WO2009127116A1

WO2009127116A1 - 13-halo-3,15-dioxy gibberellic acid esters and the preparation methods thereof

Info

Publication number: WO2009127116A1
Application number: PCT/CN2009/000242
Authority: WO
Inventors: 张洪彬; 陈静波; 孙竹先; 卿晨; 刘建平; 曾祥慧; 张雁丽
Original assignee: 云南大学; 昆明医学院
Priority date: 2008-04-18
Filing date: 2009-03-06
Publication date: 2009-10-22
Also published as: CN101260095B; CN101260095A

Abstract

Medicinal compounds with general formula (I) in medicine health and chemistry field. 13-halo-3,15-dioxy gibberellic acid esters and the preparation methods thereof. Antitumor activity experiments prove that these compounds have higher antitumor effects and low toxicity to normal cells. R¹=CH₃, Alkyl with 2-5 carbon atoms, PhCH₂ R²=F, Cl, Br, I.

Description

13-halogen-3, 15-dioxoerythronate and preparation method thereof

The present invention relates to pharmaceutical compounds in the fields of medicine, hygiene and chemistry, in particular to a 13-halo-3, 15-dioxoerythronate and a process for the preparation thereof. Background technique

Cancer is a type of disease that poses a serious threat to human health. The primary means currently used to treat cancer is chemotherapy. Most of the chemotherapy drugs used in clinical applications have toxic side effects such as nausea, vomiting, leukopenia, and myelosuppression, which affect the patient's emotional and physical health, thus greatly limiting the clinical application of chemotherapy drugs. Therefore, the search for anti-cancer compounds with high activity, non-toxic or low toxicity has become an important topic in new drug research.

Gibberellin is a class of tetracyclic diterpenoids that are widely present in plants and microorganisms, have plant growth-promoting or plant growth-inhibiting biological activities, and are produced by commercial fermentation of gibberellins (eg, GA ₃ , GA ₄ , GA). ₇ ) Structural modification and modification of raw materials, in order to find gibberellins and their derivatives with better plant growth promotion or plant growth inhibition activity and other new activities such as antibacterial and anticancer, have important academic value and practical value.

In the preliminary study of the present invention, the inventors of the present application have a strong anticancer activity in the 3 and 15 gibberellic acid derivatives which are simultaneously oxidized to a carbonyl group, which are synthesized from gibberellic acid (GA ₃ ). At the same time, the toxicity to normal cells is very low. The result has been patented and authorized in 2004, patent number ZL200410021939. In the present invention, we further studied the 13 positions of such structures. Summary of the invention

SUMMARY OF THE INVENTION The object of the present invention is to provide a compound of the formula (I): 13-halo-3, 15-dioxo gibberellate and a process for the preparation thereof, which compounds have an anticancer effect.

Alkyl; PhCH ₂

(I)

1

Confirmation Wherein R ¹ is a methyl group, a fluorenyl group of 2 carbons to 5 carbons, or a benzyl group; and R ² is fluorine, chlorine, bromine or iodine.

The present invention synthesizes a series of 13-halogenated 3, 15-dioxocitrate compounds, which have strong antitumor activity and low toxicity to normal cells.

The object of the invention is achieved in this way:

Starting from 3, 13, 15-trihydroxy gibberellic acid ester (1) or 3, 13, 15-trihydroxy gibberellic acid (2), (1) or (2) refer to patent ZL200410021939 Method preparation. (1) or (2) adding dimethyl sulfoxide at a low temperature in a low-polar solvent with an appropriate ratio of oxalyl chloride or dimethyl sulfoxide with an appropriate ratio of sulfoxide to form an oxidizing agent to oxidize the 3 and 15 hydroxyl groups. At the same time as the 3, 15-dicarbonyl group, the 13-position simultaneous chlorination reaction produces the compound (3) or (4) having the structural formula (I).

The low polar solvent is benzene, toluene, methylene chloride, trichloromethane, n-hexyl, cyclohexane, petroleum ether, and the amount is 10~100 mL solvent/g substrate; dimethyl sulfoxide and The compound formed by oxalyl chloride or dimethyl sulfoxide and thionyl chloride at 70 ° C to 40 ° C is an oxidizing agent. After adding the substrate of oxidized and chlorinated, the reaction is carried out for 5-30 minutes, and then triethylamine is added. The reaction was carried out for 5-30 minutes.

