CN110669053A - Zearalenone derivative and synthesis method thereof - Google Patents
Zearalenone derivative and synthesis method thereof Download PDFInfo
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- CN110669053A CN110669053A CN201810708729.2A CN201810708729A CN110669053A CN 110669053 A CN110669053 A CN 110669053A CN 201810708729 A CN201810708729 A CN 201810708729A CN 110669053 A CN110669053 A CN 110669053A
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Abstract
The invention relates to a zearalenone derivative and a synthesis method thereof, belonging to the synthesis technology of compounds, wherein the chemical formula of the derivative is shown as a formula I, and the derivative is synthesized by taking zearalenone as a raw material.
Description
Technical Field
The disclosure relates to a compound synthesis process, in particular to a zearalenone derivative and a synthesis method thereof.
Background
Zearalenone (ZEN, also known as zearalenone, F2 toxin), which is a fungal secondary metabolite produced by zearalenone with an estrogen-like effect, has the chemical name of 6- (10-hydroxy-6-oxy-undecenyl) beta-clavulanate, is mainly present in corn and corn products, and is distributed in wheat, sorghum and rice to a certain extent.
The zearalenone and its derivatives (such as zearalenone, etc.) have strong biological activity of female hormone substances, and have certain reproductive toxicity and teratogenic effect on mammals, for example, ingestion of feed polluted by zearalenone and its derivatives can cause the production of hyperestrogenism, abnormal reproductive function and even death of poultry, especially animals such as pigs, cattle and sheep, etc., and bring great loss to the animal husbandry.
Formula I
One of the zearalenone derivatives is a molecule (ZINC79192430) registered in a ZINC compound database, and whether the zearalenone derivative has a pharmaceutical value is not reported in the literature at present, and a synthesis process thereof is not reported in the related literature or patent.
Disclosure of Invention
According to the blank and the requirement of the field, the invention develops a synthesis method of the zearalenone derivative shown as the formula I, which comprises the following steps:
a compound of formula I:
a derivative of a compound of formula I, wherein the derivative is a pharmaceutically acceptable salt, solvate, tautomer, isomer or deuterated analog thereof.
The synthesis method of the zearalenone derivative shown as the formula I comprises the following steps:
step 1, adding dichloromethane, zearalenone and aluminum chloride into a dry round-bottom flask; argon is filled, and ice bath is carried out;
step 2: acetyl chloride is slowly dropped in, the temperature is slowly raised to 25 ℃, and the reaction is carried out for 12 hours
And step 3: evaporating dichloromethane to dryness under the protection of nitrogen, and adding ice water to quench the reaction;
and 4, step 4: adding ethyl acetate into the reaction system, washing by using HCl and brine in sequence, drying an organic phase by using anhydrous magnesium sulfate, removing a solvent, and drying in vacuum to obtain a compound 2;
and 5: adding the compound 2, 2-hydroxyquinoline-3-formaldehyde, potassium hydroxide and ethanol into another round-bottom flask, stirring for dissolving, heating to 50 ℃, and reacting for 1-5 hours; then the reaction is cooled to room temperature;
step 6: concentrating under reduced pressure, adding ice water, and neutralizing with dilute hydrochloric acid to weak acidity; filtering the precipitate, washing with water, and vacuum drying to obtain compound 4;
and 7: compound 4 was added to an empty round bottom flask, ethanol and hydrochloric acid were added, heated to reflux, reacted for 5h, cooled to room temperature, and the solvent was removed by evaporation under reduced pressure to give the final product (I).
Preferably, the step 1 is that 50ml of dichloromethane is added into a 500ml dry round-bottom flask, and then 25mmol of zearalenone and 50mmol of aluminum chloride are added; argon was introduced into the reaction system and ice-bath was carried out.
Preferably, in the step 4, 200mL of ethyl acetate is added into the reaction system, and the mixture is washed twice by using 50mL of 1M HCl and 50mL of brine respectively, and the organic phase is dried by using anhydrous magnesium sulfate, then the solvent is removed, and the organic phase is dried in vacuum to obtain the compound 2;
preferably, the step 5 is to add 10mmol of compound 2, 12mmol of 2-hydroxyquinoline-3-formaldehyde and 15mmol of potassium hydroxide into a 100mL round-bottom flask, add 30mL of ethanol, stir for dissolution, heat to 50 ℃, react for 3 hours, and then cool the reaction to room temperature;
preferably, the step 6 is concentrating the solution to 10ml under reduced pressure, adding ice water, and neutralizing to weak acidity by using dilute hydrochloric acid; filtering the precipitate, washing with water, and vacuum drying to obtain compound 4;
preferably, the step 7 is: 1mmol of compound 4 was added to an empty round-bottom flask, 10mL of ethanol and 0.5mL of hydrochloric acid were added, heated to reflux, reacted for 5h, cooled to room temperature, and the solvent was evaporated under reduced pressure to give the compound of formula I.
The invention provides a zearalenone derivative and provides a synthetic method with high yield, high purity and simple steps for the zearalenone derivative.
