* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With potassium hydroxide In water at 70℃; for 12 h;
General procedure: The compound 1,2-HOPO-6-carboxylic acid was synthesized following the method developed by Xu [34] with minor modifications. As depicted in Scheme 1 , this synthesis method consists of two main successive steps. The detailed preparation route is described as follows. A solution of 6-hydroxy-picolinic acid was prepared by dissolving 5 g (0.036 mol) of 6-hydroxy-picolinic acid in a mixture of trifluoroacetic acid (30 mL) and glacial acetic acid (10 mL). A mixture of acetic anhydride (30 mL) and 30percent H2O2 solution (10 mL) was prepared while cooling in an ice bath; this mixture was stirred for 4 h in order that a peracetic acid solution was formed. The 6-hydroxy-picolinic acid solution was added to this peracetic solution. The reaction mixture was then refluxed with stirring at 80 °C for 10 h, yielding a white precipitate. The excess trifluoroacetic acid was removed by vacuum distillation. The precipitate was filtered, washed with cold methanol and then dried. The product was a pinkish white solid of the compound 1,6-dihydroxy picolinic acid, yielding 4.63 g (82percent); mp 209-210 °C. IR (KBr pellet): ν/cm-1 3440 (br, O-H stretch); 1734.7 (br, C=O stretch); 1211.1 (m, C-O stretch); 926.4 (br, O-H oop). H1 NMR (DMSO-d6): δ 7.42 (t, 1H, J = 8.8, 7.1 Hz); 6.64 (q, 2H, J = 7, 6.8 Hz); 3.43 (s, 1H, O-H). This compound was subsequently used as a precursor for the synthesis of 1,2-HOPO-6-carboxylic acidas follows. A solution of 1,6-dihydroxy picolinic acid was prepared by dissolving 4.63 g (0.029 mol) of 1,6-dihydroxy picolinic acid in 135 mL of 20percent KOH(aq). This basic solution was refluxed at 70 °Cfor 12 h. The product was precipitated with 50 mL of cold concentrated HCl in an ice bath to keep the temperature below 20 °C throughout the process. A white precipitate was filtered and washed with 0.1 M HCl(aq), cold methanol and cold water successively. The product was dried under vacuum to yield 4.37 g (95percent); mp 217–218 °C [42]. IR (KBr pellet): m/cm-1 3437.4 (br, O-H stretch); 1785.9 (br, C=O stretch); 1618.4 (m, C=O stretch); 929.7 (br, C-H deformation oop). H1 NMR (DMSO-d6): δ 7.43 (dd, 1H, J = 7, 9 Hz); 6.71 (dd, 1H, J = 1.6, 9 Hz); 6.64 (dd, 1H, J = 1.6, 7 Hz). MS (ESI-negative mode): m/z 154.01 (C6H4NO-4 ).
Reference：
[1] Journal of Molecular Structure, 2013, vol. 1031, p. 144 - 151
2
[ 19621-92-2 ]
[ 94781-89-2 ]
Yield
Reaction Conditions
Operation in experiment
77%
at 80℃; for 12 h;
Using a modified version of a literaturemethod [60], to a suspensionof 6-hydroxypicolinic acid 12 (26.20 g, 188 mmol) in glacial acetic acid(160 mL) was carefully added peroxyacetic acid (36–40percent, 80 mL). Thetemperature was carefully raised to 80 °C and stirring was continuedfor 12 h. The flask was allowed to cool to room temperature and theresulting solid precipitate was collected by filtration and washed withdiethyl ether, affording the title compound 13 as a cream solid(18.17 g, 77percent). Mp 223–226 °C (from AcOH, Lit [64]. 216 °C).vmax(neat)/cm−1 3114 (O\\H), 1611 (CO), 1505 (CO), 1198.δH(399.8 MHz, DMSO-d6) 6.65 (1H, dd, J 7.3, 1.8, 3-H), 6.73 (1H, dd, J9.2, 1.8, 5-H), 7.46 (1H, dd, J 8.7, 6.9, 4-H). δC(100.5 MHz, DMSO-d6)106.8 (ArC), 120.8 (ArC), 137.3 (ArC), 139.5 (quat), 157.7 (quat),162.4 (quat).
