JPH0244312B2 - - Google Patents
Info
- Publication number
- JPH0244312B2 JPH0244312B2 JP57053686A JP5368682A JPH0244312B2 JP H0244312 B2 JPH0244312 B2 JP H0244312B2 JP 57053686 A JP57053686 A JP 57053686A JP 5368682 A JP5368682 A JP 5368682A JP H0244312 B2 JPH0244312 B2 JP H0244312B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- vitamin
- sulfur dioxide
- aromatic
- formula
- 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 - Lifetime
Links
- 125000002252 acyl group Chemical group 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 9
- 125000001931 aliphatic group Chemical group 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 14
- 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 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- JWUBBDSIWDLEOM-NQZHSCJISA-N 25-hydroxy-3 epi cholecalciferol Chemical compound C1([C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=CC=C1C[C@H](O)CCC1=C JWUBBDSIWDLEOM-NQZHSCJISA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 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
- UPODXJOTVHSJMI-UHFFFAOYSA-M O=[S+]=O.CC([O-])=O Chemical compound O=[S+]=O.CC([O-])=O UPODXJOTVHSJMI-UHFFFAOYSA-M 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- FCKJYANJHNLEEP-XRWYNYHCSA-N (24R)-24,25-dihydroxycalciol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CC[C@@H](O)C(C)(C)O)C)=C\C=C1\C[C@@H](O)CCC1=C FCKJYANJHNLEEP-XRWYNYHCSA-N 0.000 description 1
- GMRQFYUYWCNGIN-UHFFFAOYSA-N 1,25-Dihydroxy-vitamin D3' Natural products C1CCC2(C)C(C(CCCC(C)(C)O)C)CCC2C1=CC=C1CC(O)CC(O)C1=C GMRQFYUYWCNGIN-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229930003316 Vitamin D Natural products 0.000 description 1
- 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 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 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
- 235000020964 calcitriol Nutrition 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
- 238000004440 column chromatography Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- AVGAIPMGSIOHFZ-UHFFFAOYSA-N dichloromethane;2-propan-2-yloxypropane Chemical compound ClCCl.CC(C)OC(C)C AVGAIPMGSIOHFZ-UHFFFAOYSA-N 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
Description
【発明の詳細な説明】
本発明は一般式（）で示されるビタミンD3
誘導体に関する。[Detailed Description of the Invention] The present invention provides vitamin D 3 represented by the general formula ().
Regarding derivatives.
（式中R1は芳香族又は低級脂肪族のアシル基を
意味し、R2、R3は同一又は異なつて水素原子、
水酸基又は保護された水酸基を意味する。）
一般式（）で示される本発明の化合物は、血
中のビタミンD3類、例えば25−ヒドロキシビタ
ミンD3、1α，25−ジヒドロキシビタミンD3等を
抗原抗体反応を用いて測定する際に必要な抗体を
製造するための一般式（）で示されるハプテン
の合成中間体として又はその他種々のビタミン
D3誘導体を製造するための中間体として極めて
有用である。 (In the formula, R 1 means an aromatic or lower aliphatic acyl group, R 2 and R 3 are the same or different, and are a hydrogen atom,
means a hydroxyl group or a protected hydroxyl group. ) The compound of the present invention represented by the general formula () is effective when measuring 3 types of vitamin D in the blood, such as 25-hydroxyvitamin D3 , 1α,25-dihydroxyvitamin D3, etc. using an antigen-antibody reaction. As a synthetic intermediate for the hapten represented by the general formula () for producing the necessary antibodies, or as various other vitamins.
It is extremely useful as an intermediate for producing D 3 derivatives.
（式中R′2、R′3は同一又は異なつて水素原子又は
水酸基を意味し、ｎは２乃至４の整数を意味す
る。）
従来知られているビタミンD3類の二酸化イオ
ウの付加体としては、その３位が水酸基かまたは
テトラヒドロピラニル基等のエーテル系の保護基
で保護された水酸基のものがある。しかしながら
これらの化合物は酸に対して極めて不安定であり
酸化剤を用いた合成反応には使用し得ない。 (In the formula, R' 2 and R' 3 are the same or different and mean a hydrogen atom or a hydroxyl group, and n means an integer of 2 to 4.) Conventionally known adducts of sulfur dioxide of vitamin D 3 Examples include those in which the 3-position is a hydroxyl group or a hydroxyl group protected with an ether-based protecting group such as a tetrahydropyranyl group. However, these compounds are extremely unstable to acids and cannot be used in synthetic reactions using oxidizing agents.
