JPS62298572A - Purification of 1alpha-hydroxyvitamin d3 - Google Patents
Purification of 1alpha-hydroxyvitamin d3Info
- Publication number
- JPS62298572A JPS62298572A JP14368686A JP14368686A JPS62298572A JP S62298572 A JPS62298572 A JP S62298572A JP 14368686 A JP14368686 A JP 14368686A JP 14368686 A JP14368686 A JP 14368686A JP S62298572 A JPS62298572 A JP S62298572A
- Authority
- JP
- Japan
- Prior art keywords
- hydroxyvitamin
- mixture
- silyl ether
- 1alpha
- formulas
- 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.)
- Pending
Links
- OFHCOWSQAMBJIW-AVJTYSNKSA-N alfacalcidol 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)C[C@H](O)C1=C OFHCOWSQAMBJIW-AVJTYSNKSA-N 0.000 title claims abstract description 15
- 238000000746 purification Methods 0.000 title description 3
- 239000000203 mixture Substances 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 13
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 claims abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 3
- 125000003118 aryl group Chemical group 0.000 claims abstract description 3
- 238000004587 chromatography analysis Methods 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims 4
- 150000001875 compounds Chemical class 0.000 abstract description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 abstract description 7
- OFHCOWSQAMBJIW-AOSUDXALSA-N (1r,3s,5e)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-6-methylheptan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol 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)C[C@H](O)C1=C OFHCOWSQAMBJIW-AOSUDXALSA-N 0.000 abstract description 4
- 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 abstract description 3
- 239000003795 chemical substances by application Substances 0.000 abstract description 3
- 238000000926 separation method Methods 0.000 abstract description 3
- 239000000741 silica gel Substances 0.000 abstract description 3
- 229910002027 silica gel Inorganic materials 0.000 abstract description 3
- 238000006884 silylation reaction Methods 0.000 abstract description 3
- 229930003316 Vitamin D Natural products 0.000 abstract description 2
- 239000012442 inert solvent Substances 0.000 abstract description 2
- 235000019166 vitamin D Nutrition 0.000 abstract description 2
- 239000011710 vitamin D Substances 0.000 abstract description 2
- 150000003710 vitamin D derivatives Chemical class 0.000 abstract description 2
- 229940046008 vitamin d Drugs 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- -1 triphenylsilyl group Chemical group 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 101150041968 CDC13 gene Proteins 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- 150000005671 trienes Chemical group 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- JARXNQUBGBXALE-UHFFFAOYSA-N C(C)[SiH](CC)CC.Cl Chemical compound C(C)[SiH](CC)CC.Cl JARXNQUBGBXALE-UHFFFAOYSA-N 0.000 description 1
- 244000201986 Cassia tora Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000006371 metabolic abnormality Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- NCAIGTHBQTXTLR-UHFFFAOYSA-N phentermine hydrochloride Chemical compound [Cl-].CC(C)([NH3+])CC1=CC=CC=C1 NCAIGTHBQTXTLR-UHFFFAOYSA-N 0.000 description 1
- CASUWPDYGGAUQV-UHFFFAOYSA-M potassium;methanol;hydroxide Chemical compound [OH-].[K+].OC CASUWPDYGGAUQV-UHFFFAOYSA-M 0.000 description 1
- 238000004262 preparative liquid chromatography Methods 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- FGTJJHCZWOVVNH-UHFFFAOYSA-N tert-butyl-[tert-butyl(dimethyl)silyl]oxy-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C FGTJJHCZWOVVNH-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 235000005282 vitamin D3 Nutrition 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
- 229940021056 vitamin d3 Drugs 0.000 description 1
Abstract
Description
【発明の詳細な説明】
の１
本発明は医薬として有用な１α−ヒドロキシビタミンＤ
３の分離・精製法に関する。Detailed Description of the Invention Part 1: The present invention provides 1α-hydroxyvitamin D useful as a medicine.
Regarding the separation and purification method of No. 3.
