Synthesis method of letemovir chiral intermediate

Abstract

The invention relates to a synthesis method of a letemovir chiral intermediate. The synthesis method comprises the following steps: (1) adding 1-(2-bromo-6-fluorophenyl)-3-(2-methoxy-5-(trifluoromethyl) phenyl) urea and a solvent into a reaction flask, and uniformly stirring; sequentially adding alkali, a catalyst and a chiral ligand, and stirring while keeping the temperature; (2) slowly dropwise adding methyl acrylate, heating to reflux, and stirring for reaction; and (3) after the reaction is finished, filtering to remove insoluble substances. Decompressing and concentrating the filtrate to remove the solvent, adding a proper amount of dichloromethane into the evaporation-dried substance, separating out a solid, and filtering; adding a proper amount of acetonitrile into the solid, heating, stirring and dissolving; the preparation method comprises the following steps: adding a solvent into a reaction kettle, adding a catalyst into the reaction kettle, slowly cooling, adding a seed crystal, separating out a solid, filtering and drying to obtain the letemovir chiral intermediate (S)-methyl-2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl) phenyl)-2-oxo-1, 2, 3, 4-tetrahydroquinazoline-4-yl) acetate.

Description

Technical Field

[0001] The invention relates to a method for synthesizing a chiral intermediate of Letermovir, and belongs to the field of drug synthesis. Background Art

[0002] Human cytomegalovirus (HCMV), one of the largest known human viruses, can cause severe complications, leading to multi-organ failure and even life-threatening complications. Currently, there is no effective vaccine to prevent HCMV infection, and antiviral medications are the only viable option. Letermovir (LTV) is a potent inhibitor of DNA telomerase in CMV. LTV effectively reduces morbidity and mortality in CMV-infected patients and is well tolerated.

[0003] There are various methods for preparing Letermovir, among which patent WO2006133822A discloses a mainstream method for preparing Letermovir, which involves condensing a 2-halogen-substituted aniline with an isocyanate to produce N-(2-bromo-6-fluorophenyl)-N'-[2-methoxy-5-(trifluoromethylphenyl)]urea, which is then reacted with an alkyl acrylate to synthesize a dihydroquinoline ring. The chlorinated dihydroquinoline ring is then treated with phosphorus oxychloride to form a substituted amine to form dihydroquinazoline methyl ester, which is then used to prepare Letermovir. The existing method requires a racemate resolution process, and this resolution step is performed at the end of the process. The resolution rate is only about 30%, significantly impacting the cost of the entire route, leading to a high market price for Letermovir. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to provide a method for synthesizing a chiral intermediate of Letermovir with simple reaction operation and high efficiency.

[0005] In order to achieve these objects and other advantages of the present invention, a method for synthesizing a chiral intermediate of Letermovir is provided, characterized in that it comprises the following steps: S1. Add 1-(2-bromo-6-fluorophenyl)-3-(2-methoxy-5-(trifluoromethyl)phenyl)urea and solvent to the reaction flask and stir until uniform. Then add base, catalyst, and chiral ligand in sequence, and keep stirring. S2, slowly add methyl acrylate dropwise, raise the temperature to reflux, and stir the reaction for 10-15 hours; S3. After the reaction is completed, filter and remove insoluble matter. The filtrate is concentrated under reduced pressure to remove the solvent, and an appropriate amount of dichloromethane is added to the evaporated product to precipitate a solid, which is then filtered. An appropriate amount of acetonitrile is added to the solid, heated to 50°C-60°C, and stirred to dissolve. Slowly cool to 20°C-30°C, add seed crystals, maintain the temperature and stir, and slowly cool to 0°C-5°C again to precipitate a solid, which is filtered. The solid is washed with a small amount of cold acetonitrile and dried to obtain the chiral intermediate of Letermovir (S)-methyl 2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl)acetate.

[0006] Preferably, the solvent is one or more of dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, and diethylene glycol diethyl ether.

[0007] Preferably, the base is one or more of diisopropylethylamine, tetramethylguanidine, triethylamine, and 1,4-diazabicyclo[2.2.2]octane.

[0008] Preferably, the catalyst is one or more of bis(acetonitrile)palladium dichloride, ethylenediaminepalladium chloride, bis(cyanobenzene)palladium dichloride, (2,2-bipyridine)palladium dichloride, bis(2-methylallyl)palladium chloride, (1,5-cyclooctadiene)palladium dichloride, 1,4-bis(diphenylphosphinobutane)palladium dichloride, and [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridine)palladium dichloride.

