* 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.
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;
91%
at 20℃; for 3.5 h; Inert atmosphere
To 2-aminopyridine (100 mg, 1.06 mmol) was added a solution of Boc2O (270 μL, 1.17 mmol)in t-BuOH (8.5 mL) under argon atmosphere. After stirring at rt for 3.5 h, the mixture was concentrated by rotary evaporation to afford the crude product as a light yellow solid.Purification by column chromatography (5:1 → 3:1 → 1:1 hexanes/EtOAc) yielded S1u (187mg, 91percent) as a white solid.
74%
at 20℃; for 16 h;
General procedure: Boc2O (1.0 mmol) was added to a mixture of phenol or amine (1.0 mmol) andMgBr2 · OEt2 (0.1 mmol) in a round-bottom flask, at which point an evolution of gas occurs, and the reaction mixture was stirred magnetically at room temperature (ifnecessary, reactions was heated to∼60 °C). After complete consumption of the phenolor amine (by thin-layer chromatography, TLC; 3–16 h), the reaction mixture wasdiluted with water and extracted with EtOAc (3 × 20mL), and the combined EtOAcextracts were dried with Na2SO4 and concentrated under vacuum rotary evaporation.The residue was isolated by column chromatography through a bed of silicagel and eluted with 5–30percent ethyl acetate in hexane to afford the desired Bocprotectedproduct.
60%
for 12 h; Heating / reflux
Reference Example 80 tert-Butyl 2-pyridylcarbamate 2-Aminopyridine (6.0 g, 63.7 mmol) and di-tert-butyl dicarbonate (14.4 g, 65. 9 mol) were dissolved in tetrahydrofuran (150 ml), and the mixture was refluxed for 12 hrs.. After cooling, the precipitates were filtered, and the filtrate was concentrated.. The residue was subjected to a silica gel column chromatography.. The fractions eluted with hexane-ethyl acetate (15:1, v/v) were collected and concentrated to give the titled compound (7.5 g, 60 percent).1H-NMR (CDCl3) δ: 1.54 (9H, s), 6.94 (1H, m), 7.65 (1H, m), 7.96 (1H, d, J = 8.4 Hz), 8.29 (1H, d, J = 4.6 Hz), 8.70 (1H, br s).
51%
at 20℃; for 24 h;
Step 1 : fert-Butyl pyridin-2-ylcarbamate (9a)To a solution of (Boc)20 (218 g, 1.0 mol) in tert-butyl alcohol (1.5 L) was added 2-aminopyridine (94 g, 1.0 mol) slowly and the mixture was stirred at rt for 24 h, then concentrated under reduced pressure and purified by CC (PE/EA = 1/1) to give compound 9a (100 g, 51percent) as a white solid.
31.5%
at 20℃;
To the single-mouth bottle was added t-butanol (100 ml) and di-tert-butyl dicarbonate (51 g, 233.8 mmol).2-Aminopyridine (20 g, 212.5 mmol) was slowly added at room temperature and allowed to react at room temperature overnight.The reaction was monitored by spotting, and ethyl acetate (250 ml) was added, and water (100 ml) was extracted.The organic layer was washed with brine, dried over anhydrous magnesium sulfateResidue column chromatography (eluent is ethyl acetate: petroleum ether = 1:5 (v/v))Purified to 13g white solid,The yield was 31.5percent.
