CN101798297B - Chemical synthesis method of laetispicine - Google Patents

Chemical synthesis method of laetispicine Download PDF

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CN101798297B
CN101798297B CN2009100460841A CN200910046084A CN101798297B CN 101798297 B CN101798297 B CN 101798297B CN 2009100460841 A CN2009100460841 A CN 2009100460841A CN 200910046084 A CN200910046084 A CN 200910046084A CN 101798297 B CN101798297 B CN 101798297B
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laetispicine
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CN101798297A (en
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沈竞康
姚舒译
潘胜利
胡定宇
钱伏刚
么春艳
王昕�
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Shanghai Institute of Materia Medica of CAS
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Abstract

The invention relates to a chemical synthesis method of natural product laetispicine. The method comprises the following steps of: obtaining a key intermediate parent nucleus part 1-phenyl-5-(3,4-methylene dioxybenzene ethyl) sulfonyl tetrazole by using piperonal as a raw material through the steps of Darzens condensation, hydrolysis, decarboxylation, reduction, condensation and oxidation; obtaining a key intermediate part 5-(tetrahydropyrane-2-ol) valeraldehyde by using pentanediol as a raw material through the steps of hydroxyl protection and oxidation; and then condensing the parent nucleus part and a side chain part and obtaining the target product laetispicine through deprotection, Swern oxidation, a Wittig-Horner reaction, hydrolysis and amidation. It is known from a hydrogen spectrum, a carbon spectrum and an infrared spectrum, the laetispicine synthesized by the invention is the same as natural laetispicine.

Description

The chemical synthesis process of laetispicine
Technical field
The invention belongs to the field of chemical synthesis, more specifically, relate to a kind of chemical synthesis process of natural product laetispicine.
Background technology
Dysthymia disorders is a kind of common mental disorder, and the patient accounts for 3%～5% of world's total population.According to the World Health Organization (WHO) report, dysthymia disorders has become the fourth-largest illness in the world at present, expects the heavy depressed functional disability that causes of the year two thousand twenty and will be only second to ischemic heart disease, occupies second.
At present, people are still not fully aware of to the definite cause of disease and the pathomechanism of dysthymia disorders, it is generally acknowledged that the morbidity major cause is that the levels such as monoamine neurotransmitters such as norepinephrine (NA), serotonin (5-HT), Dopamine HCL (DA), vagusstoff, γ-aminobutyric acid descend.Up to now developed such as a series of antidepressant drugs such as MAOIs, SSRI, NARI, SNRI.But there is a lag-phase existing thymoleptic onset times, and only has 50%～65% patient obtaining significant curative effect in the anti depressant therapy first, therefore, still need develop new thymoleptic.
Da Ye Betel (Piper laetispicum C.DC.) is piperaceae Piper plant, mainly is distributed in China Guangdong, Guangxi, Yunnan and Hainan Province, among the people long-term with it be used for invigorating blood circulation, detumescence, pain relieving.2002, the people such as Pan Shengli have at first reported several extracts among the Da Ye Betel (Laetispicum), wherein laetispicine (Laetispicine) has good antidepressant, calmness and analgesic activity, and its antidepressant intensity is about 5 times (CN1389462A) of fluoxetine.2006, there is report to point out, laetispicine can suppress the synaptosome of rat brain to the reuptake (WO2006000158A1) of serotonin, Dopamine HCL and norepinephrine.But laetispicine is lower at natural content, and extraction yield is about 3/10000ths, also it is not carried out the report of chemosynthesis.These all are unfavorable for it is carried out the research of further structure of modification and other side.
Summary of the invention
The chemical synthesis process that the purpose of this invention is to provide a kind of natural product laetispicine.
According to purpose of the present invention; the chemical synthesis process of laetispicine provided by the invention is with compound 7 (1-phenyl-5-(3; 4-(methylenedioxy) styroyl) sulfuryl tetrazole) and compound 10 (5-(tetrahydropyrans-2-oxygen base) valeraldehyde) be raw material, obtain through condensation, deprotection, Swern oxidation, Wittig-Horner reaction, hydrolysis and amidation step.
