1152311-62-0

Basic information

• Product Name: VX-661
• Synonyms: VX-661;VX-661/VX661;1-(2,2-Difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl]-cyclopropanecarboxamide;(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-Methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxaMide;Cyclopropanecarboxamide, 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl]-;1-(2,2-Difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl]-cyclopropanecarboxamide VX661;(R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-;1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)indol-5-yl]cyclopropane-1-carboxamide
• CAS NO: 1152311-62-0
• Molecular Formula: C₂₆H₂₇F₃N₂O₆
• Molecular Weight: 520.4975896
• Product Categories: Inhibitors
• Mol File: 1152311-62-0.mol
• Article Data: 28

Chemical Properties

• Boiling Point: 610.8±55.0 °C(Predicted)
• Appearance: /
• Density: 1.49±0.1 g/cm3(Predicted)
• Solubility: ≥21.8 mg/mL in DMSO; insoluble in EtOH; ≥24.3 mg/mL in H2O
• PKA: 13.99±0.20(Predicted)
• CAS DataBase Reference: VX-661(CAS DataBase Reference)
• NIST Chemistry Reference: VX-661(1152311-62-0)
• EPA Substance Registry System: VX-661(1152311-62-0)

Safety Data

• Hazardous Substances Data: 1152311-62-0(Hazardous Substances Data)

Usage

Description

Tezacaftor (VX-661) is an oral medication for cystic fibrosis (CF) developed by Vertex Pharmaceuticals. In a combination therapy formulation called Symdeko (tezacaftor plus ivacaftor), it is approved in the U.S. and Canada for CF patients, ages 12 and older, who have two copies of the F508del mutation in the CFTR gene and one minimal function mutation. Symdeko is approved and marketed in the EU as Symkevi.Tezacaftor is not approved as a stand-alone treatment, but as part of a combination therapy.

Uses

Tezacaftor is used as a combination therapy with Ivacaftor for the treatment of patients with cystic fibrosis.

Definition

VX-661 is an investigational compound that promotes the maturation of delta F508 mutants of the cystic fibrosis transmembrane conductance regulator (CFTR). Delta F508 CFTR represents a class of CFTR mutation that is characterized by impaired processing of misfolded CFTR proteins and reduced accumulation of the protein at the cell surface. VX-661 is intended to facilitate trafficking of CFTR to the epithelial cell membrane. It may be combined with the CFTR potentiator ivacaftor (Item No. 15145) to stimulate both CFTR accumulation and opening at the apical epithelial surface.

Biochem/physiol Actions

VX-661 is another cystic fibrosis transmembrane conductance regulator (CFTR) corrector in development for the treatment of cystic fibrosis.

in vitro

VX-661, is CFTR modulator that is potentially useful for treatment of cystic fibrosis. VX-661 corrects F508del-CFTR trafficking and increases F508del-CFTR protein activity in vitro.

references

[1] s. donaldson, j. pilewski, m. griese, q. dong, p.-s. lee, for the vx11–661-101 study group. ws7.3 vx-661, an investigational cftr corrector, in combination with ivacaftor, a cftr potentiator, in patients with cf and homozygous for the f508del-cftr mutation: interim analysis. journal of cystic fibrosis, volume 12, supplement 1, june 2013, page s14

InChI:InChI=1S/C26H27F3N2O6/c1-24(2,13-33)22-8-14-7-18(17(27)10-19(14)31(22)11-16(34)12-32)30-23(35)25(5-6-25)15-3-4-20-21(9-15)37-26(28,29)36-20/h3-4,7-10,16,32-34H,5-6,11-13H2,1-2H3,(H,30,35)/t16-/m1/s1

Synthetic route

C33H33F3N2O6 → (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (1152311-62-0)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen In methanol at 30 - 35℃; under 1500.15 - 2250.23 Torr; for 4h;	98.2%

C34H35F3N2O7 → (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (1152311-62-0)

Conditions	Yield
With hydrogen In acetonitrile at 40 - 45℃; under 2250.23 - 3000.3 Torr; for 4h;	96.1%

N-{1-[(2R)-3-(benzyloxy)-2-hydroxypropyl]-2-[1-(benzyloxy)-2-methylpropan-2-yl]-6-fluoro-1H-indol-5-yl}-1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)cyclopropane-1-carboxamide (1294504-68-9) → (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (1152311-62-0)

Conditions	Yield
With 5%-palladium/activated carbon; hydrogen In methanol at 20℃; for 1h;	92%
With hydrogen; 5%-palladium/activated carbon In tetrahydrofuran at 50℃; under 2250.23 - 3000.3 Torr; for 96h; Product distribution / selectivity; autoclave; Inert atmosphere;
With 5%-palladium/activated carbon; hydrogen In tetrahydrofuran at 50℃; under 2250.23 Torr;	130 g

(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (1152311-90-4) → (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (1152311-62-0)

Conditions	Yield
Stage #1: (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide With toluene-4-sulfonic acid In methanol; water at 80℃; for 0.75h; Stage #2: With sodium hydrogencarbonate In water; ethyl acetate	47%
With toluene-4-sulfonic acid In methanol; water at 80℃; for 0.75h;	47%
With toluene-4-sulfonic acid In methanol; water at 80℃; for 0.75h;	47%

