CN1143070A - 13-顺式-视黄酸的光化学制备方法 - Google Patents
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- C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
- C07C403/20—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by carboxyl groups or halides, anhydrides, or (thio)esters thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/09—Geometrical isomers
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
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Abstract
光化学异构化11-顺式，13-顺-视黄酸制备13-顺式-视黄酸。
Description
本发明涉及由11-顺式，13-顺式-视黄酸光化学异构化生成13-顺式-视黄酸的方法。
式(I)的13-顺式-视黄酸是具有广泛实际用途药物中的活性成分，尤其是在治疗痤疮的药物中。
该产品的制备方法公开在“Carotenoids and Related Comp-ounds，Part XVIII，Synthesis of cis and di-cis-polyenesby reactions of Wittig type”.Paddenten G.和Weedon B.C.L.，J.Chem.Soc.，(C)，1984-1997，1968中。所述工艺包括在室温下、乙醚溶剂中、在甲醇钠存在下，由式(II)的[3-甲基-5-(2，6，6-三甲基-1-环己烯-1-基-2，4-戊二烯基]-三苯基卤化鏻(其中X是卤原子)和式(III)的5-羟基-4-甲基-2(5-H)-呋喃酮
进行维悌希(Wittig)缩合。
然而，该方法的缺点是所期望的产物以含有下列异构体的混合物形式获得，即含有式(IV)的11-顺式，13-顺式-视黄酸
和式(V)的11-反式，13-反式-视黄酸(即维生素A酸)。
因此，所得的比异构体(IV)的量小并且近于异构体(V)的量的产物(I)，不得不用常规的方法，即用硅胶色谱或分级结晶法从该混合物中将产物(I)分离，这样又进一步降低了产率。
EP 0111325公开了一种制备13-顺式-视黄酸的方法，其方法是在低温(-10℃至-50℃)下、在醇溶剂中和由含碱金属氢氧化物如氢氧化钾组成的碱的存在下，产物(II)与产物(III)进行维悌希缩合。
所得的相对起始产物(III)的转化率高于90％，该反应产物由包括10％-30％的异构体(I)和70％-90％的异构体(IV)的混合物组成。这种混合物或单独的异构体(IV)，预先从上述混合物中分离出来，在基于铑或钯的催化剂存在下进行异构化反应，由此产物(IV)转化为13-顺式-视黄酸。
这种方法获得的13-顺式-视黄酸的产率高于Paddenten andWeedon的方法。然而所述方法的缺点是11-顺式，13-顺式-视黄酸的异构化反应是在基于特别昂贵的过渡金属，诸如铑和钯的催化剂存在下进行的。此外，非常困难从含所述催化剂的反应粗产物中通过现有工业生产规程规定的方法回收化学纯的13-顺式-视黄酸。
接着需要提供一种简单的异构化反应，以提高维悌希缩合所得的异构体混合物中13-顺式-视黄酸的含量并且不存在EP 111325中所述异构化固有的不利，还能用简单常用的方法回收高纯度的产物。
本申请人意外地发现，在室温下、非极性非质子传递溶剂中、光活化剂存在下，通过在可见光谱中的照射可以将式(IV)的11-顺式，13-顺式-视黄酸转化为13-顺式-视黄酸。
在将所有多不饱和系统中的顺式双键转化成反式双键例如维生素A的制备的光化学异构化的效应公开在DE 2210800和CH 605724中。
因此，完全出乎意料，在适当的操作条件下，光化学活化作用可以主要将11-顺式，13-顺式-视黄酸(IV)中的11位顺式双键而不是13位三取代的顺式双键转化为反式双键。
实际上，通过所述操作，用产物(IV)比用全是反式的异构体(V)更快地形成13-顺式-视黄酸。
在可见光谱中，波长4000-7000的范围内，通过照射进行11-顺式，13-顺式-视黄酸生成13-顺式-视黄酸的光化学异构化。光活化剂的选择影响不大，然而优选使用Bengal玫瑰(Bengalrose)、二苯二硫、cercosporin和叶绿素。光化学异构化优选在在非极性非质子传递溶剂中进行，例如二氯甲烷、乙腈、1，2-二氯乙烷或它们的混合物。
优选使用根据本发明的光化学异构化来提高在室温下、在乙醚溶剂中及存在甲醇钠条件下，在前文提到的化合物(II)和(III)之间进行维悌希缩合所获得的混合物中产物(I)的含量(参见“Caroten-oids and Related Compounds，Part XVIII，Synthesis of cisand di-cis-polyenes by reaction of Wittig type”，Padden-ten G.和Weedon B.C.L.，J.Chem.Soc.，(C)，1984-1997，1968)。
