CN103664605A - Preparation method of brominated eneyne compound E-18-bromo-5,7,15-trialkynyl-17-ene stearate - Google Patents

Preparation method of brominated eneyne compound E-18-bromo-5,7,15-trialkynyl-17-ene stearate Download PDF

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CN103664605A
CN103664605A CN201210347339.XA CN201210347339A CN103664605A CN 103664605 A CN103664605 A CN 103664605A CN 201210347339 A CN201210347339 A CN 201210347339A CN 103664605 A CN103664605 A CN 103664605A
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formula
cuprous
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CN103664605B (en
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郭跃伟
王贺瑶
龚景旭
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Shanghai Institute of Materia Medica of CAS
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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
    • 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
    • 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
    • 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
    • C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
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Abstract

The invention relates to a synthesis method of a long-chain brominated eneyne compound E-18-bromo-5,7,15-trialkynyl-17-ene stearate with lipid-lowering and slimming activity, of which the structural formula is disclosed in the specification. The method comprises the following steps: a. carrying out bromination reaction on a compound disclosed as Formula 2 and NBS (N-bromosuccinimide) under the action of silver nitrate to generate a compound disclosed as Formula 3; b. reacting the compound disclosed as Formula 3 with 1,9-decadiyne under the actions of amine, cuprous ion and hydroxylamine hydrochloride to generate a compound disclosed as Formula 4; and c. reacting the compound disclosed as Formula 4 with 1,2-ethylene dibromide under the catalytic actions of cuprous ion, a palladium reagent and amine to obtain the compound disclosed as Formula I. The synthesis method provided by the invention is novel in synthetic route and simple to operate.

Description

Bromination eneyne compd E-18-is bromo-5,7, the preparation method of 15-tri-alkynes-17-alkene stearic acid ester
Technical field
The present invention relates to the synthetic field of medicine, particularly, the present invention relates to have the long-chain bromination eneyne compd E-18-of hypolipidemic activity bromo-5,7, the new preparation process of 15-tri-alkynes-17-alkene stearic acid ester.
Background technology
In world wide, approximately there are 1.2 hundred million people to suffer from obesity at present, have in addition 2.1 hundred million people overweight.Along with the rapid lifting of China's economic level, people's mode of life also changes thereupon.Day by day common unhealthy diet and the generally decline of physical activity level, rise rapidly the overweight incidence of China's rural and urban population, and obesity morbidity is also in rising trend in recent years.Data shows according to investigations, and 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, therefore prevention, control very urgent with treatment obesity.
In the Living marine resources that develop China, therefrom find in the process of the marine natural product with biological activity and prospect in medicine, the separated class long-chain bromination eneyne unsaturated fatty acids compound obtaining from marine organisms sponge Xestospongia Tsstudinaria: E-18-bromo-5,7,15-tri-alkynes-17-alkene stearic acid ester, its structural formula is as follows:
Figure BDA00002149616100011
Studies show that this compound has significant steapsase and suppresses active (Chinese patent application that is 201110180360.0 referring to application number).This compounds content in natural product is rare, and biogenetic derivation difficulty, has restricted it and further developed, and by synthetic method, prepares the effective way that this compounds carrys out source problem.Up to the present, the synthetic method report that does not also have this compounds.
Summary of the invention
The object of the present invention is to provide a kind of long-chain bromination eneyne compd E-18-bromo-5,7, the preparation method of 15-tri-alkynes-17-alkene stearic acid ester, described long-chain bromination eneyne compound has as shown in the formula the structure shown in 1:
Figure BDA00002149616100021
Formula 1
Wherein, R is C1-C5 alkyl, preferable methyl, ethyl, n-propyl or sec.-propyl;
Described method is undertaken by following reaction process:
Figure BDA00002149616100022
Formula 2 formulas 3
Figure BDA00002149616100023
Formula 4 formulas 1
Wherein, the definition of R is identical with the definition in formula 1;
Said method comprising the steps of:
Step a: in solvent, formula 2 compounds react with N-bromo-succinimide under Silver Nitrate effect, production 3 compounds; 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 solvent, formula 3 compounds under amine, cuprous and oxammonium hydrochloride effect with 1,9-alkyne reaction production 4 compounds in the last of the ten Heavenly stems two; 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, temperature of reaction is room temperature;
Step c: in solvent, formula 4 compounds under cuprous, palladium reagent and amine catalysis with 1,2-sym-dibromoethane reaction production I 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 palladium reagent is tetrakis triphenylphosphine palladium or two triphenylphosphine palladium chlorides; 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, temperature of reaction is room temperature.
Embodiment
Below will be bromo-5,7 with E-18-, 15-tri-alkynes-17-alkene Methyl Stearate is example, and the preparation method with the long-chain bromination eneyne compound of formula 1 structure of the present invention is described.
Reaction process:
Figure BDA00002149616100031
Formula 2 formulas 3
Figure BDA00002149616100032
Formula 4 formulas 1
Synthesizing of the bromo-5-hexynoic acid of embodiment 1:6-methyl esters (formula 3 compounds):
2.5 grams of 5-hexynoic acid methyl esters (formula 2 compounds, purchased from J & K ACROS 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 2 hours, removes by filter insolubles, filtrate decompression distillation, resistates obtains colorless oil (formula 3 compounds: 5 through column chromatography, 7,15-, tri-alkynes methyl palmitates) 2.5 grams, yield 61%.
1H?NMR(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-MS?m/z:205.0,207.0[M+1] +。
Embodiment 2:5,7,15-, tri-alkynes methyl palmitates (formula 4 compounds) synthetic:
In the reaction flask of nitrogen protection, add successively 10 ml methanol, 32 milligrams of oxammonium hydrochlorides, 10 milliliter of 70% ethamine; 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 bromo-5-hexynoic acid of the 6-methyl esters (formula 3 compounds) that are dissolved in 5 ml methanol, adds rear stirring at room 1 hour; ether extraction; dried over mgso, filters, concentrated; through column chromatography, obtain 1.3 grams of colorless oil (formula 4 compounds), yield 55%.
1H?NMR(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)； 13C?NMR(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-MS?m/z:259.2[M+1] +.
Embodiment 3:E-18-is bromo-5,7,5-tri-alkynes-17-alkene Methyl Stearate synthetic:
In the reaction flask of nitrogen protection, add 1.3 gram 5,7,15-tri-alkynes methyl palmitates (formula 4 compounds); be dissolved in 20 ml methanol, then add successively 20 milliliters of triethylamines, 1.64 milliliter 1; 2-sym-dibromoethane, 0.35 gram of four (triphenyl phosphorus) palladium, 0.12 gram of cuprous iodide; stirring at room 16 hours, filters, and filtrate is concentrated; resistates obtains colourless liquid through column chromatography, and (E-18-bromo-5; 7,5-, tri-alkynes-17-alkene Methyl Stearate) 1.2 grams, yield: 66%.
1H?NMR(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)； 13C?NMR(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-MS?m/z:363.1,365.3[M+1] +。

