MXPA06006038A - A process for resolving, optionally substituted, mandelic acids by salt formation with a chiral base cyclic amide - Google Patents

Abstract

The present invention relates to a new process for the resolution of mandelic acid derivatives from racemic mandelic acid derivative mixtures by salt formation with chiral base cyclic amides;to the resolved mandelic acid cyclic amide salts (see, for example, formula (IIa), as well as certain other metal and amine salts of the mandelic acid derivatives, and to the use of the resolved mandelic acid derivatives as intermediates suitable for large-scale manufacturing of, for example, pharmaceutical compounds;Formula (IIa), wherein R is selected from CHF2, H, C1-6Alkyl, CH2F, CHCl2 and CClF2;and wherein n is 0, 1 or 2;R1 is H or C1-6 Alkyl and X is H, halo or C1-6 Alkyl.

Description

PROCESS FOR THE RESOLUTION OF MANDELIC ACIDS THROUGH THE FORMATION OF SALT WITH A CYCLICAL AMID OF CHEMICAL BASE Field of the Invention The present invention relates to novel processes for the preparation and resolution of mandelic acid derivatives from racemic mixtures of mandelic acid derivative by formation with cyclic amides of chiral base. The present invention also relates to cyclic amide salts derived from mandelic acid, to certain other metal and amine salts of mandelic acid derivatives, as well as to the use of mandelic acid derivatives resolved as suitable intermediates for large-scale manufacture of, for example, pharmaceutical compounds. Background of the Invention Several amines have been reported as resolving agents for mandelic acid derivatives. For the resolution of mandelic acids, a number of chiral amines have been described, for example, a-methylbenzylamine, 2-benzylamino-1-butanol, (f?) - 2-yer-butyl-3-methylimidazo-idin-4-one ( BMI), (+) -cinconine, brucine, quinine, quinidine, (-) - ephedrine, (-) - 2-amino-1-butanol, amphetamine and adrenaline. These amines as well as others are described in the publication of E.J. Ebbers et al. in Tetrahedron: Asymmetry 1997, 8, pages 4047 to 4057 and references cited therein. In the publication of J. Hoover et al., In (J. Med. Chem. 1974, 17, pages 34 to 41) 21 substituted mandelic acids are described with reference to the original literature. The resolution bases described are (-) - ephedrine, brucine and (+) -a-methylbenzylamine. The publication of J. Nieuwenhuijzen et al. in (Angew.

Chem. Int. Ed. 2002, 41, pages 4281 to 4286) describes the resolution of 4-chloromandélico acid with a-methylbenzylamine with or without a 1: 1 mixture of orfo: para of a-methylbenzylamine substituted by nitro (10 mol %). Japanese Patent JP2001072644 describes the optical resolution of 2-chloromandélico acid with? / - bencil-a-methylbenzylamine and derivatives thereof. Japanese Patent JP 1221345 describes the optical resolution of derivatives of mandelic acids substituted by phenyl with amino acid hydrazines. However, there is a need for additional means to resolve the mandelic acid derivatives. Mandelic acids are used in the manufacture of a range of interesting molecules, such as pharmaceuticals. Therefore, the present invention also relates to the use of resolved mandelic acid derivatives as suitable intermediates for the large-scale manufacture of, for example, pharmaceutical compounds, e.g., compounds as described in WO 02. / 44145. A number of bases, including those described in the art, were tested in order to obtain an acceptable resolution of mandelic acid derivatives (particularly, 3-chloro-5-difluoromethoximidelic acid), for example, α-methylbenzylamine, (S) -l-naphthylethylamine, (+) - zynconine, (+) - dihydroabiethyl amine, (S) -2-amino-2-phenylethanol, (-) - ephedrine, L-phenylalaniol, and, a-diphenyl-D-prophino. None of these . produced particularly satisfactory results for large-scale manufacturing purposes (having low yields and a low enantiomer surplus). The term "large scale" includes the manufacture of quantities of Kgs of material. We have now surprisingly discovered that the racemic derivatives of mandelic acid can be resolved by the formation of salt with cyclic amides of chiral base, such as proline amide. We have also surprisingly discovered that certain metal salts and certain amine salts of the mandelic acid derivatives (particularly (R) -3-chloro, 5-difluoro-methoxy-mandelic acid) have desirable characteristics and are useful in the processes of manufacture - see example 12 and the claims in this document.

SUMMARY OF THE INVENTION Accordingly, a process for resolving mandelic acids is provided. { R) ~ or (S) - optionally substituted of racemic mixtures of said mandelic acids optionally substituted by the formation of salt with a cyclic amide (D) - or (L) ~ of quiral base, comprising the steps of: (a) forming a mixture in a solvent, or a mixture of solvents, of an optionally substituted racemic mandelic acid, and a cyclic amide (D) - or (L) - of quiral base, wherein the quiral base used is either (D) for the separation of (R) -mandectic acids, or (L) for the separation of (S) -mandelic acids, in a molar ratio of acid: base of 1: 0.25-0.75; and wherein the solvent, or mixture of solvents may optionally contain water in a range of 5% to 15% (vol.) of the solvent; and (b) separating the cyclic amide salt-mandelic acid (R) / (D) or (S) / (L). According to a first aspect of the present invention, a process for resolving substituted mandelic acids is provided. { R) ~ or (S) - of racemic mixtures of said substituted mandelic acids by salt formation with a cyclic amide (D) - or (L) - of chiral base as described above and below. It should be understood that said "mandelic acids optionally substituted by. {R) - or (S) -" may be as described in WO 02/44145, and wherein said definitions and the optionally substituted mandelic acids described are incorporated in this description as a reference. It should also be understood that said "mandelic acids substituted by (R) - or (S) -" may be those mandelic acid fragments of the molecules described in WO 02/44145, and wherein the definitions of substituted mandelic acids described are incorporated herein by reference. Also incorporated herein by reference are the details and examples of the preparation of said substituted mandelic acids, described in WO 02/44145 (for example, in example 1 of said document). A general view of the process is the following (where R, Ri, X and n are as defined here): racemic derivative of mandelic acid mandelic acid (R) or (S) - loose mandelic acid or cyclic amide salt- (L) In the above scheme, preferably Ri and X are both H. In this specification, unless stated otherwise, the term "cyclic amide" includes optionally substituted forms thereof and includes but not limited to, proline amide, azetidina- 2-carboxamide and piperidine-2-carboxamide, as well as the substituted forms thereof. The substitution may be at a nitrogen ring atom, by C -? - 6 Alkyl, or at a suitable ring carbon atom by C < -6 Alkyl or halo (for example, chlorine, fluorine or bromine). Unsubstituted cyclic amides are preferred, but when substituted, substitution at a ring nitrogen atom or a mono-substitution at a suitable ring carbon atom is preferred. In this description it should be understood that unless otherwise stated, when extracted a salt cyclic amide (D) or (L) (for example, in formula 11) then the cyclic amide may be substituted optionally in the Nitrogen atom per C-? 6 Alkyl, or at the carbon atom of the appropriate ring by C 1-6 Alkyl or halo (such as fluorine, chlorine or bromine) as shown in formula I (x) below (wherein n is 0, 1 or 2, Ri is H or C1-6 Alkyl and X is H, halo or C1-6 Alkyl) ... X 100 should be understood in this description a cyclic amide (D) optionally is substituted as described herein has a stereochemistry (2R) shown in formula I (y) below (wherein n is 0, 1 or 2; Ri is H or C? .6 Alkyl and X is H, halo or C 1-6 Alkyl) ...

