DK160039B - THE COMPOUND ALFA-BROMIDAETHYL CARBONATE AND USE OF ALFA-BROMIDAETHYL CARBONATE IN THE PREPARATION OF THE AETOXYCARBONYLOXYAETHYL ESTATE OF PENICILLIN G - Google Patents

Description

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The present invention relates to the novel compound alpha-bromo diethyl carbonate and the use of this compound as a starting material in the preparation of the ethoxycarbonyloxyethyl ester of penicillin G.

5 The ethoxycarbonyloxyethyl ester of penicillin G is the starting material in the preparation of bacampicillin, an ampicillin ester which is extremely important from a therapeutic point of view because it is well absorbed by oral administration and provides much higher levels of ampicillin in the blood than ampicillin itself.

Alpha-bromo diethyl carbonate has the formula

Br O

I II

CH_-CH-0-C-0-C "Hc I

3 2 5 and is advantageously used as the reaction component of esterification 15 of penicillin G. Use of alpha-bromo diethyl carbonate leads to particularly high yield and high purity, also of the end products such as bacampicillin.

The compound alpha-bromo diethyl carbonate can be prepared by the following methods: 20 A. By reaction between the corresponding alpha-chloro diethyl carbonate and sodium bromide. This procedure is exemplified in the above Example 1.

B. In a multi-step process comprising the following steps: a) reacting an aldehyde of formula CH 2 CHO (n) with carbonyl bromide of formula COB ^ (III) to form an α-bromo bromoformate of formula

br

CH3-CH.O.CO.Br IV

30) reacting the α-bromo-bromoformate of formula IV with an alcohol of formula C2H5OH to produce the desired α-bromo diethyl carbonate of formula I.

Process B of the invention can thus be summarized in the reaction scheme: 2

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Br + C, H, -OH Br I 2 5 j CH3CHO + COBr2-> CH3-CH.O.CO.Br -> CH3-CH.O.CO.C2H5 + HBr 5 Alpha-bromo-bromoformate of formula IV is itself a novel connection.

The reaction between the aldehyde CH3CHO and carbonyl bromide is most conveniently carried out in the presence of a catalyst which may be, for example, a tertiary amine (such as a tertiary aliphatic amine, a tertiary mixed alkyl / aryl amine or a tertiary aromatic amine), a tertiary , a substituted urea or thiourea, a phosphoric acid amide, a tertiary oxonium or sulfonium salt or a quaternary ammonium or phosphonium salt. Preferred examples of catalysts 15 for use in process A of the invention include pyridine, dimethylformamide, tetra-n-butylurea, hexamethylphosphoric triamide and benzyltrimethylammonium bromide.

The catalyst is suitably used in an amount of from 0.05 to 0.5, preferably from 0.05 to 0.15 moles of catalyst per minute. moles of aldehyde.

The reaction between the aldehyde and the carbonyl bromide is conveniently 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 conveniently carried out at a temperature between -40 and + 120 ° C, preferably at a temperature of 0-40 ° C. The carbonyl bromide will usually be used in molar excess relative to the aldehyde, conveniently in a molar excess of from 10-100%, 3q preferably from 20-50%.

The intermediate α-bromo-bromoformate of formula IV obtained in step a) of process B need not be isolated prior to the reaction with the alcohol C 2 H 2 OH; in fact, such an insulation is generally not preferred. Thus, according to a preferred embodiment of this reaction, the reaction mixture obtained in step a) is liberated from excess carbonyl bromide, for example by heating under reduced pressure or by rinsing with nitrogen. The crude α-bromo-bromoformate-containing reaction mixture is then reacted with excess alcohol. The reaction may conveniently be carried out by heating the mixture under reflux until the evolution of hydrogen bromide ceases or by adding a tertiary base to the mixture and heating it if necessary. Any residual catalyst from step a) or complex thereof with carbonyl bromide does not appear to interfere with the subsequent reaction and in some cases appears to be favorable.

