Process for the preparation of a lopinavir derivative

Abstract

The application discloses a preparation method of a lopinavir derivative, belongs to the field of compound preparation, and provides a novel drug molecule lopinavir derivative synthesis method which is reasonable in process design, high in yield, and convenient and controllable in operation process. The lopinavir derivative is synthesized through seven steps of reaction by taking an amine group protected epoxypropylamine and a carboxyl group protected L-valine as raw materials. The preparation method provided by the application is reasonable in process design, high in operability, relatively mild in reaction condition, and high in yield. The lopinavir derivative prepared by the application provides an important basis for scientific evaluation of quality, safety and efficiency of lopinavir. Meanwhile, compared with lopinavir, the lopinavir derivative synthesized by the application has better water solubility, overcomes the weakness of low water solubility and poor oral bioavailability of lopinavir, and can be developed into a substitute of lopinavir.

Description

Technical Field

[0001] This invention pertains to compound preparation methods, specifically relating to a method for preparing a lopinavir derivative. Background Technology

[0002] Lopinavir is a potent HIV protease inhibitor that works by blocking the cleavage of the gag-pol protein, leading to the production of immature, inactive viral particles. However, it is clinically used in combination with ritonavir because ritonavir inhibits CYP3A-mediated lopinavir metabolism, thereby increasing plasma concentrations of lopinavir. Lopinavir, ritonavir, and other antiretroviral drugs are used in combination to treat HIV-1 infection.

[0003] With the advancement of technology and the progress of the times, people have gained a more comprehensive understanding of the importance of scientifically evaluating the quality, safety, and efficacy of drugs before they are marketed. Among these evaluations, the control of drug derivatives is closely related to drug quality. Derivatives are often associated with drug safety and, in a few cases, with efficacy. Therefore, controlling the level of derivatives is receiving increasing attention from pharmaceutical professionals during drug development and research. Summary of the Invention

[0004] Objective of the invention: This invention provides a method for preparing lopinavir derivatives, overcoming the shortcomings of existing technologies, and providing a novel method for synthesizing lopinavir derivatives with reasonable process design, high yield, and convenient and controllable operation.

[0005] Technical solution: The preparation method of the lopinavir derivative of the present invention includes the following route:

[0006]

[0007] Wherein, R1 represents benzyl, benzyloxycarbonyl, tert-butyloxycarbonyl, and thiamethoxycarbonyl; R2 represents C1-5 alkyl, benzyl, and allyl; and R3 represents trimethylsilyl, triethylsilyl, and tert-butyldimethylsilyl.

[0008] The method for preparing the lopinavir derivative includes the following steps:

[0009] (1) After dissolving I and II in an organic solvent, the mixture was stirred at 40–100 °C for 8 to 20 hours to obtain compound III;

[0010] (2) Dissolve compound III obtained in step (1) in an organic solution, add alkali and organic halide, stir at 20-80℃ for 8 to 20 hours, and then purify and separate compound IV by column chromatography or recrystallization.

[0011] (3) Dissolve compound IV obtained in step (2) in an organic solvent, add a catalyst and a hydrogen source, and stir at 20-60 degrees Celsius for 8 to 20 hours to obtain compound V;

[0012] (4) Dissolve compound V obtained in step (3) in an organic solvent, add condensing agent and organic base, and react at 20-80℃ for 8 to 20 hours to obtain compound VI;

[0013] (5) Compound VI obtained in step (4) is deprotected in an organic solvent to obtain compound VII;

[0014] (6) Take the compound VII obtained in step (5), add a deprotecting agent to the solvent, and react at 20-80℃ for 8 to 20 hours to obtain compound VIII;

[0015] (7) The compound VIII obtained in step (6) is reacted with compound IX in the presence of a condensing agent to obtain compound X, i.e., lopinavir derivative.

[0016] In the preparation method of the lopinavir derivative, the organic solvent in step (1) is selected from dimethyl sulfoxide, dimethylformamide, dimethylacetamide, isopropanol, methanol, ethanol, acetonitrile, pyridine or tetrahydrofuran.

