CN101830873A - Preparation method of 13-chloro-3,15-dicarbonyl gibberellic acid and salt thereof - Google Patents
Preparation method of 13-chloro-3,15-dicarbonyl gibberellic acid and salt thereof Download PDFInfo
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Abstract
The invention provides a compound with a structural general formula (I) and a general formula (II), in particular a preparation method of 13-chloro-3,15-dicarbonyl gibberellic acid and a salt thereof. The compound has the effect of resisting cancer.
Description
Technical field
The present invention relates to the medicinal compound of pharmaceutical chemistry and chemical field, especially a kind of 13-chloro-3, the preparation method of 15-dicarbonyl gibberellic acid and salt thereof.
Background technology
Cancer is a class disease cancer of serious threat human health, and sickness rate is along with people's predicted life continues to rise synchronously.The main means that are used for the treatment of cancer at present are chemotherapy.The chemotherapeutics overwhelming majority of clinical application makes toxic side effect such as the patient feels sick, vomiting, leukopenia, bone marrow depression, has influenced patient's mood and healthy, thereby has limited the clinical application of chemotherapeutics greatly.Therefore, seek high reactivity, anticancer compound nontoxic or low toxic side effect becomes an important topic of new drug research.
The example of successfully developing the novel anti-tumor medicine based on the high yield composition of natural product is common occurrence.For example the 10-that is rich in from European yew branches and leaves (renewable position) removes acetyl Ba Kating (III), and 10-deacetyl-baccatinIII succeeds in developing antitumor drug Docetaxel[trade(brand)name
], from podophyllotoxin developing anti-tumor medicaments Etoposide Etoposide and teniposide Teniposide.From natural product, seek physiologically active compound, design and synthesize class natural product storehouse according to its molecule pharmacophore information, the lead compound that therefrom screens and find high-level efficiency, highly selective, low toxic side effect carries out studying before the clinical drug, has become the effective way that obtains the drug candidate molecule.Plant hormones regulators,gibberellins is the tetracyclic diterpene compounds, extensively is present in plant and the microbe, has plant-growth promotion or plant-growth and suppresses biological activity, wherein gibberic acid (GA
3) commercialization fermentative production and being widely used in the agriculture production.With the gibberic acid (GA that is easy to get
3) for raw material carries out structure of modification and modification, have important use and be worth in the hope of finding to have better plant-growth promotion or plant growth inhibiting activity and other such as new active Plant hormones regulators,gibberellins such as antibiotic, anticancer and derivative thereof.
In the present invention's research in early stage, the present inventor is with gibberic acid (GA
3) for synthetic 3 and 15 the gibberic acid derivatives that are oxidized to carbonyl simultaneously that obtain of raw material have very strong antitumour activity, lower to normal cytotoxicity simultaneously, applied for patent and obtained the authorization patent No. ZL200410021939 in 2004.We carry out further derivatize research to the carbon-7 of this class formation again in the present invention.
Summary of the invention
The objective of the invention is to propose a kind of compound with following general structural formula (I) and general formula (II), name is called: 13-chloro-3, and 15-dicarbonyl gibberellic acid and salt thereof, this compounds has antitumous effect.
R in the formula
1Be hydrogen, sodium, potassium, lithium, calcium, magnesium, barium, amino (NH
4) wait mineral alkali; R
2Be methylamine, benzylamine, butylamine, TERTIARY BUTYL AMINE, glycine methyl ester, amino acid esters such as phenylalanine methyl ester, Pyrrolidine, hexahydropyridine, morphine quinoline, piperazine, imidazoles, pyridine, pyrroles, organic basess such as Sodium Glutamate.
The present invention has synthesized 3 of 13 chloros, and 15-dicarbonyl gibberellic acid and series salt compounds thereof experiment showed, that through antitumour activity these compounds have stronger anti-tumor activity.
The object of the present invention is achieved like this:
With gibberic acid (GA
3) be starting raw material, under alkaline condition, in polar solvent, add the methoxyl group benzyl chloride, in 7 in carbon esterification taking place generates compound (1) under 0～50 ℃.
The reaction formula of compound (1) preparation is as follows:
A) polar solvent/alkali is to the methoxyl group benzyl chloride.
