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CAS No. : | 254740-64-2 | MDL No. : | MFCD16628036 |
Formula : | C32H40N4O5S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | WRFHGDPIDHPWIQ-UHFFFAOYSA-N |
M.W : | 592.75 | Pubchem ID : | 10257882 |
Synonyms : |
RE-021;DARA-a;DARA;PS-433540
|
Chemical Name : | 4'-((2-Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide |
Num. heavy atoms : | 42 |
Num. arom. heavy atoms : | 17 |
Fraction Csp3 : | 0.47 |
Num. rotatable bonds : | 12 |
Num. H-bond acceptors : | 7.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 172.32 |
TPSA : | 122.48 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -6.35 cm/s |
Log Po/w (iLOGP) : | 4.72 |
Log Po/w (XLOGP3) : | 5.02 |
Log Po/w (WLOGP) : | 6.36 |
Log Po/w (MLOGP) : | 2.66 |
Log Po/w (SILICOS-IT) : | 6.58 |
Consensus Log Po/w : | 5.07 |
Lipinski : | 1.0 |
Ghose : | None |
Veber : | 1.0 |
Egan : | 1.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -6.19 |
Solubility : | 0.000387 mg/ml ; 0.000000653 mol/l |
Class : | Poorly soluble |
Log S (Ali) : | -7.33 |
Solubility : | 0.0000276 mg/ml ; 0.0000000465 mol/l |
Class : | Poorly soluble |
Log S (SILICOS-IT) : | -10.86 |
Solubility : | 0.0000000082 mg/ml ; 0.0 mol/l |
Class : | Insoluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 3.0 |
Synthetic accessibility : | 5.49 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P233-P260-P261-P264-P270-P271-P280-P301+P312-P302+P352-P304-P304+P340-P305+P351+P338-P312-P321-P330-P332+P313-P337+P313-P340-P362-P403-P403+P233-P405-P501 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | 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 |
---|---|---|
88% | With hydrogenchloride In ethanol; water for 1h; Reflux; | 3.G Step G. 4’-[(2-Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-N-(4,5-dimethyl-3-isoxazolyl)-2’-(ethoxymethyl)[1,1’-biphenyl]-2-sulfonamide Step G. 4'-[(2-Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-N-(4,5-dimethyl-3-isoxazolyl)-2'-(ethoxymethyl) [1,1'-biphenyl]-2-sulfonamide The MOM protecting group of 4'-[(2-Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-N-(4,5-dimethyl-3-isoxazolyl)-2'-(ethoxymethyl)-N-(methoxymethyl) [1,1'-biphenyl]-2-sulfonamide (32 g, 53 mmol.) was removed according to General Method 6. The crude product was purified by silica gel chromatography using hexanes/ethyl acetate/acetic acid as eluant to provide the title compound (26 g, 88%) as an amorphous foam: MS n/e 593 (ESI+ mode); HPLC retention time 18.75 min (HPLC method E); HPLC purity>96%. [0157] To a 0.1 M solution of a SEM- or MEM-protected N-heteroaryl sulfonamide in one volume of 95% EtOH wasadded an equal volume of 6N aqueous HCl, and the resulting solution was heated at reflux for 1 h. The reaction mixturewas concentrated and the pH of the solution was adjusted to pH 8 using aqueous sodium bicarbonate solution. It wasthen reacidified to pH 5 with glacial acetic acid. The mixture was extracted with three portions of ethyl acetate. Thecombined organic extracts were washed with water and brine, dried over sodium sulfate, and concentrated. The residuewas purified by reverse-phase preparative HPLC, or by silica gel chromatography using chloroform/methanol or hexanes/acetone as eluant. |
1.0 g | With hydrogenchloride In ethanol for 2h; Heating; | |
Stage #1: 4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-N-](4,5-dimethyl-3-isoxazolyl)-2'-(ethoxymethyl)-N-(methoxymethyl) [1,1'-biphenyl]-2-sulfonamide With hydrogenchloride In ethanol; water at 75 - 80℃; for 2h; Stage #2: With sodium hydroxide In ethanol; water at 20℃; | 11 Example 11; N-(3,4-Dimethyl-5-isoxazolyl)-2-(4-(2-butyl-4-oxo-l,3-diazospiro[4.4]non-l-en- 3yl)methyl-2-ethoxymethylphenyl)phenylsulfonamide (Compound 1); [0067] To a suspension of l-bromo-4-((2-butyl-4-oxo-l,3-diazaspiro[4.4]non- l-en-3-yl)methyl)-2-ethoxymethylbenzene bisoxalic acid salt (Compound 19) (5.0 g, 8.3 