CS229698B2 - Manufacturing process of pirbuterol and its analogue - Google Patents

Description

The present invention relates to a process for the preparation of pirbuterol and its analogues of the general formula I

OH (I) wherein

R is hydrogen, methyl or hydroxymethyl, and the conversion of compounds of formula I wherein R is hydrogen or methyl to pirbuterol corresponding to formula I wherein R is hydroxymethyl.

Pirbuterol and its bronchodilator efficacy were originally described by Barth in a series of US patents (3,700,681, 3,763,173, 3,772,314, 3,786,160). At that time pirbuterol was synthesized according to the following scheme:

7.4 ~ NC _f acetic acid ------------ —->

2. aqueous hydrochloric acid

X

^HI> (I, R = Pd / C = ₂ J Noah

Pirbuterol analogs of formula I wherein R is hydrogen, methyl or methanesulfonylmethyl and their bridging activity have been described by Jen and Kaiser in U.S. Patent 3,952,101. as described for the production of pirbuterol.

Nakkanishi 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 maleic acid salt of the pirbuterol precursor, new (see Car, role et al., U.S. Pat. No. 4,011,231) and hydrogenolysis instead of hydrolysis in the final reaction stage (see Argentine). No. 214,005, 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 little reactive with tert-butylamine, which is used as the reagent, even at elevated pressure and at a higher temperature, so that a large excess of reagent is required to work for a relatively long time.

Another disadvantage of the above-mentioned improved process is the polar nature of the intermediate aminoalcohol, which results in difficult isolation of the 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 Ca'n. 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.

The present invention provides an easy process for the preparation of pirbuterol and its analogues of formula (I)

- J'i i ·

J:

in which

R represents a hydrogen atom, a methyl group or a hydroxymethyl group, characterized in that N-tert-butylbenzylamine is reacted with an epoxide of formula VII

in which

R ¹ is benzyl and R ² is hydrogen or methyl, or

R ¹ and R ² together form a grouping of the formula

(vin) in which

R ¹ and R ² have the above meanings, and this amine was then hydrogenolysis or by a combination of solvolysis and hydrogenolysis is converted to the compound of formula I.

The method of the invention comprises the following simple implementation steps:

H)

In formulas I, VII and VIII, R ¹ , R ¹ and R ^{2 are} as defined above.

This produces a less polar intermediate (VIII) which is easier to isolate and purify by standard separation, extraction and crystallization procedures than the corresponding benzyl-free intermediate on the aminoalcohol side chain.

Conversion of the pyridine epoxide of formula VII to the benzylamine of formula VIII is effected by heating the epoxide with at least one equivalent of N-tert-butylbenzylamine, optionally in the presence of an inert diluent. Generally, the reaction is carried out at an elevated temperature (e.g., 50 to 100 ° C) to allow the reaction to proceed within a reasonable time. Suitable diluents are C 1 -C 4 alkanols such as methanol, dioxane, 1,2-dimethoxyethane, and the like. methanol, wherein at a temperature equal to or higher than the boiling point of the methanol at atmospheric pressure (for example at a temperature of 65 to 80 degrees Celsius), the pressure is operated.

The benzylamine (VIII) can in any case be hydrogenolyzed using a noble metal catalyst in an inert solvent. The temperature does not play a decisive role in hydrogenolysis - it is possible to work, for example, at a temperature of 0 to 100 ° C - but conveniently the hydrogenolysis is carried out at a miscibility temperature in order to avoid cooling or heating costs.

The hydrogenation pressure is also not critical - for example, a subatmospheric pressure up to 13.79 x 10 ^R Pa or even higher pressure can be used - however, relatively low pressures are used (for example, 13.79 x 10 ⁴ to 48.26 xx) 10 ⁴ Pa), because even when the reaction proceeds them 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% by weight of palladium. Also, the hydrogenation solvent is not critical, 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 may 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 abovementioned alcohols. High boiling solvents such as ethylene glycol or diothyleinglycol dimethyl ether can also be used, but are not preferred because more energy is required to remove them from the reaction mixture. In order to minimize the hydrogenolysis of the 1-hydroxy-2-tert-butylbenzylaminoethyl side chain to the 2-tert-butyl ethyl group or to prevent this hydrogenolysis completely, the hydrogenolysis according to the invention is preferably carried out in the presence of a small amount of water (for example from 1 to 30 mol equivalents).

