CN102399139B - Preparation method of high optical purity shikonin and alkannin, and derivatives thereof - Google Patents
Preparation method of high optical purity shikonin and alkannin, and derivatives thereof Download PDFInfo
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Abstract
The invention discloses a preparation method of high optical purity shikonin and alkannin, and derivatives thereof. According to the invention, an intermediate separation means is used to prepare the high optical purity shikonin and alkannin, and the derivatives thereof, wherein the intermediate separation is that an amide diastereomer is formed from a carboxyl-contained intermediate and chiral amine, and separation is carried out through column chromatography or a recrystallization process. The derivatives of shikonin and alkannin are tetramethoxylated derivatives with shikonin and alkannin as mother nuclei, dimethoxylated-2-sidechainisomer derivatives and dimethoxylated-6-sidechainisomer derivatives with shikonin and alkannin as mother nuclei, 1,4-diacetoxylated-5,8-dimethoxylated-2-sidechainisomer derivatives and 1,4-diacetoxylated-5,8-dimethoxylated-6-sidechainisomer derivatives with shikonin and alkannin as mother nuclei, and diacetoxylated-6-sidechainisomer derivatives and diacetoxylated-2-sidechainisomer derivatives with shikonin and alkannin as mother nuclei. The preparation method of the invention, which has the advantages of easily available raw material, low price and high yield of each step reaction, is suitable for the large scale preparation.
Description
Technical field
That the present invention relates to is a kind of preparation method of pharmaceutical chemistry technical field, specifically, is by the fractionation to intermediate, and complete synthesizing process is prepared the method for Shikonin and the AK of optical purity.
Background technology
Asian puccoon is the clinical conventional Chinese medicine that the Pharmacopoeia of the People's Republic of China records.Asian puccoon can be divided into gromwell root (having another name called RADIX LITHOSPERMI from Northeast, Lithospermum erythrohizon) and Radix Arnebiae (having another name called lithospermum euchromum Royle, A.euchroma Johnst).Main effective constituent in gromwell root is Shikonin (Shikonin, I-1) and derivative thereof, contains AK (Alkannin in Radix Arnebiae, I-2) and derivative, Shikonin and AK be enantiomer each other, and Shikonin is R configuration, and AK is S configuration.They be proved there is anti-inflammatory, promote wound healing, the multiple biological activity such as antibiotic, antiviral, antithrombotic, hyperfunction, the anti-immunocompromised of antithyroid, hypoglycemic, liver protecting.Take Shikonin as main component, be used for the treatment of burn, the arnebia root oils Yi Asia of scalding, European a plurality of countries for clinical.In recent years, the antitumor activity of Shikonin and AK and derivative thereof is noticeable, take that it has become the focus in this field as lead compound exploitation research antitumor, new antiviral drug.Oxygen alkylated derivative of parent nucleus of alkannin naphthazarin and preparation method thereof, anticancer usage (Chinese invention patent publication number: CN101781308A, PCT application number PCT/CN2010/080048) are disclosed before applicant.In addition, Shikonin and AK or fabulous natural pigment, be applied in food, makeup and printing and dyeing industry.Due to Shikonin and AK purposes widely, demand is huge.Asian puccoon is as the source of Shikonin and AK, and natural distributed and limited, although initial china natural resources is compared with horn of plenty, along with a large amount of collections of people, has been on the verge of exhaustion at present.Although China has carried out a large amount of artificial cultures, be also difficult to meet growing needs, and also expensive.Japanese scholars has carried out a large amount of Shikonin Study on tissue culture, though entered suitability for industrialized production, cost is still very high.In addition, there is racemization problem in the Shikonin containing and AK derivative in natural Asian puccoon, therefrom extracts separated Shikonin and the AK that is difficult to obtain high-optical-purity.Along with take the progress of the new drug development that Shikonin and AK be raw material, market to its demand also in continuous growth.Therefore, by chemical synthesis, prepare Shikonin and AK, be one and facilitate feasible approach, receive more and more researchists' concern.
Existing bibliographical information be the complete synthesis of raceme Shikonin mostly, and be scarcely applicable to extensive preparation, applicant had invented a total synthesis method (Chinese patent ZL200510025243) that is suitable for preparing on a large scale racemize Shikonin in the past.At present, although there is the complete synthesis report of some chirality Shikonins and AK, be all not suitable for preparing on a large scale Shikonin and AK and the derivative thereof of high-optical-purity.Early report that the complete synthesis document of chirality Shikonin is one piece of patent (Japanese Patent JP63156741) of Japanese scholars.This patent does not provide yield and the product optical purity that respectively walks reaction in route, and the not yet marketization of chiral reagent used simultaneously, prepares to get up and need at least five steps react, comprising the lower asymmetric epoxidation reaction of a step yield.Braun(Shikonin and AK is synthetic subsequently, and Libiee wishes chemical record event, 1991; 11,1157-1164) and the asymmetric synthesis of Couladouros(Shikonin and AK, tetrahedron communication; 1997; 38 (41), 7263-7266.) etc. people has also reported respectively the chirality synthetic route of Shikonin and AK, but all exists chiral reagent used expensive; yield is low (is respectively 1.3%; 7.9%), the shortcoming such as optical purity low (being respectively 40%ee, 82%ee).(Shikonin and AK are succinctly effectively complete synthesis for Nicolaou etc.; the international version of Germany's applied chemistry; 1998; 37 (6), 839-841) from intermediate 1,8:4; two (the methylene radical dioxy base) naphthalenes of 5-set out; after bromo, react with Weinreb aminocompound and directly introduce hexa-atomic carbon side chain and obtain carbonyl derivative, finally by asymmetric reduction, go protecting group to obtain Shikonin and AK.Although this route step is few, optical purity higher (98%ee), yield still can (10.3%).But Weinreb aminocompound N-methoxyl group-N-methyl-4-methyl-3-that reaction is used alkene acid amides is not easy to obtain; DIP-Cl is expensive for the different firpene base of asymmetric reduction reagent two borine muriate; and electrooxidation Deprotection is difficult to amplify, be not suitable for extensive preparation.Having invented an asymmetric total synthesis method before us prepares the method for high-optical-purity Shikonin (Chinese patent: application number 201110087137.1), reaction scheme is shorter, overall yield of reaction and optical purity is all higher, have good application prospect.
On the whole, although the existing a plurality of study group of two ten years have reported the synthetic of raceme Shikonin in the past, the complete synthesis of chirality Shikonin and AK made slow progress.Chirality Shikonin and the AK of report are to be all prepared by asymmetric synthesis at present.For prepare the Shikonin of high-optical-purity and AK by method for splitting still without any report simultaneously.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, a kind of preparation method of Shikonin and AK of optical purity is provided, and first passage intermediate fractionation means are prepared the complete synthesis route of novelty of optical purity Shikonin (I-1) and AK (I-2).This route is used raw material to be easy to get, and cheap, and it is higher that each walks reaction yield, is suitable for extensive preparation.
Described Shikonin, AK and derivative optical purity >=99%ee thereof.
Described intermediate splits the amine referring to by a carboxylic intermediate and chirality and forms an acid amides diastereomer, and this diastereomer can be separated by simple column chromatography or recrystallization method.
Described Chiral Amine is (S or R)-Alpha-Methyl benzylamine or other chirality alkaloid.
Described Shikonin and AK derivative refer to Shikonin and AK parent nucleus oxygen tetramethyl-derivative (II-1 and II-2); Shikonin and 2 side chain isomer derivatives of AK parent nucleus oxygen dimethylization (III-1 and III-2) and 6 side chain isomers (IV-1 and IV-2); Shikonin and AK parent nucleus-Isosorbide-5-Nitrae-oxygen diacetylation-5,2 side chain isomer derivatives of 8-oxygen dimethylization (V-1 and V-2) and 6 side chain isomers (VI-1 and VI-2); Shikonin and 6 side chain isomer derivatives of AK parent nucleus oxygen diacetylation (VII-1 and VII-2) and 2 side chain isomers (VIII-1 and VIII-2).
The present invention is achieved by the following technical solutions, and described preparation method comprises the steps:
The first step, with Isosorbide-5-Nitrae, 5,8-tetramethoxy naphthalene-2-formaldehyde is raw material, by reacting with the organometallics of ethyl bromoacetate, preparation 3-hydroxyl-3-(Isosorbide-5-Nitrae, 5,8-tetramethoxy-2-naphthyl) ethyl propionate (2).
