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CAS No. : | 17061-62-0 | MDL No. : | MFCD00277836 |
Formula : | C16H19NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | HBKPDEWGANZHJO-UHFFFAOYSA-N |
M.W : | 257.33 | Pubchem ID : | 714952 |
Synonyms : |
|
Num. heavy atoms : | 19 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.25 |
Num. rotatable bonds : | 6 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 76.49 |
TPSA : | 30.49 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.93 cm/s |
Log Po/w (iLOGP) : | 3.16 |
Log Po/w (XLOGP3) : | 2.73 |
Log Po/w (WLOGP) : | 2.69 |
Log Po/w (MLOGP) : | 2.57 |
Log Po/w (SILICOS-IT) : | 3.49 |
Consensus Log Po/w : | 2.93 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.23 |
Solubility : | 0.153 mg/ml ; 0.000593 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.02 |
Solubility : | 0.243 mg/ml ; 0.000945 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -6.04 |
Solubility : | 0.000237 mg/ml ; 0.000000923 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 1.38 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P280-P301+P330+P331-P305+P351+P338-P310-P303+P361+P353 | UN#: | 3259 |
Hazard Statements: | H314 | Packing Group: | Ⅲ |
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 |
---|---|---|
100% | With sodium tetrahydridoborate In methanol at 5℃; for 2.75h; Heating / reflux; | 5 p-Anisaldehyde (25.0 g, 0.1836 mol), 4-methoxybenzylamine (25.3 g, 0.1836 mol) and toluene (150 mL) were combined in a 500 mL round bottom flask which was fitted with a condenser and Dean-Stark trap under a N2 atmosphere. The solution was refluxed for 3 hours during which time 3 mL of H2O was azeotroped away from the reaction mixture. The reaction was cooled and concentrated on a rotovap at 400C for 2 hours. The clear, yellow oil was taken up in MeOH (150 mL) in a 500 mL round bottom flask fitted with a condenser under a N2 atmosphere. The reaction was cooled to 5°C, and NaBH4 was added in small portions over 45 min (off-gassing occurred). The reaction was slowly heated to reflux with vigorous off-gassing. After 2 hours at reflux, the reaction was cooled to room temperature and concentrated on the rotorvap at 300C for 2 hours, and then placed under high vacuum at 3O0C for 1 hour to give the title compound as a white crystalline solid (47.13 g, quantitative yield; 98.6 % purity by HPLC). MH+ = 258.1 |
60% | With sodium tetrahydridoborate In tetrahydrofuran; methanol at 20℃; for 18h; | |
With ethanol; natrium |
With palladium on activated charcoal; ethanol Hydrogenation; | ||
With sodium tetrahydridoborate In ethanol for 1.5h; Ambient temperature; Yield given; | ||
With sodium tetrahydridoborate In ethanol at 0 - 20℃; for 2h; | 5B A solution of the material from Part A in ethanol (300 mL) was cooled to 0 0C and stirred rapidly. Solid sodium borohydride (22.1 g, 584 mmol) was added slowly over a period of several minutes, and the reaction was stirred at ambient temperature for two hours. Water (300 mL) was added, and the resulting mixture was shaken and allowed to stand overnight. The mixture was extracted with diethyl ether (3 x 100 mL), and the combined extracts were washed with water (200 mL), dried over magnesium sulfate, filtered through a layer of CELITE filter agent, concentrated under reduced pressure, and further dried under high vacuum to provide 67 g of TV, 7V-bis(4-methoxybenzyl)amine as a white solid. | |
Stage #1: N-(4-methoxybenzylidene)-1-(4-methoxyphenyl)methanamine With sodium tetrahydridoborate In ethanol at 0 - 20℃; for 2h; Stage #2: With ethanol; lithium hydroxide monohydrate | B Part BA solution of the material from Part A in ethanol (300 mL) was cooled to 0 0C and stirred rapidly. Solid sodium borohydride (22.1 g, 584 mmol) was added slowly over a period of several minutes, and the reaction was stirred at ambient temperature for two hours. Water (300 mL) was added, and the resulting mixture was shaken and allowed to stand overnight. The mixture was extracted with diethyl ether (3 x 100 mL), and the combined extracts were washed with water (200 mL), dried over magnesium sulfate, filtered through a layer of CELITE filter agent, concentrated under reduced pressure, and further dried under high vacuum to provide 67 g of iV,7V-bis(4-methoxybenzyl)amine as a white solid. | |
4.81 g | With sodium tetrahydridoborate In ethanol at 20℃; | |
With sodium tetrahydridoborate In methanol | ||
177 mg | With sodium tetrahydridoborate In ethanol at 20℃; for 3h; Inert atmosphere; | |
With hydrogen at 90℃; | ||
With sodium tetrahydridoborate In methanol; dichloromethane | ||
With sodium tetrahydridoborate In ethanol for 4h; | ||
1112 g | With sodium tetrahydridoborate In ethanol at 20 - 42℃; | Bis(4-methoxybenzyl)amine, Intermediate 5.8.1. 4- (0546) Methoxybenzylamine (neat, 600 g, 4.37 mol, 1 eq) and 4-methoxybenzaldehyde (532 mL, 4.37 mol, 1 eq) were added to a 10 L round bottomed flask at RT with stirring. The reaction spontaneously warmed and a white precipitate was observed. The mixture was stirred for 1 h. To the above mixture was added anhydrous EtOH (4.8 L) and stirring was continued at RT for 15-30 min. This was followed by the addition of sodium borohydride granules (99 g, 2.62 mol, 0.6 eq) portionwise over ~ 2 h. During the addition of NaBH4. the internal temperature of the reaction rose to 42 °C. The resulting mixture was then stirred at RT overnight. Next, the reaction was quenched slowly with water (600 mL). The mixture was then concentrated on a rotary evaporator at 50°C. The residue was partitioned between water (4 L) and DCM (4 L). The aqueous layer was extracted with more DCM (2x 2 L). The combined organic layers were dried over Na2SC>4, fdtered and concentrated in vacuo to give Intermediate 5.8.1 (1112 g, 99% yield) as a semi-solid. (0547) The material was used directly in the next step without further purification. ' H-NMR (400 MHz, CDC13) d 7.28 (t, J = 7.12 Hz, 4H), 6.89 (d, J = 8.60 Hz, 4H), 3.83 (app s, (0548) 6H), 3.76 (s, 4H) (-NH proton not observed). MS (ESI pos. ion) m/z: = 258.4 (M+H)+. |
With sodium tetrahydridoborate at 0 - 20℃; for 10h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With hydrogen In toluene at 90℃; for 20h; chemoselective reaction; | |
90% | With 10% Rh/C; hydrogen In cyclohexane at 25℃; for 24h; | |
87% | With silver hexafluoroantimonate; [Cp*Rh(NCCH3){κ2(N,C)-(NH2C(C6H5)2-2-C6H4)}](SbF6); hydrogen; triethylamine In tetrahydrofuran at 60℃; for 45h; Autoclave; Molecular sieve; Inert atmosphere; |
86% | With borane-ammonia complex; C16H29Cl2CoN2P at 25℃; for 13h; Schlenk technique; Inert atmosphere; chemoselective reaction; | |
85% | With borane-ammonia complex; (9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene)dichlorocobalt(II) at 27℃; for 16h; Glovebox; Inert atmosphere; | |
84% | With potassium-t-butoxide; 1,3,2-oxazaborolidine-borane; copper(II) bis(trifluoromethanesulfonate) In lithium hydroxide monohydrate at 20℃; for 24h; Inert atmosphere; | |
72% | With sodium tetrahydridoborate; La0.5Ca0.5CoO3 In methanol at 40℃; for 2.5h; chemoselective reaction; | General procedure for the reduction of nitriles into their correspondingsec-amines. General procedure: To a stirring mixture of the appropriate nitrile (1 mmol) and nanosized La0.5Ca0.5CoO3 perovskite (1 mol%, 1.9 mg) in MeOH (5 ml) at 40C, NaBH4 (2 mmol, 0.08 g) was added portion wise. After the completion of the reaction which was monitored by TLC using CHCl3: MeOH (30:1) as eluent, the catalyst was centrifuged off and the solvent was evaporatedunder reduced pressure. To the resulting oily liquid, water (20 ml) was added and the mixture was extracted with CH2Cl2 (2 × 20 ml). The organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure to afford the pure products. |
With ethanol; lithium hydroxide monohydrate; nickel Hydrogenation.Reagens 4: Aethylacetat; | ||
With C22H27ClN3Ru(1+)*F6P(1-); hydrogen In isopropanol at 80℃; for 12h; | 4.6 General Procedure for the catalytic hydrogenation of nitriles General procedure: All of the hydrogenation reactions were performed at constant pressures using a stainless steel 50mL Parr hydrogenation reactor. The reactor was flushed three times with hydrogen gas at 2-4bar prior to the addition of catalyst and substrate. Catalyst 1 (0.02mmol), nitrile (1mmol), and dodecane (1mmol) in case of symmetrical amine synthesis or, catalyst 1 (0.02mmol), nitrile (1mmol), amine (3mmol) and dodecane (1mmol) in case of asymmetrical amine synthesis were dissolved in iPrOH (5mL) under a nitrogen atmosphere. The solution was then injected into the reactor against a flow of hydrogen gas. The hydrogen gas was adjusted to 60bar. The temperature of the system was maintained at 80°C using a thermostat. Small aliquots of the reaction mixture were withdrawn after 12h with a syringe and diluted with 2mL of EtOAc and passed through a very short column of silica and subjected to GC-MS analysis. A few selected secondary amines were purified by flash chromatography and characterized by 1H and 13C NMR spectra. | |
86 %Chromat. | With ammonium hydroxide; Pt0956(06)Mo043; hydrogen In ethanol at 80℃; for 8h; Sealed tube; | |
With bis(benzonitrile)palladium(II) chloride; lithium hydroxide monohydrate; hydrogen; mesoporous silica; 2,2'-biquinoline-4,4'-dicarboxylic acid dipotassium salt In hexane at 100℃; for 24h; Autoclave; Green chemistry; chemoselective reaction; | ||
With hydrogen In methanol at 30℃; for 5h; | ||
99 %Chromat. | With borane-ammonia complex In methanol; lithium hydroxide monohydrate at 40℃; for 3h; Sealed tube; | |
With hydrogen In ethanol at 80℃; for 4h; Autoclave; | 2.4. Catalytic performance General procedure: The hydrogenation of nitriles was conducted in a 100 mL stainlesssteelautoclave (NS100-SV, Anhui Kemi Machinery Technology Co.,Ltd) with a Teflon inlet. In a typical test, 3 g benzonitrile, 30 mg catalystand 60 mL ethanol were co-added into the autoclave. After three timesflush of ultrahigh purity Ar, the autoclave was pressurized to 0.6 MPa with ultrahigh purity H2. The reaction proceeded at 80 C under magneticstirring with a rate of 1500 r.p.m to exclude the mass transferlimitation. During the reaction, the crude mixture was taken out by asampling pipe and analyzed by gas chromatography (GC, Shimadzu GC-2014, equipped with a Rtx-1 capillary column and a flame ionizationdetector). Dodecane was used as an internal standard. Products in BNhydrogenation were analyzed by GC-Mass (Agilent GC7890B equipped with an Agilent 5977B MSD mass spectrometer) and 1H-nuclear magneticresonance (NMR) (Bruker Avance III 400) analysis. The TOFs andDBA formation rates were calculated using the following equations,respectively: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine In dichloromethane at 0℃; for 2h; | 144.11 (0967) [0307] N,N-Bis(4-methoxybenzyl)ethanesulfonamide, Example 144.11. To a solution of Example 4.11 (210 g, 816 mmol) in DCM (2000 mL) was added TEA (385 mL, 2856 mmol) and a solution of 2-chloroethanesulfonyl chloride (146 g, 898 mmol) in DCM (1000 mL) at 0 °C, and the mixture was stirred for 2 h. The reaction mixture was then quenched with ice cold water (1000 mL) and extracted with DCM (2 x 1000 mL). The organic layer was washed with brine solution (1000 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was absorbed onto a plug of silica gel (60-120 mesh) and purified by column chromatography over silica gel (60-120 mesh) using 50% to 80% EtOAc in hexanes as an eluent to give (0968) Example 144.11 (255 g, 90% yield) as an off-white solid. NMR (400 MHz, DMSO- ck) δ 7.16 (d, J = 8.8 Hz, 4H), 6.90 (d, J = 8.8 Hz, 4H), 6.73 (dd, J = 16.4, 10.0 Hz, 1H), 6.11 (d, 3.75 (m, 6H). |
81% | With sodium hydroxide In water; 1,2-dichloro-ethane 30 min at 0 deg C then 3 h, RT; | |
75% | With triethylamine In dichloromethane at 20℃; | 13.2 N,N-Bis(4-methoxybenzyl)ethenesulfonamide, Example 13.2 To a solution of bis(4-methoxybenzyl)amine (Example 406.1, 5.11 g, 19.86 mmol) and TEA (8.30 mL, 59.6 mmol) in DCM (99 mL) at RT was added 2-chloroethanesulfonyl chloride (2.51 mL, 23.83 mmol) in DCM (25 mL) dropwise. The reaction was stirred at RT overnight. The reaction was diluted with a saturated NaCl solution and extracted with DCM, dried over MgSO4, filtered, and evaporated onto silica gel. Purification of the residue by flash silica gel chromatography on a 220 g Redisep Gold pre-packed spherical silica gel column (eluent: 0-30% EtOAc/hexanes, gradient elution) provided the title product as a white solid 5.15g 75 % yield . |
74% | With triethylamine In dichloromethane at 0℃; for 3h; | 460.0 [09331 N,N-bis(4-methoxybenzyl)ethenesulfonamide, Example 460.1. To1 L round bottomed flask was added bis(4-methoxvbenzvl)amine 12.01 (23.16 g, 90 mmol) and TEA (anhydrous (43.8 mL, 315 mmol)) in DCM (200 mL). At 0 °C (ice bath), 2-chloro-1-ethanesulfonyl chloride (10.41 mL, 99 mmol) in DCM (100 mL) was added dropwise with stirring. The reaction mixture was stirred at 0 °C for 3 h after completion of the addition. LCMS analysis indicated the reaction was complete. The reaction mixture was diluted with water and extracted with DCM. The organic extract was washed with brine and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the initial material as a light-yellow oil, which was purified by silica gel chromatography (a gradient of 0-60% EtOAc in hexanes), to provide 460.1 (23 g, 66.2 mmol, 74% yield) as a white solid. LCMS-ESI (POS), mlz: 370.1 (M+Na). |
With triethylamine In dichloromethane at 0℃; Inert atmosphere; | ||
Stage #1: 2-Chloroethanesulfonyl chloride With triethylamine In dichloromethane at -72 - 20℃; for 2.16667h; Inert atmosphere; Stage #2: N,N-bis(p-methoxybenzyl)amine In dichloromethane at 20℃; for 2h; | 10.A Step A. N,N-Bis(4-methoxybenzyl)ethenesulfonamide. To a solution of 2-chloroethanesulfonyl chloride (2mL, 19 mmol) in dichloromethane (95 mL) was added dropwise triethylamine (2.64 mL, 19 mmol) at -72°C under argon. The resulting mixture was stirred at this temperature for 10 min. Then the reaction mixture was warmed to room temperature and stirred for 2h. After this time bis-(4-methoxybenzyl)-amine (4.94 g, 19 mmol) and TEA (3.17 mL, 23 mmol) were added at 0°C. After stirring at room temperature for 2 h the solvent was evaporated to give 6.87 g of the crude product (100%). 1H NMR (700 MHz, Chloroform-d) δ 7.27 - 7.19 (m, 4H), 6.93 - 6.88 (m, 4H), 6.32 (dd, J = 16.5, 9.8 Hz, 1H), 6.22 (d, J = 16.5 Hz, 1H), 5.87 (d, J = 9.8 Hz, 1H), 4.22 (s, 4H), 3.84 (s, 6H). The crude product was used to the next step without any further purification. | |
Stage #1: 2-Chloroethanesulfonyl chloride With triethylamine In dichloromethane at -72 - 20℃; for 2.16667h; Inert atmosphere; Stage #2: N,N-bis(p-methoxybenzyl)amine With triethylamine In dichloromethane at 0 - 20℃; for 2h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.2% | With triethylamine; In dichloromethane; at 20℃; for 1.25h; | 1.3 Preparation of 2-Amino-4-chloro-6-di-(4-methoxybenzyl)amino-5-pyrimidine Carbaldehyde 2-Amino-4,6-dichloro-5-pyrimidine carbaldehyde (0.50 g; 2.60 mmol) was stirred in dry DCM (5 ml). Triethylamine (0.263 g; 2.60 mmol) and di(4-methoxybenzyl)amine (0.669 g; 2.60 mmol) were added and the reaction stirred at r.t for 1.25 h. the reaction was worked up by addition of further DCM (50 ml) and extraction with saturated sodium chloride solution (3*50 ml). The organic layer was washed with water (50 ml), dried (MgSO4) and evaporated yielding a yellow foam (0.957 g; 2.32 mmol; 89.2%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In dimethyl sulfoxide at 45℃; for 0.333333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With 3-(2Ph2PC6H4)-2-[4-(PSPEGNHCO(CH2)3)C6H4]5HIm[1,5-a]In-2-one In water at 25℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With triethylamine In 1-methyl-pyrrolidin-2-one at 120℃; for 48h; | 6 l-(2-chloro-3-nitroquinolin-4-ylamino)-2-methylpropan-2-ol (5.01 g, 17.0 mmol), bis(4-methoxybenzyl)amine (MM- 17594- 128-1, 6.02 g, 23.4 mmol), triethylamine (7.1 mL, 50.1 mmol) and NMP (7.5 mL) were combined in glass bomb. The reaction was heated at 1200C for 2 days. HPLC indicated the reaction went to 95% completion. The reaction mixture was combined with three reactions mixtures run previously, and this combined material was taken up in CH2Cl2. The organic layer was washed with H2O (2x), 0.5M citrate (2x), H2O and brine and then dried over Na2SO4, filtered and concentrated to a red gum (18.30 g). The crude material was purified by column chromatography (0-50% EtOAc/Hexanes) to give the title compound as a red syrup (10.1 g, 82% yield). MH+ 258.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With 4 A molecular sieve In acetonitrile at 20℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With hydrogen In 1,3,5-trimethyl-benzene at 140℃; for 15h; | |
93% | With 5 % Pd/TiO2 at 30℃; for 20h; Inert atmosphere; UV-irradiation; | |
92% | With Co2Rh2/C In toluene at 180℃; for 18h; Autoclave; Inert atmosphere; |
91% | With NiCuFeO(x) In 5,5-dimethyl-1,3-cyclohexadiene for 24h; Inert atmosphere; Sealed tube; Reflux; | |
86% | With [(PCy3)(CO)RuH]4(μ-O)(μ-OH)2; 4-tert-Butylcatechol In chlorobenzene at 130℃; for 16h; Glovebox; Schlenk technique; Sealed tube; chemoselective reaction; | |
77% | With bis(dichloro[η5-pentamethylcyclopentadienyl]iridium) at 170℃; for 18h; Neat (no solvent); | |
Multi-step reaction with 2 steps 1: 95 percent / toluene / 24 h / Heating 2: 60 percent / Sodium borohydride / methanol; tetrahydrofuran / 18 h / 20 °C | ||
Multi-step reaction with 2 steps 2: palladium/charcoal; ethanol / Hydrogenation | ||
Multi-step reaction with 2 steps 2: sodium; ethanol | ||
Multi-step reaction with 2 steps 1: magnesium(II) sulfate / ethanol / 4 h / 78 °C 2: sodium tetrahydridoborate / ethanol / 20 °C | ||
Multi-step reaction with 2 steps 1: ethanol / 9 h / Reflux 2: sodium tetrahydridoborate / methanol | ||
83 %Chromat. | With CuO#NiO at 150℃; for 20h; Inert atmosphere; | 71 EXAMPLES 68-75 [0046] With reference to the conditions in Examples 5-8, 80-150 mg of catalyst D obtained in Example 4 and 10 mmol of amines having different structures were weighted and added into a 40 mL glass reaction tube provided with a magnetic stirring apparatus. After sealed, the tube was purged with N2 to replace the air in the system for three times. Next, the system was heated and stirred. The temperature was raised to 150-170° C. and then kept for 18-24 hours. The reaction was then stopped and the system was cooled down to the room temperature. The catalyst was obtained from the reaction mixture by filtration. Agilent 7890A (30 m×0.25 mm×0.33 μm capillary column, hydrogen flame ionization detector) gas chromatograph was used for quantitatively analyzing the reaction mixture. The other byproducts were qualitatively analyzed with Agilent 6890/5973 Gas Chromatography-Mass Spectrometer (equipped with NIST Mass Spectral Database chemical workstation, 30 m×0.25 mm×0.33 μm capillary column). The reaction products were secondary amines. Each of the analysis results was shown in Table 4. |
Multi-step reaction with 2 steps 1: air; Pd-coated porous graphene oxide / acetonitrile / 5 h / 90 °C 2: hydrogen / 90 °C / 760.05 Torr | ||
Multi-step reaction with 2 steps 1: methanol 2: sodium tetrahydridoborate / dichloromethane; methanol | ||
Multi-step reaction with 2 steps 1: ethanol / 12 h / 90 °C / Reflux 2: sodium tetrahydridoborate / ethanol / 4 h | ||
Multi-step reaction with 2 steps 1: 1 h / 20 °C 2: sodium tetrahydridoborate / ethanol / 20 - 42 °C | ||
Multi-step reaction with 2 steps 1: methanol / 3 h / Reflux 2: sodium tetrahydridoborate / 10 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With triethylamine; In dichloromethane; at 0 - 20℃; for 3h; | Bis(4-methoxybenzyl)amine (900 mg) was dissolved in dichloromethane (20 ml) and cooled to 0C. To this solution, triethylamine (1.02 ml) was added and compound 49 (1.05 g) was added in small portions, followed by stirring at room temperature for 3 hours. After addition of water, the reaction mixture was extracted with dichloromethane. The organic layer was washed with brine and dried over magnesium sulfate. After filtration and evaporation of the solvent under reduced pressure, the resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane 1:1 to ethyl acetate) to give the desired compound (compound 50) (1.4 g, yield 81%). 1H-NMR (300MHz, CDCl3) delta: 3.24(2H, t, J=6.8Hz), 3.81(6H, s), 4.10-4.14(2H, m), 4.29(4H, s), 6.88(4H, d, J=8.7Hz), 7.23(4H, d, J=8.7Hz), 7.73(2H, dd, J=3.1, 5.3Hz), 7.87(2H, dd, J=3.1, 5.3Hz). Rf value (silica gel plate, developing solvent: ethyl acetate:n-hexane = 1:1): 0.24. |
