CN102070431B - Method for synthesizing saprorthoquinone - Google Patents

Method for synthesizing saprorthoquinone Download PDF

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CN102070431B
CN102070431B CN 201110047334 CN201110047334A CN102070431B CN 102070431 B CN102070431 B CN 102070431B CN 201110047334 CN201110047334 CN 201110047334 CN 201110047334 A CN201110047334 A CN 201110047334A CN 102070431 B CN102070431 B CN 102070431B
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CN102070431A (en
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赖宜生
桂力
赖忠辉
贾京浩
赵振平
杨红双
刘舞扬
张奕华
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China Pharmaceutical University
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Abstract

The invention belongs to the field of chemical synthesis, and in particular relates to a method for synthesizing saprorthoquinone which is shown as a formula (I) and serves as a natural product with high antitumor activity. The method comprises the following steps of: performing carbonyl alpha-site methylation, selective isopropyl substitution of an aromatic ring and Grignard reaction on 7-methoxyl-1-tetralone serving as an initiative raw material to prepare a key intermediate, namely 1-(4-methyl-3-pentenyl)-2-methyl-6-isopropyl-7-methoxyl-3,4-dihydronaphthalene; and aromatizing with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), demethylating with ethanethiol and oxidizing with 2-iodoxybenzoic acid (IBX) to prepare the saprorthoquinone.

Description

A kind of synthetic method of Saprorthoquinone
Technical field
The invention belongs to the field of chemical synthesis, be specifically related to the synthetic method of the natural product Saprorthoquinone with good anti-tumor activity shown in a kind of formula (I).
Figure BSA00000440841200011
Background technology
Quinones shows noticeable biological activity at the aspect such as antibiotic, antiviral, antitumor.In recent years, the anti-tumor activity of naphthoquinone compound is extremely people's concern especially, some naphthoquinone compound such as Shikonin, ametycin etc. are used for clinical treatment as cancer therapy drug, some compound such as β-lapachone, plumbagin etc. have then entered clinical experimental stage (research and development of natural products, 2005,17:104-107).
Saprorthoquinone (I) is Zhang Jinsheng seminar of Shanghai Pharmaceutical Inst., Chinese Academy of Sciences extracts the brand-new chemical structure that obtains (Salvia prionitis Hance) the eighties in last century from medication Arisaema balansae Engl. grass among the people natural product (Botany Gazette, 1988,30:524-527).Vitro test shows that Saprorthoquinone suppresses IC to the propagation of human leukemia HL-60 cell, leukemic lymphoblastoid P388 cell, lung cancer SPC-A4 cell and SGC-7901 cell 50Mean value is 2.11 μ M, and to G +Bacterium (Bacillus subtilus, streptococcus aureus etc.) have obvious restraining effect (Bioorg Med Chem Lett, 1999,9:2731-2736).Zhang Jinsheng etc. take Saprorthoquinone as lead compound has synthesized a series of derivatives, the result shows that majority of compounds has good anti-tumor activity, wherein Squamocin A has been carried out II phase clinical study (CN1990448, CN112742).
Chemical structure and biological activity in view of the Saprorthoquinone uniqueness have the significance of carrying out composition optimizes and pharmacodynamic study in a deep going way, therefore, effectively obtain the basic substance that this compound becomes correlative study.At present, Saprorthoquinone mainly obtains by two kinds of approach: one, by the method for plant extract, but its extraction yield only be 5/10000ths (Botany Gazette, 1988,30:524-527); Its two, obtain by the chemosynthesis means.Matsumoto etc. are at first take (+)-dehydroabietic acid methyl esters as starting raw material, through the reaction of 15 steps make Saprorthoquinone (Bull Chem Soc Jpn, 1993,66:3053-3057), its synthetic route is as follows:
Figure BSA00000440841200012
Figure BSA00000440841200021
Reagent and condition: i) CH 3COCl, AlCl 3, CS 2, reflux, 86%; Ii) m-CPBA, (cat) p-TsOH, ClCH 2CH 2Cl, reflux, 75%; Iii) NaOH, MeOH-H 2O (9: 1), 90%; Iv) CH 3I, t-BuOK, t-BuOH, 51%; V) LiAlH 4, Et 2O; Vi) p-TsCl, Pyr; Vii) Zn, NaI, DMF, 84.7% (v, vi, vii three steps); Viii) Jones reagent, 75%; Ix) SeO 2, benzene, reflux, 95%; X) AlCl 3, EtOH-CH 2Cl 2, xi) Ac 2O, Pyr, 10hr, 97% (x, xi two steps); Xii) NaBH 4, CeCl 37H 2O, CH 3OH, 0 ℃, 0.5hr; V) p-TSOH, benzene, 1hr, 59% (xi, xii two steps); Vi) LiAlH 4, Et 2O, 0 ℃, 1hr, 89%; Vii) Fremy ' s salt, KH 2PO 4, THF, H 2O, 66%.
