MX2007006675A - Method for producing thiophene glycoside derivatives - Google Patents

Abstract

The invention relates to a method for producing thiophene glycoside derivatives of general formula (I), wherein:Y represents hydrogen or alkyl;R1 represents alkyl, whereby hydrogen can be substituted by fluorine or aryl, and aryl can also contain heteroatoms, and;R2 represents hydrogen, Cl, Br and I.

Description

METHOD FOR PRODUCING THIOPHENE GLYCODE DERIVATIVES The present invention relates to a process for preparing thiophene glycoside derivatives of the general formula (I) The thiophene glycoside derivatives show biological activity, which makes possible their use, in particular, in the prevention and treatment of type 1 and 2 diabetes. The international patent application WO2004 / 007517 describes, among others, various procedures for preparing thiophene glycoside derivatives of the general formula (I). However, the process (B) described, the most efficient and short, has several disadvantages in relation to an industrial conversion. Thus, the products are purified mainly by chromatography. The yields are, in addition, so low in some cases that the withdrawal of the precursors and by-products hinders the simple isolation of the product. No optimization was undertaken in relation to the economy of atoms. The use of highly toxic compounds, such as sodium cyanoborohydride, or substances with a very strong odor, such as dimethyl sulfide, also harms its use in an industrial process. In view of the disadvantages and problems described above, there is a need to provide a method that avoids these disadvantages and problems and that, besides, without requiring great additional complexity, can be implemented in a simple manner and make available the desired products in high yields. , with high conversion and high selectivity. High yields are, in particular, an essential requirement for the procedure being sought. This object is achieved, surprisingly, by a process for preparing compounds of the general formula (I): wherein the meanings are Y H, alkyl (C Ci0); R1 alkyl (CrC8), wherein one, more than one or all of the hydrogens may be replaced by fluorine; aryl (C5-Cio), wherein the aryl may also comprise from 1 to 3 heteroatoms of the O, N, S series; R2 H, Cl, Br, I; which comprises applying a multistage procedure in which A. Preparation of hydroxy ketones A.1. the thiophene component of the formula (II) wherein Y is as defined above, and X is O-alkyl (Ci-Ce) or O-aryl (C5-C10), where the aryl may also comprise from 1 to 3 heteroatoms of the O, N, S series; is reacted with a compound of the formula (III) wherein R1 and R2 are as defined above, and R3 is Cl, Br, I; in the presence of between 0.1 and 10 equivalents, preferably from 0.8 to 1.5 equivalents, of one or more acids - where an acid is preferred - preferably with Lewis acids such as SnCl4, AICI3, T1CI4, BF3, FeCl 3 ZnCl 2, MgCl 2, ZnBr 2, MgBr 2, but also with Brónsted acids such as CF 3 SO 3 H, H 2 SO 4, toluenesulfonic acid, particularly preferably with Lewis acids such as SnCl 4 or AICI 3, in a suitable solvent, preferably in a halogenated solvent such as , for example, dichloromethane, chloroform, 1,2-dichloroethane, at between -50 ° C and + 150 ° C, preferably between -20 ° C and +80 ° C, particularly preferably between 5 ° C and 25 ° C , to give a compound of the formula (IV), wherein X, Y, R1 and R2 are as defined above; Y this compound of formula (IV) is converted, in the presence of between 0.1 and 10 equivalents, preferably from 0.8 to 1.5 equivalents, of one or more acids - where an acid is preferred - preferably a Lewis acid such as BBr3, BCI3, B £ 3, AICI3. SnCI4 > TiCl4, at -50 ° C to + 150 ° C, preferably between -20 ° C and + 80 ° C, particularly preferably between 0 ° C and 25 ° C, in the compound of the formula (IVa) wherein Y, R1 and R2 are as defined above, or A.2. the thiophene component of the formula (II) wherein X and Y are as defined above in A.1. is reacted with a compound of the formula (III) wherein R1, R2 and R3 are as defined above in A.1 .; in the presence of between 0.1 and 10 equivalents, preferably from 0.8 to 1.5 equivalents, of one or more acids - where an acid is preferred - preferably with Lewis acids such as SnCl4, AICI3, TiCl4, BF3, FeC , ZnCl2, MgC, ZnBr2, MgBr2, but also Brónsted acids such as CF3SO3H, H2S04, toluenesulfonic acid, particularly preferably with Lewis acids such as SnCl4 or AICI3, in a solvent suitable, preferably in a halogenated solvent such as, for example, dichloromethane, chloroform, 1,2-dichloroethane, at between -50 ° C and + 150 ° C, preferably between -20 ° C and +100 ° C, particularly preferably between 60 ° C and 75 ° C, to give a compound of the formula (IV), wherein X, Y, R1 and R2 are as defined above, and the latter is further directly reacted in the presence of an acid as defined above at 0 to 200 ° C, preferably at 20 ° C to 20 ° C, particularly preferably at 80 to 90 ° C, to give the composed of the formula (IVa) wherein Y, R1 and R2 are as defined above, or A.3. the thiophene component of the formula (II) wherein X and Y are as defined above, is reacted with one or more organometallic reagents of the series M-alkyl (Ci-C8), MH, MO-alkyl (CrC8) or MN (alkyl (Ci-C8) )2. wherein M is Li, Na, K, Zn, Mg, Ca, in apolar solvents such as an ether, for example, diethyl ether, tetrahydrofuran, dibutyl ether, dihexyl ether and methyl tert-butyl ether, at temperatures between -20 ° C at 45 ° C, preferably at temperatures between 15 ° C and 35 ° C, particularly preferably between 30 ° C and 35 ° C, to give the reactive intermediate of the formula (V) wherein X, Y and M are as defined above, and the latter is further reacted composed of the formula (Illa) wherein R1 and R2 are as defined above, and 'is Cl, Br, I, NH-alkyl (Ci-CB), NH-O-alkyl (d-Ce), N ((C8-C8) alkyl) 2, N-C 1 -C 8 -alkyl (C 8) alkyl, N (C 3 -C 8) -cycloalkyl, wherein the alkyl ring may comprise one or more heteroatoms of the series N, O, S, N (aryl (C6-Cio)) - alkyl (C8), N (cycloalkyl (C3-C8)) - aryl (C3-C8), N (aryl ( C6-Cio)) 2, where aromatic systems and cyclic alkanes can comprise one or more heteroatoms of the N, O, S series, to give a compound of the formula (IV) wherein X, Y, R1 and R2 are as defined above; as described in A.1., at temperatures between -20 ° C and + 30 ° C, preferably -5 ° C to + 5 ° C; and subsequently this compound of the formula (IV) is converted, in the presence of a Lewis acid such as BBr3, AICI3, SnCl4, TiCU, at between 0 ° C and 30 ° C, preferably at between 5 ° C and 15 ° C , in the compound of the formula (IVa) wherein Y, R1 and R2 are as defined above, and, where appropriate, subsequently the compounds of the formula (IVa) are purified by conventional purification methods, such as crystallization, distillation or chromatography, preferably by crystallization from a solvent or a mixture of a plurality of solvents, such as such as alkanes, aromatics, halogenated solvents, ethers, ketones, esters, alcohols or water, particularly preferably they are purified by crystallization from methanol or from mixtures of dichloromethane / heptane or methanol / water, or by conversion to the salt sodium and - after neutralization - crystallization from water; and subsequently B. Preparation of acetoglucoketones the compound of the formula (IVa) it is reacted with between 0.5 and 10 equivalents, preferably between 1 and 4 equivalents, particularly preferably from 1.5 to 2.0 equivalents of a derivative of a sugar of the formula (VI) wherein PG is an OH protecting group such as, for example, methyl, methoxymethyl (MOM), methylthiomethyl (MT), phenyldimethylsilyl-methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), t-butoxymethyl, 4-pentenyloxymethyl, 2-methoxyethoxymethyl (MEM), 2-trimethylsilylethoxymethyl (SEM), trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), or similar silyl protecting groups, 1-methyl-1-methoxyethyl (MIP), allyl , benzyl, acetyl, trifluoroacetyl, Fmoc, THP, and preferably acetyl, in the presence of between 1 and 15 equivalents, preferably between 3 and 6 equivalents, of an organic or inorganic base, preferably potassium carbonate, and between 0.01 and 5 equivalents , preferably between 0.1 and 1 equivalents, particularly preferably from 0.3 to 0.6 equivalents, of a phase transfer catalyst, preferably tetrabutylammonium bromide or chloride or benzyltributylammonium chloride or bromide, in a mixture of solvent or preferably, methylene chloride or 2-methyltetrahydrofuran, and water, in the ratio of between 10,000: 1 and 1: 1, preferably from 500: 1 to 10: 1, very particularly preferably from 200: 1 to 50: 1, at -20 ° C to + 80 ° C, preferably at between 5 ° C and -40 ° C, particularly preferably between 20 ° C and -30 ° C, to give the compound of the formula (VII); wherein PG, Y, R1 and R2 are as defined above; and subsequently C. Preparation of acetoglucomethylenes the compound of the formula (VII) described above is reacted in a suitable organic solvent such as, for example, dichloromethane, acetonitrile, tetrahydrofuran, dimethylformamide, DIVISO and chloroform, preferably in acetonitrile, with from 1 to 15 equivalents, preferably 2 to 6 equivalents, of one or more hydride donors such as, for example, potassium borohydride, sodium borohydride, sodium cyanoborohydride, triethylsilane, triacetoxy borohydride, preferably with sodium cyanoborohydride or sodium borohydride, particularly preferably with sodium borohydride, and 0.1 to 5 equivalents, preferably 0.5 to 1.5 equivalents, of one or more activators selected from the group of lithium chloride, bromine, sodium bromide or potassium bromide, iodine, sodium iodide or potassium iodide, sodium triiodide or potassium triiodide, preferably with iodine, and from 1 to 25 equivalents, preferably from 3 to 10 equivalents, of one or more acids further, Lewis acids or acid equivalents, such as, for example, trifluoroacetic acid, hydrogen chloride, BF3, halosilanes, preferably chlorosilanes, particularly preferably trimethylsilyl chloride, at -100 ° C to + 100 ° C, preferably at between -0 ° C and + 40 ° C, particularly preferably between -15 ° C and + 15 ° C, to give the compound of the formula (VIII), wherein PG, Y, R1 and R2 are as defined above; later D. Preparation of thiophene qicoside derivatives protective groups are removed under basic conditions or acids, by oxidation or reduction or with fluoride, according to the known methods which are described for example in T.W. Greene, P. Wuts, Protective Groups in Organic Synthesis 1999, Wiley, New York; preferably, as described above, with PG = acetyl, in the presence of between 0.01 and 25 equivalents, preferably 0.05 to 5 equivalents, particularly preferably 0.1 to 0.5 equivalents, of an organic base or inorganic, preferably such as, for example, sodium methanolate or potassium methanolate, sodium hydroxide or potassium hydroxide, preferably sodium methanolate, in a suitable solvent, preferably methanol, at -50 ° C to + 150 ° C, preferably at 20 ° C and + 80 ° C, particularly preferably from 0 ° C to 50 ° C; and subsequently they are converted into the compounds of the formula (I) wherein Y, R1 and R2 are as defined above, and, subsequently, the compounds of the formula (I) are purified by conventional purification methods, such as crystallization or chromatography, preferably by crystallization from a solvent or a mixture of a plurality of solvents such as alkanes, aromatics, halogenated solvents, ethers, ketones, esters, alcohols or water, so particularly preferably by crystallization from alcohols or alcohol / water mixtures, very particularly preferably by crystallization from methanol / water.