Reference：
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Reference：
[1] Journal of Organic Chemistry, 2017, vol. 82, # 18, p. 9410 - 9417
10
[ 109-04-6 ]
[ 38427-94-0 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1994, vol. 131, # 4, p. 429 - 433
11
[ 38427-94-0 ]
[ 6188-43-8 ]
Reference：
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[2] Chemical Communications, 2011, vol. 47, # 17, p. 5043 - 5045
[3] Chemical Communications, 2011, vol. 47, # 17, p. 5043 - 5045
[4] European Journal of Organic Chemistry, 2013, # 1, p. 35 - 39
[5] European Journal of Organic Chemistry, 2013, # 1, p. 35 - 39
[6] European Journal of Organic Chemistry, 2013, # 1, p. 35 - 39
[7] European Journal of Organic Chemistry, 2013, # 1, p. 35 - 39
12
[ 38427-94-0 ]
[ 68-12-2 ]
[ 116026-94-9 ]
Yield
Reaction Conditions
Operation in experiment
52%
Stage #1: With tert.-butyl lithium In diethyl ether at -78 - 0℃; for 1 h; Inert atmosphere Stage #2: at 0℃; for 0.166667 h;
Step 2: tert-Butyl 3-formylpyridin-2-ylcarbamate (9b)To a solution of compound 9a (14.0 g, 72 mmol) in Et20 (500 mL) was added tert-BuLi (1.7M, 106 mL, 180 mmol) at -78°C under N2 atmosphere and the resulting mixture was warmed to 0°C and stirred for 1 h. Anhydrous DMF (8.0 mL, 103 mmol) was added with rapid stirring. The mixture was stirred at 0°C for 10 min, then quenched with half -saturated aq. NH4CI solution. The aqueous layer was extracted with EA twice, the combined organic layers were dried over Na2S04 and concentrated under reduced pressure. The residue was purified by CC (PE/EA = 3/1) to give compound 9b (8.0 g, 52percent) as a white solid.
A solution of Boc-protected 2-pyridinamine (1.0 g, 5.15 mmol, 1.0 equiv.) in 15 mL DMF was cooled to 0 C inan ice bath. Sodium hydride (60% suspension in oil, 258.0 mg, 6.49 mmol, 1.25 equiv.) was added so that thesuspension did not warm above 5C. The suspension was stirred vigorously for an additional 20 min before allylbromide (644.0 mg, 5.32 mmol, 1.03 equiv.) was added dropwise. After stirring for 30 minutes, the reactionmixture was allowed to warm to r.t. over 1 h until TLC indicated full conversion. Afterwards, 25 mL water and150 mL diethyl ether were added, the organic layer separated and extracted with water, saturated aqueoussodium hydrogen carbonate solution, and brine. The organic phase was dried over sodium sulfate andconcentrated under reduced pressure to give 1.29 g crude material which were used without furtherpurification.
Triethylamine (82 mul, 0.59 mmol) and mesyl chloride (36 mul, 0.47 mmol) were i o added to a solution of methyl N-(2,6-dichlorobenzoyl)-4-(3 -hydroxyprop- 1 -yn- 1 -y I)-L- phenylalaninate (160 mg, 0.39 mmol) in DCM (ImI), under an argon atmosphere and at O0C. After 2 hours, the mixture was extracted with methylene chloride, evaporated and dried on MgSO4. The residue was dissolved in DMA and added to a solution of tert-butyl pyridin-2-ylcarbamate anion prepared by treating, under argon atmosphere at 0C, tert-15 butyl pyridin-2-ylcarbamate (153 mg, 0.79 mmol) in solution in DMA (2 ml) with NaH 60% in oil (30 mg, 0.74 mmol). The reaction mixture was stirred at room temperature for 3 hours, extracted with ethyl acetate and purified by silica gel flash chromatography eluting with 0 to 50 % ethyl acetate in petroleum ether to give methyl 4-{3-[(ter/- butoxycarbonyl)(pyridin-2-yl)amino]prop- 1 -yn- 1 -yl} -N-(2,6-dichlorobenzoyl)-L-20 phenylalaninate as an oil (112 mg, 49%); 1H NMR Spectrum: (DMSO-d6) 1.50 (9H, s), 2.93 (IH, dd), 3.14 (IH, dd), 3.65 (3H, s), 3.74 (IH, ddd), 4.88 (2H, s), 7.18 (IH, dd), 7.22-7.30 (4H, m), 7.39 (IH, dd), 7.42-7.46 (2H, m), 7.67 (IH, d), 7.80 (IH, ddd), 8.43 (IH, ddd), 9.18 (IH, d); Mass Spectrum [M+H]+ = 582.
