218600-44-3

Usage

Uses

Used in Pharmaceutical Industry:
Bardoxolone is used as a potential therapeutic agent for the treatment of diabetic kidney diseases, cancer, and thromboembolic events. Its application is based on its ability to improve hyperglycemia, proteinuria, glomerulus structure, and serum creatine levels, which may contribute to the amelioration of these conditions.
Used in Cancer Treatment:
Bardoxolone is used as an anticancer agent due to its apoptotic effects on malignant cells, which occur independently of PPARγ. It has the potential to be employed in the treatment of various types of cancer, targeting the dysregulation of cellular growth and differentiation.
Used in Treatment of Diabetic Kidney Diseases:
Bardoxolone is used as a therapeutic agent for the improvement of hyperglycemia, proteinuria, and glomerulus structure in patients with diabetic kidney diseases. Its application aims to alleviate the symptoms and potentially slow the progression of the disease.
Used in Thromboembolic Event Treatment:
Bardoxolone is used as a potential treatment for thromboembolic events, leveraging its multifunctional activities in controlling cellular growth and differentiation, which may contribute to the prevention or reduction of blood clot formation and related complications.

Biological Activity

bardoxolone methyl, previously known as rta 402, is the lead molecule in reata's portfolio of antioxidant inflammation modulators (aims). the aims are potent inducers of the transcription factor nrf2, an important biological target that controls the production of many of the body's antioxidant and detoxification enzymes. because oxidative stress and inflammation occur throughout the course of chronic kidney disease (ckd) and are known to contribute to loss of kidney function, agents that activate the nrf2 pathway in patients with ckd may provide a novel method for preserving or improving kidney function. bardoxolone methyl is currently being investigated as a potential oral once-a-day treatment for ckd.

InChI:InChI=1/C31H41NO4/c1-26(2)10-12-31(25(35)36)13-11-30(7)23(19(31)16-26)20(33)14-22-28(5)15-18(17-32)24(34)27(3,4)21(28)8-9-29(22,30)6/h14-15,19,21,23H,8-13,16H2,1-7H3,(H,35,36)/t19-,21-,23-,28-,29+,30+,31-/m0/s1

Synthetic route

bardoxolone methyl (218600-53-4) → bardoxolone (218600-44-3)

Conditions	Yield
With lithium iodide In N,N-dimethyl-formamide	71%
With lithium iodide In N,N-dimethyl-formamide	71%
With lithium iodide In N,N-dimethyl-formamide at 153℃; for 12h; Inert atmosphere;	70.3%
With lithium iodide In N,N-dimethyl-formamide for 4h; Heating;	68%
With lithium iodide In N,N-dimethyl-formamide Inert atmosphere; Reflux;	44%

tert‐butyl N‐[2‐(N‐hydroxycarbamimidoyl)ethyl]carbamate (915710-94-0, 1244059-91-3, 1165931-54-3) + 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid chloride (443104-14-1) → C39H54N4O5 + bardoxolone (218600-44-3)

Conditions	Yield
Stage #1: tert‐butyl N‐[2‐(N‐hydroxycarbamimidoyl)ethyl]carbamate; 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid chloride With triethylamine In dichloromethane at 20℃; for 2h; Inert atmosphere; Stage #2: With tetra(n-butyl)ammonium hydroxide In tetrahydrofuran; water at 20℃; for 5h; Inert atmosphere;	A 45% B n/a

tert‐butyl N‐[2‐(N‐hydroxycarbamimidoyl)ethyl]carbamate (915710-94-0, 1244059-91-3, 1165931-54-3) + 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid chloride (443104-14-1) → C39H56N4O6 + bardoxolone (218600-44-3)

Conditions	Yield
With triethylamine In dichloromethane at 20℃; for 2h; Inert atmosphere;

3-methoxypropionamidoxime hydrochloride (67015-15-0) + 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid chloride (443104-14-1) → C35H49N3O5 + bardoxolone (218600-44-3)

Conditions	Yield
With triethylamine; trimethylamine In dichloromethane at 20℃; Inert atmosphere;

methyl 3β-acetoxy-12-oxoolean-9(11)-en-28-oate (65023-20-3) → bardoxolone (218600-44-3)

