FI79832B - A-BROMODIETYLKARBONAT OCH DESS ANVAENDNING VID FRAMSTAELLNING AV ETOXIKARBONYLOXIETYLESTERN AV PENICILLIN G. - Google Patents

Description

79832 α-Bromo-diethyl carbonate and its use as an intermediate in the manufacture of ethoxycarbonyloxyethyl ester of penicillin G

The present invention relates to a novel compound α-bromo-diethyl carbonate and its use in the preparation of penicillin G ethoxycarbonyloxyethyl ester.

Ethoxycarbonyloxyethyl of penicillin G is a starting material in the preparation of e.g. bacampicillin, which is an ampicillin ester that is very important from a therapeutic point of view because it is well absorbed when administered orally and provides much higher levels of ampicillin in the blood than ampicillin itself. α-Bromo-diethyl carbonate has the formula

Br O

I I

CHa-CH-O-C-O-CzHs I

α-Bromo-diethyl carbonate is very preferably used as a reactant in the esterification of penicillin G. The use of α-bromo-diethyl carbonate gives a very high yield and also a very high purity of the final products such as bacampicillin.

The compound of the invention α-bromo-diethyl carbonate can be prepared as follows: A. by reacting the corresponding α-chloro-diethyl carbonate with sodium bromide. This method is described in Example 1.

B. (a) by reacting an aldehyde of formula

CHaCHO II

2,79332 to react with carbonyl bromide

COBr2 III

to give α-bromo-bromoformate of formula

br

CHa-CH.O.CO.Br IV

(b) reacting the α-bromo bromoformate of formula IV with an alcohol of formula C 2 H 5 -OH to give the desired α-bromo diethyl carbonate of formula I.

Method B can thus be represented by a reaction scheme:

Br + C2H5OH Br

I I

CHaCHO + COBra -> CHa-CH.O.CO.Br -> CHa-CH.O.CO.CaHs + HBr

The α-bromo-bromoformate of formula IV is in itself a novel compound.

The reaction between the aldehyde CH 3 CHO and the carbonyl bromide is preferably carried out in the presence of a catalyst which may be, for example, a tertiary amine (e.g. tertiary aliphatic amine, tertiary mixed alkyl / arylamine or tertiary aromatic amine), tertiary phosphine, amide, substituted urea, substituted urea , a tertiary oxonium or sulfonium salt or a quaternary ammonium or phosphonium salt. Preferred examples of catalysts that can be used in Process B include pyridine, dimethylformamide, tetra-n-butylurea, hexamethylphosphoric triamide and benzyltrimethylammonium bromide.

The catalyst is suitably used in amounts of 0.05 to 0.5, preferably 0.05 to 0.15 moles per 1 mole of aldehyde.

3,79332

The reaction between the aldehyde and the carbonyl bromide is suitably carried out in the presence of a solvent which may be, for example, an aromatic hydrocarbon such as toluene or a halogenated hydrocarbon such as dichloromethane, carbon tetrachloride or chlorobenzene. The reaction between the aldehyde and the carbonyl bromide is suitably carried out at a temperature between -40 and + 120 ° C, preferably 0-40 ° C. The carbonyl bromide is usually used in a molar excess relative to the aldehyde, with a suitable molar excess of 10-100%, preferably 20-50%.

The intermediate of formula IV, α-bromo-bromoformate, obtained in step (a) of process B, does not need to be separated prior to reaction with the alcohol C 2 H 5 OH, and it is generally preferred not to do so. Thus, according to a preferred embodiment, the reaction mixture obtained in step (a) is liberated from the excess carbonyl bromide, for example by heating under reduced pressure or purging with nitrogen. The crude α-bromo-bromoformate-containing reaction mixture is then reacted with excess alcohol. The reaction may conveniently be effected by heating the mixture to reflux until the evolution of hydrogen bromide is complete, or by adding a tertiary base to the mixture and, if necessary, heating it. Any catalyst residue from step (a) or a complex thereof with carbonyl bromide does not appear to interfere with the subsequent reaction and in some cases appears to be preferred.

The obtained crude α-bromocarbonate can be conveniently separated from the reaction mixture by fractional crystallization under reduced pressure.

Method B is described in Examples 2 and 3.

C. A third method, Method C, for preparing α-bromo-diethyl carbonate is described below. Method C is shown in Example 4.

4,79332

Method C relates to the preparation of α-bromo-diethyl carbonate by a variant of the Finkelstein reaction, i. using the reaction of an alkyl chloride or arylalkyl chloride (or a compound containing such a group) with an alkali metal bromide or an alkali metal iodide to replace the chlorine substituent with a bromine or iodine substituent, respectively, or using an alkyl bromide or an arylalkyl bromide the bromo substituent is replaced by an iodine substituent.

