JP3066047B2 - New vitamin D (lower 3) derivatives - Google Patents
New vitamin D (lower 3) derivativesInfo
- Publication number
- JP3066047B2 JP3066047B2 JP2206484A JP20648490A JP3066047B2 JP 3066047 B2 JP3066047 B2 JP 3066047B2 JP 2206484 A JP2206484 A JP 2206484A JP 20648490 A JP20648490 A JP 20648490A JP 3066047 B2 JP3066047 B2 JP 3066047B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- added
- mmol
- ethyl acetate
- solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【発明の詳細な説明】 本発明は一般式（Ｉ）で示されるビタミンD3誘導体に
関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a vitamin D3 derivative represented by the general formula (I).
（式中Ｒは水素原子または水酸基を意味し、ｎは１乃至
５の整数を意味する。） 一般式（Ｉ）で示されるビタミンD3誘導体はそれ自体
ビタミンＤ様の生理活性を有し医薬として有用であり、
かつ血中のビタミンD3を抗原抗体反応を用いて測定する
際に必要な抗体を製造するためのハプテンとしても使用
しうる。 (In the formula, R represents a hydrogen atom or a hydroxyl group, and n represents an integer of 1 to 5.) The vitamin D3 derivative represented by the general formula (I) itself has a vitamin D-like physiological activity and is a drug. Useful and
Further, it can be used as a hapten for producing an antibody necessary for measuring vitamin D3 in blood using an antigen-antibody reaction.
本発明の一般式（Ｉ）で示される化合物は例えば一般
式（II）で示される化合物を出発物質として以下式示す
る方法で製造される。The compound represented by the general formula (I) of the present invention is produced, for example, by a method represented by the following formula using a compound represented by the general formula (II) as a starting material.
（式中、Ｒは水素原子または水酸基を意味し、Ｒ′は水
酸基の保護基を意味し、Ｒ″は水酸原子または保護され
た水酸基を意味し、ｎは１乃至５の整数を意味する。） また、一般式（II）で示される化合物は、公知のジヒ
ドロイソアンドロステロンの11位に水酸基が入った下記
式（Ｖ） で示される化合物を出発原料として合成される。この工
程は後記参考例に示した。 (Wherein, R represents a hydrogen atom or a hydroxyl group, R ′ represents a hydroxyl-protecting group, R ″ represents a hydroxyl atom or a protected hydroxyl group, and n represents an integer of 1 to 5. The compound represented by the general formula (II) is a compound represented by the following formula (V) having a hydroxyl group at the 11-position of a known dihydroisoandrosterone. Is synthesized using the compound represented by the formula as a starting material. This step is described in Reference Examples below.
参考例１ ［17（20）Ｚ］−プレグナ−5,17（20）−ジエン−３
β,11α−ジオールジアセテート（化合物２）の合成 テトラヒドロフラン（25ml）にカリウムｔ−ブトキシ
ド（2.22g,19.7mmol），エチルトリフェニルホスフォニ
ウムブロミド（7.33g,19.7mmol）を溶解しアルゴンガス
気流中55℃（浴温）で30分撹拌後、３β,11α−ジヒド
ロキシアンドロスト−５−エン−17−オン（化合物１）
のテトラヒドロフラン（15ml）溶液を加えて１時間還流
した。反応液を温室に戻した後、ピリジン−無水酢酸
（2:1,18ml）及び４−ジメチルアミノピリジン（200m
g）を加え同温にて30分撹拌した。水を加えテトラヒド
ロフランを濃縮後、エーテルで抽出した。有機層を10％
塩酸、水、５％炭酸水素ナトリウム水溶液、飽和食塩水
で順次洗浄し、無水硫酸ナトリウムで乾燥した。溶媒留
去後、残渣をフラッシュクロマトグラフィーに付した。
ｎ−ヘキサン−酢酸エチル（10:1）溶出部より目的物
（1.30g、97.6％）を無色無晶形物質として得た。1 H−NMR（CDCl3）δ;0.95（3H,s,18−CH3）,1.12（3H,
S,19−CH3）,2.03（6H,S,2×OCOCH3）,4.52（1H,m,3α
−Ｈ）,4.92−5.48（3H,m,6−,11β−,20−Ｈ） 参考例２ メチル（22E）−３β,11α−ジアセトキシコラ−5,16,2
2−トリエン−24−オエート（化合物３）の合成 化合物２の（2.30g,5.74mmol）のジクロロメタン（25
ml）溶液プロピオン酸メチル（0.95ml,11.5mmol）及び
エチルアルミニウムジクロリド（1Mn−ヘキサン溶液;2
8.7ml）を加えアルゴンガス気流中室温にて2.5時間撹拌
した。反応液を５％炭酸水素ナトリウム水溶液に注入し
エーテルで抽出後、有機層を飽和食塩水で洗浄し、無塩
水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒留去
後、残渣をフラッシュクロマトグラフィーに付した。ｎ
−ヘキサン−酢酸エチル（3:2）溶出部より目的物（2.2
5g,90.9％）を無色無晶形物質として得た。1 H−NMR（CDCl3）δ;0.84（3H,s,18−CH3）,1.15（3H,
s,19−CH3）,2.02,2.03（each 3H,s,OCOCH3）,3.73（3
H,s,COOCH3）,4.59（1H,m,3α−Ｈ）,5.16−5.60（3H,
m,6−,11β−,16−Ｈ）,5.77（1H,dd,J＝16.1Hz,23−
Ｈ）,6.93（1H,dd,J＝16.8Hz,22−Ｈ）． 参考例３ メチル３β,11α−ジアセトキシコル−５−エン−24−
オエート（化合物４）の合成 ５％白金−炭素（170mg）の酢酸エチル（85ml）懸濁
液に化合物３（860mg、1.77mmol）の酢酸エチル（20m
l）溶液を加え水素ガス雰囲気下室温にて30分撹拌し
た。触媒を濾去後溶媒留去し、残渣をフラッシュクロマ
トグラフィーに付した。ｎ−ヘキサン−酢酸エチル（3:
2）溶出部より無色固形物質を得、これをメタノールよ
り再結晶し目的物（78mg,90.0％）を無色針状晶として
得た。Reference Example 1 [17 (20) Z] -pregna-5,17 (20) -diene-3
Synthesis of β, 11α-diol diacetate (compound 2) Dissolve potassium t-butoxide (2.22 g, 19.7 mmol) and ethyltriphenylphosphonium bromide (7.33 g, 19.7 mmol) in tetrahydrofuran (25 ml) and flow with argon gas. After stirring at 55 ° C (bath temperature) for 30 minutes, 3β, 11α-dihydroxyandrost-5-en-17-one (compound 1).
Was added and the mixture was refluxed for 1 hour. After returning the reaction solution to the greenhouse, pyridine-acetic anhydride (2: 1, 18 ml) and 4-dimethylaminopyridine (200 m
g) was added and stirred at the same temperature for 30 minutes. After adding water, the tetrahydrofuran was concentrated and extracted with ether. 10% organic layer
It was washed sequentially with hydrochloric acid, water, 5% aqueous sodium hydrogen carbonate solution and saturated saline, and dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was subjected to flash chromatography.