77%
at 80℃; for 12 h;
To a suspension of 6-hydroxypicolinic acid [4] (26.20 g, 188 mmolj having the formula: in glacial acetic acid (160 mU was carefully added peroxyacetic acid (36—40 percent, 80 mU. The temperature was carefully raised to 80 °C and stirring was continued for 12 hours. The flask was allowed to cool to room temperature and the resulting solid precipitate was collected by filtration and washed with diethyl ether, affording 1 -Hydroxy-6-oxo- 1,6-dihydropyridine-2 -carb oxylic acid [5] as a cream solid (18.17 g, 77 percentJ, having the formula:
73%
With peracetic acid; acetic acid; trifluoroacetic acid In water at 20 - 80℃; for 11 h;
An alternative route is described below; Acetic anhydride ( 100 ml) was mixed with 0 30percent hydrogen peroxide solution (25 ml) with cooling, the mixture was stirred for 3 hr until a homogenous peracetic acid solution formed To a solution of 6-hydroxy-picolinic acid <n="59"/>(Fluka, 25 g, 0 18 mol) in a mixture of trifluoroacetic acid ( 150 mL) and glacial acetic acid ( 100 mL), the above peracetic acid solution was added slowly with stirring (CAUTION 1 any solid particle in the mixture will caused vigorous oxygen release and lead to out of control of the reaction) The mixture stirred at room temperature for one 1 hr, and heated slowly to 75 0C and kept at 80 0C (oil bath temperature) for 10 hr White precipitate formed during this period, it was collected by filtration, washed with cold methanol, and dried in a vacuum oven, yield 20 5 g (0 132 mol, 73percent) mp 176- 177 0C [0218] 1 H NMR(300MHz, DMSO-^5) δ 6 634(dd, Jorthro = 7 Hz, Jmeta = 1 5 Hz, IH),6 710(dd, Jorthro=9, Jme,a= 7 Hz, IH) 13C NMR(75 MHz, DMSO-?r) δ 106 9, 120 6, 135 0, 137 3, 157 4, 163 3 IR (KBr pellet) v 1734 (br, C=O), 1616(m, C=O) cm ' Anal Calcd (Found) for C6H5NO4 (F W 155 15) C, 46 46 (46 31 ), H, 3 25 (3 45), N, 9 03 (9 12)
73%
Stage #1: at 20 - 80℃; for 11 h; Stage #2: With potassium hydroxide In water at 80℃; for 6 h; Stage #3: With hydrogenchloride In water
Acetic anhydride (100 mL) was mixed with 30percent H2O2 solution (25 mL) with cooling. The mixture was stirred for 4 h until a homogenous peracetic acid solution formed. This peracetic acid solution was added slowly with stirring to a solution of 6- hydroxy-picolinic acid (Fluka, 25 g, 0.18 mol) in a mixture of trifluoroacetic acid (150 mL) and glacial acetic acid (100 mL) (CAUTION. solid particles in the mixture cause vigorous oxygen evolution and can lead to an uncontrolled reaction). The mixture was stirred at room temperature for 1 h, and then heated slowly to 80 0C (oil bath temperature) and kept at 80 0C for 10 h. A white precipitate formed during this period, which was collected by filtration, washed with cold methanol, and dried. It was dissolved in aqueous 10percent KOH, heated to 80 0C for 6 hours, and re-precipitated with concentrated HCl. The product was collected by filtration, washed with water and dried in a vacuum oven. Yield 20.5 g (0.132 mol, 73percent). mp 176-177 0C. Anal. Calc'd. (Found) for C6H5NO4 (F.W. 155.15): C, 46.46 (46.31); H, 3.25 (3.45), N, 9.03 (9.12). 1H NMR (500 MHz, DMSO-Cl6): δ 6.63 (dd, J = 7.0, 1.5 Hz, IH), 6.71 (dd, J = 9.2, 1.5 Hz, IH), 7.43 (dd, J = 9.0, 7.1 Hz, I H). 13C NMR (125MHz, DMSO- d6): 5106.9, 120.5, 134.9, 137.3, 157.4, 163.3. IR (KBr pellet): 1734 cm" 1 (br, C=O); 1616 cm' 1 (m, C=O).
