叔-丁基-(2-碘乙氧基)-二甲基硅烷

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

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

实验步骤: Combine (1H-benzimidazol-2-yl)(1-(ethoxycarbonyl)piperidin-4-yl)amine (4.00 g, 13.87 mmol) and dimethylformamide (12 mL) and tetrahydrofuran (60 mL). Cool in an ice-bath. Add sodium hydride (24 mg, 15.3 mmol). After 24 hours, add 2-(t-butyldimethylsilyloxy) ethyl iodide (3.97 g, 13.87 mmol). After 60 hours, add ice to quench the reaction. Evaporate the quenched reaction mixture in vacuo to remove most of the tetrahydrofuran. Partition the evaporated reaction mixture between water and ethyl acetate. Separate the layers and extract the organic layer three times with water. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with dichloromethane and then 5% methanol/dichloromethane to give (1-(2-(t-butyldimethylsilyloxy)ethyl)-1H-benzimidazol-2-yl)(1-(ethoxycarbonyl)piperidin-4-yl)amine: Rf=0.14 (silica gel, 40% ethyl acetate/dichloromethane). Cool in an ice-bath After 60 hours add ice to quench the reaction Evaporate the quenched reaction mixture in vacuo to remove most of the tetrahydrofuran Partition the evaporated reaction mixture between water and ethyl acetate Separate the layers extract the organic layer three times with water Dry the organic layer over MgSO4 filter evaporate in vacuo to give a residue

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Combine 1-(3,4,5-trimethoxybenzyl)-3-(4-(trifluoromethyl)phenylmethyl)-2-oxopyrrolidine (1.55 g, 3.66 mmol) and tetrahydrofuran (10 mL). Cool to −78° C. using a dry-ice/acetone bath. Add a solution of sec-butyllithium (3.1 mL, 1.3 M in hexane, 4.0 mmol). After 30 minutes, add a solution of 1-iodo-2-(t-butyldimethylsilyloxy)ethane (1.15 g, 4.0 mmol) in tetrahydrofuran (1 mL). After 2 hours, warm to ambient temperature. After 12 hours, add water (5 mL). Separate the layers and extract the aqueous layer three times with ethyl acetate. Dry the combined organic layers over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 1/4 ethyl acetate/hexane to give the title compound: Rf=0.79 (silica gel, 1/1 ethyl acetate/hexane). After 2 hours warm to ambient temperature After 12 hours Separate the layers extract the aqueous layer three times with ethyl acetate Dry the combined organic layers over Na2SO4 filter evaporate in vacuo to give a residue

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Combine 3-phenylpropionitrile (2.0 g, 15.25 mmol) and tetrahydrofuran (15 mL). Cool to −78° C. using a dry-ice/acetone bath. Add a solution of lithium bis(trimethylsilyl)amide (16.0 mL, 1 M in THF, 16.0 mmol). After 1 hour, add 2-(t-butyldimethylsilyloxy)ethyl iodide (4.58 g, 16.0 mmol). After the addition of 2-(t-butyldimethylsilyloxy)ethyl iodide is complete, warm slowly to ambient temperature over about 7 hours. Add water and extract twice with ethyl acetate. Dry the combined organic layers over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 5% ethyl acetate/hexane to give the title compound: Rf=0.50 (silica gel, 10% ethyl acetate/hexane). warm slowly to ambient temperature over about 7 hours Add water and extract twice with ethyl acetate Dry the combined organic layers over Na2SO4 filter concentrate in vacuo to obtain a residue

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

实验步骤: Sodium hydride (0.31 g, 7.0 mmol) was added to a solution of 3.0 g (5.82 mmol) of the title compound produced in step (i) of Reference Example 12 in N,N-dimethylformamide (19.1 ml), and the mixture was stirred at room temperature for 30 min. Thereafter, 1.65 g (5.82 mmol) of tert-butyl(2-iodoethoxy)dimethylsilane was added thereto, and the mixture was stirred at 100° C. for 21 hr. The reaction was stopped by adding sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, was dried over anhydrous sodium sulfate and was then filtered. The filtrate was concentrated under the reduced pressure. Methanol (48 ml) was added to the concentrate, 11.6 ml (11.6 mmol) of 1 N hydrochloric acid was added thereto, and the mixture was stirred at room temperature for 30 min. Sodium hydrogencarbonate was added to stop the reaction, and methanol as the solvent was removed under the reduced pressure, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine in that order, was dried over anhydrous sodium sulfate and was then filtered. The filtrate was concentrated under the reduced pressure, and the residue was purified by column chromatography on silica gel (chloroform:methanol=100:1) to give 2.22 g (yield 68%) of the title compound. the mixture was stirred at 100° C. for 21 hr the mixture was extracted with ethyl acetate The organic layer was washed with water and saturated brine in that order was dried over anhydrous sodium sulfate was then filtered The filtrate was concentrated under the reduced pressure was added the mixture was stirred at room temperature for 30 min was removed under the reduced pressure followed by extraction with ethyl acetate The organic layer was washed with water and saturated brine in that order was dried over anhydrous sodium sulfate was then filtered The filtrate was concentrated under the reduced pressure the residue was purified by column chromatography on silica gel (chloroform:methanol=100:1)

