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CAS No. : | 7143-01-3 | MDL No. : | MFCD00007556 |
Formula : | C2H6O5S2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | IZDROVVXIHRYMH-UHFFFAOYSA-N |
M.W : | 174.20 | Pubchem ID : | 81560 |
Synonyms : |
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 30.74 |
TPSA : | 94.27 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.92 cm/s |
Log Po/w (iLOGP) : | 0.51 |
Log Po/w (XLOGP3) : | -0.78 |
Log Po/w (WLOGP) : | 1.08 |
Log Po/w (MLOGP) : | -1.31 |
Log Po/w (SILICOS-IT) : | -0.77 |
Consensus Log Po/w : | -0.25 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.3 |
Solubility : | 88.0 mg/ml ; 0.505 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.72 |
Solubility : | 33.1 mg/ml ; 0.19 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.24 |
Solubility : | 99.8 mg/ml ; 0.573 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 3.09 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P280-P305+P351+P338-P310 | UN#: | 3261 |
Hazard Statements: | H314 | Packing Group: | Ⅱ |
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 |
---|---|---|
90% | With dmap; triethylamine In tetrahydrofuran at 20℃; for 16 h; | Example 138Reagents and conditions: (a) NaH, DMF, 100 C, 16 h. (b) TFA, DCM, rt 1 h. (c) C8H7O2NCI2, HBTU, DIEA, THF, 50 C 16 h.[0567] Synthesis of tert-butyl 3-((methylsulfonyl)oxy)piperidine-l-carboxylate: To the solution of tert-butyl 3-hydroxypiperidine-l-carboxylate (2.01 g, 10 mmol, 1.0 eq) in THF (30 mL) was added DMAP (122 mg, 1.0 mmol, 0.1 eq), TEA (2.8 mL, 20 mmol, 2.0 eq) and methanesulfonic anhydride (1.91 g, 11 mmol, 1.1 eq). The mixture was stirred at rt for 16 h, filtered off and concentrated in vacuo to afford a residue which purified by column chromatography (silica gel, PE/EtOAc= 3: 1) to give the title product (2.5 g, yield: 90percent) as a colorless oil. 1H NMR (400 MHz, CDC13) δ: 4.72 (s, 1H), 3.74-3.61 (m, 3H), 3.45-3.42 (m, 1 H), 3.34-3.32 (m, 1H), 2.05-1.08 (m, 4H), 1.45-1.40 (m, 11H). ESI-MS (M+H+-56): 224.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | Stage #1: With tetramethylammonium bromide In N,N-dimethyl-formamide; acetonitrile at 0 - 20℃; Stage #2: With sodium hydroxide In water; N,N-dimethyl-formamide; acetonitrile |
Preparation of 1-methyl-4-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (Formula 17); A solution of 70percent mCPBA (11.54 g, 66.87 mmole) in ethyl acetate (25 mL) was added by drops to a solution of 7-azaindole (Formula 11, 5 g, 42.3 mmole) in ethyl acetate (40 mL) at 0° C. with a good stirrer. After addition was completed, the mixture was stirred at room temperature for 1 to 2 hours until no starting material left. The mixture was cooled, filtered, and washed with ethyl acetate to give a solid. It was dissolved in 50 mL of water and treated with 30percent K2CO3 solution (16 mL) to pH 9.5-10.5 to give a precipitate. It was stirred at room temperature for 1 hour, cooled, filtered, and washed with a small amount of cold water to give 2.484 g of 1H-pyrrolo[2,3-b]pyridine 7-oxide as a white crystal (Formula 12, 43.8percent yield). MS (m/z): 135.1 (MH+).A solution of methanesulfonic anhydride (6.066 g, 34.82 mmole) and acetonitrile (11.7 mL) was added by drops to a solution of 1H-pyrrolo[2,3-b]pyridine 7-oxide (Formula 12, 2.333 g, 17.41 mmole), tetramethyl ammonium bromide (4.023 g, 26.12 mmole) in DMF (11.7 mL) at 0° C. After stirring at 0° C. for 45 min, additional DMF (11.7 mL) was added in drops to the thick mixture at 0° C., and then stirred at room temperature overnight. To the mixture was added ice water (35 mL), followed by 10 N NaOH (4.66 mL) to pH 7. After stirring at the room temperature, a precipitate formed. It was filtered and washed with water to give 1.891 g of 4-bromo-1H-pyrrolo[2,3-b]pyridine as a pale peach solid (Formula 13, 55percent yield). MS (m/z): 197 (MH+). NMR (DMSO-d6) showed 69percent impurity which is likely to be the 4,6-dibromo compound based on LC/MS analysis.A mixture of 4-bromo-1H-pyrrolo[2,3-b]pyridine (Formula 13, 197 mg, 1 mmole), dimethylamine hydrochloride (88 mg, 1.079 mmole), and paraformaldehyde (33 mg, 1.1 mmole) in n-butanol (2 mL) was heated at 120° C. for 1.25 hours. After removal of the solvent, the residue was treated with ice water and three drops of con. HCl. After washing with ether, the aqueous layer was basified with sat. K2CO3 solution and extracted with methylene chloride. The organic layer was dried over sodium sulfate, filtered, and the solvent dried to give 106 mg of 1-(4-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylmethanamine as a light pink solid (Formula 14, 42percent). MS (m/z): 254.2 (MH+).A solution of 1-(4-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylmethanamine (Formula 14, 341 mg, 1.34 mmole) and hexamethylenetetramine (190 mg, 1.34 mmole) in 66percent propionic acid was added by drops to a refluxing solution of hexamethylenetetramine (190 mg, 1.34 mmole) in 66percent propionic acid (0.8 mL) at 120° C. The reaction mixture was heated for 2-4 hours, and monitored by MS. It was cooled, treated with water (4 mL), and filtered to give 238 mg of 4-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde as a beige solid (Formula 15, 79percent). MS (m/z): 225.0 (MH+).Sodium hydride (60percent, 27.4 mg, 0.686 mmole) was added in portions to a suspension of 4-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (Formula 15, 128.6 mg, 0.572 mmole) in 5 mL of DMF and 1 mL of THF at 0° C. After stirring at 0° C. for 20 min, methyl iodide (39.2 μL, 0.6292 mmole) was added by drops into the mixture and warmed up to room temperature for 2.5 hours. The solvents were evaporated and the residue was treated with methylene chloride, filtered, and dried. This was further treated with hexane. The mixture was filtered again and washed with hexane to give a beige solid, which was recrystallized from chloroform and hexane to yield 102 mg of 4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde as crystals (Formula 16, 74percent). MS (ESI): m/z 239 (M+H).A mixture of 4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (Formula 16, 38 mg, 0.159 mmole), phenyl boronic acid (38.8 mg, 0.318 mmole), and tetrakis(triphenylphosphine)palladium (0) (27.6 mg, 0.0238 mmole) in saturated sodium carbonate (0.37 mL) and 1,2-dimethoxylethane (1.4 mL) was heated at 120° C. in microwave for 20 min. It was filtered through a pad of silica gel and washed with 5percent MeOH in ethyl acetate. After the solvent was evaporated, acetonitrile was added to the residue, and filtered to remove a bright yellow solid. The filtrate was concentrated to yield 51.4 mg of 1-methyl-4-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde as white crystals (Formula 17, Ar=phenyl, 76percent). MS (ESI): m/z 237(M+H). |
47% | With tetrabutylammomium bromide In N,N-dimethyl-formamide at 0 - 20℃; for 4.5 h; | 1H- Pyrrolo[2,3-b]pyridine oxide (50 g, 373 mmol) and tetramethylammonium bromide (86 g, 559 mmol) were stirred into DMF (500 ml_) at room temperature and then cooled to 0 0C. Methanesulphonic anhydride was then run into the stirred mixture over about half an hour. Stirring was continued for a further 4 h during which time the reaction warmed to rt. This mixture was then poured onto water (1 L) with stirring and carefully neutralised (pH = 7) by the addition of sodium hydroxide solution. A further amount of water was added (1.5 L) followed by ice so that the temperature of the stirred suspension was reduced to about 10 0C. The solid was then removed by filtration and washed with ice/water. The solid was dried in the air and then stirred in cold DCM (80 mL) for half an hour before being collected by filtration, washed with a further small amount of DCM and then dried. This gave the product, 4-bromo-7f/-pyrrolo[2,3-b]pyridine as a tan solid (34.55 g, 175.3 mmol, 47percent), mp 173-176 0C, RF 0.45 (EtOAc). HPLC indicated 94-95percent purity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With pyridine In N2; water; acetonitrile | tert-Butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate A solution of 2-(3-(tert-butoxycarbonyl)phenyl)-3-methylpyridine-1-oxide (1 eq) and pyridine (4 eq) in acetonitrile (8 vol) was heated to 70° C. A solution of methanesulfonic anhydride (1.5 eq) in MeCN (2 vol) was added over 50 min via addition funnel while maintaining the temperature at less than 75° C. The mixture was stirred for an additional 0.5 hours after complete addition. The mixture was then allowed to cool to ambient. Ethanolamine (10 eq) was added via addition funnel. After stirring for 2 hours, water (6 vol) was added and the mixture was cooled to 10° C. After stirring for 3 hours, the solid was collected by filtration and washed with water (3 vol), 2:1 acetonitrile/water (3 vol), and acetonitrile (2*1.5 vol). The solid was dried to constant weight (<1percent difference) in a vacuum oven at 50° C. with a slight N2 bleed to afford tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate as a red-yellow solid (53percent yield). |
53% | With pyridine In water; acetonitrile | Preparation of tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate A solution of 2-(3-(tert-butoxycarbonyl)phenyl)-3-methylpyridine-1-oxide (1 eq) and pyridine (4 eq) in acetonitrile (8 vol) was heated to 70° C. A solution of methanesulfonic anhydride (1.5 eq) in MeCN (2 vol) was added over 50 min via addition funnel while maintaining the temperature at less than 75° C. The mixture was stirred for an additional 0.5 hours after complete addition. The mixture was then allowed to cool to ambient. Ethanolamine (10 eq) was added via addition funnel. After stirring for 2 hours, water (6 vol) was added and the mixture was cooled to 10° C. After stirring for 3 hours, the solid was collected by filtration and washed with water (3 vol), 2:1 acetonitrile/water (3 vol), and acetonitrile (2*1.5 vol). The solid was dried to constant weight (<1percent difference) in a vacuum oven at 50° C. with a slight N2 bleed to afford tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate as a red-yellow solid (53percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | at 105℃; for 3.5h;Inert atmosphere; | To a flame dried round bottom flask 0.5 g (3.6 mmol) of l-(2-hydroxyethyl)-lW- pyrrole-2,5-dione and 0.7 g (4.0 mmol) of methanesulfonic anhydride was added. The flask was evacuated and refilled with nitrogen. The flask was heated to 105C and stirred for 3.5 hr. The reaction was cooled to room temperature and dissolved in ethyl acetate (5 mL). The solution was taken up into a separatory funnel and washed four times with a saturated solution of sodium carbonate (40 mL). The aqueous layers were collected and washed with ethyl acetate (50 mL). The organic layers were combined and dried with MgS04 and concentrated in vacuo. The product was recrystallized from t-butyl methyl ether to yield 43 % (0.347 g, 1.58 mmol) of 2-(2,5-dioxo-2,5-dihydro-lH-pyrrol- l-yl)ethyl methanesulfonate.XH NMR (400 MHz, CD3CI) 6.78 (s, 2H), 4.41 (t, J = 5.23, 2H), 3.90 (t, J = 5.23, 2H), 3.04 (s, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate In dichloromethane Yield given. Yields of byproduct given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2,3-dihydro-2,2-dimethylbenzo[b]pyran-4-one With borane; (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole In toluene at 20℃; for 3h; Stage #2: Methanesulfonic anhydride With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -60 - -20℃; for 2h; Title compound not separated from byproducts; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine In tetrahydrofuran at 0℃; for 2h; | |
79% | With triethylamine In tetrahydrofuran at 0℃; for 2h; Inert atmosphere; | int9 Synthesis of Intermediate 9. To a solution of intermediate 8 (50 g, 0.26 mol) in THF (1000 ml) was added Et3N (79 g, 0.79 mol) and Ms2O (55 g, 0.32 mol) at 0° C. under N2. The mixture was stirred at 0° C. for 2 hrs. TLC (petroleum ether/EtOAc=3/1) showed the reaction was completed. Then it was poured into ice-water and extracted with EtOAc (400 ml×2). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuum to give intermediate 9 (50 g, 79%) as yellow oil. (0346) 1H NMR (CDCl3, 400 MHz): δ (ppm) 10.08 (bs, 1H), 7.24-7.29 (m, 2H), 6.81-6.84 (m, 1H), 6.49-6.50 (d, 1H, J=2.4 Hz), 4.67 (s, 2H), 4.28-4.31 (m, 2H), 3.48-3.52 (m, 2H), 2.79 (s, 3H), 1.51 (s, 9H). |