Not all optionally substituted alkyl chlorides or arylalkyl chlorides undergo this reaction, and it has been found particularly difficult to carry out this reaction using α-chloroesters and α-chlorocarbonates, i. compounds in which a chlorine atom is attached to a carbon atom which in turn is attached to either end of the group -C (O) -O-. An example of such an α-chlorocarbonate is α-chloro-diethyl carbonate, a known intermediate in the preparation of ethoxycarbonyloxyethyl esters of 6-aminopenicillanic acid and penicillins.

According to the invention, it has now been found that this problem can be avoided by carrying out the reaction according to Method C.

According to Method C, α-bromo-diethyl carbonate is prepared by reacting α-chloro-diethyl carbonate with an alkali metal bromide, the reaction being carried out in a two-phase solvent system comprising water and a water-immiscible organic solvent in the presence of a phase transfer catalyst.

Suitable water-immiscible organic solvents which may be used are halogenated hydrocarbons, for example halogenated paraffins, such as dichloromethane, and aromatic hydrocarbons, such as toluene. Suitable phase transfer catalysts include quaternary ammonium salts, for example 5,793,32 tetraalkylammonium salts such as cetyltrimethylammonium bromide and tetra-n-butylammonium hydrogen sulfate. The alkali metal libromide may be, for example, sodium, potassium or lithium bromide, of which lithium bromide is most preferred.

Thus, in Method C, α-chloro-diethyl carbonate of formula is introduced

Cl 0

I II

CHa-CH-O-C-O-CaHs V

react in a two-phase solvent system, one phase of which is water and the other of which is a water-immiscible organic solvent, with a time metal bromide of formula

R-Br VI

wherein R is an alkali metal such as Na, K and Li to form a compound of formula

Br 0

I II

CHa-CH-O-C-O-CaHs I

As mentioned above, the most preferred alkali metal R is Li, so LiBr is the most preferred reagent of formula VI.

In connection with Method C, it has been found that lithium bromide can be advantageously used in a conventional Finkelstein reaction (i.e., using a single-phase organic solvent system), for example, by halogenating os-chlorocarbonate.

Thus, in one embodiment of Method C, α-bromo-diethyl carbonate is prepared by reacting α-chloro-diethyl carbonate with lithium bromide. This method is described in Example 5.

6 79832

Suitable solvents for such a process include lower aliphatic alcohols, lower aliphatic ketones, lower aliphatic ethers and lower aliphatic formic acid amides.

The invention also relates to the use of a novel compound, α-bromoethyl carbonate, for the preparation of ethoxycarbonyloxyethyl ester of penicillin G. In this case, penicillin G or a salt thereof is reacted with α-bromo-diethyl carbonate to form the ethoxycarbonyloxyethyl ester of penicillin G.

The quaternary ammonium compound can be used as a catalyst in the esterification step, wherein the quaternary ammonium compound is present in an amount of 1-25%, preferably 1-10%, based on an equimolar amount of penicillin Gs.

Thus, it is not necessary to use the quaternary ammonium compound in a stoichiometric amount relative to the amount of penicillin G, but less than a stoichiometric amount is sufficient.

Suitable metal salts of penicillin G that can be used in accordance with the invention (either as precursors of the quaternary ammonium salt of penicillin G or as such) include alkali metal and alkaline earth metal salts such as sodium, potassium, lithium, magnesium and calcium salts. Suitable quaternary ammonium salts of non-penicillin Gs (which can be used either as a precursor of quaternary ammonium salts of penicillin G or as such) include, for example, tetraalkylammonium salts such as tetra-n-butylammonium bromide and cetyltrimethylammonium bromide, and quaternary ammonium bromide, and quaternary midi.

The use of α-bromo-diethyl carbonate according to this embodiment of the invention may take place in the presence or absence of a solvent. Suitable solvents are, for example, lower 7,79332 aliphatic alcohols, lower aliphatic ketones, lower aliphatic amides of formic acid and dimethyl sulfoxide. Alternatively, when no solvent is used, an excess of ester-forming halide may be used, especially if this is a liquid at the reaction temperature.

When using α-bromo-diethyl carbonate in the preparation of the ethoxycarbonyloxyethyl ester of penicillin G, the use of a catalyst is optional. Approximately equimolar amounts of the quaternary ammonium salt of penicillin G and the ester-forming halide, i.e., α-bromodiethyl carbonate, can be used in the reaction. Preferably a 5-100% excess of ester-forming halide per equivalent of carboxylic acid salt is used, and even more preferably this excess is 20-60%.