Zhang Jinsheng etc. directly carry out semi-synthetic on the basis of Matsumoto method take ferruginol as starting raw material, through 7 step reactions, with yield preferably obtained Saprorthoquinone (Chin Chem Lett, 2001,12:297-300), its synthetic route is as follows:
Figure BSA00000440841200022
Reagent and condition: i) Ac 2O, Pyr, 10hr, 92%; Ii) CrO 3, AcOH, 3hr, 85%; Iii) DDQ, cat SeO 2, benzene, 83%
Duan Wenhu etc. are take p-methoxyphenyl acetic acid as starting raw material, through the reaction of 12 steps, make Saprorthoquinone (Chin Chem Lett, 1997,8:695-696), its synthetic route is as follows:
Figure BSA00000440841200031
Reagent and condition: (i) EtOH, SOCl 2(ii) LiAlH 4, THF, 84.2% (a, b two steps); (iii) PBr3, CCl 4, 80%; (iv) 1) CH 3CH (CO 2C 2H 5) 2, NaH, 2) and OH -3) H +, 71.7%; (v) 180 ℃, quantitatively; (vi) PPA, 70.8%; (vii) i-PrOH, H 2SO 4, 54%; (viii) BrCH 2CH=CHCOOMe, Zn, ultrasonic, 51.2%; (ix) Pd-C, 280 ℃, 49%; (x) CH 3MgI, quantitatively; (xi) BF 3-Et 2O, 84.4%; (xii) CH 3CH 2SNa, 67.7%; (xiii) Fremy ' s salt, KH 2PO 4Buffer, 54.5%
In addition, Zhang Jinsheng etc. are also take citric acid as raw material, and reaction makes Saprorthoquinone (CN1327973) through 12 steps, and its synthetic route is as follows:
Figure BSA00000440841200032
Reagent and condition: i) heat, 37%; Ii) Ni/Al, 10%NaOH, 90 ℃, 93%; Iii) CH 3COCl, SOCl 2Iv) PhOCH 3, AlCl 3, PhNO 2, 55% (iii, iv two steps); V) Zn/Hg-HCl, toluene, reflux, 79%; Vi) PPA, 90 ℃, 66%; Vii) PPA, 64%; Viii) (CH 3) 2C=CHCH 2CH 2MgI, Et 2O; Ix) DDQ, 40% (viii, ix two steps); X) CH 3CH 2SNa, DMF, reflux, 64%; Xi) Fremy ' s salt, 52%
Mainly have following shortcoming in the above-mentioned synthetic method: (+)-dehydroabietic acid methyl esters that 1. adopts in method one and the method two and ferruginol price are comparatively expensive, and reactions steps is long, and most of reaction cost is too high, is difficult to adapt to scale operation; 2. starting raw material p-methoxyphenyl acetic acid low price in the method three, but this route reaction step is longer, and need Catalyzed by Ultrasonic Wave in the step (h), step (i) is used the lower dehydration of the high heat of Pd-C aromizing, severe reaction conditions; Although 3. starting raw material citric acid low price in the method four, the polystep reaction yield is lower, and step (ii) needs to adopt the reduction of Ni/Al alloy, causes a large amount of CO 2γ-ray emission causes reaction wayward.