Preference is given to a multi-step process for preparing the compounds of the formula (I), in which step A. Preparation of the hydroxyketones, consists of the A2 or A3 variants described above: Process for preparing compounds of the general formula (I): wherein the meanings are Y H, alkyl (CrC10); R1 alkyl (CrC8), wherein one, more than one or all of the hydrogens may be replaced by fluorine; aryl (C5-C10), where the aryl it may also comprise from 1 to 3 heteroatoms of the O, N, S series; R2 H, Cl, Br, I; which comprises A. Preparation of hydroxy ketones A.2. being the thiophene component of the formula (II), wherein Y is as defined above, and X is O-alkyl (C C8) or O-aryl (C5-C-io), wherein the aryl may also comprise from 1 to 3 heteroatoms of the O, N series, S; Reacted with a compound of the formula (III) wherein R1 and R2 are as defined above, and R3 is Cl, Br, l¡ in the presence of between 0.1 and 10 equivalents of one or more acids in a suitable solvent at between -50 and +150 ° C to give a compound of the formula (IV) wherein X, Y, R1 and R2 are as defined above; Y it is directly converted, in addition, in the presence of an acid as defined above, at between 0 and 200 ° C, into the compound of the formula (IVa) wherein Y, R1 and R2 are as defined above, A.3. being the thiophene component of the formula (II) (ll) wherein X and Y are as defined above, reacted with one or more organometallic reagents of the M-alkyl (C C8), MH, MO-alkyl (CrC8) or MN (alkyl (CrC8)) 2 series, that M is Li, Na, K, Zn, Mg, Ca, in apolar solvents at temperatures between -20 and 45 ° C to give the reactive intermediate of the formula (V) wherein X, Y and M are as defined above, and the latter being further reacted with a compound of the formula (Illa) wherein 1 and R2 are as defined above, and R3 'is CI, Br, I, NH-alkyl (CrCB), NH-O-alkyl (C8), N ((C8) alkyl) 2, N -alkyl (Ci-C8) -O-alkyl (C8), N-cycloalkyl (C3-C8), wherein the alkyl ring may comprise one or more heteroatoms of the series N, O, S, N (aryl (C6-) C10)) - (C8) alkyl, N (C3-C8) cycloalkyl- (C3-C8) aryl, N (C6-Ci0) aryl), where aromatic systems and cyclic alkanes can comprise one or more heteroatoms of the series N, O, S, to give a compound of the formula (IV), wherein X, Y, R1 and R2 are as defined above; as described in A.2., at temperatures between -20 ° C and + 30 ° C; and then this compound of the formula (IV) converted, in the presence of a Lewis acid, into the compound of the formula (IVa) wherein Y, R1 and R2 are as defined above, and, where appropriate, the compounds of the formula (IVa) subsequently being purified by conventional purification methods; and subsequently B. Preparation of acetoglucoketones being the compound of the formula (IVa) reacted with between 0.5 and 10 equivalents of a derivative of a sugar of the formula (VI) wherein PG is an OH protecting group in the presence of between 1 and 15 equivalents of an organic or inorganic base and from 0.01 to 5 equivalents of a phase transfer catalyst in a mixture of an organic solvent and water in the ratio of 10,000: 1 to 1: 1, at -20 ° C to + 80 ° C, to give the compound of the formula (VII); wherein PG, Y, R1 and R2 are as defined above; and subsequently C. Preparation of acetoqlucomethylenes the compound of the formula (VII) described above being made to react in a suitable organic solvent with from 1 to 15 equivalents of one or more hydride donors and from 0.1 to 5 equivalents of one or more activators selected from the group of lithium, bromine, sodium bromide or potassium bromide, iodine, sodium iodide or potassium iodide, sodium triiodide or potassium triiodide and from 1 to 25 equivalents of one or more additional acids at -100 ° C to + 100 ° C to give the compound of the formula (VIII) wherein PG, Y, R1 and R2 are as defined above; later D. Preparation of thiophene qicoside derivatives the protecting groups being removed under basic or acidic conditions, by oxidation or reduction or with fluoride, according to the known methods, in the presence of between 0.01 and 25 equivalents of an organic or inorganic base in a suitable solvent at between -50 ° C and + 150 ° C, and subsequently converted to the compounds of the formula (I) wherein Y, R1 and R2 are as defined above, and then the compounds of the formula (I) being purified by conventional purification methods.

The invention also relates to a process for preparing the intermediate compounds of the formula (VIII), wherein a compound of the formula (VII) wherein PG is an OH protecting group; Y is H, alkyl (d-C10); R1 is alkyl (C-i-Cs), where one, more than one or all of the hydrogens can be replaced by fluorine; aryl (C5-C10), wherein the aryl may also comprise from 1 to 3 heteroatoms of the O, N, S series; R2 H, Cl, Br, I; it is reacted, in a suitable organic solvent, with between 1 and 15 equivalents of one or more hydride donors and between 0.1 and 5 equivalents of one or more activators selected from the group of lithium chloride, bromine, sodium bromide or bromide potassium, iodine, sodium iodide or potassium iodide, sodium triiodide or potassium triiodide, and from 1 to 25 equivalents of one or more additional acids at -100 ° C to + 100 ° C to give the compound of the formula (VIII) wherein PG, Y, R1 and R2 are as defined above.