[0009] Preferably, the chiral ligand is one or more of S-(-)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine, S-(+)-1,1'-binaphthyl-2'-methoxy-2-diphenylphosphine, S-(-)-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethyldi-3,5-methylphenylphosphine, (S)-1-[2-(diphenylphosphino)-1-naphthyl]isoquinoline, (S)-(2'-isopropoxy-[1,1'-binaphthyl]-2-yl)diphenylphosphine, (S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl monoxide, and (S)-2,2'-bis[bis(3,5-dimethylphenyl)phosphino]-4,4',6,6'-tetramethoxybiphenyl.

[0010] Preferably, the molar ratio of the base to the 1-(2-bromo-6-fluorophenyl)-3-(2-methoxy-5-(trifluoromethyl)phenyl)urea is 1.5:1 to 2.0:1, preferably 1.8:1.

[0011] Preferably, the molar ratio of the catalyst to the 1-(2-bromo-6-fluorophenyl)-3-(2-methoxy-5-(trifluoromethyl)phenyl)urea is 0.03:1 to 0.08:1, preferably 0.05:1.

[0012] Preferably, the molar ratio of the chiral ligand to the 1-(2-bromo-6-fluorophenyl)-3-(2-methoxy-5-(trifluoromethyl)phenyl)urea is 0.05:1 to 0.1:1, preferably 0.07:1.

[0013] The present invention has the following technical effects: 1. The reaction process of the present invention is simple, the conditions are mild, and no complicated operation steps are required.

[0014] 2. The synthesis method provided by the present invention can obtain the desired target chiral intermediate in one step without the need for complicated resolution steps.

[0015] 3. By exploring various reaction conditions, the present invention enables the synthesis yield of the target (S)-methyl 2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl)acetate to reach a high level, with a yield of up to 85%. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 The synthetic route of (S)-methyl 2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl)acetate provided in the embodiment of the present invention. Specific embodiments

[0017] The preparation method of the present invention is further illustrated below by means of specific examples, but the present invention is not limited to these examples.

[0018] Example 1 Under nitrogen, add 4.05g (1 eq) of 1-(2-bromo-6-fluorophenyl)-3-(2-methoxy-5-(trifluoromethyl)phenyl)urea and 30ml of tetrahydrofuran to a reaction flask and stir until uniform. Then, add 2.07g (1.8 eq) of tetramethylguanidine, 0.13g (0.05 eq) of bis(acetonitrile)palladium dichloride, and 0.44g (0.07 eq) of S-(-)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine in sequence at room temperature. Stir at room temperature for 10 minutes. Slowly add 1.29g (1.5 eq) of methyl acrylate dropwise. After addition is complete, raise the temperature to reflux and stir for 15 hours. After the reaction is complete, filter. Concentrate the filtrate under reduced pressure to dryness. Add 15ml of dichloromethane to the evaporated material, stir at room temperature to precipitate a solid, and filter. Add 8ml of acetonitrile to the solid, heat to 50-60°C, and stir to dissolve. The temperature was slowly lowered to 20-30°C, a small amount of seed crystals was added, and the mixture was stirred for 30 minutes at this temperature to precipitate a solid. The temperature was slowly lowered to 0-5°C again, and the mixture was stirred for 1 hour at this temperature. The solid was filtered, and the solid was washed with a small amount of cold acetonitrile. After drying, 3.26 g of the chiral intermediate Letermovir (S)-methyl 2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl)acetate was obtained, with a yield of 79%, a purity of 98.8%, and a chiral purity of 97.2%.

[0019] Example 2 Under nitrogen, add 4.05g (1 eq) of 1-(2-bromo-6-fluorophenyl)-3-(2-methoxy-5-(trifluoromethyl)phenyl)urea and 30ml of ethylene glycol dimethyl ether to a reaction flask and stir until uniform. Then, add 1.82g (1.8 eq) of triethylamine, 0.12g (0.05 eq) of ethylenediaminepalladium chloride, and 0.33g (0.07 eq) of S-(+)-1,1'-binaphthyl-2'-methoxy-2-diphenylphosphine at room temperature. Stir at room temperature for 10 minutes. Slowly add 1.29g (1.5 eq) of methyl acrylate dropwise. After addition is complete, raise the temperature to reflux and stir for 11 hours. After the reaction is complete, filter. Concentrate the filtrate under reduced pressure to dryness. Add 15ml of dichloromethane to the evaporated material, stir at room temperature to precipitate a solid, and filter. Add 8ml of acetonitrile to the solid, heat to 50-60°C, and stir to dissolve. The temperature was slowly lowered to 20-30°C, a small amount of seed crystals was added, and the mixture was stirred for 30 minutes at this temperature to precipitate a solid. The temperature was slowly lowered to 0-5°C again, and the mixture was stirred for 1 hour at this temperature. The solid was filtered, and the solid was washed with a small amount of cold acetonitrile. After drying, 3.17 g of Letermovir chiral intermediate (S)-methyl 2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl)acetate was obtained with a yield of 77%, a purity of 98.1%, and a chiral purity of 96.1%.

