NZ216265A - Alpha-bromodiethylcarbonate and its manufacture - Google Patents
Alpha-bromodiethylcarbonate and its manufactureInfo
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- NZ216265A NZ216265A NZ21626583A NZ21626583A NZ216265A NZ 216265 A NZ216265 A NZ 216265A NZ 21626583 A NZ21626583 A NZ 21626583A NZ 21626583 A NZ21626583 A NZ 21626583A NZ 216265 A NZ216265 A NZ 216265A
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Description
New Zealand Paient Spedficaiion for Paient Number £16265
2 16265
Priority Date(s):
$>(?. ?P... /A//: ?- 6, * £
Complete Spa^fication Filed: Class: £.<?./?.£.
Publication Date: M.?.NPV ????
|__P-0- Journal, No:
Under the provisions of Regt^
lation 23 (I) the
Specification has been ante-dated' to
NEW ZEALAND THE PATENTS ACT 1953 COMPLETE SPECIFICATION
"alpha-bromodiethyl carbonate and its preparation and use in the synthesis of antibiotics" ~
■* -*3
We, ASTRA LAKEMEDEL AKTIEBOLAG, a Swedish Company, of S-151 85 Sodertalje, Sweden, hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it" is to be performed, to be particularly described in and by the following statement:
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Field of the Invention
This invention provides the novel compound a-bromodiethyl-carbonate of the formula III:
Br ch3-ch.o.co.o.c2h5 (iii),
which compound III can be used in the manufacture of the
1-ethoxycarbonyloxyethyl ester of penicillin G, as well as , being used with great advantage in a novel method of manufacturing the 1-ethoxycarbonyloxyethyl ester of the 6-(D-(-)-a-amino-a-phenylacetamido) penicillanic acid of the 10 formula I:
/-S CH3
O-ch-c0-nh-ch-ch (i)
i i i i 3
nh0 co-n ch-c00-ch-0-c00cohc
2 ,25
ch3
as hereinafter described, said ester compound I being known as bacampicillin and is usually isolated in the form of the hydrochloride, which is known as bacampicillin hydrochloride.
Background of the Invention
On the basis of previous known processes (cf. British Patent Specification 1363506), bacampicillin hydrochloride can be synthesized by the two following methods:
A) Reaction of potassium benzylpenicillin with a-chlorodiethyl-20 carbonate in organic solvents or in an aqueous solution of 70% - ^dioxane in the presence of sodium bicarbonate. The 1-ethoxycarbonyloxyethyl ester of benzylpenicillin which is obtained ; is subjected to the reaction of removing the phenylacetic chain, via the iminochloride-iminoether, in order to obtain the 1-25 ~ ethoxycarbonyloxyethyl ester of the 6-aminopenicillanic acid,
which is isolated as the hydrochloride. - =
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By subsequent condensation of the latter intermediate with D- (-)-a-phenylglycine, the compound according to formula I is obtained.
B) Esterification reaction of the 6-(D-(-)-a-azido-a-phenyl-acetamido)-penicillanic acid with a-chlorodiethylcarbonate in a polar solvent.
Subsequently, by catalytic hydrogenation of the 1-ethoxycarbonyloxyethyl ester of the 6-(D(-)-a-azido-a-phenylacetamido)-penicillanic acid the compound according to formula I is obtained.
As can be seen, these methods are rather complex since they involve- the use of—numerous raw materials-and-lengthy processing times.
The Invention
A prime object of this invention, in providing the novel compound of formula III, is to provide a reactant for use in a method of preparing the 1-ethoxycarbonyloxyethyl ester of penicillin G in high yield and purity on a commercial scale, as well as to provide a reactant which can be used in preparing the active compound of formula I, which is easier to carry out and industrially more advantageous. A more specific object of this invention is to provide such a reactant which can be used in a method of preparing bacampicillin using ampicillin as starting material, with considerable simplification of the said method and obtaining a high degree of purity of the desired active product.
According to the invention, two novel and inventive processes, herebelow denoted process A and process B, are provided for the preparation of alpha-bromodiethylcarbonate of the formula III.
A: The first of these processes, process A, comprises the steps of:
(a) reacting an aldehyde of the formula
CH3CHO (VI)
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with carbonyl bromide
COBr2 (VII)
to give an alpha-bromo-bromoformate of the formula:
Br
CH 3-CH. 0. CO. Br (VIII)
and;
(b) reacting the alpha-bromo-bromoformate of formula VIII with an alcohol of the formula C2H^-0H to yield the desired alpha-bromo-diethyl-carbonate of the formula III.
Thus, the process A in accordance with the invention may be summarised by the reaction scheme:
Br +C„Hc0H Br i Z O |
CH.CHO + C0Br_ CH -CH.O.CO.Br -»■ CH -CH.0. CO. C„H.- + HBr ■S Z 3 J Z D
the alpha-bromo-bromoformate of the formula VIII being, in itself, a new compound.
The reaction between the aldehyde, CH^CHO, and carbonyl bromide is most suitably carried out in the presence of a catalyst which may be, for example, a tertiary amine (for example a tertiary aliphatic amine, a tertiary mixed alkyl/aryl amine or a tertiary aromatic amine), tertiary phosphine, amide, substituted urea or thiourea, phosphoric acid amide, tertiary oxonium or sulphonium salt, or a quaternary ammonium or phosphonium salt. Preferred examples of catalysts for use in the process A according to the invention include pyridine, dimethylformamide, tetra-n-butyl urea, hexamethyl-phosphoric-tri-amide and benzyltrimethyl ammonium 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 mole of aldehyde.