Concrete synthesis step is as follows:
Figure G2009100460841D00021
Step 1: condensation
1-phenyl-5-(3,4-(methylenedioxy) styroyl) sulfuryl tetrazole (compound 7) and the condensation under the effect of organic bases of 5-(tetrahydropyrans-2-oxygen base) valeraldehyde (compound 10), obtain 1-(tetrahydropyrans-2-oxygen base)-7-(3,4-methylene dioxy phenyl group)-5E-heptene (compound 11);
Step 2: deprotection
The 1-that above-mentioned steps 1 obtains (tetrahydropyrans-2-oxygen base)-7-(3, the 4-methylene dioxy phenyl group)-5E-heptene (compound 11), under the effect of para-methylbenzenepyridinsulfonate sulfonate (PPTS), slough protecting group, obtain the terminal 7-of hydroxyl (3,4-the methylene dioxy phenyl group)-5E-heptene-1-alcohol (compound 12) that is;
Step 3:Swern oxidation
The 7-that above-mentioned steps 2 obtains (3,4-methylene dioxy phenyl group)-5E-heptene-1-alcohol (compound 12) is oxidized to aldehyde through Swern, obtains the terminal 7-of aldehyde radical (3,4-the methylene dioxy phenyl group)-5E-heptenal (compound 13) that is;
Step 4:Wittig-Horner reaction
The 7-(3 that above-mentioned steps 3 obtains, the 4-methylene dioxy phenyl group)-Wittig-Horner occurs and reacts in 5E-heptenal (compound 13) and 4-phosphoryl-2E-butenoic acid triethyl under the butyl Role of lithium, obtain 11-(3, the 4-methylene dioxy phenyl group)-2E, 4E, 9E-undecane trienic acid ethyl ester (compound 14);
Step 5: hydrolysis and amidation
The 11-(3 that above-mentioned steps 4 obtains, the 4-methylene dioxy phenyl group)-2E, 4E, 9E-undecane trienic acid ethyl ester (compound 14) is hydrolyzed under alkaline condition, obtains the terminal 11-of carboxyl (3,4-the methylene dioxy phenyl group)-2E that is, 4E, 9E-undecane trienic acid, with its in the presence of condensing agent/activator with the isobutylamine condensation, obtain the target compound laetispicine.
The below is described more specifically method of the present invention:
In described step 1, the organic bases of adding can be lithium diisopropyl amido (LDA), hexamethyldisilane diazonium lithium (LHMDS) or butyllithium etc.; Compound 7, compound 10 are 1.1～1.5 with the ratio of organic bases: 1: 1.1～1.5; The solvent of reaction is dme (DME) or tetrahydrofuran (THF); The condition of reaction is-78 ℃ and argon shield; The time of reaction is 3～12 hours;
In described step 5, the employed alkali of hydrolysis reaction can be lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methylate or sodium ethylate etc.; The condensing agent that adopts can be 1-ethyl-3-(3 '-dimethylamino-propyl) carbodiimide hydrochloride (EDCI), N, N '-dicyclohexylcarbodiimide (DCC) or N, N '-DIC (DIC) etc.; The activator that adopts can be 1-hydroxy benzo triazole (HOBt) or 1-hydroxyl-7-azo benzotriazole (HOAt) etc.
