* 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.
Reference：
[1] Bollettino Chimico Farmaceutico, 1957, vol. 96, p. 542,543
2
[ 67-56-1 ]
[ 3167-49-5 ]
[ 36052-24-1 ]
Yield
Reaction Conditions
Operation in experiment
89%
at 80℃; for 12 h; Inert atmosphere
General procedure: A mixture of 4-aminobenzoic acid (32-34, 5.0 mmol), thionyl chloride(1.487 g, 5.0 mmol), and MeOH (20.0 mL) was flushed with argon, and stirred at80°C for 12 hours. Remove reaction solvent by rota vapor. The reaction mixture wasneutralized with NaHCO3(sat) (20.0 mL) and extracted with ethyl acetate (100 mL ×3). The combined organic extracts were washed with brine, dried by Na2SO4, filtered,and evaporated, to get cmopound 35-37 (63-89percent) as a white solid.
81.5%
at 0 - 80℃;
To a stirred solution of 6-amino-nicotinic acid (25 g, 181.1 mmol) in MeOH (200 mL) is added concentrated H2504 (7 mL) at 0 °C and the reaction mixture is heated at 80°C for overnight. The reaction mixture is cooled to room temperature and neutralized with saturated NaHCO3 solution (100 mL). The precipitated solid is filtered and dried under vacuum to give the title compound as a yellow solid (22 g, 8 1.5percent). LCMS mlz 153(M+H)t
81.5%
at 0 - 80℃;
To a stirred solution of 6-amino-nicotinic acid (25 g, 181.1 mmol) in MeOH (200 mL) is added concentrated H2SO4 (7 mL) at 0 ° C. and the reaction mixture is heated at 80 ° C. for overnight. The reaction mixture is cooled to room temperature and neutralized with saturated NaHCO3 solution (100 mL). The precipitated solid is filtered and dried under vacuum to give the title compound as a yellow solid (22 g, 81.5percent). LCMS m/z 153 (M+H)+.
72%
at 0 - 80℃; for 16 h;
PREPARATION 1 Methyl 6-aminopyridine-3-carboxylate To a solution of 6-aminopyridine 3-carboxylic acid (30 g, 217.1 mmol) in methanol (30 mL) is added H2SO4 (30 mL at 0° C.) and the reaction mixture is heated to 80° C. for 16 hours. The reaction mixture is evaporated and the residue is neutralized with aqueous NaHCO3 solution (50 mL), the precipitated solid is filtered and dried to give the title compound as a pale yellow solid (24 g, 72percent). LCMS m/z 153 (M+H)+.
71%
for 16 h; Heating / reflux
[0198] A mixture of 6-aminonicotinic acid (4.0 g, 28.9 mmol), methanol (75 mL), and concentrated hydrochloric acid (4 mL) was heated under reflux for 16 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove methanol. The resulting solid was treated with water (20 mL) and enough sodium bicarbonate to adjust the pH to pH=8. The solution was then extracted with ethyl acetate (3.x.25 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 6-aminonicotinic acid methyl ester (3.12 g, 71percent) as white foam: EI-HRMS m/e calcd for C7H8N2O2 (M+) 152.0586, found 152.0586. [0199] A solution of 2-(4-methylsulfonyl-3-trifluoromethyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionic acid (prepared as in Example 12, 300 mg, 0.79 mmol) in methylene chloride (6 mL) was treated with N,N-dimethylformamide (7 drops) and then cooled to 0° C. The reaction mixture was then treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.48 mL, 0.95 mmol). The reaction mixture was stirred at 0° C. for 30 min, allowed to warm to 25° C., and then concentrated in vacuo to remove solvents and excess oxalyl chloride. The resulting residue was re-dissolved in dry tetrahydrofuran (6 mL) and was treated dropwise with a solution of 6-aminonicotinic acid methyl ester (252 mg, 1.67 mmol) in tetrahydrofuran (5 mL) and 2,6-lutidine (0.48 mL, 3.95 mmol). The resulting reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was then diluted with water (100 mL) and extracted with methylene chloride (3.x.50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 7/3 hexanes/ethyl acetate to 1/1 hexanes/ethyl acetate) afforded 6-[2-(4-methylsulfonyl-3-trifluoromethyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionylamino]-nicotinic acid methyl ester (227 mg, 55percent) as a white foam: EI-HRMS m/e calcd for C23H25F3N2O6S (M+H)+ 537.1277 found 537.1284.
64%
Stage #1: With sulfuric acid In water for 24 h; Heating / reflux Stage #2: With sodium hydrogencarbonate In water
Example 2: Scheme Al11 6A mixture of 6-aminonicotinic acid (1.0 equiv., 7.24 mmol, 1.00 g) and sulfuric acid (6.00 equiv., 65.16 mmol, 6.39 g) in methanol was refluxed for 24 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and then made alkaline by the addition of a saturated aqueous NaHCO3 solution. The aqueous layer was extracted with ethyl acetate, the combined organic layers were dried with MgSO4 and concentrated in vacuo to give methyl 6-amino-pyridine-3-carboxylate (15) (0.70 g, yield = 64percent) as a white crystalline product.
60%
at 0 - 20℃; for 16 h; Inert atmosphere
Methyl-6-amineonicotinate 6-Amineonicotinic acid ( 1 .00 g, 7.246 mmol, 1 .00 eq) was dissolved in abs. MeOH (40 ml) and cooled to 0 °C. SOCI2 (2.587 g, 1 .70 ml, 21 .739 mmol, 3.00 eq) was added and the reaction mixture was allowed to warm up to room temperature. After stirring for 16 h the solvent was evaporated to give the product as a pale yellow solid (60 percent). H-NMR (400 MHz, DMSO-d6): 3.75 (s, 3H), 6.43 - 6.46 (dd, Ji = 8.7 Hz, J2 = 0.7 Hz, 1 H), 6.84 (s, 2H), 7.81 - 7.83 (dd, Ji = 8.9 Hz, J2 = 2.4 Hz, 1 H), 8.50 (d, J = 2.1 Hz, 1 H), 3C-NMR (100.6 MHz, DMSO-d6): 51 .36, 107.13, 1 13.19, 137.60, 151 .04, 162.52, 165.72 HR-MS: calc.: [M+H]+ 153.0659 found: [M+H]+ 153.0654
Reference：
[1] Organic Letters, 2018, vol. 20, # 15, p. 4393 - 4396
[2] European Journal of Medicinal Chemistry, 2017, vol. 140, p. 42 - 51
[3] Patent: WO2015/105779, 2015, A1, . Location in patent: Page/Page column 11
[4] Patent: US2016/333005, 2016, A1, . Location in patent: Paragraph 0041
[5] Patent: US2015/166535, 2015, A1, . Location in patent: Paragraph 0039; 0040
[6] Patent: US2003/225283, 2003, A1, . Location in patent: Page 23
[7] Patent: WO2007/113290, 2007, A1, . Location in patent: Page/Page column 27
[8] Patent: WO2014/125075, 2014, A1, . Location in patent: Page/Page column 406
[9] Patent: EP1479680, 2004, A1, . Location in patent: Page 47
[10] Patent: US2009/203705, 2009, A1, . Location in patent: Page/Page column 46
3
[ 3167-49-5 ]
[ 18107-18-1 ]
[ 36052-24-1 ]
Yield
Reaction Conditions
Operation in experiment
66%
