CN101570486A - Method for preparing anomalous methyl ent-isocopalate - Google Patents

Abstract

The invention relates to a method for preparing anomalous methyl ent-isocopalate, which comprises the main step that sclareol as a raw material is prepared into a target product through oxidation reaction, elimination reaction, Wittig-Horner reaction and ring-closure reaction with organic acid in turn. The preparation method has the advantages of compact synthetic route, mild reaction condition, simple and convenient operation (an intermediate does not need to be purified), high yield (the total yield can reach 55 percent), environmental protection and the like, and is a method for preparing methyl ent-isocopalate with commercial value.

Description

The preparation method of the sour methyl esters of different trans [king's Gu] [king's crust]

Technical field

The present invention relates to a kind of preparation method of tricyclic diterpene compounds, specifically, relate to the preparation method of a kind of different trans [king's Gu] [king's crust] sour methyl esters (methyl ent-isocopalate).

Background technology

Sponge (Spongiane) diterpene-kind compound is the natural product of biologically active.Because of it has wide biological activity (comprising multiple biological activitys such as food refusal, antimycotic, antibiotic, antiviral, antitumor, anti-high blood and anti-inflammatory), caused increasing scientist's research interest.

Because tricyclic diterpene compounds methyl ent-isocopalate (methyl isoanticopalate) has tricyclic structure and special chiral centre, being the desirable precursor of preparation sponge (Spongiane) family natural product, also is the key intermediate of synthetic multiple terpenoid.

So far, the method of existing different trans [king's Gu] [king's crust] the sour methyl esters of preparation (methyl ent-isocopalate), mainly contain two kinds: the first is a raw material with natural sclareol (sclareol), successively through acetic ester protection, rearrangement, hydrolysis, oxidation (two steps), esterification, elimination and closed loop the reaction of totally eight steps obtain target compound, total recovery 49% (Natural Product Letters.1994,5,217-220); The first is a raw material with natural product labdanolic acid (labdanolic acid), totally five steps reacted and obtain target compound through esterification, elimination, oxidation (two steps) and closed loop successively, total recovery 45% (Natural Product Letters.1995,6,285-290).

In sum, the existing method for preparing methyl ent-isocopalate exists the defective that synthetic route is tediously long and total recovery is on the low side.Therefore, how to simplify the existing method for preparing methyl ent-isocopalate, making it more possess commercial value just becomes the technical issues that need to address of the present invention.

Summary of the invention

The objective of the invention is to, provide that a kind of synthetic route is succinct, reaction conditions is gentle and the preparation method of environment amenable different trans [king's Gu] [king's crust] sour methyl esters (methyl ent-isocopalate).

The structure of different trans [king's Gu] [king's crust] sour methyl esters (methyl ent-isocopalate) compound that the present invention will prepare is as shown in Equation 5:

In the formula 5, Me is a methyl.

Its synthetic route is as follows:

Its key step is: with sclareol (compound shown in the formula 1, be called for short compound 1, be raw material down together), get compound 2 through oxidation (as using tetrabutyl ammonium permanganate, potassium permanganate oxidation), compound 2 with eliminate reagent (as: iodine chloride, hydrogen iodide, iodine, N-chlorosuccinimide, N-bromo-succinimide or N-iodo succimide) through elimination react compound 3, compound 3 through Wittig-Horner react compound 4, compound 4 gets target compound (compound 5) through ring-closure reaction.

Embodiment

A kind of method for preparing said different trans [king's Gu] [king's crust] the sour methyl esters of the present invention (methyl ent-isocopalate) compound, it comprises the steps:

1) sclareol, oxygenant and organic solvent are placed reactor, to improve oxidizing reaction rate and productive rate, can add anhydrous sodium sulphate, anhydrous sodium carbonate or anhydrous magnesium sulfate again, obtained compound 2 in 4 hours～10 hours in-20 ℃～0 ℃ reaction, compound 2 can be directly used in down the step preparation;

Wherein: said organic solvent is 2-butanone, acetone or methylene dichloride; Preferred tetrabutyl ammonium permanganate of said oxygenant or potassium permanganate; The mol ratio of sclareol and oxygenant is 1: (2～10);

2) make solvent with benzene or toluene, with compound 2 with eliminate reagent under reflux state, react 5 hours～12 hours must compound 3;

Wherein: the preferred iodine chloride of said elimination reagent, hydrogen iodide, iodine, N-chlorosuccinimide, N-bromo-succinimide or N-iodo succimide; Compound 2 is 1 with the mol ratio of eliminating reagent: (0.5～1);

