Title of Invention	PROCESS FOR PREPARING BENZOTHIOPHENE CARBOXAMIDE DERIVATIVES
Abstract	The present invention relates to a process for producing a compound of formula (VI), which comprises reacting 4-mercaptophenol with a propargyl halide in the presence of, a basic agent to yield a compound of formula (II); oxidizing the compound (II) with an oxidizing agent to yield a compound of formula (III); refluxing the compound (III) in a solvent for several hours followed by adding thereto an acid to yield a compound of formula (IV); subjecting the compound (IV) to stepwise oxidation of hydroxymethyl group and optionally deprotecting the hydroxy protecting group to yield a compound of formula (I); subjecting the compound of formula (I) or a reactive derivative thereof to the following reactions: (1) reaction with a compound of formula (V) or (2) reaction with a compound of formula (V') or a salt thereof followed by oxidation and reaction with an ylide under the conditions for witting reaction; and (3) optionally deprotection.

Title of Invention

PROCESS FOR PREPARING BENZOTHIOPHENE CARBOXAMIDE DERIVATIVES

Abstract

The present invention relates to a process for producing a compound of formula (VI), which comprises reacting 4-mercaptophenol with a propargyl halide in the presence of, a basic agent to yield a compound of formula (II); oxidizing the compound (II) with an oxidizing agent to yield a compound of formula (III); refluxing the compound (III) in a solvent for several hours followed by adding thereto an acid to yield a compound of formula (IV); subjecting the compound (IV) to stepwise oxidation of hydroxymethyl group and optionally deprotecting the hydroxy protecting group to yield a compound of formula (I); subjecting the compound of formula (I) or a reactive derivative thereof to the following reactions: (1) reaction with a compound of formula (V) or (2) reaction with a compound of formula (V') or a salt thereof followed by oxidation and reaction with an ylide under the conditions for witting reaction; and (3) optionally deprotection.

