DK146802B - 2-HYDROXYMETHYL-3-HYDROXYPYRIDINE-6-EPOXYETHER DERIVATIVES FOR USING INTERMEDIATES IN THE PREPARATION OF 2-HYDROXYMETHYL-3-HYDROXY-2-YLAMEDYL-2-YLAMEDYL - Google Patents

Description

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(19) DENMARK VIS

f® da) SUBMISSION WRITING out 146802 B

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Patent Application No: 1264/76 (51) Lnt.CI.3: C 07 D 491/056 (22) Filing Date: 23 Mar 1976 C 07 D 405/04 (24) Running Date: 20 Dec 1974 (41) Alm. available: 23 Mar 1976 (44) Submitted: 09 Jan 1984 (86) International Application No: - (62) Stock Application No: 6723/74 (30) Priority 26 Dec 1973 US 428451 09 Oct 1974 US 513213 (71) The application 'PFIZER INC .; New York, US.

(72) Inventor: Susumu 'Nakanishl; US.

(74) Agent: Hofman-Bang & Boutard Patent Office (54) 2-Hydroxymethyl-3-hydroxypyridine-6-epoxy ether derivatives for use as intermediates in the preparation of 2-hydroxymethyl-3-hydro-xy-6- {1-hydroxy -2-t-butylaminoethyl) pyridine

This invention relates to novel 2-hydroxymethyl-3-hydroxypyridine-6-epoxyethane derivatives for use as intermediates in the preparation of 2-hydroxymethyl-3-hydroxy-6- (1-hydroxy-2-t-butylaminoethyl) pyridine, which compound is useful as β-adrenergic agonist bronchodilator in mammals.

In U.S. Patent No. 3,700,681, 2-hydroxy-3-methyl-3-hydroxy-6- (1-hydroxy-2-aminoethyl) -pyridines are disclosed for use as mammal bronchodilators. Included in tf Γ "* 2 U6 & 02 this group of pyridines is the t-butyl form represented by the following formula: \ 1 / CH2 \ hdch2 ^ nXj" nhc (ch3) 3

According to the aforementioned US patent, this compound is prepared from 2-hydroxymethyl-3-benzyloxy-pyridine-6-carboxaldehyde by reaction with t-butylisonitrile in acetic acid in the presence of hydrochloric acid, removal of the acetyl group from the α-hydroxy group in the Nt-butyl formed -a- (2-Hydroxy methyl-3-benzyloxy-6-pyridyl) -α-acetoxyacetamide, reduction of the carbonyl group with diborane and removal of the protecting benzyl group by catalytic hydrogenation in the presence of hydrochloric acid to form of the dihydrochloride salt of the desired compound. Thus, this process comprises four steps and gives the desired compound in a total yield of approx. 13%.

It has now been found that the dihydrochloride salt of the desired compound can be prepared in two steps from hydroxy-protected 2-hydroxymethyl-3-hydroxypyridine-6-epoxyethane, which can be prepared from hydroxy-protected 2-hydroxymethyl-3-hydroxypyridine-6 carboxaldehyde, thereby obtaining a much higher yield than in the method of U.S. Patent No. 3,700,681. The process is the subject of Danish Patent Laid-Open No. 146,158.

Said process is characterized in that a compound of the formula:

"XX

ZOCHo ^ No CH-CH2 / 2 3 wherein W is benzyl and Z is hydrogen or W and Z are

R

together form the residue of an acetal or ketal of the formula wherein R and R 'are methyl or phenyl, or R is hydrogen and R' is phenyl, heated with at least an equimolar amount of t-butylamine, upon which the resulting compound of the formula:

zoch2 ^^ n ^^ ch-ch2-nhc (ch3) 3 III

OH

is converted to the desired compound by decomposition of the protecting groups in a manner known per se by catalytic hydrogenation in the presence of a palladium catalyst when W is benzyl and Z is hydrogen, or by acid hydrolysis at pH = 1-6 when W and Z together form the remainder of an acetal or ketal, after which the compound, if desired, is converted into a pharmaceutically acceptable acid addition salt thereof.

Accordingly, the 2-hydroxy-3-hydroxy-pyridine-6-epoxy-ethane derivatives of the invention are characterized by the characterizing part of claim 1.

