CN112979665A - Griseofulvin Schmidt rearrangement derivative and preparation method thereof - Google Patents
Griseofulvin Schmidt rearrangement derivative and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of medicinal chemistry and pharmacology, and relates to a griseofulvin Schmidt rearrangement derivative and a preparation method thereof, wherein the griseofulvin derivative has a chemical structural formula shown in a formula (I), and griseofulvin and sodium azide undergo a Schmidt rearrangement reaction to obtain a griseofulvin ring expansion intermediate 1. Then griseofulvin ring expansion intermediates 1 and C1‑6Carrying out acylation reaction on acyl chloride to obtain a corresponding acyl derivative; griseofulvin ring expansion intermediate 1 and benzyl bromide or C1‑6Carrying out substitution reaction on bromohydrocarbon to obtain a corresponding hydrocarbyl derivative; Buchwald-Hartwig reaction of griseofulvin ring-expanding intermediate 1 and iodoaryl to obtain aryl derivative. The griseofulvin Schmidt rearrangement derivative obtained by the invention has stronger anti-tumor activity and can be used for preparing anti-tumor drugs.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry and pharmacology, and particularly relates to a griseofulvin Schmidt rearrangement derivative and a preparation method thereof.
Background
Griseofulvin is a spiro benzofuran-3-one natural product, the structure of which is shown in the following formula, which was first isolated from filamentous fungi by Oxford et al in 1939, is a non-polyene antifungal antibiotic with strong antifungal activity, can strongly inhibit mitosis of fungi, interfere with DNA synthesis of fungi, and can be combined with tubulin to prevent division of fungal cells. At present, griseofulvin is generally used as an antifungal medicament in clinical application. How to use cheap and easily available griseofulvin as a raw material and carry out large structural modification on the griseofulvin by a chemical method to obtain a new compound and develop the application of the compound in the technical fields of pharmaceutical chemistry and pharmacology has important significance.
Disclosure of Invention
In view of the above, the present invention aims to provide griseofulvin schmidt rearrangement derivatives and a preparation method thereof, wherein the structures of the compounds have lactam structures, and the compounds have strong activity of inhibiting tumor cell proliferation, and can be used for preparing antitumor drugs.
The invention provides a griseofulvin Schmidt rearrangement derivative, which has a structure shown in a formula (I):
wherein R represents hydrogen, benzyl, C1-6Hydrocarbyl radical, C1-6Acyl, substituted or unsubstituted aryl.
Further, the griseofulvin schmidt rearrangement derivative has a structure shown in any one of formulas 2a to 2 f:
wherein the content of the first and second substances,
when R is acetyl, the rearrangement derivative is a compound with a structure shown in a formula 2 a;
when R is pivaloyl, the rearrangement derivative is a compound with a structure shown in a formula 2 b;
when R is benzyl, the rearrangement derivative is a compound with a structure shown in a formula 2 c;
when R is 2' -propynyl, the rearrangement derivative is a compound with a structure shown in a formula 2 d;
when R is phenyl, the rearrangement derivative is a compound with a structure shown in a formula 2 e;
when R is 4' -trifluoromethylphenyl, the rearrangement derivative is a compound with a structure shown in a formula 2 f;
the invention also provides a preparation method of the griseofulvin Schmidt rearrangement derivative, which comprises the following steps:
griseofulvin and sodium azide undergo Schmidt rearrangement reaction in a mixed solvent of trifluoroacetic acid and water to obtain a griseofulvin ring expansion intermediate 1. Then, carrying out acylation reaction on the griseofulvin ring-expanding intermediate 1 and acyl chloride in pyridine to obtain a corresponding acyl derivative; griseofulvin ring expansion intermediate 1 and benzyl bromide or C1-6Bromohydrocarbon, in the presence of sodium hydride, carrying out substitution reaction in tetrahydrofuran to obtain corresponding alkyl derivative; Buchwald-Hartwig reaction is carried out on the griseofulvin ring expansion intermediate 1 and iodoaryl in dimethyl sulfoxide under the conditions that cuprous iodide is used as a catalyst and CsF is used as alkali to obtain the aryl derivative.
Wherein the reaction has the formula:
wherein R is1Is selected from C1-6Acyl group of (2), R2Selected from benzyl or C1-6Hydrocarbyl radical, R3One selected from substituted or unsubstituted aryl groups.
