Structure of 62606-02-4
*Storage: {[sel_prStorage]}
*Shipping: {[sel_prShipping]}
The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
4.5
*For Research Use Only !
Change View
Size | Price | VIP Price | US Stock |
Global Stock |
In Stock | ||
{[ item.pr_size ]} |
Inquiry
{[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price, item.pr_usd) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,1,item.pr_is_large_size_no_price, item.discount_usd) ]} {[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price, item.pr_usd) ]} |
Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price, item.vip_usd) ]} | Inquiry {[ item.pr_usastock ]} In Stock Inquiry - | {[ item.pr_chinastock ]} {[ item.pr_remark ]} In Stock 1-2 weeks - Inquiry - | Login | - + | Inquiry |
Please Login or Create an Account to: See VIP prices and availability
US Stock: ship in 0-1 business day
Global Stock: ship in 5-7 days
1-2weeks
Inquiry
{[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price, item.vip_usd) ]}
{[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price, item.pr_usd) ]}
{[ getRatePrice(item.pr_usd,1,item.mem_rate,item.pr_is_large_size_no_price, item.pr_usd) ]}
Inquiry
{[ getRatePrice(item.pr_usd,item.pr_rate,1,item.pr_is_large_size_no_price, item.vip_usd) ]}
{[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price, item.pr_usd) ]}
{[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price, item.pr_usd) ]}
In Stock
- +
Please Login or Create an Account to: See VIP prices and availability
US Stock: ship in 0-1 business day
Global Stock: ship in 2 weeks
Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.
Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.
Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.
Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.
Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.
CAS No. : | 62606-02-4 |
Formula : | C8H11NO3S |
M.W : | 201.24 |
SMILES Code : | NC1=CC(S(=O)(C)=O)=CC(OC)=C1 |
MDL No. : | MFCD23978605 |
InChI Key : | XBZBDCOVNQRWPT-UHFFFAOYSA-N |
Pubchem ID : | 57863105 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P280-P301+P312-P302+P352-P305+P351+P338 |
* 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 |
---|---|---|
76% | With ammonium chloride; zinc; In methanol; water; at 20℃; for 0.5h; | Step 3: Preparation of 1-methanesulfonyl-5-methoxy-phenylamine To a mixture of 1-methanesulfonyl-3-methoxy-5-nitro-benzene (1.5 g, 6.48 mmol), zinc dust (4.3 g, 64.87 mmol), and ammonium chloride (5.2 g, 97.31 mmol) were added methanol (20.32 mL) and water (9.9 mL) at room temperature. After addition of water, the reaction was exothermic. The suspension was stirred for 30 min and the reaction mixture was filtered through the Celite. The filter cake was washed with water and methanol. The filtrate was concentrated to remove methanol and the residue was extracted with ethyl acetate (2*50 mL). The combined extracts were washed with brine solution (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to isolate 1-methanesulfonyl-5-methoxy-phenylamine (1.0 g, 76%) as a light yellow solid: ES(+)-HRMS m/e calcd for C8H12NO3S (M+H)+ 202.0533, found 202.0532. |
44% | With hydrogen;5%-palladium/activated carbon; In methanol; under 1500.15 Torr; | 1-Methylsulfonyl-3-methoxy-5-nitro-benzene (1.3 g; 5.6 mmol) was dissolved in methanol (40 ml) and 80 mgPd/C (5% w/w) were added and the reaction mixture was hydrogenated at 2 bar. The mixture was then diluted withdichloromethane, filtrated above over a celite pad, concentrated and the residual was crystallized from methanol. 0.5 g(2.48 mmol; 44% yield) of a solid were obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Step 4: Preparation of 3-iodo-1-methanesulfonyl-5-methoxy-benzene To a solution of 1-methanesulfonyl-5-methoxy-phenylamine (1.0 g, 4.94 mmol) in water (2.66 mL) was added a concentrated hydrochloric acid (2.21 mL, 29.66 mmol, 36%) at 0 C. To this mixture was added a chilled solution of sodium nitrite (0.622 g, 8.89 mmol) in water (3.78 mL) dropwise with a vigorous stirring. Then, the resulting colored mixture was stirred for 15 min at 0 C., and a cold solution of potassium iodide (1.64 g, 9.88 mmol) in water (3.78 mL) was added carefully. During this addition, a black brown solid was formed and after addition the ice bath was removed, and the reaction mixture was stirred for 2 days at room temperature. Then, the reaction mixture was diluted with water (50 mL) and saturated sodium thiosulfate solution (100 mL). The organic compound was extracted into ethyl acetate (3*50 mL). The combined organic extracts were washed with brine solution (100 mL) and dried over anhydrous magnesium sulfate. The filtration of the drying agent and concentration of the filtrate under reduced pressure gave the crude residue which was purified by using a silica gel column, eluding with 0-35% ethyl acetate in hexanes to obtain 3-iodo-1-methanesulfonyl-5-methoxy-benzene (1.08 g, 70%) as a white solid: ES(+)-HRMS m/e calcd for C8H9IO3S (M+H)+ 312.9390, found 312.9390. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.93% | Example 4 N4-(5 Fluoro-1 H-indazol-3-yl)-N2-[3-(methoxy)-5-(methylsulfonyl)phenyl]-2,4- pyrimidinediamine DN-(2-chloro-4-pyrimidinyl)-5-fluoro-1 H-indazol-3-amine (50 mg, 0.190 mmol) and [3- (methyloxy)-5-(methylsulfonyl)phenyl]amine (38.2 mg, 0.190 mmol) were taken up in Isopropanol (3 mL) and HCI (4N in 1 ,4-dioxane; 1 drop) was added. The mixture was heated to 160 C in the microwave for 20 minutes. The mixture was concentrated under reduced pressure, taken up in DMSO and purified by HPLC using a Sunfire (δμηι, 30x150 mm, C18 column) eluting with 10-50% MeCN/water (with 0.1 % TFA). The fractions containing the product were combined and concentrated to afford the titled compound as the TFA salt (6.1 mg, 0.01 1 mmol, 5.93 % yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 3.14 (s, 3 H) 3.68 (br. s., 3 H) 6.79 (br. s., 1 H) 6.99 (s, 1 H) 7.26 (td, J=9.09, 2.32 Hz, 1 H) 7.44 - 7.50 (m, 1 H) 7.53 (dd, J=9.03, 4.15 Hz, 1 H) 7.65 (m, 2 H) 8.12 (d, J=6.10 Hz, 1 H) 9.86 (br. s., 1 H) 10.31 (br. s., 1 H) 12.86 (br. s., 1 H); MS (m/z) 429.1 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
698 mg | With chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II); potassium carbonate; In tert-butyl alcohol; at 85℃; for 16h;Inert atmosphere; | (i) tert-Butyl (4-((2-((3-methoxy-5-(methylsulfonyl)phenvnamino)pyridin-4-vnoxy)naphthalen-1-yl)carbamateA mixture of <strong>[62606-02-4]3-methoxy-5-(methylsulfonyl)aniline</strong> (Casillas, L. N. et al., WO 2011/120026, 29 Sep 201 1 ; 300 mg, 1.491 mmol), tert-butyl (4-((2-chloropyridin-4-yl)oxy)naphthalen-1- yl)carbamate (see Example 2(ii) above; 553 mg, 1.491 mmol), K2CO3 (412 mg, 2.98 mmol) and BrettPhos G1 precatalyst (23.82 mg, 0.030 mmol) were degassed under vacuum, back filling with nitrogen 3 times. tBuOH (3 ml.) was added and the suspension degassed an additional 3 times. The reaction was heated under nitrogen at 85C for 16 hours. The reaction mixture was diluted with DCM (20 ml_), filtered through celite and concentrated in vacuo. The crude product was purified by chromatography on the Companion (12 g column, 0-100% ethyl acetate in iso-hexane) to afford the sub-title compound (698 mg) as a thick yellow gum. LCMS m/z 536 (M+H)+(ES+); 534 (M-H)"(ES") |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
