Process for the preparation of aminopentofylline

Abstract

The application discloses a preparation method of amnolevir, which comprises the following steps: preparing amnolevir through ethylation reaction, condensation reaction and isopropylization reaction of compound 1. The method has the advantages of novel and short preparation route, high atom utilization rate, easy availability of raw materials and reaction reagents, convenient operation and suitability for industrialization. Meanwhile, the method does not adopt toxic reagents or dangerous processes, waste can be controlled, operation safety is good, and the method is green and friendly to the environment.

Description

Technical Field

[0001] This invention relates to a method for preparing enoxavirine, and more particularly to a method for preparing enoxavirine suitable for industrial application. Background Technology

[0002] Enavirin's chemical name is 3-{[3-ethyl-2,6-dioxo-5-(propyl-2-yl)-1,2,3,6-tetrahydropyrimidin-4-yl]carbonyl}-5-methylbenzonitrile. As a new generation of non-nucleoside reverse transcription inhibitors, it is usually used in combination with nucleoside antiretroviral drugs in the clinical treatment of treatment-naïve adult HIV-1 infected patients. It has the characteristics of low dosage, fewer drug interactions, lower hepatotoxicity and nephrotoxicity, and antiviral efficacy for patients with both high and low viral loads.

[0003]

[0004] US patent 20090163712 discloses a linear synthesis method for enovirine, using diethyl malonate as the starting material. The process involves sequential isopropylation, urea ring closure, chlorination, and methoxylation, followed by condensation with molecular fragment A, oxygen oxidation, demethylation under acidic conditions, cyanation, and finally ethyl substitution. This method has a long preparation route, employs hazardous chemical processes and reagents in multiple steps, is cumbersome, has low safety, and is not conducive to industrialization.

[0005]

[0006] WO2010085128 also discloses a convergent synthesis method for anivirine, using ethyl cyanoacetate as the starting material. The ethyl cyanoacetate undergoes isopropylation, ethyl urea cyclization, diazotization-bromination to obtain a bromopyrimidinone, followed by magnesium-bromine exchange under Grignard reagent conditions, and finally a coupling reaction with molecular fragment B to obtain anivirine. However, the conversion rate of the key coupling reaction step in this method is less than 50%. Furthermore, the preparation route for molecular fragment B, referring to patent WO2010009047, is lengthy, the raw materials are difficult to obtain, a photocatalytic reaction is required, and the oxidant PCC is pyridine chlorochromate, which causes significant chromium pollution and poses a considerable health hazard. Therefore, this method still lacks a cost advantage for industrialization.

[0007]

[0008] Given the shortcomings of existing preparation methods, it is essential to continuously develop more efficient, green, and environmentally friendly industrialization routes. Summary of the Invention

[0009] Purpose of the invention: In view of the problems of limited reaction efficiency, poor reaction economy, and cumbersome and dangerous operation in the existing preparation methods, the present invention aims to provide a method for preparing enovalin with readily available raw materials, a simple preparation route, and high atom utilization.

[0010] Technical solution: The preparation method of enovirine of the present invention includes the following steps:

[0011]

[0012] Anovalin was prepared from compound 1 (i.e., orotic acid) through ethylation, condensation and isopropylation; X in compound 2 is a halogen.

[0013] In step a, the ethylating agent used is preferably bromoethane, iodoethane, or diethyl sulfate, more preferably bromoethane; the catalyst is preferably sodium methoxide, sodium ethoxide, cesium carbonate, lithium carbonate, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, sodium hydroxide, lithium hydride, sodium hydride, sodium hydroxide, triethylamine, diisopropylethylamine, or DBU, more preferably diisopropylethylamine; the solvent is preferably at least one of acetone, N,N-dimethylformamide, and acetonitrile, more preferably acetonitrile. The preferred molar ratio of the ethylating agent, catalyst, and compound 1 is 1–5:1–5:1, more preferably 2–4:2–4:1, specifically 3:2.4:1; the preferred reaction temperature is room temperature to 100°C, more preferably 60–100°C, specifically 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, and 100°C.

