Preparation method of letemovir key intermediate dihydroquinazoline ester

Abstract

The invention relates to the technical field of chemical synthesis, and particularly discloses a preparation method of letemovir key intermediate dihydroquinazoline ester. According to the method, 2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl) phenyl)-2-oxo-1, 2, 3, 4-tetrahydroquinazolin-4-yl) methyl acetate and 1-(3-methoxyphenyl) piperazine are taken as raw materials, lithium diisopropylamide is taken as a catalyst, and dihydroquinazoline ester is obtained through one-step condensation reaction under the conditions of a phosphorus onium salt condensing agent and organic alkali. The process route is simple, the reaction condition is mild, the process can be carried out at room temperature, the requirement on reaction equipment is low, the process safety is high, a plurality of tedious reaction steps and the steps of separating and purifying the intermediate are not needed, the synthesis route is greatly shortened, atom loss caused by treatment and transfer of the intermediate is avoided, and the yield of the product is improved. And the method better conforms to the concept of green chemistry and is suitable for industrial popularization and application.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, and in particular to a method for preparing dihydroquinazoline ester, a key intermediate of letermovir. Background Art

[0002] Letermovir, chemical name: (4S)-2-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetic acid, molecular formula: C 29 H 28 F4N4O4, with the following structural formula, is a quinazoline antiviral agent, belonging to a new class of non-nucleoside CMV inhibitors (3,4-dihydroquinazoline). It mainly inhibits viral replication by targeting the viral terminase complex, and can inhibit the ability of human cytomegalovirus terminase. On November 8, 2017, the FDA approved letermovir for marketing.

[0003]

[0004] Currently, there are several methods for preparing letermovir:

[0005] Route 1: 2-bromo-6-fluoroaniline is used as a starting material, and converted into a 2-aminocinnamic acid derivative by Heck coupling; then reacted with triphenylphosphine in carbon tetrachloride to prepare phosphine imide, which is then reacted with isocyanate to release triphenylphosphine oxide to obtain carbodiimide; carbodiimide is reacted with amine to form dihydroquinazoline ester, which is separated by chromatography on a chiral phase, and then hydrolyzed under standard conditions to obtain letermovir. This route cannot be industrialized, and the synthetic route is as follows:

[0006]

[0007] Route 2: 2-bromo-6-fluoroaniline is used as the starting material, and reacts with 2-methoxy-5-trifluoromethylphenyl isocyanate to generate a urea derivative, and then a methyl acrylate side chain is added through Heck coupling, and 2-{8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl}acetic acid methyl ester is obtained through cyclization, and then dihydroquinazolin ester is obtained through phosphorus oxychloride chlorination and amination, and then the isomers are separated and hydrolyzed to generate letermovir. The synthetic route is as follows:

[0008]

[0009] Route 3: Using fluoroaniline as the starting material, reacting with isocyanate to form urea, Heck coupling, ring closure, chlorination and side chain docking to obtain dihydroquinazoline ester, and then isomers are separated and hydrolyzed to obtain letermovir. The synthetic route is as follows:

[0010]

[0011] In the above routes, dihydroquinazoline ester needs to be prepared first, and then split and hydrolyzed to obtain letermovir. It can be seen that dihydroquinazoline ester is a key intermediate for preparing letermovir. Route 2 and Route 3 are currently the most widely used processes in industrial applications, but both require a chlorination step, that is, the following steps. In the chlorination process, chlorobenzene / toluene solvents need to be used, and chlorination is carried out by phosphorus oxychloride / phosphorus pentachloride reagents, which have the following disadvantages: (1) The chlorination conditions are not friendly, and the reaction system has a high requirement for anhydrous reaction system. It is necessary to reflux and separate water in advance, and remove the trace amount of residual water in the system before feeding the chlorination; 2) The chlorination process requires a high temperature of more than 130°C for a long time, and the energy consumption is high; 3) The post-treatment quenching process releases a lot of heat, has a high safety risk, produces a large amount of waste acid, and seriously pollutes the environment; 4) The reaction cannot be completed, about 20% of the raw materials remain, the atomic utilization is low, and as the reaction time increases, the impurities gradually increase, the carbonization phenomenon is obvious, and a large amount of black insoluble matter is produced, resulting in difficult post-treatment, poor product purity, and difficult purification.

