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Chemical Structure| 936727-05-8
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Product Details of [ 936727-05-8 ]

CAS No. :936727-05-8 MDL No. :
Formula : C24H18F2N2O5 Boiling Point : -
Linear Structure Formula :- InChI Key :UFSKUSARDNFIRC-UHFFFAOYSA-N
M.W : 452.41 Pubchem ID :16678941
Synonyms :
VX-809;VRT 826809;Orkambi;​Lumacaftor

Safety of [ 936727-05-8 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 936727-05-8 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 936727-05-8 ]

[ 936727-05-8 ] Synthesis Path-Downstream   1~32

  • 1
  • [ 1160221-26-0 ]
  • [ 936727-05-8 ]
YieldReaction ConditionsOperation in experiment
98% With water at 20℃; for 24h; Synthesis of 3-(6-(l-(2,2-difluorobenzo[d] [l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 1).HClCompound 1[00269] A slurry of 3-(6-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid • HCl (1 eq) in water (10 vol) is stirred at ambient temperature. A sample is taken after stirring for 24 hours. The sample is filtered and the solid washed with water (2 x). The solid sample is submitted for DSC analysis. When DSC analysis indicates complete conversion to Compound 1, the solid is collected by filtration, washed with water (2 x 1.0 vol), and partially dried on the filter under vacuum. The solid is dried to constant weight (<1% difference) in a vacuum oven at 60 0C with a slight N2 bleed to afford Compound 1 as an off-white solid (98% yield).
98% In water at 20℃; for 24h; A slurry of 3-(6-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid • HCl (1 eq) in water (10 vol) is stirred at ambient temperature. A sample is taken after stirring for 24 hours. The sample is filtered and the solid washed with water (2 x). The solid sample is submitted for DSC analysis. When DSC analysis indicates complete conversion to Form I, the solid is collected by filtration, washed with water (2 x 1.0 vol), and partially dried on the filter under vacuum. The solid is dried to constant weight (<1% difference) in a vacuum oven at 60 0C with a slight N2 bleed to afford Form I as an off-white solid (98% yield). 1H NMR (400 MHz, DMSO-d6) 9.14 (s, IH), 7.99- 7.93 (m, 3H), 7.80-7.78 (m, IH), 7.74-7.72 (m, IH), 7.60-7.55 (m, 2H), 7.41-7.33 (m, 2H), 2.24 (s, 3H), 1.53-1.51 (m, 2H), 1.19-1.17 (m, 2H).
98% In water at 20℃; for 24h; A slurry of 3-(6-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid • HCl (1 eq) in water (10 vol) is stirred at ambient temperature. A sample is taken after stirring for 24 hours. The sample is filtered and the solid washed with water (2 x). The solid sample is submitted for DSC analysis. When DSC analysis indicates complete conversion to Compound 1, the solid is collected by filtration, washed with water (2 x 1.0 vol), and partially dried on the filter under vacuum. The solid is dried to constant weight (<1% difference) in a vacuum oven at 60 0C with a slight N2 bleed to afford Compound 1 as an off-white solid (98% yield).
98% In water at 20℃; for 24h; 1.A [00311] Preparation of Compound 1 Form I, Method A. [00312] A slurry of 3-( 6-(1-(2,2-difluorobenzo[ d] [1 ,3 ]dioxol-5-yl) cyclopropanecarboxamido )-3-methylpyridin-2-yl)benzoic acid • HCl (1 eq) in water (10 vol) was stirred at ambienttemperature. A sample was taken after stirring for 24 h. The sample was filtered and the solidwas washed with water (2 times). The solid sample was submitted for DSC analysis. WhenDSC analysis indicated complete conversion to Form I, the solid was collected by filtration,washed with water (2 x 1.0 vol), and partially dried on a filter under vacuum. The solid was thendried to a constant weight (<1% difference) in a vacuum oven at 60 oc with a slight N2 bleed toafford Compound 1 Form I as an off-white solid (98% yield). 1H NMR (400 MHz, DMSO-d6)9.14 (s, 1H), 7.99-7.93 (m, 3H), 7.80-7.78 (m, 1H), 7.74-7.72 (m, 1H), 7.60-7.55 (m, 2H), 7.41-7.33 (m, 2H), 2.24 (s, 3H), 1.53-1.51 (m, 2H), 1.19-1.17 (m, 2H).
98% With hydrogenchloride In water at 20℃; for 24h; Preparation of Compound 1 Form I, Method A. A slurry of 3-(6-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl) cyclopropanecarboxamido)- 3-methylpyridin-2-yl)benzoic acid · HC1 (1 eq) in water (10 vol) was stirred at ambient temperature. A sample was taken after stirring for 24 h. The sample was filtered and the solid was washed with water (2 times). The solid sample was submitted for DSC analysis. When DSC analysis indicated complete conversion to Form I, the solid was collected by filtration, washed with water (2 x 1.0 vol), and partially dried on a filter under vacuum. The solid was then dried to a constant weight (<1% difference) in a vacuum oven at 60 °C with a slight N2 bleed to afford Compound 1 Form I as an off-white solid (98% yield). 1H NMR (400 MHz, DMSO-d6) 9.14 (s, 1H), 7.99-7.93 (m, 3H), 7.80-7.78 (m, 1H), 7.74-7.72 (m, 1H), 7.60-7.55 (m, 2H), 7.41- 7.33 (m, 2H), 2.24 (s, 3H), 1.53-1.51 (m, 2H), 1.19-1.17 (m, 2H).
98% With water at 20℃; for 24h; Preparation of Compound 1 Form I, Method A. Preparation of Compound 1 Form I, Method A. A slurry of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid·HCl (1 eq) in water (10 vol) was stirred at ambient temperature. A sample was taken after stirring for 24 h. The sample was filtered and the solid was washed with water (2 times). The solid sample was submitted for DSC analysis. When DSC analysis indicated complete conversion to Form I, the solid was collected by filtration, washed with water (2*1.0 vol), and partially dried on a filter under vacuum. The solid was then dried to a constant weight (<1% difference) in a vacuum oven at 60° C. with a slight N2 bleed to afford Compound 1 Form I as an off-white solid (98% yield). 1H NMR (400 MHz, DMSO-d6) 9.14 (s, 1H), 7.99-7.93 (m, 3H), 7.80-7.78 (m, 1H), 7.74-7.72 (m, 1H), 7.60-7.55 (m, 2H), 7.41-7.33 (m, 2H), 2.24 (s, 3H), 1.53-1.51 (m, 2H), 1.19-1.17 (m, 2H).
98% In water at 20℃; Preparation of Compound 1 Form I, Method A. Stirring 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbamoyl)-3 at ambient temperature A slurry of -methylpyridin-2-yl)benzoic acid HCl (1 eq.) in water (10 vol). Samples were taken after stirring for 24 hours. The sample was filtered and the solid was washed with water (2 times). A solid sample was subjected to DSC analysis. When the DSC analysis indicated complete conversion to Form I, the solid was collected by filtration, washed with water (2 x 1.0 vol) and partially dried on a filter under vacuum. The solid was dried to constant weight (difference <1%) in a vacuum oven at 60 ° C under a slight N 2 purge to afford Compound 1 Form I (yield 98%) as an off-white solid.
97% Stage #1: Lumacaftor hydrochloride With sodium hydroxide; water at 20℃; for 0.25h; Stage #2: With hydrogenchloride; water at 60 - 90℃; Synthesis of 3-(6-(l-(2,2-difluorobenzo[d] [l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 1) using water and base. Compound 1[00271] To a slurry of 3-(6-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid • HCl (1 eq) in water (10 vol) stirred at ambient temperature is added 50% w/w aq. NaOH (2.5 eq). The mixture is stirred for NLT 15 min or until a homogeneous solution. Concentrated HCl (4 eq) is added to crystallize Compound 1. The mixture is heated to 60 0C or 90 0C if needed to reduce the level of the t- butylbenzoate ester. The mixture is heated until HPLC analysis indicates NMT 0.8% (AUC) t- butylbenzoate ester. The mixture is then cooled to ambient and the solid is collected by filtration, washed with water (3 x 3.4 vol), and partially dried on the filter under vacuum. The solid is dried to constant weight (<1% difference) in a vacuum oven at 60 0C with a slight N2 bleed to afford Compound 1 as an off-white solid (97% yield).
With formic acid at 70℃; for 8h; Synthesis of 3-(6-(l-(2,2-difluorobenzo[d] [l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 1) directly from benzoate.Compound 1[00273] A solution of 3-(6-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate (1.0 eq) in formic acid (3.0 vol) is heated to 70 +/- 10 0C. The reaction is continued until the reaction is complete (NMT 1.0% AUC 3-(6-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl) cyclopropanecarboxamido)-3- methylpyridin-2-yl)-t-butylbenzoate) or heating for NMT 8 h. The mixture is allowed to cool to ambient. The solution is added to water (6 vol) heated at 50 0C and the mixture stirred. The mixture is then heated to 70 +/- 10 0C until the level of 3-(6-(l-(2,2-difluorobenzo[d][l,3]dioxol-5- yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate is NMT 0.8% (AUC). The solid is collected by filtration, washed with water (2 x 3 vol), and partially dried on the filter under vacuum. The solid is dried to constant weight (<1% difference) in a vacuum oven at 60 0C with a slight N2 bleed to afford Compound 1 as an off-white solid.

