DK152672B - METHOD FOR PREPARING 2-HYDROXYMETHYL-3-HYDROXY-6- (1-HYDROXY-2-T-BUTYLAMINOETHYL) PYRIDINE OR ACID ADDITION SALTS. - Google Patents

Description

The present invention relates to a particular process for the preparation of 2-hydroxymethyl-3-hydroxy-6- (1-hydroxy-2-t-butylaminoethyl) pyridine or acid addition salts thereof by removing the benzylidene protecting group from 2-phenyl-6- (1 -hydroxy-2-t-butylaminoethyl) -4H-pyrido [3,2-d] -1,3-dioxin.

DSA Patent No. 3,948,919, issued April 6, 1976, discloses the preparation of 2-hydroxymethyl-3-hydroxy-6- (1-hydroxy-2-t-butylaminoethyl) pyridine (denoted by the generic name pir-buterol, formula IV), a bronchodilator, for the following three related reaction sequences:

In the above formulas, R and R 'are each phenyl or methyl and Z is -CHOH-CH 2 -NH-C (CH 3) 3 ·

Reaction series IA to IB to IV give good yields of the end product (IV) of good quality, but have the economic disadvantage of requiring benzyl bromide, a relatively expensive substance, as a reactant for the production of the benzyl ether (IA). By hydrogenolytic removal of the benzyl group (IB to IV), a successful removal of the colored impurities is achieved.

Reaction series IIIA to HIB to IV is less attractive from an economic standpoint than reaction series IIA to IIB to IV due to the relatively high costs associated with the production of reactant IIIA.

Reaction series HA to IIB to IV are free of the above disadvantages. However, like the other two series of reactions, it is subject, in particular to large-scale operation, to the presence of colored impurities in the final product (IV). These impurities occur during the preparation of the intermediates IB, IIB and IIIB and unless they are removed before the conversion of said compounds to IV, or which in the reaction IB to IV are eliminated by the hydrogenolytic removal of the benzyl group, they interfere with the isolation and purification of the product. IV.

Protection of aliphatic hydroxyl groups by converting them into benzylidene acetals has found widespread use in the sugar and glyceride chemistry. The benzylidene group can be removed by catalytic hydrogenolysis using palladium charcoal (Peat et al., J. Chem.Soc., 1088, 1938) or by hydrolysis with a mineral acid.

Fodor et al., Synthesis, 464-472 (1972) report the use of the benzylidene group as the protecting group for the hydroxyl groups of 2-methyl-5-hydroxy-6-hydroxymethylpyridine and 2,6-bis-hydroxy-methyl-3-hydroxypyridine. there are intermediates in the preparation of carpyric acid and related pyridines. Catalytic hydrogenation of the benzylidene acetal 2-phenyl-6- (11-tetrahydropyranyloxydodecen-1-yl) -4H-pyrido [3,2-d] -1,3-dioxin at low pressure over platinum oxide did not remove the benzylidene group but only hydrogenated the olefin group.

U.S. Patent No. 4,011,231, issued March 8, 1977, discloses the preparation of high quality pirbuterol dihydrochloride by a process comprising reacting maleic acid with 2-phenyl-6- (1-hydroxy) 2-t-Butylaminoethyl) -4H-pyrido [3,2-d] -1,3-dioxin to form the maleate salt thereof, followed by hydrolysis of the dioxin with excess hydrochloric acid. Conversion of the dihydrochloride thus produced to e.g. The acetate by simple exchange is not practically feasible for economic reasons, requiring an additional step and the yields do not. Is satisfying.

The process of the invention is characterized in that the latter is hydrogenolysed over palladium-on-carbon as a catalyst in an alcohol having up to 4 carbon atoms as solvent in the presence of from 1 to 30 molar equivalents of water per liter. mole of 2-phenyl-6- (1-hydroxy-2-t-butylaminoethyl) -4H-pyrido [3,2-d] -1,3-dioxin, then the hydrogenolyzed reaction, mixture is filtered and concentrated to remove of the water, after which 2-hydroxymethyl-3-hydroxy-6- (1-hydroxy-2-t-butylaminoethyl) -pyridine is obtained as a base by further concentration or obtained in form. of an acid addition salt by treatment with at least the stoichiometric amount of an acid.

The process of the present invention is a modification of the reaction series IIA to IIB to IV described in U.S. Patent No. 3,948,919, wherein modification achieves a significant improvement in yield and purity in large-scale pirbuteurol production. Compared to the methods disclosed in U.S. Patent No. 3,948,919, this method provides an added economic benefit. The process comprises hydrogenolysis of the benzylidene-acetal 2-phenyl-6- (1-hydroxy-2-t-butylaminoethyl) -4H-pyrido [3,2-d] -1,3-dioxin IIB to pirbuterol.

