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CAS No. : | 6373-46-2 | MDL No. : | MFCD00025318 |
Formula : | C13H13NO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FIIDVVUUWRJXLF-UHFFFAOYSA-N |
M.W : | 199.25 | Pubchem ID : | 22860 |
Synonyms : |
|
Num. heavy atoms : | 15 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.08 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 61.83 |
TPSA : | 35.25 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.31 cm/s |
Log Po/w (iLOGP) : | 2.13 |
Log Po/w (XLOGP3) : | 3.11 |
Log Po/w (WLOGP) : | 2.7 |
Log Po/w (MLOGP) : | 2.69 |
Log Po/w (SILICOS-IT) : | 2.68 |
Consensus Log Po/w : | 2.66 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.43 |
Solubility : | 0.0743 mg/ml ; 0.000373 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.52 |
Solubility : | 0.0604 mg/ml ; 0.000303 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -4.71 |
Solubility : | 0.00393 mg/ml ; 0.0000197 mol/l |
Class : | Moderately soluble |
PAINS : | 1.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.4 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium nitrite In hydrogenchloride; water | A. 4-Benzyloxyphenylhydrazine hydrochloride A solution of sodium nitrite (3.8 g, 0.055 mol in 20 mL of H2 O), is added dropwise to an ice cold stirring suspension of 4-benzyloxyaniline (13.0 g, 0.055 mol in 150 mL of concentrated HCl). The reaction mixture is stirred for 90 minutes at -8° to 10° C. A solution of SnCl2.2H2 O (32.0 g, 0142 mol in 50 mL concentrated HCl) is added and stirred for 1 hour at 0° C. The reaction mixture is removed from the ice bath and is stirred at room temperature for 20 hours. The mixture is then filtered and washed with water to give 13.0 g (95percent yield) of product, m.p. 182°-185° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium nitrite In hydrogenchloride; water | A. 4-Benzyloxyphenylhydrazine hydrochloride A solution of sodium nitrite (3.8 g, 0.055 mol in 20 mL of H2 O), is added dropwise to an ice cold stirring suspension of 4-benzyloxyaniline (13.0 g, 0.055 mol in 150 mL of concentrated HCl). The reaction mixture is stirred for 90 minutes at -8° to 10° C. A solution of SnCl2 *2H2 O (32.0 g, 0142 mol in 50 mL concentrated HCl) is added and stirred for i hour at 0° C. The reaction mixture is removed from the ice bath and is stirred at room temperature for 20 hours. The mixture is then filtered and washed with water to give 13.0 g (95percent yield) of product, m.p. 182°-185° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | With triethylamine In N,N-dimethyl-formamide at 125℃; for 6 h; | In a 250 mL round bottom flask, 4-(benzyloxy)aniline (8.8 g, 44.34 mmol, 3.00 equiv) was added to a solution of 1-[4-(benzyloxy)phenyl]propan-1-one (4.3 g, 17.89 mmol, 1.00 equiv) in DMF/TEA (40/4.3 mL). The resulting solution was stirred for 6 hours at 125° C. The reaction was then quenched by the addition of water. The resulting mixture was extracted with ethyl acetate (20 mL*3) and the organic layers were combined, washed with brine and dried over anhydrous sodium sulfate. The organic solvent was removed under reduced pressure and the residue was applied onto a silica gel column eluting with ethyl acetate/petroleum ether (1:5). This resulted in 1.7 g (23percent) of 5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-methyl-1H-indole as a light brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.5% | for 6 h; Reflux | 1- (4-benzyloxyphenyl) -2- (4-benzyloxy-phenylamino) -1-propanone (12.3g, 0.028mol), 4- benzyloxyaniline (14.0g, 0.070mol) placed in 500mL flask, ethylene glycol monomethyl ether as a solvent, refluxed 6h. The solvent was distilled off under reduced pressure, the residue was stirred with ethanol, suction filtered to give 9.5 g of a brown solid, yield 80.5percent. m.p.151-152 . ESI-MS: m / z420 ([M + H] +). 1H-NMR (400MHz, CDCl3) δ7.89 (s, 1H), 7.45 (m, 14H), 7.28 (d, J = 2.6Hz, 1H), 7.11 (d, J = 8.4Hz, 2H), 6.97 ( dd, J1 = 8.5Hz, J2 = 1.5Hz, 1H), 5.18 (s, 2H), 5.15 (s, 2H), 2.43 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydrazine hydrate In methanol at 26℃; for 0.25h; | |
99% | With hydrogen In ethyl acetate at 20℃; for 4h; chemoselective reaction; | |
99% | With Fe3O4Rh; hydrazine hydrate In ethanol at 80℃; for 10h; Inert atmosphere; |
99% | With 1,1,3,3-Tetramethyldisiloxane In ethanol; ethyl acetate at 20℃; for 4h; Inert atmosphere; Sonication; chemoselective reaction; | |
99% | With 0.2C27H36N2*Pt; hydrogen In tetrahydrofuran at 30℃; for 2.8h; chemoselective reaction; | |
99% | With hydrogen In ethanol at 20℃; for 1h; | |
99% | With hydrazine hydrate In water at 110℃; Sealed tube; Green chemistry; | |
97% | With hydrogen In tetrahydrofuran; ethanol at 100℃; for 3h; Autoclave; | |
97% | Stage #1: benzyl 4-nitrophenyl ether With tin(II) chloride dihdyrate In ethanol at 70℃; for 6h; Inert atmosphere; Stage #2: With sodium hydrogencarbonate In ethanol; water Inert atmosphere; | 4.2.2. 4-Aminophenyl benzyl ether 14 4-Nitrophenyl benzyl ether (4.00 g, 17.4 mmol) was dissolved in ethanol (50 mL) before adding tin(II) chloride dihydrate (19.1 g, 84.4 mmol). The mixture was stirred under an argon atmosphere at 70 °C for 6 days. The reaction was monitored by TLC using dichloromethane as solvent. At the completion of the reaction, the mixture was treated with a concentrated aqueous solution of sodium bicarbonate until the effervescence ceased. The mixture was extracted with ethyl acetate (4×50 mL), the organic layers were collected, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. 14 (3.36 g, 97%) was obtained as a brown oil and used without further purification. Rf (CH2Cl2) 0.60; 1H NMR (400 MHz, CDCl3) δ 4.99 (s, 2H, CH2), 6.64 (d, J 6.8 Hz, 2H, ArH), 6.81 (d, J 6.8 Hz, 2H, ArH), 7.34-7.45 (m, 5H, ArH). |
97% | With tin(II) dichloride dihydrate In ethanol for 4h; Reflux; | |
97% | With 1,1,3,3-Tetramethyldisiloxane In ethanol at 20℃; for 0.5h; chemoselective reaction; | |
96% | With hydrogen In ethyl acetate for 8h; Heating; Flow reactor; Green chemistry; | |
96% | With maghemite; methylhydrazine In ethanol at 60℃; for 1h; Sealed tube; Inert atmosphere; chemoselective reaction; | |
96% | With sodium tetrahydroborate; TPGS-750-M In tetrahydrofuran; water at 20℃; for 16h; | |
96% | With C30H29BrMnNO2P2; hydrogen; potassium carbonate In toluene at 130℃; for 24h; Glovebox; Autoclave; chemoselective reaction; | |
95% | With ethanol; tin(ll) chloride at 65℃; for 1.5h; | 5.2 Step 2: Preparation of 4-benzyloxyphenylamine In a 1 L round bottom flask, 20. 18 g (0. 088 mol) of the compound obtained in Step 1 and 75.1 g (0.396 mol, 4. 5eq) of Tin chloride (II) were added to 300 ml of ethanol, and were stirred at 65°C for 90 min. After evaporating under a reduced pressure, ice and 0.5 N NA2CO3 solution were added to the mixture, and filtrated. The solid obtained thus was dissolved in ethanol, filtrated, and concentrated under a reduced pressure to obtain 16.66 g (yield 95%) of the title compound H-NMR (CDCL3, 300MHZ) : 8 3.35 (br. s, 2H), 4.98 (s, 2H), 6.61-6. 83 (m, 4H), 7.24-7. 43 (m, 5H) ; MS (m/z): 199 (100, M+), 108 (93), 91 (85), 80 (77), 65 (57) |
95% | With trichlorosilane; N-ethyl-N,N-diisopropylamine In acetonitrile at 0 - 20℃; for 18h; Inert atmosphere; chemoselective reaction; | |
95% | With hydrogenchloride; iron for 1h; Heating; | 2 Second Step In three 500mL flask was added the compound (S-2) (22.90g, 0.10mol) and Fe (20.16g, 0.36mol), HCl (220ml, 3mol / L), heated and stirred 1h. Extracted with dichloromethane, the organic phase was separated, dried, dichloromethane was distilled off under reduced pressure. 18.91 g of (S-3) was obtained as a white solid in 95% yield. |
93% | With iron; ammonium chloride In water; acetone Inert atmosphere; Reflux; | |
91% | With tin(ll) chloride In ethanol at 70℃; for 0.5h; | |
91% | With water at 20℃; Inert atmosphere; chemoselective reaction; | |
91% | With hydrogen In toluene at 0℃; for 16h; | |
90% | With palladium 10% on activated carbon In methanol; ethanol at 20℃; for 24h; | 1 4.4 General procedure for the synthesis of 4-substituted anilines (5 and 6e,n) General procedure: The method adopted for the synthesis of 4-aminophenylmethanol (5) is described. Catalytic hydrogenation of 4 (1.50 g, 9.8 mmol) in 30mL of a mixture of MeOH and absolute EtOH (2/1) was conducted at room temperature for 24 h in the presence of 10% palladium on carbon at 10 bar. The catalyst was removed by filtration and the residue taken up with EtOAc and washed with water. The solvent was removed to give 1.03 g (85%) of a yellow solid which was recrystallized from EtOAc/petroleum ether to give 0.65 g of yellowish crystals: mp 65-66°C; GC/MS (70eV) m/z (%) 123 (M+, 100). Other spectroscopic data were in agreement with the literature [36]. |
90.3% | With tin(ll) chloride In ethanol at 45℃; for 24h; Inert atmosphere; | 1.B Preparation of 4-benzyloxy-aniline 4-Nitro-benzyloxy-benzene (10.0g, 0.044mol), stannous chloride (50g, 0.220mol) placed 1000mL round-bottomed flask, ethanol as solvent, under N2 atmosphere, 45 reaction 24h. The solvent was distilled off under reduced pressure, using sodium carbonate solution 600mL and the residue was transferred to a 1000mL beaker and stir until no bubbles, suction filtered, the filter cake was stirred with ethanol, suction filtered, and the filtrate rotary evaporated to give a white solid 7.86g yield 90.3%. m.p.51-52 . ESI-MS: m / z200 ([M + H] +). |
89% | With zinc phthalocyanine; hydrazine hydrate In PEG-400 at 100℃; for 8h; | |
89% | With ethanol; sodium t-butanolate In 1,4-dioxane at 100℃; for 10h; | |
89% | With [Co(κS,N-4-(trifluoromethyl)pyrimidine-2-thiolate)3]; methylhydrazine In methanol at 70℃; for 5h; Sealed tube; | |
87% | With cobalt(II) phthalocyanine; hydrazine hydrate In ethylene glycol at 90℃; for 1.5h; chemoselective reaction; | |
87% | With potassium <i>tert</i>-butylate; isopropyl alcohol; bis(pinacol)diborane at 110℃; for 2h; | |
87% | With iron; ammonium chloride In tetrahydrofuran; methanol; water at 50℃; for 18h; | Intermediate W: 4-(Benzyloxy)aniine Intermediate H (808 mg,3.52 mmol) was dissolved in a mixture of THF (10 ml_) and MeOH (5 ml_). Ammonium chloride (566 mg,10.6 mmol) was dissolved in water (2 ml_) and added to the reaction mixture along with iron (591 mg,10.6 mmol). The reaction mixture was heated to 50 °C for 18h. After cooling to r.t.,the mixture was filtered through Dicalite,washing with EtOAc. The filtrate was washed with water,and the aqueous layer extracted with EtOAc. The combined organics were washed (brine),dried (MgS04) and concentrated in vacuo to yield the title compound as a yellow solid (609 mg,87%). NMR dH(500 MHz,DMSO-d6) 7.45 - 7.35 (m,4H),7.34 - 7.27 (m,1 H),6.75 - 6.69 (m,2H),6.53 - 6.47 (m,2H),4.94 (s,2H),4.62 (br s,2H); LCMS: (Method A) 3.32 min,(200.2,MH+). |
86% | With nickel In N,N-dimethyl-formamide for 18h; Ambient temperature; | |
86% | With sodium tetrahydroborate In methanol; water at 0 - 50℃; for 3h; chemoselective reaction; | Reduction in presence of NaBH4 (Method A) General procedure: A mixture of nitroarene (1 mmol), SS-Pd (2 mol% Pd) and sodium borohydride (3 mmol) were taken in a 25 ml round bottomed flask. 3 ml of MeOH:H2O (3:7) was added to the mixture by a syringe at 0 oC in stirring condition. After 10 minutes the reaction mixture was heated to 50 oC. Progress of the reaction was monitored by TLC. On completion, the reaction mixture was extracted with ethylacetate and dried over anhydrous Na2SO4. Evaporation of the combined organic layer and followed by column chromatography over silica gel (60-120 mesh) afforded desired corresponding amines. |
85% | With hydrogen In methanol; ethyl acetate at 90℃; for 0.333333h; Flow reactor; Green chemistry; chemoselective reaction; | |
84% | With C32H16FeN8*Fe(2+)*7H2O*O4S(2-); hydrazine hydrate In ethanol; water at 120℃; chemoselective reaction; | |
82% | Stage #1: benzyl 4-nitrophenyl ether With hydrogenchloride; 1,1,1,3',3',3'-hexafluoro-propanol; iron In water at 20℃; for 0.5h; Stage #2: With sodium hydrogencarbonate In water chemoselective reaction; | 2. General Procedure for the Reduction of Nitro Compounds General procedure: The nitro compound (1 equiv), HFIP (10 equiv), Fe powder (5 equiv) were mixed in a tube. Then 2 N HCl aqueous solutions was added to the reaction mixture. After stirring at room temperature for 30 min, the reaction mixture was neutralized with sat. NaHCO3 (aq.) and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was then purified by column chromatography on silica gel to furnish the desired amine product. |
81% | With gold nanoparticles supported on titanium dioxide (TiO<SUB>2</SUB>); ammonium formate In acetonitrile at 25℃; for 3h; Inert atmosphere; chemoselective reaction; | |
