CN100525757C - Resolution of alpha-(phenoxy)phenylacetic acid derivatives - Google Patents

Abstract

The present invention provides a method for producing an enantiomerically enriched alpha-(phenoxy)phenylacetic acid compound of the formula (I): from its enantiomeric mixture, where R<1> is alkyl or haloalkyl and X is halide.

Description

The fractionation of α-(phenoxy group) phenylacetic acid derivatives

Technical field

The present invention relates to a kind of enantioselectivity method for splitting that is used for α-(phenoxy group) phenylacetic acid is separated from its enantiomeric mixture.

Background of invention

Ester and amide derivatives as α-(phenoxy group) phenylacetic acid of halofenate (halofenate) and so on are chipal compounds, are used to improve various physiological situations, comprise the situation relevant with blood fat matter deposition, for example type ii diabetes and hyperlipemia.For example, referring to United States Patent (USP) the 3517050th and No. 6262118.α-(phenoxy group) phenylacetic acid has a chiral centre on being positioned on the α position of carbonylic carbon atom by the carbon atom of asymmetric replacement, therefore have two kinds of enantiomeric forms.

Cytochrome P450 2C9 is a kind of known enzyme that plays an important role in the metabolism of specific drug.Those skilled in the art have known by suppressing variation in the drug metabolism that cytochrome P 450 enzymes mediated there is a strong possibility that patient is produced very significant side effects.Also know racemic α-(phenoxy group) phenylacetic acid, for example HALOFENIC ACID (halofenic acid) can suppress Cytochrome P450 2C9.For example, referring to No. the 6262118th, United States Patent (USP).Therefore, administration as raceme α-(phenoxy group) phenylacetic acid of HALOFENIC ACID or derivatives thereof and so on, can cause the various drug interaction problems with other medicines, these other medicines comprise anticoagulant, antiinflammatory and other thus enzyme cause metabolic medicine.(-)-enantiomer that has been found that HALOFENIC ACID is aspect the ability that suppresses Cytochrome P450 2C9, and (+) of its specific activity HALOFENIC ACID-enantiomer is hanged down about 20 times.Therefore, expectation is substantially devoid of the HALOFENIC ACID of (+)-enantiomer or (-)-enantiomer of its derivant, to reduce the probability that drug interaction takes place.

Therefore, need find a kind of effective method to produce a kind of product, be rich in the enantiomer of required α-(phenoxy group) phenylacetic acid in this product, for example (-)-HALOFENIC ACID.

Summary of the invention

One aspect of the present invention provide a kind of enantiomeric mixture by the α that comprises first and second enantiomers-(phenoxy group) phenylacetic acid compound produce a kind of enantiomer enrichment, general formula is

α-(phenoxy group) phenylacetic acid compound,

Wherein, R ¹Be alkyl or haloalkyl,

X is a halogen.

Method of the present invention comprises:

(a) by the enantiomeric mixture of α-(phenoxy group) phenylacetic acid compound is produced a kind of solution with contacting the amount that is enough to make free first enantiomer in the solution is approximately 1 to 3 condition to the ratio of the amount of free second enantiomer under less than the chiral amine compound of the enantiomer enrichment of 0.5 molar equivalent, comprise the solid acid-alkali salt of the enantiomer enrichment of first isomer in this solution; And

(b) the solid Acid-Base of first enantiomer is approached its saturation point or is lower than under the temperature of its saturation point to separate from solution in the concentration of the Acid-Base salt of second enantiomer that makes α-(phenoxy group) phenylacetic acid compound.

At least a portion of second enantiomer can be converted into first enantiomer, for example carries out racemization by second enantiomer is contacted with alkali.Can make the racemic mixture recirculation of gained carry out similar enantiomer enrichment process then, to improve the productive rate of the first enantiomer Acid-Base salt.

In another embodiment, the general formula of chiral amine compound is:

Wherein, R ²And R ³Independent separately is hydrogen or alkyl; Perhaps R ²And R ³Form heterocyclic moiety with the atom that they connected;

R ⁴It is hydrogen or alkyl;

R ⁵And R ⁶Independent separately is hydrogen or alkyl, perhaps R ⁵Or R ⁶In one be amine protecting group group; And

Ar is an aryl.

Description of drawings

Fig. 1 is (-)-and the solubility curve figure of (+)-CPTA/CAF D-alkali salt in the 2-propanol.

Fig. 2 represents is the result who splits gained in the process of racemic compound of CPTA with CAF D-alkali under various crystallization conditions.

Fig. 3 be expression (-)-and (+)-CPTA/CAF D-alkali salt pure isopropyl alcohol and comprising isopropyl alcohol and the solution of the mixture of CPTA (11%) in the figure of dissolubility.

Fig. 4 is the figure of the composition of the different mixture of each group component of expression.

Fig. 5 is illustrated in crystallization and heating down, the figure of (/+) salt loading performance.

Fig. 6 is the form that the 4th experimental result is compared among expression forecast model and Fig. 2.

Fig. 7 is the figure that expression forms dependency between the addition of the amount of (+)-salt and CAF D-alkali.

What Fig. 8 represented is the experimental data of the fractionation behavior shown in the Sub_clause 11 among Fig. 2.

Fig. 9 represents is actual and the amount CPTA that calculates in the mother solution, and the percent of (+)-CPTA salt that calculates and the comparison of experimental data.

Figure 10 A is the table of the dissolubility analog computation (that is, the 13rd of Fig. 2 the) of expression experimental data and Fig. 7.

Figure 10 B is the table that is illustrated among experimental data under 28.3 ℃ and Fig. 2 the 4th dissolubility analog computation.

Figure 11 represent raceme CPTA at various temperatures, 1, the dissolubility in the 2-dichloroethanes.

Figure 12 represent raceme CPTA at various temperatures, the dissolubility in heptane.

Figure 13 is a form of enumerating result among the embodiment 24, has represented to use CAF D-alkali CPTA under various crystallization conditions to split the productive rate of thing.

The air-circulation features of the fractionation crystallization behavior of each bar in Figure 14 presentation graphs 2.

Figure 15 represents is by the output of (-)-halofenate of (-)-CPTA salt gained among the embodiment 26.

Figure 16 represent raceme CPTA sodium salt at various temperatures, the dissolubility in water.

Figure 17 represents that CPTA is in the racemization feature that is showed under the different pH value, in the hydrolytic process of (-)-halofenate.

Figure 18 is illustrated under the different pH value, the recovery result of CAF D-alkali, as described in example 30 above.

Figure 19 be raceme CPTA 1, the experimental result of the solubility test in 2-dichloroethanes and the heptane is as determined among the embodiment 33.

Figure 20 is the experimental result of the dissolubility test of raceme CPTA sodium salt in water, as determined among the embodiment 41.

Figure 21 is the experimental result of (+)-halofenate basic hydrolysis, as determined among the embodiment 42.

The specific embodiment

I. definition

" alkyl " refers to have the straight chain or the branched aliphatic hydrocarbon long chain alkyl group of 1 to 10 carbon atom, preferably has 1 to 6 carbon atom, and 1 to 4 carbon atom is more preferably arranged.The example of alkyl includes, but not limited to methyl, ethyl, n-pro-pyl, 2-propyl group, the tert-butyl group, amyl group etc.

" aryl " refers to univalent monocycle or bicyclic aromatic hydrocarbon part, and the carbon atom of 6 to 10 makeup rings is wherein arranged.Unless indication is arranged in addition, aryl can be replaced by one or more substituent groups, preferably by one, two or three substituent groups replacements, is more preferably replaced by one or two substituent group that is selected from alkyl, haloalkyl, nitro and halogen.More specifically, term aryl includes, but not limited to phenyl, 1-naphthyl and 2-naphthyl etc., and any in them can be chosen wantonly by one or more above-mentioned substituent groups and replace.

" CAF D alkali " refers to chloromycetin D alkali, i.e. D-Soviet Union-(-)-2-amino-1-(nitrobenzophenone)-1, ammediol.

" chirality " or " chiral centre " refers to have the carbon atom of four different substituents.But the final criterion of chirality is that have can not eclipsed mirror image.

The replaceable in the text use of term " CPTA " and " HALOFENIC ACID " refers to (4-chlorphenyl) (3-4-trifluoromethylphenopendant) acetic acid.

" enantiomeric mixture (enantiomeric mixtrure) " refers to contain the chipal compounds of the mixture of enantiomer, comprises racemic mixture.Preferably, enantiomeric mixture refers to contain the chipal compounds of each enantiomer of equivalent basically.More preferably, enantiomeric mixture refers to racemic mixture, and wherein each enantiomer exists with identical amount.

" (the enantiomerically enriched) of enantiomer enrichment " refers to a kind of compositions, and wherein a kind of enantiomer exists with higher amount stand separation process than it before.

" enantiomerism is excessive " or " %ee " refers to the difference measured between first enantiomer and second enantiomer.Enantiomerism is excessive to be determined by following formula: %ee=(the first enantiomer %)-(the second enantiomer %).Like this, if compositions comprises 98% first enantiomer and 2% second enantiomer, then the enantiomerism of first enantiomer is excessive is 98%-2% or 96%.

Term " halogenide " and " halo " but mutual alternative in the literary composition then and refers to halogen, comprise F, Cl, Br and I, and class halogenide, such as-CN and-SCN.

" haloalkyl " refers to wherein one or more hydrogen atoms by defined alkyl in the literary composition that halogen replaced, and comprises the plain alkyl of perhalogeno, such as trifluoromethyl.

" halofenate " refers to 2-acetylamino ethyl 4-, and chlorphenyl-(3-trifluoromethyl-phenoxy group) acetas (promptly; 4-chloro-α-(3-(trifluoromethyl) phenoxy group) phenylacetic acid; 2-(acetyl-amino) ethyl ester or (4-chlorphenyl) (3-trifluoromethyl methoxyl group) acetic acid), 2-(acetyl-amino) ethyl ester).

" assorted alkyl " refers to contain one or more hetero atoms or contains one or more heteroatomic substituent branching or nonbranched non-annularity saturated alkyl parts of comprising, and wherein hetero atom is O, N or S.Contain heteroatomic substituent example to comprise=O ,-OR ^a,-C (=O) R ^a,-NR ^aR ^b,-N (R ^a) C (=O) R ^b,-C (=O) NR ^aR ^bWith-S (O) _nR ^a(wherein, n is 0 to 2 integer).R ^aAnd R ^bIndependent separately is hydrogen, alkyl, haloalkyl, aryl or aralkyl.The representative example of assorted alkyl comprises, for example, N-acetyl group-2-amino-ethyl (that is ,-CH ₂CH ₂NHC (=O) CH ₃).

Term " heterocyclic radical " and " heterocycle " replaceable use refer to have the non-aromatics loop section of 3 to 8 annular atomses, one of them, two or three annular atomses are to be selected from N, O or S (O) _nThe hetero atom of (wherein, n is 0 to 2 integer), remaining annular atoms is C, one of them or two carbon atoms can be chosen wantonly by carbonyl and replace.Unless indication is arranged in addition, the ring of heterocyclic radical can be chosen wantonly independently by one, substituent group that two or three are selected from halogen, alkyl, aryl, hydroxyl, amino or alkoxyl and replace.More specifically, the term heterocyclic radical includes, but not limited to 1,3-diox and derivant thereof or the like.

The meaning of " leaving group " is relevant with its meaning in synthetic organic chemistry usually, promptly can be by atom or the group that nucleophilic group replaced, comprise halogen (such as, chlorine, bromine and iodine), alkane sulfonyloxy (alkanesulfonyloxy), arylsulfonyloxy (arenesulfonyloxy), alkyl carbonyl oxy (for example, acetoxyl group), aryl-carbonyl oxygen, methanesulfonamido, tosyloxy (tosyloxy), trifluoro-methanesulfonyl oxy, aryloxy group are (for example, 2,4-2,4-dinitrophenoxy base), methoxyl group, N, O-dimethyl hydroxyl amino etc.

Term " metal " comprises the I of family, II and transition metal, and main group metal, such as B and Si.

" optical purity " refers to the amount that enantiomer specific in the compositions exists.For example, if compositions contains 98% first enantiomer and 2% second enantiomer, then the optical purity of first enantiomer is 98%.

Unless indication is arranged in addition, term " phenyl " refers to the optional phenyl that replaces.Suitable phenyl substituent is identical with group described in the definition " aryl ".Similarly, term " phenoxy group " refers to that general formula is-OAr ^a, Ar wherein ^aBe as defined phenyl in the literary composition.Like this, term " α-(phenoxy group) phenylacetic acid " refers to the acetic acid that phenyl that is optionally substituted and the phenoxy group of choosing replacement wantonly are partly replaced on the 2-position.

" blocking group " refers to can cover, reduce or stop this active part when when active group in the molecule links to each other.The example of blocking group can find in following document: T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis, the 3rd edition, John Wiley ﹠amp; Sons, New York, 1999 and Harrison and Harrison etc., Compendium of SyntheticOrganic Methods, (John Wiley and Sons, 1971-1996), it is included in this to volume 1-8 in full by reference.The representative example of hydroxy-protective group comprises acyl group, benzyl and trityl ether, THP trtrahydropyranyl ether, trialkylsilyl ethers and allyl ether.The representative example of amido protecting group comprises trityl, allyloxy carbonyl, 9-fluorenylmethyloxycarbonyl (FMOC), nitro-Rhizoma et radix veratri (Radix Rhizoma Veratri) oxygen base carbonyl (NVOC) of formoxyl, acetyl group, trifluoroacetyl group, benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trimethyl silyl (TMS), 2-trimethyl silyl-ethylsulfonyl (SES), trityl and replacement etc.

When term " speed " was used for the expression of salt formation, it referred to kinetics and/or thermodynamics speed.

Used term " processing ", " contact " or " reaction " refers to add or mix two or more reactants in appropriate condition in the literary composition, generates specified and/or required product.Be to be understood that the reaction that produces specified and/or required product can be directly obtained by two kinds of reactants combinations of initial adding, promptly can produce one or more intermediums in mixture, these intermediums finally cause specified and/or required product to form.

When term used in the literary composition " those of above definition " and " Ding Yi those here " when being used for representing variable, comprise the generalized definition of variable by reference, if any, also comprise preferably, more preferably with most preferred definition.

