JPH0819052B2 - α-bromodiethyl carbonate - Google Patents

Description

Detailed Description of the Invention

[0001]

This invention relates to formula I

Embedded image Of 6- (D-(-)-α-amino-α-phenylacetamido) penicillanic acid 1-ethoxycarbonyloxyethyl ester (bacampicillin) of formula

Embedded image Of α-bromodiethyl carbonate.

[0002]

[0003]

PRIOR ART The substance I is an ampicillin ester, which is extremely important from the viewpoint of therapy. The reason is that it is well absorbed when given orally and gives much higher blood ampicillin levels than ampicillin itself.

This ester was isolated in the form of the hydrochloride salt and is known as bacampyricin hydrochloride.

Based on the methods known so far (Belgian Patent No. 7772723), bacampyricin hydrochloride can be synthesized by the following two methods.

A) α-in organic solvent or in 70% aqueous dioxane solution in the presence of sodium bicarbonate
Reaction of benzylpenicillin potassium with chlorodiethyl carbonate.

The 1-ethoxycarbonyloxyethyl ester of benzylpenicillin obtained is subjected to a phenylacetic acid chain removal reaction with iminochloride-iminoether and to obtain the 1-ethoxycarbonyloxyethyl ester of 6-aminopenicillanic acid, and The aminopenicillanic acid ester is isolated as the hydrochloride salt.

The latter intermediate is then condensed with D-(-)-α-phenylglycine to give a compound of formula I.

B) 6- (D-(-)-α-azido-α-with α-chlorodiethyl carbonate in a polar solvent.
Phenylacetamide) Penicillanic acid esterification reaction.

Then, 6- (D-(-)-α-azide-α-
Catalytic hydrogenation of the 1-ethoxycarbonyloxyethyl ester of (phenylacetamido) penicillanic acid provides the compound of formula I.

[0011]

As will be appreciated, these methods are rather complicated. The reason is that they involve the use of numerous raw materials and long processing times.

[0012] Therefore, it is desired to develop a process for the production of related active substances which is easier to carry out and is more industrially advantageous.

[0013]

Means for Solving the Problems As a result of earnest studies by the present inventors, α-bromodiethyl carbonate was used as a reaction component with great advantage in a method for producing bacampicillin using ampicillin as a starting material. I found that. The use of α-bromodiethyl carbonate leads to a particularly high yield and high purity of the final product such as bacampicillin.

That is, the general formula

[Chemical 4] In preparing a 1-ethoxycarbonyloxy ester of 6- (D-(-)-α-amino-α-phenylacetamido) penicillanic acid having the following steps: (a) Ampicillin, preferably in the form of an alkaline salt, Reaction with a reactive derivative of acetoacetic acid

Embedded image (Wherein R ¹ represents an alkyl group containing ¹ to 4 carbon atoms, a substituted or unsubstituted aryl group or an aralkyl group, R ² represents hydrogen, an alkyl group containing 1 to 4 carbon atoms, Represents a substituted or unsubstituted aryl group or aralkyl group, R ³ contains an alkyl group containing 1 to 4 carbon atoms, a substituted or unsubstituted aryl group or aralkyl group, contains 1 to 4 carbon atoms An alkoxy group,
Represents an aryloxy group or an amino group, and X represents an alkali metal, an alkaline earth metal or an organic base)
To produce the corresponding enamine of (b)

[Chemical 6] By reacting with α-bromo-diethyl carbonate having

[Chemical 7] Forming a corresponding ester having the formula (wherein R ¹ , R ² and R ³ have the same meaning as above), and (c) hydrolyzing in an acidic medium to form a compound of formula (I) By doing so, the above object is achieved.

The esterification reaction between compounds II and III can be carried out with or without the presence of an esterification catalyst.

The addition of the catalyst at this stage considerably shortens the reaction time and gives a higher yield of product with greater purity.

Quaternary ammonium salts such as tetrabutylammonium bromide, alkali metal bromides or iodides and cyclic ethers can be used as catalysts for this purpose.

The catalyst is used in an amount of 0.1 per mol of compound III.
It can be used in amounts varying from 005 to 0.10 mol up to equimolar amounts with compound III. In a preferred embodiment, tetrabutylammonium bromide is compound II
It is used in an amount of 0.01 to 0.10 mol per mol of I.

In the above method, instead of the compound of the present invention, α-bromodiethyl carbonate,

Embedded image It is also advantageous to use compounds of the formula wherein Z is Cl or I. In this case, the reaction is carried out in the presence of a catalytic amount of a catalyst as defined above. This catalyst is suitably used in an amount of 0.005 to 0.10 mol per mol of compound V.

Examples of radicals R ¹ , R ² and R ³ are:

Alkyl: CH ₃ , C ₂ H ₅ , n-C ₃ H ₇ ,
_{i-C 3 H 7, n} -C 4 H 9 alkoxy (R ³ _{only): OCH 3, OC 2 H} 5, OCH 2
CH ₂ CH ₃ , OCH (CH ₃ ) ₂ , O (CH ₂ ) ₃ CH ₃

[Chemical 9]

The group X is a group well known in the art, such as alkali metal (Na, K), alkaline earth metal (Ca, M).
g), an organic base (organic bases known in penicillin synthesis such as tertiary ammonium groups, triethylamine, ethylpiperidine and methylmorpholine).