Reference：
[1] Chemical Communications, 2017, vol. 53, # 61, p. 8529 - 8532
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 11, p. 4849 - 4860
[3] Journal of Inorganic Biochemistry, 2016, vol. 160, p. 49 - 58
[4] Patent: WO2016/79502, 2016, A1, . Location in patent: Page/Page column 22 ; 23
[5] Journal of Medicinal Chemistry, 2002, vol. 45, # 18, p. 3963 - 3971
[6] Patent: WO2008/8797, 2008, A2, . Location in patent: Page/Page column 57-58
[7] Patent: WO2007/121453, 2007, A2, . Location in patent: Page/Page column 108
[8] Journal of Molecular Structure, 2013, vol. 1031, p. 144 - 151
[9] Patent: WO2017/105565, 2017, A2, . Location in patent: Paragraph 0109
3
[ 94781-88-1 ]
[ 94781-89-2 ]
Yield
Reaction Conditions
Operation in experiment
86.4%
Stage #1: With potassium hydroxide In water at 80℃; Stage #2: With hydrogenchloride In water at 0℃;
l-Hydroxy-6-carboxy-2(lJ?)pyridinone; A 10 1-g (0 046 mol) portion of 2-bromopyπdine-6-carboxylicAcid was dissolved in 5 175 mL of a 10percent aqueous KOH solution, and the resulting solution was maintained at 80 'C overnight and then cooled in an ice bath and treated with 85 mL of concentrated HC l The white suspended solid was isolated by filtration, washed with dilute HC l followed by three 15 mL portions of water, and then dried in vacuo yielding 6 21 g (86 4percent), mp 216 0C dec
Reference：
[1] Patent: WO2008/8797, 2008, A2, . Location in patent: Page/Page column 57
[2] Journal of the American Chemical Society, 2015, vol. 137, # 8, p. 2816 - 2819
Reference：
[1] Journal of the American Chemical Society, 2015, vol. 137, # 8, p. 2816 - 2819
7
[ 100-44-7 ]
[ 94781-89-2 ]
[ 210366-15-7 ]
Yield
Reaction Conditions
Operation in experiment
91%
Stage #1: With potassium carbonate In methanol for 16 h; Heating / reflux Stage #2: With hydrogenchloride In water
l-Benzyloxy-6-carboxy-2(lJ/)-pyridinone (1,2-HOPOBn acid); l -Hydroxy-6-carboxy-2(l H)-pyπdinone (15 5 g, 0 1 mol) and anhydrous potassium carbonate (27 6 g, 0 2 mol) were mixed with benzyl chloride (15 2 g, 0 12 mol) in methanol (250 mL) The mixture was refluxed for 16 h, filtered, and the filtrate evaporated to dryness The residue was dissolved in water (50 ml ) and acidified with 6 N HCl to pH 2 The white precipitate was isolated by filtration, washed with cold water, and dried in vacuum to yield 22 3 g (91 percent) of l -Benzyloxy-6-carboxy-2( l //)-pyπdinone, mp 176- 177 0C[0220] 1 H NMR(300MHz, CDCI3) δ 5 269(s, 2H), 6 546(dd, J=I 6 Hz, J= 6 7 Hz, I H),6 726(dd, J=I 6Hz, J=9 2 Hz, I H), 7 39-7 51 (m, 6H) 1 3C NMR(75 MHz, DMSO-*) δ 77 9, 106 0, 124 1 , 128 5, 129 1 , 129 6, 133 8, 138 7, 140 5, 157 7, 161 7 Anal Calcd (Found) for C13H1 1NO4 C, 63 66 (63 75), H, 4 53 (4 55), N, 5 71 (5 52)