Danish Patent Application No. 3821/72 discloses processes whereby phenoxyepoxypropane is reacted with 3-pyridyl-3-hydroxypropylamine, or phenol is reacted with 1,2-epoxy-3- (3-pyridyl-3-hydroxypropylamino) propane, and from Danish Patent Nos. 100 431, 102 471 and 118 613 disclose processes whereby various substituted phenylepoxyethanes are reacted with amines to form the corresponding 1- (substituted-phenyl) -2-aminoethanols. None of these writings relates to the use of pyridylepoxyethanes. The only known reference to an analogous process for reacting pyridylepoxyethanes is French Patent No. 1,597,967, which, however, does not give examples of its embodiment. Furthermore, this patent relates to the preparation of halogen-substituted pyridines, while the process of the present invention is to prepare 2-hydroxymethyl-3-hydroxy-6- (1-hydroxy-2-t-butylaminoethyl) pyridine, wherein the two hydroxy groups requires protective groups. The process mentioned in the French patent is obviously not a preferred method, since only other, completely unrelated methods are exemplified.

It was not to be expected that the process according to DK Patent Specification No. 146 158, which is based on the novel hydroxy-protected pyridylepoxyethanes of the invention and t-butylamine, would be useful in preparing the desired compound in very high yield and there was no need to transfer the teachings of the aforementioned French patent not relating to the use of the present 2- (epoxyethyl) pyridines, but the use of other compounds with the epoxy group bound to another position in the pyridine ring, to the particular problem of the application.

The intermediates of the invention used in the above process are 2-hydroxymethyl-3-benzyloxy-pyridine-6-epoxyethane, 2-phenyl-4H-pyrido [3,2-d] -1,3-dioxane-6-epoxyethane and 2,2-disubstituted 4H-pyrido [3,2-d] -1,3-dioxane-6-epoxyethanes, the substituents each being methyl or phenyl, especially 2,2-dimethyl-4H-pyrido [3,2-d] -l, 3-dioxan-6-epoxyethane.

These compounds can be prepared by a hydroxy-protected 2-hydroxymethyl-3-hydroxy-pyridine-6-carboxaldehyde of the formula (/ Xch.-o.

\ = / V> i or «'Ί I

Wherein R and R 'are as defined above, reacted with trimethylsulfonium iodide or chloride in the presence of sodium hydride and dimethylsulfoxide and / or tetrahydrofuran, and the resulting mixture is treated with water.

The preparation of the intermediates of the invention and their use in the preparation of the therapeutically valuable compound, 2-hydromethyl-3-hydroxy-6- (1-hydroxy-2-tert.-butylaminoethyl) pyridine or acid addition salts thereof, are further elucidated in the following examples.

Preparation of intermediates according to the invention.

Example 1 2-Hydroxymethyl-3-benzyloxypyridine-6-epoxyethane

A solution of 700 g (2.88 mol) of 2-hydroxymethyl-3-benzyloxy-pyridine-6-carboxaldehyde (U.S. Patent No. 3,700,681) in 6.15 liters of dry tetrahydrofuran is stirred under a nitrogen atmosphere at 15 + 2. ° C while adding 381 ml (3.02 mole) of trimethyl chlorosilane over 5 minutes. Stirring is continued for a further 15 minutes followed by addition of 417 ml of triethylamine. The reaction mixture is heated to 25 ° C and the trimethylamine hydrochloride salt is filtered off.

The resulting filtrate is then added dropwise to a suspension of sodium hydride (128 g of 57? Sodium hydride in oil suspension washed with dry tetrahydrofuran; 3.16 mol) in 4.6 liters of dry dimethyl sulfoxide cooled to 0-5 ° C. After the addition, which requires 20 minutes, 676 g / 3.311 moles of powdered trimethylsulfonium iodide are added and the mixture is allowed to warm to room temperature.

108 ml of water is added dropwise over 1 hour to break down the excess hydride and the mixture is stirred for an additional 1 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 a saturated aqueous sodium chloride solution and dried over aqueous sodium sulfate. Removal of the solvent under reduced pressure gives the intermediate as an oil, 575 g (78? Yield).

NMR (CDCl3): maxima - ppm ($): 3.0 (2H in epoxide); 3.9 (1H in epoxide); 4.3 (1H in OH); 4.8 (2H in CH 2 OH); 5.0 (2H in benzyl); 7.05 (2H-C ^, C ^ in pyridine) and 7.3 (5H in phenyl).

