* 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.
With iron; ammonium chloride In water; isopropyl alcohol at 90℃; for 1 h;
a) 6-Chloropyridine-2,3-diamine (A45) Iron powder (9.65 g, 173 mmol) was added to a suspension of 6-chloro-3-nitropyridin-2- amine A44 (10.0 g, 57.6 mmol) and NH4CI (6.16 g, 115 mmol) in isopropanol (180 mL) and water (90 mL). The resulting mixture was heated at 90 °C for one hour. After this time, the suspension was left to cool to room temperature, then diluted with EtOAc (100 mL), filtered through Celite and the residues washed with further EtOAc (2 x 150 mL). The filtrate was washed with water (3 x 100 mL), brine (100 mL), dried over Na2S04 and the volatiles removed under reduced pressure to give the title compound (7.50 g, 91 percent) as a dark brown solid. H NMR (400 MHz, cfe-DMSO) δ 6.68 (d, J = 7.8 Hz, 1 H), 6.35 (d, J = 7.8 Hz, 1 H), 5.78 (s, 2H), 4.76 (s, 2H).
91%
With sodium tetrahydroborate In ethanol; water at 20℃; for 4 h;
General procedure: SAC (300mg) and NaBH4 (4.0mmol) were added to a solution of nitroarenes (1.0mmol) in EtOH/water (1/1) (20ml). The reaction mixture was stirred for 4h at the temperature indicated in Table3. At the end of the reaction, the catalyst was removed by filtering and the filtrate was extracted with 3×70ml EtOAc. The combined organic layers were dried over MgSO4 and concentrated in a vacuum.
89.2%
With iron; ammonium chloride In water; ethyl acetate at 20℃; for 4 h;
Compound 1 (500 g, 2.89 mol),Ammonium chloride (300 g, 5.75 mol) was dissolved in 5000 ml of ethyl acetate and 3000 ml of water,To this mixture was added iron powder (482.5g, 8.65mol) at room temperature, the reaction was carried out at room temperature for 4 hours,The reaction was complete by TLC and the reaction mixture was filtered. The filtrate was separated and the aqueous phase was extracted twice with 1500 ml of ethyl acetate. The combined organic phases were dried over saturated brine and concentrated to give compound 2 (370 g, 2.58 mol)Yield 89.2percent
77%
Stage #1: With tin(ll) chloride In ethyl acetate; <i>tert</i>-butyl alcohol at 60℃; for 1 h; Stage #2: With sodium tetrahydroborate In ethyl acetate; <i>tert</i>-butyl alcohol at 60℃; for 12 h;
Intermediate 16-Chloropyridine-2,3-diamineIn a 2-neck, 250 mL glass round bottom flask 6-chloro-3-nitropyridin-2-amine (J Med. Chem., 2000, 43, 3053-3066, 5 g, 28.81 mmol) and tin (II) chloride dihydrate (32.5 g, 144.04 mmol) were combined and suspended in EtOAc (90 mL) and (10 mL).The reaction slurry was heated to 6O0C for 1 hour. Sodium borohydride (0.544 g, 14.40 mmol) was added in a single portion, and the reaction was heated for an additional 12 hours. The progress of the reaction was monitored by LC/MS. When the reaction was complete, the solvent was removed by rotary evaporation. The solid was dissolved in EtOAc and water. The mixture was neutralized with K2CO3 while cooling the mixture in an ice bath. The tin salts precipitated from solution and were removed by filtering the mixture though a pad of Celite. The aqueous and organic phases were then separated, and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to 3.2 grams (77percent yield) of a light green solid which was used with no further purification. LC/MS (ES+)[(M+H)+]: 144, 146 for C5H6ClN3. 1R NMR (300 MHz, d4-MeOD): 6.47 (d, IH), 6.85 (d, IH).
75%
Stage #1: With tin(II) chloride dihdyrate In ethyl acetate; <i>tert</i>-butyl alcohol at 60℃; for 1 h; Stage #2: With sodium tetrahydroborate In ethyl acetate; <i>tert</i>-butyl alcohol at 60℃; for 3 h;
To a mixture of ethyl acetate (450 mL) and tert-butanol (50 mL), 6-chloro-3- nitropyridin-2-amine (CAS 27048-04-0) (15g, 86,42 mmol), stannous chloride dehydrate (CAS 10025-69-1) (97.5 g, 432.1 mmol) were added. The resulting mixture was stirred at 60°C for 1 hour. Sodiumborohydride (1.63 g, 43.21 mmol) was added and the mixture was stirred further at 60°C for another 3h. The mixture was cooled and stripped from the EtO Ac on the rotavapor. The resulting residu was diluted with water (350 mL) and neutralized to pH = 9-10 by addition of an aqueous solution of potassium carbonate. The resulting mixture was extracted with EtO Ac (3x 250 mL), dried over Na2S04 and evaporated. The residu was stirred for 72 hours in a mixture of EtO Ac/heptane 1/1. The precipitate was filtered and dried in vacuum for 2 hours. The intermediate 1-1 was collected as a greenish powder (9.32 g, 75percent). m/z = 144 (M+H)+.
75%
Stage #1: With tin(ll) chloride In ethyl acetate; <i>tert</i>-butyl alcohol at 60℃; for 1 h; Stage #2: With sodium tetrahydroborate In ethyl acetate; <i>tert</i>-butyl alcohol at 60℃; for 3 h;
To a mixture of ethyl acetate (450 mL) and tert-butanol (50 mL), 6-chloro-3-nitro- pyridin-2-amine (15 g, 86,42 mmol), stannous chloride dehydrate (97.5 g, 432.1 mmol) were added. The resulting mixture was stirred at 60°C for 1 hour. Sodiumborohydride (1.63 g, 43.21 mmol) was added and the mixture was stirred further at 60°C for another 3h. The mixture was cooled and stripped from the EtO Ac on the rotavapor. The resulting residu was diluted with water (350 mL) and neutralized to pH = 9-10 by addition of an aqueous solution of potassium carbonate. The resulting mixture was extracted with EtO Ac (3x 250 mL), dried over Na2S04 and evaporated. The residu was stirred for 72 hours in a mixture of EtO Ac/heptane 1/1. The precipitate was filtered and dried in vacuum for 2 hours. The intermediate 27-b was collected as a greenish powder (9.32 g, 75percent).
75%
Stage #1: With tin(II) chloride dihdyrate In ethyl acetate; <i>tert</i>-butyl alcohol at 60℃; for 1 h; Stage #2: With sodium tetrahydroborate In ethyl acetate; <i>tert</i>-butyl alcohol at 60℃; for 3 h;
To a mixture of ethyl acetate (450 mL) and fert-butanol (50 mL), 6-chloro-3- nitropyridin-2-amine (CAS 27048-04-0) (15g, 86,42 mmol), stannous chloride dehydrate (CAS 10025-69-1) (97.5 g, 432.1 mmol) were added. The resulting mixture was stirred at 60°C for 1 hour. Sodiumborohydride (1.63 g, 43.21 mmol) was added and the mixture was stirred further at 60°C for another 3h. The mixture was cooled and stripped from the EtO Ac on the rotavapor. The resulting residu was diluted with water (350 mL) and neutralized to pH = 9-10 by addition of an aqueous solution of potassium carbonate. The resulting mixture was extracted with EtO Ac (3x 250 mL), dried over Na2S04 and evaporated. The residu was stirred for 72 hours in a mixture of EtO Ac/heptane 1/1. The precipitate was filtered and dried in vacuum for 2 hours. The intermediate 17 was collected as a greenish powder (9.32 g, 75percent). m/z = 144 (M+H)+.
60%
With tin(ll) chloride In tetrahydrofuran; hydrogen chloride at 20℃; for 4 h;
Intermediate 4.1: 6-Chloro-pvridine-2,3-diamine (Scheme 10); 2-arnino-3-nitro-6-chloropyridine (3 g, 17.3 mmol, 1 eq.) was dissolved in THF (50 mL) at it. Tin chloride dihydrate (15.6 g, 70 mmol, 4 eq.) pre-dissolved with HClcc (5 mL) was added slowly and reaction mixture stirred at rt for 4 hours. When thereaction was finished, reaction mixture was cooled down to 0°C and treated with sodium hydroxide 5M (12 mL) until pH 14 and the corresponding compound extracted with ethyl acetate. Organic phases were dried with magnesium sulfate, evaporated under vacuum and resulting crude material purified by flash chromatography using cyclohexane/ethyl acetate (1/1) to give 1.5 g of a red oil (Intermediate 4.1). Amount: 1.5 g; Yield: 60 percent; Formula: C5H6N3C1; HPLC Purity: 98percent; HPLC (HzO TFA 0.1percent-ACN TFA Q.05percent): Rt (min); Area percent = 0.5 min; 98percent; 1H NMR (DMSO-d6) 8 6.67 (d, 1H, H5, J=8Hz), 6.36 (d, 1H, H4, J= 8Hz), 5.78 (m, 2H, NH2), 4.75 (m, 2H, NH?): LC-MS: M/Z ESI: Rt (min) 0.1 min, 144.0 (M+l).
Reference：
[1] Patent: WO2014/128465, 2014, A1, . Location in patent: Page/Page column 73; 74
[2] Catalysis Communications, 2015, vol. 67, p. 64 - 67
[3] Patent: CN104860943, 2017, B, . Location in patent: Paragraph 0038-0042
[4] Patent: WO2009/27732, 2009, A1, . Location in patent: Page/Page column 68
[5] Patent: WO2012/80449, 2012, A1, . Location in patent: Page/Page column 25-26
[6] Patent: WO2013/186335, 2013, A1, . Location in patent: Page/Page column 85
[7] Patent: WO2014/114776, 2014, A1, . Location in patent: Page/Page column 34
[8] Organic and Biomolecular Chemistry, 2017, vol. 15, # 6, p. 1313 - 1316
[9] Journal of Organic Chemistry, 2014, vol. 79, # 3, p. 852 - 866
[10] European Journal of Organic Chemistry, 2016, vol. 2016, # 14, p. 2421 - 2434
[11] Journal of Medicinal Chemistry, 2000, vol. 43, # 16, p. 3052 - 3066
[12] Helvetica Chimica Acta, 2007, vol. 90, # 6, p. 1043 - 1068
[13] Patent: WO2006/24666, 2006, A1, . Location in patent: Page/Page column 48
[14] Collection of Czechoslovak Chemical Communications, 1991, vol. 56, # 11.1, p. 2420 - 2429
[15] Journal of Medicinal Chemistry, 1996, vol. 39, # 6, p. 1331 - 1338
[16] Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 22, p. 2749 - 2754
[17] Collection of Czechoslovak Chemical Communications, 1991, vol. 56, # 11.1, p. 2420 - 2429
[18] Patent: US2003/36652, 2003, A1,
[19] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 14, p. 4191 - 4194
[20] Patent: WO2009/155156, 2009, A1, . Location in patent: Page/Page column 67
[21] Organic Letters, 2016, vol. 18, # 18, p. 4714 - 4717
[22] Patent: US6348474, 2002, B1, . Location in patent: Page column 44
4
[ 27048-04-0 ]
[ 75-65-0 ]
[ 40851-95-4 ]
[ 1426845-56-8 ]
Yield
Reaction Conditions
Operation in experiment
30%
Stage #1: With tin(II) chloride dihdyrate In ethyl acetate at 60℃; for 1 h; Stage #2: With sodium tetrahydroborate In ethyl acetate at 60℃; for 3 h;
Step 1 - Synthesis of N3 -(tert-butyl)-6-chloropyridine-2,3-diamine and 6-chloropyridine-2,3- diamineA mixture of 6-chloro-3-nitropyridin-2-amine (15 g, 86.4 mmol) and SnCl2-2H20(98 g, 0.43 mol) in ethyl acetate / 2-methylpropan-2-ol (450 mL / 90 mL) was stirred at 60 °C for 1 h. Then NaBH4 (1.6 g, 43.2 mmol) was added at 60 °C and the resultant mixture was stirred at the same temperature for another 3 h. Water was added and the mixture was extracted. The organic layer was washed with NaHC03 solution and brine, dried over Na2S04 and concentrated in vacuo. The residue was purified by column chromatography (EA : DCM = 1 : 1) to give the product of N3-(tert-butyl)-6-chloropyridine-2,3-diamine (4.0 g, yield: 30percent) and 6- chloropyridine-2,3-diamine (5.0 g, yield: 43percent). 1H- MR (DMSO-i¾, 400 MHz) δ 6.84 (d, J = 8.0 Hz, 1H), 6.37 (d, J= 8.0 Hz, 1H), 5.99 (s, 2H), 3.98 (s, 1H), 1.20 (s, 9H), MS (M+H)+: 200 / 202. 1H- MR (DMSO-de, 400 MHz) δ 6.65 (d, J= 8.0 Hz, 1H), 6.31 (d, J= 8.0 Hz, 1H), 5.76 (s, 2H), 4.73 (s, 2H), MS (M+H)+: 144 / 146.
Reference：
[1] Chemical Communications, 1998, # 15, p. 1519 - 1520
9
[ 4548-45-2 ]
[ 4214-76-0 ]
[ 2604-39-9 ]
[ 5418-51-9 ]
[ 27048-04-0 ]
Reference：
[1] Journal of Organic Chemistry, 1985, vol. 50, # 4, p. 484 - 487
[2] Journal of Organic Chemistry, 1985, vol. 50, # 4, p. 484 - 487
10
[ 124-41-4 ]
[ 27048-04-0 ]
[ 73896-36-3 ]
Yield
Reaction Conditions
Operation in experiment
86.5%
at 15 - 30℃; for 4 - 5 h;
Sodium methoxide, 7.78 gm (0.144 mole) and methanol 50.0 ml were mixed and cooled to 15° C. To this solution, 25.0 gm of 2-amino-6-chloro-3-nitropyridine (0.144 mole) was added while maintaining the temperature at 15° C. by external cooling. The resulting mixture was heated to 25°-30° C. and maintained at this temperature for 4-5 hrs with constant stirring. The completion of reaction was monitored by TLC. After the completion of reaction, the reaction mixture was poured in water. The precipitate thus obtained was filtered and washed with water. On drying 21.0 gm of 2-amino-3-nitro-6-methoxypyridine (86.5percent yield) was obtained, with the HPLC purity of 99.0percent. Melting point 167°-169° C.; 1H-NMR (CDCl3) δ 3.89 ppm (s,-3H, OCH3), 66.14-6.16 ppm (d, 1H), 68.24-8.27 ppm (d, 1H), 68.16 ppm (s, -2H, -NH2).
84.1%
at 20℃; for 3 h;
To a solution of 2-amino-3-nitro-6-chloropyridine (300 mg, 1.73 mmol, an intermediate in preparation of 8) in 5 mL anhydrous DMF was added sodium methoxide (187mg, 3.46 mmol). This mixture was stirred at room temperature for 3 h then poured onto 20 g crushed ice and extracted with ethyl acetate. The extracts were dried, evaporated and purified by column chromatography on silica gel (PE/AcOEt=5:1) to give 2-amino-3-nitro-6-methoxylpyridine (246 mg, 84.1percent) as yellow solid. Next steps followed the general procedure, and the title compound was obtained as white solid (188 mg, 67.0percent over 2 steps). IR (KBr) ν 3246, 3184, 1708, 1635, 1599, 1488, 1462, 1341, 1260, 1024, 839cm−1; 1H NMR (400MHz, DMSO-d6) δ 3.81 (3H, s, CH3), 6.56 (1H, d, J=8.4Hz, H-7), 7.42 (1H, d, J=8.4Hz, H-8), 11.82 (1H, s, NH-1), 12.25 (1H, s, NH-4); 13C NMR (100MHz, DMSO-d6) δ 53.50, 104.56, 115.19, 126.61, 136.21, 154.35, 156.11, 158.55; HRMS-EI C8H7N3O3 calcd [M+Na]+ 216.0385, found 216.0382.
9 g
at -15 - 20℃; for 16 h;
To a stirred solution of Compound 39b (15g,86.70mmol) in MeOH (35ml) was added NaOMe (7.2g,133.92mmol) at -15°C and stirred for 16h at RT. The reaction was quenched with ice and the obtained solids were filtered and dried to afford the required compound (9g).
