Method of synthesising 4-piperidin-4-yl-benzene-1,3-diol and the salts of same and novel compound tert-butyl 4-(2,4-dihydroxy-phenyl)-4-hydroxy-piperidine-1-carboxylate

Abstract

A method is described for the synthesis of 4-piperidin-4-yl-benzene-1,3-diol of the following formula (I): ##STR00001##
and the pharmaceutically acceptable salts thereof. Also described, is tert-butyl 4-(2,4-dihydroxy-phenyl)-4-hydroxy-piperidine-1-carboxylate as a novel intermediate compound ##STR00002##

Claims

1. A method of synthesizing 4-piperidin-4-yl-benzene-1,3-diol corresponding to general formula (I) and salts thereof ##STR00022## the method comprising: (1) reacting resorcinol with azacycloalkanone of formula (9) ##STR00023## in the presence of a base and in a polar solvent to obtain a compound corresponding to general formula (10) ##STR00024## (2) reacting the compound corresponding to general formula (10) obtained in step (1) with hydrogen in the presence of a palladium-based catalyst in polar solvent and then reacting the obtained product with an inorganic or organic acid.

2. 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.

3. The method according to claim 2, wherein the alcohols are selected from the group consisting of methanol, ethanol and isopropanol.

4. The method according to claim 1, wherein the polar solvent is selected from the group consisting of water and alcohols.

5. The method according to claim 1, wherein the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, and metal alcoholates.

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 resorcinol and the azacycloalkanone (9) are used in a resorcinol/azacycloalkanone molar ratio from 1 to 8.

9. The method according to claim 2, wherein when the solvent is an alcohol, the alcohol is methanol.

10. The method according to claim 2, wherein when the solvent is a carboxylic acid, the carboxylic acid is acetic acid.

11. The method according to claim 2, wherein when the solvent is an ester, the ester is ethyl acetate.

12. The method according to claim 2, wherein when the solvent is an ether, the ether is tetrahydrofuran.

13. The method according to claim 4, wherein when the polar solvent is an alcohol, it is selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, and tert-butanol.

14. The method according to claim 5, wherein when the base is selected from the group consisting of sodium methanolate, sodium tert-butylate, potassium tert-butylate and lithium tert-butylate.

Description

DESCRIPTION OF THE FIGURES

(1) FIG. 1: Preparation of compounds of the formula (II) described in WO 2010/063774

(2) FIG. 2: Preparation of compounds of the formula (III) described in WO 2011/070080

(3) FIG. 3: Process for preparing the compounds of the invention of the formula (I) and salts thereof.

EXAMPLES

(4) 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

4-Piperidin-4-yl-benzene-1,3-diol hydrochloride

Step 1

4-(2,4-Dihydroxy-phenyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester

(5) In a 4 liter reactor equipped with a mechanical stirrer and a thermometer, resorcinol (371.25 g) is placed in tert-butanol (2 L) at room temperature. To this heterogeneous mixture is then added potassium tert-butylate (378.0 g) over 5 min. The temperature increases to 55 C. and the reaction mixture becomes black. The reaction is stirred for 30 min allowing the mixture to cool to 38 C. Next, tert-butyl carboxylate (167.9 g) is added to the reaction mixture over 2 to 3 minutes. The addition is endothermic, lowering the temperature to 35 C. The reaction is then stirred for 1 hour until room temperature is reached. The reaction mixture is then added to a solution of NaH.sub.2PO.sub.4 (700 g) in water (5 l) and the aqueous phase is then extracted with 4 liters of an ethyl acetate/heptane (1:1) mixture. The organic phase is separated and washed with water (105 l). This operation is carried out until the resorcinol of the aqueous phase completely disappears (checked by TLC). The organic phase is then dried over Na.sub.2SO.sub.4 and the solvents are evaporated to yield 263 g of residue. The residue is dissolved in a minimum of dichloromethane and filtered on a silica gel patch using an ethyl acetate/heptane (1:1) mixture. After evaporation of the solvent (concentration), a solid begins to crystallise slowly. After 30 minutes, 117 g of tert-butyl 4-(2,4-dihydroxy-phenyl)-4-hydroxy-piperidine-1-carboxylate is obtained.

(6) (Yield=45%).

(7) .sup.1H NMR (DMSO D6, 400 MHz): 1.40 (s, 9H); 1.52 (d, J=12.8 Hz, 2H); 2.10 (m, 1H); 3.08 (br s, 2H); 3.79 (br s, 2H); 5.35 (br s, 1H); 6.17 (dd, J=2.4 Hz, 8.3 Hz, 1H); 6.21 (d, J=2.4 Hz, 1H); 7.08 (d, J=8.2 Hz, 1H); 9.09 (br s, 1H); 9.47 (br s, 1H).

Step 2

4-Piperidin-4-yl-benzene-1,3-diol hydrochloride

(8) In a 1 liter hydrogenation reactor, 70 g of tert-butyl 4-(2,4-dihydroxy-phenyl)-4-hydroxy-piperidine-1-carboxylate (0.226 mol) is dissolved in 500 ml of glacial acetic acid with 4 g of 10% palladium on carbon (Pd/C) and the mixture is hydrogenated at 5 bar and 35 C. for 3 hours. During hydrogenation, the temperature increases to 65 C. After 3 hours, 500 ml of ethyl acetate is added to the reaction mixture and the solution is filtered on Celite. On said filtrate, 150 ml of a 4 M solution of HCl dissolved in ethyl acetate is then added dropwise and after 2 hours of stirring the precipitate formed is filtered, yielding 36 g of 4-piperidin-4-yl-benzene-1,3-diol hydrochloride as white crystals.

(9) Yield=69%

(10) .sup.1H NMR (DMSO D6, 400 MHz): 1.80 (m, 4H); 2.92 (m, 3H); 3.28 (d, J=12 Hz, 2H); 6.18 (dd, J=2.4 Hz, 8.3 Hz, 1H); 6.34 (d, J=2.4 Hz, 1H); 6.77 (d, J=8.2 Hz, 1H); 8.93 (br s, 1H); 9.10 (br s, 1H); 9.36 (s, 1H).

(11) .sup.13C NMR (DMSO D6, 100 MHz): 28.3; 32.4; 43.8; 102.5; 106.1; 121.1; 126.5; 155.3; 156.5.