EA028385B1 - Dcc mediated coupling for halofenate manufacture - Google Patents

Abstract

The present application discloses a process for the preparation of a halofenate compound of formula (IV)wherein R has the meanings as defined herein, the process comprising contacting a compound of formula (I)with a compound of formula ROH and N,N'-dicyclohexylcarbodiimide in an aprotic solvent in the absence of a base to form the compound of formula (IV).

Description

Halofenic acid and its ether and amide derivatives contain one chiral center in the alpha position to the carbonyl carbon atom and therefore exist in two enantiomeric forms. Administration of halofenate (i.e., a racemic mixture of the two enantiomers of 2-acetamidoethyl (4-chlorophenyl) (3trifluoromethylphenoxy) acetate) leads to a decrease in serum glucose, triglycerides and uric acid. However, this racemic mixture also leads to various side effects, including nausea, gastrointestinal ulcers and gastrointestinal bleeding. Other side effects that have been reported with racemic halofenate include potential drug side effects, including difficulties in regulating anticoagulation with coomadin ™. It was found that the (-) - enantiomer of halofenic acid is about twenty times less active in its ability to inhibit P4502C9 cytochrome compared to the (+) - enantiomer. Therefore, it is more desirable and favorable to introduce the (-) enantiomer of halofenate in place of racemic halofenate.

The literature describes various synthesis routes for the preparation of derivatives of (-) - halofenic acid, such as (-) - halofenate. However, these derivatives are often difficult to obtain in high yields and with high enantiomeric purity using known synthetic methods. Therefore, there is a need for a method for producing a- (phenoxy) phenylacetic acid and its derivatives, such as (-) halofenate, in high yields and with high enantiomeric purity.

One aspect of the invention relates to a method for producing a compound of formula (IV)

wherein

K represents C _1-6 alkylC (O) PNS _1-6 alkyl or C _6-10 arylC (O) PNS _1-6 alkyl; moreover, the method includes contacting (-) - halofenic acid of the formula (I)

with a compound of the formula KOH in which K is as defined above; and

Ν, Ν'-dicyclohexylcarbodiimide as a coupling agent;

in an aprotic solvent in the absence of a base to form a compound of formula (IV).

In one embodiment, the compound of formula (IV) obtained from the crude reaction mixture (i.e., obtained before recrystallization) can be left in the crude reaction mixture without the required treatment for a long period of time, where the compound of formula (IV) does not undergo epimerization and racemization. For example, a compound of formula (IV) can be left in the crude reaction mixture for at least 1.5 hours, 2 hours, 5 hours, 10 hours, 15 hours, 17 hours or more than 24 hours without any measurable racemization. In another embodiment, the compound of formula (IV) may remain in the crude reaction mixture at a temperature of about 0, 10, 15, 20 ° C or at about room temperature for the above period of time without any measurable racemization.

In another embodiment, K is C _1-6 alkylC (O) NHC _1-6 alkyl or C _6-10 arylC (O) NHC _1-6 alkyl and the coupling agent is Ν, Ν'-dicyclohexylcarbodiimide. In another embodiment, K is CH ₃ SONCHCH ₂ CH ₂ -. In another embodiment, the compound of formula KOH is Ν-acetylethanolamine. In another embodiment, the compound of formula (IV) is (-) - halofenate of formula (II)

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In another embodiment, the aprotic solvent is selected from the group consisting of toluene, xylenes, cyclohexane, diisopropyl ether, isopropyl acetate, tetrahydrofuran (THF), hexanes, methyl tert-butyl ether (MTBE), and combinations thereof. In one embodiment of the process, the aprotic solvent is toluene. In another embodiment, the molar ratio of Ν, Ν'-dicyclohexylcarbodiimide to the compound of formula (I) is from 1.05: 1 to 1.15: 1, and the molar ratio of the compound of formula KOH to the compound of formula (I) is from 1.02: 1 to 1.7: 1. In one embodiment of the method, the molar ratio of Ν, Ν'-dicyclohexylcarbodiimide to the compound of formula (I) is 1.1: 1, and the molar ratio of the compound of formula KOH to the compound of formula (I) is 1.5: 1.

