CN116854768A

CN116854768A - Preparation method of Nemactetvir and intermediate thereof

Info

Publication number: CN116854768A
Application number: CN202210315129.6A
Authority: CN
Inventors: 于帅; 李永刚; 高立国; 吴立才; 葛璐曦
Original assignee: Zhejiang Jiuzhou Pharmaceutical Co Ltd
Current assignee: Zhejiang Jiuzhou Pharmaceutical Co Ltd
Priority date: 2022-03-28
Filing date: 2022-03-28
Publication date: 2023-10-10

Abstract

The invention discloses a new intermediate (I) of Nemactetvir and a preparation method thereof,meanwhile, the invention discloses a novel method for preparing the Nemactetvir, namely, the Nemactetvir is obtained by the reaction of a novel intermediate (I) and ethyl trifluoroacetate,or from the reaction of the compound (VII) with the compound (IV) or a salt thereof,

Description

Preparation method of Nemactetvir and intermediate thereof

Technical Field

The invention belongs to the field of pharmaceutical chemical industry, and in particular relates to a novel oral antiviral drug of Nemactetevir and an intermediate thereof, and a preparation method thereof.

Background

The U.S. FDA announced, 22, 2021, that the new COVID-19 oral antiviral drug candidate, paxlovid (Nemactetavir tablet/ritonavir tablet combination package), was approved by the very United states FDA for the emergency authorization application for the treatment of non-hospitalization with high risk of developing severe disease adult COVID-19 infections. This is also the first new oral antiviral drug approved by the FDA.

The national drug administration (NMPA) officials announced that for 2 months 12 years, according to the relevant regulations of the drug administration, according to the drug special approval procedure, the emergency approval was carried out, and the new coronavirus therapeutic drug Paxlovid of the gabion company was approved for import registration on 11 days, for treating patients with light to moderate new coronavirus pneumonia accompanied by advanced high risk factors of adult, such as patients accompanied by high risk factors of severe diseases such as senior, chronic kidney disease, diabetes, cardiovascular disease, chronic lung disease, etc. NMPA requires that the marketing licensee continue to carry out related research work, finishes conditional requirements in a limited period, and submits subsequent research results in time.

Paxlovid consists of two main components: nemactevir (code PF-07321332), known by the English name Nirmatrelvir, is a novel coronavirus 3CL protease inhibitor that disrupts the subsequent RNA replication process of the novel coronavirus by blocking the activity of the novel coronavirus 3CL protease. The other component Ritonavir (english name Ritonavir) allows the nematavir to remain active in the body for a longer period of time, better against the virus.

A nemat Wei Huaxue structure:

ritonavir chemical structure:

as a core component of Paxlovid, WO2021250648, a material patent applied by the Convolvulus of the original research company on 8/6/2021, discloses that a compound (1R, 2S, 5S) -6, 6-dimethyl-3-azabicyclo [3,1,0] hexyl-2-carboxylic acid methyl ester hydrochloride (CAS No.: 565456-77-1) is used as a raw material, and the Namalite Wei Fangfa is prepared by the steps of hydrolysis, condensation, dehydration, crystal transformation and the like:

the method yields a nemat Wei Shoulv of about 94%.

In view of the need for new crown therapeutic drugs, there is a need to develop a method for synthesizing nemaltevir with higher yields, which is more suitable for industrial applications.

Disclosure of Invention

The invention provides a novel method for synthesizing Nemactetvir, a novel intermediate and a preparation method thereof.

In order to achieve the above object, the present invention provides a technical solution comprising:

in a first aspect, the present invention provides a novel intermediate of Nemactetvir, characterized by the following structure (I),

in a second aspect, the invention provides a preparation method of the novel Nemactetavir intermediate (I), which is obtained by deprotecting a compound (II) under the action of a deprotecting reagent,

wherein the protecting group P is an amino protecting group selected from t-butoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl, P-methoxybenzyl, benzyl, allyloxycarbonyl, P-toluenesulfonyl protecting group and the like, preferably t-butoxycarbonyl protecting group, benzyloxycarbonyl protecting group and more preferably t-butoxycarbonyl protecting group.

