CN101774875A - Method for synthesizing piperlongumine compounds - Google Patents
Method for synthesizing piperlongumine compounds Download PDFInfo
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Abstract
The invention provides a method for synthesizing piperlongumine compounds, wherein the compounds are coupled by adopting acromatic carboxylic acid and amido compounds in the presence of coupling reagent. The method has the advantages of mild reaction condition and simple and convenient operation method, and is suitable for batch production of the compounds.
Description
Technical field
The present invention relates to a kind of synthetic method of alkaloid compound, specifically, relate to a kind of synthetic method of Piperlongumine compounds.
Background technology
The Piper longum acid amides claims the bright alkali of Piper longum, Piperlongumine again, English piperlongumine by name or piplartine, and chemical formula is: C
17H
19NO
5, molecular weight is 317.34, CAS number is 20069-09-4.
The Piper longum acid amides belongs to alkaloid compound, is white flash needle crystal (alcohol-ether) 124 ℃ of fusing points.Be mainly derived from fruit, root and stem etc. that piperaceae plant Bi dials (Piper longum L.).
Piper longum has just had more widely in China from ancient times and has used as traditional simply herbal medicine, and the traditional Chinese medical science thinks that it is hot in nature, flavor is hot, returns stomach, large intestine channel.According to " the Chinese pharmacopoeia record: it has warming spleen and stomach for dispelling cold, and therapeutic method to keep the adverse qi flowing downward lenitive effect is used for coldness and pain in the epigastrium, and migraine is had loose bowels in vomiting; Control toothache outward.
In recent years, relevant for the herbal prescription emerge in multitude of Piper longum as: CN1096693A is provided for treating the prescription of toothache, CN1128164A is provided for treating the prescription of rhinitis, CN1768844A is provided for treating the prescription of stomachache, CN1579440A is provided for treating the prescription of cervical spondylosis, and CN101524508A is provided for prescription of preventing and treating avian bird flu etc.Development along with modern science and technology, Piper longum acid amides as Piper longum important activity composition more and more causes investigator's concern, WO2008/147483A2 provides Piper longum acid amides and analogue thereof to damage the method for the nervous tissue relative disease that causes at the treatment hippocampus, WO2009/038684A1 provides the Piper longum acid amides in a kind of methods of treatment of carrying out the multiple demyelinating disease PML of sexual centre neural system (progressive mutifocal leukoencephathy, progressive multifocal leukoencephalopathy); WO2009/114126A1 provides Piper longum acid amides and the application of analogue aspect the treatment cancer thereof, further studies show that, the Piper longum acid amides has the effect that well brings high blood pressure down, what is more important, a large amount of Piper longum acid amides that studies show that can effectively be resisted hematoblastic gathering, collagen protein, arachidonic acid and platelet activation factor are caused that platelet aggregation has obvious effects, can be used as the potential antithrombotic reagent, (Phytomedicine 2007 to be widely used in the treatment of cardiovascular and cerebrovascular diseases, 14,853; European Joumal ofPharmacology 2007,57,380).In addition, the Piper longum acid amides suppresses fungi effect (Phytochemistry.2000,55,621. in addition preferably; Crop.Prto.2001,20,523.) and certain antidepressant effect (Phytomedicine 2007,14,605), be expected to aspect medical, use widely.
But the Piper longum acid amides is as the potential drug of a class widespread use, and its main source still extracts (Phytochemistry.1997,44,727. from root, stem, leaf and the fruit of piperaceae plants such as Piper longum; Phytochemistry.2000,53,51.; Biochemical Systematics andEcology 2005,33,753.).Often contain the number of chemical composition in these plant extraction liquids as Piper longum acid amides (piplartine, piperlongumine), dihydro Piper longum acid amides (dihydropiperlonguminine), piperamide (piperine, pipercide), palmitinic acid (palmitic acid), tetrahydropiperic acid (tetrahydro-piperic acid), piperidines (piperine), sesamin (sesamin), Guinea's piperamide (guineensine), N-isobutyl-18 carbon-2,4-diene amide (N-isobutyloctadeca-2 (E), 4 (E)-dienamide), N-isobutyl-20 carbon-2,4-diene amide (N-isobutyleicosa-2 (E)-4 (E)-dienamide) etc., these chemical ingredientss have similar physicochemical property, tend to cause compound separation, production efficiency is hanged down inferior difficulty.And the scale operation of plant extract method, also can cause certain environmental problem.