The present invention is take 7-methoxyl group-1-tetralone as starting raw material; by carbonyl α position methylate, the selectivity sec.-propyl replaces and grignard reaction prepares key intermediate 1-(4-methyl-3-pentenyl)-2-methyl-6-sec.-propyl-7-methoxyl group-3 on the aromatic ring; the 4-dihydronaphthalene; again through 2; 3-two chloro-5,6-dicyan para benzoquinone (DDQ) aromizing, sulfur alcohol sodium demethylation and 2-iodoxy phenylformic acid (IBX) oxidation make Saprorthoquinone.Compare with aforesaid method, the reagent that the present invention adopts is not only cheap and easy to get, and reactions steps is short, and yield is higher, and the security and environment friendly also relative raising of reaction.
Summary of the invention
One of purpose of the present invention is to provide the synthetic method of the Saprorthoquinone shown in a kind of formula (I), it is characterized in that, comprises the steps:
Figure BSA00000440841200041
(1) take 7-methoxyl group-1-tetralone as raw material, take 7-methoxyl group-1-tetralone as raw material, under the alkaline reagents effect, make the 7-methoxyl group shown in the formula (II)-1-oxo-1,2,3,4-naphthane-2-ethyl formate with the diethyl carbonate reaction:
Figure BSA00000440841200042
This reaction is characterised in that, the alkaline reagents that adopts is selected from one or more in sodium hydride, potassium hydride KH, potassium tert.-butoxide or the sodium methylate, reaction solvent is selected from one or more in anhydrous tetrahydro furan, anhydrous methylene chloride or the dry toluene, temperature of reaction is the boiling temperature of solvent for use, and the reaction times is 2-8 hour;
(2) under alkaline condition, formula (II) compound and methylating reagent reaction make the 2-methyl shown in the formula (III)-7-methoxyl group-1-oxo-1,2,3,4-naphthane-2-manthanoate:
Figure BSA00000440841200043
This reaction is characterised in that, the methylating reagent that adopts is selected from methyl iodide, methyl-sulfate or diazomethane, alkaline reagents is selected from one or more in salt of wormwood, yellow soda ash or the triethylamine, reaction solvent is selected from acetone, N, in dinethylformamide, methyl alcohol or the ethanol one or more, temperature of reaction is the suitable temp between the boiling temperature of room temperature and solvent for use, and the reaction times is 3-10 hour;
(3) the backflow decarboxylation under alkaline reagents or acid reagent effect of formula (III) compound makes the 2-methyl shown in the formula (IV)-7-methoxyl group-1-tetralone:
Figure BSA00000440841200044
This reaction is characterised in that, alkaline reagents is selected from potassium hydroxide or sodium hydroxide, and acid reagent is selected from one or more in concentrated hydrochloric acid, sulfuric acid or the Glacial acetic acid, and reaction solvent is the mixed solvent of second alcohol and water, the volume ratio of ethanol and water is selected from 3: 1-7: 1, and the reaction times is 3-10 hour;
(4) under polyphosphoric acid (PPA) effect, formula (IV) compound and isopropanol reaction make the 2-methyl shown in the formula (V)-6-sec.-propyl-7-methoxyl group-1-tetralone:
Figure BSA00000440841200051
This reaction is characterised in that the mass ratio of PPA and formula (IV) compound is 5: 1-15: 1, and solvent is selected from one or more in chloroform, methylene dichloride, hexanaphthene or the tetrahydrofuran (THF), and temperature of reaction is 70 ℃-120 ℃, and the reaction times is 10-20 hour;
(5) reaction of the Grignard reagent of formula (V) compound and 5-iodo-2-methyl-2-amylene makes the 1-shown in the formula (VI) (4-methyl-3-pentenyl)-2-methyl-6-sec.-propyl-7-methoxyl group-3,4-dihydronaphthalene:
Figure BSA00000440841200052
This reaction is characterised in that the mol ratio of the Grignard reagent of 5-iodo-2-methyl-2-amylene and formula (V) compound is 1: 1-5: 1, and temperature of reaction is 25-45 ℃, the reaction times is 15-48 hour;
(6) formula (VI) compound is through 2,3-, two chloro-5, and 6-dicyan para benzoquinone (DDQ) Oxidative Dehydrogenation gets the 1-shown in the formula (VII) (4-methyl-3-pentenyl)-2-methyl-6-sec.-propyl-7-methoxynaphthalene:
Figure BSA00000440841200053
This reaction is characterised in that the mol ratio of DDQ and formula (VI) compound is 1: 1-3: 1, and solvent is selected from one or more in methylene dichloride, chloroform or the benzene, and temperature of reaction is room temperature, and the reaction times is 10-30 minute;
(7) formula (VII) compound demethylation under sulfur alcohol and sodium hydride effect makes the 3-sec.-propyl shown in the formula (VIII)-7-methyl-8-(4-methyl-3-pentenyl)-beta naphthal:
This reaction is characterised in that solvent is selected from anhydrous DMF or anhydrous dimethyl sulfoxide, and temperature of reaction is 140 ℃-190 ℃, and the reaction times is 20-60 minute;
(8) formula (VIII) compound makes the Saprorthoquinone shown in the formula (I) under the oxygenant effect:
This reaction is characterised in that oxygenant is selected from 2-iodoxy phenylformic acid or Fremy salt, and reaction solvent is selected from one or more in DMF, methyl-sulphoxide or the chloroform, and temperature of reaction is room temperature, and the reaction times is 10-30 minute.
