MXPA02010875A - Aryloxy ester and acid compounds. - Google Patents

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

COMPOUNDS OF YETACLE ESTERS AND ARILOX1 FIELD OF THE INVENTION The present invention relates to aryloxy ester and acid compounds and to a method for their production.

REPORTED DEVELOPMENTS Current methods for preparing ester and aryloxy acid compounds include a multi-step synthesis, in which an aryl or heteroaryl compound is deprotonated, halogen and oxidized, to form an aryl hydroxide or a heteroaryl hydroxide. The aryl hydroxide or the 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 various stages used in the synthesis, mentioned above, results in low yields. Additionally, many of the reactions of the prior art require the use of expensive reagents. Therefore, there is a need for a more efficient and less expensive method of preparing the ester compounds and the aryloxy acid.

COMPENDIUM OF THE INVENTION The present invention provides a family of aryloxy compounds, which exhibit beneficial anticoagulant properties and which can be used as intermediates in the synthesis of Factor Xa inhibitors, to increase their potency and oral activity. Additionally, a method for synthesizing the compounds of the present invention is provided. In accordance with the present invention, aryloxy compounds are provided, having the following structure of Formula 1: Ar-O- (CH2) n-COOR (1) where Ar is an alkyl group, unsubstituted or substituted or a heteroaryl group, unsubstituted or substituted; R is hydrogen or an aliphatic, unsubstituted or substituted group; 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 compound -heteroaryl, to form an orthoester compound; and (b) converting this orthoester to a compound of Formula 1.

DETAILED DESCRIPTION OF THE INVENTION In Formula 1, Ar can be an aryl group, unsubstituted or substituted, or a heteroaryl group, unsubstituted or substituted,. Preferably, Ar is an aryl group, unsubstituted or substituted, of C3 up to about C20, or a heteroaryl group, unsubstituted or substituted, of 3 to about 10 members. More preferably, Ar is an aryl group, unsubstituted or substituted, from C6 to about C5, or an unsubstituted or substituted heteroaryl group, from 3 to about 6 members. 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 an aryl group, Cβ up to about C12, especially phenyl. Examples of heteroaryl groups are: pyrrole, furan ,. thiophene, pyridine or its derivatives. In a particularly preferred class of compounds, Ar is a heteroaryl group of from 3 to about 6 members, especially thiophene. The Ar radicals can be substituted with essentially any conventional organic part.

Examples of substitution groups include Ci aliphatics up to about C6, such as alkyls, alkyls halogenated, alkoxy and alkenyls, C6 aryls up to about C15 halogens, particularly chlorine, C3 aliphatics up to about C8, nitros, amines (primary and secondary), to iodides, cyanos and hydroxyls. In Formula 1, R may be hydrogen or an aliphatic, unsubstituted or substituted group, which may be cyclic or acyclic. Examples of R groups are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary 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 acyclic aliphatic group, from Ci to about C2OA OR a cyclic, unsubstituted or substituted aliphatic group, from C3 to about C20. In a more preferred embodiment, R is an alkyl group, unsubstituted or substituted, of C3 at about Cio. In a particularly preferred class of compounds, R is an alkyl group from C2 to about C4, as mentioned above. Any of these alkyl or cycloalkyl groups can be substituted with essentially any conventional organic part, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-buoxi, methanesulfonyl, cyano, bromochloro or fluoro.

In the compounds of Formula 1, n is in the range of 1 to 6, preferably 1 to 3, and more preferably n is 1. The compounds of Formula 1 can exist in the isomeric form. All racemic and isomeric forms of the compounds of Formula 1, including the enantiomeric, racemic and pure 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 present invention, the ester and acid compounds of Formula 1 can be produced in two steps, starting from a starting material, comprising a 1.1. , 1-trifluoroalkoxy-aryl or 1,1,1-trifluoroalkoxy-heteroaryl, described in more detail below. In the first step, the trifluoromethyl portion (-CF3) of the starting material is converted to an orthoester part, ie a carbon having three o-aliphatic substituents, to form an orthoester intermediate. In the second step, the ortho ester intermediate is converted to a compound of the Formula, 1. Generally, the first step is carried out by introducing aliphatic oxy reactants, in an amount sufficient to completely displace the fluoride substituents from the starting material. In this way, the Ortho ester intermediates, which have the same or different ("mixed") aliphatic substituents, can be formed using aliphatic oxy-ion sources, such as, for example, metal aliphatic oxides or deprotonated aliphatic alcohols, which are derived from one or more products aliphatic 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 1, 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 trifluorous starting material, which comprises a 1,1,1- trifluoroalkoxy-aryl or a 1,1,1-trifluoroalkoxyheteroaryl, having the following general Formula 2: Ar-0- (CH2) n-CF3 (2) wherein n is the same as described above for Formula 1, ie is from 1 to about 6. Such starting materials are known in the literature and are capable of being prepared by procedures recognized in the art. 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 descriptions of these publications are incorporated herein by reference.