Deprotection of compound (II) to give compound (I) can be carried out at H ₂ Or other hydrogen donor to catalyze and hydrogenate, the catalyst is selected from palladium carbon and Raney nickel, preferably palladium carbon, the hydrogen donor can also be selected from formic acid, etc., and the reaction temperature is 15-100 ℃; or in organic solvent through acidolysis and cleavageThe temperature is 15-100 ℃; or hydrolysis is carried out in alkaline environment, and the reaction temperature is 15-100 ℃.

The acid used for acidolysis and cleavage can be selected from HBr, trifluoroacetic acid, methanesulfonic acid and HCl, and the organic solvent can be selected from one or two or more of ethyl acetate, methanol, ethanol, benzene, toluene, dichloromethane, 1, 4-dioxane and tetrahydrofuran, preferably ethyl acetate, dichloromethane and 1, 4-dioxane. The acidolysis is preferably carried out under HCl/1, 4-dioxane conditions.

The alkaline environment may be selected from the group consisting of sodium hydroxide, potassium hydroxide, and sodium hydroxide as the base.

The compound (II) is preferably subjected to acidolysis under the action of an acid to give the compound (I).

Further, the invention provides a compound (II') which is prepared by adding HCl/1, 4-dioxane into dichloromethane, deprotecting the protective group at 20-30 ℃ to obtain an intermediate (I),

in a third aspect, the invention provides a process for the preparation of the above intermediate (II), which comprises reacting a compound (III) with a compound (IV) or a salt thereof under alkaline conditions with the addition of a condensing agent,

wherein the protecting group P is an amino protecting group selected from t-butoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl, P-methoxybenzyl, benzyl, allyloxycarbonyl, P-toluenesulfonyl protecting group and the like, preferably t-butoxycarbonyl, benzyloxycarbonyl and more preferably t-butoxycarbonyl protecting group; r is alkyl or hydrogen, preferably methyl, tert-butyl, isopropyl, hydrogen, more preferably methyl, hydrogen.

Basic conditions mean that the reaction is carried out in the presence of at least one organic base selected from pyridine, N-diisopropylethylamine, triethylamine, 4-dimethylaminopyridine. Preferably in the presence of N, N-diisopropylethylamine or triethylamine, more preferably in the presence of N, N-diisopropylethylamine.

When R is hydrogen, the condensation reaction temperature is between-10 and 50 ℃; the reaction solvent is selected from one or two or more than two mixed solvents of 2-butanone, acetonitrile, DMF and dichloromethane; preferably 2-butanone or acetonitrile, more preferably 2-butanone; the reaction condensing agent is selected from one or more of HOPO (2-hydroxypyridine-N-oxide), EDCI [ 1-ethyl- (3-dimethylaminopropyl) -3-ethylcarbodiimide, HOBT (1-hydroxybenzotriazole), HATU [2- (7-azobenzotriazole) -N, N, N ', N ' -tetramethylurea hexafluorophosphate ], HBTU (benzotriazol-N, N, N ', N ' -tetramethylurea hexafluorophosphate), pyBOP (1H-benzotriazole-1-oxy-tripyrrolidinyl hexafluorophosphate), CDI (N, N ' -carbonyl diimidazole), DIC (N, N ' -diisopropylcarbodiimide) and DCC (N, N ' -dicyclohexylcarbodiimide); preferably one or two or more of HOPO, EDCI, CDI, more preferably HOPO and EDCI.

When R is alkyl, the reaction temperature is 20-150 ℃; the reaction solvent is selected from one or two or more than two of methanol, ethanol, isopropanol, DMF and acetonitrile; the condensing agent is one of calcium chloride, magnesium ethoxide and magnesium methoxide.

The salt of compound (IV) is selected from the group consisting of hydrochloride or mesylate, preferably hydrochloride.

Further, the invention discloses a method for preparing the compound (II') by adding a condensing agent of calcium chloride or magnesium ethoxide into acetonitrile or DMF under the alkaline condition of triethylamine or N, N-diisopropylethylamine of the compound (III-1) and the compound (IV) or salts thereof when P is tert-butoxycarbonyl and R is alkyl,

further, the present invention discloses a process for preparing compound (II ') wherein when P is t-butoxycarbonyl and R is methyl, compound (III-1') and compound (IV) are added with a condensing agent of calcium chloride in the presence of triethylamine in acetonitrile solvent at 40 to 60 ℃,

meanwhile, the invention discloses a method for preparing a compound (II') by adding a condensing agent HOPO/EDCI into 2-butanone at 20-30 ℃ in the presence of N, N-diisopropylethylamine when P is tert-butoxycarbonyl and R is hydrogen,

the compound (III-2) can be obtained by hydrolysis and conversion of the compound (III-1) under alkaline environment conditions,

r is alkyl or H.