Second step, is dissolved in organic solvent or water by 3-hydroxyl-3-(Isosorbide-5-Nitrae, 5,8-tetramethoxy-2-naphthyl) ethyl propionate, and under alkaline condition, hydrolysis generates 3-hydroxyl-3-(Isosorbide-5-Nitrae, 5,8-tetramethoxy-2-naphthyl) propionic acid (3).
The 3rd step, by 3-hydroxyl-3-(1,4,5,8-tetramethoxy-2-naphthyl) propionic acid is dissolved in organic solvent, adds (S)-(-)-Alpha-Methyl benzylamine, under catalyst action, condensation generates diastereomer (R, S)-3-hydroxyl-3-(Isosorbide-5-Nitrae, 5,8-tetramethoxy-2-naphthyl)-N-(1-styroyl)-propionic acid amide (4-1) and (S, S)-3-hydroxyl-3-(Isosorbide-5-Nitrae, 5,8-tetramethoxy-2-naphthyl)-N-(1-styroyl)-propionic acid amide (4-2), can be easily by two kinds of mixture separation through silica gel column chromatography or recrystallization.
The 4th step, respectively by (R, S)-3-hydroxyl-3-(1, 4, 5, 8-tetramethoxy-2-naphthyl)-N-(1-styroyl)-propionic acid amide (4-1) and (S, S)-3-hydroxyl-3-(1, 4, 5, 8-tetramethoxy-2-naphthyl)-N-(1-styroyl)-propionic acid amide (4-2) is dissolved in organic solvent, under catalyst action, react with TERT-BUTYL DIMETHYL CHLORO SILANE and generate respectively (R, S)-3-(tertiary butyl dimethyl Si base)-3-(1, 4, 5, 8-tetramethoxy-2-naphthyl)-N-(1-styroyl)-propionic acid amide (5-1) and (S, S)-3-(tertiary butyl dimethyl Si base)-3-(1, 4, 5, 8-tetramethoxy-2-naphthyl)-N-(1-styroyl)-propionic acid amide (5-2).
The 5th step, respectively by (R, S)-3-(tertiary butyl dimethyl Si base)-3-(1, 4, 5, 8-tetramethoxy-2-naphthyl)-N-(1-styroyl)-propionic acid amide (5-1) and (S, S)-3-(tertiary butyl dimethyl Si base)-3-(1, 4, 5, 8-tetramethoxy-2-naphthyl)-N-(1-styroyl)-propionic acid amide (5-2) is dissolved in organic solvent, first under basic catalyst effect with phosphorus pentachloride stoichiometric number hour, then add alcohol, after a few hours, add again water, react complete (R)-3-(tertiary butyl dimethyl Si base)-3-(1 that generates respectively, 4, 5, 8-tetramethoxy-2-naphthyl)-propionic ester (6-1) and (S)-3-(tertiary butyl dimethyl Si base)-3-(1, 4, 5, 8-tetramethoxy-2-naphthyl)-propionic ester (6-2).
The 6th step, respectively by (R)-3-(tertiary butyl dimethyl Si base)-3-(1, 4, 5, 8-tetramethoxy-2-naphthyl)-propionic ester (6-1) and (S)-3-(tertiary butyl dimethyl Si base)-3-(1, 4, 5, 8-tetramethoxy-2-naphthyl)-propionic ester (6-2) is dissolved in organic solvent, under nitrogen protection, low temperature adds reductive agent, after some hours, cancellation reaction, generate respectively (R)-3-(tertiary butyl dimethyl Si base)-3-(1, 4, 5, 8-tetramethoxy-2-naphthyl)-propionic aldehyde (7-1) and (S)-3-(tertiary butyl dimethyl Si base)-3-(1, 4, 5, 8-tetramethoxy-2-naphthyl)-propionic aldehyde (7-2).
The 7th step, respectively triphenyl sec.-propyl bromination Phosphonium is dissolved in organic solvent, ice bath is cooling, under nitrogen protection, add n-Butyl Lithium, stir after for some time, add (R)-3-(tertiary butyl dimethyl Si base)-3-(1, 4, 5, 8-tetramethoxy-2-naphthyl)-propionic aldehyde and (S)-3-(tertiary butyl dimethyl Si base)-3-(1, 4, 5, 8-tetramethoxy-2-naphthyl)-propionic aldehyde, continue to stir after some hours, generate respectively (R)-2-[1-(tertiary butyl dimethyl Si base)-4-methyl-3-pentenyl]-(1, 4, 5, 8)-tetramethoxy naphthalene (8-1) and (S)-2-[1-(tertiary butyl dimethyl Si base)-4-methyl-3-pentenyl]-(1, 4, 5, 8)-tetramethoxy naphthalene (8-2).
The 8th step, respectively by (R)-2-[1-(tertiary butyl dimethyl Si base)-4-methyl-3-pentenyl]-(1, 4, 5, 8)-tetramethoxy naphthalene (8-1) and (S)-2-[1-(tertiary butyl dimethyl Si base)-4-methyl-3-pentenyl]-(1, 4, 5, 8)-tetramethoxy naphthalene (8-2) is dissolved in organic solvent or water, under catalyst action, slough the protecting group of pendant hydroxyl group, obtain respectively (R)-2-(1-hydroxy-4-methyl-3-pentenyl)-1, 4, 5, 8-tetramethoxy naphthalene (II-1) and (S)-2-(1-hydroxy-4-methyl-3-pentenyl)-1, 4, 5, 8-tetramethoxy naphthalene (II-2).
The 9th step, respectively by (R)-2-(1-hydroxy-4-methyl-3-pentenyl)-1, 4, 5, 8-tetramethoxy naphthalene (II-1) and (S)-2-(1-hydroxy-4-methyl-3-pentenyl)-1, 4, 5, 8-tetramethoxy naphthalene (II-2) is dissolved in organic solvent, add oxygenant ceric ammonium nitrate (CAN), oxidation obtains respectively (R)-5, 8-dimethoxy-2-(1-hydroxy-4-methyl-3-pentenyl)-1, 4-naphthoquinones (III-1), (R)-5, 8-dimethoxy-6-(1-hydroxy-4-methyl-3-pentenyl)-1, 4-naphthoquinones (IV-1), (S)-5, 8-dimethoxy-2-(1-hydroxy-4-methyl-3-pentenyl)-1, 4-naphthoquinones (III-2) and (S)-5, 8-dimethoxy-6-(1-hydroxy-4-methyl-3-pentenyl)-1, 4-naphthoquinones (IV-2).
The tenth step, respectively by (R)-5, 8-dimethoxy-2-(1-hydroxy-4-methyl-3-pentenyl)-1, 4-naphthoquinones (compound III-1), (R)-5, 8-dimethoxy-6-(1-hydroxy-4-methyl-3-pentenyl)-1, 4-naphthoquinones (IV-1), (S)-5, 8-dimethoxy-2-(1-hydroxy-4-methyl-3-pentenyl)-1, 4-naphthoquinones (III-2) and (S)-5, 8-dimethoxy-6-(1-hydroxy-4-methyl-3-pentenyl)-1, 4-naphthoquinones (IV-2) is dissolved in organic solvent, add zinc powder, diacetyl oxide, under catalyzer pyridine or DMAP effect, generate respectively (R)-2-(1-acetoxyl group-4-methyl-3-amylene)-1, 4-diacetoxy-5, 8-dimethoxy-naphthalene (V-1), (R)-6-(1-acetoxyl group-4-methyl-3-amylene)-1, 4-diacetoxy-5, 8-dimethoxy-naphthalene (VI-1), (S)-2-(1-acetoxyl group-4-methyl-3-amylene)-1, 4-diacetoxy-5, 8-dimethoxy-naphthalene (V-2), (S)-6-(1-acetoxyl group-4-methyl-3-amylene)-1, 4-diacetoxy-5, 8-dimethoxy-naphthalene (VI-2).