In one embodiment, the method relates to the production of (-) - halofenate (II) or a salt thereof

Moreover, this method comprises contacting a base-free solution containing Ν-acetylethanolamine in toluene with a base-free solution of (-) - halofenic acid in toluene; cooling the resulting solution at about 0 ° C. and contacting the base-free solution of Ν, Ν'-dicyclohexylcarbodiimide in toluene with the resulting solution to form a compound of formula (IV).

In one embodiment, the method further comprises separating the dicyclohexylurea (ΌΟΗ) precipitate as a by-product from the filtrate and washing the precipitate with an aprotic solvent such as toluene. In one embodiment, the method further comprises adding an aprotic solvent, such as cyclohexane, to the filtrate, washing the filtrate with water and drying the filtrate, and isolating the compound of formula (IV) by crystallization.

In one embodiment, the step of drying the filtrate comprises azeotropic distillation of the washed filtrate.

In some embodiments, the implementation of (-) - halofenate is obtained in a yield of about 80% or more. In some embodiments of the process, (-) - halofenate is obtained with an enantiomeric excess of approximately 98% or more before purification, that is, before any purification step (e.g., recrystallization) (i.e., when a solid is first obtained from the reaction mixture). In various embodiments, the implementation of (-) - halofenate has an enantiomeric excess of approximately 98%, approximately 99%, approximately 99.5%, approximately 99.9% or more prior to purification. In some embodiments of the process, (-) - halofenate is obtained with a chemical purity of about 98% or more before it is purified. In some embodiments of the process, (-) - halofenate prior to purification has an OS level of less than 1.0%, about 0.5%, about 0.3%, or about 0.1%.

In another aspect, the method further comprises purifying (e.g., recrystallizing) a compound of formula (IV) (e.g., a compound of formula (II), (-) - halofenate).

Recrystallization can be carried out in various solvents, for example, using diisopropyl ether, cyclohexane or a mixture of toluene and cyclohexane. Recrystallization can be used to increase the enantiomeric excess or chemical purity of the target product. For example, in some embodiments, the compound of formula (IV) after recrystallization has an enantiomeric excess of about 99.9% or more. In some embodiments, the compound of formula (IV) after recrystallization has a chemical purity of about 99%.

Unless otherwise indicated, all technical and scientific terms used in the context have the same meanings as the average person skilled in the art would generally suggest. Alkyl refers to groups of unbranched, branched or cyclic aliphatic hydrocarbon chains containing from one to ten carbon atoms (C _1-10 alkyl), from one to six carbon atoms (C _1-6 alkyl), or from one to four carbon atoms (C _1-4 alkyl). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 2-propyl, tert-butyl, pentyl and the like.

Aryl refers to a monovalent monocyclic or bicyclic aromatic hydrocarbon residue containing from 6 to 10 carbon atoms in the ring. Unless otherwise indicated, the aryl group may be substituted with one or more substituents, for example, one, two or three substituents, or one or two substituents selected from alkyl, haloalkyl, nitro and halogen. More specifically, the term aryl includes, but is not limited to, phenyl, 1-naphthyl and 2-naphthyl and the like, each of which is optionally substituted with one or more substituents mentioned above.

A chiral or chiral center refers to a carbon atom having four different substituents. However, the ultimate criterion for chirality is mismatch when superimposing mirror images.

The terms CPTA and halofenic acid are used interchangeably herein and refer to (4-chlorophenyl) (3-trifluoromethylphenoxy) acetic acid or 4-chloro-a- (3 trifluoromethylphenoxy) phenylacetic acid. (-) - The CPTA optical isomer has a K-configuration at the chiral center and (+) - The CPTA optical isomer has a K-configuration at the chiral center.

An enantiomeric mixture refers to a chiral compound having a mixture of enantiomers, including a racemic mixture.

Enantiomerically enriched refers to a composition in which one enantiomer is present in greater quantity than the other enantiomer.

