苄基肼 二盐酸盐

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Similar to Example 1, equimolar amounts of benzylhydrazine dihydrochloride and 2-acetyl-3-oxo-butyric acid ethyl ester were combined in a solution of 50% pyridine in ethanol. The resulting oil was determined to be the named product by 1H-NMR (CDCl3, ppm): 1.35 t (3H); 2.44 s (3H); 2.45 s (3H); 4.38 a (2H); 5.25 s (2H); 7.08 d (2H); 7.29 m (3H).

反应条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 4-dibutylamino-2-butynenitrile in ethanol (10 mL) was added to a stirring solution of benzylhydrazine dihydrochloride (3.0 g, 15.4 mmol) and 3.0 N NaOH (5.00 mL, 15.4 mmol) in ethanol (50 mL). The resulting solution as stirred (2 hours, 25° C.), then concentrated. The residue was taken up in ethyl acetate (250 mL), washed with brine (3×90 mL), then dried (MgSO4) and concentrated in vacuo. The resulting oil was chromatographed on silica (80:20 hexane:ethyl acetate) to yield 0.70 g (14.5%) of 5-amino-3-[(dibutylamino)methyl]-1-(phenylmethyl)-1H-pyrazole as an orange oil. 1H NMR (250 MHz, CDCl3 δ 7.22 (m, 6H), 4.56 (s, 2H), 4.00 (br s, 2H), 2.30 (m, 4H), 1.34 (m, 8H), 0.90 (t, 6H). concentrated washed with brine (3×90 mL) dried (MgSO4) concentrated in vacuo The resulting oil was chromatographed on silica (80:20 hexane:ethyl acetate)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred suspension of dimethyl-7-chloro-4-hydroxyquinoline-2,3-dicarboxylate (5.00 g, 16.90 mM) and benzylhydrazine dihydrochloride (46.15 g, 236.50 mM) in ethanol (100 mL) was added triethylamine (75.8 mL, 541.0 mM). The mixture was heated to give a brown solution which was refluxed for 40 hours during which time a precipitate formed. The suspension was cooled to room temperature and filtered to give the benzylhydrazine salt of the title compound as an impure yellow solid. Multiple crystallizations from ethanolic hydrogen chloride and methanol gave the title compound (0.370 g, 6%) as a white powder, mp 347-350° C.; MS(CI): 354 (M+H). The mixture was heated to give a brown solution which was refluxed for 40 hours during which time a precipitate formed filtered

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Triethylamine (1.181 mL, 8.48 mmol) was added to 4,6-dichloropyrimidine-5-carbaldehyde (CAS no. 5305-40-8) (500 mg, 2.83 mmol) and benzylhydrazine dihydrochloride (CAS no. 20570-96-1) (551 mg, 2.83 mmol) in THF (15 mL) at room temperature under nitrogen. The resulting suspension was stirred at room temperature for 10 minutes and then heated at 65° C. for 50 mins. Silica was added to the reaction mixture and concentrated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane to afford the product (500 mg, 72.3%). 1H NMR (400 MHz, CDCl3) 5.67 (2H, s), 7.28-7.38 (5H, m), 8.16 (1H, s), 8.79 (1H, s); m/z (ES+) (M+H)+=245; HPLC tR=2.29 min. at room temperature heated at 65° C. for 50 mins Silica was added to the reaction mixture concentrated in vacuo The crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Triethylamine (1.181 mL, 8.48 mmol) was added to 4,6-dichloropyrimidine-5-carbaldehyde (CAS no. 5305-40-8) (500 mg, 2.83 mmol) and benzylhydrazine dihydrochloride (CAS no. 20570-96-1) (551 mg, 2.83 mmol) in THF (15 mL) at room temperature under nitrogen. The resulting suspension was stirred at room temperature for 10 minutes and then heated at 65° C. for 50 mins. Silica was added to the reaction mixture and concentrated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane to afford the product (500 mg, 72.3%). 1H NMR (400 MHz, CDCl3) 5.67 (2H, s), 7.28-7.38 (5H, m), 8.16 (1H, s), 8.79 (1H, s); m/z (ES+) (M+H)+=245; HPLC tR=2.29 min. at room temperature heated at 65° C. for 50 mins Silica was added to the reaction mixture concentrated in vacuo The crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirring suspension of ethyl-2-cyano-2-phenylacetate (10.34 g) and benzylhydrazine dihydrochloride (14.87 g) in ethanol (200 ml) at room temperature was added triethylamine (21.27 ml). The reaction mixture was heated to reflux for 24 hours. The solvent was removed under reduced pressure to yield the crude material as a brown oil. This was re-dissolved in ethyl acetate (100 ml) and washed with water (2×75 ml), then dried (MgSO4) and the solvent removed in vacuo to yield a pale brown oil. This was recrystallised from methanol to yield the title product as pale yellow crystals (2.5 g, ca. 20%) The reaction mixture was heated to reflux for 24 hours The solvent was removed under reduced pressure to yield the crude material as a brown oil washed with water (2×75 ml) dried (MgSO4) the solvent removed in vacuo to yield a pale brown oil This was recrystallised from methanol

