* 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.
Stage #1: With pyridine; methanesulfonic anhydride In acetonitrile at 70 - 75℃; for 1.33333 h; Stage #2: With water; ethanolamine In acetonitrile at 10 - 20℃; for 5 h;
Synthesis of terf-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate (compound 6).[00263] A solution of compound 5 (1 eq) and pyridine (4 eq) in MeCN (8 vol) is heated to 70 0C. A solution of methanesulfonic anhydride (1.5 eq) in MeCN (2 vol) is added over 50 min via addition funnel maintaining the temperature at less than 75 0C. The mixture is stirred for an additional 0.5 hours after complete addition. The mixture is then allowed to cool to ambient. Ethanolamine (10 eq) is added via addition funnel. After stirring for 2 hours, water (6 vol) is added and the mixture is cooled to 10 0C. After stirring for NLT 3 hours, the solid is collected by filtration and washed with water (3 vol), 2: 1 MeCN/water (3 vol), and MeCN (2 x 1.5 vol). The solid is dried to constant weight (<1percent difference) in a vacuum oven at 50 0C with a slight N2 bleed to afford compound 6 as a red-yellow solid (53percent yield).
53%
Stage #1: With pyridine; methanesulfonic anhydride In acetonitrile at 70 - 75℃; Stage #2: With ethanolamine In acetonitrile at 20℃;
A solution of 2-(3-(tert-butoxycarbonyl)phenyl)-3-methylpyridine-l -oxide (1 eq) and pyridine (4 eq) in MeCN (8 vol) is heated to 70 0C. A solution of methanesulfonic anhydride (1.5 eq) in MeCN (2 vol) is added over 50 min via addition funnel maintaining the temperature at less than 75 0C. The mixture is stirred for an additional 0.5 hours after complete addition. The mixture is then allowed to cool to ambient. Ethanolamine (10 eq) is added via addition funnel. After stirring for 2 hours, water (6 vol) is added and the mixture is cooled to 10 0C. After stirring for NLT 3 hours, the solid is collected by filtration and washed with water (3 vol), 2: 1 MeCN/water (3 vol), and MeCN (2 x 1.5 vol). The solid is dried to constant weight (<1percent difference) in a vacuum oven at 50 0C with a slight N2 bleed to afford tert-butyl-3-(6-amino-3- methylpyridin-2-yl)benzoate as a red-yellow solid (53percent yield).
53%
Stage #1: With pyridine; methanesulfonic anhydride In acetonitrile at 70 - 75℃; for 1.33333 h; Stage #2: With ethanolamine In acetonitrile at 20℃; for 2 h;
A solution of 2-(3-(tert-butoxycarbonyl)phenyl)-3-methylpyridine-l-oxide (1 eq) and pyridine (4 eq) in MeCN (8 vol) is heated to 70 0C. A solution of methanesulfonic anhydride (1.5 eq) in MeCN (2 vol) is added over 50 min via addition funnel maintaining the temperature at less than 75 0C. The mixture is stirred for an additional 0.5 hours after complete addition. The mixture is then allowed to cool to ambient. Ethanolamine (10 eq) is added via addition funnel. After stirring for 2 hours, water (6 vol) is added and the mixture is cooled to 10 0C. After stirring for NLT 3 hours, the solid is collected by filtration and washed with water (3 vol), 2: 1 MeCN/water (3 vol), and MeCN (2 x 1.5 vol). The solid is dried to constant weight (<1percent difference) in a vacuum oven at 50 0C with a slight N2 bleed to afford tert-butyl-3-(6-amino-3- methylpyridin-2-yl)benzoate as a red-yellow solid (53percent yield).
53%
Stage #1: With pyridine; methanesulfonic anhydride In acetonitrile at 70 - 75℃; for 1 h; Stage #2: With ethanolamine In acetonitrile for 2 h;
Preparation of tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate A solution of 2-(3-(tert-butoxycarbonyl)phenyl)-3-methylpyridine-1-oxide (1 eq) and pyridine (4 eq) in acetonitrile (8 vol) was heated to 70° C. A solution of methanesulfonic anhydride (1.5 eq) in MeCN (2 vol) was added over 50 min via addition funnel while maintaining the temperature at less than 75° C. The mixture was stirred for an additional 0.5 hours after complete addition. The mixture was then allowed to cool to ambient. Ethanolamine (10 eq) was added via addition funnel. After stirring for 2 hours, water (6 vol) was added and the mixture was cooled to 10° C. After stirring for 3 hours, the solid was collected by filtration and washed with water (3 vol), 2:1 acetonitrile/water (3 vol), and acetonitrile (2*1.5 vol). The solid was dried to constant weight (<1percent difference) in a vacuum oven at 50° C. with a slight N2 bleed to afford tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate as a red-yellow solid (53percent yield).
