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CAS No. : | 99-55-8 | MDL No. : | MFCD00007741 |
Formula : | C7H8N2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | DSBIJCMXAIKKKI-UHFFFAOYSA-N |
M.W : | 152.15 | Pubchem ID : | 7444 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.14 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 44.63 |
TPSA : | 71.84 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.9 cm/s |
Log Po/w (iLOGP) : | 1.25 |
Log Po/w (XLOGP3) : | 1.87 |
Log Po/w (WLOGP) : | 1.49 |
Log Po/w (MLOGP) : | 0.61 |
Log Po/w (SILICOS-IT) : | -0.6 |
Consensus Log Po/w : | 0.92 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.3 |
Solubility : | 0.764 mg/ml ; 0.00502 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.0 |
Solubility : | 0.152 mg/ml ; 0.000999 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -1.79 |
Solubility : | 2.47 mg/ml ; 0.0162 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 3.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.83 |
Signal Word: | Danger | Class: | 6.1 |
Precautionary Statements: | P261-P264-P270-P271-P273-P280-P301+P310+P330-P302+P352+P312-P304+P340+P311-P403+P233-P405-P501 | UN#: | 2660 |
Hazard Statements: | H301+H311+H331-H412 | Packing Group: | Ⅲ |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.9% | With acetic acid for 5h; Heating; | |
64% | In methanol at 65℃; for 4h; | Synthesis of isoindoline-1,3-dione derivatives (3a-k) General procedure: To a solution of isobenzofuran-1,3-dione (1.48 g, 10 mmol) in methanol (4 mL/1 mmol) at room temperature was added aliphatic or aromatic amine (10 mmol) and the reaction mixture was refluxed at 65 °C for 4 h. After completion of the reaction as indicated by the TLC, the reaction was cooled to room temperatureand purified by column chromatography using petroleum ether:ethyl acetate (7:3). |
With acetic acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In acetonitrile at 60℃; for 3h; Inert atmosphere; | 2. Typical procedure for the synthesis of acetamides 9 and 16a-16e General procedure: To a solution of substituted 2-methylaniline (3.92 mmol) in acetonitrile was added aceticanhydride (400 μL, 4.23 mmol) under a nitrogen atmosphere. The reaction mixture was stirredat 60 °C until the aniline was completely consumed (monitored by TLC), and then allowed tocool down to room temperature. The precipitate was collected by vacuum filtration using aBüchner funnel and washed with hexane (50 mL). The precipitate was then purified by flashcolumn chromatography on silica gel (EtOAc/hexanes = 1:1) to give the correspondingacetamide. |
89% | With N,N'-dimethyl-N,N'-di(pyridin-4-yl)ferrocene-1,1'-dicarboxamide at 20℃; for 0.583333h; | |
84% | With pyridine In chloroform at 20℃; for 6h; |
84% | With pyridine In chloroform at 20℃; | |
84% | With pyridine In chloroform at 20℃; | 4 [0079] 2-Acetamido-4-nitrobenzyl bromide. To a solution of 2-methyl-5-nitroaniline (3.04 g, 2 mmol) in 50 mL of CHCl 3 were added Ac 2O (10 equiv) and pyridine (1.78 mL, 1.1 equiv). The reaction mixture was stirred at room temperature overnight. After concentration under reduced pressure, the residue was dissolved in 100 mL of CH 2Cl 2, washed with water, saturated NaHCO 3 and water, and dried over anhydrous Na 2SO 4. After removal of solvent, the residue was triturated with CCl 4 to give the desired product 2-acetamido-4-nitrotoluene as a solid (3.36 g, 84%). m.p. 154-155° C. 1H NMR (300 MHz, CDCl 3) δ 8.76 (s, 1H), 7.94 (d, 1H, J=8.1 Hz), 7.34 (d, 1H, J=8.1 Hz), 7.09 (br, 1H), 2.37 (s, 3H), 2.26 (s, 3H). |
78% | at 90℃; for 3h; | |
75% | With triethylamine In dichloromethane at 0 - 25℃; | A.14 N-(2-methyl-5-nitrophenyl)acetamide N-(2-methyl-5-nitrophenyl)acetamide [000180] A solution of 2-methyl-5-nitroaniline (2.5 g, 16.4 mmol) and triethylamine (3.4 mL, 24.6 mmol) in DCM (50 mL) in a 250 mL round-bottomed flask was cooled to 0 °C. Acetic anhydride (2.52 g, 24.6 mmol) was added and the reaction was stirred for 4 h. Additional acetic anhydride (2.52 g, 24.6 mmol) was added at 0 °C and the reaction was allowed to reach 25 °C overnight. The mixture was washed with saturated aqueous NaHC03,dried over Na2S04, filtered and concentrated under reduced pressure. The resulting solid was chromatographed on silica using hexanes and EtOAc as eluent to give N-(2-methyl-5-nitrophenyl)acetamide (2.4 g., 75%) as an off- white solid; m/z 195. |
With benzene | ||
With pyridine for 2h; Heating; | ||
With glacial acetic acid In acetonitrile for 0.25h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With pyridine In dichloromethane at 0 - 20℃; for 12h; | 40A 2-chloro-N-(2-methyl-5-nitrophenyl)acetamide To a solution of 2-methyl-5-nitroaniline (2.00 g, 13.1 mmol) and pyridine (1.28 mL, 15.8 mmol, 1.2 equiv) in CH2CI2 (30 mL) at 0 °C was added chloroacetyl chloride (1.1 mL, 13.8 mmol, 1.05 equiv) dropwise. The resulting mixture was warmed to room temperature, and was stirred at that temperature for 12 h. The resulting solution was diluted with CH2CI2 (30 mL), washed with water (25 mL) followed by a saturated NaCI solution (25 mL), dried (MgS04anh), and concentrated under reduced pressure to afford 2-chloro-N-(2-methyl-5-nitrophenyl)acetamide (2.2 g, 72%).XH-NMR (400 MHz, DMSO-d6): δ [ppm] = 2.32 (s, 3H), 4.35 (s, 2H), 7.50 (d, J=8.6 Hz, 1H), 7.94 (dd, J=2.5, 8.3 Hz, 1H), 8.39 (d, J=2.5 Hz, 1H), 9.87 (s, 1H).LC-MS (Method 3): Rt= 1.25 min; MS (ESIpos): m/z = 229 ([M+H]+, 70%); MS (ESIneg): m/z = 227 ([M- H]-, 100%). |
72% | With pyridine In dichloromethane at 0 - 20℃; for 12h; | Intermediate 25 2-chloro-N-(2-methyl-5-nitrophenyl)acetamide To a solution of 2-methyl-5-nitroaniline (2.00 g, 13.1 mmol) and pyridine (1.28 mL, 15.8 mmol, 1.2 equiv) in CH2CI2 (30 mL) at 0 °C was added chloroacetyl chloride (1.1 mL, 13.8 mmol, 1.05 equiv) dropwise. The resulting mixture was warmed to room temperature, and was stirred at that temperature for 12 h. The resulting solution was diluted with CH2CI2 (30 mL), washed with water (25 mL) followed by a saturated NaCI solution (25 mL), dried (MgS04 anh), and concentrated under reduced pressure to afford 2-chloro-N-(2-methyl-5-nitrophenyl)acetamide (2.2 g, 72%). XH-NMR (400 MHz, DMSO-d6): δ [ppm] = 2.32 (s, 3H), 4.35 (s, 2H), 7.50 (d, J=8.6 Hz, 1H), 7.94 (dd, J=2.5, 8.3 Hz, 1H), 8.39 (d, J=2.5 Hz, 1H), 9.87 (s, 1H). LC-MS (Method 3): Rt = 1.25 min; MS (ESIpos): m/z = 229 ([M+H]+, 70%); MS (ESIneg): m/z = 227 ([M- H]-, 100%). |
With potassium carbonate In tetrahydrofuran at 40℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sulfuric acid; nitric acid at -10℃; for 2h; | 2.1.1. Preparation of 2-methyl-5-nitroaniline (1). o-Toluidine(500 mg, 4.19 mmol) was added with vigorous stirring to aballoon with concentrated sulfuric acid (3.9 ml, 71.4 mmol)cooled to 10 C (salt/ice, cold bath). An acid mixture (0.9 mlHNO3 and 0.9 ml H2SO4) was added dropwise (10 C) for 2 h. The mixture was placed on ice and basified with NaOH.The orange precipitate was collected by filtration and washedwith water (yield 90%; m.p. 85-90 C). 1H NMR (400 MHz,CDCl3): 7.52 (dd, J = 8.1 Hz, 1H, Ar-H), 3.71 (br, 2H, -NH2),2.22 (s, 3H, -CH3). 13C{H} NMR (100 MHz, CDCl3): 147.46,145.46, 130.82, 129.61, 113.35, 108.86, 17.68 (-CH3). |
81% | Stage #1: <i>o</i>-toluidine With sulfuric acid at -5℃; Stage #2: With nitric acid at -5℃; for 2h; Stage #3: With sodium hydroxide In water Cooling with ice; | |
78% | With sulfuric acid; nitric acid at -5 - 0℃; Inert atmosphere; | 6.01 Step 01: Synthesis of 2-methyl-5-nitroaniline (02) To a stirred solution of sulfuric acid (750.0 mL, 15.0 vol. equiv) was added o-toluidine (01) (50.0 g, 467.0 mmol, 1.0 equiv) at -5°C. Mixed acid (55.6 mL of 65% nitric acid and 250.0 mL of sulfuric acid) was then added drop wise at -5°C during 2 h. The resulting mixture was stirred for 1 h at 0°C. The completion of reaction was monitored by TLC. Then the mixture was poured onto crushed ice and made alkaline with aqueous sodium hydroxide. The precipitate formed was collected by filtration and dried to get titled compound (02) (55.4 g, 78.0%) as a yellow solid. NMR (300 MHz, OMSO-d6) δ 7.45-7.44 (d, 1H), 7.31-7.27 (m, 1H), 7.17-7.14 (d, 1H), 5.55 (s, 2H), 2.14 (s, 3H). |
36% | With sulfuric acid; nitric acid at 2 - 5℃; | |
With sulfuric acid; Methamphetamin; nitric acid at 0℃; man presst das ausgeschiedene Sulfat ab, verruehrt mit Wasser, zersetzt mit Alkali und krystallisiert die Base aus Alkohol um; | ||
With sulfuric acid; nitric acid; potassium nitrate at 10℃; man loest das Sulfat in Wasser, zersetzt mit Na2CO3, filtriert die Base ab; | ||
With sulfuric acid; nitric acid | ||
With sulfuric acid; nitric acid | ||
With sulfuric acid; nitric acid at -5℃; | ||
With sulfuric acid; potassium nitrate at 0℃; for 1.5h; | ||
Stage #1: <i>o</i>-toluidine With sulfuric acid at 20 - 25℃; for 4h; Stage #2: With sulfuric acid; nitric acid at -5℃; for 7h; | To a 1000L reactor, pump in 98% concentrated sulfuric acid 800 kg, 50% sulfuric acid 200 kg; Contorl the temperature to between 20 °C-25 °C. Slowly add o-toluidine 220 kg. Adding dropwise time controlled at 2 hours. After adding dropwise finished, maintain temperature. Maintain temperature for 2 hours. o-toluidine completely dissolved become salt. Open freezing salt water to prepare temperature lowering; When the temperature drops to -5 °C preparation, slowly add dropwise acid mixture (98% sulfuric acid and 98% nitric acid according to 1: 1.3 mix) 230 kg. Add dropwise time controlled at 7 hours. After adding dropwise prepare water analysis; pre-in 2000L shui Xifu adding 700 kg tap water, the nitration material put into the water analyzes the cauldron, nitration of the material in the 50% sulfuric acid solution in the solubility of most small, will be entirely to crystals, cooling to room temperature and ready to centrifugal; by the centrifuge to obtain the solid salt after the nitration material and 50% sulfuric acid solution. To 5000L in the reactor heating tap water 2t put into the nitration material 1300 kg up to 80 °C, thermal insulation to totally dissolve, stirring; and to control the temperature 55 °C the left and the right, slowly inject the liquid ammonia, adjusting PH to neutral, Golden crystal continuously separating out; lowering the temperature to room temperature after the beginning of the centrifugal, get the golden yellow crystal the finished product, the mother liquor in the ammonium sulfate recovery for agricultural production, product inspection qualified packaging is put in storage. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With diphenyl diselenide; dihydrogen peroxide In water at 60℃; for 3h; | |
Diazotization.Behandlung der neutralisierten Diazoniumsalz-Loesung mit NaNO2 in Gegenwart von CuSO4 und Cu2O in der Waerme; | ||
Diazotization.Behandlung der neutralisierten Diazoniumsalz-Loesung mit NaNO2 in Gegenwart von CuSO4 und Na2SO3; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In water monomer at 25℃; for 0.0833333h; Sonication; | |
99% | With hydrazine hydrate monohydrate In ethanol at 40℃; for 0.75h; | |
99% | With LaCu0.67Si1.33; hydrogen In isopropanol at 120℃; for 30h; Autoclave; |
99% | With C20H32Cl4Cu2N4O4 In water monomer at 60℃; for 1h; Inert atmosphere; Schlenk technique; | 2.4. General procedure for the reduction of nitro compounds withcopper complex catalyst General procedure: Copper complex (0.001 mmol, 1mol%), appropriate nitro compounds (0.1 mmol, 1.0 equiv) and NaBH4 (10.0 mmol, 10 equiv)in water (2.0 mL) were charged into a 15 mL pressure tube under air atmosphere. Subsequently, the resulting mixture was stirred atroom temperature in closed vessel. After completion of the reaction(monitored by TLC), the crude reaction mixturewas extraction with ether (3 2 mL), and analyzed by GC-MS chromatography using n-dodecaneas an internal standard. |
99% | With borane-ammonia; N-hexadecyl-N,N,N-trimethylammonium bromide; [Ru(p-cymene)(2,6-bis(1-methylimidazole-2-thione)pyridine)](PF6)2 In water monomer; acetonitrile at 79.84℃; for 8h; Inert atmosphere; Schlenk technique; | |
99% | With methanol; sodium tetrahydridoborate at 20℃; for 0.666667h; Green chemistry; | 2.3. Catalytic hydrogenation of nitroarenes for PdCS General procedure: In a typical procedure: 0.25 mmol nitrobenzene, 2 mL solvent(MeOH, CH2Cl2, xylene, etc), 0.6 mmol NaBH4, and 0.2 mol% [Pd] (Pd:substrate, mol%) were placed in a flask equipped with a magnetic stirrer.The reaction mixture was stirred for several hours at room temperatureand detected by gas chromatography (GC). For the substratesuitability test of nitro compounds, 0.25 mmol aromatic nitro compounds,2 mL MeOH, 0.6 mmol NaBH4, and 0.2 mol% [Pd] (Pd: substrate,mol%) were placed in a flask equipped with a magnetic stirrer.The reactions were stirred for several hours at room temperature, andthe yields were isolated yields, with 1H NMR spectra in the supportinginformation. |
92% | With sodium tetrahydridoborate; C22H22Cl2N2ORu In ethyl [2]alcohol; water monomer at 20℃; for 24h; Inert atmosphere; Schlenk technique; | |
91% | With sodium tetrahydridoborate; [Au(2,6-bis(1-methylimidazole-2-selone)pyridine)Cl2]*[AuCl2] In water monomer at 20℃; for 12h; Inert atmosphere; Schlenk technique; | 2.8. General procedure for the reduction of nitroarenes to anilinesusing gold catalysts General procedure: Gold complex (0.01 mmol, 0.02 equiv) was dissolved in water(2.0 mL), then appropriate nitroarenes (0.5 mmol, 1.0 equiv) andNaBH4 (2 mmol, 4.0 equiv) was added. Subsequently, the resultingmixture was stirred at room temperature. After completion of thereaction (monitored by TLC), the crude reaction mixture wasextracted with EtOAC (3 2 mL). After solvents were removed invacuo from combined organic extracts, the crude products loadeddirectly onto a column of silica gel and purified by column chromatographyto give the corresponding products [59-61]. |
91% | With C20H24ClNO2Ru; isopropanol; potassium hydroxide at 89.84℃; for 3h; Sealed tube; Green chemistry; | |
81% | With chlorobis(cyclooctene)rhodium(I) dimer In N,N-dimethyl-formamide at 120℃; for 24h; Inert atmosphere; | |
With hydrogenchloride; tin | ||
With potassium hydroxide; zinc powder | ||
With ethanol; nickel Hydrogenation; | ||
Multi-step reaction with 2 steps 1: acetic acid; sodium amalgam; alcohol 2: Umlagerung,anschliessend Behandeln mit Zinnchloruer und Salzsaeure | ||
77 %Chromat. | With formic acid; iron(II) tetrafluoroborate hexahydrate; tris(diphenylphosphinomethyl)phosphine In ethanol at 40℃; Inert atmosphere; | |
95 %Chromat. | With hydrazine hydrate monohydrate In tetrahydrofuran at 100℃; for 10h; chemoselective reaction; | |
> 99 %Chromat. | With formic acid; [Mo3S4H3(dmpe)3](BPh4); triethylamine In tetrahydrofuran at 70℃; for 18h; Inert atmosphere; chemoselective reaction; | |
89 %Spectr. | With γ-terpinene In ethanol at 80℃; for 2.5h; Sealed tube; Green chemistry; | |
With hydrogen In neat (no solvent) at 120℃; for 2h; Green chemistry; | ||
With hydrogen In neat (no solvent) at 120℃; for 1.5h; chemoselective reaction; | ||
