Phosphonate derivatives and preparation methods and uses thereof

Abstract

The present invention discloses phosphonate derivatives and preparation methods and uses thereof. Specifically, the present invention provides a preparation method of a phosphonate derivative as shown in formula I, which comprises the following steps: reacting a compound as shown in formula II and a compound as shown in formula III in an organic solvent in the presence of a promoter to obtain a phosphonate derivative as shown in formula I. The preparation method provided by the present invention has cheap and readily available starting materials, is environmentally friendly, avoids toxic and harmful reagents and harsh reaction conditions, avoids cumbersome operations, and is more suitable for industrial synthesis.

Description

Technical Field

[0001] The invention relates to phosphonate derivatives and preparation methods and uses thereof. Background Art

[0002] Tenofovir alafenamide fumurate (TAF) is a prodrug of the reverse transcriptase inhibitor tenofovir (PMPA). Clinically, it is used alone to treat chronic hepatitis B, and its combination is used to treat AIDS.

[0003] Adefovir dipivoxil is a prodrug of the reverse transcriptase inhibitor adefovir and is clinically used to treat chronic hepatitis B.

[0004]

[0005] At present, the industrial synthesis of tenofovir alafenamide fumarate (TAF) raw materials uses tenofovir (2) as the starting material. For example, the preparation method patent WO 2013052094 (CN103842366B) applied by Gilead Company discloses that tenofovir (2) reacts with triphenyl phosphite in acetonitrile, in the presence of 4-dimethylaminopyridine (DMAP) and triethylamine to obtain phenyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (3, hereinafter referred to as tenofovir phenyl ester). Tenofovir phenyl ester 3 is chlorinated with thionyl chloride to obtain 4; 4 reacts with L-alanine isopropyl ester hydrochloride (5) to obtain a mixture of tenofovir alafenamide and its diastereoisomers; the resulting mixture is subjected to crystallization-induced kinetic resolution in the presence of phenol and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) in acetonitrile to obtain tenofovir alafenamide (6) with high diastereomeric purity. According to, for example, U.S. Pat. No. 8,754,065B, tenofovir alafenamide (6) is reacted with fumaric acid to form a salt to obtain tenofovir alafenamide fumarate (TAF, 1). The above-mentioned synthetic process route has defects that restrict industrialization. First, in the reaction of preparing tenofovir phenyl ester 3 from tenofovir (2), the triphenyl phosphite used is irritating, sensitizing and environmentally toxic, and only one of the three phenyl esters can be used; and the reaction time of this step is lengthy, requiring more than 48 hours. In addition, the reaction of preparing tenofovir phenyl ester 3 from tenofovir (2) requires anhydrous reaction conditions. However, tenofovir (2) mainly exists in a stable monohydrate, and it is very difficult to remove the crystal water before use. Moreover, after the crystal water is removed, tenofovir is very easy to absorb moisture and combine with water again to form a stable tenofovir monohydrate, resulting in cumbersome operation and low efficiency of the water removal step.

[0006]

[0007] Furthermore, the current industrial synthesis process of tenofovir (2) is to use adenine (7) and (R)-propylene carbonate (8) as starting materials, react in N,N-dimethylformamide (DMF) with sodium hydroxide or potassium hydroxide as a catalyst to obtain (R)-9-(2-hydroxypropyl) adenine (9); 9 is alkylated with diethyl p-toluenesulfonyloxymethylphosphonate (DESMP, 10) under the catalysis of magnesium tert-butylate (MTB) to obtain (R)-9-[2-(diethoxyphosphinoylmethoxy)propyl] adenine (11); 11 is deethylated under the action of trimethylsilyl bromide (TMSBr) or its alternative combination of trimethylsilyl chloride and sodium bromide, or 33% hydrogen bromide acetic acid solution to obtain tenofovir (2). Tenofovir (2) mainly exists as a stable monohydrate. See the report of Brown Ripin DH et al. (Organic Process Research & Development, 2010, 14(5): 1194-1201). The above-mentioned synthesis process route of tenofovir (2) has the following defects: magnesium tert-butoxide (MTB) is expensive, easily deteriorates due to moisture absorption, and has different quality between different batches and suppliers; when removing the two ethyl groups in tenofovir diethyl ester (11) to prepare tenofovir (2), expensive, corrosive, moisture-sensitive and environmentally unfriendly reagents are required, such as trimethylsilyl bromide (TMSBr) or its alternative combination of trimethylsilyl bromide and sodium bromide, 33% hydrogen bromide acetic acid solution.

[0008]

[0009] Tenofovir alafenamide fumarate (TAF, 1) key intermediate tenofovir phenyl ester 3 can also be synthesized by bypassing tenofovir (2) through other routes. For example, Chinese invention patent CN104817593B discloses that diphenyl phosphite (12) is used as a starting material and subjected to a hydroxymethylation reaction with paraformaldehyde to obtain diphenyl hydroxymethylphosphonate (13); 13 is then esterified with p-toluenesulfonyl chloride (TsCl) to obtain diphenyl p-toluenesulfonyloxymethylphosphonate (14); 14 reacts with (R)-9-(2-hydroxypropyl)adenine (9) under base catalysis to undergo a nucleophilic substitution reaction to obtain diphenyl (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (15, hereinafter referred to as tenofovir diphenyl ester); 15 is subjected to alkaline hydrolysis to obtain tenofovir phenyl ester 3. Among them, the base used in the nucleophilic substitution reaction is potassium tert-butoxide, sodium hydride, magnesium tert-butoxide or lithium tert-butoxide, and the solvent used in the condensation reaction is N-methylpyrrolidone (NMP), DMF or tetrahydrofuran. Among them, the base used in the alkaline hydrolysis reaction is an aqueous solution of lithium hydroxide, sodium hydroxide or potassium hydroxide, and the solvent used in the alkaline hydrolysis reaction is tetrahydrofuran or methanol. A synthetic route of tenofovir phenyl ester 3 disclosed in CN104817593B is as follows:

[0010]

[0011] However, when the inventors repeated the operation steps of the embodiment of the above patent, they found that there were three technical bottlenecks: First, the reaction of diphenyl phosphite (12) and paraformaldehyde could not stably prepare diphenyl hydroxymethylphosphonate (13). Second, according to the operation

[0055] , the main product obtained by the reaction of diphenyl hydroxymethylphosphonate (13) with p-toluenesulfonyl chloride (TsCl) was confirmed to be p-toluenesulfonic acid phenyl ester (14') with a yield of 70%, and the target compound 14 was not obtained. Third, when preparing tenofovir diphenyl ester 15 by nucleophilic substitution reaction of 9 and 14 prepared by the improved method, potassium tert-butoxide, sodium hydride, magnesium tert-butoxide or lithium tert-butoxide were used as bases, and NMP, DMF or tetrahydrofuran were used as solvents, it was impossible to separate tenofovir phenyl ester 15 with high purity at a high yield.

[0012] Currently, the synthesis of Adefovir also has similar technical shortcomings. Summary of the invention

[0013] The technical problem to be solved by the present invention is to overcome the defects of using environmentally unfriendly reagents such as strong irritation, strong sensitization, strong environmental toxicity, easy hygroscopic deterioration, strong corrosiveness, long reaction time, harsh reaction conditions, etc. when synthesizing open-ring nucleotide drugs such as tenofovir alafenamide and adefovir in the prior art. In order to solve the above technical problems, the present invention provides a phosphonate derivative and a preparation method and use thereof. Compared with the prior art, the preparation method provided by the present invention has cheap and easily available starting materials, is environmentally friendly, avoids toxic and harmful reagents and harsh reaction conditions, avoids cumbersome operations, and is more suitable for industrial synthesis.

[0014] The present invention provides a method for preparing a phosphonate derivative as shown in formula I, which comprises the following steps: reacting a compound as shown in formula II and a compound as shown in formula III in an organic solvent in the presence of a promoter to obtain a phosphonate derivative as shown in formula I, that is,

[0015]

[0016] Among them, R a1 and R a2 are independently hydrogen or an amino protecting group, and R a1 and R a2 Not at the same time hydrogen;

[0017] is a 6-10 membered heteroaryl group containing 2-4 nitrogen atoms or is substituted by one or more R b Substituted 6-10 membered heterocyclic alkenyl containing 2-4 nitrogen atoms; when R b When it is multiple, the R b Same or different;

[0018] R b C1-C6 alkyl, oxo Amino or hydroxyl groups;

[0019] R 5 is hydrogen, C1-C6 alkyl or C1-C6 alkyl substituted by one or more hydroxyl groups;

[0020] R 2 and R 3 Independently C6-C 10 Aryl, C1-C6 alkyl, C1-C6 alkyl substituted by one or more halogens or by one C6-C 10 Aryl-substituted C1-C6 alkyl;

[0021] R 4 is a C1-C6 alkyl group;

[0022] The accelerator is a combination of N-halosuccinimide and acid.

[0023] In one scenario, R a1 or R a2 It is benzoyl or acetyl.

[0024] In one scenario, R a1 or R a2 For hydrogen.

[0025] In a certain embodiment, in the method for preparing the phosphonate derivative as shown in Formula I, certain groups have the following definitions, and the definitions of the groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "in a certain embodiment"),

[0026] The amino protecting group is benzoyl (Bz), acetyl (Ac) or tert-butyloxycarbonyl (Boc).

[0027] In one plan, for For example

[0028] In one embodiment, "*" indicates that the carbon atom with "*" is a chiral carbon atom, which is in R configuration, S configuration, or a mixture of R configuration and S configuration, for example for

[0029] In one plan, for

[0030] In one scenario, R 2 and R 3 All are phenyl or 2,2,2-trifluoroethyl.

[0031] In one scenario, R 5 It is hydrogen or methyl.

[0032] In one scenario, R 2 and R 3 All are phenyl.

[0033] In one scheme, when R b When it is a C1-C6 alkyl group, the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

[0034] In one scheme, when R 5 When it is a C1-C6 alkyl group or a C1-C6 alkyl group substituted by one or more hydroxyl groups, the C1-C6 alkyl group and the C1-C6 alkyl group substituted by one or more hydroxyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

[0035] In one scheme, when R 2 and R 3 Independently C6-C 10 Aryl or a C6-C 10 When the C1-C6 alkyl group is substituted with an aryl group, the C6-C 10 Aryl and a C6-C 10 The C6-C1-C6 alkyl group substituted with aryl 10 Aryl is phenyl.

[0036] In one scheme, when R 2 and R 3 are independently C1-C6 alkyl, C1-C6 alkyl substituted by one or more halogens, or C1-C6 alkyl substituted by one C6-C 10 When the C1-C6 alkyl group is substituted by an aryl group, the C1-C6 alkyl group, the C1-C6 alkyl group substituted by one or more halogens and the C1-C6 alkyl group substituted by one C6-C 10 The C1-C6 alkyl group in the aryl-substituted C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

[0037] In one scheme, when R 2 and R 3 When they are independently C1-C6 alkyl substituted by one or more halogens, the halogen in the C1-C6 alkyl substituted by one or more halogens is fluorine, chlorine, bromine or iodine, for example fluorine.

[0038] In one scheme, when R 2 and R 3 When they are independently C1-C6 alkyl substituted by one or more halogens, the C1-C6 alkyl substituted by one or more halogens is 2,2,2-trifluoroethyl.

[0039] In one scheme, when R 2 and R 3 Independently for a C6-C 10 When the C1-C6 alkyl group is substituted with an aryl group, the 10 The aryl-substituted C1-C6 alkyl group is benzyl.

[0040] In one scenario, R 4 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, for example methyl.

[0041] In one scenario, R a1 is benzoyl or acetyl;

[0042] R a2 is hydrogen;

[0043] for

[0044] for

[0045] R 5 is hydrogen or methyl;

[0046] R 2 and R 3 All are phenyl or 2,2,2-trifluoroethyl;

[0047] R 4 It is methyl.

[0048] In one embodiment, the phosphonate derivative as shown in formula I is any of the following compounds:

[0049]

[0050]

[0051] In the preparation method of the phosphonate derivatives shown in Formula I, the type of organic solvent is conventional in the art, such as one or more of ether solvents, halogenated hydrocarbon solvents, ester solvents, ketone solvents and nitrile solvents, and another example is ether solvents and / or halogenated hydrocarbon solvents. The ether solvent may be 1,4-dioxane and / or methoxycyclopentane, such as 1,4-dioxane; the halogenated hydrocarbon solvent may be one or more of dichloromethane, chloroform and 1,2-dichloroethane, such as dichloromethane; the ester solvent may be ethyl acetate and / or isopropyl acetate; the ketone solvent may be methyl isobutyl ketone and / or 2-butanone; the nitrile solvent may be acetonitrile.

[0052] In the preparation method of the phosphonate derivative shown in Formula I, the N-halosuccinimide can be one or more of N-iodosuccinimide (NIS), N-bromosuccinimide (NBS) and N-chlorosuccinimide (NCS), such as NIS. The NIS can be prepared by reacting NBS or NCS with an alkali metal iodide; the alkali metal iodide is, for example, sodium iodide.

[0053] In the preparation method of the phosphonate derivative as shown in Formula I, the acid can be a Lewis acid or a Bronsted acid. Acid; the Lewis acid may be aluminum chloride (AlCl3), trimethylsilyl trifluoromethanesulfonate (TMSOTf), scandium trifluoromethanesulfonate [Sc(OTf)3], yttrium trifluoromethanesulfonate [Y(OTf)3] or lanthanum trifluoromethanesulfonate [Ln(OTf)3], such as scandium trifluoromethanesulfonate [Sc(OTf)3]; the lanthanum trifluoromethanesulfonate [Ln(OTf)3] such as lanthanum trifluoromethanesulfonate , cerium trifluoromethanesulfonate, praseodymium trifluoromethanesulfonate, neodymium trifluoromethanesulfonate, samarium trifluoromethanesulfonate, europium trifluoromethanesulfonate, gadolinium trifluoromethanesulfonate, terbium trifluoromethanesulfonate, dysprosium trifluoromethanesulfonate, holmium trifluoromethanesulfonate, erbium trifluoromethanesulfonate, thulium trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate and lutetium trifluoromethanesulfonate. The Bronsted acid may be trifluoromethanesulfonic acid (TfOH) or perchloric acid (HClO4), such as trifluoromethanesulfonic acid (TfOH).

[0054] In the preparation method of the phosphonate derivative as shown in Formula I, the promoter may be a combination of N-halosuccinimide and Lewis acid, or a combination of N-halosuccinimide and Bronsted acid; preferably, the promoter is a combination of NIS and Sc(OTf)3, NIS and trimethylsilyl trifluoromethanesulfonate (TMSOTf), or a combination of NIS and TfOH.

[0055] In the preparation method of the phosphonate derivative as shown in Formula I, the promoter may be a combination of N-halosuccinimide and Lewis acid, or a combination of N-halosuccinimide and Bronsted acid; preferably, the promoter is a combination of NIS and Sc(OTf)3, or a combination of NIS and TfOH.

[0056] In the preparation method of the phosphonate derivative shown in formula I, when the promoter is a combination of N-halosuccinimide and Lewis acid, the molar ratio of the compound shown in formula II to N-halosuccinimide can be 1:(1.1-3), for example, 1:1.1 or 1:2.0.

[0057] In the preparation method of the phosphonate derivative shown in formula I, when the promoter is a combination of N-halosuccinimide and Lewis acid, the molar ratio of the compound shown in formula II to N-halosuccinimide can be 1:(1.1-3), for example 1:1.1.

[0058] In the preparation method of the phosphonate derivative shown in formula I, when the promoter is a combination of N-halosuccinimide and Lewis acid, the molar ratio of the compound shown in formula II to the Lewis acid can be 1:(0.05-1.5), for example, 1:1.5, 1:0.07, 1:0.3 or 1:0.7.

[0059] In the preparation method of the phosphonate derivative as shown in formula I, when the promoter is a combination of N-halosuccinimide and Lewis acid, the molar ratio of the compound as shown in formula II and the Lewis acid can be 1:(0.05-1.5), preferably 1:(0.05-1), for example 1:0.07, 1:0.3 or 1:0.7.

[0060] In the preparation method of the phosphonate derivative shown in formula I, when the promoter is a combination of N-halosuccinimide and Lewis acid, the molar ratio between the compound shown in formula II, N-halosuccinimide and Lewis acid can be 1:(1.1-3):(0.05-1.5), for example, 1:2:1.5, 1:1.1:0.07, 1:1.1:0.7 or 1:1.1:0.3.

[0061] In the preparation method of the phosphonate derivative shown in formula I, when the promoter is a combination of N-halosuccinimide and Lewis acid, the molar ratio between the compound shown in formula II, N-halosuccinimide and Lewis acid can be 1:(1.1-3):(0.05-1.5), for example, 1:1.1:0.07, 1:1.1:0.7 or 1:1.1:0.3.

[0062] In the preparation method of the phosphonate derivative shown in formula I, when the promoter is a combination of N-halosuccinimide and Lewis acid, the feeding temperature of the reaction can be 25°C to 45°C, for example, 37°C to 39°C, 36°C to 38°C or 30°C to 38°C, wherein the feeding temperature is the temperature when the compound shown in formula II is added.

[0063] In the preparation method of the phosphonate derivative shown in formula I, when the promoter is a combination of N-halosuccinimide and Lewis acid, the feeding temperature of the reaction can be 25°C to 45°C, for example, 37 to 39°C, wherein the feeding temperature is the temperature when the compound shown in formula II is added.

[0064] In the method for preparing the phosphonate derivative as shown in Formula I, when the promoter is a combination of N-halosuccinimide and Lewis acid, the reaction temperature of the reaction can be 40°C to 78°C, such as 44°C to 46°C or 78°C.

[0065] In the method for preparing the phosphonate derivative as shown in Formula I, when the promoter is a combination of N-halosuccinimide and Lewis acid, the reaction temperature of the reaction can be 40°C to 78°C, for example 78°C.

[0066] In the preparation method of the phosphonate derivative as shown in Formula I, when the accelerator is a combination of N-halosuccinimide and Lewis acid, the feeding method of the reaction can be any of the following schemes:

[0067] Scheme 1: first add a compound represented by formula III and a compound represented by formula II, and then add a mixture of N-halosuccinimide and Lewis acid;

[0068] Scheme 2: sequentially adding a compound represented by formula III, a compound represented by formula II, a Lewis acid and an N-halogenated succinimide;

[0069] The preferred method of adding materials to the reaction is Scheme 2.

[0070] In one embodiment, in the method for preparing the phosphonate derivative as shown in Formula I, when the promoter is a combination of N-halosuccinimide and Lewis acid, the promoter is a combination of NIS and Sc(OTf)3;

[0071] The molar ratio of the compound shown in formula II, N-halosuccinimide and Lewis acid is 1:1.1:0.7; the feeding temperature of the reaction is 36-38° C., wherein the feeding temperature is the temperature when the compound shown in formula II is added;

[0072] The reaction temperature of the reaction was 78°C.