at 20℃; for 1 h;
24.6 ml (3.4 equivalents) of 2.0M trimethylsilyldiazomethane in solution in cyclohexane are added to a solution of 2.0 g of 6-aminonicotinic acid in a chloroform/methanol (v/v: 10/30) mixture. The reaction medium is stirred at ambient temperature for 1 hour and is then hydrolysed with 100 μl of acetic acid and concentrated under reduced pressure. The crude product is triturated in a cyclohexane/ethyl acetate (1/2) mixture and filtered to produce 1.459 g of a yellow powder corresponding to the expected product. Yield: 66percent MS: MH+ 153
Reference：
[1] Patent: US5536718, 1996, A,
[2] Patent: US5654297, 1997, A,
[3] Patent: US5719278, 1998, A,
[4] Patent: US5753648, 1998, A,
[5] Patent: US5700796, 1997, A,
[6] Patent: US5849735, 1998, A,
6
[ 3167-49-5 ]
[ 36052-24-1 ]
Reference：
[1] Patent: US5532235, 1996, A,
7
[ 3167-49-5 ]
[ 7664-93-9 ]
[ 36052-24-1 ]
Reference：
[1] Patent: US5834468, 1998, A,
8
[ 21550-48-1 ]
[ 36052-24-1 ]
Reference：
[1] Bollettino Chimico Farmaceutico, 1957, vol. 96, p. 542,543
9
[ 1603-41-4 ]
[ 36052-24-1 ]
Reference：
[1] Bollettino Chimico Farmaceutico, 1957, vol. 96, p. 542,543
10
[ 4931-47-9 ]
[ 36052-24-1 ]
Reference：
[1] Bollettino Chimico Farmaceutico, 1957, vol. 96, p. 542,543
11
[ 36052-24-1 ]
[ 113293-71-3 ]
Yield
Reaction Conditions
Operation in experiment
67%
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran Stage #2: With methanol In tetrahydrofuran at 0℃;
Compound 15 (1.0 equiv., 3.94 mmol, 0.600 g) was added portion wise to a suspension OfLiAlH4 (3.00 equiv., 11.83 mmol, 0.449 g) in dry THF (17 ml) at 00C. The reaction mixture was stirred at room temperature overnight. Excess LiAlH4 was destroyed by addition of methanol (while cooling on ice), the reaction mixture was filtered over Celite and the filtrate concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane / methanol 75:25) to give 6-amino-3-pyridinemethanol (16) (0.330 g, yield = 67percent) as a white solid. 1H NMR (δ, CD3OD): 4.43 (2H, s), 6.58 (IH, d, J = 8.5 Hz), 7.48 (IH, dd, J = 8.5, ~ 2 Hz) 7.86 (IH, d, J ~ 2 Hz)
39.1 Step 1, Method 39: Methyl 6-[(tcrt-butoxy)carbonyljamino}pyridine-3-carboxylate
General procedure: j0296j A solution of methyl 6-aminopyridine-3-carboxylate (1 g, 6.57 mmol), di-tert butyl dicarbonate (1.72 g, 7.89 mmol) and N,N-dimethylaminopyridine (56 mg, 0.46 mmol) in telrahydrofuran (60 mL) was stirred at room temperature overnight The mixture was concentrated in vacuo to give the title compound 1.79 g (quantitative yield) as a light brown solid. Tr(METCR1278) = 1.99 mm, (ESj (M+H) 253.
79%
With dmap In acetonitrile for 4h; Ambient temperature;
78%
With dmap In acetone; <i>tert</i>-butyl alcohol for 20h;
7.4
Step 4. Synthesis of 6-tert-Butoxycarbonylamino-nicotinic acid methyl ester. To a solution of methyl-2-amιno-5-pyndιnecarboxylate (10 1 g, 63 9 mmole) in a mixture of acetone (30 mL) and tert-butanol (89 mL) was added di-tert-butyl dicarbonate (21 0 g, 96 2 mmole) and N N-dimethylaminopyridine (DMAP, 156 mg 1 3 mmole) The solution was stirred for 20 h, and to the thick slurry was added 135 mL of hexane The solution was cooled to -20°C and stirred for 2 h The solids were isolated by filtration washed with cold 3/1 hexane/DCM and dried in vacuo to afford 12 8 g (78%) of product as a whrte solid
In <i>tert</i>-butyl alcohol at 20℃; for 96h;
11.A
6-Amino-nicotinic acid methyl ester (1.0 6.S7 mmol) was added portionwise to a stirring solution of di-fer/-butyl dicarbonate (1.72 g, 7.89 mmol) in terf-butanol (20 mL).After stirring for 4 days at RT the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (elution with n-hexane/EA 9:1) to give the title compound. MS (m/z): 252.8 [M+H4]
With dmap In acetonitrile at 20℃;
4.13.C
Step C: methyl 6-(tert-butoxycarbonylamino)nicotinate Di-t-butyl dicarbonate (5.0 g, 23 mmol) was added to a room temperature suspension of methyl 6-aminonicotinate (2.65 g, 17.4 mmol) and 4-(dimethylamino)pyridine (109 mg, 0.86 mmol) in 40 mL acetonitrile. The resulting orange reaction mixture was stirred at room temperature overnight. The suspended solid was collected by filtration, washed with acetonitrile, and air dried to give methyl 6-(tert-butoxycarbonylamino)nicotinate (2.64 g, 60%) as a colorless solid. The filtrate was concentrated. The residue was dissolved in dichloromethane and passed through a plug of silica gel (~75 g) eluting with 3:1 heptane:EtOAc (400 mL).Concentration of the eluent provided an additional 1.5 g methyl 6-(tert-butoxycarbonylamino)nicotinate. 1H NMR (400 MHz, CDCl3) δ 8.89-8.92 (m, 1H), 8.49-8.58 (br s, 1H), 8.22-8.26 (m, 1H), 8.02-8.07 (m, 1H), 3.89 (s, 3H), 1.54 (s, 9H).
With dmap In acetonitrile at 20℃;
Intermediate (90): methyl 6-(tert-butoxycarbonylamino)nicotinate Di-t-butyldicarbonate (5.0 g, 23 mmol) was added to a room temperature suspension of methyl 6-aminonicotinate (2.65 g, 17.4 mmol) and N,N-dimethylaminopyridine (109 mg, 0.86 mmol) in 40 mL acetonitrile. The resulting orange mixture was stirred at room temperature overnight. The suspension was filtered. The solid was washed with acetonitrile and air dried to give 2.64 g methyl 6-(tert-butoxycarbonylamino)nicotinate as a colorless solid. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give an additional 1.50 g methyl 6-(tert-butoxycarbonylamino)nicotinate. 1H NMR (400 MHz, CDCl3) δ 8.89-8.92 (m, 1H), 8.49-8.59 (br s, 1H), 8.24 (dd, J=8.0, 2.3 Hz, 1H), 8.04 (d, J=8.0 Hz), 3.89 (s, 3H), 1.54 (s, 9H).
With dmap; triethylamine In dichloromethane
A Step A:
To a solution of methyl-6-aminonicotinate (1.86 g, 12.22 mmol) dissolved in methylene chloride (90 mL) was added di-t-butyl dicarbonate (2.69 g, 12.34 mmol), 4-dimethylaminopyridine (0.15 g, 1.22 mmol) and triethylamine (2.00 mL, 14.66 mmol). After 14 h the reaction was diluted with EtOAc (400 mL) and washed with citric acid (1 x 50 mL, 10%), water (1 x 50 mL) and brine (1 x 50 mL) and was dried over MgSO4, filtered, and concentratedin vacuo. The residue was purified by flash column chromatography (40 x 150 mm column of SiO2, EtOAc/Hex gradient elution 1:6, 1:5, 1:3) to to give the title compound as a white solid: 1H NMR (400 MHz, CDCl3) d 1.56 (s, 9H), 3.91 (s, 3H), 8.06 (d, J = 8.2 Hz, 1H), 8.24-8.27 (m, 1H), 8.57 (br s, 1H), 8.93 (dd, J = 0.7 and 2.4 Hz, 1H).
