MXPA99004323A - Process for the synthesis of benzothiophenes - Google Patents

Abstract

The instant invention provides improved processes for preparing benzothiophenes utilizing methanesulfonic acid.

Description

PROCESS FOR THE SYNTHESIS OF BENZOTOOPHENES This invention relates to the field of pharmaceutical chemistry, and provides an advantageous process for preparing a group of benzothiophenes from dialkoxyacetophenones. The process provides the desired compounds in excellent production on a large scale.

The preparation of benzothioi through a dialkoxy benzothiophene intermediate described previously in U.S. 4, 380, 635, which indicates the intramolecular cyclization of a-. { 3-methoxyphenylthio) -4-methoxyacetophenone in the presence of polyphosphoric acid (PPA). Heating the initial acetophenone material in PPA at about 85 ° C for about 1 hour provides an approximate ; 3: 1 mixture of two isomers, 6-methoxy-2- (4-methoxyphenyl) benzo [b] thiophene and 4-methoxy-2-f4-I methoxyphenyl) benzo [b] thiophene. However, when The reaction is conducted on a manufacturing scale, the isomeric benzothiophenes precipitate and produce a I have a thick paste that can not be shaken properly 'conventional manufacturing equipment.

REF .: 30210 The use of a solvent to solve the problem caused by a paste in a different reaction scheme has been attempted by Guy et al. , Synthesis, 222 (1980). However, when this approach is applied to the present scheme, the addition of a solvent i results in incomplete cyclization of the initial acetophenone, incomplete rearrangement of 6-methoxy-3- (4-methoxyphenyl) benzo [b] thiophene, and Reaction times increased dramatically.

Thus, there is a need for an improved process for the conversion of dialkoxyacetophenone derivatives to benzothiophenes with adequate yields and acceptable reaction times.

The present invention provides a process for the preparation of benzothiophenes using acid ; methanesulfonic This preparation has an intramolecular cyclization of a derivative of I, dialcoxyacetophenone to produce a benzothiophene.

Thus, the invention provides a process for! prepare a compound of formula Ib. wherein the R groups are the same or different, and represent Cj-C6 alkyl; which includes cyclizing a compound of formula II wherein the R groups are as defined above, in the presence of methanesulfonic acid.

Benzothiophene is a key intermediate in the synthesis of raloxifene (a compound of formula III, in where R. and R2 combine to form 1-piperidinyl), which is an estrogen selective receptor modulator, or SERM. In addition to providing a process for the preparation of this intermediate, the present invention further provides a process for preparing a compound of formula III m where: ! i and R_ are independently C-C6 alkyl, or combine to form, with the nitrogen to which they are attached, 1 piperidinyl, pyrrodinyl, met ilpyrrolidinyl, dimethylpyrrolidinyl, or hexamethyleneimino, or the salts 1 or pharmaceutically acceptable solvates thereof: I which includes cyclizing a compound of formula II wherein the R groups are the same or different, and represent C-C6 alkyl, in the presence of methanesulfonic acid.

Many of the starting materials and compounds prepared by the process of this invention are further provided in U.S. 4,133,814 and U.S. 4,380,635, the expositions of which are incorporated herein by reference.

In this document, all temperatures will be set in degrees Celsius. All quantities, ratios, concentrations, proportions and the like shall be established in units of weight, unless otherwise stated, except for solvent ratios, which are in units of volume.

The term "C.-C6 alkyl" represents a chain of linear or branched alkyl having from one to six carbon atoms. Typical C.sub.1 -C.sub.6 alkyl alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, t-butyl, pentyl, isopentyl, hexyl. methylpentyl, and the like. The term "C.-C / 'alkyl represents a linear or branched alkyl chain having from one to four carbon atoms, and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, ses-butyl, i- butyl, and t-butyl.

The process for preparing compounds of formula I as provided by the present invention is shown below in Scheme I: Scheme I C reation methanesulphonic acid, solvent Rearrangement K2 metansu-.fon-.co acid, solvent the' The complete reaction process comprises a first cyclization step and a subsequent rearrangement step. A compound of formula I is the desired product. The starting materials (compounds of formula II) for the processes of the present invention could be obtained by a number of routes, including those set forth in U.S. 4,133,814 and U.S. 4,380,635.

Solvents including mixtures of solvents and co-solvents employed in the practice of the present invention could affect the entire reaction, including reaction products and complete yield. Typically, the selection solvent is a very weak base. The preferred solvent for the practice of the present invention is an aromatic solvent, with reasonable results obtained in aliphatic and chlorinated solvent. Examples , solvents include but are not limited to toluene, heptane, xylene, chlorobenzene, dimethoxyethane, and tetrachloroethylene. Toluene is preferred for * practice of the present invention.