  • 2
  • [ 1160221-25-9 ]
  • [ 936727-05-8 ]
YieldReaction ConditionsOperation in experiment
Stage #1: tert-butyl 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-1-carboxamido)-3-methylpyridin-2-yl)benzoate With formic acid at 70℃; for 8h; Stage #2: With water at 50 - 70℃; A solution of 3-(6-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate (1.0 eq) in formic acid (3.0 vol) is heated to 70 +/- 10 0C. The reaction is continued until the reaction is complete (NMT 1.0% AUC 3 -(6-( 1 -(2,2-difluorobenzo [d] [ 1 ,3 ] dioxol-5 -yl) cyclopropanecarboxamido)-3 - methylpyridin-2-yl)-t-butylbenzoate) or heating for NMT 8 h. The mixture is allowed to cool to ambient. The solution is added to water (6 vol) heated at 50 0C and the mixture stirred. The mixture is then heated to 70 +/- 10 0C until the level of 3-(6-(l-(2,2-difluorobenzo[d][l,3]dioxol-5- yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate is NMT 0.8% (AUC). The solid is collected by filtration, washed with water (2 x 3 vol), and partially dried on the filter under vacuum. The solid is dried to constant weight (<1% difference) in a vacuum oven at 60 0C with a slight N2 bleed to afford Compound 1 in Form I as an off-white solid.
Stage #1: tert-butyl 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-1-carboxamido)-3-methylpyridin-2-yl)benzoate With formic acid at 70℃; Stage #2: In water at 50 - 70℃; A solution of 3-(6-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate (1.0 eq) in formic acid (3.0 vol) is heated to 70 +/- 10 0C. The reaction is continued until the reaction is complete (NMT 1.0% AUC 3-(6-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate) or heating for NMT 8 h. The mixture is allowed to cool to ambient. The solution is added to water (6 vol) heated at 50 0C and the mixture stirred. The mixture is then heated to 70 +/- 10 0C until the level of 3- (6-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin- 2-yl)-t-butylbenzoate is NMT 0.8% (AUC). The solid is collected by filtration, washed with water (2 x 3 vol), and partially dried on the filter under vacuum. The solid is dried to constant weight (<1% difference) in a vacuum oven at 60 0C with a slight N2 bleed to afford Compound 1 in Form I as an off-white solid.
With formic acid at 70℃; for 8h; Preparation of Compound 1 Form I, Method B. Preparation of Compound 1 Form I, Method B. A solution of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate (1.0 eq) in formic acid (3.0 vol) was heated with stirring to 70+-10° C., for 8 h. The reaction was deemed complete when no more than 1.0% AUC by chromatographic methods of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate) remained. The mixture was allowed to cool to ambient. The solution was added to water (6 vol), heated at 50° C., and the mixture was stirred. The mixture was then heated to 70+-10° C. until the level of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate was no more than 0.8% (AUC). The solid was collected by filtration, washed with water (2*3 vol), and partially dried on the filter under vacuum. The solid was dried to a constant weight (<1% difference) in a vacuum oven at 60° C. with a slight N2 bleed to afford Compound 1 Form I as an off-white solid.
Multi-step reaction with 2 steps 1: hydrogenchloride / acetonitrile; water / 40 - 45 °C 2: water / 24 h / 20 °C
With formic acid at 70℃; for 8h; 1.B [00313] Preparation of Compound 1 Form I, Method B. [00314] A solution of3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido )-3-methylpyridin-2-yl)-t-butylbenzoate (1.0 eq) in formic acid (3.0vol) was heated with stirring to 70 ± 10 oc , for 8 h. The reaction was deemed complete whenno more than 1.0% AUC by chromatographic methods of 3-(6-(1-(2,2-difluorobenzo[ d] [ 1,3 ]dioxol-5-yl) cyclopropanecarboxamido )-3-methylpyridin-2-yl)-tbutylbenzoate)remained. The mixture was allowed to cool to ambient. The solution was addedto water (6 vol), heated at 50 °C, and the mixture was stirred. The mixture was then heated to 70± 10 oc until the level of3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido )-3-methylpyridin-2-yl)-t-butylbenzoate was no more than 0.8%(AUC). The solid was collected by filtration, washed with water (2 x 3 vol), and partially driedon the filter under vacuum. The solid was dried to a constant weight (<1% difference) in avacuum oven at 60 oc with a slight N2 bleed to afford Compound 1 Form I as an off-white solid.
Multi-step reaction with 2 steps 1: hydrogenchloride; water / acetonitrile / 40 - 45 °C 2: water / 24 h / 20 °C
Stage #1: tert-butyl 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-1-carboxamido)-3-methylpyridin-2-yl)benzoate In formic acid at 60 - 80℃; for 8h; Stage #2: In water at 50 - 80℃; Preparation of Compound 1 Form I, Method B. [00329] A solution of 3-(6-(l -(2,2-difluorobenzo[d][l ,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate (1.0 eq) in formic acid (3.0 vol) was heated with stirring to 70 ± 10 °C , for 8 h. The reaction was deemed complete when no more than 1.0% AUC by chromatographic methods of 3-(6-(l -(2,2- difluorobenzo[d][l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t- butylbenzoate) remained. The mixture was allowed to cool to ambient. The solution was added to water (6 vol), heated at 50 °C, and the mixture was stirred. The mixture was then heated to 70 ± 10 °C until the level of 3-(6-(l-(2,2-difiuorobenzo[d][l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate was no more than 0.8% (AUC). The solid was collected by filtration, washed with water (2 x 3 vol), and partially dried on the filter under vacuum. The solid was dried to a constant weight (<1% difference) in a vacuum oven at 60 °C with a slight N2 bleed to afford Compound 1 Form I as an off-white solid.
Multi-step reaction with 2 steps 1: hydrogenchloride / water; acetonitrile / 40 - 50 °C 2: hydrogenchloride / water / 24 h / 20 °C
Stage #1: tert-butyl 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-1-carboxamido)-3-methylpyridin-2-yl)benzoate With formic acid at 70℃; for 8h; Stage #2: With water at 50 - 70℃; Preparation of Compound 1 Form I, Method B. Preparation of Compound 1 Form I, Method B. A solution of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate (1.0 eq) in formic acid (3.0 vol) was heated with stirring to 70+-10° C., for 8 h. The reaction was deemed complete when no more than 1.0% AUC by chromatographic methods of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate) remained. The mixture was allowed to cool to ambient. The solution was added to water (6 vol), heated at 50° C., and the mixture was stirred. The mixture was then heated to 70+-10° C. until the level of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate was no more than 0.8% (AUC). The solid was collected by filtration, washed with water (2*3 vol), and partially dried on the filter under vacuum. The solid was dried to a constant weight (<1% difference) in a vacuum oven at 60° C. with a slight N2 bleed to afford Compound 1 Form I as an off-white solid. The DSC trace of Compound 1 Form I is shown in . Melting for Compound 1 Form I occurs at about 204° C. An X-ray diffraction pattern was calculated from a single crystal structure of Compound 1 Form I and is shown in .
Multi-step reaction with 2 steps 1: hydrogenchloride / water; acetonitrile / 45 °C 2: water / 24 h / 20 °C
Multi-step reaction with 2 steps 1: hydrogenchloride / water; acetonitrile / Heating 2: water / 20 °C

