JPH0362716B2 - - Google Patents
Info
- Publication number
- JPH0362716B2 JPH0362716B2 JP4039386A JP4039386A JPH0362716B2 JP H0362716 B2 JPH0362716 B2 JP H0362716B2 JP 4039386 A JP4039386 A JP 4039386A JP 4039386 A JP4039386 A JP 4039386A JP H0362716 B2 JPH0362716 B2 JP H0362716B2
- Authority
- JP
- Japan
- Prior art keywords
- acid
- ammonium
- hydroxycholenic
- ammonium salt
- alkali metal
- 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
- 239000002253 acid Substances 0.000 claims description 21
- 150000003863 ammonium salts Chemical class 0.000 claims description 15
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 14
- 239000004593 Epoxy Substances 0.000 claims description 11
- 229910052783 alkali metal Inorganic materials 0.000 claims description 11
- 150000001340 alkali metals Chemical class 0.000 claims description 11
- 150000003431 steroids Chemical class 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 238000000034 method Methods 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- HIAJCGFYHIANNA-QIZZZRFXSA-N 3b-Hydroxy-5-cholenoic acid Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@@H](CCC(O)=O)C)[C@@]1(C)CC2 HIAJCGFYHIANNA-QIZZZRFXSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- -1 ligroin Chemical compound 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 230000000704 physical effect Effects 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000003507 refrigerant Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- GRONZTPUWOOUFQ-UHFFFAOYSA-M sodium;methanol;hydroxide Chemical compound [OH-].[Na+].OC GRONZTPUWOOUFQ-UHFFFAOYSA-M 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 1
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 1
- KWIPUXXIFQQMKN-UHFFFAOYSA-N 2-azaniumyl-3-(4-cyanophenyl)propanoate Chemical compound OC(=O)C(N)CC1=CC=C(C#N)C=C1 KWIPUXXIFQQMKN-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 239000004254 Ammonium phosphate Substances 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- OFHCOWSQAMBJIW-AVJTYSNKSA-N alfacalcidol Chemical class C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C OFHCOWSQAMBJIW-AVJTYSNKSA-N 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940090948 ammonium benzoate Drugs 0.000 description 1
- SWLVFNYSXGMGBS-UHFFFAOYSA-N ammonium bromide Chemical compound [NH4+].[Br-] SWLVFNYSXGMGBS-UHFFFAOYSA-N 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 235000012501 ammonium carbonate Nutrition 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 229910000148 ammonium phosphate Inorganic materials 0.000 description 1
- 235000019289 ammonium phosphates Nutrition 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- WWLOCCUNZXBJFR-UHFFFAOYSA-N azanium;benzenesulfonate Chemical compound [NH4+].[O-]S(=O)(=O)C1=CC=CC=C1 WWLOCCUNZXBJFR-UHFFFAOYSA-N 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
- TXHIDIHEXDFONW-UHFFFAOYSA-N benzene;propan-2-one Chemical compound CC(C)=O.C1=CC=CC=C1 TXHIDIHEXDFONW-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
- 238000007664 blowing Methods 0.000 description 1
- 239000011612 calcitriol Substances 0.000 description 1
- GMRQFYUYWCNGIN-NKMMMXOESA-N calcitriol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-NKMMMXOESA-N 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- OQNGCCWBHLEQFN-UHFFFAOYSA-N chloroform;hexane Chemical compound ClC(Cl)Cl.CCCCCC OQNGCCWBHLEQFN-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011647 vitamin D3 Substances 0.000 description 1
- 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 1
Landscapes
- Steroid Compounds (AREA)
Description
【発明の詳細な説明】
＜産業上の利用分野＞
本発明は、1α−ヒドロキシコレン酸及びその
製造法に関する。さらに詳細には、本発明は1α
位に水酸基を有する1α−ヒドロキシコレン酸及
びその製造法に関する。本発明で提供される1α
−ヒドロキシコレン酸は、1α−ヒドロキシビタ
ミンＤ誘導体類を合成する際の中間体として有用
な化合物である。DETAILED DESCRIPTION OF THE INVENTION <Industrial Field of Application> The present invention relates to 1α-hydroxycholenic acid and a method for producing the same. More specifically, the present invention provides 1α
This invention relates to 1α-hydroxycholenic acid having a hydroxyl group at the hydroxyl position and a method for producing the same. 1α provided by the present invention
-Hydroxycholenic acid is a compound useful as an intermediate in the synthesis of 1α-hydroxyvitamin D derivatives.
