Process for the synthesis of 7-methoxy-naphthalene-1-carbaldehyde and application in the synthesis of agomelatine

Abstract

Process for the industrial synthesis of the compound of formula (I): ##STR00001##

Claims

1. A process for the synthesis of a compound of formula (I): ##STR00008## wherein 7-methoxy-naphthalen-2-ol of formula (III): ##STR00009## is used for reaction, the formyl group being introduced at position 1 to yield a compound of formula (IV): ##STR00010## which compound of formula (IV) is subjected to a sulphonylation reaction to yield a compound of formula (V): ##STR00011## wherein R represents CH.sub.3, (CH.sub.2).sub.2CH.sub.3, CF.sub.3 or tolyl; which compound of formula (V) undergoes a deoxygenation reaction in the presence of a transition metal and a reducing agent to yield the compound of formula (I), which is isolated in the form of a solid.

2. The process according to claim 1, wherein R represents CH.sub.3 or tolyl.

3. The process according to claim 1, wherein the conversion of the compound of formula (IV) into the compound of formula (V) is carried out by means of the action of a sulphonyl chloride, a sulphonic anhydride or a sulphonimide.

4. The process according to claim 3, wherein the conversion of the compound of formula (IV) into the compound of formula (V) is carried out by means of the action of a sulphonyl chloride.

5. The process according to claim 1, wherein, in the conversion of the compound of formula (V) into the compound of formula (I), the transition metal is nickel, palladium or platinum.

6. The process according to claim 1, wherein, in the conversion of the compound of formula (V) into the compound of formula (I), the transition metal is a palladium salt.

7. The process according to claim 1, wherein the conversion of the compound of formula (V) into the compound of formula (I) is carried out in dimethylformamide, dioxane, tetrahydrofuran or toluene.

8. The process according to claim 7, wherein the conversion of the compound of formula (V) into the compound of formula (I) is carried out in dimethylformamide.

9. The process according to claim 1, wherein the conversion of the compound of formula (V) into the compound of formula (I) is carried out between 25 C. and 110 C.

10. The process according to claim 9, wherein the conversion of the compound of formula (V) into the compound of formula (I) is carried out between 40 C. and 95 C.

11. The process according to claim 1, wherein, in the conversion of the compound of formula (V) into the compound of formula (I), the reducing agent is dihydrogen.

12. The process according to claim 11, wherein the dihydrogen is obtained by decomposition of an ammonium formate.

13. The process according to claim 1, wherein the conversion of the compound of formula (V) into the compound of formula (I) is carried out in the presence of palladium and dihydrogen.

14. The process according to claim 1, wherein the conversion of the compound of formula (V) into the compound of formula (I) is carried out in the presence of (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) or 1,3-bis(diphenylphosphino)propane.

15. A compound of formula (V): ##STR00012## wherein R represents (CH.sub.2).sub.2CH.sub.3, CF.sub.3 or tolyl.

16. A process for the synthesis of agomelatine employing a compound of formula (V) ##STR00013## wherein R represents CH.sub.3, (CH.sub.2).sub.2CH.sub.3, CF.sub.3 or tolyl.

17. The compound according to claim 15, which is selected from the following compounds: 1-formyl-7-methoxynaphthalen-2-yl 4-methylbenzenesulphonate and 1-formyl-7-methoxynaphthalen-2-yl methanesulphonate.

18. A process for the synthesis of the compound of formula (I): ##STR00014## employing a compound of formula (V) ##STR00015## wherein R represents CH.sub.3, (CH.sub.2).sub.2CH.sub.3, CF.sub.3 or tolyl.

19. The process according to claim 18, wherein the process further comprises subjecting the compound of formula (I) to a series of reactions to provide agomelatine.

20. A process for the synthesis of a compound of formula (I) ##STR00016## employing a compound of formula (III): ##STR00017##

21. The process according to claim 20, wherein the process further comprises subjecting the compound of formula (I) to a series of reactions to provide agomelatine.

22. The process according to claim 16, wherein methoxy-naphthalen-2-ol of formula (III): ##STR00018## is used for reaction, and a formyl group is introduced at position 1 to yield a compound of formula (IV): ##STR00019## which compound of formula (IV) is subjected to a sulphonylation reaction to yield the compound of formula (V), which compound of formula (V) is subjected to a series of reactions to provide agomelatine.

