862574-88-7

Basic information

• Product Name: 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylicacid
• Synonyms: 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylicacid;1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic;1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid;Cyclopropanecarboxylic acid, 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-;1-(2,2-Difluorobenzodioxol-5-yl)cyclopropanecarboxylic acid;1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)cyclopropane-1-carboxylic acid;1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-1-carboxylicacid;Lumacator intermediate
• CAS NO: 862574-88-7
• Molecular Formula: C₁₁H₈F₂O₄
• Molecular Weight: 242.176
• Mol File: 862574-88-7.mol
• Article Data: 38

Chemical Properties

• Boiling Point: 331.1±42.0 °C(Predicted)
• Appearance: /
• Density: 1.59±0.1 g/cm3(Predicted)
• Refractive Index: 1.588
• Storage Temp.: Inert atmosphere,Room Temperature
• Solubility: Chloroform; Dichloromethane; Methanol
• PKA: 4.03±0.20(Predicted)
• CAS DataBase Reference: 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylicacid(CAS DataBase Reference)
• NIST Chemistry Reference: 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylicacid(862574-88-7)
• EPA Substance Registry System: 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylicacid(862574-88-7)

Safety Data

• Hazardous Substances Data: 862574-88-7(Hazardous Substances Data)

Usage

Uses

1-(2,2-Difluorobenzo[1,3]dioxol-5-yl)cyclopropanecarboxylic Acid is used in processes for preparation of Tezacaftor and intermediates thereof.

InChI:InChI=1/C11H8F2O4/c12-11(13)16-7-2-1-6(5-8(7)17-11)10(3-4-10)9(14)15/h1-2,5H,3-4H2,(H,14,15)

Synthetic route

1-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)ethanone → 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid (862574-88-7)

Conditions	Yield
With N-benzyl-N,N,N-triethylammonium chloride; sodium hydroxide In tetrachloromethane; dichloromethane at 20℃; for 16h; Inert atmosphere;	100%

C12H10F2O4 → 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid (862574-88-7)

Conditions	Yield
With sodium hydroxide at 85℃; for 2h;	95.2%
With methanol; sodium hydroxide at 20℃; for 20h;	87.3%

1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonitrile (862574-87-6) → 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid (862574-88-7)

Conditions	Yield
Stage #1: 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonitrile With sodium hydroxide In ethanol at 100℃; for 3h; Inert atmosphere; Stage #2: With hydrogenchloride In ethanol; water pH=2; Cooling; Inert atmosphere;	88%
Stage #1: 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonitrile With sodium hydroxide In ethanol at 77 - 80℃; for 16h; Stage #2: With hydrogenchloride In ethanol; dichloromethane at 10 - 25℃;	79%
Stage #1: 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonitrile With sodium hydroxide In ethanol at 80℃; Stage #2: With hydrogenchloride In tert-butyl methyl ether	69%

ethyl 1-(2,2-difluorobenzo[D] [1,3]dioxol-5-yl)cyclopropanecarboxylate → 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid (862574-88-7)

Conditions	Yield
With sodium hydroxide In methanol at 10 - 30℃; for 2h;	81.1%

2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)acetonitrile (68119-31-3) → 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid (862574-88-7)

Conditions	Yield
	79%
	79%
	79%

2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)acetonitrile (68119-31-3) + 1-Bromo-2-chloroethane (107-04-0) → 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid (862574-88-7)

Conditions	Yield
With N-benzyl-N,N,N-triethylammonium chloride; sodium hydroxide In water at 75℃; for 24h;	52%

1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarboxylic acid dicyclohexylamine salt → 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid (862574-88-7)

Conditions	Yield
With water; citric acid In tert-butyl methyl ether
With citric acid In tert-butyl methyl ether

tert-butyl methyl ether (1634-04-4) + N-cyclohexyl-cyclohexanamine (101-83-7) → 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid (862574-88-7)

Conditions	Yield
With hydrogenchloride; NaOH; citric acid In ethanol; n-heptane
With hydrogenchloride; NaOH; citric acid In ethanol; n-heptane; water

5-bromo-2,2-difluoro-2H-1,3-benzodioxole (33070-32-5) → 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid (862574-88-7)

Conditions	Yield
Multi-step reaction with 4 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 View Scheme
Multi-step reaction with 4 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 View Scheme
Multi-step reaction with 4 steps 1.1: sodium phosphate; bis(dibenzylideneacetone)-palladium(0); tributylphosphine / toluene; hexane / 0.85 h / 23 °C / Inert atmosphere 1.2: 70 °C 2.1: hydrogenchloride / dimethyl sulfoxide; water / 40 - 75 °C 3.1: potassium hydroxide; tetraoctyl ammonium bromide / water / 1 h / 70 °C 4.1: sodium hydroxide / ethanol / 80 °C View Scheme