This process unexpectedly provides an advantageous, economically, directly and industrially useful route to the acetate salt or to other acid addition salts, especially with non-mineral acids, of pirbuterol.

Removal of the benzylidene protecting group from IIB by hydrolysis requires a strong acid, preferably a mineral acid, such as hydrochloric acid, hydrobromic acid or sulfuric acid, to achieve satisfactory conversion to pirbuterol. Acid hydrolysis cannot remove the colored impurities present. These impurities are transferred into the final product (IV) and are difficult to remove. In addition, the pirbuterol product is obtained as the acid addition salt of the acid used for the hydrolysis, e.g. dihydrochloride.

Conversion of the dihydrochloride salt, or other mineral acid addition salt, to the acetate or other non-mineral acid salt by simple exchange is not economically feasible or industrially feasible with a satisfactory yield of a sufficiently pure product. The present hydrogenolysis process provides high-quality pirbuterol as the free base and thus enables its direct conversion to the acetate or any other desired acid addition salt which, like pirbuterol, finds use as a bronchodilator. Non-mineral acids, such as acetic or other alkanoic acids, do not provide satisfactory removal of the benzylidene protecting group from UB and are therefore not economically attractive for this purpose.

Various convenient embodiments of the method according to the invention can be used as set forth in claims 2-5.

In the process of the present invention, the benzylidene acetal, Formula XIB, is hydrogenated in the presence of palladium-on-carbon in a reaction inert solvent to remove the benzylidene protecting group and form high quality pirbuterol (Formula IV) which is reaction inert solvent. an alcohol of up to 4 carbon atoms. Methanol is preferred as it provides quantitative removal of the protecting group, is relatively inexpensive and readily available, and can serve as the reaction medium for subsequent salt formation. Water must be present during hydrogenolysis to minimize side reactions.

The reaction is usually carried out at a temperature of from ca. 20 ° C to 25 ° C, where it runs smoothly and quantitatively to the desired product, pirbuterol. Furthermore, this temperature is substantially equivalent to room temperature and does not require any cooling or heating. The reaction temperature is not significant. Lower or higher temperatures may be used, e.g. from approx. 10 C to approx. 100 C, but this does not bring any benefits. On the contrary, from a cost perspective, temperatures outside the range of 20 to 25 C are avoided.

Hydrogen pressure is not significant. Press from approx. 0.07 to approx. 14 kg / cm 2 can be used to remove the protecting group. However, for economic reasons and to facilitate operation, pressures from 1 to 10 kg / cm are used in 2 real practice.

As a catalyst, 50% palladium carbon is particularly effective in achieving rapid and complete removal of the benzyl in that group.

The amount of catalyst used is not essential for successful implementation of this process. In real practice, from approx.

0.01 to approx. 0.10 g palladium per grams of benzylidene acetal have been found to be highly satisfactory for the removal of the benzylidene group. Expressed in 5% palladium on charcoal, this is equivalent to from approx. 0.2 to 2.0 g of 5% palladium on charcoal grams of benzylidene acetal.

A side reaction to this hydrogenolysis process is hydrogenolysis of the hydroxyl group on the p-butylaminoethyl group at the 6-position. By the presence of water during the hydrogenolysis reaction, it is achieved that this side reaction is minimized or even avoided. While the presence of water is substantial, the amount of water can range from 1 mole equivalent to as much as 30 mole equivalent, based on the benzylidene acetal, the limiting factor being the dilution effect of the added water on the rate of the desired hydrogen o light being the ect ion. The preferred amount of water is from 1 to approx. 20 molar equivalents. The presence of smaller amounts of water serves to reduce this side reaction, but with less efficiency than amounts within the above range. Larger amounts of water tend to decrease the rate of hydrogenolysis reaction as stated.

The presence of water in the hydrogenolysis reaction to limit as much as possible the above-mentioned side reaction is conveniently met by using the palladium-on-charcoal catalyst in the form of water-wetted material, e.g. 50% water soaked material. The above-mentioned catalyst amounts will then be from approx. 0.4 to approx. 4.0 g of 5% palladium on charcoal, 50% water wet, per grams of benzylidene acetal. Alternatively, the water is added separately to the reaction mixture.