According to a preferred embodiment, the quaternary ammonium salt tetra-n-butylammonium bromide is to be used.

The use of α-bromo-diethyl carbonate in the preparation of penicillin G ethoxycarbonyloxyethyl ester is described in Examples 7, 8 and 9.

The invention is further illustrated by the following examples. Example 1 Preparation of α-bromo-diethylcarbonate acetone

NaBr + Cl-CH-OCOOCaHs -> Br-CH-OCOOCaHs + NaCl

I I

ch3 ch3

Sodium bromide (101.9 g) dissolved in acetone (600 ml) was reacted with α-chloro-diethyl carbonate (152.6 g) dissolved in 100 ml of acetone for 2-3 hours at ambient temperature (20-25 ° C). The mixture was then concentrated in vacuo at low temperature, max. 35 ° C, until a semi-solid mass was obtained. The reaction mixture was then partitioned between 8,793,32 H 2 O and ethyl ether. The aqueous phase was separated and then extracted twice with 400 ml of ethyl ether.

The combined organic phases containing α-bromo-diethyl carbonate were washed with: 800 ml of H 2 O, 1000 ml of 1% aqueous sodium metabisulphate solution, 1000 ml of saturated NaCl solution.

The organic phase was dried over Mg sulphate and then concentrated in vacuo at low temperature, max. 35 ° C to give the title compound (60%) as a liquid which was initially colorless or slightly yellowish brown.

Example 2

A mixture of acetaldehyde (44 g; 1 mol), carbon tetrachloride (300 ml) and freshly distilled carbonyl bromide (235 g; 1.25 mol) was cooled to 0 ° C and kept at this temperature with external cooling while pyridine ( 11.9 g; 0.15 mol) was added over 1 hour.

The mixture was allowed to warm to ambient temperature and then heated to 50 ° C and maintained at this temperature for 3 hours during which time a precipitate formed.

Evaporation of the reaction mixture under reduced pressure at 50 ° C gave a semi-solid, oily mass which readily dissolved in ethanol (92 g; 2 moles) under heating and reflux. After refluxing for a further 2 hours, the excess ethanol was removed in vacuo and the residue was triturated with water (100 ml) and methylene chloride (200 ml).

9 79832

Separation of the organic layer and fractional distillation gave pure ethyl α-bromoethyl carbonate (130 g; 66% yield), b.p. was 90-92 ° C at 60 kPa and identical in all respects to the authentic sample.

Example 3

A mixture of acetaldehyde (44 g; 1 mol), dichloromethane (300 ml) and hexamethylphosphoric acid triamide (17.9 g; 0.1 mol) was cooled to -10 ° C and freshly distilled was gradually added. carbonyl bromide (207 g; 1.1 moles) over 4 hours, during which time the temperature was allowed to rise to 10 ° C.

The mixture was then gently heated to reflux (about 40 ° C) for 4 hours. While still refluxing, ethanol (69 g; 1.5 moles) was carefully added over 1 hour and refluxing was continued for another 1 hour.

Fractional distillation of the resulting mixture gave pure ethyl α-bromoethyl carbonate (114 g; 58% yield).

The authenticity of the ethyl α-bromoethyl carbonate formed was confirmed by analysis and separate synthesis as follows.

Diethyl carbonate (118 g; 1.0 mol) was stirred and heated to between 110 and 120 ° C and irradiated with a 150 watt tungsten wire lamp. Bromine (96 g; 0.6 mol) was added dropwise over 3-4 hours at such a rate that the mixture did not become darker than a light orange color.

When the addition of bromine was complete, the mixture was cooled to ambient temperature and sodium bicarbonate (20 g) was added.

10 79332

Distillation and fractionation of the mixture gave authentic ethyl α-bromoethyl carbonate (84.2 g; 70% yield), b.p. was 87-88 ° C at a pressure of 5.3 kPa.

Example 4

A mixture of lithium bromide (43 g; 0.5 mol), ethyl α-chloroethyl carbonate (15.3 g; 0.1 mol), water (100 ml), dichloromethane (100 ml) and cetyltrimethylammonium bromide (1, 5 g) was stirred at ambient temperature for 24 hours. The aqueous layer was removed and replaced with a fresh solution of lithium bromide (26 g; 0.3 mol) in water (40 ml) containing cetyltrimethylammonium bromide (1 g). After stirring for a further 24 hours during which time the temperature rose to 35 ° C, the organic layer was separated, dried and distilled in vacuo to give, after repeated fractionation, a new compound, ethyl α-bromoethyl carbonate (15.0 g; 76% yield). by kp. was 90-92 ° C at 4.7 kPa.

