* 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 selenium(IV) oxide In 1,4-dioxane for 16 h; Reflux
To a stirred solution of 2-methyl-5-nitropyridine (3.0 g, 0.021 mol, 1 eq) in 1 ,4- dioxane (30 mL) at room temperature was added selenium dioxide (2.9 g, 0.026 mol, 1.2 eq) and stirred at reflux for 16 h. The reaction mixture was filtered, evaporated, diluted with ethyl acetate (50 mL) and washed with water (50 mL), dried over sodium sulphate and evaporated to get 5-nitropicolinaldehyde (3.12g, 94 percent).
94%
With selenium(IV) oxide In 1,4-dioxane for 16 h; Reflux
Step 1 To a stirred solution of 2-methyl-5-nitropyridine (3.0 g, 0.021 mol, 1 eq) in 1,4-dioxane (30 mL) at room temperature was added selenium dioxide (2.9 g, 0.026 mol, 1.2 eq) and stirred at reflux for 16 h. The reaction mixture was filtered, evaporated, diluted with ethyl acetate (50 mL) and washed with water (50 mL), dried over sodium sulfate and evaporated to get 5-nitropicolinaldehyde (3.12 g, 94percent).
35%
Stage #1: With selenium(IV) oxide; water In 1,4-dioxane for 4 h; Heating / reflux Stage #2: With sodium hydrogencarbonate In 1,4-dioxane; diethyl ether; water
A mixture of 2-methyl-5-nitropyridine (3 g), selenium (IV) (2.9 g), 1,4- dioxane (25 mL) and water (0.5 mL) was refluxed for 4 hrs. The resulting black solid was filtered through Celite° bed and washed with ether. The filtrate was treated with saturate aqueous NaHC03 and filtered again. The filtrate was extracted with ether twice and the solvent was concentrated. The residue was purified with a short silica gel column eluted with 20percent ethyl acetate in hexane to give 1.0 g of orange precipitate 2 (35percent yield). 1H NMR (CD2Cl2): 8 10.15 (s, 1H), 9.55 (s, 1H), 8.7 (d, 1H), 8.15 (s, 1H).
Reference：
[1] Patent: WO2013/13815, 2013, A1, . Location in patent: Page/Page column 230; 231
[2] Patent: US2013/29962, 2013, A1, . Location in patent: Paragraph 1110
[3] Journal of Organic Chemistry, 2012, vol. 77, # 20, p. 8968 - 8979,12
[4] Journal of Medicinal Chemistry, 1992, vol. 35, # 20, p. 3672 - 3677
[5] Patent: WO2005/97752, 2005, A1, . Location in patent: Page/Page column 42
[6] Journal of Organic Chemistry, 1959, vol. 24, p. 1007
[7] Bulletin of the Chemical Society of Japan, 1993, vol. 66, # 3, p. 797 - 803
2
[ 29682-14-2 ]
[ 35969-75-6 ]
Yield
Reaction Conditions
Operation in experiment
60%
With diisobutylaluminium hydride In dichloromethane; toluene at -78 - 20℃; for 3 h; Inert atmosphere
To a suspension of methyl 5-nitropicolinate (LIX) (1.282 g, 7.03 mmol) in DCM (25 mL) stirred at -78°C under argon was slowly added DIBAL (1M in toluene) (9.14 mL, 9.14 mmol). The solution was allowed to warm to room temperature over 3 h. An aqueous solution of potassium sodium tartrate was added, diluted further with water and DCM. The solution was stirred at room temperature for another 30 min before the organic layer was separated. The aqueous layer was extracted 2x DCM, combined with the organic layer, dried over MgS04, filtered and evaporated under reduced pressure. The residue was purified by column chromatography to produce 5- nitropicolinaldehyde (LX) as a brown oil (0.64 g, 4.2 mmol, 60percent yield). 1H NMR (DMSO-d6) 6 ppm 8.17 (d, J=9Hz, 1H), 8.81 (dd, J=9Hz, J=2Hz, 1H), 9.56 (d, J=2Hz, 1H), 10.08 (s, 1H).
