), sensitivity 0.2).

Example 4

6-alpha-bromo-6-beta-2 (1 * R) -hydroxyethyl-anhydropenicillin - this example illustrates the use of methylmagnesium chloride as a Grignard reagent

1) CHgMgCl

2) CH 3 CHO tetrahydrofuran -45 to -40 ° C

Reagents:

anhydropenicillin methylmagnesium chloride acetaldehyde tetrahydrofuran toluene

34.1 g (0.1 mol)

39.6 ml (0.116 mol,

16% excess, 2.9M solution in tetrahydrofuran) 28 ml = 22 g (0.5 mol, density 0.788)

350 ml (dried over molecular sieve)

800 ml

Method:

A solution of 34.1 g of anhydro-6,6-dibrompenicillin in 350 ml of dry tetrahydrofuran was cooled to -45 ° C and 39.6 ml of methylmangamesium chloride was added dropwise over 20 minutes while maintaining the temperature below -40 ° C. The resulting solution was stirred at -45 to -40 ° C for 10 minutes, then 28 ml of acetaldehyde (initially dropwise) was added over 5 minutes while maintaining the temperature below -30 ° C. The reaction solution was stirred at -40 ° C for 15 minutes. 35 ml of saturated ammonium chloride solution was added first, followed by 400 ml of water.

The mixture is extracted first with 350 ml and then with 150 ml of toluene, the toluene extracts are washed twice with 300 ml each of sodium chloride solution, dried over anhydrous magnesium sulphate and concentrated to a volume of about 100 ml. To this concentrated solution is added 300 ml of toluene and the mixture is again concentrated to a volume of about 300 ml / high performance liquid chromatography indicating 92% purity and the absence of the trans-isomer;

column: Porasil (Waters), solvent: 3% acetonitrile in dichloromethane, flow rate: 90 ml / h, detection: UV (275 nm), sensitivity 0.2 /.

Example 5

Preparation of anhydro-6-alpha- and -6-beta - [(1'R) -hydroxyethyl] penicillin

OH OH

To a cold (ice-in-methanol cooling bath) solution of 4.20 g (13.7 mmol) of anhydro-6-alpha-bromo-6-beta- (1'R) -hydroxyethyl penicillin in 40 mL of methanol was added 4.2 g zinc-silver combination, stirred for 15 minutes, an additional 1.1 g of zinc-silver is added and stirring is continued for 10 minutes. The resulting cold suspension is filtered through a pad of diatomaceous earth into a cold saturated aqueous ammonium chloride solution, the solid residue on the filter is washed with ether and the filtrate is separated into an organic and an aqueous phase. The aqueous phase is extracted twice with 20 ml of ether each time, the ether extracts are combined and washed successively with 1N aqueous hydrochloric acid, water, 1M aqueous sodium hydrogen carbonate solution and brine. After drying, the solvent was evaporated and the residue was triturated with a cold mixture of petroleum ether and ether (9: 1).

1.3 g (5.7 mmol) of 6-alpha-isomer are obtained in the form of a white solid melting after crystallization from a dichloromethane / ether (2: 8) mixture at 173-174 ° C. The yield was 42%. However, the reaction conditions were not optimized in this case. A repeat of the experiment at -50 ° C resulted in a yield of 6-alpha-isomer of 56.6%.

@ 1 H NMR (CDCl3, .delta. In ppm):

5.28 (1H, doublet, J = 1.7H-5), 4.35 (1H, quintet, J = 6.2, H1), 3.57 (1H, double doublet, J = 6.2, J = 1.7, H-6), 2.19 (3H, s, _CH3), 2.11 (3H, s, CH₃), 1.72 (1H, broad singlet, OH) and 1.40 ( 3H, doublet, J = 6.3 CH3).

IR (dichloromethane): _max 3500 (weak band, OH), 1755 (strong band, beta-lactam carbonyl), 1695 (strong band, lactone carbonyl) and 1635 cm ¹ (medium strength, olefin) .