In method provided by the invention, compound 7 can take piperonylaldehyde as raw material, obtain through Darzens condensation, hydrolysis, decarboxylation, reduction, condensation and oxidation step.Particularly, obtain as follows:
Figure DEST_PATH_GSB00000849282100011
Take piperonylaldehyde (compound 1) as raw material, under the effect of sodium alkoxide, through the Darzens condensation, obtain α-epoxyeicosatrienoic acid ester compound, namely 3,4-methylene dioxy phenyl group glycidic acid methyl esters (compound 2); Wherein the reagent in the Darzens condensation reaction is methyl chloroacetate or ethyl chloroacetate, and the catalysis alkali sodium alkoxide that uses is sodium methylate or sodium ethylate;
3,4-methylene dioxy phenyl group glycidic acid methyl esters (compound 2) obtains 3,4-methylene dioxy phenyl group glycidic acid salt through hydrolysis; 3,4-methylene dioxy phenyl group glycidic acid salt is under the effect of yellow soda ash, and the reflux decarboxylation obtains 3,4-(methylenedioxy) phenylacetic aldehyde (compound 4);
3,4-(methylenedioxy) phenylacetic aldehyde (compound 4) is hydroxyl going back under the reductive action of original reagent carbonyl reduction, obtains 3,4-(methylenedioxy) phenylethyl alcohol (compound 5); The wherein said original reagent of going back can be sodium borohydride, trimethoxy acyl group sodium borohydride or Lithium Aluminium Hydride etc.;
3,4-(methylenedioxy) phenylethyl alcohol (compound 5) is under the effect of triphenyl phosphorus and diisopropyl azodiformate (DIAD) or azo-dicarboxylate (DEAD), the Mitsunobu reaction occurs with 1-phenyl-5-mercapto tetrazole, obtain 1-phenyl-5-(3,4-(methylenedioxy) styroyl) mercapto tetrazole (compound 6);
1-phenyl-5-(3,4-(methylenedioxy) styroyl) mercapto tetrazole (compound 6) obtains 1-phenyl-5-(3,4-(methylenedioxy) styroyl) sulfuryl tetrazole (compound 7) through the oxidation of ammonium molybdate/hydrogen peroxide.
In method provided by the invention, compound 10 can obtain through hydroxyl protection, oxidation step take pentanediol as raw material.Particularly, obtain as follows:
Take pentanediol (compound 8) as raw material, obtain the single pentanediol of protecting of tetrahydropyrans (THP), i.e. 5-(tetrahydropyrans-2-oxygen base) Pentyl alcohol (compound 9) with 3,4-dihydropyrane (DHP) reaction;
5-(tetrahydropyrans-2-oxygen base) Pentyl alcohol (compound 9) through the Swern oxidation, obtains 5-(tetrahydropyrans-2-oxygen base) valeraldehyde (compound 10).Wherein, the oxygenant that uses is pyridinium chlorochromate (PCC) or methyl-sulphoxide (DMSO)/oxalyl chloride.
The present invention obtains the natural product laetispicine take piperonylaldehyde and pentanediol as raw material through ten four-step reactions.The characteristics of synthetic route are that total is divided into two portions, through the synthetic target product that obtains of convergence type.Wherein, obtain key intermediate nucleus part 1-phenyl-5-(3,4-(methylenedioxy) styroyl) sulfuryl tetrazole (compound 7) take piperonylaldehyde as raw material through Darzens condensation, hydrolysis, decarboxylation, reduction, condensation, oxidation; Take pentanediol as raw material, obtain key intermediate pendant moiety 5-(tetrahydropyrans-2-oxygen base) valeraldehyde (compound 10) through hydroxyl protection, oxidation.Then nucleus part and pendant moiety condensation obtains the target product laetispicine through deprotection, Swern oxidation, Wittig-Horner reaction, hydrolysis, amidation again.Ten four-step reaction total recoverys are 3.9%, and hydrogen spectrum, carbon spectrum and INFRARED SPECTRUM are consistent with the natural extract laetispicine.
