MXPA00009477A - PROCESS FOR PRODUCING 5-HYDROXYBENZO[b]THIOPHENE-3-CARBOXYLIC ACID DERIVATIVES - Google Patents

Abstract

Benzothiophenic acid derivatives (see formula I) which are useful as starting materials for producing drugs;and a process for producing 5-hydroxybenzo[b]-thiophene-3-carboxylic acid derivatives (see formula VI), which are specific PGD2 antagonists, by using the above derivatives (see formula I).

Description

PROCESS FOR PREPARING DERIVATIVES OF 5-HYDROXYBENZO [b] IOFEN-3-CARBOXYLIC ACID TECHNICAL FIELD The present invention relates to 5-hydroxybenzo [b] thiophene-3-carboxylic acid derivatives which are key starting materials for producing compounds useful in the field of pharmaceuticals.

BACKGROUND OF THE SUBSTANCE The 5-hydroxybenzo [b] thiophene-3-carboxylic acid derivatives of the general formula (I): where R is hydrogen or a hydroxy protecting group are important starting materials in the synthesis of pharmacologically active compounds. For example, a compound of formula (I) is essential in the synthesis of the benzothiophenecarboxamide derivatives of the general formula (VI): where R is as defined above and X is hydrogen or alkyl. The benzothiophenecarboxamide derivatives are specific PGD2 antagonists and known to be useful as a drug in the treatment of various diseases related to mast cell dysfunction caused by excessive production of PGD2 / eg, systemic mastocytosis, systemic activation disorder of mast cells, tracheal contraction, asthma, allergic rhinitis, allergic conjunctivitis, urticaria, lesions due to ischemic reperfusion, inflammation, and atopic dermatitis (WO97 / 00853, PCT / JP97 / 04527 (098/25919)). Among the compounds of the formula (VI), a compound where OR is 5-hydroxide and X is hydrogen (hereinafter, referred to as "Compound A") has a particularly high antagonistic effect on PGD2, showing excellent anti-nasal occlusion activity, and is contemplated as a promising drug for treating nasal occlusion.

DESCRIPTION OF THE INVENTION A process for preparing the aforementioned compound is illustrated by the following scheme of the reaction (098/25919).

To clinically apply compound A widely, it is essential to establish a process to prepare a. starting material, the compound (I), which is a safe, efficient and industrially applicable process.

However, it is difficult to synthesize the benzothiophene derivatives having the 5-hydroxy group similar to the compound (I) and there have been no industrially applicable methods here. Existing methods involve several complicated processes and are inefficient and low performance. For example, there have been methods where 5-acetoxybenzo [b] thiophene is brominated to produce 3-bromo-5-acetoxybenzo [b] thiophene, which in turn is re-protected in the 5-acetoxide group with a benzyl group for to produce 3-bromo-5-acetoxybenzo [b] thiophene, which is followed by the magnesium metallization, the introduction of carbon dioxide and the extraction of the benzyl group (J. Chem. Soc. (C)., 1967, 1899- 1905); or 5-bromobenzo [b] -thiophene was subjected to the Friedel-Crafts reaction to produce 3-acetyl-5-bromobenzo [b] thiophene, which is followed by oxidation with sodium hypochlorite to produce 5-bromobenzo [b] acid ] thiophene-3-carboxylic acid (Nippon-Kagaku Zasshi Vol. 86, No. 10, 1067-1072 (1965), J. Chem. Soc. (C), 1967, 2084-2089). 5-Hydroxybenzo [b] thiophene-3-carboxylic acid or 5-acetoxybenzo [b] thiophene-3-carboxylic acid are then synthesized starting with the products of the above reactions. However, the starting material such as 5-hydroxybenzo [b] -thiophene or 5-bromobenzo [b] thiophene is not commercially available and has to be synthesized from an appropriate reagent (eg J. Am. Chem. Soc, 57, 1611 (1935), J. Heterocyclic Chem., 25, 1271 (988)) in all cases, the longest and most complex synthetic process has been made.

The present invention solves the problems of the existing methods and provides a method for the preparation of the compounds of the formula (I), such method is industrially applicable, efficient and safe.

Thus, the present invention provides a process for the preparation of a compound of the formula (I): where R is hydrogen or a hydroxy-protecting group, or a reactive derivative thereof comprising subjecting the 4-mercaptophenol to the reactions for the introduction of a propargyl group and protecting the hydroxyl group to produce a compound of the formula ( II): wherein R1 is a hydroxy protecting group; oxidizing the compound (II) to produce a compound of the formula (III): where R1 is a hydroxide protecting group; subjecting the compound (III) to the thermal rearrangement reaction to produce a compound of the formula (IV): where R1 is as defined above; and subjecting the compound (IV) to oxidation in the form of hydroxymethyl group steps and optionally deprotection.

The present invention also provides a process for preparing a compound of formula (I): where R is hydrogen or a hydroxy protecting group or a reactive derivative thereof comprising subjecting the 5-hydroxybenzo [b] thiophene to a protection reaction to produce a compound of the formula (VII): where R is a hydroxy protecting group; reacting the compound (VII) with acetyl halide under the conditions for the Friedel-Crafts reaction to produce a compound of the formula (VIII): where R is a hydroxy protecting group; and subjecting the compound (VIII) to the oxidation of the acetyl group and optionally to the deprotection.

The present invention further provides a method for the preparation of the aforementioned 5-hydroxybenzo [b] thiophene-3-carboxylic acid derivative of the general formula (VI) using a compound of the formula (I). Thus, the present invention provides a process for preparing a compound of formula (VI): where R is as defined above and X is hydrogen or alkyl, and the double bond represents either an E- or Z- configuration, or a pharmaceutically acceptable salt thereof or a hydrate thereof, comprising subjecting a compound of the formula (I) or a reactive derivative thereof to the following reactions: (1) the reaction with a compound of the formula (V) wherein X is hydrogen or alkyl; or (2) the reaction with a compound of the formula (V): Or a salt thereof followed by oxidation and reaction with an ylide under conditions for the ittig reaction; Y (3) optionally the deprotection- THE BEST MODALITY FOR THE PRACTICE OF INVENTION The terms used here are defined below. The term "hydroxy protecting group" means alkyl, alkoxyalkyl, acyl, aralkyl, alkylsulfonyl, alkyl substituted silyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl or tetrahydropyranyl.

The term "alkyl" means linear or branched C? -C20 alkyl, particularly, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl, and the like, and C? -C6alkyl is preferred.