本申请人还发现，当根据本发明进行光化学异构化时，尤其是在所述缩合获得的混合物中使用Bengal玫瑰时，可获得相对于总量产率为75％的13-顺式-视黄酸，虽然上述起始混合物含有的13-顺式-视黄酸的量比异构体(IV)的量小，并且近似于异构体(V)的量。从这样富含13-顺式-视黄酸的混合物中很容易用分级结晶法分离该产物，产率可达50％，该产物完全可与在基于铑或钯的催化剂的存在下进行异构化获得的产物相比。预先进行光活化剂分离处理后，还可以从结晶母液中回收另外量的13-顺式-视黄酸。
从分级结晶获得的产物(I)可任选在醇溶剂中进一步重结晶，优选使用异丙醇。
根据本发明的异构化也可用于对前文所述EP 0111325公开的、在低温下醇溶剂中有碱金属氢氧化物存在下进行维悌希缩合获得的混合物进行异构化。
下列实施例是对根据本发明的异构化方法的说明，而不是限定。实施例1制备视黄酸(I)、(IV)和(V)的混合物
80g三苯膦溴水合物和50g乙烯β-碘醇被加入到300ml甲醇中。所得混合物搅拌过夜，蒸发除掉溶剂，该反应粗产物溶于500ml无水乙醚中。该反应混合物用50ml由6.9g金属钠制得的甲醇钠处理，20分钟后，8g丁烯羟酸内酯被加入到10ml乙醚中。1小时后，用200ml己烷烯释该混合物并用100ml 1∶1的甲醇-水混合物萃取三次。该视黄酸的混合物从酸化的甲醇化的水中用100ml乙醚萃取三次。该乙醚相用3∶1的甲醇-水混合物洗涤，然后用水和氯化钠洗涤。从该有机相中除去水，并蒸发掉溶剂。HPLC分析显示所得的混合物(33g)的组成为：
13-顺式-视黄酸(I)：23％
11-顺式，13-顺式-视黄酸(IV)：64％
11-反式，13-反式-视黄酸(V)：13％实施例2
3g实施例1所制备的混合物溶于3∶7二氯甲烷-乙腈混合物中，并装入一个玻璃反应器中，反应器外面配有一组8瓦特Hitachi灯，F8T5/CW，反应器放在一个Rayonet型仪器里。然后将二苯二硫加入该反应器(起始混合物∶二苯二硫的摩尔比为10∶1)。该反应混合物进行20小时光照射并用HPLC分析。
HPLC分析结果为：(I)53％，(IV)4％，(V)43％。实施例3
20g实施例1所制备的混合物溶于3∶7的二氯甲烷-乙腈混合物中并装入实施例2所述的反应器中。然后将700mg Bengal玫瑰加入该反应器中(起始混合物∶玫瑰红的摩尔比为100∶1)。该反应混合物进行40小时光照射并用HPLC分析。
HPLC分析结果为：(I)74.5％，(IV)0.89％，(V)24.6％。实施例4
根据实施例3的方法进行试验。
收集到从光化学处理中分离的含97.5％产物(I)的沉淀6.1g。由浓缩母液再得到3.7g沉淀，将该3.7g沉淀溶于15ml二氯甲烷。所得溶液用二氧化硅柱过滤以除去Bengal玫瑰，得到含91.6％产物(I)的产物2g，接着得到含82％产物(I)的产物1g。实施例5
根据实施例3的方法进行试验。
收集到含86％异构体I的沉淀11g。将该产物用异丙醇重结晶，得8.5g纯(I)。产率：42.5％。
Claims (5)
1、制备13-顺式-视黄酸(I)的方法，在室温下、非极性非质子传递溶剂中，在选自Bengal玫瑰、二苯二硫、cercosporin和叶绿素的光活化剂存在下，在可见光谱内对11-顺式，13-顺式-视黄酸(IV)进行光照射。
2、权利要求1所述的方法，其中所述的非极性非质子传递溶剂选自二氯甲烷、乙腈、1，2-二氯乙烷或其混合物。
3、权利要求1所述的方法，用于提高式(II)的[3-甲基-5-(2，6，6-三甲基-1-环己烯-1-基-2，4-戊二烯基]-三苯基卤化鏻(其中X是卤原子)
和式(III)的5-羟基-4-甲基-2(5-H)-呋喃酮维悌希缩合所得的也含产物(I)和(V)的混合物中产物(I)的含量，该方法是在室温下、在乙醚溶剂中及甲醇钠存在下进行的。
4、权利要求3所述的方法，其中所述的由光照射获得的产物(I)用分级结晶分离并从结晶母液中回收另外量的产物(I)。
5、权利要求1所述的方法，其中所述方法用于由式(II)的[3-甲基-5-(2，6，6-三甲基-1-环己烯-1-基-2，4-戊二烯基]-三苯基卤化鏻(其中X是卤原子)和式(III)的5-羟基-4-甲基-2(5-H)-呋喃酮维悌希(Wittig)缩合获得的主要含异构体(IV)和(I)的混合物，该方法是在-10℃--50℃温度范围内，在醇溶剂中，在含有碱金属氢氧化物的碱存在下进行的。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI950973A IT1274494B (it) | 1995-05-12 | 1995-05-12 | Procedimento fotochimico per la preparazione dell'acido 13-cis-retinoico |