60%
With diisobutylaluminium hydride In dichloromethane; toluene at -78 - 20℃; for 3 h; Inert atmosphere
Step 1 To a suspension of methyl 5-nitropicolinate (CX) (1.282 g, 7.03 mmol) in DCM (25 mL) stirred at -78° C. under argon was slowly added DIBAL (1M in toluene) (9.14 mL, 9.14 mmol). The solution was allowed to warm to room temperature over 3 h. An aqueous solution of potassium sodium tartrate was added, diluted further with water and DCM. The solution was stirred at room temperature for another 30 min before the organic layer was separated. The aqueous layer was extracted 2*DCM, combined with the organic layer, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography to produce 5-nitropicolinaldehyde (CXI) as a brown oil (0.64 g, 4.2 mmol, 60percent yield). 1H NMR (DMSO-d6) δ ppm 8.17 (d, J=9 Hz, 1H), 8.81 (dd, J=9 Hz, J=2 Hz, 1H), 9.56 (d, J=2 Hz, 1H), 10.08 (s, 1H).
60%
With diisobutylaluminium hydride In dichloromethane; toluene at -78 - 20℃; for 3 h; Inert atmosphere
To a suspension of methyl 5-nitropicolinate (LIX) (1.282 g, 7.03 mmol) in DCM (25 mL) stirred at -78°C under argon was slowly added DIBAL (1M in toluene) (9.14 mL, 9.14 mmol). The solution was allowed to warm to room temperature over 3 h. An aqueous solution of potassium sodium tartrate was added, diluted further with water and DCM. The solution was stirred at room temperature for another 30 min before the organic layer was separated. The aqueous layer was extracted 2x DCM, combined with the organic layer, dried over MgS04, filtered and evaporated under reduced pressure. The residue was purified by column chromatography to produce 5-nitropicolinaldehyde (LX) as a brown oil (0.64 g, 4.2 mmol, 60percent yield). NMR (DMSO-d6) δ ppm 8.17 (d, J=9Hz, 1H), 8.81 (dd, J=9Hz, J=2Hz, 1H), 9.56 (d, J=2Hz, 1H), 10.08 (s, 1H).
Reference：
[1] Journal of Organic Chemistry, 2012, vol. 77, # 20, p. 8968 - 8979,12
5
[ 60891-70-5 ]
[ 35969-75-6 ]
Reference：
[1] Journal of Organic Chemistry, 2012, vol. 77, # 20, p. 8968 - 8979,12
6
[ 4487-59-6 ]
[ 35969-75-6 ]
Reference：
[1] Patent: WO2009/141386, 2009, A1,
7
[ 30651-24-2 ]
[ 35969-75-6 ]
Reference：
[1] Patent: WO2009/141386, 2009, A1,
8
[ 35969-75-6 ]
[ 36625-57-7 ]
Yield
Reaction Conditions
Operation in experiment
60%
at 0℃; for 2 h;
To a stirred solution of 5-nitropicolinaldehyde (350 g, 2.3mmol, 1.0 eq) in methanol (10 mL) was added NaBH4 (82 mg, 2.3 mmol, 1.0 eq) at 0 °C and resulting reaction mixture was stirred for 2 h. The reaction mixture was evaporated and residue dissolved in ethyl acetate (20 mL), washed with brine (30 mL), dried over sodium sulphate, evaporated to get (5-nitropyridin-2-yl)methanol (0.210 g, 60 percent).
60%
With sodium tetrahydroborate In methanol at 0℃; for 2 h;
Step 2 To a stirred solution of 5-nitropicolinaldehyde (350 g, 2.3 mmol, 1.0 eq) in methanol (10 mL) was added NaBH4 (82 mg, 2.3 mmol, 1.0 eq) at 0° C. and resulting reaction mixture was stirred for 2 h. The reaction mixture was evaporated and residue dissolved in ethyl acetate (20 mL), washed with brine (30 mL), dried over sodium sulfate, evaporated to get (5-nitropyridin-2-yl)methanol (0.210 g, 60percent).
