CN101153030B - Polysubstitution hydrogenated naphthalene compounds, producing method and uses of the same - Google Patents
Polysubstitution hydrogenated naphthalene compounds, producing method and uses of the same Download PDFInfo
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Abstract
The present invention belongs to the field of organic chemistry and relates to a multi-substituted hydrogenated naphthalene compound, a synthesis method and use thereof. In particular, the present invention relates to a chiral multi-substituted ten-hydrogen and/or eight-hydrogen naphthalene compound, the synthetic method and uses. The present invention aims to provide a chiral multi-substituted ten-hydrogen and/or eight-hydrogen naphthalene compound; the oleanane-type or usu-type five-ring triterpenoid compound is used as a raw material for preparing the compound. The multi-substituted ten-hydrogen and/or eight-hydrogen naphthalene compound of the present invention can be used for synthesis of drugs or spices containing multi-hydrogen naphthalene fragments and the analogues. The method of the present invention is simple and easy, low in cost, high in production rate, and can realize industrialization.
Description
Technical field
The invention belongs to organic chemistry filed, relate to polysubstitution hydrogenated naphthalene compounds, its synthetic method and purposes, the polysubstituted decahydro that is specifically related to chirality is or/and octahydro naphthalene compound and preparation method and use thereof.
Background technology
Polysubstituted decahydro is or/and octahydro naphthalene structure fragment is the important structure unit that a lot of natural products such as triterpene, diterpene, sesquiterpene and analogue thereof all have.These compounds have mostly as biological activitys such as antitumor, weeding, antimycotic, antimicrobial, leukemia and anti-inflammatories.Polysubstituted decahydro is or/and octahydro naphthalene itself also has good fragrance and fixation etc.
These contain decahydro or/and this distribution in plant of the compound of octahydro naphthalene structure is very wide, but their content is low, directly extracts difficulty.Because this compounds generally contains a plurality of chiral centres and substituting group, the complete synthesis problems such as route is long, reagent is expensive, severe reaction conditions, reaction stereoselectivity difference that often exist, the at present mainly natural diterpene by containing the perhydronaphthalene structure or sesquiterpene is semi-synthetic obtains.Such as with Sclareolide synthetic vessel formation inhibitor (a.Eur.J.Org.Chem.2002,4169; B.Bioorg.Med.Chem.Lett.2003,13,2009), with sclareol synthetic ambrox (a.Synth.Comm.2001,31,749; B.Tetrahedron2001,57,5657and5663), with the synthetic marine natural product (J.Org.Chem.2003,68,1242) of sylvic acid etc. with antibiotic, antimycotic, food refusal, antiviral and antitumor isoreactivity.Up to now, the raw material rareness and the price of most semi-synthetic uses are high, and have used expensive and hypertoxic metal oxide etc.
Oleanane type (Oleanane) and ursane type (Ursane) pentacyclic triterpene are the extremely abundant natural resource of originating, as the ursolic acid (Ursolic acid), horse hair bavin acid (Barbinervicacid) etc. that belong to Oleanolic Acid (Oleanic acid), the Crategolic acid (Maslinicacid) of oleanane type and belong to the ursane type.Though these triterpenoids and derivative thereof have wide biological activity, activity intensity is not high, seldom enters clinical use, and added value is relatively low, is not developed fully.The natural product of many biologically actives, famous and precious essence and flavoring agent or medicine all have and perhydronaphthalene structures polysubstituted like the AB of oleanane type and ursane type pentacyclic triterpenoid ring or the DE lopps, many chiral centres.Such as flavor compounds ambrox ((-)-Ambrox) and 9-table-ambrox ((-)-9-epi-Ambrox) (Ohloff G, Fragrance Chemistry, Theimer, E.T., Ed.; Academic Press:New York, 1982, pp.535), Drimane type sesquiterpene (Nat.Prod.Rep.2004,21,449), Labdane type diterpene (Planta Med.1999,65,2) and Labdane type alkaloid (Bioorg.Med.Chem.2006,14,6954) etc. all have structural unit like the AB lopps with oleanane type and ursane type pentacyclic triterpenoid; Have antitumor, antiviral, antibiotic, immunomodulatory, inhibition HIV and suppress multiple bioactive Avarol and Avarone (a.J.Am.Chem.Soc.2002,124,12261 such as aldose reductase; B.Angew.Chem.Int.Ed.1999,38,3089) and some flavor compounds (Ger.1057108 (1959)) with civet fragrance have structural unit like the DE lopps of oleanane type and ursane type pentacyclic triterpenoid.Therefore adopt simple method, low-cost high productivity is realized the C ring open loop fracture of oleanane type and ursane type pentacyclic triterpenoid, and obtaining with AB and DE ring is that the decahydro of skeleton is or/and octahydro naphthalene chiral synthon is necessary.
