CN101316585A - Process for the stereoselective preparation of (-)-halofenate and intermediates thereof - Google Patents
Process for the stereoselective preparation of (-)-halofenate and intermediates thereof Download PDFInfo
- Publication number
- CN101316585A CN101316585A CNA2006800431805A CN200680043180A CN101316585A CN 101316585 A CN101316585 A CN 101316585A CN A2006800431805 A CNA2006800431805 A CN A2006800431805A CN 200680043180 A CN200680043180 A CN 200680043180A CN 101316585 A CN101316585 A CN 101316585A
- Authority
- CN
- China
- Prior art keywords
- formula
- chemical compound
- subscript
- alkyl
- described method
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention provides a compounds the formula (IV): and methods for producing an alpha-(phenoxy)phenylacetic acid compound of the formula: wherein R<1 >is a member selected from the group consisting of: each R<2 >is a member independently selected from the group consisting of (C1-C4)alkyl, halo, (C1-C4)haloalkyl, amino, (C1-C4)aminoalkyl, amido, (C1-C4)amidoalkyl, (C1-C4)sulfonylalkyl, (C1-C4)sulfamylalkyl, (C1-C4)alkoxy, (C1-C4)heteroalkyl, carboxy and nitro; the subscript n is 1 when R<1> has the formula (a) or (b) and 2 when R<1 >has the formula (c) or (d); the subscript m is an integer of from 0 to 3; * indicates a carbon which is enriched in one stereoisomeric configuration; and the wavy line indicates the point of attachment of R<1>.
Description
Cross reference to related application
The application requires the interests of No. 60/720,300, U.S. Patent Application Serial Number that JIUYUE in 2005 submitted on the 23rd; And the title of JIUYUE in 2006 submission on the 20th is the U.S. Patent Application Serial Number of " method and the intermediate thereof of stereo selectivity preparation (-)-halofenate ": the interests of (attorney 016325-02051OUS) to be granted, the content of these two pieces of patent applications is incorporated herein by reference.
Invention field
The present invention relates to the three-dimensional system of selection of preparation (-)-halofenate (halofenate) (4-chloro-α-(3-4-trifluoromethylphenopendant) phenylacetic acid) and intermediate thereof.
Background of invention
Ester derivant and the amide derivatives of (-)-4-chloro-α-(3-4-trifluoromethylphenopendant) phenylacetic acid (HALOFENIC ACID (halofenic acid)) all are chipal compounds, they can be used for improving various physiological signs, comprise and the relevant symptom of blood fat deposition, type ii diabetes and hyperlipemia referring to, as, U.S. Patent Application Serial Number 10/656,567 and United States Patent (USP) 6,262,118, these two pieces of documents are in full with reference to being incorporated into this }.HALOFENIC ACID comprises single chiral centre at the carbon atom place of the α-asymmetric replacement of carbonylic carbon atom, therefore has two kinds of enantiomeric forms.Found that (-)-enantiomer of HALOFENIC ACID compares with its (+)-enantiomer, it suppresses low 20 times of activity of Cytochrome P450 2C9.Give raceme HALOFENIC ACID or derivatives thereof every day (Id) and can cause various and other drug, comprise anticoagulant, antiinflammatory and cause the drug interaction problem of metabolic other medicines by this enzyme.Therefore, wish that HALOFENIC ACID (-)-enantiomer or derivatives thereof that is substantially devoid of (+)-enantiomer reduces the probability that drug interaction takes place.Therefore, the enantiomer enriched form of α-(phenoxy group) phenylacetic acid or derivatives thereof is the valuable intermediate that is used for preparation of pharmaceutical compounds.
As indicated in following, the various synthetic methods of preparation α-(phenoxy group) phenylacetic acid have been reported in the literature.Unfortunately, adopt known synthetic method to be difficult to these molecules of preparation high antimer purity usually.
Scheme 1. synthetic α-(phenoxy group) phenylacetic acids
Shown in scheme 1, Devine etc. utilize the deutero-lactamide of pyrrolidine can stereo selectivity to prepare α-(phenoxy group) phenylacetic acid (referring to, United States Patent (USP) 5,708,186 and 5,856,519, the content of announcement is by with reference to being incorporated into this) as chiral auxiliary.But also there is following defective in this method, comprising: a) a plurality of separating steps, and b) isolated yield is low.Therefore, need more effectively stereo selectivity prepare α-(phenoxy group) phenylacetic acid with and derivant, as the method for (-)-halofenate.Very surprised is that the present invention has satisfied this demand and other demand.
Summary of the invention
The invention provides the method that can the phenylacetic acid that replace be converted into reliably corresponding high antimer purity α-(replacement) phenylacetic acid derivatives with high yield.
Therefore, in one embodiment, the invention provides a kind of method for preparing following formula (I) chemical compound:
In the formula,
R
1Be selected from down group:
With
Each R
2Be independently selected from down group: (C
1-C
4) alkyl, halogen, (C
1-C
4) haloalkyl, amino, (C
1-C
4) aminoalkyl, acylamino-, (C
1-C
4) amidoalkyl, (C
1-C
4) sulfonyl alkyl, (C
1-C
4) sulfonamides alkyl, (C
1-C
4) alkoxyl, (C
1-C
4) assorted alkyl, carboxyl and nitro;
Work as R
1Has formula (a) or (b) time, subscript n is 1, works as R
1Has formula (c) or (d) time, subscript n is 2;
Subscript m is the integer of 0-3;
* represent carbon with stereoisomer configuration enrichment (enriched); With
Wave is represented R
1Junction point;
This method comprises:
(a) formula (II) chemical compound is contacted in compatible solvent with the carboxylic acid activating agent, described carboxylic acid activating agent is selected from thionyl halide, acid anhydride and thioesters and produces agent;
(b) with bromine the product of step (a) is carried out bromination in compatible solvent;
(c) with chiral alcohol the product of step (b) is carried out esterification in compatible solvent, described chiral alcohol is selected from following:
In another embodiment, the invention provides α-(replacement) phenylacetic acid chemical compound of following formula (IV) expression:
In the formula:
R
1Be selected from down group:
Work as R
1Has formula (a) or (b) time, subscript n is 1, works as R
1Has formula (c) or (d) time, subscript n is 2;
*Expression is with the carbon of stereoisomer configuration enrichment; With
Wave is represented R
1Junction point.