Many organic compound exist with the optical activity form, i.e. the plane that they can the Plane of rotation polarized light.In the description of optically active compound, prefix R and S are used for representing the absolute configuration of one or more chiral centres of molecule.Prefix " d " and " l " or (+) and (-) are used for representing the symbol that the combined thing of linearly polarized light is rotated, and (-) or (1) refers to that chemical compound is " left-handed ", (+) or (d) refer to that chemical compound is " dextral ".There is not dependency between the nomenclature of absolute stereo chemistry and the optical activity of enantiomer.For given chemical constitution, these chemical compounds that are called " stereoisomer " are identical, except they are each other mirror images.Specific stereoisomer also can be called " enantiomer ", and this type of mixture of isomers also often is called " enantiomer " or " raceme " mixture.Referring to for example Streitwiesser, A.﹠amp; Heathcock, C.H., INTRODUCTION TOORGANIC CHEMISTRY, second edition, the 7th chapter (MacMillan Publishing Co., U.S.A.1981).

Term " is substantially free of its (+)-stereoisomer ", " being substantially devoid of its (+)-enantiomer " replaceable in the text use, refers to that (-) in the compositions-isomer is compared with (+)-isomer to occupy very big ratio.One preferred embodiment in, term " is substantially devoid of its (+)-stereoisomer " and refers to contain in the compositions (-)-isomer and 10 weight % or still less (+)-isomer of at least 90 weight %.In a preferred embodiment, term " be substantially devoid of its (+)-stereoisomer " and refer to contain in the compositions at least 99 weight % (--isomer and 1 weight % or still less (+)-isomer.In a most preferred embodiment, term " be substantially devoid of its (+)-stereoisomer " and refer to contain in the compositions (-)-isomer of surpassing 99 weight % and.These percents are based on the total amount of isomer in the compositions.

II. foreword

Although the synthetic obvious improvement that obtained in recent years of chirality is preparing optical activity-be in the industrial process of chipal compounds, the method for splitting of racemic compound remains selected method.Usually, chipal compounds is synthetic with racemic form, and end product is split the chemical compound that produces the enantiomer enrichment.

The method for splitting of this end product is useful especially in the chipal compounds of a large amount of preparation pharmaceutical actives.Although the enantiomer of chipal compounds has identical chemical bond, the atoms in space orientation in the enantiomer is different.Therefore, a kind of enantiomer of chiral drug shows required activity, and simultaneously to compare side effect obviously much smaller with another kind of enantiomer.Although know between the chirality of optical activity medicine and its side effect to have this dependency for some time, many chiral drugs are still with their racemic form administration.

The diastereo-isomerism crystallization is widely used in industry.The process productive rate of theory that splits through the diastereomer crystallization is 50%.But, need recrystallization process more than once usually, have the compositions of enough optical purities with generation.

The invention provides a kind of method that enantiomeric mixture, the particularly racemic mixture (for example, HALOFENIC ACID) of α-(phenoxy group) phenylacetic acid compound are carried out the enantiomer enrichment.Preferably, method of the present invention provides the solid acid-alkali salt of (-)-enantiomer of a kind of α-(phenoxy group) phenylacetic acid compound.In the method, (-)-enantiomer is easy to separate from solution.

Available then carboxylic acid activated group activates the hydroxy-acid group in α-(phenoxy group) phenylacetic acid of enantiomer enrichment, generate activatory α-(phenoxy group) phenylacetic acid, it can react with alcohol, amine, mercaptan or other nucleophilic compound, generates ester, amide, thioesters or other derivant of α-(phenoxy group) phenylacetic acid of enantiomer enrichment respectively.Like this, in producing α-(phenoxy group) phenylacetic acid derivatives, be useful with α-(phenoxy group) phenylacetic acid compound of the enantiomer enrichment of method of the present invention preparation, described in No. the 3517050th, United States Patent (USP).Especially, the inventive method is useful in producing (-)-halofenate.

III. the crystallization of selecting property is washed in mapping

As mentioned above, most enantioselectivity method for crystallising needs recrystallization process more than once, and the compositions of enough optical purities is arranged with generation.But the present invention finds under the condition described in certain literary composition, have α-(phenoxy group) phenylacetic acid compound of enough optical purities to produce by single method for crystallising.Like this, on the one hand, method of the present invention is based on the inventor's the pleasantly surprised and unexpected discovery of making us, and promptly the enantiomeric mixture of α-(phenoxy group) phenylacetic acid compound can be by using chiral amine compound by the enantiomer enrichment.Especially, the inventive method provides a kind of enantiomer of required α-(phenoxy group) phenylacetic acid compound, and its optical purity is at least about 90%, and preferable is at least about 95%, and better is at least about 97%, and best is at least about 98%.

In one embodiment, method of the present invention provides the enantiomer enrichment of the racemic mixture of following α-(phenoxy group) phenylacetic acid compound of the enantiomer enrichment, particularly general formula of enantiomeric mixture:

Wherein, R ¹Be alkyl or haloalkyl, X is a halogen.This process relates generally to use chiral amine compound to form the solid acid-alkali salt of the enantiomer enrichment of α-(phenoxy group) phenylacetic acid compound.

Especially, the inventive method relates to the following α of general formula-(phenoxy group) phenylacetic acid such as HALOFENIC ACID (R wherein ₁Be CF ₃, X is Cl) fractionation:

Wherein, R ¹Be alkyl or haloalkyl, X is a halogenide.

In another embodiment, the inventive method relates to the fractionation of α-(phenoxy group) phenylacetic acid of general formula I or preferred general formula I I, and wherein X is a chlorine.

And in another embodiment, the inventive method relates to the fractionation of α-(phenoxy group) phenylacetic acid of general formula I or preferred general formula I I, wherein R ¹Be haloalkyl, preferred trifluoromethyl.

In another embodiment, α-(phenoxy group) phenylacetic acid is by the Chiral Amine crystallization.The wide range of operable chiral base comprises that those are described in the material in the following example part.Preferably, use chiral base to obtain the solid acid-alkali salt of (-)-enantiomer of α-(phenoxy group) phenylacetic acid.In this mode, (-)-enantiomer is easy to separate from solution, for example by filtering.In another embodiment, Chiral Amine is the following amines of general formula:

Wherein, R ²And R ³Independent separately is hydrogen, alkyl or hydroxy-protective group; Or R ²And R ³Form heterocyclic moiety with the atom that they connected; R ⁴It is hydrogen or alkyl; R ⁵And R ⁶Independent separately is hydrogen or alkyl, perhaps R ⁵Or R ⁶It is amine protecting group group; Ar is an aryl.

In another embodiment, R ²And R ³Form 1 with the oxygen atom that they connected, 1 of 3-diox, replacement, the 3-diox (for example, 1 of dialkyl group replacement, the 3-diox, such as 5,5-dimethyl-1,3-diox), or their derivant.

In another embodiment, R ²And R ³Be hydrogen.

And in another embodiment, R ⁴Be hydrogen.

In another embodiment, Ar is the aryl that replaces.Particularly preferred Ar partly is the optional phenyl that replaces.The Ar that is more preferably partly is the 4-nitrobenzophenone.

And above-mentioned preferred moiety combinations can form other preferred examples.For example, a kind of particularly preferred chiral base is the amines of above-mentioned general formula III, wherein R ², R ³, R ⁴And R ⁶Be hydrogen; Ar is the 4-nitrobenzophenone.Particularly preferred α-(phenoxy group) phenylacetic acid compound shown in above-mentioned general formula I I, R wherein ¹Be trifluoromethyl, X is a chlorine.In this mode, preferred chiral base and α-(phenoxy group) phenylacetic acid compound wide range all comprise within the scope of the invention.

The inventor has been found that the consumption that is used in the chiral base in α-(phenoxy group) phenylacetic acid crystallization has very big influence to the optical purity of enantiomer enrichment.For example, when general formula be

Chiral amine compound (R wherein ², R ³, R ⁴With Ar in literary composition definition) when being used in the crystallization of α-(phenoxy group) phenylacetic acid compound, if the use amount of chiral amine compound is less than 0.5 molar equivalent, can obtain high %ee, preferred use amount is about 0.48 molar equivalent or still less, preferred use amount is about 0.47 molar equivalent or still less, and most preferred use amount is about 0.45 molar equivalent or still less.Should be realized that chiral amine compound itself should have enough enantiomerism purity, with α-(phenoxy group) phenylacetic acid derivatives that obtains high enantiomer enrichment.

Crystallization is carried out in solvent usually, and this solvent has different dissolubility to the salt that forms between two kinds of enantiomers of α-(phenoxy group) phenylacetic acid and Chiral Amine.Under this mode, the preferential precipitation from solution of a kind of diastereo-isomerism salt is got off.Suitable recrystallisation solvent comprises proton solvent, such as alcohol.Particularly preferred recrystallisation solvent is an isopropyl alcohol.

In other factors, the productive rate of the α of enantiomer enrichment-(phenoxy group) phenylacetic acid also depends on the use amount of recrystallisation solvent.For example, if use a large amount of recrystallisation solvents, then mixture becomes too rare, and solid forms and reduces.If the use amount of recrystallisation solvent very little, then undesirable diastereo-isomerism salt meeting supersaturation in the solution causes the crystallization of undesirable diastereo-isomerism salt, thereby has reduced the optical purity of required enantiomer.Therefore, when using isopropyl alcohol as recrystallisation solvent, the use amount of recrystallisation solvent is preferably each gram α-(phenoxy group) phenylacetic acid compound and restrains with about 2 grams extremely about 6, and preferred about 3 restrain to about 5 grams, also to restrain most preferably about 4 grams by preferably about 3.5 grams extremely about 4.5.

In one embodiment, this method for crystallising relates to the crystallization solution mixture heated to certain temperature, and this temperature is higher than the nucleation temperature of two kinds of enantiomers, with two kinds of all basically enantiomers of dissolving.For example, crystallization solution is heated to about 60 ℃ of boiling points to solution, preferred about 70 ℃ to 80 ℃.More preferably, crystallization solution is heated to about 75 ℃.Can before chiral amine compound adds or after adding, heat solution.Heating proceeds to solid matter dissolving fully basically, is generally about 0.5 hour to about 16 hours, preferred about 1 hour to about 8 hours.

Crystallization solution cooling then, up to the nucleation temperature of the salt that is equal to or less than the first diastereo-isomerism salt such as α-(phenoxy group) phenylacetic acid (-)-enantiomer, preferably be higher than the nucleation temperature of the salt of the second diastereo-isomerism salt such as α-(phenoxy group) phenylacetic acid (+)-enantiomer.This is formed the solid acid-alkali salt of first enantiomer and chiral amine compound.Be not subject to any theory, believe that the formation speed of Acid-Base salt of the another kind of enantiomer of formation speed ratio of the Acid-Base salt that uses chiral amine compound can make a kind of enantiomer is much bigger.This speed may be owing to the difference on kinetics and/or thermodynamics speed between two kinds of enantiomers is caused.As exemplary compounds α of the present invention-dissolubility characteristics of (phenoxy group) phenylacetic acid compound is in higher temperature higher dissolubility to be arranged.Therefore, just be on the nucleation temperature of second diastereomeric salt by crystallization solution is cooled to, can obtain the higher reclamation productive rate of the solid first diastereo-isomerism salt.

After slurry forms, crystallization solution further can be cooled off, up to the temperature of solution near or greater than the saturation point of second diastereomer.This has prevented to form diastereo-isomerism solid acid-alkali salt, the formation that has improved the diastereo-isomerism solid acid-alkali salt of first enantiomer again simultaneously from second enantiomer.

The cooldown rate of crystallization solution can influence the optical purity of formed solid acid-alkali salt.For example, if crystallization is refrigerative too fast, in the lattice of the solid acid-alkali salt of required enantiomer, can catch undesirable enantiomer.But too slow cooldown rate can increase the time, raises the cost.Therefore, crystallization solution should cool off can farthest reducing optical purity loss and have simultaneously under the speed of enough economy.Usually, the cooldown rate of crystallization solution is about 0.05 ℃/minute to about 1 ℃/minute, preferred about 0.1 ℃/minute to about 0.7 ℃/minute, and more preferably from about 0.25 ℃/minute to about 0.4 ℃/minute.Be to keep on the saturation point of solid acid-alkali salt of unwanted enantiomer then with crystallization solution in second enantiomer.Usually, crystallization solution kept about 1 hour to about 72 hours in this temperature, and preferred about 2 hours to about 48 hours, more preferably from about 3 hours to about 30 hours.

As what expected, use a spot of chiral amine compound can optionally form the solid acid-alkali salt of first enantiomer.But the productive rate of gained can be less relatively.The productive rate of the required enantiomer that obtains from racemic mixture in theory, is 50%.Like this, if use the chiral amine compound of 0.5 molar equivalent, the theoretical yield of total α-(phenoxy group) phenylacetic acid is 50% (or 100% required enantiomer).In order to satisfy the needs of economic aspect, the inventive method provides the required enantiomer productive rate at least about 50%, preferably at least about 60%, more preferably at least about 70%, most preferably at least about 75%.Suppose 100% selectivity, these productive rates are corresponding to the chiral amine compound that adds about 0.25,0.30,0.35 and 0.375 molar equivalent, and on behalf of chiral amine compound, this need join minimum in the crystallization solution.

The trend that it is believed that second enantiomer and chiral amine compound formation solid acid-alkali salt is the variable one of the main reasons of conventional method for crystallising.Therefore, be the supersaturation point of undesirable enantiomer by determining second enantiomer, can farthest reduce or prevent the in advance side of second enantiomer solid acid-alkali salt in forming.Those skilled in the art more easily just can determine the supersaturation point, for example pass through solubility experiment.

Should be noted that though the inventive method is discussed with reference to the enrichment that has (-)-enantiomer in the racemic mixture, the inventive method also is applicable to enrichment (+)-enantiomer.The inventive method mainly provides the solid precipitation of a kind of enrichment (-)-enantiomer and the filter liquor of enrichment (+)-enantiomer, i.e. mother solution.From sedimentary salt, discharge required (-)-enantiomer and reclaim chiral amine compound, can be easier to by the acidify of salt just finish, for example with inorganic diluted acid or any other inorganic or organic acid that is used for this salt of hydrolysis generally known in the art.Though filter liquor is as undesirable by-product in this step, filter liquor can further be handled with acid or preferably use alkali treatment, make (+)-filter liquor of enantiomer enrichment is converted into racemic mixture.For example, (+)-enantiomer can use sodium hydrate aqueous solution to carry out racemization.This racemic mixture can be used again, and promptly recycles.In addition, chiral amine compound also can obtain reclaiming from above-mentioned step of converting and circulation step.Like this, the inventive method makes itself becomes circular type's step.

