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Classic Resolution of (4S) Tetralone

IP.com Disclosure Number: IPCOM000238020D
Publication Date: 2014-Jul-25
Document File: 4 page(s) / 133K

Publishing Venue

The IP.com Prior Art Database

Abstract

A method for resolving 4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-1(2H)-one into its enantiomers using classical methods involving the formation of diastereomers with different solubilities, and the extension of this process to include the isolation of the corresponding imine enantiomers, is described.

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Classic Resolution of (4S) Tetralone

Ajdin Kavara, David Erdman, Jana Deering

Pfizer Inc, Global Manufacturing Services Kalamazoo, Michigan

(4S) Tetralone 1 is an intermediate in the production of Sertraline/Zoloft. There are several published methods for producing (4S) tetralone, involving chromatographic

resolution of diastereomers1, chiral chromatography2 and enantioselective synthesis.3

A method for resolving tetralone 1 into its enantiomers using classical methods involving the formation of diastereomers with different solubilities, and the extension of this

process to include the isolation of the (4S) imine, is described.

O

Cl

(4S) Tetralone

1

One of the classes of diastereomeric compounds which could be formed from tetralone is a ketal with a chiral diol, hydroxy acid, or other similar ketal or aminal forming reagent. To this end, a series of ketal/aminal forming reagents were screened for their ability to form resolvable diastereomers of tetralone.

Introduction

Cl


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R2 R1

O

H

R2 R1

O

R2

O

R1

    O O

OH

Hydrolyze

+

H

+

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Resolve

    O O

1

The resolving agents tested were tartaric acid (and derivatives thereof), lactic acid, mandelic acid, aspartic acid, ascorbic acid, fructose and glucose. An NMR NOE study is used to confirm the geometry of the crystalline ketals/aminals.

Enol Ether Formation

The ketals could be readily formed by treating the enol ether of tetralone with the ketal forming reagent. The enol ether can be made by heating tetralone in the presence of an acid catalyst in an alcoholic solvent, toluene, MTBE, heptane or ethyl acetate with trimethyl, triethyl orthoformate or other similar dehydrating agent. Acids used include methanesulfonic acid, BF3, pyridinium hydrochloride or pyridinium p-toluenesulfonate. Some non-cyclic ketal was also formed in this process, this reacted similarly to the enol ether.

Ketal Formation

The ketal can be formed by combining the enol ether with the ketal forming reagent and an acid. The ketal can also be made directly from the tetralone. In this step the desired ketal diastereomer often crystallizes selectively from solution.

This step can be carried out in various solvents including ethers, esters, amides, alcohols, acids, alkyl, aromatic or mixtures thereof. Examples of these solvents include:


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acetonitrile, methyl tert-butyl ether, toluene, ethyl acetate, methyl carbonate, ethanol, methanol, dimethyl...