Conditions	Yield
Multi-step reaction with 7 steps 1: 97 percent / methanolic KOH / 0.5 h / Heating 2: 92 percent / Jones reagent / acetone / 0.17 h / 20 °C 3: 99 percent / NaOMe / benzene / 2 h / 20 °C 4: 66 percent / NH2OH*HCl / ethanol; H2O / 1 h / Heating 5: 100 percent / NaOMe / methanol; diethyl ether / 0.75 h / 20 °C 6: 92 percent / DDQ / benzene / 0.5 h / Heating 7: 68 percent / LiI / dimethylformamide / 4 h / Heating View Scheme
Multi-step reaction with 7 steps 1: aq. KOH / methanol 2: CrO3, H2SO4 3: 100 percent / sodium methoxide / benzene 4: 61 percent / NH2OH*HCl / aq. ethanol 5: 100 percent / sodium methoxide / methanol; diethyl ether 6: 1.) phenylselenenyl chloride, 2.) 30 percent aq. H2O2 / 1.) ethyl acetate, 2.) THF 7: 71 percent / LiI / dimethylformamide View Scheme
Multi-step reaction with 6 steps 1: potassium hydroxide; water / methanol 2: sodium methylate / benzene 3: hydroxylamine hydrochloride / water; ethanol 4: sodium methylate / methanol; diethyl ether 5: Phenylselenyl chloride / ethyl acetate 6: lithium iodide / N,N-dimethyl-formamide View Scheme
Multi-step reaction with 5 steps 1.1: potassium hydroxide / methanol / 1 h / Reflux 2.1: chromium(VI) oxide; sulfuric acid / water; acetone / 0 - 20 °C 3.1: lithium diisopropyl amide / tetrahydrofuran; n-heptane; ethylbenzene / 0.33 h / -78 - 20 °C / Inert atmosphere 3.2: 0.08 h / -78 - 20 °C 4.1: 2,3-dicyano-5,6-dichloro-p-benzoquinone / benzene / 0.5 h / Reflux; Inert atmosphere 5.1: lithium iodide / N,N-dimethyl-formamide / Inert atmosphere; Reflux View Scheme

methyl 3,12-dioxoolean-9(11)-en-28-oate (218600-50-1) → bardoxolone (218600-44-3)

Conditions	Yield
Multi-step reaction with 5 steps 1: 99 percent / NaOMe / benzene / 2 h / 20 °C 2: 66 percent / NH2OH*HCl / ethanol; H2O / 1 h / Heating 3: 100 percent / NaOMe / methanol; diethyl ether / 0.75 h / 20 °C 4: 92 percent / DDQ / benzene / 0.5 h / Heating 5: 68 percent / LiI / dimethylformamide / 4 h / Heating View Scheme
Multi-step reaction with 5 steps 1: 100 percent / sodium methoxide / benzene 2: 61 percent / NH2OH*HCl / aq. ethanol 3: 100 percent / sodium methoxide / methanol; diethyl ether 4: 1.) phenylselenenyl chloride, 2.) 30 percent aq. H2O2 / 1.) ethyl acetate, 2.) THF 5: 71 percent / LiI / dimethylformamide View Scheme
Multi-step reaction with 5 steps 1: sodium methylate / benzene 2: hydroxylamine hydrochloride / water; ethanol 3: sodium methylate / methanol; diethyl ether 4: Phenylselenyl chloride / ethyl acetate 5: lithium iodide / N,N-dimethyl-formamide View Scheme
Multi-step reaction with 3 steps 1.1: lithium diisopropyl amide / tetrahydrofuran; n-heptane; ethylbenzene / 0.33 h / -78 - 20 °C / Inert atmosphere 1.2: 0.08 h / -78 - 20 °C 2.1: 2,3-dicyano-5,6-dichloro-p-benzoquinone / benzene / 0.5 h / Reflux; Inert atmosphere 3.1: lithium iodide / N,N-dimethyl-formamide / Inert atmosphere; Reflux View Scheme

methyl 3β-hydroxy-12-oxoolean-9(11)-en-28-oate (65023-19-0) → bardoxolone (218600-44-3)

Conditions	Yield
Multi-step reaction with 6 steps 1: 92 percent / Jones reagent / acetone / 0.17 h / 20 °C 2: 99 percent / NaOMe / benzene / 2 h / 20 °C 3: 66 percent / NH2OH*HCl / ethanol; H2O / 1 h / Heating 4: 100 percent / NaOMe / methanol; diethyl ether / 0.75 h / 20 °C 5: 92 percent / DDQ / benzene / 0.5 h / Heating 6: 68 percent / LiI / dimethylformamide / 4 h / Heating View Scheme
Multi-step reaction with 6 steps 1: CrO3, H2SO4 2: 100 percent / sodium methoxide / benzene 3: 61 percent / NH2OH*HCl / aq. ethanol 4: 100 percent / sodium methoxide / methanol; diethyl ether 5: 1.) phenylselenenyl chloride, 2.) 30 percent aq. H2O2 / 1.) ethyl acetate, 2.) THF 6: 71 percent / LiI / dimethylformamide View Scheme
Multi-step reaction with 4 steps 1.1: chromium(VI) oxide; sulfuric acid / water; acetone / 0 - 20 °C 2.1: lithium diisopropyl amide / tetrahydrofuran; n-heptane; ethylbenzene / 0.33 h / -78 - 20 °C / Inert atmosphere 2.2: 0.08 h / -78 - 20 °C 3.1: 2,3-dicyano-5,6-dichloro-p-benzoquinone / benzene / 0.5 h / Reflux; Inert atmosphere 4.1: lithium iodide / N,N-dimethyl-formamide / Inert atmosphere; Reflux View Scheme

