* 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.
Elemental sodium (0.35 g, 15.0 mmol) was added to dry MeOH (6 mL) at 0 °C and allowed to dissolve completely. A solution of 2-chloronicotinaldehyde (0.708, 5.0 mmol) in dry MeOH (2 mL) was added via syringe and the reaction was heated at reflux temperature for 5 hours. The reaction mixture was cooled to room temperature and evaporated under reduced pressure. The residue was taken up in water (10 mL), neutralized with dilute HCl and extracted with Et2O (3 × 10 mL). The organic extracts were dried (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (petroleum ether/EtOAc, 4:1) to give the title compound, 8 (0.473, 69percent), as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 10.34 (d, J = 0.8 Hz, 1H), 8.36 (dd, J = 4.9, 2.1 Hz, 1H), 8.09 (dd, J = 7.4, 2.1 Hz, 1H), 7.00 (ddd, J = 7.4, 4.9, 0.8 Hz, 1H), 4.07 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 189.1, 164.4, 152.8, 137.6, 118.8, 117.3, 54.0
Reference：
[1] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 14, p. 3933 - 3937
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1990, # 9, p. 2409 - 2415
Reference：
[1] European Journal of Organic Chemistry, 2016, vol. 2016, # 7, p. 1292 - 1304
[2] Journal of Organic Chemistry, 1990, vol. 55, # 1, p. 69 - 73
[3] Tetrahedron Letters, 1988, vol. 29, # 7, p. 773 - 776
4
[ 109-09-1 ]
[ 71255-09-9 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1990, # 9, p. 2409 - 2415
[2] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 14, p. 3933 - 3937
5
[ 1628-89-3 ]
[ 109-72-8 ]
[ 68-12-2 ]
[ 71255-09-9 ]
[ 112219-56-4 ]
Reference：
[1] Journal of Organic Chemistry, 1988, vol. 53, # 7, p. 1367 - 1371
6
[ 1628-89-3 ]
[ 68-12-2 ]
[ 71255-09-9 ]
[ 112219-56-4 ]
Reference：
[1] Journal of Organic Chemistry, 1988, vol. 53, # 7, p. 1367 - 1371
7
[ 1628-89-3 ]
[ 109-94-4 ]
[ 71255-09-9 ]
[ 112219-56-4 ]
[ 71255-10-2 ]
Reference：
[1] Journal of Organic Chemistry, 1988, vol. 53, # 7, p. 1367 - 1371
8
[ 2591-86-8 ]
[ 1628-89-3 ]
[ 71255-09-9 ]
Reference：
[1] Journal of Organometallic Chemistry, 1991, vol. 406, # 1+2, p. 49 - 56
9
[ 71255-09-9 ]
[ 112197-16-7 ]
Yield
Reaction Conditions
Operation in experiment
99%
With sodium tetrahydroborate In tetrahydrofuran at 20℃; for 1 h;
Step 1: (2-Methoxypyridin-3-yl)methanoI To a solution of 2-methoxy-pyridine-3-carbaldehyde (2.03 g, 14.8 mmol) in THF (35 mL) was added sodium tetrahydroborate (617 mg, 16.3 mmol) at rt and the mixture was stirred for 1 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na S04 and concentrated. The crude product was purified on silica gel to give (2- methoxypyridin-3-yl)methanol (2.05 g, 99percent) as a clear oil. LCMS (FA): m/z = 140 (M+H).
94%
With sodium tetrahydroborate In ethanol at -40℃; for 0.75 h; Inert atmosphere
Sodium borohydride (0.17 g, 4.5 mmol) was dissolved in 20 ml ethanol under argon and the mixture cooled to -40 °C in a cryo-cool. A solution of 2-methoxynicotinaldehyde (2.0 g, 14.6 mmol) dissolved in 4 ml ethanol was added drop-wise and with stirring. The mixture was stirred at -40 °C for 45 min. 10 ml Brine was added carefully and the mixture was then allowed to warm to room temperature. The organics were evaporated under reduced pressure. The mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and the combined organics were dried over magnesium sulphate, filtered and evaporated to give 44 (1.90 g, 13.7 mmol, 94percent yield) as a pale yellow oil. Purity 100percent. 1H NMR (300 MHz, CDCl3) δ ppm 2.30 (t, J = 6.5 Hz, 1H, OH), 4.00 (s, 3H, MeO), 4.66 (d, J = 6.3 Hz, 2H, CH2), 6.90 (dd, J = 5.0, 7.1 Hz, 1H, H-5), 7.58 (d, J = 7.1 Hz, 1H, H-4), 8.11 (d, J = 4.9 Hz, 1H, H-6). UPLC/MS (3 min) retention time 0.77 min. LRMS: m/z 140 (M+1).
