FI67541C - PROCEDURE FOR THE FRAMSTATION OF 2-HYDROXIMETYL-3-HYDROXY-6- (1-HYDROXI-2-T-BUTYLAMINOETHYL) PYRID AND OIL SYRAADDITIONSSALTER DAERAV GENOM HYDROGENOLYS AV MOTSVARANDE BENS - Google Patents

Description

I. Γβ1 .... NOTICE OF ADVERTISEMENT s No Λ Λ W (11) UTLÄGGNINGSSKRIFT 67541 C ^ 45 | Raton Iti ayΙΥ.η. tty U Γ1 1935 ^ ^ (51) K ».lk.3 / lirt.CI. ^ C 07 D 213/65 ENGLISH - FI N LAN D (21) PKwrttIhakomus - Pstentsnsöknlng 781329 (22) Hakwnlspilvt - Ansftknlngsdsg 28.0 * 4.78 ^ ^ (23) AlkupUvt — Glltiglratsdag 28.0 * 4.78 (41) Tulhit Public - BIMt offontllg 03.11.78

The National Board of Patents and Registration of NihtMksijanon „kuLLullokun pvm.-,. «.

Patent and Registration Office AnsOksn utlsgd och utl-skrlften pubikerad 31 · 1 2.0 * 4 (32) (33) (31) Request for Privilege —Begird prlorltet 02.05.77 06.03.78 USA (US) 79281 * 4, 883690 (71) Pfizer Inc., 235 East * 42nd Street, New York, New York, USA (US) (72) Susumu Nakanishi, Niantic, Connecticut, USA (US) (7 **) Oy Koi ster Ab (5 * 4) Method 2- Hydroxy is absorbed to prepare 1-3-hydroxy-6- (1-hydroxy-2-t-butyl-aminoethyl) pyridine and its acid addition salts with the corresponding benzylic acid by hydrolysis of 2-hydroximethyl. This invention relates to an improved process for the preparation of a known bronchodilator drug, 2-hydroxymethyl-3-hydroxy-6- (1-hydroxy-2-t-butyl-aminoethyl) pyridine and its hydrated hydrogenate. -hydroxy-2-t-butylaminoethyl) pyridine and its acid addition salts benzylideneacetal-2-phenyl-6- (1-hydroxy-2-t-butylaminoethyl) - * 4H-py ridoZ.3, 2-47-1 by hydrogenolysis of 3-dioxin. The preferred acid addition salt is acetate.

U.S. Patent 3,9 * 48,919, issued April 6, 1976, describes the reaction of the following following the preparation of 2-hydroxymethyl-3-hydroxy-6- (1-hydroxy-2-t-butylaminoethyl) pyridine (commonly known as pirbuterol, Formula IV): according to the series:

- TT

2 67541 6 m iS-ai -'- CHj 6 ^ J @ -di- "ai2» ^ @ - 0 ^ 2 IA H2NC (CH3) 3 IIA H2NC (ai3) 3 IIIA H2NC (CII3) 3

Toi. 'λΌ ° 1, lB Nv HB ΙΙΪΒ "^ \ H + / \ n, 10Ύδ) ^ iv

In the above scheme, each of R and R 'is phenyl or methyl; and Z is -CHOH-CH2-NH-C (CH2) 3.

The reaction series IA -> IB -> IV gives the final product (IV) in good quality in good yields, but is economically disadvantageous provided the use of benzyl bromide, a relatively expensive substance as a reagent in the preparation of benzyl ether (IA). Removal of the benzyl group by hydrogenolysis (IB to IV) eliminates highly colored impurities.

Reaction series IIIA -> IIIB -> IV is less economically interesting than series IIA -> IIB -> IV due to the relatively high cost of preparing the reactant IIIA. There are no such disadvantages in the series IIA -> IIB -? IV. However, especially in large-scale work, as in the case of the other two series, colored impurities are present in the final product (IV). These impurities are formed during the preparation of intermediates IB, IIB and IIIB and, unless removed before the conversion of said compounds into compound IV, interfere with the isolation and purification of product IV.

