Method for the synthesis of 4-(heterocycloalkyl)-benzene-1,3,-diol compounds

Abstract

A method is described for the synthesis of 4-(heterocycloalkyl)-benzene-1,3-diol compounds of general formulae (I) and (II): ##STR00001##
wherein X can be an oxygen atom or a sulphur atom. Also described, is a method for the synthesis of the reactive intermediates of general formula (7a) or (7b) ##STR00002##
Novel compounds as synthesis intermediates are also described.

Claims

1. A method of synthesizing a 4-(heterocycloalkyl)-benzene-1,3-diol corresponding to general formula (I) ##STR00017## in which X is an oxygen atom or a sulphur atom, the method comprising reacting a compound corresponding to general formula (7a) ##STR00018## when X is an oxygen atom, with hydrogen in the presence of a palladium-based catalyst in polar solvent or, when X is a sulphur atom, with a reducing agent of a silicon hydride type and a Lewis acid in nonpolar solvent.

2. A method of synthesizing a 4-(heterocycloalkyl)-benzene-1,3-diol corresponding to general formula (II) ##STR00019## in which X is an oxygen atom or a sulphur atom, the method comprising reacting a compound corresponding to general formula (7b) ##STR00020## when X is an oxygen atom, with hydrogen in the presence of a palladium-based catalyst in polar solvent or, when X is a sulphur atom, with a reducing agent of a silicon hydride type and a Lewis acid in nonpolar solvent.

3. The method according to claim 1, wherein the polar solvent is selected from the group consisting of alcohols, carboxylic acids, esters, ethers, water, and a mixture thereof.

4. The method according to claim 3, wherein the alcohols are selected from the group consisting of methanol, ethanol and isopropanol.

5. The method according to claim 1, wherein the nonpolar solvent is dichloromethane or dichloro-1,2-ethane.

6. The method according to claim 1, wherein the palladium-based catalyst is selected from the group consisting of palladium on carbon, palladium hydroxide and palladium acetate.

7. The method according to claim 1, wherein the hydrogen pressure applied is from 1 bar to 10 bar.

8. The method according to claim 1, wherein the compound corresponding to the general formula (7a) ##STR00021## is obtained by reacting resorcinol with a heterocycloalkanone corresponding to general formula (3a) ##STR00022## in polar solvent and in the presence of a base.

9. The method according to claim 2, wherein the compound corresponding to the general formula (7b) ##STR00023## is obtained by reacting resorcinol with a heterocycloalkanone corresponding to general formula (3b) ##STR00024## in polar solvent and in the presence of a base.

10. The method according to claim 8, wherein the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide and metal alcoholates.

11. The method according to claim 10, wherein the base is sodium hydroxide or potassium hydroxide.

12. The method according to claim 8, wherein the polar solvent is selected from the group consisting of water and alcohols.

13. The method according to claim 12, wherein the polar solvent is water.

14. The method according to claim 8, wherein the resorcinol and the heterocycloalkanone (3a) is used in a resorcinol/heterocycloalkanone molar ratio of from 1 to 8.

15. A compound of general formula (7a) or (7b) ##STR00025## wherein X is an oxygen atom or a sulphur atom.

16. The compound according to claim 15, wherein the compound is 4-(4-hydroxy-tetrahydro-pyran-4-yl)-benzene-1,3-diol or 4-(3-hydroxyl-tetrahydro-pyran-3-yl)-benzene-1,3-diol.

17. The method according to claim 1, wherein X is an oxygen atom.

18. The method according to claim 2, wherein the polar solvent is selected from the group consisting of alcohols, carboxylic acids, esters, ethers, water, and a mixture thereof.

19. The method according to claim 2, wherein the nonpolar solvent is dichloromethane or dichloro-1,2-ethane.

20. The method according to claim 2, wherein the palladium-based catalyst is selected from the group consisting of palladium on carbon, palladium hydroxide and palladium acetate.

21. The method according to claim 2, wherein the hydrogen pressure applied is from 1 bar to 10 bar.

22. The method according to claim 9, wherein the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide and metal alcoholates.

23. The method according to claim 9, wherein the polar solvent is selected from the group consisting of water and alcohols.

24. The method according to claim 9, wherein the resorcinol and the heterocycloalkanone (3b) is used in a resorcinol/heterocycloalkanone molar ratio of from 1 to 8.

25. The method according to claim 3, wherein when the polar solvent is alcohol, the alcohol is methanol.

26. The method according to claim 3, wherein when the polar solvent is a carboxylic acid, the carboxylic acid is acetic acid.

27. The method according to claim 3, wherein the polar solvent is an ester, the ester is ethyl acetate.

28. The method according to claim 3, wherein the polar solvent is an ether, the ether is tetrahydrofuran.

29. The method according to claim 18, wherein the alcohols are selected from the group consisting of methanol, ethanol and isopropanol.

