Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 3984-14-3 | MDL No. : | MFCD01861286 |
Formula : | C2H8N2O2S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | QMHAHUAQAJVBIW-UHFFFAOYSA-N |
M.W : | 124.16 | Pubchem ID : | 134472 |
Synonyms : |
|
Num. heavy atoms : | 7 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 26.3 |
TPSA : | 71.78 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.88 cm/s |
Log Po/w (iLOGP) : | 0.5 |
Log Po/w (XLOGP3) : | -1.16 |
Log Po/w (WLOGP) : | -0.17 |
Log Po/w (MLOGP) : | -1.11 |
Log Po/w (SILICOS-IT) : | -1.79 |
Consensus Log Po/w : | -0.74 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | 0.19 |
Solubility : | 191.0 mg/ml ; 1.54 mol/l |
Class : | Highly soluble |
Log S (Ali) : | 0.15 |
Solubility : | 173.0 mg/ml ; 1.4 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | 0.49 |
Solubility : | 381.0 mg/ml ; 3.07 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.07 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | 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 |
---|---|---|
98% | With ammonia In methanol at 60℃; for 16 h; Sealed tube | Dimethylsulfamoyl chloride (6.96 mmol, 0.748 ml) was treated with 7N ammonia methanol solution (104 mmol , 14.92 ml) in a sealed High-Pressure flask at 605C for 16 h. The reaction mixture was evaporated. The solid obtained was suspended in DCM, filtered, washed with DCM and dried under reduced pressure affording the title compound which was used in the next step without further purification (850 mg. Yield: 98percent). 1 H NMR (300 MHz, DMSO-d6) δ 7.40 (2H, s), 2.38 (6H, s). |
94% | at 0℃; for 3 h; | Ν,Ν-Dimethylsulfamoyl chloride (1 .00 mL, 9.31 mmol) was added to a 30percent aqueous ammonia solution (5 mL) at 0 °C. The reaction was stirred for 3 hours and solvent removed in vacuo to afford a white solid. The solid was sonicated with acetone (20 mL), filtered and the solid was washed with additional acetone (20 mL). The combined organic filtrate solvent was concentrated in vacuo to afford the title compound as a white solid (1082 mg, 94percent). 1H NMR (400 MHz, acetone-d6): δ ppm 2.70 (s, 6 H), 5.90 (br s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With ammonia; In methanol; at 60℃; for 16h;Sealed tube; | Dimethylsulfamoyl chloride (6.96 mmol, 0.748 ml) was treated with 7N ammonia methanol solution (104 mmol , 14.92 ml) in a sealed High-Pressure flask at 605C for 16 h. The reaction mixture was evaporated. The solid obtained was suspended in DCM, filtered, washed with DCM and dried under reduced pressure affording the title compound which was used in the next step without further purification (850 mg. Yield: 98percent). 1 H NMR (300 MHz, DMSO-d6) delta 7.40 (2H, s), 2.38 (6H, s). |
94% | With ammonium hydroxide; at 0℃; for 3h; | Nu,Nu-Dimethylsulfamoyl chloride (1 .00 mL, 9.31 mmol) was added to a 30percent aqueous ammonia solution (5 mL) at 0 °C. The reaction was stirred for 3 hours and solvent removed in vacuo to afford a white solid. The solid was sonicated with acetone (20 mL), filtered and the solid was washed with additional acetone (20 mL). The combined organic filtrate solvent was concentrated in vacuo to afford the title compound as a white solid (1082 mg, 94percent). 1H NMR (400 MHz, acetone-d6): delta ppm 2.70 (s, 6 H), 5.90 (br s, 2H). |
With ammonia; In methanol; | EXAMPLE 145A N,N-dimethylsulfamide Dimethylsulfamoyl chloride (3.70 g) was treated with ammonia (200 mL of a 2 M in solution in methanol) in a sealed high-pressure flask and heated at 60° C. for 12 h. Solvent was removed by rotary evaporation to furnish a white solid. This material was washed with methylene chloride and dried at 50° C. under reduced pressure to provide the desired product (3.10 g) as a white solid. MS (APCI+) m/z 124 (M+H)+. |
With ammonia; In methanol; | EXAMPLE 145A N,N-dimethylsulfamide Dimethylsulfamoyl chloride (3.70 g) was treated with ammonia (200 mL of a 2 M in solution in methanol) in a sealed high-pressure flask and heated at 60° C. for 12 h. Solvent was removed by rotary evaporation to furnish a white solid. This material was washed with methylene chloride and dried at 50° C. under reduced pressure to provide the desired product (3.10 g) as a white solid. MS (APCI+) m/z 124 (M+H)+. | |
With ammonia; In methanol; at 60℃; for 16h;Sealed tube; | Dimethylsulfamoyl chloride (6.96 mmol 0.748 ml) was treated with 7N ammonia methanol solution (104 mmol, 14.92 ml) in a sealed High-Pressure flask at 605C for 16 h. The reaction mixture was evaporated. The solid obtained was suspended in DCM, filtered, washed with DCM and dried under reduced pressure affording the title compound which was used in the next step without further purification (850 mg. Yield: 98percent). 1 H NMR (300 MHz, DMSO-d6) delta 7.40 (2H, s), 2.38 (6H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | (+/-) 8-cyclohexyl-1a[[[3R,5S]-3,5-dimethyl-1-piperizinylycarbonyl]-N-(dimethylsulfamoyl)-12-methoxy-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1,-a][2]benzazepine-5-carboxamide A mixture of 8-cyclohexyl-1a[[[3R,5S]-3,5-dimethyl-1-piperizinyl]carbonyl]-12-methoxy-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1,-a][2]benzazepine-5-carboxylic acid (54 mg, 0.1 mmol), and carbonyldiimidazole (49 mg, 0.3 mmol) in anhydrous THF was heated at 60° C. for 1 hr and allowed to cool to rt. Then N,N-dimethylsulfonamide (37 mg, 0.3 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (46 mg, 0.3 mmol) were added consecutively. The resultant mixture was heated at 60° C. for 2 hr. After acidic aqueous workup, the isolated crude product was purified by Prep HPLC to afford the title compound as light yellow solid (39 mg, 60percent). MS m/z 648 (MH+), 1H NMR (500 MHz, CD3OD) delta ppm 1.05-1.59 (m, 12H) 1.69-1.88 (m, 3H) 1.91-2.17 (m, 4.2H) 2.27-2.35 (m, 0.8H) 2.51-2.64 (m, 1H) 3.01-3.07 (m, 6H) 3.10-3.63 (m, 4.2H) 3.71-3.78 (m, 0.8H) 3.94-3.98 (m, 2.4H) 3.98-4.02 (m, 0.6H) 4.13-4.19 (m, 0.2H) 4.25-4.37 (m, 0.8H) 4.90-4.97 (m, 0.2H) 5.08-5.15 (m, 0.8H) 7.01-7.09 (m, 1H) 7.12-7.18 (m, 0.8H) 7.22-7.27 (m, 0.2H) 7.41-7.51 (m, 1H) 7.56-7.62 (m, 0.8H) 7.63-7.67 (m, 0.2H) 7.89-7.98 (m, 1H) 7.99-8.03 (m, 0.8H) 8.07-8.13 (m, 0.2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | 5H-Indolo[2,1-a][2]benzazepine-10-carboxamide, 13-cyclohexyl-6-[[2-(dimethylamino)ethyl]sulfonyl]-N-[(dimethylamino)sulfonyl]-6,7-dihydro-3-methoxy-. To a solution of 5H-Indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[[2-(dimethylamino)ethyl]sulfonyl]-6,7-dihydro-3-methoxy-, methyl ester (22 mg, 0.041 mmol) in THF (1.5 mL) was added CDI (20 mg, 0.12 mmol) and the resulting solution was heated 60° C. for 1 hr. Dimethylsulfamide (64 mg, 0.52 mmol) and DBU (0.016 mL, 0.10 mmol) were added. The resulting mixture was allowed to stir at 60° C. for 1 hr and 22° C. for 16 hr. 1M HCl (15 mL) was added and the aqueous layer was extracted with CHCl3 (2x20 mL). The organic phase was concentrated under reduced pressure. This oil was purified by reverse-phase prep HPLC to afford the title compound (17 mg, 67percent) as a yellow solid. MS m/z 631 (MH+). Two rotomers present in NMR. 1H NMR (300 MHz, CDCl3) d ppm 1.12-1.51 (m, 3H), 1.62-1.74 (m, 3H), 1.87-2.06 (m, 4H), 2.45 (d, 6H), 2.76-3.16 (m, 6H), 3.02 (d, 6H), 3.19-3.39 (m, 1H), 3.53-3.67 (m, 0.6H), 3.72-4.12 (m, 1.4H), 3.85 (d, 3H), 4.70 (m, 0.4H), 5.11 (d, 16 Hz, 0.6H), 7.03-7.10 (m, 2H), 7.38-7.51 (m, 2H), 7.91 (m, 1H), 8.07 (m, 1H), 8.78 (broad s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide, 8-cyclohexyl-N-[(dimethylamino)sulfonyl]-1,1a,2,12b-tetrahydro-11-methoxy-1a-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)sulfonyl]-. To a solution of cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxylic acid,8-cyclohexyl-1a-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)sulfonyl]-1,1a,2,12b-tetrahydro-11-methoxy-(42 mg, 0.071 mmol) in THF (1.5 mL) was added CDI (58 mg, 0.355 mmol) and the resulting solution was heated 60° C. for 1 hr. Dimethylsulfamide (108 mg, 0.710 mmol) and DBU (0.44 mL, 0.355 mmol) were added. The resulting mixture was allowed to stir at 60° C. for 1 hr and 22° C. for 16 hr. 1M HCl (15 mL) was added and the aqueous layer was extracted with CHCl3 (2x30 mL). The organic phase was concentrated under reduced pressure. This oil was purified by reverse-phase prep HPLC to afford the title compound (34 mg, 69percent) as a yellow paste. MS m/z 696 (MH+). Two rotomers present in NMR. 1H NMR (300 MHz, CDCl3) d ppm 0.40 (t, 0.5H), 1.20-1.60 (m, 5.5H), 1.65-2.04 (m, 7H), 2.12-2.42 (s, 3.5H), 2.81 (m, 1H), 2.93-3.10 (m, 9.5H), 3.19 (m, 0.5H), 3.50 (m, 0.5H), 3.64 (d, 15 Hz, 0.5H), 3.71 (m, 0.5H), 3.81 (d, J=15 Hz, 0.5H), 3.83-3.94 (m, 2H), 3.90 (d, 3H), 4.11 (m, 1H), 4.22 (d, 15 Hz, 0.5H), 4.55 (m, 1H), 5.05 (d, 15 Hz, 0.5H), 5.57 (d, 15 Hz, 0.5H), 6.96 (m, 1H), 7.06 (d, 0.5H), 7.12 (d, 0.5H), 7.22 (m, 2H), 7.41 (m, 0.5H), 7.54 (m, 0.5H), 7.82 (m, 1H), 7.95 (d, 0.5H), 8.20 (d, 0.5H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; | 6J-dihvdro-3H-bengor^1imidazof4.S-/1isoquinolm-9-vpi-lambdaUV:-dimethylsulfamide The intermediate from Example 8 Step. A (300 mg, 0.4240 mmol) was combined in a microwave vial with iV^-dimethylsulfamide (50 mg, 0.4027 mmol), Cs2CO3 (400 mg, 1.228 mmol), Pd2(dba)3 (20 mg, 0.0218 mmol), and Xantphos (36 mg, 0.0622 mmol). The vial was evacuated and purged with argon several times and the vial was sealed. Dioxane (10 mL) was added and the mixture was heated to 100°C overnight. The reaction was cooled to ambient temperature and diluted with EtOAc and washed sequentially with a- saturated solution of NaHCO3 and brine. The solution was dried with MgSO4 and filtered. Evaporation of the solvent under reduced pressure provided the crude residue that was purified on silica gel (gradient elution from 10 to 50percent EtOAc/hexanes): [M+l]+ 747. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | titanium(IV) tetraethanolate; In tetrahydrofuran; for 16h;Heating / reflux; | A solution of the ketone from Step 3 (0.360 g, 1.0 mmol), N, N-dimethylsulfamide (0.620 G, 5.0 MMOL) AND TITANIUM (IV) ETHOXIDE (TECH. , 0.63 ML, 3.0 MMOL) IN DRY THF (5 mL) was stirred and heated at reflux under nitrogen for 16 hours. The reaction was allowed to cool to room temperature, poured into rapidly stirred brine (60 mL), stirred for 1 hour, then filtered through HYFLO washing with EtOAc. The layers of the filtrate were separated, and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried (MGS04), filtered and evaporated. The residue was purified by chromatography on silica, eluting with 5- 20percent EtOAc/DCM, to give the imine (0.383 g, 82percent). MS (ES+) 467, MH+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With titanium(IV) tetraethanolate; In tetrahydrofuran; for 16h;Heating / reflux; | A solution of the ketone from Step 3 of the preparation of Intermediate B (0.360 g, 1.0 mmol), N, N-dimethylsulfamide (0.620 g, 5.0 mmol) and titanium (IV) ethoxide (TECH., 0.63 mL, 3.0 mmol) in dry THF (5 mL) was stirred and heated at reflux under nitrogen for 16 hours. The reaction was allowed to cool to room temperature and poured into rapidly stirred brine (60 ML). The mixture was stirred for 1 hour, then filtered through HYFLO2, washing with EtOAc. The layers of the filtrate were separated, and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried NGSO4), filtered and evaporated. The residue was purified by chromatography on silica, eluting with 5-20percent EtOAc/DCM, to give the imine (0.383 g, 82percent). MS (ES+) 467, LT; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With titanium(IV) tetraethanolate; In tetrahydrofuran; for 16h;Heating / reflux; | EXAMPLE 12; Step 1; A solution of the ketone from Example 1 Step 4 (0.936 g, 2.7 MMOL), N, N- dimethylsulfamide (1.677 g, 13.5 mmol) and titanium (IV) ethoxide (tech. , 1.7 mL, 8.1 mmol) in dry THF (15 mL) was stirred and heated at reflux under nitrogen for 16 hours. The reaction was allowed to cool to room temperature and poured into rapidly stirred brine (50 mL). The mixture was stirred for 30 minutes, then filtered through HYFLOQ , washing with DCM. The filtrate was transferred to a separating funnel. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic extracts were washed with 2N NAOH then brine, dried (MGS04), filtered and evaporated. The residue was purified by chromatography on silica, eluting with 10- 20percent EtOAc/DCM, to give the imine (0.960 g, 78percent). (360MHZ H, B-CDCL3) 1.26- 1.50 (2H, m), 1.75-1. 85 (2H, m), 2.90 (6H, s), 2.94 (2H, m), 3.09 (3H, M), 3.89 (1H, M), 7.22 (3H, m), 7.42 (2H, m), 7.51 (1H, s), 7.65 (1H, m), 7.73 (1H, s), 7.83 (1H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With lithium hydride; In DMF (N,N-dimethyl-formamide); at 20℃; | N, N-dimethyl-N'- (6-chloro-3-nitropyridin-2-yl) sulfonic acid; Stir a mixture of 2,6-dichloro-3-nitropyridine (1 g, 2.60 mmol) and N, N- dimethylsulfamide (0.78 g, 3.12 mmol) in dry DMF (5 mL). Add lithium hydride (0.11 g, 6.76 mmol) and stir at RT overnight. Add 10 mL of water and 3N HC1 until pH = 7. Filter the yellow solid to provide the title compound (85percent). MS (ES): m/z = 279 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With lithium hydride; In DMF (N,N-dimethyl-formamide); at 20℃; | N, N-Dimethyl-N'- (6-bromo-3-nitropyridin-2-yl) sulfonic acid Stir a mixture of 2,6-dibromo-3-nitropyridine (11. 3g, 39.25 mmol) and N, N- dimethylsulfamide (0.006 g, 47.10 mmol) in DMF (40 mL). Add lithium hydride (0.81 g, 102.05 mmol) and stir at RT overnight. Add 100 mL of water and 3 N HC1 until pH = 7. Filter the yellow solid to provide the title compound (93percent). 1H NMR (DMSO-d6) 8 10.25 (br s, 1H), 8.41 (d, J= 8.59 Hz, 1H), 7.50 (d, J= 8.59 Hz, 1H), 2.95 (2,6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74 - 83% | 1H-Indole-6-carboxamide, 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-. 1,1?-Carbonyldiimidazole (1.17 g, 7.2 mmol) was added to a stirred solution of 2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (2.03 g, 6.3 mmol) in THF (6 mL) at 22 C. The evolution of CO2 was instantaneous and when it slowed the solution was heated at 50 C. for 1 hr and then cooled to 22 C. N,N-Dimethylsulfamide (0.94 g, 7.56 mmol) was added followed by the dropwise addition of a solution of DBU (1.34 g, 8.8 mmol) in THF (4 mL). Stirring was continued for 24 hr. The mixture was partitioned between ethyl acetate and dilute HCl. The ethyl acetate layer was washed with water followed by brine and dried over Na2SO4. The extract was concentrated to dryness to leave the title product as a pale yellow friable foam, (2.0 g, 74percent, >90percent purity, estimated from NMR). 