WO2023185597A1

WO2023185597A1 - Letermovir intermediate and preparation method therefor

Info

Publication number: WO2023185597A1
Application number: PCT/CN2023/083173
Authority: WO
Inventors: 胡猛; 祁道冉; 张国斌
Original assignee: 上海迪赛诺化学制药有限公司
Priority date: 2022-04-01
Filing date: 2023-03-22
Publication date: 2023-10-05

Abstract

Disclosed in the present invention are a Letermovir intermediate and a preparation method therefor. Specifically, the method comprises the step of: crystallizing methyl {8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate with chiral modified tartaric acid in an inert solvent to obtain a (S)-methyl {8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate tartrate salt. The method of the present invention has the characteristics of simple operation, a high yield, a high product purity, suitability for industrial production, etc.

Description

Letermovir intermediates and preparation methods thereof

Technical field

The invention belongs to the field of drug synthesis. Specifically, the invention relates to a letermovir intermediate and a preparation method thereof.

Background technique

Letermovir is mainly used to prevent CMV infection in adult patients who are seropositive for cytomegalovirus after allogeneic hematopoietic stem cell transplantation.

The literature reports on the synthesis route of letermovir mainly include the following four:

Route 1: (See: CN100393706C)

Route 2: (See: CN200680021104)

Route 3: (See: Angew.Chem.Int.Ed.2017,56,16032–16036)

Route 3. Chiral centers are introduced in the early stage of the reaction. Chiral catalysts are expensive and difficult to obtain. The route is long, the yield is low, and industrialization is difficult. Moreover, the use of palladium catalyst in multiple steps is costly. The product only has an ee value of 96% and still needs to be chirally resolved.

Route 4: (See: WO2015088931A1)

Route 1, Route 2, and Route 4 all require (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]-succinic acid to resolve {8-fluoro-2-[4- (3-Methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4- base} methyl acetate to obtain (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-( Trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate methyl ester (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy] -succinate, which is subsequently freed and hydrolyzed to give letermovir. As follows:

The main defect of the above process is: {8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl )Phenyl]-3,4-dihydroquinazolin-4-yl} enantiomers of methyl acetate. The salt obtained after separation is only 98.0% e.e., with a yield of 89%. It needs to be crystallized again to obtain 99.9% e.e. Product, yield 80%, long cycle.

As we all know, the enantiomeric content in raw materials containing chiral centers is a very critical quality indicator, and usually the enantiomeric content needs to be strictly controlled below 0.15%. In order to ensure the quality of the finished API, multiple recrystallization extractions are required. High optical purity will inevitably bring disadvantages such as extended production cycle, increase of three wastes, and low yield.

In view of the shortcomings of the current process, it is necessary to develop a new letermovir synthesis process to solve the problems of low yield, multiple wastes, and long production cycle.

Contents of the invention

The object of the present invention is to provide a letermovir intermediate with high yield and high optical purity and a preparation method thereof.

A first aspect of the invention provides a letermovir intermediate (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[ 2-Methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetic acid methyl ester chiral modified salt, the intermediate is (S)- {8-Fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3, D-(+)-dibenzoyl tartrate of methyl 4-dihydroquinazolin-4-yl}acetate,

(S)-{8-Fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl] -D-(+)-dibenzoyl tartrate of methyl 3,4-dihydroquinazolin-4-yl}acetate; and (S)-{8-fluoro-2-[4-(3- Methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetic acid Methyl ester D-(+)-di-p-tolyloxybenzoyl tartrate,

(S)-{8-Fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl] -D-(+)-di-p-tolyloxybenzoyl tartrate of methyl 3,4-dihydroquinazolin-4-yl}acetate.

The second aspect of the present invention provides a method for preparing the intermediate described in the first aspect of the present invention. The method includes the steps of: in an inert solvent, {8-fluoro-2-[4-(3- Methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetic acid The methyl ester is crystallized with chiral modified tartaric acid to obtain (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy Tartrate of methyl-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate;

Wherein, the chiral modified tartaric acid is selected from the following group: D-(+)-dibenzoyltartaric acid, D-(+)-di-p-methoxybenzoyltartaric acid.

