* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: With hydrogenchloride; 1,1,1,3',3',3'-hexafluoro-propanol; iron In water at 20℃; for 0.5 h; Stage #2: With sodium hydrogencarbonate In water
General procedure: The nitro compound (1 equiv), HFIP (10 equiv), Fe powder (5 equiv) were mixed in a tube. Then 2 N HCl aqueous solutions was added to the reaction mixture. After stirring at room temperature for 30 min, the reaction mixture was neutralized with sat. NaHCO3 (aq.) and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was then purified by column chromatography on silica gel to furnish the desired amine product.
Reference：
[1] Tetrahedron Letters, 2017, vol. 58, # 37, p. 3646 - 3649
[2] Journal of the Chemical Society, <1957> 4625,
[3] Pharmaceutical Bulletin, 1957, vol. 5, p. 350,352
[4] Biochemical Journal, 1950, vol. 46, p. 506
[5] Patent: US1889303, 1930, ,
[6] Green Chemistry, 2016, vol. 18, # 8, p. 2435 - 2442
[7] Applied Catalysis A: General, 2016, vol. 525, p. 85 - 93
[8] Patent: US1889303, 1930, ,
3
[ 6332-56-5 ]
[ 16867-03-1 ]
Reference：
[1] Patent: US6218539, 2001, B1,
4
[ 614-99-3 ]
[ 16867-03-1 ]
Reference：
[1] Patent: US4061644, 1977, A,
5
[ 680-31-9 ]
[ 611-13-2 ]
[ 16867-03-1 ]
Reference：
[1] Patent: US4061644, 1977, A,
6
[ 680-31-9 ]
[ 609-38-1 ]
[ 16867-03-1 ]
Reference：
[1] Patent: US4061644, 1977, A,
7
[ 874-24-8 ]
[ 16867-03-1 ]
Reference：
[1] Patent: US4022897, 1977, A,
8
[ 24016-03-3 ]
[ 16867-03-1 ]
Reference：
[1] European Journal of Organic Chemistry, 2003, # 9, p. 1681 - 1686
9
[ 10006-74-3 ]
[ 16867-03-1 ]
Reference：
[1] Chemische Berichte, 1928, vol. 61, p. 1028
10
[ 933-90-4 ]
[ 16867-03-1 ]
Reference：
[1] Biochemical Journal, 1950, vol. 46, p. 506
11
[ 40263-57-8 ]
[ 16867-03-1 ]
Reference：
[1] Roczniki Chemii, 1936, vol. 16, p. 502,507[2] Chem. Zentralbl., 1937, vol. 108, # I, p. 3634
12
[ 93596-90-8 ]
[ 16867-03-1 ]
Reference：
[1] Prace Minist. Przem. chem., <1952> Nr. 1, S. 1, 14, [2] Chem.Abstr., <1954> 1337,
13
[ 109-00-2 ]
[ 16867-03-1 ]
Reference：
[1] Pharmaceutical Bulletin, 1957, vol. 5, p. 350,352
14
[ 14773-50-3 ]
[ 16867-03-1 ]
Reference：
[1] Chemische Berichte, 1928, vol. 61, p. 1028
15
[ 74037-50-6 ]
[ 16867-03-1 ]
Reference：
[1] Chemische Berichte, 1928, vol. 61, p. 1028
16
[ 186581-53-3 ]
[ 16867-03-1 ]
[ 10201-71-5 ]
Reference：
[1] Journal of Medicinal Chemistry, 1999, vol. 42, # 19, p. 3934 - 3941
80 mL of ethyl orthoacetate was added to 15 g (136 mmol) of 2-amino-3-hydroxypyridine, followed by addition of p-toluenesulfonic acid in a catalytic amount, and the mixture was reacted at 120° C. for 4 hours. After the reaction solution was cooled, triethylamine was added to the solution, to neutralize p-toluenesulfonic acid. Then, the solution was subjected to distillation under reduced pressure by using an evaporator, and then purified by silica gel column chromatography.Amount of the product: 12.0 g, Yield: 65.8percent.
[00102] As shown in step 4-i of Scheme 4, l,l '-carbonyldiimidazole (57.4 g, 354.2 mmol) was added to a solution of 2-amino-3-hydroxypyridine (26.0 g, 236.1 mmol, obtained from Aldrich Chemical Co.) in THF (400 mL). The resulting reaction mixture was stirred at 70 0C for 14 h. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was dissolved in DCM (500 mL) and washed with 2 N NaOH (3 x 100 mL). The combined aqueous layers were cooled to 0 0C and acidified to a pH of 6 with 6 N HCl. The precipitate that was formed was collected in a fritted funnel, washed with cold water (100 mL), and dried under vacuum to afford oxazolo[4,5-δ]pyridin-2(JH)-one (Compound 1011, 26.0 g, 81percent yield): ESMS (M+Η) 137; 1H NMR (DMSO-d6) δ 12.4 (br, 1Η), 8.0 (d, 1Η), 7.6 (d, 1Η), 7.1 (dd, 1Η).
81%
at 70℃; for 14 h;
As shown in step 4-i of Scheme 4, 1,1'-carbonyldiimidazole (57.4 g, 354.2 mmol) was added to a solution of 2-amino-3-hydroxypyridine (26.0 g, 236.1 mmol, obtained from Aldrich Chemical Co.) in THF (400 mL). The resulting reaction mixture was stirred at 70 0C for 14 h. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was dissolved in DCM (500 mL) and washed with 2 N NaOH (3 x 100 mL). The combined aqueous layers were cooled to 0 0C and acidified to a pH of 6 with 6 N HCl. The precipitate that was formed was collected in a fritted funnel, washed with cold water (100 mL), and dried under vacuum to afford oxazolo[4,5-δ]pyridin-2(JH)-one (Compound 1011, 26.0 g, 81percent yield): ESMS (M+Η) 137; 1H NMR (DMSO-d6) δ 12.4 (br, 1Η), 8.0 (d, 1Η), 7.6 (d, 1Η), 7.1 (dd, 1Η).
79%
for 1 h; Heating / reflux
Carbonyldiimidazole (600 mmol) was added in several batches to a solution of 2-aminopyridin-3- ol (400 mmol) in tetrahydrofuran (600 ml) and the reaction was heated at reflux for 1 h. The mixture was concentrated and the residue was diluted with dichloromethane (500 ml). The solution was extracted with 1.5 N sodium hydroxide (3 x 200 ml). The pH of the aqueous layer was adjusted to 5 with 2 N hydrochloric acid and the precipitaed solids were collected by filtration to provide oxazolo[4,5-b]pyridin- 2(3H)-one in 79percent yield as a grey solid.
79%
Reflux
Intermediate 30: Synthesis of 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazine-7-sulfonyl chloride.CCIICCHH2XCOOCCIINaHCO3 N' " 1. Synthesis of oxazolo[4,5-blpyridm-2(3H)-one.Carbonyldiimidazole (600 mmol) was added in several batches to a solution of 2- aminopyridin-3-ol (400 mmol) in tetrahydrofuran (600 ml) and the reaction was heated at reflux for 1 h. The mixture was concentrated and the residue was diluted with dichloromethane (500 ml). The solution was extracted with 1.5 N sodium hydroxide (3 x 200 ml). The pH of the aqueous layer was adjusted to 5 with 2 N hydrochloric acid and the precipitaed solids were collected by filtration to provide oxazolo[4,5-b]pyridin-2(3H)-one in 79percent yield as a grey solid.
79%
for 1 h; Reflux
Intermediate 30: Synthesis of 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazine-7-sulfonyI chloride.CICH,COCI Pd/C, H- NaHCO, 1. Synthesis of oxazolo[4,5-b]pyridin-2('3//)-one.Carbonyldiimidazole (600 mmol) was added in several batches to a solution of 2- aminopyridin-3-ol (400 mmol) in tetrahydrofuran (600 ml) and the reaction was heated at reflux for 1 h. The mixture was concentrated and the residue was diluted with dichloromethane (500 ml). The solution was extracted with 1.5 N sodium hydroxide (3 x 200 ml). The pH of the aqueous layer was adjusted to 5 with 2 N hydrochloric acid and the precipitaed solids were collected by filtration to provide oxazolo[4,5-b]pyridin-2(3H)-one in 79percent yield as a grey solid.
73%
Reflux
Into a 3-L 3-necked round-bottom flask, was placed a solution of 2-aminopyridin-3-ol (100 g, 908.15 mmol, 1.00 equiv), 1-[(1H-imidazol-1-yl)carbonyl]-1H-imidazole (221.3 g, 1.36 mol, 1.50 equiv) in THF (1000 mL). The resulting solution was heated to reflux overnight. After cooling, the reaction was concentrated under vacuum. The residue was dissolved in 1000 mL of DCM and extracted with 1M NaOH (3*800 mL). The combined liquids were cooled with a water/ice bath and adjusted to pH 5-6 by adding 3M HCl. The solids were collected by filtration. The solid was dried in an oven under reduced pressure. This resulted in 90 g (73percent) of 2H,3H-[1,3]oxazolo[4,5-b]pyridin-2-one (1-10) as a gray solid.
71%
for 1.5 h; Reflux
A suspension of carbonyl diimidazole (118.2 mmol, 19.1 g) and 2-amino-3-hydroxy-pyridine (90.9 mmol, 10.00 g) in THF (100 mL) was heated at reflux for 1.5 hours. (0767) The mixture was cooled and concentrated under reduced pressure. The residue was taken up in dichloromethane and extracted with 2M aqueous sodium hydroxide solution. The aqueous phase was cooled (ice/water bath) and (0768) acidified to pH5 with concentrated hydrochloric acid. (0769) The resulting precipitate was isolated by filtration, washed with water and THF then dried under suction to give the title compound as a grey powder (8.81 g, 71percent).