Enantiomeric excess or% of it refers to the quantitative difference between the first enantiomer and the second enantiomer. The enantiomeric excess is determined by the equation:% e = (% of the first enantiomer) - (% of the second enantiomer). Thus, if the composition contains 98% of the first enantiomer and 2% of the second enantiomer, then the enantiomeric excess of the first enantiomer is 982% or 96%.

The terms halogen, halide and halo are used interchangeably herein and refer to P, C1, Bg and I. In one aspect, halogen refers to P and C1.

Halogenated refers to an alkyl group which has the meanings given in the present description, and in which one or more hydrogen atoms are replaced by halogen (s), including perhalogenated, such as trifluoromethyl.

Halofenate refers to 2-acetamidoethyl-4-chlorophenyl- (3-trifluoromethylphenoxy) acetate (i.e. 2 (acetylamino) ethyl ester 4-chloro-a- (3- (trifluoromethyl) phenoxy) benzeneacetic acid or 2 (acetylamino) ethyl (4-chlorophenyl) (3-trifluoromethylphenoxy) acetic acid ester).

Unless otherwise indicated, the term phenyl refers to an optionally substituted phenyl group. Suitable phenyl substituents are the same substituents as those described in the definition of aryl. Similarly, the term phenoxy refers to a group of the formula —OAg ^a , where Ag ^a is phenyl, which is as defined herein. Thus, the term a- (phenoxy) phenylacetic acid refers to acetic acid which is substituted at the 2-position with optionally substituted phenyl and optionally substituted phenoxy groups.

Used in the present description, the term processing, contacting or reaction refers to the addition or mixing of two or more reagents under suitable conditions to obtain the specified and / or desired product. It should be borne in mind that the reaction, which leads to the formation of the specified and / or the desired product, may not necessarily be the result of a combination of two reagents that were added initially, i.e. there may be one or more intermediate products that are formed in a mixture that ultimately leads to the formation of the specified and / or desired product.

Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. When describing an optically active compound, the prefixes K and δ are used to indicate the absolute configuration of the molecule relative to its chiral center (s). The prefixes ά and 1 or (+) and (-) are used to denote the sign of rotation of plane-polarized light by the compound, wherein (-) or (1) means that the compound is levorotatory and (+) or (ά) means that the compound is dextrorotatory. There is no correlation between the nomenclature for absolute stereochemistry and for the rotation of the enantiomer. For a given chemical structure, these compounds, called stereoisomers, are identical, except that they are mirror images of each other. A particular stereoisomer may also be called an enantiomer, and a mixture of such isomers is often called an enantiomeric or racemic mixture. See, for example, 81gs11 ^ 1S55SG. A. & NeaShssosk, S.N., UTKOEiSΤΙΟΝ TO OX.AMS SNEM18TKU, 2 ^ηά Εάίΐίοη, Сар1eg 7 (Masmshap RiykPpd So., Υ.δ.Α. 1981).

The terms essentially free of its (+) - stereoisomer, essentially free of its (+) enantiomer are used interchangeably in the context and they mean that the composition has a significantly higher content of the (-) - isomer relative to the (+) - isomer. In one embodiment, the term substantially free of its (+) stereoisomer means that the composition contains at least 90 wt.% Of the (-) isomer and 10 wt.% Or less of the (+) isomer. In another embodiment, the term substantially free of its (+) - stereoisomer means that the composition contains at least 99 wt.% Of the (-) - isomer and 1 wt.% Or less of the (+) - isomer. In another embodiment, the term substantially free of its (+) stereoisomer means that the composition contains more than 99, 99.5, 99.8 or 99.9% by weight of the (-) isomer. These percentages are based on the total amount of isomers in the composition.

In one embodiment, the present application describes a condensation reaction of (-) - CPTA with

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Ν-acetylethanolamine to obtain (-) - halofenate with high chemical yields, high chiral purity and providing a suitable by-product profile. In one aspect of the present application, the condensation reaction to produce (-) - halofenate can be carried out in one step.