′ の ′・−１Ｂが よＪ−、Ｆ、、 −１α−
ヒドロキシビタミンＤ３はビタミンＤの代謝異常に伴う
諸疾患の治療薬として有用な化合物である。この化合物
の合成法は近年多数知られている。例えば、コレステロ
ールを出発物質とする方法（特開昭４８−８２７５０号
、特開昭４９−９５９５６号）およびビタミンＤ３を出
発物質とする方法（特公表５４−５０００８０号）など
が代表的な合成法として挙げられる。しかしながらこれ
らの製法は、いずれも３β位に水酸基を有する化合物を
出発物質として、１α位に水酸基を導入する反応を用い
るため、１位の水酸基の配位の異なる１β−ヒドロキシ
ビタミンＤ３の副生が避けられない。また、１α−ヒド
ロキシビタミンＤ３のトリエン構造はシス体であるが反
応工程あるいは光または熱により、そのトリエン構造が
トランス体に異性化した１α−ヒドロキシ−５，６−ト
ランスビタミンＤ３が一部生成する。′ of ′・−1B is J−, F,, −1α−
Hydroxyvitamin D3 is a compound useful as a therapeutic agent for various diseases associated with vitamin D metabolic abnormalities. Many methods for synthesizing this compound have been known in recent years. For example, typical synthetic methods include a method using cholesterol as a starting material (Japanese Patent Application Laid-open No. 48-82750, JP-A No. 49-95956) and a method using vitamin D3 as a starting material (Japanese Patent Publication No. 54-500080). It is mentioned as. However, all of these production methods use a compound having a hydroxyl group at the 3β position as a starting material and use a reaction to introduce a hydroxyl group at the 1α position, so the by-product of 1β-hydroxyvitamin D3 with a different coordination of the hydroxyl group at the 1st position is produced. Inevitable. In addition, the triene structure of 1α-hydroxyvitamin D3 is the cis form, but during the reaction process or by light or heat, the triene structure is isomerized to the trans form, resulting in a portion of 1α-hydroxy-5,6-trans vitamin D3. .
これらの化合物が最終目的化合物である１α−ヒドロキ
シビタミンＤ３に混入した場合、再結晶あるいはカラム
クロマトグラフィーという通常の精製手段で完全に除去
するには、煩雑な手段の繰返しを必要とするほかそれに
伴う大幅な収量の減少が避けられなかった。If these compounds contaminate the final target compound, 1α-hydroxyvitamin D3, they cannot be completely removed by normal purification methods such as recrystallization or column chromatography, which requires repeated complicated steps and the associated A significant decrease in yield was inevitable.
本発明者はこれらの事情を鑑み鋭意研究した結果、一般
的に使用されるシリル化剤で水酸基をシリル化し、シリ
カゲルを主成分とする担体を用いたクロマトグラフィー
に付すことにより、これらの化合物が効率よく分離でき
ることを見い出し本発明に至った。As a result of intensive research in view of these circumstances, the present inventor has found that these compounds can be silylated with a commonly used silylating agent and subjected to chromatography using a carrier mainly composed of silica gel. It was discovered that efficient separation can be achieved, leading to the present invention.
［式中Ｒ１およびＲ２は各々同一または異なって一般式
：
一８ｉ −Ｒ４（式中Ｒ３，Ｒ４およびＲ５は各々同一
または異なって低級アルキル基またはアリール基を意味
する）で示される基である］で表される１α−ヒドロキ
シビタミンＤ３のシリルエーテル、１β−ヒドロキシビ
タミンＤ３のシリルエーテルおよび／または１α−ヒド
ロキシ−５，６−トランスビタミンＤ３のシリルエーテ
ルよりなる混合物をシリカゲル主成分とする担体を用い
たクロマトグラフィーに付しそれぞれの成分に分離せし
めることを特徴とする１α−ヒドロキシビタミンＤ３の
精製法に関する。[In the formula, R1 and R2 are each the same or different and are a group represented by the general formula: -R4 (wherein R3, R4 and R5 are the same or different and each means a lower alkyl group or an aryl group)] Using a carrier mainly composed of silica gel, a mixture of 1α-hydroxyvitamin D3 silyl ether, 1β-hydroxyvitamin D3 silyl ether and/or 1α-hydroxy-5,6-transvitamin D3 silyl ether represented by The present invention relates to a method for purifying 1α-hydroxyvitamin D3, which is characterized by subjecting it to chromatography to separate it into its respective components.
本発明において、１α−ヒドロキシビタミン島。In the present invention, 1α-hydroxyvitamin islet.
１β−ヒドロキシビタミンＤ３および／または１α−ヒ
ドロキシ−５，８−トランスビタミンＤ３よりなる混合
物のシリル化は常法により、例えば不活性溶媒中、塩基
の存在下一般的に用いられるシリル化剤を反応せしめる
ことにより行われる。The mixture consisting of 1β-hydroxyvitamin D3 and/or 1α-hydroxy-5,8-transvitamin D3 can be silylated by a conventional method, for example, by reacting a commonly used silylating agent in the presence of a base in an inert solvent. It is done by forcing.
一般式Ｉ、■および■におけるシリル基の代表的なもの
としては、例えばトリフェニルシリル基、トリメチルシ
リル基、トリエチルシリル基、ジメチルイソプロピルシ
リル基、ｔ−ブチルメチルシリル基等が挙げられるか本
発明の方法を実施するのに最も好ましいシリル基として
はトリメチルシリル基である。Typical examples of the silyl groups in general formulas I, (1) and (2) include triphenylsilyl group, trimethylsilyl group, triethylsilyl group, dimethylisopropylsilyl group, t-butylmethylsilyl group, etc. The most preferred silyl group for carrying out the process is trimethylsilyl.
