* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of Organic Chemistry, 1955, vol. 20, p. 1729,1731
2
[ 6635-86-5 ]
[ 3430-27-1 ]
Reference：
[1] Russian Journal of Organic Chemistry, 2009, vol. 45, # 1, p. 115 - 118
[2] Journal of Organic Chemistry, 1955, vol. 20, p. 1729,1731
3
[ 695-34-1 ]
[ 21901-40-6 ]
[ 6635-86-5 ]
Yield
Reaction Conditions
Operation in experiment
27%
at 0 - 70℃; for 4 h;
The syntheses of several 2-aminonitropyridines were described previously by Talik and Talik [29]. Their methods were applied in the syntheses of I–III compounds using commercially available 2-amino-4-methylpyridine (Fluka, >99percent). These compounds were obtained as follows: 25 g of appropriate 2-amino-4-methylpyridine were dissolved in 125 cm3 of concentrated H2SO4 (Fluka, 96percent). The reaction mixture was cooled under intensive stirring to 0 °C by adding ice mixed with NaCl. Subsequently, 37.5 cm3 of HNO3 (Chempur, 65percent, d = 1.4 g/cm3) were added in small portions keeping the temperature below 10 °C. Then the mixture was stirred for 1.5 h with continuous cooling, and kept at ambient temperature for 1 h. Next, the reaction mixture was heated in a water bath for half an hour at 40 °C, 1 h in the temperature range 60–70 °C and half an hour in a boiling water bath. Then, the whole reaction mixture was cooled to ambient temperature, poured on ice and neutralized with ammonia to a slightly alkaline pH. The solid reaction product was filtered off under vacuum. Two nitro isomers (3 and 5) were separated by steam distillation. More volatile 3- nitro isomer (I) was distilled off and condensed as a pure compound (obtained after drying 10 g), while residual 5-nitro isomer (III) was filtered off and crystallized from water (with H2SO4 and active carbon added initially for dissolving the compound and removing impurities). After neutralization, filtering off and drying, about 15 g of 5-nitro isomer (III) was obtained. The 2-amino-4-methyl-3,5-dinitropyridine (II) was obtained from 2-amino-4-methyl-5-nitropyridine (III) by a similar procedure (nitration and rearrangement to dinitropyridines). The residues were purified by crystallization from water to give 2-amino-4-methyl-3-nitropyridine, I (Yield: (27percent (10 g), m.p. 134(1) °C), 2-amino-4-methyl-3,5-dinitropyridine, II (Yield: 80percent (10.4 g), m.p. 197(1) °C) and 2-amino-4-methyl-5-nitropyridine, III (Yield: 40percent (15 g), m.p. 218(1) °C), respectively. Melting points were determined using a Köfler apparatus. The chemical composition of the obtained compounds was checked using the Carlo Erba Analyser, Model 1104.
Reference：
[1] Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 2012, vol. 96, p. 952 - 962
[2] Journal of the Chemical Society, 1954, p. 2448,2455
[3] Journal of the American Chemical Society, 1955, vol. 77, p. 3154
[4] Journal of Fluorine Chemistry, 2011, vol. 132, # 8, p. 541 - 547
[5] Journal of Molecular Structure, 2013, vol. 1043, p. 15 - 27
[6] Organic Process Research and Development, 2007, vol. 11, # 5, p. 885 - 888
4
[ 33245-30-6 ]
[ 21901-40-6 ]
[ 6635-86-5 ]
Reference：
[1] Acta Chimica Hungarica, 1986, vol. 121, # 4, p. 333 - 338
[2] Acta Chimica Hungarica, 1986, vol. 121, # 4, p. 333 - 338
[3] Australian Journal of Chemistry, 1982, vol. 35, # 10, p. 2035 - 2040
[4] Organic Process Research and Development, 2007, vol. 11, # 5, p. 885 - 888
5
[ 33245-30-6 ]
[ 13466-41-6 ]
[ 21901-40-6 ]
[ 6635-86-5 ]
Reference：
[1] Australian Journal of Chemistry, 1983, vol. 36, # 6, p. 1159 - 1166
6
[ 33245-30-6 ]
[ 7664-93-9 ]
[ 21901-40-6 ]
[ 6635-86-5 ]
Reference：
[1] Chemische Berichte, 1924, vol. 57, p. 794
7
[ 695-34-1 ]
[ 21901-40-6 ]
[ 6635-86-5 ]
Yield
Reaction Conditions
Operation in experiment
27%
at 0 - 70℃; for 4 h;
The syntheses of several 2-aminonitropyridines were described previously by Talik and Talik [29]. Their methods were applied in the syntheses of I–III compounds using commercially available 2-amino-4-methylpyridine (Fluka, >99percent). These compounds were obtained as follows: 25 g of appropriate 2-amino-4-methylpyridine were dissolved in 125 cm3 of concentrated H2SO4 (Fluka, 96percent). The reaction mixture was cooled under intensive stirring to 0 °C by adding ice mixed with NaCl. Subsequently, 37.5 cm3 of HNO3 (Chempur, 65percent, d = 1.4 g/cm3) were added in small portions keeping the temperature below 10 °C. Then the mixture was stirred for 1.5 h with continuous cooling, and kept at ambient temperature for 1 h. Next, the reaction mixture was heated in a water bath for half an hour at 40 °C, 1 h in the temperature range 60–70 °C and half an hour in a boiling water bath. Then, the whole reaction mixture was cooled to ambient temperature, poured on ice and neutralized with ammonia to a slightly alkaline pH. The solid reaction product was filtered off under vacuum. Two nitro isomers (3 and 5) were separated by steam distillation. More volatile 3- nitro isomer (I) was distilled off and condensed as a pure compound (obtained after drying 10 g), while residual 5-nitro isomer (III) was filtered off and crystallized from water (with H2SO4 and active carbon added initially for dissolving the compound and removing impurities). After neutralization, filtering off and drying, about 15 g of 5-nitro isomer (III) was obtained. The 2-amino-4-methyl-3,5-dinitropyridine (II) was obtained from 2-amino-4-methyl-5-nitropyridine (III) by a similar procedure (nitration and rearrangement to dinitropyridines). The residues were purified by crystallization from water to give 2-amino-4-methyl-3-nitropyridine, I (Yield: (27percent (10 g), m.p. 134(1) °C), 2-amino-4-methyl-3,5-dinitropyridine, II (Yield: 80percent (10.4 g), m.p. 197(1) °C) and 2-amino-4-methyl-5-nitropyridine, III (Yield: 40percent (15 g), m.p. 218(1) °C), respectively. Melting points were determined using a Köfler apparatus. The chemical composition of the obtained compounds was checked using the Carlo Erba Analyser, Model 1104.
