FI62534C - SOM MELLANPRODUKT VID FRAMSTAELLNING AV 2-HYDROXIMETYL-3-HYDROXI-6- (1-HYDROXI-2-T-BUTYLAMINOETHYL) -PYRIDE ANVAENDBAR 2-HYDROXIMETHYL-3-BENZYLOXIPYRIDINE-6-EPO - Google Patents

Description

62534 Intermediate used in the preparation of 2-hydroxymethyl-3-hydroxy-6- (1-hydroxy-2-t-butylaminoethyl) -pyridine-5-hydroxymethyl-3-benzyloxypyridine-6-epoxyethane

This invention relates to 2-hydroxymethyl-3-benzyl-10-oxypyridine-6-epoxyethane having the formula C, HcCHO0.

6 5 2

A. J-CH-CH I

15 CH 2 O 2 and useful as an intermediate in the preparation of 2-hydroxymethyl-3-hydroxy-6- (1-hydroxy-2-t-butylaminoethyl) pyridine of formula 20.

HOCH2 ^ ^ CH Z ^ HHC (CH3) 3 II

OH

25

The compound of formula II and its acid addition salts have an adrenergic, bronchodilator effect and are described in U.S. Patent 3,700,681. It has surprisingly been found that using an intermediate of the invention, a compound of formula II can be prepared by a 2-step reaction in U.S. Pat. instead of the several reaction steps used in U.S. Patent No. 3,700,681. In addition, it has been found that the use of an intermediate according to the invention surprisingly gives a very pure product in high yield.

According to the process, 2,62534 2-hydroxymethyl-3-benzyloxypyridine-6-epoxyethane according to the invention is heated with at least a molar amount of t-butylamine, after which the product obtained is hydrogenated in the presence of a palladium catalyst 2-hydroxymethyl-3-hydroxy-6- (1-hydroxy-2 t-butyl-5-aminoethyl) pyridine or its acid addition salt.

This synthesis is illustrated by the following reaction scheme: C, HcCH „0.

6 5 2 v (CH 2), CNH- i ° I 1 HOCH 9 ^ -CHL ·

Cc Hj-CH-O ^ 6 5 2 H, 15 I --ch2 \ -> X. JJ-CH NHC (CH-), Pd catalyst

HOCV ^ N ^ OH

HO ^ 20 J— CH * NHC (CH-), HOCH ^

Hydrogen chloride can also be used to open the epoxy ring, after which the resulting halohydrin is treated with t-butylamine to give the amino alcohol, from which the protecting group is removed in a manner known per se.

The following examples illustrate the invention.

Preparation of intermediate according to the invention 2-hydroxymethyl-3-benzyloxypyridine-6-epoxyethane

A solution of 700 g (2.88 moles) of 2-hydroxymethyl-3-benzyloxypyridine-6-carboxaldehyde (U.S. Patent 3,700,681) in 6.5 liters of dry tetrahydrofuran is stirred under a nitrogen atmosphere at 15-2 ° C while when 35,381 ml (3.02 moles) of trimethylchlorosilane are added over 5 minutes at 62534. Stirring is continued for a further 15 minutes and then 417 ml of triethylamine are added. The reaction mixture is warmed to 25 ° C and the trimethylamine hydrochloride salt is filtered.

The resulting filtrate is then added dropwise to a suspension of sodium hydride (128 g of 57% sodium hydride in an oil suspension washed with dry tetrahydrofuran, 3.16 mol) in 4.67 liters of dry dimethyl sulfoxide cooled to 0-5 ° C. After the addition, which requires 20 ml to 10 minutes, 676 g (3.31 moles) of trimethylsulfonium iodide are added and the mixture is allowed to warm to room temperature.

108 ml of water are added dropwise over 1 hour to decompose the excess hydride and the mixture is allowed to stand for a further hour. The mixture is then added to 43 liters of ice water and extracted several times with isopropyl ether. The combined extracts are washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure to give 575 g of 2-hydroxymethyl-3-benzyloxypyridine-6-epoxyethane (oil), yield 78%.