Reference：
[1] Patent: US2006/80790, 2006, A1, . Location in patent: Page/Page column 3
[2] European Journal of Medicinal Chemistry, 2016, vol. 117, p. 19 - 32
[3] Journal of Medicinal Chemistry, 1997, vol. 40, # 12, p. 1808 - 1819
[4] Patent: WO2014/57415, 2014, A2, . Location in patent: Page/Page column 47
11
[ 27048-04-0 ]
[ 73896-36-3 ]
Reference：
[1] Patent: WO2004/92166, 2004, A2, . Location in patent: Page 71
[2] Patent: US5599812, 1997, A,
[3] Asian Journal of Chemistry, 2013, vol. 25, # 14, p. 7959 - 7966
12
[ 67-56-1 ]
[ 27048-04-0 ]
[ 73896-36-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 1996, vol. 39, # 6, p. 1331 - 1338
13
[ 16013-85-7 ]
[ 27048-04-0 ]
Yield
Reaction Conditions
Operation in experiment
92%
With ammonia In ethanol at 0 - 20℃;
In the flask were poured into 500mL 200mL anhydrous ethanol at 0 ammonia gas was slowly passed through 2h, and then 4.8g (0.025mol) 2,6- dichloro-3-nitropyridine (V) into the solution at room temperature stir overnight. The reaction is completed clear yellow solution was rotary evaporated to dryness under reduced pressure, ice water was added, filtered, washed with water and dried to give a yellow solid 2-amino-3-nitro-6-chloropyridine (I) 4.0g, 92percent yield
89%
With ammonia In ethanol at 20℃; for 24 h;
Step-1: Synthesis of Compound 2: 10.0 g, (51.8 mmol) of 2,6-dichloro3-nitro pyridine was dissolved in 37 ml of a 7N solution of NH3 in ethanol (0.26 mol, 5.0 eqv) and the solution was stirred at rt for 24 h. H2O (40 ml) was added and the resulting mixture was filtered to collect the crude yellow product. The solid material was dissolved in CH2Cl2 and then extracted with a 1N HCl solution. The aqueous extracts were combined and then neutralized with NaHCO3 before being re-extracted with CH2Cl2. The organic fractions were combined, dried (MgSO4), filtered, and concentrated in vacuo to yield 8.0 g of a yellow solid (89percent).
88%
With ammonia In ethanol at 0℃; for 3 h;
Intermediate 4 6-Chloro-3-nitro-pyridin-2-ylamine <n="71"/>A solution of 2,6-dichloro-3-nitro pyridine (5 g, 26 mmol) in ethanol (50 mL) at 0 0C was purged with ammonia gas for 3 h, then allowed to stir overnight at room temperature. The reaction mixture was diluted with water (100 mL), and the precipitate that formed was filtered and washed with water (50 mL), followed by hexane (50 mL) and dried to obtain 6-chloro-3- nitro-pyridin-2-ylamine in 88percent yield (4 g, 23 mmol). MS(ES): 174 (M+l) for C5H4ClN3O2 1R NMR (MeOD, 400 MHz) δ: 6.71 (d, J= 8.6 Hz, IH), 8.39 (d, J= 8.6 Hz, IH).
83%
With ammonia In ethanol; water at 20℃; for 10 h;
To a solution of commercially available 2,6-dichloro-5- nitropyridine (20.0 g, 95.3 mmol) in ethanol (300 mL) was added aqueous ammonia (60 mL), and the mixture was stirred at room temperature for 10 hours. The resulting precipitate was filtered, washed with ethanol, and dried in vacuo to give 6-amino-2-chloro-5-nitropyridine (13. [8 G, 83 percent). THE COMPOUND] thus obtained was suspended in an acetic acid solution (130 mL) of [30percent] hydrogen bromide. The suspension was stirred at [100°C] for 26 hours, cooled to room temperature, and concentrated in vacuo. The resulting residue was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue thus obtained [ WAS RECRYSTALLIZED FROM ETHYL ACETATE TO GIVE THE TITLE COMPOUND] (14.93 g, 86 [percent).]
56.45%
at 20 - 40℃; for 2 h;
2,6-Dichloro-3-nitropyridine, 25.0 gm (0.129 mole) was dissolved in methanol (50.0 ml) at room temperature. To the solution thus obtained, 25.0percent aqueous ammonia solution 12.2 ml (0.179 mole) was charged at room temperature. The resulting mixture was heated to 35°-40° C. for 2.0 hrs. The reaction was monitored by TLC. After the completion of the reaction, the mixture was cooled to 20° C. The solid obtained was washed, filtered with methanol and dried to yield 12.50 gm of 2-amino-6-methoxy-3-nitro pyridine (56.45percent) with the HPLC purity of 99.3percent: Melting point 192°-195° C.; 1H-NMR: (DMSO D6) δ 6.75-6.77 ppm (d, 1H), δ 8.38-8.40 (d, 1H).
51%
With ammonia In isopropyl alcohol at 20℃;
To a flask charged with 2,6-dichloro-3-nitropyridine (3 g, 15.5 mmol) was added2M ammonia in isopropanol solution (18 ml, 36 mmol) and this mixture was stirredovernight at room temperature. The reaction was driven to completion by the addition ofammonia solution (aq). The resulting precipitate was filtered off, washed with water and then dried over vacuum for an hour. Intermediate 5 was isolated as a fluffy yellow powder (1.38 g, 51percent).LCMS (m/z): [IVIH] calcd. for C5H4C1N302, 173.56; found 174.00.
75 g
With ammonium hydroxide In isopropyl alcohol at 20 - 25℃;
A solution of 100 gm. 2, 6-dichloro-3-nitro-pyridine in 800 ml isopropyl alcohol is taken in round bottom flask. 300 ml of aqueous ammonia solution (20-25percent) is added at 20-25°C. The reaction mass is stirred for 20-24 hours at 20-25°C. After completion of the reactionThe solid is filtered and washed with 100 ml isopropyl alcohol then dried to obtain 70-75 gm 2-amino-3-nitro-6-chloro-pyridine.
30 g
at 50℃; for 5 h;
To a stirred solution of Compound 39a (50g, 261.78mmol) was added 38percent ammonia solution (150ml) and heated at 50°C for 5h. Upon completion, the obtained solids were filtered and given diethylether washings to afford the required compound as a yellow solid (30g).
Reference：
[1] Patent: CN103936766, 2016, B, . Location in patent: Paragraph 0034-0035
[2] Patent: US2015/152057, 2015, A1, . Location in patent: Paragraph 0111; 0112; 0113
[3] Patent: WO2009/27732, 2009, A1, . Location in patent: Page/Page column 69-70
[4] Patent: WO2004/2986, 2004, A2, . Location in patent: Page 127-128
[5] Collection of Czechoslovak Chemical Communications, 1991, vol. 56, # 11.1, p. 2420 - 2429
[6] Journal of Medicinal Chemistry, 2017, vol. 60, # 23, p. 9739 - 9756
[7] Patent: US2006/80790, 2006, A1, . Location in patent: Page/Page column 3
[8] ChemMedChem, 2015, vol. 10, # 2, p. 368 - 379
[9] Patent: WO2016/27089, 2016, A1, . Location in patent: Page/Page column 26; 27
[10] Journal of Medicinal Chemistry, 1992, vol. 35, # 23, p. 4455 - 4463
[11] Journal of Medicinal Chemistry, 1994, vol. 37, # 19, p. 3016 - 3022
[12] Patent: WO2004/92166, 2004, A2, . Location in patent: Page 70
[13] Patent: US2003/8882, 2003, A1,
[14] Patent: US2003/36652, 2003, A1,
[15] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 14, p. 4191 - 4194
[16] Patent: WO2013/80215, 2013, A1, . Location in patent: Page/Page column 32
[17] Patent: WO2014/57415, 2014, A2, . Location in patent: Page/Page column 47
[18] Journal of Agricultural and Food Chemistry, 2015, vol. 63, # 34, p. 7469 - 7475
14
[ 16013-85-7 ]
[ 3346-63-2 ]
[ 27048-04-0 ]
Yield
Reaction Conditions
Operation in experiment
65%
With ammonia In ethanol
Gaseous ammonia was distilled through a cold (dry-ice) trap into a solution of 2,6-dichloro-3- nitropyridine (9.65 g, 50 mmol) in anhydrous EtOH (100 mL), until the dichloro derivative was consumed (by TLC). The resultant solution was evaporated to dryness to afford a solid containing the title product and compound 4. Crystallization from iPrOH afforded the title product in pure form (65percent yield). 1H-NMR (CDCl3) 68.36 (d, IH, J = 8.7 Hz, Pri-CH), 6.73 (d, IH, J = 8.7 Hz, Pri-CH), 5.2 (s, exch, 2H, NH2). EI-HRMS: m/z calcd for C5H4ClN3O2 172.9992, found 172.9987 (100percent), 174.0023 (6percent), 174.9961 (32percent), 175.9992 (2percent).NH2-Pyr(NO2)NH2: 2,6-Diamino-3-nitropyridine (4) was formed in the reaction leading to product 3 above. Isolation of this material was by column chromatography (silica gel; eluent CHCl3). 1H-NMR (CDCl3) 68.19 (d, IH, J = 8.7 Hz, Pri-CH), 6.71 (s, exch, 2H, NH2), 6.43 (d, IH, J = 8.7 Hz, Pri-CH). EI-HRMS: m/z calcd for C5H6N4O2 154.0491, found 154.0496 (100percent).
Reference：
[1] Journal of Organic Chemistry, 1985, vol. 50, # 4, p. 484 - 487
[2] Journal of Organic Chemistry, 1985, vol. 50, # 4, p. 484 - 487
20
[ 38533-61-8 ]
[ 27048-04-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 7, p. 1924 - 1928
21
[ 73896-36-3 ]
[ 27048-04-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 7, p. 1924 - 1928
22
[ 27048-04-0 ]
[ 40851-91-0 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1996, vol. 33, # 6, p. 1995 - 2005
23
[ 27048-04-0 ]
[ 129012-04-0 ]
Reference：
[1] Patent: US6348474, 2002, B1,
24
[ 27048-04-0 ]
[ 84487-04-7 ]
Yield
Reaction Conditions
Operation in experiment
86%
Stage #1: With hydrogen bromide In water; acetic acid at 100℃; for 26 h; Stage #2: With sodium hydrogencarbonate In water; ethyl acetate
To a solution of commercially available 2,6-dichloro-5- nitropyridine (20.0 g, 95.3 mmol) in ethanol (300 mL) was added aqueous ammonia (60 mL), and the mixture was stirred at room temperature for 10 hours. The resulting precipitate was filtered, washed with ethanol, and dried in vacuo to give 6-amino-2-chloro-5-nitropyridine (13. [8 G, 83 percent). THE COMPOUND] thus obtained was suspended in an acetic acid solution (130 mL) of [30percent] hydrogen bromide. The suspension was stirred at [100°C] for 26 hours, cooled to room temperature, and concentrated in vacuo. The resulting residue was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue thus obtained [ WAS RECRYSTALLIZED FROM ETHYL ACETATE TO GIVE THE TITLE COMPOUND] (14.93 g, 86 [percent).]
Reference：
[1] Journal of Medicinal Chemistry, 2014, vol. 57, # 13, p. 5702 - 5713
[2] Patent: WO2004/2986, 2004, A2, . Location in patent: Page 127-128
[3] Patent: US6348474, 2002, B1, . Location in patent: Page column 44,45
25
[ 27048-04-0 ]
[ 140-75-0 ]
[ 33400-49-6 ]
Yield
Reaction Conditions
Operation in experiment
97.2%
With triethylamine In methanol at 80℃; for 10 h;
To a reaction flask, 200 mL of methanol, 52.08 g of compound 1, 37.54 g of p-fluorobenzylamine and 50.0 mL of triethylamine werea added. The reaction mixture was heated to 80 °C for 10 hours, and the reaction solution was added with 10 times of water to give 76.47 g of compound 3 in a yield of 97.2percent and a purity of 99.62percent (HPLC).
96.8%
With triethylamine In isopropyl alcohol for 14 h; Inert atmosphere; Reflux; Industry scale
2-Amino-6-chloro-3-nitropyridine (ACNP, 10.0 kg) was suspended in isopropanol (49 L) under stirring and a nitrogen blanket. 4-Fluorobenzylamine (7.7 kg) and triethylamine (8.4 kg) were added and the mixture was heated to reflux. Stirring at reflux was maintained for 14 h. The reaction mixture was cooled to 50°C and samples were taken for checking completion of the reaction by HPLC (amount of residual ACNP: 0.02percent). Water (163 kg) was added and the mixture was stirred for 5 min, then cooled to 5°C and stirred for 30 minutes. The precipitate was filtered off, washed with water (41 L) and dried under reduced pressure at 50°C. Yield: 14.6 kg (96.8percent of theory).
96.6%
With triethylamine In isopropyl alcohol at 70 - 80℃; for 12 h; Large scale
Was added to the reaction kettle 3.04kg and 10kg of isopropanol fluorobenzylamine, with stirring, was added 4kg2- amino-3-nitro-6-chloropyridine and 8.67kg of triethylamine, and heated at reflux temperature for 12h 70-80 , cooled to 60 , reaction was monitored sampling is complete, add 4percent sodium hydroxide aqueous solution prepared 1.07kg, 55 concentrated under reduced pressure until no solvent flows, centrifuged solids, temperature 50-60 , dried 10-12 hours to give flupirtine maleate intermediate (2-amino-3-nitro-6- (p-fluoro-benzylamino) pyridine) 5.86kg, a yield of 96.6percent
88%
With triethylamine In isopropyl alcohol at 90℃; for 0.666667 h; Microwave irradiation
To a solution of Intermediate 5 (500 mg, 2.9 mmol) in isopropanol was added 4- fluorobenzylamine (463 iil, 4.06 mmol) and triethylamine (805 iil, 5.8 mmol). This mixture was stirred at 90°C for 40 minutes in the microwave. Water was added to the mixture and the resulting precipitate was filtered off, washed with water and then driedover vacuum for an hour. Intermediate 6 was isolated as a bright yellow solid (661 mg,88percent).LCMS (m/z): [IVIH] calcd. for C12H11FN4O2, 262.24; found 263.00.
150 g
With triethylamine In water at 20 - 85℃;
100 gm of 2-amino-3-nitro-6-chloro-pyridine is taken in 800 ml of water. 90 gm of p-fluorobenzylamine is added dropwise into the reaction mixture at 20-25°C. Then 87 gm triethylamine is also added dropwise into the reaction mixture at 20-25°C. After complete addition, the reaction mass is stirred at 40-45°C for half an hour again the reaction mass is heated to 80-85°C and stirred at this temperature for 3-4 hours. After completion of the reaction, the reaction mass is cooled to 20-25°C and stirred at this temperature for 2-3 hours and then stirred at 15-20°C for 3-4 hours. The solid mass is filtered and then washed with 200 ml of water and 100 ml isopropyl alcohol and then dried in air oven till constant weight to get 140-150 gm. of 2-amino-3-nitro-6-p- fluorobenzylamino-py ridine.
Reference：
[1] Journal of Medicinal Chemistry, 2017, vol. 60, # 23, p. 9739 - 9756
[2] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 2012, vol. 67, # 12, p. 1297 - 1304
[3] Patent: CN105541705, 2016, A, . Location in patent: Paragraph 0013; 0027; 0028
[4] Patent: WO2012/4391, 2012, A1, . Location in patent: Page/Page column 39
[5] Patent: CN104086481, 2016, B, . Location in patent: Paragraph 0033 - 0037
[6] Patent: WO2016/27089, 2016, A1, . Location in patent: Page/Page column 27
[7] Arzneimittel-Forschung/Drug Research, 1993, vol. 43, # 6, p. 627 - 631
[8] Journal of Medicinal Chemistry, 1994, vol. 37, # 19, p. 3016 - 3022
[9] Patent: WO2013/80215, 2013, A1, . Location in patent: Page/Page column 32
[10] Patent: US2015/152057, 2015, A1, . Location in patent: Paragraph 0111; 0114; 0115
26
[ 27048-04-0 ]
[ 92138-35-7 ]
Yield
Reaction Conditions
Operation in experiment
80%
Stage #1: at 0℃; for 0.166667 h; Stage #2: With sodium nitrite In water at 0℃; for 0.666667 h;
Intermediate 5 6-Chloro-3-nitropyridin-2(l//)-one To ice cold concentrated sulphuric acid was added 6-chloro-3 -nitro-pyridin-2-ylamine (Intermediate 4, 5 g, 28 mmol), and the reaction mixture was stirred for 10 min at 0 0C. A solution OfNaNO2 (4 g, 58 mmol in 30 mL of water) was added slowly over a period of 10 min maintaining the temperature at 00C, then the mixture was stirred for 30 min at the same temperature. The reaction mixture was poured onto ice cold water (150 mL), the precipitate that formed was collected by filtration, washed with cold water (2x50 mL) and dried under vacuum to provide 6-chloro-3-nitropyridin-2(lf/)-one in 80percent yield (4 g, 23 mmol) as yellow color solid. MS (ES): 172.9 (M-I) for C5H3ClN2O3.1H-NMR (DMSO-d6, 400 MHz): δ 7.06 (d, J= 8.3 Hz, IH), 8.40-8.43 (m, IH).