The desired product (1.30 g, 97.6%) was obtained as a colorless amorphous substance from a fraction eluted with n-hexane-ethyl acetate (10: 1). 1 H-NMR (CDCl3) δ ; 0.95 (3H, s, 18-CH3), 1.12 (3H,
S, 19-CH3), 2.03 (6H, S, 2 × OCOCH3), 4.52 (1H, m, 3α
-H), 4.92-5.48 (3H, m, 6-, 11β-, 20-H) Reference Example 2 Methyl (22E) -3β, 11α-diacetoxychola-5,16,2
Synthesis of 2-triene-24-oate (Compound 3) Compound 2 (2.30 g, 5.74 mmol) in dichloromethane (25
ml) solution methyl propionate (0.95 ml, 11.5 mmol) and ethylaluminum dichloride (1 Mn-hexane solution; 2
8.7 ml) and stirred at room temperature for 2.5 hours in a stream of argon gas. The reaction solution was poured into a 5% aqueous sodium hydrogen carbonate solution and extracted with ether. The organic layer was washed with saturated saline, washed with brine, and dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was subjected to flash chromatography. n
-Hexane-ethyl acetate (3: 2)
5g, 90.9%) as a colorless amorphous substance. 1 H-NMR (CDCl3) δ ; 0.84 (3H, s, 18-CH3), 1.15 (3H,
s, 19-CH3), 2.02,2.03 (each 3H, s, OCOCH3), 3.73 (3
H, s, COOCH3), 4.59 (1H, m, 3α-H), 5.16-5.60 (3H,
m, 6-, 11β-, 16-H), 5.77 (1H, dd, J = 16.1Hz, 23-
H), 6.93 (1H, dd, J = 16.8 Hz, 22-H). Reference Example 3 Methyl 3β, 11α-diacetoxycol-5-ene-24-
Synthesis of Oate (Compound 4) Compound 3 (860 mg, 1.77 mmol) in 5% platinum-carbon (170 mg) in ethyl acetate (85 ml) was suspended in ethyl acetate (20 m2).
l) The solution was added and the mixture was stirred at room temperature for 30 minutes under a hydrogen gas atmosphere. After removing the catalyst by filtration, the solvent was distilled off, and the residue was subjected to flash chromatography. n-hexane-ethyl acetate (3:
2) A colorless solid substance was obtained from the eluted portion, which was recrystallized from methanol to obtain the desired product (78 mg, 90.0%) as colorless needles.
mp139−142℃。Anal.Calcd C29H44O6:C,71.28;H,9.08.F
ound:C,71.45;H,9.18.1 H−NMR（CDCl3）δ;0.75（3H,s,18−CH3）,0.90（3H,
d,J＝5Hz,21−CH3）,1.01（3H,s,19−CH3）,2.01,2.03
（each 3H,s,OCOCH3）,3.66（3H,s,COOCH3）,4.54（1H,
m,3α−Ｈ）,5.24（1H,m,11β−Ｈ）,5.42（1H,m,6−
Ｈ）． 参考例４ ３β,11α−ジヒドロキシコル−５−エン−24−オイッ
クアシド（化合物５）の合成 化合物４（1.30g,2.65mmol）のメタノール（50ml）溶
液に20％水酸化カリウム水溶液（150ml）を加え80℃
（浴温）にて30分撹拌した。メタノールを濃縮後、残渣
に10％塩酸を加え水層を酸性となし、析出した結晶を濾
取し水洗後５酸化２リン上減圧乾燥した。メタノールよ
り再結晶し、目的物（972mg,93.6％）を無色針状晶とし
て得た。mp 139-142 ° C. Anal.Calcd C29H44O6: C, 71.28; H, 9.08.F
ound:. C, 71.45; H , 9.18 1 H-NMR (CDCl3) δ; 0.75 (3H, s, 18-CH3), 0.90 (3H,
d, J = 5Hz, 21-CH3), 1.01 (3H, s, 19-CH3), 2.01,2.03
(Each 3H, s, OCOCH3), 3.66 (3H, s, COOCH3), 4.54 (1H,
m, 3α-H), 5.24 (1H, m, 11β-H), 5.42 (1H, m, 6-
H). Reference Example 4 Synthesis of 3β, 11α-dihydroxycol-5-ene-24-oic acidide (compound 5) To a solution of compound 4 (1.30 g, 2.65 mmol) in methanol (50 ml) was added a 20% aqueous potassium hydroxide solution (150 ml). 80 ℃
(Bath temperature) for 30 minutes. After concentrating methanol, 10% hydrochloric acid was added to the residue to make the aqueous layer acidic, and the precipitated crystals were collected by filtration, washed with water, and dried over phosphorus pentoxide under reduced pressure. Recrystallization from methanol gave the desired product (972 mg, 93.6%) as colorless needles.
mp254−256℃,Anal.Calcd C24H46O4:C,73.80;H,9.81.Fo
und:C,73.59;H,10.01.1 H−NMR（DMSO−d6）δ:0.64（3H,s,18−CH3）,0.90（3
H,d,J＝5Hz,21−CH3）,1.05（3H,s,19−CH3）,5.25（1
H,m,6−Ｈ）． 参考例５ メトキシメチル３β,11α−ビス（メトキシメトキシ）
−コル−５−エン−24−オエート（化合物６）の合成 化合物５（940mg）をジメチルホルムアミド−テトラ
ヒドロフラン（5:9;28ml）溶液に溶解し、氷冷下、N,N
−ジイソプロピルエチルアミン（2.45ml,14.4mmol）を
加えアルゴンガス気流中30分間撹拌した。更にクロロメ
チルエーテル（2.33ml,21.6mmol）を加え60℃（浴温）
にて4.5時間撹拌した。反応液を水に注入し、５％炭酸
水素ナトリウム水溶液で中和した。酢酸エチルで抽出
後、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウム
で乾燥した。溶媒留去後、残渣をフラッシュクロマトグ
ラフィーに付した。ｎ−ヘキサン−酢酸エチル（3:1）
溶出部より目的物（1.07g、84.9％）を淡黄色無晶形物
質として得た。1 H−NMR（CDCl3）δ:0.69（3H,s,18−CH3）,0.96（3H,
d,J＝6Hz,21−CH3）,1.13（3H,s,19−CH3）,3.37（6H,
s,2×OCH2OCH3）,3.46（3H,s,COOCH2OCH3）,3.88（1H,
m,11β−Ｈ）,4.68,4.70（each2H,s,OCH2OCH3）,5.22
（2H,s,COOCH2OCH3）,5.36（1H,m,6−Ｈ）． 参考例６ ３β,11α−ビス（メトキシメトキシ）コル−５−エン
−24−オール（化合物７）の合成 化合物６（1.02g,1.96mmol）をテトラヒドロフラン
（25ml）に溶解し氷冷下、リチウムアルミニウムヒドリ
ド（371mg,9.80mmol）を加えアルゴンガス気流中３分撹
拌した。1M水酸化ナトリウム水溶液を加え、反応液を飽
和食塩水に注入し酢酸エチルで抽出した。有機層と無水
硫酸ナトリウムで乾燥し、溶媒留去後残渣をフラッシュ
クロマトグラフィーに付した。ｎ−ヘキサン−酢酸エチ
ル（3:2）溶出部より得られる無色固形物質をｎ−ヘキ
サン−メタノールより再結晶し、目的物（804mg,88.4
％）を無色針状晶として得た。mp254-256 ° C, Anal.Calcd C24H46O4: C, 73.80; H, 9.81.Fo
und:. C, 73.59; H , 10.01 1 H-NMR (DMSO-d6) δ: 0.64 (3H, s, 18-CH3), 0.90 (3
H, d, J = 5Hz, 21-CH3), 1.05 (3H, s, 19-CH3), 5.25 (1
H, m, 6-H). Reference Example 5 methoxymethyl 3β, 11α-bis (methoxymethoxy)
Synthesis of -col-5-ene-24-oate (Compound 6) Compound 5 (940 mg) was dissolved in a solution of dimethylformamide-tetrahydrofuran (5: 9; 28 ml) and N, N was added under ice-cooling.