3 67541

The protection of aliphatic hydroxyl groups by their conversion to benzylidene acetals has been widely applied in practice in the context of sugar and glyceride chemistry. The benzylidene group can be removed by catalytic hydrogenation using a palladium-charcoal catalyst (Peat et al., J. Chem. Soc., 1088, 1938) or by hydrolysis with an inorganic acid.

Fodor et al., Synthesis, 464-472 (1972), describe the use of a benzylidene group in the synthesis of 2-methyl-5-hydroxy-6-hydroxymethyl-pyridine and 2,6-bis-hydroxymethyl-3-hydroxypyridine (intermediates for carpyric acid). nearby pyridines) as a protecting group for hydroxyl groups. Catalytic hydrogenation of benzylideneacetal-2-phenyl-6- (11-tetrahydropyranyloxydodecan-1-yl) -4H-pyrido / 3,2-d7-1,3-dioxin using low pressure and platinum oxide did not remove the benzylidene group but only hydrated the olefin group. .

U.S. Patent 4,011,231, issued March 8, 1977, describes the preparation of high quality pirbuterol dihydrochloride by a process in which maleic acid is reacted with 2-phenyl-6- (1-hydroxy-2-t-butylaminoethyl) -4H-pyrido. With 2,3-d7-1,3-dioxin to give its maleate salt, followed by hydrolysis of the dioxin with excess hydrochloric acid. Conversion of the dihydrochloride salt thus prepared to, for example, acetate by a simple exchange reaction is not a practical solution.

The process of this invention is a modification of the series IIA-113 reactions (U.S. Pat. No. 3,948,919) and is obtained in the large-scale preparation of pirbuterol in a purer product and in better yield than the previously known process. The economy of the new method is better than that disclosed in U.S. Patent No. 3,948,919. The process involves the hydrogenolysis of benzylideneacetal-2-phenyl-6- (1-hydroxy-2-t-butylaminoethyl) -4H-pyrido [L3,2-s] -3-dioxin IIB to t-buterol.

This process surprisingly provides a cost-effective, economical, direct and industrially useful way to prepare the acetate salt of pirbuterol, or other acid addition salts, especially salts that are not salts of inorganic acids.

.... ........... li "67541

Removal of the benzylidene protecting group by hydrolysis of compound IIA requires the use of a strong acid, mainly an inorganic acid such as hydrochloric acid, hydrobromic acid or sulfuric acid, in order for the conversion to pirbuterol to proceed satisfactorily. Hydrolysis with acid does not remove the colored impurities present. These impurities are transported to the final product (IV) and are difficult to remove. In addition, the pirbuterol product is obtained as an acid addition salt of the acid used for hydrolysis, e.g. as the dihydrochloride salt.

Conversion of the dihydrochloride salt, or other acid addition salt of an inorganic acid, to an acetate salt or a salt of another inorganic acid by a simple exchange reaction is neither economically feasible nor industrially feasible. The hydrogenolysis of the invention produces high quality pirbuterol as the free base, thus allowing it to be converted directly to acetate or any other desired acid addition salt. With inorganic acids such as acetic acid or other alkanoic acids, the benzylidene protecting group cannot be satisfactorily removed from IIA and their use is not economical.

The process according to the invention is characterized in that the latter compound is hydrogenolysed in the presence of a palladium catalyst and water in a reaction-inert solvent, and the base obtained is optionally then treated with at least a stoichiometric amount of acid. Suitable reaction-inert solvents are alcohols, in particular alcohols having 1 to 4 carbon atoms. Methanol is the preferred of these solvents because it can be used to remove the protecting group quantitatively, is relatively inexpensive and easy to remove, and acts as a reaction medium for subsequent salt formation. Other solvents, such as tetrahydrofuran and dioxane, can of course be used either alone or in combination with one another and / or with the abovementioned alcohols. High boiling point solvents such as ethylene glycol, ethylene glycol dimethyl ether can also be used, but are not recommended because removing them from the reaction mixture requires more energy. The solvent of choice is preferably the solvent with water 67541, because under the primary conditions of this process, as described below, water must be present during the hydrogenation to minimize side reactions.

