CN103819466A - Synthetic method of Cephalandole A as drug active compound - Google Patents
Synthetic method of Cephalandole A as drug active compound Download PDFInfo
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- CN103819466A CN103819466A CN201410039008.9A CN201410039008A CN103819466A CN 103819466 A CN103819466 A CN 103819466A CN 201410039008 A CN201410039008 A CN 201410039008A CN 103819466 A CN103819466 A CN 103819466A
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention relates to a synthetic method of Cephalandole as a drug active compound A. The synthetic method comprises the steps: in the presence of acid, carrying out a reaction on benzoxazole and (1H-benzpyrole-3-group) formate carbonyl in an organic solvent to obtain the Cephalandole A as the drug active compound. With the adoption of the synthetic method, as the purity and the yield of a product are high, and the temperature is proper, a new reaction method is provided to chemical synthesis of the compound, and the synthetic method has good research values and potentials.
Description
Technical field
The invention provides a kind of synthetic method of pharmaceutical active compounds, more particularly, provide the chemical synthesis process of a kind of pharmaceutical active compounds Cephalandole A, belong to the synthetic field of heterogeneous ring compound.
Background technology
Pharmaceutical active compounds Cephalandoles A is a kind of natural product, by people (" Indole alkaloids from cephalanceropsis gracilis " such as Pei-Lin Wu at first, J.Nat.Prod., 2006, 69, 1467-1470) from Taiwanese orchidCephalanceropsis gracilis (Orchidaceae), separate and obtain, separation method is mainly methanol extraction, concentrated, then use hexane, trichloromethane and ethyl acetate extraction, trichloromethane component is crossed to column chromatography gradient elution, can obtain this natural product, author has also investigated its cytotoxicity for human cancer cell strain.
In this article, author thinks that this compound has following structural formula:
But by more advanced analysis means, Leo Gross (" Organic structure determination using atomicresolution sacnning probe microscopy ", Nature Chem.2010,2,821-825; " Recent advances in submolecular resolution with scanning probe microcopy ", Nature Chem.2011,3,273-277), Jeffrey J.Mason (" Synthesis studies of Cephalandole alkaloidsand the revised structure of Cephalandole A ", J.Nat.Prod., 2008,71,1447-1450) etc. people has corrected said structure, thinks that the correct structural formula of Cephalandole A should be following formula:
The formalized formal name used at school of this compound is called 3-(1H-indol-3-yl) benzo [1, 4] oxazine-2-ketone, it belongs to plant biological alkaloid substance, there is pharmacologically active and biologic activity, therefore people have developed chemical synthesis process, the people (" Synthesis studies of Cephalandole alkaloids and the revised structure of Cephalandole A " such as such as Jeffrey J.Mason, J.Nat.Prod., 2008, 71, 1447-1450) method of being prepared as follows being disclosed: makes indoles-3-oxalic dialdehyde ethyl ester and 1-amino-phenol back flow reaction in dry DMF, solvent removed in vacuo, twice of ethyl alcohol recrystallization, obtain Cephalandole A.
As mentioned above, although have the method for preparing pharmaceutical active compounds Cephalandole A in prior art, method is little, for the novel synthesis of this material, still exists and continues to explore and improved needs.Therefore, still need the completely new approach of synthetic this material of exploitation, to enrich its synthesis path and route.
Summary of the invention
In order to seek the brand-new and simple method of synthetic Cephalandole A, the inventor conducts in-depth research, and is paying after a large amount of creative works, thereby is completing the present invention.
Particularly, technical scheme of the present invention and content relate to the synthetic method of CephalandoleA shown in following formula (I), describedly synthetic be legally: under acid exists, in organic solvent, benzoxazole shown in formula (II) reacts with (1H-indol-3-yl) shown in formula (III) carbonyl formic acid, thereby obtains the Cephalandole A of described formula (I):
In described synthetic method of the present invention, described acid is hydrochloric acid, acetic acid, Phenylsulfonic acid, p-nitrobenzoic acid, trifluoromethanesulfonic acid, tosic acid, p-nitrophenyl sulfonic acid, phenylformic acid or trifluoroacetic acid, most preferably is trifluoroacetic acid.