67%
With sodium nitrite In sulfuric acid; water
6-chloro-3-nitro-2(1H)-pyridone (91) 6-Chloro-3-nitro-2-pyridinamine (90a) (0.3 g, 1.73 mmol) was dissolved in 5 ml of conc. H2SO4 at 0OE C. A solution of NaNO2 (0.24 g, 3.46 mmol, 2.0 eqv) in 2 ml of H2O was added cautiously to the arylamine solution and the mixture was stirred at 0OE C. for 30 min. H2O (10 ml) was added and the solid precipitate was filtered and washed with cold H2O several times. The solid was dried under vacuum to give 0.2 g of a yellow solid (67percent): 1H NMR (400 MHz, d6-DMSO) d 7.08 (d, J=6.4 Hz, 1H), 8.43 (d, J=6.8 Hz, 1H); 13C NMR (125 MHz, d6-DMSO) d 113.93, 132.10, 138.90, 150.27, 156.47; HRMS (EI) Calcd for C5H3ClN2O3: 173.9832. Found 173.9830.
To a suspension of Compound 1 (5 g, 28.8 mmol) in acetic acid (50 mL) was added NCS (4.04 g, 30.2 mmol), and the obtained reaction mixture was stirred at 100° C. for one hour. The reaction mixture was allowed to cool to room temperature, and NCS (0.385 g, 2.88 mmol) was added thereto. The obtained reaction mixture was stirred at 100° C. for one hour again. The obtained reaction mixture was allowed to cool to room temperature, and the solvent was then removed by distillation under reduced pressure. The residue was suspended in distilled water (50 ml), and the obtained liquid was stirred and adjusted to pH=8 using a saturated sodium bicarbonate solution at 0° C. (0482) The solid residue was filtered, and the obtained residue was washed twice with distilled water, followed by vacuum drying to obtain Compound 2 (5.5 g, 92percent) as a yellow solid Compound 2; 1H-NMR (DMSO-d6) δ: 8.33 (brs, 2H), 8.59 (s, 1H).
76%
With chlorine In ethanol at 0℃; for 1 h;
A suspension of 6-chloro-3-nitropyridine-2-amine 1 (20 g, 115 mmol) in anhydrous ethanol (970 mL) was subjected to bubbling with chlorine gas while stirring at 0° C. over one hour. Thereafter, the reaction mixture was subjected to bubbling with nitrogen gas while stirring at room temperature over one hour, and then stirred at 0° C. for 30 minutes. The reaction suspension was filtered, and the obtained residue was washed with diisopropyl ether to obtain a solid. The solvent of the resulting filtrate was removed under reduced pressure, and the precipitated solid was filtered and the obtained solid was then washed with diisopropyl ether to further obtain a solid. The above-described two collected solids were combined to obtain Compound 2 (18.1 g, 76percent) as a yellow solid.Compound 2; 1H-NMR (DMSO-d6) δ: 8.33 (brs, 2H), 8.59 (s, 1H).
Reference：
[1] Patent: US9567330, 2017, B2, . Location in patent: Page/Page column 40
[2] Bioorganic and Medicinal Chemistry, 1997, vol. 5, # 12, p. 2129 - 2132
[3] Patent: US2013/184240, 2013, A1, . Location in patent: Paragraph 0621; 0622; 0623
28
[ 27048-04-0 ]
[ 790692-90-9 ]
Yield
Reaction Conditions
Operation in experiment
88%
With iodine; silver sulfate In ethanol at 20℃;
To a suspension of 6-chloro-3-nitropyridin-2-amine (6.3 g, 36.3 mmol)in ethanol (110 ml_), 9.2 g (36.3 mmol) of iodine and 1 1.32 g (36.3 mmol) of silver sulphate were added. The crude mixture was stirred at room temperature overnight and the precipitate formed was filtered off. The solid isolated was purified by flash chromatography (1 :1 hexane/ethyl acetate) to give the title compound (9.74 g, 88percent of yield). δ 1H-NMR (CDCI3): 1.56 (s, 2H), 8.76 (s, 1H).ESI/MS m/e: 300 ([IvH-H]+, C5H3CIIN3O2)
88%
Stage #1: With sulfuric acid; acetic acid; periodic acid In water at 95℃; for 0.25 h; Stage #2: With iodine In water at 95℃; for 1 h;
A mixture of 2-amino-6-chloro-3-nitropyridine (1, 5.7 g, 32.8 mmol), water (4.5 mL), c-H2SO4 (1.26 mL) and H5IO6 (1.59 g) was stirred for 15 min at 95° C. Iodine (3.6 g) was added in portions. The reaction mixture was stirred for 1 h at 95° C., cooled to room temperature, poured into sat. aqueous sodium thiosulfate solution and extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (Hex/EtOAc=3/2) to give compound 2 (8.7 g, 29.1 mmol, 88percent). 1H NMR (DMSO-d6, 300 MHz) δ8.62 (s, 1H), 8.26 (brs, 2H)
59%
With silver(II) sulfate; iodine In ethanol at 20℃;
The compound 268-100 was prepared as follows. To a solution of 6-chloro-3-nitropyridin-2-amine (630 mg, 3.63 mmol) in ethanol (11 mL) was add I2 (920 mg, 3.62 mmol) and Ag2SO4 (1132 mg, 3.63 mmol).). The resulting solution was stirred overnight at room temperature and dissolved in water (100 mL), then extracted with ethyl acetate (3×80 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated under vacuum to produce 6-chloro-5-iodo-3-nitropyridin-2-amine as a yellow solid (640 mg, 59percent). Next, to a solution of 6-chloro-5-iodo-3-nitropyridin-2-amine (640 mg, 2.14 mmol) in ethanol (40 ml) and water (10 ml) was added Fe powder (1.93 g, 34.46 mmol) and NH4Cl (887 mg, 16.58 mmol). The resulting solution was heated to reflux for 4 h and then concentrated. The residue was dissolved in water (100 mL) and extracted with ethyl acetate (3×80 ml). The combined organic layers was washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column with 33percent ethyl acetate in petroleum ether to produce 6-chloro-5-iodopyridine-2,3-diamine as a brown solid (560 mg, 97percent). The mixture of 6-chloro-5-iodopyridine-2,3-diamine (100 mg, 0.37 mmol), (2,3-dichlorophenyl)boronic acid (147.3 mg, 0.77 mmol), Pd(Ph3P)4 (42.9 mg, 0.04 mmol) and sodium carbonate (118.2 mg, 1.12 mmol) in water (5 mL) and dioxane (15 mL) was heated to reflux overnight. Then the resulting solution was quenched with water (100 mL) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column with 50percent ethyl acetate in petroleum ether to produce 6-chloro-5-(2,3-dichlorophenyl)pyridine-2,3-diamine as a brown solid (80 mg, 75percent). Finally, the solution of 6-chloro-5-(2,3-dichlorophenyl)pyridine-2,3-diamine (80 mg, 0.28 mmol) in trifluoroacetic acid (10 mL) and hydrochloric acid (conc., 2 mL) was heated to reflux overnight. Then the resulting mixture was quenched with water (100 mL), adjusted pH to 8 with sodium carbonate and extracted with ethyl acetate (3×80 mL). The combined organic layers was dried over anhydrous magnesium sulfate and concentrated to give a residue, which was purified by a silica gel column with 50percent ethyl acetate in petroleum ether to produce 5-chloro-6-(2,3-dichlorophenyl)-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyridine. Trifluoroacetic acid as a off-white solid (2 mg, 2percent).
With tert.-butylnitrite; copper(ll) bromide In acetonitrile at 65℃; for 0.5 h;
EXAMPLE P3 Preparation of 2-bromo-6-chloro-3-nitro-pyridine tert-Butyl nitrite (990 mg, 9.60 mmol) was added portionwise at 65° C. under a nitrogen atmosphere to a stirred suspension of 2-amino-6-chloro-3-nitropyridine (1.00 g, 5.76 mmol) and copper(II) bromide (1.56 g, 6.91 mmol) in acetonitrile (25 mL), and stirring was continued for 30 min. After cooling, the reaction mixture was partitioned between ethyl acetate and 2 M aq. hydrochloric acid solution. The organic layer was dried (MgSO4), and evaporated. Chromatography of the residue (SiO2, heptane-dichloromethane gradient) afforded the title compound (1.11 g, 81percent). Yellow solid, MS (EI) 235.9/237.9 (78/100, M+).
75%
With tert.-butylnitrite; copper(ll) bromide In acetonitrile at 65℃; for 0.5 h; Inert atmosphere
t-Butyl nitrite (8.5 g, 82.43 mmol, 1.80 equiv) was added to a mixture of 6-chloro-3-nitropyridin-2-amine (8 g, 46.09 mmol, 1.00 equiv) and copper(II) bromide (12.3 g, 55.07 mmol, 1.20 equiv) in acetonitrile (120 mL, 2.28 mol) under nitrogen. The resulting mixture was stirred for 30 min at 65° C. and partitioned between ethyl acetate and 2 M aqueous hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:5). This resulted in the title compound (8.2 g, 75percent) as a yellow solid.
75%
With tert.-butylnitrite; copper(ll) bromide In acetonitrile at 65℃; for 0.5 h; Inert atmosphere
t-Butyl nitrite (8.5 g, 82.43 mmol, 1.80 equiv) was added to a mixture of6-chloro-3-nitropyridin-2-amine (8 g, 46.09 mmol, 1.00 equiv) and copper(II) bromide (12.3 g,55.07 mmol, 1.20 equiv) in acetonitrile (120 mL, 2.28 mol) under nitrogen. The resulting mixture was stilTed for 30 mm at 65 °C and partitioned between ethyl acetate and 2 M aqueous hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with ethylacetate/petroleum ether (1:5). This resulted in the title compound (8.2 g, 75percent) as a yellow solid.
In the flask were poured into 500mL 200mL anhydrous ethanol at 0 ammonia gas was slowly passed through 2h, and then 4.8g (0.025mol) 2,6- dichloro-3-nitropyridine (V) into the solution at room temperature stir overnight. The reaction is completed clear yellow solution was rotary evaporated to dryness under reduced pressure, ice water was added, filtered, washed with water and dried to give a yellow solid 2-amino-3-nitro-6-chloropyridine (I) 4.0g, 92% yield
89%
With ammonia; In ethanol; at 20℃; for 24h;
Step-1: Synthesis of Compound 2: 10.0 g, (51.8 mmol) of 2,6-dichloro3-nitro pyridine was dissolved in 37 ml of a 7N solution of NH3 in ethanol (0.26 mol, 5.0 eqv) and the solution was stirred at rt for 24 h. H2O (40 ml) was added and the resulting mixture was filtered to collect the crude yellow product. The solid material was dissolved in CH2Cl2 and then extracted with a 1N HCl solution. The aqueous extracts were combined and then neutralized with NaHCO3 before being re-extracted with CH2Cl2. The organic fractions were combined, dried (MgSO4), filtered, and concentrated in vacuo to yield 8.0 g of a yellow solid (89%).
88%
With ammonia; In ethanol; at 0℃; for 3h;
Intermediate 4 6-Chloro-3-nitro-pyridin-2-ylamine <n="71"/>A solution of 2,6-dichloro-3-nitro pyridine (5 g, 26 mmol) in ethanol (50 mL) at 0 0C was purged with ammonia gas for 3 h, then allowed to stir overnight at room temperature. The reaction mixture was diluted with water (100 mL), and the precipitate that formed was filtered and washed with water (50 mL), followed by hexane (50 mL) and dried to obtain 6-chloro-3- nitro-pyridin-2-ylamine in 88% yield (4 g, 23 mmol). MS(ES): 174 (M+l) for C5H4ClN3O2 1R NMR (MeOD, 400 MHz) delta: 6.71 (d, J= 8.6 Hz, IH), 8.39 (d, J= 8.6 Hz, IH).
83%
With ammonia; In ethanol; water; at 20℃; for 10h;
To a solution of commercially available 2,6-dichloro-5- nitropyridine (20.0 g, 95.3 mmol) in ethanol (300 mL) was added aqueous ammonia (60 mL), and the mixture was stirred at room temperature for 10 hours. The resulting precipitate was filtered, washed with ethanol, and dried in vacuo to give 6-amino-2-chloro-5-nitropyridine (13. [8 G, 83 %). THE COMPOUND] thus obtained was suspended in an acetic acid solution (130 mL) of [30%] hydrogen bromide. The suspension was stirred at [100C] for 26 hours, cooled to room temperature, and concentrated in vacuo. The resulting residue was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue thus obtained [ WAS RECRYSTALLIZED FROM ETHYL ACETATE TO GIVE THE TITLE COMPOUND] (14.93 g, 86 [%).]
81.2%
With ammonia; In ethanol; at 0℃; for 3h;
A solution of compound 1 (5 g. 0.026 mol) in ethanol (50 ml) at 0 C. was purged with ammonia gas for 3 h, then allowed to stir overnight at room temperature. The reaction mixture was diluted with water, and the precipitate that formed was filtered and washed with water, followed by hexane and dried to obtain Intermediate 2 (3.65 g, 81.2% yield).
56.45%
With methanol; ammonia; water; at 20 - 40℃; for 2h;
2,6-Dichloro-3-nitropyridine, 25.0 gm (0.129 mole) was dissolved in methanol (50.0 ml) at room temperature. To the solution thus obtained, 25.0% aqueous ammonia solution 12.2 ml (0.179 mole) was charged at room temperature. The resulting mixture was heated to 35-40 C. for 2.0 hrs. The reaction was monitored by TLC. After the completion of the reaction, the mixture was cooled to 20 C. The solid obtained was washed, filtered with methanol and dried to yield 12.50 gm of 2-amino-6-methoxy-3-nitro pyridine (56.45%) with the HPLC purity of 99.3%: Melting point 192-195 C.; 1H-NMR: (DMSO D6) delta 6.75-6.77 ppm (d, 1H), delta 8.38-8.40 (d, 1H).
51%
With ammonia; In isopropyl alcohol; at 20℃;
To a flask charged with 2,6-dichloro-3-nitropyridine (3 g, 15.5 mmol) was added2M ammonia in isopropanol solution (18 ml, 36 mmol) and this mixture was stirredovernight at room temperature. The reaction was driven to completion by the addition ofammonia solution (aq). The resulting precipitate was filtered off, washed with water and then dried over vacuum for an hour. Intermediate 5 was isolated as a fluffy yellow powder (1.38 g, 51%).LCMS (m/z): [IVIH] calcd. for C5H4C1N302, 173.56; found 174.00.
With sodium hydroxide; ammonia; In ethanol; water; for 2h;Heating / reflux;
A solution of ammonium hydroxide (6.6 g, 0.124 mol) and sodium hydroxide (4.8 g, 0.120 mol) in water (45 mL) was added to 2, 6-dichloro-3-nitropyridine (12.0 g, 0.62 mol) in ethanol (240 mL). The reaction was refluxed for 2 h, cooled to room temperature and filtered. The pale yellow solid was dried overnight to give the title compound. 1H NMR (500 MHz, CDC13) 8 8.87 (d, J=9 Hz, 1H), 7.8 (br s, 1H), 6.73 (d, J=9 Hz, 1H), 5.9 (br s, 1H).
