ARYLOXY ESTER AND ACID COMPOUNDS

Abstract: This invention is directed to aryloxy ester and acid compounds of the formula (1): Ar-O-(CH2)n-COOR which can be utilized as intermediates in the synthesis of Factor Xa inhibitors to increase their potency and oral activity, and to a method for their production.

Description: Description: ARYLOXY ESTER AND ACID COMPOUNDS FIELD OF INVENTION The present invention relates to aryloxy ester and acid compounds and to a method for their production. REPORTED DEVELOPMENTS Current methods for preparing aryloxy ester and acid compounds include a multistep synthesis in which an aryl or heteroaryl compound is deprotonated, halogenated and oxidized to form an aryl hydroxide or a heteroaryl hydroxide. The aryl hydroxide or heteroaryl hydroxide is then o-alkylated with an alkyl bromoester to form an aryloxy ester, which can be halogenated and hydrolyzed as desired. Unfortunately, each of the several steps used in the aforementioned synthesis result in low yields. Additionally, many of the prior art reactions require the use of expensive reagents. Accordingly, there is a need for a more efficient and less-costly method of preparing aryloxy ester and acid compounds. SUMMARY OF THE INVENTION The present invention provides a family of aryloxy compounds, which exhibit beneficial anticoagulant properties, and which can be utilized as intermediates in the synthesis of Factor Xa inhibitors to increase their potency and oral activity. Additionally, a method for synthesizing compounds of the present invention is provided. According to the present invention, aryloxy compounds are provided having the following structure of Formula 1 : Ar-0-(CH 2 ) n -COOR (1) wherein Ar is an unsubstituted or substituted aryl group or an unsubstituted or substituted heteroaryl group; R is a hydrogen or an unsubstituted or substituted aliphatic group; and n=1 to about 6. Another aspect of the present invention is the provision of a process for preparing a compound of Formula 1. In a preferred embodiment, the process comprises: (a) reacting a trifluoroalkoxy aryl or trifluoroalkoxy heteroaryl compound to form an orthoester compound; and (b) converting the orthoester to a compound of Formula 1. DETAILED DESCRIPTION OF THE INVENTION In Formula 1, Ar can be an unsubstituted or substituted aryl group or an unsubstituted or substituted heteroaryl group. Preferably, Ar is an unsubstituted or substituted C 3 to about C 2 o aryl group or an unsubstituted or substituted 3 to about 10 member heteroaryl group. More preferably, Ar is an unsubstituted or substituted Cβ to about Ci5 aryl group or an unsubstituted or substituted 3 to about 6 member heteroaryl group. Examples of aryl groups are: phenyl, o-tolyl, m-tolyl, p-tolyl, o-xylyl, m-xylyl, p-xylyl, alpha-naphthyl or beta-naphthyl. In a particularly preferred class of compounds, Ar is C 6 to about C-i 2 aryl group, especially phenyl. Examples of heteroaryl groups are: pyrrole, furan, thiophene, pyridine or derivatives thereof. In a particularly preferred class of compounds, Ar is a 3 to about 6 member heteroaryl group, especially thiophene. Ar radicals may be substituted with essentially any conventional organic moiety. Examples of substitution groups include Cι to about Cβ aliphatics such as alkyls, halogenated alkyls, alkoxys, and alkenyls, Cβ to about C i5 aryls, halogens, particularly chlorine, C 3 to about C 8 cyclic aliphatics, nitros, aminos (primary and secondary), amidos, cyanos and hydroxyls. In Formula 1 , R can be hydrogen or an unsubstituted or substituted aliphatic group, which may be cyclic or acyclic. Examples of R groups are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, 2-ethylhexyl, cyclopropyl, cyclobutyl, cyclopentyl, methylcyclopentyl, cyclohexyl, methylcyclohexyl, dimethylcyclohexyl, cycloheptyl or cyclooctyl. Preferably, R is an unsubstituted or substituted Cι to about a C 2 o acyclic aliphatic group or an unsubstituted or substituted C 3 to about C 2 o cyclic aliphatic group. In a more preferred embodiment, R is an unsubstituted or substituted Ci to about Cι 2 alkyl group, or an unsubstituted or substituted C 3 to about C1 0 cycloalkyl group. In a particularly preferred class of compounds R is a C 2 to about C 4 alkyl group, such as those mentioned above. Any of these alkyl or cycloalkyl groups may be substituted with essentially any conventional