The term "alkoxide" means linear or branched Ci-Ce alkoxide, particularly, methoxide, ethoxide, n-propoxide, i-propoxide, n-butoxide, i-butoxide, s-butoxide, t-butoxide, n-pentyloxide, i- pentyloxide, neopentyloxide, s-pentyloxy, t-pentyloxy, n-hexyloxy, neohexyl oxide, i-hexyloxy, s-hexyloxy, t-hexyloxy and the like, and C3-C6-alkoxy is preferred.

The term "alkoxyalkyl" means the alkyl group substituted by the alkoxide group, including methoxymethyl, ethoxymethyl, methoxyethoxymethyl, ethoxyethyl, methoxypropyl, and the like.

The term "acyl" means the Ci-Cu acyl derived from the aliphatic carboxylic acid or the aromatic carboxylic acid. Examples of the acyl derivative of the aliphatic carboxylic acid include acetyl, chloroacetyl, trichloroacetyl, propionyl, butyryl, valeryl, and the like, and examples of acyl derived from the aromatic carboxylic acid include benzoyl, p-nitrobenzoyl, p-methoxybenzoyl, p-bromobenzoyl , toluoyl, naphthoyl and the like.

The term "aryl" means phenyl, the group of naphthyl or polycyclic aromatic hydrocarbons and the like. In sum, the aryl can be substituted by the following substituents.

Examples of substituents include alkyl such as methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or tert-pentyl, lower alkoxide such as methoxide or ethoxide, halogen such as fluorine, chlorine, bromine or iodine, nitro, hydroxide, carboxy, cyano, sulfonyl, amino, lower alkylamino such as methylamino, dimethylamino, ethylmethylamino or diethylamino, and the like. The aryl group may have one or more substituents in any of the possible positions. Specific examples of aryl include 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 4-pentylphenyl, 4-carboxyphenyl, 4-acetylphenyl, 4- (N, N-dimethylamino ) phenyl, 4-nitrophenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-iodophenyl and the like.

The aryl group in the "aralkyl", "arylsulfonyl", "aryloxycarbonyl" or "aralkyloxycarbonyl" described above may have similar substituents as defined above.

The term "aralkyl" means an alkyl group substituted by the aryl group, and even benzyl, 4-methylbenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, naphthylmethyl, phenethyl, and the like.

The term "alkylsulfonyl" means a sulfonyl group substituted by the alkyl group, and even methanesulfonyl, ethanesulfonyl and the like.

The term "arylsulfonyl" means a group substituted by the aryl group, and even benzenesulfonyl, p-toluenesulfonyl, and the like.

The term "silyl substituted by alkyl" means silyl substituted by mono-, di- or tri- for example, methylsilyl, dimethylsilyl, trimethylsilyl, t-butyldimethylsilyl, and the like.

The term "alkoxycarbonyl" means methoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl, and the like.

The term "aryloxycarbonyl" means phenoxycarbonyl, and the like.

The term "aralkyloxycarbonyl" means benzyloxycarbonyl, and the like.

Although all of the hydroxy protecting groups mentioned above are preferred as the hydroxy protecting group shown by R1, R2 or R in the respective above formula, aryl sulfonyl is more preferred and benzenesulfonyl is particularly preferred among them.

Examples of the salts of the compound of the general formula (VI) include the alkali metal salts such as the lithium salt, the sodium salt or the potassium salt and the like, the alkaline earth metal salts such as the salt of calcium and the like, the ammonium salt, the salts with an organic base such as tromethamine, trimethylamine, triethylamine, 2-aminobutane, tert-butylamine, diisopropylethylamine, n-butylmethylamine, n-butyldimethylamine, tri-n-butylamine, cyclohexylamine, dicyclohexylamine, N-isopropylcyclohexylamine, furfurylamine, benzylamine, methylbenzylamine, dibenzylamine, N, N-dimethylbenzylamine, 2-chlorobenzylamine, 4-methoxybenzylamine, 1-naphthalenemethylamine, diphenylbenzylamine, triphenylamine, 1-naphthylamine, 1-aminoanthracene, 2-aminoanthracene, dehydroabietylamine, N-methylmorpholine, or pyridine, or amino acid salts such as the usin salt or the arginine salt.

The salts of the amino alcohol of the formula (V) include salts with organic acid such as benzoic acid, etc., and mineral acid such as hydrochloric acid, sulfuric acid, etc.

The final compound of the present invention is represented by the formula (VI) as described above, in which the double bond of the alkenylene side chain (the 5-heptenylene chain) can be in the E- or Z configuration -.

The method of the present invention is described below in more detail. When a substitute (s) possibly interferes with the present reaction, it can be appropriately protected and then unprotected at a desired stage. Such protection or deprotection can be carried out by a method known in the art.

Process I where R and R are as defined above.

[Step 1] This step refers to the introduction of a propargyl group in the mercapto group of 4-mercaptophenol (1) and the protection of the hydroxyl group.

The introduction of a propargyl group was carried out using a propargyl halide such as propargyl bromide, propargyl chloride and the like in the presence of basic agents. The reaction can be carried out within several tens of minutes at several hours at room temperature using, as a basic agent, an organic base such as potassium carbonate, sodium carbonate or the like, or an organic base such as triethylamine, pyridine, 4-dimethylaminopyridine or the like in a solvent such as ketone, ethyl acetate, tetrahydrofuran, acetonitrile, or the like.

When a strong base such as potassium hydroxide or sodium hydroxide is used, these can also be made in a two-phase solvent system such as toluene-water or xylene-water.

The protection of the hydroxyl group can be conducted using an ordinary hydroxy protecting group in a conventional manner. The preferred protecting groups for use in the present method are those which do not undergo changes during the oxidation reactions in the 2nd and 4th steps of the present process and the 2nd step of the next IV process for the preparation of the compound of the formula (VI) and also during the Wittig reaction of step 3 of said process, and can be easily deprotected in the 4th step to give leaving groups which are easily separable from, for example, Compound A for the purification thereof, corresponding to a compound of the formula (VI) where OR is 5-hydroxide, X is hydrogen and the double bond is in the Z- configuration. Examples of such is a hydroxy protecting group includes alkyl, alkoxyalkyl, acyl, aralkyl, alkylsulfonyl, arylsulfonyl, alkyl substituted silyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl or tetrahydropyranyl.

