CN101367712A - Polysubstituted decahydronaphthalene compound, synthesis method and uses thereof - Google Patents

Abstract

The invention belongs to the field of organic chemistry and relates to a polysubstituted decalin compound, and a synthesis method and an application thereof. The structural formula of the polysubstituted decalin compound is shown above. The preparation of the polysubstituted decalin compound includes septs as follows: AB fragment which is obtained by the c-bond cleavage of an oleanane type or an ursolic alkane type pentacyclic triterpenoid compound is treated with different reduction methods to obtain a compound 2 or 3. The polysubstituted decalin compound of the invention is used to synthesize the medicine or the apice and the analogues which contain the structural fragment of the polysubstituted decalin. The invention has the advantages of simplicity, practicability, low cost, high yield and being capable of industrialization.

Description

A kind of polysubstituted perhydronaphthalene compound, its synthetic method and purposes

Technical field

The invention belongs to organic chemistry filed, relate to a kind of polysubstituted perhydronaphthalene compound, its synthetic method and purposes.

Background technology

Polysubstituted perhydronaphthalene 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 and in the scientific research of spices and industrial production and have consequence.

In these natural products and analogue thereof synthetic, normally make up a perhydronaphthalene fragment, then with the other parts coupling, the synthetic of perhydronaphthalene is one of them important process.It obtains usually by complete synthesis structure, semi-synthetic structure or from semi-synthetic the obtaining of other natural products degradeds.Complete synthesis construction process mainly contains Diels-Alder reaction, Robinson cyclisation and free radical or positively charged ion inductive polyenoid cyclisation (Eur.J.Org.Chem.2007,1069).But because suitable starting raw material, the restriction of the factors such as fractionation of control of the stereoselectivity of reaction and reaction back enantiomorph, these methods all can not be as a kind of synthetic method of more general tetramethyl-perhydronaphthalene.That the starting raw material of semi-synthetic structure adopts usually is Wieland-Miescher ketone, though this method is a kind of method commonly used than the former, and the same substituent problem that makes up that exists.At present main still by containing the segmental natural diterpene of suitable perhydronaphthalene or sesquiterpene is semi-synthetic obtains.Such as sclareol lactone (Sclareol ide) the synthetic vessel formation inhibitor (a.Eur.J.Org.Chem.2002,4169 that obtain with sclareol (Sclareol) degraded; B.Bioorg.Med.Chem.Lett.2003,13,2009), with sclareol synthetic ambrox (a.Synth.Comm.2001,31,749; B.Tetrahedron 2001,57,5657 and 5663), with the synthetic marine natural product (J.Org.Chem.2003,68,1242) of sylvic acid (abietic acid) etc. with antibiotic, antimycotic, food refusal, antiviral and antitumor isoreactivity.The raw material ratio of these semi-synthetic uses is high than rareness and price, the synthetic fragment of wherein the most often using is the sclareol lactone, but its A ring does not have functional group, and 9-position configuration is unique, and this more makes it have suitable limitation in the synthetic and structure activity study of natural product.

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.Perhydronaphthalene structures polysubstituted like the AB lopps with oleanane type and ursane type pentacyclic triterpenoid, many chiral centres that the natural product of many biologically actives, famous and precious essence and flavoring agent or medicine all have.By open loop fracture research to this compounds C ring, we in application number is the application for a patent for invention of 200610021980.9 (polysubstitution hydrogenated naphthalene compounds, Preparation Method And The Uses), obtained with their AB ring be skeleton polysubstituted, many chiral centres 9, the perhydronaphthalene structure fragment of 11-position undersaturated class sclareol lactone.

Be that the beta comfiguration side chain is in the majority with the 9-position in the natural product of finding that contains the perhydronaphthalene structure fragment at present, the product of α configuration is seldom arranged.But isomorphism type may not produce very big influence to its biological activity.Polygodial such as 9 β side chain configurations has antifeedant activity, but the polygodial of 9 α side chain configurations does not then have antifeedant activity (Nat.Prod.Rep.1991,309); And the 9-table-ambrox of 9 α side chain configurations has stronger fragrance and lower thresholding concentration value (J.Org.Chem.1991,56,912) than the ambrox of 9 β side chain configurations.We obtained the 8-position not isomorphism type 9, the perhydronaphthalene structure fragment 1 of the undersaturated polysubstituted class sclareol lactone in 11-position, further research obtain the 9-position not the synthon fragment of isomorphism type be necessary to the research synthetic and structure activity relationship of natural product.

