MXPA00007459A - Process for the preparation of benzothiophene derivatives - Google Patents

Abstract

The present invention is concerned with a novel process for the preparation of the hydroxybenzothiophene of Formula I comprising cyclocarbonylation of a compound of Formula II wherein -OR is as defined in the specification, followed by saponification. The compound of Formula I is a building block of pharmaceutically active substances, e.g. 5- 4- 2-(5-methyl-2- phenyl-4-oxazolyl) ethoxy- 7-benzothiophenylmethyl- 2,4-thiazolidinedione and the corresponding sodium salt.

Description

PROCESS FOR THE PREPARATION OF BENZOTIOFE DERIVATIVES FIELD OF THE INVENTION The present invention relates to a new process for the preparation of benzothiophene derivatives, especially with the preparation of 4-hydroxybenzothiophene. 4-Hydroxybenzothiophene is a building block for pharmaceutically active compounds, for example 5- [4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] -7-benzothiophenylmet] -2, 4 -thiazolidinedione. This compound is known in the art and is described, for example, in International Patent Application WO 94/27995. It is especially used for prophylaxis and treatment of type I and II diabetes mellitus.

BACKGROUND OF THE INVENTION The methods for the preparation of 4-hydroxybenzothiophene have been described by Iwasaki et al. (1991) J. Org. Chem. 1991. 56, 1922. Here a cyclocarbonylation of a primary allylacetate is carried out in the presence of a high catalyst charge. In addition, this process is characterized by REF. : 121661 minus five stages of processes which in part require extreme reaction conditions. Surprisingly it has been found that using the process according to the present invention 4-hydroxybenzothiophene can be prepared with fewer process steps under moderate conditions with remarkable performance. The process according to the present invention relates to the 4-hydroxybenzothiophene of formula I comprising cyclocarbonylation of a compound of formula II (II) where -OR is a group of formulas -0- (CO) -R ', -0- (C0) -0- R "or -O- (PO) - (0Rf') 2 / where R 'is alkyl, perfluoride-C1-20 alkyl aryl, R "is alkyl, aryl or benzyl or the group -OR is halogen or an aryloxy group; followed by saponification. This process provides an efficient cyclocarbonylation reaction under benign conditions. In. In addition, the substrates for the cyclocarbonylation reaction (compound of formula II) do not need to be purified, for example by distillation, because they can be used as "raw" material. According to the present invention, the term "cyclocarbonylation". refers to an introduction of a carbonyl group coupled to the formation of a cyclic ring structure. The term "saponification" refers to the hydrolysis of an ester under acidic or basic, preferably basic, conditions. The term "transition metal compound" refers to a metal-phosphine complex compound wherein the term metal refers to Pd, Pt, Ru, Co, Rh or Ni, preferably Pd. The term "ligand" refers to phosphine, arsine or stibnine derivatives, preferably phosphine derivatives, of general formula PCR1) (R2) (R3), (R1), (R2) P- (X) -P (R1) (R2), As (R1) (R2) (R3) OR Sb (R1) (R) (R3), preferably P (RX) (R2 ) (R3), where R1, R = and R3 are defined below. The term "alkyl" refers to a branched or straight-chain monovalent alkyl radical of one to new carbon atoms (unless otherwise indicated), preferably one to four carbon atoms (lower). This term is further exemplified by radicals such as methyl, ethyl, n-propyl, isopropyl, i-butyl, n-butyl and t-butyl and the like. The term "aryl" refers to a monovalent carboxylic aromatic radical, for example phenyl, optionally substituted, independently with halogen, lower alkyl, lower alkoxy, lower alkylenedioxy, carboxy, trifluoromethyl and the like. The term "aryloxy" means a group of the formula aryl-0- in which the term "aryl" has the meaning given above. Phenyloxy is an example of such an aryloxy group. The term "alkoxy", alone or in combination, means a group of the formula alkyl-0 in which the term "alkyl" has the meaning given above, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy, preferably methoxy and ethoxy. The term "alkylenedioxy" refers to C 1 - 3 dioxy groups, such as methylene dioxy, ethylenedioxy or propylenedioxy. The term "halogen" refers to fluoride, chloride and bromide.

DESCRIPTION OF THE INVENTION In more detail, the present invention relates to a process for the preparation of compounds of the formula I comprising the cyclocarbonylation of a compound of formula II where -OR is a group of formulas -0- (CO) -R ', -0- (C0) -0- R "or -O- (PO) - (OR' ') 2 / where R' is alkyl, perfluoro-C? -2_ alkyl, aryl, R "is alkyl, aryl or benzyl or the group -OR is halogen or an aryloxy group; followed by saponification.

In a preferred embodiment of the invention, the cyclocarbonylation reaction is carried out in the presence of a base and a catalyst comprising a transition metal compound and a ligand. The transition metal compounds used for the process of the present invention comprise salts of Pd, Pt, Ru, Co, Rh- or Ni and also includes Pd / C. The use of transition metal compounds as catalysts has been described for example in Matsuzaka et al. (1988) J. Org. Chem. 53, 3832. Preferred transition metal compounds are palladium salts, for example Pd (OAc) 2, Pd2dba3, PdCl2 / Pd2Cl2 (p-allyl) 2 l PdCl2 (NCMe) 2, [Pd (NCMe) 4 ] (BF4) 2, and more preferably Pd (OAc) 2. The catalyst mentioned is known in the art (for example in US Patent No. 5,380,861: "Carbonylation, Direct Synthesis of Carbonyl Compounds", HM Colqu oun, DJ Thompson, MV Trigg, Plenum Press, 1991) and / or commercially available (for example from Fluka, Buchs, Switzerland or Strem Chemicals, Kehl, Germany). The ligand of the transition metal compound in the catalyst may be selected from a group consisting of phosphine, arsine or stibin derivatives, preferably phosphine derivatives of general formulas PIR1) (R2) (R3), (R1) ( R2) P- (X) -P (R1) (R2), As (R1) (R2) (R3) or Sb (R1) (R2) (R3), preferably P (RX) (R2) (R3), wherein X, R1, R2 and R3 are defined above. Especially acceptable ligands are chiral and non-chiral, mono- and di-phosphorous compounds for example described in Houben-Weyl, "Methoden der organischen Chemie", vol. The, page 106 et seq. Georg Thieme Verlag Stuttgart, 1982, and Aspects Homog. Catal., 4, 145-202 (1981), especially those of the formulas PÍR1) (R2) (R3) and (R ^ ÍR ^ P-ÍXJ-PÍR1) (R2) wherein R1, R2 and R3 each independently are C? -8-cyclohexyl, benzyl, naphthyl, 2- or 3-pyrrolyl, 2- or 3-furyl, 2- or 3-thiophenyl, 2- or 3- o-alkyl 4-pyridyl, phenyl or phenyl which is substituted by C? -4 alkyl, C? -44 alkoxy, halogen, trifluoromethyl, alkylidenedioxy or lower phenyl and X is binaphthyl, 6,6'-dimethyl- or 6,6 '- dimethoxybiphenyl-2, 2'-diyl, or one of the groups - (CH2) n-, -CH2CH2-P (C6H5) -CH2CH2-, and n is a number from 1-8.

