JPH02270860A - Production of 1alpha-hydroxy-vitamin d3 - Google Patents

Abstract

PURPOSE:To enable selective obtaining of the subject compound useful for improving symptoms caused by vitamin D dysbolism by solvolyzing a novel intermediate with acetic acid and further acetyl group. CONSTITUTION:1alpha-Hydroxy-6-(1,3-benzodithiol-2-yl)oxy-3,5-cyclovitamin D3 expressed by formula I is solvolyzed with acetic acid and then acetyl group is further solvolyzed to provide 1alpha-hydroxyvitamin D3. The reaction is carried out by using a compound expressed by formula II as a starting material, reacting the above-mentioned compound with a base, such as pyridine, in a solvent, such as dichloromethane or chloroform, to afford a novel intermediate compound expressed by formula III and subjecting the resultant intermediate compound to allylic oxidation in a solvent, such as dichloromethane, to provide the novel compound expressed by formula I. The resultant compound is subsequently solvolyzed in the presence of acetic acid, etc., to afford the objective substance.

Description

Detailed Description of the Invention (Industrial Application Field) This invention is a novel method for producing alfacalcidol using an intermediate that can selectively determine the three-dimensional structure of alfacalcidol, that is, 1α-hydroxyvitamin D3. It is related to the method.

(Prior art) Alfacalcidol is a drug that has the effect of increasing blood calcium by absorbing calcium from the outside and mobilizing calcium from bones, and is useful for improving symptoms associated with abnormal vitamin D metabolism. It is something that Many patent applications have been filed regarding the synthesis of this compound. For example, a 1α-hydroxy or O-acyl-cyclovitamin D3 compound substituted with a methoxy group at the 6-position can be synthesized by solvolysis together with a 5,6-cis compound.゜6−
Since it gives a trans compound, it is said that fractionation operations must be performed in order to obtain the target compound, alfacalcidol, with high purity. (Tokuko Showa 5B-28
(No. 876) (Problems to be Solved by the Present Invention) The present invention provides a method for selectively producing alphacalcitol in the q-isomer. This is achieved through the creation of new compounds and processes using them.

Using (6R) (or (68))-6-hydroxy 3,5-cyclovitamin I) 3(+) shown as 1.3-
Compound (6R) (or (6S))-6-(1,,3-
Benzodithiol-2-yl)oxy-3,5-cyclovitamin p,(n) is obtained.

The compound used here to introduce the 1,3-benzodithiol-2-yl group is 1-43-benzodithiolium tetrafluoroborate.

The reaction is carried out by dissolving the compound represented by formula (1) in a solvent that does not participate in the reaction, such as dichloromethane, chloroform, or carbon tetrachloride, adding a base such as pyridine or lutidine, and diluting 1,3-benzodithiolilium tetrafluoroborate under water cooling. Add hair and let it react.

The compound represented by the formula (II) thus obtained is a new compound, and when allyl oxidation is performed, the compound represented by the formula (m) (L, S, 6R (or (6S)))-1-hydroxy- 6-(1,3-benzodithiol-2-yl)oxy-3,5-cyclovitamin ■]3 is given.

(+) Here, allyl oxidation is performed in a solvent such as dichloromethane, chloroform, tetrahydrofuran, dioxane, etc.
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 oxide in combination.

The thus obtained compound represented by the formula (ITI) is a new compound, and when this compound is solvolyzed in the presence of acetic acid, the 5 and 6 positions represented by the formula (IV) are in the cis configuration]
- Selectively provides acetate of α-hydroxyvitamin D3.

The compound thus obtained is converted to Jα-hydroxyvitamin D3 by a commonly practiced solvolysis procedure.

Since the compound obtained by the present invention is only the 5,6-cis isomer r&2, there is no need for the special separation operation of the cis isomer and the trans isomer in the prior art.

The present invention will be specifically explained below by describing examples.

Reference Example 1 Synthesis of (6R)-6-(1,3-benzodidiol-2-yl)oxy-3,5-cyclovitamin D: (6R)-6-hydroxy-3,5-cyclo vitamin D
30.50 g and 15 m of dichloromethane 1. .

0.24 g of pyridine was added, and 0.47 g of 1,3-benzodithiolylium tetrafluoroborate was added in an ice-water cooling oven. After stirring for 61 hours, 0.20 g of triethylamine was added.
was added and stirred at room temperature for 30 minutes. The reaction solution was washed with water, concentrated, extracted with hexane, concentrated, and the residue was subjected to silica gel column chromatography (eluent of hexane:ethyl acetate=60:1) to obtain 0.35 g of the compound listed above.

