* 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 hydrogenchloride In methanol at 20℃; for 4 h;
The mixture of tert-butyl ((lS,3S)-3-hydroxycyclobutyl)carbamate (seePREPARATION 4A; 187 mg, 1 mmol, 1.0 eqv) in HCl/MeOH 4 N (15 ml) was stirred at room temperature for 4 hours. Reaction mixture was concentrated to give (lS,3S)-3- aminocyclobutanol hydrochloride. (120 mg, 0.98 mmol, 98percentyield) ESI-MS (M+l): 88 calc. for C4H9NO 87
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 180℃; for 2h;microwave;
A mixture of (l S,3S)-3-aminocyclobutanol hydrochloride (120 mg, 0.98 mmol, 1.0 eqv), 2-chloro-benzothiazole (purchased from ALDRICH) (169 mg, 1 mmol, 1.02 eqv ) and DIEA (286 mg, 2 mmol, 2.04 eqv) in NMP (2 mL) was heated to 180C for 2 hours in microwave. To the reaction mixture was added water, and the residue was extracted with EtOAc (30 mL). The combined organic layer was washed with brine and dried over Na2S04. The organic layers were concentrated and purified by column chromatography on silica gel to give (lS,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutanol (160 mg, 0.72 mmol, yield 73%). ESI-MS (M+l): 221 calc. for CnHi2N2OS 221.
With hydrogenchloride; In methanol; at 20℃; for 4h;
The mixture of tert-butyl ((lS,3S)-3-hydroxycyclobutyl)carbamate (seePREPARATION 4A; 187 mg, 1 mmol, 1.0 eqv) in HCl/MeOH 4 N (15 ml) was stirred at room temperature for 4 hours. Reaction mixture was concentrated to give (lS,3S)-3- aminocyclobutanol hydrochloride. (120 mg, 0.98 mmol, 98%yield) ESI-MS (M+l): 88 calc. for C4H9NO 87
In an ice bath, 18.2 mg (0.457 mmol) sodium hydride (60% dispersion in mineral oil) were dispensed in 4.3 mL of anhydrous THF. 64.2 mg (0.519 mmol) c/s-3- aminocyclobutan-1 -ol (hydrochloride salt) were slowly added. Stirring at 0C was continued for 15 min. 70 mg (0.260 mmol) of intermediate 2 were added, the ice bath was removed and the resulting mixture was stirred for 16 h at 40 C. The reaction mixture was carefully poured into water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, and concentrated. The crude product was purified by flash chromatography to give 36 mg of the title compound as a solid material. 1H-NMR (300 MHz ,DMSO-d6), delta [ppm]= 1.85 (3H), 1.96 (2H), 2.90 (2H), 3.19-3.32 (1 H), 4.99 (1 H), 6.99 (1 H), 7.30 (2H), 7.56-7.67 (2H), 7.71 -7.80 (1 H), 8.09-8.21 (1 H). LC-MS (Method 3): Rt = 0.72 min; MS (ESIpos) m/z = 321
6-formylimidazo[1,2-b]pyridazine-3-carbonitrile[ No CAS ]
6-(((cis-3-hydroxycyclobutyl)imino)methyl)imidazo[1,2-b]pyridazine-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In ethanol; at 20℃; for 8h;
To a solution of intermediate 1D? (280 mg, 1.627 mmol) in ethanol (10 mL) were added <strong>[1219019-22-3]cis-3-aminocyclobutanol hydrochloride</strong> (220 mg, 1.780 mmol) and TEA (340 muL, 2.440 mmol). The reaction mixture was stirred at RT for 6 h. It became a suspension after 2 h. The reaction mixture was concentrated to afford a residue that was used in the next step without further purification. MS (ES): m/z=242 [M+H]+; HPLC Ret. Time 1.20 min. (HPLC Method D); 1H NMR (400 MHz, CDCl3) delta ppm 8.38 (d, J=1.3 Hz, 1H), 8.28 (s, 1H), 8.16-8.02 (m, 2H), 4.29 (t, J=7.3 Hz, 1H), 4.00-3.84 (m, 1H), 2.96-2.78 (m, 2H), 2.28-2.14 (m, 2H).
