KR101073742B1 - - resolution of -phenoxyphenylacetic acid derivatives - Google Patents

Abstract

The present invention provides a process for the preparation of enantiomerically rich α- (phenoxy) phenylacetic acid compounds of formula (I) from their enantiomeric mixtures.

Formula I

In Formula I above,

R ¹ is alkyl or haloalkyl,

X is a halide.

Description

Separation of α- (phenoxy) phenylacetic acid derivative {RESOLUTION OF α- (PHENOXY) PHENYLACETIC ACID DERIVATIVES}

The present invention relates to an enantiomeric selective separation process for separating α- (phenoxy) phenylacetic acid from an enantiomeric mixture.

Esters and amide derivatives of α- (phenoxy) phenylacetic acid (e.g. halophenates) are chiral compounds and are useful in ameliorating various physiological diseases including diseases associated with blood lipid precipitation (e.g., type II diabetes and hyperlipidemia). Do. See, for example, US Pat. Nos. 3,517,050 and 6,262,118. α- (phenoxy) phenylacetic acid contains a single chiral center at carbon atom α which is asymmetrically substituted for carbonyl carbon atoms and thus exists in two enantiomer forms.

Cytochrome P450 2C9 is an enzyme known to play an important role in the metabolism of certain drugs. Changes in drug metabolism mediated by inhibition of cytochrome P450 enzymes are known to those of skill in the art that they are likely to promote significantly adverse effects on patients. It is also known that racemic α- (phenoxy) phenylacetic acid, such as halofenic acid, inhibits cytochrome P450 2C9. See, for example, US Pat. No. 6,262,118. Thus, the administration of racemic α- (phenoxy) phenylacetic acid, for example halofenic acid or derivatives thereof, may involve various drug interactions with other drugs, including anticoagulants, anti-inflammatory agents and other drugs that are metabolized by such enzymes. May cause functional problems. It was found that the (-)-enantiomer of halofenic acid was about 20 times less active than the (+)-enantiomer in its ability to inhibit cytochrome P450 2C9. Thus, it is desirable to administer (-)-enantiomers or derivatives thereof of halofenic acid that are substantially free of (+)-enantiomers to reduce the likelihood of drug interactions.

Thus, there is a need for an efficient process for producing a desired enantiomer-rich product of α- (phenoxy) phenylacetic acid, for example (-)-halophenic acid.

Summary of the Invention

One aspect of the present invention provides an enantiomerically rich α- (phenoxy) of the following formula from an enantiomeric mixture of an α- (phenoxy) phenylacetic acid compound comprising a first enantiomer and a second enantiomer. Provided are methods for preparing a phenylacetic acid compound.

In the above formulas,

R ¹ is alkyl or haloalkyl,

X is a halide.

In one particular embodiment, the enantiomer mixture is a racemic mixture.

The method of the present invention

(a) The enantiomer mixture of the α- (phenoxy) phenylacetic acid compound is prepared under conditions sufficient to produce a ratio of the amount of free first enantiomer to free second enantiomer in the solution of about 1: 3. Contacting with less than 0.5 molar equivalent of an enantiomerically rich chiral amine compound to prepare a solution comprising an enantiomerically rich solid acid-base salt of a first enantiomer; And

(b) separating the solid acid-base salt of the first enantiomer from the solution at a temperature at which the concentration of the acid-base salt of the second enantiomer of the α- (phenoxy) phenylacetic acid compound is near or below its saturation point. Steps.

At least a portion of the second enantiomer can be converted to the first enantiomer by contacting the second enantiomer with a base, for example racemic. The enantiomeric mixture obtained is then recycled to a similar enantiomeric incubation process and run to increase the yield of the first enantiomeric acid-base salt.

In one particular embodiment, the chiral amine compound is a chiral amine compound of the formula

In the above formulas,

R ² and R ³ are each independently hydrogen or alkyl,

R ² and R ³ together with the atoms to which they are attached form a heterocyclic ring moiety,

R ⁴ is hydrogen or alkyl,

R ⁵ and R ⁶ are each independently hydrogen or alkyl,

One of R ⁵ or R ⁶ is an amine protecting group,

Ar is aryl.

1 is a graph showing solubility profiles of (-)-and (+)-CPTA / CAF D-base salts in 2-propanol.

2 shows the results of a process for separating racemic mixtures of CPTA using CAF D-base under various crystallization conditions.

3 is a graph showing solubility of (-)-and (+)-CPTA / CAF D-base salts in a solution comprising pure isopropanol and a mixture of isopropanol and CPTA (11%).

4 is a graph showing the composition of a mixture having various amounts of each component.

5 is a graph showing (-/ +)-saturation profile for crystallization and heating.

FIG. 6 is a table showing a comparison of model predictions to experimental results for description 4 of FIG. 2.

7 is a graph showing the amount of (+)-salt formation as a function of the amount of CAF D-base added.

FIG. 8 is a graphical representation of experimental data for the separation shown in Description 11 of FIG. 2.

9 shows a graphical comparison of CPTA actual measurements and calculations in mother liquor and calculated percentages of (+)-CPTA salts using experimental data. .

FIG. 10A is a table showing experimental data and solubility model calculation (ie, description 13 of FIG. 2) for FIG. 7.

FIG. 1OB is a table showing experimental data and solubility model calculation for Description 4 of FIG. 2 at 28.3 ° C. FIG.

11 is a graph showing solubility of racemic CPTA at various temperatures in 1,2-dichloroethane.

12 is a graph showing solubility of racemic CPTA at various temperatures in heptane.

FIG. 13 is a table of results in Example 24 showing CPTA separation yields using CAF D-base under various crystallization conditions.

FIG. 14 shows a cooling profile for the separate crystallization of the various disclosures in FIG. 2.

15 is a table showing the amount of (-)-halophenate obtained from the (-)-CPTA salt in Example 26.

FIG. 16 is a graph showing the solubility of racemic CPTA sodium salt in various temperatures in water.

17 is a graph showing the CPTA racemization profile at various pHs during hydrolysis of (−)-halophenate.

FIG. 18 is a table showing the results of CAF D-base recovery at various pH, as described in Example 30.

19 is an experimental result of the solubility measurement of racemic CPTA in 1,2-dichloroethane and heptane as measured in Example 33.

20 is an experimental result of the solubility measurement of racemic CPTA sodium salt in water, as measured in Example 41.

FIG. 21 shows experimental results for basic hydrolysis of (+)-halophenate as measured in Example 42.

1. Definition

"Alkyl" refers to a straight or branched chain aliphatic hydrocarbon group of 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 2-propyl, t-butyl, pentyl and the like.

"Aryl" refers to a monovalent monocyclic or bicyclic aromatic hydrocarbon residue consisting of 6 to 10 carbon ring atoms. Unless stated or indicated otherwise, the aryl group may be substituted with one or more substituents selected from alkyl, haloalkyl, nitro and halo, preferably one to three substituents, more preferably one or two substituents. More specifically, the term aryl includes, but is not limited to, phenyl, 1-naphthyl, 2-naphthyl, and the like, which is optionally substituted with one or more substituent (s) discussed above.

"CAF D base" refers to a chloramphenicol D base, ie, D-threo-(-)-2-amino-1- (nitrophenyl) -1,3-propanediol.

"Cyral" or "chiral center" refers to a carbon atom having four different substituents. However, the fundamental criterion of chirality is the non-superiomposability of the mirror.

The terms "CPTA" and "halofenoic acid" are used interchangeably herein and refer to (4-chlorophenyl) (3-trifluoromethylphenoxy) acetic acid.

"Enantiomeric mixture" means a chiral compound having a mixture of enantiomers and includes racemic mixtures. Preferably, the enantiomer mixture represents a chiral compound having substantially the same amount of each enantiomer. More preferably, the enantiomer mixture represents a racemic mixture in which each enantiomer is present in equal amounts.

"Enantiomerically rich" refers to a composition in which one enantiomer is present in greater amounts than before performing the separation process.

"Enantiomeric excess" or "% ee" refers to a different amount between the first enantiomer and the second enantiomer. Enantiomer excess is defined by the following formula:% ee = (first enantiomer (%))-(second enantiomer (%)). Thus, when the composition comprises 98% of the first enantiomer and 2% of the second enantiomer, the enantiomeric excess of the first enantiomer is 98% -2% or 96%.

The terms "halide" and "halo" are used interchangeably herein and refer to halogens, including F, Cl, Br and I, as well as pseudohalides such as -CN and -SCN.

"Haloalkyl" refers to an alkyl group, as defined herein, in which one or more hydrogen atoms are replaced with halogen and includes perhaloalkyl, such as trifluoromethyl.

"Halophenate" refers to 2-acetamidoethyl 4-chlorophenyl- (3-trifluoromethyl-phenoxy) acetate (ie, 4-chloro-α- (3- (trifluoromethyl) phenoxy) Benzeneacetic acid, 2- (acetylamino) ethyl ester or (4-chlorophenyl) (3-trifluoromethylphenoxy) acetic acid), 2- (acetylamino) ethyl ester).

"Heteroalkyl" refers to a branched or non-branched acyclic saturated alkyl moiety containing at least one heteroatom or at least one heteroatom containing substituent, wherein the heteroatom is O, N or S. Examples of heteroatom-containing substituents include = O, -OR ^a , -C (= O) R ^a , -NR ^a R ^b , -N (R ^a ) C (= O) R ^b , -C (= O) NR ^a R ^b and -S (O) _n R ^a , where n is an integer from 0 to 2. R ^a and R ^b are each independently hydrogen, alkyl, haloalkyl, aryl or aralkyl. Representative examples of heteroalkyls include N-acetyl 2-aminoethyl (ie, —CH ₂ CH ₂ NHC (═O) CH ₃ ).

The terms "heterocyclyl" and "heterocyclic ring" are used interchangeably and refer to non-aromatic cyclic moieties consisting of 3 to 8 ring atoms, with 1 to 3 ring atoms being N, O and S (O ) is a heteroatom selected from _n , where n is an integer from 0 to 2, and the remaining ring atoms are C, wherein one or two C atoms may be optionally substituted by a carbonyl group. Unless stated or indicated otherwise, the heterocyclyl ring may be optionally substituted independently with 1 to 3 substituents selected from halogen, alkyl, aryl, hydroxy, amino and alkoxy. More specifically, the term heterocyclyl includes, but is not limited to, 1,3-dioxane and derivatives thereof, and the like.

A "leaving group" has the meaning commonly associated with it in synthetic organic chemistry, i.e., an atom or group that can be substituted by a nucleophile, such as halo (eg, chloro, bromo and iodo), alkanesulfonyloxy, arerensul Phenyloxy, alkylcarbonyloxy (e.g. acetoxy), arylcarbonyloxy, mesyloxy, tosyloxy, trifluoromethanesulfonyloxy, aryloxy (e.g. 2,4-dinitrophenoxy), methoxy , N, O-dimethylhydroxyamino and the like.

The term "metal" includes group I, II and transition metals as well as main group metals such as B and Si.

"Optical purity" refers to the amount of a particular enantiomer present in the composition. For example, when the composition comprises 98% of the first enantiomer and 2% of the second enantiomer, the optical purity of the first enantiomer is 98%.

Unless stated otherwise, the term "phenyl" refers to an optionally substituted phenyl group. Suitable phenyl substituents are as described in the definition of “aryl”. Similarly, the term "phenoxy" is ^a residue of the formula -OAr ^a , wherein Ar ^a is phenyl as defined above. Thus, the term “α- (phenoxy) phenylacetic acid” refers to acetic acid substituted with phenyl optionally substituted at the 2-position and optionally substituted phenoxy moiety.

A "protecting group" refers to a moiety that, when attached to a reactive group in a molecular mask, reduces or interferes with this reactivity. Examples of protecting groups is described in these professional is incorporated by reference herein [see: TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3 rd edition, John Wiley & Sons, New York, 1999, and Harrison and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8 (John Wiley and Sons, 1971-1996). Representative hydroxy protecting groups include acyl groups, benzyl and trityl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers. Representative amino protecting groups include formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ), t-butoxycarbonyl (Boc), trimethyl silyl (TMS), 2-trimethylsilyl-ethanesulfonyl (SES ), Trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC), nitro-veratriloxycarbonyl (NVOC), and the like.

The term "velocity" refers to the speed of movement and / or thermodynamic speed when it relates to the formation of salts.

As used herein, the terms “treated”, “contacted” or “reacted” refer to the addition or mixing of two or more reagents under suitable conditions to produce the intended and / or desired product. The reaction to produce the intended and / or desired product does not necessarily occur directly from the combination of the two reagents initially added, ie the one produced in the mixture which ultimately forms the intended and / or desired product. It should be recognized that the above intermediate may be.

As used herein, the terms "as defined above" and "as defined herein" refer to not only a broad definition of a variable, when present, but also to a preferred, more preferred, and most preferred definition, if present. Quote.

