JPS5833229B2 - D- gluco-1,5- lactam - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for making monoglucote 5-lactam derivatives that are useful as antidotes.

More specifically, the present invention provides a D-gelcoat 5-lactam represented by the formula (1) (in which R1 represents hydrogen or a lower alkyl acyl group) or an acyl derivative thereof, combined with the general formula (■) (in the formula R2 and R3 are lower alkyl groups, X is a hydroxyl group, halogen, or acyloxy group);
6-O represented by the general formula (III) (R1, R2, R3 have the same meanings as above)
-(N-N-dilower alkylaminoacetyl)D-gelcoat 5-lactam derivative production method.

D-gelcoat 5-lactam, which is the starting material of the present invention, was prepared by chemical oxidation of the antibiotic nojirimycin (Meiji Seika Research Annual Report P80-84) according to the method previously discovered by the present inventors.
．． 1973) or enzymatic oxidation (patent application 1973-10692)
8) can be easily obtained.

In addition, the acyl derivative of D-gelcoat 5-lactam (2,3,4-tri〇-acyl-D-gelcoat 5-lactam), which is one of the starting materials of the present invention, is D-gelcoat 5-lactam.
6-0 triphenylmethyl derivatives of lactams (patent application 1973)
8 76577) with an acid anhydride such as acetic anhydride or propionic anhydride, or an acid...rogenide, in the presence of a base,
Obtained 2,3,4-tree〇-acyl-6-0-)+
7 phenylmethyl D-gelcoat 5-lactam in acetic acid,
It is easily prepared by selectively removing the triphenylmethyl group at the 6-position by treatment with an acid such as -.hydrogenide.

The thus obtained D-gelcoat 5-lactam or its acyl derivative (2,3,4-)so0-acylD-
The compound (III) of the present invention can be obtained from the raw material compounds of gelcoat (5-lactam) and N-N-dilower alkylaminoacetic acid by applying a known method known as an ester synthesis method.

That is, dimethylformamide, diethylacetamide, acetonitrile, dioxane, which is a mixed acid anhydride obtained by reacting compound (1) with an acid halide of N-N-dilower alkylaminoacetic acid or an alkyl chlorocarbonate; React in an organic solvent such as chloroform in the presence of a base such as pyridine, triethylamine, or quinoline, or
Alternatively, it can be achieved by reacting compound (1) and N-N-di-lower alkylaminoacetic acid in an organic solvent such as those mentioned above in the presence of a dehydration condensation agent such as carbodiimide or carbonyldiimidazole.

To separate the desired product from the reaction mixture obtained by
An organic solvent extraction method is used, and extraction with an organic solvent is particularly easy to operate and effective.

The N-N-di-lower alkylaminoacetyl D-gelcoat 5-lactam derivative produced in this way is an extremely stable compound and can be used as a free base or as a salt of hydrochloric acid, sulfuric acid, citric acid, tartaric acid, etc., and has excellent properties. It has a detoxifying effect and is effective against liver function diseases.

The results of a test on detoxification using mice are shown below.

Next, examples of the present invention will be shown.

Example 1 27.69 6-〇-triphenylmethyl-DI'lucote 5-lactam and 200 rIIj of pyridine! , 70 rnl of acetic anhydride was added, and the mixture was heated at 5°C for 3 hours, then at room temperature for 18 hours.
Stir for an hour.

After the reaction is completed, the reaction solution is added to ice water (2 J) and stirred, resulting in a large amount of precipitate.

After washing with water and drying on phosphorus pentoxide,
- 38 g of white powder of 4-tri0-acetyl-6-0 triphenylmethyl-D-gelcoat 5-lactam was obtained.

Next, this is dissolved in acetic acid 150a, and after cooling to 8 to 10°C, 16WLl of acetic acid saturated with hydrogen bromide is added, and triphenylmethyl bromide crystals are immediately precipitated.

This product was taken from house to house and the lachrymal fluid was concentrated to about 20ml under reduced pressure, then dissolved in 300M chloroform, washed with sodium bicarbonate water and water, dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure. -Acetyl-D-gelcoat 5-lactam white powder 22 is obtained.

Elemental analysis values of the obtained white powder: C48, 12%, H5
, 73%, H4, 59%, molecular formula: % formula % 2,3,4-tri-acetyl-D- obtained here
Gelcoat 5-lactam 2.21 and N-dimethylaminoacetic acid hydrochloride 1.21 were placed in a 50CC flask, and dimethylformamide 30rul and pyridine 8
Add a mixture of rr11 and then 1.9f of N·N'-dicyclohexylcarbodiimide! After addition, the mixture is reacted with stirring at 5° C. for 2 hours and at room temperature for 10 hours.

The N-N'-dicyclohexylurea precipitated in the reaction solution is separated out, and the r solution is concentrated under reduced pressure.

The resulting residual fragrance was dissolved in 50 WL of water, and some insoluble parts were separated, adjusted to pH 8.5 with IN caustic soda, and extracted twice with 30 WL of ethyl acetate.