2,2-difluoro-1,3-benzodioxole-5-carboxylic acid (656-46-2) → 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid (862574-88-7)

Conditions	Yield
Multi-step reaction with 5 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 View Scheme
Multi-step reaction with 4 steps 1: aq. NaOH / toluene 2: thionyl chloride; aq. NaOH / dmap / water 3: NaCN / water; dimethyl sulfoxide View Scheme
Multi-step reaction with 4 steps 1: aq. NaOH / toluene 2: thionyl chloride; aq. NaOH / dmap / water 3: NaCN / water; dimethyl sulfoxide View Scheme

(2,2-difluoro-1,3-benzodioxol-5-yl)methanol (72768-97-9) → 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid (862574-88-7)

Conditions	Yield
Multi-step reaction with 4 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 View Scheme
Multi-step reaction with 3 steps 1: thionyl chloride; aq. NaOH / dmap / water 2: NaCN / water; dimethyl sulfoxide View Scheme
Multi-step reaction with 3 steps 1: thionyl chloride; aq. NaOH / dmap / water 2: NaCN / water; dimethyl sulfoxide View Scheme

5-chloromethyl-2,2-difluoro-benzo[1,3]dioxole (476473-97-9) → 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid (862574-88-7)

Conditions	Yield
Multi-step reaction with 3 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 View Scheme
Multi-step reaction with 3 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 View Scheme
Multi-step reaction with 3 steps 1: dimethyl sulfoxide / 1 h / 30 - 40 °C 2: potassium hydroxide; tetraoctyl ammonium bromide / water / 1 h / 70 °C 3: sodium hydroxide / ethanol / 80 °C View Scheme

(2,2-difluoro-1,3-benzodioxol-5-yl)-1-ethyIacetate acetonitrile (1335233-51-6) → 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid (862574-88-7)

Conditions	Yield
Multi-step reaction with 3 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 View Scheme
Multi-step reaction with 3 steps 1: hydrogenchloride / dimethyl sulfoxide; water / 40 - 75 °C 2: potassium hydroxide; tetraoctyl ammonium bromide / water / 1 h / 70 °C 3: sodium hydroxide / ethanol / 80 °C View Scheme
Multi-step reaction with 3 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 View Scheme

1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonitrile (862574-87-6) + 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran (96042-30-7) → 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid (862574-88-7)

Conditions	Yield
With hydrogenchloride; NaOH In ethanol

N-cyclohexyl-cyclohexanamine (101-83-7) → 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid (862574-88-7)

Conditions	Yield
With hydrogenchloride; citric acid In ethanol; n-heptane

(2,2-difluoro-1,3-benzodioxol-5-yl)-1-ethylacetate-acetonitrile → 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid (862574-88-7)

Conditions	Yield
Multi-step reaction with 3 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 View Scheme

2,2-difluorobenzo[1,3]dioxole-5-carboxylic acid methyl ester (773873-95-3) → 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid (862574-88-7)

Conditions	Yield
Multi-step reaction with 5 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 View Scheme
Multi-step reaction with 5 steps 1.1: lithium aluminium tetrahydride / tetrahydrofuran / 1 h / 0 - 25 °C / Inert atmosphere 2.1: thionyl chloride / dichloromethane / 4 h / 20 °C 3.1: sodium cyanide / dimethyl sulfoxide / 2 h / 20 - 40 °C 4.1: sodium hydroxide; tetrabutylammomium bromide / water; ethanol / 48 h / 70 °C / Inert atmosphere 5.1: sodium hydroxide / ethanol / 3 h / 100 °C / Inert atmosphere 5.2: pH 2 / Cooling; Inert atmosphere View Scheme
Multi-step reaction with 5 steps 1: sodium hydroxide; lithium aluminum hydride / tetrahydrofuran; water 2: thionyl chloride; sodium hydrogencarbonate / dichloromethane 3: NaCN / water; dimethyl sulfoxide 4: aqueous KOH 5: sodium hydroxide View Scheme

1-(2H-1,3-benzodioxol-5-yl)cyclopropane-1-carboxylic acid (862574-89-8) → 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid (862574-88-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: thionyl chloride / 0 - 20 °C 2: phosphorus pentachloride / toluene / 80 °C 3: triethylamine tris(hydrogen fluoride) / 48 h / 20 °C 4: sodium hydroxide; methanol / 20 h / 20 °C View Scheme

methyl 1-(2H-1,3-benzodioxol-5-yl)cyclopropane-1-carboxylate → 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid (862574-88-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: phosphorus pentachloride / toluene / 80 °C 2: triethylamine tris(hydrogen fluoride) / 48 h / 20 °C 3: sodium hydroxide; methanol / 20 h / 20 °C View Scheme

methyl 1-(3,4-dimethoxyphenyl)cyclopropane-1-carboxylate → 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid (862574-88-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: boron tribromide / dichloromethane / 1 h / -20 - -10 °C / Inert atmosphere 2: potassium carbonate; tetrabutylammomium bromide / dimethyl sulfoxide / 100 °C / Autoclave 3: sodium hydroxide / 2 h / 85 °C View Scheme