Reference：
[1] Patent: WO2015/2994, 2015, A2, . Location in patent: Paragraph 00194
[2] European Journal of Medicinal Chemistry, 2016, vol. 113, p. 102 - 133
[3] Patent: US2008/103129, 2008, A1, . Location in patent: Page/Page column 47
[4] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 1, p. 405 - 408
10
[ 71255-09-9 ]
[ 354824-19-4 ]
Yield
Reaction Conditions
Operation in experiment
69%
Stage #1: With ammonium acetate; sodium cyanoborohydride In methanol for 48 h; Stage #2: With hydrogenchloride In water
Example 11: Synthesis of 3-aminomethyl-2-methoxypyridine EPO <DP n="34"/>24 25[00102] A round bottom flask was charged with 0.44g (3.23mM) of 2-methoxy-3- pyridine carboxaldehyde (24), 1.24g (16.15mM) of ammonium acetate, and 0.61g (19.69mM) of sodium cyanoborohydride. The flask was then flushed with argon, and then 5OmL of dry MeOH was added by syringe. The reaction was stirred for 2 days, at which point the MeOH was evaporated off. 25mL of water was added, and the mixture was brought to pH 2 with cone. HCl. This was extracted twice with EtOAc to remove the alcohol side product. The mixture was brought to pH 10 using sodium hydroxide pellets, saturated with NaCl, and extracted twice with DCM and once with EtOAc. The combined organics were dried and evaporated to give 0.3 Ig (69percent) of 3-aminomethyl-2- methoxypyridine (25).
69%
Stage #1: With ammonium acetate; sodium cyanoborohydride In methanol for 48 h; Stage #2: With hydrogenchloride; water In methanol Stage #3: With sodium hydroxide; water In methanol
Example 11 Synthesis of 3-aminomethyl-2-methoxypyridine A round bottom flask was charged with 0.44 g (3.23 mM) of 2-methoxy-3-pyridine carboxaldehyde (24), 1.24 g (16.15 mM) of ammonium acetate, and 0.61 g (19.69 mM) of sodium cyanoborohydride. The flask was then flushed with argon, and then 50 mL of dry MeOH was added by syringe. The reaction was stirred for 2 days, at which point the MeOH was evaporated off. 25 mL of water was added, and the mixture was brought to pH 2 with conc. HCl. This was extracted twice with EtOAc to remove the alcohol side product. The mixture was brought to pH 10 using sodium hydroxide pellets, saturated with NaCl, and extracted twice with DCM and once with EtOAc. The combined organics were dried and evaporated to give 0.31 g (69percent) of 3-aminomethyl-2-methoxypyridine (25).
69%
With ammonium acetate; sodium cyanoborohydride In methanol for 48 h;
A round bottom flask was charged with 0.44g (3.23mM) of 2-methoxy-3-pyridine carboxaldehyde (24), 1.24g (16.15mM) of ammonium acetate, and 0.61g (19.69mM) of sodium cyanoborohydride. The flask was then flushed with argon, and then 5OmL of dry MeOH was added by syringe. The reaction was stirred for 2 days, at which point the MeOH was evaporated off. 25mL of water was added, and the mixture was brought to pH 2 with cone. HCl. This was extracted twice with EtOAc to remove the alcohol side product. The mixture was brought to pH 10 using sodium hydroxide pellets, saturated with NaCl, and extracted twice with DCM and once with EtOAc. The combined organics were dried and evaporated to give 0.31g (69percent) of 3-aminomethyl-2-methoxypyπdine (25).
Elemental sodium (0.35 g, 15.0 mmol) was added to dry MeOH (6 mL) at 0 C and allowed to dissolve completely. A solution of 2-chloronicotinaldehyde (0.708, 5.0 mmol) in dry MeOH (2 mL) was added via syringe and the reaction was heated at reflux temperature for 5 hours. The reaction mixture was cooled to room temperature and evaporated under reduced pressure. The residue was taken up in water (10 mL), neutralized with dilute HCl and extracted with Et2O (3 × 10 mL). The organic extracts were dried (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (petroleum ether/EtOAc, 4:1) to give the title compound, 8 (0.473, 69%), as a colorless oil. 1H NMR (300 MHz, CDCl3) delta 10.34 (d, J = 0.8 Hz, 1H), 8.36 (dd, J = 4.9, 2.1 Hz, 1H), 8.09 (dd, J = 7.4, 2.1 Hz, 1H), 7.00 (ddd, J = 7.4, 4.9, 0.8 Hz, 1H), 4.07 (s, 3H). 13C NMR (75 MHz, CDCl3) delta 189.1, 164.4, 152.8, 137.6, 118.8, 117.3, 54.0
With sodium tetrahydroborate; In tetrahydrofuran; at 20℃; for 1h;
Step 1: (2-Methoxypyridin-3-yl)methanoI To a solution of <strong>[71255-09-9]2-methoxy-pyridine-3-carbaldehyde</strong> (2.03 g, 14.8 mmol) in THF (35 mL) was added sodium tetrahydroborate (617 mg, 16.3 mmol) at rt and the mixture was stirred for 1 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na S04 and concentrated. The crude product was purified on silica gel to give (2- methoxypyridin-3-yl)methanol (2.05 g, 99%) as a clear oil. LCMS (FA): m/z = 140 (M+H).
