SE440078B - PROCEDURE FOR THE PREPARATION OF 2-HYDROXIMETHYL-3-HYDROXY-6- (1-HYDROXY-2-T-BUTYLAMINOETHYL) -PYRIDINE BY HYDROGENOLYSIS OF ITS BENZYLIDEEN ACETAL - Google Patents

Description

vàousss-a, 0 RI 0 Cö fl sæzo Û / Ck cö fl sí ßm R / 0 \ N ca-cnz N 2 0 CH "'CH2 / nocnz 1A lnzucgoiah 11A H2Nc ~ (c fl3) 3 Im *“ zmæ fl ås c H cn o \ CH R '\ es - 6 51/0 O fl ocH' OOR 2 2 N z NZ IB ng: Ina Hz / Pd + - n E + aocaz N \ 2 Iv In the above formulas, each of R and R 'represents phenyl or methyl and Z ~ CHOH ~ CH2-NH-C (CH2) 5.

The reaction sequence IA - IB - IV gives good yields of the XD salt product IV with good quality, but it is economically unfavorable because it requires the relatively expensive substance benzyl bromide as a reactant for the production of the benzyl ether IA. Hydrogenolytic removal of the benzyl group (IB - IV) successfully eliminates the colored impurities.

Reaction sequences IIIA - IIIB - IV are less attractive from an economic point of view than sequences IIA - IIB ~ IV due to the relatively high cost of producing the component IIIA. The sequence IIA - IIB - IV is free from the above-mentioned disadvantages, but especially in large-scale application it, like the other two sequences, has the disadvantage that colored impurities are present in the final product IV. These contaminants occur during the production of the intermediates 15 \ N Mr! 7804955-8 IB, IIB and IIIB and, in so far as they are not removed before the conversion of said compounds into IV, they interfere with the isolation and purification of product IV.

Protection of aliphatic hydroxyl groups by their conversion to benzylidene acetals has been widely used in sugar and glyceride chemistry. The benzylidene group is removed by catalytic hydrogenolysis using palladium on charcoal (Peat and co-workers J. Chem. Soc., 1088, 1958) or by hydrolysis with a mineral acid.

Feed and Employees, Synthesis, 464-47? (1972) describe the use of the benzylidene group as a protecting group for hydroxyl groups in 2-methyl-5-hydroxy-6-hydroxymethylpyridine and 2,6-bis-hydroxymethyl-5-hydroxypyridine, intermediates in the synthesis of carpyric acid and related pyridines. Catalytic hydrogenation of benzylidene acetal-2-phenyl-6- (11-tetrahyaropyranioxy-aoaecen-1-yl) Luz-pyriaos, 2-47-1, α-dioxin at low pressure over platinum oxide did not remove the benzylidene group but hydrogenated only the olefin group.

U.S. Patent 4,111,251 (published 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 [,, 2-d7-1,3-dioxin to produce the maleic acid salt thereof, whereupon the dioxin is hydrolyzed with excess hydrochloric acid. It is not practical to convert the dihydrochloride salt thus obtained, for example, to the acetate by simple exchange.

SUMMARY OF THE INVENTION: The method of the present invention involves a modification of the sequence IIA - IIB - IV described in U.S. Patent No. 5,948,919, which modification significantly improves the yield and purity of the product in the preparation of pirbuterol in large scale. In addition, improved economy is achieved in comparison with the method described in the said U.S. patent specification. The process according to the invention comprises hydrogenolysis of benzylidene acetal-2-phenyl-6- (1-hydroxy-3-t-butylamino-ethyl) -lurpyridose-β-β-aioxine: Is-pin arm.

This process surprisingly enables an advantageous, economical, direct and industrially applicable method 7804955-8 for the preparation of the acetate salt and the other acid addition salts, in particular the non-mineral acid addition salts of pirbuterol.

The removal of the benzylidene protecting group from IIA 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. The acid hydrolysis does not remove the colored impurities. These are transferred to 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, for example the dihydrochloride salt.

Conversion of the dihydrochloride salt, or other mineral acid addition salt, to the acetate or other non-mineral acid salt by simple exchange cannot be carried out economically, practically or on an industrial scale. The hydrogenolysis according to the present invention gives pirbuterol as a free base with high quality and consequently enables direct conversion to the acetate or other desired acid addition salt. With non-mineral acids, such as acetic acid or other alkanoic acids, satisfactory removal of the benzylidene protecting group from IIA can not be achieved and these acids are consequently not economically attractive for this purpose.

