* 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] Journal of Medicinal Chemistry, 1999, vol. 42, # 16, p. 3023 - 3025
3
[ 98400-69-2 ]
[ 7397-68-4 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 2003, vol. 40, # 4, p. 585 - 591
4
[ 504-24-5 ]
[ 24424-99-5 ]
[ 98400-69-2 ]
Yield
Reaction Conditions
Operation in experiment
99%
With dmap; triethylamine In tetrahydrofuran at 20℃; for 0.333333 h; Inert atmosphere
4-Aminopyridine (600 mg, 6.36 mmol), DMAP (600 μg, 5.00 μmol), Boc2O (1.57 mL, 7.00mmol) and Et3N (1 mL, 7.63 mmol) were suspended in anhydrous THF (3 mL) at rt, and stirredfor 20 min under argon atmosphere. After completion of the reaction, the reaction mixture was diluted with CH2Cl2 (5 mL) and washed with 0.1 N HCl (5 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated by rotary evaporation. Purification by column chromatography (30:1 CH2Cl2/MeOH) yielded S1w (1.30 g, >99percent) asa white solid.
95%
With guanidine hydrochloride In ethanol at 35 - 40℃; for 0.25 h;
General procedure: Amine (1 mmol) was added to a magnetically stirred solution of guanidine hydrochloride (15 molpercent) and di-tert-butyl dicarbonate (1.2 mmol) in EtOH (1 mL), at 35-40°C and stirred for appropriate time (Table 1). After completion of the reaction (followed by TLC or GC), EtOH was evaporated under vacuum and the residue either was washed with water to remove the catalyst or was dissolved in CH2Cl2 (or EtOAc) and filtered off to separate out the catalyst. Evaporation of the organic solvent (if used in work up) gives almost a pure product. In the cases of using an excess (Boc)2O the product was washed with petroleum ether or hexane to recover the residual (Boc)2O. If necessary, the product was further purified either by crystallization (hexane and dichloromethane, or diethyl ether and petroleum ether) or silica gel column chromatography using EtOAc-hexane (1: 6) as eluent.
94%
at 20 - 25℃; for 3.6 h;
Preparation of isatin derivatives To a well stirred solution of Boc anhydride (2.56 g, 11.7 mmol) in THF (10 mL) was added 4- aminopyridine (1.0 g, 10.6 mmol) in portions over 3 minutes while maintaining the temperature between 20°C and 25°C. No more exotherm was observed after 5 minutes. The reaction was then stirred at room temperature for 3.5 hours. After in vacuo concentration the crude mixture was then titurated in hexane (20 mL), filtered and washed with more hexane (~5 mL). The resulting solid dried under reduced pressure to yield 1.93 g (9.9 mmol, 94percent) of pyridin-4-yl-carbamic acid tert-butyl ester as a white solid and was used without further purification. LCMS (BDS-Hypersil C18,50 mm X 2.1 mm, 5 μ, 2.5 minutes) m/z 195 [MH]+ retension time 0.90 minutes, 100percent by UV at 215 nm.
94%
at 100℃; for 0.0833333 h; Microwave irradiation; Green chemistry
General procedure: Amine (1 mmol) and di-tert-butyl dicarbonate [(Boc)2O] (1.1 mmol) were placed in a microwave reaction vial. The LG microwave oven MG 555f was programmed to 300 W at 100 °C. The reaction was monitored using TLC. After the reaction, ice water was added to the reaction mixture which resulted in the precipitation of the product. The solid product was merely filtered off and washed with excess cold water. The product was pure enough for all practical purposes. For characterization purpose, it was further purified by column chromatography (Neutral Alumina as adsorbent, solvent system: Hexane: Ethyl acetate (7.5:2.5)).#10;
90%
With triethylamine In dichloromethane at 0 - 20℃; for 3 h;
To a stirred solution of pyridin-4-amine (A; 100 g, 1.06 mol) in CH2CI2 (1 L) under inert atmosphere were added triethylamine (161.47 g, 1.59 mol) and Boc-anhydride (255 g, 1.17 mol) at 0 °C. The reaction was warmed to RT and stirred for 3 h. After complete consumption of the starting material, the reaction mixture was diluted with water (400 mL) and the compound was extracted with CH2CI2 (2x500 mL). The combined organic extracts were washed with water (300 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude. The crude was purified through column chromatography eluting with 5percent MeOH/CH2Cl2 to afford BL (190 g, 90percent) as a white solid. *H NMR (500 MHz, DMSO- ): δ 9.80 (s, 1H), 8.33 (d, J = 5.5 Hz, 2H), 7.41 (d, J = 6.5 Hz, 2H), 1.48 (s, 9H).
88%
With triethylamine In dichloromethane
To a solution of 4-aminopyridine (50.0 g, 531 mmol) in triethylamine/CH2Cl2 (1:1, 200 mL) at 0°C was slowly added a solution of di-t-butyl-dicarbonate (116 g, 531 mmol) in CH2Cl2 (150 mL). The resulting mixture was allowed to warm to it overnight then was concentrated. The crude product was taken up in hot EtOAc, filtered and precipitated with hexanes. The precipitate was collected by filtration, washed with hexanes and dried under vacuum to give 91.0 g (88percent yield) of pure t-butyl carbamate.
84%
at 20℃; for 1 h;
4-Aminopyridine (25 g, 265 mmol) was added slowly by a solid addition funnel to a stirred solution of di-t-butyl-di-carbonate (63.75 g, 292 mmol) in THF at room temperature. The solution was further stirred for 1 h at room temperature. The solvent was removed under reduced pressure and the residue was recrystalised by ether to yield 43.5 g (84 percent) of pyridine-4-yl-carbamic acid-tert-butyl ester (117) as white solid. MP: 260 °C ; 1H-NMR (DMSO-d6): d 1. 48 (s, 9H), 7.40 (dd, J = 1.2, 4.8 Hz, 1H), 8.33 (dd, J = 1. 2,4. 8 Hz, 1H), 9.93 (s, 1H) ; EIMS m/z 195 (M+1).
