JP3553110B2 - Vitamin D derivative and method for producing vitamin D derivative using the same - Google Patents

Description

（式中Ｒ_１は、水酸基を有していてもよい、直鎖あるいは分岐したＣ_４からＣ_９のアルキル基を表す。）
で示される化合物とこれを加水分解することによって一般式（ＩＩ）
【００７】
【化５】

（式中Ｒ_１は、水酸基を有していてもよい、直鎖あるいは分岐したＣ_４からＣ_９のアルキル基を表す。）
で示される２２−オキサビタミンＤ_３誘導体を製造する方法である。
【００８】
一般式（Ｉ）で示される化合物としては、
・１α，３β−ジアセチルオキシ−２０Ｓ−（３−ヒドロキシ−３−メチルブチルオキシ）−９，１０−セコプレグナ−５，７，１０（１９）−トリエン
・１α，３β−ジプロピオニルオキシ−２０Ｓ−（３−ヒドロキシ−３−メチルブチルオキシ）−９，１０−セコプレグナ−５，７，１０（１９）−トリエン
・１α，３β−ジブチリルオキシ−２０Ｓ−（３−ヒドロキシ−３−メチルブチルオキシ）−９，１０−セコプレグナ−５，７，１０（１９）−トリエン
・１α，３β−ジベンゾイルオキシ−２０Ｓ−（３−ヒドロキシ−３−メチルブチルオキシ）−９，１０−セコプレグナ−５，７，１０（１９）−トリエン
等があげられる。
【００９】
また、本発明は、これらの化合物の結晶をも包含する。本発明の結晶は、例えば、カラムクロマトグラフィー、高速液体クロマトグラフィー等の通常の方法で分離し、適宜選択した溶媒、例えば、ｎ−ヘキサン等の溶媒を用いて再結晶することにより得られる。本発明は、１α，３β−ジアセチルオキシ−２０Ｓ−（３−ヒドロキシ−３−メチルブチルオキシ）−９，１０−セコプレグナ−５，７，１０（１９）−トリエンのＸ線回析可能な良好な結晶を提供する。
【０１０】
本発明の化合物は、例えば特開昭６１−２６７５５０号公報記載の方法で製造された２２−オキサビタミンＤ誘導体の１位及び３位の水酸基を常法にしたがいアシル化して製造することができる。
【０１１】
また、本発明の化合物は、同公報記載の２２−オキサプロビタミンＤ誘導体の１位及び３位を常法にしたがいアシル化した後、光照射、熱異性化反応に付すことによっても製造することができる。
【０１２】
これらの反応におけるアシル化は、塩基性溶媒中酸無水物あるいは酸ハライドを反応する通常の方法で行うことができる。
【０１３】
塩基性溶媒としては、好ましくはピリジン、コリジン、トリエチルアミン等があげられる。
【０１４】
反応させる酸無水物としては、無水酢酸、無水プロピオン酸、無水酪酸、無水安息香酸等があげられる。酸ハライドとしては、塩化アセチル、塩化プロピオニル、塩化ブチリル、塩化ベンゾイル等があげられる。
【０１５】
一般式（ＩＩ）で示される化合物を製造するための加水分解反応は、溶媒中、アルカリ金属水酸化物等を用いて塩基性条件下で行われる。
【０１６】
溶媒としては、反応に不活性であればよく、好ましくは、メタノール、エタノール等のアルコール系溶媒が用いられる。
【０１７】
アルカリ金属水酸化物としては、水酸化リチウム、水酸化ナトリウム、水酸化カリウム等があげられ、これらを適度な濃度の水溶液として用いられる。
【０１８】
次に実施例で本発明をさらに詳しく説明するが、これにより本発明が限定されるものではない。
【０１９】
【実施例１】
１α，３β−ジアセチルオキシ−２０Ｓ−（３−ヒドロキシ−３−メチルブチルオキシ）−９，１０−セコプレグナ−５，７，１０（１９）−トリエンおよびその結晶の製造方法
【０２０】
１α，３β−ジヒドロキシ−２０Ｓ−（３−ヒドロキシ−３−メチルブチルオキシ）−９，１０−セコプレグナ−５，７，１０（１９）−トリエン４．８１ｇをピリジン２４ｍｌに溶解し、無水酢酸３．２ｍｌを加え、室温で２日間撹拌した。反応液を氷水５０ｍｌに加え、ヘキサン１２０ｍｌで抽出した。抽出液を５％塩酸５０ｍｌで２回、飽和炭酸水素ナトリウム水溶液５０ｍｌ、飽和食塩水５０ｍｌで洗浄後、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去して得られた粗結晶を４．１９ｇを蒸留したヘキサン２４ｍｌから再結晶して標記化合物４．１２ｇ（収率７１％）を得た。