Reference：
[1] Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 2012, vol. 96, p. 952 - 962
[2] Journal of the Chemical Society, 1954, p. 2448,2455
[3] Journal of the American Chemical Society, 1955, vol. 77, p. 3154
[4] Journal of Fluorine Chemistry, 2011, vol. 132, # 8, p. 541 - 547
[5] Journal of Molecular Structure, 2013, vol. 1043, p. 15 - 27
[6] Organic Process Research and Development, 2007, vol. 11, # 5, p. 885 - 888
8
[ 695-34-1 ]
[ 6635-86-5 ]
Yield
Reaction Conditions
Operation in experiment
21.2%
Stage #1: at 0 - 50℃; for 24 h; Stage #2: Cooling with ice
Example 1: Preparation of 2-(1-ethyleneimine)-4-carbamoyl-3-nitropyridine (the compound II) [Show Image] The reagents used is ( i ) HNO3/H2SO4; (ii) NaNO2; (iii) POCl3; (iv) K2Cr2O7; ( v ) SOCl2, followed by NH4OH; (vi) aziridine.Synthesis of the compound 8 A concentrated sulphuric acid (240mL) was cooled in an ice bath, the starting material compound 7 (50g, 0.462 mol) was slowly added and cooled to 0°C, 55 mL of a mixture in volumetric ratio of 1:1 of a concentrated sulphuric acid (98percent) and a concentrated nitric acid (72percent) was slowly added, then and heated slowly to 50°C, and the reaction was completed after 24 hours. The reaction solution was introduced in to 2 L ice-water, adjusted to pH=7 by adding strong aqua, and filtered. The filter cake was dried, yielding 54g of the crude product. The above filtrate mixture was subject to wet distillation, the resulted bright yellow liquid was subject to extraction with ethyl acetate and recrystallization in ethanol, resulting in 15 g compound 8 with a melting point of 136.1-136.4 °C (ethanol), or 135.4-135.7 °C (water)(M.P. 140 °C was reported in the reference [J. Chem. Soc. 1954, 2248-2451]). The yield is 21.2percent.
Reference：
[1] Acta Chimica Hungarica, 1986, vol. 121, # 4, p. 333 - 338
[2] Acta Chimica Hungarica, 1986, vol. 121, # 4, p. 333 - 338
[3] Australian Journal of Chemistry, 1982, vol. 35, # 10, p. 2035 - 2040
[4] Organic Process Research and Development, 2007, vol. 11, # 5, p. 885 - 888
10
[ 123-73-9 ]
[ 71090-35-2 ]
[ 6635-86-5 ]
Reference：
[1] Archiv der Pharmazie, 1993, vol. 326, # 4, p. 199 - 202
[2] Archiv der Pharmazie, 1993, vol. 326, # 4, p. 199 - 202
11
[ 33245-30-6 ]
[ 13466-41-6 ]
[ 21901-40-6 ]
[ 6635-86-5 ]
Reference：
[1] Australian Journal of Chemistry, 1983, vol. 36, # 6, p. 1159 - 1166
12
[ 33245-30-6 ]
[ 7664-93-9 ]
[ 21901-40-6 ]
[ 6635-86-5 ]
Reference：
[1] Chemische Berichte, 1924, vol. 57, p. 794
13
[ 6635-86-5 ]
[ 21901-18-8 ]
Yield
Reaction Conditions
Operation in experiment
97.6%
at 0℃; Reflux
Synthesis of the compound 9 The compound 8 (11 g, 0.072mol) was added into 150 mL of water, a concentrated sulphuric acid (11mL) was slowly added with agitation and cooled to 0°C in an ice bath. Sodium nitrite (9 g, 0.130 mol) was dissolved in 20mL of water and the solution was added slowly beneath the liquid surface of the reaction solution via a long stem funnel. The reaction was run at room temperature for 2 h and was boiled up until end of the reaction marked by no further emission of a brown gas was observed. Then the reaction solution was cooled, filtered, and dried to obtain 10.8 g of the compound 9 with a yield of 97.6percent. The melting point is 222.3-222.6°C (water)(being in consistent with that disclosed in reference), 231.6-231.8°C(ethanol).
Reference：
[1] Patent: EP2366691, 2011, A1, . Location in patent: Page/Page column 7
[2] Journal of the American Chemical Society, 1950, vol. 72, p. 2806
[3] Journal of Organic Chemistry, 1955, vol. 20, p. 1729,1731
[4] Chemical and Pharmaceutical Bulletin, 2008, vol. 56, # 6, p. 775 - 780
[5] Chemical and Pharmaceutical Bulletin, 2017, vol. 65, # 1, p. 66 - 81
[6] Medicinal Chemistry, 2017, vol. 13, # 4, p. 365 - 374
14
[ 6635-86-5 ]
[ 23056-39-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 13, p. 4448 - 4458
[2] Journal of Organic Chemistry, 1955, vol. 20, p. 1729,1731
[3] Patent: EP2366691, 2011, A1,
[4] Chemical and Pharmaceutical Bulletin, 2017, vol. 65, # 1, p. 66 - 81
[5] Medicinal Chemistry, 2017, vol. 13, # 4, p. 365 - 374
15
[ 6635-86-5 ]
[ 100367-40-6 ]
Yield
Reaction Conditions
Operation in experiment
96%
at 15 - 20℃; for 1.66667 - 2.25 h;
Part A:; A reaction vessel was purged with inert gas. All steps were performed under inert gas protection. The vessel was then charged with 7.50 L of acetic acid at 20-25° C. Next, 1.00 kg of the compound of formula 1 was added to the vessel. A yellow suspension was formed. This was followed by the addition of 1.07 kg of sodium acetate. A very thick, yellow suspension was formed and the reaction was noted to be slightly exothermic. The temperature was raised to about 27° C. The mixture was then cooled to about 15-20° C. and a sample was taken for high pressure liquid chomatography (HPLC) monitoring. A solution of 1.15 kg of bromine (1.1 eq.) and 2.5 L of acetic acid was prepared. A 10/11 portion of the solution, i.e., 1.0 eq. at 15-20° C. was added to the vessel over about 10-15 minutes. The addition was slightly exothermic and some cooling was necessary (Tmax=20° C.). HPLC was used to monitor the reactions progress immediately after the addition and then at 60 min. Less than 10percent of the starting material was observed. Then the remainder of the solution was added and the reaction mixture stirred until completion, approximately 30-60 additional minutes. After the reaction was complete 10.0 L of ice water was added, dropping the temperature to 11° C. and forming a suspension. The suspension was stirred for another 30-60 minutes and the product was filtered, then washed with 3.x.2.50 L of ice water. The product was dried at 40° C. to a constant LOD. The yield was 1.45 kg (96percent), yellow crystals. mp. 132° C. IR (KBr, cm-1): 1633, 1581, 1538, 1512, 1458, 1377, 1344, 1321, 1244, 869, 779. 1H-NMR (CDCl3) (δ, ppm): 2.55 (s, 3H), 5.85 (bs, 2H), 8.25 (s, 1H): 13C-NMR (CDCl3) (δ, ppm): 20.81, 112.14, 144.49, 151.91, 153.78 (2C); MS; (M+1): 232; Elemental Analysis: calcd for C6H6BrN3O2: C, 31.05; H, 2.60; N, 18.11; Br, 34.43; found: C, 30.95; H, 2.42; N, 17.45; Br, 34.80.
