CS253737B2 - A method for producing penicillanic acid derivatives - Google Patents

Abstract

A method for producing penicillanic acid derivatives of the general formula IIa in which X represents a chlorine, bromine or iodine atom or a phenylseleno group, characterized in that the intermediate of the general formula V in which X and Y independently of each other each represent a chlorine, bromine or iodine atom or a phenylseleno group is reacted with a reagent selected from the group comprising Grignard reagents of the general formula R^MgX and organolithium compounds of the general formula R^Li, in which R^ represents a lower alkyl group or an aryl group and X has the above-mentioned meaning, in an anhydrous inert organic solvent at a temperature in the range from 0 °C to -78 °C, after which acetaldehyde is added

Description

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

This intermediate is an azetidinone of general formula I “π H. °

OCCH, (I) in which R represents a common protecting group of the hydroxyl function and where the absolute configurations on the carbons in positions 1', 3 and 4 are R, R and R. The intermediates of general formula I, which are known per se, are key intermediates in the synthesis of carbapenem and penem antibiotics containing in position 6 of the carbapenem or penem nucleus an (R)-hydroxyethyl substituent and having in positions 5 and 6 the absolute configuration R and S, respectively. A wide variety of these compounds, including the natural fermentation product known under the name thienamycin, have already been described in the patent and scientific literature as substances showing extraordinary antibacterial activity.

Several total syntheses have been described for the preparation of the above-mentioned penem and carbapenem antibiotics, but until now these processes have been commercially unsatisfactory due to the large number of reaction steps required and the need to separate the diastereomeric mixtures formed in these processes.

A more detailed description of the known methods for the synthesis of the above-mentioned carbapenem and penem derivatives is given in our related Czechoslovak patent applications Nos. 253,724 and 253,736. These known methods do not proceed stereospecifically in some reaction steps, so that a mixture of diastereomers is formed, which must be separated to obtain the desired optically active product. This separation, especially when working on a larger scale, has the result that the above-mentioned procedures are much less efficient than they otherwise could be.

A new stereospecifically controlled process for the conversion of 6-aminopenicillanic acid to the known optically active intermediate azetidinone of general formula 1 has now been found. This improved process is characterized in that

a) 6-aminopenicillanic acid is converted into anhydropenicillin of the general formula V by known methods

X

in which

X and Y independently of each other always represent a chlorine atom, a bromine atom, an iodine atom or a phenylseleno group (SeCgH ₅ ),

b) the intermediate of general formula V is reacted with a reagent selected from the group consisting of Grignard reagents of general formula R^MgX and organolithium compounds of general formula R^Li, in which R^ represents a lower alkyl group or an aryl group and X has the above-mentioned meaning, in an anhydrous inert organic solvent at a temperature in the range of about 0 °C to -78 °C, and then acetaldehyde is added, thereby forming exclusively the intermediate of general formula IIa

(on) in Which

X has the meaning given above,

c) the intermediate of general formula Ha is converted to the intermediate of general formula lib

(lib) in which

R represents a protecting group for the hydroxyl function, selected from the group consisting of acyl radicals with up to 20 carbon atoms, aralkyl radicals with up to 20 carbon atoms and triorganosilyl groups with up to 21 atoms, and

X has the meaning given above,

d) the intermediate of general formula IIb is subjected to reduction in an inert solvent and the 5,6-trans-isomer of general formula IIIb thus formed

(Illb) in which

R has the above meaning, is isolated,

e) the thiazolidine ring in the intermediate of general formula IIIb is cleaved to form the intermediate acetoxyazetidinone of general formula IV

and

f) this intermediate of general formula IV is oxidized to cleave the beta-methylcrotonate residue and to form the desired optically active intermediate of general formula I.

According to one variant of the above-described procedure, the intermediate of general formula IIa can be reduced before protection of the hydroxyl function.

The above procedure provides a significant improvement over the known method of converting 6-aminopenicillanic acid to the key optically active intermediate acetoxyazetidinone of general formula I, which is used for the synthesis of various carbapenem and penem antibiotics, including the broad-spectrum carbapenem antibiotic thenamycin, corresponding to the formula

OH

sch ₂ ch ₂ nh ₂

COOH

The specific implementation of the individual reaction steps of the above-mentioned process, as well as a more detailed discussion of its advantages over known processes, are described in our above-cited related Czechoslovak patent documents.

