JPS5848550B2 - Active vitamin D analog and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an active form of vitamin D having fluorine in the 2nd position.

More details: Parent compound 2 with strong vitamin D activity
- Fluoro-1α-hydroxyvitamin D3 and its production method.

In recent years, mainly H. F. Through research by DeLuca et al., active metabolites of vitamin D were discovered, and 1α-hydroxyvitamin D3, 1α,25-dihydroxyvitamin D3, etc. can now be used to treat calcium and phosphorus metabolic disorders, bone disorders, etc. (H.F. DeLuca, H.K.
Schnoes, Annual Review
ofBiochem, 45 631 (1976))
.

However, active research is being conducted to develop active vitamin D, which is more powerful, long-lasting, and has more specific effects.

It is well known that by introducing a fluorine substituent into a drug such as a hormone, the effect of the drug can be enhanced in some cases, and the drug can have a unique bioimplantation effect.

The present inventors have conducted various studies to develop active vitamin D analogues with strong and unique physiological effects. As a result of various studies, the present inventors have developed a new active vitamin D analogue, 1α-hydroxyvitamin D3, which has fluorine at the 2nd position. The synthesis was successful.

This compound is expected to have strong vitamin D activity.

That is, the present invention relates to 2-fluoro-1α-hydroxyvitamin D3 and a method for synthesizing the same.

Synthesis of this compound or the following reaction using 1α,2α-epoxycholest-5-en-3β-ol tetrahydrohyranyl ether (4) as a starting material, the synthesis method of which has already been established by the present inventors. can be manufactured according to the formula.

Next, this reaction formula will be explained.

Compound 1) is hydrolyzed to obtain lα·2α-epoxycholest-5-en-3β-ol (2).

The reaction of this compound with an alkali fluoride such as potassium hydrogen fluoride containing 2β-fluorocholest-5-ene-1α,3β-diol (3
).

When this compound 3) is diacylated, its diacylated form, for example, 2β-fluorocholest-5-ene-1α・3β-
Diacetate (4) is obtained.

By introducing a double bond into the 7-position of this diacetate (4), 2
β-Fluorochholest-5,7-diene-1α,3β-
Diacetate (5) is obtained.

A method for introducing a double bond at the 7-position is, for example, bromination at the 7-position with N-furomosuccinimide, followed by debromination by heating with collidine to obtain compound vA5).

After irradiating this compound (5) with light, the obtained previtamin derivative was subsequently thermally isomerized and genitized to give 2β
-Fluoro-1α-hydroxyvitamin Ds (6) is obtained.

The method for producing compound vA6) will be explained in more detail based on Examples.

Example 1 Synthesis of 1α·2α-1epoxycholest-5-ene 3β-ohno M2) 1α·2α-1epoxycholest-5-ene-3β-ol tetrahydropyranyl ether (1) 103 ■ Tohyricinium p-}luenesulfonate 5 in 2 liters of methylene chloride and 2 liters of methanol and heated at 55° for 5
Warm for an hour.

The obtained product was extracted with methylene chloride and purified using a silica gel column to obtain 75 parts of 1α/2α-epoxycholesterol.
5-en-3β-ol (hereinafter referred to as compound vA2) is obtained.

The properties of this substance are as follows. mp104, 5-10
6.5° (recrystallized from methanol), NMR (C
DCI3): δ0.7 2 (3H, s, 1 8
7Me), 1.15 (3H, s.19
-Me), 3.08 and 3.20 (2H,d,
J=4Hz, 1-H. 2-H), 3.90 (L
H, m, 3-H), 5.50 ppm (L H
．． m. 6-H) o Mass m/e40
0(M+), 382, 342, 287, 269o Example 2 Synthesis of 2β-fluorocholest-5-ene-1α・3β-diol (3) Compound 2) 66■ and potassium fluoride (MerckAr
t4995 (contains potassium hydrogen fluoride) 2007nI
? is dissolved in 2rnl of ethylene glycol and heated to 1700 °C for 1 hour and 30 minutes under a stream of argon.

After cooling, the crude product obtained by treatment in a conventional manner was purified using a silica gel column, and 30 μ of 2β-fluorochorest-5-ene-1α·3β-diol (3) (hereinafter referred to as compound 3) was purified using a silica gel column.
).

The properties of this substance are as follows.

166-169.5° (recrystallized from methanol), NMR (CDCl3), δ: 0
．． 6 8 (3H, S., 1 8 -Me), 1
．． 13 (3H, s.19-Me), 3. 70 (
LH, bm. 3-H), 3.96 (L
H. m. 1-H), 4. 7 8 (IH,
dm. JHF = 50 Hz, 2-H), 5
．． 60 ppm (LH, m.6-H).

Mass m/e 420 (M+), 405
, 402, 400, 382, 307, 289, 265,
247o Example 3 Synthesis of 2β-fluoro-5-ene-1α·3β-thiol diacetate (4) Compound 3) 28■ is dissolved in 1 ml of pyridine and two acetic anhydrides and heated at 900 °C for 4 hours.