X Ky) should be understood in this description a cyclic amide (L) optionally substituted as described herein has the stereochemistry (2S) shown in the following formula (z), (wherein n is 0, 1 or 2; Ri is H or C? -6 Alkyl and X is H, halo or C 1-6 Alkyl) ... X I (z) It should be understood that all isomers within the definitions of the cyclic amide of chiral base described herein are covered by the present invention. To avoid doubts it should be understood that in this description 'C? -6' means a carbon group having 1, 2, 3, 4, 5 or 6 carbon atoms. In this description, unless otherwise stated, the term "alkyl" includes both straight and branched chain alkyl groups and may be, but is not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl , i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl or i-hexyl, t-hexyl. In accordance with another aspect of the present invention there is provided a process for resolving substituted mandelic acids. { R) - or (S) - of racemic mixtures of said substituted mandelic acids by salt formation with a cyclic amide (D) - or (L) - of chiral base, comprising the steps of: (a) forming a mixture in a solvent, or mixture of solvents, of a racemic mandelic acid derivative of the formula I: I wherein R is selected from CHF2, H, C - .. 6 Alkyl, CH2F, CHCI2 and CCIF2; and any one of a cyclic amide (D) - of quiral base or cyclic amide (L) - of the formula l (x) wherein n is 0, 1 or 2; R-i is H or C.-6 Alkyl and X is H, halo or C-i. I rent. X Kx) wherein the quiral base used is either, (D) for the separation of the mandelic acids. { R) ~, or (L) for the separation of mandelic acids (S) -; in a molar ratio of acid: base of 1: 0.25-0.75; and wherein the solvent or mixture of solvents may optionally contain water in a range of 5% to 15% (vol.) of the solvent; and (b) separating the cyclic amide salt of mandelic acid (f?) / (D) or (S) / (L) respective of the formula lia; The amounts of the racemic mandelic acid derivative and the quiral cyclic amide of step (a) of the processes are added in a molar ratio of 1: 0.25-0.75; alternatively in a molar ratio of 1: 0.4 - 0.7. In another aspect, a derivative of mandelic acid: chiral base in a molar ratio of 1: 0.48 - 0.52 (for example, in ethyl acetate solvent) is used, and in another aspect, the molar ratio is 1: 0.50. It should be understood that the molar proportions also cover experimental variations around these limits, for example, ± 0.005. In this description, unless otherwise stated, the term "ethyl acetate" means ethyl acetate, which, however, can be replaced by another acetate, such as propyl acetate or butyl acetate. In general, acetates (1-4C) can be used. Other solvents can also be used, and are suitable for the formation of Sal L-prolinamide. (S) -3-chloro, 5-difiuoro-methoxy mandelic acid. These solvents include acetonitrile, acetone, 2-butanone (MEK, methyl ethyl ketone), 4-methyl-2-pentanone (MIBK, methyl isobutyl ketone), fer-butyl methyl ether (TBME), 2-propane and ethanol. It is expected that these solvents can also be applied in the formation of D-Prolinamide Salt. (R) -3-chloro, 5-difiuoro-methoxymandelic acid. The solvents mentioned above can be used as pure solvents, or as mixtures with other solvents of the aforementioned solvents. In addition, the solvent or mixture of solvents may optionally contain water (conveniently in an amount of 5% to 15% v / v). A preferred solvent is ethyl acetate. A further aspect of the present invention provides a process for resolving mandelic acids optionally substituted by (R) - or (S) - of racemic mixtures of said mandelic acids optionally substituted by the formation of salt as a cyclic amide (D) - or ( L) - of chiral base, comprising the steps of: (a) forming an ethyl acetate / water mixture of an optionally substituted racemic mandelic acid; and a cyclic amide (D) - or (L) - of chiral base, where the base used is (D) for the separation of the acids. { R) and (L) for the separation of acids (S), in a molar ratio of acid: base of 1: 0.48-0.52; and wherein the water is in a range of 5% to 15% (vol.) of ethyl acetate; then (b) heating and mixing said mixture at reflux; and then (c) cooling the mixture / suspension from step (b), followed by filtration of the cooled suspension / mixture to obtain the cyclic amide salt of mandelic acid R / O or S /. According to another aspect of the present invention there is provided a process for resolving mandelic acid derivatives. { R) ~ or (S) - of racemic derivatives of mandelic acid by forming a salt with a cyclic amide of chiral base (D) - or (L) -, comprising the steps of: (a) forming a mixture in ethyl acetate / water of a racemic mandelic acid derivative of the formula I; wherein R is selected from CHF2, H, C- | .6 alkyl, CH2F, CHCI2 and CCIF2; and the cyclic amide (D) - or (L) - of quiral base in which the base used is (D) for the separation of the acids. { R) and (L) for the separation of acids (S), in a molar ratio of acid: base of 1: 0.48-0.52 and where the water is in a range of 5% to 15% (vol.) Of ethyl acetate; then (b) heating and stirring the mixture at reflux; then (c) cooling the mixture / suspension from step (b), followed by filtering the cooled mixture / suspension to obtain the cyclic amide salt of mandelic acid () / (D) or (SJ / (L) of the Formula II; wherein R is selected from CHF2, H, C1-6 alkyl, CH2F, CHCI2 and CCIF2; and n is 0, 1 or 2. In another aspect of the present invention, there is provided a process for resolving mandelic acid derivatives (f?) - of racemic derivatives of mandelic acid by forming a salt with a cyclic amide (D) - chiral based, which comprises the steps: (a) forming a mixture in ethyl acetate / water of the racemic mandelic acid derivative of the formula I; wherein R is selected from CHF2, H, C1-6 alkyl, CH2F, CHCI2 and CCIF2; and a cyclic amide (D) - of chiral base, in a molar ratio of acid: base of 1: 0.48-0.52; and wherein the water is in a range of 5% to 15% (vol.) of ethyl acetate; then (b) heating and stirring the mixture at reflux; then (c) cooling the mixture / suspension from step (b), followed by filtering the cooled mixture / suspension to obtain the cyclic amide salt of mandelic acid of the formula III; m wherein R is selected from CHF2, H, Alkyl, CH2F, CHCI2 and CCIF2; and n is 0, 1 or 2. In one embodiment of this aspect a process is provided wherein R of formula III is CHF2; and n of formula III is 1, represented by formula VI; SAW In another aspect of the present invention, a. process for resolving mandelic acid derivatives (S) - of racemic derivatives of mandelic acid by forming a salt with a cyclic amide (L) - of chiral base, comprising the steps of: (a) forming a mixture in acetate of ethyl / water of the racemic mandelic acid derivative of the formula I; wherein R is selected from CHF2, H, C -? _6 alkyl, CH2F, CHCI2 and CCIF2; and a cyclic amide (L) - of quiral base, in a molar ratio of acid: base of 1: 0.48-0.52; and wherein the water is in a range of 5% to 15% (vol.) of ethyl acetate; then (b) heating and stirring the mixture at reflux; then (c) cooling the mixture / suspension from step (b), followed by filtering the cooled mixture / suspension to obtain the cyclic amide salt of mandelic acid of formula IV; wherein R is selected from CHF2, H, C? -6 alkyl, CH2F, CHCI2 and CCIF2; and n is 0, 1 or 2.