The actual subject of the invention is a method for producing new penicillanic acid derivatives of the general formula IIa

(Ha) in which

X represents a chlorine, bromine or iodine atom or a phenylseleno group, characterized in that the intermediate of general formula V

X

in which

X and Y independently of each other each represent a chlorine, bromine or iodine atom or a phenylseleno group, is reacted with a reagent selected from the group comprising Grignard reagents of the general formula R^MgX and organolithium compounds of the general formula R^Li, in which R^ represents a lower alkyl group or an aryl group and X has the above-mentioned meaning, in an anhydrous inert organic solvent at a temperature in the range from 0 °C to -78 °C, after which acetaldehyde is added.

The invention is based on the unexpected finding that the aldol condensation reaction on certain 6,6-disubstituted anhydropenicillins leads to the exclusive formation of only one stereoisomer, i.e. isomers of the above-mentioned general formula IIa, which have the desired stereochemical configuration 5R, 6R, 8R. * «

This stereospecific hydroxyethylation eliminates the need for separation of stereoisomers after this reaction step and, in conjunction with the subsequent stereoselective reductive cleavage of the X residue, greatly improves the utility of the 6-aminopenicillanic acid route for the synthesis of penem and carbapenem antibiotics.

The intermediates of formula V, which are the starting materials for the novel process according to the invention, are known or are prepared by known methods. These intermediates can be prepared in particular by 6-APA to the corresponding 6,6-dihalopenicillanic acid or 6,6-bis(phenylselenyl)penicillanic acid, converting it to an acid halide or mixed anhydride, and reacting this halide or anhydride with a tertiary amine to form anhydropenicillin. British Patent Application Publication No. 2,405,755 A describes the preparation of various 6,6-dihalopenicillanic acids, such as 6,6-dibromopenicillanic acid, 6-chloro-6-iodopenicillanic acid, 6-bromo-6-iodopenicillanic 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-dihalopenicillanic acids to the corresponding anhydropenicillins is discussed, for example, in J. Chem. Soc. (C), 2123-2127 (1969), where the preparation of 6,6-dibromohydropenicillins is specifically described. U.S. Patent No. 3,311,638 describes general procedures for converting penicillins to anhydropenicillins. The 6,6-dihalopenicillins for use in the process of the invention are 6,6-dihalopenicillins, preferably 6,6-dibromohydropenicillin and 6-bromo-6-iodohydropenicillin, and most preferably 6,6-dibromohydropenicillin.

These starting anhydropenicillins are subjected to an aldol condensation reaction in accordance with the invention to form the desired hydroxyethylated intermediates of the above-mentioned general formula IIa, with the absolute configuration 5R, 6R, 8R.

This reaction represents a key step in the above synthesis, since the aldol condensation of the intermediate anhydropenicillin exclusively produces the desired optically active isomer, i.e. the stereoisomer with a cis-configuration at the carbons in positions 5 and 6 and with an (8R)-hydroxyethyl substituent in position 6. This unexpectedly stereospecific aldol condensation eliminates the need for diastereomeric separations that were required in prior art procedures, and therefore greatly increases the practical applicability of the 6-APA-based process for the synthesis of carbapenem and penem final products.

The aldol condensation according to the invention can be carried out in essentially the same way as the reactions with penicillins known from the prior art - see for example J. Org. Chem.

(18), 2960-2965 (1977). The enolate is first prepared from 6,6-dihalogenohydropenicillin by a metal-halogen exchange process carried out at temperatures approximately below 0°C, e.g., from 0°C to -78°C, using an organolithium reagent or a Grignard reagent, which is then reacted in situ with excess acetaldehyde to form the 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 about -20 °C. The enolate is prepared using about a molar equivalent of an organolithium reagent or Grignard reagent.

Preferred organolithium reagents are those of the general formula R-1Li, wherein R-1 represents a lower alkyl group, i.e. an alkyl group with 1 to 6 carbon atoms, or an aryl group, i.e. an aryl group with 6 to 10 carbon atoms, such as a phenyl group.

An example of a suitable organolithium reagent is n-butyllithium. Suitable Grignard reagents are preferably those of the general formula R^MgX, where R^ represents an alkyl group with 1 to 6 carbon atoms or an aryl group with 6 to 10 carbon atoms and X represents chlorine, bromine or iodine. The preferred Grignard reagent is methylmagnesium bromide or methylmagnesium chloride. In accordance with a preferred embodiment, methylmagnesium chloride is used and the temperature is from about -40 °C to -45 °C. Another preferred embodiment consists in using methylmagnesium bromide and operating at a temperature of about -20 °C. After the formation of the enolate, a molar excess of acetaldehyde is added, thereby forming the desired hydroxyethylated isomer.