The 11 step, respectively by (R)-2-(1-acetoxyl group-4-methyl-3-amylene)-1, 4-diacetoxy-5, 8-dimethoxy-naphthalene (V-1), (R)-6-(1-acetoxyl group-4-methyl-3-amylene)-1, 4-diacetoxy-5, 8-dimethoxy-naphthalene (VI-1), (S)-2-(1-acetoxyl group-4-methyl-3-amylene)-1, 4-diacetoxy-5, 8-dimethoxy-naphthalene (V-2), (S)-6-(1-acetoxyl group-4-methyl-3-amylene)-1, 4-diacetoxy-5, 8-dimethoxy-naphthalene (VI-2) is dissolved in organic solvent, add oxygenant ceric ammonium nitrate (CAN), generate respectively (R)-5, 8-diacetyl-6-(1-acetoxyl group-4-methyl-3-amylene)-1, 4-naphthoquinones (VII-1), (R)-5, 8-diacetyl-2-(1-acetoxyl group-4-methyl-3-amylene)-1, 4-naphthoquinones (VIII-1), (S)-5, 8-diacetyl-6-(1-acetoxyl group-4-methyl-3-amylene)-1, 4-naphthoquinones (VII-2), (S)-5, 8-diacetyl-2-(1-acetoxyl group-4-methyl-3-amylene)-1, 4-naphthoquinones (VIII-2).
The 12 step; by (R)-5; 8-diacetyl-6-(1-acetoxyl group-4-methyl-3-amylene)-1; 4-naphthoquinones (VII-1) and (R)-5; 8-diacetyl-2-(1-acetoxyl group-4-methyl-3-amylene)-1; 4-naphthoquinones (VIII-1) mixing is dissolved in organic solvent or water, under alkaline condition, is hydrolyzed, and generates the Shikonin (SK) (I-1) of optical purity (>=99%ee).
By (S)-5; 8-diacetyl-6-(1-acetoxyl group-4-methyl-3-amylene)-1; 4-naphthoquinones (VII-2) and (S)-5; 8-diacetyl-2-(1-acetoxyl group-4-methyl-3-amylene)-1; 4-naphthoquinones (VIII-2) mixing is dissolved in organic solvent; under alkaline condition, be hydrolyzed, generate the AK (AK) (I-2) of optical purity (>=99%ee).
In aforesaid method, the reaction formula of each step is:
In the described the first step, with an organic solvent, this organic solvent is ether, tetrahydrofuran (THF), toluene etc. in reaction; Temperature used is 0 ℃～110 ℃.
In described second step institute, the organic solvent of use is one or several in the solvent that can dissolve each other with water such as ethanol, methyl alcohol, tetrahydrofuran (THF), DMF; Temperature used is 0 ℃～100 ℃.
In described the 3rd step, the organic solvent using is DMF, methylene dichloride, trichloromethane etc., and the catalyzer using is one or several in dicyclohexylcarbodiimide, active phosphate, triethylamine, pyridine etc.; Temperature used is 0 ℃～100 ℃; Resolving agent used be enantiomeric excess more than 98% (R)-Alpha-Methyl benzylamine for or (S)-Alpha-Methyl benzylamine or other containing chirality alkaloid, the diastereo-isomerism physical efficiency generating after condensation is by the easily separation of method of common column chromatography or recrystallization.
In described the 4th step, the organic solvent using is the aprotic polar solvents such as DMF, dimethyl sulfoxide (DMSO); The catalyzer using is the organic weak bases such as imidazoles, pyridine; Temperature used is at 0 ℃～100 ℃.
In described the 5th step, the organic solvent using is the mixture of ether, alkane, chloroparaffin, ketone, nitrile, acid amides or their various ratios of 2～20 carbon atoms; Alcohol used is methyl alcohol, ethanol, propyl alcohol or Virahol; Alkali used is the organic weak bases such as pyridine, DMAP, aniline, DMA; PH value in reaction process is 1～4.
In described the 6th step, reductive agent used is di-isopropyl aluminum hydride; Organic solvent used is ether, tetrahydrofuran (THF), methylene dichloride or toluene; Temperature used is-78 ℃～0 ℃.
In described the 7th step, organic solvent used is ether, toluene, methylene dichloride or trichloromethane; Temperature used is-78 ℃～25 ℃.
In described the 8th step, solvent used is one or more in tetrahydrofuran (THF), methyl alcohol, DMF, dimethyl sulfoxide (DMSO), acetonitrile, methylene dichloride, trichloromethane etc.; Catalyzer used is tetrabutyl ammonium fluoride, boron trifluoride diethyl etherate, hydrogen fluoride pyridine, tertbutanol peroxide etc.
In described the 9th step, the 11 step, organic solvent used is acetonitrile, methylene dichloride, trichloromethane, ethyl acetate etc.; Oxygenant used is ceric ammonium nitrate, silver oxide, Dai Si-Martin reagent etc.; Temperature used is 0 ℃～50 ℃.
In described the tenth step, organic solvent acetonitrile used, methylene dichloride, trichloromethane, ethyl acetate, acetone, triethylamine, diacetyl oxide etc.; Catalyzer used is the organic weak bases such as DMAP, pyridine, triethylamine, diisopropyl ethyl amine; Temperature used is 0 ℃～55 ℃.
In described the 12 step, organic solvent used is ethanol, methyl alcohol, acetonitrile etc.; Alkali used is the organic basess such as the mineral alkali of the metal ions such as hydroxide radical, carbonate or triethylamine, pyridine; Temperature used is 0 ℃～100 ℃.
Compared with prior art, beneficial effect of the present invention:
The preparation method of this Shikonin and AK and derivative thereof, the chirality phenylethylamine that utilizes first industrial cheapness is resolving agent, by the fractionation to intermediate, Shikonin and AK and the derivative thereof of optical purity >=99%ee have been obtained, simple to operate, total recovery is high, is applicable to extensive preparation.
Accompanying drawing explanation
Fig. 1 is that key intermediate 4-1,4-2 optical purity detect (HPLC) collection of illustrative plates.
Fig. 2 is that Shikonin and AK optical purity detect (HPLC) collection of illustrative plates.
Embodiment
Below embodiments of the invention are elaborated, the present embodiment is implemented take technical solution of the present invention under prerequisite, provided detailed embodiment and concrete operating process, but protection scope of the present invention is not limited to following embodiment.
Embodiment 1:3-hydroxyl-3-(1,4,5,8-tetramethoxy-2-naphthalene) ethyl propionate (2) is synthetic
Under nitrogen protection, the ethyl bromoacetate of 1mol splashes in the tetrahydrofuran solution of the zinc powder (2mol) activating, and drips and finishes, and drips Bi Huiliu after mono-hour; add 0.5mol1, the tetrahydrofuran solution of 4,5,8-tetramethoxy-2-naphthaldehyde; finish, continue after backflow 2h, cooling, add 200ml water; ethyl acetate extraction, saturated common salt washing, anhydrous sodium sulfate drying; concentrating under reduced pressure, obtains 0.92mol3-hydroxyl-3-(Isosorbide-5-Nitrae; 5,8-tetramethoxy-2-naphthalene) ethyl propionate, yield 92%.
1H-NMR(300MHz,CDCl
3):δ1.27(t,J=8.1,3H,-CH
2CO
2CH
2C
H 3),2.7-2.9(m,2H,-C
H 2CO
2CH
2CH
3),3.78(s,3H,ArOC
H 3),3.90(s,3H,ArOC
H 3),3.94(s,3H,ArOC
H 3),3.96(s,3H,ArOC
H 3),4.20(dd,J
1=6.9,J
2=13.8,2H,-CH
2CO
2C
H 2CH
3),5.61(m,1H,-C
HOHCH
2-),6.82(s,2H,Ar
H),7.08(s,1H,Ar
H)。
Embodiment 2:3-hydroxyl-3-(1,4,5,8-tetramethoxy-2-naphthalene) propionic acid (3) is synthetic
By 0.5mol3-hydroxyl-3-(1,4,5,8-tetramethoxy-2-naphthalene) ethyl propionate is dissolved in methyl alcohol, adds the sodium hydroxide 100ml of 6M, after backflow 1h, add 6M hydrochloric acid 100ml, ethyl acetate extraction, saturated common salt washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, obtains the 3-hydroxyl-3-(1 of equivalent, 4,5,8-tetramethoxy-2-naphthalene) propionic acid, without further purifying, be directly used in next step reaction.