  • 3
  • [ 3430-17-9 ]
  • [ 936727-05-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: potassium carbonate / toluene; water / 1 h / 65 °C / Inert atmosphere 1.2: 2 h / 80 °C 2.1: urea hydrogen peroxide adduct; phthalic anhydride / ethyl acetate; water / 4 h / 45 °C 3.1: pyridine; Methanesulfonic anhydride / acetonitrile / 1 h / 70 - 75 °C 3.2: 2 h 4.1: dmap; triethylamine / toluene; water / 2 h / 2.5 °C 5.1: formic acid / 8 h / 70 °C
Multi-step reaction with 6 steps 1.1: potassium carbonate / toluene; water / 1 h / 65 °C / Inert atmosphere 1.2: 2 h / 80 °C 2.1: urea hydrogen peroxide adduct; phthalic anhydride / ethyl acetate; water / 4 h / 45 °C 3.1: pyridine; Methanesulfonic anhydride / acetonitrile / 1 h / 70 - 75 °C 3.2: 2 h 4.1: dmap; triethylamine / toluene; water / 2 h / 2.5 °C 5.1: hydrogenchloride / acetonitrile; water / 40 - 45 °C 6.1: water / 24 h / 20 °C
Multi-step reaction with 5 steps 1.1: potassium carbonate / toluene; water / 1 h / 65 °C / Inert atmosphere 1.2: 2 h / 80 °C / Inert atmosphere 2.1: urea hydrogen peroxide adduct; phthalic anhydride / water; ethyl acetate / 45 °C 3.1: Methanesulfonic anhydride; pyridine / acetonitrile / 1.33 h / 70 - 75 °C 3.2: 2 h / 20 °C 4.1: triethylamine; dmap / toluene / 2 h 5.1: formic acid / 8 h / 70 °C
Multi-step reaction with 6 steps 1.1: potassium carbonate / toluene; water / 1 h / 65 °C / Inert atmosphere 1.2: 2 h / 80 °C / Inert atmosphere 2.1: urea hydrogen peroxide adduct; phthalic anhydride / water; ethyl acetate / 45 °C 3.1: Methanesulfonic anhydride; pyridine / acetonitrile / 1.33 h / 70 - 75 °C 3.2: 2 h / 20 °C 4.1: triethylamine; dmap / toluene / 2 h 5.1: hydrogenchloride; water / acetonitrile / 40 - 45 °C 6.1: water / 24 h / 20 °C
Multi-step reaction with 5 steps 1.1: potassium carbonate / toluene; water / 1 h / 65 °C / Inert atmosphere 1.2: 2 h / 80 °C 2.1: urea hydrogen peroxide adduct; phthalic anhydride / water; ethyl acetate / 45 °C 3.1: pyridine; Methanesulfonic anhydride / acetonitrile / 1.33 h / 70 - 75 °C 3.2: 2 h 4.1: triethylamine; dmap / toluene / 2 h 5.1: formic acid / 8 h / 60 - 80 °C 5.2: 50 - 80 °C
Multi-step reaction with 6 steps 1.1: potassium carbonate / toluene; water / 1 h / 65 °C / Inert atmosphere 1.2: 2 h / 80 °C 2.1: urea hydrogen peroxide adduct; phthalic anhydride / water; ethyl acetate / 45 °C 3.1: pyridine; Methanesulfonic anhydride / acetonitrile / 1.33 h / 70 - 75 °C 3.2: 2 h 4.1: triethylamine; dmap / toluene / 2 h 5.1: hydrogenchloride / water; acetonitrile / 40 - 50 °C 6.1: hydrogenchloride / water / 24 h / 20 °C
Multi-step reaction with 5 steps 1.1: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / toluene; water / 2 h / 80 °C / Inert atmosphere 2.1: urea hydrogen peroxide adduct; phthalic anhydride / water; ethyl acetate / 4 h / 45 °C 3.1: pyridine; Methanesulfonic anhydride / acetonitrile / 1.33 h / 70 - 75 °C 3.2: 2 h / 20 °C 4.1: dmap; triethylamine / toluene / 2 h 5.1: formic acid / 8 h / 70 °C 5.2: 50 - 70 °C
Multi-step reaction with 6 steps 1.1: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / toluene; water / 2 h / 80 °C / Inert atmosphere 2.1: urea hydrogen peroxide adduct; phthalic anhydride / water; ethyl acetate / 4 h / 45 °C 3.1: pyridine; Methanesulfonic anhydride / acetonitrile / 1.33 h / 70 - 75 °C 3.2: 2 h / 20 °C 4.1: dmap; triethylamine / toluene / 2 h 5.1: hydrogenchloride / water; acetonitrile / 45 °C 6.1: water / 24 h / 20 °C
Multi-step reaction with 6 steps 1.1: potassium carbonate / toluene; water / 1 h / 65 °C / Inert atmosphere 1.2: 80 °C 2.1: urea hydrogen peroxide; phthalic anhydride / water; ethyl acetate / 4 h / 45 °C 3.1: triethylamine; trichlorophosphate / dichloromethane / 0 - 20 °C 4.1: palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; caesium carbonate / 1,4-dioxane / 0.17 h 4.2: 15 h / Reflux 5.1: hydrogenchloride / water; acetonitrile / 48 h / 45 - 50 °C 6.1: water / 30 h / 20 °C
Multi-step reaction with 4 steps 1.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 12 h / 20 °C 2.1: pyridine; trifluoromethylsulfonic anhydride / acetonitrile / 1 h / 80 °C 2.2: 3 h / 10 - 20 °C 3.1: pyridine / dichloromethane / 3 h / 20 °C 4.1: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / toluene; water / 1 h / 20 °C 4.2: 16 h / 80 °C
Multi-step reaction with 4 steps 1.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 12 h / 20 °C 2.1: pyridine; trifluoromethylsulfonic anhydride / acetonitrile / 1.5 h / 71 °C 2.2: 13 h / 10 - 20 °C 3.1: pyridine / dichloromethane / 3 h / 20 °C 4.1: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / toluene; water / 1 h / 20 °C 4.2: 16 h / 80 °C
Multi-step reaction with 4 steps 1.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 12 h / 20 °C 2.1: pyridine; trifluoromethylsulfonic anhydride / acetonitrile / 1 h / 80 °C 2.2: 3 h / 10 - 20 °C 3.1: thionyl chloride / N,N-dimethyl-formamide; toluene / 3 h / 80 °C 3.2: 3 h / 20 °C 4.1: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / toluene; water / 1 h / 20 °C 4.2: 16 h / 80 °C
Multi-step reaction with 4 steps 1.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 12 h / 20 °C 2.1: pyridine; trifluoromethylsulfonic anhydride / acetonitrile / 1.5 h / 71 °C 2.2: 13 h / 10 - 20 °C 3.1: thionyl chloride / N,N-dimethyl-formamide; toluene / 3 h / 80 °C 3.2: 3 h / 20 °C 4.1: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / toluene; water / 1 h / 20 °C 4.2: 16 h / 80 °C
Multi-step reaction with 6 steps 1.1: potassium carbonate / toluene / 1 h / 65 °C / Inert atmosphere 1.2: 2 h / 80 °C / Inert atmosphere 2.1: dihydrogen peroxide; phthalic anhydride / ethyl acetate; water / 4 h / 45 °C 3.1: pyridine; Methanesulfonic anhydride / acetonitrile / 70 - 75 °C 4.1: dmap; triethylamine / toluene / 2 h 5.1: hydrogenchloride / water; acetonitrile / Heating 6.1: water / 20 °C