(3,4-Dimethoxyphenyl)acetic acid (93-40-3) → 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid (862574-88-7)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: 1,1'-carbonyldiimidazole / dichloromethane / 1 h / 20 °C 1.2: 1 h / 20 °C 2.1: potassium carbonate / tetrahydrofuran / 2 h / 40 °C 3.1: potassium tert-butylate / N,N-dimethyl-formamide / 0.75 h / 20 °C / Inert atmosphere 3.2: 1 h / 35 - 45 °C / Inert atmosphere 4.1: boron tribromide / dichloromethane / 1 h / -20 - -10 °C / Inert atmosphere 5.1: potassium carbonate; tetrabutylammomium bromide / dimethyl sulfoxide / 100 °C / Autoclave 6.1: sodium hydroxide / 2 h / 85 °C View Scheme

methyl (3,4-dimethoxyphenyl)acetate (15964-79-1) → 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid (862574-88-7)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: potassium carbonate / tetrahydrofuran / 2 h / 40 °C 2.1: potassium tert-butylate / N,N-dimethyl-formamide / 0.75 h / 20 °C / Inert atmosphere 2.2: 1 h / 35 - 45 °C / Inert atmosphere 3.1: boron tribromide / dichloromethane / 1 h / -20 - -10 °C / Inert atmosphere 4.1: potassium carbonate; tetrabutylammomium bromide / dimethyl sulfoxide / 100 °C / Autoclave 5.1: sodium hydroxide / 2 h / 85 °C View Scheme

3,4-dimethoxybenzeneacrylic acid methyl ester (459453-60-2) → 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid (862574-88-7)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: potassium tert-butylate / N,N-dimethyl-formamide / 0.75 h / 20 °C / Inert atmosphere 1.2: 1 h / 35 - 45 °C / Inert atmosphere 2.1: boron tribromide / dichloromethane / 1 h / -20 - -10 °C / Inert atmosphere 3.1: potassium carbonate; tetrabutylammomium bromide / dimethyl sulfoxide / 100 °C / Autoclave 4.1: sodium hydroxide / 2 h / 85 °C View Scheme

ethyl 4-(benzyloxy)-2-(2,2-difluorobenzo[D] [1,3]dioxol-5-yl)-2-hydroxybutyrate → 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid (862574-88-7)

Conditions	Yield
Multi-step reaction with 5 steps 1: toluene-4-sulfonic acid / toluene / Reflux 2: palladium 10% on activated carbon / ethanol / 46 - 60 °C / 3750.38 - 4500.45 Torr / Inert atmosphere; Autoclave 3: phosphorus tribromide / dichloromethane / 10 - 20 °C 4: potassium carbonate / N,N-dimethyl-formamide / 100 - 120 °C 5: sodium hydroxide / methanol / 2 h / 10 - 30 °C View Scheme

ethyl 4-(benzyloxy)-2-(2,2-difluorobenzo[D] [1,3]dioxol-5-yl)-2-butenoate → 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid (862574-88-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: palladium 10% on activated carbon / ethanol / 46 - 60 °C / 3750.38 - 4500.45 Torr / Inert atmosphere; Autoclave 2: phosphorus tribromide / dichloromethane / 10 - 20 °C 3: potassium carbonate / N,N-dimethyl-formamide / 100 - 120 °C 4: sodium hydroxide / methanol / 2 h / 10 - 30 °C View Scheme

ethyl 2-(2,2-difluorobenzo[D] [1,3]dioxol-5-yl)-4-hydroxybutyrate → 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid (862574-88-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: phosphorus tribromide / dichloromethane / 10 - 20 °C 2: potassium carbonate / N,N-dimethyl-formamide / 100 - 120 °C 3: sodium hydroxide / methanol / 2 h / 10 - 30 °C View Scheme

ethyl 2-(2,2-difluorobenzo[D] [1,3]dioxol-5-yl)glyoxylate → 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid (862574-88-7)

Conditions

Yield

Multi-step reaction with 6 steps 1: tetrahydrofuran / 1 h / 10 - 30 °C 2: toluene-4-sulfonic acid / toluene / Reflux 3: palladium 10% on activated carbon / ethanol / 46 - 60 °C / 3750.38 - 4500.45 Torr / Inert atmosphere; Autoclave 4: phosphorus tribromide / dichloromethane / 10 - 20 °C 5: potassium carbonate / N,N-dimethyl-formamide / 100 - 120 °C 6: sodium hydroxide / methanol / 2 h / 10 - 30 °C View Scheme