Preparation compound (I) is characterised in that, the preferred 2-iodoxy of oxygenant phenylformic acid, and the preferred DMF of solvent, temperature of reaction is room temperature, the reaction times is 30 minutes.
Preparation formula (II) compound is characterised in that, the preferred sodium hydride of highly basic reagent, and the preferred anhydrous tetrahydro furan of solvent, temperature of reaction is reflux temperature, the reaction times is 5 hours.
Preparation formula (III) compound is characterised in that, the preferred methyl iodide of methylating reagent, and the preferred salt of wormwood of alkaline reagents, the preferred acetone of solvent, temperature of reaction is reflux temperature, the reaction times is 5 hours.
Preparation formula (IV) compound is characterised in that, the preferred potassium hydroxide of alkaline reagents, and the mixing acid of the preferred concentrated hydrochloric acid of acid reagent and Glacial acetic acid, the volume ratio of ethanol and water is preferably 5: 1, and the reaction times is 8 hours.
Preparation formula V compound is characterised in that the mass ratio of PPA and formula (IV) compound is preferably 10: 1, the preferred hexanaphthene of solvent, and temperature of reaction is 90-95 ℃, the reaction times is 15 hours.
Preparation formula (VI) compound is characterised in that the mol ratio of the Grignard reagent of 5-iodo-2-methyl-2-amylene and formula (V) compound is preferably 3: 1, and temperature of reaction is preferably 30-35 ℃, and the reaction times is 36 hours.
Another object of the present invention provides the 2-methyl shown in the formula (III)-7-methoxyl group-1-oxo-1,2,3,4-naphthane-2-ethyl formate, 1-shown in the formula (VI) (4-methyl-3-pentenyl)-2-methyl-6-sec.-propyl-7-methoxyl group-3, the 4-dihydronaphthalene, both are the new compound that has no report.
Embodiment
In order further to illustrate the present invention, the below provides a series of embodiment, and these embodiment are illustrative fully, and they only are used for the present invention is specifically described, and not should be understood to limitation of the present invention.
Embodiment 1
7-methoxyl group-1-oxo-1,2,3, the preparation of 4-naphthane-2-ethyl formate (II):
To 60%NaH (2.37g, 0.10mol) the anhydrous THF of adding 20mL, stirred 10 minutes, and added diethyl carbonate (6.28g, 50mmol), be warming up to 50 ℃, slowly drip the solution that is made into by 7-methoxyl group-1-tetralone (4.75g, 26mol) and the anhydrous THF of 15mL, drip in 30 minutes and finish, back flow reaction 5 hours, cooling drips Glacial acetic acid and regulates pH to 5 under the ice bath, add 80mL water, stirred 30 minutes, tell organic layer, the water layer ethyl acetate extraction merges organic phase, the saturated common salt water washing, anhydrous Na 2SO 4Drying, concentrating under reduced pressure get oily liquids 6.52g, directly drop into next step reaction.Analyze required sample and can get white solid, m.p.40-42 ℃ through column chromatography (sherwood oil).Compound (II) is known substance, and CAS number is 31846-34-1.
