KR0130942B1 - Preparation process of 3-azido-3-deoxythimidine - Google Patents

Abstract

The invention provides process for preparing 3'-azido-3'-deoxythymidine reacting thymidin with O-acetyl salicyloyl chloride which is useful as a antivirus agent or AIDS remedy. Protected thymidin which is protected by trityl radical at 5'-position hydroxyl group or unprotected thymidin are reacted with O-acetyl salicyloyl chloride under the solvent of acetonitrile, tetrahydrofuran etc., and then produces 3'-azido-3'-deoxythymidine of the general formula (I) reacting (PhO)2PON3 or Ph3P-NH3-diethyle azodicaboxylate.

Description

Method for preparing 3'-azido-3'-deoxythymidine

The present invention relates to a novel process for the preparation of compounds of formula (I) below which is useful as an antiviral or AIDS treatment.

Methods of preparing the compounds are described in Korean Patent Application Publication No. 91-7919, Japanese Patent Application Publication No. 63-255295, and US Patent No. 5,108,993. According to these known production methods, as shown in the following Reaction Scheme I, thymidine is used as a starting material to protect the hydroxyl group at the 5 'position using various protecting groups, and the various protecting groups are used as the hydroxyl group at the 3' position. After the protection, the compound (I) is prepared through a six-step process of azating the 3 'position using a azide agent and finally hydrolyzing the 5' position. Therefore, the known manufacturing method has a drawback in that the yield reduction and the manufacturing process are complicated due to the irrationality of the protection and removal process of the hydroxyl group.

(Wherein R is a trityl group and R1 is a mesyl group)

Accordingly, as a result of earnest research to provide a method for preparing compound (I) by improving the total yield by simplifying the process and reducing the number of processes by supplementing the drawbacks of the conventional method described above, O-acetyl salicylic acid Cyclolation of the 6 and 3 'positions with siloyl chloride does not protect the hydroxyl groups at the 3'- and 5' positions in the next reaction, or only protects the hydroxyl groups at the 5 'position and then proceeds with the reaction. The present invention has been accomplished by discovering that the above object can be achieved.

That is, an object of the present invention is to prepare a 3'-azido-3'-deoxy thymidine of the general formula (I) from thymidine, wherein the hydroxyl group at the 5'-position is protected by a trityl group (Compound of formula (III ')) Unprotected thymidine (compound of formula (III)) is reacted with O-acetyl salicyloyl chloride to give a compound of formula (II) or formula (II') To obtain; Reacting a compound of formula (II) or formula (II ′) with (PhO) 2 PON 3 or Ph 3 P-NH 3 -diethyl azodicarboxylate; And if necessary, to provide a method for producing a compound of formula (I) characterized in that it comprises a step of removing the protecting group of the investigator at the 5 'position.

(The compound in which 5′-position is —OR in the formula is (III ′).)

(The compound whose 5'-position is -OR in the formula is (II ').)

(Wherein R is a trityl group)

Hereinafter, the present invention will be described in more detail.

The process according to the invention is shown in Scheme II.

Reactivity Scheme II

In the method of the present invention, O-acetyl salicyloyl chloride is protected from thymidine without protecting its 3'- or 5'-position of hydroxyl group (-OH) or only the 5'-position of hydroxyl group with trityl group. By reacting with cyclizes the 6 and 3 'positions. This cyclization allows the reaction to proceed without protecting the hydroxyl groups at the 3'- and 5'-positions in subsequent reactions. In the present invention, the reaction can be stably progressed by using diphenyl phosphonic azide (PhO) 2 PON 3 or Ph 3 P-NH 3 -diethyl azodicarboxylate complex as an azide agent when azating the 3′-position. When the 5'-position hydroxyl group is protected by the trityl group, the target compound obtained after the reaction is removed through the normal hydrolysis reaction (compound (IV)). ) Compound can be obtained.

Protecting and deprotecting the hydroxyl group at the 5'-position of thymidine with a trityl group can be carried out according to a known method, and trityl chloride can be used as the tritylating agent.

The reaction according to the process of the present invention is tetrahydrofuran, methylene chloride, acetonitrile, dimethyl formamide, N, N-dimethyl acetamide, pyridine, dioxane, toluene, benzene, dimethyl sulfoxide, ether, ethyl acetate, methanol, One or two or more solvents selected from ethanol, isopropyl alcohol or butanol can be used.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.

Example 1

100 mL of acetonitrile was added to the three neck flask, and 24 g of thymidine was completely dissolved. Then, 78 g of O-acetyl salicyloyl chloride was added thereto, followed by stirring for 24 hours while maintaining a temperature of room temperature under a nitrogen stream. The mixture was gradually warmed up and maintained at 65-75 ° C. for 1 hour, concentrated under reduced pressure, completely distilled acetonitrile, and 100 µl of ether was added thereto, stirred for 1 hour, and filtered to collect the residue.

0.5 M hydrochloric acid and 620 ml of saturated methanol were added to the residue, and the mixture was stirred at room temperature for 3 days. The crystals were collected by filtration and dried in vacuo to give 19.1 g (85.6%) of the compound of formula (II).