In described synthetic method of the present invention, the mol ratio of formula (II) compound and formula (III) compound is 1:1-3, for example, can be 1:1,1.5,1:2,1:2.5 or 1:3.
In described synthetic method of the present invention, formula (II) compound and sour mol ratio are 1:1-3, for example, can be 1:1,1.5,1:2,1:2.5 or 1:3.
In described synthetic method of the present invention, temperature of reaction is 60-100 ℃, for example can be to indefiniteness 60 ℃, 70 ℃, 80 ℃, 90 ℃ or 100 ℃.
In described synthetic method of the present invention, described organic solvent is methyl alcohol, ethanol, n-propyl alcohol, tetrahydrofuran (THF) (THF), polyoxyethylene glycol, hexanaphthene, ethyl acetate, toluene, 1,4-dioxane, acetonitrile, dimethyl sulfoxide (DMSO) (DMSO), dimethyl formamide (DMF), 2-methyltetrahydrofuran, be preferably ethanol, tetrahydrofuran (THF) or 1,4-dioxane, most preferably is ethanol.
In described synthetic method of the present invention, reaction times there is no special restriction, for example can how much determine the suitable reaction times by the residual quantity of liquid chromatography or TLC detection raw material, it typically is 12-24 hour, is indefiniteness for example 12 hours, 15 hours, 18 hours, 20 hours, 22 hours or 24 hours.
In described synthetic method of the present invention, reaction atmosphere can be air atmosphere, oxygen atmosphere or nitrogen atmosphere, is preferably air atmosphere.
In described synthetic method of the present invention, aftertreatment after reaction finishes can adopt any known conventional processing means in organic synthesis field, such as, any processing means in crystallization, recrystallization, column chromatography purification, extraction etc. or the combination of multiple processing means.As a kind of exemplary aftertreatment means, for example, can be: after completion of the reaction, reaction system is cooled to room temperature, separate out solid, then filter with suction funnel, by alcohol flushing 2-5 time of gained solid, vacuum-drying, obtains target product formula (I) compound.
In sum, the present invention reacts with (1H-indol-3-yl) carbonyl formic acid by benzoazole compounds, thereby has obtained natural product Cephalandole A.Product purity and productive rate that described synthetic method obtains are higher, and aftertreatment is simple, and temperature of reaction is lower, for the chemosynthesis of this natural product provides new response path, have good researching value and potentiality.
Embodiment
Below by specific embodiment, the present invention is described in detail; but the purposes of these exemplary embodiments and object are only used for exemplifying the present invention; not real protection scope of the present invention is formed to any type of any restriction, more non-protection scope of the present invention is confined to this.
Embodiment 1
Benzoxazole (20mmol, 2.38g) and (1H-indol-3-yl) carbonyl formic acid (20mmol, 3.78g) are fully mixed, then add trifluoroacetic acid (20mmol, 2.28g), then add the ethanol of 40mL, at 70 ℃, react 24h.After reaction finishes, reaction system is cooled to room temperature, separates out solid, then filter with suction funnel, by alcohol flushing 3 times of gained solid, vacuum-drying, obtain 4.653g target product Cephalandole A, productive rate 88.8%, purity is 96.9% (HPLC).
Embodiment 2
Benzoxazole (20mmol, 2.38g) and (1H-indol-3-yl) carbonyl formic acid (40mmol, 7.56g) are fully mixed, then add trifluoroacetic acid (40mmol, 4.56g), then add the ethanol of 50mL, at 80 ℃, react 20h.After reaction finishes, reaction system is cooled to room temperature, separates out solid, then filter with suction funnel, by alcohol flushing 4 times of gained solid, vacuum-drying, obtain 4.690g target product Cephalandole A, productive rate 89.5%, purity is 97.2% (HPLC).