Specifically, the preparation method comprises the following steps:
(1) dissolving griseofulvin in a mixed solvent of trifluoroacetic acid and water, adding sodium azide, reacting at room temperature to obtain a first reaction solution, diluting the first reaction solution with an organic solvent, and sequentially washing with saturated sodium bicarbonate, water, saturated salt and MgSO (MgSO) in sequence4Drying, drying under reduced pressure, and performing column chromatography to obtain a light yellow solid which is a griseofulvin ring expansion intermediate 1, wherein the molar ratio of griseofulvin to sodium azide is 1:5, and the volume ratio of trifluoroacetic acid to water is 10:1；
(2) dissolving the light yellow solid in pyridine, adding acyl chloride for reaction to obtain a second reaction solution, diluting the second reaction solution with an organic solvent, and sequentially washing with water, saturated salt solution and MgSO 24Drying, drying under reduced pressure, and performing column chromatography to obtain acyl griseofulvin schmidt rearrangement derivatives, wherein the molar ratio of griseofulvin ring-expanding intermediate 1 to acyl chloride is 1: 2;
(3) dissolving the light yellow solid in tetrahydrofuran, adding sodium hydride in batches in ice bath, then adding bromohydrocarbon for reaction to obtain a third reaction solution, diluting the third reaction solution with an organic solvent, and then sequentially washing with water, saturated salt solution and MgSO4Drying, drying under reduced pressure, and performing column chromatography to obtain a schmidt rearrangement derivative of alkyl griseofulvin, wherein the molar ratio of griseofulvin ring-expanding intermediate 1 to bromohydrocarbon to sodium hydride is 1: 1.5: 2;
(4) dissolving the light yellow solid in dimethyl sulfoxide, sequentially adding cuprous iodide, cesium fluoride and iodoarene for reaction to obtain a fourth reaction solution, diluting the fourth reaction solution with an organic solvent, and sequentially washing with water, saturated salt water and MgSO4Drying, drying under reduced pressure, and performing column chromatography to obtain the aryl griseofulvin Schmidt rearrangement derivative, wherein the molar ratio of griseofulvin ring expansion intermediate 1 to cuprous iodide to cesium fluoride to iodoarene is 1: 0.1: 1: 2;
wherein the acyl chloride is C1-6One of acyl chlorides; the brominated hydrocarbon is C1-6One of hydrocarbyl or benzyl bromide; the iodo-aromatic hydrocarbon is one of substituted or unsubstituted iodo-aromatic hydrocarbons.
Preferably, in the step (1) of the preparation method, the reaction temperature is 25 ℃ and the reaction time is 6 hours.
Preferably, in the step (2) of the preparation method, the reaction temperature is 25 ℃ and the reaction time is 2 h.
Preferably, in the step (3) of the preparation method, the reaction temperature is 25 ℃ and the reaction time is 12 h.
Preferably, in the step (4) of the preparation method, the reaction temperature is 130 ℃ and the reaction time is 12 h.
Preferably, in the above preparation method, the organic solvent is at least one of ethyl acetate, diethyl ether and benzene.
Compared with the prior art, the application provides a new compound griseofulvin Schmidt rearrangement derivative and a preparation method thereof, and the compound can obviously improve the proliferation inhibition effect on tumor cells.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below.
FIG. 1 shows the NMR of the Schmidt rearrangement derivative of acylgriseofulvin (2a) provided in example 2 of the present invention1H, spectrogram;
FIG. 2 shows the NMR of the Schmidt rearrangement derivative of acylgriseofulvin (2a) provided in example 2 of the present invention13And C, spectrum.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
176mg (0.5mmol) of griseofulvin is dissolved in a mixed solvent of trifluoroacetic acid (1mL) and water (0.1mL), and then 65mg (1mmol) of sodium azide is added and reacted at room temperature overnight. TLC detection was complete, quenched with saturated sodium bicarbonate, extracted with ethyl acetate (10mL × 3), the organic phases combined, then washed sequentially with water, washed with saturated brine, spin dried, and column chromatographed (petroleum ether: ethyl acetate: 1) to give 108mg of a pale yellow solid, i.e. griseofulvin ring-expanded intermediate 1 (yield: 68%).