NMR spectrum (CDCl2) δ (ppm): 0.
51 (3H,s, 18-H3)0.80 (IT
-1, m, 4-H) 4.59 (IH, d, J=9
．． 6Hz, 6-H) 4.83 (IH, m(sha
rp), 19-H) 5.09 (IH, m(sha
rp), 19-H) 7.03-7.10 (2H, m
, aromatic ring hydrogen) 7.26-7.34 (2H, m, aromatic ring hydrogen) Mass spectrum (m/z): 536 (M
), 367.153 Reference Example 2 Synthesis of (Is, 6R) -1-hydroxy-6-(1,3benzodithiol-2-yl)oxy-3,5-cyclovitamin D3: 0.17 g of selenium dioxide, Dichloromethane 8ml 1゜t-
0.54 g of butyl hydroperoxide was stirred at room temperature for 15 minutes. To this, (6R)-6-(1゜3-benzodithiol-2-yl)oxy-3゜5-cyclovitamin D
A solution of 30.40 g dissolved in 8 ml of dichloromethane was added, and the mixture was reacted at the same temperature for 5 minutes, and then quenched with an aqueous potassium hydroxide solution to give ζ7. It was extracted with hexane, washed with an 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 compound listed above.

NMR spectrum (CDC1,) δ (ppm): 0.
51 (3H,s, 18-H3)0.64 (LH
, m, 4-H) 4.15 (LH, m, 1 (β)-H) 4.67
(LH, d, J=9.6Hz, 6-H)5.05
(LH, d, J=9.6Hz, 7-H)5.10 (
IH, d, J-2,0Hz, 19-H) 5.27 (
LH, d, J=2.0Hz, 19-H) 7.04-7.
11 (2H, m, aromatic ring hydrogen) 7.27-7.35
(2H, m, aromatic ring hydrogen) mass spectrum (m/z
): 552 CMr ), 383.153 Example 1 Synthesis of 1α-hydroxyvitamin D: <F? ) Add 110 g of acetic acid to 5.40 g of (L,S,6R)-1-hydroxy-6-(1,3benzodithiol-2-yl)oxy-3,5-cyclovitamin D, and add 5.40 g of acetic acid at 40°C.
Stirred for 0 minutes. The reaction solution was neutralized with an aqueous sodium hydrogen carbonate solution, extracted with diethyl ether, and the ether layer was washed with water.
It was concentrated, and the residue was purified by silica gel chromatography (hexane:ethyl acetate-9=1 eluent) to obtain 1.77 g of 1α-hydroxyvitamin D, -3-acetate. The NMR spectrum of the acetyl compound was as follows: NMR spectrum (CDCI,) δ (ppm): 0
．． 56 (3H,s,18-H3)2,03 (
3H,s, 30COCHa)4.41 (LH
,m,1 (β)-H)5,03 (LH,m(s
harp), 19-H)5.21 (LH,m,
3 ((E)-H)5,33 (1,H,m(sha
rp), 19-H) 6.02 (LH, d, J=1
1.1Hz, 7-H) 6.34 (LH, d, J=1
1.1Hz, 6-H) Then, the obtained 1α-hydroxyvitamin D3-3-acetate 1. 53 g of 5% potassium hydroxide/methanol was added to 17 g of the mixture, and the mixture was stirred at room temperature for 10 minutes. Extraction was carried out with diethyl ether, the ether layer was washed with water and concentrated, and the residue was crystallized with methyl formate to obtain 1.20 g of the compound listed above.

NMRX vector (CDCl a) δ (ppm
):0°54 (3H,s,18-H,)4,. 22
(LH, m, 3 ((ri -H)4.43 (L
H,m,1 (β)-H)5,00 (LH,m(s
harp), 19-H)5.32 (LH,m(s
harp), 19-H) 6.01 (LH, d, J=
11.2)-Iz, 7-H)6.38 (IH, d,
J=11.2Hz, 6-H)mp, 136.0℃

Claims (1)

[Claims] 1. 1α-hydroxy-6-(1,3-benzodithiol-2-yl)oxy-3,5-cyclovitamin D_3 represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Method 2 for producing 1α-hydroxyvitamin D3, characterized in that 1α-hydroxyvitamin D_3 is obtained by solvolyzing the acetyl group and then solvolyzing the acetyl group.
-The method according to claim 1 using hydroxy-6(1,3-benzodithiol-2-yl)oxy-3,5-cyclovitamin D_3