CN112300184B - Preparation method of three-membered ring compound - Google Patents
Preparation method of three-membered ring compound Download PDFInfo
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/14—Ortho-condensed systems
- C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
Abstract
The invention discloses a preparation method of a three-membered ring compound, which is an important intermediate for preparing a racemic camptothecin compound. The method takes 6-chloro-2-methoxynicotinic acid as a starting material, and 6-chloro-2-methoxynicotinic acid reacts with 1-penten-3-one and a lithium reagent to obtain a lactone compoundAn agent; reducing the lactone to obtain a diol compound; oxidizing a diol compound to obtain a hemiacetal compound; reoxidizing the hemiacetal compound to obtain a lactone compound; inserting carbonyl into lactone compound to obtain 6-position n-propyl ester compound; demethylating the n-propyl ester compound to form a pyridone compound; finally reacting with tert-butyl acrylate and decarboxylating to obtain the ternary compound, namely 4-ethyl-4-hydroxy-7, 8-dihydro-1H-pyrano [3,4-f]Indolizine-3, 6,10 (4H) -trione. The invention has the advantages of high yield, short synthetic route, simple and cheap raw materials and easy purification.
Description
Technical Field
The invention belongs to the technical field of organic chemistry, and particularly relates to a preparation method of a racemic camptothecin intermediate three-membered ring compound.
Background
Camptothecin (CPT) was an alkaloid obtained in 1958 from Wall and Wani in the bark of camptotheca acuminata in the middle of china. Camptothecin is a five-membered quinoline alkaloid, and has significant antitumor activity in vivo and in vitro animal experiments, so that camptothecin is one of the key points of antitumor drug research. Three camptothecin compounds have been approved for clinical treatment of malignancies, of which irinotecan 1994 was approved for colorectal cancer, topotecan 1996 for ovarian cancer, and belotecan 2005 for prostate cancer.
The synthesis and modification of camptothecin is another important area of camptothecin research. The modification of camptothecin is generally carried out on an A/B ring, and the Friedlander condensation method in a plurality of synthetic strategies is to use an A ring and a CDE ring for condensation to obtain the camptothecin, so that the method has unique advantages in the structural modification of the camptothecin. As such, the synthesis of the CDE ring of camptothecin has also become a focus of research. At present, the CDE ring of camptothecin can be obtained by chiral resolution of a racemic CDE ring, and racemic camptothecin and derivatives thereof are important reference substances for testing the biological activity of camptothecin. There are some reports on the racemic CDE ring synthesis route of camptothecin, but these routes all have some problems:
med. Chem.1980,23,554-560 provides the following synthetic route:
Chem.1993, 58, 611-617 provides the following synthetic route:
Disclosure of Invention
The invention aims to provide a preparation method of a three-membered ring compound, which is a method for producing a three-membered ring compound, namely 4-ethyl-4-hydroxy-7, 8-dihydro-1H-pyrano [3,4-f ] indolizine-3, 6,10 (4H) -trione, serving as a key intermediate of an antitumor drug camptothecin in a simple, high-yield and low-cost manner.
