CN1817859A - Synthesis of tenuazonic acid and iso-tenuazonic acid - Google Patents
Synthesis of tenuazonic acid and iso-tenuazonic acid Download PDFInfo
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- CN1817859A CN1817859A CN 200610038765 CN200610038765A CN1817859A CN 1817859 A CN1817859 A CN 1817859A CN 200610038765 CN200610038765 CN 200610038765 CN 200610038765 A CN200610038765 A CN 200610038765A CN 1817859 A CN1817859 A CN 1817859A
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Abstract
Synthesis of tenuazonic acid and isotenuazonic acid is carried out by taking amino acid as initial material, esterifying by alcohol, neutralizing by sodium alcoholate, acidylating by diketene, cyclizing and acidifying under the existence of sodium alcoholate to obtain final product. It is simple, safe and cheap, has more yield and better quality.
Description
One, technical field
The present invention relates to the manufacturing technology of a kind of tenuazonic acid and NSC 70328, belong to the synthetic technical field of compound, be exclusively used in synthetic tenuazonic acid and NSC 70328.
Two, background technology
(ibid. such as Rosett T., 1957,67:390) with Stickings C.E. (Biochem.J., 1959,72:332) successively find that tenuazonic acid (Tenuazonic acid) has anti-tumor activity, Miller F.A. subsequently, Deng (Nature, 1963,200:1338) find that tenuazonic acid also has faint antiviral activity, the strong victory equals to find that tenuazonic acid and NSC 70328 (Iso-tenuazonic acid) had wide spectrum in 2005, fast, efficiently weeding activity (CN 1644046A, 2005-07-27).Tenuazonic acid and NSC 70328 are a kind of toxin of alternaric bacteria (Alternaria) excretory, have wide biological activity, and its synthetic method is conducted a research has important theoretical meaning and application prospect.
The chemical name of tenuazonic acid is 3-ethanoyl-4-hydroxyl-5-sec-butyl pyrroline-2-one, and structural formula is:
The chemical name of NSC 70328 is 3-ethanoyl-4-hydroxyl-5-isobutyl-pyrroline-2-one, and structural formula is:
(J.Chem.Soc. such as Lacey R.N. in 1954; 1954; 850) delivered the method for a kind of synthetic 3-ethanoyl-4-hydroxyl pyrroline-2-one; starting raw material is the amino acid carbethoxy hydrochloride; through neutralization, amidation, cyclisation and acidifying; synthesize 3 kinds of 4-hydroxyls-3-acetyl pyrrole quinoline-2-ketone, but do not comprised tenuazonic acid and NSC 70328.AebiA. in 1963 etc. (Pharm.ActaHelv., 1963,38:616) synthesized NSC 70328 with reference to the method for Lacey R.N. etc.This method is a raw material with the amino acid carbethoxy hydrochloride, filters after the neutralization, because the salt particle that forms is superfine, filters very difficultly, purifies again after the amidation, makes that the entire synthesis process step is loaded down with trivial details, and total recovery is low, is not suitable for suitability for industrialized production.
Nineteen sixty-five Harris S.A. etc. (J.Med.Chem., 1965,8:478) make starting raw material with amino acid salts, through amidation, acidifying, esterification, cyclisation and acidifying, synthesized tenuazonic acid.But this method has been carried out loaded down with trivial details purification after amidation, and what esterification was used is the gaseous state diazomethane, and diazomethane is very malicious, and blast easily, and security is not good, is not suitable for suitability for industrialized production.
Three, summary of the invention
Technical problem the purpose of this invention is to provide the method for a kind of synthetic tenuazonic acid and NSC 70328, and it is easy inadequately to overcome in the prior art operating process, and security is not good, the scarce limit that product cost is high.Present method is a starting raw material with amino acid, and raw material is easy to get, and 5 steps were reflected in the same reaction vessel carries out continuously, and production unit is required simply, and production process is also easier, safety, and simultaneously, the title compound quality that obtains is good, the yield height, and production cost is low.
Technical scheme the present invention relates to the chemical process of a kind of synthetic tenuazonic acid and NSC 70328, and it comprises 5 step chemical reactions, and carries out continuously in same reaction vessel.
1, reaction equation
In the following formula, when R was sec-butyl, the synthetic product was a tenuazonic acid; When R was isobutyl-, the synthetic product was a NSC 70328.