【０２１】
融点：８８−８９℃
Ｘ線結晶回折（結晶データ）：ａ＝１６．３５９１（８）Å；ｂ＝６．９３０４（５）Å；ｃ＝１４．１３５２（８）Å；β＝７１．４９９（４）Å；Ｖ＝１５１９．７Å^３；空間群：Ｐ２_１（単斜晶系）：ｚ＝２；Ｄ（計算値）＝１．０９８ｇ／ｃｍ^３；線吸収係数＝５．６７５ｃｍ^−１［μ（ＣｕＫα）］
ＵＶ（ＥｔＯＨ）：λ_ｍａｘ＝２４９．８ｎｍ，λ＝２６６．８，２１０．９
ＩＲ（ＫＢｒ）ｃｍ^−１：３５０４．０７，２９７１．８０，２９３３．２３，１７３９．５０，１３８０．８０，１２２４．５９，１１５１．３１，１０８３．８１，９６２．３２
【０２２】
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：５．４７８（Ｈ−１，ｄ−ｄ：Ｊ１，２α＝３．９６；Ｊ１，２β＝６．２７），２．０７（Ｈ−２α：ｍ），１．９９（Ｈ−２β：ｍ），５．１７５（Ｈ−３，ｄ：Ｊ２ａ，３＝３．９６；Ｊ２ｂ，３＝８．２５；Ｊ２ａ，３＝３．９６；Ｊ２ｂ，３＝８．２５），２．６４３（Ｈ−４α，ｍ：Ｊ３，４ａ＝３．９６；Ｊ３，４ｂ＝７．９２；Ｊ４ａ，４ｂ＝１３．２０），２．３６１（Ｈ−４β，ｍ），６．３３８（Ｈ−６，ｄ：Ｊ６，７＝１１．２２），５．９３０（Ｈ−７，ｄ：Ｊ６，７＝１１．２２），１．９３（Ｈ−９α，ｍ），１．５１（Ｈ−１１，ｍ），１．８９（Ｈ−１２β，ｍ：Ｊ１１，１２′＝３．６０；１１′，１２′＝１２．５３；１２，１２′＝１２．５３），１．３１（Ｈ−１２α，ｍ：Ｊ１１１，１２′＝３．６０；１１′，１２′＝１２．５３；１２，１２′＝１２．５３），１．７６（Ｈ−１４，ｍ），２．８１７（Ｈ−１５α，ｍ），１．６８（Ｈ−１５β，ｍ：Ｊ１４，１５α＝３．３０；Ｊ１５α，１５β＝１１．２１），１．６８（Ｈ−１６β，ｍ），１．５４（Ｈ−１６α，ｍ），１．５３（Ｈ−１７，ｍ），０．５１２（Ｈ−１８，ｓ），５．３２１（Ｈ−１９α，ｄ：Ｊ＝０．３２），５．０３７（Ｈ−１９β，ｄ：Ｊ＝０．３２），３．２４５（Ｈ−２０，ｍ：Ｊ１７，２０＝７．５９；Ｊ２０，２１＝５．９４），１．１８９（Ｈ−２１，ｄ：Ｊ２０，２１＝５．９４），３．８３５（Ｈ−２３，ｍ），３．４８０（Ｈ−２３，ｍ：Ｊ２３，２４＝５．９４；Ｊ２３，２３＝９．２４），１．７３３（Ｈ−２４，ｄ−ｄ：Ｊ２３，２４＝５．６０），１．２３２（Ｈ−２６ ａｎｄ Ｈ−２７，ｓ），２．０４７（Ｈ−Ａｃ−Ｍｅ，ｓ），２．０３１（Ｈ−Ａｃ−Ｍｅ，ｓ）
【０２３】
^１３Ｃ−ＮＭＲ（ＣＤＣｌ_３）δ：１２．４５３（Ｃ１８），１８．８８６（Ｃ２１）２２．１０２（Ｃ１１），２１．１３２（Ａｃ−Ｍｅ），２１．２７５（Ａｃ−Ｍｅ），２３．２３４（Ｃ１６），２５．７３２（Ｃ９），２８．９８４（Ｃ１５），２９．１１０（Ｃ２６ ｏｒ Ｃ２７），２９．２９０（Ｃ２６ ｏｒ Ｃ２７），３６．８７３（Ｃ２），３９．５５０（Ｃ１２），４１．５２７（Ｃ４），４１．５６３（Ｃ２４），４４．８１５（Ｃ１３），５６．０４６（Ｃ１４），５７．０８８（Ｃ１７），６５．５６９（Ｃ２３），６９．３７９（Ｃ３），７０．３８５（Ｃ２５），７２．７５７（Ｃ１），７８．７９５（Ｃ２０），１１５．１１０（Ｃ１９），１１７．３９２（Ｃ７），１２４．９９３（Ｃ６），１３１．８９３（Ｃ１０），１４２．１７２（Ｃ５），１４２．６２１（Ｃ８），１６９．８４４（Ａｃ−ＣＯ），１７０．４１９（Ａｃ−ＣＯ）
【０２４】

【０２５】
【実施例２】
１α，３β−ジアセチルオキシ−２０Ｓ−（３−ヒドロキシ−３−メチルブチルオキシ）−９，１０−セコプレグナ−５，７，１０（１９）−トリエンおよびその結晶の製造方法
【０２６】
ｉ）１α，３β−ジアセチルオキシ−２０Ｓ−（３−ヒドロキシ−３−メチルブチルオキシ）プレグナ−５，７−ジエンの製造方法