IV. raceme α-(phenoxy group) phenylacetic acid is synthetic

A kind of racemic mixture method representation of α-(phenoxy group) phenylacetic acid of producing general formula I is in following scheme I.

Scheme I

Like this, phenylacetic acid 1 is converted into activatory carboxylic acid derivates, and for example, acyl chlorides obtains α-bromophenyl chloroacetic chloride (not shown) by α-bromination reaction then.Then acyl chlorides is converted into ester 2, wherein R alkyl normally.Preferably, be used for acyl chlorides is converted into the alcohol roh of ester 2 and is used in pure identical in the subsequent reactions as solvent.Under this mode, the number of different solvents type minimizes.In addition, by using identical ROH as solvent in subsequent reactions, the amount of the by-product of formation (for example passing through ester exchange reaction) is farthest reduced.For example, isopropyl esters 2, promptly R wherein is an isopropyl, if easy carrying out in isopropanol solvent in subsequent reactions is very favorable.The substitution reaction that ester 2 and oxybenzene compound 3 carry out in the presence of the alkali as hydroxide (for example potassium hydroxide) and so on generates α-(phenoxy group) phenylacetate 4.α-(phenoxy group) phenylacetic acid hydrolysis obtains α-(phenoxy group) phenylacetic acid I.

In this mode, (4-chlorphenyl)-(3-4-trifluoromethylphenopendant)-acetic acid, promptly CPTA can prepare by five steps, and does not separate the centre, crystallizes out the back productive rate and be about 85% from heptane.

V. the purposes of the α of enantiomer enrichment-(phenoxy group) phenylacetic acid

The α of enantiomer enrichment-(phenoxy group) phenylacetic acid compound is useful as intermediates in preparation in the various pharmaceutically active compounds, comprises α-(phenoxy group) phenylacetic acid compound that is disclosed in No. the 3517050th, the United States Patent (USP).Like this, another aspect of the present invention racemic mixture enantioselectivity of providing a kind of α from general formula I-(phenoxy group) phenylacetic acid compound produces the method for following α-(phenoxy group) phenylacetate chemical compound of general formula:

Wherein, R ¹Be alkyl or haloalkyl, X is a halogen, R ⁷Be assorted alkyl, preferred N-acetyl group 2-amino-ethyl (is that general formula is-CH ₂CH ₂NHC (=O) CH ₃Part).This method relates to the fractionation of racemic compound of α-(phenoxy group) phenylacetic acid compound of above-mentioned general formula I, and α-(phenoxy group) phenylacetic acid by the enantiomer enrichment and the reaction of carboxylic acid activating reagent, the enrichment of generation enantiomer, activatory α-(phenoxy group) phenylacetic acid.Suitable carboxylic acid activating reagent comprises that thionyl halide (for example, thionyl chloride), anhydride, thioester produce agent and other carboxylic acid activating reagent well known by persons skilled in the art.

Be (R with activatory α-(phenoxy group) phenylacetic acid and general formula then ⁷-O) chemical compound such as the N-acetyl ethanolamine derivatives reaction of WM, the α of the general formula III of production enantiomer enrichment-(phenoxy group) phenylacetic acid compound, wherein R ⁷As hereinbefore defined, M is hydrogen or metal, for example Na, K, Li, Ca, Mg, Cs etc., and subscript w is the oxidation state of M.The inventor finds that also activated acids and general formula are (R ⁷-O) _WReaction between the chemical compound of M can be carried out under the tangible racemization effect not having.

By the checking of following examples, other purpose of the present invention, advantage and novelty will be conspicuous for a person skilled in the art, and following examples are not intended to limit the present invention.

Embodiment

Reagent and experimental provision

Unless indication is arranged in addition, reagent or solvent are available from Aldrich Chemical or Fisher Scientific.The N-acetylethanolamine is also buied from Lancaster Synthesis.To be HALOFENIC ACID make according to the step that is described in United States Patent (USP) the 3517050th and No. 6262118 raceme CPTA, and it is included in this in full by reference.(1R, 2R)-(-)-2-amino-1-(4-nitrobenzophenone)-1, ammediol (being CAP D-alkali) is from TCI Americas.

Operate under the positive nitrogen atmosphere and carry out.One is used to control the straight wall of jacket type bottom and has jacket temperature in the glass reactor of outlet with Camile process control computer that recirculation heater is connected with cooling system.Unless indication is arranged in addition, removes down for 40 ℃ and desolvate at 15 to 25 holders, bath Wen Gaoda with the Buchi Rotary Evaporators.Solid sample in vacuum drying oven in 40 ℃ and 15 to 25 the holder under carry out drying.Cenco HYVAC vacuum pump is used to provide the vacuum less than 1 holder, is used for vacuum distilling.Water content is measured by using Metrohm 756KF Coulometer and HYDRANAL Coulomat AG reagent to be analyzed by Karl Fisher.Fusing point is determined by using Mettler Toledo FP62 fusing point equipment.PH measures by the Orion Model 290A pH meter that uses calibration.Protonand 13CNMR spectrum is record on Bruker Avance 300MHz spectrogrph.

Chirality HPLC analyzes when λ=240 nanometers and measures, inject 10 microlitres and be dissolved in the sample of mobile phase to (R, R) in 1.5 microns 250x4.6 millimeters of WHELK-O post (Regis Technologies), be 95/5/0.4 (volume/volume/volume) hexane/2-propanol/acetic acid eluting of 1.0 ml/min with flow.For the solid sample of CPTA/CAF D-alkali diastereo-isomerism salt, solid joins in the aqueous hydrochloric acid solution, the CPTA dichloromethane extraction; From dichloromethane layer, remove desolvate after, residue is dissolved in the mobile phase of analyzing usefulness.

Achirality HPLC analyzes when λ=220 nanometers and measures, and injects 5 microlitres at 25 ℃ and is dissolved in the sample of mobile phase to Phenomenex LUNA 5 microns C18,4.6 millimeters posts of (2) 250 x (RegisTechnologies).Use traffic is the gradient of 1.5 ml/min, is 66 volume % water/34 volume % acetonitriles/0.1 volume % trifluoroacetic acid during beginning, and linearity is brought up to 26 volume % water/74 volume % acetonitriles/0.1 volume % trifluoroacetic acid in the time of 20 minutes.

In order to analyze the acid solution of ester such as halofenate, acetonitrile is used as the injection solvent.When measuring, the product design of CPTA and halofenate uses external standard method to assess by the HPLC test, and the achirality analytical procedure is carried out under less than 2.5 mg/ml at sample concentration.

Embodiment 1

Be reported in No. the 3517050th, the United States Patent (USP) about the fractionation of CPTA in the past, wherein, cinchonidine is as chiral base, and (+) of sedimentary CPTA-enantiomer is as diastereo-isomerism salt.A major defect of this step is that required (-)-enantiomer is retained in the mother solution, makes the separation of pure (-)-enantiomerism body portion be difficult to carry out.

The racemic compound that this embodiment has represented to use various different chiral bases to split CPTA is with the result of (-)-isomer of obtaining the enrichment of solid enantiomer.Be different from former method, the inventive method makes (-)-CPTA of enantiomer enrichment be easy to separate from solution.

Racemic CPTA separates the raceme halofenate by potassium hydroxide water and prepares.About the screening of chiral base, then be with etc. mixture and the chiral base of mole CPTA in vial, be blended in ethanol, methanol and the acetone, and solution left standstill is not stirred.After at room temperature spending the night, will still be in the refrigerator that sample in the solution is placed on 5 ℃.After placement is spent the night in refrigerator, in the sample that still is in the alcoholic solution, add low amounts of water.After at room temperature placing 4 days, aqueous alcoholic solution is put back in the refrigerator.All samples is stayed in the refrigerator, and makes regular check on the situation that precipitation forms in one month.Enumerated in the table 1 and tested used alkali and solvent condition, and the temperature of finding crystalline salt.

Table 1.CPTA splits observed alkali

E-estimates

C-crystalline temperature (temperature)

^*-with 1 mole/1 molar sodium hydroxide aqueous solution

For chiral base, find quinine, L-tyrosine hydrazides, (-)-cinchonidine and 2-amino-1-(4-nitrobenzophenone)-1, two kinds of enantiomerism physical abilitys of ammediol provide crystalline salt from racemic CPTA.For crystalline sample, solid is separated from filtrate, and analyzes solid phase and mother solution with chirality HPLC, forms with the enantiomerism of determining two bursts of logistics.Results of screening is listed in the table 2.

Table 2. chiral base results of screening

^*-rarer

^*-slow cool down

What comprise in the table 2 calculates the percentage of solids productive rate by isomery ratio in solid and the mother liquor stream.Used calculating formula is as follows.The theoretical maximum productive rate of 100% isomery purity is 50%.Productive rate surpasses 50% and means that the isomer that has comprised other is arranged.

Calculate the equation of productive rate from the isomery ratio.

If: the area % of component 1 in the a=raw material; The area % of component 2 in the b=raw material; The area % of x=separation component 1; The area % of y=separation component 2; The area % of component 1 in the w=mother solution; The area % of component 2 in the z=mother solution; E=separate substance gram; Material gram in the F=mother solution.

And: a+b=100%; E+F=1

Then: xE+wF=a; YE+zF=b

Separate: xE+w (1-E)=a; YE+Z (1-E)=b

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

Embodiment 2

This embodiment represents to split at ethanol and 2-propanol with CAF D alkali the result of CPTA gained.

Result about ethanol and 2-propanol is summarised in the following table 3.In order to assess, at the difference of cooling figure slurry to be taken a sample, and measure solid phase and form with solution enantiomerism mutually.In the information, record the %ee of solid phase and (be 50% productive rate to the maximum, 100%ee) thus by the white proportion by subtraction productive rate of expection weight that isomer proportion calculates.What table 3 was included is the productive rate of (-)-CPTA, and this productive rate (is 100% productive rate to the maximum, 100%ee) from the content of (-)-CPTA in weight percent yield and the solid phase.

In this concrete research, best result is that every mole of CPTA uses 1 mole of CAFD alkali in the ethanol.The productive rate of being made of (-)-CPTA CAF D alkali salt that calculates biphase chirality is approximately 72%, 87.6%ee (-)-CPTA salt in the solid phase.Use just obtains lower fractionation with the 1 molar equivalent CAF D alkali of similar concentration in the 2-propanol.When using 0.55 mole of CAFD alkali of every mole of CPTA correspondence, higher enantiomer enrichment is achieved.Under these conditions, the productive rate of (-)-CPTA CAF D alkali salt that is calculated by phase composition is approximately 76-79%, and (-)-CPTA of 87-90%ee is arranged in the solid phase.Do not consider Physical Loss or Damage, the weight percent yield of calculating is 41% to 42%; Actual weight isolated yield is 37% to 39%.

The fractionation of the CPTA that table 3. carries out with CAF D alkali

Recrystallization CPTA CAF D alkali salt can be brought up to 98%ee from about 87%ee with optical purity from the 2-propanol, and material is recovered as 87% or be that benchmark reclaims 93% (table 4) with (-) in the raw material-CPTA content.

Table 4. is recrystallization (-)-CPTA CAF D alkali from the 2-propanol

Generally speaking, the productive rate maximum that obtains from raceme CPTA is that the productive rate of (-)-CPTACAF D alkali salt of 50% is 35%, and optical purity is approximately 98%ee.

The crystallization of optically enriched enantiomer can improve chiral purity usually.After removing resolving agent, (-)-CPTA crystallization from methyl cyclohexanone also improves optical purity in a way.In an experiment, the crystallization of (+)-CPTA is brought up to 100%ee with optical purity from 99.1%ee; Mother solution is 95%ee.

Embodiment 3

This embodiment has illustrated CPTA (+)-and the dissolution characteristics of CAF D alkali salt in the 2-propanol of (-)-isomer.

For the optimization that the CPTA that helps to use CAF D alkali splits, two kinds of diastereo-isomerism salt are all measured in the solubility performance of 2-propanol.The results are shown among Fig. 1.(+)-CPTA with cinchonidine-fractionation prepares (+)-CPTA CAF D alkali salt.As shown in Figure 1, the dissolubility of required (-)-CPTA diastereomer is approximately than low 3 times of (+)-CPTA form.The equation of included description dissolubility is by least-square analysis (R among the figure ²0.99) calculate.The data point of (-)-CPTA salt is not included in the determining of equation in the time of 82 ℃, but very identical with the dissolubility that calculates.

The racemization of unwanted CPTA enantiomer can be circulated back in the process.Like this, have been found that reflux down to the enantiomer enrichment of CPTA in the 1N sodium hydrate aqueous solution, undesirable isomer heats, can be at 1 hour with interior realization racemization.The CPTA that the HPLC analytical separation goes out does not detect other by-product.

Embodiment 4

This embodiment has set forth the method that obtains (+)-CPTA.

To 2 liters have top agitator round-bottomed flask in add thick (+)-CPTA cinchonidine (chinconidine) salt of 33.0 grams, 610 milliliters of ethanol and 125 ml methanol.With the slurry reflux, obtain solution, then cooling.At 42 ℃ of very condensed slurries of formation.Slurry is heated to 68 ℃, obtains the slurry of light color, then cool to room temperature.Mixture 26 ℃ of filtrations, and is carried out drip washing with 150 milliliters of ethanol, behind 40 ℃ of vacuum dryings, obtain 23.48 gram (+)-CPTA-cinchonidine salt.With 600 milliliters of ethanol and 120 ml methanol repeated recrystallization steps, obtain 18.23 gram (+)-CPTA-cinchonidine salt (from twice crystallization, obtaining 55% recovery).Chiral chromatogram does not detect (-)-CPTA, although isolating degree can't be assessed (analysis condition of halofenate also is used in the analysis of CPTA) to low content.

The sample of 3.61 salt crossed of gram purification is mixed with 50 ml waters and 50 milliliters of toluene, and add 2.9 and restrain sulphuric acid.Clean organic facies with 30 ml waters, evaporation obtains residue then.Residue crystallizes out from 20 milliliters of cyclohexane extraction, obtains 1.22 gram (+)-CPTA.Perhaps 6.3 gram (+)-CPTA-cinchonidine salt are mixed with 56 gram diethyl ether and 29 gram water, and splash into sulphuric acid, being acidified to pH is 1.9.Clean organic facies with 25 ml waters, dry organic facies (magnesium sulfate), filtration, evaporation obtain residue.Residue stirs with 22 milliliters of hexahydrotoluenes in ambient temperature, forms slurry.This slurry is heated to 40 ℃, in ice bath, cools off then, the isolated by filtration solid, behind 40 ℃ of vacuum dryings, obtain 2.62 the gram (7.92 mMs, productive rate 78%) (+)-CPTA.