Compound 15 (1.0 equiv., 3.94 mmol, 0.600 g) was added portion wise to a suspension OfLiAlH4 (3.00 equiv., 11.83 mmol, 0.449 g) in dry THF (17 ml) at 00C. The reaction mixture was stirred at room temperature overnight. Excess LiAlH4 was destroyed by addition of methanol (while cooling on ice), the reaction mixture was filtered over Celite and the filtrate concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane / methanol 75:25) to give 6-amino-3-pyridinemethanol (16) (0.330 g, yield = 67%) as a white solid. 1H NMR (delta, CD3OD): 4.43 (2H, s), 6.58 (IH, d, J = 8.5 Hz), 7.48 (IH, dd, J = 8.5, ~ 2 Hz) 7.86 (IH, d, J ~ 2 Hz)
2.6 g
With lithium aluminium tetrahydride; In tetrahydrofuran; at 70℃; for 16h;Inert atmosphere;
Under the protection of nitrogen gas, a solution of methyl 6-aminopyridine-3-formate (5.00 g) in tetrahydrofuran (50 mL) was added to a solution of LiAlH4 (1.5 g) in tetrahydrofuran (100 mL), and the mixture was stirred at 70 C. for 16 hours. TLC showed that the reaction was complete. The mixture was cooled to 20 C. Water (1.5 mL), an aqueous solution of sodium hydroxide (15%, 1.5 mL) and water (4.5 mL) were added sequentially and stirred for 0.5 hours. The mixture was filtered. The filtrate was concentrated to give a yellow solid, which was washed with (petroleum ether:ethyl acetate=1:10). The residual yellow solid was the compound of formula (a-1) (2.6 g).
With iodine; silver trifluoroacetate In methanol at 25℃; for 72h;
1
To a stirred suspension of methyl 6-aminonicotinate (10 g, 65.7 mmol) and trifluoroacetic acid silver salt (36.3 g, 164.3 mmol) in methanol (250 mL) was added iodine (41.7 g, 164.3 mmol) at 25° C. and the reaction mixture was stirred at 25° C. for 72 h. The mixture was filtered, washed with methanol and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed consecutively with a saturated sodium thiosulfate solution, brine and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo to afford 6-amino-5-iodo-nicotinic acid methyl ester (13.8 g, 77%) as a light yellow solid: 1H NMR (400 MHz, CDCl3) δ ppm 3.89 (s, 3H), 5.46 (br. s., 2H), 8.47 (br. s., 1H), 8.67 (br. s., 1H).
62%
With iodine; silver sulfate In ethanol at 20℃; for 42h;
465.1
Example 465 (S)-6-amino-N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-[(trimethylsilyl)ethynyl]nicotinamideStep 1 methyl 6-amino-5-iodonicotinate To a solution of iodine (3.55 g, 14.0 mmol) in 100 mL absolute ethanol at room temperature was added silver sulfate (4.37 g, 14.0 mmol) and methyl 6-aminonicotinate (1.52 g, 10.0 mmol). After 42 hours the reaction was filtered to isolate a tan precipitate. The solid was heated with 20% MeOH/CHCl3 then cooled to room temperature, filtered, and rinsed with MeOH and CHCl3. The filtrate was evaporated, dissolved in hot MeOH, filtered to remove brownish impurities, and then crystallized from MeOH to give the title compound as a light tan solid (1.73g,Step 2
57%
With iodine; silver sulfate In ethanol at 20℃; for 24h;
4.1.26 Methyl 6-amino-5-iodonicotinate (49)
Compound 48 (200mg, 1.31mmol) was dissolved in abs. EtOH (15mL), I2 (460mg, 1.83mmol) and AgSO4 (572mg, 1.83mmol) were added in one portion. The reaction mixture was stirred at rt for 24h then evaporated under vacuum. Purification by DCVC (CH2Cl2) afforded the product as off-white solid (208mg, 57%). mp. 161-164°C. 1H NMR (CDCl3) δ 8.65 (d, J=2.1Hz, 1H), 8.44 (d, J=2.1Hz, 1H), 5.45 (b s, 2H), 3.87 (s, 3H). 13C NMR (CDCl3) δ 165.1, 160.5, 151.1, 149.8, 148.3, 118.1, 52.4.
50%
With N-iodo-succinimide; trifluoroacetic acid In acetic acid at 20℃;
22.1 Example 22 : 3-cyclohexyl-1- [2- (4-METHYLPIPERAZIN-1-YL)-2-OXOETHYL]-2-PHENYL- 1H-pyrrolo [2, 3-b]pyridine-5-carboxylic acid; Step 1 : methyl 6-amino-5-iodonicotinate
To a solution (0.48 M) of methyl 6-aminonicotinate in glacial acetic ACID/TFA (20: 1, v/v) was added NIS (1.5 eq. ) and the solution was stirred at room temperature overnight. To the solution were added ice, saturated aqueous NH40H until pH c. 9 was reached. The precipitate was isolated by filtration, dissolved in CHC13 and washed with saturated aqueous NA2S203 solution, H20 and brine then dried and concentrated to afford the title compound (50%) as a solid. 1H NMR (400 MHz, DMSO-D6, 300 K) õ 3.77 (s, 3H), 6.90-7. 0 (br s, 2H), 8.26 (d, J 2.0 Hz, 1H), 8.49 (d, J 2.0 Hz, 1H); MS (ES+) NZ/Z 279 (M+H) +.
With trifluorormethanesulfonic acid; [bis(pyridine)iodine]+ tetrafluoroborate In dichloromethane at 0 - 20℃; for 26h;
2.ii (ii) 6-Amino-5-iodo-nicotinic acid methyl ester
To 5 g 6-Amino-nicotinic acid methyl ester and 16.2 g Bis(pyridine)iodonium(I) tetrafluoroborate in 250 ml DCM, 7.6 ml Trifluoromethanesulfonic acid were added dropwise at 0°C. The mixture was stirred for 24 h at RT. Then additional 3.2 g Bis(pyridine)iodonium(I) tetrafluoroborate and 1.5 ml Trifluoromethanesulfonic acid were added. After stirring for 2 h at RT the reaction mixture was concentrated under reduced pressure and then taken-up with concentrated aqueous Na2SO3 solution and brought to pH 8 with concentrated aqueous ammonia. The mixture was extracted with ethyl acetate (2x150 ml). The combined organic layers were washed with brine and then dried over MgSO4. After filtration the solvent was removed under reduced pressure and the residue was codestilled with 100 ml toluene. Yield: 9.6 g.
803 ml (3.4 equivalents) of 2.0M trimethylsilyldiazomethane in solution in diethyl ether are added over a period of one hour to a solution of 70 g of methyl 6-aminonicotinic acid in a 1/1 diethyl ether/methanol mixture cooled to 0 C. The reaction mixture is stirred at ambient temperature for 1 hour and is then concentrated under reduced pressure. The orange solid residue obtained is dissolved in 1.4 l of ethyl acetate and washed successively with water and an aqueous sodium carbonate solution. After extracting the aqueous phases with ethyl acetate, the organic phases are combined, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give 80.5 g of the expected product in the form of an orange solid. Yield: 100% 1H NMR (CDCl3) delta (ppm): 9.29 (dd, 1H), 8.47 (dd, 1H), 7.84 (dd, 1H), 4.02 (s, 3H)
Stage #1: methyl 6-aminonicotinoate; di-<i>tert</i>-butyl dicarbonate With 2-(Dimethylamino)pyridine In dichloromethane at 0℃;
Stage #2: With triethylamine In dichloromethane at 20℃; for 4h;
6.2
4.18 g of di(tert-butyl) dicarbonate (2.0 equivalents) and 0.117 g of dimethylaminopyridine (0.1 equivalent) are added at 0° C. to a solution of 1.459 g of the product obtained in Stage 1 in 50 ml of dichloromethane and then 2.7 ml (2.0 equivalents) of triethylamine are added dropwise. The reaction medium is stirred at ambient temperature for 4 hours, concentrated under reduced pressure, washed with water and then washed with a saturated aqueous sodium chloride solution. The reaction medium is extracted with ethyl acetate and dried over sodium sulphate, then filtered and concentrated under reduced pressure. Chromatography of the residue on silica gel (dichloromethane/methanol: 9/1) makes it possible to isolate 1.875 g of the expected product. Yield: 55% MS: MH+ 353
With dmap; triethylamine In dichloromethane at 20℃;
A-09) 7V-^rt-Butoxycarbonyl-[5-(2-Acetylamino-4-oxo-4,5,6,7-tetrahydro- pyrazolotl^-flJpyridine-S-carbonylJ-pyridin-l-ylJ-carbamic acid tert-butyl esterA-09a) 6-[Λ/,Λ/-Di-(tert-butoxycarbonyl)-amino]-nicotinic acid6-Amino-nicotinic acid methyl ester (13.7 g, 90.0 mmol), triethylamine (12.5 mL, 90.0 mmol) and DMAP (3.30 g, 27.0 mmol) are taken up in 200 mL DCM and a solution of di-tert-butyl dicarbonate (41.3 g, 189 mmol) in 40 mL DCM is added drop wise. The reaction mixture is stirred overnight at RT. An aqueous 5 % KHSO4 solution is added and the reaction mixture is extracted with DCM. The combined organic phases are washed with an aqueous 50 % saturated KHCO3 solution, dried over MgSO4 and concentrated under reduced pressure. Yield: 34.9 g.