30. The method according to claim 22, wherein the base is sodium hydroxide or potassium hydroxide.

31. The method according to claim 23, wherein the polar solvent is water.

32. The method according to claim 10, wherein the base is sodium methanolate or potassium tert-butylate.

33. The method according to claim 22, wherein the base is sodium methanolate or potassium tert-butylate.

34. The method according to claim 12, wherein when the polar solvent is alcohol, the alcohol is selected from the group consisting of methanol, ethanol and isopropanol.

35. The method according to claim 18, wherein when the polar solvent is alcohol, the alcohol is methanol.

36. The method according to claim 18, wherein when the polar solvent is a carboxylic acid, the carboxylic acid is acetic acid.

37. The method according to claim 18, wherein the polar solvent is an ester, the ester is ethyl acetate.

38. The method according to claim 18, wherein the polar solvent is an ether, the ether is tetrahydrofuran.

Description

DESCRIPTION OF THE FIGURES

(1) FIG. 1: Preparation of compounds of formula (I) described in WO 2010/063773

(2) FIG. 2: Preparation of compounds of formula (II) described in WO 2010/063773

(3) FIG. 3: Process for the preparation of the compounds of the invention of formula (I)

(4) FIG. 4: Process for the preparation of the compounds of the invention of formula (II)

EXAMPLES

(5) The following examples are now presented in order to illustrate the process as described above. Said examples which illustrate the process of the invention are not limiting.

Example 1

When X=O: 4-(Tetrahydro-pyran-4-yl)-benzene-1,3-diol

a) 4-(4-Hydroxy-tetrahydro-pyran-4-yl)-benzene-1,3-diol

(6) In a 6-liter double-walled reactor, 550 g (5 mol, 4 eq) of resorcinol is loaded under nitrogen and then 1530 ml of 3 M sodium hydroxide solution is added while maintaining the temperature at 17° C. 125 g of tetrahydro-4-pyranon-4-one (1.25 mol, 1 eq) is added to the reaction mixture. The mixture is then stirred for 2 hours at room temperature and the progress of the reaction is checked using TLC plates (eluent: 2:1 heptane/AcOEt). The reaction is quenched by adding 2 M hydrochloric acid solution until a pH=7 (pH meter) is obtained. 830 g of NaCl is then added and the reaction mixture is stirred overnight at room temperature. The solid is filtered and then washed three times with 1 liter of water. The solid is drained and then dried under a vacuum at 50° C. overnight to yield 125 g of 4-(4-hydroxy-tetrahydro-pyran-4-yl)-benzene-1,3-diol as a crystalline white powder. Yield=48%.

(7) MP=152° C.

(8) .sup.1H NMR (DMSO D6, 400 MHz): 1.50 (m, 2H); 2.21 (m, 2H); 3.69 (m, 4H); 5.50 (br s, 1H); 6.20 (m, 2H); 7.16 (d, J=8 Hz, 1H); 6.82 (d, J=8.4 Hz, 1H); 8.95 (s, 1H); 9.11 (br s, 2H).

b) 4-(Tetrahydro-pyran-4-yl)-benzene-1,3-diol

(9) 100 g (0.47 mol) of 4-(4-hydroxy-tetrahydro-pyran-4-yl)-benzene-1,3-diol and then 100 ml of acetic acid and 10 g of 10% palladium on carbon are placed in a Parr reactor under nitrogen. 400 ml of THF is added and the reaction mixture is stirred for 5 hours under 5 bar of hydrogen at room temperature. The solution is then filtered on Clarcel, the Clarcel is washed with 250 ml of THF and then the filtrate is concentrated until a final volume of 150 ml is obtained. 50 ml of ethyl acetate is then added and the reaction mixture is stirred for 1 hour at 0° C. The solid is filtered, washed with an additional 50 ml of ethyl acetate and then dried under a vacuum to yield 84 g of 4-(tetrahydro-pyran-4-yl)-benzene-1,3-diol as a crystalline product. Yield=92%.

(10) MP=223° C.

(11) .sup.1H NMR (DMSO D6, 400 MHz): 1.54 (m, 4H); 2.92 (m, 1H); 3.39 (m, 2H); 3.90 (m, 2H); 6.14 (dd, J=8.4 and 2.4 Hz, 1H); 6.25 (d, J=2.4 Hz, 1H); 6.82 (d, J=8.4 Hz, 1H); 8.95 (s, 1H); 9.11 (s, 1H).

(12) .sup.13C NMR (DMSO D6, 100 MHz): 32.6, 33.5, 67.7, 102.3, 106.0, 122.4, 126.7, 155.2, 156.0.

Example 2

When X=S: 4-(Tetrahydro-thiopyran-4-yl)-benzene-1,3-diol

a) 4-(4-Hydroxy-tetrahydro-thiopyran-4-yl)-benzene-1,3-diol

(13) 13.43 g (0.115 mol, 1 eq) of tetrahydro-thiopyran-4-one suspended in 100 ml of water is added to a degassed mixture of 25.45 g (0.231 mol, 2.0 eq) of resorcinol solubilised in 115 ml (0.231 mol, 2.0 eq) of 2 N sodium hydroxide. The reaction mixture is stirred at room temperature for 2.5 hours. The reaction mixture is treated with 100 ml of 2 N hydrochloric acid solution (pH 5) and extracted with ethyl acetate. The organic phases are combined, dried over magnesium sulphate, filtered and evaporated. 40.88 g of yellow oil is obtained.