| IT00973A/95 | 1995-05-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1143070A true CN1143070A (zh) | 1997-02-19 |
Family
ID=11371592
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96108445A Pending CN1143070A (zh) | 1995-05-12 | 1996-05-12 | 13-顺式-视黄酸的光化学制备方法 |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP0742204A1 (zh) |
| CN (1) | CN1143070A (zh) |
| IT (1) | IT1274494B (zh) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113201016A (zh) * | 2021-05-19 | 2021-08-03 | 万华化学集团股份有限公司 | 一种c15膦盐的制备方法 |
| CN116462621A (zh) * | 2023-02-20 | 2023-07-21 | 湖北恒安芙林药业股份有限公司 | 一种维a酸的制备方法 |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1289528B1 (it) * | 1996-12-27 | 1998-10-15 | Lab Mag Spa | Procedimento per la preparazione dell'acido 13,cis-retinoico |
| US6124485A (en) * | 1998-03-25 | 2000-09-26 | Abbott Laboratories | Process for producing 13-cis retinoic acid |
| DE10359433A1 (de) * | 2003-12-17 | 2005-07-21 | Basf Ag | Verfahren zur Herstellung von Vitamin A-Acetat |
| WO2020245030A1 (en) | 2019-06-07 | 2020-12-10 | Basf Se | Isomerization of polyunsaturated non-aromatic compounds |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH605724A5 (zh) * | 1974-11-12 | 1978-10-13 | Hoffmann La Roche | |
| ATE32217T1 (de) * | 1982-12-10 | 1988-02-15 | Hoffmann La Roche | Verfahren zur herstellung von 13-cis-retinsaeure. |
| DE4313089A1 (de) * | 1993-04-22 | 1994-10-27 | Basf Ag | Verfahren zur Herstellung von 13-(Z)-Retinsäure |
-
1995
- 1995-05-12 IT ITMI950973A patent/IT1274494B/it active IP Right Grant
-
1996
- 1996-04-17 EP EP96105991A patent/EP0742204A1/en not_active Withdrawn
- 1996-05-12 CN CN96108445A patent/CN1143070A/zh active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113201016A (zh) * | 2021-05-19 | 2021-08-03 | 万华化学集团股份有限公司 | 一种c15膦盐的制备方法 |
| CN113201016B (zh) * | 2021-05-19 | 2023-09-19 | 万华化学集团股份有限公司 | 一种c15膦盐的制备方法 |
| CN116462621A (zh) * | 2023-02-20 | 2023-07-21 | 湖北恒安芙林药业股份有限公司 | 一种维a酸的制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| ITMI950973A0 (it) | 1995-05-12 |
| EP0742204A1 (en) | 1996-11-13 |
| IT1274494B (it) | 1997-07-17 |
| ITMI950973A1 (it) | 1996-11-12 |
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