* 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] Bulletin de la Societe Chimique de France, 1992, # 1, p. 79 - 84
[2] Patent: EP1510516, 2005, A1, . Location in patent: Page/Page column 134
With oxygen; nitrogen(II) oxide In acetonitrile at 90℃; for 10 h;
Into the reactor, 0.93 g (10.0 mmol) of 2-methylpyridine, 5 mL of acetonitrile, 0.15 g of sulfonated graphene was added, and the reaction was stirred under an oxygen atmosphere at 5.0 MPa of nitrogen monoxide and a temperature of 90 ° C for 10 h. After the end of the reaction, nitrogen gas was introduced into the reaction mixture at a normal pressure until the nitrogen oxides completely escaped to the cold trap reaction receiver, and the catalyst was filtered off. The filtrate was washed with a 5percent (m/m) aqueous solution of sodium hydrogencarbonate to near neutral, and then washed with distilled water until the organic phase was neutral and concentrated by evaporation in vacuo. Separating the product components by column chromatography,The mass of 2-methylnitropyridine is 0.67g,Wherein 2-methyl-3-nitropyridine 0.10 g (mass fraction 16percent),2-methyl-5-nitropyridine 0.57 g (mass fraction 84percent), yield 49percent.
Reference：
[1] Acta Chemica Scandinavica, 1994, vol. 48, # 2, p. 181 - 182
[2] Acta Chemica Scandinavica, 1994, vol. 48, # 12, p. 1001 - 1006
[3] Patent: CN108003029, 2018, A, . Location in patent: Paragraph 0043; 0044
4
[ 5470-18-8 ]
[ 18699-87-1 ]
Yield
Reaction Conditions
Operation in experiment
80%
Stage #1: With sodium t-butanolate In 1-methyl-pyrrolidin-2-one at 16 - 35℃; for 2 h; Stage #2: at 29 - 50℃; for 1.16667 h; Stage #3: With sulfuric acid In water at 50 - 100℃; for 0.75 h;
Add NMP (2.0 L) to a 12-L, 3-neck flask fitted with a stirrer, a temperature probe and a reflux condenser fitted with a gas adapter for N2 and cool to 16° C.. Add sodium tert-butoxide (0.675 kg, 6.81 mol, 2.2 equiv., corrected for 97percent purity) in one portion whereupon one observes an immediate exotherm to 29° C. Stir the mixture for 30 min to partially dissolve the NaOt-Bu and then add diethyl malonate (0.943 L, 6.19 mol, 2.0 equiv.) at 20° C. to 35° C. over 70 min with continual cooling whereupon a homogeneous solution forms. Stir for 20 min and add a solution of 2-chloro-3-nitropyridine (1a-1, 0.491 kg, 3.09 mol, 1.0 equiv.) and NMP (1.0 L) to the reaction mixture at 29° C. to 44° C. over 70 min. Heat the reaction mixture to 50° C. Monitor the progress of the reaction HPLC (Agilent series 1100; Waters Symmetry C8 (5μ) column (3.9.x.150 mm), flow rate at 1.0 mL/min. Isocratic: CH3CN/0.1percent aq. TFA, 50/50; λ=220 nm. RT: diethyl malonate=2.6 min, 2-chloro-3-nitropyridine=2.7 min, 2-(3-nitro-pyridin-2-yl)-malonic acid diethyl ester =3.9 min). Typically >99percent conversion occurs within 1-2 h. Discontinue heating and add 6M H2SO4 (2.17 L) at 50° C. to 59° C. over 45 min. A thick solid precipitate forms during the addition. Heat the mixture to 100° C. The evolution of gas occurs. Monitor the progress of the reaction by HPLC as previously described (RT: 2-methyl-3-nitropyridine 2a-1=2.0 min, 2-(3-nitro-pyridin-2-yl)-malonic acid diethyl ester=3.9 min). Typically one observes >99percent conversion within 12 h. Allow the mixture to cool to 40° C. and pour into ice water (20 kg, pH 1.5). Add 25percent aq. NaOH (2.65 L) at -11° C. to -6° C. over 20 min to pH 11. Add toluene (4.0 L) and stir the mixture for 10 min. Filter the mixture through Celite.(R). to remove inorganic solids and wash the filtercake with toluene (6.0 L). Separate the phases and extract the aqueous phase twice with toluene (6.0 L and 4.0 L). Filter the combined toluene phases through Celite.(R). and wash the filter cake with toluene (1.0 L). Combine the toluene filtrates and wash with water (2.x.3.0 L). Dry (MgSO4) the toluene phase, filter and concentrate to give 2-methyl-3-nitropyridine 2a-1 (0.34 kg, 80percent yield, correct for residual NMP and toluene) as an oil. HPLC analysis shows the material to be 96percent pure. 1H NMR (CDCl3) δ 2.87 (s, 3H), 7.35 (dd, 1H, J=4.8, 8.1 Hz), 8.27 (dd, 1H, J=1.4, 8.1 Hz), δ 8.72 (dd, 1H, J=1.4, 4.8 Hz).