Found: C 30.7, H 4.8, Br 40.1%

Calculated: C 30.5, H 4.6, Br 40.6% The NMR spectrum had the following peaks: 1.2-1.6 (3H, triple band) -CHa.CHa 2.0-2.2 (3H, double band) -CH.CH3 4.1-4.5 (2H, four lines) -CH2.CH3 6.5-6.8 (1H, four lines) -CH.CHa

Example 5

Lithium bromide (17.4 g; 0.2 mol) was dissolved in dimethylformamide (150 ml) and the mixture was cooled to ambient temperature. Ethyl α-chloroethyl carbonate (30.5 g; 0.2 mol) was added and the mixture was stirred at ambient temperature for 24 hours. The precipitated lithium chloride was filtered off and the filtrate was distilled in vacuo to give, after careful fractionation, ethyl α-bromoethyl carbonate in 76% yield based on the recovered ethyl α-chloroethyl carbonate.

11 79332

Example 6

The authenticity of the above-mentioned new compound, ethyl α-bromoethyl carbonate, was separately confirmed by synthesis as follows:

A mixture of diethyl carbonate (35 g; 0.3 mol) in carbon tetrachloride (50 ml) and α-azoisobutyronitrile (AIBN) (0.1 g) was gently heated to reflux and dibromodimethylhydantoin (28.6 g; 1 mole) was added in small portions over 8 hours along with additional AIBN (8 x 0.05 g). Care was taken not to accumulate free bromine in the reaction mixture. At the end of the reaction, the mixture was subjected to vacuum fractional distillation to give pure ethyl α-bromoethyl carbonate (32.3 g; yield 82%), which was identical in all respects to the products of Examples 4 and 5.

Example 7

Benzylpenicillin-ethoxycarbonylloxyethyl ester Potassium benzylpenicillanate (25.08 g; 66.7 mmol), sodium bicarbonate (0.50 g; 6.0 mmol) and tetrabutylammonium bromide (2.15 g; 6.67 mmol) in methylene chloride were mixed thoroughly with methylene chloride (41 mL). and heated to 40 ° C. When this temperature was reached, α-bromo-diethyl carbonate (17.16 g; 86.7 mmol) was added and the slurry was stirred for 4.0 hours. Water (30 ml) was then added followed by mineral acid to about pH 5. The mixture was stirred for about 4 hours during which time sodium hydroxide (4%) was added to maintain the pH between 2.5-3.0. Methylene chloride (50 mL) was then added and the mixture was allowed to separate for a few minutes. The organic phase was washed with water (65 ml) and then evaporated under reduced pressure. The oily product thus obtained was dissolved in methylene chloride (100 ml) and evaporated again. The residual oil was dissolved in methylene chloride to a total volume of 100 mL.

12 79832

HPLC analysis of the methylene chloride solution showed that the yield of benzyl-penicillin-ethoxycarbonyloxyethyl ester was 96-97%.

Example 8

Benzylpenicillin ethoxycarbonyloxyethyl ester Potassium benzyl penicillanate (5.02 g; 13.3 mmol) and potassium bicarbonate (2.99 g; 38.3 mmol) in dimethyl sulfoxide (13.5 mL) were mixed thoroughly with an ice bath. Α-Bromo-diethyl carbonate (3.70 g; 18.6 mmol) was then added over 30-40 minutes using a needle pump. Stirring was continued while keeping the reaction mixture on an ice bath. HPLC analysis showed that the yield of benzylpenicillin ethoxycarbonyloxyethyl ester was about 70% within 5-10 minutes.

Example 9

Benzylpenicillin ethoxycarbonyloxyethyl ester Potassium benzyl penicillanate (47.03 g; 125 mmol), sodium bicarbonate (0.94 g; 11 mmol) and tetrabutylammonium bromide (2.01 g; 6.25 mmol) were stirred thoroughly in acetone (77 mL) (77 mL). ° C. When this temperature was reached, α-bromo-diethyl carbonate (26.06 g; 131 mmol) was added and the slurry was stirred for 4.5 hours. Water (56 ml) was then added followed by mineral acid to a pH of about 5. The mixture was stirred for about 3 hours during which time sodium hydroxide (4%) was added to maintain the pH between 4.5 and 4.8. Butyl acetate (100 ml) was then added and the mixture was allowed to separate for a few minutes. The organic phase was washed with water (80 ml) and then evaporated under reduced pressure. The remaining oily product was dissolved in methylene chloride to a total volume of 250 ml.