In a preferred embodiment, the group protecting the amino group of ampicillin is a 1-methoxy-carbonyl-propen-2-yl group or a 1-ethoxycarbonyl-propen-2-yl group, for which the preferred intermediate Are each of formula II (R ¹ = methyl, R ² = methyl, R ³ =
Methoxy or ethoxy, and X = Na or K) N- (1-methoxy-carbonyl-propen-2-yl) penicillanic acid and N- (1-ethoxy-carbonyl-propen-2-yl) penicillanic acid sodium or It is potassium.

Intermediate IV is stable in neutral or alkaline media, while amino acid protecting groups can be removed easily, rapidly and selectively in acid media.

The group protecting the amino group of ampicillin can be selected, for example, from the groups described in British Patent 991,586 and other groups known in the art.

More specifically, the process according to the preferred embodiment comprises the following step, the conversion of ampicillin trihydrate into its salt, for example the potassium salt, in a polar solvent, for example N, N-dimethylformamide, followed by Formation of the corresponding enamine (II) by reaction with an acetoacetic acid derivative such as methyl acetoacetate, addition of an esterification catalyst, preferably tetrabutylammonium bromide, addition of α-bromodiethyl carbonate to the reaction mixture to give the enamine form of ampicillin 1. -Formation of ethoxycarbonyloxyethyl ester (IV), hydrolysis of the protecting group with dilute HCl in an organic solvent such as n-butyl acetate / water, saturation of the aqueous phase with, for example, sodium chloride and a suitable solvent such as n-butyl acetate. Of bacampicillin hydrochloride by extraction with water Include isolated by filtration of the concentrate and the product subsequent solution at low pressure and the product in high purity in n- butyl acetate for crystallization.

The main advantage of this method is that it is practically possible to produce bacampicillin hydrochloride in one operation and with high purity.

In fact, the impurities present in the product obtained by this method are negligible when compared to the methods known in the art.

Another important advantage is that ampicillin trihydrate, which is readily available in pure form and at low cost, is used as the starting material.

Intermediates (II) are described, for example, in British Patent No. 991,5
By reacting ampicillin trihydrate with methyl or ethyl acetoacetate 10 to 50% above stoichiometric ratio in the presence of an organic base or an alkali metal carbonate such as potassium carbonate as described in U.S. Pat. It can be produced in a yield of 95% or more.

Intermediate (II) can be isolated and added to the esterification reaction in solid form. Or an intermediate
Without isolating (II), the esterification reaction can be carried out in the same solvent in which the enamine (II) forming reaction was carried out.

The formation reaction of ampicillin enamine (II) is carried out in a neutral polar solvent such as N, N-dimethylacetamide, N, N.
Carried out in dimethylformamide, dimethoxyethane, dimethylsulfoxide, tetrahydrofuran or dioxane.

To complete the reaction, it is sufficient to leave the components of the mixture in contact at temperatures between 0 ° C. and 60 ° C., preferably between 20 ° C. and 30 ° C. for 2-8 hours, preferably 3 hours. Is.

Compound II can be prepared by acylation of 6-aminopenicillanic acid with the corresponding enamine derivative of phenylglycine to form Compound II, which can be directly esterified without subsequent isolation. It can be converted to bacampicillin.

The esterification reaction after adding α-bromodiethyl carbonate to the above mixture is carried out at a temperature of 15 ° C. to 80 ° C., preferably 45 ° C. to 55 ° C. for 1 hour to 24 hours, preferably 5 hours to 10 hours. To be done.

The esterification reaction is suitably carried out in an organic solvent such as methylene chloride or acetone, dimethylacetamide, dimethylformamide, and dimethylsulfoxide or a mixture of organic solvents. It is also possible to use a water-containing organic solvent. The use of esterification catalysts is desirable when acetone is used as the solvent for the esterification reaction.

The easiest and most suitable conditions for industrial purposes are to dilute the esterified enamine (IV) with water into the reaction mixture and then to extract it with a suitable water-immiscible solvent such as n-butyl acetate. To isolate.

The acetate phase is stirred with a dilute HCl (0.2-0.3N) solution until the protecting groups have been completely hydrolyzed. This is 2 to 8 hours at normal temperature, preferably 4
Needs ~ 5 hours.

Compound (I) is separated from the aqueous phase in the form of the hydrochloride salt by the addition of sodium chloride. This is extracted with a suitable solvent such as n-butyl acetate.

Crystallization of the product of formula (I) is carried out by concentrating this organic phase at low pressure at a temperature of 40 ° C. until a small amount remains.

The crystalline product is isolated by filtration, washing and vacuum drying.

Formula of the invention

[Chemical 10] Α-Bromodiethyl carbonate can be used for the synthesis of α- (ethoxycarbonyloxy) ethyl esters of 6-aminopenicillanic acid, penicillin and cephalosporins such as the antibiotic bacampicillin. Advantageously α-
Bromodiethyl carbonate can be used in the preparation of ethoxycarbonyloxyethyl esters of 6-aminopenicillanic acid, penicillin G, penicillin V and ampicillin.

The α-bromodiethyl carbonate of the present invention can be produced by the following two methods, that is, method (A) and method (B).

Method (A) Method (A) comprises the following steps: (a) reacting an aldehyde of formula CH ₃ CHO (VI) with carbonyl bromide COBr ₂ (VII)

[Chemical 11] To produce the α-bromo-bromoformate of formula (b) and (b) reacting the α-bromo-bromoformate of formula VIII with an alcohol of formula C ₂ H ₅ OH to obtain the desired α-bromodiethyl carbonate of formula III. Is generated. That is, the method (A) can be summarized by the following reaction scheme.

