Chemical Synthesis of the Anti‐COVID‐19 Drug Remdesivir

Abstract

Remdesivir has become an important compound for the treatment of COVID‐19. Here, we describe the catalytic asymmetric synthesis of this anti‐COVID‐19 drug. First, the P‐racemic phosphoryl chloride is synthesized in a facile procedure. Then, it is possible to obtain the protected remdesivir via the organocatalytic asymmetric phosphorylation of protected nucleoside GS441524 with P‐racemic phosphoryl chloride catalyzed by chiral bicyclic imidazole. Finally, remdesivir is easily prepared by deprotection. © 2021 Wiley Periodicals LLC.

Basic Protocol 1: Synthesis of 2‐ethylbutyl (chloro(phenoxy)phosphoryl)‐l‐alaninate rac‐4

Basic Protocol 2: Synthesis of chiral bicyclic imidazole Ad‐DPI

Basic Protocol 3: Synthesis of remdesivir

INTRODUCTION

Recently, remdesivir, developed by Gilead Sciences using ProTide technology, has become one of the most effective anti‐COVID‐19 drugs. Thus far, two synthetic methods for remdesivir have been established (Siegel et al., 2017; Warren et al., 2016), but both of these methods require chiral resolution and additional synthetic steps, leading to resource waste and low synthetic efficiency. In 2012, our group developed the first catalytic asymmetric synthesis of P‐stereogenic phosphoric acid derivatives using chiral bicyclic imidazole organocatalysts (Liu et al., 2012). Inspired by this methodology for the construction of P‐stereocenters, we developed the first catalytic asymmetric synthesis of remdesivir via chiral bicyclic imidazole–catalyzed phosphorylation (Wang et al., 2020).

The core strategy in this protocol is to generate the S _P‐isomer of protected remdesivir via catalytic asymmetric phosphorylation. Basic Protocol 1 describes the synthesis of 2‐ethylbutyl (chloro(phenoxy)phosphoryl)‐l‐alaninate rac‐4. Basic Protocol 2 describes the synthesis of the chiral bicyclic imidazole Ad‐DPI. Basic Protocol 3 describes the synthesis of remdesivir.

Figures and some textual material are taken from our recently published work (Wang et al., 2020) and rewritten as step‐by‐step protocols to support reproduction of the original work.

Basic Protocol 1. SYNTHESIS OF 2‐ETHYLBUTYL (CHLORO(PHENOXY)PHOSPHORYL)‐l‐ALANINATE rac‐4

This protocol describes the synthesis of 2‐ethylbutyl (chloro(phenoxy)phosphoryl)‐l‐alaninate rac‐4 (Mackman, Parrish, Ray, & Theodore, 2012; Meppen et al., 2009), the phosphorylation reagent, which is derived from 2‐ethylbutan‐1‐ol (Fig. 1). The synthesis of rac‐4 involves two steps: (1) esterification of 2‐ethylbutan‐1‐ol 1 with l‐alanine to prepare 2‐ethylbutyl l‐alaninate hydrochloride salt 2 and (2) phosphorylation of 2‐ethylbutyl l‐alaninate hydrochloride salt 2 by phenyl dichlorophosphate 3 to obtain 2‐ethylbutyl (chloro(phenoxy)phosphoryl)‐l‐alaninate rac‐4.

Figure 1.

Synthesis of 2‐ethylbutyl (chloro(phenoxy)phosphoryl)‐l‐alaninate rac‐4.

NOTE: Anhydrous reaction conditions are required for the above two steps of this procedure. Glassware needs to be oven‐dried, and anhydrous solvents should be prepared or purchased in Sure/Seal bottles.

Materials

• 2‐Ethylbutan‐1‐ol (99.0%, Energy Chemical, A040495)

• Thionyl chloride (SOCl₂, 99.0%, Energy Chemical, W610261)

• l‐alanine (99.0%, Energy Chemical, A070054)

• Petroleum ether (AR, General‐Reagent, G84208C)

• Anhydrous dichloromethane (CH₂Cl₂, >99.5%, General‐Reagent, G81014C)

• Dry nitrogen

• Phenyl dichlorophosphate (98%, Energy Chemical, A020205)

• Triethylamine (Et₃N, 99.5%, Energy Chemical, B010065)

• Anhydrous ethyl ether (Et₂O, >99.5%, Sinopharm Chemical Reagent, 10009318)