Combination reactions using propylphosphonic anhydride (T3P) under various conditions did not provide the desired ester in high yields. It is known that a by-product of T3P can be removed by simple washing with water. The ratios of reactants to (-) - CPTA and the use of various amounts of solvents were studied. The reaction was monitored by a combination of LC-MS and HPLC. Chiral HPLC methods were used to measure chiral purity (which can be expressed as enantiomeric excess). The coupling reaction can be carried out to completion when using T3P under optimal conditions, such as an increase in the stoichiometry of the reaction, an increase in the concentration of reactants and elevated reaction temperatures. However, after the completion of the reaction, the chiral center underwent epimerization under the reaction conditions. Quenching of the reaction at 0 ° C nevertheless led to a 50-50 racemic mixture. Bases such as triethylamine, Ν, Ν-diethylisopropylamine and Ν-methylmorpholine, which were used in the coupling reaction, were believed to be the cause of racemization. However, in the absence of a base, these coupling reactions did not continue until completion.

In the coupling reaction, various other coupling reagents were studied. The base was necessary for reactions when phosphonium (BOP, RuVOR and RuAOOR), aluminum (NVTi, TWTI, NATi, TATI and NSTI), uronium (T8TI, TOTI, TOTI, TRTI and TEVTI) and mixed coupling reagents (C1B, C1P were used) , TSRN and EBRVT). Combination reactions mediated by carbodiimides (ESS, E1C and BAS) and imidazolium (CE1) proceed without foundation. Attempts to apply various conditions have shown that coupling reactions with CE1 do not proceed until completion.

The names of specific coupling agents are as follows:

VOR Benzotriazole-1yloxytri (dimethylamino) phosphonium hexafluorophosphate RuBOP Benzotriazole-1yloxytripyrrolidine phosphonium hexafluorophosphate

RuAOOR Hexafluorophosphate (7-azabenzotriazole-1yloxy) tripyrrolidine phosphonium

HBT and Hexafluorophosphate O-benzotriazole-Ν, Ν, N ', Ν' tetramethyluronium

TWT Tetrafluoroborate 2- (1H-benzotriazol-1-yl) -1,1,3,3tetramethyluronium

NATi Methanaminium hexafluorophosphate 2- (1H-7azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium

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TATTetrafluoroborate O- (7-azabenzotriazol-1-yl) Ν, Ν, Ν ', Ν'-tetramethyluronium

NST and 2- (6-chloro-1H-benzotriazol-1-yl) 1,1,3,3-tetramethylamino hexafluorophosphate

TZTi Tetrafluoroborate Ν, Ν, Ν ', Ν'-tetramethyl-O- (Ν succinimidyl) dropped

ΤΝΤυ Tetrafluoroborate O- (5-norbornene-2,3-dicarboximido) Ν, Ν, N ', N'-tetramethyluronium

TOTi Tetrafluoroborate Οί (ethoxycarbonyl) cyanomethyleneamino] -Ν, Ν, Ν ', Ν'tetramethyluronium

TRT and Tetrafluoroborate O- (2-oxo-1 (2H) pyridyl) -Ν, Ν, Ν ', Ν’tetramethyluronium

TVBTi Tetrafluoroborate,, Ν, Ν ', Ν'-tetramethyl-O- (3,4-dihydro-4-oxo-1,2, 3-benzotriazin-3-yl) uranium

C1B 2-chloro-1,3-dimethylimidazolidinium tetrafluoroborate

C1P 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate

TSGN Hexafluorophosphate Ν, Ν, Ν ', Ν'te tramethylchloroformamidinium

ΌΕΡΒΤ 3- (diethoxyphosphoryloxy) -1,2, 3-benzotriazin-4 (3N) he

ΌΟΟ Ν, Ν'-dicyclohexylcarbodiimide

GC Ν, Ν'-diisopropylcarbodiimide

EBS 1-Ethyl-Z- (3-dimethylaminopropyl) carbodiimide

SB1 Carbodiimidazole

For coupling reactions using BSS, a base such as 4- (Ν, Ν dimethylamino) pyridine (ΌΜΑΡ) is usually required. However, under certain conditions, the reaction of the combination of (-) - halofenic acid with Ν-acetylethanolamine and OSS led to complete conversion to (-) - halofenate without the use of ΌΜΑΡ.