0.5 g
for 16 h; Reflux
To a stirred solution of 2-amino 3-hydroxy pyridine 1 (2 g, 16.26 mmol) in THF (20 ml ) was added CDI (2.63 g ,16.26 mmol )and the total reaction mass stirred at reflux temperature for 16 h. Reaction mass was cooled to room temperature, THF was distilled and the crude material was partitioned between water and ethyl acetate. The organic layer was separated, dried over sodium sulphate and concentrated under vacuum to afford the desired compound 2 (0.5 g )
Reference：
[1] Patent: WO2007/67416, 2007, A2, . Location in patent: Page/Page column 56; 91
[2] Patent: WO2010/96389, 2010, A1, . Location in patent: Page/Page column 42; 44
[3] Patent: WO2010/135014, 2010, A1, . Location in patent: Page/Page column 50-51
[4] Journal of Medicinal Chemistry, 2015, vol. 58, # 20, p. 8066 - 8096
[5] Patent: WO2009/23844, 2009, A2, . Location in patent: Page/Page column 120
[6] Patent: WO2010/21797, 2010, A1, . Location in patent: Page/Page column 84-85
[7] Patent: WO2010/24980, 2010, A1, . Location in patent: Page/Page column 103
[8] Journal of Medicinal Chemistry, 1993, vol. 36, # 4, p. 497 - 503
[9] Patent: US2014/274926, 2014, A1, . Location in patent: Paragraph 0525; 0526
[10] Patent: WO2015/115673, 2015, A1, . Location in patent: Page/Page column 76
[11] Archiv der Pharmazie, 1999, vol. 332, # 2, p. 43 - 49
[12] Patent: WO2013/42035, 2013, A1, . Location in patent: Page/Page column 30-31
[13] Patent: WO2013/114332, 2013, A1, . Location in patent: Page/Page column 116; 117; 118
[14] Chemical Biology and Drug Design, 2016, vol. 87, # 6, p. 918 - 926
[15] Patent: WO2009/100536, 2009, A1, . Location in patent: Page/Page column 95
24
[ 16867-03-1 ]
[ 32315-10-9 ]
[ 60832-72-6 ]
Yield
Reaction Conditions
Operation in experiment
86.2%
With sodium hydroxide In chloroform; water; toluene at 74 - 88℃; Industrial scale
In 2L to three-opening bottle 810g30percent of aqueous sodium hydroxide solution and 110g2-amino-3-hydroxy-pyridine, stirring to dissolve, will 340g triphosgene is dissolved in 600 ml of toluene and 300 ml chloroform solution; to the slow heating three-mouth bottle 80 °C rear, dropping the toluene and the chloroform solution of triphosgene, the reaction temperature is controlled at 74 the [...] 88 °C between, the end of the dropping reaction 8 hours; cooling to the 20 [...] 30 °C, reaction with hydrochloric acid or sodium hydroxide to adjust PH value is neutral, to continue to lower the temperature to 10 °C the following, a filter, a water washing of the filter cake, drying the white solid obtained oxazole [4,5-b] pyridine -2 (3H) ketone 91.4g, the yield is 86.2percent, after separating the filtrate, dry recovery of toluene and chloroform
Reference：
[1] Tetrahedron Letters, 2014, vol. 55, # 9, p. 1528 - 1531
[2] Patent: CN105924454, 2016, A, . Location in patent: Paragraph 0013
Reference：
[1] ChemSusChem, 2015, vol. 8, # 13, p. 2204 - 2211
[2] Phosphorus and Sulfur and the Related Elements, 1988, vol. 38, p. 137 - 148
27
[ 16867-03-1 ]
[ 64269-79-0 ]
[ 60832-72-6 ]
Yield
Reaction Conditions
Operation in experiment
0.5 g
for 16 h; Reflux
Step-1 [0134] To a stirred solution of 2-amino 3-hydroxy pyridine 1 (2 g, 16.26 mmol) in THF (20 ml) was added CDI (2.63 g, 16.26 mmol) and the total reaction mass stirred at reflux temperature for 16 h. Reaction mass was cooled to room temperature, THF was distilled and the crude material was partitioned between water and ethyl acetate. The organic layer was separated, dried over sodium sulphate and concentrated under vacuum to afford the desired compound 2 (0.5 g)
Reference：
[1] Journal of Medicinal Chemistry, 2007, vol. 50, # 15, p. 3730 - 3742
37
[ 16867-03-1 ]
[ 100-44-7 ]
[ 24016-03-3 ]
Yield
Reaction Conditions
Operation in experiment
77.3%
With tetrabutylammomium bromide; sodium hydroxide In water at 40 - 75℃; for 6 h; Large scale
temperature below 40 ° C, to the 300L stainless steel reactor 48L of purified water was added slowly stirring 48kg sodium hydroxide, stirring until dissolved.To sodium hydroxide solution followed by adding 16kg 2-amino-3-hydroxypyridine, 1.6kg tetrabutylammonium bromide, 17.92L benzyl chloride, plus warming to 70 ~ 75 ° C reaction 6 hours, stirring was stopped,Let stand, liquid separation; aqueous phase extraction with toluene (20Lx3);Purified water washing (30Lx2), the organic phase was collected, concentrated to a large amount of solid precipitation, temperature 0 ~ 5 ° C, crystallization was stirred for 2 hours, centrifuged,The filter cake was rinsed with 3.2 L of pre-cooled toluene and dried under vacuum at 50~55 ° C. for 3 hours to afford Intermediate II as a bright yellow solid, 22.5 kg of 2-amino-3-benzyloxypyridine, with a molar yield of 77.3percent , Purity 99.53percent.
60%
With tetrabutylammomium bromide; sodium hydroxide In dichloromethane at 20℃; for 19 h;
2-Amino-3-hydroxypyridine (11 g, 100 mmol), chlorobenzyl (12.66 mL, 110 mmol) and tetrabutylammonium bromide (3 g, 10 mmol) were dissolved in 50 mL of 40percent sodium hydroxide solution and 50 mL of dichloromethane The mixture was stirred at room temperature for 19 h. After the reaction is completed, liquid is dispensed, The aqueous phase is diluted with water and extracted three times with dichloromethane. Combine the organic phase, Drying with anhydrous sodium sulfate, Filter and concentrate, Column chromatography of the residue gave the title compound as a brown solid (12 g, 60percent yield).
Reference：
[1] Chemistry Letters, 2006, vol. 35, # 3, p. 270 - 271
[2] Synthesis, 1981, # 12, p. 971 - 973
[3] Patent: CN107311998, 2017, A, . Location in patent: Paragraph 0035-0036
[4] Journal of Chemical Research, Miniprint, 1986, # 11, p. 3368 - 3390
[5] Patent: CN103570683, 2018, B, . Location in patent: Paragraph 0927; 0928; 0930; 0931
[6] Heterocycles, 2008, vol. 75, # 6, p. 1355 - 1370
[7] Patent: US4450164, 1984, A,
[8] Patent: WO2004/4720, 2004, A1, . Location in patent: Page/Page column 63-64
[9] Archiv der Pharmazie, 2011, vol. 344, # 3, p. 158 - 164
38
[ 16867-03-1 ]
[ 100-39-0 ]
[ 24016-03-3 ]
Reference：
[1] Journal of the American Chemical Society, 2015, vol. 137, # 27, p. 8851 - 8857
[2] European Journal of Medicinal Chemistry, 2017, vol. 128, p. 56 - 69
[3] Patent: WO2017/87905, 2017, A1, . Location in patent: Page/Page column 243
[4] European Journal of Medicinal Chemistry, 2017, vol. 141, p. 322 - 334
With potassium carbonate In acetone at 70℃; for 16 h;
Step-(i): Synthesis of 2,2-dimethyl-2H-pyridor3,2-biri,41oxazin-3(4H)-one (18.1) To a stirred solution of 2-aminopyridin-3-ol (5 g, 45.45 mmol) in acetone (50 mL) was added K2CO3 (25.09 g, 181.81 mmol) followed by ethyl 2-bromo-2-methylpropanoate (13.29 g, 68.18 mmol) at 20-35°C and the reaction mixture was allowed to stir at 70°C for 16 h. Then the reaction mixture was cooled to 20-35°C and diluted with ice water. The obtained solid was filtered and washed with water to get the desired compound as a white solid (5 g, 97percent); H NMR (400MHz, DMSO-<) δ 11.17 (s, 1H), 7.91 (d, /=4.4 Hz, 1H), 7.34 (d, /=7.8 Hz, 1H), 6.98 (dd, /=4.9 Hz, 7.9 Hz, 1H), 1.41 (s, 6H); LC-MS: 179.3 (M+l)+.
With sodium hydrogencarbonate In water; butanone at 20 - 75℃; for 1.5 h; Cooling with ice
2-Amino-3-ol (45 mmol) and sodium hydrogen carbonate (51 mmol) in water (30 ml) and 2-butanone (30 ml) mixed solution. Under ice-cooling, chloroacetyl chloride (51 mmol) of 2-butanone (10 ml) was slowly added, maintaining the temperature during the addition does not exceed 10 ° C. It was stirred at room temperature for 30 minutes, stirring for 1 hour at 75 ° C, and concentrated recrystallization (methanol / water = 1: 1) to give 4.3 g of the title compound.
Reference：
[1] Bioorganic and Medicinal Chemistry, 1998, vol. 6, # 2, p. 133 - 142
[2] Helvetica Chimica Acta, 1976, vol. 59, p. 1593 - 1612
[3] Patent: CN103130792, 2016, B, . Location in patent: Paragraph 0605-0607
50
[ 16867-03-1 ]
[ 5292-43-3 ]
[ 20348-09-8 ]
Yield
Reaction Conditions
Operation in experiment
2.3 g
With sodium hydroxide In dichloromethane; water at 20℃; for 24 h;
A mixture of 3-hydroxy-2-aminopyridine 2 (3 g, 27 mmol), tert-butylbromoacetate3 (4 mL, 27 mmol), Adogen-464 (168 mg) and NaOH solution (40percent in water, 15 mL) was dissolved in DCM (25 mL).The reaction mixture was stirred at room temperature for 24 h. Themixture was then washed with water (3 × 50 mL) and the organic layerscombined. The organic portion was dried, (MgSO4) and concentratedin vacuo. The resulting crude yellow oil was purified by columnchromatography (silica gel, 3percent MeOH in DCM) to afford amine 4:Yellow oil; yield 2.3 g, 38percent; Rf (5percent MeOH in DCM) 0.50; IR (νmax,cm–1) film: 3483 (w), 1748 (s), 1616 (s), 1476 (s), 1154 (s); 1H NMR(300 MHz, CDCl3) δ 7.67 (1H, d, J = 5 Hz, H py), 6.80 (1H, d, J = 8 Hz,H py), 6.55 (1H, dd, J = 8, 5 Hz, H py), 4.85 (2H, br. s, NH2), 4.49 (2H,s, CH2), 1.45 (9H, s, 3 × CH3); 13C NMR (75 MHz, CDCl3) δ 167.7 (s),150.7 (s), 140.9 (s), 140.1 (d), 117.7 (d), 113.3 (d), 82.9 (s), 66.3 (t), 28.2(q); LRMS (ES) m/z (percent): 266 [M + H + CH3CN]+ (30).3–5
Reference：
[1] Journal of Chemical Research, 2016, vol. 40, # 12, p. 753 - 757
To a solution of 2-amino-3-hydroxypyridine (90.1 mmol) in triethylorthoformate (720.7 mmol) was added p-toluenesulphonic acid (4.50 mmol) and the mixture was stirred under nitrogen at 160 °C overnight. The triethylorthoformate was removed in vacuo and the crude material was purified by column chromatography, eluting with cyclohexane/ethyl acetate 5percent-40percent to give the title compound as a beige solid (68percent). LRMS [M + H] 121.1 m/z; 1H NMR (DMSO, 400 MHz) δ 9.04 (s, 1H), 8.58 (dd, J = 4.8, 1.4 Hz,1H), 8.26 (dd, J = 8.2, 1.4 Hz, 1H), 7.50 (dd, J = 8.2, 4.8 Hz, 1H), 6.41 (s, 2H); 13C NMR (DMSO, 101 MHz) δ 157.7, 154.5, 147.1, 142.0, 121.5, 120.1.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 13, p. 1647 - 1650
[2] Journal of Enzyme Inhibition and Medicinal Chemistry, 2017, vol. 32, # 1, p. 513 - 521
[3] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 8, p. 2350 - 2353
61
[ 16867-03-1 ]
[ 140-89-6 ]
[ 53052-06-5 ]
Yield
Reaction Conditions
Operation in experiment
86.95%
at 110℃;
Step 1: Preparation of oxazolo[4,5-b]pyridine-2-thiol A solution of 2-aminopyridin-3-ol (5.0g, 45.45 mmol) and potassium ethyl xanthate (8.0g, 49.99 mmol) in pyridine (50mL) was heated at 110°C overnight. The reaction mixture was cooled to 0°C, added ice water and acidified with Cone. HCl. The solid was filtered and dried under vacuum to afford the title compound (6.0g, 86.95percent). 1HNMR (DMSO-d6, 300MHz): δ 8.24-8.22 (d, 1H), 7.90-7.87 (d, 1H), 7.30-7.26 (m, 1H). LCMS: m/z: 153.0 (M+l) +.