Examples of suitable phosphorous ligands are shown in Scheme 1.

Scheme 1 P (o-DMA-Ph) 3 PPh (3,5-tBu-Ph) 2 P (3,5-tBu-Ph) 3 P (2-Furil), N DPP AMPHOS The most preferred phosphorous ligands are triphenylphosphine, PPh (3,5-tBu-Ph) 2 P (3,5-tBu-P), The preparation of the transition metal complex is explained in more detail by the corresponding palladium-phosphine complex: The palladium-phosphine complex compound is conveniently formed in situ from palladium components and a phosphine ligand. These palladium components are for example palladium metal, which is optionally supported in a carrier material such as carbon, or a complex or a valent salt of 0-, 2- or 4-palladium such as palladium-bis (dibenzylideneacetone), chloride of palladium, palladium acetate and the like. For in situ preparation, the amounts (mol / mol; P / Pd) of ratio of the transition metal compound / phosphorus ligand are from about 0.1: 1 to 100: 1, preferably about 6: 1 to 15: 1. Suitable phosphine ligands are for example chiral and non-chiral, mono- and di-phosphorous compounds as described in Houben-Weyl, Methoden der organischen Chemie, volume El, page 106 et seq. Georg Thie e Verlag Stuttgart, 1982, and Aspects Ho og, Catal. , 4, 145-202 (1981), especially those described above. For the in situ preparation of the palladium-phosphine complex compound, palladium (II) chloride or palladium (II) acetate, palladium-dichloro-bis (acetonitrile) and a bis (defensylphosphino) alkane can be used. In addition, the process of the present invention comprises the use of bases for the carbonylation reaction as tertiary bases such as tri-alkyl amines, di-alkyl aryl amines, pyridines, alkyl-N-piperidines and for example inorganic bases such as NaOH, KOH or salts of carbonic acids. Examples are (alkyl) 3-amines, for example triethylamine, ethyl-di-isopropyl-amine, pyridine, N-methyl-piperidine, sodium hydrogenated carbonate, hydrogenated potassium carbonate, sodium carbonate, etc. The preferred base is triethylamine. The solvents for the above reaction are known to the skilled person. Preferred solvents are aromatic solvents, for example toluene, xylene, benzene, halogenated hydrocarbons, for example CH2C12, nitriles, for example acetonitrile, ester, for example ethylacetate, amides, for example DMF, ether, for example THF, dioxane, urethanes, for example TMU, sulfoxides, for example DMSO and mixtures thereof. The preferred solvent is toluene. The reaction conditions for the above carbonylation reaction may vary to a certain area. The reaction temperature can vary between 40 ° C and 170 ° C, preferably between 60-120 ° C, and more preferably the reaction is transformed to about 90 ° C. The amounts of the ratio (mol / mol; S / Pd) of substrate / catalyst for 1 to 10000, preferably 100 to 5000, more preferably 1000 to 2000 and most preferably 1200 to 1500. For in situ preparation, the amounts of the ratio (mol / mol; P / Pd) of the transition metal / phosphorus ligand compound mentioned above for 0.1: 1 to 100: 1, preferably 6 : 1 to 15: 1. The upper limit for the carbon monoxide (CO) pressure is only limited by the specification of the autoclave used. For the lower pressure limit of the carbonylation reaction, it is still possible to work with a CO pressure of 1 bar. Preferably, the CO pressure is from about 20 to 70 bar, more preferably from 35 to 60 bar. Surprisingly it has been found that the "crude" compound of formula II can be used for the preparation of the compound of formula I. A preparation of a crude material is carried out by collecting the compound of formula II, for example, 1- ( 2-thienyl) allyl, with an organic solvent and dried without further purification. The preparation of this material is exemplified in Example 1. Example 2B shows the use of the crude initiator material for the preparation of the compound of formula I. The cyclocarbonylation reaction is followed by saponification. The conditions for the saponification reactions are known in the art and are described for example in "Practical Organic Chemistry", A. I. Volgen, Longmans Ed., 1967, p. 390-393. In a preferred embodiment of the present invention, the saponification is carried out in a biphasic mixture of aqueous sodium hydroxide and toluene or in a homogeneous mixture of sodium ethylate in methanol. The compounds of formula II can be prepared by methods known in the art, for example by the reaction of a thiophene carbaldehyde of formula III (illustrated in Scheme 2 a, commercially available, Fluka, Aldrich). with a vinyl-metal-X reagent, with -metal-X being -MgCl "; -MgBr, -Mgl or -Li, preferably -MgCl or -MgBr, followed by reaction with an acid derivative. For example, the corresponding allyl halogenide or allyl trialkyl ammonium salts are also suitable reagents The acid derivative can be selected from a group consisting of compound of formulas, (R '-CO) 20, R''0 - (CO) -Cl, Cl- (PO) (OR '') 2 / R '- (CO) -Hal where R' is alkyl, perfluoro-C? -2o_alkyl, aryl, R "is alkyl or benzyl and Hal is Cl or Br. The preferred acid derivative is (R'-CO) 20, and especially here the acetanhydride.The most preferred vinyl-metal-X- reagent is vinylmagnesium chloride or vinylmagnesium bromide. Preferred of the present invention, the compound of formula II is prepared by reaction of vinylmagnesium chloride followed by the reaction of acetanhydride as shown in scheme 2, variant a). The methods for the preparation of compound III are summarized in scheme 2.