With ammonia; In ethanol; dichloromethane; water;
6-Chloro-3-nitro-2-pyridinamine (90a); 89% yield 2,6-Dichloro-3-nitropyridine 90 (10.0 g, 51.8 mmol) was dissolved in 37 ml of a 7N solution of NH3 in EtOH (0.26 mol, 5.0 eqv) and the solution was stirred at rt for 24 h. H2O (40 ml) was added and the resulting mixture was filtered to collect the crude yellow product. The solid material was dissolved in CH2Cl2 and then extracted with a 1N HCl solution. The aqueous extracts were combined and then neutralized with NaHCO3 before being re-extracted with CH2Cl2. The organic fractions were combined, dried (MgSO4), filtered, and concentrated in vacuo to yield 8.0 g of a yellow solid (89%): 1H NMR (400 MHz, d6-DMSO) d 6.77 (d, J=8.8 Hz, 1H), 8.27 (s, 2H), 8.39 (d, J=8.4 Hz, 1H); 13C NMR (125 MHz, d6-DMSO) d 111.89, 126.02, 138.28, 153.36, 154.88; HRMS (EI) Calcd for C5H4ClN3O2: 172.9997. Found 172.9996.
With ammonia; sodium carbonate; In ethanol; water;
A. 6-chloro-3-nitropyridin-2-yl-amine Add sodium carbonate (14 g, 130 mmol) and 2M NH3 in EtOH (20 mL) to a solution of 2,6-dichloro-3-nitropyridine (10 g, 51.8 mmol) in ethanol (115 mL). Heat the mixture at 70 C. for 5 hours. After cooling, remove the excess ethanol in vacuo, and triturate the residue in water. After stirring for 15 minutes, filter the precipitate to obtain 6-chloro-3-nitropyridin-2-yl-amine.
75 g
With ammonium hydroxide; In isopropyl alcohol; at 20 - 25℃;
A solution of 100 gm. 2, 6-dichloro-3-nitro-pyridine in 800 ml isopropyl alcohol is taken in round bottom flask. 300 ml of aqueous ammonia solution (20-25%) is added at 20-25C. The reaction mass is stirred for 20-24 hours at 20-25C. After completion of the reactionThe solid is filtered and washed with 100 ml isopropyl alcohol then dried to obtain 70-75 gm 2-amino-3-nitro-6-chloro-pyridine.
30 g
With ammonium hydroxide; at 50℃; for 5h;
To a stirred solution of Compound 39a (50g, 261.78mmol) was added 38% ammonia solution (150ml) and heated at 50C for 5h. Upon completion, the obtained solids were filtered and given diethylether washings to afford the required compound as a yellow solid (30g).
With ammonium hydroxide; In ethanol; at 30 - 35℃; for 6h;Large scale;
2,6-dichloro-3-nitropyridine (5 kg, 25.9 mol) was added to a reaction vessel containing 20 kg of ethanol, and 25% aqueous ammonia (9.07 kg, 64.8 mol) was added at room temperature to control the internal temperature. 30~35 C, heat preservation reaction for about 6h, TLC monitoring the raw material reaction completely stop the reaction, adding p-fluorobenzylamine (3.8kg, 31.1mol), heating to 60~65 C reaction for about 6h, TLC monitoring the raw material reaction is complete The reaction was stopped, and the temperature was lowered to 5 to 10 C for crystallization for 1 to 2 hours and then filtered. The obtained wet product was added to 60 kg of isopropyl alcohol, heated to reflux, and cooled to room temperature for 2 hours, filtered, and the wet product was kept in the reaction vessel. 75 kg of isopropanol, 5% Pd/C 0.3 kg and ethyl chloroformate (3 kg, 27.6 mol) were added to the reaction vessel, and hydrogen pressure was maintained at 1.2 to 1.5 MPa, and the temperature was controlled at 60 to 70 C for 5 hours. Filtration, the filtrate was cooled to 0~5 C and stirred for 2 h, and dried under reduced pressure at 60 C for 4 h to obtain white flupirtine hydrochloride 6.48 kg, the yield was 73.4%, and the chromatographic purity was 99.62%. The nuclear magnetic data is basically consistent with the data of Example 1.
To a reaction flask, 200 mL of methanol, 52.08 g of compound 1, 37.54 g of p-fluorobenzylamine and 50.0 mL of triethylamine werea added. The reaction mixture was heated to 80 C for 10 hours, and the reaction solution was added with 10 times of water to give 76.47 g of compound 3 in a yield of 97.2% and a purity of 99.62% (HPLC).
96.8%
With triethylamine; In isopropyl alcohol; for 14h;Inert atmosphere; Reflux; Industry scale;
2-Amino-6-chloro-3-nitropyridine (ACNP, 10.0 kg) was suspended in isopropanol (49 L) under stirring and a nitrogen blanket. 4-Fluorobenzylamine (7.7 kg) and triethylamine (8.4 kg) were added and the mixture was heated to reflux. Stirring at reflux was maintained for 14 h. The reaction mixture was cooled to 50C and samples were taken for checking completion of the reaction by HPLC (amount of residual ACNP: 0.02%). Water (163 kg) was added and the mixture was stirred for 5 min, then cooled to 5C and stirred for 30 minutes. The precipitate was filtered off, washed with water (41 L) and dried under reduced pressure at 50C. Yield: 14.6 kg (96.8% of theory).
96.6%
With triethylamine; In isopropyl alcohol; at 70 - 80℃; for 12h;Large scale;
Was added to the reaction kettle 3.04kg and 10kg of isopropanol fluorobenzylamine, with stirring, was added 4kg2- amino-3-nitro-6-chloropyridine and 8.67kg of triethylamine, and heated at reflux temperature for 12h 70-80 , cooled to 60 , reaction was monitored sampling is complete, add 4% sodium hydroxide aqueous solution prepared 1.07kg, 55 concentrated under reduced pressure until no solvent flows, centrifuged solids, temperature 50-60 , dried 10-12 hours to give flupirtine maleate intermediate (2-amino-3-nitro-6- (p-fluoro-benzylamino) pyridine) 5.86kg, a yield of 96.6%
88%
With triethylamine; In isopropyl alcohol; at 90℃; for 0.666667h;Microwave irradiation;
To a solution of Intermediate 5 (500 mg, 2.9 mmol) in isopropanol was added 4- fluorobenzylamine (463 iil, 4.06 mmol) and triethylamine (805 iil, 5.8 mmol). This mixture was stirred at 90C for 40 minutes in the microwave. Water was added to the mixture and the resulting precipitate was filtered off, washed with water and then driedover vacuum for an hour. Intermediate 6 was isolated as a bright yellow solid (661 mg,88%).LCMS (m/z): [IVIH] calcd. for C12H11FN4O2, 262.24; found 263.00.
79.4%
With triethylamine; In isopropyl alcohol; at 5℃; for 0.5h;
2-Amino-3-nitro-6-chloropyridine (Compound 1) (50.0 g, 288 mmol, 1.00 eq) was dissolved in isopropyl alcohol (500 mL).p-Fluorobenzylamine (39.7 g, 317 mmol, 1.10 eq) and TEA (32.0 g, 317 mmol, 1.10 eq.Thereafter, the reaction solution was poured into water (1.5 L), and slowly cooled to 5 C and stirred for 30 minutes.Filter and filter cake was washed with water (500 mL).The filter cake was collected and dried to give a yellow solid (Compound 2) 60 g, yield 79.4%.
150 g
With triethylamine; In water; at 20 - 85℃;
100 gm of 2-amino-3-nitro-6-chloro-pyridine is taken in 800 ml of water. 90 gm of p-fluorobenzylamine is added dropwise into the reaction mixture at 20-25C. Then 87 gm triethylamine is also added dropwise into the reaction mixture at 20-25C. After complete addition, the reaction mass is stirred at 40-45C for half an hour again the reaction mass is heated to 80-85C and stirred at this temperature for 3-4 hours. After completion of the reaction, the reaction mass is cooled to 20-25C and stirred at this temperature for 2-3 hours and then stirred at 15-20C for 3-4 hours. The solid mass is filtered and then washed with 200 ml of water and 100 ml isopropyl alcohol and then dried in air oven till constant weight to get 140-150 gm. of 2-amino-3-nitro-6-p- fluorobenzylamino-py ridine.
With potassium carbonate; In butan-1-ol; for 2h;Reflux;
Step-2: Synthesis of Compound 4: 2-Amino-6-chloro-3-nitropyridine 2 (17.35 g, 0.10 mol), 4-fluoro benzyl amine (0.10 mol) and powdered potassium carbonate (10.4 g, 0.035 mol) in n-butanol (100 mL) were heated under reflux for 2 hours. The suspension was filtered and after cooling to room temperature the solid 4 was collected by filtration, washed with butanol, and dried.
at 60 - 65℃; for 6h;Large scale;
2,6-dichloro-3-nitropyridine (5 kg, 25.9 mol) was added to a reaction vessel containing 20 kg of ethanol, and 25% aqueous ammonia (9.07 kg, 64.8 mol) was added at room temperature to control the internal temperature. 30~35 C, heat preservation reaction for about 6h, TLC monitoring the raw material reaction completely stop the reaction, adding p-fluorobenzylamine (3.8kg, 31.1mol), heating to 60~65 C reaction for about 6h, TLC monitoring the raw material reaction is complete The reaction was stopped, and the temperature was lowered to 5 to 10 C for crystallization for 1 to 2 hours and then filtered. The obtained wet product was added to 60 kg of isopropyl alcohol, heated to reflux, and cooled to room temperature for 2 hours, filtered, and the wet product was kept in the reaction vessel. 75 kg of isopropanol, 5% Pd/C 0.3 kg and ethyl chloroformate (3 kg, 27.6 mol) were added to the reaction vessel, and hydrogen pressure was maintained at 1.2 to 1.5 MPa, and the temperature was controlled at 60 to 70 C for 5 hours. Filtration, the filtrate was cooled to 0~5 C and stirred for 2 h, and dried under reduced pressure at 60 C for 4 h to obtain white flupirtine hydrochloride 6.48 kg, the yield was 73.4%, and the chromatographic purity was 99.62%. The nuclear magnetic data is basically consistent with the data of Example 1.
With iron; ammonium chloride; In water; isopropyl alcohol; at 90℃; for 1h;
a) 6-Chloropyridine-2,3-diamine (A45) Iron powder (9.65 g, 173 mmol) was added to a suspension of 6-chloro-3-nitropyridin-2- amine A44 (10.0 g, 57.6 mmol) and NH4CI (6.16 g, 115 mmol) in isopropanol (180 mL) and water (90 mL). The resulting mixture was heated at 90 C for one hour. After this time, the suspension was left to cool to room temperature, then diluted with EtOAc (100 mL), filtered through Celite and the residues washed with further EtOAc (2 x 150 mL). The filtrate was washed with water (3 x 100 mL), brine (100 mL), dried over Na2S04 and the volatiles removed under reduced pressure to give the title compound (7.50 g, 91 %) as a dark brown solid. H NMR (400 MHz, cfe-DMSO) delta 6.68 (d, J = 7.8 Hz, 1 H), 6.35 (d, J = 7.8 Hz, 1 H), 5.78 (s, 2H), 4.76 (s, 2H).
91%
With sodium tetrahydroborate; In ethanol; water; at 20℃; for 4h;
General procedure: SAC (300mg) and NaBH4 (4.0mmol) were added to a solution of nitroarenes (1.0mmol) in EtOH/water (1/1) (20ml). The reaction mixture was stirred for 4h at the temperature indicated in Table3. At the end of the reaction, the catalyst was removed by filtering and the filtrate was extracted with 3×70ml EtOAc. The combined organic layers were dried over MgSO4 and concentrated in a vacuum.
89.2%
With iron; ammonium chloride; In water; ethyl acetate; at 20℃; for 4h;
Compound 1 (500 g, 2.89 mol),Ammonium chloride (300 g, 5.75 mol) was dissolved in 5000 ml of ethyl acetate and 3000 ml of water,To this mixture was added iron powder (482.5g, 8.65mol) at room temperature, the reaction was carried out at room temperature for 4 hours,The reaction was complete by TLC and the reaction mixture was filtered. The filtrate was separated and the aqueous phase was extracted twice with 1500 ml of ethyl acetate. The combined organic phases were dried over saturated brine and concentrated to give compound 2 (370 g, 2.58 mol)Yield 89.2%
77%
Intermediate 16-Chloropyridine-2,3-diamineIn a 2-neck, 250 mL glass round bottom flask 6-chloro-3-nitropyridin-2-amine (J Med. Chem., 2000, 43, 3053-3066, 5 g, 28.81 mmol) and tin (II) chloride dihydrate (32.5 g, 144.04 mmol) were combined and suspended in EtOAc (90 mL) and (10 mL).The reaction slurry was heated to 6O0C for 1 hour. Sodium borohydride (0.544 g, 14.40 mmol) was added in a single portion, and the reaction was heated for an additional 12 hours. The progress of the reaction was monitored by LC/MS. When the reaction was complete, the solvent was removed by rotary evaporation. The solid was dissolved in EtOAc and water. The mixture was neutralized with K2CO3 while cooling the mixture in an ice bath. The tin salts precipitated from solution and were removed by filtering the mixture though a pad of Celite. The aqueous and organic phases were then separated, and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to 3.2 grams (77% yield) of a light green solid which was used with no further purification. LC/MS (ES+)[(M+H)+]: 144, 146 for C5H6ClN3. 1R NMR (300 MHz, d4-MeOD): 6.47 (d, IH), 6.85 (d, IH).
75%
To a mixture of ethyl acetate (450 mL) and tert-butanol (50 mL), 6-chloro-3- nitropyridin-2-amine (CAS 27048-04-0) (15g, 86,42 mmol), stannous chloride dehydrate (CAS 10025-69-1) (97.5 g, 432.1 mmol) were added. The resulting mixture was stirred at 60C for 1 hour. Sodiumborohydride (1.63 g, 43.21 mmol) was added and the mixture was stirred further at 60C for another 3h. The mixture was cooled and stripped from the EtO Ac on the rotavapor. The resulting residu was diluted with water (350 mL) and neutralized to pH = 9-10 by addition of an aqueous solution of potassium carbonate. The resulting mixture was extracted with EtO Ac (3x 250 mL), dried over Na2S04 and evaporated. The residu was stirred for 72 hours in a mixture of EtO Ac/heptane 1/1. The precipitate was filtered and dried in vacuum for 2 hours. The intermediate 1-1 was collected as a greenish powder (9.32 g, 75%). m/z = 144 (M+H)+.
75%
To a mixture of ethyl acetate (450 mL) and tert-butanol (50 mL), 6-chloro-3-nitro- pyridin-2-amine (15 g, 86,42 mmol), stannous chloride dehydrate (97.5 g, 432.1 mmol) were added. The resulting mixture was stirred at 60C for 1 hour. Sodiumborohydride (1.63 g, 43.21 mmol) was added and the mixture was stirred further at 60C for another 3h. The mixture was cooled and stripped from the EtO Ac on the rotavapor. The resulting residu was diluted with water (350 mL) and neutralized to pH = 9-10 by addition of an aqueous solution of potassium carbonate. The resulting mixture was extracted with EtO Ac (3x 250 mL), dried over Na2S04 and evaporated. The residu was stirred for 72 hours in a mixture of EtO Ac/heptane 1/1. The precipitate was filtered and dried in vacuum for 2 hours. The intermediate 27-b was collected as a greenish powder (9.32 g, 75%).
75%
To a mixture of ethyl acetate (450 mL) and fert-butanol (50 mL), 6-chloro-3- nitropyridin-2-amine (CAS 27048-04-0) (15g, 86,42 mmol), stannous chloride dehydrate (CAS 10025-69-1) (97.5 g, 432.1 mmol) were added. The resulting mixture was stirred at 60C for 1 hour. Sodiumborohydride (1.63 g, 43.21 mmol) was added and the mixture was stirred further at 60C for another 3h. The mixture was cooled and stripped from the EtO Ac on the rotavapor. The resulting residu was diluted with water (350 mL) and neutralized to pH = 9-10 by addition of an aqueous solution of potassium carbonate. The resulting mixture was extracted with EtO Ac (3x 250 mL), dried over Na2S04 and evaporated. The residu was stirred for 72 hours in a mixture of EtO Ac/heptane 1/1. The precipitate was filtered and dried in vacuum for 2 hours. The intermediate 17 was collected as a greenish powder (9.32 g, 75%). m/z = 144 (M+H)+.