With triethylamine In dichloromethane at 20℃;
A.11
6-Amino-nicotinic acid methyl ester (13.7 g, 90.0 mmol), triethyl amine (12.5 mL, 90.0 mmol) and DMAP (3.30 g, 27.0 mmol) are taken up in 200 mL DCM and a solution of i-tert-bvXyl dicarbonate (41.3 g, 189 mmol) in 40 mL DCM is added drop wise. The reaction mixture is stirred overnight at RT. An aqueous 5 % KHSO4 solution is added and the reaction mixture is extracted with DCM. The combined organic phases are washed with an aqueous 50 % saturated KHCO3 solution, dried over MgSO4 and concentrated under reduced pressure. Yield: 34.9 g.
With dmap; triethylamine In dichloromethane at 20℃;
A.08
6-Amino-nicotinic acid methyl ester (13.7 g, 90.0 mmol), triethylamine (12.5 mL, 90.0 mmol) and DMAP (3.30 g, 27.0 mmol) are taken up in 200 mL DCM and a solution of di-tert-buty dicarbonate (41.3 g, 189 mmol) in 40 mL DCM is added drop wise. The reaction mixture is stirred overnight at RT. An aqueous 5 % KHSO4 solution is added and the reaction mixture is extracted with DCM. The combined organic phases are washed with an aqueous 50 % saturated KHCO3 solution, dried over MgSO4 and concentrated under reduced pressure. Yield: 34.9 g.Of this residue 17.3 g is taken up in a mixture of 150 mL MeOH and 300 mL water, lithium hydroxide (2.33 g, 97.3 mmol) is added and the reaction mixture is stirred for 3 h at RT. The reaction mixture is acidified to pH 4 with acetic acid and the formed precipitate is filtered off, washed with water and dried in vacuo. Yield: 11.8 g. 1H NMR (DMSO-J6): δ 9.0 (s, IH), 8.2 (d, IH), 7.2 (d, 2H), 1.4 (s, 18H).
13 PREPARATION 13
PREPARATION 13 A mixture of methyl 6-aminonicotinate (510 mg), chloroacetone (620 mg) and ethanol (10 ml) was refluxed for 10 hours. After the solvent was removed, ethanol (5 ml) and water (5 ml) was added to the residue. To the solution containing methyl 2-methylimidazo[1,2-a]pyridine-6-carboxylate was added sodium hydroxide (536 mg) and the mixture was stirred for 1 hour at ambient temperature. Ethanol was evaporated and the resulting crystal was collected. A suspension of the obtained crystal in water (3 ml) was adjusted to pH 3.5 with hydrochloric acid, and the residual crystal was collected and dried to give 2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (0.42 g). mp: 147°-151° C. (dec.) NMR (DMSO-d6, δ): 2.47 (3H, s), 7.7-8.2 (3H, m), 9.47 (1H, s)
With 2-chloro-1-methyl-pyridinium iodide; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 96h;
2-Chloro-l-methylpyridinium iodide (2.99 g, 10 mmol) and DIPEA (3mL) were added to a mixture of methyl 6-aminonicotinate 1 (760 mg, 5 mmol) and <strong>[6311-35-9]6-bromonicotinic acid</strong> 2 (1 g, 5 mmol) in THF (15OmL). The reaction mixture was stirred at rt (=room temperature) for 4 days. At the conclusion of the reaction, the reaction mixture was concentrated to 1/3 of its volume and the precipitated product was filtered off. The filtrate was concentrated, diluted with chloroform (100 ml), washed with water and brine and dried over Na2SO4. Evaporation of the solvent gave a crude yellow product, which crystallized in EtOAc to give methyl 6-(6- bromonicotinamido)nicotinate 3 as a white solid (1 g, 65.4 %). Mp. 234 - 235 0C. <n="54"/>1H-NMR (400 MHz, CDCl3): delta = 11.5 (s, IH), 8.96 (d, J = 2.0 Hz, IH), 8.93 (s, IH), 8.36 (dd, J = 2.0Hz, J = 8.0 Hz, IH), 8.33 (d, J = 12Hz, IH), 8.28 (dd, J = 2.4 Hz5 J = 8.0 Hz, IH), 7.83 (d, J = 8.4 Hz, IH), 3.88 (s, 3H). MS (ESI): m/z = 338 (M+2H)
In tetrahydrofuran at 0 - 20℃; for 16h; Inert atmosphere;
122.1 Step 1: Example 122b
To a solution of Example 122a (700 mg, 4.61 mmol) in THF (65 mL) was added MeMgCl (15 mL, 45 mmol) at 0oC under argon protection. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. Then the mixture was quenched by aq. NH4Cl, extracted with EA (50 mL*2). The combined organic phase was washed by water, brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to give Example 122b (600 mg, 85.7% yield) as brown oil, which was used for the next step directly.
Stage #1: methyl 6-aminonicotinoate; methylmagnesium chloride In tetrahydrofuran at 10 - 20℃; for 15h;
Stage #2: With water; ammonium chloride In tetrahydrofuran at 0℃;
To a solution of 0.7 g of methyl 6-aminonicotinate in 65 mL of THF, cooled to 10° C. and under argon, are added dropwise 15 mL of a 3M solution of methylmagnesium chloride in THF. The reaction mixture is stirred for 15 hours, while allowing the temperature to rise to 20° C., and is then cooled again in an ice bath. 100 mL of saturated ammonium chloride solution and then 200 mL of ethyl acetate are added slowly. The organic phase is dried and concentrated to dryness. The residue is taken up in ethyl acetate. The precipitate is filtered off by suction and dried to give 0.4 g of 2-(6-aminopyridin-3-yl)propan-2-ol in the form of a pale yellow solid.1H NMR spectrum (DMSO-d6, δ in ppm): 1.36 (s, 6H); 4.82 (s, 1H); 5.67 (broad s, 2H); 6.37 (d, J=9.0 Hz, 1H); 7.42 (dd, J=2.5 and 9.0 Hz, 1H); 7.98 (d, J=2.5 Hz, 1H)Mass spectrum (EI): m/z 152: [M+.], m/z 137: [M+.]-CH3 (base peak)
In tetrahydrofuran at 10 - 20℃; for 15h;
2-(6-Aminopyridin-3-yl)propan-2-ol 15 ml of a 3M solution of methylmagnesium chloride in THF are added dropwise to a solution, cooled to 10° C. and under argon, of 0.7 g of methyl 6-aminonicotinate in 65 ml of THF. The reaction mixture is stirred for 15 h, while allowing the temperature to rise to 20° C., and then again cooled in an ice bath. 100 ml of a saturated ammonium chloride solution and then 200 ml of ethyl acetate are slowly added. The organic phase is dried and concentrated to dryness. The residue is taken up in ethyl acetate. The precipitate is filtered off and dried to give 0.4 g of 2-(6-aminopyridin-3-yl)-propan-2-ol in the form of a pale yellow solid. 1H NMR spectrum (d6-DMSO, 6 in ppm): 1.36 (s, 6H); 4.82 (s, 1H); 5.67 (broad s, 2H); 6.37 (d, J=9.0 Hz, 1H); 7.42 (dd, J=2.5 and 9.0 Hz, 1H); 7.98 (d, J=2.5 Hz, 1H) Mass spectrum (EI): m/z 152: [M+.], m/z 137: [M+.]-CH3 (base peak)
In tetrahydrofuran at 0 - 25℃; for 15h; Inert atmosphere;
20.A Step A:
Step A: 2-(6-Amino-3-pyridine)propan-2-ol To a solution of methyl 6-aminopyridine-3-carboxylate (3.2g, 21.03mmol) in tetrahydrofuran (300mL) was added dropwise methyl magnesium chloride (70.10mL, 3mol), at 0°C under nitrogen, and after it was stirred for 15 hours at 25°C, and quenched by the addition of water (50mL). The aqueous layer was extracted with ethyl acetate (50mLx2). The combined organic layers were washed with saturated brine (50mLx2), then dried over sodium sulfate, filtered and evaporated to give the title compound. LCMS (ESI) m/z: 153 (M+1). 1H NMR(400MHz, DMSO-d6) δ=7.96 (d, J=2.3 Hz, 1H), 7.45 (dd, J=2.5, 8.5 Hz, 1H), 6.39 (d, J=8.5 Hz, 1H), 5.74 (br s, 2H), 4.85 (s, 1H), 1.36 (s, 6H).