mmol) in toluene (20 niL) under nitrogen was added water (30 mL) and pH was adjusted to 8-9 by addition of a 2 M NaOH solution at room temperature. The organic phase was separated and mixed with 2-(N-(3,4-dimethyl-5-isoxazolyl)-N- methoxymethylamino)sulfonylphenylboronic acid pinacol ester (Scheme VII, Formula IX, where R8 is methoxymethyl and M = boronic acid pinacol ester) (3.6 g, 8.5 mmol), bis(dibenzylideneacetone)palladium(0) (Pd(dba)2) (0.12 g), and a standard phosphine ligand. After a 2 M sodium carbonate solution was added, the reaction mixture was warmed to 70 0C and stirred until the reaction was complete by HPLC analysis. The reaction was cooled to room temperature and quenched with water, and then separated in phases. The organic phase was treated with activated carbon, filtered through a pad of silica gel, and was concentrated to afford a crude mixture.[0068] The crude reaction mixture was dissolved in ethanol (40 mL) after palladium catalyst was removed and was treated with 6 M HCl solution (ca. 40 mL). The mixture was warmed to 75-80 °C and stirred for about 2 hours until the reaction was completed by HPLC analysis. After the mixture was cooled to room temperature, the pH of the mixture was adjusted to 8 by addition of 10 M NaOH solution. The mixture was stirred for 2 more hours and the pH was adjusted to 6 by adding 2 M HCl and the crystal seeds. Filtration of the crystalline solid followed by drying provided N-(3,4-dimethyl-5- isoxazolyl)-2-(4-(2-butyl-4-oxo-l,3-diazospiro[4.4]non-l-en-3yl)methyl-2- ethoxymethylphenyl)phenylsulfonamide (Compound 1) as a white solid. 1H NMR (400 MHz, CDCIa) 8.03 (dd, J= 8.0 and 1.2, IH), 7.60 (td, J = 7.5 and 1.5, IH), 7.50 (td, J = 7.7 and 1.5, IH), 7.36 (s, IH), 7.28 (d, J= 2.1, 1 H), 7.25 (dd, J = 7.5 and 1.2, IH), 7.09 (dd, J= 7.9 and 1.6, IH), 6.61 (bs, IH), 4.77 (AB quartet, J= 15.5 and 8.1, 2H), 4.18 (AB quartet, J= 12.0 and 35, 2H), 3.45-3.32 (m, 2H), 2.39 (t, J= 7.5, 2H), 2.26 (s, 3H), 2.02- 1.84 (m, 8H), 1.82 (s, 3H), 1.63 (quint, J= 7.5, 2H), 1.37 (sextet, J= 7.3, 2H), 1.07 (t, J = 7.0, 3H), and 0.90 (t J= 7.3, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1.1: 17 g / N-bromosuccinimide; benzoyl peroxide / CCl4 / 4 h / Heating 2.1: 77 percent / dimethylformamide / 16 h / 20 °C 3.1: 80 percent / DIBAL-H / tetrahydrofuran; hexane / 3 h / 20 °C 4.1: 82 percent / Pd(PPh3)4; aq. Na2CO3 / aq. ethanol; toluene / 3 h / 85 °C 5.1: NaBH4 / methanol / 1 h / 20 °C 6.1: 6.07 g / CBr4; PPh3 / dimethylformamide / 3 h / 0 °C 7.1: NaH / dimethylformamide / 0.5 h / 20 °C 7.2: 1.36 g / dimethylformamide / 5 h / 20 °C 8.1: 1.0 g / aq. HCl / aq. ethanol / 2 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: 77 percent / dimethylformamide / 16 h / 20 °C 2.1: 80 percent / DIBAL-H / tetrahydrofuran; hexane / 3 h / 20 °C 3.1: 82 percent / Pd(PPh3)4; aq. Na2CO3 / aq. ethanol; toluene / 3 h / 85 °C 4.1: NaBH4 / methanol / 1 h / 20 °C 5.1: 6.07 g / CBr4; PPh3 / dimethylformamide / 3 h / 0 °C 6.1: NaH / dimethylformamide / 0.5 h / 20 °C 6.2: 1.36 g / dimethylformamide / 5 h / 20 °C 7.1: 1.0 g / aq. HCl / aq. ethanol / 2 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: 82 percent / Pd(PPh3)4; aq. Na2CO3 / aq. ethanol; toluene / 3 h / 85 °C 2.1: NaBH4 / methanol / 1 h / 20 °C 3.1: 6.07 g / CBr4; PPh3 / dimethylformamide / 3 h / 0 °C 4.1: NaH / dimethylformamide / 0.5 h / 20 °C 4.2: 1.36 g / dimethylformamide / 5 h / 20 °C 5.1: 1.0 g / aq. HCl / aq. ethanol / 2 h / Heating | ||
Multi-step reaction with 5 steps 1.1: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / toluene; ethanol; water / 3 h / 85 °C / Inert atmosphere 2.1: sodium tetrahydroborate / 0 - 20 °C 2.2: 0.25 h 3.1: carbon tetrabromide; triphenylphosphine / N,N-dimethyl-formamide / 4 h / 0 °C 4.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.33 h / 0 - 20 °C 4.2: 0 - 20 °C 5.1: hydrogenchloride / ethanol; water / 1 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: 80 percent / DIBAL-H / tetrahydrofuran; hexane / 3 h / 20 °C 2.1: 82 percent / Pd(PPh3)4; aq. Na2CO3 / aq. ethanol; toluene / 3 h / 85 °C 3.1: NaBH4 / methanol / 1 h / 20 °C 4.1: 6.07 g / CBr4; PPh3 / dimethylformamide / 3 h / 0 °C 5.1: NaH / dimethylformamide / 0.5 h / 20 °C 5.2: 1.36 g / dimethylformamide / 5 h / 20 °C 6.1: 1.0 g / aq. HCl / aq. ethanol / 2 h / Heating | ||