62% | With triethylamine; In dichloromethane; at 0 - 20℃; | To bis(4-methoxybenzyl)amine (Example 406.01, 3.37g, 13.10 mmol) and TEA (5.46 mL, 39.3 mmol) in DCM (109 mL) at 0 C was added 2-phthalimidoethanesulfonyl chloride (3.94 g, 14.41 mmol, commercially available from Matrix Scientific) slowly. The reaction was stirred at RT until complete by LCMS analysis. The reaction was diluted with a saturated solution of NaCl and extracted with DCM, dried over MgSO4, filtered and concentrated in vacuo. Purification of the residue by flash chromatography on a Versapak Spherical pre-packed silica gel column (Sigma-Aldrich, St. Louis, MO, eluent: 10-55% EtOAc/hexanes, gradient elution) provided Example 95.1 (4.04g, 62%) as a white solid after evaporation. The product was used directly in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: 4-methoxy-benzaldehyde; 4-methoxy-benzylamine for 1h; Heating; Large scale; Stage #2: With sodium tetrahydridoborate; ethanol at 20℃; Large scale; | 12.0 [0404j Bis(4-methoxybenzyl)amine, Example 12.01. 4-methoxybenzylamine (neat, 600 g, 4.37 mol, 1 eq) and 4-methoxybenzaldehyde (532 mL, 4.37 mol, 1 eq) were added to a 10 L round bottomed flask at ambient temperature with stirring. The reaction spontaneously warmed and a white precipitate was observed. The mixture was stirred for 1 h. To the above mixture was added anhydrous EtOH (4.8 L) and stirring was continued at RT for 15-30 mm. This was followed by the addition of sodium borohydride granules (99 g, 2.62 mol, 0.6 eq) portionwise over 2 h (Note: During the addition of NaBH4, the internal temperature of the reaction rose up to 42 °C) and further stirred at ambient temperature overnight. The reaction was quenched slowly with water (600 mL). The mixture was concentrated on a rotary evaporator at 50 °C. The residue was partitioned between water (4 L) and DCM (4 L). The aqueous layer was extracted with more DCM (2 x 2 L). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give bis(4-methoxybenzyl)amine 12.01 (1112 g, 99% yield) as a semi-solid. The material was used directly in the next step without futher purification.‘H-NMR (400 MHz, CDC13) 7.28 (t, J= 7.12 Hz, 4H), 6.89 (d, J= 8.60 Hz, 4H), 3.83 (s, 6H), 3.76 (s, 4H) (-NH proton not observed). MS (ESI pos. ion) mlz: = 258.4 (M+H). |
99% | Stage #1: 4-methoxy-benzaldehyde; 4-methoxy-benzylamine for 1h; Heating; Large scale; Stage #2: With sodium tetrahydridoborate; ethanol for 2h; Large scale; | 467.1 Bis(4-methoxybenzyl)amine, Example 467.1 4- Methoxybenzylamine (neat, 600 g, 4.37 mol, 1 eq) and 4-methoxybenzaldehyde (532 mL, 4.37 mol, 1 eq) were added to a 10 L RBF at RT with stirring. The reactionspontaneously warmed and a white precipitate was observed. The mixture was stirred for 1 h. To the above mixture was added anhydrous EtOH (4.8 L) and stirring was continued at RT for 15-30 min. This was followed by the addition of sodium borohydride granules (99 g, 2.62 mol, 0.6 eq) portionwise over ~ 2 h (Note : During the addition of NaBH4, the internal temperature of the reaction rose up to 42 °C). The resulting mixture was then stirred at RTovernight. The reaction was quenched slowly with water (600 mL). The mixture was then concentrated on a rotary evaporator at 50°C. The residue was partitioned between water (4 L) and DCM (4 L). The aqueous layer was extracted with more DCM (2 x 2 L). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give bis(4-methoxybenzyl)amine 467.1 (1112 g, 99% yield) as a semi-solid. The material was used directly in the next step without further purification.1H-NMR (400 MHz, CDCl3) δ 7.28 (t, J = 7.12 Hz, 4H), 6.89 (d, J = 8.60 Hz, 4H), 3.83 (m, 6H), 3.76 (s, 4H) (-NH proton not observed). LCMS (ESI pos.) m/z: 258.4 (M+H)+. |
99% | Stage #1: 4-methoxy-benzaldehyde; 4-methoxy-benzylamine In neat (no solvent) for 1h; Heating; Large scale; Stage #2: With sodium tetrahydridoborate; ethanol at 20 - 42℃; Large scale; | 30.1 Bis(4-methoxybenzyl)amine, Example 30.1. 4-Methoxybenzylamine(neat, 600 g, 4.37 mol, 1 eq) and 4-methoxybenzaldehyde (532 mL, 4.37 mol, 1 eq) were added to a 10 L round bottom flask at ambient temperature with stirring. The reaction spontaneously warmed and a white precipitate was observed. The mixture was stirred for 1 h. To the above mixture was added anhydrous EtOH (4.8 L) and stirring was continued at RT for 15-30 mm. This was followed by the addition of sodium borohydride granules (99 g, 2.62 mol, 0.6 eq) portionwise over 2 h (Note : During the addition of NaBH4, the internal temperature of the reaction rose to 42 °C), and the mixture was further stirred at ambient temperature overnight. The reaction was quenched slowly with water (600 mL). The mixture was then concentrated on a rotary evaporator at 50°C. The residue was partitioned between water (4 L) and DCM (4 L). The aqueous layer was extracted with more DCM (2 x 2 L). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give bis(4-methoxybenzyl)amine 30.1 (1112 g, 99% yield) as a semi-solid. The material was used directly in the next step without further purification.1H-NMR (400 MHz, CDC13) ö 7.28 (t,J 7.12 Hz, 4H), 6.89 (d,J 8.60 Hz, 4H), 3.83 (app s, 6H), 3.76 (s, 4H) (-NH proton not observed). LCMS-ESI (pos.) m/z: = 258.4 (M+H)t |
99% | Stage #1: 4-methoxy-benzaldehyde; 4-methoxy-benzylamine at 20℃; for 1h; Large scale; Stage #2: With sodium tetrahydridoborate; ethanol at 20 - 42℃; Large scale; | 100.1 Bis(4-methoxybenzyl)amine, Example 100.1 4- Methoxybenzylamine (600 g, 4.37 mol) and 4-methoxybenzaldehyde (532 mL, 4.37 mol) were added to a 10 L round bottomed flask at ambient temperature . An exotherm was observed and a white precipitate formed. The mixture was stirred for 1 h and then anhydrous EtOH (4.8 L) was added . After an additional 15-30 min at RT, sodium borohydride granules (99 g, 2.62 mol) were added portionwise over ~ 2 h (Note : During the addition of NaBH4, the internal temperature of the reaction rose to 42 °C), and the reaction was further stirred at RT overnight. The reaction was then slowly quenched with water (600 mL) and then concentrated in vacuo. The residue was partitioned between water (4 L) and DCM (4 L), and the aqueous layer was extracted with more DCM (2 x 2 L). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide 100.1 (1.112 kg, 99% yield) as a semi-solid. The material was used directly in the next step without futher purification. 1H-NMR (400 MHz, CDCl3) δ 7.28 (t, J=7.1 Hz, 4H), 6.89 (d, J=8.6 Hz, 4H), 3.83 (m, 6H), 3.76 (s, 4H). LCMS-ESI (pos.) m/z: 258.4 (M+H)+. |
99% | Stage #1: 4-methoxy-benzaldehyde; 4-methoxy-benzylamine at 20℃; for 1h; Inert atmosphere; Stage #2: With sodium tetrahydridoborate In ethanol at 20 - 42℃; Inert atmosphere; | 361.0 Bis(4-methoxybenzyl)amine, Example 361.01. 4-Methoxybenzylamine (600 g, 4.37 mol) and 4-methoxybenzaldehyde (532 mL, 4.37 mol) were added to a 10 L RBF at ambient temperature. An exotherm was observed and a white precipitate formed. The mixture was stirred for 1 h and then anhydrous EtOH (4.8 L) was added. After an additional 15-3 0 mm at RT, sodium borohydride granules (99 g, 2.62 mol) were added portionwise over 2 h (during the addition of the NaBH4, the internal temperature of the reaction rose to 42 °C), and the mixture was further stirred at RT overnight. The reaction was then quenched slowly with water (600 mL) and then was concentrated in vacuo. The residue was partitioned between water (4 L) and DCM (4 L), and the aqueous layer was extracted with more DCM (2 x 2 L). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to provide 361.01 (1112 g, 99% yield) as a semi-solid. The material was used directly in the next step without futher purification. 1H-NMR (400 MHz, CDC13) ö 7.28 (t, J=7. 1 Hz, 4H), 6.89 (d, J=8.6 Hz, 4H), 3.83 (m, 6H), 3.76 (s, 4H). LCMS-ESI (pos.) m/z: 258.4 (M+H)t |
99% | Stage #1: 4-methoxy-benzaldehyde; 4-methoxy-benzylamine for 1h; Heating; Stage #2: With sodium tetrahydridoborate In ethanol at 20 - 42℃; | 30.0 Bis(4-methoxybenzyl)amine, Example 30.1 4-Methoxybenzylamine (neat, 600 g, 4.37 mol, 1 eq) and 4-methoxybenzaldehyde (532 mL, 4.37 mol, 1 eq) were added to a 10 L round bottom flask at ambient temperature with stirring. The reaction spontaneously warmed and a white precipitate was observed. The mixture was stirred for 1 h. To the above mixture was added anhydrous EtOH (4.8 L) and stirring was continued at RT for 15-30 min. This was followed by the addition of sodium borohydride granules (99 g, 2.62 mol, 0.6 eq) portion wise over ~ 2 h (Note : During the addition of NaBH4, the internal temperature of the reaction rose to 42 °C) and further stirred at RT overnight. The reaction was quenched slowly with water (600 mL). The mixture was concentrated in vacuo at 50°C. The residue was partitioned between water (4 L) and DCM (4 L). The aqueous layer was extracted with more DCM (2 x 2 L). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give bis(4- methoxybenzyl)amine 30.1 (1112 g, 99% yield) as a semi-solid. The material was used directly in the next step without further purification. 1H-NMR (400 MHz, CDCl3) δ 7.28 (t, J = 7.12 Hz, 4H), 6.89 (d, J = 8.60 Hz, 4H), 3.83 (m, 6H), 3.76 (s, 4H) (-NH proton not observed). LCMS-ESI (pos.) m/z: 258.4 (M+H)+. |
99% | Stage #1: 4-methoxy-benzaldehyde; 4-methoxy-benzylamine at 20℃; for 1h; Stage #2: With sodium tetrahydridoborate In ethanol at 20 - 42℃; | 4.11 [0237] Bis(4-methoxybenzyl)amine, Example 4.11 4-Methoxybenzylamine (0557) (600 g, 4.37 mol) and 4-methoxybenzaldehyde (532 mL, 4.37 mol) were added to a 10 L round bottomed flask at ambient temperature with stirring. The reaction spontaneously warmed and a white precipitate was observed. The mixture was stirred for 1 h. To the above mixture was added anhydrous EtOH (4.8 L) and stirring was continued at RT for 15-30 mins. This was followed by the addition of sodium borohydride granules (99 g, 2.62 mol, 0.6 eq) portionwise over ~ 2 h (Note : During the addition of NaBH4, the internal temperature of the reaction rose to 42 °C) and further stirred at RT overnight. The reaction was quenched slowly with water (600 mL). The mixture was concentrated in vacuo at 50 °C. The residue was partitioned between water (4 L) and DCM (4 L). The aqueous layer was extracted with more DCM (2 x 2 L). The combined organic layers were dried over Na2S04, filtered, and concentrated in vacuo to give Example 4.11 (1112 g, 99% yield) as a semi-solid. The material was used directly in the next step without further purification. -NMR (400 MHz, CDC13) δ 7.28 (t, J = 7.12 Hz, 4H), 6.89 (d, J = 8.60 Hz, 4H), 3.83 (m, 6H), 3.76 (s, 4H) (-NH proton not observed). LCMS-ESI (pos.) m +. |
94% | Stage #1: 4-methoxy-benzaldehyde; 4-methoxy-benzylamine In methanol for 3h; Reflux; Stage #2: With sodium tetrahydridoborate In methanol at 0 - 20℃; for 10h; | 4.1.1. 1-(Benzo[d][1,3]dioxol-6-yl)-N-(5-(4-(methylthio)benzoyl)-4-phenylthiazol-2-yl)cyclo propanecarboxamide (7a) A mixture of (4-methoxyphenyl) methanamine (535 mL,4 mmol) and 4-(methoxy)benzaldehyde (595 mL, 4.8 mmol) inmethanol (2 mL) was heated to reflux for 3 h, then cooled toT 0 C, NaBH4 (228 mg, 6 mmol) was added portion wise to thereaction and the resulting mixturewas stirred at room temperaturefor about 10 h. Solvent was removed under reduced pressure andthe residuewas partitioned between ethyl acetate (EtOAc) and H2O.The combined organic layers were washed with H2O, and thendried over anhydrous Na2SO4. After filtration, solvent was removedin vacuum to afford bis [4-methoxyphenyl]methylamine (962 mg,94%) as a colorless oil which was used in the next step withoutfurther purification. ESI-MS: m/z 258.0 [MH]. |
93% | Stage #1: 4-methoxy-benzaldehyde; 4-methoxy-benzylamine In methanol for 3h; Reflux; Stage #2: With sodium tetrahydridoborate In methanol at 0 - 20℃; | 5.1.2 N-(5-(2-Chlorobenzoyl)-4-(3-chlorophenyl)thiazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide (8h) To a solution of 1-(2-chlorophenyl)ethanone (10b, 3g, 19.4mmol) in Et2O (30mL) cooled at 0°C was added bromine (1.0mL, 19.4mmol) dropwise and the resulting mixture was stirred at room temperature for 1.5h. Solvent was removed in vacuo to afford 2-bromo-1-(2-chlorophenyl)ethanone (11b, 4.6g, 82%) as a brown oil which was used directly in the next step without further purification: MS(ES+) m/z 232.9, 234.9 (M+H)+. (0018) A mixture of 1-[4-(methyloxy)phenyl]methanamine (2.6g, 19.0mmol) and 4-(methyloxy)benzaldehyde (3.10g, 22.7mmol) in methanol (50mL) was heated to reflux for 3h, then cooled to 0°C, NaBH4 (1.08g, 28.4mmol) was added to the reaction portionwise and the resulting mixture was stirred at room temperature overnight. Solvent was removed under reduced pressure and the residue was partitioned between EtOAc and water. The combined organic layers were washed with satd NaHCO3 solution and brine, then dried over anhydrous Na2SO4. After filtration, solvent was removed in vacuo to afford bis((4-(methyloxy)phenyl)methyl)amine (5.3g, 93%) as a colorless oil which was used in the next step without further purification: MS(ES+) m/z 258.0 (M+H)+. (0019) To a solution of 3-chlorobenzoyl chloride (12c, 2.0g, 11.4mmol) in acetone (30mL) cooled at 0°C was added ammonium thiocyanate (1.7g, 22.9mmol) and the resulting mixture was stirred at this temperature for 1h. Then -(methyloxy)phenyl]methyl}amine (3.5g, 13.7mmol) was added at this temperature and stirred for an additional 30min. The mixture was concentrated under reduced pressure, and then purified directly by chromatography (EtOAc:petroleum ether (PE)=0-15%) to afford N-(bis(4-methoxybenzyl)carbamothioyl)-3 chlorobenzamide (13c, 5.3g, 10.8mmol, 94%) as a yellow sticky oil: MS(ES+) m/z 455.0 (M+H)+. (0020) A solution of 2-bromo-1-(2-chlorophenyl)ethanone (11b, 155mg, 0.7mmol) and N-(bis(4-methoxybenzyl)carbamothioyl)-3-chlorobenzamide (13c, 250mg, 0.5mmol) in N,N-dimethylformamide (DMF) (3mL) was stirred at 85°C under nitrogen for 30min. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine and dried over anhydrous Na2SO4. After filtration, solvent was removed in vacuo and the residue was stirred in TFA (4mL, 51.9mmol) at 80°C overnight. Most of TFA was removed under reduced pressure. The residue was neutralized with satd NaHCO3, and then extracted with EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the solution was concentrated and further purified by chromatography (EtOAc:PE=0-50%) to afford [ 2-amino-4-(3-chlorophenyl)-1, 3-thiazol-5-yl](2-chlorophenyl)methanone (15h) (198mg, 88%) as a yellow solid: MS(ES+) m/z 348.9, 351.0 (M+H)+ A mixture of 15h (116mg, 0.332mmol), (4-(ethylsulfonyl)phenyl)acetic acid 16 (83mg, 0.365mmol), EDC (89mg, 0.465mmol) and HOBt (62.8mg, 0.465mmol) in dichloromethane (DCM) (5mL) was stirred at room temperature overnight. Solvent was removed under reduced pressure. The residue was purified by MDAP to afford 8h (56mg, 29% yield) as a white solid |
84.6% | Stage #1: 4-methoxy-benzaldehyde; 4-methoxy-benzylamine In toluene at 130℃; for 6h; Dean-Stark; Stage #2: With methanol; sodium tetrahydridoborate at 0 - 20℃; for 3h; | A solution of 4-methoxybenzaldehyde (Spectrochem; 100 g, 734.5 mmol) and 4-methoxybenzyl amine (G.L.R.;100 g, 734.5 mmol) in toluene (0.8 L) was refluxed at 130 °C using a Dean-Stark apparatus for 6 h. The reaction was monitored by TLC and upon completion, excess solvent was removed under reduced pressure and the residue was dissolved in methanol (0.8 L). The resulting solution was cooled to 0°C and sodium borohydride (36.12 g, 954.8 mmol) was added in portions. After complete addition, the reaction mixture was stirred for 3 h at ambient temperature. Methanol was removed, and the residue was diluted with H20 (1.0 L) and EtOAc (2.0 L). The layers were separated and the aqueous layer was extracted with EtOAc (2 x 1.0 L). The combined organic layer was washed with H20, brine, and dried over Na2S04. Solvent was removed under reduced pressure and the crude material obtained was purified by column chromatography over Si02 gel (100-200 mesh size) eluting with a gradient of 100% Hex to 25% EtOAc in Hex affording the title compound (160 g, 84.6%) as a colorless but opaque liquid. |
84.6% | Stage #1: 4-methoxy-benzaldehyde; 4-methoxy-benzylamine In toluene at 130℃; for 6h; Dean-Stark; Stage #2: With methanol; sodium tetrahydridoborate at 0 - 20℃; for 3h; | Intermediate EE11 N,N-BIS(-METHOXYBENZYL)AMINE A solution of 4-methoxyhenzaldehyde (100 g, 734.5 mmol. Spectrochem) and 4-methoxybenzyl amine (100 g, 734.5 mmoi, G.L.R.) in toluene (0.8 L) was refluxed at 130 C using a Dean Stark apparatus for 6 h. The reaction wasmonitored by TLC and uponn completion, excess solvent was removed under reduced pressure and the residue was dissolved in methanol (0.8 L), The resulting solution was cooled to 0 °C and sodium borohydride (36.12 g, 954.8 mrnoi) was added in portions After complete addition the reaction mixture was stirred for 3 h at ambient temperature. Methanol was then removed, and the residue was dilutedwith water (i.OL) and ethyl acetate (2.0 L). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 1.0 L). The combined organic layer was washed with water, brine and dried over sodium sulfate. Solvent was removed under reduced pressure and the crude material thus obtained was purified by column chromatography over silica gel (100-200 mesh size) eluting with a gradient of 100% hexanes to 25% ethyl acetate in hexanes affording the title compound (160 g, 846%) as colorless but opaque liquid. Ri’: 0.5 in 30% Ethyl acetate in hexane. |
84.6% | Stage #1: 4-methoxy-benzaldehyde; 4-methoxy-benzylamine In toluene at 130℃; for 6h; Dean-Stark; Stage #2: With methanol; sodium tetrahydridoborate at 0 - 20℃; for 3h; | N,N-BIS(4-METHOXYBENZYL)AMINE A solution of 4-methoxybenzaldehyde (Spectrochem; 100 g, 734.5 mmol) and 4-methoxybenzyl amine (G.L.R.;100 g, 734.5 mmol) in toluene (0.8 L) was refluxed at 130 C using a Dean-Stark apparatus for 6 h. The reaction wasmonitored by TLC and upon completion, excess solvent was removed under reduced pressure and the residue was dissolved in methanol (0.8 L). The resulting solution was cooled to 0°C and sodium borohydnde (36.12 g, 954.8 mmol) was added in portions. After complete addition, the reaction mixture was stirred for 3 h at ambient temperature. Methanol was removed, and the residue was dilutedwith H20 (1.0 L) and EtOAc (2.0 L). The layers were separated and the aqueous layer was extracted with EtOAc (2 x 1.0 L). The combined organic layer was washed with H20, brine, and dried over Na2504. Solvent was removed under reduced pressure and the crude material obtained was purified by column chromatography over 5i02 gel (100-200 mesh size) eluting with a gradient of100% hexane to 25% EtOAc in hexane affording the title compound (160 g,84.6%) as a colorless but opaque liquid. |
60% | Stage #1: 4-methoxy-benzaldehyde; 4-methoxy-benzylamine In methanol for 4h; Stage #2: With 5% Pd/C; hydrogen In methanol | |
56% | With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; Inert atmosphere; | |
With sodium tetrahydridoborate In ethanol at 0 - 20℃; | 9.v; 10.1 To a solution of p-anisaldehyde (146 mmol) in ethanol (500 mL) was added 4- methoxybenzylamine (146 mmol). The mixture was then cooled in an ice water bath. NaBH4 (294 mmol) was added in portions and the reaction mixture was allowed to warm to rt, gradually. Ice water slush (100 mL) was added and the mixture was concentrated to half its original volume. The mixture was then extracted with ether and the organics were combined, washed with brine, dried, and concentrated. Hexane (~50 mL) was added and the precipitate was filtered to give 35 g of bis-(4-methoxy-benzyl)-amine, 19, as white solid. | |
Stage #1: 4-methoxy-benzaldehyde; 4-methoxy-benzylamine In ethanol for 3h; Heating / reflux; Stage #2: With sodium tetrahydridoborate In methanol at 0 - 40℃; for 3.16667h; Heating / reflux; | 2.F.3 3. Bis (4-methoxybenzyl) amine Reflux a solution of 4-methoxybenzylamine (25 g, 182 rnmol) and 4-methoxybenzaldehyde(22 mL, 182 rnmol) in 200 mL EtOH for 3 hours. Evaporate the solvent under reduced pressure to give the intermediate imine as a pale brown oil. Immediately, dissolve the intermediate imine in dry MeOH, cool to 00C, and add NaBH4 (6.9 g, 182 mmol) in portions over 30 minutes. Remove the ice bath, stir the reaction mixture at 4O0C for 40 minutes and reflux for 2 hours. After stirring at room temperature overnight, remove the solvent under vacuum, dissolve the residual oil in CH2Cl2 (200 mL) and wash with 5% NaHCO3 (10 mL). Dry the CH2Cl2 layer (Na2SO4), filter, and concentrate to afford the title product as a yellow oil, which solidifies while standing in the refrigerator. 1H NMR (400 MHz, CDCl3) δ 7.25 (m, 4H), 6.87 (m, 4H), 3.8 (s, 6H), 3.75 (d, 4H, J=8.8 Hz), 1.54 (bs, IH). | |