3-fluoro-4-nitroaniline (2369-13-3) → (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (1152311-62-0)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: N-Bromosuccinimide / ethyl acetate / 22 °C 2.1: Zn(ClO4)2·2H2O / toluene / 20 - 80 °C / Molecular sieve 2.2: 30 °C / 750.08 Torr 3.1: sodium hydrogencarbonate / ethyl acetate 3.2: 20 °C 3.3: 80 °C / Inert atmosphere 4.1: dichloro bis(acetonitrile) palladium(II) / acetonitrile / 20 - 80 °C / Inert atmosphere 5.1: triethylamine / dichloromethane / 0 - 20 °C 6.1: hydrogen / 5%-palladium/activated carbon / tetrahydrofuran / 96 h / 50 °C / 2250.23 - 3000.3 Torr / autoclave; Inert atmosphere View Scheme
Multi-step reaction with 6 steps 1.1: N-Bromosuccinimide / ethyl acetate / 22 °C 2.1: Zn(ClO4)2·2H2O / toluene / 0.5 h / 20 °C / Inert atmosphere; Molecular sieve 2.2: 7 h / 80 °C 3.1: palladium diacetate; 1,4-di(diphenylphosphino)-butane; potassium carbonate / acetonitrile / 0.5 h / 20 °C / Inert atmosphere 3.2: 80 °C 4.1: palladium chloride*2MeCN / ethyl acetate; acetonitrile / 20 - 80 °C / Inert atmosphere 5.1: triethylamine / dichloromethane / 0 - 20 °C 6.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran / 50 °C / 2250.23 Torr View Scheme
Multi-step reaction with 6 steps 1.1: N-Bromosuccinimide / ethyl acetate / 22 °C 2.1: Zn(ClO4)2·2H2O / toluene / 20 °C / Inert atmosphere; Molecular sieve 2.2: 80 °C / Inert atmosphere; Molecular sieve 3.1: sodium hydrogencarbonate / dichloromethane 3.2: 0.25 h 3.3: Inert atmosphere 4.1: copper(l) iodide; dichloro bis(acetonitrile) palladium(II) / acetonitrile / Inert atmosphere 5.1: thionyl chloride / toluene / 2 h / 60 °C 6.1: 5%-palladium/activated carbon; hydrogen; hydrogenchloride / methanol / Inert atmosphere View Scheme

5-bromo-2,2-difluoro-2H-1,3-benzodioxole (33070-32-5) → (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (1152311-62-0)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: sodium phosphate; tri-tert-butyl phosphine / bis(dibenzylideneacetone)-palladium(0) / toluene; hexanes / 0.83 h / 23 °C / Inert atmosphere 1.2: 70 °C 2.1: hydrogenchloride / water; dimethyl sulfoxide / 40 - 75 °C 3.1: tetraoctyl ammonium bromide; potassium hydroxide / water / 1 h / 70 °C 4.1: sodium hydroxide; water / ethanol / 80 °C 5.1: thionyl chloride / toluene / 60 °C 6.1: triethylamine / dichloromethane / 0 - 20 °C 7.1: hydrogen / 5%-palladium/activated carbon / tetrahydrofuran / 96 h / 50 °C / 2250.23 - 3000.3 Torr / autoclave; Inert atmosphere View Scheme
Multi-step reaction with 7 steps 1.1: sodium phosphate; tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine / toluene; hexane / 0.83 h / 23 °C / Inert atmosphere 1.2: 0.67 h / 70 °C 2.1: hydrogenchloride / dimethyl sulfoxide; water / 1 h / 40 - 75 °C 3.1: potassium hydroxide; tetraoctyl ammonium bromide / water / 1 h / 70 °C 4.1: sodium hydroxide; water / ethanol / 80 °C 5.1: thionyl chloride / toluene / 60 °C 6.1: triethylamine / dichloromethane / 0 - 20 °C 7.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran / 50 °C / 2250.23 Torr View Scheme
Multi-step reaction with 6 steps 1: bis(dibenzylideneacetone)-palladium(0); sodium phosphate; tert-butylphosphine / toluene; hexane / 23 - 70 °C / Inert atmosphere 2: hydrogenchloride / dimethyl sulfoxide / 40 - 75 °C 3: potassium hydroxide; tetraoctyl ammonium bromide / water / 1 h / 70 °C 4: sodium hydroxide / ethanol / 80 °C 5: thionyl chloride / toluene / 2 h / 60 °C 6: 5%-palladium/activated carbon; hydrogen; hydrogenchloride / methanol / Inert atmosphere View Scheme

2,2-difluoro-1,3-benzodioxole-5-carboxylic acid (656-46-2) → (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (1152311-62-0)