Considering the requirements that a protecting group should survive during the Wittig reaction conducted under strong basic conditions, it is easily deprotected, for example, in the 4th step for the preparation of compound A, and it is separated from compound A, arylsulfonyl is more preferred and Benzenesulfonyl is particularly preferred.

The benzenesulfonyl group is relatively stable to the base in the anhydride solvents and, in the deprotection, yields the benzenesulfuric acid which is soluble in water and is easily separated from the final product of the formula (VI). The protection and deprotection can be carried out by a method known in the art. For example, in the case of the benzenesulfonyl group, the introduction of the benzenesulfonyl group is carried out in a manner similar to the introduction of the propargyl group using the benzenesulfonyl chloride.

[Step 2] This step refers to the oxidation of compound (II). The oxidation methods which are used, for example, hydrogen peroxide - acetic acid (J. Am, Chem. Soc., 87, 1109-1114 (1965), hydrogen peroxide - titanium chloride ( III) (Synthesis 1981, 203-206), m-chloroperbenzoic acid (Org Synth., 64, 157-163 (1985)), or sodium metaperiodate (J. Org. Chem., 27, 282-284 ( 1962)) In the present step, it is preferred to use a slightly excessive amount of 30% aqueous hydrogen peroxide in an alcohol solvent such as a solution of ethanol, methanol, isopropanol or tert-butanol containing formic acid. performed within several tens of minutes at several hours under cooling or at room temperature.

[Step 3] This step relates to the conversion of the compound (III) into the hydroxymethyl compound (IV) by the thermal rearrangement reaction. The thermal rearrangement reaction is this step is carried out according to the method described in J.C. S. Chem. Comm. , 1974, 848-849. Examples of preferred solvents for this reaction include dioxane, 1,2-dimethoxyethane, propyl acetate and 3-pentanone.

The reaction is carried out by refluxing in a solvent for several hours followed by the addition to the resulting intermediate of an acid (p-toluenesulfonic acid, methanesulfuric acid, sulfuric acid, etc.) [Step 4] This step refers to the oxidation of the compound (IV) to supply carboxylic acid (I). Oxidation can be carried out either directly or in a stepwise manner. Examples of oxidizing agents for. -converting a primary aromatic alcohol to the corresponding carboxylic acid directly include chromic acids (Synthesis 1986, 285-288), potassium permanganate (J. Org. Chem., 18, 806-809 (1953)) and ruthenium oxides (JCS Chem. Comm., 1979, 58-59)). However, these methods have disadvantages not only in production but also in the following matters. For example, the reaction time is long, the detoxification treatment of the oxidizing agent is needed in the next reaction, the reagents are unstable and / or involve complicated operations.

On the contrary, in some cases, an oxidation in the form of steps where a primary alcohol is oxidized to an aldehyde and then to a carboxylic acid which may be advantageous in terms of production. In general, the oxidation of the alcohol to the aldehyde has been carried out using an oxidizing agent of the chromic acid series, for example, the Jones reagents (J. Org. Chem., 40, 1664-1665 (1975)), Collins reagents (JCS Chem. Comm., 1972 1126)), pyridinium chlorochromate (Tetrahedron Lett., 2647-2650 (1975)). A method using manganese dioxide (Helv. Chim. Acta., 39, 858-862 (1956)) or dimethyl sulfoxide (S ern oxidation, J. Org. Chem., 43, -2480-) is also known. 2482 (1978)). However, these existing methods have disadvantages. For example, chromic acids are toxic to the human body and after use must be detoxified. In addition, the oxidation of Swern using dimethyl sulfoxide-oxalyl chloride is not suitable for large-scale production because it is produced by the generation of harmful carbon monoxide for workers and the sulfurous smell and this must also be carried performed at low temperature, for example, between -50 ° C and -78 ° C.

The alcohol (IV) can be converted into aldehyde (IV) more quantitatively by a method where an alcohol (IV) is oxidized with an oxidizing reagent such as oxoacid halo in the presence of 2, 3, 6, 6-tetramethylpiperidin- 1 -oxyl or the like (referred to as "TEMPOs") according to the description in the literature (for example, J. Org. Chem., 52, 2559-2562 (1987)), how the problems of the existing methods are solved . Examples of usable TEMPOs include 2, 2, 6, 6-tetramethylpiperidin-1-oxyl, 4-methoxy-2, 2,6,6,6-tetramethylpiperidin-1-oxyl, 4-acetylamino-2,2,6,6 -tetramethylpiperidin-l-oxyl, 4-benzoyloxy-2, 2,6,6-tetramethylpiperidin-1-oxyl, and 4-cyano-2,2,6,6-tetramethylpiperidin-1-oxyl. Examples of usable haloalkoxy acids include sodium hypochlorite, sodium hypobromite, sodium bromide and highly bleachable powders. A solution of an oxidizing agent can be adjusted to, for example, pH 8.5 to 9.5 with a mineral acid such as sodium hydrogen carbonate, hydrogen chloride or sulfuric acid. Alternatively, a solution of an oxidizing agent may be added in the presence of sodium hydrogen carbonate. The reaction can be performed within several minutes to several tens of minutes at the temperature from cooling on ice to room temperature in a solvent such as ethyl acetate, acetonitrile or dichloromethane.

When the reaction solution containing the resulting aldehyde (IV) is acidified and the sodium chloride and the aqueous hydrogen peroxide are added thereto, the aldehyde is converted into the carboxylic acid under ice cooling within several tens of minutes to several hours.

If desired, the product can also be subjected to the deprotection of the 5-hydroxide protecting group and / or the reversal within the reactive derivatives in the 3-carboxyl group. Such a "reactive derivative" includes the corresponding acid halides (e.g., chloride, bromide, iodide), acid anhydrides (e.g., mixed acid anhydride with chromic acid or acetic acid), esters (e.g. succinimide ester), and the like, and includes the acylating agents generally used for the acylation of the amino group. For example, to obtain the acid halides, a carboxylic acid reacts with the thionyl halide (for example, thionyl chloride), phosphorus halide (for example, phosphorus trichloride, phosphorus pentachloride), oxalyl halide (for example, example, oxalyl chloride), or the like, according to a known method (eg, Shin-jikken Kagaku Koza, vol 14, p.1787 (1978); Synthesis 852-854 (1986); Shin-jikken Kagaku Koza vol. 22, p. 115 (1992)).

Process II vp v where R and R2 are as defined above. [step 1] This step refers to the protection of the 5-hydroxide group of the compound (7).

