WO2001023341A1

WO2001023341A1 - Processes for the preparation of chemical compounds

Info

Publication number: WO2001023341A1
Application number: PCT/GB2000/003701
Authority: WO
Inventors: Adrian Heseltine; Wei Tian; Julian Michael Cooper
Original assignee: British Sugar Plc
Priority date: 1999-09-28
Filing date: 2000-09-27
Publication date: 2001-04-05
Also published as: GB9922980D0; AU7534800A; GB2354761A

Abstract

The invention provides a process for the preparation of a water-soluble salt of formula (I) wherein: R1 is hydroxy or C1-C4 alkoxy, or R1 and an adjacent R2 together form a methylenedioxy ring; each R2 is independently H, C1-C3 alkyl, C1-C2 alkoxy, OH or carboxymethoxy provided that at least two R2 groups are H; R3 is H or methyl; and Xn+ is a food-acceptable cation wherein n=1,2,3 or 4, said process comprising the steps of: providing an alcoholic solution of a compound of formula (II) wherein R¿4? is OH or a carboxylate protecting group and the solvent for said solution comprises one or more C1 to C6 alcohols; and treating said solution with an alkali salt of X?n+¿ in the presence of at least 0.5 % w/v of water to precipitate said compound of formula (I) from said alcoholic solution. The presence of a small amount of water in the reaction mixture results in a more tractable product of higher yield and purity.

Description

PROCESSES FOR THE PREPARATION OF CHEMICAL COMPOUNDS

The present invention relates to processes for the preparation of certain organic salts that are useful inter alia as sweetness inhibitors. In particular, the present invention relates to processes for the preparation of the soluble salts of 4- methoxybenzoyloxyacetic acid and related compounds.

Sweetness inhibitors are food ingredients that counteract the perceived sweetness of sugars or other sweeteners in foodstuffs. The addition of sweetness inhibitors enables sugars to be used in a wide variety of foods to perform functions other than sweetening, such as to act as fillers, bulking agents, antimicrobial agents, freezing point depressants and the like, without giving rise to unacceptable sweetness. One such sweetness inhibitor is 2-(4-methoxyphenoxy)propanoic acid, which is commercially available under the Registered Trade Marks LACTISOLE and CYPHA from the Tate and Lyle Company.

GB-A-2180534 describes the use of 4-methoxybenzoyloxyacetic acid (hereinafter 4-MBA) and related compounds as sweetness inhibitors. The 4-MBA is effective as a sweetness inhibitor when added at a level of about 0.5 to 2% by weight based on the weight of sugars in the foodstuff. GB-A-2180534 also describes a method of synthesis of 4-MBA. The method comprises reacting 4- methoxybenzoic acid (anisic acid) with benzyl-2-bromoacetate in presence of potassium carbonate in refluxing acetone to produce benzyl (p- methoxybenzoyloxy)acetate. Removal of the protecting benzyl group from the benzyl (p-methoxybenzoyloxyacetate) was accomplished by catalytic hydrogenation using 10% palladium on carbon in 100% ethanol. The product was filtered to remove the catalyst, and the ethanol was removed to obtain 4-MBA as a white crystalline solid. The reference mentions the possibility of using salts of 4- MBA as sweetness inhibitors, but no example is given of the preparation or use of such salts, and 4-MBA and its salts have not hitherto been commercially available for sweetness inhibition. 4-MBA itself is only sparingly soluble in water, which can make it difficult to formulate with crystalline sugars to prepare a low-sweetness particulate, soluble sugar product for use in the food industry. However, certain salts of 4-MBA, such as the sodium, potassium and ammonium salts thereof, are very soluble in water. A need therefore exists for a method of synthesis of such soluble salts of 4-MBA.

The present inventors have found that adding alkali, such as sodium hydroxide, to precipitate the sodium salt of 4-MBA from a solution of 4-MBA in absolute ethanol solution results in an unsatisfactory product. The neutralisation reaction is slow, and it is difficult to control the pH during the neutralisation and achieve a clear end-point in the ethanolic solution. Furthermore, the sodium salt of 4-MBA precipitates as a microcrystalline or gelatinous mass that has poor mobility and filtration properties, and that has unsatisfactory purity.