• 150‐, and 200‐ml two‐necked round‐bottomed flasks

• Magnetic stirring bar

• Magnetic stirrer

• Magnetic stirrer with heating

• 150‐, and 200‐ml round‐bottomed flasks

• Rotary vacuum evaporator

• High‐vacuum oil pump

• Syringe needle

• Ice bath

• Oil bath

• Cryogenic cooling circulation pump

• Vacuum filtration system

• ¹H, ¹³C, and ³¹P NMR equipment or facilities

Synthesis of 2‐ethylbutyl l‐alaninate hydrochloride salt 2

• 1Add 75 ml (609.3 mmol) 2‐ethylbutan‐1‐ol 1 io a dry 200‐ml two‐necked round‐bottomed flask.
• 2Add 10.9 ml (150.0 mmol) SOCl₂ dropwise over 10 min to the flask containing 2‐ethylbutan‐1‐ol 1 at 0°C and stir the mixture for 1 hr at 0°C.
• 3Weigh out 8.9 g (100.0 mmol) of l‐alanine into the flask containing the mixture at 0°C.
• 4Raise the temperature of the reaction mixture to 90°C, stir the mixture for 16 hr at 90°C, and then allow it to cool to 25°C.
• 5Transfer the reaction mixture into a dry 200‐ml round‐bottomed flask.
• 6Evaporate the reaction mixture using a rotary evaporator.
• 7Wash the reaction mixture with 20 ml petroleum ether twice.
• 8Dry the resulting white solid for 1 hr in vacuo to obtain 2‐ethylbutyl l‐alaninate hydrochloride salt 2.

Synthesis of 2‐ethylbutyl (chloro(phenoxy)phosphoryl)‐l‐alaninate rac‐4

• 9Weigh out 3.15 g (15.0 mmol) of 2 into a dry 150‐ml two‐necked round‐bottomed flask.
• 10Add 50 ml anhydrous CH₂Cl₂ to the flask using a syringe needle.
• 11Cool the temperature of reaction mixture to –80°C under dry nitrogen.
• 12Add 2.24 ml (15.0 mmol) phenyl dichlorophosphate to the flask using a syringe needle.
• 13Add 4.17 ml (30.0 mmol) Et₃N to the flask using a syringe needle over 10 min, and stir the mixture for 30 min.
• 14Raise temperature of reaction mixture to 25°C and stir it for 2 hr.
• 15Transfer the reaction mixture into a dry 150‐ml round‐bottomed flask.
• 16Evaporate the reaction mixture using a rotary evaporator to obtain a white solid.
• 17Add 50 ml anhydrous Et₂O to the flask and stir the mixture for 10 min.
• 18Vacuum filter the mixture using a vacuum filtration system with the 150‐ml round‐bottomed flask to remove the solid.
• 19Evaporate the filtrate using a rotary evaporator.
• 20Dry the resulting colorless oil for 1 hr in vacuo to provide 2‐ethylbutyl (chloro(phenoxy)phosphoryl)‐l‐alaninate rac‐4.
• 21Characterize the product by ¹H NMR, ¹³C NMR, and ³¹P NMR.

  Product rac‐4 is a colorless oil (4.9 g, 94% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.41‐7.34 (m, 2H), 7.29‐7.22 (m, 3H), 4.53‐4.33 (m, 1H), 4.26‐4.06 (m, 3H), 1.62‐1.48 (m, 4H), 1.40‐1.33 (m, 4H), and 0.95‐0.87 (m, 6H). ¹³C NMR (100 MHz, CDCl₃): δ 173.0, 172.9, 172.8, 172.7, 149.9, 149.9, 149.9, 149.8, 149.8, 130.0, 129.9, 129.9, 129.9, 126.0, 126.0, 126.0, 120.6, 120.6, 68.0, 67.9, 50.9, 50.6, 50.6, 40.3, 23.3, 23.3, 23.3, 20.6, 20.6, 20.6, 20.6, 11.0, and 11.0. ³¹P NMR (162 MHz, CDCl₃): δ 8.04 (s) and 7.69 (s).