With selenium(IV) oxide; In 1,4-dioxane; for 16h;Reflux;
To a stirred solution of 2-methyl-5-nitropyridine (3.0 g, 0.021 mol, 1 eq) in 1 ,4- dioxane (30 mL) at room temperature was added selenium dioxide (2.9 g, 0.026 mol, 1.2 eq) and stirred at reflux for 16 h. The reaction mixture was filtered, evaporated, diluted with ethyl acetate (50 mL) and washed with water (50 mL), dried over sodium sulphate and evaporated to get 5-nitropicolinaldehyde (3.12g, 94 %).
94%
With selenium(IV) oxide; In 1,4-dioxane; for 16h;Reflux;
Step 1 To a stirred solution of 2-methyl-5-nitropyridine (3.0 g, 0.021 mol, 1 eq) in 1,4-dioxane (30 mL) at room temperature was added selenium dioxide (2.9 g, 0.026 mol, 1.2 eq) and stirred at reflux for 16 h. The reaction mixture was filtered, evaporated, diluted with ethyl acetate (50 mL) and washed with water (50 mL), dried over sodium sulfate and evaporated to get 5-nitropicolinaldehyde (3.12 g, 94%).
35%
A mixture of 2-methyl-5-nitropyridine (3 g), selenium (IV) (2.9 g), 1,4- dioxane (25 mL) and water (0.5 mL) was refluxed for 4 hrs. The resulting black solid was filtered through Celite bed and washed with ether. The filtrate was treated with saturate aqueous NaHC03 and filtered again. The filtrate was extracted with ether twice and the solvent was concentrated. The residue was purified with a short silica gel column eluted with 20% ethyl acetate in hexane to give 1.0 g of orange precipitate 2 (35% yield). ¹H NMR (CD2Cl2): 8 10.15 (s, 1H), 9.55 (s, 1H), 8.7 (d, 1H), 8.15 (s, 1H).
With toluene-4-sulfonic acid; In water; toluene; for 5h;Reflux;
5-Nitropicolinaldehyde (9.13 g, 60 mmol) in toluene (400 mL) was reacted with ethylene glycol (22.5 mL, 400 mmol) in the presence of toluenesulfonic acid monohydrate (570 mg, 3 mmol) at reflux for 5 h. The reaction mixture was cooled to RT, washed with aqueous NaHCO3, water, brine, dried over Na2SO4, concentrated in vacuo to afford the crdue product, which was dissolved in EtOH (420 mL), hydrogenated in the presence of 10% Pd/C (1.5 g) at RT overnight. The reaction mixture was filtered through a pad of Celite, the filtrate was concentrated in vacuo to afford the tiltle compound, 9.6 g. ESI-MS m/z 167 (M+H)+.
EXAMPLE II 5-Nitropyridine-2-carboxaldehyde was prepared from the nitro derivative, 2-methyl-3-nitropyridine, by the procedure employed for the synthesis of Example I, except that anhydrous dioxane was used as the solvent and the reaction time was 4 h. Yield: 2.0 g (42%); mp 66-67 C. (lit. 66.5-67.5 C.); TLC, Rf 0.85 (EtOAc); 1 H NMR (90 MHz, CDCl3) delta 8.0 (d, 1H, 3-H, J3,4 =4.5 HZ), 8.30 (d, 1H, 4-H, J3,4 =4.5 Hz), 9.25 (s, 1H, 6-H), 10.45 (s, 1H, 2-CHO).
6-Nitropyridine-2-carbaldehyde (600 mg, 3.95 mmol) in anhydrous CH2Cl2 (2 mL) and pyrrolidine (391 muL, 4.73 mmol) are stirred for 15 min at RT. AcOH (371 muL) and NaBH(OAc)3 (1.17 g, 5.52 mmol) are added and the mixture is stirred for 30 min at RT. The reaction solution is divided between CH2Cl2 and saturated NaHCO3 solution, the organic phase is washed with saturated NaHCO3 solution, dried, filtered and evaporated down. Yield: 850 mg (90 %)
86%
General procedure: To a solution of 5-bromonicotinaldehyde (XXV) (5.0 g, 26.9 mmol) in DCE (108 mL) was added dimethylamine-HCl (4.39 g, 53.8 mmol) and TEA (7.5 g, 53.8 mmol). The reaction was stirred at room temperature for 1 h. NaBH(OAc)3 was added and the reaction was stirred overnight at room temperature. The reaction was diluted with DCM and sat. aq. NaHCC . The organic layer was separated, washed with water, brine, dried and concentrated under vacuum to produce l-(5-bromopyridin-3-yl)-N,N-dimethylmethanamine (XXVI) as a brown liquid (92.6% yield).
