CS198158B2 - Process for preparing derivatives of pyridin-6-epoxyethane - Google Patents

Description

The present invention provides a process for the preparation of pyridine-6-epoxyethane derivatives of the general formula I

WO

ZOCHz

(AND)

W represents a benzyl group when Z is hydrogen, or

W and Z together form the remainder of the acetal or ketal.

In particular, the invention relates to a method of manufacture

2-hydroxymethyl-3-benzyloxypyridine-6-6-epoxyethane, 2-phenyl-4H-pyrido [3,2-d] -1,3-dihydro-6-epoxyethane and 2,2-disubstituted 4 ' H-pyrido [3,2-d] -1,3-dioxin-6-epoxyethanes, which are intermediates in the preparation of [beta] -adrenergic bronchodilators. formulas

WO

BOY&

NHC (CH.) 8

OH

As mentioned above, the invention relates to a process for the preparation of 2-hydroxymethyl-3-benzyloxypyridine-6-epoxyethane, 2-phenyl-4H-pyrido 3,2-d] -1,3-dioxine-6-epoxyethane, and

2,2-disubstituted 4H-pyrido [3,2-d] -1,3-dioxin-6-epoxyethanes, in particular 2,2-dimethyl-4H-pyrido [3,2-d] -1,3-dioxin -O-epoxy-ethane.

The process according to the invention for the preparation of said compounds of general formula zocw.

CH - CH 2 • in where

W represents a benzyl group when Z is hydrogen, or W and Z together form 18158

198138 is an acetal or ketal residue, characterized in that it is a compound of the formula

Z'OCH? ^ N ^ cHO where

W represents a benzyl group, when Z 'represents a trimethylsilyl group, or W and Z' together represent a residue of acetal or ketal, reacted with trimethylsulfonium iodide or trimethylsulfone chloride in the presence of sodium hydride and dimethylsulfoxide and / or tetrahydrofuran, then treated with water .

The invention is illustrated by the following examples.

Example 1

2-hydroxymeithyl-3-benzyloxypyridine-6-epoxyethane

A solution of 700 g (2.88 mol) of 2-hydroxymethyl-3-benzyloxypyridine-6-carboxaldehyde, prepared according to U.S. Pat. No. 3,700,681, in 6.5 L of anhydrous tetrahydrofuran is stirred under nitrogen at 15 ± 2 ° C. and trimethylchlorosilane (381 ml, 3.02 mol) was added over 5 minutes. The mixture was stirred for an additional 15 minutes and 417 ml of triethylamine was added. The reaction mixture was warmed to 25 ° C and trimethylamine hydrochloride was filtered off.

The resulting filtrate was then added dropwise to a suspension of sodium hydride (128 g of 57% sodium hydride in an oil suspension washed with anhydrous tetrahydrofuran; 3.16 mol) in 4.67 liters of anhydrous dimethylsulfoxide cooled to 0-5 ° C. After this addition, which lasted 20 minutes, 676 g (3.31 mol) of trimethylsulfonium iodide powder were added and the mixture was allowed to reach room temperature.

108 ml of water are added dropwise over 1 hour to quench excess hydride and the mixture is then stirred for an additional hour. The reaction mixture was then added to 43 liters of ice water and extracted several times with isopropyl ether. The combined extracts were washed with an aqueous solution, saturated sodium chloride, and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure gave the intermediate as an oil, 575 g (78% yield).

NMR spectrum (CDCl3): signals - ppm (5):

3.0 (2H, epoxide),

3.9 (1H, epoxide),

4.3 (1 H, OH),

4.8 (2H, CH 3 OH),

5.0 (2H, benzyl),

7.07 (2H, C4, C5, pyridine) and

7.3 (5Ή, phenyl).

Example 2

2-Phenyl-4H-pyrido [3,2-d] -1,3-dioxine-6-epoxyethane

A. 6-hydroxymethyl-2-phenyl-4H- *

-pyrido [3,2-d] -1,3-dioxine

To a suspension of 31 g (0.2 mol) of 2,6-bis (hydroxymethyl) -3-hydroxypyridine, prepared as described in U.S. Pat. No. 3,700,681, in 101 ml (1 mol) of benzaldehyde was stirred at 20 DEG C. with stirring. 56.7 g (0.4 mol) of boron trifluoride etherate are added dropwise over 45 minutes to 25 ° C. The mixture was stirred at room temperature for 2 hours, then excess benzaldehyde was removed by distillation under reduced pressure. The residue was allowed to stand at room temperature, added to 75 ml of 10M aqueous sodium hydroxide solution and the product was extracted with methylene dichloride. The organic phase was separated, concentrated under reduced pressure to a volume of 100 ml and the methylene dichloride was diluted with n-hexane. The crystallized crude product is filtered off and dried. Yield: 37.4 g (77% of theory); Further purification is achieved by recrystallization from a mixture of acetone and n-hexane. Yield 22.1 g, m.p. 114-118 ° C.

