A preparation method of a letermovir intermediate

Abstract

The invention provides a preparation method of a letermovir intermediate, belonging to the field of bulk drug synthesis. The present invention mixes 2-bromo-6-fluoroaniline, methyl acrylate, a palladium catalyst, an acid binding agent and an organic solvent for a coupling reaction to obtain (E)-3-(2-amino-3-fluorophenyl) methyl acrylate, and then mixes it with 2-methoxy-5-trifluoromethylphenyl isocyanate for an addition reaction. The obtained (E)-3-(3-fluoro-2-(3-(2-methoxy-5-(trifluoromethyl)phenyl)urea)phenyl) methyl acrylate is mixed with a chiral catalyst and an organic solvent for an intramolecular Michael addition reaction to obtain the letermovir intermediate. The method of the present invention has only three chemical reaction steps, a simple process route, a wide range of commercial sources of all raw and auxiliary materials, mild reaction conditions, few by-products, low cost, and is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of raw material drug synthesis, and in particular to a method for preparing a letermovir intermediate. Background Art

[0002] Letermovir is a novel inhibitor of cytomegalovirus (CMV) DNA terminase, which prevents the terminase from cleaving newly synthesized CMV DNA into individual viral genomes and directing them into empty viral capsids, thereby inhibiting viral replication. It is clinically indicated for the prevention of CMV infection or disease in adult recipients [R+] with positive cytomegalovirus serology who are undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Letermovir tablets (trade name: ) was first approved by the FDA for marketing in November 2017. Clinical trials have demonstrated that letermovir has favorable safety and efficacy, with no cytomegalovirus detected in patients after 28 days of treatment. Compared with other approved drugs, letermovir exhibits no cross-resistance and holds promising market prospects.

[0003] The compound (S)-2-(8-fluoro-3-(2-methoxy-5-trifluoromethyl)phenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl)acetate is an important intermediate for the preparation of letermovir, and its structure is shown in formula (I).

[0004]

[0005] Currently, there are two methods for preparing compound of formula (I):

[0006] Method 1, the reaction process is shown in formula (II), starting from compound II, through 6 steps of chemical reaction to obtain compound (I). The starting material compound II used in this method is an unconventional reagent and is not easy to obtain commercially; at the same time, the reaction steps are too long, the total yield is low, the process is cumbersome, and it is not suitable for industrial production

[0007]

[0008] Method 2, with the reaction process shown in Formula (III), begins with Compound III and proceeds through five chemical steps to obtain Compound (I). This method also suffers from the drawbacks of using unconventional starting materials, which are relatively expensive (approximately ¥80,000 / kg) and difficult to obtain commercially. Furthermore, the second step in this synthetic route requires a temperature of -60°C, which places high demands on workshop equipment and is difficult to achieve. Furthermore, the reaction steps are too long, the overall yield is low, and the process is cumbersome, making it unsuitable for industrial production.

[0009] Summary of the Invention

[0010] In view of this, the object of the present invention is to provide a method for preparing a letermovir intermediate. The preparation method of the present invention has simple reaction steps and process routes, all raw materials are widely commercially available, the reaction conditions are mild, there are few by-products, and the cost is low.

[0011] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0012] The present invention provides a method for preparing a letermovir intermediate, comprising the following steps:

[0013] 2-bromo-6-fluoroaniline, methyl acrylate, a palladium catalyst, an acid binding agent, and an organic solvent are mixed to carry out a coupling reaction to obtain (E)-3-(2-amino-3-fluorophenyl)methyl acrylate;

[0014] Mixing the (E)-3-(2-amino-3-fluorophenyl) methyl acrylate and 2-methoxy-5-trifluoromethylphenyl isocyanate for addition reaction to obtain (E)-3-(3-fluoro-2-(3-(2-methoxy-5-(trifluoromethyl)phenyl)urea)phenyl) methyl acrylate;

[0015] The (E)-methyl 3-(3-fluoro-2-(3-(2-methoxy-5-(trifluoromethyl)phenyl)urea)phenyl)acrylate, a chiral catalyst and an organic solvent are mixed to perform an intramolecular Michael addition reaction to obtain the Letermovir intermediate. The Letermovir intermediate has a structure shown in formula (I):

[0016]

[0017] Preferably, the palladium catalyst is 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride and / or bistriphenylphosphinepalladium dichloride.

[0018] Preferably, the molar equivalent ratio of the 2-bromo-6-fluoroaniline to the palladium catalyst is 100:0.5-1.

[0019] Preferably, the acid binding agent is triethylamine and / or diisopropylethylamine.