The cyclization reaction in the first step occurs in the presence of methanesulfonic acid, and in | General appears approximately 50-100 times faster than the subsequent rearrangement reaction.

The cyclization reaction rate could increase by increasing the amount of methanesulfonic acid used in the reaction mixture. The reaction typically runs under reflux with the azeotropic removal of water.

According to the invention, the cyclization reaction is conducted at temperatures from about 50 ° C to about 110 ° C, preferably from about 75 ° C to 110 ° C, and more preferably from about 80 to 110 ° C.

The initial acetophenone material (a component of formula II) is heated in the presence of methanesulfonic acid and toluene for at least 30 minutes, and preferably about 60 to 300 minutes. As practiced recently, acetophenone is cyclized and rearranged at about 90 ° C for about 3-5 hours. The addition of more heptane at this time is optional, but could provide an increased reaction yield. After the addition of heptane, it is preferred to maintain the temperature | around 90"C.

Several side demethylation products may be formed during cyclization reactions and rearrange. Structures of 4 different demethylation side products are provided in Scheme II below: Scheme II The isomers A and B are derived from a compound of formula la, while the isomers C and D are derived from a compound of formula I. The ratio of the isomers A: B: C: D in a typical reaction mixture was approximately 1: 1: 9: 9. The identity of the isomer was generally confirmed by HPLC. The ratio of the isomer, and by the final yield, is determined by the kinetically controlled cyclization reaction. Using methanolic acid in toluene, a ratio of preferred isomer of 75:25 to 80:20 (I / la ') was obtained in the cyclization step, compared to an isomer ratio of 75:25 obtained when polyphosphoric acid is used in the cyclization step. Furthermore, we did not observe the balance between ortho and para isomers during this process.

The rearrangement reaction is a thermodynamically controlled reaction. The equilibrium constants for the reaction are as follows: K. is > 100, while K2 is approximately 7-9. Using methanesulfonic acid and toluene / heptane as the solvent system, a compound of formula precipitates as it forms in the reaction mixture, thus conducting the reaction to completion. The rearrangement of the isomer no! desired, a compound of formula Ib ', was 3-5 times faster than the rearrangement of the desired isomer, a; composed of formula Ib. i Heptane is an additionally preferred solvent, which affects the crystallization of the benzothiophene products. This crystallization produces a reduction in solubility, thereby driving the equilibrium of the reaction. The heptane is better added to the reaction mixture before the Balance .

A suitable solvent or mixture of solvent 1 could be further added to the reaction mixture at the end of the rearrangement reaction to quench the! reaction. An example of a suitable solvent would include but not be limited to isopropanol (IPA), and the like. This addition of the solvent reduces the solubility of the product, as well as improves the purity thereof.

The entire process could be operated as a "one-bin" synthesis, from batch to batch, semi-continuously, continuously, and the like. An expert in the art would appreciate the differences "between these forms of operation, including that the reaction would be employed for a given purpose, for example, in the operation | semi-continuous or continuous the initial material and solvent are fed to a packed column of | solid acid resin. The recovery and isolation of the excess solvent and product could be carried out by distillation. In addition, the reaction optionally takes place in the presence of an organic solvent that forms an azeotrope with water, and thus facilitates the removal of by-products by azeotropic distillation during the reaction process. Examples of such solvents that could be employed include aromatic hydrocarbons such as benzene, toluene, xylene, and the like.

The benzothiophene product could be isolated with a standard extraction technique by adding water, separating the layers, optionally extracting the aqueous layer again with the organic solvent, combining the organic layers, and concentrating the combined organic layers. When the starting material is the methoxy derivative, the desired 6-alkoxy compound crystallizes in the concentrated solvent while the 4-alkoxy isomer remains in solution. The desired 6-alkoxy compound i could be collected by filtration.

In a preferred cyclization process according to the invention, the starting material is oi- (3-1-methoxyphenylthio) -4-methoxyacetophenone, which produces, in 'the technique after cyclization and rearrangement, 6- methoxy-2- (4-methoxyphenyl) benzo [b] thiophene. This material could subsequently be converted into a compound of formula III, such as, for example, 6-hydroxy-2- (4-hyd ro x y nyl) -3- [4 - (2-am inoet-oxy) benzoyl] benzo [b] t iofeno. The conversion ~ of 6-alkoxy-2- (4-alkoxyphenyl) benzo [b] thiophene to compounds of formula III could be carried out according to the reactions as provided in U.S. 4,380,635.