[0012]

[0013] Therefore, it is necessary to develop a synthesis method for dihydroquinazoline esters with mild conditions, short reaction time, low energy consumption, environmental friendliness and suitable for industrial production, which has extremely important practical significance. Summary of the invention

[0014] In view of the problems of harsh reaction conditions, high process energy consumption and safety risks, serious environmental pollution and low atomic utilization in the existing process for synthesizing dihydroquinazoline ester, the present invention provides a method for preparing dihydroquinazoline ester. The method mainly uses 2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-oxo-1,2,3,4-tetrahydroquinazoline-4-yl)acetic acid methyl ester and 3-methoxyphenylpiperazine as raw materials, uses lithium diisopropylamide as a catalyst, and undergoes a condensation reaction in a condensing agent and an organic base to prepare dihydroquinazoline ester. The process has mild reaction conditions, effectively improves production efficiency, is simple in post-processing, generates less three wastes, reduces production costs, and has high prospects for industrial application.

[0015] In order to solve the above technical problems, the technical solution provided by the present invention is:

[0016] A method for preparing dihydroquinazoline ester, a key intermediate of letermovir, comprises the following steps:

[0017] In a polar solvent, the compound represented by formula (II) and 1-(3-methoxyphenyl)piperazine are used as raw materials, lithium diisopropylamide is used as a catalyst, and a condensation reaction occurs in a phosphonium salt condensation agent and an organic base to obtain a dihydroquinazoline ester represented by formula (I). The specific reaction equation is as follows:

[0018]

[0019] Compared with the prior art, the preparation method of dihydroquinazoline ester provided by the present invention uses the compound shown in formula (II) and 1-(3-methoxyphenyl)piperazine as raw materials, uses lithium diisopropylamide as a catalyst, and obtains dihydroquinazoline ester through a one-step condensation reaction under the conditions of a phosphonium salt condensation agent and an organic base. The process route is simple, the reaction conditions are mild, it can be carried out at room temperature, the requirements for reaction equipment are low, the process safety is high, and there is no need to go through multiple cumbersome reaction steps and the steps of separating and purifying the intermediates, which greatly shortens the synthesis route, avoids the atomic loss caused by the treatment and transfer of the intermediates, is more in line with the concept of green chemistry, and is suitable for industrial promotion and application.

[0020] It should be noted that the compound represented by formula (II) described in the present invention can be prepared by conventional methods in the art. Specifically, 2-bromo-6-fluoroaniline can be used as a starting material, reacted with 2-methoxy-5-trifluoromethylphenyl isocyanate to generate a urea derivative, and then a methyl acrylate side chain is added by Heck coupling, and the compound represented by formula (II) is obtained by ring closure, i.e., 2-{8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl}acetic acid methyl ester. The process route is as follows, and the specific process can be found in CN101213180B. Other methods in the art can also be used, and the present invention does not make special restrictions.

[0021]

[0022] Furthermore, the phosphonium salt condensing agent is at least one of benzotriazole-1-oxytris(dimethylamino)phosphine hexafluorophosphate (BOP), benzotriazole-1-yl-oxytripyrrolidinophosphine hexafluorophosphate (PyBOP) or (7-azabenzotriazole-1-oxy)tripyrrolidinophosphine hexafluorophosphate (PyAOP).

[0023] Preferably, the phosphonium salt condensing agent is benzotriazole-1-oxytris(dimethylamino)phosphine hexafluorophosphate (BOP).

[0024] Furthermore, the organic base is at least one of 1,8-diazacyclo[5,4,0]undecene-7 (DBU), triethylamine or N,N-diisopropylethylamine.

[0025] Preferably, the organic base is 1,8-diazacyclo[5,4,0]undecene-7 (DBU).

[0026] The preferred condensing agent and organic base can fully activate the compound represented by formula (II), so that the compound represented by formula (II) undergoes enolate interconversion and then undergoes condensation reaction with the amino group in 1-(3-methoxyphenyl)piperazine.

[0027] Furthermore, the polar solvent is acetonitrile.

[0028] The preferred reaction solvent can provide a homogeneous environment for the reaction, so that the reaction raw materials, catalysts and additives are fully contacted, thus promoting the smooth progress of the condensation reaction and improving the selectivity and conversion rate of the reaction.