Preparation of the ortho ester intermediates The ortho ester intermediates can be prepared by the use of any aliphatic oxy compound, which can selectively replace the fluoride substituents of the trifluoro starting material, with a desired aliphatic oxide group. Suitable aliphatic oxy compounds include the aliphatic oxides of metals, such as, for example, sodium ethoxide, sodium n-butoxide, tere. -potassium butoxide. Of these, sodium ethoxide, sodium n-butoxide, tertiary sodium butoxide, are preferred. To form the orthoester intermediate, at least three moles of aliphatic oxide need to be supplied per mole of the trifluoro starting material. An excess of the aliphatic oxide can be provided to ensure a more complete reaction. In a preferred embodiment, the first step is carried out by mixing the selected trifluoro starting material, of Formula 2, and the aliphatic metal 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 and 200 ° C, preferably between about 130 and 175 ° C. Reaction times may vary from a few minutes to several days. Ordinary experts in the art will recognize that both the alcohol and the aliphatic metal oxide used in the reaction, as mentioned above, are possible sources of aliphatic oxide ions, which can displace the fluoride substituents from the trifluoro starting material to form orthoesters. When dissolved in solution, the aliphatic oxide ions formed from the metal aliphatic oxide can directly displace the fluoride substituents of the starting material or can 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 can be chosen so that the aliphatic oxide ions formed therein represent desired aliphatic oxy groups of the orthoester. Therefore, to form an orthoester, having three of the same aliphatic oxy-substituents, by the process of the present invention, it is preferred to use an aliphatic metal oxide and an alcohol derived from the same aliphatic oxide ion. In this way, the oxide ions aliphatic formed from any of the metal aliphatic oxide or alcohol, corresponds to the desired aliphatic oxy substituents of the ortho ester product. For example, to form a triethoxy orthoester, a trifluoroalkoxy compound of starting material is reacted with a metal ethoxide and ethanol. Thus, the displacement of the fluoride groups by alkoxide ions which are derived from either the metal ethoxide or the ethanol, leads to the formation of the desired product and the formation of mixed orthoesters is minimized. Mixed orthoesters, if desired, are formed in accordance with the present invention, using metal aliphatic oxides and alcohols which are derived from different aliphatic oxy groups. When aliphatic metal oxides and alcohols are used, which are derived from different aliphatic oxy groups, different mixed orthoesters and non-mixed orthoesters are possible products. However, one of ordinary skill in the art can readily determine and optimize the reaction conditions for preparing the mixed orthoester compounds of the present invention, without undue experimentation. Also, the compounds obtained from the aforementioned reaction can be purified by conventional methods known to those skilled in the art.

In light of this description, one of ordinary skill in the art can easily determine and optimize the reaction conditions for the preparation of the orthoester intermediates of the present invention, without undue experimentation. Also, the compounds obtained from the reaction, mentioned above, can 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 can be used.