The alkaline environment, namely the hydrolysis reaction is carried out in the presence of lithium hydroxide or sodium hydroxide, and the reaction solvent is selected from one or more mixed solvents of tetrahydrofuran, water, acetonitrile or 1, 4-dioxane.

Preferably the compound (III-1') is obtained by hydrolysis and conversion in the presence of lithium hydroxide in a mixed solvent of water and tetrahydrofuran,

in a fourth aspect, the present invention provides a further process for the preparation of intermediate (II) from compound (V) by dehydration at appropriate temperature and solvent conditions,

wherein the protecting group P is an amino protecting group selected from t-butoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl, P-methoxybenzyl, benzyl, allyloxycarbonyl, P-toluenesulfonyl protecting group and the like, preferably t-butoxycarbonyl, benzyloxycarbonyl and more preferably t-butoxycarbonyl.

The reaction temperature is controlled between 0 and 50 ℃, preferably, the reaction temperature is controlled between 25 and 40 ℃; the reaction solvent is selected from one or two or more of toluene, DMF, tetrahydrofuran, dichloromethane and isopropyl acetate, preferably dichloromethane and isopropyl acetate, more preferably dichloromethane; the dehydrating agent is selected from phosphorus pentoxide, phosphorus oxychloride, phosphorus pentachloride, a primary Gibbs reagent, trifluoroacetic anhydride/triethylamine, methanesulfonyl chloride, preferably a primary Gibbs reagent, trifluoroacetic anhydride/base, more preferably a primary Gibbs reagent.

Further, the invention discloses a method for obtaining a compound (II ') from a compound (V') in methylene dichloride, isopropyl acetate or toluene solvent, under the action of a dehydrating agent Bogis reagent, trifluoroacetic anhydride or phosphorus oxychloride at 25-40 ℃,

further, the invention discloses a method for obtaining a compound (II ') by dehydrating the compound (V') in methylene dichloride at 25-30 ℃ under the action of a Bungeus reagent,

in a fifth aspect, the present invention provides a process for producing compound (V) from compound (III) and compound (VI) or a salt thereof by adding a condensing agent under alkaline conditions,

wherein the protecting group P is an amino protecting group selected from t-butoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl, P-methoxybenzyl, benzyl, allyloxycarbonyl, P-toluenesulfonyl protecting group and the like, preferably t-butoxycarbonyl, benzyloxycarbonyl and more preferably t-butoxycarbonyl. Wherein R is alkyl or hydrogen, preferably methyl, tert-butyl, isopropyl, hydrogen, more preferably methyl, hydrogen.

Basic conditions mean that the reaction is carried out in the presence of at least one organic base pyridine, N-diisopropylethylamine, triethylamine, 4-dimethylaminopyridine, preferably N, N-diisopropylethylamine, triethylamine, more preferably N, N-diisopropylethylamine.

When R is hydrogen, the condensation reaction temperature is between-10 and 50 ℃; the reaction solvent is selected from one or two or more than two mixed solvents of 2-butanone, acetonitrile, DMF and dichloromethane; preferably 2-butanone or acetonitrile, more preferably 2-butanone; the reaction condensing agent is selected from one or more than two of HOPO, EDCI, HOBT, HATU, HBTU, pyBOP, CDI, DIC, DCC; preferably one or two or more of HOPO, EDCI, CDI, more preferably HOPO and EDCI.

When R is alkyl, the reaction temperature is 20-150 ℃; the reaction solvent is one or two or more than two mixed solvents selected from methanol, ethanol, isopropanol, DMF and acetonitrile; the condensing agent is one of calcium chloride, magnesium ethoxide and magnesium methoxide.

The salt of compound (VI) is selected from the group consisting of hydrochloride, mesylate, preferably hydrochloride.