The reaction between the aldehyde and the carbonyl bromide is suitably carried out in the presence of a solvent which may be,
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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 at;a temperature of from -40 to 120°C, preferably 0-40°C. The carbonyl bromide will usually be used in molar excess with respect to the aldehyde, suitably in a molar excess of from 10 to 100%, preferably from 20 to 50%.
The intermediate alpha-bromo-bromoformate of formula VIII produced in step (a) of the process A of the invention need not be isolated prior to reaction with the alcohol C2H^OH and, indeed, it is generally preferred not to do so. Thus, in accordance with a preferred embodiment of the invention, the reaction mixture obtained from step (a) is freed of excess carbonyl bromide^- for-example, by warming under reduced pressure or by purging with nitrogen. The crude alpha-bromo-bromoformate-containing reaction mixture is then reacted with an excess of the alcohol. The reaction may conveniently be effected by heating the mixture under reflux until the evolution of 1 hydrogen bromide ceases or by adding a tertiary base to the mixture and, if necessary, warming it. Any residual catalyst from step (a) or its complex with carbonyl bromide does not appear to interfere with the subsequent reaction and, in some cases, appears beneficial.
The resultant crude alpha-bromocarbonate may conveniently be isolated from the reaction mixture by fractional distillation under reduced pressure.
Process A is.illustrated in Examples 7 and 8, which are given by way of illustration only.
B: The second process, process B, of the invention for the preparation of a-bromodiethylcarbonate will now be described. Method B is exemplified in Example 9, which is given by way of illustration only.
Process B of the invention is concerned with improvements in and relating to the preparation of a-bromodiethylcarbonate by a
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modification of the Finkelstein reaction, that is, by reaction of 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 by a bromine or iodine substituent respectively; or by the 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 by an iodine substituent.
The Finkelstein reaction is useful since the resulting iodides are generally more reactive than the bromides which in turn are more reactive than the chlorides. In some cases only catalytic amounts of the alkali metal bromide or iodide are necessary and the resulting more reactive species is allowed to react with the desired substrate regenerating the alkali metal bromide or iodide, thus continuing the reaction.
Not all optionally substituted alkyl chlorides or arylalkyl chlorides undergo the reaction and, in particular, it has been found difficult to carry out the reaction with alpha-chloro esters and alpha-chloro-carbonates, that is, compounds in which the chlorine atom is attached to a carbon atom which is, in turn, attached to either end of a group -C(0)-0-. An example of such an alpha-chlorocarbonate is a-chlorodiethylcarbonate, which is a known intermediate in the preparation of ethoxycarbonyloxyethyl esters of 6-aminopenicillanic acid and of penicillins as described above.
It has now been found, in accordance with the present invention, that this problem may be overcome by carrying out the reaction using a two-phase solvent system, one phase of which is water and the other is a water-immiscible organic solvent, in the presence of a phase-transfer catalyst.
According to process B of the invention, therefore, there is provided a process for the preparation "of a-bromodiethylcarbonate by reaction of -a-ehlorodiethylcarbonate with an alkali metal bromide, which process is characterized in that the reaction is carried out in a two-phase solvent system comprising water and a
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water-immiscible organic solvent in the presence of a phase transfer catalyst.
Suitable water-immiscible organic solvents for use in accordance with the invention include 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,-tetraalkyl ammonium salts such as cetyltrimethyl ammonium bromide and tetra-n-butyl ammonium hydrogen sulphate. The alkali metal bromide may, for example, be sodium, potassium, or lithium bromide, lithium bromide being preferred.
Thus, in process B of the invention, a-chlorodiethylcarbonate of the formula:
CI 0
ch3-ch-0-c-0-c2h5 (ix)
is reacted in a two-phase solvent system, one phase of which is water and the other is a water-immiscible organic solvent, with an alkali metal bromide of the formula
R-Br (X)
in which formula R is an alkali metal such as Na, K and Li, for the formation of the compound of the formula:
Br 0
ch3-ch-o-c-o-c2h5 (iii)
As noted above, the preferred alkali metal R is Li so that LiBr is a preferred reagent of the formula X.
In connection with process B it has been found that lithium bromide may be used with advantage in a conventional Finkelstein reaction (i.e. one employing a single phase organic solvent system), for example to halogenate an alpha-chloro-carbonate.
This method is exemplified in Example 10.
Accordingly, the present invention also provides, in accordance with a further embodiment thereof, a process for the preparation
2162 6 5
of a-bromodiethylcarbonate which comprises reacting a-chloro-diethylcarbonate with lithium bromide.
Suitable solvents for such a process include lower aliphatic alcohols, lower aliphatic ketones, lower aliphatic ethers and 5 lower aliphatic amides of formic acid.
Use of the novel compound a-bromodiethylcarbonate in the preparation of the ethoxycarbonyloxyethyl ester of 6-amino-penicillanic acid will now be described.
Thus, the novel compound of formula III can be used in a method 10 of manufacturing the 1-rethoxycarbonyloxyethyl ester of the 6- (D- (-)-a-amino-a-phenylacetamido)penicillanic acid having the following formula:
/ \/
-CH-CO-NH-CH-CH C
\
CH.
x
NH.
CO-N
CH.
CH-COO-CH-0-C00C0H c CH_
(I)
which method is characterized by the steps:
a) reaction of ampicillin, preferably in the form of an alkaline salt, with a reactive derivative of acetoacetic acid to form the corresponding enamine having the following formula:
CH.
-CH-CO-NH-CH-CH
1 JK
R -C H
2 " * R -C -
N:
>
\
(ii)
CH.
