WO2009127446A1

WO2009127446A1 - METHOD FOR THE PREPARATION OF D-p-HYDROXYPHENYLGLYCINE

Info

Publication number: WO2009127446A1
Application number: PCT/EP2009/003009
Authority: WO
Inventors: Wilhelmus Hubertus Joseph Boesten; Anne Marie Welten-Schoevaars; Antonio Pallares Bayo; Ramón LOPEZ SANCHEZ
Original assignee: Deretil, S.A.
Priority date: 2008-04-17
Filing date: 2009-04-15
Publication date: 2009-10-22

Abstract

Method for the preparation of p-hydroxyphenylglycine enriched with the D- enantiomer (D-HPG), using an asymmetric transformation of a (racemic) mixture of the enantiomers of p-hydroxyphenylglycine (HPG) with the aid of D-bromocamphorsulphonic acid (D-BrCas) in the presence of a racemization agent, where a solid diastereomeric salt of D-HPG and D-BrCas is formed, and the asymmetric transformation is carried out in an aqueous medium and in the presence of inorganic salts. In a specially preferred embodiment, HPG is first prepared from glyoxylic acid, phenol and an amino group donor, and the resulting reaction mixture, which contains HPG and the inorganic salts, is then used in the asymmetric transformation as such. D-HPG is preferably added to the reaction mixture obtained in the asymmetric transformation.

Description

METHOD FOR THE PREPARATION OF D-p-HYDROXYPHENYLGLYCINE

The present invention relates to a method for the preparation of p- hydroxphenylglycine that is enriched with the D-enantiomer (D-HPG), using the asymmetric transformation of a mixture of the enantiomers of p-hydroxyphenylglycine (HPG) with the aid of D-S-bromocamphor-δ-sulphonic acid (D-BrCas) in the presence of a racemisation agent, the method leading to a solid diastereomeric salt of D-HPG and D- BrCas. Such a method is already known from EP-A-499376. A disadvantage of the known method is that it is carried out in an organic acid, such as for example acetic acid, as the solvent. The use of organic solvents is undesirable from the environmental point of view as well.

The invention aims at an asymmetric transformation in an aqueous medium. However, when the known method is conducted in an aqueous medium, it leads to large losses in the diastereomeric salt and therefore both in the product and in the (expensive) resolving agent, because the diastereomeric salt of D-HPG and D-BrCas is very soluble. This method is therefore economically unattractive. Furthermore, EP-A-499376 describes and demonstrates that the presence of water leads to a considerable reduction of the diastereomeric excess (d.e.); the presence of 0.1 wt-% of water reduces the d.e. from 99% to 88% in comparison with 0.001 wt-%. The invention provides an economically attractive asymmetric transformation of HPG with the aid of D-BrCas in an aqueous medium.

This is achieved according to the invention by conducting the asymmetric transformation in an aqueous medium in the presence of one or more salts. The fact is that it has been found that this drastically reduces the residual solubility of the diastereomeric salt of D-HPG and D-BrCas, so that a higher overall yield is obtained. A further advantage is that the method can be carried out in a highly concentrated system, so that a high production capacity is obtained. Asymmetric transformations are described for example in "Enantiomers,

Racemates and Resolutions" by Jean Jacques, Andre Collet and Samuel Wilen, published by John Wiley and Sons, New York in 1981. An asymmetric transformation is essentially a method for the classical resolution of a mixture of enantiomers of a chiral compound, with the racemization of the unwanted enantiomer in situ. The principle of the asymmetric transformation according to the invention can also be applied in the case of other known asymmetric transformations, such as that of methionine with D-BrCas, phenylglycine with D-camphorsulphonic acid, or HPG with (+)-σ-phenylethanesulphonic acid. The method according to the invention is preferably carried out in water.

The salt used can in principle be any inorganic salt, examples being the salts of inorganic acids, especially the salts formed by hydrochloric or sulphuric acid with alkali metals or alkaline earth metals, especially sodium or potassium, or else with ammonia. The salt used is preferably sodium sulphate, sodium bisulphate, ammonium sulphate or ammonium bisulphate, or else a mixture of these salts. It is preferable to keep the molar ratio between the sulphate-type salts [for example Na₂SO₄ and/or (NH₄)₂SO₄] and the bisulphate-type salts [for example NaHSO₄ and/or (NH₄)HSO₄] between 0.5 and 1.5, and especially between 0.8 and 1.2. It is also preferable to keep the concentrations of the sulphate-type salts in the water between half the saturation concentration of the mixture of sulphate-type salts at 30⁰C and the full saturation concentration of the mixture of sulphate-type salts at 3O⁰C.