In one embodiment of this aspect a process is provided wherein R of formula IV is CHF2; and n of formula IV is 1, represented by the formula VII; In another aspect of the present invention there is provided a process of the invention, wherein R of formula I is CHF2, represented by formula V; In the above aspects and embodiments, the cyclic amide used may be optionally substituted at the nitrogen atom by C-6 Alkyl, or at a suitable ring carbon atom by C-? _ 6 Alkyl or halo (such as fluorine, chlorine or bromine) as shown in formula i (x) above. The racemic derivative of mandelic acid / cyclic amide and the solvent (eg, ethyl acetate) is mixed in (a) of the processes can be heated to reflux, followed by the addition of water to obtain a suspension. This suspension is generally stirred at reflux for 10 minutes before starting the cooling process. The mixture of the racemic derivative of mandelic acid / cyclic amide and solvent (for example, ethyl acetate), in a mixture (a) of the process can optionally be heated (for example, to reflux). The presence of water (in a range of 5% to 15% (vol.) Of solvent is preferred and optional heating of the mixture can be followed by the addition of water to obtain a suspension.) This suspension is generally stirred at reflux for 10 minutes before the cooling and separation of the desired cyclic mandelic acid-amide salt The suspension of step (c) of the processes described herein can be cooled to a temperature of 20 ° C to 25 ° C for a period of 10 a 15 hours, followed by additional cooling at a temperature of 15 ° C to 19 ° C for an additional 40 to 60 minutes.Preferably, the suspension is cooled to about 23 ° C for 13 hours followed by further cooling to 18 ° C during 45 additional minutes Alternatively, the suspension at point (c) of the processes described herein is cooled to a temperature of about 15 ° C to 19 ° C for 3 to 4 hours Preferably, the suspension is cooled to a temperature of 18 ° C for 3 to 4 hours. The added amount of optional water in step (a) in the processes is in a range of 5% to 15% (vol.) Of ethyl acetate. This produces a solution where the water concentration is 5% to 10% in ethyl acetate, for example, 0.3 ml of water added in 3.7 ml of ethyl acetate is 7.5%. Preferably, the aggregate amount of water is in a range of 5% to 10% (vol.) Of ethyl acetate. It is particularly preferred when the aggregate amount of water is in a range of 6% to 7% (vol.) Of ethyl acetate. The concentration of the racemic mandelic acid derivative in the solvent mixture of water and ethyl acetate is generally in the range of 0.5 to 2.5 mmol per ml of ethyl acetate and water. Preferably, the racemic derivative of mandelic acid is added in a concentration range of 1.0 to 2.0 mmol per ml of ethyl acetate and water. It is particularly preferred when the racemic derivative of mandelic acid is added in a concentration range of 1.0 to 1.2 mmol per ml of ethyl acetate and water. The suspension comprising the salt obtained in step (c) of the processes described herein can be further washed with ethyl acetate. The salt can be dissolved in a mixture of HCl and ethyl acetate followed by separation of the organic layer and concentration of the organic layer until dried to obtain the resolved mandelic acid derivative. Preferably, the mixture of HCl and ethyl acetate is a mixture of 1: 1 (vol.) Of 1 M HCl and ethyl acetate. The resolved mandelic acid derivative can be analyzed by conventional chiral HPLC techniques.

