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Marc Ferrell ; Zeneng Wang ; James T. Anderson , et al. DOI:

Abstract: Despite intensive preventive cardiovascular disease (CVD) efforts, substantial residual CVD risk remains even for individuals receiving all guideline-recommended interventions. is an essential micronutrient fortified in food staples, but its role in CVD is not well understood. In this study, untargeted metabolomics analysis of fasting plasma from stable cardiac patients in a prospective discovery cohort (n = 1,162 total, n = 422 females) suggested that metabolism was associated with incident major adverse cardiovascular events (MACE). Serum levels of the terminal metabolites of excess , and , were associated with increased 3-year MACE risk in two validation cohorts (US n = 2,331 total, n = 774 females; European n = 832 total, n = 249 females) (adjusted hazard ratio (HR) (95% confidence interval) for 2PY: 1.64 (1.10–2.42) and 2.02 (1.29–3.18), respectively; for 4PY: 1.89 (1.26–2.84) and 1.99 (1.26–3.14), respectively). Phenome-wide association analysis of the genetic variant rs10496731, which was significantly associated with both and levels, revealed an association of this variant with levels of soluble vascular adhesion molecule 1 (sVCAM-1). Further meta-analysis confirmed association of rs10496731 with sVCAM-1 (n = 106,000 total, n = 53,075 females, P = 3.6 × 10−18). Moreover, sVCAM-1 levels were significantly correlated with both and in a validation cohort (n = 974 total, n = 333 females) (2PY: = 0.13, P = 7.7 × 10−5; 4PY: = 0.18, P = 1.1 × 10−8). Lastly, treatment with physiological levels of , but not its structural isomer , induced expression of VCAM-1 and leukocyte adherence to vascular endothelium in mice. Collectively, these results indicate that the terminal breakdown products of excess , and , are both associated with residual CVD risk. They also suggest an inflammation-dependent mechanism underlying the clinical association between and MACE.

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Product Details of [ 5006-66-6 ]

CAS No. :5006-66-6 MDL No. :MFCD00229359
Formula : C6H5NO3 Boiling Point : -
Linear Structure Formula :- InChI Key :BLHCMGRVFXRYRN-UHFFFAOYSA-N
M.W : 139.11 Pubchem ID :72924
Synonyms :
Chemical Name :6-Oxo-1,6-dihydropyridine-3-carboxylic acid

Calculated chemistry of [ 5006-66-6 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 3.0
Num. H-bond donors : 2.0
Molar Refractivity : 34.02
TPSA : 70.16 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -7.54 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.68
Log Po/w (XLOGP3) : -0.55
Log Po/w (WLOGP) : 0.07
Log Po/w (MLOGP) : -0.15
Log Po/w (SILICOS-IT) : 0.89
Consensus Log Po/w : 0.19

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -0.73
Solubility : 25.7 mg/ml ; 0.185 mol/l
Class : Very soluble
Log S (Ali) : -0.45
Solubility : 48.9 mg/ml ; 0.352 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.28
Solubility : 7.33 mg/ml ; 0.0527 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.3

Safety of [ 5006-66-6 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 5006-66-6 ]

* 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.

  • Upstream synthesis route of [ 5006-66-6 ]
  • Downstream synthetic route of [ 5006-66-6 ]