[0017] In the preparation method of the lopinavir derivative, the organic solvent in step (2) is selected from dimethyl sulfoxide, dimethylformamide, dimethylacetamide, isopropanol, methanol, ethanol, acetonitrile, pyridine, or tetrahydrofuran; the base is sodium bicarbonate, sodium carbonate, imidazole, triethylamine, or pyridine, etc. The organohalide is selected from trimethylchlorosilane, trimethylbromosilane, tert-butyldimethylchlorosilane, and triethylchlorosilane.

[0018] In the preparation method of the lopinavir derivative, the organic solvent in step (3) is selected from dimethyl sulfoxide, dimethylformamide, dimethylacetamide, isopropanol, methanol, ethanol, acetonitrile, pyridine or tetrahydrofuran; the catalyst is selected from palladium on carbon, palladium hydroxide; and the hydrogen source is ammonium formate or cyclohexene.

[0019] In the preparation method of the lopinavir derivative, the organic solvent in step (4) is selected from dimethylformamide, dichloromethane, acetonitrile, pyridine or tetrahydrofuran; the condensing agent is carbonyl diimidazole, ethyl chloroformate, p-nitrobenzene chloroformate; and the organic base is selected from triethylamine, trimethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine or cycloazine.

[0020] In the preparation method of the lopinavir derivative, the organic solvent in step (5) is selected from methanol, ethanol, dioxane, tetrahydrofuran, and dichloromethane.

[0021] In the preparation method of the lopinavir derivative, the solvent in step (6) is selected from methanol, ethanol, dioxane, tetrahydrofuran, dichloromethane, and water.

[0022] In the preparation method of the lopinavir derivative, the deprotecting reagent in step (6) is selected from hydrochloric acid, sulfuric acid, trifluoroacetic acid, sodium hydroxide, and potassium hydroxide.

[0023] The condensing agent in step (7) of the preparation method of the lopinavir derivative is selected from carbonyl diimidazole, N,N′-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 1-hydroxybenzotriazole.

[0024] Compared to lopinavir, the lopinavir derivative synthesized in this invention has better water solubility, overcoming the weaknesses of lopinavir's low water solubility and poor oral bioavailability, and can be developed as a substitute for lopinavir.

[0025] The method for synthesizing lopinavir derivatives provided by this invention has not been reported before. Further pharmacological and pharmacokinetic studies can be conducted on the synthesized lopinavir derivatives. Lopinavir derivatives may also have better pharmaceutical prospects.

[0026] Beneficial effects: Compared with the prior art, the present invention has the following technical advantages: The preparation method of lopinavir derivative provided by the present invention has a reasonable process design, simple operation method, readily available raw materials, process that can be scaled up for production, high product purity, controllable reaction process, and good environmental protection effect. The lopinavir derivative prepared by the present invention provides an important basis for the scientific evaluation of the quality, safety and efficacy of lopinavir, and can also be developed as a substitute for lopinavir, which has important application value. Attached Figure Description

[0027] Figure 1 This is the NMR spectrum of the lopinavir derivative of this invention. Detailed Implementation

[0028] The present invention will now be described in detail with reference to the accompanying drawings and specific embodiments:

[0029] The preparation method of lopinavir derivatives generally includes the following steps:

[0030]

[0031] Example 1

[0032]

[0033] (1) I (25.0 g, 153 mmol) and II (25.7 g, 153 mmol) were dissolved in 250 mL of methanol. After stirring and reacting at 60 °C for 8 hours, the mixture was concentrated and then slurried with petroleum ether to obtain compound III (41.0 g), with a yield of 90.9%.

[0034] (2) Compound III (31.0 g, 105 mmol) was dissolved in 300 mL of dimethyl sulfoxide, 14.3 g of imidazole and 12.6 g of trimethylchlorosilane were added, and the mixture was stirred at 40 °C for 4 hours. After dilution with 800 mL of methyl tert-butyl ether, the mixture was washed with 300 mL of dilute hydrochloric acid and 300 mL of water, and then slurried with 400 mL of n-hexane to obtain compound IV (37.0 g), with a yield of 95.8%.

[0035] (3) Compound IV (40.0 g, 109 mmol) was dissolved in 400 mL of methanol, 4 g of palladium on carbon and ammonium formate were added, and the mixture was reacted at room temperature for 2 hours. After filtration and drying, compound V (29.0 g) was obtained, with a yield of 96.1%.