このようにして、本発明の方法に付すシリル化混合物が
製造される。In this way, a silylation mixture is produced which is subjected to the process of the invention.
本発明の方法において、クロマトグラフィーの方式は特
に限定されないが、高速液体クロマトグラフィー、カラ
ムクロマトグラフィー、分取用薄層クロマトグラフィー
等を必要に応じて適宜使用することができる。展開溶媒
は、例えばｎ−ヘキサン、塩化メチレン、ベンゼン、エ
ーテル等を単独あるいは適宜組合せて用いられるが、特
に限定されるものではない。In the method of the present invention, the method of chromatography is not particularly limited, but high performance liquid chromatography, column chromatography, preparative thin layer chromatography, etc. can be used as appropriate as required. The developing solvent may be, for example, n-hexane, methylene chloride, benzene, ether, etc., used alone or in appropriate combinations, but is not particularly limited.
本発明の方法に従い分離した１α−ヒドロキシビタミン
Ｄ３のシリル化体から目的とする１α−ヒドロキシビタ
ミンＤ３への変換は常法により、例えばＫＯＨ−メタノ
ールにより行なうか、又は陽イオン変換樹脂と接触せし
めることにより容易に行われる。Conversion of the silylated form of 1α-hydroxyvitamin D3 separated according to the method of the present invention to the target 1α-hydroxyvitamin D3 is carried out by a conventional method, for example, by using KOH-methanol, or by contacting it with a cation conversion resin. This is easily done by
次に実施例を挙げて本発明を更に具体的に説明するが、
本発明はこれらに限定されるものではない。なお実施例
中、Ｎ Ｍ Ｒは ＨＮＭＲＭｏｄｅｌＲ−２４Ｂ（日
立製作新製）、ＩＲは２７０〜３０形（日立製作新製）
を用いた。また純度測定は島原製作所製高速液クロ５Ｃ
Ｌ−６Ａ型、昭和電工製ステンレスカラム６φＸ １５
０ ｍｍ１５μシリカ充填、検出ＵＶ２７３ｍｍにより
分析したピーク面積比である（シリル化体分析溶媒；ｎ
−ヘキサン：塩化メチレン＝９６．５：３．５゜脱シリ
ル化体分析溶媒：ｎ−ヘキサン：テトラヒドロフラン＝
Ｉ３ ： ４）。Next, the present invention will be explained in more detail with reference to Examples.
The present invention is not limited to these. In the examples, NMR is HNMR Model R-24B (newly manufactured by Hitachi Seisakusho), and IR is 270-30 type (newly manufactured by Hitachi Seisakusho).
was used. In addition, purity measurement is performed using Shimabara Seisakusho's high-speed liquid chromatography 5C.
L-6A type, Showa Denko stainless steel column 6φX 15
This is the peak area ratio analyzed by 0 mm 15μ silica packing and detection UV 273 mm (silylated product analysis solvent; n
-Hexane: methylene chloride = 96.5:3.5° Desilylated product analysis solvent: n-hexane: tetrahydrofuran =
I3: 4).
実施例１゜
ａ） １β−ヒドロキシビタミンＤ３（１β−０Ｈ−
Ｄ３ ）および１α−ヒドロキシ−５，６−トランスビ
タミンＤ３ （１α−０Ｈ−）ランスＤ３）を各々０．
１ｇ含む１α−ヒドロキシビタミンＤ３（１（２−ＯＨ
−Ｄ３ ）１．０αｇ （２，４９ｍｍｏ ｌ ｅ）を
塩化メチレン５８ｍ１に溶解し、ヘキサメチルジシラザ
ン１．１２ｒｎｌ （５，３９ｍｍｏ ｌ ｅ、塩化
トリメチルシラン０．８６ｍ１ （５，２５ｍｍｏ ｌ
ｅ）を加え、３０〜４５分間加熱還流した。反応液を
冷却し、減圧上濃縮した後ｎ−ヘキサン３０ｍ１を加え
不溶物を濾別した。Example 1゜a) 1β-hydroxyvitamin D3 (1β-0H-
D3) and 1α-hydroxy-5,6-transvitamin D3 (1α-0H-)trans D3), respectively.
Contains 1g of 1α-hydroxyvitamin D3 (1(2-OH
-D3) 1.0αg (2,49 mmol e) was dissolved in 58 ml of methylene chloride, hexamethyldisilazane 1.12rnl (5,39 mmol e), trimethylsilane chloride 0.86 ml (5,25 mmol
e) was added and heated under reflux for 30 to 45 minutes. After the reaction solution was cooled and concentrated under reduced pressure, 30 ml of n-hexane was added and insoluble materials were filtered off.