86.95%
at 110℃;
A solution of 2-aminopyridin-3-ol (5.0 g, 45.45 mmol) and potassium ethyl xanthate (8.0 g, 49.99 mmol) in pyridine (50 mL) was heated at 1100 C. overnight. The reaction mixture was cooled to 00 C., added ice water and acidified with Conc. HC1. The solid was filtered and dried under vacuum to afford the title compound (6.0 g, 86.95percent). 10206] ‘HNMR (DMSO-d5, 300 MHz): ö 8.24-8.22 (d, 1H), 7.90-7.87 (d, 1H), 7.30-7.26 (m, 1H). LCMS: mlz:153.0 (M+1).
Reference：
[1] Patent: WO2015/104688, 2015, A1, . Location in patent: Page/Page column 36
[2] Patent: US2016/340366, 2016, A1, . Location in patent: Paragraph 0205; 0206
[3] Monatshefte fur Chemie, 2011, vol. 142, # 9, p. 895 - 899
[4] Journal of Organic Chemistry, 1995, vol. 60, # 17, p. 5721 - 5725
[5] European Journal of Medicinal Chemistry, 2005, vol. 40, # 1, p. 15 - 23
[6] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 1, p. 114 - 125
[7] Patent: EP1308439, 2003, A1,
62
[ 75-15-0 ]
[ 16867-03-1 ]
[ 53052-06-5 ]
Yield
Reaction Conditions
Operation in experiment
67%
With potassium hydroxide In ethanol for 10 h; Reflux
In a 100 ml round bottom flask was placed 2- amino-3-hydroxy pyridine (2.20g, 20 mmol) and 40 ml of absoluteethanol was added and the mixture was stirred for 15minutes. In the meanwhile, 2.0g (29 mmol) KOH pelletswere powdered and transferred into the flask followed by theaddition of 15 ml of carbon disulfide. The resulting mixturewas refluxed over an oil bath for 8 hours when a yellowprecipitate appeared. The contents of the flask were cooledto room temperature. The solvent was rotary evaporated andthe residue was transferred in to a beaker and 75 ml of waterwas added followed by neutralization with acetic acid. Theprecipitated product was filtered under vacuum and washedwith 3x50 ml of water and dried under vacuum over night toyield 2.1g of light yellow solid product (yield, 65percent).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 5, p. 2075 - 2078
[2] Advanced Synthesis and Catalysis, 2017, vol. 359, # 11, p. 1837 - 1843
[3] Letters in Organic Chemistry, 2010, vol. 7, # 7, p. 519 - 527
[4] Archiv der Pharmazie, 2017, vol. 350, # 8,
63
[ 16867-03-1 ]
[ 53052-06-5 ]
Reference：
[1] Patent: US4351832, 1982, A,
64
[ 16867-03-1 ]
[ 137-26-8 ]
[ 53052-06-5 ]
Reference：
[1] Green Chemistry, 2017, vol. 19, # 23, p. 5591 - 5598
65
[ 16867-03-1 ]
[ 78-95-5 ]
[ 79707-11-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 1985, vol. 28, # 7, p. 876 - 892
[2] Patent: US4450164, 1984, A,
66
[ 16867-03-1 ]
[ 174669-74-0 ]
Yield
Reaction Conditions
Operation in experiment
65%
Stage #1: at 0℃; for 1 h;
100 ml of pyridine hydrofluoride (Py. (HF)x, from Fluka, 70percent of the sample consisting of hydrogen fluoride, 30percent of the sample consisting of pyridine), cooled at 0° C., are admixed cautiously and in succession with 3.7 g of 2-amino-3-hydroxypyridine (molecular mass: 110.12; 33.6 mmol) and 3 g of NaNO2 (molecular mass: 69.00; 43.5 mmol). The mixture is stirred at 0° C. for 1 hour and then slowly rendered basic with 10N aqueous NaOH solution, transferred to a decanter and extracted with EtOAc. The organic phases are combined, washed with water and brine, dried with Na2SO4 and concentrated to dryness. The residue is purified by passing it through a silica gel column (eluent: heptane/EtOAc: 50/50) to give 2.5 g (65percent) of 2-fluoro-3-hydroxypyridine in the form of a solid, which is used without further purification. Rf(EtOAc/heptane: 80/20): 0.65. m.p.: 131° C. 1H NMR (DMSO-d6, 298 K): δ: 10.41 (s, 1H); 7.64 (td, J: 1.7 and 4.7 Hz, 1H); 7.42 (dd, J: 1.7, 1.7 and 10.8 Hz, 1H); 7.17 (ddd, J: 1.3, 4.7 and 7.8 Hz, 1H). 13C NMR (DMSO-d6 298 K): δ: 152.8 (d, J1F-C: 233 Hz, C; 140.2 (d, J2F-C: 27 Hz, C); 135.6 (d, J3F-C) 13 Hz, CH) 126.2 (d, J3F-C: 5 Hz, CH); 122.6 (CH).MS(DCI/NH4+): C5H4FNO: 131[M+NH4+]; 114[M+H+]. Anal. (C5H4FNO) C, H, N.
55%
With hydrogen bromide; sodium nitrite In water at 0℃; for 1 h;
A solution of 2-amino-3-hydroxypyridine (2 g, 17.8 mmol) in aqueous 48percent HBr (75 mL) was cooled to 0° C. was carefully treated with NaNO2 (10.0 g, 0.14 mol) in portions. The mixture was stirred at 0° C. for 1 h, then neutralized to pH about 7 with 2N NaOH, and extracted with EtOAc (100 mL.x.3). The combined organic extract was washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give a brown solid. The crude material was purified by flash chromatography on a silica gel column eluted with 50percent EtOAc/hexanes to give 1.10 g (55percent) of 2-fluoro-3-pyridinol as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.80-7.70 (m, 1H), 7.60-7.50 (m, 1H), 7.15-7.05 (m, 1H); LRMS (ESI), m/z 114 (M+H).
Reference：
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[2] Journal of Labelled Compounds and Radiopharmaceuticals, 1998, vol. 41, # 5, p. 451 - 463
[3] Journal of Labelled Compounds and Radiopharmaceuticals, 2008, vol. 51, # 9, p. 336 - 342
[4] Patent: US2010/29650, 2010, A1, . Location in patent: Page/Page column 64
[5] Organic and Biomolecular Chemistry, 2015, vol. 13, # 12, p. 3667 - 3676
[6] Patent: US6133253, 2000, A,
[7] Patent: WO2009/140163, 2009, A1, . Location in patent: Page/Page column 45
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[4] Patent: WO2015/104688, 2015, A1,
[5] Patent: US2016/340366, 2016, A1,
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Bromine (11.2 mL, 0.21 mole) was added dropwise to a mechanically stirred suspension of 2-aminopyridin-3-ol (20 g, 0.18 mole) in acetic acid (300 mL) at 5 - 10 °C and brought to room temperature. The reaction mixture was heated at 120 - 125 °C, maintained for 12 hours and concentrated to get a crude mass that was triturated with diethyl ether (50 mL x 3) and dried under vacuum to obtain 2-amino-4-bromopyridin-3-ol hydrobromide as dark brown compound that was used as such without any purification. Yield: 48.5 g; Mass (m/z): 189.3, 191.1 (M+H)+.
With guanidine hydrochloride In ethanol at 35 - 40℃; for 2.5 h;
General procedure: Amine (1 mmol) was added to a magnetically stirred solution of guanidine hydrochloride (15 molpercent) and di-tert-butyl dicarbonate (1.2 mmol) in EtOH (1 mL), at 35-40°C and stirred for appropriate time (Table 1). After completion of the reaction (followed by TLC or GC), EtOH was evaporated under vacuum and the residue either was washed with water to remove the catalyst or was dissolved in CH2Cl2 (or EtOAc) and filtered off to separate out the catalyst. Evaporation of the organic solvent (if used in work up) gives almost a pure product. In the cases of using an excess (Boc)2O the product was washed with petroleum ether or hexane to recover the residual (Boc)2O. If necessary, the product was further purified either by crystallization (hexane and dichloromethane, or diethyl ether and petroleum ether) or silica gel column chromatography using EtOAc-hexane (1: 6) as eluent.
With sodium hydrogencarbonate; In water; butanone; at 20 - 75℃; for 1.5h;Cooling with ice;
2-Amino-3-ol (45 mmol) and sodium hydrogen carbonate (51 mmol) in water (30 ml) and 2-butanone (30 ml) mixed solution. Under ice-cooling, chloroacetyl chloride (51 mmol) of 2-butanone (10 ml) was slowly added, maintaining the temperature during the addition does not exceed 10 C. It was stirred at room temperature for 30 minutes, stirring for 1 hour at 75 C, and concentrated recrystallization (methanol / water = 1: 1) to give 4.3 g of the title compound.
With toluene-4-sulfonic acid; at 160℃;Inert atmosphere;
To a solution of 2-amino-3-hydroxypyridine (90.1 mmol) in triethylorthoformate (720.7 mmol) was added p-toluenesulphonic acid (4.50 mmol) and the mixture was stirred under nitrogen at 160 C overnight. The triethylorthoformate was removed in vacuo and the crude material was purified by column chromatography, eluting with cyclohexane/ethyl acetate 5%-40% to give the title compound as a beige solid (68%). LRMS [M + H] 121.1 m/z; 1H NMR (DMSO, 400 MHz) delta 9.04 (s, 1H), 8.58 (dd, J = 4.8, 1.4 Hz,1H), 8.26 (dd, J = 8.2, 1.4 Hz, 1H), 7.50 (dd, J = 8.2, 4.8 Hz, 1H), 6.41 (s, 2H); 13C NMR (DMSO, 101 MHz) delta 157.7, 154.5, 147.1, 142.0, 121.5, 120.1.
With toluene-4-sulfonic acid; at 140℃; for 8h;
A mixture of 2-amino-3-hydroxypyridine (11 g, 100 mmol), triethylorthoformate (80 ml) and p-toluenesulfonic acid (61 mg) was heated at 140 C. for 8 hours. Excess triethylorthoformate was removed under vacuum and oxazolo[4,5-b]pyridine was crystalized from ethyl acetate (9 g).