[0029] Furthermore, the molar ratio of the compound represented by formula (II), 3-methoxyphenylpiperazine, phosphonium salt condensation agent and lithium diisopropylamide is 1:(1.1-1.6):(1.1-1.6):(0.01-1.0).

[0030] Preferably, the molar ratio of the compound represented by formula (II), 3-methoxyphenylpiperazine, condensation agent and lithium diisopropylamide is 1:(1.2-1.4):(1.2-1.4):(0.05-0.15).

[0031] More preferably, the molar ratio of the compound represented by formula (II), 3-methoxyphenylpiperazine, condensation agent and lithium diisopropylamide is 1:1.3:1.3:0.1.

[0032] Furthermore, the molar ratio of the compound represented by formula (II) to the organic base is 1:(2-5).

[0033] Preferably, the molar ratio of the compound represented by formula (II) to the organic base is 1:(3-4).

[0034] More preferably, the molar ratio of the compound represented by formula (II) to the organic base is 1:3.9.

[0035] Furthermore, the volume mass ratio of the polar solvent to the compound represented by formula (II) is (1-10) mL:1 g.

[0036] Preferably, the volume mass ratio of the polar solvent to the compound represented by formula (II) is (2-5) mL:1 g.

[0037] More preferably, the volume mass ratio of the polar solvent to the compound represented by formula (II) is 3 mL:1 g.

[0038] Furthermore, the condensation reaction temperature is 20°C to 50°C, and the reaction time is 1h to 5h.

[0039] The preferred reaction temperature can promote the full progress of the etherification reaction and reduce the occurrence of side reactions.

[0040] As a specific embodiment of the present invention, the preparation method of the preparation method of the key intermediate dihydroquinazoline ester of Letermovir specifically comprises the following steps:

[0041] The compound represented by formula (II) and lithium diisopropylamide are added to a polar solvent and mixed evenly. 1-(3-methoxyphenyl)piperazine and a phosphonium salt condensation agent are added. The temperature is controlled at 20°C to 50°C. An organic base is added and the mixture is kept warm for condensation reaction. After the reaction is completed, ethyl acetate and water are added for extraction. Saturated brine is added to the obtained organic phase and the mixture is allowed to stand for phase separation. Anhydrous ethanol and n-hexane are added to the obtained organic phase for crystallization, solid-liquid separation, washing and drying to obtain a dihydroquinazoline ester represented by formula (I).

[0042] The preparation method of dihydroquinazoline ester provided by the present invention eliminates the step of performing a chlorination reaction in the traditional preparation of dihydroquinazoline ester, and completely solves the problems of harsh chlorination reaction conditions, high energy consumption, low atomic utilization, high safety risk, and serious environmental pollution, and provides a new process route for the preparation of dihydroquinazoline ester. The process can be efficiently carried out at room temperature, has low energy consumption, high process safety, is conducive to large-scale production, improves the feasibility and economy of production, and is of great significance for realizing the green large-scale production of letermovir.

[0043] Furthermore, the volume mass ratio of ethyl acetate to the compound represented by formula (II) is (5-15) mL:1 g.

[0044] Furthermore, the volume mass ratio of water to the compound represented by formula (II) is (5-15) mL:1 g.

[0045] Furthermore, the volume ratio of anhydrous ethanol to ethyl acetate is (0.5-3):1, and the volume ratio of n-hexane to anhydrous ethanol is (0.2-1):1.

[0046] Furthermore, the crystallization temperature is 20°C to 30°C, and the crystallization time is 2h to 3h.

[0047] The preparation method of dihydroquinazoline ester, a key intermediate of letermovir, provided by the present invention, is characterized in that dihydroquinazoline ester is prepared through a one-step condensation reaction, the atomic utilization rate is greatly improved, the condensation reaction conditions are mild, the requirements for reaction equipment are low, and the energy consumption is also reduced, which is more environmentally friendly and economical. In addition, there is no intermediate product separation process in the reaction process, the product post-treatment is simple, the amount of wastewater generated is small, and the wastewater treatment cost is low. This provides an environmentally friendly and economically efficient new process route for the synthesis of dihydroquinazoline ester, a key intermediate of letermovir, and has extremely high promotion value. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 This is the H NMR spectrum of dihydroquinazoline ester, a key intermediate of Letermovir prepared in Example 1;

[0049] Figure 2 This is the NMR carbon spectrum of dihydroquinazoline ester, a key intermediate of Letermovir prepared in Example 1. DETAILED DESCRIPTION

[0050] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0051] In order to better illustrate the present invention, further examples are given below.