Conditions	Yield
Multi-step reaction with 8 steps 1.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 15 - 40 °C 1.2: 0.5 h / 40 - 50 °C 2.1: thionyl chloride / dmap / tert-butyl methyl ether / 1.5 h / 15 - 30 °C 3.1: dimethyl sulfoxide / 1 h / 30 - 40 °C 4.1: tetraoctyl ammonium bromide; potassium hydroxide / water / 1 h / 70 °C 5.1: sodium hydroxide; water / ethanol / 80 °C 6.1: thionyl chloride / toluene / 60 °C 7.1: triethylamine / dichloromethane / 0 - 20 °C 8.1: hydrogen / 5%-palladium/activated carbon / tetrahydrofuran / 96 h / 50 °C / 2250.23 - 3000.3 Torr / autoclave; Inert atmosphere View Scheme
Multi-step reaction with 8 steps 1.1: Vitride® / toluene / 2 h / 15 - 40 °C 1.2: 0.5 h / 40 - 50 °C 2.1: dmap; thionyl chloride / tert-butyl methyl ether / 1 h / 15 - 30 °C 3.1: dimethyl sulfoxide / 1 h / 30 - 40 °C 4.1: potassium hydroxide; tetraoctyl ammonium bromide / water / 1 h / 70 °C 5.1: sodium hydroxide; water / ethanol / 80 °C 6.1: thionyl chloride / toluene / 60 °C 7.1: triethylamine / dichloromethane / 0 - 20 °C 8.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran / 50 °C / 2250.23 Torr View Scheme
Multi-step reaction with 7 steps 1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 2 h / 15 - 40 °C 2: thionyl chloride; dmap / tert-butyl methyl ether / 1 h / 15 - 30 °C 3: sodium cyanide / dimethyl sulfoxide / 1 h / 30 - 40 °C 4: potassium hydroxide; tetraoctyl ammonium bromide / water / 1 h / 70 °C 5: sodium hydroxide / ethanol / 80 °C 6: thionyl chloride / toluene / 2 h / 60 °C 7: 5%-palladium/activated carbon; hydrogen; hydrogenchloride / methanol / Inert atmosphere View Scheme

(2,2-difluoro-1,3-benzodioxol-5-yl)methanol (72768-97-9) → (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (1152311-62-0)

Conditions	Yield
Multi-step reaction with 7 steps 1: thionyl chloride / dmap / tert-butyl methyl ether / 1.5 h / 15 - 30 °C 2: dimethyl sulfoxide / 1 h / 30 - 40 °C 3: tetraoctyl ammonium bromide; potassium hydroxide / water / 1 h / 70 °C 4: sodium hydroxide; water / ethanol / 80 °C 5: thionyl chloride / toluene / 60 °C 6: triethylamine / dichloromethane / 0 - 20 °C 7: hydrogen / 5%-palladium/activated carbon / tetrahydrofuran / 96 h / 50 °C / 2250.23 - 3000.3 Torr / autoclave; Inert atmosphere View Scheme
Multi-step reaction with 7 steps 1: dmap; thionyl chloride / tert-butyl methyl ether / 1 h / 15 - 30 °C 2: dimethyl sulfoxide / 1 h / 30 - 40 °C 3: potassium hydroxide; tetraoctyl ammonium bromide / water / 1 h / 70 °C 4: sodium hydroxide; water / ethanol / 80 °C 5: thionyl chloride / toluene / 60 °C 6: triethylamine / dichloromethane / 0 - 20 °C 7: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran / 50 °C / 2250.23 Torr View Scheme
Multi-step reaction with 6 steps 1: thionyl chloride; dmap / tert-butyl methyl ether / 1 h / 15 - 30 °C 2: sodium cyanide / dimethyl sulfoxide / 1 h / 30 - 40 °C 3: potassium hydroxide; tetraoctyl ammonium bromide / water / 1 h / 70 °C 4: sodium hydroxide / ethanol / 80 °C 5: thionyl chloride / toluene / 2 h / 60 °C 6: 5%-palladium/activated carbon; hydrogen; hydrogenchloride / methanol / Inert atmosphere View Scheme

5-chloromethyl-2,2-difluoro-benzo[1,3]dioxole (476473-97-9) → (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (1152311-62-0)

Conditions	Yield
Multi-step reaction with 6 steps 1: dimethyl sulfoxide / 1 h / 30 - 40 °C 2: tetraoctyl ammonium bromide; potassium hydroxide / water / 1 h / 70 °C 3: sodium hydroxide; water / ethanol / 80 °C 4: thionyl chloride / toluene / 60 °C 5: triethylamine / dichloromethane / 0 - 20 °C 6: hydrogen / 5%-palladium/activated carbon / tetrahydrofuran / 96 h / 50 °C / 2250.23 - 3000.3 Torr / autoclave; Inert atmosphere View Scheme
Multi-step reaction with 6 steps 1: dimethyl sulfoxide / 1 h / 30 - 40 °C 2: potassium hydroxide; tetraoctyl ammonium bromide / water / 1 h / 70 °C 3: sodium hydroxide; water / ethanol / 80 °C 4: thionyl chloride / toluene / 60 °C 5: triethylamine / dichloromethane / 0 - 20 °C 6: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran / 50 °C / 2250.23 Torr View Scheme
Multi-step reaction with 5 steps 1: sodium cyanide / dimethyl sulfoxide / 1 h / 30 - 40 °C 2: potassium hydroxide; tetraoctyl ammonium bromide / water / 1 h / 70 °C 3: sodium hydroxide / ethanol / 80 °C 4: thionyl chloride / toluene / 2 h / 60 °C 5: 5%-palladium/activated carbon; hydrogen; hydrogenchloride / methanol / Inert atmosphere View Scheme

1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonitrile (862574-87-6) → (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (1152311-62-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium hydroxide; water / ethanol / 80 °C 2: thionyl chloride / toluene / 60 °C 3: triethylamine / dichloromethane / 0 - 20 °C 4: hydrogen / 5%-palladium/activated carbon / tetrahydrofuran / 96 h / 50 °C / 2250.23 - 3000.3 Torr / autoclave; Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1: sodium hydroxide; water / ethanol / 80 °C 2: thionyl chloride / toluene / 60 °C 3: triethylamine / dichloromethane / 0 - 20 °C 4: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran / 50 °C / 2250.23 Torr View Scheme
Multi-step reaction with 3 steps 1: sodium hydroxide / ethanol / 80 °C 2: thionyl chloride / toluene / 2 h / 60 °C 3: 5%-palladium/activated carbon; hydrogen; hydrogenchloride / methanol / Inert atmosphere View Scheme