Embodiment 5

Illustrated among this embodiment from the method for synthetic (+)-halofenate of (+)-CPTA.

In 25 milliliters of round-bottomed flasks, add 0.91 gram (+)-CPTA and 2.6 gram thionyl chlorides.Then mixture heated is arrived and reflux, form solution.The process that is converted into acyl chlorides is by catching sample, monitoring with the HPLC assay products with methanol.Add 4.8 gram diethyl ether in solution of acid chloride, this solution joins in ice bath refrigerative at 12 milliliters of N that contain 0.37 gram pyridine, in the gram of 2.0 in the dinethylformamide (DMF) the N-acetylethanolamine.The solution of gained is joined in 25 ml waters and the 30 milliliters of diethyl ether.Separate organic facies, with the cleaning of 25 ml waters, dry (MgSO ₄), and filter, oily except that obtaining 0.92 gram after desolvating.HPLC analyzes and shows that halofenate is 45 area %, and CPTA is 50 area %.Chirality HPLC the analysis showed that halofenate is 99.78%ee (+)-enantiomer.

Embodiment 6

This embodiment has illustrated a kind of method for preparing raceme CPTA.

To 2 liters have top agitator round-bottomed flask in add 102.7 gram halofenates, 500 ml waters and 16.3 gram 2-propanol.Slurry is stirred, and add the potassium hydroxide aqueous solution of 32.3 grams 45%.Being heated to backflow after 1 hour, solution is cooled to ambient temperature, and adds 380 milliliters of hexanes.Hydrochloric acid with 24.57 grams 37% is adjusted to 2 with pH from 12.5.Three-phase mixture is heated to 60 ℃, obtains biphase.Shift out mutually lower floor is moisture, and with 50 milliliters of hexane extractions.The organic layer that merges is under atmospheric pressure added thermal distillation, remove the distillation of 100 milliliters of muddinesses.Solution is cooled to 30 ℃, adds crystal seed with CPTA.Form slurry.Slurry is cooled off in ice bath, the isolated by filtration solid, obtain 64.0 the gram (78.45% productive rate) raceme CPTA, (4-chlorphenyl) (3-three fluoro-methylphenoxy) acetic acid.

Embodiment 7

This embodiment has shown the representative result that uses various chiral bases to carry out the chiral separation screening in ethanol.

1.16 gram (3.51 mM) CPTA sample dissolution in 6.98 gram ethanol, are obtained solution (0.431 mM/gram).Add the listed various alkali of a certain amount of table 5 respectively in each vial, and add a certain amount of ethanol CPTA solution in vial, the amount of the ethanol CPTA solution that is added should be calculated, and makes that acid is the 1:1 mol ratio to the ratio of alkali.In some cases, before adding CPTA solution, add small amount of ethanol earlier with moistening alkali.With these bottles standing over night at ambient temperature.Bottle 7G and 7I have precipitation to occur.The sample of each supernatant is moved out of, and analyzes with chirality HPLC analyser.Filter to isolate solid, and also analyze.Some results have been listed in the table 2 (referring to the foregoing description 1).The bottle of remainder placed in 5 ℃ the refrigerator.After one day, precipitation appears among the 7E.Analytic sample as previously mentioned.In the bottle of remainder, add 50 microliters of water, and before in being placed into refrigerator, kept at ambient temperature three days earlier.After one month, do not observe other precipitation yet and generate.

Alkali screening in table 5. ethanol

	Alkali	The weight of CPTA solution (gram)	The weight of alkali (gram)	The ethanol that adds	The water that adds
						7A	S-(-)-methyl benzene methanamine	0.8836	0.4620	0 gram	0.05 gram
7B	1-2-amino-1-butanols	0.8198	0.0314	0	0.05
						7C	(1R, 2S)-(-)-norephedrine	0.5273	0.0342	0.2007	0.05
7D	(1S, 2S)-(+)-isoephedrine	0.7295	0.0515	0.1459	0.05
						7E	(1S, 2S)-(+)-2-amino-1-(4-nitrobenzophenone)-1, ammediol	0.5580	0.0510	0.1228	0
7F	(1,2S)-(+)-2-amino-1-phenyl-1, the 3-propylene glycol	0.5640	0.0405	0.1287	0.05
						7G	(-)-cinchonidine	0.3484	0.4390	0.3637	0
7H	(+)-cinchonine	0.6409	0.0796	0.2103	0.05
						7I	Quinine	0.5391	0.0750	0.1735	0
7J	(-)-strychnine	0.5812	0.0828	0.2295	0.05
						7K	Brucine	0.7566	0.1287	0	0.05
7L	(S)-(+)-2-pyrrolidine-methanol	0.8681	0.0383	0	0.05

Embodiment 8

This embodiment has shown the representative result that uses various chiral bases to carry out the chiral separation screening in acetone.

1.67 gram CPTA sample dissolution in 7.57 gram HPLC grade acetones, are obtained solution.Add the listed various alkali of a certain amount of table 6 respectively in each vial, and add a certain amount of CPTA solution in vial, the amount of the CPTA solution that is added should be calculated, and makes that acid is the 1:1 mol ratio to the ratio of alkali.In some cases, add a spot of acetone, and mixture heated is arrived about 40 ℃, obtain solution.In addition, the sodium hydroxide solution that in bottle 16M, adds 0.300 milliliter of 1N.With these bottles standing over night at ambient temperature.Form precipitation among the bottle 16D, analyze as mentioned above.Some results have been listed in the table 2 (referring to the foregoing description 1).The bottle of remainder is placed in the refrigerator.Form precipitation among the bottle 16N, and analyze.Bottle 16G forms considerably less precipitation.After one week, finding has precipitation among the bottle 16L.Analytic sample as previously mentioned.Not observing other precipitation generates.

Alkali screening in table 6. acetone

	Alkali	The weight of CPTA solution (gram)	The weight of alkali (gram)	The acetone (gram) that adds
					16A	(1S, 2S)-(-)-norephedrine	0.8568	0.0704
16B	(1S, 2S)-(+)-2-amino-1-phenyl-1, the 3-propylene glycol	0.1824	0.0168
					16C	S-(-)-methyl benzene methanamine	0.8948	0.0592
16D	Quinine	0.1968	0.0347	0.85
					16E	(S)-(+)-2-pyrrolidine-methanol	0.8181	0.0452
16F	Brucine	0.2163	0.0463
					16G	(+)-cinchonine	0.3987	0.0630
16H	(1S, 2S)-(+)-isoephedrine	1.0835	0.0974
					16I	(-)-strychnine	0.1462	0.0265	0.25
16J	Chinidine	0.3753	0.0663
					16K	1-2-amino-1-butanols	0.7248	0.0353
16L	L-tyrosine hydrazides	0.4508	0.0472	0.39
					16M	L-leucine methyl ester hydrochloride	0.5585	0.0544
16N	Quinine	0.4712	0.0829	2.00
					16O	(+)-cinchonine	0.3363	0.0539	0.30

Embodiment 9

This embodiment has shown the representative result that uses various chiral bases to carry out the chiral separation screening in methanol.

2.00 gram CPTA sample dissolution in 8.03 gram HPLC level methanol, are obtained solution.Add the listed various alkali of a certain amount of table 7 respectively in each vial, and add a certain amount of CPTA solution in vial, the amount of the CPTA solution that is added should be calculated, and makes that acid is the 1:1 mol ratio to the ratio of alkali.In addition, the sodium hydroxide that in bottle 27J, adds 0.300 milliliter of 1N.With these bottles standing over night at ambient temperature.Bottle 27B solidifies, and before as mentioned above sample being analyzed, adds 300 microliter methanol again.The bottle of remainder is placed in the refrigerator.After one month, do not observe other precipitation yet and generate.

Alkali screening in table 7. methanol

	Alkali	The weight of CPTA solution (gram)	The weight of alkali (gram)
				27A	(1S, 2S)-(-)-ephedrine	0.4896 gram	0.0478 gram
27B	Quinine	0.1420	0.0282
				27C	(+)-cinchonine	0.1822	0.0324
27D	1-2-amino-1-butanols	1.0012	0.0539
				27E	S-(-)-methyl benzene methanamine	0.7892	0.0576
27F	(1S, 2S)-(+)-isoephedrine	0.7600	0.0749
				27G	Brucine	0.1891	0.0436
27H	Chinidine	0.5845	0.114
				27I	(1S, 2S)-(+)-2-amino-1-phenyl-1, ammediol	0.3032	0.0299
27J	L-leucine methyl ester hydrochloride	0.5033	0.0545
				27K	(S)-(+)-2-pyrrolidine-methanol	0.7133	0.0434
27L	(1S, 2S)-(-)-norephedrine	1.1788	0.1070
				27M	(-)-strychnine	0.4525	0.0905
27N	(S)-(+)-2-amino-3-methyl isophthalic acid-butanols	0.1478	0.0092
				27O	(S)-(+)-2-amino-1-propanol	0.9268	0.0417
27P	(S)-(-)-2-amino-3-propyl group-1-propanol	0.3406	0.0307

Embodiment 10

This embodiment has shown the result who splits the CPTA gained with quinine.

In the flask of outlet is arranged at 150 milliliters of jacket types bottom, add 2.70 gram (8.17 mM) CPTA, 2.65 gram (8.17 mM) quinine and 50 milliliters of 2-propanol.With mixture heated to 70 ℃, obtain solution, be cooled to 30 ℃ with 0.2 ℃/minute speed then, and kept 2 hours at this, obtain slurry.The chirality HPLC of sample analyzes and shows (+) and (-)-CPTA that 42.88 area % and 56.47 area % are arranged respectively in the solid phase, and (+) and (-)-CPTA of 61.54 area % and 34.19 area % is arranged respectively in the solution.Slurry is heated to 60 ℃, is cooled to 30 ℃ with 0.04 ℃/minute speed then, and keep spending the night, obtain slurry.Chirality HPLC analyzes and shows (+) and (-)-CPTA that 29.94 area % and 44.19 area % are arranged respectively in the solid phase, and (+) and (-)-CPTA of 77.54 area % and 20.88 area % is arranged respectively in the solution.With 50 milliliters of 2-propanol diluted slurries, and be heated to 57 ℃, obtain solution, be cooled to 30 ℃ with 0.2 ℃/minute speed then.Begin to form at 30 ℃ of 1 hour disposed slurries.At ambient temperature mixture was stirred 2 days, filter to isolate solid then, and clean, behind vacuum drying, obtain 2.89 gram (54% productive rate, the quinine salts of CPTA in mass) with the 2-propanol.Chirality HPLC analyzes and shows (+) and (-)-CPTA that 42.25 area % and 57.75 area % are arranged respectively in the solid phase, and (+) and (-)-CPTA of 56.56 area % and 39.20 area % is arranged respectively in the mother solution.The gained result is included in the table 2 (referring to embodiment 1).

Embodiment 11

This embodiment has shown the result who splits CPTA with CAF D alkali.

In the flask of outlet is arranged at 150 milliliters of jacket types bottom, add 19.54 gram CPTA, 6.82 gram CAF D alkali (being D-Soviet Union-(-)-2-amino-1-(nitrobenzophenone)-1, ammediol) and 80.2 restrain the 2-propanol.With mixture heated to 70 ℃, obtain solution, be cooled to 5 ℃ of jacket temperatures with 0.1 ℃/minute speed then.Mixture hazes at 62 ℃.After 9 hours, the isolated by filtration solid cleans with 5 milliliters of 2-propanol 6 ℃ of maintenances, and at 40 ℃ of vacuum dryings, obtains 12.03 gram (37.4 weight % productive rate) (-)-CPTACAF D alkali salts.Solid chirality HPLC the analysis showed that (+)-CPTA that 6.34 area % are wherein arranged and (-)-CPTA of 93.46 area %; Contain (+)-CPTA of 81.41 area % and (-)-CPTA of 17.76 area % in the mother solution.

Embodiment 12

This embodiment has shown the result of recrystallization (-)-CPTA CAF D alkali salt.

In the flask of outlet is arranged at 150 milliliters of jacket types bottom, add 8.00 gram (-)-CPTA CAF D alkali salts (from the foregoing description 11) and 54.2 and restrain the 2-propanol.Mixture heated to refluxing, is obtained solution, be cooled to 20 ℃ of jacket temperatures with 0.1 ℃/minute speed then, and kept 6 hours for 22 ℃ at internal temperature.The isolated by filtration solid cleans with 5 milliliters of 2-propanol, and at 40 ℃ of vacuum dryings, obtains 6.93 gram (reclaiming 86.6 weight %) (-)-CPTA CAF D alkali salts (fusing point 184-185 ℃).Solid contains (+)-CPTA of 0.995 area % and (-)-CPTA of 99.01 area %; Contain (+)-CPTA of 44.53 area % and (-)-CPTA of 54.47 area % in the mother solution.Reactor cleans up with acetone.Acetone evaporated to residue is 0.27 gram (3.4 weight %).

Embodiment 13

This embodiment has set forth the method for preparation (+)-CPTA CAF D alkali salt.

(+)-CPTA cinchonidine salt, 200 ml waters and 100 milliliters of dichloromethane of in 1 liter of flask, adding 10.94 grams (17.5 mM).Add 1.8 gram sulphuric acid and regulate pH to 1.9.Partly clean organic layer three times with 100 milliliters of dilution heat of sulfuric acid, dry (magnesium sulfate) filters, and to be evaporated to residue be 5.79 grams.Residue is dissolved in the 22.2 gram 2-propanol, adds 3.5 gram DAF D alkali.The slurry that obtains is heated to backflow, obtains solution, be cooled to ambient temperature then, and slurry was stirred 3 hours.After the cooling, isolated by vacuum filtration goes out solidity in ice bath, cleans with 5 milliliters of 2-propanol, and at 40 ℃ of vacuum dryings, obtains 7.39 gram (productive rate 80%) (+)-CPTA CAF D alkali salts (fusing point is 172-173 ℃).

Embodiment 14

This embodiment has shown the dissolubility of diastereomer CPTA-CAF D alkali salt in the 2-propanol.