Detailed Description of the Invention: In the process of the present invention, benzylidene octal IIA is hydrogenolyzed in the presence of palladium-carbon in a reaction-inert solvent and in the presence of water to remove the protecting group benzylidene and (JR). High quality KH preparation of pirbuterol IV Suitable for the reaction inert solvents are alcohols, especially those with 1-H carbon atoms. Among these solvents, 50 methanol is preferred, since methanol allows quantitative removal of the protecting group, is relatively inexpensive and readily available and acts as Other solvents such as tetrahydrofuran and dioxane can of course be used either alone or in combination with each other and / or with the above-mentioned alcohols. At higher temperature boiling solvents can also be used, for example ethylene glycol, dimethyl ether of ethylene glycol, but they did not prefer because of more energy required For the clay removal from the reaction mixture. The solvent chosen is \ fi 10 KN \ J '| It is suitably a water-miscible solvent, for in the process water must be present during the hydrogenolysis, in order to minimize side reactions. The reaction is generally carried out at a temperature between about 20 DEG and about 2 DEG C., as it proceeds unimpeded to give quantitative yields of the desired product pirbuterol.

In addition, this temperature substantially corresponds to that of the feed, so no cooling or heating is required.

The reaction temperature is not critical and lower or higher temperatures, for example between about 10 and about 100 ° C, can be applied, but provide no benefits. On the contrary, for economic reasons, temperatures outside the range of 20 ~ 25 ° C are avoided.

Hydrogen pressure is also not crucial.

Pressures between about 0.007 and about 1.4 MPa (about 0.01 ~ l # 0 kp / cmg) can be applied to remove the protecting group. In practice, however, it is economical and convenient to apply pressures between about 0.1 and about 1 rare (about 1-10 kp / cnF).

As a catalyst, palladium-carbon in particular is effective for the rapid and complete removal of the benzylidene group.

Palladium itself can be used as a catalyst. In addition, palladium can be used as a catalyst on supports, for example barium sulphate, as well as palladium black, palladium oxide (which is reduced to palladium during the applied process conditions). Raney nickel can also be used as a catalyst for the process. However, the preferred catalyst is palladium »carbon, in particular 5% palladium on charcoal.

The amount of catalyst is not critical to successful process, but in practice it has been found to be highly satisfactory for the removal of the benzylide group to use between about 0.01 and about 0.1 g of palladium per gram of benzylidene acetal. For a catalyst consisting of 5% palladium on charcoal, this corresponds to between about 0.3 and 2.0 g of 5% palladium on charcoal per gram of benzylidene acetal.

A side reaction in this hydrogenolysis process is hydrogenolysis of the hydroxyl group on the t-butylaminoethyl group in the 6-position. The presence of water during the hydrogenolysis reaction reduces or even eliminates this side reaction.

Although the presence of water is crucial, the amount of water is not critical but can be varied between about 1 and as much as 50 molar equivalents based on the benzylidene acetal, the limiting factor being the effect of the water dilution on the desired hydrogenolysis reaction. speed. The appropriate amount of water is between about 1 and about 20 molecular equivalents.

Water in smaller amounts reduces this side reaction but less effectively than water within the said range. Water in large quantities tends to reduce the rate of the hydrogenolysis reaction.

The presence of water in the hydrogenolysis reaction to reduce the above-mentioned side reaction is conveniently satisfied by using palladium on charcoal as a catalyst in the form of a water-wet material, for example with 50% water. The above amounts of catalyst per gram of benzylidene acetal will then be between about 0.4 and about 4.0 g of 5% palladium on charcoal containing 50% water. Alternatively, the water is added separately to the reaction mixture.

The hydrogenolysis reaction mixture containing the free base of pirbuterol is concentrated, usually under reduced pressure, to a small volume to remove water and the by-product toluene. To dry the concentrate more efficiently, ethanol is added, generally in between about 1 and about 2 volumes, and the resulting solution is concentrated. If required or desired, this is repeated for more complete removal I of the water. By completely removing all the solvents and the by-product toluene, the free base is obtained in the form of a solid which is relatively stable at ambient temperature, for example 20-25 ° C.

