KR100593849B1 - Method for preparing valienamine - Google Patents

Abstract

The present invention relates to a method for producing a valenamine represented by the following formula (1) by reacting acarbose or acarbose derivatives in the presence of a base.

      (One)

Bogliboss, Balienamine, Acarbose, Hydrolysis, Base

Description

Method for Preparing Valienamine

The present invention relates to a method for producing valenamine represented by the following formula (1). More specifically, the present invention relates to a process for producing a valenamine represented by the following formula (1) by reacting acarbose or acarbose derivatives in the presence of a base.

       (One)

Balienamine prepared in the present invention is a key intermediate used in the manufacture of vogliose (Voglibose), a diabetes treatment having a drug that suppresses rapid blood sugar rise after eating [ Carbohydrate Research , 140 , 185 (1985); J. Med. Chem ., 29 , 1038 (1988); U.S. Patent 4,701,559 (1987).

The synthesis techniques of so far known Baliienamine are divided into two types, one is presynthesis from carbohydrates, and the second is preparation from Validamycin or Acarbose containing a valenamine structure. to be.

Specifically, the method for presynthesizing the valenamine from carbohydrates is described in detail. D-glucose [ Chem. Pharm. Bull ., 36 , 4236 (1988); J. Org. Chem ., 57 . 3651, (1992) or D-Xylose [ J. Antobiot . 53 , 430 (2000)] to synthesize valenamine using low-cost carbohydrates. However, this presynthesis method is not suitable for mass production technology because the reaction step is longer and complex than 10 steps.

Proposed as a method for solving the above problems is a method for producing a valenamine from a balladamycin or acarbose, which is a known substance containing a valenamine structure. For example, a Valyldoxyamine derivative with a benzyl protecting group made from validamycin is reacted with N-bromosuccinimide (NBS) in DMF (dimethylformamide) or DMSO (dimethylsulfoxide) solvent to yield a yield of 36% to 50%. Methods for preparing enamine derivatives are known, see Chemistry Letters , 725 (1989); J. Chem. Soc., Perkin Trans I , 3287 (1991)], has the disadvantage of using DMF or DMSO as a solvent, NBS as an oxidant, and forming various side reactions.

On the other hand, as a method for solving the problems of the method to react acarbose or validamycin in a strong acid trifluoroacetic acid (TFA) solvent to produce a valenamine [Korean Patent Publication No. 2004-0000751 (2004); Korean Patent Publication 2004-0002339 (2004)] has been proposed. Although this method is a method suitable for mass production compared to the known technology, there is a disadvantage that a relatively expensive and harmful to human body should be used.

The present inventors have developed a simple and economical process for minimizing the problems of the prior art. In other words, in the present invention, since acarbose or acarbose derivatives are reacted in the presence of a base to produce a valenamine, it is an economical manufacturing method particularly suitable for mass production.

It is an object of the present invention to provide a process for preparing a valenamine by reacting acarbose or acarbose derivatives in the presence of a base in order to solve the problems of known production methods.

In order to achieve the object of the present invention as described above, the present invention is a method for producing a valenamine represented by the following formula (1) by reacting acarbose or acarbose derivative represented by the following formula (2) in the presence of a base present.

      (1) (2)

The acarbose derivative refers to a compound in which one or two sugars are bound to the valenamine skeleton, and is typically a sugar in which one or two sugars are bound, as represented by the following formula (3) or (4): Or derivative compounds of disaccharides.

            (3) (4)

Schematic diagram of the preparation method of the valenamine according to the present invention is as follows:

Scheme 1

The base used in the present invention is not particularly limited, and various inorganic bases or organic bases may be used. Bases that can be used are hydroxide salts, carbonates, bicarbonates, phosphates, organic amines and the like.

More specifically, for example, the base used in the present invention, the hydroxide salt is an alkali metal hydroxide such as sodium hydroxide (NaOH), potassium hydroxide (KOH), calcium hydroxide (Ca (OH) ₂ ), barium hydroxide (Ba (OH) Alkaline earth metal hydroxides such as ₂ ), quaternary ammonium hydroxides such as tetramethylammonium hydroxide (NMe ₄ OH), tetraethylammonium hydroxide (NEt ₄ OH); The carbonate is a metal carbonate (MCO ₃ ) such as sodium carbonate (Na ₂ CO ₃ ), potassium carbonate (K ₂ CO ₃ ), wherein M is an alkali metal or an alkaline earth metal; Bicarbonates are metal bicarbonates (MHCO ₃ ) such as sodium carbonate (NaHCO ₃ ), potassium bicarbonate (KHCO ₃ ); Phosphates are sodium triphosphate (Na ₃ PO ₄ ), potassium triphosphate (K ₃ PO ₄ ), disodium phosphate (Na ₂ HPO ₄ ); The organic amine is NR ¹ R ² R ³ , such as diisopropylethylamine, tripropylamine, triethylamine, wherein R ¹ , R ² , R ³ are the same or different alkyl groups having 1 to 4 carbon atoms.