With sodium hydrogencarbonate In methanol for 8h; Reflux;
63%
In ethanol; water for 4h; Reflux;
In ethanol for 18h; Heating / reflux;
N1
To a solution of 50% aq. chloroacetaldehyde (1.1 eq, 36 mmol, 4.6 ml) in ethanol (120 ml) is added 6-amino-nicotinic acid methyl ester (1 eq, 33 mmol, 5 g) at room temperature. The reaction mixture is heated at reflux for 18 hours. The solvent is removed in vacuo and the crude product is dissolved in water (400 ml). The aqueous solution is treated with sodium bicarbonate to pH = 8 and extracted with DCM (3 x 250 ml). The organic layer is dried (MgSO4) and evaporated to give the title compound as a beige solid.
Stage #1: 2-chloroethanal; methyl 6-aminonicotinoate In ethanol; water for 4h; Reflux;
Stage #2: With sodium hydrogencarbonate In water
To a solution of Z-1 (9.0 g, 59.21 mmol) in anhydrous EtOH (160 ml) was added chloroacetaldehyde (40% in H2O, 48.6 mL, 296 mmol). The reaction mixture was refluxed for 4h, then concentrated. The residue was dissolved in water and adjusted to pH>7 with a saturated NaHC03 solution, extracted with EtOAc and purified by silica gel chromatography to afford the title compound (6.60 g). MS (m/z): 177 (M+1 )+.
In ethanol; water for 4h; Reflux;
Methyl H-imidazo[1,2-a]pyridine-6-carboxylate (Z-2) To a solution of Z-1 (9.0 g, 59.21 mmol) in anhydrous EtOH (160 ml) was added chloroacetaldehyde (40% in H2O, 48.6 mL, 296 mmol). The reaction mixture was refluxed for 4 h, then concentrated. The residue was dissolved in water and adjusted to pH>7 with a saturated NaHCO3 solution, extracted with EtOAc and purified by silica gel chromatography to afford the title compound (6.60 g). MS (m/z): 177 (M+1)+.
Step 1: Methyl H-imidazo [1, 2-a] pyridine-6-carboxylate (288) [0443] A solution of 2- (BROMOMETHYL)-1, 3-DIOXOLANE (0.18 mL; 1.67 MMOL) in THF (3 mL) and water (0.2 mL) was treated with concentrated HCI (3 drops) and stirred at 88C for 50 min. The solution was cooled down to 0C and transferred into a vial containing 2-amino-5- METHOXYCARBONYLPYRIDINE (287,204mg ; 1. 34MMOL), BU2SNCI2 (134 mg; 0.40 MMOL) and NAHC03 (410 mg) and stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate (60mL) and washed with saturated aqueous sodium chloride. The organic layer was dried (MGS04), filtered and concentrated. After chromatographic purification of the residue using preparative TLC on silica gel (eluent 50% ethyl acetate in dichloromethane), the title compound 288 was obtained (74 mg, 31% YIELD). H NMR: (500.7 MHz, CDCI3) 6 (PPM) : 9. 00 (S, 1H); 7.80 (m, 4H); 4.00 (s, 3H). MS: CALC : 176.1 ; found: 177.1 (M+H)
Preparation of compound 50: To a suspension of NaH (94 mg, 3.94 mmole, 2 eq) in DMF (20 mL) was added methyl-2-amino-pyridine-5-carboxylate (300 mg, 1.97 mmole, 1 eq) and stirred at room temperature for 30 minutes. A solution of <strong>[22952-32-5]5-chloro-2-methoxybenzenesulfonyl chloride</strong> (570 mg, 2.36 mmole, 1.2 eq) was added slowly at room temperature and stirred for an additional 2 hrs. The reaction was monitored by TLC which showed 50% of the starting material remaining and continuation of the reaction failed to show improvement. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. The crude product 50 containing 50% of the starting ester was used without further purifications for the next step.
1
Example 1(1) [0146] A mixture of methyl-6-aminonicotinate (3.00 g, 19.72 mmol), di-tert-butyl carbonate (5.16 g, 23.66 mmol), DMAP (169 mg, 1.38 mmol) and THF (175 mL) was stirred at room temperature overnight. The mixture was concentrated and the residue was dissolved in dichloromethane, washed by 0.5 N HCl, water, brine, dried over magnesium sulfate (anhydrous). After concentration, light yellow solids were precipitated, which was collected by filtration, washed by hexanes to give the title compounds as white solids (3.60 g, 72% yield). IH NMR (500 Hz, CDC13) δ 10.02 (s, IH), 9.01 (s, IH), 8.27 (d, J = 9.0 Hz, IH), 8.12 (d, J = 9.0 Hz, IH), 3.91 (s, 3H5), 1.58 (s, 9H); ESI-MS: calcd for (C12H16N2O4Na) 275, found 275 (MNa+).
Stage #1: 2,4-dichloro-6-ethyl-1,3,5-triazine; methyl 6-aminonicotinoate With n-butyllithium In tetrahydrofuran; hexane at -78 - 15℃;
Stage #2: With ammonium chloride In tetrahydrofuran; hexane; water
14
Example 14 [0160] To a solution of methyl 6-aminonicotinate (1.20 g, 7.89 mmol) in THF (70 ml) was added a solution of n-Butyl lithium in hexane (1.6 M, 4.9 mL) dropwise at -78° C. The reaction was stirred for one hour, during which the temperature was raised to -20° C. In a separate container, compound 4 (1.65 g, 9.27 mmol) was dissolved into 30 mL of THF and then added to the reaction mixture at -20° C. The mixture was stirred for additional 6 hours and the temperature was allowed to warm up to 15° C, after addition of saturated ammonium chloride in water, the mixture was extracted with ethyl acetate (3x). The combined organic was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (0-5% methanol in dichloromethane) to give compound 14 as yellow solids (55 mg, 2.4%). IH NMR (500 MHz, DMSO-d6) δ 11.39 (s, IH), 8.87 (s, IH), 8.35 (br, 2H), 3.87 (s, 3H), 2.76 (q, J = 7.5 Hz, 2H), 1.25 (t, J = 7.5 Hz, 3H); ESI-MS: calcd for (Ci2Hi2ClN5O2) 293, found 294 (MH+), 292 ([M-H]-).