In another aspect of the present invention there is provided a cyclic amide salt of mandelic acid (f?) / (D) or (S) / (L) having the formula II; p wherein R is selected from CHF2, H, C? -6 alkyl, CH2F, CHCI2 and CCIF2; and n is 0, 1 or 2. In one embodiment of this aspect, the cyclic amide salt of mandelic acid, represented by formula III, is provided; wherein R is selected from CHF2, H, C1-6 alkyl, CH2F, CHCI2 and CCIF2; and n is 0, 1 or 2. Preferably, the cyclic amide-mandelic acid salt is a cyclic amide-mandelic acid salt, wherein R is CHF2, and n is 1, represented by the formula VI; SAW In the above aspects and embodiments, the cyclic amide used in the cyclic amide salt-mandelic acid may be optionally substituted at the nitrogen atom by C-6 Alkyl, or at a suitable ring carbon atom by C? _6 Alkyl or halo (such as fluorine, chlorine or bromine) as shown in formula I (x) above. Said cyclic amide salts of mandelic acid represented by formulas II, III and VI can be obtained by the processes of the present invention. The products obtainable by the processes described within this description and within any of the examples described herein are also provided. There is a need for a more economically efficient and more convenient process for the manufacture of large-scale quantities of high quality mandelic acid (pure) resolved derivatives, where factors such as costs, manufacturing time or use of solvent friendly the environment, etc., are vital for commercial application. The present invention provides said process. The processes of the present invention utilize an improved process for the manufacture of resolved derivatives of mandelic acid in which inexpensive raw materials and thermally safe development conditions are used to achieve these resolved quality mandelic acid derivatives ready for use in processing additional chemical. The present invention further provides the use of a cyclic amide-mandelic acid salt according to the present invention in the manufacture of pharmaceutical products; the use of the cyclic amide salt-mandelic acid according to the present invention as chemical intermediates and the use of the cyclic amide-mandelic acid salt according to the present invention as chemical intermediates in the manufacture of pharmaceutical products (e.g. , to be used in the treatment of cardiovascular diseases). The phrase "e.e." indicates an abbreviation for the enantiomeric excess and is defined as the fraction of moles indicated by the enantiomers in a mixture:% e.e. = [R] - [S] / [R] + [S] where [R] and [S] are the concentrations of enantiomers. { R) ~ and (S) -. In a reaction of a chiral compound it is often obtained as a mixture of enantiomers. If, for example, 80% of the enantiomer is formed. { R) ~ and 20% of the (S) - enantiomer is also formed, then the e.e. is: 80-20 / 80 + 20 = 60%. Detailed Description of the Invention The present invention is described in more detail in the following non-limiting examples. Examples from 1 to 3 In these examples the following method was used, with the quantities and volumes underlined in Table 1. The racemic derivative of mandelic acid 3-chloro acid, 5-difluoro-methoxy mandelic and prolinamide (D) - were added to ethyl acetate saturated in water (8.1% water in ethyl acetate). The mixture was heated to reflux and stirred for 10 minutes at reflux. The thin suspension was cooled to a temperature of 23 ° C for 13 hours followed by an additional cooling to 18 ° C for 40 minutes. The suspension was filtered and washed with ethyl acetate (3 x 30 ml) to produce the salt. A sample was dissolved in a 1: 1 mixture of 1 M HCl and ethyl acetate. The organic layer was separated, concentrated until dried and analyzed by chiral HPLC (for a suitable methodology, see Example 11A). This showed a high degree of purity of the "correct" enantiomer (see table 1), acid. { R) -3-chloro, 5-di fluoro-met oxy-mandelic. Table 1 MA = racemic derivative of mandelic acid, 3-cioro, 5-difluoro-methoxy mandelic acid. PA = prolinamide - (D). Eq. PA = Amount of prolinamide equivalents (D) -compared with the racemic derivative of mandelic acid.

EtOAc = ethyl acetate, as a solution in water. Water / EtOAc (%) = water concentration in ethyl acetate. mmol MA / mi water-EtOAc = concentration range of the racemic derivative of mandelic acid per ml of ethyl acetate and water. e.e. (%) = enantiomeric excess defined as the% of the fraction of moles indicated by the enantiomers in a mixture. 1) Corrected for purity, that is, the racemic derivative of 86% pure mandelic acid initially. Examples from 4 to 9 In these examples the following method was used, with the quantities and volumes underlined in Table 2. The racemic derivative of mandelic acid 3-chloro acid, 5-difluoro-methoxy mandelic acid and prolinamide (D) - were added to saturated ethyl acetate and the mixture was heated to reflux. At reflux, water was added and the mixture was stirred for another 10 minutes at reflux. The thin suspension was allowed to cool to a temperature of 18 ° C for 3 hours (in Examples 4 to 8, 4 hours in Example 9). The suspension was filtered and washed with ethyl acetate (3 x 30 ml) to produce the salt. The salt was dissolved in a 1: 1 mixture of 1M HCl and ethyl acetate. The organic layer was separated, concentrated until dried and analyzed by chiral HPLC (for the appropriate methodology, see example 11A). This showed a high degree of purity of the "correct" enantiomer (see Table 2), (R) -3-chloro, 5-difluoro-methoxy-mandelic acid.

For the purpose of exemplifying in greater detail, the following scheme was used in example 6: The racemic derivative of mandelic acid 3-chloro, 5-difluoro-methoxy-mandelic acid (26.18 g, 93.3 mmol, 1 eq, 90% pure according to HPLC) and prolinamide (D) - (4.80 g, 42 mmol, 0.45 eq) were added to ethyl acetate (54.5 ml) and the mixture was heated to reflux. At reflux, 5.5 ml of water was added and the mixture was stirred for another 10 minutes at reflux. The thin suspension was allowed to cool to a temperature of 18 ° C for 3 hours. The suspension was filtered and washed with ethyl acetate (3 x 30 mL) to yield 8.6 g of salt. The sample was dissolved in a 1: 1 mixture of 1M HCl and ethyl acetate. The organic layer was separated, concentrated until dried and analyzed by chiral HPLC. This showed 98.2% of the enantiomer. { R) ~ "correct". From the mother liquor there was more crystallized material, which was filtered, washed and dried. This produced another 1.6 g of salt. Mandelic acid. { R) ~ free was analyzed by HPLC (for the appropriate methodology, see example 11 A), and contained 99.0% of the "correct" enantiomer.