Reference：
[1] Patent: US2005/131012, 2005, A1, . Location in patent: Page/Page column 13-14
[2] Organic and Biomolecular Chemistry, 2005, vol. 3, # 20, p. 3701 - 3706
[3] Synthetic Communications, 1990, vol. 20, # 19, p. 2965 - 2970
[4] Patent: WO2011/73092, 2011, A1,
[5] Organic Process Research and Development, 2011, vol. 15, # 5, p. 1040 - 1045
[6] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 1, p. 339 - 342
[7] Journal of Medicinal Chemistry, 2012, vol. 55, # 22, p. 9531 - 9540
5
[ 5470-18-8 ]
[ 13061-96-6 ]
[ 18699-87-1 ]
Yield
Reaction Conditions
Operation in experiment
55%
With potassium carbonate In 1,4-dioxane for 24 h; Heating / reflux
A mixture of 2-chloro-3-nitropyridine (1.6g, 10.09mmol), Pallac tetrakis(triphenylphosphine) (1170mg, 1.01 mmol), methylboronic acid (665mg, mmol ) and potassium carbonate (4180mg, 30.3 mmol) was refluxed in dioxane 1 days. The reaction was cooled to room temperature, and then filtered. The filtrate concentrated and the residue was purified by flash column chromatography (? EtOAc/Hexanes) to afford 760mg (55percent) of 2-methyl-3-nitropyridine. 1H NMR (CDC 8.71 (tetra, 1.7Hz, 5.0Hz, 1H), 8.26 (tetra, 1.7Hz, 8.3Hz, 1H)1 7.34 (dd, 5.( 8.3Hz, 1 H), 2.85 (s, 3H). MS m/z 139.1(M+H)+.
Method 1 Into a flask containing diethyl malonate (20 g, 0.125 mol) was added sodium (2.0 g, 0.087 mol). The reaction mixture was stirred for 1 h at room temperature and then allowed to warm to 120° C. (oil bath temperature) for 50 min. To this yellow suspension of the solid mass was added toluene (120 mL) followed by addition of a solution of 2-chloro-3-nitropyridine 1 (12.8 g, 0.08 mol) in 40 mL of toluene. The reaction mixture was refluxed for 8 h, and then stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue was dissolved in 30percent H2 SO4 (60 mL). This reaction mixture was heated to 125° C. (oil bath) for 7 h, cooled and poured into ice (200 g). The reaction mixture was neutralized with saturated NaHCO3 solution, filtered through Celite, extracted several times with ether. The combined extracts were dried over anhydrous Na2 SO4. The solvent was evaporated and the residue was distilled under reduced pressure to provide 6.65 g (60percent) of the desired product 3.
Reference：
[1] Organic Letters, 2009, vol. 11, # 6, p. 1357 - 1360
[2] Patent: US5869676, 1999, A,
Reference：
[1] Organic and Biomolecular Chemistry, 2005, vol. 3, # 20, p. 3701 - 3706
[2] Synthetic Communications, 1990, vol. 20, # 19, p. 2965 - 2970
[3] Synthesis, 2003, # 11, p. 1671 - 1678
[4] Patent: US2005/131012, 2005, A1, . Location in patent: Page/Page column 13
[5] Patent: WO2009/23844, 2009, A2, . Location in patent: Page/Page column 136-137
[6] Organic Process Research and Development, 2011, vol. 15, # 5, p. 1040 - 1045
[7] Organic Letters, 2011, vol. 13, # 22, p. 6102 - 6105
[8] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 1, p. 339 - 342
9
[ 5470-18-8 ]
[ 823-96-1 ]
[ 18699-87-1 ]
Yield
Reaction Conditions
Operation in experiment
42%
With potassium carbonate In 1,4-dioxane for 24 - 48 h; Heating / reflux
Example 77; N-Methyl-3-(2-(2-oxoindolin-5-ylamino)-5-(trifluoromethvπpyridin-4-ylamino)picolinamide; 2-Methyl-3-nitropyridine; Reference: Gray, M.; Andrews, I.P.; Hook, D. F.; Kitteringham, J.; Voyle, M.; Tetrahedron Lett.; 2000, 41, 6237 - 6240.The mixture of 2-chloro-3-nitropyridine (50 g, 0.315mol, 1.0 eq), TMB (50 mL, 1.1 eq), (PPh3)4Pd (0) (36.4 g, 0.1 eq), K2CO3 (130.6 g, 3.0 eq) and dioxane (1500 mL) was refluxed under argon for 2 days. The mixture was cooled to room temperature and filtered through a celite pad to remove K2CO3 and catalyst. The celite pad was washed with EtOAc. The organic solutions were combined and concentrated to get the crude which was purified by silica gel chromatography (0percent~40percent EtO Ac/Hex) to obtain the desired product 2-methyl-3-nitropyridine (30.5g, isolated yield 70percent) (Note: isolated yield 42percent was obtained when the reaction was refluxed for 24 h).
With oxygen; nitrogen(II) oxide; In acetonitrile; at 90℃; under 37503.8 Torr; for 10h;
Into the reactor, 0.93 g (10.0 mmol) of 2-methylpyridine, 5 mL of acetonitrile, 0.15 g of sulfonated graphene was added, and the reaction was stirred under an oxygen atmosphere at 5.0 MPa of nitrogen monoxide and a temperature of 90 C for 10 h. After the end of the reaction, nitrogen gas was introduced into the reaction mixture at a normal pressure until the nitrogen oxides completely escaped to the cold trap reaction receiver, and the catalyst was filtered off. The filtrate was washed with a 5% (m/m) aqueous solution of sodium hydrogencarbonate to near neutral, and then washed with distilled water until the organic phase was neutral and concentrated by evaporation in vacuo. Separating the product components by column chromatography,The mass of 2-methylnitropyridine is 0.67g,Wherein 2-methyl-3-nitropyridine 0.10 g (mass fraction 16%),2-methyl-5-nitropyridine 0.57 g (mass fraction 84%), yield 49%.