  • 5
  • [ 1083057-13-9 ]
  • [ 936727-05-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: pyridine; Methanesulfonic anhydride / acetonitrile / 1 h / 70 - 75 °C 1.2: 2 h 2.1: dmap; triethylamine / toluene; water / 2 h / 2.5 °C 3.1: formic acid / 8 h / 70 °C
Multi-step reaction with 4 steps 1.1: pyridine; Methanesulfonic anhydride / acetonitrile / 1 h / 70 - 75 °C 1.2: 2 h 2.1: dmap; triethylamine / toluene; water / 2 h / 2.5 °C 3.1: hydrogenchloride / acetonitrile; water / 40 - 45 °C 4.1: water / 24 h / 20 °C
Multi-step reaction with 3 steps 1.1: Methanesulfonic anhydride; pyridine / acetonitrile / 1.33 h / 70 - 75 °C 1.2: 2 h / 20 °C 2.1: triethylamine; dmap / toluene / 2 h 3.1: formic acid / 8 h / 70 °C
Multi-step reaction with 4 steps 1.1: Methanesulfonic anhydride; pyridine / acetonitrile / 1.33 h / 70 - 75 °C 1.2: 2 h / 20 °C 2.1: triethylamine; dmap / toluene / 2 h 3.1: hydrogenchloride; water / acetonitrile / 40 - 45 °C 4.1: water / 24 h / 20 °C
Multi-step reaction with 3 steps 1.1: pyridine; Methanesulfonic anhydride / acetonitrile / 1.33 h / 70 - 75 °C 1.2: 2 h 2.1: triethylamine; dmap / toluene / 2 h 3.1: formic acid / 8 h / 60 - 80 °C 3.2: 50 - 80 °C
Multi-step reaction with 4 steps 1.1: pyridine; Methanesulfonic anhydride / acetonitrile / 1.33 h / 70 - 75 °C 1.2: 2 h 2.1: triethylamine; dmap / toluene / 2 h 3.1: hydrogenchloride / water; acetonitrile / 40 - 50 °C 4.1: hydrogenchloride / water / 24 h / 20 °C
Multi-step reaction with 3 steps 1.1: pyridine; Methanesulfonic anhydride / acetonitrile / 1.33 h / 70 - 75 °C 1.2: 2 h / 20 °C 2.1: dmap; triethylamine / toluene / 2 h 3.1: formic acid / 8 h / 70 °C 3.2: 50 - 70 °C
Multi-step reaction with 4 steps 1.1: pyridine; Methanesulfonic anhydride / acetonitrile / 1.33 h / 70 - 75 °C 1.2: 2 h / 20 °C 2.1: dmap; triethylamine / toluene / 2 h 3.1: hydrogenchloride / water; acetonitrile / 45 °C 4.1: water / 24 h / 20 °C
Multi-step reaction with 4 steps 1.1: triethylamine; trichlorophosphate / dichloromethane / 0 - 20 °C 2.1: palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; caesium carbonate / 1,4-dioxane / 0.17 h 2.2: 15 h / Reflux 3.1: hydrogenchloride / water; acetonitrile / 48 h / 45 - 50 °C 4.1: water / 30 h / 20 °C
Multi-step reaction with 4 steps 1: pyridine; Methanesulfonic anhydride / acetonitrile / 70 - 75 °C 2: dmap; triethylamine / toluene / 2 h 3: hydrogenchloride / water; acetonitrile / Heating 4: water / 20 °C

  • 7
  • [ 476473-97-9 ]
  • Lumacaftor [ No CAS ]
YieldReaction ConditionsOperation in experiment
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 / ethanol / 80 °C 4: thionyl chloride / toluene / 0.5 h / 60 °C 5: dmap; triethylamine / toluene; water / 2 h / 2.5 °C 6: formic acid / 8 h / 70 °C
Multi-step reaction with 7 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 4: thionyl chloride / toluene / 0.5 h / 60 °C 5: dmap; triethylamine / toluene; water / 2 h / 2.5 °C 6: hydrogenchloride / acetonitrile; water / 40 - 45 °C 7: water / 24 h / 20 °C
Multi-step reaction with 6 steps 1.1: dimethyl sulfoxide / 1 h / 30 - 40 °C 1.2: 0.5 h 2.1: potassium hydroxide; tetraoctyl ammonium bromide / water / 1 h / 70 °C 3.1: sodium hydroxide; water / ethanol / 80 °C 4.1: thionyl chloride / toluene / 0.5 h / 60 °C 5.1: triethylamine; dmap / toluene / 2 h 6.1: formic acid / 8 h / 70 °C
Multi-step reaction with 7 steps 1.1: dimethyl sulfoxide / 1 h / 30 - 40 °C 1.2: 0.5 h 2.1: potassium hydroxide; tetraoctyl ammonium bromide / water / 1 h / 70 °C 3.1: sodium hydroxide; water / ethanol / 80 °C 4.1: thionyl chloride / toluene / 0.5 h / 60 °C 5.1: triethylamine; dmap / toluene / 2 h 6.1: hydrogenchloride; water / acetonitrile / 40 - 45 °C 7.1: water / 24 h / 20 °C
Multi-step reaction with 6 steps 1.1: dimethyl sulfoxide / 1 h / 30 - 40 °C 2.1: potassium hydroxide; tetraoctyl ammonium bromide / water / 1 h / 70 °C 3.1: sodium hydroxide / ethanol / 80 °C 4.1: thionyl chloride / toluene / 0.5 h / 60 °C 5.1: triethylamine; dmap / toluene / 2 h 6.1: formic acid / 8 h / 60 - 80 °C 6.2: 50 - 80 °C
Multi-step reaction with 7 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 4: thionyl chloride / toluene / 0.5 h / 60 °C 5: triethylamine; dmap / toluene / 2 h 6: hydrogenchloride / water; acetonitrile / 40 - 50 °C 7: hydrogenchloride / water / 24 h / 20 °C
Multi-step reaction with 6 steps 1.1: dimethyl sulfoxide / 1 h / 30 - 40 °C 2.1: potassium hydroxide; tetraoctyl ammonium bromide / water / 1 h / 70 °C 3.1: water; sodium hydroxide / ethanol / 80 °C 4.1: thionyl chloride / toluene / 60 °C 5.1: dmap; triethylamine / toluene / 2 h 6.1: formic acid / 8 h / 70 °C 6.2: 50 - 70 °C
Multi-step reaction with 7 steps 1: dimethyl sulfoxide / 1 h / 30 - 40 °C 2: potassium hydroxide; tetraoctyl ammonium bromide / water / 1 h / 70 °C 3: water; sodium hydroxide / ethanol / 80 °C 4: thionyl chloride / toluene / 60 °C 5: dmap; triethylamine / toluene / 2 h 6: hydrogenchloride / water; acetonitrile / 45 °C 7: water / 24 h / 20 °C
Multi-step reaction with 7 steps 1: dimethyl sulfoxide / 1 h / 30 - 40 °C 2: potassium hydroxide; tetraoctyl ammonium bromide / 1 h / 70 °C 3: sodium hydroxide / ethanol / 80 °C 4: thionyl chloride / toluene / 0.5 h / 60 °C 5: dmap; triethylamine / toluene / 2 h 6: hydrogenchloride / water; acetonitrile / Heating 7: water / 20 °C

  • 8
  • [ 1335233-51-6 ]
  • [ 936727-05-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 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 4: thionyl chloride / toluene / 0.5 h / 60 °C 5: dmap; triethylamine / toluene; water / 2 h / 2.5 °C 6: formic acid / 8 h / 70 °C
Multi-step reaction with 7 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 4: thionyl chloride / toluene / 0.5 h / 60 °C 5: dmap; triethylamine / toluene; water / 2 h / 2.5 °C 6: hydrogenchloride / acetonitrile; water / 40 - 45 °C 7: water / 24 h / 20 °C
Multi-step reaction with 6 steps 1: hydrogenchloride / dimethyl sulfoxide; water / 1.33 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 / 0.5 h / 60 °C 5: triethylamine; dmap / toluene / 2 h 6: formic acid / 8 h / 70 °C
Multi-step reaction with 7 steps 1: hydrogenchloride / dimethyl sulfoxide; water / 1.33 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 / 0.5 h / 60 °C 5: triethylamine; dmap / toluene / 2 h 6: hydrogenchloride; water / acetonitrile / 40 - 45 °C 7: water / 24 h / 20 °C
Multi-step reaction with 6 steps 1.1: hydrogenchloride / dimethyl sulfoxide / 40 - 75 °C 2.1: potassium hydroxide; tetraoctyl ammonium bromide / water / 1 h / 70 °C 3.1: sodium hydroxide / ethanol / 80 °C 4.1: thionyl chloride / toluene / 0.5 h / 60 °C 5.1: triethylamine; dmap / toluene / 2 h 6.1: formic acid / 8 h / 60 - 80 °C 6.2: 50 - 80 °C
Multi-step reaction with 7 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 / 0.5 h / 60 °C 5: triethylamine; dmap / toluene / 2 h 6: hydrogenchloride / water; acetonitrile / 40 - 50 °C 7: hydrogenchloride / water / 24 h / 20 °C
Multi-step reaction with 6 steps 1.1: hydrogenchloride / dimethyl sulfoxide / 40 - 75 °C 2.1: potassium hydroxide; tetraoctyl ammonium bromide / water / 1 h / 70 °C 3.1: water; sodium hydroxide / ethanol / 80 °C 4.1: thionyl chloride / toluene / 60 °C 5.1: dmap; triethylamine / toluene / 2 h 6.1: formic acid / 8 h / 70 °C 6.2: 50 - 70 °C
Multi-step reaction with 7 steps 1: hydrogenchloride / dimethyl sulfoxide / 40 - 75 °C 2: potassium hydroxide; tetraoctyl ammonium bromide / water / 1 h / 70 °C 3: water; sodium hydroxide / ethanol / 80 °C 4: thionyl chloride / toluene / 60 °C 5: dmap; triethylamine / toluene / 2 h 6: hydrogenchloride / water; acetonitrile / 45 °C 7: water / 24 h / 20 °C
Multi-step reaction with 7 steps 1: hydrogenchloride / dimethyl sulfoxide / 75 °C 2: potassium hydroxide; tetraoctyl ammonium bromide / 1 h / 70 °C 3: sodium hydroxide / ethanol / 80 °C 4: thionyl chloride / toluene / 0.5 h / 60 °C 5: dmap; triethylamine / toluene / 2 h 6: hydrogenchloride / water; acetonitrile / Heating 7: water / 20 °C

