TECHNICAL FIELD

This invention relates to a process for preparing acyl derivatives of compounds having hydroxy, amino, thiol or other reactive functional groups. BACKGROUND ART

Acyl derivatives of organic compounds are often produced by reacting the organic compounds with acyl halides, usually acyl chlorides. The chemical principles of such processes are based on the Schotten-Baumann reaction (see C. Sσhotten, Ber. 17, 2544, 1884; and E. Bau ann, Ber. 19, 3218, 1886), which involves the acylation of alcohols with acyl halides in aqueous alkaline solutions as represented by the following chemical equation:

acyl chloride + R-OH (alcohol) → acyl alcohol + HCl

The reaction takes place in aqueous alkaline conditions, usually in the presence of sodium hydroxide, in order to neutralize the hydrochloric acid released during the reaction.

The disadvantage of the conventional process is that the aqueous reaction conditions normally produce very low yields of the desired acyl derivative due to fast hydrolysis of the acyl chloride in the aqueous alkaline solution. The reactions which take place in the aqueous conditions are generally unpredictable and the by-products which are formed (their number and concentration depending on the acylatable substrate) also create serious problems during the isolation of the pure product. For example, the undesired reactions often lead to the formation of unwanted organic acid salts (such as fatty acid salts, i.e. soaps) which make the isolation and purification of the desired product very difficult.

An object of the present invention is thus to provide a process for the acylation of acylatable substrates which

can result in higher yields of the desired acylated product. Another object of the present invention is to provide a process for the acylation of acylatable substrates which produces a reaction mixture from which it is relatively easy to extract the desired acylated product. DISCLOSURE OF THE INVENTION

According to one aspect of the present invention there is provided a process for acylating an acylatable substrate with an acyl halide, which comprises: contacting a first liquid phase containing at least some of said acylatable substrate with a second non-aqueous liquid phase containing said acyl halide, said phases being at least partially immiscible with each other to form a multi-phase reaction system, maintaining said contact of said phases in alkaline conditions for a period of time sufficient to result in the formation of a desired acylated product, and separating said desired acylated product from the reaction mixture.

The invention also relates to the acylated products formed by the process of the invention. By the term "contacting" liquid phases as used herein, we mean bringing the phases together to form two continuous phases having an interface, either quiescently or with agitation, or mixing the phases so that one or more of the phases becomes discontinuous. By the term "acylatable substrate" as used herein we mean a compound that is capable of undergoing acylation in the reaction conditions. Such compounds are normally organic compounds containing -OH, -NH ₂ , -SH or other reactive functional groups. Examples of substrates which can be acylated according to the present invention include glycine, lysine, valine, cystein, cystin, p-aminobenzoic acid, p- aminosalicylic acid, anthranilic acid, aniline, aminobenzophenone, diethylamine, triethylamine, etc. and various peptides and proteins. These materials are generally at least partially soluble in aqueous solvents or other suitable solvents.

The acyl halides employed in the present invention are preferably acyl chlorides, but other halides may be used if

desired. Representative acyl halides include decanoyl chloride, lauroyl chloride, myristoyl chloride, palmitoyl chloride, stearoyl chloride, benzoyl chloride and cinnamoyl chloride. These reactants are generally liquid at room temperature but a few (e.g. cinnamoyl chloride) are solid. In any event non-aqueous solvents for these reactants can be found without difficulty.

The process of the present invention, at least in the preferred forms, is an improvement of the conventional process in that it avoids most of the uncontrollable conditions of the conventional procedure and increases the final yield, usually dramatically (e.g. in the range of 77 to 96% of theoretical) , while also reducing to a minimum the formation of unwanted by-products and enabling the purification procedure to be carried out more easily.

Furthermore, the use of a multi-phase system not only helps to prevent hydrolysis and decomposition of the acyl halide, but also improves the possibilities for scale-up of the system. BEST MODES FOR CARRYING OUT THE INVENTION

The present invention relies on the separation of the acyl halide and the acylatable substrate into two at least partially immiscible liquid phases which are brought into contact with eachother. The acyl halide or the acylatable substrate, or possibly both, gradually partition between the two phases so that the reactants come into contact with each other at a controlled rate. The phase which initially contains the acyl halide is non-aqueous so that the halide does not hydrolyse while it remains in this phase. Non- polar organic solvents, e.g. ether, petroleum ether, chloroform, etc. are normally employed for this phase. The phase which initially contains the acylatable substrate is generally polar and is, most commonly, aqueous. Even when the phase containing the acylatable substrate is aqueous, which it normally is, the acyl halide reacts quickly with the acylatable substrate as it enters the aqueous phase and so does not have time to hydrolyse to a significant extent. Alkaline conditions are required for the reaction to take

place, so one of the liquid phases (normally the one containing the acylatable substrate) should be alkaline, e.g. as a result of containing a dissolved alkali metal hydroxide such as sodium hydroxide. As noted above the liquid phases should be at least partially immiscible. By the term "immiscible" we mean mutually insoluble rather than incapable of being mixed under any circumstances. For example, the liquid phases are usually capable of being mixed to form an emulsion or the like which generally separates into two continuous liquid phases when quiescent. The liquid phases employed in the present invention should be sufficiently immiscible that distinct phases (continuous or discontinuous) do appear in the reaction conditions. In some circumstances, it is desirable to use liquids that are completely immiscible. However, in other cases, the liquids may be sufficiently miscible that the liquid phases do dissolve partially in eachother. It is possible to use the degree of miscibility of partially mutually soluble non-aqueous and aqueous phases to control the kinetics of the reaction, hydrolysis of the acyl halide or decomposition of the acylatable substrate.

