CN1095465C - Chiral anonace-lactone compounds,and its synthesizing process and application - Google Patents

Abstract

The present invention relates to a chiral anemone lactone compound of the following molecular formula: wherein Y=C _6-20 alkyl, n=1-3, m=7-19. The compound consists of chiral halogenated alkanes and chiral Dihydroxyalkyl carboxylate is synthesized from raw materials and has high anticancer activity.

Description

Chiral anemone lactone compound, synthesis method and use thereof

technical field

The invention relates to a lactone compound, in particular to a chiral anemone lactone compound, a synthesis method and an application thereof.

Background technique

Annonaceous aectogenins (Annonaceous aectogenins) is a class of natural products found in Annonaceae plants, due to its anticancer activity and attention (A. Cave et al., Progress in the Chemistry of Organic natural Products: Acetogenins from Annonaceae. NewYork, Springer-Verlag, 1997,70,81-288), people such as Wu Yulin once reported a kind of anemone lactone analog (CN97106368.0) with anticancer activity, have following molecular formula: Wherein R ₁ , R ₂ , R ₃ , R ₄ are H or chiral OH; I=1-6; m=8-12; n=0-5; 0=3-12. The compound is synthesized from a chiral hydroxy acid as a raw material to an epoxy intermediate containing substituted or rearranged γ-butyrolactone, and the polyethylene glycol compound and the epoxy intermediate are coupled, catalytically hydrogenated, and eliminated. The product Annona lactone analogue is obtained, but this method does not obtain the chiral product, and the semi-lethal dose LC ₅₀ of this analogue to cancer cells is 3-6E-05. People expect new synthetic methods and approaches, and expect to obtain chiral Litchi lactone compounds, in order to further improve their anticancer activity, and finally develop into a new class of anticancer drugs.

Contents of the invention

The object of the present invention is to provide a chiral anemone lactone compound, which is an optically active compound.

The object of the present invention is also to provide a preparation method of the above-mentioned compound.

Another object of the present invention is to provide the use of the above compounds.

(8)，换言之，该化合物是

尤其是指等化合物，其中Y＝C_6-20的烷基，n＝1-3，m＝7-19。The chiral anemone lactone compound of the present invention is an optically active compound having the following molecular formula:

(8), in other words, the compound is

especially refers to Compounds such as Y = C _6-20 alkyl, n = 1-3, m = 7-19.

或

的手性卤代烷和分子式为

或

的手性二羟基基烷基羧酸酯为起始原料。Above-mentioned chiral anemone lactone compound of the present invention can be with molecular formula:

or

The chiral haloalkane and molecular formula are

or

Chiral dihydroxyalkyl carboxylates as starting materials.

The above-mentioned chiral haloalkane and chiral dihydroxyalkyl carboxylate undergo coupling reaction in the presence of dialkyl tin oxide R ₂ SnO and monovalent metal fluoride, and then protect the hydroxyl group with methoxychloromethane, and Lithium diisopropylamide reacts to form a negative ion at the α-position of the terminal ester group, and then with the molecular formula The reaction of chiral aldehydes to obtain aldol condensation products, followed by trifluoroacetic anhydride or acetic anhydride/organic amine compounds with lone pairs of electrons on the nitrogen atom, acid treatment to obtain α, β-unsaturated lactones, catalyzed desorption with inorganic acids Protecting groups obtain the final product. It can be represented by the following reaction formula:

Where n=1-3, m=7-19, Y=C _6-20 alkyl, P=MOM, THP or TBS, MOM=methoxymethyl, THP=tetrahydrofuryl, TBS=dimethyl tertiary Butylsilyl.

The preparation method of the present invention can be further described: the molar ratio of the above-mentioned chiral haloalkane 6, chiral dihydroxyalkyl carboxylate 7, monovalent metal fluoride and R ₂ SnO is 1:0.5-2:1-5:1 -2, react in one or more polar solvents at room temperature to reflux temperature for 1-24h to generate chiral compound 5. The monovalent metal fluorides are LiF, NaF, KF, CsF, etc., among which CsF is preferred. Among the dialkyltin oxides, R=C _1-6 alkyl, preferably dibutyltin oxide.