1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid (862574-88-7) → (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (1152311-62-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: thionyl chloride / toluene / 60 °C 2: triethylamine / dichloromethane / 0 - 20 °C 3: hydrogen / 5%-palladium/activated carbon / tetrahydrofuran / 96 h / 50 °C / 2250.23 - 3000.3 Torr / autoclave; Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: thionyl chloride / toluene / 60 °C 2: triethylamine / dichloromethane / 0 - 20 °C 3: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran / 50 °C / 2250.23 Torr View Scheme
Multi-step reaction with 3 steps 1: thionyl chloride / toluene / 2 h / 60 °C 2: triethylamine / toluene; dichloromethane / 0 - 20 °C 3: hydrogen; 5%-palladium/activated carbon / tetrahydrofuran / 50 °C / 2250.23 Torr / Inert atmosphere; Large scale View Scheme

2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)acetonitrile (68119-31-3) → (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (1152311-62-0)

Conditions	Yield
Multi-step reaction with 5 steps 1: tetraoctyl ammonium bromide; potassium hydroxide / water / 1 h / 70 °C 2: sodium hydroxide; water / ethanol / 80 °C 3: thionyl chloride / toluene / 60 °C 4: triethylamine / dichloromethane / 0 - 20 °C 5: hydrogen / 5%-palladium/activated carbon / tetrahydrofuran / 96 h / 50 °C / 2250.23 - 3000.3 Torr / autoclave; Inert atmosphere View Scheme
Multi-step reaction with 5 steps 1: potassium hydroxide; tetraoctyl ammonium bromide / water / 1 h / 70 °C 2: sodium hydroxide; water / ethanol / 80 °C 3: thionyl chloride / toluene / 60 °C 4: triethylamine / dichloromethane / 0 - 20 °C 5: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran / 50 °C / 2250.23 Torr View Scheme
Multi-step reaction with 4 steps 1: potassium hydroxide; tetraoctyl ammonium bromide / water / 1 h / 70 °C 2: sodium hydroxide / ethanol / 80 °C 3: thionyl chloride / toluene / 2 h / 60 °C 4: 5%-palladium/activated carbon; hydrogen; hydrogenchloride / methanol / Inert atmosphere View Scheme

2-bromo-5-fluoro-4-nitroaniline (952664-69-6) → (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (1152311-62-0)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: Zn(ClO4)2·2H2O / toluene / 20 - 80 °C / Molecular sieve 1.2: 30 °C / 750.08 Torr 2.1: sodium hydrogencarbonate / ethyl acetate 2.2: 20 °C 2.3: 80 °C / Inert atmosphere 3.1: dichloro bis(acetonitrile) palladium(II) / acetonitrile / 20 - 80 °C / Inert atmosphere 4.1: triethylamine / dichloromethane / 0 - 20 °C 5.1: hydrogen / 5%-palladium/activated carbon / tetrahydrofuran / 96 h / 50 °C / 2250.23 - 3000.3 Torr / autoclave; Inert atmosphere View Scheme
Multi-step reaction with 5 steps 1.1: Zn(ClO4)2·2H2O / toluene / 0.5 h / 20 °C / Inert atmosphere; Molecular sieve 1.2: 7 h / 80 °C 2.1: palladium diacetate; 1,4-di(diphenylphosphino)-butane; potassium carbonate / acetonitrile / 0.5 h / 20 °C / Inert atmosphere 2.2: 80 °C 3.1: palladium chloride*2MeCN / ethyl acetate; acetonitrile / 20 - 80 °C / Inert atmosphere 4.1: triethylamine / dichloromethane / 0 - 20 °C 5.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran / 50 °C / 2250.23 Torr View Scheme
Multi-step reaction with 5 steps 1.1: Zn(ClO4)2·2H2O / toluene / 20 °C / Inert atmosphere; Molecular sieve 1.2: 80 °C / Inert atmosphere; Molecular sieve 2.1: sodium hydrogencarbonate / dichloromethane 2.2: 0.25 h 2.3: Inert atmosphere 3.1: copper(l) iodide; dichloro bis(acetonitrile) palladium(II) / acetonitrile / Inert atmosphere 4.1: thionyl chloride / toluene / 2 h / 60 °C 5.1: 5%-palladium/activated carbon; hydrogen; hydrogenchloride / methanol / Inert atmosphere View Scheme