In another preferred embodiment, the method further includes post-processing.

In another preferred embodiment, the post-processing includes: filtration, washing, extraction and drying.

In another preferred embodiment, the chirally modified tartaric acid is D-(+)-di-p-methoxybenzoyltartaric acid.

In another preferred embodiment, the inert solvent is selected from the following group: C1-C10 ester solvents, C6-C10 aromatic hydrocarbon solvents, C2-C6 ether solvents, or combinations thereof.

In another preferred embodiment, the solvent is selected from the following group: ethyl acetate, methyl acetate, isopropyl acetate, acetic acid Tert-butyl ester, butyl acetate, toluene, tetrahydrofuran, methyl tert-butyl ether, diisopropyl ether, or combinations thereof.

In another preferred example, the {8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(tri The volume (v/v) ratio of fluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate to inert solvent is 1:3-10.

In another preferred example, the {8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(tri The molar ratio of methyl acetate to chiral modified tartaric acid is 1:1.0-1.5.

In another preferred example, the crystallization temperature is 0-80°C, preferably 20-40°C.

In another preferred embodiment, the crystallization process includes: stirring.

In another preferred example, the crystallization time is 2-15h, preferably 5-8h.

In another preferred embodiment, the method further includes: filtering the reaction mixture after the reaction is completed, washing the filter cake with an inert solvent at 0-10°C, then adding MTBE, and adding alkali and water for cleaning.

In another preferred embodiment, the base is NaHCO ₃ , Na ₂ HPO ₄ , or a combination thereof.

In another preferred embodiment, MTBE can also be replaced with a solvent selected from the following group: toluene, ethyl acetate, isopropyl acetate, or a combination thereof.

A third aspect of the present invention provides a method for preparing letermovir, which method includes:

(1) Use the method described in the second aspect of the present invention to obtain the (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3 -[2-Methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate methyl ester chiral modified salt;

(2) Use the (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-( Letermovir was prepared from chiral modified salt of trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate methyl ester:

In another preferred embodiment, the step (2) includes: dissolving the chiral modified salt in a first inert solvent, and then adding a base, water and a second inert solvent to react; preferably, the The first inert solvent is methyl tert-butyl ether; the second inert solvent is methanol;

After the reaction is completed, add water and a third inert solvent, and separate the aqueous phase; preferably, the third inert solvent is methyl tert-butyl ether;

Add a third inert solvent to the aqueous phase to adjust pH=4-5;

After adding acetone to dissolve, slowly add water and filter to obtain letermovir.

In another preferred embodiment, the first inert solvent is selected from the following group: methyl tert-butyl ether, toluene, isopropyl acetate, or a combination thereof; preferably methyl tert-butyl ether.

In another preferred embodiment, the second inert solvent is selected from the following group: methyl tert-butyl ether, toluene, isopropyl acetate, or a combination thereof; preferably, it is methanol.

In another preferred embodiment, the third inert solvent is selected from the following group: methanol, ethanol, isopropyl alcohol, or a combination thereof.

In another preferred example, in step (2), the base is KOH, NaOH, or a combination thereof.

In another preferred example, in step (2), the reaction time is 4-12h, preferably 6-8h.

In another preferred example, in step (2), the reaction temperature is 20-80°C, preferably 40-60°C.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described one by one here.

Detailed ways

After extensive and in-depth research and extensive screening, the present invention developed a novel letermovir intermediate and its preparation method for the first time. The method of the present invention has the characteristics of simple operation, high yield and high product purity. On this basis, the present invention was completed.

the term

Unless otherwise specified herein, each term and abbreviation has a conventional meaning well known to those skilled in the art.

As used herein, the terms "compound of formula I" and "letermovir intermediate" are used interchangeably.

The term "room temperature" or "normal temperature" refers to a temperature of 4-40°C, preferably 25±5°C.

In the present invention, in the reaction system of each reaction step, each substance (except the solvent) can independently participate in the reaction in any suitable ratio, such as 1: (0.1-10), 1: (0.2- 5), 1: (0.5-2), 1: (0.8-1.5) or 1: (1.0-1.2).

