NL9302059A - Process for preparing 4-hydroxyphenylglycine with increased optical purity. - Google Patents

Description

PROCESS FOR PREPARING 4-HYDROXYPHENYL GLYCIN WITH INCREASED OPTICAL PURITY

The invention relates to a process for preparing 4-hydroxyphenylglycine with increased optical purity, wherein a mixture of D- and L-4-hydroxyphenylglycine in a suitable solvent is converted at least partly into a salt by means of an optical activating agent and after which at least one of the enantiomers of 4-hydroxyphenylglycine in the form of a diastereomer zour is separated.

The separation of one of the enantiomers from a mixture of enantiomers (resolution) via the formation of a diastereoisomeric salt using an optical splitting agent is known. For example, there are many publications describing the resolution of D-4-hydroxyphenylglycine through the formation of a diastereoisomeric salt using 3-bromamphor-8-sulfonic acid.

A drawback of the known methods is that use must be made of process-foreign optically-active splitting agents, which in practice involves additional operations and, moreover, often problems. For example, the above 3-bromamphor-8-sulfonic acid is expensive and harmful to the environment, while it is also not very stable.

The object of the invention is to provide a simple method which does not have the above-mentioned drawbacks.

This is achieved according to the invention by the mixture of the D- and L-4-hydroxyphenylglycine, sulfuric acid in an amount equal to at most 1.3 moles per mole of the mixture of D- and L-4-hydroxyphenylglycine and, as optical splitting agent the enantiomer of 4-hydroxyphenylglycine for which an increased optical purity is intended, in an amount at most equal to the amount of that enantiomer present in the mixture of D- and L-4-hydroxyphenylglycine, are contacted in any order.

Namely, the applicant has found that it is possible to separate one of the two enantiomers from a mixture of enantiomers without using a foreign-type cleavage agent. This resolution is considered an example of 'ionic self-resolution'. The word ionic refers in the terminology to the formation of a diastereoisomeric salt as an ionic compound. The "self" designation in self-resolution refers to the use, as an optically active cleavage agent in the resolution, of one of the two enantiomers of the chiral compound present in the starting mixture. Without wishing to commit to any explanation, the applicant sees as a possible explanation that the reaction proceeds via the attached reaction scheme. It is believed herein that the mixture of D- and L-4-hydroxyphenylglycine with sulfuric acid is converted into the corresponding acidic salt (hydrogen sulfate), followed by the diastereoisomeric DD- using the optical splitting agent (D or L-4-hydroxyphenylglycine) as base LL-4-hydroxyphenylglycine sulfate, respectively, is precipitated. The order of addition of the reactants relative to each other surprisingly did not appear to have any influence. Examples of ionic self-resolution have not been described in the literature. It has further been found that a high yield per reaction volume can be realized with the method according to the invention, compared to the known processes.

It should be noted that EP-A-450684 describes a process for the preparation of D- and / or L-4-hydroxyphenylglycine via the formation of a sulfate. However, the method described in EP-A-450684 is an example of selective crystallization by seeding an unsaturated solution (entrainment) using seed crystals of the sulfate of the desired enantiomer. A drawback of such a method is that extremely good seed crystals are required for good separation. In the method according to the invention, the addition of seed crystals is not necessary.

Another mechanism is described in EP-A-450684: Addition of sulfuric acid in an equimolar amount relative to. the total amount of 4-hydroxyphenylglycine present in the reaction mixture quantitatively forms the soluble, D- and L-4-hydroxyphenylglycine hydrogen sulfate. By adding seed crystals of, for example, D-4-hydroxyphenylglycine sulfate, it is then effected that D-4-hydroxyphenylglycine sulfate precipitates on the crystals to release sulfuric acid. In the process of the invention, a lower sulfuric acid is used relative to the total amount of 4-hydroxyphenylglycine enantiomers in the reaction mixture (this is the amount of mixture of D- and L-4-hydroxyphenylglycine plus the amount of optically active 4-hydroxyphenylglycine used as a cleaving agent).

The amount of sulfuric acid to be used is preferably a substantially equimolar amount calculated with respect to the amount of the mixture of D- and L-4-hydroxyphenylglycine to be cleaved, for example a molar ratio of 0.8-1.2. In order to obtain maximum yield, a substantially equimolar amount of sulfuric acid with respect to the mixture of D- and L-4-hydroxyphenylglycine, in particular a molar ratio of 0.9-1.1, is used.

Any mixture of the enantiomers of 4-hydroxyphenylglycine can be used as a mixture of D- and L-4-hydroxyphenylglycine. In practice, however, it will usually be assumed that a substantially racemic mixture will be used, wherein the ratio of D- to L-4-hydroxyphenylglycine will then be between 0.9: 1.1 and 1.1-0.9. For a racemic mixture, this ratio is 1: 1. In order to obtain such a high yield, starting from a racemic mixture of D- and L-4-hydroxyphenylglycine, preferably 0.9-1.1 mol sulfuric acid per mole racemic mixture is used in the process according to the invention and 0.45 -0.50 mol D- or L- (depending on the desired enantiomer) 4-hydroxy-phenylglycine as a cleaving agent. The best results are obtained when 1 mol sulfuric acid and 0.50 mol splitting agent are used per mol racemic mixture.