Multi-step reaction with 6 steps 1.1: diisobutylaluminium hydride / toluene; dichloromethane / 0 °C 1.2: 0.25 h 2.1: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / toluene; ethanol; water / 3 h / 85 °C / Inert atmosphere 3.1: sodium tetrahydroborate / 0 - 20 °C 3.2: 0.25 h 4.1: carbon tetrabromide; triphenylphosphine / N,N-dimethyl-formamide / 4 h / 0 °C 5.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.33 h / 0 - 20 °C 5.2: 0 - 20 °C 6.1: hydrogenchloride / ethanol; water / 1 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: NaBH4 / methanol / 1 h / 20 °C 2.1: 6.07 g / CBr4; PPh3 / dimethylformamide / 3 h / 0 °C 3.1: NaH / dimethylformamide / 0.5 h / 20 °C 3.2: 1.36 g / dimethylformamide / 5 h / 20 °C 4.1: 1.0 g / aq. HCl / aq. ethanol / 2 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: NaH / dimethylformamide / 0.5 h / 20 °C 1.2: 1.36 g / dimethylformamide / 5 h / 20 °C 2.1: 1.0 g / aq. HCl / aq. ethanol / 2 h / Heating | ||
Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.33 h / 0 - 20 °C 1.2: 0 - 20 °C 2.1: hydrogenchloride / ethanol; water / 1 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: 6.07 g / CBr4; PPh3 / dimethylformamide / 3 h / 0 °C 2.1: NaH / dimethylformamide / 0.5 h / 20 °C 2.2: 1.36 g / dimethylformamide / 5 h / 20 °C 3.1: 1.0 g / aq. HCl / aq. ethanol / 2 h / Heating | ||
Multi-step reaction with 3 steps 1.1: carbon tetrabromide; triphenylphosphine / N,N-dimethyl-formamide / 4 h / 0 °C 2.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.33 h / 0 - 20 °C 2.2: 0 - 20 °C 3.1: hydrogenchloride / ethanol; water / 1 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | 275.G G. G. 4'-[(2-Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-N-(4,5-dimethyl-3-isoxazolyl)-2'-(ethoxymethyl) [1,1'-biphenyl]-2-sulfonamide 275F (32 g, 53 mmol) was deprotected according to General Method 7. The crude product was purified by silica gel chromatography using hexanes/ethyl acetate/acetic acid as eluant to provide the title compound (26 g, 88%) as an amorphous foam: MS n/e 593 (ESI+ mode); HPLC retention time 18.75 min (Method E); HPLC purity>96%. | |
88% | 275.227.G G. G. 4'-[(2-Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-N-(4,5-dimethyl-3-isoxazolyl)-2'-(ethoxymethyl) [1,1'-biphenyl]-2-sulfonamide 275F (32 g, 53 mmol) was deprotected according to General Method 7. The crude product was purified by silica gel chromatography using hexanes/ethyl acetate/acetic acid as eluant to provide the title compound (26 g, 88%) as an amorphous foam: MS n/e 593 (ESI+ mode); HPLC retention time 18.75 min (Method E); HPLC purity>96%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium tert-butylate; In tetrahydrofuran; at -60 - 20℃; | Example 7; N-(3,4-Dimethyl-5-isoxazolyl)-2-(4-(2-butyl-4-oxo-l,3-diazospiro[4.4]non-l-en- 3yl)methyl-2-ethoxymethylphenyl)phenylsulfonamide (Compound 1); [0062] To a solution of 5-amino-3,4-dimethylisoxazole (60 mg, 0.54 mmol) in THF at -60 C was added dropwise potassium tert-butoxide (1 mL of 1 M solution) followed by a solution of crude 2-(4-((2-butyl-4-oxo-l,3-diazaspiro[4.4]non-l-en-3- yl)methyl)-2-ethoxymethylphenyl)benzenesulfonyl chloride (Compound 16) (0.28 g, 0.54 mmol) in THF (4 mL). The resulting mixture was stirred at about -60 C for 1 hour, allowed to warm to room temperature overnight, and then quenched with IN HCl solution to about pH 4. Standard workup of extraction with ethyl acetate, washing with water, drying, and concentration provided the final compounds as a white solid. 