Triethylamine ( 258 mul, 1.85 mmol) and mesyl chloride (115 mul, 1.48 mmol) were added to a solution of methyl _/V-(2,6-dichlorobenzoyl)-4-(5-hydroxypent-l-yn-l-yl)-L- phenylalaninate (500 mg, 1.23 mmol) in methylene chloride (5ml) under argon atmosphere at 0C. After 2 hours, the mixture was extracted with DCM, evaporated and dried on MgSO4. The residue was re-dissolved in DMA and added to a solution of tert-butyl 0 pyridin-2-ylcarbamate anion prepared by treating under argon atmosphere at 0C tert-butyl pyridin-2-ylcarbamate (477 mg, 2.46 mmol) in solution in DMA (7 ml) with NaH 60% (98 mg, 2.46 mmol). The reaction mixture was stirred at 40C for 11 hours, extracted with ethyl acetate and purified by silica gel flash chromatography eluting with 0 to 50 % ethyl acetate in petroleum ether to give methyl 4-{5-[(tert-butoxycarbonyl)(pyridin-2- 5 yl)amino]pent-l-yn-l-yl}-lambdaf-(2,6-dichlorobenzoyl)-L-phenylalaninate as an oil (208 mg, 28%); 1H NMR Spectrum: (DMSO-d) 1.45 (9H, s), 1.77-1.87 (2H, m), 2.43 (2H, t), 2.94 (IH, dd), 3.13 (IH, dd), 3.65 (3H, s), 3.98 (2H, d), 4.74 (IH, ddd), 7.14 (IH, dd), 7.22-7.29 (4H, m), 7.40 (IH, dd), 7.42-7.47 (2H, m), 7.58 (IH, d), 7.76 (IH, ddd), 8.38 (IH, ddd), 9.20 (IH, d); Mass Spectrum: [M+H]+ = 610.
With sodium hydride; In N,N-dimethyl-formamide; at -10 - 20℃; for 2.08333h;
NaH (1.64 g, 40.9 mmol) and methyl 0-(3-bromopropyl)-iV-(tert-butoxycarbonyl)-L-tyrosinate (17 g, 40.9 mmol) were added dropwise over 5 minutes to a solution oftert- butyl pyridin-2-ylcarbamate (7.93 g, 40.9 mmol) in DMF (400 ml) at -10C. The reaction mixture was allowed to warm to room temperature and stir for 2 hours. The reaction <n="198"/>mixture was extracted with diethyl ether (1 1) and washed with saturated citric acid (100 ml) and water (3 x 100 ml), concentrated and the residue was purified by flash chromatography eluting with 20% diethyl ether in petroleum ether to afford methyl N-{tert- butoxycarbony I)-O- {3-[(teA"t-butoxycarbonyl)(pyridin-2-yl)amino]propyl}-L-tyrosinate as a white foam (18.8 g, 87%); 1H NMR Spectrum: (DMSO-d6) 1.32 (9H, s), 1.42 (9H, s), 1.94-2.01 (2H, m), 2.76 (IH, dd), 2.89 (IH, dd), 3.60 (3H, s), 3.94 (2H, t), 4.00 (2H, t), 4.09 (IH, ddd), 6.74-6.83 (2H, m), 7.08-7.15 (3H, m), 7.23 (IH, d), 7.56 (IH, d), 7.74 (IH, ddd), 8.35 (IH, dd); Mass Spectrum [M+H]+ = 530.
5(S)-5-[N-(t-butoxycarbonyl)-N-(pyridin-2-yl)]aminomethyl-3-[4-(1-cyanocyclopropan-1-yl)phenyl]oxazolidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
The title compound 5(S)-5-[N-(t-Butoxycarbonyl)-N-(pyridin-2-yl)]aminomethyl-3-[4-(1-cyanocyclopropan-1-yl)phenyl]oxazolidin-2-one (307 mg) was prepared from 5(R)-3-[4-(1-cyanocyclopropan-1-yl)phenyl]-5-hydroxymethyloxazolidin-2-one (258 mg) and 2-(t-butoxycarbonyl)aminopyridine (389 mg) in the same manner as described for EXAMPLE 15. [0604] MS (EI+) m/z: 434 (M+). [0605] HRMS (EI+) for C24H26N404 (M+): calcd, 434.1954; found, 434.1973.
