CN101492365A - Synthesis of (Z)-15-tetracosenoic acid - Google Patents
Synthesis of (Z)-15-tetracosenoic acid Download PDFInfo
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- CN101492365A CN101492365A CNA2009100941540A CN200910094154A CN101492365A CN 101492365 A CN101492365 A CN 101492365A CN A2009100941540 A CNA2009100941540 A CN A2009100941540A CN 200910094154 A CN200910094154 A CN 200910094154A CN 101492365 A CN101492365 A CN 101492365A
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- tetracosenoic acid
- tetracosenoic
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Abstract
The invention relates to a method for synthesizing (Z)-15-tetracosenic acid with medicine activity. The method is characterized in that the (Z)-15-tetracosenic acid is prepared by the steps as follows: simple and easily obtained raw material of erucic acid is subjected to five-step reaction, and a target compound of the (Z)-15-tetracosenic acid is obtained by the basic hydrolysis of a key intermediate compound 6. The invention is characterized in that the main product of the reaction is cis isomer (Z)-15-tetracosenic acid, and the cis proportion is more than 99 percent. The invention has the advantages of easily obtained raw material, simple synthesis technology, simple operation, high yield, and being easy for realizing industrialization, etc.
Description
Technical field
The present invention relates to have the synthetic method of (Z)-15-tetracosenoic acid of pharmaceutical activity.
Background technology
(Z)-and the 15-tetracosenoic acid, popular name Selacholeic acid, shark acid.Its content in nervous tissue and cerebral tissue is higher, it is biomembranous important composition composition, it is the significant composition of medullary substance in the brain glucoside, have the relevant different physiological roles of the microbial film of participation,, promote the function of nerve growth and growth as recovering the nerve ending activity, it is brain development, the essential nutrition of keeping to improving the active of cranial nerve, prevents that encephalasthenia from having important effect.It also has better curative effect to cardiovascular and human body self immunological disease in addition, can alleviate diseases such as adrenoleukodystrophy and multiple sclerosis disorder simultaneously.Studies show that the pharmacologically active of Selacholeic acid mainly is its cis-isomeride performance, and trans-isomer(ide) almost there is not pharmacologically active.In addition, (Z)-the 15-tetracosenoic acid also can be used as raw material, has good application aspect the fine chemicals such as synthetic muskone, insect sex pheromone, thibetolide.
Because (Z)-and unique physiology, pharmacologically active that the 15-tetracosenoic acid is had, the source is comparatively rare again, and its artificial synthesis has caused people's attention.Simultaneously, because the method for hitherto reported is the method for separation and Extraction after the saponification from animal or vegetables oil mostly, so the chemosynthesis of suitable-15-tetracosenoic acid is significant.
Nineteen thirty Hale etc. is reduced to erucyl alcohol ((Z)-13-two lanolin alcohols) with methyl erucate ((Z)-13-Decosahedaenoic acid methyl esters), be converted into its corresponding bromide then, with bromide and diethyl malonate reaction, obtain the 15-tetracosenoic acid after its product hydrolysis and the decarboxylation again.But because the final step decarboxylic reaction carries out under 170 ℃ hot conditions, the content of the cis-product that obtains in the reaction product (Z)-15-tetracosenoic acid is less than 30%, that major part obtains is thermodynamically stable trans product (E)-15-tetracosenoic acid (Hale J B, Lycan W H, Synthesis ofnervonic acid, J.Am.Chem.Soc.1930 (52): 4536-4539).
Because above-mentioned synthetic method primary product is a trans-isomer(ide), can not bring into play the pharmacologically active of Selacholeic acid.Thereby set up a kind of efficiently, succinctly the method for synthetic its cis-isomeride just seems particularly important.
Summary of the invention
The method that the purpose of this invention is to provide a kind of cis-isomeride (Z)-15-tetracosenoic acid of synthetic Selacholeic acid.
The structure of (Z)-15-tetracosenoic acid provided by the present invention is suc as formula shown in the I,
The concrete reaction formula of synthetic is as follows:
The present invention (Z)-15-tetracosenoic acid synthetic method is as follows:
With erucic acid (suitable-the 13-Decosahedaenoic acid) is raw material, generates methyl erucate (suitable-13-Decosahedaenoic acid methyl esters) through esterification.Then methyl erucate is reduced into mustard alcohol (suitable-13-docosene-1-alcohol), the pure and mild Hydrogen bromide reaction of mustard generates bromo two dodecylenes, under the sodium alkoxide effect, react at last, under the concentrated base condition, become acid hydrolysis, obtain (Z)-15-tetracosenoic acid with methyl aceto acetate.
