JPS6224440B2 - - Google Patents
Info
- Publication number
- JPS6224440B2 JPS6224440B2 JP55111789A JP11178980A JPS6224440B2 JP S6224440 B2 JPS6224440 B2 JP S6224440B2 JP 55111789 A JP55111789 A JP 55111789A JP 11178980 A JP11178980 A JP 11178980A JP S6224440 B2 JPS6224440 B2 JP S6224440B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- hydroxy
- dioxocholester
- reaction
- trienes
- 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
Links
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 description 11
- 150000001875 compounds Chemical class 0.000 description 10
- -1 compound 25-hydroxy-3,24-dioxocholesta-1,4,6-trienes Chemical class 0.000 description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N 1,4-Benzenediol Natural products OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- COBWJLWODWIMFC-ZEEVKPRMSA-N (8s,9s,10r,13r,14s,17r)-17-[(2r)-6-hydroxy-6-methyl-5-oxoheptan-2-yl]-10,13-dimethyl-8,9,11,12,14,15,16,17-octahydrocyclopenta[a]phenanthren-3-one Chemical class C1=CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@@H](CCC(=O)C(C)(C)O)C)[C@@]1(C)CC2 COBWJLWODWIMFC-ZEEVKPRMSA-N 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 3
- 239000011647 vitamin D3 Substances 0.000 description 3
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 2
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 2
- 239000012670 alkaline solution Substances 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 2
- 238000001640 fractional crystallisation Methods 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 150000005671 trienes Chemical class 0.000 description 2
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- DNXUGBMARDFRGG-UHFFFAOYSA-N 3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile Chemical compound O=C1C=CC(=O)C(C#N)=C1C#N DNXUGBMARDFRGG-UHFFFAOYSA-N 0.000 description 1
- 125000002672 4-bromobenzoyl group Chemical group BrC1=CC=C(C(=O)*)C=C1 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- CYTYCFOTNPOANT-UHFFFAOYSA-N Perchloroethylene Chemical group ClC(Cl)=C(Cl)Cl CYTYCFOTNPOANT-UHFFFAOYSA-N 0.000 description 1
- 229930003316 Vitamin D Natural products 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000008378 aryl ethers Chemical class 0.000 description 1
- RTEXIPZMMDUXMR-UHFFFAOYSA-N benzene;ethyl acetate Chemical compound CCOC(C)=O.C1=CC=CC=C1 RTEXIPZMMDUXMR-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical group OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- MDHYEMXUFSJLGV-UHFFFAOYSA-N beta-phenethyl acetate Natural products CC(=O)OCCC1=CC=CC=C1 MDHYEMXUFSJLGV-UHFFFAOYSA-N 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 1
- 150000001841 cholesterols Chemical class 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000003232 p-nitrobenzoyl group Chemical group [N+](=O)([O-])C1=CC=C(C(=O)*)C=C1 0.000 description 1
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229950011008 tetrachloroethylene Drugs 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 235000005282 vitamin D3 Nutrition 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 229940021056 vitamin d3 Drugs 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
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)
- Steroid Compounds (AREA)
Description
【発明の詳細な説明】
本発明は、25―ヒドロキシ―３，24―ジオキソ
コレスタ―１，４，６―トリエン類及びその製造
法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to 25-hydroxy-3,24-dioxocholester-1,4,6-trienes and a method for producing the same.
更に詳細には、種々の活性型ビタミンD3の製
造中間体として極めて有用な新規化合物25―ヒド
ロキシ―３，24―ジオキソコレスタ―１，４，６
―トリエン類及びその製造法に関する。 More specifically, the novel compound 25-hydroxy-3,24-dioxocholester-1,4,6 is extremely useful as an intermediate for the production of various active vitamin D3 .
- Concerning trienes and their production methods.