In a preferred process for preparing the intermediate compounds of the formula (VIII), iodine is used as an activator. A further preferred embodiment is a process for preparing the compounds of the formula (I) wherein the meanings are And H; R1 alkyl (C4), wherein one, more than one or all of the hydrogens may be replaced by fluorine, preferably CH3, C2H5, CF3; R2 H. The invention relates to compounds of the formula (I) in the form of their racemates, racemic mixtures and pure enantiomers, to their diastereomers and mixtures thereof, and to their salts of alkali metals, alkaline earth metals, ammonium, iron and similar pharmacologically acceptable. Alkyl radicals, including alkoxy, alkenyl and alkynyl, in the substituents R1, R3 \ X, Y and M can be either straight-chain or branched. The sugar residues in the compounds of the formula (I) represent both L- and D-sugars in their alpha (a) and beta (p) forms, such as, for example, allose, altrose, glucose, mannose, gulose, idosa, galactose, talose. Those which can be mentioned as preferred are: D-glucose, D-galactose, D-allose and D-mannose, particularly preferably β-D-glucose and β-D-galactose, very particularly preferably β-D- glucose. The process of the invention is remarkable, in particular, to make possible an industrially feasible route for thiophene glycoside derivatives in high yields. Alternative methods for preparing the compound (IV) provide the option of employing a large number of acid-labile or base-labile precursors of the compound (III). The following examples illustrate the procedure without restricting it: ?? EXPERIMENTAL SECTION: Example 1: a) (4-Methoxyphenol) (3-methoxythiophen-2-yl) methanone (variant A1) 24.4 parts by weight of tin tetrachloride are dissolved in 300 parts by volume of dichloromethane in a reaction vessel and, at an internal temperature of 5-10 ° C, 15.0 parts by weight of p-anisoyl chloride is added. Then 9.56 parts by weight of 3-methoxythiophene are added at an internal temperature of 5-10 ° C, and the reaction mixture is stirred at 20-25 ° C for 3-5 h. After the conversion is completed (checking the conversion), 135 parts by volume of water are added to the reaction mixture. It is then washed with 25 parts by volume hydrochloric acid of 30% concentration. The organic and aqueous phases are separated, and the organic phase is washed with 100 parts by volume of water, 100 parts by volume of a sodium bicarbonate solution of 8% concentration and 100 parts by volume of water. The organic phase is concentrated by distillation to 40 parts by volume and, at 40 ° C, 210 parts by volume of heptane are introduced. The suspension is cooled to 0 ° C, and the solid is freed from the solvent. Then the solid, pale yellow, dries. The product is obtained in a yield of 94%; melting point: 98-99 ° C, 1 H-NMR (CDCl 3): d = 8.37 (d, J = 6.3 Hz, 1 H), 7.96 (d, J = 6.9 Hz, 2H ), 6.96 (d, J = 6.9 Hz, 2H), 6.37 (d, J = 6.3 Hz, 1 H), 3.91, 3.88 (s, 6H) ppm. b) (3-Hydroxythiophen-2-yl- (4-methoxyphenyl) methanone 1.86 parts by weight of boron tribromide are added to a solution of 1.84 parts by weight of (4-methoxyphenyl) (3-methoxythiophene). 2-yl) methanone in 25 parts by volume of dichloromethane at 0-5 ° C, and the mixture is stirred at 5-15 ° C for 60 min.Then it is stirred at 20-25 ° C for a further 3 h, and then 1.0 part by volume of methanol and 12 parts by volume of water are added, it is adjusted to a pH of 8 with about 1.4 parts by volume of 33% strength sodium hydroxide solution. and the organic phase is washed twice with 10 parts by volume of water each time.The organic phase is concentrated in vacuo, and the residue is extracted in 20 parts by volume of methanol.The solution is heated to 60 ° C, and add 4 parts by volume of water.After cooling to 0 ° C, the precipitated solid is separated and dried.The product is obtained as a dark gray solid in a yield of 91%; Fusion surface: 86-87 ° C. 1 H-NMR (DMSO-d 6): d = 11, 85 (s, 1 H, OH), 7.96 (d, J = 5.4 Hz, H), 7.89 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 5.4 Hz, 1 H), 3.85 (s, 3H) ppm.

Example 2: (3-Hydroxythiophen-2-yl) (4-trifluoromethoxyphenyl) methanone (variant A2) 0.86 parts by weight of 4-trifluoromethoxybenzoyl chloride are added to a solution of 1.0 part by weight of tin tetrachloride in 10.8 parts by volume of 1,2-dichloroethane. The dissolution heat to 68-70 ° C and, at this temperature, 0.4 part by weight of 3-methoxythiophene is added over 2 h. The reaction mixture is brought to reflux at 70 ° C for 3 h (checking the conversion in (IV)) and for an additional 8 h (80-85 ° C, checking the conversion in (IVa)). At 25 ° C, 3.7 parts by weight of water and 6.3 parts by volume of hydrochloric acid of 30% concentration are added. After the addition of 24 parts by volume of heptane, the phases are separated, and the organic phase is washed with 10 parts by volume of deionized water. The solvent is concentrated to 16 parts by volume. Filtration and washing with heptane is carried out. The filtrate is stirred with 25 parts by volume of a 0.8% strength sodium hydroxide solution, and the phases are separated. The aqueous phase is washed with heptane. It is adjusted to a pH of 9.0 with hydrochloric acid of 7.5% concentration, after which the product precipitates again. The product is filtered with suction, washed and dried ((3-hydroxythiophen-2-yl) (4-trifluoromethoxyphenyl) methanone is isolated as a brownish-yellowish solid, with a yield of 53%). Melting point: 67-70 ° C y 1 H-NMR (DMSO-d 6): d = 1 1, 45 (br s, 1 H, OH), 7.97 (d, J = 5.4 Hz, 1 H ), 7.93 (d, J = 8.7 Hz, 2H), 7.51 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 5.4 Hz, 1 H) ppm.

