JPH06263791A - Production of alpha-ribazole - Google Patents

Abstract

PURPOSE:To efficiently obtain the subject compound, a structural component of vitamin B12, useful for treating pernicious anemia by coupling a specific thioglycoside derivative and a 5,6-dimethylbenzomidazole derivative in the presence of an activating agent. CONSTITUTION:A thioglycoside derivative expressed by the formula I (R is ethyl or phenyl; P<1> is benzyl, tbutyldimethysilyl or triphenylmethyl; P<2> is benzyl or isopropylidene), (e.g. thiofuranoside derivative, etc.) and a 5,6- dimethybenzoimidazole derivative (e.g. 5,6-dimethyl-1- trimethylsilyllbenzoimidazole, etc.) are subjected to coupling in the presence of an activating agent (e.g. N-bromosuccinimide, etc.) at room temperature for 18 hours under agitation. Then, a solution of sodium thiosulfate is added to the reaction mixture, which is extracted with dichloromethane to obtain the objective alpha-ribazole expressed by formula II (Me is methyl) as a structural component of vitamin B12 useful for treating pernicious anemia.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to α- which is a constituent of vitamin B12, which is effective in the treatment of pernicious anemia, which is involved in the biosynthesis of nucleic acids and proteins in vivo and plays an important role in blood production. The present invention relates to a method for producing ribazole.

[0002]

2. Description of the Related Art The following three methods are known as typical methods for producing α-rivazole. The first method is 1-β-D- in which the hydroxyl group is protected with a benzyl group.
Method for coupling ribofuranosyl chloride with 5,6-dimethylbenzimidazole [JD Stevens et al., J.
Org. Chem., 33, 1806, 1968], the second method is 1
A method for synthesizing an active isourea derivative from a ribofuranose derivative having a free hydroxyl group at the position and coupling it with 5,6-dimethylbenzimidazole [H.Tsut
Sumi et al., Nippon Kagaku Kaishi, 1682 page, 1982], the third method is the synthesis of an active glycosyloxypyridinium intermediate from a ribofuranose derivative having a free hydroxyl group at the 1-position, which is 5,6-dimethyl- Method for coupling with 1-trimethylsilylbenzimidazole [T.
Mukaiyama et al., Chem. Lett., 557 pages, 1984].

[0003]

However, according to the first method, it is difficult to selectively synthesize 1-β-D-ribofuranosyl chloride used as a sugar donor and its handling is difficult. In addition, the second and third methods have problems such as low α-anomer selectivity in the coupling reaction, and are not necessarily industrially advantageous methods.

[0004]

[Means for Solving the Problems] The inventors of the present invention prepared a thiofuranoside derivative, which is inexpensive and easy to handle, as a raw material.
As a result of various studies aimed at developing a highly selective synthetic method of ribazole, the following chemical formula 3 (in the chemical formula 3, R represents an alkyl group, an aryl group, P ¹ and P ² represent a protecting group): By using the thiofuranoside derivative represented by the general formula [1] in the reaction step as a starting material and coupling it in the presence of a 5,6-dimethylbenzimidazole derivative and N-bromosuccinimide (NBS), the general formula [2] It was found that an α-rivazole derivative represented by
The protecting group of the α-rivazole derivative represented by the general formula [2] can be easily deprotected by a conventional method and can be converted to the α-rivazole represented by the general formula [3].

[Chemical 3]

That is, the present invention is represented by the general formula [3] which is characterized in that the thiofuranoside derivative represented by the general formula [1] and the 5,6-dimethylbenzimidazole derivative are coupled in the presence of NBS. The present invention relates to a method for producing α-rivazole.

The present invention will be described in detail below. The thiofuranoside derivative which is a raw material compound in the method of the present invention is represented by the general formula [1], wherein R is an alkyl group such as a methyl group, an ethyl group or an n-propyl group, a phenyl group or p-methoxy group. There is no particular limitation such as an aryl group such as a phenyl group or a p-chlorophenyl group. P ¹ and P ² may be ordinary protective groups for hydroxyl groups, and examples thereof include silyl groups such as tert-butyldimethylsilyl group, arylalkyl groups such as benzyl group and triphenylmethyl group, ketals and benzylidene groups such as isopropylidene group. Examples thereof include acetals such as groups.

The protecting group for the 5,6-dimethylbenzimidazole derivative is not particularly limited, but trialkylsilyl group and the like are useful. The amount used is 2-10 equivalents, preferably 6 equivalents, relative to the compound of the general formula [1].