Basic Protocol 2. SYNTHESIS OF CHIRAL BICYCLIC IMIDAZOLE Ad‐DPI

This protocol describes the synthesis of chiral bicyclic imidazole Ad‐DPI (Wang et al., 2020; Wang, Zhang, Ling, Zhang, & Zhang, 2017; Zhang, Xie, Jia, & Zhang, 2010), the catalyst for asymmetric phosphorylation prepared from imidazole (Fig. 2). The synthesis involves three steps: (1) synthesis of (rac)‐HO‐DPI from acrolein and imidazole, (2) synthesis of (S)‐HO‐DPI via kinetic resolution catalyzed by Novozyme 435, and (3) synthesis of Ad‐DPI from (S)‐HO‐DPI.

Figure 2.

Synthesis of chiral bicyclic imidazole Ad‐DPI.

Materials

• Imidazole (99.0%, Energy Chemical, E020263)

• 1,4‐Dioxane (>99.5%, Sinopharm Chemical Reagent, 10008918)

• Acetic acid (AcOH, >99.5%, Sinopharm Chemical Reagent, 10000218)

• Acrolein (>98.0%, Senfeida, BXQ100500)

• Silica gel (100‐200 Mesh)

• Ethyl acetate (EtOAc, >99.5%, General‐Reagent, G23272D)

• Methanol (MeOH, >99.5%, Sinopharm Chemical Reagent, 10014118)

• Acetonitrile (MeCN, >99.0%, Sinopharm Chemical Reagent, 80000618)

• Isopropenyl acetate (>98.0%, TCI, A0035)

• Novozyme 435 (Shanghai Yuanye Bio‐Technology Co., Ltd, S27516‐10g)

• Anhydrous tetrahydrofuran (THF, >99.0%, Sinopharm Chemical Reagent, 80124418)

• Dry nitrogen

• Sodium hydride (NaH, 60% dispersion in mineral oil, Energy Chemical, E060138)

• 1‐Isocyanatoadamantane (>98.0%, TCI, A1706)

• Dichloromethane (CH₂Cl₂, >99.5%, General‐Reagent, G81014C)

• Sodium sulfate (Na₂SO₄, >99.0%, General‐Reagent, G82667C)

• Isopropanol (99.8%, Adamas‐Beta, 75885G)

• Hexane (99.0%, Adamas‐Beta, 14153F)

• 100‐, and 250‐ml two‐necked round‐bottomed flasks

• Reflux condensers

• Magnetic stirring bar

• Magnetic stirrer

• Magnetic stirrer with heating

• 50‐, 100‐, and 250‐ml round‐bottomed flasks

• Rotary vacuum evaporator

• Flash chromatography columns

• High‐vacuum oil pump

• Vacuum filtration system

• Ice bath

• Oil bath

• Syringe needle

• ¹H and ¹³C NMR, HPLC, and high‐resolution mass spectrometry (HRMS) equipment or facilities

• Additional reagents and equipment for silica gel flash chromatography (see Current Protocols article: Meyers, 2001)

Synthesis of (rac)‐HO‐DPI

• 1Weigh out 1.6 g (23.9 mmol) imidazole into a 100‐ml two‐necked round‐bottomed flask.
• 2Add 25 ml 1,4‐dioxane to this flask.
• 3Add 0.1 ml (1.7 mmol) AcOH to the flask.
• 4Add 2.5 ml (36.7 mmol) acrolein to the flask and stir the mixture.
• 5Reflux the reaction mixture for 36 hr.
• 6Transfer the reaction mixture into a 100‐ml round‐bottomed flask.
• 7Evaporate the reaction mixture using a rotary evaporator.
• 8Purify the crude product by silica gel chromatography (100‐200 Mesh; Meyers, 2001) using 3/1 (v/v) EtOAc/MeOH to obtain (rac)‐HO‐DPI.
• 9Characterize the product by ¹H NMR, ¹³C NMR, HRMS, and HPLC.

  The product (rac)‐HO‐DPI is a white solid (2.4 g, 81% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.07 (d, J = 1.2 Hz, 1 H), 6.85 (d, J = 1.2 Hz, 1 H), 5.23 (dd, J = 7.2 Hz, 3.2 Hz, 1 H), 4.24‐4.16 (m, 1 H), 3.98‐3.88 (m, 1 H), 3.00‐2.88 (m, 1 H), and 2.64‐2.54 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ 156.5, 132.5, 114.3, 63.6, 43.2, and 36.3. HRMS (ESI): m/z calculated for C₆H₉N₂O⁺ (M+H)⁺ 125.0709 was 125.0707. HPLC: Daicel CHIRALCEL OD‐H, 25 cm×4.6 μm; 0.5 ml/min isopropanol/hexane = 10/90, 210 nm; retention times: 19.1 min and 30.5 min.

