* 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] Chemische Berichte, 1940, vol. 73, p. 78
2
[ 58539-65-4 ]
[ 1721-23-9 ]
Yield
Reaction Conditions
Operation in experiment
41%
With isocyanuric acid In N,N-dimethyl-formamide at 0℃; for 2.5 h;
30) 2-methyl-nicotinonitrileCyanuric acid (418 mg, 2.2 mmol) was added in one portion to a suspension of 2-methylnicotinamide (intermediate 29) (613 mg, 4.5 mmol) in 2.5 ml of DMF cooled in ice. The 0 reaction was stirred for 2.5 hours then poured into ice. The reaction was extracted with ethyl acetate until the organic layer no longer contained product. The combined organic layers, were dried over Na2SO4, filtered and concentrated. Purified on normal phase chromatography with ethyl acetate/heptane 0 to 50 gradient then 50/50 EA/heptane. Yield (216 mg, 41 percent). IH NMR (400 MHz, CHLOROFORM-D) δ ppm 2.78 (s, 3 H), 7.25 (dd, s J=7.71, 4.98 Hz, 1 H), 7.89 (dd, J=7.81, 1.56 Hz5 1 H), 8.68 (s, 1 H)
Reference：
[1] Journal of Medicinal Chemistry, 2000, vol. 43, # 16, p. 3168 - 3185
[2] Patent: EP1193265, 2002, A2, . Location in patent: Page 77
[3] Patent: WO2007/73303, 2007, A2, . Location in patent: Page/Page column 38
3
[ 58539-65-4 ]
[ 177662-40-7 ]
[ 1721-23-9 ]
Yield
Reaction Conditions
Operation in experiment
75%
With trifluoroacetic anhydride In dichloromethane; water; triethylamine
Step 2 Preparation of 3-cyano-2-methylpyridine: To a suspension of 2-methylnicotinamide from step 1 (11.1 g, 0.081 mol) in triethylamine (24.8 g, 0.243 mol) and 400 mL of methylene chloride was added trifluoroacetic anhydride (21.0 g, 0.100 mol) rapidly at 0° C. The reaction was complete after a few minutes at this temperature. Water was added and the aqueous layer was extracted with methylene chloride. The combined organic layers were washed with water, brine and dried over magnesium sulfate. After filtration, the filtrate was concentrated and the residue was purified by chromatography on silica gel (ethyl acetate/hexane, 1:1) to give 7.2 g of 3-cyano-2methylpyridine as a pale yellow solid (75percent): mp(DSC) 56°-58° C.
Reference：
[1] Patent: US5616601, 1997, A,
4
[ 3222-56-8 ]
[ 58539-65-4 ]
Yield
Reaction Conditions
Operation in experiment
76%
With ammonia; N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0℃;
29) 2-methylnicotinamideTo a solution of 2-methylnicotinic acid (0.537 mg, 3.9 mmol) in 20 mL of DMF at 0 0C was added HATU (1.56 g, 4.1 mmol) followed by the dropwise addition of DIPEA (0.72 ml, 4.1 mmol). NH3(g) was then bubbled into the solution for 15 mins. The reaction was o allowed to stir overnight. The resulting paste was filtered and rinsed with cold DMF and discarded. The mother liquor was concentrated and purified by normal phase chromatography using CH2Cl2/7 N NH3 in MeOH: 93/7 as eluent. Yielded a white solid (405 mg, 76 percent). IH NMR (400 MHz, CHLOROFORM-D) δ ppm 1.34 (s, 9 H), 1.36 (d, J=6.64 Hz, 3 H), 2.56 (s, 3 H), 4.32 - 4.40 (m, 1 H), 7.15 - 7.19 (m, J=8.20 Hz, 1 H), 7.68 (d, J=8.20 Hz, s I H)
73.8%
Stage #1: With triethylamine In dichloromethane at 20℃; Stage #2: With ammonia In tetrahydrofuran for 2 h;
I chloride (1.90 mL, 21.8 mmol) was added to 2-methyl nicotinic acid (1.50 g, 10.9 mmol) in anhydrous dichloromethane (20 mL) with triethylamine (1.6 mL, 11.5 mmol) and the reaction mixture was kept at room temperature overnight before the solvent was removed. THF was added to the residue and ammonia gas was bubbled through for 2 h. The THF was removed and the residue was dissolved into methanol and water and the pH was adjusted to 10.0 with potassium carbonate. The mixture was concentrated. After column chromatography the desired amide was isolated (1.10 g, 73.8percent). [0439] NaH (0.428 g, 10.7 mmol, 60percent in mineral oil) was added to 4-hydroxy-3,5-dimethylbenzonitrile (1.50 g, 10 mmol) in anhydrous DMF (8 mL). Benzyl bromide (1.83 g, 10.7 mmol) was added and the reaction was kept at room temperature overnight. The reaction mixture was poured into water. The isolated solid was further washed with hexane to yield the desired ether building block (2.0 g, 84.3percent). It was used in the next reaction without further purification. The above amide (0.65 g, 4.77 mmol) in anhydrous THF (15 mL) was added drop-wise to BuLi (7.5 mL, 1.60 M) at −20° C. The reaction mixture was kept at this temperature for 1 h and then the above ether building block (1.13 g, 4.77 mmol) in THF (20 mL) was added drop-wise at −20° C. and the reaction was stirred for 1.5 h. The reaction temperature was increased to room temperature and continued for a further 1 h. Water (20 mL) was added and the mixture was stirred for a while before the solvent was removed and the residue was purified by column chromatography to yield the desired intermediate (0.50 g, 29.4percent). A 50 mL flask was charged with the above described intermediate (0.50 g, 0.0014 mol) and pyridine hydrogen chloride (2.4 g, 0.014 mol) and the mixture was heated to 180° C. for 1.5 h. The mixture was cooled and poured into methanol (4 mL), then filtered. The collected solid was further washed with ethyl acetate and dried to give 7-(4-hydroxy-3,5-dimethylphenyl)-1,6-naphthyridin-5(6H)-one (350 mg, 82.7percent) as an HCl salt. Selected data: MS (ES) m/z: 266; MP >350° C.
Reference：
[1] Patent: WO2007/73303, 2007, A2, . Location in patent: Page/Page column 38
[2] Patent: EP1193265, 2002, A2, . Location in patent: Page 76-77
[3] Patent: US2013/281397, 2013, A1, . Location in patent: Paragraph 0438; 0439
[4] Journal of Medicinal Chemistry, 2000, vol. 43, # 16, p. 3168 - 3185
[5] European Journal of Medicinal Chemistry, 2012, vol. 55, p. 58 - 66,9
[6] Patent: US2014/94456, 2014, A1,
[7] Patent: WO2015/153683, 2015, A1,
5
[ 169229-06-5 ]
[ 58539-65-4 ]
Yield
Reaction Conditions
Operation in experiment
71%
With ammonia In dichloromethane at -30℃; for 18 h;
[0620] To the solution of XI-1 (10 g, 73 mmol, 1 eq) in 50 mL of DCM was added 15 mL of oxalyl chloride (adding a drop of DMF). The mixture was stirred for 18 hrs at rt. All the volatiles were removed under reduced pressure. The residue was dried and used directly for the next step (11.3 g, 100percent yield). The solid was dissolved in 30 mL of DCM and added into 200 mL of CH2Cl2—NH3 at −30° C. The mixture was stirred for 18 hrs. LCMS analysis showed the reaction completed. All the volatiles were removed under reduced pressure to afford XI-2 (7 g, 71percent yield), which was used directly for the next step. 1H NMR (DMSO-d6, 400 MHz): δ 8.45 (m, 1H), 7.93 (s, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.54 (s, 1H), 7.23 (m, 1H), 2.48 (s, 3H).
71%
With ammonia In dichloromethane at -30℃; for 18 h;
To the solution of X-1 (10 g, 73 mmol, 1 eq) in 50 mL of DCM was added 15 mL of oxalyl chloride (adding a drop of DMF). The mixture was stirred for 18 hrs at rt. All the volatiles were removed under reduced pressure. The residue was dried and used directly for the next step (11.3 g, 100percent yield). The solid was dissolved in 30 mL of DCM and added into 200 mL ofCH2C12-NH3 at -30°C. The mixture was stirred for 18 hrs. LCMS analysis showed the reaction completed. All the volatiles were removed under reduced pressure to afford X-2 (7 g, 71percent yield), which was used directly for the next step. ‘H NMR (DMSO-d6, 400 MHz): ö 8.45 (m, 1H), 7.93 (s, 1H), 7.71 (d, J= 7.6 Hz, 1H), 7.54 (s, 1H), 7.23 (m, 1H), 2.48 (s, 3H).