96%
With bromine; sodium acetate In acetic acid at 15 - 20℃; for 1.66667 - 2.25 h;
A reaction vessel was purged with inert gas. All steps were performed under inert gas protection. The vessel was then charged with 7.50 L of acetic acid at 20-25° C. Next, 1.00 kg of the compound of formula 1 was added to the vessel. A yellow suspension was formed. This was followed by the addition of 1.07 kg of sodium acetate. A very thick, yellow suspension was formed and the reaction was noted to be slightly exothermic. The temperature was raised to about 27° C. The mixture was then cooled to about 15-20° C. and a sample was taken for high pressure liquid chromatography (HPLC) monitoring. A solution of 1.15 kg of bromine (1.1 eq.) and 2.5 L of acetic acid was prepared. A 10/11 portion of the solution, i.e., 1.0 eq. at 15-20° C. was added to the vessel over about 10-15 minutes. the addition was slightly exothermic and some cooling was necessary (Tmax=20° C.). HPLC was used to monitor the reactions progress immediately after the addition and then at 60 min. Less than 10percent of the starting material was observed. Then the remainder of the solution was added and the reaction mixture stirred until completion, approximately 30-60 additional minutes. After the reaction was complete 10.0 L of ice water was added, dropping the temperature to 10° C. and forming a suspension. The suspension was stirred for another 30-60 minutes and the product was filtered, then washed three times with 2.50 L each time of ice water. The product was dried in at a maximum temperature of 40° C. until reaching constant weight. The yield was 1.45 kg (96.00percent) yellow crystals. Analytical data: m.p. 132° C. IR (KBr, cm-1): 1633, 1581, 1538, 1512, 1458, 1377, 1344, 1321, 1244, 869, 779. 1H-NMR (CDCl3) (δ, ppm): 2.55 (s, 3H), 5.85 (bs, 2H), 8.25 (s, 1H): 13C-NMR (CDCl3) (δ, ppm): 20.81, 112.14, 144.49, 151.91, 153.78 (2C); MS ; (M+1): 232; Elemental Analysis: calcd for C6H6BrN3O2: C 31.05, H 2.60, N 18.11, Br 34.43; found: C 30.95, H 2.42, N 17.45, Br 34.80.
84%
at 15 - 20℃; for 2 h;
To a solution of 4-methyl-3-nitropyridin-2-amine (25 g, 163 mmol) in AcOH (250 ml) was added NaOAc (26.7 g, 326 mmol) and cooled to 15-20°C. Bromine (78.24 g, 489 mmol) in AcOH (200 ml) was added over 30 min and stirred at room temperature for a period of 2 h. The reaction mixture was poured into ice water, the solid formed was filtered and dried to afford title compound as a yellow solid (32 g, 84 percent); 1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.05 (s, 2H), 2.31 (s, 3H).
Reference：
[1] Journal of Organic Chemistry, 1955, vol. 20, p. 1729,1731
18
[ 6635-86-5 ]
[ 133627-45-9 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 2017, vol. 65, # 1, p. 66 - 81
[2] Medicinal Chemistry, 2017, vol. 13, # 4, p. 365 - 374
19
[ 6635-86-5 ]
[ 76006-11-6 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 2017, vol. 65, # 1, p. 66 - 81
[2] Medicinal Chemistry, 2017, vol. 13, # 4, p. 365 - 374
20
[ 6635-86-5 ]
[ 148612-17-3 ]
Yield
Reaction Conditions
Operation in experiment
75%
With N-chloro-succinimide In acetonitrile at 70℃;
General procedure: 2-Amino-5-chloro-4-methyl-3-nitropyridine (4.6 g, 75percent) was prepared using a procedure similar to that described in Example 38 part a except starting from 2-amino-4-methyl-3-nitropyridine (5 g) and using N-chlorosuccinimide (5.8 g) instead of N-bromosuccinimide.
With hydrogen;5% Pd(II)/C(eggshell); In methanol; at 20℃; under 760.051 Torr; for 2h;
Example 1. Preparation of N-Cthiazol^-yl^-CS-CtrifluoromethyOphenyO-SH- imidazo[4,5-b]pyridine-7-carboxamide (Compound 100): Step 1) Synthesis of 4-methylpyridine-2,3-diamine (2):;1 24-Methyl-3-nitropyridin-2-amine (1; 2.0 g, 13 mmol) was dissolved in methanol (30 mL). After a catalytic amount of 5% Pd/C (100 mg) was added, and the mixture was stirred under 1 atm of hydrogen at room temperature for 2 h. The reaction mixture was filtered through a pad of Celite. The filtrate was concentrated under a reduced pressure to afford 4-methylpyridine-2, 3-diamine 2 as a brown solid (1.84 g, yield: 100%). This material was used in the next step without additional purification. MS (ESI) calcd for C6H9N3: 123.2; found: 124 [M+H].
97%
With hydrogen;5%-palladium/activated carbon; In methanol; at 20℃; under 1034.32 Torr; for 3.5h;
Shake a mixture of commercially available 4-methyl-3-nitro- pyridin-2-ylamine (5. 00 g, 32.65 mmol) and 5% palladium on carbon (750 mg) in methanol (200 mL) at room temperature under hydrogen (20 psi) in a Parr bottle for 3.5 h. Filter the mixture through a plug of Celite, eluting with methanol (2 x 50 mL) and remove the filtrate solvent under reduced pressure to afford 4-methylpyridine-2,3-diamine (Step 1) as yellow solid, which is used in the next step without further purification (3.92 g, 97%): APCI MS M/Z 124 [C6HGN3 + H] +.
97%
With hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃;
Commercially available 2-amino-4-methyl-3nitropyridine (10.0 g, 65.3 mmol) was suspended in ethanol (450 mL) and the flask was filled with argon. 10% palladium carbon (13.9 g, 50% water-containing) was added to the mixture and stirred at room temperature overnight under the flow of hydrogen. Solids were filtered through Celite and this was washed with ethanol. The filtrate was concentrated under reduced pressure to obtain Compound P12 (7.81 g, 63.3 mmol, 97%). ESI-MS: m/z 124 [M + H]+ 1H NMR (CDCl3)delta(ppm): 2.17 (s, 3H), 3.27 (brs, 2H), 4.16 (brs, 2H), 6.53 (d, J = 5.3 Hz, 1H), 7.55 (d, J = 5.0 Hz, 1H).