3) having under alkali (as sodium hydride, n-Butyl Lithium, di-isopropyl butyllithium or the potassium tert.-butoxide etc.) existence condition, compound 3 and Wittig-Horner reagent (diethoxy phosphonoacetic acid methyl esters) carry out Wittig-Horner react compound 4;

Wherein: compound 3 is 1 with the mol ratio of Wittig-Horner reagent and alkali: (2～7): (3～8);

4) be 1 with compound 4 in molar ratio with organic acid: mix (10～25), and in 80 ℃～150 ℃ the reaction 2 hours～6 hours target compound (compound shown in the formula 5, or title compound 5), target compound can carry out recrystallization purifying with single or mixed solvent;

Wherein: said organic acid is: formic acid, Glacial acetic acid, propionic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, tosic acid or phenylformic acid; The solvent that is used for recrystallization is that sherwood oil, ether, normal hexane, hexanaphthene, acetone, ethyl acetate, methylene dichloride, trichloromethane, benzene are or/and toluene.

The method of different trans [king's Gu] [king's crust] the sour methyl esters of preparation provided by the present invention (methyl ent-isocopalate), it has that synthetic route is succinct, reaction conditions is gentle, (intermediate need not purifying) easy and simple to handle, yield higher (total recovery can reach 55%) and advantage such as environmentally friendly, is a kind of preparation method who possesses the methyl ent-isocopalate of commercial value.

The invention will be further elaborated below by embodiment, and its purpose only is better to understand content of the present invention.Therefore, protection scope of the present invention is not limited by the cases cited.

Embodiment

The preparation of compound 2:

With compound 1 (3.1g 0.01mol) is dissolved in acetone (100ml) solution, add successively in batches potassium permanganate (7.9g, 0.05mol) and anhydrous sodium carbonate (8.5g 0.08mol), stirred under room temperature 6 hours then.After reaction finished, reaction solution was through diatomite filtration, the ethyl acetate washing leaching cake, concentrated mother liquor, white solid crude product 2.5g, productive rate 88%.

Crude product can not purifiedly be directly used in next step reaction; Also available following single or mixed solvent carries out the recrystallization separation and purification.Recrystallization solvent can be: the single solvent of sherwood oil, ether, normal hexane, hexanaphthene, acetone, ethyl acetate, methylene dichloride, trichloromethane, benzene or toluene or mixed solvent.

The preparation of compound 3:

With compound 2 (2.8g 0.01mol) is dissolved in benzene (150ml) solution, add iodine monochloride (0.8g, 5mmol), then in 85 ℃ of following reflux 12 hours.After reaction finishes, in reaction solution, add the sodium thiosulfate solution cancellation, the ethyl acetate extraction organic phase, the saturated common salt water washing, anhydrous sodium sulfate drying concentrates, column chromatography, separation and purification gets product (weak yellow liquid) 2.0g, productive rate 78%.Crude product also can not purifiedly be directly used in next step reaction.

The structural characterization data of compound 3:

¹H?NMR(400MHz，CDCl ₃)δ：0.85(3H，s，H-15)，0.90(3H，s，H-16)，0.96(3H，s，H-17)，1.55(3H，s，H-18)，2.15(3H，s，H-14)，2.51(2H，t，J＝8.4Hz，H-12)；

¹³C?NMR(100MHz，CDCl ₃)δ：16.1(C-6)，19.0(C-2)，19.4(C-18)，19.9(C-17)，21.6(C-11)，21.7(C-15，C-16)，29.7(C-14)，33.3(C-4)，33.6(C-7)，37.0(C-10)，39.0(C-1)，41.8(C-3)，44.6(C-12)，52.0(C-5)，126.5(C-8)，139.3(C-9)，208.8(C-13)。

The preparation of compound 4:

With sodium hydride (2.4g, 0.06mol, 60%) be dissolved in tetrahydrofuran (THF) (200ml) solution, slowly drip Wittig-Horner reagent (diethoxy phosphonoacetic acid methyl esters) (12.3g down in-20 ℃, 0.05mol), dropwise back stirring reaction 2.5 hours under room temperature.(2.6g 0.01mol), stirs under room temperature and spends the night slowly to drip compound 3 down in-20 ℃ then.After reaction finishes, in reaction solution, add aqueous solution cancellation, the ethyl acetate extraction organic phase, the saturated common salt water washing, anhydrous sodium sulfate drying concentrates, column chromatography, separation and purification gets product (yellow liquid) 3.1g, productive rate 99%.Crude product also can not purifiedly be directly used in next step reaction.

