A synthetic method of monopiravir

Abstract

The present invention discloses a method for synthesizing monopiravir as shown in formula (I), comprising the following steps: in a reaction solvent, compound (V) undergoes an esterification reaction with an esterification agent under the action of lipase to generate compound (I), i.e. monopiravir; the esterification agent is at least one of vinyl isobutyrate and 2-propylene isobutyrate, and the lipase is Novozym435 lipase. In the present invention, compound (V) and the esterification agent are converted into the target product monopiravir (I) by enzyme catalysis, the product yield is high, and the reaction process is green and environmentally friendly. #imgabs0#

Description

Technical Field

[0001] The present invention relates to the field of synthesis of pharmaceutical intermediates, and in particular to a method for synthesizing monopiravir. Background Art

[0002] β-D-N4 hydroxycytidine-5'-isopropyl ester, whose structure is shown in formula (I), is a broad-spectrum antiviral drug with good tolerability. Its mechanism of action is that a broad spectrum of RNA viruses prevents the introduction of viruses by blocking the inhibitory activity of RNA, especially the polymerase that inhibits the replication of SARS-CoV-2. The drug is commercially known as Molnupiravir and was developed by Emory University. The drug was approved for marketing by the U.S. Food and Drug Administration (FDA) on October 28, 2021.

[0003]

[0004] The synthetic methods for synthesizing monopiravir (I) reported so far are mainly as follows:

[0005]

[0006] Patent WO2019113462A1 uses uridine as raw material, and undergoes five steps of reactions including acetone protection, selective esterification of the 5-hydroxyl group, triazole coupling, hydroxylation reaction, and deprotection, and then obtains monopiravir through complex crystallization.

[0007]

[0008] N. Vasudevan et al. used cytidine as the raw material. Compared with uridine, cytidine is a relatively cheap and easily available raw material. They first carried out hydroxylation reaction with hydroxylamine acetate, and then used Novozym435 lipase to carry out ester exchange reaction on the 5-hydroxyl group. Alternatively, they adjusted the reaction sequence and synthesized the target product monopiravir in two steps (ChemComm, 2020, 56: 13363-13364).

[0009]

[0010] Tamas Benkovics et al. used furanose as raw material (ChemRxiv, 2020: 1-5) and synthesized the target product monopiravir in three steps through 5-selective esterification, coupling, and hydroxylation. Summary of the invention

[0011] The purpose of the present invention is to provide a method for synthesizing monopiravir which has a simple reaction route, mild reaction conditions, high product yield and is suitable for large-scale production.

[0012] In order to achieve the above-mentioned invention object, the present invention adopts the following technical scheme:

[0013] A method for synthesizing monopiravir represented by formula (I) comprises the following steps: in a reaction solvent, compound (V) undergoes an esterification reaction with an esterification agent under the action of lipase to generate compound (I), i.e. monopiravir; the esterification agent is at least one of vinyl isobutyrate and 2-propylene isobutyrate, and the lipase is Novozym435 lipase; the reaction formula is as follows:

[0014]

[0015] Preferably, the reaction solvent is an ether solvent; more preferably, the ether solvent is at least one of 2-methyltetrahydrofuran and 1,4-dioxanetetrahydrofuran. The volume amount of the reaction solvent is preferably 10-20 mL / g based on the mass of compound (V).

[0016] Preferably, the mass ratio of the compound (V) to the lipase is 1:0.01-0.5, more preferably 0.05-0.15, most preferably 1:0.1.

[0017] Preferably, the molar ratio of the compound (V) to the esterification agent is 1:0.8-5, more preferably 1:1-2.5, most preferably 1:2.

[0018] Preferably, the temperature of the esterification reaction is 20 to 70°C, more preferably 55 to 65°C.

[0019] Preferably, the esterification reaction time is 1 to 4 hours, more preferably 2 to 3 hours.

[0020] After the esterification reaction is completed, the target product can be obtained by a simple post-treatment of the obtained reaction mixture. The post-treatment method is as follows: the obtained reaction mixture is filtered, the filtrate is extracted with ethyl acetate, washed with water, separated by layers, the aqueous phase is extracted with ethyl acetate for multiple times, TLC is monitored until there is no product in the aqueous phase, the organic phases are combined and dried with anhydrous sodium sulfate, and desolventized to obtain monopiravir.

