CS229696B2 - Production method of pirbuteol - Google Patents

Description

The pirbuterol analogs of formula I wherein the 2-hydroxymethyl group is replaced by a hydrogen atom, a methyl group, or a methanesulfonylmethyl group, and their bronchodilator activity have been described by Jen and Kaiser in U.S. Patent No. 3,952,101. by a reaction fully analogous to that described above for the preparation of pirbuterol.

Nakanishi in U.S. Patent Nos. 3,948,919 and 4,031,108 described an alternative preferred method for the synthesis of pirbuterol. An example of this synthesis is shown in the following reaction scheme:

Alternatives and improvements to this process have also been described, such as isolation of the pirbuterol precursor in the form of a salt with raspic acid (see Carroll et al., U.S. Pat. No. 4,011,231J), and instead of hydrolysis in the final reaction step 005, Luxembourg Patent No. 79,564],

The latter process still has the disadvantage that it produces harmful sulfide by-products during the epoxide preparation stage. Even under the most optimum conditions, traces of sulfur may be entrained, requiring the use of higher amounts of catalyst in the case of deprotection by hydrogenolysis, which process is advantageous when pirbuterol is to be prepared in the form of the free base. Furthermore, the epoxide is relatively low reactive with tert-butylamine, which is used as a reagent, even at elevated pressure and at a higher temperature, so that a large excess of reagent is required to work and work for a relatively long time.

Another disadvantage of the above improved process is the polar nature of the intermediate aminoalcohol, which results in difficult isolation of this intermediate in pure form.

Recently, it has also been found that pirbuterol can be used to treat congestive heart failure (see Taylor, U.S. Pat. No. 4,175,128),

Benderly et al. [see Can. J. Chem. 56, pp. 2673-2676 (1978)] described the conversion of 2-vinylpyridine to 2- (1,2-epoxyethyl) pyridine N-oxide by the action of m-chloroperbenzoic acid to 2-vinylpyridine.

An object of the present invention is an easy process for the production of pirbuterol of the above formula I, characterized in that the compound of the formula II

WITH

is heated in aqueous formaldehyde in the presence of a weak base.

Triethylamine is preferably used as the weak base.

The process according to the invention consists of hydroxymethylation according to the following reaction scheme:

UJ

This process involves a one-step synthesis from a precursor known for its biological activity and thus potentially commercially available.

Hydroxymethylation of the compound of formula II to pirbuterol (I) is readily accomplished by heating the starting material in an excess of aqueous formaldehyde in the presence of an excess of a weak base. In general, reaction temperatures in the range of from 85 to 105 ° C are used, with refluxing of the reaction mixture very suitable. The weak base used should not react to any significant extent with the starting materials or product, or cause polymerisation of formaldehyde to some extent. Tertiary aliphatic amines, conveniently readily available and inexpensive triethylamine, are very suitable as the basic catalysts for this reaction.

The starting material may be prepared as described in the aforementioned U.S. Patent (Jen and Kaiser) or preferably by the methods described herein.

The invention is illustrated by the following non-limiting example.

Example

Pirbuterol hydrochloride

A solution of 0.500 g (0.00238 mol) of 5-hydroxy-2- (1-hydroxy-2-tert-butylaminoethyl) pyridine in 5 ml of 38% aqueous formaldehyde and 1 ml of triethylamine is heated at reflux overnight, then additional 5 ml of an aqueous solution of formaldehyde and refluxing are continued for 6 hours, the solvent is evaporated off under vacuum, the crude product is dissolved in a minimum volume of cold methanol and this cold solution is saturated with gaseous dry hydrogen chloride to give 0.52 g. (70%) of pirbuterol hydrochloride melting at 174-176 ° C with decomposition.

Claims (2)

A process for preparing pirbuterol of formula I II is heated in aqueous formaldehyde in the presence of a weak base to 85-105 ° C. 2. A process according to claim 1, wherein the weak base is triethylamine.