CS229697B2 - Production method of pirbuterol - 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 is described by Jen and Kaiser in U.S. Patent No. 3,952,101. These compounds were prepared from the corresponding aldehydes following a reaction 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:

Have also been described, alternatives, and improvements to this ^one process, such as isolation preikursoru pirbuterol salified with maleic acid (see Carroll et al., U.S. Pat. No. 4,011,231) and instead of hydrolysis in the final step by hydrogenolysis (see Argentine Patent Specification 214,005, Luxembourg Patent Specification 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 optimal conditions, traces of sulfur may be entrained, requiring the use of higher amounts of catalyst for the removal of protecting groups by hydrogenolysis, a process which is preferred when pirbuterol is to be prepared as the free base. Furthermore, the epoxide is relatively little 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 i is required to work for a relatively long time.

A further disadvantage of the above-mentioned improved process is the polar character of the Intermediate Aminoalcohol, which results in difficult isolation of this intermediate in the pure state.

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, consisting of the action of m-chloroperbenzoic acid to 2-vinylpyridine.

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

v villas in which

229687

Y is a benzyl or acetyl group heated with acetic anhydride to give a compound of formula VIII

(poured) in which,

Y is as defined above, and this compound is converted to pirbuterol by solvolysis or a combination of solvolysis and hydrogenolysis.

In accordance with the process of the invention, when Y is acetyl, the intermediate of formula VIII is only subjected to solvolysis, and when Y is a benzyl group, the intermediate of formula VIII is subjected to a combination of solvolysis and hydrogenolysis.

The process of the invention comprises the following alternative reaction steps:

(Vtl)

In formulas VI and VIII in this scheme, Y is benzyl or acetyl.

This process also allows for easy synthesis of pirbuterol from a potentially commercially available compound or, alternatively, it advantageously utilizes an intermediate of formula V, which is simply made from readily available pyridine carbaldehyde of formula

as described in our related Czechoslovak Patent Specification No. 229,678.

The hydrogenation of the amine of formula V to the compound of formula II can be accomplished using a noble metal catalyst in an inert solvent. The temperature does not play a decisive role in the hydrogenolysis - it is possible to work, for example, at a temperature of 0 to 300 ° C - but conveniently the hydrogenolysis is carried out at room temperature in order to avoid the costs of cooling or heating. The hydrogenation pressure is also not critical - for example, from subatmospheric pressure to 13.79 x 10 ⁵ Pa or even higher pressure - generally low pressures are generally used (for example, 13.79 x 10 ⁴ to 48.26 xx 10 ⁴ Pa) as 1 at which the reaction proceeds a reasonable rate without the need to operate in a more complicated apparatus needed for the hydrogenation under high pressures. The noble metal catalysts used in this reaction include platinum, palladium, ruthenium and rhodium, either alone or on supports, as well as known catalytically active compounds of these metals, such as oxides, chlorides and the like. Examples of suitable catalyst supports include activated carbon and barium sulfate. A preferred catalyst for this reaction is palladium on carbon containing 1 to 10 why. % palladium. The hydrogenation solvent also does not play a critical role, but is not intended to react with the reactants or product (i.e., be inert under the conditions of the reaction). Suitable solvents include C 1 -C 4 alcohols, in particular methanol, which can serve as a solvent for the preparation of the hydrochloride, which is the usual form of pirbuterol. However, other solvents such as tetrahydrofuran or dioxane may be used, either alone or in combination with each other and / or in combination with the above-mentioned alcohols. High boiling solvents, such as ethylene glycol or diethylene glycol dimethyl ether, may also be used, but are not preferred because more energy is required to remove them from the reaction mixture. In order to minimize or completely prevent the hydrogenolysis of the 1-hydroxy-2-tert-butylaminoethyl side chain to the 2-tert-butylethyl group, the hydrogenolysis of the invention is preferably carried out in the presence of a small amount of water (e.g. from 1 to 30 mol equivalents).

The acetylations leading to compounds of formulas VI and VII are performed under mild conditions using at least 2 to 3 mol equivalents of an acetylating agent (e.g. acetyl chloride or acetic anhydride) in the presence of a tertiary amine such as triethylamine in an amount equivalent to at least molar.

The reaction is carried out in an inert solvent such as methylene chloride, ethyl acetate and the like. In the case of acetylation of the compound of formula II, the temperature is not critical and may range from 0 to 100 degrees Celsius. When ethyl acetate is used as the solvent, it is preferable to work under reflux. However, in the acetylation of a compound of formula V, it is preferred to work at a lower temperature, for example at 0 to 30 ° C, to minimize or eliminate the risk of side reactions on the N-oxide moiety.

The oxidation of the pyridine derivative of the formula VII to the pyridine N-oxide of the formula VI is carried out by treatment with a peracid, preferably m-chloroperbenzoic acid, in an inert organic solvent such as chloroform at a temperature of 10 to 60 ° C.

The key reaction of this process, the rearrangement of the pyridine N-oxide of formula VI to the acetoxymethylpyridine of formula VIII, is readily accomplished by simply heating in excess acetic anhydride. Temperatures ranging from 120 to 160 ° C are used; Conveniently, the reaction mixture is refluxed (about 140 ° C), but preferably at elevated pressure when the reaction is carried out at a temperature corresponding to or above the boiling point of the reaction mixture at atmospheric pressure. This arrangement avoids unnecessary costs of condensation and reheating of acetic anhydride.