Many organic compounds exist in optically active forms, ie they have the ability to rotate the plane of plane polarization. In describing optically active compounds, the prefixes R and S are used to indicate the absolute arrangement of the molecules with respect to their chiral center (s). The prefixes "d" and "l" or (+) and (-) are used to denote rotation symbols of planar polarization by the compound, and (-) or (l) means that the compound is "left-handed" and (+ ) Or (d) means that the compound is "priority". There is no correlation between absolute stereochemistry and nomenclature for rotation of enantiomers. In the chemical structures described, these compounds, the so-called "stereoisomers", are identical except that they are mirror images of one another. Certain stereoisomers are also referred to as "enantiomers", and mixtures of such isomers are often referred to as "enantiomeric" or "racemic" mixtures. Literature Reference: Streitwiesser, A. & Heathcock, CH , INTRODUCTION TO ORGANIC CHEMISTRY 2 nd Edition, Chapter 7 (MacMillan Publishing Co., USA 1981)].

The terms "substantially free of its (+)-stereoisomers" and "substantially free of its (+)-enantiomers" are used interchangeably herein and the composition is a (+)-isomer Relative to the (-)-isomer relative to In a preferred embodiment, the term “substantially free of its (+) stereoisomer” means that the (-)-isomer in the composition is at least 90% by weight and the (+)-isomer is at most 10% by weight. In a more preferred embodiment, the term “substantially free of its (+)-stereoisomers” means that the composition contains at least 99% by weight of (-)-isomer and up to 1% by weight of (+)-isomer. it means. In the most preferred embodiment, the term "substantially free of its (+)-stereoisomer" means that the composition contains more than 99% by weight of (-)-isomer. Such percentages are based on the total amount of isomers in the composition.

II. Introduction

Chiral synthesis has recently undergone extensive advances, but the separation of racemates remains optically active, i.e., the method of choice in industrial processes for preparing chiral compounds. Typically, chiral compounds are synthesized in racemic form and the final product is separated to give enantiomerically rich compounds.

This process of separating the final product is particularly useful for large scale preparation of pharmaceutically active chiral compounds. Although the enantiomers of chiral compounds have exactly the same chemical bonds, the spatial orientation of the atoms in the enantiomers is different. Thus, one enantiomer of a chiral drug often exhibits the desired activity, with significantly less side effect (s) than the other enantiomers. Although this relationship between the chirality of an optically active drug and its side effect (s) has previously been found, many chiral drugs are still administered in racemic form.

Diastereomeric crystallization is widely used on an industrial scale. The theoretical single pass yield of separation via diastereomeric crystallization is 50%. Typically, however, one or more recrystallization processes are required to produce a composition with sufficient optical purity.

The present invention provides a method for enantiomerically enantiomeric mixtures, preferably racemic mixtures of α- (phenoxy) phenylacetic acid compounds such as halofenic acid. Preferably, the process of the present invention provides a solid acid-base salt of the (-)-enantiomer of the α- (phenoxy) phenylacetic acid compound. In this way, the (-)-enantiomer can be easily separated from the solution.

The carboxylic acid group of the enantiomerically rich α- (phenoxy) phenylacetic acid is then activated by the carboxylic acid activation group to produce activated α- (phenoxy) phenylacetic acid, which is an alcohol, amine, thiol or other Reacting with the nucleophilic compounds can produce enantiomerically enriched α- (phenoxy) phenylacetic acid esters, amides, thioesters or other derivatives, respectively.

Thus, enantiomerically enriched α- (phenoxy) phenylacetic acid compounds prepared using the process of the present invention are, for example, α- (phenoxy) phenyl, as described in US Pat. No. 3,517,050. Useful for preparing acetic acid derivatives. In particular, the process of the present invention is useful for preparing (-)-halophenate.

III. Enantiomer Selective Crystallization

As indicated above, most enantiomer selective crystallization processes require one or more recrystallization processes to produce compositions with sufficient optical purity. However, we have found that under certain conditions described herein, α- (phenoxy) phenylacetic acid compounds with sufficient optical purity can be prepared in a single crystallization process. Thus, in one aspect, the process of the present invention is based on the surprising and unexpected finding that enantiomeric mixtures of α- (phenoxy) phenylacetic acid compounds can be enantiomericly enriched using chiral amine compounds. In particular, the process of the present invention is an α- (phenoxy) phenylacetic acid compound having an optical purity of at least about 90%, preferably at least about 95%, more preferably at least about 97%, and most preferably at least about 98%. To provide the desired enantiomer.

In one embodiment, the process of the invention provides an enantiomeric enrichment of an enantiomeric mixture, preferably a racemic mixture of the α- (phenoxy) phenylacetic acid compound of formula (I)

        Formula I

In Formula I above,

R ¹ is alkyl or haloalkyl,

X is a halide.

The process generally involves the formation of enantiomerically rich solid acid-base salts of α- (phenoxy) phenylacetic acid compounds using chiral amine compounds.

In particular, the process of the present invention relates to the separation of α- (phenoxy) phenylacetate acids of formula II, for example halofenic acid, wherein R ¹ is CF ₃ and X is Cl.

In the above formula (II)

R ¹ is alkyl or haloalkyl,

X is a halide.

In one particular embodiment, the process of the invention relates to the separation of α- (phenoxy) phenylacetate acid of formula I, or preferably formula II, wherein X is chloro.

In another embodiment, the process of the invention relates to the separation of α- (phenoxy) phenylacetic acid of formula I, or preferably formula II, wherein R ¹ is haloalkyl, preferably trifluoromethyl.

In one particular embodiment, α- (phenoxy) phenylacetic acid is crystallized using a chiral base. Various various chiral bases can be used, including those described in the Examples section below. Preferably, the chiral base used induces a solid acid-base salt of the (-)-enantiomer of α- (phenoxy) phenylacetic acid. In this way, the (-)-enantiomer is easily separated from the solution, for example by filtration. In one specific embodiment, the chiral base is an amine compound of formula III.

In Formula III above,

R ² and R ³ are each independently hydrogen, alkyl or hydroxy protecting groups,

R ² and R ³ together with the atoms to which they are attached form a heterocyclic ring moiety,

R ⁴ is hydrogen or alkyl,

R ⁵ and R ⁶ are each independently hydrogen or alkyl,

One of R ⁵ or R ⁶ is an amine protecting group,

Ar is aryl.

In one particular embodiment, R ² and R ³ together with the oxygen atom to which they are attached are 1,3-dioxane, substituted 1,3-dioxane (eg dialkyl substituted 1,3-dioxane, eg For example, 5,5-dimethyl-1,3-dioxane) or derivatives thereof.

In another embodiment, R ² and R ³ are hydrogen.

In another embodiment, R ⁴ is hydrogen.

In another embodiment, Ar is substituted aryl. Particularly preferred Ar residues are optically substituted phenyl. Particularly preferred Ar residues are 4-nitrophenyl.

In addition, the combination of the preferred groups described above will form another preferred embodiment. For example, one particular preferred chiral base is the amine compound of formula III above, wherein R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen and Ar is 4-nitrophenyl. And a particularly preferred α- (phenoxy) phenylacetic acid compound is a compound of formula II above, wherein R ¹ is trifluoromethyl and X is chloro. In this way, a wide variety of preferred chiral bases and α- (phenoxy) phenylacetic acid compounds are specified within the present invention.

의 키랄 아민 화합물(여기서, R², R³, R⁴ 및 Ar은 위에서 정의한 바와 같다)이 α-(페녹시)페닐아세트산 화합물의 결정화에 사용되는 경우, 더 높은 %ee는 키랄 아민 화합물을 0.5몰당량 미만, 바람직하게는 약 0.48몰당량 이하, 보다 바람직하게는 약 0.47몰당량 이하, 가장 바람직하게는 약 0.45몰당량 이하의 양으로 사용함으로써 수득된다. 에난티오머적으로 매우 풍부한 α-(페녹시)페닐아세트산 유도체를 수득하기 위해, 키랄 아민 화합물 그 자체는 에난티오머 순도가 충분해야 함을 인지해야 한다. The inventors of the present invention have found that the amount of chiral base used for the crystallization of α- (phenoxy) phenylacetic acid has a significant effect on the enantiomerically rich optical purity. For example, the chemical formula

When the chiral amine compound of R ² , R ³ , R ⁴ and Ar are as defined above, used for crystallization of the α- (phenoxy) phenylacetic acid compound, a higher% ee will result in a chiral amine compound of 0.5 Obtained by use in an amount less than molar equivalents, preferably up to about 0.48 molar equivalents, more preferably up to about 0.47 molar equivalents, most preferably up to about 0.45 molar equivalents. In order to obtain an enantiomerically very rich α- (phenoxy) phenylacetic acid derivative, it should be noted that the chiral amine compound itself should have sufficient enantiomer purity.

Crystallization is usually carried out in a solvent capable of forming salts of different solubility between the two enantiomers of α- (phenoxy) phenylacetic acid and chiral amine. In this way, one diastereomeric salt preferentially precipitates the solution. Suitable crystallization solvents include protic solvents such as alcohols. Particularly preferred crystallization solvent is isopropyl alcohol.

The yield of enantiomerically rich α- (phenoxy) phenylacetic acid also depends on the amount of crystallization solvent used in particular. For example, when a large amount of crystallization solvent is used, the mixture becomes too thin to reduce solid formation. If the amount of crystallization solvent used is too small, the solution will be supersaturated with the undesired diastereomeric salts to crystallize the undesired diastereomeric salts, reducing the optical purity of the desired enantiomers. Thus, when isopropanol is used as the crystallization solvent, the amount of crystallization solvent used is preferably about 2 g to about 6 g, more preferably about 3 g to about 5 g, even more preferably per g of α- (phenoxy) phenylacetic acid compound. Is from about 3.5 g to about 4.5 g, most preferably about 4 g.

In one embodiment, the crystallization process comprises heating the crystallization solution mixture to a temperature above the nucleation temperature of both enantiomers so as to substantially dissolve both enantiomers. For example, the crystallization solution is heated to a temperature in the range of about 60 ° C. to the boiling point of the solution, preferably about 70 ° C. to about 80 ° C. More preferably, the crystallization solution is heated to about 75 ° C. Before and / or after addition of the chiral amine compound, the solution can be heated. Heating is typically for about 0.5 to about 16 hours, preferably about 1 to about 8 hours, until the solid material is substantially completely dissolved.

Subsequently, until the nucleation temperature of the first diastereomeric salt [eg, the salt of the (-)-enantiomer of α- (phenoxy) -phenylacetic acid] or a temperature below this temperature is reached, preferably the second The crystallization solution is cooled until the nucleation temperature of the diastereomeric salts, such as salts of (+)-enantiomers of α- (phenoxy) phenylacetic acid, is exceeded. This forms a solid acid-base salt of the chiral amine compound and the first enantiomer. Without wishing to be bound by any theory, the use of chiral amine compounds is considered to induce the formation of acid-base salts with one enantiomer at a significantly faster rate than the formation of acid-base salts of the remaining enantiomers. This rate may be due to the different kinematic and / or thermodynamic rates between the two enantiomers. As with conventional compounds, the solubility profile of the α- (phenoxy) phenylacetic acid compounds of the present invention has higher solubility at higher temperatures. Thus, by cooling the crystallization solution to only slightly exceed the nucleation temperature of the second diastereomeric salt, the recovery yield of the solid first diastereomeric salt is higher.

After the slurry is formed, the crystallization solution can be further cooled until the temperature of the solution is near or above the saturation point of the second diastereomeric salt. This prevents the formation of diastereomeric solid acid-base salts from the second enantiomer while increasing the formation of the diastereomeric solid acid-base salts of the first enantiomer.

The cooling rate of the crystallization solution can affect the optical purity of the solid acid-base salt formed. For example, if the crystallization solution cools too quickly, unwanted enantiomers may be trapped in the lattice of the solid acid-base salt of the desired enantiomer. However, too slow cooling speeds increase manufacturing time and cost. Therefore, the crystallization solution should be cooled at a speed that is minimal but economically sufficient to reduce the loss of optical purity. Typically, the crystallization solution cooling rate is about 0.05 ° C./min to about 1 ° C./min, preferably about 0.1 ° C./min to about 0.7 ° C./min, more preferably about 0.25 ° C./min to about 0.4 ° C./min. to be. The crystallization solution is then maintained above the saturation point of the solid acid-base salt of the second enantiomer, i.e., the unwanted enantiomer. Typically, the crystallization solution is maintained at this temperature for about 1 to about 72 hours, preferably about 2 to about 48 hours, more preferably about 3 to about 30 hours.

As expected, the use of small amounts of chiral amine compounds causes the solid acid-base salt of the first enantiomer to be selectively formed. However, the yield obtained will be correspondingly small. Theoretically, the yield of the desired enantiomer from the racemic mixture is 50%. Thus, when 0.5 molar equivalents of the chiral amine compound are used, the theoretical yield is 50% of the total α- (phenoxy) phenylacetic acid (or 100% of the desired enantiomer). To be economically desirable, the process of the present invention yields a yield of at least about 50%, preferably at least about 60%, more preferably at least about 70%, most preferably at least about 75% of the desired enantiomer. to provide. Assuming 100% selectivity, these yields are equivalent to adding about 0.25 molar equivalents, 0.30 molar equivalents, 0.35 molar equivalents and 0.375 molar equivalents of the chiral amine compound, which is the minimum amount of chiral amine compound that needs to be added to the crystallization solution. Indicates.

The tendency of the second enantiomer to form a solid acid-base salt with a chiral amine compound is considered to be one of the main reasons for the change of the conventional crystallization process. Thus, by measuring the supersaturation point of the second enantiomer, i.e., the unwanted enantiomer, one skilled in the art can minimize or prevent the unpredictability of solid acid-base formation of the second enantiomer. Supersaturation points can be readily determined by one skilled in the art, for example by solubility experiments.