This shows that the plant extract method is time-consuming, effort and input-output ratio are low, thereby the chemical synthesis process of development Piperlongumine compounds just has great importance.
Summary of the invention
The synthetic method that the purpose of this invention is to provide a kind of Piperlongumine compounds, this method reaction conditions gentleness, working method are easy.
In order to realize the object of the invention, the invention provides a kind of synthetic method of Piperlongumine compounds, adopt compound coupling under the effect of coupling reagent of aromatic carboxylic acid and amido to form; The general formula of wherein said Piperlongumine compounds is as follows:
Wherein, R
1, R
2, R
3Represent hydrogen, hydroxyl, methoxyl group, oxyethyl group, propoxy-, not substituted-amino, substituted amido, halogen respectively independently.
Preferred R
1, R
2, R
3Represent hydroxyl, methoxyl group, oxyethyl group respectively independently.
More preferably R
1, R
2, R
3Represent methoxyl group respectively independently.
Linked reaction of the present invention is dissolved in aromatic carboxylic acid in the organic solvent (methylene dichloride, trichloromethane etc.) earlier, the compound that adds amido then under cold condition, adds coupling reagent two-carbodicyclo hexylimide (DCC), react, obtain Piperlongumine compounds.Described cold condition is for carrying out under-15--30 ℃.
Linked reaction of the present invention also can adopt: earlier aromatic carboxylic acid and organic bases (triethylamine, diisopropyl ethyl amine etc.) are dissolved in the organic solvent (methylene dichloride, trichloromethane etc.), be cooled to low temperature, add pivalyl chloride (2,2-dimethyl propylene acyl chlorides), the compound that adds amido again, reaction is spent the night, and obtains Piperlongumine compounds.
Described cold condition is for to carry out under 0--10 ℃.
Described amino-complex is various primary amine and secondary amine, such as 5, and 6-dihydro-2 (1)-pyridone, 6-methyl-5,6-dihydro-2 (1)-pyridone, 1,2,3,4-tetrahydropyridine, piperidines, piperazine, morphine, Pyrrolidine etc.
The present invention reacts compound that the back obtains and all adopts the post-treating method (washing, concentrate, crystallization etc.) of this area routine to purify.
Aromatic carboxylic acid of the present invention and amine group containing linked reaction, the reaction conditions gentleness, method is simple; Cost of material is cheap, and method of the present invention is suitable for the batch process of this compounds.
Synthesis path provided by the invention can be selected different raw materials as required, constructs a series of Piperlongumine compounds easily, synthetic route provided by the invention, and reaction conditions gentleness, working method are easy, are applicable to the batch process of this compounds.
Embodiment
Following examples are used to illustrate the present invention, but are not used for limiting the scope of the invention.
Laboratory apparatus and material
Nuclear magnetic resonance analyser: Varian WM-300 (300MHz), Bruker ARX-400 (400MHz) Spectrometer
Mass spectrograph: VG-ZAB-HS EI, Bruker Biflex III MALDI-TOF
Medicine and reagent: 3,4, the 5-TMB is available from Alfa Aesar company, pivalyl chloride is available from Arcos company, 1,2,3, the 4-tetrahydropyridine is available from triumphant rich in Wuhan, propanedioic acid, pyridine, piperidines, piperazine, Sorbic Acid, morpholine, Pyrrolidine, triethylamine, palladium-carbon catalyst ammoniacal liquor etc. are available from Beijing chemical reagents corporation, and common solvent is available from Beijing chemical reagents corporation, and solvent is analytical pure, as not having particular requirement, solvent directly uses.
The methylene dichloride drying means: the heavy evaporate to dryness of hydrolith is dry.
Synthesizing of embodiment 1 aromatic carboxylic acid:
Reaction reagent and condition: a) propionic acid, pyridine, piperidines; B) H
2, Pd/C, ethanol.