organic moiety, for example, methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, methanesulphonyl, cyano, bromine, chlorine or fluorine. In the compounds of Formula 1 , n is in the range of 1 to about 6, preferably 1 to about 3, and more preferably n is 1. The compounds of Formula 1 may exist in isomeric form. All racemic and isomeric forms of the compounds of Formula 1, including pure enantiomeric, racemic and geometric isomers and mixtures thereof, are within the scope of the invention. General Preparation of an ester or acid of Formula 1 According to the method of the present invention, ester and acid compounds of Formula 1 may be produced in two steps from a starting material comprising a 1 ,1 ,1- trifluoroalkoxy aryl or a 1 ,1 ,1 -trifluoroalkoxy heteroaryl described in more detail below. In the first step, the trifluoromethyl moiety (-CF 3 ) of the starting material is converted to an orthoester moiety, that is, a carbon having three o-aliphatic substituents, to form an orthoester intermediate compound. In the second step, the orthoester intermediate is converted to a compound of Formula 1. Generally, the first step is performed by introducing aliphatic oxy reagents in sufficient amount to fully displace the fluoride substituents of the starting material. In this manner, orthoester intermediates having the same or different ("mixed") o- aliphatic substituents can be formed by using sources of aliphatic oxy ions, such as, for example, metal aliphatic oxides or deprotonated aliphatic alcohols, deriving from one or more aliphatics. In the second step of the method of the present invention, the intermediate orthoester compound formed in the first step is converted to a compound of Formula I, preferably using conventional acid hydrolysis techniques. Starting Material of the Present Invention As mentioned above, the preparation of the aforementioned ester or acid compounds of Formula 1 involves the use of a trifluor starting material comprising a 1 ,1 ,1 -trifluoroalkoxy aryl or 1 ,1 ,1 -trifluoroalkoxy heteroaryi having the following general Formula 2 : Ar-0-(CH 2 ) n -CF 3 (2) wherein n is the same as described above for Formula 1, that is 1 to about 6. Such starting materials are known in the literature and are capable of being prepared by art-recognized procedures. See, for example, Keegstra, et al., Tetrahedron, Vol.14, No.17, 3633-3652 (1992); or Suzuki, et al., Synthesis, No. 5, 499-500 (May 1985). The disclosures of these publications are incorporated herein by reference. Preparation of the Orthoester Intermediates The orthoester intermediates may be prepared by the use of any aliphatic oxy compound which can replace selectively the fluorine substituents of the trifluor starting material with a desired aliphatic oxide group. Suitable aliphatic oxy compounds include metal aliphatic oxides such as, for example, sodium ethoxide, sodium n-butoxide, sodium tert-butoxide, potassium ethoxide, potassium n-butoxide, potassium tert-butoxide. Of these, sodium ethoxide, sodium n-butoxide and sodium tert-butoxide are preferred. To form the orthoester intermediate, at least three moles of aliphatic oxide need to be provided for each mole of trifluor starting material. An excess of aliphatic oxide may be provided to ensure a more complete reaction. In a preferred embodiment, the first step is performed by mixing the selected Formula 2 trifluor starting material and metal aliphatic oxide with an anhydrous alcohol solvent and heating the reaction mixture to form the orthoester intermediate. Typically, the reaction occurs at temperatures between about 100 °C and about 200 °C, preferably between about 130 °C and 175 °C. Reaction times may range from a few minutes to several days. Those of ordinary skill in the art will recognize that both the alcohol and metal aliphatic oxide used in the aforementioned reaction are possible sources of aliphatic oxide ions which can displace the fluoride substituents of the trifluor starting material to form orthoesters. When dissolved in solution, the aliphatic oxide ions formed from the metal aliphatic oxide may directly displace fluoride substituents of the starting material or may deprotonate the alcohol to form more, possibly different, aliphatic oxide ions. Therefore, both the metal aliphatic oxide and the alcohol used in the present invention should be chosen such that the