The reaction is generally carried out at a temperature in the range of about 20 ° C to 25 ° C, in which case the reaction to the desired product, pirbuterol, takes place uniformly and quantitatively. Furthermore, this temperature corresponds mainly to the "ambient" temperature and does not require cooling or heating. The reaction temperature is not critical. Lower or higher temperatures, e.g., from about 10 ° C to about 100 ° C, may be used, but are of no use. On the contrary, for reasons of cost, temperatures outside the range of 20 ° C to 25 ° C are avoided.

Hydrogen pressure is not critical. Pressures of about 6.9 to 1379 kPa can be used to remove the protecting group. In actual use, however, for economic reasons and to facilitate the performance of the work, the pressures used are about 103-1034 kPa.

Palladium carbon is a particularly effective catalyst because it allows the benzylidene group to be removed quickly and completely. Palladium alone can be used as the catalyst. In addition, palladium on a support such as barium sulfate, as well as palladium carbon, palladium oxide (which is reduced to palladium under the process conditions used) can also be used as a catalyst. Raney nickel can also be used as a catalyst in this process. The preferred catalyst is palladium on carbon, especially a catalyst with 5% palladium on charcoal.

The amount of catalyst is not critical to the successful performance of this process. In actual use, about 0.01 to about 0.10 g of palladium per gram of benzylidene acetal has proven to be a very satisfactory amount for efficient removal of the benzylidene group. In the case of 5% palladium charcoal, about 0.2 to 2.0 g of 5% palladium charcoal corresponds to a gram of benzylidene acetal.

As a side reaction of this hydrogenolysis process, hydrogenation of the hydroxyl group of the t-butylaminoethyl group in the 6-position occurs. This side reaction is minimized or eliminated when 6,67541 water is present during the hydrogenolysis reaction. Although the presence of water is critical, the amount of water is not critical, but may vary from about one molar equivalent to as much as 30 molar equivalents relative to the amount of benzylidene acetal, with the limiting factor being the retarding effect of the added water on the hydrogenolysis reaction. The recommended amount of water is from about 1 to about 20 molar equivalents. The presence of smaller amounts of water reduces this side reaction, but more inefficiently than the amount of water within the above limits. Higher amounts of water reduce the reaction rate.

To minimize the above-mentioned side reaction, the need for water to be used in the hydrogenolysis reaction is conveniently satisfied by using a palladium-charcoal catalyst in the form of a product moistened with water, e.g., moistened with 50% water. The amount of the above-mentioned catalyst then becomes about 0.4 to about 4.0 g of 5% palladium on carbon with a moisture content of 50% of water per gram of benzylidene acetal. Alternatively, water is added separately to the reaction mixture.

The hydrogenolysis reaction mixture containing pirbuterol as the free base is usually concentrated in vacuo to remove water and the toluene by-product. To dry the concentrate more efficiently, ethanol, usually about 1-2 parts by volume, is added and the resulting solution is concentrated. This step is repeated as necessary or desirable to remove the water present more completely. After complete removal of all solvents and toluene by-product, the free base is obtained as a solid that is relatively stable at room temperatures, e.g., 20-25 ° C.

The desired acid addition salt of pirbuterol is readily prepared by adding a suitable acid, e.g. acetic acid, to the concentrate. At least a stoichiometric amount of acid is added. In practice, no more than a 10% excess of acid is added to the concentrate. To accelerate the precipitation of the acid addition salt, the acid is usually added dissolved 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 at the same time as the acid addition.

7 67541 Pirbuterol prepared by this method is unexpectedly and surprisingly pure from colored impurities. Thus, removal of the benzylidene protecting group by hydrogenolysis affords, in quantitative yield, high quality pirbuterol and, if desired, a high quality acid addition salt thereof.

Crude benzylidene acetal can be used in the process, from which pure product is obtained by debenzylation. Upon removal by hydrogenolysis, the benzylidene protecting group forms toluene as a by-product, which is easily removed from the reaction mixture. Instead of removing the benzylidene group hydrolytically, benzaldehyde is formed, which is not as easily removed from the reaction mixture.