The molar ratio of the compound is: substrate / dimethyl sulfoxide / oxalyl chloride or thionyl chloride / triethylamine = 1/2 ~ 50 / 2 ~ 6 / 4 ~ 100. The molar ratio of each compound was: substrate / dimethyl sulfoxide / oxalyl chloride / triethylamine = 1/10/5 / 14.

The procedure for preparing (3) or (4) with compound (1) or (2) is as follows:

Wherein (1) R, = CH ₃ ; 2 - 5 carbon alkyl, (2) R, = PhCH ₂ ,

(3) R, = CH ₃ ; 2-5 carbon alkyls, (4) R, = PhCH"

a) DMSO, C10CC0Cl, NEt ₃ /CH ₂ Cl ₂ or DMS0, SOCl ₂ , NEt ₃ /CH ₂ Cl ₂ .

13-Chloro-3, 15-dioxomycin (3) or (4) in tetrahydrofuran, acetonitrile, acetone, N, N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoryl Reaction with a fluorinating reagent such as sodium fluoride, potassium fluoride, ammonium fluoride or tetrabutylammonium fluoride in a polar aprotic solvent such as an amine to obtain 13-fluoro-3, 15-dioxoerythritol ( 5) or (6), the reaction solvent is acetone, the reaction temperature is acetone reflux temperature; the fluorination reagent is potassium fluoride, and the molar ratio of each compound in the reaction is: substrate / potassium fluoride = 1/2~50 /, the amount of acetone is 10~100 mL / mmol substrate, compound (5) or

Wherein (3) = CH ₃ ; 2 - 5 carbon alkyl, (4) = PhCH ₂ ,

(5) R, = CH ₃ ; 2-5 carbon sulfhydryl groups, (6) R, = PhCH ₂ ,

b) KF/CH ₃ C0CH ₃ .

13-bromo-3, 15-dioxoglucopyr (7) and (8) are based on 13-chloro-3, 15-dioxoerythritol (3) or (4), respectively. In a polar aprotic solvent such as tetrahydrofuran, acetone, diethyl ether, acetonitrile, dimethyl sulfoxide, N, N-dimethylformamide, hexamethylphosphoric triamide, etc. with sodium bromide, potassium bromide, Lithium bromide, tetrabutylammonium bromide and other brominating reagents are prepared by reacting acetonitrile, brominating reagent with lithium bromide, and the reaction temperature is acetonitrile reflux temperature. The molar ratio of the compound in the reaction is: substrate / lithium bromide = 1 /2~50, the amount of acetonitrile is 10~100 mL /mmol substrate, (7) or (8) is prepared as follows,

Wherein R _t = CH ₃ ; 2 - 5 carbon alkyl groups, (4) R, = PhCH ₂ ,

(7) R, = CH ₃ ; 2- 5 carbon alkyl, (8) = PhCH ₂

c) LiBr/CH ₃ CN

13-Hydroxy-3, 15-dioxoerythritol (7) or (8), 13-hydroxy-3, 15-dioxoerythritol (11), which can also be prepared by the method of ZL200410021939 or (12) Prepared by reacting phosphorus tribromide and pyridine in methylene chloride. The molar ratio of each compound in the reaction is: substrate / pyridine / phosphorus tribromide = 1 / 1 ~ 20 / 0. 35~ 2, the amount of dichloromethane is 10~100 mL / mmol substrate, the reaction temperature is a 10t ~ 0 °C. Preparation reaction formula is as follows

(11) R, = CH ₃ ; 2-5 carbon sulfhydryl groups (7) R, = CH, 2-5 carbon alkyl groups

(12) R, = PhCH ₂ (8) R, = PhCH ₂

d) PBr ₃ / CH ₂ C1 ₂

13-iodo-3, 15-dioxoerythritol (9) and (10) are based on 13-chloro-3, 15-dioxoerythritol (3) or (4), respectively. In a polar aprotic solvent such as tetrahydrofuran, acetone, diethyl ether, acetonitrile, dimethyl sulfoxide, N, N-dimethylformamide, hexamethylphosphoric triamide, etc. with sodium iodide, potassium iodide, iodide Lithium, tetrabutylammonium iodide and other iodinating reagents are prepared by reacting, the reaction solvent is acetonitrile, the iodinating reagent is sodium iodide, the reaction temperature is acetonitrile reflux temperature, and the molar ratio of the compound in the reaction is: substrate/iodination Sodium = 1/2~50, the amount of acetonitrile is 10~100 mL / 诵ol substrate, (9) or (10) is prepared as follows,