methyl 12-oxoisoxazolo[4,5-b]olean-9(11)-en-28-oate (218600-52-3) → bardoxolone (218600-44-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: 100 percent / NaOMe / methanol; diethyl ether / 0.75 h / 20 °C 2: 92 percent / DDQ / benzene / 0.5 h / Heating 3: 68 percent / LiI / dimethylformamide / 4 h / Heating View Scheme
Multi-step reaction with 3 steps 1: 100 percent / sodium methoxide / methanol; diethyl ether 2: 1.) phenylselenenyl chloride, 2.) 30 percent aq. H2O2 / 1.) ethyl acetate, 2.) THF 3: 71 percent / LiI / dimethylformamide View Scheme
Multi-step reaction with 3 steps 1: sodium methylate / methanol; diethyl ether 2: Phenylselenyl chloride / ethyl acetate 3: lithium iodide / N,N-dimethyl-formamide View Scheme

2-cyano-3-hydroxy-12-oxoolean-2(3),9(11)-dien-28-oic acid (1309236-68-7) → bardoxolone (218600-44-3)

Conditions	Yield
With 2,3-dicyano-5,6-dichloro-p-benzoquinone In benzene for 0.25h; Reflux;	91%

methyl 2-hydroxymethylene-3,12-dioxoolean-9(11)-en-28-oate (305818-39-7) → bardoxolone (218600-44-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: 66 percent / NH2OH*HCl / ethanol; H2O / 1 h / Heating 2: 100 percent / NaOMe / methanol; diethyl ether / 0.75 h / 20 °C 3: 92 percent / DDQ / benzene / 0.5 h / Heating 4: 68 percent / LiI / dimethylformamide / 4 h / Heating View Scheme

1,2-dihydro-2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid methyl ester (305818-40-0) → bardoxolone (218600-44-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 92 percent / DDQ / benzene / 0.5 h / Heating 2: 68 percent / LiI / dimethylformamide / 4 h / Heating View Scheme

methyl 2-cyano-3,12-dioxoolean-9(11)-en-28-oate → bardoxolone (218600-44-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) phenylselenenyl chloride, 2.) 30 percent aq. H2O2 / 1.) ethyl acetate, 2.) THF 2: 71 percent / LiI / dimethylformamide View Scheme
Multi-step reaction with 2 steps 1: Phenylselenyl chloride / ethyl acetate 2: lithium iodide / N,N-dimethyl-formamide View Scheme
Multi-step reaction with 2 steps 1: 2,3-dicyano-5,6-dichloro-p-benzoquinone / benzene / 0.5 h / Reflux; Inert atmosphere 2: lithium iodide / N,N-dimethyl-formamide / Inert atmosphere; Reflux View Scheme

2-cyano-3-hydroxy-12-oxoolean-2(3),9(11)-dien-28-oic acid (1309236-68-7) → 2-cyano-3,12-dioxooleana-1,9(11)-diene-13β,28-lactone (1309943-46-1) + bardoxolone (218600-44-3)

Conditions	Yield
With 2,3-dicyano-5,6-dichloro-p-benzoquinone In benzene for 24h; Reflux;	A 58% B 28%

(4aS,6aR,6bS,8aR,12aS,14aR,14bS)-11-Formyl-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-octadecahydro-2H-picene-4a-carboxylic acid methyl ester (218600-51-2) → bardoxolone (218600-44-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: 61 percent / NH2OH*HCl / aq. ethanol 2: 100 percent / sodium methoxide / methanol; diethyl ether 3: 1.) phenylselenenyl chloride, 2.) 30 percent aq. H2O2 / 1.) ethyl acetate, 2.) THF 4: 71 percent / LiI / dimethylformamide View Scheme
Multi-step reaction with 4 steps 1: hydroxylamine hydrochloride / water; ethanol 2: sodium methylate / methanol; diethyl ether 3: Phenylselenyl chloride / ethyl acetate 4: lithium iodide / N,N-dimethyl-formamide View Scheme

Oleanolic acid (508-02-1) → bardoxolone (218600-44-3)