Claims (5)

1. a long-chain bromination eneyne compd E-18-is bromo-5,7, the preparation method of 15-tri-alkynes-17-alkene stearic acid ester, and described long-chain bromination eneyne compound has as shown in the formula the structure shown in 1:
Figure FDA00002149616000011
Formula 1
Wherein, R is C1-C5 alkyl,
Described method is undertaken by following reaction process:
Figure FDA00002149616000012
Formula 2 formulas 3
Figure FDA00002149616000013
Formula 4 formulas 1
Wherein, the definition of R is identical with the definition in formula 1;
Said method comprising the steps of:
Step a: in solvent, formula 2 compounds react with N-bromo-succinimide under Silver Nitrate effect, production 3 compounds; Described solvent is acetone or butanone; Temperature of reaction is that room temperature arrives backflow;
Step b: in solvent, formula 3 compounds under amine, cuprous and oxammonium hydrochloride effect with 1,9-alkyne reaction production 4 compounds in the last of the ten Heavenly stems two; 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 solvent, formula 4 compounds under cuprous, palladium reagent and amine catalysis with 1,2-sym-dibromoethane reaction production I 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 palladium reagent is tetrakis triphenylphosphine palladium or two triphenylphosphine palladium chlorides; 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, 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, temperature of reaction is room temperature.
CN201210347339.XA 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- Expired - Fee Related CN103664605B (en)

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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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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105218369A (en) * 2014-05-29 2016-01-06 中国科学院上海药物研究所 The new synthetic method of one class bromo unsaturated fatty acid ester

Citations (1)

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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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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)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105218369A (en) * 2014-05-29 2016-01-06 中国科学院上海药物研究所 The new synthetic method of one class bromo unsaturated fatty acid ester
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

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