79% | With triethylamine In tetrahydrofuran at 0℃; for 2h; Inert atmosphere; | Synthesis of intermediate 26. j0341j To a solution of intermediate 25 (50 g, 0.26 mol) in THF (1000 mL) was added Et3N (79 g, 0.79 mol) and Ms20 (55 g, 0.32 mol) at 0°C under N2. The mixture was stirred at 0 °C for 2 hrs. TLC (petroleum ether/EtOAc=3/1) showed the reaction was completed. Then it was poured into ice-water and extracted with EtOAc (400 mL x2). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuum to give intermediate 26 (50 g, 79%) as yellow oil.j0342j ‘H NMR (CDC13, 400 MHz): ö (ppm) 10.08 (bs, 1H), 7.24-7.29 (m, 2H), 6.8 1-6.84 (m, 1H), 6.49-6.50 (d, 1H, J=2.4Hz), 4.67 (s, 2H), 4.28-4.31 (m, 2H), 3.48-3.52 (m, 2H),2.79 (s, 3H), 1.51 (s, 9H). |
79% | With triethylamine In tetrahydrofuran at 0℃; for 2h; Inert atmosphere; | 1 Synthesis of intermediate 20 To a solution of intermediate 19 (50 g, 0.26 mol) in THF (1000 mL) was added EtrN (79 g, 0.79 mol) and Ms2.Q (55 g, 0.32 mol) at 0 °C under N2. The mixture was stirred at 0 °C for 2 hrs. The reaction was poured into ice-water and extracted with EtOAc (400 mL x2). The combined organic phases were washed with brine, dried over Na2S04 and concentrated in vacuum to give intermediate 20 (50 g, 79%) as yellow oil. NMR (CDCb, 400 MHz): 6 (ppm) 10 08 (bs. 11 1), 7.24-7.29 (m, 2H), 6.81-6.84 (m, i l l). 6 49-6 50 (d, H i, J=2.4Hz), 4.67 (s, 2H), 4.28-4.31 (m, 2H), 3.48-3.52 (m, 2H), 2.79 (s, 3H), 1.51 (s, 9H). |
79% | With triethylamine In tetrahydrofuran at 0℃; for 2h; Inert atmosphere; | Synthesis of Intermediate 26 To a solution of intermediate 25 (50 g, 0.26 mol) in THF (1000 mL) was added Et3N (79 g, 0.79 mol) and Ms2O (55 g, 0.32 mol) at 0°C. under N2. The mixture was stirred at 0°C. for 2 hrs. TLC (petroleum ether/EtOAc=3/1) showed the reaction was completed. Then it was poured into ice-water and extracted with EtOAc (400 mL2). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuum to give intermediate 26 (50 g, 79%) as yellow oil. [0444] 1H NMR (CDCl3, 400 MHz): δ (ppm) 10.08 (bs, 1H), 7.24-7.29 (m, 2H), 6.81-6.84 (m, 1H), 6.49-6.50 (d, 1H, J=2.4 Hz), 4.67 (s, 2H), 4.28-4.31 (m, 2H), 3.48-3.52 (m, 2H), 2.79 (s, 3H), 1.51 (s, 9H). |
79% | With triethylamine In tetrahydrofuran at 0℃; for 2h; Inert atmosphere; | 1 Synthesis of intermediate 20 To a solution of intermediate 19 (50 g, 0.26 mol) in THF (1000 mL) was added Et3N (79 g, 0.79 mol) and Ms2O (55 g, 0.32 mol) at 0° C. under N2. The mixture was stirred at 0° C. for 2 hrs. The reaction was poured into ice-water and extracted with EtOAc (400 mL×2). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuum to give intermediate 20 (50 g, 79%) as yellow oil. 1H NMR (CDCl3, 400 MHz): δ (ppm) 10.08 (bs, 1H), 7.24-7.29 (m, 2H), 6.81-6.84 (m, 1H), 6.49-6.50 (d, 1H, J=2.4 Hz), 4.67 (s, 2H), 4.28-4.31 (m, 2H), 3.48-3.52 (m, 2H), 2.79 (s, 3H), 1.51 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 18h; | The product from Example 8A (150 mg 0.9 mmol), methane sulfonic anhydride (159 mg, 0.9 mmol), and DIEA (475 muL 2.7 mmol) were combined. After stirring, 2-(1-piperazinyl)benzonitrile (181 mg, 1.0 mmol) in 2 ml DCM was also combined and stirred at room temperature for 18 hours. The mixture was concentrated and the residue was taken up in hot methanol. The methanol was filtered and the filter cake washed with cold methanol to provide the title compound. 1H NMR (300 MHz, CDCl3) iota 2.69 (m, 4H) 3.04 (s, 4H) 3.76 (m, 4H) 3.86 (s, 1H) 6.74 (m, 2H) 7.29 (m, 3H) 7.75 (m, 1H); (ESI) m/z 334 (M+H)+. | |
With N-ethyl-N,N-diisopropylamine; In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; | EXAMPLE 8B 2-[4-(1-benzothien-2-ylmethyl)-1-piperazinyl]benzonitrile The product from Example 8A (150 mg 0.9 mmol), methane sulfonic anhydride (159 mg, 0.9 mmol), DIEA (475 muL 2.7 mmol) and 2-(1-piperazinyl)benzonitrile (181 mg, 1.0 mmol) were combined in 2 ml DCM and stirred at room temperature for 18 hours. The mixture was concentrated and the residue was taken up in hot methanol. The methanol was filtered and the filter cake washed with cold methanol to provide the title compound. 1H NMR (300 MHz, CDCl3) delta2.69 (m, 4H) 3.04 (s, 4H) 3.76 (m, 4H) 3.86 (s, 1H) 6.74 (m, 2H) 7.29 (m, 3H) 7.75 (m, 1H); (ESI) m/z 334 (M+H)+. | |
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 18h; | The product from Example 8A (150 mg 0.9 mmol), methane sulfonic anhydride (159mg, 0.9 mmol), and DIEA (475 [GEL] 2.7 mmol) were combined. After stirring, [2- (1-] piperazinyl) benzonitrile [(181] mg, 1.0 mmol) in 2 ml DCM was also combined and stirred at room temperature for 18 hours. The mixture was concentrated and the residue was taken up in hot methanol. The methanol was filtered and the filter cake washed with cold methanol to provide the title [COMPOUND. TH] NMR (300 MHz, [CDC13)] [8] 2.69 [(M,] 4H) 3.04 (s, 4H) 3.76 [(M,] 4H) 3.86 (s, 1H) 6.74 [(M,] 2H) 7.29 [(M,] 3H) 7.75 [(M,] 1H) ; (ESI) [M/Z] 334 (M+H) +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With triethylamine; In dichloromethane; at 0 - 20℃; for 3h; | To a cooled (0 C.) solution of [2-(4-benzyloxy-phenyl)-1-S-hydroxymethyl-ethyl]-carbamic acid tert-butyl ester (102.3 g, 286.2 mmol), triethylamine (126 mL, 90.4 mmol) in methylene chloride (2000 mL) is added methanesulfonic anhydride (55.4 g, 31.8 mmol) in three portions over one hour. After the addition is complete, the resulting solution is stirred at 0 C. for thirty minutes and then allowed to warm to room temperature over ninety minutes. The solution is again cooled to 0 C. and quenched with ice-cold 1N aqueous hydrochloric acid (1996 mL) and then stirred vigorously at 0 C. for fifteen minutes. The aqueous layer is removed and extracted with methylene chloride (500 mL). The combined organics are washed with brine (500 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to provide a thick slurry which is diluted with hexanes (300 mL). The resulting solid that forms is collected by filtration, washed with hexanes (50 mL) and dried to constant weight in vacuo to afford 119.6 g (96% yield) of the desired compound which is used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With pyridine; In dichloromethane; at 0℃; for 1.5h; | To a solution of the product from Part B (3.10 g, 14.4 mmol) in CH2C12 (50 mL) were added pyridine (1.34 mL, 16. 58 mmol) and methane sulfonic anhydride (2.81 g, 16.13 mmol) sequentially at 0C. The reaction mixture was stirred for 1.5 h at 0C, then quenched with H2O, and extracted with EtOAc (3 x 50 mL). The organic phase was washed with H20, brine, and dried (Na2S04). The solvent was evaporated to afford (1S, 2S)-METHANESULFONIC acid 2-TERT-BUTOXYCARBONYLAMINO- cyclohexyl ester (4.0 g, 95%) as a white solid. MS M/Z 294.2 ([M+H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a stirred solution of ethyl-2-amino-4-(trifluoromethyl)-5-thiazole carboxylate(1.2 g) and triethylamine (2.1 mL) in THF (12 mL) was added methane sulfonic anhydride (1.74 g) in small portions at room temperature. After 2 h, the reaction mixture wasconcentrated in vacuo and the residue was stirred in dioxane (5 mL) and aqueous 1NNaOH (5 mL) for 16 h. The reaction mixture was concentrated in vacuo and to the residuein water (20 mL) and THF (30 mL) was added lithium hydroxide monohydrate (1.8 g)5 before being heated at 50 C for 12 h. To the cooled reaction mixture was added 1Naqueous hydrochloric acid (30 mL) and extracted into EtOAc (2 x 25 mL), dried oversodium sulfate, filtered, and concentrated in vacuo.1H NMR 5(DMSO-d6) 3.26 (3H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With trifluorormethanesulfonic acid at 80℃; for 16h; | 13 5-(2-Isopropyl-5-methanesulfonyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine To a mixture of 5-(2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (0.32g, 1.17 mmol), prepared according to Example 2, and methanesulfonic anhydride (0.81 g, 4.67 mmol) was added trifluoromethanesulfonic acid (0.45 g, 3.00 mmol), and the mixture was heated at 80° C. for 16 hrs. The reaction mixture was poured into ice water, basified with saturated NaHCO3 solution and extracted into dichloromethane, which was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via flash chromatography on silica gel (3%CH3OH in CH2Cl2 with 0.1%NH4OH) gave 5-(2-isopropyl-5-methanesulfonyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine as a white solid (0.248 g, 90%; 0.107 g), MS (M+H): 353. |
90% | With trifluorormethanesulfonic acid at 80℃; for 16h; | 13 5-(2-Isopropyl-5-methanesulfonyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine To a mixture of 5-(2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (0.32 g, 1.17 mmol), prepared according to Example 2, and methanesulfonic anhydride (0.81 g, 4.67 mmol) was added trifluoromethanesulfonic acid (0.45 g, 3.00 mmol), and the mixture was heated at 80° C. for 16 hrs. The reaction mixture was poured into ice water, basified with saturated NaHCO3 solution and extracted into dichloromethane, which was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via flash chromatography on silica gel (3% CH3OH in CH2Cl2 with 0.1% NH4OH) gave 5-(2-isopropyl-5-methanesulfonyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine as a white solid (0.248 g, 90%; 0.107 g), MS (M+H): 353. |
90% | With trifluorormethanesulfonic acid In dichloromethane at 80℃; for 16h; | 2 5-(2-Isopropyl-5-methanesulfonyl-4-methoxy-phe-noxy)-pyrimidine-2,4-diamine To a mixture of 5-(2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (0.32 g, 1.17 mmol), prepared according to Example 2, and methanesulfonic anhydride (0.81 g, 4.67 mmol) was added trifluoromethanesulfonic acid (0.45 g, 3.00 mmol), and the mixture was heated at 80° C. for 16 hrs. The reaction mixture was poured into ice water, basified with saturated NaHCO3 solution and extracted into dichloromethane, which was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via flash chromatography on silica gel (3% CH3OH in CH2Cl2 with 0.1% NH4OH) gave 5-(2-isopropyl-5-methanesulfonyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine as a white solid (0.248 g, 90%; 0.107 g), MS (M+H): 353. |
90% | With trifluorormethanesulfonic acid at 80℃; for 16h; | 2 5-(2-Isopropyl-5-methanesulfonyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine 11841 To a mixture of 5-(2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (0.32g, 1. l7mmol), prepared according to Example 1, and methanesulfonic anhydride (0.81g, 4.67mmol) was added trifluoromethanesulfonic acid (0.45g, 3.00 mmol), and the mixture was heated at 80°C for 16 hrs. The reaction mixture was poured into ice water, basified with saturated NaHCO3 solution and extracted into dichloromethane, which was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via flash chromatography on silica gel (3%CH3OH in CH2C12 with 0. 1%NH4OH) gave 5-(2- isopropyl-5-methanesulfonyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine as a white solid (0.248 g, 90%; 0.107 g), MS (M+H): 353. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine In chloroform at -0.16℃; | A8.2 2. Alkylating agent: A mixture of 21.4 g of 2.2-dithiodiethanol in 100 ml chloroform and 24-.1 g pyridine are cooled with stirring to 273K and then 41.0 g of mesyl anhydride are added in small amounts under constant temperature. After completion of the addition the mixture is left over night in the refrigerator to finish the reaction. The reaction mixture is mixed with a water/hydrochloric acid/ice slurry, the phases are separated, washed with water and dried. The obtained solution of methanesulfonate diester is used in the following step |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Example 6: 4-[2-(2-Methoxy-5-thien-2-yl-phenyl)-acryloyl]-benzoic acid[0247] Ex-6A: A solution of <strong>[22080-96-2]4-hydroxy-2,6-dimethoxy-benzaldehyde</strong> (2.3 g, 12.62 mmol) in dichloromethane (25 mL) was cooled to 0 C and then dimethylamino pyridine (5.6 g , 45.84 mmol) was added in 1 portion. Triflic anhydride (2.5 mL, 14.86 mmol) was then added over 15 min while maintaining an internal temperature below 5 0C. The resulting solution was aged for 1 h and then was slowly poured into cold 1 N HCl. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure affording 3.76 g (73%) of methanesulfonic acid 4-formyl-3,5-dimethoxy-phenyl ester. |