-Diisopropylethylamine (2.45 ml, 14.4 mmol) was added, and the mixture was stirred in an argon gas stream for 30 minutes. Further, chloromethyl ether (2.33 ml, 21.6 mmol) was added and the temperature was 60 ° C (bath temperature)
For 4.5 hours. The reaction solution was poured into water and neutralized with a 5% aqueous sodium hydrogen carbonate solution. After extraction with ethyl acetate, the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was subjected to flash chromatography. n-hexane-ethyl acetate (3: 1)
The desired product (1.07 g, 84.9%) was obtained as a pale yellow amorphous substance from the elution part. 1 H-NMR (CDCl3) δ : 0.69 (3H, s, 18-CH3), 0.96 (3H,
d, J = 6Hz, 21-CH3), 1.13 (3H, s, 19-CH3), 3.37 (6H,
s, 2 × OCH2OCH3), 3.46 (3H, s, COOCH2OCH3), 3.88 (1H,
m, 11β-H), 4.68,4.70 (each2H, s, OCH2OCH3), 5.22
(2H, s, COOCH2OCH3), 5.36 (1H, m, 6-H). Reference Example 6 Synthesis of 3β, 11α-bis (methoxymethoxy) col-5-en-24-ol (Compound 7) Compound 6 (1.02 g, 1.96 mmol) was dissolved in tetrahydrofuran (25 ml), and lithium aluminum was added thereto under ice cooling. Hydride (371 mg, 9.80 mmol) was added, and the mixture was stirred in an argon gas stream for 3 minutes. A 1M aqueous sodium hydroxide solution was added, and the reaction solution was poured into saturated saline and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and after evaporation of the solvent, the residue was subjected to flash chromatography. The colorless solid substance obtained from the n-hexane-ethyl acetate (3: 2) eluate was recrystallized from n-hexane-methanol to give the desired product (804 mg, 88.4).
%) As colorless needles.
mp78−80℃.Anal.Calcd C28H48O5:C,72.37;H,10.41.Fou
nd:C,72.19;H,10.89.1 H−NMR（CDCl3）δ:0.69（3H,s,18−CH3）,0.96（3H,
d,J＝6Hz,21−CH3）,1.13（3H,s,19−CH3）,3.37（6H,
s,2×OCH3）,3.90（1H,m,11β−Ｈ）,4.68（4H,s,2×OC
H2O）,5.38（1H,m,6−Ｈ）． 参考例７ ３β,11α−ビス（メトキシメトキシ）コル−５−エン
−24−アール（化合物８）の合成 PCC（520mg,2.42mmol）のジクロロメタン（20ml）懸
濁液に化合物７（750mg,1.61mmol）のジクロロメタン
（15ml）溶液を加えアルゴンガス気流中室温にて５時間
撹拌した。反応液をエーテルで希釈後、シリカゲル（2.
5g）のショートカラムを通し溶媒留去後残渣をフラッシ
ュクロマトグラフィーに付す。ｎ−ヘキサン−酢酸エチ
ル（3:1）溶出部より得られる無色固形物質をｎ−ヘキ
サンより再結晶し、目的物（682mg,91.4％）を無色針状
晶として得た。mp78-80 ° C. Anal.Calcd C28H48O5: C, 72.37; H, 10.41.Fou
nd: C, 72.19; H, 10.89. 1 H-NMR (CDCl3) δ: 0.69 (3H, s, 18-CH3), 0.96 (3H,
d, J = 6Hz, 21-CH3), 1.13 (3H, s, 19-CH3), 3.37 (6H,
s, 2 × OCH3), 3.90 (1H, m, 11β-H), 4.68 (4H, s, 2 × OC
H2O), 5.38 (1H, m, 6-H). Reference Example 7 Synthesis of 3β, 11α-bis (methoxymethoxy) col-5-en-24-al (compound 8) Compound 7 (750 mg, 1.61 mmol) was added to a suspension of PCC (520 mg, 2.42 mmol) in dichloromethane (20 ml). ) In dichloromethane (15 ml), and the mixture was stirred at room temperature for 5 hours in a stream of argon gas. After diluting the reaction solution with ether, silica gel (2.
After evaporating the solvent through a 5 g) short column, the residue is subjected to flash chromatography. The colorless solid substance obtained from the n-hexane-ethyl acetate (3: 1) eluate was recrystallized from n-hexane to give the desired product (682 mg, 91.4%) as colorless needles.
mp89−91℃.Anal.Calcd C28H46O5:C,72.69;H,10.02.Fou
nd:C,72.48;H,10.031 H−NMR（CDCl3）δ:0.69（3H,s,18−CH3）,0.95（3H,
d,J＝6Hz,21−CH3）,1.13（3H,s,19−CH3）,3.37（3H,
s,2×OCH3）,3.46（1H,m,3α−Ｈ）,3.88（1H,m,11β−
Ｈ）,4.68（4H,s,2×OCH2O）,5.41（1H,m,6−Ｈ）,9.77
（1H,t,J＝2Hz,CHO） 参考例８ ３β,11α−ビス（メトキシメトキシ）コレスタ−5,24
−ジエン（化合物９）の合成 イソプロピルトリフェニルホスフォニウムアイオダイ
ド（2.46g,5.70mmol）のテトラヒドロフラン（30ml）懸
濁液にフェニルリチウム［2Mシクロヘキサン：エーテル
（7:3）溶液;3.15ml］を加えアルゴンガス気流中室温に
て30分間撹拌した。更に化合物８（440mg、0.950mmol）
のテトラヒドロフラン（30ml）溶液を加え同温にて30分
撹拌した。反応液に水をエーテルで抽出した。有機層を
飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。
溶媒留去後、残渣をフラッシュクロマトグラフィーに付
した。ｎ−ヘキサン−酢酸エチル（5:1）溶出部より得
られる無色固形物質をメタノールより再結晶し、目的物
（446mg,95.9％）を無色針状晶として得た。mp89-91 ° C. Anal.Calcd C28H46O5: C, 72.69; H, 10.02.Fou
nd: C, 72.48; H, 10.03 1 H-NMR (CDCl3) δ: 0.69 (3H, s, 18-CH3), 0.95 (3H,
d, J = 6Hz, 21-CH3), 1.13 (3H, s, 19-CH3), 3.37 (3H,
s, 2 x OCH3), 3.46 (1H, m, 3α-H), 3.88 (1H, m, 11β-
H), 4.68 (4H, s, 2 x OCH2O), 5.41 (1H, m, 6-H), 9.77
(1H, t, J = 2Hz, CHO) Reference Example 8 3β, 11α-bis (methoxymethoxy) cholesta-5,24
Synthesis of Diene (Compound 9) To a suspension of isopropyltriphenylphosphonium iodide (2.46 g, 5.70 mmol) in tetrahydrofuran (30 ml) was added phenyllithium [2M cyclohexane: ether (7: 3) solution; 3.15 ml]. The mixture was stirred at room temperature for 30 minutes in an argon gas stream. Compound 8 (440 mg, 0.950 mmol)
Was added and the mixture was stirred at the same temperature for 30 minutes. Water was extracted into the reaction solution with ether. The organic layer was washed with brine and dried over anhydrous sodium sulfate.