Embodiment
Embodiment 13, the preparation of 4-methylene dioxy phenyl group glycidic acid methyl esters (2)
6.0g (40mmol) piperonylaldehyde (1) and 4.6ml (60mmol) methyl-chloroformate are dissolved in the absolute methyl alcohol of 15ml; during bathing, cryosel slowly splashes into the absolute methanol solution of 5ml of 6.5g (60mmol) sodium methylate under the argon shield; time for adding approximately 10 minutes; after dropwising, during bathing, stirred 1 hour cryosel.The mixing solutions that adds 20ml water and 20ml ether to reaction solution, ice bath stirs 1h, and a large amount of solids produce, suction filtration, ether is washed, the dry white solid 3 that gets, 4-methylene dioxy phenyl group glycidic acid methyl esters (2) 7.8g, crude product yield 88% directly carries out next step reaction.Wherein, described methyl-chloroformate and sodium methylate be available chlorine ethyl acetate and sodium ethylate replacement also, and the simultaneous reactions solvent is the corresponding absolute ethanol that is changed to also.
1H-NMR(CDCl 3，300MHz)δ：3.45(d，1H，J＝1.7Hz)，3.80(s，3H)，4.00(d，1H，J＝1.8Hz)，5.96(s，2H)，6.68-6.80(m，3H)。
Embodiment 23, the preparation of 4-(methylenedioxy) phenylacetic aldehyde (4)
The 14.0g sodium methylate is dissolved in the absolute methyl alcohol of 100ml; slowly splash in the 50ml anhydrous toluene solution of 56.6g (0.25mol) (2) in the ice bath under the argon shield; ice bath stirred 30 minutes, added 6ml water and 200ml ether, and ice bath stirred 2 hours; a large amount of solids produce; suction filtration, anhydrous diethyl ether is washed, the dry crude product 3 that gets; 4-methylene dioxy phenyl group glycidic acid sodium 64.9g not treatedly directly carries out next step reaction.
With 64.9g (0.28mol) crude product 3,4-methylene dioxy phenyl group glycidic acid sodium and 16.2ml (0.28mol) Glacial acetic acid are dissolved in the 50ml anhydrous toluene solution, 2.5 hours (a large amount of CO of reflux 2Produce), after the cooling, 2 * 50ml washes organic phase twice, and anhydrous sodium sulfate drying filters, and removes toluene under reduced pressure, gets yellow oil.Underpressure distillation, 100-104 ℃ (0.46mmHg) gets colorless oil 3,4-(methylenedioxy) phenylacetic aldehyde (4) 18.1g, two step total recoverys 44.1%.
1H-NMR(CDCl 3，300MHz)δ：3.60(d，2H，J＝2.1Hz)，5.96(s，2H)，6.64-6.82(m，3H)，9.71(t，1H)。
Embodiment 33, the preparation of 4-(methylenedioxy) phenylethyl alcohol (5)
Under the ice bath, 0.30g (1.8mmol) (4) is dissolved in the 15ml anhydrous methanol, slowly drips the 5ml absolute methanol solution of 0.09g (2.2mmol) sodium borohydride, ice bath stirred 15 minutes.Add 20ml water and 20ml methylene dichloride, 2 * 20ml methylene dichloride wash water phase twice merges organic phase, and anhydrous sodium sulfate drying filters, and steaming desolventizes, and gets colorless oil 3,4-(methylenedioxy) phenylethyl alcohol (5) 0.28g, yield 93%.Directly carry out next step reaction.
1H-NMR(CDCl 3，300MHz)δ：2.79(t，2H)，3.83(t，3H)，5.94(s，2H)，6.67-6.78(m，3H)。
Embodiment 4 1-phenyl-5-(3,4-(methylenedioxy) styroyl) mercapto tetrazole (6)
2.2g (13mmol) (5), 2.7g (15mmol) 1-phenyl-5 mercapto tetrazole and 3.9g (15mmol) triphen phosphorus are dissolved in the 150ml anhydrous tetrahydro furan; under the ice bath in the argon shield; slowly splash into the 50ml anhydrous tetrahydrofuran solution of 3.0ml (15mmol) DIAD in the reaction solution; ice bath stirred 1 hour, steamed except tetrahydrofuran (THF) the dissolving of 50ml anhydrous diethyl ether; 2 * 30ml water washing; anhydrous sodium sulfate drying filters, and steaming desolventizes.Get thick liquid crude product 1-phenyl-5-(3,4-(methylenedioxy) styroyl) mercapto tetrazole (6) 4.1g, yield 96.0%.Directly carry out next step reaction.
