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CAS No. : | 2620-50-0 | MDL No. : | MFCD00005840 |
Formula : | C8H9NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ZILSBZLQGRBMOR-UHFFFAOYSA-N |
M.W : | 151.16 | Pubchem ID : | 75799 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.25 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 40.18 |
TPSA : | 44.48 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.66 cm/s |
Log Po/w (iLOGP) : | 1.71 |
Log Po/w (XLOGP3) : | 0.79 |
Log Po/w (WLOGP) : | 0.72 |
Log Po/w (MLOGP) : | 0.61 |
Log Po/w (SILICOS-IT) : | 1.51 |
Consensus Log Po/w : | 1.07 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.61 |
Solubility : | 3.69 mg/ml ; 0.0244 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.31 |
Solubility : | 7.49 mg/ml ; 0.0495 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.18 |
Solubility : | 1.0 mg/ml ; 0.00664 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.84 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With nickel(II) tetrafluoroborate hexahydrate; ammonia; hydrogen; bis(2-diphenylphosphinoethyl)phenylphosphine In 2,2,2-trifluoroethanol at 100℃; for 24h; chemoselective reaction; | |
89% | With ammonia; hydrogen In <i>tert</i>-butyl alcohol at 120℃; for 15h; | |
72% | With ammonium formate In toluene at 80℃; for 3h; Inert atmosphere; chemoselective reaction; |
With methanol; ammonia; nickel at 60℃; Hydrogenation; | ||
With ammonium formate at 180℃; | ||
Multi-step reaction with 2 steps 1: hydroxylamine hydrochloride; sodium carbonate / ethanol / 20 °C 2: palladium 10% on activated carbon; hydrogen / ethanol / 20 °C | ||
Multi-step reaction with 2 steps 1: hydroxylamine hydrochloride; sodium hydroxide / ethanol; water / 2 h / 60 °C 2: palladium(II) hydroxide; hydrogen / ethanol / 6 h / 30 - 60 °C | ||
With ammonium hydroxide; hydrogen at 120℃; for 20h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With triethylamine In tetrahydrofuran at 0℃; Inert atmosphere; | 3 4.2.2 General procedure B: Synthesis of substituted chloroacetamides (26-28) [47] General procedure: To a mixture of amine (1 eq.) and TEA (1.2 eq.) in dry THF was added chloroacetyl chloride (1.1 eq.) dropwise at 0°C. After completion of reaction, triethylammonium chloride was filtered off and the filtrate was concentrated under vacuum and quenched with water. The solid obtained was filtered at suction and washed to neutral filtrate, air dried and used without any further purification. |
85% | With triethylamine In tetrahydrofuran at 0 - 20℃; Inert atmosphere; | General procedure B: synthesis of substituted chloroacetamides (39-43) General procedure: To a mixture of substituted amine (1 eq.) and TEA (1.2 eq.) in dry THF chloroacetyl chloride (1.1 eq.) was added dropwise at 0°C. After completion of reaction, triethylammonium chloride was filtered off and the filtrate was concentrated under vacuum and quenched with water. The solid obtained was filtered at suction and washed to neutral filtrate, air dried and used without any further purification. |
With sodium carbonate |
With triethylamine In acetonitrile at 20℃; for 1h; | ||
With triethylamine In dichloromethane at 0 - 20℃; for 25h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With copper(I) chloride; 4 A molecular sieve; oxygen In pyridine at 60℃; for 24h; | |
97% | With dmap; copper(l) iodide; 9-azabicyclo[3.3.1]nonane N-oxyl; oxygen; 4,4'-di-tert-butyl-2,2'-bipyridine In acetonitrile at 20℃; for 15h; | |
93% | With ammonium hydroxide; oxygen In tert-Amyl alcohol at 110℃; for 15h; Autoclave; Green chemistry; |
90% | With 2,2,6,6-tetramethyl-piperidine-N-oxyl; free radical; trichloroisocyanuric acid In dichloromethane at 10℃; for 2h; | |
85% | With 2,6-dimethylpyridine; 2,2,6,6-tetramethyl-piperidine-N-oxyl; lithium perchlorate In acetonitrile at 23℃; electrolysis, a platinum gauze electrode, +0.33 V (vs. Ag/Ag(1+)); | |
81% | With sodium bromide In methanol at 10℃; electrooxidation (0.3 A, 75 mA/cm2, 5-7 V) 6.4 F/mol; | |
81% | With pyridine; Oxone; 4-acetylamino-2,2,6,6-tetramethyl-1-piperidinoxy; Pyridine hydrobromide In dichloromethane at 20℃; for 12h; Green chemistry; | |
77% | With tetrabutylammomium bromide; 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In acetonitrile at 20℃; for 0.0833333h; Inert atmosphere; Molecular sieve; | |
With pyridine; copper(l) iodide; oxygen at 60℃; for 24h; mol. sieves; Yield given; | ||
96 %Chromat. | With ammonium hydroxide; oxygen In tert-Amyl alcohol at 110℃; for 15h; Autoclave; Green chemistry; | |
> 99 %Chromat. | With C68H64Cl2N6P2Ru2(4+)*2F6P(1-)*2Cl(1-); caesium carbonate In N,N-dimethyl-formamide at 100℃; for 24h; Inert atmosphere; Green chemistry; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; | Example 65 4-(3,4-Methylenedioxybenzyl)amino-6-cyanoquinazoline STR126 15 ml of isopropyl alcohol, 75 mg of triethylamine and 125 mg of piperonylamine were added to 140 mg of <strong>[150449-97-1]4-chloro-6-cyanoquinazoline</strong>. The obtained mixture was heated under reflux for 5 hours and filtered to recover a precipitate. This precipitate was introduced to a silica gel column, followed by eluding with ethyl acetate to give 200 mg of the title compound. molecular formula; C17 H12 N4 O2 yield (%); 89 m.p. (C.); 243~244 Mass; 305 (M+1)+ NMR delta (DMSO-d6); 4.67 (2H, d, J=5.6Hz), 5.96 (2H, s), 6.84 (2H, s), 6.95 (1H, s), 7.77 (1H, d, J=8.4Hz), 8.56 (1H, s), 8.89 (1H, s), 9.04 (1H, br) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 85% 2: 5% | With sodium tetrahydroborate; nickel dichloride In ethanol at 20℃; for 0.0833333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: (R)-3-tert-butoxycarbonyl-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid With triethylamine; chlorophosphoric acid diphenyl ester In ethyl acetate at 20℃; for 1h; Stage #2: 1,3-benzodioxol-5-ylmethyl amine With triethylamine In ethyl acetate at 20℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With lithium aluminium tetrahydride In diethyl ether for 2h; Reflux; | 128 Example 128: 3-[(2H-l,3-benzodioxol-5-yl)methyl]-l-[(2,4- difluorophenyl)methyl] - 1 -( 1 -methylpiperidin-4-yl)urea (128) 2H-l,3-benzodioxole-5-carbonitrile (1.73 g, 11.75 mmol) in diethyl ether (15 ml) was added portion wise to a mixture of lithium aluminiumhydride (55.2 mmol hydride, 13.8 mmol, 525 mg) in diethyl ether (15 ml). The mixture was refluxed for 2 hours, then cooled and worked up (H20, 15 % NaOH, 