The resulting product of general formula IIa can then be subjected to the further reactions mentioned above.

The invention is illustrated by the following examples, which are not intended to limit the scope of the invention in any way. The first of these examples illustrates the entire synthesis leading to the preparation of the azetidinone of general formula I.

Example 1

Preparation of (4R)-acetoxy-(3R)-[(1'R)-(tert-butyldimethylsilyloxy)ethyl]-2-azetidinone from anhydro-6,6-dibromopenicillin

Br

Br-

A. Anhydro-6,6-dibromopenicillin

To a solution of 20.00 g (55.56 mmol) of 6,6-dibromopenicillanic acid in 200 ml of dichloromethane, cooled in a cooling bath consisting of ice in methanol, 58.4 mmol (8.00 ml) of triethylamine is added dropwise, the solution is stirred for 15 minutes, then 8.40 ml (61.2 mmol) of trifluoroacetic anhydride is added dropwise and, after stirring for 30 minutes, 4.8 ml (61.2 mmol) of pyridine is added.

The reaction mixture was stirred at -10°C for 30 minutes and then at 5°C for 18 hours, then washed successively with 1N aqueous hydrochloric acid, 1M aqueous sodium bicarbonate solution and brine, and dried over magnesium sulfate. The solvent was evaporated, the residue was dissolved in ethyl acetate, the solution was decolorized with activated carbon and evaporated. 16.1 g (47.2 mmol: 85% yield) of the title compound was obtained, melting point 102-103°C.

¹ H NMR (deuterochloroform, 80 MHz, δ values in ppm):

5.80 (1H, singlet, H-5), 2.21 (3H, singlet, CH 3 ) and 2.15 (3H, singlet, ch ₃ ).

IR (dichloromethane): v _max 1800 (strong band, beta-lactam carbonyl), 1708 (strong band, lactone carbonyl) and 1640 cm * (weak band, olefin).

[nj ²² = +88.9° (c = 0.144, methanol).

Analysis: calculated for CgH4NC4SB4 28.17% C, 2.07% H, 4.10% N;

found 28.08% C, 1.98% H, 4.06% N.

B.

Anhydro-6-ul tu-le (>iu-6-bet,i- | (1 R, -hydroxyethyl) penicillin

15.02 g (44 mmol) of anhydro-6,6-dibromopenicillin are dissolved in 450 ml of cold (-78 °C) tetrahydrofuran, 18.0 ml of a 2.85M solution of methylmagnesium bromide (51.3 mmol) in ether are added dropwise to this solution and the mixture is stirred at -78 °C for 20 minutes. An excess (25 ml; 0.45 mol) of acetaldehyde is added to the mixture containing the resulting magnesium enolate, the reaction mixture is stirred for 20 minutes, then the cooling bath is removed and 70 ml of 1N aqueous hydrochloric acid and 300 ml of ether are added to the mixture. 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 bicarbonate solution and brine, and dried over magnesium sulfate. After evaporation of the solvent, 13.08 g (42.7 mmol; yield 97%) of the title compound is obtained as an oil.

³ H NMR (deuterochloroform, dv ppm values):

5.61 (1H, singlet, H-5), 4.28 (1H, quartet, J = 6.0, H-1' ), 2.21 (3H, singlet, CH^), 2.16 (3H, singlet, CH^), , 1.64 (wide singlet OH) , 1.31 (3H, doublet, J = 6.0 Hz, _CH3 ).

IR (dichloromethane): at 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).

= +83.8° (c = 0.128, methanol).

Analysis: calculated for 39.23% C, 3.95% H, 4.57% N; found 38.31% C, 4.63% H, 4.61% N.

C. Anhydro-6-alpha-bromo-6-beta- [(1'R)-(tert-butyldimethylsilyloxy)ethyl]penicillin

To a solution of 6.0 g (19.6 mmol) of anhydro-6-alpha-bromo-6-beta-[(1Έ)-hydroxyethyl]penicillin in 60 ml of methylene chloride, cooled in ice, is first added 4.50 ml (39 mmol) of 2,6-lutidine and then 7.8 ml (34 mmol) of tert-butyldimethylsilyl trifluoromethanesulfonate is added dropwise.

