维生素K3

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

实验步骤: First, vitamin K3 is reduced with a suitable reducing agent (e.g., zinc and hydrochloric acid) to form 1,4-dihydroxy-2-methylnaphthalene (III), which then is mono-acylated with an acylation reagent (e.g., benzoyl chloride) in the presence of a deacidification agent (e.g., pyridine), and, optionally, further benzylated with a benzylation reagent (e.g., benzyl bromide) and treated with an acid or a base (deacylation). Position 4 has thus undergone O-acylation or O-benzylation, providing 4-O-acyl-2-methylnaphthol or 4-O-benzyl-3-methylnaphthol (IV). Then, this is reacted with epichlorohydrin (chloromethyloxirane) in the presence of a deacidification agent to form 4-acyloxy-2-methyl-1-(2,3-epoxypropane)naphthol or 4-benzyloxy-3-methyl-1-(2,3-epoxypropane)naphthol (V), which in turn is reacted with a pyridylpiperazine, a pyrimidylpiperazine or a B1B2-substituted phenylpiperazine to form 1-(2-methyl-4-acyloxynaphthoxy)-3-[4-(2-pyridyl)-1-piperazinyl]-propan-2-ol, 1-(2-methyl-4-acyloxynaphthoxy)-3-[4-(2,6-pyrimidyl)-1-piperazinyl]propan-2-ol, or 1-(2-methyl-4-acyloxynaphthoxy)-3-[4-(B1B2-substituted phenyl)-1-piperazinyl]propan-2-ol or 1-(3-methyl-4-benzyloxynaphthoxy)-3-[4-(substitute moiety respectively corresponding to those aforementioned)-1-piperazinyl]propan-2-ol (VI), the protecting acyl or benzyl group at position 4 of which then is cleaved with a base or by catalytic reduction to give the present compound (I).

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

实验步骤: First, vitamin K3 is reduced with a suitable reducing agent (e.g., zinc and hydrochloric acid) to form 1,4-dihydroxy-2-methylnaphthalene (III), which then is mono-acylated with an acylation reagent (e.g., benzoyl chloride) in the presence of a deacidification agent (e.g., pyridine), and, optionally, further benzylated with a benzylation reagent (e.g., benzyl bromide) and treated with an acid or a base (deacylation). Position 4 has thus undergone O-acylation or O-benzylation, providing 4-O-acyl-2-methylnaphthol or 4-O-benzyl-3-methylnaphthol (IV). Then, this is reacted with epichlorohydrin (chloromethyloxirane) in the presence of a deacidification agent to form 4-acyloxy-2-methyl-1-(2,3-epoxypropane)naphthol or 4-benzyloxy-3-methyl-1-(2,3-epoxypropane)naphthol (V), which in turn is reacted with a pyridylpiperazine, a pyrimidylpiperazine or a B1B2-substituted phenylpiperazine to form 1-(2-methyl-4-acyloxynaphthoxy)-3-[4-(2-pyridyl)-1-piperazinyl]-propan-2-ol, 1-(2-methyl-4-acyloxynaphthoxy)-3-[4-(2,6-pyrimidyl)-1-piperazinyl]propan-2-ol, or 1-(2-methyl-4-acyloxynaphthoxy)-3-[4-(B1B2-substituted phenyl)-1-piperazinyl]propan-2-ol or 1-(3-methyl-4-benzyloxynaphthoxy)-3-[4-(substitute moiety respectively corresponding to those aforementioned)-1-piperazinyl]propan-2-ol (VI), the protecting acyl or benzyl group at position 4 of which then is cleaved with a base or by catalytic reduction to give the present compound (I).

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 4.9g of concentrated sulfuric acid were added dropwise, with stirring, to a mixture of 4.75 g (27.6 mmole) of 2-methyl-1,4-naphthoquinone, 2.71 g (41.4 mmole) of zinc powder, 15 mL of 2-methoxyethanol and 15 mL of toluene, in an ice bath. After the addition was completed, the reaction mixture was stirred for 5 hours at 100° C. The reaction product was extracted with ethyl acetate, washed with water, then brine, dried over sodium sulfate, filtered, then evaporated under reduced pressure to give 4.87 g (76% yield) of the title compound. The resultant product had a melting point of 100-101° C. and an 1HNMR as follows: (300 Hz, DMSO-d6) δ 2.33 (s, 3H), 3.34 (s, 3H), 3.79 (t, 2H, J=4.5 Hz), 4.21 (t, 2H, J=4.5 Hz), 6.78(s, 1H), 7.47 (m, 2H), 8.08 (d, 1H, J=8.0 Hz), 8.14 (d, 1H, J=8.0 Hz), 8.54 (s, 1H). The mass spectrum showed a molecular ion at m/z 232. After the addition The reaction product was extracted with ethyl acetate washed with water brine, dried over sodium sulfate filtered evaporated under reduced pressure