With hydrogen; hydrazine hydrate monohydrate In ethanol at 40℃; for 1h; Autoclave; chemoselective reaction; | ||
With hydrogen In water monomer at 100℃; for 7h; Autoclave; Green chemistry; chemoselective reaction; | ||
With hydrazine hydrate monohydrate In ethanol at 30℃; for 1.25h; Autoclave; chemoselective reaction; | 2.4. Catalytic reduction of nitro aromatics General procedure: The catalytic reduction of nitro aromatics was conducted in a 25 mlTelfon-lined stainless steel autoclave with magnetic stirring. In a typicalprocess, 6 mmol nitroarene, and desired amounts of reducing agent andsolvents were introduced in the reactor. The autoclave was transferredinto a water bath at the set temperature with an accuracy of better than0.2 °C for ∼0.5 h. Then, 10 mg catalyst was added into the reactionmixture and started the reduction at a stirring rate of 450 rpm. After thereaction, the catalyst was rapidly separated by ltration. n-Decane(500 μL) as standard was added into the ltrate and was dried withanhydrous Na 2 SO 4 . The products were analyzed by gas chromato-graphy-mass spectrometry (GC-MS) (Shimadzu GCMS-QP2010 Plus)and GC (Varian CP-3800) with a capillary column (column VF-1 ms,15 m, 0.25 mm, 0.25 μm) and a ame ionization detector (FID). | |
With sodium tetrahydridoborate at 20℃; for 0.666667h; | ||
97 %Chromat. | With sodium tetrahydridoborate; C25H37ClN3O2Ru(1+)*BF4(1-) In ethanol at 20℃; for 0.5h; | |
96 %Chromat. | With sodium tetrahydridoborate; C18H17ClN4PdS2 In ethanol at 24.84℃; for 2h; | |
90 %Chromat. | With nickel(II) tetrafluoroborate hexahydrate; ammonia; hydrogen; bis(2-diphenylphosphinoethyl)phenylphosphine In 2,2,2-trifluoroethanol at 120℃; for 24h; chemoselective reaction; | |
99 %Chromat. | With methanol; sodium tetrahydridoborate at 20℃; for 0.666667h; | 2.3. Catalytic hydrogenation of nitroarenes for PdCS General procedure: In a typical procedure: 0.25 mmol nitrobenzene, 2 mL solvent(MeOH, CH2Cl2, xylene, etc), 0.6 mmol NaBH4, and 0.2 mol% [Pd] (Pd:substrate, mol%) were placed in a flask equipped with a magnetic stirrer.The reaction mixture was stirred for several hours at room temperatureand detected by gas chromatography (GC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: 2-methyl-5-nitroaniline With hydrogenchloride; sodium nitrite In water Stage #2: With sodium azide In water at 0 - 5℃; for 24h; | |
With sulfuric acid; acetic acid; sodium nitrite Behandlung der erhaltenen Diazoniumsalz-Loesung mit ueberschuessigem Hydroxylamin-sulfat; | ||
Diazotization.Behandlung des Diazoniumperbromids mit Ammoniak; |
Stage #1: 2-methyl-5-nitroaniline With hydrogenchloride; sodium nitrite Stage #2: With sodium azide | ||
5.3 g | With hydrogenchloride; sodium azide; sodium nitrite In water at 0 - 20℃; for 2h; | 18.3 Step 3: Synthesis of 2-azido-1-methyl-4-nitrobenzene c Dissolve 2-methyl-5-nitroaniline (5g, 1eq) in HCl (6.0mol/L, 4.8eq), add an aqueous solution of NaNO2 (2.3g, 1eq) dropwise at 0°C, and then dropwise add NaN3 (2.6g, 1.2eq) aqueous solution, and stirred at room temperature for 2 hours, then water (200mL) was added, the solid was filtered, the filter cake was washed with water, and the solid was dried to obtain a yellow solid c (5.3g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.1% | 6 EXAMPLE 6 EXAMPLE 6 The conversion of 2-methyl-5-nitroaniline to 6-nitroindazole was carried out by the procedure described in Example 5. There was obtained a 96.1% yield of a product that contained 97.8% of 6-nitroindazole. | |
95% | With acetic acid; sodium nitrite at 20℃; | |
90% | With acetic anhydride; sodium nitrite In water for 4h; |
With acetic acid; sodium nitrite durch Diazotieren; | ||
With acetic acid at 10℃; Diazotization; | ||
With sulfuric acid Diazotization.Erwaermen der Reaktionsloesung mit krystallisiertem Natriumacetat; | ||
With acetic acid; isopentyl nitrite at 20℃; for 1.5h; Inert atmosphere; | ||
With acetic acid; sodium nitrite | 18.A (A) (E) -3- [2-(pyridin-2-yl) ethenyl] -1- (tetrahydropyran-2-yl) lH-indazol-6-amine : 2- methyl-5-nitroaniline as a starting material, by cyclization,iodide, and DHP (3,4- dihydropyran) protection indazole an N, Heck even United,reduced to give | |
With diazotization reagent Acidic conditions; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: 2-methyl-5-nitroaniline With hydrogenchloride; sodium nitrite In water at 0 - 5℃; Stage #2: With hydrogenchloride; stannous chloride hydrate In water at 0 - 5℃; for 0.5h; | 1 (2-Methyl-5-nitrophenyl)hydrazine (3) 2-Methyl-5-nitroaniline (3.0 g, 19.7 mmol) was dissolved in a mixture of H2O (5 mL) and 37% HCl (5 mL). A solution of NaNO2 (1.4 g, 20.3 mmol) in H2O (15 mL) was added dropwise at 0 °C, followed by the addition of SnCl2·H2O (9.0 g, 39.8 mmol) in 37% HCl (7 mL) at that temperature. After stirring at 0 °C for 0.5 h, the reaction mixture was neutralized with 1 M NaOH to pH 7-8, and extracted with DCM. The organic phase was separated and dried over anhydrous MgSO4. The organic phase was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 4:1) to give the solid (2.3 g). Yellow solid; yield: 70.0%; 1H NMR (DMSO-d6, 400 MHz, δ ppm): 7.84 (d, J = 2.4 Hz, 1H), 7.37 (dd, J = 8.1, 2.4 Hz, 1H), 7.16 (d, J = 8.1 Hz, 1H), 6.88 (s, 1H), 4.22 (s, 2H), 2.13 (s, 3H). MS (ESI): m/z 168.1 [M+H]+. |
70% | Stage #1: 2-methyl-5-nitroaniline With hydrogenchloride; sodium nitrite In water at 0℃; Stage #2: With tin(II) chloride hydrate In water at 0℃; for 0.5h; | 2-Methyl-5-nitrophenyl)hydrazine (3) 2-Methyl-5-nitroaniline (3.0 g, 19.7 mmol) was dissolved in a mixture of H2O (5 mL) and 37% HCl (5 mL). A solution of NaNO2 (1.4 g, 20.3 mmol) in H2O (15 mL) was added dropwise at 0 °C, followed by the addition of SnCl2·H2O (9.0 g, 39.8 mmol) in 37% HCl (7 mL) at that temperature. After stirring at 0 °C for 0.5 h, the reaction mixture was neutralized with 1 M NaOH to pH 7-8, and extracted with DCM. The organic phase was separated and dried over anhydrous MgSO4. The organic phase was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 4:1) to give the solid (2.3 g). Yellow solid; yield: 70.0%; 1H NMR (DMSO-d6, 400 MHz, δ ppm): 7.84 (d, J = 2.4 Hz, 1H), 7.37 (dd, J = 8.1, 2.4 Hz, 1H), 7.16 (d, J = 8.1 Hz, 1H), 6.88 (s, 1H), 4.22 (s, 2H), 2.13 (s, 3H). MS (ESI): m/z 168.1 [M+H]+. |
1) diazotization 2) reduction (Lit.: S. P. Hiremath, S. Siddopas, J. Indian Chem. Soc. 42, 836 (1965); Yield given. Multistep reaction; |
55 g | Stage #1: 2-methyl-5-nitroaniline With hydrogenchloride; CYANAMID In ethanol; water for 15h; Reflux; Stage #2: With ammonium nitrate In water at 0℃; for 2h; | 1.1 Step one, preparing 2-methyl-5-nitrophenylhydrazine; 40.0 g (0.26 mol) of 4-nitro-2-aminotoluene was sequentially added to the dried reaction flask.20.0 g (0.55 mol) of cyanamide and 150 mL of ethanol, and 29 mL of concentrated hydrochloric acid was added dropwise with stirring.After the reaction was refluxed for 15 hours, the reaction solution was dehydrated, and then water was added thereto. 150 mL (30%) of an aqueous solution of ammonium nitrate was added dropwise at 0 ° C, and the reaction was allowed to stand for 2 hours; the filter cake was washed with diethyl ether.Dry white solid2-methyl-5-nitrophenylhydrazine 55g. |
Stage #1: 2-methyl-5-nitroaniline With hydrogenchloride; sodium nitrite In water at 0℃; Stage #2: With tin(II) chloride dihdyrate In water at 0℃; for 3h; | 2. General procedures for synthesis of 4-aminoindoles (2). General procedure: 3-Nitroaniline (1, 72.2 mmol) was mixed with water (28 mL) and concentrated hydrochloric acid (37%, 28 mL) with heating. The muddy mixture was cooled by an ice-salt bath with stirring, and a solution of sodium nitrite (5.0 g, 72.2 mmol, 1.0 equiv) in water (20 mL) was added dropwise into the mixture. Afterwards, slow addition of a solution of tin(II) chloride (dihydrate, 16.2 g, 72.2 mmol, 1.0 equiv) in concentrated hydrochloric acid (20 mL) was followed at the same temperature. The mixture was stirred for 3 hours, basified by adding solid potassium hydroxide until the pH reached weak basic, and extracted with PE/EA (1:1, 200 mL x 6). The combined extracts were concentrated under reduced pressure. The solid residue was recrystallized from PE to afford the titled compound as deep yellow crystals in 70-80% yields. An above obtained 3-nitrophenyl hydrazine (50.0 mmol) was mixed with TsOHH2O (38.4 g, 150 mmol, 3.0 equiv) and 3-pentanone (4.72 g, 55.0 mmol, 1.1 equiv). The reaction mixture was stirred under reflux for 30 min, and then cooled to room temperature. Water (200 mL) was added. The mixture was basified by adding potassium hydroxide pellets (pH > 10), and extracted with EA (200 mL x 3). The combined extracts were washed with brine (100 mL x 3) and concentrated. The dark residue was separated by silica gel column chromatography (PE/EA 1:12 to 1:6). The obtained orange solid was further purified by recrystallization from cold diethyl ether-EA to afford the titled compound as bright yellow to orange crystals in 80-90% yields. An above obtained 2-ethyl-3-methyl-4-nitroindole (15.0 mmol) was stirred with grinded solid potassium hydroxide (2.5 g, 45.0 mmol, 3.0 equiv) and methyl iodide (1.4 mL, 22.5 mmol, 1.5 equiv) in acetone (120 mL) for 1 hour. The mixture was filtered, and the cake was washed with acetone (30 mL x 2). The combined filtrates were concentrated. The solid residue was separated by silica gel column chromatography (PE/EA 1:12 to 1:6). The obtained yellowish solid was further purified by recrystallization from cold diethyl ether-EA to afford the titled compound as bright yellow crystals in 80-90% yields. An above obtained 2-ethyl-1,3-dimethyl-4-nitroindole (4.0 mmol) was stirred with hydrazine hydrate (80%, 5.0 mL) and 10% Pd/C (0.4 g) in ethanol (100 mL) under reflux for 3 hours. The mixture was cooled to room temperature, filtered, and concentrated. The residue was suspended in water, and extracted with PE/EA (1:1, 50 mL x 4). The combined extracts were washed with brine (50 mL x 2), dried over sodium sulfate, filtered, and concentrated. The crude product was separated by silica gel column chromatography (PE/EA 1:8 to 1:3) to afford needle-like crystals contaminated with some colorful impurities, which were removed by recrystallization from DCM-PE to give compound 2 as colorless crystals in >90% yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | In dichloromethane at 20℃; for 3h; | |
In pyridine | ||
With tetrabutylammomium bromide; potassium carbonate In acetonitrile at 20℃; for 8h; | The synthesis of N-(2-methyl-5-nitro-phenyl)benzamide (N2M5NPBA) compound the following produce used. 2-methyl-5- nitroaniline (6 mmol), K 2 CO 3 (3 mmol), TBAB as catalyst (1 mmol), and benzoylchloride (6 mmol) in acetonitrile solvent (40 mL) was stirred for 8 hrs at room temperature. Thin layer chromatography (TLC) was used to monitor the reaction progress and poured into crushed ice (~50 g) to form a precipitate. The precipitated solid was filtered, washed with water and dried. The crude product on recrystallization from acetone gave N2M5NPBA. The melting point of the N2M5NPBA compound was found to be 475 K. Synthesis of N2M5NPBA was carried out in different solvents such as acetoni- trile, chloroform, acetone, dimethylsulphoxide (DMSO) but higher yields were obtained in acetonitrile and chloroform as a solvent. The synthesis of N2M5NPBA compound is illustrated in Scheme 1 . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.7% | In butan-1-ol at 90 - 95℃; for 4h; Large scale; | |
98.7% | Stage #1: 2-methyl-5-nitroaniline With hydrogenchloride In water; butan-1-ol for 0.5h; Stage #2: CYANAMID In water; butan-1-ol at 90 - 95℃; for 4.25h; Stage #3: With hydrogenchloride In water; butan-1-ol at 90 - 95℃; for 20h; | 2.A Step-A: Preparation of l-(2-Methyl-5-nitrophenyl)guanidine 2-Methyl-5-nitroaniline-(50g, 0.328moles.) and n-butanol (200ml) were placed in a reaction flask. 35% concentrated hydrochloric acid (19ml) was added slowly to the reaction mass for 15minutes. Reaction mass was stirred for 15minutes and 50% aqueous cyanamide solution (82.3ml, 1.978moles) was added slowly to the reaction mass for 15minutes. The reaction mixture was heated to 90-95°C and stirred at the same temperature for four hours and concentrated hydrochloric acid (19ml) was slowly added drop wise within 15 minutes. The reaction mixture was further stirred for four hours while maintaining the temperature at 90-95°C. Concentrated hydrochloric acid (29ml) was added drop wise and the reaction mixture was kept at 90°C for 4hours. Reaction mass was maintained at the same temperature for a total of 20hours. After reaction completion reaction mass was cooled down to 10°C and basified with 10% aqueous sodium hydroxide solution (400ml). The solid product was filtered off, washed with 200ml of water and dried to afford l-(2-methyl-5-nitrophenyl) guanidine. (63g, yield 98.7%, purity by HPLC: 99%) Melting point: 136-140°C |
89.8% | With hydrogenchloride In ethanol; water for 15h; Reflux; | 2 Comparative example 2 This comparative example is a synthesis using cyanamide as a raw material, the reaction efficiency is low, and the cyanamide used is highly toxic.In a clean reaction flask, add 150ml of ethanol and 15.2g of 2-amino-4-nitrotoluene, stir and dissolve, add 8.5g of cyanamide, add 11ml of concentrated hydrochloric acid dropwise, and heat to reflux for 15h. The purity was 93.2% by HPLC, and the residue of 2-amino-4-nitrotoluene was 0.35%. After the reaction, the ethanol solvent was removed by vacuum distillation. Then, 200ml of water was added, and the mass percentage was 30%. 60ml of ammonium nitrate, control the temperature at 05 and stir for 2h. After the completion, filter and rinse with ether to obtain the solid wet product and dry to obtain the corresponding product 2-methyl-5-nitrobenzene Guanidine 18.3g, the purity content is 95.2%, and the molar yield is 89.8%. |
82% | Stage #1: CYANAMID; 2-methyl-5-nitroaniline With hydrogenchloride In water; 3-methyl-phenol at 100℃; for 10h; Stage #2: With sodium hydroxide In water | Preparation of 7V-(2-Methyl-5-nitro-phenyl)-guanidine 2-methyl 5-nitroaniline (2.00 g, 13 mmol) and cyanamide (1.66 g, 3.0 eq) were dissolved in m-cresol (3 ml) in presence of HCl 12N (1.32 ml). The mixture was stirred for 1O h. at 100°C. After cooling, the mixture was treated with NaOH 2.5 N (15 mL) and extracted with ethyl acetate (2 x 30 ml). The combined organic layers were dried over MgSO4, filtered and evaporated to dryness. The brown oil residue, cooled with an ice bath was dissolved in ethyl ether (4 ml) and NaOH 2.5 N (0.4 ml) was added. The pure expected product was filtered and washed with ethyl ether (2.06 g, 82 %). m.p. = 1490C (yellow powder)1H NMR (DMSO, /) δ : 2.20 (s, 3H) ; 5.32 (s, 4H) ; 7.34 (d, J= 8.3 Hz, IH) ; 7.50 (d, J= 1.8 Hz, IH) ; 7.61 (dd, J= 2.32 Hz, J= 8.18 Hz, IH) |