The criterion for selecting an appropriate base from the various bases as described above is basic strength. The basic strength is the most important factor in determining the reaction rate and reaction conditions of the present invention, and the higher the basic strength, the faster the relative reaction rate. In general, the strength of a base is expressed by its dissociation constant (pKa). For example, hydroxyl (OH ^-) in the pKa of 15.7, acid group (CO ₃ ^2-) are pKa 10.3, pKa of the organic amine group are 10, 12.7 pKa of the triphosphate group (PO ₄ ^3-), the bicarbonate exchanger ( PKa of HCO ₃ ⁻ ) is 6.4. In the present invention, it is preferable to use a base having a dissociation constant (pKa) of 6 or more, and more preferably, pKa is 10 or more.

The content of the base is not particularly limited, but it is preferable to use an excess in excess of acarbose or a derivative thereof. Preferably, 5 equivalents or more are used based on acarbose.

In order to facilitate the reaction of acarbose or its derivatives with a base, it is common to use a solvent of water or a mixed solvent of water and a water miscible organic solvent as a reaction solvent. The water miscible organic solvent is preferably an alcohol solvent such as ethanol, methanol or ethylene glycol. The amount of the reaction solvent is not particularly limited, but is preferably 5 times or more, preferably 5 to 30 times based on the weight of acarbose. It is preferable to reflux the reaction liquid during the process. Preferable reaction temperature and reaction time are 60 degreeC or more and 12 hours or more, More preferably, they are 80-120 degreeC and 24-72 hours.

As a method for purifying the desired valenamine in the reaction solution, various known purification methods may be used. The ion exchange resin may be used in consideration of the physical properties of the water-soluble valenamine, and may be further purified by a conventional method such as crystallization as necessary.

On the other hand, as shown in Scheme 2 below, the reactivity and purification method of the acarbose derivative are the same as in the case of acarbose. Since the present invention uses a reaction mechanism to remove sugars bound to the backbone of acarbose (or acarbose derivatives) using a base, acarbose derivatives that differ only in the number of bound sugars follow the same reaction route as acarbose.

Scheme 2

Base in the scheme includes various bases as described above.

The invention is further elaborated by the following examples, which do not limit the scope of the invention.

Example

Example 1 Preparation of Balienamine from Acarbose 1

Add acarbose (10 g) and sodium hydroxide (9.3 g) to water (200 mL) and reflux for 48 hours. After cooling, neutralize with 1N aqueous hydrochloric acid solution and concentrate. The concentrated reaction solution was purified by cation exchange resin (Amberlite IR-120H) and weakly acidic cation exchange resin (Amberlite CG-50) to obtain pure valenamine (1.1 g).

¹ H NMR (D ₂ O, 300 MHz) 3.35 (m, 1 H), 3.49 (m, 2H), 3.80-3.95 (m, 2H), 4.02 (d, 1H), 5.61 (d, 1H)

Example 2 Preparation of Balienamine from Acarbose 2

Add acarbose (10 g) and potassium hydroxide (10.5 g) to water (180 mL) and reflux for 48 hours. After cooling, neutralize with 1N aqueous hydrochloric acid solution and concentrate. The concentrated reaction solution was purified by cation exchange resin (Amberlite IR-120H) and weakly acidic cation exchange resin (Amberlite CG-50) to obtain pure valenamine (1.0 g).

Example 3 Preparation of Balienamine from Acarbose 3

Acabose (1.0 g) and calcium hydroxide (1.6 g) were added to water (20 mL) and refluxed for 60 hours. Concentrate after cooling. The concentrated reaction solution was purified by cation exchange resin (Amberlite IR-120H) and weakly acidic cation exchange resin (Amberlite CG-50) to obtain pure valenamine (0.12 g).

Example 4 Preparation of Balienamine from Acarbose 4

Add akabose (1.0 g) and barium hydroxide octahydrate (6.8 g) to water (20 mL) and reflux for 55 hours. Concentrate after cooling. The concentrated reaction solution was purified by cation exchange resin (Amberlite IR-120H) and weakly acidic cation exchange resin (Amberlite CG-50) to obtain pure valenamine (0.09 g).

Example 5 Preparation of Balienamine from Acarbose 5

Add akabose (1.0 g) and sodium carbonate (2.0 g) to water (20 mL) and reflux for 72 hours. Concentrate after cooling. The concentrated reaction solution was purified by cation exchange resin (Amberlite IR-120H) and weakly acidic cation exchange resin (Amberlite CG-50) to obtain pure valenamine (0.08 g).