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirring suspension of ethyl-2-cyano-2-phenylacetate (10.34 g) and benzylhydrazine dihydrochloride (14.87 g) in ethanol (200 ml) at room temperature was added triethylamine (21.27 ml). The reaction mixture was heated to reflux for 24 hours. The solvent was removed under reduced pressure to yield the crude material as a brown oil. This was re-dissolved in ethyl acetate (100 ml) and washed with water (2×75 ml), then dried (MgSO4) and the solvent removed in vacuo to yield a pale brown oil. This was recrystallised from methanol to yield the title product as pale yellow crystals (2.5 g, ca. 20%) The reaction mixture was heated to reflux for 24 hours The solvent was removed under reduced pressure to yield the crude material as a brown oil washed with water (2×75 ml) dried (MgSO4) the solvent removed in vacuo to yield a pale brown oil This was recrystallised from methanol

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Synthesized using the procedure for 22 except benzyl hydrazine dihydrochloride was used as the hydrazine. After the reaction mixture was stopped and cooled to room temperature, solid precipitated which was filtered off and dried in vacuum oven to provide the title compound (3.6 g, 98%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.40-7.34 (m, 2H), 7.34-7.27 (m, 3H), 5.57 (s, 1H), 5.35 (s, 2H), 2.18 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 151.48, 146.65, 135.16, 129.19, 128.61, 128.00, 91.19, 49.13, 11.44. Synthesized solid precipitated which was filtered off dried in vacuum oven

反应条件: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of methyl 2-picolinoyl nicotinate, compound 6, (130 mg, 0.54 mmol), benzylhydrazine dihydrochloride (146 mg, 0.81 mmol), diisopropylethylamine (104 mg, 0.81 mmol), and ethanol (5 mL) was heated overnight at 75° C. To the reaction mixture was added acetic acid (46 μL, 0.81 mmol). The reaction mixture was heated at 75° C. for 2 h and then 100° C. for 2 h. After cooling the excess solvent was removed under reduced pressure. The residue was partitioned between 15 mL of ethyl acetate and 10% aqueous sodium carbonate. The aqueous fraction was further extracted with 2×15 mL of ethyl acetate. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by normal phase flash chromatography eluting with 0-5% methanol in dichloromethane over 20 minutes. Like fractions containing product were combined and concentrated under reduced pressure to give 6-benzyl-8-(pyridin-2-yl)pyrido[2,3-d]pyridazin-5(6H)-one, RL-10 (44 mg, 0.13 mmol). 1H NMR (400 MHz, Chloroform-d) δ 9.11 (dd, J=4.5, 1.8 Hz, 2H), 8.89 (d, J=3.9 Hz, 2H), 8.77 (dd, J=8.1, 1.8 Hz, 1H), 7.91 (s, 2H), 7.68 (dd, J=8.1, 4.5 Hz, 1H), 7.49 (dd, J=25.2, 5.7 Hz, 3H), 7.37-7.24 (m, 5H), 5.53 (s, 2H). LCMS: (M+H)+, 316. The reaction mixture was heated at 75° C. for 2 h After cooling the excess solvent was removed under reduced pressure The residue was partitioned between 15 mL of ethyl acetate and 10% aqueous sodium carbonate The aqueous fraction was further extracted with 2×15 mL of ethyl acetate dried over anhydrous sodium sulfate filtered concentrated under reduced pressure The crude residue was purified by normal phase flash chromatography eluting with 0-5% methanol in dichloromethane over 20 minutes Like fractions containing product concentrated under reduced pressure