With caesium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 100℃; for 2.2h;Sealed tube; Inert atmosphere;Product distribution / selectivity;
Step 1 Preparation of Methyl 6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin- 2-ylamtno)nicotinate. To a suspension of 2-chloro-7-cyclopentyl-W,W-dimethyl-7H-pyrrolot2,3-d]pyrimidine-6- carboxamide (5.0 g, 17 mmol) tn1 ,4-dioxane (80 mL) in a sealed tube were added methyl 6-aminonicotinate (2.86 g, 1.10 eq), Pd(OAc)2 (0.096 g, 0.025 eq) and BINAP (0.532 g, 0.050 eq). N2 was bubbled through the resulting mixture for 20 min to degas and treated with Cs2C03 (8.35 g, 1.5 eq). The reaction mixture was heated at 100 C for 2.2 h. The reaction mixture was cooled to room temperature, treated with 00 mL of heptane and sonicated. Red precipitate was collected by filtration and suspended in 200 mL of water. After sonication, the solid was collected by filtration, rinsed with water (3 x 50 mL) and dried. The solid was triturated in THF to obtain tan solid methyl 6-(7-cyclopentyl-6- (dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinate (6.6g, 94 % yield). The filtrated was concentrated in vacuo and purified by column chromatography (Ethyl acetate/Heptane) to give additional product (0.4 g, 6 % yield). 1H NMR (400 MHz, DMSO-c/6) delta ppm 10.33 (s, 1 H), 8.89 (s, 1 H), 8.83 (d, J = 2.1 Hz, 1 H), 8.44 (d, J = 8.9 Hz, 1 H), 8.22 (dd, J = 8.9, 2.2 Hz, 1 H), 6.67 (s, 1 H), 4.77 (m, 1 H), 3.86 (s, 3 H), 3.06 (s, 6 H), 2.42 (m, 2 H), 2.00 (m, 4 H), 1.68 (m, 2 H); MS m/z 409.4 (M+H)+.
toluene-4-sulfonic acid; In toluene; for 12h;Molecular sieve; Reflux;
Example 1.34 (+/-)-3-(6-(cyclopropyl(4'-(trifluoromethyl)biphenyl-4-yl)methylamino)nicotinamido)propanoic acid To a solution of <strong>[90035-34-0]4'-(trifluoromethyl)biphenyl-4-carbaldehyde</strong> (1 g, 4 mmol), p-toluene sulfonic acid (50 mg, 0.3 mmol), and activated molecular sieves in toluene (15 mL), was added methyl 6-aminonicotinate (670 mg, 4.4 mmol). The reaction was refluxed for 12 h. The reaction was cooled to room temperature and concentrated to give the intermediate imine. To a 0 C. solution of methyl 6-((4'-(trifluoromethyl)biphenyl-4-yl)methyleneamino)nicotinate (600 mg, 1.56 mmol) in tetrahydrofuran (10 mL) was added cyclopropylmagnesium bromide (5 mL, 2N in THF, 8 mmol). The reaction was stirred at 0 C. for 1 hr, then warmed to room temperature and left stirring for 12 h. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate (3*15 mL). The combined organics were dried over sodium sulfate, filtered and concentrated. Purification by preparative TLC (5:1 petroleum ether:ethyl acetate) gave methyl 6-(cyclopropyl(4'-(trifluoromethyl)biphenyl-4-yl)methylamino)nicotinate (130 mg).
With 1-bromopyrrolidine-2,5-dione In tetrahydrofuran at 0 - 20℃;
4 6-Amino-S -bromo-nicotinic acid methyl ester
To a stirred solution of methyl 6-amino nicotinate (22 g, 143.7 mmol) in THF(500 mL) at 0 °C is added NBS (27.9 g, 158.1 mmol) and the reaction mixture is stirred atroom temperature for overnight. Ammonium chloride (100 mL) is added to the reaction mixture and the mixture is extracted with EtOAc (2x100 mL). The combined organicextracts are washed with brine solution (100 mL), dried over sodium sulphate, filtered, and evaporated under reduced pressure. The crude material is purified by silica gelcolumn chromatography (combiflash) and eluted with 35% EtOAc in hexanes to give the title compound as a pale brown solid (28 g, 84.8%). LCMS m/z (79Br/81Br) 23 1/233 (M+H)+
84.8%
With 1-bromopyrrolidine-2,5-dione In tetrahydrofuran at 0 - 20℃;
4 6-Amino-5-bromo-nicotinic acid methyl ester
Preparation 4 6-Amino-5-bromo-nicotinic acid methyl ester To a stirred solution of methyl 6-amino nicotinate (22 g, 143.7 mmol) in THF (500 mL) at 0° C. is added NBS (27.9 g, 158.1 mmol) and the reaction mixture is stirred at room temperature for overnight Ammonium chloride (100 mL) is added to the reaction mixture and the mixture is extracted with EtOAc (2*100 mL). The combined organic extracts are washed with brine solution (100 mL), dried over sodium sulphate, filtered, and evaporated under reduced pressure. The crude material is purified by silica gel column chromatography (combiflash) and eluted with 35% EtOAc in hexanes to give the title compound as a pale brown solid (28 g, 84.8%). LCMS m/z (79Br/81Br) 231/233 (M+H)+.
80.91%
With N-bromobutanamide In tetrahydrofuran at 0 - 25℃; for 2h;
34 Methyl 6-amino-5-bromonicotinate
To a mixture of methyl 6-aminonicotinate (15 g, 98.59 mmol, 1 eq) in THF (300 mL) was added N-bromobutanimide (18.42 g, (0970) 103.52 mmol) in portions at 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel chromatography to give methyl 6-amino-5-bromonicotinate (19 g, 79.77 mmol, 80.91% yield).
76.39%
With 1-bromopyrrolidine-2,5-dione In tetrahydrofuran at 0 - 20℃; for 10h;
Preparation of methyl 6-amino-5-bromomcotinate (Step 1 in Scheme 13)
To a mixture of methyl 6-aminopyridine-3 -carboxylate (50 g, 328.62 mmol, 1 eq) in THF (800 mL) was added NBS (64.34 g, 361.48 mmol, 1.1 eq) in portions at 0°C. Then the mixture was stirred at 20°C for 10 hours. TLC (Petroleum etherEthyl acetate=2: 1, Rf=0.45) showed the reaction was complete. The mixture was quenched with ice water (200 mL) and the organic solvent was removed under reduced pressure. To the residue was added water (500 mL). There was some brown solid formed. The filtrate was extracted with EtOAc (200 mL x 6). The combined organic layer was washed with sat.NaHCO3 (200 mL x 4) and brine (100 mL x 1), dried over Na2SO4, filtered and concentrated under reduced pressure. The solid (47 g) was collected without further purification. The residue was triturated with EtOAc (200 mL) and dried under reduced pressure (11 g). Compound methyl 6-amino-5-bromo-pyridine-3- carboxylate (58 g, 251.03 mmol, 76.39% yield) was obtained as brown solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.49 (s, 1H), 8.08 (s, 1H), 7.15~7.14 (m, 2H), 3.78 (s, 3H).
With 1-bromopyrrolidine-2,5-dione
146.1 Step 1:
Step 1: Methyl 6-amino-5-bromonicotinate E35-1 Methyl 6-aminonicotinate (4.0 g, 26.3 mmol) and N-bromosuccinimide (5.15 g, 28.9 mmol) were dissolved in dichloromethane (100 mL). At 20 °C, under nitrogen atmosphere, the mixture was reacted for 1 hour. The reaction was completed (monitored by LCMS) and the reaction solution was sequentially washed with sodium sulfite solution, sodium carbonate solution and water. The organic phase was dried and concentrated to obtain E35-1 (6.1 g, crude). LCMS: m/z 231.0 [M+H]+.