81% | With hydrazine hydrate at 100℃; for 0.75h; Microwave irradiation; chemoselective reaction; | Typical experimental procedure for microwave-induced transfer hydrogenation of nitro arenes using SS-Rh catalyst A mixture of 1q (100 mg, 0.81 mmol), hydrazine hydrate (121.5mg, 2.43 mmol), and SS-Rh (370 mg, 2 mol% Rh) were taken in an oven dried reaction tube equipped with screw cap. 0.5 ml of PEG-400 was added into the reaction mixture. The reaction was then irradiated in a microwave apparatus at 80°C , 80 W for 10 min with a pressure of 80 Psi. After cooling to ambient temperature in the microwave cavity the reaction mixture was extracted with ethyl acetate (3x2 ml) and water (1ml). The combined organic layer wasdried over anhydrous Na2SO4 and the solvent was removed under reduced pressure and after purificationwith silica gel column chromatography (hexane: EtOAc= 95:5) 2q as colourlesssolid (70 mg, 81%), m.p. 43-45°C (lit1mp 44-45 oC). 1H and 13CNMR spectra has been compared with our previously reported study.3GCMS: m/z 199. |
81% | With hydrogen In ethanol at 20℃; for 2h; | |
81% | With hydrazine hydrate In water at 20℃; for 1h; | 4-benzyloxyaniline General procedure: To a stirred suspension of appropriate p-nitrotoluene (0.274 g, 2.0 mmol) in 3 mL water, Ni-alumina (0.125 g, 6 mol % of nickel metal) was added followed by 0.3 mL 80% hydrazine hydrate. The reaction mixture was stirred for the required period of time at room temperature till the reaction was complete (monitored with TLC). Then ethyl acetate (20 mL) was added to the reaction mixture to dissolve the product and the catalyst was separated simply by filtration. The residue (recovered catalyst) was thoroughly washed with EtOAc (4 5 mL) followed by water (2 10 mL). The aqueous reaction mixture was repeatedly extracted with ethyl acetate (3 5 mL). The combined organic extracts were washed with water (3 10 mL) and dried over anhydrous Na2SO4. The crude product was obtained by removal of the solvent under reduced pressure which was further purified by filtration chromatography on a short column. |
80% | With acetic acid; zinc In dichloromethane at 20℃; | Synthesis of Intermediate 24b Zinc powder (120 mmol) and AcOH (400 mmol) were added to a solution of 24a (8 mmol) in DCM(45 mL) in ice bath. The mixture was stirred at room temperature until the reaction was completed. Thereaction mixture was filtered. The filtrate was washed with water, dried (Na2SO4) and concentratedunder reduced pressure. The residue was further purified by column chromatography (PE/EA=4:1,V/V) to give 24b in yield of 80%. 1H-NMR (CDCl3): 7.39 - 7.31 (m, 4H) 7.27 (d, J = 6.4 Hz, 1H), 6.69(d, J = 8.4 Hz, 2H), 6.55 (d, J = 8.4 Hz, 2H), 4.27 (s, 2H), 4.16 (s, 2H) ppm; 13C-NMR (CDCl3): 147.79,142.42, 139.61, 128.62, 127.60, 127.22, 116.21, 114.37, 49.36 ppm. |
75% | With ammonium formate In ethylene glycol at 120℃; for 12h; | |
75% | With iron(III) chloride hexahydrate; pyrographite; hydrazine hydrate In ethanol for 5h; Reflux; | |
73% | With hydrogenchloride; gallium In ethanol at 20℃; for 0.5h; Sonication; chemoselective reaction; | 4-(Benzyloxy)aniline (2J) To a 25 mL RBF containing molten Ga (287 mg, 4.12 mmol, 4.0 equiv) was added 4-benzyloxynitrobenzene (236 mg, 1.03 mmol, 1.0 equiv), EtOH (10.3 mL), and 12 N HCl (1290 µL). The flask was sonicated for 30 min at rt. The rxn mixture was transferred to a 125 mL separatory funnel, basified with 2 M phosphate buffer (pH = 7.60, 40 mL), diluted with water (40 mL), treated with saturated Rochelle’s Salt (2 mL), and extracted with DCM (3 x 10 mL). The combined extracts were dried over Na2SO4, passed through a plug of silica gel (1 cm), and concentrated by rotary evaporation. The residue (oily brown solid) was purified by prep TLC (100% DCM) to provide the product as an orange/brown oil (150 mg, 73%). 1H NMR (500 MHz, CDCl3) δ 7.37 (dm, J = 8.5 Hz, 2H), 7.34 (dd, J = 8.5, 8.5 Hz, 2H), 7.28 (dt, J = 8.5, 1.0 Hz, 1H), 6.70 (d, J = 8.8 Hz, 2H), 6.56 (d, J = 8.8 Hz, 2H), 4.28 (s, 2H) 4.09 (br s, 2H) ppm. ESI-MS (m/z): 200.1 [M+H]+. |
72% | With 5%-palladium/activated carbon; hydrogen In ethanol at 20℃; for 18h; | 4.1.2 Synthesis of 1-(benzyloxy)-4-nitrobenzene 2a 4.1.2 Synthesis of 4-(benzyloxy)aniline 3a The compound 2a (10 mmol) was dissolved in ethanol and a catalytic amount of 5% Pd/C (2 mmol) was added to the mixture. The solution was stirred at room temperature under H2 atmosphere for 18 h. After the completion of the reaction, the mixture was filtered to eliminate the catalyst. The obtained crude product was then purified by recrystallization to give the desired intermediate 3a as a brown solid with 72% yield; 1H NMR (500 MHz, DMSO-d6) δ 7.40 (d, J = 7.1 Hz, 2H, Ar-H), 7.36 (t, J = 7.5 Hz, 2H, Ar-H), 7.30 (t, J = 7.1 Hz, 1H, Ar-H), 6.73 (d, J = 8.7 Hz, 2H, Ar-H), 6.54 (d, J = 8.7 Hz, 2H, Ar-H), 4.94 (s, 2H, OCH2). |
70% | With iron; ammonium chloride In ethanol; water at 70℃; for 1h; | |
63% | With ammonia borane; gold on titanium oxide In ethanol at 20℃; for 0.833333h; Inert atmosphere; | |
55% | With 2-(4'-carboxyphenyl)benzothiazoline In toluene for 0.5h; Molecular sieve; Reflux; Inert atmosphere; | General procedures of reduction General procedure: Under a nitrogen atmosphere, a mixture of nitroarene 1a (0.080 mmol), benzothiazoline2e (0.32 mmol, 4.0 equiv) and MS4A (100 mg, activated) in toluene (0.80 mL) was heated at reflux for 0.5 h, and the reaction was monitored with TLC. After completionof the reaction, the reaction mixture was filtered with dichloromethane through Celitepad. Then, the filtrate was concentrated in vacuo and the residue was purified bypreparative TLC to give aniline 3a (98%). |
40% | With hydrazine hydrate In methanol for 0.166667h; Heating; | |
40% | With hydrazine hydrate In ethanol at 78℃; for 45h; | |
37% | With palladium 10% on activated carbon; ammonium formate; silica gel In methanol for 1.5h; Milling; | 2. General procedure for the mechanochemical reduction of nitroarenes General procedure: In a typical experiment, a mixture of nitroarene compound (1.0 mmol),ammonium formate (3.3 mmol, 208 mg, 1.1 equivalent), palladium catalyst (10 % Pdon activated carbon, 2 mol%, 21 mg) and silica (175 mg) was ball milled in thepresence of dry methanol (η = 0.25 μL mg-1) for 90 minutes. After milling, a smallsample (≈ 1 mg) of the crude reaction mixture was suspended in methanol andimmediately analyzed by TLC (typically using dichloromethane : methanol = 20 : 1mixture as an eluent). The crude mixture was left in a well ventilated hood overnight,suspended in methanol and filtered over a Büchner funnel. Evaporation of the filtrateafforded the desired amino-derivative. If necessary, the final product was purified bycolumn chromatography. |
With iron; acetic acid | ||
With nickel; isopropyl alcohol Hydrogenation; | ||
With nickel; hydrazine hydrate | ||
With hydrazine hydrate In tetrahydrofuran | ||
With sodium hydroxide; carbon monoxide In water; toluene at 30℃; specific rate of reduction under biphasic condition; | ||
With iron; ammonium chloride; acetic acid In ethanol at 75℃; for 3h; | ||
With hydrogen In tetrahydrofuran; ethanol | ||
With Pd/C; hydrogen In methanol | ||
With iron(III) chloride hexahydrate; pyrographite; hydrazine hydrate In ethanol Reflux; | ||
99 %Chromat. | With hydrazine hydrate In ethanol at 80℃; for 2h; Inert atmosphere; chemoselective reaction; | |
With platinum(IV) oxide; hydrogen In methanol at 20℃; for 1h; | ||
70 g | With sodium sulfide In ethanol at 25 - 80℃; | XVIII Preparation 4-(benzyloxy)aniline In a clean round bottomed flask , ethanol (1.0 L), 1 -(benzyl oxy)-4-nitrobenzene, sodium sulfide (183 g) were added sequentially at about 25-30°C. The reaction mass was heated to about 70- 80°C for about 8-12 hrs. After completion, the reaction mass was cooled to about 25 -30°C and water was added to the reaction mass. Reaction mass was extracted with ethyl acetate and organic phase was washed with brine solution. Ethyl acetate was distilled under vacuum. Hexane was charged to residue obtained and stirred for 1 hr. The solid was filtered and washed with hexane. The titled compound was dried under vacuum at 35-40°C for 10-12 hrs to obtain 70 gm of 4-(benzyloxy) aniline. |
With iron; ammonium chloride In ethanol; water at 70℃; for 1h; | ||
With iron; ammonium chloride In ethanol; water for 1h; | 4.6 General procedure 5: Fe-mediatedreduction reaction General procedure: The nitro compounds (1.0 equiv) were taken in EtOH (6mL/mmol), and iron powder (5.0 equiv) was added at 50°C-55°C followed by NH4Cl solution (0.5 equiv in 3mL/mmol water). The reaction mixture was refluxed for about 1h [33,34]. When TLC indicated that the reaction was finished, most of the iron powder was filtered while hot and the alcohol was removed under reduced pressure. The residue was basified with NaHCO3 solution (pH 7-8) and extracted several times with ethyl acetate, the combined organic extracts were dried (Na2SO4), and concentrated under reduced pressure to yield the reduction product. These materials were taken up for the next step without any purification. | |
With iron; ammonium chloride In ethanol; water at 80℃; for 0.5h; | 13 P-fluoronitrobenzene (13a, 0.5 mmol, 70.5 mg), benzyl alcohol (0.75 mmol, 72 mg) was dissolved in dioxane (5 ml), KOH (1.5 mmol, 84 mg) was added and stirred at room temperature overnight After completion of the reaction, the solvent was removed under reduced pressure to remove the solvent dioxane, and the appropriate amount of water and ethyl acetate were extracted, dried and concentrated to give the intermediate 13b. Then, 13b (0.45 mmol, 103.5 mg) was dissolved in a mixed solvent of ethanol (3 ml) and water (1.5 ml), NH4Cl (0.225 mmol, 12 mg) and Fe (2.25 mmol, 126 mg) were added and reacted at 80 ° C for 30 min , After TLC detection reaction completely filtered to remove insoluble material, add NaHCO3 to adjust the pH to alkaline, and then remove the ethanol under reduced pressure, the water layer by ethyl acetate extraction, concentration, column chromatography to get intermediate 13c. The target compound 13 was synthesized using 13c analogously to the compound 2 of Example 2, except that the total yield was 41% | |
99 %Chromat. | With sodium tetrahydroborate In tetrahydrofuran; water at 20℃; for 2h; | |
With iron; ammonium chloride In ethanol for 1h; Reflux; | ||
With sodium tetrahydroborate In water at 20℃; for 0.0333333h; chemoselective reaction; | ||
With hydrazine hydrate In water at 110℃; for 1h; Sealed tube; | ||
With iron; ammonium chloride In ethanol; water Reflux; | ||
87 mg | With aluminum amalgam; water In tetrahydrofuran at 20℃; for 0.5h; | 4-(Benzyloxy)aniline (12): 200 mg (2 wt-equiv) of Al(Hg) coil was immediately added to a solution of nitroarene (100 mg, 0.436 mmol) in 10 mL of THF/water (9:1). Stirring was continued for 30 min. The gray suspension was filtered through a glass fritted funnel with vacuum using THF to rinse and concentrated in vacuo to provide 12 as a brown oil (87 mg, 100%). The spectroscopic data was consistent with that previously reported.7 |
With hydrogenchloride; iron In ethanol; water at 60℃; | General procedure forthe synthesis of 4-(benzyloxy)aniline (4a-d) General procedure: A solution of 3a-d (1 eq) in a mixture ofhydrochloric acid (3 eq), and ethanol (5 mL), was slowly added iron powder (3qe). The reaction mixturewas stirred at 60 °C and TLC analysis monitoring for the completion of thereaction. The mixture was filtered through a pad of celite to remove ironresidue which was washed with ethanol. The filtrate was concentrated in vacuoand the residue was neutralized by aq. sodium bicarbonate (NaHCO3)solution. The basic layer was extracted with ethyl acetate. The combinedorganics extracts were washed with brine and anhydrous sodium sulfate (Na2SO4),and concentrated under reduced pressure to get product 4a-d. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With pyridine In dichloromethane at -10 - 20℃; for 3.5h; | |
With potassium carbonate In tetrahydrofuran; water at 5 - 20℃; for 0.5h; | 10 4-[(Phenylmethyl)oxy]aniline (10 g) was stirred in dry tetrahydrofuran (100 ml), and cooled in an ice/water bath to ~5 0C. A solution of potassium carbonate (16.15 g) in water (60 ml) was added to the above mixture, followed by the dropwise addition of chloroacetyl chloride (4.22 ml) over 30 min. The mixture was allowed to warm up to room temperature and the organic phase separated. The organic phase was cooled to ~5 0C in an ice/water bath and 2-aminoethanol (9 g) added. The mixture was allowed to warm up to room temperature and heated at 60 0C for 2 h, left overnight at room temperature and heated at60 0C for a further 2 h. The reaction mixture was partitioned between EtOAc and water.The organic phase was separated, washed with water, brine, dried and concentrated.The residue was recrystallised from chloroform to give the title compound (8.1 g). LCMSRT = 2.17 min. | |