(3) R, = CH ₃ ; 2- 5 carbon sulfhydryl groups (9) R, =CH ₃ ; 2- 5 carbon alkyl groups

(4) R, = PhCH ₂ (10) R, = PhCH ₂

e) NaI/CH ₃ CN

13-Iodo-3, 15-dioxocitrate (9) or (10) 13-hydroxy-3, 15-dioxoerythrate (11) or (also prepared by the method of ZL200410021939) 12) The target is prepared by reacting triphenylphosphine, iodine and imidazole in dichloromethane. The molar ratio of the compound in the reaction is: substrate / imidazole / iodine = 1/2~30/1~5, dichloro The amount of formazan is 10~100 mL/mraol substrate, and the reaction temperature is _10 °C~0 °C. (9) or (10) is prepared as follows,

(11) R, = CH ₃ ; 2- 5 carbon sulfhydryl groups (9) R, = CH ₃ ; 2- 5 carbon sulfhydryl groups

(12) R, = PhCH ₂ (10) R, = PhCH ₂

f) PPh ₃ , imidazole, 1 ₂ / CH ₂ C1 ₂

13-Hydroxy-3, 15-dioxoerythritol (11) and (12) may be prepared by the method of ZL200410021939, and may also be composed of 13-chloro-3, 15-dioxoerythrate (3). Or (4) in acetone, acetonitrile, tetrahydrofuran, dichloromethyl 00242 A polar aprotic solvent such as alkane is prepared by reacting with water and a base such as sodium hydrogencarbonate, sodium carbonate, silver carbonate, triethylamine or diisopropylethylamine. Using acetone as solvent, the dosage is 10~100 mL /mmol substrate; using silver carbonate as the base; the reaction temperature is the reflux temperature of acetone; the molar ratio of the compound in the reaction is: substrate / silver carbonate = 1 / 1 ~ 2 The amount of water used is 1/4 of the volume of acetone, and the amount of acetone is 5 to 10 mL / mmol of substrate. The preparation steps of (11) or (12) are as follows:

(3) R, = CH ₃ ; 2- 5 carbon sulfhydryl groups (11) R, = CH ₃ ; 2-5 carbon sulfhydryl groups

(4) R, = PhCH (12) R, = PhCH

g) Ag ₂ C0 ₃ , H ₂ 0/CH ₃ C0CH ₃

Combinations of a compound of structural formula (I) with at least one pharmaceutically acceptable excipient or carrier can be used to treat cancer. detailed description

The typical compounds of the present invention are enumerated below in conjunction with the embodiments, but the present invention is not limited to or by these examples.

Compound 3 13-Chloro-3, 15-dioxobenzoate

The preparation process is as follows:

Mix dimethyl sulfoxide (7.6 g, 100 mmol) and dichloromethane (30 mL), cool to -70 ° C, add oxalyl chloride (6. 35 g, 50 mmol) dropwise with stirring, and add in about 5 minutes, control The reaction temperature is between 70 ° C and 40 ° C. After adding oxalyl chloride for 10 minutes, a solution of methyl 3, 13, 15-trihydroxy gibberellate (3.76 g, 10 mmol) and dichloromethane (20 mL) and dimethyl sulfoxide (4 mL) was added dropwise. After the addition was completed in about 5 minutes, the reaction was stirred at 70 ° C to 40 ° C for 20 minutes. Further, triethylamine (14. 14 g, 140 Å) was added, and the reaction was further stirred at 70 ° C to 40 ° C for 15 minutes, the cold bath was removed, and the temperature was naturally raised to room temperature. The reaction solution was transferred to a separatory funnel, and ice-cooled ethyl acetate (60 mL) was added, and the mixture was washed with ice-cooled hydrochloric acid (2N, 70 mL X l) and water (30 mL X 2 ), and the organic layer was separated and dried. Drying with sodium sulfate, and removing the drying agent by filtration. The solvent was evaporated to dryness to dryness crystals crystals crystals crystals Rate 87.9%.