濾液を再び濃縮し、酢酸エチル５４ｍ１に溶解し、有機
層を飽和食塩水３６ｍ１で２回洗浄し、無水硫酸マグネ
シウムで乾燥した。濃縮することによりシリル化体混合
物１．３０ｇ（収率９６％）を得た。The filtrate was concentrated again and dissolved in 54 ml of ethyl acetate, and the organic layer was washed twice with 36 ml of saturated brine and dried over anhydrous magnesium sulfate. By concentrating, 1.30 g (yield 96%) of a silylated product mixture was obtained.
ｂ） 前記ａ）で得たシリル化体混合物１．３ｇを東洋
ソーダ製分取用液クロ装置ＨＬＣ−８３７型、カラム：
東洋ソーダ製ステンレスカラム（６０μシリカ、５０φ
ｘ３００ｍｍ）、 ７Ｂ媒：ｎ−ヘキサン：塩化メチレ
ン＝９６：５にてカラムクロマトグラフィーを行った。b) 1.3 g of the silylated mixture obtained in a) above was transferred to a preparative liquid chromatography device HLC-837 model manufactured by Toyo Soda, column:
Toyo Soda stainless steel column (60μ silica, 50φ
Column chromatography was performed using 7B medium: n-hexane: methylene chloride = 96:5.
１８０〜５８０ｍ１に１ａ−ＯＨ−Ｄ３部分、４５０〜
９５０ｍ１に１α−０Ｈ−）ランスＤ３部分、４０００
〜６０・００ｍ１に１β−０Ｈ−Ｄ３部分が溶出した。1a-OH-D3 part in 180-580m1, 450-
950m1 1α-0H-) Lance D3 part, 4000
The 1β-0H-D3 portion was eluted at ~60·00 ml.
高速液体クロマトグラフィー（ＨＰＬＣ）純度１００％
の部分である１８０〜４５０ｍ１を濃縮し、１α−ヒド
ロキシビタミンＤ３−１．３−ビストリメチルシリルエ
ーテル０．９８ｇ（収率９０％）を得た。High performance liquid chromatography (HPLC) purity 100%
A portion of 180 to 450 ml was concentrated to obtain 0.98 g (yield 90%) of 1α-hydroxyvitamin D3-1.3-bistrimethylsilyl ether.
’ＨＮＭＲ（８０ＭＨｚ、ＣＤＣｌ３ ）６ ： ０゜
１２ （１８Ｈ，ｓ）、０．５０ （３Ｈ，ｓ）、０゜
７０〜３．００ （３３Ｈ，ｍ）、３．８０〜４゜２０
（２Ｈ，ｍ）、４．７０〜４．９２ （ＩＨ。'HNMR (80MHz, CDCl3) 6: 0°12 (18H, s), 0.50 (3H, s), 0°70-3.00 (33H, m), 3.80-4°20
(2H, m), 4.70-4.92 (IH.
ｍ）、５．１５〜５．３５ （ＩＨ，ｍ）、５．８０
（ＩＨ，ｄ、 Ｊ＝１２Ｈｚ）、 ６． １５
（ＩＨ。m), 5.15-5.35 (IH, m), 5.80
(IH, d, J=12Hz), 6. 15
(IH.
ｄ＋ Ｊ＝１２Ｈｚ）、ＩＲ（ｎｅａｔ）ｃｍ−’
：２８５０．１２４’０． １０６０，８３０゜Ｃ）
前記ｂ）で得た１（１−ＯＨ−Ｄ３の１゜３−ビストリ
メチルシリル体０．６８ｇ （１，２５ｍｍｏ ｌ ｅ
）を０．２％ＫＯＨ／メタノール３４ｍ１に溶解し、室
温にて３０〜４５分間攪拌した。反応液を１％食塩水１
００ｍ１．酢酸エチル２００ｍ１−ｔ−キサ７２０ｍ１
の混合溶液に展開し、充分撹拌混合した。有機層を分離
し１％食塩水１００ｍ１で２回洗浄した後、無水硫酸マ
グネ／ラムで乾燥した。溶媒を減圧上留去するとＨＰＬ
Ｃ純度１００％の１α−０Ｈ−Ｄ３０．４６ｇ（収率９
２％）を得た。d+ J=12Hz), IR(neat)cm-'
:2850.124'0. 1060,830°C)
0.68 g (1,25 mmol of 1°3-bistrimethylsilyl compound of 1-OH-D3 obtained in b) above
) was dissolved in 34 ml of 0.2% KOH/methanol and stirred at room temperature for 30-45 minutes. Dilute the reaction solution with 1% saline solution
00m1. Ethyl acetate 200ml - t-xa720ml
The mixture was developed into a mixed solution and thoroughly stirred and mixed. The organic layer was separated, washed twice with 100 ml of 1% brine, and then dried over anhydrous magnesium sulfate/rum. When the solvent is distilled off under reduced pressure, HPL
30.46 g of 1α-0H-D with 100% C purity (yield 9
2%).