Further, the invention discloses a method for preparing a compound (V') from a compound (III-1) and a compound (VI) or a salt thereof under the alkaline condition of triethylamine or N, N-diisopropylethylamine, adding a condensing agent of calcium chloride or magnesium ethoxide into acetonitrile or DMF when P is t-butoxycarbonyl and R is alkyl,

further, the invention discloses a method for preparing the compound (V ') by adding a condensing agent magnesium ethoxide into DMF in the presence of N, N-diisopropylethylamine from the compound (III-1') and the hydrochloride of the compound (VI) when P is tert-butoxycarbonyl and R is methyl,

meanwhile, the invention discloses a method for preparing a compound (V ') by adding a condensing agent HOPO/EDCI into a tert-butoxycarbonyl group, wherein R is hydrogen, a compound (III-2) and a compound (VI) hydrochloride in the presence of N, N-diisopropylethylamine, and preparing the compound (V') at 20-30 ℃ in 2-butanone,

in a sixth aspect, the present invention provides a process for preparing namide Wei Fangfa from intermediate (I) and ethyl trifluoroacetate,

the reaction temperature is 15 to 80 ℃, preferably 25 to 60 ℃, more preferably 30 to 60 ℃; the reaction solvent is selected from C1-C6 alcohol or optionally substituted benzyl alcohol, preferably methanol, ethanol, more preferably methanol; the reaction base is at least one selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, sodium hydride, pyridine, N-diisopropylethylamine, triethylamine, and 4-dimethylaminopyridine, preferably pyridine and triethylamine, and more preferably triethylamine.

Further, the invention discloses a method for preparing the nematode Wei Fangfa by reacting the compound (I) with ethyl trifluoroacetate in the presence of triethylamine, N-diisopropylethylamine or pyridine in a methanol, ethanol or isopropanol solvent at 25-60 ℃,

furthermore, the invention discloses a method for preparing the nematolide Wei Fangfa by the reaction of the hydrochloride of the compound (I) with ethyl trifluoroacetate at 30-60 ℃ and with methanol as a reaction solvent,

in a seventh aspect, the present invention also provides another preparation method of the nemaltevir, which is obtained by condensing the compound (VII) and the compound (IV) or the salt thereof under alkaline conditions,

wherein R is alkyl or H.

Basic conditions mean that the reaction is carried out in the presence of N, N-diisopropylethylamine or triethylamine, preferably in the presence of N, N-diisopropylethylamine. When R is hydrogen, the condensation reaction temperature is-10 to 50 ℃, and is carried out in 2-butanone or acetonitrile, and more preferably in 2-butanone; the reaction condensing agent is selected from one or combination of HOPO, EDCI, CDI, preferably HOPO and EDCI. When R is alkyl, the condensation reaction temperature is 20-150 ℃, and the condensation reaction is performed in methanol, ethanol, isopropanol, DMF or acetonitrile, preferably acetonitrile and DMF; the reaction condensing agent is one of calcium chloride, magnesium ethoxide and magnesium methoxide.

Further, the invention discloses a method for preparing the compound (VII') and the compound (IV) or the salt thereof, wherein the condensing agent HOPO/EDCI is added under the alkaline condition of N, N-diisopropylethylamine, the mixture is reacted in a 2-butanone solvent to obtain the nematode Wei Fangfa,

furthermore, the invention discloses a method for preparing the nematolide Wei Fangfa by adding the compound (VII') and the compound (IV) hydrochloride into condensing agent HOPO/EDCI, 2-butanone in the presence of N, N-diisopropylethylamine, reacting at 20-30 ℃,

in addition, the compound (VII') and the compound (IV) or salts thereof can be added with a condensing agent HOPO/EDCI in the presence of N, N-diisopropylethylamine, and then methyl tertiary butyl ether solvate of the Nemactetvir is prepared in 2-butanone at 25 ℃ and then converted to the Nemactetvir.

The raw materials adopted by the invention have wide and convenient sources, low price, low production cost, simple and convenient operation in the production process and environmental protection. In the whole process, all the used raw materials and catalysts are easy to obtain, the reaction is simple, the synthesis conditions are mild and controllable, the yield of the obtained product is high, the pollution is less, and the method is suitable for industrial production.

Detailed Description

In order to further understand the present invention, the synthesis method of the nemaltevir and the intermediates thereof provided by the present invention is described in detail below with reference to examples. It should be understood that these examples are presented merely to further illustrate the features of the present invention and are not intended to limit the scope of the invention or the scope of the claims.