By following detailed, can obviously find out other features of the present invention, purpose and advantage with and preferred implementation.
Detailed Description Of The Invention
I. definition
" alkyl " refers to have 1-10 carbon atom, preferred 1-6 the carbon atom and the more preferably straight or branched aliphatic hydrocarbon chain group of 1-4 carbon atom.Exemplary alkyl includes but not limited to: methyl, ethyl, n-pro-pyl, 2-propyl group, the tert-butyl group, amyl group etc.
" aryl " refers to have the unit price monocycle or the double ring arene part of 6-10 carboatomic ring atom.Except as otherwise noted or indicate, aryl can be by one or more substituent groups, be preferably one, two or three substituent groups and more preferably one or two substituent group replace, described substituent group is selected from alkyl, haloalkyl, nitro and halogen.More specifically, term aryl includes but not limited to: separately randomly by phenyl, 1-naphthyl and the 2-naphthyl etc. of one or more above-mentioned substituent groups replacements.
" chirality " or " chiral centre " refers to have the carbon atom of four different substituents.Yet final chirality standard is that mirror image is not overlapping.
Term " CPTA " and " HALOFENIC ACID " are used interchangeably in this article, refer to (4-chlorphenyl) (3-4-trifluoromethylphenopendant) acetic acid.
" mixture of enantiomers " refers to have the chipal compounds of mixture of enantiomers, comprises racemic mixture.Preferred mixture of enantiomers refers to every kind of enantiomer chipal compounds of equivalent basically.Preferred mixture of enantiomers refers to exist the racemic mixture of every kind of enantiomer of equivalent.
" enantiomer enrichment " refers to that a kind of amount score of enantiomer is from crossing the high compositions in Cheng Qian.
" enantiomeric excess " or " enantiomeric excess % " refers to the amount of the difference between first enantiomer and second enantiomer.Enantiomeric excess is by equation: enantiomeric excess %=(the first enantiomer %)-(the second enantiomer %) defined.Therefore, if compositions comprises 98% first enantiomer and 2% second enantiomer, then the enantiomeric excess of first enantiomer is 98%-2% promptly 96%.
Term " halogenide " and " halogen " are used interchangeably in this article, refer to halogen, comprise F, Cl, Br and I, and pseudohalide, as-CN and-SCN.
" haloalkyl " refers to be defined as in this article one or more hydrogen atoms by the alkyl that halogen replaced, and comprises whole haloalkyl, as trifluoromethyl.
" halofenate " refers to that the 4-chlorphenyl-(3-trifluoromethyl-phenoxy group) acetic acid 2-acetylamino ethyl ester (promptly; 4-chloro-α-(3-(trifluoromethyl) phenoxy group) phenylacetic acid; 2-(acetyl-amino) ethyl ester or (4-chlorphenyl) (3-4-trifluoromethylphenopendant) acetic acid), 2-(acetyl-amino) ethyl ester).
" assorted alkyl " refers to contain one or more hetero atoms or one or more heteroatomic substituent side chain or unbranched acyclic saturated alkyl part of containing, and wherein said hetero atom is O, N or S.Exemplary contain heteroatomic substituent group and 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 the integer of 0-2).Each R
aAnd R
bBe hydrogen, alkyl, haloalkyl, aryl or aralkyl independently.The representative example of assorted alkyl comprises, for example, N-acetyl group 2-amino-ethyl (promptly-CH
2CH
2NHC (=O) CH
3).
Term " metal " comprises I family, II family and transition metal, and main group metal, as B and Si.
" optical purity " refers to the amount of concrete enantiomer in compositions.For example, if compositions contains 98% first enantiomer and 2% second enantiomer, then the optical purity of first enantiomer is 98%.
Except as otherwise noted, term " phenyl " refers to the optional phenyl that replaces.Suitable phenyl substituent is described during with definition " aryl ", and those are identical.Similarly, term " phenoxy group " refers to general formula-OAr
aPart, Ar wherein
aIt is phenyl defined herein.Therefore, term " α-(phenoxy group) phenylacetic acid " refers to the acetic acid that phenyl that is optionally substituted on the 2-position and the phenoxy group of choosing replacement wantonly are partly replaced.
" protecting group " refers to can reduce or stop active part in molecule is sheltered when linking to each other with reactive group.The example of protecting group can be referring to " protecting group in the organic synthesis (Protective Groups in Organic Synthesis), the third edition " of T.W.Greene and P.G.M.Wuts, John Wei Li father and son (JohnWiley of publishing company; Sons), New York, 1999 and " methodology of organic synthesis summary (the Compendium of Synthetic Organic Methods) " of Harrison and Harrison etc., 1-8 rolls up (John Wei Li father and son publishing company, 1971-1996), above-mentioned document all is incorporated into this by reference in full with it.Representational hydroxyl protecting group comprises: acyl group, benzyl and trityl ether, THP trtrahydropyranyl ether, trialkylsilyl ethers and allyl ether.Representational amino protecting group comprises: the trityl of formoxyl, acetyl group, trifluoroacetyl group, benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trimethyl silyl (TMS), 2-trimethyl silyl-ethylsulfonyl (SES), trityl and replacement, allyloxy carbonyl, 9-fluorenyl methoxy carbonyl (FMOC), nitro-Rhizoma et radix veratri (Radix Rhizoma Veratri) oxygen base carbonyl (NVOC) etc.
