0001 The present invention relates to a process for preparing benzothiazolone compounds having pharmacological activity and to intermediates used in their preparation. 0002 WO 93/24473 describes a class of benzothiazolone compounds, having both 2-adrenoreceptor agonist activity and dopamine DA2 receptor agonist activity, of general formula 1

0003 wherein X and Y independently represent S(O)n or O, 0004 n represents 0, 1 or 2, 0005 p, q and r independently represent 2 or 3, 0006 Z represents phenyl optionally substituted by halogen, OR1, NO2 or NR2R3; or a 5- or 6-membered N, O or S containing heterocycle, and 0007 R1, R2 and R3 independently represent hydrogen or C1-C6 alkyl, and pharmaceutically acceptable derivatives thereof. 0008 Example 6 of WO 93/24473 describes a compound of formula (A) in which X is SO2, Y is O, p is 2, q is 3, r is 2 and Z represents a phenyl group. The compound of formula (A) is prepared by the selective reduction of a compound of formula (B) 2

0009 wherein Ph represents a phenyl group, in a borane-tetrahydrofuran solution. 0010 The present invention provides an alternative process for preparing the compound of Example 6 of WO 93/24473 which avoids the need to use the intermediate of formula (B) and the potential hazards associated with using toxic and expensive borane reagents. Furthermore, the alternative process is simpler and more convenient to operate, resulting in good yields of crystalline product with minimal work-up. 0011 In accordance with the present invention, there is therefore provided a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, 3

0012 wherein Ph represents a phenyl group, which comprises reacting a compound of formula (II) or a salt thereof such as a hydrochloride or hydrobromide salt, 4

0013 with a compound of formula (III), 5

0014 in the presence of a solvent and, optionally, a tertiary amine base; and, if desired, converting the compound of formula (I) to a pharmaceutically acceptable salt or solvate thereof. 0015 In the present specification, unless otherwise indicated, an alkyl substituent group may be linear or branched. Further, the alkyl groups in a tri-C1-C6 alkylamine compound may be the same or different. 0016 In the process of the invention, when using a salt of a compound of formula (II), a tertiary amine base will be present but when using a compound of formula (II), the base need not necessarily be present. 0017 The tertiary amine base may be an aliphatic amine (e.g. tri-C1-C6 alkylamine such as triethylamine or N,N-diisopropylethylamine) or a heterocyclic amine comprising one or more fused rings and at least one ring nitrogen atom such as 1,8-diazabicyclo5.4.0undec-7-ene (DBU), 1,5-diazabicyclo4.3.0non-5-ene (DBN) or as 1,4-diazabicyclo2.2.2octane (DABCO). The tertiary amine base is conveniently used in an amount such that the molar ratio (mol/mol) of tertiary amine base to formula (II) compound/salt is in the range from 1 to 5, preferably in the range from 2 to 4. 0018 The solvent used in the present process is preferably an organic solvent such as an alcohol, e.g. methanol or ethanol, or an amide such as dimethylformamide. The weight ratio (w/w) of solvent to formula (II) compound/salt is conveniently in the range from 5 to 30, preferably in the range from 5 to 25, and more preferably in the range from 5 to 20. The process of the present invention is preferably carried out at a temperature in the range from 15 to 100 C., more preferably from 50 to 100 C. and, in particular, at the reflux temperature of the solvent. 0019 The pharmaceutically acceptable salts of the compound of formula (I) include acid addition salts derived from an inorganic or organic acid such as hydrochloric, hydrobromic, boric, phosphoric, sulfuric, acetic, tartaric, maleic, citric, succinic, ascorbic, benzoic, 4-methoxybenzoic, 2- or 4-hydroxybenzoic, 4-chlorobenzoic, benzenesulfonic, para-toluenesulfonic, naphthalenesulfonic, methanesulfonic, sulfamic, salicylic, diphenylacetic, triphenylacetic, adipic, fumaric, lactic, glutaric, gluconic, 1-hydroxy or 3-hydroxy-2-naphthoic or oleic acid. The compound of formula (I) and its pharmaceutically acceptable salts may also form pharmaceutically acceptable solvates such as hydrates. 0020 The compound of formula (II) is a known compound which may be prepared, for example, as described by Weinstock et al., J. Med. Chem., 30, 1166-1176 (1987). 0021 The compound of formula (III) is a novel compound and hence forms another aspect of the present invention. 0022 In a preferred embodiment of the present process, the compound of formula (III) is formed in situ from a compound of general formula (IV), 6