If the mixture used consists of (NH₄)HSO₄ / NaHSO₄ / Na₂SO₄ in a molar ratio of about 1 / 1.25 / 2.25, the concentrations are preferably as follows: (NH₄)HSO₄: 0.060-0.120 mol per 100 ml of water NaHSO₄: 0.075-0.150 mol per 100 ml of water

Na₂SO₄: 0.135-0.270 mol per 100 ml of water.

The amount in which the inorganic salt is used is not particularly critical. It is preferable to ensure that the concentration of the inorganic salt in the reaction mixture is below the maximum solubility of the inorganic salt at the temperature at which the DD-salt of D- HPG and D-BrCas is isolated, for example at 20-30⁰C. The amount is preferably chosen in such a way that the solubility of the required diastereomer (the DD salt of D-HPG and D-BrCas) is less than 2.5 wt-% and especially less than 2 wt-% at room temperature. The following tabulated values give an indication of the solubility of the DD-salt in water with various salt concentrations. For comparison, the solubility of the DD salt in water at 30°C is 3 wt-%.

The concentration of the DD-salt in the slurry at the end of the reaction is preferably between 100 and 200 grams per 100 ml of water and more preferably between 120 and 180 grams per 100 ml of water. The method is carried out with D- BrCas as the resolving agent. The amount of D-BrCas to be used will preferably be between 0.8 and 2 equivalents of D-BrCas, calculated on the total amount of HPG. In principle, an equimolar amount of D-BrCas is needed for the best yield in the resolution. In view of the high price of D-BrCas, preferably between 0.95 and 1.10 equivalents of D- BrCas will be used, calculated on the total amount of HPG.

The method is carried out in the presence of a racemisation agent as well, which is for example an aldehyde or a ketone. Particularly suitable racemisation agents are salicylaldehyde, furfural and optionally substituted benzaldehyde, for example benzaldehyde substituted with a sulphonic group, or else a salt, such as an alkali metal salt, of it. The amount of racemisation agent to be used is not particularly critical and is generally between 0.005 and 0.05 rhol per 100 ml of water and preferably between 0.01 and 0.02 mol per 100 ml of water. The temperature at which the asymmetric transformation is carried out can vary within a wide range and is generally 70-110⁰C and preferably 95-105⁰C when the reaction is carried out at atmospheric pressure. If a higher pressure is used, the temperature can of course be higher, but this is not a preferred embodiment.

The pH at which the asymmetric transformation is carried out is preferably between 0 and 4 and especially between 1 and 2.

The asymmetric transformation can be carried out in a particularly suitable manner with HPG obtained from glyoxylic acid, phenol and an amino group donor, for example ammonia or sulphamic acid, as described in EP-A-530879. In this preparation of HPG, an acidic or basic solution of racemic HPG in water is obtained, possibly after - A -

an extraction step. This solution is then for example (partially) neutralized to a pH at which the asymmetric transformation is carried out, where inorganic salts are generally formed. The resulting mixture of HPG and inorganic salts can then be used as such in the asymmetric transformation according to the invention. The racemic HPG obtained therefore need not be isolated, so that losses due to solubility are prevented, and a higher yield is obtained. A further advantage is that no extra inorganic salts need to be added here.

The reaction mixture obtained in the asymmetric transformation can be processed in the conventional manner. For this purpose, the reaction mixture can be cooled, for example. After separating off the solid diastereomeric salt, the mother liquor can be circulated, for example, and the D-HPG can be removed from the isolated diastereomeric salt, for example in the conventional way by salt exchange, using a hydroxide (sodium or potassium) or ammonia.

However, D-HPG is preferably added to the reaction mixture or to the mother liquor. What is achieved by this is that - as a result of the lower solubility of the diastereomeric salt of D-HPG and D-BrCas in comparison with the diastereomeric salt of

L-HPG and D-BrCas (LD salt) - part of the diastereomeric salt of L-HPG and D-BrCas in solution is converted into the diastereomeric salt of D-HPG and D-BrCas, which can then crystallizes out and can be isolated. Free D-BrCas (which does not form a salt with HPG) can crystallize out by salt formation with the D-HPG added and be isolated. This further reduces the losses in the resolving agent. D-HPG is preferably added to the reaction mixture.

