WO2006107134A1

WO2006107134A1 - Method for preparing valienamine

Info

Publication number: WO2006107134A1
Application number: PCT/KR2005/004093
Authority: WO
Inventors: Il Suk Byun; Joo Sung Kim; Sung Hye Shin; Wan Joo Kim
Original assignee: Chemtech Research Inc
Current assignee: Chemtech Research Inc
Priority date: 2005-03-16
Filing date: 2005-12-02
Publication date: 2006-10-12
Anticipated expiration: 2007-09-16
Also published as: EP1863754A1

Abstract

The present invention provides a method for preparing valienamine from acarbose or acarbose derivatives by using a base. The present invention provides an improved method for preparing valienamine compared to conventional preparation methods of valienamine by simplifying the reaction steps and diminishing byproducts.

Description

Description METHOD FOR PREPARING VALIENAMINE

Technical Field

[1] The invention relates to a method for preparing valienamine represented by the following formula (1). More particularly, the invention relates to a method for preparing valienamine from acarbose or acarbose derivatives by using a base.

[2]

[3] (1)

Background Art

[4] Valienamine is a core precursor used for preparing voglibose which is an effective hypoglycemics for treating diabetes, suppressing a sudden rise in blood sugar level after a meal [Carbohydrate Research, 140, 185 (1985); J. Med. Chem., 29, 1038 (1988); U.S. patent No. 4,701,559 (1987)].

[5] The conventional synthetic methods of valienamine are divided into two types. The first type is a total synthesis of valienamine from carbohydrates, and the second type is a preparation of valienamine from validamycin or acarbose having a valienamine moiety therein. Disclosure of Invention Technical Problem

[6] In the total synthesis of valienamine from carbohydrates, valienamine is economically prepared from carbohydrate sources such as D-glucose [Chem. Pharm. Bull., 36,4236 (1988); J. Org. Chem., 57, 3651 (1992)] and D-Xylose [J. Antibiot., 53, 430 (2000)]. However, the total synthesis is inadequate for mass production of valienamine since the synthesis reaction is too complicated due to its at least ten reaction steps.

[7] Therefore, a method for preparing valienamine from validamycin or acarbose, which are well known compounds having a valienamine moiety therein, was suggested in order to overcome the above-mentioned drawback of the total synthesis. For example, it is known that valienamine derivatives were prepared in a yield of about 36% to about 50% by reacting a validoxyamine derivative having benzyl protection group, which is prepared from validamycin, with NBS (N-bromosuccinimide) under a solvent such as DMF (dimethylformamide) or DMSO (dimethylsulfoxide) [Chemistry Letters, 725 (1989); J. Chem. Soc, Perkin Trans I, 3287 (1991)]. However, the method also has some defects because a harmful reagent such as DMF, DMSO, and NBS is used as a solvent or an oxidizing agent, and various by-products are produced.

[8] As a solution to the above-mentioned problems, WO 2004/000782 describes a new method for preparing valienamine from acarbose or validamycin under a strong acid solvent of TFA (trifluoroacetic acid). The method is suitable for mass production compared to other conventional methods, but it also has drawbacks in that it uses a relatively expensive and harmful solvent such as TFA. Technical Solution

[9] Accordingly, the present inventors have developed a simple and economic process for preparing valienamine to minimize drawbacks of the prior arts. According to the present invention, valienamine can be easily obtained from acarbose or acarbose derivatives using a base, so the present invention is an economic method, which is suitable for the mass production of valienamine.

Advantageous Effects

[10] The object of the present invention is to provide a method for preparing valienamine from acarbose or acarbose derivatives using a base to solve the problems resulting from the conventional methods for preparing valienamine.

[11] To achieve said object, the present invention provides a method for preparing valienamine represented by the formula (1) from acarbose represented by the formula (2) or acarbose derivatives using a base.

[12]

[13] (1) [14]

[15] (2)

[16] Acarbose derivatives are compounds having one or more saccharides bonded to a valienamine backbone, and they are generally derivatives having monosaccharide or disaccharide represented by the following formulas.

