Method for continuously preparing deuteromidewvir hydrobromide
Patent Information
- Application Number
- CN202580002514.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Priority Date
- 2023-05-11
- Filing Date
- 2024-05-11
- Publication Date
- 2026-01-16
AI Technical Summary
The current deuterated reaction time is long, and the catalyst uses powder catalyst and has a long filtration time. The non-deuterium impurities produced by hydrogenation of iodoremidevir are difficult to remove, affecting product quality.
The reaction temperature and pressure of iodoremidvir and alkali is carried out by a fixed bed reactor, deuterium gas is introduced, and catalysts such as noble metal-supported catalysts and amorphous nickel are used to control the reaction temperature and pressure, and gas-liquid separation is carried out and deuterium is used. The gas is compressed back for the reaction, and then the hydrobromate solution is added to give deuterimedvir hydrobromate.
The deuterium gas residence time is effectively controlled through a fixed bed reactor, which improves the reaction conversion rate and selectivity, has very few non-deuterium impurities, optimizes product quality, realizes automated continuous production, and reduces the amount of catalyst and reactor volume.
Abstract
Description
A method for continuously preparing deuterated remdesivir hydrobromide Technical Field
[0001] The present invention relates to the field of chemical pharmacy, and more particularly to a method for continuously preparing deuterated remdevir hydrobromide. Background Art
[0002] Deuterated remdesivir hydrobromide is a novel orally available nucleoside compound that can be taken orally against the novel coronavirus. It also exhibits inhibitory activity against other viruses, such as respiratory syncytial virus, dengue virus, hepatitis C virus, and Zika virus. Therefore, research on the synthesis of deuterated remdesivir hydrobromide is of great significance for the prevention and treatment of viral infectious diseases.
[0003] The structural formula of deuterium remdevir hydrobromide is shown in formula (I):
[0004] CN114516875A and CN112778310A both report methods for preparing deuterated remdesivir hydrobromide. The deuteration reactions employed in these methods are kettle-type reactions, which are time-consuming and require a powdered catalyst, leading to lengthy filtration times. Furthermore, the hydrogenation of iodinated remdesivir to deuterated remdesivir produces non-deuterium impurities, as shown in the structure (II). These non-deuterium impurities are difficult to remove in subsequent refining steps and instead accumulate and increase, becoming key impurities that affect product quality.
[0005] The structural formula of non-deuterium impurities is shown in formula (II):
[0006] Therefore, it is necessary to develop a preparation method for deuterium remdevir hydrobromide to effectively control the content of non-deuterium impurities and achieve stable product quality.
[0007] Summary of the Invention
[0008] 1. The first aspect of the present invention is to provide a method for continuously preparing deuterated remdesivir, characterized in that it comprises the following steps:
[0009] (1) preparing a mixture of iodinated remidevir and a base, inputting the mixture into a fixed bed reactor filled with a catalyst, and simultaneously introducing deuterium gas to react;
[0010] In some embodiments, the solvent of the mixed solution in step (1) is any one or more of methyl tert-butyl ether, tetrahydrofuran, acetonitrile, and ethyl acetate; preferably, it is methyl tert-butyl ether.
[0011] In some embodiments, the reaction temperature in step (1) is 15 to 50° C., preferably 25 to 35° C.; the reaction pressure is 1.0 to 3.0 MPa, preferably 1.0 to 1.6 MPa; the space velocity of the input iodinated remidevir is 0.01 to 10.0 h -1 , preferably, 0.1 to 3 hours -1 .
[0012] In some embodiments, the catalyst in step (1) includes any one or more combinations of noble metal supported catalysts, amorphous nickel, and Raney nickel.
[0013] In some embodiments, the precious metal in the precious metal-supported catalyst includes any one or more combinations of platinum, palladium, nickel or rhodium, and the carrier includes any one or more combinations of activated carbon, silica or alumina; preferably, the precious metal-supported catalyst is palladium-carbon.
[0014] In some embodiments, the base in step (1) is a combination of one or more of ammonia, triethylamine, N,N-dimethylaniline, diisopropylamine, diisopropylethylamine, and tri-n-butylamine; preferably, it is triethylamine.
[0015] In some embodiments, the mass ratio of the solvent to iodinated remidevir in the mixed solution in step (1) is 4 to 10:1, preferably 5 to 8:1; the mass ratio of the base to iodinated remidevir is 0.1 to 1:1, preferably 0.15 to 0.5:1; the molar ratio of deuterium gas to iodinated remidevir is 2 to 100:1, preferably 25 to 50:1.
[0016] In some embodiments, the method further comprises the steps of:
[0017] (2) After the reaction is completed, the gas and liquid are separated and the deuterium gas is compressed and used again for the reaction.
[0018] The second aspect of the present invention is to provide a method for continuously preparing deuterated remdesivir hydrobromide, characterized in that a hydrobromide solution is added to the reaction solution prepared by the method according to any of the above embodiments to react to obtain deuterated remdesivir hydrobromide.
[0019] In some embodiments, the hydrobromide is hydrobromic acid acetate, the hydrobromide solution is added to the reaction solution in a continuous manner, and the reaction temperature is -5 to 10°C, preferably 0 to 5°C.
[0020] The beneficial effects of the present invention are:
[0021] (1) The fixed bed can control the residence time of deuterium gas in the reaction and adjust the reaction temperature distribution, which is beneficial to improving the conversion rate and selectivity of the reaction;
[0022] (2) The final product obtained by this preparation method contains very few non-deuterium impurities, and the product quality is better;
[0023] (3) The reaction fluid in the fixed bed flows in a plug flow manner, and there is no back-mixing, which enables automated continuous production. The raw material reaction rate is fast, and the amount of catalyst and reactor volume required for the same production capacity are small. DETAILED DESCRIPTION
[0024] In the present invention, "space velocity" refers to the mass of reactants passing through a unit mass of catalyst per unit time;
[0025] In the present invention, "conversion rate" refers to the ratio of the reactants that have reacted to the initial amount of reactants;
[0026] The following examples illustrate the technical solutions of the present invention, but the protection scope of the present invention is not limited thereto.
[0027] Example 1
[0028] Pump iodine remidevir, methyl tert-butyl ether, and triethylamine into a fixed-bed reactor loaded with a Pt / C catalyst. The mass ratio of methyl tert-butyl ether to iodine remidevir is 5:1, and the mass ratio of triethylamine to iodine remidevir is 0.2:1. Deuterium gas is also introduced at a molar ratio of deuterium gas to iodine remidevir of 30:1, maintaining continuous flow. The reaction temperature is controlled at 20°C, the reaction pressure is 1.5 MPa, and the iodine remidevir space velocity is 0.5 h -1 The reaction solution obtained by the reaction was concentrated until no liquid was dripped, and hydrobromic acid and acetic acid solution was continuously added dropwise at 5°C. After filtering and drying, the iodine-substituted remidevir conversion rate was 99.5%, the deuterated remidevir hydrobromide content was 98.15%, and non-deuterium impurities were ≤0.01%.
[0029] Weigh 8 g of the deuterated remdesivir hydrobromide prepared above, add 56 ml of acetonitrile and heat to dissolve, concentrate to remove 28 ml of acetonitrile, then add 20 ml of methyl tert-butyl ether, stir at 55 ° C to dissolve, add 100 ml of methyl tert-butyl ether dropwise to crystallize, cool to 20 ° C and stir for 2 h, filter, and dry the filter cake to obtain the product deuterated remdesivir hydrobromide with a content of 99.40% and non-deuterium impurities ≤ 0.01%.
[0030] Example 2
[0031] Example 2 uses a preparation method similar to that of Example 1, except that the mass ratio of methyl tert-butyl ether to remidevir iodide is 4:1.
[0032] Example 3
[0033] Example 3 uses a preparation method similar to that of Example 1, except that the mass ratio of methyl tert-butyl ether to remidevir iodide is 10:1.
[0034] Example 4
[0035] Example 4 uses a preparation method similar to that of Example 1, except that the molar ratio of deuterium gas to iodinated remidevir is 2:1.
[0036] Example 5
[0037] Example 5 uses a preparation method similar to that of Example 1, except that the reaction temperature is 30°C.
[0038] Example 6
[0039] Example 6 uses a preparation method similar to that of Example 1, except that the space velocity of iodine remidevir is 5h -1 , the reaction temperature is 50℃.
[0040] Example 7
[0041] Example 7 uses a preparation method similar to that of Example 1, except that the reaction pressure is 1.0 MPa.
[0042] Example 8
[0043] Example 8 uses a preparation method similar to that of Example 1, except that the reaction pressure is 3.0 MPa.
[0044] The data of Examples 1-8 are shown in Table 1:
[0045] Table 1
[0046] Comparative Example 1
[0047] Pump iodine remidevir, methyl tert-butyl ether, and triethylamine into a fixed-bed reactor loaded with a Pt / C catalyst. The mass ratio of methyl tert-butyl ether to iodine remidevir is 5:1, and the mass ratio of triethylamine to iodine remidevir is 0.2:1. Deuterium gas is also introduced at a molar ratio of deuterium gas to iodine remidevir of 25:1, maintaining continuous flow. The reaction temperature is controlled at 55°C, the reaction pressure is 1.5 MPa, and the iodine remidevir space velocity is 0.1 h -1 The reaction solution obtained by the reaction was concentrated until no liquid was dripped, and hydrobromic acid and acetic acid solution was continuously added dropwise at 5°C. After filtering and drying, the iodine-substituted remidevir conversion rate was 99.5%, the deuterated remidevir hydrobromide content was 97.13%, and the non-deuterium impurities were 0.78%.
[0048] Weigh 4 g of the deuterated remdesivir hydrobromide prepared above, add 30 ml of acetonitrile and heat to dissolve, concentrate 13.5 ml of acetonitrile, add 8 ml of methyl tert-butyl ether, stir at 55 ° C to dissolve, add 40 ml of methyl tert-butyl ether dropwise to crystallize, cool to 20 ° C and stir for 2 h, filter, and dry the filter cake to obtain pure deuterated remdesivir hydrobromide with a content of 98.9% and a non-deuterium impurity content of 1.01%.
[0049] Comparative Example 2
[0050] Pump iodine remidevir, methyl tert-butyl ether, and triethylamine into a fixed-bed reactor loaded with a Pt / C catalyst. The mass ratio of methyl tert-butyl ether to iodine remidevir is 5:1, and the mass ratio of triethylamine to iodine remidevir is 0.2:1. Deuterium gas is also introduced at a molar ratio of deuterium gas to iodine remidevir of 25:1, maintaining continuous flow. The reaction temperature is controlled at 50°C, the reaction pressure is 1.5 MPa, and the iodine remidevir space velocity is 0.01 h -1 The reaction solution obtained by the reaction was concentrated until no liquid was dripped, and hydrobromic acid and acetic acid solution were continuously added dropwise at 5°C. After filtering and drying, iodine remidevir conversion rate was 99.8%, deuterated remidevir hydrobromide content was 93.22%, and non-deuterium impurities were 3.36%.
[0051] Weigh 5.0 g of the deuterated remdesivir hydrobromide prepared above, add 35 ml of acetonitrile and heat to dissolve, concentrate 17.5 ml of acetonitrile, add 10 ml of methyl tert-butyl ether, stir at 55 ° C to dissolve, add 50 ml of methyl tert-butyl ether dropwise to crystallize, cool to 20 ° C and stir for 2 h, filter, and dry the filter cake to obtain pure deuterated remdesivir hydrobromide with a content of 93.27% and a non-deuterium impurity content of 5.79%.
[0052] Comparative Example 3
[0053] Pt / C catalyst, iodinated remidevir, methyl tert-butyl ether, and triethylamine were added into the autoclave, wherein the mass ratio of methyl tert-butyl ether to iodinated remidevir was 6:1, and the mass ratio of triethylamine to iodinated remidevir was 0.2:1. The reaction temperature was controlled at 30°C, the deuterium gas pressure was maintained at 1.3 MPa, and the reaction was carried out for 20 hours. The reaction solution was concentrated until no liquid was dripped, and hydrobromic acid and acetic acid solution was continuously added dropwise at 0°C. After filtering and drying, a conversion rate of iodinated remidevir was 98.6%, a content of deuterated remidevir hydrobromide was 94.9%, and non-deuterium impurities were 0.73%.
[0054] Weigh 10.0 g of the deuterated remdesivir hydrobromide prepared above, add 70 ml of acetonitrile and heat to dissolve, concentrate 35 ml of acetonitrile, add 20 ml of methyl tert-butyl ether, stir at 55 ° C to dissolve, add 100 ml of methyl tert-butyl ether dropwise to crystallize, cool to 20 ° C and stir for 2 h, filter, and dry the filter cake to obtain pure deuterated remdesivir hydrobromide with a content of 98.7% and a non-deuterium impurity content of 1.15%.
[0055] Comparative Example 4
[0056] Pt / C catalyst, iodinated remidevir, methyl tert-butyl ether, and triethylamine were added into the autoclave, wherein the mass ratio of methyl tert-butyl ether to iodinated remidevir was 6.5:1, and the mass ratio of triethylamine to iodinated remidevir was 0.2:1. The reaction temperature was controlled at 35°C, the deuterium gas pressure was maintained at 1.2 MPa, and the reaction was carried out for 19.5 hours. The reaction solution obtained by the reaction was concentrated until no liquid was dripped, and hydrobromic acid and acetic acid solution was continuously added dropwise at 0°C. After filtering and drying, the iodinated remidevir conversion rate was 97.8%, the deuterated remidevir hydrobromide content was 95.6%, and the non-deuterium impurities were 0.65%.
[0057] Weigh 10.0 g of the deuterated remdesivir hydrobromide prepared above, add 70 ml of acetonitrile and heat to dissolve, concentrate 35 ml of acetonitrile, add 20 ml of methyl tert-butyl ether, stir at 55 ° C to dissolve, add 100 ml of methyl tert-butyl ether dropwise to crystallize, cool to 20 ° C and stir for 2 h, filter, and dry the filter cake to obtain pure deuterated remdesivir hydrobromide with a content of 98.8% and a non-deuterium impurity content of 1.11%.
[0058] Comparative Example 5
[0059] Pt / C catalyst, iodinated remidevir, methyl tert-butyl ether, and triethylamine were added into the autoclave, wherein the mass ratio of methyl tert-butyl ether to iodinated remidevir was 6.0:1, and the mass ratio of triethylamine to iodinated remidevir was 0.2:1. The reaction temperature was controlled at 35°C, the deuterium gas pressure was maintained at 1.3 MPa, and the reaction was carried out for 24 hours. The reaction solution was concentrated until no liquid was dripped, and hydrobromic acid and acetic acid solution was continuously added dropwise at 0°C. After filtering and drying, the iodinated remidevir conversion rate was 98.6%, the deuterated remidevir hydrobromide content was 93.1%, and non-deuterium impurities were 1.22%.
[0060] Weigh 10.0 g of the deuterated remdesivir hydrobromide prepared above, add 70 ml of acetonitrile and heat to dissolve, concentrate 35 ml of acetonitrile, add 20 ml of methyl tert-butyl ether, stir at 55 ° C to dissolve, add 100 ml of methyl tert-butyl ether dropwise to crystallize, cool to 20 ° C and stir for 2 h, filter, and dry the filter cake to obtain pure deuterated remdesivir hydrobromide with a content of 97.19% and a non-deuterium impurity content of 2.03%.
[0061] It should be understood that the above embodiments are exemplary and are not intended to encompass all possible implementations of the claims. Various modifications and variations may be made to the above embodiments without departing from the scope of the present invention. Similarly, the various technical features of the above embodiments may be arbitrarily combined to form additional embodiments of the present invention that may not be explicitly described. Therefore, the above embodiments merely illustrate several implementations of the present invention and do not limit the scope of protection of the patent of the present invention.
Claims
1. A method for continuously preparing deuterated remdevir, characterized in that: The following steps are involved: (1) preparing a mixed solution of iodinated remidevir and a base, inputting the mixed solution into a fixed bed reactor filled with a catalyst, and simultaneously introducing deuterium gas to react; 2. The method according to claim 1, characterized in that The solvent of the mixed solution in step (1) is any one or more of methyl tert-butyl ether, tetrahydrofuran, acetonitrile and ethyl acetate; preferably, it is methyl tert-butyl ether.
3. The method according to claim 1, characterized in that The reaction temperature in step (1) is 15 to 50° C., preferably 25 to 35° C.; the reaction pressure is 1.0 to 3.0 MPa, preferably 1.0 to 1.6 MPa; the space velocity of the input iodine-remidevir is 0.01 to 10.0 h -1 , preferably, 0.1 to 3 h -1 .
4. The method according to claim 1, characterized in that: The catalyst in step (1) includes any one or more combinations of noble metal supported catalysts, amorphous nickel and Raney nickel.
5. The method according to claim 4, characterized in that The precious metal in the precious metal-supported catalyst includes any one or more combinations of platinum, palladium, nickel or rhodium, and the carrier includes any one or more combinations of activated carbon, silicon dioxide or aluminum oxide; preferably, the precious metal-supported catalyst is palladium carbon.
6. The method according to claim 1, characterized in that The base in step (1) is a combination of one or more of ammonia water, triethylamine, N,N-dimethylaniline, diisopropylamine, diisopropylethylamine, tri-n-butylamine; preferably, it is triethylamine.
7. The method according to claim 1, characterized in that The mass ratio of the solvent to iodine remidevir in the mixed solution in step (1) is 4 to 10:1, preferably 5 to 8:1; the mass ratio of the base to iodine remidevir is 0.1 to 1:1, preferably 0.15 to 0.5:1; the molar ratio of deuterium gas to iodine remidevir is 2 to 100:1, preferably 25 to 50:
1.
8. The method according to any one of claims 1 to 7, characterized in that It also includes the following steps: (2) After the reaction is completed, the gas and liquid are separated and the deuterium gas is compressed and used again in the reaction.
9. A method for continuously preparing deuterated remdevir hydrobromide, characterized in that: Add a hydrobromide solution to the reaction solution prepared by the method according to any one of claims 1 to 8 to react and obtain deuterium remidevir hydrobromide.
10. The method according to claim 9, characterized in that The hydrobromide is hydrobromic acid acetate, and the hydrobromide solution is added to the reaction solution in a continuous manner. The reaction temperature is -5 to 10°C, preferably, 0 to 5°C.