94%
With sodium tetrahydroborate; In ethanol; at -40℃; for 0.75h;Inert atmosphere;
Sodium borohydride (0.17 g, 4.5 mmol) was dissolved in 20 ml ethanol under argon and the mixture cooled to -40 C in a cryo-cool. A solution of <strong>[71255-09-9]2-methoxynicotinaldehyde</strong> (2.0 g, 14.6 mmol) dissolved in 4 ml ethanol was added drop-wise and with stirring. The mixture was stirred at -40 C for 45 min. 10 ml Brine was added carefully and the mixture was then allowed to warm to room temperature. The organics were evaporated under reduced pressure. The mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and the combined organics were dried over magnesium sulphate, filtered and evaporated to give 44 (1.90 g, 13.7 mmol, 94% yield) as a pale yellow oil. Purity 100%. 1H NMR (300 MHz, CDCl3) delta ppm 2.30 (t, J = 6.5 Hz, 1H, OH), 4.00 (s, 3H, MeO), 4.66 (d, J = 6.3 Hz, 2H, CH2), 6.90 (dd, J = 5.0, 7.1 Hz, 1H, H-5), 7.58 (d, J = 7.1 Hz, 1H, H-4), 8.11 (d, J = 4.9 Hz, 1H, H-6). UPLC/MS (3 min) retention time 0.77 min. LRMS: m/z 140 (M+1).
To a solution of NaBH4 (0.075 g, 2.04 mmol) in absolute EtOH (10 mL) was dropwise added a solution of <strong>[71255-09-9]2-methoxy-pyridine-3-carbaldehyde</strong> (0.98 g, 7.15 mmol) in EtOH (2 mL) at -40 C. under N2. The reaction mixture was stirred at -40 C. for 45 min and then carefully quenched with brine. After warmed up to room temperature, the reaction solvent was removed and then diluted with EtOAc and water. The aqueous layer was extracted with EtOAc (*2) and the combined organics were washed with water, brine and dried over anhydrous Na2SO4. The mixture was filtered through Celite-silica gel. The concentration under the reduced pressure provided the product, which was carried to the next step without further purification. 1H NMR (300 MHz, CDCl3) 8.13 (m, 1H), 7.63 (m, 1H), 6.90 (m, 1H), 4.67 (s, 2H), 4.02 (s, 3H).
With sodium tris(acetoxy)borohydride; In dichloromethane; for 14h;
To a stirred solution OF 4-{N-[7-(3-(S)-L-CARBAMOYL-L, L-DIPHENYLMETHYL)- pyrrolidin-l-yl) HEPT-1-YL]-N-(ETHYL) AMINO} PIPERIDINE (50.5 mg, 0.1 mmol) in dichloromethane (1 mL) was added <strong>[71255-09-9]2-methoxypyridine-3-carboxaldehyde</strong> (205.7 mg, 0.15 mmol) and sodium triacetoxyborohydride (33 mg, 0.15 mmol). The reaction mixture was stirred for 14 h and then the solvent was removed under reduced pressure. To the resulting mixture was added 1: 1 acetic acid/water (1.0 mL) and the mixture was chromatographed on reverse-phase silica gel (gradient elution, ACETONITRILE/H2O) to afford the title compound. Analyical Data: MS m/z 626.4 (MH+) ; Rf 2. 11 (2-75 ACN: H20, reverse phase HPLC).