  • 9
  • [ 33070-32-5 ]
  • [ 936727-05-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 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 5.1: thionyl chloride / toluene / 0.5 h / 60 °C 6.1: dmap; triethylamine / toluene; water / 2 h / 2.5 °C 7.1: formic acid / 8 h / 70 °C
Multi-step reaction with 8 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 5.1: thionyl chloride / toluene / 0.5 h / 60 °C 6.1: dmap; triethylamine / toluene; water / 2 h / 2.5 °C 7.1: hydrogenchloride / acetonitrile; water / 40 - 45 °C 8.1: water / 24 h / 20 °C
Multi-step reaction with 7 steps 1.1: bis(dibenzylideneacetone)-palladium(0); sodium phosphate; tri-tert-butyl phosphine / toluene; hexane / 0.85 h / 23 °C / Inert atmosphere 1.2: 0.75 h / 70 °C / Inert atmosphere 2.1: hydrogenchloride / dimethyl sulfoxide; water / 1.33 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 / 0.5 h / 60 °C 6.1: triethylamine; dmap / toluene / 2 h 7.1: formic acid / 8 h / 70 °C
Multi-step reaction with 8 steps 1.1: bis(dibenzylideneacetone)-palladium(0); sodium phosphate; tri-tert-butyl phosphine / toluene; hexane / 0.85 h / 23 °C / Inert atmosphere 1.2: 0.75 h / 70 °C / Inert atmosphere 2.1: hydrogenchloride / dimethyl sulfoxide; water / 1.33 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 / 0.5 h / 60 °C 6.1: triethylamine; dmap / toluene / 2 h 7.1: hydrogenchloride; water / acetonitrile / 40 - 45 °C 8.1: water / 24 h / 20 °C
Multi-step reaction with 7 steps 1.1: sodium phosphate; bis(dibenzylideneacetone)-palladium(0); tri-tert-butyl phosphine / toluene; hexane / 0.85 h / 23 °C / Inert atmosphere 1.2: 70 °C 2.1: hydrogenchloride / dimethyl sulfoxide / 40 - 75 °C 3.1: potassium hydroxide; tetraoctyl ammonium bromide / water / 1 h / 70 °C 4.1: sodium hydroxide / ethanol / 80 °C 5.1: thionyl chloride / toluene / 0.5 h / 60 °C 6.1: triethylamine; dmap / toluene / 2 h 7.1: formic acid / 8 h / 60 - 80 °C 7.2: 50 - 80 °C
Multi-step reaction with 8 steps 1.1: sodium phosphate; bis(dibenzylideneacetone)-palladium(0); tri-tert-butyl phosphine / toluene; hexane / 0.85 h / 23 °C / Inert atmosphere 1.2: 70 °C 2.1: hydrogenchloride / dimethyl sulfoxide / 40 - 75 °C 3.1: potassium hydroxide; tetraoctyl ammonium bromide / water / 1 h / 70 °C 4.1: sodium hydroxide / ethanol / 80 °C 5.1: thionyl chloride / toluene / 0.5 h / 60 °C 6.1: triethylamine; dmap / toluene / 2 h 7.1: hydrogenchloride / water; acetonitrile / 40 - 50 °C 8.1: hydrogenchloride / water / 24 h / 20 °C
Multi-step reaction with 7 steps 1.1: sodium phosphate; bis(dibenzylideneacetone)-palladium(0); tri-tert-butyl phosphine / toluene; hexane / 0.85 h / 23 °C / Inert atmosphere 1.2: 70 °C / Inert atmosphere 2.1: hydrogenchloride / dimethyl sulfoxide / 40 - 75 °C 3.1: potassium hydroxide; tetraoctyl ammonium bromide / water / 1 h / 70 °C 4.1: water; sodium hydroxide / ethanol / 80 °C 5.1: thionyl chloride / toluene / 60 °C 6.1: dmap; triethylamine / toluene / 2 h 7.1: formic acid / 8 h / 70 °C 7.2: 50 - 70 °C
Multi-step reaction with 8 steps 1.1: sodium phosphate; bis(dibenzylideneacetone)-palladium(0); tri-tert-butyl phosphine / toluene; hexane / 0.85 h / 23 °C / Inert atmosphere 1.2: 70 °C / Inert atmosphere 2.1: hydrogenchloride / dimethyl sulfoxide / 40 - 75 °C 3.1: potassium hydroxide; tetraoctyl ammonium bromide / water / 1 h / 70 °C 4.1: water; sodium hydroxide / ethanol / 80 °C 5.1: thionyl chloride / toluene / 60 °C 6.1: dmap; triethylamine / toluene / 2 h 7.1: hydrogenchloride / water; acetonitrile / 45 °C 8.1: water / 24 h / 20 °C
Multi-step reaction with 8 steps 1: sodium phosphate; bis(dibenzylideneacetone)-palladium(0); tri-tert-butyl phosphine / toluene; hexane / 1.67 h / 70 °C / Inert atmosphere 2: hydrogenchloride / dimethyl sulfoxide / 75 °C 3: potassium hydroxide; tetraoctyl ammonium bromide / 1 h / 70 °C 4: sodium hydroxide / ethanol / 80 °C 5: thionyl chloride / toluene / 0.5 h / 60 °C 6: dmap; triethylamine / toluene / 2 h 7: hydrogenchloride / water; acetonitrile / Heating 8: water / 20 °C

  • 10
  • [ 862574-87-6 ]
  • [ 936727-05-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: sodium hydroxide / ethanol / 80 °C 2: thionyl chloride / toluene / 0.5 h / 60 °C 3: dmap; triethylamine / toluene; water / 2 h / 2.5 °C 4: formic acid / 8 h / 70 °C
Multi-step reaction with 5 steps 1: sodium hydroxide / ethanol / 80 °C 2: thionyl chloride / toluene / 0.5 h / 60 °C 3: dmap; triethylamine / toluene; water / 2 h / 2.5 °C 4: hydrogenchloride / acetonitrile; water / 40 - 45 °C 5: water / 24 h / 20 °C
Multi-step reaction with 4 steps 1: sodium hydroxide; water / ethanol / 80 °C 2: thionyl chloride / toluene / 0.5 h / 60 °C 3: triethylamine; dmap / toluene / 2 h 4: formic acid / 8 h / 70 °C
Multi-step reaction with 5 steps 1: sodium hydroxide; water / ethanol / 80 °C 2: thionyl chloride / toluene / 0.5 h / 60 °C 3: triethylamine; dmap / toluene / 2 h 4: hydrogenchloride; water / acetonitrile / 40 - 45 °C 5: water / 24 h / 20 °C
Multi-step reaction with 4 steps 1.1: sodium hydroxide / ethanol / 80 °C 2.1: thionyl chloride / toluene / 0.5 h / 60 °C 3.1: triethylamine; dmap / toluene / 2 h 4.1: formic acid / 8 h / 60 - 80 °C 4.2: 50 - 80 °C
Multi-step reaction with 5 steps 1: sodium hydroxide / ethanol / 80 °C 2: thionyl chloride / toluene / 0.5 h / 60 °C 3: triethylamine; dmap / toluene / 2 h 4: hydrogenchloride / water; acetonitrile / 40 - 50 °C 5: hydrogenchloride / water / 24 h / 20 °C
Multi-step reaction with 4 steps 1.1: water; sodium hydroxide / ethanol / 80 °C 2.1: thionyl chloride / toluene / 60 °C 3.1: dmap; triethylamine / toluene / 2 h 4.1: formic acid / 8 h / 70 °C 4.2: 50 - 70 °C
Multi-step reaction with 5 steps 1: water; sodium hydroxide / ethanol / 80 °C 2: thionyl chloride / toluene / 60 °C 3: dmap; triethylamine / toluene / 2 h 4: hydrogenchloride / water; acetonitrile / 45 °C 5: water / 24 h / 20 °C
Multi-step reaction with 5 steps 1: sodium hydroxide / ethanol / 80 °C 2: thionyl chloride / toluene / 0.5 h / 60 °C 3: dmap; triethylamine / toluene / 2 h 4: hydrogenchloride / water; acetonitrile / Heating 5: water / 20 °C

