A method for preparing penicillic acid compound

Abstract

A method for synthesizing a penicillic acid compound, comprising: using aniline and ethoxymethylenemalonate as starting materials, subjecting them to a condensation reaction, a Gould-Jacob reaction to form a quinoline mother ring, and then undergoing bromination and a Suzuki reaction to obtain 2-(1-(tert-butyloxycarbonyl)-1 H The intermediate of ethyl 4-chloroquinoline-3-carboxylate is prepared by hydrolysis to obtain penicinoline acid.

Description

Technical Field

[0001] The invention belongs to the field of chemical synthesis, and specifically relates to a new method for synthesizing a penicillic acid compound shown in formula I. Background Art

[0002] The document Shao CL, Wang CY, Gu YC, et al. Bio. & Med. Chem. Let., 2010, 20(11): 3284-3286 discloses the structure and insecticidal activity of the active natural product penicinoline.

[0003]

[0004] Chinese patent CN 2009100183228 discloses penicinoline as shown below as an insecticide.

[0005] .

[0006] Dong-Cheol Kim, Hee-Suk Lee, Wonmin Ko, Dong-Sung Lee, Jae Hak Sohn, Joung Han Yim, Youn-Chul Kim, Hyuncheol Oh. Molecules 2014, 19 , 18073-18089. The anti-inflammatory and immunomodulatory activities of penicillic acid compounds are disclosed.

[0007] In view of the unique chemical structure and physiological activity of the active natural product penicinoline, it is of great significance to carry out in-depth structural optimization and pharmacodynamic research. At present, this compound can only be extracted from natural products, but the existing methods are cumbersome, complex, long and have very low yields.

[0008] In order to meet the needs of industrialization, the present invention is committed to developing a method for preparing a compound of formula I with high yield and purity and low cost. The present invention uses aniline ethoxy methylene malonate as a starting material, undergoes condensation reaction, Gould-Jacobs reaction to form a quinoline mother ring, and then undergoes bromination and Suzuki reaction to obtain 2-(1-(tert-butyloxycarbonyl)-1 H -pyrrol-2-yl)-4-chloroquinoline-3-carboxylic acid ethyl ester intermediate is finally hydrolyzed, rearranged and hydrolyzed to obtain penicinoline acid (I). Summary of the invention

[0009] The present invention aims to provide a method for synthesizing penicinoline, a quinolinone compound of formula I, comprising the following steps:

[0010] (1) Aniline and ethylene glycol ethoxymethylene malonate are condensed at high temperature to generate compound 2 via Gould-Jacobs reaction:

[0011] ;

[0012] The solvent used in reaction i is selected from dioxane, tetrahydrofuran, benzene, toluene, methanol, ethanol, hexane, octane, cyclohexane, cyclohexanone, acetonitrile, pyridine, phenol, DMF, DMSO, the reaction temperature is the boiling temperature of the solvent used, and the reaction time is 0.5h to 24h; the solvent used in reaction ii is selected from ethylene glycol methyl ether, diphenyl ether, anisole, 2,4-dibromoanisole, 2,5-difluoroanisole, 2,6-difluoroanisole, 2,6- The reaction temperature is from room temperature to reflux, and the reaction time is 0.5h to 24h.

[0013] (2) Compound 2 is prepared under the action of a halogenating agent to obtain compound 3:

[0014] ;

[0015] The halogenating agent used is one or more selected from thionyl chloride, oxalyl chloride, phosphorus trichloride, or phosphorus pentachloride; the solvent is one or more selected from dioxane, tetrahydrofuran, benzene, toluene, methanol, ethanol, hexane, octane, cyclohexane, cyclohexanone, acetonitrile, pyridine, phenol, DMF, and DMSO; and the temperature is the boiling temperature of the solvent used.

[0016] (3) Compound 3 is reacted with an oxidizing agent and a halogenating agent to obtain compound 4:

[0017] ;

[0018] Wherein, reactions i and ii are one-pot reactions; the oxidant used in reaction i is selected from one or more of hydrogen peroxide, ammonium dichromate, potassium perchlorate, potassium periodate, perchloric acid, potassium persulfate, anhydrous sodium peroxide, sodium hypochlorite solution, performic acid, peracetic acid, m-chloroperbenzoic acid, tert-butyl peroxide, ozone, and Dess-Martin reagent; the solvent is one or more of dioxane, tetrahydrofuran, benzene, toluene, methanol, ethanol, hexane, octane, cyclohexane, cyclohexanone, acetonitrile, pyridine, phenol, DMF, and DMSO; and the temperature is room temperature. to reflux, the reaction time is 0.5h~24h, the halogenating agent used in reaction ii is selected from one or more of bromine water, phosphorus pentabromide, phosphorus tribromide, 3-bromobenzyl sulfone, methyl 3-bromobenzoate, dibromosulfoxide, carbon tetrabromide, methyl p-bromobenzoate, phosphorus oxybromide, the solvent is one or more of dioxane, tetrahydrofuran, benzene, toluene, methanol, ethanol, hexane, octane, cyclohexane, cyclohexanone, acetonitrile, pyridine, phenol, DMF, DMSO, the temperature is from room temperature to reflux, and the reaction time is 0.5h~24h.

