WO1995014656A1

WO1995014656A1 - Process for the preparation of 4-hydroxyphenyl glycine with enhanced optical purity

Info

Publication number: WO1995014656A1
Application number: PCT/NL1994/000299
Authority: WO
Inventors: Wilhelmus Hubertus Joseph Boesten
Original assignee: Dsm N.V.
Priority date: 1993-11-29
Filing date: 1994-11-28
Publication date: 1995-06-01
Also published as: NL9302059A; AU1203295A

Abstract

Process for the preparation of 4-hydroxyphenyl glycine with enhanced optical purity, wherein in a suitable solvent a mixture of D- and L-4-hydroxyphenyl glycine, sulphuric acid in a quantity at most equal to 1.3 mol per mol of the mixture of D- and L-4-hydroxyphenyl glycine and, as optically active separation agent, the 4-hydroxyphenyl glycine enantiomer whose optical purity has to be enhanced, in a quantity at most equal to the quantity of that enantiomer that is present in the mixture of D- and L-4-hydroxyphenyl glycine, are contacted with each other and at least one of the enantiomers of 4-hydroxyphenyl glycine is separated in the form of a diastereoisomeric salt.

Description

PROCESS FOR THE PREPARATION OF 4-HYDROXYPHENYL GLYCINE WITH ENHANCED OPTICAL PURITY

The invention relates to a process for the preparation of 4-hydroxyphenyl glycine with enhanced optical purity, wherein a mixture of D- and L-4- hydroxyphenyl glycine in a suitable solvent is at least partly converted to a salt by means of an optically active separation agent, after which at least one of the enantiomers of 4-hydroxyphenyl glycine is separated in the form of a diastereomeric salt. The isolation of one of the enantiomers from a mixture of enantiomers (resolution) through preparation of a diastereoisomeric salt by means of an optically active separation agent is known. There are for instance many publications describing the resolution of D-4- hydroxyphenyl glycine through preparation of a diastereoisomeric salt by means of 3-bromocamphor-8- sulphonic acid.

A drawback of the known processes is that they involve the use of extraneous optically active separation agents, which in practice entails additional operations and in many cases problems, moreover. Thus, the above- mentioned 3-bromocamphor-8-sulphonic acid is expensive and environmentally harmful, while in addition it is not very stable. The aim of the invention is to provide a simple process which does not have said drawbacks.

This is achieved according to the invention in that the mixture of D- and L-4-hydroxyphenyl glycine, sulphuric acid in a quantity at most equal to 1.3 mol per mol of the mixture of D- and L-4-hydroxyphenyl glycine and, as optically active separation agent, the 4- hydroxyphenyl glycine enantiomer whose optical purity has to be enhanced, in a quantity at most equal to the quantity of that enantiomer that is present in the mixture of D- and L-4-hydroxyphenyl glycine, are contacted with each other. The fact is that the applicant has found that it is possible to separate one of the two enantiomers from a mixture of enantiomers without using an extraneous separation agent. This resolution is considered to be an example of 'ionogenic self-resolution'. The word 'ionogenic' in this terminology relates to the formation of a diastereoisomeric salt as an ionogenic compound. The qualification 'self' in 'self-resolution' relates to the use of one of the two enantiomers of the chiral compound present in the starting mixture as an optically active separation agent in the resolution. Without commitment to any theory, the applicant sees a possible explanation in the reaction proceeding as represented in the attached reaction scheme. In this reaction scheme it is assumed that the mixture of D- and L-4-hydroxyphenyl glycine is converted with sulphuric acid to the corresponding acid salt (hydrogen sulphate), after which the diastereoisomeric DD- or, respectively, LL-4-hydroxyphenyl glycine sulphate is precipitated by means of the optically active separation agent (D- or L-4-hydroxyphenyl glycine) as base. Optionally the remaining mother liquor may be recycled after racemisation. Examples of ionogenic self- resolution are not described in the literature. It has been found, further, that with the process according to the invention a high yield per reaction volume can be realized compared with the known processes.