  • 11
  • [ 862574-88-7 ]
  • [ 936727-05-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: thionyl chloride / toluene / 0.5 h / 60 °C 2: dmap; triethylamine / toluene; water / 2 h / 2.5 °C 3: formic acid / 8 h / 70 °C
Multi-step reaction with 4 steps 1: thionyl chloride / toluene / 0.5 h / 60 °C 2: dmap; triethylamine / toluene; water / 2 h / 2.5 °C 3: hydrogenchloride / acetonitrile; water / 40 - 45 °C 4: water / 24 h / 20 °C
Multi-step reaction with 3 steps 1: thionyl chloride / toluene / 0.5 h / 60 °C 2: triethylamine; dmap / toluene / 2 h 3: formic acid / 8 h / 70 °C
Multi-step reaction with 4 steps 1: thionyl chloride / toluene / 0.5 h / 60 °C 2: triethylamine; dmap / toluene / 2 h 3: hydrogenchloride; water / acetonitrile / 40 - 45 °C 4: water / 24 h / 20 °C
Multi-step reaction with 3 steps 1.1: thionyl chloride / toluene / 0.5 h / 60 °C 2.1: triethylamine; dmap / toluene / 2 h 3.1: formic acid / 8 h / 60 - 80 °C 3.2: 50 - 80 °C
Multi-step reaction with 4 steps 1: thionyl chloride / toluene / 0.5 h / 60 °C 2: triethylamine; dmap / toluene / 2 h 3: hydrogenchloride / water; acetonitrile / 40 - 50 °C 4: hydrogenchloride / water / 24 h / 20 °C
Multi-step reaction with 3 steps 1.1: thionyl chloride / toluene / 60 °C 2.1: dmap; triethylamine / toluene / 2 h 3.1: formic acid / 8 h / 70 °C 3.2: 50 - 70 °C
Multi-step reaction with 4 steps 1: thionyl chloride / toluene / 60 °C 2: dmap; triethylamine / toluene / 2 h 3: hydrogenchloride / water; acetonitrile / 45 °C 4: water / 24 h / 20 °C
Multi-step reaction with 4 steps 1.1: N,N-dimethyl-formamide / toluene / 0.25 h 1.2: 60 - 65 °C 1.3: 2 h / 10 - 30 °C 2.1: palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; caesium carbonate / 1,4-dioxane / 0.17 h 2.2: 15 h / Reflux 3.1: hydrogenchloride / water; acetonitrile / 48 h / 45 - 50 °C 4.1: water / 30 h / 20 °C
Multi-step reaction with 3 steps 1.1: thionyl chloride; N,N-dimethyl-formamide / 2 h / 20 °C 2.1: pyridine / dichloromethane / 3 h / 20 °C 3.1: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / toluene; water / 1 h / 20 °C 3.2: 16 h / 80 °C
Multi-step reaction with 4 steps 1.1: thionyl chloride; N,N-dimethyl-formamide / 2 h / 20 °C 2.1: pyridine / dichloromethane / 3 h / 20 °C 3.1: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; 1,4-dioxane / 1 h / 20 °C 3.2: 4 h / 85 - 90 °C 3.3: 12 h / 20 °C 4.1: water; ethyl acetate / 5 h / 20 °C
Multi-step reaction with 4 steps 1: thionyl chloride / toluene / 0.5 h / 60 °C 2: dmap; triethylamine / toluene / 2 h 3: hydrogenchloride / water; acetonitrile / Heating 4: water / 20 °C

  • 12
  • [ 1004294-65-8 ]
  • [ 936727-05-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: dmap; triethylamine / toluene; water / 2 h / 2.5 °C 2: formic acid / 8 h / 70 °C
Multi-step reaction with 3 steps 1: dmap; triethylamine / toluene; water / 2 h / 2.5 °C 2: hydrogenchloride / acetonitrile; water / 40 - 45 °C 3: water / 24 h / 20 °C
Multi-step reaction with 2 steps 1: triethylamine; dmap / toluene / 2 h 2: formic acid / 8 h / 70 °C
Multi-step reaction with 3 steps 1: triethylamine; dmap / toluene / 2 h 2: hydrogenchloride; water / acetonitrile / 40 - 45 °C 3: water / 24 h / 20 °C
Multi-step reaction with 2 steps 1.1: triethylamine; dmap / toluene / 2 h 2.1: formic acid / 8 h / 60 - 80 °C 2.2: 50 - 80 °C
Multi-step reaction with 3 steps 1: triethylamine; dmap / toluene / 2 h 2: hydrogenchloride / water; acetonitrile / 40 - 50 °C 3: hydrogenchloride / water / 24 h / 20 °C
Multi-step reaction with 2 steps 1.1: dmap; triethylamine / toluene / 2 h 2.1: formic acid / 8 h / 70 °C 2.2: 50 - 70 °C
Multi-step reaction with 3 steps 1: dmap; triethylamine / toluene / 2 h 2: hydrogenchloride / water; acetonitrile / 45 °C 3: water / 24 h / 20 °C
Multi-step reaction with 2 steps 1.1: pyridine / dichloromethane / 3 h / 20 °C 2.1: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / toluene; water / 1 h / 20 °C 2.2: 16 h / 80 °C
Multi-step reaction with 3 steps 1.1: pyridine / dichloromethane / 3 h / 20 °C 2.1: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; 1,4-dioxane / 1 h / 20 °C 2.2: 4 h / 85 - 90 °C 2.3: 12 h / 20 °C 3.1: water; ethyl acetate / 5 h / 20 °C
Multi-step reaction with 3 steps 1: dmap; triethylamine / toluene / 2 h 2: hydrogenchloride / water; acetonitrile / Heating 3: water / 20 °C