This depends on the properties of the reactants and can be determined by experimentation with different liquid pairs.

The at least partially immiscible phases are generally thoroughly agitated together during the reaction so that contact of the reactants is facilitated. This can be achieved, for example, by rapidly stirring the liquid phases together in a suitable reaction vessel.

The liquid phases employed in the present invention should be of such a nature that they provide the required degree of immiscibility, permit the desired acylation reaction to take place without significant hydrolysis of the acyl halide starting material, and prevent unwanted modification of reactive groups (e.g. by oxidation) as well as contribute to the efficiency of the reaction and higher yield (e.g. by increasing the reaction surface) . A combination of an aqueous and a non-aqueous solvent is normally employed for the liquid phases if the acylatable

substrate is readily soluble in aqueous solvents, e.g. in aqueous alkaline solution usually having a pH in the range of pH 8 to pH 12. The non-aqueous solvent, the carrier of the acyl halide (e.g. acyl chloride) , then controls the rate of the reaction as well as the potential number of by¬ products or impurities. The combination of aqueous and non- aqueous solvents creates the necessary conditions for the gradual release of the acyl halide into the polar phase for reaction with the acylatable substrate. The ratio of the aqeous solvent (e.g. water) and the non-aqueous solvent (e.g. ethyl ether) required for the reaction will depend on the mutual solubility or miscibility of the two solvents. The usual ratio of the two immiscible liquid phases is from 1:2 to 2:1 by volume when water and diethylether are employed, with the ratio normally being around 1:1 by volume.

While the present invention requires the presence of two liquid phases that are immiscible or only partially miscible, other phases containing a portion of one or other of the reactants may also be present. For example, if the amount of acylatable substrate exceeds that required to produce a saturated solution in one of the liquid phases, the excess may remain as a solid in contact with the saturated solution. A typical system employing a solid phase employs an excess of a solid acylatable substrate incompletely soluble in the aqueous liquid. In this case, the acylatable compound will be present in two forms, namely a soluble form in (possibly saturated) solution and the excess solid. The material in solution is the reactive form and, as it reacts, the solid excess gradually dissolves. This can be used for automatic regulation of the supply of the acylatable substrate to the reaction zone. In such cases, the reaction system consists of liquid/solid/liquid phases, at least at the start of the reaction procedure. In yet other cases, additional liquid phases may be present or the system may include gaseous phases. For example, in some cases, protection of functional groups

(e.g. -SH) against oxidation may be required during the

process. In such cases, an inert gas can be used to remove oxygen from the reaction mixture and prevent oxidation and by-product formation during the reaction, e.g. the gas can be bubbled through the liquid phase(s) . In other cases, oxidation may be desired, in which case air, oxygen or an oxidizing gas may be bubbled through the liquids, thus forming a gaseous phase of the reaction system. The use of such reactive or protective gases can lead to yield and process improvements in the multi-phase process of the invention. When gases are employed, the system may comprise for example liquid\liquid\gas, liquid\solid\liquid\gas or liquid\liquid\liquid\gas, etc. combinations.

The quantities of the acyl halide and the acylatable substrate required for the multi-phase reaction of the present invention are generally the same as those required for the conventional single phase reaction. Generally, stoichiometrical proportions are suitable, but an excess of the acyl halide may be employed, if desired.

The temperatures required for the reaction to take place depend to some extent on the particular reactants employed. Generally, however, the reactions proceed with good yield at room temperature, i.e. 21+1°C. If desired, temperatures higher than room temperature may be employed, but tend to be limited by lower yields and by the boiling points of the solvents employed. In some cases, temperatures between 0°C and 5°C are critical for high yields when the starting materials are sensitive to temperature.

The reaction is normally carried out by separately dissolving the acylatable substrate in one of the liquid phases and the acyl halide in the other liquid phase, and then gradually adding one of the phases (usually the acyl halide solution) to the other with stirring. After the addition is complete, the stirring is normally continued for a period of time until the reaction is essentially complete. The period of addition usually requires between 30 minutes and 2 hours (depending on the type of mechanical stirring, volumes to be mixed, etc.) and the subsequent reaction

period normally last for 3 to 6 hours depending on the reaction conditions.