CO-N-
CH-COOX
R3
wherein:
R^" represents an alkyl group containing 1 to 4 carbon atoms, a substituted or unsubstituted aryl group or an aralkyl group;
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2
R represents hydrogen, an alkyl group containing 1 to 4 carbon atoms, a substituted or unsubstituted aryl group or an arylalkyl
3
group; R represents an alkyl group containing 1 to 4 carbon atoms, a substituted or unsubstituted aryl group, an aralkyl 5 group, an alkoxy group containing 1 to 4 carbon atoms, an aryloxy group, or an amino group, and
X represents an alkali metal, an alkaline-earth metal, or an organic base;
b) reaction of the resulting intermediate with a-bromo-diethyl-10 carbonate having the following formula:
Br-CH-0-C00C2H5 (III)
ch3
to form the corresponding ester having the following formula:
S CH.
/=\ / \
K h -CH-CO-NH-CH-CH C
R -C NH C
•CH3 (IV)
R2-C ,0 CO-N CH-COO-CH-O-COOC-H^
\CS . 2 5
•3 CH1
R 4
12 3
where R , R and R have the same significance as above,
and c) hydrolysis in an acid medium, obtaining the compound according to formula (I).
'The esterification reaction between the compounds II and III can be carried out with or without an esterification catalyst present.
The addition of a catalyst at this stage considerably shortens the reaction times and provides higher yields of the product with a greater degree of purity.
For this purpose the following substances can be used as catalysts: quaternary ammonium salts, for example,tetrabutylammonium bromide, 25 the bromides or iodides or alkali metals and cyclic ethers.
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The catalyst may be used in an amount which varies from 0.005 to 0.10 moles per mole of compound III to amounts which are equimolar with the compound III. In a preferred embodiment^ tetrabutylammonium bromide is used in an amount of from 0.01 to 0.10 mole- per mole of compound III.
12 3
Illustrative examples of the radicals R , R and R are:
alkyl: CH3, C^, n-C^, i-C3H?, n-C^
alkoxy (R3 only): OCH3/ OC^, OCH2CH2CH3, OCH(CH3)2, 0(CH2)3CH3
substituted aryl: phenyl substituted with halogen such as CI and Br
The radical X is selected among groups which are well known in the art, for example alkali metal: Na, K
alkaline earth metals: Ca, Mg of penicillins, e.g. tertiary ammonium.groups, triethylamine, ethylpiperidine and methylmorpholine.
of the ampicillin is a l-methoxy-carbonyl-propen-2-yl group or a l-ethoxy-carbonyl-propen-2-yl group for which the preferred intermediate is the sodium or potassium salt of the N-(-1— methoxy-carbonyl-propen-2-yl)penicillanic acid respectively
N- (l-ethoxy-carbonylpropen-2-yl)penicillanic acid according to
1 2 3
formula II (R = methyl; R = methyl; R = methoxy or ethoxy and
X = Na or K) .
organic base: organic bases which are known in the synthesis
In the preferred embodiment, the group protecting the amino group
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The intermediate IV is stable in a neutral or alkaline medium, whereas in an acid medium it is possible to remove the group protecting the amino group simply, quickly and selectively.
The group protecting the amino group of the ampicillin can be 5 selected e.g. from the groups mentioned in the British Patent
Specification 991586, and from other groups which are known in the art.
The a-bromodiethylcarbonate, compound III, may be prepared by reacting the corresponding a-chlorodiethylcarbonate with sodium 10 bromide as described above and as exemplified in Example 1 below.
More specifically, the method of manufacturing the active compound of formula I, comprises the following stages:
^transformation of ampicillin trihydrate in a polar solvent, for example N,N^dimethylformamide, into a salt thereof, for 15 example potassium, and subsequent formation of the corresponding enamine (II) by reaction with a derivative of acetoacetic acid, for example, methyl acetoacetate;
- addition of an esterification catalyst, preferably tetrabutylammonium bromide;
- addition of a-bromodiethylcarbonate to the reaction mixture to form the 1-ethoxycarbonyloxyethyl ester of the ampicillin in the form of the enamine (IV);
- hydrolysis of the protective group with HC1 diluted in an organic solvent, for example, n-butyl acetate/water;
- recovery of the bacampicillin hydrochloride by saturation in the aqueous phase , for example, with sodium chloride and extraction with a suitable solvent, for example, n-butyl acetate; t and
- concentration of the solution at low pressure in n-butyl acetate 30 in order to crystallize the product to a high level of purity,
the product then being isolated by filtration.
I
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Among the main advantages of said method of manufacturing the active compound of formula I, the principal one is that, by this method, it is possible to obtain bacampicillin hydrochloride practically in one operation and with a high degree of purity.
In fact the impurities which are present in the product obtained by the said method are negligible as compared with the known processes of the previous state of the art.
Another equally important advantage is that ampicillin trihydrate is used as the starting material, this being a known antibiotic which is easily obtainable in pure form and at low cost.
The intermediate (II) can be easily prepared as described for example in British Patent Specification JJ91586 with a yield of over 95% by reaction of ampicillin trihydrate with methyl or ethyl acetoacetate, 10 to 50% more than the stoichiometric ratio, in the presence of an organic base or an alkali metal carbonate, for example, potassium carbonate.
The intermediate (II) can be isolated and added to the esterification reaction in solid form. Or, without isolation of the intermediate (II), the esterification reaction can be effected in the same solvent in which the reaction for the formation of enamine (II) took place.
The reaction for the formation of ampicillin enamine (II) is conducted in an aprotic polar solvent, such as N,N-dimethy1-acetamide, N,N-dimethylformamide, dimethoxyethane, dimethyl-sulphoxide, tetrahydrofuran or dioxane.
To complete the reaction, it is sufficient to leave the components
* o o of the mixture m contact at a temperature between 0 C and 60 C,
preferably between 20°C and 30°C, for 2 to 8 hours, preferably
3 hours.