With 1-bromopyrrolidine-2,5-dione In dichloromethane at 20℃; for 1h; Inert atmosphere;
146.1 Step 1: methyl 6-amino-5-bromonicotinate E35-1
methyl 6-aminonicotinate (4.0 g, 26.3 mmol) and N-bromosuccinimide (5.15 g, 28.9 mmol) were dissolved indichloromethane (100 mL). At 20 °C, under nitrogen atmosphere, the mixture was reacted for 1 hour. The reaction wascompleted (monitored by LCMS) and the reaction solution was sequentially washed with sodium sulfite solution, sodiumcarbonate solution and water. The organic phase was dried and concentrated to obtain E35-1 (6.1 g, crude).LCMS: m/z 231.0 [M+H]+.
With 1-bromopyrrolidine-2,5-dione In dichloromethane at 20℃; for 1h; Inert atmosphere;
146.1 Step 1: methyl 6-amino-5-bromonicotinate E35-1
methyl 6-aminonicotinate (4.0 g, 26.3 mmol) and N-bromosuccinimide (5.15 g, 28.9 mmol) were dissolved indichloromethane (100 mL). At 20 °C, under nitrogen atmosphere, the mixture was reacted for 1 hour. The reaction wascompleted (monitored by LCMS) and the reaction solution was sequentially washed with sodium sulfite solution, sodiumcarbonate solution and water. The organic phase was dried and concentrated to obtain E35-1 (6.1 g, crude).LCMS: m/z 231.0 [M+H]+.
methyl 6-((3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino)nicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 120 - 125℃; for 22h;Inert atmosphere;
a. Methyl 6-((3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino)nicotinate (79). To a solution of 77 (1.1216 g, 3.99 mmol), 78(0.5910 g, 3.88 mmol), CsCO3 (3.1158 g, 9.58 mmol), rac-B1NAP (0.1856 g, 0.30 mmol) in toluene (4.5 mL) in a 100 mL round-bottomed flask was added Pd2(dba)3 (0.1755 g, 0.19 mmol). The solution was sparged with nitrogen for 5 mm., then a reflux condenser was fitted to the flask, the atmosphere was evacuated and back-filled with nitrogen (three times), and the reaction was heated to reflux with stirring in an oil bath (125-120 C) for 22h. After cooling the reaction to room temperature, excess cesium carbonate and other solid particulates were filtered and washed with ethyl acetate, and the organic filtrate was concentrated in vacuo to give a crude product that was purified by column chromatography (150 mE Si02, 6.5% ethyl acetate:hexanes to 10% ethyl acetate: hexanes) to give 79 (0.5072 g, 37%) as a crystalline solid, m.p. 169-175.8 C: ?H NMR (400 MHz, CDC13) 6 8.79 (dd, J= 2.4, 0.8, JH), 8.00 (dd, J= 8.8, 2.0, 1H), 7.25 (s, 1H), 7.18 (s, 1H), 7.05 (brs, 1H), 6.49 (dd,J 8.8, 0.8, 1H), 3.87 (s, 3H), 2.20 (s, 3H),1.68 (s, 4H), 1.29 (s, 6H), 1.25 (s, 6H); ?3C NMR (100.6 MHz, CDC13) 6 166.1, 160.0, 151.3, 143.8,143.0, 138.9, 134.1, 130.3, 129.1, 123.1, 116.1, 105.5, 51.7, 35.0, 34.9, 34.0, 33.9, 31.8, 31.8, 17.6; IR (neat) 2961, 1722, 1605, 1399, 1273 cm?; ES-MS (M+Na)+ calcd for C22H28N2O2Na 375.2048, found 375.2050.
6-[(5-fluoro-2-methoxypyridin-3-ylmethyl)amino]nicotinic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
832 mg
With triethylsilane; trifluoroacetic acid; In acetonitrile; for 3h;Reflux;
In a round bottom flask, 6-amino-nicotinic acid methyl ester (90, 0.678 g, 4.46 mmol) was combined with <strong>[351410-62-3]5-fluoro-2-methoxy-pyridine-3-carbaldehyde</strong> (37, 0.532 g, 3.43 mmol), 10.6 mL of acetonitrile, trifluoroacetic acid (1.32 mL, 17.1 mmol) and triethylsilane (3.29 mL, 20.6 mol). The reaction was heated to reflux for 3 hours, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with ethyl acetate and hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (91, 832 mg). MS (ESI) [M+H+]+=292.4.
methyl 3-methyl-2-(propan-2-yl)imidazo[1,2-a]pyridine-6-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.05 g
With N-ethyl-N,N-diisopropylamine In ethanol Reflux;
427 methyl 3-methyl-2-(propan-2-yl)imidazo[1,2-a]pyridine-6-carboxylate
methyl 3-methyl-2-(propan-2-yl)imidazo[1,2-a]pyridine-6-carboxylateInto a 100-mL round-bottom flask, was placed a mixture of methyl 6-aminopyridine-3-carboxylate (3 g, 19.72 mmol, 1.00 equiv), ethanol (60 mL), 2-bromo-4-methylpentan-3-one (7 g, crude) and DIEA (3.8 g, 29.40 mmol, 1.50 equiv). The resulted solution was refluxed overnight. The mixture was then concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with ethyl acetate and petroleum ether (1:3). This resulted in 1.05 g (23%) of methyl 3-methyl-2-(propan-2-yl)imidazo[1,2-a]pyridine-6-carboxylate as yellow solid. MS (ESI) m/z 233 [M+H]+.
3 Synthesis of 2-(6-aminopyridin-3-yl)propan-2-ol
methyl 6-aminonicotinate was suspended in THF (500mL), After the addition of methyl lithium at -78°C. It was stirred for 15 hours while naturally raised. The reaction mixture was ice-water bath under a saturated ammonium chloride aqueous solution was added to,And extracted 3 times with chloroform / methanol = 5/1.The organic layers were combined, dried over anhydrous sodium sulfate.Concentrated to dryness Insoluble materials were filtered off,The resulting solid was purified by silica gel column chromatography,To give the title compound 2.2g (44%).
methyl 6-((7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4-yl)amino)nicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
With 1,1'-bis-(diphenylphosphino)ferrocene; potassium carbonate; bis(dibenzylideneacetone)-palladium(0); In 1,2-dimethoxyethane; at 83℃; for 1h;Inert atmosphere;
According to Reference Example 2-1,Commercially available 7-benzyl-4-chloro-5,6,7,8-tetrahydropyrido [3,4-d] pyrimidine and (5.37g) 6- amino nicotinic acid methyl (3.45g), Pd (dba ) 2 (1.19g), dppf (1.15g), potassium carbonate (5.70 g) was suspended in 1,2-dimethoxyethane (100 mL), under nitrogen, was stirred one hour at 83 C. After the reaction mixture was allowed to cool, water (400mL) and came out in addition solid was collected by filtration, was suspended washed with methanol / water (3 / 1,60mL), were suspended washed with toluene (60mL), heated and dried to give the title compound (5.18g, 67% yield).
With 1,1'-bis-(diphenylphosphino)ferrocene; caesium carbonate; bis(dibenzylideneacetone)-palladium(0); In 1,4-dioxane; at 105℃; for 3h;Inert atmosphere;
Commercially available <strong>[192869-80-0]7-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine</strong> (48 g), methyl 6-aminonicotinate (31 g), Pd(dba)2 (10.6 g), dppf (10.2 g), and cesium carbonate (133 g) were suspended in dioxane (1000 mL), and the reaction mixture was stirred under an argon atmosphere at 105C for 3 hours. The reaction mixture was cooled, and the precipitated solid was then collected by filtration and was suspended and washed with toluene to obtain the target compound as a light yellow solid. 1H-NMR (DMSO-d6) delta: 9.39 (1H, s), 8.84 (1H, d, J = 2.6 Hz), 8.57 (1H, s), 8.32 (1H, d, J = 9.2 Hz), 8.26 (1H, d, J = 2.6 Hz), 7.36-7.36 (5H, m), 3.85 (3H, s), 3.68 (2H, s), 2.77 (2H, d, J = 4.8 Hz), 2.74 (2H, d, J = 4.4 Hz). LCMS (A) RT 1.09, m/z [M+H]+ 376.