[0073] In the preparation method of the phosphonate derivative shown in formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the molar ratio of the compound shown in formula II to N-halosuccinimide can be 1:(1-5), preferably 1:(1.1-2), for example 1:1.2, 1:1.5, 1:1.8 or 1:2.

[0074] In the preparation method of the phosphonate derivative shown in formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the molar ratio of the compound shown in formula II to N-halosuccinimide can be 1:(0.5-5), for example, 1:2, 1:0.5, 1:1, 1:1.5 or 1:2.

[0075] In the preparation method of the phosphonate derivative shown in formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the molar ratio of the compound shown in formula II to the Bronsted acid can be 1:(0.5-3), preferably 1:(0.5-2), for example 1:0.5, 1:1, 1:1.5 or 1:2.

[0076] In the preparation method of the phosphonate derivative shown in formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the molar ratio between the compound shown in formula II, N-halosuccinimide and Bronsted acid can be 1:(1-5):(0.5-3), for example, 1:2:2, 1:1:1.5, 1:2:1.5, 1:1.8:1.5, 1:2:1.5 or 1:1.5:1.5.

[0077] In the preparation method of the phosphonate derivative shown in formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the molar ratio between the compound shown in formula II, N-halosuccinimide and Bronsted acid can be 1:(1-5):(0.5-3), preferably 1:(1.1-2):(0.5-2), for example 1:2:1.5, 1:1.8:1.5, 1:2:1.5 or 1:1.5:1.5.

[0078] In the preparation method of the phosphonate derivative shown in formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the reaction feeding temperature can be -2°C to 62°C, for example, -2°C, 10°C, 20°C, 0-30°C, 29-30°C, 37-41°C, 43-48°C, 49-50°C or 57-62°C, preferably 20-50°C, more preferably 25-48°C; for example, 29-30°C, 37-41°C or 43-48°C, wherein the feeding temperature is the temperature when the compound shown in formula II is added.

[0079] In the preparation method of the phosphonate derivative shown in formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the reaction feeding temperature can be -2°C to 62°C, preferably 20 to 50°C, more preferably 25 to 48°C, for example -2°C, 10°C, 20°C, 29 to 30°C, 37 to 41°C, 43 to 48°C, 49 to 50°C or 57 to 62°C; for example 29 to 30°C, 37 to 41°C or 43 to 48°C, wherein the feeding temperature is the temperature when the compound shown in formula II is added.

[0080] In the method for preparing the phosphonate derivative as shown in Formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the reaction temperature of the reaction can be 40°C to 78°C, for example 40°C to 60°C, for example 45°C, 46°C, 50°C or 60°C, preferably 46°C to 50°C.

[0081] In the method for preparing the phosphonate derivative as shown in formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the reaction temperature of the reaction can be 40°C to 78°C, for example 40°C to 60°C, for example 46°C, 50°C or 60°C, preferably 46°C to 50°C.

[0082] In the method for preparing the phosphonate derivative as shown in Formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the feeding method of the reaction can be any of the following schemes:

[0083] Scheme 1: First, add the compound represented by formula II, solvent and N-halosuccinimide in sequence, then add the solution formed by Bronsted acid and solvent, and finally add the compound represented by formula III;

[0084] Scheme 2: First, N-halosuccinimide and Bronsted acid are dissolved in a solvent to form a solution A, then a solution B of a compound represented by formula II and a solvent is added, and finally a compound represented by formula III is added;

[0085] Scheme 3: First, N-halosuccinimide and Bronsted acid are dissolved in a solvent to form a solution A, and then a solution B formed by a compound represented by formula III and a compound represented by formula II and a solvent is added simultaneously;

[0086] Scheme 4: First, N-halosuccinimide and Bronsted acid are dissolved in a solvent to form a solution A, then a compound represented by formula III is added, and finally a solution B formed by a compound represented by formula II and a solvent is added;

[0087] Scheme 5: First, N-halosuccinimide and Bronsted acid are dissolved in a solvent to form a solution A, then a solution B formed by a compound represented by formula II and a solvent is added, and finally a compound represented by formula III is added; preferably, in scheme 5, the solution B is added dropwise to the solution A;

[0088] The preferred method of adding materials is Scheme 5.

[0089] In the preparation method of the phosphonate derivative shown in formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, and the feeding method is scheme 1, the solvent can be an ether solvent; the molar volume ratio of the compound shown in formula II and the solvent can be 0.5 to 1 mol / L, for example, 0.56 mol / L; in the solution formed by the Bronsted acid and the solvent, the molar volume ratio of the Bronsted acid and the solvent can be 0.5 to 1.5 mol / L, for example, 0.84 mol / L.

[0090] In the preparation method of the phosphonate derivative shown in formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, and the feeding method is scheme 1, the molar volume ratio of the compound shown in formula II and the solvent can be 0.28 to 1 mol / L, for example, 0.28 mol / L; in the solution formed by the Bronsted acid and the solvent, the molar volume ratio of the Bronsted acid and the solvent can be 0.42 to 1.5 mol / L, for example, 0.42 mol / L.

[0091] In the preparation method of the phosphonate derivative shown in formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, and the feeding method is scheme 2, in the solution A, the solvent may be an ether solvent; in the solution A, the molar volume ratio of the Bronsted acid to the solvent may be 0.5 to 1.5 mol / L, for example, 0.84 mol / L; in the solution B, the solvent may be a halogenated hydrocarbon solvent; in the solution B, the molar volume ratio of the compound shown in formula II to the solvent may be 0.5 to 1 mol / L, for example, 0.56 mol / L.

[0092] In the preparation method of the phosphonate derivative shown in formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, and the feeding method is scheme 3, in the solution A, the solvent may be an ether solvent; in the solution A, the molar volume ratio of the Bronsted acid to the solvent may be 0.5 to 1.5 mol / L, for example, 0.84 mol / L; in the solution B, the solvent may be a halogenated hydrocarbon solvent; in the solution B, the molar volume ratio of the compound shown in formula II to the solvent may be 0.5 to 1 mol / L, for example, 0.56 mol / L.

[0093] In the preparation method of the phosphonate derivative shown in formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, and the feeding method is scheme 4, in the solution A, the solvent may be an ether solvent; in the solution A, the molar volume ratio of the Bronsted acid to the solvent may be 0.5 to 1.5 mol / L, for example, 0.84 mol / L; in the solution B, the solvent may be a halogenated hydrocarbon solvent; in the solution B, the molar volume ratio of the compound shown in formula II to the solvent may be 0.5 to 1 mol / L, for example, 0.56 mol / L.

[0094] In the preparation method of the phosphonate derivative shown in formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, and the feeding method is scheme 5, in the solution A, the solvent may be an ether solvent; in the solution A, the molar volume ratio of the Bronsted acid to the solvent may be 0.5 to 1.5 mol / L, for example, 0.84 mol / L; in the solution B, the solvent may be a halogenated hydrocarbon solvent; in the solution B, the molar volume ratio of the compound shown in formula II to the solvent may be 0.5 to 1 mol / L, for example, 0.56 mol / L.

[0095] In one embodiment, in the method for preparing the phosphonate derivative as shown in Formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the feeding method is as in Embodiment 5;

[0096] The accelerator is a combination of NIS and Tf(OH);

[0097] The molar ratio of the compound shown in formula II, N-halosuccinimide and Bronsted acid is 1:2:1.5;

[0098] The reaction feed temperature is 0-30°C (room temperature), wherein the feed temperature is the temperature when the compound shown in Formula II is added;

[0099] The reaction temperature of the reaction is 44°C to 46°C.

[0100] In the preparation method of the phosphonate derivative shown in formula I, the compound shown in formula III can be prepared by the following method: reacting the compound shown in formula IV with a silanization agent,

[0101]

[0102] R 2 , R 3 and R 4 is as defined in the preceding item.

[0103] In the method for preparing the phosphonate derivatives as shown in formula I, the compound as shown in formula III is directly involved in the preparation reaction of the phosphonate derivatives as shown in formula I without separation, or the purified form obtained after separation and purification is involved in the preparation reaction of the phosphonate derivatives as shown in formula I. Preferably, the compound as shown in formula III is directly involved in the preparation reaction of the phosphonate derivatives as shown in formula I without separation.

[0104] In the preparation method of the phosphonate derivative shown in formula I, the molar ratio of the compound shown in formula II to the compound shown in formula IV can be 1:(1.2-8), for example, 1:(1.5-6), 1:1.5, 1:1.8, 1:3, 1:4, 1:4.5, 1:5.25, 1:5.7, or 1:6.

[0105] In the preparation method of the phosphonate derivative as shown in formula I and the preparation method of the compound as shown in formula III, the type of the silanization agent is conventional in the art, such as N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA), N,O-bis(trimethylsilyl)acetamide (BSA), trimethylchlorosilane, hexamethyldisilazane, hexamethyldisiloxane, trimethylsilyldiethylamine, trimethylsilylethyl acetate, bis(trimethylsilyl)sulfate, hexamethyldisiloxane, trimethylsilylimidazole, or trimethylsilyl trifluoromethanesulfonate, and another example is N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA).

[0106] In the method for preparing the phosphonate derivative shown in formula I, in the method for preparing the compound shown in formula III, the molar ratio of the compound shown in formula IV and the silanization agent can be (1-3):1, preferably (1-1.5):1, for example 1:1 or 1.5:1.

[0107] In the method for preparing the phosphonate derivative shown in Formula I and the method for preparing the compound shown in Formula III, the reaction can be carried out in a solvent-free condition or in an aprotic solvent, preferably in a solvent-free condition.

[0108] In the method for preparing the phosphonate derivative as shown in formula I and the method for preparing the compound as shown in formula III, the reaction temperature can be 20-50°C, for example, 36-38°C, 28-42°C or 32-38°C.

[0109] In the method for preparing the phosphonate derivative as shown in Formula I and the method for preparing the compound as shown in Formula III, the reaction temperature can be 20 to 50°C, such as 28 to 42°C, and also such as 32 to 38°C.

[0110] In the method for preparing the phosphonate derivatives as shown in formula I, in the method for preparing the compounds as shown in formula III, preferably, diphenyl phosphite (R 2 and R 3 The reaction is carried out under solvent-free conditions at a temperature of 36 to 38° C. or 32 to 38° C. with a silylating agent BSTFA.

[0111] In the method for preparing the phosphonate derivatives as shown in formula I, in the method for preparing the compounds as shown in formula III, preferably, diphenyl phosphite (R 2 and R 3 The reaction is carried out at a temperature of 32 to 38° C. under solvent-free conditions.

[0112] In the preparation method of the phosphonate derivative shown in formula I, when the promoter is a combination of N-halosuccinimide and Lewis acid, the molar ratio between the compound shown in formula IV, the silanization agent, the compound shown in formula II, N-halosuccinimide and Lewis acid can be (1.5-5):(1.5-5):1:(1.1-3):(0.05-1.5), for example, 4:4:1:2:1.5, 1.5:1.5:1:1.1:0.07, 4:4:1:1.1:0.7 or 4:4:1:1.1:0.3.

[0113] In the preparation method of the phosphonate derivative shown in formula I, when the promoter is a combination of N-halosuccinimide and Lewis acid, the molar ratio between the compound shown in formula IV, the silanization agent, the compound shown in formula II, N-halosuccinimide and Lewis acid can be (1.5-5):(1.5-5):1:(1.1-3):(0.05-1.5), for example, 1.5:1.5:1:1.1:0.07, 4:4:1:1.1:0.7 or 4:4:1:1.1:0.3, preferably 4:4:1:1.1:0.7.

[0114] In one embodiment, in the method for preparing the phosphonate derivative as shown in Formula I, the silanization agent is BSTFA;

[0115] The molar ratio of the compound represented by formula IV, the silanization agent, the compound represented by formula II, N-halosuccinimide and Lewis acid is 4:4:1:1.1:0.7;

[0116] In the method for preparing the compound of formula III, the reaction temperature may be 36-38° C.; diphenyl phosphite (R 2 and R 3 All are Ph) and silanization agent BSTFA are reacted under solvent-free conditions.

[0117] In the preparation method of the phosphonate derivative shown in formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the molar ratio between the compound shown in formula IV, the silanization agent, the compound shown in formula II, N-halosuccinimide and Bronsted acid can be (4-6):(3-5):1:(1-2):(1.2-2), for example, 5.7:3.8:1:1:1.5, 4:4:1:2:1.5, 5.7:3.8:1:1.8:1.5, 6:4:1:2:1.5, 6:4:1:1.8:1.5, 5.25:3.5:1:2 :1.5, 4.5:3:1:2:1.5, 6:4:1:1.5:1.5 or 4:4:1:2:2 preferably (5-6):(3.8-4.2):1:(1.7-2):(1.4-1.6), preferably 5.7:3.8:1:1.8:1.5, 6:4:1:2:1.5, 6:4:1:1.8:1.5, 5.25:3.5:1:2:1.5, 4.5:3:1:2:1.5 or 6:4:1:1.5:1.5, more preferably 5.7:3.8:1:1.8:1.5, 6:4:1:2:1.5 or 6:4:1:1.8:1.5.

[0118] In the preparation method of the phosphonate derivative as shown in formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the molar ratio between the compound as shown in formula IV, the silanization agent, the compound as shown in formula II, N-halosuccinimide and Bronsted acid can be (4-6):(3-5):1:(1.5-2):(1.2-2), preferably (5-6):(3.8-4.2):1:(1.7-2):(1.4-1.6); for example, 4:4:1:2:1.5, 5.7:3.8:1:1.8:1.5, 6:4:1:2: 1.5, 6:4:1:1.8:1.5, 5.25:3.5:1:2:1.5, 4.5:3:1:2:1.5, 6:4:1:1.5:1.5 or 4:4:1:2:2, preferably 5.7:3.8:1:1.8:1.5, 6:4:1:2:1.5, 6:4:1:1.8:1.5, 5.25:3.5:1:2:1.5, 4.5:3:1:2:1.5 or 6:4:1:1.5:1.5, more preferably 5.7:3.8:1:1.8:1.5, 6:4:1:2:1.5 or 6:4:1:1.8:1.5.

[0119] In one embodiment, in the method for preparing the phosphonate derivative as shown in Formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the promoter is a combination of NIS and Tf(OH);

[0120] In the method for preparing the compound of formula III, the compound of formula IV and the silanization agent BSTFA are reacted at a temperature of 32 to 38° C. under solvent-free conditions;

[0121] The molar ratio of the compound represented by formula IV, the silanization agent, the compound represented by formula II, the N-halosuccinimide and the Bronsted acid is 6:4:1:2:1.5;

[0122] The reaction feed temperature is 0-30°C (room temperature), wherein the feed temperature is the temperature when the compound shown in Formula II is added;

[0123] The reaction temperature of the reaction is 44°C to 46°C.

[0124] In one embodiment, in the method for preparing the phosphonate derivative as shown in Formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the promoter is a combination of NIS and Tf(OH);

[0125] In the method for preparing the compound of formula III, the compound of formula IV and the silanization agent BSTFA are reacted at a temperature of 32 to 38° C. under solvent-free conditions;

[0126] The molar ratio of the compound of formula IV, the silanization agent, the compound of formula II, the N-halosuccinimide and the Bronsted acid is 5.7:3.8:1:1.8:1.5, 6:4:1:2:1.5, 6:4:1:1.8:1.5 or 5.25:3.5:1:2:1.5;

[0127] The reaction feed temperature is 30-38°C (room temperature), wherein the feed temperature is the temperature when the compound shown in Formula II is added;

[0128] The reaction temperature of the reaction is 45°C to 50°C.

[0129] In the method for preparing the phosphonate derivative as shown in Formula I, the reaction progress can be monitored by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the reaction endpoint is generally when the compound as shown in Formula II disappears or no longer reacts.

[0130] In the method for preparing the phosphonate derivatives shown in Formula I, the reaction may further include post-treatment, which may include the following steps: quenching (e.g., adding triethylamine for quenching), diluting (e.g., adding ethyl acetate for dilution), washing (e.g., washing with water, saturated sodium sulfite aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution in sequence), and drying (e.g., drying with anhydrous sodium sulfate). The post-treatment may also include purification (e.g., purification by column chromatography).

[0131] In the method for preparing the phosphonate derivative as shown in formula I, the method for preparing the phosphonate derivative as shown in formula I may further comprise the following steps: preparing a compound as shown in formula V, dimethyl sulfoxide and The reaction is carried out in the presence of a co-catalyst to obtain a compound as shown in Formula II.

[0132]

[0133] Among them, R a1 , R a2 , R 5 and is as defined in the preceding item;

[0134] R 6 is a C1-C6 alkyl group;

[0135] The co-catalyst is acetic acid or trifluoroacetic acid.

[0136] In a certain embodiment, in the method for preparing the compound of formula II, certain groups have the following definitions, and the definitions of the groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "in a certain embodiment"),

[0137] "*" indicates that the carbon atom with "*" is a chiral carbon atom, which is in R configuration, S configuration or a mixture of R configuration and S configuration, for example for

[0138] In one scheme, R 6 In the above, the C1-C6 alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, for example, methyl.

[0139] In one embodiment, the compound shown in formula II is any of the following compounds:

[0140]

[0141] In the method for preparing the compound shown in Formula II, the co-catalyst is acetic acid.

[0142] In the method for preparing the compound of formula II, the molar ratio of the compound of formula V to dimethyl sulfoxide can be 1:(5-47), for example, 1:5, 1:15, 1:20, 1:26, 1:26.4, 1:30, 1:36.8, 1:46, 1:46.9 or 1:47, preferably 1:(20-47).

[0143] In the method for preparing the compound of formula II, the molar ratio of the compound of formula V to dimethyl sulfoxide can be 1:(5-47), for example, 1:5, 1:20, 1:26, 1:26.4, 1:30, 1:36.8, 1:46, 1:46.9 or 1:47, preferably 1:(20-47).

[0144] In the method for preparing the compound of formula II, the compound of formula V and The molar ratio can be 1:(3-40), for example 1:3, 1:10, 1:15, 1:23, 1:23.4, 1:23.5, 1:30, or 1:40, preferably 1:(10-40).

[0145] In the method for preparing the compound of formula II, the molar ratio of the compound of formula V to the co-catalyst can be 1:(1.5-20), for example, 1:1.5, 1:5, 1:6.7, 1:11.7, 1:11.8 or 1:20, preferably 1:(5-20).