Table 2 MA = racemic derivative of mandelic acid, 3-chloro, 5-difluoro-methoxy mandelic acid. PA = prollnamide (D) -. Eq. PA = Amount of prolinamide equivalents compared to the racemic derivative of mandelic acid. EtOAc = ethyl acetate, in me. Water / EtOAc (%) = water concentration in ethyl acetate. mmol MA / mi water-EtOAc = concentration range of the racemic derivative of mandelic acid per ml of ethyl acetate and water. e.e. (%) = enantiomeric excess defined as the% of the fraction of moles indicated by the enantiomers in a mixture. 1) Corrected for purity, that is, the racemic derivative of mandelic acid was initially 85% to 90% pure. 2) The suspension was allowed to cool to a temperature of 18 ° C for 4 hours. Example 10 The racemic derivative of mandelic acid 3-chloro, 5-difluoro-methoxy-mandelic acid (0.2 g, 0.79 mmol) and prolinamide (L) - (0.05 g, 0.48 mmol, 0.6 eq) were added to 1 ml of dioxane and the mixture was heated to a temperature of 90 ° C. During the heating a thick suspension was formed. The suspension was filtered and the mandelic acid (S) - released by an extraction run using 1M HCl and ethyl acetate. 0.05 g of the enantiomer was obtained with an ee: of 92%. Example 11: Racemization procedure Once the desired salt of mandelic acid / prolinamide (MAP) ("correct") has been isolated by filtration, the mother liquors containing an excess of another enantiomer of mandelic acid ("wrong") (and also some of the prolinamide salt without precipitating the "correct" mandelic acid) can be racemized - see following racemization scheme. The resulting racemate can be used again in the process of the present invention to isolate more of the desired enantiomer. This racemization / recycling process can be repeated a number of times to obtain higher yields of the desired enantiomer, for example, two recycled can allow up to 70% overall yield of the "correct" mandelic acid and three recycled ones can allow a yield up to 80% Racemization Scheme Example 11A: Racemization of mother liquor The mother liquor, in ethyl acetate, of the resolution process (for example, from any of the examples from 1 to 9 above), which contains the "wrong" enantiomer of excess mandelic acid (3.35) kg, 3.53 L, corresponds to 0.462 kg of mandelic acid, 1.83 mol) was concentrated under reduced pressure at a temperature of 50 ° C to 55 ° C at a volume of 2.78 L. The solution was extracted at a temperature of 15 ° C at 25 ° C with 10% aqueous hydrochloric acid (0.62 kg, 1.69 mol, 0.92 eq) to remove prolinamide-D. The organic solution was washed with deionized water (0.58 kg) after which the phase inversion with the organic phase under the aqueous phase occurred. Sodium chloride (0.030 kg) was added to reverse the phases and the phases were separated. The organic phase was washed with 8.7% aqueous NaHCO3 (0.71 kg, 0.74 mol, 0.40 eq). The organic phase was concentrated with as much as possible under reduced pressure at a temperature of 50 ° C to 60 ° C. The remaining residue (0.483 kg) had a chemical purity of 76.5% determined by HPLC and an optical purity for the S-enantiomer of 81% determined by chiral HPLC. The residue was dissolved in methanol (1.33 kg, 1.67 L) and 30% aqueous potassium hydroxide (0.84 kg, 4.46 mol, 2.43 eq) was added at a temperature of 25 ° C to 40 ° C. The mixture was heated to a temperature of 68 ° C to 75 ° C and stirred for about 3.5 hours until complete racemization had occurred according to the chiral HPLC. The methanol was distilled under reduced pressure at a temperature of 40 ° C to 50 ° C. Dichloromethane (1.35 kg, 1.02 L) and water (0.20 kg) were added to the aqueous solution and the mixture was cooled to a temperature of 0 ° C to 5 ° C. 20% aqueous hydrochloric acid (1.17 kg, 1.10 L, 6.41 mol, 3.50 eq) was added within 20 minutes to the stirred mixture of two phases at a temperature of 0 ° C to 20 ° C (exothermic reaction, pH = 1). The mixture was stirred for a period of about 10 minutes at a temperature of 20 ° C to 25 ° C until the precipitated oily product was completely dissolved in dichloromethane. The phases were separated and the aqueous solution was extracted with dichloromethane (0.53 kg, 0.40 L). The combined organic phases were washed with water (0.48 kg), and concentrated under reduced pressure at a temperature of 40 ° C to 50 ° C. This produced 0.443 kg of an oily product with an HPLC purity of 97.1% area. The HPLC conditions used to determine the purity of the MAP salt by HPLC were: Column: Symmetry Shield RP8, 2.1 x 50 mm, 3.5 μm, Waters Flow range: 0.5 mL / min. Detection: UV, 220 nm. Volume injection: 15 μL. Column temperature: 20 ° C. "Operation time": 35 minutes; later time: 5 minutes. Mobile phase: A: 50 ml acetonitrile + 200 ml of ammonium hydrogen phosphate buffer + 750 ml of pure water.

B: 800 mL of acetonitrile (grade-HPLC) + 200 mL of ammonium dihydrogen phosphate buffer Gradient: The HPLC conditions used for the determination of the optical purity of the MAP salt by HPLC were: Column: Chiralpak AD, 250 x 4.6 mm, DAICEL Flow range: 1.0 mL / min. Detection: UV, 215 nm. Injection of volume: 10 μL Temperature of the column: 20 ° C "Time of operation": 30 minutes. Mobile phase: n-Hexane / 2-propane / trifluoroacetic acid = 900 mL / 100 mL / 1 mL. The resulting racemate can be used again in the process of the present invention to isolate more of the desired enantiomer, for example, according to the following example.

Example 11B: Mandelic acid resolution obtained after racemization A racemic solution of mandelic acid (obtained after the first racemisation) in ethyl acetate (1433 kg of a 29.9% solution (w / w), 0.429 kg of mandelic acid racemic, 1698 mol, 1.00 eq) were filtered and added in a period of 30 minutes to a stirred solution of D-prolinamide (0.095 kg)., 0.853 mol, 0.49 eq) in ethyl acetate (0.407 kg, 0.452 L), as well as water (0.153 kg) at a temperature of 72 ° C to 75 ° C. After the addition was completed a clear solution was obtained. The mixture was cooled to a temperature of 58 ° C within a period of 45 minutes. No crystallization was observed. The mixture was further cooled to a temperature of 0 ° C to 2 ° C in 2.5 hours. The salt began to precipitate at a temperature of approximately 55 ° C. After stirring for an additional 1 hour at a temperature of 0 ° C to 2 ° C, the solid was filtered and washed twice with a pre-cooled mixture (temperature 0 ° C to 5 ° C) of ethyl acetate / water = 9 : 1 (w / w, 2 x 0.20 kg). A colorless wet powder (0.264 kg) with a purity of 99.3% and an optical purity of 97.6% was obtained. If necessary, the optical purity can be further improved by forming a paste of the product with ethyl acetate / water and filtering it. For example, the optical purity can be further improved by the following new resolution procedure. Example 11C: New Resolution Procedure The D-prolinamide salt of wet mandelic acid (0.264 kg) was suspended in a mixture of ethyl acetate (1.00 kg, 1.11 L) and water (0.10 kg). The suspension was heated to a temperature of 73 ° C to 75 ° C and stirred for 30 minutes at this temperature. The suspension was cooled to a temperature of 3 ° C to 5 ° C over a period of 2 hours and then stirred for another hour at this temperature. The solid was filtered and washed twice with a pre-cooled mixture (temperature 0 ° C to 5 ° C) of ethyl acetate / water = 9: 1 (w / w, 2 x 0.38 kg). The white solid was dried under reduced pressure 0.01019716 kg / cm2 (10 mbars) at a temperature of 35 ° C at 40 ° C until the D-prolinamide salt of mandelic acid had a constant weight. This produced 0.225 kg of the product (73.9%, based on D-prolinamide), with a chemical purity of >99% and an optical purity of > 99% This racemization resolution procedure can be repeated, for example, twice. In addition, the D- or L-prolinamide can be recycled using conventional extraction techniques. Example 12: Different Salts Once the enantiomers of mandelic acid are separated then the desired enantiomer can be isolated as a different salt suitable for further processing. Depending on which enantiomer of mandelic acid is required, said different salt can be isolated, either from the prolinamide salt or from the remaining mother liquors after the prolinamide salt has been filtered. Therefore, for example, the salt of D-prolinamide. Acid (R) -3-chloro, 5-difluoro-methoxy mandelic can be isolated and then converted to a different salt for further processing. The recycled mother liquors can then be racemized, for example, as described above. Alternatively, the salt of L-prolinamide. (S) -3-Chloro, 5-difluoro-methoxy-mandelic acid can be isolated and a different salt of (R) -3-chloro, 5-difluoro-methoxy-mandelic acid can be isolated from the mother liquors. The salt of L-prolinamide. (S) -3-Coryne, 5-difluoro-methoxy mandelic acid ,. It can then be used for racemization and recycling. (R) -3-chloro, 5-difluoro-methoxy mandelic acid, acid ((2R) - [3-chloro-5- (difluoromethoxy) -phenyl] (hydroxy) acetic) is a useful intermediate but the free acid compound has a low melting point of (52 ° C) and is difficult to crystallize . In addition, (R) -3-chloro, 5-difluoro-methoxy mandelic acid is very soluble compared to unsubstituted mandelic acid.

