1294504-67-8

Basic information

• Product Name: 1H-Indole-1-ethanol, 5-aMino-2-[1,1-diMethyl-2-(phenylMethoxy)ethyl]-6-fluoro-α-[(phenylMethoxy)Methyl]-, (αR)-
• Synonyms: 1H-Indole-1-ethanol, 5-aMino-2-[1,1-diMethyl-2-(phenylMethoxy)ethyl]-6-fluoro-α-[(phenylMethoxy)Methyl]-, (αR)-;(R)-1-(5-aMino-2-(1-(benzyloxy)-2-Methylpropan-2-yl)-6-fluoro-1H-indol-1-yl)-3-(benzyloxy)propan-2-ol;1H-Indole-1-ethanol, 5-aMino-2-[1,1-diMethyl-2-(phenylMethoxy)ethyl]-6-fluoro-α-[(phenylMethoxy)Methyl]-, (αR)-8;(2R)-1-[5-Amino-2-(2-benzyloxy-1,1-dimethyl-ethyl)-6-fluoro-indol-1-yl]-3-benzyloxy-propan-2-ol;(2R)-1-{5-amino-2-[1-(benzyloxy)-2-methylpropan-2-yl]-6-fluoro-6,7-dihydro-1H-indol-1-yl}-3-(benzyloxy)propan-2-ol;(2R)-1-{5-amino-2-[1-(benzyloxy)-2-methyl-2-propanyl]-6-fluoro-1H-indol-1-yl}-3-(benzyloxy)-2-propanol;(R)-1-[5-Amino-2-(2-benzyloxy-1,1-dimethyl-ethyl)-6-fluoro-indol-1-yl]-3-benzyloxy-propan-2-ol;(2R)-1-[5-Amino-2-(2-benzyloxy-1,1-dimethyl-ethyl)-6-fluoro-indol-1-yl]-3-benzyloxy-propan-2-o
• CAS NO: 1294504-67-8
• Molecular Formula: C₂₉H₃₃FN₂O₃
• Molecular Weight: 476.5823232
• Mol File: 1294504-67-8.mol
• Article Data: 12

Chemical Properties

• Boiling Point: 648.5±55.0 °C(Predicted)
• Appearance: /
• Density: 1.16±0.1 g/cm3(Predicted)
• Storage Temp.: Hygroscopic, Refrigerator, under inert atmosphere
• Solubility: DMSO (Slightly), Methanol (Very Slightly)
• PKA: 13.99±0.20(Predicted)
• CAS DataBase Reference: 1H-Indole-1-ethanol, 5-aMino-2-[1,1-diMethyl-2-(phenylMethoxy)ethyl]-6-fluoro-α-[(phenylMethoxy)Methyl]-, (αR)-(CAS DataBase Reference)
• NIST Chemistry Reference: 1H-Indole-1-ethanol, 5-aMino-2-[1,1-diMethyl-2-(phenylMethoxy)ethyl]-6-fluoro-α-[(phenylMethoxy)Methyl]-, (αR)-(1294504-67-8)
• EPA Substance Registry System: 1H-Indole-1-ethanol, 5-aMino-2-[1,1-diMethyl-2-(phenylMethoxy)ethyl]-6-fluoro-α-[(phenylMethoxy)Methyl]-, (αR)-(1294504-67-8)

Safety Data

• Hazardous Substances Data: 1294504-67-8(Hazardous Substances Data)

Usage

Uses

(R)-1-(5-Amino-2-(1-(benzyloxy)-2-methylpropan-2-yl)-6-fluoro-1H-indol-1-yl)-3-(benzyloxy)propan-2-ol is a Tezacaftor (T321510) intermediate. Tezacaftor is used as a combination therapy with Ivacaftor for the treatment of patients with cystic fibrosis.

Synthetic route

(2R)-1-{4-amino-2-[4-(benzyloxy)-3,3-dimethylbut-1-yn-1-yl]-5-fluoroanilino}-3-(benzyloxy)propan-2-ol (1294504-66-7) → (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)

Conditions	Yield
With dichloro bis(acetonitrile) palladium(II); copper(l) iodide In acetonitrile at 80℃; for 3h; Inert atmosphere;	61.4%
With dichloro bis(acetonitrile) palladium(II); copper(l) iodide In acetonitrile Inert atmosphere;	38%
dichloro bis(acetonitrile) palladium(II) In acetonitrile at 20 - 80℃; Inert atmosphere;