Full Text	DESCRIPTION PROCESS FOR PREPARING 5-HYDROXYBENZO [b] THIOPHENE-3-CARBOXYLIC ACID DERIVATIVES 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 ART 5-Hydroxybenzo [b] thiophene-3-carboxylic acid derivatives of the general formula (I) : wherein R is hydrogen or a hydroxy-protecting group are important starting materials in the synthesis of pharmacologically active compounds. For example, a compound of the formula (I) is essential in the synthesis of benzothiophenecarboxamide derivatives of the general formula (VI): wherein R is as defined above and X is hydrogen or alkyl. The benzothiophenecarboxamide derivatives are specific antagonists of PGD2 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, for example, systemic mastocytosis, disorder of systemic mast cell activation, tracheal contraction, asthma, allergic rhinitis, allergic conjunctivitis, urticaria, injury due to ischemic reperfusion, inflammation, and atopic dermatis (WO97/00853, PCT/JP97/04527 {W098/25919)). Among compounds of the formula (VI), a compound wherein OR is 5-hydroxy and X is hydrogen (hereinafter, referred to as "Compound A") has especially high antagonistic effect on PGD2, showing an excellent anti-nasal occlusion activity, and is contemplated to be a promising drug for treating nasal occlusion. DISCLOSURE OF THE INVENTION A process for preparing the above-mentioned compound is illustrated by the following reaction scheme (W098/25919): In order to clinically apply Compound A widely, it is essential to establish a process for preparing a starting material/ the compound (I), which process is safe, efficient and industrially applicable. However, it is difficult to synthesize benzothiophene derivatives having 5-hydroxyl group like the compound (I) and there have been no methods industrially applicable so far. The existing methods involve various complicated processes and are inefficient and of low yield. For example, there have been methods wherein 5-acetoxybenzo [b] thiophene is brominated to yield 3-bromo-5-acetoxybenzo [b] thiophene, which in turn is re-protected at the 5-acetoxy group with a benzyl group to yield 3-bromo-5-benzyloxybenzo [b] thiophene, which is followed by metallization with magnesium, introduction of carbon dioxide and removal of the benzyl group (J. Chem. Soc. (C). 1967, 1899-1905); or 5-bromobenzo[b]-thiophene is subjected to Friedel-Crafts reaction to yield 3-acetyl-5-bromobenzo [b] thiophene, which is followed by oxidation with sodium hypochlorite to yield 5-bromobenzo[b]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 from the reaction products above. However, the starting material such as 5-hydroxybenzo [b]-thiophene or 5-bromobenzo[b]thiophene is not commercially available and had to be synthesized from an appropriate reagent (e.g., J. Am. Chem. Soc., 57, 1611(1935), J. Heterocyclic Chem., 25, 1271(1988)) in all cases, which have made the synthetic process longer and complex. The present invention solves the problems of the existing methods and provides a method for the preparation of the compounds of the formula (I), which method is industrially applicable, efficient and safe. Thus, the present invention provides a process for preparing a compound of the formula (I): wherein R is hydrogen or a hydroxy-protecting group, or .a reactive derivative thereof comprising subjecting 4-mercaptophenol to reactions for introduction of a propargyl group and protection of hydroxyl group to yield a compound of the formula (II): wherein R1 is a hydroxy-protecting group; oxidizing the compound (II) to yield a compound of the formula (III): wherein R1 is a hydroxy-protecting group; subjecting the compound (III) to thermal rearrangement reaction to yield a compound of the formula (IV): wherein R1 is as defined above; and subjecting the compound (IV) to stepwise oxidation of hydroxymethyl group and optionally deprotection. The present invention also provides a process for preparing a compound of the formula (I): wherein R is hydrogen or a hydroxy-protecting group or a reactive derivative thereof comprising subjecting 5-hydroxybenzo[b] thiophene to a protecting reaction to yield a compound of the formula (VII): wherein R1 is a hydroxy-protecting group; reacting the compound (VII) with acetyl halide under the conditions for Friedel-Crafts reaction to yield a compound of the formula (VIII): wherein R1 is a hydroxy-protecting group; and subjecting the compound (VIII) to oxidation of the acetyl group and optionally deprotection. The present invention further provides a method for the preparation of the above-mentioned 5-hydroxybenzo[b]-thiophene-3-carboxylic acid derivative of the general formula (VI) by using a compound of the formula (I)• Thus, the present invention provides a process for preparing a compound of the formula (VI): wherein R is as defined above and X is hydrogen or alkyl, and double bond represents either E- or Z-configuration, or a pharmaceutically acceptable salt thereof or a hydrate thereof, which comprises subjecting a compound of the formula (I) or a reactive derivative thereof to the following reactions: (1) reaction with a compound of the formula (V) wherein X is hydrogen or alkyl; or (2) reaction with a compound of the formula (V): or a salt thereof followed by oxidation and reaction with an ylide under the conditions for Wittig reaction; and (3) optionally deprotection. THE BEST EMBODIMENT FOR PRACTICING THE INVENTION The terms used herein are defined below. The term "hydroxy-protecting group" means alkyl, alkoxyalkyl, acyl, aralkyl, alkylsulfonyl, arylsulfonyl, alkyl-substituted silyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl or tetrahydropyranyl. The term "alkyl" means C1-C20 linear or branched alkyl, particularly, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tart-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 C1-C6 alkyl is preferred. The term "alkoxy" means C1-C6 linear or branched alkoxy, particularly, methoxy, ethoxy, n-propoxy, i-propoxy. 71-butoxy, i-butoxy, s-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy, neopentyloxy, s-pentyloxy, t-pentyloxy, n-hexyloxy, neohexyloxy, i-hexyloxy, s-hexyloxy, t-hexyloxy and the like, and C1-C3 alkoxy is preferred. The term "alkoxyalkyl" means alkyl group substituted by alkoxy group, including methoxymethyl, ethoxymethyl, methoxyethoxymethyl, ethoxyethyl, methoxypropyl and the like. The term "acyl" means C1-C11acyl derived from aliphatic carboxylic acid or aromatic carboxylic acid. Examples of aliphatic carboxylic acid-derived acyl include acetyl, chloroacetyl, trichloroacetyl, propionyl, butyryl, valeryl and the like, and examples of aromatic carboxylic acid-derived acyl include benzoyl, p-nitrobenzoyl, p-methoxybenzoyl, p-bromobenzoyl, toluoyl, naphthoyl and the like. The term "aryl" means phenyl, naphthyl or polycyclic aromatic hydrocarbon group and the like. In addition, aryl may be substituted by the following substituents. Examples of substituent include alkyl such as methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or tert-pentyl, lower alkoxy such as methoxy or ethoxy, halogen such as fluoro, chloro, bromo or iodo, nitro, hydroxy, 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 at any 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-dimethylammo) phenyl, 4-nitrophenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-iodophenyl and the like. The aryl group m the "aralkyl", "arylsulfonyl", "aryloxycarbonyl" or "aralkyloxycarbonyl" described below may have similar substituents as defmed above. The term "aralkyl" means an alkyl group substituted by aryl group, and mcludes benzyl, 4-methylben2yl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, naphthylmethyl, phenethyl, and the like. The term "alkylsulfonyl" means a sulfonyl group substituted by alkyl group, and mcludes methanesulfonyl, ethanesulfonyl and the like. The term "arylsulfonyl" means a sulfonyl group substituted by aryl group, and mcludes benzenesulfonyl, p-toluenesulfonyl, and the like. The term "alkyl-substituted silyl" means mono-, di- or tri"alkyl-substituted silyl, 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 the above-mentioned nydroxy-pronecrmg groups are preferred as the hydroxy-protectmg group shown by R1, R1 or R m respective formula above, aryl sulfonyl is more preferred and benzenesulfonyl is particularly preferred among them. Examples of salts of the compound of the general formula (VI) mclude alkali metal salts such as lithmm salt, sodmm salt or potassmm salt and the like, alkali earth metal salts such as calcmm salt and the like, ammonmm salt, salts with organic base such as tromethamme, trimethylamme, triethy1amme, 2-ammobutane, tert- butylamme, diisopropylethylamme, n-butylmethylamme, n-butyldimethylamme, tri-n-butylamme, cyclohexylamme, dicyclohexylamme, N-isopropylcyclohexylamme, furfurylamme, benzylamme, methylbenzylamme, dibenzylamme, W,N-dimethyIbenzylamme, 2-chlorobenzylamme, 4-methoxybenzylamme, 1-naphthalenemethylamme, diphenylbenzylamme, triphenylamme, 1-naphthylamme, 1-ammoanthracene, 2-ammoanthracene, dehydroabiethylamme, N-methylmorpholme or pyridme, or ammo acid salts such as lysme salt or argmme salt. The salts of the ammo alcohol of the formula (V) mclude salts with organic acid such as benzoic acid, etc., and mmeral acid such as hydrochloric acid, sulfuric acid, etc. The fmal compound of the present mvention is represented by the formula (VI) as described above, m which the double bond of the alkenylene side cham (5- heptenylene cham) may be m the E- or z-configuration. The method of the present mvention is described below m more detail. When a substituent(s) possibly mterfermg the reaction is present, it can be appropriately protected and then deprotected at a desired stage. Such protection or deprotection can be accomplished by a procedure known m the art. Wherem R and R1 are as defmed above. [Step 1] This step is related to the mtroduction of a propargyl group at the mercapto group of 4-mercaptophenol (1) and protection of hydroxyl group. The mtroduction of a propargyl group is accomplished by usmg propargyl halide such as propargyl bromide, propargyl chloride and the like m the presence of a basic agents. The reaction can be accomplished withm several tens mmutes to several hours at room temperature by employmg, as a basic agent, morganic base such as potassmm carbonate, sodmm carbonate or the like, or an organic base such as triethylamme, pyridme, 4-dimethylammopyridme or the like m a solvent such as acetone, ethyl acetate, tetrahydrofuran, acetonitrile, or the like. When a strong base such as potassmm hydroxide or sodmm hydroxide is used, it can be also accomplished m a two-layer solvent system such as toluene-water or xylene-water. The protection of hydroxyl group may be conducted usmg an ordmary hydroxy-protectmg group m a conventional manner. Preferred protectmg groups to be used m the present method are those which do not undergo changes durmg the oxidative reactions m the 2nd and 4th steps of the present Process and the 2nd step of Process IV below for the preparation of compound of the formula (VI) and also durmg the Wittig reaction of the 3rd step of said Process, and can be easily deprotected m the 4th step to give leavmg groups which are easily separable from, for example. Compound A for purification thereof, which corresponds to a compound of the formula (VI) wherem OR is 5-hydroxy, X is hydrogen and double bond is m Z-configuration. Examples of such a hydroxy-protectmg group mclude alkyl, alkoxyalkyl, acyl, aralkyl, alkylsulfonyl, arylsulfonyl/ alkyl-substituted silyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl or tetrahydropyranyl. Considermg the requirements that a protectmg group should survive durmg the Wittig reaction conducted under strong basic conditions, be easily deprotected, for example, m the 4th step for the preparation of Compound A, and be separable from Compound A, arylsulfonyl is more preferred and benzenesulfonyl is particularly preferred. Benzenesulfonyl group is relatively stable to base m anhydrous solvents and, upon deprotection, gives benzenesulfonic acid which is water-soluble and is easily separated from the from product of the formula (VI)• The protection and deprotection can be carried out by a method known m the art. For example, m the case of benzenesulfonyl group, the mtroduction of benzenesulfonyl group is carried out m a manner similar to that for the mtroduction of propargyl group by using benzenesulfonyl chloride. [Step 2] This step is related to oxidation of the compound (II), There have been known oxidizmg methods which use, for mstance, aqueous hydrogen peroxide - acetic acid (J. Am, Chem, Soc, 87, 1109-1114 (1965)),aqueous hydrogen peroxide - titanmm(III) chloride (Synthesis 1981, 204-206), m-chloroperbenzoic acid (Org. Synth., 64, 157-163 (1985)), or sodmm metaperiodate (J. Org. Chem., 27, 282-284 (1962)). m the present step, it is preferred to use a slightly excess amount of 30 % aqueous hydrogen peroxide m an alcoholic solvent such as ethanol, methanol, isopropanol or tert-butanol solution contammg formic acid. The reaction is accomplished withm several tens mmutes to several hours under coolmg or at room temperature. [Step 3] This step is related to the conversion of the compound (III) mto the hydroxymethyl compound (IV) by thermal rearrangement reaction. The thermal rearrangement reaction m this step is carried out accordmg to the method described m J. C, S. Chem. Comm,, 1974, 848-849. Examples of preferred solvents for this reaction mclude dioxane, 1,2-dimethoxyethane, propyl acetate and 3-pentanone. The reaction is accomplished by refluxmg m a solvent for several hours followed by addmg to the resultant mtermediate an acid (p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid, etc) [Step 4] This step is related to the oxidation of the compound (IV) to provide carboxylic acid (I). The oxidation can be carried out either directly or m a stepwise manner. Examples of oxidizmg agent for convertmg an aromatic primary alcohol to the correspondmg carboxylic acid directly mclude chromic acids (Synthesis. 1986, 285-288), potassmm permanganate (J. Org, Chem., 18, 806-809 (1953)) and ruthenmm oxides (J, C, S, Chem, Comm,, 1979, 58-59)), However, these methods have disadvantages m not only the yield but also the followmg matters. For mstance, the reaction time is long, the detoxification treatment of oxidizmg agent is needed followmg the reaction, the reagents are unstable and/or they mvolve complicated operations. On the contrary, m some cases, a stepwise oxidation wherem a primary alcohol is oxidized to an aldehyde and then to a carboxylic acid may be of advantage with regard to yield. m general, the oxidation of alcohol to aldehyde has been carried out by usmg an oxidizmg agent of chromic acid series, for example, Jones reagents (J. Org. Chem., 40, 1664^1665 . (1975)), Collms reagents (J. C. S. Chem, Comm., 1972 1126)), pyridmmm chlorochromate (Tetrahedron Lett., 2647-2650 (1975)). It has been also known a method which uses manganese dioxide (Helv. Chim. Acta., 39, 858-862 (1956)) or dimethyl sulfoxide (Swern oxidation, J. Org, Chem., 43, 2480-2482 (1978)), However, these existmg methods have disadvantages. For example, chromic acids are toxic to human body and must be detoxified after use. Further, the Swern oxidation usmg dimethyl sulfoxide-oxalyl chloride is not suited for a large scale production because it is accompanied by the generation of carbon monoxide harmful to workers and sulfurous odor and also it must be carried out at low temperature, for example, between -50°C and -7 8°C. Alcohol (IV) can be converted mto aldehyde (IV) almost quantitatively by a method wherem an alcohol (IV) is oxidized with an oxidizmg reagent such as halo oxoacid m the presence of 2, 2, 6, 6-tetramethylpiperidme-l-oxyl or the like (referred to as ""TEMPOS") accordmg to the description m a literature (e.g., J. Org. Chem., 52, 2559-2562 (1987)), whereby the problems of the existmg methods are solved. Examples of TEMPOS usable mclude 2,2,6,6-tetramethylpiperidme-l-oxyl, 4-methoxy-2,2,6,6-tetramethylpiperidme-l-oxyl, 4-acetylammo-2, 2, 6, 6-tetramethylpiperidme-1-oxyl, 4-benzoyloxy-2,2,6,6-tetramethylpiperidme-1-oxyl, and 4-cyano-2,2,6,6-tetramethylpiperidme-1-oxyl. Examples of usable halo oxoacids mclude sodmm hypochlorite, sodmm hypobromite, sodmm bromite and higher bleachmg powder. A solution of an oxidizmg agent may be adjusted to, for example, pH 8.5 to 9.5 with a mmeral acid such as sodmm hydrogen carbonate, hydrogen chloride or sulfuric acid. Alternatively, a solution of an oxidizmg agent may be added m the presence of sodmm hydrogen carbonate. The reaction can be accomplished withm several mmutes to several tens mmutes at temperature from ice-coolmg to room temperature m a solvent such as ethyl acetate, acetonitrile or dichloromethane. When the reaction solution contammg the resultant aldehyde (TV) is acidified and sodmm chlorite and aqueous hydrogen peroxide are added thereto, the aldehyde is converted mto carboxylic acid under ice-coolmg withm several tens mmutes to several hours. If desired, the product may be further subjected to the deprotection of 5-hydroxy-protectmg group and/or conversion mto reactive derivatives at 3-carboxyl group. Such "^ reactive derivative" mcludes the correspondmg acid halides (e.g., chloride, bromide/ iodide), acid anhydrides (e.g., mixed acid anhydride with formic acid or acetic acid), activated esters (e.g., succmimide ester), and the like, and mcludes acylatmg agents generally used for the acylation of ammo group. For example, to obtam acid halides, a carboxylic acid is reacted with thionyl halide (e.g., thionyl chloride), phosphorous halide (e.g., phosphorous trichloride, phosphorous pentachloride), oxalyl halide (e.g., oxalyl chloride), or the like, accordmg to a known method (e.g., Shm-jikken Kagaku Koza, vol. 14, p. 1787 (1978); Synthesis 852-854(1986); Shm-jikken Kagaku Koza vol. 22, p. 115 (1992)). wherem R and R1 are as defmed above-[Step 1] This step is related to the protection of 5-hydroxy group of compound (7). The compound (7) as the startmg material of the present step is known m a 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 this compound is protected appropriately m a manner similar to that descried m the 1st step of Process I above. For example, when benzenesulfonyl group is used, the compound is added to benzenesulfonyl chloride m the presence of an morganic base such as sodmm carbonate or potassmm carbonate, or an organic base such as triethylamme or tripropylamme. Example of preferred solvent mcludes acetone, ethyl acetate and tetrahydrofuran. The reaction is accomplished withm several mmutes to several hours at temperature from room temperature to the boilmg pomt of the solvent. The compound (VII) can be also synthesized by a broadly used method, commonly known as "Schotten-Baumann reaction". [Step 2] This step is related to the mtroduction of acetyl group to the 3-position of the compound (VII) by Friedel-Crafts reaction. The mtroduction of acetyl group is, for example, carried out usmg acetyl chloride or acetyl bromide m the presence of a catalyst, for example, a Lewis acid such as alummmm chloride, ferric chloride, zmc chloride, tm chloride and boron trifluoride. Example of usable solvent mcludes carbon disulfide, nitrobenzene or a halogenated hydrocarbons such as methylene chloride or ethylene chloride. The reaction is m general accomplished withm several hours at temperature of ice-coolmg to room temperature. The 2-acetyl compound slightly produced as a by-product is easily separable by recrystallization. [Step 3] This step is related to the conversion of the compound (VIII) mto a carboxylic acid (I) or a reactive derivative thereof through the oxidation of the acetyl group m the presence of a salt of hypohalous acid. Examples of preferred hypohalogenite mclude alkali metal or alkalme earth metal salts of hypohalous acids, and potassmm, sodmm or calcmm salt of hypochlorous or hypobromous acid is especially preferred. m an aqueous solution of such a salt, the oxidation progresses at relatively low temperature. However, dioxane or 1,2-dimethoxyethane may be used as a solvent so as to mcrease the solubility of the compound to be oxidized. The reaction is accomplished withm several hours to several tens hours at room temperature or with heatmg. wherem R and X are as defmed above and the double bond represents E- or Z-configuration. This process is related to the synthesis of a compound of the formula (VI) by reactmg a compound of the formula (I) or a reactive derivative thereof obtamed m Process I or II above with a compound of the formula (V)• The compound (V). used m the present process is obtamable accordmg to the method described m Japanese Patent Publication (KOKOKU) No. 6-23170 (23170/1994). The reaction can be carried out under ordmary conditions for acylation of ammo group. For example, when a carboxylic acid halide is used, the reaction is carried out accordmg to a method commonly known as "Schotten-Baumann reaction". m general, carboxylic acid halide is added dropwise to an aqueous alkalme solution of amme with stirrmg and under coolmg while removmg the generatmg acid with alkali. Alternatively, when a carboxylic acid is used as a free acid not a reactive derivative, the reaction can be conducted conventionally m the presence of a couplmg agent generally used m the couplmg reaction between an amme and a carboxylic acid such as dicyclohexylcarbodiimide (DCC), l-ethyl-3-(3-dimethylammopropyl) carbodiimide or W,N'-carbonyldiimidazole. wherem R and X are as defmed above and the double bond represents E- or Z-configuration. [Step 1] This step is related to the preparation of a compound of the formula (IX) by reactmg a compound of the formula (I) or a reactive derivative thereof with a compound of the formula (V) or its salt m a manner similar to that described m Process III above. The preparation of some of the compounds of the formula (V) is described m Chem. Pharm, Bull. Vol.37, No. 6 1524-1533 (1989). [Step 2] This step is. related to the preparation of an aldehyde of the formula (X) by oxidizmg a compound of the formula (IX). The reaction can be carried out for several hours under coolmg or at room temperature usmg an