72.5%
With iron; calcium chloride; In ethanol; water; at 100℃; for 6h;
To a stirred solution of 2-amino-3-nitro-6-chloropyridine (30 g, 172.8 mmol) in EtOH (300 mL) and H20 (300 mL) was added CaCh (23 g, 207.4 mmol) followed by the addition of Fe powder (22.8 g, 414.8 mmol). The resulting mixture was heated to 100 C for 6 h. The reaction mixture was filtered through a celite bed. The filtrate was diluted with EtOAc (500 mL) and washed with water (2x250 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude product. The crude was purified by column chromatography using silica gel (60-120 mesh) by eluting with 30% EtOAc in petroleum ether to afford pure product Via as a brown solid. Yield: 18 g, 72.5% NMR (400 MHz, DMSO-de): d 6.69 (d, 1H, J=8 Hz), 6.65 (d, 1H, J=8 Hz), 5.78 (2H, s), 4.76 (2H, s). LC_MS Calc for C5H6ClN3 143.57; Obs. 144.2 [M++H]
60%
With tin(ll) chloride; In tetrahydrofuran; hydrogen chloride; at 20℃; for 4h;
Intermediate 4.1: 6-Chloro-pvridine-2,3-diamine (Scheme 10); 2-arnino-3-nitro-6-chloropyridine (3 g, 17.3 mmol, 1 eq.) was dissolved in THF (50 mL) at it. Tin chloride dihydrate (15.6 g, 70 mmol, 4 eq.) pre-dissolved with HClcc (5 mL) was added slowly and reaction mixture stirred at rt for 4 hours. When thereaction was finished, reaction mixture was cooled down to 0C and treated with sodium hydroxide 5M (12 mL) until pH 14 and the corresponding compound extracted with ethyl acetate. Organic phases were dried with magnesium sulfate, evaporated under vacuum and resulting crude material purified by flash chromatography using cyclohexane/ethyl acetate (1/1) to give 1.5 g of a red oil (Intermediate 4.1). Amount: 1.5 g; Yield: 60 %; Formula: C5H6N3C1; HPLC Purity: 98%; HPLC (HzO TFA 0.1%-ACN TFA Q.05%): Rt (min); Area % = 0.5 min; 98%; 1H NMR (DMSO-d6) 8 6.67 (d, 1H, H5, J=8Hz), 6.36 (d, 1H, H4, J= 8Hz), 5.78 (m, 2H, NH2), 4.75 (m, 2H, NH?): LC-MS: M/Z ESI: Rt (min) 0.1 min, 144.0 (M+l).
With sodium hydroxide; In methanol; acetic acid;
B. 6-Chloro-pyridine-2,3-diamine Add zinc (4.0 g) to a solution of 6-chloro-3-nitropyridin-2-yl-amine (1.0 g, 5.76 mmol) in acetic acid (1.5 mL) and methanol (40 mL). Stir the resulting mixture is at room temperature for 18 hours, and filter through a pad of celite. Evaporate the filtrate to dryness under reduced pressure. Treat the resulting residue with 1N aqueous NaOH and extract with EtOAc. Wash the EtOAc extract with water and saturated aqueous NaCl. Separate the organic layer, dry over Na2SO4, filter and concentrate. Purify by flash column chromatography (50% EtOAc-hexane) to obtain 6-chloro-pyridine-2,3-diamine.
Step 1 : 6-Chloropyridme-2,3-diamineA flask was charged with 6-chloro-3-rtropyridin-2-amine (500 mg, 2.88 mmol) and tin(II) chloride dihydrate (3.25 g, 14.40 mmol) under argon. A 9:1 mixture of ethyl acetate:2-methyl-2-propanol was then added, and the reaction was allowed to stir at 600C for one hour. Sodium borohydride (55 mg, 1.44 mmol) was then added, and the reaction was allowed to stir for 3 hours at 600C. The reaction mixture was then cooled and the solvent evaporated under reduced pressure. The solid was taken up in water and saturated aqueous sodium carbonate was added until pH~7 was attained. The mixture was extracted with ethyl acetate (2x). The combined organics were washed with brine, and dried over magnesium sulfate. This mixture was filtered and the filtrate concentrated under reduced pressure. Recrystallization from ethyl acetate/hexanes afforded the title compound.
Preparation Example 8-1 2,3-Diamino-6-chloropyridine In the same manner as in the following Preparation Example 9-2, the objective compound (8.3 g) was obtained from <strong>[27048-04-0]2-amino-6-chloro-3-nitropyridine</strong> (10.2 g) as a red-brown solid. 1H-NMR(DMSO-d6): 4.77(2H, br s), 5.79(2H, br s), 6.34(1H, d, J=8 Hz), 6.69(1H, d, J=8 Hz) MASS(ESI): m/z 142(M-1)
With potassium carbonate In N,N-dimethyl-formamide at 80℃;
92%
at 70℃; for 5h;
86%
With triethylamine In isopropyl alcohol at 110℃; for 0.25h; Microwave irradiation;
74%
In methanol Ambient temperature;
57%
With triethylamine In isopropyl alcohol for 3h; Reflux; Inert atmosphere;
51%
With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 18h;
19.a a) 6-Morpholino-3-nitropyridin-2-amine (A51)
a) 6-Morpholino-3-nitropyridin-2-amine (A51) Potassium ferf-butoxide (178 mg, 1.58 mmol), THF (10 mL) and morpholine (0.150 mL, 1.73 mmol) were stirred at room temperature for five minutes, then 6-chloro-3-nitropyridin-2- amine A44 (250 mg, 1.44 mmol) was added and the orange-red mixture stirred at room temperature for 18 hours. The mixture was poured into water (140 mL), the precipitate collected by filtration and air dried. Purification by column chromatography (40 g silica cartridge, 5-100% EtOAc/hexanes) gave the title compound (166 mg, 51 %) as a yellow solid. H NMR (400 MHz, CDCI3) δ 8.20 (d, J = 9.4 Hz, 1 H), 7.95 (br s, 1 H), 6.05 (d, J = 9.4 Hz, 1 H), 5.57 (br s, 1 H), 3.80 - 3.74 (m, 4H), 3.73 - 3.66 (m, 4H). LCMS-A: rt 5.38 min; m/z (positive ion) 225.2 [M+H]+.
In acetonitrile
46 6-Morpholin-4-yl-3-nitropyridin-2-amine
Example 46 6-Morpholin-4-yl-3-nitropyridin-2-amine Morpholine (4 eq) was added to a suspension of 6-chloro-3-nitropyridin-2-amine (1 eq) in CH3CN, and the reaction mixture was stirred at 70° C. for 5 hours. The solvent was evaporated under reduced pressure, and the residue was triturated with ether to afford the desired compound as a bright yellow powder. LC/MS m/z 225.0 (MH+), Rt 1.79 minutes.
In acetonitrile
47.1 Step 1:
Step 1: 6-Morpholin-4-yl-3-nitropyridin-2-amine Morpholine (4 equivalents) was added to a suspension of 6-chloro-3-nitropyridin-2-amine (1 equivalent) in CH3CN, and the reaction mixture was stirred at 70° C. for 5 hours. The solvent was evaporated under reduced pressure, and the residue was triturated with ether to afford the desired compound as a bright yellow powder. LC/MS m/z 225.0 (MH+), Rt 1.79 minutes.
In acetonitrile at 70℃; for 5h;
7
To a suspension of 6-chloro-3-nitropyridin-2-amine (1 equivalent) in acetonitrile was added an amine, e. g. morpholine (4 equivalents). The resulting reaction mixture was stirred at 70 C for 5 hours. The solvent was evaporated under reduced pressure, and the residue triturated with ether to provide the desired compound as a bright yellow powder. LC/MS M/Z 225.0 (MH+), Rt 1.79 minutes. The nitroamine was reduced as in Method 1 to provide the crude product which was used without further purification.
In acetonitrile at 70℃; for 5h;
47.1 Example 47: Synthesis OF 4-AMINO-3-(5-MORPHOLINW4-VL-3H-IMIDAZOF45- BLPVRIDIN-2-VL) AUINOLIN-2 (1 H)-ONE; Step 1: 6-MORPHOLIN-4-YL-3-NITROPYRIDIN-2-AMINE
Morpholine (4 equivalents) was added to a suspension of 6- CHLORO-3-NITROPYRIDIN-2-AMINE (1 equivalent) in CH3CN, and the reaction mixture was stirred at 70 C for 5 hours. The solvent was evaporated under reduced pressure, and the residue was triturated with ether to afford the desired compound as a bright yellow powder. LC/MS M/Z 225. 0 (MH+), Rt 1.79 minutes.
With potassium carbonate In acetonitrile at 80℃;
With potassium carbonate In acetonitrile at 80℃;
2.1.7. Synthesis of intermediates 11
A reaction mixture of 6-chloro-3-nitropyridin-2-amine (1.0 equiv), morpholine (1.0equiv) and K2CO3 (3.0equiv) in MeCN was stirred at 80°C for 3-5h. The mixture was extracted with CH2Cl2 and the organic layer washed with brine, dried over anhydrous magnesium sulfate, and concentrated under vacuum. The solid part was purified by chromatography over silica gel using ethyl acetate/petroleum ether to generate intermediate 11.
In N,N-dimethyl-formamide at 20℃; for 1h;
Preparation of Intermediate M-21 N3-(2-methoxyethyl)-6-(morpholin-4-yl)pyridine-2,3-diamine M-21
2-Amino-6-chloro-nitropyridine (250 mg; 1.4 mmol) is added to morpholine (577 μl; 6.6 mmol) and diluted with N,N-dimethylformamid (2 ml). Reaction mixture is stirred at 20° C. for 1 hour. Water is added and the precipitate is collected and suspended in methanol. Solvent is evaporated under reduced pressure.
Intermediate 5 6-Chloro-3-nitropyridin-2(l//)-one To ice cold concentrated sulphuric acid was added 6-chloro-3 -nitro-pyridin-2-ylamine (Intermediate 4, 5 g, 28 mmol), and the reaction mixture was stirred for 10 min at 0 0C. A solution OfNaNO2 (4 g, 58 mmol in 30 mL of water) was added slowly over a period of 10 min maintaining the temperature at 00C, then the mixture was stirred for 30 min at the same temperature. The reaction mixture was poured onto ice cold water (150 mL), the precipitate that formed was collected by filtration, washed with cold water (2x50 mL) and dried under vacuum to provide 6-chloro-3-nitropyridin-2(lf/)-one in 80% yield (4 g, 23 mmol) as yellow color solid. MS (ES): 172.9 (M-I) for C5H3ClN2O3.1H-NMR (DMSO-d6, 400 MHz): delta 7.06 (d, J= 8.3 Hz, IH), 8.40-8.43 (m, IH).
67%
With sodium nitrite; In sulfuric acid; water;
6-chloro-3-nitro-2(1H)-pyridone (91) 6-Chloro-3-nitro-2-pyridinamine (90a) (0.3 g, 1.73 mmol) was dissolved in 5 ml of conc. H2SO4 at 0Ø C. A solution of NaNO2 (0.24 g, 3.46 mmol, 2.0 eqv) in 2 ml of H2O was added cautiously to the arylamine solution and the mixture was stirred at 0Ø C. for 30 min. H2O (10 ml) was added and the solid precipitate was filtered and washed with cold H2O several times. The solid was dried under vacuum to give 0.2 g of a yellow solid (67%): 1H NMR (400 MHz, d6-DMSO) d 7.08 (d, J=6.4 Hz, 1H), 8.43 (d, J=6.8 Hz, 1H); 13C NMR (125 MHz, d6-DMSO) d 113.93, 132.10, 138.90, 150.27, 156.47; HRMS (EI) Calcd for C5H3ClN2O3: 173.9832. Found 173.9830.
Sodium methoxide, 7.78 gm (0.144 mole) and methanol 50.0 ml were mixed and cooled to 15 C. To this solution, 25.0 gm of 2-amino-6-chloro-3-nitropyridine (0.144 mole) was added while maintaining the temperature at 15 C. by external cooling. The resulting mixture was heated to 25-30 C. and maintained at this temperature for 4-5 hrs with constant stirring. The completion of reaction was monitored by TLC. After the completion of reaction, the reaction mixture was poured in water. The precipitate thus obtained was filtered and washed with water. On drying 21.0 gm of 2-amino-3-nitro-6-methoxypyridine (86.5% yield) was obtained, with the HPLC purity of 99.0%. Melting point 167-169 C.; 1H-NMR (CDCl3) delta 3.89 ppm (s,-3H, OCH3), 66.14-6.16 ppm (d, 1H), 68.24-8.27 ppm (d, 1H), 68.16 ppm (s, -2H, -NH2).
84.1%
In N,N-dimethyl-formamide; at 20℃; for 3h;
To a solution of 2-amino-3-nitro-6-chloropyridine (300 mg, 1.73 mmol, an intermediate in preparation of 8) in 5 mL anhydrous DMF was added sodium methoxide (187mg, 3.46 mmol). This mixture was stirred at room temperature for 3 h then poured onto 20 g crushed ice and extracted with ethyl acetate. The extracts were dried, evaporated and purified by column chromatography on silica gel (PE/AcOEt=5:1) to give 2-amino-3-nitro-6-methoxylpyridine (246 mg, 84.1%) as yellow solid. Next steps followed the general procedure, and the title compound was obtained as white solid (188 mg, 67.0% over 2 steps). IR (KBr) nu 3246, 3184, 1708, 1635, 1599, 1488, 1462, 1341, 1260, 1024, 839cm-1; 1H NMR (400MHz, DMSO-d6) delta 3.81 (3H, s, CH3), 6.56 (1H, d, J=8.4Hz, H-7), 7.42 (1H, d, J=8.4Hz, H-8), 11.82 (1H, s, NH-1), 12.25 (1H, s, NH-4); 13C NMR (100MHz, DMSO-d6) delta 53.50, 104.56, 115.19, 126.61, 136.21, 154.35, 156.11, 158.55; HRMS-EI C8H7N3O3 calcd [M+Na]+ 216.0385, found 216.0382.
9 g
In ethanol; at -15 - 20℃; for 16h;
To a stirred solution of Compound 39b (15g,86.70mmol) in MeOH (35ml) was added NaOMe (7.2g,133.92mmol) at -15C and stirred for 16h at RT. The reaction was quenched with ice and the obtained solids were filtered and dried to afford the required compound (9g).
With N-chloro-succinimide; acetic acid; at 100℃; for 2h;
To a suspension of Compound 1 (5 g, 28.8 mmol) in acetic acid (50 mL) was added NCS (4.04 g, 30.2 mmol), and the obtained reaction mixture was stirred at 100 C. for one hour. The reaction mixture was allowed to cool to room temperature, and NCS (0.385 g, 2.88 mmol) was added thereto. The obtained reaction mixture was stirred at 100 C. for one hour again. The obtained reaction mixture was allowed to cool to room temperature, and the solvent was then removed by distillation under reduced pressure. The residue was suspended in distilled water (50 ml), and the obtained liquid was stirred and adjusted to pH=8 using a saturated sodium bicarbonate solution at 0 C. (0482) The solid residue was filtered, and the obtained residue was washed twice with distilled water, followed by vacuum drying to obtain Compound 2 (5.5 g, 92%) as a yellow solid Compound 2; 1H-NMR (DMSO-d6) delta: 8.33 (brs, 2H), 8.59 (s, 1H).
76%
With chlorine; In ethanol; at 0℃; for 1h;
A suspension of 6-chloro-3-nitropyridine-2-amine 1 (20 g, 115 mmol) in anhydrous ethanol (970 mL) was subjected to bubbling with chlorine gas while stirring at 0 C. over one hour. Thereafter, the reaction mixture was subjected to bubbling with nitrogen gas while stirring at room temperature over one hour, and then stirred at 0 C. for 30 minutes. The reaction suspension was filtered, and the obtained residue was washed with diisopropyl ether to obtain a solid. The solvent of the resulting filtrate was removed under reduced pressure, and the precipitated solid was filtered and the obtained solid was then washed with diisopropyl ether to further obtain a solid. The above-described two collected solids were combined to obtain Compound 2 (18.1 g, 76%) as a yellow solid.Compound 2; 1H-NMR (DMSO-d6) delta: 8.33 (brs, 2H), 8.59 (s, 1H).
