PROCESS FOR MANUFACTURING 1-CYCLOPROPYL-NAPHTHALENES

Abstract

A process for preparing 1-cyclopropyl-naphthalene derivatives of Formula (1) wherein R.sub.1-R.sub.7 are independently hydrogen, alkyl, alkoxy, cycloalkyl or aryl comprising the steps of a) contacting an acid salt of a 1-naphthyl-2-aminoethylketone with a base and a first solvent to obtain a solution wherein the molar ratio of base to 1-naphthyl-2-aminoethylketone acid salt is at least 0.7, b) addition of hydrazine to obtain a 3-(1-naphthyl)-1H-pyrazoline, c) optionally adding a second solvent and/or at least partially removing the first solvent, and d) heating the reaction mixture to a temperature above 190 C. to obtain the compound of Formula (1).

##STR00001##

Claims

1. A process for preparing a compound of Formula (1) ##STR00007## wherein R.sub.1-R.sub.7 are independently hydrogen, alkyl, alkoxy, cycloalkyl or aryl comprising the steps of a) contacting a compound of Formula (2) ##STR00008## wherein R.sub.1-R.sub.7 are the same as above and R.sub.8 and R.sub.9 are independently hydrogen, C.sub.1-C.sub.8 alkyl and X is a counter acid, with a base and a first solvent to obtain a solution wherein the molar ratio of base to compound of Formula (2) is at least 0.7; b) addition of hydrazine to obtain a compound of Formula (3) ##STR00009## wherein R.sub.1-R.sub.7 are the same as above; c) optionally adding a second solvent and/or at least partially removing the first solvent; and d) heating the reaction mixture to a temperature above 190 C. to obtain the compound of Formula (1).

2. A process for preparing a compound of Formula (3) ##STR00010## wherein R.sub.1-R.sub.7 are the same as defined above for the compound of Formula (1), comprising the steps of a) contacting a compound of Formula (2) ##STR00011## wherein R.sub.1-R.sub.7, R.sub.8, R.sub.9 and X are the same as above for the compound of Formula (2), with a base and a solvent to obtain a solution wherein the molar ratio of base to compound of Formula (2) is at least 0.7; and b) adding hydrazine to obtain the compound of Formula (3).

3. Process according to claim 1, wherein compound of Formula (2) is prepared from 1-acetylnaphthalene.

4. Process according to claim 1, wherein the molar ratio is from 0.95-1.1.

5. Process according to claim 1, wherein water is removed from the resulting solution of step a.

6. Process according to claim 1, wherein R.sub.1-R.sub.7 are hydrogen.

7. Process according to claim 1, wherein R.sub.8 and R.sub.9 are methyl.

8. Process according to claim 1, wherein the molar ratio of hydrazine to compound of Formula (2) is between 0.90-1.05.

9. Process according to claim 1, wherein the first solvent is selected from the group consisting of triethylene glycol, sulfolan, propylene carbonate, ethylene glycol, diethylene glycol, methyl tert.-butyl ether, dimethylformamide, dimethylacetamide and chinolin.

10. Process according to claim 1, wherein the first solvent is capable of forming an azeotrope with compound of Formula (1).

11. An azeotrope comprising a solvent and a compound of Formula (1).

12. The azeotrope according to claim 11, wherein the solvent is triethylene glycol.

13. A process for synthesizing a pharmaceutically active compound by converting a compound of Formula (2). ##STR00012## to a compound of Formula (2a) ##STR00013## which further is converted to a compound of Formula (3), ##STR00014## which further is converted to a compound of Formula (1), ##STR00015## and subsequently converting the compound of Formula (1) into the pharmaceutically active compound.

14. A process according to claim 1 for synthesizing a pharmaceutically active compound by further converting the compound of Formula (1) to obtain the pharmaceutically active compound.