Into a 5000 mL 3-necked roundbottom flask, was placed a solution of <strong>[18699-87-1]2-methyl-3-nitropyridine</strong> (500 g, 3.26 mol) in DMF (2500 mL). To the mixture was added dimethoxy-N,N-dimethylmethanamine (1350 g, 11.33 mol). The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at 115 C in a bath of oil. The mixture was concentrated by evaporation under vacuum using a rotary evaporator. This resulted in 650 g (crude) of N,N-dimethyl-2-(3- nitropyridin-2-yl)ethenamine as red oil.
With hydrogen; triethylamine;palladium 10% on activated carbon; In methanol; at 20℃; under 760.051 Torr; for 6h;
Under nitrogen atmosphere, 47.6 g of 2-chloro-3-nitropyridine was dissolved in 500 mL of tetrahydrofuran, and 150 mL of 2M methylzinc chloride in tetrahydrofuran and 6.9 g of tetrakis(triphenylphosphine)palladium(0) were added, and the reaction solution was stirred at 70C for 2 hours. The reaction solution was poured into cold water, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to column chromatography (n-hexane:ethyl acetate =3:1) to obtain 35.4 g of <strong>[18699-87-1]2-methyl-3-nitropyridine</strong> as a colorless oil. Then 35.4 g of <strong>[18699-87-1]2-methyl-3-nitropyridine</strong> was dissolved in a mixed solution of 300 mL methanol/5 mL triethylamine, added with 5 g of 10% palladium on carbon, and stirred for 6 hours under hydrogen atmosphere and at normal temperature and pressure. The reaction solution was filtered thorough Celite, the solvent was evaporated, and 33.0 g of crudely produced 2-methyl-3-aminopyridine was obtained as a pale brown oil. Next, to 100 mL of a solution of 65 g of crude 3-amino-2-methyl pyridine in dichloromethane were added 60 mL of pyridine and 71 mL of acetic anhydride at room temperature and stirred for 3 hours. The reaction solution was added with about 150 mL of silica gel powder, the solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate :methanol =100:3), to afford 74 g of the title compound as colorless crystals.1H-NMR (400 MHz, CDCl3) delta2.25 (3H, s), 2.53 (3H, s), 7.00 (1H, bs), 7.18 (1H, dd, J = 4.6, 8.0 Hz), 8.23 (1H, d, J = 8.0 Hz), 8.30 (1H, d, J = 4.6 Hz).
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃; for 6h;
Example 9; Synthesis of 3-amino-1-hydroxy-3,4-dihydro-1,5-naphthyridin-2(1H)-one, dihydrochloride salt (50); <strong>[18699-87-1]2-Methyl-3-nitropyridine</strong> 1-oxide (44); To a solution of <strong>[18699-87-1]2-methyl-3-nitropyridine</strong> (43) (0.86 g, 6.23 mmol) in DCM (30 mL) was added mCPBA (2.8 g, 12.5 mmol). The reaction was then allowed to stir at RT for 6 h. Sodium thiosulfate (900 mg) was added and the mixture was allowed to stir overnight. The reaction mixture was diluted with additional DCM and washed with a saturated aqueous NaHCO3 solution. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (Gradient: 0% to 20% MeOH in DCM) to afford the product (782 mg, 81%). LCMS m/z 155.0 (M+1). 1H NMR (400 MHz, CDCl3) delta 2.73 (m, 3H), 7.30 (br dd, J=8.1, 6.8 Hz, 1H), 7.72 (dq, J=8.4, 0.5 Hz, 1H), 8.48 (dq, J=6.6, 0.6 Hz, 1H).
With selenium(IV) oxide; In 1,4-dioxane; for 48h;Heating / reflux;
Preparation 2. l-allyl-2,3-dimemyl-lNo.-pyrrolo[2,3-c]pyridin-7-carbaldehyde; Step 1: 2-formyl-3-nitropyridine; A solution of <strong>[18699-87-1]2-methyl-3-nitropyridine</strong> (10.16 g, 72.46 mmol) prepared in Step 1 ofPreparation 1 and selenium dioxide (8.84 g, 79.71 mmol) in 1,4-dioxane (80 ml) wasrefluxed for 2 days. The reaction mixture was cooled to room temperature and thenfiltered. The filtrate was concentrated under reduced pressure. The resulting residuewas purified with silica gel column chromatography (ethyl acetate/n-hexane=l/2, v/v)to give 12.8 g of the titled compound as red oil.lH-NMR(400MHz, CDCy 5 10.27(s, 1H), 9.00(d, 1H), 8.28(t, 1H), 7.76(d, 1H)
With selenium(IV) oxide; In 1,4-dioxane; for 16h;Reflux;
3-Nitro-2-pyridinecarbaldehyde; <strong>[18699-87-1]2-Methyl-3-nitropyridine</strong> (24 g, 173.91 mmol) was dissolved in 1,4-dioxane (500 mL) and to the mixture was added selenium dioxide (23 g, 208.7 mmol) and the mixture was heated under reflux for 16 h. After completion of reaction, the mixture was cooled to rt and filtered through Celite and the filtrate was concentrated under reduced pressure to give thick oily mass. The oily mass was purified by silical gel column chromatography using 20% of ethyl acetate and hexane as eluent to give 3-nitro-2-pyridinecarbaldehyde as an off white solid: 1H-NMR (CDCl3) delta: 7.7 (m, 1H), 8.3 (d, 1H), 9.0 (d, 1H), 10.3 (s, 1H).