[0146] In the preparation method of the compound shown in formula II, the compound shown in formula V, dimethyl sulfoxide, The molar ratio of the catalyst to the co-catalyst may be 1:(3-60):(2-50):(1-30), preferably 1:(10-40):(10-40):(10-30), more preferably 1:(20-30):(20-35):(15-25); for example 1:15:40:20, 1:26.4:23:6.7, 1:30:15:5, 1:47:23.5:11.8, 1:5:3:1.5, 1:36.8:15:5, 1:20:10:5, 1:46.9:23.4:11.7, 1:46:23:20, 1:26.4:23:20, 1 :26.4:40:20, 1:26.4:30:20 or 1:26:30:20; for example, 1:30:15:5, 1:47:23.5:11.8, 1:36.8:15:5, 1:20:10:5, 1:46.9:23.4:11.7, 1:46:23:20, 1:26.4:23:20, 1:26.4:40:20, 1:26.4:30:20 or 1:26:30:20; for example, 1:26.4:23:20, 1:26.4:40:20, 1:26.4:30:20 or 1:26:30:20.

[0147] In the preparation method of the compound shown in formula II, the compound shown in formula V, dimethyl sulfoxide, The molar ratio of the catalyst to the co-catalyst may be 1:(3-60):(2-50):(1-30), preferably 1:(10-40):(10-40):(10-30), more preferably 1:(20-30):(20-35):(15-25); for example 1:26.4:23:6.7, 1:30:15:5, 1:47:23.5:11.8, 1:5:3:1.5, 1:36.8:15:5, 1:20:10:5, 1:46.9:23.4:11.7, 1:46:23:20, 1:26.4:23:20, 1:26.4:23:20 :40:20, 1:26.4:30:20 or 1:26:30:20; for example, 1:30:15:5, 1:47:23.5:11.8, 1:36.8:15:5, 1:20:10:5, 1:46.9:23.4:11.7, 1:46:23:20, 1:26.4:23:20, 1:26.4:40:20, 1:26.4:30:20 or 1:26:30:20; for example, 1:26.4:23:20, 1:26.4:40:20, 1:26.4:30:20 or 1:26:30:20.

[0148] In the method for preparing the compound shown in Formula II, the reaction may further comprise an additive; the additive is, for example, sodium acetate.

[0149] In the method for preparing the compound of formula II, when the reaction further includes an additive, the molar ratio of the compound of formula V to the additive may be 1:(0.1-5), for example 1:0.1 or 1:5, preferably 1:0.1.

[0150] In the method for preparing the compound shown in Formula II, the reaction temperature may be 9°C to 50°C, preferably 10°C to 35°C, more preferably 20°C to 30°C; for example, 9°C, 15°C, 20°C, 25°C, 23-27°C, 28°C, 29°C, 30°C or 31°C, for example, 15°C, 20°C, 23-27°C, or 29°C; for example, 20°C or 29°C.

[0151] In the method for preparing the compound of formula II, the progress of the reaction can be monitored by conventional monitoring methods in the art (e.g., TLC, HPLC or NMR), and the reaction endpoint is generally when the compound of formula V disappears or no longer reacts. The reaction time can be 15 to 125 hours, for example, 16.5 hours, 18 hours, 24 hours, 27.5 hours, 30 hours, 32 hours, 34 hours, 34.5 hours, 36 hours, 38 hours, 67 hours, 72 hours, 86 hours or 125 hours.

[0152] In one embodiment, in the method for preparing the compound as shown in Formula II, R 6 is methyl;

[0153] The co-catalyst is acetic acid;

[0154] The compound shown in formula V, dimethyl sulfoxide, and co-catalyst in a molar ratio of 1:26.4:40:20;

[0155] The temperature of the reaction was 20°C.

[0156] The present invention provides a method for preparing a compound as shown in Formula VI, which is any of the following methods:

[0157] Method (1): comprising the following two steps:

[0158] Step 1: In an organic solvent A, react the phosphonate derivative shown in Formula I in the presence of a base to obtain a compound shown in Formula VII;

[0159] Step 2: reacting the compound of formula VII obtained in step 1 in a mixed solution of an acid and an organic solvent B to obtain a compound of formula VI;

[0160]

[0161] Method (2): comprising the following two steps:

[0162] Step 1: reacting a phosphonate derivative as shown in formula I in a mixture of an acid and an organic solvent B to obtain a compound as shown in formula VIII;

[0163] Step 2: In an organic solvent A, react the compound represented by formula VIII obtained in step 1 in the presence of a base to obtain a compound represented by formula VI;

[0164]

[0165] Method (3): In a solvent, the phosphonate derivative shown in formula I is reacted in the presence of a base or an acid to obtain a compound shown in formula VI;

[0166]

[0167] Method (4): comprising the following steps: reacting the compound represented by formula VII in a mixture of an acid and an organic solvent B to obtain a compound represented by formula VI;

[0168]

[0169] Method (5): comprising the following steps: reacting the compound represented by formula VIII in an organic solvent A in the presence of a base to obtain the compound represented by formula VI;

[0170]

[0171] In the methods (1), (2) and (3), R a1 , R a2 , R 2 , R 3 , R 5 and is as defined in any of the preceding items; in the method (4), R a1 , R a2 , R 3 , R 5 and is as defined in any of the preceding items; in the method (5), R 2 , R 3 , R 5 and is as defined in the preceding item.

[0172] In one embodiment, the method for preparing the compound of formula VI further comprises the following steps: preparing the compound of formula I according to the method for preparing the phosphonate derivative of formula I.

[0173] In one embodiment, in the method (1), method (2), method (3), method (4) and method (5), "*" indicates that the carbon atom with "*" is a chiral carbon atom, which is in R configuration, S configuration or a mixture of R configuration and S configuration, for example for

[0174] In the method for preparing the compound of formula VI, in the method (1), in step 1, the organic solvent A can be an ether solvent; the ether solvent can be tetrahydrofuran.

[0175] In the method for preparing the compound of formula VI, in the method (1), in the step 1, the base may be an alkali metal hydroxide; the alkali metal hydroxide may be sodium hydroxide.

[0176] In the method for preparing the compound of formula VI, in the method (1), in step 1, the molar ratio of the phosphonate derivative of formula I to the base can be 1:(1.2-3), for example 1:2.14 or 1.19.

[0177] In the method for preparing the compound of formula VI, in the method (1), in step 1, the molar ratio of the phosphonate derivative of formula I to the base can be 1:(1.2-3), for example 1:1.9.

[0178] In the method for preparing the compound of formula VI, in the method (1), in step 1, the molar volume ratio of the phosphonate derivative of formula I and the organic solvent A can be 0.2 mol / L to 0.5 mol / L, for example 0.3 or 0.36 mol / L.

[0179] In the method for preparing the compound of formula VI, in the method (1), in step 1, the molar volume ratio of the phosphonate derivative of formula I and the organic solvent A can be 0.2 mol / L to 0.5 mol / L, for example 0.36 mol / L.

[0180] In the method for preparing the compound of formula VI, in the method (1), in step 1, the base participates in the reaction in the form of an aqueous solution of the base, and the molar volume ratio of the base to water can be 0.3 mol / L to 1.0 mol / L, for example 0.5 mol / L.

[0181] In the method for preparing the compound of formula VI, in the method (1), in the step 1, the reaction temperature can be 20 to 40°C, for example, 20 to 30°C.

[0182] In the method for preparing the compound of formula VI, in the method (1), in the step 1, the reaction temperature can be 20-40°C, for example 30°C.

[0183] In the method for preparing the compound of formula VI, in the method (1), in step 1, the progress of the reaction can be monitored by conventional monitoring methods in the art (e.g., TLC, HPLC or NMR), and the reaction endpoint is generally when the phosphonate derivative of formula I disappears or no longer reacts.

[0184] In the method for preparing the compound of formula VI, in the method (1), step 1 may further include post-treatment, and the post-treatment includes the following steps: acidifying the reaction system, removing the solvent, adding an organic solvent and then filtering out the inorganic salt, and then removing the solvent. In the method (1), in the post-treatment, step 1 may further be purified.

[0185] In the method for preparing the compound of formula VI, in the method (1), in the post-treatment of step 1, during the acidification process, a mixture of acid / organic solvent B can be used for acidification, the acid can be hydrochloric acid, and the organic solvent B can be an alcohol solvent; the alcohol solvent can be ethanol; the volume ratio of the acid to the organic solvent B can be 1:(7-11), for example 1:9.

[0186] In the method for preparing the compound of formula VI, in step 2 of method (1) and method (4), in the mixed solution of acid and organic solvent B, the acid may be hydrochloric acid; the type of organic solvent B may be an alcohol solvent; and the alcohol solvent may be ethanol.

[0187] In the method for preparing the compound of formula VI, in method (1), the molar ratio of the phosphonate derivative of formula I to the acid in step 2 can be 1:(2-10), for example 1:5.

[0188] In the method for preparing the compound of formula VI, in step 2 of method (1) and method (4), in the mixed solution of the acid and the organic solvent E, the volume ratio of the acid and the organic solvent E can be 1:(9-99), for example 1:9 or 1:99.

[0189] In the method for preparing the compound of formula VI, in step 2 of method (1) and method (4), the reaction temperature can be 80-100°C, for example 90°C.

[0190] In the method for preparing the compound represented by formula VI, step 2 of method (1) and method (4) may further include post-treatment, wherein the post-treatment comprises the following steps: removing the organic solvent of the reaction system, adding water to the obtained residue, washing with an ester solvent (e.g., ethyl acetate), adding an alcohol solvent (e.g., ethanol) to the obtained aqueous phase, adding an amine reagent (e.g., triethylamine) to adjust the pH (e.g., adjust the pH to 2-3), stirring (e.g., stirring in an ice-water bath), filtering, washing (e.g., washing with ethanol), and drying.

[0191] In the method for preparing the compound of formula VI, in the method (2), in the step 1, in the mixed solution formed by the acid and the organic solvent B, the acid can be hydrochloric acid; the type of the organic solvent B can be an alcohol solvent; and the alcohol solvent can be ethanol.

[0192] In the method for preparing the compound of formula VI, in the method (2), in step 1, the molar ratio of the phosphonate derivative of formula I to the acid can be 1:(2-6), for example 1:3.

[0193] In the method for preparing the compound of formula VI, in the method (2), in the step 1, in the mixed solution formed by the acid and the organic solvent B, the volume ratio of the acid and the organic solvent B can be 1:(9-99), for example 1:9.

[0194] In the method for preparing the compound of formula VI, in the method (2), in the step 1, the reaction temperature can be 60 to 90°C, such as 70°C, 80°C, 60°C or 75°C.

[0195] In the method for preparing the compound of formula VI, in the method (2), in the step 1, the reaction temperature can be 70-90°C, for example 80°C.

[0196] In the method for preparing the compound of formula VI, in step 2 of method (2) and method (5), the organic solvent A may be an ether solvent; the ether solvent may be tetrahydrofuran.

[0197] In the method for preparing the compound of formula VI, in step 2 of method (2) and method (5), the base may be an alkali metal hydroxide; the alkali metal hydroxide may be sodium hydroxide.

[0198] In the method for preparing the compound of formula VI, in method (2), the molar ratio of the phosphonate derivative of formula I to the base in step 2 can be 1:(1.5-5), for example 1:2.7.

[0199] In the method for preparing the compound of formula VI, in step 2 of method (2) and method (5), the base is reacted in the form of an aqueous solution of the base, and the molar volume ratio of the base to water can be 0.3 mol / L to 1.4 mol / L. Preferably, the aqueous solution of the base is reacted in the form of dropwise addition; the temperature of the base when added can be 0-15°C.

[0200] In the method for preparing the compound of formula VI, in step 2 of method (2) and method (5), the base is reacted in the form of an aqueous solution of the base, and the molar volume ratio of the base to water can be 0.3 mol / L to 1.0 mol / L, for example, 1.0 mol / L. Preferably, the aqueous solution of the base is reacted in the form of dropwise addition; the temperature of the base when added can be 5°C.

[0201] In the method for preparing the compound of formula VI, in step 2 of method (2) and method (5), the reaction temperature can be 15°C to 30°C, for example 20°C or 25°C.

[0202] In the method for preparing the compound of formula VI, in step 2 of method (2) and method (5), the reaction temperature can be 20°C to 30°C, for example 25°C.

[0203] In the method for preparing the compound of formula VI, in step 2 of method (2) and method (5), the reaction time can be 30 min to 2 h, for example 40 min.

[0204] In the method for preparing the compound represented by formula VI, in step 2 of method (2) and method (5), the reaction may further include post-treatment, and the post-treatment may include the following steps: washing (for example, washing with ethyl acetate), adjusting the pH value (for example, adjusting the pH to 2-3), and crystallization.

[0205] In the method for preparing the compound of formula VI, in step 2 of method (2) and method (5), the reaction may further include post-treatment, and the post-treatment may include the following steps: washing (for example, washing with ethyl acetate), adjusting the pH value (for example, adjusting the pH to 3), and crystallization; the crystallization may include the following steps: seeding (for example, seeding while stirring), adjusting the pH value (for example, adjusting the pH to 2), filtering, and washing (for example, washing with ethanol) to obtain the compound VI.

[0206] In the method for preparing the compound represented by Formula VI, in the method (3), the solvent may be an ether solvent; the ether solvent may be tetrahydrofuran.

[0207] In the method for preparing the compound represented by Formula VI, in the method (3), the base may be an alkali metal hydroxide; the alkali metal hydroxide may be sodium hydroxide.

[0208] In the method for preparing the compound of formula VI, in method (3), the molar ratio of the phosphonate derivative of formula I to the base can be 1:(2.5-4), for example 1:3.1.

[0209] In the method for preparing the compound of formula VI, in the method (3), the base can be added once or multiple times (eg, 2 times), preferably twice.

[0210] In the method for preparing the compound of formula VI, in method (3), the molar volume ratio of the phosphonate derivative of formula I and the solvent can be 0.1 mol / L to 0.4 mol / L, for example 0.3 mol / L.

[0211] In the method for preparing the compound of formula VI, in method (3), when the base is added twice, the base added for the first time participates in the reaction in the form of an aqueous solution of the base, and the molar volume ratio of the base to water can be 0.3 mol / L to 1.5 mol / L, for example 0.9 mol / L.

[0212] In the method for preparing the compound of formula VI, in method (3), when the base is added twice, the temperature of the first addition of the base can be -5 to 5°C, for example, 0°C.

[0213] In the method for preparing the compound of formula VI, in method (3), when the base is added twice, the temperature of the second addition of the base can be 50-70°C, for example 60°C.

[0214] In the method for preparing the compound of formula VI, in method (3), the progress of the reaction can be monitored by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the reaction endpoint is generally when the phosphonate derivative of formula I disappears or no longer reacts.

[0215] In the method for preparing the compound of formula VI, the method (3) preferably comprises the following steps: mixing the phosphonate derivative of formula I and the solvent (e.g., tetrahydrofuran), adding the base twice (e.g., adding the base for the first time at 0°C, stirring at 20°C for 1h, and adding the base for the second time at 60°C, stirring for 3h) to obtain the compound of formula VI.

[0216] In the preparation method of the compound shown in formula VI, the phosphonate derivative shown in formula I can be prepared by the preparation method of the phosphonate derivative shown in formula I as described above; the phosphonate derivative shown in formula I can be used in the preparation method of the compound shown in formula VI without separation and purification, or can be used in the preparation method of the compound shown in formula VI in a purified form obtained after separation and purification, preferably used in the preparation method of the compound shown in formula VI without separation and purification.

[0217] The present invention also provides a method for preparing a compound as shown in Formula VII, which comprises the following steps: reacting a phosphonate derivative as shown in Formula I in an organic solvent A in the presence of a base to obtain a compound as shown in Formula VII;

[0218]

[0219] Among them, R a1 , R a2 , R 2 , R 3 , R 5 , The organic solvent A and the base are as defined in the preceding clause.

[0220] In the method for preparing the compound as shown in Formula VII, the reaction conditions and operations of the method for preparing the compound as shown in Formula VII are the same as those described in step 1 of the previous method (1).

[0221] In the preparation method of the compound shown in Formula VII, the phosphonate derivative shown in Formula I can be prepared according to the preparation method of the phosphonate derivative shown in Formula I as described above.

[0222] The present invention also provides a method for preparing a compound as shown in formula VIII, which comprises the following steps: reacting a phosphonate derivative as shown in formula I in a mixed solution of an acid and an organic solvent B to obtain a compound as shown in formula VIII;

[0223]

[0224] Among them, R a1 , R a2 , R 2 , R 3 , R 5 , The organic solvent and the acid are as defined in the preceding clause.

[0225] In the method for preparing the compound as shown in Formula VIII, the reaction conditions and operations of the method for preparing the compound as shown in Formula VIII are the same as those described in step 1 of the previous method (2).

[0226] In the preparation method of the compound shown in formula VIII, the phosphonate derivative shown in formula I can be prepared according to the preparation method of the phosphonate derivative shown in formula I as described above.

[0227] The present invention also provides a method for preparing the compound as shown in Formula IX, which is any of the following methods:

[0228] Method (6): It comprises the following steps: in a solvent, the phosphonate derivative as shown in formula I is reacted in the presence of a catalyst to obtain a compound as shown in formula IX;

[0229]

[0230] Among them, R a1 , R a2 , R 2 , R 3 , R 5 and is as defined in the preceding item.

[0231] In the method for preparing the compound as shown in Formula IX, the catalyst is conventional in the art, and the catalyst may be one or more of an inorganic acid, an inorganic base and a Lewis acid, such as a hydrogen bromide acetic acid solution, an alkali metal hydroxide, trimethylsilyl bromide (TMSBr), and one or more of a combination of trimethylsilyl chloride and sodium bromide.

[0232] In the method for preparing the compound shown in Formula IX, when the catalyst is trimethylsilyl bromide (TMSBr) or a combination of trimethylsilyl chloride and sodium bromide, the solvent may be a polar aprotic solvent; the polar aprotic solvent may be one or more of NMP, DMF, acetonitrile and dichloromethane.

[0233] Method (7): comprising the following two steps:

[0234] Step 1: reacting a phosphonate derivative as shown in formula I in a mixture of an acid and an organic solvent B to obtain a compound as shown in formula VIII;

[0235] Step 2: reacting the compound represented by formula VIII obtained in step 1 in a solvent in the presence of an acid to obtain a compound represented by formula IX;

[0236]

[0237] Among them, R a1 , R a2 , R 2 , R 3 , R 5 and is as defined in the preceding item;

[0238] In the method for preparing the compound of formula IX, in the method (7), the reaction conditions and operation of step 1 can be the same as those described in the method for preparing the compound of formula VIII.

[0239] In the method for preparing the compound represented by Formula IX, in step 2 of method (7), the solvent may be water.

[0240] In the method for preparing the compound represented by Formula IX, in step 2 of method (7), the acid may be hydrobromic acid.

[0241] In the method for preparing the compound of formula IX, in method (7), the molar ratio of the phosphonate derivative of formula I to the acid in step 2 can be 1:(2-6), for example 1:4.

[0242] In the method for preparing the compound of formula IX, in step 2 of method (7), the reaction temperature can be 50°C to 90°C, such as 60°C to 80°C, preferably 75°C.