(xviii) Methyl (1-f [ (2-methoxypyridin-3-yl) methyl] amino}-4-methyl-2- oxo-1, 2-dihydropyridin-3-yl) acetate; 2-Methoxynicotinaldehyde (3.6 mmol) was added to a solution of methyl (1-amino-4-methyl-2-oxo-1, 2-dihydropyridin-3-yl) acetate (2.4 mmol; see Preparation 1 above) in methanol (40 mL) and acetic acid (10 mL) and the resulting solution was stirred at room temperature. After 4.5 hours sodium cyanoborohydride (7.4 mmol) was added and the resulting solution was stirred at room temperature for 3 hours before being concentrated. The residue was diluted with ethyl acetate and washed with NaHC03 (sat. aq.) and brine, dried, filtered and concentrated. Purification by flash chromatography (Si02, DCM: methanol, 900: 25) gave the desired product. 1H NMR (500 MHz, CDC13) 6 8. 13 (d, 1H), 7.50 (d, 1H), 7.23 (d, 1H), 6.85 (dd, 1H), 6.50 (t, 1H), 5.99 (d, 1H), 4.14 (d, 2H), 3.98 (s, 3H), 3.72 (s, 3H), 3.68 (s, 2H), 2.19 (s, 3H)
With sodium tris(acetoxy)borohydride; acetic acid; In tetrahydrofuran; at 20℃; for 1h;
Reference Example 29 2-[1-[(2-methoxy-3-pyridyl)methyl]-2-piperidyl]-1-ethanol 15.6 g of 2-methoxynicotinic aldehyde, 14 g of 2-piperidineethanol, 30 g of sodium triacetoxyborohydride, 6.6 ml of acetic acid and 200 ml of tetrahydrofuran were stirred at room temperature for one hour. A diluted sodium hydroxide solution was added thereto, and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate, subsequently, ethyl acetate:methanol=2:1). 1H-NMR (400 MHz, CDCl3) delta: 1.35-1.84 (8H, m), 1.93-2.04 (1H, m), 2.05-2.34 (1H, m), 2.76-2.85 (1H, m), 2.95-3.02 (1H, m), 3.59 (1H, d, J=16.0 Hz), 3.65-3.73 (1H, m), 3.84-3.92 (1H, m), 3.97 (3H, s), 4.02 (1H, d, J=16.0 Hz), 6.85 (1H, dd, J=6.8 Hz, 6.8 Hz), 7.58 (1H, d, J=6.8 Hz), 8.06 (1H, d, J=6.8 Hz)
Step 2 To a DMF solution (10 mL) of the 2-methoxy-5-bromopyridine obtained in step 1 was added n-butyl lithium (1.4 mol/l in hexane, 7 mL). The temperature was slowly elevated to room temperature, and the mixture was stirred at that temperature for 3 hours. The reaction solution was poured into dilute hydrochloric acid for neutralization and the mixture was extracted with a chloroform-methanol mixed solvent (chloroform/methanol=9/1). The extract was washed with a saturated aqueous sodium chloride solution and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluted with chloroform) to obtain a mixture of 3-(6-methoxypyridyl)carboxaldehyde and 3-(2-methoxypyridyl)carboxaldehyde [3-(6-methoxypyridyl)carboxaldehyde:3-(2-methoxypyridyl)carboxaldehyde =4:1, 720 mg; yield: >95%]. FAB-MS (m/z): 138 (M+1)
32
[ 71255-09-9 ]
[ 7487-94-7 ]
[ 106-95-6 ]
[ 146949-43-1 ]
Yield
Reaction Conditions
Operation in experiment
With ammonium chloride; In tetrahydrofuran; ethyl acetate;
EXAMPLE I 3-(1-Hydroxy-but-3-en-1-yl)-2-methoxypyridine STR11 29.9 g (1.1 g-atom) of aluminium flakes and 100 mg of mercury(II) chloride are suspended in 300 ml of anhydrous tetrahydrofuran under argon. The mixture is heated to 40 C. and 1-2 ml of 214.0 g (1.77 mol) of allyl bromide in 250 ml of anhydrous tetrahydrofuran are slowly added dropwise. The temperature during this rises to approximately 50 C. The allyl bromide solution is then added dropwise with stirring at such a rate that the temperature of the solution does not exceed 50 C. The solution is subsequently stirred for 1 hour at 60 C., and cooled to -60 C. and 112.4 g (0.765 mol) of <strong>[71255-09-9]2-methoxypyridine-3-carbaldehyde</strong> in 250 ml of anhydrous tetrahydrofuran are added dropwise at this temperature. The mixture is then stirred for 1 hour at 0 C. and for 2 hours at 20 C. Subsequently, 500 ml of saturated ammonium chloride solution are added dropwise with cooling, the mixture is stirred for 0.5 hours, filtered and the filtrate is concentrated in vacuo. The residue is taken up in ethyl acetate, washed with water and dried over sodium sulphate. 136.1 g of a light yellow oil is obtained which is fractionally distilled. Yield: 110.9 g (81% of theory) B.P. 91-100 C./0.5 mmHg.
Example 11: Synthesis of 3-aminomethyl-2-methoxypyridine EPO <DP n="34"/>24 25[00102] A round bottom flask was charged with 0.44g (3.23mM) of 2-methoxy-3- pyridine carboxaldehyde (24), 1.24g (16.15mM) of ammonium acetate, and 0.61g (19.69mM) of sodium cyanoborohydride. The flask was then flushed with argon, and then 5OmL of dry MeOH was added by syringe. The reaction was stirred for 2 days, at which point the MeOH was evaporated off. 25mL of water was added, and the mixture was brought to pH 2 with cone. HCl. This was extracted twice with EtOAc to remove the alcohol side product. The mixture was brought to pH 10 using sodium hydroxide pellets, saturated with NaCl, and extracted twice with DCM and once with EtOAc. The combined organics were dried and evaporated to give 0.3 Ig (69percent) of 3-aminomethyl-2- methoxypyridine (25).