‘NMR analysis (CDCl 3): peaks - ppm (δ): 3.0 (2H

epoxide), 3.9 (1H in epoxide), 4.3 (1H in OH), 4.8 (2H in CH2OH, 5.0 (2H in benzyl), 7.05 C2H to C4, C5 in pyridine) and 7.3 (5H in phenyl).

Manufacture of the final product AI. 732 g (2.85 mol) of 2-hydroxymethyl-3-benzyloxypyridine-6 are added to 3.6 liters of t-butylamine in 2-hydroxymethyl-3-benzyloxy-6- (1-hydroxy-2-t-butylaminoethylpyridine dihydrochloride). epoxyethane and the resulting mixture is heated to reflux at atmospheric pressure for 47 hours The reaction mixture is evaporated to an oil which is treated with 1 liter of tetrahydrofuran and concentrated to dryness under reduced pressure. 592 ml of 12N hydrochloric acid (7.1 mol) with stirring for 1 hour, the volume was reduced to approximately half by concentration and the crystallized 2-hydroxymethyl-3-benzyloxy-6- (1-hydroxy-2-t-butyl-5-aminoethyl) pyridine the dihydrochloride is filtered off and dried in vacuo, 1.1 kg (68% yields), mp 186-189 ° C.

A2. 2-Hydroxymethyl-3-benzyloxy-6- (1-hydroxy-2-t-butylaminoethyl) -pyridine dihydrochloride_The 500 ml Parr flask is charged with 3.7 g (0.01437 moles) of 10-hydroxymethyl-3- benzyloxypyridine-6-epoxyethane and 20 ml of t-butylamine under a nitrogen atmosphere at a pressure of 2.1 kg / cm 2 and the mixture is shaken at 75 ° C for 4.5 hours. After cooling, the t-butylamine is removed under reduced pressure, the oil obtained is dissolved in 57 ml of methanol and this solution is stirred while 13.0 ml of 2.25 molar methanolic hydrogen chloride are slowly added. The temperature of the solution rises to 50 ° C and the solution is cooled to 30 ° C with an ice bath. 70 ml of diisopropyl ether are then added. A slurry is obtained and stirred at room temperature for 20 minutes before filtration. The recovered solid was washed with diisopropyl ether and then dried under high vacuum overnight to give 3.99 g (68.7%) of 2-hydroxymethyl-3-benzyloxy-6- (1-hydroxy-2-t-butylaminoethyl) pyridine dihydrochloride.

B. 2-Hydroxymethyl-3-hydroxy-6- (1-hydroxy-2-t-butylaminoethyl) -pyridine dihydrochloride To 5.5 liters of absolute methanol was added 675 g (1.67 moles) of the benzyloxy compound obtained above, 199 ml of distilled water. water and 347.4 g of wet 5% palladium on carbon (50% catalyst, 50% water), and the mixture is stirred in a 6.6 liter hydrogenation autoclave at room temperature and hydrogen pressure at 3.5 kg / cm 3. After 3 hours and 45 minutes, the absorption of hydrogen ceases and the spent catalyst is filtered off from the hydrogenation mixture. The filtrate is concentrated in vacuo to an oil which is dissolved in 3 liters of absolute ethanol.

5,62534

The water is azeotroped off by concentration to an oil which is then dissolved in 1 liter of methanol containing 47 ml of ethanolic hydrogen chloride. After stirring the solution for 30 minutes, 4 liters of isopropyl ether are added and the resulting precipitate is allowed to stand at room temperature overnight. The product is filtered, washed with isopropyl ether and dried in vacuo, 509 g (97.5% yield). Further purification of the final product is performed by recrystallization from methanol / acetone to give 470 g of product, m.p. 185-187 ° C (decomposes).

The product is identical to the product described in U.S. Patent 3,700,681.