2, operation steps
1) in the there-necked flask or reactor that thermometer, agitator are housed of drying, add ethanol or methyl alcohol, feed exsiccant HCl or HBr gas, or add sulfuric acid, nitric acid, phosphoric acid, Phenylsulfonic acid, p-methyl benzenesulfonic acid or their mixture, add amino acid again as catalyzer, wherein alcohol, catalyzer and amino acid whose mol ratio are 1～100: 1～20: 1, heating, temperature range is 0～100 ℃, stirs, reaction 0.1～24h places 0～24h;
2) add sodium ethylate or the sodium methylate that is equivalent to 1～2 times of amino acid mole number, stir, reaction 0.1～5h;
3) drip the ketene dimer that is equivalent to 1～1.5 times of amino acid mole number, drip off in 0.1～10h, temperature range is-10～100 ℃;
4) add sodium ethylate or the sodium methylate that is equivalent to the benzene of 1～100 times of amino acid mole number and is equivalent to 1～2 times of amino acid mole number, heating, temperature range is 30～100 ℃, stirs, reaction 0.1～24h places 0～24h;
5) solvent is sloughed in decompression, use water dissolution, and with trichloromethane or methylene dichloride, tetrachloromethane extraction, the layer that deoils, water layer is with dilute sulphuric acid or dilute hydrochloric acid neutralization, extracts anhydrous sodium sulphate or anhydrous magnesium sulfate drying with ethyl acetate or ether, isopropyl ether again;
6) be tenuazonic acid as synthetic, directly boil off solvent, get yellow thick liquid, be tenuazonic acid.As synthetic is NSC 70328, boils off partial solvent, and crystallisation by cooling filters, and gets yellow solid, is NSC 70328.
Beneficial effect the present invention specifically provided a kind of in same reaction vessel the chemical process of the synthetic tenuazonic acid of serialization and NSC 70328; it comprises 5 step chemical reactions; with amino acid is starting raw material, obtains title compound through over-churning, neutralization, acidylate, cyclisation and acidifying.Compare with existing method, the characteristics of patent of the present invention are as follows:
1, the tenuazonic acid that relates to of patent of the present invention and the synthetic method of NSC 70328 are to carry out continuously in same reaction vessel, and intermediate product is without purification, production unit are required simple, operate very easy.
2, the beginning raw material directly use amino acid, raw material is easy to get, production cost is low, production process safety.
3, thin interlinkage lattice spore ketone acid of Chenging and different thin interlinkage lattice spore ketone acid quality are good, the yield height.
Four, Fa Ming specific embodiment
Embodiment one
Add dehydrated alcohol 30mL in thermometer, the agitator 100mL there-necked flask being equipped with of drying, feed exsiccant HCl gas 0.8g (0.022mol), add Isoleucine 2.63g (0.02mol) again, heating refluxes, stir, and reaction 3h, placement is spent the night.The sodium ethylate (new system) that adds 1.5g (0.022mol) stirs, reaction 0.5h.Drip the ketene dimer of 1.85g (0.022mol), drip off in the 1h, temperature is controlled at below 10 ℃ during dropping, then stirring reaction 4h at normal temperatures.Add benzene 20mL, the sodium ethylate (new system) of 1.56g (0.023mol) refluxes, stir, reaction 3h, placement is spent the night, solvent is sloughed in decompression, use the 30mL water dissolution, with ethyl acetate 2 * 10mL extraction, the aqueous solution neutralizes with 10% dilute sulphuric acid, use ethyl acetate 3 * 10mL extraction again, anhydrous sodium sulfate drying boils off solvent, gets yellow thick liquid 3.6g.After testing, the content of tenuazonic acid reaches 89.3%.Calculate by different leucin, yield is 81.2%.
Embodiment two
Add dehydrated alcohol 30mL in thermometer, the agitator 100mL there-necked flask being equipped with of drying, feed exsiccant HCl gas 0.8g (0.022mol), add leucine 2.63g (0.02mol) again, heating refluxes, stir, and reaction 3h, placement is spent the night.The sodium ethylate (new system) that adds 1.5g (0.022mol) stirs, reaction 0.5h.Drip the ketene dimer of 1.85g (0.022mol), drip off in the 1h, temperature is controlled at below 10 ℃ during dropping, then stirring reaction 4h at normal temperatures.Add benzene 20mL, the sodium ethylate (new system) of 1.56g (0.023mol) refluxes, stir, reaction 3h, placement is spent the night, solvent is sloughed in decompression, use the 30mL water dissolution, with ethyl acetate 2 * 10mL extraction, the aqueous solution neutralizes with 10% dilute sulphuric acid, use ethyl acetate 3 * 10mL extraction again, anhydrous sodium sulfate drying boils off the 20mL solvent, and crystallisation by cooling gets faint yellow solid 3.2g.After testing, the content of NSC 70328 reaches 97.5%.Press leucine and calculate, yield is 78.8%.Carry out recrystallization with methyl alcohol, get white needle-like crystals, fusing point is 133.5～134.0 ℃.