250 mg | With N-ethyl-N,N-diisopropylamine; In acetonitrile; for 3h;Reflux; | Synthesis of Compound 2 and chiral separation of Enantiomers 2A and 2B: 2-Bromo-2-(4-fluoro-2-methoxyphenyl)-1 -(6-fluoro-7-methyl-1 H-indol-3-yl)- ethanone 2b (3.07 g, 7.8 mmol), <strong>[62606-02-4]3-methoxy-5-(methylsulfonyl)aniline</strong> [CAS 62606- 02-4] (1 .63 g, 8.1 1 mmol), and diisopropylethylamine (1 .35 ml_, 7.83 mmol) were mixed in CH3CN (100 ml_) and the mixture was heated under reflux for 3 h. After cooling to room temperature, the solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica (Stationary phase: HP-Spher 25 μΜ (340 g), Mobile phase: heptane/EtOAc gradient 100/0 to 0/100). The product fractions were evaporated under reduced pressure. A small aliquot of the oily residue was solidified by trituration with CH2CI2. The solids were isolated by filtration, washed with CH2CI2 and dried under vacuum to provide 2-(4-fluoro-2-methoxyphenyl)-1 -(6-fluoro-7-methyl-1 H-indol-3-yl)-2-((3-methoxy-5- (methylsulfonyl)phenyl)amino)ethanone (Compound 2, 250 mg) as a racemic mixture.Chiral separation of the enantiomers of Compound 2 (787 mg) was performed via Preparative SFC (Stationary phase: Chiralpak Diacel OJ 30 x 250 mm, Mobile phase: CO2, MeOH with 0.2% /PrNH2) and the product fractions were combined and evaporated under reduced pressure. The first eluted enantiomer was further purified by column chromatography (Stationary phase: HP-Spher 25 μΜ (10 g), Mobile phase: heptane/EtOAc gradient 100/0 to 0/100). Evaporation of the product fractions and lyophilization of the oily residue from a mixture of CH3CN and water provided Enantiomer 2A (91 mg) as an amorphous powder. The second eluted enantiomer was further purified by column chromatography (Stationary phase: HP-Spher 25 μΜ (10 g), Mobile phase: heptane/EtOAc gradient 100/0 to 0/100). Evaporation of the product fractions and lyophilization of the oily residue from a mixture of CH3CN and water provided enantiomer 2B (141 mg) as an amorphous powder.Compound 2:1H NMR (360 MHz, DMSO-c/6) δ ppm 2.38 (s, 3 H) 3.09 (s, 3 H) 3.72 (s, 3 H) 4.00 (s, 3 H) 6.25 (d, J=7.69 Hz, 1 H) 6.59 (d, J=10.28 Hz, 2 H) 6.73 (t, J=8.32 Hz, 1 H) 6.88 - 7.10 (m, 4 H) 7.36 (t, J=7.68 Hz, 1 H) 7.97 (dd, J=8.00, 6.07 Hz, 1 H) 8.45 (s, 1 H) 12.23 (br. s, 1 H)LC/MS (method LC-A): Rt1 .1 1 min, MH+515 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
725 mg | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 65℃; for 4h; | Synthesis of Compound 3 and chiral separation of Enantiomers 3A and 3B: 2-Bromo-1 -(6-chloro-7-methyl-1 H-indol-3-yl)-2-(4-fluoro-2-methoxyphenyl)- ethanone 3b (1 .29 g, 3.15 mmol) was suspended in CH3CN (60 mL). 3-Methoxy- 5-(methylsulfonyl)aniline [CAS 62606-02-4] (0.7 g, 3.46 mmol), anddiisopropylethylamine (1 .2 mL, 6.9 mmol) were added and the stirred mixture was heated at 65C for 4 h. The mixture was concentrated under vacuum and the residue was partitioned between EtOAc and water. The organic layer was separated, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography (Stationary phase: Grace Reveleris silica (330 g), Mobile phase: EtOAc/heptane gradient 50/50 to 100/0) and subsequently by Preparative HPLC (Stationary phase: Uptisphere C18 ODB - 10 μηη, 200 g, 5 cm, Mobile phase: 0.25% NH4HCO3solution in water, CH3CN) to give 1 -(6-chloro-7-methyl-1 H-indol-3-yl)-2-(4-fluoro-2-methoxyphenyl)-2-((3- methoxy-5-(nnethylsulfonyl)phenyl)annino)ethanone (Compound 3, 725 mg) as a racemic mixture.Chiral separation of the enantiomers of Compound 3 (635 mg) was performed using Normal Phase Chiral separation (Stationary phase: AS 5 μιτι, Mobile phase: 100% MeOH, isocratic elution. Detection wavelength 308 nm, flow 1 mL/min). The product fractions were combined and evaporated to provide Enantiomer 3A(223 mg) as the first eluted product and Enantiomer 3B (247 mg) as the second eluted product. Both enantiomers 3A and 3B occurred as amorphous powders.Compound 3:1H NMR (400 MHz, CHLOROFORM-c/) δ ppm 2.49 (s, 3 H) 2.94 (s, 3 H) 3.77 (s, 3 H) 4.12 (s, 3 H) 6.03 (d, J=6.31 Hz, 1 H) 6.18 (d, J=6.27 Hz, 1 H) 6.42 (t, J=2.20 Hz, 1 H) 6.57 (td, J=8.36, 2.42 Hz, 1 H) 6.64 (dd, J=10.56, 2.42 Hz, 1 H) 6.70 (dd, J=2.21 , 1 .51 Hz, 1 H) 6.84 (t, J=1 .76 Hz, 1 H) 7.24 - 7.30 (m, 1 H) 7.28 (d, J=8.58 Hz, 1 H) 8.15 (d, J=8.61 Hz, 1 H) 8.17 (d, J=3.07 Hz, 1 H) 8.70 (br. s., 1 H)LC/MS (method LC-B): Rt2.16 min, MH+531 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
112 mg | Synthesis of Compound 5 and chiral separation of Enantiomers 5A and 5B: A solution of 2-(4-fluoro-2-methoxyphenyl)-1 -(6-methoxy-1 /-/-indol-3-yl)ethanone 5a (2.2 g, 7.02 mmol) in THF (150 mL) was stirred under N2-flow and cooled on an ice-bath. Phenyltrimethylammonium tribromide [CAS 4207-56-1 ] (2.77 g,7.37 mmol) was added portionwise and the mixture was stirred at 0C for 1 h and subsequently at room temperature for 2 h. 3-Methoxy-5-(methylsulfonyl)aniline[CAS 62606-02-4] (4.24 g, 21 .1 mmol) was added and approximately 125 mL solvent was evaporated under reduced pressure. CH3CN (50 mL) was added and the reaction mixture was stirred at room temperature for 5 days and subsequently at 50C for 2 days. After cooling to room temperature, the reaction mixture was poured out in water (200 mL). The products were extracted with 2-methyl-THF (2x) and the combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica (Stationary phase: Grace Reveleris silica 120 g, Mobile phase: heptane/EtOAc gradient 100/0 to 0/100). The fractions containing product were combined and washed with 1 N HCI (100 mL), an aqueous saturated solution of NaHCO3, dried with MgSO4, filtered and evaporated under reduced pressure. The residue was crystallized from a mixture of CH2CI2 (10 mL) and diisopropyl- ether (15 mL), filtered off and dried under vacuum at 50C to provide racemic 2-(4-fluoro-2-methoxyphenyl)-1 -(6-methoxy-1 H-indol-3-yl)-2-((3-methoxy-5- (methylsulfonyl)phenyl)amino)ethanone (Compound 5, 2.25 g). A small aliquot of Compound 5 (150 mg) was further purified by slurring up in MeOH (4 mL) for 2 h. The solids were filtered off and dried under vacuum at 50C to provide racemic 2-(4-fluoro-2-methoxyphenyl)-1 -(6-methoxy-1 H-indol-3-yl)-2-((3-methoxy-5- (methylsulfonyl)phenyl)amino)ethanone (Compound 5, 1 12 mg).Chiral separation of the enantiomers of Compound 5 (2.1 g) was done via Normal Phase Chiral separation (Stationary phase: (S,S)-Whelk-O 1 , Mobile phase: 100% EtOH). The product fractions were combined and evaporated. The first eluted product was stirred up in MeOH (6 mL), filtered off and dried under vacuum at 40C to provide Enantiomer 5A (825 mg). The second eluted product was stirred up in MeOH (5 mL), filtered off and dried under vacuum at 40C to provideEnantiomer 5B (784 mg). Compound 5:1H NMR (400 MHz, DMSO-c/6) δ ppm 3.08 (s, 3 H) 3.72 (s, 3 H) 3.76 (s, 3 H) 4.00 (s, 3 H) 6.19 (d, J=7.66 Hz, 1 H) 6.55 - 6.61 (m, 2 H) 6.72 (td, J=8.47, 2.49 Hz, 1 H) 6.83 (dd, J=8.71 , 2.30 Hz, 1 H) 6.90 (t, J=1 .65 Hz, 1 H) 6.92 - 6.98 (m, 2 H) 7.00 (d, J=7.69 Hz, 1 H) 7.36 (dd, J=8.60, 6.85 Hz, 1 H) 8.02 (d, J=8.71 Hz, 1 H) 8.29 (s, 1 H) 1 1 .85 (br. s, 1 H)LC/MS (method LC-A): Rt1 .01 min, MH+513 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
747 mg | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20 - 70℃; for 105.84h; | Synthesis of Compound 6 and chiral separation of Enantiomers 6A and 6B: A solution of 2-bromo-2-(4-fluoro-2-methoxyphenyl)-1 -(7-fluoro-5-methyl-1 /-/-indol- 3-yl)ethanone 6b (1 .02 g, 2.59 mmol), <strong>[62606-02-4]3-methoxy-5-(methylsulfonyl)aniline</strong> [CAS 62606-02-4] (782 mg, 3.89 mmol) and diisopropylethylamine (670 μΙ_, 3.89 mmol) in CH3CN (25 mL) was stirred at room temperature for 4 days and the mixture was subsequently heated at 70C for 10 h. After cooling to room temperature, the solvents were evaporated under reduced pressure. The residue was taken up with CH2CI2, washed with 0.5N HCI and water, dried over MgSO4, filtered andevaporated under reduced pressure. The residue was purified by columnchromatography on silica (Stationary phase: Biotage SNAP Ultra 100 g, Mobile phase: EtOAc:EtOH (3:1 )/heptane gradient 0/100 to 50/50). The fractions containing product were combined and evaporated under reduced pressure to provide racemic 2-(4-fluoro-2-methoxyphenyl)-1 -(7-fluoro-5-methyl-1 H-indol-3-yl)- 2-((3-methoxy-5-(methylsulfonyl)phenyl)amino)ethanone (Compound 6, 747 mg) as a white solid.Chiral separation of the enantiomers of Compound 6 (747 mg) was performed via Preparative SFC (Stationary phase: Chiralpak Diacel AD 20 x 250 mm, Mobile phase: CO2, EtOH with 0.2% /PrNH2). The product fractions were combined, evaporated under reduced pressure and dried under vacuum at 50C. The first eluted product provided Enantiomer 6A (275 mg) as a white amorphous solid. The second eluted product provided Enantiomer 6B (259 mg) as a white amorphous powder. Compound 6:LC/MS (method LC-A): Rt1 .13 min, MKT 515 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