Stage #1: 4-methoxy-benzaldehyde; 4-methoxy-benzylamine In methanol for 3h; Reflux; Stage #2: With sodium tetrahydridoborate In methanol at 0 - 20℃; | 1.1b.1 A mixture of l-[4-(methyloxy)phenyl]methanamine (40 g) and 4- (methyloxy)benzaldehyde (40.5 g) in methanol (220 mL) was heated to reflux for 3 hours. After cooling to 0 °C, NaBH4 (14.34 g) was added portionwise within 30 min and the resulting mixture was stirred at room temperature overnight. Solvent was removed under reduced pressure and the residue was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc for 3 times. The combined organic layers were washed with water and brine, then dried over anhydrous Na2SC>4. After filtration, solvent was removed in vacuo to afford bis [4-(methyloxy)phenyl]methyl} amine (75.9 g) as a colorless oil. MS(ES+) m/z 258 (MH+). | |
8.9 g | Stage #1: 4-methoxy-benzaldehyde; 4-methoxy-benzylamine In ethanol for 2h; Inert atmosphere; Reflux; Stage #2: With sodium tetrahydridoborate In ethanol at 0℃; for 2h; Reflux; | |
Stage #1: 4-methoxy-benzaldehyde; 4-methoxy-benzylamine In toluene for 1h; Reflux; Stage #2: With methanol; sodium tetrahydridoborate at 5℃; for 2.75h; Reflux; | 1.1 1.1. Synthesis of bis-(4-methoxy-benzyl)-amine (Int. 1) 1.1. Synthesis of bis-(4-methoxy-benzyl)-amine (Int. 1) p-Anisaldehyde (411 mmol), 4-methoxybenzylamine (411 mmol) and toluene (500 mL) were combined in a round bottomed flask fitted with a condenser and a Dean-Stark trap. The reaction was refluxed for 1 h during which water was removed from the reaction mixture. The reaction was cooled and concentrated. The residue was dissolved in MeOH (120 mL). The mixture was cooled to 5° C. and NaBH4 (205 mmol) was added in portions over 45 min. The reaction was slowly heated to reflux. After 2 h at reflux, the reaction was cooled to room temperature and concentrated. The residue was dissolved in EtOAc. The organic layer was washed (3*H2O and brine), dried (Na2SO4) and concentrated to yield the desired product. | |
Stage #1: 4-methoxy-benzaldehyde; 4-methoxy-benzylamine In toluene for 1h; Dean-Stark; Reflux; Stage #2: With methanol; sodium tetrahydridoborate at 5℃; for 2.75h; Reflux; | 1.1 1.1. Synthesis of bis-(4-methoxy-benzyl) -amine (mt. 1) 1.1. Synthesis of bis-(4-methoxy-benzyl) -amine (mt. 1) j00237j p-Anisaldehyde (411 mmol), 4-methoxybenzylamine (411 mmol) and toluene (500 mL) were combined in a round bottomed flask fitted with a condenser and a Dean-Stark trap. The reaction was refluxed for 1 h during which water was removed from the reaction mixture. The reaction was cooled and concentrated. The residue was dissolved in MeOH (120 mL). The mixture was cooled to 5°C and NaBH4 (205 mmol) was added in portions over 45 mm. The reaction was slowly heated to reflux. After 2 h at reflux, the reaction was cooled to room temperature and concentrated. The residue was dissolved in EtOAc. The organic layer was washed (3 x H20 and brine), dried (Na2504) and concentrated to yield the desired product. | |
Stage #1: 4-methoxy-benzaldehyde; 4-methoxy-benzylamine With sodium tetrahydridoborate In toluene for 1h; Dean-Stark; Reflux; Stage #2: With methanol; sodium tetrahydridoborate at 5℃; for 2.75h; Reflux; | 1.1 1.1. 1.1. Synthesis of bis-(4-methoxy-benzyl)-amine (Int. 1) p-Anisaldehyde (411 mmol), 4-methoxybenzylamine (411 mmol) and toluene (500 mL) were combined in a round bottomed flask fitted with a condenser and a Dean-Stark trap. The reaction was refluxed for 1 h during which water was removed from the reaction mixture. The reaction was cooled and concentrated. The residue was dissolved in MeOH (120 mL). The mixture was cooled to 5° C. and NaBH4 (205 mmol) was added in portions over 45 min. The reaction was slowly heated to reflux. After 2 h at reflux, the reaction was cooled to room temperature and concentrated. The residue was dissolved in EtOAc. The organic layer was washed (3*H2O and brine), dried (Na2SO4) and concentrated to yield the desired product. | |
With sodium tris(acetoxy)borohydride In acetic acid; 1,2-dichloro-ethane at 20 - 25℃; for 12h; | 6.1.6. General procedure for the preparation of the compounds 14a-i General procedure: To a solution of 12 (1.1 to 1.2 mol equivalent) and 13 (1 mol equivalent) in 1,2-dichloroethane (DCE) (25 fold), Sodium triacetoxyborohydride (3 mol equivalent) was added portion wise and stirred at 20-25 °C for 12 h. The reaction mixture was poured into ice cold water and extracted with DCM. The combined organic layer was washed with (2 X 20 fold) 10 % sodium metabisulfite to remove excess aldehyde. The combined organic layer was successively washed with water and brine, dried over Na2SO4, filtered and concentrated under vacuum to furnish the product. | |
Stage #1: 4-methoxy-benzaldehyde; 4-methoxy-benzylamine With sodium tetrahydridoborate at 20℃; for 1h; Stage #2: With sodium tetrahydridoborate In ethanol at 42℃; | 12.0.12.1 Example 12.0: Preparation of N,N-bis(4-methoxybenzyl)ethanesulfonamide Bis(4-methoxybenzyl)amine, Example 12.1. 4-Methoxybenzylamine (neat, 600 g, 4.37 mol, 1 eq) and 4-methoxybenzaldehyde (532 mL, 4.37 mol, 1 eq) were added to a 10 L round bottomed flask at ambient temperature with stirring. The reaction spontaneously warmed and a white precipitate was observed. The mixture was stirred for 1 h. To the above mixture was added anhydrous EtOH (4.8 L) and stirring was continued at RT for 15-30 min. This was followed by the addition of sodium borohydride granules (99 g, 2.62 mol, 0.6 eq) portionwise over ˜2 h. During the addition of NaBH4, the internal temperature of the reaction rose up to 42° C. The resulting mixture was then stirred at ambient temperature overnight. Next, the reaction was quenched slowly with water (600 mL). The mixture was concentrated on a rotary evaporator at 50° C. The residue was partitioned between water (4 L) and DCM (4 L). The aqueous layer was extracted with more DCM (2*2 L). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give bis(4-methoxybenzyl)amine 12.1 (1112 g, 99% yield) as a semi-solid. The material was used directly in the next step without further purification. 1H-NMR (400 MHz, CDCl3) δ 7.28 (t, J=7.12 Hz, 4H), 6.89 (d, J=8.60 Hz, 4H), 3.83 (app s, 6H), 3.76 (s, 4H) (-NH proton not observed). LCMS (ESI pos ion) m/z: =258.4 (M+H)+. | |
Stage #1: 4-methoxy-benzaldehyde; 4-methoxy-benzylamine at 20℃; for 1h; Large scale; Stage #2: With sodium tetrahydridoborate; ethanol at 20 - 42℃; Large scale; | 84.1 Bis(4-methoxybenzyl)amine, Example 84.1. 4-Methoxybenzylamine (0743) (neat, 600 g, 4.37 mol, 1 eq) and 4-methoxybenzaldehyde (532 mL, 4.37 mol, 1 eq) were added to a 10 L round bottomed flask at ambient temperature with stirring. The reaction spontaneously warmed and a white precipitate was observed. The mixture was stirred for 1 h. To the above mixture was added anhydrous EtOH (4.8 L) and stirring was continued at RT for 15-30 min. This was followed by the addition of sodium borohydride granules (99 g, 2.62 mol, 0.6 eq) portionwise over ~ 2 h (Note : During the addition of NaBH4, the internal temperature of the reaction rose up to 42 °C). The resulting mixture was then stirred at ambient temperature overnight. The reaction was quenched slowly with water (600 mL). The mixture was then concentrated on a rotary evaporator at 50°C. The residue was partitioned between water (4 L) and DCM (4 L). The aqueous layer was extracted with more DCM (2 x 2 L). The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo to give bis(4-methoxybenzyl)amine 84.1 (1112 g, 99% yield) as a semi-solid. The material was used directly in the next step without further purification. -NMR (400 MHz, CDC13) δ 7.28 (t, J = 7.12 Hz, 4H), 6.89 (d, J = 8.60 Hz, 4H), 3.83 (m, 6H), 3.76 (s, 4H) (-NH proton not observed). LCMS (ESI pos.) m/z: 258.4 (M+H)+. | |
Stage #1: 4-methoxy-benzaldehyde; 4-methoxy-benzylamine With methanol at 20℃; Stage #2: With sodium tetrahydridoborate at 0 - 20℃; for 6h; | ||
Stage #1: 4-methoxy-benzaldehyde; 4-methoxy-benzylamine In ethanol at 20℃; for 4h; Stage #2: With sodium tetrahydridoborate; Orthoboric acid In ethanol at 0℃; | ||
Stage #1: 4-methoxy-benzaldehyde; 4-methoxy-benzylamine In methanol at 20℃; for 12h; Stage #2: With sodium tetrahydridoborate In methanol at 0 - 20℃; for 0.5h; | Preparation of Starting materials General procedure: A 50 ml round bottom flask was charged with a magnetic bead, aromatic aldehydes (2 mmol, 1.0 equiv), aliphatic amines or benzylamines (3 mmol, 1.5 equiv) were stirred in CH3OH (10 mL) at room temperature for 12 h then NaBH4 (4.2 mmol, 159 mg, 2.1 equiv) was added to the mixture in portion at 0 . After that reaction was warmed to room temperature and stirring for additional 30 min. Then the reaction mixture quenched with water and the solvent was removed under reduced pressure to obtain the crude product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With dmap; triethylamine In dichloromethane at 20℃; | 64.1 Step 1: 4-bromo-2-fluoro-N,N-bis[(4-methoxyphenyl)methyl]benzenesulfonamide A mixture of 4-bromo-2-fluorobenzenesulfonyl chloride (5.0 g, 18.28 mmol), bis-(4-methoxybenzyl)amine (4.7 g, 18.28 mmol), triethylamine (20 mL), and 4-dimethylaminopyridine (“DMAP”) (236.0 mg, 1.83 mmol) in DCM (100 mL) was stirred at r.t. for overnight. LC-MS showed that the starting material was consumed. The reaction was added HCl (1N, 100 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the desired product 4-bromo-2-fluoro-N,N-bis[(4-methoxyphenyl)methyl]benzenesulfonamide (8.55 g, 96% yield). TLC: Rf=0.72 (ethyl acetate/heptanes 1:3). |
With triethylamine In dichloromethane at 0 - 20℃; | 9.w; 10.2 To a solution of 19 (9.41 g), 10.2 mL of triethylamine and 100 mL dichloromethane was added. 1Og of 2-fluoro-4-bromobezenesulfonyl chloride was then added in portions at 0 0C with stirring. The reaction mixture was warmed to rt slowly and stirred overnight.Dichloromethane (100 mL) was added and the mixture was washed with IN HCl solution, saturated NaHCO3, brine and dried. After removal of the solvent, the solid was mixed with hexane and filtered to give pure 4-bromo-2-fluoro-N,N-bis-(4-methoxy-benzyl)- benzenesulfonamide, 20. The mother solution was concentrated and purified to give more product. 10.3 Results[0209] Analytical data for structure 20 is provided below.10.3a 4-Bromo-2-fluoro-N,N-bis-(4-methoxy-benzyl)-benzenesulfonamide [0210] 1U NMR (CDCl3): ? 7.74 (IH, t, J = 7.6 Hz), 7.36 (2H, dt, J = 8.4, 1.6 Hz), 6.98(4H, d, J = 8.4 Hz), 6.76 (4H, d, J = 8.4 Hz), 4.33 (4H, s), 3.78 (6H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-methyl-pyrrolidin-2-one; triethylamine; at 120℃; for 14h; | 4. N,N-Bis-(4-methoxyben7yl)-(6-chloro-5-trifluoromethylpyridine-2-yl)omeganine Add bis(4-methoxybenzyl)amine (35.7 g, 138.9 mmol) in 20 mL of N-methylpyrrolidone to a solution of <strong>[55304-75-1]2,6-dichloro-3-trifluoromethylpyridine</strong> (20 g, 92.6 mmol) and triethylamine (19.4 mL, 138.9 mmol) in 100 mL of N-methylpyrrolidone. Raise the temperature to 1200C, and stir the reaction for 14 hours. Quench the reaction mixture by the addition of water (80 mL), followed by extraction with EtOAc (3 x 70 mL). Wash the combined organic extracts with water (2 x 70 mL) and brine (70 mL), and dry over anhydrous Na2SO4. Filter the dried extract and concentrate under vacuum to afford the crude product, which is purified by column chromatography to give a yellow solid. 1H NMR (400 MHz, CDCl3) delta 7.58 (d, IH, J=8.4 Hz), 7.15 (m, 4H), 6.85 (m, 4H), 6.31 (d, IH, J=8.8 Hz), 4.70 (s, 4H), 3.80 (s, 6H). Mass spec. (436.99, M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With hydrogenchloride; sodium hydroxide In tetrahydrofuran | S.46 Synthetic Example 46 Synthetic Example 46 N-(4-methoxybenzyl)-4-methoxybenzamide (30.51 g) obtained in Synthetic Example 42 was suspended in tetrahydrofuran (200 ml) and cooled to 0°C. To the suspension was added a boran/tetrahydrofuran solution (330 ml). The mixture was stirred for 1 hour at room temperature and refluxed for 2 hours, then allowed to cool to room temperature, whereupon 6 N hydrochloric acid (50.0 ml) was added and the mixture was refluxed for 1 hour. After cooling to the room temperature, the reaction mixture adjusted to about pH 10 with the addition of 6 N aqueous solution of sodium hydroxide. After concentrating under reduced pressure, the concentrate was extracted with ether. The organic layer was washed with water, dried over anhydrous K2CO3, and concentrated to dryness under reduced pressure. The concentrate was purified by passing twice through a chromatographic column (silica gel, 230-400 mesh; 800 g; φ 100 mm, length 170 mm; pressure: 0.5 kg/cm2; eluent: chloroform:methanol = 20:1) to obtain a colorless oil of N,N-bis(4-methoxybenzyl)amine (25.36 g, 97%) from an eluted fraction of 1,000-2,300 ml. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: 2,6-dicholoro-3-nitropyridine; N,N-bis(p-methoxybenzyl)amine With triethylamine In chloroform at 0 - 20℃; Stage #2: In dichloromethane at 20℃; for 48h; | 11.a 6-Chloro-/V,λ/-bis(4-methoxybenzyl)-3-nitropyridin-2-amine A solution of N,N-bis(4-methoxybenzyl)amine (7.79 g, 30.3 mmol) and triethylamine (2.89 g, 28.6 mmol) in chloroform (20 mL) was added dropwise over 20 minutes to a cold (ice- bath), stirred solution of 2,6-dichloro-3-nitropyridine (5.0 g, 26.0 mmol) in chloroform (25 mL). The mixture was warmed to room temperature and stirred overnight. The solvent was evaporated and the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4) and evaporated to give an oil. The mixture was taken up in dichloromethane (120 mL) and polymer-supported isocyanate resin (1.6 mmol/g, 8.0 g) was added and the mixture was shaken at room temperature for EPO 2 days. The mixture was filtered and the filtrate was evaporated to give the title compound (10.7 g, 100%) as a bright yellow oil. δ 1H-NMR (CDCI3): 3.78 (s, 6H), 4.51 (s, 4H), 6.68 (d, 2H), 6.80 (d, 4H), 8.23 (d,4H), 8.02 (d, 1 H). ESI/MS m/e: 414 ([M+H]+, C21H20CIN3O4) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With triethylamine In dichloromethane at 0 - 20℃; | 23.C Part CA solution of 4-amino-2,6-dichloro-3-nitropyridine (1.08 g, 5.19 mmol) from Part B and triethylamine (1.09 mL, 7.79 mmol) in dichloromethane (20 mL) was cooled in an ice bath, and bis(4-methoxybenzyl)amine (1.34 g, 5.19 mmol) was added in one portion. The resultant solution was allowed to warm to room temperature and stirred overnight under a nitrogen atmosphere. The solvents were removed by rotary evaporation, and the residue was purified via flash chromatography (silica gel, dichloromethane eluent) to provide iV25N2-bis(4-methoxyben2yl)-6-chloro-3-nitropyridine-2,4-diamine (1.82 g, 82% yield) as a viscous yellow oil that foamed under vacuum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With triethylamine In toluene for 58h; Heating / reflux; | 19.A Part ATo a solution of 2-chloro-5,6-dimethyl-3-nitro-N-prop-2-ynylpyridin-4-amine (10.0 g, 41.7 mmol), see International Publication No. WO2006/065280 (Moser et al.) Example 18, in toluene (200 mL) was added di-pαrα-methoxy benzylamine (16.1 g, 62.6 mmol) and triethylamine (8.7 mL, 62.6 mmol). The resultant solution was heated to reflux for 58 hours. Upon cooling, solvents were removed by rotary evaporation, and the residue was partitioned between CH2Cl2 and saturated aqueous NaHCO3. The aqueous phase was extracted with CH2Cl2 (3 x 100 mL), and the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to afford a waxy red solid. Purification via suction filter chromatography on silica gel (3/1 hexane / EtOAc eluent) afforded 18.5 g (96% yield) of N2,N2-bis(4-methoxybenzyl)-5,6-dimethyl-3-nitro-iV4-ρrop- 2-ynylpyridine-2,4-diamine as a bright orange solid that was quite pure by 1H NMR analysis |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 120℃; | 3.D To a solution of the 4-chloro-2-isobutylimidazo[l,2-a]quinoxaline (130 mg, 0.50 mmol) in 2 mL of l-methylpyrrolidin-2-one was added λf,λ/-diisopropylethylamine (129 mg, 1.0 mmol) and followed by bis(4-methoxybenzyl)amine (154 mg, 0.60 mmol). The reaction mixture was stirred at 120 0C overnight. And then 10 mL of water was added. The resulting mixture was extracted with ethyl ether (50 mL x 3). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography eluted with ethyl acetate and hexanes to give the titled compound (195 mg, 81%). MS: MH+ = 481. 1H NMR (300 MHz, CDCl3): δ 7.72 (s, IH), 7.65 (m, 2H), 7.21-7.39 (m, 6H), 6.84 (d, 4H), 5.34 (brs, 4H), 3.79 (s, 6H), 2.63 (d, 2H), 2.06 (m, IH), 0.94 (d, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In toluene at 115℃; for 5h; | 74.c Ethyl 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (Example 67) (3.58 g, 15.4 mmol) and bis(4-methoxybenzyl)amine (4.54 g, 17.6 mmol) were suspended in toluene (36 mL) and heated at 115° C. for 5 hours, then cooled to room temperature. Diethyl ether was added (50 mL), and the resultant precipitate was collected by filtration to give crude 4-hydroxy-N,N-bis(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-3-carboxamide (6.45 g, 95%) which was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With 5,10,15,20-tetrakisphenylporphyrin; oxygen In ethyl acetate at 20℃; for 14h; Molecular sieve; Irradiation; | |
97% | With porphyrin based sp2 carbon conjugated covalent organic framework; air In chlorobenzene; acetonitrile at 25℃; for 0.5h; Irradiation; | |
92% | With oxygen; [5,6]fullerene-C70 In chloroform; toluene for 6.5h; Molecular sieve; Irradiation; |
87.5% | With oxygen In acetonitrile for 10h; Irradiation; | |
86% | With oxygen; C26H29ClIrN In dimethyl sulfoxide at 80℃; for 10h; | |
85% | With oxygen; C27H29ClIrNO In dimethyl sulfoxide at 60℃; for 8h; Schlenk technique; | |
72% | With 4-tert-Butylcatechol; oxygen; potassium carbonate In chloroform; water at 35℃; for 16h; | |
81 %Spectr. | With 1,10-phenanthroline-5,6-dione; oxygen; pyridinium p-toluenesulfonate; zinc(II) iodide In acetonitrile at 20℃; for 24h; | |
Multi-step reaction with 2 steps 1: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; acetic acid; sodium periodate / water; acetonitrile / 20 h 2: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium chlorite; sodium hypochlorite / water; acetonitrile / 96 h | ||
With C80H52N10O4*4Co(3+)*8C4H7N2O2(1-)*4Cl(1-) In tetrahydrofuran at 20℃; for 12h; Inert atmosphere; Irradiation; | ||
With tetrahydroxymethyl tetra(1,4-dithiin)porphyrazine cobalt; oxygen In acetonitrile for 6h; UV-irradiation; | 4 Example 1: General procedure: Activity Determination of Benzylamine by Photocatalytic Oxidation of Tetramethylol Tetrakis(1,4-Dithiane) Tetraaza-Cobalt Porphyrin. The steps are as follows:Add 3mg CoPz(hmdtn)4 to the quartz jacketed photoreactorAnd 25mL of acetonitrile (abbreviated as CH3CN),CoPz(hmdtn)4 was completely dissolved in acetonitrile under stirring.1 mmol of benzylamine was added to the system and stirring was continued for 2 h without light.Then at 1 atm oxygen and λ ≥ 420 nm visible light(Use a xenon lamp as the light source, and filter the light with a wavelength less than 420 nm with a 420 nm filter.The following examples were reacted for 3 hours under the conditions of illumination.The light intensity of visible light is 0.747 W·cm-2.Qualitative analysis of the reaction product by GC-MS,And quantitatively analyzing the reaction product by GC,This group is an experiment under visible light conditions.Recorded as Entry 1; cancel visible light illumination of λ ≥ 420 nm,For the experiment under no light conditions, this group is recorded as Entry 2. | |
76 %Spectr. | With Hf6O4(OH)4(12+)*3C60H38O8(4-); oxygen In acetonitrile at 20℃; Irradiation; | |
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical In acetonitrile at 20℃; for 0.35h; | ||