Scheme 2; The compound of formula I is used for the preparation of pharmaceutically active substances, for example 5 [4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] -7-benzothiophenyl-methyl] -2, - thiazolidinedione and its salts, especially the corresponding sodium salt. A process for the preparation of this compound has been described, for example, in International Patent Application WO 98/42704.

Additionally, the compounds can be prepared in accordance with the following procedures: In a first step, the compound of formula I can be converted to 4- [2- (benzo-thiophene-4-yloxy) -ethyl] -5-methyl-2-phenyl-oxazole by reaction with a mesylate of formula V CH, under basic conditions. The. The reaction can be carried out in solvents such as DMF with for example sodium carbonate, potassium carbonate or cesium carbonate, preferably potassium carbonate; or in THF with KtBu; or in toluene and KOH with catalyst transfer phase. The above process can be followed by nitration reaction of 4- [2- (benzothiophene-4-yloxy) -ethyl] -5-methyl-2-phenyl-oxazole to give 5-methyl-4- [2- (7- nitro-benzo-thiophene-4-yloxy) -ethyl] -2-phenyl-oxazole. Normally nitric acid is used for the nitration reaction which can be transformed at room temperature to about 50 ° C, preferably at room temperature. The 5-methy1-4- [2- (7-nitro-benzothiophene-4-yloxy) -ethyl] -2-phenyl-oxazole obtained by the above process can be converted to 5-methyl-4- [2- ( 7-amino-benzo-thiophene-4-yloxy) -ethyl] -2-phenyl-oxazole by hydrogenation. The conditions of the hydrogenation reaction (H2 / ni Raney) are known in the art. The hydrogen pressure can be from 1 to 10 bar, preferably 1 bar. The above process can be continued by the reaction of 5-methyl-4- [2- (7-amino-benzothiophene-4-yloxy) -ethyl] -2-phenyl-oxazole with HHal / NaN02 followed by the reaction with CH = CHCOOCH3 / Cu (I) Hal, where Hal is Br or Cl, preferably Br. The reaction product in the case that Hal is Br is methyl-2-bromo-3- [4- [2- (5-methyl -2-phenyl-oxazol-4-yl) -ethoxy] -benzothiophene-7-yl] -propionate. The reaction of methyl-2-bromo-3 [4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -benzot-iofen-7-yl] -propionate with thiourea will produce 2-imino -5- [4- [2- (5-Methyl-2-phenyl-oxazol-4-yl) -ethoxy] -benzothiophene-7-y1] -methyl-thiazolidin-4-one. The reaction is usually carried out in alkyl alcohols such as ethanol.

This compound (2-imino-5- [4- [2- (5-methyl-2-phenyl-oxazol--i1) -ethoxy] -benzo-thiophene-7-yl] -methyl-thiazolidin-4-one) it can then be converted to 5- [7- [2- (5-methy1-2-phenyl-oxazol-4-yl) -ethoxy] -benzothiophene-4-methyl] -2,4-thiazolidinedione by reaction under acidic conditions. The reaction can be carried out at 1-4 bar, preferably at 1 bar. The acidic conditions are provided by an organic or inorganic acid in a suitable solvent, for example HCl / ethanol. The reaction may optionally be continued by conversion of 5- [7- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -benzothiophene-4-methyl] -2,4-t-aiazolidinedione in a corresponding salt, preferably sodium salt (sodium salt of 5- [7- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -benzothiophene-4-methyl] -2,4 -thiazolidine) by reaction under basic conditions, preferably with NaOH in THF. A further embodiment of the invention comprises a process for the preparation of 5- [7- [2- (5-methyl-1-2-phenyl-oxazol-4-yl) -ethoxy] -benzothiophene-4-methyl] -2, 4-thiazolidinedione and / or sodium salt of 5- [7- [2- (5-methy1-2-phenyl-oxazol-4-yl) -ethoxy] -benzothisphene-4-methyl] -2,4-thiazolidinedione comprising: a) conversion of a compound of formula I to 4- [2- (benzothiophene-4-yloxy) -ethyl] -5-methyl-2-phenyl-ozaxol by reaction of a compound of formula I with a formula V mesylate under basic conditions; followed by b) nitration of 4- [2- (benzothiophene-4-yloxy) ethyl] -5-methyl-2-phenyl-oxazole to give 5-methyl-4- [2- (7-nitro-benzothiophene-4-yloxy) -ethyl] -2-phenyl-oxazole; c) hydrogenation of 5-methyl-4- [2- (7-nitro-benzothiophene-4-yloxy) -ethyl] -2-phenyl-oxazole to give 5-methyl-4- [2- (7-amino-benzothiophene -4-yloxy) -ethyl] -2-phenyloxazole; followed by d) reaction of 5-methyl-4- [2- (7-amino-benzothiophene-4-yloxy) -ethyl] -2-phenyl-oxazole with HHal / NaN02 and CH = CHCOOCH3 / Cu (I) Hal , wherein Hal is Br or Cl to give methyl-2-bromo-3- [4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -benzothiophene-7-yl] - propionate; followed by e) reaction of methyl-2-bromo-3- [4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -benzothiophene-7-yl] -propionate with thiourea to give 2-imino-5- [4- [2- (5-methyl-1-2-phenyl-oxazol-4-yl) -ethoxy] -benzothiophene-7-yl] -methyl-thiazolidin-4-one; followed by f) reaction of 2-imino-5- [4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -benzothiophene-7-yl] -ethyl-thiazolidine-4- ona under acidic conditions to give 5- [7- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -benzothiophene-4-methyl] -2,4-thiazolidinedione; g) and optionally followed by the reaction of 5- [7- [2- (5-methyl-1-2-phenyl-2-oxazol-4-yl) -ethoxy] -benzothiophene-4-methyl] -2,4-thiazolidinedione under basic conditions to give the sodium salt of 5- [7- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -benzothiophene-4-methyl] -2,4-thiazolidinedione.

