JPS6144879B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides 25-hydroxycholester-1.4.
This invention relates to a new method for producing 6-trien-3-one (hereinafter abbreviated as 25-hydroxytrienone). This compound is an analogue of active vitamin _D3 1.25
-dihydroxycholecalciferol or
It is useful as an intermediate in the production of 25-hydroxycholecalciferol. The method for producing 25-hydroxytrienone is as follows:
Conventionally, the method starting from fucosterol by Morisaki et al. [Chem.Pharm.Bull.Japan. 21 (11) 2568-2570
(1973)] is known. This method has 8 steps.
Although the process is small and the yield is relatively good, obtaining the raw material fucosterol requires a fairly labor-intensive operation of extracting it from a type of seaweed such as Kajime. The problem is that it is difficult to do so. As a method for producing 25-hydroxytrienone, 5α-cholestan-3β-ol and Ochi et al.
3-Method starting from acetate [Collection of abstracts of the 19th Natural Organic Compounds Conference, 192-198 (1975)]
It has been known. This method has a small number of steps, 4, and is a good method in the laboratory, but the overall yield is low at 2.6%, and 25-α-cholestane-3β
-ol It includes a process unsuitable for industrial mass production of irradiating 3-acetate with light to obtain 25-hydroxycholestanol. The present inventors have developed an efficient method using lithocholic acid, which is available in high purity, in large quantities, and at low cost, as a starting material.
-We have discovered a method for producing hydroxytrienone. The reaction formula of the method of the present invention is as follows: That is, lithocholic acid (2) is esterified with a lower alkanol such as methanol or ethanol in the presence of a dehydration catalyst such as p-toluenesulfonic acid to obtain an ester (2). Then, the ester (2) is oxidized with Johns reagent to obtain the keto ester (2). Then, the ketoester () was converted into 2-methyl-
Ketalization is performed with 2-ethyl-1,3-dioxolane to obtain a ketal ester (). Then, the ketal ester () is reduced with lithium aluminum hydride to obtain the ketal alcohol (). Then, the ketal alcohol () is oxidized with pyridinium chlorochromate to obtain the ketal aldehyde (). Then, the ketalaldehyde () is treated with a triphenylphosphine isopropylidene reagent to obtain the 24-ene (). Then, the 24-ene body ( ) is oxidized with an organic peracid such as m-chloroperbenzoic acid to obtain the 24·25-epoxy body ( ). Then, the 24-25-epoxy compound () is reduced with lithium aluminum hydride to obtain the 25-ol compound (). Next, the 25-ol compound (2) is treated with an inorganic acid such as sulfuric acid, hydrochloric acid, etc. to obtain the 25-ol-3-one compound (25). Then, the 25-ol-3-one form () is converted into 2.
Oxidation with 3-dichloro-5,6-dicyanobenzoquinone yields the dienone (XI). Finally, the dienone compound (XI) is dehydrogenated with chloranil in the presence of 1,2-dihydro-2,3-dichloro-5,6-dicyanobenzoquinone to obtain the object compound of the present invention, 25-hydroxytrienone (XII). ). According to the present invention, starting from lithocholic acid, 25-hydroxy-cholester 1,4,6-trien-3-one is obtained with an overall yield of 5.5% or more. The intermediate compounds of formulas () to () in the method of the present invention are all new substances that have not been described in any literature. The following examples further illustrate the invention. Example 1 (1) Methyl 3α-hydroxy-5β-cholane-
Production of 24-oate () 600 g of lithocholic acid, 4.0 g of p-toluenesulfonic acid monohydrate and 2.5 g of methanol
The mixture was placed in a 4-necked flask, and heated under reflux for 3 hours while stirring. The resulting yellow solution was cooled to 20 °C and
The precipitated product () was collected. white columnar crystals
515.9g; mp131-3℃ By adding water to the mother liquor, the target product ()
An additional 92.9 g was obtained. Target yield: 608.8g (yield 97.8%) IR spectrum ( _νnujiolnax ): 3540cm ^-1
(OH), 1710 cm ^-1 (C=O) (2) Production of methyl 3-oxo-5β-cholan-24-oate () Methyl-3α-hydroxy-obtained in Example 1
5β-cholan-24-oate () 300.0g
(0.07M), 1.5% of tetrahydrofuran, and 0.5% of acetone were placed in a 5-volume 4-necked flask, cooled on ice (inner temperature: 2-6°C) and stirred, and mixed with 346ml of Jones's reagent (0.78M) [67.2ml of concentrated sulfuric acid,
Prepared from 280ml of water and 78.3g of chromium trioxide]
was added dropwise over 70 minutes. After the completion of the dropwise addition, the reaction mixture was stirred at the same temperature for 60 minutes, then left at room temperature overnight, and the precipitated pale yellow crystals () were collected.