oxidizmg agent selected from chromic acid series such as Jones reagents/ Collms reagents, pyridmmm chlorochromate, pyridmmm dichromate or dimethyl sulfoxide-oxalyl chloride m a solvent such as chlormated hydrocarbons (chloroform, dichloromethane, etc.), ethers (ethyl ether, tetrahydrofuran, etc.), acetone or benzene. [Step 3] This step is related to the formation of a double bond by reactmg a compound of the formula (X) with an ylide (Ph3P=CH(CH2) 3COOH) . The reaction for providmg a double bond can be carried out m a conventional manner for Wittig reaction. The ylides used m the reaction can be synthesized, m the presence of a base, by treatmg a phosphonmm salt which has been synthesized from triphenylphosphme and an alkyl halide havmg a desired alkyl group to be condensed, for example, 5-bromopentanoic acid. Examples of a base mclude dimsyl sodmm, dimsyl potassmm, sodmm hydride, n-butyl lithmm, potassmm t-butoxide and lithmm diisopropylamide. The reaction is accomplished withm several hours at room temperature m a solvent such as ether, tetrahydrofuran, n-hexane, 1,2-dimethoxyethane or dimethyl sulfoxide, [Step 4] m this step, a compound (VI) wherem R is hydroxy-protectmg group is optionally deprotected to give compound (VI-1). The reaction can be carried out m a conventional manner usmg a catalyst such as hydrochloric acid, sulfuric acid, sodmm hydroxide, potassmm hydroxide or barmm hydroxide, or the like. The reaction is accomplished withm several tens mmutes to several hours with heatmg m a solvent such as methanol-water, ethanol-water. acetone-water/ acetonitrile-water, or the like, preferably dimethyl sulfoxide-water. The followmg Examples are provided to further illustrate the present mvention m more detail and should not be mterpreted m any way as to limit the scope thereof. The abbreviations used m the Examples have the followmg meanmgs: Ph: phenyl Ac: acetyl TEMPO: 2f 2, 6, 6 —tetramethylpiperidme-1-oxyl Exap;iplg i (1) step 1: 4-(2-Propyn-l-ylthio)phenyl benzenesulfonate (2) 4-Mercaptophenol (1) (37.85 g, 300 mmol) and propargyl bromide (42.82g/ 360 mmol) were dissolved m ethyl acetate (757 ml). To the solution was added dropwise triethylamme (42.5g, 420 mmol) over 25 mmutes with stirrmg and under ice-coolmg. After stirrmg for another 1.5 hours at the same temperature, triethylamme (42.5g, 420 mmol) was added m one portion, and benzenesulfonyl chloride (63.58g, 360 mmol) was added dropwise over 20 mmutes. After keepmg 1 hour at the same temperature, the coolmg bath was removed and the mixture was stirred for 30 mmutes at room temperature and partitioned mto two layers by addmg ice- water (500 ml) and 2N hydrochloric acid (110 ml). The aqueous layer was extracted with ethyl acetate (200 ml) . The combmed organic layer was washed with water, dried over anhydrous magnesmm sulfate, and then the solvent was distilled off under reduced pressure to provide 100.04g of the title compound (2) as oil. Crude yield: 109%. IR (CHCI3); 3306, 3071, 3031, 3019, 3009, 1585, 1486, 1449, 1378 cm' 'H NMR5 (CDCI3) , 300MHz; 2.23 (IH, t, J=2.7Hz), 3.56 (2H, d, J=2.7Hz), 6.94 and 7.34 (each 2H, each d, J=8.7Hz), 7.51-7.56 (2H, m), 7.68 (IH, m), 7.82-7.85 (2H, m) (2) Step 2: 4-(2-Propyn-l-ylthio)phenyl benzenesulfonate (3) The compound (2) (60.8g, 183 mmol) prepared m step (1) above was dissolved m formic acid (30.4 ml) and methanol (122 ml), and 31% aqueous hydrogen peroxide (26.29g, 240 mmol) was then added. After 3.5 hours, ice-water (240 ml) was added and the mixture was extracted with ethyl acetate (2 x 300 ml). The combmed organic layer was washed with 5% aqueous sodmm carbonate and water, dried over anhydrous magnesmm sulfate and the solvent was then distilled off under reduced pressure to provide 65.47g of the title compound (3) as oil. Crude yield: 117%. IR (CHCI3); 3305, 3066, 3032, 3012, 1586, 1486, 1449, 1382 cm' 'H NMRSlCDCls) , 300MHz; 2.34 (IH, t, J=3.9Hz), 3.58 and 3.68 (each IH, 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 (IH, m), 7.82-7.87 (2H, m) (3) Step 3: 5-Benzenesulfonyloxy-3-hydroxymethylbenzo [b] thiophene (4) The compound (3) (65.47g, 183 mmol) obtamed m above (2) was dissolved m 1,2-dimethoxyethane (1.6L) and the solution was refluxed for 4 hours. To the solution were added water (64 ml) and p-toluenesulfonic acid monohydrate (19.2g, 100 mmol) and refluxmg was contmued for 2 hours. The reaction mixture was concentrated under reduced pressure. After water (200 ml) was added to the resultmg oil, the mixture was extracted with ethyl acetate (300 ml). The organic layer was washed with aqueous sodmm hydrogen carbonate and water, dried over anhydrous magnesmm sulfate and then the solvent was distilled off under reduced pressure to provide 60.18g of the title compound (4) as oil. Crude yield: 103%. IR (CHCI3); 3609, 3067, 3033, 3013, 2935, 2878, 1589, 1566, 1449, 1435, 1376 cm"' 'H NMR6 (CDCI3) , 300MHz; 4.78 (2H, d, J=0.9Hz), 6,98 (IH, dd, J=2.4 and 8.7Hz), 7.26 (IH, s), 7.43-7.45 (2H, m), 7^50"7.55 (2H, m), 7.66 (IH, m), 7.73 (IH, d, J=8.7H2 ), 7,83-7,86 (2H, m) (4) Step 4: 5-Benzenesulfonyloxyben2o [b] thiophene-3-carboxilic acid (6) The compound (4) (51.2 6g, 155 mmol) prepared m above (3) was dissolved m acetonitrile (1.54L), and TEMPO (2, 2, 6, 6-tetramethylpiperidme-l-oxyl, 250 mg, 0.01 eq.) was added thereto. To the mixture was added dropwise 0,81 N aqueous sodmm hypochlorite, which had been prepared by dilutmg 1.63 N aqueous sodmm hypochlorite (150ml) with water (75 ml), adjustmg pH 8.6 with 1 N sulfuric acid, and adjustmg the total volume to 300ml, over 15 mmutes, while mamtammg the mner temperature between — iT) and 8°C. After stirrmg for 25 mmutes at this temperature, 1 N aqueous sodmm sulfite (32 ml) was added. Subsequently, 79% sodmm chlorite (27.48g, 240 mmol) and 31% aqueous hydrogen peroxide (23.26g, 212 mmol) were added under ice-coolmg. The coolmg bath was removed and the mixture was stirred for 2 hours. The reaction was diluted with water (1.5L), adjusted to pH 3 with 1 N hydrochloric acid and the deposited crystals were filtered, and washed twice with water (200 ml), acetonitrile (50 ml) to provide 32.4g of crude crystals. The crude crystals (32.4g) were suspended m acetonitrile (224 ml), refluxed for 15 mmutes and cooled on ice. The crystals were filtered and washed with acetonitrile (65 ml) to provide 26.79g of the title compound (6). Yield: 51.7%, mp 202-203t;. IR (Nujol): 3102, 2925, 2854, 2744, 2640, 2577, 1672, 1599, 1558, 1500, 1460, 1451 cm' NMR5 (CDCI3), 300MHz; 7.16 (IH, dd, J=2.7 and 9.OH2), 7.55-7.61 (2H, m), 7.73 (IH, m), 7.81 (IH, d, J=9.0H2), 7.90-7.94 (2H, m), 8.16 (IH, d, J=2.7Hz), 8,60 (IH, s) Elemental Analyses for C15H10O5S2 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) 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)] (1.36g, 9.05 mmol) and triethylamme (1.89ml, 13.6 mmol) were dissolved m tetrahydrofuran (10 ml). To the solution was added dropwise a solution of benzenesulfonyl chloride (l,92g, 10.9 mmol) m tetrahydrofuran (3 ml). After bemg stirred for 2 hours, the reaction mixture was diluted with water and extracted with toluene. The organic layer was washed with water, dried over anhydrous magnesiiom sulfate and then the solvent was distilled off under reduced pressure. The residue was chromatographed over silica gel (5:1 hexane : ethyl acetate) and then recrystallized from hexane contammg small amount of ethyl acetate to provide 2.28g of the title compound (8). Yield: 86.8%, mp 80-81°C. IR (Nujol): 1599, 1579, 1564, 1497, 1448, 1440, 1415, 1352 cm"' 'H NMR5 (CDCI3) ; 300MHz; 6,92 (IH, dd, J=2.4 and 8.7H2), 7.26 (IH, dd, J=0.9 and 5.4Hz), 7.47 (IH, d, J=2.4Hz), 7.51 (IH, d, J=5.4Hz), 7.52-7.55 (2H, m), 7.67 (IH, m), 7.74 (IH, d, J=8.7Hz), 7.83-7.87 (2H, m) Elemental Analyses for C14H10O3S2 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) Powdered alummum chloride (1.34g, 10 mmol) was suspended m dichloromethane (10 ml). To the suspension was added dropwise acetyl chloride (1.02ml, 14.3 mmol) over 5 mmutes with stirrmg and under ice-coolmg. Subsequently, a solution of the compound (8) (2.075g, 7.2 mmol) prepared above m dichloromethane (6 ml) was added dropwise over 15 mmutes. After bemg stirred for 2 hours at the same temperature and then for 2.5 hours at room temperature, the solution was poured mto ice-water and extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesmm sulfate and then the solvent was distilled off under reduced pressure. The resultmg residue was recrystallized from ethyl acetate (3 ml) and hexane (3 ml) to provide 2.01g of the title compound (9). Yield: 84.4% mp 129-130°C. IR (Nujol): 3094, 1672, 1619, 1595, 1556, 1494, 1450, 1437, 1428, 1369 cm"' 'H NMR6 (CDCI3) ; 300MHz; 2.58{3H, s) , 7.22 (IH, ddd, J=0.6, 2.4 and 9.0Hz), 7.52-7.58 (2H, m) , 7.69 (IH, m) , 7.79 (IH, d, J=9.0Hz), 7.87-7.91 (2H, m), 8.27 (IH, dd, J=0.6 and 2.4Hz), 8.31 (IH, s) Elemental Analyses for C16H12O4S2 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[h]thiophene-3-carboxylic acid (6) The compound (9) (6.65g, 20 lumol) prepared m above (2) was dissolved m dioxane (50 ml), and 10% sodmm hypochlorite (46,2 ml) was added over 20 mmutes with stirrmg while mamtammg the temperature at 10-12°C. After 7 hours, the reaction mixture was diluted with ice-water (80 ml) and acidified with cone, hydrochloric acid (5.2 ml). The deposited crystals were filtered, washed with water, dried to provide 5.84g of crude crystals. The 5.84g of the crude crystals were recrystallized from methanol (66 ml) and water (16 ml) to provide 5.51g of the title compound (6). Yield: 82.4%. mp 203-204'C. This compound is identical to the compound (6) prepared m Example 1. Reference Example 1 5-Benzenesulfonyloxybenzo [b] thiophene-3-carbonyl chloride (10) 5"Benzenesulfonyloxybenzo [b] thiophene-3-carboxylic acid (6) (5,582g, 16.7 mmol) prepared m Examples above was refluxed for 1.5 hours with dimethylformamide (1 drop), thionyl chloride (3.57ml, 50 mmol) and toluene (22 ml), and the solvent was removed under reduced pressure to provide 5.89g of the title compound (10). Reference Example 2 (1) Step 1: 5"Hydroxybenzo[b]thiophene-3-carboxylic acid (11) S-Benzenesulfonyloxybenzo[b]thiophene-3-carboxylic acid (6) (100 mg, 0.3 mmol) prepared m Examples above was dissolved m 1 N sodmm hydroxide (1.2 ml) and heated at 40°C for 8 hours with stirrmg. To the reaction solution was added 1 N hydrochloric acid (1.2 ml), and the deposited crystals were filtered, washed with water and dried to provide 58 mg of the title compound (11). Yield: 96.6% mp 262-263^:. This compound (11) is identical to 5- hydroxybenzo [b] thiophene--3-carboxylic acid described m M. Martm-Smith et al. J. Chem. Soc (c) , 1899-1905 (1967). (2) Step 2: S-Acetoxybenzo [b] thiophene--3-carboxylic acid (12) 5-Hydroxybenzo [b] thiophene-3--carboxylic acid (11) (1,140 mg) prepared m above (1) was dissolved m acetic anhydride (2 ml), pyridme (4 ml). After 3 hours, water was added and the mixture was contmuously stirred under ice-coolmg for 1.5 hours. The deposited crystals were filtered, washed with water and dried to provide 1,349 mg of the title compound (12). Yield: 97,3% rap 239-240°C. ^H NMR6 (CDCI3) , 3OOMH2; 2.37(H, s) , 7,20 (IH, dd, J=2.4 and 8.7H2), 7.87 (IH, d, J=8,7Hz), 8.34 (IH, d, J=2.4H2), 8.57 (IH, s) (3) Step 3: 5-Acetoxybenzo [b] thiophene-3-carbonyl chloride (13) 5-Acetoxybenzo[b]thiophene-3-carboxylic acid (12) (1,349 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 provide 1,454 mg of the title compound (13). Example 3 (5Z)-7-[(IR,2R,25, 55)-2-(5-Hydroxybenzo[b]thiophen-3-ylcarbonylammo)-lO-norpman-3-yl]-5-heptenoic acid (17) (1) step 1: Preparation of [3-[{1R,2R,3R,5S)-3-(l-Hydroxyethyl)-lO-norpman-2-yl]carbamoylbenzo[b]thiophen-5-yl] benzenesulfonate (14) Benzoic acid salt of ( + )-2-[ (IR, 2JR, 3i?, 55)-2-Ammo-lO-norpman-3-yl] ethanol (described m Cheiti. Pharm. Bull, Vol,37, No. 6 1524-1533(1989) (V'-l) ) (5.1g, 16.7 mmol) was suspended m water (10 ml). To the suspension was added 1 N hydrochloric acid (17 ml) and deposited benzoic acid was removed by extractmg with ethyl acetate. The organic layer was washed with water (10 ml). To the combmed aqueous layer was added 4 N sodmm hydroxide (9.2 ml, 36.8 mmol) under ice-coolmg. A solution of 5- benzenesulf onyloxybenzo [b] thiophene-3-carbonyl chloride (10) (5.89g,16.7 mmol) m tetrahydrofuran (36 ml) was then added dropwise over 15 mmutes with stirrmg. After stirrmg for 1 hour at the same temperature, 1 N hydrochloric acid (4 ml) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesmm sulfate and then the solvent was distilled off under reduced pressure to provide S.OOg (95.6%) of the title compound (14) as colorless amorphous. ^H NMR5 (CDCI3) , 300MHz; 0.96 (IH, d, J=9. 9Hz) , 1.12 and 1.26 (each 3H, each s), 1.50-2.42(9H, m), 3.69-3.82 (2H, m) , 4.30 (IH, m), 6.21 (IH, d, J=8.1Hz), 7.06 (IH, dd, J=2.4 and 8.7Hz), 7.51-7.56 (2H, m), 7.67 (IH, m), 7.73 (IH, d, J-8.7HZ), 7.85 -7.88 (2H, m), 7.88 (IH, s), 8.06 (IH, d, J=2.4Hz). [alo" +35.7° (c=1.00%, CH3OH) (2) Step 2: Preparation of [3-[{1R,2R,3R,SS)-3-Formylmethyl-lO-norpman-2-yl]carbamoylbenzo[b]thiophen-5-yl] benzenesulfonate (15) To dimethyl sulfoxide (3.16 ml, 44.5 mmol) dissolved m dimethoxyethane (50 ml) was added oxalyl chloride (1.91 ml, 21.9 mmol) under coolmg at —60°C- —65°C. A solution of compound (14) (7.352g, 14,7 mmol) m 1,2-dimethoxyethane (58 ml) was added dropwise at the same temperature. After stirrmg the mixture at —55°C- —60°C for 30 mmutes, triethylamme (6.1 ml) was added and, 30 mmutes later, the coolmg bath was removed to allow the mixture to warm up to room temperature. The reaction mixture was diluted with water (100 ml) and extracted with toluene. The organic layer was washed with water, dried over anhydrous magnesmm sulfate and then the solvent was distilled off under reduced pressure- The resultmg residue was purified by chromatography on silica gel (hexane : ethyl acetate =5:5- 4:6) to provide 7.32g (100%) of the title compound (15) as colorless amorphous. IR (CHCI3); 3443, 3093, 3066, 3030, 3016, 2925, 2871, 2828, 2729, 1720, 1655, 1599, 1558, 1513, 1377 cm"' 'H NMR6 (CDCI3) , 300MHz; 0.97 (IH, d, J=10.2Hz), 1.17 and 1.28(each 3H, each s), 1.46 (IH, m) , 2.03 (IH, m) , 2.22 (IH, m), 2.36-2.60(3H, m), 2.69 (IH, ddd, J=1.2, 8.7 and 17.4Hz), 3.14 (IH, dd, J=4.5 and 17.4Hz), 4.28 (IH, m), 6.18 (IH, d, J=8.1Hz), 7.09 (IH, dd, J=2.4 and 8.7Hz), 7.50-7.55 (2H, m), 7.67 (IH, m), 7.75 (IH, d, J=8.7Hz), 7.85-7.89 (2H, m), 7.89 -(IH ,s), 8.03 (IH, d, J=2.4Hz), 9.80 (IH, d, J=1.2Hz) [a]D"+31.8° (c=1.00%, CH3OH) (3) Step 3: Preparation of (5Z)-7-[ (li?, 2i^, 3S, 5S)-2-(5-Benzenesulfonyloxybenzo[b]thiophen-3-ylcarbonylammo)-10-norpman-3-yl]-5-heptenoic acid (16) 4-Carboxybutyltriphenylphosphonmm bromide (12.17g, 27.5 mmol) and potassmm t-butoxide (7.19g, 64.1 mmol) were suspended m tetrahydrofuran (64 ml) and stirred for 1 hour under ice-coolmg. To the reaction mixture was added over 15 mmutes a solution of the compound (15) (9.11g, 18.3 mmol) prepared m above (2) m tetrahydrofuran (27 ml) and the mixture was contmuously stirred 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 adjustmg the aqueous layer to pH 8.1 with 5 N hydrochloric acid (4.8 ml), anhydrous calcmm chloride (8.1g, 73 mmol) dissolved m water (16 ml) was added, and the mixture was extracted with ethyl acetate (2 x 100 ml). Water (100 ml) was added to the organic layer, and the aqueous layer was adjusted to below pH 2 with 5 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesmm sulfate and then the solvent was distilled off under reduced pressure to provide ll,06g of the compound (16). The compound (16) was used m the next reaction without further purification. (4) Step 4: Preparation of (5Z)-7-[ (li?, 2iR, 3S, 5S)-2-(5-Hydroxybenzo [b] thiophen-3-ylcarbonylammo) -lO-norpman-3-yl]-5-heptenoic acid (17) (Compound A)) The compound (16) (11.06g, 18.3 mmol) prepared m above (3) was dissolved m dimethyl sulfoxide (22 ml). After addmg 4 N sodmm hydroxide (27.5 ml), the mixture was heated at 55°C for 2 hours with stirrmg. The reaction mixture was diluted with water (130 ml) and washed with toluene (2 x 65 ml). The aqueous layer was acidified with 5 N hydrochloric acid and extracted with ethyl acetate- The organic layer was washed with water, dried over anhydrous magnesmm sulfate, and the solvent was distilled off under reduced pressure to provide 8.26g of the crude objective compound which was then dissolved m methanol (40 ml) and water (16 ml). The solution was seeded and gradually cooled with stirrmg. The deposited crystals were filtered and washed with water: methanol (2:5) to provide 6.35g of the objective compound. Yield: 78.6%. The crystals were dissolved m methanol (40 ml). To the solution was added water (12 ml) over 7 mmutes with stirrmg. The mixture was seeded and contmuously stirred for 1 hour at 25°C. After addmg water (7 ml) over 40 mmutes, 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 provide 6.14g of the objective compound (17) which was almost colorless. Yield: 76.0%, mp 145-146°C. IR (Nujol); 3313, 3096, 3059, 3001, 1717, 1627, 1603, 1548, 1469, 1440 cm' 'H NMR5 (CDClj) , 300MHz; 1.02 (IH, d, J=10.2H2), 1.12 and 1.24 (each 3H, each s), 1.56-2.55(14H, m), 4.29 (IH, m) , 5.32-5.51 (2H, m), 6.20 (IH, d, J=9.3Hz), 7.01 (IH, dd, J=2.4 and g.OHz), 7.66 (IH, d, J=9.0Hz), 7.69 (IH ,5), 8.03 (IH, d, J=2.4H2) [alD' + 50.7° (c=1.01, CH3OH) Elemental Analyses for C25H31NO4S 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 CLAIMS 1. A process for producing a compound of the formula (I): wherein R is hydrogen or a hydroxy-protecting group, or a reactive derivative thereof, which comprises subjecting 4-mercaptophenol to reactions for introduction of a propargyl group and protection of hydroxyl group to yield a compound of the formula (II): wherein R1 is a hydroxy-protecting group; oxidizing the compound (II) to yield a compound of the formula (III): wherein R1 is a hydroxy-protecting group; subjecting the compound (III) to thermal rearrangement reaction to yield a compound of the formula (IV): wherein R1 is as defined above; and subjecting the compound (IV) to stepwise oxidation of hydroxymethyl group and optionally deprotection. 2. The process of claim 1, wherein the hydroxy-protecting group represented by R1 is alkyl, alkoxyalkyl, acyl, aralkyl, alkylsulfonyl, arylsulfonyl, alkyl-substituted silyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl or tetrahydropyranyl. 3. The process of claim 1, wherein the hydroxy-protecting group represented by R1 is arylsulfonyl. 4. (Amended) A process for producing a compound of the formula (VI): wherein R is hydrogen or a hydroxy-protecting group and X is hydrogen or alkyl, and double bond represents either E-or Z-configuration, or a pharmaceutically acceptable salt or hydrate thereof, which comprises subjecting 4-mercaptophenol to reactions for introduction of a propargyl group and protection of hydroxyl group to yield a compound of the formula (II): wherein R1 is a hydroxy-protecting group; oxidizing the compound (II) to yield a compound of the formula (III) : wherein R1 is a hydroxy-protecting group; subjecting the compound (III) to heat rearrangement reaction to yield a compound of the formula (IV): wherein R1 is as defined above; and subjecting the compound (IV) to stepwise oxidation of hydroxymethyl group and optionally deprotection to yield a compound of the formula (I) : wherein R is as defined above, or a reactive derivative thereof; subjecting the compound of the formula (I) or a reactive derivative thereof to the following reactions: (1) reaction with a compound of the formula (V) wherein X is hydrogen or alkyl; or (2) reaction with a compound of the formula (V): or a salt thereof followed by oxidation and reaction with an ylide under the conditions for Wittig reaction; and (3) optionally deprotection. 5. A process for producing a compound of the formula (I) : wherein R is hydrogen or a hydroxy-protecting group, or a reactive derivative thereof, which comprises subjecting 5-hydroxybenzo [jb] thiophene to protecting reaction to yield a compound of the formula (VII): wherein R1 is a hydroxy-protecting group; reacting the compound (VII) with acetyl halide under the conditions for Friedel-Crafts reaction to yield a compound of the formula (VIII): wherein R1 is a hydroxy-protecting group; subjecting the compound (VIII) to oxidation of acetyl group and optionally deprotection. 6. The process of claim 5, wherein the hydroxy-protecting group represented by R1 is alkyl, alkoxyalkyl, acyl, aralkyl, alkylsulfonyl, arylsulfonyl, alkyl-substituted silyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl or tetrahydropyranyl. 7. The process of claim 5, wherein the hydroxy-protecting group represented by R1 is arylsulfonyl. 8. (Amended) A process for producing a compound of the formula (VI) : wherein R is hydrogen or a hydroxy-protecting group and X is hydrogen or alkyl, and double bond represents either E-or Z-configuration, or a pharmaceutically acceptable salt or hydrate thereof, which comprises subjecting 5-hydroxybenzo [jb] thiophene to protecting reaction to yield a compound of the formula (VII): wherein R1 is a hydroxy-protecting group; reacting the compound (VII) with acetyl halide under the conditions for Friedel-Crafts reaction to yield a compound of the formula (VIII): wherein R1 is a hydroxy-protecting group; subjecting the compound (VIII) to oxidation of acetyl group and optionally deprotection to yield a compound of the formula (I): wherein R is as defined above or a reactive derivative thereof; subjecting the compound (I) or a reactive derivative thereof to the following reactions: (1) reaction with a compound of the formula (V) wherein X is as defined above; or (2) reaction with a compound of the formula (V): or a salt thereof followed by oxidation and reaction with an ylide under the conditions for Wittig reaction; and (3) optionally deprotection. 9. A compound of the formula (I) wherein R is arylsulfonyl or a reactive derivative thereof. 10. A compound of the formula (I) wherein R is benzenesulfonyl or a reactive derivative thereof. A process for producing a compound substantially is herein described and exemplified. A compound of the formula substantially as herein described and exemplified.