実施例２゜
ａ） １β−０Ｈ−Ｄ３および１ａ−ＯＨ−トランス
Ｄ３を各々０．１ｇ含む１α−０Ｈ−Ｄ３１、ＯＯｇ
（２，４９ｍｍｃ＋ ｌ ｅ）を塩化メチレン５０ｍ１
に溶解し、ピリジ７０．９８ｇ （１２゜４ｍｍｏ ｌ
ｅ）、塩化ジメチルイソプロピルシラ７０．７５ｇ
（５，５ｍｍｏ ｌ ｅ）を加え室温で１時間撹拌した
。以下実施例１ａ）に記載の方法と同様に処理し、シリ
ル化体混合物１．４１ｇ（収率９４％）を得た。Example 2゜a) 1α-0H-D31, OOg containing 0.1 g each of 1β-0H-D3 and 1a-OH-trans D3
(2,49mmc+le) in 50ml of methylene chloride
70.98g (12゜4mmol
e), 70.75 g of dimethylisopropyl sila chloride
(5.5 mmole) was added and stirred at room temperature for 1 hour. The following treatment was carried out in the same manner as described in Example 1a) to obtain 1.41 g (yield: 94%) of a silylated product mixture.
ｂ） 前記ａ）で得たシリル化体混合物１．４１ｇを実
施例１ａ）に記載するのと同じ装置を用いカラムクロマ
トグラフィーを行った（／Ｓ媒：ｎ−ヘキサン：塩化メ
チレン＝９８ ： ２）。２００〜５２０ｍ ｌに１ａ
−ＯＨ−Ｄ３部分、３７０〜８５０ｍ１に１ａ−ＯＨ−
トラ７ス［）３部分、３０００〜４５００ｍ ｌに１β
−０Ｈ−Ｄ３部分が溶出した。ＨＰＬＣ純度１００％の
２００〜３７０ｍ１部分を濃縮し、１α−ヒドロキシビ
タミンＤ３−１．３−ビスジメチルイソプロピルシリル
エーテル０．８４ｇ（収率７０％）を得た。b) 1.41 g of the silylated mixture obtained in a) above was subjected to column chromatography using the same apparatus as described in Example 1a) (/S medium: n-hexane: methylene chloride = 98:2). ). 1a for 200-520ml
-OH-D3 part, 1a-OH- in 370-850 m1
Tora 7s [) 3 parts, 3000-4500ml 1β
-0H-D3 portion was eluted. A 200 to 370 ml portion with 100% HPLC purity was concentrated to obtain 0.84 g (70% yield) of 1α-hydroxyvitamin D3-1.3-bisdimethylisopropylsilyl ether.
’ＨＮＭＲ（８０ＭＨｚ、ＣＤＣ１３）δ：ｏ。'HNMR (80MHz, CDC13) δ:o.
Ｏ６（１２Ｈ，ｓ）、０．５２ （３Ｈ，ｓ）、０゜７
０〜２．９０ （４７Ｈ，ｍ）、３．９０〜４゜４５
（２Ｈ，ｍ）、４．８０ （ＩＨ，ｄ、Ｊ＝２Ｈｚ）、
５．１０ （ＩＨ，ｄ、Ｊ＝２Ｈｚ）、５゜９０ （
ＩＨ，ｄ、 Ｊ＝１２Ｈｚ）、 ８．２０ （Ｉ
Ｈ，ｄ、 Ｊ＝１２Ｈｚ）
ＩＲ（ｎｅａｔ）ｃｍ−’ ：２９５０．１２５０゜１
０９０、 ８３０
Ｃ） 前記ｂ）で得たシリル化体０．２４ｇ（０，４０
ｍｍｏ ｌ ｅ）を０．２％ＫＯＨ／メタノール３０ｍ
１に溶解し、６時間加熱還流した。反応液を実施例１ｃ
）に記載の方法と同様に処理しＨＰＣＬ純度１００ ％
ノ１ ａ ＯＨ−Ｄ ３０ 、 １４４ｇ（収率９
０％）を得た。O6 (12H, s), 0.52 (3H, s), 0°7
0~2.90 (47H, m), 3.90~4゜45
(2H, m), 4.80 (IH, d, J=2Hz),
5.10 (IH, d, J=2Hz), 5°90 (
IH, d, J=12Hz), 8.20 (I
H, d, J=12Hz) IR (neat) cm-': 2950.1250°1
090, 830 C) 0.24 g of the silylated product obtained in b) above (0,40
mmol e) in 0.2% KOH/methanol 30m
1 and heated under reflux for 6 hours. The reaction solution was prepared from Example 1c.