(4-(benzyloxy)-3,3-dimethylbut-1-ynyl)trimethylsilane (1294504-65-6) → (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (1152311-62-0)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: potassium hydroxide / methanol / 5 - 25 °C 1.2: 0.5 h 2.1: sodium hydrogencarbonate / ethyl acetate 2.2: 20 °C 2.3: 80 °C / Inert atmosphere 3.1: dichloro bis(acetonitrile) palladium(II) / acetonitrile / 20 - 80 °C / Inert atmosphere 4.1: triethylamine / dichloromethane / 0 - 20 °C 5.1: hydrogen / 5%-palladium/activated carbon / tetrahydrofuran / 96 h / 50 °C / 2250.23 - 3000.3 Torr / autoclave; Inert atmosphere View Scheme
Multi-step reaction with 5 steps 1.1: potassium hydroxide; water / methanol / 25 °C 2.1: palladium diacetate; 1,4-di(diphenylphosphino)-butane; potassium carbonate / acetonitrile / 0.5 h / 20 °C / Inert atmosphere 2.2: 80 °C 3.1: palladium chloride*2MeCN / ethyl acetate; acetonitrile / 20 - 80 °C / Inert atmosphere 4.1: triethylamine / dichloromethane / 0 - 20 °C 5.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran / 50 °C / 2250.23 Torr View Scheme
Multi-step reaction with 5 steps 1.1: potassium hydroxide / methanol 2.1: sodium hydrogencarbonate / dichloromethane 2.2: 0.25 h 2.3: Inert atmosphere 3.1: copper(l) iodide; dichloro bis(acetonitrile) palladium(II) / acetonitrile / Inert atmosphere 4.1: thionyl chloride / toluene / 2 h / 60 °C 5.1: 5%-palladium/activated carbon; hydrogen; hydrogenchloride / methanol / Inert atmosphere View Scheme

(((2,2-dimethylbut-3-yn-1-yl)oxy)methyl)benzene (1092536-54-3) → (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (1152311-62-0)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sodium hydrogencarbonate / ethyl acetate 1.2: 20 °C 1.3: 80 °C / Inert atmosphere 2.1: dichloro bis(acetonitrile) palladium(II) / acetonitrile / 20 - 80 °C / Inert atmosphere 3.1: triethylamine / dichloromethane / 0 - 20 °C 4.1: hydrogen / 5%-palladium/activated carbon / tetrahydrofuran / 96 h / 50 °C / 2250.23 - 3000.3 Torr / autoclave; Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1.1: palladium diacetate; 1,4-di(diphenylphosphino)-butane; potassium carbonate / acetonitrile / 0.5 h / 20 °C / Inert atmosphere 1.2: 80 °C 2.1: palladium chloride*2MeCN / ethyl acetate; acetonitrile / 20 - 80 °C / Inert atmosphere 3.1: triethylamine / dichloromethane / 0 - 20 °C 4.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran / 50 °C / 2250.23 Torr View Scheme
Multi-step reaction with 4 steps 1.1: sodium hydrogencarbonate / dichloromethane 1.2: 0.25 h 1.3: Inert atmosphere 2.1: copper(l) iodide; dichloro bis(acetonitrile) palladium(II) / acetonitrile / Inert atmosphere 3.1: thionyl chloride / toluene / 2 h / 60 °C 4.1: 5%-palladium/activated carbon; hydrogen; hydrogenchloride / methanol / Inert atmosphere View Scheme

(2,2-difluoro-1,3-benzodioxol-5-yl)-1-ethyIacetate acetonitrile (1335233-51-6) → (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (1152311-62-0)

Conditions	Yield
Multi-step reaction with 6 steps 1: hydrogenchloride / water; dimethyl sulfoxide / 40 - 75 °C 2: tetraoctyl ammonium bromide; potassium hydroxide / water / 1 h / 70 °C 3: sodium hydroxide; water / ethanol / 80 °C 4: thionyl chloride / toluene / 60 °C 5: triethylamine / dichloromethane / 0 - 20 °C 6: hydrogen / 5%-palladium/activated carbon / tetrahydrofuran / 96 h / 50 °C / 2250.23 - 3000.3 Torr / autoclave; Inert atmosphere View Scheme
Multi-step reaction with 5 steps 1: hydrogenchloride / dimethyl sulfoxide / 40 - 75 °C 2: potassium hydroxide; tetraoctyl ammonium bromide / water / 1 h / 70 °C 3: sodium hydroxide / ethanol / 80 °C 4: thionyl chloride / toluene / 2 h / 60 °C 5: 5%-palladium/activated carbon; hydrogen; hydrogenchloride / methanol / Inert atmosphere View Scheme
Multi-step reaction with 6 steps 1.1: hydrogenchloride / water; dimethyl sulfoxide / 40 - 75 °C 2.1: sodium hydroxide; tetrabutylammomium bromide / water; tert-butyl methyl ether / 23 °C / Inert atmosphere 3.1: sodium hydroxide / ethanol / 16 h / 77 - 80 °C 3.2: 10 - 25 °C 4.1: thionyl chloride / toluene / 2 h / 60 °C 5.1: triethylamine / toluene; dichloromethane / 0 - 20 °C 6.1: hydrogen; 5%-palladium/activated carbon / tetrahydrofuran / 50 °C / 2250.23 Torr / Inert atmosphere; Large scale View Scheme