Analysis for CwHisOsN:

calculated:

69.13% C, 5.39% H, 5.7% N, found *

69.2.1 O / β C, 5.43 0 / o H, 5.70% N.

B. 6-Formyl-2-phenyl-4H-pyrido [3,2-d] -1,3-dioxine

To a suspension of activated manganese dioxide (38.8 g, 0.4 mole) in benzene (400 ml) was added 6-hydroxymethyl-2-phenyl-4H-pyrido [3,2-d] - 1,3-dioxin in 250 ml of the same solvent and the mixture was stirred at reflux overnight. The mixture was filtered hot (50 ° C) and the filtrate concentrated under reduced pressure to an oily foam (49.7 g). The intermediate is purified by chromatography on a column packed with silica gel (1 kg silica gel, particle size 6.60 - 200 mesh, column diameter 8 cm, height 75 cm); eluting the product with ethyl acetate. The combined eluates were evaporated to dryness to give 11.75 g of product, m.p. 110-114 ° C.

Analysis for CuHhOjN:

calculated:

89.71 o / o C, 4.60% H, 5.80% N, found:

% H, 4.69;% N, 5.73.

C. 2-Phenyl-4H-pyrido [3,2-d] -1,3-dioxin-6-epoxyethane

To a mixture of dimethyloxosulfonium methylide prepared by heating a mixture of 132 mg (13 mmol) of sodium hydride and 1.67 g (13 mmol) of trimethylsulfonium chloride in 20 ml of tetrahydrofuran (EJ Corey et al., J. Am. Chem. Sou., 87, p. 1353). [1965]) under reflux, dropwise at 55 + ± 2¾ 2.4 g (10 mmol) of 6-formyl-2-phenyl-4H-pyrido [3,2-d] -1,3-dloxine in 10 ml of anhydrous tetrahydrofuran. After the addition, which takes 1 hour, the mixture was stirred at 55 ^Q C for an additional 1.5 hours. The reaction mixture was concentrated under reduced pressure to a volume of 10 ml, 25 ml of water was added dropwise under a nitrogen atmosphere, and the resulting intermediate was extracted with ethyl acetate. The extract was separated, dried (MgSO4) and concentrated under reduced pressure to give the product as a viscous residue. Yield 2.45 g.

NMR Spectrum (CDCl3): signals - ppm i (a):

3.1 (2H, epoxide),

4.0 (1H, epoxide),

5.19 (2H, 1,3-dioxin),

6.1 (1H, dioxin)

7.2 (C4 and Cs, pyridine and

7.218 (5H, phenyl).

Example 3

2,2-dimethyl-4H-pyrido [3,2-d] -1,3-dioxin-6-epoxyethane

A. 2,2-Dimethyl-6-hydroxymethyl-4H-pyrido] 3,2-d] -1,3-dioxin

To a 250 mL flask equipped with a condenser, drying tube, thermometer and magnetic stirrer was added 3.0 g (19.3 mmol), 2,6-bis (hydroxymethyl) -3-hydroxypyridine, 45 mL (362 moles). 2,2-dimethoxypropane, 60 ml dimethylformamide and 30 mg p-toluenesulfonic acid monohydrate The resulting reaction mixture was heated at 110-115 ° C for 2.5 hours, then 500 µg of sodium bicarbonate was added and the yellow reaction mixture was cooled. After cooling, the mixture was filtered and the filtrate was added to a mixture of 100 ml of water with 100 ml of ethyl acetate and stirred for 20 minutes, the organic layer was separated, the aqueous layer was saturated with sodium chloride and extracted with ethyl acetate. It was then concentrated to a yellow oil (3.47 g).

To 51.4 mg of the obtained oily liquid in 15 ml of ethanol / water (1: 1) was added 1 ml of a 3% acetic acid solution and the mixture was allowed to stir for 3 hours. The solution was basified with sodium bicarbonate solution to pH 8 and most of the ethanol was removed under reduced pressure. The residue was saturated with sodium chloride and extracted several times with methylene chloride. The combined extracts were evaporated to dryness after drying over magnesium sulfate to give 332 mg of the desired product as a yellow oil.

NMR spectrum (CDCl3): signals - ppm (5):

1.5 (6H, 2-CH 3),

4.6 (2H, CH 2),

4.8 (2H, CH2-dioxine);

7.0 and 7.25 (2H, C4 and Cs pyridine).