  • 14
  • [ 1160221-26-0 ]
  • [ 936727-05-8 ]
YieldReaction ConditionsOperation in experiment
98% In water at 20℃; for 24h; Preparation of Compound 1 Form I, Method A. Preparation of Compound 1 Form I, Method A. A slurry of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid.HCl (1 eq) in water (10 vol) was stirred at ambient temperature. A sample was taken after stirring for 24 h. The sample was filtered and the solid was washed with water (2 times). The solid sample was submitted for DSC analysis. When DSC analysis indicated complete conversion to Form I, the solid was collected by filtration, washed with water (2*1.0 vol), and partially dried on a filter under vacuum. The solid was then dried to a constant weight (<1% difference) in a vacuum oven at 60° C. with a slight N2 bleed to afford Compound 1 Form I as an off-white solid (98% yield). 1H NMR (400 MHz, DMSO-d6) 9.14 (s, 1H), 7.99-7.93 (m, 3H), 7.80-7.78 (m, 1H), 7.74-7.72 (m, 1H), 7.60-7.55 (m, 2H), 7.41-7.33 (m, 2H), 2.24 (s, 3H), 1.53-1.51 (m, 2H), 1.19-1.17 (m, 2H).
85% In water at 20℃; for 30h; 10 Example 10:Preparation of Lumacaftor A sluny of 12.0 g of lumacaftor hydrochloride in 120 ml water was stined for 30 hours at ambient temperature. The product was filtered and washed with water. The solid was dried under vacuum at 60 °C to afford lumacaftor (11 g,85% yield).
  • 17
  • [ 72768-97-9 ]
  • Lumacaftor [ No CAS ]
YieldReaction ConditionsOperation in experiment
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 / ethanol / 80 °C 5: thionyl chloride / toluene / 0.5 h / 60 °C 6: dmap; triethylamine / toluene; water / 2 h / 2.5 °C 7: formic acid / 8 h / 70 °C
Multi-step reaction with 8 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 / ethanol / 80 °C 5: thionyl chloride / toluene / 0.5 h / 60 °C 6: dmap; triethylamine / toluene; water / 2 h / 2.5 °C 7: hydrogenchloride / acetonitrile; water / 40 - 45 °C 8: water / 24 h / 20 °C
Multi-step reaction with 7 steps 1.1: dmap; thionyl chloride / tert-butyl methyl ether / 1 h / 15 - 30 °C 2.1: dimethyl sulfoxide / 1 h / 30 - 40 °C 2.2: 0.5 h 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 / 0.5 h / 60 °C 6.1: triethylamine; dmap / toluene / 2 h 7.1: formic acid / 8 h / 70 °C
Multi-step reaction with 8 steps 1.1: dmap; thionyl chloride / tert-butyl methyl ether / 1 h / 15 - 30 °C 2.1: dimethyl sulfoxide / 1 h / 30 - 40 °C 2.2: 0.5 h 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 / 0.5 h / 60 °C 6.1: triethylamine; dmap / toluene / 2 h 7.1: hydrogenchloride; water / acetonitrile / 40 - 45 °C 8.1: water / 24 h / 20 °C
Multi-step reaction with 7 steps 1.1: dmap; thionyl chloride / tert-butyl methyl ether / 1 h / 15 - 30 °C 2.1: dimethyl sulfoxide / 1 h / 30 - 40 °C 3.1: potassium hydroxide; tetraoctyl ammonium bromide / water / 1 h / 70 °C 4.1: sodium hydroxide / ethanol / 80 °C 5.1: thionyl chloride / toluene / 0.5 h / 60 °C 6.1: triethylamine; dmap / toluene / 2 h 7.1: formic acid / 8 h / 60 - 80 °C 7.2: 50 - 80 °C
Multi-step reaction with 8 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 / ethanol / 80 °C 5: thionyl chloride / toluene / 0.5 h / 60 °C 6: triethylamine; dmap / toluene / 2 h 7: hydrogenchloride / water; acetonitrile / 40 - 50 °C 8: hydrogenchloride / water / 24 h / 20 °C
Multi-step reaction with 7 steps 1.1: dmap; thionyl chloride / tert-butyl methyl ether / 1 h / 15 - 30 °C 2.1: dimethyl sulfoxide / 1 h / 30 - 40 °C 3.1: potassium hydroxide; tetraoctyl ammonium bromide / water / 1 h / 70 °C 4.1: water; sodium hydroxide / ethanol / 80 °C 5.1: thionyl chloride / toluene / 60 °C 6.1: dmap; triethylamine / toluene / 2 h 7.1: formic acid / 8 h / 70 °C 7.2: 50 - 70 °C
Multi-step reaction with 8 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: water; sodium hydroxide / ethanol / 80 °C 5: thionyl chloride / toluene / 60 °C 6: dmap; triethylamine / toluene / 2 h 7: hydrogenchloride / water; acetonitrile / 45 °C 8: water / 24 h / 20 °C
Multi-step reaction with 8 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 / 1 h / 70 °C 4: sodium hydroxide / ethanol / 80 °C 5: thionyl chloride / toluene / 0.5 h / 60 °C 6: dmap; triethylamine / toluene / 2 h 7: hydrogenchloride / water; acetonitrile / Heating 8: water / 20 °C