At present, Garcia-Granados etc. have carried out studying (Tetrahedron2004,60,3831) to the C ring open loop fracture of Oleanolic Acid.But the method productive rate that they adopted is very low, the product complexity, and adopted cost an arm and a leg and also the severe toxicity transition metal chloride.Falck etc. then adopt pyrolysis cracking glycyrrhetinic acid (Glycyrrhetenic acid) C ring or adopt the method for the triolefin of the ozone oxidation fracture glycyrrhetinic acid C ring open loop C ring that ruptures, but have to AB ring product, the pyrolysis temperature height, ozone reaction then is difficult to control (a.Chem.Commun.1987,1324; B.TetrahedronLett.1994,35,2013).
Grane ambra is one of four the famousst and precious in the world large animal spices, is described as gray gold in the ocean, derives from the secretory product of Physter macrocephalus.Along with the enforcement of the minimizing of global Physter macrocephalus quantity and protection scheme such as prohibit hunting, obtaining of this spices has to seek substitute.((-)-Ambrox) is the main aroma component in the grane ambra, and the main substitute as natural grane ambra is used for perfume and tobacco industry to contain the ambrox of perhydronaphthalene structure.At present, the Quit company of Switzerland Firmenich company, German Henkel and Dragoco company, American I FF and Refolds tobacco company and Britain and Holland is the raw material production ambrox with sclareol (Sclareol) all.But when synthesizing ambrox, the oxidative degradation of sclareol side chain is more complicated still, and with Cr (VI), Mn metal ions such as (VII) is made oxygenant and can be produced Cr (III), Mn harmful wastes such as (II); In addition, the acid-catalyzed dehydration cyclization process causes the isomerization of ambrox and the formation of other by product easily.Structure activity study finds that in all steric isomers of ambrox, ((-)-9-epi-Ambrox) has the strongest fragrance and minimum threshold concentration value (0.15ppb) to 9-table-ambrox.But up to the present, the synthetic report of 9-table-ambrox is arranged seldom, and reaction reagent costliness, severe reaction conditions, can't realize industrialization.Civet also is one of four the famousst and precious in the world large animal spices.Some lactone compounds (Ger.1057108 (1959)) that contain the perhydronaphthalene structure have good civet fragrance, but these compounds are mainly by terpene compound (as myrcene etc.) and dienophile cycloaddition preparation, there are three-dimensional and regioselectivity problem, the mixture of several compounds often, quality can't guarantee.
Summary of the invention
The object of the invention provides the polysubstituted decahydro of chirality or/and the octahydro naphthalene compound has following structural formula:
Wherein, numbering 1 is the perhydronaphthalene compound, and numbering 2 is the octahydro naphthalene compound; R
1=alpha-acyloxy, β-acyloxy, alpha-alkoxy base, β-alkoxyl group, α-OH or β-OH; R
2=carboxyl, methyl, methylol, alkoxyl-methyl, acyl-oxygen methyl or formyl radical; R
3=carboxyl, methyl, methylol, alkoxyl-methyl, acyl-oxygen methyl or formyl radical; R
4=Alpha-Methyl or Beta-methyl; R
5=Alpha-hydroxy, beta-hydroxy or H; R
6=hydroxyl or H; R
7=carboxyl, carbalkoxy, methyl, methylol, alkoxyl-methyl or acyl-oxygen methyl; R
8=methyl, carboxyl, carbalkoxy, methylol, alkoxyl-methyl, acyl-oxygen methyl, formyl radical or H; R
9=methyl, carboxyl, carbalkoxy, methylol, alkoxyl-methyl or acyl-oxygen methyl; R
10=hydroxyl, methyl or H; R
11=methyl, hydroxyl or H.
Another object of the present invention provides above-mentioned decahydro or/and the preparation method of octahydro naphthalene compound, promptly adopt oleanane type or ursane type pentacyclic triterpenoid as raw material, will obtain perhydronaphthalene compound 1 or/and octahydro naphthalene compound 2 after its C ring open loop fracture.Concrete grammar is: 1) with its acylated hydroxy and carboxyl esterification or hydroxyl etherificate and carboxyl esterification; 2) oxidation, dehydrogenation are converted into the C ring and contain α, the cyclonene of beta-unsaturated carbonyl; 3) then under acid or base catalysis with acid anhydrides or carboxylic acid halides with the esterification of cyclonene enol, obtain the cyclohexadiene of C ring for the acyloxy replacement; 4) further this cyclohexadiene compound of illumination open loop obtains the triolefin that C encircles the acyloxy replacement of open loop; 5) last this triolefin of oxidation scission or its hydrolysate obtain perhydronaphthalene compound 1 or/and octahydro naphthalene compound 2.