The molar ratio of sulfuric acid to the total amount of 4-hydroxyphenylglycine present in the reaction mixture is then 2: 3.

When D-4-hydroxyphenylglycine with increased optical purity is contemplated, the splitting agent is D-4-hydroxyphenylglycine, and when L-4-hydroxyphenylglycine with increased optical purity is contemplated, L-4-hydroxyphenylgycin. The optical purity of the cleavage agent is preferably as high as possible, for example, the cleavage agent has an e.e. greater than 95%, preferably greater than 99%. With EE. here is meant "enantiomericexcess" which quantity is defined as the difference of the amounts of enantiomers divided by the sum of those amounts, which guotient is expressed as a percentage by multiplying by 100.

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

The pressure at which the method of the invention is carried out is not critical and is, for example, 0.01-5 MPa. Preferably the process is carried out at atmospheric pressure. The temperature can vary within wide limits and is generally 0-120 ° C, preferably 20-70 ° C. The reaction time is usually 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% by weight, preferably 15-20% by weight.

The optically active 4-hydroxyphenylglycine can be obtained in a known manner from the separated diastereoisomeric salt, for example by dissolving the salt in a mixture of water and the acidity by means of adjust a suitable base to a pH of 4-7, and filter and wash the suspension thus obtained.

The invention is now further illustrated by the following examples, without being limited thereto.

Example I

To a suspension of 50.1 grams (0.3 mol) of D-4-hydroxyphenylglycine (D-FGH) in 135 ml of water was added successively with stirring 34 ml of 96 wt% sulfuric acid (0.6 mol) and 90 ml of acetone. Subsequently, 100.2 grams (0.6 mol) (racemic) DL-4-hydroxyphenylglycine (DL-FGH) was added to this clear solution with stirring. After heating (62 ° C; 1/4 hour) with stirring, the resulting suspension was cooled to 25 ° C and stirred at this temperature for 3 hours. The DD-4-hydroxyphenylglycine sulfate (D-FGH sulfate) formed was filtered and washed on the glass filter with 3 x 25 ml 50% by volume acetone water and 2 x 25 ml acetone. After drying, the yield of colorless D-FGH sulfate was 92.0 grams. The yield (yield) was 71.0% (D-FGH sulfate contains 21.0 grams of additional D-FGH).

The specific rotation of D-FGH sulfate was: [cc] 20d = -107.0 ° (C = 1.0; 1.0N HCl]

The optical purity of D-FGH contained in the D-FGH sulfate was determined as follows: a solution of 86.4 grams (0.20 moles) of D-FGH sulfate in 200 ml of water was heated at a temperature of 70-80 ° C neutral rudders neutralized using 26 ml of 2.5 wt% ammonia to an acidity of pH = 5. After cooling to 25 ° C, the formed D-FGH was filtered and washed on glass filter with 2x 40 ml of water. The yield of colorless D-FGH after drying was 53.6 grams. The return was 80.2%.

The specific rotation of D-FGH was: [α] 20D = -158.0 ° (C = 1.0? 1.0N HCl).

Examples II-VI

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

TABLE

Claims (8)

A process for preparing 4-hydroxyphenylgycin with increased optical purity, wherein a mixture of D- and L-4-hydroxyphenylglycine in a suitable solvent is converted at least in part to a salt using an optically active cleavage agent and then at least one of the enantiomers of 4 -hydroxyphenylglycine in the form of a diastereoisomeric salt is separated, characterized in that the mixture of D- and L-4-hydroxyphenylglycine, sulfuric acid in an amount not more than 1.3 mol per mol of the mixture of D- and L-4-hydroxyphenylglycine and, as the optical active cleavage agent, the enantiomer of 4-hydroxyphenylglycine which is intended to have an increased optical purity, in an amount equal to the amount of that enantiomer present in the mixture of D- and L-4-hydroxyphenylglycine, in random order with are brought into contact with each other. The method according to claim 1, wherein a racemic mixture of enantiomers is started from, an amount of optical active cleaving agent less than or equal to 0.5 mol and a quantity of 0.6-1.3 mol sulfuric acid being used per molracemic mixture. A method according to claim 1 or 2, wherein the splitting agent is D- or L-4-hydroxyphenylglycine with an ee. greater than 99% is used. The method according to any one of claims 1 to 3, wherein the sulfuric acid to molar mixture of D- and L-4-hydroxyphenylglycine is between 0.9 and 1.1. A method according to any one of claims 1-4, wherein a water-acetone mixture is used as the solvent. The method of claim 5, wherein the water to acetone ratio in the solvent is between 2: 1 and 1: 4. 7. Process for the preparation of 4-hydroxyphenylglycine with increased optical purity as described and illustrated by the examples. Optically active 4-hydroxyphenylglycine prepared by the process according to any one of claims 1-7.