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CAS No. : | 263400-88-0 | MDL No. : | MFCD22124592 |
Formula : | C11H16O5S2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | AXUFUWARAAYMCG-UHFFFAOYSA-N |
M.W : | 292.37 | Pubchem ID : | 22732325 |
Synonyms : |
|
Num. heavy atoms : | 18 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.45 |
Num. rotatable bonds : | 6 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 68.97 |
TPSA : | 94.27 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.25 cm/s |
Log Po/w (iLOGP) : | 1.98 |
Log Po/w (XLOGP3) : | 1.18 |
Log Po/w (WLOGP) : | 3.3 |
Log Po/w (MLOGP) : | 1.66 |
Log Po/w (SILICOS-IT) : | 1.12 |
Consensus Log Po/w : | 1.85 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.25 |
Solubility : | 1.66 mg/ml ; 0.00567 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.76 |
Solubility : | 0.514 mg/ml ; 0.00176 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.97 |
Solubility : | 0.0313 mg/ml ; 0.000107 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 2.99 |
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 |
---|---|---|
83% | With triethylamine In dichloromethane for 12 h; Inert atmosphere | 4-Methylbenzene-1-sulfonyl chloride (759 mg, 3.98 mmol), 3-(methylsulfonyl)propan- 1-ol (500 mg, 3.62 mmol) and triethyl amine (0.555 ml_, 3,98 mmol) were dissolved in Dichloromethane Dry (5 mL) under nitrogen atmosphere, and the mixture was stirred for 12 hours. The solvent was removed under reduced pressure and the residue was purified by semi-preparative HPLC-UV, to afford 3-(methylsulfonyl)propyl 4- methylbenzenesulfonate (881 mg, Y = 83percent) as a white solid. MS (ESi+) m/z: 293.1 [M+H]+. (0255) Tert-butyl (4-hydroxy-2,6-dimethylphenyl)carbamate (which was synthesized as reported in the synthesis of compound 34) (269 mg, 1.13 mmol), 3- (methysulfonyl)propyl 4-methybenzenesulfonate (398 mg, 1.36 mmol) and potassium carbonate (188 mg, 1.36 mmol) were dissolved in N,N-Dimethylformamide Dry (2.5 ml) and the mixture was stirred at 80°C under nitrogen atmosphere for 12 hours. AcOEt (20 mL) was added, and the mixture was washed with brine (2 x 0 mL). The organic layer was concentrated under reduced pressure and the residue was purified by semi-preparative HPLC-UV, to afford tert-butyl (2,6-dimethyl-4-(3- (methylsulfonyl)propoxy)pheny[)carbamate (375 mg, Y = 93percent) as a white solid. MS (ESI+) m/z: 380.2 [ +Naf . (0256) Starting from tert-butyl (2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)carbamate (375 mg, 1.05 mmol), 2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)aniline, hydrochloride salt (309 mg, Y = quant.) was obtained as reported in the synthesis of compound 34. MS (ESI+) m/z: 258.1 [M+H]+. (0257) Starting from 2,6-dimethyl-4-(3-(methysulfonyl)propoxy)aniline, hydrochloride salt (46.1 mg, 0.157 mmoi) methyl 7-(3-(N-(2,6-dimethyl-4-(3- (methylsulfonyl)propoxy)phenyl)sulfamoyl) (0258) phenyl)heptanoate was obtained (33 mg, Y = 39percent) as described in Procedure A. MS (ESI+) m/z: 562.3 [M+Na]+. (0259) Compound 35 was then obtained by hydrolysis of the ester derivative (20 mg, 0.046 mmol) as described for compound 1 , as a white solid (23 mg, Y = 83percent). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.24 - 1.43 (m, 4 H) 1.51 - 1 .67 (m, 4 H) 1 .96 (s, 6 H) 2.26 - 2.41 (m, 4 H) 2.61 (t, J=7.58 Hz, 2 H) 2.97 (s, 3 H) 3.22 - 3.31 (m, 2 H) 4.04 (t, .7=5.68 Hz, 2 H) 6.32 (br s, 1 H) 6.52 (s, 2 H) 7.33 - 7.41 (m, 2 H) 7.48 - 7.58 (m, 2 H) 9.36 (br s, 2 H). MS (ESI+) m/z: 526.2 [M+H]+. |
1.6 g | With pyridine In dichloromethane at 0 - 20℃; for 12 h; | To a solution of 3-(methylsulfonyl)propan-1 -ol (1 .0 g) in dichloromethane (10 mL) and pyridine (1 .5 mL) is added at 0°C p-toluene-sulfonylchloride (1 .38 g) in portions. The mixture is stirred for 12 hours at room temperature, diluted with dichloromethane and washed with 1 M aqueous HCI solution and brine. After drying (MgSO4) the solvent is evaporated to give the title compound. Yield: 1 .6 g; LC (method 1 ): tR = 0.82 min; Mass spectrum (ESI+): m/z = 293 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With Oxone In methanol; water at 0 - 20℃; for 3 h; | To a solution of 16A (2.16 g, 8.31 mmol) in MeOH (44 mL) cooled to 0 °C was added a solution of OXONE® (10.2 g, 16.6 mmol) in water (44 mL). The ice bath was allowed to gradually warm to rt and the reaction mixture was stirred for 3 h. The MeOH was removed under reduced pressure and the reaction mixture was diluted with water. The aqueous layer was extracted with EtOAc (3x) and the combined organic layers were washed with brine, dried (MgS04), and concentrated to give 16B (2.39 g, 8.17 mmol, 98percent> yield) as a white solid. LC-MS Anal. Calc'd for CnHi605S2: 292.37, found [M+H] 293.0. |
96% | With Oxone In methanol; water at 0℃; for 20 h; | To a solution of 3- (methylthio) propyl 4- 5 methylbenzenesulfonate (12.2 g) in methanol, (250 ml) was added EPO <DP n="223"/>dropwise a solution of Oxone (trade name) (57.7 g) in water (250 ml) under ice-cooling. After completion of the dropwise addition, and the mixture was stirred for 20 hr while allowing to warm to room temperature. Methanol was evaporated under reduced pressure, and the mixture was diluted with water. The organic product was extracted with ethyl acetate. The extract was washed with saturated brine, dried (Na2SO4), and concentrated under reduced pressure. The precipitated crystals were washed with ethyl acetate-heptane to give 3- (methylsulfonyl) propyl 4-methylbenzenesul;fonate (13.1 g, yield: 96percent) as colorless crystals. MS m/z 293 (MH+). |
96% | With Oxone In methanol; water at 0 - 20℃; for 20 h; | Reference Example 16; 3- (methylsulfonyl) propyl A- methylbenzenesulfonate; To a solution of 3- (methylthio) propyl A- methylbenzenesulfonate (12.2 g, 46.9 mmol) in methanol (250 mL) was added dropwise a solution of potassium peroxysulfate (trade name: OXONE, 57.7 g, 93.8 mmol) in water (250 mL) under ice-cooling. After completion of the dropwise addition, the mixture was stirred for 20 hr, during which the mixture was allowed to gradually warm to room temperature. Methanol was <n="81"/>evaporated under reduced pressure, and the mixture was diluted with water, and the organic material was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The precipitated crystals were washed with ethyl acetate-heptane to give the title compound (13.1 g, yield 96percent) as colorless crystals. MS m/z 293 (M + H)+. |
92% | With Oxone In methanol; water at 20℃; for 20 h; Cooling with ice | (B) To an ice-cooled solution of 3-(methylthio)propyl 4-methylbenzenesulfonate (3.6 g; 13.8 mmol) in MeOH (70 mL) was added a suspension of monopersulfate compound (17 g; 27.4 mmol) in water (70 mL) in a portion-wise fashion. Upon completion of the addition, the mixture was allowed to warm to rt, and stirring was continued for 20 h. The reaction was partially concentrated to remove the MeOH and the mixture was further diluted with water and extracted with EtOAc (2x). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0– 67percent EtOAc in hexanes to afford 3- (methylsulfonyl)propyl 4-methylbenzene-sulfonate (3.72 g, 92percent) as a white solid. LC/MS: mass calcd. for C11H16O5S2: 292.38, found 315.1 [M+Na]+. |
92% | With Oxone In methanol; water at 20℃; for 20 h; Cooling with ice | (B) To an ice-cooled solution of 3-(methylthio)propyl 4-methylbenzenesulfonate (3.6 g; 13.8 mmol) in MeOH (70 mL) was added a suspension of monopersulfate compound (17 g; 27.4 mmol) in water (70 mL) in a portion-wise fashion. Upon completion of the addition, the mixture was allowed to warm to rt, and stirring was continued for 20 h. The reaction was partially concentrated to remove the MeOH and the mixture was further diluted with water and extracted with EtOAc (2*). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-67percent EtOAc in hexanes to afford 3-(methylsulfonyl)propyl 4-methylbenzene-sulfonate (3.72 g, 92percent) as a white solid. LC/MS: mass calcd. for C11H16O5S2: 292.38, found 315.1 [M+Na]+. |
92% | With monopersulfate In methanol; water at 20℃; for 20 h; | (B) To an ice-cooled solution of 350 3-(methylthio)propyl 4-methylbenzenesulfonate (3.6 g; 13.8 mmol) in 21 MeOH (70 mL) was added a suspension of monopersulfate compound (17 g; 27.4 mmol) in 12 water (70 mL) in a portion-wise fashion. Upon completion of the addition, the mixture was allowed to warm to rt, and stirring was continued for 20 h. The reaction was partially concentrated to remove the MeOH and the mixture was further diluted with water and extracted with EtOAc (2×). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-67percent EtOAc in hexanes to afford 352 3-(methylsulfonyl)propyl 4-methylbenzene-sulfonate (3.72 g, 92percent) as a white solid. LC/MS: mass calcd. for C11H16O5S2: 292.38, found 315.1 [M+Na]+. |
90% | With oxone In methanol at 20℃; Cooling with ice | 3-(methylthio)propyl-4-methylbenzenesulfonate (12.5 g, 48 mmol) was added to 250 mL in an ice bathStirring in a methanol solution, adding Oxone (59 g, 96 mmol) dropwise to the reaction solution, returning to room temperature, and stirring overnight. thenThe reaction solution was concentrated under reduced pressure, and a large amount of a white solid precipitated, which was filtered and washed with water to give a white solid (12.6 g) in a yield of 90percent. |
1.95 g | With oxone In methanol; water at 0 - 20℃; for 20 h; | Step 1: Preparation of 3-methylsulfonylpropyl 4-methylbenzenesulfonate To a solution of 3-methylsulfanylpropyl 4-methylbenzenesulfonate (2 g, 7.7 mmol) in methanol (50 mL) was added a solution of oxone (9.47 g, 15.4 mmol) in water (50 mL) dropwise at 0 oC. After being warmed to rt and stirred at rt for 20 hrs, the mixture was filtered and the filtrate was extracted with EA (50 mL) for three times. The combined organic layer was washed with water, dried over anhydrous Na2SO4 and concentrated in vacuo to give 3- methylsulfonylpropyl 4-methylbenzenesulfonate as a white solid (1.95 g) which was used in the next step directly without further purification. |
38 g | With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0℃; | To a solution of 3-(Methylthio)-1-propanol (20g, 0.19mol) and TEA (66ml, 0.48mol) in DCM (800mL) cooled at 0°C was added p-toluenesulfonyl chloride (44g, 0.23mol, dissoloved in 200mL DCM) dropwise. After addtion, the mixture was then stirred at r.t. overnight. After the reaction was complete, the resluting solution was washed with saturated Na2CO3 solution, brine, dried over MgSO4 and concentrated in vacuo to give the crude of 3-methylsulfanylpropyl 4-methylbenzenesulfonate, which was used in the next step without further purification. To the solution of the crude of 3-methylsulfanylpropyl 4-methylbenzenesulfonate (prepared above) in DCM (200 mL) cooled at 0oC was added m-CPBA (66g, 0.39mol) slowly and the mixture was then stirred at rt overnight. After the reaction was complete, the mixture was washed with saturated sodium thiosulfate (300mL) 3 times , saturated sodium bicarbonate (300mL) 3 times, dried over MgSO4 and then concentrated in vacuo to give 3-methylsulfonylpropyl 4-methylbenzenesulfonate (11b, 38g, 69percent yield over 2 steps) as a white solid. To a solution of tert-butyl 4-chloro-2-nitrophenylcarbamate (580 mg, 2.1 mmol) in DMF(5mL) cooled at 0oC was added NaH( 169 mg, 4.4 mmol). The mixture was then stirred at rt for 30mins. Then to the resulting solution was added 3-methylsulfonylpropyl 4-methylbenzenesulfonate (11b, 750 mg, 2.6 mmol) and the mixture was stirred at 50oC overnight. After the reaction was complete, to the mixture was added water (30 mL) and the resulting mixture was extracted with DCM (50 mL) 3 times. The combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution with DCM:MeOH 20 :1) to give tert-butyl N-(4-chloro-2-nitro-phenyl)-N-(3-methylsulfonylpropyl)carbamate(11c, 360 mg, 69percent yield). To a soltuion of tert-butyl N-(4-chloro-2-nitro-phenyl)-N-(3-methylsulfonylpropyl)carbamate (11c, 360 mg, 1.45 mol) in MeOH (10 mL) was added 2percent Pt/C (50mg) under N2 atmosphere, the mixture wa then hydrogenated at rt for 3 hours. After the reaction was complete, the mixture was filtred and the filtrate was concentrated in vacuo to give the crude of tert-butyl N-(2-amino-4-chloro-phenyl) -N-(3-methylsulfonylpropyl)carbamate (11d, 330 mg, 100percent yield), which was used in the next step directly without further purificaton. A mixture of tert-butyl N-(2-amino-4-chloro-phenyl)-N-(3-methylsulfonylpropyl)carbamate (11d, 320 mg, 0.92mmol) and sodium chloroacetate (130 mg, 1.1 mmol) in 4N HCl (15 mL) was stirred to 100oC overnight. After the reaction was complete, The reaction was concentrated in vacuo and the residue was redissoved in DCM (100 mL). The resulting soltuion was washed with saturated NaHCO3 (50 mL), brine (50 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by column crhomatography on silica gel (elution with DCM/EtOAc=3/1) to give 5-chloro-2-(chloromethyl) -1-(3-methylsulfonylpropyl)benzimidazole (11e, 130 mg, 44percent yield). To a mixture of 2-(methylsulfonyl)-1H-indole (72 mg, 0.37 mmol) and 5-chloro-2-(chloromethyl) -1-(2- (methylsulfonyl)ethyl)-1H-benzo[d]imidazole (11e, 120 mg, 0.37mmol) in DMF (3 mL) was added K2CO3 (104 mg, 0.74 mmol) and the mixture was stirred at rt overnight. After the reaction was completed, the mixture was filtered and the filtrate was purified by preparative HPLC to give 5-chloro-2-[(3-methylsulfonylindol-1-yl)methyl]-1-(3-methylsulfonylpropyl)benzimidazole (11, 100 mg, 78percent). MS: calcd (MH+) 480.1, exp (MH+) 480.1. 1H NMR(DMSO-d6, 400MHz):δ8.29(s, 1H), 7.80-7.86(m, 1H), 7.65-7.73(m, 3H), 7.26-7.34(m, 3H), 5.92(s, 2H), 4.86(t, J=7.6Hz, 2H), 3,73(br, 3H), 3.19(t, J=8.0Hz, 2H), 2.96(s, 3H), 2.08(t, J=7.6Hz, 2H); 13C NMR (101MHz, DMSO-d6) δ151.4, 143.2, 137.3, 134.7, 134.6, 126.9, 124.2, 123.8, 123.3, 122.6, 119.5, 119.2, 115.5, 112.4, 112.3, 51.1, 45.6, 43.6, 42.3, 23.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: With dmap; triethylamine In dichloromethane at 20℃; for 3 h; Stage #2: With 3-chloro-benzenecarboperoxoic acid In dichloromethane; water at 20℃; for 2 h; |
