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## comprising the steps of a) contacting a compound of Formula (2) ##STR00008## with a base and a first solvent to obtain a solution wherein a molar ratio of base to compound of Formula (2) is at least 0.7 and at most 1.3, wherein the first solvent is selected from the group consisting of triethylene glycol, sulfolane, propylene carbonate, ethylene glycol, diethylene glycol, methyl tert-butyl ether, dimethylformamide, dimethylacetamide and quinoline; b) addition of hydrazine to the solution to obtain a compound of Formula (3) ##STR00009## c) adding a second solvent that is different from the first solvent to the solution and/or at least partially removing the first solvent from the solution thereby obtaining a reaction mixture; and d) heating the reaction mixture to a temperature above 190 C. in the absence of a catalyst to obtain the compound of Formula (1), wherein the steps b) and c) are optionally performed concurrently; and wherein R.sub.1-R.sub.7 are independently hydrogen or C.sub.1-8 alkyl, C.sub.1-6 alkoxy, C.sub.3-6 cycloalkyl or C.sub.5-10 aryl, R.sub.8 and R.sub.9 are independently hydrogen or C.sub.1-8 alkyl; and X is a counter ion.

2. The process according to claim 1, wherein a molar ratio of base to compound of Formula (2) in the step a) is from 0.95-1.1.

3. The process according to claim 1, wherein water is removed from the solution obtained in the step a).

4. The process according to claim 1, wherein R.sub.1-R.sub.7 are hydrogen.

5. The process according to claim 1, wherein R.sub.8 and R.sub.9 are methyl.

6. The process according to claim 1, wherein a molar ratio of hydrazine to compound of Formula (2) in the step b) is between 0.90-1.05.

7. The process according to claim 1, wherein triethylene glycol as the first or the second solvent is capable of forming an azeotrope with the compound of Formula (1).

8. The process according to claim 1, wherein the steps b) and c) are performed concurrently.

9. The process according to claim 1, wherein the second solvent is a polar solvent.

Description

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

(1) General Procedure:

(2) 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).

(3) 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.

(4) 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.

(5) 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

(6) 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

(7) 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).

(8) 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.

(9) The isolated pure 1-cyclopropyl-naphtalene was obtained as clear pale yellow liquid.

(10) 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