As raw material, the preparation decahydro is or/and the reaction scheme of octahydro naphthalene compound is as follows with Oleanolic Acid, the Crategolic acid that belongs to the oleanane type triterpene and the ursolic acid that belongs to the Usu alkane type triterpenoid, the acid of horse hair bavin:
Wherein:
Compound 3 is respectively R
1=β-OH, R
3=R
8=Me, R
5=R
10=R
11=H, R
7The Oleanolic Acid of=COOH or R
1=β-OH, R
3=R
8=Me, R
5=α-OH, R
10=R
11=H, R
7The Crategolic acid of=COOH or R
1=β-OH, R
3=R
10=Me, R
5=R
8=R
11=H, R
7The ursolic acid of=COOH or R
1=R
11=α-OH, R
3=HOCH
2-, R
5=R
8=H, R
10=Me, R
7The horse hair bavin acid of=COOH; Compound 4-10 is respectively the further reaction product of Oleanolic Acid or Crategolic acid or ursolic acid or the acid of horse hair bavin, and its group is respectively R
1=β-acyloxy, R
3=R
8=Me, R
5=R
10=R
11=H, R
7=carbalkoxy or R
1=β-acyloxy, R
3=R
8=Me, R
5=α-OH, R
10=R
11=H, R
7=carbalkoxy or R
1=β-acyloxy, R
3=R
10=Me, R
5=R
8=R
11=H, R
7=carbalkoxy or R
1=R
11=alpha-acyloxy, R
3=acyl-oxygen methyl, R
5=R
8=H, R
10=Me, R
7=carbalkoxy;
A: adopt acid anhydrides or carboxylic acid halides/organic bases (as various pyridine derivates, various tertiary amine or its mixture) that the acylated hydroxy or the employing halohydrocarbon of compound 3 are protected the hydroxyl etherificate of compound 3, thionyl chloride/alcohol or oxalyl chloride/alcohol or DCC (dicyclohexylcarbodiimide)/alcohol or acid/alcohol are with the carboxyl esterification of compound 3;
B: adopt peracid (as H
2O
2/ HCOOH, H
2O
2/ CH
3COOH, mCPBA etc.) or inorganic peracid (as persulphate, hypochlorite etc.) or potassium permanganate oxidation compound 4 12 two keys be 12 carbonyl compound;
C: under HBr catalysis, adopt Br
2Dehydrogenation generates 9 (11) two keys;
D: under acid (as various sulfonic acid or the vitriol oil or its mixture) or alkali (as various pyridine derivates, various tertiary amine, acetate, DBU or its mixture) catalysis, with acid anhydrides or carboxylic acid halides with the esterification of 12 carbonyl enols;
E: in quartz or pyrex (Pyrex) vial, under the UV-irradiation, 8,14 bond ruptures realize the open loop of C ring, and when in the pyrex glass bottle, shining, have to triene compound 8, and when in quartzy bottle, shining, obtain the mixture of triene compound 8 and 9;
F: do not having or having in the presence of an acidic catalyst (as various sulfonic acid, sulfuric acid or their mixture), adopt peracid (as m-chloro-benzoic acid peroxide, peroxidation phenylformic acid, peroxidation nitrobenzoic acid, peroxidation trifluoracetic acid etc.) as oxygenant oxidation fracture triolefin, obtain compound 1 and 2, the R of compound 1
4Be Beta-methyl; When adding the amount≤3 times equivalent of peracid, the R of compound 2
6Be H, the amount that adds peracid is during greater than 3 times of equivalents, the R of compound 2
6Be H and/or OH;
G: the triene compound of basic hydrolysis gained, further with acid anhydrides or carboxylic acid halides with acylated hydroxy, obtain the hydrolysate of enol ester;
H: do not having or having in the presence of an acidic catalyst (as various sulfonic acid, sulfuric acid or their mixture), adopt peracid (as m-chloro-benzoic acid peroxide, peroxidation phenylformic acid, peroxidation nitrobenzoic acid, peroxidation trifluoracetic acid etc.) as oxygenant oxidation fracture triolefin, obtain compound 1 and 2, the R of compound 1
2Be Alpha-Methyl; When adding the amount≤3 times equivalent of peracid, the R of compound 2
6Be H, the amount that adds peracid is during greater than 3 times of equivalents, the R of compound 2
6Be H and/or OH.
Above-mentioned decahydro also is provided in the present invention or/and the purposes of octahydro naphthalene compound is used for synthetic the contain segmental medicine of many hydrogen naphthalene structure or spices and their analogue.