Weigh 3-methylthio-propanol (5·3g, 50mmol), triethylamine (13.9mL, 100mmol), DMAP (1.2g, 10mmol), was dissolved in 150mL dichloromethane burning added portionwise to toluenesulfonyl chloride (14.3g, 75mmol), stirred at room temperature for 3 hours until oxidation with potassium permanganate solution color, all of the alcohol the reaction was complete. 150mL was added in the reaction system was diluted with dichloromethane, washed with 1N aqueous hydrochloric acid, water, saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product (11. 27g) direct investment in the next reaction. Previous resulting product (11. 27g, 38. 5mmol) was dissolved in 100mL of dichloromethane, cooled to ice-water bath 0° C, with stirring. In addition to 77percent mCPBA (17. 3g, 77.1 mmol) was dissolved in 100mL of dichloromethane, dropwise using a dropping funnel to the reaction system, naturally to room temperature after the addition was complete, stirring was continued for 2 hours, until the starting material the reaction was complete. Suction filtration funnel to remove solids and the resulting dichloromethane solution was burned, washed with 1N aqueous hydrochloric acid, water, saturated brineWashed with water, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product was purified by flash column chromatography (50percent ethyl acetate / petroleum ether) to afford the product YZ-1 (12. 0g), two step yield 82percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 12h; | Reference Example 17; {2' , 3' ,5' , 6'-tetramethyl-4' - [3- (methylsulfonyl)propoxy]biphenyl-3-yl}methanol; To a solution of 3'- (hydroxymethyl) -2, 3, 5, 6- tetramethylbiphenyl-4-ol (0.616 g, 2.40 mmol) and 3- (methylsulfonyl) propyl 4-methylbenzenesulfonate (1.05 g, 3.60 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (0.597 g, 4.32 mmol), and the mixture was stirred at 9O0C for 12 hr under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with 1 M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate :hexane = 40:60 - 80:20), and the obtained crystals were recrystallized from heptane-ethyl acetate to give the title compound (0.577 g, yield 85%) as colorless crystals, melting point 132-134C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 24h; | Weigh YZ-2 (2·26g, 10mmol), YZ-1 (3·51g, 12mmol), potassium carbonate (1·8g, 13mmol), was dissolvedIn 20ml N,Nu-dimethylformamide, and the reaction was stirred at 90C in an oil bath for 24 hours, until the reaction was complete feed YZ-2. 150mL was added in the reaction system was diluted with ethyl acetate, washed successively with water, saturated brine, dried over anhydrous sodium sulfate,Filtered, and concentrated to give the crude product was purified by flash column chromatography (30% ethyl acetate / petroleum ether) to give the product YZ-3 (3.05g), yield 88%. |
78% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 24h;Inert atmosphere; | To a solution of product 20 (1.36g, 6.00mmol) and product 19 (2.1 lg, 7.20mmol) in N, N-dimethylformamide (12mL) was added potassium carbonate (1.08g, 7.80mmol), and the mixture was stirred at 90 C for 24 hr under nitrogen atmosphere .Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with 1 M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate: hexane = 40:60-80:20), and the obtained crystals were recrystallized from heptane-ethyl acetate to give a colorless solid product 21 (1.61g, yield 78%). |
77% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 24h; | Reference Example 18; 2' , 6' -dimethyl-4f - [3- (methylsulfonyl)propoxy]biphenyl-3-carbaldehyde; <n="82"/>To a solution of 4'-hydroxy-2' , 6'-dimethylbiphenyl-3- carbaldehyde (2.26 g, 10.0 itimol) and 3- (methylsulfonyl) propyl 4-methylbenzenesulfonate (3.51 g, 12.0 rartiol) in N,N- dimethylformamide (20 mL) was added potassium carbonate (1.80 g, 13.0 mmol) , and the mixture was stirred at 900C for 24 hr under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with 1 M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate :hexane = 40:60 - 80:20), and the obtained crystals were recrystallized from heptane-ethyl acetate to give the title compound (2.68 g, yield 77%) as colorless crystals.MS m/z 347 (M + H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 24h; | Reference Example 26; 3'-fluoro-2' , 6' -dimethyl-4' - [3- (methylsulfonyl) propoxy] biphenyl-3-carbaldehyde; To a solution of 3' -fluoro-4'-hydroxy-2' , 6' - dimethylbiphenyl-3-carbaldehyde (2.44 g, 10.0 mmol) and 3- (methylsulfonyl) propyl 4-methylbenzenesulfonate (3.51 g, 12.0 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (1.80 g, 13.0 mmol), and the mixture was stirred at 900C for 24 hr under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with 1 M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced <n="87"/>pressure. The residue was purified by silica gel column chromatography (ethyl acetate rhexane = 40:60 - 80:20), and the obtained crystals were recrystallized from heptane-ethyl acetate to give the title compound (3.45 g, yield 95%) as colorless crystals . MS m/z 365 (M + H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 21h; | Reference Example 37; {3'- (hydroxymethyl) -6-methyl-4- [3- (methylsulfonyl) propoxy]biphenyl-2-yl }methyl acetate; To a solution of [4-hydroxy-3' - (hydroxymethyl) -6- methylbiphenyl-2-yl]methyl acetate (1.02 g, 3.56 mmol) and 3- (methylsulfonyl) propyl 4-methylbenzenesulfonate (1.25 g, 4.27 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (0.640 g, 4.32 mmol), and the mixture was stirred at 900C for 21 hr under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate :hexane = 50:50 - 100:0) to give the title compound (0.87 g, yield 60%) as a colorless oil.1H NMR (CDCl3) delta: 1.81(1H, t, J=6.0Hz), 2.01(3H, s) , 2.03(3H, <n="93"/>. s) , 2.31-2 .43 (2H, m) , 2.97 (3H, s) , 3.24-3.32 (2H, m) , 4 .16 (2H, t, J=5.7Hz ) , 4 .72 ( 2H, d, J=6. 0Hz) , 4 .76 (2H, s) , 6.78 ( IH, d, J=2.5Hz) , 6. 83 ( IH, d, J=2 . 5Hz) , 7 . 05-7.10 ( 1H, m) , 7. 15 ( 1H, s ) , 7 . 32-7 .43 ( 2H, m) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 70h; | Reference Example 50; 2' , 6' -diethyl-4'- [3- (methylsulfonyl) propoxy] biphenyl-3-carbaldehyde; To a solution of 2' , 6' -diethyl-4' -hydroxybiphenyl-3- carbaldehyde (2.44 g, 9.59 mmol) and 3- (methylsulfonyl) propyl 4-methylbenzenesulfonate (3.36 g, 11.5 mmol) in N,N- dimethylformamide (20 mL) was added potassium carbonate (1.73 <n="100"/>g, 12.5 mmol) , and the mixture was stirred at 900C for 70 hr under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography(ethyl acetate :hexane = 30:70 - 70:30) to give the title compound (2.86 g, yield 80%) as a pale-yellow oil. MS m/z 375 (M + H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | In methanol; water; ethyl acetate; | A solution of potassium peroxymonosulphate (oxone; 33 g) in water (250 ml) was added to a solution of 3-methylthiopropyl 4-toluenesulphonate (14.29 g) in methanol (1.5 L). The resulting mixture was stirred for 18 hours, filtered and evaporated. The residue was dissolved in ethyl acetate and the solution was washed with brine, dried over magnesium sulphate and evaporated. There was thus obtained 3-methylsulphonylpropyl 4-toluenesulphonate as a solid (10.22 g, 64%); NMR: 2.01 (m, 2H), 2.43 (s, 3H), 2.95 (s, 3H), 3.1 (t, 2H), 4.13 (t, 2H), 7.47 (d, 2H), 7.78 (d, 2H); m/s: M+NH4+ 310. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium acetate; In acetonitrile;Heating / reflux; | 152 (l-r2-(lH-Indazol-4-ylV4-morpholin-4-yl-thienor3.2-d1pyrimidin-6-ylmethyl1- piperidin-4-vU-(3-methanesulfonyl-propylVmethyl-amine.Via [ 1 -(2-chloro-4-morpholin-4-yl-thieno[3 ,2-d]pyrimidin-6-ylmethyl)- piperidin-4-yl]-(3-methanesulfonyl-propyl)-methyl-amine, prepared from (3- methanesulfonyl-propyl)-methyl-piperidin-4-yl-amine. Amine preparation: Toluene-4-sulfonic acid 3-methylsulfanyl-propyl ester was prepared from 3-(methylthio)-l-propanol using standard conditions. Treatment with mCPBA in DCM yielded <strong>[263400-88-0]toluene-4-sulfonic acid 3-methanesulfonyl-propyl ester</strong>. A mixture of 4-methylamino-piperidine- 1-carboxylic acid tert-butyl ester and <strong>[263400-88-0]toluene-4-sulfonic acid 3-methanesulfonyl-propyl ester</strong> was heated in MeCN in the prescence of potassium carbonate to yield 4- [(3-methanesulfonyl-propyl) -methyl- EPO <DP n="82"/>amino]-piperidine-l-carboxylic acid tert-butyl ester. Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, isolated as the hydrochloride salt.1H NMR (400MHz, CDCl3) 1.50-1.70 (m, 4H, 2 x CH2), 1.90-1.97 (m, 2H, CH2), 2.00-2.05 (m, 2H, CH2), 2.21 (s, 3H, CH3), 2.38 (m, H, CH), 2.55 (m, 2H, CH2), 2.74 (s, 3H, CH2), 2.96-3.04 (m, 4H, 2 x CH2), 3.75 (s, 2H, CH2), 3.83-3.89 (m, 4H, 2 x CH2), 4.00-4.02 (m, 4H, 2 x CH2), 7.28 (s, H, CH), 7.41 (t, H, ArH, J=7.74Hz), 7.50 (d, H, ArH, J=8.24Hz), 8.18 (d, H, ArH, J=7.05Hz), 8.93 (s, H, ArH); MS (ESI+) 584.39 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With Oxone; In methanol; water; at 0 - 20℃; for 3h; | To a solution of 16A (2.16 g, 8.31 mmol) in MeOH (44 mL) cooled to 0 C was added a solution of OXONE (10.2 g, 16.6 mmol) in water (44 mL). The ice bath was allowed to gradually warm to rt and the reaction mixture was stirred for 3 h. The MeOH was removed under reduced pressure and the reaction mixture was diluted with water. The aqueous layer was extracted with EtOAc (3x) and the combined organic layers were washed with brine, dried (MgS04), and concentrated to give 16B (2.39 g, 8.17 mmol, 98%> yield) as a white solid. LC-MS Anal. Calc'd for CnHi605S2: 292.37, found [M+H] 293.0. |
96% | With Oxone; In methanol; water; at 0℃; for 20h; | To a solution of 3- (methylthio) propyl 4- 5 methylbenzenesulfonate (12.2 g) in methanol, (250 ml) was added EPO <DP n="223"/>dropwise a solution of Oxone (trade name) (57.7 g) in water (250 ml) under ice-cooling. After completion of the dropwise addition, and the mixture was stirred for 20 hr while allowing to warm to room temperature. Methanol was evaporated under reduced pressure, and the mixture was diluted with water. The organic product was extracted with ethyl acetate. The extract was washed with saturated brine, dried (Na2SO4), and concentrated under reduced pressure. The precipitated crystals were washed with ethyl acetate-heptane to give 3- (methylsulfonyl) propyl 4-methylbenzenesul;fonate (13.1 g, yield: 96%) as colorless crystals. MS m/z 293 (MH+). |
96% | With Oxone; In methanol; water; at 0 - 20℃; for 20h; | Reference Example 16; 3- (methylsulfonyl) propyl A- methylbenzenesulfonate; To a solution of 3- (methylthio) propyl A- methylbenzenesulfonate (12.2 g, 46.9 mmol) in methanol (250 mL) was added dropwise a solution of potassium peroxysulfate (trade name: OXONE, 57.7 g, 93.8 mmol) in water (250 mL) under ice-cooling. After completion of the dropwise addition, the mixture was stirred for 20 hr, during which the mixture was allowed to gradually warm to room temperature. Methanol was <n="81"/>evaporated under reduced pressure, and the mixture was diluted with water, and the organic material was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The precipitated crystals were washed with ethyl acetate-heptane to give the title compound (13.1 g, yield 96%) as colorless crystals. MS m/z 293 (M + H)+. |
92% | With Oxone; In methanol; water; at 20℃; for 20h;Cooling with ice; | (B) To an ice-cooled solution of 3-(methylthio)propyl 4-methylbenzenesulfonate (3.6 g; 13.8 mmol) in MeOH (70 mL) was added a suspension of monopersulfate compound (17 g; 27.4 mmol) in water (70 mL) in a portion-wise fashion. Upon completion of the addition, the mixture was allowed to warm to rt, and stirring was continued for 20 h. The reaction was partially concentrated to remove the MeOH and the mixture was further diluted with water and extracted with EtOAc (2x). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0- 67% EtOAc in hexanes to afford 3- (methylsulfonyl)propyl 4-methylbenzene-sulfonate (3.72 g, 92%) as a white solid. LC/MS: mass calcd. for C11H16O5S2: 292.38, found 315.1 [M+Na]+. |
92% | With Oxone; In methanol; water; at 20℃; for 20h;Cooling with ice; | (B) To an ice-cooled solution of 3-(methylthio)propyl 4-methylbenzenesulfonate (3.6 g; 13.8 mmol) in MeOH (70 mL) was added a suspension of monopersulfate compound (17 g; 27.4 mmol) in water (70 mL) in a portion-wise fashion. Upon completion of the addition, the mixture was allowed to warm to rt, and stirring was continued for 20 h. The reaction was partially concentrated to remove the MeOH and the mixture was further diluted with water and extracted with EtOAc (2*). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-67% EtOAc in hexanes to afford 3-(methylsulfonyl)propyl 4-methylbenzene-sulfonate (3.72 g, 92%) as a white solid. LC/MS: mass calcd. for C11H16O5S2: 292.38, found 315.1 [M+Na]+. |
92% | With monopersulfate; In methanol; water; at 20℃; for 20h; | (B) To an ice-cooled solution of 350 3-(methylthio)propyl 4-methylbenzenesulfonate (3.6 g; 13.8 mmol) in 21 MeOH (70 mL) was added a suspension of monopersulfate compound (17 g; 27.4 mmol) in 12 water (70 mL) in a portion-wise fashion. Upon completion of the addition, the mixture was allowed to warm to rt, and stirring was continued for 20 h. The reaction was partially concentrated to remove the MeOH and the mixture was further diluted with water and extracted with EtOAc (2×). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-67% EtOAc in hexanes to afford 352 3-(methylsulfonyl)propyl 4-methylbenzene-sulfonate (3.72 g, 92%) as a white solid. LC/MS: mass calcd. for C11H16O5S2: 292.38, found 315.1 [M+Na]+. |
90% | With oxone; In methanol; at 20℃;Cooling with ice; | 3-(methylthio)propyl-4-methylbenzenesulfonate (12.5 g, 48 mmol) was added to 250 mL in an ice bathStirring in a methanol solution, adding Oxone (59 g, 96 mmol) dropwise to the reaction solution, returning to room temperature, and stirring overnight. thenThe reaction solution was concentrated under reduced pressure, and a large amount of a white solid precipitated, which was filtered and washed with water to give a white solid (12.6 g) in a yield of 90%. |