The present inventors have surprisingly found that the above-identified disadvantages can be overcome without significant reduction in yield by including a small amount of water in the ethanol solvent for the neutralisation step

Accordingly, the present invention provides a process for the preparation of a water-soluble salt of formula (I)

wherein: Ri is hydroxy or C1-C4 alkoxy, or R-i and an adjacent R₂ together form a methylenedioxy ring; each R₂ is independently H, C C₃ alkyl, C C₂ alkoxy, OH or carboxymethoxy provided that at least two R₂ groups are H; R₃ is H or methyl; and Xⁿ⁺ is a food-acceptable cation wherein n=1 ,2,3 or 4, said process comprising the steps of: providing an alcoholic solution of a compound of formula (II)

wherein R₄ is OH or a carboxylate protecting group and the solvent for said solution comprises one or more C₁ to C§ alcohols; and treating said solution with an alkali salt of Xⁿ⁺ in the presence of at least 0.5% w/v of water to precipitate said compound of formula (I) from said alcoholic solution.

Preferably, R1 is alkoxy, and more preferably R₁ is methoxy. Preferably at least three of R₂ are H, and more preferably all of R₂ are H. Preferably at least one of R₃ is H, and more preferably both of R₃ are H. Preferably, the cation Xⁿ⁺ is selected from the group consisting of Na⁺, K⁺, NH₄ ⁺, and mixtures thereof. More preferably, the cation Xⁿ⁺ consists essentially of Na⁺. Most preferably, the compound of formula I is the sodium salt of 4-MBA.

The protecting group R₄ refers to any moiety that permits the compound of Formula II to react with alkali in alcoholic solution under mild conditions to form a carboxylate terminal group. The group R₄ may for example link to the molecule of formula II as part of an ester group, an amide group or an anhydride group. Preferably, the group R₄ is OH or a group OR₅ that links to form an ester linkage. The group R₅ is preferably an alkyl group, an aryl group, or an aralkyl group, each group optionally being substituted. More preferably, R₄ is OH, C1 to C₆ alkoxy or phenyl C-ι-C₆ alkyleneoxy. Most preferably, R₄ is OH.

Preferably, the solvent for the alcoholic solution consists essentially of the one or more C1 to Cβ alcohols and water. Preferably, the one or more C₁ to Cε alcohols are monohydnc alcohols. More preferably they comprise or consist essentially of methanol, ethanol, propanol or isopropanol, and most preferably the alcohol consists essentially of ethanol.

The precipitation step of the present invention is carried out in the presence of at least 0.5% w/v of water (based on the total volume of the reaction mixture). Preferably, high levels of water content are avoided in order to minimise the solubility of the salt in the aqueous alcoholic solvent. Preferably, the reaction mixture comprises from 0.5% to 20% w/v of water, more preferably from 1% to 8% w/v of water, still more preferably from 1.5% to 6% w/v of water, and most preferably from 2% to 5% w/v of water.

The water included in the alcoholic solvent for the neutralisation step is critical to ensure a suitable physical form. Its omission causes a thick, immobile precipitate of the salt to form instead of the fine, easily filtered crystalline precipitate. Typically, the filter cake without water present during neutralisation has a dry substance content of 41%, whereas with the addition of water, the dry substance content increases to 78%. Furthermore, the presence of water is critical to effective pH control during the neutralisation. It has been found that over-neutralisation causes extensive degradation of the final product and produces ethyl anisate as the main product. The better control over the precipitation step in the presence of water also improves the purity of the product, in particular by reducing solvent occlusion.

Finally, it has been found that there is distinct difference in crystal morphology between the product neutralised with and without the presence of water. Typically, in the absence of water, the crystals appear to be needle shaped with a dimension of 100x10x5 micrometers. In contrast, the crystals formed in the presence of water appear to be flake-like with typical dimensions of 100x50x5 micrometers. These flake-like crystalline structures are less likely to form dense aggregates and are therefore more free flowing and should be easier to disperse in water. This will offer advantages in terms of a more uniform distribution of 4- MBA salts when blending with carriers such as sugar or other sweeteners. Accordingly, the present invention further provides a solid compound of formula I having a platelet crystalline morphology. That is to say, the crystals have two major dimensions and one minor dimension. Preferably, the dimensions are in the ratio 1 :0.2-1.0:0.01-0.1 , based on number averages.

