* 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.
With pyridine; trichlorophosphate;dmap; at -15 - 100℃; for 0.08333330000000001h;Microwave;
Example 51 tert-Butyl 4-{4-[({4-[(E,Z)-[(3-bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}amino)carbonyl]benzyl}piperazine-1-carboxylate trifluoroacetate A solution of 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (30 mg, 88 mumol), <strong>[479353-63-4]4-[4-(tert-butoxycarbonyl)piperazin-1-yl]methyl}benzoic acid</strong> (84 mg, 0.26 mmol), and 4-dimethylaminopyridine (6.4 mg, 53 mumol) in pyridine (0.75 mL) was treated with phosphoryl chloride (25 muL, 0.27 mmol) dropwise at -15 C. The reaction mixture was heated in a microwave at 100 C. for 5 min. The reaction mixture was concentrated to residue which was rediluted with methanol (1 mL), treated with 2.0 M sodium hydroxide in water (0.3 mL, 0.6 mmol), and stirred for 30 min. The reaction mixture was quenched with acetic acid (50 muL, 0.9 mmol), filtered, and purified by preparative LCMS to give the desired product (29 mg, 45%). LCMS for C26H30BrFN7O5 (M+H)+: m/z=618.0, 620.0.
With 4-methyl-morpholine; 1,8-diazabicyclo[5.4.0]undec-7-ene; HATU; In N,N-dimethyl-formamide; at 75 - 90℃; for 4.5h;
Example 2Preparation of 4-[4-(4-carbamoyl-2-pyridin-4-yl-thiazol-5-ylcarbamoyl)-benzyl]- piperazine-1 -carboxylic acid tert.-butyl ester ("A3")A mixture of 4-((4-tert.-butoxycarbonyl)piperazin-1 -yl)methyl)benzoic acid (300 mg, 0.936 mmol, 1 .0 equiv), 5-amino-2-(pyridin-4-yl)thiazole-4-carboxamide (206, 0.936, 1 .0 equiv), HATU (356 mg, 0.936 mmol, 1 .0 equiv) and N-methylmorpholine (106 muIota, 0.936 mmol, 1 .0 equiv) in dry DMF (8 ml) is heated at 75 C for 30 min. DBU (285 muIota, 1 .873 mmol, 2.0 equiv) is added and the mixture is stirred at 90 C for 4 h.The solvent is evaporated under vacuum, the residue redissolved in water (20 ml) and extracted with EtOAc (20 ml x 3 times), the organic phases are washed with brine, dried over Na2S04, filtered and evaporated. The residue is tritured with methanol, filtered and dried to afford the title compound as an off-white powder. HPLC Method: A- 0.1 % TFA in H20, B- 0.1 % TFA in ACN: Flow - 2.0ml/min.Column: X Bridge C8 (50x4.6mm.3.5 mu).
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 18.0h;
Step 4) Preparation of tert-butyl 4-(4-(2-(2-chloropyridin-4-yl)-1H-benzo[d]imidazol-4-ylcarbamoyl)benzyl)piperazine-1-carboxylate [0365]2-(2-chloropyridin-4-yl)-1H-benzo[d]imidazol-4-amine (250 mg, 1.02 mmol), 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)benzoic acid (360 mg, 1.12 mmol), and HATU (583 mg, 1.53 mmol) in DMF (10 mL) was added N,N?-diisopropylethylamine (0.5 mL, 3.06 mmol). The mixture was stirred 18 h at room temperature, diluted with water (40 mL), and extracted with CH2Cl2 (10 mL×3). The combined organics layers were washed with brine, dried and concentrated. The residue was purified by silica gel column chromatography (17% to 50% Ethyl acetate in petroleum ether) to obtain tert-butyl 4-(4-(2-(2-chloropyridin-4-yl)-1H-benzo[d]imidazol-4-ylcarbamoyl)benzyl)piperazine-1-carboxylate as a yellow solid (270 mg, 48% yield). MS (ESI) calcd for C29H31ClN6O3: 546. found: 547[M+H].
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 18.0h;
Step 2) Preparation of tert-butyl 4-(4-(2-(2-(propylamino)pyridin-4-yl)-1H-benzo[d]imidazol-4-ylcarbamoyl)benzyl)piperazine-1-carboxylate [0373]2-(2-(propylamino)pyridin-4-yl)-1H-benzo[d]imidazol-4-amine (28 mg, 0.1 mmol), 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)benzoic acid (20.2 mg, 0.13 mmol), and HATU (60 mg, 0.16 mmol) in DMF (5 mL) was added N,N?-diisopropylethylamine (0.05 mL, 0.31 mmol). The mixture was stirred 18 h at room temperature, diluted with water, and the resulting precipitate was collected by filtration and dried. The solid was purified by prep-TLC (6.25% MeOH in CH2Cl2) to obtain tert-butyl 4-(4-(2-(2-(propylamino)pyridin-4-yl)-1H-benzo[d]imidazol-4-ylcarbamoyl)benzyl)piperazine-1-carboxylate as a yellow solid (30 mg, 53% yield). MS (ESI) calcd for MS (ESI) calcd for C32H39N7O3: 569. found: 570 [M+H].