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; | 152 (l-r2-(lH-Indazol-4-ylV4-morpholin-4-yl-thienor3.2-d1pyrimidin-6-ylmethyl1- piperidin-4-vU-(3-methanesulfonyl-propylVmethyl-amine.Via [ 1 -(2-chloro-4-morpholin-4-yl-thieno[3 ,2-d]pyrimidin-6-ylmethyl)- piperidin-4-yl]-(3-methanesulfonyl-propyl)-methyl-amine, prepared from (3- methanesulfonyl-propyl)-methyl-piperidin-4-yl-amine. Amine preparation: Toluene-4-sulfonic acid 3-methylsulfanyl-propyl ester was prepared from 3-(methylthio)-l-propanol using standard conditions. Treatment with mCPBA in DCM yielded toluene-4-sulfonic acid 3-methanesulfonyl-propyl ester. A mixture of 4-methylamino-piperidine- 1-carboxylic acid tert-butyl ester and toluene-4-sulfonic acid 3-methanesulfonyl-propyl ester was heated in MeCN in the prescence of potassium carbonate to yield 4- [(3-methanesulfonyl-propyl) -methyl- EPO <DP n="82"/>amino]-piperidine-l-carboxylic acid tert-butyl ester. Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, isolated as the hydrochloride salt.1H NMR (400MHz, CDCl3) 1.50-1.70 (m, 4H, 2 x CH2), 1.90-1.97 (m, 2H, CH2), 2.00-2.05 (m, 2H, CH2), 2.21 (s, 3H, CH3), 2.38 (m, H, CH), 2.55 (m, 2H, CH2), 2.74 (s, 3H, CH2), 2.96-3.04 (m, 4H, 2 x CH2), 3.75 (s, 2H, CH2), 3.83-3.89 (m, 4H, 2 x CH2), 4.00-4.02 (m, 4H, 2 x CH2), 7.28 (s, H, CH), 7.41 (t, H, ArH, J=7.74Hz), 7.50 (d, H, ArH, J=8.24Hz), 8.18 (d, H, ArH, J=7.05Hz), 8.93 (s, H, ArH); MS (ESI+) 584.39 (MH+). | |
With Oxone; In methanol; at 6 - 20℃; for 16h;Product distribution / selectivity; | Reference Example 6Synthesis of 3- (methylsulfonyl) propyl 4-methylbenzenesunfonate; [0414][0415]3- (Methylthio) propyl 4-methylbenzenesunfonate (29.4 g) was dissolved in methanol, and the mixture was cooled to 6C or below. While cooling to 6C or below, oxone (registered trade mark; 105.2 g) dissolved in water (400 mL) was added dropwise over 1 hr. After stirring at 6C or below for 1 hr, the mixture was stirred at room temperature for 14 hr. Water (800 mL) was added, and the mixture was stirred at 6C or below for 1 hr. The precipitated solid was collected by filtration, and washed twice with water (400 mL) . The solid was suspended in methanol (150 mL) , and the suspension was heated to 65C.Water (150 mL) was added dropwise over 30 min, and the mixture was cooled to room temperature and stirred at 6C or below for 1 hr. The solid was collected by filtration, and washed twice with water (150 mL) . The solid was vacuum-dried at 50C to give white title compound (25.21 g) .1H NMR (300MHz, CDC13) : delta 2.17-2.28 (2H, m) , 2.46 (3H, s) , 2.91 (3H, s), 3.07-3.15 (2H, m) , 4.18 (2H, t, J=5.9 Hz), 7.34-7.37 (2H, d, J=8.0 Hz), 7.78-7.80 (2H, d, J=8.3 Hz). | |
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 20℃; for 21h; | Step B: 3 -(methylsulfonyl)propyl 4-methylbenzenesulfonate (34-2)To a solution of 34-1 (35 g, 135 mmol) in dry DCM (400 mL) with ice-bath cooling was added MCPBA (46.5 g, 270 mmol) portionwise. The resulting mixture was stirred at 0 C for lh, and then warmed to the room temperature and stirred for 20 h. The reaction was quenched byaddition of aqueous solution of NaHSO3 and the DCM layer was washed with Na2CO3 (aq.), water and brine, respectively, and concentrated to afford a residue, which was purified by chromatography on silica gel (petroleum ether:ethyl acetate = 3/1) to give compound 34-2. | |
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 20℃; for 21h; | To a solution of34-1 (35 g, 135 mmol) in dry DCM (400 mL) with ice-bath cooling was addedMCPBA(46.5 g, 270 mmol) portionwise. The resulting mixture was stirred at 0 oc for 1h, andthen warmed to the room temperature and stirred for 20 h. The reaction was quenched by5 addition of aqueous solution ofNaHS03 and the DCM layer was washed with Na2C03 (aq.),water and brine, respectively, and concentrated to afford a residue, which was purified bychromatography on silica gel (petroleum ether:ethyl acetate= 3/1) to give compound 34-2. | |
With oxone; In methanol; water; at 20℃; for 20h;Cooling with ice; | To a solution of product 18 (7.32g, 28.1mmol) in methanol (150mL) was added dropwise a solution of potassium peroxysulfate (34.6g, 56.3mmol) in water (150mL) under ice-cooling. After completion of the dropwise addition, the mixture was stirred for 20 hr, during which the mixture was allowed to gradually warm to room temperature. Methanol was evaporated under reduced pressure, and the mixture was diluted with water, and the organic material was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The precipitated crystals were washed with ethyl acetate-heptane to give a colorless crystal product 19 (7.86g, yield 95%). | |
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 20℃; for 21h; | To a solution of product from Step A (35 g, 135 mmol) in dry DCM (400 mL) in an ice-bath was added MCPBA (46.5 g, 270 mmol) portionwise. The resulting mixture was stirred at 0 C for lh, and then warmed to the room temperature and stirred for 20 h. The reaction was quenched by addition of aqueous solution of NaHS( and the DCM layer was washed with Na2C( (aq.), water and brine, respectively, and concentrated to afford a residue, which was purified by chromatography on silica gel (eluting with PE:EA=3: 1) to give the title compound. | |
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 20℃; for 21h; | To a solution of product from Step A (35 g, 135 mmol) in dry DCM (400 mL) in an ice-bath was added MCPBA (46.5 g, 270 mmol) portionwise. The resulting mixture was stirred at 0for 1h, and then warmed to the room temperature and stirred for 20 h. The reaction was quenched by addition of aqueous solution of NaHSO3 and the DCM layer was washed with Na2CO3 (aq. ) , water and brine, respectively, and concentrated to afford a residue, which was purified by chromatography on silica gel (eluting with PE:EA3:1) to give the title compound. | |
With Oxone; In tetrahydrofuran; water; at 20℃; for 12h;Inert atmosphere; | 62 g of 3-(methylthio)propyl 4-methylbenzenesulfonate obtained in step 1) was loaded in THF/distilled water (150/100 ml) in a flask in nitrogen atmosphere, followed by stirring for dissolving them. Then, 310 g of oxone was added thereto. The mixture was stirred for 12 hours at room temperature. Upon completion of the reaction, distilled water was slowly added thereto, followed by extraction using ethylacetate. The extract was washed with brine, dried over anhydrous MgSO4, and concentrated to give the target compound. (0288) 1H NMR (400 MHz, CDCl3): delta 7.81 (2H, d), 7.38 (2H, d), 4.20 (2H, m), 3.13 (2H, m), 2.93 (3H, s), 2.48 (3H, s), 2.23 (2H, m). | |
With Oxone; In methanol; at 20 - 30℃; for 2h;Inert atmosphere; | A solution of 3- (methylthio) propyl p-toluenesulfonate 24a (10.0 g, 38.40 mmol) was dissolved in 100 mL of methanol,100 mL of a solution containing Oxone reagent (35.42 g, 57.60 mmol), and the reaction was stirred at room temperature for 2 hours.The reaction mixture was concentrated under reduced pressure, 100 mL of water and 100 mL of ethyl acetate were added to the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL of X 2) and the combined organic layers were washed with water (30 mL of X 3) and saturated sodium chloride solution Dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 3- (methylsulfonyl) propyl p-toluenesulfonate 24b (8.0 g, white solid) The purification was carried out directly to the next reaction. | |
1.95 g | With oxone; In methanol; water; at 0 - 20℃; for 20h; | Step 1: Preparation of 3-methylsulfonylpropyl 4-methylbenzenesulfonate To a solution of 3-methylsulfanylpropyl 4-methylbenzenesulfonate (2 g, 7.7 mmol) in methanol (50 mL) was added a solution of oxone (9.47 g, 15.4 mmol) in water (50 mL) dropwise at 0 oC. After being warmed to rt and stirred at rt for 20 hrs, the mixture was filtered and the filtrate was extracted with EA (50 mL) for three times. The combined organic layer was washed with water, dried over anhydrous Na2SO4 and concentrated in vacuo to give 3- methylsulfonylpropyl 4-methylbenzenesulfonate as a white solid (1.95 g) which was used in the next step directly without further purification. |
38 g | With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0℃; | To a solution of 3-(Methylthio)-1-propanol (20g, 0.19mol) and TEA (66ml, 0.48mol) in DCM (800mL) cooled at 0C was added p-toluenesulfonyl chloride (44g, 0.23mol, dissoloved in 200mL DCM) dropwise. After addtion, the mixture was then stirred at r.t. overnight. After the reaction was complete, the resluting solution was washed with saturated Na2CO3 solution, brine, dried over MgSO4 and concentrated in vacuo to give the crude of 3-methylsulfanylpropyl 4-methylbenzenesulfonate, which was used in the next step without further purification. To the solution of the crude of 3-methylsulfanylpropyl 4-methylbenzenesulfonate (prepared above) in DCM (200 mL) cooled at 0oC was added m-CPBA (66g, 0.39mol) slowly and the mixture was then stirred at rt overnight. After the reaction was complete, the mixture was washed with saturated sodium thiosulfate (300mL) 3 times , saturated sodium bicarbonate (300mL) 3 times, dried over MgSO4 and then concentrated in vacuo to give 3-methylsulfonylpropyl 4-methylbenzenesulfonate (11b, 38g, 69% yield over 2 steps) as a white solid. To a solution of tert-butyl 4-chloro-2-nitrophenylcarbamate (580 mg, 2.1 mmol) in DMF(5mL) cooled at 0oC was added NaH( 169 mg, 4.4 mmol). The mixture was then stirred at rt for 30mins. Then to the resulting solution was added 3-methylsulfonylpropyl 4-methylbenzenesulfonate (11b, 750 mg, 2.6 mmol) and the mixture was stirred at 50oC overnight. After the reaction was complete, to the mixture was added water (30 mL) and the resulting mixture was extracted with DCM (50 mL) 3 times. The combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution with DCM:MeOH 20 :1) to give tert-butyl N-(4-chloro-2-nitro-phenyl)-N-(3-methylsulfonylpropyl)carbamate(11c, 360 mg, 69% yield). To a soltuion of tert-butyl N-(4-chloro-2-nitro-phenyl)-N-(3-methylsulfonylpropyl)carbamate (11c, 360 mg, 1.45 mol) in MeOH (10 mL) was added 2% Pt/C (50mg) under N2 atmosphere, the mixture wa then hydrogenated at rt for 3 hours. After the reaction was complete, the mixture was filtred and the filtrate was concentrated in vacuo to give the crude of tert-butyl N-(2-amino-4-chloro-phenyl) -N-(3-methylsulfonylpropyl)carbamate (11d, 330 mg, 100% yield), which was used in the next step directly without further purificaton. A mixture of tert-butyl N-(2-amino-4-chloro-phenyl)-N-(3-methylsulfonylpropyl)carbamate (11d, 320 mg, 0.92mmol) and sodium chloroacetate (130 mg, 1.1 mmol) in 4N HCl (15 mL) was stirred to 100oC overnight. After the reaction was complete, The reaction was concentrated in vacuo and the residue was redissoved in DCM (100 mL). The resulting soltuion was washed with saturated NaHCO3 (50 mL), brine (50 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by column crhomatography on silica gel (elution with DCM/EtOAc=3/1) to give 5-chloro-2-(chloromethyl) -1-(3-methylsulfonylpropyl)benzimidazole (11e, 130 mg, 44% yield). To a mixture of 2-(methylsulfonyl)-1H-indole (72 mg, 0.37 mmol) and 5-chloro-2-(chloromethyl) -1-(2- (methylsulfonyl)ethyl)-1H-benzo[d]imidazole (11e, 120 mg, 0.37mmol) in DMF (3 mL) was added K2CO3 (104 mg, 0.74 mmol) and the mixture was stirred at rt overnight. After the reaction was completed, the mixture was filtered and the filtrate was purified by preparative HPLC to give 5-chloro-2-[(3-methylsulfonylindol-1-yl)methyl]-1-(3-methylsulfonylpropyl)benzimidazole (11, 100 mg, 78%). MS: calcd (MH+) 480.1, exp (MH+) 480.1. 1H NMR(DMSO-d6, 400MHz):delta8.29(s, 1H), 7.80-7.86(m, 1H), 7.65-7.73(m, 3H), 7.26-7.34(m, 3H), 5.92(s, 2H), 4.86(t, J=7.6Hz, 2H), 3,73(br, 3H), 3.19(t, J=8.0Hz, 2H), 2.96(s, 3H), 2.08(t, J=7.6Hz, 2H); 13C NMR (101MHz, DMSO-d6) delta151.4, 143.2, 137.3, 134.7, 134.6, 126.9, 124.2, 123.8, 123.3, 122.6, 119.5, 119.2, 115.5, 112.4, 112.3, 51.1, 45.6, 43.6, 42.3, 23.1. |
With Oxone; In tetrahydrofuran; water; at 0 - 20℃; for 12h;Inert atmosphere; | Under a nitrogen atmosphere, 62 g of 3-(methylthio)propyl 4-methylbenzenesulfonate obtained in step 1 was added in THF/distilled water (150/100 mL) in a flask and stirred to dissolve, and then 310 g of oxone was added dropwise at 0?. After stirring at room temperature for 12 hours or longer, upon completion of the reaction, distilled water was slowly added dropwise, extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate to give the title compound. (0182) 1H NMR (400MHz, CDCl3) : delta 7.81 (2H, d) , 7. 38 (2H, d) , 4.20(2H, m), 3.13(2H, m), 2.93(3H, s), 2.48(3H, s), 2.23(2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 3h; | To a solution of ethyl (2E) -3- (2-{ [3-chloro-5- (trifluoromethyl) pyridin-2-yl] oxy}-4-hydroxyphenyl) acrylate (5.00 g) in N,N-dimethylformamide (50 ml) were added potassium carbonate (2.67 g) and 3- (methylsulfonyl) propyl 4- methybenzenesulfonate (4.46 g) , and the mixture was stirred at 500C for 3 hr. After allowing to cool to room temperature, '1N hydrochloric acid was added to the reaction mixture, the resulting solid was collected by filtration and washed with water to give ethyl (2E) -3-{2-{ [3-chloro-5- (trifluoromethyl) pyridin-2-yl] oxy}-4- [3-(methylsulfonyl)propoxy] phenyl}acrylate (6.34 g, yield: 97%) as a white solid. Recrystallization from ethyl acetate-hexane gave white crystals, melting point 190.6-191.00C. |