Term " speed " refers to kinetics and/or thermodynamics speed when finger-type becomes product.
Term " processing ", " contact " or " reaction " that this paper adopts refers to add or mix two or more reagent under appropraite condition generate described and/or required product.Should be appreciated that generating reaction described and/or required product might not directly be generated by two agent combination of initial adding, that is, can be finally to form described and/or required product by one or more intermediate that generate in the mixture.
The term that this paper adopts " as top defined those " and " defined herein those " when referring to variable, it comprises the main definition of described variable and preferred by reference, more preferably and most preferably defines (if any).
Have many organic compound with the optical activity form, that is, they have the ability that the plane that can make linearly polarized light rotates.When describing optically active compounds, represent the absolute configuration of described molecule around its chiral centre with prefix R and S.Indicate the symbol (sign) of the linearly polarized light rotation that chemical compound causes with prefix " d " and " l " or (+) and (-), (-) or (l) the described chemical compound of expression be " left-handed ", (+) or (d) the described chemical compound of expression be " dextral ".There is not dependency between the name to absolute stereo chemistry and enantiomer optical activity.These particular chemical structures of chemical compound that are called " stereoisomer " are all identical except they are each other mirror image.Concrete stereoisomer can also be called " enantiomer ", and this enantiomeric mixture often is called " enantiomer " or " raceme " mixture.Referring to for example, Streitwiesser, A. and Heathcock, C.H. " organic chemistry introduction (INTRODUCTION TO ORGANICCHEMISTRY) (second edition) ", the 7th chapter (mcmillan is published company limited (MacMillan PublishingCo.), the U.S., 1981).
Term " does not contain its (+)-stereoisomer " substantially, and " not containing its (+)-enantiomer substantially " is used interchangeably in this article, refers to that described compositions contains than (+)-isomer obviously more a high proportion of (-)-isomer.In a preferred embodiment, term " is substantially free of its (+) stereoisomer " and refers to that described compositions contains at least 90 weight % (-)-isomer and 10 weight % or still less (+)-isomer.In more preferably embodiment, term " is substantially free of its (+)-stereoisomer " and refers to contain in the described compositions (-)-isomer and 1 weight % or still less (+)-isomer of at least 99 weight %.In most preferred embodiments, term " is substantially free of its (+)-stereoisomer " and refers to described compositions and contains (-)-isomer that surpasses 99 weight %.These percentage ratios are all in isomer total amount in the compositions.
II. foreword
Although the enantiomer of chipal compounds has identical chemical bond, the spatial orientation difference of atom in the enantiomer.Therefore, a kind of enantiomer of chiral drug more can be brought into play required activity than another kind of enantiomer usually and has significantly lower side effect simultaneously.Though the resolution of racemic thing is to be used to prepare optical activity, i.e. the common used in industry method of chipal compounds; Make great progress but chirality is synthetic in recent years.
The invention provides the method for a kind of synthetic α-(halo) phenylacetic acid chiral ester derivant.Chiral ester on α-(halo) phenylacetic acid is guided the alkylation of 3-trifloro methyl phenol into stereo selectivity and is prepared α-(phenoxy group) phenyl acetic acid derivatives.Therefore, use the chemical compound of the inventive method preparation can be used for produced in high yields α-(phenoxy group) phenylacetic acid derivatives, as Application No. 10/656,567 and U.S. Patent number 6,262, those derivants described in 118.Specifically, Compounds and methods for of the present invention can be used for preparation (-)-halofenate.
III. stereo selectivity is synthetic
As mentioned above, the Stereoselective method of existing preparation (-)-halofenate needs a plurality of steps, and it is low to make the productive rate of compositions, and perhaps optical purity deficiency can not commercial Application.But the inventor finds, under the certain condition that this paper discloses, can prepare enough optical purity α-(phenoxy group) phenylacetic acid compound with high yield and high-optical-purity with several steps.Described high yield is uncommon, is that productive rate is not high (referring to Harpp etc., J.Org.Chem.40 (23): 3420 (1975)) because similar compounds is carried out the bromination result with bromine.Therefore, an aspect, method of the present invention are based on the wonderful discovery of the inventor's unanticipated, and promptly the phenylacetic acid of Qu Daiing can be activated, and with bromine bromination and esterification, the result generates chirality alpha-halo acetas intermediate with high yield.
Then, this intermediate can be used for stereo selectivity and prepares α-(phenoxy group) phenylacetic acid derivatives.Particularly, the inventive method provides the required enantiomer of α-(phenoxy group) phenylacetic acid derivatives, and its productive rate is at least about 40%, preferably at least about 50%, more preferably at least about 60%, most preferably at least about 70%.Particularly, the optical purity of the required enantiomer of the α that the inventive method provides-(phenoxy group) phenylacetic acid compound is at least about 90%, preferably at least about 95%, more preferably at least about 97%, most preferably at least about 98%.
The method that a kind of stereo selectivity prepares α-(phenoxy group) phenylacetic acid derivatives (as xiv) is generally shown in the following scheme 2.
Scheme 2: general route
Therefore, in two steps, phenylacetic acid x can be converted into activatory carboxylic acid derivates, carries out halogenation with molecular bromine then, obtains α-bromophenyl acetyl halide xi.Phenylacetic acid is halogeno-benzene acetic acid preferably, more preferably 4-halo-phenylacetic acid, most preferably 4-chloro-phenylacetic acid.