With 3-chloro-benzenecarboperoxoic acid; In ethyl acetate; at 20℃; for 20h;
Reference Example 81 tert-Butyl 2-pyridylcarbamate N-oxide tert-Butyl 2-pyridylcarbamate (7.4 g, 38 mmol) and 3-chloroperbenzoic acid (77 %, 11.2 g, 50 mmol) were dissolved in ethyl acetate (100 ml), and the mixture was stirred at room temperature for 20 hrs.. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography.. The fractions eluted with methanol-ethyl acetate (1:20, v/v) were collected and concentrated to give the titled compound (7.6 g, 95 %).1H-NMR (CDCl3) delta: 1.54 (9H, s), 6.91 (1H, m), 7.29 (1H, m), 8.15 (1H, dd, J = 1.6, 8.5 Hz), 8.20 (1H, m), 9.30 (1H, br s).
b) 1-[N-(tert-Butoxycarbonyl)-N-(pyridin-2-yl)amino]-4(4nitrophenyl)butane To a suspension of NaH (170 mg, 4.25 mmoles) in dry DMF (10 mL) was added 2-(tert-butoxycarbonylamino)pyridine (750 mg, 3.86 mmoles) at 0 C. After 5 min the mixture was warmed to RT. After 15 min the mixture was cooled to 0 C. and 1-bromo-4-(4-nitrophenyl)butane (1.22 g, 4.73 mmoles) in dry DMF (5 mL) was added. The mixture was allowed to warm to RT as the bath warmed. After 18 hr the mixture was concentrated. The residue was taken up in H2O (50 mL) and extracted with EtOAc (3*50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was chromatographed on silica gel (15% EtOAc/hexanes) to give the title compound (1.25 g, 87%) as a pale yellow oil: MS (ES) m/e 372 (M+H)+.
(3-Formyl-pyridin-2-yl)-carbamic Acid tert-Butyl Ester (5-2) tert-Butyllithium (1.7 M, 14.5 mL, 24.6 mmol, 2.39 equiv) was added to a solution of pyridin-2-yl-carbamic acid tert-butyl ester (5-1, 2.00 g, 10.3 mmol, 1 equiv) in ethyl ether (100 mL) at -78 C., and the resulting mixture was warmed to 0 C. and stirred for 1 h. N,N-Dimethylformamide (8.00 mL, 103 mmol, 10.0 equiv) was added with rapid stirring. The mixture was stirred at 0 C. for 10 min, then partitioned between half-saturated aqueous ammonium chloride solution (100 mL). The aqueous layer was further extracted with ethyl acetate (100 mL), and the combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (40% ethyl acetate in hexanes) to afford (3-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (5-2) as a white solid. 1H NMR (300 MHz, CDCl3) delta 10.18 (br s, 1H), 9.91 (s, 1H), 8.64 (dd, 1H, J=4.9, 2.9 Hz), 7.98 (dd, 1H, J=7.6, 2.0 Hz), 7.12 (dd, 1H, J=7.6, 4.9 Hz), 1.55 (s, 9H); TLC (40% EtOAc/hexanes), Rf=0.41.