) The HPLC purity was 100%.
No. 1 a OH-D 30 , 144 g (yield 9
0%) was obtained.
実施例３゜
ａ） ｌβ−０Ｈ−Ｄ３および１ａ−Ｑ）（−）う
７スＤ３ ヲ各／ｒｏ、 １ ｇ含ｂ １ ａ−ＯＨ
−Ｄ３１．００ｇ （２，４９ｍｍｏ ｌ ｅ）をピリ
ジン１００ｍ１に溶解し、塩化トリエチルシラン１．７
ｍｌ （１０ｍｍｏｌｅ）を加え、５０〜６０°Ｃで３
０分間撹拌した。反応液を冷却し、酢酸エチル１５０ｍ
１に展開し、ＩＮ塩酸１００ｍ１で４回処理した。有機
層を飽和食塩水５０ｍ１で２回洗浄した。無水硫酸マグ
ネシウムで乾燥し濃縮することによりシリル化体混合物
１．４９ｇ（収率９５％）を得た。Example 3゜a) lβ-0H-D3 and 1a-Q) (-) U7S D3 wo/ro, 1 g containing b 1 a-OH
-D 31.00g (2,49mmol e) was dissolved in pyridine 100ml, and triethylsilane chloride 1.7
ml (10 mmole) and incubate at 50-60°C for 3
Stirred for 0 minutes. Cool the reaction solution and add 150ml of ethyl acetate.
1 and treated with 100 ml of IN hydrochloric acid four times. The organic layer was washed twice with 50 ml of saturated brine. By drying over anhydrous magnesium sulfate and concentrating, 1.49 g (yield: 95%) of a silylated product mixture was obtained.
ｂ） 前記ａ）で得たシリル化体混合物１．４９ｇを実
施例１ａ）に記載するのと同じ装置を用いカラムクロマ
トグラフィーを行った（溶媒：ｎ−ヘキサン：塩化メチ
レン＝９８ ： ２）。２００〜５００ ｍ ｌに１ａ
−ＯＨ−Ｄ３部分、３５０〜８００ｍ１に１ａ−ＯＨ−
トランスＤ３部分、４０００〜５５００ｍｌに１β−０
Ｈ−Ｄ３部分が溶出した。ＨＰＬＣ純度１００％の２０
０〜３５０ｍ１部分を濃縮し、１α−ヒドロキシビタミ
ンＤ３−１．３−ビストリエチルシリルエーテル０゜９
０ｇ（収率７２％）を得た。b) 1.49 g of the silylated mixture obtained in a) above was subjected to column chromatography using the same apparatus as described in Example 1a) (solvent: n-hexane:methylene chloride = 98:2). 1a for 200-500ml
-OH-D3 part, 1a-OH- in 350-800 m1
Trans D3 part, 1β-0 in 4000-5500ml
The H-D3 portion was eluted. 20 with HPLC purity of 100%
Concentrate 0 to 350 ml of 1α-hydroxyvitamin D3-1.3-bistriethylsilyl ether 0°9
0 g (yield 72%) was obtained.
’ＨＮＭＲ（８０ＭＨｚ、ＣＤＣ１３）δ：０゜３０〜
３．００ （８３Ｈ，ｍ）、３．９５〜４゜５５ （２
Ｈ，ｍ）、４．７０〜４．９５ （ＩＨ。'HNMR (80MHz, CDC13) δ: 0°30~
3.00 (83H, m), 3.95~4°55 (2
H, m), 4.70-4.95 (IH.
ｍ）、５．００〜５．２８ （２Ｈ，ｍ）、５．９５
（ＩＨ，ｄ、Ｊ＝１２Ｈｚ）、８．２０ （ＩＨ。m), 5.00-5.28 (2H, m), 5.95
(IH, d, J=12Hz), 8.20 (IH.
ｄ、Ｊ＝１２Ｈｚ）
ＩＲ（ｎｅａｔ）ｃｍ” ：２９５０，１２４０゜１０
８０、 ７２０゜
Ｃ） 前記ｂ）で得た１ａ−ＯＨ−Ｄ３の１゜３−ビス
トリエチルシリル化体０．２８ｇ （０゜４５ｍｍｏ
ｌ ｅ）を実施例１．０）に記載するのと同様な方法で
処理し、ＨＰＬＣ純度１００％の１α−０Ｈ−Ｄ３０．
１白４ｇ（収率９２％）を得た。d, J=12Hz) IR (neat) cm”: 2950, 1240°10
80, 720°C) 0.28 g of 1°3-bistriethylsilylated 1a-OH-D3 obtained in b) above (0°45 mmo
l e) was treated in a similar manner as described in Example 1.0) to obtain 1α-0H-D30.1 with 100% HPLC purity.