83%
With triethylamine In DMF (N,N-dimethyl-formamide)
To a stirring solution of 4-aminopyridine (15 g, 159 mmol) and triethylamine (24 mL, 175 mmol) in DMF (300mL) was addeddi-t-butyl dicarbonate (38 g, 175 mmol). After stirring overnight, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (500 mL); and the solution was washed with satd aq sodium bicarbonate, water and then brine. The organic phase was then dried withMgSO4, filtered and concentrated in vacuo to a volume of about 100 mL. The mixture was then sonicated and the precipitate was filtered and dried in vacuo to give 9.52 g (31percent) of the title compound. To the mother liquor was added about 50 g of silica gel and the mixture was concentrated in vacuo. The resulting dry pack was loaded onto a silica gel column prepared with a solution of 50percent ethyl acetate in hexanes and eluted with20percent ethyl acetate in dichloromethane, followed by a step gradient of50percent ethyl acetate in hexanes through ethyl acetate. The product containing fractions were combined and concentrated in vacuo to give another 16.16 g (52percent) of the title compound. 1NMR IS-MS, m/e 195.3(m+1)
83%
at 20℃; for 0.5 h;
A solution of di-tert-butyl dicarbonate (3.274g, 15 mmol) in CH2C12 (8 mL) was added to a solution of 4-aminopyridine (1.412g, 15 mmol) in CH2C12 (15 mL), and was stirred at room temperature for 30 minutes. Acidified with 1M HC1. Washed with CH2C12. Neutralized aqueous layer with K2C03. PARTITIONED between CH2C12 and water. The organic layer was washed with brine, dried (MGSO4), filtered, and concentrated under vacuum to provide 2. 41G (83percent) of PYRIDIN-4-YL-CARBAMIC acid tert-butyl ester.
70%
With triethylamine In dichloromethane at 0 - 20℃; for 16 - 18 h;
Di-tert-butyl dicarbonate (79.30 g, 0.36 mol) in dichloromethane (250 ml) was added dropwise over 45 min to a stirred suspension of 4-aminopyridine (27.05 g, 0.29 mol) and triethylamine (88 ml, 0.63 mol) in dichloromethane (250 ml) at 0 °C. The solution was stirred at room temperature for 18 h and then washed with water (2 x 250 ml). The organic layer was then dried and concentrated in vacuo to leave a residue which was slurried in ethyl acetate, filtered and dried in vacuo to give pyridin-4-yl-carbamic acid tert-butyl ester (39.62 g, 71 percent) as an off-white solid. No.H (400 MHz, CDC13) 8.44 (2H, dd J 6.4, 1. 6 Hz), 7.31 (2H, dd J 6.4, 1.6 Hz), 6.84 (1H, br s), 1.53 (9H, s) ; Tr = 0.90 min, m/z (ES+) (M+H)+ 195.18.
52%
With triethylamine In dichloromethane; ethyl acetate; N,N-dimethyl-formamide
A. 4-(Boc-amino)pyridine. To a stirring solution of 4-aminopyridine (15 g, 159 mmol) and triethylamine (24 mL, 175 mmol) in DMF (300 mL) was added di-t-butyl dicarbonate (38 g, 175 mmol). After stirring overnight, the solvent was removed in vacuo, the residue was dissolved in ethyl acetate (500 mL), and the solution was washed with satd aq sodium bicarbonate, water and then brine. The organic phase was then dried with MgSO4, filtered and concentrated in vacuo to a volume of about 100 mL. The mixture was then sonicated and the precipitate was filtered and dried in vacuo to give 9.52 g (31percent) of the title compound. To the mother liquor was added about 50 g of silica gel and the mixture was concentrated in vacuo. The resulting dry pack was loaded onto a silica gel column prepared with a solution of 50percent ethyl acetate in hexanes and eluted with 20percent ethyl acetate in dichloromethane, followed by a step gradient of 50percent ethyl acetate in hexanes through ethyl acetate. The product containing fractions were combined and concentrated in vacuo to give another 16.16 g (52percent) of the title compound. 1H-NMR IS-MS, m/e 195.3 (m+1)
Reference：
[1] Tetrahedron Letters, 2006, vol. 47, # 7, p. 1087 - 1091
[2] Organic and Biomolecular Chemistry, 2006, vol. 4, # 14, p. 2769 - 2771
[3] Chemistry Letters, 2010, vol. 39, # 11, p. 1127 - 1129
[4] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 9, p. 2114 - 2124
[5] Tetrahedron Letters, 2007, vol. 48, # 47, p. 8318 - 8322
[6] Journal of Organic Chemistry, 2011, vol. 76, # 17, p. 7132 - 7140
[7] Tetrahedron, 2001, vol. 57, # 43, p. 9033 - 9043
[8] Tetrahedron Letters, 1998, vol. 39, # 48, p. 8919 - 8922
[9] Synthesis, 2006, # 16, p. 2784 - 2788
[10] Tetrahedron Letters, 2011, vol. 52, # 12, p. 1260 - 1264
[11] Monatshefte fur Chemie, 2011, vol. 142, # 10, p. 1035 - 1043