With triethylamine In tetrahydrofuran at 0℃; | General procedure forthe synthesis of N-(4-(benzyloxy)phenyl)-2-chloroacetamide (6a-d) or4-(2-chloroacetamido)phenyl benzoate (10a-e) General procedure: Chloro acetyl chloride 5 (1eq) was added dropwise to a well stirred solution of the intermediate compound 4a-dor 9a-e (1 eq) in THF in presence of triethylamine (TEA) as a base catalyst at 0 °C. After complete addition, the reaction mixture was stirred atroom temperature for overnight then poured into ice-cold water. The obtainedsolid was filtered off, washed with water, and obtain product 6a-d or 10a-ein good yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; aq NaOH; In chloroform; N,N-dimethyl-aniline; | 2-Chloro-5-nitro-6-[[4-(phenylmethoxy)phenyl]amino]benzoic acid A mixture of 50.0 g of <strong>[55775-97-8]2,6-dichloro-3-nitrobenzoic acid</strong>, 85.7 g of 4-benzyloxyaniline, and 115 ml of N,N-dimethylaniline was heated on a steam bath for 24 hours. The cooled mixture was triturated with 600 ml of chloroform and filtered. The precipitate was stirred in a mixture of 350 ml of chloroform and 350 ml of 1N aq NaOH. The red sodium salt was collected and stirred with a mixture of 300 ml of 1N hydrochloric acid and 1.5 l of chloroform. The chloroform layer was concentrated to provide the title compound as red crystals, mp 172-174 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With water; potassium hydroxide In ethanol Reflux; | |
93% | With potassium hydroxide In ethanol; water Reflux; | General Procedure F. General procedure: An acetamide (4 mmol) along with KOH (40 mmol) and 9:1 DI water/ethanol (50 mL) was refluxed overnight. After the reaction was complete, the ethanol was removed under reduced pressure. The residue was then dissolved in DCM washed with DI water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting oil could then be used without further purification in most cases. If not, aqueous HCl was added and the solution was washed with EA. The aqueous layer was basified and then washed with EA, and the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. |
13 g | With hydrogenchloride In methanol for 3h; Heating; |
With hydrogenchloride; water In methanol for 5h; Reflux; Inert atmosphere; | ||
Multi-step reaction with 2 steps 1: hydrogenchloride / isopropyl alcohol / Reflux 2: sodium hydroxide / water | ||
With water; potassium hydroxide In ethanol for 10h; Reflux; | 2.2.4. General Method for Preparation of Compounds 11 General procedure: K2CO3 (0.41 g, 3 mmol) was added to a DMF solution (2 mL) of 10 (0.30 g, 2 mmol), and the mixture was stirred at room temperature for 10 minutes. Substituted-benzyl chloride (2.4 mmol) was added, the reaction mixture was maintained at 80 oC overnight. After completion of the reaction, the mixture was poured into ice water to yield the crude product. Dissolving KOH (1.1 g, 20 mmol) with water and dissolving the crude product with 95% ethanol, the two solutions were mixed together to reflux for 10 h. After completion of the reaction, The solvent was evaporated under reduced pressure, the residue was washed with ether (30 × 3 mL), the combined ether layer was washed by water (30 × 3 mL) and saturated sodium chloride (30 × 3 mL), dried over anhydrous sodium sulfate, filtered and evaporated to get the crude product, which was recrystallized from ether (11a-11e). (11f and 11g were commercial available) 4-(benzyloxy)aniline (11a) Gold solid, yield 82%; 1H NMR (DMSO-d6, 600 MHz): δ = 7.40 (2H, d, J = 7.8 Hz, H-2’’, H-6’’), 7.36 (2H, t,J = 7.8 Hz, H-3’’, H-5’’), 7.30 (1H , t, J = 7.8 Hz, H-4’’), 6.71 (2H, d, J = 4.8 Hz, H-3’, H-5’), 6.49 (2H, d, J = 4.8 Hz, H-2’, H-6’), 4.93 (2H, s, ArCH2O), 4.61 (2H, br, NH2); MS (ESI) m/z calcd. for C13H13ON ([M+H]+): 200.1, found: 200.3. | |
With sodium hydroxide In ethanol; water for 7h; Reflux; | 5.1.8 Preparation of 4-(benzyloxy)anilines 9a, b General procedure: A mixture of 8a, b (3.12mmol), NaOH (6.25g, 156mmol) in ethanol (125mL) and water (30mL) was heated to reflux for 7h. The mixture was cooled and the solvent was removed under vacuum. The residue was partitioned between chloroform (100mL) and water (100mL). The organic phase was washed with water (2×100mL), dried, and evaporated under vacuum to give 9a, b as oily residue which used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With sulfur monochloride | |
81% | With sulfur monochloride In acetic acid at 20 - 75℃; for 3h; | 6.1 To a solution of 4-benzyloxyaniline (18, 10.0 g, 50 mmol) in HOAc (50 mL) was added sulfur monochloride (16.9 g, 125 mmol). After stirring at RT for 1 h the mixture was heated to 75° C. for 2 h. The mixture was cooled to RT and toluene (150 mL) was added. The resulting red solid was collected, washed with toluene and dried under reduced pressure to afford 12 g (81%) of 19: LCMS RT 3.33 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydrogenchloride; sodium nitrite In water at -15 - 3℃; for 1.16667h; | 79.1 [0516] To the suspension of 4-benzyloxyaniline (10g) in concentrated hydrogen chloride (100ml) was added dropwise a solution of sodium nitrite (3.2g) in water (10ml) over lOmin at between -15 and -10° C., and then the mixture was stirred at 3° C. for 1hr. To the mixture was added dropwise a solution of tin chloride (33.5g) in concentrated hydrogen chloride (80ml) at between -20 and -10° C. over 30min, and then the mixture stirred at 0° C. for 1hr. |
With hydrogenchloride; sodium nitrite In water at 0 - 5℃; for 1h; | ||
With hydrogenchloride; sodium nitrite In water at 0 - 5℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With methylmagnesium bromide; hydrogen; palladium diacetate; nickel diacetate In water at 45℃; for 24h; | |
82% | With [2,2]bipyridinyl; hydrogen In methanol at 20℃; for 5h; | |
82% | With [2,2]bipyridinyl; hydrogen at 20℃; for 22h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With triethylamine In N,N-dimethyl-formamide at 20℃; for 2h; | 7; 18 Crude cvclopentyl A/2-(te/Y-butoxycarbonvϖ-0-(4-r((5-r4-chloro-3-(methylsulfonyl) phenvn-4-methvl-1.3-thiazol-2-yl)carbamovϖaminolphenvl)-L-homoserinate was treated with 20% TFA in DCM (10ml) at RT for 1h. The solvent was then removed in vacuo and the resulting residue purified by prep HPLC (MeCN / water) to afford the title compoud as a clear oil (9mg). LCMS purity 90%, m/z 607/609 [M+H]+, 1H NMR (300 MHz, CD3OD) δ: 8.13 (1 H, d, J=U Hz), 7.78-7.73 (2H, m), 7.35 (2H, d, J=8.7 Hz), 6.77 (2H, d, J=8.9 Hz), 5.18 (1H1 1, J=5.7 Hz), 4.39 (2H, t, J=5.9 Hz), 4.18 (1H, t, J=5.5 Hz), 3.37 (3H, s), 2.53-2.46 (2H, m), 2.42 (3H, s), 1.95-1.85 (2H, m), 1.76-1.55 (6H, m).The carbamate used in the above process was prepared as follows:Crude 1 -{5-[4-chloro-3-(methylsulfonyl)phenyl]-4-methyl-1 ,3-thiazol-2-yl}-3-(4- hydroxyphenyl)urea was dissolved in anhydrous DMF (8ml) and treated with Intermediate H (200mg, 0.57mmol) and K2CO3 (158mg, 1.14mmol). The reaction was stirred at 40 0C for 3h after which the solvent was removed in vacuo. The residue was redissolved in EtOAc (25ml) and washed with sat NaHCO3(aq) (25ml) and brine (25ml). The organic was then dried (MgSO4) and concentrated in vacuo. The resulting residue was used directly in the following stage without further purification, m/z 707 [M+H]+.The urea used as starting material used in the above process was preapred as follows:1-[4-(Benzyloxy)phenyl]-3-{5-[4-chloro-3-(methylsulfonyl)phenyl]-4-methyl-1 ,3-thiazol- 2-yl}urea (234mg, 0.44mmol) was treated with TFA (5ml) and thioanisole (500μl) at 80 0C for 2h. The solvents were removed under high vacuum conditions and the resulting residue was used directly in the following stage without further purification, m/z 438 [M+H]+. The benzyl ether used in the above process was prepared as follows::To a solution of the carbodiimide intermediate descibed in the previous example (226mg, 0.57mmol) in anhydrous DMF (9ml) was added 4-benzyloxyanaline (134mg, 0.57mmol) and Et3N (159μl, 1.14mmol). The reaction was stirred under N2 atmosphere at RT for 2h. The solvent was then removed in vacuo and the resulting residue purified by flash chromatography eluting with 3% MeOH in DCM to give the desired product (234mg, 78%). m/z 528 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With triethylamine In toluene; acetonitrile at 55℃; for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: 4-amino-phenol With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 0℃; for 0.25h; Stage #2: benzyl bromide In N,N-dimethyl-formamide | |
44% | Stage #1: 4-amino-phenol With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 0℃; for 1h; Sealed tube; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 0 - 120℃; for 16h; Sealed tube; | Intermediate 6 (0458) 4-(benzyloxy)aniline In a 30 ml seal tube previously equipped with a magnetic stirrer and nitrogen balloon Potassium tert-butoxide (0.76 mg, 0.0068 mol) was added portion wise to a solution of 4- aminophenol (0.50 g, 0.0045 mol) in DMF (5.0 ml_) at 0°C. After stirring for 1 h, benzylbromde (0.860 g, 0.005 mol) was added portion wise. The reaction mixture was allowed to come at 25 °C than heated at 120 °C for 16 hours. The reaction mixture was quenched with water (50 ml) and extracted with ethyl acetate (3 x 40 ml). The combine organic layers were washed with brine (30 ml), dried over sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified on silica gel (60-120 mesh) using 30% ethyl acetate in hexane as an eluent to obtained 0.400 g (44 % yield) of the pure title product. (0460) MS (ES+) m/z 200 [M+H]+ |
With tetra-(n-butyl)ammonium iodide; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 60℃; for 8h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; In water; | 4-Benzyloxyaniline is commercially available as the hydrochloride salt; this is treated with aqueous sodium carbonate solution, and the mixture extracted with ethyl acetate; the organic solution is dried (MgSO4) and concentrated to give the free base as a brown solid, used without further purification. | |
With sodium hydroxide; In methanol; water; | A solution of <strong>[51388-20-6]4-benzyloxyaniline hydrochloride</strong> (compound Ia, 12 g) in MeOH (200 mL) was treated with aqueous NaOH (2.04 g in 80 mL deionized water) and the resulting clear solution was concentrated to dryness to provide a residue of crude aniline free base. | |
With sodium hydroxide; In diethyl ether; water; | Intermediate 29: 6-(at) f 2-((at)2- f (2-aminoethyl)oxyl ethyl(at) oxy)ethyll oxy)-1-ethyl-4-oxo-1,4-dihydro-3- quinolinecarboxylic acid formate a) Ethyl 4-oxo-6-[(phenylmethyl)oxy]-1,4-dihydro-3-quinolinecarboxylate p-Benzyloxy aniline hydrochloride (25 g) was shaken with 1M NaOH (120 mL) and diethyl ether (200 mL). The organic layer was washed with brine, dried (MgS04) and evaporated to a solid (21.3 g). This material was heated with ethoxymethylene malonate (27.9 g) at 130C for 1.5 h using a Dean and Stark condenser. Dowtherm (100 mL) was added and the mixture heated to 250C using a Dean and Stark condenser for 70 min. The mixture was cooled and treated with petroleum ether (bp 60-80C) to precipitate a brown solid. This was slurried in dichloromethane, the pale yellow solid was filtered and dried to give the title compound (11.06 g). (at)H-NMR(400 MHz, DMSO-d6) No.: 1.28 (3H, t, J = 7.2 Hz), 4.21 (2H, q, J = 7.2 Hz), 5.21 (2H, s), 7.3 (1H, m), 7.4 (3H, m), 7.4 (2H, m), 7.59 (1H, d, J=8.8 Hz), 7.66 (1H, d, J= 2.8 Hz) , 8.49 (1H, s) and 12.3 (lH, br). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium nitrite; In hydrogenchloride; ethanol; water; | Preparation of 4-Benzyloxyphenylhydrazine Hydrochloride (Intermediate C) To a slurry of 4-benzyloxyaniline (250 g) and ethanol 300 ml) in 30percent HCl (350 ml) and 37percent HCl (150 ml) was added a solution of sodium nitrite (77 g) in water (350 ml), while maintaining the temperature between -8 and -2°C. The reaction was stirred for an additional four hours at -2°C. A solution of tin (II) chloride dihydrate (710 g) in 30percent HCl (770 ml) was added slowly followed by d-gluconic acid lactone (575 g), and the resulting white suspension was cooled overnight. The crude product was collected by vacuum filtration and washed with 1 N hydrochloric acid, ether, and vacuum dried to give 248.9 g of the desired product, m.p. 173-174°C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.6% | With pyridine In ethyl acetate at 20℃; for 2h; | 5.3 Step 3: Preparation of (4-benzyloxyphenyl) carbamate phenylester 16.66 g of 4-benzyloxyphenyl (0.0836 mol) obtained in Step 2 and 7 g of pyridine (0.0877 mol) were added to 500 ml of ethyl acetate. 13.75 g of phenyl CHLOROFORMATE (0.0877 mol) was dissolved in 30 ml of ethyl acetate, which was added dropwise thereto, and was kept at room temperature for 2 hours. The reaction mixture was mixed with water, extracted with ethyl acetate, washed with 5% phosphate, and dried over anhydrous MgS04. After filtrating, the resulting solution was concentrated to 50 ml, kept at room temperature to obtain a precipitate, and filtrated. The residue obtained thus was dried to obtain 21.263 g (yield 79.6%) of the title compound. H-NMR (CDCL3, 200MHZ) : 6 5.05 (s, 2H), 6.92-6. 97 (m, 15H); MS (m/z): 228 (27, M+-91), 225 (80), 94 (74), 90 (100), 77 (55), 65 (71) |