(2R)-1-{4-amino-2-[4-(benzyloxy)-3,3-dimethylbut-1-yn-1-yl]-5-fluoroanilino}-3-(benzyloxy)propan-2-ol (1294504-66-7) + dichlorobis(acetonitrile)palladium(II) → (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) + N-benzylglycolated-5-amino-2-(2-benzyloxy-1,1-dimethylethyl)-6-fluoroindole

Conditions	Yield
With CuI In n-heptane; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; ethyl acetate; acetonitrile	A 27% B n/a

3-fluoro-4-nitroaniline (2369-13-3) → (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)

Conditions	Yield
Multi-step reaction with 4 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 View Scheme
Multi-step reaction with 4 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 View Scheme
Multi-step reaction with 4 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 View Scheme

2-bromo-5-fluoro-4-nitroaniline (952664-69-6) → (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)

Conditions	Yield
Multi-step reaction with 3 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 View Scheme
Multi-step reaction with 3 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 View Scheme
Multi-step reaction with 3 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 View Scheme

(4-(benzyloxy)-3,3-dimethylbut-1-ynyl)trimethylsilane (1294504-65-6) → (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)

Conditions	Yield
Multi-step reaction with 3 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 View Scheme
Multi-step reaction with 3 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 View Scheme
Multi-step reaction with 3 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 View Scheme

(((2,2-dimethylbut-3-yn-1-yl)oxy)methyl)benzene (1092536-54-3) → (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)

Conditions	Yield
Multi-step reaction with 2 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 View Scheme
Multi-step reaction with 2 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 View Scheme
Multi-step reaction with 2 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 View Scheme

(R)-4-(3-(benzyloxy)-2-hydroxypropylamino)-5-bromo-2-fluorobenzenaminium 4-methylbenzenesulfonate (1294504-64-5) → (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)

Conditions	Yield
Multi-step reaction with 2 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 View Scheme
Multi-step reaction with 2 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 View Scheme
Multi-step reaction with 2 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 View Scheme

(3-chloro-3-methylbut-1-yn-1-yl)trimethylsilane (18387-63-8) → (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)

Conditions

Yield

Multi-step reaction with 4 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 View Scheme

2-methyl-4-(trimethylsilyl)but-3-yn-2-ol (5272-33-3) → (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)

Conditions

Yield

Multi-step reaction with 5 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 View Scheme

(R)-1-(4-amino-2-bromo-5-fluorophenylamino)-3-(benzyloxy)propan-2-ol (1294504-63-4) → (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)

Conditions	Yield
Multi-step reaction with 3 steps 1: dichloromethane / 16 h / 20 °C 2: palladium diacetate; 1,4-di(diphenylphosphino)-butane; potassium carbonate / acetonitrile / 16 h / 80 °C / Inert atmosphere 3: dichloro bis(acetonitrile) palladium(II) / acetonitrile / 12 h / 85 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: potassium carbonate; palladium diacetate; 1,4-di(diphenylphosphino)-butane; copper(l) iodide / acetonitrile / 20 - 80 °C / Inert atmosphere 2: copper(l) iodide; dichloro bis(acetonitrile) palladium(II) / acetonitrile / 3 h / 80 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 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 View Scheme

(R)-1-((4-amino-2-bromo-5-fluorophenyl)amino)-3-(benzyloxy)propan-2-ol p-toluenesulfonic acid salt → (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)

Conditions	Yield
Multi-step reaction with 2 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 View Scheme

(R)-1-(benzyloxy)-3-(2-bromo-5-fluoro-4-nitrophenylamino)propan-2-ol (1342896-73-4) → (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)

Conditions	Yield
Multi-step reaction with 3 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 View Scheme
Multi-step reaction with 3 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 View Scheme
Multi-step reaction with 4 steps 1: ammonium chloride; zinc / water; ethanol / 4 h / 85 °C 2: dichloromethane / 16 h / 20 °C 3: palladium diacetate; 1,4-di(diphenylphosphino)-butane; potassium carbonate / acetonitrile / 16 h / 80 °C / Inert atmosphere 4: dichloro bis(acetonitrile) palladium(II) / acetonitrile / 12 h / 85 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: platinum on carbon; hydrogen / Isopropyl acetate / 17.5 h / 20 °C / 2585.81 Torr 2: potassium carbonate; palladium diacetate; 1,4-di(diphenylphosphino)-butane; copper(l) iodide / acetonitrile / 20 - 80 °C / Inert atmosphere 3: copper(l) iodide; dichloro bis(acetonitrile) palladium(II) / acetonitrile / 3 h / 80 °C / Inert atmosphere View Scheme

(S)-benzyl glycidyl ether (2930-05-4, 14618-80-5, 89616-40-0, 16495-13-9) → (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)