HPLC analysis of the methylene chloride solution showed that the yield of benzyl-penicillin-ethoxycarbonyloxyethyl ester was 98-99%.

13 79832

α-bromodiethylcarbonate and the production of a by-product of the ethoxycarbonyloxyethyl ester of penicillin G

The uptake of a mixture of α-bromodiethylcarbonates with the addition of ethoxycarbonyloxyethyl esters of penicillin G.

The ethoxycarbonyloxyethyl ester of penicillin G is utilized in the form of a mixture of bl.a. bacampicillin, an ampicillin liner which is extremely sensitive to the therapeutic effect of oral absorption and oral administration, is also associated with ampicillin and is used in ampicillin självt. α-bromodiethylcarbonate in the form of

Br 0 I 1

CH3-CH-O-C-O-CaH5 I

The α-bromodiethylcarbonate is obtained with a reaction medium from the forest ring of penicillin G. The addition of α-bromodiethylcarbonate is carried out to a specific species and the presence of bacampicillin.

For example, α-bromodiethylcarbonate is enriched in the following conditions: A. genomic reaction with the addition of α-bromodiethylcarbonate and sodium bromide. Exemption method for exemptions 1.

B. (a) a reaction with an aldehyde in the formulation

CHaCHO II

and carbonyl bromide

COBra III

i4 79832 for the preparation of α-bromo-bromo-forms with the following formula:

br

CHa-CH.O.CO.Br IV

(b) reacting α-bromo-bromoformate with Formula IV and an alcohol with Formula C2H5-OH for the formation of α-bromodiethylcarbonate of Formula I.

For the purposes of heading B, the same conditions as in the reaction scheme are as follows:

Br + C2H5OH Br

I I

CH3CHO + COBr2 -> CHa-CH.O.CO.Br -> CHa-CH.0.CO.C2H5 + HBr α-bromo-bromoformate with formula IV is used for the preparation.

Reactions with aldehyde amine, CH3CHO, and carboxyl bromides at the same time as catalysts in the catalyst of the tertiary aliphatic amine (tertiary mixture of the alkyl / aryl-amine or the tertiary aromatic amine) , substituents urea or thiourea, phosphorusureas, tertiary oxonium or sulfonium salt, or quaternary ammonium or phosphonium salt. Preferred catalysts for pyridine, dimethylformamide, tetra-n-butylurea, hexamethylphosphoric triamide and benzyltrimethylammonium bromide are thus preferred.

The catalyst is heated to 0.05 mol, the catalyst is 0.05 mol of aldehyde.

Reactions with aldehydes and carbonyl bromides in the form of anhydrous solution are 79332 and aroxynatically fused to dichloromethane or halogenated flasks with dichloromethane, choletrachloride or chlorobenzene. Reactions with melian aldehyde and carbonyl bromide are allowed to warm to -40 to 120 ° C, to 0-40 ° C. The carbonyl bromides are treated in the same manner as the aldehyde, the aliquot is in the form of an account for 10% and the anhydrous in the account of 20%.

Det as an intermediate erhälinä α-bromo-bromoformiatet som of the formula IV is obtained in step (a) of the inventive method B behöver ej isolating upstream the reaction is with alkholen CaHsOH och det is in the själva verket i allmänhet lämpligt order not göra properties. Preferably, the preferred form of the reaction is in the form of a mixture of carbonyl bromides, in which case the free genome is introduced under reduced pressure or the genome is spooled in a quaternary manner. The reaction reaction is carried out with the addition of α-bromo-bromoforms after reacting with reactants and alcohol. Reactions can be performed on the genome uptake of the blast furnace under the same conditions as the bleaching of the genome uptake or on the basis of bleaching, and on the other hand, upstream of the blast furnace. Optionally, the rest-catalyst from step (a) or a complex of carbonyl bromides is synthesized and then the inverted end of the reaction is reacted and can be removed.

The α-bromocarbonate is shown to be isolated from the reaction genome as a fraction of the destination under reduced tryck.

Förfarandet B äskädliggöres i exemplen 2 och 3.

C. For the third time C, the fraction of α-bromo-diethyl carbonate is added. Method C exemplified by exemptions 4.

i6 79332 For use in the reaction of α-bromodiethylcarbonates with the modification of the reaction, the genomic reaction is carried out by the use of alkyl chlorides or arylalkyl chlorides (or by the addition of an enantiomer of an alkali group) brom- respecting iodine-Tuent; or a genomic reaction with an alkyl bromide or an arylalkyl bromide (or an arylalkyl bromide) with an alkali metal iodide to give a bromine substituent with an iodine substituent.