Example 2

5.25 g of dimethyl formamide was added to a three-necked flask, followed by 4 g of compound (II). The mixture was heated and stirred at 80 ° C. for 0.5 hour. Then, 0.61 g of diphenyl phosphonic azide (PhO) 2 PON 3 was added and refluxed for 5 hours. Then cooled.

30 ml of distilled water was added at 5 ° C. or lower, stirred for 1 hour at 5 ° C. or lower, recrystallized, filtered, washed with distilled water, and dried under vacuum to obtain 4.32 g (91%) of the compound of formula (I).

mp = 121 ℃

Luminous intensity = [α] + 50 (C = 1, in Water), [α] + 99 (C = 0.5 in Water)

UV max (water): 266.5mm (Sol in hot methanol, hot ethanol)

1r (KBr): 2100cml

Example 3

After mixing 9 g of triphenyl phosphine and 20 ml of dried tetrahydrofuran, 6.2 g of mixture (II) was added thereto, and 1.2 M of 30 ml of HN3 and 5.3 g of dimethyl azodicarboxylate were added in a cooling bath. After adding the complex compound diluted with the benzene solution, after stirring at -10 degreeC for 30 hours, it stirred at 0 degreeC for 2 hours, and made it react at room temperature for 12 hours.

The reaction product was concentrated, and 30 g of chloroform was added to the residue, followed by economic separation using a silica gel column to obtain 6.88 g (92%) of the compound of formula (I).

Example 4

After putting 11.5 g of pyridine and 5 g of thymidine into a three-necked flask, 5.9 g of trityl chloride was added thereto and reacted at 70 ° C. for 1 hour, at 80 ° C. for 1 hour, and at 90 ° C. for 1 hour. Subsequently, a mixed solution of 75 ml of distilled water and 75 ml of ethyl acetate was added at 55 ° C., followed by layer separation, followed by washing with 75 ml of 0.5N hydrochloric acid, 75 ml of 5% sodium bicarbonate, and 75 ml of distilled water, followed by separation. 3.3g was added and stirred. After filtration, washing with ethyl acetate and drying yielded 9.8 g (98%) of the compound of the general formula (III ').

Example 5

50 ml of acetonitrile and 10 g of 5'-0-tritylthymidine (III ') were dissolved in a three-necked flask, and 4.7 g of O-acetyl salicyloyl chloride was added thereto, followed by stirring at room temperature for 24 hours under a nitrogen stream.

After heating, the mixture was reacted for 30 minutes at 70 ° C. and 30 minutes at 80 ° C., and then concentrated under reduced pressure to recover acetonitrile, and 50 µl of ether was added thereto, followed by stirring at room temperature for 1 hour, to obtain 8.7 g of a compound of formula (II ′) (90.2). %) Was obtained.

Example 6

12 μl of dimethyl formamide was added to a three-necked flask, followed by 4 g of compound (II ′). The mixture was heated and stirred at 80 ° C. for 1 hour, and then 0.32 g of diphenylphosphonic azide (PhO) 2 PON 3) was added thereto. After 5 hours reflux.

After cooling, 20 ml of distilled water was slowly added thereto, stirred for 3 hours at 5 ° C. or lower, recrystallized, filtered, washed with 25 ml of distillation port, dried, and 3.8 g (87.2%) of Compound (IV) was obtained. .

Example 7

3 g of compound (IV) was added to a three-necked flask, and 30 ml of acetone was added thereto, followed by melting. Then, 0.6 ml of 20% hydrochloric acid was added slowly, followed by heating at 45 ° C. for 5 hours. After completion of the reaction, the pH was adjusted to 7.0-8.0 with 20% sodium hydroxide solution, and then concentrated in vacuo to completely remove acetone and stirred at 60 ° C for 30 minutes. Subsequently, the trityl alcohol was separated by filtration, and the filtrate was concentrated in vacuo at 60 ° C./70 mmHg to reduce the liquid amount to 1/5, and then made into a supersaturated solution with salt, washed three times with 10 ml of ethyl acetate, and then separated, and then ethyl acetate layer. MgSo4 and 1g of activated carbon were added thereto, and the mixture was stirred at room temperature for 2 hours and then filtered. Subsequently, recrystallization was carried out and the filtrate was dried again to obtain 1.4 g (89.1%) of the target compound (I).

Claims (2)

In the process for preparing 3'-azido-3'-deoxythymidine of the general formula (I) from thymidine, the hydroxyl group at the 5'-position is protected by a trityl group (General Formula (III ') Compound) a process of reacting unprotected thymidine (compound of formula (III)) with O-acetyl salicyloyl chromide to obtain a compound of formula (II) or formula (II '); Reacting a compound of formula (II) or formula (II ′) with (PhO) 2 PON 3 or Ph 3 P-NH 3 -diethyl azodicarboxylate; And optionally removing a protecting group of the hydroxyl group at the 5'-position. (The compound in which 5′-position is —OR in the formula is (III ′).) (The compound whose 5'-position is -OR in the formula is (II ').) (Wherein R is a trityl group) The reaction of claim 1, wherein the reaction is carried out with tetrahydrofuran, methylene chloride, acetonitrile, dimethyl formamide, N, N-dimethyl acetamine, pyridine, dioxane, toluene, benzene, dimethyl sulfoxide ether, ether, ethyl acetate, methanol Characterized in that it is carried out in one or two or more solvents selected from ethanol, isopropyl alcohol or butanol.