Embodiment 5 1-phenyl-5-(3,4-(methylenedioxy) styroyl) sulfuryl tetrazole (7)
4.1g (12.6mmol) crude product (6) is dissolved in the 15ml dehydrated alcohol, and cryosel is bathed the 5ml superoxol that splashes into 4.1g (3.3mmol) ammonium molybdate in the lower argon shield, returns back to room temperature, stirs 48 hours.Add 50ml water and 50ml ether, twice mutually of 2 * 30ml ether wash water, merge organic phase, anhydrous sodium sulfate drying filters, and steaming desolventizes, column chromatography purification (ethyl acetate: sherwood oil=5: 1), get white solid 1-phenyl-5-(3,4-(methylenedioxy) styroyl) sulfuryl tetrazole (7) 4.5g, yield 100%.
1H-NMR(CDCl 3，400MHz)δ：3.19(t，2H)，3.96(t，2H)，5.96(s，2H)，6.72-6.75(m，3H)，7.62-7.72(m，5H)。EI(m/z)：358，148，119，91，77，65。
The preparation of embodiment 6 5-(tetrahydropyrans-2-oxygen base) Pentyl alcohol (9)
Under the room temperature, the 10ml dichloromethane solution of 2.1ml (25mmol) DHP is slowly splashed in the 10ml dichloromethane solution of 2.6ml (25mmol) pentanediol (8) and 0.1g (catalytic amount) PPTS, after dropwising, room temperature reaction 6 hours, add 50ml water, 3 * 30ml dichloromethane solution is washed three times, merge organic phase, anhydrous sodium sulfate drying, filter, steaming desolventizes, column chromatography purification (ethyl acetate: sherwood oil=2: 1), get colorless oil 5-(tetrahydropyrans-2-oxygen base) Pentyl alcohol (9) 3.3g, yield 70.0%.
1H-NMR(CDCl 3，400MHz)δ：1.50-1.93(m，15H)，3.40(m，1H)，3.51(m，1H)，3.66(m，2H)，3.76(m，1H)，3.85(m，1H)，4.57(m，1H)。EI(m/z)：187，101，85，69。
The preparation of embodiment 7 5-(tetrahydropyrans-2-oxygen base) valeraldehyde (10)
Under-78 ℃ of argon shields; 1.8ml (25.7mmol) DMSO is slowly splashed in the 20ml anhydrous methylene chloride solution of 1.1ml (12.9mmol) oxalyl chloride; stirred 30 minutes; slowly drip again the 10ml anhydrous methylene chloride solution of 1.5g (8.0mmol) (9);-78 ℃ were reacted 1.5 hours; again 5.6ml (40mmol) anhydrous triethylamine is slowly splashed into reaction solution;-78 ℃ were stirred 30 minutes; rose to the room temperature restir 30 minutes, and added 30ml 3% aqueous ammonium chloride solution, 3 * 30ml methylene dichloride is washed three times; merge organic phase; anhydrous sodium sulfate drying filters, and steaming desolventizes.Get colorless oil 5-(tetrahydropyrans-2-oxygen base) valeraldehyde (10) 1.3g, yield 90.1%.
1H-NMR(CDCl 3，400MHz)δ：1.57-1.74(m，12H)，2.47(m，2H)，3.38(m，2H)，3.75(m，2H)，4.55(m，1H)，9.76(m，1H)。
The preparation of embodiment 8 1-(tetrahydropyrans-2-oxygen base)-7-(3,4-methylene dioxy phenyl group)-5E-heptene (11)
Under-78 ℃ of argon shields; with 0.35ml (0.70mmol) LDA (2M; hexane solution) slowly splashes in the anhydrous DME solution of 10ml of 0.25g (0.70mmol) (7); reacted 1 hour; slowly splash into again the anhydrous DME solution of 10ml of 0.12g (0.63mmol) (10);-78 ℃ were stirred 2 hours; stirring at room is 30 minutes again; add the 30ml anhydrous diethyl ether, the water washing of 30ml saturated common salt, 3 * 20ml anhydrous diethyl ether washing water; merge organic phase; anhydrous sodium sulfate drying filters, and steaming desolventizes; column chromatography purification (ethyl acetate: sherwood oil=20: 1); get colorless oil 1-(tetrahydropyrans-2-oxygen base)-7-(3,4-methylene dioxy phenyl group)-5E-heptene (11) 0.15g, yield 67.4%.