Ester (R) groups of appropriate activation are known in the art. Numerous reactions for the formation and removal of protective groups are described ! in a number of standard works that include, for example, Protective Groups ín Organi c Chemistry, Plenum Press (London and New York, 1973); Green, T.., Pro tecti ve Groups in Organi c Syn thesi s, Wiley, (New York, 1981); and The Pep tides, Vol. I, Schrooder and Lubke, Academic Press (London and New York, 1965). Methods for non-regioselective removal of hydroxy protecting groups, particularly methyl, are known in the art. Compounds of formula III that have previously been protected in the 6- and 4'-position with methoxy could be selectively cut to generate compounds of formula III with a 4'-methoxy group. In general, the procedure for cutting a group, methoxy in the 4 'position involves the combination of a 1 substrate 6-, 4'-dimethoxy with a demethylation reagent selected from the group of boron tribromide, boron trichloride, or boron triiodide, or with A1C13 and various thiol reagents, such as EtSH. The reaction it conducts under an inert atmosphere such as hydrogen, with one or more moles of the reactant per mole of the methoxy group to be cut.

The solvents suitable for the deprotection reaction are the solvents or mixture of solvents which remain inert throughout the demethylation reaction. Halogenated solvents such as dichloromethane, 1,2-dichloroethane, and chloroform, or aromatic solvents such as benzene or toluene are preferred. The temperature used in this reaction should be sufficient to effect the "completion of the demethylation reaction, however, it is advantageous to keep the temperature below 0 ° C to maximize the selectivity of the 4'-methoxy group and avoid formation. of undesirable byproducts especially the product analogue 6,4'-dihydroxy increasing from excessive demethylation Under the preferred reaction conditions, a selectively dealkylated product will be formed after stirring the reaction for about 1 to 24 hours. preferred involves the use of boron tribromide in the amount of about 1.5 moles with one mole of the 6-, 4'-dimethoxy substrate in dichloromethane under a nitrogen atmosphere at a temperature of -20 ° C for 1 to 4 hours.

The compounds of formula III are very frequently administered in the form of salts by addition of acid. The salts are conveniently formed, as is usual in organic chemistry, by reacting the compound prepared according to this invention with a suitable acid. The salts are formed rapidly in high yields at moderate temperatures, and are often prepared by isolating only the compound from a suitable acid wash as the final step of the synthesis. For example, salts could be formed with inorganic or organic acids.

| Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, and the like. You could also use the 1 salts derived from organic acids, such as mono aliphatic and dicarboxylic acids, hydroxyalkanoic and hydroxyalkanedioic acids, acids. aromatics, aliphatic and aromatic sulfonic acids.

Such pharmaceutically acceptable salts therefore include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate. dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutoxide, β-hydroxybutyrate, butyn-1,4-dioate, hexin-1,4-dioate, caprate , caprylate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, hippurate, lactate, malate, maleate, hydroxyalate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, monohydrogen phosphate, dihydrogen phosphate , metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzenesulfonate, p-bromophenylsulfonate,! c 1 or r ob e n c e n a n d a n d a n d a n d a n d, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, xylene sulphonate, tartarate, and the like. A preferred salt is the hydrochloride salt.

The following compounds of Formula III are provided as an additional illustration of the complete process i set forth herein: 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-dimethylamino- ethoxy) -benzoyl] enzo [b] thiophene; 3- [4- (2-ethoxymethylaminoethoxy) benzoyl] -6-idroxy-2-. { 4- hydroxyphenyl) benzo [b] thiophene; 3- [4- (2-ethoxyl isopropylaminoethoxy (benzoyl] -6-hydroxy-2- (4-hydroxyphenyl)) benzo [bl-thiophene; 3- (4- (2-dibutylaminoethoxy) benzoyl] -5-hydroxy-2- (4-hydroxyphenyl)) benzo [b] thiophene; 3- [4- (2- (1-methylpropyl) methylaminoethoxy] benzoyl] -6-hydroxy-2- (4-hydroxyphenyl)) benzo [b] thiophene; i 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- [2-di (2-methyl-propyl) aminoetho]] benzoyl] benzo [b] thiophene; i 6- idroxy-2- (4-idroxyphenyl) -3- [4- (2-pyrrolidino-ethoxy) benzoyl] benzo [b] thiophene; i 6-hydroxy-2- (4-hydroxy phenyl) -3- [4- (2-pi? eridino-i ethoxy) benzoyl] benzo [b] thiofen; 6-hydroxy-2 - (4-h-idroxy-phenyl) -3- [4 - (2-morpholinoethoxy) benzoyl] benzo [b] thiophene; 3- [4- (2-hexamethyleneiminoethoxy) benzoyl] -6-hydroxy-2- (4-hydroxyphenyl) benzo [b] thiophene.

The following Example is provided to better elucidate the practice of the present invention and should not to be interpreted in any way as limit of scope Of the same. Those skilled in the art will recognize that various modifications could be made as long as it does not deviate from the spirit and scope of the invention. All publications and patent applications mentioned ID, in the specification are indicative of the level of the experts in the art to which this invention belongs.

