GB2290790A

GB2290790A - Asymmetric synthesis of 6-substituted 2-amino-1,2,3,4-tetrahydronaphthalenes

Info

Publication number: GB2290790A
Application number: GB9512632A
Authority: GB
Inventors: Ulf H Dolling; Lisa F Frey; Yao-Jun Shi; David M Tschaen
Original assignee: Merck and Co Inc
Current assignee: Merck and Co Inc
Priority date: 1994-06-30
Filing date: 1995-06-21
Publication date: 1996-01-10
Also published as: GB9512632D0

Abstract

An asymmetric synthesis of tetrahydronaphthalene analogues of formula <IMAGE> (where R4 is halogen, hydroxy or cyano) comprises, in order, the steps of a) mesylating an alcohol of the formula <IMAGE> b) converting the mesylate to the azide; and c) reducing the azide. Such amines are important intermediates in the production of antiarrhythmic agents.

Description

TITLE OF THE INVENTION ASYMMETRIC SYNTHESIS OF TETRAHYDRONAPHTHALENE ANALOGS BACKGROUND OF THE INVENTION Spirocycles of general structural Formula I:

where R1 is selected from the group consisting of acyl such as CO-C 1-3 alkyl, cyano, carboxy, carboxy C 1-6 alkyl ester, carboxamide, C 1-6 alkyl sulfinyl, C1-6 alkyl sulfonyl, C1-6 methanesulfonamide and halogen; R2 is selected from the group consisting of keto or alcohol, R3 is cyano, are compounds which are Class III antiarrhythmic agents.

Antiarrhythmic agents of Class III are drugs which cause a selective prolongation of the duration of the action potential without a significant depression of the Vmax. Drugs in this class are limited.

Examples such as sotalol and amiodarone have been shown to possess Class III properties. Sotalol also possesses Class II effects which may cause cardiac depression and be contraindicated in certain susceptible patients. Also, amiodarone is severely limited by side effects. Drugs of this class are expected to be effective in preventing ventricular fibrillation. Pure Class III agents, by definition, are not considered to cause myocardial depression or an induction of arrhythmia due to the inhibition of the action potential conduction as seen with Class I antiarrhythmic agents.

In order to prepare these compounds, it is necessary to synthesize 2-amino tetralins of the formula

where R4 is halogen, hydroxy or cyano, which are important intermediates in the production of these antiarrhythmic agents.

These novel intermediates have previously been synthesized through a racemic approach which required resolution in order to obtain the desired enantiomer. Low yields were obtained in this approach.

SUMMARY OF THE INVENTION A novel process for the synthesis of the compound of the formula

and analogs thereof comprising in order the steps of reacting 2-hydroxy6-bromo tetralin of the formula

with mesyl chloride and triethylamine; reacting the mesylate formed with sodium azide to produce (R)-2-azido-6-bromo tetralin of the formula

which is reacted with triphenylphosphine or other suitable reducing agent to produce (R)-2-amino-6-bromo tetralin.

The term halogen shall mean bromine, chlorine, fluorine or iodine.

The starting chiral alcohol is obtained via bioconversion of 6-bromo-ss-tetralone of the formula

The (R)-2-amino-6-bromo tetralin can subsequently be reacted with a compound of the formula

to afford a compound of the formula

which is a key intermediate in the synthesis of the spirocycles discussed in the background.

DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to a novel process of synthesizing tetrahydronaphthalene analogs of the formula

where R4 is halogen, hydroxy or cyano, which are important intermediates in the synthesis of spirocyclic compounds which are Class III antiarrhythmic agents.

The following reaction scheme show the sequence of steps involved in this novel process. The reaction scheme illustrates the steps employing R4 = Br.

Preparation of Compound 1 is disclosed in copending application Serial No 08/075,196 filed June 10, 1993. 4-bromophenylacetic acid of the formula

is dissolved in methylene chloride and dimethylformamide under nitrogen. Oxalyl chloride is added and the mixture is stirred under a positive nitrogen atmosphere to produce 4-bromophenylacetyl chloride at a yield which is typically better then 99%.

The acid chloride is subsequently reacted with AlCl3 to produce the aluminum addition salt. Ethylene gas is then added and the addition and ring closure reactions are allowed to proceed until approximately 2% of the starting material remains. The reaction is then quenched with the addition of cold water (OOC).

Compound 1, 6-bromo--tetralone, subsequently undergoes bioconversion, to obtain Compound 2, (S)-2-hydroxy-6-bromo tetralin.

