JPH0826060B2 - Process for producing 1- (2-deoxy-β-D-threo-pentofuranosyl) thymine derivative - Google Patents

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to 3'-azido-3'-deoxythymidine (also known as zidobusine) used as a therapeutic agent for AIDS and other 3's having a similar pharmacological action.
The present invention relates to a method for producing 1- (2-deoxy-β-D-threo-pentofuranosyl) thymine, which is an important synthetic intermediate of -substituted-3'-deoxythymidines.

[0002]

2. Description of the Related Art Various methods have been developed for the production of 3'-substituted-3'-deoxythymidines represented by 3'-azido-3'-deoxythymidine. Can be classified. The first method uses thymidine as a raw material for production, converts the hydroxyl group at the 3′-position into 1- (2-deoxy-β-D-threo-pentofuranosyl) thymine, and converts the hydroxyl group into methanesulfonyl ester or the like. By a method of introducing an azido group after using as a leaving group [J. P. Horwiz et al. Org. Chem. ，
29, 2076, 1964], the second method is to construct a sugar in which azide has been introduced in advance, and couple the sugar moiety with thymine to give 3'-azido-3'-deoxythymidine. [C. K. Chu et al., Tetrahedron Le
tt, 29, 5349, 1988].

[0003]

However, in the above-mentioned first method, naturally-occurring expensive thymidine is used as a raw material, and in the second method, both α and β anomers are generally about 1: 1. Since it is produced as a mixture in a ratio, it is difficult to separate the both, and there are drawbacks such that only the β-anomer can be used, which is not necessarily an industrially advantageous method.

The present invention is useful for 3'-substituted-3'-deoxythymidines such as 3'-azido-3'-deoxythymidine by β-selective coupling reaction without depending on naturally-occurring nucleosides as raw materials. Another object of the present invention is to provide a method for producing a synthetic intermediate.

[0005]

Means for Solving the Problems The inventors of the present invention have conducted extensive research to develop a β-selective coupling reaction using an inexpensive sugar-derived raw material, and as a result, Represents a hydroxyl-protecting group) and is coupled with a thymine derivative using the phenyl 2-deoxy-1-thio-D-threo-pentofuranoside derivative represented by the general formula [1] as a starting material. At this time, it was found that β-N-glycoside can be selectively obtained by limiting the protecting group R represented by the general formula [1], and the present invention has been completed.

Embedded image

That is, in the present invention, the hydroxyl-protected phenyl 2-deoxy-1-thio-D-threo-pentofuranoside represented by the general formula [1] and bis (trimethylsilyl) thymine [2] are combined with N. A general formula [3] characterized by limiting the protecting group R when coupling bromosuccinimide (NBS) as an activator.
And a method for producing a 1- (2-deoxy-β-D-threo-pentofuranosyl) thymine derivative represented by

The present invention will be described in detail below. The 1-thioglycoside derivative, which is a raw material compound in the method of the present invention, is represented by the general formula [1], and specific examples of R are selected from those used as usual hydroxyl-protecting groups. In addition, there are an acyl group such as benzoyl, an arylalkyl group such as benzyl, a silyl group such as t-butyldimethylsilyl, and the like, and an alkylidene group such as benzylidene and isopropylidene is preferable.

As the thymine derivative, bis (trialkylsilyl) thymine is preferable and, for example, bis (trimethylsilyl) thymine is used. The usage is
2-3 mol is used with respect to 1 mol in the compound of the general formula [1].

As the activator in the coupling reaction, a halonium ion is preferable, and for example, a reagent which generates a bromonium ion such as N-bromosuccinimide is used. The amount of activator used is 1 to 2 mol, preferably 1.1 to 1.3 mol, per 1 mol of the compound of the general formula [1].

The reaction is carried out by adding molecular sieves 4A in an aprotic organic solvent (for example, dichloromethane, dichloroethane, etc.) under an atmosphere of an inert gas such as nitrogen or argon, at a reaction temperature of -80 to
It is + 50 ° C., preferably around room temperature.

[0011]

EXAMPLES The present invention will be described below with reference to examples.
The NMR spectrum was measured using FA-90A or EX-400 manufactured by JEOL Ltd.

