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CAS No. : | 934541-31-8 | MDL No. : | MFCD18782651 |
Formula : | C28H32N4O3S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | - |
M.W : | 504.64 | Pubchem ID : | - |
Synonyms : |
|
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280 | UN#: | N/A |
Hazard Statements: | H302-H317 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.7% | With hydrogenchloride In water; acetonitrile for 0.25h; | 1 The hydrochloride salt of Compound 88 was prepared as follows. To a stirred suspension of Compound 88 (8.7 g) in ACN (175 mL) and H2O (175 mL) was added 1N HCl (18.1 mL, 1.05 eq) affording a yellow solution. After 15 minutes, the solution was frozen on dry ice/acetone and lyophilized to provide 5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide hydrochloride as a yellow solid (9.02 g, 96.7%). The above process provided 5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide hydrochloride as the Amorphous Form, as determined by X-ray powder diffraction analysis (FIG. 1). |
96.7% | With hydrogenchloride In water; acetonitrile for 0.25h; | 1 To a stirred suspension of Compound I (8.7 g) in ACN (175 mL) and H2O (175 mL) was added IN HCl (18.1 mL, 1.05 eq) affording a yellow solution. After 15 minutes, the solution was frozen on dry ice/acetone and lyophilized to provide 5-(3-(ethylsulfonyl)phenyl)-3,8- dimethyl-N-(l-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide hydrochloride as a yellow solid (9.02 g, 96.7%). |
96.7% | With hydrogenchloride In water; acetonitrile for 0.25h; | To a stirred suspension of Compound 88 (8.7 g) in ACN (175 mL) and H2O (175 mL) was added IN HCl (18.1 mL, 1.05 eq) affording a yellow solution. After 15 minutes, the solution was frozen on dry ice/acetone and lyophilized to provide 5-(3-(ethylsulfonyl)phenyl)-3,8- dimethyl-N-(l-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide hydrochloride as a yellow solid (9.02 g, 96.7%). The above process provided 5-(3- (ethylsulfonyl)phenyl)-3,8-dimethyl-N-(l-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole- 7-carboxamide hydrochloride as an amorphous material ("Amorphorus Form"), which may be characterized as having one or more of the following physical characteristics (it being noted that a composition need not necessarily exhibit all of these characteristics in order to indicate the presence of Amorphous Form):(a) may be formed by lyophilizing a solution of Compound 88 in ACN, water, and HCl;(b) has an XRPD spectrum characterized by a diffuse halo with no discernable peaks; and/or(c) shows 7.6 wt% Cl" present using ion chromatography. |
With hydrogenchloride In methanol; water at 25℃; for 0.25 - 0.5h; | For example, the mono HCl salt of 5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl- N-(l-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide (Compound 112) was prepared as follows. To a solution of 5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(l- methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide (2.105 g) in MeOH (20 rnL) was added 4.38 mL of IN aqueous HCl. The mixture was stirred for 15-30 min at 250C. The solvent was removed to near dryness, and the resultant white solid filtered and dried to provide 2.23 g of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.8% | With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane; N,N-dimethyl-formamide at 20℃; for 0.5h; | 1 A mixture of Compound 87 (11.3 g, 27.6 mmol), 1-methylpiperidin-4-amine (9.47 g, 82.9 mmol), HATU (13.66 g, 35.9 mmol), DIEA (17.88 g, 138 mmol), DMF (250 mL), and DCM (250 mL) was stirred at room temperature for 30 minutes. The resulting suspension was filtered, rinsed with DMF (10 mL×4) and concentrated in vacuo. The residue was dissolved in DMSO (77 mL), filtered, and the filtrate was purified by preparative HPLC (ACN/H2O with TFA). Following HPLC purification, the pure fractions were combined, basified with sodium bicarbonate and concentrated in vacuo to half volume. The resulting suspension was filtered, rinsed with H2O (200 mL×5) and dried in vacuo to provide Compound 88 as a white solid (11.41 g, 81.8%). |