Yield | Reaction Conditions | Operation in experiment |
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With pyridine; sodium hydrogencarbonate; In dichloromethane; | Step 1 Synthesis of 4-methanesulfonylaminoacetophenone (36-1) 4-aminoacetophenone (300 mg) was dissolved in dichloromethane, and to the solution were added methanesulfonic anhydride (2.44 mimol) and pyridine (53.85 mul) at 0 C., followed by stirring at room temperature for 3 hours. After confirng the completion of the reaction using TLC, the reaction was quenched with saturated sodium bicarbonate solution. The reaction mixture was diluted with dichloromethane, washed with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a solid. The solid was recrystallized with ethyl acetate and hexane, to yield a pale yellow crystal (293.2 mg, 61.95%). mp: 155.1-161.2 C.; 1H NMR(400 MHz, CDCl3): delta 7.98(d, 2H, J=8.8 Hz), 7.27(d, 2H, J=8.8 Hz), 3.11(d, 3H, J=1.6 Hz),2.59(d, 3H, J=1.6 Hz) IR(KBr pellet, cm-1): 3290.93, 3003.59, 2928.38, 1667.16, 1600.63, 1469.49, 1330.64, 1279.54, 1146.47 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With dmap; triethylamine In tetrahydrofuran at 20℃; for 16h; | 138 Example 138Reagents and conditions: (a) NaH, DMF, 100 C, 16 h. (b) TFA, DCM, rt 1 h. (c) C8H7O2NCI2, HBTU, DIEA, THF, 50 C 16 h.[0567] Synthesis of tert-butyl 3-((methylsulfonyl)oxy)piperidine-l-carboxylate: To the solution of tert-butyl 3-hydroxypiperidine-l-carboxylate (2.01 g, 10 mmol, 1.0 eq) in THF (30 mL) was added DMAP (122 mg, 1.0 mmol, 0.1 eq), TEA (2.8 mL, 20 mmol, 2.0 eq) and methanesulfonic anhydride (1.91 g, 11 mmol, 1.1 eq). The mixture was stirred at rt for 16 h, filtered off and concentrated in vacuo to afford a residue which purified by column chromatography (silica gel, PE/EtOAc= 3: 1) to give the title product (2.5 g, yield: 90%) as a colorless oil. 1H NMR (400 MHz, CDC13) δ: 4.72 (s, 1H), 3.74-3.61 (m, 3H), 3.45-3.42 (m, 1 H), 3.34-3.32 (m, 1H), 2.05-1.08 (m, 4H), 1.45-1.40 (m, 11H). ESI-MS (M+H+-56): 224.0. |
63% | With triethylamine In dichloromethane at 20 - 30℃; | 58.1 Step 1: Synthesis of tert-butyl 3-(methanesulfonyloxy)piperidine-1-carboxylate A solution of tert-butyl 3-hydroxypiperidine-1-carboxylate (950 mg, 4.72 mmol, 1.00 equiv), TEA (955 mg, 9.44 mmol, 2.00 equiv), methanesulfonyl methanesulfonate (1.64 g, 9.41 mmol, 2.00 equiv) in DCM (10 mL) was stirred overnight at room temperature. The resulting solution was diluted with 50 mL of DCM. The resulting mixture was washed with 3*30 mL of sodium bicarbonate/H2O. The resulting mixture was concentrated under vacuum. This resulted in 826 mg (63%) of the title compound as a solid. LCMS (ESI, m/z): 280.10 [M+H]+. |
With triethylamine In dichloromethane | B Step B Step B 3-Methanesulfonyloxy-N-t-butoxycarbonylpiperidine Methanesulfonic anhydride (996 mg, 5.72 mmol) was added to a mixture of 3-hydroxy-N-t-butoxycarbonylpiperidine (959 mg, 4.76 mmol) and triethylamine (0.86 ml, 6.19 mmol) in methylene chloride (30 ml) at 0° C. After stirring for 1 h, the reaction mixture was washed with saturated NaHCO3 and dried (Na2 SO4). Concentration gave the title compound. 1 H NMR (CDCl3) d 1.46 (s, 9 H), 1.77-2.17 (m, 4 H), 3.05 (s, 3 H), 3.14-3.49 (m, 2 H), 3.62 (m, 2 H), 4.72 (br s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
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In methanol; dichloromethane; | b 3-[1-(3-Methanesulfonyloxymethylbenzyl)-indol-3-yl]-4-(1-methyl-indol-3-yl)-pyrrole-2,5-dione Methanesulfonic anhydride (0.35 g, 2.0 mmol) was added to a stirred solution of the product of step a) (0.234 g, 0.51 mmol) and <strong>[38222-83-2]2,6-di-tert-butyl-4-methylpyridine</strong> (0.42 g, 2.0 mmol) in dry CH2 Cl2 (15 mL) at room temperature. The reaction mixture was stirred for 16 h, and thereafter quenched by adding methanol (1.5 mL). The solvent was evaporated and the crude product chromatographed (ethyl acetate/heptane: 2/1) to yield 0.285 g of the sub-title product. 1 H-NMR (CDCl3):delta7.76 (1H, s); 7.66 (1H, s); 7.58 (1H, s); 7.38-7.24 (3H, m); 7.22-7.00 (6H, m); 6.82 (1H, d, J=8.05 Hz); 6.77 (1H, t, J=8.30 Hz); 6.68 (1H, t, J=8.05 Hz); 5.34 (2H, s); 5.18 (2H, s); 3.86 (3H, s); 2.83 (3H, s). |
Yield | Reaction Conditions | Operation in experiment |
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72% | With sodium hydrogencarbonate; triethylamine; In tetrahydrofuran; | Step E 3-[[Bis(2-methoxyethyl)amino]methyl]-2-(4-methoxyphenyl)-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide To a solution of the product of Step D (1.19 g, 3.68 mmol) and triethylamine (1.24 g, 12.3 mmol) in anhydrous THF (50 mL) was added methanesulfonic anhydride (1.07 g, 6.13 mmol). After 30 min, bis(2-methoxyethyl)amine (3 mL) was added and stirring continued for 18 h at ambient temperature. The reaction mixture was heated at reflux temperature for 1 h, cooled, poured into a saturated solution of sodium bicarbonate (100 mL) and this mixture was extracted with ethyl acetate (2*100 mL). The combined extracts were dried (MgSO4) and evaporated to a residue which was purified by column chromatography (silica, 40% ethyl acetate/hexane) to give a viscous oil (1.16 g, 72%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With triethylamine;palladium diacetate; In acetonitrile; | Example 11 To 0.186 g (1.0 mmol) of 2-(phenylsulfonyl)ethanol, 3 ml of acetonitrile was added, followed by 0.19 g (1.1 mmol) of methanesulfonic anhydride and 0.56 ml (4.0 mmol) of triethylamine, and the mixture was stirred for 5 hours at the internal temperature of 50 C. Subsequently, 0.37 g (1.5 mmol) of p-iodophenetole, 0.011g (0.05 mmol) of palladium acetate, and 0.067 g (0.22 mmol) of tri(o-tolyl)phosphine were added thereto, and the mixture was then refluxed for 17 hours. After cooled to room temperature, the reaction mixture was concentrated and purified by column chromatography (hexane/ethyl acetate=80/20) to obtain 0.158 g of [2-(phenylsulfonyl)ethenyl]-4-ethoxybenzene. Yield: 55%. |
Yield | Reaction Conditions | Operation in experiment |
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With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 2h; | Example 165-(methanesulfonyl) methyl-4-(4-fluorophenyl)-6-isopropyl-2- fmethvKmethylsulfonvDaminoipyrimidine (Compound of Formula II, where X = OSO7CH3)3,5 g 5-hydroxymethyl-4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine (Compound of Formula I) and 2,2 ml of N-ethyl- diisopropylamine in 20 ml dichloromethane are stirred on ice bath, and while stirring thereto 2,0 g of methansulfonyl anhydride are added. Reaction mixture is stirred for another 2 h at room temperature whereupon the reaction mixture is washed by 20 ml 1 % phosphoric acid and 20 ml of water, and after evaporation of organic phase under reduced pressure at 50 0C, 4.3 mg of product are obtained, which is crystallized from mixture of isopropyl acetate and hexane. |
Yield | Reaction Conditions | Operation in experiment |
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50% | In dichloromethane; at 0 - 20℃; for 6h; | Preparation I; N-(5-methoxy-2-pyridinyl)methanesulfonamide; A solution of 10.7 g (86 mmol) of 5-methoxy-2-pyridinamine in 55 ml of dichioromethane is cooled to 0 C. and 72 ml (144 mmol) of a 2 M solution of methanesulfonic anhydride in dichloromethane are added gradually. The reaction mixture is stirred for 6 hours at room temperature and sodium bicarbonate solution is then added in a sufficient amount to bring the pH to about 9. The mixture obtained is concentrated under reduced pressure, the residue is taken up in 160 ml of ethanol at 50 C., the mixture obtained is dried and filtered and the filtrate is concentrated under reduced pressure. The residue is triturated in 50 ml of cold ethanol and the solid obtained is filtered off, rinsed with a little ethanol on the filter and then dried to give 8.7 g of the expected product in the form of a white powder (yield=50%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: ethyl 2-hydroxy-4-phenylbutanoate; Methanesulfonic anhydride With triethylamine In dichloromethane at 0 - 20℃; for 0.25h; Stage #2: In dichloromethane at 20℃; for 4h; | 9.9a To a solution of ethyl-2-hydroxy-4-phenylbutyrate (2.08 g, 10 mmol) in CH2Cl2 (20 mL) was added triethylamine (2.1 mL, 15 mmol) and Ms2O (1.92 g, 11 mmol) at 0° C. The resulting reaction mixture was stirred at room temperature for 15 min. DMAP (50 mg) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 4 hours. The reaction was quenched with saturated NaHCO3. The resulting mixture was extracted with CH2Cl2 (3×50 mL). The combined organic phases were dried (Na2SO4), filtered and CH2Cl2 was removed under reduced pressure. The residue was purified by flash chromatography (CH2Cl2), giving 2.7 g (94%) of the title compound. 13C NMR (CDCl3): 6169.3, 140.0, 128.9, 128.8, 126.7, 62.3, 52.8, 39.5, 33.9, 31.2, 14.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; | EXAMPLE 10 1-(1-benzothien-2-ylmethyl)-4-(2-pyridinyl)piperazine The product from Example 8A (300 mg 1.8 mmol), methane sulfonic anhydride (313 mg, 1.8 mmol), DIEA (200 muL 5.4 mmol) and 1-(2-pyridinyl)piperazine (328 mg, 2.9 mmol) in 4 ml DCM were processed as described in Example 8B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) delta2.57 (m, 4H) 3.50 (m, 4H) 3.84 (s, 2H) 6.63 (m, 2H) 6.81 (d, J=8.48 Hz, 1H) 7.32 (m, 2H) 7.52 (m, 2H) 7.77 (m, 1H) 7.90 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine; In dichloromethane; at 20℃; for 16h; | Procedure S: Intermediate 24 (1-24) - 3-Nitrophenethyl methanesulfonate.; [00134] To a solution of 1.6 g (10 mmol, 1.0 eq.) of 2-(3-nitrophenyl) (1-23) in 20 mL of methylene chloride was added 2.8 mL (20 mmol, 2.0 eq.) of triethylamine. A solution of 1.7 g (10 mmol, 1.0 eq.) of methanesulfonic anhydride in 10 mL of methylene chloride was added and the mixture was stirred at room temperature for 16 h. The reaction mixture was washed with sat. brine and the organic layer was dried (Na2SC^). The solvent was removed in vacuo and the resulting residue was purified by flash chromatography to provide 2.2 g (9.0 mmol, 90%) of 3-nitrophenethyl methanesulfonate (1-24). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