91%
Stage #1: With potassium carbonate In methanol for 16 h; Heating / reflux Stage #2: With hydrogenchloride In water
(3) Synthesis of l-Benzyloxy-6-carboxy-2(lH)-pyridinone 36A[0370] 35A (15.5 g, 0.1 mol) and anhydrous potassium carbonate (27.6 g, 0.2 mol) was mixed with benzyl chloride (15.2 g, 0.12 mol) in methanol (250 mL). The mixture was refluxed for 16 h, filtered, and the filtrate was evaporated to dryness. The residue was dissolved in water (50 mL) and acidified with 6 N HCl to pH 2. The resulting white precipitate was isolated by filtration, washed with cold water, and dried in vacuum to yield 22.3 g (91 percent) of 36A, mp 176-177 0C. Anal. Calc'd. (Found) for C13H1 1NO4: C, 63.66 (63.75); H, 4.53 (4.55), N, 5.71 (5.52). 1H NMR (500MHz, DMSO-d6): δ 5.26 (s, 2H, CH2), 6.54 (dd, J = 6.7, 1.1 Hz, 1 H), 6.73 (dd, J = 9.2, 1.6Hz, 1 H), 7.39-7.51 (m, 6 H). 13C NMR (125MHz, DMSO-dβ): δ 77.9, 106.0. 124.1. 128.5, 129.1 , 129.6, 133.8, 138.7, 140.4, 157.6, 161.7.
Reference：
[1] Journal of Medicinal Chemistry, 2014, vol. 57, # 11, p. 4849 - 4860
[2] Journal of Medicinal Chemistry, 2002, vol. 45, # 18, p. 3963 - 3971
[3] Patent: WO2008/8797, 2008, A2, . Location in patent: Page/Page column 58
[4] Patent: WO2007/121453, 2007, A2, . Location in patent: Page/Page column 108
[5] Patent: WO2017/105565, 2017, A2, . Location in patent: Paragraph 0109
8
[ 100-39-0 ]
[ 94781-89-2 ]
[ 210366-15-7 ]
Reference：
[1] Journal of the American Chemical Society, 2015, vol. 137, # 8, p. 2816 - 2819
9
[ 94781-89-2 ]
[ 210366-15-7 ]
Reference：
[1] Journal of Labelled Compounds and Radiopharmaceuticals, 2001, vol. 44, # 1, p. 13 - 19
To a suspension of acid 13 (15.73 g, 101 mmol) in methanol(200 mL) at 0 C was added thionyl chloride (31.00 g, 426 mmol)dropwise. The mixture was heated under reflux for 4 h. The solutionwas then allowed to cool to room temperature and the solvent was removedin vacuo to afford the title compound 14 as a cream solid(16.47 g, 96%). Mp 106-108 C (from MeOH, Lit [64]. 90-92 C).vmax(neat)/cm-1 3115 (OH), 1732 (CO), 1505 (CO), 1204.deltaH(399.8 MHz, DMSO-d6) 3.87 (3H, s, CO2CH3), 6.53 (1H, dd, J 6.9, 1.4,3-H), 6.69 (1H, dd, J 9.2, 1.4, 5-H), 7.45 (1H, dd, J 9.2, 6.9, 4-H).deltaC(100.5 MHz, DMSO-d6) 53.8 (CO2CH3), 105.8 (ArC), 122.6 (ArC),137.8 (ArC), 138.8 (quat), 158.1 (quat), 161.4 (quat).