After evaporation of the solvent, the residue was subjected to flash chromatography. The colorless solid substance obtained from the n-hexane-ethyl acetate (5: 1) eluate was recrystallized from methanol to give the desired product (446 mg, 95.9%) as colorless needles.
mp76−77℃.Anal.Calcd C31H52O4:C,76.18;H,10.72.Fou
nd:C,75.93;H,11.02.1 H−NMR（CDCl3）δ:0.69（3H,s,18−CH3）,0.96（3H,
d,J＝6Hz,21−CH3）,1.13（3H,s,19−CH3）,1.60,1.68
（each 3H,s,26−or 27−CH3）,3.37（6H,s,2×OCH3）,
3.41（1H,m,3α−Ｈ）,3.88（1H,m,11β−Ｈ）,4.07,4.
68（each 2H,s,OCH2O）,5.08（1H,m,24−Ｈ）,5.36（1
H,m,6−Ｈ） 参考例９ ３β,11α−ジヒドロキシコレスター5,24−ジエン（化
合物10）の合成 化合物９（574mg,1.17mmol）のテトラヒドロフラン
（105ml）溶液に6M塩酸（20ml）を加え室温にて１日撹
拌した。炭酸水素ナトリウムを加えて反応液を中和後、
酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、
無水硫酸ナトリウムで乾燥した。溶媒留去後、残渣フラ
ッシュクロマトグラフィーに付した。ｎ−ヘキサン−酢
酸エチル（1:2）溶出部より得られる無色固形物質を酢
酸エチルより再結晶し、目的物（420mg、89.4％）無色
針状晶として得た。mp76-77 ° C. Anal.Calcd C31H52O4: C, 76.18; H, 10.72.Fou
nd:. C, 75.93; H , 11.02 1 H-NMR (CDCl3) δ: 0.69 (3H, s, 18-CH3), 0.96 (3H,
d, J = 6Hz, 21-CH3), 1.13 (3H, s, 19-CH3), 1.60,1.68
(Each 3H, s, 26-or 27-CH3), 3.37 (6H, s, 2 × OCH3),
3.41 (1H, m, 3α-H), 3.88 (1H, m, 11β-H), 4.07,4.
68 (each 2H, s, OCH2O), 5.08 (1H, m, 24-H), 5.36 (1
H, m, 6-H) Reference Example 9 Synthesis of 3β, 11α-dihydroxycholester 5,24-diene (Compound 10) To a solution of compound 9 (574 mg, 1.17 mmol) in tetrahydrofuran (105 ml) was added 6 M hydrochloric acid (20 ml). The mixture was stirred at room temperature for one day. After neutralizing the reaction solution by adding sodium hydrogen carbonate,
Extracted with ethyl acetate. Wash the organic layer with saturated saline,
It was dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was subjected to flash chromatography. A colorless solid substance obtained from the n-hexane-ethyl acetate (1: 2) eluate was recrystallized from ethyl acetate to give the desired product (420 mg, 89.4%) as colorless needles.
mp167−169℃。Anal.Calcd C27H44O2:C,80.94;H,11.07.
Found:C,80.25;H,11.25.1 H−NMR（CDCl3）δ:0.70（3H,s,18−CH3）,0.95（3H,
d,J＝5Hz,21−CH3）,1.17（3H,s,19−CH3）,1.60,1.68
（each 3H,s,26−or 27−CH3）,3.54（1H,m,3α−Ｈ）,
4.02（1H,m,11β−Ｈ）,5.0（1H,m,24−Ｈ）,5.40（1H,
m,6−Ｈ）． 参考例10. コレスト−５−エン−３β,11α,25−トリオール（化合
物11）の合成 酢酸水銀（II）（406mg,1.27mmol9）水溶液1.5mlに化
合物10（340mg,0.848mmol）のテトラヒドロフラン（6m
l）溶液を加え室温にて６時間撹拌した。更に3M水酸化
ナトリウム水溶液（6ml）及び0.5M水素化ホウ素ナトリ
ウム（3M水酸化ナトリウム水溶液;6ml）を加え20分間撹
拌した。塩化ナトリウムを加え水層を飽和後、酢酸エチ
ルで抽出した。有機層を無水硫酸ナトリウムで乾燥し、
溶媒留去後、残渣をシリカゲルカラムクロマトグラフィ
ーに付した。ｎ−ヘキサン−酢酸エチル（1:3）溶出部
より目的物（276mg,77.7％）を白色固形物質として得
た。1 H−NMR（CDCl3−CH3OD（2:1）］δ:0.73（3H,s,18−CH
3）,0.98（3H,d,J＝6Hz,21−CH3）,1.17（3H,s,19−CH
3）,1.19（6H,s,26−,27−CH3）,3,96（1H,m,11β−
Ｈ）,5.36（1H,m,6−Ｈ）． 参考例11. ３β−ｔ−ブチルジメチルシリルオキシコレスト−５−
エン−11α,25−ジオール（化合物12）の合成 化合物11（175mg、0.418mmol）のジメチルホルムアミ
ド（1.5ml）溶液にｔ−ブチルジメチルクロロシラン（6
9.3mg、0.460mmol）、イミダゾール（71.1mg、1.05mmo
l）を加え室温にて30分撹拌した。反応液を酢酸エチル
で希釈後水洗し、無水硫酸ナトリウムで乾燥した。溶媒
留去後、残渣をシリカゲルカラムクロマトグラフィーに
付した。ｎ−ヘキサン−酢酸エチル（4:1）溶出部より
得られる無色固形物質をｎ−ヘキサン−エーテルより再
結晶し、目的物（179mg、80.4％）を無色鱗片状晶とし
て得た。mp 167-169 ° C. Anal.Calcd C27H44O2: C, 80.94; H, 11.07.
Found:. C, 80.25; H , 11.25 1 H-NMR (CDCl3) δ: 0.70 (3H, s, 18-CH3), 0.95 (3H,
d, J = 5Hz, 21-CH3), 1.17 (3H, s, 19-CH3), 1.60,1.68
(Each 3H, s, 26-or 27-CH3), 3.54 (1H, m, 3α-H),
4.02 (1H, m, 11β-H), 5.0 (1H, m, 24-H), 5.40 (1H,
m, 6-H). Reference Example 10. Synthesis of cholest-5-ene-3β, 11α, 25-triol (compound 11) Compound 1.5 (340 mg, 0.848 mmol) of tetrahydrofuran (6 m) was added to 1.5 ml of an aqueous solution of mercury (II) acetate (406 mg, 1.27 mmol 9).
l) The solution was added and stirred at room temperature for 6 hours. Further, a 3M aqueous sodium hydroxide solution (6 ml) and 0.5 M sodium borohydride (3 M aqueous sodium hydroxide solution; 6 ml) were added, and the mixture was stirred for 20 minutes. The aqueous layer was saturated with sodium chloride and extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate,
After evaporation of the solvent, the residue was subjected to silica gel column chromatography. The target product (276 mg, 77.7%) was obtained as a white solid substance from the elution part of n-hexane-ethyl acetate (1: 3). 1 H-NMR (CDCl 3 —CH 3 OD (2: 1)] δ: 0.73 (3H, s, 18-CH
3), 0.98 (3H, d, J = 6 Hz, 21-CH3), 1.17 (3H, s, 19-CH
3), 1.19 (6H, s, 26-, 27-CH3), 3,96 (1H, m, 11β-
H), 5.36 (1H, m, 6-H). Reference Example 11. 3β-t-butyldimethylsilyloxycholest-5-
Synthesis of ene-11α, 25-diol (compound 12) A solution of compound 11 (175 mg, 0.418 mmol) in dimethylformamide (1.5 ml) was added to t-butyldimethylchlorosilane (6
9.3 mg, 0.460 mmol), imidazole (71.1 mg, 1.05 mmo
l) was added and the mixture was stirred at room temperature for 30 minutes. The reaction solution was diluted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was subjected to silica gel column chromatography. The colorless solid substance obtained from the n-hexane-ethyl acetate (4: 1) eluate was recrystallized from n-hexane-ether to give the desired product (179 mg, 80.4%) as colorless scaly crystals.