Stage #1: p-benzyloxyaniline With triethylamine In dichloromethane at 20℃; for 0.166667h; Inert atmosphere; Stage #2: phenyl chloroformate In dichloromethane at 0 - 20℃; for 2h; Inert atmosphere; | Synthesis of phenyl phenylcarbamate derivatives (5a-q) General procedure: To a stirred solution of anilines (3.29 mmol) in dichloromethane (6 mL) was added triethylamine (9.89 mmol) at room temperature and stirred at room temperature for 10 min and added aryl chloro formate (4.93 mmol) at 0 °C and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and the crude material washed with 10 % diethyl ether in pentane to afford the pure compounds. Without further purification used for next step. Yields of the products varied between 65 to 85 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | for 0.5h;Steam bath; | An intimate mixture of 4.25 g (22 mmol) of 5-H, 10H-diimidazo[1,5-a, 1',5'-d]pyrazine-5,10-dione and 9.04 g (45 mmol) of 4-benzyloxyaniline was heated on a steam bath for 30 min. The residue was flash chromatographed with 5% MeOH in CH2Cl2 to give 4.8 g of the title compound (66% yield). MS m/z 294 (MH+). 1H NMR(CDCl3) delta 5.07 (s, 2H), 7.0 (d, 2H), 7.30-7.50 (m, 3H), 7.7-7.8 (m, 4H), 9.8 (s 1H), 12.6 (s, 1 H). |
66% | for 0.5h;Steam bath; | A. 3-H-Imidazole-4-carboxylic acid (4-benzyloxyphenyl) amide. An intimate mixture of 4.25 g (22 mmol) of 5-H, 10H-diimidazo [1,5-a, 1', 5'- d] pyrazine-5, 10-dione and 9.04 g (45 mmol) of 4-benzyloxyaniline was heated on a steam bath for 30 min. The residue was flash chromatographed with 5% MeOH in CH2CI2 to give 4. 8 g of the title compound (66% yield). MS m/z 294 (MH+). 1H NMR (CDCl3)No. 5.07 (s, 2H), 7.0 (d, 2H), 7.30-7. 50 (m, 3H), 7.7-7. 8 (m, 4H), 9.8 (s 1H), 12.6 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; for 18h;Heating / reflux; | (4-Benzyloxyphenyl)-(6-iodoquinazolin-4-yl)-amine hydrochloride 4-Chloro-6-iodoquinazoline (8 g) was treated with 4-benzyloxyaniline (5.5 g) in acetonitrile (500 ml) at reflux under N2 for 18 hours. Subsequent cooling and filtration gave the title compound (13.13 g); δH [2H6]-DMSO 11.45 (1H, b, NH), 9.22 (1H, s, 5-H), 8.89 (1H, s, 2-H), 8.36 (1H, d, 7-H), 7.69 (1H, d, 8-H), 7.63 (2H, d, 2'-H, 6'-H), 7.52-7.29 (5H, m, Ph-H), 7.14 (2H, d, 3'-H, 5'-H), 5.18 (2H, s, CH2); m/z (M+1)+ 454. | |
In acetonitrile; for 18h;Heating / reflux; | 4-Chloro-6-iodoquinazoline (8 g) was treated with 4-benzyloxyaniline (5.5 g) in acetonitrile (500 ml) at reflux under N2 for 18 hours. Subsequent cooling and filtration gave the title compound (13.13 g); δH [2H6]-DMSO 11.45 (1H, b, NH), 9.22 (1H, s, 5-H), 8.89 (1H, s, 2-H), 8.36 (1H, d, 7-H), 7.69 (1H, d, 8-H), 7.63 (2H, d, 2'-H, 6'-H), 7.52-7.29 (5H, m, Ph-H), 7.14 (2H, d, 3'-H, 5'-H), 5.18 (2H, s, CH2); m/z (M+1)+454. | |
13.13 g | In acetonitrile; for 18h;Reflux; Inert atmosphere; | (4-Benzyloxyphenyl)-(6-iodoquinazolin-4-yl)-amine hydrochloride (0637) 4-Chloro-6-iodoquinazoline (8 g) was treated with 4-benzyloxyaniline (5.5 g) in acetonitrile (500 ml) at reflux under N2 for 18 hours. Subsequent cooling and filtration gave the title compound (13.13 g); δH [2H6]-DMSO 11.45 (1H, b, NH), 9.22 (1H, s, 5-H), 8.89 (1H, s, 2-H), 8.36 (1H, d, 7-H), 7.69 (1H, d, 8-H), 7.63 (2H, d, 2′-H, 6′-H), 7.52-7.29 (5H, m, Ph-H), 7.14 (2H, d, 3′-H, 5′-H), 5.18 (2H, s, CH2); m/z (M+1)+ 454. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With sodium hydrogencarbonate; In DMF (N,N-dimethyl-formamide); water; acetone; at 20℃; | To a solution of <strong>[89001-57-0]5-chlorosulfonyl-2-methylbenzoic acid</strong> (200 mg, 0.85 mmol) and p- benzyloxyaniline (187 mg, 0.94 mmol) in 6 ml acetone and 3 ml dimethylformamide was added a solution of sodium bicarbonate (215 mg, 0.56 mmol) in 2 ml water. The resulting mixture was stirred overnight at room temperature. The acetone was then removed under reduced pressure and the residual mixture was partitioned between 25 ml 1N aqueous hydrochloric acid solution and 25 ml ethyl acetate. The aqueous phase was separated and extracted with 2 x 25 ml ethyl acetate. The combined ethyl acetate extracts were dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 15 gm) eluting with 9: 1 chloroform/methanol to yield a white solid (154 mg). The solid was triturated with dichloromethane to yield the title compound (93 mg, 28 % yield) as a white solid. MS: 395.6 (M-1) ;'H NMR (400 MHz, CD30D) : 8 2.57 (s, 3H), 4.96 (s, 2H), 6.81 (m, 2H), 6.93 (m, 2H), 7.30 (m, 6H), 7.60 (m, 1H), 8.20 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With triethylamine In N,N-dimethyl-formamide at 140℃; for 0.416667h; Microwave irradiation; | 34 Example 34; 4-[4-(Benzyloxy)phenyl]amino}-2-butyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide; A mixture of 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.60Og, 2.001mmol), [4-(benzyloxy)phenyl] amine (1.415g, 6.004mmol) and TEA (0.840ml, 6.004mmol) in DMF (5ml) was heated in a microwave reactor at 140°C for 25mins. EtOAc was added to the mixture, and it was washed with brine, evaporated and the residue was purified by flash chromatography using a 5:1 EtO Ac/petroleum ether 40-60°C mixture as eluent to give the title compound (0.721g, 78%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | In dichloromethane; ethyl acetate; N,N-dimethyl-formamide; | EXAMPLE 1 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole A flask was charged with 4-benzyloxyaniline (45 g, 0.23 mol), 4'-benzyloxy-2-bromophenylpropiophenone (21 g, 0.066 mol), and DMF (50 mL). The reaction was heated at reflux for 30 minutes and then cooled to rt and then partitioned between EtOAc (250 mL) and 1N HCl (aq) (100 mL). The EtOAc was washed with NaHCO3 (aq) and brine, dried over MgSO4. The solution was concentrated and the residue taken up in CH2Cl2 and hexanes added to precipitate out 25 g of a crude solid. The solid was dissolved in CH2Cl2 and evaporated onto silica gel and chromatographed using CH2Cl2/Hexane (1:5) to yield 9.2 g of a tan solid (33%): Mpt=150-152 C.; 1H NMR (DMSO) 10.88 (s, 1 H), 7.56 (d, 2 H, J=8.8 Hz), 7.48 (d, 4 H, J=7.9 Hz), 7.42-7.29 (m, 6 H), 7.21 (d, 1 H, J=7.0 Hz), 7.13 (d, 2 H, J=8.8 Hz), 7.08 (d, 1 H, J=2.2 Hz), 6.94 (dd, 1 H, J=8.8, 2.4 Hz), 5.16 (s, 2 H), 5.11 (s, 2 H), 2.33 (s, 3 H); IR (KBr) 3470, 2880, 2820, 1620 cm-1; MS eI m/z 419. |
33% | In dichloromethane; ethyl acetate; N,N-dimethyl-formamide; | EXAMPLE 1 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole A flask was charged with 4-benzyloxyaniline (45 g, 0.23 mol), 4'-benzyloxy-2-bromophenylpropiophenone (21 g, 0.066 mol), and DMF (50 mL). The reaction was heated at reflux for 30 minutes and then cooled to rt and then partitioned between EtOAc (250 mL) and 1 N HCl (aq) (100 mL). The EtOAc was washed with NaHCO3 (aq) and brine, dried over MgSO4. The solution was concentrated and the residue taken up in CH2 Cl2 and hexanes added to precipitate out 25 g of a crude solid. The solid was dissolved in CH2 Cl2 and evaporated onto silica gel and chromatographed using CH2 Cl2 /Hexane (1:5) to yield 9.2 g of a tan solid (33%): Mpt=150-152 C.; 1 H NMR (DMSO) 10.88 (s, 1 H), 7.56 (d, 2 H, J=8.8 Hz), 7.48 (d, 4 H, J=7.9 Hz), 7.42-7.29 (m, 6 H), 7.21 (d, 1 H, J=7.0 Hz), 7.13 (d, 2 H, J=8.8 Hz), 7.08 (d, 1 H, J=2.2 Hz), 6.94 (dd, 1 H, J=8.8, 2.4 Hz), 5.16 (s, 2 H), 5.11 (s, 2 H), 2.33 (s, 3 H); IR (KBr) 3470, 2880, 2820, 1620 cm-1; MS eI m/z 419. |
33% | In dichloromethane; ethyl acetate; N,N-dimethyl-formamide; | EXAMPLE 14 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole STR40 A flask was charged with 4-benzyloxyaniline (45 g, 0.23 mol), 4'-benzyloxy-2-bromophenylpropiophenone (66414-19-5) (21g, 0.066 mol), and 50 mL DMF. The reaction was heated at reflux for 30 minutes and then cooled to rt and then partitioned between 250 mL EtOAc and 100 mL 1N HCl (aq). The EtOAc was washed with NaHCO3 (aq) and brine, dried over MgSO4. The solution was concentrated and the residue taken up in CH2 Cl2 and hexanes added to precipitate out 25 g of a crude solid. The solid was dissolved in CH2 Cl2 and evaporated onto silica gel and chromatographed using CH2 Cl2 /Hexane (1:5) to yield 9.2 g of a tan solid (33%): Mpt=150-152 C.; 1 H NMR (DMSO) 10.88 (s, 1 H), 7.56 (d, 2 H, J=8.8 Hz), 7.48 (d, 4 H, J=7.9 Hz), 7.42-7.29 (m, 6 H), 7.21 (d, 1 H, J=7.0 Hz), 7.13 (d, 2 H, J=8.8 Hz), 7.08 (d, 1 H, J=2.2 Hz), 6.94 (dd, 1 H, J=8.8, 2.4 Hz), 5.16 (s, 2 H), 5.11 (s, 2 H), 2.33 (s, 3 H); IR (KBr) 3470, 2880, 2820, 1620 cm-1; MS eI m/z 419. |
33% | In dichloromethane; ethyl acetate; N,N-dimethyl-formamide; | EXAMPLE 1 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole A flask was charged with 4-benzyloxyaniline (45 g, 0.23 mol), 4'-benzyloxy-2-bromophenylpropiophenone (21 g, 0.066 mol), and DMF (50 mL). The reaction was heated at reflux for 30 minutes and then cooled to rt and then partitioned between EtOAc (250 mL) and 1N HCl (aq) (100 mL). The EtOAc was washed with NaHCO3 (aq) and brine, dried over MgSO4. The solution was concentrated and the residue taken up in CH2 Cl2 and hexanes added to precipitate out 25 g of a crude solid. The solid was dissolved in CH2 Cl2 and evaporated onto silica gel and chromatographed using CH2 Cl2 /Hexane (1:5) to yield 9.2 g of a tan solid (33%): Mpt=150-152 C.; 1 H NMR (DMSO) 10.88 (s, 1H), 7.56 (d, 2H, J=8.8 Hz), 7.48 (d, 4H, J=7.9 Hz), 7.42-7.29 (m, 6H), 7.21 (d, 1H, J=7.0 Hz), 7.13 (d, 2H, J=8.8 Hz), 7.08 (d, 1H, J=2.2 Hz), 6.94 (dd, 1H, J=8.8, 2.4 Hz), 5.16 (s, 2H), 5.11 (s, 2H), 2.33 (s, 3H); IR (KBr) 3470, 2880, 2820, 1620 cm-1; MS eI m/z 419. |
33% | In hydrogenchloride; CH2Cl2and; ethyl acetate; N,N-dimethyl-formamide; | EXAMPLE 1 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole A flask was charged with 4-benzyloxyaniline (45 g, 0.23 mol), 4'-benzyloxy-2-bromophenylpropiophenone (21g, 0.066 mol), and DMF (50 mL). The reaction was heated at reflux for 30 minutes and then cooled to rt and then partitioned between EtOAc (250 mL) and IN HCl (aq) (100 mL). The EtOAc was washed with NaHCO3(aq) and brine, dried over MgSO4. The solution was concentrated and the residue taken up in CH2Cl2and hexanes added to precipitate out 25g of a crude solid. The solid was dissolved in CH2Cl2and evaporated onto silica gel and chromatographed using CH2Cl2/Hexane (1:5) to yield 9.2 g of a tan solid (33%): Mpt = 150-152C; 1H NMR (DMSO) 10.88 (s, 1 H), 7.56 (d, 2 H, J = 8.8 Hz), 7.48 (d, 4 H, J = 7.9 Hz), 7.42-7.29 (m, 6 H), 7.21 (d, 1 H, J = 7.0 Hz), 7.13 (d, 2 H, J = 8.8 Hz), 7.08 (d, 1 H, J = 2.2 Hz), 6.94 (dd, 1 H, J = 8.8, 2.4 Hz), 5.16 (s, 2 H), 5.11 (s, 2 H), 2.33 (s, 3 H); IR (KBr) 3470, 2880, 2820, 1620 cm-1; MS eI m/z 419. |
33% | In CH2Cl2and; ethyl acetate; N,N-dimethyl-formamide; | EXAMPLE 18 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole A flask was charged with 4-benzyloxyaniline (45 g, 0.23 mol), 4'-benzyloxy-2-bromophenylpropiophenone (21g, 0.066 mol), and DMF (50 mL). The reaction was heated at reflux for 30 minutes and then cooled to rt and then partitioned between EtOAc (250 mL) and 1N HCl (aq) (100 mL). The EtOAc was washed with NaHCO3(aq) and brine, dried over MgSO4. The solution was concentrated and the residue taken up in CH2Cl2and hexanes added to precipitate out 25g of a crude solid. The solid was dissolved in CH2Cl2and evaporated onto silica gel and chromatographed using CH2Cl2/Hexane (1:5) to yield 9.2 g of a tan solid (33%): Mpt = 150-152C; 1H NMR (DMSO) 10.88 (s, 1 H), 7.56 (d, 2 H, J = 8.8 Hz), 7.48 (d, 4 H, J = 7.9 Hz), 7.42-7.29 (m, 6 H), 7.21 (d, 1 H, J = 7.0 Hz), 7.13 (d, 2 H, J = 8.8 Hz), 7.08 (d, 1 H, J = 2.2 Hz), 6.94 (dd, 1 H, J = 8.8, 2.4 Hz), 5.16 (s, 2 H), 5.11 (s, 2 H), 2.33 (s, 3 H); IR (KBr) 3470, 2880, 2820, 1620 cm-1; MS eI m/z 419. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | In dichloromethane; ethyl acetate; N,N-dimethyl-formamide; | EXAMPLE 1 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole A flask was charged with 4-benzyloxyaniline (45 g, 0.23 mol), 4-benzyloxy-2-bromophenylpropiophenone (21 g, 0.066 mol), and DMF (50 mL). The reaction was heated at reflux for 30 minutes and then cooled to rt and then partitioned between EtOAc (250 mL) and 1N HCl (aq) (100 mL). The EtOAc was washed with NaHCO3 (aq) and brine, dried over MgSO4. The solution was concentrated and the residue taken up in CH2 Cl2 and hexanes added to precipitate out 25 g of a crude solid. The solid was dissolved in CH2 Cl2 and evaporated onto silica gel and chromatographed using CH2 Cl2 /Hexane (1:5) to yield 9.2 g of a tan solid (33%): Mpt=150-152 C.; 1 H NMR (DMSO) 10.88 (s, 1 H), 7.56 (d, 2 H, J=8.8 Hz), 7.48 (d, 4 H, J=7.9 Hz), 7.42-7.29 (m, 6 H), 7.21 (d, 1 H, J=7.0 Hz), 7.13 (d, 2 H, J=8.8 Hz), 7.08 (d, 1 H, J=2.2 Hz), 6.94 (dd, 1 H, J=8.8, 2.4 Hz), 5.16 (s, 2 H), 5.11 (s, 2 H), 2.33 (s, 3 H); IR (KBr) 3470, 2880, 2820, 1620 cm-1; MS eI m/z 419. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium nitrite; In hydrogenchloride; water; | A. 4-Benzyloxyphenylhydrazine hydrochloride A solution of sodium nitrite (3.8 g, 0.055 mol in 20 mL of H2 O), is added dropwise to an ice cold stirring suspension of 4-benzyloxyaniline (13.0 g, 0.055 mol in 150 mL of concentrated HCl). The reaction mixture is stirred for 90 minutes at -8° to 10° C. A solution of SnCl2.2H2 O (32.0 g, 0142 mol in 50 mL concentrated HCl) is added and stirred for 1 hour at 0° C. The reaction mixture is removed from the ice bath and is stirred at room temperature for 20 hours. The mixture is then filtered and washed with water to give 13.0 g (95percent yield) of product, m.p. 182°-185° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium nitrite; In hydrogenchloride; water; | A. 4-Benzyloxyphenylhydrazine hydrochloride A solution of sodium nitrite (3.8 g, 0.055 mol in 20 mL of H2 O), is added dropwise to an ice cold stirring suspension of 4-benzyloxyaniline (13.0 g, 0.055 mol in 150 mL of concentrated HCl). The reaction mixture is stirred for 90 minutes at -8° to 10° C. A solution of SnCl2 *2H2 O (32.0 g, 0142 mol in 50 mL concentrated HCl) is added and stirred for i hour at 0° C. The reaction mixture is removed from the ice bath and is stirred at room temperature for 20 hours. The mixture is then filtered and washed with water to give 13.0 g (95percent yield) of product, m.p. 182°-185° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.23% | With triethylamine In toluene at 120℃; for 20h; Inert atmosphere; Dean-Stark; | 1 Step 1: Synthesis of N-(4-(benzyloxy)phenyl)-4-methyl-3-oxopentanamide (3) TEA (12.70 g, 125.47 mmol) in a mixture of methyl 4-methyl-3-oxo-pentanoate (18.09 g, 125.47 mmol, 17.91 mL) and 4-benzyloxyaniline (25 g, 125.47 mmol, 17.46 mL)) in toluene (250 mL) was added, The resulting mixture was stirred at 120° C. for 20 hours under a nitrogen atmosphere using a Dean Stark apparatus. According to TLC (petroleum ether: ethyl acetate = 1:1) a new spot was formed, 4-benzyloxyaniline was consumed. The mixture was concentrated under vacuum. The residue was triturated with methyl tert-butyl ether (150 mL), Collect the filter cake, Drying in vacuo gave the title compound (29 g, 93.14 mmol, 74.23% yield) as a white solid. |
50% | With triethylamine In toluene for 24h; Heating / reflux; | H.9.A A mixture of 4-Methyl-3-oxo-pentanoic acid methyl ester from Example 3A (25g, 173 mmol), and 4-benzyloxyaniline (40.9g, 173 mmol), triethyl amine (17.54g, 173 mmol) in toluene (400 mL) was refluxed for 24hr using a Dean Stark apparatus. The solvents were removed and the crude material was dissolved in ethyl acetate and water. NaCI was added and extracted (3 x 100 mL). The organic layers was washed with 1M HCI (3 x 10OmL), water (3 x 100 mL), brine (3 x 100 mL) and dried over magnesium sulfate. It was purified by a silica pad (SiO2), eluting with EtOAc/Hexanes (0:100 to 20:80) to afford 4-Methyl-3-oxo-pentanoic acid (4-benzyloxy-phenyl)- amide as a yellow solid (27g, 50%); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In sodium hydroxide; | (a) 4,5-Dihydro-N-(4-phenylmethoxyphenyl)-1-phenyl-1H-pyrazol-3-amine A mixture of <strong>[92-43-3]1-phenyl-1H-pyrazolidin-3-one</strong> (8.1 g), 4-phenylmethoxyaniline (20 g) and 4-toluenesulphonic acid (5 g) was heated in an oil bath at 140 under a nitrogen atmosphere for 15 minutes. The reaction was cooled and the products dissolved in 1% sodium hydroxide solution and ether. The organic phase was separated and washed with 1% hydrochloric acid solution, water and then dried over sodium sulphate. The organic phase was filtered and evaporated to a pale oil which on trituration with pentane gave the sub-title compound (6.0 g), mp 187-188. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15.4% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; N,N-dimethyl-formamide at 0 - 20℃; | 17 Synthesis of Compound 117To a stirred solution of compound 905 (500 mg, 2.23 mmol) in dry THF (5mL) and DMF (10 rnL) was added 4-benzyloxy-phenylamine, DIPEA (0.38 rnL, 2.23 mmol), HOBT (300 mg, 2.23 mmol), and EDCI (639 mg, 3.34 mmol) at 00C. The reaction mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under vacuum to remove THF and DMF completely. The residue was dissolved in water and extracted with ethyl acetate (2 x 50 mL), and the organic layer was washed with brine and dried over anhydrous sodium sulfate to afford coupled product which was purified by column chromatography on silica gel eluting with 12% ethyl acetate in hexanes, to give compound 117 (140 mg, 15.4%). Mass: 406 [M+H]. 1H NMR (500 MHz, CDCl3): δ 1.4-2.0 (m, 16H), 2.21 (d, IH), 4.4 (d, IH), 5.08 (s, 2H), 6.98 (d, 2H), 7.2-7.6 (m, 7H), 8.39 (bs, IH). |
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With chloro-trimethyl-silane In methanol at 20℃; | |
50% | With trifluoroacetic acid In methanol; dichloromethane at 20℃; | 1.7 Weigh the compound tert-butyl (4-(benzyloxy)phenyl)carbamate (7) (1 equivalent), add a solvent (trifluoroacetic acid: dichloromethane = 1:1) and stir magnetically at room temperature. The TLC monitoring product point concentration no longer changes, and the reaction ends. Rotate the system to remove most of the solvent, add an equal volume of ethyl acetate and a small amount of concentrated hydrochloric acid to obtain a white solid (50-55%). |
42% | With trifluoroacetic acid In dichloromethane at 20℃; for 1h; | E [4- (benzyloxy)-phenyl]-carbamic acid tert-butyl ester (0.44g) was dissolved in 6mL dichloromethane and 2mL trifluoroacetic acid was added. The reaction stirred at room temperature for 1 hour. The excess trifluoroacetic acid was removed in vivo. Yield: 0.12g (42%). |
With trifluoroacetic acid In dichloromethane at 20℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In dichloromethane at 0 - 20℃; | I 15 g (4-Benzyloxy-phenylamine) is diluted in 260 ml dichloromethane under argon atmosphere. The solution is cooled down to 00C. 18.35 g Chloro-isocyanato-trifluoromethyl- benzene are dissolved in 26O mI dichloromethane and is slowly added to the solution. The solution is stirred overnight at ambient temperature. The solid is filtered and washed with dichloromethane and dried in high vacuo.By this method 28.37 g of the title compound are obtained (Yield: 90 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With hydrogen In methanol at 25℃; for 24h; chemoselective reaction; | |
99% | With sodium tetrahydroborate; nickel(II) chloride hexahydrate In methanol at 20℃; for 3h; Sealed tube; Darkness; | Synthesis of 4-(benzyloxy)aniline (2j) The compound was obtainedaccording procedure B using azido compound 1j (1 equiv, 0.6 mmol, 130mg), NiCl2 (0.5 mol%, 70 μL, 42 mM), and NaBH4 (3.0 equiv, 1.7 mmol, 65mg). Yielding the product as a brownish precipitate (114 mg, 99% yield). 1HNMR (CDCl3, 400 MHz): 7.46 -7.32 (br, 5H), 6.85 (d, J= 8.65 Hz, 2H), 6.65 (d, J= 8.65 Hz, 2H),5.01 (s, 2H), 3.43 (s, 2H, NH); 13C{1H} NMR (CDCl3, 100 MHz): 150.1, 140.3, 137.6, 128.6,127.8, 127.6, 116.5, 116.2, 70.9.9 |
95% | With hydrogenchloride; nickel boride In methanol; water for 0.0166667h; Microwave irradiation; Closed vessel; |
89% | With iron In water at 20℃; Inert atmosphere; | General experimental procedure for reduction of azidoarenes General procedure: The azido compound (1 mmol) was added to the freshly prepared Fe(0) nanoparticles (3 mmol) in water (5 mL) in the same pot under constant stirring at room temperature under argon atmosphere. After completion of reaction (TLC) the mixture was extracted with ethyl acetate (3 X 10 mL) (all Fe-species remained around stirring bar). Evaporation of solvent and purification by short column chromatography provided the pure product which was properly characterized by spectroscopic (IR, 1H NMR and 13C NMR) data. |
65% | With ammonium formate; copper In water for 12h; Reflux; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 110℃; for 1.5h; | 4.1 (4-Benzyloxy-phenyl)-(2-nitro-phenyl)-amine Stage 1: (4-Benzyloxy-phenyl)-(2-nitro-phenyl)-amine To 600 μL of 2-fluoro-nitrobenzene, 6 mL of DMSO are added 1.7 g of 4-(benzyloxy)aniline (1.5 equivalents) and 1.02 g of potassium tert-butanolate (1.6 equivalents). The whole is heated to 110° C. for 1 h 30. The medium is then hydrolyzed and extracted several times with ethyl acetate. The organic phases are washed with a saturated solution of sodium chloride, dried on magnesium sulfate, filtered and then concentrated under reduced pressure. A silica gel chromatography of the residue (cyclohexane/ethyl acetate: 99/1) allows 754 mg of the desired product to be isolated. Yield: 41% 1H NMR (CDCl3, 300 MHz) δ (ppm): 9.40 (s broad, 1H), 8.18 (d, 1H), 7.23-7.45 (m, 6H), 7.17-7.21 (m, 2H), 7.05 (m, 3H), 6.71 (t, 1H), 5.09 (s, 2H) MS: MH+ 321 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 1331-ethyl-6-fluoro-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 133a) N2-[4-(benzyloxy)phenyl]-5-fluoropyridine-2,3-diamine A mixture of 4-(benzyloxy)aniline (2.26 g), <strong>[136888-21-6]2-chloro-5-fluoro-3-nitropyridine</strong> (2 g) and K2CO3 (3.13 g) in DMF (20 ml) was stirred at 120 C. for 5 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was suspended in IPE and collected by filtration. The obtained solid was dissolved in EtOH (20 ml), and Pt/C (2 g) was added. Under H2 atmosphere, the mixture was stirred for 1 h, filtered and evaporated. The residue was chromatographed on silica gel eluting with Hexane/AcOEt to give the title compound (0.85 g).1H NMR (300 MHz, DMSO-d6) delta 5.04 (2H, s), 5.39 (2H, s), 6.69-6.80 (1H, m), 6.86-6.94 (2H, m), 7.29-7.50 (8H, m), 7.54 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 5h; | Example 132; 1-ethyl-6-fluoro-3-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 132a) N2-[4-(benzyloxy)phenyl]-5-fluoropyridine-2,3-diamine A mixture of 4-(benzyloxy)aniline (2.26 g), <strong>[136888-21-6]2-chloro-5-fluoro-3-nitropyridine</strong> (2 g) and K2CO3 (3.13 g) in DMF (20 mL) was stirred at 120 C. for 5 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was suspended in IPE and collected by filtration. The solid obtained above was dissolved in EtOH (20 ml), and Pt/C (2 g) was added. Under H2 atmosphere, the mixture was stirred for 1 h, filtered and evaporated. The residue was chromatographed on silica gel eluting with Hexane/AcOEt to give the title compound (0.85 g).1H NMR (300 MHz, DMSO-d6) delta 5.04 (2H, s), 5.39 (2H, s), 6.69-6.80 (1H, m), 6.86-6.94 (2H, m), 7.29-7.50 (8H, m), 7.54 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20℃; for 1h; | General procedure: To a mixture of aldehyde (1 mmol) and amine/amine hydrochloride (1 mmol) in anhydrous CH2Cl2 (10 mL) was added triethylamine (2.5 mmol) at rt, and the resulting solution was stirred vigorously for 1 h. To this was then added (Boc)2O (1.2 mmol) followed by sodium triacetoxyborohydride (2 mmol). The reaction was stirred for an additional 4 h at rt, quenched with saturated NaHCO3 solution, and extracted with CH2Cl2. The combined organic fractions were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (95:05?50:50, hexanes/EtOAc) to afford the N-Boc secondary amine. Most of the title compounds were present as a mixture of rotational isomers in their 1H and 13C NMR spectra. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | In isopropyl alcohol at 60℃; Reflux; | 15 General procedure: 3-Chloro-4-fluoroaniline (172 mg, 1.18 mmol) was added to a solution of compound 13 (373 mg, 1.07 mmol) in isopropanol (10 ml) and stirred at reflux for 8 h. The mixture was cooled to room temperature and filtered, then the solid was washed with chill isopropanol (5 ml), treated with aqueous NaHCO3 (10 ml) and extracted with EtOAc/MeOH (20:1, 30 ml). The organic layer was washed with brine, dried over MgSO4, and concentrated. Chromatography of the residue on silica gel with DCM-MeOH (50/1, v/v) gave 416 mg (yield, 85%) of the title compound as white solid: 4.2.15 8-(4-(Benzyloxy)phenylamino)-1-(3-morpholinopropyl)oxazolo[4,5-g]quinazolin-2(1H)-one (5o) White solid, 477 mg, yield, 87%; Mp: 279-282 °C; HRMS, ESI+, m/z: Calcd for C29H30N5O4 (M + H)+, 512.2292; found, 513.2283; 1H NMR (300 MHz, DMSO-d6) δ:9.57 (1H, bs), 8.45 (1H, s), 8.23 (1H, s), 7.63 (1H, s), 7.33-7.49 (5H, m), 7.07 (2H, d, J = 8.8 Hz), 5.13 (2H, s), 3.98 (2H, t, J = 6.4 Hz), 3.40 (4H, t, J = 4.3 Hz), 2.38 (2H, t, J = 6.5 Hz), 2.23 (4H, m), 2.00 (2H, p, J = 6.4 Hz); 13C NMR (75 MHz, DMSO-d6) δ:157.37, 154.96, 153.64, 153.24, 146.96, 146.25, 137.14, 132.01, 130.95, 128.37, 127.74, 127.61, 124.52, 114.69,111.54,106.39, 100.37, 69.39, 65.94, 55.53, 53.28, 40.91, 22.88. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With N-ethyl-N,N-diisopropylamine In dichloromethane Inert atmosphere; Cooling with ice; | ii. 2-[(Benzyloxy)imino]-N-(2,4-dimethylphenyl)acetamide (7b) General procedure: 2-[(Benzyloxy)imino]acetylchloride (8) (0.89 g, 4.55 mmole) was dissolved in DCM (20 ml) and added dropwise to an ice bath cooled solution of the 2,4-dimethylaniline (0.524 g, 4.32 mmole, 0.54 ml, 0.95 eq.) in DCM (30 ml) and N,N-diisopropylethylamine (0.95ml, 5.5 mmole, 1.2 eq.). On completion of the addition, the cold bath was removed, and the reaction mixture was allowed to warm to room temperature. The crude product was partitioned between 1% HCl and DCM. The organic phase was separated, washed with brine, dried over Na2SO4, and the solvents were evaporated. The resulting tan solid was triturated with 10% ether in hexane, filtered, rinsed with cold solvent mixture, and dried under vacuum to yield 0.96 g (3.40 mmole, 75%) of the title compound as an off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Stage #1: p-benzyloxyaniline With hydrogenchloride In water at 0℃; for 0.0833333h; Inert atmosphere; Schlenk technique; Stage #2: With tert.-butylnitrite at 0℃; for 0.25h; Inert atmosphere; Schlenk technique; Stage #3: trifluoromethylsilver at -78 - 20℃; for 4h; Inert atmosphere; Schlenk technique; | |