If it is necessary to speed up the reaction, this can often be done by adding an inert solid phase, e.g. a non- reactive microparticulate powder, in order to increase the area of active surface. ' The particle size of the solid phase may have an effect on the reaction performance, with smaller particles being more effective, although possibly more troublesome because of the resulting difficulty of removing the solid from the reaction mixture when the reaction is complete. The solid materials employed in this connection are generally non-reactive with the acylatable substrate, the acyl halide, as well as the other phases, and silica powder is an example of a suitable inert solid for use in this connection. The solid phase can normally be added to either one of the liquid phases, but often the addition is to the liquid phase containing the acylatable substrate. Such additions have the potential of greatly improving the efficiency of the multiphase reactions as well as the yields of the products. Reactive or partially reactive solid phases may be used in special circumstances (e.g. for the prevention of the adverse effect of the strong alkaline condition) .

Once the reaction is complete, the acylated product can be separated from the reaction mixture by conventional techniques. Most preferably, the reaction mixture is acidified, which causes the product to precipitate, following- which it call be filtered, washed and, if necessary, purified further. The invention is - illustrated in further detail with reference to the following non-limiting Examples. EXAMPLE 1 : PREPARATION OF LAUROYL GLYCINE

The aminoacid glycine was dissolved in an aqueous solution of sodium carbonate and sodium hydroxide (sodium carbonate:sodium hydroxide = 2:1 by volume) . The solution was then overlaid with diethylether, which is a non-polar solvent having a density (0.71) lower than that of water. A solution of lauroyl chloride was prepared in anhydrous

diethylether and the solution was added dropwise to the two phase mixture while stirring. The diethylether formed a layer on top of the aqueous solution and, when stirred, created a two phase emulsion (water/ether) , therefore allowing the lauroyl chloride dissolved in the diethylether to gradually engage in the reaction with the glycine dissolved in the water portion of the emulsion.

After adding the whole calculated amount of the lauroyl chloride, the reaction mixture was stirred until the lauroyl chloride in the diethylether reacted with the remainder of the glycine.

The pH in the reaction mixture was then adjusted to pH 2 to pH 4 using an acid solution (e.g. hydrochloric acid) and the solution was stirred until the pH equilibrated. A precipitate was separated from the solvent phases and washed to remove residues of glycine (water) and lauric acid (organic solvent) . The yield obtained was 62g, which amounted to 96% of the theoretical yield. EXAMPLE 2 : PREPARATION OF BENZOYL ANILINE Aniline was dissolved in petroleum ether and a solution of sodium carbonate in water was added (approximately 1:1 volume ratio) . Benzoyl chloride was dissolved in diethylether and was added dropwise into the stirred mixture of aniline and sodium carbonate. The reaction vessel was cooled to a temperature between 0°C and 5°C. The addition period was 30 minutes and the whole reaction time was approximately 3 hours. After the reaction was finished, the reaction mixture was acidified with hydrochloric acid to pH 2 to pH 4. The precipitate was separated and washed to remove residues of the starting materials aniline and benzoyl chloride. The yield obtained was 19.7g, which amounted to 93% of the theoretical yield.

EXAMPLE 3 : PREPARATION OF 1.10-DI-CINNAMOYL-DIAMINODECANE 1,10-Diaminodecane was dissolved in diethylether. The solution was added to a solution of sodium carbonate and sodium hydroxide (approximately 1:1 volume ratio) in water. Cinnamoyl chloride was dissolved in anhydrous diethylether and added dropwise to the stirred mixture of 1,10-

diaminodecane and sodium carbonate with sodium hydroxide during a 30 minute period. The reaction was performed at room temperature (approximately 21+1°C) . The whole reaction time was 3 hours. The reaction mixture was then acidified with hydrochloric acid to pH 2 to pH 4, stirred and the precipitate separated, washed to remove residues (if any) from the starting unreacted compounds. The yield obtained was 1.95g, which amounted to 78% of the theoretical yield. EXAMPLE 4 : PREPARATION OF MYRISTOYL GLUTAMIC ACID DERIVATIVE

Glutamic acid was dissolved in an aqueous solution of sodium carbonate and sodium hydroxide. Chloroform was added to the solution in the ratio 2:1'by volume. The chloroform being of higher density (d = 1.484) than the aqueous solution of sodium carbonate, formed the bottom layer of the mixture. The solubility of chloroform in water is 1 ml in 200 ml of water. A stoichiometrical amount of yristoyl chloride was dissolved in chloroform and added to the mixture either from the top or to the lower chloroform layer. After adding the whole calculated amount of myristoyl chloride to the mixture, the remainder of the reaction was carried out as in Example 4 and a similar yield of myristoyl-glutamic acid derivative was obtained. INDUSTRIAL APPLICABILITY The invention makes it possible to produce a variety of useful known and novel chemical materials in good yield on an industrial scale. The materials so-produced can then be used in conventional processes and products as are the conventional products of the Schotten-Baumann reaction.