With sulfuric acid; In water; at 20 - 105℃;Product distribution / selectivity;
Add sodium metal (3.5 g) portion-wise over 1 hour to a 3 neck flask containing 79 mL of diethyl malonate heated to 90 C. under nitrogen. Lower the temperature to 60 C. and add 2-chloro-3-nitropyridine (1a-1, 25.0 g) portion-wise over 15 min. The reaction color turns to dark red. Keep the solution for 3 h at 60 C. and then allow to stand at rt overnight. Tlc indicates remaining starting material. Heat the solution to 80 C. for an additional 3 h (completion of the reaction). Remove the diethyl malonate under reduced pressure and take-up the dark brown residue in a mixture of conc. H2SO4 (18 mL) and H2O (32 mL). Heat the mixture for 7 h at 105 C. (decarboxylation) and then allow to stand at rt overnight. Wash the mixture with 3×150 mL of Et2O and 2×200 mL of EtOAc, and discard the washings. Basify the aqueous phase to pH 8-9 with NaOH and extract with 3×200 mL EtOAc. Filter the combined organic extracts over Celite (diatomaceous earth) (Celite Corporation, 137 West Central Avenue, Lompor, Calif. 93436) and remove the solvent under reduced pressure. The residue crystallizes to give 2a-1 (15.0 g, 68%), mp 29-31 C.
With hydrogenchloride; water;Heating / reflux;
Into a 10000 mL 3-necked roundbottom flask, was placed diethyl 2-(3-nitropyridin-2-yl)malonate(500 g, 1.59 mol). To the mixture was added HC1(4N ) (4.5 L). The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at reflux in a bath of oil. The reaction progress was monitored by TLC (EtOAc/PE = 1 :1). Adjustment of the pH to 10 was accomplished by the addition of NaOH. The resulting solution was extracted three times with 10000 mL of EtOAc and the organic layers combined and dried over Na2SO4 and concentrated by evaporation under vacuum using a rotary evaporator. This resulted in 500 g (crude) of 2-methyl-3-nitropyridine as black oil.
EXAMPLE 2; 3-{4-[3-(2-Fluoro-5-trifluoromethylphenyl)-ureido]phenyl}-1H-pyrrolo[3,2-b]pyridine-2-carboxamide; Method b:; Ethyl 3-(3-nitropyridin-2-yl)-2-oxopropionate 121.7 g of ethyl oxalate and then 15.8 g of <strong>[18699-87-1]2-methyl-3-nitropyridine</strong> in solution in 100 ml of ethanol are added to a solution of sodium ethanolate, prepared by adding 4 g of sodium to 400 ml of ethanol stirred under argon. The reaction mixture is stirred for 15 hours and the solid formed is filtered off, washed successively with 100 ml of ethanol and 100 ml of diisopropyl ether, and then filter-dried. The solid is taken up in 300 ml of ethanol and acidified with a 5N hydrochloric acid solution. The solid obtained is filtered off, washed with 50 ml of a 5N hydrochloric acid solution and then with 100 ml of ethanol, and filter-dried. After drying under vacuum, 18.7 g of ethyl 3-(3-nitro yridine-2-yl)-2-oxopropionate are obtained, the characteristics of which are as follows: MS (ES+) spectrum: m/z=239 [MH]+Melting point=38 C. (Koefler bench). 1H NMR spectrum (400 MHz, DMSO-d6, delta in ppm): 1.30 (t, J=7.0 Hz, 3H); 4.29 (q, J=7.0 Hz, 2H); 7.12 (s, 1H); 7.57 (dd, J=5.5 and 8.5 Hz, 1H); 8.66 (broad d, J=8.5 Hz, 1H); 8.85 (broad d, J=5.5 Hz, 1H); 14.9 (broad m, 1H). IR spectrum (KBr): 1722; 1644; 1560; 1532; 1346; 1231; 1141; 1024 and 777 cm-1
Add NMP (2.0 L) to a 12-L, 3-neck flask fitted with a stirrer, a temperature probe and a reflux condenser fitted with a gas adapter for N2 and cool to 16 C.. Add sodium tert-butoxide (0.675 kg, 6.81 mol, 2.2 equiv., corrected for 97% purity) in one portion whereupon one observes an immediate exotherm to 29 C. Stir the mixture for 30 min to partially dissolve the NaOt-Bu and then add diethyl malonate (0.943 L, 6.19 mol, 2.0 equiv.) at 20 C. to 35 C. over 70 min with continual cooling whereupon a homogeneous solution forms. Stir for 20 min and add a solution of 2-chloro-3-nitropyridine (1a-1, 0.491 kg, 3.09 mol, 1.0 equiv.) and NMP (1.0 L) to the reaction mixture at 29 C. to 44 C. over 70 min. Heat the reaction mixture to 50 C. Monitor the progress of the reaction HPLC (Agilent series 1100; Waters Symmetry C8 (5mu) column (3.9×150 mm), flow rate at 1.0 mL/min. Isocratic: CH3CN/0.1% aq. TFA, 50/50; lambda=220 nm. RT: diethyl malonate=2.6 min, 2-chloro-3-nitropyridine=2.7 min, 2-(3-nitro-pyridin-2-yl)-malonic acid diethyl ester =3.9 min). Typically >99% conversion occurs within 1-2 h. Discontinue heating and add 6M H2SO4 (2.17 L) at 50 C. to 59 C. over 45 min. A thick solid precipitate forms during the addition. Heat the mixture to 100 C. The evolution