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 4.9g of concentrated sulfuric acid were added dropwise, with stirring, to a mixture of 4.75 g (27.6 mmole) 2-methyl-1,4 naphthoquinone, 2.71 g (41.4 mmole) of zinc powder, 15 mL of ethylene glycol and 15 mL of toluene in an ice bath. After the addition was complete, the reaction mixture was stirred for 5 hours at 100° C. The reaction product was extracted with ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered, then evaporated under reduced pressure to give 4.21 g (70% yield) of the above product. That product had a melting point of 136.3-136.8° C. and an 1HNMR as follows: (300 MHz, DMSO-d6) δ 2.37 (s, 3H), 3.86 (m, 2H), 4.10 (t, 2H, J=4.8 Hz), 4.98 (t, 1H, J=5.4 Hz), 6.76 (s, 1H), 7.42 (m, 2H), 8.14 (d, 1H, J=9.0 Hz), 8.17 (d, 1H, J=9.0 Hz), 8.51 (s, 1H). The mass spectrum showed a molecular ion at m/z 218. After the addition The reaction product was extracted with ethyl acetate washed with water, brine dried over sodium sulfate filtered evaporated under reduced pressure

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 4.9g of concentrated sulfuric acid were added dropwise, with stirring, to a mixture of 4.75 g (27.6 mmole) 2-methyl-1,4 naphthoquinone, 2.71 g (41.4 mmole) of zinc powder, 15 mL of ethylene glycol and 15 mL of toluene in an ice bath. After the addition was complete, the reaction mixture was stirred for 5 hours at 100° C. The reaction product was extracted with ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered, then evaporated under reduced pressure to give 4.21 g (70% yield) of the above product. That product had a melting point of 136.3-136.8° C. and an 1HNMR as follows: (300 MHz, DMSO-d6) δ 2.37 (s, 3H), 3.86 (m, 2H), 4.10 (t, 2H, J=4.8 Hz), 4.98 (t, 1H, J=5.4 Hz), 6.76 (s, 1H), 7.42 (m, 2H), 8.14 (d, 1H, J=9.0 Hz), 8.17 (d, 1H, J=9.0 Hz), 8.51 (s, 1H). The mass spectrum showed a molecular ion at m/z 218. After the addition The reaction product was extracted with ethyl acetate washed with water, brine dried over sodium sulfate filtered evaporated under reduced pressure

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 4.9 g of concentrated sulfuric acid were added dropwise to a stirred mixture of 4.75 g (27.6 mmole) of 2-methyl-1,4-naphthoquinone, 2.71 g (41.4 mmole) of zinc powder, 15 mL of methanol and 15 mL of toluene, in an ice bath. After the addition was complete, the reaction mixture was stirred for 4.5 hours at 60° C. The reaction product was extracted with ethyl acetate, washed with water then brine, dried over sodium sulfate, filtered, then evaporated under reduced pressure to yield 4.25 gm (81% yield) of the title compound as an off-white powder having a melting point of 102-103° C. and an 1HNMR as follows: (300 MHz, DMSO-d6) δ 2.38 (s, 3H), 3.91 (s, 3H), 6.76 (s, 1H), 7.42(m, 2H), 8.04 (d, 1H, J=8.1 Hz), 8.14 (d, 1H, J=8.1 Hz), 8.50(bs, 1H). The mass spectrum showed a molecular ion at m/z 188. After the addition The reaction product was extracted with ethyl acetate washed with water brine, dried over sodium sulfate filtered evaporated under reduced pressure

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

实验步骤: Menadione crystalline (1) (5 g, 29.04 mmol, 1 equivalent) and 2 M NaOH (7.26 mL, 14.52 mmol, 0.5 equivalents) are dissolved in a mixture of methanol/water 4:1 (50 mL) at 0-2° C. After stirring at this temperature for 10 minutes, 35% hydrogen peroxide is added (4.2 mL, 43.56 mmol, 1.5 equivalents). Work-up: after 30 minutes at 0° C. the product is extracted with ethyl ether. The organic phase is dried over Na2SO4 and evaporated under reduced pressure. A whitish powder is obtained (5 g, 26.57 mmol). Yield: 91.5%. after 30 minutes at 0° C. the product is extracted with ethyl ether The organic phase is dried over Na2SO4 evaporated under reduced pressure A whitish powder is obtained (5 g, 26.57 mmol)

