CN103664605B - The preparation method of bromo-5,7, the 15-tri-alkynes-17-alkene stearic acid esters of bromination yne compounds E-18- - Google Patents
The preparation method of bromo-5,7, the 15-tri-alkynes-17-alkene stearic acid esters of bromination yne compounds E-18- Download PDFInfo
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- CN103664605B CN103664605B CN201210347339.XA CN201210347339A CN103664605B CN 103664605 B CN103664605 B CN 103664605B CN 201210347339 A CN201210347339 A CN 201210347339A CN 103664605 B CN103664605 B CN 103664605B
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- 0 *CCCC#CBr Chemical compound *CCCC#CBr 0.000 description 1
- JAWMEGWFAIOERO-BMRADRMJSA-N FC(CCCC#CC#CCCCCCCC#C/C=C/Br)(F)F Chemical compound FC(CCCC#CC#CCCCCCCC#C/C=C/Br)(F)F JAWMEGWFAIOERO-BMRADRMJSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/52—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/303—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by hydrogenation of unsaturated carbon-to-carbon bonds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The present invention relates to the synthetic method of following bromo-5,7, the 15-tri-alkynes-17-alkene stearic acid esters of long-chain bromination yne compounds E-18-of the structural formula with lowering blood-fat and reducing weight activity.The method comprises: a. formula 2 compound reacts bromination reaction with NBS under Silver Nitrate effect, production 3 compound; B. formula 3 compound under amine, cuprous and oxammonium hydrochloride effect with 1,9-alkyne reaction production 3 in the last of the ten Heavenly stems two compound; C. formula 4 compound reacts production I with 1,2-sym-dibromoethane under cuprous, palladium reagent and amine catalysis.Synthetic method provided by the invention, synthetic route is novel, easy and simple to handle.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, specifically, the present invention relates to the new preparation process of bromo-5,7, the 15-tri-alkynes-17-alkene stearic acid esters of the long-chain bromination yne compounds E-18-with hypolipidemic activity.
Background technology
About there are 1.2 hundred million people to suffer from obesity in current world wide, have 2.1 hundred million people overweight in addition.Along with the rapid lifting of China's economic level, the mode of life of people also changes thereupon.Day by day common unhealthy diet and the generally decline of physical activity level, make the overweight incidence of China's rural and urban population increase rapidly, obesity morbidity is also in rising trend in recent years.Data display according to investigations, rate that China resident is overweight is 17.6%, obesity rates is 5.6%, and sum of the two is 23.2%.Fat and the disease serious threat brought out and affect human life's safety and quality of life, it is very urgent therefore to prevent, control and treat obesity.
Developing the Living marine resources of China, therefrom finding has in the process of the marine natural product of biological activity and prospect in medicine, class long-chain bromination eneyne unsaturated fatty acids compound: the E-18-bromo-5 obtained is separated from marine organisms sponge XestospongiaTsstudinaria, 7,15-tri-alkynes-17-alkene stearic acid ester, its structural formula is as follows:
This compound of research display has significant steapsase inhibit activities (be the Chinese patent application of 201110180360.0 see application number).This compounds content in natural product is rare, and biogenetic derivation difficulty, constrains it and develop further, prepare by synthetic method the effective way that this compounds carrys out source problem.Up to the present, the synthetic method of this compounds is not also had to report.
Summary of the invention
The object of the present invention is to provide the preparation method of bromo-5,7, the 15-tri-alkynes-17-alkene stearic acid esters of a kind of long-chain bromination yne compounds E-18-, described long-chain bromination yne compounds has as shown in the formula the structure shown in 1:
Wherein, R is C1-C5 alkyl, preferable methyl, ethyl, n-propyl or sec.-propyl;
Described method is undertaken by following reaction process:
Wherein, the definition of R is identical with the definition in formula 1;
Said method comprising the steps of:
Step a: in a solvent, formula 2 compound reacts with N-bromo-succinimide under Silver Nitrate effect, production 3 compound; Described solvent is acetone or butanone; Temperature of reaction is that room temperature arrives backflow;
Preferably, described solvent is acetone, and temperature of reaction is room temperature;
Step b: in a solvent, formula 3 compound under amine, cuprous and oxammonium hydrochloride effect with 1,9-alkyne reaction production 4 in the last of the ten Heavenly stems two compound; Described amine is methylamine, ethamine, propylamine, butylamine, dimethylamine, diethylamine, dipropyl amine, dibutylamine, Trimethylamine 99, triethylamine, tripropyl amine, Tributylamine or Diisopropylamine; Described cuprous be cuprous chloride, cuprous bromide or cuprous iodide; Described solvent is methyl alcohol or ethanol; Temperature of reaction is that room temperature arrives backflow;
Preferably, described amine is ethamine, described cuprous be cuprous chloride, described solvent is methyl alcohol, and temperature of reaction is room temperature;
Step c: in a solvent, formula 4 compound reacts production 1 compound with 1,2-sym-dibromoethane under cuprous, palladium reagent and amine catalysis; Described amine is methylamine, ethamine, propylamine, butylamine, dimethylamine, diethylamine, dipropyl amine, dibutylamine, Trimethylamine 99, triethylamine, tripropyl amine, Tributylamine or Diisopropylamine; Described cuprous be cuprous chloride, cuprous bromide or cuprous iodide; Described palladium reagent is tetrakis triphenylphosphine palladium or two (triphenylphosphine) palladium chloride; Described solvent is methyl alcohol or ethanol; Temperature of reaction is that room temperature arrives backflow;
Preferably, described amine is triethylamine, described cuprous be cuprous iodide, described palladium reagent is tetrakis triphenylphosphine palladium, and temperature of reaction is room temperature.