  • 18
  • [ 936727-05-8 ]
  • [ 1281971-08-1 ]
  • [ 1937225-61-0 ]
YieldReaction ConditionsOperation in experiment
42 mg With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In dichloromethane at 20℃; 1 Preparation of 3-(6-(1-(2,2-difluorobenzo jdj jl,3j dioxol-5-yl)cyclopropane-1- carboxamido)-3-methylpyridin-2-yl)-N-(2-((2-((5Z,8Z,1 1Z,14Z,1 7Z)-icosa-5,8,1 1,14,17- pentaenamido)ethyl)disulfanyl)ethyl)benzamide (1-20) j00193j (5Z,8Z, liz, 1 4Z, 1 7Z)-N-(2-((2-Aminoethyl)disulfanyl)ethyl)icosa-5,8, 11,14,17- pentaenamide hydrochloride salt (80 mg, 0.184 mmol) was dissolved in dichloromethane (2mL). 3 -(6-( 1 -(2,2-Difluorobenzo [d] [1,3] dioxol-5-yl)cyclopropane- 1 -carboxamido)-3 - methylpyridin-2-yl)benzoic acid (100 mg, 0.221 mmol), HBTU (105 mg, 0.276 mmol) and triethylamine (0.077 mL, 0.552 mmol) were added successively. The resulting reaction mixture stirred at room temperature overnight. Then, the solution was diluted with dichlormethane (2 mL) and washed with 1/2 saturated NH4C1 and brine. The organic layer wasdried over sodium sulfate and the solvent was evaporated under reduced pressure. The resulting residue was purified via silica gel chromatography with a gradient of 0-60% ethyl acetate in pentane to generate the title compound as a white gel (42 mg). MS (El) calc’d for C48H56F2N40552: 870.37; Found: 871 [M+H].
  • 19
  • [ 2071254-54-9 ]
  • [ 936727-05-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; caesium carbonate / 1,4-dioxane / 0.17 h 1.2: 15 h / Reflux 2.1: hydrogenchloride / water; acetonitrile / 48 h / 45 - 50 °C 3.1: water / 30 h / 20 °C
  • 20
  • [ 2071254-55-0 ]
  • [ 936727-05-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: triethylamine; trichlorophosphate / dichloromethane / 0 - 20 °C 2: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; N,N-dimethyl-formamide / 150 °C
  • 21
  • [ 936727-68-3 ]
  • [ 25487-66-5 ]
  • [ 936727-05-8 ]
YieldReaction ConditionsOperation in experiment
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In water; N,N-dimethyl-formamide at 150℃; 8 Example 8:Preparation of Lumacaftor 10 g N-(6-chloro-5-methylpyridin-2-yl)- 1 -(2,2-difluorobenzo[d] [1 ,3]dioxol-5 - yl)cyclopropanecarboxamide was dissolved in 30 ml of N,N-dimethylformamide. To the solution, 6.8 g of 3-boronobenzoic acid, 50 ml of aqueous potassium carbonate solutionand 2.1 g Pd(dppf)C12 were added and the reaction mass was heated to 150 °C for 15-30 mm. The reaction mixture was filtered and purified by colunm chromatography 10% EtOAC in hexane to yield lumacaftor.
With palladium diacetate; sodium carbonate; triphenylphosphine In water; N,N-dimethyl-formamide at 26 - 80℃; for 3h; Inert atmosphere; 24 Example-24: Preparation of Lumacaftor To a mixture of N-(6-chloro-5-methylpyridin-2-yl)-1 -(2,2-difluorobenzo[d][1 ,3] dioxol-5-yl)cyclopropanecarboxamide (2 g) and 3-boronobenzoic acid (1 .086 g) in dimethylformamide (40 mL) under nitrogen atmosphere, sodium carbonate (3.01 g) in water (4.5 mL) was added at 26°C. Palladium acetate (0.122 g) and triphenylphosphine (0.429 g) was added at the same temperature and heated to 80°C. The reaction mixture was stirred for 3 hours at 80°C for the completion of the reaction.
110 g With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In water; N,N-dimethyl-formamide at 25 - 105℃; 2 EXAMPLE 2: Preparation of Lumacaftor Dimethyl formamide (700 mL), compound of Formula 11(100 g; X= Cl) and Formula III (54.3 g) were charged in a reaction flask at 25-35°C. To the reaction mass added potassiumcarbonate solution (181 g dissolved in 620 mL water) and Pd(PPh3)4 (4.7 g) were charged at 25-35°C, heated to 100-105°C and stirred for 1-3 hrs at same temperature. After completion of the reaction, reaction mass allowed to cool to 25-35°C and charged water (700 ml) at same temperature. Reaction mass was washed with toluene (2x300 mL). Then the product containing aqueous layer was separated and charged methylene chloride (500mL) to the aqueous layer. Reaction mass pH was adjusted to 4-5 with hydrochloric acid solution at 25-35°C and stirred for 1 hr at same temperature. Then the product containing organic layer was separated and concentrated at atmospheric pressure up to 3-4 vol remains in the flask and strip off with toluene (2x100 mL) and methylene chloride (100 mL) at below 75°C to obtain a residue. The obtained residue was dissolved in methylenechloride (100 mL) at 25-35°C and stirred for 60 mm at same temperature. Reaction mass was allowed to cool to 15-25°C. The solid was isolated by filtration and washed with methylene chloride (100 mL) and dryed at 50-55°C to obtain lumacaftor. Yield: 110 gm.
  • 22
  • [ 2071254-53-8 ]
  • [ 936727-05-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; caesium carbonate / 1,4-dioxane / 0.17 h 1.2: 15 h / Reflux 2.1: hydrogenchloride / water; acetonitrile / 48 h / 45 - 50 °C 3.1: water / 30 h / 20 °C
  • 23
  • [ 91668-83-6 ]
  • [ 936727-05-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: pyridine; trifluoroacetic anhydride / acetonitrile / 1 h / 65 - 70 °C 1.2: 12 h / 10 - 20 °C 2.1: pyridine / dichloromethane / 3 h / 20 °C 3.1: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; 1,4-dioxane / 1 h / 20 °C 3.2: 4 h / 85 - 90 °C 3.3: 12 h / 20 °C 4.1: water; ethyl acetate / 5 h / 20 °C
  • 24
  • [ 18368-76-8 ]
  • Lumacaftor [ No CAS ]
  • 25
  • [ 442129-37-5 ]
  • Lumacaftor [ No CAS ]
  • 26
  • [ 936727-68-3 ]
  • [ 936727-05-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; 1,4-dioxane / 1 h / 20 °C 1.2: 4 h / 85 - 90 °C 1.3: 12 h / 20 °C 2.1: water; ethyl acetate / 5 h / 20 °C
  • 27
  • [ 2102614-89-9 ]
  • [ 936727-05-8 ]
YieldReaction ConditionsOperation in experiment
5.2 g In water; ethyl acetate at 20℃; for 5h; 22 EXAMPLE 22 Preparation of crystalline lumacaftor A slurry of lurnacaftor hydrobrornide in ethyl acetate (l8OmL) and water (i8OrnL) wasstirred for about 5h at about room temperature, The two layers were separated and theorganic layer was washed with water and concentrated under reduced pressure at about45°C to about 50°C. Hexane (l2OmL) was added to the obtained residue and the mixturewas stirred for about 2h at about room temperature. The solid obtained was filtered, washed with hexane and dried at about 55°C to about 60°C for about Sh. Yield: 5.2gHPLC purity: 99.8%Compound of formula II: 0.08%
  • 28
  • [ 25487-66-5 ]
  • [ 2093001-60-4 ]
  • [ 936727-05-8 ]
YieldReaction ConditionsOperation in experiment
Stage #1: N-(6-bromo-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-1-carboxamide With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In water; toluene at 20℃; for 1h; Stage #2: 3-Carboxyphenylboronic acid In water; toluene at 80℃; for 16h; 9 EXAMPLE 9 Preparation of Lumacaftor To the solution of N-(2-bromo-3 -methylpyridin-2-yl)- 1 -(2,2-difluoro- 1,3 -benzodioxol-5-yl)cyclopropanecarboxamide (50mg) in toluene (lmL) were added potassium carbonatesolution (80.66mg in 0.SmL of water) and bis(diphenylphosphino)ferrocenedichloropalladium(II) (1.98mg) catalyst. The reaction mixture was stirred for about 1 h at about room temperature and 3 -carboxyphenylboronic acid (22.12mg) was added to it. The reaction mixture was stirred at about 80°C for about1 6h and then filtered to remove the catalyst. The filtrate was concentrated under vacuum and the obtained residue purified by column chromatography or preparative TLC.
95 g With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In water; N,N-dimethyl-formamide at 25 - 95℃; for 1h; 1 Preparation of Lumacaftor Dimethyl formamide (500 mL), compound of Formula 11(100 g; X= Br) and potassium carbonate solution (162 g dissolved in 620 mL water) were charged in a reaction flask at 25-35°C. To the reaction mass compound of Formula III (48.4 g) and Pd(PPh3)4 (4.21 g) were charged at 25-35°C, heated to 85-95°C and stirred for 1 hr at same temperature.After completion of the reaction, filtered the reaction mass and diluted the filterate with toluene (300 mL) and water (700 mL) and stirred for 10 mm at 25-35°C. Then the product containing aqueous layer was separated and charged methylene chloride (300 mL) to the aqueous layer. Reaction mass pH was adjusted to 4-5 with hydrochloric acid solution at 25-35°C and stirred for 1 hr at same temperature. Then the product containing organiclayer was separated and concentrated at below 80°C to obtain a residue. The obtained residue was dissolved in methylene chloride (300 mL) at 25-35°C and stirred for 60 mm at same temperature. Reaction mass was allowed to cool to 15-25°C. The solid was isolated by filtration and washed with methylene chloride (100 mL) and dryed at 50-55°C to obtain lumacaftor. Yield: 95 gm.
  • 30
  • [ 89466-17-1 ]
  • Lumacaftor [ No CAS ]
  • 31
  • [ 2102614-89-9 ]
  • [ 936727-05-8 ]
YieldReaction ConditionsOperation in experiment
54.3 g With sodium hydroxide In water at 28℃; 5 Preparation of Lumacaftor from lumacaftor Hydrobromide salt Water (750 ml) was charged to crystalline lumacaftor hydrobromide (75 gm). To the reaction mixture was added IN NaOH (160 ml) at 28 °C till pH is 8. The obtained solid is filtered and washed with water. The resulting solid was dried under reduced pressure. Yield: 54.3 gm
4.1 g With sodium hydrogencarbonate In water; ethyl acetate at 26℃; for 20h; 20 Example-20: Preparation of Lumacaftor from Lumacaftor hydrobromide salt. To a mixture of hydrobromide salt of Lumacaftor (5 g) in ethyl acetate (50 mL), a solution of sodium bicarbonate (0.788 g) in water (20 mL) at 26°C and stirred for 20 minutes at the same temperature. Separated the organic layer and removed the solvent through evaporation under reduced pressure at 26°C. The solid was dried at 45°C for 3 hours under reduced pressure to obtain the title compound. Yield: 4.1 g
  • 32
  • [ 269409-73-6 ]
  • N-(6-bromo-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-1-carboxamide [ No CAS ]
  • Lumacaftor [ No CAS ]
YieldReaction ConditionsOperation in experiment
13 g With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In water; N,N-dimethyl-formamide; at 26 - 70℃; for 1h; N-(6-bromo-5-methylpyndin-2-yl)-1 -(2,2-difluorobenzo[d][1 ,3]dioxol-5-yl) cyclopropanecarboxamide (20 g) and 3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzoic acid (14.48 g) were added to a mixture of potassium carbonate (32.3 g) in dimethylformamide (100 ml_) and water (20 ml_) at 26C. Pd(dppf)CI2* CH2CI2 (1 .984 g) was added to the above reaction mixture at the same temperature and heated to 70C. The reaction m ixture was stirred for 1 hour at 70C and cooled to 26C. The reaction mixture was quenched with water (200 ml_) and ethyl acetate (200 ml_) was added. Cooled the reaction mixture to 10C and adjusted the pH of the reaction mixture to 2 using 36% hydrochloric acid. The reaction mixture was filtered and separated the organic layer. 10% aqueous hydrochloride (100 ml_) was added and stirred for 15 minutes at 26C. Separated the organic layer and again 10% aqueous hydrochloride (100 ml_) was added. Stirred the reaction mixture for 15 minutes and separated the organic layer. The solvent was evaporated completely at 52C under reduced pressure and chased with 2-propanol (50 ml_). 2-propanol (50 ml_) was added to the crude product at 26C and stirred for 1 .5 hours at the same temperature. 36% aqueous hydrochloride (5 ml_) was added at 26C and stirred for 15 hours at same temperature. The reaction mixture was cooled to 5C and stirred for 1 hour at this temperature. The solid was filtered and washed with 2-propanol (5 ml_). The solid was dried at 68C for 4.5 hour under reduced pressure to obtain the title compound. Yield: 13 g; Purity by HPLC: 99.23%
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