R ₁=alpha-acyloxy, β-acyloxy, alpha-alkoxy base, β-alkoxyl group, α-OH, β-OH, α-X or β-X; R ₂=carboxyl, methyl, methylol, alkoxyl-methyl, acyl-oxygen methyl, formyl radical or CH ₂X; R ₃=carboxyl, methyl, methylol, alkoxyl-methyl, acyl-oxygen methyl, formyl radical or CH ₂X; R ₄=Alpha-Methyl or Beta-methyl; R ₅=Alpha-hydroxy, beta-hydroxy, H or X _oX=Br, Cl or I, as follows

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 all is the raw material production ambrox with the sclareol.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.Therefore, it is necessary seeking better alternative synthetic route.

Summary of the invention

The object of the invention provides the polysubstituted perhydronaphthalene compound of different configurations, has following structural formula:

R ₁=alpha-alkoxy base, β-alkoxyl group, α-OH, β-OH, α-X or β-X; R ₂=methyl, methylol, alkoxyl-methyl or CH ₂X; R ₃=methyl, methylol, alkoxyl-methyl or CH ₂X; R ₄=Alpha-Methyl or Beta-methyl; R ₅=Alpha-hydroxy, beta-hydroxy, H or X; X=Br, Cl or I

Another object of the present invention provides the preparation method of above-claimed cpd, is that the AB fragment that obtains with oleanane type or ursane type pentacyclic triterpenoid fracture C ring in the application for a patent for invention of 200610021980.9 (polysubstitution hydrogenated naphthalene compounds, Preparation Method And The Uses) obtains compound 2 or 3 with different method of reducing with us at application number.Concrete grammar is: 1) two keys of elder generation's reduction unsaturated lactone restore lactonic ring and obtain compound 2; 2) elder generation's reduction lactonic ring restores two keys and obtains compound 3.

As raw material, the reaction scheme of preparation perhydronaphthalene compound 2,3 is as follows with the AB fragment 1 of 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 1R ₁=alpha-acyloxy, β-acyloxy, alpha-alkoxy base, β-alkoxyl group, α-OH, β-OH, α-X or β-X; R ₂=carboxyl, methyl, methylol, alkoxyl-methyl, acyl-oxygen methyl, formyl radical or CH ₂X; R ₃=carboxyl, methyl, methylol, alkoxyl-methyl, acyl-oxygen methyl, formyl radical or CH ₂X; R ₄=Alpha-Methyl or Beta-methyl; R ₅=Alpha-hydroxy, beta-hydroxy, H or X.Compound 2-4 is the further reaction product of compound 1, R ₁=alpha-alkoxy base, β-alkoxyl group, α-OH, β-OH, α-X or β-X; R ₂=methyl, methylol, alkoxyl-methyl or CH ₂X; R ₃=methyl, methylol, alkoxyl-methyl or CH ₂X; R ₄=Alpha-Methyl or Beta-methyl; R ₅=Alpha-hydroxy, beta-hydroxy, H or X; X=Br, Cl or I

A: use LiAlH ₄Deng aluminum alkoxide salt or LiBH such as metal hydride or Red-Al ₄, NaBH ₄, KBH ₄Mixture reduction lactone Deng hydroborate and lithium salts obtains compound 2;

B: use LiAlH ₄Deng aluminum alkoxide salt or NaBH such as metal hydride or Red-Al ₄Deng hydroborate/LiCl or with using LiAlH again after the Dibal-H reduction ₄Or NaBH ₄Obtain compound 4 Deng reduction;

C: (hydrogen source is H to shortening to adopt 0 valence state or its high valence state metal (as Pt, Pd, Ni, Ru, Rh, Ir etc.) ₂Or HCONH ₂) stereospecificity ground reducing compound 4 obtains 3.

The present invention also provides the purposes of above-mentioned perhydronaphthalene compound, is used for synthetic medicine or spices and their analogue that contains polysubstituted perhydronaphthalene structure fragment.

