CAS No. : | 161117-83-5 | MDL No. : | MFCD11100821 |
Formula : | C11H16N2O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | SJYKVVNRRFYDSS-UHFFFAOYSA-N |
M.W : | 224.26 | Pubchem ID : | 11064075 |
Synonyms : |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: | ![]() |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In 1,4-dioxane; for 4h;Reflux; | A 2000ml reaction vessel was charged with 2-methoxypyridin-3-amine 41 (100g, 0.8mol, 1wt), di-tert butyl dicarbonate (194g, 0.89mol, 1.94wt) and 1,4-dioxane (1140ml, 11.4vol). The reaction mixture was heated at reflux until complete (approx. 4 hours) as indicated by the absence of starting material by TLC analysis (eluent=1:4 ethyl acetate:hetanes, Rf starter 0.3; Rf product 0.55). The reaction mixture was concentrated to give the title compound as a dark oil (181g, 100%th.).1H NMR (400MHz, DMSO): d 1.47 (s, 9H), 3.91 (s, 3H), 6.95 (m, 1H), 7.84 (m, 1H), 7.98 (d, J=8.1Hz, 1H), 8.17 (br s, 1H). |
90.2% | 3.72 g (30 mmol) of 2-methoxy-3-pyridylamine in solution in 30 ml of tetrahydrofuran are placed in a 100-ml reactor, protected from moisture, and under a nitrogen atmosphere, and then 60 ml (60 mmol) of sodium bis(trimethylsilyl)amide in a 1 M solution in tetrahydrofuran are added dropwise at room temperature. After stirring the reaction mixture for 20 minutes at room temperature, 6.54 g (30 mmol) of di-tert-butyl carbonate are added dropwise to the reaction medium kept at room temperature. After stirring at room temperature for 3 hours, the tetrahydrofuran is evaporated off.. The residue is taken up in ethyl acetate, washed with water, with hydrochloric acid (0.1 M) and then with water (until a PH of the washings equal to 7 is obtained).. After drying the organic phase over sodium sulfate, and evaporation of the solvent, a black oil is obtained which is chromatographed on a silica gel (eluent ethyl acetate-hexane: 1-3).. After evaporation of the solvent, 6.1 g of an amber-coloured oil are obtained, that is to say a yield of 90.2%. TLC: (MERCK "Kieselgel 60" silica gel; AcOEt-hexane: 1-2); Rf=0.4 I.R.: upsilon NH=3425, CO=1731; NMR: (CDCl3): 1.5 (s, 9H); 3.95 (s, 3H); 6.8 (dd, 1H, J=5 Hz, J=7.8 Hz); 6.9 (s, 1H); 7.7 (dd, 1H, J=5 Hz, J=1.6 Hz); 8.2 (d, 1H, J=7.8 Hz). | |
3.9 g (87%) | With hydrogenchloride; In tetrahydrofuran; ethyl acetate; | A) Preparation of 3-(tert-Butoxycarbonylamino)-2-methoxypyridine STR12 To a stirred solution of 2.48 g (20 mmol) of 3-amino-2-methoxypyridine and 4.37 g (20 mmol) of di-tert-butyldicarbonate (Boc2 O) in 10 mL of THF was added at 0 C. 40 mL of a 1M solution of NaHMDS in THF. The mixture was then stirred at room temperature for 2 hours. The THF was removed by rotary evaporation and the residue was dissolved in EtOAc and washed twice with an equal volume of 0.1N HCl. The EtOAc layer was dried (MgSO4) and concentrated to give 3.9 g (87%) of the desired material as an oil after purification further by flash chromatography on silica gel using 95:5 hexane:EtOAc as the eluant. |
In 1,3-dioxane; for 24h;Heating / reflux; | 3-Amino-2-methoxyisonicotinic acid (1) Production of t-butyl (2-methoxypyridin-3-yl)carbamate: 2-methoxypyridine-3-amine (7.0 g, 56.4 mmol) and di-t-butyl dicarbonate (18.5 g, 84.6 g) were dissolved in 1,3-dioxane (20 mL), and heated under reflux for 24 hours. The solvent was evaporated off to obtain the intended, pale yellow oily compound (13.1 g). | |
In 1,4-dioxane; at 110℃;Inert atmosphere; | Under a nitrogen atmosphere, 50.0 g of 2-methoxy-3-aminopyridine (I) (0.4 mol, 1.0 eq) was sequentially added to the reaction bottle.105.5g of di-tert-butyl dicarbonate (0.48mol, 1.2eq) and 250mL of 1,4 dioxane, stir to dissolve.The temperature was raised to 110 C and the reaction was stirred overnight. The plate was controlled and the raw material reaction was complete.Distillate to no fraction under reduced pressure, add n-heptane, and wash twice with saturated sodium bicarbonate.It was distilled under reduced pressure until no fraction was added, and tetrahydrofuran was added to obtain a tetrahydrofuran solution of compound II. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25.4 g | A) tert-butyl (4-benzyl-2-methoxypyridin-3-yl)carbamate [0412] To a solution of <strong>[161117-83-5]tert-butyl (2-methoxypyridin-3-yl)carbamate</strong> (25.1 g) and N,N,N',N'-tetramethylethane-1,2-diamine (40.6 mL) in diethyl ether (374 mL) was added 1.6M n-butyllithium hexane solution (168 mL) at -78C, and the mixture was stirred under argon atmosphere at 0C for 1 hr. To the reaction mixture was added benzyl bromide (24.9 g) at -78C, and the mixture was stirred under argon atmosphere at room temperature for 4 hr. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate/hexane), and crystallized from ethyl acetate and hexane to give the title compound (25.4 g). 1H NMR (300 MHz, CDCl3) delta 1.50 (9H, s), 3.96 (3H, s), 4.00 (2H, s), 5.99 (1H, brs), 6.60 (1H, d, J = 5.3 Hz), 7.12-7.33 (5H, m), 7.88 (1H, d, J = 5.3 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.3 g | Under a nitrogen atmosphere, a whole batch of compound II in tetrahydrofuran solution, 93.6 g of tetramethylethylenediamine (0.8 mol, 2.0 eq) was added to the reaction flask.Cool to -78 , add 261.1g n-butyl lithium n-hexane solution (0.96mol, 2.4eq) dropwise,After the dropwise addition, the reaction was kept for 2 hours.After the heat preservation is completed, the temperature is controlled to -40 C, 58.9 g of N-N-dimethylformamide (0.8 mol, 2.0 eq) is added, and the mixture is stirred for 30 min.After the reaction is completed, the temperature is controlled at 0-20 C, the pH value is adjusted to 5-7 with 3N hydrochloric acid, the layers are separated, 200g of methylene chloride is added to the aqueous phase, and extraction is performed once.Combine the organic phases, concentrate under reduced pressure until a large amount of solid precipitates, add 300g of n-heptane and steam to a certain volume.Beating and filtering to obtain 79.3g of yellow solid (78% yield in two steps) is compound III. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.00 g (84%) | With hydrogenchloride; n-butyllithium; N,N,N,N,-tetramethylethylenediamine; | B) Preparation of 3-(tert-Butoxycarbonylamino)-2-methoxy-4-methylpyridine STR13 To a stirred solution of 1.12 g (5 mmol) of <strong>[161117-83-5]3-(tert-butoxycarbonylamino)-2-methoxypyridine</strong> in 25 mL of dry ether containing 1.8 mL, (12 mmol) of TMEDA at -78 C. under an argon atmosphere was added 4.8 mL (12 mmol) of a 2.5M solution of nBuLi in hexanes. The mixture was then warmed to -10 C. for 2 h. Recooling to -78 C. and treatment with iodomethane (0.99 g, 7 mmol) followed by warming to room temperature for 1 h produced the desired product which was purified by quenching with water, washing the ether layer with 0.1N HCl, drying (MgSO4), concentration and flash chromatography (9:1 hexanes:EtOAc). Yield: 1.00 g (84%). Recrystallization from heptane provided further purification. m.p.: 93-95 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Ketone 2-1 To a -70 C. solution of 1.12 g (5.0 mmol) of 3-(N-tertbutoxycarbonylamino)-2-methoxypyridine (Kelly, Tetrahedron Lett. 35 (48), 1994, 9003-9006) in 25 ML of dry ether was added 1.8 ML (12.0 mmol) TMEDA followed by 4.8 ML (12.0 mmol) of n-BuLi. The resulting solution was warmed to -15 C. where it was aged for 2 h.. The reaction mixture was recooled to -70 C. and treated with 0.83 ML (7.0 mmol) of ethyl trifluoroacetate.. After stirring an additional 3 h, the reaction was quenched with 25 ML of saturated NH4Cl solution and the two phases were separated.. The aqueous phase was extracted with 100 ML of EtOAc and the combined organic extracts were washed with 25 ML of brine and dried over MgSO4.. The yellow solution was concentrated and chromatographed (CH2Cl2) to afford trifluoromethyl ketone 2-1. 