When the molar ratio of chiral compound 5, diisopropylethylenediamine and methoxychloromethane is 1:1-5:1-5, react in a polar solvent at 0°C to room temperature for 1-10h, and obtain sexual compound 4,

chiral compound 4, The molar ratio of chiral aldehyde, lithium diisopropylamide (LDA) and hexamethylphosphoric triamide is 1:1-2:1-5:0-5, and the recommended molar ratio is 1:1-2:1- 3: 1-3, react in polar solvent at room temperature to -78°C for 0.5-5h, then react with inorganic acid in room temperature and polar solvent for 5-10h, add organic amine with lone pair of electrons on nitrogen atom The compound reacts with trifluoroacetic anhydride or acetic anhydride at 0°C to room temperature for 1-10 hours to obtain chiral compound 1. The inorganic acid can be H ₂ 5O ₄ , HNO ₃ , HCl, etc. The organic amine compound with a lone pair of electrons on the nitrogen atom can be laurylamine, dimethylamine, trimethylamine, triethylamine, trioctylamine, etc. Amine, methylbenzylamine, 1.8-diaza-bicyclo[5,4,0]undec-7-ene (DBU), etc., but triethylamine is preferred.

In one or more polar solvents and at room temperature, the above-mentioned chiral compound 1 is catalyzed with an inorganic acid to deprotect the group to obtain the final product 8.

The polar solvent may be CH ₂ Cl ₂ , CCl ₃ H, CH ₃ OH, C ₂ H ₅ OH, diethyl ether, toluene, N,N-dimethylformamide (DMF) and the like.

The compound of the present invention has high anticancer activity, for example, the EC ₅₀ (μg/ml) for colon cancer HCT-8 reaches 0.032-0.097. Can be used in anticancer drugs. Moreover, the preparation method is simple and convenient, and is a method suitable for industrial production.

Detailed ways

The following examples will help to understand the present invention, but do not limit the content of the present invention.

Example 1

The synthesis of the basic skeleton of the target compound is exemplified by the following reactions and compounds.

Heat 3.23mmol of compound 14, 3-5mmol of dibutyltin oxide and chloroform/methanol (10:0-10) under reflux for 1-2h to obtain a clear solution. Concentrate and dry under vacuum for 6h. Add potassium fluoride or cesium fluoride 3-6mmol and continue vacuum drying for 2h, then add 20ml DMF. After heating at 45°C for 2h, 133-10mmol of iodide was added. Reaction at room temperature for 18h. Evaporate DMF under reduced pressure, add 30ml ethyl acetate and 10ml saturated sodium chloride solution to the residue, stir for half an hour, remove solid insolubles through a sand core funnel covered with silica gel, separate the organic layer in the filtrate, and wash the water layer with ethyl acetate The ester was extracted three times (20ml×3), the organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain 1.02g of the product with a yield of 55% (50-72%).

Example 2

The hydroxyl protection of the product of Example 1 is exemplified by the following reactions and compounds.

When 1.6mmol of compound 15 was dissolved in 20ml of freshly distilled dichloromethane, 1.3ml of diisopropylethylenediamine was added, cooled at 0°C for half an hour, and 0.8-1.5ml of methoxychloromethane was added. Reaction at room temperature for 8h. TLC traced the disappearance of the reaction starting material. The reaction solution was extracted with dichloromethane (30ml×3), and the extract was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain product 16 (919mg, 93%).

1.5-5mmol lithium diisopropylamide solution in 10ml THF and 10ml hexane was cooled to -78°C with acetone, and 0.5ml hexamethylphosphoric triamide was added. Stir for 30 minutes. Compound 16 (1.5mmol) was dissolved in 10ml freshly distilled anhydrous THF, slowly added dropwise to the reaction solution, stirred for 30 minutes, and the above-mentioned aldehyde (760mg, dissolved in 10ml THF) was slowly added dropwise at -78°C, stirred for 2h Then gradually rise to room temperature, separate the aqueous phase and the organic phase, extract the aqueous phase twice with ether, combine the organic phases, wash twice with saturated sodium chloride, dry over anhydrous sodium sulfate, concentrate, add 30ml THF and 10% dilute sulfuric acid. Stir the reaction for 18 hours, add 3g of sodium chloride and stir for 30 minutes, extract the reaction solution three times with ethyl acetate (40ml×3), dry the organic layer over anhydrous sodium sulfate, concentrate, add 10ml of freshly distilled anhydrous dichloromethane and 2.5ml of anhydrous Water triethylamine, cooled at 0°C for 30 minutes, added 1.6ml of trifluoroacetic anhydride, reacted at room temperature for 8 hours, the reaction solution was concentrated, dried, and column chromatographed to obtain product 17 (430mg, 40-52% in two steps).

