JPH02237986A - Production of essential intermediate for synthesis of oxetanocin - Google Patents

Abstract

PURPOSE:To obtain the subject intermediate for synthesis of oxetanocin having antivirous, antineoplastic and antibacterial activities by coupling an alkylthiooxetane derivative, etc., with a nucleic acid base using an activator. CONSTITUTION:In the presence of an activator such as N-bromosuccinimide, a 2-alkylthiooxetane or 2-arylthiooxetane derivative is coupled with a nucleic acid base such as N<6>,9-bistrimethylsilyl-N<6>-benzoyladenine to synthesize the objective 2-(9-adenyl)oxetane derivative, etc., as an essential intermediate for synthesis of oxetanocin.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to a method for producing oxetanosine monomer. Specifically, in the presence of an activator such as N-bromosuccinimide (hereinafter abbreviated as NBS), 2-alkylthio or 2
This is a method for synthesizing 2-(9-adenyl)oxetane derivatives, which are important intermediates of oxetanosine, by coupling -7-lylthiooxedan derivatives with nucleobases such as adenine. Oxetanosine is a nucleoside antibiotic with antiviral, antitumor, and antibacterial activity, and more recently
It has also been found to have the ability to suppress the proliferation of HIV, which causes cancer, and is a substance that is attracting attention in the pharmaceutical field [J. ^nNbiot. +1987, Volume 40, 0-shi to 1077]. Three methods have been reported to date for the synthesis of oxetanosine.
Both methods involve a large number of reaction steps and also include reaction steps with low yields, and cannot be said to be industrially advantageous [Tetrahedron Lett. , 198
7, vol. 28, 3967. 4713 to 0-no",
Ibid., 1988. Volume 29, 4739.
0-shi to 4743, j. Am. Chew
．． Soc. , 1988, Volume 1lθ,
? Go to 217.

As a result of intensive research from the above point of view, the inventor has determined that 2.3
-0-alkylidene-aldehyde aldose and 1-7
By reacting 2-7-rukylthio or 2-7-lylthiooxetane, which can be easily synthesized from rukenyl sulfide, with a nucleobase such as adenine in the presence of an activating agent such as NBS, it can be used as a nuclease during the synthesis of oxetanosine. -(9-Adenyl)oxetane derivatives etc. can be synthesized with good yield, and the present invention has been achieved. That is, the gist of the present invention is a method for producing an important intermediate of oxetanosine, which is characterized by coupling a 2-alkylthio or 2-arylthiooxetane with a nucleobase using an activator. The present invention will be explained in detail below. The 2-alkylthio and 2-arylteoxetanes used in the process of this invention can easily be prepared by known methods from 2.3-0-alkylidene-7-rudehyde aldoses and 1-alkyl or aryl alkenyl sulfides. Number Showa 63-4
47011. The alkylthio group at the 2-position may be any well-known alkyl group such as methylthio, ethylthio, probilteo, isoprobilthio, etc., and is not particularly limited.
The same applies to arylthio groups, including phenylthio, tolylthio, and biridylthio groups. As the nucleobase, well-known adenine, guanine, uracil, temin, cytosine, and derivatives thereof with protected hydroxyl or amino groups can be used. There are no particular restrictions on the protecting group, but trialkylsilyl groups are useful. Examples of the activator include those commonly used in glycosylation of thioglycosides.

Namely, NBS, nitrosonium tetrafluroporate (NOBFa), mercury salts such as methyl trifluoromethanesulfonate, mercury acetate, and mercury nitrate, silver salts such as silver trifluoromethanesulfonate,
There are also bromine, iodine, etc., but NBS is the most effective. Solvents used for the reaction are ether, benzene, toluene,
Well-known aprotic organic solvents such as dichloromethane, chloroform, acetonitrile, and dimethyl sulfoxide are suitable, and there are no particular limitations. The reaction temperature and reaction time vary depending on the activator, solvent, etc. used, and are not particularly limited, but 0-100°C for 10 minutes to 50 hours is appropriate. There is no particular restriction on the amount of the activator used, but it is usually added in an amount of 1.0 to 2.0 equivalents to oxetane.

