* 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.
Synthesis of the compound 26 The compound 25 (10g, 0.065 mol) was added into 50 mL of phosphorus oxychloride and heated under reflux for 4 h, then was subject to a distillation under a reduced pressure to remove most of phosphorus oxychloride, and the remaining part was poured into 200 g of ice-water, followed by agitation for 2h. A large amount of the precipitate was precipitated, filtrated under a reduced pressure, and vacuum-dried to obtain 10 g of a white product with a yield of 89percent. The melting point is 68.5-70.5°C (water) [J.O.C. , 1955, 20, 1729-1731].
Reference：
[1] Patent: EP2366691, 2011, A1, . Location in patent: Page/Page column 11-12
[2] Journal of Medicinal Chemistry, 2000, vol. 43, # 22, p. 4288 - 4312
[3] Journal of the American Chemical Society, 1952, vol. 74, p. 3828,3830
2
[ 21901-29-1 ]
[ 39745-39-6 ]
[ 56057-19-3 ]
Reference：
[1] Journal of the American Chemical Society, 1947, vol. 69, p. 63,66
[2] Journal of Heterocyclic Chemistry, 1996, vol. 33, # 6, p. 1815 - 1821
[3] Journal of the American Chemical Society, 1947, vol. 69, p. 63,66
[4] Journal of Heterocyclic Chemistry, 1996, vol. 33, # 6, p. 1815 - 1821
3
[ 1824-81-3 ]
[ 56057-19-3 ]
Reference：
[1] Journal of the American Chemical Society, 1947, vol. 69, p. 63,66
[2] Patent: EP2366691, 2011, A1,
4
[ 21901-29-1 ]
[ 56057-19-3 ]
Reference：
[1] Journal of the American Chemical Society, 1952, vol. 74, p. 3828,3830
[2] Patent: EP2366691, 2011, A1,
5
[ 109-06-8 ]
[ 56057-19-3 ]
Reference：
[1] Journal of the American Chemical Society, 1947, vol. 69, p. 63,66
6
[ 33986-37-7 ]
[ 22280-60-0 ]
[ 56057-19-3 ]
[ 28489-45-4 ]
Reference：
[1] Archiv der Pharmazie, 1995, vol. 328, # 3, p. 247 - 255
7
[ 56057-19-3 ]
[ 39745-40-9 ]
Reference：
[1] Chemistry of Heterocyclic Compounds, 1996, vol. 32, # 10, p. 1173 - 1177
[2] Journal of the American Chemical Society, 1947, vol. 69, p. 63,66
8
[ 33986-37-7 ]
[ 22280-60-0 ]
[ 56057-19-3 ]
[ 28489-45-4 ]
Reference：
[1] Archiv der Pharmazie, 1995, vol. 328, # 3, p. 247 - 255
9
[ 21901-29-1 ]
[ 39745-39-6 ]
[ 56057-19-3 ]
Reference：
[1] Journal of the American Chemical Society, 1947, vol. 69, p. 63,66
[2] Journal of Heterocyclic Chemistry, 1996, vol. 33, # 6, p. 1815 - 1821
[3] Journal of the American Chemical Society, 1947, vol. 69, p. 63,66
[4] Journal of Heterocyclic Chemistry, 1996, vol. 33, # 6, p. 1815 - 1821
10
[ 56057-19-3 ]
[ 21203-68-9 ]
[ 39745-39-6 ]
Reference：
[1] Journal of the American Chemical Society, 1954, vol. 76, p. 596,598
11
[ 56057-19-3 ]
[ 30651-24-2 ]
Reference：
[1] Journal of the American Chemical Society, 1954, vol. 76, p. 3167
12
[ 56057-19-3 ]
[ 54957-86-7 ]
Reference：
[1] Chemistry of Heterocyclic Compounds, 1996, vol. 32, # 10, p. 1173 - 1177
13
[ 56057-19-3 ]
[ 185017-72-5 ]
Reference：
[1] Chemistry of Heterocyclic Compounds, 1996, vol. 32, # 10, p. 1173 - 1177
14
[ 56057-19-3 ]
[ 353277-27-7 ]
Yield
Reaction Conditions
Operation in experiment
90%
at 15 - 50℃; for 20 h;
2-Chloro-6-methyl-3-nitropyridine (97 g, 560 mmol) was slowly added to a flask previously charged with 18 M H2SO4 (400 mL) with stirring. Chromium trioxide (169 g, 1.69 mol) was added to the reaction mixture in small portions keeping the temperature below 50° C. The reaction mixture was stirred at 15° C. for 20 h. The resultant green gum was poured into 2 Kg of ice and the resultant solids collected by filtration and dried under vacuum to yield 6-chloro-5-nitropicolinic acid (103 g, 90percent) as a pale solid. 1H NMR (400 MHz, DMSO-d6) δ 8.70 (d, 1H), 8.24 (d, 1H).