1H-NMR(CDCl 3，400MHz)δ：1.25-1.73(m，20H)，2.04(m，2H)，3.23(m，2H)，3.40(m，1H)，3.51(m，1H)，3.74(m，1H)，3.86(m，1H)，4.57(m，1H)，5.50(m，2H)，5.92(s，2H)，6.61-6.74(m，3H)。EI(m/z)：318，149，135，85，57。
The preparation of embodiment 9 7-(3,4-methylene dioxy phenyl group)-5E-heptene-1-alcohol (12)
0.5g (catalytic amount) PPTS is added in the 20ml absolute methanol solution of 5.3g (16.7mmol) (11), stirring at room 3 hours, steaming desolventizes, and adds 20ml water and 20ml methylene dichloride, twice mutually of 2 * 20ml methylene dichloride wash water, merge organic phase, anhydrous sodium sulfate drying filters, steaming desolventizes, get colorless oil 7-(3,4-methylene dioxy phenyl group)-5E-heptene-1-alcohol (12) 3.6g, yield 93.0%.
1H-NMR(CDCl 3，300MHz)δ：1.45-1.61(m，16H)，2.07(m，2H)，3.24(d，2H，J＝5.6Hz)，3.65(t，2H)，5.51(m，2H)，5.92(s，2H)，6.64-6.75(m，3H)。
The preparation of embodiment 10 7-(3,4-methylene dioxy phenyl group)-5E-heptenal (13)
Under-78 ℃ of argon shields; 3.6ml (47.0mmol) DMSO is slowly splashed in the 20ml anhydrous methylene chloride solution of 2.2ml (25.2mmol) oxalyl chloride; stirred 30 minutes; slowly drip again the 10ml anhydrous methylene chloride solution of 3.6g (15.4mmol) (12);-78 ℃ were reacted 1.5 hours; again 10.5ml (75mmol) anhydrous triethylamine is slowly splashed into reaction solution;-78 ℃ were stirred 30 minutes; rose to the room temperature restir 30 minutes, and added 30ml 3% aqueous ammonium chloride solution, 3 * 30ml methylene dichloride is washed three times; merge organic phase; anhydrous sodium sulfate drying filters, and steaming desolventizes; column chromatography purification (ethyl acetate: sherwood oil=10: 1); get colorless oil 7-(3,4-methylene dioxy phenyl group)-5E-heptenal (13) 3.3g, yield 93.5%.
1H-NMR(CDCl 3，300MHz)δ：1.17-1.87(m，21H)，2.07(m，2H)，2.30(m，2H)，3.23(m，2H)，5.50(m，2H)，5.91(s，2H)，6.45-6.73(m，3H)。
Embodiment 11 11-(3,4-methylene dioxy phenyl group)-2E, 4E, the preparation of 9E-undecane trienic acid ethyl ester (14)
Under-78 ℃ of argon shields; with 2.2ml (3.5mmol) butyllithium (1.6M; hexane solution) slowly splashes in the 10ml anhydrous tetrahydrofuran solution of 0.8ml (3.5mmol) 4-phosphoryl-2E-butenoic acid triethyl;-78 ℃ of reactions are after 30 minutes; slowly drip again the 10ml anhydrous tetrahydrofuran solution of 0.67g (2.9mmol) (13);-78 ℃ were stirred 1 hour, rose to the room temperature restir 1 hour, steamed except tetrahydrofuran (THF); add 30ml methylene dichloride and 30ml water; 2 * 30ml methylene dichloride wash water phase twice merges organic phase, anhydrous sodium sulfate drying; filter; steaming desolventizes, column chromatography purification (ethyl acetate: sherwood oil=10: 1), get colorless oil 11-(3; the 4-methylene dioxy phenyl group)-2E; 4E, 9E-undecane trienic acid ethyl ester (14) 0.54g, yield 57.2%.