Detailed Description
The synthesis of the present invention is illustrated by the following specific embodiments. The known chemical reagents used in the present invention are commercially available chemical pure reagents unless otherwise specified.
Zearalenone, CAS #17924-92-4, available from Bailingwei science Inc
2-Hydroxyquinoline-3-carbaldehyde, CAS #91301-03-0, available from Shanghai Aladdin Biotech Co., Ltd
EXAMPLE 1 Synthesis of Compound of formula 1
The synthetic route is as follows:
the method comprises the following steps:
step 1: to a 500ml dry round bottom flask was added 50ml dichloromethane followed by addition of 25mmol zearalenone and 50mmol aluminium chloride; argon was introduced into the reaction system and ice-bath was carried out.
Step 2: slowly dripping acetyl chloride, slowly heating to 25 deg.C, reacting for 5-15 hr
And step 3: evaporating dichloromethane to dryness under the protection of nitrogen, and adding ice water to quench the reaction;
and 4, step 4: adding 200mL ethyl acetate into the reaction system, washing twice by using 50mL of 1M HCl and 50mL of saline respectively, drying an organic phase by using anhydrous magnesium sulfate, removing a solvent, and drying in vacuum to obtain a compound 2;
and 5: adding 10mmol of compound 2, 12mmol of 2-hydroxyquinoline-3-formaldehyde and 15mmol of potassium hydroxide into a 100mL round-bottom flask, adding 30mL of ethanol, stirring for dissolving, heating to 50 ℃, reacting for 3 hours, and then cooling to room temperature;
step 6: concentrating under reduced pressure to 10ml, adding ice water, and neutralizing with dilute hydrochloric acid to weak acidity; filtering the precipitate, washing with water, and vacuum drying to obtain compound 4;
and 7: 1mmol of compound 4 was added to an empty round-bottom flask, 10mL of ethanol and 0.5mL of hydrochloric acid were added, heated to reflux, reacted for 5h, cooled to room temperature, and the solvent was evaporated under reduced pressure to give the compound of formula I.
The product detection method comprises the following steps:
the instrument comprises the following steps: the name model of the instrument adopted in nuclear magnetic detection is Bruker 400Hz, and the name model of the instrument used in mass spectrometry is Agilent 6520;
detection result data:
LCMS 516.2(M+H+)。1H NMR(CDCl3，δppm)8.16(d,1H),7.56(d,1H),7.39(dd,1H),7.24(dd,1H),6.40(d,1H),6.34(d,1H),6.30(s,1H),(s,1H),7.01(dd,1H),5.72–5.63(m,1H),5.03–4.95(m,1H),4.10(m,1H),2.90–2.80(m,1H),2.66–2.57(m,1H),2.41–2.29(m,1H),2.26–2.08(d,3H)。
the detection result shows that the obtained chemical formula is C39H29O7N is a compound shown in formula I.
The yield is 21 percent, and the purity is more than 98 percent
Example 2
The synthesis route is the same as example 1, and the steps are as follows:
step 1: to a 500ml dry round bottom flask was added 50ml dichloromethane followed by addition of 25mmol zearalenone and 50mmol aluminium chloride; argon was introduced into the reaction system and ice-bath was carried out.
Step 2: acetyl chloride is slowly dropped in, the temperature is slowly raised to 25 ℃, and the reaction is carried out for 5 hours
And step 3: evaporating dichloromethane to dryness under the protection of nitrogen, and adding ice water to quench the reaction;
and 4, step 4: adding 200mL ethyl acetate into the reaction system, washing twice by using 50mL of 1M HCl and 50mL of saline respectively, drying an organic phase by using anhydrous magnesium sulfate, removing a solvent, and drying in vacuum to obtain a compound 2;
and 5: adding 10mmol of compound 2, 12mmol of 2-hydroxyquinoline-3-formaldehyde and 15mmol of potassium hydroxide into a 100mL round-bottom flask, adding 30mL of ethanol, stirring for dissolving, heating to 50 ℃, reacting for 3 hours, and then cooling to room temperature;
step 6: concentrating under reduced pressure to 10ml, adding ice water, and neutralizing with dilute hydrochloric acid to weak acidity; filtering the precipitate, washing with water, and vacuum drying to obtain compound 4;
and 7: 1mmol of compound 4 was added to an empty round-bottom flask, 10mL of ethanol and 0.5mL of hydrochloric acid were added, heated to reflux, reacted for 5h, cooled to room temperature, and the solvent was evaporated under reduced pressure to give the compound of formula I.
The detection method and results were the same as in example 1.
Example 3.
The synthesis route is the same as example 1, and the steps are as follows:
step 1: to a 50ml dry round bottom flask was added 50ml dichloromethane followed by addition of 25mmol zearalenone and 50mmol aluminium chloride; argon was introduced into the reaction system and ice-bath was carried out.