With oxygen In acetonitrile at 25℃; for 16h; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With triethylamine In dichloromethane at -15℃; for 2.16667h; | 3.2; 4.2 Step 2: 4-(Bromomethyl)-N /V-bis(4-methoxybenzyl)benzenesulfonamide To a 250 mL round-bottom flask containing bis(4-methoxybenzyl)amine (3.9 g, 15.2 mmol) in DCM (dry, 100 mL) at -15 °C (cooled by salt-ice bath) was added 4- (bromomethyl)benzene-l-sulfonyl chloride (4.1 g, 15.2 mmol) in portions over 10 mins. TEA (1.7 g, 16.7 mmol) was added dropwise. The resulting solution was stirred at -15 °C for 2 h. To the reaction solution was added H20 (100 mL). The DCM phase was separated and the aqueous phase was extracted with DCM (100 mL). The combined organic layers were washed with 5% citric acid (200 mL><2), H20 (200 mL), and brine (200 mL) in sequence, then dried over Na2S04, filtered and evaporated to give the crude which was purified by chromatography (silica gel, PE to DCM) to afford 4-(bromomethyl)-N,N-bis(4- methoxybenzyl)benzenesulfonamide (5.6 g, 75%) as a white solid. ESI-MS (EI+, m/z)A90 [M+H]+ MR (500 MHz, DMSO-^) δ 7.84 (d, J= 8.3 Hz, 2H), 7.66 (d, J= 8.3 Hz, 2H), 6.96 (d, J = 8.5 Hz, 4H), 6.78 (d, J= 8.6 Hz, 4H), 4.80 (s, 2H), 4.20 (s, 4H), 3.70 (s, 6H). |
With triethylamine In dichloromethane at 25℃; for 12h; | 15 4-(3-Formyl-2-methoxy-phenoxymethyl)-N N-bis-(4-methoxy-benzyl)-benzenesulfonamide 4-(3-Formyl-2-methoxy-phenoxymethyl)-N N-bis-(4-methoxy-benzyl)-benzenesulfonamide A solution of 4-(bromomethyl)benzenesulfonyl chloride (5.6 mmol) in 5 mL of CH2Cl2 at 25° C. is treated with Et3 N (8.4 mmol) followed by bis-(4-methoxy-benzyl)-amine (5.8 mmol). The reaction is stirred for 12 hours, diluted with H2O, extracted with CH2Cl2, dried (MgSO4), filtered and concentrated. The resultant crude material is purified by silica flash chromatography (20% EtOAc/hexanes) to yield 4-bromomethyl-N,N-bis-(4-methoxy-benzyl)-benzenesulfonamide: 1H NMR (400 MHz, CDCl3): δ 7.72 (apparent t, J=8.4 Hz, 2H), 7.44 (dd, J1=1.6 Hz, J2=8.4 Hz, 2H), 6.91-6.86 (m, 4H), 6.69 (d, J=8.8 Hz, 4H), 4.5 (s, 2H), 4.19 (s, 4H), 3.71 (s, 3H); LC/MS: (ES+) 490.1 (M+1)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triethylamine In acetonitrile at 20℃; for 0.333333h; | 204.204A 204A: Ethyl 4-(bis(4-methoxybenzyl)amino)-7-bromopyrrolo[ 1 ,2-fj [ 1 ,2,4]triazine-5 - carboxylate[00189] To a mixture of ethyl 7-bromo-4-chloropyrrolo[l,2-fj[l,2,4]triazine-5- carboxylate (2A) (2.07 g, 6.80 mmol) and bis(4-methoxybenzyl)amine (1.924 g, 7.48 mmol) in acetonitrile (30 mL) was added triethylamine (1.421 mL, 10.20 mmol). The reaction mixture was stirred at RT for 20 minutes and then concentrated to dryness. The residue was suspended in dichloromethane and the resulting white solid was collected by filtration. The filtrate was concentrated to dryness and purified by ISCO silica gel flash chromatography (EtOAc/DCM = 0-50%) to give 204A (3.29 g, 92%). HPLC Rt - 4.001 min (Chromolith SpeedROD 4.6 x 50 mm, 10-90% aqueous methanol containing 0.1% TFA, 4 min gradient, monitored at 220 nm), [M+l]+= 525. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With [RhCl2(p-cymene)]2; dimethylamine borane In tetrahydrofuran at 70℃; for 24h; Inert atmosphere; Sealed ampoule; | Representative procedure for metal-catalysed transfer hydrogenation General procedure: To an oven dried, argon purged, ampoule containing [Ru(p-cymene)Cl2]2 (15.3 mg, 0.05 mmol, 2.5 mol%), substrate (1 mmol) and dry thf (to make a total of 3 mL), a solution of dimethylamine borane in thf was added. The ampoule was sealed and heated at 70 °C for 24 hours then cooled to room temperature; Method A - The reaction mixture was diluted with CH2Cl2 (30 mL) and passed through a short pad of silica followed by diethyl ether (100 mL). The solvents were concentrated in vacuo to afford the crude product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In tert-butyl methyl ether at 20℃; Cooling with ice; | 12.12-1 Reference Example 12-1 Z-Ethyl 2- (2-methylhydrazono) -2- (bis (4- methoxybenzyl ) amino) acetateTo a solution of Compound (XVII-1) (17.6 g, 107 mmol) and bis (4-methoxybenzyl) amine (12.3 g, 47.7 mmol) in tert- butyl methyl ether (100 ml) was slowly added DBU (16.8 g, 110 mmol) under ice-cooling. The solution was stirred at room temperature for 2 hours. The reaction solution was washed with water, then saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 18.3 g of Z-ethyl 2- (2-methylhydrazono) -2- (bis ( 4-methoxybenzyl ) amino) acetate (yield: 99 %) as oil.H N R (CDC13) : δ ppm: 1.32 (3H, t, J = 7.2 Hz), 2.87 (3H, d, J = 4.1 Hz), 3.78 (6H, s), 3.94 (4H, s), 4.26 (2H, q, J = 7.2 Hz), 6.81 (4H, d, J = 8.5 Hz), 7.04 (1H, q, J = 4.1 Hz), 7.15 (4H, d, J = 8.5 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: ammonium thiocyanate; m-Chlorobenzoyl chloride In acetone at 0℃; for 1.16667h; Stage #2: N,N-bis(p-methoxybenzyl)amine In acetone at 0℃; for 0.5h; | Step 1. N-(bis(4-methoxybenzyl)carbamothioyl)-3-chlorobenzamide a. 3-chlorobenzoylchloride (0.5 g, 2.9 mmol) was dissolved in acetone (10 mL) and cooled to 0 C in an ice bath. NH4SCN (0.44 g, 5.7 mmol) was added in portions over 10 minutes and the resulting mixture was stirred for 1 hour at 0 C. Bis-(4-methoxybenzyl)amine (0.88 g, 3.4 mmol) was added and the mixture was stirred 30 min at 0 C. The solvent was removed in vacuo and the crude residue was purified by chromatography on silica gel (Hex/EtOAc 100/0 to 60/40) to afford intermediate b (2.8 g, 99%) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ = 8.38 (s, 1 H), 7.70 (s, 1 H), 7.60 (d, 1 H), 7.48 (d, 1 H), 7.32 (t, 1 H), 7.3-7.2 (br s, 2 H), 6.95-6.9 (br s, 2 H), 6.85-6.6 (m, 4 H), 5.05 (s, 2 H), 4.52 (s, 2 H), 3.75 (s, 6H); MS (ESI, M+H) 454.76. |
94% | Stage #1: ammonium thiocyanate; m-Chlorobenzoyl chloride In acetone at 0℃; for 1h; Stage #2: N,N-bis(p-methoxybenzyl)amine In acetone at 0℃; for 0.5h; | 5.1.2 N-(5-(2-Chlorobenzoyl)-4-(3-chlorophenyl)thiazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide (8h) To a solution of 1-(2-chlorophenyl)ethanone (10b, 3g, 19.4mmol) in Et2O (30mL) cooled at 0°C was added bromine (1.0mL, 19.4mmol) dropwise and the resulting mixture was stirred at room temperature for 1.5h. Solvent was removed in vacuo to afford 2-bromo-1-(2-chlorophenyl)ethanone (11b, 4.6g, 82%) as a brown oil which was used directly in the next step without further purification: MS(ES+) m/z 232.9, 234.9 (M+H)+. (0018) A mixture of 1-[4-(methyloxy)phenyl]methanamine (2.6g, 19.0mmol) and 4-(methyloxy)benzaldehyde (3.10g, 22.7mmol) in methanol (50mL) was heated to reflux for 3h, then cooled to 0°C, NaBH4 (1.08g, 28.4mmol) was added to the reaction portionwise and the resulting mixture was stirred at room temperature overnight. Solvent was removed under reduced pressure and the residue was partitioned between EtOAc and water. The combined organic layers were washed with satd NaHCO3 solution and brine, then dried over anhydrous Na2SO4. After filtration, solvent was removed in vacuo to afford bis((4-(methyloxy)phenyl)methyl)amine (5.3g, 93%) as a colorless oil which was used in the next step without further purification: MS(ES+) m/z 258.0 (M+H)+. (0019) To a solution of 3-chlorobenzoyl chloride (12c, 2.0g, 11.4mmol) in acetone (30mL) cooled at 0°C was added ammonium thiocyanate (1.7g, 22.9mmol) and the resulting mixture was stirred at this temperature for 1h. Then -(methyloxy)phenyl]methyl}amine (3.5g, 13.7mmol) was added at this temperature and stirred for an additional 30min. The mixture was concentrated under reduced pressure, and then purified directly by chromatography (EtOAc:petroleum ether (PE)=0-15%) to afford N-(bis(4-methoxybenzyl)carbamothioyl)-3 chlorobenzamide (13c, 5.3g, 10.8mmol, 94%) as a yellow sticky oil: MS(ES+) m/z 455.0 (M+H)+. (0020) A solution of 2-bromo-1-(2-chlorophenyl)ethanone (11b, 155mg, 0.7mmol) and N-(bis(4-methoxybenzyl)carbamothioyl)-3-chlorobenzamide (13c, 250mg, 0.5mmol) in N,N-dimethylformamide (DMF) (3mL) was stirred at 85°C under nitrogen for 30min. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine and dried over anhydrous Na2SO4. After filtration, solvent was removed in vacuo and the residue was stirred in TFA (4mL, 51.9mmol) at 80°C overnight. Most of TFA was removed under reduced pressure. The residue was neutralized with satd NaHCO3, and then extracted with EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the solution was concentrated and further purified by chromatography (EtOAc:PE=0-50%) to afford [ 2-amino-4-(3-chlorophenyl)-1, 3-thiazol-5-yl](2-chlorophenyl)methanone (15h) (198mg, 88%) as a yellow solid: MS(ES+) m/z 348.9, 351.0 (M+H)+ A mixture of 15h (116mg, 0.332mmol), (4-(ethylsulfonyl)phenyl)acetic acid 16 (83mg, 0.365mmol), EDC (89mg, 0.465mmol) and HOBt (62.8mg, 0.465mmol) in dichloromethane (DCM) (5mL) was stirred at room temperature overnight. Solvent was removed under reduced pressure. The residue was purified by MDAP to afford 8h (56mg, 29% yield) as a white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | In N,N-dimethyl-formamide at 60℃; for 6h; Inert atmosphere; | 4.12 6-Bromo-pyrrolo[2,3-b]pyridine-1-carboxylic acid bis-(4-methoxybenzyl)amide (14) A solution of 8 (138mg, 0.38mmol) and bis-(4-methoxybenzyl)amine (13)24 (158mg, 0.61mmol) in anhydrous DMF (1.5mL) was heated at 60°C for 6h. After addition of ethyl acetate, the solution was washed with water and brine, then it was dried over Na2SO4, filtered and evaporated. Purification by flash column chromatography (hexane: ethyl acetate 8:2) afforded 109mg (91%) of the title compound as a sticky solid; 1H NMR (CDCl3) δ 7.78 (1H, d, J=8.2Hz); 7.50 (1H, d, J=3.8Hz); 7.35 (1H, d, J=8.2Hz); 7.32-7.15 (4H, m); 6.95-6.80 (4H, m); 6.58 (1H, d, J=3.8Hz); 4.55 (4H, s); 3.80 (6H, s). Anal. Calcd for C24H22BrN3O3: C, 60.01; H, 4.62; N. 8.75.Found: C, 60.21; H, 4.66; N. 8.55. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 65 %Chromat. 2: 11 %Chromat. | In 1,3,5-trimethyl-benzene at 140℃; for 15h; Inert atmosphere; | |
In 5,5-dimethyl-1,3-cyclohexadiene at 150℃; for 24h; Autoclave; Inert atmosphere; | 2.2. Procedure for self-coupling of amine General procedure: The catalytic self-coupling of benzyl amine was carried outunder 1 atm He at 150 C in a 22 ml glass liner inside an autoclave. Typically, 2 mmol of amine was dissolved in 5 ml p-xylene and 0.150 g catalyst was added. The autoclave with the reaction mixture was purged with He three times and then filled with 1 atm. He before the reaction was carried out. After 24 h, the reaction was stopped and the autoclave was cooled to room temperature. After opening, the residual liquid was subjected to analysis by GC. The products were identified by GC-MS. | |
In 5,5-dimethyl-1,3-cyclohexadiene at 150℃; for 48h; Autoclave; Inert atmosphere; | 2.2. Procedure for self-coupling of amine General procedure: The catalytic self-coupling of benzyl amine was carried outunder 1 atm He at 150 C in a 22 ml glass liner inside an autoclave. Typically, 2 mmol of amine was dissolved in 5 ml p-xylene and 0.150 g catalyst was added. The autoclave with the reaction mixture was purged with He three times and then filled with 1 atm. He before the reaction was carried out. After 24 h, the reaction was stopped and the autoclave was cooled to room temperature. After opening, the residual liquid was subjected to analysis by GC. The products were identified by GC-MS. |
With C24H27ClIrN4(1+)*CF3O3S(1-) In 1,2-dichloro-benzene at 150℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
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91% | In N,N-dimethyl-formamide at 60℃; for 6h; | 17.A 6-bromo-N,N-bis [(4-methoxyphenyl)methyl] pyrrolo [2,3-b] pyridine- 1-carboxamide A solution of (4-nitrophenyl) 6-bromopyrrolo [2,3-b] pyridine- 1 -carboxylate (138 mg,0.38 mmol) and bis-(4-methoxybenzyl)amine (158 mg, 0.61 mmol) was heated to60°C for 6h in dry DMF. The crude reaction product was then extracted by standardwork-up with AcOEt.Purification: Hexane/AcOEt: 4/1 to get the desired adduct as a white sticky solid.Yield: 91%.1H NMR (300 MHz CDC13), 6: 7.78 (1H, d, J = 8.2 Hz); 7.50 (1H, d, J = 3.8 Hz); 7.35(1H, d, J = 8.2 Hz); 7.32-7.15 (4H, m); 6.95-6.80 (4H, m); 6.58 (1H, d, J = 3.8 Hz);4.55 (4H, s); 3.80 (6H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triethylamine In dichloromethane at 5 - 20℃; for 1.5h; | 13.0 Example 13.0: Preparation of N,N-bis(4- methoxybenzyl)methanesulfonamide. [0407j N,N-bis(4-methoxybenzyl)methanesulfonamide, Example 13.0. To a solution of bis(4-methoxybenzyl)amine 12.01 (100 g, 0.389 mol, 1 eq) in DCM (1 L) was added TEA (71 mL, 0.506 mol, 1.3 eq) followed by dropwise addition of methanesulfonyl chloride (36 mL, 0.46 mol, 1.2 eq). (The internal temperature was kept between 5-10 °C during the addition of the methane sulfonyl chloride). Once the addition was complete, the cooling bath was removed. After 1.5 h, TLC showed complete loss of starting material. Water (1 L) was added to the reaction. The layers were separated and the aqueous layer was extracted with DCM (2x 500 mL). The combined organic layers were washed with brine (2x 1 L), dried over Na2SO4, and concentrated in vacuo. The material thus obtained was absorbed onto a plug of silica gel and purified by chromatography (silica gel (60-120 mesh) eluting with a gradient of 10-80% EtOAc in hexanes) to provide 120 g (0.36 mol, 92%) of the title compound Example 13.0 as white solid. ‘H-NMR(400 MHz, CDC13) 7.26 (dd, J= 2.12, 6.60 Hz, 4H), 6.91 (dd, J= 2.12, 6.62 Hz, 4H), 4.28 (s, 4H), 3.83 (s, 6H), 2.75 (s, 3H). GC-MS (ESI p05. ion) mlz: = 335 (M+H). |
92% | With triethylamine In dichloromethane at 5 - 20℃; | 101.0 N,N-Bis(4-methoxybenzyl)methanesulfonamide, Example 101.0 To a stirred solution of 100.1 (100 g, 0.39 mol) in DCM (1 L) was added TEA (71 mL, 0.51 mol), followed by dropwise addition of methanesulfonyl chloride (36 mL, 0.47 mol). The internal temperature was kept between 5-10 °C during the addition of methane sulfonyl chloride. Once the addition was complete, the cooling bath was removed and the mixture was stirred at RT until TLC analysis indicated that the reaction was complete. Thereafter, water (1 L) was added, the layers were separated and the aqueous layer was extracted with DCM (2 x 500 mL). The combined organic layers were washed with brine (2 x 1 L), dried over Na2SO4, and concentrated in vacuo. The residue was purified on a silica gel column, employing a gradient of 10-80% EtOAc in hexanes, to afford 120 g (0.36 mol, 92%) of 101.0 as white solid.1H-NMR (400 MHz, CDCl3) δ 7.26 (dd, J=2.12, 6.60 Hz, 4H) 6.91 (dd, J=2.12, 6.62 Hz, 4H) 4.28 (s, 4H) 3.83 (s, 6H) 2.75 (s, 3H). |
92% | With triethylamine In dichloromethane at 5 - 10℃; Inert atmosphere; | 370.0 N,N-Bis(4-methoxybenzyl)methanesulfonamide, Example 370.0. To a stirred solution of Example 361.01 (100 g, 0.39 mol) in DCM (1 L) was added TEA (71 mL, 0.51 mol), followed by dropwise addition of methanesulfonyl chloride (36 mL, 0.47 mol). The internal temperature was kept between 5-10 °C during the addition of the methane sulfonyl chloride. Once the addition was complete, the cooling bath was removed, and the mixture was stirred at RT until TLC analysis indicated that the reaction was complete. Thereafter, water (1 L) was added, the layers were separated, and the aqueous layer was extracted with DCM (2 x 500 mL). The combined organic layers were washed with brine (2 x 1 L), dried over Na2SO4, and concentrated in vacuo. The residue was purified on a silica gel column employing a gradient of 10-80% EtOAc in hexanes to afford Example 370.0 (120 g, 0.36 mol, 92%) as a white solid. 1H-NMR (400 MHz, CDC13) ö 7.26 (dd,J2.12, 6.60 Hz, 4H) 6.91 (dd,J2.12, 6.62 Hz, 4H) 4.28 (s, 4H) 3.83 (app s, 6H) 2.75 (s, 3H). |
82% | With triethylamine In dichloromethane at -5 - 20℃; for 15h; | 304.01 N,N-Bis(4-methoxybenzyl)methanesulfonamide, Example 304.01 To a 1 L RBF was added Example 406.01 (48.9 g, 190 mmol) and TEA (anhydrous (31.7 mL, 228 mmol)) in DCM (317 mL). The solution was cooled to -5 °C with an ice-salt bath and then methanesulfonyl chloride (16.17 mL, 209 mmol) in DCM (158 mL) was added dropwise with stirring at -5 °C. Upon completion of the addition, the reaction mixture was stirred at -5oC to RT for 15 h. A white solid was isolated by filtration. The cake was rinsed with DCM (100 mL). The combined organic layers were washed with 1.0 N HCl (150 mL x 4) and brine and dried over Na2SO4. The solution was filtered and concentrated in vacuo. The material thus obtained was purified by silica gel chromatography (a gradient of 0% to 50% EtOAc in hexanes) to provide Example 304.01 (52 g, 155 mmol, 82 % yield) as a white solid. LCMS-ESI (pos.) m/z: 358.1 (M+Na)+. |
78% | With triethylamine In dichloromethane at 0 - 20℃; for 2h; | 1 Step 1 Methanesulfonyl chloride (1.73 mL, 22.3 mmol) was added dropwise over 5 min to a 0 oC solution of bis(4-methoxylbenzyl)amine (5.0 g, 19.4 mmol, Combi-Blocks Inc.) and triethylamine (8.12 mL, 58.3 mmol) in DCM (40 mL). The mixture was then stirred for 2 h at room temperature and then 1N HCl (50 mL) was added. The layers were separated, and the organic layer was washed with brine (1 x 50 mL), dried over anhydrous MgSO4, filtered, and then concentrated in vacuo to give a brown oil. The oil was dissolved in MeOH (50 mL) and partially concentrated in vacuo until a thick suspension formed. The suspension was stirred for 30 min, filtered, and the collected solid was dried in vacuo to provide N,N- bis(4-methoxybenzyl)methanesulfonamide (5.11 g, 15.2 mmol, 78% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) d ppm 7.19 (d, J=8.50 Hz, 4 H) 6.90 (d, J=8.50 Hz, 4 H) 4.19 (s, 4 H) 3.75 (s, 6 H) 2.89 (s, 3 H). |
63% | With triethylamine In dichloromethane at 0 - 50℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: N,N-bis(p-methoxybenzyl)amine With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Inert atmosphere; Stage #2: tert-butyl (E)-3-(4'-fluorophenyl)prop-2-enoate In tetrahydrofuran; hexane at -78℃; for 2h; Inert atmosphere; Stage #3: With (1R)-(−)-(10-camphorsulfonyl)oxaziridine In tetrahydrofuran; hexane at -78 - 20℃; for 18h; Inert atmosphere; diastereoselective reaction; | 19 4.2 General procedure I: aminohydroxylation of α,β-unsaturated esters General procedure: BuLi (1.55equiv) was added dropwise to a stirred solution of the requisite amine (1.60 equiv) in THF at -78°C and the resultant mixture was stirred at -78°C for 30 min. A solution of the requisite α,β-unsaturated ester (1.0 equiv) in THF at -78°C was then added dropwise via cannula and the resultant mixture was stirred at -78°C for 2h (-)-CSO (1.6 equiv) was then added and the reaction mixture was allowed to warm to rt then stirred at rt for 18 h. Satd aq NH4Cl was added and the reaction mixture was stirred at rt for 5min, then concentrated in vacuo. The residue was partitioned between CH2Cl2 and 10% aq citric acid, and the aqueous layer was extracted with three portions of CH2Cl2. The combined organic extracts were washed sequentially with satd aq NaHCO3 and brine, then dried and concentrated in vacuo. The residue was then triturated with cold Et2O and filtered. The resultant solution was then dried and concentrated in vacuo. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triethylamine; In dichloromethane; at 5 - 20℃; for 1.5h; | N,N-bis(4-methoxybenzyl)ethanesulfonamide, Example 12.0. To a solution of bis(4-methoxybenzyl)amine 12.01 (900 g, 3.49 mol, 1 eq) in DCM (9 L) was added TEA (634 mL, 4.55 mol, 1.3 eq), followed by dropwise addition of ethanesulfonyl chloride (399 mL, 4.19 mol, 1.2 eq). (The internal temperature was kept between 5-10 C during the addition of the ethane sulfonyl chloride). Once the addition was complete, the cooling bath was removed. After 1.5 h, TLC showed complete loss of starting material. The reaction was quenched by the addition of water (4 L) to the reaction mixture. The layers were separated and the aqueous layer extracted with DCM (2 x 2 L). The combined organic layers were washed with brine (2x 1 L), dried over Na2SO4, and concentrated in vacuo. The material thus obtained was adsorbed onto a plug of silica gel and purified by chromatography (silica gel (60-120 mesh) eluting with a gradient of 10- 80% EtOAc in hexanes) to provide the title compound 12.0 (1125 g, 3.22 mol, 92%) as white solid. ?H-NMR (400 MHz, CDC13) 7.23 (dd, J= 2.08, 6.62 Hz, 4H), 6.90 (dd, J= 2.12, 6.60 Hz, 4H), 4.29 (s, 4H), 3.83 (s, 6H), 2.92 (q, J 7.40 Hz, 2H), 1.33 (t, J 7.40 Hz, 3H). GC-MS (ESI pos. ion) m/z: 372.2 (M+Na). |