1H-NMR(CDCl 3，300MHz)δ：1.25-1.58(m，10H)，2.03(m，2H)，2.17(m，2H)，3.28(m，2H)，4.21(m，2H)，5.49(m，2H)，5.76(d，1H，J＝15.2Hz)，5.92(s，2H)，6.13(m，2H)，6.60-6.75(m，3H)，7.24(m，1H)。EI(m/z)：328，232，149，135，91，77，57。
The preparation of embodiment 12 laetispicines
0.15g (0.46mmol) (14) is dissolved in the 5ml dehydrated alcohol, adds 5ml 10% lithium hydroxide aqueous solution, stirred overnight at room temperature, steam except ethanol, add 20ml methylene dichloride and 20ml water, twice mutually of 2 * 30ml methylene dichloride wash water, merge organic phase, anhydrous sodium sulfate drying filters, steaming desolventizes, obtain yellow solid 11-(3,4-methylene dioxy phenyl group)-2E, 4E, 9E-undecane trienic acid not treatedly directly carries out next step reaction.
Under the argon shield; upper step product; 0.13g (0.69mmol) EDCI; 0.09g (0.69mmol) HOBT and 0.07ml (0.69mmol) isobutylamine is dissolved in the 10ml anhydrous tetrahydro furan; stirred overnight at room temperature; steam except tetrahydrofuran (THF); add 20ml saturated sodium bicarbonate aqueous solution and 20ml methylene dichloride; twice on 2 * 20ml methylene dichloride wash water layer; merge organic phase, anhydrous sodium sulfate drying filters; steaming desolventizes; (ethyl acetate: sherwood oil=3: 1), methylene dichloride/sherwood oil recrystallization obtains white crystal laetispicine 0.12g to column chromatography purification; mp.95-96 ℃ (document 93-94 ℃), two step total recoverys 75.0%.
1H-NMR(CDCl 3，400MHz)δ：0.89(m，6H)，1.50(m，3H)，1.81(m，1H)，2.02(m，2H)，2.16(m，2H)，3.16(t，2H，J＝6.4Hz)，3.23(d，2H，J＝6.2Hz)，5.49(m，2H，dd：J＝15.0Hz，J＝15.4Hz)，5.71(d，2H，J＝14.8Hz)，5.92(s，2H)，6.08(m，2H，dd：J＝15.0Hz，J＝15.0Hz)，6.61-6.74(m，3H)，7.18(m，1H)。 13C-NMR(DMSO-d 6)δ：20.08，32.15，32.52，38.81，47.00，101.30，108.42，109.20，121.57，123.70，129.45，130.28，131.41，135.30，140.28，141.81，146.26，148.15，166.46。IR(KBr)cm -1：3302，2955，2922，1655，1628，1614，1551，1506，1487，1250，1043，999，968，924，818。EI(m/z)：355，240，220，135，121，107，91，79，57。
By hydrogen spectrum, carbon spectrum, mass spectrum and INFRARED SPECTRUM data as can be known, the laetispicine that the present invention synthesizes is consistent with the laetispicine of natural extract.