The structural characterization data of compound 4:

¹H?NMR(400MHz，CDCl ₃)δ：0.85(3H，s，H-17)，0.90(3H，s，H-18)，0.96(3H，s，H-19)，1.59(3H，s，H-20)，2.20(3H，s，H-16)，3.70(3H，s，COO Me)，5.71(1H，s，H-14)；

¹³C?NMR(100MHz，CDCl ₃)δ：18.9(C-6，C-20)，19.0(C-2)，19.5(C-16)，20.1(C-19)，21.7(C-17，C-18)，26.4(C-11)，33.3(C-4)，33.6(C-7)，37.0(C-10)，39.1(C-1)，41.6(C-12)，41.8(C-3)，50.8(C-5)，51.9(COO Me)，114.5(C-14)，126.7(C-8)，139.5(C-9)，161.1(C-13)，167.4(C-15)。

The preparation of target compound (compound 5):

(3.2g 0.01mol) is dissolved in anhydrous formic acid (150ml) solution, reacts 8 hours down in 100 ℃ with compound 4.After reaction finishes, in reaction solution, add the sodium bicarbonate aqueous solution cancellation, the ethyl acetate extraction organic phase, the saturated common salt water washing, anhydrous sodium sulfate drying concentrates, column chromatography, separation and purification gets product (white crystal) 2.9g, productive rate 90%.The also available following single or mixed solvent of crude product carries out the recrystallization separation and purification.Recrystallization solvent can be: the single solvent of sherwood oil, ether, normal hexane, hexanaphthene, acetone, ethyl acetate, methylene dichloride, trichloromethane, benzene or toluene or mixed solvent.

The structural characterization data of compound 5:

¹H?NMR(400MHz，CDCl ₃)δ：0.82(3H，s，H-15)，0.87(3H，s，H-16)，0.92(3H，s，H-17)，0.95(3H，s，H-18)，1.61(3H，s，H-20)，2.93(1H，s，H-14)，3.68(3H，s，COO Me)，5.53(1H，s，H-12)；

¹³C?NMR(100MHz，CDCl ₃)δ：15.5(C-18)，15.8(C-17)，18.5(C-6)，18.6(C-2)，21.2(C-20)，21.7(C-11)，22.7(C-15，16)，33.2(C-4)，33.4(C-8)，36.5(C-10)，37.4(C-11)，39.8(C-7)，41.8(C-3)，51.0(COO Me)，54.3(C-9)，56.4(C-5)，62.6(C-14)，124.1(C-12)，129.0(C-13)，173.4(C-19)。

${\left[\mathrm{\α}\right]}_D^{10}=-41\left(c0.01\right)$

Claims (7)

1, the method for compound shown in a kind of preparation formula 5, its key step is: with compound 1 is raw material, successively through oxidizing reaction, after eliminating reaction, Wittig-Horner reaction and carrying out ring-closure reaction with organic acid target compound;

Its synthetic route is as follows:

Wherein, Me is a methyl.

2, the method for claim 1 is characterized in that, in said oxidizing reaction, used oxygenant is tetrabutyl ammonium permanganate or potassium permanganate.

3, method as claimed in claim 2 is characterized in that, in said oxidizing reaction, compound 1 is 1 with the mol ratio of oxygenant: (2～10); Oxidizing reaction temperature-20 ℃～0 ℃; Oxidation time is 4 hours～10 hours.

4, the method for claim 1 is characterized in that, in said elimination reaction, used elimination reagent is iodine chloride, hydrogen iodide, iodine, N-chlorosuccinimide, N-bromo-succinimide or N-iodo succimide.

5, method as claimed in claim 4 is characterized in that, in said elimination reaction, compound 2 is 1 with the mol ratio of eliminating reagent: (0.5～1); Said elimination is reflected under the reflux state reacted 5 hours～12 hours.

6, the method for claim 1 is characterized in that, wherein said organic acid is formic acid, Glacial acetic acid, propionic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, tosic acid or phenylformic acid.

7, method as claimed in claim 6 is characterized in that, wherein compound 4 is 1 with organic acid in molar ratio: (10～25); The ring-closure reaction temperature is 80 ℃～150 ℃, 2 hours～6 hours reaction times.