In this case, optionally substituted alkyl chlorides or arylalkyl chlorides are reacted and specifically charged with the addition of α-chloroesters and α-chlorocarbonates, to which a color is added to the color of the chlorine atom and the carbon monoxide to which it is present. the group is -C (O) -O-. In addition to the addition of α-chlorocarbonate to α-chloroethyl carbonate, some products of the ethoxycarbonyloxyethyl ester from 6-aminopenicillin and an penicillin are present.

In this case, in addition to the uptake of the present invention, all of these problems can be attributed to the genome in response to the presence of C.

In particular, the α-bromodietyl carbonate of the α-bromodietyl carbonate is reacted with α-chlorodiethyl carbonate and alkali metal bromides, the reaction of which is carried out in a solid-state system with the aid of other organic compounds.

Lämpliga med vatten icke blandbara organiciska lösningsmedel som kan avvändas omfattar halogenerade kolväten, bill exempel halogenerade paraffinkolväten säsom dichlorometan; och aromatiska kolväten säsom toluen. Lämpliga fasöverföringska-talysatorer omfattar quaternära ammonium salt, account exempt tetraalkylammonium salt to give cetyltrimethylammonium bromide i7 79332 and tetra-n-butylammonium sulphate. Alkali metal bromide can be exempted from sodium, potassium or lithium bromide, lithium bromide paints.

In the case of the C ring ring, the α-chlorodiethyl carbonate of the formula:

Cl 0

I II

CH3-CH-O-C-O-C2H5 V

and that the solution system with a water-based, water-free system with water and water and the water with a white or organic water-based solution

R-Br VI

color R betecnar en alkalimetall säsom Na, K och Li, för framstälining av en förening med formeln

Br 0 I 1

CH3-CH-O-C-O-C2H5 I

The anhydrous is an alkaline metal compound having the same alkali metal as the liquid reagent in formula VI.

The same method for the preparation of lithium bromides in the form of a conventional Finkel-Stein reaction (for which the organic leaching system has its own characteristics) is exempted from halogenation and α-chlorocarbonate.

In particular, methods C of the α-bromo-diethyl carbonate genome are reacted with α-chlorodiethyl carbonate and lithium bromide. This exemption is exempted from 5.

ib 79832 Lämpliga lösningsmedel för ett sädant förfarande omfattar lägalifatiska alkoholer, lägalifatiska ketoner, lägalifatis-ka etrar och lägalifatiska amider av myrsyra.

The addition of this mixture to the reaction of α-bromodiethylcarbonates with the addition of ethoxycarbonyloxyethyl esters of penicillin G is preferred.

In the case of quaternary ammonium compounds, a variety of catalysts are used, the colors of which are quaternary ammonium-free compounds in the form of 1-25%, warming 1-10% of the equimolar value in the form of a penicillin G.

For this purpose, the quaternary ammonium formulation in the stoichiometric game and the penicillin form of the quaternary ammonium formulation may be determined.

The metal metal salt of penicillin G may be an enriched aspect of the uptake process (antennas used in the form of quaternary ammonium salts of penicillin G or sugar) and alkali metal salt or alka-Liska jordartsmetalsalter säsomrium sodium. Light bulb ammo-niumsalter av andra syror än penicillin G

is 79332

The addition of α-bromodiethylcarbonate is an aspect of the uptake of the nervous system or the fracture. Lämpliga lösningsmedel omfattar lägalifatiska alkoholer, lägalifatiska ketoner, lägalifatiska amider av myrsyra och dimetylsulfoxid. Alternatively, it is possible to obtain a solution in the form of an ester which is particularly suitable for the reaction temperature.

The reaction of α-bromodiethylcarbonate with the addition of ethoxycarbonyloxyethyl esters of penicillin G is carried out with a catalyst of valfri. This equimolar amount of quaternary ammonium salts of penicillin G and the ester halide, dvs. α-bromodiethylcarbonate, is present in the reaction. The heating is carried out in a mixture of 5 and 100% of the ester halide for a shade equivalent to the salt of a carboxylic acid which is used in a mixture of 20 and 60% of the ester halide.

The preferred form of the formulation is to give quaternary ammonium tetra-n-butylammonium bromide.

The conversion of α-bromodiethylcarbonate to the ethoxycarbonyloxyethyl ester of penicillin G is exemplified in copies 7, 8 and 9.