本発明者はこれらの事情に鑑み鋭意研究した結
果、本発明の３位が芳香族又は脂肪族のアシル基
で保護された化合物は酸に対して極めて安定で酸
を用いた種々の合成反応、例えば酸性条件下にお
ける６位又は19位のアルキル化反応等の原料とし
て有用であることを見い出した。更に驚くべきこ
とに本発明の化合物はそれ自体極めて安定であり
長期の保存に耐えるなどの合成原料としては最適
の物性を有している。 In view of these circumstances, the present inventor conducted intensive research and found that the compound of the present invention in which the 3-position is protected with an aromatic or aliphatic acyl group is extremely stable against acids and is suitable for various synthetic reactions using acids. For example, it has been found to be useful as a raw material for alkylation reactions at the 6-position or 19-position under acidic conditions. Furthermore, surprisingly, the compound of the present invention itself is extremely stable and has optimal physical properties as a synthetic raw material, such as being able to withstand long-term storage.
本発明の化合物は新規化合物であり、例えば対
応するビタミンD3類、具体的にはビタミンD3、
25−ヒドロキシビタミンD3、24，25−ジヒドロ
キシビタミンD3に二酸化イオウを反応せしめ得
られる一般式（）で示される化合物を常法によ
り、例えば酸ハライド又は酸無水物と有機塩基と
の反応に付し製造するか又は前記のビタミンD3
類の３位を先にアシル化し、次いで二酸化イオウ
を反応せしめることにより製造される。 The compound of the present invention is a novel compound, for example, the corresponding vitamin D 3 class, specifically vitamin D 3 ,
A compound represented by the general formula () obtained by reacting 25-hydroxyvitamin D 3 and 24,25-dihydroxyvitamin D 3 with sulfur dioxide is reacted with an organic base by a conventional method, for example, an acid halide or an acid anhydride. Added or manufactured with vitamin D 3
It is produced by first acylating the 3-position of the group, and then reacting with sulfur dioxide.
（式中R2、R3は前記と同じものを意味する。）
本発明の化合物においてアシル基としては、芳
香族アシル基又は低級脂肪族アシル基である。芳
香族アシル基としては例えばベンゾイル基、ｐ−
ニトロベンゾイル基、ナフトイル基等であり、低
級脂肪族アシル基としては例えばアセチル基、プ
ロパノイル基、ブチリル基等である。又17位の側
鎖の水酸基の保護基としては特に制限はないが、
好ましくは芳香族又は低級脂肪族のアシル基であ
る。 (In the formula, R 2 and R 3 have the same meanings as above.) In the compound of the present invention, the acyl group is an aromatic acyl group or a lower aliphatic acyl group. Examples of the aromatic acyl group include benzoyl group, p-
Examples of the lower aliphatic acyl group include an acetyl group, a propanoyl group, and a butyryl group. There are no particular restrictions on the protecting group for the hydroxyl group on the side chain at position 17, but
Preferably it is an aromatic or lower aliphatic acyl group.
実施例 １
ビタミンD32.1ｇを10mlのピリジンに溶解し、
無水酢酸10mlを加える。室温で約２時間撹拌し氷
水中に注ぐ。酢酸エチルで抽出し希塩酸、水の順
に洗浄し、硫酸マグネシウムで乾燥する。酢酸エ
チルを留去するとビタミンD3アセテートの油状
残渣2.3ｇを得る。残渣をジクロルメタン３mlに
溶解し、ドライアイスで冷却したコールドフイン
ガーを反応容器に結合する。Example 1 2.1 g of vitamin D 3 was dissolved in 10 ml of pyridine,
Add 10 ml of acetic anhydride. Stir at room temperature for about 2 hours and pour into ice water. Extract with ethyl acetate, wash sequentially with dilute hydrochloric acid and water, and dry over magnesium sulfate. Distilling off the ethyl acetate gives 2.3 g of an oily residue of vitamin D 3 acetate. The residue is dissolved in 3 ml of dichloromethane and the cold finger cooled with dry ice is connected to the reaction vessel.