tert-butyl 4-(4-(methoxycarbonyl)benzyl)piperazine-1-carboxylate[ No CAS ]
[ 479353-63-4 ]
Yield
Reaction Conditions
Operation in experiment
44.8%
With lithium hydroxide monohydrate; In methanol; water; acetonitrile; at 20℃; for 1.0h;
A mixture of compound 6a (7.0 g, crude, 21 mmol) and LiOH-H20 (1.4 g, 31 mmol) in methanol/acetonitrile/water (100 mL, 1 :2:2) was stirred 1 h at room temperature. The organic solvent was removed and the remaining aqueous solution was washed with ethyl acetate (100 mL) and then adjusted to pH=2-3 with 2N aqueous HC1. The resulting mixture was extracted with ethyl acetate (30 mL><2). The combined extracts were dried over anhydrous sodium sulfate and concentrated to afford compound 7a (3.0 g, 44.8%> yield) as a white solid.
3 g
With lithium hydroxide monohydrate; water; In methanol; acetonitrile; at 20℃; for 1.0h;
A mixture of compound 6a (7.0 g, crude, 21 mmol) and L1OH-H2O (1.4 g, 31 mmol) in methanol/acetonitrile/water (100 mL, 1 :2:2) was stirred 1 h at room temperature. The organic solvent was removed and the remaining aqueous solution was washed with ethyl acetate (100 mL) and then adjusted to pH=2-3 with 2N aqueous HC1. The resulting mixture was extracted with ethyl acetate (30 mL><2). The combined extracts were dried over anhydrous sodium sulfate and concentrated to afford compound 7a (3.0 g, 44.8% yield) as a white solid.
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 0.25h;
A mixture of compound 16 (Het=3-methylisoxazol-5-yl, 150 mg, 0.42 mmol), compound 7a (134 mg, 0.42 mmol) and HATU (159 mg, 0.42 mmol) in DMF (2 mL) was cooled to 0C and DIPEA (217 mg, 1.68 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 15 min. Saturated aqueous sodium bicarbonate was added and the resulting mixture was extracted with ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (Petroleum ether/ethyl acetate = 1 : 1 to ethyl acetate) to afford compound Boc-806 (180 mg, 65.2% yield) as a solid. HCl/EtOAc (2N, 1 mL) was added to a solution of Boc-806 (97 mg, 0.147 mmol) in EtOAc (1 mL) at 0C with stirring. The reaction mixture was stirred for 1 h and the resulting precipitate was collected by filtration, washed with DCM and dried to afford compound 806 (HC1 salt, 80 mg, 100% yield) as a yellow solid.
65.2%
With HATU; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 0.25h;
A mixture of compound 16 (Het=3-methylisoxazol-5-yl, 150 mg, 0.42 mmol), compound 7a (134 mg, 0.42 mmol) and HATU (159 mg, 0.42 mmol) in DMF (2 mL) was cooled to 0C and DIPEA (217 mg, 1.68 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 15 min. Saturated aqueous sodium bicarbonate was added and the resulting mixture was extracted with ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (Petroleum ether/ethyl acetate = 1 : 1 to ethyl acetate) to afford compound Boc-806 (180 mg, 65.2% yield) as a solid.
tert-butyl 4-(4-(3-(4-(5-bromopyridin-3-yl)pyrimidin-2-ylamino)-4-methylphenylcarbamoyl)benzyl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 0.25h;
A mixture of compound 5 (1.0 g, 2.81 mmol), compound 7a (0.98 g, 4.19 mmol), HATU (1.28 g, 3.37mmol) in DMF (20 mL) was cooled to 0C and DIPEA (1.95 mL, 11.24 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 15 min. Saturated aqueous sodium bicarbonate (20 mL) was added and the resulting mixture was extracted with ethyl acetate (50 mL><2). The combined extracts were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 3 : 1 to 1 : 1) to afford compound 8a (1.29 g, 80% yield) as a yellow solid.
80%
With HATU; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 0.25h;
A mixture of compound 5 (1.0 g, 2.81 mmol), compound 7a (0.98 g, 4.19 mmol), HATU (1.28 g, 3.37mmol) in DMF (20 mL) was cooled to 0C and DIPEA (1.95 mL, 11.24 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 15 min. Saturated aqueous sodium bicarbonate (20 mL) was added and the resulting mixture was extracted with ethyl acetate (50 mL><2). The combined extracts were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 3 : 1 to 1 : 1) to afford compound 8a (1.29 g, 80% yield) as a yellow solid.
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