[0021] Preferably, the method for synthesizing monopiravir further comprises the following steps:

[0022] (1) N4-acetylcytosine represented by formula (II) and tetraacetylribose are subjected to coupling reaction to obtain compound (III);

[0023] (2) Compound (III) reacts with methanol in the presence of a base to obtain compound (IV);

[0024] (3) Compound (IV) reacts with hydroxylamine to generate compound (V);

[0025] The reaction formula is as follows:

[0026]

[0027] Preferably, the step (1) is implemented as follows: N4-acetylcytosine represented by formula (II) is added to an organic solvent A, trimethylsilyl chloride (TMSCl) is added dropwise at room temperature, the temperature is raised to 120-130°C until the reaction solution becomes colorless and transparent, the trimethylsilyl chloride is evaporated under reduced pressure, the colorless residue is dissolved in an organic solvent B, tetraacetyl ribose and a Lewis acid catalyst are added at room temperature, the temperature is raised to 65-75°C for coupling reaction, and after the reaction is completed, compound (III) is obtained by post-treatment.

[0028] As further preferred, in step (1), the organic solvent A is hexamethyldisiloxane (HMDS); the organic solvent B is dichloromethane, dichloroethane, acetonitrile or any mixture thereof, more preferably dichloroethane.

[0029] As further preferred, in step (1), the Lewis acid catalyst is anhydrous tin tetrachloride, anhydrous ferric chloride, trimethylsilyl trifluoromethanesulfonate or trifluoromethanesulfonic acid, more preferably anhydrous tin tetrachloride.

[0030] As a further preference, in step (1), the molar ratio of N4-acetylcytosine to tetraacetylribose is 1:0.9-2, more preferably 1:1-1.1.

[0031] As a further preference, in step (1), the feed ratio of the N4-acetylcytosine to trimethylchlorosilane and Lewis acid catalyst is 20 g: 20-30 mL: 1.5-2.5 mL.

[0032] The coupling reaction process of step (1) of the present invention is monitored by TLC, and the reaction is terminated after the conversion of the raw materials is complete. After the reaction is completed, the post-treatment operation is recommended as follows: the obtained reaction mixture is neutralized with a saturated sodium bicarbonate aqueous solution to a neutral pH, then extracted, the organic phase is dried with anhydrous sodium sulfate, and desolventized to obtain compound (III).

[0033] Preferably, in step (2), the base is at least one of sodium carbonate, potassium carbonate and sodium bicarbonate.

[0034] Preferably, in step (2), the feed ratio of compound (III) to methanol and base is 1 g: 10-20 mL: 0.1-0.2 g.

[0035] Preferably, in step (2), the reaction is carried out at room temperature, and the reaction process is monitored by TLC. The reaction is terminated after the raw materials are completely reacted. After the reaction is completed, the reaction solution is removed from the solvent and dried to obtain compound (IV).

[0036] Preferably, in step (3), the hydroxylamine is sulfate or hydrochloride of hydroxylamine.

[0037] Preferably, in step (3), the molar ratio of compound (IV) to hydroxylamine is 1:1-2.

[0038] Preferably, in step (3), the reaction is carried out in water.

[0039] Preferably, in step (3), the reaction temperature is 55-65° C. In this step, the reaction process is monitored by TLC, and after the reaction of the raw materials is complete, the reaction solution is directly filtered to obtain compound (V).

[0040] Compared with the prior art, the present invention has the following beneficial effects:

[0041] 1. The synthetic route of the present invention for synthesizing compound (I) from compound (II) has the advantages of cheap and readily available starting materials, fewer reaction steps, milder reaction conditions, higher reaction yield and is suitable for industrial production.

[0042] 2. In the present invention, compound (V) and an esterification agent are converted into the target product monopiravir (I) by enzyme catalysis, the product yield is high, and the reaction process is green and environmentally friendly. DETAILED DESCRIPTION

[0043] The technical scheme of the present invention is described below with specific examples, but the protection scope of the present invention is not limited thereto. If specific conditions are not specified in the examples, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.

[0044] Example 1

[0045] (1) The commercially available compound (II) (20 g, 0.13 mol) was dissolved in HMDS (100 mL), TMSCl (20 mL) was added dropwise at room temperature, the temperature was raised to 120°C, and the mixture became colorless and transparent after 1.5 h. The solvent HMDS was evaporated under reduced pressure, and the colorless residue was dissolved in 100 mL of dichloroethane. Tetraacetyl ribose (45.5 g, 0.14 mol) and catalyst SnCl4 (1.2 ml, 0.01 mol) were added at room temperature, the temperature was raised to 70°C, and the mixture was reacted for 3 h. TLC monitoring was performed. After the conversion of the raw materials was complete, the mixture was washed with saturated sodium bicarbonate (100 mL x 2), water (100 mL x 2), and saturated brine (100 mL x 2) in sequence. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a white solid compound (III) (49.3 g).

[0046] (2) Compound (III) (49.3 g, 0.12 mol) obtained in step (1) of Example 1 was added into a three-necked flask and dissolved in methanol (200 mL). Catalyst NaHCO3 (4.9 g, wt 10%) was added at room temperature. The mixture was stirred at room temperature (30°C) for 10 h. After TLC detection indicated that the raw material had reacted completely, the reaction solution was evaporated under reduced pressure to remove the solvent methanol. After drying, a white solid compound (IV) (28.8 g, 99%) was obtained.