of gas occurs. Monitor the progress of the reaction by HPLC as previously described (RT: 2-methyl-3-nitropyridine 2a-1=2.0 min, 2-(3-nitro-pyridin-2-yl)-malonic acid diethyl ester=3.9 min). Typically one observes >99% conversion within 12 h. Allow the mixture to cool to 40 C. and pour into ice water (20 kg, pH 1.5). Add 25% aq. NaOH (2.65 L) at -11 C. to -6 C. over 20 min to pH 11. Add toluene (4.0 L) and stir the mixture for 10 min. Filter the mixture through Celite to remove inorganic solids and wash the filtercake with toluene (6.0 L). Separate the phases and extract the aqueous phase twice with toluene (6.0 L and 4.0 L). Filter the combined toluene phases through Celite and wash the filter cake with toluene (1.0 L). Combine the toluene filtrates and wash with water (2×3.0 L). Dry (MgSO4) the toluene phase, filter and concentrate to give 2-methyl-3-nitropyridine 2a-1 (0.34 kg, 80% yield, correct for residual NMP and toluene) as an oil. HPLC analysis shows the material to be 96% pure. 1H NMR (CDCl3) delta 2.87 (s, 3H), 7.35 (dd, 1H, J=4.8, 8.1 Hz), 8.27 (dd, 1H, J=1.4, 8.1 Hz), delta 8.72 (dd, 1H, J=1.4, 4.8 Hz).
tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 70℃; for 2h;
Under nitrogen atmosphere, 47.6 g of 2-chloro-3-nitropyridine was dissolved in 500 mL of tetrahydrofuran, and 150 mL of 2M methylzinc chloride in tetrahydrofuran and 6.9 g of tetrakis(triphenylphosphine)palladium(0) were added, and the reaction solution was stirred at 70C for 2 hours. The reaction solution was poured into cold water, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to column chromatography (n-hexane:ethyl acetate =3:1) to obtain 35.4 g of 2-methyl-3-nitropyridine as a colorless oil. Then 35.4 g of 2-methyl-3-nitropyridine was dissolved in a mixed solution of 300 mL methanol/5 mL triethylamine, added with 5 g of 10% palladium on carbon, and stirred for 6 hours under hydrogen atmosphere and at normal temperature and pressure. The reaction solution was filtered thorough Celite, the solvent was evaporated, and 33.0 g of crudely produced 2-methyl-3-aminopyridine was obtained as a pale brown oil. Next, to 100 mL of a solution of 65 g of crude 3-amino-2-methyl pyridine in dichloromethane were added 60 mL of pyridine and 71 mL of acetic anhydride at room temperature and stirred for 3 hours. The reaction solution was added with about 150 mL of silica gel powder, the solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate :methanol =100:3), to afford 74 g of the title compound as colorless crystals.1H-NMR (400 MHz, CDCl3) delta2.25 (3H, s), 2.53 (3H, s), 7.00 (1H, bs), 7.18 (1H, dd, J = 4.6, 8.0 Hz), 8.23 (1H, d, J = 8.0 Hz), 8.30 (1H, d, J = 4.6 Hz).
To a solution of potassium ethoxide (2.44g, 27.7mmol) in diethyl ether (90ML) and ethanol (8mL) was added diethyl oxalate (3.79mL, 27. 7MMOL) resulting in a yellow suspension. The reaction mixture was stirred for 5min prior to the addition of <strong>[18699-87-1]2-methyl-3-nitropyridine</strong> (Preparation 29,3. 40g, 24. 6MMOL) in one portion. The resulting red suspension was stirred at rt, under argon, for 20h. The mixture was filtered, washed thoroughly with diethyl ether and dried. The red solid was dissolved in water and the mixture adjusted to pH 4 by addition of glacial acetic acid. The resulting precipitate was collected by filtration, dissolved in dichloromethane, washed with brine, dried (MgS04), and then filtered and concentrated in vacuo to give the title compound as an orange solid. SN (CDCl3): 1.40 (3H, t), 4.39 (2H, q), 7.34 (1H, s), 7.36 (1H, dd), 8.43 (1H, dd), 8. 66 (1H, dd).
With sodium ethanolate; at 20℃; for 48h;Product distribution / selectivity;
Add to a 3 neck flask containing 500 mL of absolute ethanol under N2, 2.2 g (0.0956 g-atom) of sodium. After all the sodium reacts, add diethyl oxalate (98 mL) dropwise, and then add compound 2a-1 (one equivalent). The color turns from light yellow to brown upon addition. Allow the resulting solution to stand for two days at rt. Treat the orange mixture with SN HCl (pH=1), collect the precipitate by filtration and wash the filter cake with 100 mL EtOH and 200 mL di-isopropyl ether to afford 3a-1 as 2-hydroxy-3-(3-nitro-pyridin-2-yl)-acrylic acid ethyl ester (R4H, 20 g, 86%) or its tautomeric ketoester or as a mixture of keto-enol tautomers. 1H NMR (DMSO-d6) delta 8.83 (dd, 1H, J=1.1, 5.0 Hz), 8.65 (dd, 1H, J=1.5, 8.4 Hz), 7.56 (dd, 1H, J=5.0, 8.4 Hz), 7.11 (s, 1H), 3.47 (bs, 1H), 4.28 (q, 2H, J=7.1 Hz), 1.30 (t, 3H, J=7.0 Hz).