69%
Example 11 Synthesis of 3-aminomethyl-2-methoxypyridine A round bottom flask was charged with 0.44 g (3.23 mM) of <strong>[71255-09-9]2-methoxy-3-pyridine carboxaldehyde</strong> (24), 1.24 g (16.15 mM) of ammonium acetate, and 0.61 g (19.69 mM) of sodium cyanoborohydride. The flask was then flushed with argon, and then 50 mL of dry MeOH was added by syringe. The reaction was stirred for 2 days, at which point the MeOH was evaporated off. 25 mL of water was added, and the mixture was brought to pH 2 with conc. HCl. This was extracted twice with EtOAc to remove the alcohol side product. The mixture was brought to pH 10 using sodium hydroxide pellets, saturated with NaCl, and extracted twice with DCM and once with EtOAc. The combined organics were dried and evaporated to give 0.31 g (69percent) of 3-aminomethyl-2-methoxypyridine (25).
69%
With ammonium acetate; sodium cyanoborohydride; In methanol; for 48h;
A round bottom flask was charged with 0.44g (3.23mM) of <strong>[71255-09-9]2-methoxy-3-pyridine carboxaldehyde</strong> (24), 1.24g (16.15mM) of ammonium acetate, and 0.61g (19.69mM) of sodium cyanoborohydride. The flask was then flushed with argon, and then 5OmL of dry MeOH was added by syringe. The reaction was stirred for 2 days, at which point the MeOH was evaporated off. 25mL of water was added, and the mixture was brought to pH 2 with cone. HCl. This was extracted twice with EtOAc to remove the alcohol side product. The mixture was brought to pH 10 using sodium hydroxide pellets, saturated with NaCl, and extracted twice with DCM and once with EtOAc. The combined organics were dried and evaporated to give 0.31g (69percent) of 3-aminomethyl-2-methoxypypidine (25).
tert-butyl 2-(4-(3,4-diaminophenyl)piperidin-1-yl)ethyl(methyl)carbamate[ No CAS ]
2-(4-(2-(2-methoxypyridin-3-yl)-3H-benzo[d]imidazol-5-yl)piperidin-1-yl)-N-methylethanamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
27%
Part H: Preparation of 2-(4-(2-(2-methoxypyridin-3-yl)-3H-benzo[d]imidazol-5-yl)piperidin-1-yl)-N-methylethanamine (Example 1) A mixture of tert-butyl 2-(4-(3,4-diaminophenyl)piperidin-1-yl)ethyl(methyl)carbamate (0.11 mmol) and <strong>[71255-09-9]2-methoxynicotinaldehyde</strong> (15 mg, 0.11 mmol) in methanol (5 mL) was heated at 60 C. for 4h. solvent was evaporated and the crude intermediate was then treated with TFA in 1,2-dichloroethane (25%, 1 mL) at rt for 2 h. solvent was evaporated and the residue was purified by prep-HPLC to give 2-(4-(2-(2-methoxypyridin-3-yl)-3H-benzo[d]imidazol-5-yl)piperidin-1-yl)-N-methylethanamine as a brown oil (11 mg, 27% yield). MS (ESI) m/z 366.22 (M+H) 1H NMR (CD3OD) delta 8.54 (dd, 1H, J=5.0, 1.7 Hz), 8.48 (dd, 1H, J=7.7, 1.7 Hz), 7.84 (d, 1H, J=8.1 Hz), 7.81 (s, 1H), 7.61 (dd, 1H, J=7.6, 1.1 Hz), 7.33 (dd, 1H, J=7.7,4.4 Hz), 4.25 (s, 3H), 3.80 (d, 2H,J=12.1 Hz), 3.58(s, 3H), 3.31 -3.15 (m, 3H), 2.82 (s, 3H), 2.32-2.17 (m, 4H).
2-(4-(2-(2-methoxypyridin-3-yl)-7-methyl-3H-benzo[d]imidazol-5-yl)piperidin-1-yl)-N-methylethanamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
27%
Part F: 2-(4-(2-(2-methoxypyridin-3-yl)-7-methyl-3H-benzo[d]-imidazol-5-yl)piperidin-1-yl)-N-methylethanamine (Example 2); A mixture of tert-butyl 2-(4-(3,4-diamino-5-methylphenyl)piperidin-1-yl)ethyl(methyl)carbamate (0.11 mmol) and <strong>[71255-09-9]2-methoxynicotinaldehyde</strong> (15 mg, 0.11 mmol) in methanol (5 mL) was heated at 60 C. for 4h. solvent was evaporated and the crude intermediate was then treated with TFA in 1,2-dichloroethane (25%, 1 mL) at rt for 2 h. solvent was evaporated and the residue was purified by prep-HPLC to give 2-(4-(2-(2-methoxypyridin-3-yl)-3H-benzo[d]imidazol-5-yl)piperidin-1-yl)-N-methylethanamine as a brown oil (11 mg, 27% yield). MS (ESI) m/z 380.22 (M+H) 1H NMR (CD3OD) delta 8.54 (dd, 1H, J=5.0, 1.7 Hz), 8.48 (dd, 1H, J=7.7, 1.7 Hz), 7.84 (d, 1H, J=8.1 Hz), 7.81 (s, 1H), 7.61 (dd, 1H, J=7.6, 1.1 Hz), 7.33 (dd, 1H, J=7.7, 4.4 Hz), 4.25 (s, 3H), 3.80 (d, 2H, J=12.1 Hz), 3.58 (s, 3H), 3.31 -3.15 (m, 3H), 2.82 (s, 3H), 2.32-2.17 (m, 7H).