As the activator in the coupling reaction, N-bromoimides are preferable, and for example, a reagent that generates a bromonium ion such as N-bromosuccinimide is used. The amount of the activator used is 1 to 2 equivalents, preferably 1.1 equivalents, relative to the compound of the general formula [1].

The reaction is carried out in an aprotic organic solvent (for example, ether, benzene, toluene, dichloromethane, chloroform, acetonitrile, etc.) under an atmosphere of an inert gas such as nitrogen or argon by adding Molecular Sieves 4A, The reaction temperature is -78 to + 50 ° C,
It is preferably around room temperature.

[0010]

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

[0011]

Example 1 5,6-Dimethyl-1- (2,3,5-tri-O-benzyl-α-D-ribofuranosyl) benzimidazole [5]

[Chemical 4]

5,6-dimethylbenzimidazole 17
5.4 mg (1.20 mmol) under argon atmosphere,
1,1,1,3,3,3-hexamethyldisilazane 0.
72 ml and N, N-dimethylformamide (hereinafter DMF
Abbreviated) and add 0.06 ml and heat at 140 ° C for 4 hours. Excessive 1,1,1,3 under reduced pressure while heating
Remove 3,3-hexamethyldisilazane and DMF and dry. The obtained 5,6-dimethyl-1-trimethylsilylbenzimidazole was dissolved in 3.0 ml of dichloromethane, and this was dissolved in thiofuranoside derivative [4] 152.2.
Add into mg (0.30 mmol). After adding molecular sieves 4A to this solution and stirring for 15 minutes,
Add 106.8 mg (0.60 mmol) of NBS and stir at room temperature for 18 hours. 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, concentrated, and isolated and purified by silica gel column chromatography to obtain 5,6-dimethyl-1.
111.9 mg of-(2,3,5-tri-O-benzyl-α-D-ribofuranosyl) benzimidazole [5]
(67 mol%, α: β = 4: 1). The structure was confirmed by ¹ H NMR. The spectrum data obtained is shown below.

¹ HNMR (CDCl ₃ ): δ = 2.36 (s, 3
H), 2.37 (s, 3H), 3.53 (dd, J = 2.93, 10.75Hz, 1H), 3.6
3 (dd, J = 2.93, 10.74Hz, 0.79H), 3.71-3.77 (m, 0.21
H), 4.13-4.39 (m, 5H), 4.42-4.74 (m, 4H), 6.04 (d, J =
6.35Hz, 0.21H), 6.13 (d, J = 5.37Hz, 0.79H), 7.02-7.4
0 (m, 16H), 7.54 (s, 0.21H), 7.56 (s, 0.79H), 7.97 (s,
0.21H), 8.51 (s, 0.79H).

[0014]

Example 2 5,6-Dimethyl-1- (2,3,5-tri-O-benzyl-α-D-ribofuranosyl) benzimidazole [5]

[Chemical 5]

5,6-dimethylbenzimidazole 28
0.7 mg (1.92 mmol) under argon atmosphere,
1,1,1,3,3,3-hexamethyldisilazane 1.
Add 15 ml and DMF 0.10 ml for 4 hours at 140 ° C
Heat with. Excessive 1,1, under reduced pressure while heating
1,3,3,3-hexamethyldisilazane and DMF are removed and dried. The obtained 5,6-dimethyl-1-trimethylsilylbenzimidazole was dissolved in 3.2 ml of chloroform, and this was dissolved in thiofuranoside derivative [6] 14.
Add into 9.4 mg (0.321 mmol). After adding molecular sieves 4A to this solution and stirring for 15 minutes, 62.7 mg (0.352 mmol) of NBS was added and the mixture was stirred at room temperature for 2 hours. Aqueous sodium thiosulfate solution is added, extraction is performed with chloroform, and the extract is washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, concentrated, and isolated and purified by silica gel column chromatography to give 5,6-dimethyl-1- (2,3,5-tri-O-benzyl-α-D-ribofuranosyl) benzo. Imidazole [5] 147.9
mg (84 mol%, α: β = 54: 1) is obtained. ¹ HNM
The structure was confirmed by R. The spectrum data obtained is shown below.

¹ HNMR (CDCl ₃ ): δ = 2.36 (s, 3
H), 2.37 (s, 3H), 3.52 (dd, J = 2.93, 10.74Hz, 1H), 3.6
2 (dd, J = 2.93, 10.75Hz, 1H), 4.20-4.39 (m, 6H), 4.44
-4.61 (s × 5, 2H), 4.66-4.73 (s × 2, 1H), 6.13 (d, J = 5.
37Hz, 1H), 7.02-7.08 (m, 2H), 7.14-7.38 (m, 14H), 7.
56 (s, 1H), 8.51 (s, 1H).