[0243] In the method for preparing the compound of formula IX, in step 2 of method (7), the reaction time may be 16 h to 24 h, for example 16 h or 24 h.

[0244] In the method for preparing the compound represented by Formula IX, in step 2 of method (7), the reaction may further include post-treatment, and the post-treatment may include the following steps: washing (e.g., washing with ethyl acetate), adjusting the pH value (e.g., adjusting the pH to 2-3), and crystallization.

[0245] In the method for preparing the compound of formula IX, in step 2 of method (7), the reaction may further include the following post-treatment steps: washing (for example, washing with ethyl acetate), drying (for example, removing water by rotary evaporation), redissolving (for example, redissolving with water), adjusting the pH (for example, adjusting the pH to 2-3 with a 50% sodium hydroxide aqueous solution), and filtering to obtain the compound of formula IX; or, the post-treatment may further include recrystallization (for example, recrystallization in a mixed solution of water and ethanol in a ratio of 6:4) to obtain the compound of formula IX.

[0246] Method (8): comprising the following two steps:

[0247] The present invention also provides a method for preparing the compound as shown in Formula IX, which comprises the following two steps:

[0248] Step 1: reacting a phosphonate derivative as shown in formula I in a mixture of an acid and an organic solvent B to obtain a compound as shown in formula VIII;

[0249] Step 2: In an organic solvent A, react the compound represented by formula VIII obtained in step 1 in the presence of an acid to obtain a compound represented by formula IX;

[0250]

[0251] Among them, R a1 , R a2 , R 2 , R 3 , R 5 and is as defined in the preceding item;

[0252] In the method for preparing the compound represented by Formula IX, the mixture of the acid and the organic solvent B in step 1 may be a mixture of an inorganic acid and an alcohol in different volume ratios, such as a mixture of hydrochloric acid and ethanol (1:99, v / v); the acid in step 2 may be an inorganic acid, such as hydrobromic acid.

[0253] In the method for preparing the compound of formula IX, the phosphonate derivative of formula I can be prepared according to the method for preparing the phosphonate derivative of formula I as described above.

[0254] The present invention also provides a method for preparing a compound as shown in formula II, which comprises the following steps: and a co-catalyst to obtain a compound as shown in Formula II.

[0255]

[0256] Among them, R a1 , R a2 , R 5 , R 6 , and the co-catalyst are as defined in the preceding item.

[0257] In the method for preparing the compound as shown in Formula II, the reaction conditions and operations of the method for preparing the compound as shown in Formula II are the same as described above.

[0258] The present invention also provides a phosphonate derivative as shown in formula I, a compound as shown in formula II, a compound as shown in formula A, a compound as shown in formula B, a compound as shown in formula C, a compound as shown in formula D or a compound as shown in formula VII.

[0259]

[0260] Among them, R a1 , R a2 , R 2 , R 3 , R 5 and is as defined in the preceding item.

[0261] In one embodiment, the phosphonate derivative shown in formula I and the compound shown in formula II are as described in any of the preceding items.

[0262] The compound shown in formula A is

[0263] In one embodiment, the compound shown in formula B is

[0264] In one embodiment, the compound shown in formula C is

[0265] In one embodiment, the compound as shown in formula D is In one embodiment, the compound shown in formula VII is

[0266] The present invention also provides the use of the compound shown in formula A as a standard in reaction monitoring or reaction product quality control.

[0267]

[0268] Among them, R a1 , R a2 , R 2 , R 3 , R 5 and is as defined in the preceding item;

[0269] Preferably, the reaction in the reaction monitoring is a reaction for preparing a phosphonate derivative as shown in Formula I; and the product of the reaction in the reaction quality control is a phosphonate derivative as shown in Formula I.

[0270] The present invention also provides the use of the compound represented by formula B, the compound represented by formula D or the compound represented by formula C as a standard in reaction monitoring and reaction product quality control.

[0271]

[0272] Among them, R a1 , Ra2 , R 5 and The definition is as described in any of the previous items; the reaction in the reaction monitoring is the reaction for preparing the compound shown in Formula II; the product of the reaction in the reaction quality control is the compound shown in Formula II.

[0273] The present invention also provides the use of a phosphonate derivative as shown in formula I or a compound as shown in formula II in the synthesis of a compound as shown in formula VI, a compound as shown in formula IX, a compound as shown in formula VII, a compound as shown in formula VIII, compound 4, compound 6 or tenofovir alafenamide fumarate (TAF, 1); wherein the compound 4, compound 6 and tenofovir alafenamide fumarate (TAF, 1) are all prepared from the compound as shown in formula VI;

[0274]

[0275]

[0276] Among them, the phosphonate derivatives shown in formula I and the compounds shown in formula II, for

[0277] In the application, the phosphonate derivative as shown in formula I can be prepared by the preparation method of the phosphonate derivative as shown in formula I as described above.

[0278] In the application, the compound shown in Formula II can be prepared by the preparation method of the compound shown in Formula II as described above.

[0279] In the application, the compound represented by formula VI can be prepared by the preparation method of the compound represented by formula VI as described above.

[0280] As used herein, the term "oxo" refers to a =0 group.

[0281] In the present invention, the term "alkyl" refers to a straight or branched chain alkyl group having a specified number of carbon atoms (e.g., C1-C6). Alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc.

[0282] In the present invention, the term "heteroaryl" refers to a cyclic group with a specified number of ring atoms (e.g., 6 to 10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified heteroatom type (one or more of N, O, and S), which is monocyclic or polycyclic, and at least one ring is aromatic (in accordance with Huckel's rule). The heteroaryl group is connected to other fragments in the molecule through an aromatic ring or a non-aromatic ring. Heteroaryl includes, but is not limited to, furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, indolyl, and the like.

[0283] In the present invention, the term "heterocycloalkenyl" refers to a monocyclic heterocycloalkenyl or bicyclic heterocycloalkenyl having a specified number of ring atoms (e.g., 5 to 10 members), a specified number of heteroatoms (e.g., 1, 2 or 3), a specified type of heteroatoms (one or more of N, O and S), and at least one carbon-carbon double bond, and the ring is unsaturated but not aromatic.

[0284] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0285] The reagents and raw materials used in the present invention are commercially available.

[0286] The positive progress of the present invention is that: a phosphonate derivative and a preparation method and use thereof are provided. The preparation method provided by the present invention has cheap and readily available starting materials, is environmentally friendly, avoids toxic and harmful reagents and harsh reaction conditions, avoids cumbersome operations, and is more suitable for industrial synthesis. DETAILED DESCRIPTION

[0287] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0288] Unless otherwise specified, hydrochloric acid refers to concentrated hydrochloric acid with a concentration of 36-38%, ethanol refers to anhydrous ethanol, and the ratio of hydrochloric acid to ethanol is by volume. Hydrobromic acid refers to an aqueous solution of hydrogen bromide with a concentration of not less than 40%. Diphenyl phosphite, diethyl phosphite and diisopropyl phosphite are commercially available. Di(2,2,2-trifluoroethyl) phosphite was synthesized according to the literature (Gibbs DE et al. Synthesis, 1984, (5): 410-413); di-tert-butyl phosphite was synthesized according to the literature (Dietz JP et al. Organic Process Research & Development, 2021, 25 (4): 789-798); dibenzyl phosphite was synthesized according to the literature (Perruchon J et al. Synthesis, 2007, (22): 3553-3557).

[0289] High performance liquid chromatography (HPLC, referred to as liquid phase) conditions: chromatographic column: Suzhou Nanomicro Unisil C18 column (4.6mm×250mm, 5μm); mobile phase A: 10mM ammonium formate aqueous solution (formic acid adjusted to pH=3), mobile phase B: acetonitrile, gradient elution (0-25min: B 10%-90%, 25-28min: B 90%, 28-32min: 90%-10%, 32-38min: B 10%); flow rate 1ml / min; detection wavelength 281nm, column temperature 35°C.

[0290] II-1 standard curve drawing: prepare 0.1mg / ml, 0.2mg / ml, 0.4mg / ml and 0.5mg / ml acetonitrile solutions of pure II-1, filter the above solutions with 0.45μm nylon microporous filter membrane, inject into high performance liquid chromatograph, injection volume 10μL, record the HPLC peak area of ​​each concentration group, measure twice and take the average value, and process with software Origin 8.5 to get the standard curve: y=32,577,586.5000x+392,430.4250, correlation coefficient R 2 =0.9999. II-1 Calculation of liquid phase yield: After the reaction is completed, take 100 μL of the reaction solution with a pipette, dilute it 100 times with acetonitrile, and inject 10 μL. Substitute the liquid phase peak area y into the standard curve to calculate the concentration x (mg / ml), liquid phase yield (%) = x × 100 × reaction solution volume (ml) / theoretical yield (mg) × 100%.

[0291] I-1 standard curve drawing: prepare acetonitrile solutions of pure I-1 at 0.085 mg / ml, 0.169 mg / ml, 0.423 mg / ml and 0.846 mg / ml, filter the above solutions with 0.45 μm nylon microporous filter membrane, inject into high performance liquid chromatograph, injection volume 10 μL, record the HPLC peak area of ​​each concentration group, measure twice and take the average value, and process with software Origin 8.5 to obtain the standard curve: y=17,526,901.4114x+180,004.4126, correlation coefficient R 2 =0.9996. I-1 Calculation of liquid phase yield: After the reaction is completed, an oily product is obtained by post-treatment, and the mass m1 (g) is recorded. Weigh 1g of the oily product, dilute it to 100ml with acetonitrile, dilute the resulting solution 10 times with acetonitrile, and inject 10μL. Substitute the liquid phase peak area y into the standard curve to calculate the concentration x (mg / ml), and the liquid phase yield (%) = x×1000×m1 / theoretical yield (mg)×100%.

[0292] The NMR instruments were Bruker Avance III 400 and Bruker Avance Neo 600. The mass spectrometer was Waters Micromass Q-Tof micro, electrospray ionization (ESI), positive ionization mode. The elemental analyzer was Thermo SCIENTIFIC FLASH2000 Organic Elemental Analyzer.

[0293] Example 1 Preparation of (R)-N-(9-(2-((methylthio)methoxy)propyl)-9H-purin-6-yl)benzamide (II-1)

[0294]

[0295] Va (30.0 g, 101 mmol), dimethyl sulfoxide (208.1 g, 2664 mmol), acetic anhydride (412.0 g, 4036 mmol) and acetic acid (121.2 g, 2018 mmol) were added to a 1L three-necked flask and stirred at 20°C for 38 h. The reaction was complete after TLC sampling monitoring (dichloromethane: methanol = 20:1). The solvent was removed by distillation under reduced pressure. The obtained residue was dissolved in dichloromethane, washed with water and saturated sodium chloride aqueous solution in turn, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain a yellow oil. Ethyl acetate (54 ml) was added to the obtained residue, stirred at room temperature for 12 h, and then petroleum ether (18 ml) was added and stirred at room temperature for 2 h. After suction filtration, the filter cake was washed with a small amount of ethyl acetate and vacuum dried (70°C, 6 h) to obtain a nearly white solid II-1 (26.0 g, 73%). 1H NMR (600MHz, CDCl3) δ9.27(s,1H),8.79(s,1H),8.10(s,1H),8.02(d,J=7.4Hz,2H),7.59(t,J=7.4Hz,1H),7.50(t,J= 7.6Hz, 2H), 4.54 (dd, J = 26.4, 11.7Hz, 2H), 4.45–4.35 (m, 1H), 4.27–4.17 (m, 2H), 1.84 (s, 3H), 1.24 (d, J = 5.8Hz, 3H). 13 C NMR(150MHz, CDCl3)δ164.27(s),152.12(s),151.80(s),148.97(s),143.61(s),133.29(s),132 .25(s),128.36(s),127.41(s),122.21(s),72.63(s),69.90(s),48.29(s),16.28(s),13.38(s). ESI-MS(m / z):358.33[M+H] + ,380.35[M+Na] + ,737.67[2M+Na] + .

[0296] Example 2 Preparation of (R)-N-(9-(2-((methylthio)methoxy)propyl)-9H-purin-6-yl)benzamide (II-1)

[0297] Under argon protection, Va, dimethyl sulfoxide, acetic anhydride and acetic acid are stirred at a certain temperature until the reaction is complete. The obtained reaction solution is slowly poured into a saturated potassium bicarbonate (or sodium bicarbonate) ice water solution containing potassium bicarbonate (or sodium bicarbonate) solid under stirring, stirred for 1 hour, and extracted with ethyl acetate. The organic phases are combined, washed with saturated potassium bicarbonate (or sodium bicarbonate) ice water solution, water and saturated sodium chloride aqueous solution in sequence, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried in vacuo to obtain a crude product II-1. The obtained crude product can be purified by silica gel column chromatography (n-heptane: ethyl acetate = 2:3) to obtain pure product II-1 (Table 1).

[0298] Table 1. Pummerer reaction preparation II-1

[0299] Molar Ratio* Reaction temperature (℃) Reaction time (h) Pure product yield (%) 1:26.4:23:6.7 23～27 16.5 39 1:30:15:5 23～27 24 52 1:47:23.5:11.8 30 18 46 1:5:3:1.5 28～31 86 24

[0300] Note: The molar ratio is Va:DMSO:Ac2O:AcOH.

[0301] Example 3 Preparation of (R)-N-(9-(2-((methylthio)methoxy)propyl)-9H-purin-6-yl)benzamide (II-1).

[0302]

[0303] Va (2.0 g, 6.7 mmol), dimethyl sulfoxide, acetic anhydride and acetic acid were stirred at a certain temperature until the reaction was complete. The contents of product II-1, methyl ketone impurity 29a and acetoxy impurity 29b were calculated by HPLC normalized peak area. The II-1 liquid phase yield (Table 2) was calculated by standard curve method. The impurity reference substances of methyl ketone impurity 29a and acetoxy impurity 29b were prepared by chromatographic separation and purification of Pummerer reaction crude product.

[0304] Methyl ketone impurity 29a. 1 H NMR (400MHz, DMSO-d6) δ11.16(s,1H),8.70(s,1H),8.33(s,1H),8.06(d,J=7.3 Hz, 2H), 7.64 (t, J = 7.4Hz, 1H), 7.55 (t, J = 7.5Hz, 2H), 5.33 (s, 2H), 2.29 (s, 3H). 13 C NMR(101MHz,DMSO-d6)δ201.39(s),165.55(s),152.63(s),151.49(s),150.07(s) ,145.17(s),133.40(s),132.39(s),128.45(s),124.95(s),52.18(s),26.99(s). ESI-MS(m / z):296.12[M+H] + ,318.09[M+Na] + ,613.23[2M+Na] + .

[0305] Acetoxy impurity 29b. 1 H NMR (400MHz, CDCl3) δ9.47(s,1H),8.75(s,1H),8.07(s,1H),8.02(d,J=7.4Hz,2H),7.56(t,J=7.4Hz,1H),7.47(t,J =7.6Hz,2H),5.13(dd,J=17.0,6.6Hz,2H),4.47–4.28(m,1H),4.20–4.05(m,2H),1.82(s,3H),1.27(d,J=5.6Hz,3H). ESI-MS(m / z):370.23[M+H] + ,392.22[M+Na] + ,761.45[2M+Na] + .

[0306] Table 2. Effect of Pummerer reaction parameters on product distribution and yield

[0307]

[0308] Note: a. The molar ratio is Va:DMSO:Ac2O:AcOH. b. The molar ratio is Va:DMSO:Ac2O:trifluoroacetic acid. c. The molar ratio is Va:DMSO:Ac2O:AcOH:sodium acetate.

[0309] Example 4 Preparation of (R)-(((1-(6-benzamido-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonic acid diphenyl ester (I-1)

[0310]

[0311] Under argon protection and stirring, BSTFA (0.11 g, 0.43 mmol) was added dropwise to diphenyl phosphite (12) (0.1 g, 0.42 mmol), and the mixture was stirred at 36-38°C for 1.5 h. Then, II-1 (0.1 g, 0.28 mmol), scandium trifluoromethanesulfonate (0.01 g, 0.02 mmol) and NIS (0.07 g, 0.31 mmol) were added in sequence, and the mixture was heated to 78°C and stirred for 2 h. After the reaction mixture was cooled, water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol = 80:1) to obtain I-1 (0.05 g, yield 33%).

[0312] Example 5. Preparation of diphenyl (R)-(((1-(6-benzamido-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (I-1)

[0313]

[0314] Under argon protection and stirring, BSTFA (0.58 g, 2.24 mmol) was added dropwise to diphenyl phosphite (12) (0.53 g, 2.24 mmol), and the mixture was stirred at 36-38°C for 1.5 h. Then, II-1 (0.2 g, 0.56 mmol) was added, and then a mixture of NIS (0.14 g, 0.62 mmol) and scandium trifluoromethanesulfonate (0.2 g, 0.39 mmol) was slowly added. After the addition, the temperature was raised to 78°C and stirred until the reaction was complete (1.5 h). The obtained reactant was cooled to 40°C, and water was added to quench the reaction. The organic phase was extracted with ethyl acetate, washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and rotary evaporated. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 80:1) to obtain I-1 (0.17 g, 57%).

[0315] Example 6. Preparation of (R)-(((1-(6-benzamido-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonic acid diphenyl ester (I-1)

[0316]

[0317] Under argon protection and stirring, BSTFA (28.8 g, 111.9 mmol) was added dropwise to diphenyl phosphite (12) (39.3 g, 167.8 mmol). The mixture was stirred at 32-38°C for 3 h. The reaction was completed as monitored by phosphorus spectrum to obtain a reaction mixture of silylated diphenyl phosphite 16. 31 P NMR (243MHz, CDCl3) δ124.29.

[0318] Separately, trifluoromethanesulfonic acid (TfOH) (6.3 g, 42.0 mmol) was dissolved in 1,4-dioxane (50 ml), and NIS (12.6 g, 56.0 mmol) was added under stirring at room temperature. A solution of II-1 (10.0 g, 28.0 mmol) in dichloromethane (50 ml) was added dropwise to the obtained TfOH and NIS reaction product, and then the above-mentioned silylated diphenyl phosphite 16 reaction mixture was added, and then the reaction was stirred at 44-46°C for 2 h. Triethylamine was added to quench the reaction, and ethyl acetate was added to dilute, and the reaction was washed with water, saturated sodium sulfite aqueous solution, saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution in sequence, dried over anhydrous sodium sulfate, and rotary evaporated to obtain a yellow oily crude product I-1 with a liquid phase yield of 86%. The obtained crude product was purified by silica gel column chromatography (ethyl acetate) to obtain I-1 (14.0 g, yield 92%). 1 H NMR (400MHz, CDCl3) δ9.18 (s, 1H), 8.78 (s, 1H), 8.09 (s, 1H), 8.02 (d, J = 7.5Hz, 2H), 7.6 0(t,J=7.4Hz,1H),7.52(t,J=7.5Hz,2H),7.30(dt,J=13.4,7.7Hz,4H),7.21–7.11(m,4H ),7.08(d,J=8.5Hz,2H),4.45(dd,J=14.5,3.0Hz,1H),4.25(dd,J=14.5,7.4Hz,1H),4. 20-4.14(m,1H),4.12–4.05(m,1H),3.93(dd,J=14.0,8.6Hz,1H),1.28(d,J=6.2Hz,3H). 31 PNMR (243MHz, CDCl3) δ13.60. ESI-MS(m / z):544.17[M+H] + ,566.15[M+Na] +,1109.33[2M+Na] + .

