A method for preparing a remdesivir intermediate, GS-441524

Abstract

The application relates to the technical field of medicine synthesis, and discloses a preparation method of a remdesivir intermediate GS-441524, which comprises the following steps: taking pyrrolo[2,1-F][1,2,4]triazine-4-amine and D-ribose as raw materials, reacting to obtain an intermediate II, then subjecting the intermediate II to a hydroxyl protecting group reaction, a cyanation reaction and a hydroxyl deprotecting group reaction to obtain the GS-441524, the synthetic route is short, the total yield is high, and the method is suitable for large-scale synthesis.

Description

Technical Field

[0001] This invention relates to the field of drug synthesis technology, and in particular to a method for preparing a remdesivir intermediate GS-441524. Background Technology

[0002] The novel coronavirus (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and has infected nearly 1 billion people. COVID-19 has had a significant impact on the economic development of my country and the world.

[0003] Remdesivir, an RNA-dependent RNA polymerase (RdRp) inhibitor, achieves its antiviral effect by inhibiting viral nucleic acid replication. It was one of the first drugs marketed to treat SARS-CoV-2 infection since the outbreak of the pandemic. Despite its good clinical efficacy, the application and accessibility of remdesivir are limited due to its complex prodrug form, lengthy synthesis steps (J.Med.Chem.2017,60,1648-1661), and especially the cumbersome synthesis of its intermediate GS-441524.

[0004] The structure of GS-441524 is shown in Formula I. Its chemical name is (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-F][1,2,4]triazine-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carboxynitrile, and its CAS number is 1191237-69-0.

[0005]

[0006] Structure of Formula I GS-441524

[0007] Gilead Sciences has reported a synthetic route for remdesivir (Formula 1). This route starts with 7-iodopyrrole[2,1-F][1,2,4]triazine-4-amine and 2,3,5-tribenzyloxy-D-ribonucleoside-1,4-lactone, and proceeds via lithium halide exchange, asymmetric cyanolation, and debenzylation to obtain compound GS-441524. This route involves strong bases, ultra-low temperatures, and the protection and deprotection of the hydroxyl groups of ribose, making it very cumbersome and unsuitable for industrial application.

[0008]

[0009] Formula 1: Synthetic route of Gilead Sciences GS-441524

[0010] In 2021, the German List group published a simpler method (Equation 2) in Angew.Chem.Int.Ed.2022,61,e202114619.

[0011]

[0012] Formula 2 List group synthesis GS-441524 route

[0013] First, pyrrole[2,1-F][1,2,4]triazine-4-amine is directly affinity-added to D-ribose, then the hydroxyl group is protected with an acetyl group, and finally GS-441524 is synthesized via Mn-catalyzed CH oxidation and deoxycyanation. However, the Mn-catalyzed CH oxidation in this route involves complex catalyst synthesis. The added PhIO is difficult to process, and the highly toxic benzene used as a solvent is environmentally unfriendly. Summary of the Invention

[0014] Therefore, there is a need to provide a method for preparing the remdesivir intermediate GS-441524, in order to solve the problems of long synthesis routes, low yields, and unsuitability for large-scale production in the existing technology for the synthesis of remdesivir intermediate GS-441524.

[0015] To achieve the above objectives, the present invention provides a method for preparing the remdesivir intermediate GS-441524, comprising the following steps:

[0016] (1) Using pyrrole[2,1-F][1,2,4]triazine-4-amine and D-ribose as starting materials, intermediate II was obtained by reaction, and the reaction formula is as follows:

[0017]

[0018] (2) Intermediate II undergoes a protecting group reaction on its hydroxyl group to obtain intermediate III, the structural formula of which is as follows:

[0019]

[0020] III,PG: Protective base

[0021] (3) Intermediate III undergoes a cyanation reaction to obtain intermediate IV, the structural formula of which is as follows:

[0022]

[0023] (4) Intermediate IV undergoes a hydroxyl deprotection reaction to obtain GS-441524.

[0024] Furthermore, in step (1), the reaction is catalyzed using a first catalyst in a first solvent to prepare intermediate II.