[0045]

[Chemical 12]

The α-bromo-bromoformates of formula VIII are themselves novel compounds.

The reaction between the aldehyde (CH ₃ CHO) and the carbonyl bromide is most suitably carried out in the presence of a catalyst. This catalyst is for example a tertiary amine (eg tertiary
Aliphatic amines, tertiary mixed alkyl / aryl amines or tertiary aromatic amines), tertiary phosphines, amides, substituted ureas or thioureas, phosphoric amides, tertiary oxonium or sulfonium salts or quaternary ammoniums Or it can be a phosphonium salt. Examples of preferred catalysts for use in method (A) include pyridine, dimethylformamide, tetra-n-butylurea, hexamethylphosphoric triamide and benzyltrimethylammonium bromide.

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

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 of -40 ° to 120 ° C, preferably 0 to 40 ° C. The carbonyl bromide is usually in molar excess with respect to the aldehyde, suitably 10 to 1
It is used in a molar excess of 00%, preferably 20-50%.

Formula VI prepared in step (a) of method (A)
The intermediate of II, α-bromo-bromoformate, need not be isolated prior to reaction with the alcohol C ₂ H ₅ OH, and in fact it is generally preferred not to do so. That is, according to a preferred embodiment, excess carbonyl bromide is removed by warming the reaction mixture obtained from step (a), for example under reduced pressure, or by purging 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 has stopped, or by adding a tertiary base to the mixture and warming it if necessary. . All residual catalyst from step (a) or its complex with carbonyl bromide does not interfere with the subsequent reaction, and in some cases this is advantageous.

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

Method (B) Method (B) is the reaction of an alkyl chloride or an arylalkyl chloride (or a compound containing such a group) with an alkali metal bromide or an alkali metal iodide to replace the chlorine substituents with bromine or iodine, respectively. Finkelstein by substitution with a substituent or by reacting 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.
tein) is a modified method of producing α-bromodiethyl carbonate.

The Finkelstein reaction is useful.
The reason is that the resulting iodide is generally more reactive than bromide, and bromide is more reactive than chloride. In some cases only catalytic amounts of alkali metal bromide or iodide are required. This is because the more reactive one that is obtained reacts with the desired substrate to form the alkali metal bromide or iodide and allows the reaction to continue.

Not all optionally substituted alkyl or arylalkyl chlorides undergo this reaction. And, in particular, for α-chloroesters and α-chlorocarbonates, i.e. compounds in which a chlorine atom is attached to the carbon atom attached to either end of the -CO-O- group, this reaction is carried out. Has proven difficult. An example of such an α-chlorocarbonate is α-chlorodiethyl carbonate, which is a known intermediate in the preparation of ethoxycarbonyloxyethyl esters of 6-aminopenicillanic acid and penicillin.

We have mentioned the above problem that this reaction is carried out in the presence of a phase transfer catalyst using a two phase solvent system in which one of the phases is water and the other is a water immiscible organic solvent. I found that I could overcome it by carrying out.

Therefore, according to the method (B), α-bromodiethyl carbonate can be produced by reacting α-chlorodiethyl carbonate with an alkali metal bromide. In this method, the reaction is carried out in the presence of a phase transfer catalyst in a two phase solvent system comprising water and a water immiscible organic solvent.

Suitable water-immiscible organic solvents for use in process (B) include halogenated hydrocarbons such as halogenated paraffins such as dichloromethane, aromatic hydrocarbons such as toluene. Suitable phase transfer catalysts include quaternary ammonium salts such as tetraalkyl ammonium salts such as cetyl trimethyl ammonium bromide and tetra n-butyl ammonium hydrogensulfate. The alkali metal bromide can be, for example, sodium, potassium or lithium bromide. Lithium bromide is preferred.

In method (B), the formula

[Chemical 13] Α-chlorodiethyl carbonate of the formula R-Br (X) (wherein R is an alkali metal such as Na, K) in a two-phase solvent system in which one phase is water and the other is a water immiscible organic solvent. And Li) to react with an alkali metal bromide of the formula

Embedded image To produce the compound

As mentioned above, the preferred alkali metal R
Is Li and consequently LiBr is a preferred reagent of formula X.

With respect to method (B), it has been found that lithium bromide can be advantageously used in conventional Finkelstein reactions to halogenate eg .alpha.-chlorocarbonates (ie using a single phase organic solvent system).

Therefore, α-bromodiethyl carbonate can also be produced by reacting α-chlorodiethyl carbonate with lithium bromide.

Suitable solvents used in this case include lower aliphatic alcohols, lower aliphatic ketones, lower aliphatic ethers and lower aliphatic amides of formic acid.

Next, the use of α-halogendiethyl carbonate, particularly α-bromodiethyl carbonate of the present invention, in the preparation of ethoxycarbonyloxyethyl ester of 6-aminopenicillanic acid, penicillin and cephalosporin will be explained.

In summary, this mode of use includes: Use of α-bromodiethyl carbonate in the preparation of ethoxycarbonyloxyethyl esters of 1.6-aminopenicillanic acid, penicillins such as penicillin G, penicillin V and ampicillin and cephalosporins.

2. In the esterification reaction between α-halogen diethyl carbonate and 6-aminopenicillanic acid, penicillin or cephalosporin, a quaternary ammonium compound is used in the esterification step and said quaternary ammonium compound is used.
The primary ammonium compound has an equimolar amount of 1 with respect to the amount of 6-aminopenicillanic acid, penicillin or cephalosporin.
-25%, preferably 1-10% improvement present in an amount.