53%
Stage #1: With pyridine; methanesulfonic anhydride In acetonitrile for 1.33333 h; Stage #2: at 20℃; for 2 h; Stage #3: at 10℃; for 3 h;
A solution of2-(3-(tert-butoxycarbonyl)phenyl)-3-methylpyridine-l-oxide (1 eq) andpyridine ( 4 eq) in acetonitrile (8 vol) was heated to 70 °C. A solution of methanesulfonicanhydride (1.5 eq) in MeCN (2 vol) was added over 50 min via addition funnel whilemaintaining the temperature at less than 75 °C. The mixture was stirred for an additional 0.5hours after complete addition. The mixture was then allowed to cool to ambient temperature.Ethanolamine (10 eq) was added via addition funneL After stirring for 2 hours, water (6 vol)was added and the mixture was cooled to 10 oc After stirring for 3 hours, the solid wascollected by filtration and washed with water (3 vol), 2:1 acetonitrile/water (3 vol), andacetonitrile (2 x L5 voi). The solid was dried to constant weight (<1percent difference) in a vacuumoven at 50 oc with a slight N2 bleed to aflord tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate as a red-yellow solid (53percent yield).
tert-Butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate A solution of 2-(3-(tert-butoxycarbonyl)phenyl)-3-methylpyridine-1-oxide (1 eq) and pyridine (4 eq) in acetonitrile (8 vol) was heated to 70° C. A solution of methanesulfonic anhydride (1.5 eq) in MeCN (2 vol) was added over 50 min via addition funnel while maintaining the temperature at less than 75° C. The mixture was stirred for an additional 0.5 hours after complete addition. The mixture was then allowed to cool to ambient. Ethanolamine (10 eq) was added via addition funnel. After stirring for 2 hours, water (6 vol) was added and the mixture was cooled to 10° C. After stirring for 3 hours, the solid was collected by filtration and washed with water (3 vol), 2:1 acetonitrile/water (3 vol), and acetonitrile (2*1.5 vol). The solid was dried to constant weight (<1percent difference) in a vacuum oven at 50° C. with a slight N2 bleed to afford tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate as a red-yellow solid (53percent yield).
53%
With pyridine In water; acetonitrile
Preparation of tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate A solution of 2-(3-(tert-butoxycarbonyl)phenyl)-3-methylpyridine-1-oxide (1 eq) and pyridine (4 eq) in acetonitrile (8 vol) was heated to 70° C. A solution of methanesulfonic anhydride (1.5 eq) in MeCN (2 vol) was added over 50 min via addition funnel while maintaining the temperature at less than 75° C. The mixture was stirred for an additional 0.5 hours after complete addition. The mixture was then allowed to cool to ambient. Ethanolamine (10 eq) was added via addition funnel. After stirring for 2 hours, water (6 vol) was added and the mixture was cooled to 10° C. After stirring for 3 hours, the solid was collected by filtration and washed with water (3 vol), 2:1 acetonitrile/water (3 vol), and acetonitrile (2*1.5 vol). The solid was dried to constant weight (<1percent difference) in a vacuum oven at 50° C. with a slight N2 bleed to afford tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate as a red-yellow solid (53percent yield).
Synthesis of 3-(6-(l-(2,2-difluorobenzo[d] [l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate (compound 8).[00265] Compound 7 is dissolved in toluene (2.5 vol based on acid chloride) and added via addition funnel to a mixture of compound 6 (1 eq), dimethylaminopyridine (DMAP, 0.02 eq), and triethylamine (3.0 eq) in toluene (4 vol based on compound 6). After 2 hours, water (4 vol based on compound 6) is added to the reaction mixture. After stirring for 30 minutes, the layers are separated. The organic phase is then filtered and concentrated to afford a thick oil of compound 8 (quantitative crude yield). MeCN (3 vol based on crude product) is added and distilled until crystallization occurs. Water (2 vol based on crude product) is added and the mixture stirred for 2 h. The solid is collected by filtration, washed with 1 : 1 (by volume) MeCN/water (2 x 1 vol based on crude product), 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 3-(6-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl) cyclopropanecarboxamido)-3- methylpyridin-2-yl)-t-butylbenzoate as a brown solid.
With triethylamine;dmap; In toluene; for 2h;
The crude acid chloride is dissolved in toluene (2.5 vol based on acid chloride) and added via addition funnel to a mixture of tert-butyl-3-(6-amino-3-methylpyridin-2- yl)benzoate (1 eq), dimethylaminopyridine (DMAP, 0.02 eq), and triethylamine (3.0 eq) in toluene (4 vol based on <strong>[1083057-14-0]tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate</strong>). After 2 hours, water (4 vol based on <strong>[1083057-14-0]tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate</strong>) is added to the reaction mixture. After stirring for 30 minutes, the layers are separated. The organic phase is then filtered and concentrated to afford a thick oil of 3-(6-(l-(2,2-difluorobenzo[d][l,3]dioxol-5- yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate (quantitative crude yield). MeCN (3 vol based on crude product) is added and distilled until crystallization occurs. Water (2 vol based on crude product) is added and the mixture stirred for 2 h. The solid is collected by filtration, washed with 1 : 1 (by volume) MeCN/water (2 x 1 vol based on crude product), 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 3-(6-(l-(2,2- difluorobenzo[d][l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t- butylbenzoate as a brown solid.