[0319] Example 7. Preparation of (R)-(((1-(6-benzamido-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonic acid diphenyl ester (I-1)

[0320]

[0321] Under argon protection and stirring, BSTFA (0.57 g, 2.24 mmol) was added dropwise to diphenyl phosphite (12) (0.52 g, 2.24 mmol). After the addition, the mixture was stirred at 32-38° C. for 3 h to obtain a reaction mixture of silylated diphenyl phosphite 16.

[0322] At 37-39°C, II-1 (0.2 g, 0.56 mmol) was added to the reaction mixture of the obtained silylated diphenyl phosphite 16, followed by ethyl acetate (0.5 ml), N-halosuccinimide and Lewis acid. After addition, the temperature was raised to 78°C and stirred for 1.5 h. The contents of the product I-1, the remaining raw material II-1 and the iodinated impurity 30a were calculated by HPLC normalized peak area. The impurity reference substance of the iodinated impurity 30a was prepared by chromatographic separation and purification of the crude reaction product (Table 3).

[0323] Table 3. Screening of P-alkylation reaction promoters

[0324]

[0325] Note: a.12: BSTFA: II-1: NIS: Lewis acid molar ratio is 4:4:1:1.1:0.3. b.12: BSTFA: II-1: NaI: N-bromosuccinimide (NBS): Sc(OTf)3 molar ratio is 4:4:1:1.1:1.1:0.3. c.12: BSTFA: II-1: NaI: N-chlorosuccinimide (NCS): Sc(OTf)3 molar ratio is 4:4:1:1.1:1.1:0.3.

[0326] Iodinated impurity 30a: 1 H NMR (400MHz, CDCl3) δ9.08(s,1H),8.80(s,1H),8.12(s,1H),8.03(d,J=7.5Hz,2H),7.61(t,J= 7.4Hz, 1H), 7.53 (t, J = 7.7Hz, 2H), 4.69–4.60 (m, 1H), 4.60–4.51 (m, 2H), 1.97 (d, J = 6.8Hz, 3H). ESI-MS(m / z):408.07[M+H] +,430.02[M+Na] + ,837.12[2M+Na] + Elemental analysis (%): C 44.41 (calculated 44.24), H 3.43 (calculated 3.47), N 17.00 (calculated 17.20).

[0327] Example 8. Preparation of (R)-(((1-(6-benzamido-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonic acid diphenyl ester (I-1)

[0328]

[0329] Under argon protection and stirring, BSTFA (2.88 g, 11.2 mmol) was added dropwise to diphenyl phosphite (12) (2.62 g, 11.2 mmol). After the addition, the mixture was stirred at 32-38° C. for 3 h to obtain a reaction mixture of silylated diphenyl phosphite 16.

[0330] TfOH (0.63 g, 4.2 mmol) was dissolved in 1,4-dioxane (5 ml), and NIS (1.26 g, 5.6 mmol) was added under stirring at room temperature. A solution of II-1 (1 g, 2.8 mmol) in dichloromethane (5 ml) was added dropwise to the obtained TfOH and NIS reaction product at the feeding temperature, and the above-mentioned silylated diphenyl phosphite 16 reaction mixture was added after the addition. Then the reaction was stirred for 2 h at the reaction temperature. The contents of the product I-1, the iodinated impurity 30a and the remaining raw material II-1 were calculated by HPLC normalized peak area. Post-treatment: triethylamine was added to quench the reaction, ethyl acetate was added to dilute, and the reaction was washed with water, saturated sodium sulfite aqueous solution, saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution in turn, dried over anhydrous sodium sulfate, and rotary evaporated to obtain the crude product I-1. The crude product was purified by silica gel column chromatography (ethyl acetate: methanol = 80:1) to obtain I-1.

[0331] Table 4. P-alkylation reaction temperature screening

[0332]

[0333] Note: a. Add II-1 at one time.

[0334] Example 9. Preparation of (R)-(((1-(6-benzamido-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonic acid diphenyl ester (I-1)

[0335]

[0336] Under argon protection and stirring, BSTFA (2.88 g, 11.2 mmol) was added dropwise to diphenyl phosphite (12) (2.62 g, 11.2 mmol). After the addition, the mixture was stirred at 32-38° C. for 3 h to obtain a reaction mixture of silylated diphenyl phosphite 16.

[0337] The obtained silylated diphenyl phosphite 16, II-1 (1.0 g, 2.8 mmol), NIS (1.26 g, 5.6 mmol), trifluoromethanesulfonic acid (TfOH) (0.63 g, 4.2 mmol) and solvent were added according to the feeding method of Table 5. Then the reaction was stirred at 50 ° C for 2 h. Post-treatment: triethylamine was added to quench the reaction, ethyl acetate was added to dilute, washed with water, saturated sodium sulfite aqueous solution, saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution in turn, dried over anhydrous sodium sulfate, and rotary evaporated to obtain crude product I-1. The content of product I-1, iodine impurity 30a and remaining raw material II-1 was calculated by HPLC normalized peak area. The liquid phase yield of I-1 was calculated by standard curve method (Table 5).

[0338] Table 5. Study on the feeding method of P-alkylation reaction

[0339]

[0340] Example 10. Preparation of diphenyl (R)-(((1-(6-benzamido-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (I-1)

[0341]

[0342] Under argon protection and stirring, BSTFA was added dropwise to diphenyl phosphite (12). After the addition, the mixture was stirred at 32-38°C for 3 h to obtain a reaction mixture of silylated diphenyl phosphite 16.

[0343] NIS was added to a solution of TfOH in 1,4-dioxane (5 ml) under stirring at room temperature, and a solution of II-1 (1 g, 2.8 mmol) in dichloromethane (5 ml) was added dropwise to the obtained TfOH and NIS reaction product at 30-38°C, and the obtained silylated diphenyl phosphite 16 reaction mixture was added at 30-38°C. Then the reaction was stirred at 45-50°C for 2 h. Post-treatment: triethylamine was added to quench the reaction, ethyl acetate was added to dilute, and the organic phase was washed with water, saturated sodium sulfite aqueous solution, saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution in turn, dried over anhydrous sodium sulfate, and rotary evaporated to obtain crude I-1. The liquid phase yield of I-1 was calculated by the standard curve method (Table 6).

[0344] Table 6. Equivalent Optimization of P-Alkylation Reaction

[0345] Serial number 12:BSTFA:II-1:NIS:TfOH I-1 Liquid phase yield (%) <![CDATA[1 a ]]> 5.7:3.8:1:1.8:1.5 89 2 6:4:1:2:1.5 86 3 6:4:1:1.8:1.5 84 4 5.25:3.5:1:2:1.5 79 5 4.5:3:1:2:1.5 75 6 6:4:1:1.5:1.5 70 7 1.8:1.2:1:1.5:1 10 8 1.8:1.2:1:1.5:0.5 Trace 9 3:0:1:2:1.5 0

[0346] Note: a. Use 3 ml of both 1,4-dioxane and dichloromethane.

[0347] Example 11. Preparation of diphenyl (R)-(((1-(6-benzamido-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (I-1)

[0348]

[0349] Under argon protection and stirring, BSTFA (0.58 g, 2.24 mmol) was added dropwise to diphenyl phosphite (12) (0.53 g, 2.24 mmol). After the addition, the mixture was stirred at 36-38° C. for 3 h to obtain a reaction mixture of silylated diphenyl phosphite 16.

[0350] II-1 (0.2 g, 0.56 mmol) was added to ethyl acetate (0.5 ml), and NIS (0.25 g, 1.12 mmol) and trifluoromethanesulfonic acid (TfOH) (0.168 g, 1.12 mmol) were added under stirring at room temperature, and then the above-mentioned silylated diphenyl phosphite 16 reaction mixture was added, and then stirred at 44-46°C for 2 hours. Triethylamine was added to quench the reaction, and ethyl acetate was added to dilute, and the mixture was washed with water, saturated sodium sulfite aqueous solution, saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution in sequence, dried over anhydrous sodium sulfate, and rotary evaporated to obtain a yellow oily crude product I-1, which was purified by silica gel column chromatography (ethyl acetate: methanol = 80:1) to obtain pure product I-1 (0.46 g, 49%).

[0351] Example 12. Preparation of diphenyl (R)-(((1-(6-benzamido-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (I-1)

[0352]

[0353] Under argon protection and stirring, BSTFA (2.88 g, 11.2 mmol) was added dropwise to diphenyl phosphite (12) (3.93 g, 16.8 mmol). After the addition, the mixture was stirred at 32-38° C. for 3 h to obtain a reaction mixture of silylated diphenyl phosphite 16.

[0354] TMSOTf (0.93 g, 4.2 mmol) was dissolved in 1,4-dioxane (5 ml), and NIS (1.26 g, 5.6 mmol) was added under stirring at room temperature. A solution of II-1 (1 g, 2.8 mmol) in dichloromethane (5 ml) was added dropwise to the obtained TMSOTf and NIS reaction product at 30-38°C, and the above-mentioned silylated diphenyl phosphite 16 reaction mixture was added after the addition. Then the reaction was stirred at 44-46°C for 2 h. Post-treatment: triethylamine was added to quench the reaction, ethyl acetate was added to dilute, and the reaction was washed with water, saturated sodium sulfite aqueous solution, saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution in turn, dried over anhydrous sodium sulfate, and rotary evaporated to obtain the crude product I-1. The liquid phase yield of I-1 was calculated to be 56% by the standard curve method.

[0355] Example 13. Preparation of phenyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (3)

[0356]

[0357] I-1 (2 g, 3.7 mmol) and tetrahydrofuran (10.4 ml) were added to a 50 ml three-necked flask, cooled to 0 °C with stirring, and 0.5 mol / L sodium hydroxide aqueous solution (14 ml) was added dropwise. Stir at 30 °C for 0.5 h, and the reaction of the raw materials was completely completed after sampling by TLC monitoring. The resulting reaction solution was acidified with hydrochloric acid: ethanol (1:9), the solvent was removed by rotary evaporation, anhydrous ethanol was added, the precipitated inorganic salt was filtered out, and the solvent was removed by rotary evaporation to obtain a yellow oily crude product 3a. A small amount of the crude product was purified by column chromatography to obtain a pure product of 3a. 1 H NMR (600MHz, DMSO-d6) δ11.19(s,1H),8.73(s,1H),8.60(s,1H),8.07(d,J=7.5Hz,2H),7. 64(t,J=7.4Hz,1H),7.55(t,J=7.7Hz,2H),7.16(t,J=7.8Hz,2H),7.06(d,J=8.1Hz,2H),6. 92(t,J=7.3Hz,1H),4.42(dd,J=14.2,3.5Hz,1H),4.28(dd,J=14.3,6.0Hz,1H),3.98–3.90 (m, 1H), 3.56 (dd, J = 12.9, 8.6 Hz, 1H), 3.42 ( dd, J = 13.0, 9.2 Hz, 1H), 1.01 ( d, J = 6.2 Hz, 3H).

[0358] Add hydrochloric acid:ethanol (1:9) (15 ml) to the crude product 3a obtained in the previous step, reflux at 90°C with stirring for 4 h. Remove the solvent by rotary evaporation, add water to the residue, wash with ethyl acetate, add ethanol to the aqueous phase, add triethylamine dropwise to adjust the pH to 2-3, stir and crystallize in an ice bath for 2 h. Filter, wash the filter cake with ethanol, and dry in vacuo to obtain an off-white solid 3 (1.1 g, total yield 82%). 1 H NMR(600MHz,D2O)δ8.32(s,1H),8.24(s,1H),7.24(t,J=7.8Hz,2H),7.11(t,J=7.4Hz,1H),6.73(d,J=7.9Hz,2H),4.43(dd,J=14.8,2.7Hz ,1H),4.28(dd,J=14.8,8.9Hz,1H),4.13–4.04(m,1H),3.84(dd,J=13.7,7.8Hz,1H),3.58(dd,J=13.7,9.0Hz,1H),1.30(d,J=6.2Hz,3H). 31 P NMR(243MHz,D2O)δ14.91; ESI-MS(m / z):364.12[M+H] + ,386.10[M+Na] + .

[0359] Example 14. Preparation of phenyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (3)

[0360]

[0361] I-1 (1 g, 1.8 mmol) was stirred in hydrochloric acid: ethanol (1:9) (5 ml) at 80 ° C for 4 h, the pH of the reaction solution was adjusted to 6-7, and the solvent was removed by vortexing; the residue was dissolved in 4 mol / L hydrochloric acid aqueous solution (10 ml), washed with ethyl acetate; the pH value of the aqueous phase was adjusted to 8, and extracted with ethyl acetate; the extracts were combined and the solvent was removed by vortexing to obtain VIIIa. The residue VIIIa was dissolved in tetrahydrofuran (5 ml), and 1 mol / L sodium hydroxide aqueous solution (5 ml) was added dropwise at 5 ° C, and stirred at 25 ° C for 40 min. The reaction solution was washed with ethyl acetate, and the pH was adjusted to 3 with 1 mol / L hydrochloric acid, seeded with crystals and stirred for 1 h, then acidified to pH 2 and stirred for 1 h, and then stirred in an ice-water bath and at -10 ° C for 1 h. Filtered by suction, the filter cake was washed with ethanol, and a white solid 3 (0.52 g, 79%) was obtained, with a liquid phase purity of 99.13%.

[0362] Example 15. Preparation of (R)-N-(9-(2-hydroxypropyl)-9H-purin-6-yl)acetamide (Vb)

[0363]

[0364] Add (R)-9-(2-hydroxypropyl)adenine (9) (5.0 g, 25.9 mmol) to a 100 ml three-necked flask, add pyridine (15 ml) and acetonitrile (15 ml), cool to 2 °C, slowly drop TMSCl (4.2 g, 38.8 mmol), heat to 32 °C and stir for 2 h. Cool to 2 °C, slowly drop acetyl chloride (3.0 g, 38.8 mmol), stir at 0-4 °C for 2 h. Cool to -10 °C, slowly add ammonia water (15 ml), stir at room temperature for 30 min, and remove the solvent by rotary evaporation to obtain a light yellow solid. Reflux extract the obtained residue with acetone (20 ml) and filter it while hot. Rotary evaporate the filtrate, and recrystallize the obtained yellow oily residue with ethanol to obtain a white solid Vb (4.0 g, yield 65%). 1 H NMR(600MHz,DMSO-d6)δ10.61(s,1H),8.63(s,1H),8.37(s,1H),5.06(d,J=4.8Hz,1H) ,4.22(dd,J=13.4,3.4Hz,1H),4.14–4.01(m,2H),2.26(s,3H),1.10(d,J=6.0Hz,3H).

[0365] Example 16. Preparation of (R)-N-(9-(2-((methylthio)methoxy)propyl)-9H-purin-6-yl)acetamide (II-4)

[0366]

[0367] Vb (5.0 g, 21.3 mmol), DMSO (24.9 g, 318.8 mmol), acetic anhydride (86.7 g, 849.3 mmol) and acetic acid (25.5 g, 424.6 mmol) were stirred at 20 ° C for 30 h. The reaction was completed under TLC monitoring (dichloromethane: methanol = 17: 1). The solvent was removed by distillation under reduced pressure, and the obtained oily residue was separated by flash column chromatography (ethyl acetate: petroleum ether = 3: 2) to obtain a light yellow oil. Ethanol was added and stirred for 2 h to obtain a white solid powder II-4 (3.3 g, yield 53%). 1 H NMR (600MHz, CDCl3) δ9.20 (s, 1H), 8.71 (s, 1H), 8.15 (s, 1H), 4.54 (dd, J = 36.0, 11.8Hz, 2H ),4.42–4.37(m,1H),4.25–4.19(m,2H),2.64(s,3H),1.83(s,3H),1.24(d,J=5.8Hz,3H). 13C NMR(151MHz, CDCl3)δ170.79(s),152.28(s),151.69(s),149.17(s),144.10(s) ),121.39(s),73.09(s),70.34(s),48.72(s),25.72(s),16.74(s),13.78(s). ESI-MS(m / z):296.17[M+H] + ,318.13[M+Na] + .

[0368] Example 17. Preparation of (R)-(((1-(6-acetamido-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonic acid diphenyl ester (I-4)

[0369]

[0370] Under argon protection and stirring, BSTFA (3.5 g, 13.6 mmol) was added dropwise to diphenyl phosphite (12) (4.8 g, 20.5 mmol). The mixture was stirred at 32-38°C for 1-3 h. The reaction was complete as monitored by phosphorus spectrum to obtain a reaction mixture of silylated diphenyl phosphite 16.

[0371] TfOH (0.8 g, 5.3 mmol) was dissolved in 1,4-dioxane (5 ml), and NIS (1.9 g, 8.4 mmol) was added under stirring. A solution of II-4 (1.0 g, 3.4 mmol) in dichloromethane (5 ml) was added dropwise at 30°C, and the reaction mixture of the above-mentioned silylated diphenyl phosphite 16 was added, and stirred at 45°C for 2 h. Post-treatment: triethylamine was added to quench the reaction, ethyl acetate was added to dilute, and the reaction mixture was washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution in sequence. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain crude product Ib. The obtained crude product was separated by column chromatography (dichloromethane: ethanol = 40:1) to obtain pure product I-4. 1 H NMR (400MHz, DMSO-d6) δ10.62(s,1H),8.61(s,1H),8.37(s,1H),7.35(dt,J=13.2,7.9Hz,4H),7.20(q,J=7.2Hz,2H),7.11(d,J=8.5H z,2H),7.03(d,J=8.4Hz,2H),4.43(dd,J=14.5,3.5Hz,1H),4.37–4.17(m,3H),4.17–4.08(m,1H),2.26(s,3H),1.16(d,J=6.2Hz,3H). 31P NMR (162MHz, DMSO-d6) δ15.89. ESI-MS(m / z):482.20[M+H] + ,504.17[M+Na] + .