Described polar solvent is methyl-sulphoxide, N, and dinethylformamide, acetonitrile, ethanol, acetone, tetrahydrofuran (THF) or 1,4-dioxane, consumption are 5～100mL solvent/g substrate; Used alkali is cesium carbonate, salt of wormwood, yellow soda ash, sodium hydroxide, pyridine, imidazoles or DMAP; Each compound amount by mole is: substrate/alkali/and to methoxyl group benzyl chloride=1/2～5/1～2.
With 3,13-dihydroxyl gibberellic acid ester (1) is a raw material, utilize oxygenant in organic solvent and under the room temperature oxidation allylic carbon 15 be hydroxyl generation 3,13,15-trihydroxy-gibberellic acid ester compound (2).
The reaction formula of compound (2) preparation is as follows:
B) organic solvent, oxygenant, co-oxidants.
Described organic solvent is methylene dichloride, N, dinethylformamide, acetonitrile, tetrahydrofuran (THF), 1, and 4-dioxane etc., consumption is 5～100mL solvent/g substrate; Used oxygenant is cuprous iodide, Cobaltous diacetate [Co (OAc)
2], tin anhydride, manganese acetate [Mn (OAc)
3]; Co-oxidants is peroxy tert-butyl alcohol, hydrogen peroxide.Each compound amount by mole is: substrate/oxygenant/co-oxidants=1/1～3/2～5.
With 3,13,15-trihydroxy-gibberellic acid ester compound (2) is a raw material, 3 and 15 hydroxyls of oxygenant oxidation that form through the oxalyl chloride of methyl-sulphoxide and suitable proportion or sulfur oxychloride under the low temperature in low polar solvents such as methylene dichloride are 3, in the time of the 15-dicarbapentaborane, 13 chlorination take place simultaneously generate 13-chloro-3,15-dicarbonyl gibberellic acid ester cpds (3).
The reaction formula of compound (3) preparation is as follows:
C) low polar solvent, oxygenant, triethylamine.
Described low polar solvent is benzene, toluene, methylene dichloride, trichloromethane, normal hexane, hexanaphthene or sherwood oil, and consumption is 10～100mL solvent/g substrate; Is oxygenant with methyl-sulphoxide and oxalyl chloride or methyl-sulphoxide and sulfur oxychloride at-78 ℃ to-40 ℃ compounds that form down, adds substrate afterreaction 5-30 minute of waiing upon oxidation and chloro, adds triethylamine again and reacts 5-30 minute.Each compound amount by mole is: substrate/methyl-sulphoxide/oxalyl chloride or sulfur oxychloride/triethylamine=1/2～50/2～6/4～50.
With 13-chloro-3,15-dicarbonyl gibberellic acid ester cpds (3) is a raw material, and zero degree generates 13-chloro-3,15-dicarbonyl gibberellic acid compound (4) with acid-respons under room temperature in organic solvent.
The reaction formula of compound (4) preparation is as follows:
D) organic solvent, acid.
Described organic solvent is methylene dichloride, acetonitrile, tetrahydrofuran (THF) or 1, and 4-dioxane, solvent load are 10～100mL/mmol substrate; Used acid is hydrochloric acid, trifluoracetic acid, formic acid or tosic acid, preferred trifluoracetic acid; The consumption of each compound is in molar ratio in the reaction: substrate/acid=1/2～50/.
With 13-chloro-3,15-dicarbonyl gibberellic acid [(I), R
1=H] be raw material, at tetrahydrofuran (THF), acetone, acetonitrile, N, have general structure (I) and compound (II) with corresponding mineral alkali and organic bases prepared in reaction in the organic solvents such as dinethylformamide, methylene dichloride or ethanol.
The reaction formula of general structure (I) and compound (II) is as follows:
E) organic solvent, mineral alkali and organic amine and amino acid ester.