73%
A mixture of <strong>[35969-75-6]5-nitropyridine-2-carbaldehyde</strong> and pyrrolidine in 1,2-dichloroethane (20 mL) was treated with sodium triaectoxyborohydride and acetic acid. The reaction mixture was stirred at room temperature overnight. LC-MS showed major desired product peak at m/z 208 [M+H]+. The reaction mixture was quenched by adding 1 N NaOH, diluted with dichloromethane and passed through a Celite bed. The organic phase was poured to a short silica gel column and eluted with 2% MeOH (containing 1 N NH3) in dichloromethane to give dark crude product. The solvent was concentrated and the residue was purified with a short column eluted with 20% ethyl acetate in hexanes to give 1.0 g of desired product as a orange precipitate (73% yield).
C-8) 6-Pyrrolidin- 1 -ylmethyl-pyridin-3-ylamine200 mg (1.32 mmol, 1 eq) (5-nitropyridin-2-yl)-acetaldehyde are dissolved in 1 mL DCM, 130 muL (1.58 mmol, 1.2 eq) pyrrolidine are added and the mixture is stirred for 15 min atRT. Then the reaction mixture is combined successively with 90 muL (1.58 mmol, 1.2 eq) acetic acid and 390 mg (1.84 mmol, 1.4 eq) sodium trisacetoxyborohydride. It is stirred for30 min at RT and the reaction mixture is then combined with 10 mL of saturated, aqueous sodium hydrogen carbonate solution and 20 mL DCM. After phase separation the organic phase is separated off, the aqueous phase is extracted 3 times with 15 mL DCM, the combined organic phases are dried and freed from volatile constituents in vacuo. The crude product (273 mg, 1.32 mmol) is further used directly.MS-ESI+: 208 (M+H)+
5-nitro-2-formylpyridine thiosemicarbazone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.54 g (73%)
In ethanol;
EXAMPLE XI A mixture of <strong>[35969-75-6]5-nitropyridine-2-carboxaldehyde</strong> (0.50 g, 3.3 mmol) and thiosemicarbazide (0.36 g, 4 mmol) in 20 mL of 70% aqueous ethanol solution was refluxed for 2 h, cooled and filtered. The yellow precipitate that formed was washed with water and recrystallized from ethanol to give 0.54 g (73%) of product, 5-nitro-2-formylpyridine thiosemicarbazone: mp 215-217 C.; 1 H NMR (90 MHz, DMSO-d6) delta 8.25 (d, 1H, 3-H), 8.35 and 8.55 (two br s, 2H, CSNH2, D2 O exchangeable), 8.90 (dd, 1H, 4-H), 9.75 (d, 1H, 6-H), 10.15 (s, 1H, 2-CH), 11.95 (s, 1H, NNH, D2 O exchangeable). Anal. (C7 H7 N5 O2 S) C, H, N.
With potassium carbonate; In methanol; at 70℃; for 2.5h;
To a solution of <strong>[35969-75-6]5-nitro-pyridine-2-carbaldehyde</strong> (650 mg, 4.3 mmol) in MeOH (30 ml) was added tosyl isocyanide (840 mg, 4.3 mmol) followed by K2CO3 and heated with stirring at 7O0C for 2.5 h. The mixture was poured onto ice water and extracted with EtOAc then DCM. The organic components were washed with aqueous HCl (IM) and brine before drying over MgStheta4. The combined organic fractions were concentrated under vacuum to give the desired product as a yellow solid (548 mg, 67 %). 1H NMR (400 MHz, DMSO-J6) delta ppm 8.04 (d, /=8.70 Hz, 1 H), 8.10 (s, 1 H), 8.68 - 8.74 (m, 2 H), 9.42 (d, ./=2.75 Hz, 1 H).
With sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃; for 16h;
Sodium triacetoxyborohydride (1.4 g, 6.6 mmol, 2 equiv) was added portionwise to a cold (5C) solution of <strong>[35969-75-6]5-nitro-pyridine-2-carbaldehyde</strong> (Step 39.3) (0.5 g, 3.3 mmol) and N- methyl-piperazine (0.4 ml_, 3.6 mmol, 1.1 equiv) in DCM (10 ml_). The reaction mixture was allowed to warm to rt, stirred for 16 h, diluted with DCM and saturated solution of NaHCO3, and extracted with DCM. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 91 :8:1 ) to provide 0.532 g of the title compound as a yellow solid: ESI-MS: 237.2 [M+H]+; TLC: Rf = 0.31 (DCM/MeOH/NH3aq, 91 :8:1 ).
With diisobutylaluminium hydride; Rochelle's salt; In dichloromethane; water; at -78 - 20℃;Inert atmosphere;
Diisobutylaluminium hydride (1 M in DCM, 44 ml_, 44 mmol, 1.3 equiv) was added dropwise to a cold (-780C) solution of delta-nitro-pyridine^-carboxylic acid ethyl ester (step 39.4) (6.56 g, 33.5 mmol) in DCM (130 ml_), under an argon atmosphere. The reaction mixture was allowed to warm to 5C, quenched by addition of an aqueous solution of potassium sodium tartrate, diluted with DCM and H2O, stirred for 16 h at rt, and filtered through a pad of celite. The filtrate was extracted several times with DCM. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by by silica gel column chromatography (EtOAc/Hex, 1 :1 ) to provide 2.54 g of the title compound as a beige solid: ESI-MS: 151.1 [M-H]".
With potassium carbonate; In methanol; for 4h;Reflux;
First K2CO3 (36 g, 262 mmol) and then 1 -methyl- 1 -to sylmethyliso cyanide (35 g, 167 mmol) were added to a sol. of <strong>[35969-75-6]5-nitropyridine-2-carboxaldehyde</strong> (131 mmol) in MeOH (500 ml) and the r.m. was re fluxed for 4 h. The r.m. was concentrated under reduced pressure, the residue was dissolved in DCM and the organic phase was washed with H2O, dried (Na2SO4), filtered and the solvent was evaporated in vacuo. The residue was purified by flash chromatography over Silica gel (eluent: petroleum ether/EtOAc 4/1). The product fractions were collected and the solvent was evaporated. Yield: 15 g of intermediate 27 (56 %).
56%
With potassium carbonate; In methanol; for 4h;Reflux;
Example A5 a) Preparation of intermediate 10First K2Ctheta3 (36 g, 262 mmol) and then 1 -methyl- 1 -to sylmethyliso cyanide (35 g, 167 mmol) were added to a solution of <strong>[35969-75-6]5-nitropyridine-2-carboxaldehyde</strong> (20 g, 131 mmol) in MeOH (500 ml) and the r.m. was refluxed for 4 h. The r.m. was concentrated under reduced pressure, the residue was dissolved in DCM and the organic phase was washed with H2O, dried (Na2SO4), filtered and the solvent was evaporated in vacuo. The residue was purified by flash chromatography over Silica gel (eluent: petroleum ether/EtOAc 4/1). The product fractions were collected and the solvent was evaporated. Yield: 15 g of intermediate 10 (56 %).
In methanol; at 65℃; for 12h;
To a solution of <strong>[35969-75-6]5-nitropicolinaldehyde</strong> (500 mg, 3.3 mmol) in MeOH (10 mL) was added 1-methyl-1-tosylmethyl isocyanide (825 mg, 3.9 mmol) and the resulting mixture heated at 65 C. for 12 hours. The mixture was poured into water (10 mL) and extracted with 2*20 mL EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated. The resulting crude residue was purified by silica gel chromatography (eluent: EtOAc/hexanes) to give the desired product. ES/MS: 206.1 [M+H]+
With methanol; sodium tetrahydroborate; at 0℃; for 2h;
To a stirred solution of 5-nitropicolinaldehyde (350 g, 2.3mmol, 1.0 eq) in methanol (10 mL) was added NaBH4 (82 mg, 2.3 mmol, 1.0 eq) at 0 C and resulting reaction mixture was stirred for 2 h. The reaction mixture was evaporated and residue dissolved in ethyl acetate (20 mL), washed with brine (30 mL), dried over sodium sulphate, evaporated to get (5-nitropyridin-2-yl)methanol (0.210 g, 60 %).