193.0g; mp120-21℃. 75.2 g of the target product ( ) was further separated from the mother liquor. Target yield: 268.2g (yield 89.8%) IR spectrum ( _νnudjolnax ): 1730, 1705
cm ^-1 (3) Production of methyl 3-ethylenedioxy-5β-cholan-24-oate () 571.1g (1.47M) of methyl 3-oxo-5β-cholan-24-oate (), para-toluenesulfonic acid 1 Hydrate 6.5g, 2-ethyl-1
-Methyl-1,3-dioxolane 1536g
(13.2M) was placed in a 5-volume, 4-necked flask and heated to reflux for 2.5 hours while stirring. After standing overnight, the precipitated white crystals were collected, washed with cold methanol, and heated at 100℃ for 2 hours, then at 120℃.
It was dried for 3 hours. 474.4g, mp159−61℃. An additional 73.4 g of the desired product was obtained from the mother liquor and washing liquid. Target yield: 547.8g (yield 86.6%) IR spectrum ( _νnudjolnax ): 1740cm ^-1 NMR spectrum (CDCl ₃ , δppm): 3.60
(3H, S, -CO ₂ CH ₃ ), 3.87 (4H, S,

[Formula]) (4) 3-ethylenedioxy-5β-cholane-24-
Preparation of All () 4.3 g (0.1125 M) of lithium aluminum hydride in 500 ml of dry tetrahydrofuran is
Add methyl 3-ethylenedioxy-5β-cholan-24-oate () in 300 ml of dry tetrahydrofuran to a 4-necked kolben.
62.8g (0.145M) of solution was heated at an internal temperature of 10-20℃ for 10 minutes.
It was added dropwise once for a minute and then stirred at room temperature for 4 hours. After standing overnight, the reaction mixture was refluxed for 2 hours, and thin layer chromatography showed that some starting material still remained, so 1.42 g (0.0375 M) of lithium aluminum hydride was added and the mixture was further heated at room temperature. Stirred for 2 hours. As a result, the raw material completely disappeared (confirmed by thin layer chromatography). Add 30 ml of water to the reaction mixture to decompose excess lithium aluminum hydride, filter through Celite, distill the solvent off, and add 500 ml of benzene to the remaining white slurry.
After drying with magnesium sulfate, the solvent was distilled off. Add n-hexane to the resulting viscous oil.
Add 300ml and distill off the solvent to obtain 58.9g of white solid.
(yield 100%). mp131-2°C (n-hexane). IR spectrum ( _νnujiornax ): 3550, 1100
cm ^-1 NMR spectrum (CDCl ₃ , δppm): 0.63
(3H, S, 18−CH ₃ ), 0.94 (3H, S, 19−
CH ₃ ), 1.87 (1H, S, 24-OH, D ₂ O elimination), 3.57 (2H, t, J = 7H ₂ 24-H), and 3.89 (4H, S,

[Formula]) (5) 3-ethylenedioxy-5β-cholane-24-
Preparation of R () 58.6 g (0.272 M) of pyridinium chlorochromate and 22.3 g (0.272 M) of anhydrous sodium acetate in 55 ml of chloroform are placed in a 1 volume 4-necked flat-bottomed colben, and 3-ethylenedioxy- A solution of 55.7 g (0.136 M) of 5β-cholan-24-ol () was added in one portion at room temperature with stirring. After stirring the reaction mixture at room temperature for 2 hours, pyridinium chlorochromate
14.4g (0.067M) and anhydrous sodium acetate
5.6g (0.068M) was added and stirred for an additional 30 minutes. 500 ml of ether was added to the reaction mixture, the ether layer was decanted, the resinous residue collected at the bottom was washed with ether (500 ml x 3), the ether layers were combined, and the solvent was distilled off. Dissolve the remaining dark brown viscous oil in 50 ml of benzene and add silica gel (60 ml) to 50 ml of benzene.
-80 mesh) was applied to a 700 g column and eluted with a benzene-ethyl acetate mixture (49:1).