[0014] In step b, the condensing agent X is preferably bromine or iodine; the catalyst is preferably a base reagent such as sodium hydride, lithium hydride, lithium diisopropylaminochloride, or lithium isopropylmagnesium chloride, more preferably sodium hydride; the solvent is preferably at least one of tetrahydrofuran and dimethyltetrahydrofuran, more preferably tetrahydrofuran. The molar ratio of the condensing agent, catalyst, and compound 3 is preferably 1–5:0–5:1, more preferably 1–3:0–3:1, specifically 1.2:1.2:1 or 2.5:0:1; the reaction temperature is preferably -78–30°C, more preferably -30–20°C, specifically -5°C, 0°C, or 5°C.

[0015] Compound 2 involved in this step is prepared by reacting 3-halo-5-methylphenylcyanide with isopropyl magnesium chloride and lithium chloride. The molar ratio of 3-halo-5-methylphenylcyanide to isopropyl magnesium chloride and lithium chloride is preferably 1:1 to 5, more preferably 1:1 to 2, specifically 1:1.3; the reaction temperature is preferably -78 to 30°C, more preferably -30 to 20°C, specifically -5°C, 0°C, and 5°C.

[0016] In step c, the isopropylating agent is preferably isopropylboric acid or isobutyric acid, more preferably isobutyric acid; the initiator is preferably ammonium persulfate, potassium persulfate, sodium persulfate, hydrogen peroxide or oxygen, more preferably ammonium persulfate; the catalyst is preferably manganese acetate, silver acetate, silver trifluoromethanesulfonate, silver bromide or silver fluoride, more preferably silver acetate; the solvent is preferably at least one of methanol, toluene, acetonitrile, DMF, DMSO, tetrahydrofuran, dimethyltetrahydrofuran, more preferably acetonitrile. The preferred molar ratio of the isopropylating agent, initiator, catalyst and compound 4 is 1–5:0.01–5:0.01–3:1, more preferably 1–3:0.01–3:0.01–1:1, specifically 1.5:1.5:1:1, 2:2:0.05:1, 5:5:1.5:1, 2:2:0.01:1; the preferred reaction temperature is 60–130℃, more preferably 90–110℃, specifically 60℃, 65℃, 70℃, 75℃, 80℃, 85℃, 90℃, 95℃, 100℃, 105℃, 110℃.

[0017] The intermediates (compounds 3 to 4) and the final product (anivirine) obtained from the above reactions are all purified and separated, including but not limited to chromatographic purification, extraction, recrystallization, washing, pulping, filtration and centrifugation.

[0018] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0019] 1. The preparation route is novel and concise, with high atom utilization, readily available raw materials and reagents, and convenient operation, making it suitable for industrialization;

[0020] 2. No toxic reagents or hazardous processes are used, waste is controllable, operation is safe, and it is environmentally friendly. Detailed Implementation

[0021] The technical solution of the present invention will be further described below with reference to the embodiments.

[0022] Example 1: Preparation of Compound 3

[0023]

[0024] 1. Experiment 1

[0025] Orotic acid (6.24 g, 40 mmol), 60 mL acetonitrile, diisopropylethylamine (12.4 g, 96 mmol), and bromoethane (13.0 g, 120 mmol) were added sequentially to a 250 mL dry reaction flask, and the mixture was stirred at 65 °C for 24 h. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography to obtain compound 3 as a white solid (4.07 g, 48%).

[0026] 1 H NMR (CDCl3, 400MHz): 9.44 (br s, 1H), 6.07 (d, J = 2.0Hz, 1H), 4.40 (q, J = 7.2Hz, 2H), 4.00 (q, J = 7.2Hz, 2H), 1.39 (t, J = 6.8Hz, 3H), 1.30 (q, J = 6.8Hz, 3H); 13 C NMR (CDCl3, 100MHz): 162.6, 161.6, 151.0, 146.2, 105.2, 63.5, 41.8, 14.6, 14.1.

[0027] 2. Experiment 2

[0028] Orotic acid (6.24 g, 40 mmol), 60 mL acetonitrile, diisopropylethylamine (12.4 g, 96 mmol), and iodoethane (18.8 g, 120 mmol) were added sequentially to a 250 mL dry reaction flask, and the mixture was stirred at 65 °C for 24 h. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography to obtain compound 3 as a white solid (5.26 g, 62%).