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

实验步骤: Sodium hydride (0.31 g, 7.0 mmol) was added to a solution of 3.0 g (5.82 mmol) of the title compound produced in step (i) of Reference Example 12 in N,N-dimethylformamide (19.1 ml), and the mixture was stirred at room temperature for 30 min. Thereafter, 1.65 g (5.82 mmol) of tert-butyl(2-iodoethoxy)dimethylsilane was added thereto, and the mixture was stirred at 100° C. for 21 hr. The reaction was stopped by adding sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, was dried over anhydrous sodium sulfate and was then filtered. The filtrate was concentrated under the reduced pressure. Methanol (48 ml) was added to the concentrate, 11.6 ml (11.6 mmol) of 1 N hydrochloric acid was added thereto, and the mixture was stirred at room temperature for 30 min. Sodium hydrogencarbonate was added to stop the reaction, and methanol as the solvent was removed under the reduced pressure, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine in that order, was dried over anhydrous sodium sulfate and was then filtered. The filtrate was concentrated under the reduced pressure, and the residue was purified by column chromatography on silica gel (chloroform:methanol=100:1) to give 2.22 g (yield 68%) of the title compound. the mixture was stirred at 100° C. for 21 hr the mixture was extracted with ethyl acetate The organic layer was washed with water and saturated brine in that order was dried over anhydrous sodium sulfate was then filtered The filtrate was concentrated under the reduced pressure was added the mixture was stirred at room temperature for 30 min was removed under the reduced pressure followed by extraction with ethyl acetate The organic layer was washed with water and saturated brine in that order was dried over anhydrous sodium sulfate was then filtered The filtrate was concentrated under the reduced pressure the residue was purified by column chromatography on silica gel (chloroform:methanol=100:1)

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

实验步骤: tert-Butyl (4-(2-(tert-butyldimethylsilyloxy)ethyl)-1-(2-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ylamino)furo[3,2-d]pyrimidin-4-yl)piperidin-4-yl)methylcarbamate (0.40 g, 0.587 mmol, prepared using AH from 2-iodoethanol with TBDMSCl, AF with 1-benzylpiperidine-4-carbonitrile [Ryan] with tert-butyl(2-iodoethoxy)dimethylsilane, AE, O with Boc2O, G, A with 2,4-dichlorofuro[3,2-d]pyrimidine [ArkPharm] and B with 6-amino-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one [Arkpharm]) and an aqueous solution of aqueous HCl (4 M, 7.34 mL, 29.4 mmol) were dissolved in 1,4-dioxane (15 mL) and stirred for about 4 h at rt. The mixture was concentrated under vacuum and the residue was purified by Prep-TLC (EtOAc/pet ether 1:2) to give 6-(4-(4-(aminomethyl)-4-(2-hydroxyethyl)piperidin-1-yl)furo[3,2-d]pyrimidin-2-ylamino)-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3 (4H)-one (0.121 g, 43%): LC/MS (Table 2, Method h) Rt=1.69 min.; MS m/z: 467 (M+H)+. Syk IC50=A The mixture was concentrated under vacuum the residue was purified by Prep-TLC (EtOAc/pet ether 1:2)

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

实验步骤: tert-Butyl (4-(2-(tert-butyldimethylsilyloxy)ethyl)-1-(2-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ylamino)furo[3,2-d]pyrimidin-4-yl)piperidin-4-yl)methylcarbamate (0.40 g, 0.587 mmol, prepared using AH from 2-iodoethanol with TBDMSCl, AF with 1-benzylpiperidine-4-carbonitrile [Ryan] with tert-butyl(2-iodoethoxy)dimethylsilane, AE, O with Boc2O, G, A with 2,4-dichlorofuro[3,2-d]pyrimidine [ArkPharm] and B with 6-amino-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one [Arkpharm]) and an aqueous solution of aqueous HCl (4 M, 7.34 mL, 29.4 mmol) were dissolved in 1,4-dioxane (15 mL) and stirred for about 4 h at rt. The mixture was concentrated under vacuum and the residue was purified by Prep-TLC (EtOAc/pet ether 1:2) to give 6-(4-(4-(aminomethyl)-4-(2-hydroxyethyl)piperidin-1-yl)furo[3,2-d]pyrimidin-2-ylamino)-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3 (4H)-one (0.121 g, 43%): LC/MS (Table 2, Method h) Rt=1.69 min.; MS m/z: 467 (M+H)+. Syk IC50=A The mixture was concentrated under vacuum the residue was purified by Prep-TLC (EtOAc/pet ether 1:2)