[0052] The raw material methyl 2-{8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl}acetate used in the following examples and comparative examples can be synthesized by referring to CN101213180B.

[0053] Example 1

[0054] This embodiment provides a production process of dihydroquinazoline ester, a key intermediate of letermovir, and the specific steps are as follows:

[0055] Add 10.00 g (0.024 mol) of methyl 2-{8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl}acetate, 30 mL of acetonitrile, and 1.2 mL (2.4 mmol) of a tetrahydrofuran solution of lithium diisopropylamide to the reaction bottle, stir for 30 min, then add 8.22 g (0.031 mol) of 1-(3-methoxyphenyl)piperazine dihydrochloride and 13.8 g (0.031 mol) of BOP, control the temperature at 40°C, add 14.25 g (0.094 mol) of DBU, and keep the temperature for 3 h. After the reaction is completed, add 100 mL of ethyl acetate and 100 mL of purified water to the reaction solution, extract and separate the liquids, and use 50 mL × 3 The mixture was extracted with 2N hydrochloric acid solution, separated into phases, and the organic phase was washed with saturated brine. The phases were separated, and 100 mL of anhydrous ethanol and 50 mL of n-hexane were added to the organic phase under stirring. The mixture was crystallized at 25°C for 2 h, filtered, washed, and dried to obtain a white solid, i.e., the dihydroquinazoline ester represented by formula (I), with a yield of 95.8% and a purity of 98.5%.

[0056] The hydrogen and carbon spectra of the dihydroquinazoline ester prepared in this example are shown in Figure 1-Figure 2 shown.

[0057]

[0058] Example 2

[0059] This embodiment provides a production process of dihydroquinazoline ester, a key intermediate of letermovir, and the specific steps are as follows:

[0060] To the reaction flask, 10.00 g (0.024 mol) of methyl 2-{8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl}acetate, 30 mL of acetonitrile, and 0.13 mL (0.26 mmol) of a tetrahydrofuran solution of lithium diisopropylamide were added, and the mixture was stirred for 30 min. Then, 7.12 g (0.027 mol) of 1-(3-methoxyphenyl)piperazine dihydrochloride and BOP were added. 11.8g (0.027mol), control the temperature at 20℃, add 9.87g (0.065mol) DBU, after the addition, keep the temperature for reaction for 5h. After the reaction, add 50mL of ethyl acetate and 50mL of purified water to the reaction solution, extract and separate the liquids, extract the organic phase with 50mL×32N hydrochloric acid solution, separate the phases, wash the organic phase with saturated brine, separate the phases, add 150mL of anhydrous ethanol and 150mL of n-hexane to the organic phase under stirring, crystallize at 25℃ for 3h, filter, wash and dry to obtain a white solid, i.e., the dihydroquinazoline ester shown in formula (Ⅰ), with a yield of 87.6% and a purity of 97.3%.

[0061] Example 3

[0062] This embodiment provides a production process of dihydroquinazoline ester, a key intermediate of letermovir, and the specific steps are as follows:

[0063] To the reaction flask, 10.00 g (0.024 mol) of methyl 2-{8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl}acetate, 30 mL of acetonitrile, and 12 mL (0.024 mol) of a tetrahydrofuran solution of lithium diisopropylamide were added, stirred for 30 min, and then 10.12 g (0.038 mol) of 1-(3-methoxyphenyl)piperazine dihydrochloride, BOP were added. 16.76g (0.038mol), control the temperature at 50℃, add 18.34g (0.12mol) DBU, after the addition, keep the temperature for reaction for 1h. After the reaction, add 150mL of ethyl acetate and 150mL of purified water to the reaction solution, extract and separate the liquids, extract the organic phase with 50mL×32N hydrochloric acid solution, separate the phases, wash the organic phase with saturated brine, separate the phases, add 75mL of anhydrous ethanol and 15mL of n-hexane under stirring conditions, crystallize at 30℃ for 2h, filter, wash and dry to obtain a white solid, i.e., the dihydroquinazoline ester shown in formula (Ⅰ), with a yield of 90.5% and a purity of 96.8%.