Example 2 2- phenyl-4H-pyrido [3,2-d] -1,3-dioxane-6-epoxyethane A. 6-hydroxymethyl-2-phenyl-4H-pyrido [312-d] -1,3-dioxane

To a stirred suspension of 31 g (0.2 mole) of 2,6-bis (hydroxymethyl) -3-hydroxypyridine (U.S. Patent No. 3,700,681) in 101 mL (1 mole) of benzaldehyde at 20-25 ° C 56.7 g (0.4 mole) of boron trifluoride etherate are added dropwise over 45 minutes. The mixture is stirred at room temperature for 2 hours and the excess benzaldehyde is removed under reduced pressure. After standing at room temperature, the residue is added to 75 ml of a 10 M aqueous sodium hydroxide solution and the product is extracted into methylene dichloride. The organic phase is separated, concentrated in vacuo to 100 ml and the methylene dichloride is diluted with n-hexane. The crude product which crystallizes is filtered off and dried; 37.4 g (77? Yield), m.p. 85-89 ° C. Further purification is performed by recrystallization from acetone / n-hexane; 22.1 g, m.p. 114-118 ° C.

Analysis calculated for C ^ HH ^O29N: C 69.13 - H 5.29 - N 5.76 Found: C 69.21 - H 5.43 - N 5.70 B. 6-Formyl-2-ghen ^ l-4H-pyrido [3,2-d] -l13-dioxin

To a suspension of 38.8 g (0.4 mole) of activated manganese dioxide in 400 ml of benzene is added 48.6 g (0.2 mole) of 6-hydroxymethyl-2-phenyl-4H-pyrido [3,2-d]. ] -1,3-dioxin in 250 ml of the same solvent and the mixture is stirred at reflux temperature overnight. The mixture is filtered hot (50 ° C) and the filtrate is concentrated under vacuum to an oily foam; 49.7 g. The intermediate is purified by chromatography on a silica gel column (1 kg 0.074 - 0.250 mm silica gel; 8 cm X 75 cm column) eluting with ethyl acetate. The eluates are combined and evaporated to dryness; 11.75 g (mp 110-114 ° C).

Analysis: Calculated for C 69.71 - H 4.60 - N 5.80 Found: C 69.57 - H 4.69 - N 5.73 C. 2-Phenyl-4H-pyrido [-312-d] - LI3-dioxin-6-epoxyethane

To a mixture of dimethyloxosulfonium methylide prepared by refluxing a mixture of 132 mg (13 millimoles) of sodium hydride and 1.67 g (13 millimoles) of trimethyl oxosulfonium chloride in 20 ml of tetrahydrofuran (EJ Corey et al., J. Am. Chem.

Soc., 87 (1353 (1965)), 2.4 g (10 millimoles) of 6-formyl-2-phenyl-4H-pyrido [3,2-d] -1,3-dioxin is added dropwise in 10 ml. dry tetrahydrofuran while maintaining the mixture at 55 + 2 ° C. After the addition, which requires 1 hour, the mixture is stirred at 55 ° C for an additional 1.5 hours. The reaction mixture is concentrated in vacuo to 10 ml, added dropwise under nitrogen 25 ml of water and the intermediate extracted with ethyl acetate. The extract is separated, dried over magnesium sulfate and concentrated under reduced pressure to give the product as an oily solid; 2.45 g (94¾).

NMR (CDCl3): maxima - ppm (<f): 3.1 (2H in epoxide); 4.0 (1H in epoxide); 5.19 (2H in 1,3-dioxin); 6.1 (1H in dioxin); 7.2 (C ^ and in pyridine) and 7.28 (-5H in phenyl).

EXAMPLE 3 2,2-Diphenyl-4H-pyrido [3,2-d] -1,3-dioxin-6-epoxyethane A-2-zformyl-2,2 = diphenyl-4H-pyrido [3 2-d] -lz3-dioxin

A mixture of 1.6 g (3 millimoles) of 6-hydroxymethyl-2,2-diphenyl-4H-pyrido [3,2-d] -1,3-dioxin, 120 ml of benzene and 1.74 g (20 millimoles) Activated manganese dioxide was heated to reflux for four hours. The reaction mixture was cooled, filtered and the filtrate evaporated in vacuo to give the desired aldehyde, 1.35 g (98%), m.p. 137 - 138DC. Infrared spectrum (KBr) µm: 3.5; 5.8; 6.35; 6.8; 6.9; 7.95; 8.3; 8.6; 9.0; 9.2; 9.8; 10.4; 10.6; 10.9; 11.9; 12.7; 13.3; 13.5 and 14.3.