It may be pointed out that EP-A-450684 describes a process for the preparation of D- and/or L-4- hydroxyphenyl glycine via formation of a sulphate. However, the process described in EP-A-450684 is an example of selective crystallization by grafting an unsaturated solution (entrainment) , using grafting crystals of the sulphate of the desired enantiomer. A drawback of such a process is that a good separation always requires highly pure crystals. In the process according to the invention there is no need for addition of grafting crystals. In EP-A-450684 another mechanism is described: By addition of sulphuric acid in an equimolar quantity relative to the total amount of 4-hydroxyphenyl glycine present in the reaction mixture, the soluble D- and L-4-hydroxyphenyl glycine hydrogen sulphate is formed quantitatively. Next, by adding grafting crystals of D-4- hydroxyphenyl glycine sulphate for instance, D-4- hydroxyphenyl glycine sulphate is caused to precipitate on the grafting crystals, with release of sulphuric acid. In the process according to the invention a deficiency of sulphuric acid is used relative to the total amount of 4- hydroxyphenyl glycine enantiomers in the reaction mixture (i.e. the quantity of the mixture of D- and L-4- hydroxyphenyl glycine plus the quantity of optically active 4-hydroxyphenyl glycine used as separation agent). The quantity of sulphuric acid used preferably is a virtually equimolar quantity relative to the quantity of the mixture of D- and L-4-hydroxyphenyl glycine to be resolved, for instance a molar ratio of 0.8-1.2. In order to obtain a maximum yield a virtually equimolar quantity of sulphuric acid relative to the mixture of D- and L-4- hydroxyphenyl glycine, in particular a molar ratio of 0.9- 1.1, is applied.

Any mixture of the enantiomers of 4- hydroxyphenyl glycine can be used as mixture of D- and L- 4-hydroxyphenyl glycine. In practice, however, a virtually racemic mixture will mostly be started from, with the ratio between D- and L-4-hydroxyphenyl glycine being between 0.9:1.1 and 1.1-0.9. For a racemic mixture this ratio is 1:1. In order to maximize the yield when starting from a racemic mixture of D- and L-4-hydroxyphenyl glycine in the process according to the invention, preferably 0.9- 1.1 mol of sulphuric acid and 0.45-0.50 mol of D- or L-4- hydroxyphenyl glycine (depending on the desired enantiomer) as separation agent per mol of racemic mixture are used. The best results are obtained when per mol of racemic mixture 1 mol of sulphuric acid and 0.50 mol of separation agent are used. The molar ratio of sulphuric acid to the total quantity of 4-hydroxyphenyl glycine present in the reaction mixture is 2:3 then.

If D-4-hydroxyphenyl glycine with enhanced optical purity is wanted, D-4-hydroxyphenyl glycine is used as separation agent, while if L-4-hydroxyphenyl glycine with enhanced optical purity is wanted, L-4- hydroxyphenyl glycine is used. The optical purity of the separation agent preferably is as high as possible; the separation agent for instance has an e.e. higher than 95%, preferably higher than 99%. By 'e.e. ' is meant here 'enantiomeric excess', which quantity is defined as the difference of the amounts of enantiomers divided by the sum of those amounts, which quotient is expressed as a percentage by multiplying it by 100.

As solvent can be used any water-miscible solvent which is not reactive with the compounds present in the reaction mixture, such as for instance ketones, dioxane, THF, acetonitrile and acetic acid. Preferably, the reaction is carried out in a mixture of water and acetone as solvent, for instance having a water : acetone volume ratio between 2 : 1 and 1 : 4. The best results are obtained with a water : acetone volume ratio between 2 : 2.5 and 2 : 3.5.

The pressure at which the process according to the invention is carried out is not critical and is for instance 0.01-5 MPa. Preferably, the process is carried out at atmospheric pressure. The temperature may vary within wide limits and is in general 0-120°C, preferably 20-70°C. The reaction time is mostly 0.1-8 hours, preferably 0.2-2 hours. The slurry concentration of the diastereoisomeric salts at the end of the reaction is about 5-30 wt%, preferably 15-20 wt%. The optically active 4-hydroxyphenyl glycine can be recovered from the separated diastereoisomeric salt by a known method, for instance by dissolving the salt in a mixture of water and setting the acidity to a pH of 4-7 by means of a suitable base, and filtering and washing the suspension thus obtained.