This use mode leads to an improvement in the production of esters by reaction of salts of carboxylic acids with α-bromodiethyl carbonate.

Ester forming reactions of metal salts of carboxylic acids with alkyl or arylalkyl halides are well known. However, the yield is not particularly high,
And this reaction generally requires forced conditions such as high temperatures and / or long reaction times. These forcing conditions affect the synthetic utility of this reaction and heat-sensitive and labile substances such as pyrethroids, prostaglandins, peptides,
It limits its industrial applicability to penicillins and cephalosporins.

British Patent 1,443,738 discloses the use of quaternary ammonium salts of penicillin and cephalosporins in place of their metal salts in the preparation of penicillin and cephalosporin esters. There is.

The preparation of quaternary ammonium salts of acids can be time consuming and expensive. However,
It is not necessary to first prepare the quaternary ammonium salt of penicillin or cephalosporin as disclosed in GB 1,443,738. This reaction is
It can be carried out by reacting a metal salt of a carboxylic acid, ie 6-aminopenicillanic acid, penicillin or cephalosporin with an alkyl or arylalkyl halide in the presence of a quaternary ammonium salt other than the salt of the carboxylic acid.

We do not need to use said quaternary ammonium salt in stoichiometric amount with respect to carboxylic acid, ie 6-aminopenicillanic acid, penicillin or cephalosporin, and carboxylic acid, ie 6- a
It has been found that substoichiometric amounts with respect to pa (6-aminopenicillanic acid), penicillin or cephalosporins are sufficient.

Therefore, the metal salt of 6-apa, penicillin or cephalosporin is added in the presence of a quaternary ammonium salt (other than the salt of the carboxylic acid) and the quaternary ammonium compound to 6-apa, penicillin or Be present below the stoichiometric amount for cephalosporins α
The ethoxycarbonyloxyethyl ester of 6-apa, penicillin or cephalosporin can be prepared by reacting with halogen diethyl carbonate.

In this case, 1% to 25% equivalents of quaternary ammonium salt are used per equivalent of metal salt of carboxylic acid, and more preferably 1% to 10% of quaternary ammonium salt equivalents are used. .

The quaternary ammonium salt of carboxylic acid is preferably a metal salt of carboxylic acid and an acid other than the above carboxylic acids,
It is typically prepared by reaction with a quaternary ammonium salt of a mineral acid such as hydrochloric acid, hydrobromic acid or sulfuric acid.

In this case, suitable metal salts of carboxylic acids (precursors to the carboxylic acid quaternary ammonium salt or themselves) suitable for use are alkali metal or alkaline earth salts such as sodium, potassium, lithium, magnesium and calcium. It is salt. Suitable quaternary ammonium salts of acids other than carboxylic acids, such as tetraalkylammonium salts such as tetra-n-butylammonium bromide and cetyltrimethylammonium bromide, are suitable quaternary ammonium salts (precursors for carboxylic acid quaternary ammonium salts or themselves). And quaternary pyridinium salts such as cetylpyridinium bromide. Suitable halides include fluoride, chloride, bromide and iodide, preferably activated fluoride or activated chloride, or bromide or iodide.

The esterification reaction can be carried out in the presence or absence of a solvent. Suitable solvents include lower aliphatic alcohols, lower aliphatic ketones, lower aliphatic amides of formic acid, and dimethyl sulfoxide.
Alternatively, an excess of ester-forming halide may be used if no solvent is used, especially if it is liquid at the reaction temperature.

When α-bromodiethyl carbonate is used in the preparation of the ethoxycarbonyloxyethyl ester of 6-apa, penicillin and cephalosporin, the use of a catalyst is optional. About equimolar amounts of carboxylic acid quaternary ammonium salt and ester-forming halide can be used in this reaction. Preferably a 5% to 100% excess of ester forming halide is used per equivalent of carboxylate salt used, and more preferably a 20% to 60% excess of ester forming halide is used.

The improvement in this esterification process is especially 6-
Suitable for the production of esters of apa, penicillin and cephalosporins, and according to a preferred embodiment the carboxylic acid has the formula

[Chemical 15] Or

Embedded image [Wherein R ¹ is a hydrogen atom or an acyl group, particularly a substituted acetyl group such as phenylacetyl, α-aminophenylacetyl, α-amino-p-hydroxyphenylacetyl, phenoxyacetyl, α-carboxyphenylacetyl or α-carboxy-3-. A thienylacetyl group or a group if the carboxylic acid is of formula XII

[Chemical 17] Wherein R ³ is a hydrogen atom or an amino protecting group such as benzyloxycarboxyl, trimethylsilyl or tertiary butyloxycarboxyl, and R 3
² is a hydrogen atom, an alkyl group (eg, methyl group), a substituted alkyl group, eg, hydroxymethylene, alkoxy or aryloxymethylene or acetoxymethylene group) or acetoxy or a substituted acetoxy group (eg, alkylacetoxy, arylacetoxy or arylalkylacetoxy group or Group C ₆ H ₅ CHOH ・ CO
^- a is] may be one having a.

In the production of penicillin and cephalosporin esters, the ester-forming halide is of the formula CH ₃ --CH (X)-O--CO--O--CH ₂ --CH _{3 where} X is a chlorine, bromine or iodine atom, Preferably it is a bromine atom) α-halodialkyl carbonate.

The fourth used according to a preferred embodiment for the production of esters of penicillin and cephalosporins.
The primary ammonium salt is tetra-n-butylammonium bromide.