The mixture was stirred at 5°C for 1 hour, then washed with 1N aqueous hydrochloric acid, water, 1M aqueous sodium bicarbonate solution and brine, the organic phase was dried over magnesium sulfate, diluted with an equal volume of ether/petroleum ether (2:1) and clarified with activated charcoal. The solvent was evaporated, the residue was dissolved in hot hexane and the solution was allowed to crystallize. 5.35 g of the title compound was obtained. The mother liquor was concentrated, clarified with activated charcoal and allowed to crystallize at 5°C. A further 1.28 g of product was obtained. Combining these two fractions gave 6.63 g (15.7 mmol; yield

80.6%) of the hydroxy derivative with a protected hydroxyl group, melting after crystallization from methanol at 116 to 117 °C.

''Η NMR (deuterochloroform, values 6 in ppm) :

5.53 (1H, singlet, H-5), 4.27 (1H, quartet, J = 6.1 Hz, H-1'), 2.20 (3H, singlet, CHg), 2.13 (3H, singlet, CHp, 1.28 (3H, doublet,

J = 6.1 Hz, CHg), 0.91 (9H, singlet, tert.butyl), 0.09 (3H, singlet, CHg), and 0.07 (3H, singlet, CHg).

IR (dichloromethane): at 1,785 (strong band, beta-lactam carbonyl), 1,700 (strong band, lactone carbonyl) and 1,635 cm (medium band, olefin).

²² = +119.6° (c = 0.14, methanol).

Analysis: for C ₃ gH ₂₇ NO ₃ SBrSi calculated 45.60% C, 6.45% H, 3.32% N; found 46.38% C, 6.02% H, 3.23% N. ·

D. Anhydro-6-alpha-[(1'R)-(tert,butyldimethylsilyloxy)-ethyl]penicillin

To a solution of 1.00 g (2.38 mmol) of anhydro-6-alpha-bromo-6-beta-[(1'R)-(tert-butyldimethylsilyloxy)ethyl]-penicillin in 25 ml of a 25% mixture of tetrahydrofuran and methanol, cooled to -45 °C, was added 10 g of a zinc-silver combination (prepared from 1 part silver acetate and 11.7 parts zinc). The mixture was stirred until all the starting material was consumed according to thin layer chromatography (R^ = 0.4; 2% acetonitrile in dichloromethane), after which it was filtered through a pad of diatomaceous earth into cold 1M aqueous ammonium chloride solution. The mixture was shaken, the phases were separated, and the aqueous phase was extracted three times with 10 ml of ether each time. The organic phases were combined, washed successively with 1N aqueous hydrochloric acid, water, 1M aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and the solvent was evaporated. An oily residue was obtained which solidified in vacuo to give 815 mg (2.38 mmol; 99.6% yield) of product. According to high performance liquid chromatography, this solid material had the following composition: Starting material 0.70%; ois-isomer 2.51%; title compound 96.79%. The product melted at 56-57°C after crystallization from methanol.

NMR (deuterochloroform, δ values in ppm):

5.29 (1H, doublet, J = 1.8, H-5), 4.34 (1H, doublet of quartets, J = 3.5,

J = 6.3 Hz, H-1'), 3.52 (1H, double doublet, J = 3.5, J = 1.8 Hz,

H-6), 2.17 (3H, singlet, CHg), 2.08 (3H, singlet, CHg), 1.25 (3H, doublet J = 6.3 Hz, CHg), 0.89 (9H, singlet, tert.butyl), and 0.09 (6H, singlet, ch ₃ ) .

IR (dichloromethane): v _max 1,775 (strong band, alpha-lactam carbonyl), 1,965 (strong band, lactone carbonyl) and 1,635 cm ¹ (medium band, olefin).

Analysis: for ^c i6 ^H 27 ^NO 3 ^SSi calculated 56.10% C, 8.24% H, 4.09% N, 9.38% S;

found 56.65% C, 7.82% H, 4.07% N, 9.04% S.

The corresponding 6-beta-(1'R)-isomer was isolated as an oily product with the following properties:

''H NMR (deuterochloroform, values 6 in ppm) :

5.35 (1H, doublet, J = 4.6, H-5), 4.31 (1H, doublet of quartets, J = 6.0,

J = 9.4, H-1'), 3.83 (1H, double doublet, J = 4.6, J = 9.4, H-6),

2.18 (3H, singlet, CHj), 2.08 (3H, singlet, CHj,, 1.23 (3H, doublet,

J = 6.0, CH-j ), 0.89 (9H, singlet/tert.butyl), 0.10 (3H, singlet,

CH^ ) and 0.06 (3H, singlet, CH^ ).