As mentioned above, although 3-chloro, 5-difluoro-methoxy mandelic acid has the ability to form salts with, for example, a, a-diphenyl-D-prolinol, said salts are not satisfactory for the manufacturing processes of large scale (having a low yield and a low enantiomer surplus). The above examples describe the isolation of, for example, (R) -3-chloro, 5-difluoro-methoxymandelic acid from a racemic mixture by resolution with D-prolinamide. These salts that resolve the cyclic amide are expensive and therefore, less expensive salts that allow even more efficient manufacture on a large scale are of additional interest. New salts of our substituted mandelic acids (of the formula I) are now manufactured as a further feature of the present invention. The discovery of such salts provides inexpensive and efficient isolation of our mandelic acids in the form of solids, thereby creating opportunities for economic enantioselective processes and for process improvements using resolution with, for example, D-prolinamide. The enantioselective routes for (R) -3-chloro, 5-difluoro-methoxy-mandelic acid are also of interest and in such cases, an inexpensive, efficient salt of mandelic acid is attractive. Preferably, the salt must be crystalline, improve the enantiomeric purity at the time of formation and be used directly in a reaction (subsequent coupling). The following examples describe the preparation of certain metal salts of (R) -3-cyano, 5-difluoro-methoxy mandelic acid (calcium, zinc and magnesium salts). Also disclosed is the preparation of certain amine salts of (R) -3-chloro, 5-difluoro-methoxy-mandelic acid (ie, the salts formed with 4-hydroxy-2,2,6,6-tetramethylpiperidine, triethanolamine, piperazine, 1,4-dimethylpiperazine, 2,4,6-trimethylpyridine and 4-hydroxy-1, 2,2,6,6-pentamethylpiperidine Example 12A: Ca. Zn v Mq salts of (R) -3- acid chlorine, 5- Calcium Salt To a suspension of 0.449g (1778 mmol) of (R) -mandelic acid (prepared from a salt (R) -MA- (D) -PA using HCl (aqueous) and a water wash) in water (2.5 ml) was added to 25% w / w of a solution of ammonia in water (0.133 g, 1956 mmol, 1.1 eq), with a water transfer wash ( 0.15 mi). To the resulting solution was added a solution of 0.118 g (1.067 mmol, 0.6 eq) of calcium chloride in 0.7 ml of water, with a water transfer wash (0.1 ml). A solid formed immediately. After 1 hour at room temperature, the mixture was cooled with an ice bath and kept at a temperature of 0 ° C for 2 hours. Then, the suspension was filtered and the solid material washed twice with ice water (2 x 0.9 ml). The compound was dried under vacuum at a temperature of 40 ° C to yield 0.37 g (0.681 mmol, 76.6%) of the crystalline calcium salt (confirmed by XRPD - as described below). The procedure can also be done with calcium acetate, instead of calcium chloride. Magnesium and Zinc salts The crystalline magnesium and zinc salts (confirmed by XRPD - as described below) were obtained using a procedure analogous to that described for the calcium salt. The magnesium salt of (R) -mandelic acid was obtained in a yield of 16% (PF = 186 ° C) and the zinc salt of (R) -mandelic acid was obtained in a yield of 78%. In a further experiment, the magnesium salt of a racemic 3-chloro, 5-difluoro-methoxy mandelic acid (75% yield) was obtained, using a procedure analogous to that described above by the addition of 0.6 equivalents of magnesium hydroxide to a suspension of racemic mandelic acid in water. The salt was obtained as a crystalline solid (confirmed by XRPD), with a melting point of 113 ° C. Example 12B: Amine salts of (R) -3-chloro, 5-difluoro-methoxy mandelic acid Example 12B-1: Triethanolamine salt Triethanolamine (211.8 μl, 1564 mmol) was added to a 0.356 M solution of (R) -mandelic acid (0.359 g, 1422 mmol, prepared from a salt (R) -MA- (D) -PA using HCl (aqueous ) and washed with water) in ethyl acetate at room temperature. The addition was accompanied by a weak exotherm. The solution was heated to a temperature of 66 ° C and isooctane was added until the solution started to become cloudy. The solution was slowly cooled to room temperature overnight. Then the solution was cooled to a temperature of 0 ° C and the salt precipitated after 1 hour of stirring at a temperature of 0 ° C. The suspension was stored in a refrigerator overnight, filtered, washed with EtOAc / Isooctane 1.46: 1 (2x1.23 ml), then dried under vacuum at a temperature of 40 ° C to produce 0.500 g (1.244 mmol, 88%) of the triethanolamine salt of (R) -3-chloro, crystalline 5-difluoro-methoxy mandelic acid (melting point (MP) = 68 ° C). The crystallinity of the triethanolamine salt of (R) -mandelic acid was confirmed by DSC (endothermic presentation = 68 ° C), XRPD. The following XRPD values d- and intensities were obtained: The reproducible main peaks have been tabulated using the following definitions: vs (very strong): > 50% int. I laughed s (strong): 28-50% int. I laughed m (medium): 9-28% int. I laughed w (weak): 4-9% int. I laughed vw (very weak): < 4% int. The relative intensities are calculated from the diffractograms measured with variable divisions. X-ray powder diffraction analysis (XRPD) was performed on the samples prepared according to standard methods, for example, those described in the books of Giacovazzo, C. et al (1995),, "Fundamentals of Crystallography "(Fundamentáis of Crystallography), Oxford University Press; Jenkins, R. and Zinder, R.L. (1996), "Introduction to X-ray Powder Diffractometry" (Introduction to X-Ray Powder Diffractometry), John Wiley & Sons, New York; Bunn, C.W. (1948), "Chemical Crystallography", Clarendon Press, London; or Klug, H.P. & Alexander, L.E. (1974); "X-ray Diffraction Procedures" (X-ray Diffraction Procedures), John Wiley and Sons, New York. X-ray analyzes were performed using a PANalytical X'Pert PRO MPD diffractometer. The sample was analyzed with and without internal reference. The measured peak values were adjusted and subsequently calculated in values / -d. Differential scanning calorimetry (DSC) was performed using a PerkinEImerDSC7 instrument, according to standard methods, for example, those described in Hóhne's book, G.W.H. et al (1996), (Differential Scanning Calorimetry) "Differential Scanning Calorimetry", Springer, Berlin. The initial temperatures of the DSC can vary in a range of ± 5 ° C (for example ± 2 ° C) and the distance values XRPD can vary within a range of ± 2 in the last decimal place designated. Example 12B-2: Other Amine Salts The crystalline solid salts of (R) -3-chloro, 5-difluoro-methoxy-mandelic acid with 4-hydroxy-2,6,6,6-tetramethylpiperidine (PF = 153 ° C) , piperazine (PF = 135 ° C), 1,4-dimethylpiperazine (PF = 93 ° C), 2,4,6-trimethylpyridine (PF = 66 ° C) and 4-hydroxy-1,2,2,6, 6-pentamethylpiperidine (MP = 145 ° C) were obtained analogously to Example 12B-1. The crystallinity of the above amine salts of (R) -mandelic acid was confirmed by XRPD as described herein. The above amine salts can be formed with the single (R) - or (S) - enantiomer or with a racemate of 3-chloro, 5-difluoro-methoxy-mandelic acid. For example, the solid salts of a racemate of 3-chloro, 5-difluoro-methoxy-mandelic acid were obtained by a procedure analogous to that described above with 4-hydroxy-2,2,6,6-tetramethylpiperidine, triethanolamine ( crystalline, PF = 53 ° C), 2,4,6-trimethylpyridine (crystalline, PF = 72 ° C) and 4-hydroxy-1,2,2,6,6-pentamethylpiperidine (crystalline, PF = 120 ° C) . The dicyclohexylamine salt of an acid racemate of 3-Chloro, 5-difluoro-methoxy mandelic was obtained by a procedure analogous to that described above, (but no dicyclohexylamine salts were obtained from the MA enantiomers alone).