B. 212-Diphenyl-4H-pyrido [3,2-d] -1,3-dioxin-6-epoxyethane

To the aldehyde prepared (A, above, 1.27 g, 4 millimoles) in 10 ml of tetrahydrofuran was added a mixture of dimethyl sulfonium methylide in dimethyl sulfoxide (DMSO), prepared from 1.09 g (5.2 millimoles) of trimethylsulfonium iodide, 53 g (5.2 millimoles) of NaH and 5 ml of DMSO by stirring at 5 - 2 ° C for ten minutes. The reaction mixture was stirred at 5 ° C for ten minutes, warmed to 25 ° C, the reaction quenched with water, and the reaction stirred for 5 minutes and then extracted with benzene. The extracts were washed with water, dried (Na9 SO4) and the benzene evaporated in vacuo to give the desired 2 A 2 product as an oil, 1.32 g (99%). H-NMR> (CDCl3) ppm (S): 2.7 - 3.2 (m, 2H), 3.8 - 4.0 (q, 1H), 5.0 (d, 2H), 6.8 - 7.8 (m, 12H).

EXAMPLE 4 2,2-Dimethyl-4H-pyrido [3,2-d3-1,3-dioxin-6-epoxyethane A. 2,2-dimethyl = 6-hydroxymethyl-4H-pyrido [312-d] -1, 3-dioxin

To a 250 ml flask equipped with reflux, drying tube, thermometer and magnetic stirrer is added 3.0 g (19.3 millimoles) of 2,6-bis (hydroxymethyl) -3-hydroxypyridine, 45 ml (362 millimoles) 2, 2-dimethoxy-propane, 60 ml of dimethylformamide and 30 mg of p-toluenesulfonic acid monohydrate, and the mixture is heated to 110 - 115 ° C for 2.5 hours. Add 500 mg of sodium bicarbonate and cool the yellow reaction mixture to room temperature. The mixture is filtered and the filtrate is added to 100 ml of water / 100 ml of ethyl acetate and stirred for 20 minutes. The organic layer is separated and the aqueous phase is saturated with sodium chloride and further extracted with ethyl acetate.

The combined ethyl acetate extracts are dried over magnesium sulfate and then concentrated to a yellow oil; 3.47 g.

A sample of 514 mg of the residual oil in 15 ml of ethanol / water (1: 1) is treated with 1 ml of a 5? Acetic acid solution and stirred for 3 hours. The solution is basified (pH 8) with a 5% sodium hydrogen carbonate solution and most of the ethanol is removed under reduced pressure. The residue is saturated with sodium chloride and extracted several times with methylene chloride. The combined dried (MgSO 4) extracts are concentrated to dryness to give 332 mg of the desired product as a yellow oil.

NMR (CDCl3): - maxima - ppm (<f): 1.5 (6H in 2 CH3); 4.6 (2H in CH 2); 4.8 (2H - CH2 in dioxin) and 7.0 and 7.25 (2H - C1, in pyridine).

B. 2,2-Dimethyl-4H-pyrido [3,2-d] -1,3-dioxin-6-carboxaldehyde

A mixture of 4.55 g (52.5 millimoles) of activated manganese dioxide in 160 ml of benzene contained in a flask, provided with a reflux condenser and a Dean-Stark distillation trap, is heated under reflux, 146802 -Γ ". of the benzene has been removed through the trap.

To the resulting suspension in the flask is added 2.06 g (10.5 mil limol) of 2,2-dimethyl-6-hydroxymethyl-4H-pyrido [3,2-d] -1,3-dioxin in 20 ml of benzene, and the reflux heating is continued for 3 hours. The mixture is filtered and the filtrate is concentrated in vacuo to an oil which crystallizes; 1.85 g. The product is further purified by recrystallization from hexane; 1.3 g, m.p. 78.5 - 79 ° C.

Analysis: Calculated for C 10 H 10 NO 3 N: C 62.2 - H 5.7 - N 7.3 found: C 62.1 - H 5.8 - N 7.2 NMR (CDCl 3): maxima - ppm (i): 1.6 (6H in 2 CH 2); 4.9 (2H-CH 2); 7.2 and 7.8 (2H C ^, in pyridine); and 9.9 (1H - CHO).