3,4,5, synthesizing of-trimethoxy cinnamic acid: 3,4,5,-TMB 39.2g (0.2mol) and propanedioic acid 41.6g (0.4mol) are dissolved in the 300ml pyridine, and add the 2.5ml piperidines, be heated to 50 ℃, reaction 3h is to the raw material complete reaction, be cooled to room temperature, add 2M hydrochloric acid and transfer to pH value of solution=5, ethyl acetate extraction (200ml * 3), merge organic phase, with saturated aqueous common salt and secondary water washing are washed anhydrous Na respectively
2SO
4Drying, concentrate crude product, crude product CH
3OHH
2The O recrystallization gets colourless needle crystal 34.7g, yield 72%.
1H-NMR：(400MHz，CDCl
3，ppm)δ：3.93(s，9H)，6.37(d，1H)，6.82(s，2H)，7.79(d，1H)，.11.3(b，1H)MS-ESI(m/z)：239(M+H)
+.
3 ', 4 ', 5 ' ,-trimethoxy-3-phenylpropionic acid synthetic: 3,4,5 ,-trimethoxy cinnamic acid 4.76g (0.02mol) is dissolved in the 80ml ethanol, and adds 0.4g10%Pd/C, reaction system vacuumizes, and pours high purity nitrogen, vacuumizes again, pours hydrogen, replace repeatedly three times, hydrogen gas pressure (external hydrogen balloon) in the maintenance system, room temperature reaction 24h is to the raw material complete reaction, filter, filter catalyzer, use the washing with alcohol filter residue, merge organic phase, concentrate crude product, crude product CH
3OHH
2The O recrystallization gets white solid 4.56g, yield 95%.
1H-NMR：(400MHz，CDCl
3，ppm)δ：2.57(t，2H)，2.86(t，2H)，3.84(s，9H)，6.37(s，2H)，.11.3(b，1H)MS-ESI(m/z)：241(M+H)
+.
Synthesizing of embodiment 2 amino-complexs:
5,6-dihydro-2 (1)-pyridone synthetic: 20g vinylacrylic acid ((E)-penta-2,4-diolefinic acid) (0.051mol) places the 500ml autoclave with 100ml ammoniacal liquor (0 ℃ saturated), be heated to 180 ℃, reaction 24h is cooled to room temperature, concentration of reaction solution obtains the syrupy shape thick liquid, adds the methyl alcohol of heat, and backflow 3h, be cooled to room temperature after, concentrate, remove reaction solvent methyl alcohol, 120～125 ℃/1mmHg is collected in underpressure distillation, obtains product 6g.The target compound instability is preferably now done existing usefulness.
1H-NMR：(400MHz，CDCl
3，ppm)δ：2.31(m，2H)，3.43(t，2H)，6.23(m，2H)，.7.8(b，1H，NH)，MS-EI(m/z)：97(M)
+。
6-methyl-5,6-dihydro-2 (1)-pyridone synthetic: the 20g Sorbic Acid (2E, 4E)-oneself is-2 years old, 4-diolefinic acid (0.051mol) places the 500ml autoclave with 100ml ammoniacal liquor (0 ℃ saturated), is heated to 180 ℃, reaction 24h, be cooled to room temperature, concentration of reaction solution obtains the syrupy shape thick liquid, the methyl alcohol that adds heat, and backflow 3h, be cooled to room temperature after, concentrate, remove reaction solvent methyl alcohol, underpressure distillation, 130～136 ℃/6mmHg, obtain product 6.4g.
1H-NMR：(400MHz，CDCl
3，ppm)δ：1.31(d，3H)，2.03～2.34(m，2H)，3.78(m，1H)，6.45(m，2H)，.8.0(b，1H，NH)，MS-EI(m/z)：111(M)
+。
Synthesizing of embodiment 3 Piper longum acid amides (compound 1):
3,4, (0.714g 3mmol) is dissolved in the 25ml dry methylene chloride 5-trimethoxy cinnamic acid, add 5,6-dihydro-2 (1)-pyridone (0.35g, 3.6mmol), reaction system is cooled to-20 ℃, add DCC (0.68g, 3.3mmol), reaction system gets warm again after a cold spell gradually to room temperature, continues reaction and spends the night.
After reacting completely, reaction system is used saturated NaHCO respectively
3Solution and secondary water washing are washed, and the organic phase dried over mgso concentrates, and crude product separates (eluent: petrol ether/ethyl acetate=1/1) get Piper longum acid amides 0.6g, productive rate: 63% with silicagel column.