Uppfinningen äskädliggöres närmare med följande exempel. Exemoel 1

Framställning av α-bromodietvlcarbonat acetone

NaBr + Cl-CH-OCOOCaHs -> Br-CH-OCOOCaH5 + NaCl

I I

ch3 ch3 20 79332 102.9 g of sodium bromide lost in 600 ml of acetone are added to the reactor at 2-3 temperatures at room temperature (20-25 ° C) with 152.6 g of α-chlorodiethylcarbonate in 100 ml of acetone. Bland-ningen concentrating därefter under vacuum vid slur tempera-tur, max. 35 ° C, tills en halvfast mass erhällits. Reactions are obtained after the reaction with HaO / ethyl ether. Vatten-fasen separerades och extraherades därefter tvä gänger med 400 ml etyleter.

The organic broth of the same mixture of α-bromo-diethyl carbonate is dissolved in 800 ml of H30 1 000 ml to 1% of water containing sodium metabisulphate 1 000 ml of sodium chloride

The organic phase is charged with Mg-sulfate and concentrated dehydrated under vacuum at l & g, max. 35 ° C, varvid titelprodukten erhölls (60%) i form av en vätska som frän början var färglös eller svagt gulbrun.

Exempel 2

After blending with 44 g of acetaldehyde (1 mol), 300 ml of choletetrachloride and 235 g of cold distilled carbonyl bromide (1.25 mol) at 0 ° C and cooling to room temperature, the mixture is stirred under a mixture of 1 ml of 11 .9 g of pyridine (0.15 mol).

The temperature is maintained at room temperature and up to 50 ° C and at a temperature below the temperature of 3 hours.

The reaction mixture was reduced under reduced pressure at 50 ° C to give a mass of 92 g of ethanol (2 mol) at room temperature and boiling under cooling. After uptake under ether and another 2 times, the mixture was stirred with ethanol in vacuo and ether 2 or 79832 with triturates with 100 ml of water and 200 ml of methylene chloride.

Separation from an organic scale and fractionation by distillation to 130 g of ethyl α-bromoethyl carbonate (66%) at a total temperature of 90-92 ° C at a temperature of 6.0 kPa and below identical to authentic authentication .

Exempel 3

44 g of acetaldehyde (1 mol), 300 ml of dichloromethane and 17.9 g of hexamethylphosphoric triamide (0.1 mol) are cooled to -10 DEG C. and 207 g of distilled carbonyl bromide (1.1 mol) are added. under a temperature of 4 ° C at 10 ° C.

Blandningen upphettades därefter under svagt äterflode (cirka 40 ° C) i 4 timmar. A total of 69 g of ethanol (1.5 mol) was added to the mixture to give 1 hour or more of the mixture.

The destination fraction of the desired mixture was obtained directly from ethyl α-bromoethyl carbonate and 114 g (58%).

However, ethyl α-bromoethyl carbonate can be authenticated without genomic analysis and can be synthesized.

118 g of diethyl carbonate (1.0 mol) are combined and heated to 110 ° C and 120 ° C and heated to 150 W. 96 g of bromine (0.6 mol) are added dropwise to 3- 4 timmar och med med ä sädan hastighet att blandningen ej antog en djupare färg än blekt orange.

The bromine is stirred at room temperature and at room temperature and 20 g of sodium bicarbonate.

22 79832

84.2 g of authentic ethyl α-bromoethyl carbonate with a boiling point of 87-88 [deg.] C. are obtained at a temperature of 5.3 kPa.

Exempel 4

43 g of lithium bromide (0.5 mol), 15.3 g of α-chloroethyl carbonate (0.1 mol), 100 ml of water, 100 ml of dichloromethane and 1.5 g of cetyltrimethylammonium bromide are added at room temperature and 24 g. . Vatenskiktet avlägsnades and ersattes med en nygjord löning av 26 g lithium bromide (0,3 mol) i 40 ml vatten somenälälle 1 g cetyltrimethylammonium bromid. After evaporation to 24 ° C at 35 ° C, the organic fraction was separated, subjected to vacuum distillation and further fractionated to give an ethyl acetate-bromoethyl carbonate fraction of 15.0 g (75%). The total point is 90-92 ° C at a temperature of 4.7 kPa.