[0019] (4) Compound 4 was reacted with (1-(tert-butyloxycarbonyl)-1H-pyrrol-2-yl)boronic acid under alkaline conditions to obtain compound 5 via Suzuki coupling reaction:

[0020] ;

[0021] The alkaline reagent is selected from one or more of anhydrous sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, ammonium carbonate, calcium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, magnesium hydroxide, barium hydroxide, ammonia water, basic zinc carbonate, basic magnesium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide / sodium; the catalyst is palladium powder, palladium carbon, palladium acetate, palladium oxide, palladium nitrate, palladium sulfate, palladium dibromide, palladium hydroxide, palladium chloride, palladium acetate, tetrakistriphenylphosphine palladium, triphenylphosphine palladium, bis(triphenylphosphine) One or more of palladium dichloride (II), dibromobis(tri-tert-butylphosphine)dipalladium(I), bis(tri-o-tolylphosphine)dichloropalladium(II), and bis(methyldiphenylphosphine)dichloropalladium(II); the solvent is one or more of dioxane, tetrahydrofuran, benzene, toluene, methanol, ethanol, hexane, octane, cyclohexane, cyclohexanone, acetonitrile, pyridine, phenol, DMF, DMSO, and water; the reaction temperature is from room temperature to the boiling temperature of the selected solvent; and the reaction time is 0.5h to 24h.

[0022] (5) Compound 5 was used to prepare compound 6 under Brønsted acidic high temperature conditions:

[0023] ;

[0024] The Bronsted acid is one or more of hydrogen bromide, sulfurous acid, hypophosphorous acid, fluoroboric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, silicotungstic acid, boric acid, iodic acid, phosphoric acid, periodic acid, hydrofluoric acid, hydrochloric acid, sulfuric acid, nitric acid, formic acid, acetic acid, phosphorous acid, polyphosphoric acid, fluoroboric acid, fluorophosphoric acid, hydrofluoric acid, hydroiodic acid, aminosulfonic acid, pyrophosphoric acid, phosphoric acid, phosphomolybdic acid solution, and p-toluenesulfonic acid; the solvent is one or more of dioxane, tetrahydrofuran, benzene, toluene, methanol, ethanol, hexane, octane, cyclohexane, cyclohexanone, acetonitrile, pyridine, phenol, DMF, DMSO, and water; the reaction temperature is between 50°C and 200°C; and the reaction time is 0.5h to 48h.

[0025] (6) Compound 6 is hydrolyzed under alkaline conditions and high temperature to obtain the target product penicinoline:

[0026] ;

[0027] The reaction reagent is selected from one or more of anhydrous sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, ammonium carbonate, calcium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, magnesium hydroxide, barium hydroxide, ammonia water, basic zinc carbonate, basic magnesium carbonate, sodium methoxide, sodium ethoxide, potassium / sodium tert-butoxide, the solvent is one or more of dioxane, tetrahydrofuran, benzene, toluene, methanol, ethanol, hexane, octane, cyclohexane, cyclohexanone, acetonitrile, pyridine, phenol, DMF, DMSO, and water, the reaction temperature is from room temperature to the boiling temperature of the selected solvent, and the reaction time is 0.5h to 24h. DETAILED DESCRIPTION

[0028] In order to further illustrate the present invention, some examples are given below. These examples are purely illustrative and are only used to specifically describe the present invention, and should not be understood as limiting the present invention.

[0029] Example

[0030] 4-Hydroxyquinoline-3-carboxylic acid ethyl ester

[0031] Weigh aniline (1.02 mL, 0.011 mol) and diethyl ethoxymethylenemalonate (0.5-2 eq) and add to ethanol, heat at 100-200°C for three hours, cool to room temperature, add phenethyl ether, heat at 100-200°C for 30 min, cool to room temperature, add ice water after the reaction, extract with ethyl acetate (100 mL×2), combine the organic phases, wash the organic phases with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the organic phase, and chromatograph the residue on a silica gel column to obtain a product as a white solid of 1.6 g (76% yield);

[0032] ESI-MS m / z 218.32 [M+H] +

[0033] 1 H NMR (500 MHz, DMSO-d 6 ): 10.62 (brs, 1H), 8.80 (s, 1H), 8.46-7.78 (m, 4H), 4.10 (q, J =7.1 Hz, 2H), 1.30 (t, J =7.1 Hz, 3H).