1H-NMR：(400MHz，CDCl
3，ppm)δ：2.45(m，2H)，3.92(s，9H)，4.05(m，2H)，6.12(m，1H)，6.80(s，2H)，6.94(m，1H)，7.37(m，1H)，7.75(m，1H).MS-EI(m/z)：317(M)
+。
Synthesizing of embodiment 4 compounds 2:
3,4,5,-trimethoxy cinnamic acid (0.714g, 3mmol) be dissolved in the 25ml dry methylene chloride, add 6-methyl-5,6-dihydro-2 (1)-pyridone (0.4g, 3.6mmol), reaction system is cooled to-20 ℃, and adding DCC (0.68g, 3.3mmol), reaction system gets warm again after a cold spell gradually to room temperature, continues reaction and spends the night.
After reacting completely, reaction system is used saturated NaHCO respectively
3Solution and secondary water washing are washed, and the organic phase dried over mgso concentrates, and crude product separates (eluent: petrol ether/ethyl acetate=1/1) get target product 0.41g, productive rate: 41% with silicagel column.
1H-NMR：(400MHz，CDCl
3，ppm)δ：1.29(d，3H)，2.41(m，2H)，3.87(s，9H)，4.13(m，1H)，6.21(m，1H)，6.83(s，2H)，7.03(m，1H)，7.39(m，1H)，7.79(m，1H).MS-EI(m/z)：331(M)
+.
Synthesizing of embodiment 5 compounds 3:
3,4, (0.714g 3mmol) is dissolved in the 25ml dry methylene chloride 5-trimethoxy cinnamic acid, adds 1,2,3, and the 4-tetrahydropyridine (0.3g, 3.6mmol), reaction system is cooled to-20 ℃, (0.68g, 3.3mmol), reaction system gets warm again after a cold spell gradually to room temperature, continues reaction and spends the night to add DCC.
After reacting completely, reaction system is used saturated NaHCO respectively
3Solution and secondary water washing are washed, and the organic phase dried over mgso concentrates, and crude product separates (eluent: petrol ether/ethyl acetate=1/1) get target product 0.53g, productive rate: 58% with silicagel column.
1H-NMR：(400MHz，CDCl
3，ppm)δ：1.48(m，2H)，2.05(m，2H)，3.90(s，9H)，4.23(t，2H)，5.09(m，1H)，6.81(s，2H)，7.05(m，1H)，7.35(m，1H)，7.73(m，1H).MS-EI(m/z)：303(M)
+。
Synthesizing of embodiment 6 compounds 4:
3,4,5-trimethoxy cinnamic acid (0.714g, 3mmol) (0.5ml 3.6mmol) is dissolved in the 5ml dry methylene chloride, and reaction system is cooled to 0 ℃ with triethylamine, slowly drip 10ml pivalyl chloride (0.41ml, 3.3mmol) dichloromethane solution, the reaction 2h, keeping temperature of reaction is 0 ℃, add piperidines (0.38g, 4.5mmol), reaction system gets warm again after a cold spell gradually to room temperature, continues reaction and spends the night.
After reacting completely, reaction system is washed with 1MHCl solution and secondary water washing respectively, and the organic phase dried over mgso concentrates, and crude product separates (eluent: petrol ether/ethyl acetate=1/1) get target product 0.7g, productive rate: 77% with silicagel column.
1H-NMR：(400MHz，CDCl
3，ppm)δ：1.31～1.65(m，6H)，3.32(m，4H)，3.92(s，9H)，6.83(s，2H)，7.41(m，1H)，7.75(m，1H).MS-EI(m/z)：305(M)
+。
Synthesizing of embodiment 7 compounds 5:
3,4,5-trimethoxy cinnamic acid (0.714g, 3mmol) (0.5ml 3.6mmol) is dissolved in the 5ml dry methylene chloride, and reaction system is cooled to 0 ℃ with triethylamine, slowly drip l0ml pivalyl chloride (0.41ml, 3.3mmol) dichloromethane solution, the reaction 2h, keeping temperature of reaction is 0 ℃, add piperazine (1.29g, 15mmol), reaction system gets warm again after a cold spell gradually to room temperature, continues reaction and spends the night.
