Process for the preparation of a darunavir intermediate

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of a darunavir intermediate (3aS, 4S, 6aR)-4-methoxytetrahydrofuro[3,4-b]furan-2(3H)-one. The application takes 5-(methyloxy)2-(5H)-dioxetane as a raw material, and synthesizes the darunavir intermediate compound formula I {(3aS, 4S, 6aR)-4-methoxytetrahydrofuro[3,4-b]furan-2(3H)-one} through two-step reactions of condensation and radical ring closure, has a purity of greater than 98.5%, has a high yield, is a low-cost and simple-to-operate synthesis method, and is suitable for large-scale commercial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to a method for preparing the intermediate (3aS,4S,6aR)-4-methoxytetrahydrofurano[3,4-b]furan-2(3H)-one of derenafil. Background Technology

[0002] Darunavir is an antiretroviral drug used to treat HIV-infected adults and children aged 3 years and older who weigh at least 15 kg and who have previously used other antiretroviral drugs. It belongs to a group of drugs called protease inhibitors, which work by reducing the amount of HIV in the body; they can improve the body's immune system and reduce the risk of developing HIV-related diseases.

[0003] (3aS,4S,6aR)-4-methoxytetrahydrofurano[3,4-b]furan-2(3H)-one (as shown in Formula I) is an important structural fragment for the synthesis of drinavir; all reported processes for the preparation of drinavir use Formula I as a reaction intermediate.

[0004]

[0005] There are relatively few reported methods for synthesizing Form I in the literature. The reported processes include the following routes.

[0006] Route 1: The literature Journal of Organic Chemistry, 2021, vol. 86, #1, p. 1216–1222 reports the preparation of target compounds from D-xylose or D-glucose as starting materials through a multi-step reaction including benzoyloxy protection, end-group isomerization, and Baeyer-Villiger oxidation.

[0007]

[0008] This route uses inexpensive and readily available starting materials, but the reaction steps are lengthy and the operation is very complex. Furthermore, it uses relatively expensive reagents, resulting in high operating costs and a low overall product yield. Therefore, it is not suitable for industrial production.

[0009] Route Two: The route reported in patent WO2022 / 035499 is as follows:

[0010]

[0011] This route involves a long process, complex reactions, and high costs, making it unsuitable for industrial production.

[0012] Since (3aS,4S,6aR)-4-methoxytetrahydrofurano[3,4-b]furan-2(3H)-one (Formula I) is a key intermediate in the preparation of derenavir, developing a simple, low-cost technology suitable for commercial production would have great market application value. Summary of the Invention

[0013] To address the problems existing in the prior art, the present invention aims to provide a method for preparing the derenavir intermediate compound of formula I {(3aS,4S,6aR)-4-methoxytetrahydrofurano[3,4-b]furan-2(3H)-one}. The present invention uses compound II, 5-(methoxy)2-(5H)-dioxane, as a starting material, and synthesizes the derenavir intermediate compound of formula I {(3aS,4S,6aR)-4-methoxytetrahydrofurano[3,4-b]furan-2(3H)-one} through a two-step reaction of condensation and free radical cyclization. The purity is >98.5%, and the yield is high. This is a low-cost and simple synthetic method suitable for large-scale commercial production.

[0014] The technical solution of this invention is:

[0015] A method for preparing a direnavisin intermediate compound of formula I {(3aS,4S,6aR)-4-methoxytetrahydrofurano[3,4-b]furan-2(3H)-one},

[0016]

[0017] Includes the following steps:

[0018] S1: Compound of Formula II is synthesized into Compound of Formula III via a condensation reaction:

[0019]

[0020] S2: Compound III undergoes a self-cyclization reaction to yield compound I:

[0021]

[0022] Furthermore, it includes the following steps:

[0023] S1: Compound of Formula II is synthesized into Compound of Formula III via a condensation reaction:

[0024]

[0025] S2: Compound III undergoes a self-cyclization reaction to yield compound IV:

[0026]

[0027] Subsequently, compound IV was purified to obtain compound I:

[0028]

[0029] Further, in step S1, compound II is condensed with a reagent that introduces methoxymethyl ether to obtain compound III; the amount of the reagent introducing methoxymethyl ether is 1 to 3 molar equivalents of compound II; the reaction temperature is 0 to 50°C. Preferably, the reagent introducing methoxymethyl ether in step S1 is chloromethyl methyl ether (MOMCl), bromomethyl methyl ether (MOMBr), etc.

[0030] Furthermore, in step S1, N,N-diisopropylethylamine, triethylamine, pyridine, sodium bicarbonate, sodium carbonate, or potassium carbonate are used as acid-binding agents.