1H NMR (300 MHz, DMSO-D6) ? ppm 1.28-1.49 (m, 3 H) 1.59-2.04 (m, 7 H) 2.74-2.82 (m, 1 H) 2.88 (s, 6 H) 7.57 (dd, J=8.42, 1.46 Hz, 1 H) 7.74 (d, J=8.78 Hz, 1 H) 7.91 (s, 1 H) 11.71 (s, 1 H) 12.08 (s, 1 H).An alternative method for the preparation of 1H-indole-6-carboxamide, 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]- is described below. 2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (102.0 g, 0.259 mol) and dry THF (300 mL). were added to a 1 L four necked round bottom flask equipped with a mechanical stirrer, a temperature controller, a N2 inlet, and a condenser, and the mixture was placed under N2. After stirring for 10 min, CDI (50.3 g, 0.31 mol) was added portion wise. The reaction mixture was then heated to 50 C. for 2 h. After cooling to 30 C., N,N-dimethylaminosulfonamide (41.7 g, 0.336 mol) was added in one portion followed by addition of DBU (54.1 mL, 0.362 mol) drop wise over a period of 1 h. The reaction mixture was then stirred at rt for 20 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc and 1 N HCl (1:1, 2 L). The organic layer was separated and the aqueous layer was extracted with EtOAc (500 mL). The combined organic layers were washed with brine (1.5 L) and dried over MgSO4. The solution was filtered, and then concentrated in vacuo to give the crude product (111.0 g). The crude product was suspended in EtOAc (400 mL) at 60 C., and heptane (2 L) was then added slowly. The resulting mixture was stirred and cooled to 0 C. It was then filtered. The filter cake was rinsed with a small amount of heptane and house vacuum air dried for 2 days. The product was collected as a white solid (92.0 g, 83percent). 1H NMR (MeOD, 300 MHz) ? 7.89 (s, H), 7.77 (d, J=8.4 Hz, 1H), 7.55 (dd, J=8.4 and 1.8 Hz, 1H), 3.01 (s, 6H), 2.73-2.95 (m, 1H), 1.81-2.05 (m, 8H), 1.39-1.50 (m, 2H); m/z 429 (M+H)+. | |
74 - 83% | 1H-Indole-6-carboxamide, 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-1,1'-Carbonyldiimidazole (1.17 g, 7.2 mmol) was added to a stirred solution of 2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (2.03 g, 6.3 mmol) in THF (6 mL) at 22° C. The evolution of CO2 was instantaneous and when it slowed the solution was heated at 50° C. for 1 hr and then cooled to 22° C. N,N-Dimethylsulfamide (0.94 g, 7.56 mmol) was added followed by the dropwise addition of a solution of DBU (1.34 g ,8.8 mmol) in THF (4 mL). Stirring was continued for 24 hr. The mixture was partitioned between ethyl acetate and dilute HCl. The ethyl acetate layer was washed with water followed by brine and dried over Na2SO4. The extract was concentrated to dryness to leave the title product as a pale yellow friable foam, (2.0 g, 74percent, >90percent purity, estimated from NMR). 1H NMR (300 MHz, DMSO-D6) delta ppm 1.28-1.49 (m, 3H) 1.59-2.04 (m, 7H) 2.74-2.82 (m, 1H) 2.88 (s, 6H) 7.57 (dd, J=8.42, 1.46 Hz, 1H) 7.74 (d, J=8.78 Hz, 1H) 7.91 (s, 1H) 11.71 (s, 1H) 12.08 (s, 1H). An alternative method for the preparation of 1H-indole-6-carboxamide, 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]- is described below. 2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (102.0 g, 0.259 mol) and dry THF (300 mL). were added to a 1 L four necked round bottom flask equipped with a mechanical stirrer, a temperature controller, a N2 inlet, and a condenser, and the mixture was placed under N2. After stirring for 10 min, CDI (50.3 g, 0.31 mol) was added portion wise. The reaction mixture was then heated to 50° C. for 2 h. After cooling to 30° C., N,N-dimethylaminosulfonamide (41.7 g, 0.336 mol) was added in one portion followed by addition of DBU (54.1 mL, 0.362 mol) drop wise over a period of 1 h. The reaction mixture was then stirred at rt for 20 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc and 1 N HCl (1:1, 2 L). The organic layer was separated and the aqueous layer was extracted with EtOAc (500 mL). The combined organic layers were washed with brine (1.5 L) and dried over MgSO4. The solution was filtered, and then concentrated in vacuo to give the crude product (111.0 g). The crude product was suspended in EtOAc (400 mL) at 60° C., and heptane (2 L) was then added slowly. The resulting mixture was stirred and cooled to 0° C. It was then filtered. The filter cake was rinsed with a small amount of heptane and house vacuum air dried for 2 days. The product was collected as a white solid (92.0 g, 83percent). 1H NMR (MeOD, 300 MHz) 6 7.89 (s, H), 7.77 (d, J=8.4 Hz, 1H), 7.55 (dd, J=8.4 and 1.8 Hz, 1H), 3.01 (s, 6H), 2.73-2.95 (m, 1H), 1.81-2.05 (m, 8H), 1.39-1.50 (m, 2H); m/z 429 (M+H)+. | |
65% | Carbonyl diimidazole (6.0 g, 37 mmol) was added to a solution of 2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (10 g, 31 mmol) in THF (30 mL) and the reaction was stirred at 50° C. for 2 h (a white precipitate had formed). The reaction was cooled to rt and treated with <strong>[3984-14-3]N,N-dimethylsulfamide</strong> (4.6 g, 37 mmol). Then DBU (6.7 mL) in THF (20 mL) was added dropwise and the reaction was stirred at rt overnight. The solution was diluted with EtOAc (300 mL) and washed with H2O (150 mL), 1N aqueous HCl (2.x.100 mL) and brine (100 mL). The combined aqueous layers were extracted with EtOAc (200 mL) and the organic layer was washed with 1N aqueous HCl (150 mL) and brine (50 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to an oil. The oil was diluted with Et2O and concentrated to a semi-solid which was triturated with Et2O to yield 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-indole-6-carboxamide (6.1 g, 14 mmol, 46percent) as a light yellow solid. The organic washes where concentrated and purified by silica gel chromatography (20-35percent EtOAc/hexanes) to yield additional 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-indole-6-carboxamide (2.5 g, 6 mmol, 19percent). 1HNMR (500 MHz, CD3OD) delta 7.90 (d, J=1.8 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.56 (dd, J=1.8, 8.5 Hz, 1H), 3.01 (s, 6H), 2.93-2.86 (m, 1H), 2.04-1.76 (m, 7H), 1.54-1.37 (m, 3H). LCMS: m/e 426 (M-H)-, ret time 1.55 min, column A, 2 minute gradient. |
2-Bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-1H-indole-6-carboxamide.; 1,1'-Carbonyldiimidazole (1.17 g, 7.2 mmol) was added to a stirred solution of 2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (2.03 g, 6.3 mmol) in THF (6 mL) at 22° C. The evolution of CO2 was instantaneous and when it slowed the solution was heated at 50° C. for 1 hr and then cooled to 22° C. N,N-Dimethylsulfamide (0.94 g, 7.56 mmol) was added followed by the dropwise addition of a solution of DBU (1.34 g, 8.8 mmol) in THF (4 mL). Stirring was continued for 24 hr. The mixture was partitioned between ethyl acetate and dilute HCl. The ethyl acetate layer was washed with water followed by brine and dried over Na2SO4. The extract was concentrated to dryness to leave the title product as a pale yellow friable foam, (2.0 g, 74percent, >90percent purity, estimated from NMR). 1H NMR (300 MHz, DMSO-D6) delta ppm 1.28-1.49 (m, 3H) 1.59-2.04 (m, 7H) 2.74-2.82 (m, 1H) 2.88 (s, 6H) 7.57 (dd, J=8.42, 1.46 Hz, 1H) 7.74 (d, J=8.78 Hz, 1H) 7.91 (s, 1H) 11.71 (s, 1H) 12.08 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); dichloromethane; at 22℃; for 18h; | 13-cyclohexyl-N-(dimethylaminosulfonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide. A mixture of Example 15 (50 mg, 0.14 mmol), <strong>[3984-14-3]N,N-dimethylsulfamide</strong> (21 mg, 0.17 mmol), 4-(dimethylamino)pyridine (17 mg, 0.14 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (40 mg, 0.21 mmol) in dichloromethane (1 mL) and DMF (1 mL) was stirred for 18 hours at 22° C. The mixture was poured into ethyl acetate and dilute aqueous acetic acid. The ethyl acetate layer was washed (water, brine), dried (Na2SO4), filtered, and concentrated. The residue was crystallized from ethyl acetate to provide the desired product (17 mg, 26percent yield) as pale yellow crystals. ESI-MS m/z 358 (MH+); 1H NMR (300 MHz, CDCl3) delta 1.20-2.30 (m, 10H), 2.81 (m, 1H), 3.05 (s, 3H), 3.47 (m, 2H), 4.11 (m, 1H,) 4.89 (s, 1H), 6.27 (m, 1H), 6.80 (d, J=10.61 Hz, 1H), 7.38 (m, 4H), 7.51 (m, 1H), 7.89 (d, J=8.42 Hz, 1H), 8.02 (s, 1H), 8.75 (s, 1H). |
26% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; N,N-dimethyl-formamide; at 22℃; for 18h; | EXAMPLE 19; (compound 64) (IC50=B*, EC50=E*)IS-cyclohexyl-N-zetadimethylaminosulfonylJ-YH-indoloftJ-aJftJbenzazepine- 10-carboxamide. A mixture of Example 15 (50 mg, 0.14 mmol), N5N- dimethylsulfamide (21 mg, 0.17 mmol), 4-(dimethylamino)pyridine (17 mg, 0.14 mmol), and l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (40 mg, 0.21 mmol) in dichloromethane (1 mL) and DMF (1 mL) was stirred for 18 hours at <n="89"/>22 °C. The mixture was poured into ethyl acetate and dilute aqueous acetic acid. The ethyl acetate layer was washed (water, brine), dried (Na2SO4), filtered, and concentrated. The residue was crystallized from ethyl acetate to provide the desired product (17 mg, 26percent yield) as pale yellow crystals. ESI-MS m/z 358 (MH+); 1H NMR (300 MHz5 CDCl3) delta 1.20-2.30 (m, 10H), 2.81 (m, IH), 3.05 (s, 3H), 3.47 (m, 2H), 4.11 (m, IH,) 4.89 (s, IH), ,6.27 (m, IH), 6.80 (d, J=10.61 Hz, IH), 7.38 (m, 4H), 7.51 (m, IH), 7.89 (d, J=8.42 Hz, IH), 8.02 (s, IH), 8.75 (s, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; at 20℃; for 15h; | Example 58 Preparation of Compound 58 Step 1. To a solution N-Boc-vinylcyclopropane carboxylic acid, the product of step 7a, Example 7, (1.83 g, 8.05 mmol) and THF (32 mL) was added 1,1'-carbonyldiimidazole (1.44 g, 8.86 mmol). After stirring at room temperature for 3 hours, the reaction mixture was treated with <strong>[3984-14-3]N,N-dimethylsulfamide</strong> (1.0 g, 8.05 mmol) followed by DBU (2.45 g, 16.1 mmol) and it was stirred at room temperature for an additional 15 hours. The reaction was then diluted with EtOAc (50 mL) and was washed with 2.x.25 mL 1N aqueous HCl. The aqueous layer was extracted with 2.x.50 mL EtOAc. The combined organic portion was washed with H2O (25 mL) and brine, dried over MgSO4, filtered, and concentrated to a light yellow solid (2.6 g, 97percent yield) which was used without further purification. LC-MS, MS m/z 356 (M++Na). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; | Example 7: 14-cyclohexyI-N-[(dimethylamino)suIfonyl]-3-methoxy-6-methyl-5,6,7,8- tetrahydroindolo[2,l-alpha][2,5]benzodiazocine-ll-carboxamide; 1.5 eq of DMAP was added to the trifluoroacetate salt of M-cyclohexyl-S-methoxy--methyl-S.J.delta- tetrahydroindoloP.l-aJP.SJbenzodiazocine-l l-carboxylic acid (from Example 4) in dry DCM (0.1 M). Then 1.5 eq of EDAC'HCl was added and after 5 min of stirring at RT 1.5 eq of <strong>[3984-14-3]N,N-dimethylsulfamide</strong>. The reaction mixture was stirred overnight at RT. The solvent was removed in vacuo and the residue directly purified by RP-MS-HPLC (stationary phase: column Waters XTERRA prep. C18, 5 um, 19 x 100 mm. Mobile phase: MeCNu/H2psi buffered with 0.1 percent TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound as a white powder (38 percent). 1H NMR (400 MHz, DMSO-^6, 300 K) delta 1.13-1.36 (m, 3H), 1.95-1.47 (m, 7H), 2.66-2.60 (m, IH), 2.91 (s, 6H), 3.05 (br s, 3H), 3.50-3.63 (m, IH), 3.64-3.74 (m, 3H), 3.90 (s, 3H), 4.32 (AB system, J 14.0, IH), 4.69 (AB system, J 14.0, IH), 7.25 (d, J 8.3, IH), 7.40 (d, J 8.3, IH), 7.61 (s, IH), 7.70 (d, J 7.9, IH), 7.92 (d, J 7.9, IH), 8.25 (s, IH), 9.9 (br s, IH), 11.6 (br s, IH); MS (ES+) m/z 525 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | EXAMPLE 10 8-cyclohexyl-N-[(dimethylamino)sulfonyl]-1,1a,2,12b-tetrahydro-1a-[[(cis)-2,6-dimethyl-4-morpholinyl]carbonyl]-cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide. A 2M solution of oxalyl chloride (0.1 mL, 0.2 mmol) in CH2Cl2 was added dropwise to a solution of rel-8-cyclohexyl-1a-[[(cis)-2,6-dimethyl-4-morpholinyl]carbonyl]-1,1a,2,12b-tetrahydro-11-methoxy-cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxylic acid (54 mg, 0.1 mmol) in CH2Cl2 (10 mL) containing one drop of DMF. The reaction mixture was stirred at rt. for 2 h, afterwhich it was concentrated and dried under high vacuum. The resultant residue was dissolved in THF (10 mL) and a solution of N,N-dimethylsulfonamide (24.8 mg, 0.2 mmol) and DIPEA (0.052 mL, 0.3 mmol)) in THF (2 mL) was added. This was followed by the addition of DMAP (10 mg), after which the reaction mixture was stirred at rt. for 10 min, and then at 50° C. overnight. It was then concentrated and the residue purified by preparative reverse phase HPLC to afford the title compound as a white solid, (19.0 mg, 31percent yield). MS m/z 649 (MH+), Retention time: 3.685 min; 1H NMR (500 MHz, CD3OD) delta ppm. Compound was observed to exist as inter-converting rotamers, as evidenced from the compound's NMR spectrum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9% | EXAMPLE 5 (+/-)8-cyclohexyl-N-[(dimethylamino)sulfonyl]-1,1a,2,12b-tetrahydro-1a-(4-morpholinylcarbonyl)-cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide. A 2M solution of oxalyl chloride (0.093 mL, 0.186 mmol) in CH2Cl2 was added dropwise to a solution of (+/-)-8-cyclohexyl-1,1a,2,12b-tetrahydro-1a-(4-morpholinylcarbonyl)-cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxylic acid (45 mg, 0.093 mmol) in CH2Cl2 (10 mL), containing one drop of DMF. The reaction mixture was stirred at rt. for 2 hr., after which it was concentrated and dried under high vacuum. The residue was subsequently dissolved in THF (10 mL) and a solution of N,N-dimethylsulfonamide, (23 mg, 0.186 mmol) and DIPEA (0.049 mL, 0.279 mmol)) in THF (2 mL) was added. This was followed by the addition of DMAP (10 mg), after which the reaction was stirred at rt. for 10 min., and then at 50° C. overnight. It was then cooled, and the mixture concentrated under reduced pressure. The resultant residue was purified by preparative reverse phase HPLC to afford the product as a yellow solid, (5.0 mg, 9percent yield). MS m/z 591(MH+), Retention time: 3.525 min; 1H NMR (300 MHz, CD3OD) delta ppm. Compound was observed to exist as inter-converting rotamers, as evidenced from the compound's NMR spectrum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | HATU (25 mg, 0.066 mmol) was added to a solution of the acid (6q3, 25 mg,0.039 mmol) and DIPEA (0.035 ml, 0.198 mmol) in DMF (1.4 mL) at rt. The solutionimmediately changed color from colourless to yellow. Then a solution of <strong>[3984-14-3]N,N-dimethylsulfamide</strong> (11 mg, 0.090 mmol) and DMAP (19 mg, 0.16 mmol) in DMF (0.5mL) was added and the reaction was stirred for an additional hour followed by theaddition of DBU (0.03 ml, 0.18 mmol) in DMF (0.5 mL). The reaction was then stirredfor 16h at 23°C. The solvent was removed and dissolved in DMSO (2.5 ml) andpurified by prep HPLC (H2O/CH3CN + 0.06percent TFA) to yield compound 6002 as a whitelyophilized solid (10 mg, 34 percent). MS ES+ = 749.1, ES- = 747.1. 