With triethylamine;dmap; In toluene; for 2h;
The crude acid chloride is dissolved in toluene (2.5 vol based on acid chloride) and added via addition funnel to a mixture of tert-butyl-3-(6-amino-3- methylpyridin-2-yl)benzoate (1 eq), dimethylaminopyridine (DMAP, 0.02 eq), and triethylamine (3.0 eq) in toluene (4 vol based on tert-butyl-3-(6-amino-3-methylpyridin-2- yl)benzoate). After 2 hours, water (4 vol based on tert-butyl-3-(6-amino-3-methylpyridin- 2-yl)benzoate) is added to the reaction mixture. After stirring for 30 minutes, the layers are separated. The organic phase is then filtered and concentrated to afford a thick oil of 3-(6- (l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2- yl)-t-butylbenzoate (quantitative crude yield). MeCN (3 vol based on crude product) is added and distilled until crystallization occurs. Water (2 vol based on crude product) is added and the mixture stirred for 2 h. The solid is collected by filtration, washed with 1 : 1 (by volume) MeCN/water (2 x 1 vol based on crude product), 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 3-(6-(l-(2,2-difluorobenzo[d][l,3]dioxol-5- yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate as a brown solid.
With dmap; triethylamine; In water; toluene; at 2.5℃; for 2h;
The crude acid chloride described above was dissolved in toluene (2.5 vol based on acid chloride) and added via addition funnel to a mixture of <strong>[1083057-14-0]tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate</strong> (1 eq), DMAP, (0.02 eq), and triethylamine (3.0 eq) in toluene (4 vol based on <strong>[1083057-14-0]tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate</strong>). After 2 hours, water (4 vol based on <strong>[1083057-14-0]tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate</strong>) was added to the reaction mixture. After stirring for 30 minutes, the layers were separated. The organic phase was then filtered and concentrated to afford a thick oil of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate (quantitative crude yield). Acetonitrile (3 vol based on crude product) was added and distilled until crystallization occurs. Water (2 vol based on crude product) was added and the mixture stirred for 2 h. The solid was collected by filtration, washed with 1:1 (by volume) acetonitrile/water (2×1 volumes based on crude product), and partially dried on the filter under vacuum. The solid was dried to a constant weight (N2 bleed to afford 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate as a brown solid.
With dmap; triethylamine; In toluene; for 2h;
The cmde acid chloride described above was dissolved in toluene (2.5 vol based onacid chloride) and added via addition funnel to a mixture of <strong>[1083057-14-0]tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate</strong> (1 eq), DMAP, (0.02 eq), and triethylamine (3.0 eq) in toluene (4vol based on <strong>[1083057-14-0]tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate</strong>). After 2 hours, water (4 volbased on <strong>[1083057-14-0]tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate</strong>) was added to the reactionmixture. After stirring for 30 minutes, the layers were separated. The organic phase was thenfiltered and concentrated to afford a thick oil of3-(6-(1-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxamido )-3-methylpyridin-2-yl)+butylbenzoate (quantitative crude yield).Acetonitrile (3 vol based on crude product) was added and distilled until crystallization occurs"Water (2 vol based on crude product) was added and the mixture stirred for 2 h. The solid wascollected by filtration, washed with 1: 1 (by volume) acetonitrile/water (2 x 1 volumes based oncrude product), and partially dried on the filter under vacmm1< The solid was dried to a constantweight (<1% difference) in a vacuum oven at 60 '"'C with a slight N2 bleed to afford 3-(6-(1-(2,2-difluorobenzo[d J [ 1,3 ]dioxol~ 5~yl) cyclopropanecarboxamido)-3-methylpyTidin-2 -yl)+butylbenzoate as a brown solid.
With dmap; triethylamine; In toluene; for 2h;
[00305] The crude acid chloride described above was dissolved in toluene (2.5 vol based onacid chloride) and added via addition funnel to a mixture of<strong>[1083057-14-0]tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate</strong> (1 eq), DMAP, (0.02 eq), and triethylamine (3.0 eq) in toluene (4vol based on <strong>[1083057-14-0]tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate</strong>). After 2 hours, water (4 volbased on <strong>[1083057-14-0]tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate</strong>) was added to the reactionmixture. After stirring for 30 minutes, the layers were separated. The organic phase was thenfiltered and concentrated to afford a thick oil of3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido )-3-methylpyridin-2-yl)-t-butylbenzoate (quantitative crude yield).Acetonitrile (3 vol based on crude product) was added and distilled until crystallization occurs.Water (2 vol based on crude product) was added and the mixture stirred for 2 h. The solid wascollected by filtration, washed with 1: 1 (by volume) acetonitrile/water (2 x 1 volumes based oncrude product), and partially dried on the filter under vacuum. The solid was dried to a constantweight (<1% difference) in a vacuum oven at 60 oc with a slight N2 bleed to afford 3-(6-(1-(2,2-difluorobenzo[ d] [ 1,3 ]dioxol-5-yl) cyclopropanecarboxamido )-3-methylpyridin-2-yl)-tbutylbenzoateas a brown solid.