[0020] Preferably, the molar equivalent ratio of the 2-bromo-6-fluoroaniline to the acid binding agent is 100:2.

[0021] Preferably, the coupling reaction temperature is 85-90° C., and the time is 16-17 h.

[0022] Preferably, the temperature of the addition reaction is 80-82° C., and the time is 5-6 hours.

[0023] Preferably, the chiral catalyst is (1R)-trans-N,N-1,2-cyclohexanediyl(1,1,1-trifluoromethanesulfonamide).

[0024] Preferably, the molar equivalent ratio of the methyl (E)-3-(3-fluoro-2-(3-(2-methoxy-5-(trifluoromethyl)phenyl)urea)phenyl)acrylate to the chiral catalyst is 100:1.

[0025] Preferably, the temperature of the intramolecular Michael addition reaction is 50-60° C., and the time is 7-8 hours.

[0026] The present invention provides a method for preparing a letermovir intermediate, comprising the following steps:

[0027] 2-bromo-6-fluoroaniline, methyl acrylate, a palladium catalyst, an acid-binding agent and an organic solvent are mixed for a coupling reaction to obtain (E)-3-(2-amino-3-fluorophenyl) methyl acrylate; the (E)-3-(2-amino-3-fluorophenyl) methyl acrylate and 2-methoxy-5-trifluoromethylphenyl isocyanate are mixed for an addition reaction to obtain (E)-3-(3-fluoro-2-(3-(2-methoxy-5-(trifluoromethyl)phenyl)urea)phenyl) methyl acrylate; the (E)-3-(3-fluoro-2-(3-(2-methoxy-5-(trifluoromethyl)phenyl)urea)phenyl) methyl acrylate, a chiral catalyst and an organic solvent are mixed for an intramolecular Michael addition reaction to obtain the letermovir intermediate.

[0028] Compared with the prior art, the present invention has the following beneficial effects:

[0029] This invention provides a novel synthesis strategy for letermovir intermediates, offering a reference for the industrialization of letermovir APIs. The method comprises only three chemical reaction steps, a concise process route, and a wide range of commercial raw and auxiliary materials. The reaction conditions are mild, byproducts are minimal, and the cost is low, making it suitable for industrial production. DETAILED DESCRIPTION

[0030] The present invention provides a method for preparing a letermovir intermediate, comprising the following steps:

[0031] 2-bromo-6-fluoroaniline, methyl acrylate, a palladium catalyst, an acid binding agent, and an organic solvent are mixed to carry out a coupling reaction to obtain (E)-3-(2-amino-3-fluorophenyl)methyl acrylate;

[0032] Mixing the (E)-3-(2-amino-3-fluorophenyl) methyl acrylate and 2-methoxy-5-trifluoromethylphenyl isocyanate for addition reaction to obtain (E)-3-(3-fluoro-2-(3-(2-methoxy-5-(trifluoromethyl)phenyl)urea)phenyl) methyl acrylate;

[0033] The (E)-methyl 3-(3-fluoro-2-(3-(2-methoxy-5-(trifluoromethyl)phenyl)urea)phenyl)acrylate, a chiral catalyst and an organic solvent are mixed to perform an intramolecular Michael addition reaction to obtain the Letermovir intermediate. The Letermovir intermediate has a structure shown in formula (I):

[0034]

[0035] In the present invention, unless otherwise specified, the raw materials used are commercially available products in the art.

[0036] In the present invention, the principle of the preparation method is shown in formula (IV):

[0037]

[0038] The invention comprises the following steps: mixing 2-bromo-6-fluoroaniline, methyl acrylate, a palladium catalyst, an acid binding agent and an organic solvent to carry out a coupling reaction, thereby obtaining (E)-3-(2-amino-3-fluorophenyl)methyl acrylate.

[0039] In the present invention, the molar ratio of 2-bromo-6-fluoroaniline to methyl acrylate is preferably 1:1 to 1.5.

[0040] In the present invention, the palladium catalyst is preferably 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride and / or bis(triphenylphosphine)palladium dichloride. When the palladium catalyst is a mixture of 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride and bis(triphenylphosphine)palladium dichloride, the present invention has no particular limitation on the mass ratio of 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride and bis(triphenylphosphine)palladium dichloride in the mixture, and any mixture in any proportion may be used.

[0041] In the present invention, the molar equivalent ratio of the 2-bromo-6-fluoroaniline to the palladium catalyst is preferably 100:0.5-1.