Example 3: a) (4-Trifluoromethoxyphenyl) - (3-methoxyprophen-2-yl) methanone (variant A3) 8 parts by volume of n-BuLi (1.6 M in hexane) are added to 7 parts by volume of 3-methoxythiophene in 150 parts by volume of ether diethyl at 20-25 ° C under a protective gaseous atmosphere, and the solution is heated at 40 ° C for 30 min. The reaction mixture is added to an ice-cooled (0-5 ° C) solution of 8.3 parts by weight of N-methoxy-N-methyl-4-trifluoromethoxybenzamide in 100 parts by volume of diethyl ether. The mixture is then stirred at room temperature for 1 h (conversion check). 50 parts by volume of water are added, the phases are separated and the aqueous phase is extracted 3 times with dichloromethane, the combined organic phases are dried over Na 2 SO 4, and the solvent is removed in vacuo. 76% of the product is isolated as a yellowish oil. 1 H-NMR (DMSO-d 6): d = 8.04 (d, J = 5.5 Hz, 1 H), 7.82 (d, J = 8.6 Hz, 2H), 7.45 (d, J = 8.6 Hz, 2H), 7.19 (d, J = 5.5 Hz, 1 H), 3.79 (s, 3H) ppm. b) (3-Hydroxythiophen-2-yl) (4-trifluoromethoxyphenyl) methanone 7.56 parts by weight of (3-methoxythiophen-2-yl) (4-trifluoromethoxyphenyl) -methanone in 100 parts by volume are added slowly. of dichloromethane to a solution of 8, 2 parts by weight of BBr3 x DMS in 500 parts by volume of dichloromethane at 20-25 ° C. The dark solution is stirred at 20-25 ° C for 7 h (conversion check) and then 80 parts by volume of a saturated solution of sodium bicarbonate in a single portion are added. The phases are separated, the organic phase is washed with 100 parts by volume of water and dried, and the solvent is removed in vacuo. The solid is recrystallized from methanol, and 86% of a pale yellow solid is obtained.

Example 4: 4,5-Diacetoxy-6-acetoxymethyl-2- [2- (4-methoxybenzoyl) thiophene-3-yloxy] tetrahydro-pyran-3-yl acetate 3,9 is added parts by weight of benzyltributylammonium chloride, 19.4 parts by weight of potassium carbonate and 2.6 parts by volume of water to a solution of 7.3 parts by weight of (3-hydroxyprophen-2-yl) (4-methoxyphenyl) methanone in 280 parts by weight volume of dichloromethane at 20-25 ° C. After the course of 2 h, 22.5 parts by weight of 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide are added. The reaction mixture is stirred at 20-25 ° C for 16 h (checking the conversion), the solids are removed and the organic phase is washed 3 times with water. The organic phase is concentrated and extracted in 95 parts by volume of methanol. After crystallization, the solution is cooled to 0 ° C. The solid is separated and dried. 81% of the product is obtained as a colorless solid; melting point: 149-151 ° C, H-NMR (DMSO-d6): d = 8.0 (d, 1 H), 7.7 (d, 2H), 7.1 (d, 2H), 7 , 0 (d, 1 H), 5.6 (d, 1 H), 5.3 (dd, 1 H), 4.9 (m, 1 H), 4.7 (dd, 1 H), 4 , 2 (m, 2H), 4.1 (m, 1 H), 3.8 (s, 3H, 0-CH3), 2.05, 2.00, 1, 90, 1.85 (s, 12H , acetyl-CH3) ppm.

Example 5: 4,5-Diacetoxy-6-acetoxymethyl-2- [2- (4-tnfluorometho-xibenzoyl) thiophen-3-yloxy] tetrahydro-pyrn-3-yl acetate 3,5 are added parts by weight of benzyltributylammonium chloride, .3 parts by weight of potassium carbonate and 2.5 parts by volume of water to a solution of 7.1 parts by weight of (3-hydroxythiophen-2-yl) (4-trifluoromethoxyphenyl) methanone in 250 parts by volume of dichloromethane at 20-25 ° C. During the course of 2 h, 18.7 parts by weight of 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide are added. The reaction mixture is stirred at 20-25 ° C for 16 h (checking the conversion), the solids are removed and the organic phase is washed 3 times with water. The organic phase is concentrated and extracted in 100 parts by volume of isopropanol. At 40-45 ° C, 75 parts by weight of water are added, and the solution is cooled to 0 ° C. The solid is separated and dried. 90% of the product is obtained as a colorless solid; melting point: 90-93 ° C, 1H-NMR (DMSO-d6): d = 8.09 (d, J = 5.5 Hz, 1 H), 7.78 (d, J = 6.7 Hz , 2H), 7.43 (d, J = 6.7 Hz, 2H), 7.13 (d, J = 5.5 Hz, 1 H), 5.60 (d, J = 7.9 Hz, 1 H), 5.27 (dd, J = 9.5 / 9.5 Hz, 1 H), 4.94-4.90 (m, 1 H), 4.63 (dd, J = 9.6) / 9.5 Hz, 1 H), 4.21-4.17 (m, 2H), 4.06-4.04 (m, 1 H), 2.02, 1, 99, 1, 90, 1 84 (s, 12H, acetyl-CH3) ppm.