3 x H20) and gave crude benzyl amine (1.77 g, quant.). This amine (1.0 g, 6.6 mmol) and pyridine (1.1 equiv., 17.6 mmol, 1.43 ml) was dissolved in dichloromethane (5.0 ml) and added dropwise to an ice cooled mixture of triphosgene (2.7 mmol, 801 mg,) in dichloromethane (5.0 ml). The mixture was stirred for 1 hour, then partitioned between cold 0.5 M sulfuric acid and dichloromethane. The organic phase was separated, dried and evaporated to give crude 5-(isocyanatomethyl)-2H-l,3-benzodioxole (1.08 g, 92 % yield). (0987) [00644] N-[(2,4-difluorophenyl)methyl]-l-methylpiperidin-4-amine (250 mg, 1.01 mmol) was dissolved in dichloromethane (1 ml) and 5-(isocyanatomethyl)-2H-l,3-benzodioxole (215 mg, 1.21 mmol) in dichloromethane (1 ml) was added in one portion. The mixture was stirred at room temperature for 1 hour and then purified by column chromatography using silicon dioxide gel, eluting with methanol to afford the title compound (275 mg, 66 % yield): NMR (400 MHz, Chloroform-;/) δ 7.21 (q, 1H), 6.87 - 6.73 (m, 2H), 6.73 - 6.59 (m, 3H), 5.92 (s, 2H), 4.57 (t, 1H), 4.40 (s, 2H), 4.29 (d, 2H), 4.26 (m, 1H), 2.88 (d, 2H), 2.27 (s, 3H), 2.07 (m, 2H), 1.75- 1.60 (m, 4H); LC-MS : 418.2 [M+H]+. |
95% | With ammonia; hydrogen In water; isopropyl alcohol at 110℃; for 24h; Autoclave; | |
91% | With ammonia; hydrogen In toluene at 120℃; for 16h; Autoclave; |
88.5% | With aluminum (III) chloride; lithium aluminium tetrahydride In di-isopropyl ether at -5 - 0℃; for 10h; | 1 Preparation of 3,4-methylenedioxybenzylamine: 300 ml of anhydrous isopropyl ether was added to a 250 ml three-necked flask, cooled to -5 ° C to 0 ° C, 12 g (90 mmol) of aluminum trichloride and 5.2 g (136 mmol) of lithium aluminum hydride were added, A mixed solution of 10 g (68 mmol) of 3,4- (methylenedioxy) benzonitrile and 300 ml of isopropyl ether was added dropwise at -5 ° C to 0 ° C.The reaction mixture was stirred for 10 hours and quenched with methanol at 0 ° C.The reaction mixture was basified with 1 M NaOH aqueous solution and extracted with ethyl acetate.The organic layer was combined, washed with water and saturated sodium hydrogencarbonate solution, and the organic layer was dried over anhydrous magnesium sulfate. The ethyl acetate was distilled off under reduced pressure and the vacuum pump was distilled under reduced pressure |
62% | With C46H49CoN3P4(2+)*2BF4(1-); potassium <i>tert</i>-butylate; hydrogen In isopropyl alcohol at 90℃; for 16h; | |
With lithium aluminium tetrahydride; aluminium trichloride In diethyl ether at 20℃; for 5h; | ||
With ammonia; hydrogen In methanol at 20℃; for 12h; | ||
With nitrile reductase (Bac-2 over expressed in E.coli BL21) In aq. phosphate buffer; dimethyl sulfoxide at 37℃; for 24h; Microbiological reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In benzene for 1h; Heating / reflux; | 22 [1- (3, 4-METHYLENEDIOXYPHENYL)-3- (3,] 4-methylenedioxyphenethyl) urea (compound 78B; DC-0078B) A solution [OF 3, 4-MEDIYLENEDIOXYPHENYLETHYLAMINE] (0.25 g, 1.5 mmol) and 3, 4-methylenedioxy- phenyl isocyanate (0.25 g, 1.5 mmol) in benzene [(25] ml) was refluxed for 1 hour. The precipitate formed was filtered, washed with benzene then dried to give pure DC-0078B (0.43 g, [85%)] as a pale brown solid. 1H-NMR ((CD3)2CO) 7.83 [(1H,] bs), 7.31 [(1H,] d, [J] [2HZ),] 6. [72-6.] 82 (5H, m), 5.99 (2H, s), 5.95 (2H, s), 5.68 [(1H,] [BT,] J 7Hz), 3.44 (2H, q, [J 7HZ), AND2.] 74 (2H, t, [J] 7Hz). [M/Z 327 ( (M-1)] +, [100%).] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; | EXAMPLE 1 3.02 g of 3,4-methylenedioxybenzylamine ("A") are added to a solution of 3.29 g of <strong>[76872-23-6]2,4-dichloro-6-methylthieno[2,3-d]pyrimidine</strong> in 80 ml of dichloro-methane, and, after 1.52 g of triethylamine have been added, the mixture is stirred for 12 hours at room temperature. The solvent is removed and worked up as customary. This gives 3.38 g of 2-chloro-6-methyl-4-(3,4-methylenedioxybenzylamino)thieno[2,3-d]pyrimidine, m.p. 162. | |
With triethylamine; In dichloromethane; | EXAMPLE 1 3.02 g of 3,4-methylenedioxybenzylamine ("A") are added to a solution of 3.29 g of 2,4-dichloro-6-methylthieno-[2,3-d]-pyrimidine in 80 ml of methylene chloride and, after addition of 1.52 g of triethylamine, the mixture is stirred at room temperature for 12 hours. The solvent is removed and the residue is worked up in the customary manner. 3.38 g of 2-chloro-6-methyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine are obtained, m.p. 162. | |
With triethylamine; In dichloromethane; | EXAMPLE 1 2-Chloro-6-Methyl-4-(3,4-Methylenedioxybenzylamino)-Thieno-[2,3-d]-Pyrimidine A solution of 2,4-dichloro-6-methyl-thieno-[2,3-d]-pyrimidine (3.29 g) in dichloromethane (30 ml) is charged with 3,4-methylenedioxybenzylamine ("A") (3.02 g). Triethylamine (1.52 g) is added, and the mixture is stirred at room temperature. The solvent is removed, and the usual workup yields 2-chloro-6-methyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine (3.38 g) Mp. 162 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | In ethanol; at 55℃; | A solution of <strong>[20028-68-6]2,4,6-<strong>[20028-68-6]trichloroquinazoline</strong></strong> (0.186 g, 0.80 mmol) in ethanol (20 mL) was heated to 55 iC and piperonylamine (0.145 g, 0.96 mmol) was added. The resulting mixture was stirred at 55 iC overnight. Volatiles were evaporated and the residue was partitioned between methylene chloride and saturated solution of ammonium hydroxide. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to yield 0.268 g (96% yield) of the title compound as a white solid. 1H NMR (300 EMHz, DMSO) delta 4.59-4.63 (d, 2H), 5.98 (s, 2H), 6.86 (s, 2H), 6.96 (s, 1H), 7.62-7.66 (d, 1H), 7.79-7.84 (d, 1H), 8.46 (s, 1H), 9.24-9.28 (t, 1H). |
96% | With ammonium hydroxide; In ethanol; | 2d. 4-[(1,3-benzodioxol-5-ylmethyl)amino]-2,6-dichloro Quinazoline A solution of <strong>[20028-68-6]2,4,6-<strong>[20028-68-6]trichloroquinazoline</strong></strong> (0.186 g, 0.80 mmol) in ethanol (20 mL) was heated to 55 iC and piperonylamine (0.145 g, 0.96 mmol) was added. The resulting mixture was stirred at 55 iC overnight. Volatiles were evaporated and the residue was partitioned between methylene chloride and saturated solution of ammonium hydroxide. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to yield 0.268 g (96% yield) of the title compound as a white solid. 1H NMR (300EMHz, DMSO) delta 4.59-4.63 (d, 2H), 5.98 (s, 2H), 6.86 (s, 2H), 6.96 (s, 1H), 7.62-7.66 (d, 1H), 7.79-7.84 (d, 1H), 8.46 (s, 1H), 9.24-9.28 (t, 1H). |