Utilization of the present invention be simple and easy to raw material erucic acid (2) set out, obtain having target compound cis (the Z)-15-tetracosenoic acid (I) of pharmaceutical activity by the reaction of five steps, the key intermediate of reaction is a compound 6, its alkaline hydrolysis only needs to carry out at the alcoholic acid reflux temperature, can not make 15 two key generation isomeries turn to the conversion of trans-isomer(ide).Characteristics of the present invention are that the product of reaction mainly is cis-isomeride (Z)-15-tetracosenoic acid, cis-content detects by GC-MS turn to (Z)-15-tetracosenoic acid methyl esters through deriving after, its cis ratio is greater than 99%, and have that raw material is easy to get, synthesis technique is simple, characteristics easy and simple to handle, that productive rate is high.
Below in conjunction with specific embodiments the present invention is described in detail:
1. the preparation of methyl erucate (3)
In the 250mL round-bottomed flask, add erucic acid 34g (0.1 mole) and methyl alcohol 80mL successively, under agitation slowly drip vitriol oil 4mL, reflux 6h, [TLC detects, developping agent A:V (sherwood oil): V (ethyl acetate)=3: 1, erucic acid reacts completely], it is faint yellow that reaction solution is.Pressure reducing and steaming residue methyl alcohol is cooled to room temperature, uses ethyl acetate extraction, combining extraction liquid, water (3 * 25mL), 10% sodium hydrogen carbonate solution and water washing, collected organic layer anhydrous sodium sulfate drying successively after adding water 50mL.The reclaim under reduced pressure ethyl acetate gets faint yellow oily thing, underpressure distillation, collect (190-197) ℃/the 0.07kPa cut gets colourless liquid (3), and productive rate is 85.2-86%.Proton nmr spectra (deuterated dimethyl sulfoxide is a solvent, Bruker AM 500 instrument): δ=0.83-0.86 (t, 3H, C
H 3), 1.97 (m, 4H ,-C
H 2-CH=CH-C
H 2-), 2.26-2.29 (t, 2H ,-C
H 2-COO), 3.57 (s, 3H, COOC
H 3), 5.32 (m, 2H, C
H=C
H).
2. the preparation of mustard alcohol (4)
In the 500mL three-necked flask, add anhydrous tetrahydro furan 300mL and lithium aluminum hydride 5g (0.13 mole) successively, under agitation slowly drip methyl erucate 35g (0.1 mole), add the back and continue to stir 1h, solution gray.Reaction finishes the back and slowly drip water-containing tetrahydrofuran under ice bath, and to decompose unreacted lithium aluminum hydride, the aluminium hydroxide of adularescent generates in the solution.Reaction mixture is poured in the frozen water, used hcl acidifying, layering.With ethyl acetate (3 * 50mL) extractions, combining extraction liquid, water (3 * 25mL) washings, anhydrous sodium sulfate drying.The reclaim under reduced pressure ethyl acetate gets colorless oil, underpressure distillation, collect (208-212) ℃/the 0.07MPa cut gets colourless liquid.Crystal (4) is white in color after the cooling.Yield 86-87%.Fusing point 25.1-27.5 ℃.Proton nmr spectra (deuterated dimethyl sulfoxide is a solvent, Bruker AM 500 instrument): δ=0.83-0.86 (t, 3H, C
H 3), 1.94-1.98 (m, 4H ,-C
H 2-CH=CH-C
H 2-), 3.53 (t, 2H ,-C
H 2-OH), 3.55 (s, H ,-O
H), 5.32 (m, 2H, C
H=C
H).
3. the preparation of bromo two dodecylenes (5)
In the 250mL three-necked flask, add mustard alcohol 32.5g (0.1 mole) and 40% Hydrogen bromide 120g (0.6 mole), under agitation slowly drip vitriol oil 10mL, stirring heating backflow 6h, add water 100mL after reaction finishes, tell organic layer, add yellow soda ash till do not have carbon dioxide and overflow.With ethyl acetate (3 * 50mL) extractions, water (3 * 50mL) washings, anhydrous sodium sulfate drying.The reclaim under reduced pressure ethyl acetate gets brown oil, underpressure distillation, collect (230-238) ℃/the 0.07MPa cut gets colourless liquid (5).Yield 80.2-83%.Proton nmr spectra (deuterated dimethyl sulfoxide is a solvent, Bruker AM 500 instrument): δ=0.83-0.86 (t, 3H, C
H 3-CH
2), 2.00-2.01 (m, 4H ,-C
H 2-CH=CH-C
H 2-), 3.39-3.42 (t, 2H ,-C
H 2Br), 5.34 (m, 2H, C
H=C
H).
