CN102675110A - Novel production process for chemical synthesis of zeylenone - Google Patents
Novel production process for chemical synthesis of zeylenone Download PDFInfo
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- CN102675110A CN102675110A CN2011100556733A CN201110055673A CN102675110A CN 102675110 A CN102675110 A CN 102675110A CN 2011100556733 A CN2011100556733 A CN 2011100556733A CN 201110055673 A CN201110055673 A CN 201110055673A CN 102675110 A CN102675110 A CN 102675110A
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- zeylenone
- benzoyloxy
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Abstract
The invention discloses a novel production process for chemical synthesis of zeylenone. The chemical name of the zeylenone is (4R, 5S, 6S)-4-(benzoyloxy)-6-[(benzoyloxy) methyl]-5, 6-dihydroxy-2-cyclohexen-1-one. The CAS number of the zeylenone is 193410-84-3. According to the novel production process for the chemical synthesis of the zeylenone, production cost can be reduced, yield of pharmaceutical chemicals of the zeylenone can be improved, and an effective preparation method of the novel chemical medicine can be provided.
Description
Technical field
The invention belongs to medicine synthetic chemistry field, be specifically related to that a kind of (5R)-3,4,5-trihydroxycyclohex-1-enecarboxylic acid begins for 3R, 4S, the method for the synthetic sub-ketenes of Chinese pepper on the level of feather weight from simple raw material.
Background technology
People's research for many years shows that the polyoxy substituted cyclohexene is the unique natural component of a class formation, separates obtaining so far surplus in the of existing 20 in the crotons platymiscium of the Piper of kind of the Qarnet dish genus from annonaceae, piperaceae and Euphorbiaceae.The crotepoxide (crotepoxide) that the end of the sixties, report such as Kupchan was assigned in long fringe crotons shows the intensive anti-tumor activity in animal body; Once once causing great interest (the Thebtaranonth C of people to this constituents; Thebtaranonth Y.Naturally occurring cyclohexene oxides.Accounts Chem Res; 1986,1984).A simple 1-methyl cyclohexane-4-alkene parent nucleus is all arranged in the specific examples of such components molecule.
Da Hua Qarnet dish (Uvaria grandiflora Roxb.) is a kind of climbing shrub that annonaceae Qarnet dish belongs to, and is distributed in the ground such as Hainan, Guangdong and Guangxi of China.In the product Da Hua Qarnet packing stem ethanol extraction of Hainan, tell 3 kinds of new anti-tumor activity Annona lactones and 2 kinds of new polyoxy substituted cyclohexene constituents.Research shows that from plant Chinese pepper (Uvaria grandiflora), separating the sub-ketenes of new compound Chinese pepper (following formula) that obtains has anti-tumor activity; Its characteristics have remarkable lethal effect to the multi-drug resistance tumor cell, can obviously strengthen the lethal effect of Zorubicin to the cell of tumour.
In view of the antitumor action of this compound, the effective antitumour medicine certainly will can be become.Yet this compound content in natural product is less, and the extraction separation difficulty is high, can not adapt to deep one-tenth property of medicine evaluation study.The chemical complete synthesis existing report of this compound (Chemical & Pharmaceutical Bulletin (2006), 54 (10), 1459-1461.), but because at the bottom of the productive rate, repeatable poor, can not be experimentation on animals and the required feather weight amount of clinical experiment.Therefore, must there be reliable compound method that the source of this compound is provided.
Summary of the invention
The objective of the invention is to overcome the deficiency of existing compound method; Explore through experiment, verify, finally set up the feather weight compound method of this compound; Solve the technological difficulties of the sub-ketenes synthesis technique of Chinese pepper, made it to be applicable to more large-scale industrial production.Compare with existing compound method, we are the advantage of technology: raw material is cheap, and midbody is stable, and product is purified easily, has good economy and practical value.
The present invention through following be exactly that scheme realizes: low-cost (5R)-3,4,5-trihydroxycyclohex-1-enecarboxylic acid is one kilogram of a starting raw material for 3R, 4S with in plentiful supply.Through over-churning, protection, configuration inversion, reduction, protection, oxidation, protection, deprotection becomes series reaction such as alkene, obtains midbody 260 grams (as follows).
This midbody is through nucleus magnetic resonance and mass spectral evaluation.
