* 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.
Compound 2 (350 g, 2.44 mol) and p-toluenesulfonic acid monohydrate (46.5 g, 0.244 mol) were added to triethyl orthoformate (2100 g, 14.2 mol) and refluxed for 5 hours.After completion of the reaction by TLC, the reaction solution was concentrated and the crude product was quickly purified by column to give Compound 3 (222 g, 1.45 mol). (Yield 59percent) NMR spectrum is shown in FIG. 2.
Reference：
[1] Chemische Berichte, 1927, vol. 60, p. 775[2] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1927, vol. 59, p. 417
5
[ 146015-42-1 ]
[ 40851-95-4 ]
Yield
Reaction Conditions
Operation in experiment
95.6%
With hydrogen In methanol at 20℃; for 24 h;
A mixture of 6-chloro-2-nitropyridin-3-amine (E-23) (8.8 g, 51 mmol, 1.0 eq) and Raney nickel (0.88 g) in Methanol (100 mL) was stirred under hydrogen at RT for 24h, then filtered and the filtrate was concentrated in vacuo to afford the desired product 6-chloropyridine-2,3 -diamine (E-24) (7g, 95.6percento yield ) as a pale solid. ESI-MS m/z : 144.05[M+H]+.
95.6%
With hydrogen In methanol at 20℃; for 24 h;
[00326] A mixture of 6-chloro-2-nitropyridin-3-amine (E-23) (8.8 g, 51 mmol, 1.0 eq) and Raney nickel (0.88 g) in Methanol (100 mL) was stirred under hydrogen at RT for 24h, then filtered and the filtrate was concentrated in vacuo to afford the desired product 6-chloropyridine-2,3-diamine (E-24) (7g, 95.6percent yield ) as a pale solid. ESI-MS m/z : 144.05[M+H]+.
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
7
[ 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.
Step l 5-Chloro-lH-fL231triazolor4.5-Mrhovridine6-Chloropyridine-2 ,3 -diamine (Example 23, Step 1) (226 mg, 1.57 mmol) was taken up in warm water (6.3 ml). Sulfuric acid (0.26 ml, 4.72 mmol) was added, and the solution was cooled to -15C. In a separate flask, sodium nitrite (119 mg? 1.73 mmol) was dissolved in 2 mL cold water. The sodium nitrite solution was added dropwise to the reaction mixture over 15 minutes. The mixture was allowed to stir at -15C for 1 hour, then filtered, and the yellow- brown precipitate was collected. The solid was recrystallized from water to yield the title compound as a yellow-brown solid. The filtrate from the separation was neutralized with aqueous sodium bicarbonate and extracted 3x with ethyl acetate. All organic fractions were combined, washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give an additional portion of the title compound as a yellow-brown solid.LRMS (APCI) calc'd for (CsH4ClN4) [M+H]+, 156; found 155.
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)
3 Example 3 Synthesis method of 6-chloro-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (D)
Weigh intermediate C (776.4 mg, 1.0 equiv.) and oxalic acid dihydrate (1.0 g, 1.5 equiv.) into a bottle, add 8 mL water and 0.8 mL concentrated hydrochloric acid, raise the temperature to 100° C., and stop the reaction after 6 hours. After the temperature was lowered, 968.0 mg of intermediate D was obtained by suction filtration with a yield of 90.6%.
43 5-Chloro-2-hydroxymethyl-3H-imidazo[4,5-b]pyridine
PREPARATION 43 5-Chloro-2-hydroxymethyl-3H-imidazo[4,5-b]pyridine 6.60 g of glycolic acid were added to 5.00 g of 6-chloro-2,3-diaminopyridine (prepared as described in Preparation 42), and the resulting mixture was stirred at 150° C. for 4 hours. At the end of this time, the reaction mixture was treated with 3N aqueous hydrochloric acid and subsequently made alkaline by the addition of aqueous ammonia. The aqueous mixture was evaporated to dryness, and the resulting residue was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol in ratios ranging from 1:0 to 10:1 by volume as the eluent. The product was then crystallized by trituration with ethyl acetate, to give 5.33 g of the title compound, melting at 224°-226° C.