The invention further comprises the use of any of the processes described above for the preparation of 5- [4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] -7-benzothiophenyl-methyl] -2, 4-thiazolidinedione and the sodium salt of 5- [7- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -benzothiophene-4-methyl] -2,4-thiazolidinedione. A further embodiment of the present invention comprises the compound of the sodium salt of 5- [7- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] benzothiophene-4-methyl] -2, 4 -thiazolidinedione.

The following examples will illustrate the preferred embodiments of the present invention but are not proposed to limit the scope of the invention.

EXAMPLES Example 1 1- (2-thienyl) allyl acetate A 1.5-liter, 4-neck glass flask, equipped with a mechanical stirrer, a thermometer and an argon inlet, was charged with 112.2 g of 2-thiophenecarbaldehyde (1.00 mol) and 100 ml of THF and the resulting solution was added in the form of drops at -20 ° C within 1.2 hours, 650 ml of a 1.7M vinylmagnesium chloride solution in THF. The temperature during the addition was maintained between -20 and 25 ° C with the help of an acetone / dry ice bath, then it was increased to 0 ° C for 35 minutes and kept at this temperature for 20 minutes. To the resulting brown suspension was added at about 0 ° C within 40 minutes, 132.7 g of acetic anhydride (1.30 mol). The cooling bath was stirred and after stirring for 1 hour, 400 ml of deionized water was added at 10-15 ° C within 20 minutes. The biphasic yellow-brown mixture was stirred for an additional 1 hour at room temperature and transferred to a separatory funnel with the aid of 500 ml of hexane. The brown aqueous phase was separated and extracted with 400 ml of hexane. The combined organic phases were washed with 3 x 200 ml of deionized water, dried (NaSO 4, 15 minutes of stirring) and rotary evaporated (Tvaño 35 °, 12 mbar, 1 hour). Material of this quality is defined as "crude" and is also suitable for cyclocarbonylation (see Example 2B). The orange-brown oil (199.7 g) was distilled in an apparatus consisting of a 500 ml two-neck ball flask, a distillation head with water cooling, a fraction sampler. A precursor containing low boiling components (yellowish oil) s collected at Tcabeza between room temperature and 55 ° C 0.5-0.6 mbar, the main fraction was collected at Tcabez from 59-62 ° C (Tpote 63-67 ° C) and 0.4 mbar. Yield: 161.53 g (88.6%) of l- (2-thienyl) allyl acetate as a slightly yellow oil.

Example 2A 4-hydroxybenzothiophene An autoclave - low or an argon flow was charged with 27.34 g of 1- (2-thienyl) allyl acetate (0.150 mol, distilled), 28.4 ml of acetic anhydride (30.6 g, 0.3 mol), 42.0 ml of triethylamine ( 30.7 g, 0.30 mol), 23. mg of palladium acetate (0.105 mmol) and 0.264 gd triphenylphosphine (1.00 mmol), all with the help of 53 ml of toluene. After the autoclave was sealed, evacuated twice with slow stirring (150 rpm) at 0.2 bar and pressurized with 8 bar of argon, then pressurized three times with 20 bar of carbon monoxide and vented, finally pressurized with 50 bar of carbon monoxide. The reaction mixture was stirred (500 rpm) and heated to 120 ° C the carbonylation was carried out at a constant total pressure of 50 bar for 6 hours. After cooling, the autoclave was vented and the CO atmosphere was exchanged by the evacuation to approximately 0.2 bar and the pressurization to 8 bar of argon four times. The resulting dark solution was poured into a 0.5 liter flask containing 120 ml of ice water and the biphasic solution was stirred for 1 hour at room temperature. The aqueous phase was extracted in a separatory funnel with 80 ml of toluene and such combined organic phases were washed with 3 x 30 ml, with a total of 90 ml of deionized water and reduced to a total weight of 46 g by rotary evaporation. (50 ° C / 60 mbar). The residue containing the crude acetate was transferred to a 0.35 liter glass flask under argon with the aid of 25 ml of toluene. After the addition of 82 ml of 4N sodium hydroxide (328 mmol) the mixture was stirred intensively (1200 rpm) at 50 ° for 1.5 hours and then after cooling was transferred in a 0.5 liter separatory funnel. After the removal of the organic layerThe dark aqueous phase was extracted with 80 ml of toluene and the combined organic phases were extracted again with 2 x 20 ml, a total of 40 ml of deionized water. The combined aqueous phases were treated with 1.0 g of mineral carbon, stirred at room temperature for 5 minutes under argon and filtered through a Speedex layer. The filtered paste was rinsed three times with 20 ml, a total of 60 ml of deionized water. The combined phases, brown, clear, were concentrated until no more toluene was distilled, after cooling to 5 ° C in an ice bath, 75 ml of 25% HCl were added under argon for 35 minutes, while the temperature was maintained under 15 ° with the help of an ice bath. The resulting thick crystalline suspension was stirred for one hour in an ice bath (internal temperature 2-3 ° C) and filtered on an agglomerated glass filter. The filtered pulp was washed three times with 50 ml, a total of 150 ml of water cooled on ice and dried on rotary steam at 50 ° C / 1 mbar at constant weight. Yield: 18.9 g (84%) of 4-hydroxybenzothiophene p.f. 76-78 ° C, content: 98%.