150 mg (1.09 mmol) of <strong>[71255-09-9]2-methoxy-3-pyridinecarboxaldehyde</strong>, 170 mg (1.09 mmol) of the compound from example 4A and 90 mg (1.09 mmol) of 3-aminocrotononitrile are dissolved in 4 ml of isopropanol and stirred at the reflux temperature overnight. After cooling to room temperature, the volatile components are removed in a rotary evaporator, and the crude product is taken up in 3 ml of ethyl acetate. The crystallizing solid is removed by filtration. The precipitate obtained in this way is washed with a little diethyl ether. 216 mg (58% of theory) of the title compound are obtained. LC-MS (Method 8): Rt=2.87 min; (Elpos): m/z=339 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): delta [ppm]=2.00 (s, 3H), 2.26 (s, 3H), 2.39 (s, 3H), 3.90 (s, 3H), 5.02 (s, 1H), 6.91 (m, 1H), 6.98 (s, 1H), 7.40 (d, 1H), 7.99 (m, 1H), 9.09 (s, 1H).
A mixture of methyl 5,5-dimethyl-2,4-dioxo-6-(tetrahydro-2H-pyrane-2-yloxy)hexanoate (0.29 mg, 1.0 mmol), 4-(3-thienyl)aniline (0.18 g, 1.0 mmol), <strong>[71255-09-9]2-methoxynicotinaldehyde</strong> (0.14 g, 1.0 mmol), acetic acid (0.043 mL, 0.75 mmol) and dioxane (2 ml) was heated at reflux overnight. After the reaction was completed, the reaction mixture was concentrated in vacuo. The resulting residue was purified on a silica gel column chromatography (methanol/chloroform) to give 4-(2,2-dimethyl-3-tetrahydro-2H-pyrane-2-yloxypropionyl)-3-hydroxy-5-(2-methoxy-3-pyridyl)-1-(4-thiophene-3-ylphenyl)-1,5-dihydropyrrole-2-one (0.30 g, yield: 55%) as pale yellow solid.
With potassium fluoride on basic alumina; In methanol; at 65℃; for 16h;
General procedure: To a solution of 2-nitrofluorene (211 mg, 1.0 mmol) and o-anisaldehyde(272 mg, 2.0 mmol) in 5mL of methanol was added KFAl2O3(160 mg, 1.0 mmol). The reaction mixture was stirred at 65 Cfor 16 h, and then evaporated in vacuo. The residue was purified bysilica gel column chromatography (ethyl acetate/CH2Cl2, 1:2) toprovide compound 6 as a yellow foam.
306mg
With KF-Al2O3; In methanol; at 72℃; for 8h;
To a solution of 2-nitrofluorene (278 mg, 1.32 mmol) and 2-methoxy-3- pyridinecarboxyaldehyde (200 mg, 1.46 mmol) in 15 mL of methanol was added KF-AI2O3 (190 mg, 1.18 mmol). The resulting mixture was stirred at 72 C. After 8 hrs, TLC indicated that the starting material was gone. 40 mL of CH2CI2 was added into the reaction mixture. The insoluble solid was filtrated, and the filtrate was concentrated under vacuum to give a yellow solid, which was recrystallized from alcohol and CH2CI2 to give 306 mg of CYD-1-76 as a yellow solid. 1H-NMR (600 MHz, CDC13) delta 8.88 (s, 1H), 8.32 (m, 10H), 8.10 (m, 22H), 8.01 (d, 1H, J = 7.2 Hz), 7.94 (s, 3H), 7.53 (m, 7H), 7.48 (m, 1H), 7.43 (d, 1H, J = 7.8 Hz), 7.31 (m, 1H), 7.19 (m, 4H), 3.94 (s, 14H).
A solution of 3-methoxy-/V-((2-methoxypyridin-3-yl)methylene)aniline in ethanol was prepared by heating a solution of <strong>[71255-09-9]2-methoxynicotinaldehyde</strong> (0.141 g; 1.028 mmol) and 3- methoxyaniline (0.122 g; 1.088 mmol) in ethanol (0.5 mL) at 60 C for 18 h. The formation of the imine was quantitative and the solution was used without further purification. ESI/APCI(+): 243 (M+H).