[0036] (4) Compound V (20.0 g, 72 mmol) was dissolved in 200 mL of acetonitrile, and carbonyl diimidazole (12.9 g, 79 mmol) and 4-dimethylaminopyridine (0.88 g, 7 mmol) were added. After reacting at 20 °C for 6 hours, the mixture was concentrated and then slurried with about 150 mL of isopropyl ether to obtain about 18.0 g of compound VI, with a yield of 82.3%.

[0037] (5) Compound VI (27.0 g, 78 mmol) was dissolved in 270 mL of dichloromethane and added to 235 mL of tetrabutylammonium fluoride tetrahydrofuran solution at 1 mol / L. After reacting at room temperature for 3 hours, 300 mL of dichloromethane was added for dilution, and the mixture was washed with about 200 mL of saturated saline solution. After concentration and drying, the mixture was purified by column chromatography to obtain about 15 g of compound VII, with a yield of 83.1%.

[0038] (6) Compound VII (3.0 g, 13 mmol) was dissolved in 30 mL of methanol, and 30 mL of 1 mol / L sodium hydroxide solution was added. After reacting at room temperature for 4 hours, the pH was adjusted with dilute hydrochloric acid, and the mixture was extracted three times with 100 mL of dichloromethane. After drying and concentration, 2.6 g of compound VIII was obtained, with a yield of 92.3%.

[0039] (7) Compound VIII (2.4 g, 11 mmol) and compound IX (4.9 g, 11 mmol) were dissolved in 40 mL of tetrahydrofuran. 2.9 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added. The mixture was reacted overnight at room temperature. After concentration and purification by column chromatography, 5.0 g of compound X, a lopinavir derivative, was obtained. Its chemical name is (2S)-N-((2S,4S,5S)-5-(2-(2,6-dimethylphenoxy)acetamide)-4-hydroxy-1,6-diphenylhex-2-yl)-2-(5-hydroxy-2-oxotetrahydropyrimidin-1(2H)-yl)-3-methylbutyramide, with a molecular weight of 644.81 and a yield of 70.5%. Mass spectrometry: [M+H] + 645.3, liquid chromatography 98.9%, NMR as Figure 1 As shown.

[0040] Example 2

[0041]

[0042] (1) I (25.0 g, 121 mmol) and II (25.3 g, 121 mmol) were dissolved in 200 mL of methanol. After stirring and reacting at 70 °C for 4 hours, the mixture was concentrated and then slurried with petroleum ether to obtain compound III (42.0 g), with a yield of 91.5%.

[0043] (2) Compound III (30.0 g, 79 mmol) was dissolved in 300 mL of dimethyl sulfoxide, 12.5 g of pyridine and 13.1 g of tert-butyldimethylchlorosilane were added, and the mixture was stirred at 40 °C for 4 hours. After dilution with 800 mL of methyl tert-butyl ether, the mixture was washed with 300 mL of dilute hydrochloric acid and 300 mL of water, and then slurried with 400 mL of n-hexane to obtain compound IV (38.0 g), with a yield of 97.4%.

[0044] (3) Compound IV (40.0 g, 80 mmol) was dissolved in 400 mL of ethanol, 4 g of palladium on carbon and ammonium formate were added, and the mixture was reacted at room temperature for 2 hours. After filtration and drying, compound V (28.5 g) was obtained, with a yield of 97.8%.

[0045] (4) Compound V (29.0 g, 80 mmol) was dissolved in 290 mL of acetonitrile, and carbonyl diimidazole (14.3 g, 88 mmol) and 4-dimethylaminopyridine (0.98 g, 8 mmol) were added. After reacting at 20 °C for 10 hours, the mixture was concentrated and then slurried with about 150 mL of isopropyl ether to obtain about 29.0 g of compound VI, with a yield of 93.27%.

[0046] (5) Compound VI (27.0 g, 70 mmol) was dissolved in 270 mL of dichloromethane and added to 209 mL of tetrabutylammonium fluoride tetrahydrofuran solution at 1 mol / L. After reacting at room temperature for 10 hours, 300 mL of dichloromethane was added for dilution, and the mixture was washed with about 200 mL of saturated saline solution. After concentration and drying, the mixture was purified by column chromatography to obtain about 17 g of compound VII, with a yield of 89.38%.

