KR100982720B1 - Manufacturing Process of 2-Aminomalonamide as Intermediate for Producing 4-Carbamoyl-1-?-D-ribofuranosylimidazolium-5-olate - Google Patents

Abstract

The present invention relates to a method for preparing 2-aminomalonamide as an intermediate for the production of 4-carbamoyl-1-β-D-ribofuranoslimidazolium-5-oleate represented by the following formula (1) New starting materials with different starting materials to be produced by chemical reaction by improving the production process of 4-carbamoyl-1-β-D-ribofuranoslimidazolium-5-oleate produced by fermentation One method of synthesis relates. The present invention significantly reduces the process by reducing the process that was performed in the conventional six steps to four steps, and can obtain intermediates at much milder conditions without using a pressurized hydrogenation process or harsh reaction conditions in the presence of Lewis acid. Increased safety of production, through which there is an advantage that can greatly improve the overall production efficiency.

[Formula 1]

4-carbamoyl-1-β-D-ribofuranosylimidazolium-5-oleate, 2-aminomalonamide, diethyl 2-aminomalonate

Description

Manufacturing process of 2-aminomalonamide as intermediate for the production of 4-carbamoyl-1-β-D-ribofuranoslimidazolium-5-oleate Carbamoyl-1-β-D-ribofuranosylimidazolium-5-olate}

The present invention relates to a method for preparing 2-aminomalonamide as an intermediate for the production of 4-carbamoyl-1-β-D-ribofuranoslimidazolium-5-oleate represented by the following formula (1) New starting materials with different starting materials to be produced by chemical reaction by improving the production process of 4-carbamoyl-1-β-D-ribofuranoslimidazolium-5-oleate produced by fermentation One method of synthesis relates.

4-carbamoyl-1-β-D-ribofuranosylimidazolium-5-olate was used as an immunosuppressive agent, lupus nephritis, It is known as an excellent drug for the treatment of chronic pain joint rheumatism. There are several known methods for preparing 4-carbamoyl-1-β-D-ribofuranosilimidazolium-5-oleate, and the representative synthesis method is shown in Scheme 1 below. [J. Antibiotics, 27, ( 10), 775 (1974); Chem. Pharm. Bull., 23, 245 (1975).

The conventional synthesis method, which is a total of six steps represented by Scheme 1, is subject to various limitations in the production of chemical synthesis.

First, hydrogenation reaction should be carried out under high pressure using highly flammable palladium charcoal (typically denoted as Pd / C) to obtain 2-aminomalonamide (formula 2, represented by Scheme 1 in 3), the key intermediate. To obtain 4-carbamoyl-1- (2,3,5-tri-O-acetyl-β-D-ribofuranosyl) imidazolium-5-oleate (denoted 5 in Scheme 1)- It reacts for more than 18 hours from 60 ℃ to 60 ℃, and after completion of the reaction to obtain a pure compound not only has to use column chromatography using chloroform and methanol as a developing solvent, the third final compound 4-carbamoyl- In order to obtain 1-β-D-ribofuranosilimidazolium-5-oleate, impurities must be removed by column chromatography using chloroform, methanol, and acetic anhydride as a developing solvent. Due to such inefficiency in the production process, the provision of conventional 4-carbamoyl-1-β-D-ribofuranosilimidazolium-5-oleate has been found to be effective for fermentation by microorganisms which are significantly less efficient than chemical synthesis. Most of them depended.

The present invention has been made to solve the above problems, 4-carbamoyl-1-β-D-ribofuranosilimidazolium-5-oleate through the modification of the starting material and the improvement of the reaction process It is an object to provide a method for synthesizing effectively.

It is another object of the present invention to provide a method for synthesizing the intermediate represented by the formula (2) necessary for synthesizing 4-carbamoyl-1-β-D-ribofuranosilimidazolium-5-oleate.

4-carbamoyl-1-β-D-ribofuranosilimidazolium-5-oleate production method of the present invention, in order to achieve the object as described above,

(A) reacting diethyl 2-aminomalonate with ammonia to synthesize 2-aminomalonamide;

(B) reacting the 2-aminomalonamide with formamidine acetate to synthesize 2-imidazolium-5-olate;

(C) coupling the 2-imidazolium-5-oleate with furanose tetraester in the presence of Lewis acid; And

(D) leaving the protecting group of the coupling reaction product to obtain 4-carbamoyl-1-β-D-ribofuranosilimidazolium-5-oleate

Characterized in that it comprises a.

In addition, in the method for preparing 4-carbamoyl-1-β-D-ribofuranoslimidazolium-5-oleate of the present invention, the reaction of step (A) is preferably performed in methanol.

On the other hand, the preparation method of 2-aminomalonamide of the formula (2) as an intermediate for the production of 4-carbamoyl-1-β-D-ribofuranoslimidazolium-5-oleate of the present invention It is characterized by reacting diethyl 2-aminomalonate with ammonia.

