* 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.
Stage #1: With water; tin(ll) chloride In ethyl acetate at 70℃; for 1 h; Stage #2: With sodium carbonate In water; ethyl acetate at 20℃;
Tin(ll)chloride dihydrate (6 g, 26.52 mmol) was added to a solution of 2-chloro-6-methoxy- 3-nitropyridine (1 g, 5.30 mmol) in ethyl acetate (15 ml.) and the resultant suspension heated at 70 °C with stirring for 1 h. The reaction mixture was cooled to ambient temperature, the pH adjusted to pH 9-10 by addition of saturated sodium carbonate (aq.) and extracted with ethyl acetate (3 x 5OmL). The combined extracts were dried (MgSO4) and concentrated in vacuo to give the crude product. Purification by chromatography on silica gel with EtOAc:heptane (3:7, v/v) as eluent afforded the product as a pale yellow oil (600 mg, 72 percent). Data for S-amino-σ-chloro-e-methoxypyridine: MS (ESI) m/z: 159 ([M+H]+).
69%
With hydrogen In ethanol; ethyl acetate at 15 - 25℃;
A solution of 2-chloro-6-methoxy-3-nitropyridine (1.0 g, 5.3 mmol) in EtOH (50 ml)/EtOAc (50 ml) is hydrogenated at RT and 40 psi, in the presence of 10percent Pd-C (0.394 g, 0.37 mmol). The suspension is filtered through cellulose and washed with EtOH. The solution is concentrated under vacuum to give a brown oil 0.58 g (69percent yield) that is used without further purification in the next step. MS (ESI+) for C6H7ClN2O m/z 159.0 (M+H)+. Example 310 (from 2-chloro-6-methoxypyridin-3-amine and 2-isocyanato-5-(trifluoromethyl)-1,3,4-thiadiazole) is prepared by following Method C, making non-critical modifications. The solid is triturated with CH2Cl2 to give a white solid 0.104 g (47percent yield). HRMS (ESI) calcd for C10H7N5O2SClF3+H 354.0039, found 354.0046.
Example 26; 6- [({2- [6-(methyloxy)-3-oxopyrido [2,3-b] pyrazin-4(3H)-yl] -5,6,7,8- tetrahydro-6-quinazolinyl}amino)methyl]-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one hydrochloride; (a) 6-(Methyloxy)-3 -nitro-2-pyridinamine; A solution/suspension of 2-chloro-6-(methyloxy)-3-nitropyridine (65.7 g, 348 mmol) in 2M ammonia in methanol (500 ml, 1000 mmol) and aqueous ammonia (500 ml, 348 mmol) was stirred at 65°C for 18h. The reaction was cooled down and the solid filtered off and washed with water (2x100ml). The solid was dried in the vacuum oven at 4O0C overnight to afford the product as a bright yellow solid (52.14g, 84percent purity by NMR, 74percent). MS (ES+) m/z 170 (MH+).
74%
With ammonia In methanol at 65℃; for 18 h;
Example 13A; (lR)-l-({4-[([l,3]Oxathiolo[5,4-c]pyridin-6-ylmethyl)amino]-l- piperidinyl}methyl)-l,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione hydrochloride; <n="57"/>(a) 6-(Methyloxy)-3 -nitro-2-pyridinamine; A solution/suspension of 2-chloro-6-(methyloxy)-3-nitropyridine (65.7 g, 348 mmol) in 2M ammonia in methanol (500 ml, 1000 mmol) and aqueous ammonia (500 ml, 348 mmol) was stirred at 65 0C for 18h. The reaction was cooled down and the solid filtered off and washed with water (2x100ml). The solid was dried in the vacuum oven at 4O0C overnight to afford the product as a bright yellow solid (52.14g, 84percent purity by NMR, 74percent).MS (ES+) m/z 170 (MH+).
74%
With ammonia In DMF (N,N-dimethyl-formamide); water at 70℃; for 4.25 h;
Preparation Example 1; '6-Methoxy-3-nitro-2-pyridineamine [Formula 50]; A solution of 2-chloro-6-methoxy-3- nitropyridine (25.3 g, 0.134 mol) and a concentrated aqueous ammonia solution (70 ml) in N,N- dimethylformamide (200 ml) was stirred at 70°C for 4 hours and 15 minutes. The reaction mixture was cooled to room temperature and then diluted with water. The resulted precipitate was collected by filtration to yield the title compound (16.8 g, 99.2 mmol, 74.0percent) as a yellow solid. 1H NMR(400 MHz, DMSO-d6) No.ppm; 3.90(3H, s), 6.16(lH, d, J=9Hz), 8.16 (2H, br s), 8.26(lH, d, J=9Hz).
86%
With pyridine; ammonium carbonate In dichloromethane
A. 6-Methoxy-3-nitro-pyridin-2-ylamine. Scheme 8. To a glass pressure vessel was added 2-chloro-6-methoxy-3-nitro-pyridine (10.0 g, 53 mmol), ammonium carbonate (12.4 g, 159 mmol) and pyridine (100 mL). The mixture was heated at 40° C. for 24 h. The reaction mixture was concentrated in vacuo, and the residue was taken up in CH2Cl2 and chromatographed (silica gel; CH2Cl2) yielding 7.6 g (86percent) of 6-methoxy-3-nitro-pyridin-2-ylamine. HPLC: Rt=7.89. 1H NMR (400 MHz, DMSO-d6): 8.26 (d, J=9.1 Hz, 1H), 8.17 (br s, 2H), 6.15 (d, J=9.1 Hz, 1H), 3.89 (s, 3H).
With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 2.5 h;
To a 500 mL four-neck flask were treated with THF (120 mL), MeOH (3.66 g, 115 mmol, 0.95 eq) and 2,6-dichloro-3-nitropyridine (23 g, 120 mmol, 1 eq). After cooling down to 0 oC, 60percent NaH (6.8 g, 170 mmol, 1.7 eq) was added carefully. The mixture was stirred at this temperature for 30 minutes, then at RT for 2 hours. After completion, the mixture was quenched with water (100 mL), extracted with EA (3×150 mL), the combined organic layers were dried, concentrated and purified by silica column to give 2-chloro-6-methoxy-3-nitropyridine (12 g, 56percent). 1HNMR (300 MHz, CDCl3): G 8.37- 8.24 (m, 1 H), 7.07- 7.05 (m, 1 H), 4.15 (s, 3 H).
Stage #1: at 90℃; for 3 h; Stage #2: With sodium hydroxide In water
A suspension of 2-chloro-6-methoxy-3-nitropyridine (20.85 g, 110.57 mmol) in concentrated hydrochloric acid (37percent) (171 mL, 5528.49 mmol) was stirred at 90 0C for 3 hours and allowed to cool to ambient temperature. The suspension was adjusted to pH 5 with 2M NaOH and the aqueous mixture was then continually extracted with EtOAc (250 mL). The organics were concentrated to afford a yellow solid which was filtered off and washed with Et2ψ (200 mL). The solid was stirred in EtOAc (200 mL) and the green insoluble solid filtered off. Both filtrates were combined and dried (MgSO4) before <n="144"/>concentrating to yield as 6-chloro-5-nitropyridin-2-ol a yellow solid (14.7 g, 84.22 mmol, 76 percent).1R NMR (400 MHz, DMSOd6) δ 6.52 (IH, d), 8.26 (IH, d), no OH peak observed, m/z 173 (M-H)"
60%
at 90℃; for 16 h;
A mixture of 2-chloro-6-methoxy-3-nitropyridine (5 g, 10.61 mmol) in HCl solution (12 M, 60 mL) was stirred at 90° C. for 16 h. Then the reaction mixture was neutralized with NaOH carefully and extracted with EtOAc (100 mL*2). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to yield 6-chloro-5-nitropyridin-2-ol (2.8 g, 60percent) as red solid which was used in the following reaction without further purification. MS: m/z=197.1 [M+Na]+.
Step 1: The reaction was performed in three identical experiments of equal size: <strong>[38533-61-8]2-chloro-6-methoxy-3-nitropyridine</strong> (altogether 15.0 g, 79.6 mmol), copper(I)-iodide (6.06 g, 31.8 mmol, 1.2 eq.) and potassium fluoride (3.08 g, 53.0 mmol, 2.0 eq.) were suspended in DMF (30 ml), and methyl chlorodifluoroacetate (7.1 ml, 66.3 mmol, 2.5 eq.) was added. The mixture was stirred at 125C for 13 h and was allowed to cool to room temperature. The reaction mixture was poured into a mixture of conc. aq. NH3-solution (140 ml) and saturated aq. NH4Cl-solution (210 ml), and the deep-blue solution was stirred for 1.5 h at room temperature. Extraction with EA (3x150ml) was followed by washing of the combined organic layer with 1/4-saturated NaCl-solution (100 ml) and brine (2*50 ml), drying over Na2SO4 and evaporation of the solvent. The crude product (20 g) was purified by flash chromatography (eluent hexane/DCM 6:1 to 4:1) to give 14.0 g (62.9 mmol, 79%) of 6-methoxy-3-nitro-2-(trifluoromethyl)pyridine as a yellow oil. TLC (hexane/DCM 4:1) Rf: 0.29. 1H-NMR (method B, DMSO-d6): 8.53 (dd, J = 0.5, 9.0, 1H), 7.39 (dd, J = 0.4, 9.0, 1H), 4.02 (s, 3H).
71%
General procedure: To a solution of <strong>[38533-61-8]2-chloro-6-methoxy-3-nitropyridine</strong> (0.6 g, 3.2 mmol) in DMF (1.2 mL) were added Cul (0.73 g, 3.8 mmol) and KF (0.37 g, 6.4 mmol), followed by methyl chlorodifluoro acetate (1.15 g, 7.97 mmol). The reaction mixture was heated for 13 h at 120C. The reaction mixture was then cooled to room temperature and poured onto a mixture of NH4OH and saturated aqueous NH4CI solution (1 : 1). The resulting solution was stirred for 1.5 h at room temperature. The organic layer was washed with water and brine, dried over sodium sulphate and concentrated. The crude material obtained was purified by column chromatography (silica: 100-200 mesh, DCM:hexane 3- 4%) to afford the title compound (0.5 g, 71%) as a colourless oil. 5H (CDCI3) 8.17 (d, J 8.9 Hz, 1H), 7.03 (d, J 8.9 Hz, 1H), 4.09 (s, 3H).
71%
With potassium fluoride; copper(l) iodide; In N,N-dimethyl-formamide; at 120℃; for 13h;
Intermediate 69 6-Methoxy-3-nitro-2-(trifluoromethyl)pyridine [0290] To a solution of <strong>[38533-61-8]2-chloro-6-methoxy-3-nitropyridine</strong> (0.6 g, 3.2 mmol) in DMF (1.2 mL) were added CuI (0.73 g, 3.8 mmol) and KF (0.37 g, 6.4 mmol), followed by methyl chlorodifluoroacetate (1.15 g, 7.97 mmol). The reaction mixture was heated for 13 h at 120 C. The reaction mixture was then cooled to room temperature and poured onto a mixture of NH4OH and saturated aqueous NH4Cl solution (1:1). The resulting solution was stirred for 1.5 h at room temperature. The organic layer was washed with water and brine, dried over sodium sulphate and concentrated. The crude material obtained was purified by column chromatography (silica: 100-200 mesh, DCM: hexane 3-4%) to afford the title compound (0.5 g, 71%) as a colourless oil. deltaH (CDCl3) 8.17 (d, J=8.9 Hz, 1H), 7.03 (d, J=8.9 Hz, 1H), 4.09 (s, 3H).
65%
With potassium fluoride;copper(l) iodide; In DMF (N,N-dimethyl-formamide); at 130℃; for 8h;
2-Chloro-6-methoxy-3-nitropyridine (5g) was heated with Cul (6.05g), KF (anhydrous, 3. 0G), methyl 2-chloro-2, 2-difluoroacetate (6. 8ml) in DMF (28MOI) at 130OC for 8hrs. After cooling, it was poured into 1: 9 mixture of NH4OH/NH4Cl(100ml), stirred until homogeneous and extracted with Ethyl acetate. The organic layer were combined, washed with brine and dried (MGS04), The flash column chromatography (SIO2, 1-3% EtOAc in heptane) yielded 3.90g (65%). 1H NMR (CDCL3) No. 4. 02,6. 96,8. 10 ; IR (LIQ.) 2389 (w), 2254 (w), 2196 (w), 2163 (w), 2017 (w), 1605 (s), 1586 (s), 1538 (s), 1482 (s), 1340 (s), 1290 (s), 1261 (s), 1205 (s), 1180 (s), 1155 (s) CM-1 ANAL. CALCD for G7 H5 F3 N2 Os : C, 37.85 ; H, 2.27 ; N, 12.61 ; F, 25. 66. Found: C, 37.68 ; H, 2.29 ; N, 12.30.