＜従来の技術＞
本発明で提供される1α−ヒドロキシコレン酸
は、本発明者の知るかぎり文献未載の新規化合物
であり、また、前記式［］で表わされる１，２
−エポキシステロイドを液体アンモニアの存在下
アルカリ金属及びアンモニウム塩と反応せしめる
ことを特徴とする1α−ヒドロキシコレン酸の製
造法についても知られていない。<Prior art> 1α-hydroxycholenic acid provided by the present invention is a novel compound that has not been published in any literature as far as the inventors know, and is a 1,2 compound represented by the above formula [ ].
- There is also no known process for producing 1α-hydroxycholenic acid, which is characterized by reacting an epoxy steroid with an alkali metal and an ammonium salt in the presence of liquid ammonia.
＜発明が解決しようとする問題点＞
本発明者らは、1α−ヒドロキシコレン酸を得
ることを目的として鋭意研究した結果、コレン酸
を酸化して対応する１，４，６−トリエン−３−
オン体とし、次いでアルカリの存在下過酸化水素
水で処理し、１，２−エポキシステロイドとし、
これを液体アンモニアの存在下アルカリ金属及び
アンモニウム塩と反応せしめることによつて目的
とする1α−ヒドロキシコレン酸が得られること
を見出し、本発明に到達したものである。<Problems to be Solved by the Invention> As a result of intensive research aimed at obtaining 1α-hydroxycholenic acid, the present inventors oxidized cholenic acid to obtain the corresponding 1,4,6-triene-3-
1,2-epoxy steroid by treatment with hydrogen peroxide solution in the presence of an alkali,
The present invention was achieved by discovering that the desired 1α-hydroxycholenic acid could be obtained by reacting this with an alkali metal and an ammonium salt in the presence of liquid ammonia.
しかして本発明の目的は、1α位に水酸基を有
する1α−ヒドロキシコレン酸及びその製造法を
提供することにある。 Therefore, an object of the present invention is to provide 1α-hydroxycholenic acid having a hydroxyl group at the 1α position and a method for producing the same.
＜問題点を解決するための手段＞
本発明によれば、下記式［］
で表わされる1α−ヒドロキシコレン酸及びその
製造法が提供される。<Means for solving the problem> According to the present invention, the following formula [] 1α-Hydroxycholenic acid represented by: and a method for producing the same are provided.
1α−ヒドロキシコレン酸は、下記式［］
で表わされる１，２−エポキシステロイドを液体
アンモニアの存在下アルカリ金属及びアンモニウ
ム塩と反応せしめることによつて得られる。 1α-Hydroxycholenic acid is expressed by the following formula [] It is obtained by reacting a 1,2-epoxy steroid represented by the formula with an alkali metal and an ammonium salt in the presence of liquid ammonia.
本発明の方法に用いられる１，２−エポキシス
テロイドは、コレン酸の酸化次いでエポキシ化す
ることによつて得ることができる。 The 1,2-epoxy steroid used in the method of the invention can be obtained by oxidation of cholenic acid followed by epoxidation.
本発明方法において用いられる液体アンモニア
には特に制限はないが、あらかじめ蒸留精製等を
して水分を出来るだけ除いたものが好ましく用い
られる。その使用量は、１，２−エポキシステロ
イドに対し重量で５〜500倍、特に好ましくは10
〜200倍で用いるのが良い。 The liquid ammonia used in the method of the present invention is not particularly limited, but it is preferably used that has been purified by distillation or the like to remove as much water as possible. The amount used is 5 to 500 times the weight of the 1,2-epoxy steroid, particularly preferably 10
It is best to use ~200x magnification.