Full Text

DESCRIPTION
PROCESS FOR PREPARING 5-HYDROXYBENZO [b] THIOPHENE-3-CARBOXYLIC ACID DERIVATIVES
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 ART
5-Hydroxybenzo [b] thiophene-3-carboxylic acid derivatives of the general formula (I) :

wherein R is hydrogen or a hydroxy-protecting group are important starting materials in the synthesis of pharmacologically active compounds. For example, a compound of the formula (I) is essential in the synthesis of benzothiophenecarboxamide derivatives of the general formula (VI):

wherein R is as defined above and X is hydrogen or alkyl. The benzothiophenecarboxamide derivatives are specific antagonists of PGD2 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, for example, systemic mastocytosis, disorder of systemic mast cell activation, tracheal contraction, asthma, allergic rhinitis, allergic conjunctivitis, urticaria, injury due to ischemic reperfusion, inflammation, and atopic dermatis (WO97/00853, PCT/JP97/04527 {W098/25919)). Among compounds of the formula (VI), a compound wherein OR is 5-hydroxy and X is hydrogen (hereinafter, referred to as "Compound A") has especially high antagonistic effect on PGD2, showing an excellent anti-nasal occlusion activity, and is contemplated to be a promising drug for treating nasal occlusion.
DISCLOSURE OF THE INVENTION
A process for preparing the above-mentioned compound is illustrated by the following reaction scheme (W098/25919):