The example that is suitable for carboxylic acid activating agent of the present invention includes, but are not limited to: thionyl halide, and as thionyl chloride (SOCl
2); Acid anhydride produces agent as trifluoroacetic anhydride (TFAA) and thioesters.The carboxylic acid activating agent is thionyl halide preferably, more preferably thionyl chloride.Thionyl chloride can be buied with limpid liquid, can use by pure thionyl chloride, perhaps uses in compatible solvent.
Then, acyl halide is converted into chiral ester xiii, wherein R
1Be chiral alcohol auxiliary agent (chiral alcoholauxiliary).Can use various chiral auxiliaries, be included in those of following embodiment announcement.Preferred employed chiral auxiliary can prepare only a kind of enantiomer of α-(phenoxy group) phenylacetic acid.Should be understood that this chiral alcohol auxiliary compound itself should be that enough enantiomeric purities are arranged, to generate α-(phenoxy group) phenylacetic acid derivatives of height enantiomer enrichment.In this manner, a kind of enantiomer at alpha-position for example makes by removing this chiral auxiliary easily.In one embodiment, chiral auxiliary is the chiral alcohol chemical compound of following formula:
Preferred chiral alcohol has following formula:
Ester xi and the oxybenzene compound xii that suitably replaces carry out displacement reaction in the presence of alkali (as hydroxide), obtain α-(phenoxy group) phenylacetate xiii.The example that can be used for the alkali of this displacement reaction comprises, is not limited to: hydroxide, as Lithium hydrate, potassium hydroxide, sodium hydroxide etc.; Alkoxide is as lithium alkoxide, potassium alcoholate, sodium hydroxide etc.; Or the like; Hydride is as lithium hydride, hydrofining, sodium hydride etc.
α-(phenoxy group) phenylacetate xiii hydrolysis forms α-(phenoxy group) phenylacetic acid xiv.The example of hydrolytic reagent includes but not limited to: hydroxide, as Lithium hydrate, potassium hydroxide, sodium hydroxide etc.; Hydroperoxides: as hydroperoxidation lithium, hydroperoxidation potassium, sodium hydroperoxide etc.
This synthetic route more specifically is shown in the following scheme 3:
Scheme 3: stereo selectivity is synthesized HALOFENIC ACID
For example, 4-chlorobenzene acetic acid 1 can be handled with thionyl chloride, to activate this carboxylic acid.Then, handle, form the 4-chlorophenyl acetyl chloride with bromine.This esterification can be used (S)-N, and N-tetramethylene lactamide 2 carries out easily.This reaction sequence advantageous particularly because can carry out easily, and has only a separating step in a reactor.Ester 3 carries out displacement reaction with 3-trifloro methyl phenol 4 in the presence of potassium hydroxide, obtain α-(phenoxy group) phenylacetate 5.With Lithium hydrate α-(phenoxy group) phenylacetate 5 is hydrolyzed, obtains α-(phenoxy group) phenylacetic acid 6.In this manner, can prepare (4-chlorphenyl)-(3-4-trifluoromethylphenopendant)-acetic acid (being CPTA) with 5 steps, productive rate is about 73%, then from the heptane crystallization.
Therefore, in one embodiment, the invention provides the method for a kind of preparation formula (I) chemical compound:
In the formula,
R
1Be selected from down group:
Each R
2Be independently selected from down group: (C
1-C
4) alkyl, halogen, (C
1-C
4) haloalkyl, amino, (C
1-C
4) aminoalkyl, acylamino-, (C
1-C
4) amidoalkyl, (C
1-C
4) sulfonyl alkyl, (C
1-C
4) sulfonamides alkyl, (C
1-C
4) alkoxyl, (C
1-C
4) assorted alkyl, carboxyl and nitro;
Work as R
1Has formula (a) or (b) time, subscript n is 1, works as R
1Has formula (c) or (d) time, subscript n is 2;
Subscript m is the integer of 0-3;
*Expression is with the carbon of stereoisomer configuration enrichment; With
Wave is represented R
1Junction point;
This method generally includes:
(a) with the carboxylic acid activating agent carboxylic acid of formula (II) chemical compound is activated in compatible solvent;
(a) formula (II) chemical compound is contacted in compatible solvent with the carboxylic acid activating agent, described carboxylic acid activating agent is selected from thionyl halide, acid anhydride and thioesters and produces agent;
(b) with bromine the product of step (a) is carried out bromination in compatible solvent;
(c) with chiral alcohol the product of step (b) is carried out esterification in compatible solvent, described chiral alcohol is selected from following:
The inventor finds, the bromating agent that is used to prepare α-(phenoxy group) phenylacetic acid has appreciable impact to the gross production rate of easy separation and this method.For example, when using bromine in the method for preparing α-(phenoxy group) phenylacetic acid compound, the gross production rate of this method is higher than uses the gross production rate that other halogenating agents reached.The consumption of halogenating agent is particular importance not.The halogenating agent consumption is usually greater than 1.00 molar equivalents, is preferably greater than or equals about 1.5 molar equivalents, more preferably from about 1.55 molar equivalents.
This reaction is carried out in compatible solvent usually.Compatible solvent is a kind of solvent to reaction condition inertia and the easy solubilizing reaction thing of energy.The solvent that is suitable for above-mentioned reaction is known to those skilled in the art.For example, the solvent that is suitable for carboxylic acid activation, bromination and esterification includes, but are not limited to: aprotic solvent, and as halogenation alkane, oxolane, aromatic hydrocarbons, dialkyl ether, and their mixture.Particularly preferred solvent is a halogenation alkane, more preferably 1, and the 2-dichloroethanes.