76% | With hydrogenchloride In water; isopropyl alcohol at 80 - 100℃; for 14.33h; | 1 l-(2-Methyl-5-nitrophenyl)guanidine (1) A mixture of 2-methyl-5-nitroaniline (152 g, 1.0 mol), cyanamide (247 mL. 6.0mol) and isopropyl alcohol (1000 mL) were placed in a 3L flask. The mixture was heated to 80°C. Concentrated hydrochloric acid (57 mL) was slowly added dropwise over 80 min. The reaction mixture was stirred for 1 h while maintaining the temperature at 80°C. Another portion of concentrated hydrochloric acid ( 144 mL) was added dropwise at 80°C. The reaction mixture was then stirred for 12 h at 100°C. The mixture was cooled to room temperature and treated with aqueous NaOH (2.5 N, 1200 mL). The resulting solid was collected by filtration, washed with isopropyl alcohol (500 mL) and dried to afford compound 1 (145 g, 76% yield). |
76% | With hydrogenchloride In water; isopropyl alcohol at 80℃; for 2.33333h; | 1 1-(2-Methyl-5-nitrophenyl)guanidine (1) A mixture of 2-methyl-5-nitroaniline (152 g, 1.0 mol), cyanamide (247 mL, 6.0mol) and isopropyl alcohol (1000 mL) were placed in a 3L flask. The mixture was heated to 80°C. Concentrated hydrochloric acid (57 mL) was slowly added drop wise over 80 min. The reaction mixture was stirred for 1 h while maintaining the temperature at 80°C. Another portion of concentrated hydrochloric acid (144 mL) was added dropwise at 80°C. The reaction mixture was then stirred for 12 h at 100°C. The mixture was cooled to room temperature and treated with aqueous NaOH (2.5 N, 1200 mL). The resulting solid was collected by filtration, washed with isopropyl alcohol (500 mL) and dried to afford compound 1 (145 g, 76% yield). |
With hydrogenchloride In butan-1-ol at 150℃; | ||
9.7 g | Stage #1: CYANAMID; 2-methyl-5-nitroaniline With nitric acid In ethanol; water for 48h; Reflux; Stage #2: With sodium hydroxide In water at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: 2-methyl-5-nitroaniline With nitric acid In ethanol at 0℃; Stage #2: CYANAMID In water Reflux; | |
87.07% | Stage #1: CYANAMID; 2-methyl-5-nitroaniline With hydrogenchloride In ethanol; water at 70℃; for 3h; Large scale; Stage #2: With nitric acid In ethanol; water at 45℃; for 0.0166667h; Large scale; | 2 Example 2 Synthesis of 2-methyl-5-nitrophenylguanidine nitrate Put 121.72g of 2-methyl-5-nitroaniline into the middle, then put 100.8g of 50% NH2CN,Then add 160ml of ethanol, stir and heat up to 70°C, then add 118ml of concentrated hydrochloric acid dropwise to the three-necked bottle,After the dropwise addition, the reaction was refluxed for 3h. After the reaction was completed, the temperature was lowered to 45°C, and 50ml of concentrated HNO3 was poured in and stirring continued for about 1min.Let stand to cool and crystallize, filter with suction, wash the filter cake with 150ml of ethanol,White solid was dried to give 179.16g, yield 87.07%. |
81.1% | Stage #1: CYANAMID; 2-methyl-5-nitroaniline With hydrogenchloride In water; isopropyl alcohol at 80℃; for 4.33333h; Stage #2: With nitric acid In water; isopropyl alcohol at 60℃; | 1 Example 1: 2Og of 2-Methyl-5-nitroaniline (0.131 M; 1 eq.), 11.05g of cyanamide (0.263 M; 2 eq.) and 80 mL of isopropyl alcohol were placed in a reactor flask. The reaction mixture was heated to 8O0C and 18 mL of concentrated hydrochloric acid was slowly added dropwise within 80 minutes. The reaction mixture was stirred for 1 hour while maintaining it at 800C. Next, 6 mL of concentrated hydrochloric acid was added dropwise and the reaction mixture was kept at 800C for 2 hours. The reaction mixture was cooled down to 600C and 10 mL of 65% nitric acid (0.142 M, 1.08 eq.) was added dropwise and the mixture was left with stirring until it was cooled down to room temperature. The solid product was filtered off, washed with 50 mL of isopropyl alcohol and dried in the air to afford 27.45 g (yield 81.1%) of l-(2-methyl-5-nitrophenyl)guanidine nitrate, m.p.203-206°C;1H NMR (DMSO-dβ, 200 MHz): 2.32 (3H, s, CH3), 7.44 (4H, m, 4 x NH), 7.64 (IH, d, J=8.2 Hz, 3-H), 8.09 (IH, d, J=2.5 Hz, 6-H), 8.15 (IH, dd, J=8.2 i 2.5 Hz, 4-H), 9.51 (IH, m, NH+). |
59% | With nitric acid In water; butan-1-ol at 0 - 95℃; for 12h; | 1.1; 2.1; 3.1; 4.1 Example-1: Process for the preparation of Imatinib of the formula (la);Step-1; The preparation of 2-methyl-5-nitro phenyl guanidine nitrate of the formula (IV) Charged a suspension of 34 Kg of 2-amino-4-nitro toluene in 200 L n-butanol into reactor. 14.3 Kg of cone. Nitric acid is slowly added during half an hour at 25-35C. 14.1 Kg of cyanamide dissolved in 14 L DM water is charged. Reaction mass is heated to 90-95C for 12 hours, cooled to 65-70C. n-butanol is distilled off not crossing mass temperature 40-50C to the residual volume of 80 L. Reaction mass is Cooled to 25-35C and then cooled to 0-10C. Charge 235 L isopropyl ether and 235 L methanol are charged at 10C. Maintained 1 hour at 10-15C, centrifuged and slurry washed with a mixture of 1:1 isopropyl ether and methanol (100 L). isopropyl ether and methanol mother liquors are kept aside to recover the unreacted starting material 2-amino-4-nitro toluene (III) Centrifuged product is dried at 60-70C Id : 22 Kg - 61% (based on recovery of III).: 214-220CitybyHPLC:99.8%Step-1 The preparation of 2-methyl-5-nitro phenyl guanidine nitrate (IV)Charged a suspension of 3.4 Kg of 2-amino-4-nitro toluene in 25 L n-butanol into reactor. 1.4 Kg of cone. Nitric acid is slowly added during half an hour at 25-35C. 1.4 Kg of cyanamide dissolved in 1.4 L DM water is charged. Reaction mass is heated to 90-95C for 12 hours, cooled to 65-70C. n-butanol is distilled off not crossing mass temperature 40-50C to the residual volume of 80 L. Reaction mass is Cooled to 25-35C and then cooled to 0-10C. Charge 25 L isopropyl ether and 25 L methanol are charged at 10C. Maintained 1 hour at 10-15C, centrifuged and slurry washed with a mixture of 1:1 isopropyl ether and methanol (10 L). isopropyl ether and methanol mother liquors are kept aside to recover the unreacted starting material 2-amino-4-nitro toluene (III) Centrifuged product is dried at 60-70C Yield : 2.2 Kg - 61% (based on recovery of III) MR:215-218CPurity by HPLC: 99.80% Step-1 The preparation of 2-methyl-5-nitro phenyl guanidine nitrate of the formula (IV)Charged a suspension of 3.4 Kg of 2-amino-4-nitro toluene in 20 L n-butanol into reactor. 1.4 Kg of cone. Nitric acid is slowly added during half an hour at 25-35C. 1.4 Kg of syanamide dissolved in 1.4 L DM water is charged. Reaction mass is heated to 90-95C for 14 hours, cooled to 65-70C. n-butanol is distilled off not crossing mass temperature 40-50C to the residual volume of 80 L. Reaction mass is Cooled to 25-35C and then sooled to 0-10C. Charge 25 L isopropyl ether and 25 L methanol are charged at 10C. Maintained 1 hour at 10-15C, centrifuged and slurry washed with a mixture of 1:1 isopropyl ether and methanol (10 L). isopropyl ether and methanol mother liquors are kept aside to recover the unreacted starting material 2-amino-4-nitro toluene (HI)Centrifuged product is dried at 60-70CYield : 2.1 Kg - 59% (based on recovery of HI)MR: 216-219CPurity by HPLC: 99.9% Step-1 The preparation of 2-methyl-5-nitro phenyl guanidine nitrate of the formula (IV)Charged a suspension of 3.4 Kg of 2-amino-4-nitro toluene in 25 L n-butanol into reactor. 1.4 Kg of cone. Nitric acid is slowly added during half an hour at 25-35C. 1.4 Kg of cyanamide dissolved in 1.4 L DM water is charged. Reaction mass is heated to 90-95C for 14 hours, cooled to 65-70C. n-butanol is distilled off not crossing mass temperature 40-50C to the residual volume of 80 L. Reaction mass is Cooled to 25-35C and then cooled to 0-10C. Charge 25 L isopropyl ether and 25 L methanol are charged at 10C. Maintained 1 hour at 10-15C, centrifuged and slurry washed with a mixture of 1:1 isopropyl ether and methanol (10 L). isopropyl ether and methanol mother liquors are kept aside to recover the unreacted starting material 2-amino-4-nitro toluene (III) Centrifuged product is dried at 60-70C Yield : 2.1 Kg - 59% (based on recovery of III) MR: 214-220C Purity by HPLC : 99.85% |
58% | With nitric acid In ethanol for 24h; Reflux; | |
58% | Stage #1: 2-methyl-5-nitroaniline With nitric acid In ethanol at 20℃; for 0.166667h; Stage #2: CYANAMID In ethanol; water at 80 - 85℃; for 12h; | 5.1.1. 1-(2-Methyl-5-nitrophenyl)guanidine nitrate (5) To a solution of 2-methyl-5-nitroaniline (1.5 g, 10 mmol) in ethanol (25 mL) was added drop wise nitric acid (2 mL) at room temperature. After the completion of addition, the reaction mixture was stirred for 10 min at room temperature. 50% aqueous solution of cyanamide (3 mL, 25 mmol) was added droop wise to the reaction mixture and stirred for 12 h at 80-85 °C. The crude product was collected by filtration and washed with ethyl acetate and recrystallized from ethanol to afford the compound 5 as light yellow solid (1.12 g, 58%). Mp 216-218; 1H NMR (DMSO-d6, 300 MHz): δ 2.32 (s, 3H, -CH3), 7.44 (m, 4H, ArH), 7.64 (d, 1H, J = 8.2 Hz, ArH), 8.09 (d, 1H, J = 2.5 Hz, ArH), 8.15 (dd, 1H, J = 8.2, 2.5 Hz, ArH), 9.51 (m, 1H, ArH); MS (EI): m/z 194 [M+]. |
54% | With nitric acid In propan-1-ol; water for 24h; Reflux; | 2.1.2. Preparation of N-(2-methyl-5-nitrophenyl)guanidiniumnitrate (2). To a solution of 1 (500 mg, 3.12 mmol) inpropanol (4 ml), 65% nitric acid (0.4 ml, 3.75 mmol) wasadded until a yellow solid formed, whereupon a 50% solutionof cyanamide in water (265 mg, 6.24 mmol) was added. Thereaction was refluxed for 24 h and then cooled to 0 C. Theyellow precipitate was filtered off and washed with propanoland methanol (yield 54%; m.p 210 C). 1H NMR (400 MHz,DMSO-d6): 8.13 (d, J = 8.5 Hz, 1H, Ar-H), 8.06 (s, 1H,Ar-H), 7.62 (d, J = 8.4 Hz, 1H, Ar-H), 7.43 (s, 1H, -NH-CNHNH2), 2.31 (s, 1H, -CH3). 13C{H} NMR (100 MHz,DMSO-d6): 156.42, 146.61, 144.01, 134.62, 132.52, 122.99,122.86, 17.82 (-CH3). |
53% | Stage #1: 2-methyl-5-nitroaniline With nitric acid In butan-1-ol Stage #2: CYANAMID In water; butan-1-ol at 100℃; for 12h; | |
34% | With nitric acid In ethanol; water at 80℃; for 16 - 18h; | 1.2 Step 2: N-(2-Methyl-5-nitro-phenyl)-guanidinium nitrate: 2-Methyl-5-nitro aniline (10 g, 65 mmol) was dissolved in ethanol (25 mL), and concentrated HNO3 (4.6 mL) was added to the solution dropwise followed by 50% aqueous solution of cyanamide (99 mmol). The reaction mixture was refluxed overnight and then cooled to 0° C. The mixture was filtered and the residue was washed with ethyl acetate and diethyl ether and dried to provide N-(2-Methyl-5-nitro-phenyl)-guanidinium nitrate (4.25 g, yield: 34%). |
With nitric acid In ethanol Heating; | ||
With nitric acid In diethyl ether; ethanol; water | 20.1 Step 20.1 Step 20.1 9.1 ml (0.13 mol) of 65% nitric acid are added dropwise in the course of 5 minutes to a yellow suspension of 20.0 g (0.13 mol) of 2-amino-4-nitrotoluene in 50 ml of absolute ethanol. When the exothermic reaction has subsided, 8.32 g (0.198 mol) of cyanamide dissolved in 8.3 ml of water are added. The brown reaction mixture is boiled at reflux for 25 hours, cooled to 0° and filtered. Washing with 4*100 mi of ethanol/diethyl ether (1:1) and drying yield 2-methyl-5-nitrophenyl-guanidine nitrate; m.p. 219°-226°. | |
With nitric acid In ethanol; water | I Preparation I Preparation I N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine (A) To a suspension of 10.0 g (0.065 mol) of 2-amino-4-nitrotoluene in ethanol (20 ml) was added 65% nitric acid (4.6 ml, 0.065 mol) dropwise at 0° C. and stirred for 10 minutes. Cyanamide (8.32 g, 0.198 mol) in water (5 ml) was added to the reaction mixture then was refluxed for 25 hours, cooled to 0° C. and filtered and washed with water to yield 2-methyl-5-nitrophenyl-guanidine nitrate. | |
With water; nitric acid; butan-1-ol for 25h; Heating / reflux; | To 2-amino-4-nitro toluene 1 (0.033 mol) in n-butanol (29 niL) is added2.1 g of 65% aq. nitric acid to form the nitrate salt followed by condensation with cyanamide (0.047 mmol) in water (2 mL). The resulting mixture is heated at reflux for 25 h. After cooling to 0 0C, the precipitate is collected by filtration and washed with ethanol/diethyl ether (1 : 1 v/v, 30 mL) to afford 2-methyl-5-nitrophenyl guanidine nitrate 2 | |
Stage #1: 2-methyl-5-nitroaniline With nitric acid In ethanol; water Stage #2: CYANAMID In ethanol; water for 24h; Heating / reflux; | B.1.4; E Step 1.4 2.Methyl-5-nitroaniline (100 g, 0.657 mol) was dissolved in ethanol (250 ml), and 65% aqueous nitric acid solution (48 ml, 0.65 mol) was added thereto. When the exothermic reaction was stopped, cyanamide (41.4 g) dissolved in water (41.4 g) was added thereto. The brown mixture was reacted under reflux for 24 hours. The reaction mixture was cooled to 0° C, filtered, and washed with ethanol: diethyl ether(l :l, v/v) to give 2-methyl-5-nitrophenyl-guanidine nitrate (98 g) (U.S. 4,623,486). Rf=O.1 (Methylene chloride:Methanol:25% Aqueous ammonia=150:10:l). MS: 195.2 (M+H); 1H-NMR(DMSO- d6)=1.43(s, 3H), 6.59(s, 3H), 6.72-6.76(d, IH), 7.21-7.27(m, IH), 8.63-8.64(br, IH). | |
With nitric acid In ethanol; water for 4h; Reflux; | 6 Reference Example 6 N-(2-Methyl-5-nitro-phenyI)-guanidne nitric acid salt; To a solution of 2-methyl-5-nitroaniline (1.90 g) in ethanol (3 mL) at 0 °C was added dropwise nitric acid (0.90 mL of a 70% solution in water). After complete addition, a solution of cyanamide (1.57 g) in water (1 mL) was added and the mixture was stirred at reflux for 4 h. After cooling to room temperature, the mixture was poured into diethyl ether (20 mL) and the resulting solid was filtered to give N- (2-methyl-5-nitro-phenyl)-guanidine nitric acid salt as a yellow solid (1.84 g). | |
Stage #1: 2-methyl-5-nitroaniline With nitric acid In ethanol; water Stage #2: CYANAMID In ethanol; water for 24h; Heating / reflux; | 1; 1.2 Reaction Scheme 1; Step 1.2 2-METHYL-5-NITROANILINE (100G, 0. 657MOL) was dissolved in ethanol (250MA), and 65% aqueous nitric acid solution (48MA, 0. 65MOL) was added thereto. When the exothermic reaction was stopped, cyanamide (41.4g) dissolved in water (41.4g) was added thereto. The brown mixture was reacted under reflux for 24 hours. The reaction mixture was cooled to 0°C, filtered, and washed with ethanol : diethyl ether (l : L, V/V) to give 2-metliyl-5-nitrophenyl-guanidine nitrate (98G). Rf= 0.1 (Methylene chloride: Methanol: 25% Aqueous ammonia = 150 : 10: 1) LH-NMR (DMSO-D6) = 1.43 (s, 3H), 6.59 (s, 3H), 6.72-6. 76 (d, LH), 7.21-7. 27 (m, LH), 8.63-8. 64 (br, lH) | |
Stage #1: 2-methyl-5-nitroaniline With nitric acid In ethanol; water Stage #2: CYANAMID In ethanol; water for 24h; Heating / reflux; | 1; 1.2 Reaction Scheme 1; Step 1.2 2-Methyl-5-nitroaniline (100g, 0. 657MOL) was dissolved in ethanol (250 M), and 65% aqueous nitric acid solution (48 M, 0.65mol) was added thereto. When the exothermic reaction was stopped, cyanamide (41.4g) dissolved in water (41.4g) was added thereto. The brown mixture was reacted under reflux for 24 hours. The reaction mixture was COOLED) to 0 C, filtered, and washed with ethanol: diethyl ether (L : 1, V/V) to give 2-methyl-5-nitrophenyl-guanidine nitrate (98g). [143] [144] Rf = 0.1 (Methylene chloride : Methanol : 25% Aqueous ammonia = 150 : 10 : 1) [145] 1H-NMR(DMSO-d)= 1.43(s,3H), 6.59(s,3H), 6.72-6.76 (d,1H), 7.21-7.27(m,1H), 6 8.63-8. 64 (br, 1H) | |
