MXPA01008647A - Novel process of preparing a benzothiazolone compound - Google Patents

Abstract

The invention relates to a process for preparing a benzothiazolone compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ph represents a phenyl group, having pharmacological activity and to intermediates used in their preparation.

Description

NOVEDOSO PROCESS FOR THE PREPARATION OF A BENZOTIAZOLONE COMPOUND DESCRIPTION OF THE INVENTION The present invention relates to a process for the preparation of benzothiazolone compounds having pharmacological activity and with intermediates used in their preparation.

International Publication Number WO 93/24473 discloses a class of benzothiazolone compounds, which have both β2-adrenoreceptor agonist activity and dopa ina receptor agonist activity DA2, of the general formula .

(A) wherein X and Y independently represent -S (0) n ~ o -O-, n represents 0, 1 or 2, p, q and r independently represent 2 or 3, Z represents phenyl optionally substituted by halogen, OR1, N02 or NR2R3; or a 5- or 6-membered heterocycle containing N, O or S, and REF: 131577 R1, R2 and R3 independently represent hydrogen or Ci-Cß alkyl, and pharmaceutically acceptable derivatives thereof. Example 6 of WO 93/24473 describes a compound of formula (A) in which X is S02, Y is 0, p is 2, q is 3, r is 2 and Z represents a phenyl group. The compound of the formula (A) is prepared by the selective reduction of a compound of the formula (B) OR II wherein Ph represents a phenyl group, in a solution of borane-tetrahydrofuran. The present invention provides an alternative process for the preparation of the compound of Example 6 of WO 93/24473 which avoids the need to use the intermediate of the formula (B) and the potential damages associated with the use of toxic and expensive borane reagents . In addition, the alternative process is simpler and more convenient to operate, resulting in good yields of crystalline product with a minimum of preparation.

According to the present invention, there is therefore provided a process for the preparation of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ph represents a phenyl group, which comprises the reaction of a compound of the formula (II) or a salt thereof such as a hydrochloride or hydrobromide salt, with a compound of the formula (III) (III) in the presence of a solvent and optionally, a tertiary amine base; and if the conversion of the compound of the formula (I) to a pharmaceutically acceptable salt or solvate thereof is desired. In the present specification, unless otherwise indicated, an alkyl substituent group may be linear or branched. In addition, the alkyl groups in a tri-alkylamine compound Ci-Ce can be the same or different. In the process of the invention, when a salt of a compound of the formula (II) is used, a tertiary amine base will be present but when a compound of the formula (II) is used, the base does not necessarily need to be present. The tertiary amine base may be an aliphatic amine (for example trialkylamine Ci-Ce such as a triethylamine or N, N-diisopropylethylamine) or a heterocyclic amine comprising one or more fused rings and at least one ring with nitrogen atom such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) or co or 1,4-diazabicyclo [2.2.2] octane (DABCO) The tertiary amine base is conveniently used in an amount such that the molar ratio (mol / mol) of the tertiary amine base with respect to the compound / salt of the formula (II) is in the range of 1 to 5, preferably in the interval from 2 to 4.

The solvent used in the present process is preferably an organic solvent such as an alcohol, for example methanol or ethanol, or an amide such as dimethylformamide. The weight ratio (w / w) of the solvent of the compound / salt of the formula (II) is conveniently in the range of 5 to 30, preferably in the range of 5 to 25, and more preferably in the range of 5 to 25. 20. The process of the present invention is preferably carried out in the range of 15 to 100 ° C, more preferably 50 to 100 ° C., in particular at the reflux temperature of the solvent. The pharmaceutically acceptable salts of the compound of the 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 acid , 4-methoxybenzoic, 2- or 4-hydrobenzoic, 4-chlorobenzoic, benzenesulfonic, para-toluenesulfonic, naphthalenesulfonic, methanesulfonic, sulphamic, salicylic, diphenylacetic, triphenylacetic, adipic, fumaric, lactic, glutaric, gluconic, 1-hydroxy or 3- hydroxy-2-naphthoic or oleic. The compound of the formula (I) and its pharmaceutically acceptable salts can also form pharmaceutically acceptable solvates such as hydrates.