Embodiment three
Add dehydrated alcohol 30L in thermometer, the agitator 100L reactor being equipped with of drying, feed exsiccant HCl gas 0.8kg (22mol), add Isoleucine 2.63kg (20mol) again, heating refluxes, stir, and reaction 3h, placement is spent the night.The sodium ethylate (new system) that adds 1.5kg (22mol) stirs, reaction 0.5h.Drip the ketene dimer of 1.85kg (22mol), drip off in the 1h, temperature is controlled at below 10 ℃ during dropping, then stirring reaction 4h at normal temperatures.Add benzene 20L, the sodium ethylate (new system) of 1.56kg (23mol) refluxes, stir, reaction 3h, placement is spent the night, solvent is sloughed in decompression, use the 30L water dissolution, with ethyl acetate 2 * 10L extraction, the aqueous solution neutralizes with 10% dilute sulphuric acid, use ethyl acetate 3 * 10L extraction again, anhydrous sodium sulfate drying boils off solvent, gets yellow thick liquid 3.56kg.After testing, the content of tenuazonic acid reaches 88.7%.Calculate by different leucin, yield is 79.7%.
Embodiment four
Add dehydrated alcohol 30L in thermometer, the agitator 100L reactor being equipped with of drying, feed exsiccant HCl gas 0.8kg (22mol), add leucine 2.63kg (20mol) again, heating refluxes, stir, and reaction 3h, placement is spent the night.The sodium ethylate (new system) that adds 1.5kg (22mol) stirs, reaction 0.5h.Drip the ketene dimer of 1.85kg (22mol), drip off in the 1h, temperature is controlled at below 10 ℃ during dropping, then stirring reaction 4h at normal temperatures.Add benzene 20L, the sodium ethylate (new system) of 1.56kg (23mol) refluxes, stir, reaction 3h, placement is spent the night, solvent is sloughed in decompression, use the 30L water dissolution, with ethyl acetate 2 * 10L extraction, the aqueous solution neutralizes with 10% dilute sulphuric acid, use ethyl acetate 3 * 10L extraction again, anhydrous sodium sulfate drying boils off the 20L solvent, and crystallisation by cooling gets faint yellow solid 3.15kg.After testing, the content of NSC 70328 reaches 97.1%.Press leucine and calculate, yield is 77.2%.Carry out recrystallization with methyl alcohol, get white needle-like crystals, fusing point is 133.1～134.2 ℃.
The characteristics of patent of the present invention are as follows:
1, the tenuazonic acid that relates to of patent of the present invention and the synthetic method of NSC 70328 are to advance continuously in same reaction vessel OK, intermediate product requires simply to operate very easy to production equipment without purification.
2, initiation material is directly used amino acid, and raw material is easy to get, and production cost is low, production process safety.
3, synthetic tenuazonic acid and NSC 70328 quality is good, the yield height.
Claims (2)
1, the method for a kind of synthetic tenuazonic acid and NSC 70328 specifically comprises:
1) in the there-necked flask or reactor that thermometer, agitator are housed of drying, add ethanol or methyl alcohol, feed exsiccant HCl or HBr gas, or add sulfuric acid, nitric acid, phosphoric acid, Phenylsulfonic acid, p-methyl benzenesulfonic acid or their mixture, add amino acid again as catalyzer, wherein alcohol, catalyzer and amino acid whose mol ratio are 1～100: 1～20: 1, heating, temperature range is 0～100 ℃, stirs, reaction 0.1～24h places 0～24h;
2) add sodium ethylate or the sodium methylate that is equivalent to 1～2 times of amino acid mole number, stir, reaction 0.1～5h;
3) drip the ketene dimer that is equivalent to 1～1.5 times of amino acid mole number, drip off in 0.1～10h, temperature range is-10～100 ℃;
4) add sodium ethylate or the sodium methylate that is equivalent to the benzene of 1～100 times of amino acid mole number and is equivalent to 1～2 times of amino acid mole number, heating, temperature range is 30～100 ℃, stirs, reaction 0.1～24h places 0～24h
5) solvent is sloughed in decompression, use water dissolution, and with trichloromethane or methylene dichloride, tetrachloromethane extraction, the layer that deoils, water layer is with dilute sulphuric acid or dilute hydrochloric acid neutralization, extracts anhydrous sodium sulphate or anhydrous magnesium sulfate drying with ethyl acetate or ether, isopropyl ether again;
6) be tenuazonic acid as synthetic, directly boil off solvent, get yellow thick liquid, be tenuazonic acid.As synthetic is NSC 70328, boils off partial solvent, and crystallisation by cooling filters, and gets yellow solid, is NSC 70328.