従来、種々の活性型ビタミンD3の製造中間体
として、コレスタ―１，４，６―トリエン―３―
オン，25―ヒドロキシコレスタ―１，４，６―ト
リエン―３―オン，24，25―ジヒドロキシコレス
タ―１，４，６―トリエン―３―オン等が知られ
ている。本発明者等は文献未載の化合物である25
―ヒドロキシ―３，24―ジオキソコレスタ―１，
４，６―トリエン類も、種々の活性型ビタミン
D3製造中間体として有用であると考え、本発明
者等が先に提案した（特願昭54―15420）新規化
合物３β，25―ジヒドロキシ―24―オキソコレス
ト―５―エン類を用いて鋭意研究した結果、側鎖
にオキソ基及びヒドロキシル基を有するため、副
反応が起こり易い化合物であるにもかかわらず、
かかる３β，25―ジヒドロキシ―24―オキソコレ
スト―５―エン類を不活性溶媒中２，３―ジクロ
ル―５，６―ジシアノベンゾキノンと反応せしめ
ることによつて驚くべきことに、副反応が生起す
ることなく容易に25―ヒドロキシ―３，24―ジオ
キソコレスタ―１，４，６―トリエン類を得るこ
とができ、かかる化合物が活性型ビタミンD3の
中間体となり得るという事実を見出し本発明に到
達したものである。 Conventionally, cholester-1,4,6-triene -3- has been used as an intermediate for the production of various active vitamin D3.
One, 25-hydroxycholester-1,4,6-trien-3-one, 24,25-dihydroxycholester-1,4,6-trien-3-one, and the like are known. The present inventors discovered a compound that has not been published in the literature25
-Hydroxy-3,24-dioxocholester-1,
4,6-trienes are also active vitamins.
We conducted extensive research using the novel compound 3β,25-dihydroxy-24-oxocholest-5 - ene, which the present inventors had previously proposed (Japanese Patent Application No. 15420/1984), which we believed to be useful as an intermediate for the production of D3. As a result, although it is a compound that easily causes side reactions because it has an oxo group and a hydroxyl group in its side chain,
Surprisingly, by reacting such 3β,25-dihydroxy-24-oxocholest-5-enes with 2,3-dichloro-5,6-dicyanobenzoquinone in an inert solvent, a side reaction occurs. The present invention was achieved by discovering the fact that 25-hydroxy-3,24-dioxocholester-1,4,6-trienes can be easily obtained without any oxidation, and that such compounds can serve as intermediates for active vitamin D3 . It is.
すなわち本発明は、下記式〔〕、
〔式中、Ｒは水素原子である。〕
で表わされる25―ヒドロキシ―３，24―ジオキソ
コレスタ―１，４，６―トリエン類及びその製造
法である。上記25―ヒドロキシ―３，24―ジオキ
ソコレスタ―１，４，６―トリエン類は、本発明
者らが先に提案した新規化合物、３β，25―ジヒ
ドロキシ―24―オキソコレスト―５―エン類を用
いることにより初めて合成されたものである。本
発明により提供される上記式〔〕で表わされる
新規化合物25―ヒドロキシ―３，24―ジオキソコ
レスタ―１，４，６―トリエン類におけるＲは、
水素原子である。なお、本発明の新規化合物を製
造する際において、25位の水酸基を、保護基によ
り保護された水酸基として製造することができ
る。かかる水酸基の保護基としては、例えばアセ
チル基、プロパノイル基、ブタノイル基、ペンタ
ノイル基、シクロヘキサノイル基、クロロアセチ
ル基、ブロモアセチル基、ベンゾイル基、ｐ―ブ
ロモベンゾイル基、ｐ―ニトロベンゾイル基、エ
チルベンゾイル基、トルイル基等の炭素数１〜12
の脂肪族もしくは芳香族カルボン酸残基もしくは
それらのニトロ、ハロゲン、アルコキシ置換誘導
体又はトリメチルシリル基、ｔ―ブチルジメチル
シリル基等のトリアルキルシリル基又は２―テト
ラヒドロピラニル基、２―テトラヒドロフラニル
基等の２―環状エーテル基等を挙げることができ