The amount of D-HPG to be added depends to a great extent on the excess of D-

BrCas employed. In order to recover the maximum amount of D-BrCas as a solid DD salt, at least a molar amount of D-HPG is added that is equal to the amount of the DD salt and the free D-BrCas in solution. The amount is preferably between 1 and 1.2 times the amount of the LD salt and the free D-BrCas in solution.

This tactic - the addition of the required enantiomer of the product to limit the losses of the resolving agent - can also be employed in combination with other asymmetric transformations or resolutions and is particularly attractive in the case of processes in which the resolving agent used is expensive in comparison with the required enantiomer. The invention is explained below with the aid of the following examples but is not restricted to them.

Example I

Asymmetric transformation of HPG with D-BrCas in water with inorganic salts

The following mixture was introduced into a reaction flask equipped with a stirrer, a thermometer and a reflux condenser: 137.1 g (0.41 mol) of sodium D-bromocamphor- sulphonate, 62.7 g (0.37 mol) of D,L-p-hydroxyphenylglycine, 28.7 g (0.28 mol) of 96 wt-

% sulphuric acid, 8.0 g (0.07 mol) of salicylaldehyde and 142.7 g of water, after which the mixture was heated to 100⁰C for 6 hours, with stirring.

After cooling to 2O⁰C, the resulting diastereomeric salt of D-HPG and D-BrCas

(DD salt) was filtered off and washed with three 50-ml portions of water. After drying, the yield of the filtered product was found to be 150.2 g (0.31 mol) of DD salt (yield: 84%).

The enantiomeric excess of D-p-hydroxyphenyl-glycine in the DD salt was 99.2%

(determined by HPLC). (The residual solubility of the DD salt in the reaction mixture at

20⁰C amounted to 0.5 wt-%).

Example Il

Asymmetric transformation of HPG with D-BrCas in water with inorganic salts, followed by the "exhaustion tactic" to recover D-BrCas

The following mixture was introduced into a reaction flask equipped with a stirrer, a thermometer and a reflux condenser: 93.2 g (0.28 mol) of sodium D-bromocamphor- sulphonate, 46.8 g (0.28 mol) of D,L-p-hydroxyphenylglycine, 5.6 g (0.06 mol) of 96 wt-% sulphuric acid, 13.8 g (0.12 mol) of ammonium bisulphate, 33.0 g (0.28 mol) of sodium bisulphate, 2.3 g (0.02 mol) of salicylaldehyde and 1 15 g of water, after which the mixture was heated to 100⁰C for 6 hours, with stirring. Salicylaldehyde is steam-volatile and was removed by distillation. The amount of water removed in the distillation (about

15 ml) was returned to the reaction mixture.

After cooling the reaction mixture to 30⁰C, the amount of L-HPG. D-BrCas salt was found to be 10 mmol by analysing a sample of the reaction mixture by HPLC. About 2% of the HPG suffered degradation during the reaction, amounting to about 6 mmol. This means that an extra 6 mmol of D-BrCas (i.e. not as HPG.D-BrCas salt) was present in the solution.

3.4 g (20 mmol) of D-HPG were added to the reaction mixture, and the system was heated to 85°C for 1 h, 15 with stirring. After cooling to 30⁰C, the resulting diastereomeric salt of D-HPG and D-BrCas (DD salt) was filtered off and washed with three 50-ml portions of water. The yield of the filtered product after drying amounted to

129 g (0.270 mol) of the DD salt.

Calculation of the yield: The amount of DD salt in the wash water (3 wt-%) was 4.5 g (0.009 mol). The amount of DD salt in the wash water was included in the calculation of the yield, because it could be used in the next asymmetric transformation. The total amount of DD salt isolated plus the amount in the wash water was therefore 0.279 mol.

Yield of D-HPG in the DD salt: 0.279 mol - 0.020 mol = 0.259/0.280 = 92.5%.

Yield of D-BrCas in the DD salt: 0.279/0.280 = 99.6%. The enantiomeric excess of D-p-hydroxyphenylglycine in the DD salt was 99.4%. (The residual solubility of the DD salt in the reaction mixture at 30⁰C amounted to 0.3 wt-%.)