The purpose of the invention is realized as follows:
a preparation method of a tricyclic compound takes 6-chloro-2-methoxynicotinic acid as a starting material, and 6-chloro-2-methoxynicotinic acid reacts with 1-penten-3-one and a lithium reagent to obtain a lactone compound; reducing the lactone to obtain a diol compound; oxidizing a diol compound to obtain a hemiacetal compound; reoxidizing the hemiacetal compound to obtain a lactone compound; the lactone compound is inserted into carbonyl to obtain a 6-position n-propyl ester compound; demethylating the n-propyl ester compound to form a pyridone compound; finally reacting with tert-butyl acrylate and decarboxylating to obtain the three-membered ring compound, namely 4-ethyl-4-hydroxy-7, 8-dihydro-1H-pyrano [3,4-f ] indolizine-3, 6,10 (4H) -trione. The method comprises the following specific steps:
(1) Reacting the compound (a) with a lithiation reagent and 1-pentene-3-ketone in an anhydrous tetrahydrofuran solution at-75 to-60 ℃ for 2 to 4 hours to obtain a compound (b); wherein the mol ratio of the compound (a) to the lithiation reagent and the 1-pentene-3-ketone is 1: 2-4: 3-4;
(2) Reacting compound (b) with sodium borohydride or red aluminum in methanol or ethanol; reacting for 12-18 hours to obtain a compound (c); wherein the mol ratio of the compound (b) to sodium borohydride or red aluminum is 1: 3-5;
(3) Introducing ozone into the compound (c) in dichloromethane at normal pressure, and reacting for 10-30 minutes at-75 ℃ to-65 ℃ to obtain a compound (d);
(4) Reacting the compound (d) with iodine and alkali in a mixed solvent of methanol and water in a ratio of 5: 1 for 18-24 hours to obtain a compound (e); wherein the mol ratio of the compound (d) to iodine and alkali is 1: 2-5;
(5) Reacting the compound (e) with palladium acetate, 1, 3-bis (diphenylphosphino) propane, N-propanol and alkali in N, N-dimethylformamide under normal pressure and introducing carbon monoxide at the temperature of 80-100 ℃ for 18-24 hours to obtain a compound (f); wherein the molar ratio of the compound (f) to the palladium acetate, the 1, 3-bis (diphenylphosphino) propane, the n-propanol and the alkali is 1: 0.05-0.1: 1-2;
(6) Reacting the compound (f) with trimethylchlorosilane and sodium iodide in acetonitrile for 12-16 hours to obtain a compound (g); wherein the molar ratio of the compound (f) to the trimethylchlorosilane to the sodium iodide is 1: 2-4;
(7) Reacting the compound (g) with tert-butyl acrylate in dimethyl sulfoxide at 55-60 ℃ for 30-40 hours in the presence of cesium carbonate to form a five-membered ring to obtain a compound (h); wherein the mol ratio of the compound (g) to the tert-butyl acrylate and the cesium carbonate is 1: 2-4: 1-1.5;
(8) Reacting compound (H) with trifluoroacetic acid in toluene at 100-110 ℃ for 1-3 hours to give compound (i) said three-membered ring compound, i.e., 4-ethyl-4-hydroxy-7, 8-dihydro-1H-pyrano [3,4-f ] indolizine-3, 6,10 (4H) -trione; wherein the volume ratio of the toluene to the trifluoroacetic acid is 10-20: 1;
the specific preparation process is shown as the following formula:
the lithiation reagent in the step (a) is a mixture of n-butyl lithium and 2, 6-tetramethyl piperidine, and the molar ratio of the n-butyl lithium to the 2, 6-tetramethyl piperidine is 1: 1.
The alkali is sodium carbonate, calcium carbonate or potassium carbonate.
The invention has the advantages of cheap raw materials for synthesis, short synthetic route, high yield and easy mass production. And the catalyst used in the reaction process is cheaper, the dosage is less, the toxicity of the generated waste is low, and the method is more environment-friendly.