70%
at 30℃; for 40 h;
Synthesis of the compound 27 The compound 26 (5 g, 0.029 mol) was dissolved in a concentrated sulphuric acid (10 mL) with agitation, a sodium dichromate (11.7 g, 0.039 mol) was added slowly in batches into the system, and the reaction was run at 30°C for 40 h. The above reaction liquid was added slowly into broken ice (300 g). A large amount of a white precipitate was precipitated, filtrated under reduced pressure, and vacuum-dried to obtain 3.8 g of a white product with a yield of 70percent. The melting point is 187.5-189.5 °C (water).
tetrakis(triphenylphosphine)palladium (0); In tetrahydrofuran; dichloromethane;
C. 2-Phenyl-5-nitro-6-methylpyridine A mixture of Compound B and <strong>[56057-19-3]2-chloro-3-nitro-6-methylpyridine</strong> (0.42 g, 2.40 mmol) in THF (10 mL) was degassed with nitrogen. Tetrakistriphenylphosphine palladium (28 mg, 0.024 mmol) was added and the mixture was stirred 30 minutes. 25 Phenylboronic acid (0.44 g, 3.6 mmol) and 2M Na2 CO3 (1.8 mL) were added and the mixture was heated at 75 C. for 17 hours and stirred at room temperature for 48 hours. Methylene chloride was added and the mixture was filtered through celite and partitioned. The mixture was washed with saturated aqueous NaHCO3, dried (magnesium sulfate), filtered and evaporated to afford 0.77 g of brown solid. Flash chromatography (silica, 10% ethyl acetate/hexanes) afforded 0.37 g of Compound C (72%) as an off white solid and 0.05 g of 2-phenyl-3-nitro-6-methylpyridine (10%) as an oil.
With peracetic acid; trifluoroacetic acid; In acetic acid;
Step 1 <strong>[56057-19-3]2-Chloro-3-nitro-6-picoline</strong>-N-oxide <strong>[56057-19-3]2-Chloro-3-nitro-6-picoline</strong> (2 g, 11.6 mmol) was added to an ice cooled mixture of trifluoroacetic acid (6 mL) and 30% peracetic acid in acetic acid (6 mL). The mixture was allowed to warm to room temperature over 30 minutes and was heated in a 60 C. oil bath for 5 hours. The mixture was partitioned between methylene chloride (100 mL) and water (50 mL). The pH was adjusted to 8 with 2.5 N sodium hydroxide and the aqueous layer was extracted with more methylene chloride (2*50 mL). The combined methylene chloride layers were dried with magnesium sulfate, filtered and evaporated to give the title compound as a white solid (1.6g). 1 H NMR (CDCl3, 300 MHz) delta2.62(s, Me), 7.35 (d, ArH), 7.66 (d, ArH).
EXAMPLE P1 Preparation of 7-chloro-5-methyl-1H-pyrrolo[2,3-c]pyridine (P1.1) Vinylmagnesium bromide solution (1 M in THF, 111 mL, 111 mmol) was added dropwise at -78 C. to a solution of <strong>[56057-19-3]2-chloro-3-nitro-6-picoline</strong> (6.19 g, 35.2 mmol) in THF (200 mL). The dry ice cooling bath was replaced by an ice/NaCl cooling bath, and the reaction mixture was allowed to reach RT over 18 h, then the reaction mixture was carefully treated with 20% aq. ammonium chloride solution (210 mL). The reaction mixture was extracted with ethyl acetate, the organic layer was dried (MgSO4), and evaporated. Chromatography of the residue (SiO2, heptane/ethyl acetate gradient) afforded the title compound (2.58 g, 44%). Orange solid, MS (EI) 166.1 (100, M+).
dichloromethane-methanol-38% aqueous ammonia[ No CAS ]
[ 155790-09-3 ]
Yield
Reaction Conditions
Operation in experiment
83%
With hydrogen; methylamine;palladium on activated carbon; In methanol;
Step A Preparation of 6,N2-dimethyl-pyridine-2,3-diamine <strong>[56057-19-3]2-Chloro-6-methyl-3-nitropyridine</strong> (2.5 g, 14.5 mmol) was stirred in 1.0 M solution of methylamine (40 ml, 40 mmol) in methanol at 70 C. for 60 min. After cooling to ambient temperature, and methanol (60 ml) and 10% palladium on activated carbon were added and the resulting mixture was shaken under 40 psi of hydrogen gas at ambient temperature for 30 min. The mixture was filtered through a pad of Celite and concentrated in vacuum. Chromatography on silica gel, eluding with a mixture dichloromethane-methanol-38% aqueous ammonia (9:1:0.1) yielded the title compound (1.65 g, 83%).