640 mg | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 100℃; for 0.166667h;Microwave irradiation; | Synthesis of Compound 7 and chiral separation of Enantiomers 7A and 7B:A mixture of 2-bromo-1 -(5,6-difluoro-1 /-/-indol-3-yl)-2-(4-fluoro-2-methoxyphenyl)- ethanone 7b (0.800 g, 2.01 mmol) and <strong>[62606-02-4]3-methoxy-5-(methylsulfonyl)aniline</strong> [CAS 62606-02-4] (1 .2 g, 6.03 mmol) in acetonitrile (8 ml_) was irradiated in amicrowave oven at 100C for 10 min. The reaction mixture was diluted with EtOAc and washed with 1 N HCI. The organic phase was washed with an aqueous saturated NaHCO3 solution and brine, dried over MgSO4, filtered andconcentrated under reduced pressure. The residue was crystallized fromacetonitrile to afford 1 -(5,6-difluoro-1 /-/-indol-3-yl)-2-(4-fluoro-2-methoxyphenyl)-2- ((3-methoxy-5-(methylsulfonyl)phenyl)amino)ethanone (Compound 7, 640 mg) as a racemic mixture.Chiral separation of the enantiomers of Compound 7 (596 mg) was performed via Preparative Chiral SFC (Stationary phase: Chiralpak IA 5 μιτι 250 x 20mm, Mobile phase: 70% CO2, 30% MeOH) yielding 250 mg of the first elutedenantiomer and 250 mg of the second eluted enantiomer. The first elutedenantiomer was solidified by trituration with Et2O to afford Enantiomer 7A (194 mg) as an amorphous powder. The second eluted enantiomer was solidified by trituration with Et2O to afford Enantiomer 7B (212 mg) as an amorphous powder. Compound 7:1H NMR (300 MHz, DMSO-c/6) δ ppm 3.09 (s, 3 H) 3.72 (s, 3 H) 3.98 (s, 3 H) 6.23 (d, J=7.8 Hz, 1 H) 6.57 - 6.61 (m, 2 H) 6.74 (td, J=8.5, 2.5 Hz, 1 H) 6.91 (s, 1 H) 6.96 (dd, J=1 1 .4, 2.5 Hz, 1 H) 7.06 (d, J=7.9 Hz, 1 H) 7.36 (dd, J=8.6, 6.9 Hz, 1 H) 7.54 (dd, J=10.8, 7.0 Hz, 1 H) 8.01 (dd, J=1 1 .2, 8.1 Hz, 1 H) 8.48 (s, 1 H) 12.19 (br. s., 1 H)LC-MS (method LC-D) Rt3.3 min, MH+519 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95 mg | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 100℃; for 0.166667h;Microwave irradiation; | Synthesis of Compound 8 and chiral separation of Enantiomers 8A and 8B:A mixture of 2-bromo-2-(4-fluoro-2-methoxyphenyl)-1 -(5-fluoro-7-methyl-1 /-/-indol- 3-yl)ethanone 8b (0.100 g, 0.254 mmol) and <strong>[62606-02-4]3-methoxy-5-(methylsulfonyl)aniline</strong> [CAS 62606-02-4] (0.155 g, 0.770 mmol) in acetonitrile (1 ml_) was irradiated in a microwave oven at 100C for 10 min. The reaction mixture was diluted with EtOAc and washed with 1 N HCI. The organic phase was washed with an aqueous saturated NaHCO3 solution and brine, dried over MgSO4, filtered andconcentrated under reduced pressure. The residue was crystallized from EtOAc and heptane to afford 2-(4-fluoro-2-methoxyphenyl)-1 -(5-fluoro-7-methyl-1 /-/-indol- 3-yl)-2-((3-methoxy-5-(methylsulfonyl) phenyl)amino)ethanone (Compound 8, 95 mg) as a racemic mixture.Chiral separation of the enantiomers of Compound 8 (491 mg) was performed via Preparative Chiral SFC (Stationary phase: Chiralpak IC 5 μιτι 250 x 30 mm, Mobile phase: 60% CO2, 40% /PrOH) yielding 224 mg of the first elutedenantiomer and 212 mg of the second eluted enantiomer. The first elutedenantiomer was crystallized from Et2O and a few drops of CH3CN to affordEnantiomer 8A (174 mg) as white powder. The second eluted enantiomer was crystallized from Et2O and a few drops of CH3CN to afford Enantiomer 8B (164 mg) as a white powder.Compound 8:1H NMR (300 MHz, DMSO-c/6) δ ppm 2.47 (s, 3 H) 3.09 (s, 3 H) 3.72 (s, 3 H) 4.00 (s, 3 H) 6.24 (d, J=7.7 Hz, 1 H) 6.55 - 6.64 (m, 2 H) 6.73 (td, J=8.4, 2.4 Hz, 1 H)6.87 - 6.98 (m, 3 H) 7.04 (d, J=7.7 Hz, 1 H) 7.36 (dd, J=8.6, 6.8 Hz, 1 H) 7.66 (dd, J=9.7, 2.5 Hz, 1 H) 8.46 (s, 1 H) 12.23 (br. s., 1 H)LC-MS (method LC-E): Rt8.5 min, MH+515 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
162 mg | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; acetonitrile; at 100℃; for 0.166667h;Microwave irradiation; | Synthesis of Compound 9 and chiral separation of Enantiomers 9A and 9B:A mixture of 2-bromo-2-(4-fluoro-2-methoxyphenyl)-1 -(5-fluoro-6-methyl-1 /-/-indol- 3-yl)ethanone 9b (0.204 g, 0.517 mmol) and <strong>[62606-02-4]3-methoxy-5-(methylsulfonyl)aniline</strong> [CAS 62606-02-4] (0.309 g, 1 .54 mmol) in acetonitrile (1 mL) and THF (1 mL) was irradiated in a microwave oven at 100C for 10 min. The reaction mixture was diluted with EtOAc and washed with 1 N HCI. The organic phase was washed with an aqueous saturated NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was crystallized from EtOAc to afford 2-(4-fluoro-2-methoxyphenyl)-1 -(5-fluoro-6-methyl-1 H-indol-3-yl)-2-((3- methoxy-5-(methylsulfonyl) phenyl)amino)ethanone (Compound 9, 162 mg) as a racemic mixture.Chiral separation of the enantiomers of Compound 9 (462 mg) was performed via Preparative Chiral SFC (Stationary phase: Chiralpak AD-H 5 μιτι 250 x 30 mm, Mobile phase: 60% CO2, 40% MeOH) yielding 160 mg of the first elutedenantiomer and 170 mg of the second eluted enantiomer. The first elutedenantiomer was purified again by flash chromatography on silica gel (15-40 μιτι, 4 g, CH2Cl2/MeOH 99/1 ). The pure fractions were collected and evaporated to dryness. The residue (120 mg) was solidified from Et2O and a few drops ofCH3CN to afford Enantiomer 9A (83 mg) as a white powder. The second eluted enantiomer was purified again by flash chromatography on silica gel (15-40 μιτι, 4 g, CH2Cl2/EtOAc 98/2). The pure fractions were collected and evaporated to dryness. The residue (1 10 mg) was solidified from Et2O and a few drops ofCH3CN to afford Enantiomer 9B (68 mg) as a white powder.Compound 9:1H NMR (300 MHz, DMSO-c/6) δ ppm 2.31 (d, J=1 .4 Hz, 3 H) 3.08 (s, 3 H) 3.72 (s, 3 H) 3.99 (s, 3 H) 6.20 (d, J=7.7 Hz, 1 H) 6.56 - 6.61 (m, 2 H) 6.73 (td, J=8.5, 2.4 Hz, 1 H) 6.90 (m, 1 H) 6.95 (dd, J=1 1 .6, 2.4 Hz, 1 H) 7.03 (d, J=7.7 Hz, 1 H) 7.28 - 7.42 (m, 2 H) 7.77 (d, J=10.6 Hz, 1 H) 8.39 (s, 1 H) 12.02 (s, 1 H)LC-MS (method LC-E): Rt8.6 min, MH+515 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
638 mg | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; acetonitrile; at 70℃; for 12h; | Synthesis of Compound 10 and chiral separation of Enantiomers 10A and 10B: A mixture of 2-bromo-2-(4-fluoro-2-methoxyphenyl)-1 -(6-methoxy-5-methyl-1 H- indol-3-yl)ethanone 10b (1 .0 g, 2.46 mmol), <strong>[62606-02-4]3-methoxy-5-(methylsulfonyl)aniline</strong> [CAS 62606-02-4] (743 mg, 3.69 mmol) and diisopropylethylamine (0.64 mL,3.69 mmol) in CH3CN (15 mL) and THF (15 mL) was heated at 70C for 12 h. The solvents were removed under reduced pressure. The residue was dissolved in EtOAc. The organic layer was washed twice with 1 N HCI, washed with water, dried over MgSO4, filtered and the solvent was concentrated under reduced pressure. Purification was carried out by flash chromatography on silica gel (15- 40 pm, 40 g, CH2CI2/CH3OH 99.8/0.2). The pure fractions were collected and evaporated to dryness to give 2-(4-fluoro-2-methoxyphenyl)-2-((3-methoxy-5- (methylsulfonyl)phenyl)amino)-1 -(6-methoxy-5-methyl-1 /-/-indol-3-yl)ethanone (Compound 10, 638 mg) as a racemic mixture.Chiral separation of the enantiomers of Compound 10 was performed viaPreparative Chiral SFC (Stationary phase: Chiralpak AD-H 5 m 250 x 30 mm, Mobile phase: 70% CO2, 30% /PrOH) yielding 244 mg of the first elutedenantiomer and 163 mg of the second eluted enantiomer. The first elutedenantiomer was purified again by flash chromatography on silica gel (15-40 pm, 40 g, CH2Cl2/EtOAc 98/2). The pure fractions were collected and evaporated to dryness. The residue (161 mg) was solidified from Et2O and a few drops ofCH3CN to afford Enantiomer 10A (136 mg). The second eluted enantiomer was purified again by flash chromatography on silica gel (15-40 pm, 40 g,CH2CI2/EtOAc 98/2). The pure fractions were collected and evaporated to dryness. The residue (158 mg) was solidified from Et2O and a few drops of CH3CN to afford Enantiomer 10B (135 mg).Compound 10:1H NMR (500 MHz, DMSO-d6) δ ppm 2.21 (s, 3 H) 3.08 (s, 3 H) 3.72 (s, 3 H) 3.79 (s, 3 H) 4.00 (s, 3 H) 6.18 (d, J=7.6 Hz, 1 H) 6.55 - 6.60 (m, 2 H) 6.72 (td, J=8.5, 2.5 Hz, 1 H) 6.89 - 7.00 (m, 4 H) 7.35 (dd, J=8.5, 7.1 Hz, 1 H) 7.90 (s, 1 H) 8.23 (s, 1 H) 1 1 .75 (br. s., 1 H)LC/MS (method LC-C): Rt3.04 min, MH+527Melting point: 224C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