The compound (7) as the starting material of the present step is known in the literature (J. Am. Chem. Soc., 57, 1611-1616 (1935), Ann. Chem., 527, 83-114 (1938). , J. Am. Chem. Soc., 78, 5351-5357 (1956), J. Org. Chem., 41, 1118-1124 1976)). The hydroxyl group of compound was appropriately protected in a manner similar to that described in the 1st step of process I above. For example, when the benzenesulfonyl group was used, the compound was added to the benzenesulfonyl chloride in the presence of an inorganic base such as sodium carbonate or potassium carbonate, or an organic base such as triethylamine or tripropylamine. The example of the preferred solvent includes acetone, ethyl acetate and tetrahydrofuran. The reaction was performed within several minutes to several hours at the temperature from room temperature to the boiling point of the solvent. The compound (VII) can also be synthesized by a widely known method, commonly known as "The Schotten-Baumann reaction".

[Step 2] This step refers to the introduction of the acetyl group to the 3-position of the compound (VII) by the Friedel-Krats reaction. The introduction of the acetyl group is, for example, carried out using the acetyl or acetyl bromide in the presence of a catalyst, for example, a Lewis acid such as aluminum chloride, ferric chloride, zinc chloride, tin chloride and boron trifluoride. The example of a usable solvent includes carbon disulfide, nitrobenzene or halogenated hydrocarbons such as methylene chloride and ethylene chloride. The reaction is generally carried out within several hours at the temperature of cooling with ice at room temperature. The 2-acetyl compound produced slightly as a by-product is easily separated by recrystallization. [step 3] This step refers to the conversion of the compound (VIII) into a carboxylic acid (I) or a reactive derivative thereof through the oxidation of the acetyl group in the presence of a salt of the hypohalose acid. The examples of the hypohalogenite Preferred include the alkali metals or the salts of the alkaline earth metals of the hipphobic acids, and the potassium, sodium or calcium salt of the hypochlorous or hypobromous acid is especially preferred.

In an aqueous solution of such a salt, the oxidation progresses at a relatively low temperature. However, dioxane or 1,2-dimethoxyethane can be used as a solvent to increase the solubility of the compound to be oxidized. The reaction was performed within several hours to several tens of hours at room temperature or with heat.

Process III VI where R and X are as defined above and the double bond represents the E- or Z- configuration.

This process refers to the synthesis of a compound of the formula (VI) by the reaction of a compound of the formula (I) or a reactive derivative thereof obtained in the above process I or II with a compound of the formula (V) The compound (V) used in the present process is obtained according to the method described in Japanese Patent Publication (KKOKOKU) NO. 6-23170 (23170/1994).

The reaction can be carried out under the ordinary conditions for the acylation of the amino group. For example, when a carboxylic acid halide is used, the reaction is carried out in a method commonly known as "The Schotten-Baumann reaction". In general, the carboxylic acid halide was added dropwise to an aqueous alkaline solution of amine with stirring and under cooling while stirring the acid generated with alkali. Alternatively, when a carboxylic acid is used as a non-free acid a reactive derivative, the reaction can be conducted conventionally in the presence of a linker generally used in the binding reaction between an amine and a carboxylic acid such as dicyclohexylcarbodiimide (DDC) , l-ethyl-3- (3-dimethylaminopropyl) carbodiimide or N, N '-carbonyldiimidazole.

Process IV rx VI where R and X are as defined above and the double bond represents the E- or Z- configuration.

[Step 1] This step relates to the preparation of a compound of the formula (IX) by the reaction of a compound of the formula (I) or a reactive derivative thereof with a compound of the formula (V ') or its salt in a manner similar to that described in process III above. The preparation of some of the compounds of the formula (V) are described in Chem. Pharm. Bull. Vol. 37, No. 6 1524-1533 (1989).

This step refers to the preparation of an aldehyde of the formula (X) by oxidizing a compound of the formula (IX). The reaction can be carried out for several hours under cooling or at room temperature using an oxidizing agent selected from the chromic acid series such as Jones reagents, Collins reagents, pyridinium chlorochromate, pyridinium dichromate or sodium sulfoxide. dimethyl oxalyl chloride in a solvent such as chlorinated hydrocarbons (chloroform, dichloromethane, etc.), esters (ethyl ether, tetrahydrofuran, etc.), acetone or benzene.

[Step 3] This step refers to the formation of a double bond by the reaction of a compound of the formula (X) with an ylide (Ph3P = CH (CH2) 3COOH). The reaction to provide a double bond can be carried out in a conventional manner by the Wittig reaction. The ylides used in the reaction can be synthesized, in the presence of a base, by treating a phosphorus salt that has been synthesized from the triphenylphosphine and an alkali halide having a desired alkyl group to be condensed, for example, the acid -bromopentanoic. Examples of a base include dimsyl sodium, dimsyl potassium, sodium hydride, n-butyl lithium, potassium t-butoxide and lithium diisopropylamide. The reaction is carried out within several hours at room temperature in a solvent such as ether, tetrahydrofuran, n-hexane, 1,2-dimethoxyethane or dimethyl sulfoxide.

[Step 4] In this step, a compound (VI) wherein R is the hydroxy protecting group is optionally deprotected to give the compound (VI-1). The reaction can be carried out in a conventional manner using a catalyst such as hydrochloric acid, sulfuric acid, sodium hydroxide, potassium hydroxide or barium hydroxide, or the like. The reaction is performed within tens of minutes to several hours with heating in a solvent such as methanol-water, ethanol-water, acetone-water, acetonitrile-water, or the like, preferably dimethyl-sulfoxide-water.