Conditions	Yield
Multi-step reaction with 9 steps 1.1: triethylamine; dmap / dichloromethane / 12 h / 20 °C / Inert atmosphere 2.1: potassium carbonate / acetone / 24 h / 20 °C 3.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 0 - 20 °C 4.1: hydrogen bromide; bromine / acetonitrile / 19 h / 35 °C 5.1: potassium hydroxide / methanol / 1 h / Reflux 6.1: chromium(VI) oxide; sulfuric acid / water; acetone / 0 - 20 °C 7.1: lithium diisopropyl amide / tetrahydrofuran; n-heptane; ethylbenzene / 0.33 h / -78 - 20 °C / Inert atmosphere 7.2: 0.08 h / -78 - 20 °C 8.1: 2,3-dicyano-5,6-dichloro-p-benzoquinone / benzene / 0.5 h / Reflux; Inert atmosphere 9.1: lithium iodide / N,N-dimethyl-formamide / Inert atmosphere; Reflux View Scheme
Multi-step reaction with 9 steps 1.1: triethylamine; dmap / dichloromethane / 12 h / 20 °C / Inert atmosphere 2.1: potassium carbonate / acetone / 24 h / 20 °C 3.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 12 h / 0 - 20 °C 4.1: hydrogen bromide; bromine / acetonitrile / 19 h / 35 °C 5.1: potassium hydroxide / methanol / 1 h / Reflux 6.1: chromium(VI) oxide; sulfuric acid / water; acetone / 0 - 20 °C 7.1: lithium diisopropyl amide / tetrahydrofuran; n-heptane; ethylbenzene / 0.33 h / -78 - 20 °C / Inert atmosphere 7.2: 0.08 h / -78 - 20 °C 8.1: 2,3-dicyano-5,6-dichloro-p-benzoquinone / benzene / 0.5 h / Reflux; Inert atmosphere 9.1: lithium iodide / N,N-dimethyl-formamide / Inert atmosphere; Reflux View Scheme
Multi-step reaction with 5 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 24 h / 20 °C / Inert atmosphere 2.1: 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione / dimethyl sulfoxide; fluorobenzene / 24 h / 85 °C / Inert atmosphere 3.1: 3-chloro-benzenecarboperoxoic acid; hydrogen bromide / dichloromethane / 26 h / 20 °C 3.2: 24 h / 35 °C 4.1: potassium iodide / N,N-dimethyl-formamide / 30 h / 120 °C 5.1: lithium iodide / N,N-dimethyl-formamide / 12 h / 153 °C / Inert atmosphere View Scheme

(4aS,6aS,6bR,10S,12aR)-methyl 10-acetoxy-2,2,6a,6b,9,9,12a-heptamethyl-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-4a-carboxylate (25493-69-0, 122798-61-2, 1721-57-9) → bardoxolone (218600-44-3)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 0 - 20 °C 2.1: hydrogen bromide; bromine / acetonitrile / 19 h / 35 °C 3.1: potassium hydroxide / methanol / 1 h / Reflux 4.1: chromium(VI) oxide; sulfuric acid / water; acetone / 0 - 20 °C 5.1: lithium diisopropyl amide / tetrahydrofuran; n-heptane; ethylbenzene / 0.33 h / -78 - 20 °C / Inert atmosphere 5.2: 0.08 h / -78 - 20 °C 6.1: 2,3-dicyano-5,6-dichloro-p-benzoquinone / benzene / 0.5 h / Reflux; Inert atmosphere 7.1: lithium iodide / N,N-dimethyl-formamide / Inert atmosphere; Reflux View Scheme
Multi-step reaction with 7 steps 1.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 12 h / 0 - 20 °C 2.1: hydrogen bromide; bromine / acetonitrile / 19 h / 35 °C 3.1: potassium hydroxide / methanol / 1 h / Reflux 4.1: chromium(VI) oxide; sulfuric acid / water; acetone / 0 - 20 °C 5.1: lithium diisopropyl amide / tetrahydrofuran; n-heptane; ethylbenzene / 0.33 h / -78 - 20 °C / Inert atmosphere 5.2: 0.08 h / -78 - 20 °C 6.1: 2,3-dicyano-5,6-dichloro-p-benzoquinone / benzene / 0.5 h / Reflux; Inert atmosphere 7.1: lithium iodide / N,N-dimethyl-formamide / Inert atmosphere; Reflux View Scheme

oleanolic acid 3-acetate (4339-72-4) → bardoxolone (218600-44-3)