Detailed Description
Example 1
Adding 13.5mL of 2, 6-tetramethyl piperidine into a reaction bottle, adding 150mL of tetrahydrofuran under nitrogen atmosphere, stirring, and cooling to-78 ℃. 45mL of a 2.5M n-butyllithium tetrahydrofuran solution was slowly added dropwise to the flask, and the reaction was completed for 1 hour. 5g of 6-chloro-2-methoxynicotinic acid is dissolved in 25mL of tetrahydrofuran, and slowly dropped into a reaction bottle, and the reaction is finished for 1 hour. 7.9mL of 1-penten-3-one was added to 25mL of tetrahydrofuran, and slowly added dropwise to the reaction flask, after completion of the dropwise addition reaction, the reaction was carried out for 1 hour. After the reaction, the reaction system was left at room temperature for 5 minutes, and then 20mL of concentrated hydrochloric acid was added thereto, followed by stirring for 1 hour, 50mL of water was added to dissolve the solid, extraction was performed with ethyl acetate (100 mL. Times.3), and the organic layer was collected and washed with saturated brine (100 mL. Times.2). Dried over anhydrous sodium sulfate, ethyl acetate was removed by rotary evaporation under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 20: 1, v/v) to give 4.6g of 6-chloro-1-ethyl-4-methoxy-1-vinyl [3,4-c ] as a white solid]Pyridin-3 (1H) -one, yield 68%. 1 H NMR(400MHz,CDCl 3 )δ6.96(s,1H),5.98(dd,J＝17.2,10.8Hz,1H),5.45(d,J＝17.1Hz,1H),5.29(d,J＝10.8Hz,1H),4.15(s,3H),2.19–2.03(m,1H),1.95(dq,J＝14.6,7.3Hz,1H),0.86(t,J＝7.4Hz,3H)。
Example 2
Reacting 6-chloro-1-ethyl-4-methoxy-1-vinyl [3,4-c ]]4.6g of pyridin-3 (1H) -one was added to the reaction flask, 25mL of ethanol was added, and the mixture was stirred at room temperature for 30 minutes. The reaction system is cooled to 0 ℃, and 2.8g of sodium borohydride are added in batchesThe reaction was stirred at room temperature for 24 hours. After completion of the reaction, 2mL of hydrochloric acid was added, and the mixture was extracted with dichloromethane (25 mL. Times.3), and the organic layer was collected, washed with saturated brine (25 mL. Times.2), and dried over anhydrous sodium sulfate. Dichloromethane was removed by vortex under reduced pressure to give 4.5g of 3- (6-chloro-3- (hydroxymethyl) -2-methoxypyridin-4-yl) pent-1-en-3-ol as a clear oily liquid in 98% yield. 1 H NMR(400MHz,CDCl 3 )δ6.94(s,1H),6.07(dd,J＝17.3,10.7Hz,1H),5.23(dd,J＝14.0,6.0Hz,2H),4.84–4.68(m,2H),3.96(s,3H),2.02(dq,J＝14.6,7.4Hz,1H),1.90(dq,J＝14.6,7.4Hz,1H),0.89(t,J＝7.4Hz,3H)。
Example 3
Dissolving 4.5g of 3- (6-chloro-3- (hydroxymethyl) -2-methoxypyridin-4-yl) pent-1-en-3-ol in 500mL of dichloromethane, cooling to-70 ℃, introducing ozone into the solvent for 1 hour, after the reaction is completed, adding 1mL of dimethyl sulfide, heating to room temperature, stirring for 30 minutes, removing the solvent by spinning to obtain a white solid, 6-chloro-4-ethyl-8-methoxy-3, 4-dihydro-1H-pyrano [3,4-c ] s]Pyridine-3, 4-diol 4.4g, yield 97.8%. 1 H NMR(400MHz,DMSO)δ7.07(s,1H),6.81(d,J＝4.5Hz,1H),4.99(s,1H),4.96(d,J＝4.5Hz,1H),4.51(dd,J＝38.9,16.2Hz,2H),3.87(s,3H),1.70–1.52(m,2H),0.81(t,J＝7.3Hz,3H)。
Example 4
4.4g of 3-chloro-5-ethyl-1-methoxy-5, 6,7, 8-tetrahydroisoquinoline-5, 6-diol was dissolved in a mixed solvent of 40mL of methanol and 10mL of water. 8.6g of iodine and 3.0g of calcium carbonate were added and reacted at 60 ℃ for 24 hours. After completion of the reaction, 50mL of a 10% sodium sulfite solution was added, and the mixture was extracted with methylene chloride (50 mL. Times.3) and dried over anhydrous sodium sulfate. Dichloromethane was removed under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate = 20: 1,v/v) to give 6-chloro-4-ethyl-4-hydroxy-8-methoxy-1, 4-dihydro-3H-pyrano [3,4-c ] as a white solid]4.3g of pyridine-3-one, and the yield is 97.7%. 1 H NMR(400MHz,DMSO)δ7.12(s,1H),6.51(s,1H),5.40(dd,J＝43.2,15.7Hz,2H),3.93(s,3H),1.78(dd,J＝7.3,3.5Hz,2H),0.79(t,J＝7.3Hz,3H)。