The resulting crude α-bromocarbonate may conveniently be isolated from the reaction mixture by fractional distillation under reduced pressure.

Process B is illustrated by the following Examples 2 and 3.

C. The second process for producing alpha-bromo diethyl carbonate will now be described. Method C is exemplified in the above Example 4

Process C for the preparation of alpha-bromo diethyl carbonate is a modification of the Finkelstein reaction, i.e. adding an alkyl chloride or arylalkyl chloride (or a compound containing such a group) with an alkali metal bromide or alkali metal iodide to replace the chlorine substituent with a bromine or iodine substituent, respectively; or by reaction of an alkyl bromide or arylalkyl bromide (or a compound containing such a group) with an alkali metal iodide to replace the bromine substituent with an iodine substituent.

Not all optionally substituted alkyl chlorides or arylalkyl chlorides undergo the reaction, and in particular it has proved difficult to carry out this reaction with alpha-chloro esters and alpha-chlorocarbonates, ie. compounds wherein the chlorine atom is bonded to a carbon atom which, for its part, is attached to both ends of a group of -0 (0) -0-. An example of such an alpha-chlorocarbonate is alpha-chloro diethyl carbonate, which is a known intermediate in the preparation of 35-ethoxycarbonyloxyethyl esters of 6-aminopenicillanic acid and of penicillins.

It has now been found that this problem can be overcome by proceeding according to process C. By this progress 4

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alpha-bromo diethyl carbonate is reacted by reaction of alpha-chloro diethyl carbonate with an alkali metal bromide, the reaction being carried out in a two-phase solvent system containing water and a water-immiscible organic solvent and in the presence of a phase transfer catalyst.

Suitable water-immiscible organic solvents for this purpose include halogenated hydrocarbons, e.g., halogenated paraffins such as dichloromethane, and aromatic hydrocarbons such as toluene. Suitable phase transfer catalysts 10 include quaternary ammonium salts, for example tetraalkylammonium salts such as cetyltrimethylammonium bromide and tetra-n-butylammonium hydrogen sulfate. For example, the alkali metal bromide may be sodium, potassium or lithium bromide, with lithium bromide being preferred.

Thus, in process B of the invention, α-chloro diethyl carbonate is reacted with the formula

Cl O I II

CH3-CH-O-C-O-C2H5 we a two-phase solvent system, one phase being water 20 ° 9 the other a water-immiscible organic solvent, with an alkali metal bromide of the formula R-Br (VI), wherein R is an alkali metal such as Na, K or Li to form a compound of formula 25 f 8 CH 3 -CH-O-C-O-C 2 H 5 in

As mentioned above, the preferred alkali metal is R lithium such that the preferred reagent of formula VI is LiBr.

In connection with process C, it has been found that lithium bromide can be used advantageously in a conventional Finkelstein reaction (i.e., one using a single-phase organic solvent system), for example, for the halogenation of cichlorocarbonate.

Thus, one embodiment of Method C consists of reacting alpha-chloro diethyl carbonate with lithium bromide, cf. about Example 5.

Suitable solvents for this process include low boiling aliphatic alcohols, low boiling aliphatic 5

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ketones, low boiling aliphatic ethers and lower aliphatic amides of formic acid.

As mentioned, the present invention also relates to the use of the disclosed compound alpha-bromo diethyl carbonate 5 in the preparation of the ethoxycarbonyloxyethyl ester of penicillin G. Hereby, penicillin G or a salt thereof is reacted with alpha bromo diethyl carbonate to form the ethoxycarbonyloxyethyl ester G.

A quaternary ammonium compound can be used as a catalyst in the esterification step, whereby the quaternary ammonium compound is present in an amount of 1-25%, preferably 1-10% of the equimolar amount relative to the amount of penicillin G. It is thus not necessary. to use a stoichiometric amount of the quaternary ammonium compound 15 relative to the amount of penicillin G, but less is sufficient.