2-(3,4-dichlorophenyl)-3-hydroxy-3-(2-methoxypyridin-3-yl)propanenitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
A solution of 2-(3,4-dichlorophenyl)acetonitrile (2.92 g, 15.68 mmol) in 20 mL THF and 20 mL diethyl ether was placed under nitrogen in an oven dried round bottom flask with stirrer. After cooling to -75 C in an acetone dry ice bath, butyllithium (6.77 mL, 16.93 mmol) (2.5 M in hexane) was added dropwise. Internal temperature was monitored and maintained below -60 C. After the addition, the reaction was allowed to stir for 15 min. To this, <strong>[71255-09-9]2-methoxynicotinaldehyde</strong> (2.15 g, 15.68 mmol) dissolved in 20 mL of THF was added dropwise, maintaining the temperature below - 60 C. The reaction mixture was allowed to stir for 1.5 hours at -75 C and then quenched at the same temperature with a solution of acetic acid (1.346 mL, 23.52 mmol in 10 mL of THF) and the cold bath removed. After adding 100 mL of water, the two layers were separated in a separatory funnel. The aqueous layer was extracted with ethyl acetate (3X). The combined organic layers were washed with brine, dried over MgS04, filtered and evaporated in vacuo. The crude product was purified by chromatography (elution with ethyl acetate/CH2Cl2 0-100%) to yield 2-(3,4- dichlorophenyl)-3-hydroxy-3-(2-methoxypyridin-3-yl)propanenitrile (4.64 g, 92 %). 1H NMR in CDCI3 showed the presence of the expected mixture of anti- and syn- structures. MS m/z (ESI) 323.13 (MH+).
4-bromo-2,5-dimethoxy-β-phenethylamine hydrochloride[ No CAS ]
[ 71255-09-9 ]
C17H19BrN2O3[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In ethanol;
General procedure: Et3N (1.0 equiv) was added to a suspension of 2-(4-bromo-2,5-dimethoxyphenyl)ethanamine hydrochloride (2C-B*HCl, 1.0 mmol) and the required aldehyde (1.1 equiv) in EtOH (10 mL) and the reaction was stirred until formation of the imine was complete according to TLC or GC (between 30 min and 3 h depending on the aldehyde). NaBH4 (2.0 mmol) was then added and the reactionwas stirred for another 30 min. The reaction mixture was concentratedunder reduced pressure and the residue was partitioned between CH2Cl2 and water (30 mL, 1:1). The organic layer was isolated and the aqueous layer was extracted with CH2Cl2 (2 x 15 mL). The combined organic extracts were dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (CH2Cl2/MeOH/NH3 98:2:0.04). The purified free base was dissolved in EtOH (2 mL) and HCl (1 M in EtOH, 2 mL) was added and the resulting solution was diluted with Et2O until a precipitate was formed. The crystals were collected by filtration and dried under reduced pressure to provide the desired products.
3-tert-butyl-N-[4-(2,3-diaminopyridin-4-yl)-2-fluorophenyl]methyl}-1,2,4-oxadiazole-5-carboxamide[ No CAS ]
3-(tert-butyl)-N-(2-fluoro-4-(2-(2-methoxypyridin-3-yl)-3H-imidazo[4,5-b]pyridin-7-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
8%
With formic acid; In N,N-dimethyl-formamide; at 130℃; for 2h;Inert atmosphere;
Example 151 3-(tert-butyl)-N-(2-fluoro-4-(2-(2-methoxypyridin-3-yl)-3H-imidazo[4,5-b]pyridin-7-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (151) Into a 20-mL reaction vial was added 3-tert-butyl-[1,2,4]oxadiazole-5-carboxylic acid 4-(2,3-diamino-pyridin-4-yl)-2-fluoro-benzylamide (150.00 mg; 0.39 mmol; 1.00 eq.), <strong>[71255-09-9]2-methoxy-pyridine-3-carbaldehyde</strong> (66.89 mg; 0.49 mmol; 1.25 eq.), and DMF (3.00 ml; 38.77 mmol; 99.34 eq.). The resulting solution was placed under nitrogen atmosphere and stirred overnight at 130 degrees Celsius. After 20 hr the reaction was then quenched by the addition of water (20 mL). The resulting solution was extracted with dichloromethane (3*25 mL) and the organic layers were combined. The DCM was concentrated and the residue was dissolved in DMSO (2.0 mL) and purified directly via prep HPLC (Interchim P4250; 30*150 mm C-18 column; 0.1% formic acid modified mobile phases (A=water, B=ACN); gradient 20-70% B over 15 min at 60 mL/min). The product eluted with 68% ACN. The product fractions were combined and lyophilized to yield 16 mg (8%) of 3-(tert-butyl)-N-(2-fluoro-4-(2-(2-methoxypyridin-3-yl)-3H-imidazo[4,5-b]pyridin-7-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide as a white solid. HPLC: 98% purity. MS: 502 [M+H]+ ion. 1H NMR (400 MHz, DMSO-d6) delta 13.07 (s, 1H), 9.93 (s, 1H), 8.63 (d, 1H), 8.45 (bs, 1H), 8.38 (bs, 1H), 8.32 (d, 1H), 8.24 (d, 1H), 7.59 (m, 2H), 7.25 (t, 1H), 4.62 (d, 2H), 4.10 (s, 3H), 1.39 (s, 9H).