Description

EXAMPLES 1-10: PREPARATION OF 1-CYCLOPROPYL-NAPHTHALENE FROM 3-DIMETHYLAMINO-1-(NAPHTHALEN-1-YL)PROPAN-1-ONE HYDROCHLORIDE

General Procedure:

[0050] 3-dimethylamino-1-(naphthalen-1-yl)propan-1-one hydrochloride (50 g, E1 equivalents) and triethylene glycol (100 ml) were charged to the reactor at room temperature. 50% NaOH (E2 equivalents) was added while keeping the internal temperature at room temperature. 64% hydrazine solution in water (E3 equivalents) was added dropwise followed by heating the reaction mixture to a temperature of 805 C. for a period of 5 hours. Thereafter, water was distilled off in a vacuum of 30-40 mbar at a temperature of 805 C. The precipitated salt was separated from the reaction mixture by filtration at a temperature of approximately 80 C. and subsequently washed with triethylene glycol brought to a temperature of approximately 80 C. (20 Vol % of the total amount of triethylene glycol).

[0051] Bringing the reaction mixture to a temperature of 20010 C. for a period of about 5 hours gave crude 1-cyclopropyl-napthalene which was isolated by azeotropic distillation at a temperature of 19010 C. in a vacuum of 30-40 mbar. For further purification and isolation of the obtained product water was added to the distillate and the product extracted with methyl tert.-butyl ether. The organic phase was washed with water and distilled in a vacuum of 50-100 mbar at a temperature of 80 C.

[0052] The isolated pure 1-cyclopropyl-naphtalene was obtained as clear, colorless or pale yellow liquid with a boiling point of 152 C. at 13 Torr.

TABLE-US-00001 TABLE 1 %-Yield and purity of 1-cyclopropyl-napthalene by variation of input parameters (equivalents E1-E3) applying standard work up procedure 1-Methylnapthalene 1-cyclopropyl-napthalene (side product) Example Nr. E1 E2 E3 purity (HPLC a %) %-yield content (HPLC a %) 1 1.0 1.0 1.0 98.1 80 <0.05 2 1.0 1.0 1.1 97.6 79 <0.05 3 1.0 0.9 1.0 96.5 68 0.16 4 1.0 1.1 1.0 97.8 70 0.35 5 1.0 0.9 1.1 92.6 78 2.81 6 1.0 1.1 0.9 98.3 65 <0.05 7 1.0 1.0 0.95 98.0 82 <0.05 8 1.0 1.0 1.05 98.1 91 <0.05 9 1.0 1.05 1.05 97.7 83 0.42 10 1.0 0.95 0.95 96.1 60 <0.05

[0053] All examples according to the invention result in a high yield (greater or equal to 60%) in combination with a high purity (>90%).

COMPARATIVE EXAMPLE A: PREPARATION OF 1-CYCLOPROPYL-NAPHTHALENE FROM 3-DIMETHYLAMINO-1-(NAPHTHALEN-1-YL)PROPAN-1-ONE HYDROCHLORIDE BY OMITTING THE ADDITION OF BASE AND RAISING THE AMOUNT OF ADDED HYDRAZINE

[0054] 3-dimethylamino-1-(naphthalen-1-yl)propan-1-one hydrochloride (50 g, 1.00 equiv.) and triethylene glycol (100 ml) were charged to the reactor at room temperature. 64% hydrazine solution in water (19 g, 2.00 equiv.) was added dropwise while keeping the internal temperature at room temperature. Subsequently the reaction mixture was heated to a temperature of 80-85 C. for a period of 5 hours. Thereafter, water was distilled off in a vacuum of 30-40 mbar at a temperature of 80-85 C. The precipitated salt was separated from the reaction mixture by filtration at room temperature and subsequently washed with triethylene glycol at room temperature (20 vol % of the total amount of triethylene glycol).

[0055] Bringing the reaction mixture to a temperature of 200-210 C. for a period of 5 hours gave crude 1-cyclopropyl-napthalene which was isolated by azeotropic distillation at a temperature of 180-200 C. in a vacuum of 30-40 mbar. For further purification and isolation of the obtained product water was added to the distillate and the product extracted with methyl tert-butyl ether. The organic phase was washed with water and distilled in a vacuum of 6 mbar at a temperature of 50 C.

[0056] The isolated pure 1-cyclopropyl-naphtalene was obtained as clear pale yellow liquid.

TABLE-US-00002 1-cyclopropyl- napthalene 1-Methylnapthalene purity %- (side product) Example Nr. E1 E2 E3 (HPLC a %) yield content (HPLC a %) Comp. 1.0 0 2.0 85.7 80 4.24 Example A