60%
With sodium tetrahydroborate; In methanol; at 0℃; for 2h;
Step 2 To a stirred solution of 5-nitropicolinaldehyde (350 g, 2.3 mmol, 1.0 eq) in methanol (10 mL) was added NaBH4 (82 mg, 2.3 mmol, 1.0 eq) at 0 C. and resulting reaction mixture was stirred for 2 h. The reaction mixture was evaporated and residue dissolved in ethyl acetate (20 mL), washed with brine (30 mL), dried over sodium sulfate, evaporated to get (5-nitropyridin-2-yl)methanol (0.210 g, 60%).
With diisobutylaluminium hydride; In dichloromethane; toluene; at -78 - 20℃; for 3h;Inert atmosphere;
To a suspension of methyl 5-nitropicolinate (LIX) (1.282 g, 7.03 mmol) in DCM (25 mL) stirred at -78C under argon was slowly added DIBAL (1M in toluene) (9.14 mL, 9.14 mmol). The solution was allowed to warm to room temperature over 3 h. An aqueous solution of potassium sodium tartrate was added, diluted further with water and DCM. The solution was stirred at room temperature for another 30 min before the organic layer was separated. The aqueous layer was extracted 2x DCM, combined with the organic layer, dried over MgS04, filtered and evaporated under reduced pressure. The residue was purified by column chromatography to produce 5- nitropicolinaldehyde (LX) as a brown oil (0.64 g, 4.2 mmol, 60% yield). 1H NMR (DMSO-d6) 6 ppm 8.17 (d, J=9Hz, 1H), 8.81 (dd, J=9Hz, J=2Hz, 1H), 9.56 (d, J=2Hz, 1H), 10.08 (s, 1H).
60%
With diisobutylaluminium hydride; In dichloromethane; toluene; at -78 - 20℃; for 3h;Inert atmosphere;
Step 1 To a suspension of methyl 5-nitropicolinate (CX) (1.282 g, 7.03 mmol) in DCM (25 mL) stirred at -78 C. under argon was slowly added DIBAL (1M in toluene) (9.14 mL, 9.14 mmol). The solution was allowed to warm to room temperature over 3 h. An aqueous solution of potassium sodium tartrate was added, diluted further with water and DCM. The solution was stirred at room temperature for another 30 min before the organic layer was separated. The aqueous layer was extracted 2*DCM, combined with the organic layer, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography to produce 5-nitropicolinaldehyde (CXI) as a brown oil (0.64 g, 4.2 mmol, 60% yield). 1H NMR (DMSO-d6) delta ppm 8.17 (d, J=9 Hz, 1H), 8.81 (dd, J=9 Hz, J=2 Hz, 1H), 9.56 (d, J=2 Hz, 1H), 10.08 (s, 1H).
60%
With diisobutylaluminium hydride; In dichloromethane; toluene; at -78 - 20℃; for 3h;Inert atmosphere;
To a suspension of methyl 5-nitropicolinate (LIX) (1.282 g, 7.03 mmol) in DCM (25 mL) stirred at -78C under argon was slowly added DIBAL (1M in toluene) (9.14 mL, 9.14 mmol). The solution was allowed to warm to room temperature over 3 h. An aqueous solution of potassium sodium tartrate was added, diluted further with water and DCM. The solution was stirred at room temperature for another 30 min before the organic layer was separated. The aqueous layer was extracted 2x DCM, combined with the organic layer, dried over MgS04, filtered and evaporated under reduced pressure. The residue was purified by column chromatography to produce 5-nitropicolinaldehyde (LX) as a brown oil (0.64 g, 4.2 mmol, 60% yield). NMR (DMSO-d6) delta ppm 8.17 (d, J=9Hz, 1H), 8.81 (dd, J=9Hz, J=2Hz, 1H), 9.56 (d, J=2Hz, 1H), 10.08 (s, 1H).