[0042] In the present invention, the acid binding agent is preferably triethylamine and / or diisopropylethylamine. When the acid binding agent is a mixture of triethylamine and diisopropylethylamine, the present invention has no particular limitation on the mass ratio of triethylamine and / or diisopropylethylamine in the mixture, and any mixture ratio can be used.

[0043] In the present invention, the molar equivalent ratio of the 2-bromo-6-fluoroaniline to the acid binding agent is preferably 100:2.

[0044] In the present invention, the organic solvent is preferably N,N-dimethylformamide (DMF) or 1,4-dioxane. The present invention has no particular limitation on the amount of the organic solvent used, as long as it can dissolve the raw materials.

[0045] In the present invention, the coupling reaction temperature is preferably 85-90° C., and the time is preferably 16-17 h.

[0046] In the present invention, the coupling reaction is preferably carried out in a protective atmosphere, and the protective atmosphere is preferably nitrogen.

[0047] After the coupling reaction is completed, the present invention preferably cools the obtained coupling product to room temperature, separates the solid and liquid, distills the obtained liquid under reduced pressure, mixes with water, extracts with ethyl acetate, washes with saturated sodium chloride, and distills the obtained organic phase under reduced pressure to obtain the (E)-3-(2-amino-3-fluorophenyl)acrylate.

[0048] In the present invention, the solid-liquid separation is preferably filtration.

[0049] In the present invention, the temperature for the reduced pressure distillation of the liquid and organic phase is preferably 50° C., and the distillation is performed until no fraction remains.

[0050] After obtaining (E)-3-(2-amino-3-fluorophenyl)acrylate, the present invention mixes the (E)-3-(2-amino-3-fluorophenyl)acrylate and 2-methoxy-5-trifluoromethylphenyl isocyanate to carry out an addition reaction to obtain (E)-3-(3-fluoro-2-(3-(2-methoxy-5-(trifluoromethyl)phenyl)urea)phenyl)acrylate.

[0051] In the present invention, the molar ratio of the (E)-3-(2-amino-3-fluorophenyl)acrylate to 2-methoxy-5-trifluoromethylphenyl isocyanate is preferably 1:1 to 1.5.

[0052] In the present invention, the temperature of the addition reaction is preferably 80-82° C., and the time is preferably 5-6 hours.

[0053] In the present invention, the solvent for the addition reaction is preferably acetonitrile. The present invention has no particular limitation on the amount of acetonitrile used, as long as it can dissolve the raw materials.

[0054] After the addition reaction is completed, the present invention preferably cools the obtained addition product to room temperature, filters it, and vacuum-dries the obtained filter cake to obtain the (E)-3-(3-fluoro-2-(3-(2-methoxy-5-(trifluoromethyl)phenyl)urea)phenyl)acrylate.

[0055] In the present invention, the vacuum drying temperature is preferably 35° C., and the drying time is until constant weight is reached.

[0056] After obtaining methyl (E)-3-(3-fluoro-2-(3-(2-methoxy-5-(trifluoromethyl)phenyl)urea)phenyl)acrylate, the present invention mixes the methyl (E)-3-(3-fluoro-2-(3-(2-methoxy-5-(trifluoromethyl)phenyl)urea)phenyl)acrylate, a chiral catalyst and an organic solvent to carry out an intramolecular Michael addition reaction to obtain the letermovir intermediate.

[0057] In the present invention, the chiral catalyst is preferably (1R)-trans-N,N-1,2-cyclohexanediyl (1,1,1-trifluoromethanesulfonamide), and its structural formula is shown in Formula (V):

[0058]

[0059] In the present invention, the molar equivalent ratio of the methyl (E)-3-(3-fluoro-2-(3-(2-methoxy-5-(trifluoromethyl)phenyl)urea)phenyl)acrylate to the chiral catalyst is preferably 100:1.

[0060] In the present invention, the temperature of the intramolecular Michael addition reaction is preferably 50-60° C., and the time is preferably 7-8 h.

[0061] In the present invention, the solvent for the intramolecular Michael addition reaction is preferably toluene, tetrahydrofuran, N,N-dimethylformamide or acetonitrile. The present invention has no particular limitation on the amount of the solvent, as long as it can dissolve the raw materials.

[0062] After the intramolecular Michael addition reaction is completed, the present invention preferably performs post-treatment on the obtained intramolecular Michael addition reaction product, and the post-treatment preferably includes the following steps: cooling to room temperature, adding potassium carbonate aqueous solution for washing, stirring, standing and discarding the bottom aqueous phase, then washing with saturated brine, and distilling the obtained organic phase under reduced pressure until there is no fraction, and then recrystallizing, and vacuum drying the obtained solid to obtain the said letermovir intermediate.