The compound of the formula (II) is a known compound that can be prepared, for example, as described by Weinstock et al., J. Med. Chem. , 3_0, 1166-1176 (1987). The compound of the formula (III) is a novel compound and therefore forms another aspect of the present invention. In a preferred embodiment of the present process, the compound of the formula (III) is formed in itself from a compound of the general formula (IV), (IV) wherein L represents a carboxylate projection, for example benzoate. The compounds of the formula (IV) are novel and therefore form a further aspect of the present invention. A compound of the formula (IV) can conveniently be prepared by reacting a compound of the formula (V), (V) with a suitable acylating agent, for example, an acid chloride such as benzoyl chloride. Typically the reaction will be carried out in a solvent, for example, a chlorinated solvent or an ester solvent such as ethyl acetate or isopropyl acetate, and a base such as triethylamine or sodium hydroxide. The compound of the formula (V) is a novel compound and forms another aspect of the present invention. The compound of the formula (V) can be prepared easily by contacting a compound of the formula (VI), (SAW) with an oxidizing agent. Oxidizing agents suitable for use include hydrogen peroxide, magnesium monoperoxyphthalate (MMPP), 3-chloroperoxybenzoic acid or potassium peroxymonosulfate, sold commercially under the trademark "OXONE". The reaction can be conveniently carried out in a solvent such as acetonitrile or dichloromethane, for example, at 0 ° C to 70 ° C. The compound of the formula. (VI) is a novel compound and also forms a further aspect of the present invention. The compound of the formula (VI) can be prepared by reaction of a compound of the formula (VII), (VTI: with 2-mercaptoethanol. The reaction is conveniently carried out in the presence of an initiator such as α, α'-azodiisobutyronitrile (AIBN) and a solvent such as toluene at a temperature in the range of 40 to 110 ° C. The compound of the formula (VII) is a known compound and can be prepared by techniques conventional in the art, for example, by reaction of the 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. (1995), 77, 3889-3892.

In the following, the invention will be further described with reference to the following illustrative examples.

Example 1 2- (3- (2-Phenylethoxy) propylsulfonyl) ethyl ester of 4-nitrobenzoic acid a) 2- (3- (2-Phenylethoxy) propylsulfonyl) ethanol 2- (3- (2-phenylethoxy) propylsulfonyl) ethanol can be prepared from 2- (2-propenyloxy) ethylbenzene (Cookson, R. C; Wallis, S.R., J. Chem. Soc. B; 1996; 1245-1256) by the addition of 2-mercaptoethanol radicals, followed by oxidation using an oxidant based on hydrogen peroxide. b) 2- (3- (2-Phenylethoxy) propylsulfonyl) ethyl ester of 4-nitrobenzoic acid 4-Nitrobenzoyl chloride (27.9 g, 0.15 mol) was dissolved in 2-propyl acetate (80 ml) and added to a stirred and cooled solution of 2- (3- (2-phenylethoxy) propylsulfonyl) 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 (approximately 8 minutes). The mixture was vigorously stirred for two additional hours. Subsequently, a saturated solution of sodium acid carbonate was added, and the aqueous layer was removed. The organic layer was washed with water (2 x 50 ml) and then concentrated under reduced pressure to obtain the ester product titled as a white off-white solid (42.5 g). The product was recrystallized from ethanol (400 ml) to obtain the ester as needles. Melting point: 72 - 79 ° C. ? E NMR (D6-DMSO): d 8.36, 8.15 (AA'BB ', 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 2- (3- (2-Phenylethoxy) propylsulfonyl) ethyl ester of 4-methoxybenzoic acid 4-methoxybenzoyl chloride (25.6 g, 0.15 mol) was dissolved in 2-propyl acetate (50 ml) and added to a stirred and cooled solution of 2- (3- (2-phenylethoxy) propylsulfonyl) ethanol (34 g, 0.12 mol) and triethylamine (21 ml, 0.15 mol) in 2-propyl acetate (150 ml). The mixture was vigorously stirred for two additional hours. A saturated solution of sodium hydrogen carbonate (300 ml) was added, the organic layer was separated and washed with water (2 x 50 ml) and then concentrated under reduced pressure to obtain the titled ester product, which of acetate ethyl / petroleum ether) to obtain the ester as a clear mobile oil. MS 407 (M + H) +? H NMR (D6-DMSO): d 7.93, 7.05 (AA 'BB', 4H), 7.22 (m, 5H), 4.60 (t, 2H), 3.63 (t, 2H) , 3.55 (t, 2H), 3.47 (t, 2H), 3.17 (, 2H), 2.75 (t, 2H), 1.91 (m, 2H).