98 g | Stage #1: 2-methyl-5-nitroaniline With nitric acid In ethanol; water Stage #2: CYANAMID In ethanol; water for 24h; Reflux; | 8.2.1 2-Methyl-5-nitrophenyl-guanidine nitrate (2) 2-Methyl-5-nitroaniline 1 (100g, 0.657mol) was dissolved in ethanol (250mL), and a 65% aqueous nitric acid solution (48mL, 0.65mol) was added thereto. When the exothermic reaction was stopped, cyanamide (41.4g) dissolved in water (41.4g) was added. The brown mixture was reacted under reflux for 24h. The reaction mixture was cooled to 0°C, filtered, and washed with ethanol-diethyl ether (1:1, v/v) to give 2-methyl-5-nitrophenyl-guanidine nitrate 2 (98g). |
With nitric acid In ethanol for 21h; Reflux; | ||
With nitric acid | 12.A (The A) 4- methyl-3-[4- (3-pyridinyl) -2-pyrimidinyl amino] aniline 2-methyl-5-nitroanilinewith cyanamide, guanidine nitrate was the addition, and then (E) -3-dimethylamino-1- (pyridin-3-yl) -1-oxo-2-propenyl cyclization was pyrimidinaminecompound, and finally reducing the nitro group to give. | |
With nitric acid In water; butan-1-ol for 25h; Heating / reflux; | Experimental Preparation of intermediates; Synthesis of 6-methyl-Nl-(4-(pyridin-3-yl)pyrimidin-2-yl)benzene-l,3-diamine 5; To 2-amino-4-nitro toluene 1 (0.033 mol) in n-butanol (29 mL) is added nitric acid (2.1 g, 65% in water) followed by cyanamide solution in water (2 mL, 0.047 mmol). The resulting mixture is heated at reflux for 25 h. After cooling to 0 0C, filtration and washing with 1 : 1 = ethanol : diethyl ether (30 mL), 2-methyl-5-nitrophenyl guanidine nitrate 2 is obtained. To 2-methyl-5-nitrophenyl guanidine 2 (0.0074 mol) in isopropanol (15 mL) is added 3 (0.0074 mol) and sodium hydroxide flakes (0.008 mol). The resulting mixture is heated at reflux for 12 h. After cooling to 0 0C, the product is collected by filtration and washed with isopropanol (6 mL) and methanol (3 mL) to afford 4. 1H NMR (400MHz, Cl6-DMSO) δ 9.31 (s, IH), 9.24 (s, IH), 8.78 (m, IH), 8.70 (m, IH), 8.61 (m, IH), 8.47 (m, IH), 7.88 (m, IH), 7.55 (m, 3H), 2.39 (s, 3H). MS (m/z) (M+l)+: 278.2. | |
With nitric acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: HNO3 / ethanol / Heating 2: NaOH / propan-2-ol / 24 h / Heating 3: 8.9 g / SnCl2; aq. HCl / 0.5 h 4: 61 percent / dimethylformamide / 2 h / 0 °C 5: 68 percent / acetonitrile / 6 h / Heating | ||
Multi-step reaction with 5 steps 1.1: nitric acid / ethanol / 25 - 50 °C 1.2: 3 h / Reflux 2.1: sodium hydroxide / water 3.1: 4-methyl-2-pentanone / 12 h / Reflux 4.1: hydrazine hydrate / palladium 10% on activated carbon / methanol / 8 h / 25 °C / Reflux; Inert atmosphere 5.1: potassium carbonate / acetone / 0 - 5 °C | ||
Multi-step reaction with 5 steps 1.1: nitric acid / ethanol / 25 - 50 °C 1.2: 3 h / Reflux 2.1: sodium hydroxide / water 3.1: acetic acid / 2 h / 90 - 95 °C 3.2: 12 h / Reflux 4.1: hydrazine hydrate / palladium 10% on activated carbon / methanol / 8 h / 25 °C / Reflux; Inert atmosphere 5.1: potassium carbonate / acetone / 0 - 5 °C |
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / 1,4-dioxane / 2 h / 90 °C / 5171.62 Torr / Inert atmosphere 2: palladium on activated charcoal; hydrogen / ethyl acetate / 3 h / 20 °C / Inert atmosphere 3: triethylamine / tetrahydrofuran / 3 h / 0 °C / Inert atmosphere 4: 3 h / Inert atmosphere; Reflux | ||
Multi-step reaction with 4 steps 1.1: butan-1-ol / 4 h / 90 - 95 °C / Large scale 2.1: butan-1-ol / 9 h / 120 °C / Large scale 3.1: hydrogen / methanol / 45 h / 3102.97 Torr 4.1: potassium carbonate / isopropyl alcohol / 0.25 h / 20 °C / Large scale 4.2: 1.5 h / 20 °C / Large scale 4.3: 0.5 h / 20 °C / Large scale | ||
Multi-step reaction with 4 steps 1.1: hydrogenchloride / water; butan-1-ol / 0.5 h 1.2: 4.25 h / 90 - 95 °C 1.3: 20 h / 90 - 95 °C 2.1: butan-1-ol / 9 h / 120 °C 3.1: hydrogen / methanol / 45 h / 25 °C / 3102.97 Torr 4.1: potassium carbonate / chloroform / 0.25 h / 20 °C 4.2: 8.25 h / 20 °C / Reflux | ||
Multi-step reaction with 4 steps 1.1: hydrogenchloride / water / 1.5 h / 130 - 160 °C 2.1: ammonium chloride; hydrogenchloride; iron / ethanol; water / 3.5 h / 55 - 65 °C 3.1: tetrahydrofuran / 24 h / 20 °C 4.1: bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate; triethylamine / 1,4-dioxane / 2 h / 20 °C / Inert atmosphere 4.2: 0.5 h / 20 °C / Inert atmosphere 4.3: 24 h / 100 °C / Inert atmosphere | ||
Multi-step reaction with 4 steps 1.1: nitric acid / ethanol; water 1.2: 24 h / Reflux 2.1: sodium hydroxide / isopropyl alcohol / 18 h / Reflux 3.1: tin(II) chloride dihdyrate / ethanol; ethyl acetate / 4 h / Reflux 4.1: pyridine / 18 h / 20 °C | ||
Multi-step reaction with 4 steps 1: nitric acid / ethanol / 21 h / Reflux 2: sodium hydroxide / butan-1-ol / 12 h / Reflux 3: hydrogen; platinum(IV) oxide / tetrahydrofuran / 1.5 h / 20 °C 4: pyridine / 24 h / 20 °C | ||
Multi-step reaction with 5 steps 1.1: hydrogenchloride / ethanol; water / 3 h / 70 °C / Large scale 1.2: 0.02 h / 45 °C / Large scale 2.1: potassium hydroxide / ethanol / 20 h / Reflux; Large scale 3.1: hydrazine hydrate; pyrographite; iron(III) chloride hexahydrate / methanol / 3 h / Reflux; Large scale 4.1: triethylamine / tetrahydrofuran / 1 h / 0 °C / Large scale 5.1: N-ethyl-N,N-diisopropylamine / isopropyl alcohol / 5 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 20 - 80℃; Stage #2: 2-methyl-5-nitroaniline; 5-bromo-3,3'-bipyridine With caesium carbonate In toluene at 80 - 100℃; for 42h; | 15.2 Step 2 1-methyl-4-nitro-2-[3-(3-pyridyl)pyridin-5-ylamino]benzene This compound was prepared by version of the method described in the document (J. Org. Chem., 1996, 61, 7240-7241.). To 25 mg of (+-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl [(+-)-BINAP], 2 ml of toluene was added and (+-)-BINAP was dissolved by stirring with heating at 80°C under an argon atmosphere. The solution was once air-cooled to room temperature and 6 mg of palladium (II) acetate was added and, stirring for one minute, 620 mg of 3-bromo-5-(3-pyridyl)pyridine obtained in the step 1, 482 mg of 2-methyl-5-nitroaniline, 1.20 g of cesium carbonate and 2 ml (total 4 ml) of toluene were added, followed by stirring with heating at 80°C for 18 hours and further heating at 100°C for 24 hours under an argon atmosphere. After air cooling, the reaction solution was diluted with ethyl acetate and insolubles were removed by filtration. The solvent in the filtrate was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to obtain 108 mg of the objective compound as a yellow crystal. Melting point: 195-198°C 1H-NMR(CDCl3)δ: 2.41(3H, s), 5.76(1H, br), 7.39(1H, br), 7.42(1H, ddd), 7.54(1H, dd), 7.83(1H, dd), 7.88(1H, m), 8.09(1H, d), 8.43(1H, d), 8.50(1H, d), 8.67(1H, dd), 8.83(1H, d) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 100℃; for 36h; | 16.1 Step 1 2-(3-bromophenylamino)-1-methyl-4-nitrobenzene This compound was prepared by version of the method described in the document (J. Org. Chem., 2000, 65, 1144-1157.). To 1.00 g of 1-bromo-3-iodobenzene, 591 mg of 2-methyl-5-nitroaniline, 32 mg of tris(dibenzylideneacetone)dipalladium (0), 66 mg of (+-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl [(+-)-BINAP] and 1.61 g of cesium carbonate, 14 ml of toluene was added and the mixture was stirred with heating at 100°C for 36 hours under an argon atmosphere. After air cooling, insolubles were removed by filtration and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 256 mg of the objective compound as an orange crystal. Melting point: 114-116°C 1H-NMR(CDCl3)δ: 2.34(3H, s), 5.52(1H, br), 6.99(1H, m), 7.14-7.21(3H, m), 7.33(1H, d), 7.77(1H, dd), 8.02(1H, d) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 110℃; for 24h; | Step 2 1-methyl-4-nitro-2-[2-(3-pyridyl)pyridin-6-ylamino]benzene This compound was prepared by version of the method described in the document (J. Org. Chem., 2000, 65, 1144-1157.). To 940 mg of 2-bromo-6-(3-pyridyl)pyridine obtained in the step 1, 730 mg of 2-methyl-5-nitroaniline, 37 mg of tris(dibenzylideneacetone)dipalladium (0), 75 mg of (+-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl [(+-)-BINAP] and 1.82 mg of cesium carbonate, 12 ml of toluene was added and the mixture was stirred with heating at 110C for 24 hours under an argon atmosphere. After air cooling, the reaction solution was diluted with ethyl acetate and insolubles were removed by filtration. The solvent in the filtrate was distilled off under reduced pressure and the residue was crystallized by adding diethyl ether. The resulting crystal was collected by filtration and then washed with ethyl acetate-diethyl ether to obtain 646 mg of the objective compound as a yellow crystal. Melting point: 148-150C 1H-NMR(CDCl3)delta: 2.42(3H, s), 6.53(1H, br), 6.80(1H, d), 7.35(2H, d), 7.44(1H, dd), 7.69(1H, m), 7.83(1H, dd), 8.44(1H, dt), 8.65(1H, dd), 9.09(1H, d), 9.20(1H, d) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With hydrogenchloride In DMF (N,N-dimethyl-formamide) at 60℃; for 16h; | 15.A To a solution of 2-methyl-5-nitro-phenylamine (430 mg, 2.84 mmol) in DMF (5 mL) was added solid compound 1C (680 mg, 2.84 mmol) and a drop of conc. HC1. The reaction mixture was heated to 60 °C for 16 h. The mixture was then cooled and water was added (25 mL). The solids were stirred for 3 h, filtered, washed with water / (2x10 mL), and dried in vacuo to afford 15A as a beige solid (651 mg, 64%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 70℃; for 23h; | 12.1 Step 1 2-[(4-chloro)pyridin-2-ylamino]-1-methyl-4-nitrobenzene. This compound was prepared by version of the method described in the document (J. Org. Chem., 1996, 61, 7240-7241.). To 2.00 g of 2,4-dichloropyridine (Recl. Trav. Chim. Pays-Bas., 1950, 69, 673-699.), 2.26 g of 2-methyl-5-nitroaniline, 121 mg of palladium (II) acetate, 336 mg of (+-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl [(+-)-BINAP] and 6.16 g of cesium carbonate, 120 ml of toluene was added, and then the mixture was stirred with heating at 70°C for 23 hours under an argon atmosphere. After insolubles were removed by filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2.11 g of a crude product. The crude product was washed with diethyl ether to obtain 1.22 g of the objective compound as a yellow crystal. Melting point: 130-133°C 1H-NMR(CDCl3)δ: 2.38(3H, s), 6.40(1H, br), 6.74(1H, d), 6.85(1H, dd), 7.38(1H, d), 7.90(1H, dd), 8.15(1H, d), 8.57(1H, d) | |
With caesium carbonate In toluene at 70℃; for 23h; | 22.1 2-[(4-chloro)pyridin-2-ylamino]-1-methyl-4-nitrobenzene Step 1 2-[(4-chloro)pyridin-2-ylamino]-1-methyl-4-nitrobenzene To 2.00 g of 2,4-dichloropyridine, 2.26 g of 2-methyl-5-nitroaniline, 121 mg of palladium (II) acetate, 336 mg of (+-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl [(+-)-BINAP] and 6.16 g of cesium carbonate, 120 ml of toluene was added, and then the mixture was stirred with heating at 70°C for 23 hours under an argon atmosphere. After insolubles were removed by filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain a crude product. The crude product was washed with diethyl ether to obtain 1.22 g of the objective compound as yellow crystals. Melting point: 130-133°C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In N,N-dimethyl-formamide at 55℃; for 48h; | |
85% | Stage #1: 4-chloro-5-methyl-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid ethyl ester; 2-methyl-5-nitroaniline In N,N-dimethyl-formamide at 20℃; for 24h; Stage #2: With sodium hydrogencarbonate In water; N,N-dimethyl-formamide | 207.A A suspension of chloropyrrolotriazine (2.03 g, 8.47 mmol) and 3-nitro-5- methyl aniline (1.41 g, 9.3 mmol) in DMF (25 mL) was stirred at rt for 24 h. Water (125 mL) was added over 30 min and the solution stirred for 1 h upon which the pH was adjusted to neutral with sat. aq. NaHC03. The solids were filtered, washed with water, and dried to give compound A (2.589 g, 85% yield) as a pale tan solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With N-ethyl-N,N-diisopropylamine In butan-1-ol at 110℃; for 72h; | C.3 4,6-Dichloropyrimidine (5.37 g, 36.0 mmol) and 2-methyl-5-nitroaniline (5.48 g, 36.0 mmol) are heatedin n-butanol (58 ml) with diisopropylethylamine (4.66 g, 36 mmol) for 3 days at 110 °C. The mixture isevaporated and the product is purified by standard methods.Yield: 3.1 g (27 %)mp: 128-130 °C |
at 110℃; for 16h; | 20.1 2-[(6-chloro)pyrimidin-4-ylamino]-1-methyl-4-nitrobenzene Step 1 2-[(6-chloro)pyrimidin-4-ylamino]-1-methyl-4-nitrobenzene 2.64 g of 2-methyl-5-nitroaniline and 10.33 g of 4,6-dichloropyrimidine were stirred with heating at 110°C for 16 hours. After air cooling, the reaction solution was dissolved in methanol. An aqueous saturated sodium hydrogen carbonate solution and ethyl acetate were added to separate the aqueous layer. The aqueous layer was further subjected to extraction with ethyl acetate twice. The organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain a crude product. The crude product was washed with diisopropyl ether to obtain 3.61 g of the objective compound as yellow crystals. Melting point: 161-163°C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In butan-1-ol; for 38h;Heating / reflux; | A 250 ml reactor, equipped with a mechanical stirrer and a reflux condenser, was charged with 2-chloro-4-(3-pyridyl)-pyrimidine (0.5 g, 2.6 mmol), 2-amino-4-nitrotoluene (0.5 g, 3.2 mmol), n-butanol (15 ml) and concentrated HCl (5 drops) and the mixture was refluxed for 38 hours. Then, the mixture was cooled, and 6 N NaOH was added to pH 8. The solvent was evaporated under reduced pressure and water (20 ml) was added to the residue, followed by extraction with dichloromethane (2×20 ml). The combined organic phase was concentrated to dryness to give the crude N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-pyrimidine-amine, which was purified by column chromatography to yield a product having 80% purity. The residue was re-slurried twice in methanol (2×2 ml) and in water (3 ml) and dried under reduced pressure | |