[ 5006-66-6 ] Synthesis Path-Upstream   1~39

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Reference: [1] Journal of the Chemical Society, 1948, p. 1939,1942
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Reference: [1] Patent: US4112102, 1978, A,
[2] Chemistry - A European Journal, 2010, vol. 16, # 7, p. 2170 - 2180
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Reference: [1] Journal of the Chemical Society, 1908, vol. 93, p. 1379
[2] Journal of the Chemical Society, 1948, p. 1939,1942
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Reference: [1] Journal of the Chemical Society, 1948, p. 1939,1942
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Reference: [1] Patent: US4115575, 1978, A,
[2] Patent: US4410530, 1983, A,
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  • [ 74-88-4 ]
  • [ 66572-55-2 ]
Reference: [1] Journal of Organic Chemistry, 1991, vol. 56, # 15, p. 4636 - 4645
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YieldReaction ConditionsOperation in experiment
97% With bromine In water at 0 - 20℃; for 24 h; 8A. 5-bromo-6-hydroxynicotinic acid: To 6-hydroxynicotinic acid (8 g, 57.6 mmol) suspended in water (30 mL) cooled in an ice bath was added bromine (4.2 mL, 81.4 mmol). After the addition was complete the reaction was stirred at rt for 24 h. The solid was collected by filtration, washed with water and dried at 40 0C in a vacuum oven for 24 h. A total of 12. Ig (97percent) of 8A as a tan solid was collected. 1H NMR (400 MHz, DMSO-d6) δ: 8.04 (d, J = 2.53 Hz, 1 H) 8.16 (d, J= 2.27 Hz, 1 H), 12.59 (brd s, IH), 12.90 (brd s, IH).
Reference: [1] Journal of Medicinal Chemistry, 2013, vol. 56, # 24, p. 9874 - 9896
[2] Journal of Medicinal Chemistry, 2005, vol. 48, # 15, p. 4892 - 4909
[3] Patent: WO2007/70818, 2007, A1, . Location in patent: Page/Page column 103
[4] Patent: WO2006/88919, 2006, A2, . Location in patent: Page/Page column 134-135
[5] Patent: US2008/85906, 2008, A1, . Location in patent: Page/Page column 15
[6] Patent: WO2012/141487, 2012, A2, . Location in patent: Page/Page column 39-40; 139
[7] Patent: US2014/31335, 2014, A1, . Location in patent: Paragraph 0042; 0562; 0563
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YieldReaction ConditionsOperation in experiment
85% for 18 h; Reflux A suspension of 5-hydroxynicotinic acid (200 g, 1438 mmol) in methanol (1.0 1) was treated drop wise over 25 min with sulfuric acid (84 ml, 1505 mmol, exothermic.), heated to reflux and stirred at this temperature for 18 h. The yellow solution was cooled to ca. 30°C and the solvent evaporated under reduced pressure (ca. 50-100 mbar) until a residual volume of ca. 600 ml. The solvent of the formed suspension was exchanged by water keeping the volume of ca. 600 ml. The suspension was stirred for 1 h at room temperature. The crystals were filtered, washed with water (50 ml) and dried to isolate the product in 68percent yield.MS (GC_Split): 153 (M, 64percent), 122 (100percent), 94 (36), 66 (14).
75%
Stage #1: for 16 h; Reflux
Intermediate 116Methyl 6-hydroxynicotininate 6-Hydroxy-nicotinic acid (100 g, 719 mmol) was suspended in methanol (1 L). 18M Sulfuric acid (50 rnL) was added and the reaction was heated at reflux for 16 h. The reaction mixture was then cooled, and sodium bicarbonate powder (45 g) was added slowly to neutralize some of the acid. Most of the methanol was then removed in vacuo. Water (IL) was added, and the pH adjusted to 7 with the careful addition of bicarbonate solution. The suspension was extracted with dichloromethane (4x, 200 mL), and the organic phases were combined, dried over sodium sulfate, and the solvent was removed in vacuo. The solid was dried in a vacuum oven at 5O0C for 1.5 h to give 83g (75percent) of methyl 6-hydroxynicotinate as a white solid. MS (ESP): 154.2 (MH+) for C7H7NO31H NMR (300 MHz, CDCl3): 3.88 (s, 3H), 6.59 (dd, IH), 8.02 (dd, 1 H), 8.21 (m, IH), 13.19 (bs, IH).
68% for 18 h; Reflux Example 16-Hydroxy-nicotinic acid methyl esterA suspension of 5-hydroxynicotinic acid (200 g, 1438 mmol) in methanol (1.0 l) was treated drop wise over 25 min with sulfuric acid (84 ml, 1505 mmol, exothermic.), heated to reflux and stirred at this temperature for 18 h. The yellow solution was cooled to ca. 30° C. and the solvent evaporated under reduced pressure (ca. 50-100 mbar) until a residual volume of ca. 600 ml. The solvent of the formed suspension was exchanged by water keeping the volume of ca. 600 ml. The suspension was stirred for 1 h at room temperature. The crystals were filtered, washed with water (50 ml) and dried to isolate the product in 68percent yield. MS (GC_Split): 153 (M, 64percent), 122 (100percent), 94 (36), 66 (14).
55%
Stage #1: at 20 - 55℃;
Stage #2: With sodium hydroxide; sodium hydrogencarbonate In methanol; water
Reference Example 36-1
Methyl 6-hydroxynicotinate
To a suspension of 6-hydroxynictonic acid (5.23 g, 37.6 mmol) in methanol (60 ml) was added dropwise thionyl chloride (5.0 g, 42.0 mmol) at 55°C, and the reaction mixture was stirred at 55°C for one hour.
To the reaction mixture was further added thionyl chloride (3.3 g, 27.7 mmol), and the mixture was stirred at 55°C for 3 hours, and then further stirred at room temperature overnight.
The reaction solution was neutralized (around pH 7) with a saturated aqueous sodium hydrogen carbonate solution and a 1N aqueous sodium hydroxide solution, and further it was made a saturated solution with sodium chloride.
The reaction mixture was extracted three times with ethyl acetate.
The organic layers were combined, and washed with a saturated saline, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (3.15 g, 55 percent).
1H-NMR (400MHz in CDCl3) δ 12.65 (1H, brs), 8.19 (1H, d, J = 2.5 Hz), 8.00 (1H, dd, J = 9.6, 2.5 Hz), 6.58 (1H, d, J = 9.6 Hz), 3.87 (3H, s).