Description

EXAMPLE 1: 7-METHOXYNAPHTHALENE-1-CARBALDEHYDE

Step A: 2-hydroxy-7-methoxynaphthalene-1-carbaldehyde

(1) 7-Methoxy-naphthalen-2-ol (3.5 g; 20.11 mmol), ethyl orthoformate (3.51 mL; 21.12 mmol) and aniline (1.83 mL; 20.11 mmol) are introduced into a flask equipped with a condenser. After stirring for 20 hours at reflux and cooling, the solid is ground in a 2M ethanolic solution of hydrochloric acid (20 mL). After stirring for 30 minutes at 60 C. and cooling, the solid is collected by filtration and then washed with water and dried by azeotropic distillation with ethanol and used directly without any other purification (2.95 g; 73%).

(2) .sup.1H NMR spectroscopic analysis (CDCl.sub.3, in ppm): 13.17 (s, 1H); 10.74 (s, 1H); 7.88 (d, J=9.1 Hz, 1H); 7.69 (d, J=8.9 Hz, 1H); 7.65 (d, J=2.4 Hz, 1H); 7.07 (dd, J=8.9 and 2.4 Hz, 1H); 6.97 (d, J=9.1 Hz, 1H); 3.95 (s, 3H).

Step B: 1-formyl-7-methoxynaphthalen-2-yl 4-methylbenzenesulphonate

(3) To a solution of the product of Step A above (1 g; 4.95 mmol) in dichloromethane (20 mL) there are added triethylamine (826 L; 5.94 mmol) and tosyl chloride (0.99 g; 5.2 mmol). After stirring for 24 hours, the solvent is evaporated off and then the residue is taken up in a mixture of water/ethyl acetate. The organic phase is washed with a dilute solution of hydrochloric acid, water and brine, and then dried over sodium sulphate and filtered. Evaporating off the solvents results in a crude product, which is purified by recrystallised from hot ethyl acetate to yield the title product (1.132 g; 65%).

(4) Melting point: 147-148 C.

(5) .sup.1H NMR spectroscopic analysis (CDCl.sub.3, in ppm): 10.41 (s, 1H); 8.68 (d, J=2.6 Hz, 1H); 7.95 (d, J=8.9 Hz, 1H); 7.74 (d, J=8.2 Hz, 2H); 7.72 (d, J=8.9 Hz, 1H); 7.33 (d, J=8.2 Hz, 2H); 7.19 (dd, J=8.9 and 2.6 Hz, 1H); 7.15 (d, J=8.9 Hz, 1H); 3.93 (s, 3H); 2.45 (s, 3H).

(6) .sup.13C NMR spectroscopic analysis (CDCl.sub.3, in ppm): 190.3 (d); 161.5 (s); 154.3 (s); 146.4 (s); 136.4 (d); 132.8 (s); 131.5 (s); 130.3 (2d); 129.9 (d); 128.6 (2d); 127.8 (s); 121.5 (s); 120.1 (d); 118.6 (d); 104.1 (d); 55.6 (q); 21.9 (q).

Step C: 7-methoxynaphthalene-1-carbaldehyde

(7) The product of Step B above (356 mg; 1 mmol), palladium acetate (4.5 mg; 0.02 mmol), 1,3-bis(diphenylphosphino)propane (8.2 mg; 0.02 mmol), dimethylformamide (2 mL), triethylamine (556 L; 4 mmol) and formic acid (150 L; 4 mmol) are introduced into a flask placed in an oven and purged with argon. The flask is placed in a bath heated to 90 C. for 1.5 hours. After cooling, the mixture is diluted with ethyl acetate and the organic phase is washed with 1M aqueous hydrochloric acid solution and with brine, dried over sodium sulphate and filtered. After evaporating off the solvent, the crude product is purified by filtration over neutral alumina to yield the title product (139 mg; 75%).

(8) Melting point: 65-67 C.

(9) .sup.1H NMR spectroscopic analysis (CDCl.sub.3, 300.13 MHz, in ppm): 10.29 (s, 1H); 8.75 (d, J=2.6 Hz, 1H); 7.99 (d, J=8.1 Hz, 1H); 7.9 (d, J=7.1 Hz, 1H); 7.77 (d, J=8.9 Hz, 1H); 7.45 (dd, J=8.1 and 7.1 Hz, 1H); 7.23 (dd, J=8.9 and 2.6 Hz, 1H); 3.98 (s, 3H).