The hydrogenolysis reaction mixture containing pirbuterol in the form of the free base is filtered and concentrated, usually under reduced pressure, to a small volume for removal of water and as a by-product of toluene. For more efficient drying of the concentrate, ethanol is usually added, usually from ca. 1 to 2 volumes and the solution obtained is concentrated. This step is repeated if necessary or desired for more complete removal of water present. By complete removal of all solvents and toluene formed as a by-product, the free base is obtained as a solid which is relatively stable at ambient temperatures, e.g. 20-25 ° C.

The desired acid addition salt of pirbuterol is readily prepared by adding the acid in question, e.g. acetic acid, to the concentrate. At least the stoichiometric amount is added. In practice, up to 10% excess of the acid is added to the concentrate. To accelerate the precipitation of the acid addition salt, the acid is usually added as a solution in a solvent, e.g. acetone, in which the acid addition salt is insoluble. Alternatively, said solvent is added to the concentrate before, after or simultaneously with the acid.

The pirbuterol prepared by this method is unexpectedly and surprisingly free of colored impurities. Thus, the hydrogenolytic removal of the benzylidene protecting group provides a quantitative yield of high quality pirbuterol and therefore enables the production of high quality pirbuterol acid addition salts. It enables the use of crude benzylidene acetal and the preparation of a pure debenzylated product. A further feature of the hydrogenolytic removal of the benzylidene protecting group is the formation of toluene, a by-product easily removed from the reaction mixture. In contrast, by the hydrolytic removal of the benzylidene group benzaldehyde is formed, which is more difficult to remove from the reaction mixture.

The process according to the invention is further elucidated by the following examples.

Example 1

Pirbuterol acetate.

A solution of 2-phenyl-6- (1-hydroxy-2-t-butylaminoethyl) -4H-pyrido [3,2-d] -1,3-dioxin (1.67 kg, 5.09 mol) in methanol (16.7 liters) is added to a glass-lined reactor filled with 5% palladium-on-charcoal catalyst, 50% water wet (2.13 kg, 11.6 molar equivalents of water). The mixture is stirred and the reactor is purified with nitrogen and then with hydrogen. The reactor is charged with hydrogen at 3.5 kg / cm at 20-25 C and maintained at this level for the entire reaction time of 12 hours. The reactor is pressure relieved and the reaction mixture is filtered through diatom S soil. (Thin-layer chromatography in the system methyl ethyl ketone: acetic acid? Water [6: 1: 1 v / v] on silica gel GF plates showed that the hydrogenolysis was complete). The filter cake is washed with methanol (3 x 500 ml) and the combined washing liquid and filtrate are treated with activated charcoal (167 g), stirred at 20-25 ° C for 1 hour and then filtered. A volume of filtrate containing 1 mole of pirbuterol is removed and concentrated to ca.

1/3 volume under reduced pressure. Ethanol (2550 ml) is added to the concentrate and the solution obtained is concentrated to 1/3 volume under reduced pressure. The addition of ethanol and the concentration are repeated 3 or more times to ensure an anhydrous concentrate of pirbuterol.

The pirbuterol is converted to its acetate salt by adding a solution of glacial acetic acid (67.3 g, 1.12 mole) in acetone (6125 ml) to the concentrate. The resulting mixture is stirred and heated to 50-55 ° C and then cooled to room temperature in a water bath. The acetate salt is crystallized and filtered off, washed with acetone (2 x 500 ml) and dried in vacuo at 20-25 ° C. Yield = 222 g (75%), m.p. 154-155 c. Analysis: Calculated for C₂ 2H₂ <<33N2 ′ (2H4O2: C ^ 5.99, H 8.05, N 9.33%, found: C 56.60, H 8.16, N 9.56%.

Upon recrystallization of ethanol, an analytical sample is obtained: Analysis: Found: C 56.04, H 8.05, N 9.33%.

The remaining methanol solution of pirbuterol is concentrated in the manner described above, and the ethanol-pirbuterol concentrate is treated with the stoichiometric amount of fumaric acid and the mixture is stirred and heated to 60 ° C. The fumarate salt precipitates and the slurry is stirred and left to cool to 25 ° C. It is then cooled in an ice bath to 5 ° C, granulated for 30 minutes and then filtered. The filter cake is washed with ethanol and dried in a forced air circulation oven at 50 ° C (73% yield based on the assumption that there are 4.09 moles of pirbuterol in the concentrate). The product is the hemifumarate mono-ethanolate salt. Mp. 135-136 ° C (dec.).

Analysis: Calculated for C 21 H 20 ° 3 N 2 · 1 // 2 C 4 H 4 ° 4 * C 2 H 5 OH: C 55.80, H 8.19, N 8.14%, found: C 55.72, H 8.25, N 8.06 %.