Perhydronaphthalene compound 3 of the present invention is used for synthetic ambrox class spices, and reaction formula is as follows:

Compound 3 R ₁=alpha-alkoxy base, β-alkoxyl group, α-OH, β-OH, α-X or β-X; R ₂=methyl, methylol, alkoxyl-methyl or CH ₂X; R ₃=methyl, methylol, alkoxyl-methyl or CH ₂X; R ₄=Alpha-Methyl or Beta-methyl; R ₅=Alpha-hydroxy, beta-hydroxy, H or X; Compound 5 R ₁=α-OH or β-OH; R ₄=Alpha-Methyl or Beta-methyl; Compound 6-7R ₂=Alpha-Methyl or Beta-methyl; Compound 8 R ₁=alpha-alkoxy base, β-alkoxyl group, α-OH, β-OH, α-X or β-X; R ₂=methyl, methylol, alkoxyl-methyl or CH ₂X; R ₃=methyl, methylol, alkoxyl-methyl or CH ₂X; R ₄=Alpha-Methyl or Beta-methyl; R ₅=Alpha-hydroxy, beta-hydroxy, H or X; X=Br, Cl or I

A: obtain compound 5 or compound 8 through acid (as various sulfonic acid) or SULPHURYL CHLORIDE/pyridine cyclisation;

B: 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 6;

C:, obtain compound 7 quantitatively with catalytic hydrogenation catalyst such as Pd/C shortening.

In the process by compound 3 synthetic ambrox compounds 7, the compound 5 that is obtained and 6 is the analogue of ambrox compounds, also has grane ambra class fragrance.

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 with Oleanolic Acid AB (R ₄Being the β methyl) fragment is raw material, synthetic compound 2 and 3

1) preparation of compound 2:

Under argon shield with LiAlH ₄(49mg 1.3mmol) adds at normal temperatures and is dissolved with compound 1 (100mg, among the anhydrous THF of 5mL 0.32mmol), 4 hours postcooling of back flow reaction are to room temperature under the argon shield.Add 50 μ L water then successively, 50 μ L, 15% NaOH solution, the 150 μ L shrends reaction of going out.Filter, THF washing three times, merging filtrate, (sherwood oil-acetone 2:1) gets compound 2 (79mg, 79%) to concentrate the back silica gel column chromatography.

2) preparation of compound 4:

(50mg 0.16mmol) adds in the reaction flask, after argon replaces 3 times, injects the anhydrous THF of 10mL, and normal temperature injects the toluene solution of 70% quality of 135 μ L Red-Al (0.48mmol) then with compound 1.60 ℃ of reactions added the soluble tartrate sodium water solution cancellation reaction of 2mL 23% after 7 hours, and vigorous stirring is clear to solution becomes, add the 10mL ethyl acetate then, separate organic layer, water layer ethyl acetate extraction three times, merge organic layer, it is inferior to give a baby a bath on the third day after its birth with saturated aqueous common salt, anhydrous Na ₂SO ₄Dry.The rotation solvent evaporated, (sherwood oil-acetone 2:1) obtains compound 4 (32mg, 75%) to the gained residuum by silica gel column chromatography.

3) preparation of compound 3:

(80mg 0.3mmol) is dissolved in the ethanol of 10mL 95%, adds 10mg10%Pd/C and 1mg NaNO then with compound 4 ₂, stirred 30 minutes, feed hydrogen, normal temperature hydrogenation 16 hours, elimination Pd/C, rotation evaporate to dryness filtrate, (sherwood oil-acetone 2:1) obtains compound 3 (69mg, 86%) to residuum by silica gel column chromatography.

Embodiment 2 is with Oleanolic Acid AB (R ₄Being the α methyl) fragment is raw material, synthetic compound 2 and 3

Adopt as embodiment 1 described operation steps, the compound 2,3 that obtains is as follows:

Embodiment 3 is a raw material with Crategolic acid AB fragment, synthetic compound 2 and 3

Adopt as embodiment 1 described operation steps, the compound 2,3 that obtains is as follows:

R ₄=Alpha-Methyl or Beta-methyl

Embodiment 4 is a raw material with horse hair bavin acid AB fragment, synthetic compound 2 and 3

Adopt as embodiment 1 described operation steps, the compound 2,3 that obtains is as follows:

R ₄=Alpha-Methyl or Beta-methyl

Embodiment 5 is with compound 3 synthetic ambroxs

1) preparation of compound 5:

50mg (0.19mmol) compound 3 added be placed with in the reaction flask of 5mL Nitromethane 99Min., add 5mg TSOH again, then in normal-temperature reaction 6 hours.Add the dilution of 10mL ethyl acetate, use saturated NaHCO successively ₃With saturated common salt washing, anhydrous Na ₂SO ₄Dry.Decompression steams solvent, and the residuum silica gel column chromatography obtains compound 5 (43mg, 89%).

2) preparation of compound 6:

(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 NaSO 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 NaSO successively ₄Dry.(n-hexane-AcOEt 50:1) gets 6 (37mg, 80%) to silica gel column chromatography after the filtering and concentrating.

3) preparation of compound 7:

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 7 quantitatively.