Reference：
[1] Journal of Medicinal Chemistry, 2000, vol. 43, # 16, p. 3168 - 3185
7
[ 3222-56-8 ]
[ 124-38-9 ]
[ 530-62-1 ]
[ 58539-65-4 ]
Reference：
[1] Patent: US5616601, 1997, A,
8
[ 65719-09-7 ]
[ 58539-65-4 ]
Reference：
[1] Canadian Journal of Chemistry, 1995, vol. 73, # 4, p. 531 - 538
[2] Journal of Heterocyclic Chemistry, 2006, vol. 43, # 5, p. 1311 - 1317
9
[ 110-86-1 ]
[ 1721-26-2 ]
[ 58539-65-4 ]
Reference：
[1] Nucleosides and Nucleotides, 1996, vol. 15, # 1-3, p. 149 - 167
10
[ 1721-26-2 ]
[ 58539-65-4 ]
Reference：
[1] Journal of Chemical Research, Miniprint, 1987, # 9, p. 2360 - 2384
[2] Journal of the Chemical Society, 1948, p. 198
11
[ 58539-65-4 ]
[ 4637-24-5 ]
[ 23616-31-1 ]
Yield
Reaction Conditions
Operation in experiment
32%
Stage #1: at 50℃; for 2 h; Stage #2: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 80℃; for 2.5 h;
[0621] A mixture of XI-2 (13 g, 95.6 mmol, 1 eq) and 18.2 mL of N,N-dimethylformamide dimethyl acetal was heated at 50° C. for 2 hrs. During the second hour, all the volatiles was removed. The residue was cooled to rt., diluted with 100 mL of anhydrous N,N-dimethylformamide, and then treated carefully with batch wise portions of sodium hydride (5 g, 124.3 mmol, 1.3 eq, 60percent oil dispersion; caution: vigorous evolution of hydrogen). The mixture was heated at 80° C. for 2.5 hrs, and then ice-cooled, treated cautiously with 25 mL of 2-propanol, and then maintained at 0-5° C. overnight. The solid were collected, and then dissolved in 10 mL of hot water. The solution was filtered, the filtrate was ice-cooled and then treated dropwise with concentrated hydrochloric acid to pH=7.0. After storage at 0-5° C. for 3 hrs, the precipitated solids were collected, washed with ice-cold water, and dried in vacuum to give XI-3 (3 g, 32percent yield). 1H NMR (DMSO-d6, 300 MHz): δ 8.90 (s, 1H), 8.49 (d, J=7.6 Hz, 1H), 7.51-7.43 (m, 2H), 6.61 (d, J=7.6 Hz, 1H).
32%
Stage #1: at 50℃; for 2 h; Stage #2: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 80℃; for 2.5 h;
A mixture of X-2 (13 g, 95.6 mmol, 1 eq) and 18.2 mL of N,Ndimethylformamide dimethyl acetal was heated at 50°C for 2 hrs. During the second hour, all the volatiles was removed. The residue was cooled to rt., diluted with 100 mL of anhydrous N,Ndimethylformamide, and then treated carefully with batch wise portions of sodium hydride (5 g, 124.3 mmol, 1.3 eq, 60percent oil dispersion; caution: vigorous evolution of hydrogen). The mixture was heated at 80°C for 2.5 hrs, and then ice-cooled, treated cautiously with 25 mL of 2-propanol, and then maintained at 0-5°C overnight. The solid were collected, and then dissolved in 10 mL of hot water. The solution was filtered, the filtrate was ice-cooled and then treated dropwise with concentrated hydrochloric acid to pH=-7.0. After storage at 0-5°C for 3 hrs, the precipitated solids were collected, washed with ice-cold water, and dried in vacuum to give X-3 (3 g, 32percent yield). ‘H NMR (DMSO-d6, 300 MHz): ö 8.90 (s, 1H), 8.49 (d, J=7.6 Hz, 1H), 7.51-7.43 (m, 2H), 6.61 (d, J =7.6 Hz, 1H).