Described mineral alkali is the carbonate or the oxyhydroxide of alkalies and alkaline earth, ammoniacal liquor; Organic amine and amino acid ester; R in the formula
1Be hydrogen, sodium, potassium, lithium, calcium, magnesium, barium, amino (NH
4) wait mineral alkali; R
2Be methylamine, benzylamine, butylamine, TERTIARY BUTYL AMINE, glycine methyl ester, amino acid esters such as phenylalanine methyl ester, Pyrrolidine, hexahydropyridine, morphine quinoline, piperazine, imidazoles, pyridine, pyrroles, organic basess such as Sodium Glutamate; The consumption of each compound is in molar ratio in the reaction: substrate/mineral alkali or organic bases=1/0.9-1.1, solvent load are 1～10mL/mmol substrate.
Have the drug regimen that general structure (I) and compound (II) and at least a pharmaceutically acceptable vehicle or carrier make and be used for the treatment of cancer.
Embodiment
Enumerate typical compound of the present invention below in conjunction with embodiment, but the present invention is not limited in these embodiment or is limited by these embodiment.
Compound 1: gibberic acid is to methoxy benzyl ester
Preparation process is as follows:
Gibberic acid (GA
3, 11.12g, 30mmol), (12.44g 90mmol) is dissolved in 50 milliliters of N, dinethylformamide to salt of wormwood.Add under the room temperature to the methoxyl group benzyl chloride (39mmol, 6.2g).Reacted 3～10 hours down in 40 degree, cool to room temperature adds frozen water (50～100mL).Decompress filter, product are used n-hexane/ethyl acetate=2/1 (25mL * 2) washing again, and water (20mL * 2) is washed the back drying under reduced pressure, gets white solid thing (13.3g), yield 95%.
Ultimate analysis (C
27H
30O
7)
Calculated value (%): C, 69.51; H, 6.48;
Measured value (%): C, 69.85; H, 6.43.
1H?NMR(CDCl
3+CD
3OH，300MHz)：δ7.08(2H，d，J＝8.5Hz)，6.66(2H，d，J＝8.5Hz)，6.07(1H，d，J＝9.3Hz)，5.66(1H，dd，J＝3.5，9.3Hz)，4.99(1H，s)，4.93(1H，d，J＝11.9Hz)，4.86(1H，d，J＝11.9Hz)，4.66(1H，s)，3.82(1H，d，J＝3.5Hz)，3.59(3H，s)，3.13(1H，s)，3.04(1H，d，J＝10.7Hz)，2.53(1H，d，J＝10.7Hz)，1.98-1.38(9H，m)，0.94(3H，s).
13C?NMR(CDCl
3，75MHz)：δ182.75，175.25，162.71，159.24，135.96，134.77，133.23，130.55，116.82，109.96，94.10，80.28，72.04，69.67，58.03，56.63，55.78，53.91，53.47，47.38，45.80，41.23，19.79，17.05.
Compound 2:3,13,15-trihydroxy-gibberic acid is to methoxy benzyl ester
Preparation process is as follows:
Gibberic acid is to methoxy benzyl ester (0.467g, 1mmol) be dissolved in the methylene dichloride (10mL), add tin anhydride (0.133g again, 1.2mmol) and the 70% peroxy tert-butyl alcohol aqueous solution (0.5mL, 3.6mmol), stirring at room to the silica gel thin-layer chromatography detection reaction fully after, reaction solution changes separating funnel over to, with sodium hydroxide solution (10%, 5mL * 3) after the washing, organic layer is told in water (10mL * 3) washing again, adds anhydrous sodium sulfate drying, remove by filter siccative, decompression steams solvent to doing, and gets white crystals 0.458g through silica gel column chromatography, yield 95%.
Ultimate analysis (C
27H
30O
8)
Calculated value (%): C, 67.21; H, 6.27;
Measured value (%): C, 67.05; H, 6.45.
1H?NMR(CD
3OH，300MHz)：δ7.36(2H，d，J＝8.6Hz)，6.94(2H，d，J＝8.6Hz)，6.40(1H，d，J＝9.3Hz)，5.89(1H，dd，J＝3.5，9.3Hz)，5.40(1H，s)，5.39(1H，s)，5.13(1H，d，J＝11.9Hz)，4.99(1H，d，J＝11.9Hz)，4.18(1H，s)，4.02(1H，d，J＝3.5Hz)，3.82(3H，s)，3.22(1H，d，J＝10.0Hz)，2.64(1H，d，J＝10.0Hz)，2.32(1H，d，J＝10.7Hz)，2.01-1.72(6H，m)，1.16(3H，s).