4-hydroxy-7-(4-methoxybenzyl)-5-(6-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)thieno[2,3-b]pyridin-6(7H)-one[ No CAS ]
4-(((1s,3s)-3-hydroxycyclobutyl)amino)-7-(4-methoxybenzyl)-5-(5-(4-methylpiperazin-1-yl)-1-((trifluoromethyl)sulfonyl)-1H-benzo[d]imidazol-2-yl)thieno[2,3-b]pyridin-6(7H)-one[ No CAS ]
4-(((1s,3s)-3-hydroxycyclobutyl)amino)-7-(4-methoxybenzyl)-5-(6-(4-methylpiperazin-1-yl)-1-((trifluoromethyl)sulfonyl)-1H-benzo[d]imidazol-2-yl)thieno[2,3-b]pyridin-6(7H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: General Method C (Amine substitution) A solution of benzoimidazol-2-yl arylpyridinone bistriflate derivate (1 equiv) in MeCN, DCM, or DMF was treated with amine (1.2-3 equiv). In the case where the amine is a salt (e.g. HCl), the amine salt was dissolved in MeOH or DMF and passed through a PoraPak Rxn CX ion exchange column to yield the free base which was added to the reaction mixture. The reaction mixture was stirred at rt or up to 45 C for 1-48 h. Solvent was removed and the crude product was purified by column chromatography or prep-HPLC to give the desired product.
4-hydroxy-7-(4-methoxybenzyl)-5-(6-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)thieno[2,3-b]pyridin-6(7H)-one[ No CAS ]
[ 76-05-1 ]
4-(((1s,3s)-3-hydroxycyclobutyl)amino)-5-(6-(4-methylpiperazin-1-yl)-1H-benzo [d]imidazol-2-yl)thieno[2,3-b]pyridin-6(7H)-one trifluoroacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
101 mg
General procedure: General Method C (Amine substitution) A solution of benzoimidazol-2-yl arylpyridinone bistriflate derivate (1 equiv) in MeCN, DCM, or DMF was treated with amine (1.2-3 equiv). In the case where the amine is a salt (e.g. HCl), the amine salt was dissolved in MeOH or DMF and passed through a PoraPak Rxn CX ion exchange column to yield the free base which was added to the reaction mixture. The reaction mixture was stirred at rt or up to 45 C for 1-48 h. Solvent was removed and the crude product was purified by column chromatography or prep-HPLC to give the desired product. General Method D (Global deprotection) A solution of protected benzoimidazol-2-yl arylpyridinone derivate (1 equiv) in TFA/conc. HCl (7: 1 v/v) was heated at 80-100 C for 3-24 h. Solvent was removed and the crude product was purified by column chromatography (free base) or prep-HPLC (TFA salt) to give the desired product. To generate the desired product as a HCl salt, the free base was dissolved in MeOH and 1 M HCl-Et20 (2-4 equiv) was added at rt. The solution was stirred for 5 min and azeotroped twice with MeOH.
With triethylamine; In ethanol; at 0 - 20℃; for 3h;
To a solution of <strong>[1219019-22-3]cis-3-aminocyclobutanol hydrochloride</strong> (900 mg, 7.3 mmol, 1.0 eq) in ethanol (5 mL) and Et3N (5 mL) at 0 C. was added Boc2O (800 mg, 3.7 mmol, 0.5 eq) and the mixture was allowed to warm to RT and stirred for 3 h. The mixture was concentrated under reduced pressure, diluted with water (50 mL) and extracted with EtOAc (40 mL*3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure to afford the title compound (1.2 g, 88%) as a yellow solid, which was used for the next step without further purification. LCMS: [M+H]+ 188.2.