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of pentane-2,4-dione (10.01 g) and 1,1-dimethoxy-N,N-dimethylmethanamine (12.51 g) was stirred at 80° C. for 1 hr. Tetrahydrofuran (20 mL) was added to the reaction mixture, benzylhydrazine dihydrochloride (21.46 g) was added by small portions under ice-cooling, and the mixture was stirred at 60° C. for 30 min. The reaction mixture was allowed to cool to room temperature, ethyl acetate (100 mL) and water (100 mL) were added, and the separated aqueous layer was extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with brine (20 mL) and dried over anhydrous magnesium sulfate. Insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (13.53 g) as a colorless oil. was added by small portions under ice- cooling the mixture was stirred at 60° C. for 30 min to cool to room temperature the separated aqueous layer was extracted with ethyl acetate (50 mL×2) The combined organic layers were washed with brine (20 mL) dried over anhydrous magnesium sulfate Insoluble material was removed by filtration the filtrate was concentrated under reduced pressure the residue was purified by silica gel column chromatography (ethyl acetate/hexane)

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of pentane-2,4-dione (10.01 g) and 1,1-dimethoxy-N,N-dimethylmethanamine (12.51 g) was stirred at 80° C. for 1 hr. Tetrahydrofuran (20 mL) was added to the reaction mixture, benzylhydrazine dihydrochloride (21.46 g) was added by small portions under ice-cooling, and the mixture was stirred at 60° C. for 30 min. The reaction mixture was allowed to cool to room temperature, ethyl acetate (100 mL) and water (100 mL) were added, and the separated aqueous layer was extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with brine (20 mL) and dried over anhydrous magnesium sulfate. Insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (13.53 g) as a colorless oil. was added by small portions under ice- cooling the mixture was stirred at 60° C. for 30 min to cool to room temperature the separated aqueous layer was extracted with ethyl acetate (50 mL×2) The combined organic layers were washed with brine (20 mL) dried over anhydrous magnesium sulfate Insoluble material was removed by filtration the filtrate was concentrated under reduced pressure the residue was purified by silica gel column chromatography (ethyl acetate/hexane)

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of pentane-2,4-dione (10.01 g) and 1,1-dimethoxy-N,N-dimethylmethanamine (12.51 g) was stirred at 80° C. for 1 hr. Tetrahydrofuran (20 mL) was added to the reaction mixture, benzylhydrazine dihydrochloride (21.46 g) was added by small portions under ice-cooling, and the mixture was stirred at 60° C. for 30 min. The reaction mixture was allowed to cool to room temperature, ethyl acetate (100 mL) and water (100 mL) were added, and the separated aqueous layer was extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with brine (20 mL) and dried over anhydrous magnesium sulfate. Insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (13.53 g) as a colorless oil. was added by small portions under ice- cooling the mixture was stirred at 60° C. for 30 min to cool to room temperature the separated aqueous layer was extracted with ethyl acetate (50 mL×2) The combined organic layers were washed with brine (20 mL) dried over anhydrous magnesium sulfate Insoluble material was removed by filtration the filtrate was concentrated under reduced pressure the residue was purified by silica gel column chromatography (ethyl acetate/hexane)