また、使用されるアルカリ金属とは例えばリチ
ウム、ナトリウム等が好ましく用いられる。その
使用量は、１，２−エポキシステロイドに対し過
剰に用いられる。 Further, the alkali metal used is preferably lithium, sodium, etc., for example. The amount used is in excess of the 1,2-epoxy steroid.
すなわち、５〜250倍量（原子対当量倍）特に
好ましくは10〜200倍量で用いられる。 That is, it is used in an amount of 5 to 250 times (atomic equivalent times), particularly preferably 10 to 200 times.
本発明の方法においては、反応を円滑にすすめ
るために１，２−エポキシステロイドを溶解する
有機溶媒を用いるのが好ましい。 In the method of the present invention, it is preferable to use an organic solvent that dissolves the 1,2-epoxy steroid in order to facilitate the reaction.
このような有機溶媒としては、例えばエチルエ
ーテル、テトラヒドロフラン、ジオキサン、１，
２−ジメトキシエタン等のエーテル類、リグロイ
ン、ペンタン、ヘキサン、シクロヘキサン等の脂
肪族炭化水素類あるいはこれらの任意の２種以上
の混合溶媒を好ましいものとしてあげることがで
きる。 Examples of such organic solvents include ethyl ether, tetrahydrofuran, dioxane, 1,
Preferred examples include ethers such as 2-dimethoxyethane, aliphatic hydrocarbons such as ligroin, pentane, hexane, and cyclohexane, and mixed solvents of two or more of these.
これらの溶媒は、使用する液体アンモニアに対
し等容量以上で用いるのが好ましい。 These solvents are preferably used in an amount equal to or more than the same volume as the liquid ammonia used.
本発明方法においては、さらにアンモニウム塩
が用いられる。アンモニウム塩はプロトン供与体
として作用するものである。アンモニウム塩とし
ては、有機酸のアンモニウム塩、無機酸のアンモ
ニウム塩のいずれでも用いることができる。 In the method of the present invention, further ammonium salts are used. Ammonium salts act as proton donors. As the ammonium salt, either an organic acid ammonium salt or an inorganic acid ammonium salt can be used.
これらの具体例としては、例えば塩化アンモニ
ウム、臭化アンモニウム、炭酸アンモニウム、硫
酸アンモニウム、リン酸アンモニウム、リン酸水
素アンモニウム、酢酸アンモニウム、ギ酸アンモ
ニウム、安息香酸アンモニウム、ベンゼンスルホ
ン酸アンモニウム等を挙げることができる。これ
らのうち、特に塩化アンモニウムの如き無機酸の
アンモニウム塩が好ましい。これらアンモニウム
塩の使用量は用いたアルカリ金属に対し等モル以
上、好ましくは等モル〜10倍モルの範囲である。 Specific examples of these include ammonium chloride, ammonium bromide, ammonium carbonate, ammonium sulfate, ammonium phosphate, ammonium hydrogen phosphate, ammonium acetate, ammonium formate, ammonium benzoate, ammonium benzenesulfonate, and the like. Among these, ammonium salts of inorganic acids such as ammonium chloride are particularly preferred. The amount of these ammonium salts to be used is at least equimolar, preferably in the range of equimolar to 10 times the molar amount of the alkali metal used.
アンモニウム塩の添加方法により、本発明方法
の実施態様を分ければ、以下の如く分けられる。
これらのいずれの態様も採用しうる。 The embodiments of the method of the present invention can be divided into the following types depending on the method of adding the ammonium salt.
Any of these embodiments may be adopted.
(1) 液体アンモニアとアルカリ金属との系に１，
２−エポキシステロイドを加えたのち、アンモ
ニウム塩を加える。この際、アンモニウム塩を
２回以上に分割して少量ずつ反応系に添加する
のがより好ましい。(1) In the system of liquid ammonia and alkali metal, 1,
After adding the 2-epoxy steroid, add the ammonium salt. At this time, it is more preferable to divide the ammonium salt into two or more portions and add them little by little to the reaction system.