Reference: [1] Journal of Medicinal Chemistry, 2014, vol. 57, # 15, p. 6679 - 6703
[2] Patent: WO2012/52444, 2012, A1, . Location in patent: Page/Page column 12
[3] Chemistry - A European Journal, 2009, vol. 15, # 24, p. 5950 - 5955
[4] Patent: WO2009/106885, 2009, A1, . Location in patent: Page/Page column 296
[5] Organic and Biomolecular Chemistry, 2010, vol. 8, # 15, p. 3534 - 3542
[6] Patent: US2012/101282, 2012, A1, . Location in patent: Page/Page column 6
[7] Journal of Medicinal Chemistry, 2001, vol. 44, # 19, p. 3141 - 3149
[8] Patent: EP1647546, 2006, A1, . Location in patent: Page/Page column 52
[9] Bl. Textile Res. Inst. Yokohama, 1956, # 38, p. 82,85[10] Chem.Abstr., 1961, p. 14455
[11] Journal of Medicinal Chemistry, 2006, vol. 49, # 14, p. 4425 - 4436
[12] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 10, p. 2687 - 2694
[13] Organic Process Research and Development, 2013, vol. 17, # 6, p. 940 - 945
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YieldReaction ConditionsOperation in experiment
90% With sulfuric acid In methanol; dichloromethane Stage 1.-Preparation of 6-Hydroxynicotinamide
A solution of 6-hydroxynicotinic acid (1.00 g, 7.19 mmol) and concentrated sulfuric acid (0.47 ml) in methanol (80 ml) was refluxed for 10 hours then poured into water and sodium bicarbonate (1.45 g) was added.
The solvents were evaporated in vacuo and the residue was purified by flash chromatography on silica gel (eluding with 10percent -20percent methanol in dichloromethane) to give 6-hydroxynicotinic acid, methyl ester as a colourless solid (996 mg, 90percent).
The product was dissolved in concentrated aqueous ammonia solution and heated at 60° C. for 10 hours.
Reference: [1] Patent: US2001/19823, 2001, A1,
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Reference: [1] Monatshefte fuer Chemie, 1901, vol. 22, p. 437
[2] Patent: US5512581, 1996, A,
[3] Patent: US5521173, 1996, A,
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YieldReaction ConditionsOperation in experiment
84.9% at 20℃; for 4.08333 h; Step A: 6-Hydroxy-nicotinic acid methyl esterTo the solution of 6-hydroxy nicotinic acid (1.070 g, 7.69 mmol) in benzene (45 mL) and methanol (15 mL) is added TMS diazomethane (5.00 mL, 10.00 mmol) dropwise over 5 minutes. The reaction is stirred at room temperature for 4 hours. The reaction is evaporated in vacuo to give the desired product (1 g, 84.9percent). 1H NMR δ: 8.20 (m, IH), 8.11 (m, IH), 7.20 (s, IH), 6.61 (m, IH), 3.79 (s, 3H) ppm.; Step A: 6-Hvdroxy-nicotinic acid methyl esterTo the solution of 6-hydroxy nicotinic acid (1.070 g, 7.692 mmol) in 54 niL benzene and 15 mL methanol is added TMS diazomethane (5.00 mL, 10.00 mmol) dropwise over 5 minutes. The reaction is stirred at room temperature for 4 h. The reaction is concentrated in vacuo to give the desired product (1.00 g, 84.9percent). 1H NMR δ: 8.20 (m, IH), 8.11 (m, IH), 7.20 (s, IH), 6.61 (m, IH), 3.79 (s, 3H) ppm.
Reference: [1] Synthesis, 1995, # 3, p. 285 - 293
[2] Patent: US6534545, 2003, B1,
[3] Journal of Organic Chemistry, 1996, vol. 61, # 25, p. 8940 - 8948
[4] Patent: WO2007/44491, 2007, A1, . Location in patent: Page/Page column 31; 35
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Reference: [1] Patent: US2003/171377, 2003, A1,
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  • [ 74-95-3 ]
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Reference: [1] Patent: US5420270, 1995, A,