92% | With triethylamine; In dichloromethane; at 5 - 10℃; for 1.5h;Large scale; | To a solution of bis(4-methoxybenzyl)amine 467.1 (900 g, 3.49 mol, 1 eq) in DCM (9 L) was added TEA (634 mL, 4.55 mol, 1.3 eq) followed by dropwise addition of ethanesulfonyl chloride (399 mL, 4.19 mol, 1.2 eq). The internal temperature was kept between 5-10 C during the addition of the ethanesulfonyl chloride. Once addition was complete, the cooling bath was removed. After 1.5 h, TLC showed complete loss of starting material. The reaction was quenched by addition of water (4 L) to the reaction mixture. The layers were separated and the aqueous layer was extracted with DCM (2x 2 L). The combined organic layers were washed with brine (2x 1 L), dried over Na2SO4, and concentrated in vacuo. The material thus obtained was adsorbed onto a plug of silica gel and purified by chromatography (silica gel (60-120 mesh) eluting with a gradient of 10-80% EtOAc in hexanes) to provide the title compound 467.0 (1125 g, 3.22 mol, 92%) as a white solid.1H-NMR (400 MHz, CDCl3) delta 7.23 (dd, J = 2.08, 6.62 Hz, 4H), 6.90 (dd, J = 2.12, 6.60 Hz, 4H), 4.29 (s, 4H), 3.83 (m, 6H), 2.92 (q, J = 7.40 Hz, 2H), 1.33 (t, J = 7.40 Hz, 3H). GC-LCMS (ESI pos.) m/z: = 372.2 (M+Na)+. |
92% | With triethylamine; In dichloromethane; at 5 - 10℃;Large scale; | To an ice-cooled solution of 100.1 (900 g, 3.49 mol) in DCM (9 L) was added TEA (634 mL, 4.55 mol) followed by ethanesulfonyl chloride (399 mL, 4.19 mol, 1.2 eq) dropwise (Note: The internal temperature was kept between 5-10 C during the addition of the ethane sulfonyl chloride). Once the addition was complete, the cooling bath was removed. After 1.5 h, TLC showed complete loss of starting material. The reaction was quenched with water (4 L) and the layers were separated. The aqueous layer was then extracted with more DCM (2 x 2 L). The combined organic layers were washed with brine (2 x 1 L), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was absorbed onto a plug of silica gel purified by silica gel chromatography (eluent: 10-80% EtOAc in hexanes) to provide 100.0 (1.125 kg, 92% yield) as a white solid.1H-NMR (400 MHz, CDCl3) delta 7.23 (dd, J=2.1, 6.6 Hz, 4H), 6.90 (dd, J=2.1, 6.6 Hz, 4H), 4.29 (s, 4H), 3.83 (s, 6H), 2.92 (q, J=7.4 Hz, 2H), 1.33 (t, J=7.4 Hz, 3H). (0809) LCMS-ESI (pos.) m/z: 372.2 (M+Na)+. |
92% | With triethylamine; In dichloromethane; at 5 - 10℃; for 1.5h;Inert atmosphere; | To an ice-cooled solution of 361.01 (900 g, 3.49 mol) in DCM (9 L) was added TEA (634 mL, 4.55 mol) followed by ethanesulfonyl chloride (399 mL, 4.19 mol, 1.2 eq) dropwise. (Note: The internal temperature was kept between 5-10 C during the addition of the ethane sulfonyl chloride). Once the addition was complete, the cooling bath was removed. Alter 1.5 h, TLC showed complete loss of starting material. The reaction was quenched with water (4 L), and the layers were separated. The aqueous layer was then extracted with more DCM (2 x 2 L). The combined organic layers were washed with brine (2 x 1 L), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was absorbed onto a plug of silica gel purified by silica gel chromatography (eluent: 10-80% EtOAc in hexanes) to provide 361.0 (1125 g, 92% yield) as a white solid. 1H-NMR (400 MHz, CDC13) oe 7.23 (dd,J=2.1, 6.6 Hz, 4H), 6.90 (dd,J2.1, 6.6 Hz, 4H),4.29 (s, 4H), 3.83 (s, 3H) 3.83 (s, 3H), 2.92 (q, J=7.4 Hz, 2H), 1.33 (t, J=7.4 Hz, 3H). LCMS-ESI (pos.) m/z: 372.2 (M+Na)t |
92% | With triethylamine; In dichloromethane; at 5 - 20℃; for 1.5h; | To a solution of bis(4-methoxybenzyl)amine 30.1 (900 g, 3.49 mol, 1 eq) in DCM (9 L) was added TEA (634 mL, 4.55 mol, 1.3 eq), followed by dropwise addition of ethanesulfonyl chloride (399 mL, 4.19 mol, 1.2 eq). (The internal temperature was kept between 5-10 C during the addition of the ethane sulfonyl chloride). Once the addition was complete, the cooling bath was removed. After 1.5 h, TLC showed complete loss of starting material. The reaction was quenched by the addition of water (4 L) to the reaction mixture. The layers were separated and the aqueous layer was extracted with DCM (2x 2 L). The combined organic layers were washed with brine (2x 1 L), dried over Na2SO4, and concentrated in vacuo. The material thus obtained was adsorbed onto a plug of silica gel and purified by chromatography (silica gel (60-120 mesh) eluting with a gradient of 10- 80% EtOAc in hexanes) to provide the title compound 30.0 (1125 g, 3.22 mol, 92%) as a white solid. 1H-NMR (400 MHz, CDCl3) delta 7.23 (dd, J = 2.08, 6.62 Hz, 4H), 6.90 (dd, J = 2.12, 6.60 Hz, 4H), 4.29 (s, 4H), 3.83 (m, 6H), 2.92 (q, J = 7.40 Hz, 2H), 1.33 (t, J = 7.40 Hz, 3H). GC-LCMS (ESI pos. ion) m/z: = 372.2 (M+Na)+. |
92% | With triethylamine; In dichloromethane; for 1.5h;Cooling with ice; | To a solution Example 4.11 (900 g, 3.49 mol, 1 eq) in DCM (9 L) was added TEA (634 mL, 4.55 mol, 1.3 eq), followed by dropwise addition of ethanesulfonyl chloride (399 mL, 4.19 mol). Once the addition was complete, the cooling bath was removed. After 1.5 h, TLC showed complete loss of starting material. The reaction was quenched by the addition of water (4 L) to the reaction mixture. The layers were separated and the aqueous layer extracted with DCM (2x 2 L). The combined organic layers were washed with brine (2x 1 L), dried over Na2S04, and concentrated in vacuo. The material obtained was adsorbed onto a plug of silica gel and purified by chromatography (silica gel (60-120 mesh) eluting with a gradient of 10-80% EtOAc in hexanes) to provide the title compound Example 4.12 (1125 g, 3.22 mol, 92%) as a white solid. -NMR (400 MHz, CDC13) delta 7.23 (dd, J= 2.08, 6.62 Hz, 4H), 6.90 (dd, J= 2.12, 6.60 Hz, 4H), 4.29 (s, 4H), 3.83 (m, 6H), 2.92 (q, J= 7.40 Hz, 2H), 1.33 (t, J = 7.40 Hz, 3H). GC-LCMS (ESI pos. ion) m/z: = 372.2 (M+Na)+. |
92% | With triethylamine; In dichloromethane; at 5 - 20℃; for 1.5h; | V, V-Bis(4-methoxybenzyl)ethanesulfonamide, Intermediate 5.8. To a solution of bis(4-methoxybenzyl)amine Intermediate 5.8.1 (900 g, 3.49 mol, 1 eq) in DCM (9 L) was added TEA (634 mL, 4.55 mol, 1.3 eq), followed by dropwise addition of ethanesulfonyl chloride (399 mL, 4.19 mol, 1.2 eq). The internal temperature was kept between 5-10 C during the addition of the ethane sulfonyl chloride. Once the addition was complete, the cooling bath was removed. After 1.5 h, TLC showed complete loss of starting material. The reaction was quenched by the addition of water (4 L) to the reaction mixture. The layers were separated and the aqueous layer extracted with DCM (2x 2 L). The combined organic layers were washed with brine (2x 1 L), dried over Na2S04, and concentrated in vacuo. The material thus obtained was adsorbed onto a plug of silica gel and purified by chromatography (silica gel (60-120 mesh) eluting with a gradient of 10-80% EtOAc in hexanes) to provide the title compound Intermediate 5.8 (1125 g, 3.22 mol, 92%) as a white solid. -NMR (400 MHz, CDCL) d 7.23 (dd, J = 2.08, 6.62 Hz, 4H), 6.90 (dd, J = 2.12, 6.60 Hz, 4H), 4.29 (s, 4H), 3.83 (app s, 6H), 2.92 (q, J = 7.40 Hz, 2H), 1.33 (t , J= 7.40 Hz, 3H). GC-MS (ESI pos. ion) m/z: = 372.2 (M+Na)+. |
53.4% | With dmap; triethylamine; In dichloromethane; at 0 - 20℃; for 0.5h; | To a solution of N,N-bis(4-methoxybenzyl)amine (Intermediate EE11; 200 g, 775.19 mmol) in DCM (2.5 L) was added Et3N (336.17 mL, 2325.5 mmol), and the reaction mixture was cooled to 0 C. <strong>[594-44-5]Ethanesulfonyl chloride</strong> ( 95 mL, 1007.75 mmol) was added in drop-wise manner followed by DMAP (19.0 g, 155.03 mmol). The resulting reaction mixture was stirred at ambient temperature for 30 min. The reaction was monitored by TLC and upon completion, the mixture was diluted with H 0 and the layers were separated and the aqueous phase was extracted with DCM (3 x 1.5 L). The combined organic layer was washed with H20, brine, and dried over Na2S04. The solvent was removed under reduced pressure to afford the crude material which was purified by column chromatography over Si02 gel (100-200 mesh), eluting with a gradient of 0-12% EtOAc in Hex affording the title compound (145 g, 53.4%) as a white fluffy solid. |
53.4% | With dmap; triethylamine; In dichloromethane; at 0 - 20℃; for 0.5h; | To a soiuiion of NN-his(4-methoxvbenzvi)amine (Intermediate EEl 1; 200 g, 77519 mrnoi) in DCM (2.5 L) was added triethylamine (336.17 ml, 2325.5 mnmol), and the reaction mixture was cooled to 0 ?C. <strong>[594-44-5]Ethanesulfonyl chloride</strong> (95 mE, 1007.75 mmoi. Aldrich) was then added in drop-wise manner followed by DMAI (19.0 g, 155.03 rnmoi). The resulting reaction mixture was stirred atambient temperature for 30 mm. The reaction was monitored by TLC and upon completion, the mixture was diluted with water and the layers were separated and the aqueous phase was extracted with DCM (.3 x 1.5 L). The combined organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude material which was purified by column chromatography over silica gel (1 00-200 mesh). eluting with agradient of 0-12% ethyl acetate in hexanes affording the title compound (145 g,53.4%) as white fluffy solid. Ri: 0.5 in 20% Ethyl acetate in hexane. |
53.4% | With dmap; triethylamine; In dichloromethane; at 0 - 20℃; for 0.5h; | To a solution of N,N-bis(4-methoxybenzyl)amine (Intermediate EEl 1; 200 g, 775.19 mmol) in DCM (2.5 L) was added Et3N (336.17 mL, 2325.5 mmol), andthe reaction mixture was cooled to 0 C. <strong>[594-44-5]Ethanesulfonyl chloride</strong> ( 95 mL,1007.75 mmol) was added in drop-wise manner followed by DMAP (19.0 g,155.03 mmol). The resulting reaction mixture was stirred at ambient temperaturefor 30 mm. The reaction was monitored by TLC and upon completion, themixture was diluted with H20 and the layers were separated and the aqueousphase was extracted with DCM (3 x 1.5 L). The combined organic layer waswashed with H20, brine, and dried over Na2504. The solvent was removed under reduced pressure to afford the cmde material which was purified by column chromatography over 5i02 gel (100-200 mesh), eluting with a gradient of 0-12% EtOAc in hexane affording the title compound (145 g, 5 3.4%) as a white fluffy solid. |
1125 g | With triethylamine; In dichloromethane; at 5 - 10℃; for 1.5h; | N,N-Bis(4-methoxybenzyl)ethanesulfonamide, Example 12.0 To a solution of bis(4-methoxybenzyl)amine 12.1 (900 g, 3.49 mol, 1 eq) in DCM (9 L) was added TEA (634 mL, 4.55 mol, 1.3 eq), followed by dropwise addition of ethanesulfonyl chloride (399 mL, 4.19 mol, 1.2 eq). The internal temperature was kept between 5-10 C. during the addition of the ethane sulfonyl chloride. Once the addition was complete, the cooling bath was removed. After 1.5 h, TLC showed complete loss of starting material. The reaction was quenched by the addition of water (4 L) to the reaction mixture. The layers were separated and the aqueous layer extracted with DCM (2*2 L). The combined organic layers were washed with brine (2*1 L), dried over Na2SO4, and concentrated in vacuo. The material thus obtained was adsorbed onto a plug of silica gel and purified by chromatography (silica gel (60-120 mesh) eluting with a gradient of 10-80% EtOAc in hexanes) to provide the title compound 12.0 (1125 g, 3.22 mol, 92%) as white solid. 1H-NMR (400 MHz, CDCl3) delta 7.23 (dd, J=2.08, 6.62 Hz, 4H), 6.90 (dd, J=2.12, 6.60 Hz, 4H), 4.29 (s, 4H), 3.83 (app s, 6H), 2.92 (q, J=7.40 Hz, 2H), 1.33 (t, J=7.40 Hz, 3H). GC-MS (ESI pos ion) m/z: =372.2 (M+Na)+. |
With triethylamine; In dichloromethane; at 5 - 10℃; for 1.5h; | To a solution of bis(4-methoxybenzyl)amine 30.1 (900 g, 3.49 mol, 1 eq) in DCM (9 L) was added TEA (634 mL, 4.55 mol, 1.3 eq) followed by dropwise addition of ethanesulfonyl chloride (399 mL, 4.19 mol, 1.2 eq). (The internal temperature was kept between 5-10 C during the addition of the ethanesulfonyl chloride). Once the addition was complete, the cooling bath was removed. After 1.5 h, TLC showed complete loss of starting material. The reaction was quenched by the addition of water (4 L) to the reaction mixture. The layers were separated and the aqueous layer extracted with DCM (2x 2 L). The combined organic layers were washed with brine (2x 1 L), dried over Na2SO4, and concentrated in vacuo. The material thus obtained was adsorbed onto a plug of silica gel and purified by chromatography (silica gel (60-120 mesh) eluting with a gradient of 10-80% EtOAc in hexanes) to provide the title compound 30.0 (1125 g, 3.22 mol, 92%) as white solid. 1H- NMR (400 MHz, CDC13) oe 7.23 (dd,J= 2.08, 6.62 Hz, 4H), 6.90 (dd,J= 2.12, 6.60 Hz, 4H), 4.29 (s, 4H), 3.83 (app s, 6H), 2.92 (q,J= 7.40 Hz, 2H), 1.33 (t,J= 7.40 Hz, 3H). GC-MS (ESI pos. ion) m/z: = 372.2 (M+Na). | |
1125 g | With triethylamine; In dichloromethane; at 5 - 10℃; for 1.5h;Large scale; | To a solution of bis(4-methoxybenzyl)amine 84.1 (900 g, 3.49 mol, 1 eq) in DCM (9 L) was added TEA (634 mL, 4.55 mol, 1.3 eq) followed by dropwise addition of ethanesulfonyl chloride (399 mL, 4.19 mol, 1.2 eq). The internal temperature was kept between 5-10 C during the addition of the ethane sulfonyl chloride. Once addition was complete, the cooling bath was removed. After 1.5 h, TLC showed complete loss of starting material. The reaction was quenched by addition of water (4 L) to the reaction mixture. The layers were separated and the aqueous layer was extracted with DCM (2x 2 L). The combined organic layers were washed with brine (2x 1 L), dried over Na2S04, and concentrated in vacuo. The material thus obtained was adsorbed onto a plug of silica gel and purified by chromatography (silica gel (60-120 mesh) eluting with a gradient of 10-80% EtOAc in hexanes) to provide the title compound 84.0 (1125 g, 3.22 mol, 92%) as a white solid. -NMR (400 MHz, CDC13) delta 7.23 (dd, J = 2.08, 6.62 Hz, 4H), 6.90 (dd, J = 2.12, 6.60 Hz, 4H), 4.29 (s, 4H), 3.83 (m, 6H), 2.92 (q, J = 7.40 Hz, 2H), 1.33 (t, J = 7.40 Hz, 3H). GC-LCMS (ESI pos.) m/z: = 372.2 (M+Na)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52.44% | With dmap; triethylamine In dichloromethane at 0 - 20℃; for 0.5h; | To a solution of N,N-bis(4-methoxybenzyl)amine (Intermediate EE11; 405 g, 1569.7 mmol) in DCM (4.0 L) was added Et3N (681.0 mL, 4709.3 mmol), and the reaction mixture was cooled to 0 °C. Propanesufonyl chloride (231 mL, 2040.6 mmol) was added in a drop-wise manner followed by DMAP (38.3 g, 313.9 mmol). The resulting mixture was stirred at ambient temperature for 30 min. The reaction was monitored by TLC and upon completion, the mixture was diluted with 2.0 L of H 0, the layers were separated and the aqueous phase was extracted with DCM (3 x 2.0 L). The combined organic layer was washed with H20, brine, and dried over Na2S04. The solvent was removed under reduced pressure to afford the crude material which was purified by column chromatography over Si02 gel (100-200 mesh), eluting with a gradient of 0-12% EtOAc in Hex affording the title compound (300 g, 52.44%) as white fluffy solid. |
52.44% | With dmap; triethylamine In dichloromethane at 0 - 20℃; for 0.5h; | intermediate EE14 N,N-BIS(4-METHOXYBENZYL)PROPANES ULFONAMIDE To a soluiion of N,N-his(4-methoxvbenzvi)amine (Intermediate EEl 1; 405g, 1569.7 rnrnoi) in DCM (4.0 L) was added triethylarnine (681.0 ml, 4709.3mmol). and the reaction mixture was cooled to 0 C. Propanesufonyl chloride (231niL, 2040.6 rnmoi. Aldrich) was then added in a drop-wise manner followed byDMAP (38.3 g, 313.9 mrnoi). The resulting mixture was stirred at ambienttemperature for 30 mm. The reaction was monitored by TLC and upon completion, the mixture was diluted with 2.0 L ot’water, the layers were seprated and the aqueous phase was extracted with DCM (3 x 2.0 L). The combined organic layer was washed with water, brine and dried over sodium sulfate. Thesolvent was removed under reduced pressure to afford the crude niaterial which was purified by column chromatography over silica gel (100-200 mesh), eluting with a gradient of 0-12% ethyl acetate in hexanes affording the title compound (30() g, 52.44%) as white fluffy solid. Ri: 0.5 in 20% Ethyl acetate in hexane. |
52.44% | With dmap; triethylamine In dichloromethane at 0 - 20℃; for 0.5h; | N,N-BIS (4-METHOXYBENZYL)PROPANESULFONAMIDE To a solution of N,N-bis(4-methoxybenzyl)amine (Intermediate EEl 1; 405 g, 1569.7 mmol) in DCM (4.0 L) was added Et3N (681.0 mL, 4709.3 mmol), and the reaction mixture was cooled to 0 C. Propanesufonyl chloride (231 mL, 2040.6 mmol) was added in a drop-wise manner followed by DMAP (38.3 g,313.9 mmol). The resulting mixture was stirred at ambient temperature for 30 mm. The reaction was monitored by TLC and upon completion, the mixture was diluted with 2.0 L of H20, the layers were separated and the aqueous phase was extracted with DCM (3 x 2.0 L). The combined organic layer was washed with H20, brine, and dried over Na2SO4. The solvent was removed under reducedpressure to afford the crude material which was purified by column chromatography over Si02 gel (100-200 mesh), eluting with a gradient of 0-12% EtOAc in hexane affording the title compound (300 g, 52.44%) as white fluffy solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triethylamine In isopropyl alcohol at 95℃; | 1.2 Step 2 Into a 250-mL round-bottom flask was placed tert-butyl (R)-3-((2-chloro-3-nitropyridin-4-yl)amino)piperidine-1-carboxylate (8 g, 22.42 mmol, 1.00 equiv),(100 mL), bis[(4-methoxyphenyl)methyl]amine (5.78 g, 22.46 mmol, 1.00 equiv), and TEA (2.955 g, 29.20 mmol, 1.30 equiv). The resulting solution wasovernight at 95°C. The reaction mixture was cooled and concentrated under vacuum.This resulted in 12 g (92%) of tert-butyl (R)-3-((2-(bis(4-methoxybenzyl)amino)-3- nitropyridin-4-yl)amino)piperidine-l-carboxylate as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With triethylamine In dichloromethane at 0 - 20℃; for 16h; | 32 3-Chloro-N,N-bis(4-methoxybenzyl)propane-l -sulfonamide At 0 °C, to a solution of 3-chloropropane-l -sulfonyl chloride (2.68 mL, 22 mmol) and triethylamine (7.8 mL, 56 mmol) in 80 mL dichloromethane, a solution of bis(4- methoxybenzyl)amine (5.15g, 20 mmol) in 20 mL dichloromethane was added slowly, and then the reaction was warmed up to room temperature for 16 h. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layer was washed with brine and dried over sodium sulfate. The solution was filtered through a pad of silica gel and eluted with 30% EtOAc in hexanes. After concentration, the crude was purified with 1SCO ( 120 g Si02: EtOAc/Hexanes 0 to 30%) to provide 3-chloro-N,N-bis(4- methoxybenzyl)propane-l -sulfonamide as brown oil (4.95, 62%). (2192) 'H NMR (300 MHz, CDC13) δ 7.20-7.25 (m, 4H), 6.85-6.90 (m, 4H), 4.27 (s, 4H), 3.81 (s, 6H), 3.60 (/, 2H, J = 6.8 Hz), 2.99 (/, 2H, J= 7.1 Hz), 2.1 9-2.28 (/, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56.5% | With triethylamine In dichloromethane at 0℃; for 1.08333h; | 148.2 STEP 2: 1 -CYCLOPROPYL-N,N-Bl S(4-METFIOXYBENZYL)METHANESULFONAM1DE To a solution of bis(4-methoxyhenzyi)arnine (3.02 g, 11.74 mrnoi) andtriethylarnine (5.71 rnL, 41.1 mrnol) in CH2CI2 (58.7 mnL) at 0 °C was added cyciopropylmethanesuifonyl chloride (1.00 mL, 6.47 mrnoi) dropwise over 5 minutes. The cloudy mixture was stirred at 0 °C for 1 h and then diluted with CH2CI2. The mixture was washed twice with brine. The aqueous layer was back extracted with EtOAc and the combined organic layers were dried (]‘igSO). andfiltered. Solvent was evaporated, and the crude orange oil was chromatographed (silica gel. 0 to 60 %, EtOAc/hexane) to afford the title compound (2.49 g, 565%). ni/z (ESI, +ve ion) 398.2 (M+Na |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With dmap In dichloromethane at 0 - 20℃; for 16.5h; | 714.1 STEP 1: (R)-METHYE 2-(.N-BIS(-METHOXYBENZYL)SULFAMOYL)PROPANOATE AND (5)-METHYL 2-(N,N-BIS(4-METHOXYBENZYL)S ULFAMOYL)PROPANOATE To a mixture of bis( -rnethoxybenzvi)amine (8.96 g. 34.8 mmol,Intermediate EEl 1), 4-(diinethylarnino) pyridine (().327 g, 2.68 mrnol) and triethylamine (11.2 mL, 80 mmol) in DCM (100 mL) at 0°C was added methyl 2-(chiorosulfonvi)propanoate (5 g, 26.8 mmoi) slowly over 30 mm. The reaction mixture was stirred at room temperature for I 6h. The reaction mixture was diluted with 300 mL of DCM and 100 mL of 0.5 N hydrochloric acid aqueous solutions. The layers were separated, and the aqueous layer was extracted with EtOAc (2x100 mL). The combined organic solution was dried over sodium sulfate,filtered, concentrated. The crude product was purified by chromatography on silica gel eluting with 0% to 70% EtOAc in hexane to provide the title compounds (914 g, 84%). m’z (ESI, -1-ve ion) 430.1 (M+Na)L |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With triethylamine; In dichloromethane; at 0℃; for 1.08333h; | To a solution of bis(4-methoxybenzyl)arnine (Intermediate EEl 1) (3.35 g, 13.0 mmoi) and TEA (6.34 ml, 45.6 mmoi) in DCM2 (65 ml) was addedisobutanesuifonyl chloride (1.70 rnL, 13.0 mrnoi) dropwise over 5 minutes at 0 o and the resulting cloudy mixture was stirred at the same temperature for I h. The reaction was then diluted (DCM) and washed (2xhrine). The aqueous layer was back extracted once (EtOAc) and the combined organic layers were dried (Mg504) and concentrated under reduced pressure. The residue was injected intoa 80 g ISCO Gold column and purified by combiflash. eluting with 10% to 40% EtOAc/hexanes to provide the product (2.00 g, 5.30 mmoi, 41 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.9% | With potassium carbonate; In acetonitrile; for 2h;Reflux; | A mixture of <strong>[75833-38-4]2-chloropyrimidine-4-carbonitrile</strong> (100.0 g, 0.7lmol, 1.0 eq) and bis(4- methoxybenzyl)amine (184.0 g, 0.7lmol, 1.0 eq) in CH3CN (1.0 L) was stirred under reflux for 2h, then cooled and filtered. The mixture was concentrated, diluted with 0.5 N HC1 (1.0 L), extracted with EA (1.0 L x 2). The combined EA layers were dried over anhydrous Na2SO4 and concentrated. The resulting residue was triturated with (PE/EA=10/1, v/v, 1L) to provide 2-(bis(4-methoxybenzyl)amino)pyrimidine- 4-carbonitrile as a as orange solid (220.0 g, 85.9%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With triethylamine; In dichloromethane; at 0 - 20℃; for 2h; | 5-Bromopyridine-2-sulfonyl chloride (500 mg, 1.9 mmol) was added into a solution of (PMB)2NH (732 mg, 2.9 mmol), and Et3N (0.5 g, 5 mmol) in DCM (5 mL) at 0 C. The mixture was stirred at room temperature for 2 hours. DCM (20 mL) was added and the mixture was washed with water and saturated brine. The organic layer was dried over Na2S04, filtered, and concentrated. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1 :2) to give 700 mg (75%) of 5-bronio-NJV- bis(4- methoxybenzyi)pyridiiie-2-sulfonamide (22-1) as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With triethylamine In dichloromethane at 20℃; for 1.5h; | 4.28-2 Step 28-2: Compound 28-1 (3.5 g, 18 mmol) was added to a solution of PMB2NH (5.14 g, 20 mmol) and Et3N (3.63 g, 36 mmol) in DCM (20 mL). The mixture was stirred at room temperature for 1.5 h. DCM (100 mL) was added and the mixture was washed with brine. The organic layer was dried over Na2S04, filtered, and concentrated. The residue was purified by silica gel (PE/ EtOAc = 1/ 1) to give 28-2 (3.8 g, 50%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 140℃; for 48h; Microwave irradiation; | I.3 Intermediate 3: 3-chloro-N1,N1-bis(4-methoxybenzl)-2,7-naphthyridine-1,6-diamine To a microwave tube was added 6,8-dichloro-2,7-naphthyridin-3-amine hydrochloride (800 mg, 3.19 mmol), 1-(4-methoxyphenyl)-N-[(4-methoxyphenyl)methyl]methanamine (2.47 g, 9.58 mmol), DIPEA (1.0 mL, 6.39 mmol), and 1,4-dioxane (4 mL). The mixture was stirred at 140° C. for 48 hours. The mixture was cooled, concentrated and purified by silica gel chromatography (dichloromethane/methanol/7N NH3-methanol, 200/5/1) to afford 3-chloro-N1,N1-bis[(4-methoxyphenyl)methyl]-2,7-naphthyridine-1,6-diamine (1.02 g, 73% yield) as yellow solid. LCMS (ESI) [M+H]+=435.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48.8% | With triethylamine In tetrahydrofuran at 20℃; for 1h; | 1.2 4-(bis(4-methoxybenzyl)amino)-2-butoxy-6-chloropyrimidine-5-carboxaldehyde 1c Compound 1b (1.09 g, 4.376 mmol) was dissolved in 30 mL of tetrahydrofuran, bis(4-methoxybenzyl)amine (1.24 g, 4.814 mmol) and triethylamine (663 mg, 6.564 mmol).The reaction was stirred at room temperature for 1 hour. Reaction liquid with silica gel column colorThe resulting residue was purified to give the title compound 1c (1 g, yield: 48.8%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.96% | With triethylamine In dichloromethane at 20℃; for 1h; Inert atmosphere; | 1.F F. 6-(hydroxymethyl)-N,N-bis[(4-methoxyphenyl)methyl]pyridine-3-sulfonamide 6-chloro-N,N-bis[(4-methoxyphenyl)methyl]pyridine-3-sulfonamide. A solution of 6- chloropyridine-3-sulfonyl chloride (15.00 g, 70.741 mmol, 1.00 equiv) and bis[(4-methoxyphenyl)methyl]amine (18.20 g, 70.725 mmol, 1.00 equiv) and TEA (21.47 g, 212.224 mmol, 3.00 equiv) in DCM (200.00 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was re-crystallized from EtOAc/PE (1:1 200 mL) to afford 6-chloro-N,N-bis[(4-methoxyphenyl)methyl]pyridine-3-sulfonamide (30 g, 97.96%) as a white solid. |
83% | With triethylamine In dichloromethane at 0 - 20℃; for 20.25h; | A Step A: -Chloro-N,N-bis(4-methoxybenzyl)pyridine-3-sulfonamide Bis(4-methoxybenzyl)amine (3.71 g, 14.4 mmol) was added to a solution of 2- chloropyridine-5-sulfonyl chloride (3.00 g, 13.7 mmol) and triethylamine (2.49 mL, 17.8 mmol) in DCM (50 mL) at o °C. The reaction was stirred at o °C for 15 minutes and then allowed to warm up to room temperature and stirred for 20 hours. Then the reaction mixture was diluted with DCM (150 mL), washed with a saturated aqueous NH4CI solution (3 x 40 mL) and brine (40 mL), dried over MgS04, filtered, and concentrated in vacuo to give the crude product as a cream solid. The crude product was triturated with TBME (70 mL), filtered and rinsed with TBME (2 x 40 mL) to afford the title compound (4.97 g, 83 %) as an off-white solid. (1346) NMR (DMSO-d6) δ 8.76 (dd, J = 2.6, 0.7 Hz, lH), 8.19 (dd, J = 8.4, 2.6 Hz, lH), 7.69 (dd, J = 8.4, 0.7 Hz, lH), 7.08 - 7.02 (m, 4H), 6.83 - 6.76 (m, 4H), 4.29 (s, 4H), 3.71 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With triethylamine In dichloromethane at 0 - 20℃; for 19.5h; | A Step A: 2-Chlor -N,N-bis(4-methoxybenzyl)pyridine-3-sulfonamide Bis(4-methoxybenzyl)amine (3.78 g, 14.41 mmol) and triethylamine (2.49 ml, 17.8 mmol) in anhydrous DCM (15 mL) were added to a solution of 2-chloropyridine-3- sulfonyl chloride (3.00 g, 13.72 mmol) in anhydrous DCM (35 mL) at o °C. The mixture was stirred at o °C for 0.5 hour, then warmed to room temperature. After 19 hours the reaction mixture was diluted with a further portion of DCM (150 mL), washed with saturated aqueous NH4C1 (2 x 50 mL), water (50 mL), and brine (50 mL), dried over MgS04, filtered, and concentrated in vacuo to give crude product as a pale orange solid. The crude product was triturated with TBME (50 mL), filtered, rinsing with TBME (2 x 40 mL), to afford the title compound (5.10 g, 80 %) as a cream coloured solid. (1521) NMR (DMSO-d6) δ 8.6i (dd, J = 4-8, 1.8 Hz, lH), 8.27 (dd, J = 7-8, 1.8 Hz, lH), 7.55 (dd, J = 7.8, 4-8 Hz, lH), 7.05 - 6.98 (m, 4H), 6.86 - 6.78 (m, 4H), 4-37 (s, 4H), 3-72 (s, 6H). (1522) LCMS: m/z 433.3 (M+H)+ (ES+). |
49% | With triethylamine In dichloromethane at 0 - 20℃; for 4h; | Step A: 2-chloro-N,N-bis(4-methoxybenzyl)pyridine-3-sulfonamide A suspension of 2-chloropyridine-3-sulfonyl chloride (1.5 g, 7.07 mmol) and bis(4- methoxybenzyl)amine (1.820 g, 7.07 mmol) in DCM (20 mL) was cooled to 0 °C (ice bath). TEA (2.51 mL, 17.68 mmol) was then added dropwise at 0 °C and the mixture was stirred at RT for 4 h. The mixture was diluted with water (30 mL) and the organic layer was separated. The aqueous layer was extracted with DCM (2 x 20 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to give a yellow oil. The yellow oil was purified by FC (0-50% EtOAc/isohexane) to afford the title compound (1.5 g, 49%) as a colourless solid. LCMS m/z 433/435 (M+H)+(ES+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | Stage #1: lithium 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfinate With oxalyl dichloride In tetrahydrofuran at 0 - 25℃; for 1h; Stage #2: N,N-bis(p-methoxybenzyl)amine With triethylamine In dichloromethane at 25℃; for 1h; | B Step B: N,N-Bis(4-methoxybenzyl)-1H-pyrazole-5-sulfinamide To a solution of lithium 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfinate (s g,238.53 mmol, 1 eq) in THF (6oo mL) was added oxalyl chloride (6o. g, 477.07 mmol,41.76 mL, 2 eq) at 0 °C. Then the mixture was warmed to 25 °C, stirred for 1 hour andthen concentrated in vacuo. The residue was dissolved in DCM (6oo mL). To the resulting mixture was added TEA (72.41 g, 715.60 mmol, 99.60 mL, 3 eq) followed by bis(4-methoxybenzyl)amine (61.38 g, 238.53 mmol, 1 eq) at 25 °C. The mixture was stirred for 1 hour and then concentrated in vacuo. The residue was purified by column chromatography (Si02, PE: EtOAc = 1:1 to 1:3) to give the title compound g, 59 %yield, 97 % purity on LCMS) as a light yellow oil. 1H NMR (CDC13): 6 7.77 (d, 1 H), 7.06 (d, 4 H), 6.77-6.72 (m, 4 H), 6.51 (d, 1 H), 4.03 (s,4 H) and 3.72 (s, 6 H).LCMS: m/z 372.2 (M+H)÷ (ESj. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.5% | With potassium carbonate; In tetrahydrofuran; at 50 - 55℃; for 4h; | To a 500 ml four-necked flask equipped with a stirring, a thermometer was charged with 250 g of tetrahydrofuran, 28.0 g of potassium carbonate,37.0 g (0.1 mol) of 5R-benzyloxyaminopiperidine-2S-carboxylic acid ethyl ester oxalate (III), 40 g (0.16 mol) of di(p-methoxy)benzylamine,The reaction was stirred at 50-55 C for 4 hours. Cool to 20-25 C, filter, and filter cake twice with tetrahydrofuran, 30 g each time. The organic phases were combined, the tetrahydrofuran was distilled off, 40 g of methyl tert-butyl ether was added to the residue, and the mixture was washed with water and filtered to obtain 45.7 g of N,N-di(p-methoxybenzyl)-5R-benzyloxyaminopiperidine-2S-carboxamide, liquid phase purity 99.93%, yield 93.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47.4% | With iodine In tetrahydrofuran; dimethyl sulfoxide at 20℃; for 0.333333h; | Intermediate 58: (S)-1-(2-bromo-6-(3-ethylmorpholino)pyridin-4-yl)-N,N-bis(4-methoxybenzyl) methanesulfonamide To iodine (79 mg, 0.311 mmol) in THF (lmL) was added a solution of bis(4- methoxybenzyl)amine (305 mg, 1.185 mmol, Manchester Organics) and Intermediate 57 sodium (S)- (2-bromo-6-(3-ethylmorpholino)pyridin-4-yl)methanesulfinate (88 mg, 0.237 mmol) in THF (1 ml.) and DMSO (0.4 ml_). The reaction mixture was stirred at rt for 20 min and quenched with 5% sodium metabisulfite solution (1.5 ml_), partitioned between water (5 ml.) and EtOAc (5 ml_), dried over a hydrophobic frit, and concentrated under a stream of nitrogen. The residue was purified by column chromatography and concentrated in vacuo to give (S)-1-(2-bromo-6-(3-ethylmorpholino)pyridin-4- yl)-N,N-bis(4-methoxybenzyl) methanesulfonamide (68 mg, 0.112 mmol, 47.4% yield) as a pale yellow gum. LCMS (System A, UV, ESI): Rt = 1.48 min, [M+H]+ 604 + 606 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With triethylamine In tetrahydrofuran at 20℃; for 18h; | A Step A: N.N-bisf4-Methoxvbenzvl)-6-oxo-i.6-dihvdropvridine-2-sulfonamide bis(4-Methoxybenzyl) amine (366 mg, 1.42 mmol) was dissolved in THF (20 mL) and triethylamine (261 mg, 2.58 mmol). Next, 6-oxo-i,6-dihydropyridine-3-sulfonyl chloride (250 mg, 1.29 mmol) was added portionwise. The reaction was stirred for 18 hours at room temperature. The solids were filtered off and the THF was evaporated. The residue was purified over silica using ethyl acetate as the eluent to afford the title compound (360 mg, 67%) as a pale yellow solid. (0662) NMR (300 MHz, CDCI3) d 7.84 (s, lH), 7-57 (d, lH), 7.09 (d, 4H), 6.84 (d, 4H), 6.56 (d, lH), 4.27 (s, 4H) 3-79 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | With potassium carbonate | 81.1 Example 81. Step 1. Synthesis of (R)-[4-chloro-2-(hydroxymethyl)phenyl]-[(3aR,4R,6R,6aR)-4-[4-[bis[(4-methoxyphenyl)methyl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol (81a) A mixture of K2CO3 (292.98 mg, 2.12 mmol), (R)-[4-chloro-2-(hydroxymethyl)phenyl]-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol (55e, 300 mg, 0.64 mmol) and bis-(4-methoxybenzyl)amine (331 mg, 1.29 mmol) in tert-butanol (5 mL) was stirred at 95° C. for 2 h under N2. LCMS showed the reaction was complete. The reaction was concentrated in vacuum to dryness and the residue was extracted with EtOAc (2*50 mL) and the organic layers were washed with water (2*10 mL), then brine (2*10 mL). The organics layers were dried with MgSO4, filtered, and concentrated in vacuum. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:1) to give (R)-[4-chloro-2-(hydroxymethyl)phenyl]-[(3aR,4R,6R,6aR)-4-[4-[bis[(4-methoxyphenyl)methyl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol (81a, 80 mg, 0.10 mmol, 16% yield) as a white solid. LCMS [M+H]: 687.2. |
16% | With potassium carbonate In <i>tert</i>-butyl alcohol at 95℃; for 2h; Inert atmosphere; | 81.1 Step 1. Synthesis of (R)-[4-chloro-2-(hydroxymethyl)phenyl]-[(3aR,4R,6R,6aR)-4 -[4-[bis[(4- methoxyphenyl)methyl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a- tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol (81a) A mixture of K2CO3 (292.98 mg, 2.12 mmol), (R)-[4-chloro-2- (hydroxymethyl)phenyl]-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl- 3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol (55e, 300 mg, 0.64 mmol) and bis-(4- methoxybenzyl)amine (331 mg, 1.29 mmol) in tert-butanol (5 mL) was stirred at 95 °C for 2 h under N2. LCMS showed the reaction was complete. The reaction was concentrated in vacuum to dryness and the residue was extracted with EtOAc (2x50 mL) and the organic layers were washed with water (2x10 mL), then brine (2x10 mL). The organics layers were dried with MgSO4, filtered, and concentrated in vacuum. The crude product was purified by silica gel column chromatography (ethyl acetate : petroleum ether = 1 : 1) to give (R)-[4-chloro-2- (hydroxymethyl)phenyl]-[(3aR,4R,6R,6aR)-4 -[4-[bis[(4- methoxyphenyl)methyl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a- tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol (81a, 80 mg, 0.10 mmol, 16% yield) as a white solid. LCMS [M+H]: 687.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 100℃; for 16h; | To a solution of 2,6-dichloropyrimidm-4-amine (5.0 g, 31 mmol) in 2-propanol (31 ml.) was added ACV-diisopropylethylamine (6.4 ml, 37 mmol) and bis(4- methoxybenzyl)amine (7.9 g, 31 mmol). The resulting solution was stirred at 100 C for 16 h, cooled to r.t, diluted with water (100 niL), and extracted with EtOAc (100 mL). The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated to yield the crude product, which was used in the next step without further purification. LC-MS calculated for C20H22CIN4O2 (M+H)+: 385.1 ; found 385.1. | |
With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 100℃; for 16h; | Step 1: 6-Chloro-N2,N2-bis(4-methoxybenzyl)pyrimidine-2,4-diamine To a solution of 2,6-dichloropyrimidin-4-amine (1 g, 6.10 mmol) in 2-propanol (6.10 mL) was added N,N-diisopropylethylamine (1.278 ml, 7.32 mmol) and bis(4- methoxybenzyl)amine (1.569 g, 6.10 mmol). The resulting solution was stirred at 100 oC for 16 h, cooled to RT, diluted with water (100 mL), and extracted with ethyl acetate (100 mL). The organic extract was washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield the crude product, which was used in the next step without further purification. LC-MS calculated for C20H22ClN4O2 (M+H)+: 385.1; found 385.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With triethylamine In tetrahydrofuran at 20℃; for 3h; | D Step D: i-Isopropyl-N,N-bis(4-methoxybenzyl)-iH-pyrazole-3-sulfonamide To a mixture of i-isopropyl-iH-pyrazole-3-sulfonyl chloride (17.3 g, 82.91 mmol, 1 eq) and TEA (10.91 g, 107.78 mmol, 1.3 eq) in THF (200 mL) was added bis(4- methoxybenzyl)amine (14.93 g> 58.04 mmol, 0.7 eq). The reaction mixture was stirred at 20 °C for 3 hours, and then poured into water (500 mL) and extracted with DCM (2 x 500 mL). The combined organic layers were washed with brine (2 x 500 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by column chromatography (Si02, petroleum ether: ethyl acetate, 20:1 to 4:1) to give the title compound (21.13 g, 59 % yield, 100 % purity on LCMS) as a colourless oil. (0820) NMR (400 MHz, CDCI3) d 746 (d, 1 H), 7.09-7.04 (m, 4 H), 6.80-6.74 (m, 4 H), 6.65 (d, 1 H), 4.62-4.54 (m, 1 H), 4.32 (s, 4 H), 3.79 (s, 6 H) and 1.53 (d, 6 H). (0821) LCMS: m/z 452.2 (M+Na)+ (ES+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7.8 g | Reference Example 8: 2-chloro-N,N-bis(4-methoxybenzyl)-5-nitro-N'-(propan-2-yl) pyrimidine-4,6-diamine To a solution of <strong>[4359-87-9]2,4,6-trichloro-5-nitropyrimidine</strong> (4 g) in methylene chloride (130 mL), bis (4-methoxybenzyl) amine (4.5 g) and triethylamine (2.4 mL) in methylene chloride (20 mL) was slowly added dropwise at 0 C. The reaction mixture was stirred at 0 C for 30 minutes. To the reaction mixture, isopropylamine (1.7 mL) and triethylamine (2.7 mL) in a solution of methylene chloride (20 mL) was added dropwise at 0 C. The reaction mixture was stirred for 120 minutes. To the reaction mixture, water was poured and was extracted with methylene chloride. The obtained organic layer was washed with saturated saline solution, and was dried over magnesium sulfate, and thereafter, was concentrated under reduced pressure. The resulting residue was stirred in hexane / MTBE (4/1) for 30 minutes. The precipitated solid was filtrated. The filtrate was dried to give the title compound (7.8 g) having the following physical properties. TLC: Rf 0.41 (hexane : ethyl acetate = 5 : 1); 1H-NMR (CDCl3): delta1.24-1.30, 3.80, 4.37-4.50, 6.79-6.85, 6.97-7.03, 8.18-8.24. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59.2% | With triethylamine In isopropyl alcohol at 160℃; for 1h; Microwave irradiation; | 3.1 Step 1: 6-Chloro-N4,N4-bis(1-methoxybenzyl)pyrimidine-1,5-diamine. To a solution of bis(4-methoxybenzyl)-amine (2.67 g, 10.37 mmol), and 4,6-dichloropyrimidin-5-amine (1.7 g, 10.37 mmol) in isopropanol (10.37 mL) was added triethylamine (2.89 mL, 20.7 mmol). The reaction was heated to 160° C. via microwave irradiation for 1 h. The reaction was cooled to rt and partitioned between EtOAc and water. The organic phase was separated, washed with water (2×) and brine, then dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: 0-50% EtOAc/Heptane) to provide 6-chloro-N4,N4-bis(4-methoxybenzyl)pyrimidine-4,5-diamine (2.36 g, 6.13 mmol, 59.2% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.89 (s, 1H) 7.12 (d, J=8.50 Hz, 4H) 6.82-6.87 (m, 4H) 5.19 (s, 2H) 4.41 (s, 4H) 3.72 (s, 6H) 2.31 (s, 2H). m/z (ESI, +ve ion): 384.8 (M+H)+. |
53% | With triethylamine In isopropyl alcohol for 2h; | 1 Step 1: 6-Chloro-N4,N4-bis(4-methoxybenzyl)pyrimidine-4,5-diamine An amber solution of 4,6-dichloropyrimidin-5-amine (1.7 g, 10.4 mmol; CombiBlocks, Inc., San Diego, Calif.), bis(4-methoxybenzyl)amine (2.67 g, 10.4 mmol; Sigma-Aldrich, St. Louis, Mo.), and Et3N (2.89 mL, 20.7 mmol) in isopropanol (10 mL) was stirred in the microwave at 120° C. for 1 h then at 160° C. for 1 h. The reaction mixture was diluted with EtOAc (200 mL), added to a separatory funnel, and washed with water (3*75 mL); the organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel, 0-50% EtOAc/heptane) to give 6-chloro-N4,N4-bis(4-methoxybenzyl)pyrimidine-4,5-diamine (2.11 g, 5.48 mmol, 53% yield) as an amber oil. 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H) 7.14 (br d, J=8.1 Hz, 4H) 6.85 (br d, J=8.5 Hz, 4H) 4.47 (br s, 4H) 3.91 (br s, 2H) 3.80 (s, 6H). MS (ESI, +ve) m/z: 385.0 (M+1)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With sodium carbonate In toluene at 70 - 90℃; | I-33.1 [0692] Step 1: 2-(Bis(4-methoxybenzyl)amino)-4-methyl-5-nitropyridine 1-oxide. A mixture of 2-chloro-4-methyl-5-nitropyridine 1-oxide (2.3 g, 12.20 mmol; product of step 2 in preparation of Intermediate I-32), bis(4-methoxybenzyl)-amine (3.45 g, 13.42 mmol), and sodium carbonate (anhydrous, powder; 2.6 g, 24.39 mmol) in toluene (70 mL) was stirred at 70 °C for 16 h. Additional sodium carbonate (anhydrous, powder; 2.6 g, 24.39 mmol) and bis(4-methoxybenzyl)-amine (3.45 g, 13.42 mmol) were added, and the resulting mixture was stirred at 90 °C for 2 h. The reaction mixture was then filtered, and the filter cake washed with DCM (3 x 100 mL). The combined filtrates were concentrated in vacuo and the residue chromatographically purified (silica gel, 0%-10% MeOH/DCM) to provide 2-(bis(4-methoxybenzyl)amino)-4-methyl-5-nitropyridine 1-oxide (2.75 g, 6.72 mmol, 55 % yield) as a brown solid. 1H NMR (CDCl3) d: 9.11 (s, 1H), 7.26 (d, J=8.7 Hz, 4H), 6.92 (d, J=8.7 Hz, 4H), 6.60 (s, 1H), 4.77 (s, 4H), 3.87 (s, 6H), 2.59 (s, 3H). m/z (ESI, +ve ion): 410.0 (M+H)+. |