4. the preparation of (Z)-15-tetracosenoic acid (1)
In the 250mL three-necked flask, take by weighing sodium Metal 99.5 3.5g (0.15 mole), dropwise add dehydrated alcohol 90mL, regulate rate of addition and make ethanol keep boiling, add the back and continue to stir.Drip methyl aceto acetate 26g (0.2 mole) again, and in 1h dripping bromine generation two dodecylenes (5) 39g (0.1 mole) dropwise.Adding the back continues to reflux 6 hours.Pressure reducing and steaming ethanol adds entry and hydrochloric acid, tells organic layer.Use hcl acidifying, layering.With ethyl acetate (3 * 50mL) extractions, combining extraction liquid, water (3 * 25mL), 10% sodium hydrogen carbonate solution and water washing, anhydrous sodium sulfate drying successively.Obtain white solid, suction filtration, drying.
With the NaOH solution reaction of above-mentioned product and 50% 6 hours, use hcl acidifying, layering after adding water.(3 * 50mL) extractions, combining extraction liquid washes with water, anhydrous sodium sulfate drying with ethyl acetate.After the reclaim under reduced pressure ethyl acetate, use acetone recrystallization, filter drying.Obtain white crystal (1).Productive rate is 68%.Fusing point is 39.5-41.5 ℃.Proton nmr spectra (deuterated dimethyl sulfoxide is a solvent, Bruker AM 500 instrument): δ=0.85 (t, 3H, C
H 3-CH
2), 1.94-1.98 (m, 4H ,-C
H 2-CH=CH-C
H 2-), 2.1 (t, 2H ,-C
H 2COOH), 5.32 (m, 2H, C
H=C
H).Product detects by GC-MS turn to (Z)-15-tetracosenoic acid methyl esters through deriving after, and its cis ratio is greater than 99%.
Claims (4)
1. synthetic method with (Z)-15-tetracosenoic acid of pharmaceutical activity is characterized in that the structural formula of target compound is as follows:
2. the synthetic method of (Z)-15-tetracosenoic acid according to claim 1 is characterized in that with erucic acid be raw material, by five step reactions, obtains target compound (Z)-15-tetracosenoic acid through the alkaline hydrolysis of key intermediate compound 6.
3. the synthetic method of (Z)-15-tetracosenoic acid according to claim 1 is characterized in that the product that reacts mainly is cis-isomeride (Z)-15-tetracosenoic acid, and its cis ratio is greater than 99%.
4. the synthetic method of (Z)-15-tetracosenoic acid according to claim 1 is characterized in that used solvent is: anhydrous methanol, dehydrated alcohol and anhydrous tetrahydro furan.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102068424A (en) * | 2011-01-14 | 2011-05-25 | 哈尔滨工业大学 | Brain atrophy treating medicament prepared from active ingredient of radish seed |
| CN103396304A (en) * | 2013-08-06 | 2013-11-20 | 昆明固康保健品有限公司 | Nervonic acid chemosynthesis method |
| CN110015943A (en) * | 2019-02-01 | 2019-07-16 | 重庆中科德馨生物科技有限公司 | A kind of preparation method of nervonic acid |
| CN111423320A (en) * | 2020-03-31 | 2020-07-17 | 西北农林科技大学 | Preparation method of nervonic acid and nervonic acid |
-
2009
- 2009-03-04 CN CNA2009100941540A patent/CN101492365A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102068424A (en) * | 2011-01-14 | 2011-05-25 | 哈尔滨工业大学 | Brain atrophy treating medicament prepared from active ingredient of radish seed |
| CN103396304A (en) * | 2013-08-06 | 2013-11-20 | 昆明固康保健品有限公司 | Nervonic acid chemosynthesis method |
| CN110015943A (en) * | 2019-02-01 | 2019-07-16 | 重庆中科德馨生物科技有限公司 | A kind of preparation method of nervonic acid |
| CN111423320A (en) * | 2020-03-31 | 2020-07-17 | 西北农林科技大学 | Preparation method of nervonic acid and nervonic acid |
| CN111423320B (en) * | 2020-03-31 | 2022-11-29 | 西北农林科技大学 | Preparation method of nervonic acid and nervonic acid |
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