CS253737B2 - Process for preparing derivatives of penicillanic acid - Google Patents

Abstract

Process for making penicillan derivatives an acid of formula (IIa) wherein X is chloro or bromo or iodine or phenylsel; by the fact that the intermediate product of formula V in which X and Y independently represent each other chlorine, bromine or iodine each; phenylselene group is reacted with the reagent selected from the group consisting of Grignard reagents of the formula R 1 MgX a the organolithium compounds of the formula R ^ Li Li in which R ^ is lower alkyl a group or an aryl group and X has the above as defined above, in an anhydrous inert organic solvent at a temperature in the range from 0 ° C to -78 ° C, followed by addition of acetaldehyde

Description

The invention relates to a new 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 the formula I 'π H. °

OCCH, (I) wherein R represents a conventional hydroxyl-protecting group 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 the synthesis of carbapenem and penem antibiotics containing a (R) -hydroxyethyl substituent at the 6-position and having a (R) -hydroxyethyl substituent at the 6-position; 6 absolute configuration R resp. 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 for separation of diastereomeric mixtures resulting from these processes.

A more detailed description of known methods for the synthesis of the above-mentioned carbapenem and penem derivatives is given in our related Czechoslovak patents Nos. 253,724 and 253,736. These known processes do not take place in some of the reaction steps of stereospecifics so that a mixture of diastereomers is required to obtain 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.

We have now found a new stereospecifically controlled process for converting 6-aminopenicllanic acid to the known optically active intermediate azetidinone of formula 1. This improved process is characterized by:

a) Converts 6-aminopenicillanic acid to anhydropenicillin (V) by known methods

X

in which

X and Y each independently represent chloro atom, bromo, iodo or fenylselenoskupinu (SeCgH ₅₎

(b) reacting an intermediate of formula (V) with a reagent selected from the group consisting of Grignard reagents of formula R 1 MgX and organolithium compounds of formula R 1 L 1 wherein R 1 is lower alkyl or aryl and X is as defined above; an anhydrous inert organic solvent at a temperature in the range of about 0 ° C to -78 ° C, and then acetaldehyde is added to form exclusively the intermediate of formula (IIa)

(at) in Which

X is as defined above,

c) converting an intermediate of formula IIa into an intermediate of formula IIb

(lib) in which

R represents 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 atoms, and

X is as defined above,

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

(Illb) in which

R is as defined above, is isolated,

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

and

f) this intermediate of formula IV is oxidized to cleave the beta-methyl-crotonate residue and produce the desired optically active intermediate of formula I.

In one variation of the process described above, the intermediate of formula (IIa) may be reduced prior to protection of the hydroxyl function.

The above process brings about 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 thenamycin, corresponding to the formula

OH

sch ₂ ch ₂ nh ₂

COOH

Specific embodiments of the individual reaction steps of the above process, as well as a closer discussion of its advantages over the known methods, are described in our above-cited related Czechoslovak patents.

It is an object of the present invention to provide novel penicillanic acid derivatives of formula IIa

(Ha) in which

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

X

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; and X is as defined above, in an anhydrous inert organic solvent at a temperature ranging from 0 ° C to -78 ° C, and then acetaldehyde is added.

The invention is based on the unexpected finding that an aldol condensation reaction on certain 6,6-disubstituted anhydropenicillins results in the exclusive formation of only a single stereoisomer, i.e. isomers of formula (IIa) having the desired stereochemistry of 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 residue X greatly improves the usability of the pathway through 6-aminopenicillanic acid for the synthesis of penemic and carbapenem antibiotics.

The intermediates of formula (V) which are starting materials for the novel process of the invention are known or are prepared by known methods. These intermediates can be prepared primarily by 6-APA to give the corresponding 6-APA. 6,6-dihalogenic penicillanic acid or 6,6-bis (phenylselenyl) penicillanic acid, converting it into an acid halide or mixed anhydride, and reacting the halide or anhydride with a tertiary amine to form anhydropenicillin. British Patent Application No. 2,405,755 A discloses 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-dibromanhydropenicillins. U.S. Pat. No. 3,311,638 describes general procedures for converting penicillins to anhydropenicillins for use in the process of the invention are 6,6-dihalogenanhydropenicillins, preferably 6,6-dibromanhydropenicillin and 6-bromo-6-iodoanhydropenicillins, and most preferably 6.6. -bromanhydropenicillin.

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

This reaction constitutes a key step in the above synthesis, since the aldol condensation of the intermediate anhydropeniline produces the desired optically active isomer, i.e. the desired product. a stereoisomer with a cis arrangement at the 5 and 6 positions and an (8R) -hydroxyethyl substituent at the 6-position. This unexpectedly stereospecific aldol condensation eliminates the need for separation of diastereomers required by prior art procedures and therefore greatly increases practical applicability of the 6-APA process for the synthesis of carbapenem and penem final products.