反応容器内に乾燥アルゴンで置換した後二酸化
イオウガスを反応液が約30mlになるまで導入す
る。30分から１時間そのままの状態で還流する。
コールドフインガーを除去し、過剰の二酸化イオ
ウを減圧留去する。ただちにシリカゲルを用いた
カラムクロマトグラフイーに付し、ヘキサン酢酸
エチル（２：１）で溶出する。目的物を含むフラ
クシヨンを集め溶媒を留去すると油状のビタミン
D3アセテート二酸化イオウ付加物2.24ｇを得る。 After purging the inside of the reaction vessel with dry argon, sulfur dioxide gas is introduced until the reaction solution reaches about 30 ml. Reflux for 30 minutes to 1 hour.
The cold finger is removed and excess sulfur dioxide is removed under reduced pressure. Immediately subjected to column chromatography using silica gel and eluted with hexane-ethyl acetate (2:1). When the fraction containing the target substance is collected and the solvent is distilled off, an oily vitamin is obtained.
2.24 g of D 3 acetate sulfur dioxide adduct are obtained.
本物質は６位異性の6S体および6S体（１：１）
の混合物である。 This substance has 6-position isomerism 6S form and 6S form (1:1)
It is a mixture of
6R異性体 融点123〜125℃（分解）（ジクロルメ
タン−イソプロピルエーテルより再結晶）
NMR δ：5.22〜4.87（1H、ｍ）、4.69（2H、ｍ）、
3.69（2H、ｍ）、2.05（3H、ｓ）0.55（3H、ｓ）
6S異性体 油状
NMR δ：5.22〜4.90（1H、ｍ）、4.64（2H、ｍ）、
3.65（2H、ｍ）、2.03（3H、ｓ）、0.64（3H、ｓ）
実施例 ２
ビタミンD3と二酸化イオウから常法により製
したビタミンD3二酸化イオウ付加体3.6ｇをピリ
ジン20mlに溶解し、無水酢酸20mlを加える。室温
下１〜２時間撹拌した後氷水中に注ぐ。クロロホ
ルムで抽出し、クロロホルム層を希塩酸、水の順
に洗浄し、硫酸マグネシウムで乾燥する。6R isomer Melting point 123-125℃ (decomposition) (recrystallized from dichloromethane-isopropyl ether) NMR δ: 5.22-4.87 (1H, m), 4.69 (2H, m),
3.69 (2H, m), 2.05 (3H, s) 0.55 (3H, s) 6S isomer Oily NMR δ: 5.22-4.90 (1H, m), 4.64 (2H, m),
3.65 (2H, m), 2.03 (3H, s), 0.64 (3H, s) Example 2 3.6 g of a sulfur dioxide adduct of vitamin D 3 prepared from vitamin D 3 and sulfur dioxide by a conventional method was dissolved in 20 ml of pyridine. , add 20 ml of acetic anhydride. After stirring at room temperature for 1 to 2 hours, the mixture is poured into ice water. Extract with chloroform, wash the chloroform layer sequentially with dilute hydrochloric acid and water, and dry with magnesium sulfate.
クロロホルムを留去するとビタミンD3アセテ
ート二酸化イオウ付加物3.8ｇを得る。 When the chloroform is distilled off, 3.8 g of vitamin D 3 acetate sulfur dioxide adduct is obtained.
Claims (1)
意味し、R2、R3は同一又は異なつて水素原子、
水酸基又はRCO−（式中Ｒは低級脂肪族基又は芳
香族基を意味する）］で示される化合物。[Claims] 1. General formula [(In the formula, R 1 means an aromatic or lower aliphatic acyl group, R 2 and R 3 are the same or different, and are a hydrogen atom,
A compound represented by a hydroxyl group or RCO- (in the formula, R means a lower aliphatic group or an aromatic group).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5368682A JPS58172388A (en) | 1982-04-02 | 1982-04-02 | Novel vitamin d3 derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5368682A JPS58172388A (en) | 1982-04-02 | 1982-04-02 | Novel vitamin d3 derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS58172388A JPS58172388A (en) | 1983-10-11 |
| JPH0244312B2 true JPH0244312B2 (en) | 1990-10-03 |
Family
ID=12949695
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP5368682A Granted JPS58172388A (en) | 1982-04-02 | 1982-04-02 | Novel vitamin d3 derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS58172388A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107325173A (en) * | 2016-04-28 | 2017-11-07 | 上海惠斯生物科技有限公司 | A kind of artificial antigen of 25(OH)VD 3, preparation method and application |
-
1982
- 1982-04-02 JP JP5368682A patent/JPS58172388A/en active Granted
Non-Patent Citations (1)
| Title |
|---|
| CHEMISTRY LETTERS=1979 * |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS58172388A (en) | 1983-10-11 |
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