179 mg | In tetrahydrofuran; water for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Sodium hydroxide (1.67 g) and 3-chloro-4-hydroxybenizoic acid (3.0 g) in water (30 ml) was stirred until dissolution was complete. Methanesulfonic anhydride (3.33 g) in dichloromethane (15 ml) was added with cooling (ice bath) and the mixture stirred for 48 h. The organic phase was separated and the aqueous phase acidified with colic. HCl. The precipitated colourless solid was separated by filtration, washed with water and recrystallised from methanol to give the title compound (1.85 g) as a colourless solid. m/z (API+): 249, 251 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 0℃; for 0.166667h; | Scheme i-3; Preparation of 13-thiaziol-2-ylmethyl methanesulfonate (i-3a); Methanesulfonic anhydride (282 mg, 1.62 mmol) and triethylamine (300 muL, 2.15 mmol) were added to a solution of l,3-thiazol-2-ylmethanol (108 mg, 0.935 mmol) in DCM (1 mL) at 0 0C. After 10 min, the reaction mixture was partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. The layers were separated, and the aqueous layer washed with EtOAc. The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to afford the title compound i-3a. mlz (ES) 194 (MH)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; Cooling; | Intermediate 15: 2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenyl]ethyl methanesulfonate Intermediate 15: 2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenyl]ethyl methanesulfonate To a solution of 2-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)phenyl]ethanol (1.21 g, 4.46 mmol, 1 equiv.) and 4-dimethylaminopyridine (54 mg, 0.44 mmol, 0.1 equiv.) in CH2Cl2 (15 mL) was added N,N-diisopropylethylamine (0.93 mL, 5.36 mmol, 1.2 equiv.). Methanesulfonic anhydride (934 mg, 5.36 mmol, 1.2 equiv.) was added while the solution stirred in a cold water bath. The reaction mixture was stirred at rt for 15 min. The reaction mixture was washed with satd. aq. NH4Cl (2*20 mL), followed by satd. aq. Na2CO3 (3*20 mL). The organic layer was dried, filtered, and concentrated to produce a yellow/orange solid (91%). MS (ESI): mass calcd. for C15H14N2O4S2, 350.41; m/z found, 351.0 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.58 (dd, J=4.8, 1.6, 1H), 8.05 (dd, J=7.9, 1.7, 1H), 7.44-7.31 (m, 4H), 7.23 (dd, J=7.9, 4.8, 1H), 4.46 (t, J=6.8, 2H), 3.12 (t, J=6.8, 2H), 2.94 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 5℃;Inert atmosphere; | Methanesulfonic anhydride (0.490 g, 4.28 mmol, 1.21 equiv) was added portion wise to a cold (5C) mixture of (5-hydroxymethyl-pyridin-2-yl) carbamic acid tert-butyl ester (Step 8.3) (0.8 g, 3.5 mmol) and DIPEA (1.3 mL, 10.7 mmol, 3 equiv) in DCM (10 mL), under an argon atmosphere. The reaction mixture was allowed to stir for 1 h at 5C, diluted with EtOAc and water and extracted with EtOAc. The organic phase was washed with water and brine, dried (Na2S04), filtered and concentrated and used as such for the next step without further purification. | |
With triethylamine; In dichloromethane; at 5℃; for 1.0h;Inert atmosphere; | Methanesulfonic anhydride (0.854 g, 4.9 mmol, 1.1 equiv) was added portionwise to a cold (5C) mixture of (5-hydroxymethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (Step 26.4) (1 g, 4.5 mmol) and triethylamine (0.75 ml_, 5.4 mmol, 1.2 equiv) in DCM (20 ml_), under an argon atmosphere. The reaction mixture was allowed to stir for 1 h at 5C, diluted with EtOAc and H2O, and extracted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated to provide 1.25 g of the title compound as a white solid: tR= 2.60 min (System 1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 5℃; for 0.5h;Inert atmosphere; | Methanesulfonic anhydride (1.79 g, 10.3 mmol, 1.1 equiv) was added portionwise to a cold (5C) mixture of <strong>[36625-57-7](5-nitro-pyridin-2-yl)-methanol</strong> (Step 1 12.4) (1.44 g, 9.4 mmol) and triethylamine (1.57 mL, 1 1.3 mmol, 1.2 equiv) in DCM (20 mL), under an argon atmosphere. The reaction mixture was allowed to stir for 0.5 h at 5C, quenched with H2O and extracted with DCM. The organic phase was washed with H2O, dried (Na2SO4), filtered and <n="137"/>concentrated to provide 2.16 g of the title compound as a brown solid: : ESI-MS: 231.1 [M- H]"; tR= 2.85 min (System 1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; | Intermediate 2 is obtained from 1 according to the procedure in Example 1. To a mixture of 2 and diisopropylethyiamine in CH2CI2 at 0 0C is added Ms2O. The reaction mixture is stirred until the reaction is complete, as determined by thin layer chromatography (TLC). The reaction mixture is diluted with ethyl acetate and washed with cold sat. NaHCOs and brine. The organic layer is dried over Na2SO4, filtered and concentrated to provide mesylate 8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With N-ethyl-N,N-diisopropylamine In dichloromethane; water at 0 - 20℃; | E.iv A suspension of intermediate E.iii (4.93 g, 18.7 mmol) in anhydrous DCM (110 mL) was treated with DIPEA (12.0 mL, 3.75 eq.) and the mixture was cooled to 00C. Ms2O (4.88 g, 1.5 eq.) was added portionwise. The resulting mixture was stirred at 00C for 15 min. Water was added and stirring was continued for 15 min at rt. The precipitated product was filtered, washed with water and DCM. The resulting solid was triturated with DCM/MeOH/NH4OH (1000/25/2) to give the title compound as a colourless solid (3.785 g, 60% yield).1H NMR (DMSO-d6) δ: 10.72 (s, IH), 7.29 (dd, J = 2.1, 0.6 Hz, IH), 6.94 (m, 2H), 4.95 (m, IH), 4.52 (s, 2H), 4.49 (m, 2H), 4.11 (t, J = 9.1 Hz, IH), 3.73 (m, 2H), 3.23 (s, 3H). MS (ESI, m/z): 343.3 [M+H+]. |
60% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; | 1.iv A suspension of intermediate l.iii (4.93 g, 18.7 mmol) in anhydrous DCM (HO mL) was treated with DIPEA (12.0 mL, 3.75 eq.) and the mixture was cooled to 00C. Ms2O (4.88 g,1.5 eq.) was added portionwise. The resulting mixture was stirred at 00C for 15 min. Water was added and stirring was continued for 15 min at rt. The precipitated product was filtered, washed with water and DCM. The thus obtained solid was triturated withDCM/MeOH/NH4OH (1000/25/2) to give the title compound as a colourless solid (3.785 g, 60% yield).IH NMR (DMSO-d6) δ: 10.72 (s, IH); 7.29 (dd, J = 2.1, 0.6 Hz, IH); 6.94 (m, 2H);4.95 (m, IH); 4.52 (s, 2H); 4.49 (m, 2H); 4.11 (t, J = 9.1 Hz, IH); 3.73 (m, 2H); 3.23 (s,3H).MS (ESI, m/z): 343.3 [M+H]+. |
60% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 0.25h; | 1.iv A suspension of intermediate 1.iii (4.93 g, 18.7 mmol) in anhydrous DCM (110 mL) was treated with DIPEA (12.0 mL, 3.75 eq.) and the mixture was cooled to 0° C. Ms2O (4.88 g, 1.5 eq.) was added portionwise. The resulting mixture was stirred at 0° C. for 15 min. Water was added and stirring was continued for 15 min at rt. The precipitated product was filtered, washed with water and DCM. The thus obtained solid was triturated with DCM/MeOH/NH4OH (1000/25/2) to give the title compound as a colourless solid (3.785 g, 60% yield).1H NMR (DMSO-d6) δ: 10.72 (s, 1H); 7.29 (dd, J=2.1, 0.6 Hz, 1H); 6.94 (m, 2H); 4.95 (m, 1H); 4.52 (s, 2H); 4.49 (m, 2H); 4.11 (t, J=9.1 Hz, 1H); 3.73 (m, 2H); 3.23 (s, 3H).MS (ESI, m/z): 343.3 [M+H]+. |
60% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; | Q.iv A suspension of intermediate Q.iii (4.93 g, 18.7 mmol) in anhydrous DCM (110 mL) was treated with DIPEA (12.0 mL, 3.75 eq.) and the mixture was cooled to 00C. Ms2O (4.88 g, 1.5 eq.) was added portionwise. The resulting mixture was stirred at 00C for 15 min. Water was added and stirring was continued for 15 min at rt. The precipitated product was filtered, washed with water and DCM. The thus obtained solid was triturated with DCM/MeOH/NH4OH (1000:25:2) to give the title intermediate as a colourless solid (3.785 g, 60% yield).1H NMR (DMSO-d6) δ: 10.72 (s, IH), 7.29 (dd, J = 2.1, 0.6 Hz, IH), 6.94 (m, 2H), 4.95 (m, IH), 4.52 (s, 2H), 4.49 (m, 2H), 4.11 (t, J = 9.1 Hz, IH), 3.73 (m, 2H), 3.23 (s, 3H).MS (ESI, m/z): 343.3 [M+H+]. |
53% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; | 2.iv 2.iv. Methanesulfonic acid (S)-2-oxo-3-(3-oxo-3 ,4-dihydro-2H-benzo [ 1 ,4] oxazin-6-yl)- oxazolidin-5-ylmethyl ester:; A suspension of intermediate 2.iii (5.45 g, 20.6 mmol) in anhydrous DCM (110 mL) was treated with DIPEA (3.5 eq.) and the mixture was cooled to 00C. Ms2O (1.5 eq.) was added dropwise. The resulting mixture was stirred at 00C for 15 min. Water was added and stirring was continued for 15 min at rt. The precipitated product was filtered, washed with water and DCM, and triturated with DCM/MeOH/NH4OH (1000/25/2) to give the title intermediate as a colourless solid (3.75 g, 53% yield).1H NMR (DMSO-d6) δ: 10.72 (s, IH), 7.29 (dd, J = 2.1, 0.6 Hz, IH), 6.94 (m, 2H), 4.95 (m, IH), 4.52 (s, 2H), 4.49 (m, 2H), 4.11 (t, J = 9.1 Hz, IH), 3.73 (m, 2H), 3.23 (s, 3H).MS (ESI, m/z): 343.3 PVBH+]. |
Yield | Reaction Conditions | Operation in experiment |
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With pyridine; In tetrahydrofuran; at 0 - 5℃; | Compound (VII) (112g, 0.313 mol) was suspended in tetrahydrofuran (10 vol). Methanesulfonic anhydride (65.7g, 0.374 moles) was added in one lot and stirred. The reaction mixture was cooled to 0-50C and pyridine (2.5 vol) was added slowly over a period of 45 minutes. The reaction was monitored by TLC [Mobile phase dichloromethane: methanol, 9.5:0.5] for completion. As reaction product the intermediate compound (Vila) was obtained.To the above reaction mixture 70% aqueous ethylamine solution (400 ml, 10 vol) was added slowly at 0-5C. After the complete addition, the reaction mixture was stirred at 25-300C for 12.0 h. The reaction is monitored by TLC [Mobile phase dichloromethane: methanol, 9.5:0.5] for completion. The organic layer (ethylamine and tetrahydrofuran mixture) was distilled off completely below 500C under reduced pressure. The aqueous phase was acidified with concentrated hydrochloric acid and the pH adjusted to 3.0 at 15-25C. The aqueous phase was extracted with t-butyl methyl ether twice (2 x 2.0 vol) to remove any organic impurities if present. The t-butyl methyl ether layer was extracted with 1 N HCI solution and the layers separated.The aqueous layers were combined, treated with activated charcoal and heated at 65-700C. The contents were stirred at 65-700C for 30 minutes, filtered through hyflo supercel at 65-700C and washed with preheated water(65-700C). The filtrate was cooled to 25-30C and the pH was adjusted to 8 with solid sodium bicarbonate. The reaction mixture was stirred for 12 h for crystallization. If the crystallization did not occur, the reaction mass was filtered through a Bchner funnel, extracted with ethyl acetate (3 x 5.0 vol), dried over sodium sulphate and filtered. The organic layer was distilled completely (below 500C) under reduced pressure. The crude product was obtained as a pale yellow syrup, which was washed with hexane (4 x 1.0 vol) to yield a residue which crystallized to a solid on standing.Yield of crude compound (VIIl): 8Og (66.3%) |
Yield | Reaction Conditions | Operation in experiment |
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95% | With triethylamine; In dichloromethane; at 4 - 20℃;Inert atmosphere; | Example 19; 1.0 mL of Et3N and 0.667 g of II were added to a suspension of I (1.00 g) in 15 mL DCM under N2. The suspension was cooled on an ice bath to 4 C. and 0.53 mL of Et3N was added slowly and the reaction allowed to reach r.t., water added, the mixture extracted with DCM and washed with water. The organic layer was dried with Na2SO4, concentrated in vacuo to yield the product III (0.950 g, 95%) |
95% | With triethylamine; In dichloromethane; at 4℃;Inert atmosphere; | Example 8 4-(4-Methanesulfonyl-piperazin-1-yl)-1H-indole 1.0 mL of Et3N and di-methanesulfonyl ether (0.667 g) were added to a suspension of 4-piperazin-1-yl-1H-indole (1.00 g) in 15 mL DCM under N2. The suspension was cooled on an ice bath to 4 C. and 0.53 mL of Et3N was added slowly and the reaction was allowed to reach r.t. Water was added, and the mixture was extracted with DCM and washed with water. The organic layer was dried with Na2SO4 and concentrated in vacuo to yield 4-(4-methanesulfonyl-piperazin-1-yl)-1H-indole (0.950 g, 95%) |
Yield | Reaction Conditions | Operation in experiment |
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-(Hydroxymethyl)-2-pyridinecarbonitrile (0.5g; 3RChem) was suspended in DCM (10 ml.) and triethylamine (0.831 ml.) was added at 250C. The mixture was cooled in an ice bath and methanesulfonic anhydride (0.714 g) dissolved in DCM (3 ml.) was added dropwise. The mixture was stirred at 250C for 1 hr. Further methanesulfonic anhydride(130 mg, 0.2eq.) was added and stirred for 15 min at 250C. 2% w/v aqueous sodium bicarbonate solution (10 ml.) was added and the phases were separated. The organic layer was washed with water (10 ml_), dried over sodium sulphate and evaporated to leave the title compound (0.761 g) as a pale yellow solid, m/z [M+H]+: 213.1. Retention time 0.58 min (LC/MS method 3). |
Yield | Reaction Conditions | Operation in experiment |