The compomd II can be prepared via acylation of 6-aminopenicillanic acid with a corresponding enamine derivative of phenylglycine for the formation of the compound II which thereafter can be esterified directly and converted to bacampicillin with isolation of the compound II.
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The esterification reaction after the addition of the a-bromo-diethylcarbonate to the said mixture, takes place at a temperature between 15°C and 80°C, preferably between 45°C and 55°C, for a period of time from 1 hour to 24 hours, preferably from 5 to 10 hours.
The esterification reaction is suitably carried out in an organic solvent such as methylene chloride or acetone, dimethylacetamide, dimethylformamide and dimethylsulfoxide, or in a mixture of organic solvents. It is possible to use also organic solvent containing water. The use of esterification catalyst is desirable when acetone is used as solvent for the esterification reaction.
In the easiest and most suitable conditions for industrial purposes, the esterified enamine (IV) is isolated by dilution of the reaction mixture with water and subsequent extraction with a suitable solvent which is immiscible with water, for example, n-butyl acetate.
The acetate phase is agitated with a dilute solution (0.2 - 0.3N) of HC1 until the protective group is completely hydrolysed, which requires a contact time of 2 to 8 hours, preferably 4-5 hours, at ordinary temperatures.
By addition of sodium chloride, compound (I) separates out from the aqueous phase in the form of the hydrochloride, which is extracted with a suitable solvent, for example, n-butyl acetate.
By concentrating the organic phase at low pressure at a temperature of 40°C until a small volume remains, crystallization of the product according to formula (I) takes place.
The crystalline product is isolated by filtration, washing and vacuum drying.
The following examples illustrate the present aspects of the invention without limiting it in any way.
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Example 1: Preparation of a-bromodiethylcarbonate acetone
NaBr + C1-CH-0C00C H > Br-CH-OCOOC0H +NaCl i b J i ^ D
ch3 ch3
Sodium bromide (102.9 g) dissolved in acetone (600 ml) was reacted for 2-3 hours at ambient temperature (20-25°C) with 5 a-chlorodiethylcarbonate (152.6 g) dissolved in 100 ml of acetone. The mixture was then concentrated under vacuum at low temperature, max. 35°C, until a semi-solid mass was obtained. The reaction mixture was then partitioned with I^O/ethyl ether. The aqueous phase was separated and was then extracted twice with 4 00 ml of 10 ethyl ether.
The combined organic phases containing the a-bromodiethylcarbonate were washed with:
800 ml of H20,
1000 ml of 1% sodium metabisulphate aqueous solution, and 15 1000 ml of NaCl saturated solution.
The organic phase was dried over Mg sulphate, and then concentrated under vacuum at low temperature, max. 35°C to give the title product (60%) in the form of a liquid which initially was colourless or slightly yellow-brown.
It was used directly in the esterification step according to • Example 2 below.
i
Example 2:
.08 g (0.181 m) of finely ground anhydrous potassium carbonate are suspended in 200 ml of N,N-dimethylacetamide and 32.4 ml 25 (0.3 m) of methyl acetoacetate and 60.4 g (0.15 m) of ampicillin ^ trihydrate are added.
The mixture is maintained under fast agitation for 5 hours at 20°C -25°C; after this time, 46.1 g (0.234 m) of bromodiethylcarbonate,
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6 g (0.02 m) of tetrabutyl ammonium bromide and 100 ml of N,N-^ dimethylacetamide are added.
It is heated under agitation for 10 hours at 40°C - 42°C; the reaction mass is poured into a mixture consisting of 1200 ml of water and 400 ml of n-butyl acetate.
The aqueous phase is collected and extracted with another 100 ml of n-butyl acetate.
The reunited organic phases are washed twice with 100 ml of water each time.. 150 ml N HC1 and 370 ml of water are added to the organic phase which is subjected to agitation; it is left under agitation at 22°C - 23°C for 4 hours.
The aqueous phase is collected and the organic phase is extracted with 100 ml of water.
The reunited aqueous phases are brought to pH 4 with a 10% aqueous solution of Na2CC>2» then bleaching carbon is added to them and they are filtered.
300 ml of n-butyl acetate and 80 g of sodium chloride are added to the aqueous filtrate.
The organic phase is separated and the aqueous phase is extracted with 200 ml of n-butyl acetate.
The reunited phase in n-butyl acetate are concentrated at low pressure at 40°C to a volume of approximately 300 ml. The product is left to crystallize for 15 hours at +5°C.
It is filtered, washed with n-butyl acetate (100 ml) and ethyl acetate (100 ml). It is vacuum dried at 40°C for 24 hours.
Yield: 54.2 g^(72%) of the 1-ethoxycarbonyloxyethyl ester of the 6-(D(-)-a-amino-a-phenylacetamido) penicillanic acid with m.p. 160-2°C. (d) and characteristics conforming to the authentic hydrochloride sample.
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Example 3:
36.4 g (0.075 m) of potassium N-(l-methoxycarbonyl-propen-2-yl)-6-(D(-)-a-amino-a-phenylacetamidp) penicillate are added to a solution of 17.8 g (0.116 m) of a-chlorodiethylcarbonate and 3 g (0.01 m) of 5 tetrabutylammonium bromide in 150 ml of N,N-dimethylformamide.
Under agitation the temperature is raised to 45°C and maintained at 45°C - 50°C for 5 hours.
When heating is completed, the reaction mixture is poured into a mixture comprising 300 ml of ,a 14% aqueous sodium chloride solution 10 and 600 ml of n-butyl acetate. The mixture is agitated for 10
minutes, then the organic phase is separated and the aqueous phase is extracted with 100 ml of n-butyl acetate. The reunited organic phases, after two washings with 75 ml of 14% sodium chloride aqueous solution, are concentrated at low pressure until an oil is 15 obtained.