450 mg | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; acetonitrile; at 70℃; for 72h; | Synthesis of Compound 11 and chiral separation of Enantiomers 11 A and 11 B:A mixture of 2-bromo-2-(4-fluoro-2-methoxyphenyl)-1 -(5-fluoro-6-methoxy-1 H- indol-3-yl)ethanone 11 b (0.8 g, 1 .95 mmol), <strong>[62606-02-4]3-methoxy-5-(methylsulfonyl)aniline</strong> [CAS 62606-02-4] (589 mg, 2.93 mmol) and diisopropylethylamine (0.51 mL, 2.93 mmol) in CH3CN (15 mL) and THF (15 mL) was heated at 70C for 72 h. The solvents were removed under reduced pressure. The residue was dissolved in EtOAc. The organic layer was washed twice with 1 N HCI, washed with water, dried over MgSO4, filtered and the solvent was concentrated under reduced pressure. Purification was carried out by flash chromatography on silica gel (15-40 μηη, 40 g, CH2CI2/CH3OH 99.5/0.5). The pure fractions were collected and evaporated to dryness to give 2-(4-fluoro-2-methoxyphenyl)-1 -(5-fluoro-6- methoxy-1 H-indol-3-yl)-2-((3-methoxy-5-(methylsulfonyl)phenyl)amino)ethanone (Connpound 11 , 450 mg) as a racemic mixture.Chiral separation of the enantiomers of Compound 11 (380 mg) was performed via Preparative Chiral SFC (Stationary phase: Chiralpak IC 5 μιτι 250 x 20 mm, Mobile phase: 70% CO2, 30% MeOH) yielding after crystallization fromCH3CN/diisopropylether, 174 mg of the first eluted enantiomer (Enantiomer 11 A) and 165 mg of the second eluted enantiomer (Enantiomer 11 B).Compound 11 :1H NMR (500 MHz, DMSO-c/6) δ ppm 3.08 (s, 3 H) 3.72 (s, 3 H) 3.85 (s, 3 H) 3.99 (s, 3 H) 6.20 (d, J=7.6 Hz, 1 H) 6.58 (s, 2 H) 6.73 (td, J=8.4, 2.5 Hz, 1 H) 6.87 - 6.92 (m, 1 H) 6.96 (dd, J=1 1 .3, 2.5 Hz, 1 H) 7.03 (d, J=7.6 Hz, 1 H) 7.15 (d, J=7.3 Hz, 1 H) 7.36 (dd, J=8.4, 6.9 Hz, 1 H) 7.83 (d, J=12.0 Hz, 1 H) 8.34 (s, 1 H) 1 1 .95 (br. s., 1 H)LC/MS (method LC-C): Rt2.89 min, MH+531Melting point: 172C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
820 mg | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; acetonitrile; at 45℃; for 72h; | Synthesis of Compound 12 and chiral separation of Enantiomers 12A and 12B:A mixture of 2-bromo-1 -(7-chloro-6-methoxy-1 H-indol-3-yl)-2-(4-fluoro-2-methoxy- phenyl)ethanone 12b (0.9 g, 2.1 1 mmol), <strong>[62606-02-4]3-methoxy-5-(methylsulfonyl)aniline</strong> [CAS 62606-02-4] (637 mg, 3.16 mmol) and diisopropylethylamine (0.55 mL, 3.16 mmol) in CH3CN (20 mL) and THF (20 mL) was heated at 45C for 72 h. The solvents were removed under reduced pressure. The residue was dissolved in EtOAc. The organic layer was washed twice with 1 N HCI, washed with water, dried over MgSO4, filtered and the solvent was concentrated under reduced pressure. Purification was carried out by flash chromatography on silica gel (15-40 pm, 80 g, CH2CI2/CH3OH 99.5/0.5). The pure fractions were collected and evaporated to dryness to give 1 -(7-chloro-6-methoxy-1 /-/-indol-3-yl)-2-(4-fluoro-2- methoxyphenyl)-2-((3-methoxy-5-(methylsulfonyl)phenyl)amino)ethanone(Compound 12, 820 mg) as a racemic mixture.Chiral separation of the enantiomers of Compound 12 (750 mg) was performed via Preparative Chiral SFC (Stationary phase: Chiralcel OD-H 5 m 250 x 30 mm, Mobile phase: 60% CO2, 40% MeOH) yielding after solidification indiisopropylether, 285 mg of the first eluted enantiomer (Enantiomer 12A) and 260 mg of the second eluted enantiomer (Enantiomer 12B) as amorphous powders.Compound 12:1H NMR (500 MHz, DMSO-c/6) δ ppm 3.09 (s, 3 H) 3.72 (s, 3 H) 3.87 (s, 3 H) 3.99 (s, 3 H) 6.24 (d, J=7.6 Hz, 1 H) 6.51 - 6.64 (m, 2 H) 6.73 (td, J=8.4, 2.2 Hz, 1 H) 6.92 (s, 1 H) 6.96 (dd, J=1 1 .4, 2.2 Hz, 1 H) 7.03 (d, J=7.6 Hz, 1 H) 7.1 1 (d, J=8.8 Hz, 1 H) 7.32 - 7.41 (m, 1 H) 8.05 (d, J=8.8 Hz, 1 H) 8.36 (s, 1 H) 12.20 (s, 1 H)LC/MS (method LC-C): Rt3.02 min, MH+547 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
750 mg | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 100℃; for 0.166667h;Microwave irradiation; | Synthesis of Compound 13 and chiral separation of Enantiomers 13A and 13B:A mixture of 2-bromo-1 -(6,7-difluoro-1 /-/-indol-3-yl)-2-(4-fluoro-2-methoxyphenyl)- ethanone 13b (1 .3 g, 3.29 mmol) and <strong>[62606-02-4]3-methoxy-5-(methylsulfonyl)aniline</strong> [CAS 62606-02-4] (2.0 g, 9.91 mmol) in acetonitrile (13 ml_) was irradiated in amicrowave oven at 100C for 10 min. The reaction mixture was diluted with EtOAc, washed with 1 N HCI and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was triturated with acetonitrile, ethyl acetate and diethyl ether to afford 1 -(6,7-difluoro-1 H-indol-3-yl)-2-(4-fluoro-2-methoxyphenyl)- 2-((3-methoxy-5-(methylsulfonyl)phenyl)amino)ethanone (Compound 13, 750 mg) as a racemic mixture.Chiral separation of the enantiomers of Compound 13 (1 .27 g) was performed via Preparative Chiral SFC (Stationary phase: Chiralpak IC 5 μιτι 250 x 30 mm, Mobile phase: 70% CO2, 30% MeOH) yielding after crystallization fromCH2Cl2/diisopropylether, 409 mg of the first eluted enantiomer (Enantiomer 13A) and 385 mg of the second eluted enantiomer (Enantiomer 13B).Compound 13:1H NMR (300 MHz, DMSO-c/6) δ ppm 3.09 (s, 3 H) 3.72 (s, 3 H) 3.98 (s, 3 H) 6.27 (d, J=7.9 Hz, 1 H) 6.56 - 6.63 (m, 2 H) 6.74 (td, J=8.4, 2.4 Hz, 1 H) 6.92 (s, 1 H) 6.96 (dd, J=1 1 .3, 2.4 Hz, 1 H) 7.06 (d, J=7.9 Hz, 1 H) 7.25 (m, 1 H) 7.36 (dd, J=8.6, 6.9 Hz, 1 H) 7.93 (dd, J=8.8, 4.4 Hz, 1 H) 8.51 (d, J= 2.8 Hz, 1 H) 12.8 (br. s., 1 H)LC-MS (method LC-F) Rt1 .41 min, MH+519 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
426 mg | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 85℃; | Synthesis of Compound 14 and chiral separation of Enantiomers 14A and 14B:A mixture 2-bromo-2-(4-fluoro-2-methoxyphenyl)-1 -(6-fluoro-5-methyl-1 H-indol-3- yl)ethanone 14b (1 .5 g, 3.65 mmol), <strong>[62606-02-4]3-methoxy-5-(methylsulfonyl)aniline</strong> [CAS 62606-02-4] (1 .10 g, 5.48 mmol) and diisopropylethylamine (629 μΙ_, 3.65 mmol) in CH3CN (100 ml_) was stirred at 85C overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in CH2CI2 (100 ml_), washed with 1 N HCI (100 ml_) and water (100 ml_), dried over MgSO , filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica (Stationary phase: Grace Reveleris silica 120 g, Mobile phase: EtOAc:EtOH(3:1 )/heptane gradient 0/100 to 50/50). The desired fractions were combined and evaporated under reduced pressure. The residual solid was stirred up in CH2CI2 (20 ml_). The precipitate was filtered off and washed withCH2CI2. The solid was stirred up in MeOH (20 ml_). The precipitate was filtered off and washed with MeOH. The solid (630 mg) was further purified via preparative HPLC (Stationary phase: Uptisphere C18 ODB - 10 μηη, 200 g, 5 cm, Mobile phase: 0.25% NH HCO3 solution in water, CH3CN). The desired fractions were combined, evaporated under reduced pressure, and co-evaporated with EtOAc (20 mL) to give 2-(4-fluoro-2-methoxyphenyl)-1 -(6-fluoro-5-methyl-1 H-indol-3-yl)-2- ((3-methoxy-5-(methylsulfonyl)phenyl)amino)ethanone (Compound 14, 426 mg) as a racemic mixture.Chiral separation of the enantiomers of Compound 14 (426 mg) was performed via preparative SFC (Stationary phase: Chiralpak Diacel AD 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4% /PrNH2). The product fractions were combined and evaporated to provide Enantiomer 14A as the first eluted product and Enantiomer 14B as the second eluted product. Both enantiomers 14A and 14B were solidified as follows: the evaporation residues were stirred up in H2O/MeOH 1/1 (5 mL) for 1 h, The precipitate was isolated by filtration, washed with H2O/MeOH 1/1 and dried at under vacuum at 50C to provide Enantiomer 14A (1 13 mg) andEnantiomer 14B (97 mg) as white powders.Compound 14:1H NMR (400 MHz, DMSO-c/6) δ ppm 2.30 (d, J=1 .3 Hz, 3 H) 3.08 (s, 3 H) 3.72 (s, 3 H) 3.99 (s, 3 H) 6.21 (d, J=7.7 Hz, 1 H) 6.58 (d, J=1 .8 Hz, 2 H) 6.73 (td, J=8.5, 2.5 Hz, 1 H) 6.91 (t, J=1 .8 Hz, 1 H) 6.95 (dd, J=1 1 .4, 2.4 Hz, 1 H) 6.99 (d, J=7.7 Hz, 1 H) 7.22 (d, J=10.3 Hz, 1 H) 7.36 (dd, J=8.6, 6.8 Hz, 1 H) 8.03 (d, J=7.9 Hz, 1 H) 8.37 (s, 1 H) 1 1 .95 (br s, 1 H)LC/MS (method LC-B): Rt2.07 min, MH+515 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.92 g | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20 - 80℃; | Synthesis of Compound 15 and chiral separation of Enantiomers 15A and 15B:A mixture 2-bromo-2-(4-fluoro-2-methoxyphenyl)-1 -(5-methyl-1 H-indol-3-yl)- ethanone 15b (3.5 g, 9.3 mmol), <strong>[62606-02-4]3-methoxy-5-(methylsulfonyl)aniline</strong> [CAS 62606- 02-4] (2.81 g, 14 mmol) and