Although the method of the present invention is discussed with reference to enriching (-)-enantiomers present in the racemic mixture, the method of the present invention may also be applied to enrich (+)-enantiomers. Please note. The process of the present invention essentially provides a solid precipitate rich in (-)-enantiomers and a liquid filtrate rich in (+)-enantiomers, ie the mother liquor. The recovery of the chiral amine compound from the free and precipitated salts of the desired (-)-enantiomer can be, for example, a dilute inorganic acid or any other inorganic that is commonly known to hydrolyze salts having this property. Or by acidifying the salt with an organic acid. While this process leaves the filtrate as an undesired by-product, the filtrate can be further treated with an acid, or preferably a base, to convert the (+)-enantiomer-rich filtrate into the racemic mixture. For example, (+)-enantiomers can be racemized using aqueous sodium hydroxide solution. This racemic mixture can then be reused, ie recycled. In addition, the chiral amine compound may be recovered from the conversion step described above and may be recycled. Thus, the process of the present invention easily performs a recycle process.

IV. Racemic  α- ( Phenoxy Synthesis of Phenyl Acetic Acid

One method of preparing a racemic mixture of α- (phenoxy) phenylacetic acid of formula I is shown in Scheme I below.

Thus, phenylacetic acid (1) is converted to an activated carboxylic acid derivative (e.g. acid chloride) and then α-brominated to give α-bromophenylacetyl chloride (not shown). The acid chloride is then converted to ester 2, where R is typically alkyl. Preferably, the alcohol ROH used to convert the acid chloride to ester (2) is the same alcohol as the alcohol used as solvent in the subsequent reaction. In this way, the number of different solvent forms is minimized. In addition, by using the same ROH as the solvent in the subsequent reaction, the amount of by-products formed, for example, by transesterification, is minimized. For example, isopropyl ester 2 (where R is isopropyl) is particularly advantageous because the subsequent reaction is conveniently carried out in an isopropanol solvent. Substitution reaction of ester (2) with phenolic compound (3) in the presence of a base, for example a hydroxide (such as potassium hydroxide), yields a- (phenoxy) phenylacetic acid ester (4). Hydrolysis of α- (phenoxy) phenylacetic acid ester (4) yields α- (phenoxy) phenylacetic acid (I).

In this way, after crystallization from heptane, (4-chlorophenyl)-(3-trifluoromethylphenoxy) -acetic acid, ie CPTA, can be prepared in five steps in about 85% yield without intermediate separation.

V. Utility of Enantiomerically Enriched α- (phenoxy) phenylacetic Acid

Enantiomerically rich α- (phenoxy) phenylacetic acid compounds are useful intermediates for the preparation of various pharmaceutically active compounds, including the α- (phenoxy) phenylacetic acid compounds described in US Pat. No. 3,517,050. Accordingly, another aspect of the present invention provides a method for selectively producing an enantiomer of the α- (phenoxy) phenylacetate compound of formula IV from a racemic mixture of the α- (phenoxy) phenylacetic acid compound of formula I do.

In Formula IV above,

R ^l is alkyl or haloalkyl,

X is a halide,

R ⁷ is heteroalkyl, preferably N-acetyl 2-aminoethyl (ie, the residue of the formula —CH ₂ CH ₂ NHC (═O) CH ₃ ).

The process involves separating a racemic mixture of the α- (phenoxy) phenylacetic acid compounds of formula I as described above, enantiomeric by reacting the enantiomerically rich α- (phenoxy) phenylacetic acid with a carboxylic acid activator. Preparing an enriched activated α- (phenoxy) phenylacetic acid. Suitable carboxylic acid activators include thionyl halides (eg thionyl chloride), anhydrides, thioester generators and other carboxylic acid activators known to those skilled in the art.

The activated α- (phenoxy) phenylacetic acid is then converted to a compound of formula (R ⁷ -O) _W M, wherein R ⁷ is as defined above and M is hydrogen or a metal, such as Na, K, Li , Ca, Mg, Cs and the like, and the subscript w is in the oxidation state of M) (e.g., N-acetyl ethanolamine derivative) to react with an enantiomerically rich α- (phenoxy) phenylacetate compound To obtain. The inventors of the present invention have found that the reaction between an activated acid and a compound of formula (R ⁷ -O) _W M can be carried out without significant racemization.

Further objects, advantages and novel features of the invention will become apparent to those skilled in the art upon examination of the following examples thereof, which are not intended to limit the invention.

Example

Reagents and Laboratory Instruments

Unless stated otherwise, reagents and solvents were purchased from Aldrich Chemical or Fisher Scientific. N-acetylethanolamine was also purchased from Lancaster Synhesis. Racemic CPTA, or halopenic acid, was prepared according to the processes described in US Pat. Nos. 3,517,050 and 6,262,118, which are hereby incorporated by reference in their entirety. (1R, 2R)-(-)-2-amino-1- (4-nitrophenyl) -1,3-propanediol (ie CAP D-base) was purchased from TCI Americas.

The work was carried out under a positive nitrogen atmosphere. The jacket temperature was controlled in a jacketed straight-walled bottom-drain glass reactor equipped with a jacketed vertical wall using a Camile process control computer connected to the recycle heating and cooling system. Unless stated otherwise, solvents were removed using a Buchi rotary evaporator at bath temperatures of up to 40 ° C. at 15-25 torr. The solid sample was dried in a vacuum oven at 40 ° C., 15-25 torr. A vacuum of less than 1 torr was supplied for vacuum distillation using a Senco HYVAC vacuum pump. Water levels were determined by Karl Fisher assay using a 756 KF calorimeter from Metrohm and a reagent from HYDRANAL Coulomat AG. Melting points were measured using a FP62 melting point gauge from Mettler Toledo. pH was measured using a calibrated Model 290A pH meter from Orion. Protons and ¹³ CNMR spectra were recorded on an Avance 300 MHz spectrometer from Bruker.

The chiral HPLC method involves injecting 10 μl of the sample dissolved in the mobile phase onto a (R, R) WHELK-0 1.5 μm 250 × 4.6 mm column [Regis Technologies], 95/5 / 0.4 (v / v / v) at λ = 240 nm by eluting hexane / 2-propanol / acetic acid at a flow rate of 1.0 mL / min. For solid samples of CPTA / CAF D-base diastereomeric salts, solids were added to aqueous hydrochloric acid, CPTA was extracted into methylene chloride, the solvent was removed from the methylene chloride layer, and the residue dissolved in the mobile phase for analysis.

Achiral HPLC analysis was performed at λ = 220 nm by injecting 5 μl of the sample dissolved in the mobile phase onto a LUNA 5 μm C18 (2) 250 × 4.6 mm column from Phenomenex at 25 ° C. Gradient elution starts at 66 vol% water / 34 vol% acetonitrile / 0.1 vol% trifluoroacetic acid and increases linearly to 26 vol% water / 74 vol% acetonitrile / 0.1 vol% trifluoroacetic acid from the 20th minute A 1.5 mL / min flow rate of gradient was used.

In order to analyze esters which are acidic solutions, for example halophenate, acetonitrile was used as injection solvent. When measured, product concentrations for CPTA and halophenate were assessed by HPLC analysis using external standard methods and achiral analytical processes at sample concentrations below 2.5 mg / mL.

Example 1

Pre-separation of CPTA is described in US Pat. No. 3,517,050, in which cinnaconidine is used as the chiral base and the (+)-enantiomer of CPTA is precipitated as a diastereomeric salt. One major disadvantage of this process is that the objective (-)-enantiomer remaining in the mother liquor makes it difficult to separate the pure (-)-enantiomer fraction.

This example shows that the racemic mixture of CPTA is separated using various different chiral bases to obtain enantiomerically rich solid (-)-isomers. Unlike the previous method, the present invention allows for easy separation of enantiomerically rich solid (-)-CPTA from solution.

Racemic CPTA was prepared by hydrolysis of racemic halophenate with potassium hydroxide. For chiral base screening, an equimolar mixture of CPTA and chiral base was mixed in ethanol, methanol and acetone in glass vials and the solution was allowed to stand. After holding at ambient temperature overnight, the sample remaining in solution was placed in a 5 ° C. refrigerator. After holding overnight in the refrigerator, a small amount of water was added to the sample remaining in the solution in ethanol. After 4 days at ambient temperature, the aqueous ethanol solution was put back into the refrigerator. All samples were placed in the refrigerator and periodically checked for deposit formation over a month. Table 1 lists the bases and solvent conditions tested and the temperatures at which crystalline salts were formed.

 Table 1: Bases Tested for CPTA Separation

E-Rated

Crystallized at C-(Temperature)

*-With 1 mol / mol aqueous sodium hydroxide

Both chiral bases, quinine, L-tyrosine hydrazide, (-)-cinconidine, and enantiomers of 2-amino-1- (4-nitrophenyl) -1,3-propanediol are racemic It has been found to provide crystalline salts from CPTA. For the crystallized sample, the solids were separated by filtration and both the solid phase and mother liquor were analyzed by chiral HPLC to determine the enantiomer composition of both streams. The results from the screens are shown in Table 2. The three bases shown in Table 2 were rich in (+)-enantiomers on the solid phase.

Table 2: Results from Chiral Base Screens

*-More diluted

**-slower cooling profile

Table 2 contains the percent yield of solids calculated from the isomer ratios in the solid and mother liquor streams. The formula used is shown below. The maximum theoretical yield with 100% isomer purity is 50%. Yields of 50% or higher indicate that other isomers are contained.

Formula for calculating yield from isomer ratio

Setting: a = area (%) of component (1) in the starting material; b = area (%) of component (2) in the starting material; x = area (%) of separated component (1); y = area of% of separated component 2; w = area (%) of component (1) in the mother liquor; z = area (%) of component (2) in the mother liquor; E = isolated substance (g); F = g of substance in mother liquor.

And: a + b = 100%; E + F = l

After: xE + wF = a; yE + zF = b

Resolution: xE + w (1-E) = a; yE + Z (1-E) = b

E = isolated yield = (a-w) / (x-w) = (b-z) / (y-z)

Example 2

This example shows the results of the separation of CPTA using CAF D base in ethanol and 2-propanol.

The results for ethanol and 2-propanol are summarized in Table 3 below. For this evaluation, the slurry was sampled at various points in the cooling profile and the enantiomer composition of both the solid and solution phases was measured. From this information, the% ee and expected weight percent yield (up to 50% yield with 100% ee), calculated from the isomer ratios, were determined. Table 3 contains the yield of (-)-CPTA derived from the weight percent yield of solid phase and the (-)-CPTA content (up to 100% yield with 100% ee).

In this particular study, the best results were obtained in ethanol using 1 mole of CAF D base per mole of CPTA. Approximately 72% yield of the (-)-CPTA CAF D base salt was determined from the chiral composition of both phases with a (-)-CPTA of 87.6% ee in the solid phase. Lower separation rates were obtained when using one molar equivalent of CAF D base in 2-propanol at similar concentrations. When 0.55 mole of CAF D base per mole of CPTA was used, it became richer enantiomerically. Under these conditions, about 76-79% yield of (-)-CPTA CAF D base salt was calculated from the phase composition with (-)-CPTA of 87-90% ee in the solid phase. The weight percent yield calculated without considering physical loss was 41 to 42%; Substantially measured isolated yields were 37-39%.

Table 3: Separation of CPTA Using CAF D Base

Recrystallization of the CPTA CAF D base salt from 2-propanol increased the optical purity from about 87% ee to 98% ee, with 87% mass recovery or 93% recovery based on the (-)-CPTA content of the feed (Table 4).

Table 4: Recrystallization of (-)-CPTA CAP D Base from 2-propanol

Overall, about 35% yield was obtained from racemic CPTA, up to 50% of the (-)-CPTA CAF D base salt with an optical purity of about 98% ee.

Crystallization of optically enriched enantiomers often increases chiral purity. After removal of the separating agent, crystallization of (-)-CPTA from methylcyclohexanone may increase the optical purity somewhat. In one experiment, crystallization of (+)-CPTA increased optical purity from 99.1% ee to 100% ee; The mother liquor was 95% ee.

Example 3

This example shows the solubility profile of the CAF D base salts of the (+)-and (-)-isomers of CPTA in 2-propanol.

To help optimize CPTA separation using CAF D base, the solubility profile of both diastereomeric salts in 2-propanol was measured. The results are shown in FIG. (+)-CPTA CAF D base salt was prepared using synconidine isolated (+)-CPTA. As shown in FIG. 1, the desired (-)-CPTA diastereomer can be dissolved about three times less than the (+)-CPTA form. Equations describing the solubility included in the figures were calculated by least squares analysis (R ² > 0.99). The data points for the (-)-CPTA salt at 82 ° C. are not included in determining the equation, but closely match the calculated solubility.

Undesired racemization of CPTA enantiomers can be recycled back into the process. Thus, the enantiomerically enriched undesired isomer of CPTA in 1N aqueous sodium hydroxide was heated to reflux and confirmed to racemize within 1 hour. No other byproducts were detected by HPLC analysis of isolated CPTA.