53% | Stage #1: p-benzyloxyaniline With hydrogenchloride In water at 0℃; for 0.0833333h; Schlenk technique; Stage #2: With tert.-butylnitrite In water at -196 - 20℃; Schlenk technique; Inert atmosphere; Stage #3: trifluoromethylsilver In water at -78 - 20℃; for 5h; Schlenk technique; Inert atmosphere; | Trifluoromethylation Procedure 1 (Table 1); General Procedure General procedure: An oven-dried Schlenk tube (A) equipped with a magnetic stir bar was charged with AgF (132.2 mg, 1.05 mmol, 3.5 equiv), sealed with a septum, and degassed by alternating vacuum evacuation and nitrogen backfill (three times) before freshly distilled EtCN (3 mL)was added. To the resulting suspension, which was precooled to -78 °C (dry ice-acetone bath), was added TMSCF3 (149.3 mg, 1.05 mmol, 3.5 equiv) by microsyringe. The mixture was allowed towarm to r.t. and stirring was continued for an additional 15 min. In due course, AgF solid dissolved and a gray, dark solution of [Ag-CF3] formed. Another Schlenk tube (B) equipped with a magnetic stir bar was charged with the aniline (ArNH2; 0.30 mmol, 1.0 equiv) in freshly distilled EtCN (1.5 mL). To the resulting solution, which was precooled to 0 °C (ice bath), aq HCl (12 M; 50.0 μL, 0.60mmol, 2.0 equiv) was added; precipitate formed immediately. After 5 min stirring, t-BuONO (37.7 mg, 0.33 mmol, 1.1 equiv) was added by microsyringe, and the mixture was allowed to stir at 0 °C for 15 min. The resulting suspension in Schlenk tube (B) was degassed by alternating vacuum evacuation at -196 °C (liquid nitrogen), then the solution was allowed to warm to r.t. under a nitrogen atmosphere (three times), and finally cooled to -78 °C (dry ice-acetone bath). The gray, dark solution of [AgCF3] in Schlenk tube (A), which was precooled to -78 °C (dry ice-acetone bath), was added to Schlenk tube (B) (ArN2+Cl-) by syringe at -78 °C (dry ice-acetone bath) over a period of 1 h. After the addition was complete, the reaction mixture was stirred for 3 h at -78 °C (dry ice-acetone bath), allowed to warm to r.t., and stirring was continued for an additional 1 h. An off-white precipitate was observed, and the reaction mixture was diluted with EtOAc (3 mL) and filtered through a short silica gel column. The solvent was removed under reduced pressure with a rotatory evaporator, and the crude residue was purified by silica gel column chromatography to give the desired trifluoromethylation product 3. The yields of products 3a, 3f, 3g, 3l, 3o, 3r, 3x, and 3zb are based on the 19F NMR spectra with 4-F3COC6H4OMe as internal standard. Analytical data for the representative product ethyl 4-(trifluoromethyl)benzoate (3i) are provided below. Data for other products can be found in the literature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With dicyclohexyl(2',4',6'-triisopropyl-5-methoxy-3,4,6-trimethyl-[1,1'-biphenyl]-2-yl)phosphine; C50H70NO4PPdS; C50H70NO4PPdS; dicyclohexyl(2',4',6'-triisopropyl-4-methoxy-3,5,6-trimethyl-[1,1'-biphenyl]-2-yl)phosphine; ammonia; sodium t-butanolate In 1,4-dioxane at 20℃; for 36h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | In ethanol; water at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With bromine; In formic acid; acetic acid; at -3 - 0℃;Inert atmosphere; Darkness; | General procedure: The synthesis of 6-ethoxy-1,3-benzothiazol-2-amine (1c), obtained following a general procedure for the preparation of aminobenzothiazoles described in the literature [13,14] is described. Aniline 6c (1.0 g, 7.36 mmol) and NH4SCN (1.6 g, 21.9 mmol) were dissolved in a 20% formic acid-glacial acetic acid mixture (100 mL) and cooled to-3 C with stirring, under N2. With the exclusion of light from the reaction mixture, bromine (0.30 mL dissolved in 20 mL of glacial acetic acid) was added dropwise, while the reaction temperature was kept between -3C and 0 C. The light shield was removed and the mixture was allowed to warm to room temperature overnight. Sodium hydroxide pellets and ice were added with stirring until pH 11 was attained, and the mixture was extracted with EtOAc. The organic layer was separated and filtered through celite to remove polythiocyanogen (SCN)n. The organic layer was then washed with water, saturated NaHCO3 and brine; then, the solvent was evaporated in vacuo. The residue was purified by flash chromatography (EtOAc/petroleum ether 1:1) to give 0.93 g (65%) of an orange solid: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | In dimethyl sulfoxide at 110℃; for 6h; | MRS-2 -35 (MRS-2 -35 ) Methyl ester MRS-2 -33 (500 mg, 2.51 mmol) was dissolved in DMSO (10 mL) . 4- (Benzyloxy) aniline (1.18 g, 5.02 mmol, 2.00 equiv) was added and the reaction mixture was heated to 110 °C for 6 hours. The reaction was cooled to room temperature and diluted with EtOAc. The organic layer was washed with H20 and sat. aqueous NaCl, dried over MgSC , filtered and concentrated. Flash chromatography (Si02, 10% EtOAc/hexanes ) gave 864 mg (91%) of the biaryl aniline. [Saitoh, et al., J. Med. Chem. 52:6270-6276 (2009).] |
91% | In dimethyl sulfoxide at 110℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With triphenyl phosphite In pyridine at 100℃; Sealed tube; | Scheme 2 Reagents and conditions: (a) dioxane, triethylamine, 50°C (65% yield); (b) Cs2CO3, iPrI, CH3CN, 40°C; (c) TFA, DCM (75% for 2 steps); (d) P(OPh)3, pyridine, 100°C in a sealed tube; then p-OBn aniline (78% yield); (e) TMSBr, TFA, thioanisole, 0°C (64% yield); (f) [11C]CH3I, Cs2CO3, DMF, 45°C, 3min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With potassium carbonate In 1,2-dichloro-ethane at 0℃; for 2h; | 2 General procedure for the synthesis of 2-chloro-N-(4-substituted phenyl)acetamide 6a-c General procedure: Chloroacetyl chloride (0.47 mL, 5.90 mmol) was addeddropwise to a stirred mixture of the appropriate aniline 5a-c(5.56 mmol) and K2CO3 (0.90 g, 6.51 mmol) in anhydrous DCE(20 mL) at 0 C. The reaction mixture was stirred for 2 h andallowed to warm to room temperature overnight. The inorganicmaterials were filtered through a pad of silica gel and washed withDCE (25 mL). The filtrate was evaporated under reduced pressureand the residue was purified by recrystallization from a mixtureof hexane/ethyl acetate (3:2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With pyridine In dichloromethane at 0 - 20℃; for 4h; | 20.I Synthesis of N-(4-(Benzyloxy)phenyl)-3-(trifluoromethyl)benzenesulfonamide To a solution of 4-benzyloxyaniline (515 mg, 2.58 mmol) in dichloromethane (5 mL) at 0 °C was added pyridine (412 mg, 5.20 mmol) followed by 3-(trifluoromethyl)benzene sulfonyl chloride (694 mg, 2.84 mmol). The reaction mixture was allowed to warm to room temperature, and then stirred for four hours. Next, methanol (100 tL) was added, and then the mixture was concentrated to provide a residue. The residue was purified via MPLC elutingwith a gradient of 0-35% ethyl acetate in hexanes to afford N-(4-(benzyloxy)phenyl)-3- (trifluoromethyl)benzenesulfonamide (910 mg, 86%) as an off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | Stage #1: p-benzyloxyaniline With dmap; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 0℃; for 0.0833333h; Stage #2: 2-hydroxy-4-(2-methoxyethoxy)benzoic acid In N,N-dimethyl-formamide at 0 - 80℃; for 24h; Inert atmosphere; | 2.2.5. General Method for Preparation of Compounds 12 General procedure: Add 11 (1.2 mmol), 4-dimethylamiopyridine (0.01 g, 0.1 mmol) and N,N’-dicyclohexylcarbodie (0.25 g, 1.2 mmol) to anhydrous DMF (4 mL), stirring for 5 min at 0 oC, then 8(0.21 g, 1 mmol) was added to the mixture. The mixture was stirred for 24 h under a nitrogen atmosphere at 80 oC and transferred into ice water (40 mL), the mixture was processed according to 3.2.4 to afford crude product, which was purified by column chromatography with petroleum ether/ethyl acetate (6 : 1) to obtain 12. N-(4-(benzyloxy)phenyl)-2-hydroxy-4-(2-methoxyethoxy)benzamide (12a) White solid, yield 56%; mp: 173-175 oC; 1H NMR (DMSO-d6, 600 MHz): δ = 12.58 (1H, s, NH), 10.13 (1H, s, OH), 7.97 (1H, d, J = 9.0 Hz, H-6), 7.56 (2H, d, J = 8.4 Hz,H-2’, H-6’), 7.46 (2H, d, J = 7.8 Hz, H-2’’, H-6’’), 7.39 (2H, t, J = 7.2 Hz, H-3’, H-5’), 7.33 (1H, t, J = 7.2 Hz, H-4’’), 7.02 (2H, t, J = 8.4 Hz, H-3’, H-5’), 6.49 (1H, d, J = 7.8 Hz, H-5), 6.48 (1H, s, H-3), 4.13 (2H, s, ArOCH2), 4.13 (2H, s, ArOCH2), 3.65 (2H, s, CH3OCH2), 3.3 (3H, s, CH3); 13C NMR (DMSO-d6, 100 MHz): δ = 167.7 (C, C=O), 163.4 (C, C-4), 162.5 (C, C-2), 155.5 (C, C-4’), 137.6 (C, C-1’’), 131.5 (C, C-1’), 130.1 (CH, C-6), 128.8 (C, C-3’’,C-5’’), 128.2 (CH, C-4’’), 128.1 (CH, C-2’’,C-6’’), 123.5 (C, C-2’,C-6’), 115.2 (CH, C-3’, C-5’), 109.1 (C, C-1), 107.0 (CH, C-5), 102.2 (CH, C-3), 70.6 (CH2, C-8), 69.8 (CH2, CH2Ar), 67.6 (CH2, C-7), 58.6 (CH3, C-9); HRMS (ESI) m/z calcd. for C23H23NO5 ([M+H]+): 394.1649, found: 394.1643 . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With palladium diacetate; caesium carbonate; XPhos; In toluene; at 20℃;Inert atmosphere; Reflux; | [00312j A mixture of 4-(benzyloxy)aniline (7.8 g, 39.03 mmol), 1-bromo-4- isopropylbenzene (8.5 g, 42.93 mmol), X-Phos (2.3 g, 4.68 mmol), Pd(OAc)2 (0.53 g, 2.34 mmol) and Cs2CO3 (50.9 g, 156.12 mmol) in toluene(150 mL) was purged with N2 and then reflux overnight. The reaction mixture was cooled to RT and filtered. The filtrate was concentrated and purified by silica column chromatography (PE:EA, 20:1) to give 7.1 g (57percent) of the title compound. ?H NMR (CDC13, 300 MHz): oe 1.23 (d, J= 6.9 Hz, 6H), 2.77-2.92 (m, 1H), 5.04 (s, 2H), 6.87-6.94 (m, 4H), 7.01-7.04 (m, 2H), 7.08-7.10 (m, 2H), 7.3 1-7.46 (m, 5H). [M+H] Calc?d for C22H23N0, 318; Found, 318. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With chloro-trimethyl-silane; cyclopentadienyl titanium(IV) trichloride; magnesium; triethylamine In tetrahydrofuran at 50℃; for 24h; | General procedure for alloc- orpoc-deprotection with CpTiCl3 General procedure: To a mixture of the alloc- or poc-protected compound (1.0 mmol), Et3N (0.20 mmol) and Mg powder (3.0 mmol) in THF (4 mL) were sequentially added Me3SiCl (0.15 or 1.20 mmol) and a solution of CpTiCl3 (0.05 mmol) in THF (1 mL) at room temperature and the resulting mixture was stirred at 30-50° C. After confirming the completion of the reaction by TLC analysis, saturated aqueous NaHCO3 (0.15 mL) was added followed by NaF (1 g) and Celite (1 g). After being stirred for 0.5 h, the mixture was filtered through a pad of Celite with ether or AcOEt. The filtrate was concentrated under reduced pressure to give a crude mixture, which was purified by silica gel column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With chloro-trimethyl-silane; cyclopentadienyl titanium(IV) trichloride; magnesium; triethylamine In tetrahydrofuran at 50℃; for 24h; | General procedure for alloc- orpoc-deprotection with CpTiCl3 General procedure: To a mixture of the alloc- or poc-protected compound (1.0 mmol), Et3N (0.20 mmol) and Mg powder (3.0 mmol) in THF (4 mL) were sequentially added Me3SiCl (0.15 or 1.20 mmol) and a solution of CpTiCl3 (0.05 mmol) in THF (1 mL) at room temperature and the resulting mixture was stirred at 30-50° C. After confirming the completion of the reaction by TLC analysis, saturated aqueous NaHCO3 (0.15 mL) was added followed by NaF (1 g) and Celite (1 g). After being stirred for 0.5 h, the mixture was filtered through a pad of Celite with ether or AcOEt. The filtrate was concentrated under reduced pressure to give a crude mixture, which was purified by silica gel column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.5% | In 2-ethoxy-ethanol; for 6h;Reflux; | 1- (4-benzyloxyphenyl) -2- (4-benzyloxy-phenylamino) -1-propanone (12.3g, 0.028mol), 4- benzyloxyaniline (14.0g, 0.070mol) placed in 500mL flask, ethylene glycol monomethyl ether as a solvent, refluxed 6h. The solvent was distilled off under reduced pressure, the residue was stirred with ethanol, suction filtered to give 9.5 g of a brown solid, yield 80.5%. m.p.151-152 . ESI-MS: m / z420 ([M + H] +). 