The reactant in the organic solvent layer was then diluted with pH 3 hydrochloric acid acidic water (50
ml, decolorized with a small amount of charcoal powder, adjusted to pH 5 with Amberlite IR-45 (OH type), concentrated under reduced pressure, and obtained 2.3-4-) Lee O-acetyl-6-0. −(
A white powder 2.1' of N-N-dimethylamine, noacetyl)-D-gelcoat 5-lactam hydrochloride was obtained.

Elemental analysis values: C44, 62%, H5, 80%, H6,
40% Molecular formula "C16H24N209/HCI Example 2 6-0-) To 13 fI of liphenylmethyl-D-gelcoat 5-lactam, 90 rfL of pyridine and 351 nL of propionic anhydride were added at 3 to 5°C for 4 hours, then at room temperature for 20 hours. Stir for an hour.

After the reaction is completed, the reaction solution is added to ice water (11) and stirring is continued to deposit a white precipitate.

This precipitate was collected, washed with water, dried on R20, and
3,4-tri〇-gropionyl-6-C)-)liphenylmethyl-D-gelcoat 5-lactam white powder 2
I got 02.

Next, this powder (19F) was dissolved in 160 rrll of acetic acid, 35 WLl of water was added, and the mixture was left at 50° C. for 20 hours to perform detriphenylmethylation.

After the reaction is completed, when the reaction solution is left at 3°C, triphenylcarbinol crystals are precipitated.

This is concentrated and the r solution is concentrated to dryness under reduced pressure.

The obtained residual fragrance was dissolved in 200 liters of chloroform,
After washing with sodium bicarbonate solution and water, dehydrating with sodium sulfate and concentrating to dryness, white powder 7,22 of 2,3,4-tri0-propionyl-D-gelcoat 5-lactam is obtained.

Elemental analysis values of the obtained white powder: C52, 31%, H6
, 65%, H4, 08%, molecular formula diCl5H23NO8
Met.

The 2,3,4-tri-propionyl-D-gelcoat 5-lactam 1.72S' and N-N-
Add 201rtl of dimethylformamide and 7rnl of pyridine to 0.7f of dimethylaminoacetic acid hydrochloride, then add N
After adding -1'7-dicyclohexylcarbodiimide 1,2y, the reaction mixture is stirred at room temperature for 10 hours.

After the reaction is completed, the precipitated N-N'-dicyclohexylurea is separated and the p liquid is concentrated under reduced pressure.

Thereafter, in the same manner as in Example 3, extraction with ethyl acetate, followed by dissolution into acidic water of hydrochloric acid, and 2.3.4-triO-propionyl-6-0-(N-N-dimethylaminoacetyl)-D-
1.81 of a white powder of gelcoat 5-lactam hydrochloride was obtained.

Elemental analysis values: C48,64%, H6,58%, H5,8
7% Molecular formula: C19H30N209 HC1 Example 3 1.51 of 2,3,4-triO-acetyl-DI'luquat 5-lactam obtained in the same manner as in Example 1 was added to pyridine 1
5ml of dimethylaminoacetic acid chloride hydrochloride 0.79f! under stirring at 0-5°C! Pyridine solution of 10
Add wLl dropwise and continue to react for 3 hours.

The reaction solution is 1ml of ice water! is added and concentrated to dryness.

The residual fragrance was dissolved in 30 WL of water, adjusted to pH 8.4, and extracted twice with 20 rnL of chloroform, and the reactant was transferred to the chloroform layer.

After washing the chloroform layer with water, it was extracted with hydrochloric acid acidic water (pH 3, 5), and after decolorizing with a small amount of charcoal powder, Amberlite IR-
Adjust the pH to 5 with 45 (OH type) and concentrate under reduced pressure.
- 1.82 of a white powder of 3,4-tri0-acetyl-6-0-(N-N-dimethylaminoacetyl) D gel coat 5-lactam hydrochloride was obtained.

Example 4 D-gelcoat 5-lactam 1.8. f and N・N−
A mixture of 35WLl of dimethylformamide and 8RNL of pyridine was added to 1.4ml of dimethylaminoacetic acid hydrochloride, and then 2.4f of N-N'-dicyclohexylcarbodiimide was added.
Add I and stir at room temperature for 20 hours.

After the reaction is completed, the precipitated N-N'-dicyclohexyl urea is separated and the lachrymal fluid is concentrated under reduced pressure.

The obtained residual aroma (2,4fI) is passed through a silica gel column (50ml) packed with a system of n-butanol-methanol-water (4:1:2) and developed with the same solvent system.

The fraction showing RfO,3 was collected by silica gel thin layer chromatography (developing solvent n-butanol-acetic acid-water 2:1:1) and concentrated under concentrated pressure, and 6-O-(N-N dimethylaminoacetyl)-D-gel coat 0.6 P of white powder of 5-lactam hydrochloride was obtained.

Elemental analysis values: C40, 16%, H6, 32%, H9-1
4%

Claims (1)

[Scope of Claims] 1 D-gelcoat 5-lactam or its acyl derivative represented by the formula (1) (in the formula, R1 represents hydrogen or a lower alkyl acyl group) is combined with the formula (n) (in the formula, R2, R3 is a lower alkyl group, X is a hydroxyl group, halogen, or acyloxy group). In the formula R1, R2
, R3 has the same meaning as before) 6-O-(N-N~
(lower alkylaminoacetyl)-D-gelcoat 5-
Method for producing lactam derivatives.