Compound 2 (350 g, 2.44 mol) and p-toluenesulfonic acid monohydrate (46.5 g, 0.244 mol) were added to triethyl orthoformate (2100 g, 14.2 mol) and refluxed for 5 hours.After completion of the reaction by TLC, the reaction solution was concentrated and the crude product was quickly purified by column to give Compound 3 (222 g, 1.45 mol). (Yield 59%) NMR spectrum is shown in FIG. 2.
58%
In methanol; for 3.0h;Reflux;
A solution of 6-Chloropyridine-2, 3-diamine (718 mg, 5 mmol) in Methanol (10 ml) and Trietyhl orthoformate (10 ml) was heated to reflux for 3 hours. The volatiles were evaporated and the residue was purified by flash chromatography on silica using a CHCl3-MeOH gradient. Yield: 540 mg (58%); ESI-MS m/z 151.1 [M+H]+
Preparation Example 8-2 5-Chloro-2-methyl-1H-imidazo[4,5-b]pyridine In the same manner as in the following Preparation Example 9-3, the objective compound (6.64 g) was obtained from 2,3-diamino-6-chloropyridine (8.1 g) as light brown crystals. 1H-NMR(DMSO-d6): 2.52(3H, s), 7.22(1H, d, J=8 Hz), 7.91(1H, d, J=8 Hz) MASS(ESI): m/z 166(M-1) mp 254-255 C.
PREPARATION 57 5-Bromo-2,3-diaminopyridine A procedure similar to that described in Preparation 42 was repeated, except that 12.0 g of <strong>[6945-68-2]2-amino-5-bromo-3-nitropyridine</strong> (prepared as described in Preparation 56), 62.1 g of tin(II) chloride dihydrate, 1.04 g of sodium borohydride and 300 ml of a 9:1 by volume mixture of ethyl acetate and 2-methyl-2-propanol were used, to give the title compound as a crude product.
PREPARATION 62 5-Chloro-2,3-diaminopyridine A procedure similar to that described in Preparation 42 was repeated, except that 12.5 g of <strong>[5409-39-2]2-amino-5-chloro-3-nitropyridine</strong> (prepared as described in Preparation 61) 82.0 g of tin(II) chloride dihydrate, 1.35 g of sodium borohydride and 300 ml of a 9:1 by volume mixture of ethyl acetate and 2-methyl-2-propanol were used, to give the title compound as a crude product.
Stage #1: carbon disulfide; 6-chloropyridine-2,3-diamine With sodium hydroxide In ethanol Reflux;
Stage #2: With hydrogenchloride In ethanol
6.2.14. 5-Chloro-1,3-dihydro-2H-imidazo[4,5-b]pyridine-2-thione (9b)
A mixture of 0.144 g (1 mmol) 6-chlorpyridine-2,3-diamine, 20 ml ethanol, one pellet of NaOH and 0.5 ml CS2 is heated to reflux7 as described. When the reaction is completed (TLC control) the mixture is acidified with HCl (2 mol/l), the solvent is evaporated under reduced pressure. The resulting solid is washed several times with H2O. Beige solid, yield: 0.125 g (0.67 mmol), 67%, mp: 290-295 °C. IR: inlMMLBox (cm-1) = 3130; 3063; 2945; 1604. 1H NMR: (200 MHz, DMSO-d6) δ (ppm) = 13.31 (s, 1H, NH); 12.86 (s, 1H, NH); 7.50 (d, 1H, J = 8.2 Hz, H arom.); 7.19 (d, 1H, J = 8.2 Hz, H arom.). 13C NMR: (50 MHz, DMSO-d6) δ (ppm) = 170.36; 145.80; 142.48; 124.73; 118.75; 117.43.
With pyridine In ethanol at 40℃;
a
To a solution of 6-chioropyridine-2,3 -diamine (144 mg, 1 mM) in a mixture of EtOH (5 mL) and pyridine (2 mL) was added carbon disulfide (0.5 mL) at r.t.. The mixture was stirred at 40 °C overnight The mixture was cooled to r.t, the resulting solid was filtered and washed with ether to give light yellow solid 5-chforo-l H-imidazo[4,5-b]pyTidme-2(3H)- thione.