Analysis: Calculated: C, 52.84; H, 5.76; N, 6.16.

Found: C, 52.86; H, 5.72; N, 6.08.

The cold mixture of ether and petroleum ether (1: 9) was evaporated and the pure 6-beta-isomer was isolated by preparative thin layer chromatography (2% acetonitrile in dichloromethane).

¹ HNMR (deuterochloroform, delta in ppm):

5.40 (1H, doublet, J = 4.6, H-5), 4.36 (1H, doublet of quartets, J = 6.1, J = 9.0, H-1 '), 3.74 ( 1H, double doublet, J = 9.0, J = 4.6, H-6), 2.19 (3H, singlet, CH3), 2.25-1.90 (1H, broad singlet, OH), 2 09 (3H, singlet, CH3) and 1.27 (3H, doublet, J = 6.0 / CH3).

IR (dichloromethane): v _max 3500 (weak band, OH), 1770 (strong band, beta-lactam carbonyl), 1770 (strong band, lactam carbonyl) and 1640 cm (medium thickness, olefin).

Example 6

A. alpha - [(3R) - [(1'R) -tert-butyldimethylsllyloxy) ethyl] - (4R) -acetoxy-2-azetidinon-1-yl] beta-methylcrotonic acid

To a solution of 5.00 g (14.6 mmol) of anhydro-6-.alpha .- (1'R) - (tert-butyldimethylsllyloxy) ethyl] penicillin in 75 ml of acetic acid is added 14 g (44 mmol) at 22 ° C. After stirring for 24 hours, an additional 9.3 g (29 mmol) of mercuric acetate is added and stirring is continued for 24 hours. The reaction mixture was filtered through a pad of diatomaceous earth and the solid residue was washed with acetic acid. The filtrate was diluted with 150 ml of water and extracted five times with 40 ml of ether each time. The organic extracts were combined, washed with water (3 x 40 ml) and brine, dried (MgSO4) and decolourised with charcoal. Evaporation gave an oily residue which crystallized in vacuo to give 5.33 g (13.8 mmol; 95% yield) of the desired product melting after crystallization from a 9: 1 mixture of di-chloro methane and petroleum ether at 119-120 ° C.

HHNMR (deuterochloroform, delta in ppm):

6.32 (1H, doublet, J = 1.4H-4), 4.24 (1H, middle of 5 signals, J = 6.0, H-1 '), 3.20 (1H, double doublet, J = 1.4, J = 5.8, H-3), 2.24 (3H, singlet, CH3), 2.05 (3H, singlet, CH2Cl2), 1.97 (3H, singlet, CH) ₃ >, 1.29 (3H, doublet, J = 6.3, CH ₃ ), 0.86 (9H, singlet, t-butyl), 0.08 (3H, singlet, CH ₃ ) and 0.05 (3H) singlet, CH ₃ ).

IR (dichloromethane): v 1,770 (strong band, beta-lactam carbonyl), 1,745 (medium max.

thick band, CH ₃ C = O), 1690 (medium band, CC> ₂ H) and 1620 cm ¹ (thin band, olefin).

[alpha; ²² = + 18.9 ° (c = 0.088, methanol).

H, 8.10; N, 3.63. Found: C, 56.00; H, 8.25; N, 3.73;

B. (4R) -Acetoxy- (3R) - ((1R) - (tert-Butyldimethylsilyloxy) ethyl) -2-azetidinone

CO 2 CO 2 C 2H5

To a solution of 2.0 g (5.2 mmol) of alpha-N (3r) - [(1'r) - (tert-butyldimethylsilyloxy) ethyl] -acetoxy-2-azetidinon-1-yl] -beta-methyl-crotonic acid in 30 ml. ml of dichloromethane was added 1.63 g (6.20 mmol) of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline at -15 ° C (ice-cooling in methanol). The cooling bath was removed, the reaction mixture was stirred at 22 ° C for 18 hours and then washed successively with 1N aqueous hydrochloric acid, water,

1M aqueous sodium bicarbonate solution and brine. After drying over magnesium sulfate, the solvent was evaporated, yielding 2.14 g (93.3% yield) of the mixed anhydride, a carboxyl protected intermediate.