trans-1-(4-ethoxycyclohexyl)-4-piperidinamine dihydrochloride[ No CAS ]
[ 56057-19-3 ]
N-{1-[trans-4-(ethyloxy)cyclohexyl]-4-piperidinyl}-6-methyl-3-nitro-2-pyridinamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 75℃; for 18h;
Description 27; . lambda/-{1-[rrans-4-(Ethyloxy)cyclohexyl]-4-piperidinyl}-6-methyl-3- nitro-2-pyridinamine (D27); A stirred solution of <strong>[56057-19-3]<strong>[56057-19-3]2-chloro-6-methyl-3-nitropyridin</strong>e</strong> (135mg, 0.78 mmol) in N, N- dimethylformamide (5ml) at room temperature under argon was treated with diisopropylethylamine (0.53ml, 3.0mmol) and 1-(frans-4-ethoxycyclohexyl)piperidin-4- amine dihydrochloride (the dihydrochloride salt of D17, 250mg, 0.84 mmol) and then heated at 75 0C for 18 hours. The mixture was concentrated under reduced pressure and the residue was treated with 10% Na2CO3 solution and extracted with ethyl acetate. The extract was dried (Na2SO4), concentrated under reduced pressure and the residue purified by chromatography on silica gel (2Og) eluting with 0-10% MeOH/dichloromethane to afford the title compound as an orange solid (170mg, 60%). MH+ 363. <n="64"/>1H NMR delta (CDCI3, 400MHz): 1.15-1.40 (4H, m + 3H, t), 1.55-1.70 (2H, m), 1.90-2.00 (2H, m), 2.05-2.18 (4H, m), 2.30-2.40 (1 H, m), 2.40-2.52 (2H, m + 3H, s), 2.83-2.93 (2H, m), 3.12-3.25 (1 H, m), 3.52 (2H, q), 4.21-4.32 (1 H, m), 6.47 (1 H, d), 8.27 (2H, 2 x d).
1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinamine dihydrochloride[ No CAS ]
[ 56057-19-3 ]
N-{1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-6-methyl-3-nitro-2-pyridinamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃;
Description 36. ; lambda/-{1 -[frans-4-(ethyloxy)-1 -methylcyclohexyl]-4-piperidinyl}-6- methyl-3-nitro-2-pyridinamine. (D36); <strong>[56057-19-3]2-Chloro-6-methyl-3-nitropyridine</strong> (155 mg, 0.9 mmol), 1-[frans-4-(ethyloxy)-1- methylcyclohexyl]-4-piperidinamine dihydrochloride (D26, 0.7 eq., 150 mg, 0.63 mmol), DIPEA (1 eq., 0.15 ml, 0.9 mmol) were dissolved in dimethylformamide (2 ml) and the mixture was heated at 80 0C overnight. The reaction mixture was then cooled to Rt and poured onto a saturated aqueous solution of NaHCO3. The aqueous phase obtained was extracted with EtOAc (3x), the organic extracts combined and then washed with brine (2x). The solvent was partially evaporated and the residue purified by SXC first and then by silica chromatography (25S <n="68"/>cartridge, MeOH-NH3-DCM) to afford the title compound as a yellow product (177 mgs, 75%), M+ + H = 377.
A well homogenised mixture of the Compound of Example 3 (23 mg, 0.11 mmol) and 6-chloro-5-nitro-2-picoline (26.2 mg, 0.15 mmol) was stirred at 120 C. for 0.5 h. The reaction crude was purified by flash chromatography (EtOAc-Petroleum Ether gradient from 3:7 to 4:6) affording the title product (21 mg).1H-NMR (CDCl3, delta): 2.48 (s, 3H), 2.49-2.53 (m, 2H), 2.67 (s, 3H), 2.81-2.86 (m, 2H), 3.49-3.55 (m, 2H), 3.56-3.60 (m, 2H), 5.66 (s, 1H), 6.61 (d, 1H, J=8.2 Hz), 7.13-7.18 (m, 1H), 7.29-7.35 (m, 1H), 7.60-7.70 (m, 1H), 8.09 (d, 1H, J=8.2 Hz)MS: [M+H]+=349.41
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 48h;
Example 1: (S)-3-[l-(l,4-Dimethyl-lH-indol-3-ylmethyl)-5-methyl-2-oxo-l,2- dihydro-imidazo[4,5-b]pyridin-3-yl]-hexanoic acid(S)-3-(6-Methyl-3-nitro-pyridin-2-ylamino)-hexanoic acid ethyl ester. To a solution of <strong>[56057-19-3]2-chloro-3-nitro-6-picoline</strong> (500 mg, 2.99 mmol) in DMF (3 niL) were added the (S)-3-amino-hexanoic acid ethyl ester (554 mg, 3.48 mmol) and diisopropylethyl amine (DIPEA) (1.0 mL, 5.80 mmol). The reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was then diluted with ethyl acetate and washed with water (x4). The organic phase was then dried over Na2SO4 and concentrated. The resulting residue was purified by preparative TLC using hexane and ethyl acetate (4: 1) as an eluent to afford 358 mg (42 %) of the title compound as orange oil. LCMS, M++l, m/z: 296.65.