diisopropylethylamine (1 .60 ml_, 9.3 mmol) in CH3CN was stirred overnight at room temperature. The reaction temperature was increased to 80C for 1 h and the mixture was subsequently stirred again at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in CH2CI2 (100 ml_), washed with 1 N HCI (100 ml_) and brine (100 ml_), dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography(Stationary phase: Grace Reveleris silica 120 g, Mobile phase: EtOAc/heptane gradient 35/65 to 45/55). The desired fractions were combined and evaporated under reduced pressure. The residue (3.96 g) was further purified via preparative HPLC (Stationary phase: Uptisphere C18 ODB - 10 μητι, 200 g, 5 cm, Mobile phase: 0.25% NH HCO3 solution in water, CH3CN). The desired fractions were combined, evaporated under reduced pressure, and co-evaporated with EtOAc (20 ml_). The residual solid was stirred up in a mixture of MeOH (5 ml_) and water (5 mL) for 1 h. The precipitate was filtered off and dried under vacuum to give 2-(4-fluoro-2-methoxyphenyl)-2-((3-methoxy-5-(methylsulfonyl)phenyl)amino)-1 - (5-methyl-1 /-/-indol-3-yl)ethanone (Compound 15, 1 .92 g) as a racemic mixture. Chiral separation of the enantiomers of Compound 15 (1 .50 g) was performed via Normal Phase Chiral separation (Stationary phase: AS 20 μιτι, Mobile phase: 100% methanol). The product fractions were combined and evaporated to provideEnantiomer 15A (742 mg) as the first eluted product and Enantiomer 15B (745 mg) as the second eluted product. Enantiomer 15A was further purified by column chromatography on silica (stationary phase: Grace Reveleris silica 40 g, Mobile phase: CH2CI2/MeOH gradient 100/0 to 90/10). The fractions containing product were combined and evaporated. The solid residue was stirred up in MeOH/water (1/1 ) (14 mL) for 2 h. The precipitate was filtered off and dried under vacuum at 50C to provide Enantiomer 15A (361 mg) as a white powder. Enantiomer 15B was stirred up in MeOH/water (1/1 ) (14 mL) for 5 h. The precipitate was filtered off and dried under vacuum at 50C to provide Enantiomer 15B (445 mg) as a white powder.Compound 15:1H NMR (360 MHz, DMSO-c/6) δ ppm 2.39 (s, 3 H) 3.09 (s, 3 H) 3.72 (s, 3 H) 4.00 (s, 3 H) 6.22 (d, J=7.7 Hz, 1 H) 6.55 - 6.62 (m, 2 H) 6.73 (td, J=8.5, 2.4 Hz, 1 H) 6.92 (br s, 1 H) 6.96 (dd, J=1 1 .3, 2.6 Hz, 1 H) 6.99 - 7.06 (m, 2 H) 7.31 - 7.39 (m, 2 H) 7.98 (s, 1 H) 8.37 (s, 1 H) 1 1 .94 (br s, 1 H)LC/MS (method LC-A): Rt1 .09 min, MH+497 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
309 mg | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 60 - 90℃; | Synthesis of Compound 16 and chiral separation of Enantiomers 16A and 16B:A mixture 2-bromo-1 -(5-chloro-6-methoxy-1 H-indol-3-yl)-2-(4-fluoro-2-methoxy- phenyl)ethanone 16b (3.02 g, 6.58 mmol), <strong>[62606-02-4]3-methoxy-5-(methylsulfonyl)aniline</strong> [CAS 62606-02-4] (1 .81 g, 8.99 mmol) and diisopropylethylamine (1 .13 mL, 6.58 mmol) in CH3CN (120 mL) was stirred overnight at 60C. The reaction temperature was increased to 80C for 8 h and finally to 90C with overnight stirring. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in CH2CI2 (100 mL), washed with 1 N HCI (100 mL) and water (100 mL), dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified via Preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD - 10 pm, 50 x 150 mm, Mobile phase: 0.25% NH4HCO3solution in water, CH3CN). The desired fractions were combined and evaporated under reduced pressure. The residue was stirred up in EtOAc (20 mL). The solids were isolated by filtration to provide a first crop of 1 -(5-chloro-6-methoxy-1 H-indol- 3-yl)-2-(4-fluoro-2-methoxyphenyl)-2-((3-methoxy-5-(methylsulfonyl)phenyl)- amino)ethanone (Compound 16, 309 mg) as a racemic mixture. The filtrate was evaporated under reduced pressure. MeOH was added and the resultingsuspension was stirred up for 30 min. the Solids were filtered off to provide a second crop of racemic Compound 16 (423 mg).Chiral separation of the enantiomers of Compound 16 (493 mg) was performed via Normal Phase Chiral separation (Stationary phase: AS 20 μιτι, Mobile phase: 100% methanol). The product fractions were combined and evaporated to provideEnantiomer 16A as the first eluted product and Enantiomer 16B as the second eluted product. Enantiomer 16A was stirred up in MeOH (5 ml_) for 30 min. The precipitate was filtered off, washed with MeOH (2x 2 ml_) and dried under vacuum at 50C to provide Enantiomer 16A (156 mg) as a white powder. Enantiomer 16B was stirred up in MeOH (5 ml_) for 30 min. The precipitate was filtered off, washed with MeOH (2x 2 ml_) and dried under vacuum at 50C to provide Enantiomer 16B (146 mg) as a white powder. Compound 16:1H NMR (400 MHz, DMSO-c/6) δ ppm 3.08 (s, 3 H) 3.72 (s, 3 H) 3.87 (s, 3 H) 3.99 (s, 3 H) 6.20 (d, J=7.7 Hz, 1 H) 6.59 (d, J=1 .3 Hz, 2 H) 6.73 (td, J=8.5, 2.4 Hz, 1 H) 6.91 (t, J=1 .8 Hz, 1 H) 6.96 (dd, J=1 1 .4, 2.4 Hz, 1 H) 7.01 (d, J=7.9 Hz, 1 H) 7.14 (s, 1 H) 7.36 (dd, J=8.6, 6.8 Hz, 1 H) 8.12 (s, 1 H) 8.35 (s, 1 H) 1 1 .98 (br s, 1 H) LC/MS (method LC-B): Rt2.02 min, MH+547 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
410 mg | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; acetonitrile; at 70℃; for 24h; | Synthesis of Compound 17 and chiral separation of Enantiomers 17A and 17B: A mixture of 2-bromo-2-(4-fluoro-2-methoxyphenyl)-1 -(5-(trifluoromethyl)-1 /-/-indol-3- yl)ethanone 17d (1 .2 g, 2.79 mmol), <strong>[62606-02-4]3-methoxy-5-(methylsulfonyl)aniline</strong> [CAS 62606-02-4] (617 mg, 3.07 mmol) and diisopropylethylamine (0.48 ml_, 2.79 mmol) in CH3CN (60 ml_) and THF (30 ml_) was stirred at 70C for 24 h. The solution was concentrated under reduced pressure. The residue was dissolved in EtOAc and the solution was washed with 1 N HCI. The organic layer was separated, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (15-40 μιτι, 80 g, CH2CI2/MeOH 99.5/0.5). The fractions containing Compound 17 were combined and the solvent was evaporated under reduced pressure. The compound was crystallized from diisopropylether/CH3CN to give 2-(4-fluoro-2-methoxyphenyl)-2-((3-methoxy-5- (methylsulfonyl)phenyl)amino)-1 -(5-(trifluoromethyl)-1 /-/-indol-3-yl)ethanone(Compound 17, 410 mg) as a racemic mixture.The Enantiomers of Compound 17 were separated via preparative Chiral SFC (Stationary phase: Chiralpak AD-H 5 μηη 250 x 20 mm, Mobile phase: 75% CO2, 25% /PrOH) to give, after crystallization from petroleum ether/diisopropylether, 147 mg of the first eluted enantiomer 17A and 150 mg of the second eluted enantiomer 17B.Compound 17:1H NMR (500 MHz, DMSO-c/6) δ ppm 3.09 (s, 3 H) 3.72 (s, 3 H) 3.98 (s, 3 H) 6.27 (d, J=7.9 Hz, 1 H) 6.59 (d, J=1 .3 Hz, 2 H) 6.74 (td, J=8.4, 2.4 Hz, 1 H) 6.92 (s, 1 H) 6.97 (dd, J=1 1 .3, 2.5 Hz, 1 H) 7.06 (d, J=7.9 Hz, 1 H) 7.37 (dd, J=8.5, 6.9 Hz, 1 H) 7.54 (dd, J=8.5, 1 .6 Hz, 1 H) 7.69 (d, J=8.5 Hz, 1 H) 8.49 (s, 1 H) 8.60 (s, 1 H) 12.43 (br s, 1 H)LC/MS (method LC-C): Rt3.09 min, MH+551Melting point: 160C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
608 mg | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 90℃; for 24h; | Synthesis of Compound 18 and chiral separation of Enantiomers 18A and 18B: A mixture 2-bromo-2-(4-fluoro-2-methoxyphenyl)-1 -(5-(trifluoromethoxy)-1 H-indol- 3-yl)ethanone 18b (3 g, 6.72 mmol), <strong>[62606-02-4]3-methoxy-5-(methylsulfonyl)aniline</strong> [CAS 62606-02-4] (1 .85 g, 9.18 mmol) and diisopropylethylamine (1 .16 mL, 6.72 mmol) in CH3CN (120 mL) was stirred at 90C for 24 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in CH2CI2 (100 mL), washed with 1 N HCI (100 mL) and water (100 mL), dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatograph on silica (Stationary phase: Grace Reveleris silica 120 g, Mobile phase: EtOAc:EtOH (3:1 )/heptane gradient 0/100 to 50/50). The desired fractions were combined and evaporated under reduced pressure. The residue was stirred up in EtOAc (20 ml_). The solids were isolated by filtration and dried under vacuum at 50C to provide 2-(4-fluoro-2-methoxyphenyl)-2-((3-methoxy-5- (methylsulfonyl)phenyl)amino)-1 -(5-(trifluoromethoxy)-1 /-/-indol-3-yl)ethanone (Compound 18, 608 mg) as a racemic mixture.Chiral separation of the enantiomers of Compound 18 (578 mg) was performed via Normal Phase Chiral separation (Stationary phase: AS 20 μιτι, Mobile phase: 100% methanol). The product fractions were combined and evaporated to provideEnantiomer 18A as the first eluted product and Enantiomer 18B as the second eluted product. Enantiomer 18A was precipitated by overnight stirring fromMeOH/water. The precipitate was filtered off and dried under vacuum at 50C to provide Enantiomer 18A (123 mg) as a white powder. Enantiomer 18B was precipitated by overnight stirring from MeOH/water. The precipitate was filtered off and dried under vacuum at 50C to provide Enantiomer 18B (91 mg) as a white powder. Compound 18:1H NMR (400 MHz, DMSO-c/6) δ ppm 3.09 (s, 3 H) 3.73 (s, 3 H) 3.99 (s, 3 H) 6.25 (d, J=7.7 Hz, 1 H) 6.59 (d, J=1 .3 Hz, 2 H) 6.74 (td, J=8.5, 2.5 Hz, 1 H) 6.92 (t, J=1 .3 Hz, 1 H) 6.96 (dd, J=1 1 .2, 2.4 Hz, 1 H) 7.05 (d, J=7.7 Hz, 1 H) 7.21 (dd, J=8.7, 1 .9 Hz, 1 H) 7.38 (dd, J=8.6, 6.8 Hz, 1 H) 7.59 (d, J=8.8 Hz, 1 H) 8.07 (br s, 1 H) 8.54 (s, 1 H) 12.28 (br s, 1 H)LC/MS (method LC-B): Rt2.13 min, MH+567 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9.9 g | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 50℃; for 48h; | A stirred solution of 1 -(6-fluoro-1 H-indol-3-yl)-2-(4-fluoro-2-methoxyphenyl)- ethanone 1 b (1 1 .0 g, 36.3 mmol) in THF (300 mL) was cooled to 0C under N2-atmosphere. A solution of phenyltrimethylammonium tribromide [CAS 4207- 56-1 ] (14.3 g, 38.2 mmol) in THF (100 mL) was added dropwise over a period of 45 min. The resulting suspension was stirred at room temperature for 4 h and evaporated under reduced pressure to a white residue. This residue, containing the crude 2-bromo-1 -(6-fluoro-1 H-indol-3-yl)-2-(4-fluoro-2-methoxyphenyl)- ethanone 1c, was dissolved in acetonitrile (300 mL). After addition of 3-methoxy-5- (methylsulfonyl)aniline [CAS 62606-02-4] (14.8 g, 73 mmol) and diisopropylethyl- amine (13 mL, 75 mmol), the mixture was stirred at 50C for two days - until complete conversion to Compound 1. The reaction mixture was concentrated under reduced pressure, the residue was mixed with water (500 mL) and the product was extracted with 2-methyl-THF (2x 500 mL). The combined organic layers were washed with 0.5N HCI (800 mL), a saturated aqueous solution of NaHCO3 (200 mL) and brine (200 mL), dried over MgSO , filtered and evaporated under reduced pressure. The residue was crystallized from EtOAc (50 mL). The solids were filtered off and dried under vacuum at 50C to give 1 -(6-fluoro-1 H- indol-3-yl)-2-(4-fluoro-2-methoxyphenyl)-2-((3-methoxy-5-(methylsulfonyl)phenyl)- amino)ethanone (Compound 1 , 9.9 g) as a racemic mixture. Chiral separation of the enantiomers of Compound 1 (9.67 g) was performed via Normal Phase Chiral Chromatography (Stationary phase: AS 20 μιτι (1 kg), Mobile phase: 100% MeOH). The product fractions containing the first eluted enantiomer were combined and evaporated under reduced pressure (water bath 38C) to a residual volume of 30 mL. The resulting suspension was filtered and the solids were washed with small fractions of MeOH and dried under vacuum at 40C to provide Enantiomer 1A (2.9 g) as a white solid. The combined product fractions of the second eluted product were evaporated under reduced pressure (water bath 37C) until a residual volume of 90 mL. The solids were filtered off, washed with small fractions of MeOH and dried under vacuum at 40C to provide Enantiomer 1 B (3.15 g). Compound 1 : 1H NMR (360 MHz, DMSO-c/6) δ ppm 3.09 (s, 3 H) 3.73 (s, 3 H) 3.99 (s, 3 H) 6.23 (d, J=7.75 Hz, 1 H) 6.56 - 6.62 (m, 2 H) 6.74 (td, J=8.48, 2.48 Hz, 1 H) 6.91 (t, J=1 .46 Hz, 1 H) 6.96 (dd, J=1 1 .35, 2.50 Hz, 1 H) 7.02 - 7.1 1 (m, 2 H) 7.28 (dd, J=9.62, 2.38 Hz, 1 H) 7.37 (dd, J=8.61 , 6.83 Hz, 1 H) 8.15 (dd, J=8.76, 5.59 Hz, 1 H) 8.44 (s, 1 H) 12.09 (br. s., 1 H) LC/MS (method LC-A): Rt 1 .08 min, MH+ 501 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
352 mg | With N-ethyl-N,N-diisopropylamine; In acetonitrile; for 18h;Reflux; | Synthesis of Compound 4 and chiral separation of Enantiomers 4A and 4B: A solution of 1 -(6-chloro-1 H-indol-3-yl)-2-(4-fluoro-2-methoxyphenyl)ethanone 4a (0.8 g, 2.52 mmol) in THF (40 ml_) was stirred under N2-flow and cooled on an ice- bath. Phenyltrimethylammonium tribromide [CAS 4207-56-1 ] (0.99 g, 2.64 mmol) was added portionwise and the mixture was stirred at 0C for 1 h andsubsequently at room temperature for 1 h. The solids were removed from the reaction mixture by filtration. The filtrate, containing crude 2-bromo-1 -(6-chloro-1 H- indol-3-yl)-2-(4-fluoro-2-methoxyphenyl)ethanone 4b, was mixed with 3-methoxy- 5-(methylsulfonyl)aniline [CAS 62606-02-4] (0.56 g, 2.77 mmol) anddiisopropylethylamine (1 .3 ml_, 7.55 mmol) and the solvents were evaporated under reduced pressure. The residue was taken up with CH3CN (50 ml_) and heated under reflux for 18 h. After cooling to room temperature, the reaction mixture was poured out in water (250 ml_). The products were extracted with 2-methyl-THF (2x) and the combined organic layers were dried over MgSO4, filtered and evaporated under reduced pressure. The residue was stirred up in EtOAc (7.5 ml_) and the solids were filtered off. The filtrate was evaporated under reduced pressure and the residue was purified by flash chromatography on silica (Stationary phase: Grace Reveleris silica 40 g, Mobile phase: heptane/EtOAc gradient 100/0 to 0/100). The fractions containing product were combined and evaporated, and the residue was further purified via Preparative HPLC (Stationary phase: Uptisphere C18 ODB - 10 μητι, 200 g, 5 cm, Mobile phase: 0.25%NH HCO3 solution in water, CH3CN). The product fractions were combined and evaporated under reduced pressure, and the residue was co-evaporated with MeOH. The solid residue was stirred up in Et2O (7.5 ml_), filtered off and dried under vacuum at 50C to provide racemic 1 -(6-chloro-1 H-indol-3-yl)-2-(4-fluoro-2- methoxyphenyl)-2-((3-methoxy-5-(methylsulfonyl)phenyl)amino)ethanone(Compound 4, 352 mg).Chiral separation of the enantiomers of Compound 4 (352 mg) was done via Normal Phase Chiral separation (Stationary phase: AS 500 g 20 μιτι, Mobile phase: 100% MeOH). The product fractions were combined and evaporated under reduced pressure. The first eluted product was stirred up in CH2CI2 (5 ml_), filtered off and dried under vacuum at 40C to provide Enantiomer 4A (56 mg). The second eluted product was stirred up in CH2CI2 (3.5 mL), filtered off and dried under vacuum at 40C to provide Enantiomer 4B (68 mg).Compound 4:1H NMR (500 MHz, DMSO-c/6) δ ppm 3.09 (s, 3 H) 3.73 (s, 3 H) 3.99 (s, 3 H) 6.24 (d, J=7.9 Hz, 1 H) 6.59 (s, 2 H) 6.74 (td, J=8.4, 2.2 Hz, 1 H) 6.92 (s, 1 H) 6.97 (dd, J=1 1 .2, 2.4 Hz, 1 H) 7.06 (d, J=7.9 Hz, 1 H) 7.23 (dd, J=8.5, 1 .6 Hz, 1 H) 7.37 (dd, J=8.4, 7.1 Hz, 1 H) 7.54 (d, J=1 .6 Hz, 1 H) 8.15 (d, J=8.5 Hz, 1 H) 8.47 (s, 1 H) 1 1 .82 - 12.42 (bs, 1 H)LC/MS (method LC-A): Rt1 .12 min, MH+517 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.74 g | In acetonitrile; at 20℃; for 48h;Inert atmosphere; | A mixture of 2-bromo-2-(4-chloro-2-methoxyphenyl)-1 -(7-methyl-5-(trifluoro- methoxy)-1 H-indol-3-yl)ethanone 11d (3.45 g, 6.87 mmol), 3-methoxy- 5-(methylsulfonyl)aniline [CAS 62606-02-4] (2.76 g, 13.7 mmol) and diisopropylethylannine (2.37 mL, 13.7 mmol) in CH3CN (60 mL) was stirred at room temperature for 2 days under N2-atmosphere. Water (125 mL) was added and the product was extracted with Et2O (2x). The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified via preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD - 10 pm, 50 x 150 mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN). The fractions containing product were combined and evaporated under reduced pressure to provide racemic 2-(4-chloro-2-methoxyphenyl)- 2-((3-methoxy-5-(methylsulfonyl)phenyl)amino)-1 -(7-methyl-5-(trifluoromethoxy)- 1 H-indol-3-yl)ethanone (Compound 11 , 1 .74 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.2 g | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; acetonitrile; at 70℃; for 24h; | A mixture of 2-bromo-2-(4-chloro-2-methoxyphenyl)-1 -(6-fluoro-1 H-indol-3-yl)- ethanone 1c (3 g, 7.56 mmol), <strong>[62606-02-4]3-methoxy-5-(methylsulfonyl)aniline</strong> [CAS 62606- 02-4] (2.28 g, 1 1 .35 mmol) and diisopropylethylamine (1 .95 ml_, 1 1 .35 mmol) in CH3CN (60 