[0372] Example 18. Preparation of phenyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (3)

[0373]

[0374] Dissolve I-4 (1 g, 2.1 mmol) in tetrahydrofuran (7 ml), add 0.9 mol / L sodium hydroxide aqueous solution (5 ml) dropwise at 0°C under stirring and cooling, and stir at 20°C for 1 h. Acidify the resulting reaction solution with hydrochloric acid: ethanol (1:9), remove the solvent by rotary evaporation, add anhydrous ethanol, filter out the precipitated inorganic salt, and remove the solvent by rotary evaporation to obtain a yellow oily crude product 3b. Add hydrochloric acid: ethanol (1:9) (4 ml) to the resulting crude product 3b, reflux at 90°C and stir for 3 h to obtain a reaction solution 3. The content of each component in the reaction solution 3 was calculated by HPLC normalized peak area: 3 was 79%, phenol was 8%, and I-4 and 3b were both 0.

[0375] Example 19. Preparation of phenyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (3)

[0376]

[0377] I-4 (1 g, 2.1 mmol) was dissolved in tetrahydrofuran (7 ml), and 0.9 mol / L sodium hydroxide aqueous solution (5 ml) was added dropwise at 0°C under stirring and cooling, and stirred at 20°C for 1 h; sodium hydroxide (0.09 g, 2.1 mmol) was then added, and stirred at 60°C for 3 h to obtain reaction solution 3. The contents of each component in the obtained reaction solution 3 were calculated by HPLC normalized peak area: 77% for 3, 15% for phenol, and 0% for I-4.

[0378] Example 20. Preparation of phenyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (3)

[0379]

[0380] Va (20.0 g, 0.673 mol), dimethyl sulfoxide (136.6 g, 1.750 mol), acetic anhydride (206.0 g, 2.020 mol) and acetic acid (80.8 g, 1.350 mmol) were added to a 1000 mL three-necked flask and stirred at 20-30 ° C for 38 h. The acetic acid, acetic anhydride and dimethyl sulfoxide were removed by distillation under reduced pressure of an oil pump to obtain a yellow oil. The obtained residue was dissolved in dichloromethane, washed with water and saturated sodium chloride aqueous solution in turn, dried over anhydrous sodium sulfate, and the solvent was removed by rotation to obtain a yellow oil. Ethyl acetate (36 mL) was added and stirred at room temperature for 12 h, and then petroleum ether (12 mL) was added and stirred for 2 h. Filtered with suction, washed with ethyl acetate, and the filter cake was dried under vacuum (70 ° C, 6 h) to obtain a nearly white solid II-1 (26.0 g, yield 73%).

[0381] Diphenyl phosphite (12) (74.7 g, 319.0 mmol) was added to a 100 mL three-necked flask, and BSTFA (54.7 g, 212.5 mmol) was added dropwise under argon protection, and stirred at 36°C for 3 h to obtain a reaction mixture of silylated diphenyl phosphite 16. TfOH (12.6 g, 83.9 mmol) and 1,4-dioxane (100 ml) were added to a 250 ml three-necked flask at room temperature, and NIS (12.6 g, 56.0 mmol) was added under stirring, and a solution of II-1 (20.0 g, 56.0 mmol) in dichloromethane (100 mL) was added dropwise at 20°C, and then the reaction mixture of silylated diphenyl phosphite 16 was added, and the reaction mixture was stirred at 45°C for 2 h. The obtained reactant was cooled to room temperature, triethylamine was added to adjust the pH value of the reaction solution to about 7, ethyl acetate was added to dilute, and the mixture was washed with water, saturated aqueous sodium sulfite solution, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution in sequence, dried over anhydrous sodium sulfate, and rotary evaporated (40°C) to obtain a brown oily crude product of I-1.

[0382] The obtained crude product of I-1, a mixed solvent of hydrochloric acid and ethanol (1:99, v / v) (960 mL) were added to a 2L three-necked flask, and the reaction was stirred at 60°C for 11 hours. The reaction solution was cooled to 0°C, triethylamine was added dropwise to pH 6-7, and the solvent was removed by rotation. The obtained residue was dissolved in a 4 mol / L aqueous hydrochloric acid solution and washed with ethyl acetate. The organic phases were combined and extracted with a 4 mol / L aqueous hydrochloric acid solution. The acid-water phases were combined, and ammonia water was added dropwise under an ice-water bath to adjust the pH value to 6, and ethyl acetate was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by rotation to obtain a crude yellow oil VIIIa.

[0383] The crude product of Villa obtained in the previous step was dissolved in tetrahydrofuran (120 mL), and a solution of sodium hydroxide (6.5 g, 162.5 mmol) in water (120 mL) was added dropwise at 10-15°C with stirring in an ice bath, and then stirred at 15-20°C for 1.5 h. Ethyl acetate was added to wash the obtained reactant; the aqueous phase was separated, and activated carbon (12.0 g) and neutral alumina (12.0 g) were added and stirred for decolorization for 2 h. Filter to obtain a light yellow clear filtrate, and adjust the pH to 3 with 4 mol / L hydrochloric acid aqueous solution to see solid precipitation. Stir at 25°C for 1 h, further adjust the pH to 2, and then stir and age at 10°C for 2 h. Filter, wash with ice water with pH = 1.5, and vacuum dry (70°C, 5 h) to obtain a nearly white powder 3 (11.5 g, yield 68%): 1 H NMR(400MHz,D2O)δ8.26(s,1H),8.17(s,1H),7.16(t,J=7.8Hz,1H),7.03(t,J=7.4Hz,1H),6.66(d,J=8.0Hz,1H),4.36(dd,J=14.7,2.6Hz ,1H),4.21(dd,J=14.7,8.9Hz,1H),4.05–3.97(m,1H),3.77(dd,J=13.7,7.8Hz,1H),3.51(dd,J=13.7,9.0Hz,1H),1.22(d,J=6.2Hz,1H). ESI-MS(m / z):364.12[M+H] + ,386.10[M+Na] + .

[0384] Example 21 Synthesis of (R)-(((1-(6-benzamido-9H-purine-9-yl)propan-2-yl)oxy)methyl)phosphonic acid di(2,2,2-trifluoroethyl) ester (I-10)

[0385]

[0386] 17 (12.4 g, 50.3 mmol) was added to a 50 mL three-necked bottle, BSTFA (8.6 g, 33.5 mmol) was added dropwise under nitrogen protection, and the mixture was stirred at 36 °C for 3 h to obtain a reaction mixture of silylated diphenyl phosphite 18. TfOH (1.9 g, 12.6 mmol) and 1,4-dioxane (15 mL) were added to a 100 mL three-necked bottle at room temperature, NIS (3.4 g, 15.1 mmol) was added under stirring, a solution of II-1 (3.0 g, 8.4 mol) in dichloromethane (15 mL) was added dropwise at 20 °C, and then the reaction mixture of silylated diphenyl phosphite 18 was quickly added, and the mixture was stirred at 45 °C for 2 h. The obtained reactant was cooled to below 10°C in an ice-water bath, triethylamine was added to adjust the pH value to about 7, ethyl acetate was added to dilute, and washed with water, saturated sodium sulfite aqueous solution, saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution in sequence, dried over anhydrous sodium sulfate, and rotary evaporated (40°C) to obtain a brown oily crude product. The crude product was subjected to silica gel column chromatography (ethyl acetate) to obtain a yellow oily product I-10 (4.0 g, yield 85%): 1 H NMR (600MHz, CDCl3) δ8.80 (s, 1H), 8.12 (s, 1H), 8.03 (d, J = 7.5Hz, 2H), 7.62 (t, J = 7.3Hz, 1H), 7.54 (t, J = 7.5Hz, 2H), 4.47 (d, J = 13.7Hz, 1H), 4.44–4.30 (m, 4H), 4.24 (dd, J = 14.4, 7.6 Hz, 1H), 4.01 ( dd, J = 13.4, 9.1 Hz, 2H), 3.77 ( dd, J = 13.6, 9.1 Hz, 1H), 1.29 ( d, J = 6.0 Hz, 3H). ESI-MS(m / z):555.99[M+H] + .

[0387] Example 22 Preparation of Tenofovir (PMPA)

[0388]

[0389] I-10 (1.500 g, 2.7 mmol) was placed in a 25 ml three-necked flask, and a mixed solvent (9 mL) of hydrochloric acid and ethanol (10:90, v / v) was added, and the mixture was stirred and refluxed for 6 h. The mixture was cooled to room temperature, and the obtained reactant was rotary evaporated. The obtained residue was extracted by heating with acetonitrile, and the insoluble matter was removed by hot filtration, and the filtrate was rotary evaporated. The obtained oily residue was dissolved in a 4 mol / L hydrochloric acid aqueous solution, washed with ethyl acetate, and then the solvent was removed by rotary evaporation to obtain a crude yellow oily residue 19. The crude 19 was stirred in hydrobromic acid (20 mL) at 75 ° C for 16 h. The mixture was cooled to room temperature, and the obtained reactant was washed with ethyl acetate, and then the water was removed by rotary evaporation. The obtained light yellow solid residue was dissolved in water, and the pH was adjusted to 2-3 with a 50% sodium hydroxide aqueous solution, stirred at room temperature for 5 h, and then stirred in an ice-water bath for 2 h. Filter to obtain a crude tenofovir. The obtained crude product was recrystallized from a mixed solvent of water and ethanol (60:40, v / v) and dried in vacuo (100° C., 7 h) to obtain a white powder of tenofovir (0.560 g, yield 72%). 1 H NMR(600MHz,D2O)δ8.32(s,1H),8.31(s,1H),4.41(dd,J=14.8,3.2Hz,1H),4.22(dd,J=14.8,7.0Hz,1H),3. 92(pd,J=6.4,3.4Hz,1H), 3.61(dd,J=13.2,9.2Hz,1H), 3.42(dd,J=13.2,9.7Hz,1H), 1.10(d,J=6.3Hz,3H).

[0390] Example 23 P-Alkylation of Different Phosphite Diesters

[0391]

[0392] Phosphite diester 19, 20, 21 or 22 (16.8 mmol, 6 eq) was added to a 10 mL three-necked bottle, BSTFA (11.2 mmol, 4 eq) was added dropwise under nitrogen protection, and the reaction mixture was stirred at 36 ° C for 3 h to obtain the silylated phosphite diester 23, 24, 25 or 26. TfOH (4.2 mmol, 1.5 eq) and 1,4-dioxane (5 mL) were added to a 25 mL three-necked bottle at room temperature, NIS (5.0 mmol, 1.8 eq) was added under stirring, 7 (2.8 mmol, 1 eq) in dichloromethane (5 mL) was added dropwise at 20 ° C, and then the silylated phosphite diester 23, 24, 25 or 26 reaction mixture was quickly added. The reaction was stirred at 45 ° C for 2 h. Cool in an ice-water bath to below 10°C, add triethylamine to adjust the pH value of the reaction solution to about 7, add ethyl acetate to dilute, wash with water, saturated sodium sulfite aqueous solution, saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution in turn, dry over anhydrous sodium sulfate, and rotary evaporate (40°C) to obtain a yellow oil. Dilute the yellow oil 100 times and perform liquid chromatography-mass spectrometry (LC-MS) analysis. Liquid phase conditions: Chromatographic column: Thermo Scientific Acclaim 120 C18 column (4.6mm×150mm, 3μm); mobile phase A: 0.8g / L ammonium bicarbonate aqueous solution (adjusted with formic acid to pH=3), mobile phase B: acetonitrile, gradient elution (0-5min: B 5%-95%); flow rate 1mL / min; detection wavelength 254nm; column temperature 35℃. Mass spectrometry conditions: ion source: electrospray ionization (ESI); detection mode: positive ion mode; ion source temperature: 520℃; MS scanning range: 100-2000m / z; spray voltage: 5500V; heating gas flow rate 8.0L / min; nebulizing gas flow rate 3.0L / min; drying gas flow rate: 8.0L / min.

[0393] The reaction results are shown in the following table:

[0394]

[0395] Note: a. Isolation yield; b. LC-MS did not detect the target product.

[0396] Example 24 Preparation of N-(9-(2-((methylthio)methoxy)ethyl)-9H-purin-6-yl)benzamide (II-2)

[0397]

[0398] Add Vc (20.0 g, 0.07 mol), dimethyl sulfoxide (143.4 g, 1.84 mol), acetic anhydride (216.2 g, 2.12 mol) and acetic acid (84.8 g, 1.41 mol) to a 1L three-necked flask and stir at 20°C for 26 hours. Remove acetic acid, acetic anhydride and dimethyl sulfoxide by distillation under reduced pressure using an oil pump. Take a small amount of the obtained residue and perform silica gel column chromatography (ethyl acetate) to obtain pure II-2 and pure byproduct D-1. Hydrogen spectrum of II-2 1 H NMR (600MHz, CDCl3) δ9.20 (s, 1H), 8.81 (s, 1H), 8.13 (s, 1H), 8.04 (d, J = 7.4Hz, 2H), 7.60 (t, J = 7. 4Hz,1H),7.52(t,J=7.7Hz,2H),4.62(s,2H),4.52–4.49(m,2H),3.94–3.89(m,2H),2.01(s,3H). D-1 hydrogen spectrum 1 HNMR (600MHz, CDCl3) δ9.16 (s, 1H), 8.80 (s, 1H), 8.05 (s, 1H), 8.04 (d, J = 7.5Hz, 2H), 7.61 (t ,J=7.4Hz,1H),7.53(t,J=7.7Hz,2H),4.56(t,J=5.2Hz,2H),4.50–4.46(m,2H),2.04(s,3H).

[0399] The remaining residue was dissolved in dichloromethane, washed with water and saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, and the solvent was removed by rotation to obtain a yellow oil; ethyl acetate (36 mL) was added and stirred at room temperature for 24 h, and then petroleum ether (12 mL) was added and stirred for 2 h. The filter cake was washed and dried in vacuo to obtain a nearly white solid II-2 (12.0 g, yield 50%).

[0400] Example 25 Preparation of ((2-(6-benzamido-9H-purin-9-yl)ethoxy)methyl)phosphonic acid di(2,2,2-trifluoroethyl) ester (I-11)

[0401]

[0402] Add di(2,2,2-trifluoroethyl)phosphite (2.15 g, 8.74 mmol) to a 10 mL three-necked flask, add BSTFA (1.5 g, 5.82 mmol) dropwise under nitrogen protection, and stir at 36°C for 3 h to obtain a reaction mixture of di(2,2,2-trifluoroethyl)phosphite 18. Add TfOH (0.33 g, 2.20 mmol) and 1,4-dioxane (2 ml) to a 50 mL three-necked flask at room temperature, add NIS (0.59 g, 2.62 mmol) at about 20°C under stirring, then add a suspension of II-2 (0.5 g, 1.46 mmol) in 1,4-dioxane (3 ml) and dichloromethane (1 ml) dropwise, and then add the reaction mixture of di(2,2,2-trifluoroethyl)phosphite 18 to the silylated solution, and stir at 45°C for 1.5 h. The obtained reactant was cooled to 10°C, triethylamine was added to adjust the pH value of the reactant to about 7, ethyl acetate was added to dilute, and the reactant was washed with water, saturated sodium sulfite aqueous solution, saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution in sequence, dried over anhydrous sodium sulfate, and rotary evaporated (60°C) to obtain a brown oily residue; after silica gel column chromatography (ethyl acetate), a yellow-brown oily product I-11 and a white solid byproduct A-4 were obtained. Hydrogen spectrum of I-11 1 H NMR (600MHz, DMSO-d6) δ11.14(s,1H),8.73(s,1H),8.41(s,1H),8.04(d,J=7.5Hz,2H),7.65(t,J=7.4Hz,1 H), 7.55 (t, J = 7.7Hz, 2H), 4.65 (m, 4H), 4.49 (t, J = 5.0Hz, 2H), 4.16 (d, J = 7.9Hz, 2H), 3.98 (t, J = 5.0Hz, 2H). A-4 hydrogen spectrum 1 H NMR(600MHz,DMSO-d6)δ11.17(br s,1H),8.75(s,1H),8.53(s,1H),8.05(d,J=7.5Hz,2H),7.65(t,J=7.4Hz ,1H),7.56(t,J=7.7Hz,2H),4.65(t,J=6.6Hz,2H),3.75(t,J=6.6Hz,2H).

[0403] Example 26 Preparation of Adefovir

[0404]

[0405] I-11 (0.329 g, 0.61 mmol) was placed in a 10 ml three-necked flask, and a mixed solvent (2 ml) of hydrochloric acid and ethanol (10:90, v / v) was added, and the mixture was stirred and refluxed for 6 h. The mixture was cooled to room temperature, and the reaction solution was evaporated by rotary evaporation. The obtained oily residue was dissolved in a 4 mol / L aqueous hydrochloric acid solution, washed with ethyl acetate, and then the solvent was removed by rotary evaporation to obtain a crude yellow oily residue 27. The crude 27 was stirred in hydrobromic acid (2 mL) at 75 ° C for 24 h. The mixture was cooled to room temperature, and the obtained reaction product was washed with ethyl acetate, and then the water was removed by rotary evaporation. The obtained residue was dissolved in water (1 mL), and the pH was adjusted to 2-3 with a 50% aqueous sodium hydroxide solution, stirred at room temperature for 5 h, and then stirred in an ice-water bath for 2 h. Filtered to obtain a crude adefovir (0.14 g). ESI-MS (m / z): 274.26 [M+H] + ,296.04[M+Na] + ,569.28[2M+Na] + .

[0406] Comparative Example 1. Preparation of (R)-N-(9-(2-(chloromethoxy)propyl)-9H-purin-6-yl)benzamide

[0407]

[0408] Va (2 g, 6.73 mmol), trioxymethylene (1.22 g, 13.5 mmol), anhydrous calcium chloride (1 g) and anhydrous dichloromethane (30 ml) were added to a 100 ml three-necked flask. Under argon protection and stirring, dry hydrogen chloride gas was continuously introduced for 6 h. The obtained reaction solution was taken for TLC (dichloromethane: methanol = 6:1) detection: a large amount of raw material II-1 remained, and the de-Bz protected compound 9 was produced, and no chloromethylation product was generated.

[0409] Comparative Example 2. Preparation of diphenyl (R)-((1-(6-benzamido-9H-purin-9-yl)propan-2-yl)oxy)phosphonate (I-1)

[0410]

[0411] 60% sodium hydride (0.33 g, 8.2 mmol) was suspended in tetrahydrofuran (4 mL), and diphenyl phosphite (1.91 g, 8.2 mmol) was added under argon protection at 0°C, and then stirred at 0°C for 30 min for standby use.