[17]

acarbose derivative (disacchaiide) (monosaccharide)

[18] According to the present invention, a low-priced reagent, a base, is used for preparing valienamine so the present invention is an economical method that is suitable for mass production. Best Mode for Carrying Out the Invention

[19] The method for preparing valienamine according to the present invention is schematized by the following reaction formula.

[20] Reaction formula 1 [21]

vaHeuainine

[22] In the present invention, various inorganic bases and organic bases may be used as a base, for example, it is not particularly limited, hydroxides, carbonates, bicarbonates, phosphates, organic amines, and the like.

[23] Suitable bases include hydroxides, e.g. alkali metal hydroxides such as sodium hydroxide (NaOH), potassium hydroxide (KOH), alkaline earth metal hydroxides such as calcium hydroxide (Ca(OH) ), barium hydroxide (Ba(OH) ), tetraammonium hydroxide such as tetramethylammonium hydroxide (NMe OH), tetraethylammonium

4 hydroxide (NEt OH); carbonates, e.g. metal carbonate (MCO ) (wherein M is alkali metals or alkaline earth metals) such as sodium carbonate (Na CO ), potassium carbonate (K CO ); bicarbonates, e.g. metal bicarbonate (MHCO ) such as sodium bicarbonate (NaHCO ), potassium bicarbonate (KHCO ) ; phosphates such as sodium phosphate tribasic (Na PO ), potassium phosphate tribasic (K PO ), sodium phosphate dibasic (Na HPO ); and organic amines, e.g. NR R R (wherein R ,R , andR may be the same or different, and are independently alkyl group with a carbon number of 1 to 4) such as diisopropylethylamine, tripropylamine, triethylamine.

[24] A base strength may be considered to choose a suitable base among the various bases. In the present invention, the base strength is the most important factor to determine a reaction velocity and a reaction condition. If the base strength is higher, the reaction velocity is relatively faster. Generally, the base strength is indicated as a dissociation constant (pKa). For example, the pKa of hydroxyl group (OH ) is 15.7, the pKa of carboxyl group (CO ) is 10.3, the pKa of organic amine is 10, the pKa of triphosphate group (PO ) is 12.7, and the pKa of bicarbonate group (HCO ) is 6.4. In the present invention, it is preferable to use a base having pKa of at least 6, and it is more preferable to use a base having pKa of at least 10.

[25] An amount of the base is not particularly limited, but it is preferable to use an excess amount than that of acarbose or its derivatives. Preferably, an amount of the base is preferable to 5 or more equivalents of acarbose or its derivatives.

[26] Typically, a reaction solvent, e.g. water, or a mixture of water and a water-miscible organic solvent may be used for a smooth reaction of the reactants. A preferred water- miscible organic solvent is an alcohol such as methanol, ethanol, and ethylene glycol. An amount of the reaction solvent is not particularly limited, but it is preferable to use 5 times or more by weight of acarbose or its derivatives, and more preferable to use 5 times to 30 times by weight of acarbose or its derivatives. It is preferred that the reflux of the reaction mixture is carried out during the reaction. The preferred reaction temperature is 6O⁰C or higher, and the preferred reaction time is 12 hours or longer. The more preferred reaction temperature is 8O⁰C to 12O⁰C, and the more preferred reaction time is 24 hours to 72 hours.

[27] The resulting valienamine from the reaction mixture may be easily purified by a conventional purification method in the art. For example, an ion exchange resin may be used considering the physical properties of valienamine such as water-solubility. Moreover, the resulting valienamine may be further purified using a purification method such as crystallization.

[28] According to the present invention, a saccharide(s) combined with a backbone of acarbose are removed using a base, so acarbose derivatives, which are different only from the number of saccharides combined thereto as compared with acarbose, are subject to follow the same reaction path as acarbose. Therefore, the reaction conditions and the purification process of acarbose derivatives are substantially identical with those of acarbose as shown in the following reaction formula 2.

[29] Reaction formula 2

[30]

acarbose deiivative (disacchaiide) valie ua mine

acai bose deiivative (monosaccharide) valie iia mine

[31] In the reaction formula 2, the base may be the same defined as above.