In order to clinically apply Compound A widely, it is essential to establish a process for preparing a starting material/ the compound (I), which process is safe, efficient and industrially applicable.
However, it is difficult to synthesize benzothiophene derivatives having 5-hydroxyl group like the compound (I) and there have been no methods industrially applicable so far. The existing methods involve various complicated processes and are inefficient and of low yield. For example, there have been methods wherein 5-acetoxybenzo [b] thiophene is brominated to yield 3-bromo-5-acetoxybenzo [b] thiophene, which in turn is re-protected at the 5-acetoxy group with a benzyl group to yield 3-bromo-5-benzyloxybenzo [b] thiophene, which is followed by metallization with magnesium, introduction of carbon dioxide and removal of the benzyl group (J. Chem. Soc. (C). 1967, 1899-1905); or 5-bromobenzo[b]-thiophene is subjected to Friedel-Crafts reaction to yield 3-acetyl-5-bromobenzo [b] thiophene, which is followed by oxidation with sodium hypochlorite to yield 5-bromobenzo[b]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 from the reaction products above. However, the starting material such as 5-hydroxybenzo [b]-thiophene or 5-bromobenzo[b]thiophene is not commercially available and had to be synthesized from an appropriate reagent (e.g., J. Am. Chem. Soc., 57, 1611(1935), J. Heterocyclic Chem., 25, 1271(1988)) in all cases, which have made the synthetic process longer and complex.
The present invention solves the problems of the existing methods and provides a method for the preparation of the compounds of the formula (I), which method is industrially applicable, efficient and safe.
Thus, the present invention provides a process for preparing a compound of the formula (I):

wherein R is hydrogen or a hydroxy-protecting group, or .a reactive derivative thereof comprising subjecting 4-mercaptophenol to reactions for introduction of a propargyl group and protection of hydroxyl group to yield a compound of the formula (II):

wherein R1 is a hydroxy-protecting group; oxidizing the

compound (II) to yield a compound of the formula (III):

wherein R1 is a hydroxy-protecting group; subjecting the compound (III) to thermal rearrangement reaction to yield a compound of the formula (IV):

wherein R1 is as defined above; and subjecting the compound (IV) to stepwise oxidation of hydroxymethyl group and
optionally deprotection.
The present invention also provides a process for
preparing a compound of the formula (I):

wherein R is hydrogen or a hydroxy-protecting group or a reactive derivative thereof comprising subjecting 5-hydroxybenzo[b] thiophene to a protecting reaction to yield a compound of the formula (VII):

wherein R1 is a hydroxy-protecting group; reacting the

compound (VII) with acetyl halide under the conditions for Friedel-Crafts reaction to yield a compound of the formula (VIII):

wherein R1 is a hydroxy-protecting group; and subjecting the compound (VIII) to oxidation of the acetyl group and optionally deprotection.
The present invention further provides a method for the preparation of the above-mentioned 5-hydroxybenzo[b]-thiophene-3-carboxylic acid derivative of the general formula (VI) by using a compound of the formula (I)• Thus, the present invention provides a process for preparing a compound of the formula (VI):

wherein R is as defined above and X is hydrogen or alkyl, and double bond represents either E- or Z-configuration, or a pharmaceutically acceptable salt thereof or a hydrate thereof, which comprises subjecting a compound of the formula (I) or a reactive derivative thereof to the following reactions:
(1) reaction with a compound of the formula (V)

wherein X is hydrogen or alkyl; or
(2) reaction with a compound of the formula (V):

or a salt thereof followed by oxidation and reaction with an ylide under the conditions for Wittig reaction; and
(3) optionally deprotection.
THE BEST EMBODIMENT FOR PRACTICING THE INVENTION
The terms used herein are defined below.
The term "hydroxy-protecting group" means alkyl, alkoxyalkyl, acyl, aralkyl, alkylsulfonyl, arylsulfonyl, alkyl-substituted silyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl or tetrahydropyranyl.
The term "alkyl" means C1-C20 linear or branched alkyl, particularly, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tart-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 C1-C6 alkyl is preferred.
The term "alkoxy" means C1-C6 linear or branched alkoxy, particularly, methoxy, ethoxy, n-propoxy, i-propoxy.

71-butoxy, i-butoxy, s-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy, neopentyloxy, s-pentyloxy, t-pentyloxy, n-hexyloxy, neohexyloxy, i-hexyloxy, s-hexyloxy, t-hexyloxy and the like, and C1-C3 alkoxy is preferred.
The term "alkoxyalkyl" means alkyl group substituted by alkoxy group, including methoxymethyl, ethoxymethyl, methoxyethoxymethyl, ethoxyethyl, methoxypropyl and the like.
The term "acyl" means C1-C11acyl derived from aliphatic carboxylic acid or aromatic carboxylic acid. Examples of aliphatic carboxylic acid-derived acyl include acetyl, chloroacetyl, trichloroacetyl, propionyl, butyryl, valeryl and the like, and examples of aromatic carboxylic acid-derived acyl include benzoyl, p-nitrobenzoyl, p-methoxybenzoyl, p-bromobenzoyl, toluoyl, naphthoyl and the like.
The term "aryl" means phenyl, naphthyl or polycyclic aromatic hydrocarbon group and the like. In addition, aryl may be substituted by the following substituents.
Examples of substituent include alkyl such as methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or tert-pentyl, lower alkoxy such as methoxy or ethoxy, halogen such as fluoro, chloro, bromo or iodo, nitro, hydroxy, 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 at any 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-dimethylammo) phenyl, 4-nitrophenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-iodophenyl and the like.
The aryl group m the "aralkyl", "arylsulfonyl", "aryloxycarbonyl" or "aralkyloxycarbonyl" described below may have similar substituents as defmed above.
The term "aralkyl" means an alkyl group substituted by aryl group, and mcludes benzyl, 4-methylben2yl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, naphthylmethyl, phenethyl, and the like.
The term "alkylsulfonyl" means a sulfonyl group substituted by alkyl group, and mcludes methanesulfonyl, ethanesulfonyl and the like.
The term "arylsulfonyl" means a sulfonyl group substituted by aryl group, and mcludes benzenesulfonyl, p-toluenesulfonyl, and the like.
The term "alkyl-substituted silyl" means mono-, di- or tri"alkyl-substituted silyl, 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 the above-mentioned nydroxy-pronecrmg groups are preferred as the hydroxy-protectmg group shown by R1, R1 or R m respective formula above, aryl sulfonyl is more preferred and benzenesulfonyl is particularly preferred among them.
Examples of salts of the compound of the general formula (VI) mclude alkali metal salts such as lithmm salt, sodmm salt or potassmm salt and the like, alkali earth metal salts such as calcmm salt and the like,
ammonmm salt, salts with organic base such as tromethamme, trimethylamme, triethy1amme, 2-ammobutane, tert-
butylamme, diisopropylethylamme, n-butylmethylamme, n-butyldimethylamme, tri-n-butylamme, cyclohexylamme, dicyclohexylamme, N-isopropylcyclohexylamme, furfurylamme, benzylamme, methylbenzylamme, dibenzylamme, W,N-dimethyIbenzylamme, 2-chlorobenzylamme, 4-methoxybenzylamme, 1-naphthalenemethylamme, diphenylbenzylamme, triphenylamme, 1-naphthylamme, 1-ammoanthracene, 2-ammoanthracene, dehydroabiethylamme, N-methylmorpholme or pyridme, or ammo acid salts such as lysme salt or argmme salt.
The salts of the ammo alcohol of the formula (V) mclude salts with organic acid such as benzoic acid, etc., and mmeral acid such as hydrochloric acid, sulfuric acid, etc.
The fmal compound of the present mvention is represented by the formula (VI) as described above, m which the double bond of the alkenylene side cham (5-

heptenylene cham) may be m the E- or z-configuration.
The method of the present mvention is described below m more detail. When a substituent(s) possibly mterfermg the reaction is present, it can be appropriately protected and then deprotected at a desired stage. Such protection or deprotection can be accomplished by a procedure known m the art.

Wherem R and R1 are as defmed above. [Step 1]
This step is related to the mtroduction of a propargyl group at the mercapto group of 4-mercaptophenol (1) and protection of hydroxyl group.
The mtroduction of a propargyl group is accomplished

by usmg propargyl halide such as propargyl bromide, propargyl chloride and the like m the presence of a basic agents. The reaction can be accomplished withm several tens mmutes to several hours at room temperature by employmg, as a basic agent, morganic base such as potassmm carbonate, sodmm carbonate or the like, or an organic base such as triethylamme, pyridme, 4-dimethylammopyridme or the like m a solvent such as acetone, ethyl acetate, tetrahydrofuran, acetonitrile, or the like.
When a strong base such as potassmm hydroxide or sodmm hydroxide is used, it can be also accomplished m a two-layer solvent system such as toluene-water or xylene-water.
The protection of hydroxyl group may be conducted usmg an ordmary hydroxy-protectmg group m a conventional manner. Preferred protectmg groups to be used m the present method are those which do not undergo changes durmg the oxidative reactions m the 2nd and 4th steps of the present Process and the 2nd step of Process IV below for the preparation of compound of the formula (VI) and also durmg the Wittig reaction of the 3rd step of said Process, and can be easily deprotected m the 4th step to give leavmg groups which are easily separable from, for example. Compound A for purification thereof, which corresponds to a compound of the formula (VI) wherem OR is 5-hydroxy, X is hydrogen and double bond is m Z-configuration. Examples of such a hydroxy-protectmg group

mclude alkyl, alkoxyalkyl, acyl, aralkyl, alkylsulfonyl, arylsulfonyl/ alkyl-substituted silyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl or tetrahydropyranyl.
Considermg the requirements that a protectmg group should survive durmg the Wittig reaction conducted under strong basic conditions, be easily deprotected, for example, m the 4th step for the preparation of Compound A, and be separable from Compound A, arylsulfonyl is more preferred and benzenesulfonyl is particularly preferred. Benzenesulfonyl group is relatively stable to base m anhydrous solvents and, upon deprotection, gives benzenesulfonic acid which is water-soluble and is easily separated from the from product of the formula (VI)• The protection and deprotection can be carried out by a method known m the art. For example, m the case of benzenesulfonyl group, the mtroduction of benzenesulfonyl group is carried out m a manner similar to that for the mtroduction of propargyl group by using benzenesulfonyl chloride. [Step 2]
This step is related to oxidation of the compound (II), There have been known oxidizmg methods which use, for mstance, aqueous hydrogen peroxide - acetic acid (J. Am, Chem, Soc, 87, 1109-1114 (1965)),aqueous hydrogen peroxide - titanmm(III) chloride (Synthesis 1981, 204-206), m-chloroperbenzoic acid (Org. Synth., 64, 157-163 (1985)), or sodmm metaperiodate (J. Org. Chem., 27, 282-284 (1962)). m the present step, it is preferred to use a slightly