1H NMR (400 MHz, CDCl3) 8.03 (dd, J = 8.0 and 1.2, IH), 7.60 (td, J = 7.5 and 1.5, IH), 7.50 (td, J = 7.7 and 1.5, IH), 7.36 (s, IH), 7.28 (d, J= 2.1, 1 H), 7.25 (dd, J = 7.5 and 1.2, IH), 7.09 (dd, J= 7.9 and 1.6, IH), 6.61 (bs, IH), 4.77 (AB quartet, J= 15.5 and 8.1, 2H), 4.18 (AB quartet, J= 12.0 and 35, 2H), 3.45-3.32 (m, 2H), 2.39 (t, J= 7.5, 2H), 2.26 (s, 3H), 2.02- 1.84 (m, 8H), 1.82 (s, 3H), 1.63 (quint, J = 7.5, 2H), 1.37 (sextet, J = 7.3, 2H), 1.07 (t, J = 7.0, 3H), and 0.90 (t J= 7.3, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: ethanol; N,N-dimethyl-formamide / 16 h / 0 - 20 °C 2.1: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / toluene; ethanol; water / 3 h / 85 °C / Inert atmosphere 3.1: diisobutylaluminium hydride / toluene; tetrahydrofuran / 2 h / -78 - -25 °C 4.1: carbon tetrabromide; triphenylphosphine / N,N-dimethyl-formamide / 4 h / 0 °C 5.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.33 h / 0 - 20 °C 5.2: 0 - 20 °C 6.1: hydrogenchloride / ethanol; water / 1 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: carbon tetrabromide; triphenylphosphine / N,N-dimethyl-formamide / 4 h / 0 °C 2.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.33 h / 0 - 20 °C 2.2: 0 - 20 °C 3.1: hydrogenchloride / ethanol; water / 1 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.33 h / 0 - 20 °C 1.2: 0 - 20 °C 2.1: hydrogenchloride / ethanol; water / 1 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With hydrogenchloride In ethanol; water for 1h; Reflux; | 2 To a 0.1 M solution of a SEM- or MEM-protected N-heteroaryl sulfonamide in one volume of 95% EtOH was added an equal volume of 6N aqueous HCl, and the resulting solution was heated at reflux for 1 h. The reaction mixture was concentrated and the pH of the solution was adjusted to pH 8 using aqueous sodium bicarbonate solution. It was then reacidified to pH 5 with glacial acetic acid. The mixture was extracted with three portions of ethyl acetate. The combined organic extracts were washed with water and brine, dried over sodium sulfate, and concentrated. The residue was purified by reverse-phase preparative HPLC, or by silica gel chromatography using chloroform/methanol or hexanes/acetone as eluant. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: sodium tetrahydroborate / 0 - 20 °C 1.2: 0.25 h 2.1: carbon tetrabromide; triphenylphosphine / N,N-dimethyl-formamide / 4 h / 0 °C 3.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.33 h / 0 - 20 °C 3.2: 0 - 20 °C 4.1: hydrogenchloride / ethanol; water / 1 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: N-Bromosuccinimide; dibenzoyl peroxide / tetrachloromethane / Reflux 2.1: ethanol; N,N-dimethyl-formamide / 16 h / 0 - 20 °C 3.1: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / toluene; ethanol; water / 3 h / 85 °C / Inert atmosphere 4.1: diisobutylaluminium hydride / toluene; tetrahydrofuran / 2 h / -78 - -25 °C 5.1: carbon tetrabromide; triphenylphosphine / N,N-dimethyl-formamide / 4 h / 0 °C 6.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.33 h / 0 - 20 °C 6.2: 0 - 20 °C 7.1: hydrogenchloride / ethanol; water / 1 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / toluene; ethanol; water / 3 h / 85 °C / Inert atmosphere 2.1: diisobutylaluminium hydride / toluene; tetrahydrofuran / 2 h / -78 - -25 °C 3.1: carbon tetrabromide; triphenylphosphine / N,N-dimethyl-formamide / 4 h / 0 °C 4.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.33 h / 0 - 20 °C 4.2: 0 - 20 °C 5.1: hydrogenchloride / ethanol; water / 1 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: diisobutylaluminium hydride / toluene; tetrahydrofuran / 2 h / -78 - -25 °C 2.1: carbon tetrabromide; triphenylphosphine / N,N-dimethyl-formamide / 4 h / 0 °C 3.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.33 h / 0 - 20 °C 3.2: 0 - 20 °C 4.1: hydrogenchloride / ethanol; water / 1 h / Reflux |