mp196−198℃.Anal.Calcd C33H60O3:C,74.38;H,11.35.F
ound C,73.79;H,11.62.1 H−NMR（CDCl3）δ:0.66［6H,s,OSi（CH3）２］,0.70
（3H,s,18−CH3）,0.89（9H,s,OSi−ｔ−Bu）,1.16（3
H,s,19−CH3）,1.21（6H.s.26−,27−CH3）,3.48（1H,
m,3α−Ｈ）,4.02（1H,m,11β−Ｈ）,5.33（1H,m,6−
Ｈ）． 参考例12 ３β−ｔ−ブチルジメチルシリルオキシコレスト−５−
エン−11α,25−ジオール−11−アセテート（化合物1
3）の合成 化合物12（110mg,0.206mmol）をピリジン−無水酢酸
（2:1,0.9ml）溶液に溶解し室温にて4.5時間撹拌した。
反応液に水を加えピリジンを濃縮後、エーテルで抽出し
た。有機層を水、５％炭酸水素ナトリウム水溶液、飽和
食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した。
溶媒留去後残渣をシリカゲルクロマトグラフィーに付し
た。ｎ−ヘキサン−酢酸エチル（4:1）溶出部より目的
物（110mg,92.7％）を無色無晶形物質として得た。1 H−NMR（CDCl3）δ:0.05［6H,s,OSi（CH3）２］,0.75
（3H,s,18−CH3）,0.88（9H,s,OSi−ｔ−Bu）,1.08（3
H,s,19−CH3）,1.21（6H,s,26−,27−CH3）,2.01（3H,
S,OCOCH3）,3.42（1H,m,3α−Ｈ）,5.04−5.42（2H,m,6
−,11β−Ｈ）． 参考例13 11α−アセトキン−３β−ｔ−ブチルジメチルシリルオ
キシ−５α,8α−（3,5−ジオキソ−４−フェニル−1,
2,4−トリアゾリジノ）コレスト−６−エン−25−オー
ル（化合物14）の合成 化合物13（47.4mg、0.083mmol）のｎ−ヘキサン溶液
にＮ−ブロモスクシンイミド（20.3mg,0.11mmol），
α，α′−アゾビス（イソブチロニトリル）（Ca,2mg）
を加え、アルゴンガス気流中20分間還流した。反応液を
氷冷し析出物を濾去した。溶媒を留去し残渣をキシレン
（2ml）に溶解した。γ−コリジン（0.2ml）を加えアル
ゴンガス気流中１時間還流した。反応液を酢酸エチルで
希釈後、水、冷５％塩酸、水、５％炭酸水素ナトリウム
水溶液、飽和食塩水で順次洗浄し、無水硫酸ナトリウム
で乾燥した。溶媒を留去し残渣をジクロロメタン（4m
l）に溶解した。2.5％４−フェニル−1,2,4−トリアゾ
リン−3.5−ジオンのジクロロメタン溶液を淡紅色が持
続するまで室温撹拌下に滴下した。溶媒を留去後、残渣
をプレパラティブTLC［展開溶媒:n−ヘキサン−酢酸エ
チル（3:1）,2回展開］で精製し、目的物（30.3mg,49.1
％）を無色固形物質として得た。1 H−NMR（CDCl3）δ:0.08,0.10［each 3H,s,OSi（CH3）
２］0.88［9H,s,OSiC（CH3）３］,1.20（6H,s,26−,27
−CH3）,20.4（3H,s,OCOCH3）,3.12（1H,dd,J＝14.6Hz,
9−Ｈ）,4.32（1H,m,3α−Ｈ）,4.86（1H,m,11β−
Ｈ）,6.26（2H,ABq,6−,7−Ｈ）,7,12−7.48（5H,m,phe
nyl−Ｈ）． 参考例14 ３β−ｔ−ブチルジメチルシリルオキシコレスター5,7
−ジエン−11α,25−ジオール（化合物15）の合成 リチウムアルミニウムヒドリド（100mg,2.64mmol）の
テトラヒドロフラン（4ml）懸濁液に化合物14（30.3mg,
0.041mmol）のテトラヒドロフラン（2ml）溶液を氷冷撹
拌下に滴下した。次いでアルゴンガス気流中1.5時間還
流した。反応液に酢酸エチル、10％水酸化ナトリウム水
溶液を加えて過剰のリチウムアルミニウムビドリドを分
解した後酢酸エチルで抽出した。有機層を飽和食塩水で
洗浄後無水硫酸ナトリウムで乾燥した。溶媒を留去し残
渣をフラッシュクロマトグラフィーに付した。ｎ−ヘキ
サン−酢酸エチル（4:1）溶出部より目的物（7.3mg,33.
9％）を無色油状物質として得た。1 H−MNR（CDCl3）δ:0.06,［6H,s,OSi（CH3）２］,0.62
（3H,s,18−CH3）,0.89［9H,s,OSiC（CH3）３］,3.54
（1H,m,3α−Ｈ）,4.16（1H,m,11β−Ｈ）,5.20−5.60
（2H,m,6−,7−Ｈ）． 実施例1. （5Z,7E）−３β−ｔ−ブチルジメチルシリルオキシ−
9,10−セココレスタ−5,7,10（19）−トリエン−11α,2
5−ジオール（化合物16）の合成 化合物15（7.3mg,0.014mmol）のエーテル（400ml）溶
液に氷冷下アルゴンガス気流中400W高圧水銀灯、バイコ
ールフィルターを用いて11秒光照射した。溶媒を留去後
残渣をエタノール（20ml）に溶解し、室温で７日間放置
した。溶媒を留去し残渣をプレパラティブHPLCに付し
た。ジクロロメタン−メタノール（200:3）溶出部より
目的物（2.43mg,33.3％）を無色油状物質として得た。mp 196-198 ° C. Anal.Calcd C33H60O3: C, 74.38; H, 11.35.F
. ound C, 73.79; H, 11.62 1 H-NMR (CDCl3) δ: 0.66 [6H, s, OSi (CH3) 2], 0.70
(3H, s, 18-CH3), 0.89 (9H, s, OSi-t-Bu), 1.16 (3
H, s, 19-CH3), 1.21 (6H.s.26-, 27-CH3), 3.48 (1H,
m, 3α-H), 4.02 (1H, m, 11β-H), 5.33 (1H, m, 6-
H). Reference Example 12 3β-t-butyldimethylsilyloxycholest-5-
Ene-11α, 25-diol-11-acetate (compound 1
Synthesis of 3) Compound 12 (110 mg, 0.206 mmol) was dissolved in a pyridine-acetic anhydride (2: 1, 0.9 ml) solution and stirred at room temperature for 4.5 hours.
Water was added to the reaction solution, pyridine was concentrated, and the mixture was extracted with ether. The organic layer was washed sequentially with water, a 5% aqueous sodium hydrogen carbonate solution and saturated saline, and dried over anhydrous sodium sulfate.