Example 6: 4,5-Diacetoxy-6-acetoxymethyl-2- [2- (4-methoxybenzyl) thiophene-3-yloxy] tetrahydro-pyran-3-yl acetate 4.5 parts by weight of iodine are added and 2, 1 parts by weight of sodium borohydride (added over 60 min), and 11.5 parts by weight of trimethylsilyl chloride (added over 45 min) to a solution of 10.3 parts by weight of 4-acetate, 5-diacetoxy-6-acetoxymethyl-2- [2- (4-methoxybenzoyl) thiophen-3- ilox!] tetrahydropyran-3-yl in 57 parts by weight of acetonitrile at -10 to 0 ° C. After being stirred at 0 ° C for 90 min, the reaction mixture is diluted with 75 parts by volume of dichloromethane and, while cooling, 75 parts by volume of water are added dropwise. After washing with water several times, the solvent is removed in vacuo, and the residue is extracted in 51 parts by volume of methanol. The crude product is recrystallized at 50-60 ° C and then filtered with suction at -5 ° C. The colorless solid is dried and obtained in a yield of 83%. Melting point: 16-1 18 ° C; 1 H-NMR (DMSO-d 6): d = 7.29 (d, J = 5.5 Hz, 1 H), 7.09 (d, J = 6.7 Hz, 2H), 6.87 (d, J = 5.5 Hz, 1 H), 6.84 (d, J = 6.7 Hz, 2H), 5.41-5.33 (m, 2H), 5.07-4.97 (m, 2H), 4.21-4.17 (m, 2H), 4.09 (d, J = 9.7 Hz, 1 H), 3.91-3.79 (m, 2H), 3.71 ( s, 3H), 2.00, 1, 99, 1, 96, 1, 95 (s, 12H, acetyl-CH3) ppm.

Example 7: 4,5-Diacetoxy-6-acetoxymethyl-2- [2- (4-trifluoromethyl-xibenzyl) thiophen-3-yloxy] tetrahydropyran-3-yl acetate 3.24 parts by weight of iodine and 2.0 parts by weight of sodium borohydride (added over 60 minutes), and 11.1 parts by weight of trimethylsilyl chloride (added over 45 minutes) are added to a solution of sodium hydroxide. , 98 parts by weight of 4,5-diacetoxy-6-acetoxymethyl-2- [2- (4-trifluoromethoxybenzoyl) thiophene-3-yloxy] tetrahydropyran-3-yl acetate in 41.6 parts by weight of acetonitrile between -10 and 0 ° C. After stirring at 0 ° C for 90 min, the reaction mixture is diluted with 77 parts by volume of dichloromethane and, after the time it cools, 77 parts by volume of water are added dropwise. After washing with water several times, the solvent is removed in vacuo, and the residue is extracted in 35 parts by volume of methanol. The crude product is recrystallized at 40-50 ° C and then filtered with suction at -10 ° C. The colorless solid is dried and 81% of a colorless solid is obtained. Melting point: 113-114 ° C; 1 H-NMR (DMSO-d 6): d = 7.47 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 5.5 Hz, 1 H), 7.30 (d, J = 8.1 Hz, 2H), 6.86 (d, J = 5.5 Hz, 1 H), 5.89 (d, J = 3.6 Hz, 1 H), 5.45 (dd, J = 9.8 / 9.3 Hz, 1 H), 5.38 (d, J = 8.0 Hz, 1 H), 5.11 (dd, J = 8.0 / 9.8 Hz, 1 H), 5.04 (dd, J = 9.3 / 9.3 Hz, 1 H), 4.21-4.17 (m, 2H), 4.10 (dd, J = 5.0 / 9 , 8 Hz, 1 H), 3.33 (s, 2H), 2.09, 2.01, 2.00, 1.99 (s, 12H, acetyl-CH3) 13C-NMR (DMSO-d6): d = 170.0, 169.6, 169.3, 169.3, 148.9, 147.2, 144.1, 129.5, 127.4, 123.8, 120.7, 1 18.9 , 99.6, 71, 8, 70.9, 70.8, 68.1, 66.1, 61, 7, 20.4, 20.4, 20.3, 20.3 ppm.

Example 8: 2-Hydroxymethyl-6- [2- (4-methoxybenzyl) thiophen-3-yloxy] tetrahydropyran-3,4,5-trio 0.97 parts by weight of sodium methanolate (30% in methanol) are added to a suspension of 14.5 parts by weight of 4,5-diacetoxy-6-acetoxymethyl-2- [2- (4-methoxybenzyl) thiophen-3-yloxy] tetrahydropyran-3-yl acetate in 91 parts by weight of methanol at 0 ° C. The reaction mixture is stirred at 0 ° C for 90 min and then adjusted to a pH of 7 with 0.76 parts by weight of acetic acid. The product is precipitated by adding water and filtered with suction at 0 ° C. The colorless solid is dried and obtained in a yield of 83%. Melting point: 154 - 155 ° C; 1 H-NMR (DMSO-d 6): d = 7.16-7.14 (m, 3H), 6.91 (d, J = 5.5 Hz, 1 H), 6.80 (d, J = 8 , 6 Hz, 2H), 5.35 (s, H), 5.05 (s, H), 4.99 (s, 1 H), 4.63-4.53 (m, 2H), 4, 01-3.97 (m, 2H), 3.71 (s, 3H), 3.66 (s, 1 H), 3.49-3.44 (m, 1 H), 3.32-3, 05 (m, 4H) ppm.

