JPH0637460B2 - 1α-Hydroxy-Vitamin D (3) Production method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial field of application) The present invention provides a novel alfacalcidol that uses an intermediate capable of selectively determining the three-dimensional structure of alfacalcidol, that is, 1α-hydroxyvitamin D _3. The present invention relates to various manufacturing methods.

(Prior Art) Alfacalcidol is a drug that has an effect of increasing blood calcium by absorbing calcium from the outside and mobilizing calcium from bone, and is useful for improving symptoms associated with abnormal vitamin D metabolism. It is what Although many patent applications have been filed for the synthesis of this compound, for example, 1α-hydroxy or O-acyl-cyclovitamin D ₃ compounds in which the 6-position is substituted with a methoxy group are used together with 5,6-cis compounds by solvolysis. Since it gives a 5,6-trans compound, it is said that a fractionation operation must be carried out in order to obtain the objective compound alfacalcidol in high purity. (Japanese Patent Publication Sho 58-288
No. 76) (Problems to be solved by the present invention) The present invention provides a method for stereoselectively producing alfacalcidol, which is, as shown below, created by the present inventor as a raw material. And a process of using the same.

Formula (I) A compound (6R) (or (6S))-6-hydroxy-3,5-cyclovitamin D ₃ (I) represented by is protected at the 6-position OH with a 1,3-benzodithiol-2-yl group ( 6R) (or (6S))-6- (1,3-benzodithiol-2-yl) oxy-3,5-cyclovitamin D ₃
Get (II).

The compound used for introducing the 1,3-benzodithiol-2-yl group here is 1,3-benzodithiolium tetrafluoroborate.

In the reaction, the compound represented by the formula (I) is dissolved in a solvent which does not participate in the reaction such as dichloromethane, chloroform and carbon tetrachloride, a base such as pyridine and lutidine is added, and 1,3-benzodithiolylium tetrafluoroborate is added under ice cooling. Add and react. The thus-obtained compound represented by the formula (II) is a novel compound and, when subjected to allyl oxidation, the compound represented by the formula (III) Compound (1S, 6R (or (6S)))-
1-hydroxy-6- (1,3-benzodithiol-2
- yl) gives the oxy-3,5-cyclo vitamin D _3.

Here, allyl oxidation is carried out in a solvent such as dichloromethane, chloroform, tetrahydrofuran, dioxane,
It can be carried out at room temperature using selenium dioxide. At this time, it is effective to use a peroxide such as hydrogen peroxide or t-butyl hydroperoxide together.

The thus-obtained compound represented by the formula (III) is a novel compound, which is subjected to solvolysis in the presence of acetic acid and has a cis configuration at the 5 and 6 positions represented by the formula (IV).
Hydroxyvitamin D ₃ acetate is selectively given.

Thus, the obtained compound is converted into 1α-hydroxyvitamin D ₃ by a commonly used solvolysis method.

Since the compound obtained by the present invention is only the 5,6-cis isomer, it is not necessary to separate the cis and trans isomers as in the prior art.

The present invention will be specifically described with reference to the following examples.

Synthesis of Reference Example 1 (6R) -6- (1,3- benzodithiol-2-yl) oxy-3,5-cyclo vitamin D _3: (6R) -6- hydroxy-3,5-cyclo vitamin D ₃
0.50 g of dichloromethane 15 ml, pyridine 0.2
4 g was added, and 0.47 g of 1,3-benzodithiolylium tetrafluoroborate was added under cooling with ice water. After stirring for 1 hour, 0.20 g of triethylamine was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was washed with water, concentrated, extracted with hexane, concentrated, and subjected to silica gel column chromatography (eluent of hexane: ethyl acetate = 60: 1) to obtain 0.35 g of the title compound.