0023 wherein L represents a carboxylate, e.g. benzoate, leaving group. 0024 Compounds of formula (IV) are novel compounds and therefore form a further aspect of the present invention. 0025 A compound of formula (IV) may conveniently be prepared by reacting a compound of formula (V), 7

0026 with a suitable acylating agent, e.g. an acid chloride such as benzoyl chloride. The reaction will typically be carried out in a solvent, e.g. a chlorinated solvent or an ester solvent such as ethyl acetate or isopropyl acetate, and a base such as triethylamine or sodium hydroxide. 0027 The compound of formula (V) is a novel compound and forms another aspect of the present invention. 0028 The compound of formula (V) may be readily prepared by contacting a compound of formula (VI), 8

0029 with an oxidising agent. Suitable oxidising agents to use include hydrogen peroxide, magnesium monoperoxyphthalate (MMPP), 3-chloroperoxybenzoic acid or potassium peroxymonosulphate, commercially sold under the trade mark OXONE. The reaction may conveniently be carried out in a solvent such as acetonitrile or dichloromethane, for example, at 0 C. to 70 C. 0030 The compound of formula (VI) is a novel compound and forms a still further aspect of the present invention. 0031 The compound of formula (VI) can be prepared by reacting a compound of formula (VII), 9

0032 with 2-mercaptoethanol. The reaction is conveniently carried out in the presence of an initiator such as ,- azodiisobutyronitrile (AIBN) and a solvent such as toluene at a temperature in the range from 40 to 110 C. 0033 The compound of formula (VII) is a known compound and may be prepared by techniques conventional in the art, for example, by reacting phenethyl alcohol with 3-bromopropene in the presence of a base such as sodium hydroxide and in a solvent such as toluene (see J. Amer. Chem. Soc. (1955), 77, 3889-3892). 0034 The invention will now be further described by reference to the following illustrative Examples.

EXAMPLE 1

4-Nitrobenzoic acid, 2-(3-(2-phenylethoxy)propylsulphonyl)ethyl ester 0035 a) 2-(3-(2-Phenylethoxy)propylsulphonyl)ethanol 0036 2-(3-(2-Phenylethoxy)propylsulphonyl)ethanol may be prepared from the 2-(2-propenyloxy)ethylbenzene (Cookson, R. C.; Wallis, S. R., J. Chem. Soc. B; 1966; 1245-1256) by the radical addition of 2-mercaptoethtanol, followed by oxidation using a hydrogen peroxide-based oxidant. 0037 b) 4-Nitrobenzoic acid, 2-(3-(2-phenylethoxy)propylsulphonyl)ethyl ester 0038 4-Nitrobenzoyl chloride (27.9 g, 0.15 mol) was dissolved in 2-propyl acetate (80 ml) and was added to a cooled, stirred solution of 2-(3-(2-phenylethoxy)propylsulphonyl)ethanol (34 g, 0.12 mol) and triethylamine (21 ml, 0.15 mol) in 2-propyl acetate (150 ml) at a rate to maintain the temperature below 25 C. (approx. 8 minutes). The mixture was stirred vigorously for a further two hours. A saturated solution of sodium hydrogen carbonate was then added, and the aqueous layer was removed. The organic layer was washed with water (250 ml) and then concentrated under reduced pressure to give the titled ester product as an off-white solid (42.5 g). The product was recrystallised from ethanol (400 ml) to give the ester as needles. 0039 Melting point: 72-79 C. 0040 1H NMR (D6-DMSO): 8.36, 8.15 (AABB, 4H), 7.22 (m, 5H), 4.70 (t, 2H), 3.68 (t, 2H), 3.56 (t, 2H), 3.48 (t, 2H), 3.20 (dd, 2H), 2.76 (t, 2H), 1.93 (m, 2H)