Example 9: 2-Hydroxymethyl-6- [2- (4-trifluoromethoxybenzyl) thiophen-3-yloxy] -tetrahydropyran-3,4,5-triol 1.5 parts by weight of sodium methanolate (30% in methanol) are added. ) to a suspension of 12.3 parts by weight of 4,5-diacetoxy-6-acetoxymethyl-2- [2- (4-trifluoromethoxybenzyl) thiophen-3-yloxy] tetrahydropyran-3-yl acetate in 83, 2 parts by weight of methanol at 0 ° C. The reaction mixture is stirred at 10 ° C for 90 min and then adjusted to a pH of 7 with 1.58 parts by weight of acetic acid. The product is precipitated by adding water and filtered with suction at 0 ° C. The colorless solid is dried and obtained in a yield of 89%. Melting point: 144-145 ° C; 1 H-NMR (DMSO-d 6): d = 7.41 (d, J = 8.5 Hz, 2H), 7.27 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 5.5 Hz, 1 H), 6.97 (d, J = 5.5 Hz, 1 H), 5.37 (d, J = 4.9 Hz, 1 H), 5.05 (d, J = 4.5 Hz, 1 H), 4.98 (d, J = 5.3 Hz, 1 H), 4.64 (d, J = 7.3 Hz, 1 H), 4.56 (dd) , J = 5.7 / 5.7 Hz, 1 H), 4.12-4.04 (m, 2H), 3.72-3.68 (m, 1 H), 3.51-3.47 (m, 1 H), 3.32-3.12 (m, 4H); 19 F-NMR (DMSO-d 6): d = 56.8 ppm.

Claims (6)

1. - A process for preparing compounds of the general formula (I): wherein the meanings are Y H, alkyl (C C 10); R1 alkyl (C Cs), wherein one, more than one or all of the hydrogens may be replaced by fluorine; aryl (C5-C10), wherein the aryl may also comprise from 1 to 3 heteroatoms of the O, N, S series; R2 H, Cl, Br, I; which comprises A. Preparation of hydroxy ketones A.1. being the thiophene component of the formula (II) wherein Y is as defined above, and X is O-alkyl (C-i-C-s) or O-aryl (C5-Cio), wherein the aryl also comprises from 1 to 3 heteroatoms of the O, N, S series; Reacted with a compound of the formula (III) wherein R1 and R2 are as defined above, and R3 is Cl, Br, I; in the presence of between 0.1 and 10 equivalents of one or more acids in a suitable solvent at between -50 and +150 ° C to give a compound of the formula (IV), wherein X, Y, R1 and R2 are as defined above; Y this compound of the formula (IV) being converted in the presence of between 0.1 and 10 equivalents of one or more acids at -50 and + 150 ° C in the compound of the formula (IVa) wherein Y, R1 and R2 are as defined above, or A.2. being the thiophene component of the formula (II) wherein X and Y are as defined above in A.1. Reacted with a compound of the formula (III) wherein R1, R2 and R3 are as defined above in A.1 .; in the presence of between 0.1 and 10 equivalents of one or more acids in a suitable solvent at between -50 and + 150 ° C to give a compound of the formula (IV) wherein X, Y, R1 and R2 are as defined above, and the latter being directly reacted more in the presence of an acid as defined above at between 0 and 200 ° C to give the compound of the formula (IVa) wherein Y, R1 and R2 are as defined above, A.3. being the thiophene component of the formula (II) where X and Y are as defined above, Reacted with one or more organometallic reagents of the M-alkyl (C C 8), MH, MO-alkyl (Ci-C 8) or MN (C 8) alkyl group 2 wherein M is L, Na, K , Zn, Mg, Ca, in apolar solvents at temperatures between -20 and 45 ° C to give the reactive intermediate of the formula (V) wherein X, Y and M are as defined above, and the latter being further reacted with a compound of the formula (Illa) wherein R1 and R2 are as defined above, and R3 'is CI, Br. I, NH-alkyl (C-C8), NH-O-alkyl (Ci-Ce), N-alkyl (Ci-C8)) 2, N-alkyl (Ci-C8) -0-alkyl (C8), N-cycloalkyl (C3-C8), wherein the alkyl ring may comprise one or more heteroatoms of the series N, O, S, N (aryl (C6) -C10)) - (Ci-C8) alkyl, N (C3-C8) cycloalkyl- (C3-C8) aryl, N (C6-Cio) aryl), where aromatic systems and cyclic al- als can comprise one or more heteroatoms of the series N, O, S, wherein X, Y, R1 and R2 are as defined above; as described in A.1., at temperatures between -20 ° C and + 30 ° C; and this compound of the formula (IV) subsequently converted in the presence of a Lewis acid into the compound of the formula (IVa) wherein Y, R1 and R2 are as defined above, and, where appropriate, the compounds of the formula (IVa) subsequently being purified by conventional purification methods; and subsequently B. Preparation of acetoqlucoketones being the compound of the formula (IVa) reacted with between 0.5 and 10 equivalents of a derivative of a sugar of the formula (VI) wherein PG is an OH protecting group in the presence of between 1 and 15 equivalents of an organic or inorganic base and between 0.01 and 5 equivalents of a phase transfer catalyst in a mixture of an organic solvent and water in the ratio of between 10,000: 1 and 1: 1 at -20 ° C to + 80 ° C to give the compound of the formula (VII); wherein PG, Y, R1 and R2 are as defined above; and subsequently C. Preparation of acetoqlucomethylenes the compound of the formula (VII) described above being made to react in a suitable organic solvent with from 1 to 15 equivalents of one or more hydride donors and from 0.1 to 5 equivalents of one or more activators selected from the group of lithium, bromine, sodium bromide or potassium bromide, iodine, sodium iodide or potassium iodide, sodium triiodide or potassium triiodide and from 1 to 25 equivalents of one or more additional acids at -100 ° C to + 100 ° C to give the compound of the formula (VIII) wherein PG, Y, R1 and R2 are as defined above; later D. Preparation of the thiophene glycoside derivatives with the protecting groups being removed under basic or acidic conditions, by oxidation or reduction or with fluoride, according to known methods, in the presence of between 0.01 and 25 equivalents of an organic base or inorganic, in a suitable solvent, between -50 ° C and + 150 ° C and subsequently converted to the compounds of the formula (I) wherein Y, R1 and R2 are as defined above, and the compounds of the formula subsequently being purified by conventional purification methods.