(10) .sup.13C NMR spectroscopic analysis (CDCl.sub.3, 75.5 MHz, in ppm): 194.1 (d); 160.7 (s); 138.3 (d); 135.1 (d); 132.2 (s); 130.2 (s); 129.9 (d); 129.3 (s); 122.5 (d); 119.8 (d); 103.6 (d); 55.6 (q).

EXAMPLE 2: 7-METHOXYNAPHTHALENE-1-CARBALDEHYDE

Step A: 1-formyl-7-methoxynaphthalen-2-yl methanesulphonate

(11) To a solution of the compound obtained in Step A of Example 1 (300 mg; 1.485 mmol) in dichloromethane (5 mL) there are added triethylamine (250 L; 1.782 mmol) and mesyl chloride (120 L). After stirring for one hour, the solvent is evaporated off and the residue is taken up in a mixture of ethyl acetate/water. The organic fraction is washed twice with water and then with brine, dried over sodium sulphate and filtered. Evaporating off the solvent yields the clean title product (416 mg; 95%) without the need for purification.

(12) .sup.1H NMR spectroscopic analysis (CDCl.sub.3, in ppm): 10.74 (s, 1H); 8.72 (d, J=2.4 Hz, 1H); 8.03 (d, J=8.9 Hz, 1H); 7.75 (d, J=8.9 Hz, 1H); 7.36 (d, J=8.9 Hz, 1H); 7.22 (dd, J=8.9 and 2.4 Hz, 1H); 3.97 (s, 3H); 3.32 (s, 3H).

(13) .sup.13C NMR spectroscopic analysis (CDCl.sub.3, in ppm): 190.4 (d); 161.6 (s); 153.2 (s); 136.8 (d); 133.1 (s); 130.0 (d); 128.0 (s); 121.6 (s); 120.3 (d); 118.2 (d); 104.0 (d); 55.7 (q); 38.5 (q).

Step B: 7-methoxynaphthalene-1-carbaldehyde

(14) The title product (84%) is obtained in accordance with the process described in Step C of Example 1 starting from the product of Step A above and with a reaction time of 4 hours at 90 C. instead of 1.5 hours.

(15) Melting point: 65-67 C.

(16) .sup.1H NMR spectroscopic analysis (CDCl.sub.3, 300.13 MHz, in ppm): 10.29 (s, 1H); 8.75 (d, J=2.6 Hz, 1H); 7.99 (d, J=8.1 Hz, 1H); 7.9 (d, J=7.1 Hz, 1H); 7.77 (d, J=8.9 Hz, 1H); 7.45 (dd, J=8.1 and 7.1 Hz, 1H); 7.23 (dd, J=8.9 and 2.6 Hz, 1H); 3.98 (s, 3H).

(17) .sup.13C NMR spectroscopic analysis (CDCl.sub.3, 75.5 MHz, in ppm): 194.1 (d); 160.7 (s); 138.3 (d); 135.1 (d); 132.2 (s); 130.2 (s); 129.9 (d); 129.3 (s); 122.5 (d); 119.8 (d); 103.6 (d); 55.6 (q).

EXAMPLE 3: 7-METHOXYNAPHTHALENE-1-CARBALDEHYDE

(18) Sodium hydride (60%; 17 mg; 0.415 mmol) is added, in several portions, to a solution of 7-methoxy-naphthalen-2-ol (70 mg; 0.35 mmol) in anhydrous dimethylformamide (1 mL) in a flask purged with argon. After stirring for 30 minutes at ambient temperature, tosyl chloride is then added in several portions (190.5 mg; 0.36 mmol). After stirring for 4 hours at ambient temperature, 1,3-bis(diphenylphosphino)propane (7.1 mg; 0.017 mmol), palladium acetate (3.9 mg; 0.073 mmol), triethylamine (192 L; 1.38 mmol) and formic acid (150 L; 4 mmol) are added and the reaction mixture is heated at 90 C. for 1.5 hours. After cooling, the mixture is diluted with ethyl acetate and the organic phase is washed with 1M aqueous hydrochloric acid solution and then with brine, dried over sodium sulphate and filtered. After evaporating off the solvent, the crude product is filtered over neutral alumina (eluant: ethyl acetate) to yield the title product (61.6 mg; 95%).

(19) Melting point: 65-67 C.