Example 1

Pirbuterol acetate

Solution of 2-phenyl-6- (1-hydroxy-2-t-butylaminoethyl) -4H-pyrido [2,3-d] -1,3-dioxine (1.67 kg, 5.09 mol) ) in methanol (16.7 L) is added to a glass-lined reaction vessel charged with 5% palladium on charcoal at 50% moisture (2.13 kg, 11.6 molar equivalents of water). The mixture is stirred and the reactor is purged first with nitrogen and then with hydrogen. Hydrogen is introduced into the reaction vessel at a pressure of 345 kPa at a temperature of 20-25 ° C and these conditions are maintained throughout the reaction time of 12 hours. The pressure is released from the reactor and the reaction mixture is filtered through diatomaceous earth (TLC analysis using methyl ethyl ketone: acetic acid: water / v / v = 6: 1: 17 on silica gel GF plates showed complete hydrogenolysis.) The filter cake is washed with 500 ml. and the filtrate is treated with activated charcoal (167 g), stirred at 20-25 ° C for one hour and then filtered. A portion of the filtrate containing 1 mole of pirbuterol is concentrated in vacuo to about one third of its volume. Ethanol (2,550 ml) is added to the concentrate and the resulting solution is concentrated in vacuo to one third of its volume. The addition and concentration of ethanol is repeated three or more times to ensure that the pirbuterol concentrate does not contain water.

T ------- 8 67541

Pirbuterol is converted to its acetate salt by adding a solution of glacial acetic acid (67.3 g, 1.12 moles) in acetone (6,125 mL) to the concentrate. The resulting mixture is stirred and warmed to 50-55 ° C and then cooled to room temperature in a water bath. The acetate salt crystallizes out and is filtered, washed with acetone (2 x 500 ml) and dried in vacuo at 20-25 ° C. Yield = 222 g (75%), m.p. 1 54-155 ° C.

Analysis: Calculated for 2 ^ 206) 3 ^ 2 - (^ 2 ^ 4 ^ 2: C 55.99 H 8.05 N 9.33% Found: C 56.60 H 8.16 N 9.56%

Recrystallization from ethanol gives an analytical sample: Analysis, found: C 56.04 H 8.05 N 9.33%.

The remaining methanol solution of pirbuterol is concentrated in vacuo as described above and the ethanol-pirbuterol concentrate is treated with a 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 allowed 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 compressed air oven at 50 ° C (yield 73% assuming 4.09 moles of pirbuterol in the concentrate). The product is a hemifumarate monoethanolate salt. Sp. 135-136 ° C (dec.).

Analysis: Calculated for Λ / 2: 0 55.80 H 8.19 N 8.14%

Found: C 55.72 H 8.25 N 8.06%

Example 2

However, the procedure of Example 1 is repeated using 0.049 mol of 2-phenyl-6- (1-hydroxy-2-t-butylaminoethyl) -4H-pyrido [3,2-d] -1,3-dioxine, 160 ml of methanol as solvent. , 20.38 g of 5% palladium on carbon, 50% water as moisture (11.5 molar equivalents of water) at a hydrogen pressure of 345 kPa at 22 ° 0 for 22.5 hours, whereby the conversion to pirbuterol is carried out at 100% conversion.

Treatment of the ethanol concentrate obtained according to the method of Example 1 with 0.055 mol of glacial acetic acid gives pirbuterol acetate in 73% yield.

67541

Example 3

Pirbuterol acetate (by hydrogenation using a molar equivalent of water

A solution of 2-phenyl-6- (1-hydroxy-2-t-butylaminoethyl) -4H-pyrido [2,3-d] -1,3-dioxine (8.046 g, 0.0245 mol) in methanol ( 80 ml) is added to a 500 ml high pressure flask containing dry 5% palladium on charcoal catalyst (5.095 g) and water (0.45 ml, one molar equivalent) The mixture is stirred and the reactor is first purged with nitrogen and then with hydrogen. Hydrogen is fed to the reactor at a pressure of 345 kPa at a temperature of 20-25 ° C and the conditions are maintained for 24 hours, the pressure is released from the reactor and the reaction mixture is filtered through diatomaceous earth.The filter cake is washed with methanol (2 x 30 ml), combined washings and filtrate treated with activated charcoal (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 washings are concentrated in vacuo to about 25 ml. tFavorite.