1H NMR(400MHz,CDCl3):δ6.12(s,1H,ArH),5.44(d,J＝1.2Hz,1H,C＝CH),4.02(s,3H,OCH3),3.98(s,3H,OCH3),3.96–3.91(m,1H,CH2),3.54(s,3H,OCH3),3.12(dd,J＝15.0,6.3Hz,1H,CH2),2.55-2.44(m,1H,CH),0.98(d,J＝7.2Hz,3H,CH3).13C NMR(100MHz,CDCl3):δ193.8(C＝O),168.8(C＝ON),168.1(＝COCH3),164.3(ArC),161.1(ArC),157.6(ArC),105.8(＝CC＝O),102.0(ArC),97.2(ArC),92.9(ArC),89.3(OCC＝O),57.0(OCH3),56.3(OCH3),55.9(OCH3),41.2(CH2),38.8(CH),13.0(CH3).HRMS(ESI):m/z calcd for C17H19NO6Cl:368.0901；found:368.0896[M+H]+.
Example 2
37mg (0.1mmol) of griseofulvin ring-expanding intermediate 1 was dissolved in 0.5mL of anhydrous DCM, 50. mu.L of pyridine was added, ice-cooled to 0 ℃ and 200. mu.L of acetyl chloride was added dropwise, and the reaction was carried out for 2 h. The TLC detection reaction was completed, the pH was adjusted to 1 with 1M HCl, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water, saturated sodium bicarbonate, saturated brine, dried by spinning, and subjected to column chromatography (petroleum ether: ethyl acetate ═ 2:1) to obtain 31mg (yield ═ 82%) of a white solid (2 a). Nuclear magnetic resonance of the same1H spectrum is shown in figure 1, nuclear magnetic resonance13The spectrum C is shown in FIG. 2.
1H NMR(400MHz,CDCl3):δ6.11(s,1H,ArH),5.45(s,1H,C＝CH),4.13(m,2H,CH2),4.01(s,3H,OCH3),3.97(s,3H,OCH3),3.63(s,3H,OCH3),2.61(s,3H,CH3),2.59–2.56(m,1H,CH),1.01(d,J＝7.2Hz,3H,CH3).13C NMR(100MHz,CDCl3):δ192.1(C＝O),173.2(C＝O),168.5(C＝ON),168.2(＝COCH3),164.5(ArC),162.4(ArC),157.9(ArC),104.8(＝CC＝O),101.4(ArC),97.2(ArC),92.7(ArC),89.5(OCC＝O),57.0(OCH3),56.4(OCH3),56.4(OCH3),43.2(CH3),40.6(CH2),27.0(CH),13.5(CH3).HRMS(ESI):m/z calcd for C19H21NO7Cl:410.1007；found:410.1001[M+H]+.
Example 3
37mg (0.1mmol) of griseofulvin ring expansion intermediate 1 is dissolved in 0.5mL of anhydrous DCM, 50. mu.L of pyridine is added, ice bath is carried out to 0 ℃, 200. mu.L of pivaloyl chloride is added dropwise, and reaction is carried out for 2 h. The TLC detection reaction was completed, the pH was adjusted to 1 with 1M HCl, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water, saturated sodium bicarbonate, saturated brine, dried by spinning, and subjected to column chromatography (petroleum ether: ethyl acetate ═ 2:1) to obtain 28mg (yield ═ 63%) of a white solid (2 b).
1H NMR(400MHz,CDCl3):δ6.11(s,1H,ArH),5.44(s,1H,C＝CH),4.02(s,3H,OCH3),4.00(m,1H,CH2),3.98(s,3H,OCH3),3.54(s,3H,OCH3),3.12(dd,J＝15.1,6.3Hz,1H,CH2),2.49(m,1H,CH),1.23(m,9H,CH3),0.98(d,J＝7.2Hz,3H,CH3).13C NMR(100MHz,CDCl3):δ193.8(C＝O),189.3(C＝O),168.8(C＝ON),166.5(＝COCH3),164.4(ArC),161.6(ArC),157.7(ArC),105.8(＝CC＝O),102.6(ArC),97.2(ArC),92.9(ArC),89.3(OCC＝O),57.0(OCH3),56.4(OCH3),56.0(OCH3),51.8(CH),41.2(CH2),28.0(CH),27.2(CH3),13.0(CH3).HRMS(ESI):m/z calcd for C22H27NO7Cl:452.1476；found:452.1472[M+H]+.
Example 4
37mg (0.1mmol) of griseofulvin ring-expanding intermediate 1 was dissolved in 0.5mL of anhydrous THF, ice-cooled to 0 deg.C, 5mg (0.2mmol) of NaH was added, after 30min 21mg (0.12mmol) of benzyl bromide was added, and the reaction was allowed to resume at room temperature overnight. TLC detection of the reaction was completed, quenched with saturated ammonium chloride, extracted with ethyl acetate (10mL × 3), and the organic phases were combined, washed sequentially with water, washed with saturated brine, spin-dried, and column chromatographed (petroleum ether: ethyl acetate: 2:1) to give 43mg (yield: 95%) of a white solid (2 c).