Embodiment 3
Benzoxazole (20mmol, 2.38g) and (1H-indol-3-yl) carbonyl formic acid (60mmol, 11.34g) are fully mixed, then add trifluoroacetic acid (60mmol, 6.84g), then add the ethanol of 60mL, at 100 ℃, react 14h.After reaction finishes, reaction system is cooled to room temperature, separates out solid, then filter with suction funnel, by alcohol flushing 5 times of gained solid, vacuum-drying, obtain 4.616g target product Cephalandole A, productive rate 88.1%, purity is 97.8% (HPLC).
Embodiment 4
Benzoxazole (20mmol, 2.38g) and (1H-indol-3-yl) carbonyl formic acid (30mmol, 5.67g) are fully mixed, then add trifluoroacetic acid (50mmol, 5.7g), then add the ethanol of 55mL, at 90 ℃, react 18h.After reaction finishes, reaction system is cooled to room temperature, separates out solid, then filter with suction funnel, by alcohol flushing 3 times of gained solid, vacuum-drying, obtain 4.637g target product Cephalandole A, productive rate 88.5%, purity is 96.9% (HPLC).
Embodiment 5
Benzoxazole (20mmol, 2.38g) and (1H-indol-3-yl) carbonyl formic acid (50mmol, 9.45g) are fully mixed, then add trifluoroacetic acid (20mmol, 2.28g), then add the ethanol of 65mL, at 80 ℃, react 15h.After reaction finishes, reaction system is cooled to room temperature, separates out solid, then filter with suction funnel, by alcohol flushing 4 times of gained solid, vacuum-drying, obtain 4.559g target product Cephalandole A, productive rate 87.0%, purity is 96.5% (HPLC).
Embodiment 6
Benzoxazole (20mmol, 2.38g) and (1H-indol-3-yl) carbonyl formic acid (30mmol, 5.67g) are fully mixed, then add trifluoroacetic acid (60mmol, 6.84g), then add the ethanol of 45mL, at 60 ℃, react 24h.After reaction finishes, reaction system is cooled to room temperature, separates out solid, then filter with suction funnel, by alcohol flushing 5 times of gained solid, vacuum-drying, obtain 4.637g target product Cephalandole A, productive rate 88.5%, purity is 98.2% (HPLC).
Embodiment 7
Benzoxazole (20mmol, 2.38g) and (1H-indol-3-yl) carbonyl formic acid (50mmol, 9.45g) are fully mixed, then add trifluoroacetic acid (30mmol, 3.42g), then add the ethanol of 50mL, at 70 ℃, react 18h.After reaction finishes, reaction system is cooled to room temperature, separates out solid, then filter with suction funnel, by alcohol flushing 5 times of gained solid, vacuum-drying, obtain 4.595g target product Cephalandole A, productive rate 87.7%, purity is 98.5% (HPLC).
Embodiment 8-14
Except the trifluoroacetic acid using respectively in salt acid substitution embodiment 1-7, all the other conditions are all identical, carried out embodiment 8-14.
Embodiment 15-21
Except using respectively acetic acid to replace the trifluoroacetic acid in embodiment 1-11, all the other conditions are all identical, carried out embodiment 15-21.
Embodiment 22-28
Except using respectively Phenylsulfonic acid to replace the trifluoroacetic acid in embodiment 1-11, all the other conditions are all identical, carried out embodiment 22-28.
Embodiment 29-35
Except using respectively p-nitrobenzoic acid to replace the trifluoroacetic acid in embodiment 1-11, all the other conditions are all identical, carried out embodiment 29-35.
Embodiment 36-42
Except using respectively trifluoromethanesulfonic acid to replace the trifluoroacetic acid in embodiment 1-11, all the other conditions are all identical, carried out embodiment 36-42.