aliphatic oxide ions formed therefrom represent desired aliphatic oxy groups of the orthoester. Accordingly, to form an orthoester having three of the same aliphatic oxy substituents via the process of the present invention, it is preferred to use a metal aliphatic oxide and alcohol derived from the same aliphatic oxide ion. In this manner, the aliphatic oxide ions formed from either the metal aliphatic oxide or the alcohol correspond to the desired aliphatic oxy substituents of the orthoester product. For example, to form a triethoxy orthoester, a trifluoroalkoxy starting material compound is reacted with a metal ethoxide and ethanol. Thus, displacement of the fluoride groups by alkoxide ions deriving from either the metal ethoxide or ethanol lead to formation of the desired product and formation of mixed orthoesters is minimized. Mixed orthoesters, if desired, are formed according to the present invention by using metal aliphatic oxides and alcohols deriving from different aliphatic oxy groups. When using metal aliphatic oxides and alcohols deriving from different aliphatic oxy groups, different mixed orthoesters and non-mixed ortho-esters are possible products. However, one of ordinary skill in the art can determine readily and optimize the reaction conditions for preparing mixed orthoester compounds of the present invention without undue experimentation. Furthermore, the compounds obtained from the aforementioned reaction may be purified by conventional methods known to those skilled in the art. In light of this disclosure, one of ordinary skill in the art can determine readily and optimize the reaction conditions for preparing the orthoester intermediate compounds of the present invention without undue experimentation. Furthermore, the compounds obtained from the aforementioned reaction may be purified by conventional methods known to those skilled in the art. For example, aqueous washing, drying, concentrating under reduced pressure, distillation, and the like are methods which may be used. Preparation of Compounds of Formula 1 from the Orthoester Intermediate The compounds of Formula 1 may be prepared from the orthoester intermediates using conventional acid-catalyzed hydrolysis methods. For example, the orthoester intermediate may be dissolved in solvent and treated with acid to form an ester or acid compound of Formula 1. Whether an ester or acid compound is formed from the hydrolysis step is believed to be determined by the choice of anhydrous or aqueous solvent. In general, the use of an anhydrous solvent for hydrolysis will produce a greater isolation of ester products. However, when an aqueous solvent or organic/aqueous solvent mixture is used, the major product isolated is an acid of Formula 1. Examples of suitable anhydrous alcohols for use in the present invention include methanol, ethanol, n-propanol, isopropanol, n-butanol, or t-butanol, preferably ethanol or n-butanol. Suitable aqueous solvents include mixtures of water and alcohols, such as methanol or ethanol. Mixtures of THF/alcohol/water may also be used, such as a 5:5:2 THF/alcohol/water. Hydrolysis of esters is a well-known procedure accomplished with an alkali hydroxide, such as sodium, potassium or lithium hydroxide in an aqueous alcohol (such as ethanol or methanol) medium. One of ordinary skill in the art can determine readily and optimize reaction conditions for preparing an ester or acid compound of Formula 1 from an orthoester intermediate without undue experimentation. Generally, reaction temperatures range from about 0 °C to about 50 °C, and reaction times range from a few minutes to several hours. Preparation of Halogenated Compounds of Formula 1 A halogenated aryloxy ester of Formula 1 may be prepared from a non-halogenated aryloxy ester by employing an additional halogenation step. Thereafter, the preparation of a halogenated aryloxy acid compound by using an optional hydrolysis step is described. Additionally, the use of halogenated starting materials to prepare halogenated compounds of Formula 1 is described. In one embodiment of the present invention, ester compounds of the Formula I having an Ar- group comprising a halogenated aryl or halogenated heteroaryl may be made by the method of the present invention further comprising the step of halogenating the ester compound of Formula I. This halogenation step is preferably done under