1H NMR(400MHz,CDCl3):δ7.38-7.28(m,5H,ArH),6.08(s,1H,ArH),5.59(s,1H,C＝CH),4.32(d,J＝14.6Hz,1H,CH2),4.23(dd,J＝15.4,8.0Hz,1H,CH2),4.00(s,3H,OCH3),3.96(s,3H,OCH3),3.54(s,3H,OCH3),2.96(t,J＝7.7Hz,2H,CH2),2.31(t,J＝7.4Hz,1H,CH),0.71(d,J＝7.3Hz,3H,CH3).13C NMR(100MHz,CDCl3):δ194.2(C＝O),168.9(C＝ON),165.2(＝COCH3),164.3(ArC),159.6(ArC),157.5(ArC),137.3(ArC),128.7(ArC),128.4(ArC),127.6(ArC),105.9(＝CC＝O),102.9(ArC),97.2(ArC),92.5(ArC),89.2(OCC＝O),56.9(OCH3),56.3(OCH3),55.8,(OCH3)51.9(CH2),47.1(CH2),39.1(CH),13.4(CH3).HRMS(ESI):m/z calcd for C24H25NO6Cl:458.1370；found:458.1374[M+H]+.
Example 5
37mg (0.1mmol) of griseofulvin ring-expanded intermediate 1 was dissolved in 0.5mL of anhydrous tetrahydrofuran, ice-cooled to 0 ℃ and 5mg (0.2mmol) of sodium hydride was added, after 30min, 13mg (0.12mmol) of 3-bromopropyne was added, and then the reaction was allowed to return to room temperature overnight. TLC detection reaction is finished, saturated ammonium chloride is used for quenching, ethyl acetate is used for extraction (10mL multiplied by 3), organic phases are combined, then washing by water, washing by saturated salt water, spin drying and column chromatography are carried out (petroleum ether: ethyl acetate is 2:1, R)f0.3) to yield 32mg of white solid (2d) (yield 79%).
1H NMR(400MHz,CDCl3):δ6.12(d,J＝1.4Hz,1H,ArH),5.51(s,1H,C＝CH),4.71(dt,J＝17.4,2.0Hz,1H,CH2),4.33(ddd,J＝15.4,8.0,1.4Hz,1H,CH2),4.02(d,J＝1.4Hz,3H,OCH3),3.98(d,J＝1.4Hz,3H,OCH3),3.53(d,J＝1.3Hz,3H,OCH3),3.24(d,J＝15.4Hz,1H,CH),2.61(m,1H,CH),0.99(dd,J＝7.3,1.3Hz,3H,CH3).13C NMR(100MHz,CDCl3):δ194.2(C＝O),169.0(C＝ON),164.7(＝COCH3),164.4(ArC),160.2(ArC),157.6(ArC),105.8(C＝O),102.4(ArC),97.2(ArC),92.5(ArC),89.3(OCC＝O),78.8(CHC),72.1(CHC),57.0(OCH3),56.4(OCH3),55.9(OCH3),46.9(CH2),39.0(CH2),37.1(CH),13.4(CH3).HRMS(ESI):m/z calcd for C20H21NO6Cl:406.1057；found:406.1060[M+H]+.
Example 6
37mg (0.1mmol) of griseofulvin ring-expanding intermediate 1 was dissolved in 0.5mL of anhydrous dimethylsulfoxide, and 2mg (0.01mmol) of cuprous iodide, 15mg (0.1mmol) of cesium fluoride and 42mg (0.2mmol) of iodobenzene were added to react at 130 ℃ overnight. After the reaction is finished, filtering, diluting the filtrate with ethyl acetate, then washing with water, washing with saturated salt water, spin-drying and column chromatography (petroleum ether: ethyl acetate: 2:1, R)f0.3) to yield 26mg of white solid (2e) (yield 57%).
1H NMR(400MHz,CDCl3):δ7.45-7.33(m,2H,ArH),7.27(s,3H,ArH),6.12(s,1H,ArH),5.62(s,1H,CH2),4.61(dd,J＝15.3,7.9Hz,1H,C＝CH),4.02(s,3H,OCH3),3.98(s,3H,OCH3),3.58(s,3H,OCH3),3.49(d,J＝15.2Hz,1H,CH2),2.75(m,1H,CH),1.01(d,J＝7.3Hz,3H).