Embodiment 43-49
Except using respectively tosic acid to replace the trifluoroacetic acid in embodiment 1-11, all the other conditions are all identical, carried out embodiment 43-49.
Embodiment 50-56
Except using respectively p-nitrophenyl sulfonic acid to replace the trifluoroacetic acid in embodiment 1-11, all the other conditions are all identical, carried out embodiment 50-56.
Embodiment 57-63
Except using respectively phenylformic acid to replace the trifluoroacetic acid in embodiment 1-11, all the other conditions are all identical, carried out embodiment 57-63.
The phase product yield of embodiment 8-63 products therefrom is as shown in the table:
Embodiment 64
Except the ethanol in embodiment 1 being replaced with respectively other following solvent, to have implemented embodiment 64 with the same way of embodiment 1, thereby investigate the impact of solvent for reaction, the results are shown in following table.
NR: represent not detect
When on using, in table, solvent is distinguished the ethanol in alternative embodiment 2-7, with in upper table, have identical rule, be n-propyl alcohol, methyl alcohol, tetrahydrofuran (THF), ethyl acetate, 1,4-dioxane has relatively high products collection efficiency (but all lower than at least 7 percentage points of ethanol), and ethanol has optimum reaction effect to this reaction as can be seen here.
Embodiment 65-66
In the time that reaction atmosphere is replaced with respectively to nitrogen atmosphere and oxygen atmosphere, to have carried out embodiment 65-66 with the same way of embodiment 1, result is as follows.
In the time that the reaction atmosphere of embodiment 2-7 is replaced with respectively to nitrogen atmosphere and oxygen atmosphere, find that the productive rate of corresponding product all reduces 6-10 percentage point.
Fusing point and the nuclear magnetic resonance data of the natural product Cephalandole A of above-mentioned all embodiment gained are as follows:
Fusing point: 238-239 ℃;
Nucleus magnetic resonance:
1h NMR (500MHz, DMSO-d
6) δ 12.02 (s, 1H), 8.74-8.77 (m, 1H), 8.71 (s, 1H), 7.86 (d, J=8.0Hz, 1H), 7.44-7.56 (m, 2H), 7.38-7.41 (m, 2H), 7.24-7.30 (m, 2H);
13C?NMR(125MHz,DMSO-d
6)δ152.0,147.9,144.8,136.6,133.7,131.9,128.6,127.7,126.0,125.3,123.0,122.8,121.5,115.9,112.2,110.6。
In sum, can clearly be found out by above-mentioned all embodiment, in the time adopting method of the present invention, can obtain described pharmaceutical active compounds Cephalandole A with (1H-indol-3-yl) carbonyl formic acid by benzoazole compounds, and productive rate and the purity of product are high, there is good industrial application potentiality and scientific research and be worth.
The purposes that should be appreciated that these embodiment only limits the scope of the invention for the present invention being described but not being intended to.In addition; also should understand; after having read technology contents of the present invention, those skilled in the art can make various changes, modification and/or modification to the present invention, within these all equivalent form of values fall within the protection domain that the application's appended claims limits equally.
Claims (9)
1. the synthetic method of (I) pharmaceutical active compounds Cephalandole A, described chemical synthesis process is: under acid exists, in organic solvent, benzoxazole reacts with (1H-indol-3-yl) carbonyl formic acid, thereby obtains described Cephalandole A:
2. synthetic method as claimed in claim 1, is characterized in that: described acid is hydrochloric acid, acetic acid, Phenylsulfonic acid, p-nitrobenzoic acid, trifluoromethanesulfonic acid, tosic acid, p-nitrophenyl sulfonic acid, phenylformic acid or trifluoroacetic acid, most preferably is trifluoroacetic acid.
3. synthetic method as claimed in claim 1 or 2, is characterized in that: the mol ratio of formula (II) compound and formula (III) compound is 1:1-3.