Example 5
0.86g of palladium acetate, 1.75g of 1, 3-bis (diphenylphosphino) propane and 7.00g of potassium carbonate were charged into a reaction flask, the nitrogen atmosphere was replaced, and the flask was replaced with a mono-layerAn atmosphere of oxidized carbon. 4.30g of 6-chloro-4-ethyl-4-hydroxy-8-methoxy-1, 4-dihydro-3H-pyrano [3,4-c ]]Pyridin-3-one was dissolved in 30mL of N, N-dimethylformamide and added to the reaction flask. 70mL of n-propanol was added, and the reaction was carried out at 100 ℃ for 30 hours. After the reaction was completed, the palladium reagent was removed by suction filtration through celite, and the filtrate was collected by washing with ethyl acetate (20 mL. Times.3). Ethyl acetate and n-propanol were removed by rotary evaporation under reduced pressure, 150mL of water was added to the crude product, extracted with ethyl acetate (50 mL. Times.3), and dried over anhydrous sodium sulfate. Ethyl acetate was removed by rotary evaporation under reduced pressure and purified by column chromatography (dichloromethane: methanol = 50: 1, v/v) to give 4-ethyl-4-hydroxy-8-methoxy-3-oxo-3, 4-dihydro-1H-pyrano [3,4-c ] as a white solid]3.62g of propyl pyridine-6-carboxylate, yield 70.0%. 1 H NMR(400MHz,CDCl 3 )δ7.95(s,1H),5.46(dd,J＝119.2,16.2Hz,2H),4.34(t,J＝6.7Hz,2H),4.09(s,3H),1.88–1.77(m,4H),1.04(t,J＝7.4Hz,3H),0.97(t,J＝7.4Hz,3H)。
Example 6
3.0g of 4-ethyl-4-hydroxy-8-methoxy-3-oxo-3, 4-dihydro-1H-pyrano [3,4-c ]]Pyridine-6-carboxylic acid propyl ester, 2.9g sodium iodide were added to a two-necked flask, nitrogen was replaced, 100mL acetonitrile was added, and the mixture was cooled to 0 ℃ and stirred for 30 minutes. 2.1g of trimethylchlorosilane are added dropwise, the temperature is raised to room temperature after the addition is finished, and the reaction is carried out overnight. After completion of the reaction, 150mL of water was added to the system, followed by extraction with methylene chloride (100 mL. Times.3) and drying of the organic layer over anhydrous sodium sulfate. The methylene chloride was removed by rotary evaporation under reduced pressure and purified by column chromatography (methylene chloride: methanol = 50: 1,v/v) to obtain 2.5g of 4-ethyl-4-hydroxy-3, 8-dioxo-3, 4,7, 8-tetrahydro-1H-pyrano [3,4-c ] as pale yellow crystals]Propyl pyridine-6-carboxylate, yield 87%. 1 H NMR(400MHz,CDCl 3 )δ7.37(s,1H),5.63(d,J＝17.1Hz,1H),5.24(d,J＝17.1Hz,1H),4.35(t,J＝6.7Hz,2H),1.95–1.77(m,4H),1.01(dt,J＝11.9,7.4Hz,6H)。
Example 7
3.0g of 4-ethyl-4-hydroxy-3, 8-dioxo-3, 4,7, 8-tetrahydro-1H-pyrano [3,4-c ]]Propyl pyridine-6-carboxylate, 6.6g cesium carbonate, and 1.44g tert-butyl acrylate were dissolved in 30mL dimethylsulfoxide and stirred at 47-50 ℃ for 21 hours. The mixture was cooled to room temperature, and 6mL of hydrochloric acid and 300mL of water were added. Acetic acidEthyl ester (100 mL. Times.3) was extracted and dried over anhydrous sodium sulfate. Ethyl acetate was removed by rotary evaporation under reduced pressure and purified by column chromatography (dichloromethane: methanol = 30: 1) to obtain 3.0g of 4-ethyl-4, 6-dihydroxy-3, 10-dioxo-3, 4,8, 10-tetrahydro-1H-pyrano [3,4-f ] as pale yellow crystals]Indolizine-7-carboxylic acid tert-butyl ester, yield 81%. 1 H NMR(400MHz,CDCl 3 )δ7.01(s,1H),5.67(d,J＝16.4Hz,1H),5.23(d,J＝16.5Hz,1H),4.66(s,2H),1.82(dt,J＝13.9,7.0Hz,2H),1.56(s,9H),0.97(t,J＝7.4Hz,3H)。