Suitable metal salts of penicillin G for use in accordance with this feature of the invention (either as precursors of the quaternary ammonium salt of the carboxylic acid 20 or as such) are alkali metal salts and alkaline earth metal salts such as sodium, potassium, lithium, magnesium and calcium salts. Suitable quaternary ammonium salts of acids other than Denicillin G (for use either as precursors for the quaternary ammonium salts of penicillin G or as such) are, for example, tetraalkylammonium salts such as tetra-n-butyl ammonium bromide and cetyltrimethylammonium bromide as well as quaternary pyridinium pyridine bromide

The use of alpha-bromo diethyl carbonate in the preparation of the ethoxycarbonyloxyethyl ester of penicillin G can be done in the presence or absence of a solvent. Examples of suitable solvents are low boiling aliphatic alcohols, low boiling aliphatic ketones, low boiling aliphatic amides of formic acid and dimethyl sulfoxide. If no particular solvent is used, excess of the ester-forming halide may also be used, especially if this is liquid at the reaction temperature.

Using alpha-bromo diethyl carbonate in preparation 6

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position of the ethoxycarbonyloxyethyl ester of penicillin G, a catalyst may optionally be used. Approximately equimolar amounts of the quaternary ammonium salt of penicillin G and the ester-forming halide can be used, i.e. the bromo diethyl carbonate. Conveniently, between 5% s and 100% s excess of the ester-forming halide is used for each equivalent of the carboxylic acid salt used, and it is especially preferred to use an excess of between 20% and 60% of the ester-forming halide.

It is particularly preferred to use tetra-n-butylammonium bromide as the quaternary ammonium salt.

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

15

Trial Reports

The compound alpha-chloro diethyl carbonate, hereinafter referred to as the chlorine compound, has been used on an industrial scale of bacampicillin from the beginning of its commercial production in the first half of the 1970s up to 1982. During this period the production method and in particular the esterification of penicillin G were optimized. with the chlorine compound for optimal reaction conditions.

In 1982, the commercial production method 25 was changed by replacing said chlorine compound with alpha-bromo diethyl carbonate, hereinafter referred to as the bromine compound.

By experimentally comparable to the (A) chlorine compound used in the above-described highly optimized method and (B) the bromine compound in a similar manner, the following results were obtained:

The use of

Parameter chlorine compound bromine compound 7

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Yield 85% 98-99%

Reaction time 15 hours 4.5 hours

The color of the reaction mixtures at the end of the reaction is black light yellow

Reaction temperature 50 ° C 40 ° C

Amount of reactant (chlorine or bromine compound) relative to amount of penicillin, mmol 162/125 131/125 In the subsequent step of preparing the bacampi-cillin HCl from the 1-ethoxycarbonyloxyethyl ester of penicillin G, the following results were obtained:

Parameter Preparation of bacampicillin HCl using benzylpenicil-1-intoxycarbonoyloxyacetyl ester 20 prepared from the chlorine compound bromine compound 25 Yield 48% 77%

Color in aqueous solution (absorption at 405 nm, 5 cm, 2% solution) 0.11 0.01 30 These results are surprising. It could not be foreseen that using the bromine compound could yield the ethoxycarbonyloxyethyl ester of penicillin G in a yield of 98-99%, to be compared with a yield of 85% from the chlorine compound using an industrially optimized process. Also, the reduced reaction time could be predicted as little as the improved yield in the preparation of the final product bacampicillin-HCl and the improved purity.

8

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A similar comparative experiment with alpha iodine diethyl carbonate could not be carried out because this compound, i. is known from European Publication Nos. 54512 and 34536, is not stable and does not appear to withstand clean production and storage.

The compound of the invention and its use will be elucidated in the following by some examples.