反应条件: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-Methyl-[1,4]-naphthoquinone (5 g, 29 mmol) and ether (200 ml) were mixed in a reaction vessel replaced with argon, and this solution was cooled to -10° C. A suspension (40 ml) of lithium aluminum hydride (1.0 g, 26.3 mmol) in ether was added dropwise to this solution over 40 minutes, and the mixture was stirred at room temperature for 0.5 hour. To the reaction mixture was added dropwise 1N hydrochloric acid (100 ml) to stop the reaction. The aqueous layer was extracted twice with ethyl acetate (100 ml). The organic layers were combined, washed twice with saturated brine (50 ml), 3 times with a saturated aqueous sodium hydrogencarbonate solution (30 ml) and twice with saturated brine (50 ml), and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. Water (10 ml) and conc. hydrochloric acid (10 ml) were added to the obtained residue, and the mixture was refluxed under heating for 2 hours. Water (50 ml) was added to this reaction mixture, and the aqueous layer was extracted twice with ether (50 ml). The organic layer was washed with water (30 ml), washed twice with a saturated aqueous sodium hydrogencarbonate solution (30 ml) and twice with saturated brine (30 ml), and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane/ethyl acetate=30/1-10/1) to give 3-methylnaphthalen-1-ol in a mixture of compounds structurally unidentified. The mixture was not further purified, but used for the next reaction. the reaction The aqueous layer was extracted twice with ethyl acetate (100 ml) washed twice with saturated brine (50 ml), 3 times with a saturated aqueous sodium hydrogencarbonate solution (30 ml) and twice with saturated brine (50 ml) dried over anhydrous magnesium sulfate The drying agent was filtered off the filtrate was concentrated under reduced pressure Water (10 ml) and conc. hydrochloric acid (10 ml) were added to the obtained residue the mixture was refluxed under heating for 2 hours Water (50 ml) was added to this reaction mixture the aqueous layer was extracted twice with ether (50 ml) The organic layer was washed with water (30 ml) washed twice with a saturated aqueous sodium hydrogencarbonate solution (30 ml) and twice with saturated brine (30 ml) dried over anhydrous magnesium sulfate The drying agent was filtered off the filtrate was concentrated under reduced pressure The obtained residue was purified by column chromatography (hexane/ethyl acetate=30/1-10/1)

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

实验步骤: According to Flowchart V, 2,3-epoxy-2-methyl-1,4-naphthoquinone 11 is reacted with an amine 2, where R2, R3, R4 and R5 are as described above, in absolute ethanol with heat for several hours, producing the 3-methyl-1,4-naphthalenedione derivatives 12. with heat for several hours

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

实验步骤: First, vitamin K3 is reduced with a suitable reducing agent (e.g., zinc and hydrochloric acid) to form 1,4-dihydroxy-2-methylnaphthalene (III), which then is mono-acylated with an acylation reagent (e.g., benzoyl chloride) in the presence of a deacidification agent (e.g., pyridine), and, optionally, further benzylated with a benzylation reagent (e.g., benzyl bromide) and treated with an acid or a base (deacylation). Position 4 has thus undergone O-acylation or O-benzylation, providing 4-O-acyl-2-methylnaphthol or 4-O-benzyl-3-methylnaphthol (IV). Then, this is reacted with epichlorohydrin (chloromethyloxirane) in the presence of a deacidification agent to form 4-acyloxy-2-methyl-1-(2,3-epoxypropane)naphthol or 4-benzyloxy-3-methyl-1-(2,3-epoxypropane)naphthol (V), which in turn is reacted with a pyridylpiperazine, a pyrimidylpiperazine or a B1B2-substituted phenylpiperazine to form 1-(2-methyl-4-acyloxynaphthoxy)-3-[4-(2-pyridyl)-1-piperazinyl]-propan-2-ol, 1-(2-methyl-4-acyloxynaphthoxy)-3-[4-(2,6-pyrimidyl)-1-piperazinyl]propan-2-ol, or 1-(2-methyl-4-acyloxynaphthoxy)-3-[4-(B1B2-substituted phenyl)-1-piperazinyl]propan-2-ol or 1-(3-methyl-4-benzyloxynaphthoxy)-3-[4-(substitute moiety respectively corresponding to those aforementioned)-1-piperazinyl]propan-2-ol (VI), the protecting acyl or benzyl group at position 4 of which then is cleaved with a base or by catalytic reduction to give the present compound (I).

实验步骤: 投料: 三口瓶中加入25ml 的双环戊二烯（沸点：170℃），上方安装克氏蒸馏头，连接牛角管（尾接管），取一个250ml单口瓶加入6g SM1、60ml MeOH、6ml H2O搅拌溶解，安装加热套置于牛角管下方，维持35至40℃搅拌，对三口瓶升温至185℃搅拌蒸馏，双环戊二烯分解成环戊二烯滴入单口瓶反应体系中，观察蒸干后继续补充50ml 双环戊二烯，不过夜，时刻观察安全情况，未反应完则停止加热次日重新加热。\n监测: 现象：反应液由黄色逐渐变成无色，待反应完全后停止加热。TLC点板监测（DCM:MeOH=20:1）反应完全且体系干净。\n后处理: 浓缩旋干反应液后得到4.68g白色固体，送检数据HPLC纯度99.887%

实验步骤: 投料: 加入SM1至EA中溶解，加入DMAP，乙酸酐至体系中，置换N2，加入钯碳，置换H2，室温搅拌过夜 点板（PE:EA=3:1）或GCMS监测反应进程 后处理：硅藻土垫抽滤，EA洗涤滤渣，滤液用水洗涤两次，有机相用饱和食盐水洗涤，无水硫酸钠干燥，减压蒸馏得到粗品