Synthesis of (S)‐HO‐DPI

• 10Weigh out 5.0 g (40.0 mmol) (rac)‐HO‐DPI into a 250‐ml two‐necked round‐bottomed flask.
• 11Add 150 ml of MeCN to the flask.
• 12Add 21.8 ml (200.0 mmol) isopropenyl acetate to the flask.
• 13Add 5.0 g Novozyme 435 to the flask.
• 14Raise temperature of reaction mixture to 35°C and stir the mixture gently for 12 hr.
• 15Vacuum filter the mixture using a vacuum filtration system with the 250‐ml round‐bottomed flask to remove the solid.
• 16Evaporate the reaction mixture using a rotary evaporator to remove MeCN.
• 17Purify the crude product by silica gel chromatography (100‐200 Mesh; Meyers, 2001) using 10:1 v/v EtOAc/MeOH to yield (S)‐HO‐DPI.
• 18Characterize the product by ¹H‐NMR, ¹³C‐NMR, and HPLC.

  The product (S)‐HO‐DPI is a white solid (1.6 g, 32% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.07 (d, J = 1.2 Hz, 1 H), 6.85 (d, J = 1.2 Hz, 1 H), 5.23 (dd, J = 7.2 Hz, 3.2 Hz, 1 H), 4.24‐4.16 (m, 1 H), 3.98‐3.88 (m, 1 H), 3.00‐2.88 (m, 1 H), and 2.64‐2.54 (m, 1 H). ¹³C NMR (101 MHz, CDCl₃): δ 156.5, 132.5, 114.3, 63.6, 43.2, and 36.3. HPLC: 99.9% ee, Daicel CHIRALCEL OD‐H, 25 cm×4.6 μm; 0.5 ml/min, isopropanol/hexane = 10/90, 210 nm; retention times: 19.1 min (minor) and 30.5 min (major).

Synthesis of Ad‐DPI

• 19Weigh out 200 mg (1.6 mmol) (S)‐HO‐DPI into a dry 50‐ml two‐necked round‐bottomed flask.
• 20Add 20 ml THF to the flask.
• 21Cool the reaction mixture to 0°C under dry nitrogen.
• 22Add 77 mg NaH (60% in mineral oil, 1.9 mmol) in portions over 30 min to the flask and stir the mixture for 1 hr.
• 23Add 428 mg (2.4 mmol) 1‐isocyanatoadamantane to the flask.
• 24Raise the temperature of the reaction mixture to 25°C and stir the mixture gently for 16 hr.
• 25Add 30 ml water to the flask to quench the reaction.
• 26Extract the mixture with 20 ml CH₂Cl₂ three times.
• 27Dry the organic layer over Na₂SO₄ and remove the solid by filtration.
• 28Evaporate the reaction mixture using a rotary evaporator to remove CH₂Cl₂.
• 29Purify the crude product by silica gel chromatography (100‐200 Mesh; Meyers, 2001) using 10/1 v/v EtOAc/MeOH to obtain Ad‐DPI.
• 30Characterize the product by ¹H NMR, ¹³C NMR, and HRMS.

  The product Ad‐DPI is a white solid (285 mg, 59% yield). ¹H NMR (500 MHz, CDCl₃): δ 7.18 (d, J = 1.3 Hz, 1H), 6.94 (d, J = 1.2 Hz, 1H), 5.86 (dd, J = 7.2, 2.7 Hz, 1H), 4.72 (s, 1H), 4.19‐4.06 (m, 1H), 4.03‐3.91 (m, 1H), 3.11‐2.98 (m, 1H), 2.66‐2.53 (m, 1H), 2.11‐2.05 (m, 3H), 1.95‐1.90 (m, 6H), 1.68‐1.64 (m, 6H). ¹³C NMR (126 MHz, CDCl₃): δ 153.5, 151.7, 134.8, 115.5, 67.1, 51.0, 43.1, 42.6, 41.8, 36.6, 36.3, 35.4, 29.7, 29.5. HRMS (ESI): m/z calcd. for C₁₇H₂₄N₃O₂ ⁺ (M+H)⁺ 302.1863, found 302.1868.