Decahydro of the present invention is or/and octahydro naphthalene compound 1 is used for synthetic grane ambra class spices (-)-9-table-ambrox, and reaction formula is as follows:
Wherein:
A: (hydrogen source is H with the Pd/C hydrogenation
2Or HCONH
2), Mg/CH
3OH or NaBH
4/ NiCl
26H
2Stereospecificity ground such as O reduction α, the two keys of β-unsaturated lactone obtain compound 11;
B: use LiAlH
4, LiBH
4, NaBH
4Mixture or KBH with lithium salts
4With the mixture ester reduction of lithium salts, the trihydroxy-compound that obtains, obtain compound 12 through acid (as various sulfonic acid) or SULPHURYL CHLORIDE/pyridine cyclisation;
C: at I
2Or acid (as tosic acid, sulfuric acid, sal enixum etc.) catalysis directly dewaters down, or hydroxyl is converted into behind the sulphonate at alkali (as LiCl, Li
2CO
3, organic and mineral alkalis such as t-BuOK, pyridine) effect down indirectly dehydration obtain compound 13;
The d:Pd/C shortening obtains compound 17 quantitatively;
I: at NaOH, KOH, Na
2CO
3Or K
2CO
3Under the effect in alkali, in methanol-water or ethanol aqueous systems, optionally 3 ester groups of hydrolysis obtain compound 14;
Ii: at I
2Or acid (as tosic acid, sulfuric acid, sal enixum etc.) catalysis directly dewaters down, or hydroxyl is converted into behind the sulphonate at alkali (as LiCl, Li
2CO
3, organic and mineral alkalis such as t-BuOK, pyridine) effect down indirectly dehydration obtain compound 15;
Iii: direct Pd/C shortening, perhaps NaBH
4/ NiCl
26H
2O reduces α, behind the two keys of β-unsaturated lactone again the Pd/C shortening obtain compound 16;
Iv: use LiAlH
4, LiBH
4, NaBH
4Mixture or KBH with lithium salts
4With the mixture reduction lactone of lithium salts, the dihydroxy compound that obtains obtains compound 17 through acid (as various sulfonic acid) or SULPHURYL CHLORIDE/pyridine cyclisation.
In by compound 1 synthetic 9-table-ambrox (17) process, compound 12 that is obtained and 13 analogues for 9-table-ambrox also have grane ambra class fragrance, and compound 16 then is the 9-table isomer of flavor compounds Sclareolide.
Decahydro of the present invention is or/and the octahydro naphthalene compound is used to have antitumor, antiviral, antibiotic, immunomodulatory, inhibition HIV and suppresses analogue synthetic of multiple bioactive Avarol such as aldose reductase and Avarone, and reaction formula is as follows:
R
6=H or hydroxyl are worked as R
8During=methyl, R
10=H works as R
8During=H, R
10=methyl
Wherein:
A: under the nitrogen protection, under protonic acid (as sulfuric acid, methylsulfonic acid etc.) effect, the Fu Ke acylation reaction takes place with Resorcinol and obtains compound 18 in compound 2;
B: compound 18 is a methylene radical through the huang-Minlon reaction reducing carbonyl, obtains the analogue 19 of Avarol;
C: adopting oxidation Resorcinol compounds such as oxygenant chloric acid sodium or potassium bichromate is the benzoquinone, obtains the analogue 20 of Avarone.
Characteristics of the present invention are: method is simple, and cost is low, and the productive rate height can be realized industrialization.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described, but do not limit content of the present invention.
Embodiment 1 is a raw material with the Oleanolic Acid, synthetic compound 1 and 2
1) preparation of compound 4:
5g compound 3 is dissolved in the dry chloroform of 20mL, adds the 10mL anhydrous methanol and the 1mL vitriol oil, heating allows its slow backflow 6h then.Cooling, reaction mixture be water, saturated sodium bicarbonate and saturated common salt washing successively, uses anhydrous magnesium sulfate drying.Underpressure distillation behind the filtering siccative, the solid that obtains vacuum-drying again.Then it is dissolved in the dry chloroform of 20mL, adds 5mL dry pyridine and 3mL acetic anhydride, stir 12h under the room temperature.Reaction mixture is water, saturated sodium bicarbonate aqueous solution, water and saturated common salt washing successively.Underpressure distillation gets white solid behind anhydrous magnesium sulfate drying, and this solid is directly used in the next step without separation and purification.
2) preparation of compound 5
(2g 3.9mmol) is dissolved in 10mL CHCl with compound 4
3In, add 2mL HCOOH.Oil bath is heated to 50 ℃, then with 2mL H
2O
2(30%) dropping enters.After dropwising, keep this temperature to continue to stir, and need to add a spot of H to reaction system every 2h
2O
2(30%) (0.5mL/ time) with impel the reaction finish, probably need 20h.The reaction raw materials back (TLC analysis) that disappears, the direct separatory of reaction mixture, resulting organic layer be water, saturated NaHCO successively again
3The aqueous solution, water and saturated common salt washing, MgSO
4Dry.Get white solid after the evaporated under reduced pressure, this solid is directly used in the next step without separation and purification.
3) preparation of compound 6
To compound 5 (2g, Glacial acetic acid 3.8mmol) (10mL) solution, the acetum (40%) of a HBr of adding.Then with 0.23mL (4.5mmol) Br
2Be dissolved in the 5mL acetic acid, under room temperature, drip.Behind reinforced the finishing, reaction mixture continues to stir 5h under room temperature.In the direct impouring 50mL of reaction solution mixture of ice and water, separate out faint yellow solid.The suction filtration solid is also used saturated NaHCO successively
3, saturated NaHSO
3And washing.Solid decompression oven dry with gained obtains whitening compound 6 (1.831g, 92%) with re-crystallizing in ethyl acetate.