Example 2B-Hydroxybenzothiophene An autoclave was charged under a flow of argon with 27.34 g of 1- (2-thienyl) allyl acetate (0.150 mol, crude quality, see Example 1), 28.4 ml of acetic anhydride (30.6 g, 0.30 mol), 42.0 ml. of triethylamine (30.7 g, 30 mol), 23.6 mg of palladium acetate (0.105 mmol) and 0.264 g of triphenyl fos fines (1.00 mmol), all with the aid of 53 ml of toluene. After the autoclave was sealed, it was evacuated twice with slow stirring (150 rpm) at 0.2 bar and pressurized with 8 bar of argon, then pressurized three times with 20 bar of carbon monoxide and vented, and finally pressurized with 50 bar of carbon monoxide. The reaction mixture was stirred (500 rpm) and heated to 120 ° C the carbonylation was carried out at a constant total pressure of 50 bar for 6 hours. After cooling, the autoclave was vented and the CO atmosphere was exchanged by the evacuation to approximately 0.2 bar and pressurized 8 bar of argon four times. The resulting dark solution was poured into a 0.5 liter flask containing 120 ml of ice water and the biphasic solution was stirred for 1 hour at room temperature. The aqueous phase was extracted in a separatory funnel with 80 ml of toluene and then the combined organic phases were washed with 3 x 30 ml, with a total of 90 ml of deionized water and reduced to a total weight of 46 g by evaporation. rotary (50 ° C / 60 mbar). The residue containing the crude acetate was filtered through 17 g of silica gel (0 = 3 cm) and the filter was washed with 150 ml of toluene. The combined organic phases were reduced to a total weight of 40 g by rotary evaporation and transferred to a 0.35 liter glass flask under argon with the aid of 20 ml of toluene. After the addition of 82 ml of 4N sodium hydroxide (328 mmol) the mixture was stirred intensively (1200 rpm) at 50 ° for 1.5 hours and then after cooling was transferred in a separatory funnel of 0.5 1. After the removal of the organic layer, the dark aqueous phase was extracted with 80 ml of toluene and the combined organic phases were extracted again with 2 x 20 ml, a total of 40 ml of deionized water. The combined aqueous phases were treated with 1.0 g of mineral carbon, stirred at room temperature for 5 minutes under argon and filtered through a Speedex layer. The filtered paste was rinsed three times with 20 ml, a total of 60 ml of deionized water. The combined phases, brown, clear, were concentrated until no more toluene was distilled, after cooling to 5 ° C in an ice bath, 75 ml of 25% HCl were added under argon for 35 minutes, while the temperature was maintained under 15 ° with the help of an ice bath. The resulting thick crystalline suspension was stirred for one hour in an ice bath (internal temperature 2-3 ° C) and filtered on an agglomerated glass filter. The filtered pulp was washed three times with 50 ml, a total of 150 ml of water cooled on ice and dried on rotary steam at 50 ° C / 1 mbar at constant weight. Yield: 16.5 g (73%) of 4-hydroxybenzothiophene as brown crystals, m.p. 75-76 ° C, content: 95%.

Example 3 Variation of phosphorous ligands 4. 93 mg of palladium acetate and 57.57 mg of triphenylphosphine in 10 ml of toluene were stirred for 1 hour in a glove box (02 <1 ppm). A 35 ml autoclave was charged with 0.40 g of distilled l- (2-thienyl) allyl acetate, 0.42 ml of acetanhydride, 0.62 ml of triethylamine and 1.0 ml of the catalyst solution described above. The autoclave was conditioned with 30 bar of CO and pressurized with 70 bar of CO. Cyclocarbonylation was carried out at 120 ° C for 2 hours. The GC analysis revealed a 96% conversion with a 4-acetoxybenzothiophene content of 911 A) Examples 3.1 - 3.6: In accordance with Example 3, Table 1, the following experiments are summarized, which were performed with the phosphorous ligands in place of triphenylphosphine.

Table 1 to! Determined via GC (area-%) b) See structures in Scheme 1 c) P / Pd B) Examples 3.7 - 3.23 The following additional examples 3.7 to 2.23 were made without additional phosphorous ligands. The reaction was carried out in accordance with the description given above. However, the autoclave was pressurized with CO at 50 bar and the cyclocarbonylation reaction was carried out at 90 ° C for 16-18 hours. a)% content of 4-acetoxybenzothiophene, determined via GC (% area) b) see structures in Scheme 1. c) phosphorous-to-palladium molar ratio Example 4 Cyclocarbonylation reactions: Pressure CO and ratio S /? D 0. 6- g of the distilled 1- (2-thienyl) allyl acetate were reacted for 4 hours as described in Example 2A with 6.2 mg of palladium acetate, 72.1 mg of triphenylphosphine, 6.3 ml of acetanhydride and 9.3 ml of triethylamine I presented. The GC-analysis revealed a conversion of 98% with an e-acetoxybenzothiophene content of 94%.

Examples 4.1-4.7: According to Example 4 Table 2, the experiments performed under different reaction conditions (Pressure CO and S / Pd ratio) are summarized.

Table 2 '' Determined at room temperature blDetermined via GC (% area) Example 5 4- [2- (Benzothiophen-4-yloxy) -ethyl] -5-methyl-2-phenyl-oxazole 218 g (1.45 mol) of 4-hydroxy-benzothiophene and 511 9 (1-82 g) of mesylate of formula V were dissolved in 5.4 liters of DMF, followed by the addition of 555g (4.02 mol) of potassium carbonate (dry). The reaction mixture was stirred at 100 to 105 ° C for 6 to 8 hours. The resulting suspension was cooled to 5 ° C and 7 liters of water was added. The suspension was stirred at 5 ° C for 30 minutes. The precipitate was filtered with a solution and washed with 550 ml of DMF / water (1: 1) and 1.1 liter of water. The precipitate was stirred at 0 to 5 ° C in 1 liter of MEK (Methyl Ethyl Ketone) for 30 minutes. Then, the precipitate was filtered with suction and dried at 50 ° C. Yield: 365 g (= 75%) 4- [2- (benzothiophen-4-yloxy) -ethyl] -5-methyl-1-2-phenyl-oxazole. p.f. 126 ° C / 129-131 ° C.