Embodiment 2
2-methyl-7-methoxyl group-1-oxo-1,2,3, the preparation of 4-naphthane-2-ethyl formate (III):
With previous step product 7-methoxyl group-1-oxo-1,2,3,4-naphthane-2-ethyl formate is dissolved in the 50mL acetone, then adds K 2CO 3(9g, 65mmol) and CH 3I (3.20g, 28mmol), back flow reaction 5 hours, cooling, the K that filtering is excessive 2CO 3, concentrating under reduced pressure gets light yellow oil 7.02g, directly drops into next step reaction.Analyze required sample and can obtain colorless oil through column chromatography (sherwood oil).
ESI-MS：263[M+H] +；
1H-NMR(300MHz，CDCl 3)，δ(ppm)：1.29(t，J＝8.0Hz，3H)，1.56(s，3H)，2.20-2.25(m，2H)，2.75-2.85(m，2H)，3.83(s，3H)，4.21(q，J＝8.0Hz，2H)，7.12(d，J＝7.5Hz，1H)，7.26(d，J＝7.5Hz，1H)，7.47(s，1H).
Embodiment 3
The preparation of 2-methyl-7-methoxyl group-1-tetralone (IV):
Decarboxylation under the alkaline reagents: the oily matter that embodiment 2 is made is dissolved in 50mL ethanol and 10mL water, adds KOH (4.38g, 78mmol), back flow reaction 8 hours, add 200mL water, stirred dichloromethane extraction 15 minutes, 5% salt acid elution is to neutrality, saturated common salt water washing, anhydrous Na 2SO 4Drying, silica gel column chromatography (sherwood oil) obtain light yellow oily liquid 4.0g, above-mentioned three-step reaction total recovery 78% (in 7-methoxyl group-1-tetralone).
Decarboxylation under the acid reagent: the oily matter that embodiment 2 is made is dissolved in the 150mL Glacial acetic acid, adds concentrated hydrochloric acid 15mL, back flow reaction 4 hours, add 200mL water, stirred dichloromethane extraction 10 minutes, the saturated sodium carbonate solution washing is to neutrality, saturated common salt water washing, anhydrous Na 2SO 4Drying, silica gel column chromatography (sherwood oil) obtain light yellow oily liquid 3.8g, above-mentioned three-step reaction total recovery 77% (in 7-methoxyl group-1-tetralone).
ESI-MS：191[M+H] +；
1H-NMR(300MHz，CDCl 3)，δ(ppm)：1.26(d，J＝6.8Hz，3H)，1.79-1.93(m，1H)，2.14-2.21(m，1H)，2.57(m，1H)，2.93(m，2H)，3.85(s，3H)，7.03(d，J＝2.7Hz，1H)，7.14(d，J＝2.7Hz，1H)，7.52(s，1H).
Embodiment 4
The preparation of 2-methyl-6-sec.-propyl-7-methoxyl group-1-tetralone (V)
2-methyl-7-methoxyl group-1-tetralone (10.03g, 53mmol), 100g PPA and 5mL Virahol add the 100mL hexanaphthene, stirring at room 30 minutes is warming up to 90 ℃, reacts 15 hours, be cooled to room temperature, in reaction solution, pour 200mL water into, stirred 30 minutes, tell organic layer, ethyl acetate extraction 3 times, saturated Na 2CO 3Solution washing, saturated common salt water washing, anhydrous Na 2SO 4Drying, column chromatography (sherwood oil) obtains yellow oily liquid 7.33g, yield 60%.
ESI-MS：233.1[M+H] +；
1H-NMR(300MHz，CDCl 3)，δ(ppm)：1.19-1.27(m，9H)，1.83-1.88(m，1H)，2.15-2.20(m，1H)，2.95(m，2H)，2.96-3.35(m，1H)，3.85(s，3H)，7.04(s，1H)，7.47(s，1H).