[0017]

Example 3 5,6-Dimethyl-1- (5-O-tert-butyldimethylsilyl-2,3-O-isopropylidene-α-D
-Ribofuranosyl) benzimidazole [8]

[Chemical 6]

5,6-dimethylbenzimidazole 50
3.1 mg (3.44 mmol) under an argon atmosphere,
1,1,1,3,3,3-hexamethyldisilazane 2.
Add 1 ml and 0.17 ml of DMF and heat at 140 ° C for 4 hours. Excessive 1,1,1,
The 3,3,3-hexamethyldisilazane and DMF are removed and dried. The obtained 5,6-dimethyl-1-trimethylsilylbenzimidazole was dissolved in 5.8 ml of chloroform, and this was dissolved in thiofuranoside derivative [7] 200.
Add into 4 mg (0.575 mmol). After adding molecular sieves 4A to this solution and stirring it for 15 minutes, 112.8 mg (0.634 mmol) of NBS was added, and the mixture was stirred at room temperature for 1 hour. Aqueous sodium thiosulfate solution is added, extraction is performed with chloroform, and the extract is washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, concentrated, and isolated and purified by silica gel column chromatography to obtain 5,6-dimethyl-
1- (5-O-tert-butyldimethylsilyl-2,
3-O-isopropylidene-α-D-ribofuranosyl)
202.3 mg (81 mol%, α: β = 23: 1) of benzimidazole [8] is obtained. The structure was confirmed by ¹ H NMR. The spectrum data obtained is shown below.

¹ HNMR (CDCl ₃ ): δ = 0.13 (s, 3
H), 0.15 (s, 3H), 0.99 (s, 9H), 1.27 (s, 3H), 1.44 (s,
3H), 2.35 (s, 6H), 3.81 (dd, J = 1.95, 10.74Hz, 1H),
3.94 (dd, J = 1.96, 10.75Hz, 1H), 4.39 (s, 1H), 4.81-
4.88 (m, 1H), 4.93-4.96 (s × 2, 1H), 6.39 (d, J = 3.90Hz,
1H), 7.07 (s, 1H), 7.54 (s, 1H), 8.14 (s, 1H).

[0020]

Example 4 5,6-Dimethyl-1- (2,3-O-isopropylidene-5-O-triphenylmethyl-α-D-ribofuranosyl) benzimidazole [10]

[Chemical 7]

5,6-Dimethylbenzimidazole 27
To an amount of 6.2 mg (1.89 mmol) under an argon atmosphere,
1,1,1,3,3,3-hexamethyldisilazane 1.
Add 14 ml and DMF 0.09 ml for 4 hours at 140 ° C
Heat with. Excessive 1,1, under reduced pressure while heating
1,3,3,3-hexamethyldisilazane and DMF are removed and dried. The obtained 5,6-dimethyl-1-trimethylsilylbenzimidazole was dissolved in 3.1 ml of dichloromethane, and this was dissolved in a thiofuranoside derivative [9] 1.
Add into 49.0 mg (0.313 mmol). After adding molecular sieves 4A to this solution and stirring for 15 minutes, NBS 61.1 mg (0.343 mmol)
And stir at room temperature for 3.5 hours. 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, concentrated, and isolated and purified by silica gel column chromatography to give 5,6-
Dimethyl-1- (2,3-O-isopropylidene-5-
148.1 mg (84 mol%, α: β = 4: 1) of O-triphenylmethyl-α-D-ribofuranosyl) benzimidazole [10] is obtained. The structure was confirmed by ¹ H NMR. The spectrum data obtained is shown below.

¹ HNMR (CDCl ₃ ): δ = 1.28 (s, 2.4
3H), 1.36 (s, 0.57H), 1.46 (s, 2.43H), 1.63 (s, 0.57
H), 2.24 (s, 0.57H), 2.32 (s, 2.43H), 2.36 (s, 3H),
3.29 (dd, J = 1.95, 10.74Hz, 0.81H), 3.33-3.46 (m, 0.3
8H), 3.65 (dd, J = 1.96, 10.75Hz, 0.81H), 4.42 (s, 1
H), 4.77-4.81 (s × 2, 0.81H), 4.95-5.07 (m, 1H), 5.95
(d, J = 3.42Hz, 0.19H), 6.66 (d, J = 3.42Hz, 0.81H), 7.
04 (s, 0.81H), 7.13-7.54 (m, 15.38H), 7.57 (s, 0.81
H), 7.92 (s, 0.19H), 8.19 (s, 0.81H).