A 2-t-Butoxycarbonylamino-3-ethylpyridine 2-t-Butoxycarbonylaminopyridine (10 g, 51.5 mmol) was dissolved in tetrahydrofuran (80 mL), and cooled to -78 C. N-butyllithium (80 mL of 1.49M in hexanes, 120 mmol) was added dropwise over a period of 1 h. After stirring for an additional 15 min at -78 C. and then for 2.5 hours at -10 C., the solution was then recooled back down to -78 C. and iodoethane (77.2 mmol, 6.18 mL) was added dropwise over a period of 15 min via syringe. The solution was allowed to warm to room temperature. The reaction was quenched with 100 mL of a saturated ammonium chloride and extracted with ethyl acetate (3*). The organic layers were collected, dried over magnesium sulfate, and concentrated. The resulting solid was purified by flash chromatography on silica gel (25% ethyl acetate/hexanes) to provide the 4.9 g (43%) of the titled product as a light brown solid: mp 101-102 C.; IR (KBr,cm-1) 3174, 2968, 1725, 1594, 1519, 1442, 1278, 1249, 1156; 1 H NMR (300 MHZ, DMSO-d6) delta8.98 (s, 1H), 8.17 (m, 1H), 7.61 (m, 1H), 7.15 (m, 1H), 2.52 (q, J=7.5 Hz, 2H), 1.39 (s, 9H), 1.08 (t, J=7.5 Hz, 3H); MS (FD) m/e 222 (M+);
A 2-t-Butoxycarbonylamino-3-bromopyridine 2-t-Butoxycarbonylaminopyridine (10 g, 51.5 mmol) was dissolved in tetrahydrofuran (80 mL), and cooled to -78 C. N-butyllithium (120 mmol, 80 mL of 1.49M in hexanes) was added dropwise over a period of 1 h. After stirring for an additional 15 min at -78 C. and then for 2.5 h at -10 C., the solution was recooled back down to -78 C. and 1,2-dibromoethane (77.2 mmol, 6.65 mL) was added dropwise over a period of 15 min via syringe. The solution was allowed to warm to room temperature. The reaction was quenched with 100 mL of saturated ammonium chloride and was extracted with ethyl acetate (3*). The organic layers were collected, dried over magnesium sulfate, filtered, and concentrated. The resulting solid was purified by flash chromatography on silica gel (25% ethyl acetate/hexanes) giving 4.5 g (32%) of the titled product as a light brown solid: mp 120-121 C.; IR (KBr, cm-1) 3191, 2980, 1729, 1521, 1442, 1365, 1272, 1166, 1032; 1 H NMR (300 MHZ, DMSO-d6) delta9.28 (s, 1H), 8.34 (m, 1H), 8.05 (m, 1H), 7.15 (m, 1H), 1.39 (s, 9H); MS (FD) m/e 272 (M+), 274 (M+2);
To a solution of 2-amino pyridine (47.06, 0.5 mmol) in anhydrous DCM (300 mL) at 00C under nitrogen is added a solution of trimethylacetyl chloride (60.29 g, 0.5 mol, 1.0 eq.) in 100 mL of DCM dropwise. The resulting mixture is stirred at O0C for 60 minutes, then at room temperature overnight. Water (300 mL) is added. The organic layer is collected, washed with water and brine, dried over Na2SO4, and concentrated. The crude product is recrystallized with 250 mL hexane at - 1O0C to give the product 401.
tert-BxXy iV-(2-pyridyi)carbamate is available from the literature procedure (Moraczewski, A. L. et al, J. Org. Chem., 1998, 63, 7258) or can be prepared by the following method. Under a nitrogen atmosphere, sodium bis(trimethylsilyl)arnide (225 mL of a 1.0 M solution in tetrahydrofuran) was added over a period of 20 minutes to a solution of 2-aminopyridine (10.61 g, 108.0 mmol) in dry THF (150 mL). The solution was stirred for 15 minutes and then cooled to 0 0C. A solution of di-fert-butyl dicarbonate (24.60 g, 112.7 mmol) in THF (50 mL) was added slowly, and the reaction was allowed to warm to ambient temperature slowly and stirred overnight. The THF was removed under reduced pressure, and the residue was partitioned between ethyl acetate (500 mL) and 0.1 M hydrochloric acid (250 mL). The organic layer was separated; washed sequentially with 0.1 M hydrochloric acid (250 mL), water (250 mL), and brine (250 mL); dried over magnesium sulfate; filtered; and concentrated under reduced pressure. The crude product was purified by automated flash chromatography (eluting with 80:20 hexanes/ethyl acetate) to provide 17.43 g of tert-hutyl iV-(2-pyridyl)carbamate as a white solid.
Under a nitrogen atmosphere, a solution of tert-butyl iV-(2-rhoyridyl)carbamate (15.71 g, 80.9 mmol) and iV.LambdazetaN'.N'-tetramethylethylenediamine (TMEDA) (25.3 g, 218 mmol) in THF (400 mL) was cooled to -78 0C. M-Butyllithium (81 mL of a 2.5 M solution in hexanes) was added dropwise over a period of 20 minutes. The solution was stirred for ten minutes, and then the addition funnel was rinsed with additional THF (20 mL). The solution was warmed to -6 0C, stirred for two hours, and cooled again to -78 0C. Triisopropyl borate (57.7 g, 307 mmol) was added over a period often minutes. The resulting solution was warmed to 00C and then poured into saturated aqueous ammonium chloride (500 mL). A yellow solid formed and was stirred with diethyl ether (300 mL), isolated by filtration, washed with diethyl ether and water, and air-dried overnight to provide 2-f°rt-butoxycarbonylamino-3-pyridylboronic acid as a yellow solid.
