PROCESS FOR PRODUCING BENZOTHIOPHENECARBOXYLIC ACID AMIDE DERIVATIVES

Abstract: A process for preparing a compound having PGD 2 antagonism represented by the formula (I), or a pharmaceutically acceptable salt or hydrate thereof, which process comprises reacting an amino alcohol of the formula (II) or its salt with a compound of the formula (III) or its reactive derivative, oxidizing the product with a halo oxoacid in the presence of 2, 2,6,6,-tetramethylpiperidine-1-oxyls, reacting the product with an ylide under the conditions for the Wittig reaction, and optionally deprotecting the product.

Description: The present invention relates to a process for producing benzothiophenecarboxamide derivatives useful as prostaglandin D 2 (hereinafter referred to as "PGD 2 ")antagonists. BACKGROUND ART Benzothiphenecarboxamide derivatives of the general formula (I) : wherein R is hydrogen or a hydroxy-protecting group, X is hydrogen or alkyl, and the double bond represents the E or Z configuration are PGD 2 antagonists specific to PGD 2 receptors and useful as therapeutic agents for treating diseases associated with the dysfunction of mast cells caused by excessive production of PGD 2 (W097/00853, PCT/JP97/04527 (WO98/25919)). Consequently, compounds of the formula shown above may be used as therapeutic agents for 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. Among them, a compound wherein OR is 5-hydroxy, X is hydrogen and the double bond represents the Z-configuration (hereinafter referred to as "Compound A") shows high antagonistic effect on PGD 2 , showing especially high anti-nasal occlusion activity, and is envisaged to be a promising drug for treating nasal occlusion. DISCLOSURE OF THE INVENTION The compounds (I) and processes for preparing them have been known in the literature (W097/00853, PCT/JP97/04527 (W098/25919)). However, the known processes are not necessarily suited for industrial production in terms of production efficiency, safety for workers and the environment and efficient use of resources for the reasons exemplified as follows: 1) they use silica gel chromatography which is unsuitable for mass production; 2) they are of low yield and time-consuming; 3) they involve complicated separation and purification processes of the reaction product; 4) they are accompanied by the generation of harmful gas, odor and/or waste fluid; and/or 5) they require materials harmful or difficult to handle as starting compounds, reagents, and/or solvents. The present invention provides a process for preparing a compound of the formula (I): wherein R is hydrogen or a hydroxy-protecting group; X is hydrogen or alkyl; and the double bond represents either the E- or Z-configuration, or a pharmaceutically acceptable salt thereof or a hydrate thereof, which comprises reacting an amino alcohol of the formula (II): or a salt thereof with a compound of the formula (III) wherein R is hydrogen or a hydroxy-protecting group, or a reactive derivative thereof to yield a compound of the formula (I-2): wherein R is as defined above; oxidizing the compound (I-2) with a halo oxoacid in the presence of a compound of 2,2,6,6-tetramethylpiperidine-1-oxyls to yield a compound of the formula (I-3): wherein R is as defined above; reacting the compound (I-3) with an ylide under the conditions for the Wittig reaction and, if desired, deprotecting the reaction product. THE BEST EMBODIMENT FOR PRACTISING THE INVENTION In a preferred embodiment of the present invention, a compound of the formula (I-2): wherein R is as defined above is oxidized with a halo oxoacid in the presence of 2, 2, 6, 6-tetramethylpiperidine-1-oxyls to yield a compound of the formula (I-3): wherein R is as defined above. In another preferred embodiment, the process of the present invention further comprises the step of reducing a compound of the formula (II-2) : wherein R 2 is alkyl and R 3 is hydrogen or alkyl with a reducing agent-Lewis acid system to yield an amino alcohol of the formula (II) or a salt thereof. Preferably, the reducing agent used is selected from the group consisting of alkali metal- or alkaline earth metal-substituted borohydrides; and the Lewis acid is selected from the group consisting of halides of tin, aluminum, titanium, boron, zirconium or nickel and complexes thereof with ethers. In another preferred embodiment, the process of the present invention further comprises the step of converting a compound of the formula (II-2) : wherein R 2 and R 3 are as defined above into an alcohol of the formula (II-3): wherein R 3 is as defined above; and the alcohol is reduced with a reducing system of metallic sodium-alcohol or a reducing agent-Lewis acid to provide an amino alcohol of the formula (II) or a salt thereof. 