(R)-3-amino-3-phenylpropionic acid ethyl ester hydrochloride[ No CAS ]
[ 1217530-32-9 ]
Yield
Reaction Conditions
Operation in experiment
100%
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 70℃; for 12h;
Example 2: (R)-3-[l-(l,4-Dimethyl-lEta-indol-3-ylmethyl)-5-methyl-2-oxo-l,2- dihydro-imidazo[4,5-b]pyridin-3-yl]-3-phenyl-propionic acid (R)-3-(6-Methyl-3-nitro-pyridin-2-ylamino)-3-phenyl-propionic acid ethyl ester. To a solution of <strong>[56057-19-3]2-chloro-3-nitro-6-picoline</strong> (200 mg, 1.16 mmol) in DMF (3 mL) were added (R)-3-amino-3-phenylpropanoic acid ethyl ester hydrochloride (319 mg, 1.39 mmol) and DIPEA (0.5 mL, 2.90 mmol)). The reaction mixture was stirred at 70 0C for 12 hours. The reaction mixture was then diluted with ethyl acetate and washed with water (x4). The organic phase was then dried over Na2SO4 and concentrated to afford 398 mg (100%) of the title compound as orange oil. The resulting residue was used for the next reaction without further purification. LCMS, M++l, m/z: 330.29.
4-[(2E)-3-phenyl-prop-2-enylidene]-piperidine[ No CAS ]
[ 56057-19-3 ]
[ 1239713-30-4 ]
Yield
Reaction Conditions
Operation in experiment
41.5%
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 160℃; for 0.0333333h;Microwave irradiation;
l-(6-Methyl-3-nitro-2-pyridyl)-4-f(E)-3-phenyl-prop-2-enylidene]-piperidineTo a solution of 49.8 mg (0.25 mmol) of Compound Ib in 1.5 ml of N- methylpyrrolidone was added <strong>[56057-19-3]<strong>[56057-19-3]2-chloro-6-methyl-3-nitropyridin</strong>e</strong> (52.8 mg., 0.3 mmol) and 51.8 mg (0.375 mmol) of potassium carbonate. The reaction mixture was irradiated in a microwave oven ("Personal Chemistry") at 160C for 2 min. The vial was cooled to r.t., water was added and the product was extracted with EtOAc, washed with brine, dried over Na2SO4 and evaporated to dryness affording 115 mg of a crude product, which was purified by automated flash chromatography (SPl TM - Biotage) eluting with Petroleum Ether - EtOAc 98:2 to afford 34.8 mg (41.5%) of the title product as a yellow oil that solidifies on standing. MS: [M+H]+ = 336.401H-NMR (CDCl3 S): 2.43-2.53 (m, 5H), 2.62-2.70 (m, 2H), 3.48-3.60 (m, 4H), 6.14 (d, IH),6.56 (d, IH), 6.60 (d, IH), 6.97-7.08 (m, IH), 7.20-7.27 (m, IH), 7.30-7.38 (m, 2H), 7.40-7.46 (m, 2H), 8.10 (d, IH).
With triethylamine; In N,N-dimethyl acetamide; at 20℃;
l-(6-Methyl-3-nitro -2-pyridyl)-4-[3-(3-methoxyphenyl)-prop-2-enylidenel-piperidineA solution of Compound 6d (18 mg, 0.078 mmol), <strong>[56057-19-3]<strong>[56057-19-3]2-chloro-6-methyl-3-nitropyridin</strong>e</strong> (14.8 mg, 0.086 mmol) and triethylamine (21.9 mul, 0.157 mmol) in dimethylacetamide (3 ml) was stirred at r.t. and poured into water. The aqueous layer was extracted with EtOAc. The combined extracts were washed with water, dried over Na2SO4 and evaporated to dryness in vacuo. The crude product was purified by automated flash chromatography (SPl TM -Biotage) eluting with a Petroleum Ether - EtOAc gradient from 5 to 15% affording the title compound (7 mg) as a not determined E/Z mixture.MS: [M+H]+ = 366.171H-NMR: (CDCl3 delta): 2.43-2.48 (m, 5H), 2.62-2.67 (m, 2H), 3.47-3.57 (m, 4H), 3.85 (s, 3H),6.40-6.60 (m, 3H), 6.79-7.02 (m, 3H), 7.24-7.31 (m, 2H), 8.09 (d, IH).