[0412] II-1 (0.58 g, 1.63 mmol), anhydrous dichloromethane (9 ml) and Molecular sieves (0.12 g) were added to a 25 ml three-necked flask, cooled to -5 °C under argon protection and stirring, and a solution of sulfuryl chloride (0.51 g, 3.7 mmol) in dichloromethane (5 ml) was slowly added dropwise; after stirring for 1.5 h, the reaction solution was concentrated under reduced pressure in an ice-water bath. The obtained residue was added to the reaction mixture of diphenyl phosphite and sodium hydride, and the temperature was raised to 25 °C and stirred for 2 h. The reaction solution was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phases were combined, washed with water and saturated aqueous sodium chloride solution in turn, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude yellow oil (1.13 g, 129%). The obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain I-1 (53 mg, yield 6%). 1 H NMR(400MHz, CDCl3)δ9.28(brs,1H),8.78(s,1H),8.10(s,1H),8.02(d,J=8 .0Hz,2H),7.60(t,J=7.0Hz,1H),7.51(t,J=8.0Hz,2H),7.05-7.36(m,10H) ,4.45(dd,J=16.0,4.0Hz,1H),4.12-4.26(m,2H),4.05-4.10(m,1H),3.90( dd,J=12.0Hz,8.0Hz,1H),1.27(d,J=8.0Hz,3H); ESI-MS(m / z):544.17[M+H] + ,566.15[M+Na] + ,1109.33[2M+Na] + .

[0413] Comparative Example 3. Preparation of diphenyl (R)-((1-(6-benzamido-9H-purin-9-yl)propan-2-yl)oxy)phosphonate (I-1)

[0414]

[0415] Under argon protection, diphenyl phosphite (12) (0.36 g, 1.5 mmol) and BSTFA (0.39 g, 1.5 mmol) were stirred at 35°C for 3 h to obtain a reaction mixture of silylated diphenyl phosphite 16.

[0416] II-1 (0.35 g, 1 mmol), dichloromethane (3 ml) and 3A molecular sieve (1 g) were added into a 10 ml three-necked flask, cooled to -5°C under argon protection and stirring, and a solution of sulfonyl chloride (0.18 g, 1.3 mmol) in dichloromethane (2 ml) was slowly added dropwise; after the addition was completed, the above-mentioned silylated diphenyl phosphite 16 reaction mixture was added, the temperature was raised to 32°C and stirred for 2 hours, and no desired product I-1 was produced.

Claims

1. A method for preparing a phosphonate derivative as shown in formula I, characterized in that: The method comprises the following steps: reacting a compound represented by formula II and a compound represented by formula III in an organic solvent in the presence of a promoter to obtain a phosphonate derivative represented by formula I, that is, Among them, R a1 and R a2 are independently hydrogen or an amino protecting group, and R a1 and R a2 Not at the same time hydrogen; is a 6-10 membered heteroaryl group containing 2-4 nitrogen atoms or is substituted by one or more R b Substituted 6-10 membered heterocyclic alkenyl containing 2-4 nitrogen atoms; when R b When it is multiple, the R b Same or different; R b is C1-C6 alkyl, oxo (=O), amino or hydroxy; R 5 is hydrogen, C1-C6 alkyl or C1-C6 alkyl substituted by one or more hydroxyl groups; R 2 and R 3 Independently C6-C 10 Aryl, C1-C6 alkyl substituted by one or more halogens; R 4 is a C1-C6 alkyl group; The accelerator is a combination of N-halosuccinimide and Lewis acid or a combination of N-halosuccinimide and Bronsted acid; the N-halosuccinimide is NIS; the Lewis acid is TMSOTf or Sc(OTf)3; and the Bronsted acid is TfOH.

2. The method for preparing the phosphonate derivative as shown in formula I according to claim 1, characterized in that: The preparation method meets one or more of the following conditions: (1) The amino protecting group is benzoyl, acetyl or tert-butyloxycarbonyl; (2) for (3) "*" indicates that the carbon atom with "*" is a chiral carbon atom, which is in R configuration, S configuration, or a mixture of R configuration and S configuration; (4) When R b When it is a C1-C6 alkyl group, the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; (5) When R 5 When it is a C1-C6 alkyl group or a C1-C6 alkyl group substituted by one or more hydroxyl groups, the C1-C6 alkyl group and the C1-C6 alkyl group substituted by one or more hydroxyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl groups; (6) When R 2 and R 3 Independently C6-C 10 In the case of an aryl group, the C6-C 10 Aryl is phenyl; (7) When R 2 and R 3 When they are independently C1-C6 alkyl substituted by one or more halogens, the C1-C6 alkyl in the C1-C6 alkyl substituted by one or more halogens is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; (8) When R 2 and R 3 When they are independently C1-C6 alkyl substituted by one or more halogens, the halogen in the C1-C6 alkyl substituted by one or more halogens is fluorine, chlorine, bromine or iodine; (9)R 4 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; (10) In the method for preparing the phosphonate derivative as shown in Formula I, the organic solvent is one or more of an ether solvent, a halogenated hydrocarbon solvent, an ester solvent, a ketone solvent and a nitrile solvent; (11) In the method for preparing the phosphonate derivative as shown in Formula I, the NIS is prepared by reacting NBS or NCS with an alkali metal iodide; (12) The accelerator is N-halosuccinimide; (13) In the method for preparing the phosphonate derivative as shown in formula I, when the promoter is a combination of N-halosuccinimide and Lewis acid, the molar ratio of the compound as shown in formula II to N-halosuccinimide is 1:(1.1-3); (14) In the method for preparing the phosphonate derivative as shown in formula I, when the promoter is a combination of N-halosuccinimide and Lewis acid, the molar ratio of the compound as shown in formula II to the Lewis acid is 1:(0.05-1.5); (15) In the method for preparing the phosphonate derivative as shown in formula I, when the promoter is a combination of N-halosuccinimide and Lewis acid, the molar ratio of the compound as shown in formula II, N-halosuccinimide and Lewis acid is 1:(1.1-3):(0.05-1.5); (16) In the method for preparing the phosphonate derivative as shown in Formula I, when the promoter is a combination of N-halosuccinimide and Lewis acid, the reaction feed temperature is 25°C to 45°C, wherein the feed temperature is the temperature when the compound as shown in Formula II is added; (17) In the method for preparing the phosphonate derivative as shown in Formula I, when the promoter is a combination of N-halosuccinimide and Lewis acid, the reaction temperature of the reaction is 40°C to 78°C; (18) In the method for preparing the phosphonate derivative as shown in Formula I, when the promoter is a combination of N-halosuccinimide and Lewis acid, the feeding method of the reaction is any of the following schemes: Scheme 1: first add a compound represented by formula III and a compound represented by formula II, and then add a mixture of N-halosuccinimide and Lewis acid; Scheme 2: sequentially adding a compound represented by formula III, a compound represented by formula II, a Lewis acid and an N-halosuccinimide; (19) In the method for preparing the phosphonate derivative of formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the molar ratio of the compound of formula II to N-halosuccinimide is 1:(0.5-5); (20) In the method for preparing the phosphonate derivative of formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the molar ratio of the compound of formula II to Bronsted acid is 1:(0.5-3); (21) In the method for preparing the phosphonate derivative of formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the molar ratio of the compound of formula II, N-halosuccinimide and Bronsted acid is 1:(1-5):(0.5-3); (22) In the method for preparing the phosphonate derivative as shown in Formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the reaction feed temperature is -2°C to 62°C, wherein the feed temperature is the temperature when the compound as shown in Formula II is added; (23) In the method for preparing the phosphonate derivative as shown in Formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the reaction temperature of the reaction is 40°C to 78°C; (24) In the method for preparing the phosphonate derivative of formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the reaction addition method is any of the following schemes: Scheme 1: First, add the compound represented by formula II, solvent and N-halosuccinimide in sequence, then add the solution formed by Bronsted acid and solvent, and finally add the compound represented by formula III; Scheme 2: First, N-halosuccinimide and Bronsted acid are dissolved in a solvent to form a solution A, then a solution B of a compound represented by formula II and a solvent is added, and finally a compound represented by formula III is added; Scheme 3: First, N-halosuccinimide and Bronsted acid are dissolved in a solvent to form a solution A, and then a solution B formed by a compound represented by formula III and a compound represented by formula II and a solvent is added simultaneously; Scheme 4: First, N-halosuccinimide and Bronsted acid are dissolved in a solvent to form a solution A, then a compound represented by formula III is added, and finally a solution B formed by a compound represented by formula II and a solvent is added; Scheme 5: First, N-halosuccinimide and Bronsted acid are dissolved in a solvent to form a solution A, then a solution B formed by a compound represented by formula II and a solvent is added, and finally a compound represented by formula III is added; (25) In the method for preparing the phosphonate derivative of formula I, when the promoter is a combination of N-halosuccinimide and Lewis acid, the molar ratio of the compound of formula IV, the silanization agent, the compound of formula II, N-halosuccinimide and Lewis acid is (1.5-5):(1.5-5):1:(1.1-3):(0.05-1.5); (26) In the method for preparing the phosphonate derivative of formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the molar ratio of the compound of formula IV, the silanization agent, the compound of formula II, N-halosuccinimide and Bronsted acid is (4-6):(3-5):1:(1.5-2):(1.2-2); (27) In the method for preparing the phosphonate derivative as shown in Formula I, the reaction further comprises a post-treatment, and the post-treatment comprises the following steps: quenching, diluting, washing, and drying; (28) R a1 or R a2 is benzoyl, acetyl or hydrogen; (29) for 3. The method for preparing the phosphonate derivative as shown in formula I according to claim 2, characterized in that: The preparation method meets one or more of the following conditions: (1)R 2 and R 3 All are phenyl or 2,2,2-trifluoroethyl; (2) In the method for preparing the phosphonate derivative as shown in formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, and the feeding method is scheme 1, the solvent is an ether solvent; the molar volume ratio of the compound as shown in formula II to the solvent is 0.28 to 1 mol / L; in the solution formed by the Bronsted acid and the solvent, the molar volume ratio of the Bronsted acid to the solvent is 0.42 to 1.5 mol / L; (3) In the method for preparing the phosphonate derivative as shown in formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, and the feeding method is scheme 2, in the solution A, the solvent is an ether solvent; in the solution A, the molar volume ratio of the Bronsted acid to the solvent is 0.5 to 1.5 mol / L; in the solution B, the solvent is a halogenated hydrocarbon solvent; in the solution B, the molar volume ratio of the compound as shown in formula II to the solvent is 0.5 to 1 mol / L; (4) In the method for preparing the phosphonate derivative as shown in formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, and the feeding method is scheme 3, in the solution A, the solvent is an ether solvent; in the solution A, the molar volume ratio of the Bronsted acid to the solvent is 0.5 to 1.5 mol / L; in the solution B, the solvent is a halogenated hydrocarbon solvent; in the solution B, the molar volume ratio of the compound as shown in formula II to the solvent is 0.5 to 1 mol / L; (5) In the method for preparing the phosphonate derivative as shown in formula I, when the promoter is a combination of N-halogenated succinimide and Bronsted acid, and the feeding method is scheme 4, in the solution A, the solvent is an ether solvent; in the solution A, the molar volume ratio of the Bronsted acid to the solvent is 0.5 to 1.5 mol / L; in the solution B, the solvent is a halogenated hydrocarbon solvent; in the solution B, the molar volume ratio of the compound as shown in formula II to the solvent is 0.5 to 1 mol / L; (6) In the method for preparing the phosphonate derivative as shown in formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, and the feeding method is scheme 5, in the solution A, the solvent is an ether solvent; in the solution A, the molar volume ratio of the Bronsted acid to the solvent is 0.5 to 1.5 mol / L; in the solution B, the solvent is a halogenated hydrocarbon solvent; in the solution B, the molar volume ratio of the compound as shown in formula II to the solvent is 0.5 to 1 mol / L; (7) R 5 It is hydrogen or methyl.

4. The method for preparing the phosphonate derivative as shown in formula I according to claim 2, characterized in that: The preparation method meets one or more of the following conditions: (1) for (2) for (3) When R 2 and R 3 When they are independently C1-C6 alkyl substituted by one or more halogens, the halogen in the C1-C6 alkyl substituted by one or more halogens is fluorine; (4)R 4 is methyl; (5) In the method for preparing the phosphonate derivative as shown in Formula I, the organic solvent is an ether solvent and / or a halogenated hydrocarbon solvent; (6) The ether solvent is 1,4-dioxane and / or methoxycyclopentane; the halogenated hydrocarbon solvent is one or more of dichloromethane, chloroform and 1,2-dichloroethane; the ester solvent is ethyl acetate and / or isopropyl acetate; the ketone solvent is methyl isobutyl ketone and / or 2-butanone; the nitrile solvent is acetonitrile; (7) The alkali metal iodide is sodium iodide; (8) In the method for preparing the phosphonate derivative as shown in formula I, when the promoter is a combination of N-halosuccinimide and Lewis acid, the molar ratio of the compound as shown in formula II to N-halosuccinimide is 1:1.1 or 1:2.0; (9) In the method for preparing the phosphonate derivative as shown in formula I, when the promoter is a combination of N-halosuccinimide and Lewis acid, the molar ratio of the compound as shown in formula II to the Lewis acid is 1:(0.05-1); (10) In the method for preparing the phosphonate derivative of formula I, when the promoter is a combination of N-halosuccinimide and Lewis acid, the molar ratio of the compound of formula II, N-halosuccinimide and Lewis acid is 1:2:1.5, 1:1.1:0.07, 1:1.1:0.7 or 1:1.1:0.3; (11) In the method for preparing the phosphonate derivative as shown in Formula I, when the accelerator is a combination of N-halosuccinimide and Lewis acid, the reaction feed temperature is 37-39°C, 36-38°C or 30-38°C, wherein the feed temperature is the temperature when the compound as shown in Formula II is added; (12) In the method for preparing the phosphonate derivative as shown in Formula I, when the promoter is a combination of N-halosuccinimide and Lewis acid, the reaction temperature of the reaction is 44°C to 46°C or 78°C; (13) In the method for preparing the phosphonate derivative as shown in Formula I, when the promoter is a combination of N-halosuccinimide and Lewis acid, the feeding method of the reaction is Scheme 2; (14) In the method for preparing the phosphonate derivative as shown in formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the molar ratio of the compound as shown in formula II to N-halosuccinimide is 1:(1-5); (15) In the method for preparing the phosphonate derivative of formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the molar ratio of the compound of formula II to Bronsted acid is 1:(0.5-2); (16) In the method for preparing the phosphonate derivative of formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the molar ratio of the compound of formula II, N-halosuccinimide and Bronsted acid is 1:(1.1-2):(0.5-2); (17) In the method for preparing the phosphonate derivative as shown in Formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the reaction feed temperature is 20 to 50°C, wherein the feed temperature is the temperature when the compound as shown in Formula II is added; (18) In the method for preparing the phosphonate derivative as shown in Formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the reaction temperature of the reaction is 40°C to 60°C; (19) In the method for preparing the phosphonate derivative as shown in Formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the reaction addition method is as in Scheme 5; in Scheme 5, the solution B is added dropwise to the solution A; (20) In the method for preparing the phosphonate derivative as shown in Formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, and the feeding method is Scheme 1, the solvent is an ether solvent; the molar volume ratio of the compound as shown in Formula II to the solvent is 0.5 to 1 mol / L; in the solution formed by the Bronsted acid and the solvent, the molar volume ratio of the Bronsted acid to the solvent is 0.5 to 1.5 mol / L; (21) In the method for preparing the phosphonate derivative as shown in Formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, and the feeding method is Scheme 2, in the solution A, the solvent is an ether solvent; in the solution A, the molar volume ratio of the Bronsted acid to the solvent is 0.84 mol / L; in the solution B, the solvent is a halogenated hydrocarbon solvent; in the solution B, the molar volume ratio of the compound as shown in Formula II to the solvent is 0.56 mol / L; (22) In the method for preparing the phosphonate derivative as shown in Formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, and the feeding method is Scheme 3, in the solution A, the solvent is an ether solvent; in the solution A, the molar volume ratio of the Bronsted acid to the solvent is 0.84 mol / L; in the solution B, the solvent is a halogenated hydrocarbon solvent; in the solution B, the molar volume ratio of the compound as shown in Formula II to the solvent is 0.56 mol / L; (23) In the method for preparing the phosphonate derivative as shown in Formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, and the feeding method is Scheme 4, in the solution A, the solvent is an ether solvent; in the solution A, the molar volume ratio of the Bronsted acid to the solvent is 0.84 mol / L; in the solution B, the solvent is a halogenated hydrocarbon solvent; in the solution B, the molar volume ratio of the compound as shown in Formula II to the solvent is 0.56 mol / L; (24) In the method for preparing the phosphonate derivative as shown in Formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, and the feeding method is Scheme 5, in the solution A, the solvent is an ether solvent; in the solution A, the molar volume ratio of the Bronsted acid to the solvent is 0.84 mol / L; in the solution B, the solvent is a halogenated hydrocarbon solvent; in the solution B, the molar volume ratio of the compound as shown in Formula II to the solvent is 0.56 mol / L; (25) In the method for preparing the phosphonate derivative of formula I, when the promoter is a combination of N-halosuccinimide and Lewis acid, the molar ratio of the compound of formula IV, the silanization agent, the compound of formula II, N-halosuccinimide and Lewis acid is 4:4:1:2:1.5, 1.5:1.5:1:1.1:0.07, 4:4:1:1.1:0.7 or 4:4:1:1.1:0.3; (26) In the method for preparing the phosphonate derivative of formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the molar ratio of the compound of formula IV, the silanization agent, the compound of formula II, N-halosuccinimide and Bronsted acid is 5.7:3.8:1:1:1.5, 4:4:1:2:1.5, 5.7:3.8:1:1.8:1.5, 6:4:1:2:1.5, 6:4:1:1.8:1.5, 5.25:3.5:1:2:1.5, 4.5:3:1:2:1.5, 6:4:1:1.5:1.5 or 4:4:1:2:2; (27) The post-treatment also includes purification.