4 g (yield 92%) of 1 white was obtained.
実施例４゜
ａ） １β−０Ｈ−Ｄ３および１ａ−ＯＨ−トランス
Ｄ３を各々０．１ｇ含む１α−０Ｈ−Ｄ３１．００ｇ
（２，４９ｍｍｏ ｌ ｅ）をジメチルホルムアミド５
０ｍ１に溶解しイミダゾール０． ７５ｇ （１１，０
ｍｍｏ ｌ ｅ）＋塩化で一ブチルジメチルシラ７０．
８８５ｇ （５，５ｍｍｏ ｌｅ）を加え室温で１時間
撹拌した。 反応液を酢酸エチル３００ｍ１に展開し、
５％炭酸水素ナトリウム水溶液３００ｍ１．飽和食塩水
３００ｍ１で２回洗浄し、ｌａ縮するとシリル化体混合
物１．４９ｇ（収率９５％）を得た。Example 4゜a) 1α-0H-D31.00g containing 0.1g each of 1β-0H-D3 and 1a-OH-transD3
(2,49 mmol e) in dimethylformamide 5
Dissolve imidazole in 0ml. 75g (11,0
mmol e) + monobutyldimethylsilica chloride 70.
885 g (5.5 mmole) was added and stirred at room temperature for 1 hour. The reaction solution was developed in 300ml of ethyl acetate,
5% sodium bicarbonate aqueous solution 300ml 1. It was washed twice with 300 ml of saturated brine and subjected to la condensation to obtain 1.49 g (yield 95%) of a silylated product mixture.
ｂ） 前記ａ）で得たシリル化体混合物１．４９ｇを実
施例１ａ）に記載するのと同じ装置を用いカラムクロマ
トグラフィーを行った（溶媒二〇−ヘキサン：塩化メチ
レン＝９８：２）、１５０〜４５０ｍ１に１ α−ｏ）
（−Ｄ３部分、３５０〜７００ｍ１に１ａ−ＯＨ−トラ
ンスＤ３部分、３８００〜５２００ｍ１に１β−０Ｈ−
Ｄ３部分が溶出した。ＨＰＬＣ純度１００％の１５０〜
３５０ｍ１部分を濃縮し１α−ヒドロキシビタミンＤ３
−１，３−ビスｔ−ブチルジメチルシリルエーテル０．
９３ｇ（収率７４％）を得た。b) 1.49 g of the silylated product mixture obtained in a) above was subjected to column chromatography using the same apparatus as described in Example 1a) (solvent 20-hexane: methylene chloride = 98:2), 1 α-o) for 150-450m1
(-D3 part, 1a-OH-trans D3 part in 350-700 m1, 1β-0H- in 3800-5200 m1
Part D3 was eluted. 150~ with HPLC purity 100%
Concentrate 350ml portion to 1α-hydroxyvitamin D3
-1,3-bis t-butyldimethylsilyl ether 0.
93 g (yield 74%) was obtained.
’ＨＮＭＲ（６０ＭＨｚ、ＣＤＣ１３）δ：０゜Ｏ６（
１２Ｈ，ｓ）、０．５２ （３Ｈ，ｓ）、０゜７０〜３
．００ （５１Ｈ，ｍ）、４．８０ （ＩＨ。'HNMR (60MHz, CDC13) δ: 0°O6 (
12H,s), 0.52 (3H,s), 0°70~3
．． 00 (51H, m), 4.80 (IH.
ｄ、Ｊ＝１２Ｈｚ）、５．１０ （ＩＨ，ｄ、Ｊ＝２Ｈ
ｚ）、５．９０ （ＩＨ，ｄ、Ｊ＝１２Ｈｚ）。d, J=12Hz), 5.10 (IH, d, J=2H
z), 5.90 (IH, d, J=12Hz).
６．２０ （ＩＨ，ｄ、Ｊ＝１２Ｈｚ）ＩＲ（ｎｅａｔ
）ｃｍ−１：２９５０．１２５０゜１０８０．８４０
Ｃ） 前記ｂ）で得た１ａ−ＯＨ−Ｄ３の１゜３−ビス
ｔ−ブチルジメチルシリル化体０．２０ｇ （０，３２
ｍｍｏ ｌ ｅ）をメタノールＬｏｏｍｌに溶解し、陽
イオン交換樹脂２０ｇを加え室温下３時間撹拌した。6.20 (IH, d, J=12Hz) IR (neat
) cm-1: 2950.1250°1080.840 C) 0.20 g of 1°3-bis-t-butyldimethylsilylated 1a-OH-D3 obtained in b) above (0.32
mmol e) was dissolved in methanol Looml, 20 g of a cation exchange resin was added, and the mixture was stirred at room temperature for 3 hours.