With dmap; triethylamine; In toluene; for 2h;
[00320] The crude acid chloride described above was dissolved in toluene (2.5 vol based on acid chloride) and added via addition funnel to a mixture of teri-butyl-3-(6-amino-3- methylpyridin-2-yl)benzoate (1 eq), DMAP, (0.02 eq), and triethylamine (3.0 eq) in toluene (4 vol based on /;eri-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate). After 2 hours, water (4 vol based on r -butyI-3-(6-amino-3-methylpyridin-2-yl)benzoate) was added to the reaction mixture. After stirring for 30 minutes, the layers were separated. The organic phase was then filtered and concentrated to afford a thick oil of 3-(6-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate (quantitative crude yield). Acetonitrile (3 vol based on crude product) was added and distilled until crystallization occurs. Water (2 vol based on crude product) was added and the mixture stirred for 2 h. The solid was collected by filtration, washed with 1 : 1 (by volume) acetonitrile/water (2 x 1 volumes based on crude product), 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 3-(6-(l-(2,2- difluorobenzo[d][l ,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t- butylbenzoate as a brown solid.
With dmap; triethylamine; In toluene; for 2.5h;
The crude acid chloride described above was dissolved in toluene (2.5 vol based on acid chloride) and added via addition funnel to a mixture of <strong>[1083057-14-0]tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate</strong> (1 eq), DMAP, (0.02 eq), and triethylamine (3.0 eq) in toluene (4 vol based on <strong>[1083057-14-0]tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate</strong>). After 2 hours, water (4 vol based on <strong>[1083057-14-0]tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate</strong>) was added to the reaction mixture. After stirring for 30 minutes, the layers were separated. The organic phase was then filtered and concentrated to afford a thick oil of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate (quantitative crude yield).
With dmap; triethylamine; In toluene; for 2h;
Preparation of 3-(6-(1-(2,2-difluorobenzo [d][1,3]dioxol-5-yl)-cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate The crude acid chloride described above was dissolved in toluene (2.5 vol based on acid chloride) and added via addition funnel to a mixture of <strong>[1083057-14-0]tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate</strong> (1 eq), DMAP, (0.02 eq), and triethylamine (3.0 eq) in toluene (4 vol based on <strong>[1083057-14-0]tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate</strong>). After 2 hours, water (4 vol based on <strong>[1083057-14-0]tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate</strong>) was added to the reaction mixture. After stirring for 30 minutes, the layers were separated. The organic phase was then filtered and concentrated to afford a thick oil of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate (quantitative crude yield). Acetonitrile (3 vol based on crude product) was added and distilled until crystallization occurs. Water (2 vol based on crude product) was added and the mixture stirred for 2 h. The solid was collected by filtration, washed with 1:1 (by volume) acetonitrile/water (2*1 volumes based on crude product), 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 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate as a brown solid.
With dmap; triethylamine;
Scheme IV-D depicts the coupling of 1-(2,2-difluorobenzo[d][1,3]dioxol-5- yl)cyclopropanecarbonyl chloride with tert-butyl 3-(6-amino-3-methylpyridin-2- yl)benzoate using triethyl amine and 4-dimethylaminopyridine to initially provide the tert-butyl ester of Compound IV.
With dmap; triethylamine; In toluene; for 2h;
The crude chlorobenzene described above was dissolved in toluene (2.5 vol. based on ruthenium chloride) and added to the 3-(6-amino-3-methylpyridin-2-yl)benzoic acid via an addition funnel. Tributyl ester (1 equivalent), DMAP (0.02 equivalent) and triethylamine (3.0 equivalent) in toluene (3-(6-amino-3-methylpyridin-2-yl)benzoic acid tributyl In the mixture of the base ester, 4 volumes). After 2 hours, water (4 volumes) based on 3-(6-amino-3-methylpyridin-2-yl)benzoic acid tert-butyl ester was added to the reaction mixture. After stirring for 30 minutes, the layers were separated. The organic phase is then filtered and concentrated to provide 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide a thick oil of 3-methylpyridin-2-yl)-benzoic acid tert-butyl ester (quantitative crude yield). Acetonitrile (3 volumes in terms of crude product) was added and distilled until crystallization occurred. Water (2 volumes in terms of crude product) was added and the mixture was stirred for 2 h. The solid was collected by filtration, washed with 1:1 (volume ratio) acetonitrile/water (2×1 volume as crude product) 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 3-(6-(1-(2,2-difluorobenzo[ d] [1,3]dioxol-5-yl)cyclopropanecarbamoylamino)-3-methylpyridin-2-yl)-benzoic acid tert-butyl ester.
Synthesis of terf-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate (compound 6).[00263] A solution of compound 5 (1 eq) and pyridine (4 eq) in MeCN (8 vol) is heated to 70 0C. A solution of methanesulfonic anhydride (1.5 eq) in MeCN (2 vol) is added over 50 min via addition funnel maintaining the temperature at less than 75 0C. The mixture is stirred for an additional 0.5 hours after complete addition. The mixture is then allowed to cool to ambient. Ethanolamine (10 eq) is added via addition funnel. After stirring for 2 hours, water (6 vol) is added and the mixture is cooled to 10 0C. After stirring for NLT 3 hours, the solid is collected by filtration and washed with water (3 vol), 2: 1 MeCN/water (3 vol), and MeCN (2 x 1.5 vol). The solid is dried to constant weight (<1% difference) in a vacuum oven at 50 0C with a slight N2 bleed to afford compound 6 as a red-yellow solid (53% yield).