[0064] Example 4

[0065] This embodiment provides a production process of dihydroquinazoline ester, a key intermediate of letermovir, and the specific steps are as follows:

[0066] Add 10.00 g (0.024 mol) of methyl 2-{8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl}acetate, 30 mL of acetonitrile, and 6 mL (0.012 mol) of a tetrahydrofuran solution of lithium diisopropylamide to the reaction bottle, stir for 30 min, then add 9.63 g (0.036 mol) of 1-(3-methoxyphenyl)piperazine dihydrochloride, 14.26 g (0.032 mol) of BOP, control the temperature at 30 °C, add 12.25 g (0.080 mol) of DBU, and keep the temperature for 3 h. After the reaction is completed, add 120 mL of ethyl acetate and 120 mL of purified water to the reaction solution, extract and separate the liquid, and use 50 mL × 3 The mixture was extracted with 2N hydrochloric acid solution, separated into phases, and the organic phase was washed with saturated brine. The phases were separated, and 240 mL of anhydrous ethanol and 120 mL of n-hexane were added to the organic phase under stirring. The mixture was crystallized at 20 ° C for 3 h, filtered, washed, and dried to obtain a white solid, i.e., the dihydroquinazoline ester of formula (Ⅰ), with a yield of 93.7% and a purity of 97.2%.

[0067] Example 5

[0068] This embodiment provides a production process of dihydroquinazoline ester, a key intermediate of Letermovir, which is different from that of Example 1 only in that n-hexane is not added during the crystallization process. The specific steps are as follows:

[0069] Add 10.00 g (0.024 mol) of methyl 2-{8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl}acetate, 30 mL of acetonitrile, and 1.2 mL (0.0024 mol) of a tetrahydrofuran solution of lithium diisopropylamide to the reaction bottle, stir for 30 min, then add 8.22 g (0.031 mol) of 1-(3-methoxyphenyl)piperazine dihydrochloride, 13.8 g (0.031 mol) of BOP, control the temperature at 40°C, add 14.25 g (0.094 mol) of DBU, and keep the temperature for reaction for 3 h. After the reaction is completed, add 100 mL of ethyl acetate and 100 mL of purified water to the reaction solution, extract and separate the liquids, and use 50 mL × 3 The mixture was extracted with 2N hydrochloric acid solution, separated into phases, and the organic phase was washed with saturated brine. The phases were separated, and 100 mL of anhydrous ethanol was added to the organic phase under stirring. The mixture was crystallized at 30°C for 2 h, filtered, washed, and dried to obtain a white solid, i.e., the dihydroquinazoline ester represented by formula (I), with a yield of 75.3% and a purity of 97.4%.

[0070] The phosphonium salt condensing agent and the organic base in Example 1 are replaced by other types specified in the present invention, and the yield of the prepared dihydroquinazoline ester is 85% to 90% and the purity is 95% to 96% under the same process conditions as Example 1.

[0071] Comparative Example 1

[0072] This comparative example provides a production process of dihydroquinazoline ester, a key intermediate of letermovir, which is different from Example 1 only in that lithium diisopropylamide catalyst is not added. The specific steps are as follows:

[0073] Add 10.00 g (0.024 mol) of methyl 2-{8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl}acetate and 30 mL of acetonitrile to the reaction bottle, stir for 30 min, then add 8.22 g (0.031 mol) of 1-(3-methoxyphenyl)piperazine dihydrochloride and 13.8 g (0.031 mol) of BOP, control the temperature at 40°C, add 14.25 g (0.094 mol) of DBU, and keep the temperature for 3 h. After the reaction, add 100 mL of ethyl acetate and 100 mL of purified water to the reaction solution, extract and separate the liquid, and use 50 mL × 3 The mixture was extracted with 2N hydrochloric acid solution, separated into phases, and the organic phase was washed with saturated brine. The phases were separated, and 100 mL of anhydrous ethanol and 50 mL of n-hexane were added to the organic phase under stirring. The mixture was crystallized at 25°C for 2 h, filtered, washed, and dried to obtain a white solid, i.e., the dihydroquinazoline ester represented by formula (I), with a yield of 66.3% and a purity of 91.2%.