IR (dichloromethane): » 1,785 (strong band, beta-lactam carbonyl), 1,695 (strong band, ma x 2.

lactone carbonyl) and 1,635 cm (medium band, olefin).

[a] p ^{2 = +171} ' ² ° < ^{c =} °'°θ ⁴ < methanol).

E. alpha-[(3R)-/(1'R)-(tert-butyldimethylsilyloxy)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-butyldimethylsilyloxy)ethyl*]penicillin in 75 ml of acetic acid at 22 °C is added 14 g (44 mmol) of mercuric acetate, the mixture is stirred for 24 hours, then another 9.3 g (29 mmol) of mercuric acetate are added and stirring is continued for another 24 hours. The reaction mixture is filtered through a layer of diatomaceous earth and the solid residue on the filter is washed with acetic acid. The filtrate is diluted with 150 ml of water and extracted five times with 40 ml of ether each time. The organic extracts are combined, washed three times with 40 ml of water and sodium chloride solution each time, dried over magnesium sulfate and decolorized with activated carbon. After evaporation, an oily residue is obtained, which is crystallized in vacuo to give 5.33 g (13.8 mmol; yield 95%) of the desired product melting after crystallization from a mixture of dichloromethane and petroleum ether (9:1) at 119-120 °C.

NMR (deuterochloroform, δ values in ppm):

6.32 (1H, doublet, J = 1.4, H-4), 4.24 (1H, center of 5 signals, J = 6.0, H-1'), 3.20 (1H, doublet doublet, J = 1.4, J = 5.8, H-3), 2.24 (3H, singlet, CH^, 2.05 (3H, singlet, CH ₃ CO ₂ ), 1.97 (3H, singlet, CH ₃ ),

1.29 (3H, doublet, J = 6.3, CH ₃ ), 0.86 (9H, singlet, tert.butyl), 0.08 (3H, singlet, CH ₃ ), and 0.05 (3H, singlet, CH ₃ ).

XC (dichloromethane): ^v _max 1 (strong band, beta-lactam carbonyl), 1,745 (medium band, CH ₃ C=O, 1,690 (medium band, CC^H) and 1,620 cm ¹ (weak band, olefin).

D ^{2 =} + ¹⁸ ' ⁹ ° < ^c = 0.088, methanol).

Analysis: for C 10 H 10 NO 6 Si calculated 56.07% C, 8.10% H, 3.63% N;

found 56.00% C, 8.25% H, 3.73 0 N.

F. (4R)-acetoxy-(3R)-[(1'R)-(tert-butyldimethylsilyloxy)aminoethyl J-2-azetidinone

axis—L .ococh ₃

OSi —|~

AND?

J—NH >OCOCH ₃ every ₂ h

CO2CO2C 2^5

To a solution of 2.0 g (5.2 mmol) of alpha-[(3R)-(1'R)-(tert-butyldimethylsilyloxy)ethyl]-(4R)-acetoxy-2-azetidinon-1-yl-beta-methylcrotonic acid in 30 ml of dichloromethane at -15 °C (ice-cooled in methanol) was added 1.63 g (6.20 mmol) of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline. 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 to give 2.14 g (93.3% yield) of the mixed anhydride, i.e. the intermediate with a protected carboxyl function.

³ H NMR (deuterochloroform, values of 8 in ppm):

6.23 (1H, doublet, J = 1.4, H-4), 4.32 (2H, quartet, J = 7.1, CH ₂ CH ₃ ), 4.05 to 4.39 (1H, multiplet, J = 6.1 H-1', , 3.23 (1H, doublet,

J = 1.4, J = 6.1, H-3), 2.25 (3H, singlet, CHj), 2.06 (3H, singlet, CH ₃ CO) , 1.17 (3H, singlet, CH ₃ ), 1.35 (3H, triplet, J = 7.1, CH-jCH-J ,

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

IC (dichloromethane): v _max 1800 (strong band, mixed anhydride), 1775 (strong band, beta-lactam carbonyl), 1750 (strong band, aoacetate carbonyl) and 1625 cm (weak band, olefin).