Embodiment 5
1-(4-methyl-3-pentenyl)-2-methyl-6-sec.-propyl-7-methoxyl group-3, the preparation of 4-dihydronaphthalene (VI)
7mLCH 3I and magnesium chips (43g, 0.1mol) are made Grignard reagent in the 20mL anhydrous diethyl ether, the Grignard reagent of making is cooled to below 0 ℃, drip the anhydrous ether solution that 10mL encircles the third methyl ketone (7g, 0.08mol), the control temperature is no more than 10 ℃, dropwise, stirred 30 minutes, in reaction solution, drip by the molten solution that is made into 30mL water of the 15mL vitriol oil, the control temperature is no more than 20 ℃, dropwise, stirred 30 minutes, tell organic layer, water layer ethyl acetate extraction 3 times, 5%Na 2SO 3The solution decolouring, 5%Na 2CO 3Solution washing is to neutrality, anhydrous Na 2SO 4Drying steams organic solvent, and underpressure distillation obtains 5-iodo-2-methyl-2-amylene, red oily liquids 10.54g, yield 60%.
1H-NMR(300MHz，CDCl 3)，δ(ppm)：1.62(s，3H)，1.70(s，3H)，2.58(dd，J＝7.5Hz，7.9Hz，2H)，3.10(t，J＝7.5Hz，2H)，5.1(t，J＝7.9Hz，1H).
With the above-mentioned 5-iodo-2-methyl that makes-2-amylene (4.82g, 22mmol) with magnesium chips (600mg, 25mmol) in the 20mL anhydrous diethyl ether, prepare Grignard reagent, drip the solution that is made into by 2-methyl-6-sec.-propyl-7-methoxyl group-1-tetralone (1.93g, 8.3mmol) and 20mL anhydrous diethyl ether, dripped in 30 minutes and finish, back flow reaction 36 hours, the ice-water bath cooling drips dilute hydrochloric acid and is neutralized to neutrality, ethyl acetate extraction, anhydrous Na 2SO 4Drying, silica gel column chromatography (sherwood oil) gets colorless oil 1.24g, yield 50%.
1H-NMR(300MHz，CDCl 3)，δ(ppm)：1.20(d，J＝7.0Hz，6H)，1.62(s，3H)，1.70(s，3H)，1.91(s，3H)，2.14-2.22(m，4H)，2.47(t，J＝7.9Hz，2H)，2.64(t，J＝7.9Hz，2H)，3.23-3.32(m，1H)，3.82(s，3H)，5.22(t，1H)，6.81(s，1H)，6.91(s，1H).
Embodiment 6
The preparation of 1-(4-methyl-3-pentenyl)-2-methyl-6-sec.-propyl-7-methoxyl group-naphthalene (VII)
1-(4-methyl-3-pentenyl)-2-methyl-6-sec.-propyl-7-methoxyl group-3,4-dihydronaphthalene (230mg, 0.77mmol) is dissolved in 10mL CH 2Cl 2In, add DDQ (262mg, 1.15mmol), room temperature reaction 30 minutes, suction filtration, decompression steams solvent, and column chromatography (sherwood oil) obtains colorless oil 170mg, yield 80%.
1H-NMR(300MHz，CDCl 3)，δ(ppm)：1.30(d，J＝7.0Hz，6H)，1.62(s，3H)，1.73(s，3H)，2.32(dd，J＝8.2Hz，6.2Hz，2H)，2.47(s，3H)，3.02(t，J＝8.2Hz，2H)，3.35-3.43(m，1H)，3.92(s，3H)，5.36(t，J＝6.2Hz，1H)，7.11(d，J＝8.1Hz，1H)，7.24(s，1H)，7.52(d，J＝8.1Hz，1H)，7.55(s，1H).
Embodiment 7
The preparation of 3-sec.-propyl-7-methyl-8-(4-methyl-3-pentenyl)-beta naphthal (VIII)
Dry DMF 5mL, 60%NaH (20mg, 7.82mmol), mix and blend 10 minutes drips sulfur alcohol (242mg, 3.91mmol), stirred 30 minutes, and added 1-(4-methyl-3-pentenyl)-2-methyl-6-sec.-propyl-7-methoxyl group-naphthalene (148mg, 0.50mmol), refluxed 30 minutes, be cooled to room temperature, it is 5 that dropping dilute hydrochloric acid is neutralized to pH, ethyl acetate extraction, the saturated aqueous common salt washing, anhydrous Na 2SO 4Drying, silica gel column chromatography [sherwood oil: ethyl acetate (v/v)=20: 1] gets colourless colloid 126mg, yield 90%.