[0074] Comparative Example 2

[0075] This comparative example provides a production process of dihydroquinazoline ester, a key intermediate of letermovir, which is different from Example 1 only in that LDA is replaced by sodium hydroxide. The specific steps are as follows:

[0076] Add 10.00 g (0.024 mol) of methyl 2-{8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl}acetate, 30 mL of acetonitrile, and 0.01 g of sodium hydroxide (2.5 mmol) to the reaction bottle, stir for 30 min, then add 8.22 g (0.031 mol) of 1-(3-methoxyphenyl)piperazine dihydrochloride, 13.8 g (0.031 mol) of BOP, control the temperature at 40°C, add 14.25 g (0.094 mol) of DBU, and keep the temperature for 3 h. After the reaction, add 100 mL of ethyl acetate and 100 mL of purified water to the reaction solution, extract and separate the liquid, and use 50 mL × 3 The mixture was extracted with 2N hydrochloric acid solution, separated into phases, and the organic phase was washed with saturated brine. The phases were separated, and 100 mL of anhydrous ethanol and 50 mL of n-hexane were added to the organic phase under stirring. The mixture was crystallized at 25°C for 2 h, filtered, washed, and dried to obtain a white solid, i.e., the dihydroquinazoline ester of formula (I), with a yield of 70.4% and a purity of 91.8%.

[0077] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing dihydroquinazoline ester, a key intermediate of letermovir, characterized in that: The steps include: In a polar solvent, a compound represented by formula (II) and 1-(3-methoxyphenyl)piperazine are used as raw materials, lithium diisopropylamide is used as a catalyst, and a condensation reaction occurs in a phosphonium salt condensation agent and an organic base to obtain a dihydroquinazoline ester represented by formula (I); 2. The method for preparing dihydroquinazoline ester, a key intermediate of Letermovir, according to claim 1, wherein: The phosphonium salt condensing agent is at least one of benzotriazole-1-oxytris(dimethylamino)phosphine hexafluorophosphate, benzotriazole-1-yl-oxytripyrrolidinophosphine hexafluorophosphate or (7-azabenzotriazole-1-oxy)tripyrrolidinophosphine hexafluorophosphate.

3. The method for preparing dihydroquinazoline ester, a key intermediate of Letermovir, according to claim 1, wherein: The organic base is at least one of 1,8-diazacyclo[5,4,0]undecene-7, triethylamine or N,N-diisopropylethylamine.

4. The method for preparing dihydroquinazoline ester, a key intermediate of Letermovir, according to claim 1, wherein: The polar solvent is acetonitrile.

5. The method for preparing dihydroquinazoline ester, a key intermediate of Letermovir, according to claim 1 or 2, characterized in that: The molar ratio of the compound represented by formula (II), 3-methoxyphenylpiperazine, phosphonium salt condensation agent and lithium diisopropylamide is 1:(1.1-1.6):(1.1-1.6):(0.01-1.0).

6. The method for preparing dihydroquinazoline ester, a key intermediate of Letermovir, according to claim 1 or 3, characterized in that: The molar ratio of the compound represented by formula (II) to the organic base is 1:(2-5).

7. The method for preparing dihydroquinazoline ester, a key intermediate of Letermovir, according to claim 1 or 4, characterized in that: The volume mass ratio of the polar solvent to the compound represented by formula (II) is (1-10) mL:1 g.

8. The method for preparing dihydroquinazoline ester, a key intermediate of Letermovir, according to claim 1, wherein: The temperature of the condensation reaction is 20° C. to 50° C., and the reaction time is 1 h to 5 h.

9. The method for preparing dihydroquinazoline ester, a key intermediate of Letermovir, according to claim 1, wherein: The specific steps include: The compound represented by formula (II) and lithium diisopropylamide are added to a polar solvent and mixed evenly. 1-(3-methoxyphenyl)piperazine and a phosphonium salt condensation agent are added. The temperature is controlled at 20°C to 50°C. An organic base is added and the mixture is kept warm for condensation reaction. After the reaction is completed, ethyl acetate and water are added for extraction. Saturated brine is added to the obtained organic phase and the mixture is allowed to stand for phase separation. Anhydrous ethanol and n-hexane are added to the obtained organic phase for crystallization, solid-liquid separation, washing and drying to obtain a dihydroquinazoline ester represented by formula (I).

10. The method for preparing dihydroquinazoline ester, a key intermediate of Letermovir, according to claim 9, characterized in that: The crystallization temperature is 20°C to 30°C, and the crystallization time is 2h to 3h.

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