2.10 g (4.76 mmol) of the mixed anhydride thus obtained were dissolved in 30 ml of dichloromethane, the solution was cooled to -78 °C (cooling bath consisting of solid carbon dioxide in acetone) and ozonolysis was carried out until the starting material disappeared (1.5 hours). The cold (-78 °C) ozonide solution was reduced with 6 ml of dimethyl sulfide and the mixture was stirred for 1.5 hours. After adding first 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 sodium chloride solution, dried over magnesium sulfate and the solvent was evaporated. 1.31 g (4.56 mmol; 95% yield) of the title compound is obtained as a white solid melting after crystallization from a mixture of equal parts of ether and petroleum ether at 104-106 °C [in Chem. Pharm. Bull. (Tokyo) 29,

899 (1981) gives 104-106°C[]. The product has an optical rotation of - +47.4° (c = 0.136, chloroform) [in the above cited literature it is given as = +48.8° (c = 0.41, chloroform)].

Example2

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

1) CH-jMgBr

2) CH3CHO -20°C

1=0

Reagents:

anhydropenicillin methylmagnesium bromide (CH ₃ MgBr) acetaldehyde (CH^CHO) tetrahydrofuran

10.23 g (0.03 mol)

12.21 ml (0.0 348 mol, 16% excess, 2.85M solution in ether, Aldrich)

6.6 g = 8.4 mL (0.15 mol, density 0.788, Aldrich)

150 ml (dried over molecular sieve)

Procedure:

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

Example

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

Br

Br1) CH2MgCl

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

Reagents:

anhydropenicillin methylmagnesium chloride acetaldehyde tetrahydrofuran

34.1 g (0.1 mol)

39.6 mL (0.116 mol, 16% excess, 2.9M solution in tetrahydrofuran) mL = 22 g (0.5 mol, density 0.788)

350 ml (dried over molecular sieve) toluene

800ml

Procedure:

A solution of 34.1 g of anhydro-6,6-dibromopenicillin in 350 ml of dry tetrahydrofuran is cooled to -45 °C and 39.6 ml of methylmagnesium chloride is added dropwise over 20 minutes, while maintaining the temperature below -40 °C. The resulting solution is stirred at -45 to -40 °C for 10 minutes, after which 28 ml of acetaldehyde is added (initially dropwise) over 5 minutes, while maintaining the temperature below -30 °C. The reaction solution is stirred at -40 °C for 15 minutes, after which 35 ml of saturated ammonium chloride solution and then 400 ml of water are added. The mixture is extracted first with 350 ml and then with 150 ml of toluene, the toluene extracts are washed twice with 300 ml of sodium chloride solution each time, dried with anhydrous magnesium sulfate and concentrated to a volume of about 100 ml. To this concentrated solution is added 300 ml of toluene and the mixture is concentrated again to a volume of about 300 ml [high performance liquid chromatography indicates 92% purity and absence of trans-isomer: column: Porasil (Waters), solvent: 3% acetonitrile in dichloromethane, flow rate: 90 ml/h, detection: UV (275 nm), sensitivity 0.2].

Claims (7)

OBJECT OF THE INVENTION A process for the preparation of penicillanic acid derivatives of the general formula IIa (IXa) in which X represents a chlorine, bromine or iodine atom or a phenyl-selenium group, characterized in that the intermediate of the general formula V X Y 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 R ₁ MgX and organolithium compounds of the formula R ₁ Li, wherein R ₁ is lower alkyl or aryl and X is as defined above, in an anhydrous inert organic solvent at a temperature ranging from 0 ° C to -78 ° C, after which acetaldehyde is added. 2. The process of claim 1 wherein the starting material is a compound of the formula Br kde Y is as defined above, * or a compound of formula Br Br 3. The process of claim 1 wherein the starting material is 6,6-dibromanhydropenicillin. 4. The process according to claim 1, 2 or 3, wherein the Grignard reagent is methylmagnesium bromide. 5. The process of claim 1, wherein the Grignard reagent is methylmagnesium chloride. 6. The process of claim 1, wherein 6,6-dibromohydropenicillin is reacted in an inert organic solvent with a methylmagnesium chloride equivalent at a temperature ranging from -45 ° C to -40 ° C, followed by a molar excess of acetaldehyde. 7. The process of claim 1, wherein 6,6-dibromoanhydropenicillin is reacted in an inert organic solvent with a methylmagnesium bromide mole equivalent at -20 [deg.] C. and a molar excess of acetaldehyde is added.