42.5%
2-Chloro-6-methoxy-3-nitro-pyridine (3g, 15.9mmol), Cul (3.63g, 36.7mmol), anhydrous KF (1.8g, 31mmol) and dry DMF (20ml) were placed in a reaction vessel followed by the addition of chloro-difluoro-acetic acid methyl ester (5.61g, 38.8mmol). The mixture was stirred at 127-130 C for 8 h under an atmosphere of nitrogen. The mixture was allowed cool to room temperature, poured into a mixture of aqueous NH4OH (25ml) and NH4Cl (40g), stirred for 0.5h and extracted with ethyl acetate. The extract was dried over anhydrous Na2SO4, filtered and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica (eluent hexanes: chloroform 10:9) to give 1.5g (42.5%) of 6-methoxy-2-trifluoromethyl-3-nitro-pyridine as colourless oil.
Example 26; 6- [({2- [6-(methyloxy)-3-oxopyrido [2,3-b] pyrazin-4(3H)-yl] -5,6,7,8- tetrahydro-6-quinazolinyl}amino)methyl]-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one hydrochloride; (a) 6-(Methyloxy)-3 -nitro-2-pyridinamine; A solution/suspension of 2-chloro-6-(methyloxy)-3-nitropyridine (65.7 g, 348 mmol) in 2M ammonia in methanol (500 ml, 1000 mmol) and aqueous ammonia (500 ml, 348 mmol) was stirred at 65C for 18h. The reaction was cooled down and the solid filtered off and washed with water (2x100ml). The solid was dried in the vacuum oven at 4O0C overnight to afford the product as a bright yellow solid (52.14g, 84% purity by NMR, 74%). MS (ES+) m/z 170 (MH+).
74%
With ammonia; In methanol; at 65℃; for 18h;
Example 13A; (lR)-l-({4-[([l,3]Oxathiolo[5,4-c]pyridin-6-ylmethyl)amino]-l- piperidinyl}methyl)-l,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione hydrochloride; <n="57"/>(a) 6-(Methyloxy)-3 -nitro-2-pyridinamine; A solution/suspension of 2-chloro-6-(methyloxy)-3-nitropyridine (65.7 g, 348 mmol) in 2M ammonia in methanol (500 ml, 1000 mmol) and aqueous ammonia (500 ml, 348 mmol) was stirred at 65 0C for 18h. The reaction was cooled down and the solid filtered off and washed with water (2x100ml). The solid was dried in the vacuum oven at 4O0C overnight to afford the product as a bright yellow solid (52.14g, 84% purity by NMR, 74%).MS (ES+) m/z 170 (MH+).
74.0%
With ammonia; In DMF (N,N-dimethyl-formamide); water; at 70℃; for 4.25h;
Preparation Example 1; '6-Methoxy-3-nitro-2-pyridineamine [Formula 50]; A solution of 2-chloro-6-methoxy-3- nitropyridine (25.3 g, 0.134 mol) and a concentrated aqueous ammonia solution (70 ml) in N,N- dimethylformamide (200 ml) was stirred at 70C for 4 hours and 15 minutes. The reaction mixture was cooled to room temperature and then diluted with water. The resulted precipitate was collected by filtration to yield the title compound (16.8 g, 99.2 mmol, 74.0%) as a yellow solid. ¹H NMR(400 MHz, DMSO-d6) No.ppm; 3.90(3H, s), 6.16(lH, d, J=9Hz), 8.16 (2H, br s), 8.26(lH, d, J=9Hz).
7.6 g (86%)
With pyridine; ammonium carbonate; In dichloromethane;
A. 6-Methoxy-3-nitro-pyridin-2-ylamine. Scheme 8. To a glass pressure vessel was added 2-chloro-6-methoxy-3-nitro-pyridine (10.0 g, 53 mmol), ammonium carbonate (12.4 g, 159 mmol) and pyridine (100 mL). The mixture was heated at 40 C. for 24 h. The reaction mixture was concentrated in vacuo, and the residue was taken up in CH2Cl2 and chromatographed (silica gel; CH2Cl2) yielding 7.6 g (86%) of 6-methoxy-3-nitro-pyridin-2-ylamine. HPLC: Rt=7.89. 1H NMR (400 MHz, DMSO-d6): 8.26 (d, J=9.1 Hz, 1H), 8.17 (br s, 2H), 6.15 (d, J=9.1 Hz, 1H), 3.89 (s, 3H).
With ammonia; In water; for 72h;
The regioisomeric imidazopyridine 32 was prepared by using functional group interconversions of the commercially available pyridine 28 as described in preceding schemes leading to the diaminopyridine intermediate 30 in good yield. The diaminopyridine 30 was then oxidatively condensed with the appropriate benzaldehyde. Finally, the nitrile was hydrolyzed to the primary amide by treatment with BF3AE2AcOH affording the compound 32.
With ammonia; In methanol; water; at 65℃; for 18h;
a) 6-(Methyloxy)-3 -nitro-2-pyridinamine <n="49"/>A solution/suspension of 2-chloro-6-(methyloxy)-3-nitropyridine (65.7 g, 348 mmol) in 2M ammonia in methanol (500 ml, 1000 mmol) and aqueous ammonia (500 ml, 348 mmol) was stirred at 65 0C for 18h. The reaction was cooled down and the solid filtered off and washed with water (2x100ml). The solid was dried in the vacuum oven at 4O0C overnight to afford the product as a bright yellow solid (52.14g, 84% purity by NMR, 74%). MS (ES+) m/z 170 (MH+).
With ammonia; In methanol; water; at 65℃; for 18h;
Example 11; Compound: Synthesis of (1R)-1-[4-([6-(trifluoromethyl)-3-pyridinyl]methyl}amino)-1-piperidinyl]methyl}-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione, using Preparative Scheme (2) (a) 6-(Methyloxy)-3-nitro-2-pyridinamineA solution/suspension of 2-chloro-6-(methyloxy)-3-nitropyridine (65.7 g, 348 mmol) in 2M ammonia in MeOH (500 ml, 1000 mmol) and aqueous ammonia (500 ml, 348 mmol) was stirred at 65 C. for 18 h. The reaction was cooled down and the solid filtered off and washed with water (2×100 ml). The solid was dried in the vacuum oven at 40 C. overnight to afford the product as a bright yellow solid (52.14 g, 84% purity by NMR, 74%).[ES MS] m/z 170 (MH+).
2.A
A) Synthesis of 2-[butyl-(6-methoxy-3-nitro-2-pyridyl)amino]ethanol 1.9 g (0.01 mol) of the product 2-chloro-3-nitro-6-methoxypyridine, 30 ml of dioxane, 5 ml of water and 2.62 ml (0.02 mol) of 2-butylaminoethanol are placed in a fully equipped round-bottomed flask. The mixture is refluxed for 2 hours with stirring and is then poured onto an ice/water mixture with stirring. The precipitate formed is filtered off by suction and dried under vacuum to constant weight. 1.9 g of yellow powder are obtained, ie a yield of 70%.
A) Synthesis of 3-[(6-methoxy-3-nitro-2-pyridyl)methyl-amino]propane-1,2-diol 4 g (0.0219 mol) of the product 2-chloro-3-nitro-6-methoxypyridine, 50 ml of ethanol and 4.15 ml (0.0438 mol) of 3-methylamino-1,2-dihydroxypropane are placed in a fully equipped round-bottomed flask. The mixture is refluxed for 2 hours with stirring and is then poured onto an ice/water mixture with stirring. The precipitate formed is filtered off by suction and dried under vacuum to constant weight. 4.74 g of yellow powder are obtained, ie a yield of 87.1percent.
With potassium hydroxide In N,N-dimethyl-formamide at 5 - 20℃;
1.1
6-methoxy-2-(4-methyl-2-propyl-imidazol-1-yl)-3-nitro-pyridine To a suspension prepared of 20.0 g KOH (solid), 25.8 g 4-methyl-2-propyl imidazole and 130 ml dimethyl formamide (DMF) were added 38.0 g 2-chloro-6-methoxy-3-nitro pyridine in small amounts at a reaction temperature of 5° C. The reaction mixture was stirred for 75 minutes at room temperature (RT). Then the reaction mixture was poured in 600 ml water. The mixture was further stirred for 1 hr. The desired product precipitated during this time. The resulting solid was collected by filtration, washed with 100 ml water (3 times) and dried in a dry box with vacuum (40° C.). Yield: 40 g; m.p.: 96-103° C.
Stage #1: 4-methyl-2-propyl-1H-imidazole With potassium hydroxide In N,N-dimethyl-formamide at 0℃; for 0.166667h;
Stage #2: 2-chloro-6-methoxy-3-nitropyridine In N,N-dimethyl-formamide at 20℃; for 2h;
With potassium hydroxide In N,N-dimethyl-formamide at 5 - 20℃; for 1.25h;
1
To a suspension prepared of 20.0 g KOH (solid), 25.8 g 4-methyl-2-propyl imidazole and 130 ml dimethyl formamide were added 38.0 g 2-chloro-6- methoxy-3-nitro pyridine in small amounts at a reaction temperature of 5°C.The reaction mixture was stirred for 75 minutes at room temperature. Then the reaction mixture was poured in 600 ml water. The mixture was further stirred for 1 hr. The desired product precipitated during this time. The resulting solid was collected by filtration, washed with 100 ml water for 3 times and dried in a dry box with vacuum (400C).Yield: 4O g m.p.: 96-103°C
N-isobutyl-3-nitro-6-methoxypyridin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With triethylamine; In N,N-dimethyl-formamide;
Add to a 250 mL round bottom flask equipped with a magnetic stirrer and drying tube2-chloro-3-nitro-6-methoxypyridin-2-amine (4.98 g, 26.41 mmol),Triethylamine (2.67 g, 26.41 mmol) and N,N-dimethylformamide (40 mL), after stirring for 15 min,A solution of isobutylamine (1.93 g, 26.41 mmol) and N,N-dimethylformamide (10 mL) was added dropwise under a water bath, and the reaction was continued for 2-3 hrs.The reaction solution was poured into water, and the solid was precipitated, filtered, and washed with water three times (3×100 mL).Dry filtration to obtain a yellow solid 5.0 g, purity: 98%, yield: 82%.
In N,N-dimethyl-formamide; at 0℃; for 0.5h;
Example 4: 5-Methoxy-2-[2-(5-phosphono)furanyl] imidazo[4,5-b]pyridine; Step A: General procedure of alkylamine substitution of alpha-halopyridine:; To a solution of 20 mmol of substituted alpha-halopyridine in 70 mL of DMF was added 35 mmol of alkyl or arylamine at 0 0C. After 0.5 h TLC indicated the completion of reaction. The reaction mixture was then evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water. The organic layer was dried, and evaporated to yield the displacement products.
Preparation 51; 6-Methoxy-2-(methylthio)-3-nitropyridine; Sodium methanethiolate (2.59g, 37mmol) was added to an ice-cold suspension of 2-chloro-6-methoxy-3- nitropyridine (7.26g, 38.5mmol) in tetrahydrofuran (2OmL) and the mixture was stirred for 5 hours at room temperature. Further sodium methanethiolate (1.3g, 18.5mmol) was added and the mixture was stirred for an additional 18 hours at room temperature. The reaction mixture was then diluted with dichloromethane (25OmL), washed with water (25OmL), dried over sodium sulfate and concentrated in vacuo to afford the title compound in 94% yield, 7.23g.1HNMR(400MHz, CDCI3) delta: 2.59(s, 1H), 4.08(s, 1 H), 6.52(d, 1 H), 8.41(d, 1 H); LRMS APCI m/z 201 [M+H]+
59%
In dimethyl sulfoxide; at 80℃; for 4h;
To a solution of <strong>[38533-61-8]2-chloro-6-methoxy-3-nitropyridine</strong> (2.0 g, 10.6 mmol) in DMSO (70 ml) is added sodium thiomethoxide (0.743 g, 10.6 mmol). The reaction mixture is stirred at 80 C. for 4 hr. The mixture is diluted with H2O, extracted with EtOAc, and the combined organic layers are dried (MgSO4), filtered, and concentrated under vacuum. The residue is purified by silica gel chromatography (20% EtOAc/n-heptane) followed by trituration with CH2Cl2/MeOH to afford a yellow solid 1.26 g (59% yield). HRMS (EI) calcd for C7H7N2O3S 200.0262, found 200.0262. 6-Methoxy-2-(methylthio)pyridin-3-amine (from 6-methoxy-2-(methylthio)-3-nitropyridine) is prepared by following Step 3 of Example 155, making non-critical modifications to afford a brown solid 0.6 g (86% yield). This compound is used without further purification in the next step. MS (ESI+) for C7H10N2OS m/z 171.0 (M+H)+. Example 311 (from 6-methoxy-2-(methylthio)pyridin-3-amine and 2-isocyanato-5-(trifluoromethyl)-1,3,4-thiadiazole) is prepared by following Method C, making non-critical modifications. The resulting residue is purified by silica gel chromatography (50% EtOAc/n-heptane) followed by trituration with CH2Cl2 to give a white solid 0.265 g (62% yield). HRMS (EI) calcd for C11H10F3N5O2S2 365.0228, found 365.0230.
59%
In methanol; at 0 - 20℃; for 17h;
[00584] A methanol (100 ml) solution of <strong>[38533-61-8]2-chloro-6-methoxy-3-nitropyridine</strong> (2.0 g, 10.4 mmol) was added dropwise to a methanol (20 ml) solution of sodium thiomethoxide (805 mg, 10.9 mmol) while being cooled with ice, and the temperature thereof was raised to the room temperature and the mixed solution was stirred for 17 hours and the precipitated crystal was filtered to obtain 1.26 g (yield 59%) of 6-methoxy-2-methylthio-3-nitropyridine as a yellow powdery crystal.