13C?NMR(CDCl
3，75MHz)：δ181.01，175.30，161.84，161.11，134.10，133.21，131.19，129.56，114.91，112.71，92.87，78.63，77.53，70.76，67.86，58.43，55.81，55.34，54.90，50.39，48.66，43.13，39.76，18.41，14.91.
Compound 3:13-chloro-3, the 15-dicarbonyl gibberellic acid is to methoxy benzyl ester
Preparation process is as follows:
(7.6g 100mmol) and methylene dichloride (30mL), is cooled to-70 ℃, and (6.35g 50mmol), adds about 5 minutes, and control reaction temperature is between-70 ℃ to-40 ℃ to stir down the dropping oxalyl chloride to mix methyl-sulphoxide.The oxalyl chloride adding dripped 3 after 10 minutes, 13,15-trihydroxy-gibberic acid is to methoxy benzyl ester (4.82g, 10mmol) solution that is made into methylene dichloride (20mL-40mL) and methyl-sulphoxide (4mL), after adding about 5 minutes, stirring reaction is 20 minutes between-70 ℃ to-40 ℃.(14.14g 140mmol), continued between-70 ℃ to-40 ℃ stirring reaction 15 minutes, removed cryostat, was warming up to room temperature naturally to add triethylamine again.Reaction solution changes in the separating funnel, add ice-cooled ethyl acetate (60mL), use ice-cooled hydrochloric acid (2N, 70mL * 1) Xi Heshui (30mL * 2) to wash successively, tell organic layer, add anhydrous sodium sulfate drying, remove by filter siccative, decompression steams solvent to doing, and gets yellow solid 4.8g, silica gel column chromatography (n-hexane/ethyl acetate=3/1) purifying gets white crystals 4.3g, yield 90%.
Ultimate analysis (C
27H
25ClO
7)
Calculated value (%): C, 65.26; H, 5.07; Cl, 7.13;
Measured value (%): C, 65.15; H, 5.33; Cl, 6.98.
1H?NMR(CDCl
3，300MHz)：δ7.17(1H，d，J＝9.4Hz)，7.13(2H，d，J＝8.6Hz)，6.81(2H，d，J＝8.6Hz)，6.15(1H，s)，6.04(1H，d，J＝9.4Hz)，5.82(1H，s)，4.97(2H，s)，3.77(3H，s)，3.61(1H，d，J＝10.4Hz)，2.82(1H，d，J＝10.4Hz)，2.74(1H，d，J＝11.5Hz)，2.61(1H，dd，J＝7.8，13.5Hz)，2.43(1H，d，J＝11.5Hz)，2.30-2.02(4H，m)，1.92-1.70(2H，m)，1.30(3H，s).
13C?NMR(CDCl
3，75MHz)：δ200.26，190.99，172.58，169.52，159.79，150.79，145.75，130.33，129.60，126.99，120.96，113.92，89.07，67.24，65.84，65.33，61.13，60.48，55.27，48.96，47.21，41.50，39.65，17.92，11.87.
Compound 4:13-chloro-3, the 15-dicarbonyl gibberellic acid
Preparation process is as follows:
13-chloro-3, the 15-dicarbonyl gibberellic acid is to methoxy benzyl ester (2.48g, 5mmol) be dissolved in (15mL) in the methylene dichloride, add trifluoracetic acid (1.5mL under the stirring at room, 20mmol) reaction is 5-9 hour, decompression is steamed to desolventize down and is obtained light yellow solid product crude product, gets white crystals 1.69g through silica gel column chromatography (n-hexane/ethyl acetate=4/1) purifying, yield 90%.
Ultimate analysis (C
19H
17ClO
6)
Calculated value (%): C, 60.57; H, 4.55; Cl, 9.41;
Measured value (%): C, 60.15; H, 5.03; Cl, 9.78.
1H?NMR(CDCl
3，300MHz)：δ7.12(1H，d，J＝9.6Hz)，6.03(1H，s)，5.89(1H，d，J＝9.6Hz)，5.69(1H，s)，3.42(1H，d，J＝10.5Hz)，2.69(1H，d，J＝10.5Hz)，2.61(1H，d，J＝11.7Hz)，2.48(1H，dd，J＝7.8，13.5Hz)，2.37(1H，dd，J＝11.7Hz)，2.22-1.61(4H，m)，1.16(3H，s).