[0029] 3. Experiment 3

[0030] Orotic acid (6.24 g, 40 mmol), 60 mL acetonitrile, triethylamine (9.8 g, 96 mmol), and bromoethane (13.0 g, 120 mmol) were added sequentially to a 250 mL dry reaction flask, and the mixture was stirred at 65 °C for 24 h. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography to obtain compound 3 as a white solid (2.63 g, 31%).

[0031] 4. Experiment 4

[0032] Orytic acid (6.24 g, 40 mmol), 60 mL acetonitrile, lithium hydride (0.77 g, 96 mmol), and bromoethane (13.0 g, 120 mmol) were added sequentially to a 250 mL dry reaction flask, and the mixture was stirred at 65 °C for 24 h. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography to obtain compound 3 as a white solid (1.53 g, 18%).

[0033] 5. Experiment 5

[0034] Orotic acid (6.24 g, 40 mmol), N,N-dimethylformamide (60 mL), diisopropylethylamine (12.4 g, 96 mmol), and bromoethane (13.0 g, 120 mmol) were added sequentially to a 250 mL dry reaction flask, and the mixture was stirred at 65 °C for 24 h. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography to obtain compound 3 as a white solid (3.39 g, 40%).

[0035] 6. Experiment 6

[0036] Orotic acid (6.24 g, 40 mmol), 60 mL acetonitrile, diisopropylethylamine (12.4 g, 96 mmol), and bromoethane (13.0 g, 120 mmol) were added sequentially to a 250 mL dry reaction flask, and the mixture was stirred at 40 °C for 24 h. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography to obtain compound 3 as a white solid (2.12 g, 25%).

[0037] 7. Experiment 7

[0038] Orotic acid (6.24 g, 40 mmol), 60 mL acetonitrile, diisopropylethylamine (12.4 g, 96 mmol), and bromoethane (13.0 g, 120 mmol) were added sequentially to a 250 mL dry reaction flask, and the mixture was stirred at 100 °C for 24 h. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography to obtain compound 3 as a white solid (3.22 g, 38%).

[0039] Example 2: Synthesis of Compound 4

[0040]

[0041] 1. Experiment 1

[0042] 3-Bromo-5-methylphenylcyanide (0.980 g, 5.0 mmol) was added to the reaction flask, and after purging with nitrogen, THF (5 mL) was added. The mixture was cooled to 0 °C, and 1.3 M iPrMgCl·LiCl (6.50 mmol) was added. The mixture was stirred at 0 °C for 10–12 h to prepare Grignard reagent compound 2, which was then ready for use.

[0043] Compound 3 (0.890 g, 4.20 mmol) was added to another reaction flask. After purging with nitrogen, THF (3 mL) was added, followed by the addition of 60% sodium hydride mineral (200 mg, 5.0 mmol) at 0 °C. The mixture was stirred for 0.5 h, and then compound 2 was slowly added. The mixture was stirred at 0 °C for 10–12 h. The reaction mixture was quenched with dilute hydrochloric acid, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound 4 as a white solid (0.550 g, 46%).

[0044] 1H NMR(CDCl3,400MHz):9.42(br s,1H),8.07(s,1H),7.97(s,1H),7.80(s,1H),5.68(d,J=2.0Hz,1H),3.78(q,J=7.2Hz,2H),2.52(s,3H),1.22(t,J=7.2Hz,3H). 13 C NMR (CDCl3, 100MHz): 187.0, 162.1, 150.7, 150.6, 141.4, 138.8, 134.9, 134.6, 131.0, 117.3, 114.1, 103.2, 41.5, 21.3, 14.6.

[0045] 2. Experiment 2

[0046] 3-Bromo-5-methylphenylcyanide (2.06 g, 10.5 mmol) was added to the reaction flask, and after purging with nitrogen, THF (10 mL) was added. The mixture was cooled to 0 °C, and 1.3 M iPrMgCl·LiCl (13.5 mmol) was added. The mixture was stirred at 0 °C for 10–12 h to prepare Grignard reagent compound 2, which was then ready for use.