Tin(ll)chloride dihydrate (6 g, 26.52 mmol) was added to a solution of 2-chloro-6-methoxy- 3-nitropyridine (1 g, 5.30 mmol) in ethyl acetate (15 ml.) and the resultant suspension heated at 70 C with stirring for 1 h. The reaction mixture was cooled to ambient temperature, the pH adjusted to pH 9-10 by addition of saturated sodium carbonate (aq.) and extracted with ethyl acetate (3 x 5OmL). The combined extracts were dried (MgSO4) and concentrated in vacuo to give the crude product. Purification by chromatography on silica gel with EtOAc:heptane (3:7, v/v) as eluent afforded the product as a pale yellow oil (600 mg, 72 %). Data for S-amino-?-chloro-e-methoxypyridine: MS (ESI) m/z: 159 ([M+H]+).
69%
With hydrogen;10% palladium on activated carbon; In ethanol; ethyl acetate; at 15 - 25℃; under 2068.65 Torr;
A solution of 2-chloro-6-methoxy-3-nitropyridine (1.0 g, 5.3 mmol) in EtOH (50 ml)/EtOAc (50 ml) is hydrogenated at RT and 40 psi, in the presence of 10% Pd-C (0.394 g, 0.37 mmol). The suspension is filtered through cellulose and washed with EtOH. The solution is concentrated under vacuum to give a brown oil 0.58 g (69% yield) that is used without further purification in the next step. MS (ESI+) for C6H7ClN2O m/z 159.0 (M+H)+. Example 310 (from 2-chloro-6-methoxypyridin-3-amine and 2-isocyanato-5-(trifluoromethyl)-1,3,4-thiadiazole) is prepared by following Method C, making non-critical modifications. The solid is triturated with CH2Cl2 to give a white solid 0.104 g (47% yield). HRMS (ESI) calcd for C10H7N5O2SClF3+H 354.0039, found 354.0046.
With tin(ll) chloride; In ethyl acetate; for 16h;Heating / reflux;
Reflux a mixture of 2-CHLORO-6-METHOXY-3-NITRO-PYRIDINE (7 g, 0. 37 mol) with 3 equivalents of SNC12 (22 g, 0. 111 mol) in ethyl acetate (150 mL) for 16 hours. Partition the mixture between ethyl acetate and IN NaOH. Separate the organic layer, dry (NA2SO4) and concentrate under reduced pressure. Purify the residue by filtering through a plug of silica gel using ethyl acetate as eluent to afford the title compound.
With hydrogen;platinum(IV) oxide; In ethanol; under 988.066 Torr; for 2h;
The 4-chloro-6-methoxy-l,7-naphthyridine used as a starting material was prepared as follows :; -A mixture of 2-chloro-6-methoxy-3-nitropyridine (5 g), platinum oxide (0.25 g) and ethanol (130 ml) was stirred under 1.3 atmospheres pressure of hydrogen for 2 hours. The catalyst was removed by filtration and the filtrate was evaporated to give 3-amino-2-chloro- 6-methoxypyridine (4.4 g); Mass Spectrum: M+H+ 159.
EXAMPLE 2 Preparation of 2-(1H-6-indazolylamino)-6-methoxy-3-nitropyridine To the solution of <strong>[38533-61-8]2-chloro-6-methoxy-3-nitropyridine</strong> (5 g) and 6-aminoindazole (3.9 g) in methanol (60 ml) was added triethylamine (4.1 ml), and then the solution was reacted at 55-60 C. for 14 hr.. The reaction mixture was cooled at room temperature, added H2O 30 mi slowly at 25 C., and then stirred for 0.5 hr.. The reaction mixture was filtered, washed with 50% aqueous methanol solution (15 ml) and obtained a solid product.. The solid product was dried at 50 C. in vacuo to obtain the desired compound (6.8 g, 90%). [00067] m.p.: 261264 C. [00068] 1H-NMR (DMSO-d6), ppm: delta 3.94(s, 3H), 6.39(d, 1H), 7.24(m, 1H), 7.71(d, 1H), 8.01(s, 1H), 8.19(s, 1H), 8.44(d, 1H), 10.62(s, 1H), 13.04(br s, 1H)
EXAMPLE 1 Preparation of 2-(1H-5-indazolylamino)-6-methoxy-3-nitropyridine To the solution of <strong>[38533-61-8]2-chloro-6-methoxy-3-nitropyridine</strong> (5 g) and 5-aminoindazole (3.7 g) in methanol (60 ml) was added triethylamine (4.1 ml), and then the solution was reacted at 25-30 C. for 5 hr.. The reaction mixture was cooled at room temperature with slowly adding H2O (30 ml), and then stirred for 0.5 hr.. The reaction mixture was filtered, washed with methanol (10 ml), obtained a solid product.. The solid product was dried at 50 C. in vacuo to obtain the desired compound (6.5 g, 86%). [00064] m.p.: 206208 C. [00065] 1H-NMR (DMSO-d6), ppm: delta 3.80(s, 3H), 6.32(d, 1H), 7.55(m, 2H), 8.06(s, 2H), 8.43(d, 1H), 10.52(s, 1H), 13.09(br s, 1H)
With copper; In ISOPROPYLAMIDE; at 20 - 100℃; for 8h;
To a solution of 2-chloro-3-nitro-5-methoxypyridine (500 mg, 2.6 MMOL) in DMA (5 mL), at r. t. , under N2, were added Cu (1 g, 6 eq) and CF2Br2 (500 muL, large excess). The reaction mixture was stirred at 100C for 8 hr. The brown slurry obtained was extracted with ETAO (3X50 mL). The combined organic extracts were dried under vacuum and the crude product was purified by flash chromatography (silica gel, CHSCTS 100%) to give the title compound (316 mg, 53%) as a brown oil. NMR (1H, CDCI3) : 8 8.35 (d, 1H), 7.2 (d, 1H), 4.3 (s, 3H).
With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 70℃; for 14h;
3a 3-Nitro-2- (3-trifluoromethyl-phenoxy)-pyridine [00299] A solution of <strong>[38533-61-8]2-chloro-6-methoxy-3-nitropyridine</strong> (20 g, 125 mmol) in DMF (120 mL) was treated with 3-trifluoromethylphenol (21 g, 129 mmol) and cesium carbonate (50 g, 154 mmol). The mixture was heated at 70C for 14 h. The reaction was concentrated. The residue was dissolved in ethyl acetate and washed with brine, 5% lithium chloride, and aqueous HCI and brine. After concentration, purification was achieved by column chromatography on silica gel using a continuous gradient from 0% to 40% ethyl acetate in hexanes as eluant afforded 21 g (60%-yield) of 3a as a white crystals. [M+H] + = 285.17.
With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 80℃; for 18h;
2a 2- (2-tert-Butyl-phenoxy)-6-methoxy-3-nitro-pyridine [00294] A solution of <strong>[38533-61-8]2-chloro-6-methoxy-3-nitropyridine</strong> (5.20 g, 27.6 mmol) in DMF (50 mL) was treated with 2-tert-butylphenol (4.9 mL, 31.7 mmol) and cesium carbonate (27.0 g, 82. 8 mmol). The mixture was heated at 80C for 18 h. The reaction was allowed to cool to rt, the mixture was poured into water (500 mL) with stirring. The brown precipitate formed was filtered and washed with water, and recrystallized twice from ethanol to afford 2a as brown crystals (6.66 g, 80%). [M+H] + = 303.2.
With triethylamine; In acetonitrile; at 90℃; for 72h;
Step 1; To a solution of 1.28 g (6 mmol) of (4-amino-cyclohexyl)-carbamic acid tert butyl ester (prepared as described by Anslyn, et al., J. Org. Chem., 1996,8811) in 40 mL of acetonitrile was added TEA (0.87 mL, 6 mmol) and 2-chloro-6-methoxy-3- nitropyridine (1.13 g, 6 mmol). The mixture was heated at 90 C for 3 days. The mixture was cooled, filtered, and the filtrate was concentrated. The residue was digested with 50 mL of hot ethyl acetate, filtered, and concentrated to afford 1.80 g (82%) of [4- (6-methoxy-3-nitro-pyridin-2-ylamino)-cyclohexyl]-carbamic acid tert butyl ester. NMR (CD30D) : 8.55 (br d, 1 H); 8.28 (d, 1 H); 6.61 (br d, 1 H); 6.08 (d, 1 H); 4.14 (m, 1 H); 3.95 (s, 3 H); 3.31 (m, 1 H); 2.15 (m, 2 H) ; 1.94 (m, 2 H) ; 1.55- 1.20 (m, 4 H); 1.42 (s, 9 H). APCI MS: 367 (MH+)
A. A slurry of 2,6-dichloro-3-nitropyridine (92%, 9.9 g, 47 mmol) and K2 CO3 powder (6.5 g, 47 mmol) in methanol (100 mL) was stirred for a week at RT. The reaction was filtered and concentrated. The residue was partitioned in ethyl acetate and 60% sat. aq. NaHCO3. The organic solution was washed with 60% sat. aq. NaHCO3 (2*), H2O, then sat. aq. NaCl, dried (MgSO4) and concentrated to afford 2-chloro-6-methoxy-5-nitropyridine and 2-chloro-6-methoxy-3-nitropyridine (8.9 g, 100%) as a light yellow solid: 1H NMR (CDCl3, 300 MHz, ppm) 8.31 (d, 8.3 Hz, 1H), 8.28 (d, 8.9 Hz, 1H), 7.10 (d, 8.3 Hz, 1H), 6.82 (d, 8.9 Hz, 1H), 4.15 (s, 3H), 4.06 (s, 3H).
100%
In methanol; ethyl acetate;
A. A slurry of 2,6-dichloro-3-nitropyridine (92%, 9.9 g, 47 mmol) and K2 CO3 powder (6.5 g, 47 mmol) in methanol (100 mL) was stirred for a week at RT. The reaction was filtered and concentrated. The residue was partitioned in ethyl acetate and 60% sat. aq. NaHCO3. The organic solution was washed with 60% sat. aq. NaHCO3(2*), H2O, then sat. aq. NaCl, dried (MgSO4) and concentrated to afford 2-chloro-6-methoxy-5-nitropyridine and 2-chloro-6-methoxy-3-nitropyridine (8.9 g, 100%) as a light yellow solid: 1H NMR (CDCl3, 300 MHz, ppm) 8.31 (d, 8.3 Hz, 1H), 8.28 (d, 8.9 Hz, 1H), 7.10 (d, 8.3 Hz, 1H), 6.82 (d, 8.9 Hz, 1H), 4.15 (s, 3H), 4.06 (s, 3H).
6-methoxy-3-nitro-2-n-propylaminopyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With propylamine; In water; isopropyl alcohol;
EXAMPLE 9 6-methoxy-3-nitro-2-n-propylaminopyridine Into a stirred and cooled (water bath) mixture of 188.6 g (1 mole) of <strong>[38533-61-8]2-chloro-6-methoxy-3-nitropyridine</strong> and 200 ml of isopropanol, 141.9 g (2.4 mole) of n-propylamine are added drop by drop in the course of about 3 hours at a maximum temperature of 25 C. Stirring is continued overnight and then 1000 ml of water are added; the precipitated product is filtered off by suction, washed with water and then dried. The product obtained thereby is intensively yellow colored with a melting point of 69-70 C. in a yield of 98% of theory.
Stage #1: 2-chloro-6-methoxy-3-nitropyridine; vinyl magnesium bromide In tetrahydrofuran at -20℃; for 8h;
Stage #2: With water; ammonium chloride In tetrahydrofuran
43.1
Step 1 2-Chloro-6-methoxy-3-nitropyridine (5 g, 0.027 mol) was dissolved in anhydrous tetrahydrofuran (200 mL) under nitrogen and the solution was cooled to -78° C. Excess of vinylmagnesium bromide (1.0 M in tetrahydrofuran, 100 mL, 100 mmol) was added and the reaction mixture was stirred at -20° C. for 8 hours and then the reaction mixture was quenched with 20% aqueous ammonium chloride (150 mL). The aqueous layer was extracted with ethyl acetate and the combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified via Biotage Horizon (FlasH 40 M, silica, gradient from 20% ethyl acetate/hexane to 60% ethyl acetate/hexane) to yield 7-chloro-5-methoxy-1H-pyrrolo[2,3-c]pyridine2 as a yellow solid. MS (ESI) m/z 183 ([M+H]+). 2 Zhang, Z.; et al., J. Org. Chem. 2002, 76, 2345-2347.