(2) 液体アンモニアとアルカリ金属の系に最初か
ら少割合の（望ましくは、使用したアルカリ金
属の0.7倍モル以下の）アンモニウム塩を添加
しておき、これに１，２−エポキシステロイド
を加え、次いで残りのアンモニウム塩を添加す
る。(2) Add a small proportion of ammonium salt (preferably 0.7 times the mole or less of the alkali metal used) to the system of liquid ammonia and alkali metal from the beginning, add 1,2-epoxy steroid to this, Then add the remaining ammonium salt.
(3) 液体アンモニウムとアルカリ金属との系に
１，２−エポキシステロイドとアンモニウム塩
とを同時に少量ずつ添加する。(3) A 1,2-epoxy steroid and an ammonium salt are simultaneously added little by little to a system of liquid ammonium and an alkali metal.
これらの方法のうち(1)の方法が特に好ましい。
反応温度は通常−80℃〜反応系中における液体ア
ンモニアの還流温度以下の温度で行われる。 Among these methods, method (1) is particularly preferred.
The reaction temperature is usually -80°C to below the reflux temperature of liquid ammonia in the reaction system.
また、前述のプロトン供与体をすべて添加した
のちは、通常液体アンモニアの還流下過剰に使用
したアルカリ金属が完全に分解されるまで反応を
行なうのが好ましい。 Further, after all of the above-mentioned proton donors have been added, it is usually preferable to carry out the reaction under reflux of liquid ammonia until the excess alkali metal is completely decomposed.
かくして上記式［］で表わされる1α−ヒド
ロキシコレン酸が製造されるが、反応混合物より
これを単離精製するには例えばカラムクロマトグ
ラフイー、高速液体クロマトグラフイー、或いは
再結晶等の通常の方法による。 In this way, 1α-hydroxycholenic acid represented by the above formula [] is produced, but it can be isolated and purified from the reaction mixture by conventional methods such as column chromatography, high performance liquid chromatography, or recrystallization. by.
＜発明の効果＞
本発明により提供される1α−ヒドロキシコレ
ン酸は、1α，25−ジヒドロキシビタミンD3−26，
23−ラクトンなどの活性型ビタミンD3の合成中
間体として極めて有用である。<Effects of the Invention> 1α-hydroxycholenic acid provided by the present invention contains 1α,25-dihydroxyvitamin D 3 -26,
It is extremely useful as an intermediate for the synthesis of active vitamin D3 such as 23-lactone.
以下に本発明の実施例により更に詳細に説明す
る。 The present invention will be explained in more detail below using examples.
参考例 １
コル−１，４，６−トリエン−３−オン−24−
オイツク酸の合成
10ｇのコレン酸を160ｍのジオキサンに溶解
し窒素気流下105〜110℃で加熱撹拌した。20ｇの
２，３−ジクロロ−５，６−ジシアノ−１，４−
ベンゾキノンを四等分し１時間毎に添加した。添
加後更に17時間反応を続けた。室温まで冷却後生
成物を濾過し、ジオキサンで洗浄後瀘液を濃縮し
た。Reference example 1 Col-1,4,6-trien-3-one-24-
Synthesis of Oitschic Acid 10 g of cholenic acid was dissolved in 160 m of dioxane and heated and stirred at 105 to 110°C under a nitrogen stream. 20 g of 2,3-dichloro-5,6-dicyano-1,4-
The benzoquinone was divided into four equal portions and added every hour. The reaction was continued for an additional 17 hours after the addition. After cooling to room temperature, the product was filtered, washed with dioxane, and the filtrate was concentrated.
この様にして得られた粗生成物をシリカゲルカ
ラム（メルク7734）で精製し（展開溶剤：クロロ
ホルム−ヘキサン系）7.16ｇのコル−１，４，６
−トリエン−３−オン−24−オイツク酸を得た。
収率73.2％
このものは以下の物性値を有していた。 The crude product thus obtained was purified using a silica gel column (Merck 7734) (developing solvent: chloroform-hexane system) and 7.16 g of col-1,4,6
-trien-3-one-24-oitsucic acid was obtained.
Yield: 73.2% This product had the following physical properties.