96%
With thionyl chloride; for 4h;Reflux;
To a suspension of acid [5] (15.73 g, 101 mmolj in methanol (200 mU at 0 C was added thionyl chloride (31.00 g, 426 mmolj dropwise. The mixture was heated under reflux for 4 hours. The solution was then allowed to cool to room temperature and the solvent was removed in vacuo to afford methyl 1- hydroxy-6-oxo-1,6-dihydropyridine-2-carboxylate [6] as a cream solid (16.47 g, 96 %J, having the formula:
With peracetic acid; acetic acid; at 80℃; for 12h;
Using a modified version of a literaturemethod [60], to a suspensionof 6-hydroxypicolinic acid 12 (26.20 g, 188 mmol) in glacial acetic acid(160 mL) was carefully added peroxyacetic acid (36-40%, 80 mL). Thetemperature was carefully raised to 80 C and stirring was continuedfor 12 h. The flask was allowed to cool to room temperature and theresulting solid precipitate was collected by filtration and washed withdiethyl ether, affording the title compound 13 as a cream solid(18.17 g, 77%). Mp 223-226 C (from AcOH, Lit [64]. 216 C).vmax(neat)/cm-1 3114 (OH), 1611 (CO), 1505 (CO), 1198.deltaH(399.8 MHz, DMSO-d6) 6.65 (1H, dd, J 7.3, 1.8, 3-H), 6.73 (1H, dd, J9.2, 1.8, 5-H), 7.46 (1H, dd, J 8.7, 6.9, 4-H). deltaC(100.5 MHz, DMSO-d6)106.8 (ArC), 120.8 (ArC), 137.3 (ArC), 139.5 (quat), 157.7 (quat),162.4 (quat).
77%
With peroxyacetic acid; acetic acid; at 80℃; for 12h;
To a suspension of 6-hydroxypicolinic acid [4] (26.20 g, 188 mmolj having the formula: in glacial acetic acid (160 mU was carefully added peroxyacetic acid (36-40 %, 80 mU. The temperature was carefully raised to 80 C and stirring was continued for 12 hours. The flask was allowed to cool to room temperature and the resulting solid precipitate was collected by filtration and washed with diethyl ether, affording 1 -Hydroxy-6-oxo- 1,6-dihydropyridine-2 -carb oxylic acid [5] as a cream solid (18.17 g, 77 %J, having the formula:
73%
With peracetic acid; acetic acid; trifluoroacetic acid; In water; at 20 - 80℃; for 11h;Product distribution / selectivity;
An alternative route is described below; Acetic anhydride ( 100 ml) was mixed with 0 30% hydrogen peroxide solution (25 ml) with cooling, the mixture was stirred for 3 hr until a homogenous peracetic acid solution formed To a solution of 6-hydroxy-picolinic acid <n="59"/>(Fluka, 25 g, 0 18 mol) in a mixture of trifluoroacetic acid ( 150 mL) and glacial acetic acid ( 100 mL), the above peracetic acid solution was added slowly with stirring (CAUTION 1 any solid particle in the mixture will caused vigorous oxygen release and lead to out of control of the reaction) The mixture stirred at room temperature for one 1 hr, and heated slowly to 75 0C and kept at 80 0C (oil bath temperature) for 10 hr White precipitate formed during this period, it was collected by filtration, washed with cold methanol, and dried in a vacuum oven, yield 20 5 g (0 132 mol, 73%) mp 176- 177 0C [0218] 1 H NMR(300MHz, DMSO-^5) delta 6 634(dd, Jorthro = 7 Hz, Jmeta = 1 5 Hz, IH),6 710(dd, Jorthro=9, Jme,a= 7 Hz, IH) 13C NMR(75 MHz, DMSO-?r) delta 106 9, 120 6, 135 0, 137 3, 157 4, 163 3 IR (KBr pellet) v 1734 (br, C=O), 1616(m, C=O) cm ' Anal Calcd (Found) for C6H5NO4 (F W 155 15) C, 46 46 (46 31 ), H, 3 25 (3 45), N, 9 03 (9 12)