Manufacturing Example 1-7-22-N-butoxycarbonyl-3-pyridineboronic acid; A tetrahydrofuran solution (400 mL) of pyridin-2-yl-carbamic acid tert-butyl ester (16 g) described in Manufacturing Example 1-7-1 and N,N,N',N'-tetramethylethylenediamine (25 g) was cooled to -70 C., n-butyl lithium (78 mL, 2.64M heptane solution) was then added dropwise over a period of 1 hour, which was stirred for 10 minutes. This mixture was warmed to a temperature between -10 C. and -6 C., which was stirred for 2 hours at that temperature. The solution was again cooled to -70 C., and triisobutyl borate (58 g) was added dropwise over a period of 1 hour. This mixture was warmed to 0 C., and then a saturated ammonium chloride aqueous solution was added thereto. Ether was added to the yellow solid thus produced, which was stirred, and the solid was then collected by filtration and washed with ether and water. This solid was dried under a reduced pressure, so as to obtain the title compound (14 g).1H-NMR spectrum (DMSO-d6) delta (ppm): 1.32-1.41 (9H, m), 6.80-6.84 (1H, m), 7.95-8.13 (2H, m).
A solution of pyridin-2-yl-carbamic acid tert-butyl ester described in Preparation Example 4-1-1 (16 g) and N,N,N',N'-tetramethyl ethylenediamine (25 g) in tetrahydrofuran (400 mL) was cooled to -70 C., n-butyl lithium (78 mL, 2.64M heptane solution) was then added thereto dropwise over one hour, and stirred for 10 minutes. This mixture was heated to between -10 C. and -6 C., and stirred at this temperature for two hours. Again, this solution was cooled to 70 C., and triisobutyl borate (58 g) was added thereto dropwise over one hour. This mixture was heated to 0 C., then, a saturated aqueous ammonium chloride was added thereto. To the produced yellow solid was added ether, and stirred, and then, a solid was recovered by filtration and washed with ether and water. This solid was in vacuo to obtain the title compound (14 g). 1H-NMR Spectrum (DMSO-d6) delta (ppm): 1.32-1.41 (9H, m), 6.80-6.84 (1H, m), 7.95-7.8.13 (2H, m).
To a solution of tert-butyl alcohol (650 mL) and di-tert-butyl carbonate (24 g) was added 2-Aminopyridine (9.4 g) slowly. This mixture was stirred at room temperature for 24 hours. This reaction solution was concentrated under a reduced pressure, and the residue thereof was purified by silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (18 g). 1H-NMR Spectrum (DMSO-d6) delta (ppm): 1.47 (9H, s), 6.99-7.03 (1H, m), 7.70-7.74 (1H, m), 7.77-7.80 (1H, m), 8.23-8.24 (1H, m), 9.72 (1H, brs).
Manufacturing Example 2-7-2 2-N-t-butoxycarbonyl-3-pyridineboronic acid; A solution of tetrahydrofuran (400 mL) of pyridin-2-yl-carbamic acid tert-butyl ester (16 g) described in Manufacturing Example 2-7-1 and N,N,N',N'-tetramethylethylene diamine (25 g) was cooled to -70 C., n-butyl lithium (78 mL, 2.64 M heptane solution) was added dropwise for 1 hour, and the mixture was stirred for 10 minutes. This mixture was then warmed to between -10 C. and -6 C., and stirred at that temperature for 2 hours. The solution was then cooled again to -70 C., and triisobutyl borate (58 g) was added dropwise for 1 hour. The mixture was warmed to 0 C., and saturated aqueous ammonium chloride solution was added thereto. To the resulting yellow solids was added ether and then stirred, and the solids were filtered out and washed with ether and water. The solids were dried under a reduced pressure to obtain the title compound (14 g).1H-NMR Spectrum (DMSO-d6) delta (ppm): 1.32-1.41 (9H, m), 6.80-6.84 (1H, m), 7.95-7.8.13 (2H, m).
