JPH0692393B2 - Method for producing didehydronucleosides - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel method for producing a didehydronucleoside useful as a drug such as an antiviral agent or an intermediate for the production thereof.

Prior art didehydronucleosides such as 2 ', 3'-dideoxy-2', 3'-didehydronucleosides Is a 2 ', 3'-dideoxynucleoside which is easily obtained by itself or by reducing it. Both have an antiviral effect that can be used, for example, as a therapeutic agent for AIDS, and thus can be used as a drug or a production intermediate thereof (JP-A-61-280500 and J.Med.Che.
m., 30 , 440 (1987). ). The definition of the substituent B is as described later.

As a method for producing 2 ', 3'-dideoxy-2', 3'-didehydronucleosides, a method using ribonucleoside as a raw material (see J.Org.Chem., 39 , 30 (1974)) or 2 is used. ′
-Method using deoxyribonucleoside as a raw material (J. Ame
r.Chem.Soc., 88 , 1549 (1966) and J. Org. Chem., 32 , 817.
See (1967). ), Etc. are known, but all have many steps and use expensive reagents as raw materials.
It was not an industrially advantageous method.

Problems to be Solved by the Invention There has been a demand for a method capable of industrially and conveniently obtaining 2 ', 3'-dideoxy-2', 3'-didehydronucleosides by using starting materials that are easily and inexpensively available.

Means for Solving the Problems As a result of intensive studies by the present inventors in order to solve the above problems, the compound [I] having the following skeleton in the molecule With the formula: After being converted to a compound [II] having a skeleton represented by the formula, it is reacted with an acid anhydride in a temperature range of 20 to 200 ° C. It was found that dihydronucleosides having a skeleton shown in the molecule [III] can be easily produced in high yield,
The present invention has been completed based on this discovery. However,
In the above formula, R ¹ represents an alkyl group having 1 to 12 carbon atoms.

The compound [I] used as the starting material of the present invention can be represented by the general formula The compound [II] is, for example, a compound represented by the following general formula: (In the formula, R ¹ represents an alkyl group having 1 to 12 carbon atoms, R ²
Represents a hydrogen atom or an acyl group, an alkyl group, an aralkyl group, a silyl group, etc., and B represents a nucleic acid such as a purine base bonded at the 9-position or a pyrimidine base bonded at the 1-position to the sugar residue. Each of the bases found in chemistry is represented. ) Is a nucleoside derivative represented by the following general formula contained in the dihydronucleosides by reacting it with, for example, an acid anhydride at 20 to 200 ° C. (In the formula, R ² and B have the same meanings as described above.) 2 ′, 3′-dideoxy-2 ′, 3′-didehydronucleosides represented by the following formula can be produced.

The nucleoside derivative of the compound [II ′] is represented by the formula [II ′] as described above, and for example, a method known per se (Tetr
See ahedron, 23 , 2301 (1967). )use Then, it can be prepared from the above compound [I ']. In the formula, R ¹ represents an alkyl group, and examples of the alkyl group include a methyl group, an ethyl group, and an n-propyl group.
² represents a hydrogen atom, an acyl group, an alkyl group, an aralkyl group, a silyl group or the like. In addition, B is a sugar residue with 9
A base found in nucleic acid chemistry, such as a purine base bound at a position or a pyrimidine base bound at a position, is exemplified as adenosine, guanosine, hypoxanthine, xanthine, 6-chloropurine, 6-mercapto. Purine, 6-methylthiopurine, 2,6-dichloropurine, 2-chloropurine, 2,6-diaminopurine,
2-amino-6-chloropurine, 2-aminopurine, etc. can be illustrated, and as a pyrimidine base, uracil, cytosine, thymine, 5-fluorouracil, 5-chlorouracil, 5-bromouracil, 5-iodouracil, 5- Examples include ethyl uracil and orotic acid, and others, 5-
Amino-4-imidazole carboxamide and 1,2,4-
Examples include bases such as triazole-3-carboxamide. If necessary, the amino group of the base moiety may be protected. The acid anhydride used in the present invention is not particularly limited, but an anhydride of a fatty acid having 1 to 4 carbon atoms is preferable in practical use. This reaction may use only an acid anhydride, but does not prevent addition of other solvent. The reaction temperature is 20 to 200 ° C. Reaction time is 30 minutes to 2
4 hours. The progress of the reaction can be followed by thin layer chromatography or high resolution liquid chromatography. After completion of the reaction, the desired dihydronucleoside [III '] can be obtained by a conventional method such as an extraction method or a recrystallization method, and if necessary, further deprotection is performed to obtain 2', 3'-dideoxy-
2 ', 3'-dideoxynucleoside [IV] 2 ', 3'-dideoxynucleoside [V] Can be converted to.

Examples Hereinafter, the present invention will be specifically described with reference to Examples and Reference Examples.

Example 2 Preparation of 2 ', 3'-dideoxy-2', 3'-didehydrouridine 2 ', 3'-o-methoxymethylidene uridine (5.00 g, 17.5 mmol) was added to 50 ml of acetic anhydride with stirring at room temperature. It was The solution was heated to 140 ° C. and kept at this temperature for 5 hours under solvent reflux. After cooling to room temperature, the solvent was distilled off under reduced pressure, 50 ml of water was added, and the mixture was extracted 3 times with 100 ml of chloroform. The extract solution was concentrated under reduced pressure, 30% aqueous ammonia was added, and the mixture was stirred at room temperature for 1 hr. The solvent was distilled off again under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 3.02 g (14.4 mmol) of the title target substance (yield 82.3%).

C ₉ H ₁₀ N ₂ O ₄ [m / e (M ^{+) 210]; 1 H-NMR (DMSO-} d 6) δ3.
59 (2H, d, J = 3.30Hz), 4.79 (1H, d, J = 3.30Hz), 4.98
(1H, br, s), 5.59 (1H, d, J = 8.06Hz), 5.92 (1H, d, J =
5.86Hz), 6.40 (1H, d, J = 5.86Hz), 6.82 (1H, br, s), 7.
75 (1H, d, J = 8.06Hz) and 11.30 (1H, br.s) Reference Example 2 ', 3'-o-Methoxymethylidene uridine production In tetrahydrofuran 1, uridine 50g (0.205 while stirring at room temperature) mol), methyl orthoformate 112 ml (1.03mo
l), and 10 g (52.6 mmol) of paratoluenesulfonic acid were added. After stirring at room temperature for 24 hours, the mixture was poured into an aqueous sodium hydrogen carbonate solution and extracted 5 times with chloroform. The extract was dried over sodium sulfate and concentrated to give 2 ',
3'-o-methoxymethylidene uridine 49.5g (0.173mo
l) was obtained (yield 84.5%) Effect of the invention As is apparent from the above, according to the present invention, didehydronucleosides can be produced simply and at low cost,
Therefore, the present invention is extremely useful in the pharmaceutical industry.

Claims (1)

[Claims] 1. A compound having the following skeleton in the molecule. The formula: After being converted into a compound having a skeleton represented by the formula, the compound is reacted with an acid anhydride. A method for producing a didehydronucleoside having a skeleton shown in the molecule. However, in the above formula, R ¹ represents an alkyl group having 1 to 12 carbon atoms.