Example 3

化合物13(0.29mmol)加入0.5-10ml THF：MeOH：6N HCl(1∶1∶2)，室温下反应14h，反应液用乙醚萃取，无水硫酸钠干燥，浓缩，柱层析，得产物9(146mg，91％)。¹H NMR(CDCl₃，600MHz)：δ6.98(br S，1H)，4.99(br g，J＝6.6Hz，1H)，3.82-3.74(br m，Inorganic acid catalyzed MOM removal reaction to obtain the final product, the following formula is an example.

Compound 13 (0.29mmol) was added with 0.5-10ml THF:MeOH:6N HCl (1:1:2), and reacted at room temperature for 14h. The reaction solution was extracted with ether, dried over anhydrous sodium sulfate, concentrated, and column chromatographed to obtain the product 9 (146 mg, 91%). ¹ H NMR (CDCl ₃ , 600MHz): δ6.98 (br S, 1H), 4.99 (br g, J=6.6Hz, 1H), 3.82-3.74 (br m,

         2H), 3.72-360(br m.4H), 3.54(br d, J=9.6Hz, 2H),

      3.32(brt, J=9.0Hz, 2H), 2.26(brt, J=7.5Hz, 2H), 1.54

  (q, J=7.2Hz, 2H), 1.40(d, J=6.6Hz, 3H), 1.48-1.16(br m,

40H), 0.88 (t, J=7.2Hz, 3H).IR (thin film, KBr), cm ^-1 : 3443, 2992, 2982, 1752, 1130, EIMS: 291, 325, 555.

Example 4

的手性卤化物，分别与分子式为

及

的手性二羟基烷基羧酸酯反应，操作同实施1、2和3，结果分别获得

(化合物12，15R，24R)，

(化合物10，15S，24S)及

(化合物11，15R，24S)产物。化合物12The molecular formula is and

The chiral halides, respectively with the molecular formula of

and

The chiral dihydroxyalkyl carboxylate reaction, the operation is the same as implementing 1, 2 and 3, and the results are respectively obtained

(Compounds 12, 15R, 24R),

(Compounds 10, 15S, 24S) and

(compound 11, 15R, 24S) product. Compound 12

¹ H NMR (CDCl ₃ , 600MHz), δ: 6.98 (d, J=1.2Hz, 1H), 4.99 (dq, J=7.2, 1.2Hz, 1H), 3.83-3.74 (m, 2H), 3.72-3.60 (m, 4H), 3.53(dd, J=9.6, 10.2Hz, 2H), 3.32(dd, J=9.6, 8.4Hz, 2H), 2.26(br t, J=7.8Hz, 2H), 1.55(q , J=6.6Hz, 2H), 1.40(d, J=7.2Hz, 3H), 1.50-1.20(m, 40H), 0.88(t, J=6.9Hz, 3H).

IR (thin film, KBr), cm ^-1 : 3442, 2994, 2986, 1756, 1123

EIMS: 291, 326, 555 Compound 10

¹ H NMR (CDCl ₃ , 600MHz), δ: 6.97 (d, J=1.2Hz, 1H), 4.98 (dq, J=7.2, 1.2Hz, 1H), 3.81-3.75 (m, 2H), 3.71-3.61 (m, 4H), 3.52(dd, J=9.6, 10.2Hz, 2H), 3.31(dd, J=9.6, 8.4Hz, 2H), 2.50(br s, 2H, OH), 2.26(t, J= 7.8Hz, 2H), 1.53(q, J=7.8Hz, 2H), 1.40(d, J=6.6Hz, 3H), 1.48-1.20(m, 40H), 0.87(t, J=7.2Hz, 3H) .