96% | With ammonium hydroxide; In ethanol; | 2d. 4-((1,3-benzodioxol-5-ylmethyl)amino)-2,6-dichloro quinazoline A solution of <strong>[20028-68-6]2,4,6-<strong>[20028-68-6]trichloroquinazoline</strong></strong> (0.186 g, 0.80 mmol) in ethanol (20 ml) was heated to 55 C. and piperonylamine (0.145 g, 0.96 mmol) was added. The resulting mixture was stirred at 55 C. over night. Volatiles were evaporated and the residue was partitioned between methylene chloride and saturated solution of ammonium hydroxide. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to yield 0.268 g (96% yield) of the title compound as a white solid. 1H NMR (300 MHz, DMSO) delta4.59-4.63 (d, 2 H), 5.98 (s, 2 H), 6.86 (s, 2 H), 6.86 (s, 2 H), 6.96 (s, 1 H), 7.62-7.66 (d, 1 H), 7.79-7.84 (d, 1 H), 8.46 (s, 1 H), 9.24-9.28 (t, 1 H). |
With triethylamine; | EXAMPLE 90 2,6-Dichloro-4-(3,4-methylenedioxybenzyl)aminoquinazoline STR124 A mixture comprising 3.6 g of <strong>[20028-68-6]2,4,6-<strong>[20028-68-6]trichloroquinazoline</strong></strong>, 2.4 g of piperonylamine, 1.6 g of triethylamine and 50 ml of isopropyl alcohol was heated under reflux for 1.5 hours and hot-filtered to give 5.2 g of the title compound as a filter cake. molecular formula; C16 H11 N3 O2 Cl2; yield(%); 98; m.p.( C.); 215; Mass; 349 (M+1)+; NMR delta (DMSO-D6); 4.61 (2H, s), 5.97 (2H, s), 6.85 (2H, s), 6.95 (1H, s), 7.63 (1H, d, J=8.8 Hz), 7.80 (1H, dd, J=8.8 Hz, 2.4 Hz), 8.45 (1H, d, J=2.4 Hz), 9.24 (1H, br). | |
With triethylamine; | Example 92 2,6-Dichloro-4-(3,4-methylenedioxybenzyl)aminoquinazoline STR153 A mixture comprising 3.6 g of <strong>[20028-68-6]2,4,6-<strong>[20028-68-6]trichloroquinazoline</strong></strong>, 2.4 g of piperonylamine, 1.6 g of triethylamine and 50 ml of isopropyl alcohol was heated under reflux for 1.5 hours and hot-filtered to give 5.2 g of the title compound as a filter cake. molecular formula; C16 H11 N3 O2 Cl2 yield (%); 98 m.p. (C.); 215 Mass; 349 (M+1)+ NMR delta (DMSO-D6); 4.61 (2H, s), 5.97 (2H, s), 6.85 (2H, s), 6.95 (1H, s), 7.63 (1H, d, J=8.8Hz), 7.80 (1H, dd, J=8.8Hz, 2.4Hz), 8.45 (1H, d, J=2.4Hz), 9.24 (1H, br) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 241 (2S)-N-(1,3-benzodioxol-5-ylmethyl)-4-oxo-2-pyrrolidinecarboxamide Following the general method as outlined in Example 22, starting from <strong>[876317-19-0]1-(tert-butoxycarbonyl)-4-oxoproline</strong>, and 1,3-benzodioxol-5-ylmethylamine the title compound was obtai-ned in 71% purity by LC/MS. MS(ESI+): m/z=263.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With LiOH; N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In tetrahydrofuran; dichloromethane; water; N,N-dimethyl-formamide | Preparation of the Compounds of the Invention The pyrimidine was dissolved in THF/water (1/1) and LiOH (6 mg, 0.21 mmol) was added. After heating at 60° C. for 3 hours, the solvent was removed in vacuo and acidified with methanolic HCl. The solvent was removed in vacuo, dissolved in DMF and treated with HATU (42 mg, 0.11 mmol), DIEA (37 mg, 0.21 mmol), and piperonylamine (26 mL, 0.21 mmol). After stirring for 18 hours, the solvent was removed in vacuo, the residue was dissolved in CH2Cl2, and washed with saturated NaHCO3 and brine. The organic layer was dried (MgSO4), the solvent was removed in vacuo, and the residue was chromatographed (CH2Cl2/MeOH, 19/1) to give 2 mg (4%) of N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]indole-6-carboxamide; 1H NMR (CDCl3) δ3.75 (s,2), 5.95 (s,2), 6.80-6.90 (m, 2), 7.05-7.15 (m, 2), 7.25 (m, 2), 7.75-7.85 (m, 2), 8.00 (s,2), 8.50-8.60 (m, 2), 8.70-8.80 (m, 1); MS: (439.2 M+H)+. Another specific embodiment of the generic synthesis as applied to a compound of the invention is N-[(1,3-benzodioxol-5-yl)ethyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]pyrrole-2-carboxamide [MS: (403.2 M+H)+], which was prepared in a similar manner described above for N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]indole-6-carboxamide. The following Reaction Scheme 3 depicts a method of preparing the compounds of the invention where U is CR5 (where R5 is hydrogen) and X, Y and Z are CR19 (where R19 is hydrogen): |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 2 2-Chloro-5-Methyl-4-(3,4-Methylenedioxybenzylamino)-Thieno-[2,3-d]-Pyrimidine Following the procedure of Example 1, the reaction of 3,4-methylenedioxybenzylamine with <strong>[56844-38-3]2,4-dichloro-5-methyl-thieno-[2,3-d]-pyrimidine</strong> gives 2-chloro-5-methyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; | EXAMPLE 65 4-(3,4-Methylenedioxylbenzyl)amino-6-cyanoquinazoline STR99 15 ml of isopropyl alcohol, 75 mg of triethylamine and 125 mg of piperonylamine were added to 140 mg of <strong>[150449-97-1]4-chloro-6-cyanoquinazoline</strong>. The obtained mixture was heated under reflux for 5 hours and filtered to recover a precipitate. This precipitate was introduced to a silica gel column, followed by eluding with ethyl acetate to give 200 mg of the title compound. molecular formula; C17 H12 N4 O2; yield(%); 89; m.p.( C.); 243~244; Mass; 305 (M+1)+; NMR delta (DMSO-d6); 4.67 (2H, d, J=5.6 Hz), 5.96 (2H, s), 6.84 (2H, s), 6.95 (1H, s), 7.77 (1H, d, J=8.4 Hz), 8.56 (1H, s), 8.89 (1H, s), 9.04 (1H, br). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With hydrogenchloride; In water; isopropyl alcohol; at 70℃; | EXAMPLE 1 N-(3,4-Methylenedioxybenzyl)-thieno[3,2-d]pyrimidin-4-amine To a solution of <strong>[16269-66-2]4-chlorothieno[3,2-d]pyrimidine</strong> (47 mg, 0.27 mmol) and 3,4-methylenedioxybenzylamine (40 uL, 0.32 mmol) in 2 mL of isopropanol was added one drop of concentrated HCl and the mixture was stirred overnight at 70 C. The reaction mixture was diluted with 25 mL of ethyl acetate and washed with saturated NaHCO3. The organic layer was dried over anhydrous MgSO4, filtered and concentrated. The crude product was purified by chromatography (60% ethyl acetate/hexane) on silica gel to give the title compound (34 mg, 0.12 mmol, 43%). 1H NMR (CDCl3) 8.67 (s, 1H), 7.70 (d, 1H, J=5.1), 7.43 (d, 1H, J=5.7), 6.77-6.90 (m, 3H), 5.96 (s, 2H), 5.17 (m, 1H), 4.78 (d, 2H, J=5.4). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: Piperonylic acid With thionyl chloride for 1h; Heating / reflux; Stage #2: 1,3-benzodioxol-5-ylmethyl amine With pyridine In dichloromethane for 0.5h; Heating / reflux; | 12 3, [4-METHYLENEDIOXYBENZYLAMIDE] (compound 52B; DC-0052B) A suspension [OF PIPERONYLIC ACID] (0.5 g) in thionyl chloride (15 ml) was refluxed for 1 h under nitrogen, when a clear solution had been formed. The solvents were removed in vacuo to give the acid chloride as a white solid. The solid was dissolved in dry dichloromethane (7 [ML)] and added dropwise to a stirred solution of piperonylamine (0.45 g) in dry dichloromethane (20 [ML)] containing pyridine (0.5 [ML).] The mixture was refluxed for 30 minutes, diluted with more dichloromethane (50 ml), then washed with aqueous HCl [(1M,] 50 ml) followed by aqueous [NAOH] [(1M,] 50 [ML),] dried and evaporated in vacuo to give the crude product. Crystallization from methanol/water gave DC-0052B as a white solid (733 mg, [79%).] [LH-NMR] [(CDC13)] 7. 27 (2H, m), 6.79 (4H, m), 6.01 (2H, s), 5.94 (2H, s) and 4.51 (2H, d, [J] 5Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | To a solution of 3, [4-METHYLENEDIOXYDIHYDROCINNAMIC] acid (0.4 g) in dry [CH2CK] (25 [ML)] under nitrogen, was added oxalyl chloride (0.5 [ML)] with three drops of dry DMF and the mixture was stirred for 1 hour. Solvents were removed in vacuo giving the acid chloride as a yellow solid. To a solution of the acid chloride in dry [CH2CL2] (50 [ML)] under nitrogen, cooled to [0C,] was added dropwise, a solution of 3, 4-(methylenedioxy)benzylamine (0.35 [G)] and pyridine (0.2 [ML)] in [CH2C12] (5 ml). The reaction mixture was stirred for 30 minutes at room temperature, diluted with [CHUCK] (100 [ML),] washed with aqueous HCl (100 [ML] ; [10%)] and sodium bicarbonate solution (100 [ML)] then dried and evaporated in vacuo to give DC-0058B as an off white powder (0.536g, 80%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A library of compounds in which R4 was various groups having the formula [CONHR »] was prepared by the process described above using 4-fluoro-3-nitrobenzoic acid, as follows: [72] Aldehyde resin was mixed with a primary amine (R17-NH2) in [DICHLOROETHANE] (DCE), triethylorthoformate (TEOF), and DMF (containing [1%] acetic acid) in a 1: 1: 1 ratio. After shaken overnight, sodium triacetoxyborohydride (20 eq. ) dissolved in DMF was added (Abdel-Magid, A. F. , et al., Tetrahedron Lett, 3 1: 5595-5598 (1990) ). After the mixture was shaken at room temperature overnight, the resin was filtered and washed with DMF (3 x 5 mL), [MEOH] [(3 X 5] mL), DMF [(3 X 5] mL), [MEOH] [(3 X 5] mL), and [CH2CL2] [(3 X 5] mL). The resin was washed twice with 5 mL DMF containing [1%] Hunig's base. To the filtered resin was added a mixture of 4-fluoro-3-nitrobenzoic acid (FNBA, 10 eq. ) and diisopropylcarbodiimide (DIC, 5 eq. ) in 2: 1 DMF : DCM. After shaking at room temperature overnight, the resin was filtered and washed with DMF (3 x 5 mL) and [CH2C12] (3 x 5 mL). [73] The resin was shaken with a primary amine [(R2-NH2)] in DMF for 8 hrs, filtered, and washed with DMF (6 x 5 mL), [MEOH] [(3 X 5] mL), and CH2C12 (3 x 5 mL). The aryl nitro group was reduced by the addition of tin (II) chloride dihydrate (20 eq. , >2 M) and N-methyl morpholine (NMM, 20 eq. ) in N-methyl pyrrolidinone (NMP). After shaken at room temperature overnight, the resin was filtered and washed with NMP (3 x 5 mL), [MEOH] (3 x 5 mL), and [CH2CI2 (3 X 5] mL). The resulting resin was shaken at room temperature with cyanogen bromide (5 eq. ) overnight, filtered, and washed with CH2Cl2 (3 x 5 mL), [MEOH] (3 x 5 mL), and CH2CI2 (3 x 5 mL). To produce a free amine, the resin was shaken for 30 min. in CHCl2 with the addition of sodium methoxide in methanol, filtered, and washed with CH2Cl2 [(4 X 5] mL). [[74]] In the final diversification step, the resin was heated at 500 C in DMF with a mono- substituted epoxide [[RLCH (-CH2O-)].] After shaking for 2 to 4 days the resin was filtered and washed with DMF (5 x 5 mL), [MEOH] [(3 X 5] mL), and CH2Cl2 (3 x 5 mL). T he resin-bound benzimidazole was cleaved from the solid-support by treatment with TFA: [CH2C12] (2: 3) for 1 hour at room temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | General procedure: To solutions of the corresponding 2-phenoxyalkylcarboxylicacids in DMF (5 mL/mmol) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI; 1.1 equiv) and 1-hydroxy-7-azabenzotriazole (1.1 equiv). The solutions were stirredat room temperature for 30 min, then the corresponding benzylamines(1.2 equiv) and diisopropylethylamine (3.0 equiv) wereadded. The resulting mixtures were stirred at room temperaturefor an additional 16 h, then poured into 10% aqueous citric acidsolutions. The aqueous mixtures were extracted with EtOAc, andthe extracts were washed with 5% aqueous NaHCO3 and brine, thendried over MgSO4, filtered, and evaporated to provide white solids.The solids were crystallized from EtOAc/hexane to provide theproducts 1, 2, and 6a. | |
45% | To a solution of (i?)-2-(2,4-dichlorophenoxy)propionic acid (compound 10a; 128 mg, 0.55 mmol), l-hydroxy-7-azabenzotriazole (82 mg, 0.60 mmol, 1.1 eq), and JV-(3- dimethylaminopropyl)-Lambda/"-ethylcarbodiimide hydrochloride (115 mg, 0.60 mmol, 1.1 eq) in dry DMF (3 mL) was added piperonylamine (0.81 mL, 0.65 mmol, 1.2 eq). The solution was stirred at room temperature for 30 minutes. Diisopropylethylamine (0.28 mL, 1.7 mmol, 3.0 eq) was then added, and the solution was stirred at room temperature for 16 hours. The reaction was poured into 10% aqueous citric acid (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic extracts were dried over Na2SO4, and evaporated to provide a residue which was subjected to chromatography on silica gel with 20% EtOAc/hexane. The fractions were pooled and evaporated to yield 91 mg (45%) of compound 11a (designated MBX 1684) as a white solid: Rf 0.52 (50% EtOAc-Hexanes); mp 136-138 C; MS (ESI) m/z 368.0 [M+H]+; 1H NMR (CDCl3) delta 7.37 (d, IH), 7.19 (dd, IH), 6.91 (s, IH), 6.85 (d, IH), 6.76-6.68 (m, 3H), 5.95 (s, 2H), 4.73 (q, IH), 4.39 (m, 2H), 1.64 (d, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | Example 81 l-(benzo[d][l,3]dioxol-5-y.methyI)-3-(4-((2-(methylthio)ethoxy)methyl) thiazol-2- yl)urea; [00178] Step 1: Synthesis of l-(Benzo[d][l,3]dioxol-5-ylmethyl)-3-(4-(chloromethyl)thiazol-2-yl)urea intermediate; Phosgene (54.0 rnmol, 27.9 mL of a 1.93 M solution in toluene) was placed in a 3-neck-flask and cooled to 00C. THF (10 mL) was added, <n="57"/>followed by a mixture of piperonylamine (27.0 tnmol, 4.0 g) and DIPEA (56.7 mmol, 7.3 g) in THF (20 mL) at 00C. After complete addition the mixture was stirred for another 40 min at 00C. The reaction mixture was then concentrated. To the crude material THF (40 mL) and DIPEA (4.4 mL) were added. This mixture was then added to a slurry of 2-amino-4- (chloromethyl)thiazole hydrochloride (24.3 mmol, 4.5 g) in THF (50 mL). After stirring for 72 h at room temperature the reaction mixture was filtered through celite. The celite was washed with ethylacetate. The combined filtrate was concentrated and the material was directly applied to column chromatography (MeOH/DCM ) providing 2.6 g (32percent) of the desired intermediate. 