1H NMR (CDCl3) delta7.95 (d, J=8 Hz, 1H), 7.10 (bs, 1H), 6.95 (d, J=8Hz, 1H), 4.05 (s, 3H), 1.50 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid; In tetrahydrofuran; water; pentane; | 49. Preparation of t-Butyl N-(4-Fluoro-2-methoxy-3-pyridinyl)carbamate To a solution of 8 g (35.7 mmol) of t-butyl N-(2-methoxy-3-pyridyl)carbamate in 200 mL of dry tetrahydrofuran was added with stirring at -60 C., 46.2 mL (78.5 mmol) of 1.7M t-butyl lithium in pentane. The resulting solution was allowed to warm slowly with stirring to -20 C. over a 20 to 30 min period. It was then cooled to about -60 C. and 12.2 g (38.7 mmol) of N-fluorodibenzenesulfonimide was added with stirring all at once. The mixture was allowed to warm to -20 C. and was poured into 500 mL of ether. The resulting ethereal solution was washed with a mixture of 2.5 g (41.7 mmol) of acetic acid and 150 mL of water. The aqueous phase was extracted with 200 mL of ether. The ethereal extracts were combined, dried over magnesium sulfate, filtered, and concentrated by evaporation. The residue was purified by flash chromatography to obtain 6.7 g (77 percent of theory) of the title compound as a colorless solid melting at 75-77 C. Elemental Analysis C11 H15 FN2 O3 Calc.: %C, 54.5; %H, 6.24; %N, 11.6 Found: %C, 54.2; %H, 6.39; %N, 11.4 1 H NMR (CDCl3): 7.88 (dd, 1H, j=5.8, 7.6); 6.68 (dd, 1H, j=5.8, 8.9); 5.9 (br, 1H); 3.9 (s, 3H); 1.45 (s, 9H). | |
With acetic acid; In tetrahydrofuran; water; pentane; | 9. Preparation of t-butyl N-(4-Fluoro-2-methoxy-3-pyridinyl)carbamate To a solution of 8 g (35.7 mmol) of t-butyl N-(2-methoxy-3-pyridyl)carbamate in 200 mL of dry tetrahydrofuran was added with stirring at -60 C., 46.2 mL (78.5 mmol) of 1.7M t-butyl lithium in pentane. The resulting solution was allowed to warm slowly with stirring to -20 C. over a 20 to 30 min period. It was then cooled to about -60 C. and 12.2 g (38.7 mmol) of N-fluorodibenzenesulfonimide was added with stirring all at once. The mixture was allowed to warm to -20 C. and was poured into 500 mL of ether. The resulting ethereal solution was washed with a mixture of 2.5 g (41.7 mmol) of acetic acid and 150 mL of water. The aqueous phase was extracted with 200 mL of ether. The ethereal extracts were combined, dried over magnesium sulfate, filtered, and concentrated by evaporation. The residue was purified by flash chromatography to obtain 6.7 g (77 percent of theory) of the title compound as a colorless solid melting at 75-77 C. Elemental Analysis C11 H15 FN2 O3 Calc.: %C, 54.5; %H, 6.24; %N, 11.6 Found: %C, 54.2; %H, 6.39; %N, 11.4. 1 H NMR (CDCl3): 7.88 (dd, 1H, j=5.8, 7.6); 6.68 (dd, 1H, j=5.8, 8.9); 5.9 (br, 1H); 3.9 (s, 3H); 1.45 (s, 9H |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium; N,N,N,N,-tetramethylethylenediamine; | EXAMPLE 2 Ketone 2-1 To a -70 C. solution of 1.12 g (5.0 mmol) of <strong>[161117-83-5]3-(N-tert-butoxycarbonylamino)-2-methoxypyridine</strong> (Kelly, Tetrahedron Lett. 35 (48), 1994, 9003-9006) in 25 mL of dry ether was added 1.8 mL (12.0 mmol) TMEDA followed by 4.8 mL (12.0 mmol) of n-BuLi. The resulting solution was warmed to -15 C. where it was aged for 2 h. The reaction mixture was recooled to -70 C. and treated with 0.83 mL (7.0 mmol) of ethyl trifluoroacetate. After stirring an additional 3 h, the reaction was quenched with 25 mL of saturated NH4Cl solution and the two phases were separated. The aqueous phase was extracted with 100 mL of EtOAc and the combined organic extracts were washed with 25 mL of brine and dried over MgSO4. The yellow solution was concentrated and chromatographed (CH2Cl2) to afford trifluoromethyl ketone 2-1. 1H NMR (CDCl3) delta 7.95 (d, J=8 Hz, 1H), 7.10 (bs, 1H), 6.95 (d, J=8 Hz, 1H), 4.05 (s, 3H), 1.50 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.3% | 4.48 g (20 mmol) of the compound obtained in the preceding step in solution in 100 ml of diethyl ether and 9.05 ml (60 mmol) of tetramethylethylene-diamine are placed in a reactor, protected from moisture, and under a nitrogen atmosphere. After having cooled the solution to -70 C., 37.5 ml (60 mmol) of n-butyllithium in hexane (1.6 M) are added dropwise.. The reaction medium is stirred for 2 hours at -10 C. and then 14.1 g (60 mmol) of dihexyl sulfide are added dropwise at -70 C. After