EXAMPLE 2

4-Methoxybenzoic acid, 2-(3-(2-phenylethoxy)propylsulphonyl)ethyl ester 0041 4-Methoxybenzoyl chloride (25.6 g. 0.15 mol) was dissolved in 2-propyl acetate (50 ml) and was added to a cooled stirred solution of 2-(3-(2-phenylethoxy)propylsulphonyl)-ethanol (34 g, 0.12 mol) and triethylamine (21 ml, 0.15 mol) in 2-propyl acetate (200 ml). The mixture was vigorously stirred for two hours. A saturated solution of sodium hydrogen carbonate (300 ml) was added, the organic layer was separated and washed with water (250 ml) and then concentrated under reduced pressure to give the titled ester product, which was purified by chromatography (over silica using mixtures of ethyl acetate/petroleum ether) to give the ester as a clear mobile oil. 0042 MS 407 (MH)0043 1H NMR (D6-DMSO): 7.93, 7.05 (AABB, 4H), 7.22 (m, 5H), 4.60 (t, 2H), 3.63 (t, 2H), 3.55 (t, 2H), 3.47 (t, 2H), 3.17 (m, 2H), 2.75 (t, 2H), 1.91 (m, 2H)

EXAMPLE 3

Benzoic acid, 2-(3-(2-phenylethoxy)propylsulphonyl)ethyl ester 0044 2-(3-(2-Phenylethoxy)propylsulphonyl)ethanol (60 g, 0.22 mol) was dissolved in dichloromethane (400 ml) and benzoyl chloride (30.7 ml, 0.265 mol) was added in one portion. With stirring under nitrogen, triethylamine (36.8 ml) was added over 12 minutes, the temperature rising to 41 C. The resulting suspension was stirred for 20 hours, washed sequentially with water (100 ml) and saturated sodium hydrogen carbonate (1100 ml) and then dried over sodium sulphate. Filtration and concentration afforded an oil which readily crystallised. The titled product was purified by recrystallisation from ethanol to give needles (60.4 g, 72% yield). 0045 Melting point: 65.5 C. 0046 1H NMR (CDCl3): 8.03 (d, 2H), 7.60 (t, 1H), 7.45 (t, 2H), 7.25 (m, 4H), 4.74 (t, 2H), 3.60 (t, 2H), 3.51 (t, 2H), 3.38 (t, 2H), 3.10 (m, 2H), 2.81 (t, 2H), 2.09 (m, 2H)