1H-NMR (400MHz, CDCl3) delta7.89 (s, 1H), 7.45 (m, 14H), 7.28 (d, J = 2.6Hz, 1H), 7.11 (d, J = 8.4Hz, 2H), 6.97 ( dd, J1 = 8.5Hz, J2 = 1.5Hz, 1H), 5.18 (s, 2H), 5.15 (s, 2H), 2.43 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.2% | With dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 60℃; | 1 [Example 1] Preparation of N- (4-benzyloxy)Propionamide A solution of benzyloxyaniline (19.9 g, 100 mmol) in N, N-dimethylformamide (DMF, 100 mL) was added dicyclohexylcarbodiimide (DCC, 20.6 g, 100 mmol) and Propionic acid (7.4 g, 100 mmol). The reaction solution was heated to 60 ° C and the reaction end point was determined by thin layer chromatography (TLC). After completion of the reaction, the reaction solution was poured into ice water, filtered, dried and whiteThe color was 22.4 g and the yield was 88.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With toluene-4-sulfonic acid In toluene at 130℃; for 4.5h; Sealed tube; Molecular sieve; Microwave irradiation; | 2-[(2,3-Dimethylphenyl)amino]cyclohex-2-en-1-one (7a) General procedure: In a threaded ACE glass pressure tube with a sealed Teflon screw cap equipped with a magnetic stirring bar, a mixture of 11a (0.200 g, 1.65 mmol), 12a (0.185 g, 1.65 mmol), p-TsOH (0.028 g, 0.16 mmol), and MS 4Å (0.20 g) in toluene (10 mL) was stirred and heated at 130 °C for 4.5 h under microwave irradiation (100 W). The solvent was removed under vacuum and the residue purified by column chromatography (silica gel, hexane-EtOAc, 98:2) to give 7a (0.32 g, 91%) as a brownish oil; Rf = 0.75 (hexane-EtOAc, 7:3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In ethanol at 20℃; | 4.3 General procedures for the preparation of compound 1-18 General procedure: The respective salicylaldehyde derivatives (5.0 mmol) wereadded to a solution of compound 3a (5.0 mmol) in ethanol(10 mL). The mixture was stirred under room temperature for 2-5 h then followed by filtration and recrystallization in EtOAc orMeOH to obtain the pure compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In ethanol at 20℃; | 4.4 General procedures for the preparation of compound 1-18 General procedure: The respective salicylaldehyde derivatives (5.0 mmol) wereadded to a solution of compound 3a (5.0 mmol) in ethanol(10 mL). The mixture was stirred under room temperature for 2-5 h then followed by filtration and recrystallization in EtOAc orMeOH to obtain the pure compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In ethanol at 20℃; | 4.7 General procedures for the preparation of compound 1-18 General procedure: The respective salicylaldehyde derivatives (5.0 mmol) wereadded to a solution of compound 3a (5.0 mmol) in ethanol(10 mL). The mixture was stirred under room temperature for 2-5 h then followed by filtration and recrystallization in EtOAc orMeOH to obtain the pure compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | In ethanol at 20℃; | 4.8 General procedures for the preparation of compound 1-18 General procedure: The respective salicylaldehyde derivatives (5.0 mmol) wereadded to a solution of compound 3a (5.0 mmol) in ethanol(10 mL). The mixture was stirred under room temperature for 2-5 h then followed by filtration and recrystallization in EtOAc orMeOH to obtain the pure compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Stage #1: p-benzyloxyaniline With ethylmagnesium bromide In tetrahydrofuran for 0.333333h; Inert atmosphere; Stage #2: 2,4-dichlorobenzylnitrile In tetrahydrofuran at 20℃; for 20h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | With triethylamine; In N,N-dimethyl-formamide; at 125℃; for 6h; | In a 250 mL round bottom flask, 4-(benzyloxy)aniline (8.8 g, 44.34 mmol, 3.00 equiv) was added to a solution of 1-[4-(benzyloxy)phenyl]propan-1-one (4.3 g, 17.89 mmol, 1.00 equiv) in DMF/TEA (40/4.3 mL). The resulting solution was stirred for 6 hours at 125 C. The reaction was then quenched by the addition of water. The resulting mixture was extracted with ethyl acetate (20 mL*3) and the organic layers were combined, washed with brine and dried over anhydrous sodium sulfate. The organic solvent was removed under reduced pressure and the residue was applied onto a silica gel column eluting with ethyl acetate/petroleum ether (1:5). This resulted in 1.7 g (23%) of 5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-methyl-1H-indole as a light brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; | 3.1.5. General Procedure for the Preparation of 2-(Benzo[4,5]imidazo[2,1-b]thiazol-3-yl)acetamideDerivatives (D01 to D18) General procedure: A stirred mixture of compound 5 (0.23 g, 0.001 mol), EDCI (0.23 g, 0.0012 mol), HOBt (0.16 g,0.0012 mol), aniline or aniline derivative (0.001 mol), and 20 mL DMF was reacted at room temperature overnight, and then 40 mL water was added and stirred for a quarter, before the crude was filtered and washed twice with water. The anticipated product was purified by column chromatography on silicagel using petroleum ether/ethyl acetate (2/1, volume ratio) as the eluent to afford the target compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With N-ethyl-N,N-diisopropylamine; In ethanol; for 18.0h;Reflux; | General procedure: 4-chloroquin(az)olinederivative (1.0 eq.), aniline derivative (1.1 eq.), and iPr2NEt (2.5 eq.) were suspended inethanol (10 mL) and refluxed for 18 h. The crude mixture was purified by flash chromatographyusing EtOAc:hexane followed by 1-5 % methanol in EtOAc; After solventremoval under reduced pressure, the product was obtained as a free following solid orrecrystallized from ethanol/water. 4-[4-(benzyloxy)phenyl]amino}quinazolin-6-ol(1) as a yellow solid (68 %, 220 mg, 0.640 mmol) MP 231-233 C; 1H NMR (400 MHz,DMSO-d6) delta 11.21 (s, 1H), 10.91 (s, 1H), 8.75 (s, 1H), 8.04 (d, J = 2.5 Hz, 1H), 7.88 (d, J= 9.0 Hz, 1H), 7.70 (dd, J = 9.1, 2.5 Hz, 1H), 7.62 - 7.57 (m, 2H), 7.52 - 7.44 (m, 2H),7.44 - 7.37 (m, 2H), 7.37 - 7.30 (m, 1H), 7.14 - 7.09 (m, 2H), 5.16 (s, 2H). 13C NMR (101MHz, DMSO-d6) delta 158.8, 157.8, 156.7, 148.1, 136.9, 131.6, 129.7, 128.5 (2C, s), 127.9,127.7 (2C, s), 126.5, 126.2 (2C, s), 121.2, 114.92, 114.85 (2C, s), 107.1, 69.4. HRMS m/z[M+H]+ calcd for C21H18N3O2: 344.1399 found = 344.1386; LC tR = 4.24 min,>98 %Purity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With N-ethyl-N,N-diisopropylamine; In ethanol; for 18h;Reflux; | General procedure: 4-chloroquin(az)olinederivative (1.0 eq.), aniline derivative (1.1 eq.), and iPr2NEt (2.5 eq.) were suspended inethanol (10 mL) and refluxed for 18 h. The crude mixture was purified by flash chromatographyusing EtOAc:hexane followed by 1-5 % methanol in EtOAc; After solventremoval under reduced pressure, the product was obtained as a free following solid orrecrystallized from ethanol/water. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With N-ethyl-N,N-diisopropylamine; In ethanol; for 18.0h;Reflux; | General procedure: 4-chloroquin(az)olinederivative (1.0 eq.), aniline derivative (1.1 eq.), and iPr2NEt (2.5 eq.) were suspended inethanol (10 mL) and refluxed for 18 h. The crude mixture was purified by flash chromatographyusing EtOAc:hexane followed by 1-5 % methanol in EtOAc; After solventremoval under reduced pressure, the product was obtained as a free following solid orrecrystallized from ethanol/water. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With bis[dichloro(pentamethylcyclopentadienyl)ruthenium(III)]; (oxydi-2,1-phenylene)bis(diphenylphosphine); lithium tert-butoxide at 100℃; for 24h; Inert atmosphere; Glovebox; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With triethylamine In dichloromethane at 0℃; for 2h; | General synthesis procedure 3a General procedure: 4-phenoxyphenol (186mg, 1mmol) was stirred with TEA (278μL, 2mmol) in Anhydrous DCM (10mL) at 0°C, then 2-Chloroethanesulfonyl chloride (105μL, 1mmol) which was diluted with DCM (2mL) was slowly added into the mixture. The reaction mixture was stirred for 2h then evaporated. The residue was diluted and extracted with EtOAc then washed with water for 3 times. The organic layers were dried over Na2SO4 and evaporated. The residue was chromatographed (silicagel, Petroleum ether/EtOAc=3:1) to give 4-phenoxyphenyl ethenesulfonate (DC-TEADin03) (193mg, 70%) as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | Stage #1: p-benzyloxyaniline With tert.-butylnitrite; boron trifluoride diethyl ether complex In acetonitrile at 20℃; for 1h; Cooling with ice; Inert atmosphere; Stage #2: With potassium metabisulphite; acetic acid; N-fluorobis(benzenesulfon)imide In water monomer; acetonitrile at 50℃; for 12h; Inert atmosphere; | General procedures for the fluorosulfonylation of Aromatic amine General procedure: Arylamine 1 (0.4 mmol, 1.0 equiv.) were added to a dry Shrek tube, K2S2O5 (1.0 mmol, 2.5 equiv.) and NFSI (0.4 mmol, 1.0 equiv.) were added to a Solid feeder ready to serve, then Shrek tube and Solid feeder were well connected. The system was then evacuated into an ice bath and backfilled with Ar (3 times) and distilled CH3CN (3 mL), Under continuous stirring, the Boron trifluoride etherate (0.6 mmol, 1.5 equiv.) and tert-butyl nitrite (0.48 mmol, 1.2 equiv.) was added dropwise successively to the solution. Removed ice bath after 30 min and the reaction lasted for 45 min at room temperature. Turning Solid feeder and toppling solid, then H2O (0.1 mL) and HOAc (0.2 mL) were added in turn via syringe under Ar atmosphere and the reaction mixture was stirred at 50 , 12 h. Yields of the desired product were measured by 19F NMR spectroscopy before working-up. Then the reaction mixture was filtered through a pad of celite, diluted with DCM (20 mL) and H2O (50 mL). The resulting mixture was extracted with DCM (2 × 20 mL). The organic layers were combined, washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography to give the desired product. |
62% | Stage #1: p-benzyloxyaniline With tert.-butylnitrite; boron trifluoride diethyl ether complex In acetonitrile at 20℃; Cooling with ice; Inert atmosphere; Stage #2: With potassium metabisulphite; acetic acid; N-fluorobis(benzenesulfon)imide In water monomer; acetonitrile at 50℃; for 12h; Inert atmosphere; | General procedures for the fluorosulfonylation of Aromatic amine General procedure: Arylamine 1 (0.4 mmol, 1.0 equiv.) were added to a dry Shrek tube, K2S2O5 (1.0 mmol, 2.5 equiv.) and NFSI (0.4 mmol, 1.0 equiv.) were added to a Solid feeder ready to serve, then Shrek tube and Solid feeder were well connected. The system was then evacuated into an ice bath and backfilled with Ar (3 times) and distilled CH3CN (3 mL), Under continuous stirring, the Boron trifluoride etherate (0.6 mmol, 1.5 equiv.) and tert-butyl nitrite (0.48 mmol, 1.2 equiv.) was added dropwise successively to the solution. Removed ice bath after 30 min and the reaction lasted for 45 min at room temperature. Turning Solid feeder and toppling solid, then H2O (0.1 mL) and HOAc (0.2 mL) were added in turn via syringe under Ar atmosphere and the reaction mixture was stirred at 50 , 12 h. Yields of the desired product were measured by 19F NMR spectroscopy before working-up. Then the reaction mixture was filtered through a pad of celite, diluted with DCM (20 mL) and H2O (50 mL). The resulting mixture was extracted with DCM (2 × 20 mL). The organic layers were combined, washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography to give the desired product. |
67 mg | Stage #1: p-benzyloxyaniline With hydrogen tetrafluoroborate; tert.-butylnitrite In ethanol; water monomer at 0 - 20℃; for 1h; Stage #2: With 6,6'-dimethyl-2,2'-bipyridine; potassium hydrogen difluoride; 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct; copper chloride (II) In acetonitrile at 20℃; for 12h; Sealed tube; Inert atmosphere; |
39 mg | Stage #1: p-benzyloxyaniline With hydrogen tetrafluoroborate; tert.-butylnitrite In ethanol; water monomer at 0 - 20℃; for 1h; Stage #2: With disodium metabisulfite; 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo-[2.2.2]octane bis(tetrafluoroborate) In methanol at 70℃; for 9h; Schlenk technique; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With copper(l) iodide; copper; potassium carbonate In N,N-dimethyl-formamide for 2h; Inert atmosphere; | 2-(4-Fluorophenylamino)benzoic acid (9a) General procedure: To a solution of 7 (1.00 g, 4.03 mmol) in DMF (15 mL) was added K2CO3 (1.11 g, 8.08 mmol), CuI (38 mg, 0.02 mmol), Cu (26 mg, 0.04 mmol) and 8a (974 mg, 0.61 mmol). The resulting solution was heated to 130 °C under N2 for 2 h. After filtration through celite, the filtrate was diluted with EtOAc (150mL × 1) and washed with distd H2O (450 mL × 5). The organic layer was dried over Na2SO4, filtered and the solvent removed in vacuo. The residue was purified by silica gel chromatography (MeOH: CH2Cl2 = 0:100 - 2: 98) to give 9a (766 mg, 83%) as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium carbonate In acetonitrile at 80℃; | |