(R)-4-(3-(benzyloxy)-2-hydroxypropylamino)-5-bromo-2-fluorobenzenaminium 4-methylbenzenesulfonate (1294504-64-5) → (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (1152311-62-0)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sodium hydrogencarbonate / ethyl acetate 1.2: 20 °C 1.3: 80 °C / Inert atmosphere 2.1: dichloro bis(acetonitrile) palladium(II) / acetonitrile / 20 - 80 °C / Inert atmosphere 3.1: triethylamine / dichloromethane / 0 - 20 °C 4.1: hydrogen / 5%-palladium/activated carbon / tetrahydrofuran / 96 h / 50 °C / 2250.23 - 3000.3 Torr / autoclave; Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1.1: palladium diacetate; 1,4-di(diphenylphosphino)-butane; potassium carbonate / acetonitrile / 0.5 h / 20 °C / Inert atmosphere 1.2: 80 °C 2.1: palladium chloride*2MeCN / ethyl acetate; acetonitrile / 20 - 80 °C / Inert atmosphere 3.1: triethylamine / dichloromethane / 0 - 20 °C 4.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran / 50 °C / 2250.23 Torr View Scheme
Multi-step reaction with 4 steps 1.1: sodium hydrogencarbonate / ethyl acetate / 20 °C / Inert atmosphere 1.2: 80 °C / Inert atmosphere 2.1: dichloro bis(acetonitrile) palladium(II) / acetonitrile / 80 °C / Inert atmosphere; Large scale 3.1: triethylamine / toluene; dichloromethane / 0 - 20 °C 4.1: hydrogen; 5%-palladium/activated carbon / tetrahydrofuran / 50 °C / 2250.23 Torr / Inert atmosphere; Large scale View Scheme
Multi-step reaction with 4 steps 1.1: sodium hydrogencarbonate / ethyl acetate 1.2: 80 °C 2.1: dichloro bis(acetonitrile) palladium(II) / acetonitrile / 80 °C / Inert atmosphere 3.1: triethylamine / dichloromethane / 0 - 20 °C 4.1: hydrogen; 5%-palladium/activated carbon / tetrahydrofuran / 96 h / 50 °C / 2250.23 Torr / Inert atmosphere; Autoclave View Scheme
Multi-step reaction with 5 steps 1.1: sodium hydrogencarbonate / ethyl acetate 2.1: palladium diacetate; potassium carbonate; 1,4-di(diphenylphosphino)-butane / acetonitrile / 1 h / Inert atmosphere; Large scale 2.2: 16 h / 80 °C / Large scale 3.1: dichloro bis(acetonitrile) palladium(II) / acetonitrile / 20 - 80 °C / Inert atmosphere; Large scale 4.1: triethylamine / dichloromethane / 0 - 20 °C 5.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran / 50 °C / 2250.23 Torr / Inert atmosphere; Sealed tube View Scheme

(2R)-1-{4-amino-2-[4-(benzyloxy)-3,3-dimethylbut-1-yn-1-yl]-5-fluoroanilino}-3-(benzyloxy)propan-2-ol (1294504-66-7) → (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (1152311-62-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: dichloro bis(acetonitrile) palladium(II) / acetonitrile / 20 - 80 °C / Inert atmosphere 2: triethylamine / dichloromethane / 0 - 20 °C 3: hydrogen / 5%-palladium/activated carbon / tetrahydrofuran / 96 h / 50 °C / 2250.23 - 3000.3 Torr / autoclave; Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: palladium chloride*2MeCN / ethyl acetate; acetonitrile / 20 - 80 °C / Inert atmosphere 2: triethylamine / dichloromethane / 0 - 20 °C 3: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran / 50 °C / 2250.23 Torr View Scheme
Multi-step reaction with 3 steps 1: copper(l) iodide; dichloro bis(acetonitrile) palladium(II) / acetonitrile / Inert atmosphere 2: thionyl chloride / toluene / 2 h / 60 °C 3: 5%-palladium/activated carbon; hydrogen; hydrogenchloride / methanol / Inert atmosphere View Scheme

1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid (862574-88-7) + N-benzylglycolated-5-amino-2-(2-benzyloxy-1,1-dimethylethyl)-6-fluoroindole → (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (1152311-62-0)

Conditions	Yield
With thionyl chloride; triethylamine In dichloromethane; water; toluene

(2,2-difluoro-1,3-benzodioxol-5-yl)-1-ethylacetate-acetonitrile → (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (1152311-62-0)

Conditions	Yield
Multi-step reaction with 6 steps 1: hydrogenchloride / dimethyl sulfoxide; water / 1 h / 40 - 75 °C 2: potassium hydroxide; tetraoctyl ammonium bromide / water / 1 h / 70 °C 3: sodium hydroxide; water / ethanol / 80 °C 4: thionyl chloride / toluene / 60 °C 5: triethylamine / dichloromethane / 0 - 20 °C 6: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran / 50 °C / 2250.23 Torr View Scheme

1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)cyclopropane carboxylic acid chloride (1004294-65-8) → (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (1152311-62-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 0 - 20 °C 2: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran / 50 °C / 2250.23 Torr / Inert atmosphere; Sealed tube View Scheme

(3-chloro-3-methylbut-1-yn-1-yl)trimethylsilane (18387-63-8) → (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (1152311-62-0)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: magnesium / tetrahydrofuran / 3.5 h / Inert atmosphere 1.2: 16 h / 25 °C 2.1: potassium hydroxide / methanol / 25 °C 3.1: palladium diacetate; potassium carbonate; 1,4-di(diphenylphosphino)-butane / acetonitrile / 1 h / Inert atmosphere; Large scale 3.2: 16 h / 80 °C / Large scale 4.1: dichloro bis(acetonitrile) palladium(II) / acetonitrile / 20 - 80 °C / Inert atmosphere; Large scale 5.1: triethylamine / dichloromethane / 0 - 20 °C 6.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran / 50 °C / 2250.23 Torr / Inert atmosphere; Sealed tube View Scheme