[0047] (6) Compound VII (3.0 g, 11 mmol) was dissolved in 30 mL of water, and 30 mL of 1 mol / L sodium hydroxide solution was added. After reacting at room temperature for 4 hours, the pH was adjusted with dilute hydrochloric acid, and the mixture was extracted three times with 100 mL of dichloromethane. After drying and concentration, 2.2 g of compound VIII was obtained, with a yield of 92.4%.

[0048] (7) Compound VIII (2.4 g, 11 mmol) and compound IX (4.9 g, 11 mmol) were dissolved in 40 mL of tetrahydrofuran. 2.9 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added, and the mixture was reacted at 50°C for 6 hours. After concentration and purification by column chromatography, 5.2 g of compound X, a lopinavir derivative, was obtained. Its chemical name is (2S)-N-((2S,4S,5S)-5-(2-(2,6-dimethylphenoxy)acetamide)-4-hydroxy-1,6-diphenylhex-2-yl)-2-(5-hydroxy-2-oxotetrahydropyrimidin-1(2H)-yl)-3-methylbutyramide, with a molecular weight of 644.81 and a yield of 73.3%. Mass spectrometry: [M+H] + 645.3, liquid phase 99.2%, NMR same as in Example 1.

[0049] Example 3

[0050]

[0051] (1) I (25.0 g, 144 mmol) and II (35.2 g, 144 mmol) were dissolved in 200 mL of ethanol. After stirring and reacting at 70 °C for 4 hours, the mixture was concentrated and then slurried with petroleum ether to obtain compound III (50.0 g), with a yield of 91.1%.

[0052] (2) Compound III (31.0 g, 81 mmol) was dissolved in 300 mL of dichloromethane, 11 g of imidazole and 13.5 g of tert-butyldimethylchlorosilane were added, and the mixture was stirred at 40 °C for 4 hours. After washing with 300 mL of water, the mixture was slurried with 400 mL of n-hexane to obtain compound IV (38.0 g), with a yield of 96.7%.

[0053] (3) Compound IV (40.0 g, 81 mmol) was dissolved in 120 mL of methane, and 120 g of trifluoroacetic acid was added. After reacting at room temperature for 4 hours, the solution was concentrated and evaporated to dryness to obtain compound V (29.0 g), with a yield of 90.9%.

[0054] (4) Compound V (20.0 g, 47 mmol) was dissolved in 200 mL of dichloromethane, and carbonyl diimidazole (8.5 g, 52 mmol) and 4-dimethylaminopyridine (0.58 g, 5 mmol) were added. After reacting at 20 °C for 20 hours, the mixture was concentrated and then slurried with about 150 mL of isopropyl ether to obtain about 13.5 g of compound VI, with a yield of 92.7%.

[0055] (5) Compound VI (27.0 g, 64 mmol) was dissolved in 270 mL of dichloromethane and added to 193 mL of tetrabutylammonium fluoride tetrahydrofuran solution at 1 mol / L. After reacting at 40 °C for 2 hours, 300 mL of dichloromethane was added for dilution. After washing with about 200 mL of saturated saline, the solution was concentrated, dried, and purified by column chromatography to obtain about 17.0 g of compound VII, with a yield of 86.5%.

[0056] (6) Compound VII (3.0 g, 10 mmol) was dissolved in 30 mL of methanol, 3 g of palladium on carbon and cyclohexene were added, and the mixture was reacted at room temperature for 2 hours. After filtration and drying, 2.0 g of compound VIII was obtained, with a yield of 94.5%.

[0057] (7) Compound VIII (2.4 g, 11 mmol) and compound IX (4.9 g, 11 mmol) were dissolved in 40 mL of tetrahydrofuran. 2.1 g of 1-hydroxybenzotriazole was added, and the mixture was reacted overnight at room temperature. After concentration and purification by column chromatography, 4.8 g of compound X, a lopinavir derivative, was obtained. Its chemical name is (2S)-N-((2S,4S,5S)-5-(2-(2,6-dimethylphenoxy)acetamide)-4-hydroxy-1,6-diphenylhex-2-yl)-2-(5-hydroxy-2-oxotetrahydropyrimidin-1(2H)-yl)-3-methylbutyramide, with a molecular weight of 644.81 and a yield of 67.6%. Mass spectrometry: [M+H] + 645.3, liquid phase 98.8%, NMR same as in Example 1.