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

(18), 2,960 to 2,965 (1977). From 6,6-dihalogenanhydropenicillin, using 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 then reacted in situ with excess acetaldehyde 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 about -20 ° C. The enolate is prepared using about a mole equivalent of an organolithium reagent or a Grignard reagent.

Preferred organolithium reagents are those corresponding to the general formula R1-Li, wherein R1 is a lower alkyl group, i.e. an alkyl group having 1 to 6 carbon atoms, or an aryl group, i.e. an aryl group having 6 to 10 carbon atoms, as a group 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, methylmagnesium 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 resulting product of formula (IIa) can then be subjected to the further reactions mentioned above.

The invention is illustrated by the following non-limiting examples. The first of these examples illustrates the entire synthesis leading to the preparation of the azetidinone of formula I.

Example 1

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

Br

Br-

A. Anhydro-6,6-dibrompenicillin

To a solution of 20.00 g (55.56 mmol) of 6,6-dibrompenicillanic acid in 200 ml of dichloromethane cooled in an ice-water cooling bath in methanol was added dropwise 58.4 mmol (8.00 ml) of triethylamine, the solution was stirred for 15 minutes 8.40 ml (61.2 mmol) of trifluoroacetic anhydride was added dropwise, followed by 4.8 ml (61.2 mmol) of pyridine after stirring 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 decolorized with charcoal and evaporated. 16.1 g (47.2 mmol, 85% yield) of the title compound of melting point 102 DEG-103 DEG C. are obtained.

¹ H NMR (CDCl 3, 80 MHz, δ ppm):

5.80 (IH, s, H-5), 2.21 (3H, s, CH?) And 2.15 (3H, s, _CH3).

IR (dichloromethane): v _max 1,800 (strong band, beta-lactam carbonyl), 1,708 (strong band, lactone carbonyl) and 1,640 cm @ -1 (weak band, olefin).

[.alpha.] D @ ²² = + 88.9 DEG (c = 0.144, methanol).

H, 2.07; N, 4.10.

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

B.

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

15.02 g (44 mmol) of anhydro-6,6-dibrompenicillin are 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. An excess (25 ml; 0.45 mol) of acetaldehyde was added to the mixture containing the formed magnesium enolate, 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 bicarbonate 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.

@ ¹ H NMR (CDCl3) .delta.

5.61 (1H, singlet, H-5), 4.28 (1H, quartet, J = 6.0, H-1 ' ), 2.21 (3H, singlet, CH3), 2.16 (3H, singlet, CH3), , 1.64 (broad singlet OH), 1.31 (3H, doublet, J = 6.0 Hz, CH ₃ ).

IR (dichloromethane): v 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: C, 39.23; H, 3.95; N, 4.57. Found: C, 38.31; H, 4.63; N, 4.61.

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 - [(1 ') -hydroxyethyl] penicillin in 60 ml of ice-cold methylene chloride was added, first, 4.50 ml (39 ml). mmol) of 2,6-lutidine, and 7.8 ml (34 mmol) of tert-butyldimethylsilyl trifluoromethanesulfonate are then added dropwise.

The mixture was stirred at 5 ° C for 1 hour, then washed with 1N aqueous hydrochloric acid, water, 1M aqueous sodium hydrogen carbonate solution and brine, dried over magnesium sulfate, diluted with an equal volume of a 2: 1 mixture of ether and petroleum ether. ) and clarified with activated carbon. 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 is obtained. The mother liquor is concentrated, clarified with activated carbon and allowed to crystallize at 5 ° C. An additional 1.28 g of product is obtained. Combine both to give 6.63 g (15.7 mmol);

80.6%) of a hydroxyl-protected hydroxy derivative melting after crystallization from methanol at 116-117 ° C.

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

5.53 (1H, singlet, H-5), 4.27 (1H, quartet, J = 6.1 Hz, H-1 '), 2.20 (3H, singlet, CH3), 2.13 (3H) , singlet, CHp, 1.28 (3H, doublet,

J = 6.1 Hz, CH3), 0.91 (9H, singlet, tert-butyl), 0.09 (3H, singlet, CHg) and 0.07 (3H, singlet, CHg).

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

^[ Α] D = + 119.6 ° (c = 0.14, methanol).

Analysis: Calculated for C ₃ H ₂₇ NO ₃ SBrSi: C, 45.60; H, 6.45; N, 3.32. Found: C, 46.38; H, 6.02; N, 3.23.

D. Anhydro-6-alpha- [1,1'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, When cooled to -45 ° C, 10 g of zinc-silver combination (prepared from 1 part silver acetate and 11.7 parts zinc) are added. The mixture was stirred until all starting material was consumed by thin layer chromatography (Rf = 0.4; 2% acetonitrile in dichloromethane), then filtered through a pad of diatomaceous earth into cold 1M aqueous ammonium chloride solution. The mixture is shaken, the phases are separated, and the aqueous phase is 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 is obtained which solidifies in vacuo to give 815 mg (2.38 mmol; yield 99.6%) of the product. According to high performance liquid chromatography, this solid material had the following composition: Starting material 0.70%; ois-isomer 2.51%; the title compound 96.79%. The product melts after crystallization from methanol at 56-57 ° C.