1H-NMR (CD3OD, 300 MHz) delta 6.96 (s, IH), 6.79 (m, 3H), 5.91 (s, 2H)5 4.55 (s, 2H), 4.32 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | To a solution of <strong>[120-36-5]2-(2,4-dichlorophenoxy)propionic acid</strong> (compound Ib; 1.275 g, 5.45 mmol), l-hydroxy-7-azabenzotriazole (0.82 g, 6.0 mmol, 1.1 eq), and JV-(3- dimethylaminopropyl)-Lambda/"-ethylcarbodiimide hydrochloride (1.15 g, 6.0 mmol, 1.1 eq) in dry DMF (25 mL) was added piperonylamine (0.81 mL, 6.5 mmol, 1.2 eq). The solution was stirred at room temperature for 30 minutes. Diisopropylethylamine (2.84 mL, 16.4 mmol, 3.0 eq.) was then added, and the solution was stirred at room temperature for 16 h. The reaction was poured into a mixture of 10% aq. citric acid (200 mL) and EtOAc (300 mL). The organic layer was washed with 10% aqueous citric acid, water, saturated aqueous NaHCOs, water, then brine. The organic solution was then dried over Na2SO4, and concentrated on a rotary evaporator. The concentrated solution was triturated with hexanes (chi3) to give a precipitate. The solid was collected by filtration to yield 1.84 g (92%) of compound 2b as a white powder: Rf 0.52 (50% EtOAc/hexanes); mp 120-121 C; MS (ESI) m/z 367.9 [M+H]+; 1H NMR (CDCl3) delta 7.38-7.37 (d, IH), 7.20-7.17 (dd, IH), 6.91 (s, IH), 6.86-6.83 (d, IH), 6.76-6.68 (m, 3H), 5.95 (s, 2H), 4.76-4.69 (q, IH), 4.40-4.37 (m, 2H), 1.65-1.63 (d, 3H). | |
91% | General procedure: To solutions of the corresponding 2-phenoxyalkylcarboxylicacids in DMF (5 mL/mmol) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI; 1.1 equiv) and 1-hydroxy-7-azabenzotriazole (1.1 equiv). The solutions were stirredat room temperature for 30 min, then the corresponding benzylamines(1.2 equiv) and diisopropylethylamine (3.0 equiv) wereadded. The resulting mixtures were stirred at room temperaturefor an additional 16 h, then poured into 10% aqueous citric acidsolutions. The aqueous mixtures were extracted with EtOAc, andthe extracts were washed with 5% aqueous NaHCO3 and brine, thendried over MgSO4, filtered, and evaporated to provide white solids.The solids were crystallized from EtOAc/hexane to provide theproducts 1, 2, and 6a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With 2',3',4'-trihydroxyacetophenone In water at 20℃; for 24h; | |
97% | With oxygen; iron(II) bromide In neat (no solvent) at 110℃; for 5h; Green chemistry; | |
90% | With pyrimidine-2,4,5,6(1H,3H)-tetraone; oxygen; copper(l) chloride at 30℃; for 8h; |
79% | With oxygen In neat (no solvent) at 110℃; for 5.5h; Schlenk technique; Green chemistry; | |
70% | With copper(II) on 4-A° molecular sieves In neat (no solvent) at 120℃; for 14h; | General procedure for the preparation of imines General procedure: The mixture of the appropriate amines (2 mmol in the case of homo-coupling and 1 mmol in the case of hetero coupling)and Cu2+/4A (0.05 g) were stirred at 120 ∘C for 14 h. The mixture was left to cool down to room temperature, diluted with 10 cm3 diethyl ether, then thes olid was filtered, and the filtrate was evaporated. The material thus obtained has been characterized. Based on XRF examinations, some copper dissolved from the catalyst during the reaction (leaching). The amount of this copper depended on the nature of the amine. To remove this metal contaminant, the product was dissolved in diethyl ether, MS 4 A ° was added, and the mixture was stirred at room temperature for 30 min. Then, the solidwas filtered, and the filtrate was evaporated |
With oxygen; titanium(IV) oxide In acetonitrile for 15h; UV-irradiation; | ||
With oxygen; titanium(IV) oxide In acetonitrile at 40℃; for 6h; Irradiation; | ||
With copper(I) 2-hydroxy-3-methylbenzoate; C8H7NO3 In methanol at 20℃; for 10h; chemoselective reaction; | ||
91 %Spectr. | With 2-tert-butyl-5-hydroxy-1,4-benzoquinone; oxygen In acetonitrile at 20℃; for 20h; chemoselective reaction; | |
With tungsten(IV) sulfide; oxygen In 1-methyl-pyrrolidin-2-one; acetonitrile at 50℃; for 48h; Irradiation; | ||
97 %Chromat. | With oxygen In 1-methyl-pyrrolidin-2-one; acetonitrile at 20℃; for 24h; Irradiation; | |
70 %Chromat. | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [RuII(phen)(PPh3)2(CO)(H)]ClO4; oxygen In toluene at 110℃; for 24h; | |
With 2,2,6,6-tetramethyl-piperidine-N-oxyl; 3,4-dihydroxybenzonitrile; oxygen; titanium(IV) oxide In acetonitrile at 20℃; for 1.5h; Sonication; Darkness; Irradiation; chemoselective reaction; | ||
96.4 %Spectr. | With tetrabutylammonium tetrafluoroborate In acetonitrile at 20℃; for 3h; Electrochemical reaction; | |
Stage #1: 1,3-benzodioxol-5-ylmethyl amine With titanium(IV) dioxide; 4-amino-2,2,6,6-tetramethyl-1-piperidine-1-oxyl; 2,3-dihydroxynaphthalene-6-sulphonic acid sodium salt In acetonitrile Sonication; Darkness; Stage #2: at 25℃; for 0.466667h; Irradiation; | ||