1H NMR, 400 MHz,DMSO-d6: 10.28 (s, 1H); 8.78, (s, 1H); 7.95 (d, J = 5.1 Hz, 1H), 7.35 (d, J = 5.1 Hz,1H); 6.88 (d, J = 8.8 Hz, 1H); 6.47 (s, 1H); 5.53 - 5.62 (m, 1H); 5.41 (s, 1H); 5.22 (d, J= 17.3 Hz, 1H);5.11 (d, J = 10.9 Hz, 1H); 4.65 (s, br, 1H); 4.34-4.39 (m, 4H); 4.20-4.22 (m, 1H); 4.07 (d, J = 9.8 Hz, 1H); 3.96- 3.98 (m, 1H); 2.77 (s, 6H); 2.13-2.19(m, 2H); 1.65 - 1.71 (m, 2H); 1.25 - 1.63 (m, 11 H); 0.95 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; at 55℃; for 12h; | Step 16: Synthesis of N-[17-[2-(3-isopropylpyrazo]-l-yl)-7-methoxy-8-methylquinolin- 4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.Cf'6]octadec-7-ene-4- carbonyl](dimethylamino)sulfonamide (29).; A mixture of 27 (181 mg, 0.29 mmol) and CDI (117 mg, 0.72 mmol) in dry THF (15 mL) was heated at reflux under nitrogen for 50 min. LCMS analysis showed one peak of the intermediate 28, which if needed, can be isolated by column chromatography or can be reacted with the appropriate sulfonamide in a one- pot reaction. The reaction mixture was cooled down to room temperature and dimethylaminosulfonamide (98 mg, 0.79 mmol) was added. Then, DBU (141 mg, 0.92 mmol) was added and the reaction mixture was heated to 550C. After 12 h, the solvent was evaporated, and the residue partitioned between AcOEt and acidic water (pH = 4). The organic layer was EPO <DP n="98"/>dried (Na2SO4) and evaporated under reduced pressure to give a crude material, which was purified by column chromatography (AcOEtZCH2Cb, 25:75) to give 70 mg (33 percent) of the target compound 29 as a white powder: m/z = 736 (M+H)+. 1H NMR (CDCl3): 1.20-1.50 (m, 10H), 1.60- 1.75 (m, IH), 1.79-1.91 (m, 2H), 1.92-2.03 (m, IH), 2.19-2.48 (m, 3H), 2.52-2.63 (m, 5H), 2.89-2.96 (m, 7H), 3.03 (s, 3H), 3.04-3.14 (m, IH), 3.35-3.42 (m, 2H), 3.97 (s, 3H), 4.60 (dt, J = 13.2 Hz, J = 2.2 Hz, IH), 5.05 (t, / = 10.4 Hz, IH), 5.26-3.35 (m, IH), 5.64-5.70 (m, IH), 6.26 (s, IH), 6.32 (d, J = 2.5 Hz, IH), 7.11-7.15 (m, IH), 7.30 (s, IH), 7.95 (d, / = 9.1 Hz, IH), 8.69 (d, / = 2.5 Hz, IH), 10.6 (br s, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl acetamide; at 20 - 45℃; for 3h; | To a stirred solution of 7H-indolo[2,1-a][2]benzazepine-10-carboxamide-6-carboxylic acid, N6-[2-(acetylamino)ethyl]-13-cyclohexyl-3-methoxy (33 mg, 0.06 mmol), <strong>[3984-14-3]N,N-dimethylsulfamide</strong> (64 mg, 0.51 mmol) and DMAP (40 mg, 0.32 mmol) in dimethylacetamide (0.5 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (50 mg, 0.26 mmol). The reaction solution was stirred at rt 1 h and then at 45° C. for 2 h, diluted with MeOH (1 mL) and purified by preparative HPLC (CH3CN/H2O with TFA buffer) to yield 7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxamide, N6-[2-(acetylamino)ethyl]-13-cyclohexyl-N10-[(dimethylamino)sulfonyl]-3-methoxy- (12 mg, 0.02 mmol, 30percent) as a yellow solid. 1HNMR (500 MHz, CDCl3) delta 10.12 (s, 1H), 8.71 (s. 1H), 7.92 (d, J=8.5 Hz, 1H), 7.84 (s, 1H), 7.81 (dd, J=1.2, 8.5 Hz, 1H), 7.77 (br s, 1H), 7.50 (d, J=8.5 Hz, 1H), 7.08 (dd, J=2.8, 8.6 Hz, 1H), 7.03 (d, J=2.8 Hz, 1H), 6.35 (br t, J=6.1 Hz, 1H), 5.24-5.11 (m, 1H), 4.39-4.25 (m, 1H), 3.95 (s, 3H), 3.62-3.23 (m, 4H), 3.03 (s, 6H), 2.87-2.79 (m, 1H), 2.21-1.70 (m, 6H), 2.19 (s, 3H), 1.61-1.14 (m, 4H). LCMS: m/e 620 (M-H)-, ret time 2.43 min, column E, 4 minute gradient. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With dmap; PS-carbodiimide; In N,N-dimethyl acetamide; at 20℃; | To a solution of 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-3-methoxy-6-[[[2-(methylamino)-2-oxoethyl]amino]carbonyl]- (110 mg, 0.22 mmol), <strong>[3984-14-3]N,N-dimethylsulfamide</strong> (136 mg, 1.10 mmol) and DMAP (134 mg, 1.10 mmol) in dimethylformamide (2 mL) was added PS-carbodiimide (576 mg, 1.3 mmol/g, 0.88 mmol). The reaction solution was shaken at rt overnight, filtered, concentrated and purified by preparative HPLC (MeOH/H2O with an NH4OAc buffer) to yield 7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxamide, 13-cyclohexyl-N10-[(dimethylamino)sulfonyl]-3-methoxy-N6-[2-(methylamino)-2-oxoethyl]- (40 mg, 0.07 mmol, 30percent) as a yellow solid. 1HNMR (500 MHz, CD3OD) delta 8.13 (s. 1H), 7.85 (d, J=8.6 Hz, 1H), 7.60-7.52 (m, 3H), 7.15 (dd, J=2.8, 8.8 Hz, 1H), 7.10 (d, J=2.8 Hz, 1H), 5.64-5.53 (m, 1H), 4.19-4.07 (m, 1H), 3.96-3.86 (m, 2H), 3.91 (s, 3H), 2.99 (s, 6H), 2.89-2.80 (m, 1H), 2.71 (s, 3H), 2.16-1.70 (m, 6H), 1.54-1.16 (m, 4H). LCMS: m/e 606 (M-H)-, ret time 1.57 min, column A, 3 minute gradient. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With dmap; PS-carbodiimide; In N,N-dimethyl acetamide; at 45℃; | To a solution of 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[[[2-(dimethylamino)-2-oxoethyl]methylamino]carbonyl]- (180 mg, 0.36 mmol), <strong>[3984-14-3]N,N-dimethylsulfamide</strong> (134 mg, 1.08 mmol) and DMAP (122 mg, 1.08 mmol) in dimethylformamide (2 mL) was added PS-carbodiimide (830 mg, 1.3 mmol/g, 1.08 mmol). The reaction solution was shaken at 45° C. overnight, filtered, concentrated and purified by preparative HPLC (MeOH/H2O with an NH4OAc buffer) to yield 7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxamide, 13-cyclohexyl-N6-[2-(dimethylamino)-2-oxoethyl]-N10-[(dimethylamino)sulfonyl]-N6-methyl- (90 mg, 0.15 mmol, 41percent) as a yellow solid. 1HNMR (300 MHz, CDCl3) delta 8.12 (br s. 1H), 7.88 (d, J=8.8 Hz, 1H), 7.71-7.52 (m, 2H), 7.50-7.35 (m, 3H), 6.86 (s, 1H), 5.15-5.01 (m, 1H), 4.67-4.51 (m, 1H), 3.79-3.62 (m, 1H), 3.14-2.92 (m, 12H), 2.88-2.75 (m, 1H), 2.48 (br s, 3H), 2.10-1.65 (m, 6H), 1.55-1.08 (m, 4H). LCMS: m/e 604 (M-H)-, ret time 2.57 min, column A, 4 minute gradient. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl acetamide; at 50℃; | To a stirred solution of 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[[4-(2-pyrimidinyl)-1-piperazinyl]carbonyl] (125 mg, 0.23 mmol), <strong>[3984-14-3]N,N-dimethylsulfamide</strong> (140 mg, 1.14 mmol) and DMAP (140 mg, 1.14 mmol) in dimethylacetamide (2 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (175 mg, 0.91 mmol). The reaction solution was stirred at 50° C. overnight, concentrated, purified by preparative HPLC (MeOH/2O with NH4OAc buffer) and repurified by preparative HPLC (MeOH/2O with TFA buffer) to yield 7H-indolo[2,1-a][2]benzazepine-10-carboxamide, 13-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-[[4-(2-pyrimidinyl)-1-piperazinyl]carbonyl] (44 mg, 0.067 mol, 29percent) as a yellow solid. 1H NMR (500 MHz, CDCl3) delta 9.23 (br s, 1H), 8.43 (d, J=4.9 Hz, 2H), 8.04 (s, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.60 (br d, J=8.5 Hz, 1H), 7.54-7.45 (m, 3H), 7.42 (br d, J=7.6 Hz, 1H), 6.92 (s, 1H), 6.68 (t, J=4.9 Hz, 1H), 5.16 (br s, 1H), 4.41 (br s, 1H), 3.88-3.46 (m, 8H), 3.03 (s, 6H), 2.90-2.81 (m, 1H), 2.16-1.13 (m, 10H). LCMS: m/e 654 (M+H)+, ret time 2.87 min, column B, 2 minute gradient. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl acetamide; at 50℃; | To a stirred solution of 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[[4-[(1,1-dimethylethoxy)carbonyl]-1-piperazinyl]carbonyl] (100 mg, 0.18 mmol), <strong>[3984-14-3]N,N-dimethylsulfamide</strong> (110 mg, 0.89 mmol) and DMAP (110 mg, 0.90 mmol) in dimethylacetamide (2 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (135 mg, 0.71 mmol). The reaction solution was stirred at 50° C. overnight, concentrated, purified by preparative HPLC (MeOH/2O with NH4OAc buffer) to yield 1-piperazinecarboxylic acid, 4-[[13-cyclohexyl-10-[[[(dimethylamino)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]carbonyl]-, 1,1-dimethylethyl ester (49 mg, 0.073 mol, 40percent) as a yellow solid. 1H NMR (500 MHz, CDCl3) delta 8.10 (s, 1H), 7.91 (d, J=8.6 Hz, 1H), 7.58 (br d, J=7.6 Hz, 1H), 7.63-7.46 (m, 3H), 7.40 (br d, J=7.3 Hz, 1H), 6.87 (s, 1H), 5.15 (br s, 1H), 4.37 (br s, 1H), 3.56-3.22 (m, 8H), 3.06 (s, 6H), 2.89-2.81 (m, 1H), 2.15-1.15 (m, 10H), 1.44 (s, 9H). LCMS: m/e 676 (M+H)+, ret time 2.05 min, column B, 2 minute gradient. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 95℃; for 2h; | To a stirred solution of 3,7-dichloro-5H-pyrido[4',3' :4,5]cyclohepta[l,2-]pyridin-5-one(80 mg, 0.29 mmol) in dioxane (5 mL) were added Pd2(dba)3 (13 mg, 0.014 mmol), 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (25 mg, 0.043 mmol), NN-dimethylsulfamide (36 mg, 0.29 mmol), and Cs2CO3 (0.28 g, 0.87 mmol). The reaction mixture was heated to 95 0C for 2 h, cooled to room <n="62"/>temperature, treated with water, and extracted with EtOAc. The combined organics were washed with brine, dried (Na2SO4), concentrated, and purified by flash chromatography to afford the title compound. 1H NMR (600 MHz, CDCl3) delta 8.79 (d, IH); 8.86 (d, 1H);8.76 (s, IH); 8.66 (br s, IH); 8.54 (d, IH); 7.96 (s, IH); 7.38 (d, IH); 7.27 (d, IH); 2.99 (s, 6H). LRMS (ESI) calc'd for (C15Hi3ClN4O3S) [M+H]+, 365.0; found 365.1. | |
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 95℃; for 2h; | Example 6; N'-(3-chloro-5-oxo-5H-pyridor4',3':4,51cycloheptarL2-^lpyridine-7-yl)-<strong>[3984-14-3]N,N-dimethylsulfamide</strong> (Compound 7); To a stirred solution of 3,7-dichloro-5H-pyrido[4' ,3' :4,5]cyclohepta[l,2-]pyridin-5-one(80 mg, 0.29 mmol) in dioxane (5 mL) were added Pd2(dba)3 (13 mg, 0.014 mmol), 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (25 mg, 0.043 mmol), <strong>[3984-14-3]N,N-dimethylsulfamide</strong> (36 mg, 0.29 mmol), and Cs2CO3 (0.28 g, 0.87 mmol). The reaction mixture was heated to 95 0C for 2 h, cooled to room <n="59"/>temperature, treated with water, and extracted with EtOAc. The combined organics were washed with brine, dried (Na2SO4), concentrated, and purified by flash chromatography to afford the title compound. 1H NMR (600 MHz, CDCl3) delta 8.79 (d, IH); 8.86 (d, 1H);8.76 (s, IH); 8.66 (br s, IH); 8.54 (d, IH); 7.96 (s, IH); 7.38 (d, IH); 7.27 (d, IH); 2.99 (s, 6H). LRMS (ESI) calc'd for (C15H13ClN4O3S) [M+H]+, 365.0; found 365.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Example 16; Preparation of Compound 16: N-(4,6-dimethyl-2-pyridinyl)valyl-(4R)-N-((1R,2S)-1-((dimethylsulfamoyl)carbamoyl)-2-vinylcyclopropyl)-4-((6-methoxy-1-isoquinolinyl)oxy)-L-prolinamide; Step 1:; To a solution of N-Boc-vinylcyclopropane carboxylic acid (1.83 g, 8.05 mmol) and THF (32 mL) was added 1,1'-carbonyldiimidazole (1.44 g, 8.86 mmol). After stirring at room temperature for 3 hours, the reaction mixture was treated with N,N-dimethylsulfamide (1.0 g, 8.05 mmol) followed by DBU (2.45 g, 16.1 mmol) and was stirred at room temperature for an additional 15 hours. The reaction was then diluted with ethyl acetate (50 mL) and washed with 1.0M aqueous HCl (2.x.25 mL). The aqueous layer was extracted with ethyl acetate (2.x.50 mL). The combined organic portion was washed with H2O (25 mL) and brine, dried over MgSO4, filtered, and concentrated to a light yellow solid (2.6 g, 97percent yield) which was used without further purification. LC-MS, MS m/z 356 (M++Na). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | To a 1 L four necked round bottom flask equipped with a mechanical stirrer, a temperature controller, a N2 inlet , and a condenser, under N2, was added 2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (102.0 g, 0.259 mol) and dry THF (300 mL). After stirring for 10 min, CDI (50.3 g, 0.31 mol) was added portion wise. The reaction mixture was then heated to 50° C. for 2 h. After cooling to 30° C., N,N-dimethylaminosulfonamide (41.7 g, 0.336 mol) was added in one portion followed by addition of DBU (54.1 mL, 0.362 mol) drop wise over a period of 1 h. The reaction mixture was then stirred at rt for 20 h. The solvent was removed in vacua and the residue was partitioned between EtOAc and 1 N HCl (1:1, 2 L). The organic layer was separated and the aqueous layer was extracted with EtOAc (500 mL). The combined organic layers were washed with brine (1.5 L) and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude product (111.0 g). The crude product was suspended in EtOAc (400 mL) at 60° C. To the suspension was added heptane (2 L) slowly. The resulting suspension was stirred and cooled to 0° C. It was then filtered. The filter cake was rinsed with small amount of heptane and house vacuum air dried for 2 days. The product was collected as a white solid (92.0 g, 83percent). 1H NMR (MeOD, 300 MHz) delta 7.89 (s, H), 7.77 (d, J=8.4 Hz, 1H), 7.55 (dd, J=8.4 and 1.8 Hz, 1H), 3.01 (s, 6H), 2.73-2.95 (m, 1H), 1.81-2.05 (m, 8H), 1.39-1.50 (m, 2H); m/z 429 (M+H)+. | |