Reference：
[1] Journal of Heterocyclic Chemistry, 2006, vol. 43, # 5, p. 1311 - 1317
[2] Patent: US2014/94456, 2014, A1, . Location in patent: Paragraph 0619; 0621
[3] Patent: WO2015/153683, 2015, A1, . Location in patent: Paragraph 0367
With isocyanuric acid; In N,N-dimethyl-formamide; at 0℃; for 2.5h;
30) 2-methyl-nicotinonitrileCyanuric acid (418 mg, 2.2 mmol) was added in one portion to a suspension of 2-methylnicotinamide (intermediate 29) (613 mg, 4.5 mmol) in 2.5 ml of DMF cooled in ice. The 0 reaction was stirred for 2.5 hours then poured into ice. The reaction was extracted with ethyl acetate until the organic layer no longer contained product. The combined organic layers, were dried over Na2SO4, filtered and concentrated. Purified on normal phase chromatography with ethyl acetate/heptane 0 to 50 gradient then 50/50 EA/heptane. Yield (216 mg, 41 %). IH NMR (400 MHz, CHLOROFORM-D) delta ppm 2.78 (s, 3 H), 7.25 (dd, s J=7.71, 4.98 Hz, 1 H), 7.89 (dd, J=7.81, 1.56 Hz5 1 H), 8.68 (s, 1 H)
[0621] A mixture of XI-2 (13 g, 95.6 mmol, 1 eq) and 18.2 mL of N,N-dimethylformamide dimethyl acetal was heated at 50° C. for 2 hrs. During the second hour, all the volatiles was removed. The residue was cooled to rt., diluted with 100 mL of anhydrous N,N-dimethylformamide, and then treated carefully with batch wise portions of sodium hydride (5 g, 124.3 mmol, 1.3 eq, 60percent oil dispersion; caution: vigorous evolution of hydrogen). The mixture was heated at 80° C. for 2.5 hrs, and then ice-cooled, treated cautiously with 25 mL of 2-propanol, and then maintained at 0-5° C. overnight. The solid were collected, and then dissolved in 10 mL of hot water. The solution was filtered, the filtrate was ice-cooled and then treated dropwise with concentrated hydrochloric acid to pH=7.0. After storage at 0-5° C. for 3 hrs, the precipitated solids were collected, washed with ice-cold water, and dried in vacuum to give XI-3 (3 g, 32percent yield). 1H NMR (DMSO-d6, 300 MHz): delta 8.90 (s, 1H), 8.49 (d, J=7.6 Hz, 1H), 7.51-7.43 (m, 2H), 6.61 (d, J=7.6 Hz, 1H).
32%
A mixture of X-2 (13 g, 95.6 mmol, 1 eq) and 18.2 mL of N,Ndimethylformamide dimethyl acetal was heated at 50°C for 2 hrs. During the second hour, all the volatiles was removed. The residue was cooled to rt., diluted with 100 mL of anhydrous N,Ndimethylformamide, and then treated carefully with batch wise portions of sodium hydride (5 g, 124.3 mmol, 1.3 eq, 60percent oil dispersion; caution: vigorous evolution of hydrogen). The mixture was heated at 80°C for 2.5 hrs, and then ice-cooled, treated cautiously with 25 mL of 2-propanol, and then maintained at 0-5°C overnight. The solid were collected, and then dissolved in 10 mL of hot water. The solution was filtered, the filtrate was ice-cooled and then treated dropwise with concentrated hydrochloric acid to pH=-7.0. After storage at 0-5°C for 3 hrs, the precipitated solids were collected, washed with ice-cold water, and dried in vacuum to give X-3 (3 g, 32percent yield). ?H NMR (DMSO-d6, 300 MHz): oe 8.90 (s, 1H), 8.49 (d, J=7.6 Hz, 1H), 7.51-7.43 (m, 2H), 6.61 (d, J =7.6 Hz, 1H).
With ammonia; In dichloromethane; at -30℃; for 18h;
[0620] To the solution of XI-1 (10 g, 73 mmol, 1 eq) in 50 mL of DCM was added 15 mL of oxalyl chloride (adding a drop of DMF). The mixture was stirred for 18 hrs at rt. All the volatiles were removed under reduced pressure. The residue was dried and used directly for the next step (11.3 g, 100% yield). The solid was dissolved in 30 mL of DCM and added into 200 mL of CH2Cl2-NH3 at -30 C. The mixture was stirred for 18 hrs. LCMS analysis showed the reaction completed. All the volatiles were removed under reduced pressure to afford XI-2 (7 g, 71% yield), which was used directly for the next step. 1H NMR (DMSO-d6, 400 MHz): delta 8.45 (m, 1H), 7.93 (s, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.54 (s, 1H), 7.23 (m, 1H), 2.48 (s, 3H).
71%
With ammonia; In dichloromethane; at -30℃; for 18h;
To the solution of X-1 (10 g, 73 mmol, 1 eq) in 50 mL of DCM was added 15 mL of oxalyl chloride (adding a drop of DMF). The mixture was stirred for 18 hrs at rt. All the volatiles were removed under reduced pressure. The residue was dried and used directly for the next step (11.3 g, 100% yield). The solid was dissolved in 30 mL of DCM and added into 200 mL ofCH2C12-NH3 at -30C. The mixture was stirred for 18 hrs. LCMS analysis showed the reaction completed. All the volatiles were removed under reduced pressure to afford X-2 (7 g, 71% yield), which was used directly for the next step. ?H NMR (DMSO-d6, 400 MHz): oe 8.45 (m, 1H), 7.93 (s, 1H), 7.71 (d, J= 7.6 Hz, 1H), 7.54 (s, 1H), 7.23 (m, 1H), 2.48 (s, 3H).