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53% | With pyridine; In N2; water; acetonitrile; | tert-Butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate A solution of 2-(3-(tert-butoxycarbonyl)phenyl)-3-methylpyridine-1-oxide (1 eq) and pyridine (4 eq) in acetonitrile (8 vol) was heated to 70 C. A solution of methanesulfonic anhydride (1.5 eq) in MeCN (2 vol) was added over 50 min via addition funnel while maintaining the temperature at less than 75 C. The mixture was stirred for an additional 0.5 hours after complete addition. The mixture was then allowed to cool to ambient. Ethanolamine (10 eq) was added via addition funnel. After stirring for 2 hours, water (6 vol) was added and the mixture was cooled to 10 C. After stirring for 3 hours, the solid was collected by filtration and washed with water (3 vol), 2:1 acetonitrile/water (3 vol), and acetonitrile (2*1.5 vol). The solid was dried to constant weight (<1% difference) in a vacuum oven at 50 C. with a slight N2 bleed to afford tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate as a red-yellow solid (53% yield). |
53% | With pyridine; In water; acetonitrile; | Preparation of tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate A solution of 2-(3-(tert-butoxycarbonyl)phenyl)-3-methylpyridine-1-oxide (1 eq) and pyridine (4 eq) in acetonitrile (8 vol) was heated to 70 C. A solution of methanesulfonic anhydride (1.5 eq) in MeCN (2 vol) was added over 50 min via addition funnel while maintaining the temperature at less than 75 C. The mixture was stirred for an additional 0.5 hours after complete addition. The mixture was then allowed to cool to ambient. Ethanolamine (10 eq) was added via addition funnel. After stirring for 2 hours, water (6 vol) was added and the mixture was cooled to 10 C. After stirring for 3 hours, the solid was collected by filtration and washed with water (3 vol), 2:1 acetonitrile/water (3 vol), and acetonitrile (2*1.5 vol). The solid was dried to constant weight (<1% difference) in a vacuum oven at 50 C. with a slight N2 bleed to afford tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate as a red-yellow solid (53% yield). |
Yield | Reaction Conditions | Operation in experiment |
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91% | With triethylamine; In dichloromethane; | Step 2: Ethyl 2-((methylsulfonyloxy)methyl)cyclopropanecarboxylate (C-6) To a solution of alcohol C-5 (0.50 g, 3.47 mmol) and triethylamine (1.45 mL, 10.41 mmol) in anhydrous methylene chloride (12.0 mL) at 0 C. was added methanesulfonic anhydride (0.908 g, 5.21 mmol) in one portion. The reaction mixture was then stirred at room temperature for 1 h, diluted with diethyl ether (50 mL) and quenched with an aqueous pH 7 phosphate buffer solution (30 mL). The aqueous layer was extracted with diethyl ether (2*50 mL). The combined organic extracts were then successively washed with an aqueous pH 7 phosphate buffer solution (70 mL) and brine (70 mL), dried over MgSO4, filtered, and concentrated to give ethyl 2-((methylsulfonyloxy)methyl)cyclopropanecarboxylate (C-6) as a colorless oil (0.698 g, 91% yield). This material was immediately placed under argon and dissolved with anhydrous DMF (1.57 mL) to give a 2.0 M stock solution, which was used as such for the next step. |
Yield | Reaction Conditions | Operation in experiment |
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98% | With triethylamine; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere; | B.2. 2-bromo-5-chlorobenzyl methanesulfonate:Starting from intermediate B.l (145.95 g) and proceeding in analogy to Procedure J, the title compound was obtained, without additional purification, as a white solid (193.0 g; 98% yield).1H NMR (d6-DMSO) delta: 7.72 (d, J = 8.5 Hz, 1H); 7.67 (d, J = 2.6 Hz, 1H); 7.44 (dd, J = 8.5, 2.6 Hz, 1H); 5.27 (s, 2H); 3.29 (s, 3H). Procedure J (mesylation):A solution of the alcohol (1.0 mmol; 1.0 eq.) in dry THF (4 mL), under inert atmosphere (N2), is treated with TEA (1.5 eq.) and a solution of methanesulfonic anhydride (1.5 eq.) in dry THF (1 mL) at 0C. The reaction mixture is stirred at rt and monitored by LC-MS. Upon reaction completion, the reaction mixture is concentrated under reduced pressure and diluted with EA and water. The layers are separated and the aq. layer is extracted with EA. The combined org. layers are washed with water and brine, dried over Na2S04, filtered and concentrated under reduced pressure. Purification of the residue gives the desired product. |
With triethylamine; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere; | A solution of the alcohol (1.0 mmol; 1.0 eq.) in dry THF (4 mL) in a round-bottomed flask, under inert atmosphere (N2), is treated with TEA (1.5 eq.) and a solution of methanesulfonic anhydride (1.5 eq.) in dry THF (1 mL) at 0C. The reaction mixture is stirred at rt and monitored by LC-MS. Upon reaction completion, the reaction mixture is concentrated under reduced pressure and diluted with EA and water. The layers are separated and the aq. layer is extracted with EA. The combined org. layers are washed with water and brine, dried over MgS04, filtered and concentrated under reduced pressure. Purification of the residue gives the desired product. Starting from intermediate S. l (23.48 g) and proceeding in analogy to Procedure AG, the title compound was obtained, without additional purification, as a white solid (34.53 g). 1H NMR (d6-DMSO) delta: 7.72 (d, J = 8.5 Hz, 1H); 7.67 (d, J = 2.6 Hz, 1H); 7.44 (dd, J = 8.5, 2.6 Hz, 1H); 5.27 (s, 2H); 3.29 (s, 3 H). | |
34.53 g | With triethylamine; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere; | A solution of the alcohol (1.0 mmol; 1.0 eq.) in dry THF (4 mL) in a round-bottomed flask, under inert atmosphere (N2), is treated with TEA (1.5 eq.) and a solution of methanesulfonic anhydride (1.5 eq.) in dry THF (1 mL) at 0 C. The reaction mixture is stirred at rt and monitored by LC-MS. Upon reaction completion, the reaction mixture is concentrated under reduced pressureand diluted with EA and water. The layers are separated and the aq. layer is extracted with EA. The combined org. layers are washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residue gives the desired product.S.2. 2-bromo-5-chlorobenzyl methanesulfonate Starting from intermediate S.1 (23.48 g) and proceeding in analogy to Procedure AG, the title compound was obtained, without additional purification, as a white solid (34.53 g). 1H NMR (d6-DMSO) delta: 7.72 (d, J=8.5 Hz, 1H); 7.67 (d, J=2.6 Hz, 1H); 7.44 (dd, J=8.5, 2.6 Hz, 1H); 5.27 (s, 2H); 3.29 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 2 2,6-Dichloro-4-[1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]pyridine 327 mg of t-butyl 4-(2,6-dichloropyridin-4-yl)-5,6-dihydropyridine-1(2H)-carbamate was dissolved in 4 ml of methylene chloride, and 2 ml of trifluoroacetic acid was added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into 2N sodium hydroxide aqueous solution, and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 221 mg of a brown solid. The obtained solid was dissolved in 10 ml of methylene chloride, and 270 mul of triethylamine, 251 mg of methanesulfonic anhydride and 1 mg of 4-dimethylaminopyridine were added thereto, and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added a saturated aqueous solution of sodium bicarbonate, and then the mixture was subjected to extraction with ethyl acetate, and the organic layer was washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 236 mg of the objective compound as pale brown powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; In tetrahydrofuran; at 20℃; for 20h; | 10.75 g of cyclopent-3-enyl-methanol from Example 3 Step A was dissolved in 200 mL of THF and 21 mL of N-methylmorpholine was added. 25.26 g of methanesulfonic anhydride was added in portions and the reaction mixture was stirred for 20 h at rt. EtOAc was added and the organic phase washed with saturated NaHCO3 solution and 1 M HC1. The organic phase was dried and evaporated. 18.37g of Example 3 Step B product was obtained as slightly yellow oil. [0083] 1H-NMR (200 MHz, CDC13, delta, ppm, characteristic signals): 2.12 (m, 2H), 2.55 (m, 2H), 2.70 (m, 1H), 3.01 (s, 3H), 4.12 (d, 2H, J=8Hz), 5.66 (s, 2H). MS-ESI+ (m/z): 375 (2M + Na), 199 (M + Na). TLC: toluene /EtOAc = 3:1, Rf = 0.5. | |
With 4-methyl-morpholine; In tetrahydrofuran; at 20℃; for 20h; | 10.75 g of cyclopent-3-enyl-methanol from Example 3 Step A was dissolved in 200 mL of THF and to the mixture obtained 21 mL of N-methylmorpholine was added. To the mixture obtained 25.26 g of methanesulfonic anhydride was added in portions and the mixture obtained was stirred for 20 h at rt. To the mixture obtained EtOAc was added, phases obtained were separated and the organic phase obtained was washed with saturated NaHC03 solution and 1 M HC1. The organic phase obtained was dried and solvent was evaporated. 18.37g of Example 3, Step B product was obtained in the form of a slightly yellow oil. 1 H-NMR (200 MHz, CDC13, delta, ppm, characteristic signals): 2.12 (m, 2H), 2.55 (m, 2H), 2.70 (m, 1H), 3.01 (s, 3H), 4.12 (d, 2H, J=8Hz), 5.66 (s, 2H). MS-ESI+ (m/z): 375 (2M + Na), 199 (M + Na). TLC: toluene /EtOAc = 3: 1, Rf = 0.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine In dichloromethane at 0 - 20℃; | 1 cis-4-tert-Butylcyclohexyl methanesulfonateCis-4-i-butylcyclohexanol (6.0 g, 38.5 mmol, 1.0 eq.) was dissolved indichloromethane (10 mL). Then methanesulfonic anhydride (8.03 g, 46.2 mmol, 1.1 eq.) was added to the mixture slowly at 0 °C. Then triethylamine (6.4 mL, 46.2 mmol, 1.5 eq.) was added to the mixture and the mixture stirred at room temperature for 3h. The mixture was extracted with dichloromethane and the organic layer was concentrated to give product as a white power (8.0 g, yield: 90%). The product was used to next step without further purification. 1H NMR (400 MHz, CDC13) δ 4.99-4.98 (m, 1H), 3.02 (s, 3H), 2.14- 2.12 (m, 2H), 1.65-1.28 (m, 7H), 0.84 (s, 9H). |
90% | With triethylamine In dichloromethane at 0 - 20℃; for 3h; | 37.1 Example 37: 4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)meth yl)amino)bicyclo[2.2.2]octane-l-carboxylic acid Step l:cis-4-fe/ -Butylcyclohexyl methanesulfonate Example 37: 4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)meth yl)amino)bicyclo[2.2.2]octane-l-carboxylic acid Step l:cis-4-fe/ -Butylcyclohexyl methanesulfonate Cis-4-i-butylcyclohexanol (6.0 g, 38.5 mmol, 1.0 eq.) was dissolved in dichloromethane (10 mL). Then methanesulfonic anhydride (8.03 g, 46.2 mmol, 1.1 eq.) was added to the mixture slowly at 0 °C. Then triethylamine (6.4 mL, 46.2 mmol, 1.5 eq.) was added to the mixture and the mixture stirred at room temperature for 3h. The mixture was extracted with dichloromethane and the organic layer was concentrated to give product as a white power (8.0 g, yield: 90%). The product was used to next step without further purification. 1H NMR (400 MHz, CDC13) δ 4.99-4.98 (m, 1H), 3.02 (s, 3H), 2.14-2.12 (m, 2H), 1.65-1.28 (m, 7H), 0.84 (s, 9H). Step 2: 2-Bromo-6-(trans-4-fe/t-butylcyclohexyloxy)naphthalene t-butanol/2-butanone 1 10°C, 15h 6-bromonaphthalen-2-ol (CAS no. 15231-91-1) (3.0 g, 14.8 mmol, 1.0 eq.) was dissolved in a mixture of i-butanol/2-butanone (4 mL/2 mL). Then cesium carbonate (12 g, 37.2 mmol, 2.5 eq.) was added to the mixture and the mixture was stirred at 110 °C for 10 min. Then trans-4-te/t-butylcyclohexyl methanesulfonate (3.48 g, 16.2 mmol, 1.1 eq.) was added to the mixture. The suspension was stirred at 110 °C under a nitrogen atmosphere for 15 h. The reaction mixture was extracted with ethyl acetate and the organic layer was purified by silica gel column chromatography using petroleum ether as eluent to give 2-bromo-6-(trans-4-tert-butylcyclohexyloxy)naphthalene as a slight yellow solid (1.7 g, yield: 32%). ESI-MS: 361.0 (M+H)+. 1H NMR (400 MHz, CDC13) δ 7.89 (s, 1H), 7.63 (d, 1H), 7.56 (d, 1H), 7.47 (d, 1H), 7.15-7.11 (m, 2H), 4.26-4.24 (m, 1H), 2.27-2.25 (m, 2H), 1.89-1.87 (m, 2H), 1.45-1.09 (m, 5H), 0.89 (s, 9H). -(trans-4-fert-But lcyclohexyloxy)-2-naphthaldeh de 2-bromo-6-(trans-4-tert-butylcyclohexyloxy)naphthalene (2.249 g, 6.25 mmol, 1.0 eq.) was dissolved in THF (10 mL) under nitrogen atmosphere. Then the mixture was cooled down to -78 °C and a solution of n-BuLi in THF (2.5 M, 7.5 mL, 18.8 mmol, 3.0 eq.) was added to the mixture dropwise. The mixture was stirred at -78 °C for 15 min. Then DMF (2.4 mL, 31.2 mmol, 5.0 eq.) was added to the mixture and stirred at -78 °C for 1 h. When the reaction completed, 1 M HCl was added to adjust the pH to 6. The mixture was extracted with EtOAc and the organic layer was concentrated and purified by silica gel chromatography using petroleum ether/ethyl acetate (10/1) as eluent to give 6-(trans-4-te/t-butylcyclohexyloxy)-2-naphthaldehyde as a white solid (1.16 g, 60 %). EDI-MS: 311.1 (M+H)+. 