The desired acid addition salt of pirbuterol is easily prepared by adding the concentrate with a suitable acid, for example acetic acid. A minimum stoichiometric amount of acid is added. In practice, the concentrate is added with acid in excess of up to 10%. To accelerate the precipitation of the acid addition salt, the acid is usually added as a solution in a solvent, for example 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 thus formed is surprisingly and unexpectedly free of colored impurities. Thus, the hydrogenolytic removal of the protecting group benzylidene provides quantitative replacement of high quality pybuterol and of course enables the preparation of high quality pybuterol acid addition salts. It enables the use of crude benzylidene acetal and a pure, debenzylated product is obtained. In addition, the hydrogenolytic removal of the benzylidene protecting group gives rise to the formation of toluene, a by-product which is easy to remove from the reaction mixture. In contrast, the hydrolytic removal of the benzylidene group gives benzaldehyde, which is less easily removed from the reaction mixture.

Example 1: Pirbuterol acetate. A solution of 2-phenyl-E (1-hydroxy-2-t-butylaminoethyl) -4H-pyrido [2,4-b] [5-dioxin (1, C7 kg, 5.09 mol) in methanol ( 16.7 l) was charged to a glass-lined reaction vessel containing a catalyst consisting of 5% palladium on charcoal and 50% water (2.15 kg, 11.6 mqquivalent water). The mixture was stirred and the reaction vessel was purified, first blown with nitrogen and then with hydrogen. Vüte was blown into the reaction vessel at a pressure of 0.55 MPa at 20-25 ° C and maintained at this pressure throughout the reaction, which lasted for 12 hours. The pressure in the reaction vessel was released and the reaction mixture was filtered through diatomaceous earth (thin layer chromatography in the methyl ethyl ketone system: acetic acid water in the volume ratio ßzlzl on silica gel plates "GF" showed that the hydrogenolysis was complete). The filter cake was washed with methanol (5x500ml), the combined washing water and the filtrate were treated with activated carbon (167 g), stirred at 20 ~ 25 ° C for one hour and then filtered. A portion of the filtrate containing one mole of pirbuterol was taken out and evaporated to about 1/5 of its volume under reduced pressure. Ethanol (2550 ml) was added to the concentrate and the solution thus obtained was concentrated to 1/3 of its volume under reduced pressure. The addition of ethanol and evaporation was repeated three or more times, this to ensure an anhydrous concentrate of pirbuterol.

Pirbuterol was converted to its acetate by adding the concentrate with a solution of glacial acetic acid (67.5 3, 1.12 mol) in acetone (6125 ml). The mixture thus obtained was stirred and heated to 50-55 ° C and then cooled to room temperature in a water bath. The acetate crystallized out and 55 vsousss-s. 8 was filtered off, washed with acetone (2x500 ml) and dried in vacuo at 20-25 ° C. Yield 222 8 (75%), melting point l54 ~ l55 ° C.

Analysis:% C% II% Calculated for Cl2H2OO5NÉ'C2H4O2 55'99 8'O5 9'53 Found: 56.60 8.16 9.56 By recrystallization from ethanol an analytical sample was obtained.

Analysis:% C 751! Found: 56.04 8.05 9.05 The remaining methanol solution of pirbuterol was concentrated as above and the ethanol-pirbuterol concentrate was treated with a stoichiometric amount of fumaric acid and the mixture was stirred and heated to 60 ° C. The fumarate precipitated, the slurry was stirred and its temperature was allowed to drop to 25 ° C, then cooled in an ice bath to 5 ° C, granulated for 50 minutes and filtered. The filter cake was washed with ethanol and dried in an oven with forced air circulation and a temperature of 50 ° C (75% yield calculated on an assumed amount of 4.09 moles of pirbuterol in the concentrate). The product consisted of hemifumarate monoethanolate, m.p. 155 DEG-15 DEG C. (dec.).

Analysis: Calculated for 7áC fTáII '1-.4 I clzxxaoošmg. 1/2 0411404. n cnæso fi; 55.80 e, 19 a, 11+ mouth 55.72 8.25 μl Example 2: The procedure described in Example 1 was repeated but using 0.049 mol of 2-phenyl-6- (1-hydroxy-2- t-butylaminoethyl) -4H-pyridose, 2- <17-1.5- <1io>> as solvent, 20.58 g of 5% palladium. on charcoal containing 50% water (11, 5 molar equivalents of water), a hydrogen pressure of 0.55 MPa at 22 ° C for 22.5 hours, whereby 100% conversion to pirbuterol was obtained.