[0025] Furthermore, the first catalyst is selected from one of trimethylsilyl trifluoromethanesulfonate, triethylsilyl trifluoromethanesulfonate, and trimethylsilylmethanesulfonate; and / or

[0026] The first solvent is selected from one or more of N,O-bis(trimethylsilyl)trifluoroacetamide, trifluoroacetamide, acetamide, N,N-dimethylacetamide, and N,N-dimethylformamide.

[0027] Preferably, the reaction solvent is selected from N,O-bis(trimethylsilyl)trifluoroacetamide.

[0028] Preferably, the catalyst is selected from trimethylsilyl trifluoromethanesulfonate.

[0029] Preferably, in step (1), the reaction temperature is 0℃~100℃.

[0030] Preferably, the ratio of pyrrole[2,1-F][1,2,4]triazine-4-amine to D-ribose is 1:1 to 1.5:1.

[0031] Furthermore, in step (2), intermediate II and the hydroxyl protecting agent react under the action of the first base and the second catalyst to obtain intermediate III with a hydroxyl protecting group.

[0032] Furthermore, the protecting group on intermediate III is selected from one of acetyl, trifluoroacetyl, methoxycarbonyl, allyl, allyloxycarbonyl, tert-butoxycarbonyl, trimethylsilylethoxymethyl, and benzyloxycarbonyl.

[0033] Preferably, the protecting group is selected from acetyl, trifluoroacetyl, or methoxycarbonyl; more preferably, the protecting group is selected from acetyl.

[0034] Furthermore, in step (2), the first base is selected from one or more of triethylamine, pyridine, and morpholine; and / or

[0035] In step (2), the second catalyst is selected from 4-dimethylaminopyridine.

[0036] Preferably, in step (2), the reaction temperature is 0℃~150℃.

[0037] Furthermore, in step (3), intermediate III and trimethylcyanosilane react in a second solvent under the combined action of a third catalyst, ligand and oxidant to obtain intermediate IV.

[0038] Furthermore, the third catalyst is selected from one or more of cuprous acetate, ketone iodide, cuprous trifluoromethanesulfonate, cuprous bromide, cuprous chloride, copper acetate, copper iodide, copper trifluoromethanesulfonate, copper bromide, and copper chloride; and / or

[0039] In step (3), the ligand is selected from one of (3AS,3'AS,8AR,8'AR)-2,2'-cyclopentylbis[3A,8A-dihydro-8H-indeno[1,2-D]oxazole, (3AR,3'AR,8AS,8'AS)-2,2'-isopropylidenebis[3A,8A-dihydro-8H-indeno[1,2-D]oxazole], (4R,4'R)-2,2'-cyclopentylbis[4,5-dihydro-4-benzyl]oxazole, and (4S,4'S)-2,2'-cyclopentylbis[4-tert-butyl-4,5-dihydrooxazole]; and / or

[0040] In step (3), the oxidant is selected from one or more of N-fluorobisbenzenesulfonamide, potassium persulfate complex salt, peroxybenzoic acid, and peroxytert-butanol; and / or

[0041] In step (3), the second solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, acetone, 1,4-dioxane, acetonitrile, diethylene glycol dimethyl ether, toluene, xylene and dichloromethane.

[0042] Preferably, the third catalyst is selected from cuprous acetate or iodide.

[0043] Preferably, in step (3), the reaction temperature is 20℃~200℃.

[0044] Furthermore, in step (4), intermediate IV and the second base react in a third solvent to obtain GS-441524.

[0045] Furthermore, in step (4), the third solvent is selected from one or more of methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, 1,4-dioxane, and acetonitrile; and / or

[0046] In step (4), the second base is selected from one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium carbonate, cesium carbonate, and sodium hydride.

[0047] Preferably, in step (4), the reaction temperature is 10℃~150℃.

[0048] The above technical solution has the following beneficial effects:

[0049] In step 1 of this invention, pyrrole[2,1-F][1,2,4]triazine-4-amine reacts directly with D-ribose to obtain intermediate II. The reaction process is simple and does not require a metal catalyst. After intermediate II is protected with a protecting group, then cyano-treated, and finally deprotected to obtain remdesivir intermediate GS-441524. The entire synthetic route is short, effectively improving the synthetic yield of remdesivir intermediate GS-441524. Moreover, the process conditions are mild, the raw material cost is low, and it is suitable for large-scale production. Attached Figure Description

[0050] Figure 1 The synthetic route diagram for the remdesivir intermediate GS-441524 described in the specific implementation method is shown below. Detailed Implementation

[0051] To explain in detail the technical content, structural features, objectives, and effects of the technical solution, the following description is provided in conjunction with specific embodiments and accompanying drawings.