Example 1 10 ---------- a-Bromo diethyl carbonate acetone

NaBr + Cl- <j: H-OCOOC2H5-> Br-CH-OCOOC2H5 + NaCl 15 CH3 CH3 102.9 g of sodium bromide dissolved in 600 ml of aceotne was reacted for 2-3 hours at room temperature (20-25 ° C) at 152 ° C. 6 g of a-chloro-diethyl carbonate dissolved in 100 ml of acetone. Then, the mixture was concentrated in vacuo at low temperature, at most 35 ° C, until a semi-solid mass was obtained. The reaction mixture was then partitioned between H 2 O and ethyl ether. The aqueous phase was separated and then extracted with 2 x 400 ml ethyl ether.

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

The organic phase was dried over magnesium sulfate and then concentrated in vacuo at low temperature, not more than 30 ° C, to give the title product (60%) in the form of a liquid that was initially colorless or slightly yellowish brown.

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Example 2

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

The temperature of the mixture was allowed to rise to ambient and then heated to 50 ° C, at which temperature the mixture was kept for 3 hours; during this period a precipitate formed.

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

Separation of the organic layer and fractional distillation gave 130 g (66% yield) of pure ethyl α-bromoethyl carbonate at a boiling point of 90-92 ° C / 45mm Hg, and the compound was identical in all respects to an authentic sample.

Example 3

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

Then the mixture was heated under gentle reflux (about 40 ° C) for 4 hours. While the mixture was still under reflux, 69 g (1.5 moles) of ethanol was gently added over 1 hour and the refluxing was continued for an additional 1 hour.

Fractional distillation of the resulting mixture gave directly 114 g (58%) of pure ethyl α-bromomethyl carbonate.

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

10

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118 g (1.0 mole) of diethyl carbonate was stirred and heated to between 110 and 120 ° C and illuminated with a 150 watt tungsten filament lamp. 96 g (0.6 mole) of bromine was added dropwise over a period of 3-4 hours and at such a rate that the mixture did not darken beyond a light orange color. After the bromine addition was complete, the mixture was cooled to ambient temperature and 20 g of sodium bicarbonate was added.

Distillation and fractionation of the resulting mixture yielded 84.2 g (70%) of authentic ethyl α-bromoethyl carbonate with TO boiling point 87-88 ° C / 40 mm Hg.

Example 4

A mixture of 43 g (0.5 mole) of lithium bromide, 15.3 g of 15 (0.1 mole) of ethyl α-chloroethyl carbonate, 100 ml of water, 100 ml of dichloromethane and 1.5 g of cetyltrimethylammonium bromide was stirred at ambient temperature. 24 hours. The aqueous layer was removed and replaced with a fresh solution of 26 g (0.3 mole) of lithium bromide in 40 ml of water containing 1 g of cetyltrimethylammonium bromide. After stirring for a further 24 hours, during which time the temperature was raised to 35 ° C, the organic layer was separated, dried and vacuum distilled and, after repeated fractionation, gave the novel compound ethyl-α-bromo-ethyl carbonate in an amount of 15.0 g (76%) with boiling point 90-92 ° C / 25 mm Hg.

Calculated: C 30.5 H 4.6 Br 40.6

Found: C 30.7 H 4.8 Br 40.1%.

The NMR spectrum showed peaks as follows: 1.2-1.6 (3H, triplet? -CH2CH3), 2.0-2.2 (3H, doubled; -CHCH3), 4.1-4.5 (2H, 30 quartet; -CH2CH3) and 6.5-6.8 (1H, quartet; -CH.CH3).

Example 5 17.4 g (0.2 mole) of lithium bromide was dissolved in 150 ml of dimethylformamide and the mixture was cooled to ambient temperature.

35.5 g (0.2 mole) of ethyl α-chloroethyl carbonate were added and the mixture was stirred at ambient temperature for 24 hours. The precipitated lithium chloride was filtered off and the filtrate vacuum evaporated

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Then, after careful re-fractionation, ethyl α-bromoethyl carbonate was recovered in 76% yield, calculated from recovered ethyl α-chloroethyl carbonate.

