CS198159B2 - Process for preparing 2-hydroxymethyl-3-hydroxy-6-/1-hydroxy-2-terc.butylaminoethyl/-pyridine and additive salt with acid thereof - Google Patents

Description

SUMMARY OF THE INVENTION The present invention provides a process for the preparation of 2-hydroxymethyl-3-hydroxy-6- (1-hydroxy-2-tert-butylaminoethyl) pyridine and its acid addition salts thereof, which compounds are suitable β-adrenerdic bronchodilators for mammals.

U.S. Pat. No. 3,700,681 describes 2-hydroxymethyl-3-hydroxy-6- (1-hydroxy-2-aminoethyl) pyridines as bronchodilators for use in mammals. The group of these pyridines described in the aforementioned US patent includes the tert-butyl derivative of the above pyridines, represented by the formula

H

OH

The invention relates to a process, neither described nor suggested in the aforementioned U.S. Pat. No. 3,700,681, for producing a tert-butyl derivative of said pyridines. The process according to the invention is particularly important, since it has surprisingly been found that the tert-butyl derivative of said pyridines can be prepared by a two-step reaction process, as opposed to the multi-step process described in patent specification US 3,700,681. According to the invention, the product is obtained in a surprisingly high yield and with a high purity.

The process of the present invention is characterized in that the 2,2-disulfated 4H pyrido (3,2-d] -1,3-dioxin-6-epoxyethane is heated with at least an equimolar ointment of tert-butylamine, followed by hydrolysis under acidic conditions. conditions at a pH in the range of 1 to 6, preferably 2 to 4, to obtain the product of the invention.

Τ 1 <Ο44 ^ΝΗ

20Cwr ^ CM-CH, ->

me

ZOCJ <

A ^C Awcfc ^ and Jj —p »

OH

(I) wherein W and Z taken together form a residue of acetal or ketal.

The invention also relates to a process for the preparation of addition salts with one or two acid molecules, which addition salts of the tert-butyl derivative of the compounds of the invention are very suitable bronchodilators for mammals.

These addition salts may be obtained, inter alia, by adding an appropriate acid, for example hydrochloric acid, to the product of the first step of the above reaction process or by adding hydrochloric acid to the product of the second step of the above process. Other suitable acids which can be used are listed below.

Finally, the invention also relates to 2-phenyl-4H-pyrido [3,2-d] -1,3-diolino-6-epoxyethane and 2,2-isubstituted 4H-pyrido [3,2-d] -1, 3-dioxin-6-epoxyethane, in particular 2,2-dlmethyl-4H-pyrido [3,2-d] -1,3-dioxin-6-epoxystane, used as intermediates in the above reaction procedure.

The heating or temperature conditions used in the reaction with tert-butylamine are not very important and depend entirely on the desired reaction rate. In an open reaction system, temperatures ranging from 35 ° C to reflux temperature are preferred. However, when the reaction is carried out in a closed system, preferred temperatures are from a reflux temperature of up to 85 ° C. At a temperature of 75 ° C in a closed vessel, a reaction time of from 1 to 5 hours is usually required.

In acid hydrolysis, the product of the preceding step is hydrolyzed at a pH in the range of 1 to 6, preferably 2 to 4. The hydrolysis is carried out in a conventional manner; any mineral acid conventionally used for hydrolysis in an acidic medium may be used. Preferred acids are hydrochloric, sulfuric, phosphoric and nitric because of their ease of availability.

Of course, it is within the scope of the invention to prepare the hydrochloride or other acid addition salt with one or two acid molecules. This can be achieved, inter alia, by adding a suitable acid, for example hydrochloric acid, to the product of the second step of the above process. Examples of other acids which provide pharmaceutically acceptable anions are hydrobromic, hydroiodic, nitric, sulfuric, sulfuric, phosphoric, acetic, lactic, citric, tartaric, succinic, maleic and gluconic acids. If it is desired to prepare the free base after the acid addition salt has been prepared, the addition salt can be neutralized by reacting the compound with a base such as sodium hydroxide. Then, the free base can be converted into any other acid addition salt. It should be noted that the acid addition salt with two acid molecules is the preferred form of the tert-butylpyridine compounds disclosed.

Phenyl moieties may include non-reactive, interfering or protecting substituents. It will be appreciated that the 2-phenyl substituent of the parent compound may be substituted with any non-reactive interfering substituent. A preferred protecting group in this context is the p-nitrophenyl group.

The invention is illustrated by the following examples.