74 - 83% | Intermediate 3; lH-Indole-6-carboxamide, 2-bromo-3-cyclohexyl-N- [(dimethylamino)sulfonyl]-.; l,l'-Carbonyldiimidazole (1.17 g, 7.2 mmol) was added to a stirred solution of 2-bromo-3-cyclohexyl-lH-indole-6-carboxylic acid (2.03 g, 6.3 mmol) in THF (6 mL) at 22 0C. The evolution of CO2 was instantaneous and when it slowed the solution was heated at 500C for 1 hr and then cooled to 220C. N,N-Dimethylsulfamide (0.94 g, 7.56 mmol) was added followed by the dropwise addition of a solution of DBU (1.34 g ,8.8 mmol) in THF (4 mL). Stirring was continued for 24 hr. The mixture was partitioned between ethyl acetate and dilute HCl. The ethyl acetate layer was washed with water followed by brine and dried over Na2SO4. The extract was concentrated to dryness to leave the title product as a pale yellow friable foam, (2.0 g, 74 percent, >90 percent purity , estimated from NMR). 1H NMR (300 MHz, DMSO-D6) delta ppm 1.28 - 1.49 (m, 3 H) 1.59 - 2.04 (m, 7 H) 2.74 - 2.82 (m, 1 H) 2.88 (s, 6 H) 7.57 (dd, J=8.42, 1.46 Hz, 1 H) 7.74 (d, J=8.78 Hz, 1 H) 7.91 (s, 1 H) 11.71 (s, 1 H) 12.08 (s, 1 H).; An alternative method for the preparation of lH-indole-6-carboxamide, 2- bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]- is described below. <n="44"/>To a 1 L four necked round bottom flask equipped with a mechanical stirrer, a temperature controller, a N2 inlet , and a condenser, under N2, was added 2-bromo-3- cyclohexyl-lH-indole-6-carboxylic acid (102.0 g, 0.259 mol) and dry TetaF (300 mL). After stirring for 10 min, CDI (50.3 g, 0.31 mol) was added portion wise. The reaction mixture was then heated to 50 oC for 2 h. After cooling to 30 oC, N,N- dimethylaminosulfonamide (41.7 g, 0.336 mol) was added in one portion followed by addition of DBU (54.1 mL, 0.362 mol) drop wise over a period of 1 h. The reaction mixture was then stirred at rt for 20 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc and 1 nu HCl (1 : 1, 2 L). The organic layer was separated and the aqueous layer was extracted with EtOAc (500 mL). The combined organic layers were washed with brine (1.5 L) and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude product (111.0 g). The crude product was suspended in EtOAc (400 mL) at 60 oC. To the suspension was added heptane (2 L) slowly. The resulting suspension was stirred and cooled to 0 oC. It was then filtered. The filter cake was rinsed with small amount of heptane and house vacuum air dried for 2 days. The product was collected as a white solid (92.0 g, 83percent). 1H nuMR (MeOD, 300 MHz) delta 7.89 (s, H), 7.77 (d, J= 8.4 Hz, IH), 7.55 (dd, J= 8.4 and 1.8 Hz, IH), 3.01 (s, 6H), 2.73-2.95 (m, IH), 1.81-2.05 (m, 8H), 1.39-1.50 (m, 2H); m/z 429 (M +H)+. | |
74 - 83% | 1,1'-Carbonyldiimidazole (1.17 g, 7.2 mmol) was added to a stirred solution of 2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (2.03 g, 6.3 mmol) in THF (6 mL) at 22° C. The evolution of CO2 was instantaneous and when it slowed the solution was heated at 50° C. for 1 hr and then cooled to 22° C. N,N-Dimethylsulfamide (0.94 g, 7.56 mmol) was added followed by the dropwise addition of a solution of DBU (1.34 g, 8.8 mmol) in THF (4 mL). Stirring was continued for 24 hr. The mixture was partitioned between ethyl acetate and dilute HCl. The ethyl acetate layer was washed with water followed by brine and dried over Na2SO4. The extract was concentrated to dryness to leave the title product as a pale yellow friable foam, (2.0 g, 74percent, >90percent purity, estimated from NMR). 1H NMR (300 MHz, DMSO-D6) delta ppm 1.28-1.49 (m, 3H) 1.59-2.04 (m, 7H) 2.74-2.82 (m, 1H) 2.88 (s, 6H) 7.57 (dd, J=8.42, 1.46 Hz, 1H) 7.74 (d, J=8.78 Hz, 1H) 7.91 (s, 1H) 11.71 (s, 1H) 12.08 (s, 1H).An alternative method for the preparation of 1H-indole-6-carboxamide, 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]- is described below.To a 1 L four necked round bottom flask equipped with a mechanical stirrer, a temperature controller, a N2 inlet, and a condenser, under N2, was added 2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (102.0 g, 0.259 mol) and dry THF (300 mL). After stirring for 10 min, CDI (50.3 g, 0.31 mol) was added portion wise. The reaction mixture was then heated to 50° C. for 2 h. After cooling to 30° C., N,N-dimethylaminosulfonamide (41.7 g, 0.336 mol) was added in one portion followed by addition of DBU (54.1 mL, 0.362 mol) drop wise over a period of 1 h. The reaction mixture was then stirred at rt for 20 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc and 1 N HCl (1:1, 2 L). The organic layer was separated and the aqueous layer was extracted with EtOAc (500 mL). The combined organic layers were washed with brine (1.5 L) and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude product (111.0 g). The crude product was suspended in EtOAc (400 mL) at 60° C. To the suspension was added heptane (2 L) slowly. The resulting suspension was stirred and cooled to 0° C. It was then filtered. The filter cake was rinsed with small amount of heptane and house vacuum air dried for 2 days. The product was collected as a white solid (92.0 g, 83percent). 1H NMR (MeOD, 300 MHz) delta 7.89 (s, H), 7.77 (d, J=8.4 Hz, 1H), 7.55 (dd, J=8.4 and 1.8 Hz, 1H), 3.01 (s, 6H), 2.73-2.95 (m, 1H), 1.81-2.05 (m, 8H), 1.39-1.50 (m, 2H); m/z 429 (M+H)+. |
74% | 2-Bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-1H-indole-6-carboxamide 1,1'-Carbonyldiimidazole (1.17 g, 7.2 mmol) was added to a stirred solution of 2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (2.03 g, 6.3 mmol) in THF (6 mL) at 22.box. C. The evolution of CO2 was instantaneous and when it slowed the solution was heated at 50° C. for 1 hr and then cooled to 22.box. C. N,N-Dimethylsulfamide (0.94 g, 7.56 mmol) was added followed by the dropwise addition of a solution of DBU (1.34 g, 8.8 mmol) in THF (4 mL). Stirring was continued for 24 hr. The mixture was partitioned between ethyl acetate and dilute HCl. The ethyl acetate layer was washed with water followed by brine and dried over Na2SO4. The extract was concentrated to dryness to leave the titled product as a pale yellow friable froth (2.0 g, 74percent) of substantial purity (90percent). 1H NMR (300 MHz, DMSO-D6) .box. ppm 1.28-1.49 (m, 3 H) 1.59-2.04 (m, 7 H) 2.74-2.82 (m, 1 H) 2.88 (s, 6 H) 7.57 (dd, J=8.42, 1.46 Hz, 1 H) 7.74 (d, J=8.78 Hz, 1 H) 7.91 (s, 1 H) 11.71 (s, 1 H) 12.08 (s, 1 H). | |
74% | 2-Bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-1H-indole-6-carboxamide;. 1,1'-Carbonyldiimidazole (1.17 g, 7.2 mmol) was added to a stirred solution of 2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (2.03 g, 6.3 mmol) in THF (6 mL) at 22° C. The evolution of CO2 was instantaneous and when it slowed the solution was heated at 50° C. for 1 hr and then cooled to 22° C. N,N-Dimethylsulfamide (0.94 g, 7.56 mmol) was added followed by the dropwise addition of a solution of DBU (1.34 g, 8.8 mmol) in THF (4 mL). Stirring was continued for 24 hr. The mixture was partitioned between ethyl acetate and dilute HCl. The ethyl acetate layer washed with water followed by brine and dried over Na2SO4. The extract was concentrated to dryness to leave the title product as a pale yellow friable foam, (2.0 g, 74percent, >90percent purity, estimated from NMR). 1H NMR (300 MHz, DMSO-D6) delta ppm 1.28-1.49 (m, 3H) 1.59-2.04 (m, 7H) 2.74-2.82 (m, 1H) 2.88 (s, 6H) 7.57 (dd, J=8.42, 1.46 Hz, 1H) 7.74 (d, J=8.78 Hz, 1H) 7.91 (s, 1H) 11.71 (s, 1H) 12.08 (s, 1H). | |
74 - 83% | 1H-Indole-6-carboxamide, 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-.; 1,1'-Carbonyldiimidazole (1.17 g, 7.2 mmol) was added to a stirred solution of 2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (2.03 g, 6.3 mmol) in THF (6 mL) at 22° C. The evolution of CO2 was instantaneous and when it slowed the solution was heated at 50° C. for 1 hr and then cooled to 22° C. N,N-Dimethylsulfamide (0.94 g, 7.56 mmol) was added followed by the dropwise addition of a solution of DBU (1.34 g, 8.8 mmol) in THF (4 mL). Stirring was continued for 24 hr. The mixture was partitioned between ethyl acetate and dilute HCl. The ethyl acetate layer was washed with water followed by brine and dried over Na2SO4. The extract was concentrated to dryness to leave the title product as a pale yellow friable foam, (2.0 g, 74percent, >90percent purity, estimated from NMR). 1H NMR (300 MHz, DMSO-D6) delta ppm 1.28-1.49 (m, 3 H) 1.59-2.04 (m, 7 H) 2.74-2.82 (m, 1 H) 2.88 (s, 6 H) 7.57 (dd, J=8.42, 1.46 Hz, 1 H) 7.74 (d, J=8.78 Hz, 1 H) 7.91 (s, 1 H) 11.71 (s, 1 H) 12.08 (s, 1 H).; An alternative method for the preparation of 1H-indole-6-carboxamide, 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]- is described below.; To a 1 L four necked round bottom flask equipped with a mechanical stirrer, a temperature controller, a N2 inlet, and a condenser, under N2, was added 2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (102.0 g, 0.259 mol) and dry THF (300 mL). After stirring for 10 min, CDI (50.3 g, 0.31 mol) was added portion wise. The reaction mixture was then heated to 50 oC for 2 h. After cooling to 30 oC, N,N-dimethylaminosulfonamide (41.7 g, 0.336 mol) was added in one portion followed by addition of DBU (54.1 mL, 0.362 mol) drop wise over a period of 1 h. The reaction mixture was then stirred at rt for 20 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc and 1 N HCl (1:1, 2 L). The organic layer was separated and the aqueous layer was extracted with EtOAc (500 mL). The combined organic layers were washed with brine (1.5 L) and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude product (111.0 g). The crude product was suspended in EtOAc (400 mL) at 60 oC. To the suspension was added heptane (2 L) slowly. The resulting suspension was stirred and cooled to 0 oC. It was then filtered. The filter cake was rinsed with small amount of heptane and house vacuum air dried for 2 days. The product was collected as a white solid (92.0 g, 83percent). 1H NMR (MeOD, 300 MHz) delta 7.89 (s, H), 7.77 (d, J=8.4 Hz, 1H), 7.55 (dd, J=8.4 and 1.8 Hz, 1H), 3.01 (s, 6H), 2.73-2.95 (m, 1H), 1.81-2.05 (m, 8H), 1.39-1.50 (m, 2H); m/z 429 (M+H)+. | |
74 - 83% | Intermediate 3 1H-Indole-6-carboxamide, 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-. 1,1'-Carbonyldiimidazole (1.17 g, 7.2 mmol) was added to a stirred solution of 2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (2.03 g, 6.3 mmol) in THF (6 mL) at 22° C. The evolution of CO2 was instantaneous and when it slowed the solution was heated at 50° C. for 1 hr and then cooled to 22° C. N,N-Dimethylsulfamide (0.94 g, 7.56 mmol) was added followed by the dropwise addition of a solution of DBU (1.34 g, 8.8 mmol) in THF (4 mL). Stirring was continued for 24 hr. The mixture was partitioned between ethyl acetate and dilute HCl. The ethyl acetate layer was washed with water followed by brine and dried over Na2SO4. The extract was concentrated to dryness to leave the title product as a pale yellow friable foam, (2.0 g, 74percent, >90percent purity, estimated from NMR). 1H NMR (300 MHz, DMSO-D6) delta ppm 1.28-1.49 (m, 3H) 1.59-2.04 (m, 7H) 2.74-2.82 (m, 1H) 2.88 (s, 6H) 7.57 (dd, J=8.42, 1.46 Hz, 1H) 7.74 (d, J=8.78 Hz, 1H) 7.91 (s, 1H) 11.71 (s, 1H) 12.08 (s, 1H).An alternative method for the preparation of 1H-indole-6-carboxamide, 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]- is described below.To a 1 L four necked round bottom flask equipped with a mechanical stirrer, a temperature controller, a N2 inlet, and a condenser, under N2, was added 2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (102.0 g, 0.259 mol) and dry THF (300 mL). After stirring for 10 min, CDI (50.3 g, 0.31 mol) was added portion wise. The reaction mixture was then heated to 50 oC for 2 h. After cooling to 30 oC, N,N-dimethylaminosulfonamide (41.7 g, 0.336 mol) was added in one portion followed by addition of DBU (54.1 mL, 0.362 mol) drop wise over a period of 1 h. The reaction mixture was then stirred at rt for 20 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc and 1 N HCl (1:1, 2 L). The organic layer was separated and the aqueous layer was extracted with EtOAc (500 mL). The combined organic layers were washed with brine (1.5 L) and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude product (111.0 g). The crude product was suspended in EtOAc (400 mL) at 60 oC. To the suspension was added heptane (2 L) slowly. The resulting suspension was stirred and cooled to 0 oC. It was then filtered. The filter cake was rinsed with small amount of heptane and house vacuum air dried for 2 days. The product was collected as a white solid (92.0 g, 83percent). 1H NMR (MeOD, 300 MHz) delta 7.89 (s, H), 7.77 (d, J=8.4 Hz, 1H), 7.55 (dd, J=8.4 and 1.8 Hz, 1H), 3.01 (s, 6H), 2.73-2.95 (m, 1H), 1.81-2.05 (m, 8H), 1.39-1.50 (m, 2H); m/z 429 (M+H)+. | |
74% | 1,1'-Carbonyldiimidazole (1.17 g, 7.2 mmol) was added to a stirred solution of 2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (2.03 g, 6.3 mmol) in THF (6 mL) at 22° C. The evolution of CO2 was instantaneous and when it slowed the solution was heated at 50° C. for 1 hr and then cooled to 22° C. N,N-Dimethylsulfamide (0.94 g, 7.56 mmol) was added followed by the dropwise addition of a solution of DBU (1.34 g, 8.8 mmol) in THF (4 mL). Stirring was continued for 24 hr. The mixture was partitioned between ethyl acetate and dilute HCl. The ethyl acetate layer was washed with water followed by brine and dried over Na2SO4. The extract was concentrated to dryness to leave the title product as a pale yellow friable foam, (2.0 g, 74percent, >90percent purity, estimated from NMR). 1H NMR (300 MHz, DMSO-D6) delta ppm 1.28-1.49 (m, 3 H) 1.59-2.04 (m, 7 H) 2.74-2.82 (m, 1 H) 2.88 (s, 6 H) 7.57 (dd, J=8.42, 1.46 Hz, 1 H) 7.74 (d, J=8.78 Hz, 1 H) 7.91 (s, 1 H) 11.71 (s, 1 H) 12.08 (s, 1 H). | |
74 - 83% | 1,1'-Carbonyldiimidazole (1.17 g, 7.2 mmol) was added to a stirred solution of 2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (2.03 g, 6.3 mmol) in THF (6 mL) at 22° C. The evolution of CO2 was instantaneous and when it slowed the solution was heated at 50° C. for 1 hr and then cooled to 22° C. N,N-Dimethylsulfamide (0.94 g, 7.56 mmol) was added followed by the dropwise addition of a solution of DBU (1.34 g, 8.8 mmol) in THF (4 mL). Stirring was continued for 24 hr. The mixture was partitioned between ethyl acetate and dilute HCl. The ethyl acetate layer was washed with water followed by brine and dried over Na2SO4. The extract was concentrated to dryness to leave the title product as a pale yellow friable foam, (2.0 g, 74percent, >90percent purity, estimated from NMR). 1H NMR (300 MHz, DMSO-D6) delta ppm 1.28-1.49 (m, 3 H) 1.59-2.04 (m, 7 H) 2.74-2.82 (m, 1 H) 2.88 (s, 6 H) 7.57 (dd, J=8.42, 1.46 Hz, 1 H) 7.74 (d, J=8.78 Hz, 1 H) 7.91 (s, 1 H) 11.71 (s, 1 H) 12.08 (s, 1 H).; An alternative method for the preparation of 1H-indole-6-carboxamide, 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]- is described below.To a 1 L four necked round bottom flask equipped with a mechanical stirrer, a temperature controller, a N2 inlet, and a condenser, under N2, was added 2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (102.0 g, 0.259 mol) and dry THF (300 mL). After stirring for 10 min, CDI (50.3 g, 0.31 mol) was added portion wise. The reaction mixture was then heated to 50 oC for 2 h. After cooling to 30 oC, N,N-dimethylaminosulfonamide (41.7 g, 0.336 mol) was added in one portion followed by addition of DBU (54.1 mL, 0.362 mol) drop wise over a period of 1 h. The reaction mixture was then stirred at rt for 20 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc and 1 N HCl (1:1, 2 L). The organic layer was separated and the aqueous layer was extracted with EtOAc (500 mL). The combined organic layers were washed with brine (1.5 L) and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude product (111.0 g). The crude product was suspended in EtOAc (400 mL) at 60 oC. To the suspension was added heptane (2 L) slowly. The resulting suspension was stirred and cooled to 0 oC. It was then filtered. The filter cake was rinsed with small amount of heptane and house vacuum air dried for 2 days. The product was collected as a white solid (92.0 g, 83percent). 1H NMR (MeOD, 300 MHz) delta 7.89 (s, H), 7.77 (d, J=8.4 Hz, 1H), 7.55 (dd, J=8.4 and 1.8 Hz, 1H), 3.01 (s, 6H), 2.73-2.95 (m, 1H), 1.81-2.05 (m, 8H), 1.39-1.50 (m, 2H); m/z 429 (M+H)+. | |