Example 6

The authenticity of the previous novel compound ethyl a-bromoethyl carbonate was confirmed by independent synthesis as follows: A mixture of 35 g (0.3 mole) of diethyl carbonate in 50 ml of carbon tetrachloride and 0.1 g of α-azoisobutyronitrile (AIBN) was heated. under gentle reflux and 28.6 g (0.1 mole) of dibromo dimethylhydantoin were added in small portions over a period of 8 hours together with further additions of 15 AIBN (8 x 0.05 g), taking care to ensure that no free bromine accumulated in the reaction mixture.

At the end of the reaction, the mixture was subjected to fractional vacuum distillation to give 32.3 g (82%) of pure ethyl α-bromoethyl carbonate, in all respects identical to the product of Examples 4 and 5.

Example 7

Benzylpenicillin-ethoxycarbonyloxyethyl ester 25.08 g (66.7 mmol) of potassium benzylpenicillinate, 0.50 g (6.0 mmol) of sodium bicarbonate and 2.15 g (6.67 mmol) of tetrabutyl-ammonium bromide was stirred gently in 41 ml of methylene chloride. 40 ° C. When this temperature was reached, 17.16 g (86.7 mmol) of α-bromo diethyl carbonate was added and the slurry 3q was stirred for 4.0 hours. 30 ml of water was added followed by a mineral acid to pH ca. 5. The mixture was stirred for approx. 4 hours during which period 4% of sodium hydroxide was added to maintain the pH between 2.5 and 3.0. Then 50 ml of methylene chloride was added and the mixture was allowed to settle for a few minutes. The organic phase was washed with 65 ml of water and then evaporated under reduced pressure. The oily product thus obtained was dissolved in 100 ml of methylene chloride and evaporated again. The remaining oil was dissolved in methylene chloride to a total volume of 100 ml.

HPLC analysis of the methylene chloride solution showed a yield of 96-97% benzylpenicillin-ethoxycarbonyloxyethyl ester.

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Example 8 Benzylpenicillin-ethoxycarbonyloxyethyl ester 5.02 g (13.3 nurtole) of potassium benzylpenicillinate and 2.99 g (38.3 mmol) of potassium bicarbonate in 13.5 ml of dimethyl sulfoxide were stirred carefully in an ice bath. Over a period of 30-40 minutes, 3.70 g (18.6 mmol) of α-bromo diethyl carbonate was added using a syringe pump. Stirring was continued while the reaction mixture was kept in the ice bath. HPLC analysis showed that in 5-10 minutes a yield of approx. 70% benzylpenicillin ethoxycarbonyloxyethyl ester.

Example 9

Benzylpenicillin-ethoxycarbonyloxyethyl ester 47.03 g (125 mmol) of potassium benzylpenicillinate, 0.94 g (11 mmol) of sodium bicarbonate and 2.01 g (6.25 mmol) of tetrabutyl-ammonium bromide was stirred carefully in 77 ml of acetone and heated to 40 ° C. When this temperature was reached, 26.06 g (131 mmol) of α-bromo diethyl carbonate was added and the slurry was stirred for 4.5 hours. 56 ml of water was added followed by a mineral acid to pH ca. 5. The mixture was stirred for approx. 3 hours during which period 4% sodium hydroxide was added to maintain the pH between 4.5 and 4.8. Then 100 ml of butyl acetate was added and the mixture was allowed to separate over a few minutes. The organic phase was washed with 80 ml of water 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 a yield of benzylpenicillin-ethoxycarbonyl-oxyethyl ester of 98-99%.

Claims (2)

Chemical compound, characterized in that it is alpha-bromo diethyl carbonate of the formula 5 O Br-CH-O-C-O-C 'Hc I 2. Use of alpha-bromo diethyl carbonate as starting material in the preparation of the ethoxycarbonyloxyethyl ester of penicillin G.