1H-NMR(300MHz,CDCl
3):δ2.90(m,2H,-C
H 2CO
2H),3.76(s,3H,ArOC
H 3),3.90(s,9H,3×ArOC
H 3),5.65(m,1H,-C
HOHCH
2-),6.81(s,2H,Ar
H),7.04(s,1H,Ar
H)。
Embodiment 3:(R, S)-3-hydroxyl-3-(Isosorbide-5-Nitrae, 5,8-tetramethoxy-2-naphthalene)-N-(1-styroyl)-propionic acid amide (4-1) and (S, S)-3-hydroxyl-3-(1,4,5,8-tetramethoxy-2-naphthalene)-N-(1-styroyl)-propionic acid amide (4-2) is synthetic
By 0.5mol3-hydroxyl-3-(1, 4, 5, 8-tetramethoxy-2-naphthalene) propionic acid, 0.5mol (S)-Alpha-Methyl benzylamine, 0.55mol benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate, 1.1mol triethylamine is dissolved in the anhydrous N of 100ml, in dinethylformamide, after stirring at room 2h, steam N, dinethylformamide, add ethyl acetate, washing, saturated common salt washing, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains crude product, column chromatography, obtain 0.40mol (R, S)-3-(tertiary butyl dimethyl Si base)-3-(1, 4, 5, 8-tetramethoxy-2-naphthalene)-N-(1-styroyl)-propionic acid amide (4-1), yield 40%.[α]
20 D=1.975；
1H-NMR(300MHz,CDCl
3):δ1.45(d,J=6.9,3H,-NHCHC
H 3-Ar),2.55-2.75(m,2H,-C
H 2CO-),3.76(s,3H,ArOC
H 3),3.88(s,6H,2×ArOC
H 3),3.92(s,3H,ArOC
H 3),5.07(t,J=6.9,1H,-NHC
HCH
3-Ar),5.53(s,1H,-C
HOHCONH-),6.12(s,1H,-CHOHCON
H-),6.81(s,2H,Ar
H),7.11(m,3H,Ar
H),7.18(s,3H,Ar
H)。Obtain 0.55mol (S, S)-3-(tertiary butyl dimethyl Si base)-3-(Isosorbide-5-Nitrae, 5,8-tetramethoxy-2-naphthalene)-N-(1-styroyl)-propionic acid amide (4-2), yield 47%.[α]
20 D=-39.8；
1H-NMR(300MHz,CDCl
3):δ1.33(d,J=6.9,3H,-NHCHC
H 3-Ar),2.54-2.70(m,2H,-C
H 2CO-),3.67(s,3H,ArOC
H 3),3.84(s,3H,ArOC
H 3),3.88(s,6H,2×ArOC
H 3),5.04(t,J=6.9,1H,-NHC
HCH
3-Ar),5.47(s,1H,-C
HOHCONH-),6.06(s,1H,-CHOHCON
H-),6.76(s,2H,Ar
H),7.06(m,3H,Ar
H),7.23(s,5H,Ar
H)。
As shown in Figure 1, be the high-efficient liquid phase chromatogram of key intermediate 4-1-(R, S), the 4-2-(S, S) (non-corresponding isomer) that generate in reaction.4-1,4-2 and derivative thereof can be by the simple and effective separation of method of ordinary silicon plastic column chromatography or recrystallization.
Testing conditions: separator column: Sepax GP-C18,4.6 * 250mm; 25 ℃ of column temperatures; Moving phase: methyl alcohol: water=6:4, detects wavelength 254nm.
Embodiment 4:(R, S)-3-(tertiary butyl dimethyl Si base)-3-(1,4,5,8-tetramethoxy-2-naphthalene)-N-(1-styroyl)-propionic acid amide (5-1) and (S, S)-3-(tertiary butyl dimethyl Si base)-3-(Isosorbide-5-Nitrae, 5,8-tetramethoxy-2-naphthalene)-N-(1-styroyl)-propionic acid amide (5-2) is synthetic
By 0.2mol (R, S)-3-hydroxyl-3-(1, 4, 5, 8-tetramethoxy-2-naphthalene)-N-(1-styroyl)-propionic acid amide is dissolved in anhydrous N, in dinethylformamide, add 0.4mol imidazoles, 0.3mol TERT-BUTYL DIMETHYL CHLORO SILANE, 0.05mol4-Dimethylamino pyridine, after stirring at room 12h, steam solvent, ethyl acetate extraction, saturated common salt washing, washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, column chromatography, obtain 0.19mol (R, S)-3-(tertiary butyl dimethyl Si base)-3-(1, 4, 5, 8-tetramethoxy-2-naphthalene)-N-(1-styroyl)-propionic acid amide (5-1), yield 95%.
1H-NMR(300MHz,CDCl
3):δ-0.10(s,3H,C
H 3Si-),0.06(s,3H,C
H 3Si-),0.89(s,9H,t-Bu-Si-),1.45(d,J=6.9,3H,-NHCHC
H 3-Ar),2.55-2.75(m,2H,-C
H 2CO-),3.76(s,3H,ArOC
H 3),3.88(s,6H,2×ArOC
H 3),3.92(s,3H,ArOC
H 3),5.07(t,J=6.9,1H,-NHC
HCH
3-Ar),5.53(s,1H,-C
HOHCONH-),6.12(s,1H,-CHOHCON
H-),6.81(s,2H,Ar
H),7.11(m,3H,Ar
H),7.18(s,3H,Ar
H)。
With legal system, obtain compound 5-2, yield 95%.
1H-NMR(300MHz,CDCl
3):δ-0.11(s,3H,C
H 3Si-),0.07(s,3H,C
H 3Si-),0.89(s,9H,t-Bu-Si-),1.33(d,J=6.9,3H,-NHCHC
H 3-Ar),2.54-2.70(m,2H,-C
H 2CO-),3.67(s,3H,ArOC
H 3),3.84(s,3H,ArOC
H 3),3.88(s,6H,2×ArOC
H 3),5.04(t,J=6.9,1H,-NHC
HCH
3-Ar),5.47(s,1H,-C
HOHCONH-),6.06(s,1H,-CHOHCON
H-),6.76(s,2H,Ar
H),7.06(m,3H,Ar
H),7.23(s,5H,Ar
H)。
Embodiment 5:(R)-3-(tertiary butyl dimethyl Si base)-3-(Isosorbide-5-Nitrae, 5,8-tetramethoxy-2-naphthalene) propionic ester (: 6-1) and (S)-3-(tertiary butyl dimethyl Si base)-3-(1,4,5,8-tetramethoxy-2-naphthalene) propionic ester (6-2) is synthetic
By 0.2mol (R, S)-3-(tertiary butyl dimethyl Si base)-3-(1, 4, 5, 8-tetramethoxy-2-naphthalene)-N-(1-styroyl)-propionic acid amide is dissolved in anhydrous 50ml methylene dichloride, with-50 ℃～50 ℃ add 0.2mol～1.0mol phosphorus pentachloride, 0.22mol～2.2mol pyridine, after stirring for some time, in-25 ℃～25 ℃, add 50ml methyl alcohol, after 1～8 hour, add water 100ml, after 2h～24h, dichloromethane extraction, saturated common salt washing, anhydrous sodium sulfate drying, column chromatography, obtain 0.172mol (R)-3-(tertiary butyl dimethyl Si base)-3-(1, 4, 5, 8-tetramethoxy-2-naphthalene) propionic ester (6-1), yield 86%.
1H-NMR(300MHz,CDCl
3):δ-0.11(s,3H,C
H 3Si-),0.07(s,3H,C
H 3Si-),0.88(s,9H,t-Bu-Si-),2.71(m,2H,-C
H 2CO
2CH
3),3.72(s,3H,-CH
2CO
2C
H 3),3.81(s,3H,ArOC
H 3),3.90(s,3H,ArOC
H 3),3.94(s,6H,2×ArOC
H 3),5.73(m,1H,-C
HOHCH
2-),6.82(s,2H,Ar
H),7.10(s,1H,Ar
H)。
With legal system, obtain compound 6-2, yield 85%.