濾過後ＨＰＬＣ純度１００％の１α−ＯＨ−Ｄ３０．１
１５ｇ（収率９０％）を得た。1α-OH-D30.1 with 100% HPLC purity after filtration
15 g (yield 90%) was obtained.
比較例
ＨＰＬＣ純度９９．２７％の１α−０Ｈ−Ｄ３１．００
ｇ （２，４９ｍｍｏｌｅ）（１β−０Ｈ−Ｄ３と１α
−０Ｈ−トランスＤ３合わせて０゜７３％混入）を実施
例１ａ）に記載するのと同じ装置を用いカラムクマドグ
ラフィーを行なった（溶媒：酢酸エチル：ｎ−ヘキサン
＝２：１）。３３０〜４２０ｍ１に１β−０Ｈ−Ｄ３お
よび１α−０Ｈ−トランスＤ３部分、３ＥｔＯ〜４８０
ｍ１に１α−０Ｈ−Ｄ３部分が溶出した。１α−０Ｈ−
Ｄ３部分の分画についてリサイクル操作を４回繰返し、
２０００〜２２５０ｍ１の溶出部分を濃縮するとＨＰＬ
Ｃ純度９９．４７％の１α−０Ｈ−Ｄ３ ０．６３ｇ
（収率６３％）を得る。このものはＨＰＬＣで１β−０
Ｈ−Ｄ３ ト１ａ−ＯＨ−トランスＤ３合わせて０．５
３％混入していた。Comparative Example 1α-0H-D with HPLC purity of 99.27% 31.00
g (2,49 mmole) (1β-0H-D3 and 1α
-0H-trans D3 (combined 0.73%) was subjected to column chromatography using the same apparatus as described in Example 1a) (solvent: ethyl acetate: n-hexane = 2:1). 1β-0H-D3 and 1α-0H-transD3 moieties in 330-420ml, 3EtO-480
The 1α-0H-D3 portion was eluted in m1. 1α-0H-
Repeat the recycling operation four times for the D3 fraction,
Concentrating the eluted portion of 2000-2250ml results in HPL
0.63 g of 1α-0H-D3 with C purity of 99.47%
(yield 63%). This one is 1β-0 by HPLC.
H-D3 To1a-OH-Trans D3 total 0.5
It contained 3%.
Claims (1)
： ▲数式、化学式、表等があります▼（式中Ｒ３、Ｒ４お
よびＲ５は各々 同一または異なって低級アルキル基またはアリール基を
意味する）で示される基である］で表される１α−ヒド
ロキシビタミンＤ３のシリルエーテル、１β−ヒドロキ
シビタミンＤ３のシリルエーテルおよび／または１α−
ヒドロキシ−５，６−トランスビタミンＤ３のシリルエ
ーテルよりなる混合物をシカリゲルを主成分とする担体
を用いたクロマトグラフィーに付しそれぞれの成分に分
離せしめることを特徴とする１α−ヒドロキシビタミン
Ｄ３の精製法。[Claims] The following general formulas I, II and/or III ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) ▲ Numerical formulas, chemical formulas, tables, etc. ▼(III) [In the formula, R1 and R2 are the same or different and are general formulas: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R3, R4 and R5 are the same or different and are lower alkyl groups or aryl groups silyl ether of 1α-hydroxyvitamin D3, silyl ether of 1β-hydroxyvitamin D3 and/or 1α-
A method for purifying 1α-hydroxyvitamin D3, which comprises separating a mixture of silyl ethers of hydroxy-5,6-transvitamin D3 into its respective components by subjecting it to chromatography using a carrier containing silicari gel as a main component. .
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP14368686A JPS62298572A (en) | 1986-06-19 | 1986-06-19 | Purification of 1alpha-hydroxyvitamin d3 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP14368686A JPS62298572A (en) | 1986-06-19 | 1986-06-19 | Purification of 1alpha-hydroxyvitamin d3 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS62298572A true JPS62298572A (en) | 1987-12-25 |
Family
ID=15344592
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP14368686A Pending JPS62298572A (en) | 1986-06-19 | 1986-06-19 | Purification of 1alpha-hydroxyvitamin d3 |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS62298572A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004504295A (en) * | 2000-07-18 | 2004-02-12 | ボーン ケア インターナショナル インコーポレイテッド | Stabilized 1α-hydroxyvitamin D |
-
1986
- 1986-06-19 JP JP14368686A patent/JPS62298572A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004504295A (en) * | 2000-07-18 | 2004-02-12 | ボーン ケア インターナショナル インコーポレイテッド | Stabilized 1α-hydroxyvitamin D |
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