The water may be present in the alcoholic solution in which the compound of formula II is dissolved. However, preferably the water is present in a solution of the alkali (the "base solution") that is added to the alcoholic solution of the compound of formula II to precipitate the salt of formula I. The presence of the water in the base solution assists dissolution of the alkali in the base solution, gives a faster precipitation reaction with easier control over pH, and reduces the hydrolysis of the compound of formula II to p-anisic acid and hydroxyacetic acid. Preferably, the base solution comprises at least 2% w/v of water based on the volume of the base solution, more preferably at least 5% w/v of water, and most preferably at least 8% w/v of water.

A number of routes are available to the compound of formula (II). Preferably, the compound of formula (II) is produced by reaction between 4- methoxybenzoic acid and a compound of formula BrCH₂COR₆, wherein the group Re is a protecting group the same as R< as hereinbefore defined, except that the definition of R_& does not include OH. The reaction is carried out in the presence of a base and a suitable solvent under appropriate conditions. Preferred conditions include K₂CO₃ in refluxing acetone, or Cs₂CO₃ in dimethylformamide at room temperature. Reactions of this type are described in detail in GB-A-2180534 and by Tzougraki and Meinhofer in J. Org. Chem., 1977, vol.42, pp. 1286-1290, and also by A.G. Katopodis and S.W. May in Biochem., 1990, vol.29, pp.4541-4548.

In cases where a compound of formula (II) in which R₄ = OH is desired, it is necessary to carry out a further step to remove the protecting group Re and replace it by OH. This further step is preferably achieved by catalytic hydrogenation preferably at temperatures of 0 to 100 °C using a palladium catalyst such as 10% palladium on carbon, hydrogen preferably at 0.1 to 1.0 MPa, and a solvent which is preferably absolute ethanol or methanol. Reactions of this type are described in the above-referenced publications.

Alternatively, removal of a protecting alkoxy group R₆ can be achieved simply by alkali hydrolysis, for example using KOH in ethanol/water (4:1 ) at room temperature to yield a solution of the potassium salt in ethanol/water, followed by work-up to yield the free carboxylic acid, as described by D.J. Ringshaw and H.J. Smith in J. Chem. Soc, 1964, pp. 1559-1562. However, the expected yield for this route is rather low because of competing hydrolysis and transesterification reactions.

Further routes to compounds of formula (II) in which R = OH are described in the following references: H.G. Thomas and S. Kessel in Chem. Ber., 1985, vol. 118, pp. 2777-2788; N.M. Nielsen and H. Bundegaard in J. Pharm. Sci., 1988, vol. 77, pp. 285-298; J.E. Shaw, D.C. Kunerth and J.J. Sherry in Tet. Lett., 1973, vol. 9, pp. 689-692; J.E. Shaw and D.C. Kunerth in J. Org. Chem., 1974, vol. 39, pp. 1968-1970; and Y-H. Kuo and C-J. Shieh in Heterocycles, 1986, vol. 24, pp. 1271-1274.

The concentration of the compound of formula II in the alcoholic solution is preferably in the range 0.05 to 0.6 g/ml, more preferably 0.1 to 0.4 g/ml. It has been found that higher concentrations result in esterification or transesterification of the compound of formula II with the alcoholic solvent to form the corresponding ester. For the same reason, the alcoholic solutions are preferably processed quickly and not allowed to stand for more than 48 hours, preferably not more than 6 hours and most preferably not more than 1 hour.

The neutralisation step of the process according to the present invention is preferably carried out at a temperature of 0 to 100 °C, more preferably 10 to 50 °C and most preferably 15 to 35 ^°C. Preferably the alkali is added over a period of 5 to 100 minutes, preferably 10 to 60 minutes, and most preferably 15 to 30 minutes.

Preferably, the solution is neutralised to pH 4.5 to 8.5, more preferably to pH 6.0 to 8.5. Preferably the pH of the reaction mixture is not allowed to exceed 8.5 in order to minimise hydrolysis and transesterification of the product.

Preferably, the precipitated salt of formula I is separated from the reaction mixture by filtration. Preferably, the filtered solid is washed with cold, pure alcohol and dried. In certain preferred embodiments of the present invention, the salt is then combined with a particulate sugar such as granulated sucrose at a level of 0.05 to 2.0 % w/w based on the weight of the sugar to provide a sugar having reduced sweetness. The step of combining may, for example, be performed by physical dry mixing of particles, or by coating an aqueous solution of the salt onto particles of the sugar, for example by spray coating. Alternatively, a salt of formula I can be co-crystallised with sugar from the aqueous solution of sugar and salt of formula I.