Embodiment 6:(R)-3-(tertiary butyl dimethyl Si base)-3-(Isosorbide-5-Nitrae, 5,8-tetramethoxy-2-naphthalene) propionic aldehyde (7-1) and (S)-3-(tertiary butyl dimethyl Si base)-3-(1,4,5,8-tetramethoxy-2-naphthalene) propionic aldehyde (7-2) is synthetic
By 0.2mol (R)-3-(tertiary butyl dimethyl Si base)-3-(1; 4; 5; 8-tetramethoxy-2-naphthalene) propionic ester is dissolved in anhydrous methylene chloride; nitrogen protection, adds 0.3mol di-isopropyl aluminum hydride in-78 ℃～0 ℃, after 12h; add water; dichloromethane extraction, saturated common salt washing, anhydrous sodium sulfate drying; column chromatography; obtain 0.19mol (R)-3-(tertiary butyl dimethyl Si base)-3-(Isosorbide-5-Nitrae, 5; 8-tetramethoxy-2-naphthalene) propionic aldehyde (7-1), yield 95%.
1H-NMR(300MHz,CDCl
3):δ-0.09(s,3H,C
H 3Si-),0.11(s,3H,C
H 3Si-),0.90(s,9H,t-Bu-Si-),2.70-2.89(m,2H,-C
H 2CO
2CH
3),3.79(s,3H,ArOC
H 3),3.90(s,3H,ArOC
H 3),3.94(s,6H,2×ArOC
H 3),5.77(m,1H,-C
HOHCH
2-),6.83(s,2H,Ar
H),7.10(s,1H,Ar
H),9.84(m,1H,-CH
2C
HO)。
With legal system, obtain compound 7-2, yield 95%,
1h-NMR is with compound 7-1.
Embodiment 7:(R)-2-[1-(tertiary butyl dimethyl Si base)-4-methyl-3-pentenyl]-(1,4,5,8)-tetramethoxy naphthalene (8-1) and (S)-2-[1-(tertiary butyl dimethyl Si base)-4-methyl-3-pentenyl]-(1,4,5,8) synthesizing of-tetramethoxy naphthalene (8-2)
0.15mol triphenyl sec.-propyl bromination phosphorus is dissolved in anhydrous diethyl ether, under nitrogen protection, in-78 ℃～-0 ℃, add 0.14mol n-Butyl Lithium, stir after 2 hours, add 0.1mol (R)-3-(tertiary butyl dimethyl Si base)-3-(1, 4, 5, 8-tetramethoxy-2-naphthalene) propionic aldehyde (7-1), continue to stir after 8h～12h, add water, ethyl acetate extraction, saturated common salt washing, anhydrous sodium sulfate drying, column chromatography, obtain 0.085mol (R)-2-[1-(tertiary butyl dimethyl Si base)-4-methyl-3-pentenyl]-(1, 4, 5, 8)-tetramethoxy naphthalene (8-1), yield 75%.
1H-NMR(300MHz,CDCl
3):δ-0.12(s,3H,C
H 3Si-),0.05(s,3H,C
H 3Si-),0.88(s,9H,t-Bu-Si-),1.58(s,3H,-C
H 3),1.70(s,3H,-C
H 3),2.28-2.48(m,2H,-C
H 2CH=C-),3.77(s,3H,ArOC
H 3),3.91(s,3H,ArOC
H 3),3.94(s,6H,2×ArOC
H 3),5.22-5.31(m,2H,-C
HOHCH
2-and-CH
2C
H=C),6.80(s,2H,Ar
H),7.12(s,1H,Ar
H)。
With legal system, obtain compound 8-2, yield 75%,
1h-NMR is with compound 8-1.
Embodiment 8:(R)-2-(1-hydroxy-4-methyl-3-pentenyl)-Isosorbide-5-Nitrae, 5,8-tetramethoxy-2-naphthalene (9-1) and (S)-2-(1-hydroxy-4-methyl-3-pentenyl)-Isosorbide-5-Nitrae, 5,8-tetramethoxy-2-naphthalene (9-2) synthetic
By 0.15mol (R)-2-[1-(tertiary butyl dimethyl Si base)-4-methyl-3-pentenyl]-(1,4,5,8)-tetramethoxy naphthalene is dissolved in anhydrous tetrahydro furan, adds the tetrabutyl ammonium fluoride of 0.2mol, after stirring at room 12h, steaming desolventizes, add water, ethyl acetate extraction, saturated common salt washing, washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, obtains 0.143mol (R)-2-(1-hydroxy-4-methyl-3-pentenyl)-1,4,5,8-tetramethoxy-2-naphthalene (9-1), yield 95%.
1H-NMR(300MHz,CDCl
3):δ1.65(s,3H,-CH
3),1.72(s,3H,-C
H 3),2.55(m,2H,-C
H 2CH=),3.76(s,3H,ArOC
H 3),3.93(s,3H,ArOC
H 3),3.95(s,6H,2×ArOC
H 3),5.22-5.31(m,2H,-C
HOHCH
2-,-CH
2C
H=),6.82(s,2H,Ar
H),7.02(s,1H,Ar
H)。
With legal system, obtain compound 9-2, yield 95%,
1h-NMR is with compound 9-1.
Embodiment 9:(R)-5,8-dimethoxy-2-(1 '-hydroxyl-4 '-methyl-3 '-amylene)-1,4-naphthoquinones (10-1-1) and (R)-5,8-dimethoxy-6-(1 '-hydroxyl-4 '-methyl-3 '-amylene)-1,4-naphthoquinone (10-1-2) is synthetic
By 0.1mol (R)-2-(1-hydroxy-4-methyl-3-pentenyl)-Isosorbide-5-Nitrae, 5,8-tetramethoxy-2-naphthalene is dissolved in methylene dichloride or acetonitrile, adds the aqueous solution of 0.25mol ceric ammonium nitrate, after stirring at room 0.5h～2h, ethyl acetate extraction, saturated common salt washing, washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, column chromatography, obtain 0.053mol (R)-5,8-dimethoxy-2-(1 '-hydroxyl-4 '-methyl-3 '-amylene)-1,4-naphthoquinone (10-1-1), yield 53%.
1H-NMR(300MHz,CDCl
3):δ1.62(s,3H,-C
H 3),1.72(s,3H,-C
H 3),2.31-2.45(m,2H,-C
H 2CH=),3.98(s,6H,2×ArOC
H 3),4.75(t,J=7.2Hz,1H,-CH
2C
H=),5.17(m,J=7.8Hz,1H,-C
HOHCH
2-),6.79(s,1H,Ar
H),7.32(s,2H,Ar
H)。Obtain 0.043mol (R)-5,8-dimethoxy-6-(1 '-hydroxyl-4 '-methyl-3 '-amylene)-1,4-naphthoquinone (10-1-2), yield 43%.
1H-NMR(300MHz,CDCl
3):δ1.65(s,3H,-C
H 3),1.76(s,3H,-C
H 3),2.19-2.35(m,2H,-C
H 2CH=),3.89(s,3H,ArOC
H 3),3.97(s,3H,ArOC
H 3),5.10(t,J=5.7Hz,1H,-CH
2C
H=),5.24(m,1H,-C
HOHCH
2-),6.79(s,2H,Ar
H),7.55(s,1H,Ar
H)。
Embodiment 10:(S)-5,8-dimethoxy-2-(1 '-hydroxyl-4 '-methyl-3 '-amylene)-1,4-naphthoquinones (10-2-1) and (S)-5,8-dimethoxy-6-(1 '-hydroxyl-4 '-methyl-3 '-amylene)-1,4-naphthoquinone (10-2-2) is synthetic
According to the preparation method of compound 10-1-1, make compound 10-2-1, yield 53%.
1h-NMR (300MHz, CDCl
3): δ 1.62 (s, 3H ,-C
h 3), 1.72 (s, 3H ,-C
h 3), 2.31-2.45 (m, 2H ,-C
h 2cH=), 3.98 (s, 6H, 2 * ArOC
h 3), 4.75 (t, J=7.2Hz, 1H ,-CH
2c
h=), 5.17 (m, J=7.8Hz, 1H ,-C
hoHCH
2-), 6.79 (s, 1H, Ar
h), 7.32 (s, 2H, Ar
h); Make compound 10-2-2, yield 43%.