Example 6 5-methyl-4- [2- (7-nitro-benzothiophen-4-yloxy) -ethyl] -2-phenyl-oxazole 286 g (0.853 mol) of 4- [2- (benzothiophen-4-yloxy) -ethyl] -5-methyl-2-phenyl-oxazole were suspended in 6.3 liters of glacial acetic acid. The temperature was raised to 60 ° C. The resulting clear solution was cooled to 25 ° C. 132 ml (3.18 ml) of 100% nitric acid was added within 3 minutes. The reaction mixture was cooled to below 30 ° C. After crystallization the suspension was stirred at 18 to 20 ° C for 1 hour. The precipitate was filtered off with suction and washed with 2 x 600 ml of tert-butylmethyl ether. The residue was suspended in 4 liters of acetic acid for 15 minutes. 200 g (1.9 mol) of sodium carbonate in 3 liters of water were added. The resulting suspension was stirred for 1 hour. Acetic ester was distilled followed by the addition of 2 liters of water. The suspension was stirred for 30 minutes. The precipitate was filtered by suction, washed with water and dried (50 ° C, 24 hours). Yield: 210 g of 5-methyl-4- [2- (7-ni tro-benzothiophen-4-yloxy) ethyl] -2-phenyl-oxazole (= 70%). p.f. 149-151 ° C.

Example 7 5-Methyl-4- [2- (7-amino-benzothiophene-4-yloxy) -ethyl] -2-phenyl-oxazole 50 g of (1052 mol) of 5-met il-4- [2- (7-nitro-benzothiophen-4-yloxy) -ethyl] -2-f nyl-oxazole was solved or dissolved in 1 liter of THF a 20 to 25 ° C. 75 ml were washed with Lewatit M 600 (OH form ") (Bayer AG) with approximately 100 ml of THF, added to the solution of 5-methyl-4- [2- (7-ni tro-benzothiophen-4-yloxy) ) ethyl] -2-phenyl-oxazole and stirred at room temperature for 1 hour, then the Lewatit M 60 material was filtered with suction and washed with 100 ml of THF.S added 1.25 g of Raney nickel to the solution of Combined TH followed by hydrogenation of 5-methyl-4- [2- (7-nitro-benzothiophen-4-yloxy) -ethyl] -2-phenyl-oxazole standard pressure.The temperature of the reaction mixture should not exceed 35 40 ° C. The hydrogen pressure was increased to 6 bar within 6 hours After the hydrogenation the reaction mixture was stirred for 1 hour, then the catalyst was filtered with suction, the THF was distilled completely, 180 ml of ethanol was added and the residue boiled for 30 minutes.The reaction mixture was stirred at 0 ° C for 1 hour.The precipitate was filtered off with suction and the residue was washed with 25 ml. of ethanol and dried for 24 hours at 50 ° (vacuum). Yield: 42.4 g of 5-methyl-4- [2- (7-amino-benzothiophen-4-yloxy) -ethyl] -2-phenyl-oxazole (= 92%). p.f. 122-126 ° C.

Use 8 Methyl-2-bromo-3- [4- [2- (5-methyl-2-phenyl-oxazol-4-yl) ethoxy] -benzothiophen-7-y1] -propionate 320 g (0.91 mol) of 5-methyl-4- [2- (7-amino-benzothiophen-4-yloxy) -ethyl] -2-phenyl-oxazole was solved in 6.4 liters of acetone. Within 30 seconds a third of 320 ml (2.74 mol) of 48% HBr in 900 ml of water was added. After cooling to 0 to 4 ° C and crystallization the suspension was stirred at 0 to 4 ° C for 1 hour. Then, the remaining 48% of the HBr solution in water was added within 15 minutes at 0 to 4 ° C and stirred at this temperature for 15 minutes followed by the addition of 63.9 g (0.93 mol) of sodium nitrite in 180 Mi of water within 15 minutes at 3 to 5 ° C and stirring for 30 minutes at 3 to 5 ° C. 1230 ml of the methacrylate CH = CHCOOCH3 (13.6 mol) was added to this reaction mixture at 10 to 14 ° C followed by the addition of 3.2 g of Cu (I) bromide. The temperature was increased to 20 to 25 ° C within 30 minutes, followed by stirring at this temperature for 1 hour and 10 minutes at 30 ° C. 1.8 liters of water was added to the reaction mixture, followed by the distillation of acetone / ethacrylate CH = CHC00CH3 at a temperature of 40 ° C. The final volume taken to 21.1 liters of water was added to separate the remaining methacrylate CH = CHC00CH3. The final volume was brought to 2 liters. The dark precipitate was solved by the addition of 4.5 liters of acetic ester and stirring for 15 minutes. The two phase reaction mixture was filtered and the aqueous phase was extracted with 2 liters of acetic ester. After extraction with 2 liters of an aqueous 2% NaCl solution, the acetic ester solutions were combined and distilled. 2 liters of acetic ester were added to the residue and again distilled. 3 liters of ethanol was added to the residue and boiled. 15 g of the activated charcoal was added and stirred for 15 minutes. After filtration and cooling to room, a precipitate formed. The suspension was stirred for 1 hour at room temperature and an additional hour at 0 ° C. After washing with cold ethanol, the precipitate was dried for 24 hours at 50 ° C (vacuum). Yield: 310 g of methyl-2-bromo-3- [4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -benzothiophen-7-yl] propionate (= 68%) . p.f. 97 to 99 ° C.