る。 That is, the present invention provides the following formula [], [In the formula, R is a hydrogen atom. ] 25-Hydroxy-3,24-dioxocholester-1,4,6-trienes represented by the following and their production method. As the above 25-hydroxy-3,24-dioxocholest-1,4,6-trienes, 3β,25-dihydroxy-24-oxocholest-5-enes, which are new compounds previously proposed by the present inventors, can be used. It was first synthesized by In the novel compound 25-hydroxy-3,24-dioxocholesta-1,4,6-trienes represented by the above formula [] provided by the present invention, R is:
It is a hydrogen atom. In addition, when producing the novel compound of the present invention, the hydroxyl group at position 25 can be produced as a hydroxyl group protected with a protecting group. Examples of such hydroxyl-protecting groups include acetyl group, propanoyl group, butanoyl group, pentanoyl group, cyclohexanoyl group, chloroacetyl group, bromoacetyl group, benzoyl group, p-bromobenzoyl group, p-nitrobenzoyl group, and ethyl group. 1 to 12 carbon atoms such as benzoyl group and toluyl group
aliphatic or aromatic carboxylic acid residues or their nitro-, halogen-, or alkoxy-substituted derivatives, or trialkylsilyl groups such as trimethylsilyl group, t-butyldimethylsilyl group, or 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, etc. 2-cyclic ether group, etc. can be mentioned.
このような25―ヒドロキシ―３，24―ジオキソ
コレスタ―１，４，６―トリエン類としては、例
えば以下に挙げるものがある。 Examples of such 25-hydroxy-3,24-dioxocholesta-1,4,6-trienes include the following.
すなわち例えば、
(1) 25―ヒドロキシ―３，24―ジオキソコレスタ
―１，４，６―トリエン
などを挙げることができる。 For example, (1) 25-hydroxy-3,24-dioxocholesta-1,4,6-triene and the like can be mentioned.
しかして、本発明によれば、上記式〔〕で表
わされる新規な25―ヒドロキシ―３，24―ジオキ
ソコレスタ―１，４，６―トリエン類を製造する
方法が同様に提供される。 According to the present invention, there is also provided a method for producing the novel 25-hydroxy-3,24-dioxocholester-1,4,6-trienes represented by the above formula [].
すなわち、下記式（）
〔式中、Ｒは水素原子である。〕
で表わされる３β，25―ジヒドロキシ―24―オキ
ソコレスト―５―エン類を不活性溶媒中、２，３
―ジクロル―５，６―ジシアノベンゾキノンと反
応せしめることを特徴とする上記式〔〕で表わ
される25―ヒドロキシ―３，24―ジオキソコレス
タ―１，４，６―トリエン類を製造する方法であ
る。 In other words, the following formula () [In the formula, R is a hydrogen atom. ] 3β,25-dihydroxy-24-oxocholest-5-ene represented by 2,3
This is a method for producing 25-hydroxy-3,24-dioxocholesta-1,4,6-trienes represented by the above formula [], which is characterized by reacting with -dichloro-5,6-dicyanobenzoquinone.
上記式〔〕におけるＲは、前記式〔〕にお
ける場合と同じである。 R in the above formula [] is the same as in the above formula [].