73%
Acetic anhydride (100 mL) was mixed with 30% H2O2 solution (25 mL) with cooling. The mixture was stirred for 4 h until a homogenous peracetic acid solution formed. This peracetic acid solution was added slowly with stirring to a solution of 6- hydroxy-picolinic acid (Fluka, 25 g, 0.18 mol) in a mixture of trifluoroacetic acid (150 mL) and glacial acetic acid (100 mL) (CAUTION. solid particles in the mixture cause vigorous oxygen evolution and can lead to an uncontrolled reaction). The mixture was stirred at room temperature for 1 h, and then heated slowly to 80 0C (oil bath temperature) and kept at 80 0C for 10 h. A white precipitate formed during this period, which was collected by filtration, washed with cold methanol, and dried. It was dissolved in aqueous 10% KOH, heated to 80 0C for 6 hours, and re-precipitated with concentrated HCl. The product was collected by filtration, washed with water and dried in a vacuum oven. Yield 20.5 g (0.132 mol, 73%). mp 176-177 0C. Anal. Calc'd. (Found) for C6H5NO4 (F.W. 155.15): C, 46.46 (46.31); H, 3.25 (3.45), N, 9.03 (9.12). 1H NMR (500 MHz, DMSO-Cl6): delta 6.63 (dd, J = 7.0, 1.5 Hz, IH), 6.71 (dd, J = 9.2, 1.5 Hz, IH), 7.43 (dd, J = 9.0, 7.1 Hz, I H). 13C NMR (125MHz, DMSO- d6): 5106.9, 120.5, 134.9, 137.3, 157.4, 163.3. IR (KBr pellet): 1734 cm" 1 (br, C=O); 1616 cm' 1 (m, C=O).
l-Benzyloxy-6-carboxy-2(lJ/)-pyridinone (1,2-HOPOBn acid); l -Hydroxy-6-carboxy-2(l H)-py?dinone (15 5 g, 0 1 mol) and anhydrous potassium carbonate (27 6 g, 0 2 mol) were mixed with benzyl chloride (15 2 g, 0 12 mol) in methanol (250 mL) The mixture was refluxed for 16 h, filtered, and the filtrate evaporated to dryness The residue was dissolved in water (50 ml ) and acidified with 6 N HCl to pH 2 The white precipitate was isolated by filtration, washed with cold water, and dried in vacuum to yield 22 3 g (91 %) of l -Benzyloxy-6-carboxy-2( l //)-py?dinone, mp 176- 177 0C[0220] 1 H NMR(300MHz, CDCI3) delta 5 269(s, 2H), 6 546(dd, J=I 6 Hz, J= 6 7 Hz, I H),6 726(dd, J=I 6Hz, J=9 2 Hz, I H), 7 39-7 51 (m, 6H) 1 3C NMR(75 MHz, DMSO-*) delta 77 9, 106 0, 124 1 , 128 5, 129 1 , 129 6, 133 8, 138 7, 140 5, 157 7, 161 7 Anal Calcd (Found) for C13H1 1NO4 C, 63 66 (63 75), H, 4 53 (4 55), N, 5 71 (5 52)
91%
(3) Synthesis of l-Benzyloxy-6-carboxy-2(lH)-pyridinone 36A[0370] 35A (15.5 g, 0.1 mol) and anhydrous potassium carbonate (27.6 g, 0.2 mol) was mixed with benzyl chloride (15.2 g, 0.12 mol) in methanol (250 mL). The mixture was refluxed for 16 h, filtered, and the filtrate was evaporated to dryness. The residue was dissolved in water (50 mL) and acidified with 6 N HCl to pH 2. The resulting white precipitate was isolated by filtration, washed with cold water, and dried in vacuum to yield 22.3 g (91 %) of 36A, mp 176-177 0C. Anal. Calc'd. (Found) for C13H1 1NO4: C, 63.66 (63.75); H, 4.53 (4.55), N, 5.71 (5.52). 1H NMR (500MHz, DMSO-d6): delta 5.26 (s, 2H, CH2), 6.54 (dd, J = 6.7, 1.1 Hz, 1 H), 6.73 (dd, J = 9.2, 1.6Hz, 1 H), 7.39-7.51 (m, 6 H). 13C NMR (125MHz, DMSO-dbeta): delta 77.9, 106.0. 124.1. 128.5, 129.1 , 129.6, 133.8, 138.7, 140.4, 157.6, 161.7.