2,2-Dimethyl-4H-pyrido [3,2-d] -1,1-dioxin-6-epoxyethane 384 mg of a 50 µl suspension of sodium hydride in oil is washed free of the oil with pentane under a nitrogen atmosphere. To the oil-free sodium hydride is added 10 ml of dimethyl sulfoxide and the resulting suspension is heated to 65 - 70 ° C for 45 minutes. The resulting gray solution is cooled to between -5 and -8 ° C and 20 ml of tetrahydrofuran is added. To this mixture is then added 1.92 g (9.5 millimoles) of trimethylsulfonium iodide in 15 ml of dimethyl sulfoxide, followed by about 1 minute of 1.3 g (6.7 millimoles) of 2,2-dimethyl-4H-pyrido [3 , 2-d] -1,3-dioxin in 15 ml of tetrahydrofuran. After 10 minutes, cooling is stopped and the reaction mixture is allowed to warm to room temperature. 30 ml of water and 40 ml of diethyl ether are added and the neat dimethyl sulfoxide layer is separated for further extractions with ether. The ether extracts are combined, dried over magnesium sulfate and concentrated to give 1.1 g (80%) of the product as a yellow oil.

11

Analysis calculated for C 6 · 5 ′ H “N 6.8 found s C 63.2 - H 6.3 - N 6.6 NMR (CDCl 3): maxima - ppm (<£): 1.56 (6H in 2 CH3); 3.03 (2H epoxide); 3.9 (1H epoxide); 4.87 (2H CH2); and 7.05 (2H C5 in pyridine).

Use of intermediates of the invention in the preparation of 2-hydroxymethyl-3-hydroxy-6- (1-hydroxy-2-tert.-butylaminoethyl) pyridine and acid addition salts thereof.

EXAMPLE 5 A. 2-Hydroxymethyl-3-benzyloxy-6- (1-hydroxy-2-t-butylaminoethyl) -pyridine dihydrochloride I. To 3.6 liters of t-butylamine are added 732 g (2.85 mole) of 2- hydroxymethyl-3-benzyloxypyridine-6-epoxyethane, and the resulting mixture is heated under 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 under reduced pressure to dryness.

The residual oil is redissolved in tetrahydrofuran (4.32 liters) and then treated with 592 ml of 12 N hydrochloric acid (7.1 mol) with stirring for 1 hour. The volume is reduced by concentration to about half, and the crystallized 2-hydroxymethyl-3-benzyloxy-6- (1-hydroxy-2-t-butylaminoethyl) pyridine dihydrochloride is filtered off and dried in vacuo, 1.1 kg (68by yield), mp. 186 - 189 ° C.

II. Into a 500 ml Parr flask is introduced 3.7 g (0.01437 mol) of 2-hydroxy-methyl-3-benzyloxypyridine-6-epoxyethane and 20 ml of t-butylamine under a nitrogen pressure of 2.1 kp / cm shake at 75 ° C for 4.5 hours. After cooling, the t-butylamine is removed under reduced pressure, the resulting oil is dissolved in 57 ml of methanol, and this solution is stirred while slowly adding 13.0 ml of 2.25 M methanolic hydrogen chloride. The temperature of the solution reaches 30 ° C and the solution is cooled to 30 ° C in an ice bath. Then 70 ml of diisopropyl ether is added. The resulting slurry is stirred at room temperature for 30 minutes and then filtered. The recovered solid is washed with diisopropyl ether and then dried under high vacuum overnight to give a yield of 3.99 g (68.7%) of 2-hydroxymethyl-3-benzyloxy-6- (1-hydroxy-2-t-one). butylaminoethyl) pyridine dihydrochloride.

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

To 5.5 liters of absolute methanol are added 675 g (1.67 mole) of the above benzyloxy compound, 199 ml distilled water and 347.4 g wet 5% palladium-on-charcoal (50% catalyst} 50% water) and the mixture is stirred in a 7.6 liter hydrogenation autoclave at room temperature and at a hydrogen pressure of 3.5 kp / cm. After 3 hours and 45 minutes, hydrogen uptake ceases and the spent catalyst is filtered from the hydrogenation mixture. The filtrate is concentrated in vacuo to an oil which is dissolved in 3 liters of absolute ethanol. The water is azeotropically removed 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 stirred at room temperature overnight. The product is filtered off, washed with isopropyl ether and dried in vacuo, 509 g (97.5% yield). Further purification of the final product is carried out by recrystallization from methanol / acetone, · 470 g, m.p. 185 DEG-187 DEG C. (decomp.).