92%
With methanol;5%-palladium/activated carbon; for 2h;
4-Methyl-3-nitropyridine-2-amine (25 g, 163.4 mmol) was dissolved in 100 ml of MeOH, and a catalytic amount of 5% Pd/C was added thereto, and the mixture was stirred for 2 hrs. The reaction solution was filtered through a celite pad, the pad was thoroughly washed with MeOH, and the combined mixture was concentrated under a reduced pressure to remove the solvent. The resulting residue was vacuum dried to obtain the title compound (18.49 g, 150.33 mmol; yield: 92 %). 1H-NMR (CDCl3): 2.17 (s, 3H), 3.27 (br, 2H), 4.14 (br, 2H), 6.54 (d,2H), 7.55 (d, 2H) M. W.: 124
67%
With hydrogen;5%-palladium/activated carbon; In acetic acid; at 20℃; under 760.051 Torr; for 3h;
7.5 g of 5 % palladium-carbon catalyst (water content 50 %) was added to acetic acid (300 ml) solution of 15.0 g (97.9 mmol) of <strong>[6635-86-5]2-amino-4-methyl-3-nitropyridine</strong>, and the resulting mixture was stirred under atmospheric pressure of hydrogen at room temperature for 3 hours. After filtrating and concentrating under reduced pressure, the residue was dissolved in aqueous 10 % sodium carbonate solution and concentrated under reduced pressure. The residue was dissolved in mixed solution of chloroform/methanol (3/1, v/v) , and the insoluble material was removed through filtration. This was applied to a silica gel column chromatography. From the eluate with chloroform/methanol (20/1, v/v) , a pink-brown solidwas obtained. From the 1H-NMR, since the presence of acetic acid therein was confirmed, this solid was again dissolved in aqueous 10 % sodium carbonate solution and concentrated under reduced pressure. The residue was dissolved in chloroform, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure and the resulting residue was dried to obtain 8.13 g (67 %) of the entitled compound as a yellow-brown solid. MS(FAB)m/z:124(M+1)+.1H-NMR(CD3OD)delta: 2.14(3H, s) , 6.46(2H, t, J=5.4Hz) , 7.27(2H, t, J=5.4Hz).
37%
With iron; ammonium chloride; In water; isopropyl alcohol; at 70℃; for 2h;
c) 4-Methylpyridine-2,3-diamine (A21) Iron powder (0.365 g, 6.53 mmol) and NH4CI (0.349 g, 6.53 mmol) were added to a stirred suspension of 4-methyl-3-nitropyridin-2-amine A17 (0.200 g, 1.31 mmol) in /-PrOH (10 mL) and water (5 mL). The reaction was heated to 70 C and stirred for 2 hours. The reaction was then cooled and filtered through a plug of celite, which was washed with EtOAc (75 mL). The filtrate was washed with saturated aqueous NaHC03 (75 mL), brine (75 mL), dried (Na2S04), filtered and concentrated in vacuo to give the title compound (0.060 g, 37%) as a dark purple solid. H NMR (400 MHz, CDCI3): delta 7.55 (d, J = 5.1 Hz, 1 H), 6.53 (d, J = 5.1 Hz, 1 H), 4.19 (br s, 2H), 3.26 (brs, 2H), 2.16 (s, 3H). LCMS-B: rt 0.74 min, m/z (positive ion) 124.1 [M+H]+.
palladium dihydroxide; In methanol;
EXAMPLE 17 STR19 2,3-Diamino-4-methylpyridine A solution of <strong>[6635-86-5]2-amino-4-methyl-3-nitropyridine</strong> (Aldrich 10 Chemical Co., 500 mg) in methanol (3 mL) was treated with palladium hydroxide on carbon (50 mg) and stirred under a hydrogen atmosphere (1 atm) at room temperature for 6 h. The mixture was filtered through a pad of celite filter aid and the solvent removed by rotoevaporation to give the title compound (340 mg). Mass spectrum (FAB): m/e=124 (M+1).
palladium-carbon; In ethanol;
Step A: Preparation of 2,3-diamino-4-picoline (cf. Lappin, G. R.; Slezak, F. B. J. Am. Chem. Soc., 1950, 72, 2806-7) To a slurry of <strong>[6635-86-5]2-amino-4-methyl-3-nitropyridine</strong> (10.0 g, 65.3 mmol) in 350 mL of 95% EtOH was added 500 mg of a 10% Pd/C catalyst. The mixture was stirred under a H2 atmosphere (1 atm) for 36 hours. Filtration and evaporation gave 8.05 g of a black solid which was used directly in the next step.
palladium-carbon; In ethanol;
Step A: Preparation of 2,3-diamino-4-picoline (cf. Lappin, G. R.; Slezak, F. B. J. Am. Chem. Soc., 1950, 72,2806-7) To a slurry of <strong>[6635-86-5]2-amino-4-methyl-3-nitropyridine</strong> (10.0 g, 65.3 mmol) in 350 ml of 95% EtOH was added 500 mg of a 10% Pd/C catalyst. The mixture was stirred under a H2 atmosphere (1 atm) for 36 hours. Filtration and evaporation gave a black solid which was used directly in the next step.
With hydrogen;nickel; In methanol; under 2280.15 Torr; for 1.5 - 2h;Product distribution / selectivity;
Raney Nickel (2.5 g) is added to a mixture of commercially available 4-methyl-3- nitro-pyridin-2-ylamine x175 (7.0 g, 45.7 mmol) in methanol (300 ml), and the obtained reaction mixture is hydrogenated in the Parr apparatus at the hydrogen pressure 3 atm EPO <DP n="134"/>until the total conversion of compound x175 is attained for approximately 1.5-2 h. The catalyst is separated by filtration, the filtrate is washed with methanol, and the alcohol solution is evaporated to dryness. CH(OMe)3 (100 ml) and PTSA (0.5 g) are added to the residue, and an air reflux condenser is mounted. The apparatus is argon-blown, and the obtained reaction mixture is heated to 125 0C under vigorous stirring for 1O h. The formed solution is evaporated, and the residue is dissolved in 5 % HCI (100 ml). The solution is refluxed for 1 h and evaporated to one-third volume. The solution is neutralized to pH 7 and extracted with 10 % tert-butanol in chloroform (4 x 100 ml). The organic layer is dried over anhydrous Na2SO4, and the solvent is evaporated. The residue is purified by chromatography on silicagel (chloroform/methanol) to afford 7-methyl-3H-imidazo[4,5- b]pyridine x176.Yield: 70 %.LC-IvIS (MH+): 134.; Raney Ni (1.5 g) is added to a mixture of commercially available nitrogen- containing 4-methyl-3-nitropyridin-2-amine x220 (4.0 g, 26.1 mmol) in methanol (150 ml), and the obtained reaction mixture is hydrogenated in the Parr apparatus at the hydrogen pressure 3 atm until the total conversion of compound x220 is attained for approximately 1.5-2 h. The catalyst is separated by filtration, the filtrate is washed with methanol, and the alcohol solution is evaporated to dryness. The residue is dissolved in sulfolane (10 ml), then PhC(OMe)3 (5.7 g, 1.2 eq, 31.3 mmol) and PTSA (0.3 g) are added, and an air reflux condenser is mounted. The apparatus is argon-blown, and the obtained reaction mixture is heated to 165 0C under vigorous stirring for 10 h. Water (100 ml), saturated aqueous NaHCC>3 (5 ml), and hexane (50 ml) are added to the reaction mixture. The obtained suspension is stirred for 5 min, and the residue is separated by filtration. The residue is washed with water (50 ml) and hexane (100 ml), and vacuum-dried over P2O5 to a constant weight at 45 0C to give 7-methyl-2-phenyl-3H-imidazo[4,5-b]pyridine x221 (2.2 g).Yield: 40 %. LC-MS (MH+): 210.