In particular, the ethoxycarbonyloxyethyl esters of 6-aminopenicillanic acid and penicillin G have a 6-NH ₂ group after removal of the side chain of the resulting penicillin G ester, as is known in the art. Used in preparing the desired semi-synthetic penicillin ester by acylation.

[0081]

EXAMPLES The following examples and reference examples illustrate the embodiments of the present invention without any limitation.

Example 1 Preparation of α-bromodiethyl carbonate

Embedded image Sodium bromide (10 ml) dissolved in acetone (600 ml)
2.9g) at room temperature (20-25 ° C) for 2-3 hours, 10
It was reacted with α-chlorodiethyl carbonate (152.6 g) dissolved in 0 ml of acetone. The mixture was then concentrated under vacuum at low temperature up to 35 ° C. until a semi-solid mass was obtained. The reaction mixture is then was partitioned between H ₂ O / ethyl ether. The aqueous phase was separated and then extracted twice with 400 ml ethyl ether.

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

The organic phase is dried over magnesium sulphate,
Subsequent vacuum concentration at low temperatures up to 35 ° C. gave the title product (60%) in liquid form. It was initially colorless or slightly tan.

This was used as such in the esterification stage of Reference Example 1 below.

Example 2 Acetaldehyde (44 g, 1 mol), carbon tetrachloride (3
00 ml) and freshly distilled carbonyl bromide (2
35 g, 1.25 mol) was cooled to 0 ° C. and pyridine (11.9 g, 0.15 mol) over 1 hour.
This temperature was maintained by external cooling during the addition of.

The mixture was allowed to warm to ambient temperature, then heated to 50 ° C. and held 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 was ethanol (9
(2 g, 2 mol) was warmed up and heated to reflux, whereupon it dissolved readily. After heating at reflux for a further 2 hours, excess ethanol was removed in vacuo and the residue was triturated with water (100 ml) and methylene chloride (200 ml).

45 mm when the organic layer is separated and fractionally distilled
Pure α-bromodiethyl-carbonate (130 g, 66% yield) with a boiling point of 90-92 ° C. in Hg and in all respects identical to the standard was obtained.

Example 3 Acetaldehyde (44 g, 1 mol), dichloromethane (300 ml) and hexamethylphosphoric triamide (1
7.9 g, 0.1 mol) was cooled to -10 ° C and freshly distilled carbonyl bromide (207 g, 1.1 mol).
Was gradually added over 4 hours. During this time, the temperature was raised to 10 ° C.

The mixture was then gently heated to reflux (about 40 ° C.) for 4 hours. While refluxing, ethanol (6
9 g, 1.5 mol) was carefully added over 1 hour and heating at reflux continued for another hour.

Fractional distillation of the resulting mixture gave directly pure α-bromodiethyl carbonate (114 g, 58% yield).

The α-bromodiethyl carbonate formed was confirmed by analysis and an independent synthesis as follows.

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

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

Distillation and fractional distillation of the resulting mixture are 40 m
This gave an α-bromodiethyl carbonate standard (84.2 g, 70% yield) with a boiling point of 87-88 ° C. in mHg.

Example 4 Lithium bromide (43 g, 0.5 M), α-chlorodiethyl carbonate (15.3 g, 0.1 m), water (100 m
A mixture of l), 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 (26g, 0.3m) in water (40ml) containing cetyltrimethylammonium bromide (1g). It was stirred for another 24 hours, during which the temperature was raised to 35 ° C. After that, the organic layer is separated, dried and vacuum distilled, and after repeated fractional distillation, a new compound α having a boiling point of 90 to 92 ° C. at 33 mmHg is obtained.
-Bromodiethyl carbonate (15.0 g, 76% yield) was produced.

Measured value: C 30.7 H 4.8 B
r 40.1% Calculated: C 30.5 H 4.6 Br 40.6
%

The NMR spectrum showed the following peaks.

1.2-1.6 (3H, triplet) -C
_{H 2 · CH 3 2.0~2.2 (3H} , _{doublet) -CH · CH 3 4.1~4.5 (2H} , _{quartet) -CH 2 · CH 3 6.5~6.8 (} 1H, Quartet) -CH・ CH ₃

Example 5 Lithium bromide (17.4 g, 0.2 m) was dissolved in dimethylformamide (150 ml) and the mixture was cooled to ambient temperature. α-Chlorodiethyl carbonate (30.5 g, 0.2 m) was added and the mixture was stirred at ambient temperature for 24 hours. The precipitated lithium chloride is filtered off,
Then, the filtrate was distilled under vacuum to obtain α-bromodiethyl carbonate in a yield of 76% based on α-chlorodiethyl carbonate recovered after careful re-fractionation.

Reference Example 1 The validity of the above-mentioned novel compound α-bromodiethyl carbonate was confirmed by the following independent synthesis.

A mixture of diethyl carbonate (35 g, 0.3 m) and α-azo-isobutyronitrile (AIBN) (0.1 g) in carbon tetrachloride (50 ml) was gently heated to reflux and dibromodimethylhydantoin. (2
8.6 g, 0.1 m) was added in small portions over 8 hours with the addition of 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 Example 4
And pure α-bromodiethyl carbonate (32.3 g, 8) identical in all respects to the product of Example 5.
2% yield) was produced.

Reference Example 2 25.08 g (0.181 mol) of finely ground anhydrous potassium carbonate was suspended in 200 ml of N, N-dimethylacetamide, and 32.4 ml (0.3M) of methyl acetoacetate and 60 ml. 0.4 g (0.15 M) of ampicillin 3
Add hydrate.