【０２７】
１α，３β−ジヒドロキシ−２０Ｓ−（３−ヒドロキシ−３−メチルブチルオキシ）プレグナ−５，７−ジエン９．３ｇとジメチルアミノピリジン０．９３ｇをピリジン４６．６ｍｌに溶解し、撹拌しながら室温で無水酢酸４．６６ｍｌを加えた。３０分後、水１８０ｍｌを加え、室温で３０分間撹拌した。析出してきた結晶を濾取し、水１８０ｍｌで良く洗浄した。結晶を減圧乾燥（５０℃、３時間）する事により、標記化合物１０．０ｇ（収率８９％）を得た。
【０２８】
融点：８１−８４℃（アセトニトリルから再結晶）
ＩＲ（ＫＢｒ）ｃｍ^−１：３５１４，３４９８，３３８８，２９６６，２８７３，１７３９，１４６７，１４６２，１４３３，１３７１，１２３６，１１４９，１０９５，１０３０，９７０，９４３，６１７，６１５
【０２９】
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：０．６０（３Ｈ，ｓ，Ｈ−１８），１．００（３Ｈ，ｓ，Ｈ−１９），２．０４（３Ｈ，ｓ，Ａｃ），２．０６（３Ｈ，ｓ，Ａｃ），２．３−２．７（３Ｈ，ｍ），３．２−３．６（２Ｈ，ｍ），３．７−３．９（２Ｈ，ｍ），４．９−５．１（２Ｈ，ｍ），５．４−５．７（２Ｈ，ｍ）
【０３０】
ｉｉ）１α，３β−ジアセチルオキシ−２０Ｓ−（３−ヒドロキシ−３−メチルブチルオキシ）−９，１０−セコプレグナ−５，７，１０（１９）−トリエンおよびその結晶の製造方法
【０３１】
光反応用のセル中で、１α，３β−ジアセチルオキシ−２０Ｓ−（３−ヒドロキシ−３−メチルブチルオキシ）プレグナ−５，７−ジエン２３０ｍｇをテトラヒドロフラン（ＴＨＦ）２３０ｍｌに溶解した。この液を氷冷下、アルゴン雰囲気下で３分間光照射（４００Ｗ高圧水銀ランプ、ｖｙｃｏｒフィルター）した。反応液を５０ｍｌのＴＨＦで洗浄しながら容器を移し、１５０分間加熱還流した。反応液を濃縮し、分取用高速液体クロマトグラフィー（カラム：シリカゲル６０，溶媒；ｃ−ヘキサン：酢酸エチル＝４：１）によって精製し、ｎ−ヘキサンにより再結晶することにより標記化合物６０ｍｇ（収率２６％）を得た。
【０３２】
機器データは、実施例１と一致した。
【０３３】
【実施例３】
１α，３β−ジヒドロキシ−２０Ｓ−（３−ヒドロキシ−３−メチルブチルオキシ）−９，１０−セコプレグナ−５，７，１０（１９）−トリエンの製造方法
【０３４】
１α，３β−ジアセチルオキシ−２０Ｓ−（３−ヒドロキシ−３−メチルブチルオキシ）−９，１０−セコプレグナ−５，７，１０（１９）−トリエン４．０２ｇをメタノール２０ｍｌに溶解し、１Ｍ水酸化カリウム−メタノール溶液２０ｍｌを加え、氷水冷下、２時間撹拌した。反応液に飽和食塩水１００ｍｌを加え、酢酸エチル２００ｍｌとヘキサン４０ｍｌの混合液で抽出した。抽出液を純水２００ｍｌ、飽和食塩水１００ｍｌで洗浄後、氷水冷下、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、溶媒を減圧留去して油状の標記化合物３．４５ｇを得た。このものを酢酸エチル３３．５ｍｌに溶解し、３５℃にて加温撹拌しているところにヘキサン７７．０ｍｌを加えた後、２時間かけて２５℃まで放冷し、更に６時間撹拌晶折した。結晶を濾別し、イソプロピルエーテル３３．５ｍｌで洗浄後、１２時間真空乾燥して標記化合物の精結晶２．０６ｇ（収率６２％）を得た。
【０３５】
このものの純度は、高速液体クロマトグラフィー（逆相（ＯＤＳ）：溶媒；ＴＨＦ、水、アセトニトリルの混合）にて測定して、９９．６％であった。
【０３６】
機器データは、特開昭６１−２６７５５０号公報記載のデータと一致した。[0101]
[Industrial applications]
The present invention relates to a method for producing a 22-oxavitamin D derivative expected as a pharmaceutical and a 22-oxavitamin D derivative excellent in crystallinity.