In one embodiment, bromination method comprises that the reacting by heating mixture is to about 70 ℃ of temperature ranges to this solution boiling point, preferably about 80-85 ℃.Heat up to finishing reaction, this course of reaction is about 1-24 hour usually, preferably about 2-18 hour.When lower temperature, need the longer response time.To those skilled in the art, the process of understanding other reactions of this reaction and the inventive method easily for example can adopt that HPLC monitors, when the amount of unreacted initial reagent can think that less than about reaction finishes 1% the time.
Bromine can be removed before adding the chiral alcohol auxiliary agent.Can be by reactor being linked to each other with vacuum pump and under reduced pressure, removing bromine.The speed of pressure, removal and degree be particular importance not.
Solution can and/or cool off before adding the chiral alcohol auxiliary agent afterwards.This has considered the exothermic character of esterification.The rate of cooling of reaction solution and amount of cooling water be particular importance not, and in one embodiment, esterification comprises that reaction mixture is to about 0 ℃ of temperature range to room temperature.React up to finishing common needs about 5-60 minute, about 30 minutes usually.
In one embodiment, this method can be carried out in a reactor.In another embodiment, only separate end product, that is, and the chemical compound of formula (I).
Particularly, the inventive method relates to the intermediate of α-(phenoxy group) phenylacetic acid of synthetic formula V:
In the formula, R
3Be haloalkyl, R
2Be halogenide.In one embodiment, method of the present invention relates to synthesis type I, or the α of preferred formula V-(phenoxy group) phenylacetic acid, in the formula, and R
2Be chlorine.In one embodiment, method of the present invention relates to formula I, or the fractionation of the α of preferred formula V-(phenoxy group) phenylacetic acid, in the formula, and R
3Trifluoromethyl preferably.In another embodiment, this method relates to the chemical compound of stereo selectivity synthesis type V, as HALOFENIC ACID, and R wherein
2Be Cl, R
3Be CF
3
In a specific embodiment, use α-(replacement) phenylacetic acid compound of chiral auxiliary synthesis type (IV) expression:
In the formula:
R
1Be selected from down group:
Work as R
1Has formula (a) or (b) time, subscript n is 1, works as R
1Has formula (c) or (d) time, subscript n is 2;
*Expression is with the carbon of stereoisomer configuration enrichment; With
Wave is represented R
1Junction point.Preferred especially chemical compound, wherein R with following formula I and IV
1Be
Unexpectedly, make α-(replacement) phenylacetic acid compound of formula (IV) with highly-solid selectively and high yield:
In the formula:
R
1Be selected from down group:
Work as R
1Has formula (a) or (b) time, subscript n is 1, works as R
1Has formula (c) or (d) time, subscript n is 2;
*Expression is with the carbon of stereoisomer configuration enrichment; With
Wave is represented R
1Junction point.For reaching requirement economically, method of the present invention provides the productive rate of required enantiomer to be at least about 50%, preferably is at least about 60%, more preferably is at least about 70%, most preferably is at least about 75%.
In one embodiment, this chemical compound is selected from down group:
With
Wherein, dotted line and thick line are represented the relative spatial chemistry (relative stereochemistry) of chemical compound.In another embodiment, described chemical compound is selected from down group:
Wherein, dotted line and thick line are represented the absolute stereo chemistry (absolute stereochemistry) of chemical compound.
Though it should be noted that about (-)-enantiomer of enrichment HALOFENIC ACID the inventive method has been discussed, the inventive method also is applicable to enrichment (+)-enantiomer.The inventive method mainly provides based on the enantiomer enrichment of chiral auxiliary and the stereo selectivity of reaction, with the chemical compound of (-)-enantiomer enrichment.The use of (+)-enantiomer can easily reach by the relative enantiomer that uses the chiral alcohol auxiliary agent.For example, (+)-enantiomer can use (R)-N, and N-tetramethylene lactamide makes.
Chiral auxiliary can reclaim and re-use/recirculation from above-mentioned step of converting.Therefore, method of the present invention itself is applicable to the recirculation type process easily.
IV. the chiral alcohol auxiliary agent is synthetic
[0054] a kind of method of preparation chiral alcohol auxiliary agent 2 is shown in following scheme 4.
Scheme 4: synthesis of chiral auxiliary agent
Lactate 7 and excessive suitable cyclic amine reaction obtain chiral auxiliary 2.By using excessive cyclammonium/equivalent ester, can reach high conversion, make the outer choosing amount minimum that disappears.For example, pyrrolidine 8 (that is, when in conjunction with R, when forming five-membered ring) advantageous particularly because pyrrolidine is the good solvent of lactate, and can react easily with pure state.In this manner, can be in a step, productive rate preparation (the S)-N with about 95%, N-tetramethylene lactamide.
V. the practicality of the α of enantiomer enrichment-(phenoxy group) phenylacetic acid
The α of enantiomer-pure-(phenoxy group) phenylacetic acid compound is the non-useful as intermediates of the various pharmaceutical active compounds of preparation, comprises disclosed α in Application No. 10/656,567 and the U.S. Patent number 6,262,118-(phenoxy group) phenylacetic acid compound.Therefore, the present invention provides the method that is prepared the α of general formula VI-(phenoxy group) phenylacetate chemical compound by the enantioselectivity of the α of formula V-(phenoxy group) phenylacetic acid compound on the other hand,
In the formula, R
3Be alkyl or haloalkyl, R
2Be halogen, R
7Be assorted alkyl, preferred N-acetyl group-2-amino-ethyl (that is formula-CH,
2CH
2NHC (=O) CH
3Part).This method relates to α-(phenoxy group) phenylacetic acid compound of aforesaid stereo selectivity synthesis type V, and makes α-(phenoxy group) phenylacetic acid and carboxylic acid activating agent's reaction of enantiomer enrichment.Suitable carboxylic acid activating agent comprises: thionyl halide (as, thionyl chloride), acid anhydride (as TFAA), thioesters produce agent, and other carboxylic acid activating agents well known by persons skilled in the art.