[0052] The synthetic route diagram of the remdesivir intermediate GS-441524 in this invention is attached. Figure 1 As shown.

[0053] Example 1: Preparation of intermediate formula II

[0054]

[0055] In a 2000 mL three-necked flask, trimethylsilyl trifluoromethanesulfonate (6.8 mL, 37.5 mmol), pyrrole[2,1-F][1,2,4]triazine-4-amine (24.1 g, 180 mmol), D-ribose (22.5 g, 150 mmol), and N,O-bis(trimethylsilyl)trifluoroacetamide (400 mL, 1500 mmol) were added sequentially, and the mixture was reacted at 50 °C for 72 hours. After the reaction was complete, hydrochloric acid solution (1500 mL, 4 M 1,4-dioxane, 6000 mmol) was added to the system, and the reaction was continued for 24 hours. The mixture was filtered, and the solid was washed with 300 mL of methyl tert-butyl ether and dried to give 35.9 g of a white solid product, i.e., intermediate formula II, with a purity of 93% and a yield of 90%. The product was confirmed by mass spectrometry, and the result was: MS (ESI): [M+H]+267.10.

[0056] Example 2 Preparation of intermediate formula III

[0057]

[0058] In a 500 mL three-necked flask, 1.8 g (15 mmol) of 4-dimethylaminopyridine, 220 mL (158 mmol) of triethylamine, 64 mL (677 mmol) of acetic anhydride, and 35.9 g (135 mmol) of intermediate II prepared in Example 1 were added sequentially, and the mixture was reacted at 30 °C for 20 hours. After the reaction was completed, the reaction mixture was added to 500 mL of ethyl acetate, followed by 500 mL of water. The mixture was extracted and separated. The residue obtained by rotary evaporation of the organic phase was added to 200 mL of isopropyl ether, and a solid precipitated was obtained. The solid was filtered and dried to give 50.6 g of white solid product, namely intermediate III, with a purity of 90% and a yield of 86%. The product was confirmed by mass spectrometry, and the result was: MS (ESI): [M+H]+435.15.

[0059] Example 3: Preparation of intermediate formula IV

[0060]

[0061] In a 500 mL three-necked flask, intermediate III (50.6 g, 116 mmol) prepared in Example 2, (3AS,3'AS,8AR,8'AR)-2,2'-cyclopentylbis[3A,8A-dihydro-8H-indeno[1,2-D]oxazole (6.7 g, 17.4 mmol), cuprous acetate (2.2 g, 17.4 mmol), N-fluorobisbenzenesulfonamide (54.8 g, 174 mmol), trimethylcyanosilane (23.0 g, 232 mmol), and 200 mL of toluene were added sequentially, and the mixture was reacted at 40 °C for 20 hours. After the reaction was complete, 200 mL of dilute acid solution was added to the system. The mixture was separated, and the organic phase was washed with 200 mL of water. After separation, the residue obtained by rotary evaporation of the organic phase was added to a mixture of toluene and n-hexane in 200 mL. A solid precipitated, which was filtered and dried to give 45.5 g of a white solid product, i.e., intermediate IV, with a purity of 95% and a yield of 85%. The product was confirmed by mass spectrometry, and the result was: MS(ESI): [M+H]+460.15.

[0062] Example 4: Preparation of intermediate formula IV

[0063] In a 500 mL three-necked flask, intermediate III (50.6 g, 116 mmol) prepared in Example 2, (3AS,3'AS,8AR,8'AR)-2,2'-cyclopentylbis[3A,8A-dihydro-8H-indeno[1,2-D]oxazole (6.7 g, 17.4 mmol), cuprous iodide (3.3 g, 17.4 mmol), N-fluorobisbenzenesulfonamide (54.8 g, 174 mmol), trimethylcyanosilane (23.0 g, 232 mmol) and 200 mL of toluene were added sequentially, and the mixture was reacted at 40 °C for 20 hours. After the reaction was completed, 200 mL of dilute acid solution was added to the system, and the mixture was separated. The organic phase was washed with 200 mL of water, separated, and the residue obtained by rotary evaporation of the organic phase was added to a mixture of 200 mL of toluene and n-hexane. A solid precipitated, which was filtered and dried to obtain 42.8 g of white solid product, i.e. intermediate IV, with a purity of 93% and a yield of 80%.