Example 12C: Enantiomeric Selectivity of the Conglomerate Triethanolamine Salt The triethanolamine salt of 3-chloro-5-difluoromethoxy mandelic acid is particularly interesting, since it occurs as a crystalline conglomerate. It is possible to improve the enantiomeric excess of (R) -3-chloro, 5-difluoro-methoxy-mandelic acid as the product of an enantioselective process. There is a difference between a conglomerate and a racemic compound. Seeing a 50:50 mixture of both enantiomers, a conglomerate consists of a mixture of crystals of the two enantiomers in equal amounts. Although the volume of the conglomerate is optically neutral, the individual crystals contain only the R or S enantiomer. This is in contrast to a racemic compound, where the individual crystals contain equal amounts of both enantiomers and the racemic crystals form a perfectly ordered arrangement of R and S molecules. Racemic compounds and conglomerates can be distinguished by determining their melting point diagrams (phase diagram) or by using X-ray powder diffraction or solid state IR spectroscopy; the data of the pure enantiomers are identical to the data of the conglomerate, but different from those of the racemic compound.

For the triethanolamine salt of 3-chloro-5-difluoromethoxy mandelic acid, in the form of a conglomerate, it is possible to isolate the triethanolamine salt of mandelic acid (R) from an enantiomerically enriched mandelic acid mixture by direct crystallization. The maximum amount of theoretical production can be calculated by: 100-100x (amount of the wrong enantiomer present in the mixture + the same amount of the desired enantiomer) / total amount of the solid. For example, starting with 95% w / w of the desired enantiomer, the maximum yield is 90%. Starting with 90% w / w of the desired enantiomer, the maximum yield is 80%, etc. The (R) -3-chloro-5-difluoromethoximidelic acid with an e.e. 90% can, for example, be the product of an enantioselective process. Example 12C-1 The racemic acid of 3-chloro-5-difluoromethoxy mandelic acid (51.25 mg, 0.203 mmol) was added to a 0.351 M solution of mandelic acid- (R) (0.607 g, 2.405 mmol, prepared from the salt (R) -MA-D-PA using HCl (aqueous) and washing water) in ethyl acetate at room temperature. The enantiomeric excess of mandelic acid- (R) in the solution was determined as 92.4% by a chiral HPLC analysis (performed as in Example 11 above). Triethanolamine (0.417 g, 2.739 mmol) was added to the solution at a temperature of 23 ° C. The temperature was raised to 25 ° C at the time of the addition. The solution was heated to a temperature of 70 ° C. At 70 ° C, isooctane (1.5 ml) was added and the solution was seeded with a few granules of triethanolamine salt of (R) -3-chloro-5-difluoromethoxy mandelic acid (99.8% ee, see Example 12B). The solution was cooled to 65 ° C and because the crystallization had not started the seeding was repeated. The solution was cooled to a temperature of 26 ° C for 3 hours, but as there was still no precipitation of the salt, the solution was again heated to 70 ° C seeded and then allowed to cool. Finally, the crystallization began at a temperature of 58 ° C after another seeding. The suspension was cooled to room temperature and allowed to stir overnight. A sample was filtered the next morning, whose optical purity was determined as ee of 98.1%, by chiral HPLC analysis (see Example 11). The volume of the suspension was cooled to and stirred at a temperature of 1 ° C for 2% hours. The salt was isolated by filtration, washed with EtOAc / isooctane 2.5: 1 (2x2.07 ml) and dried under vacuum at a temperature of 40 ° C overnight to produce the triethanolamine salt of (R) -3-chloro acid. -5-difluoromethoxy mandelic acid in the form of a white powder (0.897 g, 88.8%). The optical purity of the salt was determined in an ee of 99.5%, by analysis of chiral HPLC (see Example 11).