53%
A solution of 2-(3-(tert-butoxycarbonyl)phenyl)-3-methylpyridine-l -oxide (1 eq) and pyridine (4 eq) in MeCN (8 vol) is heated to 70 0C. A solution of methanesulfonic anhydride (1.5 eq) in MeCN (2 vol) is added over 50 min via addition funnel maintaining the temperature at less than 75 0C. The mixture is stirred for an additional 0.5 hours after complete addition. The mixture is then allowed to cool to ambient. Ethanolamine (10 eq) is added via addition funnel. After stirring for 2 hours, water (6 vol) is added and the mixture is cooled to 10 0C. After stirring for NLT 3 hours, the solid is collected by filtration and washed with water (3 vol), 2: 1 MeCN/water (3 vol), and MeCN (2 x 1.5 vol). The solid is dried to constant weight (<1% difference) in a vacuum oven at 50 0C with a slight N2 bleed to afford tert-butyl-3-(6-amino-3- methylpyridin-2-yl)benzoate as a red-yellow solid (53% yield).
53%
A solution of 2-(3-(tert-butoxycarbonyl)phenyl)-3-methylpyridine-l-oxide (1 eq) and pyridine (4 eq) in MeCN (8 vol) is heated to 70 0C. A solution of methanesulfonic anhydride (1.5 eq) in MeCN (2 vol) is added over 50 min via addition funnel maintaining the temperature at less than 75 0C. The mixture is stirred for an additional 0.5 hours after complete addition. The mixture is then allowed to cool to ambient. Ethanolamine (10 eq) is added via addition funnel. After stirring for 2 hours, water (6 vol) is added and the mixture is cooled to 10 0C. After stirring for NLT 3 hours, the solid is collected by filtration and washed with water (3 vol), 2: 1 MeCN/water (3 vol), and MeCN (2 x 1.5 vol). The solid is dried to constant weight (<1% difference) in a vacuum oven at 50 0C with a slight N2 bleed to afford tert-butyl-3-(6-amino-3- methylpyridin-2-yl)benzoate as a red-yellow solid (53% yield).
53%
Preparation of tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate A solution of 2-(3-(tert-butoxycarbonyl)phenyl)-3-methylpyridine-1-oxide (1 eq) and pyridine (4 eq) in acetonitrile (8 vol) was heated to 70 C. A solution of methanesulfonic anhydride (1.5 eq) in MeCN (2 vol) was added over 50 min via addition funnel while maintaining the temperature at less than 75 C. The mixture was stirred for an additional 0.5 hours after complete addition. The mixture was then allowed to cool to ambient. Ethanolamine (10 eq) was added via addition funnel. After stirring for 2 hours, water (6 vol) was added and the mixture was cooled to 10 C. After stirring for 3 hours, the solid was collected by filtration and washed with water (3 vol), 2:1 acetonitrile/water (3 vol), and acetonitrile (2*1.5 vol). The solid was dried to constant weight (<1% difference) in a vacuum oven at 50 C. with a slight N2 bleed to afford tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate as a red-yellow solid (53% yield).
53%
A solution of2-(3-(tert-butoxycarbonyl)phenyl)-3-methylpyridine-l-oxide (1 eq) andpyridine ( 4 eq) in acetonitrile (8 vol) was heated to 70 C. A solution of methanesulfonicanhydride (1.5 eq) in MeCN (2 vol) was added over 50 min via addition funnel whilemaintaining the temperature at less than 75 C. The mixture was stirred for an additional 0.5hours after complete addition. The mixture was then allowed to cool to ambient temperature.Ethanolamine (10 eq) was added via addition funneL After stirring for 2 hours, water (6 vol)was added and the mixture was cooled to 10 oc After stirring for 3 hours, the solid wascollected by filtration and washed with water (3 vol), 2:1 acetonitrile/water (3 vol), andacetonitrile (2 x L5 voi). The solid was dried to constant weight (<1% difference) in a vacuumoven at 50 oc with a slight N2 bleed to aflord tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate as a red-yellow solid (53% yield).
53%
With pyridine; Methanesulfonic anhydride; In acetonitrile; at 70 - 75℃;
The solution of 2-(3-(t-butoxycarbonyl)phenyl)-3-methylpyridine-1-oxide (1 equivalent) and pyridine (4 equivalents) in MeCN (8 vol) was heated to 70 C. A solution of methanesulfonic anhydride (1.5 equivalents) in MeCN (2 vol) was added via an addition funnel over 50 min while maintaining the temperature below 75 C. The mixture was stirred for an additional 0.5 hours after the addition was completed. The mixture is then allowed to cool to ambient temperature. Ethanolamine (10 equivalents) was added via an addition funnel. After stirring for 2 hours, water (6 vol) was added and the mixture was cooled to 10 C. After stirring for 3 hours, the solid was collected by filtration and washed with water (3 vol), 2:1 acetonitrile/water (3 vol) and acetonitrile (2 x 1.5 vol). The solid was dried to constant weight (difference <1%) in a vacuum oven at 50 C under a slight N 2 purge to afford 3-(6-amino-3-methylpyridine-2- as a red-yellow solid. Base) tert-butyl benzoate (yield 53%).