Then, activatory α-(phenoxy group) phenylacetic acid and formula (R
7-O)
wThe chemical compound reaction of M, as N-acetylethanolamine derivatives reaction, the α of the enantiomer enrichment of preparation formula VI-(phenoxy group) phenylacetate chemical compound, wherein R
7As top definition, M is hydrogen or metal such as Na, K, Li, Ca, Mg, Cs etc., and subscript w is the oxidation state of M.The inventor finds, activatory acid and formula (R
7-O)
wReaction between the M can be carried out, and significant raceme does not take place.
Those skilled in the art are by can obviously finding out other purpose of the present invention, advantage and novel features to following non-limiting example analysis of the present invention.
Embodiment
Reagent and experimental program
Except as otherwise noted, reagent and solvent are available from Aldrich chemical company (Aldrich Chemical) or Fischer scientific company (Fisher Scientific).Under positive nitrogen atmosphere, operate.Camille (Camile) process control computer that use links to each other with circulation heating and cooling system comes chuck (jacket) temperature in the straight wall bottom discharging glass reactor of adjustable clamp shell type (jacketed straight-walled bottom-drain glass reactors).Except as otherwise noted, under 15-25 torr and bath the highest 40 ℃ warm condition, utilize Bush's rotary evaporator (Buchi rotary evaporator) to remove and desolvate.At 40 ℃, drying solid sample in the 15-25 torr vacuum drying oven.Adopt Cenco HYVAC vacuum pump to provide vacuum less than 1 torr for vacuum distilling.Carrying out the Ka Er Fischer with Metrohm 756KF coulant meter (Metrohm 756KF Coulometer) and HYDRANALCoulomat AG reagent analyzes and measures water content.Measure fusing point with Mettler Toledo FP62 fusing point device (Mettler Toledo FP62 melting point apparatus).Orion290A type pH meter with calibration is measured pH.On Bruker Avance 300MHz spectrometer the record proton and
13The CNMR spectrum.
The sample that 10 μ L are dissolved in the mobile phase is expelled to (R, R) on WHELK-O 1.5 μ m 250 * 4.6mm post (Li Jisi technology company (Regis Technologies)), with 95/5/0.4 (v/v/v) hexane/2-propanol/acetic acid eluting of 1.0mL/ minute flow, carry out chirality HPLC at λ=240nm place and analyze.
The sample that 5 μ L are dissolved in the mobile phase is expelled on Phenomenex LUNA 5 μ m C18 (2) 250 * 4.6mm posts, carries out chirality HPLC at 25 ℃ and λ=220nm place and analyzes.That adopts 1.5mL/ minute flow starts from 66 volume % water/34 volume % acetonitriles/0.1 volume % trifluoroacetic acid, and 20 minutes linear increment are to the gradient of 26 volume % water/74 volume % acetonitriles/0.1 volume % trifluoroacetic acid.
In order to analyze the acid solution of ester such as halofenate, use acetonitrile as injection solvent.When measuring, analyze and measure the production concentration of halofenate by HPLC with external standard method (external standard method) less than the chiral analysis step under the sample concentration of 2.5mg/mL.
Embodiment 1: synthesis of chiral alcohol auxiliary agent.
(S)-and N, N-tetramethylene lactamide (2)
In 0 ℃, with pyrrolidine (120g, 1.69mol; 2eq.) be added drop-wise to 100g (0.847mol) (S)-(-)-ethyl lactate in, stirring at room 3 days.After vacuum is removed the ethanol of excessive pyrrolidine and generation,, the oily residue through distillation purifying (104 ℃, 2mmHg), obtain 113g (93%) (S)-N, N-tetramethylene lactamide (2) is light yellow oil.
1H?NMR(CDCl
3)：δ4.30(IH，q，J＝6.63Hz)，3.74(IH，br，OH)，3.31-3.61(4H，m)，1.85-2.03(4H，m)，1.34(IH，d，J＝6.24Hz)ppm。
Embodiment 2: preparation (-)-halofenate (6)
Preparation chemical compound (3)
In air, in about 1 minute, add 500mL anhydrous 1 in the 2-L there-necked flask that charging hopper and condenser are housed in being immersed in oil bath, the 2-dichloroethanes, once add 4-chlorobenzene acetic acid (174.04g, 98%, 1.0mol (Acros)), once add DMF (0.40mL, about 0.5mol%) and thionyl chloride (95mL, 1.3mol, 1.3eq.).In 15 minutes, add the mixture to 70 ℃ (oil bath temperature) of thermosetting.Began acutely to discharge gas about 5 minutes after the heating (in about 40-45 ℃).The violent release of gas slows to stable logistics, stops gas release then.In 70 ℃ stir 2 hours after, in about 1 minute, with bromine (80mL, about .249g, 1.55mol; 1.55eq.) join in the pale yellow solution (in 65 ℃) of generation, obtain brown solution.Spend the night (about 18 hours) in 80-85 ℃ of (oil bath temperature) stirred reaction mixture, be cooled to room temperature then.Should alpha-brominated acyl chlorides (α-bromo acid chloride) solution in room temperature storage, and do not need to be further purified and can be used for the next step that ester forms.