[0064] Example 5: Preparation of intermediate formula IV

[0065] In a 500 mL three-necked flask, intermediate III (50.6 g, 116 mmol) prepared in Example 2, (3AR,3'AR,8AS,8'AS)-2,2'-isopropylidene bis[3A,8A-dihydro-8H-indeno[1,2-D]oxazole] (6.2 g, 17.4 mmol), cuprous acetate (2.2 g, 17.4 mmol), N-fluorobisbenzenesulfonamide (54.8 g, 174 mmol), trimethylcyanosilane (23.0 g, 232 mmol) and 200 mL of toluene were added sequentially, and the mixture was reacted at 40 °C for 20 hours. After the reaction was completed, 200 mL of dilute acid solution was added to the system, and the mixture was separated. The organic phase was washed with 200 mL of water, separated, and the residue obtained by rotary evaporation of the organic phase was added to a mixture of 200 mL of toluene and n-hexane. A solid precipitated, which was filtered and dried to obtain 41.8 g of white solid product, i.e. intermediate IV, with a purity of 90% and a yield of 78%.

[0066] Example 6: Preparation of intermediate GS-441524

[0067]

[0068] Intermediate IV (45.5 g, 99 mmol) prepared in Example 3, sodium methoxide (1.6 g, 29.7 mmol), and 200 mL of methanol were added to a 500 mL three-necked flask and reacted at 30 °C for 5 h. After the reaction was complete, the mixture was filtered, and the solid was added to 100 mL of a mixed solvent of methanol and n-hexane. After 20 hours, the mixture was filtered again, and the solid was dried to obtain 26.5 g of GS-441524 with a purity of 96% and a yield of 92%. The structure of the obtained product was confirmed by mass spectrometry and nuclear magnetic resonance, and the results were as follows:

[0069] 1 H-NMR (600MHz, DMSO-d6) δ7.91(s,1H),7.89(s,2H),6.90(d,J=4.5Hz,1H),6.88(d,J=4.5Hz,1H),6.09(s,1H),5.19(d,J=4.5Hz,1H),4.91(t,J=5 .7Hz,1H),4.64(d,J=5.1Hz,1H),4.09–4.03(m,1H),3.96(d,J=5.9Hz,1H ), 3.64(ddd,J=12.2,5.1,3.4Hz,1H), 3.51(ddd,J=12.1,6.1,4.5Hz,1H).

[0070] 13 C-NMR (151MHz, DMSO-d6) δ155.6,147.9,123.9,117.3,116.5,110.8,100.8,85.4,78.5,74.2,70.1,60.9.

[0071] HRMS(ESI+) calculated for C 12 H 14 N5O4[M+H]+292.1040,found292.1039.

[0072] Example 7 Preparation of intermediate formula III

[0073]

[0074] In a 500 mL three-necked flask, 1.8 g (15 mmol) of 4-dimethylaminopyridine, 220 mL (158 mmol) of triethylamine, 70 mL (677 mmol) of trifluoroacetic anhydride, and 35.9 g (135 mmol) of intermediate II prepared in Example 1 were added sequentially, and the mixture was reacted at 30 °C for 20 hours. After the reaction was completed, the reaction mixture was added to 500 mL of ethyl acetate, followed by 500 mL of water. The mixture was extracted and separated. The residue obtained by rotary evaporation of the organic phase was added to 200 mL of isopropyl ether, and a solid precipitated was obtained. The solid was filtered and dried to give 74.7 g of a white solid product, namely intermediate III, with a purity of 89% and a yield of 85%. The product was confirmed by mass spectrometry, and the result was: MS (ESI): [M+H]+651.10.