Claims

1. A process for the preparation of a lopinavir derivative, characterized in that, The process comprises the following steps: ； wherein R1 represents benzyl, benzyloxycarbonyl, tert-butyloxycarbonyl, fluorenylmethoxycarbonyl; R2 represents C1-5 alkyl, benzyl, allyl; R3 represents trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl; (1) taking I and II dissolved in an organic solvent, stirring at 40-100℃ for 8-20 hours to obtain compound III; (2) taking compound III obtained in step (1) dissolved in an organic solution, adding a base and an organic halide, stirring at 20-80℃ for 8-20 hours, and then purifying and separating compound IV by column chromatography or recrystallization; (3) taking compound IV obtained in step (2) dissolved in an organic solvent, adding a catalyst and a hydrogen source, stirring at 20-60℃ for 8-20 hours to obtain compound V; (4) taking compound V obtained in step (3) dissolved in an organic solvent, adding a condensing agent and an organic base, reacting at 20-80℃ for 8-20 hours to obtain compound VI; (5) taking compound VI obtained in step (4) deprotected in an organic solvent to obtain compound VII; (6) taking compound VII obtained in step (5) in a solvent, adding a deprotecting agent, and reacting at 20-80℃ for 8-20 hours to obtain compound VIII; (7) reacting compound VIII obtained in step (6) with compound IX in the presence of a condensing agent to obtain compound X, i.e. a lopinavir derivative.

2. The method of preparing a lopinavir derivative according to claim 1, characterized in that, The organic solvent in step (1) is selected from dimethyl sulfoxide, dimethylformamide, dimethylacetamide, isopropanol, methanol, ethanol, acetonitrile, pyridine or tetrahydrofuran.

3. The method for preparing the lopinavir derivative according to claim 1, characterized in that, The organic solvent in step (2) is selected from dimethyl sulfoxide, dimethylformamide, dimethylacetamide, isopropanol, methanol, ethanol, acetonitrile, pyridine or tetrahydrofuran; the base is sodium bicarbonate, sodium carbonate, imidazole, triethylamine or pyridine; and the organic halide is selected from trimethylchlorosilane, trimethylbromosilane, tert-butyldimethylchlorosilane and triethylchlorosilane.

4. The method for preparing the lopinavir derivative according to claim 1, characterized in that, The organic solvent in step (3) is selected from dimethyl sulfoxide, dimethylformamide, dimethylacetamide, isopropanol, methanol, ethanol, acetonitrile, pyridine or tetrahydrofuran; the catalyst is selected from palladium on carbon and palladium hydroxide; and the hydrogen source is ammonium formate or cyclohexene.

5. The method for preparing the lopinavir derivative according to claim 1, characterized in that, The organic solvent in step (4) is selected from dimethylformamide, dichloromethane, acetonitrile, pyridine or tetrahydrofuran; the condensing agent is carbonyldiimidazole, ethyl chloroformate or p-nitrophenyl chloroformate; and the organic base is selected from triethylamine, trimethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine and diazabicyclo.

6. The method for preparing the lopinavir derivative according to claim 1, characterized in that, The organic solvent in step (5) is selected from methanol, ethanol, dioxane, tetrahydrofuran and dichloromethane.

7. The method for preparing the lopinavir derivative according to claim 1, characterized in that, The solvent in step (6) is selected from methanol, ethanol, dioxane, tetrahydrofuran, dichloromethane and water.

8. The method for preparing the lopinavir derivative according to claim 1, characterized in that, The deprotecting agent in step (6) is selected from hydrochloric acid, sulfuric acid, trifluoroacetic acid, sodium hydroxide and potassium hydroxide.

9. The method for preparing the lopinavir derivative according to claim 1, characterized in that, The condensing agent in step (7) is selected from carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole.

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