[0092]
[Prior art]
Until now, 22-oxavitamin D derivatives have been produced, for example, by the method described in JP-A-61-267550. However, the resulting 22-oxavitamin D derivatives have low crystallinity and have a drawback that the purity varies. have. Further, this disadvantage is inherent to the 22-oxavitamin D derivative, and there is no such problem when producing a normal vitamin D derivative.
[0093]
[Problems to be solved by the invention]
The present invention has been made to provide a novel vitamin D derivative having high crystallinity, and at the same time, to provide a method for producing a 22-oxavitamin D derivative having high purity by using the same to overcome the conventional disadvantages. It is a thing.
[0093]
[Means for Solving the Problems]
The present inventors have made intensive studies and found that the 22-oxavitamin D derivative in which the hydroxyl groups at the 1- and 3-positions were protected with an acyl group has good crystallinity, and that the 22-oxavitamin D derivative obtained by hydrolyzing the compound is obtained. The oxavitamin D derivative was found to be extremely high in purity, and based on this finding, the present invention was achieved.
[0056]
That is, the present invention relates to a novel 22-oxavitamin D derivative represented by the general formula (I):
[0086]
Embedded image

(In the formula, R ₁ represents a linear or branched C ₄ to C ₉ alkyl group which may have a hydroxyl group.)
And a compound represented by the general formula (II)
007
Embedded image

(In the formula, R ₁ represents a linear or branched C ₄ to C ₉ alkyl group which may have a hydroxyl group.)
In a method for producing the 22-oxa-vitamin D ₃ derivative represented.