The oil is mixed with 200 ml of tetrahydrofuran and 100 ml of water; the solution obtained (pH 4.8) is brought under agitation to pH 1.5 by adding, in all, 12 ml of 6N HC1 in 1 hour.
After leaving the solution to stand for another hour at ordinary 20 temperature, the tetrahydrofuran is removed at low pressure at
40°C, 150 ml of n-butyl acetate are added to the remaining aqueous phase (150 ml) and then 15 g of sodium chloride are added.
The organic phase is separated and the aqueous phase is extracted with 100 ml of n-butyl acetate.
The reunited organic phases are concentrated under vacuum at 40°C to a volume of 120 ml.
The product is left to crystallize for 15 hours at 5°C.
It is then filtered, washed with n-butyl acetate (50 ml) and ethyl acetate (50 ml).
It is vacuum dried at 40°C.
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The following is obtained: 25.2 g (66.9%) of the 1-ethoxycarbonyloxyethyl ester of the 6-(D-(-)-a-amino-a-phenylacetamido) penicillanic acid hydrochloride with m.p. 160-2°C.
Analytical determinations:
Titre: 97.82%
Rotatory power: +166.3° (c=l, EtOH95°)
pH: 4.05 (2% aqueous solution)
Moisture content: 0.82%
Residual solvents: ethyl acetate 0.45; n-butyl acetate 0.98%
IR and NMR spectra are standard Residual-^ampicillin: 0*06%
Example 4:
16.2 ml (0.15 m) of methyl acetoacetate and 30.2 g (0.075 m) of ampicillin trihydrate are added to a suspension of 12.54 g (0.0907 m) of finely pulverized anhydrous potassium carbonate in 100 ml of N,N-dimethylformamide.
It is maintained with agitation at 22°C-23°C for 3 hours and after this time, considerable fluidization of the mass can be observed.
17.8 g (0.117 m) of a-chloro-diethylcarbonate, 3 g (0.01 m) of tetrabutylammoniumbromide and 50 ml of N,N-dimethylformamide are now added in that order.
The mixture is heated under agitation for 5 hours at 4 5°C - 50°C, then left to stand at +5°C for 15 hours.
The reaction mass is poured into a mixture consisting of 60 0 ml of water and 200 ml of n-butyl acetate, and it is agitated until a complete solution is obtained, the aqueous phase is collected and extracted with another 50 ml of n-butyl acetate.
The reunited organic phases are washed twice with 50 ml of water each time. 75 ml of N HC1 and 185 ml of water are added to the organic phase subjected to agitation; it is left under agitation at 22°C - 23°C for 4 hours.
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The aqueous phase is collected and the organic phase is extracted with 50 ml of water. The reunited aqueous phases are brought to pH4 with a 10% aqueous solution of Na2CC>3,
then bleaching carbon is added to them and they are filtered.
150 ml of n-butyl acetate and 40 g sodium chloride are added to the aqueous filtrate.
The organic phase is separated and the aqueous phase is extracted with 100 ml of n-butyl acetate.
The reunited phases in butyl acetate are concentrated at low 10 pressure at 40°C to a volume of approximately 150 ml.
The product is left to crystallize for 15 hours at +5°C.
It is filtered, washed with n-butyl acetate (50 ml) and ethyl acetate (50 ml).
It is dried under a vacuum of 10 mm Hg in the presence of 15 moisture at 25°C for 24 hours.
Yield: 20.8 g (55%) of the 1-ethoxycarbonyloxyethyl ester of the 6-(D-(-)-a-amino-a-phenylacetamido) penicillanic acid hydrochloride with m.p. 159-161°C and characteristics conforming to an authentic sample.
When tested for esterification of amphicillin dane salt with ethyl acetoacetate, the results were:
■Obtained: 16.1 grams of white crystalline product
M.P.: 144-148°C (Tottoli apparatus)
IR/TLC: Conform
K.F.: 0.35%
pH: 3.55 (2% water solution)
Assay to: 95.2%
Total residual solvents: 3.5%
Example 4A:
Example 4 was repeated except that the addition of a-chloro-diethylcarbonate was carried out in two phases. In the first
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phase, 9 gms was added immediately, and in the second phase another 9 gm was added after 2 hours, whereupon the mixture was heated for 3 hours at 45°C.
When tested for esterification of ampicillin dane salt with ethyl acetoacetate, the results were:
Obtained: 13.7 grams of crystalline beige product
M.P.: 143-146°C (Tottali apparatus)
IR/TLC: Conform
K.F.: 0.2%
pH: 3.43 (2% water solution)
Assay to: 94.8%
Residual solvents: 2.6%
Example 5:
A mixture of 160 ml acetone, 22.6 g (0.0 75 mol) of the potassium 15 salt of D(-)-N-methoxycarbonylpropen-2-yl-aminophenylacetic acid, 6.9 ml (0.088 mol) ethyl chloroformate and 3 drops of N-methyl-morpholine, is stirred for 15 minutes at a temperature of -20 to -30°C. To this reaction mixture a solution of 16.2 g 6-amino-penicillanic acid, dissolved in 35 ml water through the gentle 20 addition of 7.6 g (0.075 mol) triethylamine with agitation, is added in one portion, after which the mixture is diluted with 90 ml acetone and chilled to -20°C.
After stirring for 45 minutes, without any additional cooling, 23.4 g (0.117 mol) of a-bromodiethylcarbonate, 3 g (0.01 mol) or 25 tetrabutylammonium bromide and 250 ml of N,N-dimethylformamide ^ are added in that order. The mixture is stirred for 18 hours at 25°C. After that time the'-reaction mass is poured into a mixture consisting of 600 ml of water and 200 ml of n-butyl acetate and it is agitated until a complete solution is obtained. The aqueous 30 phase is collected and extracted with another 50 ml of n-butyl ^ acetate.