With sodium tris(acetoxy)borohydride; trifluoroacetic acid; In 1-methyl-pyrrolidin-2-one; at 20℃; for 72h;Cooling with ice;
Example 1 2-[6-(3-trifluoromethoxy-benzylamino)-pyridin-3-yl]-3H-benzimidazole-5-carboxylic acid [Step a] To a solution of compound 1 (7.50 g, 39.4 mmol) and compound 2 (5.00 g, 32.9 mmol) in N-methylpyrrolidone (50.0 mL) was added trifluoroacetic acid (3.75 mg, 32.9 mmol), and the mixture was ice-cooled. To the reaction solution was added sodium triacetoxyborohydride (8.36 g, 39.4 mmol), and the mixture was stirred for 3 days while raising the temperature to room temperature. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography. The obtained solid was suspended and washed in hexane to give compound 3 (4.20 g, 39.2%). MS(ESI)m/z: 327(M+1)+
methyl (R)-6-(3-methyl-2-phenylbutanamido)nicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 12.0h;Inert atmosphere;
General procedure: A mixture of 2-phenylacetic acid (2.72 g, 20.0 mmol), methyl 4-aminobenzoate(3.02 g, 20.0 mmol), triethylamine (6.07 g, 60 mmol), and HATU (7.60 g, 20.0 mmol)in dimethylformamide (40.0 mL) was flushed with argon, and stirred at r.t. for 12hours. The reaction mixture was extracted with ice water (200.0 mL) and ethyl acetate(50.0 mL x 3). The combined organic extracts were washed with 2M HCl(aq) (50.0mL), NaHCO3(sat) (50.0 mL), dried with Na2SO4, filtered, and evaporated. The crudeproduct was purified with flash column chromatography on silica gel, and using 20%Ethyl acetate/Hexanes to afford 46 [methyl 4-(2-phenylacetamido)benzoate] (5.027 g,18.7 mmol, 93%) as a white solid.
6-(2-chloro-5-methylbenzamido)pyridine-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.03 g
To a solution of <strong>[6342-60-5]2-chloro-5-methylbenzoic acid</strong> (0.83 g) in DCM (3 mL) were added (COC1)2 (0.51 mL) and DMF (19 1iL) under nitrogen atmosphere, and the mixture was stilTed at room temperature for 1 hour. The mixture was concentrated and the resulted residue was added dropwise to a solution of methyl 6-aminonicotinate (0.74 g) in Pyr (4.0 mL) under ice cooling, and the mixture was stirred at room temperature for 1 day. Water was added to the reaction solution, and the precipitate was filtered and washed with water. To the resulted solid were added MeOH (12 mL) and 5N aqueous NaOH solution (4.9 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction soluion was neutralized by addition of SN HC1 (4.9 mL) and water under ice cooling, and the precipitate was filtered and washed with water to give 6-(2-chloro-S-methylbenzamido)pyridine-3-carboxylic acid (1.03 g).
N-{5-[(5R)-7-chloro-4,4-difluoro-5-hydroxy-5-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-1-carbonyl]pyridin-2-yl}-2-(trifluoromethyl)pyridine-3-carboxamide[ No CAS ]
6-[2-(trifluoromethyl)pyridin-3-amido]pyridine-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
11.21 g
To a suspension of <strong>[131747-43-8]2-(trifluoromethyl)pyridine-3-carboxylic acid</strong> (9.76 g) in DCM (200 mL) were added (COC1)2 (13.41 mL) and DMF (0.119 mL) at 0C, and the mixture was stirred at 0C for 1 hour, followed by stirring at 30-40C for 2 hours. The reaction solution was concentrated, and then the concentrate was diluted with DCM. The resulted solution was added to a suspension of methyl 6-aminonicotinate (7.77 g) in Pyr (20.65 mL) and DCM (200 mL). The mixture was stirred at room temperature for 2 hours, and then DCM was removed under reduced pressure. Water was added to the residue, and the mixture was extracted with AcOEt. The organic layer was dried over anhydrous Na2SO4, and then filtered and concentrated. The resulted residue was dissolved in MeOH-THF (4:1; 200 mL), and then thereto was added SN aqueous NaOH solution (20.43 mL), and the mixture was stirred at 60C for 2 hours. The reaction solution was concentrated and MeOH was removed. Then, the residue was diluted with water and adjusted to pH (4-5) by addition of HC1 aq. The precipitated solid was filtered and washed with water to give6- [2-(trifluoromethyl)pyridin-3-amidojpyridine-3-carboxylic acid (11.21 g).
methyl 6-(3-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)ureido)nicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
13%
Stage #1: methyl 6-aminonicotinoate; 4-Nitrophenyl chloroformate With pyridine In chloroform at 0 - 20℃; for 16h;
Stage #2: 6-[4-(propan-2-yl)-4H-1,2,4-triazol-3-yl]pyridin-2-amine With pyridine In chloroform at 0 - 20℃; for 2h;
9 Methyl-6-(3-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)ureido)nicotinate (Compound 9a):
To a solution of methyl 6-aminonicotinate (76.0 mg, 0.50 mmol) in CHCb (2 mL) was added pyridine (80.0 mg, 1.01 mmol). Then a solution of 4-nitrophenyl chloroformate (100 mg, 0.50 mmol) in CHCb (1 mL) was added dropwise to the mixture at 0°C. The mixture was stirred at room temperature for 16 h. Then a mixture of pyridine (80.0 mg, 1.01 mmol) and 6-[4-(propan-2-yl)-4H-l,2,4-triazol-3-yl]pyridin-2-amine (100 mg, 0.50 mmol) in CHCb (1 mL) was added dropwise to the mixture at 0°C. The resulting mixture was stirred at room temperature for another 2 h. The reaction mixture was diluted with DCM. The resulted mixture was washed with brine, dried over anhydrous sodium sulfate and filtered. (0243) The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with dichloromethane/methanol (93/7, v/v) to afford the title compound (25 mg, 13%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 382.1
With triethylamine In dichloromethane at 20℃; Cooling with ice;
15.2 Step 2
To the ice-cold solution of 240 (4.0 g, 26.2 mmol) , TEA (5.3 g, 52.4 mmol) in DCM (50 mL) was added 239 in DCM (20 mL) dropwise. The resulting mixture was warmed to room temperature for overnight, then washed with water thrice, dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (PE/EA=4: 1) to give white solid (6.2 g, 73%) .
methyl 6-[{imino(2-(trifluoromethyl)phenyl)ethyl}amino]pyridine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.6%
To a solution of methyl 6-aminopyridine-3-carboxylate (5.0 g, 33 rnmol) in DMF (20 mL) was added NaH (2.6 p. 66 mmol, 60% purity) . The mixture was stirred at 0C for 1 h. After that, <strong>[447-60-9]2-(trifluoromethyl)benzonitrile</strong> (6.8 g, 39 mmol) was added to the above solution, and the mixture was stirred at 25C for 11 h. The reactionmixture was partitioned between PA (100 mL) and H,O (100 mL) . The organic phase was separated, washed with brine (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography(Si02, Petroleum ether/Ethyl acetate=l0:l to 2:1) to give the title compound (0.35 g, 0.87 mmol, 2.6% yield) as an oil.?H NMR: (400 MHz, DMSO-d6) oe (ppm) 3.85 (s, 3H), 6.98 (d, J = 8.4 Hz, 1H), 7.61-7.68 (m, 2H), 7.73-7.75 (m, 1H),7.80-7.82 (m, 1H), 8.10-8.12 (m, 1H), 8.49 (s, 1H), 8.87 (s, 1H) , 9.84 (s, 1H)
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