The following values of representative chiral purity (% of it) were obtained for the combination products (in the form of crude reaction mixtures) using BSS, 1) 1С and ЕБС (with ΌΜΑΡ and without ΌΜΑΡ)

Agent % her % her Combinations / Conditions with ΌΜΑΡ without ΌΜΑΡ BOS (0 ° C) 99% 98% B1C (Komi, temp.) Did not 96% EBS (Komi.Temp.) Did not 80%

In the OCC coupling reaction using a catalytic amount of ΌΜΑΡ after completion of the reaction, the resulting crude reaction mixture was stored for a period of time. Storage of the crude reaction mixture slowed the epimerization of (-) - halofenate. However, when ΌΜΑΡ was not used in the reaction, there was no further epimerization after the reaction was completed. It was noted that the reaction with ΌΜΑΡ was slightly faster than the reaction when ΌΜΑΡ was absent. After completion of the condensation reaction, it was noted that the reaction that was carried out without незнач gave a slightly lower chiral purity (98% of it) compared with the coupling reaction carried out with ΌΜΑΡ, which had a chiral purity of 99% of it. However, one advantage of carrying out the reaction without ΌΜΑΡ was that no further epimerization of the resulting product after the reaction was completed was not observed, so immediate treatment was not required. Accordingly, OSS can be used in the absence of a base at the stage of ether formation for the synthesis of (-) - halofenate.

The authors also studied the effect of the ratio of coupling reagent to (-) - CPTA on the reaction. A higher scale reaction using 0.1 mol of (-) - CPTA in a BSS-mediated coupling reaction was carried out using the conditions described above. An LC-MS analytical method was developed to determine the residual ΌΟΠ, by-product of OSS in the crude and final product. It was established 5 028385 that BSI was present in an amount of 0.8% in the crude product and was reduced to 0.48% in the final isolated product after a single recrystallization from diisopropyl ether.

Examples

Starting materials and reagents:

(-) - CPTA, Sya§, L1 # 07B2213 (> 99% of it)

Ν-Acetylethanolamine, Sya§, waxy solid, L0 1 # 07C4811

Ν-Acetylethanolamine, TC1, viscous liquid, catalog number: А0075, bо1 # И01 ЭСС, Ашпсь, 99%, bо1 # 13896ΚΜΥ

Combination reaction with ESA:

(-) - CPTA oss Ν-Acetylethanolamine ΌΜΑΡ Toluene ΌΜΑ 3.3 g 2.27 g 2.1 g 2.5 mg 5 + 5ml 2 ml 1.0 eq 1.1 eq 2 eq. 0.2%

ESA in toluene (5 ml) was added to a solution containing (-) - CPTA and Ν-acetyl ethanolamine in toluene (5 ml) and ΌΜΑ (2 ml) using a syringe pump for 20 min at 0 ° C and the resulting mixture was stirred at 0 ° C for 3 hours

Analysis 3 hours (0 ° C) 1 day, kt 2 day, c.t. Exit (halofenate) > 99% > 99% > 99% Chiral purity ((-) - halofenate) 99% of her 97% of her 92.6% of her

The above representative result shows that the coupling reaction using ESA and ΌΜΑΡ provides the desired combination product. The epimerization of the chiral center occurs slowly over time, although the product remains in the reaction mixture. Crude solid obtained from toluene / cyclohexane: 3.45 g, 94.8% ee. Crystallization from diisopropyl ether gave 2.4 g (yield 70% from crude solid), 96.4% of it.

When the coupling reaction was carried out with dimethylacetamide (ΌΜΑ), the reaction was carried out to completion and the product was obtained in high chemical yield, high chiral purity. However, it was found that the coupling reaction can also be carried out without the presence of ΌΜΑ as a solvent, co-solvent or as an additive to the reaction, and the resulting product was obtained with a similar chemical yield and chiral purity.

Combination reaction with and without ESA ΌΜΑ

(-) - CPTA oss Ν-Acetylzanolamine LOBSTER Toluene 3, 3 g 2.27 g 2.1 g 2.5 mg 5 + 5 ml 1.0 eq 1.1 eq 2 eq. 0.2%

□ OS in toluene (5 ml) was added to the solution using a syringe pump for 20 min at 0 ° С and the resulting mixture was stirred at 0 ° С for 3 h.

Analysis 30 min (0 ° C) Yield (Halofenate) > 99% Chiral purity ((-) - halofenate) 99% of her

Condensation reaction with and without ESA ΌΜΑΡ

(-) - CPTA OSS Ν-Acetylethanolamine Base Toluene 3.3 g 2.27 g 2.1 g Absent. 7 + 5 ml 1,0 eq. 1.1 eq 2 eq. Absent.

OES in toluene (5 ml) was added to the solution using a syringe pump for 20 min at 0 ° C and the resulting mixture was stirred at 0 ° C for 3 h and at room temperature.

Analysis 30 min (0 ° C) 1,5 hour (0 ° C) 17 hour (ct) 4 days Exit (halofenate) 98.9% > 99% > 99% Not determined Chiral purity ((-) - halofenate) > 98% of her Not determined 98% of her 98% of her

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ESA reaction and low reagent ratio

(-) - CPTA rss Ν-Acetylethanolamine Toluene 3.3 g 2.17 g 1.55 g 15 ml + 5 ml 1,0 eq. 1.05 equiv. 1.5 eq.

EES in toluene (5 ml) was added to the solution using a syringe pump for 20 min at 0 ° C and the resulting mixture was stirred at 0 ° C for 3 h and at room temperature.

Analysis 1.5 hours (0 ° C) Exit Halofenate> 99% Chiral purity ((-) - halofenate) > 98% of her

The reaction with the use of ESA and Ν-acetylethanolamine from TC1

(-) - CPTA oss Ν-Acetylethanolamine Toluene 3.3 g 2, 17 g 1.55 g 15 ml + 5 ml 1.0 eq 1.05 equiv. 1.5 eq.

EES in toluene (5 ml) was added to the solution using a syringe pump for 20 min at 0 ° C and the resulting mixture was stirred at 0 ° C for 3 h and at room temperature.

Analysis 1.5 hours (0 ° C) Yield (Halofenate) > 99%

The essence of the method:

Scheme 1 illustrates a general method for preparing compounds of formula (IV).

In one embodiment, a process for preparing a compound of formula (IV), such as (K) -2-acetamidoethyl-2- (4-chlorophenyl) -2- (3- (trifluoromethyl) phenoxy) acetate, can be performed first by dissolving OCC in an aprotic solvent, such like toluene. Separately, a solution of KOH, such as Ν acetylethanolamine, is dissolved in an aprotic solvent such as toluene, and a solution of Ν acetylethanolamine is mixed with a solution of (-) - CPTA in an aprotic solvent such as toluene. Alternatively, a solution of a compound of formula I, such as (-) - 4-chlorophenyl- (3trifluoromethylphenoxy) acetic acid, is prepared in an aprotic solvent such as toluene, and a compound of formula KOH in which K has the same meanings as described herein description, then added to the mixture. The OCC solution is then added to the solution containing the compound of formula (I) with the compound of formula KOH.

In one aspect, the addition of an OCC solution to a solution containing a compound of formula (I) with KOH is carried out at a temperature below room temperature, such as below about 15 ° C, below 10 ° C, below 5 ° C, or at about 0 ° C for approximately 1, 2, 3, 5 hours or more. In one embodiment, the addition of the OCC solution is performed at a temperature of about 0 ° C. for about 1.5 hours, or until the entire OCC solution is added.