Example 4

This example shows a method for obtaining (+)-CPTA.

A 2 L round bottom flask equipped with an overhead stirrer was charged with 33.0 g of crude (+)-CPTA-cinconidine salt, 610 ml of ethanol and 125 ml of methanol. The slurry was heated to reflux to afford a solution, which was then cooled. Very thick slurry formed at 42 ° C. The slurry was heated to 68 ° C. to obtain a light colored slurry which was then cooled to ambient temperature. The mixture was filtered at 26 ° C., washed with 150 ml of ethanol and dried at 40 ° C. in vacuo to yield 23.48 g of (+)-CPTA-cinconidine salt. The recrystallization process was repeated using 600 ml of ethanol and 120 ml of methanol to give 18.23 g of (+)-CPTA-cinconidine salt (55% recovery from two recrystallizations). No (-)-CPTA was detected from chiral chromatography even if the degree of separation was not evaluated at low levels (halophenate chiral assay conditions were used for CPTA analysis at this time as well).

3.61 g of purified salt sample was mixed with 50 ml of water and 50 ml of toluene and 2.9 g of sulfonic acid was added. The organic phase was washed with 30 ml of water and then the residue was evaporated. The residue was crystallized from 20 ml of cyclohexane to give 1.22 g of (+)-CPTA. Optionally, 6.3 g of (+)-CPTA-cinconidine salt (10.2 mmol) was mixed with 56 g of diethyl ether and 29 g of water, and the pH was acidified to 1.9 with a few drops of sulfuric acid. The organic phase is washed with 25 ml of water, dried (magnesium sulfate), filtered and evaporated to a residue. The residue was stirred with 22 ml of methylcyclohexane at ambient temperature to form a slurry. The slurry was warmed to 40 ° C., cooled in an ice bath, and the solids were separated by filtration and dried at 40 ° C. under vacuum to yield 2.62 g (7.92 mmol, 78% yield) of (+)-CPTA.

Example 5

This example shows a method for synthesizing (+)-halophenate from (+)-CPTA.

A 25 ml round bottom flask was charged with 0.91 g of (+)-CPTA and 2.6 g of thionyl chloride, and the mixture was heated to reflux to obtain a solution. Conversion to acid chloride was monitored by quenching the sample with methanol and then analyzing the product by HPLC. To the acid chloride solution was added 4.8 g of diethyl ether and this solution was added to 2.0 g of N-acetylethanolamine in 12 ml of N, N-dimethylformamide (DMF) together with 0.37 g of pyridine cooled in an ice bath. The resulting solution was added to 25 ml of water and 30 ml of diethyl ether. The organic phase was separated, washed with 25 ml of water, dried (MgSO ₄ ), filtered and the solvent removed to give 0.92 g of oil. HPLC analysis showed 45 area% of halophenate and 50 area% of CPTA. Chiral HPLC analysis showed that halophenate was 99.78% ee of the (+)-enantiomer.

Example 6

This example shows a method for producing racemic CPTA.

A 2 L round bottom flask equipped with an overhead stirrer was charged with 102.7 g halophenate, 500 mL water and 16.3 g 2-propanol. The slurry was stirred and 32.3 g of 45% aqueous potassium hydroxide was added. After heating to reflux for 1 hour, the solution was cooled to ambient temperature and filled with 380 ml of hexane. The pH was adjusted from 12.5 to 2 with 24.57 g 37% hydrochloric acid. The three phase mixture was heated to 60 ° C. to obtain a two phase. The lower aqueous phase was removed and extracted with 50 mL of hexanes. The combined organic layers were heat distilled at atmospheric pressure to remove 100 ml of cloudy distillate. The solution was cooled to 30 ° C. and seeded with CPTA. A slurry was formed. The slurry was cooled in an ice bath and the solids were separated by filtration to give 64.0 g (78.4% yield) of racemic CPTA, i.e. (4-chlorophenyl) (3-trifluoro-methylphenoxy) acetic acid.

Example 7

This example shows representative results of chiral separation screening using various chiral bases in ethanol.

1.16 g (3.51 mmol) of CPTA samples were dissolved in 6.98 g of ethanol to give a solution (0.431 mmol / g). Glass vials were individually filled with the respective base amounts listed in Table 5, and the amount of ethanol CPTA solution calculated to give a molar ratio of acid to base of 1: 1 was added. In some cases, small amounts of ethanol are added to wet the base prior to addition of the CPTA solution. The vial was allowed to stand overnight at ambient temperature. Precipitates formed in vials 7G and 7I. Each supernatant sample was removed and analyzed by chiral HPLC analysis. The solid was separated by filtration and also analyzed. Some results are shown in Table 2 (see Example 1 above). The remaining vials were placed in the refrigerator at 5 ° C. After 1 day, a precipitate formed in vial 7E. Samples were analyzed as previously described. The remaining vials were filled with 50 μl of water, kept at ambient temperature for 3 days and then placed in the refrigerator. After 1 month no further precipitate appeared.

Table 5: Base Screening in Ethanol

Example 8

This example shows representative results of chiral separation screening using various chiral bases in acetone.

1.67 g of CPTA sample was dissolved in 7.57 g of HPLC grade acetone to obtain a solution. Glass vials were individually filled with the respective base amounts listed in Table 6, and the amount of ethanol CPTA solution calculated to give a molar ratio of acid to base of 1: 1 was added. In some cases, a small amount of acetone was added and the mixture was warmed to about 40 ° C. to obtain a solution. In addition, 0.300 ml of 1N sodium hydroxide was added to the vial 16M. The vial was allowed to stand overnight at ambient temperature. A precipitate formed in vial 16D, which was analyzed as described above. Some results are summarized in Table 2 (see Example 1). The remaining vials were placed in the refrigerator. A precipitate formed in vial 16N, which was analyzed. A very light precipitate formed in the vial 16G. One week later, 16L of vials were found to contain precipitates. Samples were analyzed as shown previously. No additional precipitate appeared.

Table 6: Base Screening in Acetone

Example 9

This example shows representative results of chiral separation screening using various chiral bases in methanol.

2.00 g of CPTA sample was dissolved in 8.03 g of HPLC grade methanol to give a solution. The glass vials were individually filled with the respective base amounts listed in Table 7, and the amount of ethanol CPTA solution calculated to give a molar ratio of acid to base of 1: 1 was added. In addition, 0.300 ml of 1N sodium hydroxide was added to the vial 27J. The vial was allowed to stand overnight at ambient temperature. Vial 27B was solidified and additional 300 μl of methanol was added before analyzing the sample as described above. The remaining vials were placed in the refrigerator. After 1 month no further precipitate appeared.

Table 7: Base screening in methanol

Example 10

This example shows the results of CPTA separation using quinine.

A 150 ml jacketed bottom-drain flask was filled with 2.70 g (8.17 mmol) CPTA, 2.65 g (8.17 mmol) quinine and 50 ml 2-propanol. The mixture was heated to 70 ° C. to obtain a solution, then cooled to 30 ° C. at a rate of 0.2 ° C./min and held for 2 hours to obtain a slurry. The sample was subjected to chiral HPLC analysis to give 42.88 area% and 56.47 area%, respectively, of (+)-CPTA and (-)-CPTA in solid phase, and 61.54 area% and (+)-CPTA and (-)-CPTA, respectively, of the solution. It was 34.19 area%. The slurry was heated to 60 ° C., then cooled to 30 ° C. at a rate of 0.04 ° C./min and maintained overnight to obtain a slurry. Chiral HPLC analysis showed that the (+)-CPTA and (-)-CPTA in the solid phase were 29.94 area% and 44.19 area%, respectively, and the (+)-CPTA and (-)-CPTA in the solution were 77.54 area% and 20.88 area, respectively. It was%. The slurry was diluted with 50 mL 2-propanol and heated to 57 ° C. to obtain a solution, then cooled to 30 ° C. at a rate of 0.2 ° C./min. A slurry began to form after 1 hour at 30 ° C. The mixture was stirred at ambient temperature for 2 days, then the solids were separated by filtration, washed with 2-propanol and dried under vacuum to yield 2.89 g (54 mass% yield) of the quinine salt of CPTA. Chiral HPLC analysis showed that the (+)-CPTA and (-)-CPTA in the solid phase were 42.25 area% and 57.75 area%, respectively, and in the mother liquor, the (+)-CPTA and (-)-CPTA were 56.56 area and 39.20 area, respectively. It was%. The results are also included in Table 2 (see Example 1).

Example 11

This example shows the results of CPTA separation using CAF D base.

19.54 g of CPTA, 6.82 g of CAF D base (i.e., D-threo-(-)-2-amino-l- (nitrophenyl) -1, 3-propanediol) and 2-propanol in 150 mL bottom-drain flasks Filled 80.2 g. The mixture was heated to 70 ° C. to obtain a solution, and then the jacket temperature was cooled to 5 ° C. at a rate of 0.1 ° C./min. The mixture was cloudy at 62 ° C. After 9 hours of storage at 6 ° C., the solids were separated by filtration, washed with 5 ml of 2-propanol and dried at 40 ° C. under vacuum to yield 12.03 g (37.4 wt% yield of (−)-CPTA CAF D base salt. ) Was obtained. Chiral HPLC analysis showed that the solid contained 6.34 area% of (+)-CPTA, 93.46 area% of (-)-CPTA, the mother liquor contained 81.41 area% of (+)-CPTA, and 17.76 of (-)-CPTA. It was found to contain area%.

Example 12

This example shows the result of recrystallization of (-)-CPTA CAF D base salt.

The 150 ml bottom-drain flask was charged with 8.00 g of (-)-CPTA CAF D base salt (from Example 11 above) and 54.2 g of 2-propanol. The mixture was heated to reflux to give a solution, the jacket temperature was cooled to 20 ° C. at a rate of 0.1 ° C./min and then held at an internal temperature of 22 ° C. for 6 hours. The solid was separated by filtration, washed with 2-propanol and dried at 40 ° C. in vacuo to yield 6.93 g (86.6 wt% recovery) of (−)-CPTA CAF D base salt (melting point: 184 to 185 ° C.). . The solid contained 0.995 area% of (+)-CPTA, 99.01 area% of (-)-CPTA, the mother liquor contained 44.53 area% of (+)-CPTA and 54.47 area% of (-)-CPTA. The reaction was washed with acetone. Acetone was evaporated to give 0.27 g (3.4 wt%) of the residue.

Example 13

This example shows the preparation of the (+)-CPTA CAF D base salt.

The 1 L flask was charged with 10.94 g (17.5 mmol) of (+)-CPTA synconidine salt, 200 mL of water and 100 mL of methylene chloride. 1.8 g of sulfuric acid was added to adjust the pH to 1.9. The organic layer was washed three times with 100 ml portions of dilute aqueous sulfuric acid, dried (magnesium sulfate), filtered and evaporated to give 5.79 g of residue. The residue was dissolved in 22.2 g of 2-propanol and 3.5 g of CAF D base was added. The resulting slurry was heated to reflux to give a solution, cooled to ambient temperature and then the slurry was stirred for 3 hours. After cooling in an ice bath, the solids were separated by vacuum filtration, washed with 5 ml of 2-propanol and dried at 40 ° C. under vacuum to yield (+)-CPTA CAF D base salt (melting point: 172-173 ° C.) 7.39 g (80% yield) was obtained.

Example 14

This example shows the solubility of diastereomeric CPTA-CAF D base salts in 2-propanol.

Sample (-)-CPTA CAF D base and (+)-CPTA CAF D base (> 98% ee) were added to 2-propanol in the amounts shown in Table 8 and mixed using an ultrasonic bath. All samples remain as a slurry. The slurry was maintained at the temperature described overnight, the supernatant sample was removed and analyzed by quantitative HPLC analysis to determine CPTA concentrations. The results are shown in the table and in FIG. 1.

In addition, 8.00 g of (-)-CPTA CAF D base salt requires 54.2 g of 2-propanol per solution at 82 ° C. (14.7 wt%). These data points are included in FIG. 1 but are not included in the solubility formula.

Table 8: Solubility in 2-propanol

Example 15

This example shows a method of racemization of enantiomerically rich CPTA.

A 50 ml round bottom flask was charged with 0.31 g of (-)-CPTA (68.7% ee) and 9.4 g of 1N sodium hydroxide. The solution was heated to reflux for 1 hour, cooled to ambient temperature and then acidified with 1 g of 37% hydrochloric acid. CPTA was extracted into methylene chloride and the solvent was evaporated to yield 0.46 g of oil. HPLC analysis revealed 99.4 area% CPTA and chiral HPLC analysis revealed a 50/50 mixture of CPTA enantiomers.

Example 16

This example shows the separation of racemic mixtures of CPTA using CAF D-base under various crystallization conditions.

Normal crystallization process was filled with CPTA, CAF D-base and 2-propanol at room temperature and the solution was heated to 75 ° C. The solution was cooled to about 60 ° C. and maintained until nucleation occurred. Several batches were seeded with (-)-salts (ie, salts of (-)-CPTA and CAF D-base) to cause nucleation. After the slurry developed over about 1 hour, the vessel was cooled to the separation temperature. Initial description 5 of FIG. 2 reached the separation temperature using a slow cooling quench of about 0.05 to 0.10 ° C./min. The remaining experiments used faster cooling rates of 0.25-0.40 ° C./min. The fiber density probe was introduced directly into the crystallizer to measure the slurry density.