stirring the solution for 12 hours at room temperature, the reaction medium is taken up in water and extracted with diethyl ether.. The organic phase is washed with hydrochloric acid (0.1 M) and then with water until a PH of the washings equal to 7 is obtained, and then finally dried over sodium sulfate.. After evaporation of the solvent, an oil is obtained which is chromatographed on a silica gel (eluent ethyl acetate-hexane: 1-5).. After evaporation of the solvent, 5.6 g of an oil is obtained which crystallizes, that is to say a yield of 82.3%.. Its melting point is between 72 and 74 C. TLC: (MERCK "Kieselgel 60" silica gel; AcOEt-hexane: 1-3); Rf=0.3 I.R.: upsilon NH=3171, CO=1720; NMR: (CDCl3): 0.85 (t, 3H); 1.3 (m, 4H); 1.45 (m, 11H); 1.7-1.8 (m, 2H); 3.0 (t, 2H); 4.25 (s, 3H); 6.7 (d, 1H, J=6.8 Hz); 7.85 (d, 1H, J=6.8 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lead(IV) tetraacetate; for 2h;Inert atmosphere; Reflux; | To a suspension of 2- methoxynicotinamide (87; 10 mmol) in anhydrous tert-butyl alcohol (25 mL) is added lead tetraacetate (4.44 g, 10 mmol) under nitrogen atmosphere. The reaction mixture is heated to reflux for 2 h, then cooled and filtered through diatomaceous earth. The filtrate is concentrated and the residue dissolved in diethyl ether. The solution is washed with saturated aqueous sodium bicarbonate and brine, then dried with sodium sulfate, filtered, and concentrated to give the desired product 88 which can be purified by recrystallization. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of 2- methoxypyridin-3-ylcarbamate (88; 100 mmol) in dry THF (350 mL) is cooled to - 78 0C, followed by drop wise addition of tert-butyllithium (120 mL, 2 M in pentane, 240 mmol) at a rate such that the temperature does not exceed -65 0C. The reaction is stirred at -78 0C for an additional 15 min., then at -20 0C for 1.5 h. Dry N- formylpiperidine (300 mmol) is added while maintaining the temperature below -15 0C, then the reaction is allowed to stir at room temperature overnight. The reaction is then cooled to 0 0C and quenched by addition of 1 N HCl to bring the pH to 2. Solid sodium carbonate is added to adjust the pH to 7. The solution is extracted with ethyl acetate and the combined organic layers washed with water and brine, dried with sodium sulfate, filtered and concentrated. The product 89 can be purified by silica gel column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | A 5000ml reaction vessel was charged with <strong>[161117-83-5]tert-butyl (2-methoxypyridin-3-yl)carbamate</strong> (180g, 0.8mol, 1wt) and diethyl ether (2700ml, 15vol). N, N, N, N-tetramethylethylenediamine (360ml, 2vol) was charged at room temperature and the reaction mixture cooled to -78ºC. n-Butyl lithium (2.5M in hexanes, 972ml, 5.4vol) was charged slowly over 2 hours maintaining an internal temperature below -65ºC. After complete addition the reaction mixture was allowed to warm to -15ºC and the temperature maintained at -15ºC for 2 hours. The reaction mixture was re-cooled to -70ºC and ethylene oxide charged (136g, 3.1mol, 0.75wt) over 1 hour, after complete addition the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was cooled to 0-5ºC and quenched by the slow addition of water (1000ml, 5.5vol). The organic layer was separated and the aqueous extracted with ethyl acetate (4x 1000ml, 4x 5.5vol), the combined organics were washed with water (1000ml, 5.5vol) and dried over magnesium sulphate (100g, 0.55wt). After filtration, the organics were concentrated to give the crude material as an orange oil (272g, 1.5wt). The crude material was purified by column chromatography on silica (700g, 3.9wt) with ethyl acetate:heptanes (1:3) as eluent. Concentration of the desired fractions gave the title compound 42 as a pale yellow viscous oil (121.7g, 57%th.).1H NMR (400MHz, DMSO): d 1.41 (s, 9H), 2.71 (t, J=5.5Hz, 2H), 3.58 (m, 2H), 3.85 (s, 3H), 4.72 (m, 1H), 6.91 (d, J=4.9Hz, 1H), 7.84 (m, 1H), 7.94 (m, 1H), 8.18 (br s, 1H). |
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