[0047] Compound 3 (0.890 g, 4.20 mmol) was added to another reaction flask, purged with nitrogen, and then THF (3 mL) was added. Pre-prepared compound 2 was slowly added at 0 °C, and the reaction was stirred at 0 °C for 10–12 h. The mixture was quenched with dilute hydrochloric acid, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound 4, a white solid (0.452 g, 38%).

[0048] 3. Experiment 3

[0049] 3-Bromo-5-methylphenylcyanide (0.980 g, 5.0 mmol) was added to the reaction flask, and after purging with nitrogen, THF (5 mL) was added. The mixture was cooled to 0 °C, and 1.3 M iPrMgCl·LiCl (6.50 mmol) was added. The mixture was stirred at 0 °C for 10–12 h to prepare Grignard reagent compound 2, which was then ready for use.

[0050] Compound 3 (0.890 g, 4.20 mmol) was added to another reaction flask. After purging with nitrogen, THF (3 mL) was added, followed by 1.3 M iPrMgCl·LiCl (5.0 mmol) at 0 °C. The mixture was stirred for 0.5 h, and then compound 2 was slowly added. The mixture was stirred at 0 °C for 10–12 h. The reaction mixture was quenched with dilute hydrochloric acid, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound 4 as a white solid (0.41 g, 34%).

[0051] Example 3: Preparation of enovalin

[0052]

[0053] 1. Experiment 1

[0054] Compound 4 (113 mg, 0.4 mmol), AgOAc (6.6 mg, 0.4 mmol), and (NH4)2S2O8 (137 mg, 0.6 mmol) were added to the reaction flask. After purging with nitrogen, 0.5 mL of acetonitrile and isobutyric acid (53 mg, 0.6 mmol) were added. The mixture was stirred at 100 °C for 24 h, cooled to room temperature, diluted with ethyl acetate, filtered through silica gel (eluting with ethyl acetate), concentrated under reduced pressure, and purified by column chromatography to obtain enovirine, a white solid (88 mg, 74%).

[0055] 1 H NMR(CDCl3,400MHz):9.16(br s,1H),8.06(s,1H),7.96(s,1H),7.80(s,1H),3.96-3.86(m,1H),3.22-3.11(m,1H ),2.53(s,3H),2.23(sept,J=6.8Hz,1H),1.22(d,J=6.8Hz,3H),1.16-1.11(m,6H). 13 C NMR (CDCl3, 100MHz): 188.5,162.3,150.5,145.7,141.6,138.9,135.4,133.8,130.2,117.3,116.8,114.3,41.8,29.3,21.3,20.4,19.7,14.2.

[0056] 2. Experiment 2

[0057] Compound 4 (113 mg, 0.4 mmol), AgOAc (3.3 mg, 0.02 mmol), and (NH4)2S2O8 (183 mg, 0.8 mmol) were added to the reaction flask. After purging with nitrogen, 0.5 mL of acetonitrile and isobutyric acid (70.5 mg, 0.8 mmol) were added. The mixture was stirred at 100 °C for 36 h, cooled to room temperature, diluted with ethyl acetate, filtered through silica gel (eluting with ethyl acetate), concentrated under reduced pressure, and purified by column chromatography to obtain enovirine, a white solid (0.0920 g, 71%).

[0058] 3. Experiment 3

[0059] Compound 4 (113 mg, 0.4 mmol), AgOAc (6.6 mg, 0.4 mmol), and (NH4)2S2O8 (137 mg, 0.6 mmol) were added to the reaction flask. After purging with nitrogen, 0.5 mL of acetonitrile and isobutyric acid (53 mg, 0.6 mmol) were added. The mixture was stirred at 80 °C for 24 h, cooled to room temperature, diluted with ethyl acetate, filtered through silica gel (eluting with ethyl acetate), concentrated under reduced pressure, and purified by column chromatography to obtain enovirine, a white solid (137 mg, 62%).