Example 1: preparation of Compound (I)

To a 100mL round bottom flask was added dichloromethane (20 mL), compound (II') (10.0 g,19.86 mmol) in sequence, and stirring was turned on. 1, 4-dioxane solution (4M, 24.8mL,99.3 mmol) of HCl was added dropwise at room temperature (20-30 ℃) and stirred at room temperature (20-30 ℃) for 16h, followed by distillation under reduced pressure at 40℃to give 11.0g of compound (I) hydrochloride.

Example 2: preparation of Nemactetvir

To a 250mL round bottom flask was added methanol (50 mL), compound (I) hydrochloride (10.7 g,18.87 mmol), triethylamine (7.4 g,72.78 mmol) in this order, and stirring was turned on. Ethyl trifluoroacetate (4.3 g,30.19 mmol) was added dropwise at room temperature (20-30 ℃ C.), and after the addition, the mixture was heated to 50 ℃ C., kept at 16h and distilled under reduced pressure at 50 ℃ C. Steaming until no liquid flows out, diluting with water (50 mL), adding 1M hydrochloric acid to adjust the PH to 3-4, and extracting the aqueous layer with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain 6.7g of Nemactetvir.

Example 3: preparation of Compound (II')

Acetonitrile (90 mL), compound (III-1') (10.0 g,26.16 mmol) were added sequentially to a 250mL round bottom flask, and stirring was turned on. To the reaction flask was added compound (IV) (5.5 g,28.78 mmol), calcium chloride (2.9 g,26.16 mmol) and the ice-water bath was cooled to 0 to 5 ℃. Triethylamine (6.1 g,60.43 mmol) was added dropwise, and after the addition, the ice-water bath was removed, and the mixture was heated to 50℃and stirred for 5 hours. The reaction mixture was quenched by addition of a mixture of hydrochloric acid (1M) and saturated brine (50 mL, 2:1), distilled at 40℃under reduced pressure until no liquid was eluted, and acetonitrile was distilled off. The remaining aqueous phase was extracted 2 times with ethyl acetate (50 mL), the organic phases were combined, washed with saturated sodium bicarbonate solution, saturated brine mixed solution (50 mL, 2:1), and the organic layer was dried over anhydrous sodium sulfate and filtered. The organic phase was concentrated to obtain 11.6g of compound (II').

Example 4: preparation of Compound (II')

To a 250mL round bottom flask was added 2-butanone (90 mL), compound (III-2) (10.0 g,27.16 mmol), compound (IV) hydrochloride (5.8 g,30.80 mmol) in this order, and stirring was turned on. HOPO (754.0 mg,6.79 mmol) was added and the temperature was reduced to 0deg.C. After N, N-diisopropylethylamine (10.5 g,81.47 mmol) was added dropwise, EDCI (6.3 g,32.59 mmol) was added, and the mixture was heated to 25℃and stirred at constant temperature for 16h. The reaction mixture was diluted with ethyl acetate and methyl t-butyl ether (83.5 mL, 1:1), washed with water and saturated brine (50 mL, 2:1), and the organic phase was washed with saturated brine (50 mL), then with hydrochloric acid (1M), a mixed solution of saturated brine (50 mL, 2:1), and the organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to give 13.4g of compound (II').

Example 5: preparation of Compound (II')

To a 250mL round bottom flask was added dichloromethane (90 mL), compound (V') (10.0 g,19.18 mmol) in order, and stirring was turned on. The Buerger reagent (11.4 g,47.69 mmol) was added to the reaction flask. After reaction at 25℃for 1h, the mixture was quenched with saturated sodium bicarbonate solution and saturated brine (50 mL, 2:1) and separated. The organic phase was distilled under reduced pressure, the resulting concentrate was diluted with ethyl acetate (50 mL) and methyl tert-butyl ether (50 mL), washed twice with a saturated sodium bicarbonate solution and a saturated brine mixture (50 mL, 2:1), washed twice with 1M hydrochloric acid and a saturated brine mixture (50 mL, 2:1), and the organic layer was dried over anhydrous sodium sulfate and filtered. After the organic phase was concentrated, column chromatography was performed to obtain 7.3g of compound (II').

