KR20060072554A - The preparation method of 1-methoxy-2-deoxy-l-ribose - Google Patents

Abstract

The present invention relates to a method for preparing 1-methoxy-2-deoxy-L-ribose of formula (IV),

(a) reacting a compound of formula (I) with vinylmagnesium bromide, 1-propenyl magnesium bromide, or the like or by reacting vinyllithium, lithium divinylcapper, etc. to prepare a compound of formula (II);

(b) reacting the compound (II) produced in step (a) with ozone to prepare a compound of formula (III), and reacting the compound (III) with methanol and an acid to produce a compound of formula (IV). Manufacturing,

Deprotecting compound (II) with an acid to prepare a compound of formula (V),

Reacting the resulting compound (V) with ozone to produce the compound of formula (IV):

Wherein R ₃ and R ₄ are protecting groups of 1,2-dihydroxy, and R ₁ and R ₂ are H, C ₁ -C ₁₅ alkyl, C ₃ -C ₁₅ cycloalkyl, phenyl and the like.

Nucleic acid, ribose

Description

The preparation method of 1-methoxy-2-deoxy-L-ribose

The present invention relates to a method for preparing 1-methoxy-2-deoxy-L-ribose.

Recently, L-isomers of natural or modified nucleosides have attracted attention as antiviral agents. L-thymidine, L-3'-thiacytidine (3TC) and the like exhibit excellent antiviral effects with significantly less toxicity than D-nucleosides.

L-nucleosides also have a good effect on antisense oligonucleotide therapy. Because of this, many attempts have been made to effectively synthesize L-nucleosides that do not exist in nature, and in particular 2-deoxy-L-ribose and 1-methoxy-2-de, which are the main intermediates of L-nucleosides. There is a focus on methods for producing large quantities of derivatives of oxy-L-ribose.

Conventional methods for preparing 1-methoxy-2-deoxy-L-ribose include the synthesis of 2-deoxy-L-ribose after various synthesis steps and synthesis thereof as starting materials, or 2-deoxy-L- Ribose was purified through a known aniline derivative and purified using it as a starting material.

As described above, 2-deoxy-L-ribose, which is used as a starting material, is separated or used, and the yield is low, various reagents are used, and the process time is inefficient.

Accordingly, it is an object of the present invention to provide a method for preparing 1-methoxy-2-deoxy-L-ribose at low cost in a continuous process without refining in Structural Formula (II) in order to solve the problems of the conventional method. .

The present invention relates to a process for preparing 1-methoxy-2-deoxy-L-ribose represented by the following structural formula (IV) in a high yield and simple process without any other side products.

The method for preparing 1-methoxy-2-deoxy-L-ribose ribose of the following structural formula (IV) of the present invention is two, and the first method is configured as follows.

Method 1.

(a) R ₃ and R ₄ are reacted with vinylmagnesium bromide, 1-propenylmagnesium bromide or the like by reacting a compound of the following structural formula (I) wherein 1,2-dihydroxy is a protecting group; Preparing a compound of formula (II);

(b) reacting the compound produced in step (a) with ozone to produce a compound of formula (III);

(c) reacting the compound produced in step (b) with methanol and acid to prepare a compound of formula (IV).

Hereinafter, the present invention will be described in detail.

The compound of formula (I) used as a starting material in the present invention is J. Org. Chem. 1988, 53, 2598-2602 and J. Chem. Soc. It can be produced inexpensively according to the known method described in Perkin Trans 1 1995, 1783-1785.

In the compound of formula (I), R ₃ and R ₄ are protecting groups of 1,2-dihydroxy, and preferably isopropylidene, ethylpropylidene and cyclopentylidene, cyclohexylidene and the like.

In the method for preparing 1-methoxy-2-deoxy-L-ribose according to the present invention, first, the structural formula (1) compound is dissolved in a solvent such as tetrahydrofuran, ethyl ether, toluene, and then a catalytic amount of copper iodide is added thereto. Vinylmagnesium bromide is added at a temperature range of -78 to 25 ^° C., preferably -78 to 30 ^° C., and then stirred for 1-24 hours at the same temperature to yield the compound of formula II in about 95% yield. Get

Wherein the compound of formula (II) was added to a solvent such as methanol, dichloromethane was added ozone at -78~0 ^o C, preferably at -78~-30 ^o C and stirred for 1-24 hours, preferably from 3 hours To yield the compound of formula III in about 93% yield.