1H NMR (400 MHz, CDC13) δ 10.08 (s, IH), 8.24 (s, IH), 7.92- 7.87 (m, 2H), 7.77 (d, IH), 7.22-7.19 (m, 2H), 4.42-4.30 (m, IH), 2.30-2.28 (m, 2H), 1.93- 1.90 (m, 2H), 1.48-1.11 (m, 5H), 0.82 (s, 9H). -Bromo-2-(trans-4-fer?-butylcvclohexyloxy -l-iodonaphthalene A solution of 2-bromo-6-(trans-4-tert-butylcyclohexyloxy)naphthalene (160.0 g, 444.4 mmol) in methylene chloride (2.5 L) was purged under an atmosphere of argon. N-iodosuccinimide (202.1 g, 888.8 mmol) and zirconium tetrachloride (20.4 g, 88.9 mmol) was added and the reaction was stirred at room temperature under an atmosphere of argon. The reaction was monitored by 1H NMR and showed complete conversion to product after 30 minutes. The mixture was then concentrated under reduced pressure to give -250 g crude as a brown solid. The crude material was purified by silica gel chromatography with hexanes to give 200 g of desired product as a brown solid (yield: 92.6%). EDI-MS: 487.1 (M+H)+. Step 5: 6-Bromo-2-(trans-4-fer?-butylcvclohexyloxy)-l-(trifluoromethyl)naphthalene A solution of 6-bromo-2-(trans-4-tert-butylcyclohexyloxy)-l-iodonaphthalene (210.0 g, 433 mmol), hexamethylphosphoramide (386.4 g, 2.16 mol; 5 eq) in N,N-dimethylformamide (2.0 L) was degassed by stirring under vacuum and replacing the vacuum with argon (4 times). To this mixture was added copper(I) iodide (140.0 g, 735 mmol; 1.7 eq) and methyl fluorosulphonyldifluoroacetate (415 g, 2.16 mol; 5 eq). The reaction mixture was warmed to 80 °C under an atmosphere of argon. After stirring for 6 hrs, thin layer chromatography showed complete conversion to product. Saturated NaHC03 solution was added to adjust the final pH to 9-10 followed by adding EtOAc (3.5 L). The mixture was extracted with EtOAc (2.5 L x 3), and washed with brine (1.0 L x 4), then dried over Na2S04 (500 g). The solvent was removed under reduced pressure to give crude 195 g as a sticky off white solid with purity of >90%, which was purified by silica gel chromatography with 0-30% EtOAc in hexanes to give the final product (156 g, yield: 84.3%). EDI-MS: 430.0 (M+H)+. -(trans-4-fert-Butylcyclohexyloxy -5-(trifluoromethyl -2-naphthaldehyde To a solution of 6-bromo-2-(trans-4-ieri-butylcyclohexyloxy)-l-(trifluoromethyl)naphthalene (1 g, 2.3 mmol) in THF (30 mL) was added n-BuLi (2.8 mL, 2.5M in THF, 3.0 equiv) dropwise at -78 °C in 30 min, then DMF (840 mg, 11.5 mmol, 5.0 equiv) was added slowly at -78 °C. The reaction mixture was stirred at -78 °C for 1.5 h. Then saturated NH4C1 solution was added to the mixture to quench the reaction. The mixture was extracted with EtOAc and purified by silica gel chromatography (petroleum ethenethyl acetate 10:1) to give product 6-(trans-4-ieri-butylcyclohexyloxy)-5-(trifluoromethyl)-2-naphthaldehyde as a yellow solid (608 mg, yield: 70%). ESI-MS: 379.2 (M+H)+. 1H NMR (400 MHz, CDC13) δ: 10.13 (s, IH), 8.28 (d, 2H), 8.08 (d, IH), 7.98-8.01 (dd, IH), 7.41 (d, IH), 4.39 (m, IH), 2.21 (d, 2H), 1.90 (d, 2H), 1.49-1.58 (q, 2H), 1.10-1.17 (m, 3H), 0.86 (s, 9H) Step 7: ethyl 4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)a mino)bicyclo Γ2.2.21 octane- 1 -c arboxylate Y: 35% The preparation of ethyl 4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)a mino)bicyclo[2.2.2]octane-l-carboxylate was similar to that of methyl 4-(((6-hydroxynaphthalen-2-yl)methyl)amino) bicyclo[2.2.2]octane-l-carboxylate. yellow solid, 60 mg, Y: 35%. ESI-MS (M+H)+: 560.3.1H NMR (400 MHz, CDC13) δ: 8.12 (d, / = 8.0 Hz, 1H), 7.88 (d, / = 9.2 Hz, 1H), 7.83 (s, 1H), 7.54 (d, / = 9.2 Hz, 1H), 7.24 (d, /= 9.2 Hz, 1H), 4.28-4.20 (m, 1H), 4.07 (q, / = 6.8 Hz, 2H), 3.84 (s, 2H), 2.14-2.12 (m, 2H), 1.86-1.84 (m, 2H), 1.75-1.70 (m, 12H), 1.24-1.02 (m, 8H), 0.87 (s, 9H). Step 8: 4-(((6-((trans-4-(tert-butyl cvclohexyl oxy -5-(trifluoromethyl naphthalen-2-yl methyl a mino)bicyclo Γ2.2.21 octane- 1 -c arboxylic acid 4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)meth yl)amino)bicyclo[2.2.2]octane-l-carboxylic acid, as a white solid, 35 mg, Y: 60%. ESI-MS (M+H)+: 532.3. HPLC: 100.00%; 1H NMR (400 MHz, CD3OD) δ: 8.22 (d, /= 8.0 Hz, 1H), 8.07 (d, /= 9.2 Hz, 1H), 7.98 (s, 1H), 7.60 (d, / = 9.2 Hz, 1H), 7.55-7.52 (m, 1H), 4.50-4.42 (m, 1H), 4.27 (s, 2H), 2.22-2.19 (m, 2H), 2.05-1.98 (m, 12H), 1.92-1.89 (m, 2H), 1.53-1.46 (m, 2H), 1.23-1.11 (m, 3H), 0.90 (s, 9H). |
With triethylamine In dichloromethane at 0 - 20℃; for 3h; | 1 Example 1: cis-4-tør/-butylcyclohexyl methanesulfonateCis-4-?-butylcyclohexanol (6.0 g, 38.5 mmol, 1.0 eq.) was dissolved in dichloromethane (10 mL). Then methanesulfonic anhydride (8.03 g, 46.2 mmol, 1.1 eq.) was added to the mixture slowly at 0 0C. Then triethylamine (6.4 mL, 46.2 mmol, 1.5 eq.) was added to the mixture and the mixture stirred at room temperature for 3h. The mixture was extracted with dichloromethane and the organic layer was concentrated to give product as a white power (8.0 g, yield: 90%). The product was used to next step without further purification. 1H NMR (400 MHz, CDCl3) δ 4.99- 4.98 (m, IH), 3.02 (s, 3H), 2.14-2.12 (m, 2H), 1.65-1.28 (m, 7H), 0.84 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: (5-amino-2-butyl-benzofuran-3-yl)-[4-(3-dibutylamino-propoxy)-phenyl]-methanone; methanesulfonic acid In dichloromethane Stage #2: Methanesulfonic anhydride With N-benzyl-N,N,N-triethylammonium chloride In n-heptane at 80 - 90℃; for 5.5h; Stage #3: With sodium hydrogencarbonate In n-heptane; ethyl acetate | 4 0.9 g of (5-amino-2-butyl)-l-benzofuran-3-yl)[4-[3-(di-n-butylamino)propoxy]- phenyl] methanone is dissolved in 10 ml of dichloromethane. 0.37 g of methanesulfonic acid is added in 5 minutes and the, mixture is stirred for 5 minutes. The solvent is evaporated. To the residual salt mixed with 10 ml of heptane and 0.1 1 g of triethylbenzyl ammonium chloride is added and the mixture is heated to 80-90 °C. At this temperature 0.62 g of methansulfonic anhydride is added in 5 minutes and the mixture is stirred at this temperature for additional 5 hours. After cooling to room temperature 15 ml of ethyl acetate and 1 ml of sodium hydrocarbonate (5%) is added. The organic layer is washed with 5 ml of water and evaporated. Yield: 0.98 g (94.8 %). This product is purified through its oxalate salt according to example 1 (yield: 90.6%). Purity of the obtained title product (HPLC): 99.8 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35 g | With triethylamine; In dichloromethane; at 0 - 20℃; for 19.083h; | To a stirred mixture of <strong>[77510-50-0](R)-3-hydroxypyrrolidin-2-one</strong> (19.5 g, 193 mmol) and triethylamine (90 ml) at 0C was added a solution of methanesulfonic anhydride (33.6 g, 193 mmol) in DCM (90 ml) over 35 minutes maintaining an internal temperature below 5C. After stirring at 0C for 30 min the reaction was allowed to warm to room temperature and stirred for an additional 18 h and then concentrated in vacuo. This material was combined with 12 g crude material from previous batches and then purified via silica gel chromatography to yield 35 g of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; at 80℃; | A mixture of Example 59A (1.50 g, 7.17 mmol), pyridine (1.74 mL, 21.51 mmol) and methanesulfonic anhydride (2.50 g, 14.34 mmol) in 60 mL 1 ,2-dichloroethane was stirred overnight at 80 C. The reaction mixture was concentrated and the residue was purified by flash chromatography (0-7% methanol/CH2Cl2) to afford the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20℃; for 0.25h; | Preparation of pyrimidin-5-ylmethyl methanesulfonate: To a solution of pyrimidin-5- ylmethanol (200 mg, 1.82 mmol) and triethylamine (0.558 mL, 4.00 mmol) in dichloromethane was added methansulfonic anhydride (348 mg, 1.20 mmol) and the reaction was stirred at room temperature for 15 minutes. The product was diluted with water, extracted with dichloromethane (2X), washed with brine, dried over sodium sulfate and concentrated to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calc'd for C6H8N203S: 189.03; found: 189.00. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; for 1h;Cooling with ice; | 2.08 g of 4-Hydroxy-azepane-l-carboxylic acid tert-butyl ester, dissolved in 10 mL of DCM, was treated with external ice cooling with 2.02 g of methanesulfonic anhydride followed by 2.02 mL of TEA and stirred for one h. The phases obtained were separated, the organic phase obtained was washed with brine, dried over Na2S04 and brought to dryness. The title compound in the form of a semicrystalline oil was obtained. | |
With triethylamine; In dichloromethane; for 1h;Cooling with ice; | 2.08 g of 4-Hydroxy-azepane-1-carboxylic acid tert-butyl ester, dissolved in 10 mL of DCM, was treated with external ice cooling with 2.02 g of methanesulfonic anhydride followed by 2.02 mL of TEA and stirred for one h. The phases obtained were separated, the organic phase obtained was washed with brine, dried over Na2SO4 and brought to dryness. The title compound in the form of a semicrystalline oil was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0℃; for 0.5h; | To a solution of <strong>[19295-57-9]3-hydroxy-2,2-dimethylpropanenitrile</strong> (1.3 g, 13.11 mmol) and DIPEA(2.290mL, 13.11 mmol) at 0 C in THE (50 mL) was added hypochlorous methanesulfonicanhydride (2.358 mL, 13.11 mmol) and the mixture was then stirred at 0 C for 30 mm. The reaction mixture was diluted with aq. NaHCO3 (20 mL), extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to give the title compound 075 (2.0 g, 10.16 mmol, 77 % yield) as oil, which was used in next step without further purification.1H NMR (400MHz, CHLOROFORM-d): 4.13 (s, 2H), 3.13 (s, 3H), 1.45 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32.3 g | With dmap; triethylamine; In dichloromethane; at -10 - 0℃; for 2.0h;Inert atmosphere; | A 500 mL glass reactor fitted with an argon inlet was purged with dry argon, charged with 25 g (94 mmol) of product 2 obtained from the previous step and 210 mL of dichloromethane (DCM), followed by addition of 53 mL of triethylamine (TEA) and 1.15 g (2.0 mol) of DMAP. The reaction mixture was cooled down to -10 C. with acetone-dry ice mixture. While maintaining the reaction temperature below 0 C., a methanesttlfonic anhydride solution (prepared by dissolving methanesulfonic anhydride (32.7 g, 188 mmol) in DCM (45 mL)) was added drop wise over a period of more than 1 hour. After the completion of addition, the mixture was incubated at 0 C. for 1 hour. Then, 80 mL of ice-water was added in the reaction mixture, the aqueous layer was extracted by 45 mL of DCM. The organic layers were combined, and the combined organic layer was washed twice with diluted HCl solution (prepared by dissolving 9 mL HCl in 36 mL of water) (2×45 mL), once with water (2×35 mL), and once with brine solution (prepared by dissolving 50 g NaCl in 45 mL of water) (45 mL), then dried over sodium sulfate (12.5 g). Then, the organic layer was concentrated to remove the organic solvent with a vacuum pump, resulted in 32.3 g of product 3. |
32.3 g | With dmap; triethylamine; In dichloromethane; at -10 - 0℃; for 1.0h; | A 500 ml reactor was charged with 25 g of product 2 and 210 ml of dichloromethane (DCM), then 53 ml of triethylamine and 1.15 g of DMAP (2.0 mol) were added and the solution was cooled to -10C.32.7g of methanesulfonic anhydride dissolved in 45ml DCMSlowly added to the reactor and keeping the temperature of the reaction liquid below 0C. After the addition was completed, the reaction was continued at 0C for 1 hour.After the reaction was completed, 80 ml of ice water was added to the reaction solution.The aqueous phase was extracted with DCM. The organic phases were combined and the organic phase was washed with diluted hydrochloric acid, water and saturated brine and dried over anhydrous sodium sulfate. filter,The organic phase was concentrated to remove the organic solvent to give product 3 (32.3 g). |