ml_) and THF (30 ml_) was stirred at 70C for 24 h. The reaction was diluted with EtOAc. The organic layer was washed with 1 N HCI (twice) and water, dried over MgSO4, filtered and the solvent was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (15- 40 μπτι, 80 g, Mobile phase: CH2CI2/MeOH 99.5/0.5). A second purification was carried out by flash chromatography on silica gel (15-40 μιτι, 80 g, Mobile phase: CH2Cl2/MeOH 99.7/0.3). The pure fractions were combined and concentrated under reduced pressure to give 2-(4-chloro-2-methoxyphenyl)-1 -(6-fluoro-1 H- indol-3-yl)-2-((3-methoxy-5-(methylsulfonyl)phenyl)amino)ethanone (Compound 1 , 2 g) as a racemic mixture. The enantiomers of Compound 1 were separated via Chiral SFC (Stationary phase: Chiralpak AD-H 5 μηη 20 x 250 mm, Mobile phase: 50% CO2, 50% MeOH) yielding 740 mg of the first eluted enantiomer and 720 mg of the second eluted enantiomer. The first eluted enantiomer was crystallized from CH3CN/Et2O. The precipitate was filtered off and dried to give Enantiomer 1A (645 mg). The second eluted enantiomer was crystallized from CH3CN/Et2O. The precipitate was filtered off and dried to give Enantiomer 1 B (632 mg). Compound 1 : 1H NMR (500 MHz, DMSO-c/6) δ ppm 3.09 (s, 3 H) 3.72 (s, 3 H) 4.00 (s, 3 H) 6.24 (d, J=7.9 Hz, 1 H) 6.58 (s, 2 H) 6.91 (s, 1 H) 6.97 (dd, J=8.7, 1 .9 Hz, 1 H) 7.02 - 7.09 (m, 2 H) 7.12 (d, J=1 .9 Hz, 1 H) 7.27 (dd, J=9.5, 1 .9 Hz, 1 H) 7.35 (d, J=8.5 Hz, 1 H) 8.14 (dd, J=8.7, 5.5 Hz, 1 H) 8.44 (s, 1 H) 12.10 (br. s., 1 H) LC/MS (method LC-C): Rt 3.08 min, MH+ 517 Melting point: 174C Enantiomer 1A: 1H NMR (500 MHz, DMSO-c/6) δ ppm 3.09 (s, 3 H) 3.72 (s, 3 H) 4.00 (s, 3 H) 6.24 (d, J=7.9 Hz, 1 H) 6.59 (s, 2 H) 6.91 (s, 1 H) 6.97 (dd, J=8.8, 2.2 Hz, 1 H) 7.02 - 7.10 (m, 2 H) 7.12 (d, J=2.2 Hz, 1 H) 7.27 (dd, J=9.6, 2.2 Hz, 1 H) 7.35 (d, J=8.2 Hz, 1 H) 8.14 (dd, J=8.8, 5.7 Hz, 1 H) 8.44 (s, 1 H) 12.10 (br. s., 1 H) LC/MS (method LC-C): Rt 3.09 min, MH+ 517 [a]D20: +130.3 (c 0.277, DMF) Chiral SFC (method SFC-D): Rt 3.41 min, MH+ 517, chiral purity 100%. Melting point: 220C Enantiomer 1 B: 1H NMR (400 MHz, DMSO-c/6) δ ppm 3.09 (s, 3 H) 3.72 (s, 3 H) 4.00 (s, 3 H) 6.24 (d, J=7.6 Hz, 1 H) 6.53 - 6.65 (m, 2 H) 6.91 (s, 1 H) 6.97 (dd, J=8.6, 2.0 Hz, 1 H) 7.01 - 7.09 (m, 2 H) 7.12 (d, J=2.0 Hz, 1 H) 7.27 (dd, J=9.6, 2.0 Hz, 1 H) 7.35 (d, J=8.1 Hz, 1 H) 8.14 (dd, J=8.6, 5.6 Hz, 1 H) 8.43 (s, 1 H) 12.09 (br. s., 1 H) LC/MS (method LC-C): Rt 3.09 min, MH+ 517 [a]D20: -135.3 (c 0.283, DMF) Chiral SFC (method SFC-D): Rt 4.89 min, MH+ 517, chiral purity 99.35%. Melting point: 218C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.7 g | In tetrahydrofuran; acetonitrile; at 100℃; for 0.833333h;Microwave irradiation; | A mixture of 2-bromo-2-(4-chloro-2-methoxyphenyl)-1 -(6-fluoro-7-methyl-1 /-/-indol- 3- yl)ethanone 2b (1 .8 g, 4.36 mmol) and <strong>[62606-02-4]3-methoxy-5-(methylsulfonyl)aniline</strong> [CAS 62606-02-4] (2.6 g, 13.0 mmol) in THF (9 ml_) and CH3CN (9 ml_) was heated at 100C under microwave irradiation for 50 min. The reaction mixture was diluted with EtOAc and washed with 1 N HCI. The phases were separated. The organic phase was washed with an aqueous saturated NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was taken up with a minimum of acetonitrile. The precipitate was filtered off, washed with acetonitrile and dried under vacuum to give 2-(4-chloro-2-methoxy- phenyl)-1 -(6-fluoro-7-methyl-1 H-indol-3-yl)-2-((3-methoxy-5-(methylsulfonyl)- phenyl)amino)ethanone (Compound 2, 1 .7 g) as a racemic mixture. The chiral separation of the enantiomers of Compound 2 (1 .59 g) was performed via Preparative SFC (Stationary phase: (S,S)-Whelk-O1 5 μηη 250 x 21 .1 mm, Mobile phase: 50% CO2, 50% MeOH). The product fractions were combined and evaporated under reduced pressure. The first eluted enantiomer (746 mg) was further purified by column chromatography on silica gel (15-40 μιτι, 24 g, Mobile phase: CH2CI2/MeOH 99.5/0.5). The pure fractions were combined and evaporated under reduced pressure (560 mg). The residue was solidified by trituration with a mixture of Et2O and a few drops of CH3CN. The solids were filtered off and dried under vacuum to give Enantiomer 2A (473 mg). The second eluted enantiomer (732 mg) was further purified by column chromatography over silica gel (15-40 μπτι, 24 g, Mobile phase: CH2CI2/MeOH 99.5/0.5). The pure fractions were combined and evaporated under reduced pressure (550 mg). The residue was solidified by trituration with a mixture of Et2O and a few drops of CH3CN. The solids were filtered off and dried under vacuum to give of Enantiomer 2B (457 mg). Compound 2: 1H NMR (300 MHz, DMSO-c/6) δ ppm 2.38 (d, J=1 .5 Hz, 3 H) 3.10 (s, 3 H) 3.73 (s, 3 H) 4.01 (s, 3 H) 6.27 (d, J=7.9 Hz, 1 H) 6.55 - 6.63 (m, 2 H) 6.93 (m, 1 H) 6.94 - 7.09 (m, 3 H) 7.13 (d, J=1 .9 Hz, 1 H) 7.35 (d, J=8.3 Hz, 1 H) 7.97 (dd, J=8.7, 5.3 Hz, 1 H) 8.45 (s, 1 H) 12.23 (br. s, 1 H) LC/MS (method LC-D): Rt 1 .68 min, MH+ 531 Enantiomer 2A: 1H NMR (500 MHz, DMSO-c/6) δ ppm 2.37 - 2.39 (m, 3 H) 3.09 (s, 3 H) 3.72 (s, 3 H) 4.01 (s, 3 H) 6.26 (d, J=7.9 Hz, 1 H) 6.54 - 6.63 (m, 2 H) 6.92 (s, 1 H) 6.97 (dd, J=8.4, 1 .9 Hz, 1 H) 7.02 (dd, J=9.9, 9.0 Hz, 1 H) 7.07 (d, J=7.9 Hz, 1 H) 7.13 (d, J=1 .9 Hz, 1 H) 7.35 (d, J=8.4 Hz, 1 H) 7.96 (dd, J=8.5, 5.4 Hz, 1 H) 8.45 (s, 1 H) 12.24 (br. s., 1 H) LC/MS (method LC-C): Rt 3.20 min, MH+ 531 [a]D20: +104.5 (c 0.2545, DMF) Chiral SFC (method SFC-A): Rt 4.22 min, MH+ 531 , chiral purity 100%. Enantiomer 2B: 1H NMR (500 MHz, DMSO-c/6) δ ppm 2.36 - 2.41 (m, 3 H) 3.09 (s, 3 H) 3.72 (s, 3 H) 4.01 (s, 3 H) 6.26 (d, J=7.9 Hz, 1 H) 6.57 - 6.64 (m, 2 H) 6.92 (s, 1 H) 6.97 (dd, J=8.2, 1 .9 Hz, 1 H) 6.99 - 7.04 (m, 1 H) 7.07 (d, J=7.9 Hz, 1 H) 7.13 (d, J=1 .9 Hz, 1 H) 7.35 (d, J=8.2 Hz, 1 H) 7.96 (dd, J=8.7, 5.2 Hz, 1 H) 8.45 (s, 1 H) 12.24 (br. s., 1 H) LC/MS (method LC-C): Rt 3.20 min, MH+ 531 [a]D20: -104.1 (c 0.2536, DMF) Chiral SFC (method SFC-A): Rt 5.12 min, MH+ 531 , chiral purity 99.53%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
681 mg | A stirred mixture of 2-(4-chloro-2-methoxyphenyl)-1 -(6-methoxy-1 /-/-indol-3-yl)- ethanone 3c (2 g, 6.07 mmol) in THF (80 ml_) was cooled on an ice-bath under N2-atm. Phenyltnmethylammonium tribromide [CAS 4207-56-1 ] (2.39 g, 6.37 mmol) was added and the reaction mixture was stirred at 0C for 1 h and subsequently at room temperature for 1 .5 h. 3-Methoxy-5-(methylsulfonyl)aniline [CAS 62606-02-4] (3.66 g, 18.2 mmol) was added and the solvent was evaporated under reduced pressure. The residue was dissolved in CH3CN (100 ml_). Diisopropylethylamine (2.09 ml_, 12.1 mmol) was added and the reaction mixture was heated at 55C for 27 h. The reaction mixture was allowed to cool to room temperature and poured out into stirring water (400 ml_). The product was extracted with 2-MeTHF (2x). The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure. The residue (8 g) was purified by flash chromatography (stationary phase: Grace Reveleris silica 120 g, Mobile phase: heptane/EtOAc gradient from 100/0 to 0/100). The desired fractions were combined and evaporated under reduced pressure. The residue (5.4 g) was further purified by Preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD - 10 pm, 50 x 150 mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN). The product fractions were combined and evaporated under reduced pressure and subsequently co-evaporated with MeOH. The residue was crystallized from a mixture of EtOAc (15 ml_), CH3CN (2 ml_) and MeOH (2 ml_). The solids were filtered off, washed with EtOAc (3x) and dried under vacuum at 50C to provide 2-(4-chloro-2-methoxyphenyl)-1 -(6-methoxy-1 H-indol-3-yl)-2- ((3-methoxy-5-(methylsulfonyl)phenyl)amino)ethanone (Compound 3, 681 mg) as a racemic mixture. The chiral separation of the enantiomers of Compound 3 (0.63 g) was performed via Normal Phase Chiral separation (Stationary phase: AS 20 μΜ, Mobile phase: 100% methanol). The product fractions were combined and evaporated under reduced pressure. The first eluted enantiomer was purified by flash chromatography (Stationary phase: Grace Reveleris silica 12 g, Mobile phase: heptane/EtOAc/EtOH gradient from 100/0/0 to 40/45/15). The desired fractions were combined and evaporated, and co-evaporated with EtOAc. The