NMR（CDCl3：δppm）
0.790（3H，ｓ）0.948（3H，ｄ Ｊ＝5.9Hz）
1.198（3H，ｓ）5.9〜6.4（4H，ｍ）7.07（1H，ｄ
Ｊ＝10.3Hz）
UV（λmax EtOH）223nｍ，257nｍ，301nｍ
IR（KBr：cm-1）
2980，2945，1730，1650，1600
参考例 ２
1α，2α−エポキシコル−４，６−ジエン−３
−オン−24−オイツク酸の合成
29.25ｇのコル−１，４，６−トリエン−３−
オン−24−オイツク酸を1.461のメタノール及び
0.291のテトラヒドロフランに溶解した。77.2ml
の５％水酸化ナトリウム−メタノールを加え更に
40mlの30％過酸化水素水を加え室温で撹拌した。
２時間後更に20mlの５％水酸化ナトリウム−メタ
ノール、20mlの30％過酸化水素水を加え室温で16
時間放置した。７mlの酢酸を加え反応液のPHを６
とした後、約1/4に濃縮した。水を加え酢酸エチ
ルで抽出した。抽出液を飽和食塩水で洗浄し芒硝
より乾燥した。濾過濃縮後得られた粗生成物をシ
リカゲルカラム（メルク7734）で精製し（展開溶
剤：ベンゼン−酢酸エチル系）21.6ｇの1α，2α−
エポキシコル−４，６−ジエン−３−オン−24−
オイツク酸を得た。収率70.8％
このものは以下の物性値を有していた。NMR (CDCl 3 : δppm) 0.790 (3H, s) 0.948 (3H, d J = 5.9Hz)
1.198 (3H, s) 5.9~6.4 (4H, m) 7.07 (1H, d
J=10.3Hz) UV (λmax EtOH) 223nm, 257nm, 301nm IR (KBr: cm -1 ) 2980, 2945, 1730, 1650, 1600 Reference example 2 1α,2α-epoxycol-4,6-diene-3
Synthesis of -one-24-oitsucic acid 29.25 g of col-1,4,6-triene-3-
1.461 of methanol and
0.291 dissolved in tetrahydrofuran. 77.2ml
Add 5% sodium hydroxide-methanol and further
40 ml of 30% hydrogen peroxide solution was added and stirred at room temperature.
After 2 hours, add 20 ml of 5% sodium hydroxide-methanol and 20 ml of 30% hydrogen peroxide solution and stir at room temperature.
I left it for a while. Add 7 ml of acetic acid to reduce the pH of the reaction solution to 6.
After that, it was concentrated to about 1/4. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The crude product obtained after filtration and concentration was purified using a silica gel column (Merck 7734) (developing solvent: benzene-ethyl acetate system) to obtain 21.6 g of 1α, 2α-
Epoxycol-4,6-dien-3-one-24-
Oitsucic acid was obtained. Yield: 70.8% This product had the following physical properties.