Conditions

Yield

Multi-step reaction with 5 steps 1: iron(III) chloride / ethyl acetate / 2 h / 20 - 28 °C 2: N-Bromosuccinimide / ethyl acetate / 1 h / 20 °C 3: platinum on carbon; hydrogen / Isopropyl acetate / 17.5 h / 20 °C / 2585.81 Torr 4: potassium carbonate; palladium diacetate; 1,4-di(diphenylphosphino)-butane; copper(l) iodide / acetonitrile / 20 - 80 °C / Inert atmosphere 5: copper(l) iodide; dichloro bis(acetonitrile) palladium(II) / acetonitrile / 3 h / 80 °C / Inert atmosphere View Scheme

(2R)-1-(benzyloxy)-3-(3-fluoro-4-nitroanilino)propan-2-ol → (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)

Conditions

Yield

Multi-step reaction with 4 steps 1: N-Bromosuccinimide / ethyl acetate / 1 h / 20 °C 2: platinum on carbon; hydrogen / Isopropyl acetate / 17.5 h / 20 °C / 2585.81 Torr 3: potassium carbonate; palladium diacetate; 1,4-di(diphenylphosphino)-butane; copper(l) iodide / acetonitrile / 20 - 80 °C / Inert atmosphere 4: copper(l) iodide; dichloro bis(acetonitrile) palladium(II) / acetonitrile / 3 h / 80 °C / Inert atmosphere View Scheme

(((2,2-dimethylbut-3-yn-1-yl)oxy)methyl)benzene (1092536-54-3) + (R)-4-(3-(benzyloxy)-2-hydroxypropylamino)-5-bromo-2-fluorobenzenaminium 4-methylbenzenesulfonate (1294504-64-5) → (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)

Conditions	Yield
Multi-step reaction with 2 steps 1: palladium diacetate; copper(l) iodide; sodium hydroxide; 1,4-di(diphenylphosphino)-butane / acetonitrile / Reflux 2: zinc dibromide; 1-methyl-pyrrolidin-2-one; sodium hydroxide / chlorobenzene / 24 h / Reflux 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) + (7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carboxylic acid → (7R)-N-{1-[(2R)-3-(benzyloxy)-2-hydroxypropyl]-2-[1-(benzyloxy)-2-methylpropan-2-yl]-6-fluoro-1H-indol-5-yl}-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carboxamide

Conditions	Yield
Stage #1: (7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carboxylic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1h; Stage #2: (2R)-1-{5-amino-2-[1-(benzyloxy)-2-methylpropan-2-yl]-6-fluoro-1H-indol-1-yl}-3-(benzyloxy)propan-2-ol With pyridine In dichloromethane at 60℃; for 19h;	82%

(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) + (7S)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carboxylic acid → (7S)-N-{1-[(2R)-3-(benzyloxy)-2-hydroxypropyl]-2-[1-(benzyloxy)-2-methylpropan-2-yl]-6-fluoro-1H-indol-5-yl}-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carboxamide

Conditions	Yield
Stage #1: (7S)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carboxylic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1h; Stage #2: (2R)-1-{5-amino-2-[1-(benzyloxy)-2-methylpropan-2-yl]-6-fluoro-1H-indol-1-yl}-3-(benzyloxy)propan-2-ol With pyridine In dichloromethane at 60℃; for 16h;	63%

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) → 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)

Conditions	Yield
With triethylamine In dichloromethane at 0 - 20℃;
With triethylamine In dichloromethane at 0 - 20℃;
With triethylamine In dichloromethane at 0 - 20℃;

(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) → 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
Multi-step reaction with 3 steps 1.1: triethylamine / dichloromethane / 0 - 20 °C 2.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran / 50 °C / 2250.23 Torr / Inert atmosphere; Sealed tube 3.1: Dess-Martin periodane / dichloromethane / 20 °C 3.2: 4 h 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)-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 4 steps 1.1: triethylamine / dichloromethane / 0 - 20 °C 2.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran / 50 °C / 2250.23 Torr / Inert atmosphere; Sealed tube 3.1: Dess-Martin periodane / dichloromethane / 20 °C 3.2: 4 h 4.1: silver (II) carbonate / ethyl acetate; toluene / 7 h / 90 °C View Scheme
Multi-step reaction with 6 steps 1.1: triethylamine / dichloromethane / 0 - 20 °C 2.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran / 50 °C / 2250.23 Torr / Inert atmosphere; Sealed tube 3.1: dichloromethane / -10 - 20 °C 3.2: 4 h / 25 °C 4.1: sulfur trioxide pyridine complex; N-ethyl-N,N-diisopropylamine / dichloromethane; dimethyl sulfoxide / 0 - 10 °C 5.1: sodium permanganate / acetone / 0.5 h / -5 - 5 °C 6.1: sodium carbonate / methanol / 24 h View Scheme
Multi-step reaction with 6 steps 1.1: triethylamine / dichloromethane / 0 - 20 °C 2.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran / 50 °C / 2250.23 Torr / Inert atmosphere; Sealed tube 3.1: dichloromethane / -10 - 20 °C 3.2: 4 h / 25 °C 4.1: sulfur trioxide pyridine complex; N-ethyl-N,N-diisopropylamine / dichloromethane; dimethyl sulfoxide / 0 - 10 °C 5.1: sodium permanganate / water; acetone / 0 °C 6.1: sodium carbonate / methanol View Scheme