With ammonia; In tetrahydrofuran; for 2h;
Oxalyl chloride (1.90 ml_, 21.8 mmol) was added to 2-methyl nicotinic acid (1.50 g, 10.9 mmol) in anhydrous dichloromethane (20 ml_) with triethylamine (1.6 mL, 11.5 mmol) and the reaction mixture was kept at room temperature overnight and the solvent was removed. THF was added to the residue and ammonia gas was bubbled into for 2 hours. THF was removed and the residue was dissolved into methanol and water and adjusted pH to 10.0 by potassium carbonate and concentrated. After column chromatography the desired amide was isolated (1.10 g, 73.8%). NaH (0.428 g, 10.7 mmol, 60% in mineral oil) was added to 4~hydroxy-3,5-dimethylbenzonitrile (1.50 g, 10 mmol) in anhydrous DMF (8 mL) and then benzyl bromide (1.83 g, 10.7 mmol) was added and the reaction was kept at room temperature overnight. The reaction mixture was poured into water and filter the solid was further washed with hexane to yield the desired ether (2.0 g, 84.3%). It was used for next step reaction without further purification. The above amide (0.65 g, 4.77 mmol) in anhydrous THF (15 mL) was added dropwise to BuLi (7.5 mL, 1.60 M) at -200C. The reaction mixture was kept at this temperature for one hour and then the above described ether (1.13 g, 4.77 mmol) in THF (20 mL) was added drop-wise at -200C and the reaction was further kept for 1.5 hours. The reaction temperature was increased to room temperature EPO <DP n="95"/>and kept for another hour. Water (20 mL) was added and the mixture was stirred for a while and the solvent was removed and the residue was purified by column to yield the desired intermediate (0.50 g, 29.4%). In a 50 mL flask was charged with the above described intermediate (0.50 g, 0.0014 mol) and pyridine hydrogen chloride (2.4 g, 0.014 mol) and the mixture was heated to 18O0C for 1.5 hour. The mixture was cooled and poured into methanol (4 mL) then filtered. The collected solid was further washed with ethyl acetate and dried to give 7-(4-hydroxy-3,5- dimethylphenyl)-1 ,6-naphthyridin-5(6H)-one (350 mg, 82.7%) as the hydrochloride salt; MS (ES) m/r. 266 (M); MP >350C
Oxalyl chloride (1.90 mL, 21.8 mmol) was added to 2-methyl nicotinic acid (1.50 g, 10.9 mmol) in anhydrous dichloromethane (20 mL) with triethylamine (1.6 mL, 11.5 mmol) and the reaction mixture was kept at room temperature overnight before the solvent was removed. THF was added to the residue and ammonia gas was bubbled through for 2 h. The THF was removed and the residue was dissolved into methanol and water and the pH was adjusted to 10.0 with potassium carbonate. The mixture was concentrated. After column chromatography the desired amide was isolated (1.10 g, 73.8%).NaH (0.428 g, 10.7 mmol, 60% in mineral oil) was added to 4-hydroxy-3,5-dimethylbenzonitrile (1.50 g, 10 mmol) in anhydrous DMF (8 mL). Benzyl bromide (1.83 g, 10.7 mmol) was added and the reaction was kept at room temperature overnight. The reaction mixture was poured into water. The isolated solid was further washed with hexane to yield the desired ether building block (2.0 g, 84.3%). It was used in the next reaction without further purification. The above amide (0.65 g, 4.77 mmol) in anhydrous THF (15 mL) was added drop-wise to BuLi (7.5 mL, 1.60 M) at -20 C. The reaction mixture was kept at this temperature for 1 h and then the above ether building block (1.13 g, 4.77 mmol) in THF (20 mL) was added drop-wise at -20 C. and the reaction was stirred for 1.5 h. The reaction temperature was increased to room temperature and continued for a further 1 h. Water (20 mL) was added and the mixture was stirred for a while before the solvent was removed and the residue was purified by column chromatography to yield the desired intermediate (0.50 g, 29.4%). A 50 mL flask was charged with the above described intermediate (0.50 g, 0.0014 mol) and pyridine hydrogen chloride (2.4 g, 0.014 mol) and the mixture was heated to 180 C. for 1.5 h. The mixture was cooled and poured into methanol (4 mL), then filtered. The collected solid was further washed with ethyl acetate and dried to give 7-(4-hydroxy-3,5-dimethylphenyl)-1,6-naphthyridin-5(6H)-one (350 mg, 82.7%) as an HCl salt. Selected data: MS (ES) m/z: 266; MP>350 C.