A) Methyl 5-chloro-2-(2-fluorophenyl)-2-(6-methyl-3-nitropyridin-2-yl) pentanoate (XII) To 11.6 g of sodium hydride at 60% in oil in suspension in 100 ml of DMF is added at -10 C., dropwise, the mixture of 20 g of <strong>[56057-19-3]<strong>[56057-19-3]2-chloro-6-methyl-3-nitropyridin</strong>e</strong> and 21.5 g of methyl 2-fluorophenyl acetate in solution in 100 ml of DMF. The reaction mixture is stirred for 1 h 30 min, allowing the temperature to rise to RT; and then 19.1 ml of 1-chloro-3-iodopropane are added. The mixture is stirred at RT for 18 h. The mixture is poured over 600 ml of a 10% aqueous NH4Cl solution and the mixture is extracted with 300 ml of AcOEt. The organic phase is washed with brine, dried over MgSO4, filtered and then concentrated under reduced pressure. The residue is purified by silica gel chromatography, eluting with a heptane/dichloromethane mixture to give the expected compound in the form of an orange-coloured oil. MH+=381; tr=9.15 min (M4)
With triethylamine; In ISOPROPYLAMIDE; at 20℃; for 24h;
1 -(6-methyl-3-nitro-2-pyridyl)-4-[(l -benzothien-2-yl)-methylenel -piperidineA solution of <strong>[56057-19-3]2-chloro-3-nitro-6-picoline</strong> (152 mg, 0.88 mmol), Compound 34c (202 mg, 0.88 mmol) and triethylamine (0.368 ml, 2.64 mmol) in 5 ml of dimethylacetamide was stirred for 24h at r.t. Water was dropped into the solution until precipitation of a solid; the solid was filtered and dried in a oven at 50C at 1 mbar of residual pressure, obtaining 231mg of the title compound as yellow powder.1H-NMR (CDC delta): 2.50 (s, 3H), 2.55-2.65 (m, 2H), 2.87-2.97 (m, 2H), 3.5-3.68 (m, 4H), 6.56 (s, 1 H), 6.61 (d, J=8Hz, 1H), 7.15 (s,l H), 7.25-7.40 (m, 2H), 7.70-7.85 (m, 2H), 8.10 (d, J=8Hz, 1 H).MS: [M+H]+ = 366.5
With N-ethyl-N,N-diisopropylamine; In ISOPROPYLAMIDE; at 20℃;
J-f6-methyl-3-niiro-2^yridyl)-4-fn^henyl-1.2.4-oxadiazol-5-yl)-methyleneJ^iperidineA mixture of Compound 47b (21 mg, 0.09 mmol), <strong>[56057-19-3]<strong>[56057-19-3]2-chloro-6-methyl-3-nitropyridin</strong>e</strong> (18 mg, 0.104 mmol) and diisopropylethylamine (30 mu, 0.174 mmol) in N,N-dimethylacetamide (5 ml) was stirred at r.t. for 2 hours. After overnight resting, it was poured into water, extracted with EtOAc, dried ( a2S04) and evaporated to dryness in vacuo. The crude was purified by automated flash chromatography (Horizon T - Biotage) eluting with a PE - EtOAc gradient from 92:8 to 70:30, affording 13 mg of the title compound.-NMR (CDCU
With triethylamine; In N,N-dimethyl acetamide; at 20℃; for 24h;
Phenylethynyl-8-(6-methyl-3-nitro-2-pyridyl)-l-oxa-2, 8-diazaspirof 4.5] dec-2-eneA solution of Compound lc (50 mg, 0.21 mmol), <strong>[56057-19-3]<strong>[56057-19-3]2-chloro-6-methyl-3-nitropyridin</strong>e</strong> (39.5 mg, 0.23 mmol) and triethylamine (31.9 L, 0.23 mmol) in N,N-dimethylacetamide (1.14 ml) was stirred at r.t. for 24 h and poured into water. The aqueous layer was extracted with EtOAc. The combined extracts were washed with water, dried over Na2S04 and evaporated to dryness in vacuo. The crude product was purified by automated flash chromatography (SP1TM - Biotage) eluting with a Petroleum Ether - Me2CO 95 : 5 mixture. A further purification with CH2CI2 as eluent afforded 47.7 mg of the title compound (67.7 %) as yellow solid.MS: [M+H]+ = 377.221H-NMR: (CDCl delta): 1.90-2.11 (m, 4H), 2.50 (s, 3H), 3.00 (s, 2H), 3.50-3.71 (m, 4H), 6.63 (d, J=8Hz, 1H), 7.34-7.46 (m, 3H), 7.51-7.57 (m, 2H), 8.1 1 (d, 8Hz, 1H).