ESI-MS：281[M-H] -；
1H-NMR(300MHz，CDCl 3)，δ(ppm)：1.26(d，J＝7.0Hz，6H)，1.53(s，3H)，1.65(s，3H)，2.22(q，J＝8.3Hz，J＝6.9Hz，2H)，2.38(s，3H)，2.88(t，J＝8.3Hz，2H)，3.20-3.27(m，1H)，4.97(s，1H)，5.24(t，J＝6.9Hz，1H)，7.03(d，J＝8.3Hz，1H)，7.18(s，1H)，7.45(d，J＝8.3Hz，1H)，7.50(s，1H).
Embodiment 8
The preparation of Saprorthoquinone (I)
3-sec.-propyl-7-methyl-8-(4-methyl-3-pentenyl)-beta naphthal (100mg, 0.35mmol) be dissolved among the 5mL DMF, disposable adding IBX (118mg, 0.42mmol), the room temperature vigorous stirring is dissolved fully to IBX, and the end reaction adds 20mL water, ethyl acetate extraction, 5%NaHCO 3Solution washing, saturated common salt water washing, anhydrous Na 2SO 4Drying, silica gel column chromatography [sherwood oil: ethyl acetate (v/v)=20: 1] obtains red solid 100mg, yield 95%.
m.p.97℃-98℃；
ESI-MS：297.4[M+H] +；
1H-NMR(300MHz，CDCl 3)，δ(ppm)：1.16(d，J＝6.9Hz，6H)，1.63(s，3H)，1.71(s，3H)，2.20(dd，2H)，2.38(s，3H)，3.06(m，3H)，5.30(t，J＝7.3Hz，1H)，7.03(d，J＝7.6Hz，1H)，7.08(s，1H)，7.34(d，J＝7.6Hz，1H)
IR(KBr)v：3734，3391，3289，2961，2916，2860，1067，943，827，812，700，574，453cm -1

Claims (9)

1. the synthetic method of the Saprorthoquinone shown in the formula (I), its route is as follows:
This route comprises the steps:
Step (1): take 7-methoxyl group-1-tetralone as raw material, under the alkaline reagents effect, make the 7-methoxyl group shown in the formula (II)-1-oxo-1,2,3,4-naphthane-2-ethyl formate with the diethyl carbonate reaction;
Step (2): under the alkaline reagents condition, formula (II) compound and methylating reagent reaction make the 2-methyl shown in the formula (III)-7-methoxyl group-1-oxo-1,2,3,4-naphthane-2-ethyl formate;
Step (3): the backflow decarboxylation under alkaline reagents or acid reagent effect of formula (III) compound makes the 2-methyl shown in the formula (IV)-7-methoxyl group-1-tetralone;
Step (4): under polyphosphoric acid PPA effect, formula (IV) compound and isopropanol reaction make the 2-methyl shown in the formula (V)-6-sec.-propyl-7-methoxyl group-1-tetralone;
Step (5): the Grignard reagent reaction of formula (V) compound and 5-iodo-2-methyl-2-amylene makes the 1-shown in the formula (VI) (4-methyl-3-pentenyl)-2-methyl-6-sec.-propyl-7-methoxyl group-3,4-dihydronaphthalene;
Step (6): formula (VI) compound is through 2,3-, two chloro-5, and 6-dicyan para benzoquinone DDQ Oxidative Dehydrogenation gets the 1-shown in the formula (VII) (4-methyl-3-pentenyl)-2-methyl-6-sec.-propyl-7-methoxyl group-naphthalene;
Step (7): formula (VII) compound demethylation under sulfur alcohol and sodium hydride effect makes the 3-sec.-propyl shown in the formula (VIII)-7-methyl-8-(4-methyl-3-pentenyl)-beta naphthal;
Step (8): formula (VIII) compound makes the Saprorthoquinone shown in the formula (I) under the oxygenant effect.