[0020] Example 3 Under nitrogen, add 4.05 g (1 eq) of 1-(2-bromo-6-fluorophenyl)-3-(2-methoxy-5-(trifluoromethyl)phenyl)urea and 30 ml of ethylene glycol diethyl ether to a reaction flask and stir until uniform. Then, add 2.01 g (1.8 eq) of 1,4-diazabicyclo[2.2.2]octane, 0.19 g (0.05 eq) of bis(cyanophenyl)palladium dichloride, and 0.45 g (0.07 eq) of S-(-)-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethyldi-3,5-methylphosphine at room temperature. Stir at room temperature for 10 min. Slowly add 1.29 g (1.5 eq) of methyl acrylate dropwise. Once addition is complete, raise the temperature to reflux and stir for 10 h. After the reaction is complete, filter. The filtrate was concentrated to dryness under reduced pressure. 15 ml of dichloromethane was added to the evaporated product, stirred at room temperature to precipitate a solid, and filtered. 8 ml of acetonitrile was added to the solid, heated to 50-60°C, and stirred to dissolve. The temperature was slowly lowered to 20-30°C, a small amount of seed crystals was added, and the mixture was stirred at this temperature for 30 minutes to precipitate a solid. The temperature was slowly lowered again to 0-5°C, stirred at this temperature for 1 hour, and filtered. The solid was washed with a small amount of cold acetonitrile and dried to obtain 3.38 g of the chiral intermediate Letermovir (S)-methyl 2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl)acetate, with a yield of 82%, a purity of 97.0%, and a chiral purity of 98.2%.

[0021] Example 4 Under nitrogen, add 4.05g (1 eq) of 1-(2-bromo-6-fluorophenyl)-3-(2-methoxy-5-(trifluoromethyl)phenyl)urea and 30ml of diethylene glycol dimethyl ether to a reaction flask and stir until uniform. Then, add 1.94g (1.5 eq) of diisopropylethylamine, 0.15g (0.03 eq) of bis(2-methylallyl)palladium chloride, and 0.25g (0.05 eq) of (S)-(2'-isopropoxy-[1,1'-binaphthyl]-2-yl)diphenylphosphine at room temperature. Stir at room temperature for 10 minutes. Slowly add 1.29g (1.5 eq) of methyl acrylate dropwise. After addition is complete, raise the temperature to reflux and stir for 14 hours. After the reaction is complete, filter. The filtrate is concentrated to dryness under reduced pressure, and 15ml of dichloromethane is added to the evaporated material. Stir at room temperature to precipitate a solid, which is then filtered. 8 ml of acetonitrile was added to the solid, heated to 50-60°C, and stirred to dissolve. The temperature was slowly lowered to 20-30°C, a small amount of seed crystals was added, and the mixture was stirred at this temperature for 30 minutes to precipitate a solid. The temperature was slowly lowered to 0-5°C again, stirred at this temperature for 1 hour, and filtered. The solid was washed with a small amount of cold acetonitrile and dried to obtain 3.38 g of the chiral intermediate Letermovir (S)-methyl 2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl)acetate, with a yield of 82%, a purity of 97.3%, and a chiral purity of 97.7%.