To the concentrate is added glacial acetic acid (1.618 g, 0.02695 mol) in acetone (1.50 ml) and the resulting mixture is stirred and heated to 50-55 ° C. The mixture is then cooled overnight to room temperature and then to 0-5 ° C. The solution is then concentrated in vacuo to an oil (since no crystallization occurred) and chloroform (100 mL) is added to the oil. The mixture is stirred at room temperature for two hours and the acetate salt is filtered off, washed with chloroform (2 x 15 ml) and dried. Yield = 7.0 g (91.5%); mp. 1 52-154 ° C.

Example 4

However, the procedure of Example 3 is repeated using the amounts of water mentioned below.

τ ~ · —-- 10 67541 ml water Mooliekviva- Sp. Yield of pirbuterol acetate in dilute water (° C),% a) 13.23 30 153-155 60% +) quality good b) - - 148-151 64% ^ poor quality 0.1 0.23 148-151 61.8% ^ poor quality +) The acetate crystallized from the concentrate on cooling. The relatively low yield is due to the incomplete removal of water from the concentrate before the formation of the acetate salt.

++) NMR shows that 2-hydroxymethyl-3-hydroxy-6- (2-t-butylaminoethyl) pyridine is present as an impurity.

Example 5

However, the procedure of Example 2 is repeated using the following conditions for hydrogen pressure, time, temperature, catalyst and water: 11 67541

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Claims (9)

A process for the preparation of 2-hydroxymethyl-3-hydroxy-6- (1-hydroxy-2-t-butylaminoethyl) pyridine and its acid addition salts by removing the benzylidene protecting group 2-phenyl-6- (1-hydroxy-2-t-butylaminoethyl) -4H -pyrido ε3, 2-47-dioxin, characterized in that the latter compound is hydrogenated in the presence of a palladium catalyst and water in a reaction-inert solvent, and the base obtained is optionally then treated with at least a stoichiometric amount of acid. Process according to Claim 1, characterized in that the catalyst is a palladium-carbon catalyst. Process according to Claim 2, characterized in that the hydrogenolysis is carried out in such a way that, per mole, 2-phenyl-6- (1-hydroxy-2-t-butylaminoethyl) -4H-pyrido [2,3-d] 1,3-dioxin is present in about 1-30 molar equivalents of water. Process according to Claim 3, characterized in that palladium carbon is used as the substance containing 50% of water. Process according to Claim 4, characterized in that the hydrogenolysis is carried out at room temperature with a hydrogen pressure of between about 103 and 1034 kPa. Process according to Claim 5, characterized in that the solvent is methanol. Process according to Claim 5, characterized in that the hydrogenolysed reaction mixture is filtered, concentrated and the concentrate is treated with at least a stoichiometric amount of 2-hydroxymethyl-3-hydroxy-6- (1-hydroxy-2-t-butylaminoethyl) pyridine present. pharmaceutically acceptable acid. Process according to Claim 7, characterized in that the pharmaceutically acceptable acid is acetic acid. A process according to claim 1 for the preparation of 2-hydroxymethyl-3-hydroxy-6- (1-hydroxy-2-t-butylaminoethyl) pyridine acetate by removal of the benzylidene protecting group 13 67541 2-phenyl-6- (2-hydroxy- 2-t-butylaminoethyl) -4H-pyrido [2,3-d] -1,3-dioxine, characterized in that the latter compound is hydrogenolysed with palladium on carbon in methanol at room temperature and a hydrogen pressure of about 103 to 1034 kPa in the presence of about 1 -30 molar equivalents of water, relative to the amount of 2-phenyl-6- (1-hydroxy-2-t-butylaminoethyl) -4H-pyridoZ * 3,2-dj-1,3-dioxin used, the hydrogenolysed reaction mixture is filtered and concentrated, and the concentrate is treated with at least with a stoichiometric amount of acetic acid. 14 67541