74 - 83% | A mixture of the 2-Bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-1H-indole-6-carboxamide (4.28 g, 0.01 mol), 4-methoxy-2-formylphenyl boronic acid (2.7 g, 0.015 mol), 2-dicyclohexylphosphino-2',6'-dimethoxy-biphenyl (41 mg, 0.0001 mol), palladium acetate (11.2 mg), and finely ground potassium carbonate (4.24 g, 0.02 mol) in toluene (30 mL) was stirred under reflux and under nitrogen for 30 min, at which time LC/MS analysis showed the reaction to be complete. The reaction mixture was then diluted with ethyl acetate and water, and then acidified with an excess of dilute HCl. The ethyl acetate layer was then collected and washed with dilute HCl, water and brine. The organic solution was then dried (magnesium sulfate), filtered and concentrated to give a gum. The gum was diluted with hexanes (250 ml) and ethyl acetate (25 mL), and the mixture was stirred for 20 hr at 22° C. during which time the product was transformed into a bright yellow granular solid (4.8 g) which was used directly without further purification.An alternative procedure for the preparation of 1H-indole-6-carboxamide, 3-cyclohexyl-N-[(dimethylamino)sulfonyl]-2-(2-formyl-4-methoxyphenyl)- is provided below:To a slurried solution of 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-indole-6-carboxamide (54.0 g, 126 mmol), 4-methoxy-2-formylphenylboronic acid (29.5 g, 164 mmol) and LiCl (13.3 g, 315 mmol) in EtOH/toluene (1:1, 1 L) was added a solution of Na2CO3 (40.1 g, 379 mmol) in water (380 mL). The reaction mixture was stirred 10 min. and then Pd(PPh3)4 (11.3 g, 10.0 mmol) was added. The reaction solution was flushed with nitrogen and heated at 70° C. (internal monitoring) overnight and then cooled to rt. The reaction was diluted with EtOAc (1 L) and EtOH (100 mL), washed carefully with 1N aqueous HCl (1 L) and brine (500 mL), dried (MgSO4), filtered and concentrated. The residual solids were stirred with Et2O (600 mL) for 1 h and collected by filtration to yield 1H-indole-6-carboxamide, 3-cyclohexyl-N-[(dimethylamino)sulfonyl]-2-(2-formyl-4-methoxyphenyl)- (52.8 g, 109 mmol, 87percent) as a yellow powder which was used without further purification.1HNMR (300 MHz, d6-DMSO) delta 11.66 (s, 1H), 8.17 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.59 (dd, J=1.4, 8.4 Hz, 1H), 7.23-7.16 (m, 2H), 7.08 (dd, J=2.6, 8.4 Hz, 1H), 6.54 (d, J=8.8 Hz, 1H), 3.86 (s, 3H), 3.22-3.08 (m, 1H), 2.91 (s, 6H), 2.00-1.74 (m, 7H), 1.60-1.38 (m, 3H). 13CNMR (75 MHz, CDCl3) delta 165.7, 158.8, 147.2, 139.1, 134.3, 132.0, 123.4, 122.0, 119.2, 118.2, 114.8, 112.3, 110.4, 109.8, 79.6, 45.9, 37.2(2), 34.7, 32.0(2), 25.9(2), 24.9. LCMS: m/e 482 (M-H)-, ret time 2.56 min, column A, 4 minute gradient. | |
74 - 83% | 1,1'-Carbonyldiimidazole (1.17 g, 7.2 mmol) was added to a stirred solution of 2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (2.03 g, 6.3 mmol) in THF (6 mL) at 22° C. The evolution of CO2 was instantaneous and when it slowed the solution was heated at 50° C. for 1 hr and then cooled to 22° C. N,N-Dimethylsulfamide (0.94 g, 7.56 mmol) was added followed by the dropwise addition of a solution of DBU (1.34 g, 8.8 mmol) in THF (4 mL). Stirring was continued for 24 hr. The mixture was partitioned between ethyl acetate and dilute HCl. The ethyl acetate layer was washed with water followed by brine and dried over Na2SO4. The extract was concentrated to dryness to leave the title product as a pale yellow friable foam, (2.0 g, 74percent, >90percent purity, estimated from NMR). 1H NMR (300 MHz, DMSO-D6) delta ppm 1.28-1.49 (m, 3H) 1.59-2.04 (m, 7H) 2.74-2.82 (m, 1H) 2.88 (s, 6H) 7.57 (dd, J=8.42, 1.46 Hz, 1H) 7.74 (d, J=8.78 Hz, 1H) 7.91 (s, 1H) 11.71 (s, 1H) 12.08 (s, 1H).An alternative method for the preparation of 1H-indole-6-carboxamide, 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-is described below.To a 1 L four necked round bottom flask equipped with a mechanical stirrer, a temperature controller, a N2 inlet, and a condenser, under N2, was added 2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (102.0 g, 0.259 mol) and dry THF (300 mL). After stirring for 10 min, CDI (50.3 g, 0.31 mol) was added portion wise. The reaction mixture was then heated to 50 oC for 2 h. After cooling to 30 oC, N,N-dimethylaminosulfonamide (41.7 g, 0.336 mol) was added in one portion followed by addition of DBU (54.1 mL, 0.362 mol) drop wise over a period of 1 h. The reaction mixture was then stirred at rt for 20 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc and 1 N HCl (1:1, 2 L). The organic layer was separated and the aqueous layer was extracted with EtOAc (500 mL). The combined organic layers were washed with brine (1.5 L) and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude product (111.0 g). The crude product was suspended in EtOAc (400 mL) at 60 oC. To the suspension was added heptane (2 L) slowly. The resulting suspension was stirred and cooled to 0 oC. It was then filtered. The filter cake was rinsed with small amount of heptane and house vacuum air dried for 2 days. The product was collected as a white solid (92.0 g, 83percent). 1H NMR (MeOD, 300 MHz) delta 7.89 (s, H), 7.77 (d, J=8.4 Hz, 1H), 7.55 (dd, J=8.4 and 1.8 Hz, 1H), 3.01 (s, 6H), 2.73-2.95 (m, 1H), 1.81-2.05 (m, 8H), 1.39-1.50 (m, 2H); m/z 429 (M+H)+. | |
74 - 83% | Intermediate 3 1H-Indole-6-carboxamide, 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-. 1,1'-Carbonyldiimidazole (1.17 g, 7.2 mmol) was added to a stirred solution of 2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (2.03 g, 6.3 mmol) in THF (6 mL) at 22° C. The evolution of CO2 was instantaneous and when it slowed the solution was heated at 50° C. for 1 hr and then cooled to 22° C. N,N-Dimethylsulfamide (0.94 g, 7.56 mmol) was added followed by the dropwise addition of a solution of DBU (1.34 g ,8.8 mmol) in THF (4 mL). Stirring was continued for 24 hr. The mixture was partitioned between ethyl acetate and dilute HCl. The ethyl acetate layer was washed with water followed by brine and dried over Na2SO4. The extract was concentrated to dryness to leave the title product as a pale yellow friable foam, (2.0 g, 74percent, >90percent purity, estimated from NMR). 1H NMR (300 MHz, DMSO-D6) delta ppm 1.28-1.49 (m, 3 H) 1.59-2.04 (m, 7 H) 2.74-2.82 (m, 1 H) 2.88 (s, 6 H) 7.57 (dd, J=8.42, 1.46 Hz, 1 H) 7.74 (d, J=8.78 Hz, 1 H) 7.91 (s, 1 H) 11.71 (s, 1 H) 12.08 (s, 1 H).An alternative method for the preparation of 1H-indole-6-carboxamide, 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]- is described below.To a 1 L four necked round bottom flask equipped with a mechanical stirrer, a temperature controller, a N2 inlet, and a condenser, under N2, was added 2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (102.0 g, 0.259 mol) and dry THF (300 mL). After stirring for 10 min, CDI (50.3 g, 0.31 mol) was added portion wise. The reaction mixture was then heated to 50° C. for 2 h. After cooling to 30° C., N,N-dimethylaminosulfonamide (41.7 g, 0.336 mol) was added in one portion followed by addition of DBU (54.1 mL, 0.362 mol) drop wise over a period of 1 h. The reaction mixture was then stirred at rt for 20 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc and 1 N HCl (1:1, 2 L). The organic layer was separated and the aqueous layer was extracted with EtOAc (500 mL). The combined organic layers were washed with brine (1.5 L) and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude product (111.0 g). The crude product was suspended in EtOAc (400 mL) at 60° C. To the suspension was added heptane (2 L) slowly. The resulting suspension was stirred and cooled to 0° C. It was then filtered. The filter cake was rinsed with small amount of heptane and house vacuum air dried for 2 days. The product was collected as a white solid (92.0 g, 83percent). 1H NMR (MeOD, 300 MHz) delta 7.89 (s, H), 7.77 (d, J=8.4 Hz, 1H), 7.55 (dd, J=8.4 and 1.8 Hz, 1H), 3.01 (s, 6H), 2.73-2.95 (m, 1H), 1.81-2.05 (m, 8H), 1.39-1.50 (m, 2H); m/z 429 (M+H)+. | |
74 - 83% | 1,1'-Carbonyldiimidazole (1.17 g, 7.2 mmol) was added to a stirred solution of 2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (2.03 g, 6.3 mmol) in THF (6 mL) at 22° C. The evolution of CO2 was instantaneous and when it slowed the solution was heated at 50° C. for 1 hr and then cooled to 22° C. N,N-Dimethylsulfamide (0.94 g, 7.56 mmol) was added followed by the dropwise addition of a solution of DBU (1.34 g, 8.8 mmol) in THF (4 mL). Stirring was continued for 24 hr. The mixture was partitioned between ethyl acetate and dilute HCl. The ethyl acetate layer was washed with water followed by brine and dried over Na2SO4. The extract was concentrated to dryness to leave the title product as a pale yellow friable foam, (2.0 g, 74percent, >90percent purity, estimated from NMR). 1H NMR (300 MHz, DMSO-D6) delta ppm 1.28-1.49 (m, 3H) 1.59-2.04 (m, 7H) 2.74-2.82 (m, 1H) 2.88 (s, 6H) 7.57 (dd, J=8.42, 1.46 Hz, 1H) 7.74 (d, J=8.78 Hz, 1H) 7.91 (s, 1H) 11.71 (s, 1H) 12.08 (s, 1H).An alternative method for the preparation of 1H-indole-6-carboxamide, 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]- is described below.To a 1 L four necked round bottom flask equipped with a mechanical stirrer, a temperature controller, a N2 inlet, and a condenser, under N2, was added 2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (102.0 g, 0.259 mol) and dry THF (300 mL). After stirring for 10 min, CDI (50.3 g, 0.31 mol) was added portion wise. The reaction mixture was then heated to 50 oC. for 2 h. After cooling to 30 oC., N,N-dimethylaminosulfonamide (41.7 g, 0.336 mol) was added in one portion followed by addition of DBU (54.1 mL, 0.362 mol) drop wise over a period of 1 h. The reaction mixture was then stirred at rt for 20 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc and 1 N HCl (1:1, 2 L). The organic layer was separated and the aqueous layer was extracted with EtOAc (500 mL). The combined organic layers were washed with brine (1.5 L) and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude product (111.0 g). The crude product was suspended in EtOAc (400 mL) at 60 oC. To the suspension was added heptane (2 L) slowly. The resulting suspension was stirred and cooled to 0 oC. It was then filtered. The filter cake was rinsed with small amount of heptane and house vacuum air dried for 2 days. The product was collected as a white solid (92.0 g, 83percent). 1H NMR (MeOD, 300 MHz) delta 7.89 (s, H), 7.77 (d, J=8.4 Hz, 1H), 7.55 (dd, J=8.4 and 1.8 Hz, 1H), 3.01 (s, 6H), 2.73-2.95 (m, 1H), 1.81-2.05 (m, 8H), 1.39-1.50 (m, 2H); m/z 429 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21.87% | lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-10- [[[(dimethylamino)sulfonyl] amino] carbonyl]-3-methoxy-7H-indolo[2,l- a][2]benzazepin-6-yl]-l,3-dimethyl-, methyl ester.; To a solution of 7H-indolo[2,l-alpha][2]benzazepine-10-carboxylic acid, 13- cyclohexyl-S-methoxy--^-^ethoxycarbony^-l^-dimethyl-lH-pyrazol-S-yl]- (120 mg, 0.222 mmol) in TetaF (5 mL), CDI (54.1 mg, 0.334 mmol) was added. The reaction mixture was heated at 6O0C for one hour, and then allowed to cool to room temperature. <strong>[3984-14-3]N,N-dimethylsulfamide</strong> (83 mg, 0.667 mmol) and DBU (0.067 mL,0.445 mmol) were then added and the resultant mixture was heated at 6O0C overnight. The reaction was then quenched with IN HCl solution and the product extracted with ethyl acetate (2 x 3OmL). The organic layers were combined, washed with IN HCl solution, brine, dried (MgSC^) and then filtered. Evaporation of solvents gave the curde product as an orange colored thick oil. This material was then purified by preparative etaPLC using Ceta3CN-eta2O-TFA as a solvent system.Homogeneous fractions were combined and concentrated under vacuum to provide the title compound as an orange colored solid, (31.4 mg, 0.049 mmol, 21.87 percent yield). MS m/z 646(MH+), Retention time: 2.245min. (basic). IH NMR (500 MHz, CHLOROFORM-D) delta ppm 1.18 - 1.60 (m, 4 H) 1.70 - 2.14 (m, 6 H) 2.49 (s, 3 H) 2.80 - 2.91 (m, 1 H) 3.05 (s, 6 H) 3.24 (s, 3 H) 3.68 (s, br, 3 H) 3.91 (s, 3 H) 4.64 -4.74 (m, br, 1 H) 4.86 - 5.00 (m, br, 1 H) 6.74 (s, 1 H) 6.94 (d, J=2.75 Hz, 1 H) 7.08 (dd, J=8.85, 2.75 Hz, 1 H) 7.35 (dd, J=8.55, 1.53 Hz, 1 H) 7.53 (d, J=8.55 Hz, 1 H)7.75 (d, J=1.22 Hz, 1 H) 7.89 (d, J=8.54 Hz, 1 H) 8.44 (s, 1 H). | |
lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-10- [[[(dimethylamino)sulfonyl] amino] carbonyl]-3-methoxy-7H-indolo[2,l- a][2]benzazepin-6-yl]-l,3-dimethyl-, methyl ester.To a solution of 7H-indolo[2,l-alpha][2]benzazepine-10-carboxylic acid, 13- cyclohexyl-S-methoxy--^-^ethoxycarbony^-l^-dimethyl-lH-pyrazol-S-yl]- (120 mg, 0.222 mmol) in TEtaF (5 mL), CDI (54.1 mg, 0.334 mmol) was added. The reaction mixture was heated at 6O0C for one hour, and then allowed to cool to room temperature. <strong>[3984-14-3]N,N-dimethylsulfamide</strong> (83 mg, 0.667 mmol) and DBU (0.067 mL,0.445 mmol) were then added and the resultant mixture was heated at 6O0C overnight. The reaction was then quenched with IN HCl solution and the product extracted with ethyl acetate (2 x 3OmL). The organic layers were combined, washed with IN HCl solution, brine, dried (MgSC^) and then filtered. Evaporation of solvents gave the curde product as an orange colored thick oil. This material was then purified by preparative EtaPLC using CEta3CN-Eta2O-TFA as a solvent system.Homogeneous fractions were combined and concentrated under vacuum to provide the title compound as an orange colored solid, (31.4 mg, 0.049 mmol, 21.87 percent yield). MS m/z 646(MH+), Retention time: 2.245min. (basic). IH NMR (500 MHz, CHLOROFORM-D) delta ppm 1.18 - 1.60 (m, 4 H) 1.70 - 2.14 (m, 6 H) 2.49 (s, 3 H) 2.80 - 2.91 (m, 1 H) 3.05 (s, 6 H) 3.24 (s, 3 H) 3.68 (s, br, 3 H) 3.91 (s, 3 H) 4.64 -4.74 (m, br, 1 H) 4.86 - 5.00 (m, br, 1 H) 6.74 (s, 1 H) 6.94 (d, J=2.75 Hz, 1 H) 7.08 (dd, J=8.85, 2.75 Hz, 1 H) 7.35 (dd, J=8.55, 1.53 Hz, 1 H) 7.53 (d, J=8.55 Hz, 1 H)7.75 (d, J=1.22 Hz, 1 H) 7.89 (d, J=8.54 Hz, 1 H) 8.44 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | A mixture of compound 24-3 (0.465 g, 0.98 mmol) and CDI (0.245 g, 1.57 mmol) in THF (2 mL) was heated at 50° C. for 0.5 h, cooled down and added N,N dimethylsulfamide (0.194 g, 157 mmol) and DBU (0.264 mL, 1.77 mmol). The mixture was stirred for over night. Another portion of DBU (0.13 mL, 0.9 mmol) and the mixture was stirred for another 3 days. The mixture was diluted with EtOAc, washed with cold 1N HCl, brine, dried removed the solvent and purified by flash to afford the Compound 24-4 (0.52 g, 91percent). LC-MS retention time: 3.470; MS m/z 579 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl acetamide; at 60℃; for 2h; | Example 4; 10-Cyclohexyl-N-((dimethylamino)sulfonyl)-l-methyl~4H-indolo[l,2- d] ' [1,2,4] triazolo[4,3-a] [1,4] benzodiazepine-? -carboxamide.; To a solution of 10- cyclohexyl- 1 -methyl-4i/-indolo [ 1 ,2-d] [ 1 ,2 ,4]triazolo[4 ,3-a] [ 1 ,4]benzodiazepine-7- carboxylic acid (54 mg, 0.13 mmol) and lambda^iV-dimethylsulfamide (81 mg, 0.65 mmol) in DMA (2 mL), was added DMAP (80 mg, 0.65 mmol), and EDCI-HCl (100 mg, 0.52 mmol). The reaction mixture was stirred at 60 0C for 2h, cooled to rt, diluted with DMSO and MeOH and purified by prep HPLC (MeOH/H2O with 10 mM TFA buffer) to yield 10-cyclohexyl~iV~((dimethylamino)sulfonyl)-l-methyl-4H-indolo[l,2- i][l,2,4]triazolo[4,3-alpha][l,4]benzodiazepme-7-carboxamide (29 mg, 0.056 mmol, 43percent) as a bright yellow solid. 1H NMR (500 MHz, CD3OD) 6 1.22 - 1.34 (m, IH), 1.41 - 1.62 (m, 3H), 1.77 - 1.85 (m, 2H), 1.95 - 2.18 (m, 4H), 2.71 (s, 3H), 2.90 - 3.00 (m, IH), 3.05 (s, 6H), 5.09 (d, J- 15.9 Hz, IH), 6.03 (d, = 15.9 Hz, IH), 7.67 (dd, J - 8.2, 1.5 Hz, IH), 7.79 - 7.87 (m, 4H), 8.00 (d, /= 8.6 Hz, IH), 8.33 (s, IH). LCMS: m/e 519 (M+H)+, ret time 1.96 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 60℃; for 2h; | Example 8; 10- Cyc.ohexyl~N- ((dimethylamino)sulfonyl)-2-m ethyl-4H- imidazofl, 2- a] indolofl ,2-d] [1,4] benzodiazepine-7-carboxamide.; To a solution of 10-cyclohexyl- 2-methyl-4H-imidazo[l,2-alpha]indoIo[l >2-cfp,4]benzodiazepme-7-carboxylic acid (58 g, 0.14 mmol) and MN-dimethylsulfamide (82 g, 0.66 mol) in DMF (2 mL) added DMAP (80 mg, 0.66 mmol) and then EDCI-HCl (100 mg, 0.52 mmol). The reaction mixture was stirred at 60 0C for 2h, coole to rt, diluted with DMSO and MeOH and purified by prep HPLC (MeOH/H2O with 10 niM TFA buffer) to yield 10- cyclohexyl-iV-((diniethylamino)sulfonyl)-2-methyl-4H-imidazo[ 1 ,2-cz]indolo[ 1 ,2- J][lf4]benzodiazepine-7-carboxamide (32 mg, 0.062 mmol, 44percent) as a pink solid. 1H NMR (300 MHz5 CD3OD) delta 1.14 - 1.32 (m, IH), 1.36 - 1.57 (m, 3H), 1.73 - 1.85 (m, 2H), 1.94 - 2.20 (m, 4H)5 2.34 (s, 3H)5 2.84 - 2.98 (m, IH), 3.04 (s, 6H), 5.20 (d, J- 16.1 Hz, IH), 5.97 (d, J- 16.1 Hz5 IH), 7.66 (dd, J- 8.6, 1.7 Hz, IH), 7.71 (s, IH), 7.77 - 7.90 (m, 4H)} 8.01 (d, J= 8.8 Hz, IH), 8.27 (s, IH). LCMS: m/e 518 (M+H)+, ret time 1.80 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Step 4: Preparation of compound 18-4To a mixture of compound 18-3 (0.086 g, 0.152 mmol) in and THF (ImI) was addedCDI (0.050 g, 0.308 mmol) the mixture was stirred at 500C for 0.5 h, cooled down and added <strong>[3984-14-3]N,N-dimethylsulfamide</strong> (0.040 g, 0.322 mmol) and DBU (0.1 ml, 0.663 mmol). The mixture was stirred at ambient temperature overnight and directly loaded on Thomson 25 g column (MeOH/DCM: 0 to 25percent) to afford the compound 18-4 as a yellow glass (0.086 g, 84percent). LC-MS retention time: 3.438 min; MS m/z 673 (M+H)+; IH NMR (400 MHz, CHLOROFORM-d) delta ppm 8.44 (1 H, br. s.), 7.87 (1 H, d, J=8.31 Hz), 7.82 (1 H, d, J=1.51 Hz), 7.48 - 7.54 (1 H, m), 7.33 - 7.38 (1 H, m), 7.03 (1 H, dd, J=8.56, 2.77 Hz), 6.91 (1 H, d, J=2.52 Hz), 6.75 (1 H, s), 4.92 (1 H, br. s.), 4.63 (1 H, br. s.), 4.23 - 4.45 (2 H, m), 3.90 (3 H, s), 3.03 (6 H, s), 2.82 - 2.90 (1 H, m), 1.11 - 2.16 (14 H, m), 0.46 - 0.94 (4 H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | (+-)-13-Cyclohexyl-N-[(dimethylamino)sulfonyl]-6,7-dihydro-6-hydroxy-5H-indolo[2,1-a][2]benzazepine-10-carboxamide 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (11.5 mg, 0.06 mmol) was added to a solution of (+-)13-cyclohexyl-6,7-dihydro-6-hydroxy-5H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (7.5 mg, 0.02 mmol) and DMAP(7.4 mg, 0.06 mmol) in DMF (0.5 mL) and CH2Cl2 (0.5 mL) at 22° C. The vial was shaken for a minute at 22° C. N,N-Dimethylsulfamide (4.9 mg, 0.04 mmol) was then added. Stirring was continued for 18 hr. The solution was filtered and purified on the Shimadzu preparative liquid chromatograph. The product containing fraction was concentrated on a Speed Vac.(R). to leave the titled compound as a white film (3.0 mg, 30percent). ESI-MS m/z 482 (MH+); 1H NMR (500 MHz, MeOD) delta 1.26-1.34 (m, 1 H) 1.40-1.55 (m, 2 H) 1.63 (m, 1 H) 1.82 (m, 2 H) 1.96 (m, 1 H) 2.01-2.19 (m, 3 H) 2.36 (m, 1 H) 2.95-3.08 (m, 2 H) 3.03 (s, 6 H) 3.76 (dd, J=15.26, 3.36 Hz, 1 H) 4.41-4.69 (m, 2 H) 7.40-7.50 (m, 4 H) 7.60 (m, 1 H) 7.93 (m, 1 H) 8.11 (m, 1 H). | |
30% | (+/-)-13-Cyclohexyl-N-[(dimethylamino)sulfonyl]- 6, 7-dihydro-6-hydroxy -5H- indolo[2, 1-a] [2]benzazepne-l 0-carboxamide.l-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (11.5mg, 0.06 mmol) was added to a solution of (+/-)13-cyclohexyl-6,7-dihydro-6-hydroxy - 5H-indolo[25l-a][2]benzazepine-10-carboxylic acid (7.5 mg, 0.02 mmol) and DMAP(7.4 mg, 0.06 mmol) in DMF (0.5 mL) and CH2Cl2 (0.5 mL) at 22 °C. The vial was shaken for a minute at 22 0C. N5N-Dimethylsulfamide (4.9 mg, 0.04 mmol) was then added. Stirring was continued for 18 hr. The solution was filtered and purified on the Shimadzu preparative liquid chromatograph. The product containing fraction was concentrated on a Speed Vac.(R). to leave the titled compound as a white film (3.0 mg, 30 percent). ESI-MS m/z 482 (MH+); IH NMR (500 MHz, MeOD) delta 1.26- <n="300"/>1.34 (m, 1 H) 1.40-1.55 (m, 2 H) 1.63 (m, 1 H) 1.82 (m, 2 H) 1.96 (m, 1 H) 2.01-2.19 (m, 3 H) 2.36 (m, 1 H) 2.95-3.08 (m, 2 H) 3.03 (s, 6 H) 3.76 (dd, J=15.26, 3.36 Hz, 1 H) 4.41-4.69 (m, 2 H) 7.40-7.50 (m, 4 H) 7.60 (m, 1 H) 7.93 (m, 1 H) 8.11 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | 13-Cyclohexyl-N-[(dimethylamino)sulfonyl]-6,7-dihydro-6-(morpholinylcarbonyl)-5H-indolo[2,1-a][2]benzazepine-10-carboxamide 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (11.8 mg, 0.06 mmol) was added to a solution of Enantiomer 2 (10 mg, 0.02 mmol) and DMAP(25.1 mg, 0.21 mmol) in DMA (1.0 mL) and CH2Cl2 (1.0 mL) at 22° C. The vial was shaken for a minute at 22° C. N,N-Dimethylsulfamide (7.5 mg, 0.06 mmol) was then added. Stirring was continued at 40° C. for 18 hr. The solution was filtered and purified on the Shimadzu preparative liquid chromatograph. The product containing fraction was concentrated on a Speed Vac.(R). to leave the titled compound as a white film (4.0 mg, 35percent). ESI-MS m/z 579 (MH+); 1H NMR (500 MHz, CD3OD) delta 1.24-1.35 (m, 1 H) 1.42-1.54 (m, 2 H) 1.60-1.68 (m, 1 H) 1.82 (m, 2 H) 1.97 (m, 1 H) 2.02-2.18 (m, 3 H) 2.74-2.86 (m, 1 H) 2.94-3.01 (m, 1 H) 3.04 (s, 6 H) 3.51-3.57 (m, 1 H) 3.60-3.90 (m, 9 H) 4.49-4.66 (m, 1 H) 4.81-4.97 (m, 1 H) 7.31-7.43 (m, 1 H) 7.45-7.53 (m, 3 H) 7.59 (m, 1 H) 7.92 (m, 1 H) 8.07 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | 7H-pyrido[2',3':3,4]azepino[l,2-a]indole-10-carboxamide, 13-cyclohexyl-N- [(dimethylamino)sulfonyl]-6-(4-morpholinylcarbonyl)-.To a solution of 7H-pyrido[2l,3':3,4]azepino[l,2-alpha]indole-10-carboxylic acid, 13-cyclohexyl- 6-(4-morpholinylcarbonyl)- (56 mg, 0.096 mmol) in CH2Cl2 (10 niL), one drop of DMF was added. A 2M solution of oxalyl chloride (0.096 mL, 0.191 mmol) in CH2Cl2 was then added dropwise. The reaction mixture was stirred at rt. for 2hr. It was concentrated and dried under high vacuum. The resultant residue was dissolved in THF(IO mL) and a solution of N,N-dimethylsulfonamide (23.7 mg, 0.191 mmol) and DIPEA (0.033 mL, 0.191 mmol)) in THF (2 mL) was added. DMAP (10 mg) was added after the reaction mixture was stirred at rt. for 10 min. Stirring was continued at 5O0C for 2hr. after which the reaction mixture was concentrated under reduced pressure, and the resultant residue was purified by Prep. reverse phase HPLC to afford the title compound as a yellow solid, (0 mg, 36percent yield). MS m/z 578(MH+); 1H NMR (500 MHz, CD3OD) 6 ppm 1.32-1.47 (m, 3 H) 1.75 - 1.90 (m, 5 H) 1.98-2.08 (m, 2 H) 3.04 (s, 6 H) 3.32 (m, IH) 3.46-3.79 (m, 8 H) 4.88 (s, 2H) 7.03 (s, 1 H) 7.53 (dd, J=7.93, 4.58 Hz, 1 H) 7.62 (dd, J=8.55, 1.53 Hz, 1 H) 7.95 (m, 1 H) 8.00 (d, J=8.55 Hz, 1 H) 8.19 (s, 1 H) 8.78 (dd, J=4.73, 1.68 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 16h; | Step a: To a stirred solution of 3-(cyclohex-1 -en-1 -yl)-2-phenyl-2/-/-indazole-6-carboxylic acid (1 ) (300 mg, 0.94 mmol) in DMF (10 mL) at 0 °C was added EDCI (360 mg, 1.88 mmol) and DMAP (230 mg, 1.88 mmol) followed by W,W-dimethylsulfamamide (175 mg, 1.41 mmol). The reaction mixture was then allowed to warm to RT and stirred for 16 h whereupon the reaction mixture was concentrated in vacuo and residue purified by automated column chromatography (Combi-Flash.(TM)., silica gel) eluting with ethyl acetate: hexane (2:1 v/v) to give 3-(cyclohex-1 -en-1-yl)-/V-(dimethylsulfamoyl)-2-phenyl-2/-/-indazole-6-carboxamide (8) as a white solid (251 mg, 62 percent); ESI-MS m/z calculated for [M+H]+: 425.16; found: 425.30. 1 H NMR (400 MHz, cf-DMSO) delta 1 1.91 (brs, 1 H), 8.39 (s, 1 H), 7.78 (d, J = 8.9 Hz, 1 H), 7.70- 7.51 (m, 6H), 6.14 (brs, 1 H), 2.94 (s, 6H), 2.30-2.16 (m, 2H), 2.00-1.90 (m, 2H), 1.69-1.52 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | Stage 3: N-(Dimethylsulphamoyl)-1-(pyridin-3-yl)-1H-pyrazole-4-carboxamide 0.250 g (1.32 mmol) of <strong>[1014631-89-0]1-(pyridin-3-yl)-1H-pyrazole-4-carboxylic acid</strong> was initially charged in 5 ml of tetrahydrofuran, and 0.43 ml (1.98 mmol) of N,N'-carbonyldiimidazole was added. The mixture was heated under reflux for 1 h. 0.246 g (1.98 mmol) of N,N-dimethylsulphonamide was dissolved in 3 ml of tetrahydrofuran and added dropwise at room temperature to the first solution. The mixture was stirred at room temperature for 10 min. After addition of 0.30 ml (1.98 mmol) of 1,8-diazabicyclo(5.4.0)undec-7-ene, the mixture was stirred at room temperature for 12 h. The solvent was removed on a rotary evaporator and water was added to the residue. The aqueous phase was extracted with dichloromethane. The organic phase was discarded and the aqueous phase was acidified with concentrated HCl. The precipitate formed was filtered off with suction. Yield: 0.120 g (30% of theory), logP1) (HCOOH) 1.03 1H NMR ((CD3)2SO): 2.89 (s, 6H), 7.58-7.62 (m, 1H), 8.24-8.27 (m, 1H), 8.38 (s, 1H), 8.60-8.62 (m, 1H), 9.10-9.11 (m, 1H), 9.22 (s, 1H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 3h; | To a solution of 4-[4-chloro-3-(trifluoromethyl)phenoxy]methyl}benzoic acid (Preparation 16, 237 mg, 0.72 mmol) in dichloromethane (8 ml_) was added EDCI (344 mg, 1 .79 mmol) followed by addition of <strong>[3984-14-3]N,N-dimethylsulfamide</strong> (222 mg, 1 .79Calculation isn't correct mmol). The reaction was left to stir at room temperature for 3 hours. A solution of KHSO4 (10ml_) was added and the mixture separated using a phase separation cartridge. The organics were dried in vacuo to yield a white solid as the title compound (285 mg, 97percent). 1 NMR (400 MHz, CDCI3): delta 2.95 (s, 6H), 5.10 (s, 2H), 7.00 (dd, 1 H), 7.23 (d, 1 H), 7.36 (d, 1 H), 7.49 (d, 2H), 7.89 (d, 2H). LCMS Rt = 1 .74 minutes MS m/z 406 [M35CI-H]" |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 2h; | To a solution of ethyl 4-[3-chloro-4-(trifluoromethyl)phenoxy]methyl}benzoate (Preparation 18, 125 mg, 0.35 mmol) in methanol (5.0 ml) was added water (2.0 ml_) followed by sodium hydroxide (140 mg, 3.5 mmol). The reaction mixture was heated to 55°C for 18 hours, then cooled and diluted with EtOAc (50 ml_) and 2M HCI (50 ml_). The aqueous layer was separated and washed with EtOAc (2 x 50 ml_). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo to yield 4-[3-chloro-4-(trifluoromethyl)phenoxy]methyl}benzoic acid as an off-white solid (90 mg, 78percent yield). This solid was dissolved in dichloromethane (3ml_) then EDCI (344 mg, 1 .79 mmol) and DMAP (88 mg, 0.70 mmol) were added, followed by the addition of N,N- dimethylsulfamide (86 mg, 0.70 mmol). The reaction was left to stir at room temperature for 2 hours. A solution of 2M HCI (10ml) was added and the mixture separated using a phase separation cartridge. The organics were dried in vacuo to yield a solid which was triturated with heptane:IPA (4:1 , 100 mL) and sonicated. The supernatant was decanted and the residue dried in vacuo to yield an off-white solid as the title compound (57 mg, 38percent yield). 1 H NMR (400 MHz, CDCI3): delta 3.05 (s, 6H), 5.17 (s, 2H), 6.90 (m, 1 H), 7.10 (d, 1 H), 7.54 (d, 2H), 7.61 (d, 1 H), 7.86 (d, 2H), 8.51 (br s,1 H). LCMS Rt = 1 .56 minutes MS m/z 435 [M35CI-H]- |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | To a suspension of <strong>[103877-80-1]2,5-difluoro-4-methylbenzoic acid</strong> (6.0 g, 3.5 mmol) in 1,2-dichloroethane (100 mL) was added 4-dimethylaminopyridine (10.65 g, 8.7 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide:hydrochloride (16.65 g, 8.7 mmol) in 1 ,2- dichloroethane (60 mL) and N,N-diisopropylethylamine (15 mL, 8.60 mmol) and the mixture stirred at room temperature for 20 minutes. N,N-Dimethylsulfamide (8.64 g, 6.9 mmol) was added to the solution and the mixture heated at 60C under nitrogen. After 3 hours the mixture was cooled to room temperature and extracted with dichloromethane (100 mL). The extract was washed successively with 2M hydrochloric acid (2 x 300 mL), brine (100 mL), dried over magnesium sulfate, filtered and evaporated to afford an oil (8.40 g) which solidified at room temperature. The crude product was purified by silica gel column chromatography eluting with ethyl acetate/heptane 1 :4 as eluent to afford the title compound (7.17g, 79%) as a white solid. 1 H NMR (400 MHz, CDCI3):5 2.32 (s, 3H), 3.01 (s, 6H), 7.01 (dd, 1 H), 7.65 (dd, 1 H), 8.74 (br s, 1 H). LCMS Rt = 2.10 minutes MS m/z 277 [M-H]" |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | To a solution of 2,4,5-trifluorobenzoic acid (5 g, 28.4 mmol) in dichloromethane (50 ml_) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (6.53 g, 42.6 mmol) and triethylamine (8.64 g, 1 1 .9 ml_, 85.2 mmol). After 15 minutes <strong>[3984-14-3]N,N-dimethylsulfamide</strong> (5.3 g, 56.8 mmol) was added followed by 4-dimethylaminopyridine (347 mg, 2.8 mmol). The resulting mixture was allowed to stir at room temperature for 18 hours. The solvent was evaporated and the residue was partitioned between ethyl acetate (50 ml_) and 2M HCI (150 ml_). The aqueous phase was separated and extracted with ethyl acetate (2 x 50 ml_). The combined organic extracts were dried over magnesium sulfate, filtered, evaporated and the residue purified by reverse-phase chromatography using a gradient of acetonitrile + 0.1 percent formic acid to 100percent acetonitrile to yield the title compound (993 mg, 31 percent) as a white solid. 1H NMR (400 MHz, CDCI3): delta 3.02 (s, 6H), 7.08 (dd, 1 H), 7.92 (dd, 1 H), 8.60-8.80 (br s, 1 H). LCMS Rt = 2.60 minutes MS m/z 281 [M-H]- | |
14% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 96h;Inert atmosphere; | A solution of 2,4,5-trifluorobenzoic acid (993 mg, 5.64 mmol), A/-(3- Dimethylaminopropyl)-/V'-ethylcarbodiimide hydrochloride (1 .62 g, 8.45 mmol), 4- (Dimethylamino)pyridine (69.0 mg, 0.565 mmol) and triethylamine (1 .00 ml_, 7.17 mmol) in dichloromethane (20 ml_) was stirred at room temperature under nitrogen for 15 minutes. Nu,Nu-dimethylsulfamide (Preparation 29, 1 .05 g, 8.46 mmol) and triethylamine (1 .36 ml_, 9.76 mmol) in dichloromethane (20 ml_) was added and the reaction was stirred for 4 days at room temperature under nitrogen. The reaction was concentrated in vacuo and partitioned between ethyl acetate (20 ml_) and 2M aqueous hydrochloric acid (20 ml_). The aqueous layer was extracted with ethyl acetate (2 x 20 ml_). The combined organic layers were washed with brine (30 ml_), dried over magnesium sulphate, filtered and concentrated in vacuo to afford a brown oil. Azeotroping the oil with ethyl acetate and heptane afforded a solid which was recrystallised from ethyl acetate and heptanes to afford the title compound as a white solid (228 mg, 14percent) 1H NMR (400 MHz, CDCI3): delta ppm 3.05 (s, 6 H), 7.10 (dd, 1 H), 7.95 (dd, 1 H), 8.70 (br s, 1 H). LCMS Rt = 2.58 minutes MS m/z no mass ion observed |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | To a solution of 4-fluorobenzoic acid (700 mg, 5.0 mmol) in 1 ,2-dichloroethane (30 mL) was added EDCI (2.38 g, 12.5 mmol), DMAP (1 .52 mg, 12.5 mmol) and N,N- diisopropylethylamine (2.17 mL, 12.5 mmol) and stirred for 20 minutes at room temperature. Lambda/,/V-dimethylaminosulfonamide (1 .24 g, 10.0 mmol) was added to the solution and the mixture heated at 60 °C for 2.5 hours. The mixture was cooled, diluted with water (20 mL) and 2M HCI (20 mL) and extracted with DCM (3 x 30 mL), washed with water (20 mL) and dried over MgSO . The solvent was removed in vacuo to afford the title compound as a white solid (585 mg, 47percent). No further purification was necessary. 1 H NMR (400 MHz, CDCI3) delta ppm 3.02 (s, 6H), 7.15 (dd, 2H), 7.90 (dd, 2H). 19F NMR (400 MHz, CDCI3) delta ppm -104 (s, 1 F). LCMS Rt = 2.35 minutes MS m/z 247 [MH]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 72h; | To a solution of 91 (100 mg, 0.21 mmol) in DCM (5 mL) was added N,N- dimethylsulfamide (28.8 mg, 0.23 mmol), DMAP (6.3 mg, 0.063 mmol) and DCC (52 mg, 0.25 mmol) and the mixture was stirred at RT for 72 h, TLC (DCM:MeOH= 20: 1) showed that the starting material was consumed. The mixture was filtered, the filtrate was concentrated in vacuo and the residue was purified by preparative HPLC to give 1 14 (56 mg, 46percent) as a white solid. LC-MS (Agilent, P-2): Rt 2.86 min; m/z calculated for C3i H37FN404S [M+H]+ 581.3, found [M+H]+ 581.3. HPLC (JULY-L) (214 and 254 nm): Rt 8.88 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39 mg | Stage #1: N,N-dimethylsulfamide; 4-(2-methoxyphenoxy)benzoic acid With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 40℃; for 4h; Stage #2: diethylamine In water; acetonitrile | 8 To a solution of 4-(2-methoxyphenoxy)benzonitrile, (Preparation 12, 161 mg, 0.72 mmol) in ethylene glycol (3 mL) was added potassium hydroxide (500 mg, 8.8 mmol) followed by water (2 mL). The resulting mixture was heated at 120 °C with stirring for 6 hours. The mixture was cooled, diluted with dichloromethane (5 mL), and water (5 mL), and separated. The aqueous layer was acidified with 1 M HCI, then washed with DCM (2 x 20 mL). The organic extracts were combined, passed through a phase separation cartridge, and evaporated in vacuo to afford the corresponding carboxylic acid intermediate as a white solid (150 mg). To a solution of the carboxylic acid (150 mg) in dichloromethane (3 mL) was added 4-dimethylaminopyridine (175 mg, 1 .43 mmol), and 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide:hydrochloride (274 mg, 1 .43 mmol). The reaction mixture was stirred in a sealed Reactivial until solubilised, then N,N- dimethylsulfamide (Preparation 29, 178 mg, 1 .43 mmol) was added. The reaction mixture was stirred at 40 °C for 4 hours, then diluted with dichloromethane (5 mL), and 10% aqueous KHSO4 solution (5 mL). The organic extracts were passed through a phase separation cartridge, and evaporated in vacuo to afford a pale yellow solid (200 mg). Crude residues were dissolved in dimethylsulfoxide (50 mg/mL) and purified by B- HPLC to afford the title compound as the diethylamine salt (39 mg). LCMS Rt = 1 .54 minutes MS m/z 351 [MH]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 30℃; for 16h; | To a solution of 4-((5-chloro-6-fluoropyridin-3-yl)oxy)-2,5-difluorobenzoic acid (Preparation 19, 490 mg, 1 .62 mmole) in DCM (100 mL) was added N,N- dimethylsulfamide (Preparation 29, 241 mg, 1 .94 mmol), followed by addition of HOBt (2 mg, 120 umol), DMAP (237 mg, 1 .94 mmol) and EDCI (31 1 mg, 1 .62 mmol). The reaction mixture was stirred at 30 C for 16 hours. The solvent was removed in vacuo then 2M HCI (20 mL) was added and extracted with EtOAc (3x 15 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (570 mg, 86percent) that was used directly in library protocol 1 . 1 H NMR (400 MHz, DMSO) delta ppm 2.85 (s, 6H), 7.35 (s, 1 H), 7.75 (s, 1 H), 8.20 (s, 1 H), 8.25 (s, 1 H), 1 1 .95 (s, 1 H). LCMS Rt 2.82 min MS m/z 408 [M-H]" |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; | A mixture of 32 (50 mg, 0.107 mmol), N.iV-dimethylsulfamide (16 mg, 0.128 mmol), DMAP (4 mg, 0.032 mmol) and DCC (26 mg, 0.128 mmol) in DCM (1 mL) was stirred at RT overnight, TLC (DCM:MeOH=20:l) showed that the starting material was consumed. The mixture was diluted with DCM (20 mL), washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by chromatography (DCM:MeOH=l:0 to 50 :1) to give 62 (36 mg, 59percent) as a white solid. LC-MS (Agilent, P- 2): Rt 2.66 min; m/z calculated for C32H33N404S [M+H]+ 573.2, found [M+H]+ 573.3. HPLC (JULY-L) (214 and 254 nm): R, 9.12 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; | A mixture of 16 (70 mg, 0.14 mmol), JV,N-dimethylsulfamide (17 mg, 0.17 mmol), DMAP (5 mg, 0.042 mmol) and DCC (35 mg, 0.17 mmol) in DCM (1 mL) was stirred at RT overnight, TLC (DCM:MeOH=10:l) showed that the starting material was consumed. The mixture was partitioned between DCM (20 mL) and brine (20 mL) and the organic layerwas separated, dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by chromatography (DCM:MeOH=l :0 to 50 :1) to give 28 (40 mg, 47percent) as a yellow solid. LC-MS (Agilent, P-2): Rt 2.77 min; m/z calculated for C32H36N604S [M+H]+ 601.3, found [M+H]+ 601.3. HPLC (JULY-L) (214 and 254 nm): R, 9.41 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 24h; | 31 Synthesis of 5-chloro-N-(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide To a mixture of 5-chloro-2,4-difluorobenzoic acid (3.48 g, 18.1 mmol) in anhydrous dichloromethane (100 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.20 g, 27.1 mmol), N,N-dimethylpyridin-4-amine (5.04 g, 41.3 mmol), and N,N-dimethylsulfamide (3.37 g, 27.1 mmol) at room temperature. The resulting mixture was stirred at room temperature for 24 h. The mixture was then cooled to 0° C. and quenched with hydrochloride acid (1N, 100 mL) followed by extraction with dichloromethane (2*200 mL). The organic layer was washed with ammonium chloride solution (3*30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo and the crude product was crystallized from ethyl acetate and hexanes to afford the title compound as a white solid (1.20 g, 22%): 1H NMR (300 MHz, DMSO-d6) δ 12.05 (s, 1H), 7.98-7.93 (m, 1H), 7.74-7.68 (m, 1H), 2.89 (s, 6H); MS (ES-) m/z 297.1, 299.1 (M-1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | To a reactor with a nitrogen inlet and temperature probe was charged lH-indole-6- carboxylic acid (1.00 kg, 6.21 mol, 1.00 equiv), N,N-dimethylaminopyridine (0.038 kg, 0.31 mol, 0.050 equiv), and tetrahydrofuran (7.00 L/kg, 6.22 kg/kg) followed by Iota, Gamma-carbonyldiimidazole (1.03 kg, 6.21 mol, in 4 x 0.257 kg aliquots, 1.00 equiv corrected for potency). The mixture was held at 5-20 °C until reaction completion was achieved and then cooled to 5-10 °C. Di-tert-butyldicarbonate (2.97 kg, 13.7 mol, 2.20 equiv) in THF (3 L/kg) was charged dropwise keeping the temperature between 2-8 °C. The mixture was held at 5-20 °C until reaction completion was achieved. N,N-Dimethylsulfamide (0.865 kg, 6.83 mol, 1.10 equiv) was charged at 25 ±5 °C. The mixture was aged for 0.5 h followed by addition of 1,8-diazabicyclo- undec-7-ene (1.24 kg, 8.07 mol, 1.30 equiv) keeping the temperature 98.0 and HPLC wtpercent >95.0. IR 3422, 3375, 3299, 2946, 1686, 1617, 1569, 1504, 1455, 1418, 1406, 1343, 1324, 1289, 1261, 1223, 1 187, 1150, 1135, 1 103, 1060, 978, 941, 898, 874, 818, 775, 733, 719, 660, 614 cm"1; NMR (400 MHz, DMSO-d6) delta 1 1.67 (s, 1H), 11.56 (s, 1H), 8.06 (s, 1H), 7.56-7.63 (m, 3H), 6.53 (s, 1H), 2.89 (s, 6H); 13C NMR (100 MHz, DMSO-d6) delta 167.2, 135.5, 131.7, 129.9, 124.7, 120.3, 119.5, 1 13.4, 102.1, 38.6; HRMS calculated for CnH1403N3S: 268.07504, found 268.07489 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In tetrahydrofuran; at 55℃; for 24h;Inert atmosphere; | Compound 2 (123 mg, 0.309 mmol) was combined with <strong>[3984-14-3]N,N-dimethylsulfamide</strong> (42 mg, 0.340 mmol), Pd2dba3 (14 mg, 0.015 mmol), SPhos (18 mg, 0.046 mmol), and K3PO4 (132 mg, 0.618 mmol) in a round bottom flask and degassed for 20 min. Dry degassed THF was added and the mixture was purged with N2 for 30 min followed by heating at 55° C. for 24 h. The solvent was evaporated with a stream of N2, the crude product taken up in water (pH 5), and extracted with EtOAc (15 mL×3). Purification by chromatography (95:5 CH2Cl2/EtOAc) gave ES517 (54 mg, 47percent) as a yellow solid (mp 195 C): 1H NMR (500 MHz, CDCl3) delta 9.91 (s, 1H), 7.52-7.58 (m, 3H), 7.27-7.31 (m, 2H), 7.19 (d, 1H, J=2.0 Hz), 7.15 (d, 1H, J=9.0 Hz), 6.93 (dd, 1H, J=9.0, 2.0 Hz), 2.93 (s, 6H); 13C NMR (125 MHz, CDCl3) delta 188.2, 161.5, 158.4, 155.9, 144.1, 131.6, 130.8, 129.9, 128.8, 128.4, 116.9, 115.1, 114.5, 104.8, 38.1; IR (KBr, cm?1) 3260, 1732, 1610, 1528, 1377, 1140; HRMS calculated for C18H16N2O5SNa (M+Na+): 395.0672. Found: 395.0670. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With titanium tetrachloride; triethylamine; In dichloromethane; at 0 - 40℃;Inert atmosphere; | General procedure: To a stirred solution of the appropriate sulfonamide 4a-d (5.0 mmol) and (E,E)-cinnamylideneacetophenone 3a-c (5.0 mmol) in CH2Cl2 (15 mL), under nitrogen atmosphere and cooled to 0 °C, was successively added Et3N (10 mmol) and TiCl4 (5.0 mmol). The reaction mixture was heated at reflux overnight. Then the solution was cooled to room temperature, quenched with water (100 mL) and extracted with CH2Cl2 (3x 30 mL). The combined organic layer was dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (hexane-AcOEt = 6:4 as eluent). The purified material was crystallized to afford pure N-sulfonylazatrienes 2a-f. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; | To a solution of compound 33h (250 g. 4.83 mmoi) in DCM (30 mL) was added N.Ndimethyl niethanesultonamide (0 60 g 4 83 rnniol) DCC (1 20 g 5 80 mniol) and DM \P (0.17 g, 1.45 mmol) and the mixture was stirred at RT overnight. TLC (DCM: McOH= 20:1) showed that most of the starting material was consumed. The mixture was washed with a satmated aqueous NaHCO3 solution (30 mL) brine (30 niL x 2) dried o; ci Na2SO4, filtered and concentrated in wwun. The residue was purified by chromatography (PE : EA= 1 0 to 3 1) to givu compound 40(1 68 g 55percent) as a \4hlte solid LC-MS (kgilent SThLCMS-P-2) R1 3 16 min, rnz calculited br C34l-1N 0h8 IM-tHl hl4 2 found [M+l-fl4614:3. HPLC (JULY-L) (214 and 254 nm): R 9.22 ruin. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; | A mixture of compound 50 (150 rng 027 mmoi) NN-dimcthyisuliarnide (41 rng. 0.33 mmcl), DMAP (10 mg, 0.08 mmol) and DCC (68 mg, 033 mmcl) in DCM (3mL) was stined at RT overnight, TLC (DCM: MeOH= 10: 1) show ed that most of the starting material was consumed. The mixture was diluted with DCM (30 mL). washed with brIne.dried over Na2SO4. filtered and concentrated in vacua. The residue was purified by chrmnatogiaphv (DCM MeOH=1 0 to 50 1) In give compound 48 (75 rng 13°?c) as a while solid LC-MS (Agiient, SYN-LCMS-P-2): R 2.89 mm; rn/i. calculated for CH,,N3O6S jM-i-Hj 6382 [M+Naj 6602 tumid [M+Hj 638 3 [M+Narhb() 3 }-1P1.C CJULY-L) (214 and 254 run): R 959 mm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; | A mixture of compound 51 (70 mg. 0.127 mmol), N,N?dimethylsulfainide (19 mg, ft 153 20 nimol). DMA? (5 mg. 0.038 mmol) and DCC (32. ing, 0.153 mmol) in DCM (1 mL) wasstirred at RT overnight. TLC (DCM: MeOH= 10:1) showed thai. most of the starting rndknal wa consunkd Tht mixUnu \4dS diluted with DCM (10 mL) wapercenthed with bunc dried over Na2SO4, filtered and concentrated in vocuo. The residue was purified by preparative HPLC to give Compound 49 i40 org. 48?/c?) as a whac solid LC-MS Agilent SYN-LCMS-P-2): R 2.95 mill; ink calculated for C151134PNiO6S [M+Hj 6562. JM+NaJ 6782 lound fM+Hj 6562 [M+NaJ678 2 I-IPLC (IUL\-L) (214 and 254 mm) R 9597ruin. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; | To a solution of the compound of Reference Example 82-1 (21.6 mg, 0.052 mmol) in dichloromethane (2 mL), WSC·HCl (19.9 mg, 0.104 mmol), N,N-dimethyl-4-aminopyridine (7.0 mg, 0.057 mmol) and <strong>[3984-14-3]N,N-dimethylsulfamide</strong> (9 mg, 0.073 mmol) were added, and the mixture was stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride twice and with a saturated aqueous solution of sodium bicarbonate and a saturated saline solution once, then dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (10.4 mg, 38percent). MS (ESI+) 523 (M+1, 7percent) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; | Compound of Reference Example 8 (120.0 mg, 0.203 mmol) in dichloromethane (5 mL) solution of <strong>[3984-14-3]N,N-dimethylsulfamide</strong> (35.0 mg, 0.28 mmol), WSC · HCl (78 mg, 0.406 mmol), N,N- dimethyl-4-aminopyridine (27 mg, 0.22 mmol) was added, and the mixture was stirred overnight at room temperature.Add water to the reaction mixture and extracted with ethyl acetate. Organic layer with saturated salt water after cleaning, dry with anhydrous sodium sulfate, filters and enriched by the vacuum. Got the residue obtained by silica gel column chromatography purification of the title compounds 68.0 mg (48percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 16h; | 2-(1H-indoi-6-yl)-3-[4-(tetrahvdro-pyran-4-yioxymethyi)-phenyiethynvi-benzoic acid (45.1 rng, 0.1 mrnol) and dimethylsulfarnoyl amine (149 mg, 0.14 rnrnoi) were dissolved in N,Ndimethyiforinarnide (1 mL), followed by the addition of 1-ethyl-3-(3-dimethyiaminopropyl)carbodiimide hydrochloride (1.2 eq), 4-dimethylarninopyii dine (2 eq) and hydroxybenzotriazole (1.2 eq). The reaction was stirred at room temperature for 16 hours. The solvent was then evaporated to dryness and reaction mixture was purified by preparative HPLC to give product as an off-white solid in 68percent yield. ?H NMR (300 MHz, CDCI3) d ppm 8.39 (hr. s., I H) 7.71-7.86 (in, 3 Fl) 7.54 (s, I H) 7.39-7.51 (m, 2 H) 7.20-733 (m, 4 H) 716 (d, .J=7.92 Hz, 2 H) 7.01 (d, J=8.21 Hz, 2 H) 6.63 (br. s.,1 H) 4.49 (s, 2 H) 3.88-4.06 (m, 2 H) 3.37-3.61 (in, 3 H) 2.56 (s, 6 H) 1.82-1.99 (m, 2 H) 1.54-1.75 (in. 2 H,). MS m/z (M-i-H) 558.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63.6% | Example 1 (30 mg, 0.061 mmol) was dissolved in THF (305 mu) and N,N- carbonyldiimidazole (14.83 mg, 0.091 mmol) was added. The mixture was heated to reflux for 1 hour. After 1 hour, the resulting solution was added to a solution of N,N- dimethyl aminosulfonamide (11.36 mg, 0.091 mmol) in THF (305 mu) and then DBU (14.71 mu, 0.098 mmol) was added. The reaction was allowed to stir at room temperature. After 3 hours, the reaction was diluted with EtOAc. Organics were washed with IN HCl, concentrated in vacuo, dissolved in DMF, filtered and purified directly via preparative HPLC to give example 46 (23.2 mg, 0.039 mmol, 63.6percent). LC-MS Anal. Calc'd for C27H37CIFN5O5S 597.22, found [M+H] 598.3. Tr = 2.090 min (Method C). 1H NMR (500 MHz, DMSO-de) delta: 9.61 (s, IH), 8.52 (s, IH), 7.98 (t, J=8.8 Hz, IH), 7.70 (d, J=2.9 Hz, IH), 7.45 (dd, J=10.9, 2.1 Hz, IH), 7.24 (d, J=9.1 Hz, IH), 7.11 (d, J=8.8 Hz, IH), 6.49 (dd, J=8.7, 2.8 Hz, IH), 4.59 (s, 2H), 2.76 (s, 6H), 1.90 (d, J=4.8 Hz, 2H), 1.67 (d, J=3.9 Hz, 2H), 1.51 (d, J=11.6 Hz, IH), 1.29 (dt, J=13.2, 6.5 Hz, IH), 0.86-1.21 (m, 8H), 0.79 (br. s., 6H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 16h; | A solution of acid (1), <strong>[3984-14-3]N,N-dimethylsulfamide</strong> (24.90 mg, 0.201 mmol), EDC (38.5 mg, 0.201 mmol), and DMAP (24.51 mg, 0.201 mmol) in DCM was stirred at rt for 16 h. The reaction was quenched with brine and extracted with EtOAc (3×). The combined organic layers were washed with brine and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with hexanes/acetone (100percent acetone 50percent acetone) to give example 318 (33 mg, 0.051 mmol, 51percent yield) as a white solid: LCMS 642.07 (M-1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 16h; | A solution of compound 2 (59 mg, 0.1 mmol), <strong>[3984-14-3]N,N-dimethylsulfamide</strong> (24.7 mg, 0.2 mmol), EDC (38.2 mg. 0.200 mmol), and DMAP (24.3 mg, 0.200 mmol) in DCM (2.0 mL) was stirred at rt for 16 h, then quenched with brine, and extracted with EtOAc. The combined organic layers were washed with brine and concentrated. The residue was purified by chromatography on silica gel using hexane/acetone (100/0 to 50/50, 10 min) to give product 6 as a white solid (45 mg, 65percent). LC-MS, ES": 696.11 (M-l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 16h; | To the acid 1 (111 mg, 0.2 mmol) in DCM (2 mL) and DMF (1 mL) was added EDCI (77 mg, 0.4 mmol), DMAP (48.9 mg, 0.4 mmol) and N,N-dimethylsulfonamide (49.7 mg, 0.4 mmol) and the resulting mixture was stirred at room temperature for 16 hrs. The reaction wasquenched with brine, extracted with ethyl acetate. The organic layers were combined, washed with brine, dried (Na2SO4), filtered and the filtrate was concentrated. The resulting residue was chromatographed with CombiFlash eluting with hexane to 50percent acetone in hexane to give example la (117 mg, 88percent). LC/MS observed [M-H], 660.07. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With diazoacetic acid ethyl ester; manganese(II) perchlorate hexahydrate In cyclohexane at 90℃; for 12h; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With titanium(IV) tetraethanolate; In tetrahydrofuran; for 12h;Reflux; | 100 mL round bottom flask was weighed A (1 g, 3.8 mmol).Add N,N-dimethylsulfonamide (470 mg, 3.8 mmol,1 equivalent),25mL of anhydrous tetrahydrofuran dissolved,Add tetraethyl titanate (1.6 mL, 7.6 mmol, 2 equivalents),The reaction was refluxed in an oil bath for 12 hours and then cooled to room temperature.The precipitate was precipitated by adding saturated brine.Diatomaceous earth filtration,Extracted with ethyl acetate,Dry over anhydrous sodium sulfate,Fast column chromatography,1.22 g of a white solid 1a were obtained. white solid, the yield was 87percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | Stage #1: MRE-269 With 1,1'-carbonyldiimidazole In tetrahydrofuran for 1h; Inert atmosphere; Reflux; Stage #2: N,N-dimethylsulfamide With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran for 1h; Inert atmosphere; | 3 Preparation Example 3 preparation of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butoxy}-N-(dimethylaminosulfonyl)acetamid Under the protection of nitrogen, 2-{4-[N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino]butoxy}acetic acid (419 mg, 1.00 mmol) and N,N'-carbonyldiimidazole (CDI) (178 mg, 1.10 mmol) was dissolved in 5mL Anhydrous tetrahydrofuran, heated to reflux for 1 h, After cooling, dimethylaminosulfonamide (124 mg, 1.00 mmol) was added, and after stirring for 1 h, (DBU) (0.15 mL, 1.00 mmol) was added dropwise and allowed to react at room temperature overnight. The reaction mixture was poured into 1N HCl and extracted with EtOAc. EtOAc EtOAc. Drying 220 mg of yellow solid 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butoxy}-N-(dimethylamino)sulfonyl acetamide, yield: 42.0% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃; for 6h;Inert atmosphere; | Under the protection of nitrogen, 2-{2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]-2-methylpropoxy}acetic acid (926 mg, 2.00 mmol), dimethylaminosulfonamide (248 mg, 2.00 mmol) and 2-(7-Oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (1000 mg, 2.60 mmol) Dissolve in 50 mL of anhydrous dichloromethane, react at room temperature for 6 h, pour the reaction solution into 1N HCl (100 mL), and extract with dichloromethane (100 mL*3), and mix the organic phase with water (100mL*2), saturated brine (100mL) *2) After washing, dry MgSO4, filter, decompress the solvent, and thenPurified by chromatography on silica gel column and collected under reduced pressure.Drying in vacuo gave 854 mg of yellow solid 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]-2-yl Propyloxy}-N-(dimethylaminosulfonyl)acetamide, purity: 99.4percent, yield: 75.0percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | To a solution of (lS,3'R,6'R,7'S,8'E,l5'S)-6-chloro-l5'-hydroxy-7'-methoxy-l2'-methyl-l3'-oxo-3,4- dihydro-277-spiro [naphthalene- 1,22'- [20]OXA[l,l2]diazatetracyclo[l4.7.2.03'6.019'24]pentacosa[8, l6,l8,24]tetraene]-l5'-carboxylic acid (Example 4, 32 mg, 0.053 mmol) in DCM (2 mL) was added l,l'-carbonyldiimidazole (10.22 mg, 0.063 mmol). The reaction mixture was stirred at room temperature for 2 hours. A'.A'-d i m c th y 1 s ul fam i dc (19.57 mg, 0.158 mmol) and l,8-diazabicyclo[5.4.0]undec-7-ene (23.99 pL. 0.158 mmol) were then added and the reaction mixture was stirred overnight. After this time, the reaction mixture was diluted with water (10 mL) and extracted with CH2CI2 (3 x 10 mL). The organic extract was dried over MgSCL. filtered and concentrated in vacuo to give the crude material as a light-yellow oil. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 100% acetone in hexanes, to provide the title compound (27 mg, 0.038 mmol, 72% yield) as white solid. NMR (300 MHz, CDCl3) d 8.90 (br. s., 1H), 7.73 (d,.7=8.48 Hz, 1H), 7.17 (dd, 7=2.19, 8.33 Hz, 1H), 7.08 (d, 7=1.90 Hz, 1H), 7.01 (dd, 7=1.90, 8.18 Hz, 1H), 6.94- 6.86 (m, 1H), 6.54 (d, 7=14.91Hz, 2H), 6.49-6.34 (m, 1H), 5.76-5.61 (m, 1H), 4.03 (d, 7=3.07 Hz, 2H), 3.83-3.53 (m, 7H), 3.30 (d, 7=14.47 Hz, 2H), 3.22 (s, 3H), 3.10-3.01 (m, 2H), 2.99 (s, 3H), 2.93 (s, 6H), 2.85-2.75 (m, 3H), 2.64 (s, 1H), 2.52 (d, 7=16.52 Hz, 1H), 2.44-2.13 (m, 5H). LRMS: (ESI, +ve ion) m/z 715.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | To a solution of (lS,3'R,6'R,7'S,8'E, l5'S)-6-chloro-l5'-hydroxy-7'-(tert-butyldimethylsilyl)oxy -12'- mcthyl- 13'-oxo-3.4-dihydro-2//-spiro|naphthalcnc- 1.22'- [20]OXA[l,l2]diazatetracyclo[l4.7.2.03'6.019'24]pentacosa[8, l6,l8,24]tetraene]-l5'-carboxylic acid (Example 43, Step 2, 40 mg, 0.056 mmol) in DCM (2 mL) was added di(l//-imidazol- 1 -yl)mcthanonc (13.71 mg, 0.085 mmol). The reaction mixture was stirred at room temperature for 2 hours. N V- dimethylsulfamide (21.00 mg, 0.169 mmol) and l,8-diazabicyclo(5.4.0)undec-7-ene (0.0258 mL, 0.169 mmol) were then added and the reaction was stirred overnight. After this time, the reaction mixture was diluted with saturated aqueous NEECl (5 mL), then water (15 mL) and extracted with EtOAc (3 x 20 mL). The organic extract was dried over MgSCL, filtered and concentrated in vacuo to give the crude material as a light-yellow oil. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 100% acetone in hexanes, to provide (lS,3'R,6'R,7'S,8'E,l5'R)-6-chloro-N-(dimethylsulfamoyl)-l5'- hydroxy-7'-(tert-butyldimethylsilyl)oxy- 12'-methyl- 13 '-oxo-3,4-dihydro-2i7-spiro [naphthalene- 1,22'- [20]OXA[l,l2]diazatetracyclo[l4.7.2.03'6.019'24] pentacosa[8,l6, l8,24]tetraene]-l5'-carboxamide (28 mg, 0.034 mmol, 61% yield). To the obtained solid was directly added tetrabutylammonium fluoride (1.0 M in THE) (0.169 mL, 0.169 mmol) and the reaction mixture was allowed to stir overnight. The latter was then diluted with saturated aqueous NH4CI (5 mL), then water (15 mL) and extracted with EtOAc (3 x 20 mL). The organic extract was dried over MgSCE, filtered and concentrated in vacuo. The crude material was purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, Cl 8, 100 A, 150 x 30 mm, eluting with a gradient of 35% to 90% acetonitrile in water (both solvents containing 0.1% TLA) over a period of 30 minutes to provide the title compound (15 mg, 0.021 mmol, 38% yield) as a white solid after drying in the lyophilizer overnight. ' H NMR (300 MHz, CD2CI2) d 8.94 (s, 1H), 7.73 (d, 7=8.48 Hz, 1H), 7.16 (dd,.7=2.34, 8.48 Hz, 1H), 7.08 (d, 7=2.19 Hz, 1H), 7.01-6.94 (m, 1H), 6.90-6.78 (m, 1H), 6.53 (s, 1H), 6.36 (t, 7=11.84 Hz, 1H), 5.89 (dd, 7=8.62, 14.91Hz, 1H), 4.35 (d, 7=8.77 Hz, 1H), 4.13-3.93 (m, 2H), 3.78-3.48 (m, 4H), 3.33 (d, 7=14.18 Hz, 1H), 3.20-3.06 (m, 2H), 2.96 (s, 3H), 2.86 (s, 6H), 2.82-2.72 (m, 2H), 2.64-2.44 (m, 3H), 2.34-2.23 (m, 4H), 2.06-1.87 (m, 6H), 1.80- 1.71 (m, 1H), 1.49-1.34- (m, 1H). LRMS: (ESI, +ve ion) m/z 701.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In N,N-dimethyl-formamide at 20℃; for 2h; | 248 Synthesis of 248.2: To a stirred solution of 247.1 (500 mg, 2.06 mmol) and 248.1 (256 mg, 2.06 mmol) in DMF (3 mL) was added Et3N (0.86 mL, 6.19 mmol) at RT. After stirring at RT for 2 h, the reaction mixture was evaporated under reduced pressure to afford 248.2, which used as such in the next step. LCMS: (13+39)%, m/z [M-H] = 364.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With iron(III) chloride In nitromethane at 50℃; for 2h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With iron(III) chloride In nitromethane at 80℃; for 2h; Inert atmosphere; |
Tags: 3984-14-3 synthesis path| 3984-14-3 SDS| 3984-14-3 COA| 3984-14-3 purity| 3984-14-3 application| 3984-14-3 NMR| 3984-14-3 COA| 3984-14-3 structure
[ 1393813-41-6 ]
Potassium (N-propylsulfamoyl)amide
Similarity: 0.58
[ 1393813-41-6 ]
Potassium (N-propylsulfamoyl)amide
Similarity: 0.58
[ 67104-97-6 ]
2-Methyl-1,2,5-thiadiazolidine 1,1-dioxide
Similarity: 0.67
[ 137830-77-4 ]
2-Methyl-1,2,6-thiadiazinane 1,1-dioxide
Similarity: 0.63
[ 5823-51-8 ]
1,2,5-Thiadiazolidine 1,1-dioxide
Similarity: 0.60
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
Home
* Country/Region
* Quantity Required :
* Cat. No.:
* CAS No :
* Product Name :
* Additional Information :