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

A mixture of 4.55 g (52.5 mmol) of activated manganese dioxide and 100 ml of benzene contained in a flask equipped with a reflux condenser and a Dean-Stark distillate trap was heated to reflux until about 80 ml of benzene was distilled into the trap. 2.06 g (10.5 mmol of 2,2-dimethyl-6-hydroxymethyl-4H-pyrido [3,2-d] -1,3-dioxin) in 20 ml of benzene are added to the suspension remaining in the flask, whereupon The mixture was filtered, and the filtrate was concentrated under reduced pressure to an oily liquid which crystallized to yield 1.85 g. The product was further purified by recrystallization from hexane to give the title compound as a white solid, m.p.

1.3 g of product, m.p. 78.5-79 ° C. Analysis for C 10 H 11 O 3 N:.

calculated:

62.2% C, 5.7% H, 7.3% N, found:

H, 5.8%; N, 7.2%;

NMR (Deuterochloroform): signals (ppm)?

1.6 (6'H, 2CH 3),

4.9 (2iH, _CH2),

7.2 and 7.8 (2H, C4 and Cs, pyridine) and

9.9 (1 H, CHO).

C. 2,2-Dimethyl-4H-pyrido [3,2-d] -1,3-dioxin-6-epoxyethane

384 mg of 50% oil suspension of sodium hydride with washing with pentane under nitrogen atmosphere ^; knows oils. To the oil-free sodium hydride is added 10 ml of dimethylsulfoxide and the resulting suspension is heated at 65-70 ° C for 45 minutes. The gray solution obtained is cooled to -5 to -8 ° and 20 ml of tetrahydrofuran are added. Then 1.92 g (9.5 mmol) of trimethylsulfonlumide iodide in 15 ml of dimethylsulfoxide and ca.

198138 1.3 g (6.7 mmol) of 2,2-dimethyl-4H-pyrido [3,2-dioxine in 15 ml of tetrahydrofuran is added after 1 minute. After 10 minutes, cooling was discontinued and the reaction mixture was allowed to reach room temperature.

Then 30 ml of water and 40 ml of ethyl ether were added and the aqueous dimethylsulfoxide layer was separated for further extracts with ether. The ether extracts were combined, dried (MgSO4) and evaporated to give the product as a yellow oil (1.11 g).

Analysis for CnHHizOsN:

found:

63.2% G, 6.3% H, 6.6% N, calculated:

% C, 63.8;% H, 6.3%; N. 6.8%.

NMR spectrum (CDCl3): .delta. Ppm, (.delta.):

1.56 (6H, 2 CH 3),

3.03 (2H, epoxide),

3.9 (1H, epoxide),

4.87 (1H, Cl2),

7.05- [2H. C4 and Cs, pyridine).

Example 4

Following the procedure of Examples 2A-C, 2,2-diphenyl-4H-pyrido [3,2-d], 3-dioxin-6-epoxyethane and 2-methyl-2-phenyl-4H- were prepared using benzophenone and acetophenone instead of benzaldehyde. pyrldo [3,2-d] -1,3-dioxin-6-epoxyethane.

2,2-Diphenyl-4H-pyrido [3,2-d] -1,3-dioxin-6-epoxyethane was obtained in 99% yield as an oily solid.

1h-mr spectrum (deuterochloroform): signals - ppm [5]:

2.7 - 3.2 (multiplet 2H),

3.8-4.0 (1H quartet)

5.0 (doublet 2H),

6.8-7.8 (multiplet, 12H-aromatic protons).

Claims (4)

A process for the preparation of pyridine-6-epoxyethane derivatives of the general formula ZOCW CW- where W represents a benzyl group when Z is hydrogen, or W and Z together form a residue of acetal or ketal, characterized in that the compound of formula (I) is a compound of formula (I). where W represents a benzyl group, when Z 'is trimethylsilyl, or W and Z' together form an acetal or ketal residue, reacted with trimethylsulfonium iodide or trimethylsulfonium chloride in the presence of sodium hydride and dimethylsulfoxide and / or tetrahydrofuran, followed by treatment with water . 2. The process of item 1 for preparing a compound of formula Γ, wherein is R is methyl or phenyl; and R is hydrogen or methyl, wherein when R is phenyl, R * is hydrogen; A method according to claim 1, wherein the compound of formula II *, wherein R and R R are as defined above, is reacted with trimethylsulfonium iodide or trimethylsulfonium chloride in the presence of sodium hydride and dimethylsulfoxide and / or tetrahydrofuran and treated with water. 3. The method of item 2 for preparing a compound of formula I ', 5. The method of item 1 for preparing a compound of formula I '', BOY. X -CH. characterized in that a compound of formula II 'is used as the starting material. 4. A method according to claim 2 to give a compound of formula Γ ', ^{c' h} 'Y ^of Yhi / £ \ wherein the compound of formula II "" ICH / SOUTH-OCH 3 CHO III) is reacted with trimethylsulfonium iodide or trimethylsulfonium chloride in the presence of sodium hydride and dimethylsulfoxide and / or tetrahydrofuran, and the resulting mixture is reacted with water. characterized in that a compound of formula I 'is used as the starting material.