With the thick acyl chlorides (138g, about 0.138mol) for preparing above 1, the solution 100mL1 of 2-dichloroethanes, the dilution of 2-dichloroethanes.Remove excessive bromine by vacuum distilling, up to the about 100mL solution of residue.Then,, this solution of acid chloride is added drop-wise to (S)-N in 0 ℃, N-tetramethylene lactamide (20.1g, 0.140mol) and triethylamine (14.78g is 0.147mol) at 100mL 1, in the solution of 2-dichloroethanes.In 1 hour, the brown mixture that forms is warmed to room temperature at most.Reactant mixture water (100mL) quencher separates organic layer, and uses 100mL 10%Na
2S
2O
3, use saturated NaHCO then
3(100mL) washing.Organic layer Na
2SO
4Drying, vacuum concentration obtains the crude product that 45.8g is a brown oil then, and this crude product does not need to be further purified and just can be used for next step.
Preparation chemical compound (6)
Under the room temperature, to α, α, α-three fluoro-metacresol (3.3g; 0.0204mol) dropping tert-butyl alcohol lithium (20mL, the THF solution of 1.0M in the solution of anhydrous THF (20mL); 0.02mol).In-5 ℃, the phenol lithium drips of solution that produces is added to bromide 3 (slightly, 7.5g; 0.02mol) in the solution of 40mL THF.After 1 hour, in 20 minutes, (Fisher 30% to add hydrogen peroxide in room temperature in-5 ℃ of stirrings; 105mL, 0.4mol) and LiOHH
2(21g, the 0.05mol) premixed solution in water (50mL) in 0-4 ℃ of stirred reaction mixture 1 hour, with saturated aqueous solution of sodium bisulfite (150mL) quencher, add 1N HCl to O then, and the pH that regulates this solution is to being about 2.Vacuum distilling is removed THF, then, dilutes this reactant mixture with EtOAc (100mL).Na is used in organic layer water and salt water washing
2SO
4Drying, evaporation obtains the 7g crude acid.This crude acid obtains the 4.6g white solid from the heptane crystallization.It is 96.5: 3.5 enantiomer that chirality HPLC analyzes.
Other chiral auxiliaries that adopt similar condition and list above, the preparation HALOFENIC ACID.
Embodiment 3: the another kind of method of halofenate (6) for preparing
In room temperature, to α, α, α-three fluoro-metacresol (6.71g; 0.041mol) adding hydronium(ion) oxidation lithium in the solution of anhydrous THF (20mL) and toluene (30mL) (1.68g, 40mmol).Remove after 1 hour and desolvate, residue is dissolved in the anhydrous THF of 30mL (30mL).Phenol lithium drips of solution with generation under stirring at room is added to bromide 3 (slightly, 14.9g; 0.04mol) and NaI (0.3g) in the solution of 100mL THF, stirred 1 hour in-5 ℃, in-5 ℃ to 0 ℃ restir 3 hours.
1H NMR shows that bromide 3 disappears.
(Fisher 30% with hydrogen peroxide; 209mL, 0.8mol) add Lithium hydrate (4.2g, 0.09mol) in the solution of water (100mL), this mixture of stirring at room 20 minutes.Then, in 0 ℃, this solution is slowly added lactamide 4 in the cold soln of THF.In 0-4 ℃ of stirred reaction mixture 1 hour,, and regulate pH to 2 with 1N HCl quencher.Vacuum distilling is removed THF, and then, reactant mixture dilutes with EtOAc (150mL).Organic layer water, saturated Na
2S
2O
3With the salt water washing, use Na
2SO
4Drying obtains crude acid after the evaporation.This crude acid obtains 8.4g white solid (99: 1 enantiomer are measured by chirality HPLC) from the heptane crystallization.
Should be appreciated that, embodiment as herein described and embodiment only are in order to illustrate, various modifications that those skilled in the art can propose according to these embodiment and embodiment or change includes in the application's spirit and scope and in the scope of appended claims.To all occasions, all publications, patent and patent application that this paper quotes all are incorporated into this paper by reference in its entirety.
Claims (16)
1. the method for a preparation formula (I) chemical compound,
In the formula,
R
1Be selected from down group:
Each R
2Be independently selected from down group: (C
1-C
4) alkyl, halogen, (C
1-C
4) haloalkyl, amino, (C
1-C
4) aminoalkyl, acylamino-, (C
1-C
4) amidoalkyl, (C
1-C
4) sulfonyl alkyl, (C
1-C
4) sulfonamides alkyl, (C
1-C
4) alkoxyl, (C
1-C
4) assorted alkyl, carboxyl and nitro;
Work as R
1Has formula (a) or (b) time, subscript n is 1, works as R
1Has formula (c) or (d) time, subscript n is 2;
Subscript m is the integer of 0-3;
* represent carbon with the enrichment of a stereoisomer configuration; With
Wave is represented R
1Junction point;
This method comprises:
(a) formula (II) chemical compound is contacted in compatible solvent with the carboxylic acid activating agent, described carboxylic acid activating agent is selected from thionyl halide, acid anhydride and thioesters and produces agent;
(b) with bromine the product of step (a) is carried out bromination in compatible solvent;
(c) with chiral alcohol the product of step (b) is carried out esterification in compatible solvent, stereo selectivity forms formula (I) chemical compound, and described chiral alcohol is selected from following:
2. the method for claim 1 is characterized in that, R
1Be
3. each described method in the claim as described above is characterized in that formula (II) chemical compound is the 4-chlorophenylacetic acid.
4. each described method in the claim as described above is characterized in that the carbonyl activator is a thionyl halide.