NMR (deuterochloroform, δ 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, siglet, CH3), 2.08 (3H, singlet, CH3), 1.25 (3H, doublet J = 6.3 Hz, CH3), 0.89 (9H, singlet, t-butyl) and 0.09 (6H, s, CH _3).

IR (dichloromethane): v _max 1775 (strong band, alpha-lactam carbonyl), 1965 (strong band, lactone carbonyl) and 1635 cm ¹ (medium strength, olefin).

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

Found: C, 56.65; H, 7.82; N, 4.07; S, 9.04.

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

@ 1 H NMR (CDCl3, .delta. 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, CH2), 2.08 (3H, singlet, CH2), 1.23 (3H, doublet,

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

CH 2) and 0.06 (3H, singlet, CH 2).

IR (dichloromethane): »1785 (strong band, beta-lactam carbonyl), 1695 (strong band, m × 2).

lactone carbonyl) and 1635 cm (medium thickness, olefin).

[ ^.alpha. ] ^D @ ^{20 = +171} DEG ^-2 DEG ( ^{c =} DEG DEG. @ ⁴ <methanol).

E. alpha - [(3R) - [(1'R) - (tert-butyldimethylsilyloxy) ethyl] - (4R) -acetoxy-2-azetidinon-1-yl] -β-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) mercuric acetate, the mixture is stirred for 24 hours, then 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 from 9: 1 dichloromethane / petroleum ether (9: 1) at 119-120 ° C.

NMR (deuterochloroform, δ 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, double doublet, J = 1.4, J = 5.8, H-3), 2.24 (3H, s, CH ^, 2.05 (3H, s, CH ₃ CO _2), 1.97 (3H, s, CH ₃ ),

1.29 (3H, doublet, J = 6.3, CH _3), 0.86 (9H, singlet, t-butyl), 0.08 (3H, s, _CH3) 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).

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

For C 8 ^ gHH ^NOgSi: C, 56.07; H, 8.10; N, 3.63.

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

F. (4R) -Acetoxy- (3R) - [(1'R) - (tert-butyldimethylsilyloxy) -acetyl] -2-azetidinone

Axis — L .ococh ₃

OSi - | ~

AND?

J - NH> OCOCH ₃ every ₂ h

CO2CO2C2 ^ 5

To a solution of 2.0 g (5.2 nunol) alpha - [(3R) - (1'R) - (tert-butyldimethylsilyloxy) ethyl] - (4R) -acetoxy-2-azetidinon-1-yl-beta-methylcrotonic acid of the acid in 30 ml of dichloromethane is 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 protected carboxylic acid intermediate.

@ ³ H NMR (CDCl3, .delta. 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, double doublet,

J = 1.4, J = 6.1, H-3), 2.25 (3H, singlet, CH ₃ ), 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, CH3), 0.86 (9H, singlet, tert-butyl), 0.08 (3H, singlet, CH3) and 0.05 (3H, singlet, CH) ₃ ).

IC (dichloromethane): v _max 1,800 (thick band, mixed anhydride), 1,775 (strong band, beta-lactam carbonyl), 1,750 (strong band, acetone carbonyl) and 1,625 cm (weak 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 sodium chloride, dried over magnesium sulfate and the solvent was evaporated. 1.31 g (4.56 mmol; yield 95%) 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 DEG-106 DEG C. [Chem. Pharm. Bull. (Tokyo) 29

899 (1981) reported 104-106 ° C []. The product has an optical rotation of - + 47.4 ° (c = 0.136, chloroform) [reported above = + 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) CH 3 CHO -20 ° C

1 = 0

Reagents:

anhydropenicillin methylmagnesium bromide (CH ₃ MgBr) acetaldehyde (CH 2 CHO) tetrahydrofuran

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 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 over 10 minutes 12.21 ml of methylmagnesium bromide, maintaining the temperature of the mixture between -15 and -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 the temperature between -15 and -20 ° C. The reaction mixture was stirred at -20 ° C for 15 min, 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, consisting of 92% cis-isomer (no trans-isomer) and 8% impurities (high performance liquid chromatography; column: Por Porilil Waters; solvent: 3% acetonitrile in dichloromethane) , flow rate: 90 ml / h, detection: UV 275 275 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) CH3MgCl

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

800 ml

Method:

A solution of 34.1 g of anhydro-6,6-dibromopeniline in 350 ml of dry tetrahydrofuran was cooled to -45 ° C and 39.6 ml of methylmagnesium 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. : 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.