[12] Patent: WO2005/97107, 2005, A2, . Location in patent: Page/Page column 36
[13] Tetrahedron Letters, 2012, vol. 53, # 43, p. 5803 - 5806
[14] Organic Letters, 2006, vol. 8, # 15, p. 3259 - 3262
[15] Patent: WO2014/117090, 2014, A1, . Location in patent: Page/Page column 123-124
[16] European Journal of Medicinal Chemistry, 2005, vol. 40, # 9, p. 908 - 917
[17] Patent: WO2007/61554, 2007, A2, . Location in patent: Page/Page column 12
[18] Journal of Organic Chemistry, 2004, vol. 69, # 20, p. 6772 - 6780
[19] Patent: WO2005/21546, 2005, A1, . Location in patent: Page/Page column 124; 207-208
[20] Patent: WO2005/49604, 2005, A2, . Location in patent: Page/Page column 105-106
[21] Patent: WO2004/76424, 2004, A1, . Location in patent: Page 266
[22] Patent: WO2005/113552, 2005, A1, . Location in patent: Page/Page column 20
[23] Journal of Medicinal Chemistry, 1988, vol. 31, # 11, p. 2136 - 2145
[24] Patent: WO2005/121141, 2005, A1, . Location in patent: Page/Page column 13; 20
[25] Journal of Medicinal Chemistry, 2003, vol. 46, # 8, p. 1293 - 1305
[26] Chemical Communications, 2014, vol. 50, # 39, p. 5068 - 5071
[27] Tetrahedron Letters, 1994, vol. 35, # 48, p. 9003 - 9006
[28] Journal of Organic Chemistry, 1999, vol. 64, # 26, p. 9430 - 9443
[29] Patent: EP1577301, 2005, A1, . Location in patent: Page/Page column 70
[30] Patent: EP1270557, 2003, A1,
[31] Patent: EP1140905, 2003, B1,
[32] Patent: US2005/20645, 2005, A1,
[33] Patent: US2008/194547, 2008, A1, . Location in patent: Page/Page column 14
[34] Patent: EP1405852, 2004, A1, . Location in patent: Page 63
[35] Patent: EP1577302, 2005, A1, . Location in patent: Page/Page column 67
[36] Synthetic Communications, 2011, vol. 41, # 5, p. 715 - 719
[37] Patent: US2015/274720, 2015, A1, . Location in patent: Paragraph 0325
[38] Tetrahedron Letters, 2016, vol. 57, # 48, p. 5304 - 5307
[39] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 17, p. 4886 - 4897
5
[ 504-24-5 ]
[ 24424-99-5 ]
[ 75-65-0 ]
[ 98400-69-2 ]
Yield
Reaction Conditions
Operation in experiment
99%
With potassium hydroxide In water
EXAMPLE 10 4-Anilinopyrido[4,3-d]pyrimidine 4-(N-t-Butoxycarbonylamino)pyridine. To a mixture of 4-aminopyridine (2 g, 21.24 mmol), potassium hydroxide (3.57 g, 63.72 mmol), water (10 mL), and 2-methyl-2-propanol (4 mL) on ice is added di-t-butyl-dicarbonate (6.95 g, 31.87 mmol). The resulting biphasic solution is stirred at 25° C. for 1 week, then water (20 mL) is added. The solution is extracted with 1X CH2 Cl2 and 2X EtOAc. The organic layer is dried (MgSO4) and concentrated under reduced pressure to give 4-(N-t-butoxycarbonylamino)pyridine (4.08 g, 99percent). 1 H NMR (DMSO) δ 9.84 (1H, s), 8.35 (2H, d, J=6 Hz), 7.44 (2H, d, J=7 Hz), 1.49 (9H, s).
Reference：
[1] Patent: US5654307, 1997, A,
6
[ 504-24-5 ]
[ 1538-75-6 ]
[ 98400-69-2 ]
Reference：
[1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 2012, vol. 51, # 8, p. 1168 - 1172,5
7
[ 504-24-5 ]
[ 89985-91-1 ]
[ 98400-69-2 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1985, vol. 58, # 12, p. 3570 - 3575
Stage #1: With n-butyllithium; N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran; hexanes at -78 - -10℃; for 2.25 h; Stage #2: With iodine In tetrahydrofuran; hexanes at -78℃; for 2.5 h;
n-Butyllithium (1.6 M in hexanes; 220 ml, 0.35 mol) was slowly dropwise over 30 min to a stirred solution of pyridin-4-yl-carbamic acid tert-butyl ester (26.08 g, 0.13 mol) and N,N,N,N-tetramethylethylenediamine (55 ml, 0.36 mol) in tetrahydrofuran (750 ml) at -78 °C. The solution was stirred at-78 °C for 15 min and 2 h at-10 °C. The mixture was cooled to -78 °C and a solution of iodine (95.11 g, 0.37 mol) in tetrahydrofuran (250 ml) was added dropwise over 30 min. The mixture was stirred for a further 2 h and then the mixture was quenched with water (250 ml) at 0 °C. A saturated solution of sodium sulfite (100 ml) was added and the organic layer separated. The aqueous layer was extracted with dichloromethane (2 x 500 ml) and then the combined organic extracts were dried and concentrated in vacuo to give a brown oil. Purification by flash column chromatography on silica gel eluting with 20 percent ethyl acetate : heptane gave (3-iodo-pyridin-4-yl)-carbamic acid tert-butyl ester (25.00 g, 58 percent) as an off-white solid, No.H (400 MHz, CDC13) 8.76 (1H, s), 8.35 (1H, d J 5.7 Hz), 8.11 (1H, d J 5.7 Hz), 7.04 (lH, br s), 1.55 (9H, s) ; Tr = 0.99 min, m/z (ES+) (M+H)+ 321.08.