Eluate 5 after elution 2.5 was taken and the solvent was distilled off to obtain 39.0 g of white crystals (yield 70.6%).
mp141-2℃ (n-hexane) IR spectrum ( _νnudjolnax ): 2710,
1720, 1095 cm ^-1 NMR spectrum (CDCl ₃ , δppm): 0.64
(3H, S, 18−CH ₃ ), 0.92 (3H, S, 19−
CH ₃ ), 3.86 (4H, S,

[Formula] ), 9.64 (1H, t, CH ₂ -CHO) MS: m/e 402 (M ⁺ ) Elemental analysis value: C ₂₆ H ₄₂ O ₃ (as molecular weight 402.60) Calculated value: C 77.56% H 10.52% Measured values: C 77.55% H 10.52% (6) 3-ethylenedioxy-5β-cholesto-24
Preparation of -ene () (i) Preparation of triphenylphosphine isopropylidene reagent 100 ml of dry ether and 7.8 g of isopropyltriphenylphosphonium bromide
(0.02M) was added to a 500 ml pressure flask under an argon atmosphere, and this was added with 15% n-
13 ml of butyl lithium solution was added via syringe, capped tightly and shaken for 16.5 hours to obtain a deep red solution containing the title reagent. (ii) 3-ethylenedioxy-5β-cholesto-
Preparation of 24-ene To the reagent solution obtained in (i), 3-ethylenedioxy-5β-cholan-24- dissolved in 150 ml of dry ether under stirring in a stream of argon was added.
A solution of 5.1 g (0.0127 M) of Earl () was added, the mixture was tightly stoppered, and the mixture was shaken for 3 hours. When 150 ml of primary ether was added to the resulting red reaction solution to decompose unreacted reagents, the red color disappeared.
A white precipitate formed. After filtering, the precipitate on the paper was washed with 50 ml of ether, the liquid and washing liquid were combined and filtered again, and the solvent was distilled off to obtain 6.5 g of a white viscous oily residue. This was chromatographed on a 100 g column of silica gel (Wako Gel C-200), fractionated with a benzene-ethyl acetate mixture (99:1), and after elution of 200 mg,
400 ml was taken and the solvent was distilled off to obtain 5.1 g of white viscous oily product (yield 93.9%). This product crystallizes when left at room temperature and becomes white flaky crystals when recrystallized from methanol.
mp64-6℃ (from methanol) IR spectrum ( _νnudyolnax ): 1095cm ^-1 MS: m/e 428 (M ⁺ ), 413 (M ⁺ -15) NMR spectrum (CDCl ₃ , δppm): 0.66
(3H, S, 18−CH ₃ ), 0.95 (3H, S, 19
_−CH3 ), 1.59 and 1.65 (3H, respectively)
S, 26・27−CH ₃ ), 3.90 (4H, S,

[Formula] ), 5.05 (bm, 1H, 24-H) Elemental analysis value: C ₂₉ H ₄₈ O ₂ (assuming molecular weight 428.67) Calculated value: C 81.25% H 11.29% Measured value: C 80.91% H 11.23% (7 ) 3-ethylenedioxy-24・25-epoxy-
Preparation of 5β-cholestane () 10 g of 3-ethylenedioxy-5β-cholest-24-ene () in 80 ml of dichloromethane
(0.024 M) and 5.7 g of sodium bicarbonate in 80 ml of dichloromethane at -2 to -5°C under stirring.
A solution of (0.028M) was added dropwise over 30 minutes, and stirring was continued for 1 hour at the same temperature.The reaction mixture was then returned to room temperature and further stirred for 2 hours. The resulting reaction solution was washed with a 10% aqueous sodium sulfite solution (100 ml x 2; starch-KI paper negative), then washed with saturated saline (100 ml x 2), and the solvent was distilled off to give a pale yellow color. 10.7 g of a viscous oily product was obtained. This product was combined with 10.7 g of the product obtained by repeating the above procedure once more and chromatographed on a 500 g column of silica gel (60-80 mesh). benzene 3.2
Elute with benzene-ethyl acetate (39:
1), the 3.2 fraction after the 0.4 elution was taken, and the solvent was distilled off to obtain a pale yellow candy-like product, which solidified after being left overnight. 19.6g