With toluene-4-sulfonic acid; at 140℃; for 8h;
A mixture of 2-amino-3-hydroxypyridine (11 g, 100 mmol), triethylorthoformate (80 mL) and p-toluenesulfonic acid (61 mg) was heated at 140 C for 8 h. Excess triethylorthoformate was removed under vacuum and oxazolo [4, 5-b] pyridine was crystalized from ethyl acetate (9 g).
With toluene-4-sulfonic acid; at 140℃; for 8h;
Example I; Synthesis of 2(S)-(tert-butoxycarbonyl)amino-1-(oxazolo[4,5-b]pyridin-2-yl)butan-1-ol; Step 1; A mixture of 2-amino-3-hydroxypyridine (11 g, 100 mmol), triethylorthoformate (80 mL) and p-toluenesulfonic acid (61 mg) was heated at 140 C for 8 h. Excess triethylorthoformate was removed under vacuum and oxazolo[4,5-b]pyridine was crystalized from ethyl acetate (9 g).; A mixture of 2-amino-3-hydroxypyridine (11 g, 100 mmol), triethylorthoformate (80mL) and p-toluenesulfonic acid (61 mg) was heated at 140 C for 8 h. Excesstriethylorthoformate was removed under vacuum. The product was crystallized from ethylacetate to yield 9g of l-oxazolo[4,5-b]pyridine.; A mixture of 2-amino-3-hydroxypyridine (25 g, 227 mmol), triethylorthoformate (75mL) and p-toluenesulfonic acid (61 mg) was heated at 140 C for 8 h. Excesstriethylorthoformate was removed under vacuum. The product was crystallized from ethylacetate to yield 22.5 g of oxazolo[4,5-b]pyridine.
With toluene-4-sulfonic acid; at 140℃; for 8h;
Step 3 A mixture of 2-amino-3-hydroxypyridine (11 g, 100 mmol), triethylorthoformate (80 mL) andp-toluenesulfonic acid (61 mg) was heated at 140 C for 8 h. Excess triethylorthoformate was removed under vacuum. The product was crystallized from ethyl acetate to yield 1-oxazolo [4,5-b] pyridine (9 g).
toluene-4-sulfonic acid; at 140℃; for 8h;
A mixture of 2-amino-3-hydroxypyridine (11 g, 100 mmol), triethylorthoformate (80 mL) and p-toluenesulfonic acid (61 mg) was heated at 140 C for 8 h. Excess triethylorthoformate was removed under vacuum and oxazolo [4. 5-b] pyridine was crystalized from ethyl acetate (9 g).
With toluene-4-sulfonic acid; at 140℃; for 8h;
Reference O Synthesis of [2-AMINO-2-METHYL-1-OXAZOLO] [4,5-b] [PYRIDIN-2-YL-PROPAN-1-OL] Step 1 [2-AMINO-2-METHYL-1-PROPANOL] (17. [8] g, 200 mmol) was dissolved in a mixture of water and dioxane (100 mL) and cooled to [0 C. NAOH] (8g, [200MMOL)] and di-t-butyl- dicarbonate (52.4 g, 240 mmol) were added and the reaction was allowed to warm to room temperature with stirring for 2 h. After removing the dioxane, the residue was extracted with EtOAc, washed with brine, dried with anhydrous [MGS04,] filtered and concentrated to yield 35g of [2-BOC-AMINO-2-METHYL-1-PROPANOL.] Step 2 A solution of oxalyl chloride (15.24 g, 120 mmol) in 200 mL of MeCl2 was stirred and cooled to-60 C followed by the drop wise addition [OF DIMETHYLSULFOXIDE] (19.7 g, 252 mmol) in 60mL of MeCl2. After 10 min, a solution of [2-BOC-AMINO-2-METHYL-1-PROPANOL] (18.9 g, 100 mmol) in MeCl2 (60 mL) was added drop wise [AT-70 C.] The reaction mixture was allowed to warm [TO-40 C] for 10 min followed by cooling to-70 C before the addition of a solution of triethylamine (28.28 g, 280 mmol) in [MECL2] (60 mL). The reaction mixture was allowed to warm to room temperature over a two-hour period and 40 mL of saturated sodium dihydrogen phosphate was added. The organic layer was washed with brine and dried over [MGS04.] The solvent was removed to yield 17.3 g of 2-Boc-amino-2- methylpropionaldehyde. Step 3 A mixture of 2-amino-3-hydroxypyridine (11 g, 100 mmol), triethylorthoformate (80 mL) and p-toluenesulfonic acid (61 mg) was heated at [140 C] for 8 h. Excess [TRIETHYLORTHOFORMATE] was removed under vacuum. The product was crystallized from ethyl acetate to yield 9g of 1-oxazolo [4,5-b] pyridine. Step 4 To a stirred solution [OF THE 1-OXAZOLO] [4,5-b] pyridine (2.4 g, [20MMOL)] in THF (100 mL) was added n-BuLi (1.6 M solution in 12.5 mL of hexane) drop wise under N2 [AT-78 C.] After 1 h, MgBr. [ET20] (5.16 g, 20 mmol) was added and the reaction mixture was allowed to warm to-45 [C] for 1 h before being treated with 2-Boc-amino-2-methylpropionaldehyde (2.24 g, 12 mmol) in THF (20 mL). The reaction mixture was stirred for 1 h, quenched with saturated [NH4C1,] and extracted with ethyl acetate. The organic layer was washed with brine, dried with MgS04 and concentrated. The residue was purified by silica gel column chromatography to yield 2-Boc-amino-2-methyl-1-oxazolo [4,5-b] [PYRIDIN-2-YL-1-PROPANOL] [(1. 18G).] Step 5 [2-BOC-AMINO-2-METHYL-1-OXAZOLO] [4,5-b] pyridin-2-yl-1-propanol (156 mg, 0.508 mmol) and [MECL2] (5 mL) were mixed and TFA (0.5 [ML)] was added at room temperature. After stirring for 1 h, the solvent and excess TFA were removed under vacuum to produce 2- amino-2-methyl-1-oxazolo [4,5-b] [PYRIDIN-2-YL-PROPAN-1-OL.] TFA salt (165 mg).
With toluene-4-sulfonic acid; at 140℃; for 8h;
Reference R Synthesis of [(S)-2-AMINO-1-OXAZOLO] [4,5-b] pyridin-2-yl-butan-1-ol Step 1 A mixture of 2-amino-3-hydroxypyridine (25 g, 227 mmol), triethylorthoformate (75 mL) and p-toluenesulfonic acid (61 mg) was heated at [140 C] for 8 h. Excess triethylorthoformate was removed under vacuum. The product was crystallized from ethyl acetate to yield 22.5 g of oxazolo [4,5-b] pyridine. Step 2 To a stirred solution of the oxazolo [4,5-b] pyridine (12 g, 100 mmol) in THF (300 mL) was added n-BuLi (1.6 M solution in 62.5 mL of hexane) drop wise under N2 at-78 [C.] After 1 h, MgBr. [ET20] (25.8 g, 100 mmol) was added and the reaction mixture was allowed to warm [TO-45 C] for 1 h before being treated with [(S)-2-BOC-AMINO-BUTYLALDEHYDE] (11.46 g, 60 mmol) in THF (50 mL). The reaction mixture was stirred for 1 h, quenched with saturated [NH4C1,] and extracted with ethyl acetate. The organic layer was washed with brine, dried with MgS04 and concentrated. The residue was purified by silica gel column chromatography to yield (S)-2-Boc-amino-l-(oxazolo [4,5-b] pyridin-2-yl)-1-butanol (14.1 g). Step 3 [(S)-2-BOC-AMINO-L-(OXAZOLO] [4,5-b] pyridin-2-yl)-1-butanol (311 mg, 1 mmol) and MeCl2 (5mL) were mixed and TFA [(LML)] was added at room temperature. After stirring for 1 h, the solvent and excess TFA were removed under vacuum to produce 355 mg of [(USD)-2-] [AMINO-L-OXAZOLO] [4,5-b] [PYRIDIN-2-YL-BUTAN-1-OL.] TFA salt.
With toluene-4-sulfonic acid; at 140℃; for 8h;Product distribution / selectivity;
A mixture of 2-amino-3-hydroxypyridine (11 g, 100 mmol), triethylorthoformate (80 ml) andp-toluenesulfonic acid (61 mg) was heated at 140 C for 8 h. Excess triethylorthoformate was removed under vacuum and oxazolo [4, 5-b] pyridine was crystalized from ethyl acetate (9 g).Reference H Synthesis of ()-2-amino-1-oxazolo [4,5-b] pyridin-2-ylbutan-1-ol Step 1 A mixture of 2-amino-3-hydroxypyridine (25 g, 227 mmol), triethylorthoformate (75 ml) andp-toluenesulfonic acid (61 mg) was heated at 140 C for 8 h. Excess triethylortho- formate was removed under vacuum. The product was crystallized from ethyl acetate to yield oxazolo [4,5-b] pyridine (22.5 g).
A suspension of 2-amino-pyridin-3-ol (20.0 g, 181 mmol) in THF (200 mL) was added to l,l'-carbonyldiimidazole (44.1 g, 272 mmol). The mixture was heated to reflux overnight. After cooling, the reaction was concentrated and the residue was taken up with CH2Cl2 (400 mL) and extracted with IM NaOH (3x). The combined liquids were cooled in an ice-bath and adjusted to pH 5-6 by adding 3M HCl. The resulting precipitate was isolated by filtration, washed with THF, and dried under vacuum at 50 0C overnight to give the title compound (20.0 g, 81%) as a tan solid: 1H NMR (300 MHz, DMSO-cfc) delta 8.04 (dd, J= 5.4, 1.2 Hz, IH), 7.64 (dd, J= 8.1, 1.2 Hz, IH), 7.14-7.05 (m, IH); ESI MS m/z 137 (M + H)+.
81%
In tetrahydrofuran; at 70℃; for 14h;
[00102] As shown in step 4-i of Scheme 4, l,l '-carbonyldiimidazole (57.4 g, 354.2 mmol) was added to a solution of 2-amino-3-hydroxypyridine (26.0 g, 236.1 mmol, obtained from Aldrich Chemical Co.) in THF (400 mL). The resulting reaction mixture was stirred at 70 0C for 14 h. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was dissolved in DCM (500 mL) and washed with 2 N NaOH (3 x 100 mL). The combined aqueous layers were cooled to 0 0C and acidified to a pH of 6 with 6 N HCl. The precipitate that was formed was collected in a fritted funnel, washed with cold water (100 mL), and dried under vacuum to afford oxazolo[4,5-delta]pyridin-2(JH)-one (Compound 1011, 26.0 g, 81% yield): ESMS (M+Eta) 137; 1H NMR (DMSO-d6) delta 12.4 (br, 1Eta), 8.0 (d, 1Eta), 7.6 (d, 1Eta), 7.1 (dd, 1Eta).