Preparation of compounds of Formula 1 from orthoester intermediates The compounds of Formula 1 can be prepared from the ortho ester intermediates, using conventional, acid catalyzed hydrolysis methods. For example, the orthoester intermediate can be dissolved in a solvent and treated with acid to form an ester or acid compound of Formula 1. If an ester or acid compound is formed from the hydrolysis step, it is believed will be determined by the selection of the anhydrous or aqueous solvent. In general, the use of an anhydrous solvent for hydrolysis will result in greater isolation of the ester products. Nevertheless, when the aqueous solvent or the organic / aqueous solvent in mixture is used, the main 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, Ethanol or n-butanol are preferred. Suitable aqueous solvents include mixtures of water and alcohols, such as methanol or ethanol. The THF / alcohol / water mixtures can also be used, such as the 5: 5: 2 THF / alcohol / water mixture. Hydrolysis of esters is a well-known process achieved with an alkali hydroxide, such as sodium, potassium or lithium hydroxide, in an aqueous alcohol medium (such as ethanol or methanol). One of ordinary skill in the art can easily determine and optimize the reaction conditions for preparing an ester or acid compound of Formula 1, from an ortho ester intermediate, without undue experimentation. Generally, the reaction temperatures vary from about 0. at 50 ° C, and the reaction times vary from a few minutes to several hours.

Preparation of halogenated compounds of Formula 1 A halogenated aryloxy ester of Formula 1 can be prepared from a non-halogenated aryloxy ester by employing an additional step of halogenation. Next, the preparation of a halogenated aryloxy acid compound, using an optional hydrolysis step is described. Additionally, the use of halogenated starting materials for preparing the halogenated compounds of Formula 1 will be described. In one embodiment of the present invention, the ester compounds of Formula 1, having an Ar group, comprising a halogenated aryl or a halogenated heteroaryl can be obtained by the method of the present invention, which further comprises the step of halogenating the ester compound of Formula 1. This halogenation step is preferably carried out 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, or in the presence or absence of an acid catalyst. Halogenation agents suitable for use in the present invention preferably comprise reagents, which can selectively halogenate the aryl or heteroaryl portions, in good yield, under moderate Examples of preferred halogenating agents are n-chlorosuccinimide and n-bromosuccinimide. The substitution of aryls and heteroaryls with halogens is well known in the art and can be achieved by conventional methods. Thus, one of ordinary skill in the art can readily determine and optimize reaction conditions to prepare a halogenated ester compound of Formula 1, without undue experimentation. Because the acids of Formula 1 tend to react readily with the halogenating agents, the direct halogenation of the acidic compounds of the present invention is a relatively inefficient method for recovering the desired halogenated acid compounds. However, in another embodiment of the present invention, the halogenated acid compounds of Formula 1 can be obtained by subjecting the corresponding halogenated ester compounds of Formula 1 to a further hydrolysis step. Hydrolysis of the halogenated esters can be achieved, using conventional methods. Those of ordinary skill in the art can readily determine and optimize the reaction conditions for the hydrolysis of the halogenated esters to obtain halogenated acid compounds of Formula 1. Generally, the reaction temperature ranges from about 0 to 50 ° C and the Reaction times vary from a few minutes to several hours. The chlorinated or fluorinated compounds of Formula 1 can also be obtained directly by means of the present method, using starting materials having chlorine or fluorine substituents of aryl or heteroaryl at the site, prior to the formation of the orthoester. In this manner, the chlorinated and fluorinated compounds can be produced without the need for an additional chlorination or fluorination step, after conversion of the orthoester to the compounds of Formula 1. Suitable starting materials, chlorinated and fluorinated, include the following: , 1,1-trifluoroalkoxy-chlorothiophenes, such as 2-chloro-5- (1,1,1-trifluoroethoxy) -thiophene. These starting materials may also include conventional organic substituent parts, 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, which illustrates a five-step process for the purification of the claimed compound, 5-chlorothiophen-2-yloxyacetic acid. The structure of the compound produced in each stage conforms to the analysis of the mass spectrum.

Step 1. The preparation of 2- (2,2,2-trifluoroethoxy) thiophene from 2,2,2-trifluoroethanol. Sodium spheres, washed with hexane (3.2 g, 140 mmol) were added slowly to 2, 2, 2- trifluoroethanol (35 ml, 500 mmol) under a nitrogen atmosphere. The mixture was heated to 55-60 ° C during the addition of the alcohol. Following dissolution of the sodium metal, the excess of 2,2,2-trifluoroethanol was removed under reduced pressure. To the resulting white solid was added copper iodide (I) (13.7 g, 7 mmol) and 2-iodothiophene (14.7 g, 70 mmol). The mixture was heated at 110 ° C for 24 hours and evaporated at 25 ° C. The residue was diluted with hexane and filtered through a pad of silica gel. The filtrate was evaporated to give 7.0 g (55%) of the 2- (2,2,2-trifluoroethoxy) thiophene as a colorless liquid. This material can also be purified by distillation (boiling point of 67 ° C, at 30 mm Hg).