[32] The present invention is further illustrated by the following examples, but these examples should not be construed as limiting the scope of the invention. Mode for the Invention

[33] Examples

[34] Example 1: Preparation of valienamine from acarbose (I^s)

[35] Acarbose (1Og) and sodium hydroxide (9.3g) were added to water (20OmL) and then refluxed during 48 hours. The reaction mixture was cooled to room temperature, neutralized with IN hydrochloric acid solution, and then concentrated. The concentrated reaction mixture was purified with cation exchange resin (Amberlite IR- 120H) and weak acid cation exchange resin (Amberlite CG-50). As a result, pure valienamine (l.lg) was obtained.

[36] Hydrogen NMR spectrum of the resulting product (valienamine) was as follows:

[37] ¹U NMR (D O, 300MHz) 3.35 (m,lH), 3.49(m,2H), 3.80-3.95 (m,2H), 4.02(d,lH),

5.61(d,lH)

[38] Example 2: Preparation of Valienamine from Acarbose (2)

[39] Acarbose (1Og) and potassium hydroxide (10.5g) were added to water (18OmL) and then refluxed during 48 hours. The reaction mixture was cooled to room temperature, neutralized with IN hydrochloric acid solution, and then concentrated. The concentrated reaction mixture was purified with cation exchange resin (Amberlite IR- 120H) and weak acid cation exchange resin (Amberlite CG-50). As a result, pure valienamine (1.Og) was obtained.

[40] Example 3: Preparation of Valienamine from Acarbose (3)

[41] Acarbose (1.Og) and calcium hydroxide (1.6g) were added to water (2OmL) and then refluxed during 60 hours. The reaction mixture was cooled to room temperature, and then concentrated. The concentrated reaction mixture was purified with cation exc hange resin (Amberlite IR- 120H) and weak acid cation exchange resin (Amberlite CG- 50). As a result, pure valienamine (0.12g) was obtained.

[42] Example 4: Preparation of Valienamine from Acarbose (4)

[43] Acarbose (1.Og) and barium hydroxide octahydrate (6.8g) were added to water

(2OmL) and then refluxed during 55 hours. The reaction mixture was cooled to room temperature, and then concentrated. The concentrated reaction mixture was purified with cation exchange resin (Amberlite IR- 120H) and weak acid cation exchange resin (Amberlite CG-50). As a result, pure valienamine (0.09g) was obtained.

[44] Example 5: Preparation of Valienamine from Acarbose (5)

[45] Acarbose (1.Og) and sodium carbonate (2.Og) were added to water (2OmL) and then refluxed during 72 hours. The reaction mixture was cooled to room temperature, and then concentrated. The concentrated reaction mixture was purified with cation exchange resin (Amberlite IR- 120H) and weak acid cation exchange resin (Amberlite CG-50). As a result, pure valienamine (0.08g) was obtained.

[46] Example 6: Preparation of Valienamine from Acarbose (6)

[47] Acarbose (1.Og) and sodium bicarbonate (1.8g) were added to water (2OmL) and then refluxed during 72 hours. The reaction mixture was cooled to room temperature, and then concentrated. The concentrated reaction mixture was purified with cation exchange resin (Amberlite IR- 120H) and weak acid cation exchange resin (Amberlite CG-50). As a result, pure valienamine (0.09g) was obtained.

[48] Example 7: Preparation of Valienamine from Acarbose Derivative (disaccharide)

Ol

[49] Acarbose derivative (disaccharide, 2.Og) and potassium hydroxide (2.Og) were added to water (4OmL) and then refluxed during 48 hours. The reaction mixture was cooled to room temperature, neutralized with IN hydrochloric acid solution, and then concentrated. The concentrated reaction mixture was purified with cation exchange resin (Amberlite IR- 120H) and weak acid cation exchange resin (Amberlite CG-50). As a result, pure valienamine (0.2g) was obtained.