Letermovir intermediates

Letermovir intermediate of the present invention has a structure selected from the following group:

(S)-{8-Fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl] -D-(+)-Dibenzoyl tartrate of methyl 3,4-dihydroquinazolin-4-yl}acetate

(S)-{8-Fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl] -D-(+)-di-p-tolyloxybenzoyl tartrate of methyl 3,4-dihydroquinazolin-4-yl}acetate

Preparation

In order to solve the deficiencies in the prior art, the present invention provides a new preparation method of letermovir intermediate, which requires only one crystallization, has a short production cycle, and obtains letermovir intermediate with high e.e. value.

The letermovir intermediate of the present invention can be prepared by the following method. However, the conditions of the method, such as reactants, solvents, bases, acids, amounts of compounds used, reaction temperature, reaction time required, etc. are not limited to the following explanations.

Typically, the preparation method of the letermovir intermediate is as follows:

{8-Fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3, 4-Dihydroquinazolin-4-yl}acetic acid methyl ester and chiral modified tartaric acid were crystallized in an inert solvent. After stirring for 5 hours, they were filtered and dried to obtain the target product (S)-{8-fluoro-2- [4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline -4-yl}acetic acid methyl ester tartrate.

In this step, the proportion of reaction materials is not particularly limited, for example, {8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy The molar ratio of methyl-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate and chiral modified tartaric acid is 1:1.0-1.5; {8- Fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-di The volume (v/v) ratio of hydroquinazolin-4-yl}acetate to inert solvent is 1:3-10.

In this step, the inert solvent, reaction time, reaction crystallization temperature, etc. can be selected according to specific circumstances. For example, the inert solvent is selected from the following group: C1-C10 ester solvents, C6-C10 aromatic hydrocarbon solvents, C2-C6 ether solvents, or combinations thereof; preferably ethyl acetate, methyl acetate, isopropyl acetate, tertiary acetate Butyl ester, butyl acetate, toluene, tetrahydrofuran, methyl tert-butyl ether, diisopropyl ether, or combinations thereof. The reaction temperature is 0-80°C, preferably 20-40°C; the crystallization time is 2-15h, preferably 5-8h.

Compared with the existing technology, the advantages of the present invention mainly include:

(1) The preparation method of the present invention requires only one crystallization to make the e.e. value of the previous step intermediate of letermovir API reach more than 99.9%, fully ensuring the optical purity of letermovir API.

(2) The preparation method of the present invention has a short production cycle and high yield, and is suitable for industrial production.

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the invention and are not intended to limit the scope of the invention. Experimental methods without specifying specific conditions in the following examples usually follow conventional conditions or conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

Raw materials used {8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)benzene [base]-3,4-dihydroquinazolin-4-yl}acetate methyl ester was prepared with reference to WO2015088931A1.

Example 1: Preparation of letermovir intermediates

{8-Fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3 , 4-Dihydroquinazolin-4-yl}methyl acetate (20.00g, 84%ee) was dissolved in ethyl acetate (100ml), and D-(+)-di-p-methoxybenzoyltartaric acid was added (14.26g), and the mixture was stirred at 20-30°C for 5h. Filter, and wash the filter cake with cold ethyl acetate (0-10°C, 20 ml). The obtained filter cake was added to MTBE (80 mL), and Na ₂ HPO ₄ (12.10 g) and water (80 mL) were added. The mixture was stirred at 20-30°C for 1 hour, separated into layers, and the organic layer was washed once with water (40 mL). The organic layer was concentrated to dryness, and the obtained solid was vacuum dried at 50°C for 18 hours. The total amount of solid obtained was 17.48g (99.93%ee, yield 95.0%).

Example 2: Preparation of letermovir

The (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoro Methyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate (15.00g) was dissolved in methyl tert-butyl ether (45ml). KOH (5.74g), _H2O (90mL) and methanol (12mL) were added.