Basic Protocol 3. SYNTHESIS OF REMDESIVIR

This protocol describes the synthesis of remdesivir (Wang et al., 2020), the ProTide prodrug prepared from rac‐4 and nucleoside 5 (Fig. 3). The synthesis involves two steps: (1) catalytic asymmetric phosphorylation of nucleoside GS441524 5 with 2‐ethylbutyl (chloro(phenoxy)phosphoryl)‐l‐alaninate (rac‐4) catalyzed by Ad‐DPI to prepare protected remdesivir S _P‐6. (2) deprotection of S _P‐6 with 37% HCl in THF to provide remdesivir (Warren et al., 2016).

Figure 3.

Synthesis of remdesivir.

Materials

• GS441524 (5, 98.0%, Aikonchem, AK01FWCB)

• (S)‐6,7‐Dihydro‐5H‐pyrrolo[1,2‐a]imidazol‐7‐yl adamantan‐1‐ylcarbamate (Ad‐DPI, Basic Protocol 2)

• 4 Å molecular sieves

• Dry nitrogen

• Dichloromethane (CH₂Cl₂, >99.5%, General‐Reagent, G81014C)

• 2,6‐Lutidine (99.0%, Energy Chemical, W330004)

• 2‐Ethylbutyl (chloro(phenoxy)phosphoryl)‐l‐alaninate (rac‐4; Basic Protocol 1)

• Silica gel (100‐200 Mesh)

• Petroleum ether (AR, General‐Reagent, G84208C)

• Isopropyl ether (99.0%, Energy Chemical, W330208)

• Ethyl acetate (EtOAc, >99.5%, General‐Reagent, G23272D)

• Isopropanol

• Hexane

• Tetrahydrofuran (THF, >99.0%, Sinopharm Chemical Reagent, 80124418)

• 37% aqueous hydrochloric acid solution (Sinopharm Chemical Reagent, 10011061)

• Saturated aqueous sodium bicarbonate solution (99.0%, Adamas‐Beta, 24073D)

• Na₂SO₄ (>99.0%, General‐Reagent, G82667C)

• 100‐, and 1000‐ml two‐necked round‐bottomed flasks

• Magnetic stirring bar

• Magnetic stirrer

• Magnetic stirrer with heating

• 500‐, and 1000‐ml round‐bottomed flasks

• Rotary vacuum evaporator

• High‐vacuum oil pump

• Flash chromatography columns

• Preparative HPLC column: Daicel CHIRALCEL IE, 1 cm × 25 cm

• Separatory funnels

• Ice bath

• Oil bath

• Syringe needle

• Cryogenic cooling circulation pump

• Vacuum filtration system

• ¹H, ¹³C, and ³¹P NMR and HPLC and HRMS equipment or facilities

• Additional reagents and equipment for silica gel flash chromatography (see Current Protocols article: Meyers, 2001)

Synthesis of protected remdesivir S_P‐6

• 1Add 10.0 g (30.2 mmol) 5 to a dry 1000‐ml two‐necked round‐bottomed flask equipped with a magnetic stir bar.
• 2Add 909.6 mg (3.0 mmol) Ad‐DPI to the flask.
• 3Add 11.0 g 4 Å molecular sieve to the flask.
• 4Evacuate and backfill the flask with dry nitrogen three times.
• 5Add 300 ml CH₂Cl₂ to the flask with the aid of a syringe needle.
• 6Add 7.0 ml (60.4 mmol) 2,6‐lutidine to the flask with the aid of a syringe needle.
• 7Cool the temperature of reaction mixture to –40°C under dry nitrogen and stir the mixture for 10 min.
• 8Add 15.7 g (45.3 mmol) rac‐4 to the flask with the aid of a syringe needle and stir the reaction mixture for 48 hr.
• 9Add 30 ml water to the flask to quench the reaction.
• 10Transfer the reaction mixture into a 1000‐ml round‐bottomed flask.
• 11Evaporate the reaction mixture using a rotary evaporator and concentrate the residue in vacuo using a high‐vacuum oil pump.
• 12Analyze the crude product by ³¹P NMR showing a d.r. of 21.2:1.
• 13Purify the crude product by silica gel chromatography (100‐200 Mesh) using 1/5 v/v petroleum ether/ethyl acetate and then recrystallize the product from dichloromethane/isopropyl ether at –30°C to provide protected remdesivir S _P‐6 as a white solid (16.5 g, 85% yield, >99:1 d.r.).
• 14Purify the residue from mother liquor by preparative HPLC (Daicel CHIRALCEL IE, 1 cm × 25 cm, 10 ml/min, isopropanol/hexane = 30/70, 220 nm, collected from 49.2 to 63.9 min) to yield S _p‐6 as a white solid (0.8 g, 4% yield, >99:1 d.r.).
• 15Combine two parts of product providing 17.3 g S _p‐6 (89% yield, >99:1 d.r.).
• 16Characterize the product by ¹H NMR, ¹³C NMR, ³¹P NMR, HPLC, and HRMS.