The amount of CAF D-base added and solute concentration are some important variables that lead to the final batch composition. The tendency of the (+)-salts (ie, salts of (+)-CPTA and CAF D-bases) to remain supersaturated over time changes is believed to be the major cause for the variable in some experiments. This was demonstrated in description 5 of FIG. 2, whereby the slurry was kept at 13 ° C. for 8 hours, yielding high purity crystals (99.7% (−)-salt). After 3 hours, the increase in signal of the fiber optic probe indicated the nucleation of the appropriate (+)-salt. After an additional 27 hours, the slurry was separated and the crystalline product contained a (-/ +)-CPTA ratio of 83.3 / 16.7%. Analysis of the crystal product by HPLC gives the ratio of (-)-CPTA and (+)-CPTA. Since the free CPTA in solution is less saturated, the crystal assay thus provided the diastereomeric salt ratio. The mother liquor contained both dissolved salt and free CPTA. Analysis by HPLC shows the combined amount of each enantiomer as CPTA. Similarly, description 6 of FIG. 2 shows that the slurry is maintained at 1 ° C. for 20 hours to obtain a high purity salt (> 98% (−)-CPTA). After heating to 17 ° C., the (+)-salt was nucleated and a poorer quality product [(− / +)-CPTA = 81.2 / 18.8%] was obtained.

In other tests, nucleation of the (+)-salt occurred more rapidly as in descriptions 2, 8 and 10 of FIG. The crystallization will preferably be carried out close to the saturation temperature of the (+)-salts in which separation can be carried out, preferably above that temperature.

At a loading of 3.9 g of 2-propanol per gram of CPTA, and using 0.45 equivalents of CAF D-base, separation at room temperature appears to be very close to the saturation level (or metastable region) of the (+)-salt. Description 12 of FIG. 2 was initiated with 0.43 equivalents of base and the crystal product at 21 ° C. remained pure (> 99% (−)-salt), even after seeding with (+)-salt. After adding more CAF D-base to 0.45 equiv, the slurry was held for 14 hours and then for at least 6 hours after seeding with (+)-salt. The crystal product was analyzed at 98.7% (-)-CPTA ratio. The total base was increased to 0.47 equiv to afford a crystalline product in which the (+)-salt composition slowly increased to (− / +)-CPTA = 92.3 / 7.7%.

Description 11 of FIG. 2 (3.9 g 2-propanol per 0.4 g CPTA, 0.45 equiv base) maintains high purity (-)-salt (99.1%) after 14 hours, but at the addition of more base at 0.48 equiv The yield ratio of (-/ +)-salt was 89.2 / 10.8%. Description 9 (0.45 equivalent base) of FIG. 2 maintained 99.5% (-)-salt purity after 16 hours at 22 ° C. The calculated yield of (-)-CPTA from three batches under these conditions was 70.7 to 71.6%. The calculated yield is derived from the forced mass balance from the racemic CPTA feed by knowing the crystals and mother liquor composition of (-)-CPTA and (+)-CPTA.

About 0.45 equivalents of CAF D-base and about 4 g of 2-propanol per gram of CPTA are loaded to provide a high purity (-)-salt (> 98.5%) product, which can be used without further recrystallization.

Example 17

This example provides a model for describing the separation / crystallization of CPTA salts.

The concentration of free CPTA depends on the amount of base charged and the dissolution loading. For example, separating CPTA by charging 4.0 g of 2-propanol and 0.50 equivalent of CAF D-base, salts are formed in 2-propanol, which contains 11% free CPTA. This solvent has greater solubility in both (-)-and (+)-salts and was measured as shown in FIG. 3. Figure 3 also includes solubility data in pure 2-propanol, expressed in grams of component per gram of 2-propanol. 3 shows that the curves for each salt are in a similar form.

Using other combinations of CPTA, CAF D-base and 2-propanol loading, a system generated in 11.0% free CPTA in 2-propanol may also be achieved, as shown in FIG. 4. As FIG. 4 shows, the loadings for the various experiments in FIG. 2 generally do not belong exactly in this line. However, the (-)-salt and (+)-salt solubility can be estimated as follows: The loading of points above the "11.0% free CPTA" line (ie, less than 11.0% free CPTA in 2-propanol) is more Dilute, with lower solubility than the "11.0%" line. Conversely, points below the “11.0%” line occur in solvents containing more than 11.0% free CPTA, and salt solubility is greater than that measured in FIG. 3. To estimate the solubility of the component, a multiplication factor k was used. Thus, the modified solubility formulas for (-)-salts and (+)-salts are S _(-) = ^0.01421 k e ^0.02613T and S ₍₊₎ = 0.02868 k e ^0.02771T .

Although the k- adjustment gives excellent estimates of the (-)-and (+)-salt solubility, the ratios of (-)-and (+)-salts formed upon addition of the resolving agent base are known. Since it is not, it still cannot describe crystallization. One of the more detailed experiments is shown in FIG. 5 (see also FIG. 2). This experiment used 0.75 equivalents of base and provided a product with a (-/ +)-salt ratio of 66.4 / 33.6% at 21.5 ° C. By heating the slurry and subsequently taking a sample, a saturation line for both the (-)-and (+)-salts in the solvent can be constructed.

In order to match the solubility model with the actual data, the regression technique was used to adjust the feed ratios of solubility factor ( k ) and (-)-and (+)-salts, in accordance with the observed data. (Ie, crystal composition, mother liquor composition, and crystal yield). k is 0.68 and in the 58.1% (-)-salt / 41.9% (+)-salt, 0.75 equivalents of salt (ie, 0.436 equivalents of (-)-salt and 0.314 equivalents of (+)-salt are formed upon addition of CAF D-base Feed ratio) was selected, which was in good agreement. 6 shows a comparison. Solubility models include the amounts of (-)-and (+)-salts in crystals, (-)-and (+)-salts in mother liquor and also (-)-free CPTA and (+)-in mother liquor. Allows the calculation of the perfect mass balance to separate the amount of free CPTA. One procedure for quantifying (-/ +)-salts and (-/ +)-free CPTA in mother liquor by extraction post-treatment using solubility differences is provided in Example 19 below.

Regression techniques by solubility model were applied to other experiments that supplied different amounts of separator. By using a combination of solubility factor k and the composition of the salt as feed (ie, the ratio of (-)-and (+)-salts formed upon addition of base), the model tends to be a unique solution consistent with the experimental results . From this, the graph of FIG. 7 was created. This result shows that as more separators are added (more than 0.34 equivalent, extrapolated minimum point), the amount of (+)-salt increases. Without wishing to be bound by any theory, in some embodiments, when less than 0.34 equivalents are added, the CAF D-base will substantially coordinate only with (-)-CPTA, which forms almost entirely a (-)-salt. In addition, by using the curves in FIG. 7, the amounts of (-)-CPTA and (+)-CPTA (free acid) can be calculated. At 0.35 to 0.75 equivalents of packed base, the% ratio of {(-)-CPTA / total CPTA free acid} is about 25% (23.3 to 27.1%). The "selectivity" to the ratio of (-/ +)-salts thus formed depends on the amount of free (-)-CPTA remaining (in solution), and about (-)-CPTA / (+)-CPTA ends Is 1/3. Once the (-)-CPTA concentration is reduced to a (-/ +)-CPTA ratio of 1/3 by addition of about 0.34 equivalents of base, the continued addition of base results in a 3/1 ratio of (-/ +)-salts. Form (to maintain free (-/ +)-CPTA at constant 1/3 ratio in solution).

Example 18

This example shows the separation of the racemic mixture of CPTA.

A 200 ml container was charged with 17.0 g of CPTA (51.4 mmol), 4.91 g (23.1 mmol, 0.450 equiv) of CAF D-base and 85 ml of 2-propanol. The mixture was heated to give a solution of 78 ° C. and then cooled to 54 ° C. at 0.5 ° C./min. After about 1/2 hour, the solution was seeded with (-)-salts to induce nucleation. After holding at 54 ° C. for about 1 to 1/2 hour, the slurry was cooled to 22 ° C. at 0.25 ° C./min. After holding at 22 ° C. for 14 hours, a small sample (about 5 ml) was taken and separated in a 15 ml middle frit funnel. The mother liquor was weighed and saved and then the solid was washed with 2 mL 2-propanol. The wash was weighed and saved and then suctioned to dry the crystals. Analysis by standardized HPLC system calculated the weight percent of (-)-CPTA and (+)-CPTA in each stream. The mass balance for this sample (the total accountability of CPTA in the crystals, mother liquor and wash liquor was 0.85 g) provided an isolated yield of 31.9% of crystalline product from total CPTA. The purity of crystal was (-/ +)-CPTA weight ratio 99.1 / 0.9%. 8 shows the analysis and mass balance in a rectangular box. Calculated yields (from CPTA) based on feed / mother liquor / crystal composition are listed inside the circle. The abbreviations in FIG. 8 are as follows: R.A. = Separating agent, x or xtal = crystal, ML = mother liquor, Yld = yield.

The vessel was seeded several times with crystals containing (+)-salts, and after about 2 hours 0.31 g (1.46 mmol, about 0.03 equiv) of CAF D-base was added. The vessel was sampled twice before final separation in a 60 ml medium frit funnel (see FIG. 8). The mother liquor was 59.1 g of transparent and light golden color. The solid was washed with 19.2 g of 2-propanol while recovering 18.8 g of wash. The washed solid (10.07 g) was aspirated for 1 hour on a funnel and further dried to yield 8.36 g (15.4 mmol salt). Analyzing all streams from the final separation yielded CPTA of 13.45 g (40.67 mmol). The final crystal product ratio was 89.2 / 10.8% of (-/ +)-CPTA for the separated yield of (-)-CPTA = 33.8 ° / a (from CPTA). The calculated yield of (-)-CPTA was 35.0% based on the feed, mother liquor and crystal composition.

Example 19

This example shows an extractable workup process for quantifying (-/ +)-salts and (-/ +)-CPTA in mother liquor.

The mixture of (-/ +)-salts of 80/20 was very little dissolved in methylene chloride at about 0.016%, while racemic CPTA was significantly more dissolved at slightly less than 3.4%. The final mother liquor (see FIGS. 2 and 5) from the separation of Description 4 of FIG. 2 at 55.3 ° C. was analyzed by evaporating 0.1286 g to obtain 0.0242 g of glassy residue. The residue was dissolved in 5 ml of methylene chloride and seeded with 80/20 (-/ +)-salts and then left overnight. The supernatant portion was removed, 3 ml of methylene chloride was added, then the liquid portion was removed and combined with the first extract. The methylene chloride extract was evaporated to afford 0.0074 g of a glassy solid which was then analyzed by HPLC. The remaining thick slurry was evaporated to afford 0.0162 g and analyzed by HPLC. The results from the post-treatment extraction process are generally similar to the compositions predicted by the solubility model, as shown in FIG. 9.

Example 20

 This example shows the solubility of (-)-and (+)-CPTA.CAF D-base salts in alcohol containing CPTA.

"Solvent" was prepared by dissolving 2.40 g of racemic CPTA in 19.42 g of 2-propanol (Fisher's HPLC grade) or 4.90 g of racemic CPTA in 31.4 g of ethanol. The respective concentrations of CPTA in the solution were 11.0% and 13.5%. The solubility of the (-)-CPTA.CAF D-base salt (ie, (-)-salt) or (+)-CPTA.CAF D-base salt (ie (+)-salt) was determined by gravimetry. At the temperature described, a portion of the supernatant was removed from the saturated solution against a known weight of vial. The solution weight was measured and the volatile solvent was evaporated by purging with nitrogen. The solid was further dried to constant weight at about 50 ° C./1 mm Hg in a vacuum oven. The vial was reweighed to determine the loss of whiskey solvent and the amount of solid remaining. From this, the amount of CPTA dissolved from the "solvent" can be calculated. The total solid mass was subtracted from CPTA to give the mass of soluble salt in solvent. Data is shown in FIGS. 10A and 10B.

Example 21

This example shows a process for preparing enantiomerically rich (-)-halophenate.

CPTA was prepared in five steps in about 85% yield after crystallization from heptane, without intermediate separation, as discussed above. Separation yielded an average of 32% yield (up to 50%) of more than 98% optically pure (-)-CPTA diastereomeric salts. After removing the separator, (-)-CPTA was esterified with thionyl chloride and N-acetylethanolamine to give (-)-halophenate in about 55% yield. The mother liquor residues can be hydrolyzed with aqueous sodium hydroxide so that (-)-CPTA can be recovered from the final product mother liquor and circulated back through the process. The separating agent was separated from the water at about 90% recovery by pH adjustment. Recovery and racemization of (+)-CPTA with aqueous sodium hydroxide showed about 90% recovery. Overall, the first pass yield from 4-chlorophenylacetic acid was 15-17%. The entire eight step process used three organic solvents and three solid separation steps.

Example 22

This embodiment shows a method of producing CPTA.

The synthetic route to CPTA is summarized above. Acid chloride (1) in 1,2-dichloroethane was brominated to give compound (2), and 2-propanol was added to give isopropyl ester (3). Substitution reactions with α, α, α-trifluoro-m-cresol were accomplished using potassium hydroxide in 2-propanol. After quenching with water, washing and removing 1,2-dichloroethane, liquid (3) was added to the solution of α, α, α-trifluoro-m-cresol and potassium hydroxide in 2-propanol to give a compound ( 4) was obtained. Hydrolysis to CPTA was completed by removing the 2-propanol solvent and heating with aqueous sodium hydroxide.