excess amount of 30 % aqueous hydrogen peroxide m an alcoholic solvent such as ethanol, methanol, isopropanol or tert-butanol solution contammg formic acid. The reaction is accomplished withm several tens mmutes to several hours under coolmg or at room temperature. [Step 3]
This step is related to the conversion of the compound
(III) mto the hydroxymethyl compound (IV) by thermal
rearrangement reaction. The thermal rearrangement reaction
m this step is carried out accordmg to the method
described m J. C, S. Chem. Comm,, 1974, 848-849. Examples
of preferred solvents for this reaction mclude dioxane,
1,2-dimethoxyethane, propyl acetate and 3-pentanone. The reaction is accomplished by refluxmg m a solvent for several hours followed by addmg to the resultant mtermediate an acid (p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid, etc) [Step 4]
This step is related to the oxidation of the compound
(IV) to provide carboxylic acid (I). The oxidation can be
carried out either directly or m a stepwise manner.
Examples of oxidizmg agent for convertmg an aromatic
primary alcohol to the correspondmg carboxylic acid
directly mclude chromic acids (Synthesis. 1986, 285-288),
potassmm permanganate (J. Org, Chem., 18, 806-809 (1953))
and ruthenmm oxides (J, C, S, Chem, Comm,, 1979, 58-59)),
However, these methods have disadvantages m not only the
yield but also the followmg matters. For mstance, the

reaction time is long, the detoxification treatment of oxidizmg agent is needed followmg the reaction, the reagents are unstable and/or they mvolve complicated operations.
On the contrary, m some cases, a stepwise oxidation wherem a primary alcohol is oxidized to an aldehyde and then to a carboxylic acid may be of advantage with regard to yield. m general, the oxidation of alcohol to aldehyde has been carried out by usmg an oxidizmg agent of chromic acid series, for example, Jones reagents (J. Org. Chem., 40, 1664^1665 . (1975)), Collms reagents (J. C. S. Chem, Comm., 1972 1126)), pyridmmm chlorochromate (Tetrahedron Lett., 2647-2650 (1975)). It has been also known a method which uses manganese dioxide (Helv. Chim. Acta., 39, 858-862 (1956)) or dimethyl sulfoxide (Swern oxidation, J. Org, Chem., 43, 2480-2482 (1978)), However, these existmg methods have disadvantages. For example, chromic acids are toxic to human body and must be detoxified after use. Further, the Swern oxidation usmg dimethyl sulfoxide-oxalyl chloride is not suited for a large scale production because it is accompanied by the generation of carbon monoxide harmful to workers and sulfurous odor and also it must be carried out at low temperature, for example,
between -50°C and -7 8°C.
Alcohol (IV) can be converted mto aldehyde (IV) almost quantitatively by a method wherem an alcohol (IV) is oxidized with an oxidizmg reagent such as halo oxoacid m the presence of 2, 2, 6, 6-tetramethylpiperidme-l-oxyl

or the like (referred to as ""TEMPOS") accordmg to the description m a literature (e.g., J. Org. Chem., 52, 2559-2562 (1987)), whereby the problems of the existmg methods are solved. Examples of TEMPOS usable mclude 2,2,6,6-tetramethylpiperidme-l-oxyl, 4-methoxy-2,2,6,6-tetramethylpiperidme*-l-oxyl, 4-acetylammo-2, 2, 6, 6-tetramethylpiperidme-1-oxyl, 4-benzoyloxy-2,2,6,6-tetramethylpiperidme-1-oxyl, and 4-cyano-2,2,6,6-tetramethylpiperidme-1-oxyl. Examples of usable halo oxoacids mclude sodmm hypochlorite, sodmm hypobromite, sodmm bromite and higher bleachmg powder. A solution of an oxidizmg agent may be adjusted to, for example, pH 8.5 to 9.5 with a mmeral acid such as sodmm hydrogen carbonate, hydrogen chloride or sulfuric acid. Alternatively, a solution of an oxidizmg agent may be added m the presence of sodmm hydrogen carbonate. The reaction can be accomplished withm several mmutes to several tens mmutes at temperature from ice-coolmg to room temperature m a solvent such as ethyl acetate, acetonitrile or dichloromethane.
When the reaction solution contammg the resultant aldehyde (TV) is acidified and sodmm chlorite and aqueous hydrogen peroxide are added thereto, the aldehyde is converted mto carboxylic acid under ice-coolmg withm several tens mmutes to several hours.
If desired, the product may be further subjected to the deprotection of 5-hydroxy-protectmg group and/or conversion mto reactive derivatives at 3-carboxyl group.

Such "^ reactive derivative" mcludes the correspondmg acid halides (e.g., chloride, bromide/ iodide), acid anhydrides (e.g., mixed acid anhydride with formic acid or acetic acid), activated esters (e.g., succmimide ester), and the like, and mcludes acylatmg agents generally used for the acylation of ammo group. For example, to obtam acid halides, a carboxylic acid is reacted with thionyl halide (e.g., thionyl chloride), phosphorous halide (e.g., phosphorous trichloride, phosphorous pentachloride), oxalyl halide (e.g., oxalyl chloride), or the like, accordmg to a known method (e.g., Shm-jikken Kagaku Koza, vol. 14, p. 1787 (1978); Synthesis 852-854(1986); Shm-jikken Kagaku Koza vol. 22, p. 115 (1992)).

wherem R and R1 are as defmed above-[Step 1]
This step is related to the protection of 5-hydroxy group of compound (7).
The compound (7) as the startmg material of the

present step is known m a 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 this compound is protected appropriately m a manner similar to that descried m the 1st step of Process I above. For example, when benzenesulfonyl group is used, the compound is added to benzenesulfonyl chloride m the presence of an morganic base such as sodmm carbonate or potassmm carbonate, or an organic base such as triethylamme or tripropylamme. Example of preferred solvent mcludes acetone, ethyl acetate and tetrahydrofuran. The reaction is accomplished withm several mmutes to several hours at temperature from room temperature to the boilmg pomt of the solvent. The compound (VII) can be also synthesized by a broadly used method, commonly known as "Schotten-Baumann reaction". [Step 2]
This step is related to the mtroduction of acetyl group to the 3-position of the compound (VII) by Friedel-Crafts reaction. The mtroduction of acetyl group is, for example, carried out usmg acetyl chloride or acetyl bromide m the presence of a catalyst, for example, a Lewis acid such as alummmm chloride, ferric chloride, zmc chloride, tm chloride and boron trifluoride. Example of usable solvent mcludes carbon disulfide, nitrobenzene or a halogenated hydrocarbons such as methylene chloride or ethylene chloride. The reaction is m general accomplished withm several hours at temperature of ice-coolmg to room

temperature. The 2-acetyl compound slightly produced as a by-product is easily separable by recrystallization. [Step 3]
This step is related to the conversion of the compound (VIII) mto a carboxylic acid (I) or a reactive derivative thereof through the oxidation of the acetyl group m the presence of a salt of hypohalous acid. Examples of preferred hypohalogenite mclude alkali metal or alkalme earth metal salts of hypohalous acids, and potassmm, sodmm or calcmm salt of hypochlorous or hypobromous acid is especially preferred.
m an aqueous solution of such a salt, the oxidation progresses at relatively low temperature. However, dioxane or 1,2-dimethoxyethane may be used as a solvent so as to mcrease the solubility of the compound to be oxidized. The reaction is accomplished withm several hours to several tens hours at room temperature or with heatmg.

wherem R and X are as defmed above and the double bond represents E- or Z-configuration.
This process is related to the synthesis of a compound of the formula (VI) by reactmg a compound of the formula

(I) or a reactive derivative thereof obtamed m Process I or II above with a compound of the formula (V)•
The compound (V). used m the present process is obtamable accordmg to the method described m Japanese Patent Publication (KOKOKU) No. 6-23170 (23170/1994).
The reaction can be carried out under ordmary conditions for acylation of ammo group. For example, when a carboxylic acid halide is used, the reaction is carried out accordmg to a method commonly known as "Schotten-Baumann reaction". m general, carboxylic acid halide is added dropwise to an aqueous alkalme solution of amme with stirrmg and under coolmg while removmg the generatmg acid with alkali. Alternatively, when a carboxylic acid is used as a free acid not a reactive derivative, the reaction can be conducted conventionally m the presence of a couplmg agent generally used m the couplmg reaction between an amme and a carboxylic acid such as dicyclohexylcarbodiimide (DCC), l-ethyl-3-(3-dimethylammopropyl) carbodiimide or W,N'-carbonyldiimidazole.

wherem R and X are as defmed above and the double bond represents E- or Z-configuration. [Step 1]
This step is related to the preparation of a compound of the formula (IX) by reactmg a compound of the formula (I) or a reactive derivative thereof with a compound of the formula (V) or its salt m a manner similar to that described m Process III above. The preparation of some of the compounds of the formula (V) is described m Chem. Pharm, Bull. Vol.37, No. 6 1524-1533 (1989). [Step 2]
This step is. related to the preparation of an aldehyde of the formula (X) by oxidizmg a compound of the formula (IX). The reaction can be carried out for several hours under coolmg or at room temperature usmg an oxidizmg agent selected from chromic acid series such as Jones reagents/ Collms reagents, pyridmmm chlorochromate, pyridmmm dichromate or dimethyl sulfoxide-oxalyl chloride

m a solvent such as chlormated hydrocarbons (chloroform, dichloromethane, etc.), ethers (ethyl ether, tetrahydrofuran, etc.), acetone or benzene. [Step 3]
This step is related to the formation of a double bond by reactmg a compound of the formula (X) with an ylide (Ph3P=CH(CH2) 3COOH) . The reaction for providmg a double bond can be carried out m a conventional manner for Wittig reaction. The ylides used m the reaction can be synthesized, m the presence of a base, by treatmg a phosphonmm salt which has been synthesized from triphenylphosphme and an alkyl halide havmg a desired alkyl group to be condensed, for example, 5-bromopentanoic acid. Examples of a base mclude dimsyl sodmm, dimsyl potassmm, sodmm hydride, n-butyl lithmm, potassmm t-butoxide and lithmm diisopropylamide. The reaction is accomplished withm several hours at room temperature m a solvent such as ether, tetrahydrofuran, n-hexane, 1,2-dimethoxyethane or dimethyl sulfoxide, [Step 4]
m this step, a compound (VI) wherem R is hydroxy-protectmg group is optionally deprotected to give compound (VI-1). The reaction can be carried out m a conventional manner usmg a catalyst such as hydrochloric acid, sulfuric acid, sodmm hydroxide, potassmm hydroxide or barmm hydroxide, or the like. The reaction is accomplished withm several tens mmutes to several hours with heatmg m a solvent such as methanol-water, ethanol-water.

acetone-water/ acetonitrile-water, or the like, preferably dimethyl sulfoxide-water.
The followmg Examples are provided to further illustrate the present mvention m more detail and should not be mterpreted m any way as to limit the scope thereof. The abbreviations used m the Examples have the followmg meanmgs:
Ph: phenyl
Ac: acetyl
TEMPO: 2f 2, 6, 6 —tetramethylpiperidme-1-oxyl Exap;iplg i (1) step 1: 4-(2-Propyn-l-ylthio)phenyl benzenesulfonate (2)

4-Mercaptophenol (1) (37.85 g, 300 mmol) and propargyl bromide (42.82g/ 360 mmol) were dissolved m ethyl acetate (757 ml). To the solution was added dropwise triethylamme (42.5g, 420 mmol) over 25 mmutes with stirrmg and under ice-coolmg. After stirrmg for another 1.5 hours at the same temperature, triethylamme (42.5g, 420 mmol) was added m one portion, and benzenesulfonyl chloride (63.58g, 360 mmol) was added dropwise over 20 mmutes. After keepmg 1 hour at the same temperature, the coolmg bath was removed and the mixture was stirred for 30 mmutes at room temperature and partitioned mto two layers by addmg ice-

water (500 ml) and 2N hydrochloric acid (110 ml). The aqueous layer was extracted with ethyl acetate (200 ml) . The combmed organic layer was washed with water, dried over anhydrous magnesmm sulfate, and then the solvent was distilled off under reduced pressure to provide 100.04g of the title compound (2) as oil. Crude yield: 109%.
IR (CHCI3); 3306, 3071, 3031, 3019, 3009, 1585, 1486, 1449, 1378 cm'
'H NMR5 (CDCI3) , 300MHz; 2.23 (IH, t, J=2.7Hz), 3.56 (2H, d, J=2.7Hz), 6.94 and 7.34 (each 2H, each d, J=8.7Hz), 7.51-7.56 (2H, m), 7.68 (IH, m), 7.82-7.85 (2H, m) (2) Step 2: 4-(2-Propyn-l-ylthio)phenyl benzenesulfonate (3)