Example III

Synthesis of DL-HPG from glyoxylic acid, phenol and sulphamic acid, where the resulting reaction mixture is used for asymmetric transformation with D-BrCas after partial neutralization and extraction but without the isolation of DL-HPG

The following mixture was introduced into a reaction flask equipped with a stirrer, a thermometer and a reflux condenser: 38.5 g (0.40 mol) of sulphamic acid, 36.5 g (0.39 mol) of phenol and 35.2 g of water, after which the mixture was heated to 45°C, with stirring. After holding the reaction mixture at 45°C for 2 h, 52.2 g (0.35 mol) of a 50% solution of glyoxylic acid in water were added to the reaction mixture, with stirring. The reaction mixture was then successively stirred for 2 h at 5O⁰C and for 2 h 20 at 80⁰C. 175 ml of methyl isobutyl ketone (MIBK) were added to the reaction mixture for the extraction. The extraction was carried out by stirring the liquid for 15 minutes at 50- 7O⁰C. After separating off the organic phase, 9.1 g (0.23 mol) of NaOH were added, with stirring, to the acidic aqueous phase for partial neutralization. The resulting aqueous phase contained 0.24 mol of D,L-p-hydroxyphenylglycine according to HPLC analysis, and could be used in the asymmetric transformation without isolating it. A solution of 99.6 g (0.30 mol) of sodium bromocamphorsulphonate (34 wt-%),

5.8 g (0.03 ml) of D-p-hydroxyphenylglycine (2 wt-%) and 185.4 g of water, obtained by the recovery of D-HPG from the DD salt, was concentrated by distilling off 100 ml of water from it. The aqueous phase obtained above was added to this concentrated solution at 80-90⁰C, with stirring, whereupon solid DD salt crystallized out. The reaction mixture was further concentrated by distilling 55 ml of water from it. 2.5 g (0.02 mol) of salicylaldehyde were added to the reaction mixture, which was then stirred for 6 h at

100⁰C. After 10 cooling to 3O⁰C, the resulting diastereomeric salt of D-HPG and D-

BrCas (DD salt) was filtered off and washed with three 50-ml portions of water. After drying, the yield of the filtered product was found to be 118 g (0.247 mol) of DD salt.

The amount of the DD salt in the wash water (3 wt-%) amounted to 4.5 g (0.009 mol). The DD salt present in the wash water was included in the calculation of the yield, because it could be used in the next asymmetric transformation.

The total amount of the DD salt isolated plus the amount in the wash water was therefore 0.256 mmol. Yield of D-HPG in the DD salt: 0.256/0.276 = 92.8%. (The residual solubility of the DD salt in the reaction mixture at 3O⁰C amounted to 0.7 wt-%.)

Claims

1. Method for the preparation of p-hydroxyphenylglycine enriched with the D enantiomer (D-HPG) in ^• an asymmetric transformation of a mixture of the enantiomers of p-hydroxyphenylglycine (HPG) with the aid of D- bromocamphorsulphonic acid (D-BrCas) in the presence of a racemisation agent, where the solid diastereoisomeric salt of D-HPG and D-BrCas is formed, characterized in that the asymmetric transformation is carried out in an aqueous medium and in the presence of one or more inorganic salts.

2. Method according to Claim 1 , characterized in that a racemic mixture of the enantiomers of p-hydroxyphenylglycine is used.

3. Method according to Claim 1 or 2, where HPG is first prepared from glyoxylic acid, phenol and an amino group donor, after which the resulting reaction mixture, which contains HPG and inorganic salts, is used for the asymmetric transformation as such.

4. Method according to any one of Claims 1-3, where D-HPG is added to the reaction mixture obtained in the asymmetric transformation.

5. Method according to any one of Claims 1-3, where D-HPG is added to the mother liquor obtained after separating off the solid diastereomeric salt of D-HPG and D- BrCas from the reaction mixture obtained in the asymmetric transformation, and the resulting solid diastereomeric salt of D-HPG and D-BrCas is then separated off.

6. Method according to Claim 4 or 5, where the molar amount of the D-HPG added is at least equal to the amount of diastereomeric salt of L-HPG and D-BrCas in solution, plus the amount of D-BrCas that does not form a salt with HPG, in solution.