[0063] In the present invention, the mass percentage of potassium carbonate in the potassium carbonate aqueous solution is 1%.

[0064] In the present invention, the temperature of the reduced pressure distillation is preferably 50°C.

[0065] In the present invention, ethanol is preferably used for the recrystallization.

[0066] In the present invention, the vacuum drying temperature is preferably 40° C., and the product is preferably dried to a constant weight.

[0067] To further illustrate the present invention, the preparation method of the Letermovir intermediate provided by the present invention is described in detail below with reference to examples, but they should not be construed as limiting the scope of protection of the present invention.

[0068] Example 1

[0069] Synthesis of Compound (E)-3-(2-amino-3-fluorophenyl)methyl acrylate

[0070] 2-Bromo-6-fluoroaniline 4 (19 g, 0.1 mol), methyl acrylate 2 (12.9 g, 0.15 mol), triethylamine (20 g, 0.2 mol), and 100 mL of DMF were added sequentially to a 250 mL three-necked flask, stirred evenly, and the atmosphere was purged with nitrogen three times. 1,1'-Bis(diphenylphosphino)ferrocenedichloropalladium (0.7 g, 1 mmol) was added, and the atmosphere was purged with nitrogen once. Heat to 85°C in an oil bath and react for 16 h. Cool to room temperature, continue stirring for 1 h, and filter. The filtrate was distilled under reduced pressure at 50°C until almost no fraction was present. 100 mL of water was added, and the mixture was extracted with 200 mL of ethyl acetate and washed with 100 mL of saturated sodium chloride. The organic phase was distilled under reduced pressure at 50°C until almost no fraction was present, yielding 18 g of a brown oil, which was used directly in the next reaction.

[0071] Synthesis of Compound (E)-3-(3-fluoro-2-(3-(2-methoxy-5-(trifluoromethyl)phenyl)urea)phenyl)acrylate

[0072] Add 18 g of the prepared compound (E)-3-(2-amino-3-fluorophenyl)acrylate to 100 mL of acetonitrile and transfer the entire amount to a 250 mL reaction flask. Add 2-methoxy-5-trifluoromethylphenyl isocyanate (21.7 g, 0.1 mol). Heat to reflux in an oil bath at 80°C and react for 5 h. Cool to room temperature, continue stirring for 1 h, and filter. The wet cake is vacuum-dried at 35°C to constant weight to yield 33 g of a white solid, with a two-step yield of 80%.

[0073] Preparation of target product Letermovir intermediate

[0074] Compound (E)-methyl 3-(3-fluoro-2-(3-(2-methoxy-5-(trifluoromethyl)phenyl)urea)phenyl)acrylate (20.6 g, 0.05 mol) and 150 mL of toluene were added to a 500 mL three-necked flask and dissolved under stirring. Chiral catalyst (1R)-trans-N,N-1,2-cyclohexanediyl(1,1,1-trifluoromethanesulfonamide) (0.19 g, 0.5 mmol) was added. The mixture was heated to 50°C in a water bath and reacted for 8 h. After cooling to room temperature, 50 mL of a 1 wt% aqueous potassium carbonate solution was added to the reaction flask, stirred, and allowed to stand. The bottom aqueous phase was discarded and washed once with 50 mL of saturated brine. The organic phase was then distilled under reduced pressure at 50°C until essentially free of fractions, yielding a white solid. Recrystallization was performed by adding 100 mL of ethanol. The filter cake was dried under vacuum at 40°C to yield 17.5 g of the desired product I. Yield: 85%, HPLC purity: 99.3%, chiral purity: 99.5%.

[0075] Example 2

[0076] Synthesis of Compound (E)-3-(2-amino-3-fluorophenyl)methyl acrylate

[0077] 2-Bromo-6-fluoroaniline 4 (19 g, 0.1 mol), methyl acrylate 2 (12.9 g, 0.15 mol), diisopropylethylamine (25.8 g, 0.2 mol), and 100 mL of dioxane were added sequentially to a 250 mL three-necked flask, stirred evenly, and the atmosphere was purged with nitrogen three times. Bistriphenylphosphine palladium dichloride (0.7 g, 1 mmol) was added, and the atmosphere was purged with nitrogen once. Heat to 85°C in an oil bath and react for 16 h. Cool to room temperature, continue stirring for 1 h, and filter. The filtrate was vacuum distilled at 50°C until almost no fraction remained. 100 mL of water was added. Extraction was performed with 200 mL of ethyl acetate and washed with 100 mL of saturated sodium chloride. The organic phase was vacuum distilled at 50°C until almost no fraction remained, yielding 18 g of a brown oil, which was used directly in the next reaction.