[0098]
As the compound represented by the general formula (I),
1α, 3β-diacetyloxy-20S- (3-hydroxy-3-methylbutyloxy) -9,10-secopregna-5,7,10 (19) -triene 1α, 3β-dipropionyloxy-20S- ( 3-hydroxy-3-methylbutyloxy) -9,10-secopregna-5,7,10 (19) -triene-1α, 3β-dibutyryloxy-20S- (3-hydroxy-3-methylbutyloxy)- 9,10-Secopregna-5,7,10 (19) -triene-1α, 3β-dibenzoyloxy-20S- (3-hydroxy-3-methylbutyloxy) -9,10-secopregna-5,7,10 (19) -triene and the like.
[0099]
The present invention also includes crystals of these compounds. The crystals of the present invention can be obtained by, for example, separating by a usual method such as column chromatography, high performance liquid chromatography or the like, and recrystallizing using a solvent selected as appropriate, for example, a solvent such as n-hexane. The present invention provides a good X-ray diffractometer for 1α, 3β-diacetyloxy-20S- (3-hydroxy-3-methylbutyloxy) -9,10-secopregna-5,7,10 (19) -triene. Provide crystals.
[0102]
The compound of the present invention can be produced, for example, by acylating the hydroxyl groups at the 1-position and 3-position of the 22-oxavitamin D derivative produced by the method described in JP-A-61-267550 according to a conventional method.
[0111]
The compound of the present invention can also be produced by subjecting a 22-oxaprovitamin D derivative described in the same publication to acylation at the 1-position and 3-position according to a conventional method, followed by light irradiation and thermal isomerization. Can be.
[0122]
The acylation in these reactions can be performed by a usual method of reacting an acid anhydride or an acid halide in a basic solvent.
[0113]
Preferred examples of the basic solvent include pyridine, collidine, triethylamine and the like.
[0141]
Examples of the acid anhydride to be reacted include acetic anhydride, propionic anhydride, butyric anhydride, benzoic anhydride and the like. Examples of the acid halide include acetyl chloride, propionyl chloride, butyryl chloride, benzoyl chloride and the like.
[0152]
The hydrolysis reaction for producing the compound represented by the general formula (II) is performed in a solvent under a basic condition using an alkali metal hydroxide or the like.
[0162]
The solvent may be any solvent as long as it is inert to the reaction, and preferably an alcoholic solvent such as methanol or ethanol is used.
[0173]
Examples of the alkali metal hydroxide include lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, and these are used as an aqueous solution having an appropriate concentration.
[0182]
Next, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.
[0119]
Embodiment 1
Method for producing 1α, 3β-diacetyloxy-20S- (3-hydroxy-3-methylbutyloxy) -9,10-secopregna-5,7,10 (19) -triene and crystals thereof
4.81 g of 1α, 3β-dihydroxy-20S- (3-hydroxy-3-methylbutyloxy) -9,10-secopregna-5,7,10 (19) -triene was dissolved in 24 ml of pyridine, and acetic anhydride was added. 2 ml was added and the mixture was stirred at room temperature for 2 days. The reaction solution was added to 50 ml of ice water, and extracted with 120 ml of hexane. The extract was washed twice with 50 ml of 5% hydrochloric acid, 50 ml of a saturated aqueous solution of sodium hydrogen carbonate and 50 ml of saturated saline, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the obtained crude crystals were recrystallized from 24 ml of hexane obtained by distillation of 4.19 g to obtain 4.12 g (yield 71%) of the title compound.
[0219]
Melting point: 88-89 ° C
X-ray crystal diffraction (crystal data): a = 16.3591 (8) Å; b = 6.9304 (5) Å; c = 14.1352 (8) Å; β = 71.499 (4) Å; V = 1519.7Å ³ ; Space group: P2 ₁ (monoclinic): z = 2; D (calculated value) = 1.098 g / cm ³ ; Linear absorption coefficient = 5.675 cm ^-1 [μ (CuKα)]
UV (EtOH): λ _max = 249.8 nm, λ = 266.8, 210.9
IR (KBr) cm- ¹ : 3504.07, 2971.80, 2933.23, 1739.50, 138.80, 1224.59, 1151.31, 1083.81, 962.32.