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 C 1 -C 20 linear or branched alkyl, particularly, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl and eicosyl, and C 1 -C 6 , alkyl is preferred. As alkyl for R 2 , C 1 -C 3 alkyl is preferred. The term "alkoxy" means C 1 -C 6 linear or branched alkoxy, particularly, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy, neopentyloxy, s-pentyloxy, t-pentyloxy, n-hexyloxy, neohexyloxy, i-hexyloxy, s-hexyloxy or t-hexyloxy and C 1 -C 3 alkoxy is preferred. The term "alkoxyalkyl" means an alkyl group substituted by alkoxy group, including methoxymethyl, ethoxymethyl, methoxyethoxymethyl, ethoxyethyl, and methoxypropyl. The term "acyl" means C 1 -C 11 acyl derived from an aliphatic carboxylic acid or aromatic carboxylic acid. Examples of aliphatic carboxylic acid-derived acyl include acetyl, chloroacetyl, trichloroacetyl, propionyl, butyryl and valeryl and examples of aromatic carboxylic acid-derived acyl include benzoyl, p-nitrobenzoyl, p-methoxybenzoyl, p-bromobenzoyl, toluoyl and naphthoyl. The term "aryl" means e.g. phenyl, naphthyl or polycyclic aromatic hydrocarbon group. In addition, aryl may be substituted by the following substituents. Examples of substituents include alkyl such as methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or tert-pentyl, lower 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. The aryl group may have one or more substituents at any possible position. Specific examples of aryl include 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 4-pentylphenyl, 4-carboxyphenyl, 4-acetylphenyl, 4-(N,N-dimethylamino)phenyl, 4-nitrophenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-fluorophenyl and 4-chlorophenyl and 4-iodophenyl. The aryl group in the "aralkyl", "arylsulfonyl", "aryloxycarbonyl" or "aralkyloxycarbonyl" described below may have similar substituents as defined above. The term "aralkyl" means an alkyl group substituted by an aryl group, and includes benzyl, 4-methylbenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, naphthylmethyl and phenethyl. The term "alkylsulfonyl" means a sulfonyl group substituted by an alkyl group, and includes methanesulfonyl and ethanesulfonyl. The term "arylsulfonyl" means a sulfonyl group substituted by an aryl group, and includes benzenesulfonyl and, p-toluenesulfonyl. The term "alkyl-substituted silyl" means mono-,, di- or tri-alkyl-substituted silyl, for example, methylsilyl, dimethylsilyl, trimethylsilyl and t-butyldimethylsilyl. The term "alkoxycarbonyl" means e.g. methoxycarbonyl, isopropoxycarbonyl and t-butoxycarbonyl. The term "aryloxycarbonyl" means e.g. phenoxycarbonyl. The term "aralkyloxycarbonyl" means e.g. benzyloxycarbonyl. As the hydroxy-protecting group represented by R, the above-mentioned alkyl, alkoxyalkyl, acyl, aralkyl, alkylsulfonyl, arylsulfonyl, alkyl-substituted silyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl or tetrahydropyranyl are preferred and aryl sulfonyl is more preferred. Examples of salts of compounds of the general formula (I) include alkali metal salts such as lithium salts, sodium salts or potassium salts, alkaline earth metal salts, such as calcium salts, ammonium salts, salts with organic bases such as tromethamine, trimethylamine, triethylamine, 2-aminobutane, tert-butylamine, diisopropylethylamine, n-butylmethylamine, n-butyldimethylamine, tri-n-butylamine, cyclohexylamine, dicyclohexylamine, N-isopropylcyclohexylamine, furfurylamine, benzylamine, methylbenzylamine, dibenzylamine, N,N-dimethylbenzylamine, 2-chlorobenzylamine, 4-methoxybenzylamine, 1-naphthalenemethylamine, diphenylbenzylamine, triphenylamine, 1-naphthylamine, 1-aminoanthracene, 2-aminoanthracene, dehydroabiethylamine, N-methylmorpholine or pyridine, or amino acid salts such as lysine salts or arginine salts. The salts of amino alcohols of the formula (II) include salts with organic acids such as benzoic acid, and mineral acids such as hydrochloric acid and sulfuric acid. The objective compound of the present invention is illustrated by the general formula (I), in which the double bond of the alkenylene side chain (i.e. the 5-heptenylene chain) may be in the E- or Z-configuration. The method of the present invention is described below in more detail. When a substituent(s) possibly interfering with the reaction exists, it may be appropriately protected and deprotected at a desired stage. Such protection or deprotection can be accomplished by procedures known in the art. I. Preparation of Compound (I) wherein R and X are as defined above. Step 1 This step relates to the preparation of amide (I-2) by acylating an amino alcohol (II) or a salt thereof with carboxylic acid (III) or a reactive derivative thereof. The carboxylic acid (compound III) used in the acylation can be synthesized by a method known in the literature [for example, Nippon-Kagaku Zasshi vol. 88, No.7, 758-763 (1967); Nippon-Kagaku Zasshi vol. 86, No. 10, 1067-1072 (1965) ; J. Chem. Soc. (C) . 1899-1905 (1967) ; J. Heterocycle. Chem. vol.10, 679-681(1973)]. The term "reactive derivative" of carboxylic acid (III) refers to e.g. to corresponding acid halides (e.g., chloride, bromide, iodide), acid anhydrides (e.g., mixed acid anhydride with formic acid or acetic acid), or activated esters (e.g., succinimide ester), and includes acylating agents generally used for the acylation of amino groups. For example, to obtain acid halides, a carboxylic acid is reacted e.g. with a thionyl halide (e.g., thionyl chloride), phosphorous halide (e.g., phosphorous trichloride, phosphorous pentachloride), or an oxalyl halide (e.g., oxalyl chloride), according to a known method (e.g., Shin-jikken Kagaku Koza, vol. 14, p. 1787 (1978); Synthesis 852-854 (1986); Shin-jikken Kagaku Koza vol. 22, p. 115 (1992)). The acylation can be carried out under ordinary conditions used for the acylation of an amino group. For example, when a carboxylic acid halide is used, the reaction is carried out according to the method commonly known as the "Schotten-Baumann Reaction". In general, carboxylic acid halide is added dropwise to an aqueous alkaline solution of the amine with stirring and under cooling while removing with alkali the generated acid. Alternatively, when a carboxylic acid is used as a free acid not a reactive derivative, the reaction can be conducted conventionally in the presence of a coupling agent customarily used in the coupling reaction between an amine and a carboxylic acid, such as dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide or N,N'-carbonyldiimidazole. Step 2 This step relates to the oxidation of an alcohol (I-2) to an aldehyde (1-3). Hitherto such reactions have been conducted using an oxidizing agent of the chromic acid series such as the Jones reagent (J. Org. Chem., 40, 1664-1665(1975)), the Collins reagent (J. C. S. Chem. Communication., 1972 1126) or pyridinium chlorochromate (Tetrahedron Lett., 2647-2650 (1975)). Further, methods wherein manganese dioxide (Helv. Chim. Acta., 39, 858-862 (1956)) or dimethyl sulfoxide (Swern oxidation, J. Org. Chem., 43, 2480-2482 (1978)) have been known. However, these existing methods have disadvantages. For example, chromic acids are toxic to the human body and must be detoxified after use. Further, the Swern oxidation using dimethyl sulfoxide-oxalyl chloride is not suited for large scale production because it is accompanied by the generation of carbon monoxide which is harmful to workers and a sulfurous odor and also it must be carried out at low temperature, for example, between - 50°C and -78°C. According to the method of the present invention, the alcohol (I-2) is oxidized with an oxidizing agent(s) such as a halo oxoacid in the presence of 2, 2, 6, 6-tetramethylpiperidine-1-oxyls (referred to as "TEMPOs") as described in the literature (e.g., J. Org. Chem., 52, 2559-2562 (1987)), whereby the problems of existing methods are solved. Examples of TEMPO include 2,2,6,6-tetramethylpiperidine-1-oxyl, 4-methoxy-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-acetylamino-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-benzoyloxy-2,2,6,6-tetramethylpiperidine-1-oxyl, and 4-cyano∼2,2,6,6-tetramethylpiperidine-1-oxyl. Examples of the halo oxoacid include sodium hypochlorite, sodium hypobromite, sodium bromite and higher bleaching powder. A solution of an oxidizing agent may be adjusted to, for example, pH 8.5 to 9.5 with a mineral acid such as sodium hydrogen carbonate, hydrochloric acid or sulfuric acid. Alternatively, a solution of an oxidizing agent may be added in the presence of sodium hydrogen carbonate. The reaction can be accomplished within several minutes to several tens of minutes at temperatures from ice-cooling to room temperature in a solvent such as ethyl acetate, acetonitrile or dichlaromethane. The advantageous characteristics of the new oxidation method of the present invention are as follows: 1) the process requires simple operations and short periods of time since the reaction produces a product in high yield within a short reaction time without maintaining very low temperatures; 2) the process is safe since the reaction solvents used are water and ethyl acetate; 3) the separation and purification of reaction products can be conducted only by extraction; 4) the oxidation is carried out with a cheap reagent, sodium hypochlorite, with only a relatively small amount of catalyst, TEMPO, at 1 - 0.2 % molar equivalent to the alcohol(I-2); 5) it allows the operators to work in a better environment because the reaction generates little carbon monoxide or odor in contrast with the Swern oxidation, and, further, sodium chloride resulting from the sodium hypochlorite used in the oxidation does not need to be detoxified. Step 3 This step relates to the formation of a double bond by reacting a compound of the formula (I-3) with an ylide (Ph 3 P=CH(CH 2 ) 3 COOH). The reaction for providing a double bond can be carried out in a conventional manner for the Wittig reaction. The ylides used in the reaction can be synthesized, in the presence of a base, by treating a phosphonium salt which has been synthesized from triphenylphosphine and an alkyl halide having a desired alkyl group to be condensed, for example, 5-bromopentanoic acid. Examples of a base include dimsyl sodium, dimsyl potassium, sodium hydride, n-butyl lithium, potassium t-butoxide and lithium diisopropylamide. The reaction is accomplished within several hours at room temperature in a solvent such as ether, tetrahydrofuran, n-hexane, 1,2-dimethoxyethane or dimethyl sulfoxide. Step 4 In this step, a compound (I) wherein R is a hydroxy-protecting group is deprotected to provide compound (I-1). The reaction can be carried out in a conventional manner using, as a catalyst, e.g. hydrochloric acid, sulfuric acid, sodium hydroxide, potassium hydroxide or barium hydroxide. The reaction is accomplished within several tens of minutes to several hours with heating in a solvent such as methanol-water, ethanol-water, acetone-water, or acetonitrile-water, preferably dimethyl sulfoxide-water. The OR may be positioned at any of the 4-, 5-, 6- and 7-positions, though it is preferred to be at the 5-position. II. Preparation of Compound (II) The starting material in this process, amino alcohol (II), can be prepared by a known procedure starting from, for example, (-)-myrtenol. A precursor, methoxime ester of the formula (II-2) wherein R 3 is methyl, is then reduced with sodium metal in isopropanol to give the corresponding amino alcohol (II) (Hagishita, et al., Chem. Pharm. Bull., 37(6), 1524-1533 (1989)). However, this method has problems such as low yield (39.6 %) or poor selectivity. As reducing agents used in the reduction of esters to alcohols, there have been known e.g. sodium borohydride (J. Org. Chem., 28, 3261 (1982)), lithium aluminum hydride (Org. Syn., 63, 140), and lithium borohydride (J. Org. Chem., 47,4702 (1982)). Further, as methods for reducing oximes to amines, there have been known catalytic reduction (Syn. Communication., 27, 817 (1997); Org. Syn., coll. vol. 5, 376 (1973 or methods which use a reducing agent(s) such as diborane (J. Org. Chem., 30, 2877 (1965)), sodium borohydride (J. Org. Chem., 48, 3412 (1983)), lithium aluminum hydride (Tetrahedron, 51, 8363 (1995)), sodium borohydride-titanium chloride (IV) (Synthesis 1980 695), and sodium borohydride-nickel chloride (II) (Chem. Ber., 117, 856 (1984)). None of the literature above, however, teaches a method for reducing both ester and oxime moieties present in one molecule such as a compound of the formula (II-2) simultaneously in high yield with high stereoselectivity. The inventors have succeeded in reducing the oxime ester of the formula (II-2) to the objective amino alcohol (II) in high yield with high selectivity by using a reducing agent-Lewis acid system (especially, sodium borohydride-Lewis acid) as shown in Scheme II below. wherein R 2 and R 3 are defined above. According to the present process, an oxime ester (II-2) is reduced directly or via alcohol (II-3) to give an amino alcohol (II) or a salt thereof. Reducing agents usable in the reaction above include alkali metal- or alkaline earth metal-substituted borohydrides (e.g. sodium borohydride, lithium borohydride or calcium borohydride). Examples of the Lewis acid include halides of tin, aluminium, boron, titanium, zirconium or nickel (e.g., stannous chloride, stannic chloride, aluminium chloride, titanium tetrachloride, boron trifluoride, zirconium tetrachloride and nickel dichloride) or ether complexes thereof (e.g., sodium bis(2-methoxyethoxy)aluminium hydride). Examples of solvents include ethers (e.g., ethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, dioxane and diethylene glycol dimethyl ether) hydrocarbons (e.g., toluene and xylene), and mixed solvents of ethers and hydrocarbons. Regarding the reduction of an alcohol (II-3) to an amino alcohol (II) or its salt, a method which uses metal sodium-alcohol is also available in addition to the above-mentioned reducing agent-Lewis acid system. Examples of alcohols include methanol, ethanol, n-propanol, and i-propanol. Examples of solvents include hydrocarbons (e.g., toluene and xylene). The reaction process will be described in detail below. The raw material, oxime ester (or alkyl-substituted oxime) (II-2a or II-2b) is dissolved in 2 volumes or more of a solvent. To the solution are added 2 or more molar equivalents of a reducing agent and then a Lewis acid at 0.1 to 0.4 molar equivalents to the reducing agent at 0°C to 150°C. Alternatively, a mixture previously prepared by combining a Lewis acid and a solvent may be added. Further, the order for adding the raw material, the oxime ester, the reducing agent and the Lewis acid can be changed. The reaction mixture is then treated at 0°C to 150°C for several minutes to several hours for reaction. The reaction solution can be worked up by adding water and dilute mineral acid (e.g., dilute hydrochloric acid) followed by stirring, whereby the reducing agent is destroyed. Alternatively, the reaction solution may be poured into dilute mineral acid. The solution is then neutralized with an alkali (e.g., sodium hydroxide) and extracted with an organic solvent (e.g., ethyl acetate). When the solvent is distilled off, an amino alcohol (II) is obtained. If necessary, the product can be further purified by converting into a crystalline salt (II') with an appropriate acid (e.g., benzoic acid) and then neutralizing with an alkali to give amino alcohol (II). According to the above-mentioned process of the present invention, the objective amino alcohol (II) can be prepared in high yield (about 89 %) with high stereoselectivity (99 % or more). Although the process for preparing a compound of the formula (II) shown in scheme II above is novel and useful for the preparation of a compound (II) in itself, it also contributes to establish safe and efficient production of the compound (I), the final product, when combined with a process for preparing the compound (I). The following Examples are provided to further illustrate the present invention in more detail and should not be interpreted in any way as to limit the scope thereof. The abbreviations used in the Examples have the following meanings: Ph: phenyl Ac; acetyl TEMPO: 2,2,6,6-tetramethylpiperidine-1-oxyl Reference Example 1 Preparation of ethyl [(1R,3R,5S)-2-methylidene-10-norpinan-3-yl)] acetate (2) A mixture of (-)-myrtenol (1) (6.44 g, 42.3 mmol), triethyl orthoacetate (23 ml, 126 mmol) and hydroquinone (27 mg) was heated with stirring at 165°C for 2 hours, at 185°C for 2 hours and at 195°C for 25 hours, and the resulting ethanol was distilled off. The resulting oil was purified by chromatography on silica gel (hexane: toluene=10:0-1:1) to provide 7.66g of the title compound (2). Yield: 81.4 %. IR (Film): 3070, 2980, 2921, 2869, 1737, 1638 cm -1 1 H NMR δ (CDC1 3 ), 300MHz: 0.76 and 1.24 (each, 3H,each, s), 1.20(1H, d,J=9.9Hz), 1.27(3H, t, J=7.2Hz),1.52(1H, m), 2.00(1H, m), 2.23-2.50(3H,m), 2.66( 1H, dd,J=5.1 and 15.3Hz), 3.03(1H, m), 4.16(2H, q,J=7.2Hz),4.71(2H, d, 11.4Hz). Elemental Analyses for C 14 H 22 O 2 Calculated (%) C, 75.63; H, 9.97 Found (%) C, 75.61; H, 9.99 [α]D 24 +29.1° (c=1.05, CH 3 OH) Reference Example 2 Preparation of 5-benzenesulfonyloxybenzo[ b ] thiophene-3-carbonyl chloride (6) 5-Hydroxybenzo[ b ]thiophene-3-carboxylic acid (11)(M.Martin-Smith et al. J. Chem. Soc (C) 1899-1905 (1967)) 8.63g(44.4 mmol) was dissolved in aqueous tetrahydrofuran (water content, 20 %; 160 ml) and 1 N sodium hydroxide (44 ml). To the solution were added dropwise 0.56 N sodium hydroxide (87 ml) and benzenesulfonyl chloride (6.2 ml, 48.4 mmol) simultaneously with stirring under ice-cooling while maintaining the pH at 11-12. After the completion of the reaction, the mixture was diluted with water, basified, and washed with toluene. The aqueous layer was made slightly acidic by adding concentrated hydrochloric acid with stirring, and the deposited crystals were filtered, washed with water and dried to provide 14.33g of 5-benzenesulfonyloxybenzo[b]thiophene-3-carboxylic acid (12). M.p. 202-203°C. NMRδ (CDC1 3 ),300MHz: 7.16(1H,dd,J=2.7 and 9.0Hz),7.55-7.61(2H,m), 7.73(1H,m), 7.81 (1H,d,J=9.0Hz), 7.90-7.94(2H,m), 8.16(1H,d,J=2.7Hz), 8.60(1H,s). IR(Nujol):3102,2925,2854,2744,2640,2577,1672, 1599,558,1500,1460,1451 cm -1 Elemental Analyses for C 15 H 10 O 5 S 2 Calculated (%) C,53.88; H,3.01; S,19.18 Found (%) C,53.83; H,3.03; S,19.04 The 5-benzenesulfonyloxybenzo[b]thiophene-3-carboxylic acid (12) (5.582 g, 16.7 mmol) prepared above was refluxed with dimethylformamide (1 drop), thionyl chloride (3.57ml,50 mmol) and toluene (22 ml) for 1.5 hours. When the solvent was removed under reduced pressure, 5.89g of the objective compound (6) was obtained. Example 1 Preparation of Amino Alcohol (1) Step 1: Preparation of ethyl [(1R,3R,5S)-2-oxo-10 -norpinan-3-yl] acetate (3) The compound (2) (333.5 g, 1.5mol) prepared in Reference Example 1 was dissolved in dichloromethane (3.340L) and methanol (660 ml). The mixture was cooled to -70 to -73°C and ozone gas was introduced for 4 hours. After introducing nitrogen gas for 1 hour, trimethyl phosphite (265 ml, 2.26mol) was added and the reaction was allowed to warm to room temperature. The reaction mixture was partitioned into two layers by adding ice-water (150 ml) and 10 % sulfuric acid (300g). The organic layer was sequentially washed with water (1.2 L), 2 % sodium sulfite (1.2Kg) and water (1.2 L)., The aqueous layer was extracted with ethyl acetate (1.11 L). The organic layers were combined and the solvent was distilled off under reduced pressure to provide 456.51g of oil, which was then dissolved in tetrahydrofuran (1.05 L). After adding cold 14 % aqueous ammonium hydroxide (106.8g), the resulting pale yellow solution was stirred at room temperaturefor 1 hour. The reaction mixture was diluted with ice-water (750 ml). After adding ethyl acetate (1.1 L), the mixture was stirred and partitioned into layers. The same procedures were repeated once more and the aqueous layer was further extracted with ethyl acetate. The combined organic layer was washed with 10 % brine (750 ml), dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure. The resulting oil was dissolved in toluene (500 ml) and the solvent was distilled off under reduced pressure to provide 347.96g of oil. Crude yield: 103.4 %. 1 H NMR δ (CDC1 3 ), 300MHz; 0.95 and 1.34 (each 3H, each s), 1.27(3H, t, J=7.0Hz),1.40(1H, d, J=9.9Hz), 1.67(1H, m), 2.25(1H, m), 2.33-2.42(2H, m), 2.56-2.65(2H, m), 2.86-3.02(2H, m), 4.14-4.21(2H, m) (2) Step 2 1) Preparation of ethyl [(1R,3R,5S)-2-hydroxyimino-10-norpinan-3-yl] acetate (4a) The compound (3) (10.05 g, 44.9 mmol) was dissolved in ethanol (45 ml). To the solution were added hydroxylamine hydrochloride (4.99 g, 71.9 mmol) and pyridine (4.7 ml, 58.1 mmol) and the mixture was heated at 60°C for 2.5 hours with stirring. The reaction mixture was concentrated under reduced pressure, diluted with water and acidified withhydrochloric acid, and then extracted with ethyl acetate. The organic layer was sequentially washed with water, aqueous sodium hydrogen carbonate and water, dried over anhydrous magnesium sulfate and the solvent was then distilled off under reduced pressure to provide 10.72g of the title compound (4a) as colorless oil. Crude yield:100 %. [α] D 24 +55.30° (c=1.01, CH 3 OH) 2) Preparation of ethyl [(1R,3R,5S)-2-methoxyimino-10-norpinan-3-yl] acetate (4b) The compound (3) (107.0 g, 477 mmol) was dissolved in ethanol (500 ml). To the solution were added 0-methylhydroxylammonium chloride (50.1 g, 600 mmol) and pyridine (47.5 g, 600 mmol) and the mixture was refluxed for 3 hours with stirring. The reaction mixture was concentrated under reduced pressure, diluted with water, acidified with hydrochloric acid and then extracted with ethyl acetate. The organic layer was sequentially washed with water, aqueous sodium hydrogen carbonate and water, dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure. The resulting colorless oil was distilled under reduced pressure to provide 106.1g of the title compound (4b). Boiling point 118-123°C (reduced pressure 1.2mmHg). Yield: 87.8%. IR (Film): 1738, 1630 cm -1 Elemental Analyses for C 14 H 23 NO 3 Calculated (%) C, 66.37; H, 9.15; N, 5.53 Found (%) C, 65.92; H, 9.13; N, 5.60 [α] D 24 +69.50° (c=1.00 %, CH 3 OH) (3) Step 3: Preparation of [(1R,2R,3R,5S)-2-amino-10-norpinan-3-yl]ethanol benzoic acid salt (II') 1) Preparation from a compound (4b) Sodium borohydride (799 mg, 21.1 mmol) was suspended in 1,2-dimethoxyethane (5 ml). To the suspension were added with stirring under ice-cooling a suspension of aluminum chloride (507 mg, 3.8 mmol) in 1,2-dimethoxyethane (5 ml) followed by a solution of the compound (4b) (1.07 g, 4.2 mmol) in 1,2-dimethoxyethane (3 ml), and the mixture was warmed in a bath at 70°C for 3 hours. To the reaction were sequentially added water (4 ml), 2 N hydrochloric acid (8 ml) and concentrated hydrochloric acid (1 ml) with stirring under ice-cooling, and the mixture was then stirred at room temperature for 40 minutes. The reaction mixture was washed with ether, neutralized with sodium hydroxide and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then distilled off under reduced pressure to provide 789 mg of the title compound (II) as colorless oil. The product was dissolved in ethyl ether (5 ml). To the solution was added a solution of benzoic acid (516 mg, 4.2 mmol) in ether (5 ml), and the mixture was stirred. The deposited crystals were filtered and washed with ether and dried to provide 1.146g of colorless benzoic acid salt of amino alcohol (11') . Yield: 89 % (purity: 99.2 %) , mp 183-185°C. The purity of the benzoic acid salt of amino alcohol (II') was measured by converting the salt into benzamide in the presence of a condensing agents such as dicyclohexylcarbodiimide (DCC) and 1-hydroxybenztriazole (HOBT) in tetrahydrofuran, and determining the purity of the resulting amide using high performance liquid chromatography (HPLC). IR (KBr): 3420, 2600(br), 1621, 1523, 1386 cm -1 'H NMR δ (CDC1 3 ) : 300MHz; 0.72 (1H, d, J=9.9Hz), 1.06 and 1.13(each 3H, each s), 1.40(1H, m), 1.56-1.92(3H, m), 2.12-2.36(4H, m), 3.29(1H, m), 3.62(1H,m), 3.78(1H, m), 7.32-7.47(3H, m), 7.97-8.04(2H, m) Elemental Analyses for C 18 H 27 NO 3 Calculated (%) C, 70.79; H, 8.91; N, 4.59. Found (%) C, 70.54; H, 8.93; N, 4.56. [α] D 25 +27.6° (c=1.00 %, CH 3 OH) Reference values: mp 180-183°C, [α] D 26 +27.1° (Chem. Pharm. Bull., 37, 1524 (1989)). [HPLC conditions] apparatus; LC-6A type (Shimazu); column: YMC-pack ODS-AMAM-302 (4.6mm ø x 150mm) ; flow rate: 1.0 ml/min; detection : UV 254nm; mobile phase: acetonitrile/water(1:1); retention time: 5.23 minutes 2) Preparation from a compound (4a) (part 1) Sodium borohydride (1.55 g, 41.0 mmol) was suspended in diethylene glycol dimethyl ether (13 ml). To the suspension was added boron trifluoride etherate (1.71 ml, 13.5 mmol) with stirring under ice-cooling over 10 minutes, and the mixture was stirred at room temperature for 20 minutes. After addition of a solution of compound (4a) (1.015 g, 4.1 mmol) in diethylene glycol dimethyl ether (825 ml), the mixture was stirred at room temperature for 20 minutes. The mixture was then heated in a bath at 110°C with stirring for 2 hours. The solution was treated as described in 1) above to provide 741 mg of the benzoic acid salt of amino alcohol (II'). Yield: 59 % (purity: 99.2 %), mp 178-180°C. 3) Preparation from a compound (4a) (part 2) Sodium borohydride (1.00 g, 26.4 mmol) was suspended in 1,2-dimethoxyethane (10 ml). To the suspension were added compound (4a) (1.00 g, 4.03 mmol) and titanium tetrachloride-1,2-dimethoxyethane complex (1:1) (700 mg, 2.51 mmol) with stirring under ice-cooling. The mixture was stirred at room temperature for 30 minutes and, furthermore, heated in a bath at 70°C with stirring for 3 hours. The mixture was treated as described in above 1) to provide 750 mg of benzoic acid salt of amino alcohol (II'). Yield: 61 % (purity: 94.2 %), mp 176-180°C. (4) Step 4: Preparation of [(1R,3R,5S)-2-methoxyimino-10-norpinan-3-yl]ethanol (5) The compound (4b) (23.8 g, 94 mmol) was dissolved in toluene (111 ml). To the solution was added a solution of 70 % sodium bis(2-methoxyethoxy)aluminum hydride in toluene (34.4 g, 119 mmol) at temperature below 25°C over 20 minutes, and stirring was continued for 30 minutes at the same temperature. To the reaction mixture was added acetone (7g) to decompose the reagent, followed by water(30 ml) and then 48 % sodium hydroxide (43.8g). The resulting two layers were separated and the aqueous layer was extracted with toluene (111 ml). The combined organic layer was washed with water (3 x 30 ml). The organic layer was dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure to provide 18.9g of the title compound (5) as a colorless oil. Yield:95.1 %. The product was used in the subsequent reaction without purification. IR (CHC1 3 ): 3619, 3502, 3020, 2974, 2937, 2872, 2818, 1623, 1460 cm -1 [α] D 23.5 +86.40° (c=1.00 %, CH 3 OH) (5) Step 3': Preparation of [(1R,2R,3R,5S)-2-amino-10-norpinan-3-yl]ethanol benzoic acid salt (II') The compound (5) (9.63 g, 45.58 mmol) prepared in (4) was dissolved in toluene (33 ml) and n-propanol (72 ml). To the solution was added sodium metal (7.47 g, 325 mmol) in portions under reflux over 25 minutes. After 1 hour, additional sodium metal (1.15 g, 50 mmol) was added, and stirring was continued for 1 hour under reflux. The reaction mixture was cooled and then partitioned into two layers by adding ice water (39 ml) and toluene (95 ml). The aqueous layer was extracted with toluene (95 ml). The combined organic layer was washed with brine (3 x 95 ml) and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to provide 8.4g of the title compound (II) as colorless oil. The compound (II) 8.4g (45.8 mmol) was dissolved in toluene (33.3 ml) and acetone (111 ml) and the solution was heated to 50°C. After adding a solution of benzoic acid (4.82 g, 39.47 mmol) in acetone (22.2 ml), the mixture was stirred at the same temperature for 1 hour. The deposited crystals were filtered and washed with cold acetone (33.3 ml) and dried to provide 9.155g of colorless amino alcohol benzoic acid salt (II'). Yield: 65.8 %. IR (Nujol): 3428, 2999, 2921, 2864, 2727, 2633, 2596, 2107, 1663, 1623, 1592, 1555, 1523, 1456, 1444 cm -1 [α] D 23.5 +27.1° (c=1.01 %, CH 3 OH), mp181-183°C. Example 2 (1) Step 1:Preparation of [3-[(1R,2R,3R,5S)-3-(2-hydroxyethyl)-10-norpinan-2-yl]carbamoylbenzo[b]thiophen-5-yl] benzenesulfonate (7) (+)-2-[(1R,2R,3R,5S)-2-Amino-10-norpinan-3-yl]ethanol benzene sulfonic acid salt (II, 5.1 g, 16.7 mmol) prepared in Example 1 was suspended in water (10 ml). To the suspension was added 1 N HCl (17 ml) and the deposited benzoic acid was removed by extracting with ethyl acetate. The organic layer was washed with water (10 mL). To the combined aqueous layer was added 4 N sodium hydroxide (9.2 ml, 36.8 mmol) under ice-cooling, and a solution of 5-benzenesulfonyloxybenzo[b]thiophene-3-carbonyl chloride (6)(5.89 g, 16.7 mmol) prepared in Reference Example 2 in tetrahydrofuran (36 ml) was then added dropwise over 15 minutes with stirring. After stirring for another 1 hour at the same temperature, 1 N hydrochloric acid (4 ml) was added and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure to provide 8.00g (95.6 %) of colourless amorphous title compound (7). 1 H NMRδ (CDC1 3 ), 300MHz; 0.96 (1H, 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(1H, m), 6.21(1H, d, J=8.1Hz), 7.06(1H, dd, J=2.40 and 8.7Hz), 7.51-7.56(2H, m), 7.67(1H, m), 7.73(1H, d, J=8.7Hz), 7.85-7.88(2H, m), 7.88(1H, s), 8.06(1H, d, J=2.4Hz) [α] D 25 +35.7° (C=1.00 %,CH 3 OH) (2) Step 2: Preparation of [3-[(1R,2R,3R,5S)-3 -formylmethyl-10-norpinan-2-yl]carbamoylbenzo[b]thiophen-5-yl] benzenesulfonate (8) The compound (7) (9.72 g, 18.3 mmol) was dissolved in ethyl acetate (70 ml). To the solution were added TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl), (14.3 mg, 0.005 equivalent) and potassium bromide (218 mg, 0.1 equivalent). 0.41 N Aqueous sodium hypochlorite (45 ml of a solution adjusted to pH 9.5 with sodium hydrogen carbonate, 1 equivalent) was added dropwise over 3 minutes with stirring while maintaining the inner temperature at -1°C - 6°C. After 10 minutes at this temperature, the two layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure to provide 9.10g (100 %) of colorless amorphous title compound (8). IR (CHC1 3 ); 3443, 3093, 3066, 3030, 3016, 2925, 2871, 2828, 2729, 1720, 1655, 1599, 1558, 1513, 1377 cm -1 1 H NMR δ (CDC1 3 ), 300MHz; 0.97(1H, d, J=10.2Hz), 1.17 and 1.28(each 3H, each s), 1.46(1H, m), 2.03(1H, m), 2.22(1H, m), 2.36-2.60(3H, m), 2.69(1H, ddd, J=1.2, 8.7 and 17.4Hz), 3.14(1H, dd, J=4.5 and 17.4Hz), 4.28(1H, m), 6.18(1H, d, J=8.1Hz), 7.09(1H,dd, J=2.4 and 8.7Hz), 7.50-7.55(2H, m), 7.67(1H, m), 7.75(1H, d, J=8.7Hz), 7.85-7.89(2H, m), 7.89(1H s), 8.03(1H, d, J=2.4Hz), 9.80(1H, d, J=1. 