Elemental analysis of C ₂ . H ₁₉ C10 ₆ Calculated value (%): C, 61.47; H, 4.90; CI, 9.07

Found (%): C, 61.45; H, 4.93; CI, 9.06

'HNMR (CDCls, 300MHz): δ 7.19 (d, J=9.4Hz, 1H), 6.23 (S, 1H), 6.07 (d, J=9.4Hz, 1H), 5.87(s, 1H), 3.63 (s , 3H), 3.62 (d, J = 10.2 Hz, 1H), 2.82 (d, J = 10.2 Hz, 1H), 2.79 (d, J = l 1.5 Hz, 1H), 2.69-2.62 (m, 1H), 2.50 (d, J=ll.5Hz, 1H), 2.40- 2.10 (m, 4H), 1.88(m, 1H), 1.33 (s, 3H).

¹³ CN R (CDCL, 500MHz): δ 200.35, 191.08, 172.71, 170.23, 150.73, 145.81, 129.75, 121.41, 89.17, 65.95, 65.45, 61.28, 60.54, 52.49, 48.87, 47.25, 41.60, 39.86, 18.02, 11.93.

Compound 4 13-Chloro-3, 15- benzoic acid benzyl benzoate

Starting from 3, 13, 15-trihydroxy gibberellic acid benzyl ester (4.52g, 10mmol), preparation method (reaction step, molar ratio of feed, order of addition, reaction temperature, etc.) with compound 3 (13-chloro - 3, 15-dioxobenzoic acid methyl ester) was prepared in the same manner, the crude product was obtained as a pale yellow solid, 4.43 g, silica gel column chromatography (n-hexane / ethyl acetate = 8 / 1) g, yield 88.7%.

Elemental Analysis C ₂₆ H ₂₃ C10 ₆

Calculated value (%): C, 66.88; H, 4.97; C1, 7.59

Found (%): C, 66.85; H, 5.00; C1, 7.58

NMR NMR (CDCU 300MHz): δ 7.35-7.20 (m, 5H), 7.18 (d, J=9.4Hz, 1H), 6.16 (s, 1H), 6.07 (d, J=9.4Hz, 1H), 5.84 ( s, 1H), 5.05 (s, 2H), 3.65 (d, J = 10.4 Hz, 1H), 2.86 (d, J = 10.4 Hz, 1H), 2.77 (d, J = 11.5 Hz, 1H), 2.70 - 2.62 (m, 1H), 2.46 (d, J=11.5Hz, 1H), 2.38-2.09 (m, 4H), 1.93— 1.79 (m, 1H), 1.33(s, 3H).

¹³ C NMR (CDCl ₃₎ 75 MHz): δ 200.42, 191.06, 172.69, 169.61, 150.82, 145.79, 134.92, 129.77, 129.70, 128.67, 128.63, 121.26, 89.17, 67.58, 65.90, 65.45, 61.24, 60.60, 49.04, 47.32 , 41.60, 39.73, 18.04, 12.01.

Compound 5 13-fluoro-3, 15-dioxoglucosinate

Methyl 13-chloro-3, 15-dioxobenzoate (3, 391 mg, 1 mmol), potassium fluoride (1.51 g, 25.6 mmol) and 50 mL of acetone were mixed and refluxed for 50 hr. Dry, add 20mL of dichloromethane and 10mL of water, stir well, then separate the organic layer, the aqueous layer is extracted with dichloromethane (10mLX2), the organic layer is combined, saturated brine (10mL), then anhydrous sodium sulfate After drying, the drying agent was filtered off, and the solvent was evaporated to dryness to dryness crystals crystals crystalsssssssssssssssssssssssssss

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Elemental analysis of C ₂ . H ₁₉ Br0 ₆

Calculated value (%): C 55.19; H, 4.40; Br, 18.36

Found (%): C, 55.22; H, 4.42; Br, 18.40

NMR NMR (CDC1 ₃₎ 300MHz ): δ 7.18 (d, J=9.4Hz, IH), 6.30 (s, IH), 6.08 (d, J=9.4Hz, IH), 5.97(s, 1H), 3.65( s, 3H), 3.63 (d, J = 10.4 Hz, IH), 2.91 (d, J = ll.7 Hz, 1H), 2.82 (d, J = 10.4 Hz, 1H), 2.67 (d, J = ll. 7Hz, IH), 2.50- 2.20 (m, 4H), 1.90- 1.75 (m, IH), 1.35 (s, 3H).

¹³ C NMR (CDC1 ₃ , 75 MHz): δ 199.61, 191.07, 172.70, 170.22, 150.29, 145.76, 129.80, 122.93, 89.22, 65.46, 61.19, 60.86, 57.45, 52.54, 48.95, 47.00, 42.74, 41.34, 18.43, 11.95.