[0222]
¹ H-NMR (CDCl ₃ ) δ: 5.478 (H-1, dd: J1, 2α = 3.96; J1, 2 = 6.27), 2.07 (H−2α: m), 1.99 (H-2β: m), 5.175 (H-3, d: J2a, 3 = 3.96; J2b, 3 = 8.25; J2a, 3 = 3.96; J2b, 3 = 8 .25), 2.643 (H-4α, m: J3, 4a = 3.96; J3, 4b = 7.92; J4a, 4b = 13.20), 2.361 (H-4β, m), 6.338 (H-6, d: J6,7 = 11.22), 5.930 (H-7, d: J6,7 = 11.22), 1.93 (H-9α, m), 1 .51 (H-11, m), 1.89 (H-12β, m: J11, 12 '= 3.60; 11', 12 '= 12.53; 12, 12' = 12.53), 1 .31 (H-12 , M: J111, 12 '= 3.60; 11', 12 '= 12.53; 12, 12' = 12.53), 1.76 (H-14, m), 2.817 (H-15α , M), 1.68 (H-15β, m: J14, 15α = 3.30; J15α, 15β = 11.21), 1.68 (H-16β, m), 1.54 (H-16α, m), 1.53 (H-17, m), 0.512 (H-18, s), 5.321 (H-19α, d: J = 0.32), 5.037 (H-19β, d: J = 0.32), 3.245 (H-20, m: J17, 20 = 7.59; J20, 21 = 5.94), 1.189 (H-21, d: J20, 21 = 5.94), 3.835 (H-23, m), 3.480 (H-23, m: J23, 24 = 5.94; J23, 23 = 9.24), 1.733 ( H-24, dd: J23, 24 = 5.60), 1.232 (H-26 and H-27, s), 2.047 (H-Ac-Me, s), 2.031 (H -Ac-Me, s)
[0230]
¹³ C-NMR (CDCl ₃ ) δ: 12.453 (C18), 18.886 (C21) 22.102 (C11), 21.132 (Ac-Me), 21.275 (Ac-Me), 23. 234 (C16), 25.732 (C9), 28.984 (C15), 29.110 (C26 or C27), 29.290 (C26 or C27), 36.873 (C2), 39.550 (C12). , 41.527 (C4), 41.563 (C24), 44.815 (C13), 56.046 (C14), 57.088 (C17), 65.569 (C23), 69.379 (C3), 70.385 (C25), 72.757 (C1), 78.795 (C20), 115.110 (C19), 117.392 (C7), 124.993 (C6), 131.89 (C10), 142.172 (C5), 142.621 (C8), 169.844 (Ac-CO), 170.419 (Ac-CO)
[0242]

[0252]
Embodiment 2
Method for producing 1α, 3β-diacetyloxy-20S- (3-hydroxy-3-methylbutyloxy) -9,10-secopregna-5,7,10 (19) -triene and crystals thereof
i) Method for producing 1α, 3β-diacetyloxy-20S- (3-hydroxy-3-methylbutyloxy) pregna-5,7-diene
9.3 g of 1α, 3β-dihydroxy-20S- (3-hydroxy-3-methylbutyloxy) pregna-5,7-diene and 0.93 g of dimethylaminopyridine are dissolved in 46.6 ml of pyridine and stirred at room temperature. 4.66 ml of acetic anhydride was added. After 30 minutes, 180 ml of water was added, and the mixture was stirred at room temperature for 30 minutes. The precipitated crystals were collected by filtration and washed well with 180 ml of water. The crystals were dried under reduced pressure (50 ° C., 3 hours) to obtain 10.0 g (yield: 89%) of the title compound.
[0280]
Melting point: 81-84 ° C (recrystallized from acetonitrile)
IR (KBr) cm- ¹ : 3514, 3498, 3388, 2966, 2873, 1739, 1467, 1462, 1433, 1371, 1236, 1149, 1095, 1030, 970, 943, 617, 615.