[00303] A solution of2-(3-(tert-butoxycarbonyl)phenyl)-3-methylpyridine-1-oxide (1 eq) andpyridine ( 4 eq) in acetonitrile (8 vol) was heated to 70 C. A solution of methanesulfonicanhydride (1.5 eq) in MeCN (2 vol) was added over 50 min via addition funnel whilemaintaining the temperature at less than 75 C. The mixture was stirred for an additional 0.5hours after complete addition. The mixture was then allowed to cool to ambient. Ethanolamine(10 eq) was added via addition funnel. After stirring for 2 hours, water (6 vol) was added andthe mixture was cooled to 10 C. After stirring for 3 hours, the solid was collected by filtrationand washed with water (3 vol), 2:1 acetonitrile/water (3 vol), and acetonitrile (2 x 1.5 vol). The solid was dried to constant weight (<1% difference) in a vacuum oven at 50 oc with a slight N2bleed to afford tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate as a red-yellow solid (53%yield).
[00318] A solution of 2-(3-(ier 1-butoxycarbonyl)phenyl)-3-methylpyridine-l -oxide (1 eq) and pyridine (4 eq) in acetonitrile (8 vol) was heated to 70 C. A solution of methanesulfonic anhydride (1.5 eq) in MeCN (2 vol) was added over 50 min via addition funnel while maintaining the temperature at less than 75 C. The mixture was stirred for an additional 0.5 hours after complete addition. The mixture was then allowed to cool to ambient. Ethanolamine (10 eq) was added via addition funnel. After stirring for 2 hours, water (6 vol) was added and the mixture was cooled to 10 C. After stirring for 3 hours, the solid was collected by filtration and washed with water (3 vol), 2: 1 acetonitrile/water (3 vol), and acetonitrile (2 x 1.5 vol). The solid was dried to constant weight (<1 % difference) in a vacuum oven at 50 C with a slight N2 bleed to afford fe7-t-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate as a red-yellow solid (53% yield).
A solution of 2-(3-(tert-butoxycarbonyl)phenyl)-3-methylpyridine-1-oxide (1 eq) and pyridine (4 eq) in acetonitrile (8 vol) was heated to 70 C. A solution of methanesulfonic anhydride (1.5 eq) in MeCN (2 vol) was added over 50 min via addition funnel while maintaining the temperature at less than 75 C. The mixture was stirred for an additional 0.5 hours after complete addition. The mixture was then allowed to cool to ambient. Ethanolamine (10 eq) was added via addition funnel. After stirring for 2 hours, water (6 vol) was added and the mixture was cooled to 10 C. After stirring for 3 hours, the solid was collected by filtration and washed with water (3 vol), 2:1 acetonitrile/water (3 vol), and acetonitrile (2*1.5 vol). The solid was dried to constant weight (<1% difference) in a vacuum oven at 50 C. with a slight N2 bleed to afford tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate as a red-yellow solid (53% yield).
Preparation of tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate A solution of 2-(3-(tert-butoxycarbonyl)phenyl)-3-methylpyridine-1-oxide (1 eq) and pyridine (4 eq) in acetonitrile (8 vol) was heated to 70 C. A solution of methanesulfonic anhydride (1.5 eq) in MeCN (2 vol) was added over 50 min via addition funnel while maintaining the temperature at less than 75 C. The mixture was stirred for an additional 0.5 hours after complete addition. The mixture was then allowed to cool to ambient. Ethanolamine (10 eq) was added via addition funnel. After stirring for 2 hours, water (6 vol) was added and the mixture was cooled to 10 C. After stirring for 3 hours, the solid was collected by filtration and washed with water (3 vol), 2:1 acetonitrile/water (3 vol), and acetonitrile (2*1.5 vol). The solid was dried to constant weight (<1% difference) in a vacuum oven at 50 C. with a slight N2 bleed to afford tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate as a red-yellow solid (53% yield).
tert-Butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate A solution of 2-(3-(tert-butoxycarbonyl)phenyl)-3-methylpyridine-1-oxide (1 eq) and pyridine (4 eq) in acetonitrile (8 vol) was heated to 70 C. A solution of methanesulfonic anhydride (1.5 eq) in MeCN (2 vol) was added over 50 min via addition funnel while maintaining the temperature at less than 75 C. The mixture was stirred for an additional 0.5 hours after complete addition. The mixture was then allowed to cool to ambient. Ethanolamine (10 eq) was added via addition funnel. After stirring for 2 hours, water (6 vol) was added and the mixture was cooled to 10 C. After stirring for 3 hours, the solid was collected by filtration and washed with water (3 vol), 2:1 acetonitrile/water (3 vol), and acetonitrile (2*1.5 vol). The solid was dried to constant weight (<1% difference) in a vacuum oven at 50 C. with a slight N2 bleed to afford tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate as a red-yellow solid (53% yield).