46%
With N-chloro-succinimide; acetic acid; at 100℃; for 2h;
[0248] To a suspension of 6-chloro-3-nitropyridin-2-amine (20 g, 115 mmol) in acetic acid (100 mL) was added N-chlorosuccinimide (16.157 g, 121 mmol), and the obtained reaction mixture was stirred at 100 C for one hour. The reaction mixture was allowed to cool to room temperature, and N- chlorosuccinimide (2.0 g) was added thereto. The obtained reaction mixture was stirred at 100 C for 1 h. The obtained reaction mixture was allowed to cool to r.t. and acetic acid was removed via distillation. The residue was suspended in water, added sat. sodium bicarbonate aq. until pH=8 and the solid residue was filtered. The solid was then washed twice with water. The solid was collected, dissolved in acetone and precipitated with water, and filtered to afford 2-61-a as a pure yellow solid (11 g, 46%). 'H NMR (400 MHz, DMSO -di) d 8.59 (s, 1H), 8.34 (s, 2H).
To a solution of commercially available 2,6-dichloro-5- nitropyridine (20.0 g, 95.3 mmol) in ethanol (300 mL) was added aqueous ammonia (60 mL), and the mixture was stirred at room temperature for 10 hours. The resulting precipitate was filtered, washed with ethanol, and dried in vacuo to give <strong>[27048-04-0]6-amino-2-chloro-5-nitropyridine</strong> (13. [8 G, 83 %). THE COMPOUND] thus obtained was suspended in an acetic acid solution (130 mL) of [30%] hydrogen bromide. The suspension was stirred at [100C] for 26 hours, cooled to room temperature, and concentrated in vacuo. The resulting residue was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue thus obtained [ WAS RECRYSTALLIZED FROM ETHYL ACETATE TO GIVE THE TITLE COMPOUND] (14.93 g, 86 [%).]
With hydrogen bromide; In acetic acid; at 20 - 100℃; for 72h;
Preparation Example 9-1 2-Amino-6-bromo-3-nitropyridine A 30% solution of hydrogen bromide in acetic acid (10 ml) was added to <strong>[27048-04-0]2-amino-6-chloro-3-nitropyridine</strong> (1.0 g) at room temperature and the mixture was heated at 100 C. After 24 hr, a 30% solution of hydrogen bromide in acetic acid (5 ml) was added.. After 48 hr, the reaction mixture was cooled and concentrated.. The residue was neutralized with 28% aqueous ammonia and extracted three times with ethyl acetate.. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated.. The residue was crystallized from isopropyl ether to give the objective compound (1.14 g) as yellow crystals. 1H-NMR(DMSO-d6): 6.90(1H, d, J=8 Hz), 8.25(1H, d, J=8 Hz) MASS(ESI): m/z 217(M-1)
Intermediate 2 (8.62 g, 0.05 mol), phenylboronic acid (5.05 g), dicyclohexyl(2?,6?-dimethoxy-[1,1?-biphenyl]-2-yl)phosphine (0.567 g), potassium phosphate tribasic monohydrate (23.85 g), 30 mL toluene and 3 mL water were added to a 3-neck 100 mL round bottom flask. Nitrogen was bubbled directly into the mixture for 20 minutes. Pd2(dba)3 (0.316 g) was added and the mixture refluxed overnight under nitrogen. The reaction mixture was diluted with ethyl acetate/water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and evaporated to a residue. The residue was purified by column chromatography eluting with 20% ethyl acetate/hexanes initially and ethyl acetate was added to flush off the product. The product was washed with hexane to get intermediate 3 (8.02 g, 75% yield).
53%
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; water; toluene; at 90℃; for 12h;
Reference Example 112 Under an argon stream, a mixture of 6-chloro-3-nitro-2-pyridine amine (2.0 g), phenylboric acid (2.1 g), tetrakis(triphenylphosphine)palladium(0) (1.3 g), 2 M sodium carbonate (35 ml), toluene (40 ml) and tetrahydrofuran (20 ml) was stirred at 90C for 12 hours.. The mixture was distributed into ethyl acetate - tetrahydrofuran (3: 1, v/v) and water.. The organic layer was washed with water and dried over MgSO4.. The solvent was distilled off under reduced pressure and the resulting crystals were collected by filtration to obtain 3-nitro-6-phenyl-2-pyridine amine (1.3 g, 53 %).1H NMR (CDCl3) delta 7.20 (1H, d, J = 8.4 Hz), 7.49-7.54 (3H, m), 8.00-8.05 (2H, m), 8.49 (1H, d, J = 8.4 Hz) ppm IR (KBr) nu 3501, 3382, 1617, 1586, 1578, 1271, 1244 cm-1HPLC (220 nm) Purity 97 % (Retention time 3.86 minutes) MS (ESI, m/e) 216 (M+1)
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 80 - 85℃; for 12h;Inert atmosphere;
Example 1 Preparation of Compounds 1, 1', 2, 2', 3, 4, 6 and 7 Preparation of 1 A 100 L jacketed reactor equipped with temperature probe, argon inlet and reflux condenser was charged with toluene (30 L, 30 vol.), EtOH (6 L, 6 vol.), 2-amino-3-nitro-6-chloro-pyridine (1.0 kg, 5.76 mol.), phenylboronic acid (772 g, 6.34 mol.) followed by a solution of K2CO3 (1.75 kg, 12.67 mol) in DI water (6.0 L, 6 vol.). The resulting mixture was stirred at room temperature for 10 minutes. The reaction mixture was degassed with argon for 30 minutes before Pd(PPh3)4 (67.1 g, 1 mol) was added to the reaction mixture and then resulting mixture was degassed for additional 10 minutes. The reaction was then heated to 80-85 C. The reaction was deemed complete by HPLC in 12 hours. The reaction was cooled to room temperature and diluted with water (10 L, 10 vol.). The organic layer was removed and the aqueous layer was extracted with MTBE (2*10 L, 20 vol.). Combined organic layers were treated with charcoal and heated to 50 C. for 1 hour. The hot solution was filtered through a Celite bed and washed the bed with hot (?50 C.) MTBE (2 L, 2 vol.) and dried the filtrate over sodium sulfate. The organic layer was concentrated under reduced pressure at below 50 C. to give dark brown solid (1.094 kg, 88.9%). The crude compound was triturated in heptanes (3.5 L, 3.5 vol.) for 3 hours, filtered off the solids, washed with heptanes (1.5 L, 1.5 vol.) and dried to afford 1 (980.0 g, 79.6%, 89.6% purity) and compound was characterized by 1H NMR (CDCl3) and MS.
Sodium metal (0.5 g, 21.7 mmol) was added portion wise to anhydrous methanol 30 ML) under argon. When the sodium was consumed, 1-AMINO-6-CHLORO-3-NITROPYRIDINE (3.0 g, 17.2 mmol) and methanol (30 mL) were added, and the suspension refluxed for 2 h. The reaction was cooled to room temperature and stirred for 3 h. The yellow solid was filtered and air dried to give the title compound. MS 170 (M+1) 1H NMR (500 MHz, CDC13) 8 8.29 (d, J=9 Hz, 1H), 7.8 (br s, 1H), 6.14 (d, J=9 Hz, 1H), 5.6 (br s, 1H).
With sodium; In methanol; water; ethyl acetate;
Stage A: 2-amino-6-methoxy-3-nitropyridine 1.65 g (0.0717 mol; 2 equivalents (eq)) of sodium are dissolved in 100 cm3 of methanol. 6.2 g (35.7 mmol) of 2-amino-6-chloro-3-nitropyridine are added and the solution is brought to reflux for 8h. The methanol is evaporated under reduced pressure and the residue is taken up in the minimum amount of water (20 cm3). The solution is extracted with 100 cm3 of ethyl ether. The ether phase is washed with water (20 cm3), separated by settling, dried over MgSO4, decolored with animal charcoal and evaporated on a rotary evaporator to give a 1 st crop. The aqueous phase is extracted under the same conditions with 2 times 50 cm3 of ethyl acetate, giving a 2nd and 3rd crop. 4.7 g (0.0278 mol; yield: 77.7%) of a yellow powder are obtained. Melting point: 172 C.
4.A Step A
Step A 6-Iodo-3-nitro-pyridin-2-ylamine (5-2) A mixture of 2-amino-6-chloro-3-nitropyridine (L) (5.00 g, 28.8 mmol) and 57% HI (100 mL) was stirred for 48 hours at RT. The red-orange colored suspension was filtered to collect the precipitate which was washed with a small amount of water. The resulting yellow solid was suspended in CH2Cl2 (100 mL) and water (50 mL), and triethylamine (5.0 mL) was added while stirring. The layers were separated and the aqueous phase was reextracted with 4:1 CHCl3-isopropanol. The organic layers were combined and concentrated to yield a yellow solid. 1H-NMR (d6-DMSO): δ 8.17 (br s, 2 H), δ 7.97 (d, J=8.5 Hz, 1 H), δ 7.13 (d, J=8.5 Hz, 1 H). MS (M++H) 265.9.
P.27 2-Amino-6-ethoxy-3-nitropyridine
Production Example 27 2-Amino-6-ethoxy-3-nitropyridine 2.4 g of 60% sodium hydride was slowly added to 100 ml of ethanol and stirred as it was at room temperature for 10 minutes. 10 g of 2-amino-6-chloro-3-nitropyridine was added thereto and reacted at room temperature for 30 minutes. After concentration, water was added thereto, and it was extracted with ethyl acetate. It was washed with water and brine sucsessively, and dried over anhydrous sodium sulfate. After concentration, 9.7 g of the title compound was obtained. 1H-NMR(400 MHz, CDCl3) d; 8.28(d,J=9,1H), 6.11(d,J=9,1H), 4.36(q,J=7,2H), 1.38(t,J=7,3H).
2-amino-3-nitro-6-(2-chloro-4-trifluoromethylphenoxy)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; dimethyl sulfoxide;
PREPARATION EXAMPLE 2 Preparation of 2-Amino-3-nitro-6-(2-chloro-4-trifluoromethylphenoxy)pyridine 12.5 g of <strong>[35852-58-5]2-chloro-4-trifluoromethylphenol</strong>, 10.0 g of 2-amino-3-nitro-6-chloropyridine, 10.5 g of potassium carbonate, and 200 ml of dimethyl sulfoxide were charged in a flask, and the mixture was allowed to react at 30° C. for twenty-four hours while stirring. After completion of the reaction, the reaction product was poured into water, followed by extracting with methylene chloride. The extracted phase was washed with water and dried, and the methylene chloride was distilled off under reduced pressure to obtain 14.7 g of a titled compound having a melting point of 80° to 84° C.
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 100℃; for 3h;Schlenk tube;
An oven dried resealable Schlenk tube was charged with 6-chloro-3-nitropyridin-2-amine (5 g, 28.81 mmol), 3-pyridineboronic acid (5.31 g, 43.2 mmol), dioxane (250 ml_) and a 2M aqueous solution of cesium carbonate (43 ml_, 86.4 mmol). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon, and 1 ,1'- bis(diphenylphosphino)ferrocene-palladium(ll) dichloride dichloromethane complex (2.3 g, 2.81 mmol) was added. After three new cycles of evacuation-backfilling with argon, the Schlenk tube was capped and placed in a 1000C oil bath. After 3h, the mixture was cooled, partitioned between water and ethyl acetate, the aqueous phase extracted twice with ethyl acetate, the organic layers washed with brine, dried (MgSO4) and evaporated. The residue was purified by silica gel flash chromatography (95:5 dichloromethane/methanol) to give the title compound (4.8 g, 77%) as a solid. delta 1H-NMR (CDCI3): 1.64 (s, 2H), 7.20-7.25 (d, 1 H), 7.44-7.46 (m, 1 H), 8.32-8.36 (d, 1H), 8.52-8.56 (d, 1 H), 8.70-8.74 (m, 1H), 9.22-9.26 (m, 1H). ESI/MS m/e: 217 ([M+H]+, C10 H8 N4 O2)
43%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 120℃; for 0.333333h;Inert atmosphere; Microwave irradiation;
a) 5-Nitro-[2,3'-bipyridin]-6-amine (A82) A mixture of 2-amino-3-nitro-6-chloropyridine A44 (0.10 g, 0.58 mmol), Na2C03 (0.244 g, 2.31 mmol), pyridin-3-ylboronic acid A81 (0.092 g, 0.75 mmol) and PdCI2(dppf) DCM solvate (0.036 g, 0.043 mmol) in dioxane (4.75 ml_) and H20 (0.25 ml_) was degassed for 10 mins under a stream of nitrogen. The mixture was irradiated in the microwave at 120 C for 20 minutes. The cooled mixture was concentrated under reduced pressure and purified by silica gel chromatography (silica 24 g cartridge, 0-100% EtOAc in petroleum benzine 40-60 C) to give the title compound as a yellow-brown solid (0.053 g, 43%); H NMR (400 MHz, cfe- DMSO) delta 9.29 (dd, J = 2.4, 0.9 Hz, 1 H), 8.70 (dd, J = 4.7, 1.6 Hz, 1 H), 8.49 (d, J = 8.7 Hz, 1 H), 8.45 (ddd, J = 8.0, 2.3, 1.6 Hz, 1 H), 8.03 (brs, 2H), 7.56 (ddd, J = 8.0, 4.8, 0.9 Hz, 1 H), 7.42 (d, J = 8.7 Hz, 1 H). LCMS-A rt 4.69 min, m/z (positive ion) 217.2 [M+H]+.
To a suspension of 6-chloro-3-nitropyridin-2-amine (6.3 g, 36.3 mmol)in ethanol (110 ml_), 9.2 g (36.3 mmol) of iodine and 1 1.32 g (36.3 mmol) of silver sulphate were added. The crude mixture was stirred at room temperature overnight and the precipitate formed was filtered off. The solid isolated was purified by flash chromatography (1 :1 hexane/ethyl acetate) to give the title compound (9.74 g, 88% of yield). delta 1H-NMR (CDCI3): 1.56 (s, 2H), 8.76 (s, 1H).ESI/MS m/e: 300 ([IvH-H]+, C5H3CIIN3O2)
88%
A mixture of 2-amino-6-chloro-3-nitropyridine (1, 5.7 g, 32.8 mmol), water (4.5 mL), c-H2SO4 (1.26 mL) and H5IO6 (1.59 g) was stirred for 15 min at 95 C. Iodine (3.6 g) was added in portions. The reaction mixture was stirred for 1 h at 95 C., cooled to room temperature, poured into sat. aqueous sodium thiosulfate solution and extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (Hex/EtOAc=3/2) to give compound 2 (8.7 g, 29.1 mmol, 88%). 1H NMR (DMSO-d6, 300 MHz) delta8.62 (s, 1H), 8.26 (brs, 2H)
59%
With silver(II) sulfate; iodine; In ethanol; at 20℃;
The compound 268-100 was prepared as follows. To a solution of 6-chloro-3-nitropyridin-2-amine (630 mg, 3.63 mmol) in ethanol (11 mL) was add I2 (920 mg, 3.62 mmol) and Ag2SO4 (1132 mg, 3.63 mmol).). The resulting solution was stirred overnight at room temperature and dissolved in water (100 mL), then extracted with ethyl acetate (3×80 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated under vacuum to produce 6-chloro-5-iodo-3-nitropyridin-2-amine as a yellow solid (640 mg, 59%). Next, to a solution of 6-chloro-5-iodo-3-nitropyridin-2-amine (640 mg, 2.14 mmol) in ethanol (40 ml) and water (10 ml) was added Fe powder (1.93 g, 34.46 mmol) and NH4Cl (887 mg, 16.58 mmol). The resulting solution was heated to reflux for 4 h and then concentrated. The residue was dissolved in water (100 mL) and extracted with ethyl acetate (3×80 ml). The combined organic layers was washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column with 33% ethyl acetate in petroleum ether to produce 6-chloro-5-iodopyridine-2,3-diamine as a brown solid (560 mg, 97%). The mixture of 6-chloro-5-iodopyridine-2,3-diamine (100 mg, 0.37 mmol), (2,3-dichlorophenyl)boronic acid (147.3 mg, 0.77 mmol), Pd(Ph3P)4 (42.9 mg, 0.04 mmol) and sodium carbonate (118.2 mg, 1.12 mmol) in water (5 mL) and dioxane (15 mL) was heated to reflux overnight. Then the resulting solution was quenched with water (100 mL) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column with 50% ethyl acetate in petroleum ether to produce 6-chloro-5-(2,3-dichlorophenyl)pyridine-2,3-diamine as a brown solid (80 mg, 75%). Finally, the solution of 6-chloro-5-(2,3-dichlorophenyl)pyridine-2,3-diamine (80 mg, 0.28 mmol) in trifluoroacetic acid (10 mL) and hydrochloric acid (conc., 2 mL) was heated to reflux overnight. Then the resulting mixture was quenched with water (100 mL), adjusted pH to 8 with sodium carbonate and extracted with ethyl acetate (3×80 mL). The combined organic layers was dried over anhydrous magnesium sulfate and concentrated to give a residue, which was purified by a silica gel column with 50% ethyl acetate in petroleum ether to produce 5-chloro-6-(2,3-dichlorophenyl)-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyridine. Trifluoroacetic acid as a off-white solid (2 mg, 2%).