Example 9 2-imino-5- [4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -benzothiophen-7-yl] -methyl-thiazolidin-4-one 190 g (0.380 mol) of 5-methyl-4- [2- (7-amino-benzothiophen-4-yloxy) -ethyl] -2-phenyl-oxazole were suspended in 2.85 liters of ethanol. 31.6 g (0.415 mol) of thiourea and 34.8 g of sodium acetate were added. After boiling for approximately 18 hours (reflux), the reaction mixture was cooled to 0 to 4 ° C and stirred for 1.5 hours at this temperature. The precipitate was filtered with suction and washed twice with 250 ml of cold ethanol. 1.9 liters of water were added to the residue, the mixture was stirred for 10 minutes and the precipitate was filtered with suction and dried for 24 hours at 80 ° C (vacuum). Yield: 147 g of 2-imino-5- [4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -benzo-phofen-7-yl] -methyl-thiazolidin-4 -one (84%). p.f. 224-227 ° C.

Example 10 5- [7- [2- (5-Methyl-2-phenyl-oxazol-4-yl) -ethoxy] -benzothiophen-4-methyl] -2,4-thiazolidinedione 283. 3 g (0.61 mol) of 2-imino-5- [- [2- (5-methy1-2-phenyl-oxazol-4-yl) -ethoxy] -benzothiophen-7-yl] -methyl-thiazolidin-4- ona were suspended in 2.83 liters of ethanol. 2.83 liters of 2N hydrochloric acid were added. The resulting suspension was stirred for 18 hours (reflux). The suspension was cooled for 1 hour at 0 to 4 ° C and stirred for another 2 hours at this temperature. The precipitate was filtered with suction and washed twice with 285 ml of ethanol. 283 liters of water were added to the residue, the suspension was stirred for 30 minutes, the precipitate was dried for 24 hours at 80 ° C and then solved in 545 ml of DMF (at 85 to 90 ° C). 4.95 liters of ethanol (25 ° C) were added to the solution. The resulting suspension was stirred for 2 hours at 0 to 4 ° C. The precipitate was filtered with suction, washed with 270 ml of cold ethanol and dried at 80 ° C for 24 hours (vacuum). Yield: 246 g of 5- [7- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -benzothiophen-4-methyl] -2,4-thiazolidinedione (87%); p.f. 224-227 ° C. .

EXAMPLE 11 Sodium salt of 5- [7- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -benzothiophen-4-methyl] -2,4-thiazolidinedione It was dissolved (5- {7 { [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -benzo [b] thiophen-4-ylmethyl} -2. -thiazolidinedione) (5.8 g) in hot THF (87 ml). A solution of sodium hydroxide (0.5 g) in water (6 ml) was added, and the solution was cooled to room temperature. Another portion (87 ml) of THF was given to the solution, and then a crystallization was observed in a short time. 150 ml of the solvent was distilled in the heat. The suspension was cooled to about 0 ° C and stirred for an additional 2 hours. The solid was filtered and dried at 80 ° C. Yield: 5.6 g of sodium salt of 5- [7- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -benzothiophen-methyl] -2,4-thiazolidinedione pf: > 300 ° C (decomposition).

It is noted that in relation to this date, the best method known to the applicant for carrying out the aforementioned invention is that which was clear from the present description of the invention. Having described the foregoing, the following is claimed as property:

Claims (27)

1. A process for the preparation of compounds of formula I characterized in that it comprises cyclocarbonylation of a compound of formula II wherein -OR is a group of formula -O- (CO) -R ', -0- (CO) -0-R' or -O- (PO) - (OR ") wherein R 'is alkyl, perfluoride-C C-20 alkyl, aryl, R "is alkyl, aryl or benzyl or the group -OR is halogen or an aryloxy group; followed by saponification.

2. Process according to claim 1, characterized in that the cyclocarbonylation reaction is carried out in the presence of a base and a catalyst comprising a transition metal compound and a ligand.

3. The process according to any of claims 1-2, characterized in that the transition metal compound is a palladium salt.

4. The process according to claim 3, characterized in that the transition metal compound is selected from a group consisting of Pd (OAc) 2, Pd2dba3, PdCl2, Pd2Cl2 (p-allyl) 2, PdCl2 (NCMe) 2 , [Pd (NCMe) 4] (BF4) 2, or Pd / C.

5. The process according to claim 4, characterized in that the palladium compound is Pd (Oac) 2-

6. The process according to claims 1-5, characterized in that the ligand is P (R1) (R2) (R3) or (R1), (R2) P- (X) -P (R1) (R2), wherein R1, R2 and R3 each independently are C ± -β, cyclohexyl, benzyl, naphthyl, 2- or 3- alkyl pyrrolyl, 2- or 3-furyl, 2- or 3-thiophenyl, 2- or 3- or 4-pyridyl, phenyl or phenyl which is substituted. by C 1-4 alkyl, C 1-4 alkoxy, halogen, trifluoromethyl, alkylidenedioxy or lower phenyl and X is binaphthyl, 6,6'-dimethyl- or 6,6'-dimethoxybiphenyl-2,2'-diyl, or one of the groups - (CH2) n-, -CH2CH2-P (C6H5) -CH2CH2-, and n is a number of 1

7. The process according to claims 1-5, characterized in that the ligand is selected from a group consisting of triphenylphosphine, and P (o-DMA-Ph) 3 PPhas-tBu-Phfe P (3,5-tBu- Ph), P (2-Fu? Fl), NMDPP MOP PAMP (S, S) -DDPP1 DPEphos

8. The process according to claim 1-7, characterized in that the ligand is triphenylphosphine. PPh. { 3,5-tBu-Ph) 2 P (3,5-tBu-Ph),

9. The process according to claims 1-8, characterized in that the cyclocarbonylation reaction is carried out in the presence of a base selected from the group consisting of tri-alkyl-amines, • di-alkyl-aryl-amines, pyridines, alkyl-N-piperidines, sodium hydroxide, potassium hydroxide or salts of carbonic acids.

10. The process according to claims 1-9, characterized in that the cyclocarbonylation reaction is carried out in the presence of triethylamine.