53%
With pyridine; In water; acetonitrile;
Preparation of tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate A solution of 2-(3-(tert-butoxycarbonyl)phenyl)-3-methylpyridine-1-oxide (1 eq) and pyridine (4 eq) in acetonitrile (8 vol) was heated to 70 C. A solution of methanesulfonic anhydride (1.5 eq) in MeCN (2 vol) was added over 50 min via addition funnel while maintaining the temperature at less than 75 C. The mixture was stirred for an additional 0.5 hours after complete addition. The mixture was then allowed to cool to ambient. Ethanolamine (10 eq) was added via addition funnel. After stirring for 2 hours, water (6 vol) was added and the mixture was cooled to 10 C. After stirring for 3 hours, the solid was collected by filtration and washed with water (3 vol), 2:1 acetonitrile/water (3 vol), and acetonitrile (2*1.5 vol). The solid was dried to constant weight (<1% difference) in a vacuum oven at 50 C. with a slight N2 bleed to afford tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate as a red-yellow solid (53% yield).
3-(6-(1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate The crude acid chloride described above was dissolved in toluene (2.5 vol based on acid chloride) and added via addition funnel to a mixture of <strong>[1083057-14-0]tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate</strong> (1 eq), DMAP, (0.02 eq), and triethylamine (3.0 eq) in toluene (4 vol based on <strong>[1083057-14-0]tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate</strong>). After 2 hours, water (4 vol based on <strong>[1083057-14-0]tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate</strong>) was added to the reaction mixture. After stirring for 30 minutes, the layers were separated. The organic phase was then filtered and concentrated to afford a thick oil of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate (quantitative crude yield).
2,2-difluoro-5-methyl-6,7-dihydro-2H,5H-indeno[5,6-d][1,3]dioxole-5-carboxylic acid[ No CAS ]
tert-butyl 3-{6-[(2,2-difluoro-5-methyl-6,7-dihydro-2H,5H-indeno[5,6-d][1,3]dioxole-5-carbonyl)amino]-3-methylpyridin-2-yl}benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
10%
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 60℃;
Example 51A tert-butyl 3-{6-[(2,2-difluoro-5-methyl-6,7-dihydro-2H,5H-indeno[5,6-d][1,3]dioxole-5-carbonyl)amino]-3-methylpyridin-2-yl}benzoate The product from Example 35F (0.055 g, 0.215 mmol), <strong>[1083057-14-0]tert-butyl 3-(6-amino-3-methylpyridin-2-yl)benzoate</strong> (CAS [1083057-14-0], 0.070 g, 0.247 mmol), and EDCI (0.082 g, 0.429 mmol) were stirred in DMF (0.5 mL) and pyridine (0.500 mL) at 60 C. overnight. After this time, the reaction mixture was concentrated in vacuo, and the residue was purified by reverse-phase preparative HPLC on a Waters Nova-Pak HR C18 6 mum 60 A Prep-Pak cartridge column (40 mm*100 mm) using a gradient of 10% to 100% acetonitrile in 10 mM aqueous ammonium acetate over 12 minutes at a flow rate of 70 mL/minute to yield the title compound (0.011, g, 10% yield). 1H NMR (400 MHz, DMSO-d6) delta 9.69 (s, 1H), 8.04-7.88 (m, 3H), 7.75 (dd, J=14.2, 8.1 Hz, 2H), 7.65-7.50 (m, 2H), 7.28 (s, 1H), 2.92 (q, J=6.8, 5.8 Hz, 2H), 2.70 (ddd, J=13.1, 8.0, 5.4 Hz, 1H), 2.23 (s, 3H), 2.18-2.02 (m, 1H), 1.60 (s, 3H), 1.55 (s, 9H). MS (ESI+) m/z 523.1 (M+H).
2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carboxylic acid[ No CAS ]
tert-butyl 3-{6-[(2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl)amino]-3-methylpyridin-2-yl}benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
Example 1F tert-butyl 3-{6-[(2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl)amino]-3-methylpyridin-2-yl}benzoate Example 1E (55.6 mg, 0.215 mmol) was dissolved in dichloromethane (1 mL). Oxalyl chloride (80 muL) and N,N-dimethylformamide (25 muL) were added which resulted in bubbling of the reaction mixture. The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated; the residue was dissolved in dichloromethane (1 mL) and concentrated two times. The residue was dissolved in dichloromethane (1 mL) and pyridine (0.5 mL), <strong>[1083057-14-0]tert-butyl 3-(6-amino-3-methylpyridin-2-yl)benzoate</strong> (CAS [1083057-14-0], 54.8 mg, 0.193 mmol) was added, and the reaction mixture was stirred at 60 C. for 16 hours. The reaction mixture was concentrated, and the residue was purified by reverse-phase preparative HPLC on a Waters Nova-Pak HR C18 6 mum 60 A Prep-Pak cartridge column (40 mm*100 mm) using a gradient of 10% to 100% acetonitrile in 10 mM aqueous ammonium acetate over 12 minutes at a flow rate of 70 mL/minute to yield 71.0 mg (70%) of the title compound. 1H NMR (400 MHz, DMSO-d6) delta ppm 10.14 (s, 1H), 8.02 (t, J=1.7 Hz, 1H), 7.98-7.90 (m, 2H), 7.81-7.73 (m, 2H), 7.65 (s, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.03 (s, 1H), 5.10 (d, J=9.3 Hz, 1H), 4.41 (d, J=9.3 Hz, 1H), 2.25 (s, 3H), 1.71 (s, 3H), 1.56 (s, 9H); MS (ESI+) m/z 525.0 (M+H)+.