l-Hydroxy-6-carboxy-2(lJ?)pyridinone; A 10 1-g (0 046 mol) portion of 2-bromopy?dine-6-carboxylicAcid was dissolved in 5 175 mL of a 10% aqueous KOH solution, and the resulting solution was maintained at 80 'C overnight and then cooled in an ice bath and treated with 85 mL of concentrated HC l The white suspended solid was isolated by filtration, washed with dilute HC l followed by three 15 mL portions of water, and then dried in vacuo yielding 6 21 g (86 4%), mp 216 0C dec
The white suspended solid was isolated by filtration, washed with dilute HCl followed by three 15-ml portions of water, and then dried in vacuo to yield 6.21 g (86.4%) of 1-hydroxy-2(1H)-pyridinone-6-carboxylic acid (Formula 7A), mp 216 C. dec. Anal. Calcd. for C6 H5 NO4: C, 46.45; H, 3.25; N, 9.03. Found: C, 46.29; H, 3.26; N, 8.96.
24
[ 21190-87-4 ]
CF3 COOH[ No CAS ]
[ 7722-84-1 ]
[ 94781-89-2 ]
Yield
Reaction Conditions
Operation in experiment
In water;
EXAMPLE 1 Preparation of 1-hydroxy-2(1H)-pyridinone-6-carboxylic acid (Formula 7A): A 9.7 g (0.048 mol.) portion of 6-bromopyridine-2-carboxylic acid was added to a solution of 125 ml of CF3 COOH and 18 ml of 30% H2 O2 and heated to 80 C. for 6.5 h. The reaction mixture was concentrated to ca. 25 ml by rotary evaporation and then added to 1 l of water. The product immediately precipitated as a finely divided, white crystalline solid. It was isolated by filtration, washed with water, and dried in vacuo. This yielded 10.2 g of product, 2-bromopyridine-6-carboxylic acid (Formula 16), mp 180 C. dec. Anal. Calcd. for C6 H4 BrNO3: C, 33.05; H, 1.85; Br, 36.65; N, 6.43. Found: C, 33.30; H, 1.88; Br, 36.37; N, 6.52.
With thionyl chloride; In tetrahydrofuran; for 4h;Reflux;
Step 2: Thionyl chloride (10mL) is added to a suspension of l-hydroxy-2( 1H) -pyridinone-6-carboxylic acid (3.2mmol) in dry THF (10mL) and the mixture heated at reflux for 4 hours. Volatiles are removed by bulb- to-bulb distillation and the resulting residue suspended in dry acetone, filtered, washed with additional acetone and dried in vacuo, to give l-hydroxy-2(1H)-rhoyridinone-6-carboxylic acid chloride.
With potassium hydroxide; In water; at 70℃; for 12h;
General procedure: The compound 1,2-HOPO-6-carboxylic acid was synthesized following the method developed by Xu [34] with minor modifications. As depicted in Scheme 1 , this synthesis method consists of two main successive steps. The detailed preparation route is described as follows. A solution of 6-hydroxy-picolinic acid was prepared by dissolving 5 g (0.036 mol) of 6-hydroxy-picolinic acid in a mixture of trifluoroacetic acid (30 mL) and glacial acetic acid (10 mL). A mixture of acetic anhydride (30 mL) and 30% H2O2 solution (10 mL) was prepared while cooling in an ice bath; this mixture was stirred for 4 h in order that a peracetic acid solution was formed. The 6-hydroxy-picolinic acid solution was added to this peracetic solution. The reaction mixture was then refluxed with stirring at 80 C for 10 h, yielding a white precipitate. The excess trifluoroacetic acid was removed by vacuum distillation. The precipitate was filtered, washed with cold methanol and then dried. The product was a pinkish white solid of the compound 1,6-dihydroxy picolinic acid, yielding 4.63 g (82%); mp 209-210 C. IR (KBr pellet): nu/cm-1 3440 (br, O-H stretch); 1734.7 (br, C=O stretch); 1211.1 (m, C-O stretch); 926.4 (br, O-H oop). H1 