For overcoming the deficiency of existing method, be converted into target compound I from the compound I I of following formula, we obtain compound III with the intermediate II halogenation, wherein X=Cl and Br.Halogenated method comprises uses POCl
3, PCl
5, PCl
3, NBS, NCS, HBr, HCl, Cl
2, and Br
2Compound III hydrolysis under alkaline condition obtains oxy-compound IV, R=H wherein, and when the pH value was alkalescence, R can be metals ions such as Li, Na and K.Oxy-compound IV handles with oxidising agent and obtains ketenes (V), obtains the sub-ketenes of Chinese pepper (I) with acid hydrolysis at last.
The used solvent of halogenating reaction is CH
3CN, benzene, toluene, THF, dioxane etc.Temperature of reaction is spent to 110 degree Celsius-5, and the reaction times is 10 minutes to 12 hours.Hydrolysis reaction is used NaOH, LiOH, KOH, Li
2CO
3, Na
2CO
3, K
2CO
3, LiHCO
3, NaHCO
3, KHCO
3In alkali.Be reflected at water, methyl alcohol, CH
3Carry out in any two or three s' the mixing solutions among the CN or among the three.Temperature of reaction is spent to 100 degree Celsius 5, and the reaction times is 30 minutes to 12 hours.The oxygenant of oxidizing reaction is KMnO
4, MnO
2, OsO
4, PCC, PDC, CrO
3Deng.Be reflected in the water CH
3CN, CH
2Cl
2, CHCl
3, CCl
4, carry out in the acetone etc.Temperature of reaction is spent to 100 degree Celsius-5, and the reaction times is 40 minutes to 12 hours.Last acid hydrolytic reaction is used hydrochloric acid, and sulfuric acid, nitric acid, acetic acid, trifluoroacetic acid, phosphoric acid etc. is at water, methyl alcohol, CH
3Carry out in any two or three s' the mixing solutions among the CN or among the three.Temperature of reaction is spent to 100 degree Celsius-5, and the reaction times is 20 minutes to 12 hours.Compare with the compound method of delivering, the present invention has actual property characteristics and marked improvement, can obtain the feather weight product, aspect industrialization, has broad application prospects.
The practical implementation method
The present invention can be better understood through specific embodiment, but content of the present invention can not be limited.
Embodiment 1 preparation intermediate III:
Compound I I 50 grams, n-NBS (NBS) 150 grams, benzene 250mL puts into three mouthfuls of round-bottomed flasks of 500mL, and 25 ℃ were stirred 5 hours down.Undissolved thing is filtered out three times (100mL * 3) of solution with water extraction.Organic phase is used anhydrous sodium sulfate drying, gets faint yellow solid compound III 55 grams with ethyl alcohol recrystallization.
1H?NMR(400mHz，CDCl
3)ppm：7.98(m，ArH，4H)，7.48-7.35(m，ArH，6H)，5.61(m，CH＝CH，2H)，5.01(m，1H)，4.82(s，1H)，4.60-4.30(m，3H)。
Embodiment 2 preparation intermediate compound IV:
Compound III 50 grams, the aqueous sodium hydroxide solution 150mL of 1N and 100mL methyl alcohol are put into three mouthfuls of round-bottomed flasks of 500mL and were stirred 10 hours down at 55 ℃.Hydrocerol A with 10% is transferred to pH=4 with reaction mixture, and the thing that is settled out is filtered, and filter cake is with water washing three times (50mL * 3).Air drying gets white solid compound IV 45 grams with ethyl alcohol recrystallization.
1H?NMR(400mHz，CDCl
3)ppm：7.97(m，ArH，4H)，7.45-7.33(m，ArH，6H)，5.59(m，CH＝CH，2H)，5.00(m，1H)，4.81(s，1H)，4.58-4.25(m，3H)。
Embodiment 3 preparation midbody V:
Add compound IV 40 gram and chloroform 150mL in three mouthfuls of round-bottomed flasks of 500mL, stir down at 50 ℃.Every Manganse Dioxide 9 grams of putting at a distance from a hour add 7 times altogether.React 10 hours after-filtration and fall undissolved material, on silicagel column, separate after the solution concentration,, get white solid compound V 25 grams with ETHYLE ACETATE and sherwood oil drip washing.