(Yield 92.7%). mp: 68-70℃ IR spectrum ( _νnudjolnax ): 1465, 1100
cm ^-1 NMR spectrum (CDCl ₃ , δppm): 0.68
(3H, S, 18−CH ₃ ), 0.97 (3H, S, 19−
CH ₃ ), 1.26 (6H, S, 26・27−CH ₃ ), 2.65
(1H, t, J = 5H ₂ , 24-H), 3.91 (4H,
S,

[Formula]) (8) 3-ethylenedioxy-5β-cholestane-
Production of 25-ol () Lithium aluminum hydride 0.85g
A solution of 10.0 g (0.022 M) of 3-ethylenedioxy-24ξ·25-epoxy-5β-cholestane (0.0122 M) suspended in 100 ml of dry tetrahydrofuran and dissolved in 50 ml of dry tetrahydrofuran with stirring at room temperature. was added dropwise over a period of 20 minutes. After completion of the dropwise addition, the reaction solution was heated under reflux for 75 minutes, then cooled to room temperature, 0.2 g (0.005 M) of lithium aluminum hydride was added, and the mixture was further refluxed for 60 minutes. After the reaction solution was left at room temperature overnight, 5 ml of water was gradually added, and then filtered through Celite, and the solvent was distilled off from the solution. 300 ml of benzene was added to the resulting residue, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off to obtain 11.3 g of a colorless and transparent viscous oil. This was purified by column chromatography using 160 g of silica gel (60-80 mesh) (developing solvent: ethyl acetate:benzene = 1:9) to obtain 9.6 g of the desired product (). IR spectrum ( _νnudjolnax ): 3380 cm ^-1 (broad) NMR spectrum (CDCl ₃ , δppm): 0.64
(3H, S, 18−CH ₃ ), 0.93 (3H, S, 19−
CH ₃ ), 1.19 (6H, S, 26・27−CH ₃ ), 3.86
(4H, S,

[Formula]) MS: m/e446 (M ⁺ ), 248 (M ⁺ -18) (9) Preparation of 25-hydroxy-5β-cholestan-3-one () 3- dissolved in 400 ml of tetrahydrofuran
To a solution of 9.6 g (0.0215 M) of ethylenedioxy-5β-cholestan-25-ol () was added 300 ml of 2N sulfuric acid, and the mixture was stirred at room temperature overnight. The reaction mixture was then extracted with isopropyl ether (once with 300 ml and then twice with 200 ml), and the combined extracts were washed with saturated aqueous sodium bicarbonate (3 x 300 ml).
After confirming that the pH is 8 or more, wash with saturated saline (200ml x 2), confirm that the pH is 7, dry with anhydrous magnesium sulfate, filter, and remove the solvent on a water bath. The residue was dried under reduced pressure and then washed with n-hexane to obtain 7.3 g of white needle crystals. This was purified by chromatography using 300 g of silica gel (60-80 mesh) (developing solvent: ethyl acetate: n-hexane = 1:4), and then recrystallized from n-hexane: benzene to obtain the desired product ( ) 6.4 g (yield 70.6%) were obtained as white needle crystals. mp: 116-7℃ IR spectrum (v ^CHCl _3nax ): 3640, 1705cm
^-1 elemental analysis value: C ₂₇ H ₄₆ O ₂ (as molecular weight 402.64) Calculated value: C 80.53% H 11.51% Measured value: C 80.55% H 11.63% NMR spectrum (CDCl ₃ , δppm): 0.68
(3H, S, 18−CH ₃ ), 1.00 (3H, S, 19−
CH ₃ ), 1.20 (6H, S, 26・27−CH ₃ ), 1.32
(1H, S, 25-OH, D ₂ O elimination) MS: m/e 384 (M ⁺ -18) (10) 25-hydroxycholester-1,4-diene-
Production of 3-one (XI) 25-hydroxy-5β-cholestan-3-one () 3.0 g (7.45 mM), 2,3-dichloro-5,6-dicyanobenzoquinone 5.1 g (22.4
mM) and 50 ml of special grade dioxane,
The mixture was heated under reflux for 4 hours while stirring. Remove the light brown scaly crystals from the reaction mixture, distill the solvent off from the brown liquid, dissolve the residue in 100 ml of benzene, and add 10% aqueous sodium hydroxide solution (50 ml x 3).