In ethanol;
2,3-Diamino-4-methylpyridine (56) A mixture of <strong>[6635-86-5]2-amino-4-methyl-3-nitropyridine</strong> (919 mg, 6.0 mmol), ethanol (20 mL) and Raney Ni (about 200 mg) was shaken under H2 (30-40 psi) for 1 h, then filtered. The filtrate was evaporated to dryness, giving 740 mg (100%) of the diamine 56, mp 114-5 C. 1 H NMR (DMSO-d6), 1.997 (s, 3H), 4.359 (s, 2H), 5.250 (s, 2H), 6.264 (d, 1H, J=3), 7.173 (d, 1H, J=3).
palladium-carbon; In ethanol;
Step A: Preparation of 2,3-diamino-4-picoline (cf. Lappin, G. R.; Slezak, F. B. J. Am. Chem. Soc., 1950, 72, 2806-7) To a slurry of <strong>[6635-86-5]2-amino-4-methyl-3-nitropyridine</strong> (10.0 g, 65.3 mmol) in 350 mL of 95% EtOH was added 500 mg of a 10% Pd/C catalyst. The mixture was stirred under a H2 atmosphere (1 atm) for 36 hours. Filtration and evaporation gave 8.05 g of a black solid which was used directly in the next step.
With sulfuric acid; water; sodium nitrite; at 0℃;Reflux;
Synthesis of the compound 9 The compound 8 (11 g, 0.072mol) was added into 150 mL of water, a concentrated sulphuric acid (11mL) was slowly added with agitation and cooled to 0°C in an ice bath. Sodium nitrite (9 g, 0.130 mol) was dissolved in 20mL of water and the solution was added slowly beneath the liquid surface of the reaction solution via a long stem funnel. The reaction was run at room temperature for 2 h and was boiled up until end of the reaction marked by no further emission of a brown gas was observed. Then the reaction solution was cooled, filtered, and dried to obtain 10.8 g of the compound 9 with a yield of 97.6percent. The melting point is 222.3-222.6°C (water)(being in consistent with that disclosed in reference), 231.6-231.8°C(ethanol).
With 2,4-dichlorophenoxyacetic acid dimethylamine;
Example 63 N-(4-Methyl-3-nitropyridin-2-yl)-(2-chloro-5-nitrophenyl)carboxamide The title compound (0.482 g) was obtained as a crystalline solid according to the procedure described in Example 2 using <strong>[6635-86-5]2-amino-4-methyl-3-nitropyridine</strong> (0.306 g), DMA (5 ml) and 2-chloro-5-nitrobenzoyl chloride (0.528 g). 1H-NMR (400 MHz, DMSO-d6, TMS): delta(ppm) 7.51 (1H, d, J=5.0 Hz), 7.90 (1H, d, J=8.8 Hz), 8.26 (1H, d, J=2.8 Hz), 8.38 (1H, dd, J=2.8, 8.8 Hz), 8.56 (1H, d, J=5.0 Hz).
Step 1 Preparation of 2-amino-4-methyl-3,5-dinitro-pyridine To a stirred solution of <strong>[6635-86-5]2-amino-4-methyl-3-nitropyridine</strong> (25.6 g, 167 mmol) in conc. H2 SO4 (50 mL) at 0 C. was added HNO3 (7.77 mL, d=1.49) drop-wise over 30 min. The mixture was warmed to r.t. for 1 h then heated to 50 C. for 60 min. The reaction mixture was cooled and poured into 500 g of ice. The resulting precipitate was filtered, washed with 50 mL of H2 O, and air dried to give 2-amino-4-methyl-3,5-dinitro-pyridine as a yellow solid.
Preparation 11 A mixture of <strong>[6635-86-5]2-amino-4-methyl-3-nitropyridine</strong> (5.0 g) and N,N-dimethylaniline (8.5 ml) was heated at 100 C. under nitrogen atmosphere. To the solution was added butyryl chloride (3.5 ml) and the mixture was stirred at 100 C. for 5 hours. After being cooled to room temperature, ethyl acetate was added to the reaction mixture. The organic layer was separated and washed successively with water and brine. The solution was dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was washed with n-hexane to give 2-butyrylamino-4-methyl-3-nitropyridine (7.0 g). mp: 92.5-99 C. NMR (CDCl3, delta): 1.01 (3H, t, J=7.5 Hz), 1.64-1.85 (2H, m), 2.43 (2H, t, J=7.5 Hz), 2.48 (3H, s), 7.10 (1H, d, J=5.0 Hz), 8.26 (1H, br s), 8.35 (1H, d, J=5.0 Hz)
In ethyl acetate; N,N-dimethyl-aniline;
Preparation 109 A mixture of <strong>[6635-86-5]2-amino-4-methyl-3-nitropyridine</strong> (5.0 g) and N,N-dimethylaniline (8.5 ml) was heated at 100 C. under nitrogen atmosphere. To the solution was added butyryl chloride (3.5 ml) and the mixture was stirred at 100 C. for 5 hours. After being cooled to room temperature, ethyl acetate was added to the reaction mixture. The organic layer was separated and washed successively with water and brine. The solution was dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was washed with n-hexane to give 2-butyrylamino-4-methyl-3-nitropyridine (7.0 g). mp: 92.5-99 C. NMR (CDCl3, delta): 1.01 (3H, t, J=7.5 Hz), 1.64-1.85 (2H, m), 2.43 (2H, t, J=7.5 Hz), 2.48 (3H, s), 7.10 (1H, d, J=5.0 Hz), 8.26 (1H, br s), 8.35 (1H, d, J=5.0 Hz)
Step 1 Preparation of 2-amino-3,5-dinitro-4-methylpyridine To a stirred solution of <strong>[6635-86-5]2-amino-3-nitro-4-methylpyridine</strong> (25.6 g, 167 mmol) in conc. H2 SO4 (100 mL) at 0 C. was added HNO3 (7.77 mL, d=1.49) dropwise over 30 min. The mixture was warmed to r.t. for 20 min then heated to 45 C. for 90 min. The reaction mixture was cooled and poured into 500 g of ice. The resulting percipitate was filtered and air dried to give 2-amino-3,5-dinitropyridine as a yellow solid.