He did

2-Hydroxymethyl-3198159 dihydrochloride

-hydroxy-6- (1-hydroxy-2-tert-butylaminoethyl) pyridine

A) 6- (1-Hydroxy-2-tert-butylaminoethyl) -2-phenyl-4H-pyrido [3,2-d] -1,3-dioxin

To 2.3 g (9 mmol) of 2-phenyl-4H-pyrido [3,2-d] -1,3-dioxin-6-epoxyethane in 25 mL of ethanol was added 0.95 mL of t-butylamine and the resulting reaction mixture. The mixture was heated at reflux for 2 hours. An additional 1 ml of t-butylamine was then added and the mixture was maintained at 50 ° C for 3 hours. The solvent and excess amine were removed under reduced pressure to give 2.21 g of the desired intermediate.

B) 2-Hydroxymethyl-3-hydroxy-6- (1-hydroxy-2-t-butylaminoethyl) pyridine dihydrochloride

1.5 g (4.8 mmol) of the above intermediate, i.e. 6- (1-hydroxy-2-tert-butylaminoethyl) -2-phenyl-4H-pyrido [3,2-d] -1,3 -dioxin is dissolved in 20 ml of acetone / water (1 vol: 1 vol) and 1 ml of 12 N hydrochloric acid is added. After heating the mixture under reflux for 5 hours, the mixture was evaporated to an oily liquid which was dissolved in 100 ml of ethanol. Water was removed azetropically using 3X 100 mL ethanol and the free base of the product was obtained by the addition of triethylamine. The solution is concentrated under reduced pressure to an oily suspension and the free base is extracted from triethylamine hydrochloride by extraction with acetone. The acetone extracts are combined, concentrated to an oily liquid and dissolved in 10 ml of anhydrous ethanol. 0.184 ml of hydrogen chloride-containing ethanol (188 mg HCl / ml ethanol) was added and the solution was added dropwise to 2 liters of anhydrous isopropyleither. The product obtained is filtered off and dried. Yield 1.05 g. Further purification by recrystallization from methanol-acetone gave 950 mg of product which, according to IR and NMR, and by thin layer chromatography, was identical to the product prepared according to U.S. Pat. No. 3,700,681 .

Example 2

2-Hydroxymethyl-3-hydroxy-6- (1-hydroxy-2-tert-butylaminoethyl) pyridine dihydrochloride

A) 2,2-Dimethyl-6- (1-hydroxy-2-t-butylamino) ethyl-4H-pyrido [3,2-d] -1,3-dioxin

To 1.0 g (4.8 mmol) of 2,2-dimethyl-4H-pyrido [3,2-d] -1,3-dioxin-6-epoxyethane was added 20 ml of t-butylamine and the reaction mixture was heated under The tert-butylamine is added periodically to replace the possibly vaporized amount until a total of 80 ml is used. Mon 90. hours, the heating was discontinued and the excess amine was removed under reduced pressure. The product obtained is a yellow solid, m.p. 89.5-92 ° C. Yield 1.168 g. The product is purified by recrystallization from petroleum ether to increase its melting point to 99-100 ° C.

Analysis for C15H24O3N2:

calculated:

C 64.3%, H 8.6%, N 10.0%; found:

C.64.1%, H 8.5%, N 9.9%.

NMR Spectrum (CDCl3): signals - ppm (): 1.1 [9H, C (CH3) 3];

1.6 (6H, 2 CH 3); 3.13-2.46 (4H3; 4.6 (1H); 4.83 (2H, CH2, dioxin) and 7.03 and 7.23 ((2H, C4 and Cs, pyridine)).

B) 2-Hydroxymethyl-3-hydroxy-6- (1-hydroxy-2-tert-butylaminoethyl) pyridine dihydrochloride

To 10 ml of methanol and 10 ml of 10% hydrochloric acid is added 227 mg of 2,2-dimethyl-6- (1-hydroxy-2-tert-butylaminoethyl) -4H-pyrido [3,2-d] -1,3 -dioxin and the resulting reaction mixture was stirred at room temperature for 1.5 hours. Removal of the solvents under reduced pressure at 70 ° C afforded 230 mg of the product produced, which, according to nuclear magnetic resonance spectrum, was identical to the product described in U.S. Pat. No. 3,700,681.

Claims (1)

Process for the preparation of 2-hydroxymethyl-3-hydroxy-6- (1-hydroxy-2-tert-butylaminoethyl) pyridine of the formula I Hoc? OH (1) and pharmaceutically acceptable acid addition salts thereof, characterized in that the compound of formula (II) is heated, BACKGROUND OF THE INVENTION wherein W and Z taken together form a residue of acetal or ketal, with at least an equimolar amount of t-butylamine, the obtained compound is converted to a compound. by hydrolysis at a pH in the range of 1 to 6, preferably 2 to 4, and this compound is then optionally converted into an addition salt with a pharmaceutically acceptable acid, preferably hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, sulfuric, phosphoric, acetic, lactic, lemon, tartar, amber, maleic or gluconic. ZOCH ^ T ^ CH- ^ K.