[0022] Example 5 Under nitrogen, add 4.05g (1 eq) of 1-(2-bromo-6-fluorophenyl)-3-(2-methoxy-5-(trifluoromethyl)phenyl)urea and 30ml of ethylene glycol dimethyl ether to a reaction flask and stir until uniform. Then, add 1.73g (1.5 eq) of tetramethylguanidine, 0.09g (0.03 eq) of (1,5-cyclooctadiene)palladium dichloride, and 0.32g (0.05 eq) of (S)-2,2'-bis(diphenylphosphine)-1,1'-binaphthyl monoxide at room temperature. Stir at room temperature for 10 minutes. Slowly add 1.29g (1.5 eq) of methyl acrylate dropwise. After addition is complete, raise the temperature to reflux and stir for 12 hours. After the reaction is complete, filter. Concentrate the filtrate to dryness under reduced pressure, add 15ml of dichloromethane to the evaporated material, stir at room temperature to precipitate a solid, and filter. 8 ml of acetonitrile was added to the solid, heated to 50-60°C, and stirred to dissolve. The temperature was slowly lowered to 20-30°C, a small amount of seed crystals was added, and the mixture was stirred for 30 minutes at this temperature to precipitate a solid. The temperature was slowly lowered to 0-5°C again, stirred for 1 hour at this temperature, and filtered. The solid was washed with a small amount of cold acetonitrile and dried to obtain 3.30 g of the chiral intermediate Letermovir (S)-methyl 2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl)acetate, with a yield of 80%, a purity of 98.0%, and a chiral purity of 98.3%.

[0023] Example 6 Under nitrogen, 4.05 g (1 eq) of 1-(2-bromo-6-fluorophenyl)-3-(2-methoxy-5-(trifluoromethyl)phenyl)urea and 30 ml of dioxane were added to the reaction flask and stirred thoroughly. At room temperature, 2.02 g (2 eq) of triethylamine, 0.48 g (0.08 eq) of 1,4-bis(diphenylphosphinobutane)palladium dichloride, and 0.75 g (0.1 eq) of (S)-2,2'-bis[bis(3,5-dimethylphenyl)phosphino]-4,4',6,6'-tetramethoxybiphenyl were added sequentially. After addition was complete, the mixture was stirred at room temperature for 10 min. 1.29 g (1.5 eq) of methyl acrylate was slowly added dropwise. After addition was complete, the mixture was heated to reflux and stirred for 10 h. After the reaction was complete, the mixture was filtered. The filtrate was concentrated to dryness under reduced pressure, and 15 ml of dichloromethane was added to the evaporated material. The solid was stirred at room temperature and filtered. 8 ml of acetonitrile was added to the solid, heated to 50-60°C, and stirred to dissolve. The temperature was slowly lowered to 20-30°C, a small amount of seed crystals was added, and the mixture was stirred at this temperature for 30 minutes to precipitate a solid. The temperature was slowly lowered to 0-5°C again, stirred at this temperature for 1 hour, and filtered. The solid was washed with a small amount of cold acetonitrile and dried to obtain 2.68 g of the chiral intermediate Letermovir (S)-methyl 2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl)acetate, with a yield of 65%, a purity of 98.9%, and a chiral purity of 99.1%.

[0024] Example 7 Under nitrogen, add 4.05g (1 eq) of 1-(2-bromo-6-fluorophenyl)-3-(2-methoxy-5-(trifluoromethyl)phenyl)urea and 30ml of dioxane to a reaction flask and stir until uniform. Then, add 2.33g (1.8 eq) of diisopropylethylamine, 0.17g (0.05 eq) of (2,2-bipyridine)dichloropalladium, and 0.31g (0.07 eq) of (S)-1-[2-(diphenylphosphino)-1-naphthyl]isoquinoline at room temperature. Stir at room temperature for 10 minutes. Slowly add 1.29g (1.5 eq) of methyl acrylate dropwise. After addition is complete, raise the temperature to reflux and stir for 12 hours. After the reaction is complete, filter. The filtrate is concentrated to dryness under reduced pressure, and 15ml of dichloromethane is added to the evaporated material. Stir at room temperature to precipitate a solid, which is then filtered. 8 ml of acetonitrile was added to the solid, heated to 50-60°C, and stirred to dissolve. The temperature was slowly lowered to 20-30°C, a small amount of seed crystals was added, and the mixture was stirred at this temperature for 30 minutes to precipitate a solid. The temperature was slowly lowered to 0-5°C again, stirred at this temperature for 1 hour, and filtered. The solid was washed with a small amount of cold acetonitrile and dried to obtain 3.50 g of the chiral intermediate Letermovir (S)-methyl 2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl)acetate, with a yield of 85%, a purity of 98.8%, and a chiral purity of 98.9%.