1H-NMR(300MHz,CDCl
3):δ1.65(s,3H,-C
H 3),1.76(s,3H,-C
H 3),2.19-2.35(m,2H,-C
H 2CH=),3.89(s,3H,ArOC
H 3),3.97(s,3H,ArOC
H 3),5.10(t,J=5.7Hz,1H,-CH
2C
H=),5.24(m,1H,-C
HOHCH
2-),6.79(s,2H,Ar
H),7.55(s,1H,Ar
H)。
Embodiment 11:(R)-5,8-dimethoxy-2-(1 '-acetoxyl group-4 '-methyl-3 '-amylene)-1,4-diacetoxy naphthalene (11-1-1) and (R)-5,8-dimethoxy-6-(1 '-acetoxyl group-4 '-methyl-3 '-amylene) synthesizing of-Isosorbide-5-Nitrae-diacetoxy naphthalene (11-1-2)
By 0.1mol (R)-5,8-dimethoxy-2-(1 '-hydroxyl-4 '-methyl-3 '-amylene)-1,4-naphthoquinones (10-1-1) is dissolved in diacetyl oxide, add 0.01mol4-Dimethylamino pyridine, in 0 ℃～30 ℃, stir after 0.5h～12h, remove solvent under reduced pressure, add water, ethyl acetate extraction, saturated common salt washing, washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, column chromatography obtains 0.084mol (R)-5,8-dimethoxy-2-(1 '-acetoxyl group-4 '-methyl-3 '-amylene)-Isosorbide-5-Nitrae-diacetoxy naphthalene (11-1-1), yield 84%.
1H-NMR(300MHz,CDCl
3):δ1.58(s,3H,-C
H 3),1.68(s,3H,-C
H 3),2.05(s,3H,-OAc),2.34(s,3H,-ArOAc),2.36(s,3H,-ArOAc),2.58-2.43(m,2H,-C
H 2-),3.81(s,3H,-OC
H 3),3.83(s,3H,-OC
H 3),5.05(dd,J=7.5Hz,1.5Hz,1H,-C
H=),6.03(m,1H,ArC
HOAc),6.76(s,2H,Ar
H),7.11-7.04(m,1H,Ar
H)。
With legal system, obtain compound 11-1-2, yield 88%.
1H-NMR(300MHz,CDCl
3):δ1.53(s,3H,C
H 3),1.66(s,3H,C
H 3),2.09(s,3H,-OAc),2.34(s,3H,ArOAc),2.35(s,3H,ArOAc),2.39-2.67(m,2H,-C
H 2-),3.81(s,3H,-OC
H 3),3.9(s,3H,-OC
H 3),5.09(t,J=7.2Hz,1H,-C
H=),6.25(dd,J=9.0Hz,6.0Hz,1H,ArC
HOAc),6.82(s,1H,Ar
H),7.03(d,J=6.5Hz,1H,Ar
H),7.09(1H,J=6.5Hz,d,Ar
H)。
Embodiment 12:(S)-5,8-dimethoxy-2-(1 '-acetoxyl group-4 '-methyl-3 '-amylene)-1,4-diacetoxy naphthalene (11-2-1) and (S)-5,8-dimethoxy-6-(1 '-acetoxyl group-4 '-methyl-3 '-amylene) synthesizing of-Isosorbide-5-Nitrae-diacetoxy naphthalene (11-2-2)
According to the preparation method of compound 11-1-1, make compound 11-2-1, yield 84%,
1h-NMR (300MHz, CDCl
3): δ 1.58 (s, 3H ,-C
h 3), 1.68 (s, 3H ,-C
h 3), 2.05 (s, 3H ,-OAc), 2.34 (s, 3H ,-ArOAc), 2.36 (s, 3H ,-ArOAc), 2.58-2.43 (m, 2H ,-C
h 2-), 3.81 (s, 3H ,-OC
h 3), 3.83 (s, 3H ,-OC
h 3), 5.05 (dd, J=7.5Hz, 1.5Hz, 1H ,-C
h=), 6.03 (m, 1H, ArC
hoAc), 6.76 (s, 2H, Ar
h), 7.11-7.04 (m, 1H, Ar
h).
With legal system, obtain compound 11-2-2, yield 88%.
1H-NMR(300MHz,CDCl
3):δ1.53(s,3H,C
H 3),1.66(s,3H,C
H 3),2.09(s,3H,-OAc),2.34(s,3H,ArOAc),2.35(s,3H,ArOAc),2.39-2.67(m,2H,-C
H 2-),3.81(s,3H,-OC
H 3),3.9(s,3H,-OC
H 3),5.09(t,J=7.2Hz,1H,-C
H=),6.25(dd,J=9.0Hz,6.0Hz,1H,ArC
HOAc),6.82(s,1H,Ar
H),7.03(d,J=6.5Hz,1H,Ar
H),7.09(1H,J=6.5Hz,d,Ar
H)。
Embodiment 13:(R)-5; 8-diacetyl-2-(1 '-acetoxyl group-4 '-methyl-3 '-amylene)-1; 4-naphthoquinones (12-1-1) and (R)-5,8-diacetyl-6-(1 '-acetoxyl group-4 '-methyl-3 '-amylene)-1,4-naphthoquinone (12-1-2) is synthetic
By 0.1mol (R)-5; 8-dimethoxy-2-(1 '-acetoxyl group-4 '-methyl-3 '-amylene)-1; 4-diacetoxy naphthalene is dissolved in methylene dichloride or acetonitrile; the aqueous solution that adds 0.25mol ceric ammonium nitrate; after stirring at room 0.5h～2h; ethyl acetate extraction; saturated common salt washing, washing, anhydrous sodium sulfate drying; concentrating under reduced pressure; column chromatography, obtains 0.09mol (R)-5,8-diacetyl-2-(1 '-acetoxyl group-4 '-methyl-3 '-amylene)-1; 4-naphthoquinones (12-1-1), yield 90%.
1H-NMR(CDCl
3):δ1.49(s,3H,-C
H 3),1.64(s,3H,-C
H 3),2.03(s,3H,-OAc),2.54-2.37(m,8H,C
H 2,2×-OAc),5.00(t,1H,j=7.2Hz,C
H=),6.02(m,1H,-C
HO),6.74(s,2H,Ar
H),7.39(s,1H,Ar
H)。
With legal system, obtain compound 12-1-2, yield 94%.
1H-NMR(300MHz,CDCl
3):δ1.65(s,3H,-C
H 3),1.75(s,3H,-C
H 3),2.09(s,3H,-OAc),2.38-2.44(s,8H,2×-ArOAc,-C
H 2-),5.07(m,1H,-CH=),5.87(m,1H,ArC
HOAc),6.66(s,1H,Ar
H),7.38(s,2H,Ar
H)。
Embodiment 14:(S)-5; 8-diacetyl-2-(1 '-acetoxyl group-4 '-methyl-3 '-amylene)-1; 4-naphthoquinones (12-2-1) and (S)-5,8-diacetyl-6-(1 '-acetoxyl group-4 '-methyl-3 '-amylene)-1,4-naphthoquinone (12-2-2) is synthetic
According to the preparation method of compound 12-1-1, make compound 12-2-1, yield 90%.
1H-NMR
(CDCl
3):δ1.49(s,3H,-CH
3),1.64(s,3H,-C
H 3),2.03(s,3H,-OAc),2.54-2.37(m,8H,C
H 2,2×-OAc),5.00(t,1H,j=7.2Hz,C
H=),6.02(m,1H,-C
HO),6.74(s,2H,Ar
H),7.39(s,1H,Ar
H)。
With legal system, obtain compound 12-2-2, yield 94%.
1H-NMR(300MHz,CDCl
3):δ1.65(s,3H,-C
H 3),1.75(s,3H,-C
H 3),2.09(s,3H,-OAc),2.38-2.44(s,8H,2×-ArOAc,-C
H 2-),5.07(m,1H,-C
H=),5.87(m,1H,ArC
HOAc),6.66(s,1H,Ar
H),7.38(s,2H,Ar
H)。
Embodiment 15:(R)-5,8 dihydroxyl-(1-hydroxy-4-methyl-3-pentenyl)-1,4-naphthoquinone (Shikonin, I-1) and (S)-5, synthesizing of 8 dihydroxyl-(1-hydroxy-4-methyl-3-pentenyl)-1,4-naphthoquinone (AK, I-2)
By 0.09mol (R)-5, 8-diacetyl-2-(1 '-acetoxyl group-4 '-methyl-3 '-amylene)-1, 4-naphthoquinones and 0.094mol (R)-5, 8-diacetyl-6-(1 '-acetoxyl group-4 '-methyl-3 '-amylene)-1, 4-naphthoquinones is dissolved in methyl alcohol, add 30ml1M sodium hydroxide, in 10 ℃～30 ℃, stir after 0.5h～2h, add 30ml1M hydrochloric acid, finish, ethyl acetate extraction, saturated common salt washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, column chromatography, obtain 0.175mol (R)-5, 8 dihydroxyl-(1-hydroxy-4-methyl-3-pentenyl)-1, 4-naphthoquinones (Shikonin, I-1), yield 95%.