The sodium salt of CPTA can be separated as a solid by simply cooling the reaction mixture. However, by separation of carboxylic acids, better separated yields are obtained. For separation, the basic aqueous CPTA reaction mixture was acidified with hydrochloric acid and CPTA was extracted with 1,2-dichloroethane. The separated organic phase from 1,2-dichloroethane to heptane was solvent exchanged to give CPTA as a white solid in about 85% yield from 4-chlorophenylacetic acid.

Example 23

This example shows the solubility of CPTA in 1,2-dichloroethane and heptane.

The solubility of racemic CPTA in 1,2-dichloroethane and heptane is shown in FIGS. 11 and 12, respectively. These figures contain equations for the least squares values of the data.

Based on the solubility profile of FIG. 11, the concentration of about 25 wt% CPTA in 1,2-dichloroethane at a temperature of about 35 ° C. was selected for CPTA extraction conditions.

CPT crystallization from heptane was exothermic. A solution of about 170 g of CPTA in 500 ml of heptane was seeded at 46 ° C., increasing the temperature to 54 ° C. as crystallization progressed. As measured by HPLC analysis, crystallization increased CPTA purity from 93-95 area (%) to more than 99 area%. HPLC analysis of the crystallized mother liquor revealed less than 3% yield for the mother liquor containing 15 area% CPTA. Since purity is improved by crystallization, the separated yield is high and the losses to the mother liquor are small.

Example 24

This example shows CPTA separation yield under various crystallization conditions.

Results of CPTA separation using CAF D-base under various crystallization conditions are shown in FIG. 13. Final chiral purity for each preparation obtained after 0, 1 or 2 recrystallizations is shown in bold. The molar ratio of CAF D-base was changed from 0.5 to 0.56. The amount of 2-propanol solvent described for crystallization and recrystallization is both based on the initial charge of racemic CPTA. Chiral HPLC results for both separated solid and mother liquor were normalized to 100%. The calculated yield and overall yield are calculated from the ratios of the (+)-enantiomer and (-)-enantiomer forms in the separated solids and mother liquor. The actual% yield in the last column is a weighed and dried material, based on up to 50% yield.

The overall yield of diastereomeric salts in optical purity greater than 98% ranges from 28 to 35%, with an average of 32%. In one case, by using the lowest ratio of separation agent, this was obtained without recrystallization (Experiment 2 in FIG. 13). The chiral purity of the first separated solids ranges from 73% to 98%. Single recrystallization was generally sufficient to obtain the desired optical purity. High overall yield was obtained when the mother liquor's (-)-CPTA to (+)-CPTA reached a 20/80 ratio.

FIG. 14 shows cooling profiles for separation crystallization described in order of decreasing yield of (−)-CPTA. The experiment number of FIG. 14 corresponds to the experiment number of FIG. 13. The separated yield of (-)-CPTA was determined using the calculated yield of FIG. 13 and the% of (-)-CPTA in the separated material. In general, longer retention times at lower temperatures increased yields.

0.45 molar equivalents of CAF D-base consistently provided more than 98% optically pure material in 35 to 37% yield without the need for recrystallization.

Example 25

This example shows the separation of (-)-CPTA from CAF D-base.

To separate the (-)-CPTA from the CAF D-base, the diastereomeric salt was mixed with 1,2-dichloroethane and the pH was lower than 2 in aqueous phase with the addition of aqueous hydrochloric acid. The aqueous phase containing hydrochloride of CAF D-base was separated. After washing the organic phase with water, the bulk 1,2-dichloroethane was distilled off and the residual water was removed. Solvent removal was complete to afford an oil.

Example 26

This example shows a process for esterifying (-)-CPTA without any significant racemization.

(-)-CPTA was reacted with thionyl chloride in 1,2-dichloroethane under reflux to afford the corresponding acid chloride. The progress of the reaction can be monitored by HPLC analysis. A small amount of distillate was removed to remove excess thionyl chloride. The mixture was cooled and a large amount of vacuum distilled N-acetylethanolamine was added. Stirring at ambient temperature gave (-)-halophenate.

The reaction mixture was added to an aqueous potassium carbonate solution to quench the esterification reaction mixture. (-)-Halophenate was isolated by solvent exchange and crystallization from heptane: 2-propanol (6: 1). The results are summarized in FIG.

The separated first recovery yield ranged from 47 to 59%, with an average of 55%. This isolated yield represents 75-80% reaction yield for this step. The second recovery yield provided higher overall yield, but the product quality was worse for the second recovered material.

The molar accountability of the separated halophenate and loaded CPTA found as halophenate and CPTA in the mother liquor ranged from 90 to 99%.

Example 27

This example illustrates the recovery and recycling of (+)-CPTA.

Heating of CPTA in aqueous base caused racemization. Residual CPTA from the separation step of Example 25 was about 47% ee of (+)-enantiomer, which also contained residual CAF D-base.

To recover and race (+)-CPTA, 2-propanol solvent was removed and replaced with 1,2-dichloroethane. Washing with water at a pH of less than about 2 removed the CAF-D-base for later recovery. Aqueous sodium hydroxide was added and the aqueous solution was heated to reflux. 1,2-dichloroethane was removed by distillation before adding the basic solution or by phase separation after addition of the basic solution. After heating the aqueous solution for 4 hours using 1.4 molar equivalents of sodium hydroxide, 89% yield of racemic CPTA was separated from heptane. Separation of CPTA as a crystallized intermediate provided a more consistent amount of feed for the separation step.

The solubility of the sodium salt of racemic CPTA in water, measured and expressed in acid form, is shown in FIG. 16. When the separated sodium salt is added to water the pH is about 9.5 and the solubility profile shows the upper solubility curve. The addition of a small amount of sodium hydroxide resulted in a pH of about 12.6, and the aqueous solubility was reduced with the solubility shown in the lower curve.

Example 28

This example shows the preparation of CPTA from (+)-halophenate.

1-3 molar equivalents of sodium hydroxide were added to about 10% by weight of 87% ee (+)-halophenate in water and heated to 50-60 ° C. to substantially complete hydrolysis with CTPA. Partial racemization yielded about 70% ee of (+)-CPTA (time = 0 in FIG. 17). The solution was heated to reflux and the enantiomer ratio was monitored over time. Nearly complete racemization (<3% ee by chiral HPLC analysis) was achieved within 2 hours under reflux with 3 molar equivalents of base. During racemization, the pH dropped from 12.8 to 12.6. Using 2 molar equivalents (pH 12.6-11.6) required a slightly longer reaction time. When 1 molar equivalent was used, the racemization stopped at about 60-70% ee while the final pH was 9.4.

0.5 molar equivalents of sodium hydroxide left approximately 40% of the halophenate unhydrolyzed after 2 hours at 60 ° C., and overnight reflux left approximately 1% of the halophenate unhydrolyzed at a final pH of 4.8. . This did not significantly minimize racemization. The amount of CPTA obtained was 72.6% ee of (+)-enantiomer.

Example 29

This example shows the recovery of (-)-CPTA from the (-)-halophenate crystallization mother liquor.

As previously shown and shown in FIG. 15, the (-)-halophenate crystallization mother liquor contains a large amount of (-)-halophenate and (-)-CPTA. By hydrolyzing the (-)-halophenate, additional (-)-CPTA can be generated as feed in the separation step.

The (-)-halophenate crystallization mother liquor [(-)-halophenate 88.3% ee] at 50 ° C. and final pH 12.7 was hydrolyzed to quickly give 65.8% ee of (−)-CPTA. By adding CAF D-base to the 2-propanol solution, (-)-CPTA was recovered as CAF D-base diastereomeric salt (96.4% ee). From the amount of initially loaded diastereomeric salts 55 mol% were recovered as (-)-halophenate, 28 mol% as (-)-CPTA / CAF D-base salt and 14 mol% as CPTA in the mother liquor. Remaining.

Example 30

This example shows a method for recovering CAF D-base.

CAF D-bases were found in the acidic phase from the separation of (-)-CPTA from diastereomeric salts and from the acidic washing step of CPTA recovery from the separation mother liquor. Aqueous sodium hydroxide was used to basify to a pH above about 12, yielding a well recovered precipitate in an easily filtered form. The results are shown in FIG. The recovery from diastereomeric salts is generally greater than 90% and the recovery from the separating mother liquor is lower. The concentration in the aqueous solution is in the range of about 5-20%.

 The enantiomer purity of the CAF D-base was determined by DSC [D. Pitre, M. Nebuloni, and V. Ferri; Arch. Pharm. (Weinheim) 324, 525 (1991)] can be measured by careful analysis of the melting point. Melting point has been found to be a sensitive method for evaluating enantiomer purity because (+)-and (-)-form masses, for example racemates, melt at a temperature of at least 20 ° C. lower than pure isomers. However, the determination of enantiomer purity of the two samples by chromatographic separation of the derivatives did not show any loss of chiral purity. The enantiomer purity of the recovered CAF D-base, close to the detection limit of HPLC analysis, was indistinguishable from the feed.

Example 31

This example shows another method for producing racemic CPTA.

In a heating mantle equipped with an overhead stirrer and condenser, a 500 ml round bottom flask was charged with 73.28 g (0.430 mol) of 4-chlorophenylacetic acid, 70 ml of 1,2-dichloroethane and 41 ml (0.56 mol) of thionyl chloride. The mixture was heated up at 50-55 ° C. for 19 hours. The reaction mixture was analyzed by HPLC analysis. Bromine 29ml (0.57mol) was added to the acid chloride solution, and the solution was heated at 70-75 占 폚 for 20 hours. The resulting α-bromo product was cooled in an ice bath and 100 mL (1.31 mol) of 2-propanol were added dropwise. The maximum temperature reached was 17 ° C. After cooling to 4 ° C., the reaction mixture was added to water. The solution was raised to ambient temperature and the aqueous layer was removed. The organic phase was washed with 37 ml of water. The separated 1,2-dichloroethane solution was evaporated to give 134.1 g of oil.

A 1 liter round bottom flask with an overhead stirrer was charged with 34.0 g (0.515 mol) of 85% potassium hydroxide and 370 ml of 2-propanol. The mixture was warmed to 41 ° C. using a water bath to dissolve a large amount of solids. The mixture was cooled in an ice bath and 73.8 g (0.455 mol) of α, α, α-trifluoro-m-cresol were added dropwise. The maximum temperature reached was 13 ° C. Prior to the dropwise addition of 134.1 g of the oil obtained above, the solution was cooled to 5 ° C. The material was washed with 18 g 2-propanol. The slurry was evaporated to give a residue, then charged with 250 ml of water and 42.8 g (0.535 mol) of 50% aqueous sodium hydroxide. The mixture was heated to reflux for 1 hour.

After cooling to ambient temperature, the mixture was diluted with 250 ml of 1,2-dichloroethane and the pH was reduced to 0.3 by dropwise addition of 71 g (0.72 mol) of 37% hydrochloric acid. After phase separation, the solvent was removed from the 1,2-dichloroethane phase to give 202.2 g of residue. The residue was treated with 131 g heptane and evaporated to give 164 g residue. This process was repeated with 97 g of heptanes to give 160 g of oil. The residual oil was stirred at ambient temperature with 257 g of heptane to give a slurry which was cooled in an ice bath before being filtered to separate solids. The filter cake was washed with 49 g of heptane and then dried under vacuum to yield 125.58 g (0.380 mol, 88% yield) of CPTA.

Example 32

This example shows the preparation of the racemic mixture of compound (4) of Example 22.

A 50 ml round bottom flask with magnetic stirrer and reflux condenser was charged with 2.10 g (6.35 mmol) of racemic CPTA, 21 g of 2-propanol and 0.50 g (4.2 mmol) of thionyl chloride. HPLC analysis after 90 minutes under reflux showed compound (7) to 84.2 area% and CPTA to 12.7 area%. Addition of additional 1.0 g (8.4 mmol) of thionyl chloride results in less than 1 area percent CPTA. The solution was cooled to ambient temperature and treated with 1.0 g (12 mmol) of solid sodium bicarbonate. The solvent was evaporated and the residue dissolved in 25 ml of toluene. After washing with water (2 × 10 mL), the solvent was evaporated to give 2.31 g (6.2 mmol, 98%) of the compound (4) of Example 22 (compound (7): 95.8 area%, toluene: 2.4 area%). Yield).

Example 33

This example shows the solubility measurement method of racemic CPTA.

A 100 ml water jacketed resin pot with a magnetic stirrer was connected to the recycle water bath and filled with 9.44 g of racemic CPTA and 16.78 g of 1,2-dichloroethane. The temperature of the bath was raised to 35 ° C. and the slurry was stirred for 1 hour. The stirrer was removed and the solid was allowed to stand for 30 minutes. 0.1360 g of the supernatant sample was removed and diluted to 25.00 mL with acetonitrile and the solution analyzed by HPLC analysis. The results and a series of other measurements are shown in FIGS. 11 and 19. For analysis at about 2 ° C., 0.54 g of CPTA samples in 1.92 g of 1,2-dichloroethane were stored in the refrigerator overnight before the supernatant was analyzed by HPLC analysis. The solubility of CPTA in heptanes, included in FIG. 19 shown in FIG. 12, was measured by a similar method.