13C?NMR(CDCl
3，75MHz)：δ202.16，193.17，174.65，173.17，152.39，147.91，130.68，122.33，90.92，67.38，66.92，62.69，61.80，50.40，48.55，42.66，41.21，19.29，13.04.
Preparation general rule with general structure (I) and compound (II)
13-chloro-3,15-dicarbonyl gibberellic acid (376.8mg, 1mmol) in acetonitrile, ethanol, acetone, tetrahydrofuran (THF), 1, (1-5mL) corresponding mineral alkali of adding or organic amine or inorganic salt (1mmol) reacted 10-50 minute down in zero degree in the 4-dioxane equal solvent, and steaming desolventizes and obtains solid product under the decompression.
Ultimate analysis C
25H
32ClNO
6
Calculated value (%): C, 62.82; H, 6.75; N, 2.93
Measured value (%): C, 63.17; H, 6.30; N, 2.76
1H?NMR(CDCl
3，300MHz)：δ7.16(1H，d，J＝9.6Hz)，6.09(1H，s)，6.00(1H，d，J＝9.6Hz)，5.75(1H，s)，3.63(1H，d，J＝10.5Hz)，3.15-2.86(6H，m)，2.77(1H，d，J＝10.5Hz)，2.72(2H，s)，2.62(1H，dd，J＝8.1，13.8Hz)，2.41-2.01(3H，m)，1.89-1.75(1H，m)，1.39(3H，s)，1.21(9H，t，J＝7.2Hz).
13C?NMR(CDCl
3，75MHz)：δ201.53，192.38，174.60，173.75，152.19，146.51，129.35，118.82，89.82，66.61，66.09，62.75，60.66，51.94，47.32，44.83，42.17，40.10，18.12，11.93，8.47.
The antitumour activity experiment of prepared compound
Prepared compound is according to the half-inhibition concentration (IC of MTT method to HL-60 (leukemia), SMMC-7721 (liver cancer), A-549 six kinds of tumor cell lines such as (lung cancer)
50) measurement result shows: the IC of all compounds
50=0.5～41.3 μ g/mL all have the stronger restraining effect to tumour cell.
Claims (9)
1. compound with following general structural formula (I) and general formula (II), name is called: 13-chloro-3,15-dicarbonyl gibberellic acid and salt thereof,
2. the preparation method with general structure (I) and compound (II) as claimed in claim 1 is characterized in that:
A. with gibberic acid GA
3Be starting raw material, under alkaline condition, in polar solvent, add that then 0～50 ℃ of reaction, 7 in carbon esterification takes place generates compound (1) to the methoxyl group benzyl chloride;
B. with 3,13-dihydroxyl gibberellic acid ester (1) is a raw material, utilizes oxygenant and co-oxidants in organic solvent, and oxidation allylic carbon 15 generates 3,13,15-trihydroxy-gibberellic acid ester compound (2) for hydroxyl under the room temperature;
C. with 3,13,15-trihydroxy-gibberellic acid ester (2) is a raw material, in low polar solvent, subzero 40～78 ℃ low temperature adds oxalyl chloride or the methyl-sulphoxide of suitable proportion and the oxygenant that sulfur oxychloride forms of methyl-sulphoxide and suitable proportion down, and 3 and 15 hydroxyls of oxidation are 3, in the time of the 15-dicarbapentaborane, 13 chlorination take place generate 13-chloro-3,15-dicarbonyl gibberellic acid ester cpds (3);
D. with 13-chloro-3,15-dicarbonyl gibberellic acid ester (3) is a raw material, and zero degree generates 13-chloro-3,15-dicarbonyl gibberellic acid compound (4) with acid-respons under room temperature in organic solvent;
E. with 13-chloro-3,15-dicarbonyl gibberellic acid compound (4) is a raw material, and mineral alkali and organic bases and amino acid ester prepared in reaction have general structure (I) and compound (II) in organic solvent with accordingly.