NMR（CDCl3：δppm）
0.779（3H，ｓ）0.956（3H，ｄ Ｊ＝5.4Hz）
1.182（3H，ｓ）3.444（1H，dd Ｊ＝3.9＆2.0Hz）
3.585（1H，ｄ Ｊ＝3.9Hz）5.642（1H，ｄ Ｊ＝
2.0Hz）6.076（2H，ｓ）
UV（λmax EtOH）291nｍ
IR（KBr：cm-1）
2960，2930，1730，1645，1610
実施例 １
1α−ヒドロキシコレン酸の合成
滴下ロートとドライアイス冷却器を備えた２
の三つ口フラスコに、アセトン−ドライアイス冷
媒でフラスコを冷却しながら600mlのアンモニア
をトラツプした。12.6のリチウムを三等分し10分
毎に添加した。１時間撹拌後10.0ｇの1α，2α−エ
ポキシコル−４，６−ジエン−３−オン−24−オ
イツク酸を600mlのテトラヒドロフランに溶解し
た溶液を1.5時間で滴下した。更に1.5時間撹拌
後、充分乾燥した209ｇの塩化アンモニウム粉末
を１時間40分かけてゆつくり添加した。１時間撹
拌後、アセトン−ドライアイス冷媒を除去し一晩
窒素を吹き込んでアンモニアを留去した。殘渣に
水を加え更に酢酸エチルを加えた。6N−塩酸を
加え水層のPHを２とした後抽出しさ。抽出液を飽
和食塩水で洗浄し芒硝より乾燥した。濾過濃縮後
得られた粗生成物をシリカゲルカラム（メルク
7734）で精製し（展開溶剤：ベンゼン−アセトン
系）6.83ｇの1α−ヒドロキシコレン酸を得た。NMR (CDCl 3 : δppm) 0.779 (3H, s) 0.956 (3H, d J = 5.4Hz)
1.182 (3H, s) 3.444 (1H, dd J=3.9 & 2.0Hz)
3.585 (1H, d J = 3.9Hz) 5.642 (1H, d J =
2.0Hz) 6.076 (2H, s) UV (λmax EtOH) 291nm IR (KBr: cm -1 ) 2960, 2930, 1730, 1645, 1610 Example 1 Synthesis of 1α-hydroxycholenic acid Addition funnel and dry ice cooler Prepared 2
600 ml of ammonia was trapped in a three-necked flask while cooling the flask with an acetone-dry ice refrigerant. 12.6 liters of lithium was divided into three equal portions and added every 10 minutes. After stirring for 1 hour, a solution of 10.0 g of 1α,2α-epoxycol-4,6-dien-3-one-24-otucic acid dissolved in 600 ml of tetrahydrofuran was added dropwise over 1.5 hours. After stirring for an additional 1.5 hours, 209 g of thoroughly dried ammonium chloride powder was slowly added over 1 hour and 40 minutes. After stirring for 1 hour, the acetone-dry ice refrigerant was removed, and ammonia was distilled off by blowing nitrogen overnight. Water was added to the residue, and then ethyl acetate was added. Add 6N hydrochloric acid to adjust the pH of the aqueous layer to 2, then extract. The extract was washed with saturated brine and dried over sodium sulfate. The crude product obtained after filtration and concentration was transferred to a silica gel column (Merck
7734) (developing solvent: benzene-acetone system) to obtain 6.83 g of 1α-hydroxycholenic acid.
収率67.2％ このものは以下の物性値を有していた。Yield 67.2% This product had the following physical properties.
NMR（CDCl3：δppm）
0.67（3H，ｓ）1.1（3H，ｓ）3.5〜4.2（2H，ｍ）
5.3〜5.6（1H，ｍ）
IR（KBr：cm-1）3300，2930，1735。NMR (CDCl 3 : δppm) 0.67 (3H, s) 1.1 (3H, s) 3.5-4.2 (2H, m)
5.3-5.6 (1H, m) IR (KBr: cm -1 ) 3300, 2930, 1735.
Claims (1)
アンモニアの存在下、アルカリ金属及びアンモニ
ウム塩と反応せしめることを特徴とする下記式
［］ で表わされる1α−ヒドロキシコレン酸の製造法。[Claims] 1. The following formula [] 1α-Hydroxycholenic acid represented by 2 The following formula [] The following formula [] is characterized by reacting a 1,2-epoxy steroid represented by with an alkali metal and an ammonium salt in the presence of liquid ammonia. A method for producing 1α-hydroxycholenic acid represented by
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4039386A JPS62198698A (en) | 1986-02-27 | 1986-02-27 | 1alpha-hydroxycholeic acid and production thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4039386A JPS62198698A (en) | 1986-02-27 | 1986-02-27 | 1alpha-hydroxycholeic acid and production thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS62198698A JPS62198698A (en) | 1987-09-02 |
| JPH0362716B2 true JPH0362716B2 (en) | 1991-09-26 |
Family
ID=12579417
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP4039386A Granted JPS62198698A (en) | 1986-02-27 | 1986-02-27 | 1alpha-hydroxycholeic acid and production thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS62198698A (en) |
-
1986
- 1986-02-27 JP JP4039386A patent/JPS62198698A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS62198698A (en) | 1987-09-02 |
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