Accordingly, the present invention provides a reduced sweetness sugar product consisting essentially of sugar particles coated with a salt of formula I. Preferably, the sugar is granulated sucrose. Preferably, the compound of formula I is present in an amount of 0.5 to 2.0 % w/w based on the weight of the product.

Specific embodiments of the present invention will now be described further with reference to the following examples.

Example 1

The sodium salt of 4-MBA was prepared as follows. In a first stage, 4- methoxybenzoic acid (p-anisic acid) was reacted with benzyl-2-bromoacetate by reflux in acetone in the presence of a 100% molar excess of potassium carbonate. The potassium carbonate served as an acid scavenger for hydrogen bromide as it was formed. The benzyl function served as a protecting group to prevent dimerisation or oligomerisation of the bromoacetate moiety. The reaction time was about 18 hours. After reaction, the batch was filtered to remove the inorganic salts, the acetone is then distilled off, and the resulting slurry of the product was filtered and washed with 100% ethanol. An overall yield of about 90% was achieved.

The next stage in the process was the removal of the protective benzyl group by selective cleavage of the respective ester function using hydrogen and a palladium on charcoal catalyst. Once the reaction was complete, the catalyst was removed by filtration. No further work-up was carried out prior to the final stage. The typical procedure uses 200 g of the 4-methoxybenzoyloxy acetic acid benzyl ester from the first stage, 800 mis of absolute ethanol solvent, 2.0 g of 10% palladium on activated charcoal, and hydrogen pressurised to 50 psi at 20-25°C. The reaction was very rapid. It was preferred to use relatively dilute ethanol solutions and to process the solutions promptly, in order to minimise derivatisation to the corresponding ethyl ester by reaction with the ethanol solvent. (The water content of the 100% ethanol used throughout this work was determined by Karl Fischer titration at 0.18% w/w).

In the final stage, the process involved neutralisation of the 4-MBA free acid in absolute ethanol with sodium hydroxide to give the sodium salt of 4-MBA. The sodium hydroxide was added as a solution in ethanol (the "base solution") containing a little water. The reaction was monitored using pH measurement. The precipitate was isolated by filtration. A 5% molar excess of sodium hydroxide was used, and the base solvent for the sodium hydroxide contained 8% w/v of water. It was found that the sodium hydroxide readily dissolved in the base solution containing 8% w/v of water. The concentration of the sodium hydroxide in the base solution was approximately 2.8 molar. The concentration of the 4-MBA free acid in the ethanolic solution before addition of the base solution was approximately 0.8 molar.

The base solution was added at 20-25° to the ethanolic solution from stage 2 while monitoring the pH continuously with an electrode. Over-neutralisation must be avoided since this results in cleavage of the benzoyl ester. Therefore, neutralisation was stopped when the pH reached 8.5 ± 0.3. The total duration of the neutralisation was about 30 minutes. When the pH was steady in this range, the reaction mixture containing the precipitated salt was cooled below 10°C and filtered under vacuum and washed with ethanol chilled below 10°C. The resulting white powder from the vacuum filter and drier was dried at 40-45°C. The yield is nearly quantitative.

The product had a purity of over 99% as determined by HPLC. Titration showed that the product contained no more than 3% of non-neutralised 4-MBA (HPLC cannot distinguish between the acid and salt forms of 4-MBA). Other impurities were ethanol (max 1%), acetone (max 100ppm) and toluene (max 5 ppm). The product comprised mainly platelet-like crystals of typical dimensions 100x50x5 micrometers.

Example 2

The above neutralisation step was repeated with a 4.8% w/w in the base solution and with 2.4% w/w water in the base solution. It was found that reducing the amount of water in the base solution meant that it took longer to dissolve the sodium hydroxide in the solution. However, at all water contents, it was found that the presence of water maintains the mobility of the 4-MBA sodium salt precipitate, speeds up filtration, improves pH control, and gives a more free-flowing product.

Example 3 (comparative)

The above neutralisation step was carried out in the absence of any added water in the ethanolic or base solutions. It was found that the sodium hydroxide took a longer time to dissolve in the base solution. When the base solution was added over 50 minutes to the ethanolic solution, significant thickening occurred when a buffering point of pH 7.5 was reached. Adjusting to pH was extremely difficult, and the precipitate had a very fine consistency. The overall yield on filtration was only 94.4%.

When the base solution was added quickly, over 27 minutes, the resulting precipitate was an immobile mass. Filtration was slow, and gave a very fine almost waxy solid which appeared to retain a larger proportion of solvent. The yield of material was only 86.9%.