With C31H29Br2N3Ru; oxygen In (2)H8-toluene at 80℃; for 15h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 10h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 10 h / 20 °C 2: trifluoroacetic acid; sodium nitrite / dichloromethane / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With sodium sulfate; In methanol; at 20℃;Sealed tube; | General procedure: To a solution of imidazole carbaldehyde (1a-d) (100 mg, 1 equiv) in methanol (3 mL) were added successively Na2SO4 (0.2 g), amine 2a-d (1.2 equiv), alkynoic acid 3a-c (1.2 equiv) and isonitrile 4a-c (1.2 equiv) in a screw capped vial equipped with a magnetic stir bar. The reaction mixture was stirred at room temperature for 24-48 h in closed vial. After completion of the reaction, the mixture was diluted with dichloromethane (100 mL) and was extracted with water (50 mL). Organic layer was washed with brine (50 mL), dried over magnesium sulfate and evaporated under reduced pressure to obtained residue which was subjected to silica gel column chromatography (1-5 % methanol in dichloromethane) to afford the desired product 5a-r as solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In neat (no solvent) at 20℃; for 24h; Green chemistry; | PREPARATION OF THE BENZAMIDES General procedure: In a round-bottomed flask, a mixture of a suitable amine (1 eq.) and 3 eq. of vinyl benzoate were stirred at room temperature for 24 hours. The evolution of the reaction was monitored by TLC. After complete consumption of the amine, the crude reaction mixture was concentrated in vacuo and purified by flash chromatography on silica gel (CH2Cl2 as eluent) or by crystallization using Hexane as the crystallisation solvent to gave the pure benzamides. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride; In 1-methyl-pyrrolidin-2-one; at 0℃; for 5h; | General procedure: To a stirred solution of <strong>[142-45-0]acetylenedicarboxylic acid</strong> (1, 0.57 g, 5 mmol) in NMP (10 mL) at 0 C a solution of the amine (12 mmol, 2.4 equiv) in NMP (5 mL) [for ammonium salts additionally NMM (2 mL) was used] was added dropwise. After 10 min DMTMM 5(4.0 g, 14 mmol, 2.8 equiv) was added and the mixture was stirred for 5 h. Workup A: The mixture was partitioned between EtOAc and H2O(100 mL each), and the organic layer was washed successively with brine (100 mL), sat. NaHCO3 (100 mL), 1 M HCl (100 mL), and brine (2 × 100 mL) [for compounds 7b,q,s-v,y brine was used instead of H2O, and the organic phase was washed with brine (4 × 100mL) only]. The solution was dried (MgSO4), the solvent was evaporated, and the residue was dissolved in a small amount of refluxingTHF. The major portion of 6-dimethoxy-1,3,5-triazin-2(1H)-one(8) was crystallized at -20 C, and the liquid phase containing the product was separated and evaporated. The remaining residue wasfurther purified by column chromatography and/or recrystallization as appropriate. Workup B: The mixture was poured into 1 M HCl (150 mL; for compounds 7h,x H2O was used instead) with stirring at 0 C, and stirring was continued for 15 min. The resulting solid was collected by filtration, washed with H2O, and dried under vacuum. The residue was dissolved in a small amount of refluxing THF and further purified as described above, except for compounds 7f,g,o, which were simply washed with CHCl3 (3 × 10 mL). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With potassium carbonate; In acetonitrile; at 160.0℃; for 1h;Microwave irradiation; Inert atmosphere; | General procedure: 4-Methyl-N-phenylquinazolin-2-amine (17a). A mixture of 16 (20 mg, 0.11 mmol), aniline (0.012 mL, 0.13 mmol) and K2CO3 (23 mg, 0.17 mmol) in CH3CN (0.90 mL) was placed in sealed vial. The mixture was heated using microwave irradiation at 160 C for 1 h. The reaction mixture was filtered and concentrated and the residue was purified by chromatography on SiO2 (benzene/ether, 4:1) to afford 17a (17 mg, 65%) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With copper(l) iodide; 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine; oxygen In toluene at 100℃; for 18h; | General procedure: Copper(I) iodide (1.9 mg, 0.01 mmol) and1,5,7-triazabicyclo[4.4.0] dec-5-ene (TBD, 7.0 mg, 0.05 mmol) was added to a solution of p-OMe-benzyl amine 1a (131 μl, 1.0 mmol) and thiophenol 1b (52 μl, 0.5 mmol) in toluene(0.5 M, 1 ml). A slow stream of O2 was passed through this solution for 10 min. Then, thereaction mixture was stirred at 100 °C for 18 h under O2 atmosphere. The solvent wasremoved under vacuum, and the residue was purified by flash silica gel columnchromatography by using 1% ether/hexane as an eluent to obtain sulfenylimine 1c (82.7 mg,68 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | at 110℃; for 0.25h; | 22 Ethyl 2-((benzo[d][1,3]dioxol-5-ylmethyl)amino)-5-bromonicotinate (30) A mixture of ethyl 5-bromo-2-chloronicotinate 29 (27 g, 102 mmol) and 3,4-(methylenedioxy)-benzylamine (30.9 g, 204 mmol) was stirred at 110 °C for 15 min. During the reaction a pale brown solution changed to a black solid. The black solid was pound with a mortar and suspended in AcOEt (500 mL). The suspension was stirred for 30 min. and the solid was filtered off. The filtrate was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (CHCl3) to yield 30 as a white solid (17.34 g, 45%). 1H NMR (400 MHz, CDCl3) δ = 8.30 (d, J = 2.8 Hz, 1H), 8.24 (br s, 1H), 8.21 (d, J = 2.8 Hz, 1H), 6.84 (d, J = 1.2 Hz, 1H), 6.81 (dd, J = 1.6, 8.0 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 5.93 (s, 2H), 4.61 (d, J = 5.6 Hz, 2H), 4.32 (q, J = 7.2 Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H); MS (ESI+) 381.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With sodium carbonate In methanol at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With sodium sulfate; In methanol; at 20℃; | General procedure: To a solution of aldehydes (1a-g, 1 equiv) in methanol (3 mL) were added successively Na2SO4 (0.3 g), amines (2a-f, 1.2 equiv), 2-alkynoic acids (3a-d, 1.2 equiv) and isonitriles (4a-e, 1.2 equiv) in a screw capped vial equipped with a magnetic stir bar. The reaction mixture was stirred at room temperature or 50 C for 24-48 hours in closed vial. After completion of the reaction, the mixture was diluted with dichloromethane (50 mL) and was extracted with water (50 mL). Organic layer was washed with brine (50 mL), dried over magnesium sulfate and evaporated under reduced pressure to obtained residue which was subjected to silica gel column chromatography to afford the desired product alpha,beta-unsaturated gamma-lactams (5a-s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With triethylamine In tetrahydrofuran at 0 - 70℃; for 24h; | 2-(1,3-Benzodioxolyl-5-methylamino)-3-cyanopyridine (12c) Following Method S2, to a solution of 2-chloro-3-cyanopyridine (1.0 eq., 1.0 g, 7.38 mmol) and NEt3 (3.0 eq., 4.21 mL, 22.14 mmol) in anhydrous THF (7mL) at 0 °C was added piperonylamine (1.5 eq., 1.38 mL, 11.07 mmol). The resulting mixture was heated to 70 °C and stirred until conversion of starting material was observed by TLC. Usual workup and purification afforded the title compound (1.19 g, 63%) as an off-white solid. Mp: 92-95 °C. δH (400MHz, CDCl3): 8.28 (d, 1H, J= 7.1 Hz, CH Ar), 7.63 (d, 1H, J = 7.1Hz, CH Ar), 6.80 (s, 1H, CH Ar), 6.78 (d, 1H, J = 7.1 Hz, CH Ar), 6.73 (d, 1H, J = 7.1 Hz, CH Ar), 6.59 (m, 1H, CH Ar), 5.91 (s, 2H, CH2),5.45 (br s, 1H, NH), 4.58 (s, 2H, CH2). δC (100 MHz, CDCl3): 157.2 (qC Ar), 152.3 (CH Ar), 147.4 (q Ar), 146.5 (qC Ar), 140.9 (CH Ar), 131.7 (qC Ar), 120.6 (CHAr), 116.5 (qC CN), 111.7 (CH Ar), 107.8 (2 CH Ar), 100.6 (CH2), 91.3 (qC Ar), 44.6 (CH2). vmax (ATR)/cm-1: 3366 (NH), 2899, 2852, 2780, 2217 (CN), 1973, 1887, 1593, 1581, 1522, 1488, 1444, 1372, 1347, 1321, 1288, 1182, 1132, 1093, 1038, 940, 811, 804, 763, 712, 673. HRMS(m/z ESI+): Found: 254.0919 (M+ + H, C14H12N3O2 Requires: 254.0930). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: 1,3-benzodioxol-5-ylmethyl amine; acetone Reflux; Stage #2: With palladium 10% on activated carbon; hydrogen In methanol at 20℃; Autoclave; | 1.4 N-piperonyl isopropylamine A mixture of benzo[d][1,3]dioxol-5-ylmethanamine (8 g, 52.9 mmol) and acetone (20 g, 344 mmol) was stirred at reflux until all starting amine had disappeared as monitored by GC analysis. The excess of acetone was removed by evaporation under reduced pressure. The residual oil was taken in 30 ml of methanol and placed in a 200 ml autoclave. Palladium 10% on carbon (1 g) was added and then the autoclave was pressurized with 3 bar of hydrogen. The mixture was stirred at ambient temperature until no more hydrogen was consumed. The reaction mixture was filtered to remove the catalyst. The filtrate was evaporated in vacuo. The residual brownish oil was purified by silica gel column chromatography using dichloromethane and heptane as eluent affording the title compound (6.5 g; yield 80%) as a slightly yellow oil. (0043) 1H-NMR in CDCl3: 1.05-1.10 (6H, d, 2×-CH-CH3), 2.70-2.9 (1H, m, N-CH-), 3.60-3.70 (2H, s, Ar-CH2-N), 5.85-5.95 (2H, s, O-CH2-O), 6.65-6.85 (3H, 2×m, 3× aromatic H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | General procedure: To a suspension of corresponding N-Boc-protected amino acid(14a-d, 5.0 mmol) in DCM (20.0 mL), HOBt (0.75 g, 5.5 mmol) andEDCI (1.44 g, 7.5 mmol) were added. The reaction mixture wasstirred for 30 min. Then corresponding amine (5.0 mmol) and diisopropylethylamine(1.9 mL, 10.0 mmol) were added and stirred foranother 3 h. The resulting mixture was washed with aqueousNaHCO3 solution (1 x 15 mL), brine (1 x 15 mL) and dried overNa2SO4. The solvent was evaporated in vacuo and the crude product was purified by flash chromatography (ethyl acetate: petroleum ether = 1:5-1:2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With sodium hydroxide In water at 5 - 10℃; for 0.5h; | 3 Preparation of SL-D022: To the 100ml three-necked flask, 20ml of water and 3g of 4-methylenedioxybenzylamine (0. 0132πο1) were added with stirring. The temperature of the reaction flask was lowered to 5-10 ° C, Dropwise 3-fluorobenzoyl chloride 2. 35g (0.0148m0l), while dropping acid chloride and sodium hydroxide solution (sodium hydroxide 0. 6 g 0. 015m0l water 2.5 ml), plus the completion of , Stirring was continued for 30 minutes, and the TLC layer was monitored to the end of the reaction. The reaction was stopped, filtered and the filter cake was washed successively with 3 ml of X? Water, 3 ml of saturated sodium bicarbonate, 3 ml of X? Water, 5% HC? The crude product was recrystallized from methanol to yield 2.6 g of pure product. |
With sodium carbonate In dichloromethane; water at 20℃; | 2.2. General protocol for the synthesis of N-phenylbenzamide derivatives (3xy) General procedure: All materials, reagents and solvents were purchased fromSigma-Aldrich, Merck, and Tedia Brazil and were used as received.The classical Schotten-Baumann reaction was used for the synthesisof amides [23-25]. Typical procedure: A solution of the acylchloride (0.5 mmol) in dichloromethane (2 mL) was added dropwiseto a well-stirred mixture of the aniline (0.5 mmol) indichloromethane (2 mL) and 2 mL of aqueous sodium carbonate(10%) at room temperature. The reaction media was stirred for90 min and then the organic phase was separated and extractedwith brine (3 x 2 mL). The combined organic fractions were dried over MgSO4, filtered, and evaporated to dryness under reducedpressure to give the N-phenylbenzamides in 19-90% yields. Onehundred and seventeen compounds were synthesized followingthis procedure. Detailed physicochemical properties, 1H and 13CNMR data, FT-IR data, and yield are presented for each N-phenylbenzamidein the supplementary data. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 72% 2: 9% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; C63H51N2O3P2Ru(1+)*ClO4(1-); oxygen In toluene at 90℃; for 20h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; at 20℃; for 24h; | General procedure: Into a clear solution of 2-(Boc-amino)benzaldehyde 1 (1 mmol) in methanol (5 mL) was added amine 2 (1 mmol) and stirred for 5 minutes at room temperature. Then, 3-chloropropanoic acid (3, 1 mmol) and methylisocyanide (4, 1 mmol) were added to the reaction pot. The reaction was allowed to stir until no noticeable amounts of starting material were visible using TLC. Upon completion ofthe reaction, methanol was evaporated under reduced pressure and the crude Ugi products, without any purification, was dissolved in a CH2Cl2 and trifluoroacetic acid mixture(1:1, 2 mL). The reaction was then allowed to stir at room temperature for 5 h and monitored by TLC. Upon completion of the reaction, the solvent was evaporated under reduced pressure and the crude compound, without any purification, was dissolvedin acetonitrile (2 mL) and K2CO3 (2 mmol) was added. The reaction was then allowed to stir under refluxing conditions for 1 h and reaction completion was monitored usingTLC. The reaction mixture was then allowed to cool to room temperature and the solvent evaporated under reduced pressure. The crude products were subjected to flash column chromatography (EtOAc/hexanes) to yield pure compounds 8a-j. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: 1,3-benzodioxol-5-ylmethyl amine With bis(trimethylaluminum)–1,4-diazabicyclo[2.2.2]octane adduct In toluene at 40℃; for 0.333333h; Stage #2: benzyl-carbamic acid benzyl ester In toluene at 90℃; for 2h; | 4.3. General procedure for the preparation of urea compounds from Cbz-protected amine (6a-6q) General procedure: To a solution of morpholine (0.115 g, 1.321 mmol) in toluene (5 mL) DABAL-Me3 (0.406 g. 1.321 mmol) was added. The mixture was stirred for 20 min at 40 °C. 4a (0.250 g, 1.100 mmol) were added and allowed to stir for 2 h at 90 °C. The reaction mixture was quenched by the addition of 1M HCl (4 mL) and extracted with CH2Cl2 (2 × 20 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was then purified by flash column chromatography on silica gel with hexane-EtOAc as eluent to afford the desired product 6a (0.213 g, 94 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.1% | Stage #1: anthracen-9-carboxylic acid With N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate In N,N-dimethyl-formamide for 0.0833333h; Stage #2: 1,3-benzodioxol-5-ylmethyl amine In N,N-dimethyl-formamide at 20℃; for 24h; | 1 Example 1Preparation of N-(benzo[d][1,3]dioxol-5-ylmethyl)anthracene-9-carboxamide The anthracene-9-carboxylic acid (114 mg, 0.51 mmol) was dissolved in anhydrous DMF and HATU (235 mg, 0.6 mmol), 1 mLDIEA, after stirring for 5 minutes,Adding piperine(79mg, 0.52mmol), reacted at room temperature for 24h, monitored by TLC, after the reaction of the raw materialsAfter completion, the reaction solution was poured into 50 mL of 1 N dilute hydrochloric acid solution, a large amount of white solid was precipitated, and the mixture was allowed to stand overnight, filtered, and baked.Compound 1 was obtained in a dry yield of 84.1%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.3% | In ethyl acetate; at 20℃; | 4-Chloroisobenzofuran-1,3-dione (230 mg, 1.25 mmol) dissolved in 5 mL of ethyl acetate and stirred at room temperatureSolution, drop into piperine (188mg, 1.25mmol), will immediately produce a large amount of white solids, TLC monitoring, after the reaction is completed, staticThe mixture was filtered and dried to give Compound 4 in a yield: 80.3%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: 3-(trifluoromethyl)benzoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: 1,3-benzodioxol-5-ylmethyl amine In N,N-dimethyl-formamide at 20℃; for 5h; | Benzamide derivatives 25-30 using HOBt/EDC as activating agents: General method L General procedure: A solution of 24 (1.0 equiv.), HOBt (1.1 equiv.) and EDC (1.5 equiv.) in DMF (1.3 mmol/mL) was stirred at rt for 15 minutes. The appropriate amine (2.0 equiv.) was added and the resulting solution was stirred at rt for 5 hours. Reaction media was diluted with water and aqueous phase was extracted 3 times with EtOAc. Combined organic layers were washed successively with a solution of HCl 1N, a saturated solution of NaHCO3 and brine, dried over Na2SO4 and concentrated. The resulting solid was then purified by column chromatography on silica gel using the appropriate heptanes:EtOAc mixture. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With sodium carbonate In N,N-dimethyl-formamide at 130℃; | 5.1.4. Nucleophilic substitution of dichlorophthalazine 12a withbenzylamine and phenethylamine derivatives: general method C forthe preparation of compounds 14a-g and 15a-d General procedure: A mixture of 2,6-dichlorophthalazine 12a (1.0 equiv.), theappropriate benzylamine or phenethylamine derivative (1.1 equiv.)and Na2CO3 (2.0 equiv.) in DMF (0.3 mmol/mL) was heated overnightat 130 °C. After cooling, the reaction media was diluted withwater and the aqueous phase was extracted 3 times with EtOAc.The organic layers were combined, washed with brine, dried overNa2SO4, filtered, concentrated and purified by silica gel columnchromatography, using the appropriate heptanes: EtOAc mixture. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With 4-nitrophenyl azide In toluene at 100℃; for 24h; Molecular sieve; Inert atmosphere; | |
90% | With 4-nitrophenyl azide; acetic acid In toluene at 100℃; for 24h; Molecular sieve; Microwave irradiation; | Synthesis of compounds 1a-f (General method). General procedure: Anappropriate primary amine (1.4 equiv), p-nitrophenyl azide (1 equiv), glacial AcOH (30 mol %), and molecular sieves4 Å were added to a 1 M solution of a 1-arylethan-1-one(1 equiv) in PhMe. Next, the vial was placed in microwavereactor and reaction mixture was stirred at 100° for 24 h.The product was purified by chromatography on silica gel(initially CH2Cl2, then petroleum ether - EtOAc mixture). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 24h;Inert atmosphere; | To a reaction of 1/7-1, 2, 4-triazole-3 -carboxylic acid (226 mg, 2.0 mmol) and Piperonylamine (0.26 mL, 2.1 mmol) in dry DMF (10 mL) was added 1- hydroxybenzotriazole monohydrate (337 mg, 2.2 mmol) and EDC (N-(3- Dimethylaminopropyl)-N'-ethylcarbodiimide) (422 mg, 2.2 mmol) followed by N- methylmorpholine (0.88 mL, 8.0 mmol via syringe). The mixture was stirred at room temperature under nitrogen and the solids were gradually dissolved. The contents were stirred at room temperature for 24.0 h, and then slowly diluted into iced water and extracted with DCM (2 x 50 mL). The DCM phase was washed with ice cold water (2 x 100 mL). The DCM phase was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure and chromatographed on silica gel using EtOAc as eluents to get the desired amide 6 (95 mg, 19 % yield) as a white solid. -NMR (400 MHz, DMSO- de): <515.58-13.83 (m, 1H), 9.10 (br s, 1H), 8.47 (br s, 1H), 6.90- 6.78 (m, 3H), 5.97 (s, 2H), 4.36 (d, J= 6.4 Hz, 2H) ppm. MH+ = 247.1 m/z. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2,6-Dihydroxybenzoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In tetrahydrofuran at 20℃; for 0.25h; Stage #2: 1,3-benzodioxol-5-ylmethyl amine In tetrahydrofuran at 20℃; | 4.4.1. Procedure for synthesis of compounds 3a-3k General procedure: To a solution of corresponding carboxylic acid (1 mmol), EDC-HCl(268.4 mg, 1.4 mmol), HOBt (189.2 mg, 1.4 mmol) and triethylamine(195 μL, 1.4 mmol) in dry THF (5 mL) were stirred for 15 min at roomtemperature, and the piperonylamine (150 μL, 1.2 mmol) was thenadded into the solution. The reaction mixture was stirred for 8-12 h atroom temperature, and monitored by thin-layer chromatography. Theresulting mixture was concentrated by reduced pressure and dissolveinto EtOAc (15 mL) then partitioned by 1 N HCl aqueous solution(3 × 10 mL) and concentrated NaHCO3 aqueous solution (3 × 10 mL),sequentially. The organic layers were dried over anhydrous MgSO4,filtered, and concentrated under reduced pressure. The residue wasrecrystallized from the solution of CHCl3-Hexane to give the amides 3a-3k. |
Tags: 2620-50-0 synthesis path| 2620-50-0 SDS| 2620-50-0 COA| 2620-50-0 purity| 2620-50-0 application| 2620-50-0 NMR| 2620-50-0 COA| 2620-50-0 structure
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