The hydrogenolysis in the final reaction step is carried out under the same conditions as described above. The solvolysis in the final solvolytic or hydrogenolytic-solvolytic reaction step is carried out in an aqueous or alcoholic medium, optionally in the presence of a cosolvent, usually in the presence of an acid catalyst. Particularly suitable is a combination of methanol and hydrogen chloride from which the intermediate is readily isolated in the form of the hydrochloride. Temperature is not critical. For example, temperatures of from 0 ° C to 50 ° C or even higher can be used, but the reaction is conveniently carried out at room temperature. The acid-catalyzed solvolysis is preferred over the base-catalyzed solvolysis, since the products tend to decompose to some extent under basic conditions.

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

Example 1

To a suspension of 2- (1-hydroxy-2-tert-butylamino-ethyl) -5-hydroxy-6-methyl-pyridine-dihydro-trifluoride (7.70 g, 0.026 mol) in 300 ml of ethyl acetate and 7.7 ml of triethylamine was added 10.8 ml of acetic anhydride. The resulting solution was refluxed for 30 hours, an additional 5 mL of acetic anhydride was added and heating was continued for 24 hours. The reaction mixture was allowed to cool to room temperature, poured into a solution of 100 g of sodium bicarbonate in 700 ml of water, and the resulting mixture was stirred for 1 hour. The ethyl acetate layer was separated, washed first with aqueous sodium bicarbonate solution and then with water, and dried over magnesium sulfate. Evaporation of the dried ethyl acetate solution in vacuo afforded 6.0 g (66%) of 3-acetoxy-2-methyl-6- [1-acetoxy-2- (N-tert-butylacetamido) ethyl] pyridine, m.p. 124 Mp 5-127.5 ° C.

Analysis:

calculated for C ₁₈ H ₂₆ N ₂ O ₅ :

% C, 61.70;% H, 7.48;% N, 8.00; found:

% C, 61.93;% H, 7.39;% N, 8.44.

Example 1 and d 2

3-Acetoxy-2-methyl-6- [1-acetoxy-2- (N-tert-butylacetamido) ethyl] pyridine N-oxide

A solution of 5.50 g (0.0157 mol) of 3-acetoxy-2-methyl-6- [1-acetoxy-2- (N-tert-butylacetamido) ethyl] pyridine and 3.90 g (0.0192 mol) of 85 % of m-chloroperbenzoic acid in 150 ml of chloroform was stirred at room temperature for 24 hours, after washing the reaction mixture with two portions of aqueous sodium bicarbonate solution and drying over magnesium sulfate, the chloroform solution was evaporated to give < 2.9 g (50%) of 3- acetoxy-2-methyl-6- [1-acetoxy-2- (N-tert-butylacetamido) ethyl] pyridine-N-oxide melting after recrystallization from ether at 113-116.5 ° C.

Analysis: for C ₁₈ H ₂₆ N ₂ O ₆ Calculated:

% H, 7.15;% N, 7.65; found *

H, 7.08; N, 8.14. Example 3

3-Acetoxy-2-acetoxymethyl-6- [1-acetoxy-2- (N-tert-butylacetamido) ethyl] pyridine

3-Acetoxy-2-methyl-6- (1-acetoxy-2- (N-tert-solution) 1.0 g (0.0027 mol of 3-acetoxy-2-butylacetamido) ethyl] pyridine-methyl-6- [1 -acetoxy-2- (N-tert-butylacetamido) ethyl} pyridine-N-oxide in 10 ml of acetic anhydride was heated at reflux for 2.5 hours, then allowed to cool to room temperature and allowed to cool to room temperature over this temperature. The reaction mixture was poured into a biphasic mixture of ethyl acetate and aqueous sodium bicarbonate solution, and the resulting mixture was stirred for 1 hour.The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo. Chromatography on a silica gel column eluting with ether gave 300 mg (27%) of the desired product, m.p. 60-64 ° C.

For C20H28N2O7 calculated:

58,81%! H, 6.91; N, 6.86; ntalezeno:

59.02 ° C, 6.83% H, 7.30% N.

Example 4

Pirbuterol hydrochloride

A solution of 2.0 g (0.005 mol) of 2-acetoxymethyl-3-acetoxy-6- (1-acetoxy-2-N-acetyl-tert-butylaminoethyl) pyridine in 50 ml of methanol containing 1 ml of concentrated hydrochloric acid was heated for 12 hours The solvents were evaporated in vacuo and the residue was recrystallized from ethyl acetate to give 900 mg (58%) of pirbuterol hydrochloride melting with decomposition at 172-175 [deg.] C. NMR spectrum and thin layer chromatography results (m.p. ethyl acetate-methanol-diethylamine 6: 3: 1) corresponds to pirbutefol.

Prolonged heating results in 2-hydroxymethyl-3-hydroxy-6- (1-hydroxy-2-aminoethyl) pyridine melting at 184-186 ° C with decomposition.

Claims (2)

pRedmEt v A process for the production of pirbuterol of formula I, characterized in that the compound of formula VI in which: Y represents a benzyl or acetyl group, heated with acetic anhydride at a temperature of 120 to 160 ° C to form a compound of formula VIII Y is as defined above, which is then subjected to solvolysis in an aqueous or alcoholic medium in the presence of an acid catalyst, or a combination of solvolysis and hydrogeholysis in an inert solvent, in the presence of a noble metal catalyst, to form pirbuterol. 2. A process according to claim 1, wherein if Y is acetyl in the starting material of formula VI, the intermediate of formula VIII is subjected to solvolysis only and, if in the starting material of formula VI, Y is benzyl, it is subjected to an intermediate of formula VIII a combination of solvolysis and hydrogelnolysis.