With ammonia; N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0℃;
29) 2-methylnicotinamideTo a solution of 2-methylnicotinic acid (0.537 mg, 3.9 mmol) in 20 mL of DMF at 0 0C was added HATU (1.56 g, 4.1 mmol) followed by the dropwise addition of DIPEA (0.72 ml, 4.1 mmol). NH3(g) was then bubbled into the solution for 15 mins. The reaction was o allowed to stir overnight. The resulting paste was filtered and rinsed with cold DMF and discarded. The mother liquor was concentrated and purified by normal phase chromatography using CH2Cl2/7 N NH3 in MeOH: 93/7 as eluent. Yielded a white solid (405 mg, 76 %). IH NMR (400 MHz, CHLOROFORM-D) delta ppm 1.34 (s, 9 H), 1.36 (d, J=6.64 Hz, 3 H), 2.56 (s, 3 H), 4.32 - 4.40 (m, 1 H), 7.15 - 7.19 (m, J=8.20 Hz, 1 H), 7.68 (d, J=8.20 Hz, s I H)
73.8%
I chloride (1.90 mL, 21.8 mmol) was added to 2-methyl nicotinic acid (1.50 g, 10.9 mmol) in anhydrous dichloromethane (20 mL) with triethylamine (1.6 mL, 11.5 mmol) and the reaction mixture was kept at room temperature overnight before the solvent was removed. THF was added to the residue and ammonia gas was bubbled through for 2 h. The THF was removed and the residue was dissolved into methanol and water and the pH was adjusted to 10.0 with potassium carbonate. The mixture was concentrated. After column chromatography the desired amide was isolated (1.10 g, 73.8%). [0439] NaH (0.428 g, 10.7 mmol, 60% in mineral oil) was added to 4-hydroxy-3,5-dimethylbenzonitrile (1.50 g, 10 mmol) in anhydrous DMF (8 mL). Benzyl bromide (1.83 g, 10.7 mmol) was added and the reaction was kept at room temperature overnight. The reaction mixture was poured into water. The isolated solid was further washed with hexane to yield the desired ether building block (2.0 g, 84.3%). It was used in the next reaction without further purification. The above amide (0.65 g, 4.77 mmol) in anhydrous THF (15 mL) was added drop-wise to BuLi (7.5 mL, 1.60 M) at -20 C. The reaction mixture was kept at this temperature for 1 h and then the above ether building block (1.13 g, 4.77 mmol) in THF (20 mL) was added drop-wise at -20 C. and the reaction was stirred for 1.5 h. The reaction temperature was increased to room temperature and continued for a further 1 h. Water (20 mL) was added and the mixture was stirred for a while before the solvent was removed and the residue was purified by column chromatography to yield the desired intermediate (0.50 g, 29.4%). A 50 mL flask was charged with the above described intermediate (0.50 g, 0.0014 mol) and pyridine hydrogen chloride (2.4 g, 0.014 mol) and the mixture was heated to 180 C. for 1.5 h. The mixture was cooled and poured into methanol (4 mL), then filtered. The collected solid was further washed with ethyl acetate and dried to give 7-(4-hydroxy-3,5-dimethylphenyl)-1,6-naphthyridin-5(6H)-one (350 mg, 82.7%) as an HCl salt. Selected data: MS (ES) m/z: 266; MP >350 C.
With 4-methyl-morpholine; ammonium chloride; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 2.5h;Inert atmosphere;
To a solution of acid 2-methylpyridin-3-carboxylic (0.40 g, 2.90 mmol, 1 eq) in DMF dry (4.0 mL), ammonium chloride (0.93 g, 17.50 mmol, 6 eq), HOBt (0.57 g, 4.20 mmol, 1.44 eq), EDCI (0.81 g, 4.20 mmol, 1.44 eq) and N-methylmorpholine (0.46 mL, 4.20 mmol, 1.44 eq) were subsequently added. The reaction was stirred at room temperature, under nitrogen for 2.5 h. Evaporation of the solvent gave a residue which was purified by column chromatography (neutral alumine oxide, Brockmann grade III) using EtOAc as eluant to give 9 as white solid after crystallization with EtOAc (0.27 g, 69%). Mp. 163-166 C. 1H NMR (300 MHz, CD3OD) delta 8.45 (dd, J = 4.9/1.8 Hz, 1-H), 7.83 (dd, J = 7.6/1.5 Hz, 1-H), 7.30 (dd, J = 7.6/4.9 Hz, 1-H), 2.61 (s, 3-H); 13C NMR (75 MHz, CD3OD) delta 172.0, 155.4, 149.2, 135.7, 132.2, 121.2, 21.2; GC-MS m/z 136 (M)+; IR (KBr) 2768, 2389, 1926, 1692, 1448, 1365 cm-1. Anal. Calcd for C7H8N2O: C, 61.75; H, 5.92; N, 20.58. Found: C, 61.91; H, 6.20; N, 20.10.
