CN104418680B - The synthetic method of 4-hydroxybenzyl vitamine A ketone - Google Patents
The synthetic method of 4-hydroxybenzyl vitamine A ketone Download PDFInfo
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- CN104418680B CN104418680B CN201310410982.7A CN201310410982A CN104418680B CN 104418680 B CN104418680 B CN 104418680B CN 201310410982 A CN201310410982 A CN 201310410982A CN 104418680 B CN104418680 B CN 104418680B
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- hydroxybenzyl
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Abstract
This patent relates to following three kinds of compounds: 4 hydroxybenzyl vitamine A ketones (4 HBR), the synthesis of the vitamin A nitrile alcohol of 4 (tertiary butyl dimethyl Si) benzyl bromide a-bromotoluenes and tert-butyldimethyl silyl protection and utilize this type of compou nd synthesis reacted.4 (tertiary butyl dimethyl Si) benzyl bromide a-bromotolueneThe vitamin A nitrile alcohol of tert-butyldimethyl silyl protection
Description
Technical field
The present invention relates to PTS 4-hydroxybenzyl vitamine A ketone and the novel synthesis of derivant thereof.
Background technology
Clinical display, fenretinide (4-HPR) (I) (accompanying drawing 1) is to women's premenopause the second malignant breast tumor, conduit
Cancer and carcinoma of prostate have preventive and therapeutic action.But because it can be hydrolyzed into retinoic acid (atRA), thus produce and can not eliminate
Toxic and side effects, such as nyctalopia and dermatosis etc..
Non-hydrolytic compound 4-hydroxy base benzyl vitamine A ketone (4-HBR) (II) (accompanying drawing 2) of fenretinide (4-HPR) (I)
Not only overcome the toxic and side effects of fenretinide, and have more high-drug-effect performance (U.S. Patent number: 6,117,845).Due to this
The compound property of medicine is wide, and toxicity is low, therefore, and this compound Zeng Zuowei broad spectrum prevention and the hope for the treatment of cancer.
But, synthetic method (accompanying drawing 5,6) the extremely difficult repetition that former patent (U.S. Patent number: 6,117,845) is reported,
Particularly when heavy dose synthesizes, it is hardly obtained product.
The problem of the synthetic method that former patent (U.S. Patent number: 6,117,845) is reported is mainly the 4-(tert-butyl group two
Methyl silica) nitrile compound (IV) (accompanying drawing 4) of benzyl bromine (III) (accompanying drawing 3) and vitamin A is difficult repeats or productivity is extremely low.
The pungent university of University of Wisconsin-Madison once spent huge fund attempt to improve this, in order to synthesize more compound 4-hydroxy base benzyl
Vitamine A ketone (4HBR) (II) carries out clinical trial, but ends without result, to such an extent as to this compound is because composition problem never has
Clinical trial can be carried out.More than ten years go over, the research in this field never progress.The present invention is by the research for this field
Refilling vigor, the discovery for broad spectrum prevention and the medicine for the treatment of cancer provides solid foundation.
Summary of the invention
Under room temperature, 4-(tertiary butyl dimethyl Si) benzylalcohol (V) and phosphorus tribromide (PBr3) and pyridine react in ether,
Just available required 4-(tertiary butyl dimethyl Si) benzyl bromide a-bromotoluene (III) (accompanying drawing 7).This reaction energy heavy dose is carried out, and
Productivity is high, can repeat completely, easily separated.
Under room temperature, vitamine A ketone (Retinal) is lower and fert-butyidimethylsilyl nitrile in catalyst lithium bromide (LiBr) effect
Silane (TBDMSCN) reacts the axerophthal of just available required tert-butyldimethyl silyl protection in tetrahydrofuran solution
Nitrile alcohol (VI) (accompanying drawing 8).This reaction can heavy dose be carried out, and can repeat completely, and productivity is high, separates easily.
Accompanying drawing explanation
Accompanying drawing 1 is the structural formula of compound fenretinide (4-HPR) (I).
Accompanying drawing 2 is the structural formula of 4-hydroxybenzyl vitamine A ketone (4-HBR) (II).
Accompanying drawing 3 is 4-(tertiary butyl dimethyl Si) structural formula of benzyl bromide a-bromotoluene (III).
The structural formula of the nitrile compound (IV) of accompanying drawing 4 vitamin A.
Accompanying drawing 5 is the 4-(tertiary butyl dimethyl Si that former patent (U.S. Patent number: 6,117,845) is reported) benzyl
Bromine (III) synthetic method.The extremely difficult repetition of the method.
Accompanying drawing 6 is the 4-hydroxybenzyl vitamine A ketone synthesis side that former patent (U.S. Patent number: 6,117,845) is reported
Method.The method productivity is extremely low.
Accompanying drawing 7 is neoteric 4-(tertiary butyl dimethyl Si) heavy dose of synthesis side that the productivity of benzyl bromide a-bromotoluene (III) is high
Method.
Accompanying drawing 8 is the heavy dose that the productivity of axerophthal nitrile alcohol (VI) of neoteric tert-butyldimethyl silyl protection is high
Synthetic method.