With pyridine In ethanol at 40℃;
(a) To a solution of 6-chloropyridine-2,3-diamine (144 mg, 1 mM) in a mixture of EtOH (5 mL) and pyridine (2 mL) was added carbon disulfide (0.5 mL) at r.t.. The mixture was stirred at 40 °C overnight. The mixture was cooled to r.t., the resulting solid was filtered and washed with ether to give light yellow solid 5-chloro-1H-imidazo[4,5-b]pyridine-2(3H)-thione.LC/MS: (ESI) (M +H)+= 187.1
Stage #1: 6-chloropyridine-2,3-diamine; glycolic Acid at 150℃; for 4h;
Stage #2: With hydrogenchloride In water at 60℃;
6.1
A mixture of intermediate 1-1 (14.5 g, 101 mmol) and 2-hydroxyacetic acid (16 g, 210 mmol) was stirred at 150°C for 4 hours. The resulting mixture was cooled to 60°C and treated with an aqueous solution of 3N HC1 (70 mL), then basified to pH=7-8 by the addition of aqueous ammonia. The mixture was filtered and the solid was collected, washed with water and methyl ter-butyl ether. The product 3-1 was collected as yellow powder (17.5 g, 94%). m/z = 184 (M+H)+.
86%
In 5,5-dimethyl-1,3-cyclohexadiene at 150℃; for 4h;
1 Step 1: synthesis of (5-chloro- 1H-imidazo [4,5-bj pyridin-2-yl)methanol(intermediate 9a)
A mixture of 2-hydroxyacetic acid (69.22 1 g, 910 mmoles) and 6-chloropyridine-2,3-diamine (65.34 g, 455 mmoles) in xylene (950 mL) was stirred at 150°C for 4 hours.The mixture was then cooled to about 60°C and treated with 3N HC1 (290 ml), thenbasified to pH = 7-8 by the addition of aqueous ammonia. The resulting solid was filtered off and washed with H20 and methyl t-butyl-methyl ether to give 80.88 g (86% yield) of the desired intermediate( 9a).
A mixture of 6-chloropyridine-2,3-diamine (CAS 40851-95-4) (10 g; 69.65 mmol), 2- bromo-1-(1 -methyl-1 H-pyrazol-4-yl)ethan-1 -one (CAS 706819-66-1 ) (14.1 g; 69.65 mmol) and DIPEA (24 mL; 139.3 mmol) in ACN (280 mL) was heated at 90C for 18 hours. The heating was stopped and Mn02 (18.2 g; 208.95 mmoi) was added portion wise (carefully) and the reaction mixture was stirred at room temperature for 15 minutes. Mn02 was removed by filtration through a pad of celite and the filtrate wasconcentrated. The precipitate was filtered, washed with Et20 and dried to give 10.4 g (61 %) of intermediate 5.
61%
This intermediate 4 was alternatively also prepared using the following procedure: A mixture of 6-chloropyridine-2,3-diamine (CAS 40851-95-4) (10 g; 69.65 mmol), 2- bromo-1-(1 -methyl-1 H-pyrazol-4-yl)ethan-1 -one (CAS 706819-66-1 ) (14.1 g; 69.65 mmol) and DiPEA (24 mL; 139.3 mmol) in CH3CN (280 mL) was heated at 90C for 18 hours. The heating was stopped and Mn02 (18.2 g; 208.95 mmol) was added portion wise (carefully) and the reaction mixture was stirred at room temperature for 15 minutes. Mn02 was removed by filtration over a pad of celite and the filtrate was concentrated. The precipitate was filtered, washed with Et20 and dried to give 10.4 g (61 %) of intermediate 4.
Stage #1: 6-chloropyridine-2,3-diamine; isocaproic aldehyde With acetic acid In dichloromethane for 0.5h;
Stage #2: With sodium tris(acetoxy)borohydride In dichloromethane at 20℃;
9.2 synthesis of 6-chloro-N3-isopentylpyridine-2,3-diamine 27-c
The intermediate 27-b (5 g, 34.82 mmol) was dissolved in dichloromethane (200 mL), acetic acid (20 drops) and 4-methylpentanal (3 g, 34.8 mmol, were added. The resulting mixture was stirred for 30 minutes and then sodium triacetoxyhydroborate (22.14 g, 104.5 mmol) was added. The reaction mixture was stirred at room temperature overnight and a solution of 50% Na2C03 was added dropwise until gas evolution stopped. The organic layer was separated, dried on MgSC^, filtrated and evaporated to dryness. The residu was purified by column chromatography using heptane/EtOAc 7/3 to pure EtOAc. Intermediate 27-c was recovered as a white solid and dried in vacuo overnight (4.8 g, 65%).