Compound 8 13-Bromo-3, 15-dioxobenzoate benzyl ester

Starting from the compound 11- 13-hydroxy-3, 15-dioxobenzoic acid benzyl ester (448mg, lmrnol), the preparation method (reaction step, molar ratio of feed, order of addition, reaction temperature, etc.) The preparation of the compound 7 (13-bromo-3, 15-dioxobenzoic acid methyl ester) was carried out to give a crude product (yield: 430 mg, m.p. The white crystals were purified to 305 mg, yield 59.7%.

Elemental Analysis C ₂₆ H ₂₃ Br0 ₆

Calculated value (%): C, 61.07; H, 4.53; Br, 15.63

Found (%): C, 61.08; H, 4.55; Br, 15.66

NMR NMR (CDC1 ₃ , 300MHz ): δ 7.50-7.20 (m, 5H), 7.17 (d, J=9.4Hz, 1H), 6.23 (s, IH), 6.08 (d, J=9.4Hz, IH), 5.94 (s, IH), 5.05 (s, 2H), 3.66 (d, J = 10.4 Hz, 1H), 2.92 (d, J = 11.7 Hz, IH), 2.86 (d, J = 10.4 Hz, 1H), 2.65 (d, J=11.7Hz, IH), 2.50-2.20 (m, 4H), 1.90-1.75 (m, 1H), 1.35(s, 3H).

¹³ C NMR (CDC1 ₃ , 75 MHz): δ 199.68, 191.05, 172.68, 169.60, 150.38, 145.74, 134.97, 129.82, 129.79, 128.72, 128.70, 122.78, 89.22, 67.56, 65.46, 61.15, 60.92, 57.47, 49.12, 47.07, 42.74, 41.21, 18.45, 12.03.

Compound 9 13-iodo-3, 15-dioxobenzoate methyl ester Mix 13-chloro-3, 15-dioxobenzoic acid methyl ester (3, 391 mg, 1 mmol), sodium iodide (3.00 g, 20 瞧ol) and 30 mL of anhydrous acetonitrile, reflux for 50 hours, decompression Distill the solvent to dryness, add 20 mL of dichloromethane and 10 mL of water, stir well, then separate the organic layer. The aqueous layer was extracted with dichloromethane (10 mL×2), and the organic layer was combined and washed with saturated brine (10 mL). The mixture was dried over anhydrous sodium sulfate (MgSO4), EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

Elemental analysis of C ₂ . H _l9 10 ₆

Calculated value (%): C, 49.81; H, 3.97; I, 26.31

Found (%): C, 49.79; H, 3.99; I, 26.35

NMR NMR (CDC1 ₃ , 300MHz ): δ 7.17 (d, J=9.4Hz, IH), 6.36 (s, 1H), 6.08 (d, J=9.4Hz, IH), 6.03 (s, IH), 3.66 ( s, 3H), 3.62 (d, J = 10.4 Hz, IH), 3.02 (d, J = 12.8 Hz, IH), 2.82 (d, J = 11.6 Hz, 1H), 2.80 (d, J = 10.4 Hz, 1H), 2.40-2.10 (m, 4H), 1.90-1.75 (m, IH), 1.35(s, 3H).

¹³ C NMR (CDC1 ₃ , 75MHz): δ 198.22, 191.07, 172.69, 170.22, 153.19, 145.70, 129.80, 124.77, 89.34, 65.41, 60.98, 60.95, 52.55, 48.99, 46.56, 45.11, 44.82, 33.67, 18.67, 11.94 .

Compound 10 13-Iodo-3, 15-dioxobenzoate benzyl ester

Starting from the compound 4-1,4-chloro-3, 15-dioxobenzoic acid benzyl ester (467 mg, lmmol), the preparation method (reaction step, molar ratio of feed, order of addition, reaction temperature, etc.) Compound 9 (13-iodo-3, 15-dioxobenzoic acid methyl ester) was prepared in the same manner, and finally 430 mg of crude product as a pale yellow solid was obtained, and silica gel column chromatography (n-hexane/ethyl acetate = 8/1) Purification of 303 mg of white crystals, yield 54.3%.