2. - A process for preparing compounds of the general formula (I): wherein the meanings are Y H, alkyl (C C 10); R1 alkyl (CrCe), wherein one, more than one or all of the hydrogens may be replaced by fluorine; aryl (C5-C10), wherein the aryl may also comprise from 1 to 3 heteroatoms of the O, N, S series; R2 H, Cl, Br, I; which comprises A. Preparation of hydroxy ketones A.2. being the thiophene component of the formula (II) wherein Y is as defined above, and X is O-alkyl (C-i-Cs) or O-aryl (C5-C10), where aryl can be also comprise 1 to 3 heteroatoms of the O, N, S series; Reacted with a compound of the formula (III) wherein R1 and R2 are as defined above, and R3 is Cl, Br, I; in the presence of between 0.1 and 10 equivalents of one or more acids, in a suitable solvent, at between -50 and +150 ° C, to give a compound of the formula (IV), wherein X, Y, R1 and R2 are as defined above; Y it is further directly converted, in the presence of an acid as defined above, to between 0 and 200 ° C, into the compound of the formula (IVa) wherein Y, R1 and R2 are as defined above, or A.3. being the thiophene component of the formula (II) wherein X and Y are as defined above, reacted with one or more organometallic reagents of the series M-alkyl (Ci-C8), MH, MO-alkyl (Ci-C8) or MN (alkyl (Ci-C8) )) 2 in which M is Li, Na, K, Zn, Mg, Ca, in apolar solvents at temperatures between -20 and 45 ° C to give the reactive intermediate of the formula (V) wherein X, Y and M are as defined above, and the latter being further reacted with a composed of the formula (Illa) wherein R1 and R2 are as defined above, and R3 'is Cl, Br, I, NH-alkyl (Ci-C8), NH-O-alkyl (C8), N (C1-C8) alkyl) 2, N- (C1-C8) alkyl-0-alkyl (C8), N-cycloalkyl (C3-C8), wherein the alkyl ring may comprise one or more heteroatoms of the series N, O, S, N (aryl) (C6-Ci0)) - (Ci-C8) alkyl, N (C3-C8) cycloalkyl - (C3-C8) aryl, N (C6-Ci0) aryl (2), where the aromatic systems and the cyclic alkanes may comprise one or more heteroatoms of the series N, O, S, to give a compound of the formula (IV) wherein X, Y, R1 and R2 are as defined above; as described in A.2., at temperatures between -20 ° C and + 30 ° C; and this compound of the formula (IV) subsequently converted in the presence of a Lewis acid into the compound of the formula (IVa) wherein Y, R1 and R2 are as defined above, and, where appropriate, the compounds of the formula (IVa) subsequently being purified by conventional purification methods; and subsequently B. Preparation of acetoglucoketones being the compound of the formula (IVa) reacted with between 0.5 and 10 equivalents of a derivative of a sugar of the formula (VI) wherein PG is an OH protecting group in the presence of between 1 and 15 equivalents of an organic or inorganic base and between 0.01 and 5 equivalents of a phase transfer catalyst in a mixture of an organic solvent and water in the ratio of between 10,000: 1 and 1: 1, at between -20 ° C and + 80 ° C, to give the compound of the formula (VII); wherein PG, Y, R1 and R2 are as defined above; and subsequently C. Preparation of acetoglucomethylenes the compound of the formula (VII) described above being made to react in a suitable organic solvent with between 1 and 15 equivalents of one or more hydride donors and between 0.1 and 5 equivalents of one or more activators selected from the group of lithium chloride, bromine, sodium bromide or potassium bromide, iodine, sodium iodide or potassium iodide, sodium triiodide or potassium triiodide and between 1 and 25 equivalents of one or more additional acids, among 100 ° C and + 100 ° C, to give the compound of the formula (VIII) wherein PG, Y, R1 and R2 are as defined above; later D. Preparation of thiophene glycosic derivatives the protecting groups being removed under basic or acidic conditions, by oxidation or reduction or with fluoride, according to the known methods, in the presence of between 0.01 and 25 equivalents of an organic or inorganic base in a suitable solvent at between -50 ° C and + 150 ° C and subsequently converted to the compounds of the formula (I) wherein Y, R1 and R2 are as defined above, and then the compounds of the formula (I) being purified by conventional purification methods.

3. The process for preparing the compounds of the formula (I) according to claim 1 or 2, wherein the activator in step C, Preparation of the acetoglucomethylenes, is iodine.

4. - A process for preparing the intermediate compounds of the formula (VIII), which comprises a compound of the formula (VII), wherein PG is an OH protecting group; Y is H, alkyl (Ci-C 0); R1 is alkyl (CrC8), where one, more than one or all of the hydrogens may be replaced by fluorine; aryl (C5-C10), where the aryl can also comprise from 1 to 3 heteroatoms of the series O, N, S; R2 H, Cl, Br, I; being made to react in a suitable organic solvent with between 1 and 15 equivalents of one or more hydride donors and between 0.1 and 5 equivalents of one or more activators selected from the group of lithium chloride, bromine, sodium bromide or potassium bromide, iodine, iodide sodium or potassium iodide, sodium triiodide or potassium triiodide and between 1 and 25 equivalents of one or more additional acids, at -100 ° C to + 100 ° C, to give the compound of the formula (VIII) wherein PG, Y, R1 and R2 are as defined above.

5. - The process for preparing the intermediate compounds of the formula (VIII) according to claim 4, wherein the activator is iodine.

6. - The process for preparing the compounds of the formula (I) according to claims 1 to 3, wherein the meanings are Y H; R1 (C1-C4) alkyl, wherein one, more than one or all of the hydrogens may be replaced by fluorine; and R2 H.