With potassium carbonate; In N,N-dimethyl-formamide; at 40 - 50℃; for 5 - 8h;
The nucleophilic aromatic substitution reaction of 2- amino-6-chloro-3-nitropyridine with amines. Typically, a mixture of 10 mmol of 2- amino-6-chloro-3-nitropyridine, 30 mmol (3 mol equiv) of anhydrous K2CO3, and 20 mmol (2 mol equiv) of the requisite amine reactant in 50 mL of dimethylformamide (DMF) was stirred at 40-50 C for 5-8 h. The reaction mixture was poured into iced water, and extracted with EtOAc or CHCl3. The organic extracts, after drying (over anhydrous Na2SO4) and evaporation afford the respective 6-substituted-3- nitropyridin-2-amine derivatives which were usually purified by silica gel flash chromatography. MP-Pyr(NO2)NH2: 2-Amino-6-(4-methylpiperazinyl)-3-nitropyridine (5) was prepared in 88% isolated yield according to general procedure B described above. 1H- NMR (DMSO-d6) 68.05 (d, IH, J = 9 Hz, Pri-CH), 7.73 (s, exch, 2H, NH2), 6.32 (d, IH, J = 9 Hz, Pri-CH), 3.35 (m, 4H, CH2), 2.37 (m, 4H, CH2), 2.19 (s, 3H, CH3). 13C- NMR (125 MHz, CDCl3) 6159.9 (+, C), 154.8 (+, C), 136.7 (+, C), 119.6 (-, CH), EPO <DP n="78"/>99.4 (-, CH), 55.08 (+, CH2), 46.3 (+, CH2), 44.9 (-, CH3). EI-HRMS: m/z calcd for Ci0Hi5N5O2 237.1226, found 237.1223 (25%, M+).
With potassium carbonate; In N,N-dimethyl-formamide; at 150℃; for 16.5h;
6-Chloro-3-nitropyridin-2-amine (5 g, 0.029 mol, 1 eq) was dissolved in anhydrous DMF (40 mL).Potassium carbonate (8.8 g, 0.064 mol, 2.2 eq) was added at room temperature.After stirring for 30 minutes,N-methylpiperazine (2.7 mL, 0.032 mol, was added dropwise slowly).1.1eq), heated to 150 deg.] C and then stirred for 16 hours. After the TLC monitoring reaction was completed, water (1 L) was added, and the resulting yellow color was collected.solid. Wash with ether and dry in air to give 6-(4-methylpiperazin-1-yl)-3-nitropyridin-2-amine (6 g, crude).It was directly used in the next step by purification.
With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 65℃; for 0.5h;
EXAMPLE P3 Preparation of 2-bromo-6-chloro-3-nitro-pyridine tert-Butyl nitrite (990 mg, 9.60 mmol) was added portionwise at 65 C. under a nitrogen atmosphere to a stirred suspension of 2-amino-6-chloro-3-nitropyridine (1.00 g, 5.76 mmol) and copper(II) bromide (1.56 g, 6.91 mmol) in acetonitrile (25 mL), and stirring was continued for 30 min. After cooling, the reaction mixture was partitioned between ethyl acetate and 2 M aq. hydrochloric acid solution. The organic layer was dried (MgSO4), and evaporated. Chromatography of the residue (SiO2, heptane-dichloromethane gradient) afforded the title compound (1.11 g, 81%). Yellow solid, MS (EI) 235.9/237.9 (78/100, M+).
75%
With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 65℃; for 0.5h;Inert atmosphere;
t-Butyl nitrite (8.5 g, 82.43 mmol, 1.80 equiv) was added to a mixture of 6-chloro-3-nitropyridin-2-amine (8 g, 46.09 mmol, 1.00 equiv) and copper(II) bromide (12.3 g, 55.07 mmol, 1.20 equiv) in acetonitrile (120 mL, 2.28 mol) under nitrogen. The resulting mixture was stirred for 30 min at 65 C. and partitioned between ethyl acetate and 2 M aqueous hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:5). This resulted in the title compound (8.2 g, 75%) as a yellow solid.
75%
With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 65℃; for 0.5h;Inert atmosphere;
t-Butyl nitrite (8.5 g, 82.43 mmol, 1.80 equiv) was added to a mixture of6-chloro-3-nitropyridin-2-amine (8 g, 46.09 mmol, 1.00 equiv) and copper(II) bromide (12.3 g,55.07 mmol, 1.20 equiv) in acetonitrile (120 mL, 2.28 mol) under nitrogen. The resulting mixture was stilTed for 30 mm at 65 C and partitioned between ethyl acetate and 2 M aqueous hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with ethylacetate/petroleum ether (1:5). This resulted in the title compound (8.2 g, 75%) as a yellow solid.
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 90℃; for 16h;
An oven dried resealable Schlenk tube was charged with 6-chloro-3-niotatropyriotadiotan-2-amiotane (5 00 g, 28 81 mmol), (2-fluorophenyl)boroniotac acid (6 05 g, 43 22 mmol), dioxane (288 ml.) and a 2M aqueous solution of cesium carbonate (43 22 ml_, 86 43 mmol) The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon, and 1 ,1'- biotas(diotaphenylphosphiotano)ferrocene-palladiotaum(ll) dichlo?de dichloromethane complex (1 41 g, 1 73 mmol) was added After three new cycles of evacuation-backfilling with argon, the Schlenk tube was capped and placed in a 9O0C oil bath After 16h, the mixture was cooled and the solvent was evaporated The crude residue was purified by silica gel flash <n="14"/>chromatography (3:1 hexane/ethyl acetate) to give the title compound (5.59 g, 83 %) as a yellow solid. delta 1H-NMR (CDCI3): 8.48 (d, 1 H), 7.99 (dt, 1 H), 7.52-7.49 (m, 1 H), 7.32-7.12 (m,3H), 1.60 (s, 2H), ESI/MS m/e: 234 ([M+H]+, C11H8FN3O2)
45%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃; for 2h;Inert atmosphere;
A mixture of 6-chloro-3-nitropyridin-2-amine (0.5 g, 2.9 mmol), 2-fluorophenylboronic acid (487 mg, 3.48 mmol) and K2CO3 (1.20 g, 8.7 mmol) in dioxane/H20 (10 mL/1 mL) was treated with Pd(PPh3)4 (17 mg, 0.01 mmol) under a N2 atmosphere. The reaction mixture was stirred at 90 C for 2 h and then concentrated in vacuo. The crude residue was taken up in EtOAc (200 rriL), and the resulting solution was washed with brine (100 mL x 3). The organic layer was then dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE : EtOAc = 10 : 1 ~ 3 : 1) to give 130 (301 mg, 45%) as a yellow solid. MS 234.2 [M + H]+.
Stage #1: 4-Methyl-1-pentanol With sodium hydride; 1,1,1,3,3,3-hexamethyl-disilazane In tetrahydrofuran at 20 - 31℃; for 1h;
Stage #2: 2-amino-6-chloro-3-nitropyridine In tetrahydrofuran at 20 - 30℃; for 3.75h;
P17
Example P17: Preparation of 6-(4-Methyl-pentyloxy)-3-nitro-pyridin-2-ylamine:A) In a 100 ml three-necked round-bottomed flask equiped with a condensor and a thermometer, sodium hydride (2.51 g of a 55% suspension in mineral oil) is suspended in dry tetrahydrofuran (15 ml) and hexamethyldisilazane (0.60 ml) is added and the mixture stirred for 20 minutes at room temperature under argon. Under stirring, 4-methyl-1-pentanol (7.23 ml) was added dropwise by syringe over 10 minutes whereupon gas formation and a temperature increase to 31 0C is observed. Stirring is continued for an additional 50 minutes.B) In a 200 ml five-necked reaction flask equiped with a mechnical stirrer, dropping funel, condensor and thermometer, 6-chloro-3-nitro-pyridin-2-ylamine (5.00 g, cf. registry number 27048-04-0) is suspended in dry tetrahydrofuran (15 ml) at room temperature under argon. Under stirring, the suspension obtained as described under A), is added in small portions over 15 minutes. Occasional cooling with an ice/ water bath is used to keep the temperature under 30 0C. To make stirring easier more dry tetrahydrofuran is added (20 ml). Stirring is continued for 3.5 h. Afterwards, quenching is carried out by carefully adding an excess of water (50 ml). Extraction is done then by using ether (60 ml twice). The organic phase is washed with brine, dried over sodium sulfate, filtered. The solvent is then removed in vacuo to give 10.78 g of a yellow-brown oil. Chromatography on silica gel (eluent: hexanes/ ethyl acetate 97:3 (v:v)) gives then 6.89 g of the title compound in the form of a yellow solid (MP: 57-58°C).1H NMR (400MHz, CDCI3): δ 0.91 (d, 6H), 1.28(m, 2 H), 1.60(m, 1 H), 1.75(m, 2H), 4.28(t,2H), 4.90-8.20(broad, 2H), 6.1 1 (d, 1 H), 8.28(d, 1 H).LC: UV Detection: 220 nm; R, = 1.97 min.TLC: Plates: Merck DC-Plates, silica gel F254, saturated atmosphere in developing tank, UV detection, eluent: heptane/ ethyl acetate 9:1 (v:v); Rf of title compound = 0.22.
Stage #1: 2-amino-6-chloro-3-nitropyridine With triethylamine In acetonitrile at 0 - 5℃; for 0.166667h; Inert atmosphere;
Stage #2: 2,4-difluoroethynylbenzene In acetonitrile at 30℃; for 1h;
9
Preparation 96-Chloro-3-nitro-pyridin-2-ylamine (1254 g, 7.23 mol), triethylamine (1510 mL, 10.84 mol) and acetonitrile (10 L) are charged into a 20 L, 4-neck round bottom flask equipped with a mechanical stirrer under nitrogen. To the resulting yellow suspension, copper(I) iodide (13.9 g, 72.3 mmol) andbis(triphenylphosphine)palladium (II) chloride (50.72 g, 72.3 mmol) are added. The resulting pale orange suspension is cooled to 0-5 °C and then degassed during 10 min with nitrogen. A solution of l-ethynyl-2,4-difluoro-benzene (1 100 g, 7.95 mol) dissolved in acetonitrile (2.5 L) is added dropwise during 60 min. The resulting mixture is left stirring at RT (30 °C) overnight. The mixture is cooled to 0-5 °C. Toluene (6 L) is added to the suspension and the mixture is stirred for 45 min and filtered though a frit. The solid is washed with toluene (3 x 3 L), water (2 x 3 L) and is dried overnight in a vacuum oven, to obtain the title compound as a yellow solid(1750 g, 92%). LC-ES/MS m/z 276 (M+l).
3-nitro-6-(2-(pyridin-2-yl)morpholino)pyridin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
Intermediate 38: 3-Nitro-6-(2-(pyridin-2-yl)morpholino)pyridin-2-amine To a solution of <strong>[1018656-53-5]2-(pyridin-2-yl)morpholine</strong> (0.1 g, 0.609 mmol) in dimethylsulfoxide (5 mL) was added triethylamine (0.17 mL, 1.2 mmol). The resulting solution was stirred for 10 min at room temperature, and then 6-chloro-3-nitropyridin-2-amine (105 mg, 0.609 mmol) was added. The reaction mixture was heated at 1 10C for 4 h, and then was cooled to room temperature. Ice water was added and the mixture was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via flash chromatography (80% ethyl acetate in petroleum ether) to afford the title compound (0.1 g, 55%). MS (ES+) (M+H) 302.25.
(R)-1-(6-amino-5-nitropyridin-2-yl)piperidine-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; at 80℃; for 16h;
Step 2: (R)-1 -(6-Amino-5-nitropyridin-2-yl)piperidine-3-carboxylic acid A solution of 6-chloro-3-nitropyridin-2-amine (0.175 M, 35 mL, 6.125 mmol) was added to (R)-piperidine-3-carboxylic acid, prepared during the previous step, followed by diisopropylethyl amine (2.275 mL, 12.25 mmol). The reaction mixture was stirred at 80°C for 16 h. The solvent was removed under reduced pressure to afford (R)-1-(6- amino-5-nitropyridin-2-yl)piperidine-3-carboxylic acid which was used for the next step without further purification.
N-(2-((6-amino-5-nitropyridin-2-yl)amino)ethyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃; for 0.75h;
General procedure: General method A: A solution of 2-amino-6-chloro-3-nitropyridine A44 (1 equiv), amine (1.2 equiv) and diisopropylethylamine (2 equiv) in DMF (10 ml_/g) was heated at 80 C for 45 minutes or until the reaction had gone to completion as judged by TLC or LCMS. The reaction was cooled to room temperature and treated with water (20 mL/g). The product was collected by vacuum filtration and washed with water until the liquors ran clear. The product was dried under vacuum.
6-(1-methyl-1H-pyrazol-3-yl)-3-nitropyridin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 120℃; for 0.833333h;Inert atmosphere; Microwave irradiation;
a) 6-(1 -Methyl- 1H-pyrazol-3-yl)-3-nitropyridin-2-amine (A87) A mixture of 2-amino-3-nitro-6-chloropyridine A44 (0.20 g, 1.1 mmol), Na2C03 (0.489 g, 4.61 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 --pyrazole A86 (0.312 g, 1.50 mmol) and PdCI2(dppf) DCM solvate (0.072 g, 0.086 mmol) in dioxane (9.5 ml_) and H20 (0.5 ml_) was degassed for 10 minutes under a stream of nitrogen. The mixture was irradiated in the microwave at 120 C for 50 minutes. The cooled mixture was evaporated under reduced pressure, then purified by silica gel chromatography (40 g silica cartridge, 0- 100% EtOAc in petroleum benzine 40-60 C) to give the title compound as a yellow solid (0.155 g, 61 %); H NMR (400 MHz, cf DMSO) delta 8.42 (d, J = 8.8 Hz, 1 H), 8.09 (br. s, 2H), 7.52 (d, J = 2.0 Hz, 1 H), 7.16 (d, J = 8.8 z, 1 H), 7.00 (d, J = 2.0 Hz, 1 H), 4.23 (s, 3H). LCMS-A: rt 5.63 min, m/z (positive ion) 220.1 [M+H]+.
1-(6-amino-5-nitropyridin-2-yl)-4-methylpiperidin-4-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 3h;
101.c c) 1-(6-Amino-5-nitropyridin-2-yl)-4-methylpiperidin-4-ol (A 143)
c) 1-(6-Amino-5-nitropyridin-2-yl)-4-methylpiperidin-4-ol (A 143) 6-Chloro-3-nitropyridin-2-amine A44 (174 mg, 1.00 mmol), 4-methylpiperidin-4-ol hydrochloride A142 (167 mg, 1.10 mmol), potassium carbonate (415 mg, 3.00 mmol) and DMF (5 ml_) were heated to 100°C for 3 hours. The mixture was returned to room temperature, diluted with water (30 ml_) and cooled at 4 °C for 3 hours. The precipitate was collected by filtration to give the title compound as a yellow solid (152 mg, 60%). H NMR (400 MHz, CDCIs) δ 8.16 (d, J = 9.5 Hz, 1 H), 6.11 (d, J = 9.5 Hz, 1 H), 4.15 (s, 2H), 3.53-3.35 (m, 2H), 1.70-1.60 (m, 4H), 1.58 (s, 3H), 1.21 (s, 1 H), NH2 protons not observed. LCMS-A: rt 5.29 min, m/z (positive ion) 253.2 [M+H]+.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃; for 2h;Inert atmosphere;
To a mixture of thiophen-2-ylboronic acid (14.1 g, 110 mmol), 6-chloro-3-nitropyridin-2-amine (17.3 g, 100 mmol) and K2C03 (41.4 g, 300 mmol) in dioxane/H20 (500 mL/50 mL) was added Pd(PPh3)4 (5.8 g, 5.0 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at 100 C for 2 h and then concentrated in vacuo. The residue was dissolved with EtOAc (200 mL) and the solution was washed with brine (100 mL x 3). The organic layer was dried over anhydrous Na2S04 and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE : EtOAc = 10: 1 to 5 : 1) to give 2200-A (20.4 g, 84 %) as a yellow solid. MS 222.0 [M + H]+.