2-methyl-4-(trimethylsilyl)but-3-yn-2-ol (5272-33-3) → (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (1152311-62-0)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: hydrogenchloride / water / 16 h 2.1: magnesium / tetrahydrofuran / 3.5 h / Inert atmosphere 2.2: 16 h / 25 °C 3.1: potassium hydroxide / methanol / 25 °C 4.1: palladium diacetate; potassium carbonate; 1,4-di(diphenylphosphino)-butane / acetonitrile / 1 h / Inert atmosphere; Large scale 4.2: 16 h / 80 °C / Large scale 5.1: dichloro bis(acetonitrile) palladium(II) / acetonitrile / 20 - 80 °C / Inert atmosphere; Large scale 6.1: triethylamine / dichloromethane / 0 - 20 °C 7.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran / 50 °C / 2250.23 Torr / Inert atmosphere; Sealed tube View Scheme

(2R)-1-{5-amino-2-[1-(benzyloxy)-2-methylpropan-2-yl]-6-fluoro-1H-indol-1-yl}-3-(benzyloxy)propan-2-ol (1294504-67-8) → (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (1152311-62-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 0 - 20 °C 2: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran / 50 °C / 2250.23 Torr / Inert atmosphere; Sealed tube View Scheme

(R)-1-(4-amino-2-bromo-5-fluorophenylamino)-3-(benzyloxy)propan-2-ol (1294504-63-4) → (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (1152311-62-0)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: palladium diacetate; potassium carbonate; 1,4-di(diphenylphosphino)-butane / acetonitrile / 1 h / Inert atmosphere; Large scale 1.2: 16 h / 80 °C / Large scale 2.1: dichloro bis(acetonitrile) palladium(II) / acetonitrile / 20 - 80 °C / Inert atmosphere; Large scale 3.1: triethylamine / dichloromethane / 0 - 20 °C 4.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran / 50 °C / 2250.23 Torr / Inert atmosphere; Sealed tube View Scheme
Multi-step reaction with 4 steps 1: sodium hydroxide; 1,4-di(diphenylphosphino)-butane; copper(l) iodide; palladium diacetate / acetonitrile / Inert atmosphere; Reflux 2: sodium hydroxide; copper(l) iodide / 1-methyl-pyrrolidin-2-one; chlorobenzene / 30 h / 130 °C 3: triethylamine 4: hydrogen; palladium on activated charcoal; hydrogenchloride / methanol View Scheme

1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid (862574-88-7) + (2R)-1-{5-amino-2-[1-(benzyloxy)-2-methylpropan-2-yl]-6-fluoro-1H-indol-1-yl}-3-(benzyloxy)propan-2-ol (1294504-67-8) → (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (1152311-62-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: thionyl chloride / toluene / 2 h / 60 °C 2: 5%-palladium/activated carbon; hydrogen; hydrogenchloride / methanol / Inert atmosphere View Scheme

(R)-1-((4-amino-2-bromo-5-fluorophenyl)amino)-3-(benzyloxy)propan-2-ol p-toluenesulfonic acid salt → (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (1152311-62-0)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sodium hydrogencarbonate / dichloromethane 1.2: 0.25 h 1.3: Inert atmosphere 2.1: copper(l) iodide; dichloro bis(acetonitrile) palladium(II) / acetonitrile / Inert atmosphere 3.1: thionyl chloride / toluene / 2 h / 60 °C 4.1: 5%-palladium/activated carbon; hydrogen; hydrogenchloride / methanol / Inert atmosphere View Scheme

1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)cyclopropane carboxylic acid chloride (1004294-65-8) + (2R)-1-{5-amino-2-[1-(benzyloxy)-2-methylpropan-2-yl]-6-fluoro-1H-indol-1-yl}-3-(benzyloxy)propan-2-ol (1294504-67-8) → (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (1152311-62-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / toluene; dichloromethane / 0 - 20 °C 2: hydrogen; 5%-palladium/activated carbon / tetrahydrofuran / 50 °C / 2250.23 Torr / Inert atmosphere; Large scale View Scheme
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 0 - 20 °C 2: hydrogen; 5%-palladium/activated carbon / tetrahydrofuran / 96 h / 50 °C / 2250.23 Torr / Inert atmosphere; Autoclave View Scheme

(R)-1-(benzyloxy)-3-(2-bromo-5-fluoro-4-nitrophenylamino)propan-2-ol (1342896-73-4) → (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (1152311-62-0)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: hydrogen / Isopropyl acetate / 30 °C / 750.08 Torr / Inert atmosphere; Molecular sieve 2.1: sodium hydrogencarbonate / ethyl acetate / 20 °C / Inert atmosphere 2.2: 80 °C / Inert atmosphere 3.1: dichloro bis(acetonitrile) palladium(II) / acetonitrile / 80 °C / Inert atmosphere; Large scale 4.1: triethylamine / toluene; dichloromethane / 0 - 20 °C 5.1: hydrogen; 5%-palladium/activated carbon / tetrahydrofuran / 50 °C / 2250.23 Torr / Inert atmosphere; Large scale View Scheme
Multi-step reaction with 5 steps 1.1: hydrogen; platinum on carbon / Isopropyl acetate / 30 °C / 750.08 Torr / Inert atmosphere 2.1: sodium hydrogencarbonate / ethyl acetate 2.2: 80 °C 3.1: dichloro bis(acetonitrile) palladium(II) / acetonitrile / 80 °C / Inert atmosphere 4.1: triethylamine / dichloromethane / 0 - 20 °C 5.1: hydrogen; 5%-palladium/activated carbon / tetrahydrofuran / 96 h / 50 °C / 2250.23 Torr / Inert atmosphere; Autoclave View Scheme