4) preparation of compound 7
0.5g (0.95mmol) compound 6 is added 5mL Ac
2Among the O, add a vitriol oil after compound 5 be dissolved in Ac
2O generates the solution of light brown red, and then adds the 10mg tosic acid.Gained red-brown reaction mixture at room temperature continues to stir 10h.Then with the direct impouring 50mL of reaction solution mixture of ice and water.The solid that suction filtration is separated out is also used saturated NaHCO successively
3The aqueous solution and washing.Vacuum drying is after re-crystallizing in ethyl acetate obtains 0.470g compound 7 (87%).
5) preparation of compound 8
(200mg 0.35mmol) is dissolved in the 20mL ethyl acetate, places the Pyrex vial with compound 7.Under argon shield, adopt the 500W high voltage mercury lamp radiation.Keep room temperature during illumination, raw material disappears after 8 hours.To obtain the oily residuum behind the reaction solution evaporate to dryness, obtain compound 8 (188mg, 94%) by silica gel column chromatography (Petroleumether/EtOAc 25:1).
6) preparation of compound 9
The 30mL ethyl acetate solution of 200mg (0.35mmol) compound 7 is placed quartz flask, under the condition of room temperature and argon shield, with 500w high voltage mercury lamp radiation 4h.Silica gel column chromatography (Petroleum ether/EtOAc25:1) obtained compound 8 (98mg, 49%) and 9 (69mg, 35%) after decompression steamed solvent.
7) target compound 1 and 2 preparation
With compound 8 (100mg, 0.18mmol) and a spot of tosic acid add 5mL CH
2Cl
2In, under room temperature, stirred 5 minutes.Add then mCPBA (93mg, 0.54mmol).After stirring 12h under the room temperature, in reaction system, add the saturated NaHSO of 5mL
3The aqueous solution continues to stir 10 minutes, then separatory.Resulting organic layer is used saturated NaHCO successively
3Anhydrous MgSO is used in the aqueous solution, water and saturated common salt washing
4Dry.Rotation solvent evaporated gained residuum obtains compound 1 (44mg, 82%) and 2 (29mg, 67%) by the silicagel column separation and purification.
8) preparation of compound 10
(100mg 0.18mmol) is dissolved in the 2mL methyl alcohol, and (15mg 0.27mmol) and water (0.2mL), stirs 12h under room temperature to add KOH then with compound 8.Add 5mL water in the reaction mixture, use CH then
2Cl
2Extract three times.With CH
2Cl
2Extraction liquid is water and saturated common salt washing successively, anhydrous MgSO
4Dry.With MgSO
4After removing by filter, directly add 0.5mL pyridine and 0.2mL Ac
2O stirs 5h under room temperature.The gained reaction mixture is water, saturated NaHCO successively
3And the saturated common salt washing, use anhydrous MgSO at last
4Dry.Steaming desolventizes the back and obtains compound 10 (84mg, 91%) by silica gel column chromatography.
9) compound 1 ' and 2 preparation
With compound 10 (82mg, 0.16mmol) and a spot of tosic acid add 5mL CH
2Cl
2In, under room temperature, stirring 5 minutes, solution becomes faint yellow.(83mg, 0.48mmol), reaction system becomes light green gradually, becomes sap green at last to add mCPBA then.After stirring 12h under the room temperature, in reaction system, add the saturated NaHSO of 5mL
3The aqueous solution continues to stir 10 minutes, then separatory.Resulting organic layer is used saturated NaHCO successively
3Anhydrous MgSO is used in the aqueous solution, water and saturated common salt washing
4Dry.Rotation solvent evaporated gained residuum obtains compound 1 ' (33mg, 69%), 2 (22mg, 56%) by silicagel column separation and purification (Petroleum ether/AcOEt 10:1 andthen petroleum ether/AcOEt 4:1).
Embodiment 2 is a raw material with the Crategolic acid, synthetic compound 1 and 2
Adopting as enforcement 1 described operation steps, is raw material with the Crategolic acid, and the compound 1 and 2 that obtains is as follows:
Embodiment 3 is a raw material with the ursolic acid, synthetic compound 1 and 2
Adopting as enforcement 1 described operation steps, is raw material with the ursolic acid, and the compound 1 and 2 that obtains is as follows:
Embodiment 4 is a raw material with the acid of horse hair bavin, synthetic compound 1 and 2
Adopting as enforcement 1 described operation steps, is raw material with the acid of horse hair bavin, and the compound 1 and 2 that obtains is as follows:
Embodiment 5 is with compound 1 synthetic 9-table-ambrox
1) compound 11 is synthetic
(50mg 0.16mmol) is dissolved in the 2mL ethyl acetate, adds 10mg10%Pd/C then, places autoclave with compound 1.Use N
2Get rid of the air in the autoclave, feed the N in the hydrogen eliminating still then
2, keeping hydrogen pressure at last is 3MPa, reacts 10h under room temperature.Reaction finishes, and feeds N
2Get rid of the hydrogen in the reactor, take out reaction solution then, filtering Pd/C obtains pure compound 11 (100%) behind the evaporate to dryness.
