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218600-44-3

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218600-44-3 Usage

Description

Bardoxolone is a synthetic oleanane triterpenoid that possesses multifunctional activities in the regulation of cellular growth and differentiation. It is known for its ability to activate the transcription factor peroxisome proliferator activator receptor-γ (PPARγ), and its apoptotic effects in malignant cells occur independently of PPARγ. Bardoxolone is characterized by its tan solid chemical properties.

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.

Check Digit Verification of cas no

The CAS Registry Mumber 218600-44-3 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 2,1,8,6,0 and 0 respectively; the second part has 2 digits, 4 and 4 respectively.
Calculate Digit Verification of CAS Registry Number 218600-44:
(8*2)+(7*1)+(6*8)+(5*6)+(4*0)+(3*0)+(2*4)+(1*4)=113
113 % 10 = 3
So 218600-44-3 is a valid CAS Registry Number.
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

218600-44-3SDS

SAFETY DATA SHEETS

According to Globally Harmonized System of Classification and Labelling of Chemicals (GHS) - Sixth revised edition

Version: 1.0

Creation Date: Aug 18, 2017

Revision Date: Aug 18, 2017

1.Identification

1.1 GHS Product identifier

Product name (4aS,6aR,6bS,8aR,12aS,14aR,14bS)-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,7,8,8a,14a,14b-decahydropicene-4a-carboxylic acid

1.2 Other means of identification

Product number -
Other names 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid

1.3 Recommended use of the chemical and restrictions on use

Identified uses For industry use only.
Uses advised against no data available

1.4 Supplier's details

1.5 Emergency phone number

Emergency phone number -
Service hours Monday to Friday, 9am-5pm (Standard time zone: UTC/GMT +8 hours).

More Details:218600-44-3 SDS

218600-44-3Synthetic route

bardoxolone methyl
218600-53-4

bardoxolone methyl

bardoxolone
218600-44-3

bardoxolone

Conditions
ConditionsYield
With lithium iodide In N,N-dimethyl-formamide71%
With lithium iodide In N,N-dimethyl-formamide71%
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

tert‐butyl N‐[2‐(N‐hydroxycarbamimidoyl)ethyl]carbamate

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

2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid chloride

A

C39H54N4O5

C39H54N4O5

B

bardoxolone
218600-44-3

bardoxolone

Conditions
ConditionsYield
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

tert‐butyl N‐[2‐(N‐hydroxycarbamimidoyl)ethyl]carbamate

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

2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid chloride

A

C39H56N4O6

C39H56N4O6

B

bardoxolone
218600-44-3

bardoxolone

Conditions
ConditionsYield
With triethylamine In dichloromethane at 20℃; for 2h; Inert atmosphere;
3-methoxypropionamidoxime hydrochloride
67015-15-0

3-methoxypropionamidoxime hydrochloride

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

2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid chloride

A

C35H49N3O5

C35H49N3O5

B

bardoxolone
218600-44-3

bardoxolone

Conditions
ConditionsYield
With triethylamine; trimethylamine In dichloromethane at 20℃; Inert atmosphere;
methyl 3β-acetoxy-12-oxoolean-9(11)-en-28-oate
65023-20-3

methyl 3β-acetoxy-12-oxoolean-9(11)-en-28-oate

bardoxolone
218600-44-3

bardoxolone

Conditions
ConditionsYield
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

methyl 3,12-dioxoolean-9(11)-en-28-oate

bardoxolone
218600-44-3

bardoxolone

Conditions
ConditionsYield
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

methyl 3β-hydroxy-12-oxoolean-9(11)-en-28-oate

bardoxolone
218600-44-3

bardoxolone

Conditions
ConditionsYield
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

methyl 12-oxoisoxazolo[4,5-b]olean-9(11)-en-28-oate

bardoxolone
218600-44-3

bardoxolone

Conditions
ConditionsYield
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

2-cyano-3-hydroxy-12-oxoolean-2(3),9(11)-dien-28-oic acid

bardoxolone
218600-44-3

bardoxolone

Conditions
ConditionsYield
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

methyl 2-hydroxymethylene-3,12-dioxoolean-9(11)-en-28-oate

bardoxolone
218600-44-3

bardoxolone

Conditions
ConditionsYield
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

1,2-dihydro-2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid methyl ester