With propionic acid;aluminum nickel; In tetrahydrofuran; methanol; PPA;
a 2-Ethyl-7-methyl-3H-imidazo[4,5-b]pyridine 10 g (65.3 mmol) of <strong>[6635-86-5]2-amino-4-methyl-3-nitropyridine</strong> are hydrogenated in 40 ml of tetrahydrofuran and 40 ml of methanol in the presence of Raney nickel. The catalyst is filtered off, the solvent is removed, the residue is treated with ethanolic HCl solution and the precipitated 2,3-diamino-4-methylpyridine hydrochloride is filtered off with suction. 7 g of this hydrochloride are dissolved in 57 g of polyphosphoric acid (from 28.5 g of P2 O5 and 28.5 g of H3 PO 4 (85% strength)) and treated with 1.26 ml of propionic acid, and the solution is stirred at 100 C. for 2h. After cooling, it is poured into ice-water, rendered alkaline by addition of Na2 CO3 and extracted several times with EA. The combined EA phases are washed with saturated NaCl solution, dried over Na2 SO4 and concentrated and the residue is chromatographed on SiO2 (EA/MeOH 5:1). 4.2 g of the title compound result. Rf (SiO2, EA/MeOH 5:1)=0.4 MS(DCl): 162 (M+H)
EXAMPLE 102 Synthesis of 2-Cyclopropanecarboxamido-4-Methyl-3-Nitropyridine STR84 A mixture comprising 5.0 g (32.6 mmol) of <strong>[6635-86-5]2-amino-4-methyl-3-nitropyridine</strong> and 5.2 g of pyridine was heated at 110 C. in a nitrogen atmosphere. 3.8 g (36 mmol) of cyclopropanecarbonyl chloride was dropwise added thereto, followed by further stirring at 110 C. for 5 hours. The reaction mixture was brought to room temperature, followed by the addition of chloroform (50 ml) and water (50 ml). The organic phase was separated and the aqueous phase was further extracted with chloroform (50 ml) twice. The organic phases were combined and washed with water (20 ml) and a saturated aqueous solution (20 ml) of common salt, successively. The resultant organic phase was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 5.4 g of the title compound (yield 75%). m.p.; 179 C. 1 H-NMR (400 MHz, CDCl3); delta(ppm) 0.89~0.94 (2H, m), 1.11~1.15 (2H, m), 1.67~1.73 (1H, m), 2.49 (3H, d, J=0.6 Hz), 7.08 (1H, dd, J=5.0, 0.6 Hz), 8.36 (1H, d, J=5.0 Hz), 8.61 (1H, br-s) FAB-MS; 222 (MH+)
Stage A: 4-methyl-3-nitro-2-(1-pyrrolyl)pyridine 11.82 g (0.0581 mol; yield: 90.4%) of a yellow powder, which turns red in air, are obtained by carrying out the reaction in the same way as in Stage B of Example 92 but starting from 9.85 g (0.0643 mol) of 4-methyl-3nitro-2-aminopyridine and using 10.2 g (0.0772 mol; 1.2 eq) of 2,5-dimethoxytetrahydrofuran and 200 cm3 of glacial CH3 CO2 H, and bringing the solution to reflux for 3 h. Melting point: 63 C.
With bromine; acetic acid; at 15 - 20℃; for 1.66667 - 2.25h;
Part A:; A reaction vessel was purged with inert gas. All steps were performed under inert gas protection. The vessel was then charged with 7.50 L of acetic acid at 20-25 C. Next, 1.00 kg of the compound of formula 1 was added to the vessel. A yellow suspension was formed. This was followed by the addition of 1.07 kg of sodium acetate. A very thick, yellow suspension was formed and the reaction was noted to be slightly exothermic. The temperature was raised to about 27 C. The mixture was then cooled to about 15-20 C. and a sample was taken for high pressure liquid chomatography (HPLC) monitoring. A solution of 1.15 kg of bromine (1.1 eq.) and 2.5 L of acetic acid was prepared. A 10/11 portion of the solution, i.e., 1.0 eq. at 15-20 C. was added to the vessel over about 10-15 minutes. The addition was slightly exothermic and some cooling was necessary (Tmax=20 C.). HPLC was used to monitor the reactions progress immediately after the addition and then at 60 min. Less than 10% of the starting material was observed. Then the remainder of the solution was added and the reaction mixture stirred until completion, approximately 30-60 additional minutes. After the reaction was complete 10.0 L of ice water was added, dropping the temperature to 11 C. and forming a suspension. The suspension was stirred for another 30-60 minutes and the product was filtered, then washed with 3×2.50 L of ice water. The product was dried at 40 C. to a constant LOD. The yield was 1.45 kg (96%), yellow crystals. mp. 132 C. IR (KBr, cm-1): 1633, 1581, 1538, 1512, 1458, 1377, 1344, 1321, 1244, 869, 779. 1H-NMR (CDCl3) (delta, ppm): 2.55 (s, 3H), 5.85 (bs, 2H), 8.25 (s, 1H): 13C-NMR (CDCl3) (delta, ppm): 20.81, 112.14, 144.49, 151.91, 153.78 (2C); MS; (M+1): 232; Elemental Analysis: calcd for C6H6BrN3O2: C, 31.05; H, 2.60; N, 18.11; Br, 34.43; found: C, 30.95; H, 2.42; N, 17.45; Br, 34.80.
96.00%
With bromine; sodium acetate; In acetic acid; at 15 - 20℃; for 1.66667 - 2.25h;
A reaction vessel was purged with inert gas. All steps were performed under inert gas protection. The vessel was then charged with 7.50 L of acetic acid at 20-25 C. Next, 1.00 kg of the compound of formula 1 was added to the vessel. A yellow suspension was formed. This was followed by the addition of 1.07 kg of sodium acetate. A very thick, yellow suspension was formed and the reaction was noted to be slightly exothermic. The temperature was raised to about 27 C. The mixture was then cooled to about 15-20 C. and a sample was taken for high pressure liquid chromatography (HPLC) monitoring. A solution of 1.15 kg of bromine (1.1 eq.) and 2.5 L of acetic acid was prepared. A 10/11 portion of the solution, i.e., 1.0 eq. at 15-20 C. was added to the vessel over about 10-15 minutes. the addition was slightly exothermic and some cooling was necessary (Tmax=20 C.). HPLC was used to monitor the reactions progress immediately after the addition and then at 60 min. Less than 10% of the starting material was observed. Then the remainder of the solution was added and the reaction mixture stirred until completion, approximately 30-60 additional minutes. After the reaction was complete 10.0 L of ice water was added, dropping the temperature to 10 C. and forming a suspension. The suspension was stirred for another 30-60 minutes and the product was filtered, then washed three times with 2.50 L each time of ice water. The product was dried in at a maximum temperature of 40 C. until reaching constant weight. The yield was 1.45 kg (96.00%) yellow crystals. Analytical data: m.p. 132 C. IR (KBr, cm-1): 1633, 1581, 1538, 1512, 1458, 1377, 1344, 1321, 1244, 869, 779. 1H-NMR (CDCl3) (delta, ppm): 2.55 (s, 3H), 5.85 (bs, 2H), 8.25 (s, 1H): 13C-NMR (CDCl3) (delta, ppm): 20.81, 112.14, 144.49, 151.91, 153.78 (2C); MS ; (M+1): 232; Elemental Analysis: calcd for C6H6BrN3O2: C 31.05, H 2.60, N 18.11, Br 34.43; found: C 30.95, H 2.42, N 17.45, Br 34.80.