Reference：
[1] Patent: WO2005/121141, 2005, A1, . Location in patent: Page/Page column 13; 20
[2] Journal of Organic Chemistry, 2004, vol. 69, # 20, p. 6772 - 6780
14
[ 110-18-9 ]
[ 98400-69-2 ]
[ 211029-67-3 ]
Reference：
[1] Patent: US6541505, 2003, B1,
15
[ 98400-69-2 ]
[ 197507-59-8 ]
Reference：
[1] Journal of Medicinal Chemistry, 1999, vol. 42, # 16, p. 3023 - 3025
16
[ 124-38-9 ]
[ 98400-69-2 ]
[ 171178-34-0 ]
Yield
Reaction Conditions
Operation in experiment
35%
Stage #1: With n-butyllithium In tetrahydrofuran at -78 - 0℃; for 0.5 h; Inert atmosphere Stage #2: at -78 - 20℃; for 2 h;
To a stirred solution of BL (12 g, 0.06 mol) in dry THF (200 mL) under inert atmosphere was added n-butyl lithium (79.12 mL, 0.18 mol) at -78 °C. The reaction was warmed to 0 °C and stirred for 30 min. Carbon dioxide gas was added to the reaction mass at -78 °C for 1 h, then at RT for 1 h. The reaction was monitored by TLC. After complete consumption of the starting material, the reaction mass was diluted with water (200 mL) and washed with diethyl ether (2x150 mL). The aqueous layer was acidified with citric acid to pH~4. The obtained solid was filtered and dried under vacuum to afford BM (5.1 g, 35percent) as a white solid. *H NMR (400 MHz, DMSO-i: δ 11.76 (br s, 1H), 8.96 (s, 1H), 8.52 (d, / = 15.0 Hz, 1H), 8.22 (d, / = 15.0 Hz, 1H), 1.49 (s, 9H).
30%
Stage #1: With n-butyllithium; N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran at -40 - 20℃; for 0.333333 h; Stage #2: at -78 - 20℃; for 3.25 h;
-Buli (1.6 M soln, 155 mL, 249 mmol) was added to a stirred solution of TMEDA (37.36 mL, 249 mmol) in THF AT-40 °C. The solution was allowed to come at room temperature over 10 min and stirred for another 10 min. The solution was cooled TO-78 °C. A solution OF PYRIDINE-4-YL-CARBAMIC acid-tert-butyl ester (117) (22 g, 113.26 mmol) in THF was added slowly. The solution was allowed to come at room temperature within 3 h. After stirring at room temperature for 15 min the solution was again cooled to -78 OC and a freshly crushed dry ice was added. The solution was allowed to come at room temperature, stirred for 30 min and poured into ice cold 10 percent NH4C1 solution. The solution was basified by IN NaOH solution and washed by dichloromethane. The pH of aqueous phase was adjusted to 4 by cold 10 percent HC1 solution. The solids formed were filtered, washed by water and dried under vacuum at room temperature to yield 16.3 g (30 percent) 4-tert-butoxycarbonylamino-nicotinic acid (118) as white solids. MP: 260 °C ; 1H- NMR (DMSO-d6): d 1.49 (s, 9H), 8.23 (d, J= 6.0 Hz, 1H), 8.55 (D, J= 6.0 Hz, 1H), 8. 96 (s, 1H); EIMS M/Z 238 (M+1).
Reference：
[1] Journal of Medicinal Chemistry, 1999, vol. 42, # 16, p. 3023 - 3025
[2] Patent: WO2014/117090, 2014, A1, . Location in patent: Page/Page column 123-124
[3] Patent: WO2005/21546, 2005, A1, . Location in patent: Page/Page column 124; 207-208
17
[ 109-72-8 ]
[ 98400-69-2 ]
[ 171178-34-0 ]
Reference：
[1] Patent: US5654307, 1997, A,
18
[ 594-19-4 ]
[ 98400-69-2 ]
[ 171178-34-0 ]
Yield
Reaction Conditions
Operation in experiment
64%
With carbon dioxide In tetrahydrofuran; pentane
B. 4-(Boc-amino)pyridine-3-carboxylic Acid. To a stirring solution of 4-(Boc-amino)pyridine (1.027 g, 5.30 mmol) in THF at -36 °C (internal temperature) was added a 1.7 M solution of t-butyl lithium in pentane(6.5 mL, 11 mmol), and the rate of addition was controlled so as to keep the internal temperature below -28 °C. After an additional hour (temperature kept between -30 °C and -50 °C) carbon dioxide (g) was bubbled through the solution and the cold bath was removed. After about 15 min, the mixture was poured into ice water and the aqueous phase was washed with dichloromethane. The pH was adjusted to 4-5 with citric acid and the resulting precipitate was washed with dichloromethane and methanol and dried in vacuo to give 0.811 g (64percent) of an off-white solid. 1H-NMR IS-MS, m/e 239.0 (m+1)
Reference：
[1] Patent: EP1140905, 2003, B1,
19
[ 98400-69-2 ]
[ 257937-08-9 ]
Yield
Reaction Conditions
Operation in experiment
52%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; Stage #2: With carbon tetrabromide In tetrahydrofuran
With tert.-butyl lithium In tetrahydrofuran -78 deg C to -15 deg C, 3 h, -78 deg C to RT, 2 h;
75%
Stage #1: N-(4-pyridyl) t-butyl carbamate With tert.-butyl lithium In tetrahydrofuran; pentane at -78 - -15℃; for 3.5h;
Stage #2: oxirane In tetrahydrofuran; pentane at -78 - 20℃; for 2h;
To a stirred solution of BL (12 g, 0.06 mol) in dry THF (200 mL) under inert atmosphere was added n-butyl lithium (79.12 mL, 0.18 mol) at -78 C. The reaction was warmed to 0 C and stirred for 30 min. Carbon dioxide gas was added to the reaction mass at -78 C for 1 h, then at RT for 1 h. The reaction was monitored by TLC. After complete consumption of the starting material, the reaction mass was diluted with water (200 mL) and washed with diethyl ether (2x150 mL). The aqueous layer was acidified with citric acid to pH~4. The obtained solid was filtered and dried under vacuum to afford BM (5.1 g, 35%) as a white solid. *H NMR (400 MHz, DMSO-i: delta 11.76 (br s, 1H), 8.96 (s, 1H), 8.52 (d, / = 15.0 Hz, 1H), 8.22 (d, / = 15.0 Hz, 1H), 1.49 (s, 9H).