Elemental analysis C ₂₆ H ₂₃ 10β

Calculated value (%): C 55.93; Η, 4.15; I, 22.73

Found (%): C, 55.93; Η, 4.17; I, 22.77

'Η NMR (CDCL, 300MHz): δ 7.40-7.20 (m, 5Η), 7.16 (d, J-9.4Hz, IH), 6.29 (s, IH), 6.08 (d, J=9.4Hz, 1H), 6.00 (s, IH), 5.04(s, 2H), 3.65 (d, J = 10.4 Hz, 1H), 3.06 (d, J = 12.8 Hz, IH), 2.80 (d, J = 11.6 Hz, IH), 2.79 (d, J = 10.4 Hz, 1H), 2.40-2.10 (m, 4H), 1.90-1.75 (m, 1H), 1.35 (s, 3H).

¹³ C NMR (CDC1 ₃ , 75 MHz): δ 198.29, 191.05, 172.69, 170.20, 153.28, 145.68, 134.93, 129.82, 129.80, 128.71, 128.65, 124.62, 89.34, 67.55, 65.41, 61.01, 60.94, 49.06, 46.63, 45.11, 44.77, 33.67, 18.69, 12.02. Compound 11 13-hydroxy-3, 15-dioxoglucosinate

13-Chloro-3,15-dioxocitrate (3, 391 mg, 1 mmol) was dissolved in acetone/water (8/2, 10 mL), then silver carbonate (304 mg, 1. lmmol) was added and the mixture was stirred. The reaction was refluxed for 24 hours, hydrazine reaction, cooled to room temperature, filtered, and the filter cake was washed with acetone. The filtrate was concentrated to dryness. EtOAc (EtOAc) (EtOAc) After washing with saturated brine, MgSO4 The solid was 345 mg, and the yield was 95.4%.

Elemental analysis of C ₂ . H ₂ . 0 ₇

Calculated value (%): C, 64.51; H, 5.41

Found (%): C, 64.50; H, 5.43

_3⁄4 NMR (CDC1 ₃ , 300MHz): δ 7.20 (d, J=9.4Hz, 1H), 6.13 (s, 1H), 6.08 (d, J=9.4Hz, 1H), 5.70(s, 1H), 3.64( s, 3H), 3.65 (d, J = 10.2 Hz, 1H), 2.83 (d, J = 10.2 Hz, 1H), 2.54 (d, J = 10.8 Hz, 1H), 2.40-2.20 (m, 3H), 2.16 (d, J = 10.8 Hz, 1H), 1.90- 1.75 (m, 3H), 1.35 (s, 3H).

1 ³ C NMR (CDC1 ₃ , 75 MHz): δ 202.15, 191.28, 173.00, 170.60, 152.69, 146.07, 129.74,

118.53, 89.31, 76.00, 65.60, 61.63, 60.86, 52.44, 48.98, 48.09, 40.39, 36.75, 17.61, 12.01.

Compound 12 13-hydroxy-3, 15-dioxobenzoate benzyl ester

Starting from the compound 4-1,4-chloro-3, 15-dioxobenzoic acid benzyl ester (467 mg, lmmol), the preparation method (reaction step, molar ratio of feed, order of addition, reaction temperature, etc.) The compound 11 (13-hydroxy-3, 15-dioxobenzoic acid methyl ester) was prepared in the same manner, and finally 420 mg of crude product was obtained as a white solid, which was purified by silica gel column chromatography (hexane/ethyl acetate = 3/1). 295 mg of white crystals were obtained in a yield of 65.8%.

Elemental Analysis C ₂₆ H ₂₄ 0 ₇

Calculated value (%): C 69.63; H, 5.39

Found (%): C, 69.64; H, 5.41

NMR NMR (CDCI3, 300MHz): δ 7.40-7.10 (m, 6H), 6.08 (d, J=9.9Hz, 1H), 6.06 (s, 1H), 5.65 (s, lH), 5.06(s, 2H) , 3.68 (d, J = 10.2 Hz, 1H), 2.86 (d, J = 10.8 Hz, 1H), 2.51 (d, J = 11.1 Hz, 1H), 2.40-2.15 (m, 3H), 2.07 (d , J=ll.1Hz, 1H), 1.90-1.70(m, 3H), 1.34(s, 3H).

1 ³ C NMR (CDC1 ₃ , 75MHz): δ 202.50, 191.27, 172.98, 170.00, 152.86, 146.05, 135.10, 129.74, 128.84, 128.71, 128.67, 118.18, 89.32, 75.99, 67.55, 65.59, 61.61, 60.87, 49.15, 48.18, 40.46, 36.53, 17.59, 12.06.