The mixture is stirred for 20 hours under rapid stirring for 20 hours.
Hold at 25 ° C. After that, 46.1g (0.234M)
Α-bromodiethyl carbonate, 6 g (0.02
M) tetrabutylammonium bromide and 100
Add ml N, N-dimethylacetamide.

It is further heated under stirring at 40 ° -42 ° C. for 10 hours and the reaction mass is brought to 1200 ml of water and 400 ml of n-.
Pour into a mixture consisting of butyl acetate.

The aqueous phase was collected and another 100 ml of n-
Extract with butyl acetate.

The combined organic phases are washed twice with 100 ml of water each time. 150 ml of 1N HCl and 370 ml of water are added to this organic phase, which is stirred. This is 22 ℃ -23 ℃
Leave to stir for 4 hours.

The aqueous phase is collected and the organic phase is taken up with 100 ml of water.
Extract with.

The recombined aqueous phases are brought to pH 4 with a 10% Na ₂ CO ₃ aqueous solution, then bleaching charcoal is added to this and filtered.

300 ml of n-butyl acetate and 8
0 g sodium chloride is added to this aqueous filtrate.

The organic phase is separated and the aqueous phase is extracted with 200 ml of n-butyl acetate.

The phases in the recombined n-butyl acetate are concentrated at low pressure at 40 ° C. to a volume of about 300 ml. The product is left to crystallize at + 5 ° C. for 15 hours.

It was filtered and n-butyl acetate (1
Wash with 00 ml) and ethyl acetate (100 ml). This is vacuum dried at 40 ° C. for 24 hours. 6- (D (-)-α
-Amino-α-phenylacetamido) penicillanic acid 1
-Ethoxycarbonyloxyethyl ester yield 5
4.2 g (72%). mp. 160-2 ° C (decomposition) and properties consistent with a standard hydrochloride salt sample.

Reference Example 3 160 ml of acetone, 22.6 g (0.075 mol) of D
(-)-N-Ethoxycarbonylpropen-2-yl-
Aminophenylacetic acid potassium salt, a mixture of 6.9 ml (0.088 mol) of ethyl chloroformate and 3 drops of N-methylmorpholine was added at a temperature of -20 ° to -30 ° C at 15 ° C.
Stir for a minute. To this reaction mixture is added at once a solution of 16.2 g of 6-aminopenicillanic acid dissolved in 35 ml of water by the gentle addition of 7.6 g (0.075 mol) of triethylamine with stirring. Thereafter, the mixture is diluted with 90 ml acetone and cooled to -20 ° C.

After stirring for 45 minutes without further cooling, 23.4 g (0.117 mol) of α-bromodiethyl carbonate, 3 g (0.01 mol) of tetrabutylammonium bromide and 250 ml of N, N- Dimethylformamide is added in this order. This mixture at 25 ° C
Stir for 18 hours. Then the reaction is poured into a mixture consisting of 600 ml of water and 200 ml of n-butyl acetate and it is stirred until a complete solution is obtained. The aqueous phase is collected and extracted with another 50 ml of n-butyl acetate.

The combined organic phases are washed twice with 50 ml of water each time. 185 ml of water are added to this organic phase and 1N HC
1 is added dropwise with stirring to a pH of 1.9. The mixture is left under stirring at 22-23 ° C. for 4 hours.

The aqueous phase is collected and the organic phase is extracted with 50 ml of water. The recombined aqueous phases were washed with 10% aqueous Na ₂ CO ₃
The solution is brought to pH 4, activated charcoal is added and it is filtered. 150 ml n-butyl acetate and 40 g sodium chloride are added to this aqueous filtrate.

The organic phase is separated and the aqueous phase is extracted with 100 ml of n-butyl acetate. The phases in the recombined butyl acetate are concentrated at low pressure at 40 ° C. to a volume of about 150 ml. The product is left to crystallize at + 5 ° C. for 15 hours.

This was filtered, and n-butyl acetate (2
Wash with 5 ml) and ethyl acetate (25 ml). This is 10
Dry under mmHg vacuum for 24 hours at 25 ° C.

Yield of 6- (D (-)-α-amino-α-phenylacetamido) penicillanic acid 1-ethoxycarbonyloxyethyl ester hydrochloride 1.17 g, mp. 1
59-161 ° C. This product has characteristics that match the standard (NM
R, TLC).

Reference Example 4 The method of Reference Example 4 was repeated except that 6-aminopenicillanic acid was dissolved in 20 ml of water instead of 35 ml of water.
Yield of 6- (D (-)-α-amino-α-phenylacetamidopenicillanic acid 1-ethoxycarbonyloxyethyl ester hydrochloride (white crystalline powder) 1.05 g.m.
p. 148-151 ° C (decomposition). It has properties (TLC, IR) that match the standard sample.

REFERENCE EXAMPLE 5 6.25 g (0.045 mol) of finely divided anhydrous potassium carbonate are suspended in 50 ml of dimethylsulfoxide and 8.
1 ml (0.075 mol) of methyl acetoacetate and 15.1 g (0.0375 mol) of ampicillin trihydrate were added.

The mixture is stirred rapidly and maintained at 20-25 ° C. for 5 hours, after which 11.5 g (0.059 mol) of bromodiethyl carbonate and 25 ml of dimethylsulfoxide are added.

It is stirred and heated at 35 to 37 ° C. for 17 hours and the reaction 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 combined organic phases are washed twice with 25 ml of water each time.