本発明においては、上記式〔〕で表わされる
３β，25―ジヒドロキシ―24―オキソコレスト―
５―エン類を不活性溶媒中で２，３―ジクロル―
５，６―ジシアノベンゾキノンと反応せしめるこ
とにより行なわれる。不活性溶媒としては、反応
を阻害しないものであればよく、例えばヘキサ
ン、ヘプタン、シクロヘキサン、デカリン、メチ
ルシクロヘキサンの如き脂肪族炭化水素類、ベン
ゼン、トルエン、キシレン、エチルベンゼンの如
き、芳香族炭化水素類、テトラハイドロフラン、
ジオキサン、ジグライム、アニソール等の脂肪族
及び芳香族エーテル類、テトラクロルエタン、パ
ークロルエチレン等のハロゲン化炭化水素類、メ
チルエチルケトン、ペンタノン、シクロヘキサノ
ン、アセトフエノン等のケトン類、酢酸エチル、
酢酸ブチル等のエステル類を如ましいものとして
挙げることができる。これらのうち脂肪族及び芳
香族炭化水素並びにエーテル類が特に好ましく用
いられる。 In the present invention, 3β,25-dihydroxy-24-oxocholest-
5-enes in an inert solvent with 2,3-dichloro-
This is carried out by reaction with 5,6-dicyanobenzoquinone. Any inert solvent may be used as long as it does not inhibit the reaction, such as aliphatic hydrocarbons such as hexane, heptane, cyclohexane, decalin, and methylcyclohexane, and aromatic hydrocarbons such as benzene, toluene, xylene, and ethylbenzene. , tetrahydrofuran,
Aliphatic and aromatic ethers such as dioxane, diglyme, anisole, halogenated hydrocarbons such as tetrachloroethane and perchlorethylene, ketones such as methyl ethyl ketone, pentanone, cyclohexanone, acetophenone, ethyl acetate,
Preferred examples include esters such as butyl acetate. Among these, aliphatic and aromatic hydrocarbons and ethers are particularly preferably used.
本発明の方法を実施するに際して使用される
２，３―ジクロル―５，６―ジシアノベンゾキノ
ンは上記式〔〕で示されるコレステロール誘導
体に対して、１〜10倍当量が好適で特に好ましく
は、2.5〜５倍当量用いるのが良い。反応温度は
充分な速度で反応が進行し、副生成物が多量に生
成しない温度を用いることがよく、一般に70〜
200℃の温度で用いるのが好ましい。反応時間
は、反応温度や触媒量により左右されるが通常１
時間から50時間の範囲で行なわれる。目的物の単
離精製は、反応終了後反応により生じたハイドロ
キノン体が反応系より析出して得られる場合は
過、遠心分離、或いはデカンテーシヨン等の簡単
な手段により分離したのち生成物をカラムクロマ
トグラフイーで精製するか又はアルカリ水溶液で
洗浄し、分別結晶、カラムクロマトグラフイー等
の手段により精製される。ハイドロキノン体が反
応系より析出しない場合は反応溶媒を濃縮後、ア
ルミナクロマトグラフイーで処理するか又はアル
カリ水溶液で洗浄してハイドロキノン体を除きク
ロマトグラフイー又は分別結晶等の手段により容
易に精製することができる。 The 2,3-dichloro-5,6-dicyanobenzoquinone used in carrying out the method of the present invention is preferably 1 to 10 times equivalent to the cholesterol derivative represented by the above formula [], and particularly preferably 2.5 times It is preferable to use ~5 times the equivalent. The reaction temperature is preferably a temperature at which the reaction proceeds at a sufficient rate and does not produce large amounts of by-products, and is generally 70 to 70°C.
Preferably it is used at a temperature of 200°C. The reaction time depends on the reaction temperature and amount of catalyst, but is usually 1.
It will take place for a period of 50 hours. For isolation and purification of the target product, if the hydroquinone compound produced by the reaction is precipitated from the reaction system after the reaction is completed, it is separated by simple means such as filtration, centrifugation, or decantation, and then the product is separated in a column. It is purified by chromatography or washed with an alkaline aqueous solution, and then purified by means such as fractional crystallization and column chromatography. If hydroquinone does not precipitate from the reaction system, concentrate the reaction solvent and treat with alumina chromatography or wash with aqueous alkaline solution to remove the hydroquinone and easily purify by means such as chromatography or fractional crystallization. I can do it.