It is better to use an excess of nucleobase relative to oxetane,
It is usually 2.0 to 6.0 equivalents. As described above, the method of the present invention allows the important intermediate of oxetanosine to be obtained easily and in good yield, and has great industrial value. The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited in any way by the following 51 Examples unless the gist of the invention is exceeded. Example 1 MPIIQ-MeOC6H4-N6benzoyladenine 675 #g (3 m
m o + ) under an argon atmosphere with dry benzene 3
Suspend in 0 ml and add 1.90 ml of chlorotrimethylsilane.
l (15mmo+) and triethylamine 2.10*
Add I (15 mmol) and heat under reflux for 2 hours. After cooling, it was filtered through celite under reduced pressure, the solvent of the liquid was distilled off, and the solution was further boiled at 100°C under reduced pressure (1 sellg).
Dry in intervals. The obtained bistrimethylsilyl derivative of adenine 2 was dissolved in 51 dichloromethane, and this was dissolved in 2
-Phenylthioxetane derivative 1 507. (0.
98 mmo+) into a dichloromethane solution (10-1>).Add Molexler Sieves 4A.0 to this m solution.
Add 50g and stir for 15 minutes. Add NBS to this solution.
Add 210+g (1.18 mmo+), stir at room temperature for 30 minutes, filter, and wash the filtrate with an aqueous sodium thiosulfate solution. After drying with magnesium sulfate, it was concentrated and isolated and purified by silica gel column chromatography to obtain 2-(9-adenyl)oxetane derivative 3 at 359
■ Obtain (58 mol%). 'HNMR (CDC I3): δ
1.4+ (s, 3H), 1.51 (s,
3N), 2.03 2.09 (sx2,
3H), 2.78-3.08 (+w, II
I), 3.77 and 3.79 (sx
2, 38), 3.9-4.3 (m, 4
H), 4.3-4.76 (m, 4tl),
5.51 and 5.56 (sx2, I
H). ．． 6.76-7.04 (m, 3N)
, ? ．． 2res 7.65 (m, 5N), 8.00
-8.50 (s+, 3N9, 8.94 and
9.28 (sx2, IH). Example 2-7 Enylthioxetane derivative 4 206 (0.4
1 mmol) and adenine derivative 2 (2 mmof), Molecular Sieves 4A 0.20 g, N B S 8
0 mg (0.45 mmol)
By the same reaction procedure as in Example 1, 149 μ (57 mol%) of 2-(9-adenyl)oxetane derivative 6 was obtained.
obtain. 'NMR (CDCa): δ 1.43
(S, 9N>. 1.46 (s, 3}1
), 2.80-3.08 (w, 1N),
3.82-4.99 (m, 8H). 6.94
(d. J: 1.4 Hz, IH),
7.07-7.75 (-,OH), 7.95-
8.41 (s, 5H), 9.23 (s
, IN). Example 3 2-phenylthioxetane derivative 8110. (0.2
0 mmol) and adenine derivative 2 (0.4 mmol),
Molecular sieves 4A 0.15g, NBS 40
mg (0.23 mmol), 49 w < (38 mol %) of 2-(9-adenyl)oxetane derivative 7 was obtained by the same reaction procedure as in Example 1.

Claims (1)

[Scope of Claims] A method for producing a key intermediate of oxetanosine, which comprises coupling a 1,2-alkylthio or 2-arylthiooxetane derivative with a nucleobase using an activator. 2. The manufacturing method according to claim 1, characterized in that N-bromosuccinimide is used as the activator. 3. The manufacturing method according to claim 1, characterized in that N^6,9-bistrimethylsilyl-N^6-benzoyladenine is used as the nucleobase.