P1-<1,2-O-isopropylidene-3(R)-(nicotinamid-2-ylmethyl)-α-D-ribofuranos-5-yl>-P2-(2',3'-isopropylideneadenosin-5'-yl)methylenediphosphonate triethylammonium salt[ No CAS ]
[(2R,3S,4R,5R)-3-(3-Carbamoyl-pyridin-2-ylmethyl)-3,4,5-trihydroxy-tetrahydro-furan-2-ylmethoxy]-hydroxy-phosphorylmethyl}-phosphonic acid mono-[(2R,3S,4R,5R)-5-(6-amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-ylmethyl] ester[ No CAS ]
[(2R,3S,4R,5S)-3-(3-Carbamoyl-pyridin-2-ylmethyl)-3,4,5-trihydroxy-tetrahydro-furan-2-ylmethoxy]-hydroxy-phosphorylmethyl}-phosphonic acid mono-[(2R,3S,4R,5R)-5-(6-amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-ylmethyl] ester[ No CAS ]
With trifluoroacetic anhydride; In dichloromethane; water; triethylamine;
Step 2 Preparation of 3-cyano-2-methylpyridine: To a suspension of 2-methylnicotinamide from step 1 (11.1 g, 0.081 mol) in triethylamine (24.8 g, 0.243 mol) and 400 mL of methylene chloride was added trifluoroacetic anhydride (21.0 g, 0.100 mol) rapidly at 0 C. The reaction was complete after a few minutes at this temperature. Water was added and the aqueous layer was extracted with methylene chloride. The combined organic layers were washed with water, brine and dried over magnesium sulfate. After filtration, the filtrate was concentrated and the residue was purified by chromatography on silica gel (ethyl acetate/hexane, 1:1) to give 7.2 g of 3-cyano-2methylpyridine as a pale yellow solid (75%): mp(DSC) 56-58 C.
Step 1 Preparation of 2-methylnicotinamide: To a stirred mixture of 2-methylnicotinic acid (15.0 g, 0.111 mol) and 1,1'-carbonyldiimidazole (36.0 g, 0.222 mol) was added 300 mL of methylene chloride dropwise. The reaction mixture was stirred at room temperature overnight. Ammonia gas was distilled into the reaction mixture for 30 minutes using a dry ice condenser and the mixture was stirred at room temperature for an additional hour. Solvent was removed under vacuum and the residue was dissolved with 500 mL of acetonitrile. The solution was concentrated to half volume at low temperature and the product precipitated out as white solid. The crude mixture was recrystallized from ethanol/ether to give 11.5 g of 2-methylnicotinamide as a colorless crystal (76%): mp 160-163 C. Anal. Calc'd. For C7 H8 N2 O: C, 61.75, H, 5.92, N, 20.57. Found: C, 61.44, H, 6.14, N, 20.66.
Oxalyl chloride (1.90 mL, 21.8 mmol) was added to <strong>[58539-65-4]2-methyl nicotinic acid</strong> (1.50 g, 10.9 mmol) in anhydrous dichloromethane (20 mL) with triethylamine (1.6 mL, 11.5 mmol) and the reaction mixture was kept at room temperature overnight before the solvent was removed. THF was added to the residue and ammonia gas was bubbled through for 2 h. The THF was removed and the residue was dissolved into methanol and water and the pH was adjusted to 10.0 with potassium carbonate. The mixture was concentrated. After column chromatography the desired amide was isolated (1.10 g, 73.8%).NaH (0.428 g, 10.7 mmol, 60% in mineral oil) was added to 4-hydroxy-3,5-dimethylbenzonitrile (1.50 g, 10 mmol) in anhydrous DMF (8 mL). Benzyl bromide (1.83 g, 10.7 mmol) was added and the reaction was kept at room temperature overnight. The reaction mixture was poured into water. The isolated solid was further washed with hexane to yield the desired ether building block (2.0 g, 84.3%). It was used in the next reaction without further purification. The above amide (0.65 g, 4.77 mmol) in anhydrous THF (15 mL) was added drop-wise to BuLi (7.5 mL, 1.60 M) at -20 C. The reaction mixture was kept at this temperature for 1 h and then the above ether building block (1.13 g, 4.77 mmol) in THF (20 mL) was added drop-wise at -20 C. and the reaction was stirred for 1.5 h. The reaction temperature was increased to room temperature and continued for a further 1 h. Water (20 mL) was added and the mixture was stirred for a while before the solvent was removed and the residue was purified by column chromatography to yield the desired intermediate (0.50 g, 29.4%). A 50 mL flask was charged with the above described intermediate (0.50 g, 0.0014 mol) and pyridine hydrogen chloride (2.4 g, 0.014 mol) and the mixture was heated to 180 C. for 1.5 h. The mixture was cooled and poured into methanol (4 mL), then filtered. The collected solid was further washed with ethyl acetate and dried to give 7-(4-hydroxy-3,5-dimethylphenyl)-1,6-naphthyridin-5(6H)-one (350 mg, 82.7%) as an HCl salt. Selected data: MS (ES) m/z: 266; MP>350 C.