[0031] Furthermore, in step S2, the compound of formula III undergoes a free radical self-cyclization reaction in the presence of a photocatalyst to obtain the compound of formula I; the mass ratio of the photocatalyst to the compound of formula III in step S2 is 1:0.1-3.

[0032] Furthermore, the photocatalyst in step S2 is one of AIBN, TBADT (tetrabutylammonium decatungstate), Thioxanthone, and 9-fluorenone.

[0033] Furthermore, the photocatalyst in step S2 is TBADT.

[0034] Furthermore, in step S2, the compound of formula III undergoes a free radical self-cyclization reaction in the presence of a base to obtain the compound of formula I.

[0035] Furthermore, the alkali in step S2 is sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, N,N-diisopropylethylamine, triethylamine, pyridine, etc.

[0036] Furthermore, step S2 uses LED, UV, or natural light as the light source; the UV is 254nm or 365nm.

[0037] Further, step S1 uses one or more of dichloromethane (1,2-dichloromethane), ethyl acetate, ethanol, methanol, tetrahydrofuran, water, toluene, and chloroform as solvents;

[0038] And / or,

[0039] Step S2 uses one or more of the following solvents: acetonitrile, water, dichloromethane, ethyl acetate, ethanol, methanol, tetrahydrofuran, toluene, chloroform, isopropanol, and glacial acetic acid.

[0040] The technical solution of this invention has the following beneficial effects:

[0041] This invention uses compound 5-(methoxy)2-(5H)-dioxane-ketone of formula II as a starting material to synthesize the intermediate compound of formula I {(3aS,4S,6aR)-4-methoxytetrahydrofurano[3,4-b]furan-2(3H)-one} of derenafil through a two-step reaction of condensation and free radical cyclization. The purity is >98.5%, and the yield is high. This is a low-cost and simple synthetic method suitable for large-scale commercial production. Attached Figure Description

[0042] Figure 1 This is the structural formula of compound I of the present invention. Detailed Implementation

[0043] The present invention will be further described below through specific embodiments, but this is not a limitation of the present invention. Those skilled in the art can make various modifications or improvements based on the basic idea of ​​the present invention, but as long as they do not depart from the basic idea of ​​the present invention, they are all within the protection scope of the present invention.

[0044] Unless otherwise specified, the reagents used in the following examples and comparative examples are conventional reagents and can be purchased from conventional reagent manufacturers and distributors.

[0045] Example 1

[0046] Preparation of compound III, 5-(methoxymethoxy)methyl)furan-2(5H)-one:

[0047] Dichloromethane, compound II (11.4 g, 0.1 mol), and triethylamine (20.2 g, 0.2 mol) were added to a reaction vessel and stirred until dissolved. MOMCl (9.66 g, 0.12 mol) was slowly added dropwise, and the mixture was stirred until homogeneous. The reaction was then carried out at 10–20 °C for 2 hours, monitored by TLC until complete. After the reaction was complete, a saturated aqueous solution of ammonium chloride was slowly poured into the reaction solution, and the mixture was stirred for another 0.5 hours. The solution was then allowed to stand and separated. The organic phase was concentrated to give 14.22 g of compound III, with a yield of 90% and a purity of 95.6%.

[0048] Mass spectrometry: m / s 159.06 [M] + .

[0049] Preparation of compound (3aS,6aR)-tetrahydro-4-methoxyfurano[3,4-b]furan-2(3H)-one of formula I:

[0050] Compound III (7.9 g, 0.05 mol) and acetonitrile (150 mL) were dissolved by stirring. TBADT (0.79 g) and sodium bicarbonate (8.4 g, 0.1 mol) were added as photocatalysts and stirred until homogeneous. The mixture was purged with nitrogen three times and irradiated under a 405±5 nm LED for 10–20 h. HPLC monitoring was maintained until the reaction was complete. Insoluble solids were filtered off, and the filtrate was concentrated to dryness. The resulting residue (compound IV) was dissolved in methanol, and p-toluenesulfonic acid was added and stirred for 1 h. After removing the methanol by evaporation, water / dichloromethane was added for extraction. The dichloromethane layer was concentrated, and the resulting residue was recrystallized from isopropanol. The residue was filtered and dried to obtain compound I, 5.14 g, yield 65%, purity 98.9%.

[0051] Mass spectrometry: m / s 159.06 [M] + .

[0052] MRI 1 HNMR(DMSO,600Mz):5.18(1H,dd),4.95(1H,s),3.96(1H,d),3.78(1H,dd),3.21(3H,s),2.90(2H,m),2.55(1H,dd).