Example 6: preparation of Compound (V')

DMF (90 mL), compound (III-1') (10.0 g,26.16 mmol) were added sequentially to a 250mL round bottom flask, and stirring was turned on. To the reaction flask was added compound (VI) (5.7 g,27.47 mmol), magnesium ethoxide (30.0 g,26.16 mmol) and N, N-diisopropylethylamine (5.1 g,39.24 mmol), and after the addition, the ice-water bath was removed, and the mixture was heated to 50℃and stirred for 5 hours. The reaction mixture was quenched by addition of a mixture of hydrochloric acid (1M) and saturated brine (50 mL, 2:1), distilled at 40℃under reduced pressure until no liquid was eluted, and acetonitrile was distilled off. The aqueous phase was extracted 2 times with ethyl acetate (50 mL), the organic phases were combined, washed with saturated sodium bicarbonate solution, saturated brine mixed solution (50 mL, 2:1), dried over anhydrous sodium sulfate, and filtered. The organic phase was concentrated to obtain 11.8g of Compound (V').

Example 7: preparation of Compound (V')

To a 250mL round bottom flask was added 2-butanone (90 mL), compound (III-2) (15 g,40.74 mmol), compound (VI) hydrochloride (9.6 g,46.20 mmol) in this order, and stirring was turned on. HOPO (1.13 g,10.19 mmol) was added and the temperature was reduced to 0 ℃. After N, N-diisopropylethylamine (15.8 g,122.21 mmol) was added dropwise, EDCI (9.4 g,48.89 mmol) was added, and the mixture was heated to 25℃and stirred at constant temperature for 16h. The reaction mixture was diluted with ethyl acetate and methyl t-butyl ether (125 mL, 1:1), washed with water and saturated brine (75 mL, 2:1), and the organic phase was washed with saturated brine (75 mL), then with a mixture of hydrochloric acid (1M) and saturated brine (75 mL, 2:1), and the organic layer was washed with saturated brine (75 mL), dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to give 20.8g of compound (II').

Example 8: preparation of Compound (III-2)

Tetrahydrofuran (52.4 mL), compound (III-1') (20 g,52.32 mmol) were added sequentially to a 100mL round bottom flask, and stirring was turned on. A solution of lithium hydroxide (3.8 g,156.7 mmol) in water (11.3 mL) was prepared and added dropwise to the reaction flask. After the addition is finished, stirring is carried out for 2 hours at 25 ℃, then reduced pressure distillation is carried out at 40 ℃ until no liquid flows out, and tetrahydrofuran is distilled off. PH was adjusted to ph=2 by adding 1M hydrochloric acid and extracted with ethyl acetate (35 ml x 2). The organic phases were combined, washed with saturated brine (110 mL), dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to give 19.2g of compound (III-2).

Example 9: nemactetvir

To a 250mL round bottom flask was added 2-butanone (90 mL), compound (VII) (10 g,27.46 mmol), compound (IV) hydrochloride (5.8 g,31.14 mmol) in this order, and stirring was turned on. HOPO (762.3 mg,6.87 mmol) was added and the temperature was reduced to 0 ℃. After N, N-diisopropylethylamine (10.6 g,82.37 mmol) was added dropwise, EDCI (6.3 g,32.95 mmol) was added, and the mixture was heated to 25℃and stirred at constant temperature for 16h. The reaction mixture was diluted with ethyl acetate and methyl t-butyl ether solution (84.4 mL, 1:1), washed with water and saturated brine (50 mL, 2:1), and the organic phase was washed with saturated brine (50 mL), then with hydrochloric acid (1M) and a mixed solution of saturated brine (50 mL, 2:1), and the organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. And adding a mixed solution (65 mL, 1:10) of ethyl acetate and methyl tertiary butyl ether into the concentrated product, heating to 50 ℃, keeping the temperature, stirring for 1h, cooling to 25 ℃, and keeping the temperature, stirring for 12h. Filtration gave a white solid, which was a nemat Wei Jiaji tert-butyl ether solvate. Isopropyl acetate (18.0 mL) was added to the t-butyl ether solvate of nemalt Wei Jiaji with stirring. Heating to 70 ℃, preserving heat for 8 hours, cooling to 10 ℃, preserving heat for 4 hours, and filtering to obtain 11.5g of Nemactetvir.

Claims

1. An intermediate of Nemactetvir, which is characterized by having the following structure (I),

2. a synthesis method of a Nemactetvir intermediate (I) is characterized in that the Nemactetvir intermediate is obtained by deprotecting a compound (II) under the action of a deprotecting reagent,

wherein P is an amino protecting group.