2) compound 12 is synthetic
50mg (0.16mmol) compound 11 is dissolved among the anhydrous THF of 2mL, under argon shield, drips and enter LAH (19mg is in THF 0.50mmol) (3mL) solution.Dropwise, heating also keeps slowly refluxing, and reacts 2h under this temperature.Allow reaction mixture naturally cool to room temperature, add cold saturated Na
2SO
4The aqueous solution and a spot of alkene hydrochloric acid are used extracted with diethyl ether rapidly three times.Combined ether layer is used saturated NaHCO successively
3The aqueous solution and saturated Na
2SO
4The aqueous solution is washed, and uses anhydrous Na then
2SO
4Dry.Decompression at a lower temperature steams solvent, obtains colorless oil.Directly add 5mL Nitromethane 99Min. and 19mg (0.10mmol) TsOH, under room temperature, react 6h then.Reaction finishes, and adds the ether dilution, uses saturated NaHCO successively
3Wash with saturated common salt.Decompression steams solvent, and silica gel column chromatography obtains compound 12 (32mg, 77%).
3) compound 13 is synthetic
(50mg 0.20mmol) is dissolved in pyridine (0.2mL) and CH with compound 12
2Cl
2In the mixing solutions (3mL), cryosel is bathed cooling.Under-5 → 0 ℃ of temperature, add methylsulfonyl chloride (0.05mL).Under this temperature, react 2h, add CH
2Cl
2Gained solution passes through 5%HCl (aq.), water, saturated NaHCO successively
3And saturated common salt washing.Use MgSO
4Drying is filtered, and concentrates and obtains light yellow solid.This solid is dissolved in 8mL DMF, add anhydrous LiCl (20mg, 0.47mmol).Reaction mixture is reaction 4h under 100 ℃, is cooled to room temperature.After adding ethyl acetate, through water (3 times) and saturated common salt washing, use MgSO successively
4Dry.(n-hexane-AcOEt 50:1) gets 13 (37mg, 80%) to silica gel column chromatography after the filtering and concentrating.
4) compound 9-table-ambrox (17) is synthetic
In the autoclave of 20mL, add 13 (50mg), ethyl acetate (5mL) and 10%Pd/C (10mg).Then, use H
2Air in the displacement autoclave three times, the maintenance hydrogen pressure is 4MPa.Reaction 12h stops to stir, and slow releasing hydrogen gas.Remove by filter Pd/C, concentrating under reduced pressure obtains compound 17 quantitatively.
The analogue of embodiment 6 usefulness compounds, 2 synthetic Avarol and Avarone
1) compound 18 is synthetic
Compound 2 (500mg 2mmol) is dissolved in the 20mL methyl alcohol, and adding 1mL water and NaOH (96mg, 2.4mmol).React 10h under the room temperature, add dilute hydrochloric acid, use ethyl acetate extraction, through saturated sodium bicarbonate, water and saturated common salt washing.Through anhydrous magnesium sulfate drying, concentrating under reduced pressure obtains the esterolytic solid product of compound 2.This solid chemical compound is dissolved in dry ether (10mL) after vacuum-drying, (264mg, 10mL dry ether solution 2.4mmol) is added drop-wise to CH together with Resorcinol
3SO
3H/P
2O
5In the mixture (10:1), need about 1h.After dropwising again at room temperature reaction 4h.Reaction mixture is used anhydrous magnesium sulfate drying through water and saturated common salt washing.Concentrating under reduced pressure obtains the solid state compound, obtains compound 18 (295mg, 45%) through silica gel column chromatography.
2) compound 19 is synthetic
(328mg 1mmol) is dissolved in the 10mL glycol ether, adds 0.6mL hydrazine hydrate (80%) with compound 18.Under nitrogen protection, behind the reflux 2h, steam water and unreacted hydrazine hydrate.Stop heating, after the system for the treatment of is cooled off, in system, add 120mg (3mmol) NaOH, collect the water that reaction generates down, stop behind the 3h heating at 100 ℃.After the cooling, it is acid adding dilute hydrochloric acid regulation system pH, uses ethyl acetate extraction three times, and extraction liquid is through saturated sodium bicarbonate aqueous solution, water and saturated common salt washing.Behind anhydrous magnesium sulfate drying, decompression steams solvent, and the gained solid obtains compound 19 (246mg, 82%) through ethanol water recrystallization.