32.3 g | With dmap; triethylamine; In dichloromethane; at -10 - 0℃; for 1.0h; | 25 g of intermediate product 2 and 210 ml of dichloromethane (DCM) were added to the 500 ml reactor, then 53 ml of triethylamine and 1.15 g of DMAP (2.0 mol) were added and the solution was cooled to -10 C. 32.7 g of methanesulfonic anhydride was dissolved in 45 ml of DCM, slowly added dropwise to the reactor, and the temperature of the reaction solution was kept below 0 C. After the addition was completed, continued to maintain 0 C reaction for 1 hour. After the reaction was completed, 80 ml of ice water was added to the reaction solution, and the aqueous phase was extracted with DCM. The combined organic phases were washed with dilute aqueous HCl, water and saturated brine and dried over anhydrous sodium sulfate. Filtration and concentration was carried out for the organic phase to remove organic solvent afforded product 3 (32.3 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With pyridine; In dichloromethane; at 0 - 20℃; | Step II: To a solution of <strong>[15166-68-4]3-hydroxy-pyrrolidin-2-one</strong> (200 mg, 1.97 mmol) in DCM (5 mL) was added Ms20 (539 mg, 3.1 mmol) and pyridine (2 mL) at 0 C. The reaction mixture was stirred at 0 C for 20 min and then overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in isopropanol/CHCl3 (1 :3; 40 mL),washed with saturated NaHC03, dried over anhydrous Na2S04, and evaporated to dryness under reduced pressure to give 2-oxopyrrolidin-3-yl methanesulfonate 33 in 38% yield (137 mg). |
38% | With pyridine; In dichloromethane; at 0 - 20℃; | To a solution of <strong>[15166-68-4]3-hydroxy-pyrrolidin-2-one</strong> (200 mg, 1.97 mmol) in DCM (5 mL) was added Ms20 (539 mg, 3.1 mmol) and pyridine (2 mL) at 0 C. The reaction mixture was stirred at 0 C for 20 mm and then overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in isopropanol/CHC13 (1:3; 40 mL),washed with saturated NaHCO3, dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure to afford 2-oxopyrrolidin-3-yl methanesulfonate 33 in 38% yield (137 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In tetrahydrofuran; at 20℃; for 1h; | tert-Butyl (1-hydroxy-3-phenylpropan-2-yl) carbamate, 5 (3 g,11.9 mmol) in THF (30 mL) was mixed with TEA(4.98 mL, 3.57 mmol) and Ms2O (2.5 g, 14.28 mmol), and stirred at rt for 1 h. Distilled water (20 mL) was added to the reaction mixture and then extracted with ethyl acetate (20 mL × 2). The extracted product was dissolved in dimethylformamide (DMF; 30 mL), and sodium azide (3.9 mL, 59.5 mmol) was added. This solution was stirred at 50C, extracted with ethyl acetate (50 mL × 2), poured into diethyl ether (5 mL), and recrystallized to afford the tert-butyl (1-azido-3-phenylpropan-2-yl)carbamate,6 (21 mg, 95%). Compound 6: 1H-NMR (600 MHz,DMSO-d6): delta 7.72 (d, J = 44.4 Hz, 5 H), 6.99 (s, 1H),3.76 (s, 1 H), 3.28 (s, 2 H), 2.66-2.72 (m, 2 H), 1.27(s, 9 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With triethylamine In tetrahydrofuran at 0 - 20℃; for 12h; Inert atmosphere; | 1 Preparation of Compound lb 10205] Compound la (6.04 g, 34.469 mmol) and triethylamine (TEA, 14.4 mE, 103.407 mmol) were dissolved in tetrahydroffiran at 0° C. under nitrogen atmosphere and then, slowly treated with methanesulfonic anhydride (7.21 g, 41.363 mmol). The obtained mixture was stirred at room temperature under nitrogen atmosphere for 12 hours. After the reaction was completed, the solvent was concentrated under reduced pressure. The residue was subjected to colunm chromatography, thereby obtaining Compound lb (9.01 g, 98%).10206] ‘H NMR (400 MHz, CDC13) ö 4.73 (s, 1H), 4.30 (t, J=5.9 Hz, 2H), 3.31-3.24 (m, 2H), 3.04 (s, 3H), 1.94 (t, J=6.l Hz, 2H), 1.44 (s, 9H). El-MS mlz: 254(M+) |
98% | With triethylamine In tetrahydrofuran at 0 - 20℃; for 12h; Inert atmosphere; | 1 Preparation of Compound lb (See U.S. Patent No. 7.8 16.344. hereby incorporated by reference) Compound la (6.04g, 34.469mmo1) and triethylamine (TEA, 14.4mL, 103.4O7mmol) were dissolved in tetrahydrofuran at 0°C under nitrogen atmosphere and then, slowly treated with methanesulfonic anhydride (7.21g, 41.363mmo1). The obtained mixture was stirred at room temperature under nitrogen atmosphere for 12 hours. After the reaction was completed, the solvent was concentrated under reduced pressure. The residue was subjected to column chromatography, thereby obtaining Compound lb (9.Olg, 98%).‘HNMR (400MHz, CDC13) 4.73 (s, 1H), 4.30 (t, J = 5.9Hz, 2H), 3.3 1-3.24 (m, 2H), 3.04 (s, 3H), 1.94 (t, J= 6.1Hz, 2H), 1.44 (s, 9H). El-MS m/z: 254(M+) |
98% | With triethylamine In tetrahydrofuran at 0 - 20℃; for 2h; Inert atmosphere; | 66 Preparation of Compound 45b Preparation of Compound 45b Compound 45a (6.04 g, 34.47 mmol) and triethylamine (14.4 mL, 103.4 mmol) were dissolved in THF at 0 °C under nitrogen and then, slowly treated with methanesulfonic anhydride (7.21 g, 41.36 mmol). The obtained mixture was stirred at room temperature under nitrogen for 12 hours. After the reaction was completed, the solvent was concentrated under reduced pressure. The residue was subjected to column chromatography, which produced the compound 45b (9.01 g, 98 %). 1H-NMR (400 MHz, CDCI3) δ 4.73 (s, 1H), 4.30 (t, J= 5.9 Hz, 2H), 3.31-3.24 (m, 2H), 3.04 (s, 3H), 1.94 (t, J = 6.1 Hz, 2H), 1.44 (s, 9H). |
98% | With triethylamine In tetrahydrofuran at 0 - 20℃; for 12h; Inert atmosphere; | 66 Preparation of Compound 45b Compound 45a (6.04 g, 34.47 mmol) and triethylamine (14.4 mL, 103.4 mmol) were dissolved in THF at 0 °C under nitrogen and then, slowly treated with (1408) methanesulfonic anhydride (7.21 g, 41.36 mmol). The obtained mixture was stirred at room temperature under nitrogen for 12 hours. After the reaction was completed, the solvent was concentrated under reduced pressure. The residue was subjected to column (1409) chromatography, which produced the compound 45b (9.01 g, 98 %). 1H-NMR (400 MHz, CDCI3) δ 4.73 (s, 1H), 4.30 (t, J= 5.9 Hz, 2H), 3.31-3.24 (m, 2H), 3.04 (s, 3H), 1.94 (t, J = 6.1 Hz, 2H), 1.44 (s, 9H). |
98% | With triethylamine In tetrahydrofuran at 0 - 20℃; for 12h; Inert atmosphere; | 24 Preparation of Compound 67 Compound 66 (6.04 g, 34.47 mmol) and triethylamine (14.4 mL, 103.4 mmol) were dissolved in tetrahydrofuran (100 mL) and then methanesulfonic anhydride (7.21 g, 41.36 mmol) was gradually added thereto at 0°C under a nitrogen atmosphere. The temperature was gradually raised to room temperature, and then the mixture was stirred for 12 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain Compound 67 (9.01 g, 98%). 1H-NMR (400 MHz, CDCl3) δ 4.73 (s, 1H), 4.30 (t, J = 5.9 Hz, 2H), 3.31-3.24 (m, 2H), 3.04 (s, 3H), 1.94 (t, J = 6.1 Hz, 2H), 1.44 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With triethylamine In tetrahydrofuran at 0 - 20℃; for 4h; Inert atmosphere; | 2; 3 Preparation of Compound 31 [10254] After Compound 3k (2.75 g, 15.697 mmol) was dissolved in THF (30 mE) at 0°C. undernitrogen atmosphere, TEA (3.3 mE, 23.518 mmol) and Ms20 (3.28 g, 18.814 mmol) were added thereto, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, ethylacetate (200 mE) and distilled water (100 mE) were added thereto to extract an organic layer, and the extracted organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, thereby obtaining Compound 31(3.83 g, 9 6%). |
96% | With triethylamine In tetrahydrofuran at 0 - 20℃; for 4h; Inert atmosphere; | 2; 3 Preparation of Compound 31 Compound 3k (2.75g, 15.697mmo1) was dissolved in THF (3OmL) at 0°C under nitrogen atmosphere, and then TEA (3.3mL, 23.Sl8mmol) and Ms20 (3.28g, 18.8l4mmol) were added thereto, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, ethylacetate (200mL) and distilled water (lOOmL) were added thereto to extract an organic layer, and the extracted organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, thereby obtaining Compound 31(3.83g, 96%). ‘HNMR(400IVIHz, CDCl3) 7.37(s, 1H), 4.48-4.46(m, 2H), 4.13-4.09(m, 2H), 3.11 (s, 3H), 1.50(s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triethylamine In dichloromethane at 25 - 30℃; | 1 Example 1. Synthesis of 4 - ((methylsulfonyl) oxy) benzyl methanesulfonate (Ms-HBA-ASA) A 100 ml three-necked flask equipped with a reflux condenser was charged with 25 ml of methylene chloride,Open the thermostat oil bath and magnetic stirrer,Then 2.5 g of p-hydroxybenzyl alcohol (HBA)Triethylamine 7ml,Heat and stir at 25-30 ° C until p-hydroxybenzyl alcohol is dissolved.7.5 g of methanesulfonic anhydride (MsOMs) were dissolved in 15 ml of dichloromethane.Remove the oil bath was changed to ice bath methyl methanesulfonic anhydride dichloromethane solution.After dropping,Remove the ice bath,Change to 25 oil bath heating,Magnetic stirring reaction for 4 to 6 hours,After the reaction was rinsed three times,The concentrated organic layer was collected,Column chromatography (petroleum ether: ethyl acetate = 2: 1)Vacuum rotary evaporation,concentrate,A white solid was obtained, which was 5.19 g of 4 - ((methanesulfonyl) oxy) benzyl methanesulfonate (Ms-HBA-Ms)The reaction yield was 92%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine In dichloromethane at 20℃; for 1h; | Intermediate I-25B: (5-bromo-7-methylquinoxalin-2-yl)methyl methanesulfonate Intermediate I-25A (262.5 mg, 1.037 mmol) and TEA (0.434 mL, 3.11 mmol) were dissolved in DCM (20 mL) and methanesulfonic anhydride (217 mg, 1.245 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The reactionmixture was diluted with DCM and washed with saturated NaHCO3, dried with sodium sulfate, filtered, and concentrated in vacuo to yield Intermediate I-25B (0.343 g, 1.04mmol, 100%) as an orange solid. The material will be used cmde in the next step. LC-MS: method H, RT = 1.00 mm, MS (ESI) m/z: 331.0 (M+H) |
With triethylamine In dichloromethane at 20℃; for 1h; | Intermediate I-13B: (5-bromo-7-methylquinoxalin-2-yl)methyl methanesulfonate Intermediate I-13A (262.5 mg, 1.037 mmol) and TEA (0.434 mL, 3.11 mmol) were dissolved in DCM (20 mL) and methanesulfonic anhydride (217 mg, 1.245 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with DCM and washed with saturated NaHCO3, dried with sodium sulfate, filtered, and concentrated in vacuo to yield Intermediate I-13B (0.343 g, 1.04 mmol, 100%) as an orange solid. The material will be used crude in the next step. (0381) LC^MS: method H, RT = 1.00 min, MS (ESI) m/z: 331.0 (M+H)+ | |
With triethylamine In dichloromethane at 20℃; for 1h; | Intermediate 1-16: I-16A (0.050 g, 0.198 mmol) was dissolved in DCM (3 ml) and treated with TEA (0.083 ml, 0.593 mmol). To this solution was added methanesulfonic anhydride (0.041 g, 0.237 mmol) and the reaction was allowed to stir at room temperature for lh. Reaction was diluted with EtOAc and sat’d sodium bicarbonate. The layers were seperated and theorganic layer was washed with brine, dried with sodium sulfate and concentrated under reduced pressure. Used without further purification in the next step. MS (ESI) m/z: 331.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 8 - 18℃; for 18h; | To a solution of trans-methyl 4-aminocyclohexanecarboxylate hydrochloride (7.0 g, 36.14mmol) in 200 mL of anhydrous CH2Cl2was added (MeSO2)2O (7.5 g,43.37mmol) and Et3N (11.0 g, 108.42mmol). The resulting mixture was stirred at 8-18oC for 18 h. The reaction mixture was adjusted to pH = 6-7 by 1N aq. HCl. The mixture was concentrated under reduced pressure and extracted with EtOAc (3 × 150 mL). The combined organic layers was washed with brine (2 × 100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give trans-methyl 4- (methylsulfonamido)cyclohexanecarboxylate as white solid.Yield: 9.0 g (100% crude);1H NMR (CD3OD): delta ppm 3.65 (s, 3H), 3.15-3.25 (m, 1H), 2.95 (s, 3H), 2.20-2.35 (m, 1H), 1.95-2.10 (m, 4H), 1.40-1.60 (m, 2H), 1.25-1.40 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; | 1.6 equivalents of alcohol 5 were treated with 1.65 equivalents of both Ms2O and N,N-diisopropylethylamine (DIPEA) in dichloromethane (DCM) to form mesylate 4, followed by addition of compound 3 and additional DIPEA. The mixture was then stirred at 38 C until complete consumption of 3; typically the reaction took 22 h to complete. After base and acid wash, the product was crystallized from 1:2 DCM/methanol as the free base. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With triethylamine In tetrahydrofuran at 0 - 25℃; for 2h; | 3 Step 3 The reaction was carried out in two parallel batches; an example batch follows: To a solution of (5)- oxetan-2-ylmethanol (from Step 2, assumed 69 g, 780 mmol) in THF (1.4 E) was added Et3N (197 g, 1.95 mol) at 0° C. Methanesulfonic anhydride (204 g, 1.17 mol) was added, dropwise, keeping the internal temperature below 10° C. The mixture was stirred at 25° C. for 2 h. The two batches were combined and the mixture was treated with water (1 E) and the layers separated. The aq. phase was extracted with DCM (3x2 E). The combined organic solution was dried, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (EtOAc/PE 50-100% gradient) to yield Intermediate 20 (250 g, 96% for two steps) as a yellow oil. ‘H NMR (400 MHz, CDC13) ö 4.98-5.09 (m, 1H), 4.69 (ddd, 1H), 4.59 (td, 1H), 4.37 (d, 2H), 3.11 (s, 3H), 2.72-2.82 (m, 1H), 2.64 (tdd, 1H). |
