Process for the manufacture of 4-(6-bromohexyloxy)-butylbenzene

Details Process for the manufacture of 4-(6-bromohexyloxy)-butylbenzene Process for the manufacture of 4-(6-bromohexyloxy)-butylbenzene

2003-03-04

2004-12-28

Keys, Rosalynd (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Oxygen containing

Reexamination Certificate

active

06835857

ABSTRACT:

The present invention relates to an improved process for the manufacture of 4-(6-bromohexyloxy)-butylbenzene by reacting 4-phenylbutanol with 1,6-dibromohexane in the presence of a base and a phase transfer catalyst, and the use of the 4-(6-bromohexyloxy)-butylbenzene thus prepared for producing salmeterol in a method known per se.
BACKGROUND TO THE INVENTION
4-(6-Bromohexyloxy)-butylbenzene is a valuable intermediate product for preparing the active substance salmeterol, which is used as a bronchodilator for treating asthma or chronic bronchitis.
According to the teaching of German patent application DE 34 14 752, 4-(6-bromohexyloxy)-butylbenzene is obtained by reacting 4-phenylbutanol with 1,6-dibromohexane with a sodium hydride dispersion as base. For safety reasons it is not really possible to carry out production on an industrial scale using sodium hydride dispersions.
European patent application EP 1 132 373 describes a laboratory process for producing 4-(6-bromohexyloxy)-butylbenzene in which a mixture consisting of 4-phenylbutanol, 1,6-dibromohexane, potassium hydroxide and tetrabutyl ammonium hydrogen sulphate is stirred for 20 hours at ambient temperature. However, this laboratory method cannot be carried out on an industrial scale as the reaction is strongly exothermic, leading to a sharp increase in the reaction temperature, producing residues which are difficult to stir and secondary products (elimination products) which lower the yield.
The aim of the present invention is thus to provide a process which makes it possible to prepare 4-(6-bromohexyloxy)-butylbenzene in good yields on an industrial scale while avoiding the drawbacks which occur with the processes known from the prior art.


REFERENCES:
patent: 1132373 (2001-09-01), None
patent: 2140800 (1984-12-01), None
patent: WO-9519336 (1995-07-01), None
Jones, Robert M. et al; Mutational Evidence for a Common K antagonist Binding Pocket in the Wild-Type K and Mutant u[K303E] Opioid Receptors; Journal of Medicinal Chemistry; 1998; pp. 4911-4914; vol. 41; No. 25.
Rong, Yajing et al; A New Synthetic Approach to Salmeterol; Synthetic Communications; 1999; pp. 2155-2162; vol. 29; No. 12.

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