Example 34

This example shows the separation of racemic mixtures of CPTA.

48.2 g (146 mmol) CPTA, (1R, 2R)-(-)-2-amino-1- (4-nitrophenyl) -1,3-propanediol (CAF D-base) in a 1 liter bottom-drain reactor g (77.3 mmol) and 193 g of 2-propanol were charged. The slurry was heated to 70 ° C. to obtain a solution, then cooled to 60 ° C. and maintained for 1 hour. The resulting slurry was heated to a jacket temperature of 2 ° C. at 0.25 ° C./min and held for 14 hours, with an internal temperature of 4 ° C. The solid was separated by vacuum filtration and washed with 27 g of 2-propanol. The mother liquor and wash were sampled for HPLC analysis and the results are shown in FIG. 13. 50.48 g of the wet cake was reloaded with 193 g of 2-propanol into the 1 L reactor and the slurry was heated to gentle reflux with a jacket temperature of 85 ° C. to obtain a solution. The solution is sampled for HPLC analysis and the results are shown in FIG. 13. Upon cooling to 65 ° C., a slurry is formed. After raising the temperature to 68 ° C. for 30 minutes, the slurry was cooled to 40 ° C. at 0.25 ° C./min, to 18 ° C. at 0.4 ° C./min and then to 2 ° C. at 1 ° C./min (in other preparation methods) , The linear cooling rate described in FIG. 14 was used). The solid was separated by vacuum filtration, washed with 18 g of 2-propanol and then dried under vacuum to afford 27.29 g (50.4 mmol, 34.5% yield) of (-)-CPTA / CAF D-base. Results of HPLC analysis of the separated solids, mother liquor and wash are included in FIG. 13.

Example 35

This example shows the preparation and separation of racemic CPTA from halophenate.

A 1 L round bottom flask with an overhead stirrer was charged with 129.75 g (0.312 mol) of racemic halophenate, 325 g of water and 32.6 g (0.408 mol) of 50% aqueous sodium hydroxide. The slurry was heated to 60 ° C. for 1 hour to give a solution, then cooled. At a temperature of 40 ° C., 328.5 g of 1,2-dichloroethane and 44 g (0.45 mol) of 37% hydrochloric acid were added and the biphasic mixture was cooled to 29 ° C. The pH of the aqueous phase was 0.85. The organic phase was separated, washed with 250 ml of water and then evaporated to give 118.2 g of residue. 2-propanol (149 g) was added and evaporated to afford 131.2 g of residue. Based on the amount of halophenate loaded, the residue, theoretically containing 103.2 g of racemic CPTA, was charged to a 1 L bottom-drain reactor with 33.10 g (0.1556 mol) of CAF D-base and 400 g of 2-propanol. . The mixture was warmed to 67 ° C. to give a light slurry, which was then cooled to 1 ° C. at 0.075 ° C./min. The mixture was cooled to -7 ° C, the solids were separated by vacuum filtration, and then washed with 60 mL of 2-propanol. HPLC analysis results for the separated solid, 492.8 g of mother liquor and wash are shown in FIG. 13 (Experiment 9). 92.74 g of wet cake were reloaded with 477 g of 2-propanol into a 1 L reactor and the mixture was heated to 75 ° C. to obtain a solution. The solution was cooled to 5 ° C. at 0.5 ° C./min, the crystallized solid was separated by vacuum filtration, washed with 60 ml of 2-propanol and dried to give 51.81 g of (-)-CPTA CAF D-base diastereomeric salt. (0.0956 mol, 31% yield) was obtained. Results of HPLC analysis for the separated solids, 529.9 g of mother liquor and wash are included in FIG. 13.

Example 36

This example shows a racemization method of (+)-CPTA and a recovery method of racemic CPTA.

Of 103.2 g of CPTA described in Example 35 above, containing 71.6 g (0.217 mol) of CPTA ((+)-enantiomer 44% ee), based on yield and purity of the separated diastereomeric salts. Separation and recrystallization of the mother liquor from the isolate was evaporated to give 108.7 g of residue. The residue was treated with 176 g of 1,2-dichloroethane, 35.2 g of water and 6.8 g of 37% hydrochloric acid. The organic phase was removed and evaporated to afford 79.0 g of residue. Water (80 g) was added and the solvent was evaporated to give 78.1 g of residue. The residue was treated with 141.9 g of water and 24.6 g (0.308 mol) of 50% aqueous sodium hydroxide, and the solution was heated to reflux for 4 hours to obtain racemate by chiral HPLC analysis. The solution was cooled and treated with 140 ml of 1,2-dichloroethane, and 32.0 g (0.325 mol) 37% hydrochloric acid. The organic phase was removed and evaporated to yield 80.1 g of residue, which was then treated with 250 ml of heptane in a water bath at 40 ° C. to obtain a slurry. The solid was separated by vacuum filtration and dried to give 63.83 g (0.193 mol, 89% yield) of racemic CPTA. Separation of samples gave results consistent with the separation of fresh CPTA (Description 10 in FIG. 13).

Example 37

This example shows the separation of (-)-CPTA from diastereomeric salts.

A 500 mL flask equipped with a magnetic stirrer was charged with 40.0 g (73.7 mmol) of (-)-CPTA / CAF D-base, 100 g of 1,2-dichloroethane, 40 g of water and 7.6 g (77 mmol) of 37% hydrochloric acid. After complete dissolution of the solid, the lower organic phase was removed and washed with 10 ml of water. The pH of the combined aqueous phases was 0.9. HPLC analysis for 128.2 g of organic phase found 24.32 g (-)-CPTA (73.6 mmol, 99.8% of theory) as a solution in 1,2-dichloroethane.

Example 38

This example shows vacuum purification of N-acetylethanolamine.

A 50 ml round bottom flask with a magnetic stirrer, heating mantle and short path distillation head was charged with 29.09 g of N-acetylethanolamine and placed under vacuum of about 0.8 torr. Although no concentrate was collected, bubbles formed as the liquid was heated. The distillate was collected at a head temperature of about 130 ° C. to give 26.71 g (92% recovery) of N-acetylethanolamine as a clear liquid.

Example 39

This example shows a process for preparing (-)-halophenate.

A 500 mL round bottom flask with a magnetic stirrer was charged with 35.5 g (65.4 mmol) of (-)-CPTA / CAF D-base diastereomeric salt (99.4% ee), 89.0 g of 1,2-dichloroethane and 35.5 mL of water. . To the slurry was added 6.7 g (68 mmol) of 37% hydrochloric acid and the mixture was stirred at ambient temperature to give a clear biphasic. The lower organic phase was removed and washed with 7.0 g of water. The organic phase was evaporated to give 26.13 g of residue, which was dissolved in 55.6 g of 1,2-dichloroethane and then placed in a 250 mL round bottom flask in a heating mantle with a magnetic stirrer and reflux / distillation head. HPLC analysis of the solution revealed that it was 22.06 g (66.7 mmol, 102% of theory) of CPTA. 7.5 ml (100 mmol) of thionyl chloride were added to the solution, and the solution was heated to reflux for 2 hours. The heating was continued to collect 6.1 g of distillate. The solution was cooled to ambient temperature and cooled in an ice bath to add 25.85 g (251 mmol) of distilled N-acetylethanolamine (KF assay 1176 and 1288 ppm water). After addition, the temperature was increased to about 26 ° C. The solution was added to 9.90 g (71.6 mmol) of potassium carbonate in 36 g of water cooled in an ice bath with gentle stirring. The maximum temperature reached was 15 ° C. The reaction mixture was washed with 5 ml of 1,2-dichloroethane. The lower organic phase was removed and washed with 37 ml of water. The solution was evaporated to give an oil (32.84 g). The oil was treated with 54 g of heptane and the solvent was removed to give 31.56 g of a solid residue. 76 g of heptane was added to the solid, and the solvent was removed to obtain 29.19 g of the solid residue. The solid was dissolved in 28 mL 2-propanol at 40 ° C. and then diluted with additional 28 mL 2-propanol and 334 mL heptane. Cool to ambient temperature to give a thin slurry. A thick slurry formed upon cooling in an ice bath. After stirring for 2 hours, the solid was separated by vacuum filtration, washed with 29 g of heptane and then dried to yield 14.21 g (34.2 mmol, 52.3% yield) of (-)-halophenate. No (+)-halophenate was detected by chiral HPLC analysis (> 99.8% ee).

 HPLC analysis of 294.1 g of mother liquor and washings revealed 11.2 g of halophenate and 1.26 g of CPTA. The solvent was evaporated and 12.47 g of the residue was dissolved in 14 ml 2-propanol. After stirring overnight at ambient temperature, additional 84 ml of heptane was added to give a slurry. The slurry was cooled in an ice bath, the solids collected, washed with 9 g of heptane and dried to 5.64 g (13.6 mmol, 20.7% yield, 89.9% halophenate by HPLC analysis and CPTA 3.9) (-)-halophenate. %, 99.6% ee). HPLC analysis of 81.74 g of mother liquor and wash liquid revealed 3.66 g (8.8 mmol, 13.5%) of halophenate and 0.93 g (2.8 mmol, 4.8%) of CPTA.

Example 40

This example shows the separation of racemic CPTA sodium salts.

Based on the number of separations, the mother liquor from the separation crystallization and recrystallization containing 63.9 g (0.193 mol) of CPTA theory was evaporated to give 91 g of residue. The residue was dissolved in 146 g of 1,2-dichloroethane at 40 ° C. and treated with 28.6 g of water and 6.3 g of 37% hydrochloric acid. 219 g of organic phase was removed and evaporated to give 71.86 g of residue. To the residue was added 120 g of water and 21.5 g (0.269 mol) of 50% sodium hydroxide. The solution was heated to reflux and then cooled to ambient temperature to give a thick slurry. The solid formed upon cooling was separated by vacuum filtration, washed with 25 ml of water and dried to give 31.78 g (0.0901 mol, 46.7% recovery) of the sodium salt of CPTA. Chiral HPLC analysis revealed the substance to be racemate. HPLC analysis of 188.6 g of mother liquor and washings revealed 28.3 g (0.0856 mol, 44.4%) of CPTA.

Example 41

This example shows the solubility measurement method of racemic CPTA sodium salt.

A 100 ml water jacketed resin pot with a magnetic stirrer was connected to the recycle water bath and filled with 3.48 g of racemic CPTA sodium salt and 20.0 g of water. The temperature of the bath was raised to 35 ° C. and the slurry was stirred for 1 hour. The stirrer was removed and the solid was allowed to stand for 30 minutes. pH was 9.4. 0.3036 g of the supernatant sample was removed, diluted to 25.00 mL with acetonitrile and the solution analyzed by HPLC analysis. The analysis was repeated at 47 ° C. and 19 ° C. To keep the slurry at higher temperature, additional 3.01 g of CPTA sodium salt was added and 25 g of water were added to obtain a thinner slurry at lower temperature. 50% aqueous sodium hydroxide was added to increase the pH at ambient temperature to 12.7 and the analysis continued at 13.5 ° C, 25 ° C, 34 ° C and 42 ° C. The results are shown in FIGS. 16 and 20.

Example 42

This example shows hydrolysis and racemization of (+)-halophenate.

A 250 ml round bottom flask with magnetic stirrer and heating mantle was charged with 7.28 g (17.5 mmol) of (+)-halophenate (86.9% ee), 72.2 g of water and 4.21 g (52.6 mmol) of 50% aqueous sodium hydroxide. The slurry was heated to 50-60 ° C. The pH of the obtained solution was 12.8. Chiral HPLC analysis showed 80.4% of (+)-CPTA and 10.5% of (-)-CPTA. The solution was heated to reflux for 90 minutes. Chiral HPLC analysis indicated that (+)-CPTA was 49.6% and (-)-CPTA 47.0%. pH was 12.6. After cooling to ambient temperature, about 50 ml of 1,2-dichloroethane was added and pH was adjusted to 0.8 by adding 7.3 g (74 mmol) of 37% hydrochloric acid. The organic phase was evaporated to give 6.0 g of residue. The residue was treated with 25 ml of heptane and warmed up to dissolve the oil, then cooled in an ice bath. The solid was collected by vacuum filtration and dried to give 5.10 g (15.4 mmol, 88% yield) of racemic CPTA. Data for this hydrolysis and two similar hydrolysis are shown in FIGS. 17 and 21.

Similarly, 6.75 g (16.3 mmol) of (+)-halophenate were heated with 0.65 g (8.1 mmol) of 50% aqueous sodium hydroxide in 67.5 g of water at 60 ° C. for 2 hours to 37.5% halophenate and CPTA. 54.2% was obtained. Heating at reflux overnight yielded 92.1% CPTA and 1.1% halophenate with a final pH of 4.8. Chiral HPLC analysis revealed a (+) / (−)-CPTA ratio of 80.3 / 12.8.

Example 43

This example shows a process for the preparation of (-)-halophenate by recovery of the (-)-CPTA / CAF D-base diastereomeric salt from the (-)-halophenate crystallization mother liquor.