Example 3 2- (3- (2-Phenylethoxy) propylsulfonyl) ethyl ester of benzoic acid 2- (3- (2-Phenylethoxy) propylsulfonyl) ethanol (60 g, 0.22 mol) in dichloromethane (400 ml) was added and added in a portion benzoyl chloride (30.7 ml, 0.265 mol). Triethylamine (36.8 ml) was added with stirring in nitrogen for 12 minutes, raising the temperature to 41 ° C. The resulting suspension was stirred for 20 hours, washed sequentially with water (100 ml) and sodium hydrogen carbonate (1100 ml) and dried over sodium sulfate. Filtration and concentration produced an oil that crystallized easily. The titled product was purified by recrystallization of the ethanol to obtain needles (60.4 g, 72% yield). Melting point: 65.5 ° C. XH NMR (CDC13): d 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) propylsulfonyl) ethylamino) ethyl) -1,3-benzothiazole-2 (3H) -one hydrochloride a) 2- (3- Ethenylsulfonylpropoxy) ethylbenzene 2- (3- (2-phenylethoxy) propylsulfonyl) ethyl ester of benzoic acid, (Example 3) (500 g, 1.33 mol) in ethyl acetate (3.5 L) was dissolved in nitrogen. 1,8-Diazabicyclo [5, 4, 0] -undec-7-ene (212.8 ml, 1.39 mol) was added and the mixture was stirred at room temperature for four hours. The precipitated solid was separated by filtration, washed with ethyl acetate (1.5 L), and. The combined organic phases were washed with dilute hydrochloric acid (2 x 1 L), saturated sodium carbonate solution (2 x 1 L), and brine (1 L). The organic phase was dried over magnesium carbonate, and filtered and concentrated under reduced pressure to obtain the titled product as an oil (329 g, 97% yield) which crystallized on standing. Melting point 28-28.5 ° C MS (FAB) 255 (M + H) + XH NMR (Dg-DMSO): d 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). b) 4-Hydroxy-7- (2- (2- (3- (2-phenylethoxy) propylsulfonyl) ethylamino) ethyl) -1,3-benzothiazole-2 (3H) -one Hydrochloride of 7- (2- aminoethyl) -4-hydroxy-l, 3-benzothiazol-2 (3H) -one (100 g) was suspended in methanol (480 ml) at the reflux point. A solution of 2- (3-ethenylsulfonylpropoxy) ethylbenzene (107 g) and triethylamine (53.8 ml) in methanol (240 ml) was added to the mixture under reflux for 35 minutes. After 2.75 hours, methanol (960 ml) was added, followed by hydrochloric acid (37 ml), and the sample was allowed to cool. Filtration, washing with propan-2-ol (400 ml), and subsequently with ether (400 ml), and drying gave the hydrochloride salt (135.7 g, 69% yield). MS 465 (M + H) + XH NMR (500 MHz spectrum) (D6-DMSO): d 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, 2 x 2H), 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) propylsulfonyl) ethylamino) ethyl hydrochloride) -1, 3-benzothiazol-2 (3H) -one 7- (2-aminoethyl) -4-hydroxy-l, 3-benzothiazol-2 (3H) -one hydrochloride (1.0 g), 2- (3- (2- (2- (3- (2- phenylethoxy) propylsulfonyl) ethyl ester of benzoic acid (Example 3) (1.52 g), triethylamine (2.26 ml), and methanol (20 ml) were heated to reflux temperature for 30 minutes. This temperature was maintained for 5.5 hours, at which time liquid chromatography at high pressure indicated that the reaction was complete. The mixture was allowed to cool slightly, and was subsequently acidified by the addition of concentrated hydrochloric acid (1.71 ml). Upon cooling and stirring, a salt of the solution crystallized. Separation 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) propylsulfonyl) ethylamino) ethyl) -1,3-benzothiazole-2 (3H) -one hydrochloride 7- (2- Hydrochloride aminoethyl) -4-hydroxy-l, 3-benzothiazole-2 (3H) -one (3.0 g), 2- (3- (2-phenylethoxy) propylsulfonyl) ethyl ester of 4-nitrobenzoic acid (Example 1) (5.7 g ), triethylamine (5.96 ml), and ethanol (industrial methylated essences, 60 