7-(4-hydroxy-3,5-dimethylphenyl)-1,6-naphthyridin-5(6H)-one hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
350 mg
Example 5 7-(4-hydroxy-3,5-dimethylphenyl)-1,6-naphthyridin-5(6H)-one I chloride (1.90 mL, 21.8 mmol) was added to <strong>[58539-65-4]2-methyl nicotinic acid</strong> (1.50 g, 10.9 mmol) in anhydrous dichloromethane (20 mL) with triethylamine (1.6 mL, 11.5 mmol) and the reaction mixture was kept at room temperature overnight before the solvent was removed. THF was added to the residue and ammonia gas was bubbled through for 2 h. The THF was removed and the residue was dissolved into methanol and water and the pH was adjusted to 10.0 with potassium carbonate. The mixture was concentrated. After column chromatography the desired amide was isolated (1.10 g, 73.8%). NaH (0.428 g, 10.7 mmol, 60% in mineral oil) was added to 4-hydroxy-3,5-dimethylbenzonitrile (1.50 g, 10 mmol) in anhydrous DMF (8 mL). Benzyl bromide (1.83 g, 10.7 mmol) was added and the reaction was kept at room temperature overnight. The reaction mixture was poured into water. The isolated solid was further washed with hexane to yield the desired ether building block (2.0 g, 84.3%). It was used in the next reaction without further purification. The above amide (0.65 g, 4.77 mmol) in anhydrous THF (15 mL) was added drop-wise to BuLi (7.5 mL, 1.60 M) at -20 C. The reaction mixture was kept at this temperature for 1 h and then the above ether building block (1.13 g, 4.77 mmol) in THF (20 mL) was added drop-wise at -20 C. and the reaction was stirred for 1.5 h. The reaction temperature was increased to room temperature and continued for a further 1 h. Water (20 mL) was added and the mixture was stirred for a while before the solvent was removed and the residue was purified by column chromatography to yield the desired intermediate (0.50 g, 29.4%). A 50 mL flask was charged with the above described intermediate (0.50 g, 0.0014 mol) and pyridine hydrogen chloride (2.4 g, 0.014 mol) and the mixture was heated to 180 C. for 1.5 h. The mixture was cooled and poured into methanol (4 mL), then filtered. The collected solid was further washed with ethyl acetate and dried to give 7-(4-hydroxy-3,5-dimethylphenyl)-1,6-naphthyridin-5(6H)-one (350 mg, 82.7%) as an HCl salt. Selected data: MS (ES) m/z: 266; MP >350 C.
2-methyl-N-[1-(dimethylamino)methylidene]pyridine-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
In methanol; at 120℃; for 1.5h;
To N,N-dimethylformamide dimethyl acetal (a compound represented by formula (1da)-101, 12.5 mL), 2-methyl-3-pyridine carboxamide a compound represented by formula (1d)-101, 4.69g, 34.5mmol) was added, while the methanol accumulates in an eggplant-shaped flask of distillation apparatus and stirred for 1.5 hours at 120 C. The resulting solution was then cooled, filtered, as colorless crystals 2-methyl-N-[1-(dimethylamino)methylidene]pyridine-3-carboxamide obtaining (compound represented by following formula (1c)-101) (yield 2.87 g, 92% yield).
The 2 - methyl nicotinic acid amide (200 mg, 1 . 47 mmol) dissolved in anhydrous tetrahydrofuran (5 ml) in, 0 C under argon conditions, dropping borane tetrahydrofuran solution (1 M, 7.4 ml, 7.4 mmol), the reaction 30 minutes, up to 60 C reaction 8 hours. Saturated ammonium chloride aqueous solution quenching, ethyl acetate extraction, anhydrous sodium sulfate drying, filtering of evaporation to dryness to obtain colourless oil of 200 mg, crude product is directly used for the next step reaction
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