30%
-Buli (1.6 M soln, 155 mL, 249 mmol) was added to a stirred solution of TMEDA (37.36 mL, 249 mmol) in THF AT-40 C. The solution was allowed to come at room temperature over 10 min and stirred for another 10 min. The solution was cooled TO-78 C. A solution OF PYRIDINE-4-YL-CARBAMIC acid-tert-butyl ester (117) (22 g, 113.26 mmol) in THF was added slowly. The solution was allowed to come at room temperature within 3 h. After stirring at room temperature for 15 min the solution was again cooled to -78 OC and a freshly crushed dry ice was added. The solution was allowed to come at room temperature, stirred for 30 min and poured into ice cold 10 % NH4C1 solution. The solution was basified by IN NaOH solution and washed by dichloromethane. The pH of aqueous phase was adjusted to 4 by cold 10 % HC1 solution. The solids formed were filtered, washed by water and dried under vacuum at room temperature to yield 16.3 g (30 %) 4-tert-butoxycarbonylamino-nicotinic acid (118) as white solids. MP: 260 C ; 1H- NMR (DMSO-d6): d 1.49 (s, 9H), 8.23 (d, J= 6.0 Hz, 1H), 8.55 (D, J= 6.0 Hz, 1H), 8. 96 (s, 1H); EIMS M/Z 238 (M+1).
Stage #1: N-(4-pyridyl) t-butyl carbamate With tert.-butyl lithium In tetrahydrofuran; pentane at -78 - -15℃; for 3.5h;
Stage #2: 2-bromoethanol With n-butyllithium In tetrahydrofuran; hexane; pentane at -78 - 20℃; for 2h;
36%
Stage #1: N-(4-pyridyl) t-butyl carbamate With tert.-butyl lithium In tetrahydrofuran; pentane at -78 - -15℃; for 2.4h;
Stage #2: 2-bromoethanol With n-butyllithium In tetrahydrofuran; hexane; pentane at 20℃; for 2h;
9 EXAMPLE 9, METHODS
[00199] Synthesis of tert-butyl N~[3~(2-hydroxyethy])pyridm~4~y]j carbamate (11): Adapted from Spivey et at To a solution of 4-(Boc-amino)pyridme (1) (2.0 g, 10.3 mmol, 1 eq.) in 25 mL of dry THF at -78 °C was added /-Bu f .i (14.5 mL, 1.7 M, 24.7 mmol, 2.4 eq.) in pentane over 30 min. The resulting bright yellow suspension was stirred at -78 °C for 15 mi , at -15 °C for 2h and the recooled to -78 °C, I a separate flask, n-BuLi (7.38 mL, 2.5M. 18.54 mmol, 1 .8 eq) in hexanes was added to a solution of 2-bromocfhanol (1.294 mL, 15.45 mmol, 1.5 eq) in 20 mL of dry THF at -78 °C and stirred for 10 min. After 10 min, the bromoethanol solution was transferred "via cannula to the flask containing lithiated N-boc-4- aminopyridine over 10 min. The reaction was allowed to warm to room temperature and the mixture was stirred for 2h. The reaction was recooled to -78 °C and quenched with 5 ml, of water. The solution was partitioned between water (20 mL) and CH2CI2 (30 mL). The phases were separated and the extraction was completed with additional portions of CH2C12. The combined organic extracts were washed with brine, dried over MgS04 and evaporated under vacuum. The crude product was dissolved in a small amount of€{ purified by silica gel chromatography (EtOAc) to afford the product 11 (0.678 g, 36% yield). Rf = 0.15 (EtOAc). -Ν ΙΙ (500 MHz, CDCI3) δ: 1.51 (9H, s), 2.81 (2H, t, J ------ 5.0 Hz), 3.80 (1 H, br s), 3.94 (2H, t, J= 5.0 Hz), 7.92 (1H, d, J= 5.5 Hz), 8.15 (1H, s), 8.27 flH, d, J= 5.5 Hz), 8.63 (1H, s).
19%
Stage #1: N-(4-pyridyl) t-butyl carbamate With tert.-butyl lithium In tetrahydrofuran at -78 - -15℃; for 1.75h;
Stage #2: 2-bromoethanol With n-butyllithium In tetrahydrofuran at -78 - 20℃; for 2.16667h;
466.466A Example 466; 3-[3-(2-hydroxyethyl)pyridin-4-yl]amino}-8-(1-hydroxy-1-methylethyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one; Example 466A; 2-(4-aminopyridin-3-yl)ethanol
Solution A was prepared by combining PYRIDIN-4-YL-CARBAMIC acid tert-butyl ester (388mg, 2MMOL) in THF (5 mL) and cooling TO-78 C. t-BuLi (2.8 mL, 1.7M solution in pentane) was added dropwise. Once the addition was complete, the solution was stirred at-78oC for 15 minutes, then warmed to-15oC and stirred for 90 minutes. In a separate flask, solution B was prepared by combining bromoethanol (0. 21ML, 3 mmol) in THF (5 mL) and cooling to- 78 C. n-BuLi (1.44 ML, 2.5M solution in hexanes) was added dropwise. Once the addition was complete, the solution was stirred at-78oC for 10 minutes. Solution A was recooled TO-78 C, and solution B was added to solution A via cannula. Stirred with warming to room temperature for 2 hours. The reaction was recooled, and quenched with water. Partitioned between CH2C12 and water. The organic layer was washed with brine, dried (MGS04), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 100% ethyl acetate to provide 91mg (19%) of [3- (2-HYDROXY-ETHYL)-PYRIDIN-4-YL]-CARBAMIC acid tert-butyl ester.