(14) Said oil is solubilised in 1 liter of dichloromethane and employed in the following step.

b) 4-(Tetrahydro-thiopyran-4-yl)-benzene-1,3-diol

(15) 55 ml (0.345 mol, 3 eq) of triethylsilane and then 44 ml (0.345 mol, 3 eq) of trifluoroborane etherate are added dropwise to a solution (0.115 mol, 1 eq) of crude 4-(4-hydroxy-tetrahydro-thiopyran-4-yl)-benzene-1,3-diol as obtained in the preceding step in 1 liter of dichloromethane. The reaction mixture is stirred at room temperature for 10 minutes. 400 ml of water is added to the reaction mixture followed by 250 ml of saturated sodium bicarbonate solution. The mixture is decanted and the aqueous phase is extracted with dichloromethane. The organic phases are combined, washed with water, dried over magnesium sulphate and concentrated. The insoluble material is filtered. 6.85 g of 4-(tetrahydro-thiopyran-4-yl)-benzene-1,3-diol is obtained as a white powder. Yield=28% from the two steps

(16) MP=171° C.

(17) .sup.1H NMR (DMSO D6, 400 MHz): 1.61 (m, 2H); 1.92 (m, 2H); 2.55 (m, 2H), 2.72 (m, 3H); 6.14 (dd, J=8.4 and 2.4 Hz, 1H); 6.25 (d, J=2.4 Hz, 1H); 6.80 (d, J=8.4 Hz, 1H); 8.95 (s, 1H); 9.10 (s, 1H).

(18) .sup.13C NMR (DMSO D6, 100 MHz): 28.7, 33.8, 35.6, 102.3, 106.0, 123.5, 126.7, 154.8, 156.0.

Example 3

When X=O: 4-(3-Hydroxy-tetrahydro-pyran-3-yl)-benzene-1,3-diol

a) 4-(3-Hydroxy-tetrahydro-pyran-3-yl)-benzene-1,3-diol

(19) 2.1 g (0.02 mol, 1 eq) of dihydro-pyran-3-one in solution in 2 ml of water is added dropwise to a degassed mixture of 8.8 g (0.08 mol, 4.0 eq) of resorcinol solubilised in 25 ml (0.075 mol, 3.7 eq) of 3 N sodium hydroxide. The reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is treated with 5 ml of concentrated hydrochloric acid solution (pH 7) and then 9 g of sodium chloride is added. The mixture is cooled in an ice bath and extracted with ethyl acetate. The organic phases are combined, dried over magnesium sulphate, filtered and evaporated. The residue is chromatographed on silica gel (AnaLogix SF40-150 g, Spot II column) and eluted with 80:20 and then 20:80 heptane/ethyl acetate. 2.91 g of 4-(3-hydroxy-tetrahydro-pyran-3-yl)-benzene-1,3-diol is obtained as a white amorphous solid. Yield=69%

b) 4-(Tetrahydro-pyran-3-yl)-benzene-1,3-diol

(20) A mixture of 2.9 g (0.14 mol, 1 eq) of 4-(3-hydroxy-tetrahydro-pyran-3-yl)-benzene-1,3-diol in 60 ml of ethyl acetate and 6 ml of methanol in the presence of 580 mg (20% by weight) of 10% palladium on carbon is stirred under 5 bar of hydrogen at room temperature for 5 hours and then heated at 50° C. for 24 hours (formation of 10% of the product). 580 mg (20% by weight) of 10% palladium on carbon is added and the reaction mixture is heated at 60° C. under 5 bar of hydrogen for 6 days. 580 mg (20% by weight) of 10% palladium on carbon is added and the reaction mixture is heated at 60° C. under 5 bar of hydrogen for 24 hours. The reaction mixture is filtered on filter paper and the filtrate is evaporated. The residue is chromatographed on silica gel (AnaLogix SF40-150 g, Spot II column) and eluted with 78:22 to 50:50 heptane/ethyl acetate. The oil obtained is crystallised in dichloromethane/heptane, filtered and dried under a vacuum at 40° C. 1.21 g of 4-(tetrahydro-pyran-3-yl)-benzene-1,3-diol is obtained as a white solid. (MP=148-149° C.). Yield=44%

(21) .sup.1H NMR (DMSO D6, 400 MHz): 1.54-1.77 (m, 4H); 2.94 (m, 1H); 3.12 (t, J=10.6 Hz, 1H); 3.30 (m, 1H), 3.75 (m, 1H); 3.81 (d, J=11 Hz, 1H); 6.15 (dd, J=8.4 and 2.4 Hz, 1H); 6.26 (d, J=2.4 Hz, 1H); 6.84 (d, J=8.4 Hz, 1H); 9.00 (s, 1H); 9.18 (s, 1H).

(22) .sup.13C NMR (DMSO D6, 100 MHz): 26.2; 28.8; 34.9; 67.2; 72.1; 102.3; 106.0; 119.0; 127.3; 155.6; 156.4.