IR (thin film, KBr), cm ^-1 : 3445, 2993, 2984, 1750, 1138

EIMS: 290, 325, 555 Compound 11

¹ H NMR (CDCl ₃ , 600MHz), δ: 6.98(d, J=1.2Hz, 1H), 4.99(dq, J=1.2, 6.6Hz, 1H), 3.78(m, 2H), 3.72-3.62(m , 4H), 3.53(dd, J=2.4, 9.6Hz, 2H), 3.32(dd, J=9.6, 8.4Hz, 2H), 2.26(br t, J=7.8Hz, 2H), 2.15(br S, 2H, OH), 1.55(q, J=7.2Hz, 2H), 1.40(d, J=6.6Hz, 3H), 1.48-1.20(m, 40H), 0.88(t, J=6.9Hz, 3H).

IR (thin film, KBr), cm ^-1 : 3440, 2987, 1752, 1130

EIMs: 290, 325, 555

Example 5

和 的手性卤化物，分别与分子式为

及 的手性二羟基烷基羧酸酯反应，操作如同实施例1、2和3。结果分别获得

的化合物18，

化合物19、化合物20和化合物21。化合物18The molecular formula is

and The chiral halides, respectively with the molecular formula of

and The chiral dihydroxyalkyl carboxylate reaction, operation is as embodiment 1,2 and 3. The results were obtained separately

Compound 18,

Compound 19, Compound 20 and Compound 21. Compound 18

¹ H NMR (300MHz, CDCl ₃ ,), δ: 0.87(t, 3H), 1.2～1.6(m, 35H), 2.30(t, 2H),

3.30(q, 2H), 3.40(t, 2H), 3.58(m, 4H), 4.12(m, 2H), 4.98(m, 1H), 6.93(s, 1H).

¹³ C NMR (75Mhz, CDCl ₃ ), δ: 168.84, 117.68, 78.43, 77.32, 76.29, 75.63, 73.38,

39.63, 37.62, 27.34, 26.53, 21.09.

IR (Kbr, thin film), cm ^-1 : 3418, 2993, 2982, 1758, 1480, 1440, 1220, 920.

EIMS: 499 (M+1), 480 (MH ₂ O), 429, 357, 353, 309, 295, 267, 111, 95, 69, 55 Compound 19

¹ H NMR (300MHz, CDCl ₃ ), δ: 0.89(t, 3H), 1.2～1.72(m, 49H),

2.32(t, 2H), 3.33(q, 2H), 3.34(m, 2H), 3.42(t, 2H), 3.62(m, 4H), 4.13(t, 2H),

  4.92(m, 1H), 6.98(s, 1H).

¹³ C NMR (75MHz, CDCl ₃ ), δ: 168.38, 118.78, 77.62, 76.68, 76.38, 75.38, 74.29,

39.39, 38.03, 28.89, 22.64, 21.38.

IR (KBr, thin film), cm ^-1 : 3423, 2995, 2984, 2982, 1753, 1486, 1438, 1198, 920.

EIMS: 611 (M+1), 593 (M-18+1), 483, 375, 357, 309, 295 Compound 20

¹ H NMR (300MHz, CDCl ₃ ), δ: 0.87(t, 3H), 1.2～1.8(m, 61H), 3.34(q, 2H),

3.34(q, 2H), 3.38(t, 2H), 3.58(q, 4H), 4.22(m, 2H), 4.96(m, 1H), 6.95(s, H).

¹³ C NMR (75MHz, CDCl ₃ ), δ: 169.73, 120.60, 78.52, 77.60, 76.32, 75.48, 74.38,

73.21, 38.29, 28.83, 27.86, 21.38.

IR (KBr, thin film), cm ^-1 : 3446, 2994, 2983, 2882, 1756, 1483, 1160.

EIMS: 680 (M+1), 663 (MH ₂ O+1), 611, 585, 465, 375, 309, 295. Compound 21

¹ H NMR (300MHz, CDCl ₃ ), δ: 0.88(t, 3H), 1.25～1.7(m, 67H), 2.34(t, 2H),

3.33(q, 2H), 3.36(t, 2H), 3.56(q, 2H), 4.24(m, 2H), 4.89(m, 1H), 6.97(s, 1H).

¹³ C NMR (75MHz, CDCl ₃ ), δ: 168.74, 119.50, 77.53, 77.10, 76.68, 75.46, 75.41,

38.41, 38.16, 27.89, 21.69.