The compound obtained in Referential Example 1 (61.6 g) was dissolved in tetrahydrofuran (2000 mL), and the solution was stirred at -78C for 10 minutes. n-Butyllithium (as 1.59N hexane solution, 500 mL) was added dropwise to the reaction mixture, followed by stirring for 10 minutes. The mixture was further stirred for 2 hours under ice cooling. The reaction mixture was cooled to -78C, and after sulfur powder (12.2 g) was added thereto, the mixture was heated to room temperature, followed by stirring for 1 hour. Water (1000 mL) was added to the reaction mixture to partition the mixture. 3N HCl was added to the aqueous phase, to thereby adjust pH to 3 to 4. Methylene chloride was added for partitioning the mixture. The organic layer was dried over sodium sulfate anhydrate, and the solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride : methanol = 50:1), to thereby give the title compound (33.2 g).1H-NMR(DMSO-d6) delta:1.52(9H, s), 7.89(1H, d, J=6.4Hz), 7.99(1H, d, J=6.4Hz), 8.20(1H, s), 9.91(1H, br.s). MS(FAB)m/z:227(M+H)+.
[Referential Example 2] tert-Butyl 3-sulfanylpyridin-4-ylcarbamate: The compound (61.6 g) obtained in Referential Example 1 was dissolved in tetrahydrofuran (2,000 ml), and the solution was stirred at -78C for 10 minutes.. A hexane solution (1.59 mol/l, 500 ml) of n-butyllithium was added dropwise to the solution, and the mixture was stirred for 10 minutes and then for 2 hours with ice cooling.. After the reaction mixture was cooled to -78C, sulfur powder (12.2 g) was added, and the resultant mixture was warmed to room temperature and stirred for 1 hour.. water (1,000 ml) was added to the reaction mixture to separate a water layer.. After 3N hydrochloric acid was added to the water layer to adjust the PH of the water layer to 3 to 4, methylene chloride was added to separate an organic layer.. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.. The residue was purified by column chromatography on silica gel (methylene chloride:methanol = 50:1) to obtain the title compound (33.2 g).1H-NMR (DMSO-d6) delta: 1.52(9H,s), 7.89(1H,d,J=6.4Hz), 7.99(1H,d,J=6.4Hz), 8.20(1H,s), 9.91(1H,br.s). MS (FAB) m/z: 227(M+H)+.
The compound (61.6 g) obtained in Referential Example 24 was dissolved in tetrahydrofuran (2000 ml) and the mixture was stirred for 10 minutes at -78C. n-Butyl lithium (a 1.59N hexane solution, 500 ml) was added dropwise to the reaction mixture. After stirring for 10 minutes, stirring was performed for 2 hours under ice cooling. The reaction mixture was cooled to -78C and then, a sulfur powder (12.2 g) was added thereto. The resulting mixture was heated to room temperature and stirred for 1 hour. Water (1000 ml) was added to the reaction mixture to separate the layers. The aqueous layer was adjusted to pH 3 to pH4 by the addition of 3N hydrochloric acid. Methylene chloride was added to the mixture to separate the layers. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by chromatography (methylene chloride: methanol = 50:1) on a silica gel column, whereby the title compound (33.2 g) was obtained.1H-NMR(DMSO-d6) delta: 1.52(9H,s), 7.89(1H,d,J=6.4Hz), 7.99(1H,d,J=6.4Hz), 8.20(1H,s), 9.91(1H,br.s). MS(FAB)m/z: 227(M+H)+
n-Butyllithium (1.6 M in hexanes; 220 ml, 0.35 mol) was slowly dropwise over 30 min to a stirred solution of pyridin-4-yl-carbamic acid tert-butyl ester (26.08 g, 0.13 mol) and N,N,N,N-tetramethylethylenediamine (55 ml, 0.36 mol) in tetrahydrofuran (750 ml) at -78 C. The solution was stirred at-78 C for 15 min and 2 h at-10 C. The mixture was cooled to -78 C and a solution of iodine (95.11 g, 0.37 mol) in tetrahydrofuran (250 ml) was added dropwise over 30 min. The mixture was stirred for a further 2 h and then the mixture was quenched with water (250 ml) at 0 C. A saturated solution of sodium sulfite (100 ml) was added and the organic layer separated. The aqueous layer was extracted with dichloromethane (2 x 500 ml) and then the combined organic extracts were dried and concentrated in vacuo to give a brown oil. Purification by flash column chromatography on silica gel eluting with 20 % ethyl acetate : heptane gave (3-iodo-pyridin-4-yl)-carbamic acid tert-butyl ester (25.00 g, 58 %) as an off-white solid, No.H (400 MHz, CDC13) 8.76 (1H, s), 8.35 (1H, d J 5.7 Hz), 8.11 (1H, d J 5.7 Hz), 7.04 (lH, br s), 1.55 (9H, s) ; Tr = 0.99 min, m/z (ES+) (M+H)+ 321.08.