290 g | With copper(l) iodide; 2-(dimethylamino)ethyl methacrylate; potassium carbonate; In 1,4-dioxane; at 100℃; for 20h;Inert atmosphere; | 190 g of 2-chloro-4-(pyridin-3-yl)pyridine under a nitrogen atmosphere,167 g of 2-methyl-5-nitroaniline, 47 g of cuprous iodide,Anhydrous potassium carbonate 276gAnd 22 g of dimethylaminoethyl methacrylate added to 1,4-dioxane solution 2000 mLMedium, heating at 100 C, reaction for 20 h, TLC detection,The raw material is completely reacted; first under reduced pressure,Evaporate most of the solvent dioxane, after cooling to room temperature,The reaction mixture was poured into ice water and a large amount of white solid precipitated.Filtration, a small amount of n-hexane rinse, vacuum dry to pureN-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidinamine 290 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8% | 94; N-(5-Amino-2-methyl-phenyl)-4-oxo-lH-quinoline-3-carboxamide; To a solution of <strong>[34785-11-0]4-hydroxy-quinoline-3-carboxylic acid</strong> (A-1) (50 mg, 0.26 mmol), HBTU (99mg, 0.26 mmol) and DIEA (138 jaL, 0.79 mmol) in THF (2.6 mL) was added 2-methyl-5-nitro-phenylamine (40 mg, 0.26 mmol). The mixture was heated at 150 C in the microwave for 20min and the resulting solution was concentrated. The residue was dissolved in EtOH (2 mL) andSnCl2-2H2O (293 mg, 1.3 mmol) was added. The reaction was stirred at room temperatureovernight. The reaction mixture was basified with sat. NaHCOs solution to pH 7-8 and extractedwith ethyl acetate. The combined organic layers were washed with brine, dried over NaaSO,*,filtered and concentrated. The residue was dissolved in DMSO and purified by HPLC (10-99 %CHsCN / H2O) to yield the product, N-(5-amino-2-methyl-phenyl)-4-oxo-lH-quinoline-3-carboxamide (94) (6 mg, 8 %). HPLC ret. time 2.06 min, 10-99 % CH3CN, 5 min run; ESI-MS294.2 m/z (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With potassium hydroxide In water; copper | N-(2'-methyl-5'-nitrophenyl)-5-methoxyanthranilic acid N-(2'-methyl-5'-nitrophenyl)-5-methoxyanthranilic acid Potassium salt of 2-bromo-5-methoxybenzoic acid (23 g) and 2-methyl-5-nitroaniline (40 g) are stirred and heated at 110° C. in the presence of 50 mg of catalytic copper for 50 minutes. Next, the reaction mixture is poured on 5% solution of potassium hydroxide in water (600 ml) and cooled. The formed precipitate is filtered off, washed with water, and the collected solutions are acidified with hydrochloric acid to pH 5. The formed solid is filtered off and crystallized from methanol-acetone (2:1) to give N-(2'-methyl-5'-nitrophenyl)-5-methoxyanthranilic acid (11.2 g, 56% yield), m.p. 219-221° C. 1H NMR (d6DMSO): δ9.20 (bs, 1H), 7.88 (d, 1 H, J=1.9 Hz), 7.65 (dd, 1 H, J1=7.8 Hz, J2=1.9 Hz), 7.44 (d, 1 H, J=8.3 Hz), 7.43 (d, 1 H, J=2.9 Hz), 7.26 (d, 1 H, J=8.8 Hz), 7.19 (dd, 1 H, J1=8.8 Hz, J2=2.9 Hz), 3.68 (s, 3 H), 2.27 (s, 3 H). |
56% | With potassium hydroxide In water; copper | N-(2'-methyl-5'-nitrophenyl)-5-methoxyanthranilic acid N-(2'-methyl-5'-nitrophenyl)-5-methoxyanthranilic acid Potassium salt of 2-bromo-5-methoxybenzoic acid (23 g) and 2-methyl-5-nitroaniline (40 g) are stirred and heated at 110 C. in the presence of 50 mg of catalytic copper for 50 minutes. Next, the reaction mixture is poured on 5% solution of potassium hydroxide in water (600 ml) and cooled. The formed precipitate is filtered off, washed with water, and the collected solutions are acidified with hydrochloric acid to pH 5. The formed solid is filtered off and crystallized from methanol - acetone (2:1) to give N-(2'-methyl-5'-nitrophenyl)-5-methoxyanthranilic acid (11.2 g, 56% yield), m.p. 219-221 OC. 1H NMR (d6DMSO): δ9.20 (bs, 1H), 7.88 (d, 1 H, J=1.9 Hz), 7.65 (dd, 1 H, J1=7.8 Hz, J2 =1.9 Hz), 7.44 (d, 1 H, J=8.3 Hz), 7.43 (d, 1 H, J=2.9 Hz), 7.26 (d, 1 H, J=8.8 Hz), 7.19 (dd, 1H, IJb=8.8 Hz, J1 =2.9 Hz), 3.68 (s, 3 H), 2.27 (s, 3 H). |
56% | With potassium hydroxide In water; copper | N-(2'-methyl-5'-nitrophenyl)-5-methoxyanthranilic acid N-(2'-methyl-5'-nitrophenyl)-5-methoxyanthranilic acid Potassium salt of 2-bromo-5-methoxybenzoic acid (23 g) and 2-methyl-5-nitroaniline (40 g) are stirred and heated at 110° C. in the presence of 50 mg of catalytic copper for 50 minutes. Next, the reaction mixture is poured on 5% solution of potassium hydroxide in water (600 ml) and cooled. The formed precipitate is filtered off, washed with water, and the collected solutions are acidified with hydrochloric acid to pH 5. The formed solid is filtered off and crystallized from methanol-acetone (2:1) to give N-(2'-methyl-5'-nitrophenyl)-5-methoxyanthranilic acid (11.2 g, 56% yield), m.p. 219-221° C. 1H NMR (d6 DMSO): δ9.20 (bs, 1H), 7.88 (d, 1 H, J=1.9 Hz), 7.65 (dd, 1 H, J1=7.8 Hz, J2=1.9 Hz), 7.44 (d, 1 H, J=8.3 Hz), 7.43 (d, 1 H, J=2.9 Hz), 7.26 (d, 1 H, J=8.8 Hz), 7.19 (dd, 1H, J1=8.8 Hz, J2=2.9 Hz), 3.68 (s, 3 H), 2.27 (s, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: 4-oxo-3,4-dihydroquinazoline-6-carbonyl chloride; 2-methyl-5-nitroaniline In N,N-dimethyl-formamide at 25℃; for 12h; Stage #2: With sodium hydroxide In water; N,N-dimethyl-formamide | 10 A solution of 4-methyl-3-nitro-phenylamine (365 mg, 2.40 mmol) in DMF (6 ml) was treated with 4-oxo-3,4-dihydroquinazoline-6-carbonyl chloride (Method 8) (500 mg, 2.40 mmol). The mixture was stirred at 25 °C for 12 hours. The reaction was then quenched with 10% NaOH(aq). The resulting solid was collected by vacuum filtration to give 638 g (82%) of a light yellow solid; m/z 325. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.9% | In isopropyl alcohol; for 12.0h;Heating / reflux; | Method 63; (7-Methoxy-quinazolin-4-ylV(2-methyl-5-nitro-phenyl*)-amine; A mixture of <strong>[55496-52-1]4-chloro-7-methoxy-quinazoline</strong> (Method 32; 3.5 g, 18 mmol) and 2- methyl-5-nitro-phenylamine (2.3 g, 15 mmol) in isopropanol (150 ml) was refluxed for 12 h. The reaction mixture was cooled to 25 0C and the resulting precipitate was collected by vacuum filtration. The solid was washed with ether and dried under reduced pressure to give 4.6 g (98.9%) of a light yellow solid. NMR: 11.55 (s, br, IH), 8.85 (s, IH), 8.75 (d, IH), 8.30 (s, IH), 8.20 (d, IH), 7.75 (d, IH), 7.52 (d, IH), 7.30 (s, IH), 4.02 (s, 3H), 2.40 (s, 3H); m/z 310. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; at 95℃; for 12h; | Method 20; 6-Methoxy-4-[(2-memyl-5Hnitrophenyl)ammo]quinazolin-7-ol; A solution of <strong>[162364-72-9]7-benzyloxy-4-chloro-6-methoxyquinazoline</strong> (2.00 g, 6.65 mmol) and 2- methyl-5-nitroaniline (1.01 g, 6.65 mmol) in EtOH (20 ml) was heated to 95 C for 12 h. The organics were removed under reduced pressure. The resulting solid was utilized without further purification; m/z 417. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium <i>tert</i>-butylate In 1,4-dioxane at 100℃; for 24h; | 1 Cvcloprorjyl-{6-r2-f2-methyl-5-nitro-phenylaminoVpyridin-3-vn-pyrimidin-4-vU-amine; [0086] A mixture of [6-(2-Chloro-pyridin-3-yl)-pyrimidm-4-yl] -cyclopropylamine (1000 mg, 4.06mmol), 2-Methyl-5-nitro-phenylamine (1240 mg, 8.12mmol), palladium acetate (450 mg, 2.03mmol), Xantophos (1.76g, 3.04τnmol) and potassium t- butoxide (909 mg, 8.12mmol) are mixed in 2OmL anhydrous 1, 4-dioxane under nitrogen and heated at 1000C for 24 hours. TLC analysis followed the reaction until starting material [6-(2-Chloro-pyridin-3-yl)-pyrimidin-4-yl]-cyclopropyl-amine is consumed completely and desired product formed. The crude product is purified on silica gel column by 5% MeOH in DCM. Yellow solid is obtained, 1.03g. MS m/z 363.2 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.6% | With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; In 1,4-dioxane; water; at 110℃; | To a mixture of <strong>[22536-63-6]<strong>[22536-63-6]2-chloro-4-methoxypyrimidin</strong>e</strong> (9.54 g, 66 mmol), 2-methyl-5- nitrobenzenamine (10.0 g, 66 mmol), Pd2(dba)3 (1.0 g), S-Phos (1.0 g, 24.4 mmol), and Cs2C03 (31.8 g, 99 mmol) in 1,4-dioxane/water (140 mL/60 mL) was heated at 110C overnight. The mixture was cooled to room temperature and then filtered through a pad of celite. The filtrate was diluted with ethyl acetate and washed with water. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel to afford compound 12 (12 g.70.6% yield) as a light yellow solid. |
70.6% | With tris-(dibenzylideneacetone)dipalladium(0); 2-dicyclohexylphosphino-2?,6?-dimethoxybiphenyl; caesium carbonate; In 1,4-dioxane; water; at 110℃; | To a mixture of <strong>[22536-63-6]<strong>[22536-63-6]2-chloro-4-methoxypyrimidin</strong>e</strong> (9.54 g, 66 mmol), 2-methyl-5- nitrobenzenamine (10.0 g, 66 mmol), Pd2(dba)3 (1.0 g), S-Phos (1.0 g, 24.4 mmol), and Cs2C03 (31.8 g, 99 mmol) in 1,4-dioxane/water (140 mL/60 mL) was heated at 110C overnight. The mixture was cooled to room temperature and then filtered through a pad of celite. The filtrate was diluted with ethyl acetate and washed with water. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel to afford compound 12 (12 g.70.6% yield) as a light yellow solid. |
With sodium t-butanolate;palladium diacetate; bis[2-(diphenylphosphino)phenyl] ether; In 1,4-dioxane; at 150℃; for 0.333333h;Microwave irradiation; | To the mixture of <strong>[22536-63-6]<strong>[22536-63-6]2-chloro-4-methoxypyrimidin</strong>e</strong> 18 (10.0 mmol), 2- methyl-5-nitrobenzenamine (15.0 mmol), Pd(OAc)2 (1 mmol), DPE-Phos (1.5 mmol) and NaO-tBu (20.0 mmol) under nitrogen is added 1,4-dioxane (15 mL). The resulting mixture is heated at 150 0C for 20 min under microwave conditions. The reaction mixture is filtered through a pad of celite and the filtrate is diluted in ethyl acetate (100 ml) and washed with water, dried over NaSO4 and concentrated. The crude product is purified by silica gel column chromatography (ethyl acetate : hexanes = 1 : 4 v/v) to afford 4-methoxy-N-(2- methyl-5-nitrophenyl)pyrimidin-2-amine 19 as a light yellow solid. MS (m/z) (M+l)+: 261.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In ISOPROPYLAMIDE; at 60℃;Combinatorial reaction / High throughput screening (HTS); | Step 2. Catalytic amination of the solid supported 8-iodo-l-methyl-4,5-dihydro- lH-pyrazolo [4,3-h] quinazoline-3-carboxamide; <n="82"/>Using a 4 niL Argonaut Trident synthesizer cassette, 200 mg (0.11 mmol) of the resin from step 1 above, were charged into separate vials. To each of the reactor vials flushed with argon, finely divided potassium carbonate (0.15 g, 1.1 mmol), palladium acetate [Pd(OAc)2] (2.5mg, 0.011 mmol, 10%), (HK)-BINAP (6.8 mg, 0.011 mmol, 10%) and the corresponding amine (0.22 mmol, 2 equivalents) in degassed (argon) dimethyacetamide (2 mL) were added. The resulting mixture was agitated at 600C for 10 hours on the Argonaut Trident Automated Library Synthesizer (ALS) station. The Trident ALS station was programmed to continuously mechanically agitate the resin at 6O0C while a nitrogen gas "sparge" was incorporated to re-suspend the scarcely soluble potassium carbonate. Nitrogen gas sparging was incorporated once per hour, for a 30 second duration, throughout the 16-hour heating cycle.The resin was drained from the synthesis cocktail and washed using the Argonaut Trident External Agitation Thermal Unit (EATU) synthesis station with DMA (3 x 2 mL, 5 min.). The above catalytic amination cycle was repeated a second time using the previously described procedure.Upon completion of the second amination cycle, the resin was drained from the synthesis cocktail and washed using the Argonaut Trident EATU synthesis station with DMF (1 x 2 mL, 5 min.), with water (1 x 2 mL, 5 min.), with DMF/water (1 : 1) (3 x 2 mL, 5 min.), with DMF (3 x 2 mL, 5 min.), with methanol (3 x 2 mL, 5 min.) and with DCM (3 x 2 mL, 5 min.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With N-ethyl-N,N-diisopropylamine In tetrahydrofuran; dichloromethane at 20℃; | 237 To a solution of 4-(4-phenylquinazolin-2-ylamino)benzoyl chloride (1.56 g, 4.35 mmol) and Hunig's base (1.3 mL, 7.5 mmol) in tetrahydrofuran (50 mL) and dichloromethane (10 mL) was added 2-methyl-5-nitroaniline (726 mg, 4.78 mmol), and the reaction was allowed to stir at rt overnight. The mixture was concentrated on a rotary evaporator and purified by flash column chromatography to give 7V-(2-methyl-5-nitrophenyl)- 4-[(4-phenylquinazolin-2-yl)amino]benzamide (522 mg, 58%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.46 (s, IH), 10.03 (s, IH), 8.49 (d, IH), 8.27 (d, 2H), 8.10 (d, 3H), 7.80 (m, 5H), 7.73 (m, 3H), 7.66 (d, IH), 7.50 (dt, IH), 2.50 (s, 3H). MS (EI) for C28H2IN5O3: 476.0 (MH+). [00580] N-(5-amino-2-methylphenyl)-4-[(4-phenylquinazolin-2-yl)amino]benzamide. A stirred mixture of /Y-(2-methyl-5-nitrophenyl)-4-[(4-phenylquinazolin-2-yl)amino]benzamide (500 mg, 1.05 mmol), formic acid (140 μL, 3.71 mmol), potassium formate (312 mg, 3.71 mmol) and 5% platinum on carbon (150 mg, catalytic) in tetrahydrofuran (10 mL) and ethanol (10 mL) was heated to reflux for 1 h. The mixture was filtered while hot through Celite and washed with hot ethanol. Water was added until the mixture became cloudy, then the volatile solvents were removed on a rotary evaporator. The solid was collected by filtration to give λL(5-amino-2-methylphenyl)-4-[(4-phenylquinazolin-2-yl)amino]benzamide (397 mg, 85%). 1H NMR (400 MHz, DMSOd6): δ 10.20 (s, IH), 9.46 (s, IH), 8.15 (d, 2H), 7.97 (d, 2H), 7.84 (m, 5H), 7.65 (m, 3H), 7.42 (m, IH), 6.89 (d, IH), 6.65 (d, IH), 6.39 (dd, IH), 2.08 (s, 3H). MS (EI) for C28H23N5O: 446.1 (MH+).[00581] N-{5-[(7V,7V-dimethylglycyl)amino]-2-methylphenyl}-4-[(4-phenylquinazolin-2- yl)amino]benzamide. To a stirred mixture of 7V-(5-amino-2-methylphenyl)-4-[(4- phenylquinazolin-2-yl)amino]benzamide (200 mg, 0.45 mmol), iV, JV-dimethylglycine (70 mg, 0.68 mmol) and Hunig's base (365 μL, 2.1 mmol) in dimethylformamide (1 mL) was added HATU (310 mg, 0.82 mmol). The stirred mixture was heated to 80 0C for 1 h, the cooled to rt and purified by preparative reverse phase HPLC to give N-{5-[(N,N- dimethylglycyl)amino]-2-methylphenyl}-4-[(4-phenylquinazolin-2-yl)amino]benzamide (83 mg, 35%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.32 (s, IH), 9.71 (s, IH), 8.18 (d, 2H), 7.99 (d, 2H), 7.85 (m, 6H), 7.65 (m, 3H), 7.45 (dq, 2H), 7.18 (d, IH), 3.06 (s, 2H), 2.28 (s, 6H), 2.0 (s, 3H). MS (EI) for C32H30N6O2: 531.1 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With triethylamine In acetonitrile at 20℃; for 3h; | 63.a Reference example 63: Synthesis of propane-1 -sulfonic acid {2-methyl-5-r6-(3-nitro- phenyl)-pyϖmidin-4-ylamino1-phenyl)-amidea.; Synthesis of propane-1 -sulfonic acid (2-methyl-5-nitro-phenyl)-amide.Propane-1 -sulfonyl chloride (5.63 ml_, 50 mmol) was added to a solution of 2-methyl-5- nitro-phenylamine (7.61 g, 50 mmol) and triethylamine (7 ml_) in acetonitrile (100 ml_). The resulting solution was vigorously stirred for 3 h at room temperature and diluted with cold water (500 ml_), which lead to the formation of a precipitate. The precipitate was filtered out, washed with 1 N HCI (100 ml_), water (2x200 ml_) and dried to give 10.2 g (79%) of propane-1 -sulfonic acid (2-methyl-5-nitro-phenyl)-amide as colorless solid.Cl MS m/z 259 (MH+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With triethylamine In dichloromethane at 0 - 20℃; for 4h; Inert atmosphere; | Step 1 : 4-chloro-/V-(2-methyl -5-nitrophenyl)butanamide To a solution of 2-methyl-5-nitroaniline (5.0 g, 32.9 mmol) in DCM (50 mL) was added triethylamine (3.99 g, 39.4 mmol) and 4-chlorobutanoyl chloride (5.1 g, 36.1 mmol) at 0°C. The solution was stirred at room temperature for 4 hours under N2. The mixture was diluted with DCM (120 mL) and water (50 mL). The organic layer was separated and the aqueous layer was extracted with DCM. The combined organic phases were washed with 0.5 M HCI, water, brine, dried over sodium sulfate and concentrated to give a residue which was purified by column chromatography on silica gel (DCM/MeOH, 300:1) to give 4-chloro-A/- (2-methyl -5-nitrophenyl)butanamide (6.9 g, 82%) as pale-gray solid LCMS (Method B): 2.20 min [MH]+ = 257.1/259.1 , [MNa]+ = 279.1/281.1 |