Add tetrahydrofuran (2.7 L) to a 22-L, 3-neck flask fitted with a stirrer, temperature probe and an addition funnel fitted with a gas inlet adapter for N2, and cool to about 2 C. Add sodium ethoxide (0.409 kg, 6.02 mol, 2.0 equiv.) in one portion. One observes a slight exotherm to 2.7 C. Stir the mixture for 20 min, add diethyl oxalate (1.22 L, 9.03 mol, 3.0 equiv.) at -0.34 C. over 50 min (slightly exothermic) and then stir the mixture for 10 min. Add a solution of <strong>[18699-87-1]2-methyl-3-nitropyridine</strong> (2a-1, 0.415 kg, 3.01 mol, 1.0 equiv.) and THF (0.625 L) at 4-9 C. over 22 min without cooling. Allow the mixture to warm to rt over 1 h. Monitor progress of the reaction by HPLC (Agilent series 1100 using the following conditions: Waters Symmetry C8 (5mu) column (3.9×150 mm), flow rate at 1.0 mL/min; CH3CN/0.1% aq. TFA, 55/45; lambda=210 nm; RT: <strong>[18699-87-1]2-methyl-3-nitropyridine</strong> 2a-1=1.8 min, 3a-1=2.7 min). Typically one observes >99% conversion to product within 2-3 h. During the reaction, a thick red precipitate forms. Cool the reaction mixture to about 1 C. and add saturated NH4Cl solution (2.0 L) at 1 C. to 9 C. Add water (5.9 L) (pH 7.4) and then add IPA (3.5 L). Stir the mixture for 1 h and collect the red colored solid by filtration. Wash the filter cake with IPA/H2O (1:4, 8.0 L), H2O (15 L) and air dry. Dry the filter cake (40 C./0.1 in Hg) to give 3a-1 (0.635 kg, 89%). 1H NMR (CDCl3) delta 1.40 (t, 3H, J=7 Hz), 4.38 (q, 2H, J=7 Hz), 7.36 (m, 2H), 8.42 (dd, 1H J=1.5, 8.4 Hz), 8.66 (dd, 1H, J=1.5, 4.8 Hz), 14.52 (2, 1H, OH).
Method 1 Into a flask containing diethyl malonate (20 g, 0.125 mol) was added sodium (2.0 g, 0.087 mol). The reaction mixture was stirred for 1 h at room temperature and then allowed to warm to 120 C. (oil bath temperature) for 50 min. To this yellow suspension of the solid mass was added toluene (120 mL) followed by addition of a solution of 2-chloro-3-nitropyridine 1 (12.8 g, 0.08 mol) in 40 mL of toluene. The reaction mixture was refluxed for 8 h, and then stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue was dissolved in 30% H2 SO4 (60 mL). This reaction mixture was heated to 125 C. (oil bath) for 7 h, cooled and poured into ice (200 g). The reaction mixture was neutralized with saturated NaHCO3 solution, filtered through Celite, extracted several times with ether. The combined extracts were dried over anhydrous Na2 SO4. The solvent was evaporated and the residue was distilled under reduced pressure to provide 6.65 g (60%) of the desired product 3.
Method 2 A mixture of 2-chloro-3-nitropyridine 1 (793 mg, 5.0 mmol), methylboronic acid (329 mg, 5.5 mmol), Pd(PPh3)4 (578 mg, 0.5 mmol) and K2 CO3 (2.073 g, 15.0 mmol) in dioxane (25 mL) was refluxed for 2 days. It was then cooled to room temperature and filtered. The solvent was removed and the residue was isolated by flash chromatography (50% ethyl acetate in hexanes) to provide 623 mg (90%) of 2-methyl-3-nitropyridine 3. 1 H NMR (CDCI3) delta 2.88 (s, 3H), 7.36 (dd, 1H, J=4.8 & 8.4 Hz), 8.28 (dd, 1H, J=1.2 & 8.1 Hz), 8.73 (dd, 1H, J=1.2 & 4.8 Hz).
With N-Bromosuccinimide; dibenzoyl peroxide; In chlorobenzene;
3.c 2-Bromomethyl-3-nitropyridine 51 g (290 mmol) of N-bromosuccinimide and 0.5 g of benzoyl peroxide were added, a little at a time, to a mixture of 40 g (290 mmol) of <strong>[18699-87-1]2-methyl-3-nitropyridine</strong> (Example 3.b) and 400 ml of chlorobenzene, at the boiling point (liberation of bromine). After approximately 2 hours, the reaction mixture was cooled to room temperature (approximately 25 C.) and filtered, and the resulting solution was freed from solvent under reduced pressure. The resulting residue was chromatographed twice (cyclohexane/methylene chloride; cyclohexane/ethyl acetate). This gave 10.4 g (17%) of the title compound as a yellow oil. 1 H NMR (CDCl3; delta in ppm): 5.0 (s,2H, CH2 Br); 7.55 (dd,1H, pyridyl); 8.4 (d,br,1H, pyridyl); 8.85 (d,1H, pyridyl).