The reunited organic phases are washed twice with 50 ml of water each time. 185 ml of water is added to the organic phase and 1 N
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HCl is added dropwise with agitation to a pH of 1.9. The mixture is left under agitation at 22-23°C for 4 hours.
The aqueous phase is collected and the organic phase is extracted with 50 ml of water. The reunited aqueous phases are brought to 5 pH 4 with a 10% aqueous solution of Na2CC>3, active carbon is added to them and they are filtered. 150 ml of n-butyl acetate and 40 g of sodium chloride are added to the aqueous filtrate.
The organic phase is separated and the aqueous phase is extracted with 100 ml of n-butyl acetate. The reunited phases in butyl 10 acetate are concentrated at low pressure at 40°C to a volume of approximately- 150 ml-. --The product is left to crystallize for 15 hours at +5°C.
It is filtered, washed with n-butyl acetate (25 ml) and ethyl acetate (25 ml). It is dried under a vacuum of 10 mm Hg at 25°C 15 for 24 hours.
Yield: 1.17 g of the 1-ethoxycarbonyloxyethyl ester of 6—(D(—)— a-amino-a-phenylacetamido)penicillanic acid hydrochloride with m.p. 159-161°C and characteristics (NMR, TLC) conforming to an authentic sample.
Example 5a:
The procedure of example 5 was repeated with the difference that the 6-aminopenicillanic acid was dissolved in 20 ml water instead of in 35.
Yield: 1.05 g of the ethoxycarbonyloxyethyl ester of 6-(D(-)-25 a-amino-a-phenylacetamido)penicillanic acid hydrochloride as a white crystalline powder witIT "m.p. 148-151°C, with decomposition, and characteristics (TLC, IR) conforming to an authentic sample.
Example 6:
6.25 g (0.045 m) of finely ground anhydrous potassium carbonate 30 are suspended in 50 ml of dimethyl sulphoxide and 8.1 ml (0.075 m) of methyl acetoacetate and 15.1 g (0.0375 m) of ampicillin trihydrate are added.
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The mixture is maintained under fast agitation for 5 hours at 20°C - 25°C; after this time 11.5 g (0.059 m) of bromodiethyl-carbonate and 25 ml of dimethyl sulphoxide are added.
It is heated under agitation for 17 hours at 35-37°C; the reaction mass is poured into a mixture consisting of 300 ml of water and 100 ml of n-butyl acetate.
The aqueous phase is collected and extracted with another 100 ml of n-butyl acetate.
The reunited organic phases are washed twice with 25 ml of water each time.
92.5 ml of water and NHC1 (7.0 ml) to a pH of 1.9 are added to the organic phase which is subjected to agitation; it is left under agitation at 22°C - 23°C for 2.5 hours.
The aqueous phase is collected and the organic phase is extracted with 25 ml of water.
The reunited aqueous phases are brought to pH 4 with 10% aqueous solution of Na2C03r then active carbon is added to them and they are filtered.
75 ml of n-butyl acetate and 37 g of sodium chloride are added to the aqueous filtrate.
The organic phase is separated and the aqueous phase is extracted with 50 ml of n-butyl acetate.
The reunited phases in n-butyl acetate are concentrated at low pressure at 40°C to a volume of approximately 75.ml. The product
* o is left to crystallize for 15 hours at +5 C.
It is filtered,, washed with n-butyl acetate (25 ml) and ethyl acetate (25 ml). It is vacuum dried at 40°C for 3 hours.
Yield: 1.9 g (10%) of the 1-ethoxycarbonyloxyethyl ester of the 6-(D(-)-a-amino-a-phenylacetamido) penicillanic acid with m.p. 160-162°C and characteristics conforming to an authentic sample of the hydrochloride (e.g. IR:V 1790 cm \ 3-lactam carbonyl).
2 1 626
Example 7:
A mixture of acetaldehyde (44 g, 1 mole), carbon tetrachloride (300 ml) arid freshly distilled carbonyl bromide (235 g, 1.25 mole) was cooled to 0°C and maintained at this temperature by 5 external cooling during the addition over a period of 1 hour of pyridine (11.9 g, 0.15 mole).
The mixture was allowed to warm up to ambient temperature and then heated to 50°C and maintained at this temperature for a period of 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 mole) on warming and heating under reflux.
After heating under reflux for a further 2 hours, excess ethanol was removed in vacuo and the residue triturated with water (100 ml) 15 and methylene dichloride (200 ml) .
Separation of the organic layer and fractional distillation afforded pure ethyl alpha-bromo-ethyl-carbonate (130 g, 66%
yield) having a boiling point of 90-92°C at 45 mms of mercury pressure and identical in all respects with an authentic specimen.
Example 8:
A mixture of acetaldehyde (44 g, 1 mole) , dichloromethane (300 ml) and hexamethylphosphoric-tri-amide (17.9 g, 0.1 mole) was cooled to —10°C and freshly distilled carbonyl bromide (207 g, 1.1 mole) " was gradually added over a period of 4 hours during which time 25 the temperature was allowed to rise to 10°C.
The mixture was then heated under gentle reflux (ca. 40°C) for
4 hours. While still under reflux, ethanol (69 g, 1.5 mole) was carefully added over a period of 1 hour and heating under reflux continued for a further 1 hour.
Fractional distillation of the resulting mixture afforded pure ethyl alpha-bromoethy1-carbonate directly (114 g, 58% yield).