[0047] (3) The solid compound (IV) (28.8 g, 0.12 mol) obtained in step (2) of Example 1 was dissolved in water (200 mL), and hydroxylamine sulfate (21.3 g, 0.13 mol) was added. The mixture was reacted at 70° C. for 6 h. The reaction solution changed from colorless and transparent to yellow turbid. After the reaction was completed as monitored by TLC, the reaction solution was directly filtered to obtain a white solid compound (V) (31.1 g, 99%).

[0048] (4) Compound (V) (31.1 g, 0.12 mol) obtained in step (3) of Example 1, vinyl isobutyrate (27.4 g, 0.24 mol), and Novozym 435 lipase (3.1 g) were added to a three-necked flask in sequence, and 2-methyltetrahydrofuran (200 mL) was added, and the mixture was reacted at 60° C. for 2 h. After filtration, ethyl acetate (100 mL x 2) and water (20 mL x 2) were added to the filtrate, and the layers were separated. The aqueous phase was extracted with ethyl acetate several times, and TLC was monitored until no product was left in the aqueous phase. The organic phases were combined and dried over anhydrous sodium sulfate, and the solvent was removed to obtain white solid (I) monopiravir (28 g).

[0049] 1HNMR(600MHz,Methanol-d4)δ6.96(d,J=8.2Hz,1H),5.87(d,J=4.9Hz,1H),5.66(d,J=8.2Hz,1H),4.3 4(d,J=3.7Hz,2H),4.18(t,J=5.0Hz,1H),4.16–4.09(m,2H),2.67(m,1H),1.23(dd,J=7.0,1.8Hz,6H).

[0050] Example 2

[0051] In a 250 mL reaction bottle equipped with a reflux condenser and a thermometer connected to the atmosphere, compound (V) (20.0 g, 72.2 mmol), vinyl isobutyrate (16.5 g, 144.4 mmol), Novozym435 lipase (2.0 g), and 2-methyltetrahydrofuran (100 mL) were added in sequence, and stirred at 60°C for 2 to 6 hours. Filter, extract the filtrate with ethyl acetate (100 mL x 2), wash with water (20 mL x 2), separate the layers, extract the aqueous phase with ethyl acetate several times, monitor by TLC until there is no product in the aqueous phase, combine the organic phases, dry with anhydrous sodium sulfate, and desolventize to obtain 18.1 to 19 g of white solid (I) monopiravir.

[0052] Comparative Example 1

[0053] Novozym435 lipase (2.0 g) was replaced with LPL lipase (2.0 g). Other conditions were the same as in Example 2, i.e., compound (V) (20.0 g, 72.2 mmol), vinyl isobutyrate (16.5 g, 144.4 mmol) and 2-methyltetrahydrofuran (100 mL) were reacted at room temperature to 60° C. for 2 to 6 h. No target product was found to be generated.

Claims

1. A method for synthesizing monopiravir represented by formula (I), comprising the following steps: In a reaction solvent, compound (V) undergoes an esterification reaction with an esterification agent under the action of lipase to generate compound (I), i.e., monopiravir; the esterification agent is vinyl isobutyrate, and the lipase is Novozym 435 lipase; the reaction solvent is at least one of 2-methyltetrahydrofuran, tetrahydrofuran, and 1,4-dioxane; the reaction formula is as follows:

2. The synthesis method according to claim 1, characterized in that: The volume amount of the reaction solvent is 10-20 mL / g based on the mass of compound (V).

3. The synthesis method according to claim 1, characterized in that: The mass ratio of the compound (V) to the lipase is 1:0.01-0.

5.

4. The synthesis method according to claim 3, characterized in that: The mass ratio of the compound (V) to the lipase is 1:0.05-0.

15.

5. The synthesis method according to claim 1, characterized in that: The molar ratio of the compound (V) to the esterification agent is 1:0.8-5.

6. The synthesis method according to claim 5, characterized in that: The molar ratio of the compound (V) to the esterification agent is 1:1 to 2.

5.

7. The synthesis method according to claim 1, characterized in that: The temperature of the esterification reaction is 20 to 70° C., and the time of the esterification reaction is 1 to 6 hours.

8. The synthesis method according to claim 1, characterized in that: The temperature of the esterification reaction is 55-65°C, and the time of the esterification reaction is 2-3h.

9. The synthesis method according to claim 1, characterized in that: The synthetic method of monopiravir also includes the following steps: (1) N4-acetylcytosine represented by formula (II) and tetraacetylribose are subjected to coupling reaction to obtain compound (III); (2) Compound (III) reacts with methanol in the presence of a base to obtain compound (IV); (3) Compound (IV) reacts with hydroxylamine to generate compound (V); The reaction formula is as follows:

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