3. preparation method according to claim 2 is characterized in that a step solvent for use is methyl-sulphoxide, N, and dinethylformamide, acetonitrile, ethanol, acetone, tetrahydrofuran (THF) or 1,4-dioxane, consumption are 5～100mL solvent/g substrate; Used alkali is cesium carbonate, salt of wormwood, yellow soda ash, sodium hydroxide, pyridine, imidazoles or DMAP.
4. preparation method according to claim 2 is characterized in that the used organic solvent of b step is methylene dichloride, N, dinethylformamide, acetonitrile, tetrahydrofuran (THF) or 1,4-dioxane; Used oxygenant is cuprous iodide, Cobaltous diacetate [Co (OAc)
2], tin anhydride or manganese acetate [Mn (OAc)
3], co-oxidants is peroxy tert-butyl alcohol or hydrogen peroxide.
5. preparation method according to claim 2 is characterized in that the low polar solvent that the c step is adopted is benzene, toluene, methylene dichloride, trichloromethane, normal hexane, hexanaphthene or sherwood oil, and consumption is 10～100mL solvent/g substrate; Compounds with methyl-sulphoxide and oxalyl chloride or methyl-sulphoxide and sulfur oxychloride formation under-78 ℃ to-40 ℃ are oxygenant, add and wait upon the oxidation substrates afterreaction 5-30 minute, and adding triethylamine again reacted 5-30 minute; Each compound amount by mole is: substrate/methyl-sulphoxide/oxalyl chloride or sulfur oxychloride/triethylamine=1/2～50/2～6/4～100.
6. preparation method according to claim 2 is characterized in that the used organic solvent of steps d is methylene dichloride, acetonitrile, tetrahydrofuran (THF) or 1, the 4-dioxane; Used acid is hydrochloric acid, trifluoracetic acid, formic acid or tosic acid; The consumption of each compound is in molar ratio in the reaction: substrate/acid=1/2～50/, solvent load are 10～100mL/mmol substrate.
7. preparation method according to claim 2 is characterized in that the used organic solvent of step e is tetrahydrofuran (THF), acetone, acetonitrile, N, dinethylformamide, methylene dichloride or ethanol.
8. preparation method according to claim 2 is characterized in that the used mineral alkali of step e is the carbonate or the oxyhydroxide of alkalies and alkaline earth, ammoniacal liquor; Organic amine and amino acid ester comprise R in the formula
1Be hydrogen, sodium, potassium, lithium, calcium, magnesium, barium, amino (NH
4) wait mineral alkali; R
2Be methylamine, benzylamine, butylamine, TERTIARY BUTYL AMINE, glycine methyl ester, amino acid esters such as phenylalanine methyl ester, Pyrrolidine, hexahydropyridine, morphine quinoline, piperazine, imidazoles, pyridine, pyrroles, organic basess such as Sodium Glutamate; The consumption of each compound is in molar ratio in the reaction: substrate/mineral alkali or organic bases=1/0.9-1.1, solvent load are 1～10mL/mmol substrate.
9. as claimed in claim 1 have an application aspect preparation treatment cancer drug of general structure (I) and compound (II).
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108276370A (en) * | 2018-02-09 | 2018-07-13 | 云南大学 | 17- alkylthio group gibberellic acid ester type compounds and preparation method thereof and anticancer usage |
| CN108276369A (en) * | 2018-02-09 | 2018-07-13 | 云南大学 | Mostly thio gibberellic acid ester type compound and preparation method thereof and anticancer usage |
-
2010
- 2010-02-02 CN CN201010104230A patent/CN101830873A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108276370A (en) * | 2018-02-09 | 2018-07-13 | 云南大学 | 17- alkylthio group gibberellic acid ester type compounds and preparation method thereof and anticancer usage |
| CN108276369A (en) * | 2018-02-09 | 2018-07-13 | 云南大学 | Mostly thio gibberellic acid ester type compound and preparation method thereof and anticancer usage |
| CN108276370B (en) * | 2018-02-09 | 2022-02-15 | 云南大学 | 17-alkylthio gibberellin ester compound, preparation method and anti-tumor application thereof |
| CN108276369B (en) * | 2018-02-09 | 2022-04-01 | 云南大学 | Polythiagibberellic acid ester compound, preparation method and anti-tumor application thereof |
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Application publication date: 20100915 |