2 162 6 5
The authenticity of the ethyl alpha-bromoethyl carbonate formed was confirmed by analysis and independent synthesis as follows:
Diethylcarbonate (118 g, 1.0 mole) was stirred and heated to filament lamp. Bromine (96 g, 0.6 mole) was added dropwise over a period of 3 to 4 hours and at such a rate that the mixture did not deepen beyond a pale orange colour.
After addition of bromine was complete, the mixture was cooled to ambient temperature and sodium bicarbonate (20 g) added.
Distillation and fractionation of the resulting mixture gave authentic ethyl alpha-bromo-ethyl carbonate (84.2 g, 70% yield) having a boiling point of 87-88°C at 40 mms of mercury pressure.
Example 9:
A mixture of lithium bromide (43 g, 0.5 m) , ethyl alphachloro-ethyl carbonate (15.3 g, 0.1 m), water (100 ml), dichloromethane (100 ml) and cetyl trimethyl ammonium bromide (1.5 g) was stirred at ambient temperature for 24 hours. The aqueous layer was removed and replaced by a fresh solution of lithium bromide (26 g, 0.3m) in water (40 ml) containing cetyl trimethyl ammonium bromide (1 g). 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 to afford after repeated fractionation the new compound, ethyl alpha-bromo-ethyl carbonate (15^0 g, 76% yield) having a boiling point of 90-92°C at 35 mms of mercury pressure.
between 110°C and 120°C and illuminated by a 150 watt tungsten
Found: Calculated:
C 30.7; H 4.8;
C 30.5; ' H 4.6;
Br .40.1% Br 40.6%
The NMR spectrum exhibited peaks as follows:-
1.2 - 1.6 (3H, triplet)
-ch2.ch3
2.0 - 2.2 (3H, doublet)
-ch.ch
3
4.1 - 4.5 (2H, Quartet)
-ch2.ch3
6.5 - 6.8 (1H, Quartet)
-CH.CH
3
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Example 10: *
Lithium bromide (17.4 g, 0.2 m) was dissolved in dimethyl formamide (150 ml) and the mixture cooled to ambient temperature. Ethyl alpha-chloroethyl carbonate (30.5 g, 0.2 m) was added and 5 the mixture stirred at ambient temperature for 24 hours. The precipitated lithium chloride was filtered off and the filtrate vacuum distilled to afford after careful re-fractionation, ethyl alpha-bromoethyl carbonate in 76% yield based upon recovered ethyl alphachloroethyl carbonate.
Example 11:
The authenticity of the foregoing new compound ethyl alpha-bromoethyl carbonate was confirmed by independent synthesis as follows:-
A mixture of diethyl carbonate (35 g, 0.3 m) in carbon tetrachloride 15 (50 ml) and alpha-azo-isobutyronitrile (AIBN) (0.1 g) was heated to gentle reflux and dibromodimethyl hydantoin (28.6 g, 0.1 m) was added in small aliguots over a period of 8 hours together with further additions of AIBN (8x0.05 g): care being taken to ensure that free bromine did not accumulate in the reaction mixture. At 20 the end of the reaction, the mixture was subjected to vacuum fractional distillation to afford pure ethyl alpha-bromoethyl carbonate (32.3 g, 82% yield) identical in all respects with the product of Examples 9 and 10.
Example 12: Benzylpenicillin ethoxycarbonyloxyethyl ester
^^5 A mixture of potassium penicillin G (7.4 g, 20 mmole), ethyl alpha-bromo-ethyl carbonate (5.9 g, 30 mmole), tetra-n-butyl ammonium bromide (0.. 8 g, 2.5 mmole) and acetone (80 ml) were stirred and heated under gentle reflux for 4 hours. Excess acetone was removed under partial vacuum and the residue triturated with ice-cold water and methyl isobutylketone.
Evaporation of the dried methyl isobutylketone under vacuum gave a semi-crystalline oil (6.0 g) which on trituration with ethanol deposited white crystals (2.5 g, 35% yield) of the alpha-(ethoxy-carbonyloxy)-ethyl ester of penicillin G having a purity of 35 98-99% by HPLC.
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Found: C 43.0 H 7.4 N 7.7%
Calculated: C 43.4 H 7.4 N 8.0%
Example 13: Benzylpenicillin ethoxycarbonyloxyethyl ester
Potassium benzylpenicillinate (25.08 g, 66.7 mmol) sodium bicarbonate (0.50 g, 6.0 mmol) , and tetrabutylammonium bromide (2.15 g, 6.67 mmol) were carefully stirred in methylene chloride (41 ml) and warmed to 40°C. When this temperature was reached a-bromodiethyl carbonate 17.16 g, 86.7 mmol was added and the slurry was stirred for 4.0 hours. Water (30 ml) was added,
followed by a mineral acid to a pH of approx. 5. The mixture was stirred for approx. 4 hours, during which time sodium hydroxide (4%) was added in order to maintain 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 was then evaporated under reduced pressure. The oily product thus obtained was dissolved in methylene chloride (100 ml) and was 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 benzylpenicillin ethoxycarbonyloxyethyl ester of 96-97%.
Example 14: Benzylpenicillin ethoxycarbonyloxyethyl ester
Potassium benzylpenicillinate (5.02 g, 13.3 mmol) and potassium bicarbonate (2.99 g, 38.3 mmol) in dimethyl sulfoxide (13.5 ml)
were carefully stirred in an ice-bath. a-Bromodiethyl carbonate (3.70 g, 18.6 mmol) was added over a period of 30-40 min using a syringe pump. Stirring was continued while keeping the reaction mixture in the ice-bath. HPLC-analyses showed that a yield of
* ^
about 70% of the benzylpenicillin ethoxycarbonyloxyethyl ester was obtained within 5-10 min.