60%
With diisobutylaluminium hydride; In dichloromethane; toluene; at -78 - 20℃; for 3h;Inert atmosphere;
To a suspension of methyl 5-nitropicolinate (CII) (1.282 g, 7.03 mmol) in DCM (25 mL) stirred at -78 C. under argon was slowly added DIBAL (1M in toluene) (9.14 mL, 9.14 mmol). The solution was allowed to warm to room temperature over 3 h. An aqueous solution of potassium sodium tartrate was added, diluted further with water and DCM. The solution was stirred at room temperature for another 30 min before the organic layer was separated. The aqueous layer was extracted 2*DCM, combined with the organic layer, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography to produce 5-nitropicolinaldehyde (CIII) as a brown oil (0.64 g, 4.2 mmol, 60% yield). 1H NMR (DMSO-d6) delta ppm 8.17 (d, J=9 Hz, 1H), 8.81 (dd, J=9 Hz, J=2 Hz, 1H), 9.56 (d, J=2 Hz, 1H), 10.08 (s, 1H).
To a stirred solution of 4-amino-piperidine-l -carboxylic acid tert-butyl ester (0.35g,1.75mmol) and <strong>[35969-75-6]5-nitro-pyridine-2-carbaldehyde</strong> (0.27g,1.75mmol) in ethanol(6ml) was added titanium isopropoxide(0.35ml) at 0C and stirred. The reaction was gradually brought to RT and stirred for 16h. Then sodium borohydride(0.066g,1.75mmol) was added followed by catalytic amount of acetic acid and stirred for 3h at ambient temperature. Upon completion, the solvents in the reaction were distilled out. The crude was diluted with 10%MuepsilonOmicronEta-Omicrontheta2 solution and washed with water. The organic layer was then dried over sodium sulfate and concentrated under reduced pressure. The obtained crude was taken was purified by (100-200mesh) silicagel column chromatography eluting the required compound with 7% MeOH-CH2Cl2 as a brown solid (0.35g).
With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃; for 16h;
Preparation Example 189 To a mixture of <strong>[35969-75-6]5-nitropyridine-2-carbaldehyde</strong> (761 mg), 2-(piperazin-1-yl)ethanol (1.23 mL), acetic acid (570 mul), and dichloromethane (20 mL), sodium triacetoxy borohydride (2.23 g) was added followed by stirring at room temperature for 16 hours. To the reaction mixture, a saturated aqueous sodium hydrogen carbonate solution was added followed by extraction with chloroform/2-propanol. An organic layer obtained was washed with saturated brine, dried over anhydrous sodium sulfate, and then filtered. After the filtrate was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to give 2-{4-[(5-nitropyridin-2-yl)methyl]piperazin-1-yl}ethanol (726 mg).
(1S,3R)-N3-[5-ethyl-4-(1H-indol-3-yl)pyrimidin-2-yl]-1-methylcyclohexane-1,3-diamine[ No CAS ]
C27H29N7O2[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With titanium(IV) isopropylate; In methanol; at 15℃; for 17h;
A mixture of (lS,3R)-N3-[5-ethyl-4-(lH-indol-3-yl)pyrimidin-2-yl]-l-methyl- cyclohexane-l,3-diamine (550 mg, 1.57 mmol), <strong>[35969-75-6]5-nitropyridine-2-carbaldehyde</strong> (263.3 mg, 1.73 mmol) and tetraisopropoxytitanium (447.3 mg, 1.57 mmol) in MeOH (10 mL) was stirred at 15 C for 17 h. Then NaBH3CN (148.3 mg, 2.36 mmol) was added and the mixture was stirred at 15 C for 7 h. The reaction mixture was poured into water (50 mL), extracted with DCM (20 mL*4), the organic layer was washed with brine (50 mL), dried over Na2S04, and concentrated. The residue was purified by silica gel chromatography (DCM/MeOH = 80/1-30/1) to give title compound (320 mg, 41.9%) as yellow solid..