  The product S_p‐6 is a white solid (17.3 g, 89% yield, >99:1 d.r.). ¹H NMR (400 MHz, CD₃OD): δ 7.88 (s, 1H), 7.29‐7.23 (m, 2H), 7.17‐7.10 (m, 3H), 6.93‐6.90 (m, 2H), 5.33 (d, J = 6.7 Hz, 1H), 4.98 (dd, J = 6.6, 3.4 Hz, 1H), 4.60‐4.55 (m, 1H), 4.36‐4.25 (m, 2H), 4.02 (dd, J = 10.9, 5.8 Hz, 1H), 3.91 (dd, J = 10.9, 5.7 Hz, 1H), 3.88‐3.79 (m, 1H), 1.70 (s, 3H), 1.49‐1.41 (m, 1H), 1.39 (s, 3H), 1.35‐1.24 (m, 8H), and 0.85 (t, J = 7.5 Hz, 6H). ¹³C NMR (100 MHz, CD₃OD): δ 174.9, 174.8, 156.6, 152.0, 151.9, 147.6, 130.6, 126.0, 124.9, 121.3, 121.2, 118.0, 117.7, 116.9, 112.5, 103.0, 85.7, 84.8, 84.8, 83.0, 82.5, 68.1, 67.0, 66.9, 51.4, 41.6, 26.5, 25.6, 24.2, 24.1, 20.5, 20.4, 11.3, and 11.3. ³¹P NMR (162 MHz, CD₃OD): δ 3.23 (s). HPLC analysis: >99:1 d.r. [Daicel CHIRALPAK IE column; 4.6 μm×25 cm; solvent system: isopropanol/hexane = 30/70; 1.0 ml/min; retention times: 21.2 min (minor) and 26.5 min (major)]. HRMS (ESI): m/z calculated for C₃₀H₄₀N₆O₈P⁺ (M+H)⁺ 643.2640 was 643.2609.

Synthesis of remdesivir

• 17Weigh out 1.2 g (1.8 mmol) S _p‐6 into a 100‐ml two‐necked round‐bottomed flask.
• 18Add 24 ml THF to the flask.
• 19Cool the reaction mixture to 0°C and stir the mixture.
• 20Add 2.1 ml 37% aqueous hydrochloric acid solution slowly to the flask.
• 21Raise temperature of reaction mixture to 25°C and stir the mixture for 8 hr.
• 22Transfer the reaction mixture into a 500‐ml round‐bottomed flask and dilute the reaction mixture with 60 ml water.
• 23Add saturated aqueous sodium bicarbonate solution to adjust the pH of reaction mixture to 8.
• 24Extract the resulting mixture with 60 ml ethyl acetate three times.
• 25Dry the combined organic phase over Na₂SO₄ and remove the solid by filtration.
• 26Evaporate the reaction mixture using a rotary evaporator.
• 27Purify the crude product by silica gel chromatography (100‐200 Mesh) using 1/3 v/v) petroleum ether/ethyl acetate to provide remdesivir.
• 28Characterize the product by ¹H NMR, ¹³C NMR, ³¹P NMR, and high‐resolution mass spectrometry (HRMS).