81%
In tetrahydrofuran; at 70℃; for 14h;
As shown in step 4-i of Scheme 4, 1,1'-carbonyldiimidazole (57.4 g, 354.2 mmol) was added to a solution of 2-amino-3-hydroxypyridine (26.0 g, 236.1 mmol, obtained from Aldrich Chemical Co.) in THF (400 mL). The resulting reaction mixture was stirred at 70 0C for 14 h. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was dissolved in DCM (500 mL) and washed with 2 N NaOH (3 x 100 mL). The combined aqueous layers were cooled to 0 0C and acidified to a pH of 6 with 6 N HCl. The precipitate that was formed was collected in a fritted funnel, washed with cold water (100 mL), and dried under vacuum to afford oxazolo[4,5-delta]pyridin-2(JH)-one (Compound 1011, 26.0 g, 81% yield): ESMS (M+Eta) 137; 1H NMR (DMSO-d6) delta 12.4 (br, 1Eta), 8.0 (d, 1Eta), 7.6 (d, 1Eta), 7.1 (dd, 1Eta).
79%
In tetrahydrofuran; for 1h;Heating / reflux;
Carbonyldiimidazole (600 mmol) was added in several batches to a solution of 2-aminopyridin-3- ol (400 mmol) in tetrahydrofuran (600 ml) and the reaction was heated at reflux for 1 h. The mixture was concentrated and the residue was diluted with dichloromethane (500 ml). The solution was extracted with 1.5 N sodium hydroxide (3 x 200 ml). The pH of the aqueous layer was adjusted to 5 with 2 N hydrochloric acid and the precipitaed solids were collected by filtration to provide oxazolo[4,5-b]pyridin- 2(3H)-one in 79% yield as a grey solid.
79%
In tetrahydrofuran;Reflux;
Intermediate 30: Synthesis of 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazine-7-sulfonyl chloride.CCIICCHH2XCOOCCIINaHCO3 N' " 1. Synthesis of oxazolo[4,5-blpyridm-2(3H)-one.Carbonyldiimidazole (600 mmol) was added in several batches to a solution of 2- aminopyridin-3-ol (400 mmol) in tetrahydrofuran (600 ml) and the reaction was heated at reflux for 1 h. The mixture was concentrated and the residue was diluted with dichloromethane (500 ml). The solution was extracted with 1.5 N sodium hydroxide (3 x 200 ml). The pH of the aqueous layer was adjusted to 5 with 2 N hydrochloric acid and the precipitaed solids were collected by filtration to provide oxazolo[4,5-b]pyridin-2(3H)-one in 79% yield as a grey solid.
79%
In tetrahydrofuran; for 1h;Reflux;
Intermediate 30: Synthesis of 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazine-7-sulfonyI chloride.CICH,COCI Pd/C, H- NaHCO, 1. Synthesis of oxazolo[4,5-b]pyridin-2('3//)-one.Carbonyldiimidazole (600 mmol) was added in several batches to a solution of 2- aminopyridin-3-ol (400 mmol) in tetrahydrofuran (600 ml) and the reaction was heated at reflux for 1 h. The mixture was concentrated and the residue was diluted with dichloromethane (500 ml). The solution was extracted with 1.5 N sodium hydroxide (3 x 200 ml). The pH of the aqueous layer was adjusted to 5 with 2 N hydrochloric acid and the precipitaed solids were collected by filtration to provide oxazolo[4,5-b]pyridin-2(3H)-one in 79% yield as a grey solid.
73%
In tetrahydrofuran;Reflux;
Into a 3-L 3-necked round-bottom flask, was placed a solution of 2-aminopyridin-3-ol (100 g, 908.15 mmol, 1.00 equiv), 1-[(1H-imidazol-1-yl)carbonyl]-1H-imidazole (221.3 g, 1.36 mol, 1.50 equiv) in THF (1000 mL). The resulting solution was heated to reflux overnight. After cooling, the reaction was concentrated under vacuum. The residue was dissolved in 1000 mL of DCM and extracted with 1M NaOH (3*800 mL). The combined liquids were cooled with a water/ice bath and adjusted to pH 5-6 by adding 3M HCl. The solids were collected by filtration. The solid was dried in an oven under reduced pressure. This resulted in 90 g (73%) of 2H,3H-[1,3]oxazolo[4,5-b]pyridin-2-one (1-10) as a gray solid.
72%
In tetrahydrofuran; at 75℃; for 16h;
To the solution of 2-amino-3-hydrogen-5-chloropyridine (19.8 g, 180.0 mmol) in THF (200 mL) was added N, N'-Carbonyl diimidazole (43.8 g, 270.0 mmol) . The mixture was heated to 75 and stirred for 16h. After the reaction was completed, the mixture was purified by column chromatography to give 17.63g 2, 3-dihydropyridino [2, 3-d] [1, 3] azole-2-ketone, yield: 72%.
71%
In tetrahydrofuran; for 1.5h;Reflux;
A suspension of carbonyl diimidazole (118.2 mmol, 19.1 g) and 2-amino-3-hydroxy-pyridine (90.9 mmol, 10.00 g) in THF (100 mL) was heated at reflux for 1.5 hours. (0767) The mixture was cooled and concentrated under reduced pressure. The residue was taken up in dichloromethane and extracted with 2M aqueous sodium hydroxide solution. The aqueous phase was cooled (ice/water bath) and (0768) acidified to pH5 with concentrated hydrochloric acid. (0769) The resulting precipitate was isolated by filtration, washed with water and THF then dried under suction to give the title compound as a grey powder (8.81 g, 71%).
0.5 g
In tetrahydrofuran; for 16h;Reflux;
To a stirred solution of 2-amino 3-hydroxy pyridine 1 (2 g, 16.26 mmol) in THF (20 ml ) was added CDI (2.63 g ,16.26 mmol )and the total reaction mass stirred at reflux temperature for 16 h. Reaction mass was cooled to room temperature, THF was distilled and the crude material was partitioned between water and ethyl acetate. The organic layer was separated, dried over sodium sulphate and concentrated under vacuum to afford the desired compound 2 (0.5 g )
In tetrahydrofuran; at 70℃; for 2h;
To a solution of 2-hydroxy-6-methylaniline (583mg) in THF (8mL) was added 1,1'-carbonyldiimidazole (1.14g). The reaction mixture was stirred at 70C for 20h. After cooling down, DCM was added and the mixture was washed three times with 2N NaOH. The aq. phases were combined, cooled down to 0C and the pH was brought to 6 by addition of 2N HCl. The suspension was filtered, the resulting powder was washed with cold water and dried in high vacuo to afford 587mg of beige solid. LC-MS (B): tR = 0.64min. 1H-NMR (DMSO-d6): 1 1.7 (s, NH); 7.09 (m, 1 H); 6.97 (m, 2H); 2.29 (s, 3H).
In tetrahydrofuran; at 20℃;Inert atmosphere; Reflux;
To a solution of 2-amino-3-hydroxypyridine (19, 2 g, 18.16 mmol) in THF (36.3 ml) under nitrogen at room temperature was added CDI (20, 4.42 g, 27.2 mmol). The reaction mixture was heated to reflux for 6 hours then concentrated. The residue was dissolved in DCM.The organic layer was washed with 1.5 N NaOH (5 x 100 mL). The combined aqueous layers were cooled with an ice bath and acidified to pH 5-6 with HCl 3 N. This aqueous mixture was stirred overnight; then the solid suspension was filtered, the precipitate was rinsed with water and dried to afford title compound 21 (1.23 g, 9.04 mmol, 49.8% yield) as a beige solid. IHNMR (DMSO-d6) delta (ppm): 12.42 (s, IH), 8.03 (dd, J = 5.3, 1.2 Hz, IH), 7.63 (dd, J = 7.8, 1.2Hz, IH), 7.10 (dd, J = 7.8, 5.3 Hz, IH).
Step 1: Preparation of oxazolo[4,5-b]pyridine-2-thiol A solution of 2-aminopyridin-3-ol (5.0g, 45.45 mmol) and potassium ethyl xanthate (8.0g, 49.99 mmol) in pyridine (50mL) was heated at 110C overnight. The reaction mixture was cooled to 0C, added ice water and acidified with Cone. HCl. The solid was filtered and dried under vacuum to afford the title compound (6.0g, 86.95%). 1HNMR (DMSO-d6, 300MHz): delta 8.24-8.22 (d, 1H), 7.90-7.87 (d, 1H), 7.30-7.26 (m, 1H). LCMS: m/z: 153.0 (M+l) +.
86.95%
With pyridine; at 110.0℃;
A solution of 2-aminopyridin-3-ol (5.0 g, 45.45 mmol) and potassium ethyl xanthate (8.0 g, 49.99 mmol) in pyridine (50 mL) was heated at 1100 C. overnight. The reaction mixture was cooled to 00 C., added ice water and acidified with Conc. HC1. The solid was filtered and dried under vacuum to afford the title compound (6.0 g, 86.95%). 10206] ?HNMR (DMSO-d5, 300 MHz): oe 8.24-8.22 (d, 1H), 7.90-7.87 (d, 1H), 7.30-7.26 (m, 1H). LCMS: mlz:153.0 (M+1).
74%
In ethanol; for 24h;Reflux;
A mixture of 2-amino-pyridin-3-ol (1) (2.00 g, 18.16 mmol) and potassium ethyl xanthate (2.91 g, 18.16 mmol) in ethanol (40 mL) was heated under reflux for 24 h. The solvent was removed in vacuo and water (30 mL) was added. The mixture was acidified with AcOH to pH 5. The resultant precipitate was filtered, washed with water (20 mL) and dried to give oxazolo[4,5-b]pyridine-2-thiol (2) (2.05 g, 74% yield). 300 MHz 1H-NMR (DMSO-d6, ppm): 8.21 (dd, J=5.2, 1.3 Hz, 1H) 7.85 (dd, J=8.1, 1.3 Hz, 1H) 7.25 (dd, J=8.1, 5.2 Hz, 1H).
With hydrogenchloride; In pyridine; water;
(1) 2-Amino-3-hydroxypyridine (5.51 g) was dissolved in pyridine (100 mL), and potassium ethylxanthate (8.82 g) was added thereto. The mixture was refluxed for 2 hr. Iced water (400 mL) was added to the reaction mixture, and concentrated hydrochloric acid (40 mL) was added thereto. The mixture was extracted with chloroform and the extract was washed with brine and concentrated under reduced pressure to give 1,3-oxazolo[4,5-b]pyridine-2-thiol (5.13 g) as a pale-brown powder.