The mixture was heated to 50°C and stirred for 6 h. Methyl tert-butyl ether (22 mL) and H ₂ O (45 mL) were added to the mixture. The layers were separated, and the aqueous layer was washed once with methyl tert-butyl ether (22 mL). Methyl tert-butyl ether (45 mL) was added to the aqueous layer, and the pH of the aqueous layer was adjusted to 4-5 with 1M hydrochloric acid. The layers were separated, and the organic layer was concentrated to dryness under vacuum. Add acetone (34 mL) to dissolve the solution, and slowly add 90 mL of water at 20°C. Stir for 5 hours at 20-25°C, filter, wash the filter cake with water (15 ml), and vacuum dry the obtained solid at 50°C for 18 hours. The total amount of solid obtained was 13.20 g (99.93%ee, yield 90.2%).

{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl) obtained from Example 1 Phenyl]-3,4-dihydroquinazolin-4-yl}acetic acid methyl ester, the total yield was 85.7%.

Example 3: Preparation of letermovir intermediates

{8-Fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3 , 4-Dihydroquinazolin-4-yl}methyl acetate (20.00g, 84% e.e.) was dissolved in isopropyl acetate (100ml), and D-(+)-dibenzoyltartaric acid (12.22g) was added ), stir the mixture at 20-30°C for 5h. Filter, and wash the filter cake with cold isopropyl acetate (0-10°C, 20 ml).

The obtained filter cake was added to MTBE (80 mL), and Na ₂ HPO ₄ (12.10 g) and water (80 mL) were added. The mixture was stirred at 20-30°C for 1 hour, separated into layers, and the organic layer was washed once with water (40 mL). The organic layer was concentrated to dryness, and the obtained solid was vacuum dried at 50°C for 18 hours. The total amount of solid obtained was 17.57g (99.94%ee, yield 95.5%)

Example 4: Preparation of letermovir

The (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoro Methyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate (15.00g) was dissolved in methyl tert-butyl ether (45ml). KOH (5.74g), _H2O (90mL) and methanol (12mL) were added. The mixture was heated to 50°C and stirred for 6 h. add Methyl tert-butyl ether (22 mL) and H ₂ O (45 mL) were in the mixture. The layers were separated, and the aqueous layer was washed once with methyl tert-butyl ether (22 mL). Methyl tert-butyl ether (45 mL) was added to the aqueous layer, and the pH of the aqueous layer was adjusted to 4-5 with 1M hydrochloric acid. The layers were separated, and the organic layer was concentrated to dryness under vacuum. Add acetone (34 mL) to dissolve the solution, and slowly add 90 mL of water at 20°C. Stir for 5 hours at 20-25°C, filter, wash the filter cake with water (15 ml), and vacuum dry the obtained solid at 50°C for 18 hours. The total amount of solid obtained was 13.37g (99.94%ee, yield 91.3%).

From {8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3 , the total yield of 4-dihydroquinazolin-4-yl}acetic acid methyl ester was 87.2%.

Comparative Example 1: (See: CN 101863843 B)

{8-Fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3 , 4-Dihydroquinazolin-4-yl}methyl acetate (20.00g, 84% e.e.) was dissolved in ethyl acetate (100ml), and (2S, 3S)-2,3-bis[(4- Methyl)oxy]succinic acid (13.17g), the mixture was stirred at 20-30°C for 5h. Filter, and wash the filter cake with cold ethyl acetate (0-10°C, 50 ml). The resulting solid was vacuum dried at 50°C for 18 hours. A total of 27.17 g of salt (98.30% ee) was thus obtained as solid.

The obtained 27.17 g of salt was added to ethyl acetate (80 ml), and the mixture was stirred at 20-30°C for 5 h. Filter, and wash the filter cake with cold ethyl acetate (0-10°C, 15 ml). The obtained filter cake was added to MTBE (80 mL), and Na ₂ HPO ₄ (12.10 g) and water (80 mL) were added. The mixture was stirred at 20-30°C for 1 hour, separated into layers, and the organic layer was washed once with water (40 mL). The organic layer was concentrated to dryness, and the obtained solid was vacuum dried at 50°C for 18 hours. The total amount of solid obtained was 14.73g (99.90%ee, yield 80.0%).