Example 12C-2 The racemic acid of 3-chloro-5-difluoromethoxy mandelic acid (371.29 mg, 1470 mmol) was added to a 0.351 M solution of mandelic acid- (R) (3,500 g, 13856 mmol, salt preparation) (R) -MA- (D) -PA using HCl (aqueous), and washing water) in ethyl acetate at room temperature. The enantiomeric excess of the mandelic acid (R) of the solution was determined in 91.1% by chiral HPLC analysis (see Example 11). Triethanolamine (2566 g, 16,856 mmol) was added to the solution at a temperature of 23 ° C. The temperature rose to 29 ° C at the time of addition. The solution was heated to 70 ° C. At 70 ° C isooctane (8.6 ml) was added and the solution was seeded with a few granules of triethanolamine salt of (R) -3-chloro-5-difluoromethoxyamandlic acid (99.8% ee; see Example 12B). The solution was cooled to 65 ° C and because the crystallization had not started the seeding was repeated. The solution was cooled by stages and planted four times more. Finally, at a temperature of 40 ° C, the salt crystallized. The suspension was cooled to room temperature and allowed to stir overnight. A mixture was filtered the next morning, the optical purity of it was determined in an ee of 97.0%, by chiral HPLC analysis (see Example 11). The volume of the suspension was cooled and stirred at a temperature of 1 ° C for 2% hours, the salt was isolated by filtration, washed with EtOAc / isooctane 4: 1 (2x7.5 ml) and dried under vacuum at a temperature of 40 ° C overnight to produce the triethanolamine acid salt of (R) -3-chloro-5-difluoromethoxyd mandelic acid in the form of a white powder (5.451 g, 92.0%). The optical purity of the salt was determined in an ee of 98.7%, by chiral HPLC analysis (see Example 11). It should be noted that any of the salts described herein can be in the form of polymorphs, solvates or hydrates and said forms are also covered by the present invention. Any tautomers of the mandelic acid derivatives described herein are also covered by the present invention.

Claims (16)

w.
1. CLAIMS 1. A process for the resolution of optionally substituted (R) - or (S) - mandelic acids of racemic mixtures of said mandelic acids optionally substituted by salt formation with a cyclic amide (D) - or (L) - of quiral base, which comprises the steps of: (a) forming a mixture in a solvent, or mixture of solvents, of an optionally substituted racemic mandelic acid and a cyclic amide (D) - or (L) - of quiral base, in where the quiral base used is either (D) for the separation of the macronic acids- (R), or (L) for the separation of mandelic acids- (S); in a molar ratio of acid: base of 1: 0.25-0.75; wherein the solvent or mixture of solvents may optionally contain water in a range of 5% to 15% (volume) of the solvent; and (b) separating the respective salt of cyclic amide-mandelic acid (R) / (D) or (S) / (L). 2. A process, as described in claim 1, for the resolution of substituted (R) - or (S) - mandelic acids of racemic mixtures of said substituted mandelic acids by salt formation with a cyclic amide (D) ) - or (L) - of a pyralic base, which comprises the steps of: (a) forming a mixture in a solvent, solvent mixture of a racemic derivative of mandelic acid of the formula I; wherein R is selected from CHF2, H, C? _6 alkyl, CH2F, CHCI2 and CCIF2; and any one of a cyclic amide- (D) of cyclic bases or cyclic amides- (L) the formula I (x) wherein n is 0, 1, or 2; R-i is H or C - .. 6 Alkyl and X is H, halo or C 1-6 Alkyl,
2. I (x) wherein the quiral base used is either (D) for the separation of mandelic acids- (R) or (L) for the separation of mandelic acids- (S); in a molar ratio of acid: base of 1: 0.25-0.75; wherein the solvent or mixture of solvents may optionally contain water in the range of 5% to 15% (volume) of the solvent; and (b) separating the cyclic amide salt-mandelic acid (R) / (D) or (S) / (L) of the formula lia;
3. 3. A process as described in claim 1 or 2, characterized in that the cyclic amide / mandelic acid salt (R) / (D) is of the formula VI; SAW
4. 4. A process as described in any of claims 1 to 4, characterized in that the solvent used is selected from ethyl acetate, acetonitrile, acetone, 2-butanone, 4-methyl-2-pentanone, tert-butyl methyl ether, 2-propanol and ethanol or a mixture of any of these solvents.
5. 5. A process as described in claims 1 to 5, characterized in that the solvent used is ethyl acetate.
6. 6. A process as described in any of claims 1 to 5, characterized in that the mezcal is heated (preferably under reflux) before cooling and filtering the cyclic amide salt-mandelic acid (R) / (D) or (S) / (L). 7. A process as described in any of claims 1 to 6, characterized in that the molar ratio of acid: base is 1: 0.4-0.
7. 7.
8. 8. A process as described in any of claims 1 to 3, characterized in that the cyclic amide salt-mandelic acid is separated, the mother liquors are racemized and the process repeated, at least once for also obtain a resolved cyclic amide-mandelic acid salt.
9. 9. A cyclic amide / mandelic acid salt A (R) / (D) or (S) / (L) having the formula lb; wherein R is selected from CHF, H, C1-6 alkyl, CH2F, CHCI2 and CCIF2; and wherein n is 0.1 or 2; R, is H or C 1-6 alkyl and X is H, halo or C-? - 6 alkyl.
10. 10. A cyclic amide salt / mandelic acid A (R) / (D) as described in claim 9, which is of the formula VI: SAW
11. 11. A metal salt of a mandelic acid derivative of the formula la; the wherein R is selected from CHF2, H; C - .. 6 Alkyl, CH2F, CHCI2 and CCIF2; wherein the metal ion M is selected from calcium, zinc, magnesium.
12. 12. A metal salt as described in claim 11, characterized in that the mandelic acid derivative of the formula la is the mandelic acid derivative (R) or mandelic acid- (S), preferably the mandelic acid- ( R). 13. An amine salt of a mandelic acid derivative of the formula Ib;
13. Amina-H + wherein R is selected from CHF2, H, C? -6-Alkyl, CH2F, CHCI2 and CCIF2; wherein the amine is selected from triethanolamine, 4-hydroxy-2,2,6,6-tetramethylpiperidine piperazine, 1,4-dimethylpiperazine, 2,4,6-trimethylpyridine, 4-hydroxy-1, 2,2, 6, 6-pentamethylpiperidine or dicyclohexylamine.
14. 14. An amine salt as described in claim 10, characterized in that the mandelic acid derivative of formula Ib is (R) - or (S) - mandelic acid, wherein the amine is selected from triethanolamine, -hydroxy-2, 2, 6,6-tetramethyl piperidine, piperazine, 1,4-dimethylpiperazine, 2,4,6-trimethylpyridine or 4-hydroxy-1, 2,2,6,6-pentamethylpiperidine.
15. 15. An amine salt as described in claim 13 or 14, characterized in that the mandelic acid derivative of the formula Ib is mandelic acid - (R), and the amine is triethanolamine.
16. 16. The salt as described in any of claims 9 to 15, characterized in that the mandelic acid is (R) -3-chloro, 5-difluoro-methoxy-mandelic acid ((2R) - [3] -chloro-5- (d if lu oromet ox i) f enyl] (hydroxy) acetic).