Step 2. Preparation of 2- (2,2-triethoxy) ethoxythiophene from 2-22.2.2-triluoroethoxyptiofen 2- (2,2,2-trifluoroethoxy) thiophene (20 g, 110 mmol) and ethoxide sodium (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 diluted immediately with water (500 ml). The aqueous phase was extracted with four portions of dimethyl ether (200 ml). The organic phases were combined, washed three times with 2N aqueous sodium hydroxide, dried with magnesium sulfate, filtered and evaporated to give 16.5 g (57%) of the 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-triethoxythoxythioethene) 2- (2,2,2-triethoxy) ethoxythiophene (18.4 g, 71 mmol) was dissolved in ethanol (180 ml.) Hydrochloric acid (10 ml) was added and the mixture was stirred for 5 minutes. The reaction was diluted with a solution of saturated aqueous sodium bicarbonate and diethyl ether. The organic phase was washed once with brine, dried with sodium sulfate, filtered and evaporated to give 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-ylacetate (1.13 g, 6 mmol) was placed in acetic acid (20 ml) and N-chlorosuccinimide (0.85 g, 6 mmol) was added. The mixture was stirred for 2 hours and diluted with diethyl ether. The organic phase was washed three times with aqueous sodium hydroxide 2N, dried with magnesium sulfate and evaporated. Purification by silica gel chromatography, eluting with 2: 1 hexane / ethyl acetate, gave 1. 1 g of ethyl 5-chlorothiophen-2-ylaoxyacetate (83%) as a clear, colorless oil. The material can also be isolated by distillation (boiling point of 114 ° C, 2-3 mm Hg).

Step 5. The preparation of 5-chlorothiophen-2-yloxyacetic acid from ethyl 5-chlorothiophen-2-yloxyacetate. The ethyl 5-chlorothiophen-2-yloxyacetate (10.9 g, 49 mmol) was placed in 100 ml of the mix of THF / methanol / water 5: 5: 2, Lithium hydroxide (4.2 g, 98 mmol) was added. The mixture was stirred at room temperature for 18 hours and acidified with 2N aqueous hydrochloric acid to a pH of 2 to 3. The aqueous phase was extracted, 3 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 give 7.75 g (83%) of 5-chlorothiophen-2-yloxyacetic acid.

Claims (20)

1. CLAIMS 1. A method for preparing a compound, having the formula (1): Ar-O- (CH2) n-COOH (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 5, this method comprises the steps of: a) reacting a trifluoroalkoxy compound, of the formula Ar-O- (CH2) n-CF3, with one or more aliphatic oxides, to form an intermediate compound of the formula Ar-O- (CH2) n ~ C- (-OR) 3, where R represents groups aliphatic, the same or different; and b) converting said intermediate compound to form a compound of the 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 an alkyl group, substituted or unsubstituted, straight or branched chain, with Ci up to about C? 5. The method of claim 4, wherein R represents an alkyl group, straight or branched chain, from C2 to C. 6. The method of claim 5, wherein R represents an ethyl, t-butyl or n-butyl group. 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 the formula (1) contains at least one substituent. of a halogen atom in the group Ar. The method of claim 9, wherein the halogenating step is carried out after step (b). 11. The method of claim 9, wherein the halogenation step is performed simultaneously with step (b). 12. A compound, which has the formula (1): Ar-O- (CH2) "- COOR (1) in which Ar represents an aryl or heteroaryl group, unsubstituted or substituted, R represents hydrogen or a group aliphatic, unsubstituted or substituted, 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 group of thiophene. 15. The compound of claim 12, wherein R represents an alkyl group, straight or branched chain, from Ci to about Cio. 16. The compound of claim 15, wherein R represents an alkyl group, straight or branched chain, C2 to C. 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. The compound of claim 18, wherein n is 1. The compound of claim 12, wherein Ar contains one or more halogen substituents. in the group Ar.