55% | With sodium carbonate In toluene at 70 - 90℃; for 18h; | 1 Step 1: 2-(Bis(4-methoxybenzyl)amino)-4-methyl-5-nitropyridine 1-oxide A mixture of 2-chloro-4-methyl-5-nitropyridine 1-oxide (2.3 g, 12.20 mmol; product of step 2 in preparation of Intermediate I-32), bis(4-methoxybenzyl)-amine (3.45 g, 13.42 mmol), and sodium carbonate (anhydrous, powder; 2.6 g, 24.39 mmol) in toluene (70 mL) was stirred at 70° C. for 16 h. Additional sodium carbonate (anhydrous, powder, 2.6 g, 24.39 mmol) and bis(4-methoxybenzyl)-amine (3.45 g, 13.42 mmol) were added, and the resulting mixture was stirred at 90° C. for 2 h. The reaction mixture was then filtered, and the filter cake washed with DCM (3*100 mL). The combined filtrates were concentrated in vacuo and the residue chromatographically purified (silica gel, 0%-10% MeOH/DCM) to provide 2-(bis(4-methoxybenzyl)amino)-4-methyl-5-nitropyridine 1-oxide (2.75 g, 6.72 mmol, 55% yield) as a brown solid. 1H NMR (CDCl3) δ: 9.11 (s, 1H), 7.26 (d, J=8.7 Hz, 4H), 6.92 (d, J=8.7 Hz, 4H), 6.60 (s, 1H), 4.77 (s, 4H), 3.87 (s, 6H), 2.59 (s, 3H). m/z (ESI, +ve ion): 410.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 110℃; for 4h; | 42 Synthesis of the compound 42-b At room temperature, bis(p-methoxybenzyl)amine (215.8 mg, 0.84 mmol) and diisopropylethylamine (271 mg, 2.1 mmol) were added into compound 26-a (300 mg, 0.79 mmol) in dioxane (20 mL) solution. The reaction mixture was heated to 110°C and stirred for 4 hours, then cooled down to room temperature. Saturated ammonium chloride solution (20 mL) was added to quench the reaction. After extraction with EtOAc (50 mL*2), the organic phases were combined and washed by water (30 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (PE:EtOAc=20:1-10:1) to give a yellow solid 42-b (320 mg, yield: 77%). LC-MS (ESI): m/z= 398 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 60℃; for 5h; | 34 Synthesis of compound 34-c Compound 34-d (120 mg, 0.30 mmol), bis (p-methoxybenzyl) amine (168 mg, 0.65 mmol), and diisopropylethylamine (84 mg, 0.65 mmol) were added to dry tetrahydrofuran (10 mL). After the reaction mixture was reacted at 60 ° C for 5 hours, it was cooled to room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain the product 34-c (152 mg, yield: 78%) as a yellow solid. |
78% | With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 60℃; for 5h; | 34 Synthesis of the compound 34-c Compound 34-d (120 mg, 0.30 mmol), bis(p-methoxybenzyl)amine (168 mg, 0.65 mmol) and diisopropylethylamine(84 mg, 0.65 mmol) were added into dry tetrahydrofuran (10 mL). The reaction mixture was reacted at 60°C for5 hours, then cooled down to room temperature. The reaction solution was then concentrated, and the residue waspurified by silica gel chromatography (PE:EtOAc=10:1) to give a yellow solid product 34-c (152 mg, yield: 78%).[0422] LC-MS (ESI): m/z= 588 [M+1]+.. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 60℃; for 5h; | 40 Synthesis of the compound 40-c Compound 40-d (300 mg, 0.86 mmol), bis(p-methoxybenzyl)amine (444 mg, 1.7 mmol) and diisopropylethylamine(134 mg, 1.03 mmol) were added into dry tetrahydrofuran (15 mL). The reaction mixture was reacted at 60°C for5 hours, then cooled down to room temperature. The reaction solution was then concentrated, and the residue waspurified by silica gel chromatography (PE:EtOAc=15:1) to give a yellow solid product 40-c (410 mg, yield: 84%).[0475] LC-MS (ESI): m/z= 570 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | In tetrahydrofuran at 50℃; for 5h; | 60 Synthesis of compound 60-c Compound 60-d (120 mg, 0.29 mmol) and bis (p-methoxybenzyl) amine (224 mg, 0.87 mmol) were added to dry tetrahydrofuran (10 mL). After the reaction mixture was reacted at 50 ° C for 5 hours, it was cooled to room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain 360-c as a yellow solid product (120mg, yield: 65%). |
65% | In tetrahydrofuran at 50℃; for 5h; | 60 Synthesis of the compound 60-c Compound 60-d (120 mg, 0.29 mmol), bis(p-methoxybenzyl)amine (224 mg, 0.87 mmol) were added into drytetrahydrofuran (10 mL). The reaction mixture was reacted at 50°C for 5 hours, then cooled down to room temperature.The reaction solution was then concentrated under reduced pressure, and the residue was purified by silica gel chromatography(PE:EtOAc=10:1) to give a yellow solid product 360-c (120 mg, yield: 65%).[0597] LC-MS (ESI): m/z= 634 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 60℃; for 5h; | 61 Synthesis of compound 61-d Compound 61-e (160 mg, 0.37 mmol), bis (p-methoxybenzyl) amine (192 mg, 0.74 mmol) and diisopropylethylamine (58 mg, 0.45 mmol) were added to dry tetrahydrofuran (10 mL). After the reaction mixture was reacted at 60 ° C for 5 hours, it was cooled to room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15: 1) to obtain the product 61-d as a yellow solid.(175mg, yield: 72%). |
72% | With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 60℃; for 5h; | 61 Synthesis of the compound 61-d Compound 61-e (160 mg, 0.37 mmol), bis(p-methoxybenzyl)amine (192 mg, 0.74 mmol) and diisopropylethylamine(58 mg, 0.45 mmol) were added into dry tetrahydrofuran (10 mL). The reaction mixture was reacted at 60°C for5 hours, then cooled down to room temperature. The reaction solution was then concentrated under reduced pressure,and the residue was purified by silica gel chromatography (PE:EtOAc=15:1) to give a yellow solid product 61-d (175mg, yield: 72%).[0609] LC-MS (ESI): m/z= 652 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With N-ethyl-N,N-diisopropylamine In butan-1-ol at 20 - 120℃; for 73h; | 99.1 Step 1: 6-bromo-N2,N2-bis(4-methoxybenzyl,)pyrazine-2, 3-diamine To a stirred suspension of 3,5-dibromopyrazin-2-amine (6 g, 23.25 mmol) andbis(4-methoxybenzyl)amine (6.72 g, 25.6 mmol) in n-butanol (23.25 ml) at roomtemperature was added N,N-diisopropylethylamine (8.18 ml, 46.5 mmol). The reaction mixture was heated at 120 °C for 72 hours. The reaction mixture was cooled to room temperature. The resulting slurry was stirred at room temperature for 1 horn. The suspension was filtered to remove the excess 3,5-dibromopyrazin-2-amine. The filtrate was concentrated in vacuo. The residue was purified by Biotage Isolera (with 330 g silica gel column) eluting with 0 - 50% EtOAc/Hexane to give the product as a brown very viscous oil (6.282 g, 77% yield). LC-MS calculated for C20H22BrN4O2(M+H)t mlz = 429.1; found 429.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 20 - 80℃; for 2h; | 126.4 Step 4: 6-bromo-2-(((tert-butyldimethylsilyl,)oxy,) (2, 6-dzfiuorophenyl)methyl,)-N, Nbis(4-methoxybenzyl)-[1, 2, 4]triazolo[1 , 5-a]pyrazin-8 -amine To a stirred solution of 6,8-dibromo-2-(((tert-butyldimethylsilyl)oxy)(2,6-difluorophenyl)methyl)-[1,2,4jtriazolo[1,5-ajpyrazine (0.98 g, 1.741 mmol) in 2-Propanol (10 ml) at rt was added bis(4-methoxybenzyl)amine (0.594 g, 2.264 mmol) and N,N-Diisopropylethylamine (0.6 13 ml, 3.48 mmol). The reaction mixture was heated at 80 °C for 2 hours. The reaction mixture was cooled to rt, and concentrated in vacuo. The residue was purified by Biotage Isolera (with 120 g silica gel column)eluting with 0 - 30% EtOAc/Hexane to give the product as a white foamy solid (1.190g, 96%). LCMS calculated for C34H39BrF2N5O3Si: mlz = 710.2, found 710.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 85℃; | 27.4; 49.4 Step 4. 3-(8-(Bis(4-methoxybenzyl)amino)-2-bromo-[1, 2, 4]tri azolo[1 , 5-a]pyrazin-6- yl)benzonitrile A mixture of 3-(2-bromo-8-chloro-[1 ,2,4jtriazolo[1 ,5-ajpyrazin-6-yl)benzonitrile (8.99 g, 26.9 mmol), bis(4-methoxybenzyl)amine (10.37 g, 40.3mmol), and DIPEA (9.4 mL, 53.7 mmol) in DMF (134 mL) was stirred at 85 °Covernight. The reaction mixture was cooled to room temperature, and diluted withwater. The resulting precipitate was collected via filtration, and dried to afford theproduct (14.1 g, 94%). LC-MS calculated for C28H24BrN6O2 (M+H): mlz = 555.1; found 555.1. |
94% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 85℃; | A9.4; A10.4 Step 4.3-(8-(Bis(4-methoxybenzyl)amino)-2-bromo-[1,2,4]triazolo[1,5-a]pyrazin-6- yl)benzonitrile A mixture of 3-(2-bromo-8-chloro-[1,2,4]triazolo[1,5-a]pyrazin-6- yl)benzonitrile (8.99 g, 26.9 mmol), bis(4-methoxybenzyl)amine (10.37 g, 40.3 mmol), and DIPEA (9.4 mL, 53.7 mmol) in DMF (134 mL) was stirred at 85 °C overnight. The reaction mixture was cooled to room temperature, and diluted with water. The resulting precipitate was collected via filtration, and dried to afford the product (14.1 g, 94%). LC-MS calculated for C28H24BrN6O2(M+H)+: m/z = 555.1; found 555.1. |
94% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 85℃; | A9.4; A10.4 Step 4. 3-(8-(Bis(4-methoxybenzyl)amino)-2-bromo-[ 1, 2, 4 ]triazolo[ 1, 5-a]pyrazin-6-yl)benzonitrile A mixture of 3-(2-bromo-8-chloro-[1,2,4]triazolo[1,5-α]pyrazin-6-yl)benzonitrile (8.99 g, 26.9 mmol), bis(4-methoxybenzyl)amine (10.37 g, 40.3 mmol), and DIPEA (9.4 mL,53.7 mmol) in DMF (134 mL) was stirred at 85 °C overnight. The reaction mixture was cooled to room temperature, and diluted with water. The resulting precipitate was collected via filtration, and dried to afford the product (14.1 g, 94%). LC-MS calculated for C28H24BrN6O2(M+H)+: m/z = 555.1; found 555.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 110℃; for 4h; | 42 Synthesis of compound 42-b At room temperature, bis (p-methoxybenzyl) amine (215.8 mg, 0.84 mmol) and diisopropylethylamine (271 mg, 2.1 mmol) were added to dioxane of compound 26-a (300 mg, 0.79 mmol). (20 mL) solution. The reaction solution was raised to 110 ° C and stirred for 4 hours, and then cooled to room temperature. The reaction was quenched by the addition of a saturated ammonium chloride solution (20 mL). It was extracted with ethyl acetate (50 mL × 2), and the organic phases were combined, washed with water (30 mL) and saturated brine (20 mL), and dried over anhydrous sodium sulfate. It was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1-10: 1) to obtain 42-b (320 mg, yield: 77%) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.8% | With triethylamine In tetrahydrofuran at 20℃; for 4h; | 1.1 2-Butoxy-6-chloro-N,N-bis(4-methoxybenzyl)-5-nitropyrimidin-4-amine 1b 2-Butoxy-4,6-dichloro-5-nitropyrimidine 1a (4.62 g, 17.43 mmol, prepared according to the known method disclosed in ) was dissolved in tetrahydrofuran (50 mL), and triethylamine (2.64 g, 26.14 mmol) and N,N-bis(4-methoxybenzyl)amine (4.49 g, 17.43 mmol) were added therein in turn, and then was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by eluting system A using CombiFlash rapid preparation to give the title product 1b (6.20 g), 73.8% yield. MS m/z (ESI): 487.5 [M+1]. |
Yield | Reaction Conditions | Operation in experiment |
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91% | With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 95℃; for 1h; | Intermediate P9 (1683) 4-(bis(4-methoxybenzyl)amino)-5-(4-(((tert-butyldimethylsilyl)oxy)methyl)-5-cvclopropylisoxazol-3-yl)-7- isopropyl-7H-pyrrolo[2.3-dlpyrimidine-6-carbaldehvde A solution of 5-(4-(((tert-butyldimethylsilyl)oxy)methyl)-5-cyclopropylisoxazol-3-yl)-4-chloro-7-isopropyl- 7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde (Intermediate P8; 106 mg, 0.22 mmol) in DMSO (444 m) was treated with bis(4-methoxybenzyl)amine (336.2 mg, 1.110 mmol) and DIEA (387.9 m, 2.221 mmol). The resulting mixture was stirred for 1 h at 95 °C. After subsequently cooling to RT, the reaction was quenched with water and extracted with EtOAc (x3). The combined organic extracts were washed with brine, dried over anhydrous Na2S04(S), filtered, and concentrated in vacuo. The crude residue was purified by silica chromatography (0-50% EtOAc in hexanes as the gradient eluent) to afford the title compound (140 mg, 91% yield). MS (apci) m/z = 696.3 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With triethylamine In tetrahydrofuran at -35 - 0℃; for 2.5h; | 1 Step 1: 4-fluoro-N,N-bis[(4-methoxyphenyl)methyl]-3-nitro-benzenesulfonamide To a cooled (-35 °C) solution of 4-Fluoro-3-nitrobenzenesulfonyl chloride (4.89 g, 20.42 mmol) in THF (50 mL) was added Triethylamine (3.13 mL, 22.46 mmol), followed by addition of Bis-(4-methoxybenzyl)amine (4.97 mL, 20.7 mmol) in THF (50 mL) solution over 30 min. while the temperature was kept at -35 °C. After completion of the addition, the temperature was allowed slowly to warm to 0 °C over 1 h., and the mixture was stirred at 0 °C for an additional hour. The mixture was neutralized with 1 N HC1 to pH about 4-5 and diluted with EtOAc (100 mL). The organic layer was separated, washed with 1 N HC1 (10 mL), 7.5% NaHC03 aqueous solution (20 mL), and brine, dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was treated with DCM (30 mL), and hexane was added to the suspension until it became cloudy. The resulting suspension was sonicated for 2 min. and left at r.t. for 1 h. The mixture was filtered and washed with hexane to afford the desired title product (6.85 g) without further purification. The mother liquid was concentrated under reduced pressure. The residue was treated with DCM (5 mL) and hexane was added as the procedures mentioned above to afford the additional 0.51 g of the title product. Total product 4-fluoro-N,N-bis[(4-methoxyphenyl)methyl]-3-nitro-benzenesulfonamide obtained is 7.36 g (78%). NMR (400 MHz, DMSO-de): d 8.18-8.23 (m, 2 H), 7.75-7.79 (q, 1 H), 7.08 (d, 4 H), 6.81 (d, 4 H), 4.31 (s, 4 H), 3.71 (s, 6 H). 19F NMR (376 MHz, DMSO-d6): d -112.54 (s, 1 F). LCMS calculated for C22H22FN2O6S (M+H)+: m/z = 461.11; found: 461.1. |
78% | With triethylamine In tetrahydrofuran at -35 - 0℃; for 2.5h; | 7 Step 7: 4-fluoro-N,N-bis[ ( 4-methoxyphenyl)methyl ]-3-nitro-benzenesulfonamide To a cooled (-35 °C) solution of 4-Fluoro-3-nitrobenzenesulfonyl chloride (4.89 g, 20.42 mmol) in THF (50 mL) was added Triethylamine (3.13 mL, 22.46 mmol), followed by addition of bis-(4-methoxybenzyl)amine (4.97 mL, 20.73 mmol) in THF (50 mL) solution over 30 min. while the temperature was kept at -35 °C. After completion of the addition, the temperature was allowed slowly to warm to 0 °C over 1 h., and the mixture was stirred at 0 °C for an additional hour, TLC (PE : EA = 5 : 1, Rf = 0.5)). The mixture was neutralized with 1 N HC1 to pH about 4-5 and diluted with EtOAc (100 mL). The organic layer was separated, washed with IN HC1 (10 mL), 7.5% NaHCCh aqueous solution (20 mL), and brine, dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was treated with DCM (30 mL), and hexane was added to the suspension until it became cloudy. The resulting suspension was sonicated for 2 min. and left at r.t. for 1 h. The mixture was filtered and washed with hexane to afford the desired title product (6.85 g) without further purification. The mother liquid was concentrated under reduced pressure. The residue was treated with DCM (5 mL) and hexane was added as the procedures mentioned above to afford the additional 0.51 g of the title product. Total product 4-fluoro-N,N-bis[(4- methoxyphenyl)methyl]-3-nitro-benzenesulfonamide obtained is 7.36 g (78%). 'H NMR (400 MHz, DMSO-de): d 8.18-8.23 (m, 2 H), 7.75-7.79 (q, 1 H), 7.08 (d, 4 H), 6.81 (d, 4 H), 4.31 (s, 4 H), 3.71 (s, 6 H).19F NMR (376 MHz, DMSO-d6): d -112.54 (s, 1 F). LCMS calc for C22H22FN2O6S (M+H)+: m/z = 461.11 ; Found: 461.1. |
78% | With triethylamine In tetrahydrofuran at -35 - 0℃; for 2.5h; | 1 Step 1: 4-fluoro-N,N-bis[(4-methoxyphenyl)methyl ]-3-nitro-benzenesulfonamide To a cooled (-35 °C) solution of 4-Fluoro-3-nitrobenzenesulfonyl chloride (4.89 g, 20.42 mmol) in THF (50 mL) was added Triethylamine (3.13 mL, 22.46 mmol), followed by addition of Bis-(4-methoxybenzyl)amine (4.97 mL, 20.7 mmol) in THF (50 mL) solution over 30 min. while the temperature was kept at -35 °C. After completion of the addition, the temperature was allowed slowly to warm to 0 °C over 1 h., and the mixture was stirred at 0 °C for an additional hour. The mixture was neutralized with 1 N HC1 to pH about 4-5 and diluted with EtOAc (100 mL). The organic layer was separated, washed with 1 N HC1 (10 mL), 7.5% NaHC03 aqueous solution (20 mL), and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was treated with DCM (30 mL), and hexane was added to the suspension until it became cloudy. The resulting suspension was sonicated for 2 min. and left at r.t. for 1 h. The mixture was filtered, and washed with hexane to afford the desired title product (6.85 g) without further purification. The mother liquid was concentrated under reduced pressure. The residue was treated with DCM (5 mL) and hexane was added as the procedures mentioned above to afford the additional 0.51 g of the title product. Total product 4-fluoro-N,N- bis[(4-methoxyphenyl)methyl]-3-nitro-benzenesulfonamide obtained is 7.36 g (78%). 1H NMR(400 MHz, DMSO-d6): δ 8.18-8.23 (m, 2 H), 7.75-7.79 (q, 1 H), 7.08 (d, 4 H), 6.81 (d, 4 H),4.31 (s, 4 H), 3.71 (s, 6 H). 19F NMR (376 MHz, DMSO-d6): -11 δ2.54 (s, 1 F). LCMS calculated for C22H22FN2O6S (M+H)+: m/z = 461.11; found: 461.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | In dichloromethane at 20℃; for 2h; Cooling with ice; | A Step A: Ethyl 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-methyl-1H-pyrazole-5- carboxylate Ethyl 3-(chlorosulfonyl)-1-methyl-1H-pyrazole-5-carboxylate (9.2 g, 36.4 mmol) was added dropwise to a solution of bis(4-methoxybenzyl)amine (9.4 g, 36.5 mmol) and triethylamine (10 mL, 71.7 mmol) in DCM (200 mL), cooled in an ice bath. The resulting mixture was stirred for 30 minutes, warmed to room temperature and stirred for 90 minutes before being washed with water (200 mL), aqueous hydrochloric acid (1 M, 200 mL), water (200 mL), dried (MgSO4), filtered and evaporated to give a yellow oil. This was purified by chromatography on silica gel (220 g column, 0-60% ethyl acetate/isohexane) to afford the title compound (15.9 g, 91 %) as a white solid. 1H NMR (DMSO-d6) d 7.19 - 7.00 (m, 5 H), 6.85 - 6.77 (m, 4 H), 4.33 (q, 2 H), 4.25 (s, 4 H), 4.15 (s, 3 H), 3.71 (s, 6 H) and 1.33 (t, 3 H). LCMS m/z 496.4 (M+Na)+ (ES+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Stage #1: lithium 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfinate With N-chloro-succinimide In dichloromethane for 4h; Cooling with ice; Stage #2: N,N-bis(p-methoxybenzyl)amine With triethylamine In dichloromethane at 20℃; for 1h; Cooling with ice; | Step B: N,N-bis(4-methoxybenzyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5- sulfonamide NCS (12.0 g, 90 mmol) was added to a suspension of lithium 1-(tetrahydro-2H-pyran- 2-yl)-1H-pyrazole-5-sulfinate (20 g, 90 mmol) in DCM (250 mL) cooled in an ice bath. The mixture was stirred for 4 h, quenched with water (100 mL), and then partitioned between DCM (300 mL) and water (200 mL). The organic phase was washed with water (200 mL), dried (MgSO4), filtered and evaporated to ~50mL. The solution was added to a mixture of bis(4-methoxybenzyl)amine (24 g, 93 mmol) and triethylamine (40 mL, 287 mmol) in DCM (300 mL) cooled in an ice bath. After stirring for 1 h, the mixture was warmed to RT, and then partitioned between DCM (300 mL) and water (250 mL). The organic layer was washed with water (250 mL), aq 1M HCl (2 x 250 mL), water (250 mL), dried (MgSO4), filtered, and evaporated to afford the crude title compound (41.02 g, 97 %) as a brown oil. LCMS m/z 494.2 (M+Na)+(ES+). |
41 g | Stage #1: lithium 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfinate With N-chloro-succinimide In dichloromethane for 4h; Cooling with ice; Stage #2: N,N-bis(p-methoxybenzyl)amine With triethylamine In dichloromethane for 1h; Cooling with ice; | B Step B: N,N-bis(4-Methoxybenzyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5- sulfonamide NCS (12.0 g, 90 mmol) was added to a suspension of lithium 1-(tetrahydro-2H-pyran- 2-yl)-1H-pyrazole-5-sulfinate (20 g, 90 mmol) in DCM (250 mL), cooled in an ice bath. The mixture was stirred for 4 hours, quenched with water (100 mL), and then partitioned between DCM (300 mL) and water (200 mL). The organic phase was washed with water (200 mL), dried (MgSO4) and evaporated to about 50 mL. The solution was added to a mixture of bis(4-methoxybenzyl)amine (24 g, 93 mmol) and triethylamine (40 mL, 287 mmol) in DCM (300 mL), cooled in an ice bath. After stirring for 1 hour, the mixture was warmed to room temperature, and partitioned between DCM (300 mL) and water (250 mL). The organic layer was washed with water (250 mL), aq 1 M HCl (2 x 250 mL), water (250 mL), dried (MgSO4) and evaporated to afford the title compound (41.0 g, 97 %) as a brown oil. LCMS m/z 494.2 (M+Na)+ (ES+). |