5. The method for preparing the phosphonate derivative as shown in formula I according to claim 2, characterized in that: In the preparation method of the phosphonate derivative as shown in Formula I, the phosphonate derivative as shown in Formula I is any of the following compounds: And / or, the compound shown in formula II is any of the following compounds:

6. The method for preparing the phosphonate derivative as shown in formula I according to claim 2, characterized in that: The preparation method meets one or more of the following conditions: (1) The ether solvent is 1,4-dioxane; the halogenated hydrocarbon solvent is dichloromethane; (2) In the method for preparing the phosphonate derivative as shown in Formula I, when the promoter is a combination of N-halosuccinimide and Lewis acid, the molar ratio of the compound as shown in Formula II to the Lewis acid is 1:1.5, 1:0.07, 1:0.3 or 1:0.7; (3) In the method for preparing the phosphonate derivative as shown in formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the molar ratio of the compound as shown in formula II to N-halosuccinimide is 1:(1.1-2); (4) In the method for preparing the phosphonate derivative of formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the molar ratio of the compound of formula II to Bronsted acid is 1:0.5, 1:1, 1:1.5 or 1:2; (5) In the method for preparing the phosphonate derivative of formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the molar ratio of the compound of formula II, N-halosuccinimide and Bronsted acid is 1:2:2, 1:1:1.5, 1:2:1.5, 1:1.8:1.5, 1:2:1.5 or 1:1.5:1.5; (6) In the method for preparing the phosphonate derivative as shown in Formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the reaction feed temperature is 25 to 48°C, wherein the feed temperature is the temperature when the compound as shown in Formula II is added; (7) In the method for preparing the phosphonate derivative as shown in Formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the reaction temperature of the reaction is 45°C, 46°C, 50°C or 60°C; (8) In the method for preparing the phosphonate derivative as shown in Formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, and the feeding method is Scheme 1, the solvent is an ether solvent; the molar volume ratio of the compound as shown in Formula II to the solvent is 0.56 mol / L; in the solution formed by the Bronsted acid and the solvent, the molar volume ratio of the Bronsted acid to the solvent is 0.84 mol / L; (9) In the method for preparing the phosphonate derivative of formula I, when the promoter is a combination of N-halosuccinimide and Lewis acid, the molar ratio of the compound of formula IV, the silanization agent, the compound of formula II, N-halosuccinimide and Lewis acid is 4:4:1:1.1:0.7; (10) In the method for preparing the phosphonate derivative as shown in formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the molar ratio between the compound as shown in formula IV, the silanization agent, the compound as shown in formula II, N-halosuccinimide and Bronsted acid is (5-6):(3.8-4.2):1:(1.7-2):(1.4-1.6).

7. The method for preparing the phosphonate derivative as shown in formula I according to claim 2, characterized in that: The preparation method meets one or more of the following conditions: (1) In the method for preparing the phosphonate derivative as shown in formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the molar ratio of the compound as shown in formula II to N-halosuccinimide is 1:1.2, 1:1.5, 1:0.5, 1:1, 1:1.8 or 1:2; (2) In the method for preparing the phosphonate derivative as shown in Formula I, when the accelerator is a combination of N-halosuccinimide and Bronsted acid, the reaction feed temperature is -2°C, 10°C, 20°C, 0-30°C, 29-30°C, 37-41°C, 43-48°C, 49-50°C or 57-62°C, wherein the feed temperature is the temperature when the compound as shown in Formula II is added; (3) In the method for preparing the phosphonate derivative as shown in Formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the reaction temperature of the reaction is 46°C to 50°C; (4) In the method for preparing the phosphonate derivative shown in formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the molar ratio of the compound shown in formula IV, the silanization agent, the compound shown in formula II, N-halosuccinimide and Bronsted acid is 5.7:3.8:1:1.8:1.5, 6:4:1:2:1.5, 6:4:1:1.8:1.5, 5.25:3.5:1:2:1.5, 4.5:3:1:2:1.5 or 6:4:1:1.5:1.

5.

8. The method for preparing the phosphonate derivative as shown in formula I according to claim 7, characterized in that: The preparation method satisfies one or both of the following conditions: (1) In the method for preparing the phosphonate derivative as shown in Formula I, when the accelerator is a combination of N-halosuccinimide and Bronsted acid, the reaction feed temperature is 29-30°C, 37-41°C or 43-48°C, wherein the feed temperature is the temperature when the compound as shown in Formula II is added; (2) In the method for preparing the phosphonate derivative as shown in formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the molar ratio between the compound as shown in formula IV, the silanization agent, the compound as shown in formula II, N-halosuccinimide and Bronsted acid is 5.7:3.8:1:1.8:1.5, 6:4:1:2:1.5 or 6:4:1:1.8:1.

5.

9. The method for preparing the phosphonate derivative as shown in formula I according to claim 2, characterized in that: The preparation method meets one or more of the following conditions: (1) R a1 is benzoyl or acetyl; The R a2 is hydrogen; Said for Said for The R 5 is hydrogen or methyl; The R 2 and R 3 All are phenyl or 2,2,2-trifluoroethyl; The R 4 is methyl; (2) In the method for preparing the phosphonate derivative as shown in Formula I, the promoter is a combination of N-halosuccinimide and Lewis acid, and the promoter is a combination of NIS and Sc(OTf)3; the feeding method is Scheme 1; The molar ratio of the compound shown in formula II, N-halosuccinimide and Lewis acid is 1:1.1:0.7; The reaction feed temperature is 36-38°C, wherein the feed temperature is the temperature when the compound shown in Formula II is added; The reaction temperature of the reaction is 78°C; (3) In the method for preparing the phosphonate derivative as shown in Formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the feeding method is Scheme 5; The accelerator is a combination of NIS and Tf(OH); The molar ratio of the compound shown in formula II, N-halosuccinimide and Bronsted acid is 1:2:1.5; The reaction feed temperature is 0-30°C, wherein the feed temperature is the temperature when the compound shown in Formula II is added; The reaction temperature of the reaction is 44°C to 46°C.

10. The method for preparing the phosphonate derivative of formula I according to any one of claims 1 to 5, characterized in that: The preparation method meets one or more of the following conditions: (1) In the method for preparing the phosphonate derivative of formula I, the compound of formula III is prepared by the following method for preparing the compound of formula III: reacting the compound of formula IV with a silanization agent, Among them, R 2 , R 3 and R 4 as defined in any one of claims 1 to 5; (2) In the method for preparing the phosphonate derivatives as shown in formula I, the method for preparing the phosphonate derivatives as shown in formula I also includes a method for preparing the compound as shown in formula II, which comprises the following steps: preparing the compound as shown in formula V, dimethyl sulfoxide and The reaction is carried out in the presence of a co-catalyst to obtain a compound as shown in Formula II. Among them, R a1 , R a2 , R 5 and The definition as in any one of claims 1 to 5; R 6 is a C1-C6 alkyl group; and the co-catalyst is acetic acid or trifluoroacetic acid.

11. The method for preparing the phosphonate derivative as shown in formula I according to claim 10, characterized in that: The preparation method meets one or more of the following conditions: (1) In the method for preparing the phosphonate derivatives of formula I, the compound of formula III is directly involved in the preparation reaction of the phosphonate derivatives of formula I without separation, or the purified form obtained after separation and purification is involved in the preparation reaction of the phosphonate derivatives of formula I; (2) In the method for preparing the phosphonate derivative of formula I, the molar ratio of the compound of formula II to the compound of formula IV is 1:(1.2-8); (3) In the method for preparing the phosphonate derivatives of formula I, in the method for preparing the compounds of formula III, the silanization agent is BSTFA, BSA, trimethylsilyl chloride, hexamethyldisilazane, hexamethyldisiloxane, trimethylsilyldiethylamine, trimethylsilylethyl acetate, bis(trimethylsilyl) sulfate, hexamethyldisilazane urea, trimethylsilylimidazole, or trimethylsilyl trifluoromethanesulfonate; (4) In the method for preparing the phosphonate derivative of formula I, in the method for preparing the compound of formula III, the molar ratio of the compound of formula IV to the silanization agent is (1-3):1; (5) In the method for preparing the phosphonate derivative of Formula I, in the method for preparing the compound of Formula III, the reaction is carried out in a solvent-free condition or in an aprotic solvent; (6) In the method for preparing the phosphonate derivative of formula I, in the method for preparing the compound of formula III, the reaction temperature is 20 to 50°C; (7) In the method for preparing the phosphonate derivatives of formula I, in the method for preparing the compounds of formula III, diphenyl phosphite (R 2 and R 3 Ph) and silanization agent BSTFA are reacted under solvent-free conditions at a temperature of 36-38°C or 32-38°C; (8) In the method for preparing the phosphonate derivatives of Formula I, in the method for preparing the compounds of Formula II, "*" indicates that the carbon atom with "*" is a chiral carbon atom, which is R configuration, S configuration, or a mixture of R configuration and S configuration; (9) In the method for preparing the phosphonate derivative of formula I, in the method for preparing the compound of formula II, R 6 wherein the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; (10) In the method for preparing the phosphonate derivative of formula I, in the method for preparing the compound of formula II, the co-catalyst is acetic acid; (11) In the method for preparing the phosphonate derivative of formula I, in the method for preparing the compound of formula II, the molar ratio of the compound of formula V to dimethyl sulfoxide is 1:(5-47); (12) In the method for preparing the phosphonate derivative of formula I, in the method for preparing the compound of formula II, the compound of formula V and The molar ratio is 1:(3-40); (13) In the method for preparing the compound of formula II, the molar ratio of the compound of formula V to the co-catalyst is 1:(1.5-20); (14) In the method for preparing the compound of formula II, the compound of formula V, dimethyl sulfoxide, The molar ratio of the catalyst to the co-catalyst is 1:(3-60):(2-50):(1-30); (15) In the method for preparing the compound of formula II, the reaction further comprises an additive; (16) In the method for preparing the compound of formula II, when the reaction further includes an additive, the molar ratio of the compound of formula V to the additive is 1:(0.1-5); (17) In the method for preparing the compound of formula II, the reaction temperature is 9°C to 50°C; In the method for preparing the compound of formula II as described in (18), the reaction time is 15 to 125 hours.

12. The method for preparing the phosphonate derivative as shown in formula I according to claim 11, characterized in that: The preparation method meets one or more of the following conditions: (1) In the method for preparing the phosphonate derivative as shown in Formula I, the compound as shown in Formula III is directly involved in the preparation reaction of the phosphonate derivative as shown in Formula I without separation; (2) In the method for preparing the phosphonate derivative of formula I, the molar ratio of the compound of formula II to the compound of formula IV is 1:(1.5-6), 1:1.5, 1:1.8, 1:3, 1:4, 1:4.5, 1:5.25, 1:5.7, or 1:6; (3) In the method for preparing the phosphonate derivative of Formula I, in the method for preparing the compound of Formula III, the silanization agent is BSTFA; (4) In the method for preparing the phosphonate derivative of formula I, in the method for preparing the compound of formula III, the molar ratio of the compound of formula IV to the silanization agent is (1-1.5):1; (5) In the method for preparing the phosphonate derivative of formula I, in the method for preparing the compound of formula III, the reaction is carried out in the absence of solvent; (6) In the method for preparing the phosphonate derivative of formula I, in the method for preparing the compound of formula III, the reaction temperature is 36-38°C or 28-42°C; (7) In the method for preparing the phosphonate derivative of formula I, in the method for preparing the compound of formula II, for (8) In the method for preparing the phosphonate derivative of formula I, in the method for preparing the compound of formula II, R 6 In which the C1-C6 alkyl group is a methyl group; (9) In the method for preparing the phosphonate derivative of formula I, in the method for preparing the compound of formula II, the molar ratio of the compound of formula V to dimethyl sulfoxide is 1:5, 1:15, 1:20, 1:26, 1:26.4, 1:30, 1:36.8, 1:46, 1:46.9 or 1:47; (10) In the method for preparing the phosphonate derivative of formula I, in the method for preparing the compound of formula II, the compound of formula V and The molar ratio is 1:3, 1:10, 1:15, 1:23, 1:23.4, 1:23.5, 1:30, or 1:40; (11) In the method for preparing the compound of formula II, the molar ratio of the compound of formula V to the co-catalyst is 1:1.5, 1:5, 1:6.7, 1:11.7, 1:11.8 or 1:20; (12) In the method for preparing the compound of formula II, the compound of formula V, dimethyl sulfoxide, The molar ratio of the catalyst to the co-catalyst is 1:(10-40):(10-40):(10-30); (13) The additive is sodium acetate; (14) In the method for preparing the compound of formula II, when the reaction further includes an additive, the molar ratio of the compound of formula V to the additive is 1:0.1 or 1:5; (15) In the method for preparing the compound of formula II, the reaction temperature is 10°C to 35°C; (16) In the method for preparing the compound of Formula II, the reaction time is 16.5 h, 18 h, 24 h, 27.5 h, 30 h, 32 h, 34 h, 34.5 h, 36 h, 38 h, 67 h, 72 h, 86 h or 125 h.

13. The method for preparing the phosphonate derivative of formula I according to claim 11, characterized in that: The preparation method meets one or more of the following conditions: (1) In the method for preparing the phosphonate derivative of formula I, in the method for preparing the compound of formula III, the molar ratio of the compound of formula IV to the silanization agent is 1:1 or 1.5:1; (2) In the method for preparing the phosphonate derivative of formula I, in the method for preparing the compound of formula III, the reaction temperature is 32-38°C; (3) In the method for preparing the phosphonate derivative of formula I, in the method for preparing the compound of formula II, the molar ratio of the compound of formula V to dimethyl sulfoxide is 1:(20-47); (4) In the method for preparing the phosphonate derivative of formula I, in the method for preparing the compound of formula II, the compound of formula V and The molar ratio is 1:(10-40); (5) In the method for preparing the compound of formula II, the molar ratio of the compound of formula V to the co-catalyst is 1:(5-20); (6) In the method for preparing the compound of formula II, the compound of formula V, dimethyl sulfoxide, The molar ratio of the catalyst to the co-catalyst is 1:(20-30):(20-35):(15-25); (7) In the method for preparing the compound of formula II, when the reaction further includes an additive, the molar ratio of the compound of formula V to the additive is 1:0.1; (8) In the method for preparing the compound of formula II, the reaction temperature is 20°C to 30°C.

14. The method for preparing the phosphonate derivative of formula I according to claim 11, characterized in that: The preparation method satisfies one or both of the following conditions: (1) In the method for preparing the compound of formula II, the compound of formula V, dimethyl sulfoxide, and the co-catalyst in a molar ratio of 1:15:40:20, 1:26.4:23:6.7, 1:30:15:5, 1:47:23.5:11.8, 1:5:3:1.5, 1:36.8:15:5, 1:20:10:5, 1:46.9:23.4:11.7, 1:46:23:20, 1:26.4:23:20, 1:26.4:40:20, 1:26.4:30:20 or 1:26:30:20; (2) In the method for preparing the compound of formula II, the reaction temperature is 9°C, 15°C, 20°C, 25°C, 23-27°C, 28°C, 29°C, 30°C or 31°C.

15. The method for preparing the phosphonate derivative of formula I according to claim 11, characterized in that: The preparation method satisfies one or both of the following conditions: (1) In the method for preparing the compound of formula II, the compound of formula V, dimethyl sulfoxide, and the co-catalyst in a molar ratio of 1:30:15:5, 1:47:23.5:11.8, 1:36.8:15:5, 1:20:10:5, 1:46.9:23.4:11.7, 1:46:23:20, 1:26.4:23:20, 1:26.4:40:20, 1:26.4:30:20 or 1:26:30:20; (2) In the method for preparing the compound of formula II, the reaction temperature is 15°C, 20°C, 23-27°C, or 29°C.

16. The method for preparing the phosphonate derivative of formula I according to claim 11, characterized in that: The preparation method satisfies one or both of the following conditions: (1) In the method for preparing the compound of formula II, the compound of formula V, dimethyl sulfoxide, and the co-catalyst in a molar ratio of 1:26.4:23:20, 1:26.4:40:20, 1:26.4:30:20 or 1:26:30:20; (2) In the method for preparing the compound of formula II, the reaction temperature is 20°C or 29°C.

17. The method for preparing the phosphonate derivative of formula I according to any one of claims 11 to 16, characterized in that: The preparation method meets one or more of the following conditions: (1) In the method for preparing the compound of formula II, R 6 is methyl; The co-catalyst is acetic acid; The compound shown in formula V, dimethyl sulfoxide, and co-catalyst in a molar ratio of 1:26.4:40:20; The reaction temperature is 20°C; (2) In the method for preparing the phosphonate derivative as shown in Formula I, the silanization agent is BSTFA; The molar ratio of the compound represented by formula IV, the silanization agent, the compound represented by formula II, N-halosuccinimide and Lewis acid is 4:4:1:1.1:0.7; In the method for preparing the compound shown in Formula III, the reaction temperature is 36-38°C; diphenyl phosphite (R 2 and R 3 All are Ph) and silanization agent BSTFA are reacted under solvent-free conditions; (3) In the method for preparing the phosphonate derivative as shown in Formula I, the promoter is a combination of N-halosuccinimide and Bronsted acid, and the promoter is a combination of NIS and Tf(OH); In the method for preparing the compound of formula III, the compound of formula IV and the silanization agent BSTFA are reacted at a temperature of 32 to 38° C. under solvent-free conditions; In the preparation method of the phosphonate derivative shown in formula I, the molar ratio of the compound shown in formula IV, the silanization agent, the compound shown in formula II, N-halosuccinimide and Bronsted acid is 6:4:1:2:1.5; The reaction feed temperature is 0-30°C, wherein the feed temperature is the temperature when the compound shown in Formula II is added; The reaction temperature of the reaction is 44°C to 46°C; (4) In the method for preparing the phosphonate derivative as shown in Formula I, when the promoter is a combination of N-halosuccinimide and Bronsted acid, the promoter is a combination of NIS and Tf(OH); In the method for preparing the compound of formula III, the compound of formula IV and the silanization agent BSTFA are reacted at a temperature of 32 to 38° C. under solvent-free conditions; The molar ratio of the compound of formula IV, the silanization agent, the compound of formula II, the N-halosuccinimide and the Bronsted acid is 5.7:3.8:1:1.8:1.5, 6:4:1:2:1.5, 6:4:1:1.8:1.5 or 5.25:3.5:1:2:1.5; The reaction feed temperature is 30-38°C, wherein the feed temperature is the temperature when the compound shown in Formula II is added; The reaction temperature of the reaction is 45°C to 50°C.

18. A method for preparing a compound as shown in formula II, characterized in that: The method comprises the following steps: a compound as shown in formula V is reacted with dimethyl sulfoxide, and a co-catalyst to obtain a compound as shown in Formula II. Among them, R a1 , R a2 , R 5 , R 6 and the co-catalyst as defined in any one of claims 10 to 17; for In the method for preparing the compound as shown in Formula II, the reaction conditions and operations of the method for preparing the compound as shown in Formula II are as described in any one of claims 10 to 17.

19. A compound as shown in formula II, in, R a1 , R a2 and R 5 as defined in any one of claims 1 to 5; for 20. The compound of formula II as claimed in claim 19, The compound shown in formula II is any of the following compounds:

21. Use of the compound of formula II in the synthesis of the compound of formula VI, the compound of formula VII, the compound of formula VIII, the compound of formula IX, compound 4, compound 6 or tenofovir alafenamide fumarate; R a1 , R a2 , R 5 and as defined in any one of claims 1 to 5; in, The compound 4, compound 6 and tenofovir alafenamide fumarate are all prepared from the compound shown in formula VI; When used to synthesize compound 4, compound 6 or tenofovir alafenamide fumarate, the for The for 22. Use of the compound of formula II as claimed in claim 21 in the synthesis of a compound of formula VI, a compound of formula VII, a compound of formula VIII, a compound of formula IX, compound 4, compound 6 or tenofovir alafenamide fumarate; The application described meets the following conditions: In the application, the compound shown in formula II is prepared by the preparation method of the compound shown in formula II as described in any one of claims 10-17.

Images