[50] Example 8: Preparation of Valienamine from Acarbose Derivative (disaccharide)

(8)

[51] Acarbose derivative (disaccharide, 2.Og) and sodium hydroxide (1.6g) were added to water (4OmL) and then refluxed during 40 hours. The reaction mixture was cooled to room temperature, and then concentrated. The concentrated reaction mixture was purified with cation exchange resin (Amberlite IR- 120H) and weak acid cation exchange resin (Amberlite CG-50). As a result, pure valienamine (0.18g) was obtained. [52] Example 9: Preparation of Valienamine from Acarbose (9)

[53] Acarbose (5g) and tetramethylammonium hydroxide (2Og) were added to water

(5OmL) and then refluxed during 40 hours. The reaction mixture was cooled to room temperature, neutralized with IN hydrochloric acid solution, and then concentrated. The concentrated reaction mixture was purified with cation exchange resin (Amberlite IR- 120H) and weak acid cation exchange resin (Amberlite CG-50). As a result, pure valienamine (0.4g) was obtained.

[54] Example 10: Preparation of Valienamine from Acarbose (10)

[55] Acarbose (2g) and potassium phosphate tribasic (9.8g) were added to water (2OmL) and then refluxed during 45 hours. The reaction mixture was cooled to room temperature, neutralized with IN hydrochloric acid solution, and then concentrated. The concentrated reaction mixture was purified with cation exchange resin (Amberlite IR- 120H) and weak acid cation exchange resin (Amberlite CG-50). As a result, pure valienamine (0.17g) was obtained.

[56] Example 11: Preparation of Valienamine from Acarbose (H)

[57] Acarbose (2g) and sodium phosphate tribasic (7.5g) were added to water (2OmL) and then refluxed during 48 hours. The reaction mixture was cooled to room temperature, neutralized with IN hydrochloric acid solution, and then concentrated. The concentrated reaction mixture was purified with cation exchange resin (Amberlite IR- 120H) and weak acid cation exchange resin (Amberlite CG-50). As a result, pure valienamine (0.19g) was obtained.

[58] Example 12: Preparation of Valienamine from Acarbose (12)

[59] Acarbose (5g) and sodium phosphate dibasic (16.5g) were added to water (5OmL) and then refluxed during 4 days. The reaction mixture was cooled to room temperature, neutralized with IN hydrochloric acid solution, and then concentrated. The concentrated reaction mixture was purified with cation exchange resin (Amberlite IR- 120H) and weak acid cation exchange resin (Amberlite CG-50). As a result, pure valienamine (0.35g) was obtained. [60] Example 13: Preparation of Valienamine from Acarbose Derivative (disaccharide)

(13)

[61] Acarbose (2g) and diisopropyl ethylamine (2OmL) were added to water (5mL) and then refluxed during 3 days. The reaction mixture was concentrated under reduced pressure and then diluted with water (5OmL). The resultant reaction mixture was purified with cation exchange resin (Amberlite IR- 120H) and weak acid cation exchange resin (Amberlite CG-50). As a result, pure valienamine (0.16g) was obtained. Industrial Applicability [62] The conventional synthetic methods of valienamine are inadequate for mass production of the product since they are too complicated due to so many reaction steps and they produce many by-products. The present invention provides a method of preparing valienamine suitable for mass production by simplifying the reaction steps and diminishing byproducts. Moreover, the present invention uses a base for the reaction of acarbose or acarbose derivatives so it is a less harmful method in comparison with the conventional methods that uses harmful organic solvents.

Claims

Claims [1] A method for preparing valienamine represented by the following formula (1) from acarbose or acarbose derivatives by using a base.

(1)

[2] The method according to claim 1, wherein the base is selected from the group consisting of metal hydroxide, metal carbonate, and metal bicarbonate.

[3] The method according to claim 2, wherein the metal hydroxide is sodium hydroxide or potassium hydroxide.

[4] The method according to claim 2, wherein the metal hydroxide is calcium hydroxide or barium hydroxide.

[5] The method according to claim 2, wherein the metal carbonate is sodium carbonate or potassium carbonate.

[6] The method according to claim 2, wherein the metal bicarbonate is sodium bicarbonate or potassium bicarbonate. [7] The method according to claim 1, wherein the base is sodium phosphate tribasic or potassium phosphate tribasic. [8] The method according to claim 1, wherein the base is NR R R (in which R ,R , and R may be the same or different and are independently an alkyl group with a carbon number of 1 to 4) [9] The method according to claim 1, wherein a dissociation constant (pKa) of the base is at least 6. [10] The method according to claim 9, wherein the dissociation constant (pKa) of the base is at least 10.