HNMR (deuterochloroform, delta values in ppm):

6.23 (1H, doublet, J = 1.4, H-4), 4.32 (2H, quartet, J = 7.1, CH ₂ CH ₃₎ 4.05 - 4.39 (1H, multiplet J = 6.1, H-1 '), 3.23 · (1H, double doublet, J = 6.1 H-3), 2.25 (3H, singlet, CH3), 2.06, (3H) , singlet, CH ₃ CO), 1.17 (3H, singlet, CH p, 1.35 (3H, triplet, J = 7.1, CH ₃ CH ₂ ),

1.29 (3H, doublet, J = 6.1, CH ₃ ,, 0.86 (9H, singlet, t-butyl), 0.08 (3H, s, CH) and 0.05 (3H, s, CH ₃ ).

IR (dichloromethane): v _max 1,800 (thick belt, mixed anhydride), 1,775 (thick belt, beca-lactam carbonyl), 1,750 (thick belt, acetate carbonyl) and 1,625 cm ³ (thin belt, acetate carbonyl) and 1,625 cm ³ (thin band, olefin).

2.10 g (4.76 mmol) of the mixed anhydride thus obtained are dissolved in 30 ml of dichloromethane, cooled to -78 ° C (solid carbon dioxide cooling bath in acetone) and ozonolyzed until the starting material disappears (1, 5 hours). The cold (-78 ° C) ozonide solution was reduced with 6 mL dimethylsulfide and stirred for 1.5 hours. After the first addition of 30 ml of methanol and then 1.2 ml of 2,6-lutidine, the reaction mixture was stirred at 22 ° C for 2 hours, then diluted with ether, washed with 1N aqueous hydrochloric acid, water, 1M aqueous sodium bicarbonate solution and chloride, sodium, dried over magnesium sulfate and the solvent was evaporated.

1.31 g (4.56 mmol; yield 95%) of the title compound are obtained as a white solid melting after crystallization from a mixture of equal portions of ether and petroleum ether at 104 DEG-104 DEG.

106 ° C [in Pharm. Bull. (Tokyo) 29, 2899 (1981) reported 104-106 ° C. The product has an optical rotation of [.alpha.] D @ ²⁰ = + 47.4 DEG C. (c = 0.136, chloroform). [.Alpha.] D @ 20 = + 48.8 DEG (c = 0.41, chloroform).

Claims (1)

SUBJECT OF THE INVENTION A method of stereospecifically controlled production of penicillanic acid derivatives of general formula III (III) in which R 'represents a hydrogen atom or a hydroxyl protecting group selected from the group consisting of acyl radicals of at most 20 carbon atoms, aralkyl radicals of at most 20 carbon atoms and triorganosilyl radicals of at most 21 carbon atoms, characterized in that: 6-disubstituted anhydropenicillin (V) -T (V) in which X and Y each independently represent a chlorine, bromine or iodine atom or a phenyl-selenium group, react with a reagent selected from the group consisting of Grignard reagents of the formula RjMgX and organolithium compounds of the formula RjLi in which R 1 represents lower alkyl or aryl and X is as defined above, in an anhydrous inert organic solvent at a temperature ranging from 0 to -78 ° C, followed by the addition of acetaldehyde to form exclusively the cis-isomer of formula (IIa) wherein: X is as defined above, (b) the intermediate of formula (IIa) is subjected to reduction in an inert solvent, whereby the 5,6-trans-isomer of formula (III) thus formed is isolated, wherein R 'is hydrogen, which is optionally converting the corresponding protecting groups into the corresponding product of formula III, wherein R 'is a hydroxyl function protecting group as defined above. Severography, n. P., MOST