Dissolve the compound of formula (III) in methanol and use an acid such as hydrochloric acid, phosphoric acid, acetic acid, tomic acid, formic acid, lactic acid, or citric acid at 25-100 ^o C, preferably 25-60 ^o C Reaction 1-24 hours to obtain the structural formula (IV) in a yield of about 80%.

Wherein R ₃ , R ₄ are preferably isopropylidene, ethylpropylidene, cyclopentylidene, cyclohexylidene and the like and R ₁ and R ₂ are each H, C ₁ -C ₁₅ alkyl, C ₃ − C ₁₅ cycloalkyl, phenyl and the like, M is a metal such as CuLi, MgBr, Li, and n is 1 to 2.

The second method of the present invention is constructed as follows.

Method 2.

(a) R ₃ and R ₄ are reacted with vinylmagnesium bromide, 1-propenylmagnesium bromide or the like by reacting a compound of the following structural formula (I) wherein 1,2-dihydroxy is a protecting group; Preparing a compound of formula (II);

(b) deprotecting compound (II) produced in step (b) in the presence of an acid to prepare a compound of formula (III);

(c) reacting the compound (V) produced in step (e) with ozone in the presence of an acid

It comprises the step of preparing a compound of formula (IV).

The structural formula (II) is prepared and obtained according to the method described in Method 1.

The compound of formula (II) is 25-100 ^o C, preferably using a solvent such as methanol, dichloromethane and the like with hydrochloric acid, phosphoric acid, acetic acid, tomic acid, formic acid, lactic acid, or citric acid. The deprotection reaction was carried out at 25-60 ^° C. for 1-24 hours to obtain the above formula (V) in a yield of about 98%.

The compound of formula (V) was dissolved in a solvent of methanol, and adjusted to pH 0.1-1 using an acid such as hydrochloric acid, phosphoric acid, acetic acid, tomic acid, formic acid, lactic acid, or citric acid, and then -78 to ^{0 °} C. Cool, add ozone for 1-5 hours at -78 to -30 ^o C, stir, raise the temperature to 20-25 ° C and stir for 2-5 hours to obtain the compound of formula IV Obtained in% yield.

Wherein R ₃ , R ₄ are preferably isopropylidene, ethylpropylidene, cyclopentylidene, cyclohexylidene and the like and R ₁ and R ₂ are each H, C ₁ -C ₁₅ alkyl, C ₃ − C ₁₅ cycloalkyl, phenyl and the like, M is a metal such as CuLi, MgBr, Li, and n is 1 to 2.

Hereinafter, the present invention will be described in more detail based on the following examples.

Example 1 Synthesis of 2-deoxy-4,5,6-trihydroxy-5,6-O-isopropylidene-hexene (II)

106.0 g (0.735 mol) of (2S, 3S) -3,4-epoxy-1,2-isopropylidene-butane-1,2-diol to 0.5 L of tetrahydrofuran, followed by 1.4 g (0.01 equiv) of copper iodide 882 mL (1.2 equivalents) of 1 mol tetrahydrofuran solution of vinylmagnesium bromide was added slowly at -45 ^° C, and the mixture was stirred at the same temperature for 1 hour. 1N HCl was added to the reaction solution to adjust pH to 7-7.5, ethyl acetate 2L was added thereto, stirred for 30 minutes, and the layers were separated. The oil layer was washed with brine.

The oil layer was dried over a forget-me-not and concentrated under a reduced pressure to obtain 120.3 g (theoretical yield: 95%) of a pale yellow liquid 2-deoxy-4,5,6-trihydroxy-5,6-O-isopropylidene-hexene. .

Rf 0.3 (hexane: diethyl ether = 1: 1, v / v)

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 1.32 (s, 3H, CH3), 1.41 (s, 3H, CH3), 2.08 (d, 1H, OH), 2.13-2.38 (m, 2H, C3) , 3.70-3.82 (m, 1H, C4), 3.85-4.05 (m, 3H, C5, C6), 5.14 (dd, 1H, C1), 5.20 (dd, 1H, C1), 5.73-5.94 (m, 1H , C2)

Example 2: Synthesis of 1-methoxy-2-deoxy-L-ribose (IV)

120.3 g of 2-deoxy-4,5,6-trihydroxy-5,6-O-isopropylidene-hexene obtained in Example 1 was dissolved in 1 L of methylene chloride and then cooled to −50 ^° C. Ozone was slowly added to the reactor and stirred at the same temperature for 3 hours. When the reaction was completed, 1 L of 7% sodium thiosulfate aqueous solution was added dropwise to the reaction solution, followed by stirring for 10 minutes. The reaction solution was separated and the oil layer was washed with 2 L of purified water, dried over forget-me-not and concentrated under reduced pressure to obtain 113 g of a liquid compound (III) (theoretical yield; 93%).