2,2-difluorobenzo[1,3]dioxole-5-carboxylic acid methyl ester (773873-95-3) → (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (1152311-62-0)

Conditions

Yield

Multi-step reaction with 8 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 1 h / 0 - 20 °C 2: thionyl chloride / dichloromethane / 0 - 20 °C 3: dimethyl sulfoxide / 20 °C 4: sodium hydroxide; N-benzyl-N,N,N-triethylammonium chloride / 70 °C 5: sodium hydroxide / water / 2.5 h / Reflux 6: thionyl chloride / toluene / 0.5 h / 60 °C 7: triethylamine / dichloromethane / 0 - 20 °C 8: hydrogen; 5%-palladium/activated carbon / tetrahydrofuran / 96 h / 50 °C / 2250.23 Torr / Inert atmosphere; Autoclave View Scheme

(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (1152311-62-0) → 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-((4R)-8-fluoro-2-hydroxy-4-(hydroxymethyl)-1,1-dimethyl-1,2,4,5-tetrahydro-[1,4]oxazepino[4,5-α]indol-9-yl)cyclopropane carboxamide (1432656-97-7)

Conditions	Yield
Stage #1: (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide With Dess-Martin periodane In dichloromethane at 20℃; Stage #2: With sodium sulfite In dichloromethane; water for 4h; Reagent/catalyst; Temperature; Solvent;	15%

(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (1152311-62-0) → (R)-2-(5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1-(2,3-dihydroxypropyl)-6-fluoro-1H-indol-2-yl)-2-methylpropanoic acid (1432656-98-8)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: Dess-Martin periodane / dichloromethane / 20 °C 1.2: 4 h 2.1: silver (II) carbonate / ethyl acetate; toluene / 7 h / 90 °C View Scheme
Multi-step reaction with 4 steps 1.1: dichloromethane / -10 - 20 °C 1.2: 4 h / 25 °C 2.1: sulfur trioxide pyridine complex; N-ethyl-N,N-diisopropylamine / dichloromethane; dimethyl sulfoxide / 0 - 10 °C 3.1: sodium permanganate / acetone / 0.5 h / -5 - 5 °C 4.1: sodium carbonate / methanol / 24 h View Scheme
Multi-step reaction with 4 steps 1.1: dichloromethane / -10 - 20 °C 1.2: 4 h / 25 °C 2.1: sulfur trioxide pyridine complex; N-ethyl-N,N-diisopropylamine / dichloromethane; dimethyl sulfoxide / 0 - 10 °C 3.1: sodium permanganate / water; acetone / 0 °C 4.1: sodium carbonate / methanol View Scheme

(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (1152311-62-0) → C27H23F3N2O7 (1432657-00-5)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: dichloromethane / -10 - 20 °C 1.2: 4 h / 25 °C 2.1: sulfur trioxide pyridine complex; N-ethyl-N,N-diisopropylamine / dichloromethane; dimethyl sulfoxide / 0 - 10 °C View Scheme

(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (1152311-62-0) → C27H22F3N2O8(1-)*Na(1+)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: dichloromethane / -10 - 20 °C 1.2: 4 h / 25 °C 2.1: sulfur trioxide pyridine complex; N-ethyl-N,N-diisopropylamine / dichloromethane; dimethyl sulfoxide / 0 - 10 °C 3.1: sodium permanganate / water; acetone / 0 °C View Scheme

(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (1152311-62-0) → C27H23F3N2O8 (1432657-01-6)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: dichloromethane / -10 - 20 °C 1.2: 4 h / 25 °C 2.1: sulfur trioxide pyridine complex; N-ethyl-N,N-diisopropylamine / dichloromethane; dimethyl sulfoxide / 0 - 10 °C 3.1: sodium permanganate / acetone / 0.5 h / -5 - 5 °C View Scheme

(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (1152311-62-0) + 1,1'-carbonyldiimidazole (530-62-1) → C27H25F3N2O7 (1432656-99-9)

Conditions	Yield
Stage #1: (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide; 1,1'-carbonyldiimidazole In dichloromethane at -10 - 20℃; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 25℃; for 4h;

Upstream product

• 1152311-65-3 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cycIopropanecarboxamide 
• 1260655-24-0 2-nitro-4-fluoro-5-chlorobenzeneacetonitrile 
• 1152311-83-5 (R)-2-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropan-1-ol 
• 1004294-65-8 1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)cyclopropane carboxylic acid chloride 

Relevant articles and documents

NOVEL PROCESSES FOR PREPARATION OF TEZACAFTOR

The present invention generally relates to processes for preparation of Tezacaftor and pharmaceutical composition comprising the same. The present invention also encompasses novel intermediates of tezacaftor, processes for its preparation and use of said intermediates in the preparation of tezacaftor.

SOLID FORMS OF TEZACAFTOR, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS THEREOF

The present invention relates to solid forms of Tezacaftor, including its co-crystals, solvates, hydrates and/or polymorphs, processes for their preparation, pharmaceutical compositions containing the same and use of such solid forms of Tezacaftor in the preparation of another form of Tezacaftor such as amorphous form of Tezacaftor. The present invention also provides stable amorphous form of Tezacaftor, its preparation and pharmaceutical composition containing the same.

Preparation method of 5-substituted cyclopropyl formylamino indole derivative

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