In ethanol; water; at 0℃; for 4h;Heating / reflux;
Example 16A; (2R)-2-({4- [( [1 ,3] Oxathiolo [5,4-c] pyridin-6-ylmethyl)amino] - 1- piperidinyl}methyl)-l,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione hydrochloride; <n="65"/>(a) 2- { [6-(Methyloxy)-3 -nitro-2-pyridinyl] amino } - 1 ,3 -propanediol; beta-Methoxy-l-chloro-S-nitropyridine (36.94g, 195.9mmol) and 2-aminopropane- 1.3-diol (35.65g, 391.3mmol, 2 eq.) were stirrred in ethanol (500ml) at reflux under argon for 3 hours. The mixture was allowed to cool to room temperature and left overnight. The solvent was partially removed under reduced pressure (to ca. 150ml) and the resulting bright yellow slurry was poured into ice-water (1.5L) with vigorous stirring. The mixture was stirred for 1 hour then filtered with suction while cold. The solid was washed with ice-cold water (200ml) and air-dried.to give the title compound as a bright yellow solid (45.03g, 94%). LCMS showed desired product (93%) plus 7% starting material. The product was used without further purification. MS (ES+) m/z 244 (MH+)
94%
In ethanol; for 3h;Inert atmosphere; Reflux;
6-Methoxy-2-chloro-3-nitropyridine (36.94g, 195.9mmol) and 2-aminopropane- 1.3-diol (35.65g, 391.3mmol, 2 eq.) were stirrred in ethanol (500ml) at reflux under argon for 3 hours. The mixture was allowed to cool to room temperature and left overnight. The solvent was partially removed under reduced pressure (to ca. 150ml) and the resulting bright yellow slurry was poured into ice-water (1.5L) with vigorous stirring. The mixture was stirred for 1 hour then filtered with suction while cold. The solid was washed with ice-cold water (200ml) and air-dried.to give the title compound as a bright yellow solid (45.03g, 94%). LCMS showed desired product (93%) plus 7% starting material. The product was used without further purification. MS (ES+) m/z 244 (MH+)
88.2%
In ethanol; for 2h;Heating / reflux;
A) Synthesis of 2-(6-methoxy-3-nitro-2-pyridylamino)propane-1,3-diol 4 g (0.0212 mol) of the product 2-chloro-3-nitro-6-methoxypyridine, 40 ml of ethanol and 3.86 g (0.042 mol) of 2-aminopropane-1,3-diol are placed in a fully equipped round-bottomed flask. The mixture is refluxed for 2 hours with stirring and is then poured onto an ice/water mixture with stirring. The precipitate formed is filtered off by suction and dried under vacuum to constant weight. 4.54 g of yellow powder are obtained, ie a yield of 88.2%.
In ethanol; for 3h;Reflux; Inert atmosphere;
Example 2; Compound: Synthesis of (2R)-2-[(4-[(5-chloro-6-methyl-3-pyridinyl)methyl]amino}-1-piperidinyl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione hydrochloride, using Preparative Scheme (1) (a) 2-[6-(Methyloxy)-3-nitro-2-pyridinyl]amino}-1,3-propanediol6-Methoxy-2-chloro-3-nitropyridine (36.94 g, 195.9 mmol) and 2-aminopropane-1,3-diol (35.65 g, 391.3 mmol) were stirred in ethanol (500 ml) at reflux under argon for 3 h. The mixture was allowed to cool to room temperature and left overnight. The solvent was partially removed under reduced pressure (to ca. 150 ml) and the resulting bright yellow slurry was poured into ice-water (1.5 L) with vigorous stirring. The mixture was stirred for 1 h then filtered with suction while cold. The solid was washed with ice-cold water (200 ml) and air-dried to give the title compound as a bright yellow solid (45.03 g, 94%). LCMS showed desired product (93%) plus 7% starting material. The product was used without further purification.[ES MS] m/z 244 (MH+).
A) Synthesis of N-[2-(6-methoxy-3-nitro-2-pyridyl-amino)ethyl]acetamide 4 g (0.0212 mol) of the product 2-chloro-3-nitro-6-methoxypyridine, 50 ml of ethanol and 4.51 ml (0.0424 mol) of N-acetylethane-1,2-diamine are placed in a fully equipped round-bottomed flask. The mixture is refluxed for 2 hours with stirring and is then poured onto an ice/water mixture with stirring. The precipitate formed is filtered off by suction and dried under vacuum to constant weight. 3.9 g of yellow powder are obtained, ie a yield of 72.5%.
With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 20 - 90℃; for 6h;
(d) 1,1 -Dimethylethyl [(3- [6-(methyloxy)-3-nitro-2-pyridinyl]amino} -7,8-dihydro-5H- pyrano [4,3 -b]pyridin- 8 -y l)methyl] carb amate; To a solution of 1,1 -dimethylethyl [(3-amino-7,8-dihydro-5H-pyrano[4,3- b]pyridin-8-yl)methyl]carbamate (3.91 g, 14.00 mmol) in DMF at room temperature under argon was added 2-chloro-6-(methyloxy)-3-nitropyridine (2.64 g, 14.00 mmol) then sodium bicarbonate (2.352 g, 28.0 mmol). The resulting solution was heated to 600C overnight, then at 900C for 6hours. The reaction was concentrated and then diluted with DCM (50ml) and H2O (50ml). The aqueous layer was separated and washed a further three times with DCM (50ml). The organic layers were combined, dried (Na2SO4), filtered and the solvent removed to give a yellow oil (6.6g). This residue was then split into two and purified by chromatography eluting with 0 - 100% EtOAc in hexane then <n="93"/>0% - 20% MeOH in EtOAc affording a yellow oil (4.32g, 72%). MS (ES+) m/z 432 (MH+).
With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 20 - 50℃; for 2h;
(g) 1,1 -Dimethylethyl (2,3-dihydro[ 1 ,4]dioxino[2,3-c]pyridin-7-ylmethyl)(6- { [6- (methyloxy)-3-nitro-2-pyridinyl]amino}-l,2,3,4-tetrahydro-2-naphthalenyl)carbamate; 1,1-Dimethylethyl (6-amino- 1 ,2,3 ,4-tetrahydro-2-naphthalenyl)(2,3- dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)carbamate (2.76g, 6.72mmol) was dissolved in DMF (20ml) at room temperature under argon where 2-chloro-6-methoxy-3- nitropyridine (1.27g, 6.72mmol) and NaHCO3 (1.13g, 13.4mmol) were added. The reaction was then heated to 500C, after 5h the reaction was cooled to room temperature. The reaction was diluted with H2O (40ml) and DCM (40ml). The aqueous layer was separated and washed a further 3 times with DCM (40ml). The organics were combined, dried (Na2SO4), filtered and solvent removed. The residue was then purified using flash column chromatography eluting with 0-100% EtOAc in hexane then 0-20% MeOH in EtOAc gradient to give a yellow / orange solid (3.15g, 83%). MS (ES+) m/z 564 (MH+).
With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 20 - 60℃;
(b) 1,1 -Dimethylethyl (3- { [6-(methyloxy)-3-nitro-2-pyridinyl]amino} -5,6,7,8- tetrahydro-7-quinolinyl)carbamate; To a solution of 1,1 -dimethylethyl (3-amino-5,6,7,8-tetrahydro-7- quinolinyl)carbamate (4.89 g, 18.6 mmol) in DMF (60 niL) at room temperature under argon was added 2-chloro-6-(methyloxy)-3-nitropyridine (3.50 g, 18.6 mmol) then sodium hydrogen carbonate (3.12 g, 37.2 mmol). The resulting reaction mixture was heated at 600C overnight then cooled to room temperature and concentrated. The residue was partitioned between DCM and H2O then separated. The aqueous layer was extracted several times with DCM and the combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated to deliver an orange oil. This residue was divided into two equal portions, and each portion was purified by flash column chromatography eluting with 0-100% EtOAc:Hexane to afford a yellow solid [5.51 g (combined mass), 71%]. MS (ES+) m/z 416 (MH+).
With bis-triphenylphosphine-palladium(II) chloride; In acetonitrile; at 65℃;
Tributyl(l-ethoxyvinyl)tin (395 mL, 1.34 mol) was added into the mixture of L2 (200 g, 1.07 mol) and Pd(PPh3)2Cl2 (7.34 g, 10.67 mmol) in CH3CN (1000 mL) at 65 C. The resulting suspension was stirred at 65 C overnight then cooled to room temperature. The reaction mixture was quenched with 10% KF aqueous solution (670 mL) and stirred at room temperature for 1 h. Then the mixture was filtered, and the filtrate was extracted with EtOAc. The combined organic phases were dried over Na2S04, concentrated and purified by column chromatography to give 230 g of compound L3 in 96% yield. 1H NMR (400 MHz CDC13) delta 7.92 (d, J = 8.8 Hz, 1H), 6.72 (d, J = 8.8 Hz, 1H), 4.96 (s, 1H), 4.48 (s, 1H), 4.00 (s, 3H), 3.90-3.84 (m, 2H), 1.28 (d, J= 7.2 Hz, 3H).
93%
bis-triphenylphosphine-palladium(II) chloride; In acetonitrile; at 65℃; for 6h;
Example 8; (6R)-6-({4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7- ylmethyl)amino]-l-piperidinyl}methyl)-3-fluoro-5,6-dihydro-8H- [l,4]oxazino[2,3,4-flfe]-l,5-naphthyridin-8-one; <n="40"/>(a) 2-[ 1 -(Ethyloxy)ethenyl]-6-(methyloxy)-3-nitropyridineUnder N2 was charged <strong>[38533-61-8]2-chloro-6-methoxy-3-nitropyridine</strong> (600 g, 3.18 mol), MeCN (4200 ml, 7 vol) and PdCl2(PPh3)2 (33.5 g, 477 mmol, 0.015 eq.). The yellow coloured suspension was heated to 65 0C and (l-ethoxyvinyl)-tributyl-stannane (1182 ml, 1264 g, 3.50 mol, 1.1 eq.) was added dropwise over 2 hours, maintaining the temperature at ~65 0C by the rate of addition. The resulting brown coloured suspension was left to stir at 65 0C for 4 hours then left to cool to room temperature, with stirring, overnight. The reaction mixture was quenched with 10 % KF aq. solution (3600 ml, 6 vol) with vigorous stirring and left to stir for 1 hour. The resulting solid was removed by vacuum filtration and washed with MeCN (7 x 1000 ml). The layers were separated and the organic layer was evaporated to 5 volumes (3000 ml). This was filtered through glass microfbre filter paper and the small amount of brown solid removed was washed with MeCN (1800 ml, 3 vol). EtOAc (3600 ml, 6 vol) was added and the volume reduced to 3 volumes (1800 ml). EtOAc (3600 ml) was added and the volume reduced to 3 volumes (1800 ml). Cyclohexane (3600 ml, 6 vol) was added and the volume reduced to 5 volumes (3000 ml). Cyclohexane (2400 ml, 4 vol) and silica gel (600 g, 1 wt) were added and allowed to stir at r.t. for 1.5 h. The solid was removed by vacuum filtration and washed with EtOAc: cyclohexane, 1 :8 (4200 ml, 7 vol). The filtrate was reduced to 3 volumes (1800 ml). Cyclohexane (2400 ml, 4 vol) was added and the volume reduced to 3 volumes (1800 ml). Cyclohexane (3600 ml, 6 vol) and EtOAc (600 ml, 1 vol) and silica gel (600 g, 1 wt) were added and left to stir for 1.5 h. The solid was removed by vacuum filtration and washed with EtOAc: cyclohexane, 1 :8 (4200 ml, 7 vol). The solvents were evaporated to dryness. MeCN (2000 ml) was added and evaporated to give the title compound as an orange coloured oil (93% yield)
To a suspension of <strong>[38533-61-8]2-chloro-6-methoxy-3-nitropyridine</strong> (600 g) and PdCl2(PPh3)2 (33.5 g) in acetonitrile (4200 ml) at 65C under N2 was added dropwise over 2h (1-ethoxyvinyl)-tributyl-stannane (1182 ml). The resulting suspension was stirred at 65 C for 4h then left to cool to room temperature overnight. The reaction mixture was quenched with 10% KF aqueous solution (3600 ml) with vigorous stirring and stirred for 1 h. The resulting solid was removed by vacuum filtration and washed with acetonitrile (7 x 1000 ml). The layers were separated and the organic layer was evaporated to 3000 ml. This was filtered through Whatman, GF/B glass microfibre filter paper and the small amount of brown solid removed was washed with MeCN (1800 ml). EtOAc (3600 ml) was added and the volume reduced to 1800 ml. Cyclohexane (3600 ml) was added and the volume reduced to 3000 ml. Cyclohexane (2400 ml) and silica gel (600 g, 1 wt) were added and allowed to stir at room temperature for 1.5h. The solid was removed by vacuum filtration and washed with EtOAc/cyclohexane, 1:8 (4200 ml). The filtrate was reduced to 1800 ml. Cyclohexane (2400 ml) was added and the volume reduced to 1800 ml. Cyclohexane (3600 ml) and EtOAc (600 ml) and silica gel (600 g, 1 wt) were added and stirred for 1.5h. The solid was removed by vacuum filtration and washed with EtOAc/cyclohexane 1:8 (4200 ml). The solvents were evaporated to dryness. MeCN (2000 ml) was added and evaporated to give an orange coloured oil.
bis-triphenylphosphine-palladium(II) chloride; In acetonitrile; at 20 - 65℃;
2-Chloro-6-methoxy-3-nitropyridine (60Og, 3.18mol) and dichlorobis(triphenylphosphine)palladium (II) (33.5g, 477mmol) were dissolved in acetonitrile (4200ml). The yellow coloured suspension was heated to 650C and (1- ethoxyvinyl)-tributyl-stannane (1182ml, 1264g.) was added dropwise over 2 hours, maintaining the temperature at ~65C by the rate of addition. The resulting brown coloured suspension was left to stir at 650C for 4 hours then left to cool to room temperature, with stirring, overnight.The reaction mixture was quenched with 10% potassium fluoride aq. solution (3600ml) with vigorous stirring and left to stir for 1 hour. The resulting solid was removed by vacuum filtration and washed with acetonitrile (2 x 3000ml). The layers were separated and the organic layer was evaporated to 3000ml. This was filtered, ethyl acetate (3600ml) was added and the volume reduced by rotary evaporation to 1800ml. Cyclohexane (3600ml) was added and the volume reduced by rotary evaporation to 3000ml. Cyclohexane (2400ml) and silica gel (60Og) were added and allowed to stir at r.t. for 1.5 h. The solid was removed by vacuum filtration and washed with ethyl acetate: cyclohexane, 1 :8 (4200ml). The filtrate was reduced to 1800 ml. The last four steps were repeated, and finally the solvents were evaporated. Acetonitrile (2000ml) was added and evaporated to give an orange coloured oil (730.3g, 102.4%).1H NMR confirmed correct structure with ~8% MeCN.