Moreover, it is preferable that reaction of the said diethyl 2-aminomalonate and ammonia is made in methanol.

The present invention significantly reduces the process by reducing the process that was performed in the conventional six steps to four steps, and can obtain intermediates at much milder conditions without using a pressurized hydrogenation process or harsh reaction conditions in the presence of Lewis acid. Increased safety of production, through which there is an advantage that can greatly improve the overall production efficiency.

Compared to the conventional synthesis method represented by Scheme 1, which is a total of six steps, the synthesis method of the present invention represented by Scheme 2 includes four steps. In order to obtain 2-aminomalonamide, which is a key intermediate in Scheme 1, represented by Schemes 1 and 2 and 3, diethyl 2-aminomalonate was used. By synthesizing in only one step using 2 to 6), large-scale synthesis was possible by greatly reducing the process step and securing the safety of the process.

Specifically, the method for preparing 4-carbamoyl-1-β-D-ribofuranoslimidazolium-5-oleate of the present invention is a diethyl 2- (hydroxyimino) malonate from a malonic ester in a conventional manufacturing method. Obtaining dinate 2- (hydroxyimino) malonate (step 1); Obtaining 2- (hydroxyimino) malonamide from diethyl2- (hydroxyimino) malonate (step 2); Diethyl 2-aminomalonate (diethyl 2-aminomalonamide) is a three-step step of synthesizing 2-aminomalonamide from 3- (hydroxyimino) malonamide using a pressurized hydrogenation reaction. By using aminomalonate), it is possible to shorten the process by securing the safety of the process by simplifying it in one step without using hydrogenation reaction.

Hereinafter, preferred embodiments of the present invention will be described in detail. In addition, many specific details such as specific components are described in the following description, which is provided to help a more general understanding of the present invention. It is self-evident to those who have knowledge of the world. In the following description of the present invention, a detailed description of known functions and configurations incorporated herein will be omitted when it may make the subject matter of the present invention rather unclear.

Example

Example : 2- Of 2-aminomalonamide  synthesis

15 g of diethyl 2-aminomalonate was dissolved in 30 ml of methanol at room temperature, 200 ml of ammonia water was added dropwise, and the temperature was raised to 45 ° C and stirred for 8 hours. The reaction solution was cooled to 5 ° C., stirred for 1 hour, and the resulting solid was filtered to yield the target compound as an off-white solid in 65% yield.

¹ H NMR (DMSO-d ₆ ): δ ppm 7.41 (bs, 1 H), 7.25 (bs, 1 H), 3.79 (s, 1 H), 2.15 (bs, 2 H).

When the ammonia gas was reacted with a solution saturated with methanol instead of ammonia water, the target compound was obtained in a similar yield.

Example of reaction  1: 2- Imidazolium -5- Oleate  synthesis

11.3 g of formamidine acetate was added to 10.5 g of 2-aminomalonamide synthesized in Example 1 at room temperature, and 300 ml of ethanol was added thereto, and the mixture was refluxed for 3 hours. The mixture was cooled to room temperature and then stirred at room temperature for 12 hours. The resulting solid was obtained by filtration, and the obtained solid was recrystallized from 200 ml of water to give a target compound of a blue-gray solid in a yield of 60% (melting point: 255 ° C.).

¹ H NMR (DMSO-d ₆ ): δ ppm 7,86 (s, 1 H), 7.05 (bs, 1 H), 6.69 (s, 1 H).

Example of reaction  2: 4- Carbamoyl -1- (2,3,5-Tri-O-acetyl-β-D- Ribofuranosil ) Imidazolium Synthesis of -5-Olate

12 g of 2-imidazolium-5-oleate and 70 g of hexamethyldisilazane (HMDS) synthesized in Reaction Example 1 were added to 200 ml of m-xylene, and 250 mg of ammonium sulfate was further added. After the addition, the mixture was stirred at reflux for 12 hours. After concentrating the mixture, 16 g of ß-D-ribofuranose 1,2,3,5-tetraacetate (ß-D-ribofuranose 1,2,3,5-tetraacetate) was added to 100 ml of 1,2-dichloroethane. It was dissolved in and added to the concentrated mixture, and 7.2 ml of tin tetrachloride (SnCl ₄ ) was further added, followed by stirring at room temperature for 6 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, 400 ml of ethyl acetate was added to the obtained oily compound, 300 ml of a 5% by weight aqueous solution of sodium carbonate (Na ₂ CO ₃ ) was added thereto, the mixture was stirred vigorously for 10 minutes, and the organic layer was extracted. The obtained organic layer was washed again with 300 ml of a 5 wt% aqueous solution of sodium carbonate (Na ₂ CO ₃ ) and concentrated. The oily compound thus obtained was recrystallized from dichloromethane and n-hexane to give the title compound as a light gray solid in 70% yield.

m.p. > 201 ℃

[α] = -26.3 °

¹ H NMR (CDCl ₃ ): δ ppm 8.01 (s, 1 H), 6.04-6.16 (s, 3 H), 5.38 (bs, 1 H), 4.66-4.81 (m, 3 H), 1.98-2.02 ( m, 9 H).