[0034] Ethyl 4-chloroquinoline-3-carboxylate

[0035] Weigh 4-hydroxyquinoline-3-carboxylic acid ethyl ester (1.6 g, 7.3 mmol) and dissolve it in tetrahydrofuran, then add phosphorus oxychloride (0.5-10 eq) and mix, and heat at 100°C for one hour. After the reaction is completed, pour the reaction solution into ice water, adjust the pH to neutral with saturated potassium bicarbonate solution, extract with ethyl acetate (100 mL×2), combine the organic phases, wash the organic phases with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the organic phase, and chromatograph the residue on a silica gel column to obtain the product as a white solid of 1.1 g (64% yield);

[0036] ESI-MS m / z 237.42 [M+H] +

[0037] 1 H NMR (500 MHz, DMSO- d 6) δ12.56 (s, 1H), 8.57 (s, 1H), 8.19 (d, J=8.0Hz, 1H), 7.74 (dd, J=8.0, 7.0Hz 1H), 7.68 (d, J=8Hz, 1H), 7.45 (t, J=7Hz, 1H), 4.25(q, J=7Hz, 2H), 1.31(t, J=7Hz, 3H).

[0038] Ethyl 2-bromo-4-chloroquinoline-3-carboxylate

[0039] Weigh 4-chloroquinoline-3-carboxylic acid ethyl ester (1.1 g, 4.7 mmol) and dissolve it in chloroform (20 mL). Add 85% peroxybenzoic acid (0.5-2 eq) to the mixture at room temperature and stir at room temperature for 4 hours. Add phosphorus oxybromide (0.5-2 eq) to the reaction solution and stir for 1 hour. After the reaction is completed, pour the reaction solution into ice water, adjust the pH value to 8 with saturated potassium carbonate solution, extract with ethyl acetate (100 mL×2), combine the organic phases, wash the organic phases with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the organic phase, and obtain the product as a white solid (1.1 g, 74% yield) by column chromatography.

[0040] ESI-MS m / z: 316.0 [M+H]+

[0041] 1 H NMR (500 MHz, CDCl3) δ 8.32-8.19 (m, 1H), 8.15-8.04 (m, 1H), 7.91-7.81 (m, 1H), 7.78-7.68 (m, 1H), 4.56 (q, J = 7.1 Hz, 2H), 1.49 (t, J = 7.1 Hz, 3H).

[0042] 2-(1-(tert-Butyloxycarbonyl)-1 H -pyrrol-2-yl)-4-chloroquinoline-3-carboxylic acid ethyl ester

[0043] Weigh 2-bromo-4-chloroquinoline-3-carboxylic acid ethyl ester (1.1 g, 3.2 mmol) and (1-(tert-butyloxycarbonyl)-1 H 2-Pyrrol-2-yl)boronic acid (0.69 g, 3.3 mmol) was dissolved in 1,4-dioxane (15 mL), cesium carbonate (4.0 g, 6.5 mmol) and palladium acetate (360 mg, 0.3 mmol) were added thereto, and the reaction solution was stirred at 75 o C for 3 hours. After the reaction is completed, the reaction solution is poured into ice water and extracted with ethyl acetate (100 mL×2). The organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue is subjected to column chromatography to obtain the product as a colorless oil (734 mg, 53% yield);

[0044] ESI-MS m / z: 345.2 [M+H] +

[0045] 1 H NMR (500 MHz, CDCl3), δ 11.65 (s, 1H), 11.59 (s, 1H), 8.07 (d, J =7.6 Hz, 1H), 7.77 – 7.61 (m, 2H), 7.36 (t, J = 7.3 Hz, 1H), 7.13 (s, 1H), 6.49 (d, J = 2.5 Hz, 1H), 6.33 – 6.18 (m, 1H), 4.14 (q, J = 7.1 Hz, 2H), 1.14 (t, J = 7.1 Hz, 3H).