13C NMR(100MHz,CDCl3):δ194.0(C＝O),169.0(C＝ON),164.9(＝COCH3),164.4(ArC),160.0(ArC),157.6(ArC),144.3(ArC),129.2(ArC),126.7(ArC),126.3(ArC),105.8(C＝O),103.2(Ar),97.3(ArC),92.6(ArC),89.3(OCC＝O),57.0(OCH3),56.4(OCH3),56.0(OCH3),51.5(CH2),39.7(CH),13.6(CH3).HRMS(ESI):m/z calcd for C23H23NO6Cl:444.1214；found:444.1216[M+H]+.
Example 7
37mg (0.1mmol) of griseofulvin ring-expanding intermediate 1 was dissolved in 0.5mL of anhydrous dimethylsulfoxide, and 2mg (0.01mmol) of cuprous iodide, 15mg (0.1mmol) of cesium fluoride and 42mg (0.2mmol) of p-trifluoromethyliodobenzene were added and reacted at 130 ℃ overnight. After the reaction is finished, filtering, diluting the filtrate with ethyl acetate, then washing with water, washing with saturated salt water, spin-drying and column chromatography (petroleum ether: ethyl acetate: 2:1, R)f0.3) to yield 27mg of white solid (2f) (yield 61%).1H NMR(400MHz,CDCl3):δ7.36-7.28(m,2H,ArH),7.24(d,J＝8.6Hz,2H,ArH),6.12(s,1H,ArH),5.61(s,1H,C＝CH),4.59(dd,J＝15.3,7.8Hz,1H,CH2),4.03(s,3H,OCH3),3.99(s,3H,OCH3),3.59(s,3H,OCH3),3.49(d,J＝15.2Hz,1H,CH2),2.74(m,1H,CH),1.02(d,J＝7.3Hz,3H,CH3).13C NMR(100MHz,CDCl3):δ193.8(C＝O),168.9(C＝ON),165.1(＝COCH3),164.5(ArO),160.4(ArO),157.7(ArO),147.2(Ar),142.7(Ar),129.9(Ar),127.7(Ar),121.8(CF3),105.7(＝CC＝O),102.8(Ar),97.3(Ar),92.4(Ar),89.3(OCC＝O),57.0(OCH3),56.4(OCH3),56.0(OCH3),51.5(CH2),39.7(CH),13.6(CH3).HRMS(ESI):m/z calcd for C24H22NO6F3Cl:512.1088；found:512.1090[M+H]+.
In order to better understand the essence of the invention, the pharmacological experiment results of the inhibition effect of griseofulvin schmidt rearrangement derivatives on the growth of six tumor cell strains are respectively used for explaining the new application of the griseofulvin schmidt rearrangement derivatives in the research field of antitumor drugs. The pharmacological examples give partial activity data for representative compounds. It must be noted that the pharmacological examples of the invention are intended to illustrate the invention and not to limit it. Simple modifications of the invention in accordance with its spirit fall within the scope of the claimed invention.
Drug experimental example 1: test of cytotoxic Activity of Compounds 2a to 2f and paclitaxel on human esophageal cancer cell (TE-13)
Human esophageal carcinoma cells TE-13 were cultured in RPMI1640 medium containing 10% fetal bovine serum, 100U/mL penicillin and 100U/mL streptomycin. Cells were plated at 5X 10 per well3Is added to a 96-well plate containing 5% CO at 37 deg.C2For 24 hours in a humidified air incubator.
Drug experimental examples 2 to 6: the compounds 2a to 2f and paclitaxel are tested for the cytotoxic activity against human gastric cancer cells (MGC803), human lung adenocarcinoma cells (A549), human cervical cancer cells (Hela), human colon cancer cells (HCT-116) and human liver cancer cells (HepG 2).
Pharmacological experiments were carried out on the growth inhibitory effect of human gastric cancer cells (MGC803), human lung adenocarcinoma cells (A549), human cervical cancer cells (Hela), human colon cancer cells (HCT-116) and human liver cancer cells (HepG2) by the method shown in pharmaceutical Experimental example 1, and the median Inhibitory Concentration (IC) was calculated50) Specifically, the examples are shown in Table 1.