[0078] Synthesis of Compound (E)-3-(3-fluoro-2-(3-(2-methoxy-5-(trifluoromethyl)phenyl)urea)phenyl)acrylate

[0079] Add 18 g of the prepared compound (E)-3-(2-amino-3-fluorophenyl)acrylate to 100 mL of acetonitrile and transfer the entire amount to a 250 mL reaction flask. Add 2-methoxy-5-trifluoromethylphenyl isocyanate (21.7 g, 0.1 mol). Heat to reflux in an oil bath at 82°C and react for 5 h. Cool to room temperature, continue stirring for 1 h, and filter. The wet cake is vacuum-dried at 35°C to constant weight to yield 32 g of a white solid, with a two-step yield of 78%.

[0080] Preparation of target product Letermovir intermediate

[0081] Compound (E)-methyl 3-(3-fluoro-2-(3-(2-methoxy-5-(trifluoromethyl)phenyl)urea)phenyl)acrylate (20.6 g, 0.05 mol) and 150 mL of toluene were added to a 500 mL three-necked flask and dissolved under stirring. Chiral catalyst (1R)-trans-N,N-1,2-cyclohexanediyl(1,1,1-trifluoromethanesulfonamide) (0.19 g, 0.5 mmol) was added. The mixture was heated to 55°C in a water bath and reacted for 8 h. After cooling to room temperature, 50 mL of a 1 wt% aqueous potassium carbonate solution was added to the reaction flask, stirred, allowed to stand, and the bottom aqueous phase was discarded; the mixture was then washed once with 50 mL of saturated brine. The organic phase was distilled under reduced pressure at 50°C until essentially free of fractions, yielding a white solid. Recrystallization was performed by adding 100 mL of ethanol, and the filter cake was dried under vacuum at 40°C to yield 18.5 g of the desired product I. Yield 90%, HPLC purity 99.2%, chiral purity 99.6%.

[0082] The above description is merely a preferred embodiment of the present invention and does not constitute any limitation thereto. It should be noted that those skilled in the art may make various improvements and modifications without departing from the principles of the present invention, and such improvements and modifications shall also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing a letermovir intermediate, characterized in that: The following steps are involved: 2-bromo-6-fluoroaniline, methyl acrylate, a palladium catalyst, an acid binding agent, and an organic solvent are mixed to carry out a coupling reaction to obtain (E)-3-(2-amino-3-fluorophenyl)methyl acrylate; Mixing the (E)-3-(2-amino-3-fluorophenyl) methyl acrylate and 2-methoxy-5-trifluoromethylphenyl isocyanate for addition reaction to obtain (E)-3-(3-fluoro-2-(3-(2-methoxy-5-(trifluoromethyl)phenyl)urea)phenyl) methyl acrylate; The (E)-3-(3-fluoro-2-(3-(2-methoxy-5-(trifluoromethyl)phenyl)urea)phenyl)acrylate is mixed with a chiral catalyst and an organic solvent to undergo an intramolecular Michael addition reaction to obtain the Letermovir intermediate, wherein the chiral catalyst is (1R)-trans-N,N-1,2-cyclohexanediyl(1,1,1-trifluoromethanesulfonamide). The Letermovir intermediate has a specific structure shown in formula (I):

2. The preparation method according to claim 1, characterized in that The palladium catalyst is 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride and / or bis(triphenylphosphine)palladium dichloride.

3. The preparation method according to claim 1 or 2, characterized in that The molar equivalent ratio of the 2-bromo-6-fluoroaniline to the palladium catalyst is 100:0.5-1.

4. The preparation method according to claim 1, characterized in that The acid binding agent is triethylamine and / or diisopropylethylamine.

5. The preparation method according to claim 1 or 4, characterized in that The molar equivalent ratio of the 2-bromo-6-fluoroaniline to the acid binding agent is 100:

2.

6. The preparation method according to claim 1, characterized in that The coupling reaction temperature is 85-90° C. and the reaction time is 16-17 h.

7. The preparation method according to claim 1, characterized in that The temperature of the addition reaction is 80-82° C., and the time is 5-6 hours.

8. The preparation method according to claim 1, characterized in that The molar equivalent ratio of the (E)-methyl 3-(3-fluoro-2-(3-(2-methoxy-5-(trifluoromethyl)phenyl)urea)phenyl)acrylate to the chiral catalyst is 100:

1.

9. The preparation method according to claim 1, characterized in that The temperature of the intramolecular Michael addition reaction is 50-60° C., and the time is 7-8 hours.

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