In the 2-propanol, add (-)-CPTA CAF D alkali and (+)-CPTACAF D sample (〉 98%ee according to the amount shown in the table 8), and use ultrasound wave to mix.All samples remains slurry.Slurry keeps spending the night under listed temperature, shifts out supernatant sample then, and carries out quantitative HPLC and analyze, to determine CPTA concentration.The results are shown among this harmony in the exterior Fig. 1 of gained.In addition, in the time of 82 ℃, 8.00 gram (-)-CPTA CAF D alkali salts need 54.2 gram 2-propanol to dissolve formation solution (14.7 weight %).Data point is included among Fig. 1, but is not included in the dissolubility equation.

The dissolubility of table 8. in the 2-propanol

Embodiment 15

This embodiment has set forth the racemization method of the CPTA of enantiomer enrichment.

In one 50 milliliters round-bottomed flask, add 0.31 gram (-)-CPTA (68.7%ee) and 9.4 gram 1N sodium hydroxide.With this vlil 1 hour, be cooled to ambient temperature then, and with the hcl acidifying of 1 gram 37%.Use dichloromethane extraction CPTA, evaporating solvent obtains 0.46 gram oil then.HPLC analyzes the CPTA that finds to have 99.4 area %, and chirality HPLC analyzes 50/50 mixture of finding to have the CPTA enantiomer.

Embodiment 16

This embodiment has set forth the process of using CAF D-alkali resolving racemic mixtures under various crystallization conditions.

At room temperature add CPTA, CAF D-alkali and 2-propanol and at the about 75 ℃ general crystallisation steps that are heated to solution.Solution is cooled to about 60 ℃, and keeps, up to nucleation takes place in this temperature.With (-)-salt (i.e. the salt of (-)-CPTA and CAF D-alkali) some batch of materials are added crystal seed, to lure the generation nucleation into.After slurry was by aging about 1 hour, container is cooled to separation temperature.The slower about 0.05-0.10 of cooldown rate ℃/minute of preceding 5 uses among Fig. 2 reaches separation temperature.Other experiment is adopted the about 0.25-0.40 of cooldown rate ℃/minute faster.A fibre-optical probe is directly inserted in the crystallizer, to determine the density of slurry.

The addition of CAF D-alkali and the concentration of solute are some important changing factors, and these changing factors produce final batch of material and form.(+)-salt (i.e. the salt of (+)-CPTA and CAF D-alkali) keeps oversaturated trend to be considered to be in some experiments for time variable and has variable main cause.This is illustrated among the 5th of Fig. 2, and thus, slurry kept 8 hours at 13 ℃, produced highly purified crystal (99.7% (-)-salt).After three hours, the fibre-optical probe signal increases, show (+)-nucleation may take place in salt.After 27 hours, the ratio of (/+) that separating slurry, crystalline product contain-CPTA is 83.3/16.7%.The HPLC of crystalline product analyzes the ratio that provides (-)-CPTA and (+)-CPTA.Because free CPTA is undersaturated in solution, so crystal analysis obtains is the ratio of diastereomer salt.Mother solution contains two kinds of dissolved salt and free CPTA.HPLC analyzes and has provided each merging amount as the CPTA enantiomer, and the 6th of Fig. 2 shows, slurry kept 20 hours at 1 ℃, produced highly purified salt (〉 98% (-)-CPTA).After being heated to 17 ℃, (+)-salt nucleation obtains low-quality product [(/+)-CPTA=81.2/18.8%].

In other test, the nucleation of (+)-salt takes place sooner, shown among Fig. 2 the 2nd, 8 and 10.For can be in separation approaching, that carry out under preferably just above the saturation temperature of (+)-salt, crystallization be desired.

As if when 3.9 gram 2-propanol/gram CPTA and 0.45 equivalent CAF D-alkali were arranged, separation at room temperature was in close proximity to the saturated level (or in metastable region) of (+)-salt.The 12nd begins with 0.43 normal alkali among Fig. 2, and crystalline product is at 21 ℃ of maintenances purer (〉, 99% (-)-salt), or even after with (+)-salt formation crystal seed.After adding more CAF D-alkali, obtain 0.45 equivalent, slurry kept 14 hours, kept 6 hours after adding crystal seed with (+)-salt then.The analyzing crystal product obtains 98.7% (-)-CPTA ratio.The total amount of alkali is brought up to 0.47 equivalent, then obtain (+)-salt forms and slowly to bring up to the crystalline product of (/+)-CPTA=92.3/7.7%.

Sub_clause 11 among Fig. 2 (3.9 gram 2-propanol/gram CPTA, 0.45 equivalent alkali) kept the high-purity of (-)-salt (99.1%) after 14 hours, but after the amount that adds alkali is brought up to 0.48 equivalent, and the product of gained is than being (/+)-salt=89.2/10.8%.The 9th (0.45 equivalent alkali) keeps 99.5% (-)-purity salt at 22 ℃ after 16 hours among Fig. 2.Calculating productive rate from (-)-CPTA of three batch of materials is 70.7-71.6% with this understanding.The productive rate that calculates is formed by (-)-CPTA and (+)-CPTA that knows crystal and mother solution, is obtained by the pressure mass balance of raceme CPTA charging.

Reinforced high-purity (-)-salt (〉 98.5% that provides of these have an appointment 0.45 equivalent CAF D-alkali and about 4 gram 2-propanol/CPTA) product, it can be used and need not further recrystallization.

Embodiment 17

This embodiment provides a kind of description CPTA salt fractionation/crystalline model.

The concentration of free CPTA depends on the amount of alkali He the solvent that is equipped with of adding.For example, by adding the fractionation of the CPTA that 4.0 gram 2-propanol and 0.50 equivalent CAF D-alkali carry out, can be formed on the salt in the 2-propanol, it contains 11% free CPTA.This solvent all has bigger dissolubility for (-)-salt and (+)-salt, and as determined among Fig. 3.Fig. 3 also is included in the dissolubility in the pure 2-propanol, represents with gram component/gram 2-propanol.As shown in Figure 3, the curve of various salt has same shape.

By other reinforced combination of CPTA, CAF D-alkali and 2-propanol, also can obtain in the 2-propanol system of 11.0% free CPTA, as shown in Figure 4 the same.As shown in Figure 4, to the reinforced common inaccuracy of different experiments among Fig. 2 drop on this straight line.But, the dissolubility of (-) salt and (+) salt can be estimated by following: " 11.0% free CPTA " point line more than pairing feed in raw material be rarer (promptly,＜11.0% free CPTA is in the 2-propanol), and show than the lower dissolubility of " 11.0% " line.On the contrary, the point in " 11.0% " line below obtains containing in the solvent〉11% free CPTA, the dissolubility of salt is than determined bigger among Fig. 3.In order to estimate the dissolubility of component, use the multiplier factor k of constant.Therefore, the dissolubility equation of improved (-)-salt and (+)-salt is S _(-)=0.01421ke ^0.02613TAnd S ₍₊₎=0.02868ke ^0.02771T

Even, can very well estimate (-)-salt and (+)-salt solubility by adjusting k, also still crystallization can't be described because other ignorant be (-)-salt that when adding resolving agent alkali, forms and the ratio of (+)-salt.An experiment more specifically is shown in (also referring to Fig. 2) among Fig. 5.0.75 normal alkali is used in this experiment, and when 21.5 ℃ of samplings, obtain (/+)-the salt ratio is the product of 66.4/33.6%.By heating slurry and continuous sampling, can obtain (-)-salt and the saturated line of (+)-salt in solvent.

For dissolubility model and real data are complementary, used regression technique, promptly dissolubility factor k is operated with the charge proportion of (-)-salt and (+)-salt, so that obtain with the corresponding to result of observed data (be that crystal is formed, mother solution is formed and crystal yield).By selecting k=0.68 and being 58.1% (-)-salt/41.9% (+)-salt (that is, when adding CAFD-alkali, forming 0.436 equivalent (-)-salt and 0.314 equivalent (+)-salt), obtain good concordance for the charge proportion of 0.75 equivalent salt.Fig. 6 represents contrast.The dissolubility model can calculate isolating complete mass balance: the amount of (-)-salt and (+) salt in the crystal; The amount of (-)-salt and (+)-salt in the mother solution, and the amount of (-)-free CPTA and (+)-free CPTA in the mother solution.In following embodiment 19, provide a kind of difference of utilizing dissolubility by the extraction post processing to mother solution in (/+)-salt and (/+)-free CPTA carry out quantitative step.

The normalization technology is used in the different experiment of other addition that splits liquid with the dissolubility model.Use dissolubility factor k and (that is) combination, (-)-salt that forms and the ratio of (+)-salt, this model are tended to provide and met the single of experimental result and separate as the composition of the salt of charging when adding salt.Thus, set up the chart among Fig. 7.This result shows many more (the surpassing extrapolation smallest point 0.34 equivalent) that resolving agent adds, and the amount of (+)-salt formation increases.Be not subject to any theory, in some embodiments, believe if the amount that adds less than 0.34 equivalent, CAFD-alkali will be main only and (-)-CPTA coordination, all form (-)-salt basically.In addition, by means of the curve among Fig. 7, can calculate (-)-amount of CPTA and (+)-CPTA (free acid).Add the normal alkali of 0.35-0.75, the % ratio of { the total CPTA free acid of (-)-CPTA/ } is approximately 25% (23.3%-27.1%).Therefore, (/+)-" selectivity " of salt ratio that forms depended on the amount (in solution) of remaining free (-)-CPTA, it is up to the end points of (-)-CPTA/ (+)-CPTA=1/3 approximately.In case it is believed that by adding about 0.34 normal alkali (-)-CPTA concentration be depleted to (/+)-after the CPTA ratio is 1/3, continue to add alkali then to form ratio be (/+)-salt of 1/3) so that (keep in the solution dissociate (/+)-the CPTA ratio is constant 1/3.

Embodiment 18

This embodiment has illustrated the fractionation of CPTA racemic mixture.

In 200 ml containers, add 17.0 gram CPTA (51.4 mM), 4.91 gram CAF D-alkali (23.1 mMs, 0.450 equivalent) and 85 milliliters of 2-propanol.With mixture heated to 78 ℃, become solution, be cooled to 54 ℃ with 0.5 ℃/minute speed then.After about 1/2 hour, in solution, add (-)-salt crystal seed to lure nucleation into.54 ℃ keep about 1-1/2 hour after, slurry is cooled to 22 ℃ with 0.25 ℃/minute speed.After 14 hours, take out small amount of sample (5 milliliters) 22 ℃ of maintenances, in 15 milliliters of medium size sinter funnel, separate.The mother solution of weighing is also preserved, and cleans solids with 2 milliliters of 2-propanol.Cleanout fluid is weighed and is preserved, and continues to bleed with dried crystals.With standardized HPLC systematic analysis, the weight % of (-)-CPTA and (+)-CPTA in each stream of calculating.It is 31.9% that the mass balance of this sample (the total CPTA value of weighing in crystal, mother solution and the cleanout fluid be 0.85 gram) is drawn the isolated yield of crystalline product from total CPTA.Crystal purity is 99.1 weight %/0.9 weight %=(/+)-CPTA ratio.The result who accounts with physics that Fig. 8 represents to analyze in rectangle frame.Forming the productive rate (by CPTA) that calculates based on free/mother solution/crystal is shown in the circle.Abbreviation among Fig. 8 is as follows: R.A. resolving agent, x or xtal=crystal, ML=mother solution, Yld=productive rate.

Container adds the crystal seed several times with the crystal that contains (+)-salt, after about 2 hours, adds 0.31 gram CAF D-alkali (1.46 mMs ,-0.03 equivalent).Before in 60 milliliters of medium size sinter funnel the most finally, separating, to twice (referring to Fig. 8) of container sampling.Mother solution is transparent, light golden rod yellow, weighs 59.1 grams.Clean solid with 19.2 gram 2-propanol, and reclaim 18.8 gram cleaning solutions.The solid that cleaned (10.07 gram) continues to obtain 8.36 grams (15.4 mM salt) by sucking filtration on funnel dry 1 hour.All are analyzed from final isolating logistics, draw the CPTA of 13.45 grams (40.67 mM).For the isolated yield of (-)-CPTA=33.8/a (by CPTA), final crystalline product ratio is (/+)-CPTA=89.2/10.8%.Form based on reinforced, mother solution and crystal, the calculating productive rate of (-)-CPTA is 35.0%.

Embodiment 19

This embodiment has illustrated and has been used for to (/+) in the mother solution-salt and (/+)-quantitative extraction processing method of CPTA.

80/20 (/+)-salt mixture can only be slightly soluble in the dichloromethane with about 0.016% concentration, dissolves manyly and racemic CPTA is easier, can be a little less than 3.4% concentration dissolving.Can (referring to Fig. 5 and Fig. 2) analyze up to becoming the glassy residue of 0.0242 gram by the 4th among Fig. 2 final mother solution that obtains 55.3 ℃ of separation by evaporating 0.1286 gram.Residue is dissolved in 5 milliliters of dichloromethane, with (/+)-salt=80/20 adds crystalline substance (seeded), and standing over night.Shift out a large amount of supernatantes, add 3 milliliters of dichloromethane, and big quantity of fluid is moved out of with first extract and merges.Evaporation dichloromethane extraction liquid obtains 0.0074 gram vitreous solid, analyzes with HPLC then.The underflow material of remainder is evaporated to 0.0162 gram, analyzes with HPLC.By the result that obtains of extraction treatment step general and the dissolubility model is predicted form similar, as shown in Figure 9.

Embodiment 20

This embodiment has shown the dissolubility of (-) and (+)-CPTA CAF D-alkali salt in containing the alcohol of CPTA.

Be dissolved in the 31.4 gram ethanol and prepare " solvent " by 2.40 gram raceme CPTA being dissolved in 19.42 gram 2-propanol (Fisher HPLC level) or 4.90 gram raceme CPTA.The concentration of CPTA in solution is respectively 11.0 and 13.5%.The dissolubility of (-)-CPTA CAF D-alkali salt (that is, (-)-salt) or (+)-CPTA CAF D-alkali salt (i.e. (+)-salt) is determined by gravimetry.Under given temperature, the part supernatant of saturated solution is moved in the bottle of a known weight.Determine the weight of solution, volatile solvent is opened in evaporation under logical nitrogen.Under 50 ℃ and/1 millimetres of mercury, solid further is dried to constant weight in vacuum drying oven.The bottle of weighing once more, determining the loss amount of solvent flashing, and the remaining solid weight of weighing.Thus, can calculate amount from the dissolved CPTA of " solvent ".From CPTA, deduct total solid weight, obtain the weight of soluble salt in the solvent.Data are listed among Figure 10 A and the 10B.

Embodiment 21

This embodiment has illustrated the method for (-)-halofenate of preparation enantiomer enrichment.

As above-mentioned branch five steps preparation CPTA, does not separate the centre, and productive rate is about 85% after crystallization from heptane.It is 32% (maximum 50%), optical purity that fractionation obtains average yield〉98% (-)-CPTA diastereomeric salt.After removing resolving agent, use thionyl chloride and N-ehtylethanolamine that (-)-CPTA is carried out esterification and obtain (-)-halofenate, productive rate is about 55%.By with sodium hydrate aqueous solution hydrolysising mother liquid residue, can from the end product mother solution, reclaim (-)-CPTA, and be circulated back in the step.By regulating pH value, the response rate that can about 90% is isolated resolving agent from water.Use sodium hydrate aqueous solution recovery and racemization (+)-CPTA can obtain 90% the response rate.Generally speaking, the first round productive rate from the 4-chlorobenzene acetic acid is 15-17%.Whole eight use three kinds of organic solvents and three solid separating steps step by step suddenly.

Embodiment 22

This embodiment illustrates the method for a kind of CPTA of preparation.

The synthetic route of CPTA as mentioned above.Acyl chlorides 1Bromination obtains in the 1.2-dichloroethanes 2After, add the 2-propanol and obtain the isopropyl alcohol ester 3Use potassium hydroxide in the 2-propanol, to finish α, α, the substitution reaction of α-trifluoro m-cresol.In water quencher reaction and clean and remove 1, behind the 2-dichloroethanes, with liquid 3Join α, α, α-trifluoro m-cresol and potassium hydroxide obtain in the solution of 2-propanol 4Remove 2-propanol solvent, finish the reaction that is hydrolyzed to CPTA by using sodium hydrate aqueous solution and heating.

Can simply pass through reaction mixture, the sodium salt of CPTA is separated as solid.But, can obtain better isolated yield by separating carboxylic acid.In order to separate, with hydrochloric acid the alkaline aqueous solution of CPTA reactant mixture is carried out acidify, and with 1,2-dichloroethanes extraction CPTA.Isolating organic facies carries out 1, and the 2-dichloroethanes can obtain white solid CPTA to the solvent exchange of heptane from the 4-chlorobenzene acetic acid, and productive rate is approximately 85%.

Embodiment 23

This embodiment has shown CPTA 1, the dissolubility in 2-dichloroethanes and the heptane.

The dissolubility of raceme CPTA in dichloroethanes and heptane is shown in respectively among Figure 11 and Figure 12.Comprised the equation that data is carried out least square fitting among the figure.

Based on solubility curve shown in Figure 11,1, the concentration in the 2-dichloroethanes is about the selected condition of coming as the CPTA extraction of the CPTA of 25 weight % when about 35 ℃ of temperature.

CPTA crystallization from heptane is heat release.The CPTA that is used in about 170 grams in 500 milliliters of heptane adds crystal seed at 46 ℃ to solution, and along with the carrying out of crystallization process, temperature is elevated to 54 ℃.Measure by HPLC, find that crystallization makes the purity of CPTA bring up to 99 area % from 93-95 area %.The crystalline mother solution that contains 15 area %CPTA is carried out the HPLC test, find that loss of yield is lower than 3% in the mother solution.By crystallization, purity is improved, high isolated yield, and the loss of mother solution is also very little.

Embodiment 24

This embodiment has shown the productive rate that CPTA splits under various crystallization conditions.

Use CAF D-alkali salt under various crystallization conditions, to split the results are shown among Figure 13 of CPTA solution.To each the preparation do not carry out recrystallization, carry out once or behind the secondary recrystallization the final chiral purity of gained show with the surplus body surface.The mol ratio of CAF D-alkali can change to 0.56 from 0.5.The amount of the listed 2-propanol that is used for crystallization and recrystallization all is based on the initial charge of raceme CPTA.The chirality HPLC result that isolating solid and mother solution are carried out normalizes to 100%.Calculate productive rate and gross production rate by the ratio that (+) in isolating solid and mother solution-enantiomer and (-)-enantiomer form.In the end the actual percentage productive rate in the hurdle is the dry matter of weighing, and is based on 50% maximum yield value.

Optical purity〉gross production rate of 98% diastereomeric salt is 28% to 35%, average out to 32%.In one case, use the resolving agent of minimum ratio, obtain this result (embodiment 2 among Figure 13) by not carrying out recrystallization.Isolating first solid chiral purity is 73% to 98%.One time in general recrystallization is enough to obtain required optical purity.When mother solution reaches (-)-CPTA of 20/80 to (+)-CPTA ratio, can obtain higher gross production rate.

Figure 14 has shown the crystalline cooling curve of listed fractionation, to reduce the productive rate of (-)-CPTA.Experiment among Figure 14 number is corresponding to the experiment among Figure 13 number.The isolated yield that calculating productive rate among use Figure 13 and the percent of (-)-CPTA in separate substance are determined (-)-CPTA.Generally speaking, the following retention time of low temperature is long more, can make gain in yield.

Use the CAF D-alkali of 0.45 molar equivalent can make optical purity〉the constant 35-37% of reaching of productive rate of 98% material, and do not need to carry out recrystallization.

Embodiment 25

This embodiment shows the method for being separated (-)-CPTA by CAF D-alkali.

In order to separate (-)-CPTA from CAF D-alkali, with diastereomeric salt and 1, the 2-dichloroethanes mixes, and adds aqueous hydrochloric acid solution, and the pH value that makes aqueous phase is approximately less than 2.The water that separates the hydroxide salt that contains CAF D-alkali.After the washing organic facies, to remove in a large number 1 by distillation, the 2-dichloroethanes is to remove remaining water.Obtain oil except that after desolvating fully.

Embodiment 26

This embodiment has shown the method for a kind of esterification (-)-CPTA, and does not have obvious racemization.

(-)-CPTA and thionyl chloride react in the 2-dichloroethanes under refluxing, 1, obtain corresponding acyl chlorides.Course of reaction can be analyzed by HPLC and monitor.Can remove a small amount of distillation to remove excessive thionyl chloride.With the mixture cooling, add the N-ehtylethanolamine that a large amount of excessive vacuum distillinges are crossed.Stir at ambient temperature and obtain (-)-halofenate.

By reactant mixture being joined in the wet chemical with the esterification reaction mixture quencher.By solvent exchange and heptane from 6:1: crystallization separates (-)-halofenate the 2-propanol.The result is summarised among Figure 15.

First isolated yield is 47% to 59%, and meansigma methods is 55%.This isolated yield represents that the reaction yield of the first step is 75% to 80%.Second batch obtains higher gross production rate; But the product quality of second batch of material is weaker.

The CPTA mole accountability that adds, as the halofenate in isolating halofenate and the mother solution and, its scope is 90% to 99%.

Embodiment 27

This embodiment has shown a kind of method that reclaims and circulate (+)-CPTA.

Heating CPTA can cause racemization in alkaline aqueous solution.(+)-enantiomer of the nearly 47%ee of remaining CPTA that obtains from the splitting step of embodiment 25 also contains residual CAF D-alkali among this CPTA.

In order to reclaim and racemization (+)-CPTA, remove 2-propanol solvent, and with 1, the 2-dichloroethanes replaces.PH approximately less than 2 situation under water clean, remove CAF D-alkali, with as later recovery.Add sodium hydrate aqueous solution, and aqueous solution liquid is heated to backflow.1,2-dichloroethanes or before adding alkaline solution, remove by distillation, or after adding alkaline solution, remove by being separated.With the heating of aqueous solution and 1.4 molar equivalent sodium hydroxide after 4 hours, the raceme CPTA of 89% productive rate can separate from heptane.CPTA is as the charging that splitting step provides constant-quality that is separated into of crystal intermedium.

Measure and the dissolubility of sodium salt in water of the raceme CPTA that represents is shown among Figure 16 with the form of acid.Xiang Shuizhong adds isolating sodium salt, obtains being about 9.5 pH value, and the dissolubility characteristics are shown in the solubility curve of top among the figure.Add small amounts of sodium hydroxide, obtain about 12.6 pH value, the dissolubility that this has reduced aqueous solution is shown in the lower curve among the figure.

Embodiment 28

This embodiment has shown a kind of method of being produced CPTA by (+)-halofenate.

Add the sodium hydroxide of 1-3 molar equivalent in 87%ee (+)-halofenate of about 10 weight % among the Xiang Zaishui, and be heated to 50 ℃ to 60 ℃, result's complete hydrolysis basically is CPTA.Carry out partial racemizationization, obtain (+)-CPTA (time=0 is as Figure 17) of big 70 about %ee.This solution is heated to backflow, monitors the enantiomer ratio in time.Having in the presence of the 3 molar equivalent alkali, carrying out (＜3%ee is by chirality HPLC analytic process) at counterflow condition racemization in basically fully less than 2 hours time.In the process of racemization, pH drops to 12.6 from 12.8.If the amount of alkali is 2 molar equivalents, then need to grow again the time (pH drops to 11.6 from 12.6) of a bit.If the amount of alkali is 1 molar equivalent, racemization is approximately stopping under the 60%ee to 70%ee, and final pH value is 9.4.

Use the sodium hydroxide of 0.5 molar equivalent, leave about 40% not hydrolysis of halofenate after 2 hours in reaction under 60 ℃; Reflux a whole night, approximately leave 1% halofenate, final pH value is 4.8.This can not minimize racemization significantly.The amount of the CPTA that produces is (+)-enantiomer of 72.6%ee.

Embodiment 29

This embodiment has set forth by the method that reclaims (-)-CPTA in (-)-halofenate crystalline mother solution.

With shown in Figure 15, (-)-halofenate crystalline mother solution contains a large amount of (-)-halofenate and (-)-CPTA as mentioned before.By the hydrolysis of (-)-halofenate, can generate extra (-)-CPTA and be used in the splitting step as charging.

Can generate (-)-CPTA of 65.8%ee rapidly in the hydrolysis of 50 ℃ of (-) that carry out-halofenate crystalline mother solution (88.3%ee (-)-halofenate), final pH is 12.7.By in the 2-propanol solution, adding CAF D-alkali, (-)-CPTA is reclaimed as the diastereomeric salt (96.4%ee) of CAF D-alkali.From the amount of the diastereomeric salt of initial adding, 55 moles of % obtain as (-)-halofenates, and 28% reclaims as (-)-CPTA/CAF D-alkali salt, and 14 moles of % stay in the mother solution as CPTA.

Embodiment 30

This embodiment has illustrated the method that reclaims CAF D-alkali.

From diastereomeric salt, separating among (-)-CPTA and from split mother solution, reclaiming in the acid pickling step of CPTA, find that CAF D-alkali is in acid mutually.With sodium hydroxide alkalization, it is about 12 that pH value is surpassed, and can produce the precipitation that exists with easy filtered version that is easy to reclaim.The results are shown among Figure 18.The response rate from diastereomeric salt generally surpasses 90%, and the response rate from split mother solution is generally low.Concentration in aqueous solution is about 5% to 20%.

The enantiomeric purity of CAF D-alkali can be determined (D.Pitre, M.Nebuloni, and V.Ferri by using DSC to anatomize fusing point; Arch.Pharm. (Weinheim) 324,525 (1991)).As (+)-and the agglomerate of (-)-form, for example, racemic modification, its fusing point is lower more than 20 ℃ than pure enantiomer, finds that fusing point is the very high method of a kind of sensitivity of evaluation enantiomeric purity.But the measurement of the enantiomeric purity of two kinds of samples being carried out by the chromatographic isolation derivant shows the loss that does not have chiral purity.The enantiomeric purity of the CAF D-alkali that reclaims approaches the lower limit of HPLC analytical method, can not distinguish with raw material.

Embodiment 31

This embodiment has illustrated the another kind of method for preparing raceme CPTA.

To one be contained in the heat packs and be furnished with top agitator and 500 milliliters of round-bottomed flasks of condensing tube in add the 4-chlorobenzene acetic acid, 70 milliliter 1 of 73.28 grams (0.430 mole), 2-dichloroethanes and 41 milliliters of (0.56 mole) thionyl chlorides.Mixture is incubated 19 hours at 50 ℃ to 55 ℃.Analyze with HPLC reactant mixture is analyzed.In solution of acid chloride, add 29 milliliters of (0.57 mole) bromines, and solution is incubated 20 hours at 70 ℃ to 75 ℃.The α of gained-bromine product cools off in ice bath, splashes into 100 milliliters of (1.31 moles) 2-propanol.Temperature is up to 17 ℃.

After being cooled to 4 ℃, reactant mixture is added to the water.Solution is heated to ambient temperature, shifts out water layer.Clean organic facies with 37 ml waters.With separation obtain 1,2-dichloroethane solution evaporation obtains 134.1 gram oil.

Potassium hydroxide and 370 milliliters of 2-propanol of in 1 liter of round-bottomed flask being furnished with top agitator, adding 34.0 gram (0.515 moles) 85%.With water-bath with mixture heated to 41 ℃, to dissolve most of solid.Mixture cools off in ice bath, splashes into the α of 73.8 grams (0.455 mole), α, α-trifluoro m-cresol.Temperature is up to 13 ℃.Before splashing into 134.1 gram oil of above gained, earlier solution is cooled to 5 ℃.Clean material with 18 gram 2-propanol.The slurry evaporation obtains residue, adds the sodium hydrate aqueous solution of 250 ml waters and 42.8 gram (0.535 moles) 50% then.Mixture is arrived backflow at 1 hour internal heating.

After being cooled to ambient temperature, with 250 milliliter 1,2-dichloroethanes washed mixture makes pH be reduced to 0.3 by the hydrochloric acid that drips 71 gram (0.72 moles) 37%.After being separated, from 1, the 2-dichloroethanes removes in mutually and desolvates, and obtains 202.2 gram residues.Handle residue with 131 gram heptane, and be evaporated to residue 164 grams.Handle this step with 97 gram heptane, obtain 160 gram oil.Remaining oil stirs with 257 gram heptane in ambient temperature, obtains slurry, and this slurry cools off in ice bath earlier before the isolated by filtration solid.With 49 gram washed with heptane filter cakes, dry under vacuum then, obtain the CPTA of 125.58 grams (0.380 mole, productive rate is 88%).

Embodiment 32

This embodiment has illustrated the preparation method of the racemic mixture of chemical compound 4 among a kind of embodiment 22.

The thionyl chloride that in 50 milliliters of round-bottomed flasks that dispose magnetic stirring apparatus and reflux condenser, adds raceme CPTA, 21 gram 2-propanol and 0.50 gram (4.2 mM) of 2.10 grams (6.35 mM).After refluxing 90 minutes, carry out the HPLC test, show 84.2 area %'s 7CPTA with 12.7 area %.Add 1.0 gram (8.4 mM) thionyl chlorides, obtaining being less than the CPTA of 1 area %.Solution is cooled to ambient temperature, and handles with the solid sodium bicarbonate of 1.0 grams (12 mM).Evaporating solvent is dissolved in residue in 25 milliliters of toluene.After water (2 * 10 milliliters) cleans, with solvent evaporation to the chemical compound 4 that remains 2.31 gram (6.2 mMs, productive rate are 98%) embodiment 22 (95.8 area %'s 7Toluene with 2.4 area %).

Embodiment 33

This embodiment has illustrated the method for definite raceme CPTA dissolubility.

The 100 ml water jacket type resin kettle that will have magnetic stirring apparatus link to each other with circulator bath, and to wherein adding 9.44 gram raceme CPTA and 16.78 grams 1,2-dichloroethanes.Bath temperature is 35 ℃, and slurry was stirred 30 minutes.Take out 0.1360 gram supernatant sample, and with dilution in acetonitrile to 25.00 milliliter, solution is analyzed with HPLC.The results are shown in Figure 11 and 19 of this result and other a series of measurements.For in about 2 ℃ of tests, before the supernatant being analyzed with HPLC, with 0.54 gram CPTA sample at 1.92 grams 1, in the 2-dichloroethanes in refrigerator store overnight.Being included in the dissolubility of CPTA in heptane that Figure 19 is shown among Figure 12 records in a similar manner.

Embodiment 34

This embodiment has illustrated the method that splits the CPTA racemic mixture.

(1R, 2R)-(-)-2-amino-1-(4-nitrobenzophenone)-1, ammediol (CAF D-alkali) and 193 restrains the 2-propanol to add 48.2 gram (146 mM) CPTA, 16.4 grams (77.3 mM) in 1 liter of round-bottomed flask.Slurry is heated to 70 ℃, obtains solution, be cooled to 60 ℃ then, and kept 1 hour.It is 2 ℃ that the slurry of gained is cooled to jacket temperature with 0.25 ℃/minute speed, and keeps 14 hours; Internal temperature is 4 ℃.The isolated by vacuum filtration solid, and clean with 27 gram 2-propanol.Mother solution and cleaning solution are taken a sample, be used for HPLC and analyze, the results are shown among Figure 13.Reload the wet cake of 50.48 grams in the 1 liter of reactor that has 193 gram 2-propanol, and slurry is heated to gentle reflux state, this moment, jacket temperature was 85 ℃, obtained solution.To this solution sampling, be used for HPLC and analyze; Gained the results are shown among Figure 13.After being cooled to 65 ℃, form slurry.Behind 30 minutes internal heating to 68 ℃, with 0.25 ℃/minute speed slurry is cooled to 40 ℃, be cooled to 18 ℃ with 0.4 ℃/minute speed then, be cooled to 2 ℃ with 1 ℃/minute speed again.(in other preparation, adopt the linear cooldown rate that is recorded among Figure 14.) the isolated by vacuum filtration solid, cleaning with 18 gram 2-propanol, vacuum drying obtains (-)-CPTA/CAF D-alkali of 27.29 grams (50.4 mMs, productive rate are 34.5%).HPLC analysis result to separating solids and mother solution and cleaning thing is included among Figure 13.

Embodiment 35

This embodiment has illustrated preparation and fractionation CPTA from halofenate.

The sodium hydrate aqueous solution that in 1 liter of round-bottomed flask of being furnished with top agitator, adds 129.75 gram (0.312 mole) raceme halofenates, 325 gram water and 32.6 gram (0.408 moles) 50%.Slurry at 1 hour internal heating to 60 ℃, is obtained solution, again cooling.Under 40 ℃, add 328.5 grams 1,2-dichloroethanes and 44 restrains the hydrochloric acid of (0.45 moles) 37%, and two-phase mixture is cooled to 29 ℃.The pH of water is 0.85.Separate and the cleaning organic facies with 250 ml waters, be evaporated to residue 118.2 grams then.Add 2-propanol (149 gram), be evaporated to residue 131.2 grams.This residue should contain 103.2 gram raceme CPTA in theory based on the amount of the halofenate that is added, and this residue is joined 1 liter of bottom that 33.10 gram (0.1556 mole) CAF D-alkali and 400 gram 2-propanol are housed to be had in the reactor of outlet.With mixture heated to 67 ℃, obtain light slurry, be cooled to 1 ℃ with 0.075 ℃/minute then.Mixture is cooled to-7 ℃, the isolated by vacuum filtration solid, and clean with 60 milliliters of 2-propanol.The HPLC analysis result of separating solids and 492.8 gram mother solutions and cleaning solution is shown in (embodiment 9) among Figure 13.92.74 wettable cakes are joined in 1 liter of reactor again with 477 gram 2-propanol, and, obtain solution mixture heated to 75 ℃.Solution is cooled to 5 ℃ with 0.5 ℃/minute speed, and isolated by vacuum filtration crystalline solid is cleaned with 60 milliliters of 2-propanol, and dry, obtains (-)-CPTA CAF D-alkali diastereomeric salt of 51.81 grams (0.0956 mole, productive rate is 31%).The HPLC analysis result of separating solids and 529.9 gram mother solutions and cleaning solution is included among Figure 13.

Embodiment 36

This embodiment has illustrated a kind of racemization (+)-CPTA and has reclaimed the method for raceme CPTA.

To contain the fractionation and the recrystallization mother liquor that obtain in splitting based on 71.6 gram (0.217 mole) CPTA (44%ee (+)-enantiomer) of the productive rate of isolating diastereomeric salt and purity and from the gram of 103.2 described in the foregoing description CPTA and be evaporated to residue 108.7 grams, with 176 grams 1, the hydrochloric acid of 2-dichloroethanes, 35.2 gram water and 6.8 grams 37% is handled residue.Shift out organic facies, and be evaporated to residue 79.0 grams.Add entry (80 gram), evaporating solvent is up to residue 78.1 grams.Sodium hydrate aqueous solution with 141.9 gram water and 24.6 gram (0.308 moles) 50% is handled residue, solution is heated to refluxed 4 hours, obtains being used for the racemic modification that chirality HPLC analyzes.The solution cooling, with 140 milliliter 1, the salt acid treatment of 2-dichloroethanes and 32.0 gram (0.325 moles) 37%.Shift out organic facies, be evaporated to residue 80.1 grams, this residue is handled in 40 ℃ of water-baths with 250 milliliters of heptane, obtains slurry.The isolated by vacuum filtration solid, drying, obtain 63.83 the gram (0.193 mole, productive rate is 89%) raceme CPTA.The split result of sample consistent with the result of fresh CPTA (among Figure 13 the 10th).

Embodiment 37

This embodiment has illustrated the method for separating (-)-CPTA from diastereomeric salt.

In 500 milliliters of 500 ml flasks that dispose magnetic stirring apparatus, pack into 40.0 gram (73.7 mM) (-)-CPTA/CAF D-alkali, 100 grams 1, the hydrochloric acid of 2-dichloroethanes, 40 gram water and 7.6 gram (77 mMs) 37%.After solid dissolves fully, shift out lower floor's organic facies, and clean with 10 ml waters.The pH of total water is 0.9.128.2 gram organic faciess are carried out HPLC test, find 24.32 grams (73.6 mMs, theoretical value 99.8%) (-)-CPTA as solution 1, in the 2-dichloroethanes.

Embodiment 38

This embodiment has illustrated the vacuum purification of N-acetylethanolamine.

In 50 milliliters of round-bottomed flasks that are equipped with magnetic stirring apparatus, heat packs and short-path distillation head, add 29.09 gram N-acetylethanolamines, and place under the vacuum of about 0.8 holder.Although do not collect condensate, liquid forms bubble when heating.When head temperature is about 130 ℃, collect distillation, obtain being the N-acetylethanolamine that 26.71 of transparency liquid shape restrains (response rate 92%).

Embodiment 39

This embodiment has illustrated the method for production (-)-halofenate.

In 500 milliliters of round-bottomed flasks that have a magnetic stirring apparatus, add 35.5 gram (653.4 mM) (-)-CPTA/CAF D-alkali diastereomeric salts (99.4%ee), 89.0 grams 1,2-dichloroethanes and 35.5 ml waters.In slurry, add the hydrochloric acid of 6.7 gram (68 mMs) 37%, mixture is stirred at ambient temperature, form two-layer clarification phase.Shift out lower floor organic to, and with 7.0 the gram water clean.Organic facies evaporation is dissolved in 55.6 grams 1 then up to residue 26.13 grams, in the 2-dichloroethanes, and put into one be placed in the heat packs and be furnished with magnetic stirring apparatus and 250 milliliters of round-bottomed flasks of backflow/still head in.Solution is carried out HPLC test, find to have the CPTA of 22.06 grams (66.7 mMs, theoretical value 102%).The thionyl chloride that in this solution, adds 7.5 milliliters (100 mMs), and solution is heated to refluxed 2 hours.Continue heating, collect 6.1 gram distillations.Solution is cooled to ambient temperature, cools off in ice bath then, so that add the distilled N-acetylethanolamine (KF analysis 1176 and 1288ppm water) of 25.85 grams (251 mM).After the adding, temperature is elevated to about 26 ℃.Under agitation, solution slowly being joined 9.90 in the 36 gram water of cooling in ice bath restrains in (71.6 mM) potassium carbonate.Temperature is up to 15 ℃.With 5 milliliter 1,2-dichloroethanes cleaning reaction mixture.Shift out lower floor's organic facies, and clean with 37 ml waters.Solution evaporation obtains oil (32.84 gram).With 54 gram heptane handling oil, shift out solvent, obtain 31.56 gram solid residues.In solid, add 76 gram heptane, and shift out solvent, obtain 29.19 gram solid residues.Solid is dissolved in 28 milliliters of 2-propanol at 40 ℃, is adding 28 milliliters of 2-propanol and 334 milliliters of heptane dilutions then.Be cooled to ambient temperature, obtain grout.The cooling back forms the thick paste material in ice bath.After stirring 2 hours, the isolated by vacuum filtration solid with 29 gram washed with heptane, drying, obtains (-)-halofenate of 14.21 grams (34.2 mMs, productive rate are 52.3%).Chirality HPLC analyzes and does not detect (+)-halofenate (〉 99.8%ee).

294.1 gram mother solutions and cleanout fluid are carried out the HPLC test, find to have 11.2 gram halofenates and 1.26 gram CPTA.Evaporating solvent, and with 12.47 the gram residues be dissolved in 14 milliliters of 2-propanol.Add 84 milliliters of heptane, obtain slurry after stirring is spent the night at ambient temperature.The cooling of this slurry in ice bath, is collected solid, and with 9 gram washed with heptane, drying, (13.6 mMs, productive rate are 20.7%, and the HPLC analysis has 89.9% halofenate and 3.9% CPTA, (-) 99.6%ee)-halofenate to obtain 5.64 grams.81.47 gram mother solutions and cleanout fluid are carried out the HPLC test, find to have the halofenate of 3.66 grams (8.8 mMs, 13.5%) and the CPTA of 0.93 gram (2.8 mMs, 4.8%).

Embodiment 40

This embodiment illustrates a kind of method of separation of racemic CPTA sodium salt.

Will be from splitting crystallization and recrystallization and containing the mother liquid evaporation of the CPTA of 63.9 grams (0.193 mole) in theory that reclaims based on splitting, up to residue 91 grams.Residue is dissolved in 146 grams 1, the 2-dichloroethanes, and handle with 28.6 gram water and 6.3 grams, 37% hydrochloric acid at 40 ℃.219 gram organic facies evaporations are up to residue 71.86 grams.The sodium hydroxide that in residue, adds 120 gram water and 21.5 gram (0.269 moles) 50%.Solution is heated to backflow, is cooled to ambient temperature then, obtain the thick paste material.The solid that vacuum filtration cooling back forms cleans with 25 ml waters, and drying obtains the sodium salt of 31.78 gram (0.0901 mole, the response rate 46.7%) CPTA then.Chirality HPLC analyzes and finds that this material is racemic.188.6 gram mother solutions and cleanout fluid are carried out the HPLC test, find to have 28.3 gram (0.0856 mole, 44.4%) CPTA.

Embodiment 41

This embodiment has illustrated the method for definite raceme CPTA sodium salt dissolubility.

100 milliliters of water leg formula resin kettle of being furnished with magnetic stirring apparatus are linked to each other with circulator bath, and to wherein adding 3.48 gram raceme CPTA sodium salts and 20.0 gram water.Bath temperature is heated to 35 ℃, and slurry was stirred 1 hour.Close agitator, solid left standstill 30 minutes.PH is 9.4.Shift out 0.3036 gram supernatant sample, and, analyze test solution with HPLC with dilution in acetonitrile to 25.00 milliliter.Repeat this test at 47 ℃ and 19 ℃.Add 3.01 gram CPTA sodium salts again, so that slurry maintains under the higher temperature, and adds 25 gram water, under lower temperature, to obtain more condensed slurry.By adding 50% sodium hydrate aqueous solution is that pH at room temperature is elevated to 12.7, also tests at 13.5 ℃, 25 ℃, 34 ℃ and 42 ℃.The results are shown in Figure 16 and 20.

Embodiment 42

This embodiment has illustrated the hydrolysis and the racemization of (+)-halofenate.

The sodium hydrate aqueous solution that in 250 milliliters of round-bottomed flasks that are equipped with magnetic stir bar and heat packs, adds 7.28 gram (17.5 mM) (+)-halofenates (86.9%ee), 72.2 gram water and 4.21 gram (52.6 mMs) 50%.Slurry is heated to 50 ℃ to 60 ℃.The pH of gained solution is 12.8.Chirality HPLC the analysis showed that (+)-CPTA of 80.4% and (-)-CPTA of 10.5%.Solution is heated to backflow 90 minutes.Chirality HPLC the analysis showed that (+)-CPTA of 49.6% and (-)-halofenate of 47.0%.PH is 12.6.After being cooled to ambient temperature, add about 50 milliliters 1, the 2-dichloroethanes, the hydrochloric acid by adding 7.3 gram (74 mMs) 37% is with pH regulator to 0.8.The evaporation organic facies is up to residue 6.0 grams.Handle residue with 25 milliliters of heptane, rising temperature for dissolving oil is cooled in the ice bath then.Vacuum filtration is collected solid, and drying obtains 5.10 gram (15.4 mMs, productive rate are 88%) raceme CPTA.The data of these data and two similar hydrolytic processes are listed in Figure 17 and 21.

Similarly, the sodium hydrate aqueous solutions of 6.75 gram (16.3 mM) (-)-halofenates with 0.65 gram (8.1 mM) 50% were heated 2 hours at 60 ℃ in 67.5 gram water, obtain 37.5% halofenate and 54.2% CPTA.Reflux is spent the night, and obtains 92.1% CPTA and 1.1% halofenate, and final pH is 4.8.It is 80.3/12.8 that chirality HPLC analyzes the ratio of finding (+)/(-)-CPTA.

Embodiment 43

This implementation prepare (-)-halofenate by from (-)-halofenate crystalline mother solution, reclaiming (-)-CPTA/CAF D-alkali diastereomeric salt.

In 1 liter of round-bottomed flask that has a magnetic stirring apparatus, add 50.0 gram (92.3 mM) (-)-CPTA/CAF D-alkali diastereomeric salts (97.1%ee), 124 grams 1, the hydrochloric acid of 2-dichloroethanes, 50 ml waters and 9.6 gram (98 mMs) 375.Separate organic facies, and clean, be placed on 205 milliliters of round-bottomed flasks that are arranged in heat packs and have magnetic stirring apparatus then with 50 ml waters.Backflow/still head in the connection with the solution heating, shifts out 35.4 gram distillations by distillation.After being cooled to 40 ℃, with 25 milliliter 1,2-dichloroethanes dilute solution adds 11 milliliters of (150 mM) thionyl chlorides.After 2 hours, shift out distillation in reflux, solution is cooled off in ice bath, so that drip 38.6 gram (374 mM) distilled N-acetylethanolamines.In reinforced process, reaction temperature rises to 18 ℃ from 7 ℃.After stirring is spent the night at ambient temperature, under agitation solution is joined in the gram of 12.7 in 51 ml waters of cooling in ice bath (71.6 mM) potassium carbonate.Shift out organic facies, and clean with 51 gram water.Organic facies (HPLC analyzes 85.2% halofenate and 6.1% CPTA) evaporation obtains 44.3 gram oil, handles with 133 gram heptane, and evaporation obtains solid 43.3 and restrains then.Solid residue is dissolved in the 61.5 gram 2-propanol, and joins 1 liter of bottom with 320 gram heptane and have in the reactor of outlet, be warmed up to 50 ℃, be cooled to 20 ℃, be cooled to-3 ℃ with 1 ℃/minute speed then with 3 ℃/minute speed.Solution becomes muddy at 27 ℃, forms the thick paste material at 15 ℃.The isolated by vacuum filtration solid, with 40 milliliters of washed with heptane that contain 5 milliliters of 2-propanol, drying, (50.6 mMs, productive rate are 55%, (-) HPLC98.93%)-halofenate (99.9%ee) to obtain 21.01 grams.To record the halofenates (88.3%ee) that contain 14.65 grams (35.3 mM) and 395.7 gram mother solutions and the cleaning solution evaporations of 1.78 gram (5.4 mM) CPTA restrain up to residue 21.57 by HPLC.Residue is heated to 50 ℃ with the sodium hydrate aqueous solution of 100 ml waters and 5.0 gram (63 mMs) 50%, obtains solution.After about 10 minutes, carry out HPLC test, find to have 83.6% CPTA and 0.3% halofenate.Solution is cooled off, with 50 milliliter 1, the dilution of 2-dichloroethanes, with the hydrochloric acid of 7.3 gram (74 mMs) 37% make pH from 12.7 drop to 1.6, after with the cleaning of 30 ml waters, HPLC is recorded the organic facies evaporation that contains 11.32 gram (34.2 mM) CPTA, obtain residue, handle, evaporate then up to residue 14.9 grams with 36 gram heptane.By heating residue is dissolved in the 38 gram heptane.Cooling obtains oil.Shift out solvent, remaining oil is dissolved in the 34.8 gram hexahydrotoluenes.Cooling forms oil.Shift out solvent, replace with 4.6 gram 2-propanol.Chirality HPLC analyzes discovery, (-) of 65.8%ee-CPTA ((+)/(-)-ratio is 16.9/81.6).In solution, add 6.50 gram (30.6 mM) CAF D-alkali at ambient temperature.Form the thick paste material rapidly.Under agitation slurry is warmed up to 40 ℃, in ice bath, cool off then, the isolated by vacuum filtration solid, can clean by 7 gram 2-propanol again, dry, obtain 13.91 gram (25.7 mM) (-)-CPTA/CAF D-alkali diastereomeric salts, it is corresponding to 28% the response rate of the initial salt that adds of 50.0 grams.(+)/(-)-CPTA ratio is 1.77/97.86.45.34 gram mother solutions and cleanout fluid are carried out the HPLC test, find to have 4.34 gram (13.1 mM) CPTA, it is corresponding to the response rate of 14 moles of % of the initial salt that adds of 50.0 grams.

Embodiment 44

This embodiment has illustrated the method that reclaims CAF from CPTA/CAF D-alkali salt.

In 1 liter of round-bottomed flask that has a magnetic stirring apparatus, add 80.16 gram (0.148 mole) (-)-CPTA/CAF D-alkali, 237 grams 1,2-dichloroethanes and 80 ml waters.In this slurry, add the hydrochloric acid of 15.2 gram (0.154 moles) 37%, obtain two-layer clarification phase.The pH of water layer is 1.2.Shift out lower floor's organic layer, clean with 16 ml waters.Sodium hydrate aqueous solution with 12.8 gram (0.161 moles) 50% is handled total water, makes pH reach 12.1.Filter the slurry of gained, clean with 25 ml waters, drying obtains 30.79 gram (0.145 mole, 98%) CAF D-alkali (fusing point 160.4-161.0 ℃).

Embodiment 45

This embodiment has illustrated the method that reclaims CAF D-alkali from split mother solution.

Split 60.0 gram raceme CPTA samples with above-mentioned 20.88 gram CAF D-alkali in 240 gram 2-propanol, obtain the wet cake of 74.7 grams.Wet cake is recrystallization in 218 gram 2-propanol, obtains 32.35 gram (productive rate is 32.8%) (-)-CPTA/CAF D-alkali.To obtain according to the amount of gained salt contain 40.32 gram CPTA and 8.23 gram (38.8 mM) CAF D-alkali in theory and from the evaporation of the mother solution in crystallization and the recrystallization and cleaning solution up to residue 72.9 grams.Residue is dissolved in 265 grams 1, in 2-dichloroethanes, 50 ml waters and 4.0 gram (40.6 mM) 37% hydrochloric acid.Separate the water-bearing layer, make pH be elevated to 12.3 from 0.6 by the sodium hydrate aqueous solution that adds 3.88 gram (48.5 mMs) 50%.Filter the slurry of gained, collect solid, water cleans, and obtains 7.12 gram (33.6 mMs, the response rate 87%) CAF D-alkali (fusing point 162.4-163.0 ℃).

Be to be understood that embodiment described here and embodiment are just for illustrative purposes, therefore, various trickle modifications or change it is contemplated that to those skilled in the art and to obtain, and should be included in the application's the spirit and scope and comprise within the scope of the appended claims.For all purposes, the full text of all publications, patent and the patent application of being quoted in the literary composition is included in this by reference.

Claims (18)

1. an enantiomerism selectivity is produced the method for following α-(phenoxy group) phenylacetate chemical compound of general formula:

Described method comprises:

(a) split the racemic compound of the following α of general formula-(phenoxy group) phenylacetic acid with the chiral amine compound of enantiomer enrichment:

Produce α-(phenoxy group) phenylacetic acid of enantiomer enrichment, wherein total consumption of the chiral amine compound of enantiomer enrichment is less than 0.5 molar equivalent;

(b) contact with the carboxylic acid activating agent by α-(phenoxy group) phenylacetic acid that makes the enantiomer enrichment, produce α-(phenoxy group) phenylacetic acid compound of activatory enantiomer enrichment;

(c) making α-(phenoxy group) phenylacetic acid compound and the general formula of activatory enantiomer enrichment is (R ⁷-O) _wThe chemical compound contact of M produces α-(phenoxy group) phenyl-acetic acid ester compounds,

Wherein,

R ¹Be C ₁-C ₆Alkyl or trifluoromethyl;

X is a chlorine;

R ⁷It is N-acetyl group-2-amino-ethyl;

M is hydrogen or metal; And

Subscript w is the oxidation state of M.

2. the method for claim 1 is characterized in that, described α-(phenoxy group) phenylacetate chemical compound is (-)-halofenate.

3. the method for claim 1 is characterized in that, the step (a) of the racemic compound of described resolution of alpha-(phenoxy group) phenylacetic acid comprises:

(I) by being contacted with the chiral amine compound of enantiomer enrichment, α-enantiomeric mixture of (phenoxy group) phenylacetic acid compound produces a kind of crystallization solution mixture, solid acid-the alkali salt that comprises the enantiomer enrichment of first isomer in this solution mixture, wherein total consumption of the chiral amine compound of enantiomer enrichment is less than 0.5 molar equivalent; And

(II) with the solid Acid-Base of first enantiomer in the concentration of the Acid-Base salt of second enantiomer that makes α-(phenoxy group) phenylacetic acid compound in its saturation point or be lower than under the temperature of its saturation point and from solution, separate.

4. method as claimed in claim 3 is characterized in that, the described step (I) that produces the crystallization solution mixture of the solid enantiomer enrichment Acid-Base salt that comprises first enantiomer comprising:

(i) solution mixture is heated to temperature more than the nucleation temperature of first enantiomer; And

(ii) the temperature with solution mixture is reduced to the nucleation temperature that is equal to or less than first enantiomer.

5. method as claimed in claim 3 is characterized in that, separate first enantiomer solid acid-alkali salt described step (II) or be higher than under the saturation temperature of Acid-Base salt of second enantiomer and carry out.

6. the method for claim 1 also comprises by remove chiral amine compound from the solid acid-alkali salt of isolating first enantiomer and reclaims chiral amine compound.

7. method as claimed in claim 6 is characterized in that, the described Chiral Amine that is used in the enantiomer enrichment in the Acid-Base salt of producing described step (a) comprises the chiral amine compound of recovery.

8. the method for claim 1 also comprises by second enantiomer is contacted with alkali, comes at least a portion of second enantiomer in the isolating solution mixture of racemization.

9. method as claimed in claim 8 is characterized in that, the described enantiomeric mixture that is used in α-(phenoxy group) phenylacetic acid compound in the step (a) comprises the α of racemization-(phenoxy group) phenylacetic acid compound.

10. the method for claim 1 is characterized in that, the general formula of described chiral amine compound is:

Wherein,

R ²And R ³Independent separately is hydrogen or C ₁-C ₆Alkyl; Perhaps R ²And R ³Form 1 with the atom that they connected, the 3-diox;

R ⁴Be hydrogen or C ₁-C ₆Alkyl;

R ⁵And R ⁶Independent separately is hydrogen or C ₁-C ₆Alkyl, perhaps R ⁵Or R ⁶In one be amine protecting group group; And

Ar is the 4-nitrobenzophenone.

11. the method for claim 1 is characterized in that, described α-(phenoxy group) phenylacetic acid is the enantiomeric mixture of 4-chloro-α-(3-4-trifluoromethylphenopendant) phenylacetic acid, and the step of described method (a) comprising:

(x) by with the enantiomeric mixture of 4-chloro-α-(3-4-trifluoromethylphenopendant) phenylacetic acid and chiral amine compound (1R less than the enantiomer enrichment of 0.5 molar equivalent, 2R)-2-amino-1-(4-nitrobenzophenone)-1, ammediol contacts in alcoholic solvent in the ratio that per 1 gram (-)-4-chloro-α-(3-4-trifluoromethylphenopendant) phenylacetic acid closes 4 gram alcoholic solvents, produce a kind of crystallization solution mixture, comprise the Acid-Base salt of (-)-4-chloro-α-(3-4-trifluoromethylphenopendant) phenylacetic acid of enantiomer enrichment in this solution;

(y) the Acid-Base salt of enantiomer enrichment is separated from the solution mixture that is enriched with (+)-4-chloro-α-(3-4-trifluoromethylphenopendant) phenylacetic acid, and

(z) incite somebody to action (1R, 2R)-2-amino-1-(4-nitrobenzophenone)-1, ammediol shifts out from Acid-Base salt, to produce (-)-4-chloro-α-(3-4-trifluoromethylphenopendant) phenylacetic acid of enantiomer enrichment.

12. method as claimed in claim 11 is characterized in that, described alcoholic solvent is an isopropyl alcohol.

13. method as claimed in claim 12 is characterized in that, use be equal to or less than 0.47 molar equivalent (1R, 2R)-2-amino-1-(4-nitrobenzophenone)-1, ammediol forms Acid-Base salt.

14. method as claimed in claim 13, it is characterized in that the step (x) of crystallization solution mixture that produces the Acid-Base salt of (-)-4-chloro-α-(3-4-trifluoromethylphenopendant) phenylacetic acid comprise the enantiomer enrichment comprises: the temperature that solution mixture is heated to the nucleation temperature that is equal to or higher than (-)-Acid-Base salt.

15. method as claimed in claim 14 is characterized in that, the step (y) of the Acid-Base salt of described separation enantiomer enrichment or be higher than under the temperature of saturation temperature of Acid-Base salt of (+)-enantiomer and carry out.

16. method as claimed in claim 12, it is characterized in that, (the 1R of described enantiomer enrichment, 2R)-2-amino-1-(4-nitrobenzophenone)-1, ammediol comprises the (1R that shifts out from the Acid-Base salt of described step (z), 2R)-and 2-amino-1-(4-nitrobenzophenone)-1, at least a portion of ammediol.

17. method as claimed in claim 12 also comprises at least a portion of (+)-4-chloro-α-(3-4-trifluoromethylphenopendant) phenylacetic acid that obtains in the described step of racemization (y).

18. method as claimed in claim 17 is characterized in that, the enantiomeric mixture of described 4-chloro-α-(3-4-trifluoromethylphenopendant) phenylacetic acid comprises at least a portion of (+) of racemization-4-chloro-α-(3-4-trifluoromethylphenopendant) phenylacetic acid.

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