1HNMR(400mHz，CDCl
3)ppm：7.97(m，ArH，4H)，7.47-7.37(m，ArH，6H)，6.75(m，CH＝CH，1H)，6.35(m，CH＝CH，1H)，5.22(m，1H)，5.01(s，1H)，4.68(m，1H)，4.45(m，1H)。
The sub-ketenes of embodiment 4 preparation final product Chinese pepper:
Add compound V 20 grams in three mouthfuls of round-bottomed flasks of 250mL, 1N hydrochloric acid 75mL and methyl alcohol 150mL stir down at 25 ℃.React concentration of reaction solution after 6 hours, add 200mL ETHYLE ACETATE, three times (100mL * 3) of solution with water extraction.Organic phase is used anhydrous sodium sulfate drying, gets sub-ketenes 16 grams of white solid compound Chinese pepper with ethyl alcohol recrystallization.
1H?NMR(400mHz，CDCl
3)ppm：7.99(m，ArH，2H)，7.91(m，ArH，2H)，7.51-7.37(m，ArH，6H)，6.89(m，CH＝CH，1H)，6.32(m，CH＝CH，1H)，5.92(m，1H)，4.81(d，1H)，4.58(d，1H)，4.35(dd，1H)。FAB-MS：383(M+H)，405(M+Na)。
Claims (8)
- One kind CAS number be the new preparation technology of compound of [193410-84-3]; The chemical name that it is characterized in that this compound for (4R, 5S, 6S)-4-(benzoyloxy)-6-[(benzoyloxy) methyl]-5; 6-dihydroxy-2-cyclohexen-1-one has following structure:synthesis technique is:
Wherein X=Cl, Br; R=H, Li, Na, K. - 2. according to the said synthesis technique of claim 1, it is characterized in that the mole ratio between this compound and I, II, III, IV and the V is 1: 1～10.
- 3. according to the said synthesis technique of claim 1, it is characterized in that described solvent is water, methyl alcohol, benzene, toluene, THF, dioxane, CH 3CN, CH 2Cl 2, CHCl 3, CCl 4, acetone.
- 4. according to the said synthesis technique of claim 1, it is characterized in that temperature of reaction is subzero 5 degrees centigrade to 120 degrees centigrade.
- 5. according to the said synthesis technique of claim 1, it is characterized in that wherein used alkali is selected from NaOH, LiOH, KOH, Li 2CO 3, Na 2CO 3, K 2CO 3, LiHCO 3, NaHCO 3, KHCO 3, in triethylamine or the pyridine one or more.
- 6. according to the said synthesis technique of claim 1, wherein used halide reagent is POCl 3, PCl 5, PCl 3, NBS, NCS, HBr, HCl, Cl 2, Br 2One or more.
- 7. according to the said synthesis technique of claim 1, it is characterized in that used acid is selected from one or more in hydrochloric acid, sulfuric acid, nitric acid, acetic acid, trifluoroacetic acid, phosphoric acid, the Hydrocerol A.
- 8. according to the said synthesis technique of claim 1, it is characterized in that used oxygenant is selected from KMnO 4, MnO 2, OsO 4, PCC, PDC, CrO 3In one or more.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2011100556733A CN102675110A (en) | 2011-03-09 | 2011-03-09 | Novel production process for chemical synthesis of zeylenone |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111527967A (en) * | 2020-05-14 | 2020-08-14 | 广西大学 | Strong seedling cultivation method for Japanese pepper container seedlings |
| CN112479851A (en) * | 2020-11-16 | 2021-03-12 | 中国医学科学院药用植物研究所 | Zanthoxylum bungeanum ketene derivative, preparation method and application thereof |
| CN113662964A (en) * | 2020-05-13 | 2021-11-19 | 中国医学科学院药用植物研究所 | Medicine for treating tumor |
-
2011
- 2011-03-09 CN CN2011100556733A patent/CN102675110A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113662964A (en) * | 2020-05-13 | 2021-11-19 | 中国医学科学院药用植物研究所 | Medicine for treating tumor |
| CN111527967A (en) * | 2020-05-14 | 2020-08-14 | 广西大学 | Strong seedling cultivation method for Japanese pepper container seedlings |
| CN112479851A (en) * | 2020-11-16 | 2021-03-12 | 中国医学科学院药用植物研究所 | Zanthoxylum bungeanum ketene derivative, preparation method and application thereof |
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Application publication date: 20120919 |