JPS5953261B2 - Method for producing 2(1H)-pyridone derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing 2-(IH)-pyridone derivatives, and the gist thereof is 6-0-triphenylmethyl-D-gluco-δ.
-lactam (Japanese Patent Application No. 48-76577) was reacted with benzyl halide and the resulting reaction product was treated with acid to form 13-daibenzyl-3 represented by the general formula IR2□R゜(1). -Hydroxy-2
(1H)-Pyridone (1a) (where R=1CH,O,R
'=H), 1,3-daibenzyl-3-hydroxy{
-Hydroxymethyl-2(1H)-pyridone(Ib)
(in the formula R=1CHr《=》R'=-CH,OH) and 1
-benzyl-3-hydroxy-6-hydroxymethyl-2(1H)-pyridone (Ic) (in the formula B: H, R'
11 CH! 0H).

To explain the present invention in more detail, in the first step, 6-0-triphenylmethyl-D-gluco-δ-lactam as a raw material is prepared in a solvent such as dimethylformamide, dimethyl sulfoxide, dioxane, etc. or without a solvent. 6 by reacting benzyl chloride or benzyl bromide with heat (70-150°C) in the presence of a base such as caustic soda, caustic potash, barium oxide, or sodium hydride.
A benzylated product of -O-triphenylmethyl-D-gluco-δ-lactam is obtained.

Book bezoji? - It is possible to obtain the highest yield by using an antagonistic reaction reagent.

stomach? ? The best method is to use sodium hydride as a solvent and as a base.This benzylated product has a melting point of 74°C, and its structure has not been completely determined, but elemental analysis values and nuclear The tentative equation estimated from magnetic resonance analysis etc. is as shown in Equation 2.

However, elucidation of the structure of this benzylated product is not an essential condition of the present invention. In the second step of the present invention, the benzylated product is treated with acids such as acetic acid formic acid, hydrochloric acid, sulfuric acid, phosphoric acid, hydrogen chloride, hydrogen bromide, etc. at room temperature or under heating. Three compounds of Ic are obtained.

In this case, the most advantageous method for production is acetic acid monobromide, acetic acid monochloride, acetic acid monochloride, and acetic acid monochloride. It is a combination of water.
The production ratio of the above three compounds (1a, Ib, c) of the present invention can be changed by selecting the type and amount of acid used and the reaction temperature. For example, in 80% acetic acid water at 40°C, 17 In the reaction for 17 hours, the production ratio of 1a:Ib:Ic is 35:15:50, and as the temperature is further increased, the production of Ic increases (for example, at 60°C for 17 hours, 1a, Ib,
The production ratio of Ic is 25:10:65). On the other hand, in the reaction with hydrogen bromide in acetic acid, almost no formation of Ic compounds was observed, and by adjusting the amount of hydrogen bromide added, 1a, 1a,
It is also possible to change the production ratio of 1b, and specific examples thereof are shown in Examples. Each of the reaction products 1a, 1b, and Ic can be isolated in its pure form by fractional crystallization.

Among the compounds of the present invention, 1,3-dibenzyl-3-hydroxy-2(1H)-pyridone (1a) has significant anti-bradykinin, anti-acetylcholine, anti-serotonin effects, and 1,3-dibenzyl-3-hydroxy-2(1H)-pyridone (1a) -6-
Hydroxymethyl-2(1H)-pyridone (Ib) and 1-benzyl-3-hydroxy-6-hydroxymethyl-2(1H)-pyridone (Ic) have antiserotonin effects. By the Magnus method using rat uterus (
Table 1 shows the results of determining the 50% concentration that antagonizes the nutrient solution Marsick's solution), bradykinin, acetylcholine, and serotonin.

Example 1 6-0-triphenylmethyl-D-gluco-δ-lactam 18f! Benzyl chloride 180TI1! , and added with sodium hydride 89°C, heated at 80-90°C for 1 hour and then at 120-130°C for 4 hours with stirring.

After cooling the reaction solution, 100 ml of chloroform was added and the insoluble portion was removed. Ethanol is added to the leaked liquid to decompose the remaining sodium hydride and then concentrated, and then unreacted benzyl chloride and by-product benzyl alcohol are distilled off. The residue was dissolved in 100 ml of benzene, decolorized with charcoal powder, concentrated to approximately 30 d, added with 150 d of n-hexane, and the resulting precipitate was dried in a desiccator to obtain 6-0 triphenylmethyl-D-gluco-δ-lactam. Benzylated compound 2
I got 29.