TABLE 1 cytotoxic Activity test results for Compounds 2 a-2 f and paclitaxel
As can be seen from Table 1, the griseofulvin Schmidt rearrangement derivative provided by the invention has important biological activity, and in vitro cytotoxicity tests on six tumor cells including human gastric cancer cells (MGC803), human esophageal cancer cells (TE-13), human colon cancer cells (HCT-116), human lung adenocarcinoma cells (A549), human cervical cancer cells (Hela) and human liver cancer cells (HepG2) show that: the griseofulvin Schmidt rearrangement derivative with the structure shown in the formula (1) has an inhibiting effect on the growth of tumor cells, and can be possibly developed into a new tumor prevention and treatment drug. From the pharmacological examples, the compounds show stronger cytotoxic activity on the six tumor cells, the cytotoxic activity exceeds or is equivalent to that of positive control taxol, and the compounds have the potential of being developed into antitumor drugs.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (8)
1. A griseofulvin schmidt rearrangement derivative, wherein the griseofulvin schmidt rearrangement derivative has a structure represented by formula (I):
wherein R represents hydrogen, benzyl, C1-6Hydrocarbyl radical, C1-6Acyl, substituted or unsubstituted aryl.
2. The griseofulvin schmidt rearrangement derivative according to claim 1, wherein the griseofulvin schmidt rearrangement derivative has a structure as shown in any one of formulas 2a to 2 f:
3. a preparation method of griseofulvin Schmidt rearrangement derivative is characterized in that the reaction formula of the preparation method is shown as the following formula:
wherein R is1Is selected from C1-6Acyl group of (2), R2Selected from benzyl or C1-6Hydrocarbyl radical, R3One selected from substituted or unsubstituted aryl groups.
The preparation method comprises the following steps:
(1) dissolving griseofulvin in a mixed solvent of trifluoroacetic acid and water, adding sodium azide, reacting at room temperature to obtain a first reaction solution, and reacting the first reaction solution with a solvent containing trifluoroacetic acid and waterDiluting with organic solvent, washing with saturated sodium bicarbonate, water, washing with saturated salt solution, and MgSO4Drying, drying under reduced pressure, and performing column chromatography to obtain a light yellow solid which is a griseofulvin ring expansion intermediate 1, wherein the molar ratio of griseofulvin to sodium azide is 1:5, and the volume ratio of trifluoroacetic acid to water is 10: 1;
(2) dissolving the light yellow solid in pyridine, adding acyl chloride for reaction to obtain a second reaction solution, diluting the second reaction solution with an organic solvent, and sequentially washing with water, saturated salt solution and MgSO 24Drying, drying under reduced pressure, and performing column chromatography to obtain the acyl derivative, wherein the molar ratio of griseofulvin ring expansion intermediate 1 to acyl chloride is 1: 2;
(3) dissolving the light yellow solid in tetrahydrofuran, adding sodium hydride in batches in ice bath, then adding bromohydrocarbon for reaction to obtain a third reaction solution, diluting the third reaction solution with an organic solvent, and then sequentially washing with water, saturated salt solution and MgSO4Drying, drying under reduced pressure, and performing column chromatography to obtain the alkyl derivative, wherein the molar ratio of the griseofulvin ring-expanding intermediate 1 to the bromohydrocarbon to the sodium hydride is 1: 1.5: 2;
(4) dissolving the light yellow solid in dimethyl sulfoxide, sequentially adding cuprous iodide, cesium fluoride and iodoarene for reaction to obtain a fourth reaction solution, diluting the fourth reaction solution with an organic solvent, and sequentially washing with water, saturated salt water and MgSO4Drying, drying under reduced pressure, and performing column chromatography to obtain the aryl derivative, wherein the molar ratio of griseofulvin ring expansion intermediate 1, cuprous iodide, cesium fluoride and aryl iodide is 1: 0.1: 1: 2;
wherein the acyl chloride is C1-6One of acyl chlorides; the brominated hydrocarbon is C1-6One of hydrocarbyl or benzyl bromide; the iodo-aromatic hydrocarbon is one of substituted or unsubstituted iodo-aromatic hydrocarbons.
4. The method according to claim 3, wherein in the step (1), the reaction temperature is 25 ℃ and the reaction time is 6 hours.
5. The method according to claim 3, wherein in the step (2), the reaction temperature is 25 ℃ and the reaction time is 2 hours.
6. The method according to claim 3, wherein in the step (3), the reaction temperature is 25 ℃ and the reaction time is 12 hours.
7. The method according to claim 3, wherein in the step (4), the reaction temperature is 130 ℃ and the reaction time is 12 hours.
8. The method according to claim 3, wherein the organic solvent is at least one of ethyl acetate, diethyl ether and benzene.
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| CN113861144A (en) * | 2021-08-04 | 2021-12-31 | 南通大学 | Griseofulvin ring-opening derivative and preparation method thereof |
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