Funnet: C 30.7, H 4.8, Br 40.1%

Yield: C 30.5, H 4.6, Br 40.6% NMR spectrum viscous solution Top: 1.2-1.6 (3H, triplet) -CH2.CH3 2.0-2.2 (3H, doublet) -CH.CH3 4.1-4.5 (2H, quartet) -CH2.CH3 6.5-6.8 (1H, quartet) -CH.CH3

Exempel 5 17.4 g of lithium bromide (0.2 mol) are taken up in 150 ml of dimethylformamide and the mixture is cooled to room temperature. 30.5 g of ethyl α-chloroethyl carbonate (0.2 mol) are added and the mixture is stirred at room temperature for 24 minutes. The lithium chlorides are filtered off and filtered under vacuum distillation to give a further refractionation of ethyl α-bromoethyl carbonate to give 76% basal ethyl ethyl α-chloroethyl carbonate.

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Exempel 6

The following is a description of ethyl-α-bromoethyl carbonate:

Bleaching with 35 g of diethyl carbonate (0.3 mol) in 50 ml of tetrachloride and 0.1 g of α-azoisobutyronitrile (AIBN) was added to the mixture with 28.6 g of dibromodimethylhydantoin (0.1 mol). tillsattes i smM portioner under en tid av 8 timmar tillsammans med ytterligare tillsatser av AIBN (8 x 0.05 g): härvid tillses att fritt Brom ej ansamlas i reaktionsblandningen. 32.3 g of ethyl ethyl α-bromoethyl carbonate (82%) are obtained, which are, inter alia, identical to the product obtained in the same manner as in Example 4 and 5.

Exempel 7

Benzylpenicillin-ethoxycarbonylloxyethyl ester 25.08 g of potassium benzylpenicillinate (66.7 mmol), 0.50 g of sodium bicarbonate (6.0 mmol) and 2.15 g of tetrabutylammonium bromide (6.67 mmol) are converted into 41 ml of methylene chloride and color. to 40 ° C. DM at a temperature of 17.16 g of α-bromodiethyl carbonate (86.7 mmol) was added and the mixture was stirred at 4.0 g. 30 ml of cotton wool, top up with minerals to a pH of about 5. The mixture is made up to about 4 times with 4% sodium hydroxide in water at a pH of 2.5 and 3.0 50 ml of methylene chloride in water and a mixture of water. under nMgra fM minuter. The organic phase is taken with 65 ml of water and induced by reducing the mixture. The resulting oil was dissolved in 100 mL of methylene chloride and charged with Mnyo. The oil is dissolved in methylene chloride to a total volume of 100 ml.

HPLC analysis of methylene chloride was performed to give benzylpenicillin-ethoxycarbonyloxyethyl ester pM 96-97%.

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Exempel 8

Benzylpenicillin-ethoxycarbonylloxyethyl ester 5.02 g of potassium benzylpenicillinate (13.3 mmol) and 2.99 g of potassium bicarbonate (38.3 mmol) in 13.5 ml of dimethyl sulfoxide are added to the mixture. 3.70 g of α-bromodiethyl carbonate (18.6 mmol) are added under a solution for 30-40 minutes with an injection pump. Omrörningen fortsattes under det reactionblandningen hölls i isbadet. HPLC analysis was performed to give about 70% of benzylpenicillin-ethoxycarbonyloxyethyl ester in 5-10 minutes.

Exempel 9

Benzylpenicillin-ethoxycarbonylloxyethyl ester 47.03 g of potassium benzylpenicillinate (125 mmol), 0.94 g of sodium bicarbonate (11 mol) and 2.01 g of tetrabutylammonium bromide (6.25 mmol) in 77 ml of acetone and anhydrous solution of 40 ° C. At 26 ° C, 26.06 g of α-bromodiethyl carbonate (131 mmol) are added and the mixture is stirred at 4.5 g. 56 ml of water are added, topping with Mineral syrup to a pH of about 5. The mixture is diluted to about 3 with 4% sodium hydroxide and the pH is adjusted to 4.5 and 4.8. 100 ml of butyl acetate are added after cooling and bleaching under a separate minute. The organic mixture is dried with 80 ml of water and induced by reducing the mixture. The essential oil is dissolved in methylene chloride to a total volume of 250 ml. HPLC analysis of methylene chloride was carried out to give benzylpenicillin-ethoxycarbonyloxyethyl ester at 98-99%.

Claims (2)

25 7 9 8 3 2 1. A compound of formula 0 II Br-CH-O-C-O-C2H5 CH3 A compound of formula 0 Br-CH-O-C-O-C 2 H 3 CH 3 2. Use of alpha-bromo-diethyl carbonate in the preparation of ethoxycarbonyloxyethyl ester of penicillin G. 2. The conversion of α-bromodiethylcarbonate to the ethoxycarbonyloxyethyl ester of penicillin G.