Stage #1: N-(4-pyridyl) t-butyl carbamate With n-butyllithium; N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran; hexane at -78 - 5℃; for 2.41667h;
Stage #2: With Triisopropyl borate In tetrahydrofuran; hexane at -78℃; for 0.166667h;
1.A
A 500 rnL two-necked round bottom flask equipped with nitrogen inlet adaptor and magnetic stirring bar was charged with tert-butyi pyridin-4-ylcarbamate (3.88 g, 20.0 mmol, prepared as described in Spivey, A. C. et al. J. Org. Chem. 64, pp. 9430-9443 (1999)), λWλ^-tetramethylethylenediamine (TMEDA) (8.15 mL, 54.0 mmol), and anhydrous tetrahydrofuran (THF) (10 mL). The resultant clear, colorless solution was degassed with several cycles of evacuation under reduced pressure followed by a nitrogen purge, then cooled to -78 0C with a dry ice/acetone bath. A solution of n-butyllithium in hexanes (20.0 mL of a 2.5 M solution, 50.0 mmol) was added via syringe under nitrogen atmosphere over 15 minutes (min), resulting in the formation of a thick tan slurry. After 10 min, the cooling bath was replaced with a 5 0C ice bath, and the slurry was allowed to stir for 2 hours. The slurry was then cooled again to -78 0C, and triisopropylborate (17.5 mL, 76.0 mmol) was added dropwise via syringe over 10 min. The reaction mixture was then warmed to ambient temperature and allowed to stir for 20 min. The reaction mixture initially became clear, and then a white precipitate formed. The resultant slurry was then poured into saturated aqueous ammonium choride (100 mL) and allowed to stir vigorously for an additional 20 min. The white precipitate was isolated by filtration, washed sequentially with water (100 mL) and diethyl ether (100 mL), and then dried overnight under reduced pressure, providing 3.10 g of 4-[(tert-butoxycarbonyl)amino]pyridin-3- ylboronic acid as a white solid.
4-[N-(tert-butoxycarbonyl)amino]-1-[2-(3-methoxy-4-nitrophenyl)-2-oxoethyl]pyridinium bromide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
In acetone; acetonitrile at 20℃; for 1h;
47.A
2.90 g (10.6 mmol) of 2-bromo-1-(3-methoxy-4-nitrophenyl)-1-ethanone [described in Bull. Soc. Chim. Fr., (1962), pp 2255-2261] are added in portions to 2.07 g (10.6 mmol) of 4-[N-(tert-butoxycarbonyl)amino]pyridine [described in Tetrahedron; (2001), vol 57(43), pp 9033-9044] in suspension in 10 mL of acetonitrile and 20 mL of acetone. The reaction medium becomes homogeneous by stirring at room temperature and then precipitation occurs. The medium is stirred for 1 hour at room temperature. The precipitate formed is filtered, washed with acetone and dried. 4.6 g of a white powder are obtained. Yield: 93% Melting point: 224° C.
4-(N-t-Butoxycarbonylamino)nicotinic acid. n-Butyl lithium (2.18M, 24 mL, 52.51 mmol) is added slowly to a solution of 4-(N-t-butoxycarbonylamino)pyridine (4.08 g, 21 mmol) in THF (50 mL, stirred under N2 at -78 C. The solution is allowed to warm to 0 C., stirred for 3 h, then cooled again to -78 C. and poured into ether (100 mL) containing dry ice. The solution is warmed to room temperature with constant stirring. Water is added and the mixture is neutralized with acetic acid. The resulting solid is collected by vacuum filtration and dried in a vacuum oven to give 4-(N-t-butoxycarbonylamino)nicotinic acid (2.72 g, 54%) as a brown solid. 1 H NMR (DMSO) delta 11.75 (1H, brs), 8.95 (1H, s), 8.50 (1H, d, J=6.0 Hz), 8.20 (1H, d, J=6.0 Hz), 1.49 (9H, s).
With hydrogenchloride; n-butyllithium; In tetrahydrofuran; hexane; dichloromethane; water;
[Referential Example 2] 4-[(tert-Butoxycarbonyl)amino]-3-mercaptopyridine: 4-[(tert-Butoxycarbonyl)amino]pyridine (61.6 g) was dissolved in tetrahydrofuran (2,000 ml), and the solution was stirred at -78C for 10 minutes. A hexane solution (1.59 mol/l 500 ml) of n-butyllithium was added dropwise to the solution, and the mixture was stirred for 10 minutes and then for 2 hours with icecooling. After the reaction mixture was cooled to -78C, sulfur powder (12.2 g) was added, and the resultant mixture was warmed to room temperature and stirred for 1 hour. Water (1,000 ml) was added to the reaction mixture to separate a water layer. After 3N hydrochloric acid was added to the water layer to adjust the pH of the water layer to 3 to 4, dichloromethane was added to separate an organic layer. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol = 50:1) to obtain the title compound (33.2 g) as a pale yellow foamy substance. 1H-NMR (DMSO-d6) delta: 1.52(9H,s), 7.89(1H,d,J=6.4Hz), 7.99(1H,d,J=6.4Hz), 8.20(1H,s), 9.91(1H,br.s). MS (FAB) m/z: 227(M+H)+.
With hydrogenchloride; n-butyllithium; In tetrahydrofuran; hexane; dichloromethane; water;
REFERENTIAL EXAMPLE 2 tert-Butyl 3-sulfanylpyridin-4-ylcarbamate: The compound (61.6 g) obtained in Referential Example 1 was dissolved in tetrahydrofuran (2,000 ml), and the solution was stirred at -78 C. for 10 minutes. A hexane solution (1.59 mol/l, 500 ml) of n-butyllithium was added dropwise to the solution, and the mixture was stirred for 10 minutes and then for 2 hours with ice cooling. After the reaction mixture was cooled to -78 C., sulfur powder (12.2 g) was added, and the resultant mixture was warmed to room temperature and stirred for 1 hour. Water (1,000 ml) was added to the reaction mixture to separate a water layer. After 3N hydrochloric acid was added to the water layer to adjust the pH of the water layer to 3 to 4, methylene chloride was added to separate an organic layer. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride:methanol=50:1) to obtain the title compound (33.2 g). 1H-NMR (DMSO-d6) delta: 1.52(9H,s), 7.89(1H,d,J=6.4 Hz), 7.99(1H,d,J=6.4 Hz), 8.20(1H,s), 9.91(1H,br.s). MS (FAB) m/z: 227(M+H)+.