Detailed description of the invention
Embodiment 1
Prepared by 4-(tertiary butyl dimethyl Si) benzyl bromide a-bromotoluene (III)
4-(tertiary butyl dimethyl Si) benzylalcohol (V) of 23.8 grams (0.1 moles) is dissolved in dry ether, then
In above-mentioned diethyl ether solution, add 10 milliliters of anhydrous pyridines, and place stirring on ice-water bath, in stirring liquid, be slowly added to 10 millis
Rise phosphorus tribromide (PBr3).Remove ice-water bath, make reactant liquor continue stirring 10 minutes, add 10 milliliters of frozen water and terminate reaction.Receive
Collection ether layer, water layer ether extraction three times.Steam ether, when solution is 20 milliliters, stop distillation.Through silica gel column chromatography
(95:5 hexane/ether) is isolated and purified obtains 27.9 grams of white oil compounds (III).1HNMR(Bruker DX400)
(acetone-d6) δ (ppm) 0.16 (s, 3H), 0.20 (s, 3H), 0.90 (s, 9H), 4.62 (s, 2H), 7.25
(d, 2H, J=8.2Hz), 7.36 (d, 2H, J=8.2). ESI-MS m/z (%): 302.05 (C13H21BrOSi value of calculation:
301.29)。
Embodiment 2
Axerophthal nitrile alcohol (VI) of tert-butyldimethyl silyl protection
10 grams of vitamin A aldehyde are dissolved in 20 milliliters of tetrahydrofuran solutions of dry nitrogen protection, then stir,
It is sequentially added into 0.5 gram of lithium bromide (LiBr) and 70 grams of fert-butyidimethylsilyl nitrile silane again in stirring liquid.Reactant mixture continues
It is stirred at room temperature 20 hours, adds 20 milliliters of water and terminate reaction.Reactant mixture extracts three times by 30 milliliters of ethyl acetate.Steam
Going out solvent, thick product by silica gel chromatography (95:5 hexane/ethyl acetate) is isolated and purified obtains 14.3 grams of orange oily compounds
(VI).1HNMR (Bruker DX400) (acetone-d6), δ (ppm) 0.16 (s, 3H), 0.20 (s, 3H), 0.90 (s,
9H), 1.02 (s, 6H), 1.45-1.48 (m, 2H), 1.58-1.63 (m, 2H), 1.70 (s, 3H) 1.99 (s, 6H),
5.57-5.61(m,2H), 6.13- 6.23(m,3H), 6.38(d,1H, J=15.2Hz), 6.86(dd,1H, J=11.3,
15.2 Hz).ESI-MS m/z (%): 425.31 (C13H21BrOSi value of calculation: 425.30).
Claims (1)
1. the method preparing 4-(t-butyldimethyl silane) benzyl bromide a-bromotoluene, it is characterised in that comprise the following steps: by 23.8
Gram 4-(tertiary butyl dimethyl Si) benzylalcohol be dissolved in dry ether, then in above-mentioned diethyl ether solution add 10 milliliters of nothings
Water pyridine, and place stirring on ice-water bath, in stirring liquid, it is slowly added to 10 milliliters of phosphorus tribromides, removes ice-water bath, make reaction
Liquid continues stirring 10 minutes, adds 10 milliliters of frozen water and terminates reaction；Collect ether layer, water layer ether extraction three times, steam second
Ether, when solution is 20 milliliters, stops distillation；Using hexane/ether=95/5 chromatographic solution, thick product separates through silica gel column chromatography
Purification obtains 27.9 grams of white oil products.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201310410982.7A CN104418680B (en) | 2013-09-11 | 2013-09-11 | The synthetic method of 4-hydroxybenzyl vitamine A ketone |
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| CN201310410982.7A CN104418680B (en) | 2013-09-11 | 2013-09-11 | The synthetic method of 4-hydroxybenzyl vitamine A ketone |
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| CN104418680A CN104418680A (en) | 2015-03-18 |
| CN104418680B true CN104418680B (en) | 2016-08-10 |
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| CN111253427A (en) * | 2020-03-13 | 2020-06-09 | 苏州大学 | Application of n-butyl lithium in catalysis of cyanosilicification reaction of aldehyde and silane |
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| CA2607556A1 (en) * | 2005-05-03 | 2006-11-09 | Wisconsin Alumni Research Foundation | C-linked glucoronide of n-(4-hydroxybenzyl) retinone, analogs thereof, and method of using the same to inhibit neoplastic cell growth |
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Non-Patent Citations (2)
| Title |
|---|
| Lithium Chloride: An Active and Simple Catalyst for Cyanosilylation of Aldehydes and Ketones;Nobuhito Kurono et al.;《 J. Org. Chem》;20050603;第70卷(第16期);6530-6532 * |
| Synthesis, electrochemistry and anticancer activity of novel ferrocenyl phenols prepared via azide-alkyne 1,3-cycloaddition reaction;Damian Plazuk et al.;《Journal of Organometallic Chemistry》;20121231;第715卷;102-112 * |
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