(R)-1-((4-amino-2-(4-(benzyloxy)-3,3-dimethylbut-1-yn-1-yl)-5-fluorophenyl)amino)-3-(benzyloxy)propan-2-ol (1294504-66-7) → (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)

Conditions	Yield
With dichloro bis(acetonitrile) palladium(II); copper(l) iodide In acetonitrile at 80℃; for 3h; Inert atmosphere;	61.4%
With dichloro bis(acetonitrile) palladium(II); copper(l) iodide In acetonitrile Inert atmosphere;	38%
dichloro bis(acetonitrile) palladium(II) In acetonitrile at 20 - 80℃; Inert atmosphere;

(R)-1-((4-amino-2-(4-(benzyloxy)-3,3-dimethylbut-1-yn-1-yl)-5-fluorophenyl)amino)-3-(benzyloxy)propan-2-ol (1294504-66-7) + dichlorobis(acetonitrile)palladium(II) → (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) + N-benzylglycolated-5-amino-2-(2-benzyloxy-1,1-dimethylethyl)-6-fluoroindole

Conditions	Yield
With CuI In n-heptane; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; ethyl acetate; acetonitrile	A 27% B n/a

(R)-1-((4-amino-2-bromo-5-fluorophenyl)amino)-3-(benzyloxy)propan-2-ol p-toluenesulfonic acid salt (1294504-64-5) → (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)

Conditions	Yield
Multi-step reaction with 2 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 View Scheme
Multi-step reaction with 2 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 View Scheme
Multi-step reaction with 2 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 View Scheme

(R)-1-(benzyloxy)-3-(2-bromo-5-fluoro-4-nitrophenylamino)propan-2-ol (1342896-73-4) → (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)

Conditions	Yield
Multi-step reaction with 3 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 View Scheme
Multi-step reaction with 3 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 View Scheme
Multi-step reaction with 4 steps 1: ammonium chloride; zinc / water; ethanol / 4 h / 85 °C 2: dichloromethane / 16 h / 20 °C 3: palladium diacetate; 1,4-di(diphenylphosphino)-butane; potassium carbonate / acetonitrile / 16 h / 80 °C / Inert atmosphere 4: dichloro bis(acetonitrile) palladium(II) / acetonitrile / 12 h / 85 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: platinum on carbon; hydrogen / Isopropyl acetate / 17.5 h / 20 °C / 2585.81 Torr 2: potassium carbonate; palladium diacetate; 1,4-di(diphenylphosphino)-butane; copper(l) iodide / acetonitrile / 20 - 80 °C / Inert atmosphere 3: copper(l) iodide; dichloro bis(acetonitrile) palladium(II) / acetonitrile / 3 h / 80 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1.1: platinum on carbon; hydrogen / Isopropyl acetate / 30 °C / 750.08 Torr 2.1: sodium hydrogencarbonate / water; dichloromethane 2.2: 80 °C / Inert atmosphere 3.1: copper(l) iodide; dichloro bis(acetonitrile) palladium(II) / acetonitrile / 80 °C / Inert atmosphere View Scheme

(((2,2-dimethylbut-3-yn-1-yl)oxy)methyl)benzene (1092536-54-3) + (R)-1-((4-amino-2-bromo-5-fluorophenyl)amino)-3-(benzyloxy)propan-2-ol p-toluenesulfonic acid salt (1294504-64-5) → (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)

Conditions	Yield
Multi-step reaction with 2 steps 1: palladium diacetate; copper(l) iodide; sodium hydroxide; 1,4-di(diphenylphosphino)-butane / acetonitrile / Reflux 2: zinc dibromide; 1-methyl-pyrrolidin-2-one; sodium hydroxide / chlorobenzene / 24 h / Reflux 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