In another aspect, the resulting solution or suspension is stirred at a temperature below room temperature, such as about 10 ° C. or 0 ° C., for at least about 3 hours, 5 hours, 7 hours, about 12 hours or more, until until the reaction, as defined, is complete. Monitoring the completion of the reaction can be carried out by chromatography methods such as TLC, HPLC, or spectroscopic methods. Precipitated by-product ΌΟΗ can be removed from the solution using standard methods, such as filtering through Whatman paper, filtering on a Buchner funnel, optionally with silica gel and / or celite, to remove the AIS. Depending on the solvent or solvent mixtures used in the process, more than one filtration step may be required to remove the AIS when the AIS is deposited over time. In one embodiment, the OCI precipitate is washed with a solvent such as toluene. An organic solvent, such as cyclohexane, was added to the filtrate containing the product, and the resulting solution was washed with water, and water was separated from the organic solution. Residual water is then removed from the organic solution by drying, such as drying using a drying agent (sodium sulfate, magnesium sulfate, etc.) and / or azeotropic distillation with a cyclohexane-toluene solution.

A solid compound of formula (IV), such as (K) -2-acetamidoethyl-2- (4-chlorophenyl) -2- (3 (trifluoromethyl) phenoxy) acetate, can be obtained from solution. In one embodiment, an organic solvent, such as cyclohexane, is added to the reaction solution, and the resulting mixture is heated to a temperature above room temperature, such as about 35, 37, or about 40 ° C. Crystals of the desired product are optionally introduced into the resulting solution, such as crystals of (K) -2-acetamidoethyl-2- (4-chlorophenyl) -2- (3- (trifluoromethyl) phenoxy) acetate, and the solution is stirred at such the same temperature for at least 1, 2, 3, or about 4 hours or more, and the mixture allows it to slowly cool to room temperature or below room temperature, for at least about 1, 2, 3 and about 4 hours or more and the resulting crystals are separated by filtration and washed with cold (approx. 10 ° C or less) with a solvent such as cyclohexane. The crystalline product can be dried to obtain the desired product.

Various reaction conditions, crystallization conditions and conditions of isolation using various modifications of the methods described in the present description, allow you to select (-) halofenate with a yield of more than approximately 80%, with a yield of more than approximately 85%, with a yield of more than approximately 90%, with a yield more than about 95% and with a yield of more than about 97%. In various aspects, the above methods make it possible to isolate (-) - halofenate with a content of approximately 98% ee, approximately 99% ee, approximately 99.5% ee, approximately 99.9% ee or more. In various aspects, the above methods make it possible to isolate (-) - halofenate, which has an ISI level of approximately 1%, approximately 0.5%, approximately 0.4%, approximately 0.3%, approximately 0.2%, approximately 0.1% about 0.05% or about 0.01% or less. In some aspects, its indicated contents and chemical purity levels are reached before further purification (e.g., pecrystallization) of the compound. In one aspect of the method described herein, the resulting product, (-) - halofenate, essentially does not contain its (+) - stereoisomer.

It was found that, depending on the reaction conditions and the solvent or solvent mixtures used for each isolation step, ΙΧΈ can be precipitated from the solution at various rates over time, and after precipitation, the ISI can be separated from the desired solution containing the product by a filtration method.

Reaction in the presence of ASC 0.1 mol of CPTA with Ν-acetylethanolamine from TC1

Preparation of (K) -2-acetamidoethyl-2- (4-chlorophenyl) -2- (3- (trifluoromethylphenoxy) acetate