3. The synthesis of the nemaltevir intermediate (I) according to claim 2, characterized in that the amino protecting group is selected from t-butoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl, p-methoxybenzyl, benzyl, allyloxycarbonyl or p-toluenesulfonyl protecting group.

4. A process for the synthesis of the nelmacavir intermediate (I) according to claim 2, wherein the deprotecting reagent is selected from H _2/ Catalyst, HBr, trifluoroacetic acid, methanesulfonic acid, HCl.

5. The method for synthesizing the nelmacavir intermediate (I) according to claim 4, wherein the deprotection reagent is an HCl/1, 4-dioxane system.

6. The process for synthesizing the Nemactetvir intermediate (I) according to claim 2, wherein the compound (II) is obtained by dehydrating the compound (V) in a solvent by a dehydrating agent,

7. the synthesis method of the nemaltevir intermediate (I) according to claim 6, wherein the solvent is selected from one of toluene, DMF, tetrahydrofuran, methylene dichloride and isopropyl acetate, and any two or more of the solvents are mixed; the dehydrating agent is selected from phosphorus pentoxide, phosphorus oxychloride, phosphorus pentachloride, a bergs reagent, a trifluoroacetic anhydride/triethylamine system, and methanesulfonyl chloride.

8. The process for synthesizing the Nemactetvir intermediate (I) according to claim 2, wherein the compound (II) is obtained by adding a condensing agent to a reaction solvent in the presence of an organic base from the compound (III) and the compound (IV) or a salt thereof,

wherein the method comprises the steps ofR is alkyl or H.

9. The process for synthesizing the Nemactetvir intermediate (I) according to claim 6, wherein the compound (V) is obtained by adding a condensing agent to a reaction solvent in the presence of an organic base from the compound (III) and the compound (VI) or a salt thereof,

wherein R is alkyl or H.

10. The synthesis of the nelmactevir intermediate (I) according to claim 8 or 9, characterized in that the organic base is selected from one of pyridine, N-diisopropylethylamine, triethylamine, 4-dimethylaminopyridine.

11. The process for the synthesis of the nelumbo acid intermediate (I) according to claim 8 or 9, characterized in that the salt is the hydrochloride or mesylate salt.

12. The synthesis method of the nemaltevir intermediate (I) according to claim 8 or 9, wherein when R is H, the reaction solvent is one selected from 2-butanone, acetonitrile, DMF, dichloromethane, and a mixture of any two or more thereof; the condensing agent is selected from one or more than two of HOPO, EDCI, HOBT, HATU, HBTU, pyBOP, CDI, DIC, DCC.

13. The synthesis method of the nemaltevir intermediate (I) according to claim 8 or 9, wherein when R is alkyl, the reaction solvent is one selected from methanol, ethanol, isopropanol, DMF and acetonitrile, and any two or more of them are mixed; the condensing agent is one of calcium chloride, magnesium ethoxide and magnesium methoxide.

14. A synthesis method of Nemactetvir is characterized in that the Nemactetvir is obtained by condensing a compound (I) and ethyl trifluoroacetate under alkaline conditions,

15. the process for the preparation of nemaltvir according to claim 14, characterized in that the reaction is carried out in the presence of an organic solvent selected from C1-C6 alcoholic solvents or optionally substituted benzyl alcohols.

16. The method for preparing the nemaltvir according to claim 14, wherein the alkaline condition is at least one selected from the group consisting of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, sodium hydride, pyridine, N-diisopropylethylamine, triethylamine, and 4-dimethylaminopyridine.

17. A synthesis method of Nemactetvir is characterized in that the Nemactetvir is obtained by condensing a compound (VII) and a compound (IV) or salts thereof under alkaline conditions,

wherein R is alkyl or H.

18. The process for the preparation of nemaltevir according to claim 17, wherein the organic base is selected from N, N-diisopropylethylamine or triethylamine.

19. The process for preparing nemaltevir of claim 17, wherein the salt is a hydrochloride or mesylate salt.

20. The process for the preparation of nemaltevir according to claim 17, wherein when R is H, the reaction solvent is selected from 2-butanone or acetonitrile; the condensing agent is selected from one or a combination of HOPO, EDCI, CDI.

21. The process for the preparation of nemaltvir according to claim 17 wherein when R is alkyl, the reaction solvent is selected from methanol, ethanol, isopropanol, DMF or acetonitrile; the condensing agent is one of calcium chloride, magnesium ethoxide and magnesium methoxide.