After reacting completely, reaction system is washed with 1MHCl solution and secondary water washing respectively, and the organic phase dried over mgso concentrates, and crude product separates (eluent: petrol ether/ethyl acetate=1/1) get target product 0.65g, productive rate: 71% with silicagel column.
1H-NMR：(400MHz，CDCl
3，ppm)δ：2.91(m，4H)，3.39(m，4H)，3.54(b，1H，NH)，3.90(s，9H)，6.81(s，2H)，7.37(m，1H)，7.70(m，1H).MS-EI(m/z)：306(M)
+。
Synthesizing of embodiment 8 compounds 6:
3,4,5-trimethoxy cinnamic acid (0.714g, 3mmol) (0.5ml 3.6mmol) is dissolved in the 5ml dry methylene chloride, and reaction system is cooled to 0 ℃ with triethylamine, slowly drip 10ml pivalyl chloride (0.41ml, 3.3mmol) dichloromethane solution, the reaction 2h, keeping temperature of reaction is 0 ℃, add morpholine (0.31g, 3.6mmol), reaction system gets warm again after a cold spell gradually to room temperature, continues reaction and spends the night.
After reacting completely, reaction system is washed with 1MHCl solution and secondary water washing respectively, and the organic phase dried over mgso concentrates, and crude product separates (eluent: petrol ether/ethyl acetate=1/1) get target product 0.75g, productive rate: 82% with silicagel column.
1H-NMR：(400MHz，CDCl
3，ppm)δ：3.2(t，4H)，3.6(t，4H)，3.93(s，9H)，6.79(s，2H)，7.31(m，1H)，7.64(m，1H).MS-EI(m/z)：307(M)
+。
Synthesizing of embodiment 9 compounds 7:
3,4,5-trimethoxy cinnamic acid (0.714g, 3mmol) (0.5ml 3.6mmol) is dissolved in the 5ml dry methylene chloride, and reaction system is cooled to 0 ℃ with triethylamine, slowly drip 10ml pivalyl chloride (0.41ml, 3.3mmol) dichloromethane solution, the reaction 2h, keeping temperature of reaction is 0 ℃, add Pyrrolidine (0.26g, 3.6mmol), reaction system gets warm again after a cold spell gradually to room temperature, continues reaction and spends the night.
After reacting completely, reaction system is washed with 1MHCl solution and secondary water washing respectively, and the organic phase dried over mgso concentrates, and crude product separates (eluent: petrol ether/ethyl acetate=1/1) get target product 0.75g, productive rate: 82% with silicagel column.
1H-NMR：(400MHz，CDCl
3，ppm)δ：1.73(m，4H)，3.41(m，4H)，3.89(s，9H)，6.80(s，2H)，7.16(m，1H)，7.53(m，1H).MS-EI(m/z)：291(M)
+。
Synthesizing of embodiment 10 compounds 8:
3 ', 4 ', 5 ',-trimethoxy-3-phenylpropionic acid (0.72g, 3mmol) be dissolved in the 25ml dry methylene chloride, add 5,6-dihydro-2 (1)-pyridone (0.35g, 3.6mmol), reaction system is cooled to-20 ℃, and adding DCC (0.68g, 3.3mmol), reaction system gets warm again after a cold spell gradually to room temperature, continues reaction and spends the night.
After reacting completely, reaction system is used saturated NaHCO respectively
3Solution and secondary water washing are washed, and the organic phase dried over mgso concentrates, and crude product separates (eluent: petrol ether/ethyl acetate=1/1) get target compound 0.64g, productive rate: 67% with silicagel column.
1H-NMR：(400MHz，CDCl
3，ppm)δ：2.31(m，2H)，2.53(m，2H)，2.90(t，2H)，3.47(t，2H)，3.85(s，9H)，6.16(m，1H)，6.54(s，1H)，6.83(m，2H).MS-EI(m/z)：319(M)
+。
Synthesizing of embodiment 11 compounds 9:
3 ', 4 ', 5 ',-trimethoxy-3-phenylpropionic acid (0.72g, 3mmol) be dissolved in the 25ml dry methylene chloride, add 6-methyl-5,6-dihydro-2 (1)-pyridone (0.4g, 3.6mmol), reaction system is cooled to-20 ℃, and adding DCC (0.68g, 3.3mmol), reaction system gets warm again after a cold spell gradually to room temperature, continues reaction and spends the night.