After evaporation of the solvent, the residue was subjected to silica gel chromatography. The desired product (110 mg, 92.7%) was obtained as a colorless amorphous substance from a fraction eluted with n-hexane-ethyl acetate (4: 1). 1 H-NMR (CDCl 3) δ: 0.05 [6H, s, OSi (CH 3) 2], 0.75
(3H, s, 18-CH3), 0.88 (9H, s, OSi-t-Bu), 1.08 (3
H, s, 19-CH3), 1.21 (6H, s, 26-, 27-CH3), 2.01 (3H,
S, OCOCH3), 3.42 (1H, m, 3α-H), 5.04-5.42 (2H, m, 6
-, 11β-H). Reference Example 13 11α-acetoquin-3β-t-butyldimethylsilyloxy-5α, 8α- (3,5-dioxo-4-phenyl-1,
Synthesis of 2,4-triazolidino) cholest-6-en-25-ol (Compound 14) N-bromosuccinimide (20.3 mg, 0.11 mmol) was added to an n-hexane solution of compound 13 (47.4 mg, 0.083 mmol).
α, α'-azobis (isobutyronitrile) (Ca, 2mg)
Was added and refluxed for 20 minutes in an argon gas stream. The reaction solution was cooled on ice and the precipitate was removed by filtration. The solvent was distilled off, and the residue was dissolved in xylene (2 ml). γ-collidine (0.2 ml) was added and the mixture was refluxed for 1 hour in an argon gas stream. The reaction solution was diluted with ethyl acetate, washed sequentially with water, cold 5% hydrochloric acid, water, 5% aqueous sodium hydrogen carbonate solution and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was diluted with dichloromethane (4 m
l) dissolved. A dichloromethane solution of 2.5% 4-phenyl-1,2,4-triazoline-3.5-dione was added dropwise with stirring at room temperature until the pink color persisted. After evaporating the solvent, the residue was purified by preparative TLC [developing solvent: n-hexane-ethyl acetate (3: 1), developing twice] to obtain the desired product (30.3 mg, 49.1 mg).
%) As a colorless solid. 1 H-NMR (CDCl3) δ : 0.08,0.10 [each 3H, s, OSi (CH3)
2] 0.88 [9H, s, OSiC (CH3) 3], 1.20 (6H, s, 26-, 27
−CH3), 20.4 (3H, s, OCOCH3), 3.12 (1H, dd, J = 14.6Hz,
9-H), 4.32 (1H, m, 3α-H), 4.86 (1H, m, 11β-
H), 6.26 (2H, ABq, 6-, 7-H), 7,12-7.48 (5H, m, phe
nyl-H). Reference Example 14 3, β-t-butyldimethylsilyloxycholester 5,7
Synthesis of -diene-11α, 25-diol (compound 15) Compound 14 (30.3 mg, suspension of lithium aluminum hydride (100 mg, 2.64 mmol) in tetrahydrofuran (4 ml) was added.
0.041 mmol) in tetrahydrofuran (2 ml) was added dropwise with stirring under ice cooling. Then, the mixture was refluxed in an argon gas stream for 1.5 hours. Ethyl acetate and a 10% aqueous sodium hydroxide solution were added to the reaction solution to decompose excess lithium aluminum hydride, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was subjected to flash chromatography. From the eluted part of n-hexane-ethyl acetate (4: 1), the desired product (7.3 mg, 33.
9%) as a colorless oil. 1 H-MNR (CDCl3) δ : 0.06, [6H, s, OSi (CH3) 2], 0.62
(3H, s, 18-CH3), 0.89 [9H, s, OSiC (CH3) 3], 3.54
(1H, m, 3α-H), 4.16 (1H, m, 11β-H), 5.20-5.60
(2H, m, 6-, 7-H). Example 1. (5Z, 7E) -3β-t-butyldimethylsilyloxy-
9,10-secocholesta-5,7,10 (19) -triene-11α, 2
Synthesis of 5-diol (compound 16) A solution of compound 15 (7.3 mg, 0.014 mmol) in ether (400 ml) was irradiated with light using a 400 W high-pressure mercury lamp and a Vycor filter in an argon gas stream under ice cooling for 11 seconds. After evaporating the solvent, the residue was dissolved in ethanol (20 ml) and left at room temperature for 7 days. The solvent was distilled off, and the residue was subjected to preparative HPLC. The desired product (2.43 mg, 33.3%) was obtained as a colorless oily substance from a dichloromethane-methanol (200: 3) eluate.
1H−NMR（CDCl3）δ:0.06,0.07［each 3H,s,CSi（CH3）
２］,0.57（3H,s,18−CH3）,0.89［9H.s,OSiC（CH3）
３］,0.97（3H,d,J＝6.1Hz,21−CH3）,1.21（6H,s,26
−,27−CH3,）,3.79−3.95（2H,m,3−,11β−Ｈ）,4.77
［1H,brs,19（Ｅ）−Ｈ］,5.01［1H,brs,19（Ｚ）−
Ｈ］,6.07（1H,d,J＝11.1Hz,7−Ｈ）,6.17（1H,d,J＝1
1.1Hz,6−Ｈ）． 実施例2. （5Z,7E）−３β−ｔ−ブチルジメチルシリルオキシ−
9,10−セココレスター5,7,10（19）−トリエン−11α,2
5−ジオール11−ヘミグルタレート（化合物17）の合成 化合物16（2.34mg、4.4μmol）のピリジン（0.1ml）
溶液に無水グルタル酸（102.8mg、09mmol）を加え室温
で11時間撹拌した。反応液に少量の水を加え、氷冷下で
１時間撹拌した。酢酸エチルで抽出し有機層を水洗後無
水硫酸ナトリウムで乾燥した。溶媒を留去後、残渣をプ
レパラティブTLC［展開溶媒：クロロホルム−メタノー
ル（15:1）］で精製し目的物（1.89mg,66.5％）を無色
油状物質として得た。 1 H-NMR (CDCl 3) δ: 0.06, 0.07 [each 3 H, s, CSi (CH 3)
2], 0.57 (3H, s, 18-CH3), 0.89 [9H.s, OSiC (CH3)
3], 0.97 (3H, d, J = 6.1 Hz, 21-CH3), 1.21 (6H, s, 26
−, 27-CH3,), 3.79−3.95 (2H, m, 3-, 11β-H), 4.77
[1H, brs, 19 (E) -H], 5.01 [1H, brs, 19 (Z)-
H], 6.07 (1H, d, J = 11.1 Hz, 7−H), 6.17 (1H, d, J = 1
1.1 Hz, 6-H). Example 2. (5Z, 7E) -3β-t-butyldimethylsilyloxy-
9,10-secocholester 5,7,10 (19) -triene-11α, 2
Synthesis of 5-diol 11-hemiglutarate (compound 17) Compound 16 (2.34 mg, 4.4 μmol) in pyridine (0.1 ml)
Glutaric anhydride (102.8 mg, 09 mmol) was added to the solution, and the mixture was stirred at room temperature for 11 hours. A small amount of water was added to the reaction solution, and the mixture was stirred under ice cooling for 1 hour. After extraction with ethyl acetate, the organic layer was washed with water and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by preparative TLC [developing solvent: chloroform-methanol (15: 1)] to obtain the desired product (1.89 mg, 66.5%) as a colorless oil.