With sodium metabisulfite; water; In ethanol; at 20℃; for 1h;
General procedure: The appropriate substituted pyridine aldehyde (10 mmol) was dissolved in ethanol (20 mL) and sodium metabisulfite (15 mmol) in 5 mL water was added in portion over 5 minutes.The reaction mixture was stirred at room temperature for 1 h, and subsequently stirred at 4oC overnight and the formed precipitate was filtered and dried to get sodium bisulfite adducts.
With sodium hydrogensulfite; In ethanol; water; at 4 - 20℃;
General procedure: The appropriate substituted pyridine aldehyde (10 mmol) was dissolved in ethanol (20 mL) and sodium metabisulfite (15 mmol) in 5 mL water was added in portion over 5 minutes. The reaction mixture was stirred at room temperature for 1 h, and subsequently stirred at 4C overnight and the formed precipitate was filtered and dried to get sodium bisulfite adducts.
(E)-2-(2-(2-methoxypyridin-3-yl)vinyl)-1-methylquinolinium iodide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol; at 80℃; for 4h;
General procedure: A mixture of 1,2-dimethyl-quinolinium iodide (4a, 0.29 g,1.0 mmol) and corresponding aromatic aldehyde (1 eq.) in 5 mLanhydrous ethanol was heated in flask for 4 h at 80 C. The reactionmixture was allowed to cool to room temperature, precipitatedfurther with anhydrous diethyl ether (10 mL), and filtered, thecrude product was purified by using flash column chromatographyto afford solid compound.
methyl 6-benzyloctahydro-1,6-naphthyridine-4a(2H)-carboxylate[ No CAS ]
methyl 6-benzyl-1-[(2-methoxypyridin-3-yl)methyl]decahydro-1,6-naphthyridine-4a-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
27%
General procedure: Reactions were performed in parallel in 15 mlreaction tubes in a 24 position Mettler-Toledo Miniblock equipped with a heat transferblock and inert gas manifold. Each reaction tube was loaded with the corresponding aldehyde (2.0 eq), NaBH(OAc)3 (2.5 eq.), acetic acid (2.0 eq) and 1.0 mL of 1,2-dichloroethene(DCE). The reaction mixture was stirred for 30 min, then a previously prepared solution of 30mg of the corresponding intermediate in 1.0 mL DCE was added. The reactions were stirredat room temperature overnight. The mixtures were diluted with dichloromethane (2.0 mL)and washed with water (1.0 mL). The organic layers were evaporated until dryness. Thecrudes were rediluted in 1.0 mL of acetonitrile, filtered and purified with preparative HPLC.
General procedure: Reaction mixtures of ketal-protected thioamide 3 (50 mg,0.246 mmol, 1 equiv) and a-bromoketones 4 (0.246 mmol) wereprepared in 0.6 mL of DMF and heated to 150 C for 5 min in sealedvials. After cooling, aldehydes 5 (0.295 mmol, 1.2 equiv) and ureas6 (0.295 mmol, 1.2 equiv) were added and the reaction mixturesheated to 200 C for an additional 10 min. Once cooled, the crudereaction mixtures were purified using reverse-phase preparativeHPLC, lyophilized, and tested for anti-HIV activity. When measuringthe efficiency of the process, the crude reaction mixtures wereadsorbed onto silica gel, loaded onto a pre-packed silica gel column(12 g), and chromatographed using either hexanes:EtOAc or CH2-Cl2:MeOH.
4-{4-(methylamino)thieno[3,2-d]pyrimidin-2-yl}benzohydrazide[ No CAS ]
N'-[(2-methoxypyridin-3-yl)methylene]-4-{4-(methylamino)thieno[3,2-d]pyrimidin-2-yl}benzohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
With toluene-4-sulfonic acid; In ethanol; at 120℃; for 1h;Inert atmosphere;
General procedure: To a solution of 4-{4-(methylamino)thieno[3,2-d]pyrimidin-2-yl}benzohydrazide (11) (100 mg, 0.33 mmol) in ethanol (4 mL) were added an aldehyde (0.33 mmol) and PTSA (catalytic amount). The mixture was heated at 120 C for 1 h. The reaction mixture was poured into ice cold water (4 mL). The precipitate was filtered off and washed with ethyl acetate to afford a compounds 11a-11k.
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