[0075] Example 8: Preparation of intermediate formula IV

[0076]

[0077] In a 500 mL three-necked flask, intermediate III (74.7 g, 115 mmol) prepared in Example 7, (3AS,3'AS,8AR,8'AR)-2,2'-cyclopentylbis[3A,8A-dihydro-8H-indeno[1,2-D]oxazole (6.7 g, 17.4 mmol), cuprous acetate (2.2 g, 17.4 mmol), N-fluorobisbenzenesulfonamide (54.8 g, 174 mmol), trimethylcyanosilane (23.0 g, 232 mmol), and 200 mL of toluene were added sequentially, and the mixture was reacted at 40 °C for 20 hours. After the reaction was complete, 200 mL of dilute acid solution was added to the system. The mixture was separated, and the organic phase was washed with 200 mL of water. After separation, the residue obtained by rotary evaporation of the organic phase was added to 200 mL of a mixture of toluene and n-hexane, precipitating a solid. The solid was filtered and dried to obtain 65.3 g of a white solid product, i.e., intermediate IV, with a purity of 92% and a yield of 84%. The obtained product was confirmed by mass spectrometry, and the result was: MS(ESI): [M+H]+676.16.

[0078] Example 9: Preparation of GS-441524

[0079]

[0080] Intermediate IV (65.3 g, 96.6 mmol) prepared in Example 8, sodium methoxide (1.6 g, 29.7 mmol), and 200 mL of methanol were added to a 500 mL three-necked flask and reacted at 30 °C for 5 h. After the reaction was complete, the mixture was filtered, and the solid was added to 100 mL of a mixed solvent of methanol and n-hexane. After 20 hours, the mixture was filtered again, and the solid was dried to obtain 25.3 g of GS-441524 with a purity of 94% and a yield of 90%.

[0081] Example 10 Preparation of intermediate formula II

[0082] Unlike Example 1, triethylsilyl trifluoromethanesulfonate was used as a catalyst and trifluoroacetamide as a solvent to prepare intermediate formula II with a purity of 90% and a yield of 87%.

[0083] Example 11 Preparation of intermediate formula II

[0084] Unlike Example 1, trimethylsilylmethanesulfonate was used as a catalyst and N,O-bis(trimethylsilyl)trifluoroacetamide was used as a solvent to prepare intermediate formula II with a purity of 91% and a yield of 85%.

[0085] Example 12 Preparation of intermediate formula II

[0086] Unlike Example 1, trimethylsilylmethanesulfonate was used as a catalyst and N,O-bis(trimethylsilyl)trifluoroacetamide was used as a solvent to prepare intermediate formula II with a purity of 87% and a yield of 83%.

[0087] Example 13 Preparation of intermediate formula II

[0088] Unlike Example 1, the reaction feed amounts were pyrrole[2,1-F][1,2,4]triazine-4-amine (150 mmol) and D-ribose (150 mmol) in a molar ratio of 1:1, yielding intermediate formula II with a purity of 89% and a yield of 82%.

[0089] Example 14 Preparation of intermediate formula II

[0090] Unlike Example 1, the reaction feed amounts were pyrrole[2,1-F][1,2,4]triazine-4-amine (225 mmol) and D-ribose (150 mmol) in a molar ratio of 1.5:1, yielding intermediate formula II with a purity of 88% and a yield of 92%.

[0091] It should be noted that, in this document, relational terms such as "first" and "second" are used only to distinguish one entity or operation from another, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Furthermore, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or terminal device that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or terminal device. Unless otherwise specified, an element defined by the phrase "comprising..." or "including..." does not exclude the presence of additional elements in the process, method, article, or terminal device that includes said element. Additionally, in this document, "greater than," "less than," "exceeding," etc., are understood to exclude the stated number; "above," "below," "within," etc., are understood to include the stated number.

[0092] Although the above embodiments have been described, those skilled in the art, once they understand the basic inventive concept, can make other changes and modifications to these embodiments. Therefore, the above descriptions are merely embodiments of the present invention and do not limit the scope of patent protection of the present invention. Any equivalent structural or procedural transformations made using the content of the present invention's specification and drawings, or direct or indirect applications in other related technical fields, are similarly included within the scope of patent protection of the present invention.