The following examples are provided to further illustrate the present invention in a more detailed manner and may not be interpreted in any way as to limit the scope thereof. The abbreviations used in the examples have the following meanings: Ph: phenyl Ac: acetyl TEMPO: 2,2,6,6, -tetramethylpiperidin-1-oxyl Example 1 (1) Step 1: 4- (2-propin-1-ylthio) phenyl benzenesulfonate (2) 1 4-Mercapto-phenol (1) (37.85 g, 300 mmol) and propargyl bromide (42.82 g, 360 mmol) were dissolved in ethyl acetate (757 mL). To the solution was added dropwise triethylamine (42.5 g, 420 mmol) for 35 minutes with stirring and under ice-cooling. After stirring for another 1.5 hours at the same temperature, triethylamine (42.5 g, 420 mmol) was added in one portion, benzenesulfonyl chloride (63.58 g, 360 mmol) was added dropwise over 20 minutes. After maintaining 1 hour at the same temperature, the cooling bath was stirred and the mixture was stirred for 30 minutes at room temperature and subdivided into two phases by adding cold water (500 ml) and hydrochloric acid (110 ml). The aqueous phase was extracted with ethyl acetate (200 ml). The combined organic phase was washed with water, dried with anhydrous magnesium sulfate, and then the solvent was distilled under reduced pressure to deliver 100.04 g of the title compound (2) as an oil. Crude Production: 109%. IR (CHC13); 3306, 3071, 3031, 3019, 3009, 1585, 1486, 1449, 1378 cm "1 XH NMR d (CDCI3), 300MHz, 2.23 (1H, t, J = 2.7Hz), 3.56 (2H, d, J = 2.7Hz), 6.94 and 7.34 (every 2H, every d, J = 8.7Hz), 7.51-7.56 (2H, m), 7.68 (1H, m), 7.82-7.85 (2H, m) (2) Step 2: 4- (2-Propyn-l-ylthio) phenyl benzene sulfonate (3) Ph Compound (2) (60.8 g, 183 mmol) prepared in step (1) above was dissolved in formic acid (30.4 ml) and in methanol (122 ml, and 31% aqueous hydrogen peroxide (26.29 g, 240 mmol ) was added then after 3.5 hours, ice water (240 ml) was added and the mixture was extracted with ethyl acetate (2 x 300 ml), the organic phase was washed with 5% aqueous sodium carbonate and the solvent afterwards. it was distilled under reduced pressure to provide 65.47 g of the title compound (3) as an oil Crude yield: 117% IR (CHC13); 3305, 33066, 3032, 3012, 1586, 1486, 1449, 132 cm "1 .2H NMR d (CDCl3), 300MHZ, 2.34 (1H, t, J = 3.9Hz), 3.58 and 3.68 (each 1H, each dd, J = 3.9 and 23.7Hz), 7.18 and 7.67 (each 2H, each d, J = 9.9Hz), 7.51-7.59 (2H, m), 7. 66. (1H, m), 7.82-7.87 (2H, m) (2) Step 3: 5-Benzenesulfonyloxy-3-hydroxymethylbenzo [b] thiophene (4) The compound (3) (65.47 g, 183 mmol) obtained before (2) was dissolved in 1,2-dimethoxyethane (1.6 L) and the solution was refluxed for 4 hours. To the solution was added water (64 ml) and p-toluenesulfonic acid monohydrate (19.2 g, 100 mmol) and the reflux was continued for 2 hours. The reaction mixture was concentrated under reduced pressure. After water (200 ml) was added to the resulting oil, the mixture was extracted with ethyl acetate (300 ml). The organic phase was washed with sodium, aqueous hydrogen carbonate and water, dried with anhydrous magnesium sulfate and then the solvent was distilled under reduced pressure to deliver 60.18 g of the title compound (4) as an oil. Crude yield: 103%. IR (CHC13); 3609, 3067, 3033, 3013, 2935, 2878, 1589, 1566, 1449, 1435, 1376 cm "1- XH NMR 6 (CDCI3) / 300MHz, 4.78 (2H, d, J = 0.9Hz), 6.98 (1H, dd, J = 2.4 and 8.7Hz), 7.26 ( 1H, s), 7.43-7.45 (2H, m), 7.50-7.55 (2H, m), 7.66 (1H, m), 7.73 (1H, d, J = 8.7Hz 7.83-7.86 (2H, m). (4) Step 4 5-Benzenesulfonyloxybenzo [b] thiophene-3-carboxylic acid (6) bear ^ Step 4 OHO. OSO2PI1 HO ' 4 5 - - HOOC- or ^ - ^^ OSO ^ Pti 6 Compound (4) (51.26 g, 155 mmol) prepared in the above (3) was dissolved in acetonitrile (1.54 L), and TEMPO (2, 2, 6, 6-tetramethylpiperidin-1-oxyl, 250 mg , 0.001 eq) was added thereto. To a mixture was added dropwise 0.81 N aqueous sodium hypochlorite, which has been prepared by diluting aqueous sodium hypochlorite 1.63 N (150 ml) with water (75 ml), adjusting the pH to 8.6 with 1 N sulfuric acid, and adjusting the total volume to 300 mi, during 15 minutes, while maintaining the internal temperature between -1 ° C and 8 ° C. After stirring for 25 minutes at room temperature, 1N aqueous sodium sulfite (32 ml) was added. Subsequently, 79% sodium chlorite (27.48 g, 240 mmol) and 31% aqueous hydrogen peroxide (23.26 g, 212 mmol) were added under ice cooling. The ice bath was stirred and the mixture was stirred for 2 hours. The reaction was diluted with water (1.5 L), adjusted to pH 3 with 1 N hydrochloric acid and the crystals deposited were filtered, and washed twice with water (20 mL), acetonitrile (50 mL) to provide 32.4 g, of raw crystals. The crude crystals (32.4 g) were suspended in acetonitrile (224 ml), refluxed for 15 minutes and cooled in ice. The crystals were filtered and washed with acetonitrile (65 ml) to give 26.79 g of the title compound, compound (6). Yield: 51.7%, m.p. 202-203 ° C. IR (Nujol): 3102, 2925, 2854, 2744, 2640, 2577, 1672, 1599, 1558, 1500, 1460, 1451 cm "1. NMR d (CDC13) / 300MHz; 7.16 (1H, dd, J = 2.7 and 9.0Hz), 7.55-7.61 (2H, m), 7.73 (1H, m), 7.81 (1H, d, J = 9.0Hz), 7.90-7.94 (2H, m), 8.16 (1H, d, J = 2.7 Hz), 8.60 (1H, S) Elemental analysis for C? 5H? 0O5S2 Calculated (%) C, 53.88; H, 3.01; S, 19.18 Found (%) C, 53.73; H, 3.24; S, 19.09 Example 2 (1) Step 1: 5-Benzenesulfonyloxybenzo [b] thiophene (8) 8 The compound (7) [J. Am. Chem. Soc., 57, 1611-1616 (1935); Ann. Chem., 52, 83-114 (1938), J. Am. Chem. Soc., 78, 5351-5357 (1956); J. Org. Chem., 41, 1118-1124 (1976)] (1.36 g, 9.05 mmol) and triethylamine (1.89 ml, 13.6 mmol) were dissolved in tetrahydrofuran (10 ml). A solution of benzenesulfonyl chloride was added dropwise to a solution. (1.92 g, 10.9 mmol) in tetrahydrofuran (3 mL). After being stirred for 2 hours, the reaction mixture was diluted with water and extracted with toluene. The organic phase was washed with water, dried with anhydrous magnesium sulfate and then the solvent was distilled under reduced pressure. The residue was chromatographed with silica gel (5: 1 hexane: ethyl acetate) and then recrystallized from hexane containing a small amount of ethyl acetate to give 2.28 g of the title compound (8). Yield: 86.8%, m.p. 80-81 ° C IR (Nujol): 1599. 1579, 1564, 1497, 1448, 1440, 1415, 1352 cm "1. XH NMR d (CDC13); 300MHz; 6.92 (1H, dd, J = 2.4 and 8.7Hz ) 7.26 (1H, dd, J = 0.9 and 5.4Hz), 7.47 (1H, d, J = 2.4Hz), 7.5K1H, d, J = 5.4Hz), 7.52-7.55 (2H, m), 7.67 (1H , m), 7.74 (1H, d, J = 8.7Hz), 7.83-7.87 (2H, m) Elemental analysis for C? 4H? 0O3S2 Calculated (%): C, 57.91; H, 3.47; S, 22.09 Found (%): C, 57.72; H, 3.45; S, 21.98 (2) Step 2: 3-Acetyl-5-benzenesulfonyloxy-benzo [b] thiophene (9) d Aluminum chloride powder (1.34 g, 10 mmol) was suspended in dichloromethane (10 ml). To a suspension was added dropwise acetyl chloride (1.02 ml, 14.3 mmol) for 5 minutes with stirring and under ice-cooling. Subsequently, a solution of compound (8) (2.075 g, 7.2 mmol) prepared above in dichloromethane (6 mL) was added over 15 minutes. After being stirred for 2 hours at the same temperature and then for 2.5 hours at room temperature, the solution was poured into ice water and extracted with dichloromethane. The organic phase was washed with water, dried with anhydrous magnesium sulfate and then the solvent was distilled under reduced pressure. The resulting residue was recrystallized from ethyl acetate (3 mL) and hexane (3 mL) to give 2.01 g of the title compound (9). Yield: 84.4% Yield: 84.4% p.f. 129-130 ° C. IR (Nujol): 3094, 1672, 1619, 1596, 1556, 1494, 1450, 1437, 1428, 1369 cm "1. 2 H NMR d (CDCl 3) 300 MHz; 2.58 (3H, s), 7.22 (1H, ddd, J = 0.6, 2.4 and 9.0Hz), 7.52-7.58 (2H, m), 7.69 (1H, m), 7. 79 (IH, d, J = 9.0Hz), 7.87-7.91 (2H, m), 8.27 (1H, dd, J = 0.6 and 2.4Hz), 8.31 (1H, s) Elemental analysis for Ci6H? 204S2 Calculated (%): C, 57.82; H, 3.64; S, 19.29 Found: C, 57.62; H, 3.71; S, 19.23 (3) Step 3: 5-Benzenesulfonyloxybenzo [b] thiophene-3-carboxylic acid (6) 9 The compound (9) (6.65 g, 20 mmol) prepared above (2) was dissolved in the dioxane (50 ml), and 10% of the sodium hypochlorite (46.2 ml) was added during 20 minutes with stirring while maintaining the temperature at 10-12 ° C. After 7 hours, the reaction mixture was diluted with ice water (80 ml) and acidified with conc. Hydrochloric acid. (5.2 mi). The deposited crystals were filtered, washed with water, dried to give 5.84 g of crude crystals. The 5.84 g of the crude crystals were recrystallized from methanol (66 ml) and water (16 ml) to give 5.51 g of the title compound (6). Performance: 82.4%. p.f. 203-204 ° C. This compound is identical to the compound (6) prepared in Example 1.