To a suspension of <strong>[38533-61-8]2-chloro-6-methoxy-3-nitropyridine</strong> (600 g) and PdCI2(PPh3)2 (33.5 g) in acetonitrile (4200 ml) at 650C under N2 was added dropwise over 2h (1-ethoxyvinyl)- tributyl-stannane (1182 ml). The resulting suspension was stirred at 65 0C for 4h then left to cool to room temperature overnight. The reaction mixture was quenched with 10% KF aqueous solution (3600 ml) with vigorous stirring and stirred for 1 h. The resulting solid was removed by vacuum filtration and washed with acetonitrile (7 x 1000 ml). The layers were separated and the organic layer was evaporated to 3000 ml. This was filtered through Whatman, GF/B glass microfibre filter paper and the small amount of brown solid removed was washed with MeCN (1800 ml). EtOAc (3600 ml) was added and the volume reduced to 1800 ml. Cyclohexane (3600 ml) was added and the volume reduced to 3000 ml. Cyclohexane (2400 ml) and silica gel (600 g, 1 wt) were added and allowed to stir at room temperature for 1.5h. The solid was removed by vacuum filtration and washed with EtOAc/cyclohexane, 1 :8 (4200 ml). The filtrate was reduced to 1800 ml. Cyclohexane (2400 ml) was added and the volume reduced to 1800 ml. Cyclohexane (3600 ml) and EtOAc (600 ml) and silica gel (600 g, 1 wt) were added and stirred for 1.5h. The solid was removed by vacuum filtration and washed with EtOAc/cyclohexane 1 :8 (4200 ml). The solvents were evaporated to dryness. MeCN (2000 ml) was added and evaporated to give an orange coloured oil.
A suspension of 2-chloro-6-methoxy-3-nitropyridine (20.85 g, 110.57 mmol) in concentrated hydrochloric acid (37%) (171 mL, 5528.49 mmol) was stirred at 90 0C for 3 hours and allowed to cool to ambient temperature. The suspension was adjusted to pH 5 with 2M NaOH and the aqueous mixture was then continually extracted with EtOAc (250 mL). The organics were concentrated to afford a yellow solid which was filtered off and washed with Et2theta (200 mL). The solid was stirred in EtOAc (200 mL) and the green insoluble solid filtered off. Both filtrates were combined and dried (MgSO4) before <n="144"/>concentrating to yield as 6-chloro-5-nitropyridin-2-ol a yellow solid (14.7 g, 84.22 mmol, 76 %).1R NMR (400 MHz, DMSOd6) delta 6.52 (IH, d), 8.26 (IH, d), no OH peak observed, m/z 173 (M-H)"
60%
With hydrogenchloride; water; at 90.0℃; for 16.0h;
A mixture of 2-chloro-6-methoxy-3-nitropyridine (5 g, 10.61 mmol) in HCl solution (12 M, 60 mL) was stirred at 90 C. for 16 h. Then the reaction mixture was neutralized with NaOH carefully and extracted with EtOAc (100 mL*2). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to yield 6-chloro-5-nitropyridin-2-ol (2.8 g, 60%) as red solid which was used in the following reaction without further purification. MS: m/z=197.1 [M+Na]+.
With potassium hydroxide; In N,N-dimethyl-formamide; at 0 - 20℃;Product distribution / selectivity;
Method A 6-Methoxy-2-(4-methyl-1H-imidazol-1-yl)-3-nitropyridine (1B) To a N,N-dimethylformamide (500 mL) solution of 4-methylimidazole (8.5 g, 103 mmol) was added freshly powdered KOH (6.72 g, 120 mmol) in two portions under N2 at 0 C., followed by addition of <strong>[38533-61-8]2-chloro-6-methoxy-3-nitropyridine</strong> (18.9 g, 100 mmol). The resulting solution was warmed to room temperature and stirred for 2 hours. Majority of solvent was removed under vacuum and the residue was diluted with water and extracted with ethyl acetate three times. The organic layer was combined and washed two more times with water to remove additional dimethyl formamide and dried over magnesium sulfate. Solvent was evaporated under vacuum and the residue was purified by column (15-25% gradient eluent of ethyl acetate in dichloromethane) to provide compound 1B as a yellow oil (21.9 g, 93% yield) which becomes yellow solid after standing on bench.
93%
To 4.02 g (1.6 eq.) 4-methylimidazole dissolved in CHCl3 (8 mL, instead of DMF [38]) a solution of 4-(dimethylamino) pyridine (DMAP, 0.37 g, 10 mol %) in CHCl3 (2 mL) was added dropwise. The reaction mixture was stirred at 0 C for 10 min followed by the addition of triethylamine (TEA, 12.73 mL, 3 eq.; instead of solid KOH [38]) and stirring at 0 C for further 10 min. To this reaction mixture was added dropwise <strong>[38533-61-8]2-chloro-6-methoxy-3-nitropyridine</strong> (5.77 g, 1 eq.) in CHCl3 (14 mL). After 30 min at 0 C the mixture was stirred at ambient temperature overnight. The mixture was washed twice with water and aq. NaCl saturated solution (20 mL). The aqueous phase was extracted with CHCl3 (20 mL). The organic phase was dried over Na2SO4 and filtered. Evaporation of the solvent and subsequent purification by column chromatography (EtOAc/n-hexane, 1:2, v/v) afforded 1 as a yellow solid (6.65 g, 93%). 1H-NMR (400 MHz, CDCl3): delta (ppm) = 2.27 (s, 3H); 4.03 (s, 3H); 4.75 (s, 2H); 6.78 (d, 3J = 8.8, 1H); 6.90 (dd, 4J = 2.0, 4J = 1.2, 1H); 7.94 (d,4J = 1.2, 1H); 8.23 (d, 3J = 8.8, 1H).
With potassium hydroxide; In N,N-dimethyl-formamide; at 70℃; for 16h;
Step 2 3-(6-Methoxy-3-nitro-pyridin-2-yl)-5-trifluoromethyl-3H-imidazole-4-carboxylic Acid Ethyl Ester 5-Trifluoromethyl-3H-imidazole-4-carboxylic acid ethyl ester (Scheme 6, step 1) (5 g, 24 mmol) and <strong>[38533-61-8]2-chloro-3-nitro-6-methoxypyridine</strong> (4.5 g, 24 mmol) were dissolved in DMF (60 mL). To this was added freshly powdered KOH (1.3 g, 24 mmol). The reaction was heated to 70 C. for 16 hrs then cooled to room temperature and diluted with water. The solution was then extracted with ethyl acetate 2*. The organic layers were combined and washed with water then brined and dried over MgSO4. The solution was filtered and the solvent removed under reduced pressure. The crude was purified using flash chromatography on silica gel in hexane/ethyl acetate 2:1. A yellow oil (3.4 g, 39%) was recovered as desired product. EIMS 361.0 [M+H]+.
With potassium hydroxide; In N,N-dimethyl-formamide; at 20℃; for 2h;
Step 2 6-Methoxy-2-(4-methyl-2-(3,3,3-trifluoropropyl)-1H-imidazol-1-yl)-3-nitropyridine To a solution of 4-methyl-2-(3,3,3-trifluoropropyl)-1H-imidazole (1 g, 5.6 mmol) in DMF (25 mL) was added freshly powdered KOH (366 mg, 6.54 mmol) at 0 C. under nitrogen, followed by addition of <strong>[38533-61-8]2-chloro-6-methoxy-3-nitropyridine</strong> (1.03 g, 5.45 mmol). The resulting brown solution was stirred at room temperature for 2 hours and then poured into ice-water. The mixture was extracted with ethyl acetate, washed with brine and dried over MgSO4. Column purification using 10-25% ethyl acetate in hexane as eluent provided the product as a yellow powder (1.46 g, 82% yield). EIMS 331.0 [M+H]+.
95.a.1 Step 1:
Step 1: 6-methoxy-2-(4-methyl-2-propyl-imidazol-1-yl)-3-nitro-pyridine To a suspension prepared of 20.0 g KOH (solid), 25.8 g 4-methyl-2-propyl imidazole and 130 ml dimethyl formamide were added 38.0 g 2-chloro-6-methoxy-3-nitro pyridine in small amounts at a reaction temperature of 5° C. The reaction mixture was stirred for 75 minutes at room temperature. Then the reaction mixture was poured in 600 ml water. The mixture was further stirred for 1 hr. The desired product precipitated during this time. The resulting solid was collected by filtration, washed with 100 ml water for 3 times and dried in a dry box with vacuum (40° C.). Yield: 40 g m.p.: 96-103° C.
Example 2; Compound: Synthesis of (2R)-2-[(4-[(5-chloro-6-methyl-3-pyridinyl)methyl]amino}-1-piperidinyl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione hydrochloride, using Preparative Scheme (4) (a) (2R)-2-[6-(Methyloxy)-3-nitro-2-pyridinyl]amino}-3-[(phenylmethyl)oxy]-1-propanolTo a solution of <strong>[58577-87-0](R)-2-amino-3-benzyloxy-1-propanol</strong> (698.4 g, 3.931 mol) in EtOH (3.6 L) was added Et3N (1.27 L, 9.11 mol) in portions over 10 min. Then a solution of 2-chloro-6-methoxy-3-nitropyridine (672.7 g, 3.567 mol) in EtOH (0.6 L) was added in portions over 10 min. The mixture was heated at 78 C. for 2 h. The reaction mixture was cooled to room temperature and added to stirred ice/H2O (8.4 L). The mixture was extracted with EtOAc (9+6+3 L). The extracts were washed with brine (6 L), dried over MgSO4 (900 g), filtered and evaporated to give (2R)-2-[6-(methyloxy)-3-nitro-2-pyridinyl]amino}-3-[(phenylmethyl)oxy]-1-propanol (1373.1 g, 115%) as an orange oil.
With potassium carbonate; In N,N-dimethyl-formamide; acetonitrile; at 60℃; for 3h;
A mixture of 4-amino-l-Boc-piperidine (commercial; 6.7 g, 35 mmol), 2-chloro- 6-methoxy-3-nitro-pyridine (1 eq.) and K2CO3 (1 eq.) in MeCN (10O mL) and DMF (30 mL) was heated at 600C for 3 h. The mixture was filtered and concentrated in vacuo. The residue was taken up in ether/water 1 :1, the org. phase dried over MgSO4 and concentrated. The residue was triturated with EA and filtered to afford 4.5 g of pure product. The filtrate was concentrated and purified by CC (Etaept/EA 9:1, 4:1, 2:1) to give another 4 g of product. In total 8.5 g (70% yield) of a yellow solid were obtained. 1H NMR (CDCl3) delta: 8.62 (m, 1Eta), 8.31 (d, J = 9.4 Hz, IH), 6.07 (d, J = 9.1 Hz, IH), 4.32 (m, IH), 4.05 (m, 2H), 3.95 (s, 3H), 3.02 (s, 2H), 2.10 (m, 2H), 1.60 (s, 3H), 1.47 (m, 9H).