Conditions	Yield
Multi-step reaction with 8 steps 1.1: potassium carbonate / acetone / 24 h / 20 °C 2.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 0 - 20 °C 3.1: hydrogen bromide; bromine / acetonitrile / 19 h / 35 °C 4.1: potassium hydroxide / methanol / 1 h / Reflux 5.1: chromium(VI) oxide; sulfuric acid / water; acetone / 0 - 20 °C 6.1: lithium diisopropyl amide / tetrahydrofuran; n-heptane; ethylbenzene / 0.33 h / -78 - 20 °C / Inert atmosphere 6.2: 0.08 h / -78 - 20 °C 7.1: 2,3-dicyano-5,6-dichloro-p-benzoquinone / benzene / 0.5 h / Reflux; Inert atmosphere 8.1: lithium iodide / N,N-dimethyl-formamide / Inert atmosphere; Reflux View Scheme
Multi-step reaction with 8 steps 1.1: potassium carbonate / acetone / 24 h / 20 °C 2.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 12 h / 0 - 20 °C 3.1: hydrogen bromide; bromine / acetonitrile / 19 h / 35 °C 4.1: potassium hydroxide / methanol / 1 h / Reflux 5.1: chromium(VI) oxide; sulfuric acid / water; acetone / 0 - 20 °C 6.1: lithium diisopropyl amide / tetrahydrofuran; n-heptane; ethylbenzene / 0.33 h / -78 - 20 °C / Inert atmosphere 6.2: 0.08 h / -78 - 20 °C 7.1: 2,3-dicyano-5,6-dichloro-p-benzoquinone / benzene / 0.5 h / Reflux; Inert atmosphere 8.1: lithium iodide / N,N-dimethyl-formamide / Inert atmosphere; Reflux View Scheme

methyl 3-O-β-acetyl-11-dehydro-12-oxo-18β-oleanolate (25493-94-1) → bardoxolone (218600-44-3)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: hydrogen bromide; bromine / acetonitrile / 19 h / 35 °C 2.1: potassium hydroxide / methanol / 1 h / Reflux 3.1: chromium(VI) oxide; sulfuric acid / water; acetone / 0 - 20 °C 4.1: lithium diisopropyl amide / tetrahydrofuran; n-heptane; ethylbenzene / 0.33 h / -78 - 20 °C / Inert atmosphere 4.2: 0.08 h / -78 - 20 °C 5.1: 2,3-dicyano-5,6-dichloro-p-benzoquinone / benzene / 0.5 h / Reflux; Inert atmosphere 6.1: lithium iodide / N,N-dimethyl-formamide / Inert atmosphere; Reflux View Scheme

oleanolic acid methyl ester (1724-17-0, 73584-64-2) → bardoxolone (218600-44-3)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione / dimethyl sulfoxide; fluorobenzene / 24 h / 85 °C / Inert atmosphere 2.1: 3-chloro-benzenecarboperoxoic acid; hydrogen bromide / dichloromethane / 26 h / 20 °C 2.2: 24 h / 35 °C 3.1: potassium iodide / N,N-dimethyl-formamide / 30 h / 120 °C 4.1: lithium iodide / N,N-dimethyl-formamide / 12 h / 153 °C / Inert atmosphere View Scheme

(4aS,6aS,6bR,8aR,12aR,12bR,14bS)-methyl2,2,6a,6b,9,9,12a-heptamethyl-10-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14b-octadecahydropicene-4a-carboxylate (69660-90-8) → bardoxolone (218600-44-3)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 3-chloro-benzenecarboperoxoic acid; hydrogen bromide / dichloromethane / 26 h / 20 °C 1.2: 24 h / 35 °C 2.1: potassium iodide / N,N-dimethyl-formamide / 30 h / 120 °C 3.1: lithium iodide / N,N-dimethyl-formamide / 12 h / 153 °C / Inert atmosphere View Scheme

C31H43NO4 → bardoxolone (218600-44-3)

Conditions	Yield
With 2,3-dicyano-5,6-dichloro-p-benzoquinone In benzene for 0.333333h; Reflux;

bardoxolone (218600-44-3) → 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid chloride (443104-14-1)

Conditions	Yield
With oxalyl dichloride In dichloromethane	100%
With oxalyl dichloride In dichloromethane at 20℃;	100%
With oxalyl dichloride In dichloromethane	100%

bardoxolone (218600-44-3) → (4aS,6aR,6bS,8aR,12aS,14aR,14bS)-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicene-4a-carbonyl azide (1192122-92-1)

Conditions	Yield
With diphenyl phosphoryl azide; triethylamine at 0 - 20℃;	90%
With diphenyl phosphoryl azide; triethylamine In toluene at 20℃; for 6h;	90%

bardoxolone (218600-44-3) + 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (572-09-8) → (4aS,6aR,6bS,8aR,12aS,14aR,14bS)-11-Cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydro-2H-picene-4a-carboxylic acid (2S,3R,4S,5R,6R)-3,4,5-triacetoxy-6-acetoxymethyl-tetrahydro-pyran-2-yl ester

Conditions	Yield
With Aliquat 336; potassium carbonate In dichloromethane	75%
With potassium carbonate; Aliquat 336 In dichloromethane; water	75%

bardoxolone (218600-44-3) → (4aS,6aR,6bS,8aR,12aS,14aR,14bS)-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicene-4a-carbonyl fluoride (1191917-53-9)