(4-(5-chloro-3H-imidazo[4,5-b]pyridin-2-yl)phenyl)(phenyl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
12%
Stage #1: 6-chloropyridine-2,3-diamine; 4-carboxybenzophenone With N-ethyl-N,N-diisopropylamine; HATU In acetonitrile at 40℃; for 18h;
Stage #2: With acetic acid at 140℃; for 1h; Microwave irradiation;
44.a a) (4-(5-Chloro-3H-imidazo[4,5-b]pyridin-2-yl)phenyl)(phenyl)methan (A 101)
a) (4-(5-Chloro-3H-imidazo[4,5-b]pyridin-2-yl)phenyl)(phenyl)methan (A 101) HATU (0.924 g, 2.43 mmol) was added to a solution of the 6-chloropyridine-2,3-diamine A45 (0.317 g, 2.21 mmol), 4-benzoylbenzoic acid (0.500 g, 2.21 mmol) and DIPEA (1.16 mL, 6.63 mmol) in MeCN (40 mL) and the resulting solution stirred at 40 °C for 18 hours. The mixture was diluted with saturated aqueous NaHC03 (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with saturated brine (150 mL), dried (Na2S04), filtered and the volatiles removed in vacuo to give a brown solid. The solid was dissolved in acetic acid (6 mL) and heated under microwave irradiation at 140 °C for 1 hour. The volatiles were removed in vacuo and the residue treated with saturated aqueous NaHC03 (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with brine (150 mL), dried (Na2S04), filtered and the volatiles removed in vacuo to give a brown semi-solid which was purified by silica gel chromatography (40 g silica cartridge eluting with 0-70% EtOAc in petroleum benzine 40-60 °C) to give a pale yellow solid which was sonicated in diethyl ether (15 mL) and the supernatant carefully removed and discarded. The resulting solid was dried in vacuo to give the title compound as a white solid (0.086 g, 12%). H NMR (400 MHz, cfe-DMSO) δ 13.84 (s, 1 H), 8.38 (d, J = 8.5 Hz, 2H), 8.1 1 (d, J = 8.3 Hz, 1 H), 7.93 (d, J = 8.4 Hz, 2H), 7.81 - 7.77 (m, 2H), 7.74 - 7.69 (m, 1 H), 7.60 (t, J = 7.6 Hz, 2H), 7.35 (d, J = 8.3 Hz, 1 H). LCMS-A rt 6.15 min, m/z (positive ion) 334, 336 [M+H]+.
2-amino-3-benzyloxycarbonylamino-6-chloro-pyridine[ No CAS ]
[ 452-58-4 ]
[ 40851-95-4 ]
Yield
Reaction Conditions
Operation in experiment
1: 45%
2: 42%
With palladium 10% on activated carbon; hydrogen; sodium hydrogencarbonate In methanol at 20℃; for 2h; Sealed tube; Overall yield = 87 %Spectr.; chemoselective reaction;
General procedure forhydrodechlorination of 2-chloropyridine derivatives
General procedure: To a solution of the 2-chloropyridine derivative (1 equiv.) in MeOH (10 mL) was added 10% Pd/C (1 mol%) and NaHCO3 (1 equiv. per pyridine chlorine).The reaction vessel was sealed and flushed with hydrogen gas three times. The black suspension was stirred at room temperature under an atmosphere of hydrogen (1 atm.) for two hours. The mixture was filtered through celite washing with methanol and concentrated in vacuo. Purification by column chromatography was performed as required to yield the hydrodechlorinated pyridine product.
5-chloro-2-isopropyl-1H-imidazo[4,5-b]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With acetic acid at 135℃; for 12h;
96.1 Step 1: 5-chloro-2-isopropyl-lH-imidazo[4,5-b]pyridine
A solution of 6-chloropyridine-2, 3-diamine (1.0 g, 6.96 mmol) in acetic acid (20 mL) was stirried for 12 hours at 135 °C in an oil-bath. After cooling to room temperature, the precipitate was collected by filtration, washed with MeOH and dried in vacuo to give 5-chloro-2- isopropyl-lH-imidazo[4,5-b]pyridine (1.1 g, 77%) as a brown solid.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