84%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃; for 2h;Inert atmosphere;
To a mixture of thiophen-2-ylboronic acid (14.1 g, 110 mmol), 6-chloro-3-nitropyridin-2-amine (17.3 g, 100 mmol) and K2C03 (41.4 g, 300 mmol) in dioxane/H20 (500 mL/50 mL) was added Pd(PPh3)4 (5.8 g, 5.0 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at 100 C for 2 h and then concentrated in vacuo. The residue was dissolved with EtOAc (200 mL) and the solution was washed with brine (100 mL x 3). The organic layer was dried over anhydrous Na2S04 and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE : EtOAc = 10: 1 to 5 : 1) to give 2200-A (20.4 g, 84 %) as a yellow solid. MS 222.0 [M + H]+.
79%
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 95℃; for 2h;Inert atmosphere;
Synthesis of 156-A. A mixture of 6-chloro-3-nitropyridin-2-amine (10.00 g, 57.6 mmol), thiophen-2-ylboronic acid (8.12 g, 63.4 mmol) and Cs2CO3 (37.56 g, 115.2 mmol) in dioxane/H2O (200 mL/20 mL) was added Pd(PPh3)4 (2.44g, 2.88 mmol) under N2 atmosphere. The mixture was stirred at 95 oC for 2 h and then concentrated in vacuo. The residue was dissolved with EtOAc (200 mL) and the solution was washed with brine (100 mL × 3). The organic layer was dried over anhydrous Na2SO4 and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE : EtOAc = 5 : 1 ~ 3 : 1) to give 156-A (10.0 g, 79%) as a yellow solid
79%
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 95℃; for 2h;Inert atmosphere;
(0064) A mixture of 6-chloro-3-nitropyridin-2-amine (10.00 g, 57.6 mmol), thiophen-2-ylboronic acid (8.12 g, 63.4 mmol) and Cs2CO3 (37.56 g, 115.2 mmol) in dioxane/H2O (200 mL/20 mL) was added Pd(PPh3)4 (2.44 g, 2.88 mmol) under an N2 atmosphere. The mixture was stirred at 95 C. for 2 h and then concentrated in vacuo. The residue was dissolved with EtOAc (200 mL) and the solution was washed with brine (100 mL_3). The organic layer was dried over anhydrous Na2SO4 and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE:EtOAc=5:1÷3:1) to give 156-A (10.0 g, 79%) as a yellow solid
78%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,4-dioxane; water; at 110℃; for 3h;Inert atmosphere;
Intermediate 2 (600 mg), Thiophene-2-boronic acid (533 mg), Cs2CO3 (1.8 g), 10 ml 1,4-Dioxane and 2 ml water were added to a 3-neck 100 mL round bottom flask. Nitrogen was bubbled directly into the mixture for 20 minutes. Pd(dppf)Cl2.CH2Cl2 (140 mg) was added and the mixture refluxed at 110 C. for 3 h under nitrogen. The reaction mixture was diluted with ethyl acetate/water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and evaporated to a residue. The residue was purified by column chromatography and isolated intermediate 20 as off white solid (300 mg, 78% yield).
63%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; copper(l) chloride; In N,N-dimethyl-formamide; at 100℃; for 12h;
Thiophene boronic acid (742 mg, 5.8 mmol, 2.0 equiv), 6-chloro-3-nitropyridin-2-amine (500 mg, 2.9 mmol, 1.0 equiv), CesiumCarbonate (5.8 mmol, 2.0 equiv.), PdCl2dppf (10 mol%), Copper Chloride (2.9 mmol, 1.0 equiv.) in DMF were heated at 100C for 12 h. After cooling to r.t. the reaction mixture was diluted with EtOAc and washed with water and next brine. The organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (hexanes/ EtOAc: 8/2) to afford 3-nitro-6-(thiophen- 2-yl)pyridin-2-amine in 63 % yield. ?H NMR (400 MHzCDC13) oe 8.42 (d, J = 8.7 Hz, 1H),7.70 (dd, J= 3.8, 1.1 Hz, 111), 7.54 (dd, J= 5.0, 1.1 Hz, 111), 7.15 (dd. J= 5.0, 3.8 Hz, 111),7.09 (d, J = 8.7 Hz, 111). ESI-MS (mlz): 222 [M+Hj.
63%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; copper(l) chloride; In N,N-dimethyl-formamide; at 100℃; for 12h;
Thiophene boronic acid (742 mg, 5.8 mmol, 2.0 equiv), 6-chloro-3-nitropyridin-2-amine (500 mg, 2.9 mmol, 1.0 equiv), Cesium Carbonate (5.8 mmol, 2.0 equiv.), PdCLdppf (10 mol%), Copper Chloride (2.9 mmol, 1.0 equiv.) in DMF were heated at 100C for 12 h. After cooling to r.t. the reaction mixture was diluted with EtOAc and washed with water and next brine. The organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (hexanes/ EtOAc: 8/2) to afford 3-nitro-6-(thiophen-2-yl)pyridin-2-amine in 63 % yield. H NMR (400 MHzCDCl3) delta 8.42 (d, / = 8.7 Hz, 1H), 7.70 (dd, / = 3.8, 1.1 Hz, 1H), 7.54 (dd, / = 5.0, 1.1 Hz, 1H), 7.15 (dd, / = 5.0, 3.8 Hz, 1H), 7.09 (d, / = 8.7 Hz, 1H). ESI-MS (m z): 222 [M+H]+.
63%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; copper(l) chloride; In N,N-dimethyl-formamide; at 100℃; for 12h;
Thiophene boronic acid (742 mg, 5.8 mmol, 2.0 equiv), 6-chloro-3-nitropyridin-2-amine (500 mg, 2.9 mmol, 1.0 equiv), Cesium Carbonate (5.8 mmol, 2.0 equiv.), PdCl2dppf (10 mol%), Copper Chloride (0348) (2.9 mmol, 1.0 equiv.) in DMF were heated at 100C for 12 h. After cooling to r.t. the reaction mixture was diluted with EtOAc and washed with water and next brine. The organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (hexanes/ EtOAc: 8/2) to afford 3-nitro-6-(thiophen-2-yl)pyridin-2-amine in 63 % yield. 1H NMR (400 MHzCDCl3) delta 8.42 (d, J = 8.7 Hz, 1H), 7.70 (dd, J = 3.8, 1.1 Hz, 1H), 7.54 (dd, J = 5.0, 1.1 Hz, 1H), 7.15 (dd, J = 5.0, 3.8 Hz, 1H), 7.09 (d, J = 8.7 Hz, 1H). ESI-MS (m/z): 222 [M+H]+.
10
General procedure: To a solution of 2-amino-3-nitro-6-chloropyridine (300 mg, 1.73 mmol, an intermediate in preparation of 8) in 5 mL anhydrous DMF was added sodium methoxide (187mg, 3.46 mmol). This mixture was stirred at room temperature for 3 h then poured onto 20 g crushed ice and extracted with ethyl acetate. The extracts were dried, evaporated and purified by column chromatography on silica gel (PE/AcOEt=5:1) to give 2-amino-3-nitro-6-methoxylpyridine (246 mg, 84.1%) as yellow solid. Next steps followed the general procedure, and the title compound was obtained as white solid (188 mg, 67.0% over 2 steps). 5.2.2.10 6-Ethoxy-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (10) The title compound was prepared from 2-amino-3-nitro-6-chloropyridine and sodium ethoxide in a manner similar to 9 as white solid (160 mg, 44.9%). IR (KBr) ν 3174, 1712, 1688, 1594, 1467, 1261 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 1.29 (3H, t, J = 7.2 Hz, CH3), 4.23 (2H, q, J = 7.2 Hz, CH2), 6.53 (1H, d, J = 8.4 Hz, H-7), 7.41 (1H, d, J = 8.4 Hz, H-8), 11.81 (1H, s, NH-1), 12.21 (1H, s, NH-4); 13C NMR (100 MHz, DMSO-d6) δ 14.47, 61.58, 104.75, 115.05, 126.56, 136.16, 154.34, 156.11, 158.17; HRMS-EI C9H9N3O3 calcd [M+Na]+ 230.0542, found 230.0540.
tert‐butyl 3‐(6‐amino‐5‐nitropyridin‐2‐yl)‐8‐azabicyclo[3.2.1]oct‐2‐ene‐8‐carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
3.5 g
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; at 100℃; for 12h;Inert atmosphere;
The product obtained in the above step was dissolved in 1,4-dioxane (200 mL).Add 6-chloro-3-nitropyridin-2-amine (4.6 g, 26.63 mmol, 1.0 eq),Potassium carbonate (14.7 g, 106.53 mmol, 4.0 eq) and water (60 mL),[1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (974.3 mg, 1.33 mmol, 0.05 eq) was added under nitrogen.The temperature was raised to 100 C for 12 h.Cool down to 50 C, add saturated brine (100 mL),Ethyl acetate (100 mL) and activated carbon (2 g) were stirred at 50 C for 0.5 h.The mixture was filtered with EtOAc. EtOAc (EtOAc)EtOAc.The crude product was purified by silica gel column chromatography (EA:PE = 1:30), then washed with methyl t-butyl ether and filtered.The filter cake was dried to obtain a product (3.5 g, 3-step yield: 38%).
5-(6-amino-5-nitropyridin-2-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96.17%
With potassium carbonate; In N,N-dimethyl acetamide; at 80℃; for 3h;
Starting material 6-chloro-3-nitropyridin-2-amine (1.5 g, 8.64 mmol, 1.0 eq)Dissolved in N,N-dimethylacetamide (5 mL),Add 2,5-diazabicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester (1.8 g, 8.64 mmol, 1.0 eq)And anhydrous potassium carbonate (4.7 g, 34.56 mmol, 4.0 eq),The temperature was raised to 80 C for 3 h, and the reaction was completely monitored by TLC.After being cooled to room temperature, water (50 mL) was added, and ethyl acetate (100 mL×3) was taken, and the organic layer was combined, washed with saturated brine (100 mL×3), dried and filtered.The filtrate was concentrated under reduced pressure to give a product (2.9 g, yield: 96.17).
With potassium carbonate In N,N-dimethyl acetamide at 80℃; for 12h;
16.1 Step 1: Synthesis of 3-nitro-6-(7-azaspiro[3.5]decane-7-yl)pyridin-2-amine
Starting material 6-chloro-3-nitropyridin-2-amine (3 g, 17.28 mmol, 1.0 eq) and 7-azaspiro[3.5]decane hydrochloride (3.35 g, 20.74 mmol, 1.4 eq)Potassium carbonate (9.54 g, 69.12 mmol, 4.0 eq) was dissolved in DMAC (20 mL).The reaction was carried out at 80 ° C for 12 hours, and the reaction was confirmed by TLC.The reaction solution was poured into water (100 mL), stirred for 30 min, and filtered to give product (4.2 g, yield: 93%).
6-chloro-N-(4-fluoro-3-methylbenzyl)-3-nitropyridin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃;
258.A Example 258
Step A: To a stirred solution of 2-amino-6-chloro-3-nitropyridine (535 mg, 3.1 mmol) in DMF (5 mL) was added 4-fluoro-3-methylbenzyl bromide (657 mg, 3.2 mmol). The mixture was cooled to 0° C. and NaH 78 mg, 3.2 mmol) was added in 3 portions 5 min apart. The reaction was allowed to warm slowly to RT and stirred overnight. The reaction was diluted with EtOAc and water. The aqueous layer was separated and extracted with EtOAc (3*). The combined organics were washed with water (2*), brine (2*), dried over Na2SO4 and concentrated under vacuum. The residue was chromatographed on silica gel (80 g), eluting with a 1-to-5% EtOAc/hexane gradient to give 6-chloro-N-(4-fluoro-3-methylbenzyl)-3-nitropyridin-2-amine, 808 mg (89%) as a yellow solid. MS (ESI) (M+H+) m/z=296. LCMS Ret time (UV 215/254): 1.24 min.
With NBS; glacial acetic acid at 60℃; for 16h; Inert atmosphere;
45.1 Step 1: 5-Bromo-6-chloro-3-nitropyridin-2-amine (45a)
A suspension of 6-chloro-3-nitropyridin-2-amine (10.0 g, 57.6 mmol) in AcOH (200 mL) was treated with N-bromo succinimide (11.3 g, 63.4 mmol) at RT. The reaction mixture was stirred at about 60 C for about 16 h. The precipitate was collected by filtration and washed with water (2 x 100 mL) and then dried under vacuum to provide the title compound (13.4 g, 92%).1H NMR (400 MHz, DMSO-d6) δ = 8.63 (s, 1H), 8.31 (br s, 2H).
92%
With NBS; glacial acetic acid at 60℃; for 16h; Inert atmosphere;
45.1 Step 1: 5-Bromo-6-chloro-3-nitropyridin-2-amine (45a)
A suspension of 6-chloro-3-nitropyridin-2-amine (10.0 g, 57.6 mmol) in AcOH (200 mL) was treated with N-bromo succinimide (11.3 g, 63.4 mmol) at RT. The reaction mixture was stirred at about 60 C for about 16 h. The precipitate was collected by filtration and washed with water (2 x 100 mL) and then dried under vacuum to provide the title compound (13.4 g, 92%).1H NMR (400 MHz, DMSO-d6) δ = 8.63 (s, 1H), 8.31 (br s, 2H).
87%
With NBS In N,N-dimethyl-formamide at 20℃; for 3h;
With N-ethyl-N,N-diisopropylamine In ethanol at 80℃; for 12h;
The compound 2-amino-3-nitro-6-chloropyridine (2g, 11.5mmol), compound (R)-5-fluoro-2-methoxy-3-(pyrrolidin-3-yl)pyridine hydrochloride Salt (2.66g, 11.5mmol) and DIEA (4.4g, 34.5mmol) were dissolved in 50mL of ethanol and reacted at 80°C for 12 hours with stirring.After the reaction was confirmed by TLC detection, it was cooled to 0°C, filtered, washed with ethanol, and drained to obtain 4 g of a yellow solid product with a yield of 100%.
With N-ethyl-N,N-diisopropylamine In ethanol at 80℃; for 12h;
The compound 2-amino-3-nitro-6-chloropyridine (1.24g, 7.1mmol), compound (R)-2-(1-aminoethyl)-4-fluorophenol hydrochloride (1.37g, 7.1mmol) mmol) and DIEA (2.68 g, 21.3 mmol) were dissolved in 20 mL of ethanol, and the reaction was stirred at 80° C. for 24 hours.After the reaction was confirmed by TLC detection, it was spin-dried and separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether=1/3, V/V) to obtain 1.7 g of yellow solid product with a yield of 81.7%.
Stage #1: ethanol With sodium hydride In mineral oil at 20℃; for 0.166667h;
Stage #2: 2-amino-6-chloro-3-nitropyridine In mineral oil at 20℃; for 0.5h;
17.1 Step 1: 6-ethoxy-3-nitropyridin-2-amine
NaH (1.2 g, 60%dispersion in mineral oil, 30 mmol) was slowly added to 100 mL of ethanol and stirred for 10 min at room temperature. 2-amino-6-chloro-3-nitropyridine (5 g, 28.9 mmol) was added portionwise and the mixture was stirred for 30 min at ambient temperature. After concentration, water was added and the mixture was extracted with ethyl acetate. The combined organic layers were dried, filtered and concentrated. The residue was purified by silica gel column chromatography (PE : EtOAc = 3 : 1) to afford the title product (3.0 g, 56% yield). LC-MS (M+H) + = 184.1.
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