Manufacturing Example 1-7-2 2-tert-butoxycarbonylamino-3-pyridineboronic acid A solution of tetrahydrofuran (400 mL) of pyridin-2-yl-carbamic acid tert-butyl ester (16 g) described in Manufacturing Example 1-7-1 and N,N,N',N'-tetramethylethylene diamine (25 g) was cooled to -70 C., n-butyl lithium (78 mL, 2.64 M heptane solution) was added dropwise for 1 hour, and the mixture was stirred for 10 minutes. This mixture was then warmed to between -10 C. and -6 C., and stirred at that temperature for 2 hours. The solution was then cooled again to -70 C., and triisobutyl borate (58 g) was added dropwise for 1 hour. The mixture was warmed to 0 C., and saturated aqueous ammonium chloride solution was added thereto. To the resulting yellow solids was added ether and then stirred, and the solids were filtered and washed with ether and water. The solids were dried under a reduced pressure to obtain the title compound (14 g). 1H-NMR Spectrum (DMSO-d6) delta (ppm): 1.32-1.41 (9H, m), 6.80-6.84 (1H, m), 7.95-7.8.13 (2H, m).
Manufacturing Example 1-7-1 Pyridin-2-yl-carbamic acid tent-butyl ester To a solution of tert-butyl alcohol (650 mL) and di-tert-butylcarbonate (24 g) was added 2-aminopyridine (9.4 g) slowly. This mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (18 g). 1H-NMR Spectrum (DMSO-d6) delta (ppm): 1.47 (9H, s), 6.99-7.03 (1H, m), 7.70-7.74 (1H, m), 7.77-7.80 (1H, m), 8.23-8.24 (1H, m), 9.72 (1H, brs).
Sodium hydride in mineral oil (60%, 2.22 g, 55.6 mmol) was added portionwise to a solution of 1,1 -dimethylethyl JV-2-pyridinylcarbamate (9.0 g, 46.3 mmol, prepared by the method of Krein, D. M.; Lowary, T. L. J. Org. Chem. 2002, 67, 4965-4967) in NJSf- dimethylformamide (40 mL) in a round bottom flask cooled to 0 0C in an ice/water bath. The suspension was stirred vigorously for an additional 30 min, followed by the addition of 2-chloro-5-(chloromethyl)thiazole (7.4 g, 55.6 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 16-24 h. Water (200 mL) was then added, and the reaction mixture was extracted three times with 50 mL of ethyl acetate. The combined organic extracts were washed four times with 20 mL of water, dried over Na2SC>4, and concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel by elution with ethyl acetate/hexane to provide the title compound as an amber oil (9.3 g). <n="68"/>1H NMR (CDCl3) delta 8.40 (d, IH), 7.78 (d, IH), 7.64 (t, IH), 7.49 (s, IH), 7.03 (t, IH), 5.18 (s, 2H), 1.54 (s, 9 H).
To a solution of pyridine-2-yl-carbamic acid tert-butyl ester (4D l) (32.26 g, 181 mmol) in anhydrous THF (200 mL) cooled to -780C under nitrogen, is added BuLi (1.6 M in hexane, 250 mL, 400 mmol, 2.2 eq.)- The resulting solution is stirred at -780C for 30 minutes, gradually warmed to - 1O0C and stirred for additional 2 hours. The reaction mixture is cooled to -78C again, and 67.7 g of iodopropane (400 mmol, 2.2 eq.) in 200 mL of anhydrous THF is added dropwise. The reaction mixture is stirred at -780C for 2 hours, and at room temperature overnight. The reaction is quenched with a saturated ammonium chloride solution (100 mL). Upon removal of the solvent, the residue is extracted with EtOAc (200 mL x 3), washed with water and brine, and dried over Na2SO4. Concentration and purification through silica gel chromatography (hexan.es/EtOAc, from 4:1 to 1:1) affords the product 402. 1H NMR (400 MHz, CDCl3) delta 8.26 (IH, dd, J = 1.6, 4.8 Hz), 7.86 (IH, s, EPO <DP n="86"/>br), 7.57 (IH, dd, J = 1.6, 7.6Hz), 7.12 (IH, J = 5.2, 8.0Hz), 2.54 (2H, t, J - 7.8Hz), 1.61 (2H, m), 1.34 (9H, s), 0.92 (3H, t, J = 7.2Hz).