The ethanol concentrate prepared in the same manner as in Example 1 was treated with 0.055 moles of glacial acetic acid to give a 75% yield of pirbuterol acetate.

Example 3: Pirbuterol acetate prepared by hydrogenolysis with RFI 10 using a molar equivalent of water. A solution of β-phenyl-3- (1-hydroxy-2-t-butylaminoethyl) -HH-pyrido [5,2-gf-1,1-dioxin (8.046 g, 0.0245 ml) in methanol (80 ml ) charged: in a 500 ml high pressure flask containing dry catalyst consisting of FL palladium on charcoal (5.095 g) and water (0.45 ml, one molar equivalent). The mixture was stirred and the reaction curl was purified first with nitrogen and then with hydrogen. Hydrogen was blown into the reaction vessel to a pressure of 0.55 MPa at 20-25 ° C and this pressure was maintained throughout the reaction, which lasted for 24 hours. The pressure in the reaction vessel was released and the mixture was filtered through kieselguhr. The filter cake was washed with methanol (2 x 50 ml), the combined wash water and the filtrate were treated with activated carbon (0.6 g), stirred at 30-25 ° C for 15 minutes and then filtered through kieselguhr.

The filter cake was washed with ethanol (2 x 1.3 ml) and the combined filtrate and wash water were evaporated under reduced pressure to a volume of about 25 ml.

Glacial acetic acid (1., Gl8 g, 0.02695 mol) 3 acetone (1.50) was added to the concentrate and the mixture thus obtained was evaluated and heated to 50-55 ° C. It was then allowed to stand overnight, at which point its temperature dropped to a value corresponding to the room temperature, after which it was cooled to 0-5 ° C. The solution was evaporated under reduced pressure to give an evaporation residue as an oil (since crystallization did not occur) and chloroform (100 ml) was added to the oil. The mixture was stirred at room temperature for 2 hours and the acetate was filtered off, washed with chloroform (2x15 ml) and dried. yield 7.0 c, 95.196, amp. 152-1S1wc.

Example 4: The procedure described in Example 5 was repeated but using the amounts of water given in the table below: water, ml of water, molar melt yield of pier equivalents point, ° C nuterol acetate, í5 .J,,. a) 15.25 50 155-55 50% good kv fi_ i- tert Mr. . b) ~ --- --- 148-51 a "" then quality '37 [Q V1 f. "Û / 'í- °' |.!,. c) O 5 1 O 5 '__) 1 tLJ" } _. 'C21 fl çjl / ü (purple. .X.l__, quality' 7804955-8 \ J'l 10 * The acetate crystallized from the concentrate on cooling.

The relatively low yield is due to incomplete removal of the water from the acetate formation concentrate.

** NHR shows the presence of 2-hydroxymethyl-β-hydroxy-G- (f-t-butylaminoebyl) pyridine as an impurity.

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Claims (7)

10 15 20 25 7804952-sk, ä Patent claim A process for preparing acid addition salts of pirbuterol by removing from the 2-phenyl-6- (1-hydroxy-2-t-butylaminoethyl) -4H-pyrido [3,2-d] 1,3-dioxin protecting group the benzylide characterized in that said compound is hydrogenolyzed over palladium as a catalyst in a reaction-inert solvent and in the presence of water and that the hydrogenolysed reaction mixture is filtered and concentrated and the concentrate is treated with at least one stoichiometric amount of pirbuterol of a pharmaceutically acceptable acid. The method of claim 1, wherein the catalyst is palladium on carbon. A process according to claim 2, in that the hydrogenolysis is carried out in the presence of between 1 characteristic and 30 molar equivalents of water per mole of 2-phenyl-6- (1-hydroxy-zt-butylaminoethyl) -4H-pyrrolose, 2-a -1, s-aioxin. 4. A method according to claim 3, in that palladium on carbon is used as a 50% water-resistant wet material. 5. A method according to claim 4, in that the hydrogenolysis is carried out at the ambient temperature of SEK 11 million with a hydrogen pressure of between 0.1 and 1.0 MPa. A method according to claim 5, in that the solvent is methanol. The method of claim 1, wherein the pharmaceutically acceptable acid is acetic acid. k ä n n e t e c k n a t k ä n n e t e c k n a t 1983-05-20