ml) were heated to reflux temperature for 20 minutes. This temperature was maintained for 4 hours. The mixture was allowed to cool slightly, and was subsequently acidified by the addition of concentrated hydrochloric acid (4.6 ml). Upon cooling, a salt of the solution crystallized. Separation 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) propylsulfonyl) ethylaxy) ethyl) -1,3-benzothiazole-2 (3H) -one hydrochloride The method described in the Example 6 was repeated using the compound of Example 2 in place of the compound of Example 1. The titled product was obtained in a 61% yield. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (14)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property. A process for the preparation of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ph represents a phenyl group, characterized in that it comprises the reaction of a compound of the formula (II) or a salt thereof, with a compound of the formula (III), in the presence of a solvent and optionally, a tertiary amine base; and if desired, the conversion of the compound of the formula (I) to a pharmaceutically acceptable salt or solvate thereof.
2. 2. A process according to claim 1, characterized in that the tertiary amine base is an aliphatic amine.
3. 3. A process according to claim 1 or claim 2, characterized in that the solvent is an alcohol. .
4. A process according to any of claims 1 to 3, characterized in that the pharmaceutically acceptable salt is an acid addition salt derived from hydrochloric acid, hydrochloric, boric, phosphoric, sulfuric, acetic, tartaric, maleic, citric, succinic, ascorbic acid. , benzoic, 4-methoxybenzoic, 2- or 4-hydrobenzoic, 4-chlorobenzoic, benzenesulfonic, para-toluenesulfonic, naphthalenesulfonic, methanesulfonic, sulphamic, salicylic, diphenylacetic, triphenylacetic, adipic, fumaric, lactic, glutaric, gluconic, 1-hydroxy or 3-hydroxy-2-naphthoic or oleic.
5. 5. A process, according to any of claims 1 to 4, characterized in that the compound of the formula (III) is formed in si t u.
6. 6. A process according to claim 5, characterized in that the compound of the formula (III) is formed in-si t u from a compound of the general formula (IV), wherein L represents a carboxylate leaving group.
7. 7. A compound of the formula (III), in accordance as defined in claim 1.
8. 8. A compound of the formula (IV), in accordance as defined in claim 6.
9. 9. A process for the preparation of a compound of the formula (IV) according to claim 6, characterized in that it comprises the reaction of a compound of the formula (V), (V) with a suitable acylating agent.
10. 10. A process according to claim 9, characterized in that the compound of the formula (V) is prepared by contacting a compound of the formula (VI), (SAW) with an oxidizing agent.
11. 11. A process according to claim 10, characterized in that the compound of the formula (VI) is prepared by reacting a compound of the formula (VII), with 2-mercaptoethanol.
12. 12. A process for the preparation of a compound of the formula (IV) according to claim 6, characterized in that it comprises: (a) the reaction of phenethyl alcohol with 3-bromopropene to obtain a compound of the formula VII), (b) reacting the compound of the formula (VII) with 2-mercaptoethanol to obtain a compound of the formula (VI), (c) oxidation of the compound of the formula (VI) to obtain a compound of the formula (V), (V) and (d) the reaction of a compound of the formula (V) with a suitable acylating agent to obtain a compound of the formula (IV).
13. 13. A compound of formula (V) in accordance as defined in claim 9 or claim 12.
14. 14. A compound of formula (VI) in accordance as defined in claim 10 or claim 12. -, - w »i