1H-NMR(300MHz,CDCl
3):δ1.65(s,3H,-C
H 3),1.75(s,3H,-C
H 3),2.62-2.66(m,1H,-C
H b),2.31-2.38(m,1H,-C
Ha),4.91(d,J=7.2Hz,1H,-C
HOH),5.20(t,J=8.1Hz,1H,-C
H=),7.16(s,1H,Ar
H),7.19(s,2H,Ar
H),12.58(s,1H,Ar
OH),12.59(s,1H,Ar
OH)。
With method, make (S)-5,8 dihydroxyl-(1-hydroxy-4-methyl-3-pentenyl)-1,4-naphthoquinone (AK, I-2), yield 95%.
As shown in Figure 2, for target product Shikonin (figure A) and AK (scheming B) high-efficient liquid phase chromatogram.Wherein, Shikonin enantiomeric excess 100%ee almost; AK enantiomeric excess is not less than 99%ee.
Optical purity condition determination: chiral column
25 ℃ of column temperatures; A (SK), B (AK), moving phase: Virahol: normal hexane=1:9, detects wavelength 516nm.
The above is only the preferred embodiment of the present invention, and protection scope of the present invention is not only confined to above-described embodiment, and all technical schemes belonging under thinking of the present invention all belong to protection category of the present invention.It should be pointed out that for those skilled in the art, some improvements and modifications without departing from the principles of the present invention, these improvements and modifications also all should be considered as protection scope of the present invention.
Claims (10)
1. the Shikonin of optical purity and a preparation method for AK, is characterized in that: described preparation method comprises the steps:
The first step, with Isosorbide-5-Nitrae, 5,8-tetramethoxy naphthalene-2-formaldehyde is raw material, by reacting with the organometallics of ethyl bromoacetate, preparation 3-hydroxyl-3-(Isosorbide-5-Nitrae, 5,8-tetramethoxy-2-naphthyl) ethyl propionate;
Second step, is dissolved in organic solvent or water by 3-hydroxyl-3-(Isosorbide-5-Nitrae, 5,8-tetramethoxy-2-naphthyl) ethyl propionate, and under alkaline condition, hydrolysis generates 3-hydroxyl-3-(Isosorbide-5-Nitrae, 5,8-tetramethoxy-2-naphthyl) propionic acid;
The 3rd step, by 3-hydroxyl-3-(1,4,5,8-tetramethoxy-2-naphthyl) propionic acid is dissolved in organic solvent, adds (S)-(-)-Alpha-Methyl benzylamine, under catalyst action, condensation generates diastereomer (R, S)-3-hydroxyl-3-(Isosorbide-5-Nitrae, 5,8-tetramethoxy-2-naphthyl)-N-(1-styroyl)-propionic acid amide and (S, S)-3-hydroxyl-3-(Isosorbide-5-Nitrae, 5,8-tetramethoxy-2-naphthyl)-N-(1-styroyl)-propionic acid amide, through silica gel column chromatography by two kinds of mixture separation;
The 4th step, respectively by (R, S)-3-hydroxyl-3-(1, 4, 5, 8-tetramethoxy-2-naphthyl)-N-(1-styroyl)-propionic acid amide and (S, S)-3-hydroxyl-3-(1, 4, 5, 8-tetramethoxy-2-naphthyl)-N-(1-styroyl)-propionic acid amide is dissolved in organic solvent, under catalyst action, react with TERT-BUTYL DIMETHYL CHLORO SILANE and generate respectively (R, S)-3-(tertiary butyl dimethyl Si base)-3-(1, 4, 5, 8-tetramethoxy-2-naphthyl)-N-(1-styroyl)-propionic acid amide and (S, S)-3-(tertiary butyl dimethyl Si base)-3-(1, 4, 5, 8-tetramethoxy-2-naphthyl)-N-(1-styroyl)-propionic acid amide,
The 5th step, respectively by (R, S)-3-(tertiary butyl dimethyl Si base)-3-(1, 4, 5, 8-tetramethoxy-2-naphthyl)-N-(1-styroyl)-propionic acid amide and (S, S)-3-(tertiary butyl dimethyl Si base)-3-(1, 4, 5, 8-tetramethoxy-2-naphthyl)-N-(1-styroyl)-propionic acid amide is dissolved in organic solvent, first under basic catalyst effect with phosphorus pentachloride stoichiometric number hour, then add alcohol, after a few hours, add again water, react complete (R)-3-(tertiary butyl dimethyl Si base)-3-(1 that generates respectively, 4, 5, 8-tetramethoxy-2-naphthyl)-propionic ester and (S)-3-(tertiary butyl dimethyl Si base)-3-(1, 4, 5, 8-tetramethoxy-2-naphthyl)-propionic ester,
The 6th step, respectively by (R)-3-(tertiary butyl dimethyl Si base)-3-(1,4,5,8-tetramethoxy-2-naphthyl)-propionic ester and (S)-3-(tertiary butyl dimethyl Si base)-3-(Isosorbide-5-Nitrae, 5,8-tetramethoxy-2-naphthyl)-propionic ester is dissolved in organic solvent, adds reductive agent, after a few hours under nitrogen protection, cancellation reaction, generate respectively (R)-3-(tertiary butyl dimethyl Si base)-3-(Isosorbide-5-Nitrae, 5,8-tetramethoxy-2-naphthyl)-propionic aldehyde and (S)-3-(tertiary butyl dimethyl Si base)-3-(1,4,5,8-tetramethoxy-2-naphthyl)-propionic aldehyde;
The 7th step, respectively triphenyl sec.-propyl bromination Phosphonium is dissolved in organic solvent, ice bath is cooling, under nitrogen protection, add n-Butyl Lithium, after stirring, add (R)-3-(tertiary butyl dimethyl Si base)-3-(1, 4, 5, 8-tetramethoxy-2-naphthyl)-propionic aldehyde and (S)-3-(tertiary butyl dimethyl Si base)-3-(1, 4, 5, 8-tetramethoxy-2-naphthyl)-propionic aldehyde, continue to stir, generate respectively (R)-2-[1-(tertiary butyl dimethyl Si base)-4-methyl-3-pentenyl]-(1, 4, 5, 8)-tetramethoxy naphthalene and (S)-2-[1-(tertiary butyl dimethyl Si base)-4-methyl-3-pentenyl]-(1, 4, 5, 8)-tetramethoxy naphthalene,
The 8th step, respectively by (R)-2-[1-(tertiary butyl dimethyl Si base)-4-methyl-3-pentenyl]-(1,4,5,8)-tetramethoxy naphthalene and (S)-2-[1-(tertiary butyl dimethyl Si base)-4-methyl-3-pentenyl]-(Isosorbide-5-Nitrae, 5,8)-tetramethoxy naphthalene is dissolved in organic solvent, under catalyst action, slough the protecting group of pendant hydroxyl group, obtain respectively (R)-2-(1-hydroxy-4-methyl-3-pentenyl)-1,4,5,8-tetramethoxy naphthalene (II-1) and (S)-2-(1-hydroxy-4-methyl-3-pentenyl)-Isosorbide-5-Nitrae, 5,8-tetramethoxy naphthalene (II-2);
The 9th step, respectively by (R)-2-(1-hydroxy-4-methyl-3-pentenyl)-1, 4, 5, 8-tetramethoxy naphthalene (II-1) and (S)-2-(1-hydroxy-4-methyl-3-pentenyl)-1, 4, 5, 8-tetramethoxy naphthalene (II-2) is dissolved in organic solvent, add oxygenant ceric ammonium nitrate CAN, oxidation obtains respectively (R)-5, 8-dimethoxy-2-(1-hydroxy-4-methyl-3-pentenyl)-1, 4-naphthoquinones (III-1), (R)-5, 8-dimethoxy-6-(1-hydroxy-4-methyl-3-pentenyl)-1, 4-naphthoquinones (IV-1), (S)-5, 8-dimethoxy-2-(1-hydroxy-4-methyl-3-pentenyl)-1, 4-naphthoquinones (III-2) and (S)-5, 8-dimethoxy-6-(1-hydroxy-4-methyl-3-pentenyl)-1, 4-naphthoquinones (IV-2),