Embodiment
Below with bromo-5,7, the 15-tri-alkynes-17-alkene Methyl Stearates of E-18-for example, the preparation method with the long-chain bromination yne compounds of formula 1 structure of the present invention will be described.
Reaction process:
The synthesis of embodiment 1:6-bromo-5-hexynoic acid methyl esters (formula 3 compound):
2.5 grams of 5-hexynoic acid methyl esters (formula 2 compounds, purchased from J & KACROS company) be dissolved in 10 milliliters of acetone, add 1.96 grams of NBS (N-bromo-succinimide) and 0.15 gram of Silver Nitrate, stirring at room temperature 2 hours, crosses and filters insolubles, and filtrate decompression is distilled, resistates obtains colorless oil (formula 3 compound: 5 through column chromatography, 7,15-tri-alkynes methyl palmitate) 2.5 grams, yield 61%.
1HNMR(300MHz,CDCl
3):δ1.78-1.88(m,2H),2.41-2.46(t,J＝7.4Hz,2H),2.26-2.31(t,J＝7.1Hz,2H),3.67(s,3H)；ESI-MSm/z:205.0,207.0[M+1]
+。
Embodiment 2:5,7,15-tri-synthesis of alkynes methyl palmitate (formula 4 compound):
10 ml methanol are added successively, 32 milligrams of oxammonium hydrochlorides, 10 milliliter of 70% ethamine in the reaction flask of nitrogen protection; 45 milligrams of cuprous chlorides and 1.2 gram 1; 9-diine in the last of the ten Heavenly stems, slowly drips the 1.9 grams of 6-bromo-5-hexynoic acid methyl esters (formula 3 compound) being dissolved in 5 ml methanol, adds rear stirring at room temperature 1 hour; ether extraction; dried over mgso, filters, concentrated; colorless oil (formula 4 compound) 1.3 grams is obtained, yield 55% through column chromatography.
1HNMR(300MHz,CDCl
3):δ1.39-1.42(m,4H),1.47-1.55(m,4H),1.82-1.89(m,2H),1.93-1.95(t,J＝2.5Hz,1H),2.16-2.21(dt,J＝2.7,6.9Hz,2H)，2.23-2.27(t,J＝6.9Hz,2H)，2.31-2.36(t,J＝6.9Hz，2H),2.42-2.47(t,J＝7.3Hz,2H),3.67(s,3H)；
13CNMR(125MHz,CDCl
3):18.5,18.8,19.3,23.6,28.3,28.4,32.8,51.7,65.3,66.3,68.3,76.1,77.9,84.7,173.5.ESI-MSm/z:259.2[M+1]
+.
The synthesis of bromo-5,7, the 5-tri-alkynes-17-alkene Methyl Stearates of embodiment 3:E-18-:
1.3 gram of 5,7,15-tri-alkynes methyl palmitate (formula 4 compound) is added in the reaction flask of nitrogen protection; be dissolved in 20 ml methanol, then add 20 milliliters of triethylamines successively, 1.64 milliliter 1; 2-sym-dibromoethane, 0.35 gram of four (triphenyl phosphorus) palladium, 0.12 gram of cuprous iodide; stirring at room temperature 16 hours, filters, and filtrate concentrates; resistates obtains colourless liquid (E-18-bromo-5 through column chromatography; 7,5-tri-alkynes-17-alkene Methyl Stearate) 1.2 grams, yield: 66%.
1HNMR(300MHz,CDCl
3):δ1.35-1.39(m,4H),1.48-1.54(m,4H),1.81-1.89(m,2H),2.23-2.26(m,2H)，2.30-2.36(m,2H)，6.14-6.15(dt,J＝1.8，14.1Hz,1H),6.54-6.59(d,J＝14.1Hz,1H),3.67(s,3H)；
13CNMR(125MHz,CDCl
3):18.6,19.1,19.3,23.5,28.1,28.2,32.6,51.6,65.2,66.1,76.0,77.7,93.0,117.0,118.0.ESI-MSm/z:363.1,365.3[M+1]
+.