General procedure: Method B (microwave irradiation): A mixture of 2 (1.0 mmol), substituted aniline (1.5 mmol), and anhydrous potassium carbonate (414 mg, 3.0 mmol) in 3 mL of t-BuOH was heated at 120-160 C with microwave-assistance for 10-30 min with stirring. The reaction mixture was then poured into ice-water, pH adjusted to ?3.0 with aq HCl (2 N), and solid crude product was filtered. The product was then purified by the same methods as in Method A above.
1005141 Step A: Preparation of 2-(2-methoxyethoxy)-6-methyl-3-nitropyridine:Anhydrous 2-methoxyethanol (3 mL) was cooled to 0 C and sodium hydride (56.8 mg, 2.25 mmol) was added in small portions (vigorous, spontaneous gas evolution). The mixture was stirred for 5 minutes and <strong>[56057-19-3]<strong>[56057-19-3]2-chloro-6-methyl-3-nitropyridin</strong>e</strong> (264 mg, 1.50 mmol) was added. The mixture was stirred for 2 hours during which time the bath temp reached 10 C. The cold reaction mixture was treated with 1120 (9 mL) and the resulting suspension was stirred at ambient temperature for 5 minutes. The solid was collected, washed with 1120 and dried in vacuum to provide the title compounds a brown powder (230 mg, 72%). ?H NMR (CDC13) 6 8.20 (d, J=8.0 Hz, 111), 6.84 (d, J8.1 Hz, 1H), 4.64 (dd, J=4.8, 4.8 Hz, 211), 3.81 (dd, J4.9,4.9 Hz, 2H), 3.45 (s, 311), 2.52 (s, 3H) ppm.
tert-butyl 4-((6-methyl-3-nitropyridin-2-yl)amino)piperidne-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54%
With triethylamine; In dimethyl sulfoxide; at 150℃; for 15h;
tert-Butyl 4-((6-methyl-3-nitropyridin-2-yl)amino)piperidne-l-carboxylate (10). Et3 (4.52 mL, 74.578 mmol) was added to a stirred solution of 9 (4.29 g, 24.859 mmol), 2 (5.0 g, 24.859 mmol) in anhydrous DMSO (45 mL) at rt. The resulting reaction mixture was stirred at 150 for 15 hr. After the reaction was complete, it was cooled to rt and ice-cold 0 was added. The resulting mixture was extracted with EtOAc (2 x 50 mL).The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo in order to afford crude compound as a thick brown liquid. This was washed with n- hexane to give 4.50 g (54% yield) of 10 as a yellow solid. LCMS m/z 281 [M - 56 + H], 237 [M - 100 + H].
1-((2,2-difluorobenzo[b][1,3]dioxol-5-yl)sulfonyl)piperidin-4-amine[ No CAS ]
[ 56057-19-3 ]
N-(1-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)sulfonyl)piperidin-4-yl)-6-methyl-3-nitropyridin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In dimethyl sulfoxide; at 110℃; for 4h;
N-(l-((2,2-Difluorobenzo[< | [l,3]dioxol-5-yl)sulfonyl)piperidin-4-yl)-6-methyl-3- nitropyridin-2-amine (48). Ets (2.8 niL, 20.31 mmol) was added to a stirred solution of 47 (5 g, 15.62 mmol) and 9 (2.6 g, 15.62 mmol) in anhydrous DMSO (26 mL) at rt. The resulting reaction mixture was stirred at 110 for 4 hr. After the reaction was complete, it was cooled to rt and poured into brine solution and the resulting mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous a2S04 and concentrated in vacuo to give 48 (2.5 g, 85% yield) as a yellow solid. This was used in the next step as is without any further purification. LCMS m/z 457 [M + H].