The invention will be elucidated by means of the following non-restrictive examples.

Example I

34 ml of 96 wt.% sulphuric acid (0.6 mol) and 90 ml of acetone were successively added with stirring to a suspension of 50.1 g (0.3 mol) of D-4-hydroxyphenyl glycine (D-HPG) in 135 ml of water. Next, 100.2 g (0.6 mol) of (racemic) DL-4-hydroxyphenyl glycine (DL-HPG) was added with stirring to this clear solution. After heating (62°C; 1/4 hour) with stirring, the suspension obtained was cooled to 25°C and stirred at this temperature for 3 hours. The resulting DD-4-hydroxyphenyl glycine sulphate (D-HPG sulphate) was filtered and washed on the glass filter with 3 x 25 ml of 50 vol.% of acetone/water and 2 x 25 ml of acetone. After drying, 92.0 g of colourless D-HPG sulphate was obtained. The yield was 71.0% (D-HPG sulphate contains 21.0 g of extra D-HPG). The specific rotation of D-HPG sulphate was:

[α]²⁰ _D = -107.0° (C = 1.0; 1.0N HCl) The optical purity of the D-HPG present in the D-HPG sulphate was determined as follows: a solution of 86.4 g (0.20 mol) D-HPG sulphate in 200 ml of water was neutralized at a temperature of 70-80°C with stirring by means of 26 ml of 2.5 wt.% ammonia to an acidity of pH = 5. After cooling to 25°C the D-HPG obtained was filtered and washed on the glass filter with 2 x 40 ml of water. After drying, 53.6 g of colourless D- HPG was obtained. The yield was 80.2%.

The specific rotation of D-HPG was: [α]²⁰ _D = -158.0° (C = 1.0; 1.0N HCl) Examples II-VI

Example I was repeated. The results are given in the table.

TABLE

Claims

C L A I M S

1. Process for the preparation of 4-hydroxyphenyl glycine with enhanced optical purity, wherein a mixture of D- and L-4-hydroxyphenyl glycine in a suitable solvent is at least partly converted to a salt by means of an optically active separation agent, after which at least one of the enantiomers of 4-hydroxyphenyl glycine is separated in the form of a diastereoisomeric salt, characterized in that the mixture of D- and L-4-hydroxyphenyl glycine, sulphuric acid in a quantity at most equal to 1.3 mol per mol of the mixture of D- and L-4-hydroxyphenyl glycine and, as optically active separation agent, the 4-hydroxyphenyl glycine enantiomer whose optical purity has to be enhanced, in a quantity at most equal to the quantity of that enantiomer that is present in the mixture of D- and L-4-hydroxyphenyl glycine, are contacted with each other.

2. Process according to claim 1, wherein a racemic mixture of enantiomers is started from, and per mol of racemic mixture a quantity of optically active separation agent smaller than or equal to 0.5 mol and a quantity of 0.6-1.3 mol of sulphuric acid are applied.

3. Process according to claim 1 or 2, wherein as separation agent D- or L-4-hydroxyphenyl glycine with an enantiomeric excess higher than 99% is applied.

4. Process according to any one of claims 1-3, wherein the molar ratio of sulphuric acid to the mixture of D- and L-hydroxyphenyl glycine is between 0.9 and 1.1.

5. Process according to any one of claims 1-4, wherein a water/acetone mixture is applied as solvent.

6. Claim according to claim 5, wherein the water : acetone ratio in the solvent is between 2:1 and 1:4.

7. Process for the preparation of 4-hydroxyphenyl glycine with enhanced optical purity as described and elucidated by means of the examples.

8. Optically active 4-hydroxyphenyl glycine prepared by the process according to any one of claims 1-7.