[0046] 4-Oxo-2-(1 H -pyrrol-2-yl)-1,4-dihydroquinoline-3-carboxylic acid ethyl ester

[0047] 2-(1-(tert-butyloxycarbonyl)-1 H 4-Pyrrol-2-yl)-4-chloroquinoline-3-carboxylic acid ethyl ester (643 mg, 1.7 mmol) was dissolved in acetic acid (10 mL), ethanol (6 mL), and water (5 ml) and heated to 80 o C for 18 hours, remove acetic acid and ethanol by distillation under reduced pressure, dilute the residue with water, adjust to neutrality with saturated potassium carbonate solution, extract with ethyl acetate (100 mL×2), combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate the organic phase. The residue is subjected to column chromatography to obtain the product as a light yellow solid (258 mg, 54% yield);

[0048] ESI-MS m / z 283.82 [M+H] +

[0049] 1 H NMR (500 MHz, DMSO-d6) δ 16.12 (s, 1H), 12.40 (s, 1H), 11.81 (s, 1H), 8.25 (d, J = 8.0 Hz, 1H), 7.95 – 7.78 (m, 2H), 7.60 – 7.48 (m, 1H), 7.15(d, J = 1.4 Hz, 1H), 6.82 (s, 1H), 6.33 – 6.24 (m, 1H).

[0050] 4-Oxo-2-(1 H -pyrrol-2-yl)-1,4-dihydroquinoline-3-carboxylic acid

[0051] 4-Oxo-2-(1 H -pyrrol-2-yl)-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (50 mg, 0.18 mmol) was dissolved in methanol (10 mL), and 1M sodium hydroxide aqueous solution (10 mL) was added and stirred at room temperature for 5 hours. 1M hydrochloric acid (1 mL) was added to the reaction solution for neutralization and extraction with ethyl acetate (50 mL×2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. The residue was purified by silica gel column chromatography to obtain the product as a yellow solid (36 mg, 76% yield).

[0052] ESI-MS m / z 250.14 [M+H] +

[0053] 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.25 (dd, J = 8.0 ,1.6Hz, 1H), 7.89 (dd,J = 8.0,1.6Hz ,1H), 7.78 (ddd, J = 8.0 ,8.0,1.6Hz ,1H), 7.51 (ddd, J = 8.0 ,8.0,1.6Hz ,1H),7.47 (dd, J = 3.5,1.0Hz, 1H),7.09 (dd, J = 3.5,1.0, 1H), 6.43(dd, J = 3.5,1.0Hz, 1H),3.99(s,3H).

[0054] 13 C NMR(125MHz, DMSO-d 6 ) δ169.9, C,159.5, 153.8, C, C,140.4, C,132.7,CH,125.9, CH,125.6, CH,128.7, C,125.6, C,120.2, CH,117.7, CH,116.6, CH,111.6,CH,104.3, C。

Claims

1. A method for preparing a penicillic acid compound having a structure of formula I, It is characterized in that The compound of formula I is prepared according to the following synthetic route, which comprises the steps of: Step (1): condensing aniline and ethylene glycol ethoxymethylene malonate, and then subjecting the mixture to a Gould-Jacobs reaction to form compound 2; Step (2): Compound 2 is reacted with a halogenating agent to prepare compound 3; Step (3): Compound 3 is prepared under the action of an oxidizing agent and a halogenating agent to obtain compound 4; Step (4): Compound 5 is prepared by Suzuki coupling reaction of compound 4 under alkaline conditions; Step (5): Compound 5 is used to prepare compound 6 under acidic and high temperature conditions; Step (6): Compound 6 is hydrolyzed to obtain a compound of formula I; 2. The preparation method according to claim 1, characterized in that In step (1), the solvent used in reaction i is selected from dioxane, tetrahydrofuran, benzene, toluene, methanol, ethanol, hexane, octane, cyclohexane, cyclohexanone, acetonitrile, pyridine, phenol, DMF, DMSO, the reaction temperature is the boiling temperature of the solvent used, and the reaction time is 0.5h to 24h; the solvent used in reaction ii is selected from ethylene glycol methyl ether, diphenyl ether, anisole, 2,4-dibromoanisole, 2,5-difluoroanisole, 2,6-difluoroanisole, 2 ,6-dichloroanisole, 2-fluoro-5-bromoanisole, 2-fluoroanisole, 2-fluoroanisole, 2-aminodiphenyl sulfide, 2-chloro-4-fluoroanisole, 2-chloro-5-fluoroanisole, 2-chloroethyl ethyl sulfide, 2-chloroethyl methyl ether, 2-chloroethyl phenyl sulfide, 2-chloroanisole, 2-bromo-4-fluoroanisole, phenyl ether, one or more of paraffin oil, the reaction temperature is from room temperature to reflux, and the reaction time is 0.5h to 24h.