84%
With bromine; sodium acetate; acetic acid; at 15 - 20℃; for 2h;
To a solution of 4-methyl-3-nitropyridin-2-amine (25 g, 163 mmol) in AcOH (250 ml) was added NaOAc (26.7 g, 326 mmol) and cooled to 15-20C. Bromine (78.24 g, 489 mmol) in AcOH (200 ml) was added over 30 min and stirred at room temperature for a period of 2 h. The reaction mixture was poured into ice water, the solid formed was filtered and dried to afford title compound as a yellow solid (32 g, 84 %); 1H NMR (400 MHz, DMSO-d6) delta 8.28 (s, 1H), 7.05 (s, 2H), 2.31 (s, 3H).
EXAMPLE 6 Method F Methyl 4'-[({3-[(cyanoacetyl)amino]-4-methylpyridin-2-yl}amino)methyl]-2',3-difluoro-1,1'-biphenyl-2-carboxylate [0212] [CHEMMOL-00020] [0213] To a stirred solution of 1-bromo-2-fluoro-4-methylbenzene (0.945 g, 5 mmol) in DMF (10 mL) in a sealed tube, bis(pinacolato)diboron (2.29 g, 9 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.146 g, 0.2 mmol), and potassium acetate (1.47 g, 15 mmol) were added at room temperature. The resulting mixture was heated at 80 C. for 16 hours to provide 2-(2-fluoro-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and the solution was cooled to room temperature for the next step without any workup. [0214] To the above solution, methyl 2-fluoro-6-iodobenzoate (1.40 g, 5 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.10 g, 0.15 mmol), and sodium carbonate solution (2 M, 12.5 mL, 25 mmol) were added. The resulting mixture was heated at 80 C. for 16 hours. After cooling to room temperature, the mixture was partitioned between water and diethyl ether. The organic extract was washed with brine, dried over MgSO4, filtered and concentrated under vacuum. The residue was subjected to silica gel chromatography eluted with 10% ethyl acetate in hexanes to provide methyl 2',3-difluoro-4'-methyl-1,1'-biphenyl-2-carboxylate as a yellow oil with a mass ion of ion (ES+) of 263.0 for M+H+. [0215] A mixture of the carboxylate (0.90 g, 3.43 mmol), N-bromo-succinimide (0.672 g, 3.78 mmol), and 2,2'-azobisisobutyronitrile (0.0169, 0.10 mmol) was suspended in 50 mL carbon tetrachloride, and heated to reflux for 5 hours. The reaction mixture was filtered to remove the residue. The resulting filtrate was concentrated under vacuum, and then partitioned between ethyl acetate and water. The organic extract was washed with brine, dried over MgSO4, filtered and concentrated under vacuum. The residue was subjected to silica gel chromatography eluted with 10% ethyl acetate in hexanes to afford methyl 4'-(bromomethyl)-2',3-difluoro-1,1'-biphenyl-2-carboxylate as a brown oil with a mass ion of ion (ES+) of 341 for M+H+. [0216] To a stirred solution of <strong>[6635-86-5]2-amino-4-methyl-3-nitropyridine</strong> (0.306 g, 2 mmol) in DMF (2 mL) at 0 C., sodium hydride (60% dispersion in mineral oil, 0.040 g, 1 mmol) was added, and stirred at 0 C. for 20 minutes. To the resulting mixture, methyl 4'-(bromomethyl)-2',3-difluoro-1,1'-biphenyl-2-carboxylate (0.341 g, 1 mmol) was added, and stirring continued at 0 C. for another 30 minutes. The reaction was quenched by the addition of saturated ammonium chloride (5 mL), and partitioned between ethyl acetate and water. The organic extract was washed with brine, dried over MgSO4, filtered and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with 20% ethyl acetate in hexanes to provide methyl 2',3-difluoro-4'-[(4-methyl-3-nitropyridin-2-yl)amino]-methyl}-1,1'-biphenyl-2-carboxylate as a yellow oil with a mass ion of ion (ES+) of 414 for M+H+. [0217] To a stirred solution of the above product (0.11 g, 0.266 mmol) in methanol (2 mL), tin(II) chloride dihydrate (0.24 g, 1.06 mmol) was added and heated in a sealed tube at 70 C. for 2 hours. The resulting solution was concentrated under vacuum. The residue was dissolved in ethyl acetate (20 mL), and 10% aq. sodium carbonate solution was added with vigorous stirring until pH=10. The white suspension was filtered through a pad of Celite, and the filtrate was partitioned between ethyl acetate and water. The organic extract was washed with brine, dried over MgSO4, filtered and concentrated under vacuum. The residue was subjected to silica gel chromatography eluted with 55% ethyl acetate in hexanes to provide methyl 4'-[(3-amino-4-methylpyridin-2-yl)amino]methyl}-2',3-difluoro-1,1'-biphenyl-2-carboxylate as a yellow solid. [0218] To a solution of the above carboxylate (0.038 g, 0.10 mmol) in DMF (1 mL), cyanoacetic acid (0.026 g, 0.30 mmol), 1-ethyl-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.038 g 0.20 mmol), 1-hydroxy-7-azabenzotriazole (0.0136 g, 0.10 mmol) were added, and N,N-diisopropylethylamine was added until pH=10. The resulting solution was stirred at room temperature for 20 hours, and partitioned between ethyl acetate and water. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue was subjected to silica gel chromatography eluted with 60% ethyl acetate in hexanes. The appropriate fractions were concentrated under vacuum, and the residue was dissolved in 60 mL of 50% acetonitrile in hydrochloric acid (2 mL conc. hydrochloric acid in 4 L water). Lyophilization of the resulting solution afforded the HCl salt of the title compound as a white solid that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 451 for M+H+: 1H NMR (400 MHz, DMSO) 69.98 (br s, 1H), 7.81 (d, J=6.12 H...