50.0 g (92.3 mmol) of (-)-CPTA / CAF D-base diastereomeric salt (97.1% ee), 124 g of 1,2-dichloroethane, 50 ml of water and 37% hydrochloric acid in a 1 liter round bottom flask with magnetic stirrer 9.6 g (98 mmol) was charged. The organic phase was separated and washed with 50 mL of water and then placed into 250 mL round bottom flask in a heating mand with a magnetic stirrer. The reflux / distillation head was attached, the solution was heated and 35.4 g of distilled distillate was removed. After cooling to 40 ° C., the solution was diluted with 25 mL of 1,2-dichloroethane and 11 mL (150 mmol) of thionyl chloride were added. After heating at reflux for 2 hours and removing 22.6 g of distillate, the solution was cooled in an ice bath to add 38.6 g (374 mmol) of distilled N-acetylethanolamine. The reaction temperature was increased to 7-18 ° C. during the addition. After stirring overnight at ambient temperature, the solution was added to 12.7 g of potassium carbonate in 51 ml of water cooled in an ice bath with stirring. The organic phase was removed and washed with 51 g of water. The organic phase (85.2% halophenate and 6.1% CPTA by HPLC analysis) was evaporated to give 44.3 g of oil, treated with 133 g of heptane and then evaporated to give 43.3 g of solid. The solid residue was dissolved in 61.5 g of 2-propanol and charged into a 1 L bottom-drain reactor with 320 g of heptane, then heated to 50 ° C., cooled to 20 ° C. at 3 ° C./min, and then at 1 ° C./min. Cooled to -3 ° C. The solution was cloudy at 27 ° C. and a thick slurry formed at 15 ° C. The solid was separated by vacuum filtration, washed with 40 ml of heptane containing 5 ml of 2-propanol and then dried to give 21.01 g (50.6 mmol. 55% yield, HPLC) of (-)-halophenate (99.9% ee). By 98.93%). HPLC analysis evaporated 395.7 g of the mother liquor and washings containing 14.65 g (35.3 mmol) of halophenate (88.3% ee) and 1.78 g (5.4 mmol) of CPTA to evaporate 21.57 g of residue. The residue was heated to 50 ° C. using 100 mL of water and 5.0 g (63 mmol) of 50% aqueous sodium hydroxide to give a solution. After about 10 minutes of HPLC analysis, it was found that CPTA was 83.6% and halophenate was 0.3%. The solution was cooled and diluted with 50 mL of 1,2-dichloroethane and then the pH was reduced from 12.7 to 1.6 with 7.3 g (74 mmol) 37% hydrochloric acid. After washing with 30 ml of water, 72.9 g of organic phase containing 11.32 g (34.2 mmol) of CPTA was evaporated to give a residue by HPLC analysis, treated with 36 g of heptane and then evaporated to give 14.9 g of residue. The oily residue was dissolved in 38 g of heptanes while heating. It was cooled to give an oil. The solvent was removed and the residual oil was dissolved in 34.8 g of methylcyclohexane. Cooling produces oil. Solvent was removed and replaced with 45.6 g of 2-propanol. Chiral HPLC analysis revealed that the (-)-CPTA ((+) / (-)-ratio 16.9 / 81.6) was 65.8% ee. 6.50 g (30.6 mmol) of CAF D-base were added to the solution at ambient temperature. A thick slurry formed quickly. The slurry was warmed to 40 ° C. with stirring, then cooled in an ice bath, the solids were separated by vacuum filtration, washed with 7 g of 2-propanol and dried to give (-)-CPTA / CAF D-base diastereomeric salt 13.91 g (25.7 mmol) is obtained, corresponding to 28% recovery of 50.0 g of the initially loaded salt. The (+) / (−)-CPTA ratio was 1.77 / 97.86. 45.34 g of mother liquor and wash were analyzed by HPLC to find 4.34 g (13.1 mmol) of CPTA corresponding to 14 mole% of 50.0 g of initially loaded salt.

Example 44

This example shows a method for recovering CAF D-base from CPTA / CAF D-base salt.

A 1 L round bottom flask equipped with a magnetic stirrer was charged with 80.16 g (0.148 mol) of (-)-CPTA / CAF D-base salt, 237 g of 1,2-dichloroethane and 80 mL of water. 15.2 g (0.154 mol) of 37% hydrochloric acid was added to the slurry to obtain two transparent phases. The pH of the aqueous layer was 1.2. The lower organic layer was removed and washed with 16 ml of water. The combined aqueous phase (140.7 g) was treated with 12.9 g (0.161 mol) of 50% aqueous sodium hydroxide to reach a pH of 12.1. The resulting slurry was filtered and the solid was washed with 25 ml of water and then dried to give 30.79 g (0.145 mol, 98% recovery) of CAF D-base (melting point: 160.4-161.0 ° C.).

Example 45

This example shows a method for recovering CAF D-base from separated mother liquor.

60.0 g of racemic CPTA sample were separated into 20.88 g of CAF D-base in 240 g of 2-propanol as described above to give 74.7 g of wet cake. The wet cake was recrystallized in 218 g of 2-propanol to give 32.35 g (32.8% yield) of (-)-CPTA / CAF D-base salt. From the amount of salt obtained the mother liquor and wash from crystallization and recrystallization, theoretically containing 40.32 g of CPTA and 8.23 g (38.8 mmol) of CAF D-base, were evaporated to give 72.9 g of residue. The residue was dissolved in 265 g of 1,2-dichloroethane, 50 mL of water and 4.0 g (40.6 mmol) of 37% hydrochloric acid. The aqueous layer was separated and the pH was increased from 0.6 to 12.3 by adding 3.88 g (48.5 mmol) of 50% aqueous sodium hydroxide. The resulting slurry was filtered, the solids were collected and washed with water to yield 7.12 g (33.6 mmol, 87% recovery) of CAF D-base (melting point: 162.4-163.0 ° C.).

The examples and aspects described herein are for illustrative purposes only and various modifications or changes in this fact will be suggested to those skilled in the art, and the spirit and scope of this application and scope of the appended claims. Will be included within. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims (23)

Under conditions sufficient to bring the ratio of the amount of free first enantiomer to free second enantiomer in the solution to be 3: 1, the enantiomer mixture of α- (phenoxy) phenylacetic acid compound is less than 0.5 molar equivalent. Contacting with an enantiomerically rich chiral amine compound to prepare a solution comprising an enantiomerically rich solid acid-base salt of a first enantiomer and (a) separating the solid acid-base salt of the first enantiomer from a solution at a temperature where the concentration of the acid-base salt of the second enantiomer of the α- (phenoxy) phenylacetic acid compound is near or below its saturation point. Including step (b), A process for preparing an enantiomerically rich α- (phenoxy) phenylacetic acid compound of the following formula from an enantiomeric mixture of an α- (phenoxy) phenylacetic acid compound comprising a first enantiomer and a second enantiomer .

In the above formulas, R ¹ is alkyl or haloalkyl, X is a halide. The process of claim 1 wherein step (a) of preparing a solution comprising an enantiomerically enriched solid acid-base salt of a first enantiomer (I) heating the solution to a temperature higher than the nucleation temperature of the first enantiomer and (Ii) reducing the solution temperature to a temperature at or below the nucleation temperature of the first enantiomer to prepare a solid acid-base salt of the first enantiomer. The process of claim 2, wherein (b) separating the solid acid-base salt of the first enantiomer is performed at or near the saturation temperature of the acid-base salt of the second enantiomer. The method of claim 1, further comprising recovering the chiral amine compound by separating the chiral amine compound from the separated solid acid-base salt of the first enantiomer. 5. The process of claim 4 wherein the enantiomerically rich chiral amine compound used to prepare the acid-base salt of step (a) comprises the recovered chiral amine compound. The method of claim 1, further comprising contacting the second enantiomer with a base to racemize some or all of the second enantiomer in a separated solution. 7. The process of claim 6 wherein the enantiomeric mixture of the α- (phenoxy) phenylacetic acid compound used in step (a) comprises a racemized α- (phenoxy) phenylacetic acid compound. The method of claim 1 wherein the chiral amine compound is a compound of formula

In the above formulas, R ² and R ³ are each independently hydrogen or alkyl, or R ² and R ³ together with the atoms to which they are attached form a heterocyclic ring moiety, R ⁴ is hydrogen or alkyl, R ⁵ and R ⁶ are each independently hydrogen or alkyl, or R ⁵ or R ⁶ is an amine protecting group, Ar is aryl. Enantiomer of 4-chloro-α- (3-trifluoromethylphenoxy) phenylacetic acid in 4 g of alcohol solvent per gram of (-)-4-chloro-α- (3-trifluoromethylphenoxy) phenylacetic acid (-)-4-chloro-α- by contacting the mixture with less than 0.5 molar equivalent of enantiomerically rich (1R, 2R) -2-amino-1- (4-nitrophenyl) -1,3-propanediol (A) preparing a solution comprising an enantiomerically rich acid-base salt of (3-trifluoromethylphenoxy) phenylacetic acid, (B) separating the enantiomerically rich acid-base salt from a solution rich in (+)-4-chloro-α- (3-trifluoromethylphenoxy) phenylacetic acid, and (1R, 2R) -2-amino-1- (4-nitrophenyl) -1,3-propanediol was isolated from acid-base salts to give enantiomerically rich (-)-4-chloro-α- ( (-) From an enantiomeric mixture of 4-chloro-α- (3-trifluoromethylphenoxy) phenylacetic acid, comprising the step (c) of preparing 3-trifluoromethyl-phenoxy) phenylacetic acid. Enantiomerically enriched 4-chloro-α- (3-trifluoromethylphenoxy) phenylacetic acid. The method of claim 9, wherein the alcohol solvent is isopropanol. The process of claim 10, wherein up to 0.47 molar equivalents of (1R, 2R) -2-amino-1- (4-nitrophenyl) -1,3-propanediol are used to form acid-base salts. The process of claim 11, wherein step (a) of preparing a solution comprising an enantiomerically rich acid-base salt of (-)-4-chloro-α- (3-trifluoromethylphenoxy) phenylacetic acid Heating the mixture to a temperature at or above the nucleation temperature of the (-)-acid-base salt. 13. The process of claim 12, wherein (b) separating the enantiomerically rich acid-base salt is performed at or near the saturation temperature of the acid-base salt of the (+)-enantiomer. The enantiomerically enriched (1R, 2R) -2-amino-1- (4-nitrophenyl) -1,3-propanediol is isolated from the acid-base salt of step (c). , 2R) -2-amino-1- (4-nitrophenyl) -1,3-propanediol. The method of claim 10, further comprising racemizing part or all of the (+)-4-chloro-α- (3-trifluoromethylphenoxy) phenylacetic acid obtained in step (b). 16. The enantiomeric mixture of 4-chloro-α- (3-trifluoromethylphenoxy) phenylacetic acid according to claim 15, wherein the enantiomeric mixture of racemic (+)-4-chloro-α- (3-trifluoromethylphenoxy C) a method comprising part or all of phenylacetic acid. Acid-base salts derived from α- (phenoxy) phenylacetic acid compounds of formula (I) and chiral amine compounds of formula (III).

      Formula I

     Formula III In the above formulas (I) and (III), R ¹ is alkyl or haloalkyl, X is a halide, R ² and R ³ are each independently hydrogen or alkyl, or R ² and R ³ together with the atoms to which they are attached form a heterocyclic ring moiety, R ⁴ is hydrogen or alkyl, R ⁵ and R ⁶ are each independently hydrogen or alkyl, or R ⁵ or R ⁶ is an amine protecting group, Ar is aryl. 18. The acid-base salt of claim 17, wherein the α- (phenoxy) phenylacetic acid compound and the chiral amine compound are enantiomerically rich. The acid-base salt of claim 18, wherein the α- (phenoxy) phenylacetic acid compound is (−)-4-chloro-α- (3-trifluoromethylphenoxy) phenylacetic acid. The acid-base salt of claim 18, wherein the chiral amine compound is (1R, 2R) -2-amino-1- (4-nitrophenyl) -1,3-propanediol. Enantiomerically rich (-)-4-chloro-α- (3-trifluoromethylphenoxy) phenylacetic acid having an enantiomeric excess of at least 95%. (A) preparing a racemic mixture of α- (phenoxy) phenylacetic acid of formula (I), Separating racemic mixture of α- (phenoxy) phenylacetic acid using less than 0.5 molar equivalent of enantiomerically rich chiral amine compound to produce enantiomerically enriched α- (phenoxy) phenylacetic acid (b ), (C) contacting enantiomerically rich α- (phenoxy) phenylacetic acid with a carboxylic acid activating reagent to produce enantiomerically enriched α- (phenoxy) phenylacetic acid, and Enantiomerically enriched activated α- (phenoxy) phenylacetic acid is contacted with a compound of the formula (R ⁵ -O) _w M, where M is hydrogen or metal and subscript w is the oxidation state of M A process for selectively preparing an α- (phenoxy) phenylacetate compound of formula (IV), including an enantiomer, comprising the step (d) of preparing an α- (phenoxy) phenylacetate compound:

          Formula IV

         Formula I In the above formulas (I) and (IV), R ¹ is alkyl or haloalkyl, X is a halide, R ⁷ is heteroalkyl. The method of claim 22, wherein the α- (phenoxy) phenylacetate compound is (−)-halophenate.

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