The tenth step, respectively by (R)-5, 8-dimethoxy-2-(1-hydroxy-4-methyl-3-pentenyl)-1, 4-naphthoquinones (compound III-1), (R)-5, 8-dimethoxy-6-(1-hydroxy-4-methyl-3-pentenyl)-1, 4-naphthoquinones (IV-1), (S)-5, 8-dimethoxy-2-(1-hydroxy-4-methyl-3-pentenyl)-1, 4-naphthoquinones (III-2) and (S)-5, 8-dimethoxy-6-(1-hydroxy-4-methyl-3-pentenyl)-1, 4-naphthoquinones (IV-2) is dissolved in organic solvent, add zinc powder, diacetyl oxide, under catalyzer pyridine or DMAP effect, generate respectively (R)-2-(1-acetoxyl group-4-methyl-3-amylene)-1, 4-diacetoxy-5, 8-dimethoxy-naphthalene (V-1), (R)-6-(1-acetoxyl group-4-methyl-3-amylene)-1, 4-diacetoxy-5, 8-dimethoxy-naphthalene (VI-1), (S)-2-(1-acetoxyl group-4-methyl-3-amylene)-1, 4-diacetoxy-5, 8-dimethoxy-naphthalene (V-2), (S)-6-(1-acetoxyl group-4-methyl-3-amylene)-1, 4-diacetoxy-5, 8-dimethoxy-naphthalene (VI-2),
The 11 step, respectively by (R)-2-(1-acetoxyl group-4-methyl-3-amylene)-1, 4-diacetoxy-5, 8-dimethoxy-naphthalene (V-1), (R)-6-(1-acetoxyl group-4-methyl-3-amylene)-1, 4-diacetoxy-5, 8-dimethoxy-naphthalene (VI-1), (S)-2-(1-acetoxyl group-4-methyl-3-amylene)-1, 4-diacetoxy-5, 8-dimethoxy-naphthalene (V-2), (S)-6-(1-acetoxyl group-4-methyl-3-amylene)-1, 4-diacetoxy-5, 8-dimethoxy-naphthalene (VI-2) is dissolved in organic solvent, add oxygenant ceric ammonium nitrate CAN, generate respectively (R)-5, 8-diacetyl-6-(1-acetoxyl group-4-methyl-3-amylene)-1, 4-naphthoquinones (VII-1), (R)-5, 8-diacetyl-2-(1-acetoxyl group-4-methyl-3-amylene)-1, 4-naphthoquinones (VIII-1), (S)-5, 8-diacetyl-6-(1-acetoxyl group-4-methyl-3-amylene)-1, 4-naphthoquinones (VII-2), (S)-5, 8-diacetyl-2-(1-acetoxyl group-4-methyl-3-amylene)-1, 4-naphthoquinones (VIII-2),
The 12 step, by (R)-5,8-diacetyl-6-(1-acetoxyl group-4-methyl-3-amylene)-1,4-naphthoquinones (VII-1) and (R)-5,8-diacetyl-2-(1-acetoxyl group-4-methyl-3-amylene)-1,4-naphthoquinones (VIII-1) mixing is dissolved in organic solvent or water, under alkaline condition, is hydrolyzed, and generates the Shikonin (I-1) of optical purity >=99%ee;
By (S)-5,8-diacetyl-6-(1-acetoxyl group-4-methyl-3-amylene)-1,4-naphthoquinones (VII-2) and (S)-5,8-diacetyl-2-(1-acetoxyl group-4-methyl-3-amylene)-1,4-naphthoquinones (VIII-2) mixing is dissolved in organic solvent, under alkaline condition, be hydrolyzed, generate the AK (I-2) of optical purity >=99%ee;
Related structural formula of compound is as follows above:
2. the Shikonin of optical purity according to claim 1 and the preparation method of AK, it is characterized in that: in the described the first step, with an organic solvent, this organic solvent is one or several mixing in ether, tetrahydrofuran (THF), toluene, ethyl acetate in reaction; Temperature of reaction is 0 ℃～110 ℃.
3. the Shikonin of optical purity according to claim 1 and the preparation method of AK, it is characterized in that: in described second step, organic solvent is one or several in the solvent that dissolves each other of ethanol, methyl alcohol, tetrahydrofuran (THF), DMF these and water; This step reaction temperature is 0 ℃～100 ℃.
4. the Shikonin of optical purity according to claim 1 and the preparation method of AK, it is characterized in that: in described the 3rd step, the organic solvent using is N, one or several in dinethylformamide, methylene dichloride, trichloromethane, toluene mix, and the catalyzer using is one or several in dicyclohexylcarbodiimide, triethylamine, pyridine; This step reaction temperature is 0 ℃～100 ℃; (S)-(-)-Alpha-Methyl benzylamine used be enantiomeric excess at more than 98% (S)-Alpha-Methyl benzylamine, the method for the diastereo-isomerism physical efficiency generating after condensation by common column chromatography or recrystallization is easily separated.
5. the Shikonin of optical purity according to claim 1 and the preparation method of AK, it is characterized in that: in described the 4th step, the organic solvent using is N, one or several mixing in dinethylformamide, dimethyl sulfoxide (DMSO), HMPA, DMI; A kind of in imidazoles, pyridine, DMAP of the catalyzer using; This step reaction temperature is at 0 ℃～100 ℃.
6. the Shikonin of optical purity according to claim 1 and the preparation method of AK, it is characterized in that: in described the 5th step, the organic solvent using is a kind of in the ether, alkane, chloroparaffin, ketone, nitrile, acid amides of 2～20 carbon atoms, or the mixture of their various ratios; Alcohol used is methyl alcohol, ethanol, propyl alcohol or Virahol; Alkali used is a kind of in pyridine, DMAP, aniline, DMA; PH value in reaction process is 1～4.
7. the Shikonin of optical purity according to claim 1 and the preparation method of AK, is characterized in that: in described the 6th step, reductive agent used is di-isopropyl aluminum hydride; Organic solvent used is ether, tetrahydrofuran (THF), methylene dichloride or toluene; This step reaction temperature used is-78 ℃～0 ℃.
8. the Shikonin of optical purity according to claim 1 and the preparation method of AK, is characterized in that: in described the 7th step, organic solvent used is ether, toluene, methylene dichloride or trichloromethane; This step reaction temperature used is-78 ℃～25 ℃.
9. the Shikonin of optical purity according to claim 1 and the preparation method of AK, it is characterized in that: in the 8th described step, organic solvent used is one or more in tetrahydrofuran (THF), methyl alcohol, DMF, dimethyl sulfoxide (DMSO), acetonitrile, methylene dichloride, trichloromethane; Catalyzer used is one or several mixing in tetrabutyl ammonium fluoride, boron trifluoride diethyl etherate, hydrogen fluoride pyridine, tertbutanol peroxide;
In described the 9th step, the 11 step, organic solvent used is one or several mixing in acetonitrile, methylene dichloride, trichloromethane, ethyl acetate; Oxygenant used is a kind of in ceric ammonium nitrate, silver oxide, Dai Si-Martin reagent; Step reaction temperature used is 0 ℃～50 ℃.
10. the Shikonin of optical purity according to claim 1 and the preparation method of AK, it is characterized in that: in described the tenth step, one or several mixing in organic solvent acetonitrile used, methylene dichloride, trichloromethane, ethyl acetate, acetone, triethylamine, diacetyl oxide; Catalyzer used be 4 ?a kind of in Dimethylamino pyridine, pyridine, triethylamine, diisopropyl ethyl amine; This step reaction temperature used is 0 ℃～55 ℃;
In described the 12 step, organic solvent used is one or several mixing in ethanol, methyl alcohol, acetonitrile Virahol; Alkali used is a kind of in the mineral alkali that forms of hydroxide radical, carbonate and metal ion or triethylamine, pyridine; This step reaction temperature used is 0 ℃～100 ℃.
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