Example 6 Preparation of Balienamine from Acarbose 6

Add akabose (1.0 g) and sodium bicarbonate (1.8 g) to water (20 mL) and reflux for 72 hours. Concentrate after cooling. The concentrated reaction solution was purified by cation exchange resin (Amberlite IR-120H) and weakly acidic cation exchange resin (Amberlite CG-50) to obtain pure valenamine (0.09 g).

Example 7 Preparation of Balienamine from Acarbose Derivatives (Disaccharide) 7

In a water (40 mL), add acarbose derivative (disaccharide, 2.0 g) and potassium hydroxide (2.0 g) and reflux for 48 hours. After cooling, neutralize with 1N aqueous hydrochloric acid solution and concentrate. The concentrated reaction solution was purified by cation exchange resin (Amberlite IR-120H) and weakly acidic cation exchange resin (Amberlite CG-50) to obtain pure valenamine (0.2 g).

Example 8 Preparation of Balienamine from Acarbose Derivatives (Disaccharide) 8

Into a water (40 mL) add acarbose derivative (2 sugars, 2.0 g) and sodium hydroxide (1.6 g) to reflux for 40 hours. Concentrate after cooling. The concentrated reaction solution was purified by cation exchange resin (Amberlite IR-120H) and weakly acidic cation exchange resin (Amberlite CG-50) to obtain pure valenamine (0.18 g).

Example 9 Preparation of Balienamine from Acarbose 9

Add akabose (5 g) and tetramethylammonium hydroxide (20 g) to water (50 mL) and reflux for 40 hours. After cooling, neutralize with 1N aqueous hydrochloric acid solution and concentrate. The concentrated reaction solution was purified by cation exchange resin (Amberlite IR-120H) and weakly acidic cation exchange resin (Amberlite CG-50) to obtain pure valenamine (0.4 g).

Example 10 Preparation of Balienamine from Acarbose 10

Acabose (2 g) and tertiary potassium phosphate (9.8 g) are added to water (20 mL) and refluxed for 45 hours. After cooling, neutralize with 1N aqueous hydrochloric acid solution and concentrate. The concentrated reaction solution was purified by cation exchange resin (Amberlite IR-120H) and weakly acidic cation exchange resin (Amberlite CG-50) to obtain pure valenamine (0.17 g).

Example 11 Preparation of Balienamine from Acarbose 11

Add akabose (2 g) and sodium triphosphate (7.5 g) to water (20 mL) and reflux for 48 hours. After cooling, neutralize with 1N aqueous hydrochloric acid solution and concentrate. The concentrated reaction solution was purified by cation exchange resin (Amberlite IR-120H) and weakly acidic cation exchange resin (Amberlite CG-50) to obtain pure valenamine (0.19 g).

Example 12 Preparation of Balienamine from Acarbose 12

Add akabose (5 g) and disodium phosphate (16.5 g) to water (50 mL) and reflux for 4 days. After cooling, neutralize with 1N aqueous hydrochloric acid solution and concentrate. The concentrated reaction solution was purified by cation exchange resin (Amberlite IR-120H) and weakly acidic cation exchange resin (Amberlite CG-50) to obtain pure valenamine (0.35 g).

Example 13: Preparation of Balienamine from Acarbose 13

Acabose (2 g) and diisopropylethylamine (20 mL) were added to water (5 mL) and refluxed for 3 days. Concentrated under reduced pressure, diluted with water (50 mL), and purified with cation exchange resin (Amberlite IR-120H) and weakly acidic cation exchange resin (Amberlite CG-50) to obtain pure valenamine (0.16 g).

According to the present invention, a method of preparing a valenamine is economical and suitable for mass production as a technique for producing a valenamine by reacting acarbose or acarbose derivatives with a low-cost base.

Claims (10)

A process for producing a valenamine represented by the following formula (1) by reacting acarbose or acarbose derivatives in the presence of a base.

      (One) The method of claim 1 wherein the base is a base selected from metal hydroxides, metal carbonates, and metal bicarbonates. The method of claim 2, wherein the metal hydroxide is sodium hydroxide or potassium hydroxide. The method of claim 2, wherein the metal hydroxide is calcium hydroxide or barium hydroxide. 3. A process according to claim 2 wherein the metal carbonate is sodium carbonate or potassium carbonate. The method of claim 2, wherein the metal bicarbonate is sodium bicarbonate or potassium bicarbonate. The method of claim 1 wherein the base is sodium triphosphate or potassium triphosphate. The method of claim 1, wherein the base is NR ¹ R ² R ³ , wherein R ¹ , R ² , and R ³ are the same or different alkyl groups having 1 to 4 carbon atoms. The method according to claim 1, wherein the base is a base having a dissociation constant (pKa) of 6 or more. 10. The method of claim 9, wherein the base is a base having a dissociation constant (pKa) of 10 or more.