The compound (2) (60.8g, 183 mmol) prepared m step (1) above was dissolved m formic acid (30.4 ml) and methanol (122 ml), and 31% aqueous hydrogen peroxide (26.29g, 240 mmol) was then added. After 3.5 hours, ice-water (240 ml) was added and the mixture was extracted with ethyl acetate (2 x 300 ml). The combmed organic layer was washed with 5% aqueous sodmm carbonate and water, dried over anhydrous magnesmm sulfate and the solvent was then distilled off under reduced pressure to provide 65.47g of the title compound (3) as oil. Crude yield: 117%.
IR (CHCI3); 3305, 3066, 3032, 3012, 1586, 1486, 1449,

1382 cm'
'H NMRSlCDCls) , 300MHz; 2.34 (IH, t, J=3.9Hz), 3.58 and 3.68 (each IH, 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 (IH, m), 7.82-7.87 (2H, m) (3) Step 3: 5-Benzenesulfonyloxy-3-hydroxymethylbenzo [b] thiophene (4)

The compound (3) (65.47g, 183 mmol) obtamed m above (2) was dissolved m 1,2-dimethoxyethane (1.6L) and the solution was refluxed for 4 hours. To the solution were added water (64 ml) and p-toluenesulfonic acid monohydrate (19.2g, 100 mmol) and refluxmg was contmued for 2 hours. The reaction mixture was concentrated under reduced pressure. After water (200 ml) was added to the resultmg oil, the mixture was extracted with ethyl acetate (300 ml). The organic layer was washed with aqueous sodmm hydrogen carbonate and water, dried over anhydrous magnesmm sulfate and then the solvent was distilled off under reduced pressure to provide 60.18g of the title compound (4) as oil. Crude yield: 103%.
IR (CHCI3); 3609, 3067, 3*033, 3013, 2935, 2878, 1589, 1566, 1449, 1435, 1376 cm"'
'H NMR6 (CDCI3) , 300MHz; 4.78 (2H, d, J=0.9Hz), 6,98

(IH, dd, J=2.4 and 8.7Hz), 7.26 (IH, s), 7.43-7.45 (2H, m),
7^50"7.55 (2H, m), 7.66 (IH, m), 7.73 (IH, d, J=8.7H2 ),
7,83-7,86 (2H, m)
(4) Step 4:
5-Benzenesulfonyloxyben2o [b] thiophene-3-carboxilic acid (6)

The compound (4) (51.2 6g, 155 mmol) prepared m above (3) was dissolved m acetonitrile (1.54L), and TEMPO (2, 2, 6, 6-tetramethylpiperidme-l-oxyl, 250 mg, 0.01 eq.) was added thereto. To the mixture was added dropwise 0,81 N aqueous sodmm hypochlorite, which had been prepared by dilutmg 1.63 N aqueous sodmm hypochlorite (150ml) with water (75 ml), adjustmg pH 8.6 with 1 N sulfuric acid, and adjustmg the total volume to 300ml, over 15 mmutes, while
mamtammg the mner temperature between — iT) and 8°C. After stirrmg for 25 mmutes at this temperature, 1 N aqueous sodmm sulfite (32 ml) was added. Subsequently, 79% sodmm chlorite (27.48g, 240 mmol) and 31% aqueous hydrogen peroxide (23.26g, 212 mmol) were added under ice-coolmg. The coolmg bath was removed and the mixture was stirred for 2 hours. The reaction was diluted with water

(1.5L), adjusted to pH 3 with 1 N hydrochloric acid and the deposited crystals were filtered, and washed twice with water (200 ml), acetonitrile (50 ml) to provide 32.4g of crude crystals. The crude crystals (32.4g) were suspended m acetonitrile (224 ml), refluxed for 15 mmutes and cooled on ice. The crystals were filtered and washed with acetonitrile (65 ml) to provide 26.79g of the title
compound (6). Yield: 51.7%, mp 202-203t;.
IR (Nujol): 3102, 2925, 2854, 2744, 2640, 2577, 1672, 1599, 1558, 1500, 1460, 1451 cm'
NMR5 (CDCI3), 300MHz; 7.16 (IH, dd, J=2.7 and 9.OH2), 7.55-7.61 (2H, m), 7.73 (IH, m), 7.81 (IH, d, J=9.0H2),
7.90-7.94 (2H, m), 8.16 (IH, d, J=2.7Hz), 8,60 (IH, s) Elemental Analyses for C15H10O5S2 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)

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)] (1.36g, 9.05 mmol) and triethylamme (1.89ml, 13.6 mmol)
were dissolved m tetrahydrofuran (10 ml). To the solution

was added dropwise a solution of benzenesulfonyl chloride (l,92g, 10.9 mmol) m tetrahydrofuran (3 ml). After bemg stirred for 2 hours, the reaction mixture was diluted with water and extracted with toluene. The organic layer was washed with water, dried over anhydrous magnesiiom sulfate and then the solvent was distilled off under reduced pressure. The residue was chromatographed over silica gel (5:1 hexane : ethyl acetate) and then recrystallized from hexane contammg small amount of ethyl acetate to provide
2.28g of the title compound (8). Yield: 86.8%, mp 80-81°C. IR (Nujol): 1599, 1579, 1564, 1497, 1448, 1440, 1415,
1352 cm"'
'H NMR5 (CDCI3) ; 300MHz; 6,92 (IH, dd, J=2.4 and 8.7H2), 7.26 (IH, dd, J=0.9 and 5.4Hz), 7.47 (IH, d, J=2.4Hz), 7.51
(IH, d, J=5.4Hz), 7.52-7.55 (2H, m), 7.67 (IH, m), 7.74 (IH,
d, J=8.7Hz), 7.83-7.87 (2H, m)
Elemental Analyses for C14H10O3S2
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)

Powdered alummum chloride (1.34g, 10 mmol) was suspended m dichloromethane (10 ml). To the suspension was added dropwise acetyl chloride (1.02ml, 14.3 mmol) over

5 mmutes with stirrmg and under ice-coolmg. Subsequently, a solution of the compound (8) (2.075g, 7.2 mmol) prepared above m dichloromethane (6 ml) was added dropwise over 15 mmutes. After bemg stirred for 2 hours at the same temperature and then for 2.5 hours at room temperature, the solution was poured mto ice-water and extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesmm sulfate and then the solvent was distilled off under reduced pressure. The resultmg residue was recrystallized from ethyl acetate (3 ml) and hexane (3 ml) to provide 2.01g of
the title compound (9). Yield: 84.4% mp 129-130°C.
IR (Nujol): 3094, 1672, 1619, 1595, 1556, 1494, 1450, 1437, 1428, 1369 cm"'
'H NMR6 (CDCI3) ; 300MHz; 2.58{3H, s) , 7.22 (IH, ddd, J=0.6, 2.4 and 9.0Hz), 7.52-7.58 (2H, m) , 7.69 (IH, m) ,
7.79 (IH, d, J=9.0Hz), 7.87-7.91 (2H, m), 8.27 (IH, dd,
J=0.6 and 2.4Hz), 8.31 (IH, s)
Elemental Analyses for C16H12O4S2
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[h]thiophene-3-carboxylic acid (6)

The compound (9) (6.65g, 20 lumol) prepared m above (2) was dissolved m dioxane (50 ml), and 10% sodmm hypochlorite (46,2 ml) was added over 20 mmutes with
stirrmg while mamtammg the temperature at 10-12°C. After 7 hours, the reaction mixture was diluted with ice-water (80 ml) and acidified with cone, hydrochloric acid (5.2 ml). The deposited crystals were filtered, washed with water, dried to provide 5.84g of crude crystals. The 5.84g of the crude crystals were recrystallized from methanol (66 ml) and water (16 ml) to provide 5.51g of the
title compound (6). Yield: 82.4%. mp 203-204'C.
This compound is identical to the compound (6) prepared m Example 1. Reference Example 1
5-Benzenesulfonyloxybenzo [b] thiophene-3-carbonyl chloride (10)

5"Benzenesulfonyloxybenzo [b] thiophene-3-carboxylic acid (6) (5,582g, 16.7 mmol) prepared m Examples above was refluxed for 1.5 hours with dimethylformamide (1 drop), thionyl chloride (3.57ml, 50 mmol) and toluene (22 ml), and the solvent was removed under reduced pressure to provide 5.89g of the title compound (10). Reference Example 2 (1) Step 1:

5"Hydroxybenzo[b]thiophene-3-carboxylic acid (11)

S-Benzenesulfonyloxybenzo[b]thiophene-3-carboxylic acid (6) (100 mg, 0.3 mmol) prepared m Examples above was dissolved m 1 N sodmm hydroxide (1.2 ml) and heated at
40°C for 8 hours with stirrmg. To the reaction solution was added 1 N hydrochloric acid (1.2 ml), and the deposited crystals were filtered, washed with water and dried to provide 58 mg of the title compound (11). Yield: 96.6% mp
262-263^:.
This compound (11) is identical to 5-
hydroxybenzo [b] thiophene--3-carboxylic acid described m M.
Martm-Smith et al. J. Chem. Soc (c) , 1899-1905 (1967). (2) Step 2:
S-Acetoxybenzo [b] thiophene--3-carboxylic acid (12)

5-Hydroxybenzo [b] thiophene-3--carboxylic acid (11) (1,140 mg) prepared m above (1) was dissolved m acetic anhydride (2 ml), pyridme (4 ml). After 3 hours, water was added and the mixture was contmuously stirred under ice-coolmg for 1.5 hours. The deposited crystals were filtered, washed with water and dried to provide 1,349 mg

of the title compound (12). Yield: 97,3% rap 239-240°C.
^H NMR6 (CDCI3) , 3OOMH2; 2.37(H, s) , 7,20 (IH, dd, J=2.4 and 8.7H2), 7.87 (IH, d, J=8,7Hz), 8.34 (IH, d,
J=2.4H2), 8.57 (IH, s)
(3) Step 3:
5-Acetoxybenzo [b] thiophene-3-carbonyl chloride (13)

5-Acetoxybenzo[b]thiophene-3-carboxylic acid (12) (1,349 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 provide 1,454 mg of the title compound (13). Example 3
(5Z)-7-[(IR,2R,25, 55)-2-(5-Hydroxybenzo[b]thiophen-3-ylcarbonylammo)-lO-norpman-3-yl]-5-heptenoic acid (17)

(1) step 1: Preparation of [3-[{1R,2R,3R,5S)-3-(l-Hydroxyethyl)-lO-norpman-2-yl]carbamoylbenzo[b]thiophen-5-yl] benzenesulfonate (14)
Benzoic acid salt of ( + )-2-[ (IR, 2JR, 3i?, 55)-2-Ammo-lO-norpman-3-yl] ethanol (described m Cheiti. Pharm. Bull,
Vol,37, No. 6 1524-1533(1989) (V'-l) ) (5.1g, 16.7 mmol) was suspended m water (10 ml). To the suspension was added 1 N hydrochloric acid (17 ml) and deposited benzoic acid was removed by extractmg with ethyl acetate. The organic layer was washed with water (10 ml). To the combmed aqueous layer was added 4 N sodmm hydroxide (9.2 ml, 36.8 mmol) under ice-coolmg. A solution of 5-
benzenesulf onyloxybenzo [b] thiophene-3-carbonyl chloride (10) (5.89g,16.7 mmol) m tetrahydrofuran (36 ml) was then added dropwise over 15 mmutes with stirrmg. After stirrmg for 1 hour at the same temperature, 1 N hydrochloric acid (4 ml) was added and the mixture was extracted with ethyl acetate. The organic layer was washed

with water, dried over anhydrous magnesmm sulfate and then the solvent was distilled off under reduced pressure to provide S.OOg (95.6%) of the title compound (14) as colorless amorphous.
^H NMR5 (CDCI3) , 300MHz; 0.96 (IH, d, J=9. 9Hz) , 1.12 and 1.26 (each 3H, each s), 1.50-2.42(9H, m), 3.69-3.82 (2H, m) ,
4.30 (IH, m), 6.21 (IH, d, J=8.1Hz), 7.06 (IH, dd, J=2.4 and 8.7Hz), 7.51-7.56 (2H, m), 7.67 (IH, m), 7.73 (IH, d, J-8.7HZ), 7.85 -7.88 (2H, m), 7.88 (IH, s), 8.06 (IH, d, J=2.4Hz).
[alo" +35.7° (c=1.00%, CH3OH) (2) Step 2: Preparation of [3-[{1R,2R,3R,SS)-3-Formylmethyl-lO-norpman-2-yl]carbamoylbenzo[b]thiophen-5-yl] benzenesulfonate (15)
To dimethyl sulfoxide (3.16 ml, 44.5 mmol) dissolved m dimethoxyethane (50 ml) was added oxalyl chloride (1.91
ml, 21.9 mmol) under coolmg at —60°C- —65°C. A solution of compound (14) (7.352g, 14,7 mmol) m 1,2-dimethoxyethane (58 ml) was added dropwise at the same temperature. After
stirrmg the mixture at —55°C- —60°C for 30 mmutes, triethylamme (6.1 ml) was added and, 30 mmutes later, the coolmg bath was removed to allow the mixture to warm up to room temperature. The reaction mixture was diluted with water (100 ml) and extracted with toluene. The organic layer was washed with water, dried over anhydrous magnesmm sulfate and then the solvent was distilled off under reduced pressure- The resultmg residue was purified by chromatography on silica gel (hexane : ethyl acetate =5:5-

4:6) to provide 7.32g (100%) of the title compound (15) as colorless amorphous.
IR (CHCI3); 3443, 3093, 3066, 3030, 3016, 2925, 2871, 2828, 2729, 1720, 1655, 1599, 1558, 1513, 1377 cm"'
'H NMR6 (CDCI3) , 300MHz; 0.97 (IH, d, J=10.2Hz), 1.17 and 1.28(each 3H, each s), 1.46 (IH, m) , 2.03 (IH, m) , 2.22
(IH, m), 2.36-2.60(3H, m), 2.69 (IH, ddd, J=1.2, 8.7 and
17.4Hz), 3.14 (IH, dd, J=4.5 and 17.4Hz), 4.28 (IH, m),
6.18 (IH, d, J=8.1Hz), 7.09 (IH, dd, J=2.4 and 8.7Hz),
7.50-7.55 (2H, m), 7.67 (IH, m), 7.75 (IH, d, J=8.7Hz),
7.85-7.89 (2H, m), 7.89 -(IH ,s), 8.03 (IH, d, J=2.4Hz),
9.80 (IH, d, J=1.2Hz)
[a]D"+31.8° (c=1.00%, CH3OH) (3) Step 3: Preparation of (5Z)-7-[ (li?, 2i^, 3S, 5S)-2-(5-Benzenesulfonyloxybenzo[b]thiophen-3-ylcarbonylammo)-10-norpman-3-yl]-5-heptenoic acid (16)
4-Carboxybutyltriphenylphosphonmm bromide (12.17g, 27.5 mmol) and potassmm t-butoxide (7.19g, 64.1 mmol) were suspended m tetrahydrofuran (64 ml) and stirred for 1 hour under ice-coolmg. To the reaction mixture was added over 15 mmutes a solution of the compound (15) (9.11g, 18.3 mmol) prepared m above (2) m tetrahydrofuran (27 ml) and the mixture was contmuously stirred 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 adjustmg the aqueous layer to pH 8.1 with 5 N hydrochloric acid (4.8 ml), anhydrous calcmm chloride (8.1g, 73 mmol) dissolved m water (16 ml) was added, and the mixture was

extracted with ethyl acetate (2 x 100 ml). Water (100 ml) was added to the organic layer, and the aqueous layer was adjusted to below pH 2 with 5 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesmm sulfate and then the solvent was distilled off under reduced pressure to provide ll,06g of the compound (16). The compound (16) was used m the next reaction without further purification. (4) Step 4: Preparation of (5Z)-7-[ (li?, 2iR, 3S, 5S)-2-(5-Hydroxybenzo [b] thiophen-3-ylcarbonylammo) -lO-norpman-3-yl]-5-heptenoic acid (17) (Compound A))
The compound (16) (11.06g, 18.3 mmol) prepared m above (3) was dissolved m dimethyl sulfoxide (22 ml). After addmg 4 N sodmm hydroxide (27.5 ml), the mixture
was heated at 55°C for 2 hours with stirrmg. The reaction mixture was diluted with water (130 ml) and washed with
toluene (2 x 65 ml). The aqueous layer was acidified with
5 N hydrochloric acid and extracted with ethyl acetate-
The organic layer was washed with water, dried over
anhydrous magnesmm sulfate, and the solvent was distilled
off under reduced pressure to provide 8.26g of the crude
objective compound which was then dissolved m methanol (40
ml) and water (16 ml). The solution was seeded and
gradually cooled with stirrmg. The deposited crystals
were filtered and washed with water: methanol (2:5) to
provide 6.35g of the objective compound. Yield: 78.6%.
The crystals were dissolved m methanol (40 ml). To the
solution was added water (12 ml) over 7 mmutes with

stirrmg. The mixture was seeded and contmuously stirred
for 1 hour at 25°C. After addmg water (7 ml) over 40 mmutes, 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 provide 6.14g of the objective compound (17) which was almost colorless. Yield:
76.0%, mp 145-146°C.
IR (Nujol); 3313, 3096, 3059, 3001, 1717, 1627, 1603,
1548, 1469, 1440 cm'
'H NMR5 (CDClj) , 300MHz; 1.02 (IH, d, J=10.2H2), 1.12 and 1.24 (each 3H, each s), 1.56-2.55(14H, m), 4.29 (IH, m) ,
5.32-5.51 (2H, m), 6.20 (IH, d, J=9.3Hz), 7.01 (IH, dd,
J=2.4 and g.OHz), 7.66 (IH, d, J=9.0Hz), 7.69 (IH ,5), 8.03
(IH, d, J=2.4H2)
[alD' + 50.7° (c=1.01, CH3OH)
Elemental Analyses for C25H31NO4S
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

CLAIMS
1. A process for producing a compound of the formula (I):

wherein R is hydrogen or a hydroxy-protecting group, or a reactive derivative thereof, which comprises subjecting 4-mercaptophenol to reactions for introduction of a propargyl group and protection of hydroxyl group to yield a compound of the formula (II):

wherein R1 is a hydroxy-protecting group; oxidizing the compound (II) to yield a compound of the formula (III):

wherein R1 is a hydroxy-protecting group; subjecting the compound (III) to thermal rearrangement reaction to yield a compound of the formula (IV):

wherein R1 is as defined above; and subjecting the compound (IV) to stepwise oxidation of hydroxymethyl group and optionally deprotection.
2. The process of claim 1, wherein the hydroxy-protecting group represented by R1 is alkyl, alkoxyalkyl, acyl, aralkyl, alkylsulfonyl, arylsulfonyl, alkyl-substituted silyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl or tetrahydropyranyl.
3. The process of claim 1, wherein the hydroxy-protecting group represented by R1 is arylsulfonyl.
4. (Amended) A process for producing a compound of
the formula (VI):

wherein R is hydrogen or a hydroxy-protecting group and X is hydrogen or alkyl, and double bond represents either E-or Z-configuration, or a pharmaceutically acceptable salt or hydrate thereof, which comprises subjecting 4-mercaptophenol to reactions for introduction of a propargyl group and protection of hydroxyl group to yield a compound of the formula (II):

wherein R1 is a hydroxy-protecting group; oxidizing the compound (II) to yield a compound of the formula (III) :

wherein R1 is a hydroxy-protecting group; subjecting the compound (III) to heat rearrangement reaction to yield a compound of the formula (IV):

wherein R1 is as defined above; and subjecting the compound (IV) to stepwise oxidation of hydroxymethyl group and optionally deprotection to yield a compound of the formula
(I) :

wherein R is as defined above, or a reactive derivative thereof; subjecting the compound of the formula (I) or a reactive derivative thereof to the following reactions: (1) reaction with a compound of the formula (V)

wherein X is hydrogen or alkyl; or
(2) reaction with a compound of the formula (V):

or a salt thereof followed by oxidation and reaction with an ylide under the conditions for Wittig reaction; and
(3) optionally deprotection.
5. A process for producing a compound of the formula (I) :

wherein R is hydrogen or a hydroxy-protecting group, or a reactive derivative thereof, which comprises subjecting 5-hydroxybenzo [jb] thiophene to protecting reaction to yield a compound of the formula (VII):

wherein R1 is a hydroxy-protecting group; reacting the compound (VII) with acetyl halide under the conditions for Friedel-Crafts reaction to yield a compound of the formula (VIII):
wherein R1 is a hydroxy-protecting group; subjecting the compound (VIII) to oxidation of acetyl group and optionally

deprotection.
6. The process of claim 5, wherein the hydroxy-protecting group represented by R1 is alkyl, alkoxyalkyl, acyl, aralkyl, alkylsulfonyl, arylsulfonyl, alkyl-substituted silyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl or tetrahydropyranyl.
7. The process of claim 5, wherein the hydroxy-protecting group represented by R1 is arylsulfonyl.
8. (Amended) A process for producing a compound of
the formula (VI) :

wherein R is hydrogen or a hydroxy-protecting group and X is hydrogen or alkyl, and double bond represents either E-or Z-configuration, or a pharmaceutically acceptable salt or hydrate thereof, which comprises subjecting 5-hydroxybenzo [jb] thiophene to protecting reaction to yield a compound of the formula (VII):

wherein R1 is a hydroxy-protecting group; reacting the compound (VII) with acetyl halide under the conditions for Friedel-Crafts reaction to yield a compound of the formula (VIII):

wherein R1 is a hydroxy-protecting group; subjecting the compound (VIII) to oxidation of acetyl group and optionally deprotection to yield a compound of the formula (I):

wherein R is as defined above or a reactive derivative thereof; subjecting the compound (I) or a reactive derivative thereof to the following reactions:
(1) reaction with a compound of the formula (V)

wherein X is as defined above; or
(2) reaction with a compound of the formula (V):

or a salt thereof followed by oxidation and reaction with an ylide under the conditions for Wittig reaction; and
(3) optionally deprotection.
9. A compound of the formula (I) wherein R is
arylsulfonyl or a reactive derivative thereof.
10. A compound of the formula (I) wherein R is
benzenesulfonyl or a reactive derivative thereof.

A process for producing a compound substantially is herein described
and exemplified.
A compound of the formula substantially as herein described and
exemplified.

Documents:

in-pct-2000-560-che-abstract.pdf

in-pct-2000-560-che-claims filed.pdf

in-pct-2000-560-che-claims granted.pdf

in-pct-2000-560-che-correspondence others.pdf

in-pct-2000-560-che-correspondence po.pdf

in-pct-2000-560-che-description complete filed.pdf

in-pct-2000-560-che-description complete granted.pdf

in-pct-2000-560-che-form 1.pdf

in-pct-2000-560-che-form 26.pdf

in-pct-2000-560-che-form 3.pdf

in-pct-2000-560-che-form 5.pdf

in-pct-2000-560-che-other documents.pdf

in-pct-2000-560-che-pct.pdf

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Patent Number

210538

Indian Patent Application Number

IN/PCT/2000/560/CHE

PG Journal Number

49/2007

Publication Date

07-Dec-2007

Grant Date

08-Oct-2007

Date of Filing

24-Oct-2000

Name of Patentee

M/S. SHIONOGI & CO., LTD

Applicant Address

1-8 DOSHOMACHI 3-CHOME, CHUO-KU,OSAKA-SHI OSAKA 541-0045 JAPAN

Inventors:

#	Inventor's Name	Inventor's Address
1	HONMA	117-42, AOYAMADAI,IKOMA-SHI,NARA 630-0239,JAPAN
2	YOSHIHARU HIRAMATSU	1-4-13 MIZUHAI,HIGASHIOSAKA-SHI,OSAKA 578-0921 JAPAN

PCT International Classification Number

C07D 333/68

PCT International Application Number

PCT/JP99/01616

PCT International Filing date

1999-03-30

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	10/85819	1998-03-31	Japan