61%
With potassium carbonate; In N,N-dimethyl-formamide; acetonitrile; at 60℃; for 3h;
A mixture of tert-butyl 4-aminopiperidine-1 -carboxylate (2.34 g, 11 .7mmol), <strong>[38533-61-8]2-chloro-6-methoxy-3-nitropyridine</strong> (3 g, 10.6 mmol) and K2C03(1.47 g, 10.6 mmol) in MeCN (60 mL) and DMF (15 mL) was heated at 60C for 3 h. The mixture was filtered and concentrated in vacuo. The residue was suspended in diethyl ether/water 1:1, the organic phase was dried over Mg504 and concentrated. The residue was purified byflash chromatography (silica-gel) to afford the title compound (2.3 g, 6.5 mmol, 61% yield). LC-MS (M-H) = 353.3
With potassium hydroxide; In N,N-dimethyl-formamide; at 0 - 20℃;
Step 1: 2-(2-bromo-4-methyl-1H-imidazol-1-yl)-6-methoxy-3-nitropyridine To a mixture of 2-chloro-3-nitro-6-methoxypyridine (9.43 g, 50 mmol) and <strong>[23328-88-3]2-bromo-4-methylimidazole</strong> (9.66 g, 60 mmol) in 300 mL of DMF was added freshly powdered KOH (3.36 g, 60 mmol) at 0 C. The resulting mixture was stirred at RT for 4 h. Solvent was removed by rotavap and the residue was washed with water and extracted with ethyl acetate (3*). Standard work-up followed by column chromatography using 30-50% ethyl acetate in hexane as eluent provided the product (13.82 g, 88% yield). MS (ESI) 313.0 [M+H]+
Preparation 59; 4-(2-f(6-Methoxy-3-nitropyridin-2-yl)oxy1ethyl)morpholine; A solution of 4-(2-hydroxyethyl)morpholine (1.57g, 12mmol) in tetrahydrofuran (2OmL) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil, 520mg, 13mmo.) in tetrahydrofuran (4OmL) and the mixture was stirred at room temperature for 2 hours. 2-Chloro-6-methoxy- 3-nitropyridine (2g, 10.6mmol) was then added and the mixture was stirred for a further 2 hours at room temperature. The reaction mixture was then concentrated in vacuo and the residue was partitioned between dichloromethane and water. The aqueous solution was extracted with dichloromethane (2x50mL) EPO <DP n="65"/>and the combined organic solution was dried over sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0 to 96:4:0.4, afforded the title compound as a pale yellow solid in 49% yield, 1.46g. 1HNMR(400MHz, CDCI3) delta: 2.60-2.70(m, 4H), 2.87(t, 2H), 3.70-3.75(m, 4H), 3.98(s, 3H)1 4.64(t, 2H), 6.37(d, 1 H), 8.33 (d, 1 H); LRMS ESI m/z 284 [M+H]+
A) Methyl 5-chloro-2-(2-fluorophenyl)-2-(6-methoxy-3-nitropyridin-2-yl) pentanoate (XII) To 9.3 g of sodium hydride at 60% in oil in suspension in 900 ml of DMF is added at 0 C., dropwise, the mixture of 20 g of 2-chloro-6-methoxy-3-nitropyridine and 19.6 g of methyl 2-fluorophenyl acetate in solution in 100 ml of DMF. The reaction mixture is stirred for 3 h, allowing the temperature to rise to RT, and then 34 ml of 1-chloro-3-iodopropane are added. The mixture is stirred at RT for 48 h. 500 ml of a 5% aqueous NaHCO3 solution are added and the mixture is extracted with 500 ml of AcOEt. The organic phase is washed with 300 ml of a 5% aqueous NaHCO3 solution, it is dried over Na2SO4 and then the solvents are evaporated under reduced pressure. The residue is purified by silica gel chromatography, eluting with a cyclohexane/ethyl acetate mixture to give the expected compound in liquid form which is used as it is in the next step.
A) Methyl 6-chloro-2-(2-fluorophenyl)-2-(6-methoxy-3-nitropyridin-2-yl)hexanoate (XII) To 9.3 g of sodium hydride at 60% in oil in suspension in 900 ml of DMF is added at 0 C., dropwise, the mixture of 20 g of 2-chloro-6-methoxy-3-nitropyridine and 19.6 g of methyl 2-fluorophenyl acetate in solution in 100 ml of DMF. The reaction mixture is stirred for 3 h, allowing the temperature to rise to room temperature and then 34 ml of iodochlorobutane are added. The mixture is stirred at RT for 48 h. 500 ml of a 5% aqueous NaHCO3 solution are added and the mixture is extracted with 500 ml of AcOEt. The organic phase is washed with 300 ml of a 5% aqueous NaHCO3 solution, dried over Na2SO4 and then the solvents are then evaporated under reduced pressure. The residue is purified by silica gel chromatography, eluting with a cyclohexane/ethyl acetate mixture to give the expected compound in the form of a liquid which is used as it is in the next step.
Preparation 1.1 Methyl (2-fluorophenyl)(6-methoxy-3-nitropyridin-2-yl)acetate. R2=OMe; R3=H; R4=F; R5=H; R=Me (IX) To 12.7 g of sodium hydride at 60% in oil in suspension in 600 ml of DMF is added at 0 C., dropwise, the mixture of 20 g of 2-chloro-6-methoxy-3-nitropyridine and 20.6 g of methyl 2-fluorophenyl acetate in solution in 100 ml of DMF. The reaction mixture is stirred for 3 h, allowing the temperature to rise to RT. 500 ml of a 5% aqueous NaHCO3 solution are added and the mixture is extracted with 250 ml of AcOEt. The organic phase is washed with 300 ml of a 5% aqueous NaHCO3 solution, it is dried over Na2SO4, and then the solvents are evaporated under reduced pressure. The residue is purified by silica gel chromatography, eluting with a cyclohexane/ethyl acetate mixture to give the expected compound in the form of a liquid.
6-methoxy-3-nitro-N-phenylpyridin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
In N,N-dimethyl-formamide; at 140℃; for 1h;Microwave irradiation;
PREPARATION 11 6-Methoxy-3-nitro-N-phenylpyridin-2-amine Aniline (6.9 mL, 80.00 mmols) was added to a solution of <strong>[38533-61-8]2-chloro-6-methoxy-3-nitropyridine</strong> (11.00 g, 60.00 mmols) in dry DMF and it was stirred in the microwave at 140ºC for 1 h. It was concentrated in vacuo. Water and ethyl acetate were added. The organic phase was dried, filtered and concentrated in vacuo. It was purified by chromatography (Silica gel, Hexane:ethyl acetate 20:1) to afford the expected compound (1 0.46g, 73%). LRMS (m/z): 246 (M+1)+ 1H NMR (400 MHz, DMSO-d6) d ppm 3.90 (s, 3 H) 6.38 (d, 1 H) 7.11 - 7.22 (m, 1 H) 7.27 - 7.48 (m, 2 H) 7.72 (d, 2 H) 8.45 (d, 1 H) 10.46 (s, 1 H)
73%
In N,N-dimethyl-formamide; at 140℃; for 1h;Microwave irradiation;
Aniline (6.9 ml_, 80.00 mmols) was added to a solution of 2-chloro-6-methoxy-3- nitropyridine (1 1 .00 g, 60.00 mmols) in dry DMF and it was stirred in the microwave at 140C for 1 h. It was concentrated in vacuum. Water and ethyl acetate were added. The organic phase was dried, filtered and concentrated in vacuum. It was purified by chromatography (Silica gel, Hexane:ethyl acetate 20:1 ) to afford the expected compound (10.46g, 73%).LRMS (m/z): 246 (M+1 )+ 1H NMR (400 MHz, DMSO-d6) delta ppm 3.90 (s, 3 H) 6.38 (d, 1 H) 7.1 1 - 7.22 (m, 1 H)7.27 - 7.48 (m, 2 H) 7.72 (d, 2 H) 8.45 (d, 1 H) 10.46 (s, 1 H)
70%
With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 5h;
To a mixture of <strong>[38533-61-8]2-chloro-6-methoxy-3-nitropyridine</strong> (17, 10.0 g, 53.0 mmol) and aniline (7.25 mL, 79.6 mmol) in DMF (200 mL) was added K2CO3 (7.33 g, 53.0 mmol), and the mixture was stirred at 110 C for 5 h. After cooling at room temperature, the mixture was concentrated in vacuo. The residue was partitioned between EtOAc and water, and the organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was washed with hexane-EtOAc to give 18 (9.15 g, 70%) as a yellow solid. 1H NMR (DMSO-d6) delta 3.89 (s, 3H), 6.38 (d, 1H, J = 9.1 Hz), 7.17 (t, 1H, J = 7.4 Hz), 7.37-7.43 (m, 2H), 7.72 (d, 2H, J = 7.7 Hz), 8.44 (d, 1H, J = 9.1 Hz), 10.45 (br s, 1H); MS (FAB) m/z 246 [M+H]+.
With potassium carbonate; In tetrahydrofuran; at 50℃; for 12h;
Methyl-3-((6-methoxy-3-nitropyridin-2-yl)amino)-2-methylpropanoate (Step 1). To a solution of <strong>[38533-61-8]2-chloro-6-methoxy-3-nitropyridine</strong> (3 g, 15.91 mmol) in tetrahydrofuran (20 mL) was added methyl-3-amino-2-methylpropanoate (2.05 g, 17.50 mmol) and potassium carbonate (4.40 g, 31.82 mmol). The mixture was stirred at 50C for 12 hours. The reaction mixture was concentrated in vacuo and washed with water (20 mL), extracted with acetic ester (20 mL x 3). The combined organic phase was dried by anhydrous sodium sulphate, and then filtered. The filtrate was concentrated and purified by column chromatograph silica gel (elute:dichloromethane / Methanol: 100:1?80:1) to give methyl-3-((6-methoxy-3-nitropyridin-2- yl)amino)-2-methylpropanoate (4.2 g, 97 %) as a yellow oil.
N-[1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-6-(methyloxy)-3-nitro-2-pyridinamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With triethylamine; In ethanol; at 80℃;
A mixture of 2-chloro-6-(methyloxy)-3-nitropyridine (5.00 mmol) and [(35 -l- (cyclopropylcarbonyl)-3-pyrrolidinyl]methyl} amine (5.50 mmol, -80% ee) intriethylamine (1.4 mL) and ethanol (50 mL) was stirred at 80 C overnight. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was purified by silica gel chromatography (1 :6 ethyl acetate :petroleum ether) to afford the desired product (1.4 g, 88%). 1H NMR (CDC13 w/ TMS, 300 MHz): delta 0.73-0.77 (2H, m), 0.98-1.01 (2H, m), 1.54-1.94 (2H, m), 2.06-2.26 (1H, m), 2.54-2.80 (1H, m), 3.22-3.88 (6H, m), 3.97 (3H, s), 6.08 (1H, d, J= 9.0 Hz), 8.31 (1H, d, J= 9.0 Hz), 8.82 (1H, s, br); LCMS: m e = 321 [M+H]+.
N-cyclopropyl-6-methoxy-3-nitropyridin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
In toluene; at 0 - 20℃; for 7h;Inert atmosphere;
To a stirred solution of 2-chioro-6-methoxy-3-ni- tropyridine (5 g, 26.5 mmol) in toluene (50 mE) under an inert atmosphere was added cyclopropyl amine (3.69 mE, 53 mmol) at 0 C. The reaction mixture was stirred at 0 C. for 1 h and warmed to room temperature and stirred for 6 h. After consumption of starting material (by TEC), the reaction mixture was diluted with water (50 mE) and extracted with EtOAc (2x50 mE). The combined organic extracts were washed with brine (20 mE), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was triturated with n-pentane to afford N-cyclopropyl-6-methoxy-3-nitropyridin-2-amine (800 mg, 3.82 mmol, 83%) as a yellow solid.
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 20 - 120℃;Inert atmosphere;
To a stirred solution of 2-chloro-6-methoxy-3-nitropyridine (10.0 g, 53.03 mmol, 1.0 eq), and <strong>[4433-63-0]ethylboronic acid</strong> (4.70 g, 63.636 mmol, 1.2 eq) in dioxane (100.0 mL) was added a 2 M solution of sodium carbonate (11.24 g, 106.06 mmol, 2.0 eq) in water (53.0 mL) at rt. The resulting mixture was purged with nitrogen for 10 minute followed by addition of Pd(dppf)Cl2.DCM (0.87 g, 1.06 mmol, 0.02 eq), again purged with nitrogen for 10 minute. The resulting mixture was heated at l20C for overnight. The progress of reaction was monitored by LCMS. The reaction mixture was filtered through celite the residue was washed with EtOAc (100 mL), the filtrate was concentrated and purified by combi flash chromatography [silica gel 100-200 mesh: elution 100% Hexane] to afford the desired compound 2-ethyl-6-methoxy-3-nitropyridine (5.0 g, 51.75%) as light yellow solid. LCMS: (M+l)+ 182.9
48%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; at 100℃; for 12h;
To a degassed solution of 2-chloro-6-methoxy-3-nitropyridine (3 g, 15.95 mmol), <strong>[4433-63-0]ethylboronic acid</strong> (3 g, 47.80 mmol) and K2C03 (6 g, 47.80 mmol) in 1,4-dioxane (60 mL) was added Pd(dppf)Cl2 (1 g, 1.59 mmol). The reaction mixture was stirred at 100C for 12 h, then filtered through Celite. The filtrate was concentrated in vacuo and the crude material was purified using column chromatography (silica 100-200 mesh; 10% EtOAc in hexane) to yield the title compound (1.4 g, 48%). deltaEta (CDC13) 8.20 (d, J 8.1 Hz, IH), 6.82 (d, J 7.9 Hz, IH), 4.05 (s, 3H), 3.19 (q, 2H), 1.28 (t, 3H). LCMS: [M+l] 183.20 (95.43% LCMS purity).