The above embodiments have been described by way of example only. Many other embodiments falling within the scope of the accompanying claims will be apparent to the skilled reader. In particular, it will be apparent to the skilled reader that the salts obtained by the processes of the present invention may have other uses in addition to their use as sweetness inhibitors.

Claims

A process for the preparation of a water-soluble salt of formula (I)

wherein: Ri is hydroxy or C1-C4 alkoxy, or R-i and an adjacent R₂ together form a methylenedioxy ring; each R₂ is independently H, C1-C₃ alkyl, d-C₂ alkoxy, OH or carboxymethoxy provided that at least two R₂ groups are H; R₃ is H or methyl; and Xⁿ⁺ is a food-acceptable cation wherein n=1 ,2,3 or 4,, said process comprising the steps of: providing an alcoholic solution of a compound of formula (II)

wherein R₄ is OH or a carboxylate protecting group and the solvent for said solution comprises one or more C₁ to Cβ alcohols; and treating said solution with an alkali salt of Xⁿ⁺ in the presence of at least 0.5% w/v of water to precipitate said compound of formula (I) from said alcoholic solution.

2. A process according to claim 1 , wherein Ri is C₁ to C₄ alkoxy.

3. A process according to claim 1 or 2, wherein all of R₂ are H.

4. A process according to claim 1 , 2 or 3, wherein R^ is methoxy, all of R₂ are H, and all of R₃ are H.

5. A process according to any preceding claim , wherein Xⁿ⁺ comprises Na\ K⁺ or NH₄ ⁺.

6. A process according to claim 5, wherein Xⁿ⁺ consists essentially of Na⁺.

7. A process according to any preceding claim, wherein R₄ is OH, optionally substituted C-i to C₆ alkoxy, or optionally substituted phenyl Ci to Cβ alkyleneoxy.

8. A process according to claim 7, wherein R₄ is OH.

9. A process according to any preceding claim, wherein the solvent for said alcoholic solution consists essentially of said one or more Ci to C_& alcohols and water.

10. A process according to any preceding claim, wherein said one or more Ci to C₆ alcohols consist essentially of ethanol, methanol, isopropanol, propanol or mixtures thereof.

11. A process according to any preceding claim, wherein the concentration of the compound of formula II in the alcoholic solution is in the range 0.05 to 0.6 g/ml.

12. A process according to claim 11 , wherein the concentration of the compound of formula II in the alcoholic solution is in the range 0.1 to 0.4 g/ml.

13. A process according to any preceding claim, wherein said water is present in an amount of 0.5% to 20% w/v, based on the volume of the reaction mixture.

14. A process according to claim 13, wherein said water is present in an amount of 1.0% to 5% w/v, based on the volume of the reaction mixture.

15. A process according to any preceding claim, wherein said alkali is dissolved in an alcoholic solvent to provide a base solution that is then added to the alcoholic solution of compound of formula II.

16. A process according to claim 15, wherein said base solution comprises from 2% to 20% w/v of water.

17. A process according to claim 16, wherein said base solution comprises from 4% to 10% w/v of water.

18. A process according to any preceding claim, wherein said alkali is selected from the group consisting of hydroxides, carbonates and hydrogen carbonates of X^π+ and mixtures thereof.

19. A process according to any preceding claim, wherein said step of providing an alcoholic solution of the compound of formula II comprises reacting 4- methoxybenzoic acid with a compound of formula BrCH₂COR, provided that R is not OH, in the presence of a base, to form a compound of formula II.

20. A process according to claim 19, further comprising the step of reacting the compound of formula II with hydrogen over a catalyst to cleave the protecting group R and provide a compound of formula II in which R is OH.

21. A process according to any preceding claim, wherein R is OH and said alkali is added with monitoring of pH until a final pH of from 4.5 to 8.5 is reached.

22. A process according to any preceding claim, further comprising the step of providing the compound of formula I dispersed in or on a particulate sugar substrate by co-crystallising the compound of formula I with a sugar, or by dispersing a compound of formula I on a particulate sugar substrate, or by dry mixing.

23. A solid compound of formula I having a platelet crystalline morphology.

24. A reduced sweetness sugar product consisting essentially of particulate sugar having a compound of formula I dispersed thereon.

25. A reduced sweetness sugar product according to claim 24, wherein the particulate sugar is granulated sucrose.