92.5 ml water and NH at pH 1.9
₄ Cl (7.0 ml) is added to the organic phase and stirred. It is left under stirring at 22-23 ° C. for 2.5 hours.

The aqueous phase is collected and the organic phase is extracted with 25 ml of water.

The combined aqueous phases are brought to pH 4 with a 10% aqueous solution of Na ₂ CO ₃ and then activated charcoal is added to it and filtered.

75 ml of n-butyl acetate and 37
g sodium chloride is added to the aqueous filtrate.

The organic phase is separated and the aqueous phase is treated with 50 ml of n
-Extract with butyl acetate.

The phases in the recombined n-butyl acetate are concentrated at low pressure at 40 ° C. to a volume of about 75 ml. The product is crystallized at + 5 ° C. for 15 hours.

It is filtered and washed with n-butyl acetate (25 ml) and ethyl acetate (25 ml). It is vacuum dried at 40 ° C. for 3 hours.

Yield of 1-ethoxycarbonyloxyethyl ester of 6- (D-(-)-α-amino-α-phenylacetamido) penicillanic acid 1.9 g (10%). m.
p. 160-162 ° C. A standard sample of hydrochloride (eg I
R: ν 1790 cm ^-1 , β-lactam carbonyl).

Reference Example 6 Benzylpenicillin ethoxycarbonyloxyethyl ester Penicillin G potassium (7.4 g, 20 mmol), ethyl α-chloro-ethyl carbonate (4.6 g, 30 g)
Mmol), tetra-n-butylammonium bromide (0.8 g, 2.5 mmol) and acetone (80 ml).
The mixture was heated under stirring with gentle reflux for 4 hours. Excess acetone was partially removed under vacuum and the residue was triturated with ice cold water and methyl isobutyl ketone. Evaporation of dry methyl isobutyl ketone under vacuum gave a semi-crystalline oil (3.8 g). This was triturated with ethanol leaving white crystals (0.9 g) of α- (ethoxycarbonyloxy) ethyl ester of penicillin G having a purity of 98-99% by HPLC.

Found: C 43.0 H 7.4 N 7.7% Calculated: C 43.4 H 7.4 N 8.0%

Reference Example 7 Benzylpenicillin ethoxycarbonyloxyethyl ester The above experiment of Reference Example 6 was repeated except that α-bromodiethyl carbonate (5.9
g, 30 mmol). Evaporation of methyl isobutyl ketone gave 6.0 g of semi-crystalline oil. The oil was triturated with warm ethanol then cooled to give white crystals of the α- (ethoxycarbonyloxy) -ethyl ester of penicillin G (2.5 g, 35
% Yield).

Reference Example 8 Benzylpenicillin ethoxycarbonyloxyethyl ester Benzylpenicillic acid potassium salt (25.08 g, 66.7)
Mmol), sodium bicarbonate (0.50 g, 6.0 mmol) and tetrabutylammonium bromide (2.
15 g, 6.67 mmol of methylene chloride (41 m)
Carefully stirred in 1) and warmed to 40 ° C. Once this temperature was reached, α-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 mineral acid to bring the pH to about 5. About 4 parts of this mixture
Stir for a period of time, during which time sodium hydroxide (4%) was added to maintain the pH at 2.5-3.0. Then methylene chloride (50 ml) was added and the mixture was allowed to separate for a few minutes. The organic phase was washed with water (65 ml) then evaporated under reduced pressure. The oil thus obtained was dissolved in methylene chloride (100 ml) and evaporated again. The remaining oil was dissolved in methylene chloride to a total volume of 100 ml.

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

Reference Example 9 Benzylpenicillin ethoxycarbonyloxyethyl ester Potassium benzylpenicillate (5.02 g, 13.3 mmol) and potassium bicarbonate (2.99 g, 38.3) in dimethyl sulfoxide (13.5 ml). (Mmol) was carefully stirred in an ice bath. Α-Bromodiethyl carbonate (3.70 g, 18.6 mmol) was added over 30-40 minutes using a syringe pump. The reaction mixture was kept in an ice bath while stirring was continued. HPLC analysis showed that about 70% yield of benzylpenicillin ethoxycarbonyloxyethyl ester was obtained within 5-10 minutes.

Reference Example 10 Benzylpenicillin ethoxycarbonyloxyethyl ester Benzylpenicillic acid potassium salt (47.03 g, 125
Mmol), sodium bicarbonate (0.94 g, 11 mmol) and tetrabutylammonium bromide (2.
Acetone (77 m) carefully with 01 g, 6.25 mmol
l) stirred in and warmed to 40 ° C. When this temperature was reached, α-bromodiethyl carbonate (26.
06 g, 131 mmol) was added and the slurry was stirred for 4.5 hours. Water (56 ml) was added, followed by mineral acid to bring the pH to about 5. The mixture was stirred for about 3 hours, during which time sodium hydroxide (4%) was added to keep the pH at 4.5-4.8. Butyl acetate (100 ml) was then added and the mixture 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 this methylene chloride solution showed a benzylpenicillin ethoxycarbonyloxyethyl ester yield of 98-99%.

Reference Example 11 36.4 g (0.075 M) of potassium N- (1-methoxycarbonyl-propen-2-yl) -6- (D (-))
17.-α-Amino-α-phenylacetamido) penicylate in 150 ml of N, N-dimethylformamide.
Add to a solution of 8 g (0.116 M) α-chlorodiethyl carbonate and 3 g (0.01 M) tetrabutylammonium bromide. The temperature is raised to 45 ° C under stirring and kept at 45 ° C to 50 ° C for 5 hours.