With triethylamine In ethyl acetate at 0 - 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With ammonium hydroxide In water at 20℃; for 9h; Green chemistry; | |
79% | With trimethylsilylazide; copper; ethanolamine In N,N-dimethyl acetamide at 95℃; for 24h; Inert atmosphere; | 4.2. General procedure for the copper-mediated reductive amination of aryl halides with TMSN3 (Table 4) General procedure: A mixture of copper powder (63.5 mg, 1.00 mmol), the aryl halide (500 μmol), 2-aminoethanol (74.9 μL, 1.25 mmol), and TMSN3 (133 μL, 1.00 mmol) in DMA (1 mL) in a 15 mL test tube was stirred under an Ar atmosphere (balloon) at 95 °C using a Chemistation personal organic synthesizer (EYELA, Tokyo). After complete consumption of the aryl halide was confirmed by TLC analyses or after 24 h (if the reaction was incomplete within 24 h), the mixture was diluted with EtOAc (10 mL) and then filtered through a Celite pad. The pad was successively washed with EtOAc (20 mL), H2O (25 mL), and concd aq ammonia solution (5 mL). After the two layers were separated, the aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography with n-hexane/EtOAc or n-pentane/Et2O as the eluent. |
75% | With copper (II)-fluoride; trimethylsilylazide; ethanolamine In N,N-dimethyl acetamide at 95℃; for 24h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium <i>tert</i>-butylate In toluene at 90℃; Inert atmosphere; | 13 Reference Example 13; 5-(2-Methyl-5-nitrophenylamino)-2-phenyl-2,3-dihydroisoindol-1-oneA solution of 5-bromo-2-phenyl-2,3-dihydroisoindol-1-one (200 mg, 0.69 mmol, obtained in reference example 3) in toluene (17 mL) was refluxed for 30 min under argon and then allowed to cool to room temperature. Palladium acetate (II) (12 mg, 0.05 mmol), (+/-) 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (32 mg, 0.05 mmol), potassium tert-butoxide (110 mg, 0.98 mmol) and 2-methyl-5-nitroaniline (126 mg, 0.83 mmol) were added. The mixture was inertized with argon and it was heated at 90° C. overnight. The reaction mixture was allowed to cool to room temperature and CHCl3 and water were added. The phases were separated and the aqueous phase was reextracted with CHCl3. The combined organic phases were washed with 3N HCl and 1N NaOH and dried over Na2SO4. The solvent was evaporated and the crude product thus obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 200 mg of the title compound (yield: 80%).LC-MS (method 1): tR=9.91 min; m/z=358.0 [M-H]-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: thieno[2,3-b]pyrazine-6-carboxylic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide for 0.25h; Stage #2: 2-methyl-5-nitroaniline In N,N-dimethyl-formamide at 60℃; for 60h; | 56.1 Step 1: synthesis of N-(2-methyl-5-nitrophenyl)thieno[2,3-b]pyrazine-6- carboxamide (75)A solution of thieno[2,3-b]pyrazine-6-carboxylic acid (250 mg, 1.387 mmol), HATU (633 mg, 1.665 mmol) and DIPEA (0.459 mL, 2.77 mmol) in DMF (5 mL) was stirred for 15 min. 2-methyl-5-nitroaniline (211 mg, 1.387 mmol) was added and stirred at 60°C for 4h. Quenched in citric acid solution and the resulting precipitate was collected to give N-(2-methyl-5-nitrophenyl)thieno[2,3-b]pyrazine-6-carboxamide 75 (400 mg, 92 %). (m/z) = 315 (M+H)+. |
92% | Stage #1: 2-methyl-5-nitroaniline; thieno[2,3-b]pyrazine-6-carboxylic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide for 0.25h; Stage #2: 2-methyl-5-nitroaniline In N,N-dimethyl-formamide at 60℃; for 4h; | 56.1 Step 1: synthesis of N-(2-methyl-5-nitrophenyl)thieno[2,3-b]pyrazine-6-carboxamide (75) Step 1: synthesis of N-(2-methyl-5-nitrophenyl)thieno[2,3-b]pyrazine-6-carboxamide (75) A solution of thieno[2,3-b]pyrazine-6-carboxylic acid (250 mg, 1.387 mmol), HATU (633 mg, 1.665 mmol) and DIPEA (0.459 mL, 2.77 mmol) in DMF (5 mL) was stirred for 15 min. 2-methyl-5-nitroaniline (211 mg, 1.387 mmol) was added and stirred at 60° C. for 4 h. Quenched in citric acid solution and the resulting precipitate was collected to give N-(2-methyl-5-nitrophenyl)thieno[2,3-b]pyrazine-6-carboxamide 75 (400 mg, 92%). (m/z)=315 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With triethylamine In dichloromethane at 20℃; for 4h; | 1.c.1 C) Synthesis of Compound 24; 1) Preparation of the Amide of Formula (IV) (FIG. 1a); 2-Methyl-5-nitroaniline (1.26 g, 1 eq., 8 3 mmol) is dissolved in 40 ml of dichloromethane. Triethylamine (1.4 ml, 1.2 eq., 10 mmol) is then added, followed, dropwise, by 4-phenylbenzoyl chloride (2.1 g, 10 mmol, prepared from the corresponding acid of oxalyl chloride) in solution in 20 ml of dichloromethane, and the medium is stirred at ambient temperature for 4 hours. The organic phase is then diluted with CH2Cl2, washed with water, and then dried with Na2SO4. The organic phase is then concentrated, and the crystals recovered are then recrystallized from methanol, so as to obtain 2.36 g (yield=85%) of amide of formula (IV).Mp=186° C.; [ES/MS] m/z 332 [M+1]+2) Preparation of the Aniline of Formula (VI) (FIG. 1a) |
With pyridine In dichloromethane at 0 - 20℃; Inert atmosphere; | 2.1.3. General procedure for the synthesis of nitro derivatives 13and 17a-b General procedure: The proper acylchloride (11 or 16a-b, 9.2 mmol, 1.2 equiv) was dissolved in dry CH2Cl2 (50 mL) and the solution was cooled downto 0 °C. 2-Methyl-5-nitro aniline 12 (1.17 g, 7.7 mmol, 1 equiv) andpyridine (1.2 mL, 15.4 mmol, 2 equiv) were added. After 10 min, the reaction mixture was heated up to rt and stirred overnight under N2. After dilution with CH2Cl2 (50 mL), the reaction mixture was washed with 1 N HCl (3 30 mL), a saturated solution of NaHCO3 (3x30 mL), and brine (2 30 mL). The organic phase was driedover dry Na2SO4 and, after filtration and evaporation under reduced pressure, the crude product was purified by flash chromatography |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With sodium tris(acetoxy)borohydride; acetic acid In chloroform at 20℃; | 3.2.2. General Procedure for the Synthesis of 6a-d General procedure: Amixture of methyl 4-formylbenzoate (1) (1.1 equivalents) and amine R1NH2 (a-d) (1.0 equivalent)was dissolved in dry CHCl3. Sodium triacetoxyborohydride (2.8 equivalents) and AcOH (sixequivalents) were added to this solution, and the resulting solution was stirred at room temperaturefor 2±3 h. The reaction mixture was quenched with an ice-cold saturated solution of NaHCO3 (topH 7), and extracted with CHCl3. The combined organic layers were dried over Na2SO4, filtered,and concentrated under vacuum. The residue was dissolved in ethyl acetate, and the product was precipitated with hexane. The solid was ltered and washed with ethyl acetate/hexane. |
Stage #1: methyl 4-formylbenzoate; 2-methyl-5-nitroaniline In benzene at 60℃; Stage #2: With sodium tetrahydroborate; acetic acid In benzene at 0 - 50℃; | ||
With sodium tris(acetoxy)borohydride |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With hydrogenchloride In water at 120 - 160℃; for 1.5h; Inert atmosphere; | 7 6-Methyl-2-(2-methyl-5- nitrophenylamino)pyrimidin-4-one 6-Methyl-2-methylthiopyrimidin-4-one (5.0 g, 0.032 mol) and 2-methyl-5- nitrophenylamine (7.3g. 0.048 mol) were heated to 120 °C. Hydrochloric acid (0.28 ml, 35%, 0.003 mol) was added to homogenous melt and heating was continued at 160 °C for 1.5 h while the melt solidified. The methanethiol liberated in reaction was vented by argon stream into a caustic scrubber system. Hot acetone (60 ml) was added to the mixture when cooled down till 50 °C, the mixture was stirred for 0.5h and cooled to room temperature. Solid was filtered off, washed with acetone (25 ml) and water (15 ml) to obtain 7.0 g (84%) of 6-methyl-2-(2-methyl-5- nitrophenylamino)pyrimidin-4-one, m.p. 248-250 °C. 1H NMR (DMSO-Ok): 2.12 (s, 3H), 2.36 (s, 3H), 5.74 (s, 1 H), 7.49 (d J=8.4 Hz, 1 H), 7.86 (dd J=8.4;2.5 Hz, 1 H), 8.34 (br.s, 1 H), 9.04 (d J=2.5 Hz, 1 H), 1 1.13 (br.s, 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With hydrogenchloride; In water; at 130 - 160℃; for 1.5h; | 2-Methythiopyrimidin-4-one (18.6 g, 0.13 mol) and 2-methyl-5- nitrophenylamine (29.7 g, 0.195 mol) were heated to melt at approximately 130 °C. The reaction is conducted in a sealed system with a vent line to exhaust the methanethiol liberated in the reaction. The methanethiol is absorbed in two caustic scrubbers in series connected to vent line, with an empty trap between the reaction vessel and scrubbers to avoid reverse flow of caustic solution into the reaction vessel. Hydrochloric acid (1 ml, 35percent, 0.01 1 mol) was added and the melt heated at 160 °C for 1.5 h forming a solid. Hot acetone (200 ml) was added at 45-50 °C and the mixture was stirred for 0.5 h. Solid was filtered off and washed with acetone (130 ml) and water (60 ml) yielding 24.5 g (76percent) of 2-(2-methyl-5- nitrophenylamino)pyrimidin-4-one. M.p. 271 -273 °C. 1H NMR (DMSO-Ok): 2.12 (s, 3H), 2.36 (s, 3H), 5.74 (s, 1 H), 7.49 (d J=8.4 Hz, 1 H), 7.86 (dd J=8.4;2.5 Hz, 1 H), 8.34 (br.s, 1 H), 9.04 (d J=2.5 Hz, 1 H), 1 1.13 (br.s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | at 170℃; for 3h; | 6-Amino-4-chloropyrimidin-2(1H)-one (3, 200 mg, 0.84 mmol) and 2-methyl-5-nitroaniline (627 mg, 2.52 mmol) were heated at 170 °C for 3 h. The mixture was then cooled to rt and diethyl ether was added. The mixture was sonicated for 5 min. The suspension was filtered, and the filter cake was dissolved in MeOH and purified by column chromatography (silica gel, dichloromethane/methanol 9:1 v/v) to afford 4 (128 mg, 60percent) as a brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 12h; | F.2 Step 2: Protocol for the preparation of 2-acetyl-iH-pyrrolo[2,3-b]pyridine-5-carboxylic acid (2-methyl-5-nitro-phenyl)-amide Step 2: Protocol for the preparation of 2-acetyl-iH-pyrrolo[2,3-b]pyridine-5-carboxylic acid (2-methyl-5-nitro-phenyl)-amide 2-Acetyl-7H-pyrrolo[2,3-b]pyridine-5-carboxylic acid was dissolved in anhydrous DMF (0.06 mol/L) with DIEA (5 eq) and HATU (2 eq). After 15 min, 2-methyl-5-nitro-phenylamine was slowly added and mixture was stirred for 12 h at RT. DMF was evaporated and NaHC03(aq) was added. Product was extracted with EtOAc, dried, filtered and evaporated to obtain a dark mixture. After purification by washing with MeOH or EtOAc or by silica column, expected product was obtained. Yield = 90%. ESI-MS: m/z 309 ([M+H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56.1% | Stage #1: 2-hydroxy-3,6-bisphenylaminocarbonylnaphthalene With sodium hydroxide In 1-methyl-pyrrolidin-2-one at 40℃; Stage #2: 2-methyl-5-nitroaniline In 1-methyl-pyrrolidin-2-one at 5 - 20℃; | Synthesis of 4a 3-Hydroxy-N2,N7-diphenyl-naphthalene-2,7-dicarboxamide (3.0 g, 0.008 mol) was charged into a flask (100 ml) with NMP (24.0 g) and sodium hydroxide (0.69 g, 0.017 mol). The mixture was stirred at 40 °C and then cooled below 5 °C. After 2-methyl-5-nitroaniline diazonium fluoroboric salt (2.36 g, 0.009 mol) had been added to the flask while stirring and keeping the temperature below 5 °C, the solution was stirred overnight at room temperature, and neutralization using acetic acid was performed. The red powder generated was filtrated and washed sequentially with acetone, methanol and water. Finally, the powder was dispersed in methanol, filtrated, and dried in anoven at 80 °C. The powder thus obtained (2.6 g, 0.005 mol) was further treated in DMF (20 g) at 120-130 °C for 3h while stirring. The product was washed with DMF and methanol, and dried in an oven at 80 °C. Bluish red 4-(2-methly-5-nitrophenyl)azo-3-hydroxy-N2,N7-diphenylnaphthalene-2,7-dicarboxamide (2.4 g) was obtained as an extremely insoluble crystalline powder. Yield 56.1%; decomposition point 320 °C; MALDI-TOF MS m/z 544.120 [M-H] (100%), calcd for [C31H22N5O5] 544.162. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.4% | Stage #1: 2-methyl-5-nitroaniline With hydrogenchloride; sodium nitrite In water at 5℃; Stage #2: tetrafluoroboric acid In water | Preparation of 2-methyl-5-nitoroaniline diazonium fluoroboric salt for 4a and 4b 2-Methyl-5-nitroaniline (12.5 g, 0.08 mol) was put into a flask (300 ml) with 125.0 g of water and 25.7 g of 35% hydrochloride.16% Sodium nitrite (39.0 g, 0.09 mol) was added dropwise to the above mixture keeping the system below 5 °C. After removing insoluble substances, the intermediate was kept below 5 °C, and 42% fluoroboric acid (32.4 g, 0.17 mol) was added dropwise, and then filtrated. The precipitate was washed with water, and subsequently isopropyl alcohol, and dried. White crystalline powder was obtained. The yield was 19.8 g (98.4%). The salt was used for following diazotization without identification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | Stage #1: 2-(2-(pyrrolidin-1-yl)ethoxy)quinoline-6-carboxylic acid hydrochloride With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 72h; Stage #2: 2-methyl-5-nitroaniline With pyridine In dichloromethane at 20℃; for 6h; | Compound 145 Preparation of Compound 145, N-(2-methyl-5-nitrophenyl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoline-6-carboxamide Preparation of Compound 145, N-(2-methyl-5-nitrophenyl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoline-6-carboxamide[00193] Oxalyl chloride (10.7 g, 84.3 mmol) was added to a suspension of Compound 70 (2.26 g, 7.00 mmol) in DCM (12 mL) and DMF (0.014 mL) and the reaction mixture was stirred at rt for 3 days, concentrated, dissolved in DCM (15 mL) and added dropwise to a solution of 2-methyl-5-nitroaniline (1.07 g, 7.03 mmol) and pyridine (2.3 mL) in DCM (10 mL). The reaction mixture was stirred at rt for 6 h, and then concentrated. The residue was suspended in MeOH, and the solid isolated by filtration. The crude material was purified by silica gel column chromatography using 4% MeOH in DCM and then 6% 2 M NH3/MeOH in DCM to afford the title compound (1.20 g, 41%) as a white solid. 1H NMR (500 MHz, DMSO) δ 10.30 (s, 1H), 8.59 (d, J= 2.1 Hz, 1H), 8.43- 8.37 (m, 2H), 8.23 (dd, J= 8.7, 2.1 Hz, 1H), 8.05 (dd, J= 8.5, 2.5 Hz, 1H), 7.88 (d, J = 8.7 Hz, 1H), 7.60 (d, J= 8.5 Hz, 1H), 7.13 (d, J= 8.8 Hz, 1H), 4.57 (t, J= 5.8 Hz, 2H), 2.88 (t, J= 6.0 Hz, 2H), 2.56 (br s, 4H), 2.43 (s, 3H), 1.72-1.67 (m, 4H). HRMS : calcd for C23H25N4O4 (M + H)+, 421.1870; found 421.1864. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 150℃; for 0.333333h;Microwave irradiation; | To a solution of 4-hydroxy-quinoline-3-carboxylic acid (A-1) (50 mg, 0.26 mmol), HBTU (99 mg, 0.26 mmol) and DIEA (138 muL, 0.79 mmol) in THF (2.6 mL) was added 2-methyl-5-nitro-phenylamine (40 mg, 0.26 mmol). The mixture was heated at 150° C. in the microwave for 20 min and the resulting solution was concentrated. The residue was dissolved in EtOH (2 mL) and SnCl2.2H2O (293 mg, 1.3 mmol) was added. The reaction was stirred at room temperature overnight. The reaction mixture was basified with sat. NaHCO3 solution to pH 7-8 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was dissolved in DMSO and purified by HPLC (10-99percent CH3CN/H2O) to yield the product, N-(5-amino-2-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (94) (6 mg, 8percent). HPLC ret. time 2.06 min, 10-99percent CH3CN, 5 min run; ESI-MS 294.2 m/z (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Stage #1: 2-methyl-5-nitroaniline With hydrogenchloride; sodium nitrite In water for 0.166667h; Stage #2: ethyl acetoacetate With sodium acetate In ethanol; water at 20℃; Cooling; | General procedure: Ethyl 3-oxo-2-(2-(substituted phenyl)hydrazono)butanoates 3a-e. General Procedure A. A solution of sodium nitrite (1.035 g, 0.015 mol) in water (15 mL) was added to a stirred ice-cooled solution of the appropriate aniline (0.01 mol) in 5N hydrochloric acid (30 mL). After 10 min, the reaction mixture was rendered alkaline by addition of a saturated solution of sodium acetate. The obtained diazonium solution was then added slowly to a stirred cold slurry of ethyl acetoacetate (1.3 g, 0.01 mol) in ethanol (50 mL) and sodium acetate (1.25 g, 0.015 mol) in water (50 mL). The reaction mixture was stirred at room temperature for 1 h and the solid obtained was collected by filtration, washed with water, dried and crystallized from methanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With pyridine In dichloromethane at 20℃; Inert atmosphere; | 3 2-Methyl-7V-(2-methyl-5-nitrophenyl)propane-2-sulfinamide (SG3-115) 2-Methyl-7V-(2-methyl-5-nitrophenyl)propane-2-sulfinamide (SG3-115): To a solution of 2-methyl-5-nitroaniline (0.152 g, 1 mmol) and pyridine (0.242 mL, 3 mml) in DCM (1 mL) was added a solution of /-butylsulfinyl chloride (0.185 mL, 1.5 mmol) at room temperature under Argon. The mixture was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc (10 mL) and washed with HC1 (1 M aq. solution, 1 x 10 mL), water (1 x 10 mL), and brine (1 x 10 mL). The organic layer was dried (Na2S04) and concentrated under reduced pressure. The resulting residue was purified via column chromatography (S1O2) eluting with hexanes/EtOAc (0: 10 to 4:6 v/v) to give the title compound as a light yellow solid (2.81 g, 81%). Mp: 169 °C (dec). XH NMR (400 MHz, CDCb) δ: 8.02 (d, J= 2.2 Hz, 1H), 7.83 (dd, J= 8.2, 2.2 Hz, 1H), 7.30 (d, J= 8.2 Hz, 1H), 5.37 (s, 1H), 2.36 (s, 3H), 1.39 (s, 9H). HPLC-MS (ESI+): m/z 532.2 [40%, (2M+Na)+], 513.2 [100%, (2M+H)+], 257.2 [40%, (M+H)+]. |
81% | With pyridine In dichloromethane at 20℃; Inert atmosphere; | 2-Methyl-/Y-(2-methyl-5-nitrophenyl)propane-2-sulfinamide (SG3-115): To a solution of 2-methyl-5-nitroaniline (0.152 g, 1 mmol) and pyridine (0.242 mL, 3 mml) in DCM (1 mL) was added a solution of i-butylsulfinyl chloride (0.185 mL, 1.5 mmol) at room temperature under Argon. The mixture was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc (10 mL) and washed with HC1 (1 M aq. solution, 1 x 10 mL), water (1 x 10 mL), and brine (1 x 10 mL). The organic layer was dried (Na2S04) and concentrated under reduced pressure. The resulting residue was purified via column chromatography (S1O2) eluting with hexanes/EtOAc (0: 10 to 4:6 v/v) to give the title compound as a light yellow solid (2.81 g, 81%). Mp: 169 °C (dec). NMR (400 MHz, CDCb) δ: 8.02 (d, / = 2.2 Hz, 1H), 7.83 (dd, / = 8.2, 2.2 Hz, 1H), 7.30 (d, / = 8.2 Hz, 1H), 5.37 (s, 1H), 2.36 (s, 3H), 1.39 (s, 9H). HPLC-MS (ESI+): m/z 532.2 [40%, (2M+Na)+], 513.2 [100%, (2M+H)+], 257.2 [40%, (M+H)+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With dmap; triethylamine In tetrahydrofuran at 70℃; | N, N-Di-tert-butoxycarbonyl-2-methyl-5-nitroaniline(S6) A solution of di-tert-butyl-dicarbonate (4.6mL) was added to a solution of S5(1.522 g, 10 mmol), Et3N(1.67 mL) and 4-(dimethylamino)-pyridin(cat.) in dry THF (50 mL). The mixture was heated to 70 °C and allowed to stirovernight, and the solvent was removed using a rotary evaporator. The residuewas purified by flash column chromatography on silica gel to give compound S6as a yellow solid (2.116 g, 60 %). 1H NMR(400 MHz, DMSO-d6), δ 8.14 (d, 1 H, J = 8.4 Hz), 8.09(s, 1 H), 7.60 (d, 1 H, J = 8.4 Hz), 2.23 (s, 3 H), 1.45 (s, 18 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; XPhos In 1,4-dioxane at 104℃; for 3h; Inert atmosphere; | 14 N-(2-methyl-5-nitrophenyl)-6-(l-(phenylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-5- yl)pyrimidin-4-amine Compound numbers 1 to 6 recited in Example 14 apply only to Example 14. To a solution of 5-(6-chloropyrimidin-4-yl)-l-(phenylsulfonyl)-lH- pyrrolo[2,3-b]pyridine (1.5 g, 4 mmol) in 1,4-Dioxane was added 2-methyl-5- nitroaniline (1.23 g, 8 mmol), Cs2C03(1.4 g, 4.4 mmol), Pd2(dba)3(0.07 g, 0.08 mmol), and 2-dicyclohexylphosphino- 2',4',6'-triipropyl-l, -biphenyl(0.14 g, 0.24 mmol). The resulted mixture was heated at 104 °C for 3 hours under N2. Then it was diluted with EtOAc (1500 mL) at room temperature, washed with water and brine, dried (Na2S04), and concentrated. The residue was purified by a silica gel column to afford (0.81 g, 42%) of the title compound as a slightly yellow solid |
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; XPhos In 1,4-dioxane at 104℃; for 3h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 60℃; | Following the General Procedure of Description 20, tert-butyl (3 )-3-(tert- butoxycarbonylamino)-4-[(2-methyl-5-nitro-phenyl)amino]-4-oxo-butanoate (22a) was prepared from (2R)-4-tert-butoxy-2-(tert-butoxycarbonylamino)-4-oxo-butanoic acid (commercially available or see Example 5 (Variant B)) (1 16 mg, 0.4 mmol), 2-methyl-5- nitro-aniline (61 mg, 0.4 mmol), HATU (228 mg, 0.6 mmol), and DIPEA (210 uL, 155 mg, 1.2 mmol) in anhydrous DMF (1.5 mL) from 0 C? room temperature to 60 C for overnight. Aqueous work-up and purification by silica gel column chromatography using mixtures of ethyl acetate (EtOAc) and hexane (EtOAc/hexane = 1 :4, v/v? EtOAc/hexane = 1 :3, v/v) yielded 123 mg (73% yield) of the title compound (22a) as a dark yellow oil. Rf. -0.74 (EtOAc/Hxn = 1 :2, v/v). 1H MR (300 MHz, CDC13): delta 8.75 (br. s, 1H), 7.90 (dd, J = 8.1, 2.7 Hz, 1H), 7.49 (d, J = 2.4 Hz, 1H), 7.30 (d, J= 8.7 Hz, 1H), 5.97 (br. d, J= 6.9 Hz, 1H), 4.70-4.55 (m, 1H), 2.95 (dd, J = 17.1, 4.5 Hz, 1H), 2.71 (dd, J= 17.1, 6.6 Hz, 1H), 2.36 (s, 3H), 1.48 (s, 9H), 1.47 (s, 9H) ppm. LC/MS: Rt = 2.741 min; ESI (neg.) mlz = 422.0 (M-H+)". |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: 2-methyl-5-nitroaniline With hydrogenchloride; sodium nitrite In water at 0 - 5℃; Stage #2: ferrocene With cetyltrimethylammonim bromide In diethyl ether; water at 0 - 5℃; | 2.2 Synthesis of nitrophenylferrocenes 1a-1b General procedure: The synthesis of the nitrophenylferrocenes 1a-1b was accomplished by adopting the method reported previously by our group with some modifications [29]. Nitroanilines (a-b) (100mmol) were added in small portions to 60mL of 18% aqueous hydrochloric acid solution to form a slurry, while maintaining the temperature at 0-5°C using a salt water-ice bath. A solution of sodium nitrite (100mmol) in 25mL of water was introduced dropwise to the slurry. After complete addition, the reaction mixture was stirred for 45min at low temperature (1a-1b as dark red needles (Scheme 1). |
Stage #1: 2-methyl-5-nitroaniline With hydrogenchloride; sodium nitrite In water at 0 - 5℃; for 0.5h; Stage #2: ferrocene In diethyl ether |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28.8% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 16h;Inert atmosphere; | To a solution under nitrogen gas of compound 510-CN-I-1 (600 mg , 3.797mmol) in 1,4-dioxane (15 ml), compound-3 (578 mg, 3.797mmol) and cesium carbonate (2.148 g, 6.592 mmol) were added. The resulting mixture was degassed 30 min with Argon gas, then Xantphos (440 mg, 0.759 mmol) and Pd2(dba) 3 (348 mg, 0.379 mmol) were added and the reaction mixture was stirred at 100C for 16 h. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned between brine and AcOEt and the aqueous layer was extracted with AcOEt. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a brown oil. The crude compound was purified by flash chromatography using (silica-gel: 100-200 mesh, AcOEt - petroleum ether; 70%) to give 0.3 g (yield 28.8%) of a pale yellow solid corresponding to 4- methoxy-6-methyl-N-(2-methyl-5-nitrophenyl)pyrimidin-2-amine. Mass: (ES+) C13H14N4O3 required 274.11; found 275.1 [M+H], HPLC/MS method 8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 100℃; for 4h; Inert atmosphere; | Synthesis of N-(2-methyl-5-nitrophenyl)-4-(pyridin-3-yl)pyrimidin-2-amine, intermediate 512-CN-I- To a solution under nitrogen gas of compound 512-CN-I-1 (300 mg , 1.648mmol) in 1,4-dioxane (10 ml), 2-amino-4-nitrotoluene (159 mg, 1.648mmol) and cesium carbonate (1.074 g, 3.296 mmol) were added. The resulting mixture was degassed 30 min with Argon gas, then Xantphos (191 mg, 0.329 mmol) and Pd2(dba)3 (151 mg, 0.1648 mmol) were added and the resulting reaction mixture was stirred at 100°C for 4 h. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned between brine and AcOEt and the aqueous layer was extracted with AcOEt. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a brown oil. The crude compound was purified by flash chromatography using (silica-gel: 100-200 mesh, AcOEt -petroleum ether; 70%) to give 0.3 g (yield 61%) of a pale yellow solid corresponding to 4,6-dimethyl-N-(2-methyl-5-nitrophenyl)furo[2,3-d]pyrimidin-2-amine. Mass: (ES+) C15H14N4O3 required 298.11; found 299.1 [M+H], HPLC/MS method 8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.3% | With potassium carbonate; sodium iodide In acetone at 50℃; for 24h; | 1.2 Step 1-2: N-((2,4-dichloropyrimidin-5-yl) methyl)-2-methyl-5-nitroaniline 2,4-Dichloro-5-(chloromethyl)pyrimidine (2.4 g, 12.2 mmol) and 2-methyl-5-nitroaniline (1.48 g, 9.76 mmol) were dissolved in acetone (12 mL), then sodium iodide (2.2 g, 14.6 mmol) and potassium carbonate (2.5 g, 18.3 mmol) were added, and the mixture was stirred at 50° C. for 24 hours. When the reaction was completed, the mixture was cooled to room temperature and filtered using a celite pad. The filtrate was extracted with dichloromethane and water. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography to obtain the desired compound (2.83 g, 74.3%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 7.42 (dd, J=2 Hz, J=8 Hz, 1H), 7.26 (d, J=8 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 6.23 (t, J=5.6 Hz, 1H), 4.50 (d, J=5.6 Hz, 2H), 2.25 (s, 3H). |
74% | With potassium carbonate; sodium iodide In acetone at 50℃; for 10h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium iodide; In acetonitrile; for 168h;Reflux; | General procedure: To a stirred solution of diol 10 (12.5 mmol) in anhydrous CH2Cl2 (50 mL) was added thionyl chloride (2.5 mL, 34.7 mmol) dropwise. The mixture was heated at reflux for 1 h. The reaction was concentrated and the residue was diluted with MeCN (200 mL). To this was then added KI (100 mg, 0.62 mmol) followed by nitroaniline (13 mmol), and the resulting mixture was refluxed for 7 days. The reaction was concentrated and the crude product was used for next reaction without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Stage #1: 2-methyl-5-nitroaniline With hydrogenchloride; sodium nitrite In water at 0 - 5℃; for 0.166667h; Stage #2: cyclohexanone-2-carboxamide In water; acetic acid at 0 - 20℃; for 0.25h; | Synthesis of compounds 6a-j (General method) General procedure: The appropriate amine (0.01 mol) was dissolved in a mixture ofwater (5 ml) and concd HCl (6 ml). The solution wasvigorously stirred, cooled with ice, and treated by theaddition of anhydrous NaNO2 (0.69 g, 0.01 mol). Asolution of carboxamide 5 (1.41 g, 0.01 mol) in glacialacetic acid (20 ml) was added to the stirred and cooledsolution of the obtained diazonium salt. The reactionmixture was stirred for 15 min, then adjusted with 15%NaOH solution to neutral pH, and the obtained precipitatewas filtered off. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: 2-methyl-5-nitroaniline With hydrazine In ethanol at 50 - 78℃; for 0.75h; Green chemistry; Stage #2: With hydrogenchloride Green chemistry; | Reduction of nitroarylaminopyrimidines 6-8 and nitroanilines 1, 9, 10. b. To a suspension of 0.5 mM of nitro derivative in 1 mL of ethanol, the Ni/Co or PVP(Ni/Co) sol (0.05 mmol in 1 mL of ethanol) was added under stirring and heating to 50°C. After 5-7 min, 0.18 mL of hydrazine hydrate (3.5 mmol, 5 equiv.) was added. The reaction mixture was refluxed for 0.3-0.75 h (TLC control). Upon completion of the reaction, warm reaction mixture was filtered through Celite, washed with ethanol, and the combined filtrate was evaporated. The residue was dissolved in 10 mL of ethyl acetate, washed with water, evaporated to reduce by 2/3 its original volume, and the product was pre-cipitated by the addition of petroleum ether. To isolate the products of reduction of compounds 1, 9, and 10, the filtrate was acidified with 0.4 mL of concentrated HCl to pH 1. The dihydrochloride precipitated was washed with dilute HCl (1 : 1), dried, and recrystallized from a methanol-hexane mixture. |
82% | Stage #1: 2-methyl-5-nitroaniline With hydrazine hydrate In ethanol at 50℃; Reflux; Green chemistry; Stage #2: With hydrogenchloride In ethanol; water Green chemistry; | Reduction of nitroarenes 1 and 2 (general procedure). General procedure: A suspension of 0.5 mmol of nitro compound 1 or 2 in 1 mL of ethanol was heated to 50°C, 0.05 mmol of Ni/Co nanocatalyst in 1 mL of ethanol was added with stirring, the mixture was stirred for 5-7 min, and 0.18 mL (3.5 mmol, 5 equiv) of hydrazine hydrate was added dropwise. The mixture was refluxed for 20-45 min, the progress of the reaction being monitored by TLC. When the reaction was complete, the warm mixture was filtered through a layer of celite, the sorbent was washed with ethanol, and the filtrate was combined with the washings and evaporated. The residue was dissolved in 10 mL of ethyl acetate, the solution was washed with water and evaporated to 1/3 of the initial volume, and the product was precipitated with petroleum ether. In the isolation of compound 3, the filtrate was acidified with 0.4 mL of concentrated aqueous HCl to pH 1, and the precipitate of 4-methylbenzene-1,3-diamine dihydrochloride was filtered off, washed with dilute (1 : 1) aqueous HCl, dried, and recrystallized from methanol-hexane. 4-Methylbenzene-1,3-diamine dihydrochloride (3). Yield 82%, white crystals, mp >200°C (decomp.). IR spectrum (KBr), ν, cm-1: 3300, 2980 (NH), 1612,1580, 1475, 1200, 1190. Mass spectrum, m/z (Irel, %): 122.05 (100), 108.02 (52) [M - CH3]+, 78.01 (26), 51 (15). Found, %: C 43.00; H 6.22; Cl 36.37; N 14.35. C7H12Cl2N2. Calculated, %: C 43.10; H 6.20; Cl 36.35; N 14.36. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: 2-methyl-5-nitroaniline With hydrogenchloride; sodium nitrite In water at 20℃; for 0.333333h; Stage #2: β-naphthol In water at 20℃; for 0.166667h; | 25 A method for synthesizing C.I. Pigment Orange 3 by one-pot method promoted by solid particles, the steps are as follows: 10 g of polytetrafluoroethylene particles (about 70 mg/particle) and 2.107 g (3 molar equivalents) of hydrochloric acid were added to the reaction vessel.(36%), 1.161 g (1.1 molar equivalents) of 2-methyl-5-nitroaniline, 0.550 g (1.15 molar equivalents) of sodium nitrite, 5 mLWater, using a modified mechanical stirring paddle for 20 minutes at room temperature, using a thin plate chromatography to detect the complete conversion of 2-methyl-5-nitroaniline1.00 g (1 molar equivalent) of 2-naphthol was added, and stirring was continued at room temperature. After 10 minutes of reaction, the reaction was confirmed by thin-plate chromatography.Into, filter and rinse with 2mL water, filter cake dried to obtain 2.100g C.I. Pigment Orange 3, reaction mother liquor and rinse solution for next timerecycle. The product yield is greater than 99%. |