bardoxolone
218600-44-3

bardoxolone

Conditions
ConditionsYield
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

methyl 2-cyano-3,12-dioxoolean-9(11)-en-28-oate

bardoxolone
218600-44-3

bardoxolone

Conditions
ConditionsYield
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-hydroxy-12-oxoolean-2(3),9(11)-dien-28-oic acid

A

2-cyano-3,12-dioxooleana-1,9(11)-diene-13β,28-lactone
1309943-46-1

2-cyano-3,12-dioxooleana-1,9(11)-diene-13β,28-lactone

B

bardoxolone
218600-44-3

bardoxolone

Conditions
ConditionsYield
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

(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

bardoxolone
218600-44-3

bardoxolone

Conditions
ConditionsYield
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

Oleanolic acid

bardoxolone
218600-44-3

bardoxolone

Conditions
ConditionsYield
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

(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

bardoxolone
218600-44-3

bardoxolone

Conditions
ConditionsYield
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

oleanolic acid 3-acetate

bardoxolone
218600-44-3

bardoxolone

Conditions
ConditionsYield
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

methyl 3-O-β-acetyl-11-dehydro-12-oxo-18β-oleanolate

bardoxolone
218600-44-3

bardoxolone

Conditions
ConditionsYield
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

oleanolic acid methyl ester

bardoxolone
218600-44-3

bardoxolone

Conditions
ConditionsYield
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

(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

bardoxolone
218600-44-3

bardoxolone

Conditions
ConditionsYield
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

C31H43NO4

bardoxolone
218600-44-3

bardoxolone

Conditions
ConditionsYield
With 2,3-dicyano-5,6-dichloro-p-benzoquinone In benzene for 0.333333h; Reflux;
bardoxolone
218600-44-3

bardoxolone

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

2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid chloride

Conditions
ConditionsYield
With oxalyl dichloride In dichloromethane100%
With oxalyl dichloride In dichloromethane at 20℃;100%
With oxalyl dichloride In dichloromethane100%
bardoxolone
218600-44-3

bardoxolone

(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

(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

Conditions
ConditionsYield
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

bardoxolone

2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide
572-09-8

2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide

(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

(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
ConditionsYield
With Aliquat 336; potassium carbonate In dichloromethane75%
With potassium carbonate; Aliquat 336 In dichloromethane; water75%
bardoxolone
218600-44-3

bardoxolone

(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

(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

Conditions
ConditionsYield
With diethylamino-sulfur trifluoride In chloroform at 20℃; for 6.5h;94%
bardoxolone
218600-44-3

bardoxolone

C31H41NO5

C31H41NO5

Conditions
ConditionsYield
With dihydrogen peroxide In methanol; water; acetonitrile at 20℃; for 30h;90%
methanol
67-56-1

methanol

bardoxolone
218600-44-3

bardoxolone

bardoxolone methyl
218600-53-4

bardoxolone methyl

Conditions
ConditionsYield
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

O2-(2,4-dinitro-5-(2-bromoethylamino)phenyl)-1-(piperidine-1-yl)diazen-1-ium-1,2-diolate

bardoxolone
218600-44-3

bardoxolone

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

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
ConditionsYield
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

O2-(2,4-dinitro-5-(2-bromoethylamino)phenyl)-1-(N-methylethanolamino)diazen-1-ium-1,2-diolate

bardoxolone
218600-44-3

bardoxolone

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

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
ConditionsYield
With potassium carbonate In acetone at 45℃; for 4h;74%
bardoxolone
218600-44-3

bardoxolone

C31H43NO4

C31H43NO4

Conditions
ConditionsYield
With palladium 10% on activated carbon; hydrogen In tetrahydrofuran84%
4-chloromethyl-5-methyl-1,3-dioxol-2-one
80841-78-7

4-chloromethyl-5-methyl-1,3-dioxol-2-one

bardoxolone
218600-44-3

bardoxolone

C36H45NO7

C36H45NO7

Conditions
ConditionsYield
With 1,8-diazabicyclo[5.4.0]undec-7-ene In toluene Heating / reflux;83%
propionyl chloride
79-03-8

propionyl chloride

bardoxolone
218600-44-3

bardoxolone

1-isosorbide mononitrate 2-cyano-3-propionyloxy-12-oxoolean-2(3),9(11)-diene-28-carboxylic acid

1-isosorbide mononitrate 2-cyano-3-propionyloxy-12-oxoolean-2(3),9(11)-diene-28-carboxylic acid

Conditions
ConditionsYield
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%
acetyl chloride
75-36-5

acetyl chloride

bardoxolone
218600-44-3

bardoxolone

1-isosorbide mononitrate 2-cyano-3-acetoxy-12-oxoolean-2(3),9(11)-diene-28-carboxylic acid

1-isosorbide mononitrate 2-cyano-3-acetoxy-12-oxoolean-2(3),9(11)-diene-28-carboxylic acid

Conditions
ConditionsYield
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

bardoxolone

(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

(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

Conditions
ConditionsYield
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

bardoxolone

A

(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

(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

B

(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

(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

Conditions
ConditionsYield
With diphenyl phosphoryl azide; triethylamine In toluene at 0 - 20℃; Overall yield = 94 %; Overall yield = 19.7 g;
bardoxolone
218600-44-3

bardoxolone

N-(2-(2-(2-(2-amidoethoxy)ethoxy)ethoxy)ethoxy)biotinamide
359860-27-8

N-(2-(2-(2-(2-amidoethoxy)ethoxy)ethoxy)ethoxy)biotinamide

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

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
ConditionsYield
With 2`,3`-dideoxycytidine; dmap In dichloromethane at 20℃; for 48h;79%
bardoxolone
218600-44-3

bardoxolone

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

2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid chloride

2-cyano-3,10-dioxooleana-1,9(11)-dien-28-oic acid anhydride
1224947-97-0

2-cyano-3,10-dioxooleana-1,9(11)-dien-28-oic acid anhydride

Conditions
ConditionsYield
With triethylamine In tetrahydrofuran at 20℃; for 1.5h;96%
bardoxolone
218600-44-3

bardoxolone

benzyl halide

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

(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
ConditionsYield
With 1,8-diazabicyclo[5.4.0]undec-7-ene In toluene Heating;97%
bardoxolone
218600-44-3

bardoxolone

ethyl halide

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

(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
ConditionsYield
With 1,8-diazabicyclo[5.4.0]undec-7-ene In toluene Heating;100%
bardoxolone
218600-44-3

bardoxolone

n-octyl halide

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

(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
ConditionsYield
With 1,8-diazabicyclo[5.4.0]undec-7-ene In toluene Heating;89%
bardoxolone
218600-44-3

bardoxolone

cyclopropylmethyl halide

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

(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
ConditionsYield
With 1,8-diazabicyclo[5.4.0]undec-7-ene In toluene Heating;81%
bardoxolone
218600-44-3

bardoxolone

n-butyl halide

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

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

218600-44-3Relevant articles and documents

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

Honda, Tadashi,Rounds, BarbieAnn V.,Gribble, Gordon W.,Suh, Nanjoo,Wang, Yongping,Sporn, Michael B.

, p. 2711 - 2714 (1998)

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.

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

-

Paragraph 0105-0108, (2020/07/21)

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.

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

Wong, Michael H. L.,Bryan, Holly K.,Copple, Ian M.,Jenkins, Rosalind E.,Chiu, Pak Him,Bibby, Jaclyn,Berry, Neil G.,Kitteringham, Neil R.,Goldring, Christopher E.,O'Neill, Paul M.,Park, B. Kevin

, p. 2396 - 2409 (2016/04/10)

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.

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