[0025] Example 8 Under nitrogen, add 4.05 g (1 eq) of 1-(2-bromo-6-fluorophenyl)-3-(2-methoxy-5-(trifluoromethyl)phenyl)urea and 30 ml of diethylene glycol diethyl ether to a reaction flask and stir thoroughly. Then, add 2.24 g (2 eq) of 1,4-diazabicyclo[2.2.2]octane, 0.55 g (0.08 eq) of [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridine)palladium dichloride, and 0.31 g (0.07 eq) of (S)-1-[2-(diphenylphosphino)-1-naphthyl]isoquinoline. Stir at room temperature for 10 min. Slowly add 1.29 g (1.5 eq) of methyl acrylate dropwise. Once addition is complete, raise the temperature to reflux and stir for 15 h. After the reaction is complete, filter. The filtrate was concentrated to dryness under reduced pressure. 15 ml of dichloromethane was added to the evaporated product, and the mixture was stirred at room temperature to precipitate a solid, which was then filtered. 8 ml of acetonitrile was added to the solid, heated to 50-60°C, and stirred to dissolve. The temperature was slowly lowered to 20-30°C, a small amount of seed crystals was added, and the mixture was stirred at this temperature for 30 minutes to precipitate a solid. The temperature was slowly lowered again to 0-5°C, stirred at this temperature for 1 hour, and filtered. The solid was washed with a small amount of cold acetonitrile and dried to obtain 3.01 g of the chiral intermediate Letermovir (S)-methyl 2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl)acetate, with a yield of 73%, a purity of 97.7%, and a chiral purity of 96.8%.

Claims

1. A method for synthesizing a chiral intermediate of Letermovir, characterized in that: The following steps are involved: S1. Add 1-(2-bromo-6-fluorophenyl)-3-(2-methoxy-5-(trifluoromethyl)phenyl)urea and solvent to the reaction flask and stir until uniform. Then add base, catalyst, and chiral ligand in sequence, and keep stirring. S2, slowly add methyl acrylate dropwise, raise the temperature to reflux, and stir the reaction for 10-15 hours; S3. After the reaction is completed, filter and remove insoluble matter. The filtrate is concentrated under reduced pressure to remove the solvent, and an appropriate amount of dichloromethane is added to the evaporated product to precipitate a solid, which is then filtered. An appropriate amount of acetonitrile is added to the solid, heated to 50°C-60°C, and stirred to dissolve. Slowly cool to 20°C-30°C, add seed crystals, maintain the temperature and stir, and slowly cool to 0°C-5°C again to precipitate a solid, which is filtered. The solid is washed with a small amount of cold acetonitrile and dried to obtain the chiral intermediate of Letermovir (S)-methyl 2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl)acetate.

2. The synthesis method according to claim 1, characterized in that The solvent is one or more of dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, and diethylene glycol diethyl ether.

3. The synthesis method according to claim 1, wherein The base is one or more of diisopropylethylamine, tetramethylguanidine, triethylamine, and 1,4-diazabicyclo[2.2.2]octane.

4. The synthesis method according to claim 1, wherein The catalyst is one or more of bis(acetonitrile)palladium dichloride, ethylenediaminepalladium chloride, bis(cyanobenzene)palladium dichloride, (2,2-bipyridine)palladium dichloride, bis(2-methylallyl)palladium chloride, (1,5-cyclooctadiene)palladium dichloride, 1,4-bis(diphenylphosphinobutane)palladium dichloride, and [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridine)palladium dichloride.

5. The synthesis method according to claim 1, wherein The chiral ligand is one or more of S-(-)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine, S-(+)-1,1'-binaphthyl-2'-methoxy-2-diphenylphosphine, S-(-)-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethyldi-3,5-methylphenylphosphine, (S)-1-[2-(diphenylphosphino)-1-naphthyl]isoquinoline, (S)-(2'-isopropoxy-[1,1'-binaphthyl]-2-yl)diphenylphosphine, (S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl monoxide, and (S)-2,2'-bis[bis(3,5-dimethylphenyl)phosphino]-4,4',6,6'-tetramethoxybiphenyl.

6. The synthesis method according to claim 1, characterized in that The molar ratio of the base to the 1-(2-bromo-6-fluorophenyl)-3-(2-methoxy-5-(trifluoromethyl)phenyl)urea is 1.5:1 to 2.0:1, preferably 1.8:

1.

7. The synthesis method according to claim 1, characterized in that The molar ratio of the catalyst to the 1-(2-bromo-6-fluorophenyl)-3-(2-methoxy-5-(trifluoromethyl)phenyl)urea is 0.03:1 to 0.08:1, preferably 0.05:

1.

8. The synthesis method according to claim 1, characterized in that The molar ratio of the chiral ligand to the 1-(2-bromo-6-fluorophenyl)-3-(2-methoxy-5-(trifluoromethyl)phenyl)urea is 0.05:1 to 0.1:1, preferably 0.07:1.

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