2Hz) [α] D 23 +31.8 (c=1.00 %, CH 3 OH) (3) Step 3: Preparation of (5Z) -7- [(1R,2R,3S, 5S)-2-(5-benzenesulfonyloxybenzo[b]thiophen-3-ylcarbonylamino)-10-norpinan-3-yl]1-5-heptenoic acid (9) 4-Carboxybutyltriphenylphosphonium bromide (12.17 g, 27.5 mmol) and potassium t-butoxide (7.19 g, 64.1 mmol) were suspended in tetrahydrofuran (64 ml) and the mixture was stirred under ice-cooling for 1 hour. To the reaction mixture was added a solution of compound (8) (9.11 g, 18.3 mmol) prepared in (2) above in tetrahydrofuran (27 ml) over 15 minutes, and stirring was continued 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 the aqueous layer was adjusted to pH 8.1 with 5 N hydrochloric acid (4.8 ml), anhydrous calcium chloride (8.1 g, 73 mmol) dissolved in water (16 ml) was added and the mixture was extracted with ethyl acetate (2 x 100 ml). To the organic layer was added water (100 ml) 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 magnesium sulfate and then the solvent was distilled off under reduced pressure to provide 11.06g of the compound (9), which was used without purification. (4) Step 4: Preparation of (5Z)-7-[(1R,2R,3S,5S)-2-(5-hydroxybenzo[b]thiophen-3-ylcarbonylamino)norpinan-3-yl]-5-heptenoic acid (10) (Compound A)) The compound (9) (11.06 g, 18.3 mmol) prepared in (3) above was dissolved in dimethyl sulfoxide (22 ml). To the solution was added 4 N sodium hydroxide (27.5 ml), and the mixture was heated at 55°C for 2 hours with stirring. The reaction mixture was diluted with water (130 ml) and washed with toluene (2 x 65 ml). The aqueous layer was acidified with 5 N hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure to provide 8.26g of the crude objective compound (10). The product was dissolved in methanol (40 ml) and water (16 ml), and the mixture was seeded and gradually cooled with stirring. The deposited crystals were filtered and washed with water: methanol (2:5) to provide 6.35g of the objective compound(10). Yield: 78.6 %. The crystals were dissolved in methanol (40 ml), and water (12 ml) was added with stirring over 7 minutes. After adding seeds, the solution was continuously stirred at 25°C for 1 hour. Additional water (7 ml) was added over 40 minutes and stirring was continued 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 almost colorless objective compound (10). Yield: 76.0 %, mp 145-146°C. IR (Nujol); 3313, 3096, 3059, 3001, 1717, 1627, 1603, 1548, 1469, 1440 cm -1 1 H NMR δ (CDC1 3 ), 300MHz; 1.02(1H, d, J=10.2Hz), 1.12 and 1.24(each 3H, each s), 1.56-2.55(14H, m), 4.29(1H, m), 5.32-5.51(2H, m), 6.20(1H, d, J=9.3Hz), 7.01(1H, dd, J=2.4 and 9.0Hz), 7.66(1H, d, J=MHz), 7.69(1H s), 8.03(1H, d, J=2.4Hz) [α] D 24 +50.7° (c=1.01,CH 3 OH) Elemental Analyses for C 25 H 31 NO 4 S 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: A process for preparing a compound of the formula (I): wherein R is hydrogen or a hydroxy-protecting group; X is hydrogen or alkyl; and the double bond represents either the E- or Z-configuration, or a pharmaceutically acceptable salt or hydrate thereof, which comprises reacting an amino alcohol of the formula (II): or a salt thereof with a compound of the formula (III): wherein R is hydrogen or a hydroxy-protecting group or a reactive derivative thereof to yield a compound of the formula (I-2): wherein R is as defined above; oxidizing the compound (I-2) with a halo oxoacid in the presence of 2, 2, 6, 6-tetramethylpiperidine-1-oxyls to yield a compound of the formula (I-3): wherein R is as defined above; reacting the compound (I-3) with an ylide under the conditions for the Wittig reaction and, if desired, deprotecting the reaction product. The process of claim 1, wherein the hydroxy-protecting group is alkyl, alkoxyalkyl, acyl, aralkyl, alkylsulfonyl, arylsulfonyl, alkyl-substituted silyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl or tetrahydropyranyl. The process of claim 1, wherein the hydroxy-protecting group is arylsulfonyl. A process for preparing a compound of the formula (I-3): wherein R is hydrogen or a hydroxy-protecting group, which comprises oxidizing a compound of the formula (I-2): wherein R is as defined above with a halo oxoacid in the presence of 2, 2, 6, 6-tetramethylpiperidine-1-oxyls. The process of claim 1 which further comprises a step wherein a compound of the formula (II-2): wherein R 2 is alkyl and R 3 is hydrogen or alkyl is reduced with a reducing agent-Lewis acid system to yield an amino alcohol of the formula (II) or a salt thereof. The process of claim 5, wherein the reducing agent is selected from the group consisting of alkali metal- or alkaline earth metal-substituted borohydrides and the Lewis acid is selected from the group consisting of halides of tin, aluminum, titanium, boron, zirconium or nickel and complexes thereof with ethers. The process of claim 1 which further comprises a step wherein a compound of the formula (II-2) : wherein R 2 and R 3 are as defined above is converted into an alcohol of the formula (II-3): wherein R 3 is as defined above, and reducing the said alcohol with metal sodium-alcohol or reducing agent-Lewis acid system.

Inventors: HIRAMATSU YOSHIHARU, HONMA TSUNETOSHI, KAKINUMA MAKOTO, OKADA TETSUO, HIRAMATSU, YOSHIHARU, HONMA, TSUNETOSHI, KAKINUMA, MAKOTO, OKADA, TETSUO
Applicants: SHIONOGI & CO, SHIONOGI & CO., LTD.
Application year: 1999
Main classification: C07D333
IPC codes: C07C213, C07C215, C07D333