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 72h;Heating / reflux;
Step 2: 2-bromomethyl-3-nitropyridine; 2,2'-azobis(isobutyronitrile) (2.7 g, 16.4 mmol) was added to a solution of<strong>[18699-87-1]2-methyl-3-nitropyridine</strong> (12.97 g, 92.6 mmol) prepared in Step 1 and N- bromo-succinimide (23.06 g, 130 mmol) in carbon tetrachloride (100 ml) and then the reactionmixtue was refluxed for 3 days. The reaction mixture was cooled to room temperatureand then concentrated under reduced pressure. The resulting residue was diluted withethyl acetate (100 ml) and then washed with a saturated sodium bicarbonate solutionand a saturated sodium thiosulfate solution. The organic layer was dried on anhydrousmagnesium sulfate and then purified with silica gel column chromatography(dichloromethane/n-hexane=2/l, v/v) to give 7.5 g of the titled compound as brown oil. lH-NMR(400MHz, CDC1) 5 8.82(d, 1H), 8.39(d, 1H), 7.56(t, 1H), 5.07(s, 2H)
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 72h;Heating / reflux;
Step 2: 2-bromomethyl-3-nitropyridine; 2,2'-Azobis(isobutyronitrile) (2.7 g, 16.4 mmol) was added to a solution of<strong>[18699-87-1]2-methyl-3-nitropyridine</strong> (12.97 g, 92.6 mmol) prepared in Step 1 and N- bromo-succinimide (23.06 g, 130 mmol) in carbon tetrachloride (100 ml). The reactionmixture was refluxed for 3 days, cooled to room temperature, and then concentratedunder reduced pressure. The resulting residue was diluted with ethyl acetate (100 ml)and then washed with a saturated sodium bicarbonate solution and a saturated sodiumthiosulfate solution. The organic layer was dried on anhydrous magnesium sulfate andthen purified with purified with silica gel column chromatography(dichloromethane/n-hexane=2/l, v/v) to give 7.5 g of the titled compound as brown oil.lH-NMR(400MHz, CDCy 5 8.82(d, 1H), 8.39(d, 1H), 7.56(t, 1H), 5.07(s, 2H)
In 4-methyl-morpholine; platinum/charcoal; hexane;
5a N-(2-methylpyridin-3-yl)hydroxylamine STR68 A mixture of 19.6 g (14.2 mmol) of <strong>[18699-87-1]2-methyl-3-nitropyridine</strong> (Synth. Commun. 1990, 20, 2965) in 200 ml of N-methylmorpholine is hydrogenated in the presence of 1 g of 5% platinum/charcoal. During this process, the temperature of the reaction mixture rises to approximately 35 C. After approximately 4.5 hours, the uptake of hydrogen has ceased, and the reaction mixture is filtered with suction through kieselguhr. The filter residue is washed with N-methylmorpholine, and the combined organic phases are concentrated in vacuo (T<45 C.). The residue is taken up in 100 ml of Solvesso 150 (b.p.=185-205 C.) and the resulting mixture is concentrated under a high vacuum (T<80 C.). The residue crystallizes and is digested in hexane. This gives 17.2 g (98%) of the title compound as a pale beige solid. 1 H NMR (CDCl3; delta in ppm): 8.35 (d,1H,NH); 8.15 (s,broad,1H,OH); 7.85 (dd,1H, pyridyl); 7.25 (d,broad,1H, pyridyl); 7.05 (dd,1H, pyridyl); 2.2 (s,3H, CH3).
With N-benzyl-trimethylammonium hydroxide; In dimethyl sulfoxide; at 90℃; for 4h;
Example 1; Scheme A; A mixture of a-1 (0.0072 mol) and paraformaldehyde (0.0058 mol) in DMSO (3.5ml) and triton B (0.27ml) was stirred at 90C for 4 hours, then cooled to room temperature and purified by column chromatography over silica gel (eluent: CH2CI2 then CH2CI2/ CH3OH/NH4OH (99/1/0.1); 15mum). The pure fractions were collected and the solvent was evaporated, yielding: 0.3 g of intermediate a-2 (20%).
INTERMEDIATE 13 Ethyl 2Z)-2-hydroxy-3-(3-nitropyridin-2-yl)acrylate Sodium metal (400 mg, [17.] 4 mmol) was added portionwise to [ETOH] (50 ml), followed by diethyl oxalate (2.4 [ML,] 17.4 mmol), and stirred at r. t. for 5 min. 2-Methyl-3- nitropyridine [(2. 00] g, 14.6 mmol) was added, giving a deep purple solution that changed over time to red-orange. After stirring for 3 days at r. t. a red precipitate had formed which was collected by filtration and washed with ether (4 x 20 [ML).] The solid residue was suspended in water and the suspension acidified to pH 4 with AcOH. The resulting orange precipitate was collected by filtration, washed with ethanol (10 [ML)] and dried in vacuo to give the title compound (1.17 g, [34%).] [6H] [(CDC13)] 8. [77-8.] 75 [(1H,] m), [8.] [54-8.] 50 [(1H,] m), 7.47-7. 43 (2H, m), 4.48 (2H, q, [J 7.] 1 Hz), 1.49 (3H, t, J7. 1 Hz). LCMS [(ES] RT 3.32 minutes, 239 [(MI]
A mixture of <strong>[18699-87-1]2-methyl-3-nitropyridine</strong> (760rmg, 5.5mmol) and selenium oxide (733mg, 6.6mmol) was refluxed in dioxane for 2 days. The solvent was removed. T residue was re-taken up in MeOH, loaded on silica gel and purified by column chromatography (EtOAc/Heptane=1/1 ) to afford a mixture (960mg, 95%) of methoxyi nitropyridin-2-yl)methanol and 3-nitropicolinaldehyde. MS m/z 185.0 (M+H)+.