3) compound 20 is synthetic
Compound 19 (150mg, 0.5mmol), V
2O
5(5mg) and NaClO
3(30mg 0.28mmol) is dissolved in the 3mL2% aqueous sulfuric acid.Vigorous stirring is warmed up to 40 ℃ then, and reacts 3.5h under this temperature.After the reaction solution cooling, filter and obtain needed two naphtoquinone compounds, and use cold wash.Vacuum-drying obtains compound 20 (137mg, 92%).
Claims (8)
1. polysubstitution hydrogenated naphthalene compounds is characterized in that having following structural formula:
Wherein,
R
1=α-acetoxyl group, β-acetoxyl group, Alpha-hydroxy or beta-hydroxy; R
2=methyl; R
3=methyl, acetyl-o-methyl; R
4=Alpha-Methyl or Beta-methyl; R
5=Alpha-hydroxy, beta-hydroxy or H.
2. the preparation method of the described hydrogenated naphthalene compounds of claim 1 is: with oleanane type or ursane type pentacyclic triterpenoid is raw material, 1) with its acylated hydroxy and carboxyl esterification or hydroxyl etherificate and carboxyl esterification; 2) oxidation, dehydrogenation are converted into the C ring and contain α, the cyclonene of beta-unsaturated carbonyl; 3) then under acid or base catalysis with acid anhydrides or carboxylic acid halides with the esterification of cyclonene enol, obtain the cyclohexadiene of C ring for the acyloxy replacement; 4) further this cyclohexadiene compound of illumination open loop obtains the triolefin that C encircles the acyloxy replacement of open loop; 5) last this triolefin of oxidation scission or its hydrolysate obtain perhydronaphthalene compound 1 or/and octahydro naphthalene compound 2.
3. the preparation method of the described hydrogenated naphthalene compounds of claim 1 is: as raw material, the preparation decahydro is or/and the reaction scheme of octahydro naphthalene compound is as follows with Oleanolic Acid, Crategolic acid, ursolic acid or the acid of horse hair bavin:
Wherein:
Compound 3 is respectively R
1=beta-hydroxy, R
3=R
8=methyl, R
5=R
10=R
11=hydrogen, R
7The Oleanolic Acid of=carboxyl or R
1=beta-hydroxy, R
3=R
8=methyl, R
5=Alpha-hydroxy, R
10=R
11=hydrogen, R
7The Crategolic acid of=carboxyl or R
1=beta-hydroxy, R
3=R
10=methyl, R
5=R
8=R
11=hydrogen, R
7The ursolic acid of=carboxyl or R
1=R
11=Alpha-hydroxy, R
3=methylol, R
5=R
8=hydrogen, R
10=methyl, R
7The horse hair bavin acid of=carboxyl; Compound 4-10 is respectively the further reaction product of Oleanolic Acid or Crategolic acid or ursolic acid or the acid of horse hair bavin, and its group is respectively R
1=β-acetoxyl group, R
3=R
8=methyl, R
5=R
10=R
11=hydrogen, R
7=methoxycarbonyl or R
1=β-acetoxyl group, R
3=R
8=methyl, R
5=Alpha-hydroxy, R
10=R
11=hydrogen, R
7=methoxycarbonyl or R
1=β-acetoxyl group, R
3=R
10=methyl, R
5=R
8=R
11=hydrogen, R
7=methoxycarbonyl or R
1=R
11=α-acetoxyl group, R
3=acetyl-o-methyl, R
5=R
8=hydrogen, R
10=methyl, R
7=methoxycarbonyl;
A: adopt acid anhydrides or carboxylic acid halides/organic bases that the acylated hydroxy or the employing halohydrocarbon of compound 3 are protected the hydroxyl etherificate of compound 3, thionyl chloride/alcohol or oxalyl chloride/alcohol or dicyclohexylcarbodiimide/alcohol or acid/alcohol are with the carboxyl esterification of compound 3;
B: adopting 12 two keys of peracid or potassium permanganate oxidation compound 4 is 12 carbonyl compound;
C: under HBr catalysis, adopt Br
2Dehydrogenation generates 9 (11) two keys;
D: under acid or base catalysis, with acid anhydrides or carboxylic acid halides with the esterification of 12 carbonyl enols;
E: in quartz or pyrex glass bottle, under the UV-irradiation, 8,14 bond ruptures realize the open loop of C ring, and when in the pyrex glass bottle, shining, have to triene compound 8, and when in quartzy bottle, shining, obtain the mixture of triene compound 8 and 9;
F: do not having or having in the presence of an acidic catalyst, adopting peracid, obtaining compound 1 and 2, the R of compound 1 as oxygenant oxidation fracture triolefin
4Be Beta-methyl; When adding the amount≤3 times equivalent of peracid, the R of compound 2
6Be H, the amount that adds peracid is during greater than 3 times of equivalents, the R of compound 2
6Be H and/or OH;
G: the triene compound of basic hydrolysis gained, further with acid anhydrides or carboxylic acid halides with acylated hydroxy, obtain the hydrolysate of enol ester;
H: do not having or having in the presence of an acidic catalyst, adopting peracid, obtaining compound 1 and 2, the R of compound 1 as oxygenant oxidation fracture triolefin
2Be Alpha-Methyl; When adding the amount≤3 times equivalent of peracid, the R of compound 2
6Be H, the amount that adds peracid is during greater than 3 times of equivalents, the R of compound 2
6Be H and/or OH.