(7S)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carboxylic acid[ No CAS ]
tert-butyl 3-(6-[(7S)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-3-methylpyridin-2-yl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
11%
Example 3C tert-butyl 3-(6-[(7S)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-3-methylpyridin-2-yl)benzoate A solution of the product from Example 3A (0.052 g, 0.2 mmol) in 0.5 mL dichloromethane was treated with N,N-dimethylformamide (0.025 mL, 0.320 mmol) and then dropwise with oxalyl chloride (0.077 mL, 0.880 mmol). The mixture was stirred at ambient temperature for 1 hour and then concentrated (rotary evaporator). An additional 0.5 mL dichloromethane was added, and the mixture was concentrated again. The addition/concentration procedure was repeated twice more. Then the residue was taken up in 0.5 mL dichloromethane and treated with pyridine (0.485 mL, 6.00 mmol) and <strong>[1083057-14-0]tert-butyl 3-(6-amino-3-methylpyridin-2-yl)benzoate</strong>) (CAS [1083057-14-0], 0.057 g, 0.200 mmol). The reaction stirred at 60 C. overnight. The reaction mixture then was concentrated (rotary evaporator), and the residue was purified by reverse-phase preparative HPLC on a Waters Nova-Pak HR C18 6 mum 60 A Prep-Pak cartridge column (40 mm*100 mm) and eluting with a gradient of 10% to 100% acetonitrile in 10 mM aqueous ammonium acetate over 12 minutes, at a flow rate of 70 mL/minute to yield the title compound (11 mg, 11%). 1H NMR (400 MHz, DMSO-d6) delta ppm 10.14 (s, 1H), 8.06-7.87 (m, 3H), 7.84-7.70 (m, 2H), 7.69-7.54 (m, 2H), 7.03 (s, 1H), 5.10 (d, J=9.3 Hz, 1H), 4.40 (d, J=9.3 Hz, 1H), 2.24 (s, 3H), 1.70 (s, 3H), 1.56 (s, 9H); MS (ESI+) m/z 525.1 (M+H)+.
(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carboxylic acid[ No CAS ]
tert-butyl 3-(6-[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-3-methylpyridin-2-yl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
Example 5 tert-butyl 3-(6-[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-3-methylpyridin-2-yl)benzoate The product from Example 3B (54.5 mg, 0.211 mmol) was dissolved in dichloromethane (1 mL). Oxalyl chloride (80 muL) and N,N-dimethylformamide (25 muL) were added. The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated. The resulting residue was dissolved in dichloromethane (1 mL) and concentrated two times. The residue was dissolved in dichloromethane (1 mL) and pyridine (0.5 mL). tert-Butyl 3-(6-amino-3-methylpyridin-2-yl)benzoate (CAS [1083057-14-0], 53.8, 0.189 mmol) was added, and the reaction mixture was stirred at 60 C. for 16 hours. The reaction mixture was concentrated and purified by reverse-phase preparative HPLC on a Waters Nova-Pak HR C18 6 mum 60 A Prep-Pak cartridge column (40 mm*100 mm), eluting with a gradient of 10% to 100% acetonitrile in 10 mM aqueous ammonium acetate over 12 minutes, at a flow rate of 70 mL/minute to yield the title compound (50.8 mg, 51%). 1H NMR (400 MHz, DMSO-d6) delta ppm 10.14 (s, 1H), 8.02 (t, J=1.7 Hz, 1H), 7.98-7.90 (m, 2H), 7.78 (dt, J=7.7, 1.5 Hz, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.65 (s, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.03 (s, 1H), 5.10 (d, J=9.3 Hz, 1H), 4.41 (d, J=9.3 Hz, 1H), 2.25 (s, 3H), 1.71 (s, 3H), 1.56 (s, 9H); MS (ESI+) m/z 525.0 (M+H)+.
tert-butyl 3-(6-bromo-3-methylpyridin-2-yl)benzoate[ No CAS ]
3-(6-bromo-3-methylpyridin-2-yl)benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
185 mg; 1 g
Tert-butyl 3-(6-amino-3-methylpyridin-2-yl) benzoate (3. 0 g) was added to 47% aqueous solution of hydrogen bromide (15 mL) portion wise at 27C in 15 minutes. The reaction mixture was cooled to -20C and bromine (1 .52 mL) was added drop wise. Stirred the reaction mixture at -20C for 90 minutes and sodium nitrite solution (1 .96 g in 7.5 mL of water) was added for 20 minutes at the same temperature. Reaction mixture was warmed to 15C and stirred for 1 hour and 45 minutes at the same temperature. Again cooled the reaction mixture to -20C and sodium hydroxide solution (8.44 g in 30 mL of water) was added slowly. The reaction mass was extracted with ethyl acetate (3 x 50 mL) and dried over sodium sulfate. The solution was concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography using (10% to 50%) ethyl acetate / hexane as eluent to obtain 185 mg of tert-butyl 3-(6- bromo-3-methylpyridin-2-yl)benzoate as a colorless liquid with 96.07% purity by HPLC and 1 .0 g of 3-(6-bromo-3-methylpyridin-2-yl)benzoic acid as a white solid with 98.36% purity by HPLC.
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