Compound 2 is treated with mesyl chloride and triethylamine in dichloroethane or other suitable solvent at a temperature of about 0 to 5"C for 1 to 1.5 hours. The mesyl chloride is added at a rate as to maintain the temperature of the reaction mixture below 5"C. The starting material was completely consumed as shown by HPLC and NMR. The mixture was diluted with CH2Cl2, washed with NaHCO3 and brine. After drying, the organic layer is evaporated in vacuo to afford the solid product, Compound 3, in high yield.

Compound 3, the mesylate, can subsequently be transformed to the azide via a reaction well known in the literature. This reaction has been shown to proceed with inversion of the configuration from (S) to (R). The reaction mixture containing the mesylate and sodium azide in DMSO was heated at 500C for 3 1/2 hours at which time HPLC showed complete consumption of the starting material. The reaction was quenched and diluted with methylene chloride. The organic layer is separated and washed. After drying and filtration of the drying agent (e.g. sodium sulfate), the solvent is evaporated in vacuo leaving the azide in good yield.

The azide, Compound 4, can be reduced to the desired amine, Compound 5, by any of the numerous methods known. For example, the azide can be reduced with triphenylphosphine in THF.

Alternatively, the reduction can be carried out with platinum oxide or other suitable noble metal catalyst in an alcoholic solvent such as ethanol.

EXAMPLES The following examples are for illustrative purposes and are not to be construed as limiting the invention described and claimed herein. All temperatures are given in degrees centigrade ("C) unless otherwise noted.

EXAMPLE 1 Mesvlation of the alcohol

30.6 g of (S)-2-hydroxy-6-bromo tetralin was treated with 12.5 ml of mesyl chloride and 28.2 ml of triethylamine in 140 ml dichloromethane at OOC. The mesyl chloride was added at a rate to maintain the mixture below 50C. HPLC and NMR showed that the starting material was completely consumed in 1 1/4 hours. The reaction mixture was diluted with additional dichloromethane, washed three times with 200 ml of NaHCO3 and then with brine. After drying over sodium sulfate, the organic layer was evaporated in vacuo to afford 37 g of the mesylate, as a solid, in 90% yield.

EXAMPLE 2 Preparation of the azide

3.00 g of the mesylate with 6.40 g of sodium azide in 200 ml DMSO was heated at 50"C for 3 1/2 hours. The starting material was determined to be completely consumed by HPLC. The reaction was quenched with a 50% saturated NaCl solution and extracted into methylene chloride. The organic layer was separated and washed three times with sodium bicarbonate and once with brine. After drying over sodium sulfate, the sodium sulfate was filtered off and the solvent evaporated in vacuo. NMR indicated the presence of 5-6% of the elimination product 6-bromo-3,4-dihydronaphthalene. The yield of the azide was 2.2 g (89%).

EXAMPLE 3 Reduction of the azide

1.0 g of Compound 4, with 1.15 g triphenylphosphine, 0.1 ml of water in 40 ml of THF is heated at 400C for about 10 hours.

The starting material was determined to be completely consumed by HPLC at this time. 1 ml of 50% aq. NaOH and 1 ml H2O were added and the mixture was heated to 40"C for 24 hours, Silica gel chromatography using (95:5:0.5) CH2Cl2:Methanol:NH4OH afforded 0.70 g (78%) of Compound 5 after removal of solvent under vacuum.

150 ml of ethanol was added to 15.0 g of Compound 4.

Platinum oxide (1.5 g) was added and the batch was hydrogenated (1 atm. H2, 25"C) for five hours. The platinum was removed by filtration. The solvent was removed by distillation under vacuum to give 11.7 g (87%) of Compound 5.

Claims

WHEAT IS CLAIMED IS:

1. A process for the synthesis of a compound of the formula

where R4 is halogen, hydroxy or cyano, which comprises in order the steps of a) mesylating an alcohol of the formula

b) converting the mesylate to the azide; and c) reducing the azide.

2. The process as claimed in Claim 1 wherein the alcohol is mesylated using mesyl chloride.

3. The process as claimed in Claim 1 wherein the mesylate is converted to the azide by reaction with sodium azide.

4. The process as claimed in Claim 1 wherein the azide is reduced by employing triphenylphosphine, a noble metal catalyst or Raney nickel.

5. A process for the synthesis of the compound of the formula

which comprises in order the steps of a) mesylating an alcohol of the formula

b) converting the mesylate to an azide of the formula

c) reducing the azide.

6. The process as claimed in Claim 5 wherein the azide is reduced using triphenylphosphine or platinum oxide.