2,2-difluoro-1,3-benzodioxole (1583-59-1) → 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid (862574-88-7)

Conditions

Yield

Multi-step reaction with 7 steps 1: aluminum (III) chloride / dichloromethane / 1 h / 0 - 10 °C 2: tetrahydrofuran / 1 h / 10 - 30 °C 3: toluene-4-sulfonic acid / toluene / Reflux 4: palladium 10% on activated carbon / ethanol / 46 - 60 °C / 3750.38 - 4500.45 Torr / Inert atmosphere; Autoclave 5: phosphorus tribromide / dichloromethane / 10 - 20 °C 6: potassium carbonate / N,N-dimethyl-formamide / 100 - 120 °C 7: sodium hydroxide / methanol / 2 h / 10 - 30 °C View Scheme

2,2-difluoro-5-(2-methylcyclobut-1-en-1-yl)benzo[d][1,3]dioxole → 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid (862574-88-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 0.17 h / Inert atmosphere 2: boron trifluoride diethyl etherate / diethyl ether / 0.17 h / Inert atmosphere 3: N-benzyl-N,N,N-triethylammonium chloride; sodium hydroxide / dichloromethane; tetrachloromethane / 16 h / 20 °C / Inert atmosphere View Scheme

1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid (862574-88-7) → 1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)cyclopropane carboxylic acid chloride (1004294-65-8)

Conditions	Yield
With thionyl chloride; N,N-dimethyl-formamide for 1h;	100%
With thionyl chloride In toluene at 65℃; for 3h;	99%
With thionyl chloride In N,N-dimethyl-formamide at 20℃; for 2h;	83%

1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid (862574-88-7) + 2-(2-chlorophenyl)chroman-4-ylamine hydrochloride → N-[2-(2-chlorophenyl)-3,4-dihydro-2H-chromen-4-yl]-1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarboxamide

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl acetamide at 100℃; Flow reactor;	99%

1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid (862574-88-7) + tert-butyl 5'-amino-2'-methyl-[1,1'-biphenyl]-3-carboxylate → tert-butyl 5'-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-1-carboxamido)-2'-methyl-[1,1'-biphenyl]-3-carboxylate

Conditions	Yield
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 24h; Inert atmosphere;	99%

Upstream product

• 862574-87-6 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonitrile 
• 1634-04-4 tert-butyl methyl ether 
• 101-83-7 N-cyclohexyl-cyclohexanamine 
• 33070-32-5 5-bromo-2,2-difluoro-2H-1,3-benzodioxole 
• 656-46-2 2,2-difluoro-1,3-benzodioxole-5-carboxylic acid 
• 72768-97-9 (2,2-difluoro-1,3-benzodioxol-5-yl)methanol 
• 476473-97-9 5-chloromethyl-2,2-difluoro-benzo[1,3]dioxole 
• 68119-31-3 2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)acetonitrile 
• 1335233-51-6 (2,2-difluoro-1,3-benzodioxol-5-yl)-1-ethylacetate acetonitrile 
• 96042-30-7 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran 
• 773873-95-3 2,2-difluorobenzo[1,3]dioxole-5-carboxylic acid methyl ester 
• 862574-89-8 1-(2H-1,3-benzodioxol-5-yl)cyclopropane-1-carboxylic acid 
• 107-04-0 1-Bromo-2-chloroethane 
• 93-40-3 (3,4-Dimethoxyphenyl)acetic acid 

Downstream Products

• 1189328-81-1 tert-Butyl 3-(2-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-5-methylpyridin-4-yl)benzoate 
• 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 
• 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 
• 936727-05-8 Lumacaftor 
• 1160221-26-0 Lumacaftor hydrochloride 

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Compound I of the formula (I) and/or pharmaceutically acceptable salt(s) of Compound I comprised in a pharmaceutical composition and methods of using the same to treat cystic fibrosis.

Oxidative Ring Contraction of Cyclobutenes: General Approach to Cyclopropylketones including Mechanistic Insights

An original oxidative ring contraction of easily accessible cyclobutene derivatives for the selective formation of cyclopropylketones (CPKs) under atmospheric conditions is reported. Comprehensive mechanistic studies are proposed to support this novel, yet unusual, rearrangement. Insights into the mechanism ultimately led to simplification and generalization of the ring contraction of cyclobutenes using mCPBA as an oxidant. This unique and functional group tolerant transformation proceeds under mild conditions at room temperature, providing access to a new library of polyfunctionalized motifs. With CPKs being attractive and privileged pharmacophores, the elaboration of such a simple and straightforward strategy represents a highly valuable tool for drug discovery and medicinal chemistry. Additionally, the described method was employed to generate a pool of bioactive substances and key precursors in a minimum number of steps.