[0012] Phenyl 2-deoxy, a raw material compound
Synthesis of -1-thio-D-threo-pentofuranoside

[0013] 2,3: 4,5-di-O-isopropylidene
23-37 g (0.
101 mol) and phenyl vinyl sulfide 16.58
g (0.122 mol) was added to anhydrous diamine under an argon atmosphere.
Dissolve in chloromethane (500 mL) and cool to -78 ° C
I do. Boron trifluoride-diethyl ether complex 15.7
7 g (0.111 mol) anhydrous dichloromethane solution
(50 mL) is added dropwise over 40 minutes. 1 at -78 ° C
After stirring for an hour, add triethylamine (15 mL) little by little.
Then, the temperature is raised to room temperature. Saturated sodium hydrogen carbonate water
After adding the solution, separate the organic layer and dilute the aqueous layer with dichlorometa.
Extract twice. After drying the organic layer with magnesium sulfate
Concentrate and concentrate on silica gel column chromatography (hexa
Phenyl: ethyl acetate = 9: 1)
-Deoxy-3,5: 6.7-di- O-isopropylide
1-thio-L-gluco-heptofuranoside was added to 28.
16 g was obtained (yield 76%). Subsequently, this compound 5.
16 g (14.5 mmol) of ethanol (50 mL)
Dissolve in and add 20% trifluoroacetic acid (50 mL).
, And stir at room temperature for 4 hours. Add sodium bicarbonate
After neutralization, under ice-cooling 7.75 g of sodium periodate
(36 mmol) aqueous solution was added dropwise, and at 0 ° C. for 30 minutes
Stir. 2.70 g (72 m) of sodium borohydride
mol) is added little by little and the reaction mixture is warmed to room temperature.
It After 1 hour, ethanol was removed under reduced pressure and the residue was converted to acetic acid.
Extract 5 times with ethyl. Dry the organic layer with sodium sulfate
After concentration, column chromatography (hexane: acetic acid
2.30 g (yield) of the title compound with ethyl = 1: 1.
70%). White solid; melting point 72.5-73.0 ° C
(Hexane.ethyl acetate).

[0014] ¹ HNMR (CDCl _Three ) Δ = 2.23
(Dd, 1H, J = 6.3, 14.2), 2.2-2.
3 (br, 1H), 2.47 (ddd, 1H, J = 2
6.8, 14.2), 3.21-3.27 (m, 1
H), 3.99-4.11 (m, 2H), 4.12-
4.17 (m, 1H), 4.54-4.60 (m, 1
H), 5.84 (dd, 1H, J = 6.4, 6.8),
7.23-7.36 (m, 3H), 7.50-7.55
(M, 2H).

[0015] Phenyl 2-obtained in this way
Of deoxy-1-thio-D-threo-pentofuranoside
Introduce a protecting group into the hydroxyl group by the conventional method and use it in the following reaction
Was.

[0016]

Example 1 Preparation of 1- (2-deoxy-3,5-O-isopropylidene-β-D-threo-pentofuranosyl) thymine

To 252 mg (2.0 mmol) of thymine, 1.2 ml of 1,1,1,3,3,3-hexamethyldisilazane and 0.1 ml of N, N-dimethylformamide were added to an atmosphere of argon and heated under reflux for 16 hours. To do. The solution is allowed to come to room temperature and excess reagent is removed under reduced pressure. This residue and phenyl 2-deoxy-2,3-O-isopropylidene-
1-thio-α-D-threo-pentofuranoside 266m
g (1.0 mmol) is dissolved in dry dichloromethane (10 ml) under an argon atmosphere, molecular sieves 4A is added, and the mixture is stirred for 10 minutes. Into this mixture, N
-Bromosuccinimide 196 mg (1.1 mmol)
Is added under argon and further stirred at room temperature for 20 minutes. Aqueous sodium thiosulfate solution is added, extraction is performed with dichloromethane, and the extract is washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated, and silica gel thin layer chromatography (developing solvent;
Hexane: ethyl acetate = 1: 3) to give the title compound 2
38 mg (yield 85%) was obtained. The structure was confirmed by ¹ H NMR. The spectrum data obtained is shown below.

[0018] _{^{1 HNMR (CDCl 3): δ}} = 1.39
(S, 3H), 1.49 (s, 3H), 1.96 (s,
3H), 2.18 (d, J = 15Hz, 1H) 2.55
-2.62 (m, 1H), 3.82 (s, 1H) 4.1
9 (s, 2H) 4.45-4.47 (m, 1H) 5.3
0 (s, 2H) 6.16 (d, J = 6.4Hz, 1H)
8.01 (s, 1H) 8.4-8.5 (br, 1H).

[0019]

Example 2 Preparation of 1- (2-deoxy-3,5-O-benzylidene-β-D-threo-pentofuranosyl) thymine

[0020] of Example 1 phenyl 2-deoxy -
Phenyl 2-deoxy-2,3-O-benzylidene-1-thio-α-D-instead of 2,3-O-isopropylidene-1-thio-α-D-threopentofuranoside
The title compound could be obtained by the same reaction using threo-pentofuranoside. Yield 88
%. ^The structure was confirmed by ¹ H NMR. The data is shown below.