Dimethylformamiddimethylacetal (DMF-DMA)[ No CAS ]
[ 65156-92-5 ]
Yield
Reaction Conditions
Operation in experiment
In N,N-dimethyl-formamide;
(c) (E)-N,N-Dimethyl-2-(3-nitropyridin-2-yl)ethenamine A modified procedure of ) was used. <strong>[18699-87-1]2-Methyl-3-nitropyridine</strong> (0.7 g, 5.1 mmol) was dissolved in 15 ml dry DMF and stirred under nitrogen. Dimethylformamiddimethylacetal (DMF-DMA) (1.35m1, 1.22g, 10.2 mmol) was added dropwise. The reaction was heated to 90C for 4 h. After approximately 15 min a deep redish color appeared. After evaporating the solvent (E)-N,N-Dimethyl-2-(3-nitropyridin-2-yl)ethenamine is obtained as a red oil (0.16 g, 0.8 mmol, 73%) which can be used without further purification. 1H NMR (300 MHz, CDCl3) 8.40 (pdd ; 3J = 1.7 Hz; 3J = 4.4 Hz; 1 H; H-6); 8.16 (pdd; 3J = 1.7 Hz; 3J = 8.3 Hz; 1 H; H-4) ; 8.04 (d; 3JAX = 12.5 Hz; 1 H; H-8) ; 6.76 (pdd; 3J = 4.4 Hz; 3J = 8.3 Hz; 1 H; H-5) ; 6.15 (d; 3JAX = 12.5 Hz; 1 H; H-7) ; 3.01 (s; 6H; CH3).
dimethyl 2-(3-nitropyridin-2-yl)malonate[ No CAS ]
[ 18699-87-1 ]
Yield
Reaction Conditions
Operation in experiment
92%
A modified procedure of Cash et al. (Org. Biomol. Chem. 2005, 3. 3701-3706) was used. Di- methyl-2-(3-nitropyridin-2-yl)malonate (1.4 g, 5.5 mmol) was dissolved in 70 ml 6 M HC1 and refluxed for 8 h. After neutralization with saturated Na2C03 solution the solution was extracted three times with dichloromethane. The combined organic layers were dried over Na2S04, filtered, concentrated and purified by bulb tube distillation (0.35 mbar; 70-80C). 2-Methyl-3-nitropyridine (0.7 g, 5.1 mmol, 92 %) was obtained as a pale yellow oil. ]H NMR (300 MHz, CDC13) 8.72 (pdd; 3J = 1.2 Hz; 3J = 4.7 Hz; 1H; H-6); 8.27 (pdd; 3J = 1.2 Hz; 3J = 8.2 Hz; 1H; H-4); 7.35 (pdd; 3J = 4.7 Hz; 3J = 8.2 Hz; 1H; H-5); 2.86 (s; 3H; CH3).
92%
With hydrogenchloride; In water; for 8h;Reflux;
(b) 2-Methyl-3-nitropyridine A modified procedure of ) was used. Dimethyl-2-(3-nitropyridin-2-yl)malonate (1.4 g, 5.5 mmol) was dissolved in 70 ml 6 M HCl and refluxed for 8 h. After neutralization with saturated Na2CO3 solution the solution was extracted three times with dichloromethane. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by bulb tube distillation (0.35 mbar; 70-80C). 2-Methyl-3-nitropyridine (0.7 g, 5.1 mmol, 92 %) was obtained as a pale yellow oil. 1H NMR (300 MHz, CDCl3) 8.72 (pdd; 3J = 1.2 Hz; 3J = 4.7 Hz; 1H; H-6); 8.27 (pdd; 3J = 1.2 Hz; 3J = 8.2 Hz; 1H; H-4); 7.35 (pdd; 3J = 4.7 Hz; 3J = 8.2 Hz; 1H; H-5); 2.86 (s; 3H; CH3).
(b) 2-Methyl-3-nitropyridine A modified procedure of ) was used. Dimethyl-2-(3-nitropyridin-2-yl)malonate (1.4 g, 5.5 mmol) was dissolved in 70 ml 6 M HCI and refluxed for 8 h. After neutralization with saturated Na2CO3 solution the solution was extracted three times with dichloromethane. The combined organic layers were dried over Na2S04, filtered, concentrated and purified by bulb tube distillation (0.35 mbar; 70-80C). 2-Methyl-3-nitropyridine (0.7 g, 5.1 mmol, 92 %) was obtained as a pale yellow oil.'H NMR (300 MHz, CDCl3) 8.72 (pdd; 3J = 1.2 Hz; 3J = 4.7 Hz; 1 H; H-6); 8.27 (pdd; 3J = 1.2 Hz; 3J = 8.2 Hz; 1 H; H-4); 7.35 (pdd; 3J = 4.7 Hz; 3J = 8.2 Hz; 1 H; H-5); 2.86 (s; 3H; CH3).
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