With sodium hydride; In tetrahydrofuran; mineral oil; at 0 - 80℃; for 16h;
To NaR (4.24 g, 60% w/w in mineral oil, 106.0 mmol) in THF (80 mE) was added diethyl malonate (16.16mE, 106.0 mmol) dropwise at 00 C. and the reaction mixture stirred for 1 h. <strong>[38533-61-8]2-chloro-6-methoxy-3-nitropyridine</strong> (10.00 g, 53.0 mmol) in THF (20 mE) was added dropwise and the resulting mixture stirred at 80 C. for 16 h. The reaction mixture was paititioned between cold H20 (250 mE) and EtOAc (100 mE), the aqueous layer thither extracted with EtOAc (2x100 mE), combined organics dried (Na2504) and the solvent removed in vacuo. The crude product was purified by column chromatography (normal phase silica, 0 to 20% EtOAc in hexane) to give diethyl 2-(6-methoxy-3- nitropyridin-2-yl)malonate (13.21 g, 80%) as a light green solid.
N-((2-chlorothiazol-5-yl)methyl)ethylamine[ No CAS ]
6-methoxy-N-((2-chlorothiazole-5-yl)methyl)-N-ethyl-3-nitropyridin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58.3%
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 80℃;
Example 5 Compound No. 05 in Table 1 (Method B) [0071] <strong>[38533-61-8]2-chloro-6-methoxy-3-nitropyridine</strong> and 10 mL N,N-dimethylformamide (DMF), and 2.00 g of potassium carbonate were added into a 100 mL single neck flask, under stirring at room temperature, 1.20 g of 2-chloro-5-ethylaminomethylthiazole, prepared according to the example 1, in 5.0 mL DMF were added dropwise. After that, the reaction solution was heated to 40-80 C. and then reacted for 3-6 hr. After cooling down, the resulting mixture was added to water (50 mL), then treated by the method according to the example 1 to obtain 1.27 g of 6-methoxy-N-((2-chlorothiazole-5-yl)methyl)-N-ethyl-3-nitropyridine-2-amine, as a golden yellow solid, having the content of 98.6%, a yield of 58.3%, and the structure was confirmed by GC-Mass and 1H NMR.
6-methoxy-N-((2-chlorothiazole-5-yl)methyl)-3-nitropyridine-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
25.7%
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 80℃;
1.13 g of 2-chloro-6-methoxy-3-nitropyridine, prepared according to the example 3, and 15 mL of N,N-dimethylformamide, 1.50 g of potassium carbonate were added into a 100 mL single neck flask. Under stirring at room temperature, 0.99 g of <strong>[120740-08-1](2-chlorothiazol-5-yl)methanamine</strong> in 10.0 mL of DMF was added dropwise. After that, the reaction mixture was heated to 50-80 C. and then reacted for 3-5 hr. After cooling down, the resulting mixture was added to ice water (100 mL), and then extracted by ethyl acetate, dried over anhydrous sodium sulfate, concentrated under a reduced pressure to obtain the residue 1.76 g, which was purified by a silica gel column chromatography using petroleum ether/ ethyl acetate (5/1) as an eluent to obtain 6-methoxy-N-((2-chlorothiazole-5-yl)methyl)-3-nitropridine-2-amine, having the content of 99.0%, as a golden yellow solid, m.p.: 150.2-151.0 C., yield 25.7% GC-MS (M+) (EI, 70 eV, m/z) calc: 300; found: 300; 1H NMR (CDCl3) 4.024 (s, 3H, CH3), 4.911-4.935 (m, 2H, CH2), 6.153 (d, J=9.0 Hz, 1H, Py H), 7.493 (s, 1H, Thiazole-H), 8.329 (d, J=9.0 Hz, 1H, Py H).
13.2 g
2-chloro-3-nitro-6-methoxypyridine (9.4 g, 50 mmol) was added to a 250 mL three-neck round bottom flask equipped with a magnetic stirring.Potassium carbonate (8.28 g, 60 mmol) and N,N-dimethylformamide (85 mL), stirred at room temperature for 10-15 min,A solution of 2-chlorothiazole-5-methylamine (7.40 g, 50 mmol) in N,N-dimethylformamide (15 mL)Drip in 30min, react at room temperature for 3-4hr, add water, and stir for 0.5-1hr.Filtration, washing with water, drying, and obtaining 13.2 g of a pale yellow solid.Purity: 98%, yield 86%.
With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine; In acetonitrile; at -20 - 20℃; for 12h;Inert atmosphere; Sealed tube;
, a mixture of <strong>[38533-61-8]2-chloro-6-methoxy-3-nitro-pyridine</strong> (2.0 g, 10.4 mmol), triethylamine (10 mL), 15 copper(I) iodide (0.4 g, 2.00 mmol) and acetonitrile (30 mL) was s parged with nitrogen for 15 min. Then tetrakis(triphenylphos pine)palladium(0) (1.21 g, 1.00 mmol) was added to the flask. The mixture was, again, s parged with nitrogen for 10 min and then cooled to -20 C. 121 of 363 {//-- DRAFT --//4069/3020WO/00228726/v2} 4069.3020 WO Propyne gas (5.03 g, 0.125 mol) was bubbled into the reaction mixture and then the tube was sealed. The reaction mixture was allowed to slowly warm to room temperature and then stir for 12 h. The progress of the reaction was monitored by TLC. Upon completion the reaction mixture was diluted with water and extracted with ethyl acetate (3 x 50 mL). The combined 5 organic layers were washed with water, brine, and then dried over sodium sulfate. After filtration the organic layer was concentrated in vacuo. The remaining crude product mixture was purified by the column chromatography using 100-200 mesh silica gel and eluted with 30% ethyl acetate in hexanes to afford compound XXXV (1.0 g, 50%) as an off-white solid. 1H NMR (400 MHz, CDCl3) delta 8.23 (d, J= 9.1 Hz, 1H), 6.72 (d, J= 9.1 Hz, 1H), 4.02 (s, 1H), 10 2.19(s, 1H); MS (ESI, positive mode) m/z 193 (MH+).
6-methoxy-N-((thiazol-5-yl)methyl)-N-ethyl-3-nitro-pyridin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
2-Chloro-6-Oxy-3-nitropyridine (0.05mol), N- (thiazol-5-ylmethyl) ethanamine (0.05mol), potassium carbonate (0.05mol) and N, N-Dimethylformamide (100 mL), at room temperature for 16 ~ 20hr, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and solvent removedAgent, the resulting crude product was purified by column chromatography to give 5.2 g of the title substance as a yellow solid,
A solution of 2-chioro-6-rnethoxy-3-nitropyridine (5.0 g, 26.5 mmoi) in conc hydrochloric acid (40rnL) was heated at 120 C for 6 h, The reaction was then cooled to rt and poured onto ice, When theice has melted, dark brown solid was filtered, washed with water and air-dried on the filter for 2h to give the title compound (2.8 g. 60%). MS (ES1): mass calcd. for C5H3C1N203, 174.5 mIz found, 175.5 [M±H]. ?H NMR (500 MHz, DMSO-d6) d 13.10 (s, 11-I?), 8.42 (d, ,j:::: 8.8 Hz, 1Ff), 680 (d, J8.9 Hz, I H).
1-(6-methoxy-3-nitropyridin-2-yl)-1H-benzimidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 1h;
General procedure: The salt K2CO3 (2.07 g, 0.015 mol) and 2-chloro-3-nitro-6R-pyridine (2): 2a (1.59 g, 0.01 mol) and 2b (1.89 g, 0.01 mol) were added to a solution of benzimidazole 1 (1.18 g, 0.01 mol) in DMF (30 mL), at 60 C. The reaction mixture was stirred for 1 h at 110 C. After cooling, the reaction mixture was poured into water, a precipitate formed was filtered and dried. The product recrystallized from isopropyl alcohol.
With sodium hydride; In tetrahydrofuran; mineral oil; at 0 - 20℃; for 2.5h;
To a 500 mL four-neck flask were treated with THF (120 mL), MeOH (3.66 g, 115 mmol, 0.95 eq) and 2,6-dichloro-3-nitropyridine (23 g, 120 mmol, 1 eq). After cooling down to 0 oC, 60% NaH (6.8 g, 170 mmol, 1.7 eq) was added carefully. The mixture was stirred at this temperature for 30 minutes, then at RT for 2 hours. After completion, the mixture was quenched with water (100 mL), extracted with EA (3×150 mL), the combined organic layers were dried, concentrated and purified by silica column to give 2-chloro-6-methoxy-3-nitropyridine (12 g, 56%). 1HNMR (300 MHz, CDCl3): G 8.37- 8.24 (m, 1 H), 7.07- 7.05 (m, 1 H), 4.15 (s, 3 H).
trans-4-(tert-butoxycarbonylamino)cyclohexylamine[ No CAS ]
[ 38533-61-8 ]
tert-butyl {trans-4-[(6-methoxy-3-nitropyridin-2-yl)amino]cyclohexyl}carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With triethylamine; In acetonitrile; at 90℃;
To a solution of tert-butyl (trans-4-aminocyclohexyl)carbamate (1 .7 g,8 mmol) and TEA (1.1 mL, 8 mmol) in acetonitrile (53 mL) <strong>[38533-61-8]2-chloro-6-methoxy-3-nitropyridine</strong> (1 .5 g, 7.95 mmol) was added. The reaction mixture was heated at 9000 overnight then was cooled, filtered, and the filtrate was concentrated. The residue was treated with 50 mL of hot ethyl acetate, filtered and concentrated. The residue was dissolved inDCM and washed with sat. NH4CI. The organic phase was dried over Na2504 and concentrated to afford the title compound (1 .5 g, 6.7 mmol, 84% yield). LC-MS (M-H) = 367.4
N-(6-methoxy-3-nitropyridin-2-yl)-1H-benzo[d][1,2,3]triazol-5-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
With trimethylamine; In methanol; at 120℃; for 24h;
2-Chloro-6-methoxy-3-nitropyridine (0.13 g, 0.69 mmol)5-Amino-1H-benzotriazole (0.09 g, 0.69 mmol) and triethylamine (0.11 mL, 0.76 mmol) were dissolved in methanol and the mixture was stirred at 120 ° C for 24 hours. After cooling in the atmosphere, water was added slowly and stirred for 30 minutes. The resulting solid product was filtered off, washed with methanol and dried to give compound 5e (61percent yield).
N-(6-methoxy-3-nitropyridin-2-yl)-1H-indol-5-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
With trimethylamine; In methanol; at 120℃; for 18h;
2-Chloro-6-methoxy-3-nitropyridine (0.10 g, 0.53 mmol), 5-aminobenzimidazole (0.07 g, 0.53 mmol) and trimethylamine (TMA) (0.08 mL, 0.58 mmol) were dissolved in methanol, and the mixture was stirred at 120 C for 18 hours. After cooling in the atmosphere, water was added slowly and stirred for 30 minutes. The resulting solid product was filtered off, washed with methanol and dried to give compound 5b (61% yield).
2-(benzylthio)-6-methoxy-3-nitropyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h;
A mixture of <strong>[38533-61-8]2-chloro-6-methoxy-3-nitropyridine</strong>(0.20 g, 1.06 mmol), benzylmercaptan(0.14ml_, 1.17 mmol), K2CO3 (0.18 g, 1.29 mmol) and DMF (1 ml_) was stirred at rt for 3 h. The mixture was poured into water and filtered to give the sub-title compound (0.29 g, 98 %).
43.55%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
Step-1 (1083) To a solution of 6-methoxy-2-chloro-3-nitro pyridine (1 ; 5.0 g, 26.596 mmol) in dimethylformamide (20 mL) was added potassium carbonate (4.441 g, 32.181 mmol) and benzyl mercaptan (3.595g, 28.989 mmol) at room temperature. The reaction mixture was stirred for overnight at room temperature. Progress of reaction was monitored by LCMS. The reaction mixture was quenched with ice cold water (30 ml) and was extracted with ethyl acetate (300 mL). The organic layer was washed with water (3 x 50 mL) followed by brine (1 x 50 mL). The organic layer was dried over anhydrous sodium sulphate and was evaporated under reduced pressure to give the crude product which was purified by column chromatography eluting with 2% ethyl acetate in hexane affording the step-1 compound (3.2 g, 43.55%) as yellow solid.