After reacting completely, reaction system is used saturated NaHCO respectively
3Solution and secondary water washing are washed, and the organic phase dried over mgso concentrates, and crude product separates (eluent: petrol ether/ethyl acetate=1/1) get target compound 0.37g, productive rate: 37% with silicagel column.
1H-NMR：(400MHz，CDCl
3，ppm)δ：1.32(d，3H)，2.06～2.21(m，2H)，2.45(m，2H)，2.85(t，2H)，3.58(m，1H)，3.90(s，9H)，6.18(m，1H)，6.59(s，1H)，6.85(m，2H).MS-EI(m/z)：333(M)
+.
Synthesizing of embodiment 12 compounds 10:
3 ', 4 ', 5 ',-trimethoxy-3-phenylpropionic acid (0.72g, 3mmol) (0.5ml 3.6mmol) is dissolved in the 5ml dry methylene chloride with triethylamine, reaction system is cooled to 0 ℃, slowly drips 10ml pivalyl chloride (0.41ml, dichloromethane solution 3.3mmol), reaction 2h, keeping temperature of reaction is 0 ℃, and the adding morpholine (0.31g, 3.6mmol), reaction system gets warm again after a cold spell gradually to room temperature, continues reaction and spends the night.
After reacting completely, reaction system is washed with 1MHCl solution and secondary water washing respectively, and the organic phase dried over mgso concentrates, and crude product separates (eluent: petrol ether/ethyl acetate=1/1) get target product 0.7g, productive rate: 75% with silicagel column.
1H-NMR：(400MHz，CDCl
3，ppm)δ：2.51(m，2H)，2.77(t，2H)，3.41(t，4H)，3.68(t，4H)，3.91(s，9H)，6.65(s，2H)，.MS-EI(m/z)：309(M)
+。
Utilize the synthetic Piperlongumine compounds of method preparation provided by the invention, simple to operate, with low cost, be suitable for the batch process of Piperlongumine compounds.
Though above the present invention is described in detail with a general description of the specific embodiments, on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements all belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.
Claims (10)
1. the synthetic method of a Piperlongumine compounds is characterized in that, adopts compound coupling under the effect of coupling reagent of aromatic carboxylic acid and amido to form;
The general formula of wherein said Piperlongumine compounds is as follows:
-NHCH
2CH
2CH
2CH
3-N(CH
2CH
2CH
2CH
3)
2-NHCH
2CH(CH
3)
2
R
1, R
2, R
3Represent hydrogen, hydroxyl, methoxyl group, oxyethyl group, propoxy-, not substituted-amino, substituted amido, halogen respectively independently.
2. method according to claim 1 is characterized in that R
1, R
2, R
3Represent hydroxyl, methoxyl group, oxyethyl group respectively independently.
3. method according to claim 1 and 2 is characterized in that R
1, R
2, R
3Represent methoxyl group respectively independently.
4. according to any described method of claim 1-3, it is characterized in that, described linked reaction is dissolved in aromatic carboxylic acid in the organic solvent earlier, the compound that adds amido then, under cold condition, add coupling reagent two-carbodicyclo hexylimide, react, obtain Piperlongumine compounds.
5. method according to claim 4 is characterized in that, described organic solvent is methylene dichloride or trichloromethane.
6. according to claim 4 or 5 described methods, it is characterized in that the compound of described amido is primary amine or secondary amine.
7. according to any described method of claim 1-3, it is characterized in that described linked reaction is dissolved in aromatic carboxylic acid and organic bases in the organic solvent earlier, be cooled to low temperature, add pivalyl chloride, add the compound of amido again, reaction is spent the night, and obtains Piperlongumine compounds.
8. method according to claim 7 is characterized in that, described organic bases is triethylamine or diisopropyl ethyl amine.
9. method according to claim 7 is characterized in that, described organic solvent is methylene dichloride or trichloromethane.
10. method according to claim 7 is characterized in that, the compound of described amido is primary amine and secondary amine.
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