Example 2

The procedure of Example 1 is repeated, however, using 0.049 moles of 2-phenyl-6- (1-hydroxy-2-t-butylaminoethyl) -4H-pyrido [3,2-d] -1,3-dioxin, 160 20 ml of methanol as solvent, 20.38 g of 5% palladium-on-charcoal, 50% of water (11.5 molar equivalent water) and a hydrogen pressure of 3.5 kg / cm 2 at 22 ° C for 22.5 hours to obtain of 100% conversion to pirbuterol.

By treating the ethanol concentrate obtained as described in Example 1 with 0.055 moles of glacial acetic acid 73% yield of pirbutyl acetate is obtained.

Example 3

Pirbuterol acetate (by hydrogenolysis using 1 mole equivalent of water).

A solution of 2-phenyl-6- (1-hydroxy-2-t-butylaminoethyl) -4H-pyrido [3,2-d] -1,3-dioxin (8.046 g, 0.0245 mol) in methanol (80 ml) is added to a 500-ml high-pressure bottle filled with dry 5% palladium-on-charcoal catalyst (5.095 g) and water (0.45 ml, 1 mole equivalent). The mixture is stirred and the reactor is first purified with nitrogen and then with hydrogen. The reactor is charged with hydrogen at 3.5 kg / cm at 20-25 C and maintained at this level for the entire reaction time of 24 hours. The reactor is pressurized and the reaction mixture is filtered through diatomaceous earth. The filter cake is washed with methanol (2 x 30 ml), the combined washing liquid and filtrate treated with activated carbon (0.6 g), stirred at 20-25 ° C for 15 minutes and then filtered through diatomaceous earth. The filter cake is washed with ethanol (2 x 12.5 ml) and the combined filtrate and wash liquid concentrated under reduced pressure to a volume of approx. 25 ml.

Glacial acetic acid (1.618 g, 0.02695 mol) in acetone (1.50 ml) is added to the concentrate and the resulting mixture is stirred and heated to 50-55 ° C. It is then cooled to room temperature overnight and then to 0-5 ° C. The solution is then concentrated under reduced pressure to an oil (since no crystallization occurred) and chloroform (100 ml) is added to the oil. The mixture is stirred at room temperature for 2 hours and the acetate salt is filtered off, washed with chloroform (2 x 15 ml) and dried. Yield = 7.0 g (95.1%), m.p. 152-154 ° C.

Example 4

The procedure of Example 3 is repeated, however, using the quantities of water listed below.

The acetate crystallized from the concentrate upon cooling. The relatively low yield is due to incomplete removal of the water from the concentrate before formation of the acetate salt.

NMR shows the presence of 2-hydroxymethyl-3-hydroxy-6- (2-t-butylaminoethyl) pyridine as impurity.

dioxin = 2-phenyl-6- (1-hydroxy-2-t-butylaminoethyl) -4H-pyrido [3,2-d] -1,3-dioxin. ^ water added separately; catalyst added in dry state.

In each case, high quality pirbuterol is produced.

Claims (5)

A process for preparing 2-hydroxymethyl-3-hydroxy-6- (1-hydroxy-2-t-butylaminoethyl) pyridine or acid addition salts thereof by removing the benzylidene protecting group from 2-phenyl-6- (1-hydroxy) -2-t-butylaminoethyl) -4H-pyrido [3,2-d] -1,3-dioxin, characterized by hydrogenolysing the latter compound over palladium-on-carbon as a catalyst in an alcohol of up to 4 carbon atoms as a solvent in the presence of from 1 to 30 molar equivalents of water per mole of 2-phenyl-6- (1-hydroxy-2-t-butylaminoethyl) -4H-pyrido [3,2-d] -1,3-dioxin, then the hydrogenolysed reaction mixture is filtered and concentrated to remove the water, then 2-hydroxymethyl-3-hydroxy-6- (1-hydroxy-2-t-butylaminoethyl) pyridine is obtained as a base by further concentration or obtained in the form of an acid addition salt by treatment with at least the stoichiometric amount of an acid . Process according to claim 1, characterized in that palladium-on-coal is used as 50% water-wet material. Process according to claim 1 or 2, characterized in that the hydrogenolysis is carried out at ambient temperature at a hydrogen pressure of 1 to 10 kg / cm. Process according to any one of claims 1-3, characterized in that the solvent is methanol. Process according to any one of claims 1-4, characterized in that the acid is acetic acid.