Claims (5)
1. the preparation method of bromo-5,7, the 15-tri-alkynes-17-alkene stearic acid esters of long-chain bromination yne compounds E-18-, described long-chain bromination yne compounds has as shown in the formula the structure shown in 1:
Wherein, R is C1-C5 alkyl,
Described method is undertaken by following reaction process:
Wherein, the definition of R is identical with the definition in formula 1;
Said method comprising the steps of:
Step a: in a solvent, formula 2 compound reacts with N-bromo-succinimide under Silver Nitrate effect, production 3 compound; Described solvent is acetone or butanone; Temperature of reaction is that room temperature arrives backflow;
Step b: in a solvent, formula 3 compound under amine, cuprous and oxammonium hydrochloride effect with 1,9-alkyne reaction production 4 in the last of the ten Heavenly stems two compound; Described amine is methylamine, ethamine, propylamine, butylamine, dimethylamine, diethylamine, dipropyl amine, dibutylamine, Trimethylamine 99, triethylamine, tripropyl amine, Tributylamine or Diisopropylamine; Described cuprous be cuprous chloride, cuprous bromide or cuprous iodide; Described solvent is methyl alcohol or ethanol; Temperature of reaction is that room temperature arrives backflow;
Step c: in a solvent, formula 4 compound reacts production 1 compound with 1,2-sym-dibromoethane under cuprous, palladium reagent and amine catalysis; Described amine is methylamine, ethamine, propylamine, butylamine, dimethylamine, diethylamine, dipropyl amine, dibutylamine, Trimethylamine 99, triethylamine, tripropyl amine, Tributylamine or Diisopropylamine; Described cuprous be cuprous chloride, cuprous bromide or cuprous iodide; Described palladium reagent is tetrakis triphenylphosphine palladium or two (triphenylphosphine) palladium chloride; Described solvent is methyl alcohol or ethanol; Temperature of reaction is that room temperature arrives backflow.
2. preparation method according to claim 1, wherein,
R is methyl, ethyl, n-propyl or sec.-propyl.
3. preparation method according to claim 1, wherein,
In described step a, described solvent is acetone, and temperature of reaction is room temperature.
4. preparation method according to claim 1, wherein,
In described step b, described amine is ethamine, described cuprous be cuprous chloride, described solvent is methyl alcohol, and temperature of reaction is room temperature.
5. preparation method according to claim 1, wherein,
In described step c, described amine is triethylamine, described cuprous be cuprous iodide, described palladium reagent is tetrakis triphenylphosphine palladium, and temperature of reaction is room temperature.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210347339.XA CN103664605B (en) | 2012-09-17 | 2012-09-17 | The preparation method of bromo-5,7, the 15-tri-alkynes-17-alkene stearic acid esters of bromination yne compounds E-18- |
| PCT/CN2013/081764 WO2014040477A1 (en) | 2012-09-17 | 2013-08-19 | Process for preparing brominated enyne compound e-18-bromo-5,7,15-triyne-17-ene octadecanoic acid ester |
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|---|---|---|---|
| CN201210347339.XA CN103664605B (en) | 2012-09-17 | 2012-09-17 | The preparation method of bromo-5,7, the 15-tri-alkynes-17-alkene stearic acid esters of bromination yne compounds E-18- |
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| Publication Number | Publication Date |
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| CN103664605A CN103664605A (en) | 2014-03-26 |
| CN103664605B true CN103664605B (en) | 2015-12-09 |
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| CN105218369B (en) * | 2014-05-29 | 2018-04-17 | 中国科学院上海药物研究所 | The new synthetic method of a kind of bromo unsaturated fatty acid ester |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102311314A (en) * | 2011-07-06 | 2012-01-11 | 帕潘纳(北京)科技有限公司 | Synthetic method of Falcarinol |
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- 2012-09-17 CN CN201210347339.XA patent/CN103664605B/en not_active Expired - Fee Related
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102311314A (en) * | 2011-07-06 | 2012-01-11 | 帕潘纳(北京)科技有限公司 | Synthetic method of Falcarinol |
Non-Patent Citations (2)
| Title |
|---|
| A Novel C-27 Nor Steroid from the Marine Sponge Petrosia Testudinaria;N.S.REDDY et al.;《Natural Product Letters》;19991231;第14卷(第2期);第131-134页 * |
| Fabio Bellina et al..First Total Synthesis of Naturally Occurring (-)-Nitidon and Its Enantiomer.《Eur. J. Org. Chem.》.2004,第2610-2619页. * |
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| WO2014040477A1 (en) | 2014-03-20 |
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