A process for the preparation of maribavir
Patent Information
- Application Number
- CN202610228489.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2026-02-26
- Publication Date
- 2026-08-28
Smart Images
Figure SMS_2 
Figure QLYQS_1 
Figure QLYQS_2
Abstract
Description
Technical Field
[0001] This invention belongs to the field of drug synthesis, and specifically relates to a method for preparing maribavir. Background Technology
[0002] Maribavir, as shown in Formula I, is used to treat refractory, with or without resistance (R / R) cytomegalovirus (CMV) infection following organ transplantation or hematopoietic cell transplantation. It was approved by the US FDA in November 2021, by the EU EMA in November 2022, and launched in China in December 2023.
[0003] (Formula I) Summary of the Invention
[0004] This invention provides a method for preparing maribavir, which involves preparing a maribavir methyl tert-butyl ether solvate from a compound of formula III, and then preparing maribavir. This method is simple and easy to scale up for industrial production.
[0005] A first aspect of the present invention provides a method for preparing maribavir, comprising:
[0006]
[0007] (1) The compound of formula III reacts with isopropylamine, the reaction product is concentrated, the concentrated reaction product is mixed with methyl tert-butyl ether, and the compound of formula II is precipitated by cooling.
[0008] (2) The compound of formula II is mixed with organic solvent B, heated to dissolve, and then mixed with toluene. The compound of formula I is precipitated by cooling.
[0009] In one specific embodiment of the present invention, in step (1), the reaction of the compound of formula III with isopropylamine includes one or more of the following reaction conditions:
[0010] (a) The reaction is carried out under nitrogen and / or helium protection;
[0011] (b) The molar ratio of compound III to isopropylamine is 1:(10-35);
[0012] (c) The reaction solvent for the reaction of compound III with isopropylamine is 1,4-dioxane;
[0013] (d) The reaction temperature of compound III with isopropylamine is 50-60℃ and the reaction time is 4-6 hours.
[0014] In one specific embodiment of the present invention, in step (1), the reaction of the compound of formula III with isopropylamine is carried out under nitrogen and / or helium protection.
[0015] In one specific embodiment of the present invention, in step (1), the molar ratio of compound III to isopropylamine is 1:(10-35).
[0016] In one specific embodiment of the present invention, in step (1), the reaction solvent for the reaction of compound III with isopropylamine is 1,4-dioxane.
[0017] In one specific embodiment of the present invention, in step (1), the reaction temperature of the compound of formula III with isopropylamine is 50-60°C and the reaction time is 4-6 hours.
[0018] In one specific embodiment of the present invention, in step (1), the reaction of the compound of formula III with isopropylamine includes the following reaction conditions: (a) the reaction is carried out under nitrogen and / or helium protection; (b) the molar ratio of the compound of formula III to isopropylamine is 1:(10-35); (c) the reaction solvent for the reaction of the compound of formula III with isopropylamine is 1,4-dioxane; (d) the reaction temperature for the reaction of the compound of formula III with isopropylamine is 50-60°C, and the reaction time is 4-6 hours.
[0019] In one specific embodiment of the present invention, in step (1), after the compound of formula III reacts with isopropylamine, the concentrated reaction product is a solvent removed under reduced pressure.
[0020] In one specific embodiment of the present invention, in step (1), the molar ratio of compound III to methyl tert-butyl ether is 1: (10-15).
[0021] In one specific embodiment of the present invention, in step (1), after adding methyl tert-butyl ether, the cooling is to lower the temperature to 0-10°C. o C.
[0022] In one specific embodiment of the present invention, in step (2), the organic solvent B is an ester solvent R. 1 C(O)OR 2 The R 1 Selected from methyl, ethyl, n-propyl, isopropyl, and n-butyl; The R 2 Selected from methyl, ethyl, n-propyl, isopropyl, and n-butyl.
[0023] In one specific embodiment of the present invention, in step (2), the mass-to-volume ratio of compound II to organic solvent B is 1 kg : (2-4) L. In another specific embodiment of the present invention, in step (2), the mass-to-volume ratio of compound II to organic solvent B is 1 kg : (2-3) L.