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 80℃; for 4h; | General procedure: To a stirred solution of 33b (0.68 g, 1.74 mmol) and K2CO3 (322 mg, 2.33 mmol) in DMF (15 mL) was added 2-chloro-N,N-diethylacetamide (0.31 g, 2.07 mmol) and the mixture was stirred at room temperature for 2 h, at 50 C for 30 min, and at 80 C for 1 h. Then, additional 2-chloro-N,N-diethylacetamide (0.30 g, 2.01 mmol) was added to the mixture, which was stirred at 80 C for additional 30 min. After being cooled to room temperature, the reaction was acidified with 1 M HCl, and extracted with EtOAc, and the combined organic layer was washed with sat. NaHCO3 and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane-EtOAc, 9:1 to 1:2) to give crude 7c (1.39 g, quant.) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; sodium iodide; In water; N,N-dimethyl-formamide; at 100℃; for 2h; | Example 802-[3-(Methylsulfonyl)propyl]sulfanyl}-3-[4-(2,2,2-trifluoroethoxy)phenyl]-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one; A 1 M aqueous solution of sodium hydrogen carbonate (1.0 ml) was added to a mixture of 2-thioxo-3-[4-(2,2,2-trifluoroethoxy)phenyl]-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (341 mg) obtained by the method of Example 2, or a method pursuant to thereto, <strong>[263400-88-0]3-(methylsulfonyl)propyl 4-methylbenzenesulfonate</strong> (292 mg) obtained by a method described in a published document, WO 08/1931, or a method pursuant to thereto, sodium iodide (150 mg) and N,N-dimethylformamide (10 ml), and the resulting mixture was stirred for 2 hours at 100 C. The reaction mixture was returned to room temperature, and then the solvent was distilled off under reduced pressure. The residue was diluted with ethyl acetate, and the dilution was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by chromatography, and then was recrystallized from ethyl acetate. Thus, the title compound (235 mg) was obtained as a white powder.1H NMR (300 MHz, DMSO-d6) delta ppm 2.00-2.12 (2H, m), 2.98 (3H, s), 3.17 (4H, t, J=7.4 Hz), 4.87 (2H, q, J=8.7 Hz), 6.35 (1H, d, J=3.0 Hz), 7.14-7.25 (2H, m), 7.30-7.44 (3H, m), 12.14 (1H, br. s.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; sodium iodide; In water; N,N-dimethyl-formamide; at 100℃; for 15h; | Example 1543-[4-(Cyclopropylmethoxy)phenyl]-2-[3-(methylsulfonyl)propyl]sulfanyl}-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one; A 1 M aqueous solution of sodium hydrogen carbonate (0.64 ml) was added to a mixture of 3-[4-(cyclopropylmethoxy)phenyl]-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (200 mg) obtained by the method of Example 6, or a method pursuant to thereto, <strong>[263400-88-0]3-(methylsulfonyl)propyl 4-methylbenzenesulfonate</strong> (187 mg) obtained by a method described in a published document, WO 08/1931, or a method pursuant to thereto, sodium iodide (96 mg) and N,N-dimethylformamide (10 ml), and the resulting mixture was stirred for 15 hours at 100 C. The reaction mixture was returned to room temperature, and then was diluted with ethyl acetate. The dilution was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by chromatography, and then was recrystallized from a mixed solvent of ethyl acetate/hexane. Thus, the title compound (164 mg) was obtained as a white powder.1H NMR (300 MHz, DMSO-d6) delta ppm 0.33-0.39 (2H, m), 0.57-0.64 (2H, m), 1.19-1.34 (1H, m), 2.00-2.12 (2H, m), 2.97 (3H, s), 3.10-3.23 (4H, m), 3.89 (2H, d, J=6.8 Hz), 6.34 (1H, d, J=2.8 Hz), 7.04 (2H, d, J=9.1 Hz), 7.25 (2H, d, J=9.1 Hz), 7.39 (1H, d, J=2.8 Hz), 12.12(1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; sodium iodide; In water; N,N-dimethyl-formamide; at 100℃; | Example 1512-[3-(Methylsulfonyl)propyl]sulfanyl}-3-{4-[(2,2,2-trifluoroethoxy)methyl]phenyl}-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one; A mixture of 2-thioxo-3-{4-[(2,2,2-trifluoroethoxy)methyl]phenyl}-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (250 mg) obtained in Example 16, <strong>[263400-88-0]3-(methylsulfonyl)propyl 4-methylbenzenesulfonate</strong> (225 mg) obtained by the method described in a published document, WO 08/1931, or a method pursuant to thereto, sodium iodide (149 mg), a 1 M aqueous solution of sodium hydrogen carbonate (1.0 ml) and N,N-dimethylformamide (10 ml), was stirred overnight at 100 C., and then was concentrated under reduced pressure. Ethyl acetate and water were added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by chromatography, and then was recrystallized from ethyl acetate. Thus, the title compound (187 mg) was obtained as a white solid.1H NMR (300 MHz, DMSO-d6) delta ppm 2.00-2.12 (2H, m), 2.97 (3H, s), 3.13-3.21 (4H, m), 4.20 (2H, q, J=9.5 Hz), 4.77 (2H, s), 6.36 (1H, d, J=2.3 Hz), 7.37-7.43 (3H, m), 7.51 (2H, d, J=8.3 Hz), 12.17(1H, br. s.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; sodium iodide; In water; N,N-dimethyl-formamide; at 100℃; for 15h; | Example 2153-[4-(Cyclopropylmethoxy)phenyl]-2-[3-(methylsulfonyl)propyl]sulfanyl}-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one; A 1 M aqueous solution of sodium hydrogen carbonate (0.64 ml) was added to a mixture of 3-[4-(cyclopropylmethoxy)phenyl]-2-thioxo-1,2,3, 7-tetrahydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (200 mg) obtained by the method of Example 31, or a method pursuant to thereto, <strong>[263400-88-0]3-(methylsulfonyl)propyl 4-methylbenzenesulfonate</strong> (187 mg) obtained by the method described in a published document, WO 08/1931, or a method pursuant to thereto, sodium iodide (96 mg) and N,N-dimethylformamide (10 ml), and the resulting mixture was stirred for 15 hours at 100 C. The reaction mixture was returned to room temperature, and then was diluted with ethyl acetate. The dilution was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by chromatography, and then was recrystallized from a mixed solvent of ethyl acetate/hexane. Thus, the title compound (160 mg) was obtained as a white powder.1H NMR (300 MHz, DMSO-d6) delta ppm 0.32-0.39 (2H, m), 0.57-0.64 (2H, m), 1.21-1.32 (1H, m), 2.01-2.13 (2H, m), 2.97 (3H, s), 3.12-3.21 (4H, m), 3.88(2H, d, J=6.8 Hz), 6.43 (1H, d, J=3.4 Hz), 6.98 (1H, d, J=3.4 Hz), 7.04 (2H, d, J=9.1 Hz), 7.22 (2H, d, J=9.1 Hz), 11.84 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 2h; | Example 181{ (3S) -6- [ (3-{2-ethoxy-4- [3- (methylsulfonyl) propoxy] -IH- benzimidazol-1-yl } -2-methylbenzyl ) amino] -2 , 3-dihydro-l- benzofuran-3-yl} acetic acid; [ 1203 ][1204]Methyl [ (3S) -6-{ [3- (2-ethoxy-4-hydroxy-lH-benzimidazol-l- yl) -2-methylbenzyl] (trifluoroacetyl) amino} -2, 3-dihydro-l- benzofuran-3-yl] acetate (116 mg, 0.2 mmol) , 3- (methylsulfonyl) propyl p-toluenesulfonate (88 mg, 0.3 mmol), potassium carbonate (55 mg, 0.4 mmol) were suspended in N, N- dimethylformamide (3 mL) and the suspension was stirred at 60C for 2 hr. The reaction mixture was allowed to cool, diluted with saturated brine, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the volatile component was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90:10 - 40:60) to give an oil (130 mg) . The obtained oil was dissolved in methanol (5 mL) -tetrahydrofuran (5 mL) , 1 M aqueous sodium hydroxide solution (0.5 mL) was added, and the mixture was stirred at 5O0C for 1 hr. Water (10 mL) was added, and the volatile component was evaporated under reduced pressure. 1 M Aqueous hydrochloric acid solution (0.5 mL) was added, and the mixture was diluted with saturated brine, extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the volatile component was evaporated under reduced pressure to give the title compound (77 mg, yield 65%) as a white solid.1H NMR (300 MHz, DMSO-d6) delta 1.32 (3H, t, J = 7.0 Hz), 1.93 (3H, s), 2.17-2.29 (2H, m) , 2.36-2.47 (IH, m) , 2.57-2.69 (IH, m) , 3.05 (3H, s), 3.34-3.39 (3H, m) , 3.54-3.67 (IH, m) , 4.05-4.14 (IH, m) , 4.22-4.40 (4H, m) , 4.46-4.65 (3H, m) , 6.00-6.19 (3H, m) , 6.43 (IH, d, J = 7.9 Hz), 6.76 (IH, d, J = 7.9 Hz), 6.88- 7.04 (2H, in) , 7.20-7.26 (IH, m) , 7.34 (IH, t, J = 7.5 Hz), 7.42-7.48 (IH, m) . MS m/z 594 (M + H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 24h;Inert atmosphere; | To a solution of 4-bromo-3,5-dimethylphenol (2.01g, lOmmol) and 3 -(methyl sulfonyl)propyl 4-methylbenzenesulfonate (3.5 lg, 12.0mmol) in N,N-dimethylformamide (20mL) was added potassium carbonate (1.80g, 13.0mmol), and the mixture was stirred at 90 C for 24 hr under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with 1M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate : hexane=40:60-80:20), and the obtained crystals were recrystallized from heptane-ethyl acetate to give a colorless crystals product 25 (2.73g, yield 85%). |
67% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 24h; | Weighing 4-bromo-3,5(dimethyl)phenol (2.0g, 10mmol), YZ-1 (2.92g, 10mmol), potassium carbonate (2.76g, 20mmol), dissolved in 20ml N,N-dimethyl formamide, in the reaction system 90 C stirring in oil bath 24 hours. In the reaction system by adding 150 ml ethyl acetate dilution, water sequentially, saturated salt water washing, anhydrous sulfuric acid nano dry, filtered, concentrated to obtain crude products, rapid column chromatography purification (petroleum ether: ethyl acetate: dichloromethane = 1:1:1), to obtain the product 12e (2.15g), yield 67%. |
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 46h;Product distribution / selectivity; | Example 9Synthesis of 2-bromo-l, 3-dimethyl-5- [3- (methylsulfonyl) propoxy] benzene; [0420][0421]4-Bromo-3, 5-dimethylphenol (40.00 g) , 3- (methylsulfonyl) propyl 4-methylbenzenesulfonate (72.71 g) and potassium carbonate (35.75 g) were added toN, N-dimethylformamide (400 mL) , and the mixture was stirred. The mixture was heated to 70C, stirred for 46 hr, and cooled to 5C. Water (200 mL) was added dropwise at 10C or below, seed crystal (60 mg) was added, and water (400 mL) was continuously added. After stirring for 2 hr, the precipitated crystals were collected by filtration, washed with water (400 mL) and dried to give the title compound (63.08 g) .XH NMR (300 MHz, CDC13) : delta 2.28-2.36 (m, 2H) , 2.38 (s, 6H) , 2.93-2.97 (m, 3H) , 3.20-3.26 (m, 2H) , 4.07 (t, J=5.8 Hz, 2H) , 6.63 (s, 2H) , 7.26 (s, 1H) . |
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 18h; | Step C: 2-bromo- 1,3 -dimethyl-5 -(3 -(methylsulfonyl)propoxy)benzene (34-3)To a solution of compound 34-2 (32.1 g, 110 mmol) in DMF (300 mL) was added 4-bromo-3,5- dimethylphenol (20.1 g, 100 mmol), and K2C03 (16.5 g, 120 mmol). The resulting mixture was stirred at 100 C for 18 hours. Then water was added and the mixture was extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine, dried and concentrated to give a residue. The residue was purified by chromatography on silica gel(petroleum ether:ethyl acetate = 3/1) to give compound 34-3. MS (ESI) m1z(M+H):32 1.0/323.0. | |
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 18h; | To a solution of compound 34-2 (32.1 g, 110 mmol) in DMF (300 mL) was added 4-bromo-3,5-dimethylphenol (20.1 g, 100 mmol), and K2C03 (16.5 g, 120 mmol). The resulting mixture wasstirred at 100 C for 18 hours. Then water was added and the mixture was extracted with ethylacetate (150 mL x 3). The combined organic layers were washed with brine, dried andconcentrated to give a residue. The residue was purified by chromatography on silica gel15 (petroleum ether:ethyl acetate= 3/1) to give compound 34-3. MS (ESI) m/z(M+Hf:321.0/323.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; | A mixture of 2-amino-3-hydroxy-5-( isopropylsulfonyl) benzonitrile (0.73 g) , 3- (methylsulfonyl) propyl 4-methylbenzenesulfonate (1.06 g) , potassium carbonate (0.50 g) and N,N-dimethylformamide (10 mL) was stirred overnight at 700C. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluate: ethyl acetate) to give the title compound (0.95 g, yield 87%) as colorless crystals. Melting point 142-143C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.50 g | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 13h; | A mixed solution of <strong>[263400-88-0]3-(methylsulfonyl)propyl 4-methylbenzenesulfonate</strong> (1.86 g) that can be obtained by a publicly known method, 4-bromophenol (1.0 g), potassium carbonate (1.20 g), and N,N-dimethylformamide (15 mL) was heated with stirring at 80 C. for 13 hours. The reaction mixture was left to reach room temperature, and to the reaction mixture, water was added, followed by filtering the deposited solid to obtain the subject compound (1.50 g) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h; | Step 1 c Synthesis of (2'-Methyl-4'-(3-(methylsulfonyl) propoxy)-[1 , 1 '-biphenyl]-3-yl) methanol To a solution of 3'-(hydroxymethyl)-2-methyl-[1 , 1 '-biphenyl]-4-ol (compound of Step 1 b, 50 mg, 0.233 mM) and <strong>[263400-88-0]3-(methylsulfonyl)propyl 4-methylbenzenesulfonate</strong> (75 mg, 0.257 mM) in anhydrous DMF (2 ml), cesium carbonate (76 mg, 0.233 mM) was added at RT. The reaction mixture was stirred at RT for 2 h. Reaction was then quenched by addition of water (5 ml) and allowed to stir for 10 min and then extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated. The residue was purified by flash column chromatography (silica gel, 40% ethyl acetate in n-hexane) to obtain the compound ethyl 2-(3-(4-((2'-methyl-4'- (3-(methylsulfonyl) propoxy)-[1 , 1 '-biphenyl]-3-yl) methoxy) phenyl) oxetan-3-yl) acetate (98 mg, 0.170 mM) as colorless oil. Yield: 99%; 1 H NMR (300 MHz, CDCI3): delta 7.44-7.39 (m, 1 H), 7.39-7.31 (m, 2H), 7.25 (d, J= 7.5 Hz, 1 H), 7.18 (d, J= 8.4 Hz, 1 H), 6.81 (d, J= 5.4 Hz, 1 H), 6.77 (s, 1 H), 4.76 (d, J= 4.8 Hz, 2H), 4.18-4.14 (t, J= 5.4, 1 1 .1 Hz, 2H), 3.32-3.27 (t, J= 15.6, 15.3 Hz, 2H), 2.98 (s, 3H), 2.40-2.35 (m, 2H), 2.27 (s, 3H), 1 .70 (t, J= 5.4, 1 1 .1 Hz, 1 H) ; MS: (m/z) 357 (M+Na). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With caesium carbonate; In N,N-dimethyl-formamide; for 2h; | Step 1 b Synthesis of 3', 5'-Dimethyl-4'-(3-(methylsulfonyl) propoxy)-[1 , 1 '-biphenyl]-3- carbaldehyde A mixture of 4'-hydroxy-3',5'-dimethyl-[1 ,1 '-biphenyl]-3-carbaldehyde (compound of Step 1 a, 50 mg, 0.221 mM), 3-(methylsulfonyl)propyl 4- methylbenzenesulfonate (78 mg, 0.265 mM) and cesium carbonate (108 mg, 0.331 mM) in DMF was stirred for 2 h. The reaction mixture was concentrated. The crude compound was purified by column chromatography to obtain the compound 3', 5'- dimethyl-4'-(3-(methylsulfonyl) propoxy)-[1 , 1 '-biphenyl]-3-carbaldehyde (55 mg) as colorless liquid. Yield: 71 %; 1 HNMR (300 MHz, CDCI3): delta 10.08 (s,1 H), 8.15 (s, 1 H), 7.98 (d, J= 7.8 Hz, 1 H), 7.87 (d, J= 7.5 Hz, 1 H), 7.81 (d, J= 8.1 Hz, 1 H), 7.68-7.63 (t, J= 7.5, 15 Hz, 1 H), 7.51 (d, J= 8.1 Hz. 1 H), 3.91 -3.87 (t, J= 6, 12Hz, 2H), 3.40-3.37 (m, 2H), 3.04 (s, 3H), 2.31 (s, 6H), 2.20-2.15 (m, 2H); MS: (m/z) 369 (M+Na) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h; | Example 80 Ethyl 2-(3-(4-((3'-methoxy-4'-(3-(methylsulfonyl) propoxy)-[1 , 1 '-biphenyl]-3-yl) methoxy) phenyl) oxetan-3-yl) acetate (Compound 80) To a solution of ethyl 2-(3-(4-((4'-hydroxy-3'-methoxy-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)oxetan-3-yl)acetate (40 mg, 0.089 mM; prepared by the method analogus to method described in Step 1 d of Example 1 ) and 3-(methyl sulfonyl)propyl 4-methylbenzenesulfonate (28.7 mg, 0.098 mM) in anhydrous DMF (2 ml), cesium carbonate (58 mg, 0.178 mM) was added at RT. The reaction mixture was stirred at RT for 2 h and then quenched by addition of 5 ml water, stirred for 10 min and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated. The residue was purified by flash column chromatography (silica gel, 40% ethyl acetate in n-hexane) to obtain the compound ethyl 2-(3-(4-((3'- methoxy-4'-(3-(methylsulfonyl) propoxy)-[1 ,1 '-biphenyl]-3-yl)methoxy)phenyl) oxetan- 3-yl)acetate (50 mg, 0.087 mM) as colorless oil. Yield: 98 %; 1 H NMR (300 MHz, DMSO-de): delta 7.72 (s, 1 H), 7.62 (d, J= 7.2 Hz, 1 H), 7.47 (d, J= 7.5 Hz, 1 H), 7.42-7.38 (t, J= 6.9 Hz, 1 H), 7.24 (s, 1 H),7.18-7.16 (m, 3H), 7.07 (d, J= 8.1 , 1 H), 7.02 (d, J= 8.4 Hz, 2H), 5.15 (s, 2H), 4.75 (s, 4H), 4.14-4.10 (t, J= 6Hz, 2H), 3.93-3.88 (m, 2H), 3.86 (s, 3H), 3.28-3.26(m, 2H), 3.08 (s, 2H), 3.03 (s, 3H), 2.15 (s, 2H), 1 .04 (t, J= 7.2 Hz, 3H); MS: (m/z) 569 (M+Na). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h; | Step 1 c Synthesis of (4'-(3-(Methylsulfonyl) propoxy)-3'-(trifluoromethyl)-[1 , 1 '-biphenyl]-3-yl) methanol To a solution of 3'-(hydroxymethyl)-3-(trifluoromethyl)-[1 , 1 '-biphenyl]-4-ol (compound of Step 1 b, 100 mg, 0.373 mM) in DMF (2 ml), Cs2C03 (121 mg, 0.373 mM) was added, followed by addition of 3-(methylsulfonyl) propyl 4- methylbenzenesulfonate (120 mg, 0.410 mM) and allowed to stir at RT for 2 h. The reaction mixture was quenched with water and extracted with ethyl acetate, concentrated and purified by column chromatography to obtain the pure compound (4'-(3-(methylsulfonyl) propoxy)-3'-(trifluoromethyl)-[1 , 1 '-biphenyl]-3-yl) methanol (122.5 mg, 0.302 mM). Yield: 81 %; 1 H NMR (300 MHz, DMSO-d6): delta 7.94 (d, J= 8.4 Hz, 1 H), 7.83 (s, 1 H), 7.61 (s, 1 H), 7.55 (d, J= 7.5 Hz, 1 H), 7.44 (d, J= 7.5 Hz, 1 H), 7.38-7.30 (m, 2H), 5.27 (t, J= 5.4 Hz, 1 H), 4.58 (d, J= 5.4 Hz, 2H), 4.31 (t, J= 5.7 Hz, 2H), 3.28-3.23 (m, 2H), 3.03 (s, 3H), 2.22 (t, J= 7.5 Hz, 2H); MS: (m/z) 41 1 (M+Na). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 2h; | Step 1 b Ethyl 2-(3-(4-((3-(6-(3-(methylsulfonyl)propoxy)pyridin-3-yl)benzyl)oxy) phenyl) oxetan-3-yl)acetate (Compound 109) To a solution of ethyl 2-(3-(4-((3-(6-hydroxypyridin-3-yl)benzyl) oxy)phenyl) oxetan-3-yl)acetate (compound of Step 1 a, 40 mg, 0.095 mM) and 3- (methylsulfonyl)propyl 4-methylbenzenesulfonate (30.7 mg, 0.105 mM) dissolved in DMF (3 ml), cesium carbonate (62.07 mg, 0.322 mM) was added and stirred at 80 QC for 2 h. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate, concentrated and purified by column chromatography to obtain the compound ethyl 2-(3-(4-((3-(6-(3-(methylsulfonyl) propoxy)pyridin-3-yl)benzyl)oxy)phenyl)oxetan-3-yl)acetate (42 mg) as pale yellow semisolid. Yield: 81 %; 1 HNMR (300 MHz, DMSO-d6) delta: 8.47 (s, 1 H), 8.04-8.01 (m, 1 H) 7.73 (s, 1 H), 7.63-742 (m, 1 H), 7.52-7.34 (m, 2H), 7.17 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 6.93 (d, J = 8.7 Hz, 1 H), 5.15 (s, 2H), 4.75 (s, 4H), 4.40 (t, J = 6.0 Hz, 2H), 3.99 (q, J = 6.9 Hz, 2H), 3.30-3.25 (m, 2H), 3.07 (s, 2H), 3.02 (s, 3H), 2.19- 1 .198 (m, 2H), 1 .01 (t, J = 6.9 Hz, 3H); MS: (e/z) 540.2 (M+1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 2h; | Example 61 Ethyl 2-(3-(4-((2'-chloro-4'-(3-(methylsulf onyl)propoxy)-[1 , 1 '-biphenyl]-3-yl)methoxy) phenyl)oxetan-3-yl)acetate (Compound 61 ) To the stirred solution of ethyl 2-(3-(4-((2'-chloro-4'-hydroxy-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)oxetan-3-yl)acetate (compound of Example 60, 405 mg, 0.894 mM) and <strong>[263400-88-0]3-(methylsulfonyl)propyl 4-methylbenzenesulfonate</strong> (314 mg, 1 .073 mM) dissolved in DMF (5 ml), cesium carbonate (583 mg, 1 .788 mM) was added and stirred at 60 QC for 2 h. The reaction mixture was quenched with water and extracted with ethyl acetate, concentrated and purified by column chromatography to obtain the compound, ethyl 2-(3-(4-((2'-chloro-4'-(3-(methylsulfonyl)propoxy)-[1 ,1 '-biphenyl]- 3-yl)methoxy) phenyl) oxetan-3-yl)acetate (465 mg, 0.810 mM). Yield: 91 %; 1 H NMR (300 MHz, CDCI3) delta: 7.48-7.42 (m, 4H), 7.27 (d, J = 2.5 Hz, 1 H), 7.13 (d, 1 H), 7.07 (d, J = 8.3 Hz, 2H), 6.98 (d, J = 2.1 Hz, 2 H), 6.89 (dd, J = 8.3 Hz, 2.5 Hz, 1 H), 5.1 1 (s, 2H), 5.01 (d, J = 6.0 Hz, 2H), 4.87 (d, J = 6.0 Hz, 2H), 4.18 (t, J = 5.3 Hz, 2H), 4.05 (q, J = 5.3 Hz, 2H), 3.28 (t, J = 7.2 Hz, 2H), 3.1 1 (s, 3H), 2.99 (s, 2H), 2.39-2.35 (m, 2H), 1 .13 (t, J = 7.2 Hz, 3 H); MS: m/z: 573 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With triethylamine; In dichloromethane; for 12h;Inert atmosphere; | 4-Methylbenzene-1-sulfonyl chloride (759 mg, 3.98 mmol), 3-(methylsulfonyl)propan- 1-ol (500 mg, 3.62 mmol) and triethyl amine (0.555 ml_, 3,98 mmol) were dissolved in Dichloromethane Dry (5 mL) under nitrogen atmosphere, and the mixture was stirred for 12 hours. The solvent was removed under reduced pressure and the residue was purified by semi-preparative HPLC-UV, to afford 3-(methylsulfonyl)propyl 4- methylbenzenesulfonate (881 mg, Y = 83%) as a white solid. MS (ESi+) m/z: 293.1 [M+H]+. (0255) Tert-butyl (4-hydroxy-2,6-dimethylphenyl)carbamate (which was synthesized as reported in the synthesis of compound 34) (269 mg, 1.13 mmol), 3- (methysulfonyl)propyl 4-methybenzenesulfonate (398 mg, 1.36 mmol) and potassium carbonate (188 mg, 1.36 mmol) were dissolved in N,N-Dimethylformamide Dry (2.5 ml) and the mixture was stirred at 80C under nitrogen atmosphere for 12 hours. AcOEt (20 mL) was added, and the mixture was washed with brine (2 x 0 mL). The organic layer was concentrated under reduced pressure and the residue was purified by semi-preparative HPLC-UV, to afford tert-butyl (2,6-dimethyl-4-(3- (methylsulfonyl)propoxy)pheny[)carbamate (375 mg, Y = 93%) as a white solid. MS (ESI+) m/z: 380.2 [ +Naf . (0256) Starting from tert-butyl (2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)carbamate (375 mg, 1.05 mmol), 2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)aniline, hydrochloride salt (309 mg, Y = quant.) was obtained as reported in the synthesis of compound 34. MS (ESI+) m/z: 258.1 [M+H]+. (0257) Starting from 2,6-dimethyl-4-(3-(methysulfonyl)propoxy)aniline, hydrochloride salt (46.1 mg, 0.157 mmoi) methyl 7-(3-(N-(2,6-dimethyl-4-(3- (methylsulfonyl)propoxy)phenyl)sulfamoyl) (0258) phenyl)heptanoate was obtained (33 mg, Y = 39%) as described in Procedure A. MS (ESI+) m/z: 562.3 [M+Na]+. (0259) Compound 35 was then obtained by hydrolysis of the ester derivative (20 mg, 0.046 mmol) as described for compound 1 , as a white solid (23 mg, Y = 83%). 1H NMR (300 MHz, CHLOROFORM-d) delta ppm 1.24 - 1.43 (m, 4 H) 1.51 - 1 .67 (m, 4 H) 1 .96 (s, 6 H) 2.26 - 2.41 (m, 4 H) 2.61 (t, J=7.58 Hz, 2 H) 2.97 (s, 3 H) 3.22 - 3.31 (m, 2 H) 4.04 (t, .7=5.68 Hz, 2 H) 6.32 (br s, 1 H) 6.52 (s, 2 H) 7.33 - 7.41 (m, 2 H) 7.48 - 7.58 (m, 2 H) 9.36 (br s, 2 H). MS (ESI+) m/z: 526.2 [M+H]+. |
1.6 g | With pyridine; In dichloromethane; at 0 - 20℃; for 12h; | To a solution of 3-(methylsulfonyl)propan-1 -ol (1 .0 g) in dichloromethane (10 mL) and pyridine (1 .5 mL) is added at 0C p-toluene-sulfonylchloride (1 .38 g) in portions. The mixture is stirred for 12 hours at room temperature, diluted with dichloromethane and washed with 1 M aqueous HCI solution and brine. After drying (MgSO4) the solvent is evaporated to give the title compound. Yield: 1 .6 g; LC (method 1 ): tR = 0.82 min; Mass spectrum (ESI+): m/z = 293 [M+H]+. |
With dmap; triethylamine; In tetrahydrofuran; at 50℃; for 14h; | Step C. 3-(Methylsulfonyl)propyl 4-methylbenzenesulfonate 3-(Methylsulfonyl)propan-l-ol (102 mg, 0.737 mmol), DMAP (0.88 g, 7.2 mmol), and TEA (6.1 ml, 43.4 mmol) were dissolved in THF (29.0 ml). Tosyl chloride (6.1 g, 31.8 mmol) was added and the mixture heated at 50C for 14 hours. The mixture was cooled to RT, diluted with water (300 ml), and extracted with EtOAc (3 x 150 ml). The organic fractions were combined, washed with brine, dried over magnesium sulfate, filtered and the volatiles removed in vacuo. The crude product was purified by column chromotagraphy on silica gel, BIOTAGE (Uppsala, Sweden) HP 340 g, using a gradient eluant of 5-100% EtOAc:Hexanes to the title compound. MS Ret: (m/z): 293 (M+H)+- |
With dmap; triethylamine; In tetrahydrofuran; at 50℃; for 14h; | Step C. 3-(Methylsulfonyl)propyl 4-methylbenzenesulfonate 3-(Methylsulfonyl)propan-l-ol (102 mg, 0.737 mmol), DMAP (0.88 g, 7.2 mmol), and TEA (6.1 ml, 43.4 mmol) were dissolved in THF (29.0 ml). Tosyl chloride (6.1 g, 31.8 mmol) was added and the mixture heated at 50C for 14 hours. The mixture was cooled to RT, diluted with water (300 ml), and extracted with EtOAc (3 x 150 ml). The organic fractions were combined, washed with brine, dried over magnesium sulfate, filtered and the volatiles removed in vacuo. The crude product was purified by column chromotagraphy on silica gel, BIOTAGE (Uppsala, Sweden) HP 340 g, using a gradient eluant of 5-100% EtOAc:Hexanes to the title compound. MS Ret: (m/z): 293 (M+H)+- | |
With triethylamine; In dichloromethane; at 0 - 15℃; for 12h; | To a stirred solution of 3-methylsulfonylpropan-1-ol (500 mg, 3.62 mmol) in DCM (10 mL) was added triethylamine (549 mg, 5.43 mmol). Then to the mixture was added a solution of tosyl chloride (759 mg, 3.98 mmol) in DCM (10 mL) at 0 C. The resulting mixture was stirred at 15 C for 12 hrs, and then partitioned between DCM and H20. The separated organic layer was washed sequentially with water, hydrochloric acid and brine, then dried over anhydrous Na2SO4 and concentrated under reduced pressure give 3-methylsulfonylpropyl 4-methylbenzenesulfonate (900 mg) as a light yellow oil, which was used directly in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
268 mg | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 12h; | To a solution of 3-bromo-4-methylphenol (200 mg) and K2CO3 (1 93 mg) in N,N- dimethylformamide (5 mL) is added 3-(methylsulfonyl)propyl 4- methylbenzenesulfonate (375 mg). The mixture is stirred for 12 hours at 90C and then partitioned between water and ethyl acetate. The organic phase is washed with brine and dried (MgSO4) . Th e solvent is eva porated a nd th e res id u e is chromatographed on silica gel (cyclohexane/ethyl acetate 80:20?20:80) to give the title compound. Yield: 268 mg; LC (method 1 ): tR = 1 .12 min; Mass spectrum (ESI+): m/z = 307 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Step 1: synthesis of (4-chloro-2-nitro-phenyl)-(3-methanesulfonyl-propyl)-carbamic acid tertbutyl ester (4-Chloro-2-nitro-phenyl)- (3-methanesulfonyl-propyl)-carbamic acid tert-butyl ester was prepared according to Scheme 1. To a solution of tert-butyl 4-chloro-2-nitrophenylcarbamate (580 mg, 2.1 mmol) in DMF (5 mL) was added NaH (170 mg, 4.3 mmol, 60 wt%). The mixturewas stilTed for 30 mm at RT, then <strong>[263400-88-0]3-(methylsulfonyl)propyl 4-methylbenzenesulfonate</strong> (0.75 g,2.56 mmol) was added. The solution was heated to 50 C and stirred for overnight. After cooledto RT, H20 (30 mL) was added and the solution was extracted with DCM (40 mLx3). Theorganic layer was dried over anhydrous and concentrated. The residue was purified by prep-TLC(DCM) to give tert-butyl 4-chloro-2-nitrophenyl(3-(methylsulfonyl)propyl)carbamate (360 mg, yield: 69%) as pale oil. MS obsd. (ESIj [(M+H)]: 393.0. | |
69% | To a solution of tert-butyl 4-chloro-2-nitrophenylcarbamate (580 mg, 2.1 mmol) in DMF (5 mL) was added NaH (170 mg, 4.3 mmol, 60 wt %). The mixture was stirred for 30 min at RT, then <strong>[263400-88-0]3-(methylsulfonyl)propyl 4-methylbenzenesulfonate</strong> (0.75 g, 2.56 mmol) was added. The solution was heated to 50 C. and stirred for overnight. After cooled to RT, H2O (30 mL) was added and the solution was extracted with DCM (40 mL*3). The organic layer was dried over anhydrous and concentrated. The residue was purified by prep-TLC (DCM) to give tert-butyl 4-chloro-2-nitrophenyl(3-(methylsulfonyl)propyl)carbamate (360 mg, yield: 69%) as pale oil. MS obsd. (ESI+) [(M+H)+]: 393.0. | |
69% | (4-Chloro-2-nitro-phenyl)-(3-methanesulfonyl-propyl)-carbamic acid tert-butyl ester was prepared according to Scheme 1. To a solution of tert-butyl 4-chloro-2-nitrophenylcarbamate (580 mg, 2.1 mmol) in DMF (5 mL) was added NaH (170 mg, 4.3 mmol, 60 wt %). The mixture was stirred for 30 min at RT, then <strong>[263400-88-0]3-(methylsulfonyl)propyl 4-methylbenzenesulfonate</strong> (0.75 g, 2.56 mmol) was added. The solution was heated to 50 C. and stirred for overnight. After cooled to RT, H2O (30 mL) was added and the solution was extracted with DCM (40 mL×3). The organic layer was dried over anhydrous and concentrated. The residue was purified by prep-TLC (DCM) to give tert-butyl 4-chloro-2-nitrophenyl(3-(methylsulfonyl)propyl)carbamate (360 mg, yield: 69%) as pale oil. MS obsd. (ESI+) [(M+H)+]: 393.0. |