11. The process according to claims 1-10, characterized in that the compounds of Formula II are prepared by the reaction of thiophene carbaldehyde of Formula III III with a reagent of the formula vinyl-metal-X with a metal X being MgCl; -MgBr, -Mgl or -Li, followed by reaction with acid derivatives, selected from a group consisting of (R'-C0) 20, R "0- (CO) -Cl, Cl- (PO) ( OR ") 2 or R" - (CO) -Hal, wherein R 'is alkyl, perfluoroalkyl-20-aryl, R "is alkyl or benzyl, and Hal is Cl or Br.

12. The process according to claim 11, characterized in that the acid derivative is acetanhydride.

13. The process according to claims 1-12, characterized in that the vinyl-metal-X reagent is vinyl magnesium chloride.

14. The process according to claims 1-13, characterized in that the compound of Formula II is prepared by the reaction of thiophene carbaldehyde by the reaction of vinylmagnesium chloride followed by the reaction with acetanhydride.

15. The process according to claims 1-14, characterized in that the compound of formula I is 4-hydroxybenzothiophene.

16. The process according to claims 1-15, characterized in that the saponification reaction is carried out in a biphasic mixture of sodium hydroxide in toluene or in a homologous mixture of sodium methylate in methanol.

17. The process according to claims 1-16, characterized in that the compound, of Formula I is converted to 4- [2- (benzothiophen-4-yloxy) -ethyl] -5-methyl-2-phenyl-oxazole by the reaction of a compound of formula I with a mesylate of formula V. under basic conditions

18. The process according to claim 17, characterized in that 4- [2- (benzothiophen-allyloxy) -ethyl] -5-methyl-2-phenyl-oxazole is converted to 5-methyl-4- [2- ( 7-Nitro-benzothiophen-4-yloxy) -ethyl] -2-phenyl-oxazole, by nitration.

19. The process according to claim 18, characterized in that 5-methyl-4- [2- (7-nitro-be zothiophen-4-yloxy) -ethyl] -2-phenyl-oxazole is converted to 5-methyl- 4- [2- (7-amino-benzothiophen-4-yloxy) -ethyl] -2-phenyl-oxazole, by hydrogenation.

20. The process according to claim 19, characterized in that 5-methyl-4- [2- (7-amino-benzothiophen-4-yloxy) -ethyl] -2-phenyl-oxazole is converted to methyl-2-bromo- 3- [4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -benzothiophen-7-yl] -propionate by the reaction with HHal / NaN02, followed by the reaction with CH = CHC00CH3 / Cu (I) Hal, where Hal is Br or Cl.

21. The process according to claim 20, characterized in that methyl-2-bromo-3- [4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -benzothiophene-7-yl ] -propionate is converted to 2-imino-5- [4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -benzothiophene-7-yl] -methyl-thiazolidine-4- ona by the reaction with thiourea.

22. The process according to claim 21, characterized in that 2-imino-5- [4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -benzothiophene-7-yl] - methyl-thiazolidin-4-one is converted to 5- [7- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -benzothiophene-4-methyl] -2,4-thiazolidinedione by reaction under acidic conditions.

23. The process according to claim 22, characterized in that 5- [7- [2- (5- eti-2-phenyl-oxazol-4-yl) -ethoxy] -benzothiophene-4-methyl] -2,4- thiazolidinedione is converted to the sodium salt of 5- [7- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -benzothiophene-4-methyl] -2,4-thiazolidine) by reaction under basic conditions.

24. The process according to claims 1 to 23, for the preparation of 5- [7- [2- (5-methyl-1-2-phenyl-oxazol-4-yl) -ethoxy] -benzot-4-ethyl-4-ethyl] -2,4-thiazolidinedione characterized in that it comprises: a) conversion of a compound of formula I to 4- [2- (benzothiophene-4-yloxy) -ethyl] -5-methyl-2-phenyl-ozaxol by reaction of a compound of formula I with a formula V mesylate under basic conditions; followed by b) nitration of 4- [2- (benzothiophene-4-yloxy) ethyl] -5-methyl-2-phenyl-oxazole to give 5-methyl-4- [2- (7-nitro-benzothiophene-4-yloxy) ) -ethyl] -2-phenyl-oxazole; c) hydrogenation of 5-methyl-4- [2- (7-nitro-benzothiophene-4-yloxy) -ethyl] -2-phenyl-oxazole to give 5-methyl-4- [2- (7-amino- benzothiophene-4-yloxy) -ethyl] -2-phenyloxazole; followed by d) reaction of 5-methyl-4- [2- (7-amino-benzothiophene-4-yloxy) -ethyl] -2-phenyl-oxazole with HHal / NaN02 and CH = CHCOOCH3 / Cu (I) Hal, wherein Hal is Br or Cl to give methyl-2-bromo-3- [4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -benzothiophene-7-yl] -propionate; followed by e) reaction of methyl-2-bromo-3- [4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -benzothiophene-7-yl] -propionate with thiourea for give 2-imino-5- [4- [2- (5-methy1-2-phenyl-oxazol-4-yl) -ethoxy] -benzothiophene-7-yl] -methyl-thiazolidin-4-one; followed by f) reaction of 2-imino-5- [4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -benzothiophene-7-yl] -methylthiazolidine-4- ona under acidic conditions to give 5- [7- [2- (5-methyl-1-2-phenyl-oxazol-4-yl) -ethoxy] -benzothiophene-4-methyl] -2,4-thiazolidinedione; g) and optionally followed by the reaction of 5- [7- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -benzothiophene-4-methyl] -2,4-thiazolidinedione under basic conditions to give the sodium salt of 5- [7- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -benzothiophene-4-methyl] -2,4-thiazolidinedione.

25. The use of the processes according to any of claims 1-24 for the preparation of 5- [4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] -7-benzothiophenyl-methyl] - 2,4-thiazolidinedione.

36. The use of a process according to any of claims 1-24 for the preparation of the sodium salt of 5- [7- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] benzothiophene-4-methyl] -2,4-thiazolidinedione.

27. Sodium salt of 5- [7- [2- (5-met il-2-phenyl-oxazol-4-yl) -ethoxy] benzothiophene-4-methyl] -2,4-thiazolidinedione.