Upon completion of heating, the reaction mixture is poured into a mixture containing 300 ml of 14% aqueous sodium chloride solution and 600 ml of n-butyl acetate. The mixture is stirred for 10 minutes, then the organic phase is separated and the aqueous phase is extracted with 100 ml of n-butyl acetate. The recombined organic phases are washed twice with 75 ml of 14% aqueous sodium chloride solution and then concentrated at low pressure until an oil is obtained.

This oil is mixed with 200 ml of tetrahydrofuran and 100 ml of water. The resulting solution (pH 4.8) is brought to pH 1.5 by adding a total of 12 ml of 6N HCl in 1 hour with stirring.

After leaving this solution at room temperature for another hour,
Tetrahydrofuran was removed at low pressure at 40 ° C, 1
50 ml of n-butyl acetate was added to this residual aqueous phase (15
0 ml) and then 15 g of sodium chloride.

The organic phase is separated off and 100 ml of the aqueous phase
Of n-butyl acetate.

The recombined organic phases are concentrated under vacuum at 40 ° C. to a volume of 120 ml.

The product is crystallized at 5 ° C. for 15 hours.

It is then filtered and washed with n-butyl acetate (50 ml) and ethyl acetate (50 ml).

It is vacuum dried at 40 ° C.

25.2 g (66.9%) of 6- (D-
(−)-Α-Amino-α-phenylacetamido) penicillanic acid 1-ethoxycarbonyloxyethyl ester hydrochloride (mp. 160-2 ° C.) is obtained. The analytical measurement results are as follows.

Titer 97.82% Optical rotation + 166.3 ° (c = 1, EtOH 95 °) pH 4.05 (2% aqueous solution) Water content 0.82% Remaining solvent ethyl acetate 0.45%, n -Butylacetate 0.98% IR and NMR spectra conforming to standard 0.06% residual penicillin.

Reference Example 12 16.2 ml (0.15 m) of methyl acetoacetate and 30.2 g (0.075 M) of ampicillin trihydrate were finely powdered anhydrous in 100 ml of N, N-dimethylformamide. 12.54 g of potassium carbonate (0.0907
M) to the suspension.

This is maintained for 3 hours with stirring at 22 ° C. to 23 ° C. After this time a considerable overall fluidization can be observed.

17.8 g (0.117 M) of α-chlorodiethyl carbonate, 3 g (0.01 M) of tetrabutylammonium bromide and 50 ml of N, N-dimethylformamide are added here in this order.

The mixture is stirred and heated at 45 ° C. to 50 ° C. for 5 hours and then left at + 5 ° C. for 15 hours.

This reaction was mixed with 600 ml of water and 200 ml.
Of n-butyl acetate and stirred until a complete solution is obtained, the aqueous phase is collected and extracted with another 50 ml of n-butyl acetate.

The recombined organic phases are washed twice with 50 ml of water each time. 75 ml 1N HCl and 185 ml water are added to this organic phase and stirred. It is left stirring at 22 ° C-23 ° C for 4 hours.

The aqueous phase is collected and the organic phase is extracted with 50 ml of water. The recombined aqueous phases are brought to pH 4 with a 10% aqueous solution of Na ₂ CO ₃ , then bleaching charcoal is added to it and it is filtered.

150 ml of n-butyl acetate and 4
0 g sodium chloride is added to this aqueous filtrate.

The organic phase is separated and the aqueous phase is treated with 100 ml.
Of n-butyl acetate.

The phases in the recombined butyl acetate are combined under low pressure.
Concentrate to about 150 ml volume at 0 ° C.

The product is left to crystallize for 15 hours at + 5 ° C.

This was filtered, and n-butyl acetate (5
Wash with 0 ml) and ethyl acetate (50 ml).

This was allowed to stand at 25 ° C. for 24 hours in the presence of water to 1
Dry under vacuum of 0 mm Hg.

Yield of 6- (D-(-)-α-amino-α-phenylacetamido) penicillanic acid 1-ethoxycarbonyloxyethyl ester hydrochloride 20.8 g (55
%), Mp. 159-161 ° C. It has characteristics that match the standard sample.

Reference Example 13 The esterification of ampicillin Dane salt (ampicillin protected at the amino group with a 1-methoxycarbonyl-propen-2-yl group) with ethyl acetoacetate was carried out by the method of Reference Example 12 above. The results are as follows. Yield of white crystalline product 16.1 g. m.
p. 144-148 ° C. IR / TLC conforms to standard sample. KF 0.35%, pH 3.55 (2% aqueous solution). Purity 95.2%. Total residual solvent 3.5%.

Alternatively, the addition of chlorodiethyl carbonate was done in two steps. Immediately add 9g in the first stage,
After 2 hours in the second stage another 9 g was added. Heated at 45 ° C. for 3 hours. The results were as follows. Yield 13.7 g of a brown crystalline product. mp. 143-146 ° C. IR
/ TLC conforms to standard sample. KF. 0.2%, pH 3.4
3 (2% aqueous solution). Purity 94.8%. Residual solvent 2.6%.

 ─────────────────────────────────────────────────── ─── Continuation of front page (31) Priority claim number 8300331 (32) Priority date January 7, 1983 (33) Priority claim country United Kingdom (GB) (72) Inventor Robert Graham Tyson United Kingdom Press Tate Inn Clyde. Aber Conway Drive 15 (56) References JP-A-49-24988 (JP, A) JP-A-49-289 (JP, A)

Claims (1)

[Claims] (1) Formula (1) Compound of.