Reference H Synthesis of 2 [(S)-(TERT-BUTOXYCARBONYL) AMINO-L-(OXAZOLO] [4, [5-B] PYRIDIN-2-YL) BUTAN-1-OL] Step 1 A mixture of 2-amino-3-hydroxypyridine (11 g, 100 mmol), triethylorthoformate (80 mL) and p-toluenesulfonic acid (61 mg) was heated at [140 C] for 8 h. Excess triethylorthoformate was removed under vacuum and oxazolo [4, [5-B]] pyridine was crystalized from ethyl acetate (9 g). Step 2 In a clean roundbottom flask equipped with stir bar was placed oxazolo [4,5- [B]] pyridine (600 mg, 5 mmol) in THF (30 mL) and the reaction mixture was cooled to [0 C] under N2 atomosphere. Isopropylmagnesium chloride (2 M in THF, 2.5 mL, 5 mmol) was added. After stirring for 1 h at 0 [C,] [(USD)-2-(TERT-BUTOXYCARBONYL)] aminobutyraldehyde (573 mg, 3 mmol) in THF (20 mL) was added. The ice bath was removed and the reaction mixture was allowed to warm to room temperature. After 2 h, the reaction mixture was quenched with saturated ammonium chloride solution and concentrated to dryness. The residue was extracted with EtOAc, then washed with brine, dried with anhyd. [MGS04,] filtered and concentrated. The crude product was purified by chromatograph to yield 383 mg of the desired compound.
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 18h;
2-Amino-3-hydroxypyridine (1.0Og, 9.16 mmol) was dissolved in 20 mL of DMF along with 2.06 g of mono-methyl 5-nitroisorhohthlate (9.16 mmol), 5.2g of HATU (13.7 mmol) and 3.2 mL of DIEA (18.3 mmol). The reaction mixture was stirred at room temperature for 18 hours. It was then diluted with 200 mL of EtOAc and washed with water (3 x25 mL). The organic layer was dried (Na2SO4) and concentrated. The resulting residue was taken up in 10 mL of PPA and stirred at 160 degree for 6 hours. The reaction mixture was then poured carefully into 200 mL of water and the pH was brought to 5 with solid NaOH. The solids were collected by filtration and dried to afford the product as a 1:1 mixture of the methyl ester and the acid. This mixture was separated by suspending in 150 mL of CH2Cl2 and then filtered. The filtrate was the methyl ester (MS, M+ + H = 300) and the solids were the desired acid, namely, 3-nitro- 5-(oxazolo[4,5-b]pyridin-2-yl)benzoic acid (MS, M++ H = 286).
EXAMPLE 20 STR22 2-Amino-3-methoxypyridine A solution of 2-amino-3-hydroxypyridine (Aldrich, 200 mg) in 20% methanol/benzene (4 mL) was treated with trimethylsilyldiazomethane (1.8 mL, 2.0 M), boron trifluoride diethyletherate (0.026 mL) and stirred at room temperature for 16 hr. The solvent was evaporated in vacuo and the crude oil was purified by medium pressure liquid chromatography on a 21*300 mm silica column eluted with 50% ethyl acetate/lmethylene chloride to give the title compound (50 mg). 1 H NMR (400 MHz, CDCl3): delta 7.62 (d, 1H), 6.88 (d, 1H), 6.60 (dd, 1H), 4.60 (br, 2H), 3.82 (s, 3H). Mass spectrum (FAB): m/e=124 (M+1).
2-amino-3-(2,5-dichlorobenzyloxy)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In sodium hydroxide; dichloromethane; water;
(a) 2-Amino- 3-(2,5-dichlorobenzyloxy)pyridine A mixture of <strong>[85482-13-9]2,5-dichlorobenzyl bromide</strong> (14.8 g, 75.9 mmol) and 2-amino-3hydroxypyridine (7.7 g, 69.7 mmol) in 40% aqueous sodium hydroxide solution (52 ml) and dichloromethane (52 ml) was treated with Adogen 464 (5 ml) and stirred vigorously at room temperature for 16 hours. More water was added and the product extracted into dichloromethane, dried, and the solvent evaporated to obtain the product after trituration with ether (8.6 g, 46%), m.p. 103-104 C.
(a) 2-Amino- 3-(2,4,6-trimethylbenzyloxy)pyridine A mixture of 2-amino-3-hydroxy pyridine (29.6 g, 0.269 mol), dichloromethane (200 ml) and 40% aqueous sodium hydroxide solution (200 ml) was stirred for five minutes, then 2,4,6-trimethylbenzyl bromide (50 g, 0.296 mol) and Adogen 464 (5 ml) were added and stirring continued for 16 hours. The mixture was diluted with water and extracted with dichloromethane. Drying and evaporation of the organic extracts, and trituration with ether gave the desired product. Yield 29.6 g (41%), m.p. 160-166 C.
a) A mixture of 2-amino-3-pyridinol (0.10 mol), sodium hydroxide (50%) (30 ml), 1-chlorododecane (0.20 mol) and methyl-tri-octylammonium chloride (8 g) in benzene (300 ml) was stirred overnight at 80 C. The reaction mixture was cooled. The organic layer was separated, washed with 2N NaOH, dried (MgSO4), filtered and the solvent was evaporated. The residue was cooled and the resulting precipitate was filtered off, washed with hexane, petroleum ether and dried, yielding 21 g (75%) of 3-(dodecyloxy)-2-pyridinamine (interm. 2).
With carbon disulfide; potassium hydroxide; In methanol; water;
EXAMPLE 15 6,7-Dimethoxy-2-[4-(oxazolo[4,5-b]pyridin-2-yl)-1-piperazinyl]-4-quinazolinamine (Ia: R3 =oxazolo[4,5-b]pyridin-2-yl; R4, R5, R6 and R9 =H; R7 and R8 =OMe; and n=1) A mixture of 2-amino-3-hydroxypyridine and MeOCS2 K [prepared from potassium hydroxide (6.2 g), methanol (96 ml), water (17.4 ml) and carbon disulfide (7.1 g)] was refluxed for 20 hr and filtered. The filtrate was neutralized with acetic acid and the resulting precipitate was collected, washed with water and dried to give 2-mercapto-oxazolo[4,5-b]pyridine (8.2 g).
With PPA; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; dichloromethane; cyclohexane;
EXAMPLE 1 2-(5,6,7,8-Tetrahydronaphth-1-yl)oxazolo[4,5-b]pyridin A mixture of 15.5 g. (0.141 mole) of 2-amino-3-hydroxypyridine, 25.0 g. (0.141 mole) of <strong>[4242-18-6]5,6,7,8-tetrahydronaphthalen-1-carboxylic acid</strong> and 75 g. of polyphosphoric acid was placed in oil bath at about 100° C. and heated to 180° C. over a period of 70 minutes. The mixture was poured into 1 l. of ice-water and adjusted to pH 6 with solid sodium bicarbonate and finally to pH 10 with concentrated ammonium hydroxide. Methylene chloride (500 ml.) was added and stirring was continued for 2 hours. The aqueous phase was separated and extracted with 2 * 250 ml. of methylene chloride. The combined extracts were dried over magnesium sulfate, filtered, and concentrated to dryness to give 30.0 g. of product, m.p. 87°-90° C. Recrystallization from 300 ml. of cyclohexane gave 24.2 g. of 2-(5,6,7,8-tetrahydronaphth-1-yl)oxazolo[4,5-b]pyridin, m.p. 88°-91° C. Employing the procedure substantially as described in Example 1, but substituting for the 5,6,7,8-tetrahydronaphthalene-1-carboxylic used therein a molar equivalent of a carboxylic acid of formula: STR6 and a pyridine of formula: STR7 described in Table I, there are produced the 2-substituted oxazolo[4,5-b]pyridines also described in Table I in accordance with Equation I. STR8
A. Into a solution of 110.0 g of 2-amino-3-pyridinol in 250 ml of 10% aqueous sulfuric acid at 20 is bubbled a stream of chlorine gas so adjusted that only a few bubbles escape. The addition of 75.0 g of chlorine requires 2 hours. The mixture is cooled to 0 C., the pH adjusted to 5.5, and the whole extracted thoroughly with chloroform. The chloroform solution is washed with saturated aqueous sodium chloride, dried, and concentrated to give 125.4 g of 2-amino-5-chloro-3-pyridinol.
B. The 2-amino-5-bromo-3-pyridinol is prepared by dissolving 110.0 g of 2-amino-3-pyridinol in 250 ml of 95percent ethanol. The solution is cooled to about 5° C. and at that temperature is treated with 160 g of liquid bromine during 2 hours. The mixture is stirred for 1 hour after the addition is completed and then concentrated to give 170.6 g of 2-amino-5-bromo-3-pyridinol.
With PPA; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; hexane; water;
EXAMPLE 284 2-[3,5-di(t-butyl)phenyl]oxazolo[4,5-b]pyridine A mixture of 30 g. of polyphosphoric acid, 5.0 g. of 3,5-di(t-butyl)benzoic acid and 2.1 g. of 2-amino-3-hydroxypyridine, under nitrogen and with rapid stirring, was heated at 180 C. for 40 minutes. The mixture was poured into 500 ml. of an ice-water mixture. The mixture was adjusted to pH 8.0 with concentrated ammonium hydroxide and stirred until the precipitate was finely divided. The precipitate was collected on a filter, washed with 2 * 100 ml. of water, and dried. The crude product was dissolved in 200 ml. of n-hexane, treated with decolorizing carbon, filtered and concentrated to about 75 ml. On cooling, the product crystallized to give 3.5 g. of 2-[3,5-di(t-butyl)phenyl]oxazolo[4,5-b]pyridine, m.p. 154-156 C.
EXAMPLE 59 2-Ethyloxazolo [4,5-b]pyridine A mixture of 4.4 g. of 2-amino-3-hydroxypyridine, 10.4 g. of propionic anhydride and 15 g. of polyphosphoric acid was heated at 168 C. for 15 minutes. The reaction mixture was cooled slightly and poured into ice water and stirred until the polyphosphoric acid had decomposed. The solution was made alkaline with solid sodium bicarbonate and extracted with 150 ml. of methylene chloride. The dried methylene chloride solution was concentrated to dryness and the residue was dissolved in ether and filtered through aluminum oxide. From the ether filtrate there was obtained 1.2 g. of 2-ethyloxazolo[4,5-b]pyridine, m.p. 52-53 C.
a)Preparation of 2-amino-3-hydroxypyridine To a solution of <strong>[6332-56-5]2-hydroxy-3-nitropyridine</strong> (5 g, 45.4 mmol) in methanol(250 ml) was added 10% Pd/C (1 g). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5% MeOH/CH2Cl2) gave the desired product(3.2 g, 89%). 1H NMR (CD3OD): delta 6.96 (d, 1H), 6.90 (dd, 1H), 6.77 (d, 1H).