70% | In acetonitrile at 80℃; | General procedure: Ethyl 8-chloro-[1,3]dioxolo[4,5-g]quinoline-7- carboxylate (1.0 eq.) was added to a solution of the arylamine compound (2.5 eq.) in dry acetonitrile (10 mL) and stirred at 80 °C for 8-10 h. Thin layer chromatography was used to monitor the progress of the reaction. The solvent was added to 10 mL water with 5 mL dichloromethane and extracted 3 times. The organic layer was dried anhydrous magnesium sulfate and filtered. The residue was purified by column chromatography (EtOAc:petroleum ether = 1:8) to produce a yellowish solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With N-ethyl-N,N-diisopropylamine In dimethylsulfoxide-d6 at 20 - 80℃; for 2h; | A Step A: ethyl 4-((4-(benzyloxy)phenyl)amino)-2-(methylthio)pyrimidine-5- carboxylate To a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (1.0 g, 4.3 mmol, 1.0 eq.) in DMSO (10 mL) was added 4-(benzyloxy)aniline (950 mg, 4.7 mmol, 1.1 eq.) and DIPEA (1.6 g, 12.9 mmol, 3.0 eq.) at room temperature. The reaction mixture was stirred at 80 °C for 2 hrs. Then the reaction mixture was quenched with ice water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2S04 and concentrated under reduced pressure, the residue was purified by flash column chromatography on silica gel to give ethyl 4-((4- (benzyloxy)phenyl)amino)-2-(methylthio)pyrimidine-5-carboxylate (1.6 g, 95% yield) as a white solid. LC-MS (ESI): m/z 396 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With pyridine hydrochloride In isopropyl alcohol for 12h; Reflux; | 1.1 (1) Synthesis of N-(4-(4-(benzyloxy)phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)acetamide (a-1) Add N-(4-chloro-3-cyano-7-ethoxyquinolin-6-yl)acetamide (0.024mol, 6.90g) into a 500mL three-necked flask equipped with a thermometer and electromagnetic stirring. (Benzyloxy)aniline (0.026mol, 5.17g) and (0.026mol, 3.0g) pyridine hydrochloride, 250mL isopropanol, TLC tracking detection, the developing solvent is petroleum ether: ethyl acetate volume ratio 1:1 The mixed solution was stirred and reacted under reflux for 12h, stood still, filtered with suction, and recrystallized from methanol to obtain N-(4-(4-(benzyloxy)phenylamino)-3-cyano-7-ethoxyquinoline-6 -Base) acetamide 9.05 g, 83%. |
83% | With pyridine hydrochloride In isopropyl alcohol for 12h; Reflux; | 1.2 (2) Synthesis of N-(4-(4-(benzyloxy)phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)acetamide (a-2) In a 500mL three-necked flask equipped with a thermometer and electromagnetic stirring, add N-(4-chloro-3-cyano-7-ethoxyquinolin-6-yl)acetamide (0.024mol, 6.90g),4-(Benzyloxy)aniline (0.026mol, 5.17g) and (0.026mol, 3.0g) pyridine hydrochloride, 250mL isopropanol, TLC tracking detection, developing solvent is petroleum ether: ethyl acetate volume ratio 1: 1. Stir, reflux and react for 12h, stand still, filter with suction, and recrystallize from methanol to obtain N-(4-(4-(benzyloxy)phenylamino)-3-cyano-7-ethoxyquinoline-6- Yl)acetamide 9.05g, 83%. |
83% | With pyridine In isopropyl alcohol for 12h; Reflux; | 1.2 (2) Synthesis of N-(4-(4-(benzyloxy)phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)acetamide (a-2) Add N-(4-chloro-3-cyano-7-ethoxyquinolin-6-yl)acetamide (0.024mol, 6.90g) into a 500mL three-necked flask equipped with a thermometer and electromagnetic stirring. (Benzyloxy)aniline (0.026mol, 5.17g)And (0.026mol, 3.0g) pyridine hydrochloride, 250mL isopropanol, TLC tracking detection, the developing solvent is a mixture of petroleum ether: ethyl acetate 1:1 volume ratio, stirring, refluxing reaction for 12h,Let stand, filter with suction, and recrystallize from methanol to obtain N-(4-(4-(benzyloxy)phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)acetamide 9.05g, 83 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: p-benzyloxyaniline; 4,5-dichloro-1,2,3-dithiazol-1-ium chloride In dichloromethane at 20℃; for 2h; Stage #2: With pyridine In dichloromethane at 20℃; for 1h; | ||
Stage #1: p-benzyloxyaniline; 4,5-dichloro-1,2,3-dithiazol-1-ium chloride In dichloromethane at 20℃; for 1h; Stage #2: With pyridine In dichloromethane at 20℃; for 2h; | General method for the synthesis of 4-chloro-1,2,3-dithiazoles (8-39). General procedure: To a stirred suspension of 4,5-dichloro-1,2,3-dithiazolium chloride (Appel’s salt) (6)51a (100 mg, 0.48 mmol) in dichloromethane (4 mL) at ca. 20°C, the corresponding arylamine (0.48 mmol) was added. After 1 h, pyridine (77.3 μL, 0.96 mmol) was added to the reaction mixture dropwise. After a further 2 h the reaction mixture was adsorbed onto silica and purified by dry flash chromatography to afford the corresponding (Z)-4-chloro-N-aryl-5H-1,2,3-dithiazol-5-imine. Compounds 7-9,45 and 11-15,45 25-2645 and 35-3851l were consistent with literature reports. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With uranyl nitrate hydrate; water; trifluoroacetic acid In acetonitrile for 48h; Irradiation; Inert atmosphere; | 31 Example 31 In a 25mL reaction tube, add 4-benzyloxyaniline (0.2mmol, 39.8mg), water (0.6mmol, 10.8mg), uranyl nitrate hydrate (4mol%/0.008mmol, 4.0mg),Trifluoroacetic acid (0.2mmol, 22.8mg), acetonitrile (2mL), Stir under the irradiation of a 6-watt blue LED lamp (wavelength: 460nm) in a nitrogen atmosphere for 2 days. After the reaction is complete, extract, concentrate, and separate by column chromatography (VPE/VEA=10/1) to obtain a white solid 3ae (34.0mg, 85 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49.1% | With iodine In toluene at 80℃; for 2h; Inert atmosphere; | 6-(Benzyloxy)-2-methylquinoline (18) To a stirred solution of 4-(benzyloxy)aniline 17 (0.83 g, 4.16 mmol) and ethyl vinyl ether(0.88 mL, 9.15 mmol) in anhyd. toluene (6 mL) was added iodine (0.053 g, 0.21 mmol) underargon atmosphere at room temperature. The reaction mixture was warmed to 80 °C andstirred for 2 h. After completion of the reaction, cooled to room temperature and aqueoussaturated Na2S2O3 solution was added to it. Two layers separated and the aqueous layer wasextracted with EtOAc (3 x 25 mL). The combined organic layer was washed with H2O (3 x20 mL) and brine (20 mL), dried over anhyd. Na2SO4 and concentrated in vacuo. The crudewas purified by column chromatography (EtOAc/hexane = 1/4) to afford the desired product18 (0.51 g, 49.1 %) as beige solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.6% | With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 85℃; for 6h; | 1 Take 6-nitro-7-chloro-quinazolin-4-one (2.5g, 11.1mmol) in a 100mL single-necked flask,Add 25mL of thionyl chloride,0.3mL DMF,Raise the temperature at 80 and reflux for 5h,Spin dry thionyl chloride under reduced pressure,4,7-dichloro-6-nitroquinazoline (3) is obtained as a white solid,Not purified,Add directly to 2.4g of 4-benzyloxyaniline (12.2mmol),30mL isopropanol and 5.7g N,N-diisopropylethylamine (44.33mmol) reaction flask,Heat up 85 and react for 6h,Cool to room temperature,Pour the reaction solution into 300mL ice water,Suction filtration solid,Recrystallized from methanol to obtain 3.8 g of 4-(4-benzyloxy)phenylamino-6-nitro-7-chloro-quinazoline (4),The yield is 84.6%, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With hydrogen; water-d2 at 120℃; for 24h; Autoclave; regioselective reaction; | General procedure for the deuteration reactions. General procedure: In a 4 ml vial fitted with a magnetic stir bar and septum cap, iron catalyst (60 mg, 20 mol%) and substrate (0.25 mmol) were added. Then, a needle was inserted in the septum, allowing gaseous reagents to enter. After adding the solvent deuterium oxide (1.5 ml), the vials (up to eight) were set in an alloy plate and then placed into a 300 ml steel Parr autoclave. The autoclave was flushed with hydrogen six times at 10 bar and finally pressurized to the desired value (20 bar). Then, it was placed into an aluminium block and heated to the desired temperature. At the end of the reaction, the autoclave was quickly cooled down to r.t. with an ice bath and vented. Finally, the samples were removed from the autoclave, and ethyl acetate was added to the crude mixture. This mixture was centrifuged, and the organic layer was removed from the vials (three times). After removal of all volatiles in vacuo, the desired products were obtained. In case of anilines with deuterium labelling on the nitrogen, 1 ml H2O was added during work up and N-D was replaced by N-H. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | Stage #1: p-benzyloxyaniline; 2-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-6-methylpyrimidine-4-carboxylic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dimethyl sulfoxide at 20℃; Stage #2: With trifluoroacetic acid In dichloromethane at 20℃; for 1h; | 132 Example 132 2-((2-aminoethyl)amino)-N-(4-(benzyloxy)phenyl)-6-methylpyrimidine-4-carboxamide. To a solution of Z10 (50 mg, 0.17 mmol) and 4-(benzyloxy)aniline (34 mg, 0.17 mmol) in DMSO (2 mL) were added HATU (97 mg, 0.26 mmol) and DIPEA(89 μL, 0.51 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was monitored by UPLC. Upon completion, the reaction mixture was purified by preparative HPLC to give intermediate. The intermediate was dissolved in DCM (0.5 mL), then addition of TFA (0.5 mL). The mixture was stirred at room temperature for 1h. The reaction was monitored by UPLC. Upon completion, the reaction mixture was purified by preparative HPLC to give Example 132 (38 mg, 0.1 mmol, 59% yield) as yellow solid.1H NMR (800 MHz, DMSO-d6) δ 10.11 (s, 1H), 7.95 (d, J = 28.4 Hz, 3H), 7.75 - 7.66 (m, 2H), 7.45 (d, J = 7.5 Hz, 2H), 7.39 (t, J = 7.5 Hz, 2H), 7.33 (t, J = 7.4 Hz, 1H), 7.16 (s, 1H), 7.04 (d, J = 8.5 Hz, 2H), 5.11 (s, 2H), 3.77 - 3.62 (m, 2H), 3.04 (p, J = 5.7 Hz, 3H), 2.38 (s, 2H). MS (ESI) m/z 378.33 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 16h; | 133 N-(4-(Benzyloxy)phenyl)-2-chloro-5-nitropyridin-4-amine (201). A solution of 4- (benzyloxy)aniline (1.32 g, 5.61 mmol) in dry DCM (10 mL) was added to a stirred solution of nitropyridine 2 (1.03 g, 5.34 mmol) and iPr2NEt (2.09 mL, 12.0 mmol) in dry DCM (50 mL) at 20 °C. The mixture was stirred at 20 °C for 16 h before being diluted with DCM (100 mL) and washed with water (3 × 100 mL), dried (MgSO4) and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (10-100%) of EtOAc/pet. ether, to give chloride 201 (1.86 g, 97%) as yellow crystals: mp 189-191 °C;1H NMR (CDCl3) δ 9.52 (br s, 1 H, 4-NH), 9.08 (s, 1 H, H-6), 7.44-7.47 (m, 2 H, H-3, H-5), 7.41 (br dd, J = 7.7, 1.7 Hz, 2 H, H-2, H-6), 7.37 (br t, J = 7.0, 1.7 Hz, 1 H, H-4), 7.19 (ddd, J = 8.8, 3.3, 2.1 Hz, 2 H, H-2, H-6), 7.08 (ddd, J = 8.8, 3.3, 2.2 Hz, 2 H, H-3, H-5), 6.78 (s, 1 H, H-3) 5.12 (s, 2 H, CH2O); MS m/z 256.1 (MH+, 100%), 258.1 (MH+, 35%). |
97% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 16h; | 133 N-(4-(Benzyloxy)phenyl)-2-chloro-5-nitropyridin-4-amine (201). A solution of 4- (benzyloxy)aniline (1.32 g, 5.61 mmol) in dry DCM (10 mL) was added to a stirred solution of nitropyridine 2 (1.03 g, 5.34 mmol) and iPr2NEt (2.09 mL, 12.0 mmol) in dry DCM (50 mL) at 20 °C. The mixture was stirred at 20 °C for 16 h before being diluted with DCM (100 mL) and washed with water (3 × 100 mL), dried (MgSO4) and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (10-100%) of EtOAc/pet. ether, to give chloride 201 (1.86 g, 97%) as yellow crystals: mp 189-191 °C;1H NMR (CDCl3) δ 9.52 (br s, 1 H, 4-NH), 9.08 (s, 1 H, H-6), 7.44-7.47 (m, 2 H, H-3, H-5), 7.41 (br dd, J = 7.7, 1.7 Hz, 2 H, H-2, H-6), 7.37 (br t, J = 7.0, 1.7 Hz, 1 H, H-4), 7.19 (ddd, J = 8.8, 3.3, 2.1 Hz, 2 H, H-2, H-6), 7.08 (ddd, J = 8.8, 3.3, 2.2 Hz, 2 H, H-3, H-5), 6.78 (s, 1 H, H-3) 5.12 (s, 2 H, CH2O); MS m/z 256.1 (MH+, 100%), 258.1 (MH+, 35%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Stage #1: p-benzyloxyaniline; benzaldehyde With borane-THF In acetonitrile at 65℃; for 0.166667h; Stage #2: 2-oxo-propionic acid In acetonitrile for 24h; | A15 Example A15 Production of 6-benzyloxy-2-phenylquinoline-4-carboxylic acid To a solution of 4-benzyloxyaniline (2.04 g, 10.2 mmol) in acetonitrile (5.7 mL), benzaldehyde (1.21 g, 11.4 mmol) and boron trifluoride-tetrahydrofuran complex (313 μL, 2.84 mmol) were added, and the mixture was heated to 65° C. 10 minutes later, a solution of pyruvic acid (0.500 g, 5.68 mmol) in acetonitrile (9.5 mL) was added dropwise thereto over 3 hours. 21 hours later, the reaction solution was cooled to room temperature, and the precipitated solid was collected by filtration. The solid was washed with acetonitrile and then dried under reduced pressure to obtain the title compound (1.32 g, yield: 66%) as a pale yellow solid. 1H-NMR (400 MHz, DMSO-D6) δ: 13.9 (1H, s), 8.46 (1H, s), 8.26-8.24 (3H, m), 8.10 (1H, d, J=9.5 Hz), 7.61-7.49 (6H, m), 7.45-7.34 (3H, m), 5.28 (2H, s) ESI-MS (m/z): 356 (M+H)+ |
Tags: 6373-46-2 synthesis path| 6373-46-2 SDS| 6373-46-2 COA| 6373-46-2 purity| 6373-46-2 application| 6373-46-2 NMR| 6373-46-2 COA| 6373-46-2 structure
[ 51388-20-6 ]
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H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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