[0292]
¹ H-NMR (CDCl ₃ ) δ: 0.60 (3H, s, H-18), 1.00 (3H, s, H-19), 2.04 (3H, s, Ac), 2.06 (3H, s, Ac), 2.3-2.7 (3H, m), 3.2-3.6 (2H, m), 3.7-3.9 (2H, m), 4.9 -5.1 (2H, m), 5.4-5.7 (2H, m)
[0301]
ii) 1α, 3β-Diacetyloxy-20S- (3-hydroxy-3-methylbutyloxy) -9,10-secopregna-5,7,10 (19) -triene and a method for producing crystals thereof
In a photoreaction cell, 230 mg of 1α, 3β-diacetyloxy-20S- (3-hydroxy-3-methylbutyloxy) pregna-5,7-diene was dissolved in 230 ml of tetrahydrofuran (THF). This solution was irradiated with light (400 W high-pressure mercury lamp, vycor filter) under an argon atmosphere under ice cooling for 3 minutes. The vessel was transferred while washing the reaction solution with 50 ml of THF, and heated under reflux for 150 minutes. The reaction solution is concentrated, purified by preparative high performance liquid chromatography (column: silica gel 60, solvent; c-hexane: ethyl acetate = 4: 1), and recrystallized from n-hexane to give the title compound (60 mg, yield). 26%).
[0332]
The device data was the same as in Example 1.
[0332]
Embodiment 3
Method for producing 1α, 3β-dihydroxy-20S- (3-hydroxy-3-methylbutyloxy) -9,10-secopregna-5,7,10 (19) -triene
4.02 g of 1α, 3β-diacetyloxy-20S- (3-hydroxy-3-methylbutyloxy) -9,10-secopregna-5,7,10 (19) -triene is dissolved in 20 ml of methanol, and 1M hydroxylated. 20 ml of a potassium-methanol solution was added, and the mixture was stirred for 2 hours under ice-water cooling. 100 ml of saturated saline was added to the reaction solution, and extracted with a mixed solution of 200 ml of ethyl acetate and 40 ml of hexane. The extract was washed with 200 ml of pure water and 100 ml of saturated saline, and dried over anhydrous magnesium sulfate under ice-cooling. After filtering off the drying agent, the solvent was distilled off under reduced pressure to obtain 3.45 g of the title compound as an oil. This was dissolved in 33.5 ml of ethyl acetate, and 77.0 ml of hexane was added to the mixture while heating and stirring at 35 ° C, and then allowed to cool to 25 ° C over 2 hours, and further stirred for 6 hours. did. The crystals were separated by filtration, washed with 33.5 ml of isopropyl ether, and dried under vacuum for 12 hours to obtain 2.06 g (yield: 62%) of purified crystals of the title compound.
[035]
Its purity was 99.6% as measured by high performance liquid chromatography (reverse phase (ODS): solvent: a mixture of THF, water and acetonitrile).
[0361]
The equipment data was consistent with the data described in JP-A-61-267550.

Claims (6)

General formula (I)

(In the formula, R ₁ represents a linear or branched C ₄ to C ₉ alkyl group which may have a hydroxyl group. R ₂ and R ₃ are the same or different and represent an acyl group.)
By hydrolyzing the compound represented by the general formula (II)

(In the formula, R ₁ represents a linear or branched C ₄ to C ₉ alkyl group which may have a hydroxyl group.)
Process for preparing 22-oxa-vitamin _{D 3} derivative represented in. The method according to claim 1, wherein the acyl group is a lower acyl group such as formyl, acetyl, propionyl, and butyroyl, or an aromatic acyl group such as benzoyl. 2. The method according to claim 1, wherein both acyl groups are acetyl. General formula (I)

(In the formula, R ₁ represents a linear or branched C ₄ to C ₉ alkyl group which may have a hydroxyl group. R ₂ and R ₃ may be the same or different and represent an acyl group.)
A compound represented by the formula: The compound according to claim 4, wherein the acyl group is a lower acyl group such as formyl, acetyl, propionyl, and butyroyl, or an aromatic acyl group such as benzoyl. The crystal of the compound according to claim 4, wherein both the acyl groups are acetyl and the alkyl groups are 3-hydroxy-3-methylbutyl groups.