[0021] _{^{1 HNMR (CDCl 3): δ}} = 1.62
(D, J = 1 Hz, 3 H), 2.32 (dd, J = 1,
15Hz, 1H), 2.66 (ddd, J = 5, 8, 1)
5Hz, 1H), 3.85-4.01 (m, 1H),
4.26 (dd, J = 2, 13.5 Hz, 1H), 4.
45-4.73 (m, 2H), 5.65 (s, 1H),
6.28 (dd, J = 2,8 Hz, 1H), 7.22-
7.56 (m, 5H), 7.98 (d, J = 1 Hz, 1
H), 9.00-9.23 (br, 1H).

[0022]

Example 3 Preparation of 1- (2-deoxy-3,5-di-O-benzyl-β-D-threo-pentofuranosyl) thymine

[0023] of Example 1 phenyl 2-deoxy -
Instead of 2,3-O-isopropylidene-1-thio-α-D-threo-pentofuranoside, phenyl 2-deoxy-2,3-di-O-benzyl-1-thio-α-D-
By using threo-pentofuranoside and carrying out a similar reaction, the title compound could be obtained at α: β = 1: 4. Yield 92%. ^The structure was confirmed by ¹ H NMR.
The data is shown below.

[0024] _{^{1 HNMR (CDCl 3): δ}} = 1.6
8, 1.91 (d, J = 1 Hz, 3H), 1.90-
2.85 (m, 2H), 3.70-3.95 (m, 2
H) 3.05-3.35 (m, 2H) 4.47 (s, 2
H), 5.10 (s, 2H), 6.10-6.38.
(M, 1H), 7.08-7.45 (m, 10H),
7.56 (d, J = 1 Hz, 1H) 8.05-8.42
(Br, 1H).

[0025]

Example 4 1- (2-deoxy-3,5-di-O-t
-Butyldimethylsilyl-β-D-threo-pentofuranosyl) thymine

[0026] of Example 1 phenyl 2-deoxy -
Phenyl 2-deoxy-2,3-di-Ot-butyldimethylsilyl-1 instead of 2,3-O-isopropylidene-1-thio-α-D-threo-pentofuranoside
-Thio-α-D-threo-pentofuranoside,
By carrying out the same reaction, the title compound is converted into α: β = 1:
It was possible to obtain it in 5. Yield 92%. ^The structure was confirmed by ¹ H NMR. The data is shown below.

[0027] _{^{1 HNMR (CDCl 3): δ}} = 0.10
(S, 12H), 0.88 (s, 9H), 0.92
(S, 9H), 1.90 (d, J = 1 Hz, 3H),
2.00-2.85 (m, 2H), 3.75-3.95
(M, 3H), 4.25-4.42 (m, 1H), 6.
08-6.25 (m, 1H), 7.16, 7.57
(D, J = 1 Hz, 1 H), 8.77-8.90 (b
r, 1H).

[0028]

Example 5 Preparation of 1- (2-deoxy-3,5-di-O-benzoyl-β-D-threo-pentofuranosyl) thymine

[0029] of Example 1 phenyl 2-deoxy -
Phenyl 2-deoxy-2,3-di-O-benzoyl-D-threo-pentofuranoside was used in place of 2,3-O-isopropylidene-1-thio-α-D-threo-pentofuranoside. , The title compound could be obtained with α: β = 1: 2. Yield 8
6%. ^The structure was confirmed by ¹ H NMR. The data is shown below.

[0030] _{^{1 HNMR (CDCl 3): δ}} = 1.8
3, 1.96 (s, 3H), 2.14-3.14 (m,
2H), 4.42-5.04 (m, 3H), 5.70-
6.00 (m, 1H), 6.19-6.44 (m, 1
H), 7.10-7.75 (m, 7H), 7.85-8
15 (m, 4H), 9.20-0.40 (br, 1
H).

[0031]

INDUSTRIAL APPLICABILITY According to the present invention, 3'-azido-3'-deoxythymidine or other 3'-is formed by a β-selective coupling reaction without depending on a naturally-occurring nucleoside as a raw material.
It has become possible to provide a method for producing a 1- (2-deoxy-β-D-threo-pentofuranosyl) thymine derivative, which is a useful synthetic intermediate for -substituted-3'-deoxythymidines.

Claims (1)

[Claims] 1. A hydroxyl-protected phenyl 2-deoxy-1-thio-D-threo-pentofuranoside represented by Chemical formula 1 and bis (trimethylsilyl) thymine are used as an activator of N-bromosuccinimide. 1- (2-deoxy-
Method for producing β-D-threo-pentofuranosyl) thymine derivative. (Wherein R is a benzoyl group, a benzyl group,
A t-butyldimethylsilyl group, an isopropylidene group, or a benzylidene group is shown. (Wherein R is a benzoyl group, a benzyl group,
A t-butyldimethylsilyl group, an isopropylidene group, or a benzylidene group is shown. )