3. The preparation method according to claim 1, characterized in that The halogenating agent used in step (2) is selected from one or more of dichlorothionyl, oxalyl chloride, phosphorus trichloride, or phosphorus pentachloride, the solvent is selected from one or more of dioxane, tetrahydrofuran, benzene, toluene, methanol, ethanol, hexane, octane, cyclohexane, cyclohexanone, acetonitrile, pyridine, phenol, DMF, and DMSO, and the temperature is the boiling temperature of the solvent used.

4. The preparation method according to claim 1, characterized in that In step (3), reactions i and ii are one-pot reactions; the oxidant used in reaction i is selected from one or more of hydrogen peroxide, ammonium dichromate, potassium perchlorate, potassium periodate, perchloric acid, potassium persulfate, anhydrous sodium peroxide, sodium hypochlorite solution, performic acid, peracetic acid, m-chloroperbenzoic acid, tert-butyl peroxide, ozone, and Dess-Martin reagent; and the solvent is dioxane, tetrahydrofuran, benzene, toluene, methanol, ethanol, hexane, octane, cyclohexane, cyclohexanone, acetonitrile, pyridine, phenol, One or more of DMF and DMSO, the temperature is from room temperature to reflux, the reaction time is 0.5h to 24h, the halogenating agent used in reaction ii is selected from one or more of bromine water, phosphorus tribromide, dibromosulfoxide, and phosphorus oxybromide, the solvent is one or more of dioxane, tetrahydrofuran, benzene, toluene, methanol, ethanol, hexane, octane, cyclohexane, cyclohexanone, acetonitrile, pyridine, phenol, DMF, and DMSO, the temperature is from room temperature to reflux, and the reaction time is 0.5h to 24h.

5. The preparation method according to claim 1, characterized in that In step (4), the alkaline reagent is selected from one or more of anhydrous sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, ammonium carbonate, calcium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, magnesium hydroxide, barium hydroxide, ammonia water, basic zinc carbonate, basic magnesium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide / sodium; the catalyst is palladium powder, palladium carbon, palladium oxide, palladium nitrate, palladium sulfate, palladium dibromide, palladium hydroxide, palladium chloride, palladium acetate, tetrakistriphenylphosphine palladium, bis(triphenylphosphine) dichloride One or more of palladium (II), dibromobis(tri-tert-butylphosphine)dipalladium (I), bis(tri-o-tolylphosphine)dichloropalladium (II), bis(methyldiphenylphosphine)dichloropalladium (II); the solvent is one or more of dioxane, tetrahydrofuran, benzene, toluene, methanol, ethanol, hexane, octane, cyclohexane, cyclohexanone, acetonitrile, pyridine, phenol, DMF, DMSO, and water; the reaction temperature is from room temperature to the boiling temperature of the selected solvent; and the reaction time is 0.5h to 24h.

6. The preparation method according to claim 1, characterized in that In step (5), the Bronsted acid is one or more of hydrogen bromide, sulfurous acid, hypophosphorous acid, hydrobromic acid, silicotungstic acid, boric acid, iodic acid, periodic acid, hydrochloric acid, sulfuric acid, nitric acid, formic acid, acetic acid, phosphorous acid, polyphosphoric acid, fluoroboric acid, fluorophosphoric acid, hydrofluoric acid, hydroiodic acid, aminosulfonic acid, pyrophosphoric acid, phosphoric acid, phosphomolybdic acid solution, and p-toluenesulfonic acid; the solvent is one or more of dioxane, tetrahydrofuran, benzene, toluene, methanol, ethanol, hexane, octane, cyclohexane, cyclohexanone, acetonitrile, pyridine, phenol, DMF, DMSO, and water; the reaction temperature is between 50° C. and 200° C.; and the reaction time is 0.5 h to 48 h.

7. The preparation method according to claim 1, characterized in that In step (6), the reaction reagent is selected from one or more of anhydrous sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, ammonium carbonate, calcium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, magnesium hydroxide, barium hydroxide, ammonia water, basic zinc carbonate, basic magnesium carbonate, sodium methoxide, sodium ethoxide, potassium / sodium tert-butoxide, the solvent is one or more of dioxane, tetrahydrofuran, benzene, toluene, methanol, ethanol, hexane, octane, cyclohexane, cyclohexanone, acetonitrile, pyridine, phenol, DMF, DMSO, and water, the reaction temperature is from room temperature to the boiling temperature of the selected solvent, and the reaction time is 0.5h to 24h.

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