B. 4-(Boc-amino)pyridine-3-carboxylic Acid. To a stirring solution of 4-(Boc-amino)pyridine (1.027 g, 5.30 mmol) in THF at -36 C (internal temperature) was added a 1.7 M solution of t-butyl lithium in pentane(6.5 mL, 11 mmol), and the rate of addition was controlled so as to keep the internal temperature below -28 C. After an additional hour (temperature kept between -30 C and -50 C) carbon dioxide (g) was bubbled through the solution and the cold bath was removed. After about 15 min, the mixture was poured into ice water and the aqueous phase was washed with dichloromethane. The pH was adjusted to 4-5 with citric acid and the resulting precipitate was washed with dichloromethane and methanol and dried in vacuo to give 0.811 g (64%) of an off-white solid. 1H-NMR IS-MS, m/e 239.0 (m+1)
Stage #1: N-(4-pyridyl) t-butyl carbamate With n-butyllithium; N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran; hexane at -78 - -4℃; for 2.5h; Inert atmosphere;
Stage #2: Trimethyl borate In tetrahydrofuran; hexane at -78 - 0℃; for 0.25h;
Stage #3: With water; ammonium chloride In tetrahydrofuran; hexane for 0.0333333h;
A
Preparation of 4-Aminopyridin-3-ylboronic acid hydrochloride saltPart AUnder a nitrogen atmosphere, a solution of n-butyllithium in hexane (100 mL of 2.5 M, 250 mmol) was added over 20 minutes to a stirred solution of tert-butyl pyridin-4-ylcarbamate (19.4 g, 100 mmol) and N,N,N',N'-tetramethylethylenediamine (TMEDA) (31.4 g, 270 mmol) in tetrahydrofuran (THF) (500 mL) at -78° C. tert-Butyl pyridin-4-ylcarbamate is available from a literature procedure (Spivey, A. C. et al. J. Org. Chem. 1999, 64, 9430-9443). A white solid appeared and the mixture was stirred for 10 minutes at -78° C., was transferred to a salt bath, and allowed to warm slowly to -4° C. over about two hours before cooling to -78° C. again. Trimethyl borate (39.5 g, 380 mmol) was added over 15 minutes. The solution was warmed to 0° C. and poured into saturated aqueous ammonium chloride (500 mL). The mixture was stirred for 2 minutes. After standing at room temperature overnight, the mixture was partitioned between diethyl ether and brine. The organic layer was separated and washed with brine and then diluted to a volume of 3 liters with the addition of diethyl ether. A white solid formed in the organic layer and was isolated by filtration. The solid was washed sequentially with diethyl ether, water, and diethyl ether, then was dried to provide 17.1 g of 4-[(tert-butoxycarbonyl)amino]pyridin-3-ylboronic acid as a white solid.
2-ethyl-5-((tert-butyloxycarbonyl)amino)-pyrazolo[1,5-a]pyridin-3-carboxylate ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
34.2%
Stage #1: N-(4-pyridyl) t-butyl carbamate With O-(2,4-dinitrophenyl)hydroxylamine In acetonitrile at 40℃; for 18h;
Stage #2: ethyl pent-2-ynoate With potassium carbonate In N,N-dimethyl-formamide at 20℃;
1.5 Step 5: 2-ethyl-5-((tert-butyloxycarbonyl)amino)-pyrazolo[1,5-a]pyridine-3-carboxylate ethyl ester (B1)
4-(tert-butoxycarbonylamino)pyridine (1.2g, 6.2mmol) and O-(2,4-dinitrophenyl)hydroxylamine (DNPH, 1.23g, 6.2mmol) were dissolved in 28mL of acetonitrile and was heated to 40°C. After reacting for 18h, solvent was spin-dried. To the reaction system was added anhydrous DMF (15mL), 2-pentynoic acid ethyl ester (0.78g, 6.2mmol), and anhydrous K2CO3 (1.71g, 12.4mmol). It was stirred overnight at room temperature. TLC was used to determine reaction completion. Large amount of water was added then extracted three times with ethyl acetate. The organic phase was collected and washed with brine three times. Purification by column chromatography gave the product B1, 0.71g (34.2%).
Stage #1: N-(4-pyridyl) t-butyl carbamate With O-(2,4-dinitrophenyl)hydroxylamine In acetonitrile at 40℃; for 18h;
Stage #2: ethyl pent-2-ynoate With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 18h;
With n-butyllithium; N,N,N,N,-tetramethylethylenediamine; iodine; In tetrahydrofuran;
Reference Example 49 (3-iodo-pyridin-4-yl)-carbamic acid tert-butyl ester. To a solution of pyridin-4-yl-carbamic acid tert-butyl ester (14.8 g, 76.3 mmol) (reference example 44b) in THF (300 mL) is added N,N,N',N'-tetramethylethylene-diamine (34.5 mL, 230 mmol) and the solution cooled to -78 C. To this solution is added slowly (2.5M) n-butyllithium (91.5 mL, 230 mmol), the reaction temperature allowed to rise to -20 C. and the resulting mixture stirred for 1.5 hours. The mixture is cooled to -78 C. and a solution of iodine (29.04 g, 114 mmol) in THF (60 mL) is added then stirred for 10 min. The mixture is warmed to 20 C., stirred 30 min then diluted with ethyl acetate, washed with water, sat. sodium thiosulfate and brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluding with 20% ethyl acetate in hexanes) to give 17.7 g of title compound as a light yellow crystalline solid. 1H NMR (CDCl3) delta 1.54 (s, 9H), 7.03 (bs, 1H), 8.10 (d, J=6 Hz, 1H), 8.34 (d, J=6 Hz, 1H), 8.74 (s, 1H). MS (EI) m/z 320 (M+).
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