Comparative example 2:

(S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoro Methyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate (14.73g) was dissolved in methyl tert-butyl ether (45ml). KOH (5.64g), _H2O (88mL) and methanol (12mL) were added. The mixture was heated to 50°C and stirred for 6 h. Methyl tert-butyl ether (22 mL) and H ₂ O (44 mL) were added to the mixture. The layers were separated, and the aqueous layer was washed once with methyl tert-butyl ether (22 mL). Methyl tert-butyl ether (43 mL) was added to the aqueous layer, and the pH of the aqueous layer was adjusted to 4-5 with 1M hydrochloric acid. The layers were separated, and the organic layer was concentrated to dryness under vacuum. Add acetone (33 mL) to dissolve the solution, and slowly add 88 mL of water at 20°C. Stir for 5 hours at 20-25°C, filter, wash the filter cake with water (15 ml), and vacuum dry the obtained solid at 50°C for 18 hours. The total amount of solid obtained was 12.95 g (ee 99.90% yield 90.1%).

From {8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3 , the total yield of 4-dihydroquinazolin-4-yl}acetic acid methyl ester was 72.1%.

Comparison between the present invention and the literature process CN 101863843 B:

In pharmaceutical production, the single impurity content is required to be less than 0.1%. In the process of the reference document, secondary crystallization is required to increase the ee value of the product to 99.90% (i.e., the single impurity qualifying standard). However, in the method of the present invention , one crystallization can make the ee value of the product far exceed the qualified standard, so it is very suitable for industrial production.

In summary, the preparation method of the letermovir intermediate of the present invention requires fewer crystallizations, requires only one crystallization, and has low three-waste treatment costs; in addition, the preparation method of the present invention has a short production cycle, but the product purity is high, and is suitable for industrial production.

Claims

A letermovir intermediate (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-( Trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate methyl ester chiral modified salt, which is characterized in that,

The intermediate is (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(tri D-(+)-dibenzoyl tartrate of fluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetic acid methyl ester,

(S)-{8-Fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl] -D-(+)-dibenzoyl tartrate of methyl 3,4-dihydroquinazolin-4-yl}acetate;

and (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)benzene base]-3,4-dihydroquinazolin-4-yl}methyl acetate D-(+)-di-p-tolyloxybenzoyl tartrate,

(S)-{8-Fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl] -D-(+)-di-p-tolyloxybenzoyl tartrate of methyl 3,4-dihydroquinazolin-4-yl}acetate.
A method for preparing intermediates as claimed in claim 1, characterized in that the method includes the steps of: in an inert solvent, {8-fluoro-2-[4-(3-methoxyphenyl) Piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetic acid methyl ester and chiral modification The tartaric acid was crystallized to obtain (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(tri Tartrate of fluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetic acid methyl ester;

Wherein, the chiral modified tartaric acid is selected from the following group: D-(+)-dibenzoyltartaric acid, D-(+)-di-p-methoxybenzoyltartaric acid.
The method of claim 2, wherein the chirally modified tartaric acid is D-(+)-di-p-methoxybenzoyltartaric acid.
The method of claim 2, wherein the inert solvent is selected from the group consisting of C1-C10 ester solvents, C6-C10 aromatic hydrocarbon solvents, C2-C6 ether solvents, or combinations thereof.
The method of claim 2, wherein the solvent is selected from the group consisting of: ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate, butyl acetate, toluene, tetrahydrofuran, methyl Tert-butyl ether, diisopropyl ether, or combinations thereof.
The method of claim 2, wherein the {8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy The volume (v/v) ratio of base-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate to inert solvent is 1:3-10.
The method of claim 2, wherein the {8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy The molar ratio of methyl acetate to chiral modified tartaric acid is 1:1.0-1.5.
The method of claim 2, wherein the crystallization temperature is 0-80°C, preferably 20-40°C.
The method according to claim 2, characterized in that the crystallization time is 2-15h, preferably 5-8h.
A preparation method of letermovir, characterized in that the method includes:

(1) Use the method as described in any one of claims 2-9 to obtain the (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl ]-3-[2-Methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate methyl ester chiral modified salt;

(2) Use the (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-( Letermovir was prepared from chiral modified salt of trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate methyl ester: