Process for the preparation of a ns5b polymerase inhibitor drug intermediate
By improving the synthesis process of sofosbuvir and using TMSOTf and N,O-bis(trimethylsilyl)acetamide as activators for glycosylation, the stereochemical control problem of cytosine glycosylation was solved, achieving efficient and environmentally friendly preparation of nucleoside products and reducing production costs.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- JIANGSU ALPHA PHARM CO LTD
- Filing Date
- 2026-05-28
- Publication Date
- 2026-07-31
AI Technical Summary
In the current synthesis of sofosbuvir, the stereochemistry of the cytosine glycosylation reaction is difficult to control, leading to the formation of α-isomers. Furthermore, the use of tin tetrachloride catalyst presents problems of moisture sensitivity and environmental pollution.
Trimethylsilyl trifluoromethanesulfonate (TMSOTf) was used as a catalyst, combined with N,O-bis(trimethylsilyl)acetamide as an activator, and glycosylation reactions of compounds I and II were carried out in anhydrous 1,2-dichloroethane solvent and anhydrous methanol solvent. Compound III was then treated with sodium methoxide hydrolysis reagent to ensure β-configuration selectivity and absence of active hydrogen.
It achieves highly selective generation of target nucleosides, reduces α-isomer byproducts, avoids corrosive reagents and metal waste, lowers production costs and environmental burden, and simplifies the operation process.
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Figure CN122483121A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical intermediate synthesis technology, specifically a process for preparing NS5B polymerase inhibitor pharmaceutical intermediates. Background Technology
[0002] Sofosbuvir (trade name Sovaldi) is a nucleoside inhibitor of hepatitis C virus (HCV) NS5B polymerase, developed by Gilead Sciences. It was approved by the US FDA in December 2013 and is the world's first oral drug that can effectively treat hepatitis C without the need for combination therapy with interferon. Sofosbuvir is a nucleoside prodrug, its core structure consisting of a cytidine nucleoside analog unit and an aminophosphate prodrug fragment. From retrosynthetic analysis, the nucleoside moiety of sofosbuvir can be constructed through a glycosylation reaction between a cytosine base and a fluoroglycosyl donor (i.e., cytosine glycosylation). The existing reaction route is as follows: This reaction route is one of the key technological pathways in the original sofosbuvir process and related generic routes, and it is also an important technological foundation for the current production of sofosbuvir and related intermediates in the industry. The core challenge of the cytosine glycosylation reaction lies in stereochemical control. In the synthesis of sofosbuvir, it is usually necessary to obtain a nucleoside product with a specific β-configuration, but in actual reactions, the formation of α-isomers often occurs. In the original process, the ratio of the target product to the isomer is approximately 4:1, and about 20% of the material in the reaction solution is isomer byproducts. In addition, in the current original process, the coupling reaction of cytosine with the fluoroglycoside donor uses highly active tin tetrachloride as a Lewis acid catalyst. Although tin tetrachloride has good catalytic activity in the reaction system, its industrial application faces significant obstacles: First, tin tetrachloride is highly sensitive to moisture, and the reaction system must be strictly anhydrous; otherwise, it is very easy to cause side reactions leading to a decrease in yield. Second, the post-reaction processing will generate a large amount of tin-containing solid waste, which not only increases the post-processing cost but also imposes a significant burden on the environment. Summary of the Invention
[0003] To address the above shortcomings, the present invention provides the following technical solution: A process for preparing an NS5B polymerase inhibitor drug intermediate includes the following steps: First, compound II was dissolved in an organic solvent, a silane activator was added, and the mixture was stirred at room temperature for 15–30 min. Then, compound I and a catalyst were added, and the mixture was heated under reflux. The reaction was monitored by HPLC. After the reaction was completed, the product was separated to obtain compound III. In the second step, compound III was dissolved in an organic solvent, a hydrolysis reagent was added, and the reaction was monitored by HPLC. After the reaction was completed, the product was separated to obtain compound IV.
[0004] Furthermore, the solvent used in the first step reaction is anhydrous 1,2-dichloroethane (DCE).
[0005] Furthermore, the catalyst used in the first step reaction is trimethylsilyl trifluoromethanesulfonate (TMSOTf), and the amount used is 1.0 to 1.5 eq.
[0006] Furthermore, the equivalent ratio of compound I to compound II used in the first step reaction is 1:1.
[0007] Furthermore, the activator used in the first step reaction is N,O-bis(trimethylsilyl)acetamide (BSA), in an amount of 1.5–2.0 eq.
[0008] Furthermore, the solvent used in the second step of the reaction is anhydrous methanol.
[0009] Furthermore, the hydrolysis reagent used in the second step reaction is a methanol solution of sodium methoxide.
[0010] Furthermore, in the second step reaction, the hydrolysis reagent used is sodium methoxide in a ratio of 0.1g to 10-50mL to methanol.
[0011] Furthermore, the ratio of the amount of hydrolysis reagent used in the second step reaction to the amount of compound III is compound III: sodium methoxide: methanol = 1g:0.1g:10-50mL.
[0012] Furthermore, the second step reaction is carried out in an ice bath.
[0013] The beneficial effects of this invention are as follows: 1. The reaction route of this invention can obtain the target nucleoside with extremely high β-stereoselectivity, while the absence of an active hydrogen at the N3 position of the pyrimidine ring ensures the regiospecificity of the N1-glycosidic bond. This specific selectivity significantly reduces the generation of byproducts such as the difficult-to-separate α-isomer from the source; 2. The reaction route of this invention avoids the problems of the highly corrosive, easily decomposed, and post-processing-produced solid waste fluorinating agent DAST in the original research route, as well as Lewis acids (such as SnCl4) that generate large amounts of metal waste and tin-containing waste liquid, thus reducing safety risks and the cost of "three wastes" treatment; 3. The reaction route of this invention is short, the reaction steps are simple and efficient, simplifying the operation process, reducing the difficulty of solvent recovery, effectively reducing the total production cost, and conforming to the concept of sustainable development. Attached Figure Description
[0014] Figure 1 This is a schematic diagram of the reaction route of the present invention; Figure 2 This is a schematic diagram of the prior art reaction route of the present invention. Detailed Implementation
[0015] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.
[0016] Example 1
[0017] In the first step, 13.1 g (0.1 mol) of compound II was dissolved in 300 ml of organic solvent, and 1.5 eq of silane activator N,O-bis(trimethylsilyl)acetamide (BSA) was added. The mixture was stirred at room temperature for 15–30 min, and then 1 eq of compound I and 1 eq of catalyst trimethylsilyl trifluoromethanesulfonate (TMSOTf) were added. The mixture was heated to reflux and the reaction was monitored by HPLC. After the reaction was completed, the mixture was carefully quenched with saturated NaHCO3 solution, and the organic phase was separated. The organic phase was washed 2–3 times with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated by evaporation. The product was recrystallized from 50 ml of toluene to obtain 46.0 g of compound III, with a yield of 94.1% and a purity of 98.9%. In the second step, 48.7 g (0.1 mol) of compound III was dissolved in 300 ml of organic solvent, wastewater methanol. A methanol solution of sodium methoxide (0.1 g : 10 mL) was added as a hydrolysis reagent. The ratio of compound III : sodium methoxide : methanol = 1 g : 0.1 g : 10 mL. The reaction was monitored by HPLC. After the reaction was completed, dilute hydrochloric acid was added or the mixture was neutralized. The methanol solvent was evaporated, and the mixture was extracted with 100 ml of dichloromethane. The organic phase was washed 2-3 times with saturated brine, dried over anhydrous sodium sulfate, evaporated and concentrated. The product was recrystallized from 50 ml of toluene to obtain 24.6 g of compound IV, with a yield of 94.5% and a purity of 98.8%.
[0018] Example 2
[0019] First, 13.1 g (0.1 mol) of compound II was dissolved in 300 ml of organic solvent, and 2.0 eq (0.2 mol) of silane activator N,O-bis(trimethylsilyl)acetamide (BSA) was added. The mixture was stirred at room temperature for 15–30 min, and then 1 eq of compound I and 1 eq of catalyst trimethylsilyl trifluoromethanesulfonate (TMSOTf) were added. The mixture was heated to reflux and the reaction was monitored by HPLC. After the reaction was completed, the mixture was carefully quenched with saturated NaHCO3 solution, and the organic phase was separated. The organic phase was washed 2–3 times with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated by evaporation. The product was recrystallized from 50 ml of toluene to obtain 45.8 g of compound III, with a yield of 93.9% and a purity of 98.8%. Example 3
[0020] In the first step, 13.1 g (0.1 mol) of compound II was dissolved in 300 ml of organic solvent, and 1.5 eq of silane activator N,O-bis(trimethylsilyl)acetamide (BSA) was added. The mixture was stirred at room temperature for 15–30 min, and then 1 eq of compound I and 1.5 eq of catalyst trimethylsilyl trifluoromethanesulfonate (TMSOTf) were added. The mixture was heated to reflux and the reaction was monitored by HPLC. After the reaction was completed, the mixture was carefully quenched with saturated NaHCO3 solution, and the organic phase was separated. The organic phase was washed 2–3 times with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated by evaporation. The product was recrystallized from 50 ml of toluene to obtain 46.3 g of compound III, with a yield of 94.7% and a purity of 98.9%. Example 4
[0021] In the second step, 48.7 g (0.1 mol) of compound III was dissolved in 300 ml of organic solvent, wastewater methanol. A methanol solution of sodium methoxide (0.1 g : 20 mL) was added as a hydrolysis reagent. The ratio of compound III : sodium methoxide : methanol = 1 g : 0.1 g : 20 mL. The reaction was monitored by HPLC. After the reaction was completed, dilute hydrochloric acid was added or the mixture was neutralized. The methanol solvent was evaporated, and the mixture was extracted with 100 ml of dichloromethane. The organic phase was washed 2-3 times with saturated brine, dried over anhydrous sodium sulfate, evaporated and concentrated. The product was recrystallized from 50 ml of toluene to obtain 24.6 g of compound IV, with a yield of 95.3% and a purity of 98.9%.
[0022] Example 5
[0023] In the second step, 48.7 g (0.1 mol) of compound III was dissolved in 300 ml of organic solvent, wastewater methanol. A methanol solution of sodium methoxide (0.1 g : 50 mL) was added as a hydrolysis reagent. The ratio of compound III : sodium methoxide : methanol = 1 g : 0.1 g : 50 mL. The reaction was monitored by HPLC. After the reaction was completed, dilute hydrochloric acid was added or the mixture was neutralized. The methanol solvent was evaporated, and the mixture was extracted with 100 ml of dichloromethane. The organic phase was washed 2-3 times with saturated brine, dried over anhydrous sodium sulfate, evaporated and concentrated. The product was recrystallized from 50 ml of toluene to obtain 24.5 g of compound IV, with a yield of 94.1% and a purity of 98.6%.
[0024] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from its spirit or essential characteristics. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, all variations falling within the meaning and scope of equivalents of the claims are intended to be included within the present invention. No reference numerals in the claims should be construed as limiting the scope of the claims.
[0025] Furthermore, it should be understood that although this specification describes embodiments, not every embodiment contains only one independent technical solution. This narrative style is merely for clarity. Those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.
Claims
1. A process for the preparation of an NS5B polymerase inhibitor pharmaceutical intermediate characterized in that Includes the following steps: First, compound II was dissolved in an organic solvent, a silane activator was added, and the mixture was stirred at room temperature for 15–30 min. Then, compound I and a catalyst were added, and the mixture was heated under reflux. The reaction was monitored by HPLC. After the reaction was completed, the product was separated to obtain compound III. In the second step, compound III was dissolved in an organic solvent, a hydrolysis reagent was added, and the reaction was monitored by HPLC. After the reaction was completed, the product was separated to obtain compound IV.
2. A process for the preparation of an NS5B polymerase inhibitor pharmaceutical intermediate according to claim 1, characterized by: The solvent used in the first step reaction is anhydrous 1,2-dichloroethane (DCE).
3. A process for the preparation of an NS5B polymerase inhibitor pharmaceutical intermediate according to claim 1, characterized by: The catalyst used in the first step reaction is trimethylsilyl trifluoromethanesulfonate (TMSOTf), and the amount used is 1.0 to 1.5 eq.
4. The process according to claim 1 for the preparation of a NS5B polymerase inhibitor pharmaceutical intermediate, characterized by: The equivalent ratio of compound I to compound II used in the first step reaction is 1:
1.
5. The process for the preparation of a NS5B polymerase inhibitor pharmaceutical intermediate according to claim 1, characterized in that: The activator used in the first step reaction is N,O-bis(trimethylsilyl)acetamide (BSA), in an amount of 1.5–2.0 eq.
6. A process for the preparation of an NS5B polymerase inhibitor pharmaceutical intermediate according to claim 1, characterized by: The solvent used in the second step of the reaction is anhydrous methanol.
7. The preparation process of an NS5B polymerase inhibitor drug intermediate according to claim 1, characterized in that: The hydrolysis reagent used in the second step reaction is a methanol solution of sodium methoxide.
8. The preparation process of an NS5B polymerase inhibitor drug intermediate according to claim 7, characterized in that: In the second step of the reaction, the ratio of sodium methoxide to methanol in the hydrolysis reagent is 0.1 g : 10-50 mL.
9. The preparation process of an NS5B polymerase inhibitor drug intermediate according to claim 8, characterized in that: The ratio of the amount of hydrolysis reagent used in the second step reaction to the amount of compound III is compound III: sodium methoxide: methanol = 1g: 0.1g: 10-50mL.
10. The preparation process of an NS5B polymerase inhibitor drug intermediate according to claim 1, characterized in that: The second step of the reaction was carried out in an ice bath.