NMR (DMSO-d6): delta 7.42 (t, 1H, J = 8.8, 7.1 Hz); 6.64 (q, 2H, J = 7, 6.8 Hz); 3.43 (s, 1H, O-H). This compound was subsequently used as a precursor for the synthesis of 1,2-HOPO-6-carboxylic acidas follows. A solution of 1,6-dihydroxy picolinic acid was prepared by dissolving 4.63 g (0.029 mol) of 1,6-dihydroxy picolinic acid in 135 mL of 20% KOH(aq). This basic solution was refluxed at 70 Cfor 12 h. The product was precipitated with 50 mL of cold concentrated HCl in an ice bath to keep the temperature below 20 C throughout the process. A white precipitate was filtered and washed with 0.1 M HCl(aq), cold methanol and cold water successively. The product was dried under vacuum to yield 4.37 g (95%); mp 217-218 C [42]. IR (KBr pellet): m/cm-1 3437.4 (br, O-H stretch); 1785.9 (br, C=O stretch); 1618.4 (m, C=O stretch); 929.7 (br, C-H deformation oop). H1 NMR (DMSO-d6): delta 7.43 (dd, 1H, J = 7, 9 Hz); 6.71 (dd, 1H, J = 1.6, 9 Hz); 6.64 (dd, 1H, J = 1.6, 7 Hz). MS (ESI-negative mode): m/z 154.01 (C6H4NO-4 ).
Cr(1-hydroxy-2-pyridinone-6-carboxylic acid(-1H))3*H2O[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
24.5%
at 80℃; for 24h;Reflux; Inert atmosphere;
Method A: A solution of chromium(III) was prepared by dissolving 0.54 g (2.03 mmol) of CrCl3?6H2O in 3 mL of deionized water. A suspension of ligand was made by dispersing 1.0 g (6.44 mmol) of 1,2-HOPO-6-carboxylic acid into 40 mL of deionized water with stirring. The solution of chromium(III) was then added to the suspension of ligand with stirring. The chromium-ligand mixture was refluxed with stirring at 80 C under nitrogen atmosphere for about 24 h, allowing the formation of a green precipitate. This precipitate was separated from the reaction mixture by filtration and then washed with cold ethanol. After washing, the precipitate was re-crystallized in boiling chloroform. Chloroform was subsequently evaporated from the product solution at 40 C using a rotary evaporator until the volume of solution was reduced to about 20 mL. The concentrated product solution had been left at room temperature for several days, allowing tiny crystals of the chromium(III) complex to be developed. These product crystals were filtered and dried in a vacuum oven. The crystal dimensions were, however, not sufficiently large for the single crystal X-ray diffraction measurement. The yield of product was 0.81 g (24.5%). Anal. Calcd. for C18H12N3O12Cr?H2O: C 40.61; H 2.65; N 7.89. Found: C 39.20; H 2.89; N 7.59. IR (KBr pellet): nu/cm-1 3439.3 (br, O-H stretch); 1753.6 (s, C=O stretch); 1616.1 (m, C=O stretch). MS (ESI-negative mode): m/z 512.98 (C18H11N3O12Cr-). Method B: 1,2-HOPO-6-carboxylic acid (0.2329 g) was dissolved in 0.25 M CH3COOH(aq) (30 mL) with pH = 3.5, giving 0.05 M ligand solution. To prepare 0.05 M chromium(III) solution, CrCl3·6H2O (1.332 g) was dissolved in 0.25 M CH3COOH(aq) (10 mL). Afterwards, the ligand solution was gently added to the chromium(III) solution without stirring. The resulting mixture was left at room temperature, allowing slow diffusion of the two components. After about 3 weeks the dark green crystals of the complex were produced. These crystals were slightly larger than those obtained by method A. The spectroscopic results for the complex prepared by method B also reproduced those for the complex prepared by method A.
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