In a particular case of the preparation of pirbuterol, the reaction is stopped after the theoretical amount of hydrogen has been consumed. If desired, hydrogenation can be continued (preferably in the presence of an acid such as hydrochloric acid) to effect the following conversion:

X (I, r * hqch _z )

X (I, R = _CH3)

When R @ ¹ and R @ ² are joined together, the benzylidine group can be removed by solvolysis to give the compound of formula XI

1β

of

The solvolysis can be carried out in aqueous. or an 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 can be used, but still higher temperatures, but conveniently at room temperature. Acid-catalyzed solvolysis is preferred over base-catalyzed solvase, since the products tend to decompose to some extent under basic conditions. The benzyl group is then removed as the final reaction step under the conditions described above.

The starting material of formula VII is available from the references cited above.

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

Example 1

6- [1-hydroxy-2- (N-tert-butylbenzylamino) ethyl] -2-phenyl-4H-1,3-dioxino [5,4-b] pyridine

A solution of 33.0 g (0.13 mol) of 6- (1,2-epoxyethyl) -2-phenyl-4H-1,3-dioxino [5,4-b] pyridine and 22.0 g (0.135 mol) of The N-tert-butylbenzylamine in 200 ml of methanol was heated to reflux overnight.

After cooling, 6- [1-hydroxy-2- (N-tert-butylbenzylamino) ethyl] pyridine is precipitated from the reaction mixture which, after recrystallization from isopropanol, yields 29.4 g (54%) of the desired amino alcohol, m.p. 130 [deg.] C.

Analysis:

for C 26 H ₃₀ N 2 O ₃ Calculated:

% C, 74.61;% H, 7.23;% N, 6.69; found:

H, 7.21; N, 7.15. Example 2

2-hydroxymethyl-3-hydroxy-6- [1-hydroxy-2- (N-tert-butylbenzylamino) ethyl] pyridine dihydrochloride

A solution of 8.40 g (0.02 mol) of 6- [1-hydroxy-2- (N-tert-butylbenzylamino) ethyl-2-phenyl-4H-1,3-dioxilno [5,4-b] ipyridine in 75 ml of methanol containing 10 ml of concentrated hydrochloric acid was stirred at room temperature for 4 hours, the solvent was evaporated in vacuo and the solid residue was recrystallized from isopropanol / methanol to give 6.30 g (74%) of 2-hydroxyethyl-3- hydroxy-6- [l-hydroxy-2- (N-j tert.butylbenzylamino ethyl] pyridine dihydrochloride, melting with decomposition at 173-175 C. Analysis ² 'for C _t gH ₂₆ N ₂ Q ₃ .2 HC1. 1/2 H ₂ O calculated:

i ·; H, 7.09; N, 6.80. found:

55.73% C, 7.28% H, 6.90% N. Example 3

Pirbuterol hydrochloride

To a 250 ml Parr autoclave is charged 0.50 g (0.0012 mol) of 6- (1-hydroxy-2- (N-tert-butylbenzylamino) ethyl] -2-phenyl-4H-1,3-dioxino [5,4-b] pyridine and 500 mg of 5% palladium-on-carbon in 20 ml of methanol The mixture is reacted under hydrogen pressure at 50 psi for 2 hours, then the catalyst is filtered off under nitrogen and the filtrate is saturated with dry hydrogen chloride 250 mg (67%) of pirbuterol hydrochloride melting at 174-176 ° C decomposed.

Claims (2)

OBJECT OF THE INVENTION 1. A process for the preparation of pirbuterol and its analogues of the general formula I ÍIJ I INVENT in which R represents a hydrogen atom, a methyl group or a hydroxymethyl group, characterized in that N-tert-butylbenzylamine is reacted with an epoxide of the formula VII at a temperature of 50 to 100 ° C 229898 ia in which R ¹ is benzyl and R ² is hydrogen or methyl, or R ¹ and R ² together form a group of the formula wherein R ¹ and R ² are as defined above, which is subjected to hydrogenolysis in an inert ro-solvent, in the presence of a noble metal catalyst, or a combination of hydrogenolysis and solvolysis in an aqueous or alcoholic medium in the presence of an acid catalyst. 2. Method according to claim 1 for the manufacture of pirbuterol formula I wherein R represents hydroxymethyl, characterized in that as starting material a compound of formula VII wherein R ¹ and R ² together form a group of the formula