Melting point: 74°C Elemental analysis value: C8l. 76, H5.98, N2.25 Then, this benzylated product 109 was dissolved in 50 ml of acetic acid, 5 d of acetic acid solution saturated with hydrogen bromide gas was added, and the mixture was heated at 10°C for 30 min.
If left for a minute, a precipitate will form.

After filtering this material, it was concentrated to dryness under reduced pressure and the benzene 100%
7!11 and washed with bicarbonate of soda water and then with water. After dehydration with anhydrous sodium sulfate, the benzene layer is approximately 30%
When concentrated to d and left at low temperature, crystals will precipitate. This product was collected by filtration to obtain 0.89 g of white needle crystals of 1,3-daibenzyl-3-hydroxy-6-hydroxymethyl-2(1H)-pyridone. Melting point: 160-16
1℃ Elemental analysis value: C75. O8, H5.98, N4.34%
Molecular formula: C.

Hl, NO3, then concentrate the filtrate and add 1071L of acetone.
When dissolved in 1 and left at low temperature, crystals will precipitate.

This product was collected by filtration to obtain 1.39 g of white needle-like crystals of 1,3-daibenzyl-3-hydroxy-2(1H)-pyridone. Melting point: 106-107℃ Elemental analysis: C78.32, H5.84, N4.7l%
Molecular formula: C,, Hl, NO, Example 2 Benzylated compound 59 obtained in Example 1 was dissolved in 25 ml of acetic acid, 8 d of acetic acid solution saturated with hydrogen bromide gas was added, and the mixture was heated at room temperature (
20° C.), a precipitate separates out (for 1 hour).

This was filtered and the filtrate was subjected to silica gel thin layer chromatography (developing solvent: chloroform-methanol 10
:1), almost no formation of 1,3-daibenzyl-3-hydroxy-6-hydroxymethyl-2(1H)-pyridone (RffLO.32) was observed, and the product was 1,3-daibenzyl-3. -Hydroxy-2
(1H)-pyridone (Rf value 0.53) was the main component.

The filtrate was concentrated to dryness, dissolved in 30 d of chloroform, washed with aqueous sodium bicarbonate, then washed with water, dehydrated with anhydrous aqueous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was reconsolidated from acetone to give 1,3-daibenzyl-3-hydroxy-2 (1H).
- 1.2 g of white needle-like crystals of pyridone were obtained. Example 3 Benzylated product 109 obtained by the method of Example 1 is dissolved in 100 W 1 t of 80% acetic acid water, heated at 50°C for 15 hours, and then left at a low temperature (5 to 10°C) to precipitate.

The precipitate was filtered off, the filtrate was concentrated to dryness under reduced pressure, dried in a desiccator in the presence of caustic soda or caustic potash, and then chloroform 5077! Extract with l. Add 20% ethanol to the insoluble part.
After decolorizing with charcoal powder and concentrating to about 5 d, 15 d of chloroform is added and left at a low temperature to precipitate poor crystals.
Filter this product and 1-benzyl-3-hydroxy-6
-Hydroxymethyl-2(1H)-pyridone white needle crystals 1.1f! I got it. Melting point: 149-150
°C Elemental analysis value: C67. l3, H5.6l, N5.93%
Molecular formula: C,,H,,NO3 Next, the chloroform extracted layer was decolorized with charcoal powder, concentrated to dryness, and the residue was dissolved in 20 d of hot benzene and left to stand to give 1,3-dibenzyl-3-hydroxy-6-hydroxy. Crystals of methyl-2(1H)-pyridone precipitate (yield: 0.49).

Claims (1)

[Scope of Claims] 1 6-O-Triphenylmethyl-D-gluco-δ-lactam is reacted with a benzyl halide and the resulting reaction product is treated with an acid to obtain the general formula ▲ mathematical formula, chemical formula, There are tables etc. ▼ 1,3-Dibenzyl-3-hydroxy- shown as
2(1H)-pyridone (in the formula R=▲There are mathematical formulas, chemical formulas, tables, etc.▼R'=H) and 1,3-dibenzyl-3
-Hydroxy-6-hydroxymethyl-2(1H)
-Pyridone (in the formula R=▲There are mathematical formulas, chemical formulas, tables, etc.▼, R'=-CH_2OH) and 1-benzyl-3-hydroxy-6-hydroxymethyl-2(1H)-pyridone (in the formula R=H , R'=-CH_2OH).