[0024] In one specific embodiment of the present invention, in step (2), the temperature at which the compound of formula I is cooled and precipitated is 0-45°C. o C. In one specific embodiment of the present invention, in step (2), the temperature at which the compound of formula I is cooled and precipitated is 0-35°C. o C. In one specific embodiment of the present invention, in step (2), the temperature at which the compound of formula I is cooled and precipitated is 0-25°C. o C. In one specific embodiment of the present invention, in step (2), the temperature at which the compound of formula I is cooled and precipitated is 0-15°C. o C. In one specific embodiment of the present invention, in step (2), the temperature at which the compound of formula I is cooled and precipitated is 0-5°C. o C.
[0025] In one specific embodiment of the present invention, in step (2), the precipitated compound of formula I is separated from the liquid and then dried. In another specific embodiment of the present invention, the drying can be performed by heating or not heating, and can be performed by atmospheric pressure or reduced pressure; for example, atmospheric pressure drying at room temperature, reduced pressure drying at room temperature, atmospheric pressure drying above room temperature, and reduced pressure drying above room temperature; preferably, atmospheric pressure drying above room temperature or reduced pressure drying above room temperature. Exemplarily, this can be reduced pressure drying at 50–60°C for 4–8 hours, or reduced pressure drying at 75–85°C for 12–36 hours.
[0026] In a second aspect, the present invention provides a malivavir methyl tert-butyl ether solvate.
[0027] In one specific embodiment of the present invention, the maribavir methyl tert-butyl ether solvate is as shown in Formula II.
[0028] (Formula II)
[0029] The terms “containing” or “including (comprise)” can be open-ended, semi-closed, or closed. In other words, the terms also include “consistently made of” or “made of”.
[0030] "Percentage by volume" or "% (w / v)" or "% w / v" is a way of expressing mass-volume concentration, indicating the number of grams of solute contained in 100 ml of solution. For example, 20% (w / v) means that 100 ml of solution contains 20 g of solute.
[0031] "Optional" or "optionally" means that the event or condition described below may occur but is not required to occur, and the description includes both the scenario in which said event or condition occurs and the scenario in which said event or condition does not occur.
[0032] This invention provides a method for preparing maribavir, which involves preparing a maribavir methyl tert-butyl ether solvate from a compound of formula III, and then preparing maribavir. This method is simple and easy to scale up for industrial production. Detailed Implementation
[0033] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer.
[0034] Example 1
[0035] Under nitrogen protection, compound III (37.89 kg) and 1,4-dioxane (195.85 kg) were added to a reactor, stirred, and the temperature was controlled at 20±3℃. Isopropylamine (52.28 kg) was then added to the reactor. After the addition was complete, the mixture was stirred at 20±3℃ for 1.5±0.5 h, and then stirred at 55±5℃ for 5±1 h.
[0036] Cool the reaction solution to 20±3℃, then add isopropylamine (26.14 kg) to the reactor; after addition, stir the reaction mixture at 20±3℃ for 1.5±0.5 h, then stir it again at 55±5℃ for 5±1 h. (This step is repeated 5 times.)
[0037] The reaction solution was concentrated under reduced pressure at 50±5℃ until almost no droplets remained. Ethyl acetate (170.85 kg) and purified water (189.40 kg) were added to the reaction vessel, stirred, and allowed to stand to separate the aqueous and organic phases. The aqueous phase was washed once with ethyl acetate (102.50 kg); the organic phases were combined and washed with purified water (189.40 kg). The organic phase was concentrated under reduced pressure, and methyl tert-butyl ether (84.10 kg) was added. The temperature was lowered to 5±5℃, and the mixture was stirred to induce crystallization for 2 hours. The solid and liquid phases were separated by centrifugation to obtain the wet product of compound II. (A small amount of the wet product can be taken, and its loss on drying can be measured using a moisture analyzer, and the dry weight calculation can be performed; the dry weight of compound II is 35.95 kg).
[0038] The wet product of Formula II compound is decolorized with activated carbon and then dried under reduced pressure at 50±5℃.
[0039] Example 2
[0040] Under nitrogen protection, compound III (37.89 kg) and 1,4-dioxane (195.85 kg) were added to a reactor, stirred, and the temperature was controlled at 20±3℃. Isopropylamine (52.28 kg) was then added to the reactor. After the addition was complete, the mixture was stirred at 20±3℃ for 1.5±0.5 h, and then stirred at 55±5℃ for 5±1 h.
[0041] Cool the reaction solution to 20±3℃, then add isopropylamine (26.14 kg) to the reactor; after addition, stir the reaction mixture at 20±3℃ for 1.5±0.5 h, then stir it again at 55±5℃ for 5±1 h. (This step is repeated 4 times.)
[0042] The reaction solution was concentrated under reduced pressure at a controlled temperature of 50±5℃ until almost no droplets remained. Ethyl acetate (170.85 kg) and purified water (189.40 kg) were added to the reaction vessel, stirred, and allowed to stand to separate the aqueous and organic phases. The aqueous phase was washed once with ethyl acetate (102.50 kg); the organic phases were combined and washed with purified water (189.40 kg). The organic phase was concentrated under reduced pressure, and methyl tert-butyl ether (84.10 kg) was added. The temperature was lowered to 5±5℃, and the mixture was stirred to induce crystallization for 2 hours. The solid and liquid phases were separated by centrifugation to obtain the wet product of compound II.
[0043] The wet product of Formula II compound can be dried under reduced pressure at 50±5℃; it can also be decolorized with activated carbon and then dried under reduced pressure.
[0044] Example 3
[0045] Under nitrogen protection, compound III (37.89 kg) and 1,4-dioxane (195.85 kg) were added to a reactor, stirred, and the temperature was controlled at 20±3℃. Isopropylamine (52.28 kg) was then added to the reactor. After the addition was complete, the mixture was stirred at 20±3℃ for 1.5±0.5 h, and then stirred at 55±5℃ for 5±1 h.
[0046] Cool the reaction solution to 20±3℃, then add isopropylamine (26.14 kg) to the reactor; after addition, stir the reaction mixture at 20±3℃ for 1.5±0.5 h, then stir it again at 55±5℃ for 5±1 h. (This step is repeated 3 times.)
[0047] The reaction solution was concentrated under reduced pressure at a controlled temperature of 50±5℃ until almost no droplets remained. Ethyl acetate (170.85 kg) and purified water (189.40 kg) were added to the reaction vessel, stirred, and allowed to stand to separate the aqueous and organic phases. The aqueous phase was washed once with ethyl acetate (102.50 kg); the organic phases were combined and washed with purified water (189.40 kg). The organic phase was concentrated under reduced pressure, and methyl tert-butyl ether (84.10 kg) was added. The temperature was lowered to 5±5℃, and the mixture was stirred to induce crystallization for 2 hours. The solid and liquid phases were separated by centrifugation to obtain the wet product of compound II.
[0048] The wet product of Formula II compound can be dried under reduced pressure at 50±5℃; it can also be decolorized with activated carbon and then dried under reduced pressure.
[0049] Example 4
[0050] Under nitrogen protection, compound III (37.89 kg) and 1,4-dioxane (195.85 kg) were added to a reactor, stirred, and the temperature was controlled at 20±3℃. Isopropylamine (52.28 kg) was then added to the reactor. After the addition was complete, the mixture was stirred at 20±3℃ for 1.5±0.5 h, and then stirred at 55±5℃ for 5±1 h.
[0051] Cool the reaction solution to 20±3℃, then add isopropylamine (26.14 kg) to the reactor; after addition, stir the reaction mixture at 20±3℃ for 1.5±0.5 h, then stir it again at 55±5℃ for 5±1 h. (This step is repeated twice.)
[0052] The reaction solution was concentrated under reduced pressure at a controlled temperature of 50±5℃ until almost no droplets remained. Ethyl acetate (170.85 kg) and purified water (189.40 kg) were added to the reaction vessel, stirred, and allowed to stand to separate the aqueous and organic phases. The aqueous phase was washed once with ethyl acetate (102.50 kg); the organic phases were combined and washed with purified water (189.40 kg). The organic phase was concentrated under reduced pressure, and methyl tert-butyl ether (84.10 kg) was added. The temperature was lowered to 5±5℃, and the mixture was stirred to induce crystallization for 2 hours. The solid and liquid phases were separated by centrifugation to obtain the wet product of compound II.
[0053] The wet product of compound II can be dried under reduced pressure at 50±5℃; it can also be decolorized with activated carbon and then dried under reduced pressure.
[0054] Example 5
[0055] Under nitrogen protection, compound III (37.89 kg) and 1,4-dioxane (195.85 kg) were added to a reactor, stirred, and the temperature was controlled at 20±3℃. Isopropylamine (52.28 kg) was then added to the reactor. After the addition was complete, the mixture was stirred at 20±3℃ for 1.5±0.5 h, and then stirred at 55±5℃ for 5±1 h.
[0056] Cool the reaction solution to 20±3℃, then add isopropylamine (26.14 kg) to the reactor; after addition, stir the reaction mixture at 20±3℃ for 1.5±0.5 h, then stir the reaction mixture at 55±5℃ for 5±1 h. (This step is repeated once.)
[0057] The reaction solution was concentrated under reduced pressure at a controlled temperature of 50±5℃ until almost no droplets remained. Ethyl acetate (170.85 kg) and purified water (189.40 kg) were added to the reaction vessel, stirred, and allowed to stand to separate the aqueous and organic phases. The aqueous phase was washed once with ethyl acetate (102.50 kg); the organic phases were combined and washed with purified water (189.40 kg). The organic phase was concentrated under reduced pressure, and methyl tert-butyl ether (84.10 kg) was added. The temperature was lowered to 5±5℃, and the mixture was stirred to induce crystallization for 2 hours. The solid and liquid phases were separated by centrifugation to obtain the wet product of compound II.
[0058] The wet product of compound II can be dried under reduced pressure at 50±5℃; it can also be decolorized with activated carbon and then dried under reduced pressure.
[0059] Example 6
[0060] Under nitrogen protection, compound III (37.89 kg) and 1,4-dioxane (195.85 kg) were added to a reactor, stirred, and the temperature was controlled at 20±3℃. Isopropylamine (52.28 kg) was then added to the reactor. After the addition was complete, the mixture was stirred at 20±3℃ for 1.5±0.5 h, and then stirred at 55±5℃ for 5±1 h.
[0061] The reaction solution was concentrated under reduced pressure at a controlled temperature of 50±5℃ until almost no droplets remained. Ethyl acetate (170.85 kg) and purified water (189.40 kg) were added to the reaction vessel, stirred, and allowed to stand to separate the aqueous and organic phases. The aqueous phase was washed once with ethyl acetate (102.50 kg); the organic phases were combined and washed with purified water (189.40 kg). The organic phase was concentrated under reduced pressure, and methyl tert-butyl ether (84.10 kg) was added. The temperature was lowered to 5±5℃, and the mixture was stirred to induce crystallization for 2 hours. The solid and liquid phases were separated by centrifugation to obtain the wet product of compound II.
[0062] The wet product of compound II can be dried under reduced pressure at 50±5℃; it can also be decolorized with activated carbon and then dried under reduced pressure.
[0063] Example 7
[0064] Compound II (30.74 kg) and isopropyl acetate (67.10 kg) were added to a reaction vessel and stirred at 35±5℃ for about 20-40 minutes; the mixture was then filtered to obtain a filtrate. The filtrate was heated to 45-55℃, and toluene (53.60 kg) was added dropwise to the reaction vessel; after the addition was complete, the mixture was stirred at 40-45℃ for 5 hours (a large amount of solid was observed to precipitate in the reaction vessel). The temperature was controlled at 40-45℃, and toluene (268.00 kg) was added dropwise to the reaction vessel; after the addition was complete, the mixture was stirred at 40-45℃ for 1.5-2 hours to induce crystallization.
[0065] Slowly cool the reaction solution to 30–35°C and stir to allow crystals to precipitate for 1.5–2 hours; slowly cool the reaction solution to 20–25°C and stir to allow crystals to precipitate for 1.5–2 hours; slowly cool the reaction solution to 10–15°C and stir to allow crystals to precipitate for 1.5–2 hours; slowly cool the reaction solution to 0–5°C and stir to allow crystals to precipitate for 1.5–2 hours.
[0066] The solid and liquid were separated by centrifugation, and the wet product was dried under reduced pressure at 55±5℃ for 5h. The dried product was then pulverized, and the pulverized material was dried under reduced pressure at 75~85℃ for 24h to obtain 23.350kg of maribavir finished product (yield 93.8%; compound of formula I).
[0067] Example 8
[0068] Thermal analysis was performed on the finished product of maribavir from Example 2.
[0069] Differential scanning calorimetry (DSC) showed that the sample had an endothermic peak starting at 197.59℃, with the peak value at 198.04℃. DSC detection indicated that the sample's melting point was 198.04℃.
[0070] Thermogravimetric analysis (TGA) showed that significant weight loss began around 200℃, followed by decomposition. Prior to decomposition, there was no significant weight loss, and corresponding DSC analysis showed no solvent endothermic peaks. This indicates that the sample is a non-solvent compound and does not contain water of crystallization. Above 200℃, sample decomposition intensified, resulting in significant weight loss.
[0071] In Example 7, the finished product of maribavir was subjected to X-ray powder diffraction analysis; the sharp peaks in the X-ray powder diffraction pattern indicated that the finished product of maribavir was a crystalline compound.
Claims
1. A method for preparing maribavir, comprising: (1) The compound of formula III reacts with isopropylamine, the reaction product is concentrated, the concentrated reaction product is mixed with methyl tert-butyl ether, and the compound of formula II is precipitated by cooling. (2) The compound of formula II is mixed with organic solvent B, heated to dissolve, and then mixed with toluene. The compound of formula I is precipitated by cooling.
2. The method according to claim 1, characterized in that, In step (1), the reaction of compound III with isopropylamine includes one or more of the following reaction conditions: (a) The reaction is carried out under nitrogen and / or helium protection; (b) The molar ratio of compound III to isopropylamine is 1:(10-35); (c) The reaction solvent for the reaction of compound III with isopropylamine is 1,4-dioxane; (d) The reaction temperature of compound III with isopropylamine is 50-60℃ and the reaction time is 4-6 hours.
3. The method according to claim 1, characterized in that, In step (1), after the compound of formula III reacts with isopropylamine, the concentrated reaction product is a solvent removed under reduced pressure.
4. The method according to claim 1, characterized in that, In step (1), the molar ratio of compound III to methyl tert-butyl ether is 1: (10-15).
5. The method according to claim 1, characterized in that, In step (1), after adding methyl tert-butyl ether, the cooling process involves lowering the temperature to 0-10°C. o C.
6. The method according to claim 1, characterized in that, In step (2), the organic solvent B is an ester solvent R. 1 C(O)OR 2 ; The R 1 Selected from methyl, ethyl, n-propyl, isopropyl, and n-butyl; The R 2 Selected from methyl, ethyl, n-propyl, isopropyl, and n-butyl.
7. The method according to claim 1, characterized in that, In step (2), the mass-to-volume ratio of compound II to organic solvent B is 1 kg : (2-4) L; Preferably, the mass-to-volume ratio of compound II to organic solvent B is 1 kg : (2-3) L.
8. The method according to claim 1, characterized in that, In step (2), the temperature at which compound I precipitates is 0-45°C. o C; Preferably 0-35 o C; Preferably 0-25 o C; Preferably 0-15 o C; Preferably 0-5 o C.
9. The method according to claim 1, characterized in that, In step (2), the precipitated compound of formula I is separated from the liquid and then dried.
10. A methyl tert-butyl ether solvate of maribavirin, characterized in that, The malivavir methyl tert-butyl ether solvate is shown in Formula II. (Formula II).