69% | To a solution of 3-(Methylthio)-1-propanol (20g, 0.19mol) and TEA (66ml, 0.48mol) in DCM (800mL) cooled at 0C was added p-toluenesulfonyl chloride (44g, 0.23mol, dissoloved in 200mL DCM) dropwise. After addtion, the mixture was then stirred at r.t. overnight. After the reaction was complete, the resluting solution was washed with saturated Na2CO3 solution, brine, dried over MgSO4 and concentrated in vacuo to give the crude of 3-methylsulfanylpropyl 4-methylbenzenesulfonate, which was used in the next step without further purification. To the solution of the crude of 3-methylsulfanylpropyl 4-methylbenzenesulfonate (prepared above) in DCM (200 mL) cooled at 0oC was added m-CPBA (66g, 0.39mol) slowly and the mixture was then stirred at rt overnight. After the reaction was complete, the mixture was washed with saturated sodium thiosulfate (300mL) 3 times , saturated sodium bicarbonate (300mL) 3 times, dried over MgSO4 and then concentrated in vacuo to give <strong>[263400-88-0]3-methylsulfonylpropyl 4-methylbenzenesulfonate</strong> (11b, 38g, 69% yield over 2 steps) as a white solid. To a solution of tert-butyl 4-chloro-2-nitrophenylcarbamate (580 mg, 2.1 mmol) in DMF(5mL) cooled at 0oC was added NaH( 169 mg, 4.4 mmol). The mixture was then stirred at rt for 30mins. Then to the resulting solution was added <strong>[263400-88-0]3-methylsulfonylpropyl 4-methylbenzenesulfonate</strong> (11b, 750 mg, 2.6 mmol) and the mixture was stirred at 50oC overnight. After the reaction was complete, to the mixture was added water (30 mL) and the resulting mixture was extracted with DCM (50 mL) 3 times. The combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution with DCM:MeOH 20 :1) to give tert-butyl N-(4-chloro-2-nitro-phenyl)-N-(3-methylsulfonylpropyl)carbamate(11c, 360 mg, 69% yield). To a soltuion of tert-butyl N-(4-chloro-2-nitro-phenyl)-N-(3-methylsulfonylpropyl)carbamate (11c, 360 mg, 1.45 mol) in MeOH (10 mL) was added 2% Pt/C (50mg) under N2 atmosphere, the mixture wa then hydrogenated at rt for 3 hours. After the reaction was complete, the mixture was filtred and the filtrate was concentrated in vacuo to give the crude of tert-butyl N-(2-amino-4-chloro-phenyl) -N-(3-methylsulfonylpropyl)carbamate (11d, 330 mg, 100% yield), which was used in the next step directly without further purificaton. A mixture of tert-butyl N-(2-amino-4-chloro-phenyl)-N-(3-methylsulfonylpropyl)carbamate (11d, 320 mg, 0.92mmol) and sodium chloroacetate (130 mg, 1.1 mmol) in 4N HCl (15 mL) was stirred to 100oC overnight. After the reaction was complete, The reaction was concentrated in vacuo and the residue was redissoved in DCM (100 mL). The resulting soltuion was washed with saturated NaHCO3 (50 mL), brine (50 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by column crhomatography on silica gel (elution with DCM/EtOAc=3/1) to give 5-chloro-2-(chloromethyl) -1-(3-methylsulfonylpropyl)benzimidazole (11e, 130 mg, 44% yield). To a mixture of 2-(methylsulfonyl)-1H-indole (72 mg, 0.37 mmol) and 5-chloro-2-(chloromethyl) -1-(2- (methylsulfonyl)ethyl)-1H-benzo[d]imidazole (11e, 120 mg, 0.37mmol) in DMF (3 mL) was added K2CO3 (104 mg, 0.74 mmol) and the mixture was stirred at rt overnight. After the reaction was completed, the mixture was filtered and the filtrate was purified by preparative HPLC to give 5-chloro-2-[(3-methylsulfonylindol-1-yl)methyl]-1-(3-methylsulfonylpropyl)benzimidazole (11, 100 mg, 78%). MS: calcd (MH+) 480.1, exp (MH+) 480.1. 1H NMR(DMSO-d6, 400MHz):delta8.29(s, 1H), 7.80-7.86(m, 1H), 7.65-7.73(m, 3H), 7.26-7.34(m, 3H), 5.92(s, 2H), 4.86(t, J=7.6Hz, 2H), 3,73(br, 3H), 3.19(t, J=8.0Hz, 2H), 2.96(s, 3H), 2.08(t, J=7.6Hz, 2H); 13C NMR (101MHz, DMSO-d6) delta151.4, 143.2, 137.3, 134.7, 134.6, 126.9, 124.2, 123.8, 123.3, 122.6, 119.5, 119.2, 115.5, 112.4, 112.3, 51.1, 45.6, 43.6, 42.3, 23.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 18h; | Step A: 1 -fluoro-3 -(3 -(methylsulfonyl)propoxy)-5 -(trifluoromethyl)benzene (10-2)To a solution of compound 10-1 (400 mg, 2.22 mmol) in DMF (5.0 mL) was added compound la (973 mg, 3.33 mmol), and K2C03 (613 mg, 4.44 mmol). The resulting mixture was stirred at 100 C for 18 hours. H20 was added and the resulting mixture was extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine, dried and concentrated to give a residue, which was purified by preparative TLC on silica gel eluted with petroleum ether:ethylacetate (5:1) to give compound 10-2. | |
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 18h; | To a solution of compound 10-1 (400 mg, 2.22 mmol) in DMF (5.0 mL) was added compound 1a(973 mg, 3.33 mmol), and K2C03 (613 mg, 4.44 mmol). The resulting mixture was stirred at 100C for 18 hours. H20 was added and the resulting mixture was extracted with EtOAc (15 mL x3). The combined organic layers were washed with brine, dried and concentrated to give aresidue, which was purified by preparative TLC on silica gel eluted with petroleum ether:ethyl15 acetate ( 5: 1) to give compound 10-2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | (Reference Example 28) (5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-d imethyl-2-(1-{5-[3-(methylsulfonyl)propoxy]pyrimidin-2-yl}piperidin-4-yl)-5,6,7,8-tetr ahydroquinolin-5-ol To a solution of 145 mg (0.224 mmol) of (5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Reference Example 23, in 0.7 ml of N,N-dimethylformamide, 130 mg (0.445 mmol) of 3-(methylsulfonyl)propyl p-toluenesulfonate and 135 mg (0.977 mmol) of potassium carbonate were added, and the mixture was stirred at 80C for 4 hours. 44 mg (0.337 mmol) of 2-chloro-5-hydroxypyrimidine was further added thereto, and the mixture was stirred at 80C for 3 hours. After completion of the reaction, the reaction solution was poured into water and extracted with toluene twice. The obtained organic phases were combined and washed with saturated sodium chloride aqueous solution, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate = 55/45-25/75 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 137.0 mg of the title compound as a white solid (yield: 80%). 1H-NMR spectrum (400 MHz, CD2 Cl2) delta: 8.03 (2H, s), 7.68-7.63 (2H, m), 7.42-7.36 (2H, m), 7.22 (1H, d, J = 47 Hz), 5.17-5.09 (1H, m), 4.69-4.62 (1H, m), 4.41-4.33 (1H, m), 4.04 (2H, t, J = 6 Hz), 3.69-3.59 (1H, m), 3.20 (2H, t, J = 8 Hz), 2.91 (3H, s), 2.83-2.56 (4H, m), 2.33-1.56 (17H, m), 1.13 (3H, s), 1.00 (3H, s), 0.65-0.58 (1H, m). Mass spectrum (EI, m/z): 768 [M+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.8% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; | To a mixture of 4-bromo-3-(trifluoromethyl)phenol (commercial source, 570 mg, 2.365 mmol) and <strong>[263400-88-0]3-(methylsulfonyl)propyl 4-methylbenzenesulfonate</strong> (commercial source, 691 mg, 2.365 mmol) in anhydrous DMF was added cesium carbonate (1926 mg, 5.91 mmol) and reaction was stirred overnight at RT. After completion of reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic solvent was removed and the residue was purified by column chromatography to obtain the title compound (630 mg) as white solid. Yield: 73.8 % yield; 1 H NMR (CDCI3, 300 MHZ): delta 7.62 (d, J = 8.2 Hz, 1 H), 7.22 (d, J= 1 .6 Hz, 1 H), 6.91 (d, J = 8.2 Hz, 1 H), 4.17 (t, J = 6.0 Hz, 2H), 3.28 (t, J = 7.5 Hz, 2H), 2.99 (s, 3H), 2.42 -2.37 (m, 2H); MS: (m/z) 383.5 [M+ Na]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.6 g | With caesium carbonate; In acetonitrile;Reflux; | A mixture of 4-chloro-2-nitroaniline (3.44 g, 20.0 mmol), 3-(methylsulfonyl)propyl 4- methylbenzenesulfonate (5.53 g, 20.0 mmol) and cesium carbonate (9.78 g, 30.0 mmol) in acetonitrile (40 mL) was heated with stirring under reflux overnight. The resulting mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with 0 - 8% methanol in dichloromethane) to afford 4.60 g of 4-chloro-N-[2- (methylsulfonyl)propyl]-2-nitroaniline as an orange solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.3% | With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 1h; | Cs2CO3 (72.4 mg, 0.222 mmol) was added to a solution of ethyl 2-(3-(4-(2-(3-(4- hydroxyphenyl)oxetan-3-yl)ethoxy)phenyl)oxetan-3-yl)acetate (Compound 76, 70.54 mg, 0.171 mmol) in DMF. The reaction mixture was stirred at RT for 10 minutes, followed by the addition of <strong>[263400-88-0]3-(methylsulfonyl)propyl 4-methylbenzenesulfonate</strong> (50 mg, 0.171 mmol). The reaction mixture was refluxed at 80 C for 1 h. After completion of reaction, the solvent was evaporated and the residue was dissolved in EtOAc. The organic layer was washed with water, dried over anhydrous Na2504 and concentrated. The crude compound was purified by flash column chromatography (1-50 % EtOAc in petroleum ether as eluent) to obtain the title compound (68 mg) as sticky liquid. Yield: 74.3 %; 1H NMR (CDC13, 300 MHz): 7.05 (d, J = 9.0 Hz, 2H), 6.99 (d, J =9.0Hz, 2H), 6.84 (d, J = 9.0Hz, 2H), 6.74 (d, J = 9.0 Hz, 2H), 5.01 (d, J = 6.0Hz, 2H), 4.96 (d, J = 6.0 Hz, 2H), 4.88 (d, J = 9.0 Hz, 2H), 4.84 (d, J = 6.0 Hz, 2H), 4.11 (t, J= 6.0, 6.0 Hz, 2H), 3.99-4.06 (m, 2H), 3.75 (t, J= 6.0, 6.0 Hz, 2H), 3.27 (t, J=9.0, 9.0 Hz, 2H), 3.09 (s, 2H), 2.97 (s, 3H), 2.52 (t, J = 6.0, 6.0 Hz, 2H), 2.33-2.38 (m, 2H),1.15 (t, J= 6.0, 6.0 Hz, 3H); MS (mlz): 555.1 [M+ Na]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
160 mg | With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 2h; | Step 2: (6-(R)-(4-(4-(3-Methanesulfonyl-propoxy)-phenyl)-5-trifluoromethyl-indan-1-yloxy)benzofuran-3-yl)acetic acid methyl ester [0276] The solution of 265 mg (0.55 mmol) of (6-(R)-(4-(4-hydroxyphenyl-5-trifluoromethyl-indan-1-1-yloxy)benzofuran-3-yl)acetic acid methyl ester (product of step 1), 265 mg (0.91 mmol) of <strong>[263400-88-0]3-(methylsulfonyl)propyl 4-methylbenzenesulfonate</strong> and 233 mg (0.71 mmol) of cesium carbonate in 3.0 ml DMF is stirred for 2 h at 60 C. The solvent is evaporated, the residue is dissolved in MeOH and purified by HPLC (reversed phase; ACN/H2O/TFA) to give the title compound. Yield: 160 mg; LC (method 1): tR=1.18 min; Mass spectrum (ESI+): m/z=603 [M+H]+. [0277] The compound may also be obtained from (6-(R)-(4-bromo-5-trifluoromethyl-indan-1-yloxy)benzofuran-3-yl)acetic acid methyl ester (Intermediate 7a) and 2-[4-(3-methanesulfonyl-propoxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane or the corresponding boronic acid [e.g., prepared from 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol or the corresponding boronic acid and <strong>[263400-88-0]3-(methylsulfonyl)propyl 4-methylbenzenesulfonate</strong> using Cs2CO3 or K2CO3 in DMF or NMP, or in analogy to Intermediate 23] applying the conditions described in Step 6 of Intermediate 1 or Step 1 of Intermediate 8. |
160 mg | With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 2h; | Step 2: (6-(R)-(4-(4-(3-Methanesulfonyl-propoxy)-phenyl)-5-trifluoromethyl-indan-1-yloxy)-benzofuran-3-yl)-acetic acid methyl ester The solution of 265 mg (0.55 mmol) of (6-(R)-(4-(4-hydroxy-phenyl-5-trifluoromethyl- indan-1 -1 yloxy)-benzofuran-3-yl)-acetic acid methyl ester (product of step 1 ), 265 mg (0.91 mmol) of <strong>[263400-88-0]3-(methylsulfonyl)propyl 4-methylbenzenesulfonate</strong> and 233 mg (0.71 mmol) of cesium carbonate in 3.0 ml DMF is stirred for 2 h at 60C. The solvent is evaporated, the residue is dissolved in MeOH and purified by HPLC (reversed phase; ACN/H20/TFA) to give the title compound.Yield: 160 mg; LC (method 1 ): tR= 1 .18 min; Mass spectrum (EST): m/z = 603 [M+H]+.The compound may also be obtained from (6-(R)-(4-bromo-5-trifluoromethyl-indan-1 - yloxy)-benzofuran-3-yl)-acetic acid methyl ester (Intermediate 7a) and 2-[4-(3- methanesulfonyl-propoxy)-phenyl]-4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolane or the corresponding boronic acid [e.g., prepared from 4-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-phenol or the corresponding boronic acid and 3- (methylsulfonyl)propyl 4-methylbenzenesulfonate using Cs2C03or K2C03in DMF or NMP, or in analogy to Intermediate 23] applying the conditions described in Step 6 of Intermediate 1 or Step 1 of Intermediate 8 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium carbonate; In acetonitrile; at 20 - 100℃; for 16h; | PREPARATION 7 2-[4-(3-Methanesulfonyl-propoxy)-2,6-dimethyl-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid methyl ester To a solution of 2-(4-hydroxy-2,6-dimethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid methyl ester (0.2 g, 0.673 mmol) in acetonitrile (5 mL) is added <strong>[263400-88-0]toluene-4-sulfonic acid 3-methanesulfonyl-propyl ester</strong> (0.196 g, 0.673 mmol) and potassium carbonate (0.278 g, 2.019 mmol) at room temperature and the reaction mixture is heated at 100 C. for 16 hours. The reaction mixture is diluted with water (10 mL) and extracted with EtOAc (2*20 mL). The combined organic extracts are washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4, filtered, and evaporated to dryness. The crude material is purified by silica gel chromatography (combiflash purifier 24 g redisep column) and is eluted with 40-60% EtOAc in hexane to give the title compound as a light yellow solid (198 mg, 70%). LCMS m/z 418 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 14h; | Step D. 5-Bromo-4-methyl-2-r3-(methylsulfonyl)propoxylpyridine 3-(Methylsulfonyl)propyl 4-methylbenzenesulfonate (1.1 g, 3.7 mmol) was dissolved in DMF (5.0 ml). TEA (0.52 ml, 3.7 mmol) and 5-bromo-4-methylpyridin-2-ol (0.52 ml, 3.7 mmol) were added and the mixture stirred at RT for 14 hours. The mixture was diluted with EtOAc (100 ml), washed with water (3x50 ml), brine, dried over magnesium sulfate, filtered and the volatiles removed in vacuo. The crude oil was purified by column chromotagraphy on silica gel, BIOTAGE (Uppsala, Sweden) HP 25 g, using a gradient eluant of 5- 100% EtOAc:Hexanes to afford the title compound. MS (m/z): 325 (Mu+Eta20))+· | |
With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 14h; | Step D. 5-Bromo-4-methyl-2-r3-(methylsulfonyl)propoxylpyridine 3-(Methylsulfonyl)propyl 4-methylbenzenesulfonate (1.1 g, 3.7 mmol) was dissolved in DMF (5.0 ml). TEA (0.52 ml, 3.7 mmol) and 5-bromo-4-methylpyridin-2-ol (0.52 ml, 3.7 mmol) were added and the mixture stirred at RT for 14 hours. The mixture was diluted with EtOAc (100 ml), washed with water (3x50 ml), brine, dried over magnesium sulfate, filtered and the volatiles removed in vacuo. The crude oil was purified by column chromotagraphy on silica gel, BIOTAGE (Uppsala, Sweden) HP 25 g, using a gradient eluant of 5- 100% EtOAc:Hexanes to afford the title compound. MS (m/z): 325 (Mu+Eta20))+· |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step E. (l S, laS,6aR)-ethyl 4-ff4-methyl-3-n-f3-fmethylsulfonyl)propyl)-lH-pyrrolor2,3- blpyridin-5-yl)benzyl)oxy)- 1 , 1 a,6,6a-tetrahydrocvcloproparalindene- 1 -carboxylic acid, ethyl ester To a solution of (l S,laS,6aR)-ethyl 4-((4-methyl-3-(lH-pyrrolo[2,3-b]pyridin-5- yl)benzyl)oxy)-l,la,6,6a-tetrahydrocyclopropa[a]indene-l -carboxylic acid, ethyl ester (200 mg, 0.46 mmol) in DMF (5.0 mL) was added NaH (55 mg, 0.37 mmol), the resulting mixture was stirred atatatat RT for 15mins, then <strong>[263400-88-0]3-(methylsulfonyl)propyl 4-methylbenzenesulfonate</strong> (201 mg, 0.49 mmol) was added and stirred for 2 hours. TLC showed 3-(methylsulfonyl)propyl 4- methylbenzenesulfonate was consumed completely. The solution was quenched with 0 and extracted with EtOAc (3 x lOmL). The combined organic layer was washed with brine, dried and concentrated to give the residue, which was purified by preparative TLC to give the title compound. MS m/z: 559 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32.3% | With potassium carbonate; In acetonitrile; at 20 - 90℃; | To a stirred solution of (S)-3-(4-{2-[4-(3-methane- sulfonyl-propoxy)-2-methyl-phenyl]-[1 ,2,4]triazolo[1 ,5-a] pyridin-6-ylmethoxy}-phenyl)-hex-4-ynoic acid ethyl ester (0.3 g, 0.630 mmol) and toluene-4-sulfonic acid 3-methane- sulfonyl-propyl ester (0.18 g, 0.63 4 mmol) in acetonitrile (10 mE) is added potassium carbonate (0.26 g, 1.89 mmol) at room temperature and the reaction mixture is heated at 90 C. overnight. The reaction mixture is filtered through diatomaceous earth, washed with EtOAc (10 mE), and the filtrate is evaporated to dryness. The residue is dissolved in EtOAc (10 mE), washedwithwater (2x3OmE), brine solution, dried over sodium sulphate, and evaporated under reduced pressure. Thecrude compound is purified by silica gel (combiflash purifier) and is eluted with 50% EtOAc in hexane to give the titlecompound as a yellow solid (0.12 g, 32.3%). ECMS mlz 590 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.3% | With potassium carbonate; In acetonitrile; at 80℃; | A mixture of (S)-3-{4-[6-(4-hydroxy-2-methyl-phenyl)-[l,2,4]triazolo[l,5- a]pyridin-8-ylmethoxy]-phenyl}-hex-4-ynoic acid ethyl ester (0.15 g, 0.31 mmol), <strong>[263400-88-0]toluene-4-sulfonic acid 3-methanesulfonyl-propyl ester</strong> (0.28 g, 0.95 mmol) and potassium carbonate (0.129 g, 0.95 mmol) in acetonitrile (15 mL) is stirred overnight at 80 C. The reaction mixture is diluted with water (50 mL) and extracted with EtOAc (2x30 mL). The combined organic extracts are washed with saturated brine solution (20 mL), dried over sodium sulphate, filtered, and evaporated to dryness. The crude material is purified by silica gel column chromatography (combiflash) eluting with 90%EtOAc/hexanes to obtain the title compound as an off white solid (0.15 g, 83.3%).LCMS m/z 590 (M+H)+. |