Conditions	Yield
With diethylamino-sulfur trifluoride In chloroform at 20℃; for 6.5h;	94%

bardoxolone (218600-44-3) → C31H41NO5

Conditions	Yield
With dihydrogen peroxide In methanol; water; acetonitrile at 20℃; for 30h;	90%

methanol (67-56-1) + bardoxolone (218600-44-3) → bardoxolone methyl (218600-53-4)

Conditions	Yield
Stage #1: bardoxolone With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1.16667h; Cooling with ice; Stage #2: methanol In dichloromethane for 1h;	96%

O2-(2,4-dinitro-5-(2-bromoethylamino)phenyl)-1-(piperidine-1-yl)diazen-1-ium-1,2-diolate + bardoxolone (218600-44-3) → O2-(2,4-dinitro-5-{2-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]-oxoethylamino}phenyl)-1-(piperidine-1-yl)diazen-1-ium-1,2-diolate

Conditions	Yield
With potassium carbonate In acetone at 45℃; for 4h;	68%

O2-(2,4-dinitro-5-(2-bromoethylamino)phenyl)-1-(N-methylethanolamino)diazen-1-ium-1,2-diolate + bardoxolone (218600-44-3) → O2-(2,4-dinitro-5-{2-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]-oxoethylamino}phenyl)-1-(N-methylethanolamino)diazen-1-ium-1,2-diolate

Conditions	Yield
With potassium carbonate In acetone at 45℃; for 4h;	74%

bardoxolone (218600-44-3) → C31H43NO4

Conditions	Yield
With palladium 10% on activated carbon; hydrogen In tetrahydrofuran	84%

4-chloromethyl-5-methyl-1,3-dioxol-2-one (80841-78-7) + bardoxolone (218600-44-3) → C36H45NO7

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene In toluene Heating / reflux;	83%

propionyl chloride (79-03-8) + isosorbide mononitrate (16106-20-0, 16908-90-0, 16908-91-1, 35993-37-4, 38709-03-4, 114718-64-8, 127001-76-7, 16051-77-7) + bardoxolone (218600-44-3) → 1-isosorbide mononitrate 2-cyano-3-propionyloxy-12-oxoolean-2(3),9(11)-diene-28-carboxylic acid

Conditions	Yield
Stage #1: isosorbide mononitrate; bardoxolone With potassium carbonate In N,N-dimethyl-formamide at 20℃; Stage #2: propionyl chloride In N,N-dimethyl-formamide	35%

isosorbide mononitrate (16106-20-0, 16908-90-0, 16908-91-1, 35993-37-4, 38709-03-4, 114718-64-8, 127001-76-7, 16051-77-7) + acetyl chloride (75-36-5) + bardoxolone (218600-44-3) → 1-isosorbide mononitrate 2-cyano-3-acetoxy-12-oxoolean-2(3),9(11)-diene-28-carboxylic acid

Conditions	Yield
Stage #1: isosorbide mononitrate; bardoxolone With potassium carbonate In N,N-dimethyl-formamide at 20℃; Stage #2: acetyl chloride In N,N-dimethyl-formamide for 6h;	35%

bardoxolone (218600-44-3) → (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-isocyanato-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile (1192122-95-4)

Conditions	Yield
Stage #1: bardoxolone With diphenyl phosphoryl azide; triethylamine In toluene at 0 - 20℃; Stage #2: In benzene at 80℃; for 2h;
Multi-step reaction with 2 steps 1: diphenyl phosphoryl azide; triethylamine / 0 - 20 °C 2: benzene / 2 h / 80 °C View Scheme

bardoxolone (218600-44-3) → (4aS,6aR,6bS,8aR,12aS,14aR,14bS)-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicene-4a-carbonyl azide (1192122-92-1) + (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-isocyanato-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile (1192122-95-4)

Conditions	Yield
With diphenyl phosphoryl azide; triethylamine In toluene at 0 - 20℃; Overall yield = 94 %; Overall yield = 19.7 g;

bardoxolone (218600-44-3) + N-(2-(2-(2-(2-amidoethoxy)ethoxy)ethoxy)ethoxy)biotinamide (359860-27-8) → 11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydro-2H-picene-4a-carboxylic acid {2-[2-(2-{2-[5-(2-oxo-hexahydro-thieno[3,4-d]imidazol-6-yl)-pentanoylamino]-ethoxy}-ethoxy)-ethoxy]-ethyl}-amide

Conditions	Yield
With 2`,3`-dideoxycytidine; dmap In dichloromethane at 20℃; for 48h;	79%

bardoxolone (218600-44-3) + 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid chloride (443104-14-1) → 2-cyano-3,10-dioxooleana-1,9(11)-dien-28-oic acid anhydride (1224947-97-0)