1-((benzo[d][1,3]dioxol-5-yl)sulfonyl)piperidin-4-amine[ No CAS ]
[ 56057-19-3 ]
N-(1-(benzo[d][1,3]dioxol-5-ylsulfonyl)piperidin-4-yl)-6-methyl-3-nitropyridin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In dimethyl sulfoxide; at 150℃; for 4h;
N-(l-(Benzo[^[l,3]dioxol-5-ylsulfonyl)piperidin-4-yl)-6-methyl-3-nitropyridin-2-amine (54). Et3N (0.25 mL, 1.828 mmol) was added to a stirred solution of 53 (0.4 g, 1.406 mmol) and 9 (0.24 g, 1.406 mmol) in anhydrous DMSO (15 mL) at rt. The resulting reaction mixture was stirred at 150 for 4 hr. After the reaction was complete, it was cooled to rt and poured into brine solution and the resulting mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo to give the crude product as a yellow solid. This was washed with Et20 and n-hexane (1 : 10) to give 0.5 g (85% yield) of 54 as a yellow solid. LCMS m/z 421 [M + H].
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; N,N-dimethyl-formamide; at 110℃; for 0.166667h;Microwave irradiation;
Step A: 6-Methyl-3-nitro-2-phenylpyridine A deoxygenated mixture of <strong>[56057-19-3]<strong>[56057-19-3]2-chloro-6-methyl-3-nitropyridin</strong>e</strong> (500 mg, 2.90 mmol), phenylboronic acid (353 mg, 2.90 mmol), 2M potassium carbonate (2.90 mL, 5.79 mmol), and tetrakis(triphenylphosphine)palladium (0) (167 mg, 0.145 mmol) in DMF (6 mL) was heated in the microwave for 10 min at 110 C. The reaction mixture was partitioned between water (15 mL) and EtOAc (30 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified purified by column chromatography (ISCO 80 g silica, 0 to 30 % EtOAc in hexanes) to give the title compound. MS: m/z = 215.1 (M+H).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 0.166667h;Microwave irradiation;
A deoxygenated mixture of <strong>[56057-19-3]<strong>[56057-19-3]2-chloro-6-methyl-3-nitropyridin</strong>e</strong> (500 mg, 2.90 mmol), phenylboronic acid (353 mg, 2.90 mmol), 2M potassium carbonate (2.90 mL, 5.79 mmol), and tetrakis(triphenylphosphine)palladium (0) (167 mg, 0.145 mmol) in DMF (6 mL) was heated in the microwave for 10 min at 1 10 C. The reaction mixture was partitioned between water (15 mL) and EtOAc (30 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified purified by column chromatography (ISCO 80 g silica, 0 to 30 % EtOAc in hexanes) to give the title compound. MS: mlz = 215.1 (M+H).
methyl N-(6-methyl-3-nitropyridin-2-yl)glycinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.65 g
With triethylamine; In N,N-dimethyl-formamide; at 80℃;
To a solution of methyl glycinate hydrochloride (1.91 g) and <strong>[56057-19-3]<strong>[56057-19-3]2-chloro-6-methyl-3-nitropyridin</strong>e</strong> (2.5 g) in N,N-dimethylformamide (16 mL) was added triethylamine (5.05 mL). The reaction mixture was stirred overnight at 80C, and the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate, and the mixture was washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.65 g). 1H NMR (300 MHz, DMSO-d6) delta 2.38 (3H, s), 3.66 (3H, s), 4.29 (2H, d, J = 6.1 Hz), 6.70 (1H, d, J = 8.3 Hz), 8.34 (1H, d, J= 8.7 Hz), 8.76 (1H, t, J = 5.7 Hz).
6-[3-(4-piperidylidene)prop-1-ynyl]pyridine-3-carbonitrile[ No CAS ]
[ 56057-19-3 ]
6-[3-[1-(6-methyl-3-nitro-2-pyridyl)-4-piperidylidene]prop-1-ynyl]pyridine-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90.2%
With triethylamine; In 1-methyl-pyrrolidin-2-one; at 25℃;Inert atmosphere;
4.5.18.3 6-[3-[1-(6-Methyl-3-nitro-2-pyridyl)-4-piperidylidene]prop-1-ynyl]pyridine-3-carbonitrile (21) A mixture of 21b (40 mg, 0.179 mmol), <strong>[56057-19-3]2-chloro-3-nitro-6-methylpyridine</strong> (35.5 mg, 0.206 mmol), TEA (38.6 muL, 0.269 mmol), 4.55 mL of NMP were reacted overnight at 25 C under a nitrogen atmosphere. The reaction mixture was poured into H2O and extracted with EtOAc (3*). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by flash chromatography eluting with EtOAc/PE gradient from 5:95 to 40:60 affording 58 mg of the title product as pale yellow oil. Yield: 90.2%. 1H NMR (400 MHz, CDCl3) delta: 8.84 (d, J = 2.1 Hz, 1H), 8.10 (d, J = 8.2 Hz, 1H), 7.90 (dd, J = 2.1, 8.2 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 6.63 (d, J = 8.2 Hz, 1H), 5.67 (s, 1H), 3.46-3.64 (m, 4H), 2.79 (t, J = 5.8 Hz, 2H), 2.52 (t, J = 5.8 Hz, 2H), 2.48 (s, 3H). MS (ESI) m/z 360.24 [M+H]+. HPLC 98.6% (UV).