Anticancer activity test of compound 3~10

Compounds 3 to 10 were assayed for the half-inhibitory concentration (IC ₅ ) of six tumor cell lines such as K562 (human leukemia cell line) according to the MTT method, and showed IC _{5 of the} compound 3 to ₁₀ . =3.5~45.3 g/mL, both have strong inhibitory effects on tumor cells.

Claims

Rights request

A compound having the following structural formula (I): 13-halo-3, 15-dioxoerythritol,

Up to 5 carbons

18 ( I ).

2. A process for the preparation of a compound of the formula (I) according to claim 1, characterized by: a. with 3, 13, 15-trihydroxy gibberellic acid ester (1) or 3, 13, 15 - benzyl trihydroxy gibberellate (2) as a starting material, first in a low polar solvent, adding dimethyl sulfoxide at a low temperature with an appropriate ratio of oxalyl chloride or an appropriate ratio of dimethyl sulfoxide and thionyl chloride The oxidant formed, oxidizes the 3 and 15 hydroxyl groups to 3, 15-dicarbonyl, and chlorination at the 13 position to form the compound (3) having the structural formula (I): 13-chloro-3, 15-di Oxofibrate or (4): 13-chloro-3, 15- benzoic acid benzyl ester, the structural formula of (1) or (2) is as follows,

In the formula (1), R, = CH ₃ , 2 carbon to 5 carbon alkyl, (2) R, = PhCH ₂ ,

(3) or (4) The structural formula is as follows, CH ₃ ; 2 carbons to S carbons

Base and PhCH ₂

Among them, (3) CH ₃ , 2 carbon to 5 carbon sulfhydryl groups, (4) PhCH ₂ ,

b. Prepared by 13-chloro-3, 15-dioxoglucopyr (3) or 13-chloro-3, 15-dioxobenzoic acid benzyl ester (4). Compounds of I): 13-fluoro-3, 15-dioxoerythritol (5, 6), 13-bromo-3, 15-dioxosporate (7, 8), 13-iodine - 3, 15-dioxomycin (9, 10), c. Prepared by 13-hydroxy-3, 15-dioxobenzoate (11) or 13-hydroxy-3, 15-dioxobenzoic acid benzyl ester (12). Compound of I): 13-bromo-3, 15-dioxoerythritol (7, 8) or 13-iodo-3, 15-dioxoerythritol (9, 10).

3. A method for preparing 13-hydroxy-3, 15-dioxoerythronate (11) from 13-chloro-3, 15-dioxomycin (3) or (4), ( 12) method.

4. The preparation method according to claim 2, wherein the low polar solvent used is benzene, toluene, dichloromethane, trichloromethane, n-hexyl, cyclohexane or petroleum ether, and the amount is 10 ~100mL solvent / g substrate; the compound formed by dimethyl sulfoxide and oxalyl chloride or dimethyl sulfoxide and thionyl chloride at -70 ° C to 40 ° C as an oxidant, adding oxidative and chlorinated The substrate is reacted for 5-30 minutes, and then triethylamine is added to carry out the reaction for 5-30 minutes.

5. The preparation method according to claim 2 or 4, wherein the molar ratio of each compound is: substrate / dimethyl sulfoxide / oxalyl chloride or thionyl chloride / triethylamine = 1/2 to 50 /2~6/4~100.

6. The preparation method according to claim 2 or 4, wherein the molar ratio of each compound is: substrate / dimethyl sulfoxide / oxalyl chloride / triethylamine = 1/10/5 / 14.

The preparation method according to claim 2, wherein when 13-fluoro-3, 15-dioxoerythritol (5), (6) is prepared, 13-chloro-3, 15-di The oxomycin (3) or (4) is in an aprotic solvent such as tetrahydrofuran, acetone, diethyl ether, acetonitrile, dimethyl sulfoxide, N, N-dimethylformamide or hexamethylphosphoric triamide. The target is prepared by reacting with a fluorinating reagent such as sodium fluoride, potassium fluoride, cesium fluoride, fluorinated hinge or tetrabutylammonium fluoride; the reaction temperature is determined by the reflux temperature of acetone; the fluorinating reagent is potassium fluoride, and the compound in the reaction The molar ratio of the molar ratio is: substrate / potassium fluoride = 1/2 ~ 50, acetone dosage is 10 ~ 100 mL / mmol substrate, compound (5) or (6) structural formula is as follows,

Ri = CH ₃ ; 2 carbon to 5 carbon

Alkyl and PhCH ₂

Wherein (1) R _{1 =} CH ₃ , 2 carbon to 5 carbon sulfhydryl groups, and (6) R _{1 =} PhCH ₂ .