(1S,3R)-N3-[5-ethyl-4-[2-(2-trimethylsilylethoxymethyl)indazol-3-yl]pyrimidin-2-yl]-1-methylcyclohexane-1,3-diamine[ No CAS ]
(1S,3R)-N3-[5-ethyl-4-[2-(2-trimethylsilylethoxymethyl)indazol-3-yl]pyrimidin-2-yl]-1-methyl-N1-[(5-nitro-2-pyridyl)methyl]cyclohexane-1,3-diamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
200 mg
A solution of (lS,3R)-N3-[5-ethyl-4-[2-(2-trimethylsilylethoxymethyl)indazol-3- yl]pyrimidin-2-yl]-l-methyl-cyclohexane-l,3-diamine (500 mg, 1.04 mmol) in DCE (30 mL) was added <strong>[35969-75-6]5-nitropyridine-2-carbaldehyde</strong> (158.21 mg, 1.04 mmol) and HOAc (62.46 mg, 1.04 mmol). The reaction mixture was stirred at 5 C for 12 h. Then NaBH(OAc)3 (440.88 mg, 2.08 mmol) was added and the mixture was stirred at 5 C for another 2 h. The mixture was evaporated and the residue was purified by column (DCM/MeOH = 80: 1-60: 1-50: 1) to give title compound (200 mg, 31.18%) as yellow oil.
(1R,3S)-N1-[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]cyclohexane-1,3-diamine[ No CAS ]
(1R,3S)-N1-[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]-N3-[(5-nitro-2-pyridyl)methyl]cyclohexane-1,3-diamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46%
To a stirred solution of (lR,3S)-Nl-[5-chloro-4-(lH-indol-3-yl)pyrimidin-2- yl]cyclohexane -1,3-diamine (2.5 g, 7.31 mmol) and <strong>[35969-75-6]5-nitropyridine-2-carbaldehyde</strong> (1.22 g, 8.04 mmol) in DCE (30 mL) was added AcOH (0.44 g, 7.31 mmol) at 11 C. Then the mixture was stirred at 11 C for 16 h. Then NaBH(OAc)3 (2.32 g, 10.97 mmol) was added, the reaction mixture was stirred at 11 C for 6 h. The mixture was added to NaHC03 solution (50 mL), extracted with DCM (50 mL%5), and the organic layer was washed with brine (100 mL), dried over Na2SC"4, filtered and evaporated. The residue was purified by silica gel chromatography (PE/EA = 1: 1 to DCM/MeOH = 50: 1) to give title compound (1.6 g, 46%) as brown solid.
(E)-N-[6-[[[(1S,3R)-3-[[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino]cyclohexyl]methylamino]methyl]-3-pyridyl]-4-(dimethylamino)but-2-enamide[ No CAS ]
(E)-N-(6-((((1S,3R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)pyridin-3-yl)-4-(dimethylamino)-N-methylbut-2-enamide hydrochloride[ No CAS ]
(E)-4-(dimethylamino)-N-[6-[[[(1S,3R)-3-[[4-(1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-1-methylcyclohexyl]amino]methyl]-3-pyridyl]but-2-enamide hydrochloride[ No CAS ]
tert-butyl ((1S,3R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)cyclohexyl)((5-((E)-4-(dimethylamino)-N-methylbut-2-enamido)pyridin-2-yl)methyl)carbamate[ No CAS ]
tert-butyl (1S,3R)-3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl((5-((E)-4-(dimethylamino)but-2-enamido)pyridin-2-yl)methyl)carbamate[ No CAS ]
(1S,3R)-N3-[4-(1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]-1-methylcyclohexane-1,3-diamine[ No CAS ]
(1S,3R)-N3-[4-(1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]-1-methyl-N1-[(5-nitro-2-pyridyl)methyl]cyclohexane-1,3-diamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
42%
To a solution of (lS,3R)-N3-[4-(lH-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]-l- methyl- cyclohexane- 1,3 -diamine (300 mg, 0.77 mmol) and <strong>[35969-75-6]5-nitropyridine-2-carbaldehyde</strong> (152.34 mg, 1.0 mmol) in DCE (10 mL) was added HOAc (46.26 mg,0.77 mmol) at 0 C and the mixture was stirred at 15 C for 1 h. Then NaBH(OAc)3 (489.82 mg, 2.31 mmol) was added at 0 C and the mixture was stirred at 15 C for 1 h. The mixture was concentrated, and the residue was purified by column to give title compound (200 mg, 42%) as yellow solid.
Chemistry
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