remaining oil was solidified by stirring up in H2O (4 ml_) and slow addition of MeOH (1 .6 ml_). After stirring for 20 minutes, the product was filtered off, washed (3x) with a 1/2 mixture of MeOH/H2O and dried under vacuum at 50C to provide Enantiomer 3A (168 mg) as an amorphous solid. The second eluted enantiomer was purified by flash chromatography (Stationary phase: Grace Reveleris silica 12 g, Mobile phase: heptane/EtOAc/EtOH gradient from 100/0/0 to 40/45/15). The desired fractions were combined, evaporated under reduced pressure and co-evaporated with EtOAc. The remaining foam was solidified by stirring up in H2O (4 ml_) and slow addition of MeOH (2 ml_). After stirring for 15 minutes, the product was filtered off, washed (3x) with a 1/2 mixture of MeOH/H2O and dried at 50C under vacuum to provide Enantiomer 3B (146 mg) as an amorphous solid. Compound 3: 1H NMR (400 MHz, DMSO-c/6) δ ppm 3.09 (s, 3 H) 3.72 (s, 3 H) 3.77 (s, 3 H) 4.01 (s, 3 H) 6.21 (d, J=7.9 Hz, 1 H) 6.54 - 6.64 (m, 2 H) 6.83 (dd, J=8.7, 2.3 Hz, 1 H) 6.91 (t, J=1 .4 Hz, 1 H) 6.94 - 6.99 (m, 2 H) 7.04 (d, J=7.7 Hz, 1 H) 7.12 (d, J=2.0 Hz, 1 H) 7.35 (d, J=8.1 Hz, 1 H) 8.02 (d, J=8.8 Hz, 1 H) 8.30 (s, 1 H) 1 1 .84 (s, 1 H) LC/MS (method LC-A): Rt 1 .20 min, MH+ 529 Enantiomer 3A: 1H NMR (360 MHz, DMSO-c/6) δ ppm 3.09 (s, 3 H) 3.72 (s, 3 H) 3.77 (s, 3 H) 4.01 (s, 3 H) 6.22 (d, J=8.1 Hz, 1 H) 6.55 - 6.61 (m, 2 H) 6.84 (dd, J=8.8, 2.2 Hz, 1 H) 6.91 (t, J=1 .8 Hz, 1 H) 6.94 - 7.00 (m, 2 H) 7.07 (d, J=7.0 Hz, 1 H) 7.13 (d, J=1 .8 Hz, 1 H) 7.35 (d, J=8.4 Hz, 1 H) 8.02 (d, J=8.8 Hz, 1 H) 8.32 (d, J=2.9 Hz, 1 H) 1 1 .87 (d, J=2.6 Hz, 1 H) LC/MS (method LC-A): Rt 1 .08 min, MH+ 529 [a]D20: +134.9 (c 0.545, DMF) Chiral SFC (method SFC-E): Rt 4.31 min, MH+ 529, chiral purity 100%. Enantiomer 3B: 1H NMR (360 MHz, DMSO-c/6) δ ppm 3.09 (s, 3 H) 3.72 (s, 3 H) 3.77 (s, 3 H) 4.01 (s, 3 H) 6.21 (d, J=8.1 Hz, 1 H) 6.54 - 6.62 (m, 2 H) 6.83 (dd, J=8.6, 2.4 Hz, 1 H) 6.91 (t, J=1 .5 Hz, 1 H) 6.94 - 6.99 (m, 2 H) 7.07 (d, J=7.0 Hz, 1 H) 7.13 (d, J=1 .8 Hz, 1 H) 7.35 (d, J=8.1 Hz, 1 H) 8.02 (d, J=8.8 Hz, 1 H) 8.32 (d, J=2.9 Hz, 1 H) 1 1 .87 (br d, J=2.2 Hz, 1 H) LC/MS (method LC-A): Rt 1 .08 min, MH+ 529 [a]D20: -1 16.7 (c 0.51 , DMF) Chiral SFC (method SFC-E): Rt 4.63 min, MH+ 529, chiral purity 94.7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.1 g | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; acetonitrile; at 45℃; for 72h; | A mixture of 2-bromo-2-(4-chloro-2-methoxyphenyl)-1 -(6-methoxy-5-methyl-1 H- indol-3-yl)ethanone 4b (4.0 g, 9.46 mmol), <strong>[62606-02-4]3-methoxy-5-(methylsulfonyl)aniline</strong> [CAS 62606-02-4] (2.86 g, 14.2 mmol) and diisopropylethylamine (2.44 ml_, 14.2 mmol) in CH3CN/THF (1/1 ) (100 ml_) was stirred at 45C for 72 h. The solvents were removed under reduced pressure. The residue was dissolved in EtOAc. The organic layer was washed twice with 1 N HCI, washed with water, dried over MgSO4, filtered and concentrated under reduced pressure. The compound was crystallized from CH3CN/diisopropylether to give 2-(4-chloro- 2-methoxyphenyl)-2-((3-methoxy-5-(methylsulfonyl)phenyl)amino)-1 -(6-methoxy- 5-methyl-1 /-/-indol-3-yl)ethanone (Compound 4, 1 .1 g) as a racemic mixture. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.3 g | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; acetonitrile; at 50℃; for 240h; | A mixture of 2-bromo-2-(4-chloro-2-methoxyphenyl)-1 -(5-fluoro-6-methoxy-1 H- indol-3-yl)ethanone 5b (2.5 g, 5.86 mmol), <strong>[62606-02-4]3-methoxy-5-(methylsulfonyl)aniline</strong> [CAS 62606-02-4] (1 .415 g, 7.03 mmol) and diisopropylethylamine (1 .515 ml_, 8.79 mmol) in CH3CN (55 ml_) and THF (100 ml_) was stirred at 50C for 10 days. The solvents were removed under reduced pressure. The residue was purified by flash chromatography on silica gel (15-40 μιτι, 80 g, Mobile phase: CH2CI2/CH3OH 99.25/0.75). The pure fractions were combined and evaporated. The compound was dissolved in EtOAc and stirred with HCI 1 N for 15 min. A precipitate appeared, and was filtered off and dried under vacuum to give 2-(4-chloro-2-methoxyphenyl)- 1 -(5-fluoro-6-methoxy-1 /-/-indol-3-yl)-2-((3-methoxy-5-(methylsulfonyl)phenyl)- amino)ethanone (Compound 5, 1 .3 g) as a racemic mixture. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1 g | With N-ethyl-N,N-diisopropylamine; In acetonitrile;Reflux; | A mixture of 2-bromo-2-(4-chloro-2-methoxyphenyl)-1 -(6-methoxy-7-methyl-1 /-/- indol-3-yl)ethanone 6b (1 .96 g, 4.65 mmol), <strong>[62606-02-4]3-methoxy-5-(methylsulfonyl)aniline</strong> [CAS 62606-02-4] (1 .40 g, 6.97 mmol) and diisopropylethylamine (1 .20 ml_, 6.97 mmol) in CH3CN (50 ml_) was heated overnight under reflux. The solvents were removed under reduced pressure. The residue was dissolved in CH2CI2 and washed with 0.5N HCI and water, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (Stationary phase: Biotage SNAP Ultra 100 g, Mobile phase: EtOAc:EtOH(3:1 )/heptane gradient 0/100 to 50/50). The pure fractions were combined and evaporated under reduced pressure to give 2-(4-chloro-2-methoxy- phenyl)-2-((3-methoxy-5-(methylsulfonyl)phenyl)amino)-1 -(6-methoxy-7-methyl- 1 H-indol-3-yl)ethanone (Compound 6, 1 .0 g) as a racemic mixture. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 85℃; | A mixture 2-bromo-2-(4-chloro-2-methoxyphenyl)-1 -(6-fluoro-5-methyl-1 H-indol- 3-yl)ethanone 7b (1 .6 g, 3.90 mmol), <strong>[62606-02-4]3-methoxy-5-(methylsulfonyl)aniline</strong> [CAS 62606-02-4] (1 .18 g, 5.84 mmol) and diisopropylethylamine (671 μΙ_, 3.90 mmol) in CH3CN (100 ml_) was stirred overnight at 85C. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in CH2CI2 (100 ml_), washed with 1 N HCI (100 ml_) and water (100 ml_), dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatograph (Stationary phase: Grace Reveleris silica 120 g, Mobile phase: EtOAc:EtOH(3:1 )/heptane gradient 0/100 to 50/50). The desired fractions were combined and evaporated under reduced pressure. The residue was precipitated from CH2Cl2/heptane. The solids were isolated by filtration and washed with CH2Cl2/heptane (1/1 ). The crude product was further purified by Preparative HPLC (Stationary phase: Uptisphere C18 ODB - 10 μηη, 200 g, 5 cm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN). The product fractions were combined and evaporated under reduced pressure. The solid residue was mixed with EtOAc (20 ml_) and the solids were isolated by filtration and washed with a small amount of EtOAc to provide 2-(4-chloro-2-methoxy- phenyl)-1 -(6-fluoro-5-methyl-1 H-indol-3-yl)-2-((3-methoxy-5-(methylsulfonyl)- phenyl)amino)ethanone (Compound 7, 341 mg) as a racemic mixture. The filtrate was evaporated under reduced pressure and the residue was taken up with MeOH. After stirring for 30 min, the solids were isolated by filtration to provide a second crop of Compound 7 (92 mg). |
A249531 [20945-70-4]
2-Methoxy-5-(methylsulfonyl)aniline
Similarity: 0.94
A768397 [3950-59-2]
5,5'-Sulfonylbis(2-methoxyaniline)
Similarity: 0.92
A110846 [41608-73-5]
2-Methoxy-4-(methylsulfonyl)aniline
Similarity: 0.92
A471055 [284462-84-6]
4-(4-(Methylsulfonyl)phenoxy)aniline
Similarity: 0.92
A280723 [1157510-20-7]
2-(4-(Methylsulfonyl)phenoxy)aniline
Similarity: 0.90
A249531 [20945-70-4]
2-Methoxy-5-(methylsulfonyl)aniline
Similarity: 0.94
A768397 [3950-59-2]
5,5'-Sulfonylbis(2-methoxyaniline)
Similarity: 0.92
A110846 [41608-73-5]
2-Methoxy-4-(methylsulfonyl)aniline
Similarity: 0.92
A471055 [284462-84-6]
4-(4-(Methylsulfonyl)phenoxy)aniline
Similarity: 0.92
A249531 [20945-70-4]
2-Methoxy-5-(methylsulfonyl)aniline
Similarity: 0.94
A768397 [3950-59-2]
5,5'-Sulfonylbis(2-methoxyaniline)
Similarity: 0.92
A110846 [41608-73-5]
2-Methoxy-4-(methylsulfonyl)aniline
Similarity: 0.92
A471055 [284462-84-6]
4-(4-(Methylsulfonyl)phenoxy)aniline
Similarity: 0.92
A280723 [1157510-20-7]
2-(4-(Methylsulfonyl)phenoxy)aniline
Similarity: 0.90
A249531 [20945-70-4]
2-Methoxy-5-(methylsulfonyl)aniline
Similarity: 0.94
A768397 [3950-59-2]
5,5'-Sulfonylbis(2-methoxyaniline)
Similarity: 0.92
A118040 [30203-11-3]
3,3'-((Sulfonylbis(4,1-phenylene))bis(oxy))dianiline
Similarity: 0.92
A110846 [41608-73-5]
2-Methoxy-4-(methylsulfonyl)aniline
Similarity: 0.92
A471055 [284462-84-6]
4-(4-(Methylsulfonyl)phenoxy)aniline
Similarity: 0.92