5. each described method in the claim as described above is characterized in that the carbonyl activator is a thionyl chloride.
6. each described method in the claim as described above is characterized in that, bromine exists with the concentration of the molar equivalent that is at least about formula (II) chemical compound amount.
7. each described method in the claim as described above is characterized in that solvent is the alkyl halide hydrocarbon solvent.
8. each described method in the claim as described above is characterized in that solvent is 1, the 2-dichloroethanes.
9. each described method in the claim as described above is characterized in that described condition is included at least about 70 ℃ carries out bromination.
10. each described method in the claim as described above, this method also is included in carries out step (c) before, the step that excessive bromine is removed in decompression.
11. each described method in the claim is characterized in that as described above, this method is carried out in a reactor.
12. each described method in the claim is characterized in that as described above, the chemical compound of a separate type (I).
13. the chemical compound of a formula (IV):
In the formula,
R
1Be selected from down group:
Work as R
1Has formula (a) or (b) time, subscript n is 1, works as R
1Has formula (c) or (d) time, subscript n is 2;
* represent carbon with the enrichment of a stereoisomer structure; With
Wave is represented R
1Junction point.
14. a chemical compound has and is selected from following structural formula:
Wherein, dotted line and thick line are represented the relative spatial chemistry of this chemical compound.
15. a chemical compound has and is selected from following structural formula:
Wherein, dotted line and thick line are represented the absolute stereo chemistry of this chemical compound.
16. a compositions comprises claim 14 or 15 described chemical compounds at least about 95% enantiomeric excess.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US72030005P | 2005-09-23 | 2005-09-23 | |
| US60/720,300 | 2005-09-23 | ||
| US11/525,200 | 2006-09-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101316585A true CN101316585A (en) | 2008-12-03 |
Family
ID=40107302
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800431805A Pending CN101316585A (en) | 2005-09-23 | 2006-09-21 | Process for the stereoselective preparation of (-)-halofenate and intermediates thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN101316585A (en) |
| ZA (1) | ZA200803329B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102241590A (en) * | 2011-05-17 | 2011-11-16 | 永农生物科学有限公司 | Synthetic method of spirocyclic tetronic acid compound key intermediate |
-
2006
- 2006-09-21 CN CNA2006800431805A patent/CN101316585A/en active Pending
- 2006-09-21 ZA ZA200803329A patent/ZA200803329B/en unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102241590A (en) * | 2011-05-17 | 2011-11-16 | 永农生物科学有限公司 | Synthetic method of spirocyclic tetronic acid compound key intermediate |
| CN102241590B (en) * | 2011-05-17 | 2013-06-19 | 永农生物科学有限公司 | Synthetic method of spirocyclic tetronic acid compound key intermediate |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200803329B (en) | 2009-09-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Wade | Preparation of fluoro amines by the reaction of aziridines with hydrogen fluoride in pyridine solution | |
| CN101495427B (en) | Resolution of alpha-(phenoxy)phenylacetic acid derivatives with naphthyl-alkylamines | |
| EP1940387B1 (en) | Process for the stereoselective preparation of (-)-halofenate and intermediates thereof | |
| Koh et al. | Stereoselective SN2 Reactions of the (R)-Pantolactone Ester of Racemic. alpha.-Halo Carboxylic Acids with Aryl Oxides. A Synthesis of (S)-2-Aryloxy and (S)-2-Hydroxy Acids | |
| US7115771B2 (en) | Process for producing fluorine-containing alkylsulfonylaminoethyl α-substituted acrylate | |
| WO2003020685A1 (en) | Fluorine compound and fluorinating agent comprising the compound | |
| CN101316585A (en) | Process for the stereoselective preparation of (-)-halofenate and intermediates thereof | |
| JP4584464B2 (en) | Process for preparing R-(-)-carnitine from S-(-)-chlorosuccinic acid or its derivatives | |
| JP3885497B2 (en) | Method for producing 1,2,4-butanetriol | |
| CS227036B2 (en) | Method of preparing amides | |
| JPH03251569A (en) | Production of acrylic piperidyl ester derivative | |
| JP4000113B2 (en) | (3S) -3-methoxycarbonyl-4-phenylbutyric acid metal salt and method of use thereof | |
| JP4126921B2 (en) | Process for producing optically active β-phenylalanine derivative | |
| CN116375611A (en) | Method for synthesizing difluoroalkyl compound from fatty amine | |
| JP2001011016A (en) | Production of tartaric acid lower alkyl diester | |
| JP2003238500A (en) | Method for producing fluorine-containing tertiary amine compound and fluorine-containing quaternary ammonium salt | |
| MX2008003796A (en) | Process for the stereoselective preparation of (-)-halofenate and intermediates thereof | |
| JP2022110339A (en) | METHOD FOR PRODUCING α-(MERCAPTOMETHYL) ACRYLATE | |
| JP2000247988A (en) | Production of optically active vinylphosphine oxide | |
| JP3588762B2 (en) | Process for producing racemic 2- (4-fluorophenyl) -3-methylbutyric acid ester and racemic 2- (4-fluorophenyl) -3-methylbutyric acid | |
| JP4480200B2 (en) | 4-aminopyridine derivatives and uses thereof | |
| US20060229468A1 (en) | Process for preparing optionally substituted arylsulphonic anhydrides | |
| JPH0267237A (en) | Production of optically active 1,1,1-trifluoro-2-alkanol | |
| WO2006103986A1 (en) | Process for production of optically active fluoroproline derivative | |
| JPH06172300A (en) | Production of 3-@(3754/24)s-containing substituent)-2-benzylpropionic acid, its intermediate and its production |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20081203 |