The yellow organic layer was made neutral by washing with water (50 ml x 3), dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated. 2.7g of the obtained brown residue was added to 100g of silica gel (60-80 mesh)
Upper chromatography (developing solvent, ethyl acetate:
The product was purified with n-hexane = 1:4)
2.02 g was obtained, which was further recrystallized from ethyl acetate:ether to obtain 1.62 g (yield 53.9%) of the target compound (XI) containing a small amount of trienone form (XII) as pale yellow scale-like crystals. mp: 156-7℃ IR spectrum ( _νnujiolnax : 3520, 1660,
1620, 1600cm ^-1 UV spectrum λ ^EtOH _nax 247nm (logε=
4.16), 302nm (logε=3.40) NMR spectrum (CDCl ₃ , δppm): 1.29
(1H, S, D ₂ O elimination, 25−OH), 5.96 (1H,
Broad S, 4-H), 6.11 (1H, d, J=
10Hz, 2-H), 6.91 (1H, d, J=10Hz,
1-H) Elemental analysis value: C ₂₇ H ₄₂ O ₂ (as molecular weight 398.61) Calculated value: C 81.35% H 10.62% Measured value: C 81.19% H 10.60% (11) 25-Hydroxycholester-1・4・Production of 6-trien-3-one (XII) 25-hydroxycholester-1,4-diene-
0.300g (0.75mM) of 3-one (XI), 0.94g (3.8mM) of chloranil, 1,2-dihydro-
A mixture of 0.34 g (1.5 mM) of 2,3-dichloro-5,6-dicyanobenzoquinone and 20 ml of sec-amyl alcohol was heated at 110° C. for 7.5 hours with stirring. Then, the reaction solution was cooled to room temperature,
Remove the precipitated golden crystals (0.468g),
The solvent was distilled off from the solution. Add 50 ml of benzene to the residue, remove the precipitated brown crystals (0.286 g), cool the liquid on ice, wash it three times with 50 ml of 10% aqueous sodium hydroxide solution, and then add the yellow organic layer four times with 50 ml of saturated brine. After washing and confirming that the pH is 7, drying with anhydrous magnesium sulfate,
and evaporated. The resulting reddish-brown viscous oil (0.300 g) containing partially crystallized product was chromatographed on a column of silica gel (60-80 mesh) and eluted sequentially with the following solvents: ethyl acetate: n-hexane (1 :9)700
ml; ethyl acetate:n-hexane (3:7) 1300
ml: The eluate is fractionated into 10 ml portions, and the fractions are
Nos. 151 to 201 were combined and the solvent was distilled off to obtain 0.153 g of a yellowish brown solid, which was recrystallized from ethyl acetate:ether to yield 0.111 g of the desired product (XII).
37.2%) was obtained as pale yellow needles. mp：187
-9℃ IR spectrum ( _νnujiolnax ): 3520,
1650, 1620 (weak), 1600, 1580 cm ^-1 NMR spectrum (CDCl ₃ , δppm): 0.56
(3H, S, 18−CH ₃ ), 0.82 (1H, S, D ₂ O
Erasure 25−OH), 0.86 (3H, S, 19−CH ₃ ),
0.93 (3H, d, J=6Hz, 21-CH ₃ ), 1.10
(6H, S, 26・27−CH ₃ ), 5.56 and 5.79
(1H, dd, J = 2Hz, 12Hz and 1H, dd,
J=2Hz, 12Hz, 6・7-H), 6.05(1H,
6S, 4-H), 6.21 (1H, dd, J=2Hz, 10
Hz, 2-H), 6.39 (1H, d, 10Hz, 1-
H) MS: m/e396 (M ⁺ ), 378 (M ⁺ -18) UV spectrum λ ^EtOH _nax 302; 257; 224 nm Elemental analysis value: C ₂₇ H ₄₀ O ₂ (as molecular weight 396.59) Calculated value: C 81.76% H 10.17% Measured value: C 81.58% H 10.19%

Claims (1)

[Claims] Linear formula () The following formula () was obtained by treating lithocholic acid with a lower alkanol in the presence of a dehydrating agent. The lower alkyl 3α-hydroxy-5β-cholan-24-oate of was oxidized with Johns reagent to obtain the following formula () lower alkyl 3-oxo-5β-cholane-24-
Oate was reacted with 2-methyl-2-ethyl-1,3-dioxolane to obtain the following formula () Lower alkyl 3-ethylenedioxy-5β-cholan-24-oate was reduced with lithium aluminum hydride to obtain the following formula () oxidizing 3-ethylenedioxy-5β-cholan-24-ol with pyridinium chlorochromate,
The obtained formula () The following formula () was obtained by treating 3-ethylenedioxy-5β-cholan-24-al with triphenylphosphine isopropylidene reagent. 3-ethylenedioxy-5β-cholesto-24-
The following formula () obtained by oxidizing ene with an organic peracid 3-ethylenedioxy-24ξ・25-epoxy-
The following formula () was obtained by treating 5β-cholestane with lithium aluminum hydride. 3-ethylenedioxy-5β-cholestane-25
-The following formula () obtained by acting on the ol with an inorganic acid The following formula (XI) was obtained by reacting 2,3-dichloro-5,6-dicyanobenzoquinone with 25-hydroxy-5β-cholestan-3-one. 25-hydroxycholester-1,4-diene-3
-on to chloranil and 1,2-dihydro-
The following formula (XII) characterized by acting on 2,3-dichloro-5,6-dicyanobenzoquinone A method for producing 25-hydroxycholester-1,4,6-trien-3-one.