Claims (5)

1. polysubstituted perhydronaphthalene compound is characterized in that having following structural formula:

Or

R ₁=alpha-alkoxy base, β-alkoxyl group, α-OH, β-OH, α-X or β-X; R ₂=methyl, methylol, alkoxyl-methyl or CH ₂X; R ₃=methyl, methylol, alkoxyl-methyl or CH ₂X; R ₄=Alpha-Methyl or Beta-methyl; R ₅=Alpha-hydroxy, beta-hydroxy, H or X; X=Br, Cl or I.

2. the preparation method of claim 1 described polysubstituted perhydronaphthalene compound is: is that the AB fragment that obtains with oleanane type or ursane type pentacyclic triterpenoid fracture C ring in 200610021980.9 the application for a patent for invention obtains compound 2 or 3 with different method of reducing with us at application number; Concrete grammar is: 1) two keys of elder generation's reduction unsaturated lactone restore lactonic ring and obtain compound 2; 2) elder generation's reduction lactonic ring restores two keys and obtains compound 3.

3. the preparation of polysubstituted perhydronaphthalene compound according to claim 2, it is characterized in that: with the AB fragment of Oleanolic Acid or the Crategolic acid that belongs to oleanane type or ursolic acid that belongs to the ursane type or the acid of horse hair bavin as raw material, the reaction scheme of preparation perhydronaphthalene compound 2,3 is as follows:

Wherein: compound 1 R ₁=alpha-acyloxy, β-acyloxy, alpha-alkoxy base, β-alkoxyl group, α-OH, β-OH, a-X or β-X; R ₂=carboxyl, methyl, methylol, alkoxyl-methyl, acyl-oxygen methyl, formyl radical or CH ₂X; R ₃=carboxyl, methyl, methylol, alkoxyl-methyl, acyl-oxygen methyl, formyl radical or CH ₂X; R ₄=Alpha-Methyl or Beta-methyl: R ₅=Alpha-hydroxy, beta-hydroxy, H or X.Compound 2-4 is the further reaction product of compound 1, R ₁=alpha-alkoxy base, β-alkoxyl group, α-OH, β-0H, α-X or β-X; R ₂=methyl, methylol, alkoxyl-methyl or CH ₂X; R ₃=methyl, methylol, alkoxyl-methyl or CH ₂X; R ₄=Alpha-Methyl or Beta-methyl; R ₅Alpha-hydroxy, beta-hydroxy, H or X; X=Br, Cl or I

A: obtain compound 5 or compound 8 through acid or SULPHURYL CHLORIDE/pyridine cyclisation;

B: at I ₂Or directly dehydration under the acid catalysis, or hydroxyl is converted into behind the sulphonate under the effect of alkali

Dehydration obtains compound 6 indirectly;

C:, obtain compound 7 quantitatively with catalytic hydrogenation catalyst such as Pd/C shortening.

4, the purposes of the described polysubstituted perhydronaphthalene compound of claim 1 is: be used for synthetic medicine or spices and their analogue that contains polysubstituted perhydronaphthalene structure fragment.

5, the purposes of polysubstituted perhydronaphthalene compound according to claim 4 is characterized in that: the reaction formula that is used for synthetic ambrox class spices is as follows:

Compound 3 R ₁=alpha-alkoxy base, β-alkoxyl group, α-OH, β-OH, α-X or β-X; R ₂=methyl, methylol, alkoxyl-methyl or CH ₂X; R ₃=methyl, methylol, alkoxyl-methyl or CH ₂X; R ₄=Alpha-Methyl or Beta-methyl; R ₅=Alpha-hydroxy, beta-hydroxy, H or X; Compound 5 R ₁=α-OH or β-OH; R ₄=Alpha-Methyl or Beta-methyl; Compound 6-7R ₂=Alpha-Methyl or Beta-methyl; Compound 8R ₁=alpha-alkoxy base, β-alkoxyl group, α-OH, β-OH, α-X β-X; R ₂=methyl, methylol, alkoxyl-methyl or CH ₂X; R ₃=methyl, methylol, alkoxyl-methyl or CH ₂X; R ₄: Alpha-Methyl or Beta-methyl: R ₅=Alpha-hydroxy, beta-hydroxy, H or X; X:Br, Cl or I

A: obtain compound 5 or compound 8 through acid or SULPHURYL CHLORIDE/pyridine cyclisation;

B: 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 6;

C:, obtain compound 7 quantitatively with catalytic hydrogenation catalyst such as Pd/C shortening.