[0053] Example 2

[0054] Preparation of compound III, 5-(methoxymethoxy)methyl)furan-2(5H)-one:

[0055] Dichloromethane, compound II (11.4 g, 0.1 mol), and triethylamine (20.2 g, 0.2 mol) were added to a reaction vessel and stirred until dissolved. MOMBr (15.0 g, 0.12 mol) was slowly added dropwise, and the mixture was stirred until homogeneous. The reaction was then carried out at 10–20 °C for 2 hours, monitored by TLC until complete. After the reaction was complete, a saturated aqueous solution of ammonium chloride was slowly poured into the reaction solution, and the mixture was stirred for another 0.5 hours. The solution was then allowed to stand and separated. The organic phase was concentrated to give 15.02 g of compound III, with a yield of 95% and a purity of 97.6%.

[0056] The remaining steps are the same as in Example 1.

[0057] Mass spectrometry: m / s 159.06 [M+1] + .

[0058] Example 3

[0059] Preparation of compound (3aS,6aR)-tetrahydro-4-methoxyfurano[3,4-b]furan-2(3H)-one of formula I:

[0060] Compound III (1.58 g, 0.01 mol) and acetonitrile (20 mL) were dissolved by stirring. TBADT (0.16 g) and sodium bicarbonate (1.68 g, 0.02 mol) were added and stirred until homogeneous. The mixture was purged with nitrogen three times and then irradiated with ultraviolet light (λEXC = 365 nm) for 10–20 h. The reaction was monitored by HPLC until completion. Insoluble solids were filtered off, and the filtrate was concentrated to dryness. The residue was subjected to ethyl acetate / n-heptane (1 / 5–1 / 1) column chromatography. The target product was collected, concentrated, and dried to obtain compound IV, 1.23 g, yield 78%.

[0061] The remaining steps are the same as in Example 1.

[0062] Mass spectrometry: m / s 159.06 [M] + .

[0063] Example 4

[0064] Preparation of compound (3aS,6aR)-tetrahydro-4-methoxyfurano[3,4-b]furan-2(3H)-one of formula I:

[0065] Compound III (1.58 g, 0.01 mol) and acetonitrile (20 mL) were dissolved by stirring. TBADT (0.16 g) and sodium bicarbonate (1.68 g, 0.02 mol) were added and stirred until homogeneous. The mixture was purged with nitrogen three times and then irradiated with ultraviolet light (λEXC = 310 nm) for 10–20 h. HPLC monitoring was maintained until the reaction was complete. Insoluble solids were filtered off, and the filtrate was concentrated to dryness. The residue was subjected to ethyl acetate / n-heptane (1 / 5–1 / 1) column chromatography. The target product was collected, concentrated, and dried to obtain compound IV, 1.16 g, yield 73%.

[0066] The remaining steps are the same as in Example 1.

[0067] Mass spectrometry: m / s 159.06 [M] + .

[0068] The above embodiments are merely illustrative of the principles and effects of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by those skilled in the art without departing from the spirit and technical concept disclosed in the present invention should still be covered by the claims of the present invention.

Claims

1. A method for preparing derenavir intermediate of formula I, ； Its features are: Includes the following steps: S1: Compound of Formula II is synthesized into Compound of Formula III via a condensation reaction. ； S2: Compound of Formula III undergoes a self-cyclization reaction to obtain compound of Formula I: ； Compound III was prepared by radical self-cyclization reaction in the presence of a photocatalyst and a base to obtain compound I. The photocatalyst is TBADT.

2. The method for preparing derenafil intermediate formula I as described in claim 1, characterized in that: In step S1, compound II is condensed with a reagent that introduces methoxymethyl ether to obtain compound III; the amount of the reagent that introduces methoxymethyl ether is 1 to 3 molar equivalents of compound II; the reaction temperature is 0 to 50°C.

3. The method for preparing derenafil intermediate formula I as described in claim 1, characterized in that: Step S1 uses N,N-diisopropylethylamine, triethylamine, pyridine, sodium bicarbonate, sodium carbonate, or potassium carbonate as an acid-binding agent.

4. The method for preparing derenafil intermediate formula I as described in claim 1, characterized in that: In step S2, the mass ratio of the photoreaction catalyst to the compound of formula III is 1:0.1~3.

5. The method for preparing derenafil intermediate formula I as described in claim 1, characterized in that: The base in step S2 is sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, N,N-diisopropylethylamine, triethylamine, or pyridine.

6. The method for preparing derenafil intermediate formula I as described in claim 1, characterized in that: Step S2 uses LED, UV, or natural light as the light source; the UV is 254nm or 365nm.

7. The method for preparing derenafil intermediate formula I as described in claim 1, characterized in that: Step S1 uses one or more of dichloromethane, ethyl acetate, ethanol, methanol, tetrahydrofuran, water, toluene, and chloroform as solvents. And / or, Step S2 uses one or more of the following solvents: acetonitrile, water, dichloromethane, ethyl acetate, ethanol, methanol, tetrahydrofuran, toluene, chloroform, isopropanol, and glacial acetic acid.

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