  The product remdesivir is a white solid (0.82 g, 73% yield). ¹H NMR (400 MHz, CD₃OD): δ 7.87 (s, 1H), 7.33‐7.27 (m, 2H), 7.21‐7.12 (m, 3H), 6.91 (d, J = 4.6 Hz, 1H), 6.88 (d, J = 4.6 Hz, 1H), 4.79 (d, J = 5.4 Hz, 1H), 4.44‐4.35 (m, 2H), 4.33‐4.25 (m, 1H), 4.20‐4.15 (m, 1H), 4.02 (dd, J = 10.9, 5.8 Hz, 1H), 3.95‐3.85 (m, 2H), 1.49‐1.40 (m, 1H), 1.34‐1.27 (m, 8H), 0.85 (t, J = 7.5 Hz, 6H). ¹³C NMR (100 MHz, CD₃OD): δ 175.0, 174.9, 157.1, 152.1, 152.1, 148.2, 130.7, 126.0, 125.5, 121.3, 121.3, 117.9, 117.6, 112.3, 102.7, 84.3, 84.2, 81.2, 75.6, 71.6, 68.1, 67.2, 67.1, 51.5, 41.6, 24.2, 24.2, 20.6, 20.5, 11.3, 11.3. ³¹P NMR (162 MHz, CD₃OD): δ 3.52 (s). HRMS (ESI): m/z calcd. for C₂₇H₃₆N₆O₈P⁺ (M+H)⁺ 603.2327, found 603.2300.

COMMENTARY

Background Information

Remdesivir is one of the most effective treatments for COVID‐19 (Holshue et al., 2020), which attracts researchers to develop an effective synthetic approach for this compound. Until now, two synthetic methods for remdesivir have been established (Siegel et al., 2017; Warren et al., 2016). Both of these methods require not only chiral resolution but also additional synthetic steps, which lead to the waste of resources and low synthetic efficiency. In 2010, a novel chiral bicyclic imidazole organocatalyst was developed by our group (Zhang et al., 2010). Over the past decade, this kind of organocatalyst was successfully applied in a number of asymmetric reactions (Liu et al., 2012; Wang et al., 2017; Wang et al., 2020; Wang, Zhang, Liu, Xie, & Zhang, 2014; Wang, Zhang, Xie, & Zhang, 2014; Wang, Zhou, Zhang, Zhang, & Zhang, 2020; Zhang et al., 2019; Zhang, Wang, Xie, Sun, & Zhang, 2014; Zhou et al., 2019; Zhou et al., 2021). In 2012, the first catalytic asymmetric synthesis of P‐stereogenic phosphoric acid derivatives was developed by our group using the chiral bicyclic imidazole catalyst (Liu et al., 2012). Later, scientists at Merck & Co. utilized bicyclic imidazole catalyst in the asymmetric synthesis of nucleoside‐based phosphoramidate prodrugs (DiRocco et al., 2017). Inspired by our previous work, we successfully developed the first catalytic asymmetric synthesis of remdesivir using the chiral bicyclic imidazole Ad‐DPI (Wang et al., 2020).

Critical Parameters and Troubleshooting

In Basic Protocol 1, both steps are sensitive to water. In Basic Protocol 2, the step for synthesis of Ad‐DPI is sensitive to water. In Basic Protocol 3, the catalytic asymmetric synthesis of S _P‐6 step is sensitive to water. Anhydrous reaction conditions are required for the aforementioned steps. Glassware needs to be oven‐dried, and anhydrous solvents should be prepared or purchased in Sure/Seal bottles. In the step for synthesis of S _P‐6 in Basic Protocol 3, 4 Å molecular sieves are necessary for the reaction.

Understanding Results

After the synthesis, the purified compounds are identified by ¹H‐NMR, ¹³C‐NMR, and HRMS as shown in each synthesis. The d.r. value of crude S _p‐6 is analyzed by ³¹P‐NMR. The optically pure S _p‐6 is verified by ³¹P‐NMR and HPLC.

Time Considerations

Synthesis of 2‐ethylbutyl (chloro(phenoxy)phosphoryl)‐l‐alaninate (rac‐4) (Basic Protocol 1) can be completed within 28 hr. Synthesis of chiral bicyclic imidazole Ad‐DPI (Basic Protocol 2) can be completed within 4 days. Synthesis of remdesivir (Basic Protocol 3) can be completed within 3 days.

Author Contributions

Mo Wang: investigation, writing original draft; Lu Zhang: investigation; Xiaohong Huo: writing review and editing; Zhenfeng Zhang: writing review and editing; Wanbin Zhang: project administration, writing review and editing.

Conflict of Interest

The authors declare no conflict of interest.

Wang, M. , Zhang, L. , Huo, X. , Zhang, Z. , & Zhang, W. (2021). Chemical synthesis of the anti‐COVID‐19 drug remdesivir. Current Protocols, 1, e303. doi: 10.1002/cpz1.303

Data Availability Statement

Data openly available in a public repository that issues datasets with DOIs.