Stage #1: lithium 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfinate With N-chloro-succinimide In dichloromethane for 4h; Cooling with ice; Stage #2: N,N-bis(p-methoxybenzyl)amine With triethylamine In dichloromethane for 1h; Cooling with ice; | Step B: N,N-bis(4-methoxybenzyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5- sulfonamide NCS (12.0 g, 90 mmol) was added to a suspension of lithium 1-(tetrahydro-2H-pyran- 2-yl)-1H-pyrazole-5-sulfinate (20 g, 90 mmol) in DCM (250 mL) cooled in an ice bath. The mixture was stirred for 4 h, quenched with water (100 mL), and then partitioned between DCM (300 mL) and water (200 mL). The organic phase was washed with water (200 mL), dried (MgSO4), filtered and evaporated to ~50mL. The solution was added to a mixture of bis(4-methoxybenzyl)amine (24 g, 93 mmol) and triethylamine (40 mL, 287 mmol) in DCM (300 mL) cooled in an ice bath. After stirring for 1 h, the mixture was warmed to RT, and then partitioned between DCM (300 mL) and water (250 mL). The organic layer was washed with water (250 mL), aq 1M Hd (2 x 250 mL), water (250 mL), dried (MgSO4), filtered, and evaporated to afford the crude title compound (41.02 g, 97 %) as a brown oil. LCMS m/z 494.2 (M+Na)+ (ES+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 16h; | 10.1 Step 1 To a solution of bis(4-methoxybenzyl)amine (8.95 g, 34.8 mmol) in DCM (50 mL) were added DIPEA (6.06 mL, 43.5 mmol) and methyl 2-(chlorosulfonyl)acetate (5.0 g, 29 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h before it was quenched with ice water and extracted with DCM. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, water, and brine. The organic extract was dried over Na2SO4, filtered, and concentrated. The concentrate was purified by flash column chromatography using a gradient of 15% ethyl acetate in petroleum ether to provide methyl 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)acetate (5.5 g, 14 mmol, 48% yield) as pale yellow gum.1H NMR (400 MHz, DMSO-d6): d ppm 7.14 (d, J=8.4 Hz, 4 H), 6.86 (d, J=8.4 Hz, 4 H), 4.31 (s, 2 H), 4.25 (s, 4 H), 3.73 (s, 6 H), 3.70 (s, 3 H). m/z (ESI): 392.1 (M-H)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With triethylamine In 1,4-dioxane at 110℃; for 3h; | 24.A Step A 6-chloro-N-(2,4-dimethoxybenzyl)-N-(4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5- c]pyridin-4-amine The mixture of 4,6-dichloro-3H-[1,2,3]triazolo[4,5-c]pyridine (600 mg, 3.17 mmol), bis(4-methoxybenzyl)amine (899 mg, 3.49 mmol) and triethylamine (531 µl, 3.81 mmol) in 1,4-dioxane (1.7 mL) was stirred at 110 °C for 3 days. Direct purification on silica gel column afforded the desired product (875 mg, 63%). LC-MS calculated for C22H23ClN5O3: 440.1 (M+H)+; found: 440.3 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With triethylamine In tetrahydrofuran at 20℃; for 2h; | F Step F: 7-bromo-2-chloro-N, N-bis (4-methoxybenzyl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine To a stirred solution of 7-bromo-2, 4-dichloroimidazo [2, 1-f] [1, 2, 4] triazine (30 g, 0.11 mol) in THF (500 ml) , TEA (22.6 g, 0.22 mol) was added dropwise. The mixture was stirred at rt for 10 min. A solution of bis (4-methoxybenzyl) amine (31.6 g, 0.12 mol) in THF (80 ml) was added dropwise to the above solution. The mixture was stirred at rt for 2 h. The solution was quenched with H2O (300 ml) and then extracted with EA (200 ml X 2) . The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was slurried in PE (300 ml) and filtered to afford the product (41.4 g, 76%) as a white solid. MS: M/e 488 (M+1)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 90℃; | A Step A: 6-chloro-N, N-bis (4-methoxybenzyl) imidazo [1, 2-b] pyridazin-8-amine To a stirred solution of 8-bromo-6-chloroimidazo [1, 2-b] pyridazine (2 g, 8.7 mmol) in DMF (20 mL) , bis (4-methoxybenzyl) amine (2.7 g, 10.44 mmol) and DIEA (2.3 g, 17.4 mmol) were added. The reaction mixture was stirred at 90 overnight. The mixture was diluted with H2O (50 mL) and extracted with EtOAc (20 ml x 3) . The combined organic phase was washed with brine, dried over Na2SO4and concentrated in vacuo. The crude product was purified by column chromatography to give the product (2.8 mg, 80%) as white solids. MS: M/e 308 (M+1)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With potassium fluoride In dimethyl sulfoxide at 110℃; for 4h; | 5 Preparation of Intermediate 5: 1.00g intermediate 4, 1.00g bis(p-methoxybenzyl)amine, 1.00g KF reagent was added to 20mL dimethyl sulfoxide successively, and reacted at 110 for 4h; The reaction mixture was cooled, diluted with 100 mL of water, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, and the combined organic phase was washed with saturated brine; then the organic phase was dried with anhydrous sodium sulfate, and then reduced The solvent was removed by pressure concentration, and the residue was purified by silica gel column chromatography with an eluent of petroleum ether/dichloromethane/ethyl acetate=3/2/1 by volume to obtain Intermediate 5. It is a yellow solid 1.30g, the yield is 74%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With triethylamine In isopropyl alcohol at 95℃; for 16h; Inert atmosphere; | 25.2 STEP 2: Synthesis of tert-Butyl ( s.3s)-3-(2-(bis(4-methoxybenzyl )amino)-3- nitropyridin-4-ylamino)cvclobutyl(methvncarbamate To a mixture of tert-butyl N-[3-[(2-chloro-3-nitro-4- pyridyl)amino]cyclobutyl]-N-methyl-carbamate (3.98 g, 11.15 mmol) in isopropyl alcohol (50 mL) was added l-(4-methoxyphenyl)-N-[(4- methoxyphenyl)methyl]methanamine (2.87 g, 11.15 mmol) and triethylamine (1.47 g, 14.5 mmol) under N2. The resulting mixture was stirred for 16 h at 95 °C. LCMS showed the reaction was complete. The reaction mixture was cooled to room temperature and concentrated under vacuum to afford tert-butyl N-[3-[[2-[bis[(4- methoxyphenyl)methyl]amino]-3-nitro-4-pyridyl]amino]cyclobutyl]-N-methyl-carbamate (6.0 g, 93%) as a yellow oil.1HNMR (300 MHz, DMSO-d6) d 7.86 (d, J= 6.0 Hz, 1H), 7.48 (d, J= 6.3 Hz, 1H), 7.12-6.99 (m, 4H), 6.91-6.79 (m, 4H), 6.27 (d, J= 6.0 Hz, 1H), 4.32 (s, 4H), 3.72 (s, 7H), 2.76 (s, 3H), 2.65-2.55 (m, 3H), 2.25-2.10 (m, 2H), 1.40 (s, 9H). ESI-MS[M+H]+calc’d for (C31H39N5O6) 579.29 found: 579.25 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With pyridine In dichloromethane at 20℃; | 17 To a solution of 4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]furan-2-sulfonyl chloride (29) (600 mg, 1.0 eq) in DCM (15 mL) and pyridine (2 mL) was added bis(4- methoxybenzyl)amine (930 mg, 1.5 eq). The resulting mixture was stirred at room temperature overnight. The reaction was diluted with DCM (50 mL), washed with water (2 x 30 mL), 1N HCl, and brine. The crude mixture was purified by column chromatography to afford N,N-bis(4- methoxybenzyl)-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]furan-2-sulfonamide (30) (560 mg, 50%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.4% | With triethylamine In tetrahydrofuran; dichloromethane at 20℃; for 12h; | Step C: ethyl 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazole-4-carboxylate To a solution of 1-(4-methoxyphenyl)-N-[(4-methoxyphenyl)methyl]methanamine (4.85 g, 18.9 mmol) in DCM (50 mL) was added TEA (6.36 g, 62.9 mmol), followed by another solution of ethyl 3-(chlorosulfonyl)-1H-pyrazole-4-carboxylate (5.0 g, 17.3 mmol, 82.5% purity) in THF (100 mL). The reaction mixture was stirred at 20 °C for 12 h, then concentrated in vacuum. The residue was purified by reverse phase flash chromatography (0.1% TFA). The eluting phase was adjusted to pH 8 with solid NaHCO3, and the aqueous phase was extracted with EtOAc (200 mL x 3). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give the title compound (8.0 g, 97.4% yield) as a yellow solid. LCMS: m/z 460.1 (M+H)+(ES+).1H NMR (DMSO-d6): d 8.52 (s, 1H), 7.01 (d, 4H), 6.77 (d, 4H), 4.36 (s, 4H), 4.23 (q, 2H), 3.70 (s, 6H), 1.26 (t, 3H). One exchangeable proton not observed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | Stage #1: lithium 4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfinate With N-chloro-succinimide In dichloromethane for 18h; Cooling with ice; Stage #2: N,N-bis(p-methoxybenzyl)amine With triethylamine In dichloromethane for 18h; Cooling with ice; | Step C: 4-fluoro-N,N-bis(4-methoxybenzyl)-1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazole-5-sulfonamide NCS (2.78 g, 20.82 mmol) was added to a suspension of lithium 4-fluoro-1-(tetrahydro- 2H-pyran-2-yl)-1H-pyrazole-5-sulfinate (5.00 g, 20.82 mmol) in DCM (100 mL) cooled in an ice bath. The mixture was stirred for 18 h, quenched with water (10 mL) then partitioned between DCM (50 mL) and water (20 mL). The aqueous layer was extracted with DCM (2 x 100 mL) and the organic layers were dried (MgSO4) and concentrated in vacuo to ~100 mL. The solution was added to a mixture of bis(4-methoxybenzyl)amine (5.63 g, 21.86 mmol) and triethylamine (3.4 mL, 24.39 mmol) in DCM (30 mL) cooled in an ice bath. The mixture was allowed to warm to RT and stirred for 18 h, then partitioned between DCM (60 mL) and water (40 mL). The aqueous layer was extracted with DCM (2 x 30 mL) and the combined organic layers were dried (MgSO4) and concentrated to dryness to afford a yellow oil. The crude product was purified by FC (0- 50% EtOAc/isohexane) to afford the title compound (5.05 g, 40%) as a yellow crystalline solid. LCMS m/z 512.1 (M+Na)+(ES+).1H NMR (DMSO-d6) d 7.86 (d, J = 4.5 Hz, 1H), 7.03 - 6.95 (m, 4H), 6.86 - 6.78 (m, 4H), 5.79 (dd, J = 9.6, 2.6 Hz, 1H), 4.42 (d, J = 15.4 Hz, 2H), 4.23 (d, J = 15.5 Hz, 2H), 3.95 - 3.80 (m, 1H), 3.72 (s, 6H), 3.61 - 3.50 (m, 1H), 2.41 - 2.19 (m, 1H), 2.08 - 1.93 (m, 1H), 1.93 - 1.80 (m, 1H), 1.70-1.65 (m, 1H), 1.55 - 1.44 (m, 2H). |
40% | Stage #1: lithium 4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfinate With N-chloro-succinimide In dichloromethane for 18h; Cooling with ice; Stage #2: N,N-bis(p-methoxybenzyl)amine With triethylamine In dichloromethane at 20℃; for 18h; Cooling with ice; | Step C: 4-fluoro-N,N-bis(4-methoxybenzyl)-1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazole-5-sulfonamide NCS (2.78 g, 20.82 mmol) was added to a suspension of lithium 4-fluoro-1-(tetrahydro- 2H-pyran-2-yl)-1H-pyrazole-5-sulfinate (5.00 g, 20.82 mmol) in DCM (100 mL) cooled in an ice bath. The mixture was stirred for 18 h, quenched with water (10 mL) then partitioned between DCM (50 mL) and water (20 mL). The aqueous layer was extracted with DCM (2 x 100 mL) and the organic layers were dried (MgSO4) and concentrated in vacuo to ~100 mL. The solution was added to a mixture of bis(4-methoxybenzyl)amine (5.63 g, 21.86 mmol) and TEA (3.4 mL, 24.39 mmol) in DCM (30 mL) cooled in an ice bath. The mixture was allowed to warm to RT and stirred for 18 h, then partitioned between DCM (60 mL) and water (40 mL). The aqueous layer was extracted with DCM (2 x 30 mL) and the combined organic layers were dried (MgSO4) and concentrated to dryness to afford a yellow oil. The crude product was purified by FC (0-50% EtOAc/isohexane) to afford the title compound (5.05 g, 40%) as a yellow crystalline solid. LCMS m/z 512.1 (M+Na)+ (ES+). 1H NMR (DMSO-d6) d 7.86 (d, J = 4.5 Hz, 1H), 7.03 - 6.95 (m, 4H), 6.86 - 6.78 (m, 4H), 5.79 (dd, J = 9.6, 2.6 Hz, 1H), 4.42 (d, J = 15.4 Hz, 2H), 4.23 (d, J = 15.5 Hz, 2H), 3.95 - 3.80 (m, 1H), 3.72 (s, 6H), 3.61 - 3.50 (m, 1H), 2.41 - 2.19 (m, 1H), 2.08 - 1.93 (m, 1H), 1.93 - 1.80 (m, 1H), 1.70-1.65 (m, 1H), 1.55 - 1.44 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With triethylamine In dichloromethane at 0 - 20℃; for 18h; | Step A: methyl 5-(N,N-bis(4-methoxybenzyl)sulfamoyl)pentanoate A suspension of methyl 5-(chlorosulfonyl)pentanoate (0.25 g, 1.165 mmol) and bis(4- methoxybenzyl)amine (0.30 g, 1.165 mmol) in DCM (20 mL) was cooled to 0 °C. TEA (0.40 mL, 2.81 mmol) was then added dropwise at 0 °C and the mixture was stirred at RT for 18 h. The mixture was concentrated in vacuo, dissolved in DCM (5 mL) and a few drops of MeOH, then purified by FC (0-100% EtOAc/isohexane) to afford the title compound (0.30 g, 56%) as a colourless oil. LCMS m/z 458.3 (M+Na)+ (ES+). 1H NMR (CDd3) d 7.24 - 7.16 (m, 4H), 6.91 - 6.86 (m, 4H), 4.26 (s, 4H), 3.82 (s, 6H), 3.67 (s, 3H), 2.87 - 2.77 (m, 2H), 2.29 (t, J = 7.3 Hz, 2H), 1.85 - 1.75 (m, 2H), 1.71 - 1.63 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Stage #1: 2-(3-(benzylthio)phenyl)ethanol With 1,3-dichloro-5,5-dimethylhydantoin; acetic acid In acetonitrile at -10℃; for 4h; Stage #2: N,N-bis(p-methoxybenzyl)amine With triethylamine for 17h; | Intermediate A20: 3-(2-hydroxyethyl)-N,N-bis(4-methoxybenzyl)benzene- sulfonamide A solution of 2-(3-(benzylthio)phenyl)ethanol (1.21 g, 4.95 mmol) in MeCN (25 mL), AcOH (0.3 mL) and water (0.6 mL) was cooled to -10 °C (ice /acetone bath).1,3- Dichloro-5,5-dimethylimidazolidine-2,4-dione (1.50 g, 7.61 mmol) was then added and the mixture was stirred at -10 °C for 4 h. The mixture was then partitioned between DCM (50 mL) and water (50 mL) and the organic layer was collected. The aqueous layer was extracted with DCM (100 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to give a thick yellow paste. The thick yellow paste was suspended in DCM (25 mL) and cooled with an ice bath. Bis(4- methoxybenzyl)amine (1.30 g, 5.05 mmol) was added, followed by TEA (1.5 mL, 10.76 mmol). The mixture was stirred for 17 h, quenched with water (20 mL) then partitioned between DCM (50 mL) and water (40 mL). The organic phase was collected, dried (MgSO4), filtered and concentrated in vacuo to give a brown oil. The brown oil was purified by FC (0-50% EtOAc/isohexane) to afford the title compound (1.40 g, 60%) as a white solid. LCMS m/z 464.1 (M+Na)+ (ES+). 1H NMR (DMSO-d6) d 7.72 - 7.61 (m, 2H), 7.57 - 7.44 (m, 2H), 7.02 - 6.93 (m, 4H), 6.83 - 6.75 (m, 4H), 4.69 (t, J = 5.1 Hz, 1H), 4.18 (s, 4H), 3.71 (s, 6H), 3.63 (td, J = 6.7, 5.0 Hz, 2H), 2.80 (t, J = 6.7 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With triethylamine In tetrahydrofuran at 25℃; for 1h; | Step D: 1-cyclopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide To a solution of 1-cyclopropyl-1H-pyrazole-3-sulfonyl chloride (28 g, 135.49 mmol, 1 eq) in THF (300 mL) was added TEA (27.42 g, 270.99 mmol, 2 eq) and bis(4- methoxybenzyl)amine (34.87 g, 135.49 mmol,1 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with H2O (500 mL) and extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine (2 × 500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reversed phase flash chromatography (0.5% NH3.H2O-MeCN) to give the title compound (30 g, 52 % yield, 99.8 % purity on LCMS). LCMS m/z 428.2 (M+H)+ (ES+). 1H NMR (CDd3): d 7.49 (d, 1 H), 7.08-7.06 (m, 4 H), 6.79-6.77 (m, 4 H), 6.62 (d, 1 H), 4.32 (s, 4 H), 3.80 (s, 6 H), 3.68-3.64 (m, 1 H), 1.15-1.13 (m, 2 H) and 1.09-1.06 (m, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With N-ethyl-N,N-diisopropylamine In iso-butanol at 110℃; for 16h; | 9 5-(bis(4-methoxybenzyl)amino)-3-(4-phenoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (3d) A mixture of 5-chloro-3-(4-phenoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.7 g, 2.0 mmol), bis(4-methoxybenzyl)amine (1.02 g, 4.0 mmol) and DIPEA (0.5 g, 4.0 mmol) in 2-BuOH (20 mL) was stirred at 110 °C for 16 h. The mixture was then concentrated, and the residue was purified by column chromatography (silica gel, MeOH/DCM = 1/20) to afford desired product 3d as yellow solid (0.58 g, yield 52%). LCMS (m/z): 574.1 [M + H] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With N-ethyl-N,N-diisopropylamine In dichloromethane at -78 - -10℃; for 2.66667h; Inert atmosphere; | 2 Step 2: Preparation of 4-(bromomethyl)-2-fluoro-N,N-bis(4- methoxybenzyl)benzenesulfonamide To a solution of 4-(bromomethyl-2-fluorobenzenesulfonyl chloride (1.0 equiv) in CH2Cl2 (0.3 M) under nitrogen and cooled in a dry ice/acetone bath was added N-(4- methoxybenzyl)-1-(4-methoxyphenyl)methanamine (1.0 equiv). Once cooled, diisopropylethylamine (1.1 equiv) was added portion-wise over 10 minutes and the mixture was allowed to stir in the dry ice/acetone bath for 30 minutes. After this time, the cooling bath was exchanged with a salt/wet ice bath (-10 °C) and stirring was continued for 2 hours. This mixture was quenched with ice (1 volume), water (1 volume) and then extracted with CH2Cl2 (2 × 1 volume). The combined organic extracts were washed with water (0.25 volumes), dried over MgSO4, filtered and concentrated under vacuum to afford an oil. The resulting oil was dissolved in CH2Cl2 (0.1 volumes), applied to a silica gel pre-cartridge and purified by column chromatography through silica gel, eluting with 0-20% EtOAc in CH2Cl2 as a gradient to provide the title compound as a white solid (73% yield). |
73% | With N-ethyl-N,N-diisopropylamine In dichloromethane at -78 - -10℃; for 2.66667h; Inert atmosphere; | 2 Step 2: Preparation of 4-(bromomethyl)-2-fluoro-N,N-bis(4- methoxybenzyl)benzenesulfonamide To a solution of 4-(bromomethyl-2-fluorobenzenesulfonyl chloride (1.0 equiv) in CH2Cl2 (0.3 M) under nitrogen and cooled in a dry ice/acetone bath was added N-(4- methoxybenzyl)-1-(4-methoxyphenyl)methanamine (1.0 equiv). Once cooled, diisopropylethylamine (1.1 equiv) was added portion-wise over 10 minutes and the mixture was allowed to stir in the dry ice/acetone bath for 30 minutes. After this time, the cooling bath was exchanged with a salt/wet ice bath (-10 °C) and stirring was continued for 2 hours. This mixture was quenched with ice (1 volume), water (1 volume) and then extracted with CH2Cl2 (2 × 1 volume). The combined organic extracts were washed with water (0.25 volumes), dried over MgSO4, filtered and concentrated under vacuum to afford an oil. The resulting oil was dissolved in CH2Cl2 (0.1 volumes), applied to a silica gel pre-cartridge and purified by column chromatography through silica gel, eluting with 0-20% EtOAc in CH2Cl2 as a gradient to provide the title compound as a white solid (73% yield). |
73% | With N-ethyl-N,N-diisopropylamine In dichloromethane at -78 - -10℃; for 2.66667h; Inert atmosphere; | 2 Step 2: Preparation of 4-(bromomethyl)-2-fluoro-N,N-bis(4- methoxybenzyl)benzenesulfonamide To a solution of 4-(bromomethyl-2-fluorobenzenesulfonyl chloride (1.0 equiv) in CH2Cl2 (0.3 M) under nitrogen and cooled in a dry ice/acetone bath was added N-(4- methoxybenzyl)-1-(4-methoxyphenyl)methanamine (1.0 equiv). Once cooled, diisopropylethylamine (1.1 equiv) was added portion-wise over 10 minutes and the mixture was allowed to stir in the dry ice/acetone bath for 30 minutes. After this time, the cooling bath was exchanged with a salt/wet ice bath (-10 °C) and stirring was continued for 2 hours. This mixture was quenched with ice (1 volume), water (1 volume) and then extracted with CH2Cl2 (2 × 1 volume). The combined organic extracts were washed with water (0.25 volumes), dried over MgSO4, filtered and concentrated under vacuum to afford an oil. The resulting oil was dissolved in CH2Cl2 (0.1 volumes), applied to a silica gel pre-cartridge and purified by column chromatography through silica gel, eluting with 0-20% EtOAc in CH2Cl2 as a gradient to provide the title compound as a white solid (73% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With tert.-butylhydroperoxide; sodium chloride; sodium hydroxide In water monomer at 90℃; Green chemistry; | Gram scale synthesis of benzoic acid from dibenzylamines General procedure: A 100 ml of round bottom flask was charged with a magnetic bead, 1.5 gm (7.62mmol) of dibenzyl amine, 177 mg of NaCl (40 mol% ), 2.4 gm of NaOH (8 equiv) and 6.85 gm of aq. TBHP (10 equiv) in 5 mL of deionised H2O and it was heated at 90 C for 18-20 h. After wards, the reaction mixture was neutralized by aq. HCl and extracted with EtOAc The organic layer was dried over anhydrous Na2SO4 and after evaporation of the solvent, benzoic acid was obtained in 72% yield (1.33 gm). |
Tags: 17061-62-0 synthesis path| 17061-62-0 SDS| 17061-62-0 COA| 17061-62-0 purity| 17061-62-0 application| 17061-62-0 NMR| 17061-62-0 COA| 17061-62-0 structure
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