An nitrogen-purged 22 L 5-necked flask was charged with DMF ( 9L) followed by slow addition of 2-aminopyridin-3-ol (250.0 g, 2270 mmol) and stirred with mechanical overhead agitator at ambient temperature for 30 minutes to dissolve material. <n="44"/>60% Sodium hydride (87.17 g, 2180 mmol) was added in portions with vigorous stirring and a nitrogen sweep of the reaction vessel. The pot temperature rose from 16 C to 25 0C during the NaH addition. After the addition was complete, the reaction was stirred at ambient temperature for 60 minutes to ensure all NaH was consumed. 2,4-Dibromo-l-fluorobenzene (225.3 mL, 1816 mmol) was added and heated to 110 0C under nitrogen for 24 hours. The reaction was cooled to 60 0C and transferred to a 20 L flask and the majority of the DMF removed. The resultant sludge was diluted with IN NaOH (8 L) and EtOAc (8 L) and the mixture was passed through a plug of celite and washed with EtOAc. The layers were separated and the aqueous was extracted with EtOAc (4 L). The combined organic layers were washed with 1 N NaOH (4 L) and 50% saturated brine (4 L), water (2 L) and concentrated until solids started to form. Hexanes (4L) were added slowly and the mixture was concentrated to around 2 L volume. Hexanes (4 L) were added and the mixture was stirred for 1 hour to allow to cool to ambient temperature. The resulting slurry was filtered, dried on the filter and then dried under high vacuum overnight to afford 3-(2,4- dibromophenoxy)pyridin-2-amine (277.3 g, 44.4% yield).
44.4%
An inerted 22 L 5-necked round-bottomed flask was charged with DMF (9 L) followed by slow addition of 2-aminopyridin-3-ol (250.0 g, 2270.4 mmol) and stirred with mechanical overhead stirrer at room temperature for 30 minutes to dissolve material. 60% sodium hydride (87.174 g, 2179.6 mmol) was slowly added in portions with vigorous stirring and a nitrogen sweep of the reaction vessel and stirred at room temperature for 60 min to ensure all sodium hydride is consumed. 2,4-Dibromo-1-fluorobenzene (225.28 ml, 1816.3 mmol) was added and heated to 110 C under nitrogen overnight. The reaction was cooled to 60 C and transferred to a 20 L rotovap flask and the DMF removed (mostly) on high vacuum rotovap with a bath temperature of 45 C. The residue was diluted with 1N NaOH (8 L) and ethyl acetate (8 L) and the mixture was passed through a plug of Celite and washed with ethyl acetate. The layers were separated and the aqueous was extracted with ethyl acetate (4 L). The combined organic layers were washed with 1N NaOH (4 L) and 50% saturated brine (4 L), water (2 L) and concentrated on the rotovap until solids started to form and then 4L hexanes were added slowly and the mixture concentrated to 2 L volume and hexanes (4L) were added and the mixture was stirred for 1 h and cooled to room temperature. The resulting slurry was filtered, dried on the filter and then dried under high vacuum overnight to afford 3-(2,4-dibromophenoxy)pyridin-2-amine (277.4 g, 44.4% yield) as tan solids. 1H NMR (d6-DMSO) d ppm 7.95 (d, J = 2.3 Hz, 1H), 7.78 (dd, J = 4.9, 1.6 Hz, 1H), 7.55 (dd, J =8.8, 2.3 Hz, 1H), 6.96 (dd, J = 7.8, 1.6 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 6.52 (dd, J = 7.6, 4.9 Hz, 1H), 5.96 (br s, 2H); MS (acpi) m/e 345.0 (M+H)+.
In Scheme 90c, the oxazine (24) can be prepared from compound (22) using a similar strategy previously used for (21). Base catalyzed addition of (22) to [CHLOROACETIC] acid followed by cyclization affords intermediate (22). Compound (22) can undergo halogenation using bromine in an aprotic solvent such as DMF to give compound (24).
Step A: Preparation of 3-(5-bromo-2-chlorophenoxy)pyridin-2-amine: 4-2-aminopyridin-3-ol (7.56 g, 68.6 mmol) was added to a mixture of sodium hydride (1.72 g, 71.9 mmol) in DMF (20 mL) and stirred for 10 minutes. 4-Bromo-1-chloro-2-fluorobenzene (13.69 g, 65.4 mmol) was added and the reaction mixture was stirred at 100 C. for 38 hours. The reaction mixture was cooled to room temperature and partition between 1N NaOH and ether. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was triturated with hexanes to give 3-(5-bromo-2-chlorophenoxy)pyridin-2-amine (11.30 g, 57.7%) as a yellow solid.
In tetrahydrofuran; for 1h;Reflux; Inert atmosphere;
An oven dried round bottom flask was charged withdi(IH-imidazol-l-yl)methanimine (500 mg, 3.10 mmol),2-aminopyridin-3-01 (171 mg, 1.551 mmol) and anhydrousTHF (20 ml) at room temperature. The resulting suspensionwas refluxed under N2 for I hr. LC/MS indicated completeconsumption ofstarting material. The solvent was removed invacuo and the residue was used in the next step withoutfurther purification.
<strong>[37904-72-6]2-bromo-1-[4-(dimethylamino)phenyl]ethanone</strong> (300 mg, 1.2 mmol) and 2-amino-3-hydroxypyridine (114 mg, 1.0 mmol) were combined in EtOH (6 ml) under nitrogen. The reaction mixture was slowly heated to 75 C (starting at 45 C and temperature was increased by 10 C every 20 minutes) and stirred under reflux for 2 h. Sodium bicarbonate (150 mg, 1.8 mmol) was added after mixture was cooled. The resulting mixture was slowly heated to 75 C and stirred under reflux for 4 h. After mixture was cooled, the reaction was diluted 1 : 1 with 7 ml water. Product is pH sensitive and precipitated out upon addition of 5 N NaOH. The precipitate was collected by filtration, washed with water, and air dried under vacuum to afford a dark red/brown solid. The crude product was purified by gradient column chromatography (Si02, EtOAc:Hx = 1: 1 - EtOAc:Hx:MeOH = 1: 1 :0.5) and washed several times with CH2C12 yielding a light brown product (99 mg, 0.39 mmol, 39%). NMR (400 MHz, d6-DMSO)/£ (ppm): 2.90 (6H), 6.41 (1H, d, J= 7.6), 6.60 (1H, t, J= 7.6), 6.74 (2H, d, J= 9.2), 7.74 (2H, d, J= 8.8), 7.92 (1H, d, J= 6.0), 8.09 (1H, s). 13C NMR (100 MHz, d6-DMSO)/£(ppm): 150.3, 146.4, 144.5, 140.1, 128.9, 122.6, 118.3, 112.7, 108.4, 104.6, 40.5. HRMS: Calcd for [M+H]+, 254.1293; Found, 254.1293. UV-visible in EtOH: (/ x, epsilon (M' 1)) (282, 2.6 x 104), (322, 2.1 x 104). FTIR (KBr, cm"1): 3433 (s, br), 3127 (vw), 3105 (vw), 2890 (vw), 2800 (vw), 1613 (vs), 1547 (m), 1507 (s), 1491 (s, sh), 1442 (m), 1429 (m, sh), 1378 (m), 1359 (s), 1328 (w), 1298 (m), 1275 (m), 1256 (w), 1227 (w), 1206 (m), 1173 (w), 1131 (vw), 1098 (w), 1077 (vw), 1006 (vw), 993 (vw), 977 (vw), 962 (vw), 946 (w), 915 (vw), 901 (vw), 885 (vw), 855 (vw), 823 (w), 773 (w), 747 (m), 733 (w), 718 (vw), 669 (vw), 654 (vw), 638 (vw), 608 (vw).
With guanidine hydrochloride; In ethanol; at 35 - 40℃; for 2.5h;
General procedure: Amine (1 mmol) was added to a magnetically stirred solution of guanidine hydrochloride (15 mol%) and di-tert-butyl dicarbonate (1.2 mmol) in EtOH (1 mL), at 35-40C and stirred for appropriate time (Table 1). After completion of the reaction (followed by TLC or GC), EtOH was evaporated under vacuum and the residue either was washed with water to remove the catalyst or was dissolved in CH2Cl2 (or EtOAc) and filtered off to separate out the catalyst. Evaporation of the organic solvent (if used in work up) gives almost a pure product. In the cases of using an excess (Boc)2O the product was washed with petroleum ether or hexane to recover the residual (Boc)2O. If necessary, the product was further purified either by crystallization (hexane and dichloromethane, or diethyl ether and petroleum ether) or silica gel column chromatography using EtOAc-hexane (1: 6) as eluent.
With potassium hydroxide; In ethanol; at 90.0℃; for 2h;
A solution of 2-aminopyri din-3 -ol (3.00 g, 27.24 mmol), carbon disulfide (41.45 g, 544.8 mmol), and potassium hydroxide (5.40 g, 96.24 mmol) in ethanol (50 mL) was stirred for 2 h at 90 C. The reaction was then quenched by the addition of 150 mL of water. The resulting solution was extracted with 3x150 mL of ethyl acetate. The pH value of the combined aqueous layers was adjusted to 6 with 6 M aqueous HC1 solution and then extracted with 3x150 mL of ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate, filtered, and concentrated to give oxazolo[4,5-b]pyridine-2-thiol (3.0 g, 71%) as a red solid. MS: (ESI, m/z): 153[M+H]+.
67%
With potassium hydroxide; In ethanol; for 10h;Reflux;
In a 100 ml round bottom flask was placed 2- amino-3-hydroxy pyridine (2.20g, 20 mmol) and 40 ml of absoluteethanol was added and the mixture was stirred for 15minutes. In the meanwhile, 2.0g (29 mmol) KOH pelletswere powdered and transferred into the flask followed by theaddition of 15 ml of carbon disulfide. The resulting mixturewas refluxed over an oil bath for 8 hours when a yellowprecipitate appeared. The contents of the flask were cooledto room temperature. The solvent was rotary evaporated andthe residue was transferred in to a beaker and 75 ml of waterwas added followed by neutralization with acetic acid. Theprecipitated product was filtered under vacuum and washedwith 3x50 ml of water and dried under vacuum over night toyield 2.1g of light yellow solid product (yield, 65%).
With potassium carbonate; In N,N-dimethyl-formamide; at 95℃;
3-amino-4-hydroxypyridine 2.18g (0.02 mol) and 4,6-dimethoxypyrimidine-2-yl methyl sulfone g (0.02 mol) were dissolved in DMF 100 ml, and K2CO3 3.3g (1.2 eq) was added thereto. Then, the temperature was maintained at 95C while the mixture was stirred over night. The reacted solution was added to water 100 ml, extracted with diethyl ether, dried with MgSO4, and distilled under reduced pressure to obtain residue. Through purification with silica gel column chromatography, a solid material 4.02g (81%) was obtained: 1H NMR (CDCl3); 3.73 (s, 6H), 5.49 (s, 1H), 6.51 (s, 2H), 6.75-7.50 (m, 3H).
General procedure: To 34 mL of polyphosphoric acid (1.5 g/mmol of limiting reagent)was added 2-amino-3-hydroxypyridine (1.0 eq) and the relevant benzoic acid (1.1 eq). The mixture was heated to 180 C and stirred for 4 h, cooled and poured into 5 M sodium hydroxide. The resulting precipitate was filtered and recrystallised from ethyl acetate to give the desired benzoxazole core.
General procedure: To 34 mL of polyphosphoric acid (1.5 g/mmol of limiting reagent)was added 2-amino-3-hydroxypyridine (1.0 eq) and the relevant benzoic acid (1.1 eq). The mixture was heated to 180 C and stirred for 4 h, cooled and poured into 5 M sodium hydroxide. The resulting precipitate was filtered and recrystallised from ethyl acetate to give the desired benzoxazole core.