[0179] To a solution of <strong>[6635-86-5]2-amino-4-methyl-3-nitropyridine</strong> (1.53 g, 10 mmol) in DMF (10 mL) at 0 C., sodium hydride (60% dispersion in mineral oil, 0.20 g, 5 mmol) was added, and stirred at 0 C. for 20 minutes. To the resulting mixture, 2-fluoro-4-bromobenzyl bromide (1.34 g, 5 mmol) was added, and stirred at 0 C. for another 10 minutes. The reaction was quenched by the addition of saturated ammonium chloride (10 mL), and partitioned between ethyl acetate and water. The organic extract was washed with brine, dried over MgSO4, filtered and concentrated under vacuum to provide N-(4-bromo-2-fluorobenzyl)-4-methyl-3-nitropyridin-2-amine with a mass ion (ES+) of 340.1 for M+H+. [0180] The above residue was suspended in methanol (20 mL), and tin(II) chloride dihydrate (4.51 g, 20 mmol) was added and heated in a sealed tube at 70 C. for 5 hours. The resulting solution was concentrated under vacuum. The residue was dissolved in ethyl acetate (100 mL), and 10% aq. sodium carbonate solution were added with vigorous stirring until pH=10. The white suspension was filtered through a pad of Celite, and the filtrate was partitioned between ethyl acetate and water. The organic extract was washed with brine, dried over MgSO4, filtered and concentrated under vacuum. The residue was subjected to silica gel chromatography eluted with 40% ethyl acetate in hexanes to provide N-2-(4-bromo-2-fluorobenzyl)-4-methylpyridine-2,3-diamine (0.42 g, 1.35 mmol) as a yellow solid with a mass ion (ES+) of 310.2 for M+H+. [0181] To a stirred solution of the above diamine (0.42 g, 1.35 mmol) in DMF (4 mL) in a sealed tube, bis(pinacolato)diboron (0.688 g, 2.71 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.0396 g, 0.05 mmol), and potassium acetate (0.399 g, 4.06 mmol) were added at room temperature. The resulting mixture was heated at 80 C. for 16 hours to provide N-2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-4-methylpyridine-2,3-diamine, and the solution was cooled to room temperature. To this solution, methyl 2-fluoro-6-iodobenzoate (0.756 g, 2.70 mmol), dichloro[1,1'-bis(diphenyl-phosphino)ferrocene]palladium (II) dichloromethane adduct (0.0395 g, 0.05 mmol), and sodium carbonate solution (2 M, 3.38 mL, 6.75 mmol) was added. The resulting mixture was heated at 80 C. for 16 hours. After cooling to room temperature, the mixture was partitioned between water and diethyl ether. The organic extract was washed with brine, dried over MgSO4, filtered and concentrated under vacuum. The residue was subjected to silica gel chromatography eluted with 45% ethyl acetate in hexanes to provide methyl 4'-[(3-amino-4-methylpyridin-2-yl)amino]methyl}-3,3'-difluoro-1,1'-biphenyl-2-carboxylate (0.50 g, 1.31 mmol) as a yellow oil with a mass ion (ES+) of 384.4 for M+H+. [0182] To a solution of the above carboxylate (0.153 g, 0.40 mmol) in DMF (2 mL), 3,3,3-trifluoropropanoic acid (0.154 g, 1.20 mmol), 1-ethyl-(3-dimethyl-aminopropyl)carbodiimide hydrochloride (0.153 g, 0.80 mmol), 1-hydroxy-7-aza-benzotriazole (0.0544 g, 0.40 mmol) were added, and N,N-diisopropylethylamine was added until pH=8. The resulting solution was stirred at room temperature for 1 hour, and then partitioned between ethyl acetate and water. The organic extract was washed with brine, dried over MgSO4, filtered and concentrated under vacuum. The residue was subjected to silica gel chromatography eluted with 40% ethyl acetate in hexanes. The appropriate fractions were concentrated under vacuum, and the residue was dissolved in 60 mL of 50% acetonitrile in hydrochloric acid (2 mL conc. hydrochloric acid in 4 L water). Lyophilization of the resulting solution afforded HCl salt of the title compound that gave a proton NMR spectrum consistent with theory and a mass ion (ES+) of 494.4 for M+H+: 1H NMR (600 MHz, CD3CN) delta 9.37 (br s, 1H), 7.76 (br s, 1H), 7.69 (d, J=6.6 Hz, 1H), 7.56 (m, J=5.8 Hz, 7.9 Hz, 1H), 7.50 (t, J=7.8 Hz, 1H), 7.28 (d, J=7.6 Hz, 1H), 7.25 (t, J=9.0 Hz, 1H), 7.15 (d, J=10 Hz, 1H), 7.12 (d, J=7.8 Hz, 1H), 6.80 (d, J=6.6 Hz, 1H), 4.96 (d, J=5.2 Hz, 2H), 3.67 (s, 3H), 3.60 (q, J=11 Hz, 2H), 2.25 (s, 3H).
Example 1: Preparation of 2-(1-ethyleneimine)-4-carbamoyl-3-nitropyridine (the compound II) [Show Image] The reagents used is ( i ) HNO3/H2SO4; (ii) NaNO2; (iii) POCl3; (iv) K2Cr2O7; ( v ) SOCl2, followed by NH4OH; (vi) aziridine.Synthesis of the compound 8 A concentrated sulphuric acid (240mL) was cooled in an ice bath, the starting material compound 7 (50g, 0.462 mol) was slowly added and cooled to 0C, 55 mL of a mixture in volumetric ratio of 1:1 of a concentrated sulphuric acid (98%) and a concentrated nitric acid (72%) was slowly added, then and heated slowly to 50C, and the reaction was completed after 24 hours. The reaction solution was introduced in to 2 L ice-water, adjusted to pH=7 by adding strong aqua, and filtered. The filter cake was dried, yielding 54g of the crude product. The above filtrate mixture was subject to wet distillation, the resulted bright yellow liquid was subject to extraction with ethyl acetate and recrystallization in ethanol, resulting in 15 g compound 8 with a melting point of 136.1-136.4 C (ethanol), or 135.4-135.7 C (water)(M.P. 140 C was reported in the reference [J. Chem. Soc. 1954, 2248-2451]). The yield is 21.2%.
With selenium(IV) oxide; In 1,4-dioxane; water; at 100℃; for 16h;
Intermediate G2To a solution of 4-methyl-3-nitropyridin-2-amine (10.0 g, 65.0 mmol) in a mixture of dioxane (400 m L) and water (50 mL) was added selenium dioxide (29.0 g, 260 mmol) and the reaction mixture was heated to 100C for 16 hr and then cooled to RT and filtered through a pad of celite. The pad was washed with a mixture of EtOAc/THF (3:1 v/v, 100 mL) and the combined filtrate and washings were evaporated in vacuo. The residue was partitioned between EtOAc/THF (3:1 v/v, 100 mL) and sat aq. NaHC03 (150 mL) diluted with water (150 mL). The aq layer was separated and was extracted with EtOAc/THF (3:1 v/v, 4 x 100 mL) and the combined organic extracts were dried and evaporated in vacuo to afford 2-amino-3- nitroisonicotinaldehyde as a brown solid (2.73 g, 25%); R' 0.75 min (Method 2); m/z 168 (M+H)+, (ES+).
25%
With selenium(IV) oxide; In 1,4-dioxane; water; at 100℃; for 16h;
To a solution of 4-methyl-3-nitropyridin-2-amine (10.0 g, 65.0 mmol) in a mixture of dioxane (400 mL) and water (50 mL) was added selenium dioxide (29.0 g, 260 mmol) and the reaction mixture was heated to 100 C. for 16 hr and then cooled to RT and filtered through a pad of celite. The pad was washed with a mixture of EtOAc/THF (3:1 v/v, 100 mL) and the combined filtrate and washings were evaporated in vacuo. The residue was partitioned between EtOAc/THF (3:1 v/v, 100 mL) and sat aq. NaHCO3 (150 mL) diluted with water (150 mL). The aq layer was separated and was extracted with EtOAc/THF (3:1 v/v, 4*100 mL) and the combined organic extracts were dried and evaporated in vacuo to afford 2-amino-3-nitroisonicotinaldehyde as a brown solid (2.73 g, 25%); Rt 0.75 min (Method 2); m/z 168 (M+H)+, (ES+).
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