1H−NMR（CDCl3）δ:0.07,0.08［each 3H,s,OSi（CH3）
２］,0.61（3H,s,18−CH3）,0.88［9H.s,OSiC（CH3）
３］,0.94（3H,d,J＝5.9Hz,21−CH3）,1.21（6H,s,26
−,27−CH3）,3.83（1H,m,3−Ｈ）,4.75［1H,brs,19
（Ｅ）−Ｈ］,4.96−5.05［2H,brs＋m,11β−,19（Ｚ）
−Ｈ］,6.11（2H,ABq,6−,7−Ｈ）． 実施例3. （5Z,7E）−9,10−セココレスター5,7,10（19）−トリ
エン−３β,11α,25−トリオール11−ヘミグルタレート
（化合物18）の合成 化合物17（1.89mg,2.9μmol）のテトラヒドロフラン
（0.1ml）溶液にテトラ−ｎ−ブチルアンモニウムフロ
リド（1Mテトラヒドロフラン溶液,0.09ml）を加え室温
で７時間撹拌した。反応液を酢酸エチルで希釈し、水、
飽和食塩水で洗浄後無水硫酸ナトリウムで乾燥した。溶
媒を留去後、残渣をプレパラティブTLC［展開溶媒：ク
ロロホルム−メタルトール（15:2）］で精製し、目的物
（0.99mg,63.2％）を無色油状物質として得た。 1 H-NMR (CDCl3) δ : 0.07,0.08 [each 3H, s, OSi (CH3)
2], 0.61 (3H, s, 18-CH3), 0.88 [9H.s, OSiC (CH3)
3], 0.94 (3H, d, J = 5.9 Hz, 21-CH3), 1.21 (6H, s, 26
−, 27−CH3), 3.83 (1H, m, 3-H), 4.75 [1H, brs, 19
(E) -H], 4.96-5.05 [2H, brs + m, 11β-, 19 (Z)
-H], 6.11 (2H, ABq, 6-, 7-H). Example 3. Synthesis of (5Z, 7E) -9,10-secocholester 5,7,10 (19) -triene-3β, 11α, 25-triol 11-hemiglutarate (compound 18) Compound 17 (1.89 mg, (2.9 μmol) in tetrahydrofuran (0.1 ml) was added with tetra-n-butylammonium fluoride (1 M solution in tetrahydrofuran, 0.09 ml) and stirred at room temperature for 7 hours. Dilute the reaction with ethyl acetate, add water,
After washing with saturated saline, the extract was dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by preparative TLC [developing solvent: chloroform-metaltol (15: 2)] to obtain the desired product (0.99 mg, 63.2%) as a colorless oily substance.
1H−NMR（CDCl3）δ:0.60（3H,s,18−CH3）,0.94（3H,
d,J＝5.4Hz,21−CH3）,1.21（6H,s,26−,27−CH3）,3.9
4（1H,m,3−Ｈ）,4.78［1H,brs,19（Ｅ）−Ｈ］,4.97
（1H,m,11β−H,）5.04［1H,brs,19（Ｚ）−Ｈ］,6.10
（1H,d,J＝11.2Hz,7−Ｈ）,6.20（1H,d,J＝11.2Hz,6−
Ｈ）． 実施例4. ３β−ｔ−ブチルジメチルシリルオキシ−11α−［イミ
ダソール−１−イルチオカルボニルオキシ］−コレスト
−５−エン−25−オール（化合物19）の合成 化合物12（18.5mg,0.035mmol）の1,2−ジクロロエタ
ン（1ml）溶液に1,1′−チオカルボニルジイミダゾール
（TCDI;25mg,0.14mmol）を加え２時間還流した。室温に
戻し同温で１夜撹拌後、更にTCDI（25mg,0.14mmol）を
加えて１時間還流した。溶媒を留去後残渣をフラッシュ
クロマトグラフィーに付した。トルエン−酢酸エチル
（3:1−1:1）溶出部より目的物（17.1mg,76.6％）を無
色固形物質として得た。1 H−NMR（CDCl3）δ:0.04（6H,s,OSi（CH3）２］,0.80
（3H,s,18−CH3）,0.87［9H,s,OSic（CH3）３］,1.16
（3H,s,19−CH3）,1.20（6H,s,26−,27−CH3）,3.41（1
H,m,3α−Ｈ）,5.37（1H,m,6−Ｈ）,6.00（1H,m,11β−
Ｈ）,7.04,7.64,8.31（each 1H,m,imidazole−Ｈ）． 実施例5. ３β−ｔ−ブチルジメチルシリルオキシコレスト−５−
エン−25−オール（化合物20）の合成 トリ−ｎ−ブチルチンヒドリド（0.128ml,0.46mmol）
をトルエン（1ml）に加え還流した。化合物19（17.1mg,
0.026mmol）のトルエン（1ml）溶液を約20分間を要し滴
下した。滴下終了後、１時間還流した。溶媒を留去し、
残渣フラッシュクロマトグラフィーに付した。ｎ−ヘキ
サン−酢酸エチル（8:1）溶出部より目的物（11.3mg,8
2.2％）を無色固形物質として得た。1 H−NMR（CDCl3）δ:0.06［6H,s,OSi（CH3）２］,0.68
（3H,s,18−CH3）,0.89［9H,s,OSic（CH3）３］,1.00
（3H,s,19−CH3）,1.21（6H,s,26−,27−CH3）,3.44（1
H,m,3α−Ｈ）,5.24（1H,m,6−Ｈ）． 実施例6. コレスト−５−エン−３β,25−ジオール（化合物21）
の合成 化合物20（10.5mg,0.02mmol）のテトラヒドロフラン
（0.2ml）溶液にテトラ−ｎ−ブチルアンモニウムフル
オリド（1Mテトラヒドロフラン溶液,0.2ml）を加え室温
で５時間撹拌した。テトラヒドロフランを留去し残渣を
酢酸エチルで希釈した。水、飽和食塩水で洗浄した後無
水硫酸ナトリウムで乾燥した。溶媒を留去後残渣をプレ
パラティブTLC［展開溶媒:n−ヘキサン−酢酸エチル
（2:1）］で精製し、目的物（6.1mg,74.5％）を無色固
形物質として得た。メタノールより再結晶し、無色針状
晶を得た。 1 H-NMR (CDCl3) δ : 0.60 (3H, s, 18-CH3), 0.94 (3H,
d, J = 5.4Hz, 21-CH3), 1.21 (6H, s, 26-, 27-CH3), 3.9
4 (1H, m, 3-H), 4.78 [1H, brs, 19 (E) -H], 4.97
(1H, m, 11β-H,) 5.04 [1H, brs, 19 (Z) -H], 6.10
(1H, d, J = 11.2Hz, 7−H), 6.20 (1H, d, J = 11.2Hz, 6−
H). Example 4. Synthesis of 3β-t-butyldimethylsilyloxy-11α- [imidasol-1-ylthiocarbonyloxy] -cholest-5-en-25-ol (Compound 19) Compound 12 (18.5 mg, 0.035 mmol) 1,1'-thiocarbonyldiimidazole (TCDI; 25 mg, 0.14 mmol) was added to a solution of 1,2-dichloroethane (1 ml), and the mixture was refluxed for 2 hours. After returning to room temperature and stirring overnight at the same temperature, TCDI (25 mg, 0.14 mmol) was further added, and the mixture was refluxed for 1 hour. After evaporation of the solvent, the residue was subjected to flash chromatography. The target product (17.1 mg, 76.6%) was obtained as a colorless solid substance from a toluene-ethyl acetate (3: 1-1: 1) eluate. 1 H-NMR (CDCl3) δ : 0.04 (6H, s, OSi (CH3) 2], 0.80
(3H, s, 18-CH3), 0.87 [9H, s, OSic (CH3) 3], 1.16
(3H, s, 19-CH3), 1.20 (6H, s, 26-, 27-CH3), 3.41 (1
H, m, 3α-H), 5.37 (1H, m, 6-H), 6.00 (1H, m, 11β-
H), 7.04, 7.64, 8.31 (each 1H, m, imidazole-H). Example 5. 3β-t-Butyldimethylsilyloxycholest-5-
Synthesis of ene-25-ol (compound 20) tri-n-butyltin hydride (0.128 ml, 0.46 mmol)
Was added to toluene (1 ml) and refluxed. Compound 19 (17.1 mg,
0.026 mmol) in toluene (1 ml) was added dropwise over about 20 minutes. After the addition was completed, the mixture was refluxed for 1 hour. Evaporate the solvent,
The residue was subjected to flash chromatography. The desired product (11.3 mg, 8: 1) was eluted from the n-hexane-ethyl acetate (8: 1) eluate.