Step 2: acetyl chloride is slowly dropped in, the temperature is slowly raised to 25 ℃, and the reaction is carried out for 15 hours
And step 3: evaporating dichloromethane to dryness under the protection of nitrogen, and adding ice water to quench the reaction;
and 4, step 4: adding 200mL ethyl acetate into the reaction system, washing twice by using 50mL of 1M HCl and 50mL of saline respectively, drying an organic phase by using anhydrous magnesium sulfate, removing a solvent, and drying in vacuum to obtain a compound 2;
and 5: adding 10mmol of compound 2, 12mmol of 2-hydroxyquinoline-3-formaldehyde and 15mmol of potassium hydroxide into a 100mL round-bottom flask, adding 30mL of ethanol, stirring for dissolving, heating to 50 ℃, reacting for 3 hours, and then cooling to room temperature;
step 6: concentrating under reduced pressure to 10ml, adding ice water, and neutralizing with dilute hydrochloric acid to weak acidity; filtering the precipitate, washing with water, and vacuum drying to obtain compound 4;
and 7: 1mmol of compound 4 was added to an empty round-bottom flask, 10mL of ethanol and 0.5mL of hydrochloric acid were added, heated to reflux, reacted for 5h, cooled to room temperature, and the solvent was evaporated under reduced pressure to give the compound of formula I. The detection method and results were the same as in example 1.
Claims (8)
1. A compound of formula I:
2. a derivative of a compound of formula I as claimed in claim 1, which refers to a pharmaceutically acceptable salt, solvate, tautomer, isomer or deuterated analog thereof.
3. The synthesis method of the compound shown in the formula I comprises the following steps:
the method comprises the following steps:
step 1, adding dichloromethane, zearalenone and aluminum chloride into a dry round-bottom flask; argon is filled, and ice bath is carried out;
step 2: slowly dripping acetyl chloride, slowly heating to 25 ℃, and reacting for 12 hours;
and step 3: evaporating dichloromethane to dryness under the protection of nitrogen, and adding ice water to quench the reaction;
and 4, step 4: adding ethyl acetate into the reaction system, washing by using HCl and brine in sequence, drying an organic phase by using anhydrous magnesium sulfate, removing a solvent, and drying in vacuum to obtain a compound 2;
and 5: adding the compound 2, 2-hydroxyquinoline-3-formaldehyde, potassium hydroxide and ethanol into another round-bottom flask, stirring for dissolving, heating to 50 ℃, and reacting for 1-5 hours; then the reaction is cooled to room temperature;
step 6: concentrating under reduced pressure, adding ice water, and neutralizing with dilute hydrochloric acid to weak acidity; filtering the precipitate, washing with water, and vacuum drying to obtain compound 4;
and 7: compound 4 was added to an empty round bottom flask, ethanol and hydrochloric acid were added, heated to reflux, reacted for 5h, cooled to room temperature, and the solvent was removed by evaporation under reduced pressure to give the final product (I).
4. The synthesis method of claim 3, wherein the step 1 is adding 50ml of dichloromethane to a 500ml dry round bottom flask, then adding 25mmol of zearalenone and 50mmol of aluminum chloride; argon was introduced into the reaction system and ice-bath was carried out.
5. The method of claim 3, wherein the step 4 comprises adding 200mL of ethyl acetate into the reaction system, washing twice with 50mL of 1M HCl and 50mL of brine respectively, drying the organic phase with anhydrous magnesium sulfate, removing the solvent, and vacuum drying to obtain the compound 2.
6. The synthesis method of claim 3, wherein the step 5 is to add 10mmol of compound 2, 12mmol of 2-hydroxyquinoline-3-carbaldehyde and 15mmol of potassium hydroxide into a 100mL round bottom flask, add 30mL of ethanol, stir to dissolve, heat to 50 ℃ for reaction for 3 hours, and then cool the reaction to room temperature.
7. The synthesis method of claim 3, wherein the step 6 is concentrating the solution to 10ml under reduced pressure, adding ice water, and neutralizing to weak acidity by using dilute hydrochloric acid; the precipitate was filtered, washed with water, and dried under vacuum to give compound 4.
8. The method of synthesis of claim 3, said step 7 being: 1mmol of compound 4 was added to an empty round-bottom flask, 10mL of ethanol and 0.5mL of hydrochloric acid were added, heated to reflux, reacted for 5h, cooled to room temperature, and the solvent was evaporated under reduced pressure to give the compound of formula I.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1413117A (en) * | 1999-10-29 | 2003-04-23 | 宝酒造株式会社 | Drugs, drinks or foods |
| CN109280058A (en) * | 2017-07-20 | 2019-01-29 | 中国检验检疫科学研究院 | A kind of medicament of Antiphytoviral |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1413117A (en) * | 1999-10-29 | 2003-04-23 | 宝酒造株式会社 | Drugs, drinks or foods |
| CN109280058A (en) * | 2017-07-20 | 2019-01-29 | 中国检验检疫科学研究院 | A kind of medicament of Antiphytoviral |
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Application publication date: 20200110 |