conditions sufficient to achieve halogenation of the Ar- group without reaction or decomposition of the rest of the molecule. One embodiment of the halogenation step comprises reacting an ester of the present invention with a halogenating agent, either in the presence or absence of an acid catalyst. Halogenating agents suitable for use in the present invention preferably comprise reagents, which can halogenate selectively aryl or heteroaryl moieties in good yield under mild conditions. Examples of preferred halogenating agents are n-chlorosuccinimide and n-bromosuccinimide. Substitution of aryls and heteroaryls with halogens is known in the art and can be accomplished through conventional methods. Thus, one of ordinary skill in the art can determine readily and optimize reaction conditions for preparing a halogenated ester compound of Formula 1 without undue experimentation. Because acids of Formula 1 tend to react readily with halogenating agents, direct halogenation of acid compounds of the present invention is a relatively inefficient method for recovering desired halogenated acid compounds. However, in another embodiment of the present invention, halogenated acid compounds of Formula 1 can be made by subjecting corresponding halogenated ester compounds of Formula 1 to a further hydrolysis step. Hydrolysis of halogenated esters can be achieved using conventional methods. Those of ordinary skill in the art can determine readily and optimize reaction conditions for the hydrolysis of halogenated esters to make halogenated acid compounds of Formula 1. Generally, reaction temperature range from about 0 °C to about 50 °C and reaction times range from a few minutes to several hours. Chlorinated or fluorinated compounds of Formula 1 can also be made directly via the present method by using starting materials having aryl or heteroaryl chlorine or fluorine substituents in place prior to orthoester formation. In this manner, chlorinated and fluorinated compounds can be produced without the need for an additional chlorination or fluorination step after conversion of the orthoester to compounds of Formula 1. Suitable chlorinated and fluorinated starting materials include 1,1,1 -trifluoroalkoxy chlorothiophenes, such as 2-chloro-5-(1 ,1 ,1-trifluoroethoxy)-thiophene. These starting materials may also include conventional organic substituent moieties, such as aryl, alkyl, alkoxy, nitro, amido, cyclic aliphatic, or amino groups. EXAMPLE The following example is illustrative of the claimed process of the present invention, illustrating a five-step process for the production of the claimed compound 5- chlorothiophen-2yloxyacetic acid. The structure of the compound produced in each step conformed with mass spectrum analysis. Step 1. The preparation of 2-(2,2,2-trifluoroethoxy)thiophene from 2,2,2- trifluoroethanol. To hexane-washed sodium spheres (3.2 g, 140 mmol) was slowly added 2,2,2- trifluoroethanol (35 mL, 500 mmol) under a nitrogen atmosphere. The mixture was warmed to 55 °C - 60 °C during the addition of the alcohol. Following dissolution of the sodium metal, the excess 2,2,2-trifluoroethanol was removed under reduced pressure. To the resulting white solid was added copper(l) iodide (13.7 g, 7 mmol) and 2-iodothiophene (14.7 g, 70 mmol). The mixture was heated at 110 °C for 24 h and was evaporated at 25 °C. The residue was diluted with hexane and filtered through a pad of silica gel. The filtrate was evaporated to yield 7.0 g (55%) of 2- (2,2,2-trifluoroethoxy)thiophene as a colorless liquid. The material can also be purified by distillation (boiling point 67 °C, 30 mm Hg). Step 2. The preparation of 2-(2,2,2-triethoxy)ethoxythiophene from 2-(2,2,2- trifluoroethoxy)thiophene. 2-(2,2,2-trifluoroethoxy)thiophene (20 g, 110 mmol) and sodium ethoxide (45 g, 660 mmol) were placed in a steel reaction vessel. Anhydrous ethanol (100 mL) was added and the mixture was heated at 150 °C for 72 hours. The mixture was cooled and subsequently diluted with water (500 mL). The aqueous phase was extracted with four portions of diethyl ether (200 mL). The organic phases were combined, washed three times with 2N aqueous sodium hydroxide, dried with magnesium sulfate, filtered and evaporated to provide 16.5 g (57%) of 2-(2,2,2- triethoxy)ethoxythiophene as a pale-yellow oil. Step 3. The preparation of ethyl thiophen-2-yloxyacetate from 2-(2,2,2- triethoxy)ethoxythiophene. 