2.2%) as a colorless solid. 1 H-NMR (CDCl 3) δ: 0.06 [6H, s, OSi (CH 3) 2], 0.68
(3H, s, 18-CH3), 0.89 [9H, s, OSic (CH3) 3], 1.00
(3H, s, 19-CH3), 1.21 (6H, s, 26-, 27-CH3), 3.44 (1
H, m, 3α-H), 5.24 (1H, m, 6-H). Example 6 Cholest-5-ene-3β, 25-diol (Compound 21)
To a solution of compound 20 (10.5 mg, 0.02 mmol) in tetrahydrofuran (0.2 ml) was added tetra-n-butylammonium fluoride (1 M solution in tetrahydrofuran, 0.2 ml), and the mixture was stirred at room temperature for 5 hours. Tetrahydrofuran was distilled off, and the residue was diluted with ethyl acetate. After washing with water and a saturated saline solution, it was dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by preparative TLC [developing solvent: n-hexane-ethyl acetate (2: 1)] to obtain the desired product (6.1 mg, 74.5%) as a colorless solid substance. Recrystallization from methanol gave colorless needles.
mp181.5−183.5℃1 H−NMR（CDCl3）δ:0.68（3H,s,18−CH3）,0.93（3H,
d,J＝6Hz,21−CH3）,1.01（3H,s,19−CH3）,1.21（6H,
s,26−,27−CH3）,3.48（1H,m,3α−Ｈ）,5.30（1H,m,6
−Ｈ）． mp,1H−NMRともに20（Ｒ）体の文献値＊と一致した。従
って今回合成した一連の化合物は20（Ｒ）配置であるこ
とが立証された。mp 181.5-183.5 ° C 1 H-NMR (CDCl3) δ: 0.68 (3H, s, 18-CH3), 0.93 (3H,
d, J = 6Hz, 21-CH3), 1.01 (3H, s, 19-CH3), 1.21 (6H,
s, 26-, 27-CH3), 3.48 (1H, m, 3α-H), 5.30 (1H, m, 6
-H). Both mp and 1 H-NMR agreed with the literature value * of the 20 (R) form. Therefore, a series of compounds synthesized this time was proved to have the 20 (R) configuration.
＊１）T.A.Narwid et al.,Helv,Chim,Acta,57,771（197
4）． ２）M.M.Midland and Y.C.Kwon,Tetrahedron Lett.,2
0,2077（1982）．* 1) TANarwid et al., Helv, Chim, Acta, 57 , 771 (197
Four). 2) MMMidland and YCKwon, Tetrahedron Lett., 2
0 , 2077 (1982).
───────────────────────────────────────────────────── フロントページの続き (58)調査した分野(Int.Cl.7，ＤＢ名) C07C 401/00 A61K 31/00 G01N 33/00 ＣＡ（ＳＴＮ) ＲＥＧＩＳＴＲＹ（ＳＴＮ)──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int. Cl. 7 , DB name) C07C 401/00 A61K 31/00 G01N 33/00 CA (STN) REGISTRY (STN)
Claims (1)
至５の整数を意味する。）で示されるビタミンD3の誘導
体。1. The compound of the general formula (I) (Wherein, R represents a hydrogen atom or a hydroxyl group, and n represents an integer of 1 to 5).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2206484A JP3066047B2 (en) | 1990-08-03 | 1990-08-03 | New vitamin D (lower 3) derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2206484A JP3066047B2 (en) | 1990-08-03 | 1990-08-03 | New vitamin D (lower 3) derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0491074A JPH0491074A (en) | 1992-03-24 |
| JP3066047B2 true JP3066047B2 (en) | 2000-07-17 |
Family
ID=16524141
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2206484A Expired - Fee Related JP3066047B2 (en) | 1990-08-03 | 1990-08-03 | New vitamin D (lower 3) derivatives |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3066047B2 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000053578A1 (en) * | 1999-03-11 | 2000-09-14 | Kuraray Co., Ltd. | Vitamin d derivatives and process for the preparation thereof |
| US8772476B2 (en) | 2011-10-28 | 2014-07-08 | Honeywell International Inc. | Gas and liquid phase catalytic Beckmann rearrangement of oximes to produce lactams |
-
1990
- 1990-08-03 JP JP2206484A patent/JP3066047B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0491074A (en) | 1992-03-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP3983796B2 (en) | Production of 3α-hydroxy-3β-substituted-pregnane | |
| KR102527821B1 (en) | 6.alpha.-alkyl-6,7-dione steroids as intermediates for the production of steroidal fxr modulators | |
| KR102526632B1 (en) | 5.beta.-6-alkyl-7-hydroxy-3-one steroids as intermediates for the production of steroidal fxr modulators | |
| EP2667876A2 (en) | Methods and compounds for preparing 3alpha-oxygen substituted steroids | |
| EP3848382B1 (en) | Intermediates for the synthesis of bile acid derivatives, in particular of obeticholic acid | |
| JPH0369919B2 (en) | ||
| CZ297316B6 (en) | Steroidal compounds and pharmaceutical composition containing thereof | |
| EA034739B1 (en) | 6-alpha.-alkyl-3,7-dione steroids as intermediates for the production of steroidal fxr modulators | |
| DE3921059A1 (en) | 11 (BETA) -ARYL-4-ESTRENE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICINAL PRODUCT | |
| JPH035400B2 (en) | ||
| JPH02268194A (en) | Novel 19-norsteroids having a carbon chain containing amide or carbamate functional group at 11bata position, their production and intermediates, use for remedy and composite | |
| US4284577A (en) | Novel vitamin D3 derivative and process for preparing the same | |
| AU725606B2 (en) | Process for the preparation of 17-esters of 9alpha,21- dihalo-pregnane-11beta,17alpha-diol-20-ones | |
| Zhou et al. | A stereoselective synthesis of squalamine | |
| EP0189951B1 (en) | New process for the preparation of certain steroids, especially intermediates for the preparation of proligestone and related compounds, and new intermediates formed in this process | |
| Burkhart et al. | Novel steroidal vinyl fluorides as inhibitors of steroid C17 (20) lyase | |
| US6768014B2 (en) | PROCESS FOR PREPARING 17α-ACETOXY-11β-[4-N,N(DIMETHYLAMINO)PHENYL]-21-METHOXY-19-NORPREGNA-4,9-DIENE-3,20-DIONE, INTERMEDIATES USEFUL IN THE PROCESS , AND PROCESSES FOR PREPARING SUCH INTERMEDIATES | |
| JP3066047B2 (en) | New vitamin D (lower 3) derivatives | |
| JP3037427B2 (en) | Starting compounds for producing calcitriol and its derivatives, methods for producing these starting compounds and intermediates for this method | |
| JPS6254317B2 (en) | ||
| EP0532562B1 (en) | PROCESS FOR PRODUCING 10$g(b)-H-STEROIDS | |
| JP2000503636A (en) | 17-Side-chain alkynyl- and 20-oxopregna derivatives of vitamin D, their preparation and pharmaceutical compositions | |
| Durán et al. | Synthesis of 6-thia analogs of the natural neurosteroid allopregnanolone | |
| JPS59122500A (en) | 16-ketoandrosten-17-dithioketals | |
| JPS6148497B2 (en) |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| LAPS | Cancellation because of no payment of annual fees |