113 g of the compound (III) obtained above was dissolved in 1 L of methanol without purification, p-toluenesulfonic acid was added to adjust the pH to 0.1, and stirred at 20-25 ^° C. for 2 hours. After the reaction was completed, triethylamine was added to the reaction solution to adjust the pH to 7-8. The reaction solution was obtained under reduced pressure 19.7-methoxy-2-deoxy-L-ribose 69.7 g (theoretical yield: 80%).

Example 3: Synthesis of 1,2,3-trihydroxy-5-hexene (V)

100 g of 2-deoxy-4,5,6-trihydroxy-5,6-O-isopropylidene-hexene synthesized in the same manner as in Example 1 was dissolved in 1 L of methanol and 200 ml of water, followed by pH with 5N HCl. Adjust to 0.1-1.0 and stir at 25-30 ^o C for 4 hours. After stirring, the reactor was concentrated under reduced pressure to obtain 75 g (theoretical yield: 98%) of a liquid compound (V).

Rf 0.5 (methanol: ethyl acetate = 1: 4, v / v);

¹ H NMR (300 MHz, CH ₃ OD) δ (ppm) 2.1-2.5 (m, 2H, C4), 3.4-3.8 (m, 4H, C1, C2, C3), 5.0-5.2 (m, 2H, C6) , 5.7-6.0 (m, 1H, C5)

Example 4: Synthesis of 1-methoxy-2-deoxy-L-ribose (IV)

75 g of 1,2,3-trihydroxy-4-hexene obtained in Example 3 was dissolved in 1 L of methanol, and p-toluenesulfonic acid was added to adjust the pH to 0.1 and cooled to -70 to -50 ^° C. O ₃ was generated and stirred for 2 hours. After completion of stirring, the reaction solution was heated to 20-25 ℃ and stirred for 2 hours. Triethylamine was added to adjust pH to 7-8. The reaction solution was concentrated under reduced pressure to obtain 71.5 g (theoretical yield: 85%) of 1-methoxy-2-deoxy-L-ribose.

The present invention is a method for preparing 1-methoxy-2-deoxy-L-ribose, the reaction is easy and there are few by-products, there is no cost and hassle to remove by-products. In addition, the yield is very high and the process is simple, the advantage is higher economical than the conventional method.

Claims (5)

(a) reacting a compound of formula (I) with vinyl metals to produce a compound of formula (II); (b) reacting compound (II) produced in step (a) with ozone to produce a compound of formula (III); And (c) A process for preparing 1-methoxy-2-deoxy-L-ribose, which comprises reacting a compound of formula III with an acid and methanol to produce formula IV:

Where R ₁ , R ₂ are each H, C ₁ -C ₁₅ alkyl, C ₃ -C ₁₅ cycloalkyl or phenyl, and R ₃ , R ₄ are each H, C ₁ -C ₁₅ alkyl, C ₃ -C ₁₅ cycloalkyl Or phenyl, and R ₃ , R ₄ may form a 5,6,7, or 8-membered ring and may have one or more substituents. The method according to claim 1, wherein the vinyl metals are vinyllithium and lithium divinylcapers.        (a) reacting a compound of formula (I) with vinyl metals to produce a compound of formula (II); (b) deprotecting compound (II) produced in step (a) to prepare a compound of formula (III); (c) a method of preparing 1-methoxy-2-deoxy-L-ribose comprising reacting compound (V) produced in step (b) with ozone to produce a compound of formula (IV):

Where R ₁ , R ₂ are each H, C ₁ -C ₁₅ alkyl, C ₃ -C ₁₅ cycloalkyl or phenyl, and R ₃ , R ₄ are each H, C ₁ -C ₁₅ alkyl, C ₃ -C ₁₅ cycloalkyl Or phenyl, and R ₃ , R ₄ may form a 5,6,7, or 8-membered ring and may have one or more substituents. The solvent of claim 3, wherein the solvent is reacted with ozone to synthesize 1-methoxy-2-deoxy-L-ribose of formula IV, using anhydrous methanol. And reacting in the presence. The method according to claim 3, wherein the vinyl metals are vinyllithium and lithium divinylcapers.