Conditions	Yield
With triethylamine In tetrahydrofuran at 20℃; for 1.5h;	96%

bardoxolone (218600-44-3) + benzyl halide → (4aS,6aR,6bS,8aR,12aS,14aR,14bS)-11-Cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydro-2H-picene-4a-carboxylic acid benzyl ester

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene In toluene Heating;	97%

bardoxolone (218600-44-3) + ethyl halide → (4aS,6aR,6bS,8aR,12aS,14aR,14bS)-11-Cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydro-2H-picene-4a-carboxylic acid ethyl ester

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene In toluene Heating;	100%

bardoxolone (218600-44-3) + n-octyl halide → (4aS,6aR,6bS,8aR,12aS,14aR,14bS)-11-Cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydro-2H-picene-4a-carboxylic acid octyl ester

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene In toluene Heating;	89%

bardoxolone (218600-44-3) + cyclopropylmethyl halide → (4aS,6aR,6bS,8aR,12aS,14aR,14bS)-11-Cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydro-2H-picene-4a-carboxylic acid cyclopropylmethyl ester

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene In toluene Heating;	81%

bardoxolone (218600-44-3) + n-butyl halide → (4aS,6aR,6bS,8aR,12aS,14aR,14bS)-11-Cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydro-2H-picene-4a-carboxylic acid butyl ester

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene In toluene Heating;	74%

Upstream product

• 1309236-68-7 2-cyano-3-hydroxy-12-oxoolean-2⁽³⁾,9⁽¹¹⁾-dien-28-oic acid 
• 508-02-1 Oleanolic acid 
• 25493-69-0 (4aS,6aS,6bR,10S,12aR)-methyl 10-acetoxy-2,2,6a,6b,9,9,12a-heptamethyl-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-4a-carboxylate 
• 25493-94-1 methyl 3-O-β-acetyl-11-dehydro-12-oxo-18β-oleanolate 
• 4339-72-4 oleanolic acid 3-acetate 
• 1724-17-0 oleanolic acid methyl ester 
• 69660-90-8 (4aS,6aS,6bR,8aR,12aR,12bR,14bS)-methyl2,2,6a,6b,9,9,12a-heptamethyl-10-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14b-octadecahydropicene-4a-carboxylate 
• 67015-15-0 3-methoxypropionamidoxime hydrochloride 
• 443104-14-1 2-cyano-3,12-dioxooleana-1,9⁽¹¹⁾-dien-28-oic acid chloride 
• 915710-94-0 tert‐butyl N‐[2‐(N‐hydroxycarbamimidoyl)ethyl]carbamate 
• 218600-51-2 (4aS,6aR,6bS,8aR,12aS,14aR,14bS)-11-Formyl-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-octadecahydro-2H-picene-4a-carboxylic acid methyl ester 
• 305818-40-0 1,2-dihydro-2-cyano-3,12-dioxooleana-1,9⁽¹¹⁾-dien-28-oic acid methyl ester 
• 305818-39-7 methyl 2-hydroxymethylene-3,12-dioxoolean-9⁽¹¹⁾-en-28-oate 
• 218600-52-3 methyl 12-oxoisoxazolo[4,5-b]olean-9⁽¹¹⁾-en-28-oate 

Downstream Products

• 1309943-46-1 2-cyano-3,12-dioxooleana-1,9(11)-diene-13β,28-lactone 
• 1707-75-1 2,2-diphenyl-1-picrylhydrazine 
• 1474034-05-3 omaveloxolone 
• 1192123-13-9 (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-amino-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile 
• 932730-51-3 RTA 405 
• 1883650-95-0 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]-4-(pyridin-3-yl)-1H-imidazole 
• 218600-53-4 bardoxolone methyl 

Relevant academic research and scientific papers

Design and synthesis of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid, a novel and highly active inhibitor of nitric oxide production in mouse macrophages

New derivatives with electron-withdrawing substituents at the C-2 position of 3-oxoolean-1-en-28-oic acid were synthesized. Among them, 2- cyano-3,12-dioxoleam-1,9-dien-28-oic acid (CDDO) was 400 times more potent than previous compounds we have made as an inhibitor of production of nitric oxide induced by interferon γ in mouse macrophages (IC50, 0.4 nM). The potency of CDDO was similar to that of dexamethasone, although CDDO does not act through the glucocorticoid receptor.

C17 POLAR-SUBSTITUTED HETEROAROMATIC SYNTHETIC TRITERPENOIDS AND METHODS OF USE THEREOF

Disclosed herein are compounds of the formula: (I) wherein the variables are defined herein. Also provided are pharmaceutical compositions thereof. In some aspects, the compounds and compositions provided herein may be used as antioxidant inflammation modulators. In some aspects, the present disclosure provides methods wherein the compounds and composition described herein are used for the treatment of diseases and disorders, including those associated with inflammation and cancer.