ASC (22.7 g, 110 mmol) was dissolved in toluene (50 ml) at 20 ° C. 500-Acetylethanolamine (15.5 g, 150 mmol), toluene (150 ml) and (-) - 4-chlorophenyl) - (3 trifluoromethylphenoxy) acetic acid (33.1 g, 100 mmol) were added to a 500 ml round bottom flask. stirred at 20 ° C until a clear solution is formed. The solution was cooled in an ice-water bath. ASC was added dropwise to the solution in a toluene solution at 0 ° C for 90 minutes. The resulting suspension was stirred at 0 ° C. for 3 hours and then at 20 ° C. overnight. Dicyclohexylurea (ISI) obtained as a by-product was separated by filtration and washed with toluene (25 ml) twice. Cyclohexane (100 ml) was added to the filtrate (containing the desired product, (-) - halofenate). The solution was washed with water (100 ml) three times. Residual water was removed by azeotropic distillation with cyclohexane and toluene (approximately 180 ml). Cyclohexane (200 ml) was added to the resulting solution at 40 ° C and (-) - halofenate (33 mg) was seeded. The resulting suspension was stirred at 40 ° C for 2 hours, then cooled to 10 ° C for 1 hour and stirred for an additional hour. Precipitated crystals were separated by filtration and washed with cold (<10 ° C) cyclohexane. The wet product was dried in vacuo overnight to give the title compound as a white solid. Yield: 35.4 g (80.5%), 99.5% of it; chemical purity 98.6% (ISI 0.80%). The dry solid (35 g) was recrystallized from diisopropyl ether (350 ml), to thereby give the title compound as a white crystalline solid. Yield: 28.5 g (81.4%), 99.9% of it; chemical purity 99.3% (ISI 0.48%).

Claims (13)

CLAIM 1. A method of obtaining a compound of formula (IV) where K is C _1-6 alkylC (O ^ IS _1-6 alkyl- or C _6-10 aryl (O ^ IS _1-6 alkyl-, including contacting (-) - halofen acids of the formula (I) - 8 028385 initiations, and Ν, Ν'-dicyclohexylcarbodiimide in an aprotic solvent in the absence of a base to form a compound of formula (IV). 2. The method according to claim 1, in which the compound of formula (IV) is a (-) - halofenate of formula (II) 3. The method according to claim 1 or 2, in which the aprotic solvent is selected from the group consisting of toluene, xylenes, cyclohexane, diisopropyl ether, isopropyl acetate, tetrahydrofuran, hexanes, methyl tert-butyl ether and combinations thereof. 4. The method according to claim 3, in which the aprotic solvent is toluene. 5. The method according to any one of claims 1 to 4, in which the molar ratio of Ν, Ν'-dicyclohexylcarbodiimide to (-) - halofenic acid is from 1.05: 1 to 1.15: 1 and the molar ratio of the compound of formula KOH to ( -) - halofenic acid is from 1.02: 1 to 1.7: 1. 6. The method according to claim 5, in which the molar ratio of Ν, Ν'-dicyclohexylcarbodiimide to (-) halofenic acid is 1.1: 1 and the molar ratio of the compound of formula KOH to (-) halofenic acid is 1.5: 1. 7. The method according to any one of claims 2 to 6, in which the compound of formula (IV) is (-) halofenate, comprising the steps of: (a) contacting a base-free solution containing Ν-acetylethanolamine in toluene with a base-free solution of (-) - halofenic acid in toluene; (b) cooling the resulting solution at approximately 0 ° C; and (c) contacting the obtained cooled solution of step (b) with a base-free solution of Ν, Ν'-dicyclohexylcarbodiimide in toluene to form a solution containing (-) halofenate. 8. The method according to claim 7, further comprising the steps of: (4) filtering out the Ν, Ν'-dicyclohexylurea from a solution containing (-) - halofenate to obtain a filtrate containing (-) - halofenate, and (e) washing the Ν, Ν'-dicyclohexylurea with toluene. 9. The method of claim 8, further comprising the steps of: (ί) adding cyclohexane to the filtrate containing (-) - halofenate, (e) washing the filtrate with water, (K) drying the filtrate, and (ΐ) crystallizing and isolating (-) - halofenate. 10. The method according to claim 9, in which the stage of drying the filtrate includes azeotropic distillation of the washed filtrate. 11. The method according to claim 9 or 10, in which the selected (-) - halofenate has an enantiomeric excess of 98% or more before cleaning. 12. The method according to claim 11, in which the selected (-) - halofenate has an enantiomeric excess of 99% or more before cleaning. 13. The method according to item 12, in which (-) - halofenate has an enantiomeric excess of 99.5% or more before cleaning.