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

实验步骤: To a stirred solution of 2-iodoethanol (17.2 g; 100 mmol) and imidazole (8.17 g; 120 mmol) in dichloromethane (100 mL) was added tert-butyldimethylsilyl chloride (15.83 g; 105 mmol) at such a rate that the reaction temperature did not rise above 30° C. Upon complete addition the solution was left stirring for 17 h, then washed with water (2×50 mL) and brine (50 mL) and dried over MgSO4. Evaporation of the solvent afforded the target compound (28.0 g; 97.8 mmol; 98%) as a colourless liquid. did not rise above 30° C Upon complete addition the solution was left washed with water (2×50 mL) and brine (50 mL) dried over MgSO4 Evaporation of the solvent afforded the target compound (28.0 g; 97.8 mmol; 98%) as a colourless liquid

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Process 2: Under an argon atmosphere and at −78° C., n-butyl lithium (a 1.57M hexane solution, 4.62 ml, 7.26 mmol) was added to a dimethoxyethane solution (50 ml) of the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (2.00 g, 6.60 mmol) obtained in Example 5. The temperature of the resulting mixture was elevated to room temperature, and stirring was performed for 15 minutes. After cooling the reaction mixture to −78° C., a dimethoxyethane solution (5 ml) of t-butyl-(2-iodoethyloxy)dimethylsilane (2.08 g, 7.26 mmol) was added thereto. The resulting mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture, followed by extraction with ether. The extracts were combined, washed successively with water and brine, dried over magnesium sulfate and then, concentrated. The residue thus obtained was subjected to short silica gel chromatography (hexane:ethyl acetate=7:1) to remove high-polarity impurities. The resulting oil was dissolved in tetrahydrofuran (50 ml), and to the resulting solution was added tetrabutylammonium fluoride (a 1M tetrahydrofuran solution, 14.5 ml, 14.5 mmol). After stirring for 2 days, the solvent was distilled off. The residue thus obtained was dissolved in dichloromethane, followed by successive washing with 1N hydrochloric acid, water, and brine, driying over magnesium sulfate and concentration. The residue thus obtained was subjected to chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate=1:1 eluate was concentrated, whereby the title compound (2.07 g, 5.82 mmol, 88%) was obtained as a colorless solid. was elevated to room temperature The resulting mixture was stirred at room temperature for 15 hours followed by extraction with ether washed successively with water and brine dried over magnesium sulfate concentrated The residue thus obtained to remove high-polarity impurities The resulting oil was dissolved in tetrahydrofuran (50 ml) to the resulting solution was added tetrabutylammonium fluoride (a 1M tetrahydrofuran solution, 14.5 ml, 14.5 mmol) After stirring for 2 days the solvent was distilled off The residue thus obtained by successive washing with 1N hydrochloric acid, water, and brine driying over magnesium sulfate and concentration The residue thus obtained ethyl acetate=1:1 eluate was concentrated

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

实验步骤: Alternately, combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (1.72 g, 5.43 mmol) and sodium hydride (0.36 g, 60% in oil, 8.15 mmol) in dimethylformamide (40 mL). After 4 hours, add 2-(t-butyldimethylsilyloxy)ethyl iodide (1.56 g, 5.43 mmol). After 72 hours, heat to 80° C. After 3 hours, cool to ambient temperature and add ice to quench. Partition the reaction mixture between ethyl acetate (250 mL) and a saturated aqueous solution of sodium bicarbonate (200 mL). Separate the layers and extract the organic layer with water. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 40% ethyl acetate/dichloromethane to give 1-(t-butoxycarbonyl)-4-(1-(2-(t-butyldimethylsilyloxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane. After 72 hours After 3 hours cool to ambient temperature add ice to quench Partition the reaction mixture between ethyl acetate (250 mL) Separate the layers extract the organic layer with water Dry the organic layer over MgSO4 filter evaporate in vacuo to give a residue