4. the preparation method of the described hydrogenated naphthalene compounds of claim 3, it is characterized in that: the organic bases described in the step a is various pyridine derivates, various tertiary amine or its mixture; Peracid described in the step b is H
2O
2/ HCOOH, H
2O
2/ CH
3COOH, mCPBA, persulphate; Acid described in the steps d is various sulfonic acid or the vitriol oil or its mixture; Alkali described in the steps d is various pyridine derivates, various tertiary amine, acetate, DBU or its mixture; An acidic catalyst described in the step f is various sulfonic acid, sulfuric acid or their mixture; Peracid described in the step f is m-chloro-benzoic acid peroxide, peroxidation phenylformic acid, peroxidation nitrobenzoic acid, peroxidation trifluoracetic acid; An acidic catalyst described in the step h is various sulfonic acid, sulfuric acid or their mixture; Peracid described in the step h is m-chloro-benzoic acid peroxide, peroxidation phenylformic acid, peroxidation nitrobenzoic acid, peroxidation trifluoracetic acid.
5. the purposes of the described hydrogenated naphthalene compounds of claim 1 is: be used for synthetic contain segmental medicine of many hydrogen naphthalene structure or spices.
6. the purposes of the described hydrogenated naphthalene compounds of claim 1 is: compound 1 is used for synthetic Sclareolide or grane ambra class essence and flavoring agent.
7. the purposes of the described hydrogenated naphthalene compounds of claim 1 is: compound 1 is used for synthetic grane ambra class essence and flavoring agent compound 9-table-ambrox, and its synthetic route is as follows:
Wherein:
A: with Pd/C hydrogenation, Mg/CH
3OH or NaBH
4/ NiCl
26H
2O stereospecificity ground reduction α, the two keys of β-unsaturated lactone obtain compound 11;
B: use LiAlH
4, LiBH
4, NaBH
4Mixture or KBH with lithium salts
4With the mixture ester reduction of lithium salts, the trihydroxy-compound that obtains, obtain compound 12 through acid or SULPHURYL CHLORIDE/pyridine cyclisation;
C: at I
2Or directly dehydration under the acid catalysis, or be converted into behind the sulphonate under the effect of alkali hydroxyl indirectly that dehydration obtains compound 13;
The d:Pd/C shortening obtains compound 17 quantitatively;
I: at NaOH, KOH, Na
2CO
3Or K
2CO
3Under the effect of alkali, in methanol-water or ethanol aqueous systems, optionally 3 ester groups of hydrolysis obtain compound 14;
Ii: at I
2Or directly dehydration under the acid catalysis, or be converted into behind the sulphonate under the effect of alkali hydroxyl indirectly that dehydration obtains compound 15;
Iii: direct Pd/C shortening, perhaps NaBH
4/ NiCl
26H
2O reduces α, behind the two keys of β-unsaturated lactone again the Pd/C shortening obtain compound 16;
Iv: use LiAlH
4, LiBH
4, NaBH
4Mixture or KBH with lithium salts
4With the mixture reduction lactone of lithium salts, the dihydroxy compound that obtains obtains compound 17 through acid or SULPHURYL CHLORIDE/pyridine cyclisation.
8. the purposes of the described hydrogenated naphthalene compounds of claim 7, it is characterized in that: the hydrogen source of the Pd/C hydrogenation described in the step a is H
2Or HCONH
2Acid described in the step b is various sulfonic acid; Acid described in the step c is tosic acid, sulfuric acid; Alkali described in the step c is LiCl, Li
2CO
3, t-BuOK, pyridine; Acid described in the step I i is tosic acid, sulfuric acid; Alkali described in the step I i is LiCl, Li
2CO
3, t-BuOK, pyridine; Acid described in the step I v is various sulfonic acid.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5616737A (en) * | 1995-07-06 | 1997-04-01 | Basf Aktiengesellschaft | Stereoselective preparation of (-) 3a,6,6,9a-tetramethyl-perhydronaphtho[2,1-b]furan |
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2006
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US5616737A (en) * | 1995-07-06 | 1997-04-01 | Basf Aktiengesellschaft | Stereoselective preparation of (-) 3a,6,6,9a-tetramethyl-perhydronaphtho[2,1-b]furan |
Non-Patent Citations (1)
| Title |
|---|
| Andres Garcia-Granados et al..Oxidation of several triterpenic diene and trienesystem.Oxidative cleavage to obtain chiral intermediates fordrimaneand phenanthrene semi-synthesis.Tetrahedron60.2004,603831-3845. * |
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