(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) → C27H25F3N2O7 (1432656-99-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: triethylamine / dichloromethane / 0 - 20 °C 2.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran / 50 °C / 2250.23 Torr / Inert atmosphere; Sealed tube 3.1: dichloromethane / -10 - 20 °C 3.2: 4 h / 25 °C 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) → C27H23F3N2O7 (1432657-00-5)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: triethylamine / dichloromethane / 0 - 20 °C 2.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran / 50 °C / 2250.23 Torr / Inert atmosphere; Sealed tube 3.1: dichloromethane / -10 - 20 °C 3.2: 4 h / 25 °C 4.1: sulfur trioxide pyridine complex; N-ethyl-N,N-diisopropylamine / dichloromethane; dimethyl sulfoxide / 0 - 10 °C 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) → C27H22F3N2O8(1-)*Na(1+)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: triethylamine / dichloromethane / 0 - 20 °C 2.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran / 50 °C / 2250.23 Torr / Inert atmosphere; Sealed tube 3.1: dichloromethane / -10 - 20 °C 3.2: 4 h / 25 °C 4.1: sulfur trioxide pyridine complex; N-ethyl-N,N-diisopropylamine / dichloromethane; dimethyl sulfoxide / 0 - 10 °C 5.1: sodium permanganate / water; acetone / 0 °C 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) → C27H23F3N2O8 (1432657-01-6)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: triethylamine / dichloromethane / 0 - 20 °C 2.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran / 50 °C / 2250.23 Torr / Inert atmosphere; Sealed tube 3.1: dichloromethane / -10 - 20 °C 3.2: 4 h / 25 °C 4.1: sulfur trioxide pyridine complex; N-ethyl-N,N-diisopropylamine / dichloromethane; dimethyl sulfoxide / 0 - 10 °C 5.1: sodium permanganate / acetone / 0.5 h / -5 - 5 °C 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) → 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)

Conditions	Yield
Stage #1: 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid With thionyl chloride In toluene at 60℃; for 2h; Stage #2: (2R)-1-{5-amino-2-[1-(benzyloxy)-2-methylpropan-2-yl]-6-fluoro-1H-indol-1-yl}-3-(benzyloxy)propan-2-ol With triethylamine In dichloromethane; toluene

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

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
Multi-step reaction with 2 steps 1: triethylamine / toluene; dichloromethane / 0 - 25 °C 2: hydrogenchloride; hydrogen; 5%-palladium/activated carbon / methanol 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 (1152311-99-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 2 h / 0 - 25 °C / Inert atmosphere 2: palladium on activated charcoal; hydrogenchloride; hydrogen / water; methanol / 20 °C 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) + (7S)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carboxylic acid → (7S)-N-{1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl}-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carboxamide

Conditions	Yield
Multi-step reaction with 2 steps 1.1: N,N-dimethyl-formamide; oxalyl dichloride / dichloromethane / 1 h / 20 °C 1.2: 16 h / 60 °C 2.1: boron trichloride / dichloromethane / 0.5 h / -70 °C / Cooling with acetone-dry ice View Scheme

Upstream product

• 1092536-54-3 [{(2,2-dimethylbut-3-yn-1-yl)oxy}methyl]benzene 
• 1294504-64-5 (R)-1-((4-amino-2-bromo-5-fluorophenyl)amino)-3-(benzyloxy)propan-2-ol p-toluenesulfonic acid salt 
• 2930-05-4 (S)-benzyl glycidyl ether 
• 1342896-73-4 (R)-1-(benzyloxy)-3-(2-bromo-5-fluoro-4-nitrophenylamino)propan-2-ol 
• 1294504-63-4 (R)-1-(4-amino-2-bromo-5-fluorophenylamino)-3-(benzyloxy)propan-2-ol 
• 5272-33-3 2-methyl-4-(trimethylsilyl)but-3-yn-2-ol 
• 18387-63-8 (3-chloro-3-methylbut-1-yn-1-yl)trimethylsilane 
• 1294504-66-7 (R)-1-((4-amino-2-(4-(benzyloxy)-3,3-dimethylbut-1-yn-1-yl)-5-fluorophenyl)amino)-3-(benzyloxy)propan-2-ol 
• 1294504-65-6 (4-(benzyloxy)-3,3-dimethylbut-1-ynyl)trimethylsilane 
• 952664-69-6 2-bromo-5-fluoro-4-nitroaniline 
• 2369-13-3 3-fluoro-4-nitroaniline 

Downstream Products

• 1294504-68-9 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 
• 1152311-62-0 (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 

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