2. the synthetic method of Saprorthoquinone according to claim 1 is characterized in that:
The described alkaline reagents of step (1) is selected from one or more in sodium hydride, potassium hydride KH, potassium tert.-butoxide or the sodium methylate, reaction solvent is selected from one or more in anhydrous tetrahydro furan, anhydrous methylene chloride or the dry toluene, temperature of reaction is the boiling temperature of solvent for use, and the reaction times is 2-8 hour;
The described methylating reagent of step (2) is selected from methyl iodide, methyl-sulfate or diazomethane, alkaline reagents is selected from one or more in salt of wormwood, yellow soda ash or the triethylamine, reaction solvent is selected from acetone, N, in dinethylformamide, methyl alcohol or the ethanol one or more, temperature of reaction is the suitable temp between the boiling temperature of room temperature and solvent for use, and the reaction times is 3-10 hour;
The described alkaline reagents of step (3) is selected from potassium hydroxide or sodium hydroxide, acid reagent is selected from one or more in concentrated hydrochloric acid, sulfuric acid or the Glacial acetic acid, reaction solvent is the mixed solvent of second alcohol and water, and the volume ratio of ethanol and water is selected from 3: 1-7: 1, and the reaction times is 3-10 hour;
The mass ratio of PPA and formula (IV) compound is 5 in the step (4): 1-15: 1, and solvent is selected from one or more in chloroform, methylene dichloride, hexanaphthene or the tetrahydrofuran (THF), and temperature of reaction is 70 ℃-120 ℃, and the reaction times is 10-20 hour;
5-iodo-2-methyl in the step (the 5)-Grignard reagent of 2-amylene and the mol ratio of formula (V) compound are 1: 1-5: 1, and temperature of reaction is 25-45 ℃, the reaction times is 15-48 hour;
The mol ratio of DDQ and formula (VI) compound is 1 in the step (6): 1-3: 1, and solvent is selected from one or more in methylene dichloride, chloroform or the benzene, and temperature of reaction is room temperature, and the reaction times is 10-30 minute;
Solvent is selected from anhydrous DMF or anhydrous dimethyl sulfoxide in the step (7), and temperature of reaction is 140 ℃-190 ℃, and the reaction times is 20-60 minute;
The described oxygenant of step (8) is selected from 2-iodoxy phenylformic acid or Fremy salt, and reaction solvent is selected from one or more in DMF, methyl-sulphoxide or the chloroform, and temperature of reaction is room temperature, and the reaction times is 10-30 minute.
3. method according to claim 2 prepares compound (I) and is characterised in that, the preferred 2-iodoxy of oxygenant phenylformic acid, and the preferred DMF of solvent, temperature of reaction is room temperature, the reaction times is 30 minutes.
4. method according to claim 2, preparation formula (II) compound is characterised in that, the preferred sodium hydride of alkaline reagents, the preferred anhydrous tetrahydro furan of solvent, temperature of reaction is reflux temperature, the reaction times is 5 hours.
5. method according to claim 2, preparation formula (III) compound is characterised in that, the preferred methyl iodide of methylating reagent, the preferred salt of wormwood of alkaline reagents, the preferred acetone of solvent, temperature of reaction is reflux temperature, the reaction times is 5 hours.
6. method according to claim 2, preparation formula (IV) compound is characterised in that, the preferred potassium hydroxide of alkaline reagents, the mixed solvent of the preferred concentrated hydrochloric acid of acid reagent and Glacial acetic acid, the volume ratio of ethanol and water is preferably 5: 1, and the reaction times is 8 hours.
7. method according to claim 2 prepares the formula V compound and is characterised in that the mass ratio of PPA and formula (IV) compound is preferably 10: 1, the preferred hexanaphthene of solvent, and temperature of reaction is 90-95 ℃, the reaction times is 15 hours.
8. method according to claim 2, preparation formula (VI) compound is characterised in that, the mol ratio of the Grignard reagent of 5-iodo-2-methyl-2-amylene and formula (V) compound is preferably 3: 1, and temperature of reaction is preferably 30-35 ℃, and the reaction times is 36 hours.
9. the 1-of a formula (VI) (4-methyl-3-pentenyl)-2-methyl-6-sec.-propyl-7-methoxyl group-3, the 4-dihydronaphthalene:
Figure FSB00001005713000031
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