2, the method for a kind of synthetic tenuazonic acid according to claim 1 and NSC 70328 is characterized in that: above-mentioned 1)～5) respectively go on foot to react and all in same reaction vessel, carry out continuously, intermediate product is without purification.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102516148A (en) * | 2011-11-23 | 2012-06-27 | 华南农业大学 | Half antigen and antigen of tenuazonic acid and preparation method and application thereof |
| CN103787946A (en) * | 2013-12-31 | 2014-05-14 | 华南农业大学 | Isokwas tenuazonowy artificial antigen and antibody as well as preparation method and application thereof |
| CN103922990A (en) * | 2005-09-26 | 2014-07-16 | 南京农业大学 | Method for molecular modification and weed control of biological source compound |
| CN105130871A (en) * | 2015-07-29 | 2015-12-09 | 南京农业大学 | Pyrrolidone sulfur derivatives and their preparation method and application |
| CN105524848A (en) * | 2016-02-02 | 2016-04-27 | 福建农林大学 | Fungus strain for producing substance having antiviral activity and application of fungus strain |
| CN112778188A (en) * | 2021-01-18 | 2021-05-11 | 安徽农业大学 | Preparation method of alternaria tenuifolia keto acid and derivatives thereof |
| CN114009452A (en) * | 2021-11-01 | 2022-02-08 | 新疆农业科学院植物保护研究所 | Application of fermentation broth of alternaria alternata JTF001 in inhibition of germination of seeds of orobanum cucurbitacearum |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH02115162A (en) * | 1988-09-06 | 1990-04-27 | Lonza Ag | 5-alkyltetramic acid and its production |
| KR19990022058A (en) * | 1996-03-27 | 1999-03-25 | 마에다 가쯔노스께 | Ketone derivatives and their medical uses |
| CN1886391A (en) * | 2003-11-28 | 2006-12-27 | 弗·哈夫曼-拉罗切有限公司 | Tetronic and tetramic acids as inhibitors of beta-secrease |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103922990A (en) * | 2005-09-26 | 2014-07-16 | 南京农业大学 | Method for molecular modification and weed control of biological source compound |
| CN102516148A (en) * | 2011-11-23 | 2012-06-27 | 华南农业大学 | Half antigen and antigen of tenuazonic acid and preparation method and application thereof |
| CN103787946A (en) * | 2013-12-31 | 2014-05-14 | 华南农业大学 | Isokwas tenuazonowy artificial antigen and antibody as well as preparation method and application thereof |
| CN103787946B (en) * | 2013-12-31 | 2016-03-02 | 华南农业大学 | NSC 70328 artificial antigen and antibody and its preparation method and application |
| CN105130871A (en) * | 2015-07-29 | 2015-12-09 | 南京农业大学 | Pyrrolidone sulfur derivatives and their preparation method and application |
| CN105130871B (en) * | 2015-07-29 | 2018-11-09 | 南京农业大学 | A kind of sulfur derivatives and its preparation method and application of pyrrolin ketone |
| CN105524848A (en) * | 2016-02-02 | 2016-04-27 | 福建农林大学 | Fungus strain for producing substance having antiviral activity and application of fungus strain |
| CN105524848B (en) * | 2016-02-02 | 2019-06-07 | 福建农林大学 | One plant of fungal bacterial strain for producing antiviral active substance and its application |
| CN112778188A (en) * | 2021-01-18 | 2021-05-11 | 安徽农业大学 | Preparation method of alternaria tenuifolia keto acid and derivatives thereof |
| CN114009452A (en) * | 2021-11-01 | 2022-02-08 | 新疆农业科学院植物保护研究所 | Application of fermentation broth of alternaria alternata JTF001 in inhibition of germination of seeds of orobanum cucurbitacearum |
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