Reference example 1 5-Benzylsulphonyloxybenzo [b] thiophene-3-carbonyl chloride more OSOjPh 6 The 5-Benzylsulphonyloxybenzo [b] thiophene-3-carboxylic acid (6) (5,582 g, 16.7 mmol) prepared in the previous examples was refluxed for 1.5 hours with dimethylformamide (1 drop), thionyl chloride (3.57 ml, 50 g. mmol) and toluene (22 ml), and the solvent was removed under reduced pressure to give 5.89 g of the title compound (10).

Reference Example 2 (1) Step 1: 5-Hydroxybenzo [b] thiophene-3-carboxylic acid (11) 11 5-Benzensulfonyloxybenzo [b] thiophene-3-carboxylic acid (6) (100 mg, 0.3 mmol) prepared in the previous examples, it was dissolved in 1 N sodium hydroxide (1.2 ml) and heated at 40 ° C for 8 hours with stirring, to the solution was added 1N hydrochloric acid (1.2 ml)., and the deposited crystals were filtered, washed with water and dried to give 58 mg of the title compound (11). Yield: 96.6% p.f. 262-263 ° C. This compound (11) is identical to the 5-hydroxybenzo [b] thiophene-3-carboxylic acid described in M. Martín-Smith et al. J. Chem. Soc (C), 1989-1905 (1967). (2) Step (2) 5-Acetoxybenzo [b] thiophene-3-carboxylic acid (12) HO 11 12 The 5-Hydroxybenzo [b] thiophene-3-carboxylic acid (11) (1140 mg) prepared in the previous (1) was dissolved in acetic anhydride (2 ml), pyridine (4 ml). After 3 hours, the water was added and the mixture was stirred continuously under cooling with ice for 1.5 hours. The deposited crystals were filtered, washed with water and dried to provide 1349 mg of the title compound (12). Yield 97.3% p.f. 239-240 ° C. XH NMR 5 (CDC1), 300MHz; 2.37 (H, s), 7.20 (1H, dd, J = 2.4 and 8.7Hz), 7.87 (1H, d, J = 8.7Hz), 8.34 (1H, d, J = 2.4Hz), 8.57 (1H, s ) (3) Step 3: 5-Acetoxybenzo [b] thiophene-3-carbonyl chloride (13) OCOCH3 CIO Step 3 ^ "&" a? OCOCH3 12 13 The 5-Acetoxybenzo [b] thiophene-3-carboxylic acid (12) (1349 mg) prepared above was refluxed for 1.5 hours with dimethylformamide (1 drop), thionyl chloride (1.22 ml) and toluene (25 ml). The solvent was removed under reduced pressure to deliver 1454 mg of the title compound (13).