IR (KBr, thin film), cm ^-1 : 3440, 2992, 2986, 2890, 1754.

FAB: 723(M+1), 1295.

Example 6 Example biological activity test

Compounds 9, 10, 11 and 12 are listed in the following table according to the half-lethal dose determination of the cancer cell lines of KB, A2780, HCT-8 and HT-29 according to the MTT method

EC ₅₀ (μg/ml) compound

                                                                                                                 , 

9 ＞1 ＞1 0.066 0.272

10 ＞1 ＞1 0.097 1.12

11 ＞1 ＞1 0.032 0.11

12 ＞1 ＞1 0.065 7.83

Claims (9)

1. chiral anonace-lactone compounds, the optically active compound that it is characterized in that having following molecular formula:

, Y=C wherein _6-20Alkyl, n=1-3, m=7-19.

2. chiral anonace-lactone compounds as claimed in claim 1 is characterized in that molecular formula is:

3. chiral anonace-lactone compounds as claimed in claim 1 is characterized in that molecular formula is:

4. chiral anonace-lactone compounds as claimed in claim 1 is characterized in that molecular formula is:

5. chiral anonace-lactone compounds as claimed in claim 1 is characterized in that molecular formula is:

6. the preparation method of a chiral anonace-lactone compounds as claimed in claim 1 is characterized in that by molecular formula being

Or

Chirality haloalkane and molecular formula be

Or Chirality dihydroxyl alkyl carboxylic acid ester, linked reaction takes place in the presence of tin alkyl and monovalence metal fluoride; Again with methoxychlor methane protection hydroxyl; Make the alpha-position of terminal ester group form negative ion with the diisopropylamine lithium reaction, with molecular formula be then

Chiral aldehydes reaction obtain the aldol condensation product, obtain α, β-unsaturated lactone with organic amine compound, acid treatment that lone-pair electron are arranged on trifluoroacetic anhydride (TFAA) or the aceticanhydride/nitrogen-atoms successively; Acid catalysis deprotection group, wherein X=Cl, Br, I, n=1-3, Y=C _6-20Alkyl, P=THP, MOM or TBS, the MOM=methoxymethyl, the THP=THP trtrahydropyranyl, the TBS=dimethyl tertiary butyl is silica-based.

7. the method for the preparation of chiral anonace-lactone compounds as claimed in claim 6 is characterized in that making by following method:

(1) described chirality haloalkane, described chirality dihydroxyl alkyl carboxylic acid ester, monovalence metal fluoride and molecular formula are R ₂The tin alkyl mol ratio of SnO is 1: 0.5-2: 1-5: 1-2, in one or more polar solvents and room temperature reaction 1-24h to the reflux temperature make

(2) product of above-mentioned (1), diisopropyl ethylenediamine and methoxychlor methane mol ratio are 1: 1-5: during 1-5, react 1-10h with 0 ℃ to room temperature in polar solvent, obtain

(3) product of above-mentioned (2), molecular formula are Chiral aldehydes, diisopropylamine lithium and HMPA mol ratio be 1: 1-2: 1-5: 0-5, in polar solvent, under-78 ℃, react 0.5-5h with room temperature, after in room temperature and polar solvent, reacting 5-20h with mineral acid again, adding relative mol ratio is respectively on the nitrogen-atoms of 1-10 the organic amine compound of lone-pair electron and trifluoroacetic anhydride (TFAA) or the aceticanhydride of 1-3 is arranged, to room temperature, react 1-10h at 0 ℃, obtain

(4) in one or more polar solvent and under the room temperature, the product of above-mentioned (3) mineral acid catalytic reactions 10-20h,

Y=C in the above-mentioned molecular formula _6-20Alkyl, n=1-3, m=7-19, P=MOM, THP or TBS, the MOM=methoxymethyl, THP=tetrachloro pyranyl, the TBS=dimethyl tertiary butyl is silica-based, R=C _1-6Alkyl.

8. the preparation method of chiral anonace-lactone compounds as claimed in claim 6, the organic amine compound that it is characterized in that containing on the described nitrogen-atoms lone-pair electron is a triethylamine, described dialkyl tin is a dibutyl oxygen tin.

9. a chiral anonace-lactone compounds as claimed in claim 1 purposes in the preparation cancer therapy drug.