EXAMPLES , All the experiments were run under positive pressure of dry nitrogen. All solvents and fifteen! Reagents were used as they were obtained. The percentages are generally calculated on a weight basis (w / w); except for high-performance liquid chromatography (HPLC) solvents that are calculated on a volume (v / v) basis. The nuclear magnetic resonance spectrum of proton (? NMR) and the 13C nuclear magnetic resonance spectrum (; 'C NMR) were obtained on a Bruker AC-300 FTNMR spectrometer at 300.135 MHz or a GE spectrometer QE-300 at 300.15 MHz. Rapid chromatography on silica gel could be performed as described by Still et al. using Silica Gel 60 (230-400 mesh, E. Merck).

Still et al. , J. Org. Chem. , 43, 2923 (1978). The elemental analyzes for carbon, hydrogen, and nitrogen were determined in a Control Equipment Corporation 440 Elemental Analyzer. The elemental analyzes for sulfur were determined in a Brinkman Clori etric Elemental Analyzer. The melting points were determined in open glass capillaries in a , hot air bath melting point Gallenkamp or a Mettler FP62 Automatic instrument, and are not corrected. The field of the desorption mass spectrum (FDMS) was obtained using a Varian Instruments VG 70-SE or "VG ZAB-3F mass spectrometer." The high-resolution free atom bombardment (FABMS) mass spectrum was obtained using a Varian Instruments VG ZAB-2SE mass spectrometer.

The yield of 6-me t ox i - 2 - (4 - 'methoxypheni 1) benzo [b] thiophene could be determined by 'High performance liquid chromatography (HPLC) compared to an authentic sample of this compound prepared by published synthetic routes. See, for example, U.S. Pat. No. 4,133,814.

EXAMPLE 1 40 g of a- (3-methoxyphenylthio) -4-methoxyacetophenone, 5 g of methanesulfonic acid, and 120 ml of Toluol (Drum Stock) were added to 1 liter, 3-neck round bottom flask, equipped with a reflux condenser and a Dean Stark trap. The trap was pre-filled with toluene, or extra solvent was added to the reactor, the mixture was heated to reflux and stirred for 2 hours while the water was azeotropically removed. This mixture was then cooled to 90 ° C. Additional 9 g of methanesulfonic acid were added to the reaction mixture, which was stirred for 3-5 hours at 90 ° C. 56 ml of heptane (Drum Stock) were added during 5-20 hours. The mixture was then stirred at 90 ° C for 1 hour, then stirred at 80 ° C for 3-4 hours. , of isopropanol (IPA) (Drum Stock) was added during -20 minutes, and then refluxed for 30 minutes at approximately 835C. The mixture was then cooled to 0'C at a speed no faster than 50"C per hour. 'After this was stirred for at least 1 hour at 0 ° C, it was filtered, washed twice with 75 ml 70/30 - (Toluol / IPA ), and dried overnight at 60 ° C under full vacuum i Yield = 70%, 100% power, 0.4% demethylation.

It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims (11)

1. A process for preparing a compound of formula Ib Ib wherein the R groups are the same or different and represent Ca-C6 alkyl, characterized in that it comprises: cyclizing a dialkoxy compound of formula II II in the presence of methanesulfonic acid.

2. A process according to Claim 1, characterized in that it also comprises preparing a compound of formula I RO f -OR wherein the R groups are the same or different and represent C-Cd alkyl, rearregating a compound of formula Ib Ib

3. A process according to Claim 1, characterized in that R is methyl.

4. A process according to claim 1, characterized in that it also comprises the addition of toluene.

5. A process according to claim 4, characterized in that it also comprises the addition of heptane.

6. A process according to Claim 5, characterized in that it also comprises the addition of isopropanol.

7. A process according to claim 1, characterized in that the cyclization is carried out at a temperature of about 70 ° C to about 90 ° C.

8. A process according to claim 1, characterized in that the process is carried out as a batch operation.

9. A process according to Claim 1, characterized in that the process is carried out as a continuous operation.

10. In a process for preparing a compound of formula III III where: R? and R 2 -on independently C 1 -C 6 alkyl, or combine to form, with the nitrogen to which they are attached, piperidinyl, pyrrolidinyl, methylpyrrolidinyl, dimethylpyrrolidinyl, or hexamethylene, or the pharmaceutically acceptable salts or solvates thereof; characterized in that the improvement comprises: cyclize a compound of formula II - - where the R groups are the same or different, they represent C.-Cß alkyl, in the presence of methanesulfonic acid.

11. A process according to Claim 10, characterized in that R is methyl.