EXAMPLE 3 Acid (5Z) -7 - [(1R, 2R, 3S, 5S) -2- (5-Hydroxy-benzo [b] thiophen-3-ylcarbonylamino) -10-norpinan-3-yl] -5-heptenoic acid (17 ) 17 (1) Step 1: Preparation of [3- (IR, 2R, 3S, 5S) -3- (2-Hydroxyethyl) -10-norpinan-2-yl] carbamoylbenzo [b] thiophen-5-yl] benzenesul? Onate (14) The benzoic acid salt of (+) -2- [(IR, 2R, 3R, 5R,) -2-Amino-10-norpinan-3-yl] ethanol (described in Chem. Pharm. Bull. Vol. 37, No. 6 1524-1533 (1989) (Vl)) (5.1 g, 16.7 mmol) it was suspended in water (10 ml). To the suspension was added 1N hydrochloric acid (17 ml) and the deposited benzoic acid was removed by extracting it with ethyl acetate. The organic phase was washed with water (10 ml.). To the combined aqueous phase was added 4N sodium hydroxide (9.2 ml, 36.8 mmol) under ice-cooling. A solution of 5-Benzylsulfonyloxybenzo [b] thiophene-3-carbonyl chloride (10) (5.89 g, 16.7 mmol) in tetrahydrofuran (36 ml) was then added dropwise over 15 minutes with stirring. After stirring for 1 hour at the same temperature, 1N hydrochloric acid (4 mL) was added and the mixture was extracted with ethyl acetate. The organic phase was washed with water, dried with anhydrous magnesium sulfate and then the solvent was distilled under reduced pressure to give 8.00 g (95.6%) of the title compound (14) as a colorless amorphous. XH NMR d (CDC13), 300MHz; 0.96 (1H, d, J = 9.9Hz), 1.12 and 1.26 (every 3H, every s), 1.50-2.42 (9H, m), 3.69-3.82 (2H, m), 4.30 (1H, m), 6.21 ( 1H, d, J = 8.1Hz), 7.06 (1H, dd, J = 2.4 and 8.7Hz), 7.51-7.56 (2H, m), 7.67 (1H, m), 7.73 (1H, d, J = 8.7Hz ), 7.85-7.88 (2H, m), 7.88 (1H, s), 8.06 (1H, d, J = 2.4Hz). [a] D25 +35. 7th (c = 1.00%, CH30H) (2) Step 2: Preparation of [3- [(IR, 2R, 3R, 5S) -3-Formylmethyl-10-norpinan-2-yl] carbamoylbenzo [b] thiophen-5-yl] benzenesulfonate (15) To sulfoxide dimethyl (3.16 ml, 44.5 ml) dissolved in dimethoxyethane (50 ml) was added oxalyl chloride (1.91 ml, 21.9 mmol) under cooling at -60 ° C. -65 ° C. A solution of compound (14) (7352 g, 14.7 mmol) in 1,2-dimethoxyethane (58 ml) was added dropwise at the same temperature. After stirring the mixture at -55 ° C - -60 ° C for 30 minutes, triethylamine (6.1 ml) was added and, 30 minutes later, the ice bath was stirred to allow the mixture to warm to room temperature . The reaction mixture was diluted with water (100 ml) and extracted with toluene. The organic phase was washed with water, dried with anhydrous magnesium sulfate and then the solvent was distilled under reduced pressure. The resulting residue was purified by chromatography on silica gel (hexane: ethyl acetate = 5: 5-4: 6) to give 7.32 g (100%) of the title compound (15) as a colorless amorphous. IR (CHC13); 3443, 3093, 3066, 3030, 3016, 2925, 2871, 2828, 2729, 1720, 1655, 1599, 1558, 1513, 1377 cm "1. aH NMR d (CDC13), 300MHz, 0.97 (1H, d, J = 10.2Hz), 1.17 and 1.28 (every 3H, every s), 1.46 (1H, m), 2. 03 (1H, m), 2. 22 (1H, m), 2.36-2.60 (3H, m), 2.69 (1H, ddd, J = 1.2, 8.7 and 17. 4Hz), 3.14 (1H, dd, J = 4.5 and 17.4Hz), 4.28 (1H, m), 6.18 (1H, d, J = 8.1Hz), 7.09 (1H, dd, J = 2..4 and 8.7Hz), 7.50-7.55 (2H,), 7.67 (1H, m), 7.75 (1H, d, J = 8.7Hz), 7.85-7.89 (2H, m), 7.89 (1H s), 8.03 (1H, d, J = 2.4Hz), 9.80 (1H, d, J = 1.2Hz) [a] D23 + 31.8 ° (c = 1.00%, CH30H) (3) Step 3: Preparation of (5Z) -7 - [(IR, 2R, 3S, 5S) -2- (5-Benzylsulphonyloxybenzo [b] thiophen-3-ylcarbonylamino) -10-norpinan-3-yl acid. ] -5-heptenoic (16) 4-Carboxybutyltriphenylphosphcnium bromide (12.17 g, 27.5 mmol) and potassium t-butoxide (7.19 g, 64.1 mmol) were suspended in tetrahydrofuran (64 mL) and stirred for 1 hour under a cooling with ice. To the reaction mixture was added over 15 minutes a solution of compound (15) (9.11 g, 18.3 mmol) prepared above (2) in tetrahydrofuran (27 ml) and the mixture was stirred continuously for 2 hours at the same temperature . The reaction mixture was diluted with water (80 ml) and washed with toluene (2 x 105 ml). After adjusting the aqueous phase to a pH of 8.1 with hydrochloric acid (4.8 ml), the anhydrous calcium chloride (8.1 g, 73 mmol) dissolved in water (16 ml) was added, and the mixture was extracted with ethyl acetate. (2 x 100 mi). The water (100 ml) was added to the organic phase, and the aqueous phase was adjusted to below pH 2 with hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water, dried with anhydrous magnesium sulfate and then the solvent was distilled under reduced pressure to deliver 11.06 g of the title compound (16). The compound (16) was used in the next reaction without promoting purification. (3) Step (4): The preparation of the acid (5Z) -7- [(IR, 2R, 3S, 5S) -2- (5-Hydroxybenzo [b] thiophen-3-ylcarbonylamino) -10-norpinan-3 -yl] -5-heptenoic (17) (Compound A) The compound (16) (11.06 g, 183 mmol) prepared in the above (3) was dissolved in the dimethyl sulfoxide (22 ml). After adding 4 N sodium hydroxide (27.5 ml), the mixture was heated at 55 ° C for 2 hours with stirring. The reaction mixture was diluted with water (130 ml) and washed with toluene (2 x 65 ml). The aqueous phase was acidified with 5 N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water, dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to provide 8.26 g of the crude objective compound which was then dissolved in methanol (40 ml) and water (16 ml). The solution was seeded and cooled gradually with stirring. The deposited crystals were filtered and washed with water: methanol (2: 5) to give 6.35 g of the objective compound. Yield: 78.6%. The crystals were dissolved in methanol (40 ml). Water (12 ml) was added to the solution for 7 minutes with stirring. The mixture was seeded and stirred continuously for 1 hour, the mixture was stirred for 1.5 hours at 25 ° C. The deposited crystals were filtered and washed with water: methanol (3: 5) (8 ml) to give 6.14 g of the objective compound (17) which were almost colorless. Yield: 76.0%, m.p. 145-146 ° C. IR (Nujol); 3313, 3096, 3059, 3001, 1717, 1627, 1603, 1548, 1469, 1440 cm "1 .H NMR d (CDC13); 300MHz; 1.02 (1H, d, J = 10.2Hz), 1.12 and 1.24 (every 3H , each s), 1.56-2.55 (14H, m), 4.29 (1H, m), 5.32-5.51 (2H, m), 6.20 (1H, d, J = 9.3Hz), 7.01 (1H, dd, J = 2.4 and 9.0Hz), 7.66 (1H, d, J = 9.0Hz), 7.69 (1H s), 8 03 (1H, d, J = 2.4Hz) [a] D24 + 50.7 ° (c = 1.01, CH30H) Elemental Analysis for C25H3? N04S Calculated (%): C, 68.00; H, 7.08; N, 3.17; S, 7.26 Found (%): C, 67.84; H, 7.08; N, 3.24; S, 7.31 It is noted that in relation to this date, the best method known to 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, property is claimed as contained in the following:

Claims (10)

2. A process for producing a compound of the formula (I) wherein R is a hydrogen or a hydroxy-protective group, or a reagent derived therefrom, which comprises attaching 4-mercaptophenol to the reactions by introducing a propargyl group and a hydroxyl protecting group to produce a compound of the formula (II): \ a0R 'p wherein R1 is a hydroxy-protective group; which oxidizes the compound (II) to produce a compound of the formula (III): . wherein R1 is a hydroxy-protective group; which binds the compound (III) to a thermal rearrangement reaction to produce a compound of the formula (IV): wherein R1 is as defined above; and which subject the compound (IV) to a gradual oxidation of a hydroxymethyl group and optionally deprotection. 2. The process of claim 1, wherein the hydroxy-protective group represented by R1 is alkyl, alkoxyalkyl, acyl, aralkyl, alkylsulfonyl, arylsulfonyl, substituted alkyl silyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl or tetrahydropyranyl.
3. 3. The process of claim 1, wherein the hydroxy-protecting group represented by R1 is arylsulfonyl.
4. 4. A process for producing a compound of the formula (IV): wherein R is a hydrogen or a hydroxy-protective group and X is a hydrogen or alkyl, and a double bond represents any E or Z configuration, or a pharmaceutically acceptable salt or hydrate thereof, which comprises attaching 4-mercaptophenol to the reactions by introducing a propargyl group and protecting a hydroxyl group to produce a compound of the formula (II): nde R 1 is a xgrucpo hr p in do idroxi-protector; which oxidizes the compound (II) to produce a compound of the formula (III): wherein R1 is a hydroxy-protective group; which binds the compound (III) to a heat rearrangement reaction to produce a compound of the formula (IV): "° XO ° IV wherein R1 is as defined above; subjecting the compound (IV) to a gradual oxidation of a hydroxymethyl group and optionally the deprotection of the formula (I): wherein R is as defined above, or a reagent derived therefrom; by subjecting the compound of the formula (I) or a reagent derived therefrom to the following reactions: (1) reaction with a compound of the formula (V) wherein X is a hydrogen or alkyl; or (2) reaction with a compound of the formula (V) or a salt thereof followed by oxidation and reaction with a halide under the conditions by the Witting reaction; Y (3) optionally the deprotection.
5. 5. A process for producing a compound of the formula (I): HOOC. tO0R wherein R is a hydrogen or a hydroxy-protective group, or a reagent derived therefrom, which comprises attaching 5-hydroxybenzo [b] thiophene to a protection reaction to produce a compound of the formula (VII): wherein R2 is a hydroxy-protective group; reacting the compound (VII) with acetyl halide under the conditions by the Friedel-Crafts reaction to produce a compound of the formula (VIII): wherein R2 is a hydroxy-protective group; subjecting the compound (VIII) to an oxidation of the acetyl group and optionally the deprotection.
6. 6. The process of claim 5, wherein the hydroxy-protective group represented by R2 is alkyl, alkoxyalkyl, acyl, aralkyl, alkylsulfonyl, arylsulfonyl, substituted alkyl silyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl or tetrahydropyranyl.
7. 7. The process of Claim 5, wherein the hydroxy-protective group represented by R2 is arylsulfonyl.
8. 8. A process for producing a compound of the formula (VI): wherein R is hydrogen or a hydroxy-protective group and X is hydrogen or alkyl, and the double bond represents any E or Z configuration, or a pharmaceutically acceptable salt or hydrate thereof, which comprises attaching 5-hydroxybenzo [£ > ] thiofen to a protection reaction to produce a compound of the formula (VII): wherein R2 is a hydroxy-protective group; reacting the compound (VII) with acetyl halide under the conditions by the Friedel-Crafts reaction to produce a compound of the formula (VIII): wherein R is a hydroxy-protective group; subjecting the compound (VIII) to an oxidation of the acetyl group and optionally the deprotection to produce a compound of the formula (I): wherein R is as defined above or a reagent derived therefrom; subjecting the compound (I) or a reagent derived therefrom to the following reactions: • (1) the reaction with a compound of the formula (V) where X is as defined above; or (2) the reaction with a compound of the formula (V) or a salt thereof followed by oxidation and reaction with an ylide under the conditions by the Witting reaction; and (3) optionally deprotection.
9. 9. A compound of the formula (I) wherein R is arylsulfonyl or a reagent derived therefrom.
10. 10. A compound of the formula (I) wherein R is benzenesulfonyl or a reagent derived therefrom.