2-(2,2,2-triethoxy)ethoxythiophene (18.4 g, 71 mmol) was dissolved in ethanol (180 mL). One Normal hydrochloric acid (10 mL) was added and the mixture stirred for 5 minutes. The reaction was diluted with saturated aqueous sodium bicarbonate and diethyl ether. The organic phase was washed once with brine, dried with sodium sulfate, filtered and evaporated to yield ethyl thiophen-2-yloxyacetate (100%) as a yellow oil. Step 4. The preparation of ethyl 5-chlorothiophen-2-yloxyacetate from ethyl thiophen-2-yloxyacetate. Ethyl thiophen-2-yloxyacetate (1.13 g, 6 mmol) was placed in acetic acid (20 mL) and Λ/-chlorosuccinimide (0.85 g, 6 mmol) was added. The mixture was stirred for 2 hours and was diluted with diethyl ether. The organic phase was washed three times with 2N aqueous sodium hydroxide, dried with magnesium sulfate and evaporated. Purification by silica gel chromatography, eluting with 2:1 hexane/ethyl acetate, gave 1.1 g ethyl 5-chlorothiophen-2-yloxyacetate (83%) as a clear, colorless oil. The material can also be isolated by distillation (boiling point 114 °C, 2-3 mm Hg). Step 5. The preparation of 5-chlorothiophen-2yloxyacetic acid from ethyl 5- ehlorothiophen-2-yloxyacetate. Ethyl 5-chlorothiophen-2-yloxyacetate (10.9 g, 49 mmol) was placed in 100 mL of a 5:5:2 THF/methanol/water solvent mixture. Lithium hydroxide (4.1 g, 98 mmol) was added. The mixture was stirred at room temperature for 18 hours and acidified with 2N aqueous hydrochloric acid to pH 2 to 3. The aqueous phase was extracted three times with diethyl ether. The organic phases were combined, washed with brine, dried with magnesium sulfate and evaporated. The residue was recrystallized from hexane/diethyl ether to yield 7.75 g (83%) of 5-chlorothiophen-2-yloxyacetic acid.

Claims: CLAIMS What is claimed is: 1. A method for preparing a compound having the formula (1): Ar-0-(CH 2 ) n -COOR (1) wherein Ar represents an unsubstituted or substituted aryl or heteroaryl group, R represents hydrogen or an unsubstituted or substituted aliphatic group, and n is from 1 to about 6, comprising the steps of: (a) reacting a trifluoroalkoxy compound of the formula Ar-O-(CH 2 ) π -CF 3 with one or more aliphatic oxides to form an intermediate compound of the formula Ar-O-(CH 2 )n-C(-OR) 3 , wherein R represents the same or different aliphatic groups; and (b) converting said intermediate compound to form a compound of formula (1). 2. The method of claim 1 wherein Ar is a heteroaryl group. 3. The method of claim 2 wherein Ar is a thiophene group. 4. The method of claim 1 wherein R represents a substituted or unsubstituted, straight or branched Cι to about Cm alkyl group. 5. The method of claim 4, wherein R represents a straight or branched C 2 to C 4 alkyl group. 6. The method of claim 5 wherein R represents an ethyl, t-butyl or n-butyl group. 7. The method of claim 1 wherein n is from 1 to 3. 8. The method of claim 7, wherein n is 1. 9. The method of claim 1 further comprising the step of halogenating said Ar group such that the compound of formula (1) contains at least one halogen atom substituent on the Ar group. 10. The method of claim 9 wherein said step of halogenating is performed after step (b). 11. The method of claim 9 wherein said step of halogenating is performed simultaneously with step (b). 12. A compound having the formula (1): Ar-O-(CH 2 ) n -COOR (1) wherein Ar represents an unsubstituted or substituted aryl or heteroaryl group, R represents hydrogen or an unsubstituted or substituted aliphatic group, and n is from 1 to about 6. 13. The compound of claim 12 wherein Ar is a heteroaryl group. 14. The compound of claim 13, wherein Ar is a thiophene group. 15. The compound of claim 12 wherein R represents a straight or branched Cι to about C-io alkyl group. 16. The compound of claim 15, wherein R represents a straight or branched C 2 to C 4 alkyl group. 17. The compound of claim 16 wherein R represents an ethyl, t-butyl or n-butyl group. 18. The compound of claim 12, wherein n is from 1 to 3. 19. The compound of claim 18, wherein n is 1. 20. The compound of claim 12, wherein Ar contains one or more halogen substituents on the Ar group .

Inventors: KAPINSKY JOSEPH M, KAPINSKY, JOSEPH, M.
Applicants: AVENTIS PHARMA GMBH, AVENTIS PHARMA DEUTSCHLAND GMBH
Application year: 2001
Main classification: C07D333
IPC codes: C07D333