250 g | With triethylamine In tetrahydrofuran at 0 - 25℃; for 2h; | 103.3 Step 3 The reaction was carried out in two parallel batches; an example batch follows: To a solution of (S)-oxetan-2-ylmethanol (from Step 2, assumed 89 g, 780 mmol) in THF (1.4 L) was added Et3N (197 g, 1.95 mol) at 0 °C. Methanesulfbnic anhydride (204 g, 1.17 mol) was added, dropwise, keeping the internal temperature below 10 °C. The mixture was stirred at 25 °C for 2 h. The two batches were combined and the mixture was treated with water (1 L) and the layers separated. The aq. phase was extracted with DCM (3 x 2 L). The combined organic solution was dried, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (EtOAc/PE 50-100% gradient) to yield Intermediate 20 (250 g, 96% for two steps) as a yellow oil. 1H NMR (400 MHz, CDCl3) d 4.98-5.09 (m, 1 H), 4.69 (ddd, 1 H), 4.59 (td, 1 H), 4.37 (d, 2H), 3.11 (s, 3H), 2.72-2.82 (m, 1 H), 2.64 (tdd, 1 H). |
With triethylamine In tetrahydrofuran at 0 - 25℃; for 16h; | 1 (S)-oxetan-2-ylmethyl methanesulfonate (1d). To a solution of (S)-oxetan-2- ylmethanol (1c, 2.47 g, 28.03 mmol, 1 eq) in THF (85 mL) was added Et3N (7.09 g, 70.09 mmol, 9.76 mL, 2.5 eq) at 0°C. A solution of methylsulfonyl methanesulfonate (7.33 g, 42.05 mmol, 1.5 eq) in THF was added in the mixture dropwise, and the internal temperature was kept below 10°C. The mixture was stirred at 25°C for 16 hours. TLC (petroleum ether: ethyl acetate = 0:1) showed 1c was consumed and one new spot was formed. The mixture was quenched with H2O (100 mL) and extracted with DCM (100 mL * 3). The combined organic layers were washed with brine (30 mL), dried over with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (Petroleum ether: Ethyl acetate = 6:4~1:1) to give 1d as a yellow oil.1H NMR (400MHz, CDCl3-d) 5.09-4.99 (m, 1H), 4.75-4.66 (m, 1H), 4.59 (td, J = 6.0, 9.0 Hz, 1H), 4.37 (d, J = 3.8 Hz, 2H), 3.11 (s, 3H), 2.83-2.73 (m, 1H), 2.69-2.58 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With triethylamine; In dichloromethane; at 0 - 20℃; for 6h; | To a solution of (3S,4S)-1-benzylpyrrolidine-3,4-diol (3a) (6 g,31 mmol) and Et3N (12.8 mL, 93 mmol) in 200mL dry DCM wasadded dropwise a solution of methanesulfonic anhydride (12.9 g,74 mmol) in 100mL dry DCM at 0 C. The reaction was allowed towarm at R.T. for 6 h. The reaction mixture was washed with saturatedaqueous NaHCO3, 5% HCl and brine in sequence, dried overanhydrous Na2SO4, evaporated in vacuum, and purified by flashchromatography (petroleum ether:EtOAc 3:1) to afford 4a as lightyellow oil (8.5 g, 78%). 1H NMR (400 MHz, CDCl3) d 2.75 (dd,J 4.0 Hz, 11.2 Hz, 2H), 3.05 (s, 6H), 3.07-3.11 (m, 2H), 3.60-3.67(m, 2H), 5.12 (t, J 4.0 Hz, 2H), 7.26-7.34 (m, 5H); 13C NMR(100 MHz, CDCl3) d 38.3, 57.8, 59.1, 82.4, 127.5, 128.5, 128.7, 136.7;HRMS (ESI) m/z calcd for C13H19NO6S2 [MH] 350.0727, found350.0732. [a]D 20 24.6 (c 0.56, CHCl3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere; | General procedure: Silylated allylic alcohol (1 equiv) was added to a round bottom flask along with methanesulfonic anhydride (1.5 equiv) and DCM. The reaction mixture was then cooled to 0 C before adding NEt3 (1.5 equiv). After 5 minutes stirring the reaction mixture was allowed to warm to rt and stirred overnight before being concentrated directly onto silica and purified by column chromatography (30 % Et2O/petroleum ether) to afford a pale yellow liquid. (E)-3-(trimethylsilyl)allyl methanesulfonate. 1H NMR (CDCl3, 400 MHz): delta 6.22 - 5.95 (m, 2H), 4.72 (d, J = 4.2 Hz, 2H), 3.02 (s, 3H), 0.10 (s, 9H). 13C NMR (CDCl3, 101 MHz): delta 137.1, 137.0, 72.0, 38.0, -1.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2,6-dimethylpyridine; In dichloromethane; for 3h; | First, methanesulfonic anhydride (0.321 mL) was added to a methylene chloride solution (2 mL) of methyl 2hydroxynicotinate (200 mg) and 2,6-lutidine (0.228 mg) and the mixture was stirred for 3 hours . A saturated sodium hydrogen carbonate aqueous solution was added to the reaction solution, and the organic layer was separated. The organic layer was dried with anhydrous sodium sulfate, and concentrated under reduced pressure. Then, [1,1?-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloride (a dichloromethane adduct) (53.3 mg), sodium carbonate (415.3 mg), 1-tert-butyloxycarbonyl-4-(4,4,5,5,-tetramethyl-1,3,2-dioxa borolan-2-yl)-1,2,3,6-tetrahydro pyridine (484.6 mg), N,N-dimethylformamide (3.5 mL), and water (1.2 mL) were added to the obtained residue in sequence, and the resultant mixture was stirred under microwave irradiation at 100C for 10 minutes . A saturated sodium hydrogen carbonate aqueous solution was added to the reaction solution, the mixture was filtered through celite, and then the organic layer was separated. The organic layer was dried with anhydrous sodium sulfate and was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) to obtain methyl 1?-(tertbutyloxycarbonyl)-1?,2?,3?,6?-tetrahydro-[2,4?-bip yridine]-3-carboxylate (313 mg). 1H-NMR (400MHz, CDCl3) delta: 1.49(s,9H),2.50-2.60(m,2H),3.61-3.72(m,2H),3.87(s,3H),4.07( q,J=2.8Hz,2H),5.78(m,1H),7.28(dd,J=7.9,4.8Hz,1H),8. 05(m,1H) ,8.67(dd,J=4.8,1.8Hz,1H). MS (ESI)m/z:319[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium hydroxide; In acetone; at 20℃; | 1.29 g (10.0 mmol) of metformin, 1.74 g (10.0 mmol) of methanesulfonic anhydride, 300 mL of anhydrous acetone, and 0.056 g (1 mmol) of potassium hydroxide were placed in a 500 mL flask, and stirred at room temperature overnight. The reaction progress was detected by TCL. When there was no significant change in the reaction product, the pH was adjusted to neutral with dilute hydrochloric acid to quench the reaction, and then the mixture was dried under reduced pressure to give a crude product, then petroleum ether: ethyl acetate = 2:1 (v/v) as an eluent over a silica gel column,1.9 g of compound 18 as a white powder were obtained in a yield of 90%. Rf was 0.7 (dichloromethane:methanol: glacial acetic acid = 9:1:0.025). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With triethylamine In tetrahydrofuran; dichloromethane at 18 - 25℃; for 20.5h; | |
81% | With triethylamine In tetrahydrofuran; dichloromethane at 20℃; for 20.5h; | 3 <Step-3>: ((1r,4r)-4-(5-chloro-2-methylnicotinamido)cyclohexyl)methyl methanesulfonate To a mixture of 5-chloro-N-((1r,4r)-4-(hydroxymethyl)cyclohexyl)-2-methylnicotinamide (10.2 g, 35.9 mmol, Step-2 of Intermediate-A) and TEA (15 mL) in DCM (120 mL) / THF (60 mL) is added portionwise methanesulfonic anhydride (14.1 g, 81 mmol) at room temperature. The mixture is stirred at room temperature for 18 hrs. To the resultant mixture is added methanesulfonic anhydride (3.13 g, 18.0 mmol) and stirred at room temperature. After 1 hr, to the mixture is added methanesulfonic anhydride (3.13 g, 18.0 mmol) and stirred at room temperature. After 1.5 hrs, the reaction is quenched with saturated aqueous sodium bicarbonate (100 mL) and extracted with DCM (3 x 150 mL). The combined organic phase is dried over sodium sulfate, filtered and concentrated in vacuo. The residual solid is purified by column chromatography on silica-gel eluting with 0-100% EtOAc in DCM to give 10.5 g (81% yield) of the title compound as a white solid. 1H-NMR (400 MHz, CDCl 3) delta 8.50 (1H, d, J = 2.3 Hz), 7.62 (1H, d, J = 2.3 Hz), 5.61 (1H, d, J = 7.8 Hz), 4.07 (2H, d, J = 6.6 Hz), 4.01-3.85 (1H, m), 3.02 (3H, s), 2.62 (3H, s), 2.24-2.15 (2H, m), 1.98-1.89 (2H, m), 1.85-1.71 (1H, m), 1.32-1.18 (4H, m). MS (ESI) m/z: 361.1 (M+H) +. |
81% | With triethylamine In tetrahydrofuran; dichloromethane at 18 - 25℃; for 20.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With triethylamine In tetrahydrofuran; dichloromethane at 0 - 25℃; for 1.5h; | |
95% | With triethylamine In tetrahydrofuran; dichloromethane at 0 - 20℃; for 1.5h; | 2 <Step-2>: ((1r,4r)-4-(5-chloro-2-(trifluoromethyl)nicotinamido)cyclohexyl)methyl methanesulfonate To a mixture of 5-chloro-N-((1r,4r)-4-(hydroxymethyl)cyclohexyl)-2-(trifluoromethyl)nicotinamide (1.62 g, 4.81 mmol, Step-1 of Intermediate-C) and TEA (2.34 mL, 16.9 mmol) in DCM (10 mL) / THF (20 mL) is added portionwise methanesulfonic anhydride (1.26 g, 7.22 mmol) at 0 oC. The mixture is stirred at room temperature for 1.5 hrs. The mixture is quenched with saturated aqueous sodium bicarbonate and extracted with DCM (x2). The combined organic phase is dried over MgSO 4, filtered and concentrated. The residual solid is purified by column chromatography on silica-gel eluting with 10-80% EtOAc in n-hexane to give 1.89 g (95% yield) of the title compound as an off-white solid. 1H-NMR (400 MHz, CDCl 3) delta 8.69 (1H, d, J = 2.3 Hz), 7.89 (1H, d, J = 2.3 Hz), 5.64 (1H, d, J = 7.8 Hz), 4.07 (2H, d, J = 6.4 Hz), 4.00-3.89 (1H, m), 3.02 (3H, s), 2.23-2.14 (2H, m), 1.99-1.88 (2H, m), 1.85-1.68 (1H, m), 1.33-1.15 (4H, m). MS (ESI) m/z: 415.4 (M+H) +. |
95% | With triethylamine In tetrahydrofuran; dichloromethane at 0 - 25℃; for 1.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.0 g | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 0.25h; | 11.2 Step 2: Preparation of 2-(6-chloro-3-pyridyl)ethyl methanesulfonate (compound 11c) To a mixture of 2-(6-chloro-3-pyridyl)ethanol (compound 11b, 4.0 g, 25.4 mmol) and DIPEA (13.3 ml, 76.1 mmol) in DCM (50.0 mL) was added methanesulfonic anhydride (6.6 g, 38.1 mmol) slowly at rt. After the reaction mixture was stirred at rt for 15 minutes., it was diluted with NaHCO3 and extracted with EtOAc. The organic layer was dried and concentrated to give compound 11c as a light brown oil (5.0 g), LCMS (M+H)+: 236 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In dichloromethane at -5℃; for 1.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With triethylamine In dichloromethane at 20℃; for 2h; | 2 To a stirred solution of compound 360-1 (900 mg, 4.04mmol) in DCM (15 ml) was added (1944) MS2O (844 mg, 4.85 mmol) and TEA (1.24 g, 12.12 mmol). The resulting reaction mixture was stirred at rt for 2 h. Then concentrated in vacuo , thus was further purified by C.C. to give 360-2 (950 mg, yield: 84%) as yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With dmap; triethylamine In dichloromethane at 20℃; for 16h; | 1 To a solution of compound 0470-1 (400 mg, 1.99 mmmol) in DCM (10 mL) was added TEA (606 mg, 6.00 mmol), DMAP (25 mg, 0.20 mmol) and MS2O (348 mg, 2.00 mmol). The resulting reaction mixture was stirred for 16 h at rt. Then it was concentrated to dryness and purified by silica-gel column (DCM: MeOH = 100: 1) to give the desired product 0470-2 (460 mg, yield: 83.0%) as a yellow solid. |
Tags: 7143-01-3 synthesis path| 7143-01-3 SDS| 7143-01-3 COA| 7143-01-3 purity| 7143-01-3 application| 7143-01-3 NMR| 7143-01-3 COA| 7143-01-3 structure
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