4. the synthetic method as described in claim 1-3 any one, is characterized in that: formula (II) compound and sour mol ratio are 1:1-3.
5. the synthetic method as described in claim 1-4 any one, it is characterized in that: described organic solvent is methyl alcohol, ethanol, n-propyl alcohol, tetrahydrofuran (THF) (THF), polyoxyethylene glycol, hexanaphthene, ethyl acetate, toluene, 1,4-dioxane, acetonitrile, dimethyl sulfoxide (DMSO) (DMSO), dimethyl formamide (DMF), 2-methyltetrahydrofuran, be preferably ethanol, tetrahydrofuran (THF) or 1,4-dioxane, most preferably is ethanol.
6. the synthetic method as described in claim 1-5 any one, is characterized in that: temperature of reaction is 60-100 ℃.
7. the synthetic method as described in claim 1-6 any one, is characterized in that: the reaction times is 12-24 hour.
8. the synthetic method as described in claim 1-7 any one, is characterized in that: reaction atmosphere is air atmosphere, oxygen atmosphere or nitrogen atmosphere, is preferably air atmosphere.
9. the synthetic method as described in claim 1-8 any one, it is characterized in that: the aftertreatment after reaction finishes is: after completion of the reaction, reaction system is cooled to room temperature, separate out solid, then filter with suction funnel, by alcohol flushing 2-5 time of gained solid, vacuum-drying, obtains target product formula (I) compound.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1886403A (en) * | 2003-09-29 | 2006-12-27 | 阳智化学有限公司 | Use of a compound of formula (i) as an inhibitor of aromatase for therapeutic purposes and compounds of formula (1) thereas |
| WO2008131134A1 (en) * | 2007-04-17 | 2008-10-30 | Cylene Pharmaceuticals, Inc. | Hydrazide compounds and uses thereof |
| WO2009150144A1 (en) * | 2008-06-10 | 2009-12-17 | Inovacia Ab | New gpr119modulators |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1886403A (en) * | 2003-09-29 | 2006-12-27 | 阳智化学有限公司 | Use of a compound of formula (i) as an inhibitor of aromatase for therapeutic purposes and compounds of formula (1) thereas |
| WO2008131134A1 (en) * | 2007-04-17 | 2008-10-30 | Cylene Pharmaceuticals, Inc. | Hydrazide compounds and uses thereof |
| WO2009150144A1 (en) * | 2008-06-10 | 2009-12-17 | Inovacia Ab | New gpr119modulators |
Non-Patent Citations (4)
| Title |
|---|
| FREDERIC BRUYNEEL ET AL.: "Regioselective synthesis of 3-Hydroxyorthanilic acid and its biotransformation into a novel phenoxazinone dye by use of laccase", 《EUROPRAN JOURNAL OF ORGANIC CHEMISTRY》, no. 1, 27 November 2007 (2007-11-27), pages 72 - 79, XP002574313, DOI: doi:10.1002/ejoc.200700865 * |
| HUA WANG ET AL.: "Oxone-mediated oxidative carbon-heteroatom bond cleavage:synthesis of benzoxazinones from benzoxazoles with α-oxocarboxylic acids", 《THE ROYAL SOCIETY OF CHEMISTRY》, vol. 4, no. 17, 20 January 2014 (2014-01-20), pages 8720 - 8722 * |
| JEFFREY J.MASON ET AL.: "synthesis studies of cephalandole alkaloids and the revised structure of cephaladole A", 《JOURNAL OF NATURAL PRODUCTS》, vol. 7, no. 8, 24 July 2008 (2008-07-24), pages 1447 - 1450 * |
| SHINSAKU FUJITA: "Synthesis and Reaction of o-Benzoquinone Monosulfonimides", 《THE JOURNAL OF ORGANIC CHEMISTRY》, vol. 48, no. 2, 31 January 1983 (1983-01-31), pages 177 - 183 * |
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