81.8% | With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane; N,N-dimethyl-formamide at 20℃; for 0.5h; | 1 A mixture of Compound 87 (11.3 g, 27.6mmol), 1- methylpiperidin-4-amine (9.47 g, 82.9 mmol), HATU (13.66 g, 35.9 mmol), DIEA (17.88 g, 138 mmol), DMF (250 mL), and DCM (250 mL) was stirred at room temperature for 30 minutes. The resulting suspension was filtered, rinsed with DMF (10 mL x 4) and concentrated in vacuo. The residue was dissolved in DMSO (77 mL), filtered, and the filtrate was purified by preparative HPLC (ACN/H2O with TFA). Following HPLC purification, the pure fractions were combined, basified with sodium bicarbonate and concentrated in vacuo to half volume. The resulting suspension was filtered, rinsed with H2O (200 mL x 5) and dried in vacuo to provide Compound I as a white solid (11.41 g, 81.8%). |
81.8% | With diethylamine; HATU In dichloromethane; N,N-dimethyl-formamide at 20℃; for 0.5h; | A mixture of Compound 87 (11.3 g, 27.6mmol), 1- methylpiperidin-4-amine (9.47 g, 82.9 mmol), HATU (13.66 g, 35.9 mmol), DIEA (17.88 g, 138 mmol), DMF (250 mL), and DCM (250 mL) was stirred at room temperature for 30 minutes. The resulting suspension was filtered, rinsed with DMF (10 mL x 4) and concentrated in vacuo. The residue was dissolved in DMSO (77 mL), filtered, and the filtrate was purified by preparative HPLC (ACN/H2O with TFA). Following HPLC purification, the pure fractions were combined, basified with sodium bicarbonate and concentrated in vacuo to half volume. The resulting suspension was filtered, rinsed with H2O (200 mL x 5) and dried in vacuo to provide Compound 88 as a white solid (11.41 g, 81.8%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,4-dioxane at 40℃; for 168h; | 8.3 Compound I (Form A, 0.313 g) was charged into a 20 mL-scintillation vial equipped with magnetic stir bar followed by the addition of dioxane (10 mL, 32 vol.) in one portion at 40 0C. The resultant mixture was then slurried at 40 0C for one week. Solids were isolated by filtration and dried under vacuum at ambient temperature for 16 h before being submitted for analysis by XRPD. Form A was found. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.3% | With sodium hydrogencarbonate In water; acetonitrile at 20℃; for 0.25h; | 1 Compound I was prepared from the HCl salt of Compound I by dissolving 2.52 g of the HCl salt of Compound I with stirring in 100 mL of MeCN: water (1 : 1, v/v). This mixture was filtered to remove a small amount of undissolved particles. To clarify the solution solid NaHCθ3 (1.99 g, 5.0 equiv.) was added in one portion followed by additional stirring at ambient temperature for 15 minutes. The suspension was concentrated to about half volume by rotary evaporation, and the resultant solution filtered and washed with water (2 x 25 mL). The filter cake was dried at ambient temperature under vacuum (30 inches Hg) for 24 hours to afford 2.12 g of Compound I (94.3 % yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; acetonitrile for 0.0833333h; | To a stirred suspension of Compound 88 (100 mg) in ACN (2.5 mL) and H2O (2.5 mL) was added benzoic acid (25 mg, 1.05 eq) affording a clear solution containing a very small amount of suspended benzoic acid crystals. After 5 minutes, the solution was frozen on dry ice/acetone and lyophilized to provide 5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(l- methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide benzoate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; acetonitrile for 0.0833333h; | To a stirred suspension of Compound 88 (108 mg) in ACN (2.5 mL) and H2O (2.5 mL) was added L-tartaric acid (34 mg, 1.05 eq) affording a clear solution. After 5 minutes, the solution was frozen on dry ice/acetone and lyophilized to provide 5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(l- methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide tartrate (137 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; acetonitrile for 0.0833333h; | To a stirred suspension of Compound 88 (100 mg) in ACN (2.5 mL) and H2O (2.5 mL) was added benzoic acid (25 mg, 1.05 eq) affording a clear solution containing a very small amount of suspended benzoic acid crystals. After 5 minutes, the solution was frozen on dry ice/acetone and lyophilized to provide 5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(l- methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide benzoate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; acetonitrile for 0.0833333h; | To a stirred suspension of Compound 88 (104 mg) in ACN (2.5 mL) and H2O (2.5 mL) was added fumaric acid (25 mg, 1.05 eq) affording a very slightly cloudy solution. After 5 minutes, the