With triethylamine; In N,N-dimethyl acetamide; at 25℃; for 24h;Inert atmosphere;
4.6.1.8 6-Methyl-2-[(3E)-3-[3-(6-methyl-2-pyridyl)prop-2-ynylidene]-1-piperidyl]-3-nitro-pyridine (24) A mixture of compound 24d (16 mg, 0.075 mmol) and <strong>[56057-19-3]<strong>[56057-19-3]2-chloro-6-methyl-3-nitropyridin</strong>e</strong> (18.2 mg, 0.105 mmol), TEA (32.5 muL, 0.226 mmol) in 3 mL of N,N-dimethylacetamide was stirred at 25 C for 24 h. The reaction mixture was poured into H2O, extracted with EtOAc and washed with H2O and brine. The combined organic layers were dried over anhydrous Na2SO4 and the solvent was removed in vacuo. After the work-up, the residue was purified by automated flash liquid chromatography (SP1 Biotage) eluting with EtOAc/PE gradient from 3:7 to 4:6 affording 3 mg of the title product. Yield: 11%. 1H NMR (400 MHz, CDCl3) delta: 8.09 (d, J = 8.2 Hz, 1H), 7.58 (t, J = 8.2 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 6.60 (d, J = 8.2 Hz, 1H), 5.69 (s, 1H), 4.10 (s, 2H), 3.43-3.59 (m, 2H), 2.77 (t, J = 6.3 Hz, 2H), 2.61 (s, 3H), 2.48 (s, 3H), 1.84-2.02 (m, 2H). MS (ESI) m/z 349.34 [M+H]+. HPLC 95.4% (UV).
With triethylamine; In N,N-dimethyl acetamide; at 25℃; for 24h;
4.6.1.9 6-Methyl-2-{(3Z)-3-[3-(6-methylpyridin-2-yl)prop-2-yn-1-ylidene]piperidin-1-yl}-3-nitropyridine (25) A mixture of compound 25d (24 mg, 0.113 mmol) and <strong>[56057-19-3]<strong>[56057-19-3]2-chloro-6-methyl-3-nitropyridin</strong>e</strong> (27.3 mg, 0.158 mmol), TEA (22.7 muL, 0.158 mmol) in 3 mL of N,N-dimethylacetamide was stirred at 25 C for 24 h. The reaction mixture was poured into H2O, extracted with EtOAc and washed with H2O and brine. The combined organic layers were dried over anhydrous Na2SO4 and the solvent was removed under vacuum. After the work-up, the residue was purified by automated flash liquid chromatography (SP1 Biotage) eluting with EtOAc/PE gradient 3:7 to 4:6 affording 7 mg of the title product. Yield: 18%. 1H NMR (400 MHz, CDCl3) delta: 8.07 (d, J = 8.2, 1H), 7.61 (bs, 1H), 7.35-7.37 (s, 1H), 7.11-7.13 (m, 1H), 6.57-6.59 (d, J = 8.2, 1H), 5.62 (s, 1H), 4.35 (s, 2H), 3.61 (m, 2H), 2.60 (s, 3H), 2.46-2.53 (m, 5H), 1.87 (m, 2H). MS (ESI) m/z 349.41 [M+H]+. HPLC 96.2% (UV).
With N-Bromosuccinimide; dibenzoyl peroxide; In dichloromethane; at 80℃;
<strong>[56057-19-3]<strong>[56057-19-3]2-chloro-6-methyl-3-nitropyridin</strong>e</strong> (Compound 1) (3 g, 17.38 mmol) and dichloroethane (30 ml) was charged to a 100 ml three-neck round bottom flask, followed by addition of N-bromosuccinimide (4.02 g, 22.59 mmol) and dibenzoylperoxide 70% (0.6 g, 1.74 mmol) portion wise at room temperature. The mixture was heated to 80C and stirred overnight. It was then cooled to room temperature and poured onto a saturated aqueous NaHCO3 solution (100 ml). The aqueous layer was extracted with dichloromethane (2 x 100 ml) and the combined organic layers were washed with brine (100 ml), dried over MgSO4, filtered and then concentrated under reduced pressure to provide 5.1 g of 6-(bromomethyl)-2-chloro-3-nitropyridine (Compound 2) as a brown oil (HPLC purity ~35%, 254nm). The crude product was used in the next step without purification. MS ESI: m/z 251 ([M+H]+)
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