The process according to claim 2, wherein 13-bromo-3, 15-dioxoerythritol (7) is prepared, (8), 13-chloro-3, 15-dioxoerythritol (3) or (4) in tetrahydrofuran, acetone, diethyl ether, acetonitrile, dimethyl sulfoxide, N, N-dimethyl The amide or hexamethylphosphoric triamide solvent is reacted with a brominating reagent such as sodium bromide, potassium bromide, lithium bromide or tetrabutylammonium bromide to prepare a target, the brominating agent is lithium bromide, and the reaction temperature is acetonitrile reflux temperature. The molar ratio of the compound in the reaction is: substrate / lithium bromide = 1/2 ~ 50, the amount of acetonitrile is 10 ~ 100 mL / 匪ol substrate, (7) or (8) the structural formula is as follows,

R! = CH ₃ ; 2 carbons to 5 carbons

Sulfhydryl and PhCH ₂

In the formula (7), R, = CH ₃ , 2 carbon to 5 carbon sulfhydryl groups, and (8) R >= PhCH ₂ .

The preparation method according to claim 2, wherein when 13-iodo-3, 15-dioxoerythritol (9) and (10) are prepared, 13-chloro-3, 15-di Oxygen erythromycin (3), (4) in tetrahydrofuran, acetone, diethyl ether, acetonitrile, dimethyl sulfoxide, N, N-dimethylformamide or hexamethylphosphoric triamide in a solvent with sodium iodide The target is prepared by reacting an iodinating agent such as potassium iodide, lithium iodide or tetrabutylammonium iodide. The iodinating agent is sodium iodide, the solvent is acetonitrile, the reaction temperature is acetonitrile reflux temperature, and the amount of the compound in the reaction is INR. : Substrate / sodium iodide = 1/2 ~ 50, acetonitrile dosage 10~100 mL / wake up ol substrate, (9) and (10) structural formula is as follows,

R! = CH ₃ ; 2 carbons to 5 carbons

Sulfhydryl and PhCH ₂

Wherein (9) is R, = CH ₃ , 2 carbon to 5 carbon alkyl, and (10) is R = PhCH ₂ .

10. The preparation method according to claim 3, wherein when 13-hydroxy-3, 15-dioxoerythritol (11), (12) is prepared, 13-chloro-3, 15-di is used. An oxomycin (3) or (4) in acetone, acetonitrile, ethanol, methanol, tetrahydrofuran or dichloromethane, with water and sodium bicarbonate, sodium carbonate, silver carbonate, triethylamine or diisopropyl Preparation of 13-hydroxy-3, 15-dioxocitrate by using ethylamine reaction (11, 12), (11, 12) The structural formula is as follows, Ri = CH ₃ ; 2 carbon to S carbon

Alkyl and PhCH ₂

Among them, (11) CH ₃ , 2 carbon to 5 carbon sulfhydryl groups, (12) PhCH ₂ .

11. The preparation method according to claim 10, characterized in that acetone/water is used as a solvent and silver carbonate is used as a base; the reaction temperature is determined by the reflux temperature of acetone, and the molar ratio of the compound is used as a substrate/silver carbonate=1/1. 1 ; The acetone / water ratio is 8/2 by volume, and the amount is 10~100 raL / mmol substrate.

The preparation method according to claim 2, wherein 13-bromo-3, 15- is prepared from 13-light-based-3, 15-dioxoerythritol (11), (12). Dioxomycin (7), (8), 13-hydroxy-3, 15-dioxoerythritol (11) or (12) with phosphorus tribromide and pyridine in dichloromethane The reaction produces 13-bromo-3, 15-dioxoerythritol (7) or (8). The molar ratio of the compound in the reaction is: substrate / pyridine / phosphorus tribromide = 1 / 1 ~ 20 /0. 35~2, the amount of dichloromethane is 10~100 mL / difficult ol substrate, the reaction temperature is _ 10 ° C ~ 0 ° C.

13. Use of a compound of the formula (I) according to claim 1 for the manufacture of a medicament for the treatment of cancer.