99% | Stage #1: 2-methyl-5-nitroaniline With hydrogenchloride; sodium nitrite In water at 20℃; for 0.333333h; Green chemistry; Stage #2: β-naphthol In water at 20℃; for 0.166667h; Green chemistry; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With triethylamine In chloroform at 20℃; | Step 2 (synthesis of benzamide). General procedure: To a solution of chloroanhydride in dry CHCl3 was addedamine R2NH2 (one equivalent) and Et3N (1.5 equivalents). The reaction mixture was stirred atroom temperature. The reaction progress was monitored by TLC. Cold water was added to thereaction mixture. The organic layer was separated from the water. The combined organic layers weredried over Na2SO4, filtered, and concentrated under vacuum. The product was purified by columnchromatography on silica gel. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With triethylamine In chloroform at 20℃; | Step 2 (synthesis of benzamide). General procedure: To a solution of chloroanhydride in dry CHCl3 was addedamine R2NH2 (one equivalent) and Et3N (1.5 equivalents). The reaction mixture was stirred atroom temperature. The reaction progress was monitored by TLC. Cold water was added to thereaction mixture. The organic layer was separated from the water. The combined organic layers weredried over Na2SO4, filtered, and concentrated under vacuum. The product was purified by columnchromatography on silica gel. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 50% 2: 50% | With nickel-nitrogen-doped carbon framework In water at 145℃; for 18h; Inert atmosphere; Sealed tube; Green chemistry; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58.8% | With hydrogenchloride In water; isopropyl alcohol at 80℃; | 11 (9) 5-Chloro-N4-(2-isopropoxy-5-methyl-4-piperidine-phenyl)-N2-(2-methyl-5-nitrophenyl)pyrimidine-2, 4-diamine(CR-B9) Synthesis method: Weigh 1mmol (495.20mg) Intermediate b and 1.5mmol (228.23mg) 2-methyl-5-nitroaniline in a 25ml round-bottomed flask, add an appropriate amount of isopropanol as a solvent, and then add a catalytic amount (about 1%) concentrated hydrochloric acid, the reaction was continued overnight at 80°C. TLC monitors the progress of the reaction. After the reaction is complete, cool the reaction solution to room temperature, add a small amount (about 5 drops) of trifluoroacetic acid, stir at room temperature for 1 hour, and precipitate the corresponding solid, filter to remove the solvent to collect the solid, wash with water several times, and vacuum dry to obtain the target product CR -B9. The yield was 58.8%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In 1,4-dioxane at 90 - 110℃; for 27h; | Ethyl 6-bromo-4-((4-methyl-3-nitrophenyl)amino)quinoline-3-carboxylate (3a) General procedure: Ethyl 6-bromo-4-chloro-3-quinolinecarboxylate 2 (800 mg; 2.543 mmol) and 4-methyl-5- nitroaniline (387 mg; 2.543 mmol) were mixed in dioxane (15 ml_) and heated to 90°C. After 7 h, TLC analysis (50% EtOAc/Hexane) no longer detected starting materials. The yellow suspension was cooled to r.t., diluted with H20 and NaOH (1 M) added until pH = 8 was reached. EtOAc was added and the phases were separated. The aqueous phase was further extracted with EtOAc (2 x) and the combined organics were washed with brine and dried over MgS04. After filtration, the solvent was evaporated to afford the title compound as a bright-yellow solid (980 mg; 90% yield). 1H NMR (300 MHz, CDCIs): d 10.38 (s, 1 H), 9.29 (s, 1 H), 7.90 (d, J = 9.4 Hz, 1 H), 7.74 (dq, J = 4.3, 2.2 Hz, 2H), 7.65 (d, J = 2.5 Hz, 1 H), 7.25 (d, J = 8.3 Hz, 1 H), 7.08 (dd, J = 8.3,2.5 Hz, 1 H), 4.45 (q, J = 7.1 Hz, 2H), 2.58 (s, 3H), 1.46 (t, J = 7.1 Hz, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Stage #1: formaldehyd; 2-methyl-5-nitroaniline With sodium methylate In methanol at 20℃; for 12h; Inert atmosphere; Stage #2: With sodium tetrahydroborate In methanol at 20℃; for 12h; Inert atmosphere; | 22.1 Dissolve 22a (3.04g, 20.00mmol), paraformaldehyde (2.40g, 80.00mmol), sodium methoxide (540mg, 10.00mmol) in methanol (100mL), replace with nitrogen three times, stir at room temperature for 12 hours, and then add Sodium borohydride (1.52g, 40.00mmol), replaced with nitrogen three times, stirred at room temperature for 12 hours, directly concentrated under reduced pressure to obtain a residue, and the residue was purified by column chromatography (ethyl acetate: petroleum ether=0-100%) 22b (2.00g), yield: 60%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With pyridinium p-toluenesulfonate In methanol for 1.5h; Reflux; | Synthesis of aminochromanes 2 (general procedure). General procedure: A mixture of2-piperidinochromane 1a-d (0.5 mmol), aromatic amine (0.5 mmol) andPPTS (125 mg, 0.5 mmol) in DCE (for products 2a,j,l-n), MeOH-DCE(2 : 1) (for 2v) or MeOH (4 ml) was stirred under reflux for 1.5 h. Whenthe reaction was complete, the mixture was stored at -30 °C for 1 h, thesolid was filtered off, washed with ice-cold MeOH (2 × 3 ml) and purifiedby recrystallization from a suitable solvent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 16h; | 5.1.17 (5-bromo-N-(2-methyl-5-nitrophenyl)nicotinamide) ) A solution of 2-methyl-5-nitroaniline (1.52g, 10.0mmol), 5-bromonicotinic acid (2.02g, 10.0mmol), EDC (2.11g, 11.0mmol) and DMAP (1.83g, 15.0mmol) in DMF (20mL) was stirred at rt for 16h. After concentrating in vacuo the residue was purified by flash column chromatography (DCM - 10% MeOH in DCM) to obtain the product as a white solid (2.00g, 59%). 1H NMR (400MHz, DMSO-d6): δ=10.40 (s, 1H), 9.10 (d, 1H, J=1.7Hz), 8.94 (d, 1H, J=2.0Hz), 8.57 (s, 1H), 8.38 (d, 1H, J=2.1Hz), 8.06 (dd, 1H, J=2.2, 8.4Hz), 7.59 (d, 1H, J=8.4Hz), 2.41 (s, 3H); 13C NMR (101MHz, DMSO-d6): δ=163.1, 153.0, 147.5, 145.7, 141.6, 138.0, 136.7, 131.6, 131.4, 120.7, 120.6, 120.0, 18.2; ESI-HRMS: m/z calculated for C13H10BrN3NaO3: 357.9803; found: 357.9799 [M+Na]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.6% | With sodium hydroxide In methanol; water at 45 - 50℃; for 5h; | 1 Comparative example 1 This comparative example is a synthesis using chloramidine hydrochloride as a raw material, indicating that the yield and purity of the product obtained by this method are both poor.In a clean reaction flask, add 100ml of methanol and 15.2g of 2-amino-4-nitrotoluene, stir and dissolve, then add 17.25g of chloroformamidine hydrochloride and 60g of sodium hydroxide aqueous solution with a mass percentage of 30% , Then, heat to 4550 for 5h to keep the reaction temperature, control, HPLC test purity 70.2%, 2-amino-4-nitrotoluene residue is 1.5%, after the reaction is over, reduce Pressure distillation to remove methanol, then add 200ml of water, stir at room temperature for 2h, filter, collect the solid wet product, and dry to obtain the corresponding product 2-methyl-5-nitrophenylguanidine 18.5g, purity content 72%, mole The yield was 68.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Stage #1: oxalyl dichloride; 2-methyl-5-nitroaniline With potassium carbonate In dichloromethane at 0℃; for 0.166667h; Stage #2: (R)-1-(1-Naphthyl)ethylamine In dichloromethane at 0℃; for 0.25h; | 19; 20 N1-(2-Methyl-5-nitrophenyl) N2-(R)-(1-(naphthalen-1-yl)ethyl)oxalamide A solution of 2-methyl-5-nitroaniline (101 mg, 0.66 mmol) in CH2CI2 (3 mL) was added to a stirred solution of oxalyl chloride (0.17 mL, 1.98 mmol) and K2CO3 (0.273 g, 1.98 mmol) in CH2CI2 (3 mL) at 0 °C. After 10 min the reaction mixture was concentrated under vacuum and dissolved in CH2CI2 (12 mL) followed by addition of (R)-(+)-1-(1-naphthyl)ethylamine (0.11 mL, 0.69 mmol) at 0 °C. The reaction mixture was stirred for 15 min then diluted with EtOAc and washed with 1 N HCI and brine. The organic layer was dried with Na2SO4, filtered, and concentrated. The crude residue was adsorbed on CELITE and purified over silica gel eluting with 70% to 100% CH2CI2 in hexanes to give the title compound (0.151 g, 0.40 mmol, 60%) as a white solid. [a]D23 = -59.71 (c = 0.07, CHCI3), 1H NMR (500 MHz, CDCl3) δ 9.42 (s, 1 H, NH), 8.99 (d, J = 2.4 Hz, 1 H, H-6'), 8.07 (d, J = 8.5 Hz, 1 H, H-9'"), 7.95 (dd, J = 8.4, 2.4 Hz, 1 H, H-4'), 7.90 - 7.85 (m, 2H, NH', H-4'"), 7.82 (d, J = 8.2 Hz, 1 H, H-6'"), 7.59 - 7.54 (m, 2H, H-2'", H-3'"), 7.53 - 7.44 (m, 2H, H-7'", H-8'"), 7.34 (d, J = 8.4 Hz, 1 H, H-3'), 5.93 (qd, J = 6.9, 6.9, 1.6 Hz, 1 H, H- 1”), 2.42 (s, 3H, H-7'), 1.77 (d, J = 6.9 Hz, 3H, H-2"). 13C NMR (126 MHz, CDCl3) δ 158.5 (C-2), 157.7 (C-1), 147.1 (C-5'), 137.1 (C-1'"), 135.4 (C-1'), 135.2 (C-2'), 134.1 (C-5'"), 131.2 (C-3'), 130.8 (C-10'"), 129.2 (C-4'"), 128.9 (C-6'"), 126.8 (C-3'"), 126.1 (C-8'"), 125.4 (C-7'"), 122.8 (C- 2'"), 122.8 (C-9'"), 120.2 (C-4'), 115.9 (C-6'), 46.0 (C-1"), 21.1 (C-2"), 17.8 (C-7'). HRMS (ESI) m/z: Calcd for C21H19N3O4Na [M+Na]+ 400.1269; Found 400.1263. |
60% | Stage #1: oxalyl dichloride; 2-methyl-5-nitroaniline With potassium carbonate In dichloromethane at 0℃; for 0.166667h; Stage #2: (R)-1-(1-Naphthyl)ethylamine In dichloromethane at 0℃; for 0.25h; | 19; 20 N1-(2-Methyl-5-nitrophenyl) N2-(R)-(1-(naphthalen-1-yl)ethyl)oxalamide A solution of 2-methyl-5-nitroaniline (101 mg, 0.66 mmol) in CH2CI2 (3 mL) was added to a stirred solution of oxalyl chloride (0.17 mL, 1.98 mmol) and K2CO3 (0.273 g, 1.98 mmol) in CH2CI2 (3 mL) at 0 °C. After 10 min the reaction mixture was concentrated under vacuum and dissolved in CH2CI2 (12 mL) followed by addition of (R)-(+)-1-(1-naphthyl)ethylamine (0.11 mL, 0.69 mmol) at 0 °C. The reaction mixture was stirred for 15 min then diluted with EtOAc and washed with 1 N HCI and brine. The organic layer was dried with Na2SO4, filtered, and concentrated. The crude residue was adsorbed on CELITE and purified over silica gel eluting with 70% to 100% CH2CI2 in hexanes to give the title compound (0.151 g, 0.40 mmol, 60%) as a white solid. [a]D23 = -59.71 (c = 0.07, CHCI3), 1H NMR (500 MHz, CDCl3) δ 9.42 (s, 1 H, NH), 8.99 (d, J = 2.4 Hz, 1 H, H-6'), 8.07 (d, J = 8.5 Hz, 1 H, H-9'"), 7.95 (dd, J = 8.4, 2.4 Hz, 1 H, H-4'), 7.90 - 7.85 (m, 2H, NH', H-4'"), 7.82 (d, J = 8.2 Hz, 1 H, H-6'"), 7.59 - 7.54 (m, 2H, H-2'", H-3'"), 7.53 - 7.44 (m, 2H, H-7'", H-8'"), 7.34 (d, J = 8.4 Hz, 1 H, H-3'), 5.93 (qd, J = 6.9, 6.9, 1.6 Hz, 1 H, H- 1”), 2.42 (s, 3H, H-7'), 1.77 (d, J = 6.9 Hz, 3H, H-2"). 13C NMR (126 MHz, CDCl3) δ 158.5 (C-2), 157.7 (C-1), 147.1 (C-5'), 137.1 (C-1'"), 135.4 (C-1'), 135.2 (C-2'), 134.1 (C-5'"), 131.2 (C-3'), 130.8 (C-10'"), 129.2 (C-4'"), 128.9 (C-6'"), 126.8 (C-3'"), 126.1 (C-8'"), 125.4 (C-7'"), 122.8 (C- 2'"), 122.8 (C-9'"), 120.2 (C-4'), 115.9 (C-6'), 46.0 (C-1"), 21.1 (C-2"), 17.8 (C-7'). HRMS (ESI) m/z: Calcd for C21H19N3O4Na [M+Na]+ 400.1269; Found 400.1263. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With pyridine In dichloromethane at 0 - 20℃; for 0.333333h; | 19; 20 N--(2-Methyl-5-nitrophenyl)-2-(naphthalen-1-yl)acetamide 2-Methyl-5-nitroaniline (3.0 g, 19.7 mmol) was dissolved in pyridine (4 mL) and anhydrous CH2CI2 (4 mL) and reaction mixture was cooled down to 0 °C before 2-(naphthalen-1-yl)acetyl chloride2 (3.6 mL, 21.7 mmol) was added dropwise. The reaction mixture then was allowed to warm up to 20 °C and was stirred for 20 min before MeOH (10 mL) was added and the precipitate was filtered off. The precipitate was washed with MeOH (30 mL) and suspended hot EtOH (30 mL) giving a slightly yellow suspension. The white precipitate was filtered off, washed with EtOH (3x30 mL) and dried in vacuo to give the title compound as a white solid (4.5 g, 70%). Rf 0.38 (hexanes : EtOAc 7 : 3 (v/v); UV). 1H NMR (500 MHz, DMSO-d6) δ 9.89 (s, 1 H, CONH), 8.46 (d, J = 2.5 Hz, 1 H, H-6”), 8.17 (d, J = 8.3 Hz, 1 H, H-8”), 8.02 - 7.77 (m, 3H, H-2', H-4”, H- 7'), 7.61 - 7.25 (m, 5H, H-3”, H-3', H-4', H-5', H-6' ), 4.28 (s, 2H, -CH2CO), 2.35 (s, 3H, -CH3). 13C NMR (126 MHz, DMSO-c/6) 5 169.8 (C-1), 145.7 (C-5”), 138.9 (C-1”), 137.2 (C-4a'), 133.4 (C-1'), 132.2 (C-8a'), 132.0 (C-3”), 131.4 (C-2”), 128.5 (C-4'), 127.3 (C-5'), 126.1 (C-2'), 125.7 (C-7'), 125.6 (C-6'), 124.1 (C-8'), 119.3 (C-6”), 118.3 (C-4”), 40.1 (C-2), 18.1 (CH3). HRMS (ESI) m/z: Calcd for C19H16N2NaO3 [M+Na]+ 343.1059; Found 343.1044. |
70% | With pyridine In dichloromethane at 0 - 20℃; for 0.333333h; | 19; 20 N--(2-Methyl-5-nitrophenyl)-2-(naphthalen-1-yl)acetamide 2-Methyl-5-nitroaniline (3.0 g, 19.7 mmol) was dissolved in pyridine (4 mL) and anhydrous CH2CI2 (4 mL) and reaction mixture was cooled down to 0 °C before 2-(naphthalen-1-yl)acetyl chloride2 (3.6 mL, 21.7 mmol) was added dropwise. The reaction mixture then was allowed to warm up to 20 °C and was stirred for 20 min before MeOH (10 mL) was added and the precipitate was filtered off. The precipitate was washed with MeOH (30 mL) and suspended hot EtOH (30 mL) giving a slightly yellow suspension. The white precipitate was filtered off, washed with EtOH (3x30 mL) and dried in vacuo to give the title compound as a white solid (4.5 g, 70%). Rf 0.38 (hexanes : EtOAc 7 : 3 (v/v); UV). 1H NMR (500 MHz, DMSO-d6) δ 9.89 (s, 1 H, CONH), 8.46 (d, J = 2.5 Hz, 1 H, H-6”), 8.17 (d, J = 8.3 Hz, 1 H, H-8”), 8.02 - 7.77 (m, 3H, H-2', H-4”, H- 7'), 7.61 - 7.25 (m, 5H, H-3”, H-3', H-4', H-5', H-6' ), 4.28 (s, 2H, -CH2CO), 2.35 (s, 3H, -CH3). 13C NMR (126 MHz, DMSO-c/6) 5 169.8 (C-1), 145.7 (C-5”), 138.9 (C-1”), 137.2 (C-4a'), 133.4 (C-1'), 132.2 (C-8a'), 132.0 (C-3”), 131.4 (C-2”), 128.5 (C-4'), 127.3 (C-5'), 126.1 (C-2'), 125.7 (C-7'), 125.6 (C-6'), 124.1 (C-8'), 119.3 (C-6”), 118.3 (C-4”), 40.1 (C-2), 18.1 (CH3). HRMS (ESI) m/z: Calcd for C19H16N2NaO3 [M+Na]+ 343.1059; Found 343.1044. |
Tags: 99-55-8 synthesis path| 99-55-8 SDS| 99-55-8 COA| 99-55-8 purity| 99-55-8 application| 99-55-8 NMR| 99-55-8 COA| 99-55-8 structure
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