The crude product obtained after the conventional treatment was purified using a silica gel ram to obtain 27 m9 of oily 2β-fluoro-5-ene-1α,3β-diol diacetate (4) (hereinafter referred to as compound vA4). obtain.

The physical properties of this material are as follows.

NMR (CDCl3), δ:0. 6 8 (3H
, s, 18-Me), 1.17 (3H, B.
19Me), 2.07, 2.10 (6H.s.
acetyl), 4.73 (IH, dm, JHF =
5 1Hz, 2-H), 4. 8 8 (LH,
bm. 3-H), 5. 1 7 (IH, m.
12H), 5.58 ppm (IH,m,6-
H).

Mass m/e 4 4 4 (M eleven Ac O
H ), 384, 369, 364, 271, 251, 2
47.

Example 4 2β-fluorocholest-5,7-diene-lα,3β
-Synthetic compound of diol diacetate (5)'$4)62
While m9 was dissolved in 2 rulls of carbon tetrachloride and heated under reflux, 311n90N-promosuccinimide was added and heated under reflux for 1 hour and 20 minutes under an argon atmosphere.

After cooling, the precipitated imide was separated, the solvent of the r liquid was distilled off under reduced pressure, the residue was dissolved in 1 ml of xylene, and 1.5 TL of xylene and 0.5 y of collidine were heated under reflux under an argon stream.
Add dropwise to the mixture of step d and heat under reflux for an additional 15 minutes.

The crude product obtained by extraction with ethyl acetate and conventional treatment is dissolved in 5 ml of acetone, a catalytic amount of p-}luenesulfonic acid is added, and the mixture is stirred at room temperature under argon for 11 hours.

The crude product obtained by extraction with ethyl acetate was purified by thin layer chromatography (hexane-ethyl acetate 15:1, developed 3 times) to obtain 7.7μ of amorphous solid 2β-fluorocholest-5.7- Diene-1α,3β-diol diacetate (5) (hereinafter referred to as compound vA5) is obtained.

The UV spectrum of this product is λm. (EtOH): 2
6 2 (sh), 27l1281.5, 2 9
3 n no Example 5 2β-fluoro-1α-hydroxyvitamin Da (6)
A combination of compounds 5) 7. 7 my was dissolved in 40 TL of ethanol and 90 ml of benzene, and exposed to ultraviolet light (Hanova 654A36, 200 W) under water cooling while introducing argon gas.
irradiate for 2.5 minutes.

After heating under reflux for 1 hour under argon, the solvent was distilled off under reduced pressure, and the resulting crude product was purified by thin layer chromatography (developed twice with hexane-ethyl acetate 14:1).
- Obtain diacetate of fluoro-α-hydroxyvitamin D3.

This was dissolved in 3 TL of tetrahydrofuran, 2 ml of 5% potassium hydroxide-methanol solution was added, and the mixture was left at room temperature for 15 hours under argon.

This was extracted with ethyl acetate, and the crude product obtained by conventional treatment was subjected to high performance liquid chromatography (column, Zorbox Si
l. 1 5 (XX 4.6mlL i.d.:
Solvent: methylene chloride-hexane (4:1) to purify 1.2
8■ 2β-Fluoro-, an active vitamin D analogue of
1α-hydroxyvitamin Ds (6) is obtained.

The properties of this product are as follows.

UVλmax (EtOH): 26 5, λ-2
26nmoMass m/e: 4 1 8 (M
+), m1n 403, 400,398, 380,365, 287, 1
50,135o NMR (CDCl3): δ0.49 (3H,s,
1 8Me), 0.8 2 (6H, d.J=7
Hz, 26, 27-Me), 0.87 (
3H, d, J = 6Hz. 2 11 Me), 4.1 8
~4.6 2 (IH, hidden, 2
-H), 4.2 6 (LH, m, 3-Horl
-H), 4.5 1 (I H.m.l-Hor3
-H), 5.1 4 (LH, br s, 1
9-H), 5.54 (LH, brs, 19-H), 5.
99 (IH, d, J=12Hz, 7H), 6. 3
6 ppm (L H.d.J-1 2 Hz, 6
-H).

The method for producing vitamin D3 of the present invention has a great industrial advantage in that it can provide extremely highly active vitamin D3 having double bonds at the root and 7 positions.

Claims (1)

[Scope of Claims] 1. An active vitamin D analogue consisting mainly of 2β-fluoro-1α hydroxyvitamin D3 having fluorine at the 2nd position. 2 1α・2α-epoxycholest-5-en-3β-
Using all-tetrahydropyranyl ether as a starting material, it is hydrolyzed to produce 1α・2α-monoethoxycholest-
Obtain 5-en-3β-ol, which is fluorinated to give 2β
-Fluorocholest-5-en-1α/3β-diol was obtained, which was diacylated to 2β-fluorocholest-5.
-ene-1α·3β-diacetate is obtained, and a double bond is introduced into the 7-position of this diacetate to obtain 2β-fluorochorest-5,7-diene-1α·3β-diacetate,
A method for producing an active vitamin D analog, which comprises irradiating this with light, followed by thermal isomerization of the obtained previtamin derivative and saponification to obtain 2β-fluoro-1α-hydroxyvitamin D3. .