83.3% | With potassium carbonate; In acetonitrile; at 80℃; | A mixture of (S)-3-{4-[6-(4-hydroxy-2-methyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-8-ylmethoxy]-phenyl}-hex-4-ynoic acid ethyl ester (0.15 g, 0.31 mmol), <strong>[263400-88-0]toluene-4-sulfonic acid 3-methanesulfonyl-propyl ester</strong> (0.28 g, 0.95 mmol) and potassium carbonate (0.129 g, 0.95 mmol) in acetonitrile (15 mL) is stirred overnight at 80 C. The reaction mixture is diluted with water (50 mL) and extracted with EtOAc (2*30 mL). The combined organic extracts are washed with saturated brine solution (20 mL), dried over sodium sulphate, filtered, and evaporated to dryness. The crude material is purified by silica gel column chromatography (combiflash) eluting with 90% EtOAc/hexanes to obtain the title compound as an off white solid (0.15 g, 83.3%). LCMS m/z 590 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54.27% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h; | To a stirred solution of ethyl 8-(4-hydroxy-2,6-dimethylphenyl)-2-isopropyl-[1,2,4ltriazolo [1,5-alpyridine-6-carboxylate (1.1 g, 3.11 mmol) and <strong>[263400-88-0]3-(methylsulfonyl)propyl-4-methylbenzenesulfonate</strong> (1.09 g, 3.73 mmol) in DMF (15 mL)is added potassium carbonate (1.29 g, 9.34 mmol) at room temperature. The reactionmixture is heated at 80 C for 16 hours. The mixture is then quenched with water and extracted with EtOAc (2x70 mL). The organic extracts are washed with brine, dried over sodium sulphate, and evaporated under reduced pressure. The crude compound is purified by silica gel column chromatography (combiflash) eluting with 45% EtOAc in nhexane to give the title compound (0.8 g, 54.27%). LCMS mlz 474.41 (M+H)t |
54.27% | With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 80℃; for 16h; | To a stirred solution of ethyl 8-(4-hydroxy-2,6-dimethylphenyl)-2-isopropyl-[1,2,4]triazolo [1,5-a]pyridine-6-carboxylate (1.1 g, 3.11 mmol) and <strong>[263400-88-0]3-(methylsulfonyl)propyl-4-methylbenzenesulfonate</strong> (1.09 g, 3.73 mmol) in DMF (15 mL) is added potassium carbonate (1.29 g, 9.34 mmol) at room temperature. The reaction mixture is heated at 80 C. for 16 hours. The mixture is then quenched with water and extracted with EtOAc (2*70 mL). The organic extracts are washed with brine, dried over sodium sulphate, and evaporated under reduced pressure. The crude compound is purified by silica gel column chromatography (combiflash) eluting with 45% EtOAc in n-hexane to give the title compound (0.8 g, 54.27%). LCMS m/z 474.41 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63.8% | With caesium carbonate; In N,N-dimethyl acetamide; at 70℃; for 2h;Inert atmosphere; | Example 22 4-(3-(3-Fluoro-4-(3-(methylsulfonyl)propoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimid azolidin-1-yl)-2-(trifluoromethyl)benzonitrile 4-(3-(3-Fluoro-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2 -(trifluoromethyl)benzonitrile 1e (100 mg, 0.24 mmol) was placed in a reaction flask, followed by addition of <strong>[263400-88-0]3-(methylsulfonyl)propyl-4-methylbenzenesulfonate</strong> 22a (138 mg, 0.47 mmol, prepared by a method disclosed in'), cesium carbonate (231 mg, 0.71 mmol) and 2 mL of N,N-dimethylacetamide successively. The reaction solution was warmed up to 70C and stirred for 2 hours. The reaction solution was cooled down to room temperature, mixed with 15 mL of water and extracted with ethyl acetate (15 mL*3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL*2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under the reduced pressure and the residue was purified by thin layer chromatography with elution system B and subsequent elution system A to obtain the title compound 4-(3-(3-fluoro-4-(3-(methylsulfonyl)propoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimid azolidin-1-yl)-2-(trifluoromethyl)benzonitrile 22 (50 mg, yield 63.8%) as a white solid. MS m/z (ESI): 544.2 [M+1] |
63.8% | With caesium carbonate; In N,N-dimethyl acetamide; at 70℃; for 2h; | 4-(3-(3-Fluoro-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile 1e (100 mg, 0.24 mmol) was placed in a reaction flask, followed by addition of <strong>[263400-88-0]3-(methylsulfonyl)propyl-4-methylbenzenesulfonate</strong> 22a (138 mg, 0.47 mmol, prepared by a method disclosed in PCT Patent Application Publication WO 2008/1931 A2), cesium carbonate (231 mg, 0.71 mmol), and 2 mL of N,N-dimethylacetamide, successively. The reaction solution was warmed up to 70 C. and stirred for 2 hours. The reaction solution was cooled down to room temperature, mixed with 15 mL of water and extracted with ethyl acetate (15 mL*3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL*2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by thin layer chromatography with elution system B, and subsequently with elution system A to obtain the title compound 4-(3-(3-fluoro-4-(3-(methylsulfonyl)propoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile 22 (50 mg, yield 63.8%) as a white solid. MS m/z (ESI): 544.2 [M+1]; 1H NMR (400 MHz, CDCl3): delta 7.95-8.00 (m, 2H), 7.84 (d, 1H), 7.05-7.10 (m, 3H), 4.26-4.29 (m, 2H), 3.29-3.32 (m, 2H), 2.99 (s, 3H), 2.41-2.46 (m, 2H), 1.59 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With caesium carbonate; In N,N-dimethyl-formamide; at 50℃; for 15h; | The compound obtained in 108-6 (100 mg, 0.37 mmol) was dissolved in DMF (4 mL), added with <strong>[263400-88-0]3-(methylsulfonyl)propyl 4-methylbenzenesulfonate</strong> (131 mg, 0.45 mmol) and Cs2CO3 (182 mg, 0.56 mmol), and stirred at 50C for 15 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with a saturated NH4Cl aqueous solution and brine. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue thus obtained was purified by silica gel chromatography to obtain the title compound (white foam, 165 mg, 99% yield). 1H NMR (300 MHz, CDCl3) delta 8.01 (d, 1H), 7.93 (dd, 1H), 7.35 (d, 1H), 7.30 (d, 1H), 6.87 (dd, 1H), 6.80 (d, 1H), 4.17 (t, 2H), 3.93 (s, 3H), 3.29 (t, 2H), 2.98 (s, 3H), 2.54 (t, 2H), 2.46 (t, 2H), 2.43 - 2.34 (m, 2H), 2.25 - 2.16 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | The compound (800 mg, 2.28 mmol) obtained in was dissolved in DMF (10 mL), and K2CO3 (945 mg, 6.83 mmol) was added, and stirred at room temperature for 1 hour. 3-(Methylsulfonyl)propyl 4-methylbenzenesulfonate (799 mg, 2.73 mmol) was added thereto, and stirred at 90C for 15 hours. The reaction mixture was cooled to room temperature, and a saturated NH4Cl aqueous solution was then added, and extracted with EtOAc. An organic layer was washed with saline, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified using silica gel chromatography to obtain the title compound (white foam, 848 mg, and 95% yield).1H NMR (300 MHz, CDCl3) delta 7.82 (dd, 1H), 7.69 (dd, 1H), 7.09 (t, 1H), 6.77 (d, 1H), 6.61 (d, 1H), 4.98 (s, 2H), 4.15 (t, 2H), 3.92 (s, 3H), 3.27 (t, 2H), 2.97 (s, 3H), 2.58 (s, 3H), 2.41-2.32 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | The compound (11 mg, 0.03 mmol) obtained in was dissolved in DMF (2 mL), and K2CO3 (6 mg, 0.045 mmol) was added thereto, and stirred at ambient temperature for 3 hours. 3-(Methylsulfonyl)propyl 4-methylbenzenesulfonate (11 mg, 0.036 mmol) was added to the reaction mixture, stirred at 90C for 16 hours, and then cooled to ambient temperature. The mixture was concentrated under reduced pressure, and purified using silica gel chromatography to obtain the title compound (colorless oil, 10 mg, and 82% yield). 1H NMR (300 MHz, CDCl3) delta 7.73 (dd, 1H), 7.44 (dd, 1H), 7.23 (t, 1H), 6.77 (d, 1H), 6.69 (d, 1H), 4.69 (dd, 1H), 4.43 (ddd, 1H), 4.16 (t, 2H), 3.92 (s, 3H), 3.28 (m, 2H), 2.97 (s, 3H), 2.83 (td, 1H), 2.41 - 2.30 (m, 2H), 2.33 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 15h; | The compound (90 mg, 0.318 mmol) obtained in 1-7 was dissolved in DMF (4 mL), and <strong>[263400-88-0]3-(methylsulfonyl)propyl 4-methylbenzenesulfonate</strong> (112 mg, 0.383 mmol) and K2CO3 (66 mg, 0.478 mmol) were added thereto, and stirred at 90C for 15 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc, and then washed with a saturated NH4Cl aqueous solution and saline. An organic layer was dried over sodium sulfate, and concentrated under reduced pressure. Then, the residue was purified using silica gel chromatography to obtain the title compound (white foam, 124 mg, and 97% yield).1H NMR (300 MHz, CDCl3) delta 7.73 (dd, 1H), 7.40 - 7.27 (m, 2H), 6.74 (d, 1H), 6.63 (d, 1H), 4.15 (m, 2H), 3.92 (s, 3H), 3.27 (m, 2H), 2.97 (s, 3H), 2.55 - 2.28 (m, 4H), 2.27 (s, 3H), 2.18 (m, 3H), 2.01 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With caesium carbonate; In N,N-dimethyl-formamide; at 50℃; for 1h; | The compound obtained in (300 mg, 0.99 mmol) was dissolved in DMF (5 mL), added with <strong>[263400-88-0]3-(methylsulfonyl)propyl 4-methylbenzenesulfonate</strong> (318 mg, 1.09 mmol) and Cs2CO3 (354 mg, 1.09 mmol), and then stirred at 50C for 1 hour. The reaction mixture was filtered and washed with EtOAc. The filtrate was concentrated and purified by silica gel chromatography to obtain the title compound (white solid, 411 mg, 73% yield). 1H NMR (300 MHz, CDCl3) delta 7.97 (dd, 1H), 7.83 (d, 1H), 7.39 (d, 1H), 7.04 (d, 1H), 6.55 - 6.51 (m, 2H), 4.17 (t, 2H), 3.89 (s, 3H), 3.72 (s, 3H), 3.72 - 3.67 (m, 2H), 3.32 - 3.27 (m, 2H), 2.99 (s, 3H), 2.80 - 2.75 (m, 2H), 2.43 - 2.36 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 6h; | (C) A mixture of 5-hydroxymethyl-3-(4-hydroxy-2-methylphenyl)benzo[b]thiophene (from Example 3) (108 mg; 0.4 mmol), 3-(methylsulfonyl)propyl 4- methylbenzenesulfonate (292 mg; 1.0 mmol) and K2CO3 (82 mg; 0.6 mmol) in DMF (1.0 mL) was stirred at 90 C for 6 h. After cooling to rt, the reaction was partitioned between EtOAc and aq NH4Cl and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 5-60% EtOAc in heptanes to afford 5-hydroxymethyl-3-(2- methyl-4-(3-(methylsulfonyl)propoxy)phenyl)benzo[b]thiophene (87 mg, 56%). LC/MS: mass calcd. for C20H20O4S2: 390.52, found 413.1 [M+Na]+. |
56% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 6h; | (C) A mixture of 5-hydroxymethyl-3-(4-hydroxy-2-methylphenyl)benzo[b]thiophene (from Example 3) (108 mg; 0.4 mmol), <strong>[263400-88-0]3-(methylsulfonyl)propyl 4-methylbenzenesulfonate</strong> (292 mg; 1.0 mmol) and K2CO3 (82 mg; 0.6 mmol) in DMF (1.0 mL) was stirred at 90 C. for 6 h. After cooling to rt, the reaction was partitioned between EtOAc and aq NH4Cl and the aqueous layer was extracted with EtOAc (2*). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 5-60% EtOAc in heptanes to afford 5-hydroxymethyl-3-(2-methyl-4-(3-(methylsulfonyl)propoxy)phenyl)benzo[b]thiophene (87 mg, 56%). LC/MS: mass calcd. for C20H20O4S2: 390.52, found 413.1 [M+Na]+. |
56% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 6h; | (C) A mixture of 145 5-hydroxymethyl-3-(4-hydroxy-2-methylphenyl)benzo[b]thiophene (from Example 6A) (108 mg; 0.4 mmol), 352 <strong>[263400-88-0]3-(methylsulfonyl)propyl 4-methylbenzenesulfonate</strong> (292 mg; 1.0 mmol) and 149 K2CO3 (82 mg; 0.6 mmol) in 150 DMF (1.0 mL) was stirred at 90 C. for 6 h. After cooling to rt, the reaction was partitioned between EtOAc and aq NH4Cl and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 5-60% EtOAc in heptanes to afford 354 5-hydroxymethyl-3-(2-methyl-4-(3-(methylsulfonyl)propoxy)phenyl)benzo[b]thiophene (87 mg, 56%). LC/MS: mass calcd. for C20H20O4S2: 390.52, found 413.1 [M+Na |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 2h; | (A) To a mixture of 4-bromo-3-methylphenol (1 g, 5.35 mmol) and K2CO3 (1.1 g, 7.96 mmol) in DMF (10 mL) was added <strong>[263400-88-0]3-(methylsulfonyl)propyl 4-methylbenzenesulfonate</strong> (1.72 g, 5.88 mmol) and the resultant mixture was stirred at 80 C for 2 h. After cooling to rt, satd. aq. NH4Cl (10 mL) was added and the resultant solution was extracted with EtOAc (3 x 20 mL). The combined organic extracts were concentrated under reduced pressure and the residue thus obtained was purified by silica gel chromatography (0-30% ethyl acetate/petroleum ether) to afford 1-bromo-4-(3-methanesulfonylpropoxy)-2- methylbenzene (1.5 g, 91 %) as a white solid. 1H NMR (CDCl3) 7.40 (d, J = 8.7 Hz, 1H), 6.78 (d, J = 2.7 Hz, 1H), 6.59 (dd, J = 3.0, 8.7 Hz, 1H), 4.06 - 4.16 (m, 2H), 3.24(t, J =7.8 Hz, 2H), 2.95 (s, 3H), 2.29 - 2.38(m, 5H). |
91% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 2h; | (A) To a mixture of 4-bromo-3-methylphenol (1 g, 5.35 mmol) and K2CO3 (1.1 g, 7.96 mmol) in DMF (10 mL) was added <strong>[263400-88-0]3-(methylsulfonyl)propyl 4-methylbenzenesulfonate</strong> (1.72 g, 5.88 mmol) and the resultant mixture was stirred at 80 C. for 2 h. After cooling to rt, satd. aq. NH4Cl (10 mL) was added and the resultant solution was extracted with EtOAc (3*20 mL). The combined organic extracts were concentrated under reduced pressure and the residue thus obtained was purified by silica gel chromatography (0-30% ethyl acetate/petroleum ether) to afford 1-bromo-4-(3-methanesulfonylpropoxy)-2-methylbenzene (1.5 g, 91%) as a white solid. 1H NMR (CDCl3) delta 7.40 (d, J=8.7 Hz, 1H), 6.78 (d, J=2.7 Hz, 1H), 6.59 (dd, J=3.0, 8.7 Hz, 1H), 4.06-4.16 (m, 2H), 3.24 (t, J=7.8 Hz, 2H), 2.95 (s, 3H), 2.29-2.38 (m, 5H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | Weighing 4c (500 mg, 2.1mmol), dissolved in 20 ml methylene chloride, ice water bath cooling to 0 C, inputs 1M BBr3 dichloromethane solution (6.3 ml, 6 . 3mmol), natural to room temperature, stirring for about 6 hours, until the raw material 4c the reaction is complete. In the reaction system by adding 50 ml water dilution, each 100 ml ethyl acetate extraction a total of 3 times, combined with the phase, saturated salt water washing, anhydrous sulfuric acid nano drying, filtration, concentration to obtain the crude product purification is not required directly used for the next step reaction. The resulting crude product is dissolved in a step 10ml N,N-dimethyl formamide, adding YZ-1 (844 mg, 4.2mmol), potassium carbonate (870 mg, 6.3mmol), the reaction system 90 C stirring in oil bath 24 hours, until the raw material the reaction is complete. In the reaction system by adding 150 ml ethyl acetate dilution, water sequentially, saturated salt water washing, anhydrous sulfuric acid nano dry, filtered, concentrated to obtain crude products, rapid column chromatography purification (40% ethyl acetate/petroleum ether), to obtain the product 4d (396 mg), two-step total yield 52%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Weigh 3-methylthio-propanol (5·3g, 50mmol), triethylamine (13.9mL, 100mmol), DMAP (1.2g, 10mmol), was dissolved in 150mL dichloromethane burning added portionwise to toluenesulfonyl chloride (14.3g, 75mmol), stirred at room temperature for 3 hours until oxidation with potassium permanganate solution color, all of the alcohol the reaction was complete. 150mL was added in the reaction system was diluted with dichloromethane, washed with 1N aqueous hydrochloric acid, water, saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product (11. 27g) direct investment in the next reaction. Previous resulting product (11. 27g, 38. 5mmol) was dissolved in 100mL of dichloromethane, cooled to ice-water bath 0 C, with stirring. In addition to 77% mCPBA (17. 3g, 77.1 mmol) was dissolved in 100mL of dichloromethane, dropwise using a dropping funnel to the reaction system, naturally to room temperature after the addition was complete, stirring was continued for 2 hours, until the starting material the reaction was complete. Suction filtration funnel to remove solids and the resulting dichloromethane solution was burned, washed with 1N aqueous hydrochloric acid, water, saturated brineWashed with water, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product was purified by flash column chromatography (50% ethyl acetate / petroleum ether) to afford the product YZ-1 (12. 0g), two step yield 82%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.27 g | With potassium carbonate; In N,N-dimethyl-formamide; at 95℃; for 2h;Inert atmosphere; | A mixture of crude 3-(methylsulfonyl)propyl-p-toluenesulfonate 24b (1.87 g, 6.42 mmol), 4-bromo-3-methylbenzoic acid (1.0 g, 5.34 mmol) and potassium carbonate (1.47g, 10.68 mmol) was dissolved in 20 mL of N, N-dimethylformamide, heated to 95 C and stirred for 2 hours. The aqueous phase was extracted with ethyl acetate (30 mL of X2) and the organic phases were combined, washed sequentially with water (30 mL of X3), saturated sodium chloride solution (30 mL), and the mixture was extracted with ethyl acetate (50 mL) and stirred for 30 min. Dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent system B to give the title product bromo-2-methyl-4-(3-(methylsulfonyl)propoxy)benzene 24c (1.27 g, yellow solid), yield: 77.4%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
540 mg | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 2h;Inert atmosphere; | A mixture of crude 3-(methylsulfonyl)propyl-p-toluenesulfonate 24b (676 mg, 2.31 mmol), 4-bromo-3-chlorobenzoic acid (400 mg, 1.93 mmol) and potassium carbonate 532 mg, 3.86 mmol) was dissolved in 10 mL of N, N-dimethylformamide and heated to the reaction was stirred at 90 C for 2 hours. 50 mL of water and 50 mL of ethyl acetate were added, the mixture was extracted, and the aqueous phase was extracted with ethyl acetate (30 mL(30 mL X 3), saturated sodium chloride solution (30 mL X 3), dried over anhydrous sodium sulphate, dried over anhydrous sodium sulfate,Filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent system B to give the title product, 1-bromo-2-chloro-4-(3-(methylsulfonyl)propoxy)benzene 25a (540 mg, white solid), yield: 85.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
107 mg | With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; | Step 2: Preparation of 6-[3,4-difluoro-5-(3-methylsulfonylpropoxy)phenyl]-5-methyl- 2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine A mixture of 2,3-difluoro-5-(5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3- d]pyrimidin-6-yl)phenol (400 mg, 1.13 mmol), 3-methylsulfonylpropyl 4- methylbenzenesulfonate (494 mg, 1.69 mmol) and K2CO3 (311 mg, 2.254 mmol) in DMF (10 mL) was heated at 110 oC overnight. After being cooled to rt, the reaction mixture was diluted with H2O (10 mL) and extracted with DCM (30 mL) for three times. The combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by prep- HPLC to give 6-[3,4-difluoro-5-(3-methylsulfonylpropoxy)phenyl]-5-methyl-2-pyrimidin-2-yl- 7,8-dihydro-5H-pyrido[4,3-d]pyrimidine (107 mg) as yellow solid. 1H NMR (400 MHz, Methanol-d4) : 9.05 (d, 2H), 8.84-8.90 (m, 1H), 7.62-7.71 (m, 1H), 6.53-6.66 (m, 2H), 5.16- 5.30 (m, 1H), 4.22-4.32 (m, 2H), 3.81-3.93 (m, 1H), 3.49-3.62 (m, 1H), 3.34-3.39 (m, 2H), 3.11- 3.28 (m, 2H), 3.05 (s, 3H), 2.28-2.39 (m, 2H), 1.48 (d, 3H); MS obsd. (ESI+) [(M+H)+]: 476. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 4h; | A mixture of methyl 6-ethyl-10-hydroxy-11-methoxy-2-oxo-7,8-dihydro-6H-pyrido[2,1-a] [2]benzazepine-3-carboxylate (100 mg, 0.29 mmol), <strong>[263400-88-0]3-methylsulfonylpropyl 4-methylbenzenesulfonate</strong> (102 mg, 0.35 mmol) and K2CO3 (60 mg, 0.44 mmol) in DMF (3 mL) was heated at 60 C with stirring for 4 hrs. After being cooled to rt, the mixture was diluted with H20 (10 mL), and extracted with EtOAc (20 mL) for three times. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude methyl 6-ethyl- 11-methoxy-10-(3-methylsulfonylpropoxy)-2-oxo-7,8-dihydro-6H-pyrido[2,1-a][2]benzazepine-3-carboxylate (240 mg) as a yellow oil, which was used directly in the next step without purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7.8 mg | To a solution of crude 9-hydroxy-6-isobutyl- 1 0-methoxy-2-oxo-7H-pyrido [2,1 -a]phthalazine-3-carboxylic acid (60 mg) in DMF (3 rnL) was added potassium carbonate (74.2 mg, 537 imol) and 3-(methylsulfonyl)propyl 4-methylbeiizenesulfonate (118 mg, 402 imol).The mixture was heated at 100 C with stirring for 3 hrs, and then cooled to rt. To the above mixture was added water (3 mL) and sodium hydroxide (10.7 mg, 268 jimol). The resulting mixture was stirred at rt for 2 hrs, and then acidified with 6 M hydrochloric acid, The mixture was partitioned between brine and DCM. The organic layer was separated and concentratedunder reduced pressure. The residue was purified by prep-HPLC to give 6-isobutyl-lO-methoxy-9-(3 -methylsulfonylpropoxy)-2-oxo-7H-pyrido [2,1 -a]phthalazine-3 -carboxylic acid (7.8 mg), ?HNMR (400MHz, DMSO-d6) oe ppm 8.40 (s, 1H), 7.64 (s, 1H), 7.55 (s, 1H), 7.09 (s, 1H), 4,44 -4.38 (m, 2H), 4.22 - 4.15(m, 2H), 3.91 (s, 3H), 3.27 - 3.22 (m, 2H), 3.04 (s, 3H), 2.54 (d, 2H),2.23 - 2.16 (m, 2H), 1.66 - 1.56 (m, 1H), 0.91 (d, 6H); MS obsd. (ESIj [(M+H)t]: 465. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13 mg | With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 4h;Inert atmosphere; | To a mixture of ds-ethyl ll-hydroxy-10-methoxy-3,3-dimethyl-7-oxo- 1,2,3, 3a,7, 12b- hexahydrocyclopenta[c]pyrido[2,l-a]isoquinoline-6-carboxylate (115 mg, 0.3 mmol) and K2C03 (83 mg, 0.6 mmol) in DMF (2 mL) was added <strong>[263400-88-0]3-methylsulfonylpropyl 4-methylbenzenesulfonate</strong> (175 mg, 0.6 mmol). The mixture was heated at 120 C with stirring for 4 hrs, and then cooled to rt. To the above mixture was added LiOH aqueous solution (2.4 M, 0.5 mL, 1.2 mmol). The resulting mixture was stirred at rt for 16 hrs, then acidified with acetic acid and extracted with CH2C12 for three times. The combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by prep- HPLC to afford c 5,-10-methoxy-3,3-dimethyl-ll-(3-(methylsulfonyl)propoxy)-7-oxo- 1,2,3, 3a,7,12b-hexahydrocyclopenta[c]pyrido[2,l-a]isoquinoline-6-carboxylic acid (13 mg) as a yellow solid. 1H NMR (400MHz, DMSO-J6) delta ppm 8.54 (s, 1H), 7.59 (s, 1H), 7.53 (s, 1H), 7.02 (s, 1H), 4.63 (d, 1H), 4.30 - 4.14 (m, 2H), 3.90 (s, 3H), 3.81 - 3.73 (m, 1H), 3.31 - 3.25 (m, 2H), 3.04 (s, 3H), 2.35 - 2.12 (m, 4H), 1.64 - 1.53 (m, 1H), 1.35 (td, 1H), 1.16 (s, 3H), 0.39 (s, 3H). MS obsd. (ESI+) [(M+H)+]: 476. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; In N,N-dimethyl-formamide; at 90℃; for 2.5h; | Methyl-3- (5 - ((4'-hydroxy-2 ', 6'-dimethylbiphenyl-3-yl) methoxy) thiophen-2-yl) hex-4-ynoate (81 mg , 0.19 mmol),3- (methylsulfonyl) propyl 4-methylbenzenesulfonate (73 mg, 0.25 mmol)And anhydrous tripotassium phosphate (61 mg, 0.29 mmol) were dissolved in 2 mL of N, N-methylformamide,Heated to 90 C for 2.5 h,Cooled to room temperature,Adding ethyl acetate and saturated sodium chloride solution,The organic phase was washed twice with saturated sodium chloride solution,Anhydrous sodium sulfate drying, spin dry,(5 '- (2', 6'-dimethyl-4 '- (3- (methylsulfonyl) propoxy) biphenyl-3-yl) methoxy ) Thiophen-2-yl) hexahydro-4-ynoate.The crude product was dissolved in 1.2 mL of methanol / tetrahydrofuran = 1: 2,Add 0.8 mL of water,Lithium hydroxide monohydrate (24 mg, 0.57 mmol) was added,Room temperature reaction overnight,Dilute hydrochloric acid to adjust the pH to acidic,Ethyl acetate was extracted three times,Combined organic phase,Dried over anhydrous sodium sulfate,Spin dry, get the race to get the racemate S17,The total yield of the two-step reaction was 51%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 12h;Inert atmosphere; | 4-Methylbenzene-1-sulfonyl chloride (759 mg, 3.98 mmol), 3-(methylsulfonyl)propan- 1-ol (500 mg, 3.62 mmol) and triethyl amine (0.555 ml_, 3,98 mmol) were dissolved in Dichloromethane Dry (5 mL) under nitrogen atmosphere, and the mixture was stirred for 12 hours. The solvent was removed under reduced pressure and the residue was purified by semi-preparative HPLC-UV, to afford 3-(methylsulfonyl)propyl 4- methylbenzenesulfonate (881 mg, Y = 83%) as a white solid. MS (ESi+) m/z: 293.1 [M+H]+. (0255) Tert-butyl (4-hydroxy-2,6-dimethylphenyl)carbamate (which was synthesized as reported in the synthesis of compound 34) (269 mg, 1.13 mmol), 3- (methysulfonyl)propyl 4-methybenzenesulfonate (398 mg, 1.36 mmol) and potassium carbonate (188 mg, 1.36 mmol) were dissolved in N,N-Dimethylformamide Dry (2.5 ml) and the mixture was stirred at 80C under nitrogen atmosphere for 12 hours. AcOEt (20 mL) was added, and the mixture was washed with brine (2 x 0 mL). The organic layer was concentrated under reduced pressure and the residue was purified by semi-preparative HPLC-UV, to afford tert-butyl (2,6-dimethyl-4-(3- (methylsulfonyl)propoxy)pheny[)carbamate (375 mg, Y = 93%) as a white solid. MS (ESI+) m/z: 380.2 [ +Naf . (0256) Starting from tert-butyl (2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)carbamate (375 mg, 1.05 mmol), 2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)aniline, hydrochloride salt (309 mg, Y = quant.) was obtained as reported in the synthesis of compound 34. MS (ESI+) m/z: 258.1 [M+H]+. (0257) Starting from 2,6-dimethyl-4-(3-(methysulfonyl)propoxy)aniline, hydrochloride salt (46.1 mg, 0.157 mmoi) methyl 7-(3-(N-(2,6-dimethyl-4-(3- (methylsulfonyl)propoxy)phenyl)sulfamoyl) (0258) phenyl)heptanoate was obtained (33 mg, Y = 39%) as described in Procedure A. MS (ESI+) m/z: 562.3 [M+Na]+. (0259) Compound 35 was then obtained by hydrolysis of the ester derivative (20 mg, 0.046 mmol) as described for compound 1 , as a white solid (23 mg, Y = 83%). 1H NMR (300 MHz, CHLOROFORM-d) delta ppm 1.24 - 1.43 (m, 4 H) 1.51 - 1 .67 (m, 4 H) 1 .96 (s, 6 H) 2.26 - 2.41 (m, 4 H) 2.61 (t, J=7.58 Hz, 2 H) 2.97 (s, 3 H) 3.22 - 3.31 (m, 2 H) 4.04 (t, .7=5.68 Hz, 2 H) 6.32 (br s, 1 H) 6.52 (s, 2 H) 7.33 - 7.41 (m, 2 H) 7.48 - 7.58 (m, 2 H) 9.36 (br s, 2 H). MS (ESI+) m/z: 526.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; | Resorcinol (440 mg, 4 mmol), <strong>[263400-88-0]3-(methylsulfonyl)propyl-4-methylbenzenesulfonate</strong> (585 mg, 2 mmol)Anhydrous potassium carbonate (359 mg, 2.6 mmol) was added to 10 mL of DMF solution, and the mixture was stirred overnight at room temperature. Then, the reaction solution was poured into 50 mL of water, extracted with ethyl acetate (15 mL×3), and the organic phases were combined.It was washed with saturated brine (10 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. After silica gel column chromatography, a white solid (410 mg) was obtained with a yield of 89%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; | m-hydroxyaniline (1.09 g, 10 mmol), 3-(methylsulfonyl)propyl-4-methylbenzenesulfonyl ester (2.92 g, 10 mmol) and anhydrous potassium carbonate (2.76 g, 20 mmol)Add 50 mL of DMF solution respectively and stir overnight at room temperature.Then, the reaction solution was poured into 100 mL of ice water and a solid precipitated. After drying, the white solid (1.51 g) was obtained. The yield was 66%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With potassium phosphate; In N,N-dimethyl-formamide; at 20℃; | m-hydroxybenzoic acid (138 mg, 1 mmol),3-(Methanesulfonyl)propyl-4-methylbenzenesulfonyl ester (229 mg, 1 mmol) and anhydrous potassium carbonate (276 mg, 2 mmol) were added to 10 mL of DMF solution and stirred at room temperature overnight.Then, the reaction liquid was poured into 50 mL of water, and the pH was adjusted to 3-4 with dilute hydrochloric acid (1.0 M), and solid was precipitated, filtered, washed with water and dried to give a solid (210 mg), yield 81%. |
Tags: 263400-88-0 synthesis path| 263400-88-0 SDS| 263400-88-0 COA| 263400-88-0 purity| 263400-88-0 application| 263400-88-0 NMR| 263400-88-0 COA| 263400-88-0 structure
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