To a solution of S1u (420 mg, 2.16 mmol) in anhydrous DMF (8.7 mL) was added NaH (104mg, 2.60 mmol) at 0 C. The resulting suspension was stirred at 0 C vigorously for 1 h. After propargyl bromide (290 muL, 2.60 mmol) was added dropwise, the reaction mixture was stirred at 0 C for 30 min and at rt for 6 h. Upon completion of the reaction, the reaction mixture was diluted with water (22 mL), neutralized with 2 N HCl to pH 6, and extracted with CH2Cl2 (2 ×50 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation. Purification by column chromatography (20:1hexanes/EtOAc) yielded 9u (345 mg, 69%) as a light yellow oil.
Step 2: tert-Butyl 3-formylpyridin-2-ylcarbamate (9b)To a solution of compound 9a (14.0 g, 72 mmol) in Et20 (500 mL) was added tert-BuLi (1.7M, 106 mL, 180 mmol) at -78C under N2 atmosphere and the resulting mixture was warmed to 0C and stirred for 1 h. Anhydrous DMF (8.0 mL, 103 mmol) was added with rapid stirring. The mixture was stirred at 0C for 10 min, then quenched with half -saturated aq. NH4CI solution. The aqueous layer was extracted with EA twice, the combined organic layers were dried over Na2S04 and concentrated under reduced pressure. The residue was purified by CC (PE/EA = 3/1) to give compound 9b (8.0 g, 52%) as a white solid.
To a solution of 0.61 g of tert-butyl pyridin-2-ylcarbamate (3.2 mmol) in 10 ml of dry DMF was added 0.18 g of NaH (60%, 4.4 mmol) in portions at 0 C., and the mixture was stirred at 0 C. for 30 min. Subsequently, 1.1 g (3.5 mmol) of 4-bromo-1-(bromomethyl)-2-(trifluoromethyl)benzene (WO2006/18725) were added as a solution in dry DMF (5.0 ml) at 0 C. The reaction mixture was warmed slowly to room temperature and stirred for 2 h. Thereafter, it was admixed with water and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The resulting crude product was purified by means of silica gel chromatography (n-hexane/ethyl acetate 30:1 to 10:1) to obtain 1.1 g (77%) of the N-Boc-protected amine.
Example 1016-Chloro-2-oxo-8-(pyridin-2-ylaminomethyl)-1 ,2-dihydro-quinoline-3-carboxylic acid a) 8-[(tert-Butoxycarbonyl-pyridin-2-yl-amino)-methyl]-6-chloro-2-methoxy- quinoline-3-carboxylic acid methyl ester.[00346] To an ice cooled solution of pyridin-2-yl-carbamic acid tert-butyl ester (178 mg, 0.9 mmol) in abs. DMF (1 .5 ml_) under an argon atmosphere is added NaH (45 mg, 60% oil dispersion; 1 .1 mmol). The suspension is stirred vigorously for 20 min, then methyl 8-bromomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (300 mg, 0.9 mmol) is added. Ice bath is removed and the mixture is stirred at rt for 18 h, then suspension is diluted with water (10 ml_) and ethyl acetate (20 ml_).The organic layer is washed with water, 3% aqueous citric acid and concentrated in vacuo. The residue is purified by column chromatography (petroleum ether : ethyl acetate, 4 :1 ) to give the title compound as a white solid (370 mg, 93%).1H NMR (400 MHz, DMSO-d6), delta (ppm): 1 .29 (s, 9H); 3.87 (s, 3H); 3.95 (s, 3H); 5.57 (s, 2H), 7.14- 7.17 (m, 1 H), 7.46 (s, 1 H), 7.70- 7.82 (m, 2H), 8.07 (s, 1 H), 8.33 (d, 2 Hz, 1 H) and 8.76 (s, 1 H).LC-MS: 458.6 [M+1 ].
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