Example of reaction  3: 4- Carbamoyl -1-β-D- Ribofuranosyl imidazolium -5- Oleate  synthesis

100 ml of methanol of 10 g of 4-carbamoyl-1- (2,3,5-tri-O-acetyl-β-D-ribofuranosyl) imidazolium-5-oleate obtained in Reaction Example 2 was used. After dissolving in, 4.2 g of sodium hydroxide was added thereto and stirred at room temperature for 6 hours. The mixture was distilled under reduced pressure, 100 ml of dichloromethane and 100 ml of water were added, and the pH was adjusted to 5.0 with concentrated hydrochloric acid. The organic layer was removed and the aqueous layer was washed again with 50 ml of dichloromethane. The water layer obtained was distilled under reduced pressure and concentrated to 1/5 the original volume. After cooling to room temperature, 100 ml of toluene was added, refluxed for 1 hour, and the solid obtained by cooling was recrystallized again with methanol to obtain a target compound as a white solid in a yield of 40%.

m.p. > 200 ℃

[α] = -27.5 °

¹ H NMR (D ₂ O): δ ppm 8.03 (s, 1 H), 5.58 (s, 1 H), 4.38 (s, 1 H), 4.15 (s, 1 H), 4.15 (s, 1 H) , 3.67 (dd, 2H, J = 1.6, 3.6 Hz).

Although the above has been illustrated and described with respect to the preferred embodiments of the present invention, the present invention is not limited to the specific embodiments described above, those skilled in the art without departing from the gist of the present invention various modifications Of course, implementation is possible. Accordingly, the scope of the present invention should not be construed as being limited to the above-described embodiments, but should be determined by equivalents to the appended claims, as well as the following claims.

Claims (4)

(A) After dissolving diethyl 2-aminomalonate in methanol at room temperature, ammonia water was added dropwise, the temperature was raised to 45 ° C. and stirred for 8 hours, the reaction solution was cooled to 5 ° C. and stirred for 1 hour. To synthesize 2-aminomalonamide; (B) formamidine acetate was added to the synthesized 2-aminomalonamide at room temperature, refluxed for 3 hours by adding ethanol, the mixture was cooled to room temperature, stirred for 12 hours, and the resulting solid. Recrystallizing the solid obtained by filtration with water to synthesize 2-imidazolium-5-olate; (C) the synthesized 2-imidazolium-5-oleate and hexamethyldisilazane (HMDS) were added to xylene, and further ammonium sulfate was added, followed by stirring under reflux for 12 hours, and the mixture After concentrating the ß-D-ribofuranose 1,2,3,5-tetraacetate (ß-D-ribofuranose 1,2,3,5-tetraacetate) in 1,2-dichloroethane, the concentrated mixture was After adding to the addition of tin tetrachloride (SnCl ₄ ) and stirred at room temperature for 6 hours, after completion of the reaction to remove the solvent by distillation under reduced pressure, ethyl acetate was added to the obtained oily compound, sodium carbonate (Na ₂ CO ₃ ) was added thereto, stirred vigorously for 10 minutes, and then the organic layer was extracted. The organic layer was washed again with an aqueous solution of sodium carbonate (Na ₂ CO ₃ ) and concentrated. The obtained oily compound was diluted with dichloromethane and n-hexane. Recrystallization to 4-carbamoyl-1- (2,3,5- Lee -O- acetyl -β-D- ribo Pew pyrano room) step of already synthesized imidazolium-5-oleate; And (D) 4-carbamoyl-1- (2,3,5-tri-O-acetyl-β-D-ribofuranosyl) imidazolium-5-oleate synthesized above was dissolved in methanol After adding sodium and stirring at room temperature for 6 hours, the mixture was distilled under reduced pressure, dichloromethane and water were added, the pH was adjusted to 5.0 with concentrated hydrochloric acid, the organic layer was removed, and the water layer was washed with dichloromethane again. Distillation under reduced pressure, concentrating to 1/5 of the original volume, cooling to room temperature, adding toluene, refluxing for 1 hour, and cooling the solid obtained by recrystallization again with methanol 4-carbamoyl-1-β-D- Obtaining Ribofuranosilimidazolium-5-Olate (4-carbamoyl-1-β-D-ribofuranosylimidazolium-5-olate) Method for preparing 4-carbamoyl-1-β-D-ribofuranosilimidazolium-5-oleate of the formula (1) comprising: [Formula 1]

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