本発明の製造法により得られる目的物は上記式
〔〕で示される25―ヒドロキシ―３，24―ジオ
キソコレスター１，４，６―トリエン類であり、
これは丁度原料である相当する式〔〕で示され
る化合物の側鎖には何の変化も起つていないもの
に相当する。 The target product obtained by the production method of the present invention is 25-hydroxy-3,24-dioxocholester 1,4,6-trienes represented by the above formula [],
This corresponds to the compound represented by the corresponding formula [], which is a raw material, with no changes occurring in the side chain.
かくして本発明の上記式〔〕で表わされる25
―ヒドロキシ―３，24―ジオキソコレスタ―１，
４，６―トリエン類が製造されるが、かかる化合
物中に水酸基の保護基が存在する場合には、上記
反応に引き続き、該保護基を脱離することができ
る。この水酸基の脱離反応は、それ自体公知の反
応であり、例えば、保護基がアシル基の場合には
メタノール、エタノールの如き低級脂肪族アルコ
ールのアルカリ性溶液中で処理するか、あるいは
エーテル中LiAlH4等の水素化金属で処理すれば
よい。また例えば、保護基が水酸基の酸素原子と
結合してエーテル基を形成している場合は、還元
的にあるいは酸又はアルカリと接触せしめること
により容易に除去することができる。 Thus, 25 represented by the above formula [] of the present invention
-Hydroxy-3,24-dioxocholester-1,
4,6-trienes are produced, and if a hydroxyl protecting group is present in such a compound, the protecting group can be removed following the above reaction. This elimination reaction of the hydroxyl group is a known reaction per se. For example, when the protecting group is an acyl group, it is treated in an alkaline solution of a lower aliphatic alcohol such as methanol or ethanol, or LiAlH 4 in ether is used. It may be treated with a metal hydride such as. Further, for example, when the protecting group is bonded to the oxygen atom of the hydroxyl group to form an ether group, it can be easily removed reductively or by contacting with an acid or an alkali.
以上に詳述した如く、本発明によれば上記式
〔〕で表わされる25―ヒドロキシ―３，24―ジ
オキソコレスタ―１，４，６―トリエン類が得ら
れ、かかる化合物は種々の活性型ビタミンD3、
例えば１α，24，25―トリヒドロキシVD3，１
α，25―ジヒドロキシ―24―オキソVD3などの製
造中間体として極めて有用なものである。 As detailed above, according to the present invention, 25-hydroxy-3,24-dioxocholester-1,4,6-trienes represented by the above formula [] can be obtained, and such compounds can be used for various active forms of vitamin D. 3 ,
For example, 1α,24,25-trihydroxy VD 3 ,1
It is extremely useful as an intermediate in the production of α,25-dihydroxy-24-oxo VD 3 , etc.
以下に本発明を実施例によつて更に詳細に説明
する。 The present invention will be explained in more detail below using Examples.
実施例
３β，25―ジヒドロキシ―24―オキソコレスト
―５―エン11.17ｇ（26.9mM）を300mlのジオキ
サンに溶解し、加熱還流させ、２，３―ジクロル
―５，６―ジシアノベンゾキノン20.11ｇ
（88.6mM）を１時間ごとに２回に分けて加え
た。15時間加熱還流した後室温まで冷却し、生成
した固体を濾過し濾液を減圧下濃縮し、粗25―ヒ
ドロキシ―３，24―ジオキソコレスタ―１，４，
６―トリエン20.7ｇを得た。このものをアルミナ
を充填したカラムクロマトグラフイー（溶剤：ベ
ンゼン―酢エチ系）に付すことによつて25―ヒド
ロキシ―３，24―ジオキソコレスタ―１，４，６
―トリエン6.1ｇ（収率55％）を得た。このもの
の物性値は次の通りであつた。Example 3 11.17g (26.9mM) of β,25-dihydroxy-24-oxocholest-5-ene was dissolved in 300ml of dioxane, heated to reflux, and 20.11g of 2,3-dichloro-5,6-dicyanobenzoquinone was dissolved.