Example 8
7.0g of 4-ethyl-4, 6-dihydroxy-3, 10-dioxo-3, 4,8, 10-tetrahydro-1H-pyrano [3,4-f ] is introduced]Indolizine-7-carboxylic acid tert-butyl ester, 3mL trifluoroacetic acid dissolved in 300mL toluene, heating to 110 degrees C reaction for 2 hours. After the reaction was completed, toluene and trifluoroacetic acid were removed by rotary removal under reduced pressure. The crude product was purified by column chromatography (dichloromethane: methanol = 50: 1,v/v) to give 3.7g brown crystals of 4-ethyl-4-hydroxy-7, 8-dihydro-1H-pyrano [3,4-f ]]Indolizine-3, 6,10 (4H) -trione, yield 93%. 1 H NMR(400MHz,CDCl 3 )δ7.23(s,1H),5.66(d,J＝17.1Hz,1H),5.31–5.19(m,1H),4.34(t,J＝6.7Hz,2H),3.01–2.92(m,2H),1.80(ddd,J＝14.4,7.2,2.6Hz,2H),0.97(t,J＝7.4Hz,3H)。
Claims (2)
1. A process for the preparation of a three-membered ring compound, which process comprises the specific steps of:
(1) Reacting the compound (a) with a lithiation reagent and 1-pentene-3-ketone in an anhydrous tetrahydrofuran solution at-75 to-60 ℃ for 2 to 4 hours to obtain a compound (b); wherein the mol ratio of the compound (a) to the lithiation reagent and the 1-pentene-3-ketone is 1: 2-4: 3-4;
(2) Reacting compound (b) with sodium borohydride or red aluminum in methanol or ethanol; reacting for 12-18 hours to obtain a compound (c); wherein the mol ratio of the compound (b) to the sodium borohydride or the red aluminum is 1: 3-5;
(3) The compound (c) is added with ozone in methylene dichloride under normal pressure and reacts for 10 to 30 minutes under the condition of-75 ℃ to-65 ℃ to obtain a compound (d);
(4) Reacting the compound (d) with iodine and alkali in a mixed solvent of methanol and water in a ratio of 5: 1 for 18-24 hours to obtain a compound (e); wherein the mol ratio of the compound (d) to iodine and alkali is 1: 2-5;
(5) Reacting the compound (e) with palladium acetate, 1, 3-bis (diphenylphosphino) propane, N-propanol and alkali in N, N-dimethylformamide under normal pressure and introducing carbon monoxide at 80-100 ℃ for 18-24 hours to obtain a compound (f); wherein the molar ratio of the compound (e) to the palladium acetate, the 1, 3-bis (diphenylphosphino) propane, the n-propanol and the alkali is 1: 0.05-0.1: 1-2;
(6) Reacting the compound (f) with trimethylchlorosilane and sodium iodide in acetonitrile for 12-16 hours to obtain a compound (g); wherein the molar ratio of the compound (f) to the trimethylchlorosilane to the sodium iodide is 1: 2-4;
(7) Reacting the compound (g) with tert-butyl acrylate in dimethyl sulfoxide at 55-60 ℃ for 30-40 hours in the presence of cesium carbonate to form a five-membered ring to obtain a compound (h); wherein the mol ratio of the compound (g) to the tert-butyl acrylate and the cesium carbonate is 1: 2-4: 1-1.5;
(8) Reacting compound (H) with trifluoroacetic acid in toluene at 100-110 ℃ for 1-3 hours to give compound (i) said three-membered ring compound, i.e., 4-ethyl-4-hydroxy-7, 8-dihydro-1H-pyrano [3,4-f ] indolizine-3, 6,10 (4H) -trione; wherein the volume ratio of the toluene to the trifluoroacetic acid is 10-20: 1;
the specific preparation process is shown as the following formula:
wherein the alkali is sodium carbonate, calcium carbonate or potassium carbonate.
2. The method of claim 1, wherein the lithiation reagent of step (a) is a mixture of n-butyl lithium and 2, 6-tetramethyl piperidine in a molar ratio of 1: 1.
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