EXAMPLE 4

4-Hydroxy-7-(2-(2-(3-(2-phenylethoxy)propylsulphonyl)ethylamino)ethyl)-1.3- benzothiazol-2(3H)-one, hydrochloride 0047 a) 2-(3-Ethenylsulphonylpropoxy)ethylbenzene 0048 Benzoic acid, 2-(3-(2-phenylethoxy)propylsulphonyl)ethyl ester, (Example 3) (500 g, 1.33 mol) was dissolved in ethyl acetate (3.5 L) under nitrogen. 1,8-Diazabicyclo5,4,0-undec-7-ene (212.8 ml, 1.39 mol) was added and the mixture was stirred at ambient temperature for four hours. The precipitated solid was isolated by filtration, washed with ethyl acetate (1.5 L), and the combined organic phases washed with dilute hydrochloric acid (21 L), saturated sodium carbonate solution (21 L), and brine (1 L). The organic phase was dried over magnesium carbonate, and filtered and concentrated under reduced pressure to give the titled product as an oil (329 g, 97% yield) which crystallised on standing. 0049 Melting point: 28-28.5 C. 0050 MS (FAB) 255 (MH)0051 1H NMR (D6-DMSO): 7.25 (m, 5H), 6.97 (dd, 1H), 6.23 (m, 2H), 3.57 (t, 2H), 3.46 (t, 2H), 3.08 (t, 2H), 2.80 (t, 2H), 1.80 (m, 2H) 0052 b) 4-Hydroxy-7-(2-(2-(3-(2-phenylethoxy)propylsulphonyl)ethylamino)ethyl)-1,3-benzothiazol-2(3H)-one, hydrochloride 0053 7-(2-Aminoethyl)-4-hydroxy-1,3-benzothiazol-2(3H)-one, hydrochloride (100 g) was suspended in methanol (480 ml) at the reflux point. A solution of the 2-(3-ethenylsulphonylpropoxy)ethylbenzene (107 g) and triethylamine (53.8 ml) in methanol (240 ml) was added to the refluxing mixture over 35 minutes. After 2.75 hours, methanol (960 ml) was added, followed by hydrochloric acid (37 ml), and the mixture allowed to cool. Filtration, washing with propan-2-ol (400 ml), and then ether (400 ml), and drying afforded the hydrochloride salt (135.7 g, 69% yield). 0054 MS 465 (MH)0055 1H NMR (500 MHz spectrum) (D6-DMSO): 11.75 (s, 1H), 10.12 (s, 1H), 9.42 (s, 2H), 7.17-7.30 (m, 5H), 6.88, 6.78 (ABq, 2H), 3.60 (t, 22H), 3.50 (t, 2H), 3.36 (t, 2H), 3.21 (m, 2H), 3.17 (t, 2H), 2.89 (t, 2H), 2.81 (t, 2H), 1.92 (m, 2H)

EXAMPLE 5

4-Hydroxy-7-(2-(2-(3-(2-phenylethoxy)propylsulphonyl)ethylamino)ethyl)-1,3- benzothiazol-2(3H)-one, hydrochloride 0056 7-(2-Aminoethyl)-4-hydroxy-1,3-benzothiazol-2(3H)-one, hydrochloride (1.0 g), benzoic acid, 2-(3-(2-phenylethoxy)propylsulphonyl)ethyl ester (Example 3) (1.52 g), triethylamine (2.26 ml), and methanol (20 ml) were heated to reflux temperature over 30 minutes. This temperature was maintained for 5.5 hours, by which time high pressure liquid chromatography indicated that the reaction was complete. The mixture was allowed to cool slightly, and then acidified by the addition of concentrated hydrochloric acid (1.71 ml). On cooling and stirring, a salt crystallised from solution. Isolation by filtration, washing with propan-2-ol, and drying gave the titled product (1.1 g, 54% yield).

EXAMPLE 6

4-Hydroxy-7-(2-(2-(3-(2-phenylethoxy)propylsulphonyl)ethylamino)ethyl)-1,3- benzothiazol-2(3H)-one, hydrochloride 0057 7-(2-Aminoethyl)-4-hydroxy-1,3-benzothiazol-2(3H)-one, hydrochloride (3.0 g), 4-nitrobenzoic acid, 2-(3-(2-phenylethoxy)propylsulphonyl)ethyl ester (Example 1) (5.7 g), triethylamine (5.96 ml), and ethanol (industrial methylated spirits, 60 ml) were heated to reflux temperature over 20 minutes. This temperature was maintained for 4 hours. The mixture was allowed to cool slightly, and then acidified by the addition of concentrated hydrochloric acid (4.6 ml). On cooling, a salt crystallised from solution. Isolation by filtration, washing with propan-2-ol, and drying gave the titled product (3.8 g 62% yield)

EXAMPLE 7

4-Hydroxy-7-(2-(2-(3-(2-phenylethoxy)propylsulphonyl)ethylamino)ethyl)-1,3- benzothiazol-2(3H)-one, hydrochloride 0058 The method described in Example 6 was repeated using the compound of Example 2 in place of the compound of Example 1. The titled product was obtained in 61% yield.