solution was frozen on dry ice/acetone and lyophilized to provide 5-(3- (ethylsulfonyl)phenyl)-3,8-dimethyl-N-(l-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole- 7-carboxamide fumarate (123 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; acetonitrile for 0.0833333h; | To a stirred suspension of Compound 88 (101 mg) in ACN (2.5 mL) and H2O (2.5 mL) was added methanesulfonic acid (0.014 mL, 1.05 eq) affording a clear solution. After 5 minutes, the solution was frozen on dry ice/acetone and lyophilized to provide 5-(3- (ethylsulfonyl)phenyl)-3,8-dimethyl-N-(l-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole- 7-carboxamide methane sulfonate (116 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; acetonitrile for 0.0833333h; | To a stirred suspension of Compound 88 (100 mg) in ACN (2.5 mL) and H2O (2.5 mL) was added succinic acid (25 mg, 1.05 eq) to give a clear solution. After 5 minutes, the solution was frozen on dry ice/acetone and lyophilized to provide 5-(3-(ethylsulfonyl)phenyl)-3,8- dimethyl-N-(l-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide succinate (119 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; acetonitrile for 0.0833333h; | To a stirred suspension of Compound 88 (104 mg) in ACN (2.5 mL) and H2O (2.5 mL) was added citric acid (42 mg, 1.05 eq) affording a clear solution. After 5 minutes, the solution was frozen on dry ice/acetone and lyophilized to provide 5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(l- methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide citrate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride In water; acetonitrile for 0.0833333h; | To a stirred suspension of Compound 88 (101 mg) in ACN (2.5 mL) and H2O (2.5 mL) was added 12. IN HCl (0.42 mL, 2.1 eq) affording a yellow solution. After 5 minutes, the solution was frozen on dry ice/acetone and lyophilized to provide 5-(3-(ethylsulfonyl)phenyl)-3,8- dimethyl-N-(l-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide dihydrochloride as a yellow solid (0.108 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid In water; acetonitrile for 0.0833333h; | To a stirred suspension of Compound 88 (107 mg) in ACN (2.5 mL) and H2O (2.5 mL) was added sulfuric acid (0.012 mL, 1.05 eq) affording a yellow solution. After 5 minutes, the solution was frozen on dry ice/acetone and lyophilized to provide 5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N- (l-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide sulfate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With phosphoric acid In water; acetonitrile for 0.0833333h; | To a stirred suspension of Compound 88 (104 mg) in ACN (2.5 mL) and H2O (2.5 mL) was added phosphoric acid (0.015 mL, 1.05 eq) affording a slightly cloudy solution that was warmed to assist solubility. After 5 minutes, the solution was frozen on dry ice/acetone and lyophilized to provide 5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(l-methylpiperidin-4- yl)-9H-pyrido[2,3-b]indole-7-carboxamide phosphate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; acetonitrile for 0.0833333h; | To a stirred suspension of Compound 88 (98 mg) in ACN (2.5 mL) and H2O (2.5 mL) was added benzenesulfonic acid (32 mg, 1.05 eq) to give a slightly cloudy solution that was warmed to assist solubility. After 5 minutes, the solution was frozen on dry ice/acetone and lyophilized to provide 5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(l-methylpiperidin-4- yl)-9H-pyrido[2,3-b]indole-7-carboxamide benzenesulfonate (118 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: caesium carbonate / bis(dibenzylideneacetone)-palladium(0); tricyclohexylphosphine / 1,4-dioxane / 4.5 h / Reflux 2: iron; acetic acid / water / 2 h / 80 °C 3: 3 h / Reflux 4: sulfuric acid / 0.5 h / 120 °C 5: diethylamine; HATU / dichloromethane; N,N-dimethyl-formamide / 0.5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: iron; acetic acid / water / 2 h / 80 °C 2: 3 h / Reflux 3: sulfuric acid / 0.5 h / 120 °C 4: diethylamine; HATU / dichloromethane; N,N-dimethyl-formamide / 0.5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 3 h / Reflux 2: sulfuric acid / 0.5 h / 120 °C 3: diethylamine; HATU / dichloromethane; N,N-dimethyl-formamide / 0.5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: sulfuric acid / 0.5 h / 120 °C 2: diethylamine; HATU / dichloromethane; N,N-dimethyl-formamide / 0.5 h / 20 °C |