Example 15: Benzylpenicillin ethoxycarbonyloxyethyl ester
Potassium benzylpenicillinate (47.03 g, 125 mmol) sodium bicarbonate (0.94 g, 11 mmol), and tetrabutylammonium bromide (2.01 g, 6.25 mmol), were carefully stirred in acetone (77 ml)
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and warmed to 40°C. When this temperature was reached, a-bromo-diethyl carbonate (26.06 g, 131 mmol) was added and the slurry was stirred for 4.5 hours. Water (56 ml) was added, followed by a mineral acid to a pH of approx. 5. The mixture was stirred 5 for approx. 3 hours, during which time sodium hydroxide (4%) was added in order to maintain pH between 4.5-4.8. 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. 10 The remaining oily product was dissolved in methylene chloride to a total volume of 2 50 ml.
HPlC-analysis of the methylene chloride solution showed a yield of benzylpenicillin ethoxycarbonyloxyethyl ester of 98-99%.
The specifications of New Zealand Patents Nos. 164760, 170033 15 and 186998, as well as the specifications of British Patents Nos. 1425571 and 1426869, are seen to disclose haloesters of the general formula:
P 1
Y-CH-O-C-OR
k2
wherein Y is halogen or a functional equivalent group capable
of reacting with a carboxy group to form an ester linkage;
1 2
R is a lower alkyl group; and R is hydrogen or a lower alkyl group.
However, none of those patent specifications disclose the compound a-bromodiethyl carbonate of the formula III:
Br I
CH3-CH-O.CO.O.C2H5 (III)
which has the novel and unpredictable property of being able to react with the intermediate of the formula II without an esterification catalyst, for the preparation of bacampicillin of the formula I in- high degree of yield and purity.
Claims (14)
1. The compound of the formula: Br 0 ch3 -ch-o-c-o- c2h5.
2. A process for the preparation of the compound of the formula: Br 0 ch3 -ch-o-c-o - c2h5 (iii) characterized by the steps of: a) reacting the aldehyde of the formula: ch3cho (vi) with carbonyl bromide COBr2 (VII) for the formation of the compound of the formula: Br CH3 - CH - OCO - Br ?(VIII) b) followed by reacting the compound VIII with C2H^OH for the formation of a compound of the formula III.
3. A process according to claim 2, characterized in that it is carried out in the presence of a catalyst.
4. A process according to claim 3, characterized in that the catalyst is used in an amount of from 0.05 to 0.5 mole per mole of the compound VI.
5. A process according to claim 4, characterized in that the catalyst is used in an amount of from 0.05 to 0.15 mole per mole of the compound VI. - 28 - 2 1 6265
6. A process according to any one of claims 3 to 5, characterized in that the catalyst is a tertiary amine, a tertiary phosphine, an amide, substituted urea or thiourea, a phosphoric acid amide, a tertiary oxonium or sulphonium salt, 5 or a quaternary ammonium or phosphonium salt.
7. A process for the preparation of a compound of the formula: Br 0 ch3 - ch-o-c-o - c2h5 (iii) by reacting the compound of the formula: CI 0 ch. -ch-o-c-o- c0hc (ix) 3 Z O 10 with an alkali bromide of the formula: R - Br (X) in which R is an alkali metal for the formation of the compound of the formula III, which process is characterized in that the reaction is carried out in a two-phase solvent system comprising 15 water and a water-immiscible organic solvent in the presence of a phase transfer catalyst.
8. A process according to claim 7, characterized in that the alkali metal is lithium.
9. A process according to claim 7 or 8, characterized in that the ' organic solvent is a halogenated hydrocarbon or an aromatic hydrocarbon.
10. A process according to claim-9, characterized in that the organic solvent is dichloromethane.
11. A process according to any one of claims 7 to 10, characterized in that the phase transfer catalyst is a quaternary ammonium salt.
12. A process according to claim 2 or 7 substantially as described herein. - 29 - 2 1 6265
13. The compound of the formula: Br 0 CH3 - CH-O-C-O - C2H5 (III) when obtained by the process of any one of claims 2 to 12.
14. The use of a-bromo-diethyl carbonate in the preparation of the ethoxycarbonyloxyethyl ester of penicillin G. DATED thic day of A.D.—1-9 86 ASTRA LAKEMEDEL AKTIEBOLAG, By its Patent Attorney, HENRY HUGHES LIMITED - 30 -
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT22141/82A IT1190897B (en) | 1982-06-29 | 1982-06-29 | PROCEDURE FOR THE PREPARATION OF THE 1-ETHOXYCARBONYLOXYETHYL ACID ACID 6- (D (-) - ALPHA AMINOALPHA-PHENYLACETAMIDE) -PENICILLANIC |
GB8226751 | 1982-09-20 | ||
GB8228622 | 1982-10-06 | ||
GB8232629 | 1982-11-16 | ||
GB838300331A GB8300331D0 (en) | 1983-01-07 | 1983-01-07 | Preparation of bromo carbonates |
NZ204736A NZ204736A (en) | 1982-06-29 | 1983-06-28 | The preparation of the 1-ethoxycarbonyloxyether ester of 6-(d-(-)-alpha-amino-alpha-phenylacetamido)-penicilanic acid |
Publications (1)
Publication Number | Publication Date |
---|---|
NZ216265A true NZ216265A (en) | 1986-11-12 |
Family
ID=27546824
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NZ21626583A NZ216265A (en) | 1982-06-29 | 1983-06-28 | Alpha-bromodiethylcarbonate and its manufacture |
Country Status (1)
Country | Link |
---|---|
NZ (1) | NZ216265A (en) |
-
1983
- 1983-06-28 NZ NZ21626583A patent/NZ216265A/en unknown
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