Claims

1. A method of preparing GS-441524, an intermediate of remdesivir, characterized in that, The method comprises the following steps: (1) using pyrrolo[2,1-F][1,2,4]triazine-4-amine and D-ribose as raw materials, a first catalyst is used to catalyze the reaction in a first solvent to obtain intermediate II; (2) intermediate II and a hydroxyl protection reagent are reacted under the action of a first base and a second catalyst to obtain intermediate III with a hydroxyl protection group; the hydroxyl protection group PG on intermediate III is selected from one of acetyl, trifluoroacetyl, pivaloyl, allyl, allyloxycarbonyl, tert-butyloxycarbonyl, trimethylsilyl ethoxymethyl and benzyl oxycarbonyl; (3) intermediate III and trimethyl cyanosilane are reacted in a second solvent under the joint action of a third catalyst, a ligand and an oxidant to obtain intermediate IV through cyanation; the third catalyst is selected from one or more of acetic acid cuprous, iodine cuprous, trifluoromethanesulfonic acid cuprous, bromide cuprous, chloride cuprous, acetic acid copper, iodine copper, trifluoromethanesulfonic acid copper, bromide copper and chloride copper; the ligand is selected from one of (3AS,3'AS,8AR,8'AR)-2,2'-cyclopentylidene bis[3A,8A-dihydro-8H-indeno[1,2-D]oxazole, (3AR,3'AR,8AS,8'AS)-2,2'-isopropylidene bis[3A,8A-dihydro-8H-indeno[1,2-D]oxazole], (4R,4'R)-2,2'-cyclopentylidene bis[4,5-dihydro-4-benzyl]oxazole and (4S,4'S)-2,2'-cyclopentylidene bis[4-tert-butyl-4,5-dihydrooxazole]; the oxidant is selected from one or more of N-fluorobenzene sulfonamide, potassium monopersulfate composite salt, peroxybenzoic acid and peroxy tert-butyl alcohol; (4) intermediate IV is subjected to a hydroxyl deprotection group reaction to obtain GS-441524, The reaction formula is as follows: 。 2. The process for the preparation of Remdesivir intermediate GS-441524 as claimed in claim 1 wherein, In step (1), the first catalyst is selected from one of trimethylsilyl triflate, triethylsilyl triflate and trimethylsilyl methane sulfonate.

3. The process for the preparation of Remdesivir intermediate GS-441524 as claimed in claim 1 wherein, The first solvent is selected from one or more of N,O-bis(trimethylsilyl) trifluoroacetamide, trifluoroacetamide, acetamide, N,N-dimethylacetamide and N,N-dimethylformamide.

4. The process for the preparation of Remdesivir intermediate GS-441524 as claimed in claim 1 wherein, The feeding amount of pyrrolo[2,1-F][1,2,4]triazine-4-amine and D-ribose is 1:1 to 1.5:

1.

5. The process for the preparation of Remdesivir intermediate GS-441524 as claimed in claim 1 wherein, In step (1), the reaction temperature is 0-100°C.

6. The process for the preparation of Remdesivir intermediate GS-441524 as claimed in claim 1 wherein, In step (2), the reaction temperature is 0-150°C.

7. The process for the preparation of Remdesivir intermediate GS-441524 as claimed in claim 1 wherein, In step (2), the first base is selected from one or more of triethylamine, pyridine and morpholine.

8. The process for the preparation of Remdesivir intermediate GS-441524 as claimed in claim 1 wherein, In step (2), the second catalyst is selected from 4-dimethylaminopyridine.

9. The process for the preparation of Remdesivir intermediate GS-441524 as claimed in claim 1 wherein, In step (3), the second solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, acetone, 1,4-dioxane, acetonitrile, diethylene glycol dimethyl ether, toluene, xylene and dichloromethane.

10. The process for the preparation of Remdesivir intermediate GS-441524 as claimed in claim 1 wherein, The third catalyst is selected from acetic acid cuprous or iodine cuprous.

11. The process for the preparation of Remdesivir intermediate GS-441524 as claimed in claim 1 wherein, In step (3), the reaction temperature is 20-200°C.

12. The process for the preparation of Remdesivir intermediate GS-441524 as claimed in claim 1 wherein, In step (4), intermediate IV and a second base are reacted in a third solvent to provide GS-441524.

13. The method of making remdesivir intermediate GS-441524 of claim 12, wherein, In step (4), the third solvent is selected from one or more of methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, 1,4-dioxane, and acetonitrile.

14. The method of making remdesivir intermediate GS-441524 of claim 12, wherein, In step (4), the second base is selected from one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium carbonate, cesium carbonate, and sodium hydride.

15. The method of making remdesivir intermediate GS-441524 of claim 12, wherein, In step (4), the temperature of the reaction is between 10 °C and 150 °C.

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