Claims (6)

1. chemical synthesis process with laetispicine of formula (I) structure; it is characterized in that; take compound 7 and compound 10 as raw material, obtain through the condensation shown in the following reaction formula, deprotection, Swern oxidation, Wittig-Horner reaction, hydrolysis and amidation step:
Figure FSB00000849282000011
Step 1: condensation
Compound 7 and compound 10 condensation under the effect of organic bases obtain compound 11;
Step 2: deprotection
Compound 11 is sloughed protecting group under the effect of para-methylbenzenepyridinsulfonate sulfonate, obtain the terminal compound 12 of hydroxyl that is;
Step 3:Swern oxidation
Compound 12 is oxidized to aldehyde through Swern, obtains the terminal compound 13 of aldehyde radical that is;
Step 4:Wittig-Horner reaction
The Wittig-Horner reaction occurs with 4-phosphoryl-2E-butenoic acid triethyl in compound 13 under the butyl Role of lithium, obtain compound 14;
Step 5: hydrolysis and amidation
Compound 14 is hydrolyzed under alkaline condition, obtains terminal the be 11-of carboxyl (3,4-methylene dioxy phenyl group)-2E, 4E, 9E-undecane trienic acid; With 11-(3,4-methylene dioxy phenyl group)-2E, 4E, 9E-undecane trienic acid in the presence of condensing agent/activator with the isobutylamine condensation, obtain the target compound laetispicine shown in the formula (I).
2. the chemical synthesis process of laetispicine according to claim 1 is characterized in that, in step 1: described organic bases is lithium diisopropyl amido, hexamethyldisilane diazonium lithium or butyllithium; Compound 7, compound 10 are 1.1～1.5 with the mol ratio of described organic bases: 1: 1.1～1.5; Reaction solvent is dme or tetrahydrofuran (THF); Reaction conditions is-78 ℃ and argon shield; Reaction times is 3～12 hours.
3. the chemical synthesis process of laetispicine according to claim 1 is characterized in that, in step 5: the employed alkali of hydrolysis reaction is lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methylate or sodium ethylate; The condensing agent that adopts is 1-ethyl-3-(3 '-dimethylamino-propyl) carbodiimide hydrochloride, N, N '-dicyclohexylcarbodiimide or N, N '-DIC; The activator that adopts is 1-hydroxy benzo triazole or 1-hydroxyl-7-azo benzotriazole.
4. the chemical synthesis process of laetispicine according to claim 1 is characterized in that, compound 7 wherein obtains through the described Darzens condensation of following reaction formula, hydrolysis, decarboxylation, reduction, condensation and oxidation step take piperonylaldehyde as raw material:
Figure FSB00000849282000031
Take compound 1 piperonylaldehyde as raw material, under the sodium alkoxide effect, through the Darzens condensation, obtain α-epoxyeicosatrienoic acid ester compound, namely compound 2; Wherein, the reagent in the Darzens condensation reaction is methyl chloroacetate or ethyl chloroacetate, and the catalysis alkali sodium alkoxide that uses is sodium methylate or sodium ethylate;
Compound 2 hydrolysis obtain hydrolysate; Hydrolysate is under the effect of yellow soda ash, and the reflux decarboxylation obtains compound 4;
Compound 4 is under the effect of going back original reagent, and carbonyl reduction is hydroxyl, obtains compound 5; The wherein said original reagent of going back is sodium borohydride, trimethoxy acyl group sodium borohydride or Lithium Aluminium Hydride;
The Mitsunobu reaction occurs with 1-phenyl-5-mercapto tetrazole and obtains compound 6 under the effect of triphenyl phosphorus and condensing agent in compound 5;
Compound 6 obtains compound 7 through the oxidation of ammonium molybdate/hydrogen peroxide.
5. the chemical synthesis process of laetispicine according to claim 1 is characterized in that, compound 10 obtains through the described hydroxyl protection of following reaction formula and oxidation step take pentanediol as raw material:
Figure FSB00000849282000032
Pentanediol 8 and the reaction of 3,4-dihydropyrane obtain the pentanediol compound 9 of tetrahydropyrans list protection;
Compound 9 is by using the oxygenant oxidation to obtain compound 10.
6. the chemical synthesis process of laetispicine according to claim 5 is characterized in that, the oxygenant that uses is pyridinium chlorochromate or methyl-sulphoxide/oxalyl chloride.
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