NMR spectrum _{(CDCl 3) δ (ppm)} : 0.51 (3H, s, 18-H 3) 0.80 (1H, m, 4-H) 4.59 (1H, d, J = 9.6Hz, 6-H) 4.83 (1H, m (sharp), 19-H) 5.09 (1H, m (sharp), 19-H) 5.14 (1H, d, J = 9.6Hz, 7- H) 6.55 (1H, s, ) 7.03 to 7.10 (2H, m, aromatic ring hydrogen) 7.26 to 7.34 (2H, m, aromatic ring hydrogen) mass spectrum (m / z): 536 (M ⁺ ), 367,
153 Reference Example 2 Synthesis of (1S, 6R) -1-hydroxy-6- (1,3benzodithiol-2-yl) oxy-3,5-cyclovitamin D ₃ : 0.17 g selenium dioxide, 8 ml dichloromethane, t −
0.54 g of butyl hydroperoxide was stirred at room temperature for 15 minutes. In addition to this, (6R) -6- (1,3-benzodithiol-2-yl) oxy-3,5-cyclovitamin D ₃
A solution prepared by dissolving 0.40 g in 8 ml of dichloromethane was added, the mixture was reacted at the same temperature for 5 minutes, and quenched with an aqueous potassium hydroxide solution. It was extracted with hexane, washed with aqueous potassium hydroxide solution, washed with water, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1 eluent) to obtain 0.20 g of the title compound.

NMR spectrum _{(CDCl 3) δ (ppm)} : 0.51 (3H, s, 18-H 3) 0.64 (1H, m, 4-H) 4.15 (1H, m, 1 (β) -H ) 4.67 (1H, d, J = 9.6Hz, 6-H) 5.05 (1H, d, J = 9.6Hz, 7-H) 5.10 (1H, d, J = 2.0Hz) , 19-H) 5.27 (1H, d, J = 2.0 Hz, 19-H) 6.49 (1H, s, ) 7.04 to 7.11 (2H, m, aromatic ring hydrogen) 7.27 to 7.35 (2H, m, aromatic ring hydrogen) mass spectrum (m / z): 552 (M ⁺ ), 383.
Synthesis of 153 Example 1 1.alpha.-hydroxyvitamin D _3: (1S, 6R) -1-hydroxy-6- (1,3-benzodithiol-2-yl) oxy-3,5-cyclo vitamin D ₃ 5.40 g 110 g of acetic acid was added, and the mixture was stirred at 40 ° C. for 50 minutes. The reaction solution was neutralized with an aqueous sodium hydrogen carbonate solution, extracted with diethyl ether, the ether layer was washed with water and concentrated, and the residue was purified by silica gel chromatography (hexane: ethyl acetate = 9: 1 eluent) to obtain 1α. - was obtained hydroxyvitamin D _3-3-acetate 1.77 g. The NMR spectrum of the acetylated product was as follows.

NMR spectrum _{(CDCl 3) δ (ppm)} : 0.56 (3H, s, 18-H 3) 2.03 (3H, s, 3-OCOCH 3) 4.41 (1H, m, 1 (β) - H) 5.03 (1H, m (sharp), 19-H) 5.21 (1H, m, 3 (α) -H) 5.33 (1H, m (sharp), 19-H) 6.02 (1H, d, J = 11.1Hz , 7-H) 6.34 (1H, d, J = 11.1Hz, 6-H) then, the obtained 1α- hydroxyvitamin D _3-3-acetate 1. 53 g of 5% potassium hydroxide / methanol was added to 77 g, and the mixture was stirred at room temperature for 10 minutes. It was extracted with diethyl ether, the ether layer was washed with water and concentrated, and the residue was crystallized from methyl formate to obtain 1.20 g of the title compound.

NMR spectrum _{(CDCl 3) δ (ppm)} : 0.54 (3H, s, 18-H 3) 4.22 (1H, m, 3 (α) -H) 4.43 (1H, m, 1 (β ) -H) 5.00 (1H, m (sharp), 19-H) 5.32 (1H, m (sharp), 19-H) 6.01 (1H, d, J = 11.2Hz, 7- H) 6.38 (1H, d, J = 11.2 Hz, 6-H) mp. 136.0 ° C. [α] + 51.5 ° (C = 0.52, EtOH) mass spectrum (m / z): 400.3347 (M ⁺ ) C ₂₇ H ₄₄
Theoretical value as O ₂ 400.3339

Claims (2)

[Claims] 1. A formula The 1α-hydroxy-6- (1,3-benzodithiol-2-yl) oxy-3,5-cyclovitamin D _{3 represented} by is solvolytically decomposed with acetic acid, and then the acetyl group is hydrolyzed to give 1α-hydroxy. characterized in that to obtain a vitamin D ₃ 1.alpha.-manufacturing method hydroxyvitamin D ₃ 2. In claim 1 (1S, 6
The method according to claim 1, wherein R) -1-hydroxy-6- (1,3-benzodithiol-2-yl) oxy-3,5-cyclovitamin D ₃ is used.