[0023]

Example 5 α-rivazole [3]

[Chemical 8]

780 mg (1.41 mmol) of 5,6-dimethyl-1- (2,3,5-tri-O-benzyl-α-D-ribofuranosyl) benzimidazole [5] was dissolved in 5 ml of ether to obtain -78. Cool to ° C. To this, 42 ml of ammonia was added and stirred, and sodium 120.
7 mg (5.25 mmol) are added in small portions. After 20 minutes, ammonium chloride is added and the temperature is returned to room temperature to remove ammonia. Ethanol and water were added carefully, the solvent was removed, and the residue was purified by silica gel column chromatography to obtain α-rivazole [3] 283.2 mg.
(72 mol%) is obtained. The structure was confirmed by ¹ H NMR. The spectrum data obtained is shown below.

¹ HNMR ((CD ₃ ) ₂ CO): δ = 2.30
(s, 3H), 2.33 (s, 3H), 3.69 (dd, J = 3.66, 11.96Hz, 1
H), 3.82 (dd, J = 3.18, 11.97Hz, 1H), 4.24-4.29 (m, 1
H), 4.47 (t, J = 5.38Hz, 1H), 4.56 (t, J = 4.89Hz, 1H),
6.28 (d, J = 4.39Hz, 1H), 7.31 (s, 1H), 7.34 (s, 1H), 8.
23 (s, 1H). ¹³ CNMR ((CD ₃ ) ₂ CO): δ = 20.2
(q), 20.5 (q), 62.7 (t), 72.0 (d), 72.8 (d), 85.6 (d),
86.8 (d), 111.4 (d), 120.4 (d), 130.9 (s), 131.9 (s), 1
43.0 (s), 143.5 (s).

[0026]

Example 6 α-rivazole [3]

[Chemical 9]

5,6-Dimethyl-1- (2,3,5-tri-O-benzyl-α-D-ribofuranosyl) benzimidazole [5] 942.3 mg (1.72 mmol)
Was dissolved in 14 ml of methanol, 10% palladium-activated carbon 949 mg, and palladium (II) chloride 945
mg (5.33 mmol) is added. The reaction system is replaced with hydrogen, and after 2 hours, excess reagent is filtered off. The solvent was removed, the residue was purified by silica gel column chromatography, α-rivazole [3] 346.9 mg (72
Mol%). The structure was confirmed by ¹ H NMR. The spectrum data obtained is shown below.

¹ HNMR ((CD ₃ ) ₂ CO): δ = 2.30
(s, 3H), 2.33 (s, 3H), 3.69 (dd, J = 3.66, 11.96Hz, 1
H), 3.82 (dd, J = 3.18, 11.97Hz, 1H), 4.24-4.29 (m, 1
H), 4.47 (t, J = 5.38Hz, 1H), 4.56 (t, J = 4.89Hz, 1H),
6.28 (d, J = 4.39Hz, 1H), 7.31 (s, 1H), 7.34 (s, 1H), 8.
23 (s, 1H). ¹³ CNMR ((CD ₃ ) ₂ CO): δ = 20.2
(q), 20.5 (q), 62.7 (t), 72.0 (d), 72.8 (d), 85.6 (d),
86.8 (d), 111.4 (d), 120.4 (d), 130.9 (s), 131.9 (s), 1
43.0 (s), 143.5 (s).

[0029]

INDUSTRIAL APPLICABILITY According to the present invention, an inexpensive and easy-to-handle thiofuranoside derivative is used as a sugar donor as a raw material, and a coupling reaction with a 5,6-dimethylbenzimidazole derivative is carried out in the presence of NBS.
The α-rivazole derivative could be easily synthesized in good yield. This α-rivazole derivative could be easily converted to α-rivazole by removing the hydroxyl-protecting group by a conventional method.

Claims (3)

[Claims] Claims: The thioglycoside derivative represented by Chemical Formula 1 (wherein R is an ethyl group, a phenyl group, P ¹ is a benzyl group, a tert-butyldimethylsilyl group, a triphenylmethyl group, P ² is a benzyl group, an isopropylidene group Shown) and 5,6-
A method for producing α-rivazole represented by Chemical formula 2, which comprises coupling a dimethylbenzimidazole derivative in the presence of an activator. [Chemical 2] 2. The method according to claim 1, wherein 5,6-dimethyl-1-trimethylsilylbenzimidazole is used as the 5,6-dimethylbenzimidazole derivative. 3. The method according to claim 1, wherein N-bromosuccinimide is used as the activator.