2-ethanesulfanyl-6-methoxy-3-nitropyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84.24%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
To a solution of 6-methoxy-2-chloro-3-nitro pyridine (5 g, 26.59 mmol) in dimethylformamide (50 mL) was added potassium carbonate (4.44 g, 31.95 mmol) and ethane thiol (1.81g, 29.25 mmol) at room temperature. The reaction mixture was stirred overnight at room temperature. Progress of reaction was monitored by LCMS. The reaction mixture was quenched with ice cold water (35 mL) where in solid precipitated from the reaction mixture. The solid were filtered and washed with ice cold water (3 x 30 mL) and was dried under reduced pressure affording the the sub-title compound as a yellow solid (4.8 g, 84.24%). 1 H NMR (DMSO-de, 400 MHz) delta 8.49 (d, J= 9.0 Hz, 1 H), 6.75 (d, J= 9.0 Hz, 1 H), 4.04 (s, 3H), 3.21 (q, J= 7.3 Hz, 2H), 1.34 (t, J= 7.3 Hz, 3H); LCMS [m/z (M+H)+] 215 (MW calc = 214) Rt = 1.69
69.73%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
Step-1 (1112) To a solution of 6-methoxy-2-chloro-3-nitro pyridine (250 mg, 1.33 mmol) in dimethylformamide (5 mL) was added potassium carbonate (220 mg, 1.59 mmol) and ethane thiol (1.33 mg, 2.66 mmol) at room temperature. The reaction mixture was stirred overnight at room temperature. Progress of reaction was monitored by LCMS. The reaction mixture was quenched with ice cold water (10 ml) and was extracted with ethyl acetate (20 mL). The organic layer was washed with water (3 x 10 mL) followed by brine (1 x 10 mL). The organic layer was dried over anhydrous sodium sulphate and was evaporated under reduced pressure to give the crude product which was purified by column chromatography eluting with 2% ethyl acetate in hexane affording the step-1 compound (187 mg, 69.73%) as yellow solid
6-methoxy-3-nitro-2-octylsulfanylpyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h;
To a solution of 6-methoxy-2-chloro-3-nitro pyridine (10 g, 53.191 mmol) in dimethylformamide (50 mL) was added potassium carbonate (8.8 g, 63.829 mmol) and octane- 1 -thiol (8.54 g, 58.51 mmol) at room temperature. The reaction mixture was stirred for 12 hours at room temperature. Progress of reaction was monitored by LCMS. The reaction mixture was quenched with ice cold water (100 mL) and was extracted with ethyl acetate (200 mL). The organic layer was washed with water (3 x 75 mL) followed by brine (1 x 50 mL). The organic layer was dried over anhydrous sodium sulphate and was evaporated under reduced pressure to give the crude product which was purified by column chromatography eluting with 10% ethyl acetate in hexane affording the sub-title compound as yellow solid (13 g, 82%). 1 H NMR (DMSO-d6, 400 MHz) delta 8.48 (d, J= 9.0 Hz, 1 H), 6.74 (d, J= 9.0 Hz, 1 H), 4.02 (s, 3H), 3.18 (t, J= 7.4 Hz, 2H), 1.75-1.65 (m, 2H), 1.42-1.35 (m, 2H), 1.3-1.2 (m, 8H), 0.86- 0.83 (m, 3H); 13C NMR (DMSO-d6, 100 MHz) delta 164.0, 158.0, 137.3, 135.8, 106.4, 54.5, 31.1 , 30.0, 28.57, 28.52, 28.38, 21.9, 13.8; LCMS [m/z (M+H)+] 299 (MW calc = 298) Rt = 2.12
37.8%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
Step-1 (1098) To a solution of 6-methoxy-2-chloro-3-nitro pyridine(1 ; 250 mg, 0.1.33 mmol) in dimethylformamide (5 mL) was added potassium carbonate (220 mg, 1.596 mmol) and octane-1 -thiol (213 mg, 1.463 mmol) at room temperature. The reaction mixture was stirred overnight at room temperature. Progress of reaction was monitored by LCMS. The reaction mixture was quenched with ice cold water (10 ml) and was extracted with ethyl acetate (20 mL). The organic layer was washed with water (3 x 10 mL) followed by brine (1 x 10 mL). The organic layer was dried over anhydrous sodium sulphate and was evaporated under reduced pressure to give the crude product which was purified by column chromatography eluting with 4% ethyl acetate in hexane affording the step-1 compound (150 mg, 37.8%) as yellow solid.
6-methoxy-3-nitro-2-(pyridin-2-ylthio)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 0.5h;
A mixture of <strong>[38533-61-8]2-chloro-6-methoxy-3-nitropyridine</strong> (0.25 g, 1.33 mmol), 2-mercaptopyridine (0.16 g, 1.46 mmol), K2CO3 (0.22 g, 1.62 mmol) and DMF (1 ml_) was stirred at rt for 0.5 h. The mixture was poured into water and filtered to give the sub-title compound (0.34 g, 98 %).
35.7%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
Step-1 (1090) To a solution of 6-methoxy-2-chloro-3-nitro pyridine (1 ; 5.0g, 26.596 mmol) in dimethylformamide (20 mL) was added potassium carbonate (4.441g, 32.181 mmol) and 2-mercapto pyridine (3.22g, 28.989 mmol) at room temperature. The reaction mixture was stirred for overnight at room temperature. Progress of reaction was monitored by LCMS. The reaction mixture was quenched with ice cold water (30 ml) and was extracted with ethyl acetate (300 mL). The organic layer was washed with water (3 x 50 mL) followed by brine (1 x 50 mL). The organic layer was dried over anhydrous sodium sulphate and was evaporated under reduced pressure to give the crude product which was purified by column chromatography eluting with 5% ethyl acetate in hexane affording the step-1 compound (2.5 g, 35.7%) as yellow solid.
4-(6-methoxy-3-nitropyridin-2-yl)morpholin-3-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 2h;Inert atmosphere;
A mixture of <strong>[38533-61-8]2-chloro-6-methoxy-3-nitropyridine</strong> (1.89 g, 10 mmol), morpholin-3-one (1.01 g, 10 mmol), Xantphos (578 mg, 1.0 mmol), Pd2(dba)3 (457 mg, 0.5 mmol), Cs2CO3 (6.5 g, 20 mmol), in 1,4-dioxane (50 mL) was stirred under nitrogen at 100 C for 2h. The mixture was then cooled to room temperature and filtered through Celite. The filtrate was concentrated and purified by flash chromatography (3:1 petroleum ether:ethyl acetate) to afford 4-(6- methoxy-3-nitropyridin-2-yl)morpholin-3-one (1.2 g, yield 47%) as a yellow solid. LCMS (ESI) [M+H] = 254.2.
6-methoxy-3-nitro-2-(tetrahydropyran-4-ylsulfanyl)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83.5%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h;
To a solution of 6-methoxy-2-chloro-3-nitro pyridine (ig, 5.31 9mmol) in dimethylformamide(5 mL) was added potassium carbonate (880 mg, 6.382 mmol) and oxane-4-thiol (690 mg,5.85 1 mmol) at room temperature. The reaction mixture was stirred for 12 hours at roomtemperature. Progress of reaction was monitored by LCMS. The reaction mixture was quenched with ice cold water (20 mL) and was extracted with ethyl acetate (50 mL). The organic layer was washed with water (3 x 30 mL) followed by brine (1 x 50 mL). The organic layer was dried over anhydrous sodium sulphate and was evaporated under reduced pressure to give the crude product which was purified by column chromatographyeluting with 10% ethyl acetate in hexane affording the sub-title compound as an off whitesolid (1.2 g, 83.5%).1H NMR (DMSO-d6, 400 MHz) O 8.48 (d, J= 9.0 Hz, 1H), 6.75 (d, J= 9.0 Hz, 1 H), 4.21-4.11(m, 1H), 4.02 (5, 3H), 3.91-3.86 (m, 2H), 3.53-3.47 (m, 2H), 2.05-2.02 (m, 2H), 1.70-1.65(m, 2H);130 NMR (DMSO-d6, 100 MHz) O 164.0, 157.0, 137.3, 135.5, 106.7, 66.6 (20), 54.6, 39.4,32.0 (20);LCMS [m/z (M+H)] 271 (MW calc = 270); R = 1.66
1-[4-(6-methoxy-3-nitropyridin-2-ylsulfanyl)piperidin-1-yl]ethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72.5%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h;
To a solution of 6-methoxy-2-chloro-3-nitro pyridine (1 g, 5.319 mmol) in dimethylformamide (5 mL) was added potassium carbonate (880 mg, 6.382 mmol) and 1-(4-sulfanylpiperidin-1-yl) ethan-1-one (930 mg, 5.85lmmol) at room temperature. Thereaction mixture was stirred for 12 hours at room temperature. Progress of reaction was monitored by LCMS. The reaction mixture was filtered. The filtrate was evaporated under reduced pressure to give the crude product which was purified by column chromatography eluting with 2% methanol in dichloromethane and triturated with ether to afford the sub-title compound as yellow solid (1.2 g, 72.5%).1H NMR(DMSO-d6,400MHz)O8.49(d, J=9.1 Hz, 1H),6.77(d, J=9.1 Hz, 1H),4.27-4.24 (m, 1H), 4.16-4.09 (m, 1H), 4.03 (5, 3H), 3.84-3.80 (m, 1H), 3.27-3.23 (m, 1H), 2.92-2.86 (m, 1H), 2.13-2.07 (m, 2H), 2.01 (5, 3H), 1.69-1.59 (m, 1H), 1.54-1.50 (m, 1H);130 NMR (DMSO-d6, 100 MHz) O 167.9, 164.1, 156.9, 137.4, 135.5, 106.7, 54.7, 45.5,40,6, 40.4, 31.6, 31.0, 21.2;LCMS [m/z(M+H)] 312 (MWcalc= 311); R= 1.57
6-methoxy-2-(2-methyltetrahydrofuran-3-ylsulfanyl)-3-nitropyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 12h;
4.a (a) 6-Methoxy-2-(2-methyl-tetrahydro-furan-3-ylsulfanyl)-3-nitro-pyridine
To a solution of 6-methoxy-2-chloro-3-nitro pyridine (lg, 5.31 9mmol) in dimethylformamide(5 mL) was added potassium carbonate (880 mg, 6.382 mmol) and2-methyloxolane-3-thiol (690 mg, 5.851 mmol) at room temperature. The reaction mixturewas stirred for 12 hours at room temperature. Progress of reaction was monitored by LCMS. The reaction mixture was quenched with ice cold water (20 mL) and was extracted with ethyl acetate (50 mL). The organic layer was washed with water (3 x 30 mL) followed by brine (1 x 50 mL). The organic layer was dried over anhydrous sodium sulphate and was evaporated under reduced pressure to give the crude product which was purified bycolumn chromatography eluting with 7% ethyl acetate in hexane affording the sub-title compound as yellow solid (700 mg, 48%).1H NMR (DMSO-d6, 400 MHz) O 8.51-8.48 (m, 1H), 6.79-6.76 (m, 1H), 4.56-3.85 (m, 6H),3.78-3.63 (m, 1H), 2.71-2.62 (m, 1H), 1.98-1.92 (m, 1H), 1.28-1.14 (m, 3H);130 NMR (DMSO-d6, 100 MHz) O 164.2,164.1, 157.5, 157.5,137.4, 136.0, 107.0, 106.9,78.1, 78,1 75.8, 65.9, 65.1, 54.9, 54.8, 47.7, 45.9, 33.6, 32.2, 19.5, 16.8;LCMS [mlz (M+H)] 271 (MW calc = 270); Diastereomeric mixture R = 2.42, 2.45;HPLC purity atA=2lOnm: Diastereomeric mixture R=8.84, 22.98%; R=8.81, 75.37%.
2-((4-chlorophenyl)sulfonyl)-6-methoxy-3-nitropyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81.21%
With hydrogenchloride; tetrabutyl-ammonium chloride; In N,N-dimethyl acetamide; water; at 80℃; for 1h;
To a stirred solution of 6-methoxy-2-chloro-3-nitro pyridine(1 ; 5.0 g, 26.596 mmol) in dimethyl acetamide (75ml_) was added sodium 4-chlorobenzene-sulphinate (2;7.92g, 39.894 mmol) and tetra-N-butylammonium chloride (2.22g, 7.979 mmol) and Cone HCI 0.75 ml at room temperature. The reaction mixture was stirred at 80C for 1 hour. Progress of reaction was monitored by LCMS. The whole reaction mixture was poured on crushed ice to get solid. This solid compound was filtered through sintered funnel and thoroughly dried under vacuum to isolate 2-((4-Chlorophenyl)sulfonyl)-6-methoxy- 3-nitropyridine as desired product (7.1 g, 81.21 %). 1H NMR (400 MHz, CDCI3) d 8.10 (d, J= 8.6 Hz, 1 H), 8.0 (d, J= 7.9 Hz, 2H), 7.56 (d, J= 7.9 Hz, 2H), 6.95 (d, J= 8.7 Hz, (1079) 1 H), 3.69 (s, 3H). LCMS [m/z (M+H)+ =(Calculated for C12H9N205SCI+H: 329) found: 329], Purity at l=220hht 98.73%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 20 - 120℃;
To a stirred solution of <strong>[38533-61-8]2-chloro-6-methoxy-3-nitropyridine</strong> (10.0 g, 53.03 mmol, 1.0 eq), and cyclopropylboronic acid (5.50 g, 63.636 mmol, 1.2 eq) in dioxane (50.0 mL) was added a 2 M solution of sodium carbonate (11.25 g, 106.06 mmol, 2.0 eq) in water (53.0 mL) at rt. The resulting mixture was purged with nitrogen for 10 minute followed by addition of Pd(dppf)Cl2.DCM (0.87 g, 1.06 mmol, 0.02 eq), again purged with nitrogen for 10 minute. The resulting mixture was heated at l20C for overnight. The progress of reaction was monitored by LCMS. The reaction mixture was diluted with EtOAc (500 mL), washed with water (100 mL), with brine (100 mL), dried over Na2S04, concentrated and purified by combi flash chromatography [silica gel 100-200 mesh: elution 100% Hexane] to afford the desired compound (7.80 g, 75.72%) as yellow solid. LCMS: (M+l)+ 194.9
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