Oleanolic acid derivative with conjugated diene structure C ring and preparation method and application thereof

The invention belongs to the field of medicinal chemistry, and particularly relates to an oleanolic acid derivative with a conjugated diene structure C ring and a preparation method and application thereof. In particular, the invention also provides a pharmaceutical composition comprising an effective amount of the derivative or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; moreover, the derivative or the pharmaceutically acceptable salt thereof can be used for treating inflammation-related diseases and has antitumor activity, and the safety of the compound is improved or equivalent.

Improvement of synthesis method of 2-cyano-3,12-dioxo oleanane-1,9 (11)-diene-28-carboxylic acid

The invention discloses a synthesis technology of 2-cyano-3,12-dioxo oleanane-1,9 (11)-diene-28-carboxylic acid (CDDO), and relates to the technical field of medicines and chemical engineering. The CDDO compounds (CDDOs) are semisynthetic tritererpenoids with the highest known anticancer and anti-inflammatory activity at present and are compounds with broad development and application prospects. The synthesis method of the CDDO reported in the literature at present has the defects of being long in path, fussy in post-treatment, unfriendly to environment and high in cost. The method is a simplified six-step synthesis path, the post-treatment and purification processes are simple, the cost is relatively low, the yield is greatly improved and an important basis is provided for industrial production and subsequent scientific research. The formula is as shown in the specification.

Therapeutic compounds and methods of use

Compounds and methods useful for chemopreventative treatment of diseases such as cancer, Alzheimer's disease, Parkinson's disease, inflammatory bowel diseases, and multiple sclerosis.

Design and Synthesis of Irreversible Analogues of Bardoxolone Methyl for the Identification of Pharmacologically Relevant Targets and Interaction Sites

Semisynthetic triterpenoids such as bardoxolone methyl (methyl-2-cyano 3,12-dioxooleano-1,9-dien-28-oate; CDDO-Me) (4) are potent inducers of antioxidant and anti-inflammatory signaling pathways, including those regulated by the transcription factor Nrf2. However, the reversible nature of the interaction between triterpenoids and thiols has hindered attempts to identify pharmacologically relevant targets and characterize the sites of interaction. Here, we report a shortened synthesis and SAR profiling of 4, enabling the design of analogues that react irreversibly with model thiols, as well as the model protein glutathione S-transferase P1, in vitro. We show that one of these analogues, CDDO-epoxide (13), is comparable to 4 in terms of cytotoxicity and potency toward Nrf2 in rat hepatoma cells and stably modifies specific cysteine residues (namely, Cys-257, -273, -288, -434, -489, and -613) within Keap1, the major repressor of Nrf2, both in vitro and in living cells. Supported by molecular modeling, these data demonstrate the value of 13 for identifying site(s) of interaction with pharmacologically relevant targets and informing the continuing development of triterpenoids as novel drug candidates.

DDQ-promoted dehydrogenation from natural rigid polycyclic acids or flexible alkyl acids to generate lactones by a radical ion mechanism

A novel and facile DDQ-mediated dehydrogenation from natural rigid polycyclic acids or flexible alkyl acids to generate lactones is described. The formation of lactones proceeds by a radical ion mechanism, which has been established by DPPH?-mediated chemical identification, ESR spectroscopy and an enol intermediate trapping.

Synthetic oleanane and ursane triterpenoids with modified rings A and C: A series of highly active inhibitors of nitric oxide production in mouse macrophages

We have designed and synthesized 16 new olean- and urs-1-en-3-one triterpenoids with various modified rings C as potential antiinflammatory and cancer chemopreventive agents and evaluated their inhibitory activities against production of nitric oxide induced by interferon-γ in mouse macrophages. This investigation revealed that 9(11)-en-12-one and 12-en-11-one functionalities in ring C increase the potency by about 2-10 times compared with the original 12-ene. Subsequently, we have designed and synthesized novel olean- and urs-1-en-3-one derivatives with nitrile and carboxyl groups at C-2 in ring A and with 9(11)-en-12-one and 12-en-11-one functionalities in ring C. Among them, we have found that methyl 2-cyano-3, 12-dioxooleana-1,9(11)-dien-28-oate (25), 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) (26), and methyl 2-carboxy-3,12-dioxooleana-1,9(11)-dien-28-oate (29) have extremely high potency (IC50 = 0.1 nM level). Their potency is similar to that of dexamethasone although they do not act through the glucocorticoid receptor. Overall, the combination of modified rings A and C increases the potency by about 10 000 times compared with the lead compound, 3-oxooleana-1,12-dien-28-oic acid (8) (IC50 = 1 μM level). The selected oleanane triterpenoid, CDDO (26), was found to be a potent, multifunctional agent in various in vitro assays and to show antiinflammatory activity against thioglycollate-interferon-γ-induced mouse peritonitis.