[0060] 4. Experiment 4

[0061] Compound 4 (113 mg, 0.4 mmol), Mn(OAc)3 2H2O (161 mg, 0.6 mmol), and (NH4)2S2O8 (456 mg, 2 mmol) were added to the reaction flask. After purging with nitrogen, 1 mL of a mixed solvent of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane and DME, and isopropylboronic acid (176 mg, 2 mmol) were added. The mixture was stirred at 120 °C for 12 h, cooled to room temperature, diluted with ethyl acetate, filtered through silica gel (eluting with ethyl acetate), concentrated under reduced pressure, and purified by column chromatography to obtain enovirine, a white solid (40.4 mg, 34%).

[0062] 5. Experiment 5

[0063] Compound 4 (113 mg, 0.4 mmol), AgOTf (10.3 mg, 0.04 mmol), and (NH4)2S2O8 (183 mg, 0.8 mmol) were added to the reaction flask. After purging with nitrogen, 0.5 mL of acetonitrile and isobutyric acid (70.5 mg, 0.8 mmol) were added. The mixture was stirred at 100 °C for 12 h, cooled to room temperature, diluted with ethyl acetate, filtered through silica gel (eluting with ethyl acetate), concentrated under reduced pressure, and purified by column chromatography to obtain enovirine, a white solid (51.1 mg, 43%).

[0064] 6. Experiment 6

[0065] Compound 4 (113 mg, 0.4 mmol), AgNO3 (6.8 mg, 0.04 mmol), and (NH4)2S2O8 (137 mg, 0.8 mmol) were added to the reaction flask. After purging with nitrogen, 0.5 mL of acetonitrile and isobutyric acid (70.5 mg, 0.8 mmol) were added. The mixture was stirred at 100 °C for 36 h, cooled to room temperature, diluted with ethyl acetate, filtered through silica gel (eluting with ethyl acetate), concentrated under reduced pressure, and purified by column chromatography to obtain enovirine, a white solid (69 mg, 58%).

Claims

1. A method for preparing enovirine, characterized in that, Includes the following steps: ， Compound 1 was prepared into enovalin via ethylation, condensation and isopropylation; X in compound 2 is a halogen.

2. The preparation method according to claim 1, characterized in that, The ethylation reaction uses bromoethane, iodoethane, or diethyl sulfate as the ethylating agent, sodium methoxide, sodium ethoxide, cesium carbonate, lithium carbonate, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, sodium hydroxide, lithium hydride, sodium hydride, triethylamine, diisopropylethylamine, or DBU as the catalyst, and acetone as the solvent. N,N -At least one of dimethylformamide and acetonitrile.

3. The preparation method according to claim 2, characterized in that, The molar ratio of the ethylating agent, catalyst and compound 1 is 1~5:1~5:

1.

4. The preparation method according to claim 1, characterized in that, In the condensation reaction, X in compound 2 is bromine or iodine, the catalyst is sodium hydride, lithium hydride, lithium diisopropylamino, or lithium isopropyl magnesium chloride, and the solvent is at least one of tetrahydrofuran and dimethyltetrahydrofuran.

5. The preparation method according to claim 4, characterized in that, The molar ratio of compound 2, catalyst and compound 3 is 1~5:0~5:

1.

6. The preparation method according to claim 1, characterized in that, The isopropylation reaction uses isopropylboric acid or isobutyric acid as the isopropylating agent, ammonium persulfate, potassium persulfate or sodium persulfate as the initiator, manganese acetate, silver acetate, silver trifluoromethanesulfonate, silver bromide or silver fluoride as the catalyst, and at least one of methanol, toluene, acetonitrile, DMF, DMSO, tetrahydrofuran, and dimethyltetrahydrofuran as the solvent.

7. The preparation method according to claim 6, characterized in that, The molar ratio of the isopropylating agent, initiator, catalyst to compound 4 is 1~5:0.01~5:0.01~3:

1.

8. The preparation method according to claim 1, characterized in that, Compound 2 was prepared by reacting 3-halo-5-methylphenylcyanide with isopropyl magnesium chloride and lithium chloride.

9. The preparation method according to claim 8, characterized in that, The molar ratio of 3-halo-5-methylphenylcyanide to isopropyl magnesium chloride and lithium chloride is 1:1~5.

10. The preparation method according to claim 1, characterized in that, The reaction steps also include purification and separation processes.

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