General procedure: To 34 mL of polyphosphoric acid (1.5 g/mmol of limiting reagent) was added 2-amino-3-hydroxypyridine (1.0 eq) and the relevant benzoic acid (1.1 eq). The mixture was heated to 220 C and stirred for 4 h, cooled and poured into 10% sodium bicarbonate solution. The suspension was stirred until gas evolution ceased, then filtered and washed with water. The aqueous medium was extracted three times with ethyl acetate. The combined organic layers were then washed with brine, dried with sodium sulphate and the solvent was removed in vacuo. Purification by column chromatography on silica gel, eluting cyclohexane/ethyl acetate 20-50% to give the desired benzoxazole core.
General procedure: To 34 mL of polyphosphoric acid (1.5 g/mmol of limiting reagent) was added 2-amino-3-hydroxypyridine (1.0 eq) and the relevant benzoic acid (1.1 eq). The mixture was heated to 220 C and stirred for 4 h, cooled and poured into 10% sodium bicarbonate solution. The suspension was stirred until gas evolution ceased, then filtered and washed with water. The aqueous medium was extracted three times with ethyl acetate. The combined organic layers were then washed with brine, dried with sodium sulphate and the solvent was removed in vacuo. Purification by column chromatography on silica gel, eluting cyclohexane/ethyl acetate 20-50% to give the desired benzoxazole core.
General procedure: To 34 mL of polyphosphoric acid (1.5 g/mmol of limiting reagent) was added 2-amino-3-hydroxypyridine (1.0 eq) and the relevant benzoic acid (1.1 eq). The mixture was heated to 220 C and stirred for 4 h, cooled and poured into 10% sodium bicarbonate solution. The suspension was stirred until gas evolution ceased, then filtered and washed with water. The aqueous medium was extracted three times with ethyl acetate. The combined organic layers were then washed with brine, dried with sodium sulphate and the solvent was removed in vacuo. Purification by column chromatography on silica gel, eluting cyclohexane/ethyl acetate 20-50% to give the desired benzoxazole core.
General procedure: To 34 mL of polyphosphoric acid (1.5 g/mmol of limiting reagent)was added 2-amino-3-hydroxypyridine (1.0 eq) and the relevant benzoic acid (1.1 eq). The mixture was heated to 180 C and stirred for 4 h, cooled and poured into 5 M sodium hydroxide. The resulting precipitate was filtered and recrystallised from ethyl acetate to give the desired benzoxazole core.
4-chloro-3-(oxazolo[4,5-b]pyridin-2-yl)benzenamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
20%
With polyphosphoric acid; at 220℃; for 4h;
To 34 mL of polyphosphoric acid (1.5 g/mmol of limiting reagent) was added 2-amino-3-hydroxypyridine (1.0 eq) and the relevant benzoic acid (1.1 eq). The mixture was heated to 220 °C and stirred for 4 h, cooled and poured into 10percent sodium bicarbonate solution. The suspension was stirred until gas evolution ceased, then filtered and washed with water. The aqueous medium was extracted three times with ethyl acetate. The combined organic layers were then washed with brine, dried with sodium sulphate and the solvent was removed in vacuo. Purification by column chromatography on silica gel, eluting cyclohexane/ethyl acetate 20-50percent to give the desired benzoxazole core.
General procedure: To 34 mL of polyphosphoric acid (1.5 g/mmol of limiting reagent)was added 2-amino-3-hydroxypyridine (1.0 eq) and the relevant benzoic acid (1.1 eq). The mixture was heated to 180 C and stirred for 4 h, cooled and poured into 5 M sodium hydroxide. The resulting precipitate was filtered and recrystallised from ethyl acetate to give the desired benzoxazole core.
With sodium hydroxide; In chloroform; water; toluene; at 74 - 88℃;Industrial scale;
In 2L to three-opening bottle 810g30% of aqueous sodium hydroxide solution and 110g2-amino-3-hydroxy-pyridine, stirring to dissolve, will 340g triphosgene is dissolved in 600 ml of toluene and 300 ml chloroform solution; to the slow heating three-mouth bottle 80 C rear, dropping the toluene and the chloroform solution of triphosgene, the reaction temperature is controlled at 74 the [...] 88 C between, the end of the dropping reaction 8 hours; cooling to the 20 [...] 30 C, reaction with hydrochloric acid or sodium hydroxide to adjust PH value is neutral, to continue to lower the temperature to 10 C the following, a filter, a water washing of the filter cake, drying the white solid obtained oxazole [4,5-b] pyridine -2 (3H) ketone 91.4g, the yield is 86.2%, after separating the filtrate, dry recovery of toluene and chloroform
15.6 g (141.6 mmol) of 2-amino-3-hydroxypyridine are initially charged in 300 ml of glacial acetic acid, 15.6 g (141.6 mmol) of 2-amino-3-hydroxypyridine are initially charged in 300 ml of glacial acetic acid, [0294] 5.1 g of 5% rhodium/ carbon catalyst are added and the mixture is hydrogenated in a 600 ml vessel (material: Hastelloy) at room temperature (20 C.) at 4.5 bar for about 16 hours. The entire reaction mixture is then filtered (removal of the catalyst) and concentrated under reduced pressure, and the residue that remains is recrystallized from an ethanol/ether mixture. This gives 5.9 g (23.9% of theory) of a (2:1) mixture of 2-amino-3-hydroxypyridine and 2-amino-3,4,5,6-tetrahydropyridin-2-ol acetate CH NMR spectrum: some Py-H) which can be used for the next reaction. [0295] 1H NMR (600 MHz, D2O) delta 1.79 (br., m, 1H), 1.90-1.92 (m, 1H), 1.99-2.00 (br., m, 1H), 2.22 (br., m, 1H), 3.37 (m, 2H), 4.52 (m, 1H), 6.77-6.78 (m, 1H), 7.18-7.19 (m, 1H), 7.28-7.29 (m, 1H) ppm; At room temperature, 1.0 g (5.74 mmol) of the (2:1) mixture of 2-amino-3-hydroxypyridine and 2-amino-3,4,5,6-tetrahydropyridin-2-ol acetate (cf. step 1) are stirred with 1.26 g (7.79 mmol) of 1,1?-carbonyldiimidazole (CDI), 39.9 mg of 4-dimethylaminipyridine (DMAP) in 6 ml of dichloromethane, and 1.2 ml of triethylamine are added. The entire reaction mixture is then stirred at room temperature for another about 24 hours. The reaction mixture is then concentrated under reduced pressure, the residue that remains is taken up in ethyl acetate and the organic phase is washed with water. The organic phase is separated off and then dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue that remains is purified chromatographically by medium-pressure chromatography (cyclohexane/acetone gradient). This gives 753.0 mg (93.2% of theory) of a mixture of oxazolo[4,5-b]-5,6,7,7a-tetrahydropyridin-2(4H)-one [0301] and oxazolo[4,5-b]pyridin-2(3H)-one (cf. WO 2010/135014 A1) (1H NMR spectrum: some Py-H and LC-MS m/z: 137.0) which can be used for the next reaction. [0302] LC-MS (ESI positive): m/z found: 141.0 [M++H]. [0303] C6H8N2O2 calculated: 140.0.
Step-1 [0134] To a stirred solution of 2-amino 3-hydroxy pyridine 1 (2 g, 16.26 mmol) in THF (20 ml) was added CDI (2.63 g, 16.26 mmol) and the total reaction mass stirred at reflux temperature for 16 h. Reaction mass was cooled to room temperature, THF was distilled and the crude material was partitioned between water and ethyl acetate. The organic layer was separated, dried over sodium sulphate and concentrated under vacuum to afford the desired compound 2 (0.5 g)
With C8Br6O2; sodium hydroxide; In dichloromethane; at 20℃; for 20h;
The flask was dissolved in sodium hydroxide (6g, 0.150 mol) in water (10 mL) and methylene chloride (15 mL), stirred and then added dropwise to 2-amino-3-hydroxypyridine little by little, tetrabromophthalic bromide ( by adding 156 mg, 0.48 mmol) and the mixture was stirred at room temperature for 15 minutes. 3-fluorobenzyl bromide dissolved in methylene chloride (10 mL) was slowly added dropwise to the reaction mixture with stirring at room temperature, and stirred for 20 hours. After completion of the reaction, the organic layer was separated and an aqueous layer, allows to extract the water layer with methylene chloride. All combined, and the organic layer is concentrated under reduced pressure after drying with sodium sulfate and filtered under reduced pressure. By separation and purification of the residue by column chromatography (ethyl acetate / n-hexane = 1/2) to obtain 2.46 g of the desired compound in a yield of 70.1%.
70%
General procedure: Sodium hydroxide (6 g, 0.15 mol)was dissolved in water (10 mL) and mixed with dichloromethane (15 mL). 2-Amino-3-hydroxypyridine (6, 3 g, 27.24 mmol) was added to the reaction mixture in portions, under stirring, followed by the catalyst, tetrabutylammonium bromide (156 mg, 0.48 mmol). The reaction mixture was stirred for 15 min at 25-30 C, and treated with a solution of the appropriate benzyl bromide derivative (5.4 g, 28.61 mmol) in dichloromethane (10 mL). The reaction mixture was stirred 18 h at 25 C and then diluted with water (15 mL). The organic phase was separated, and the aqueous phase was extracted with dichloromethane.The organic extracts were combined, washed with water and brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography (SiO2, EA/n-Hex 1/2). For 3-(benzyloxy)pyridin-2-amine 7a, it has been purchased from Alfa Aesar Co. 4.1.1.1. 3-(3-fluorobenzyloxy)pyridin-2-amine (7b). Light pink solid,yield: 70%, 1H NMR (400 MHz, CDCl3) delta 4.68 (2H, brs, NH2), 5.06(2H, s, OCH2Ph), 6.58 (1H, dd, J = 5.1 Hz, 7.8 Hz, ArH), 6.93 (1H, dd,J = 1.1 Hz, 7.8 Hz, ArH), 7.04 (1H, td, J = 2.4 Hz, 8.4 Hz ArH), 7.14 (1H,dd, J = 2.0 Hz, 9.4 Hz, ArH), 7.18 (1H, d, J = 7.6 Hz, ArH), 7.36 (1H, td,J = 5.8 Hz, 8.0 Hz, ArH), 7.69 (1H, dd, J = 1.3 Hz, 5.1 Hz, ArH).
2-[(3,5-dinitropyridin-2-yl)amino]pyridin-3-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With triethylamine; In methanol; at 20℃;
General procedure: Triethylamine (0.42 ml, 3 mmol) was added to a solution of 1 (0.6 g, 1 mmol) and corresponding o-aminophenol (3 mmol) in MeOH (30 ml). The reaction mixture was stirred at room temperature for 1-2 h (TLC monitoring). Then the mixture was poured into water (150 ml) and acidified with HCl to pH 5-6. The precipitate was filtered off, washed with water and dried in air.
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