(88.6mM) was added in two portions every hour. After heating under reflux for 15 hours, it was cooled to room temperature, the solid produced was filtered, and the filtrate was concentrated under reduced pressure to obtain crude 25-hydroxy-3,24-dioxocholester-1,4,
20.7 g of 6-triene was obtained. By subjecting this product to column chromatography packed with alumina (solvent: benzene-ethyl acetate system), 25-hydroxy-3,24-dioxocholester-1,4,6
-6.1 g (yield 55%) of triene was obtained. The physical properties of this product were as follows.
IR（CHCl3；cm-1）：
3475，3025，2950，2875，1710，1660，1620
NMR（CDCl3，δppm）：
0.80（ｓ，3H，Ｃ―18―Hs），
1.21（ｓ，3H，Ｃ―19―Hs），
1.38（ｓ，6H，Ｃ―26，27―Hs），
6.00〜6.30（4H，ｍ，Ｃ―２，４，６，７―
Hs），
7.05（1H，ｄ，Ｊ＝10Hz，Ｃ―１―Ｈ）
高分解能マススペクトル：
M+＝410.2832
（計算値C27H38O3＝410.2821）IR (CHCl 3 ; cm -1 ): 3475, 3025, 2950, 2875, 1710, 1660, 1620 NMR (CDCl 3 , δppm): 0.80 (s, 3H, C-18-Hs), 1.21 (s, 3H, C-19-Hs), 1.38 (s, 6H, C-26, 27-Hs), 6.00~6.30 (4H, m, C-2, 4, 6, 7-
Hs), 7.05 (1H, d, J = 10Hz, C-1-H) High resolution mass spectrum: M + = 410.2832 (calculated value C 27 H 38 O 3 = 410.2821)
Claims (1)
コレスタ―１，４，６―トリエン。 ２ 下記式〔〕 〔式中、Ｒは水素原子である。〕 で表わされる３β，25―ジヒドロキシ―24―オキ
ソコレスト―５―エン類を不活性溶媒中、２，３
―ジクロル―５，６―ジシアノベンゾキノンと反
応せしめることを特徴とする下記式〔〕 〔式中、Ｒは水素原子である。〕 で表わされる25―ヒドロキシ―３，24―ジオキソ
コレスタ―１，４，６―トリエンの製造法。[Claims] 1. The following formula [] [In the formula, R is a hydrogen atom. ] 25-hydroxy-3,24-dioxocholester-1,4,6-triene. 2 The following formula [] [In the formula, R is a hydrogen atom. ] 3β,25-dihydroxy-24-oxocholest-5-ene represented by 2,3
-The following formula [] characterized by reacting with dichloro-5,6-dicyanobenzoquinone [In the formula, R is a hydrogen atom. ] A method for producing 25-hydroxy-3,24-dioxocholester-1,4,6-triene.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP11178980A JPS5738799A (en) | 1980-08-15 | 1980-08-15 | 25-hydroxy-3,24-dioxocholesta-1,4,6-trienes and their preparations |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP11178980A JPS5738799A (en) | 1980-08-15 | 1980-08-15 | 25-hydroxy-3,24-dioxocholesta-1,4,6-trienes and their preparations |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5738799A JPS5738799A (en) | 1982-03-03 |
| JPS6224440B2 true JPS6224440B2 (en) | 1987-05-28 |
Family
ID=14570190
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP11178980A Granted JPS5738799A (en) | 1980-08-15 | 1980-08-15 | 25-hydroxy-3,24-dioxocholesta-1,4,6-trienes and their preparations |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5738799A (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59160094A (en) * | 1983-03-03 | 1984-09-10 | Sanyo Electric Co Ltd | Fan |
| JPH0748954Y2 (en) * | 1988-04-20 | 1995-11-08 | 三和シヤツター工業株式会社 | Safety devices in electric shutters for buildings |
-
1980
- 1980-08-15 JP JP11178980A patent/JPS5738799A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5738799A (en) | 1982-03-03 |
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