The product is identical to that reported in the description of U5 Patent No. 3,700,681.

EXAMPLE 6.

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

To 2.3 g (9 millimoles) of 2-phenyl-4H-pyrido [3,2-di-1,3-dioxin-6-epoxy-ethane in 25 ml of ethanol is added 0.95 ml of t-butylamine and the resulting The reaction mixture is heated to reflux temperature for 2 hours. An additional 1 ml of t-butylamine is added and the mixture is kept at 50 ° C for 3 hours. The solvent and excess amine are removed in vacuo to give 2.21 g (70¾) of the desired intermediate.

B. 2-Hydroxymethyl-3-hydroxy-6- (1-hydroxy-2-t-butylaminoethyl) -pyridine dihydrochloride 1.5 g (4.8 millimoles) of the above intermediate, 6- (1-hydroxy-2) -t-Butylaminoethyl) -2-phenyl-4H-pyrido [3,2-d] -1,3-dioxin, dissolved in 20 ml of acetone / water (1: 1 v / v) and treated with 1 ml of 12N hydrochloric acid. After heating the solution to reflux for 5 hours, the mixture is concentrated to an oil and dissolved in 100 ml of ethanol. The water is azeotropically removed with three times 100 ml portions of ethanol and the free base of the product is obtained by the addition of triethylamine. The solution is concentrated in vacuo to an oily slurry and the free base is extracted from the triethylamine hydrochloride by extraction with acetone. The acetone extracts are combined, concentrated to an oil and the oil dissolved in 10 ml of dry ethanol.

0.184 ml of ethanol containing hydrogen chloride (188 g HCl / ml ethanol) is added and the solution is added dropwise to 2 liters of dry isopropyl ether. The product is filtered off and dried; Further purification by recrystallization from methanol / acetone gives 950 mg (70¾) of the product which, by infrared and magnetic nuclear resonance spectroscopy and thin layer chromatography, is identical to that disclosed in U.S. Patent No. 3,700. 681st

EXAMPLE 7 A. 6- (1-Hydroxy-2-t-butylaminoethyl) -2,2-diphenyl-4H-pyrido-____ [3

A mixture of the product prepared in Example 3 (1.1 g, 3.3 millimoles), 5 ml of t-butylamine and 20 ml of ethanol was heated to reflux for 18 hours and then concentrated to dryness in vacuo. 146802 to obtain 1.32 g (99¾) of the title compound. Thin layer chromatography in two different solvent systems showed that the product was homogeneous: Ethyl acetate / diethylamine (95: 5): R 0.3 Isopropyl ether: R 0.1.

B. Z ~ hydroxymethyl-3-hydroxy-6- (1-hydroxy-2-t-butylaminoethyl) -pyridine dihydrochloride

The product from A was taken up in 10 ml of methanol and 6.0 ml of 1.5 N methanol hydrochloride was added. The mixture was heated to reflux for 4 hours and then concentrated to dryness in vacuo.

The residual solid was crystallized from methanol / acetone and dried in vacuo to give 918 mg (90¾) of the desired product, m.p. 186 - 188 ° C.

EXAMPLE 8 A. 2,2-Dimethyl-6- (1-hydroxy-2-t-butylaminoethyl) -4H-pyrido [3,2-d] -1,3-dioxin

To 1.0 g (4.8 millimoles) of 2,2-dimethyl-4H-pyrido [3,2-d] -dioxin-6-epoxyethane is added 20 ml of t-butylamine and the reaction mixture is heated to reflux, adding periodically t-butylamine to replace everything evaporated until a total of 80 ml is used. After 90 hours, the heating is stopped and the excess amine is removed under reduced pressure. The product is isolated as a yellow solid; 1.168 g (87¾), m.p. 89.5 - 92 ° C. The product is further purified by recrystallization from petroleum ether; mp. 99 - 100 ° C.

Analysis calculated for: C 64.3 - H 8.6 - N 10.0 Found: C 64.1 - H 8.5 - N 9.9 NMR (CDCl 3): maxima - ppm (<f): 1 , 1 (9H in C (CH2) - j); 1.6 (6H in Z CH 2); 3.13-2.46 (4H) j 4.6 (1H); 4.83 (2H CH2 in dioxin); and 7.03 and 7.23 (2H C ^, in pyridine).