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YieldReaction ConditionsOperation in experiment
89%
Stage #1: at 60℃; for 6.83333 h; Reflux
Stage #2: With sodium hydrogencarbonate In ethanol; waterCooling with ice
Example 148; Preparation of 5-(fro[2,3-b]pyridin-5-yl)-3-((4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-propylphenoxy) pyridin-2-yl)methyl)-5-methylimidazolidine-2,4-dione; 148-a-1) Preparation of ethyl 6-hydroxynicotinate; To a solution of 6-hydroxynicotinic acid (5.0 g, 35.9 mmol) in ethanol (180 mL), sulfuric acid (1.0 mL) was added. The resultant mixture was stirred at 60° C. for 20 minutes, then added with surfuric acid (33.0 mL), and stirred for 6.5 hours while heated to reflux. The reaction solution was then added with a saturated aqueous solution of sodium hydrogen carbonate under ice-cold conditions and ethanol was concentrated in vacuo. After extracted with ethyl acetate, the organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. Ethyl 6-hydroxynicotinate (5.33 g, yield 89percent) was obtained as a white crystal.1H-NMR (CDCl3) δ: 1.36 (3H, t, J=7.1 Hz), 4.33 (2H, q, J=7.1 Hz), 6.58 (1H, d, J=9.5 Hz), 8.01 (1H, dd, J=2.4, 9.5 Hz), 8.19 (1H, d, J=2.4 Hz), 12.43 (1H, brs).
86% for 48 h; Reflux To a stirred solution of 6-hydroxynicotinic acid (10 g, 72 mmol) in absolute ethanol (500 mL) was added sulfuric acid (4 mL) at room temperature. The mixture was heated to reflux for 48 h. After cooling down to room temperature, water (50 mL) was added and the reaction mixture was neutralised to pH= 6-7 by portionwise addition of sodiumhydrogen carbonate (caution: gas evolution). The mixture was evaporated under reduced pressure (most of ethanol was removed), and the residue was extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated under reduced pressure leading to the pure ethyl 6-hydroxynicotinate[30] (10 g, 86percent). 1H NMR (400 MHz, CDCl3): δ 13.07 (s,1H), 8.14 (s, 1H), 7.94 (d, 1H, J = 9.9 Hz), 6.51 (d, 1H, J = 9.4 Hz),4.25 (q, 2H, J =7.1 Hz), 1.29 ppm.To a stirred solution of lithium aluminium hydride (1.4 g, 37 mmol,1.2 equiv.) in anhydrous THF (20 mL) at room temperature was added dropwise over 1 h a solution of ethyl 6-hydroxynicotinate (5.1 g,31 mmol) in anhydrous THF (150 mL) at the same temperature. The mixture was stirred at room temperature for 2 h and then heated toreflux for 30 min. The reaction mixture was cooled down to 0 °C andquenched with ethyl acetate (12 mL) and water (6 mL). The solventswere removed and the residue was taken up in refluxing ethanol(200 mL). The solution was filtered through Celite® and ethanol was evaporated under reduced pressure. The crude material was purified bycolumn chromatography on silica gel with ethyl acetate/methanol(75:25) as eluent to afford the pure title compound 12 (2.3 g, 60percent).
80%
Stage #1: Heating / reflux; Neat (no solvent)
Stage #2: With sodium hydrogencarbonate In water; ethyl acetate
31.1 6-hydroxy-nicotinic acid ethyl ester
To a 100mL three-necked flask, 0.84g (0.006 mol) of 6-hydroxynicotinic acid, 30mL of anhydrous ethanol were added, 3mL of concentrated sulfuric acid was added dropwise slowly, refluxed overnight, evaporated under vacuum to remove excessive ethanol, the residue was poured into water, extracted with ethyl acetate, washed with saturated sodium hydrogen carbonate, dried with anhydrous sodium sulfate, and concentrated to obtain 0.8g of 6-hydroxy-nicotinic acid ethyl ester. Yield: 80percent.
Reference: [1] Patent: US2010/48610, 2010, A1, . Location in patent: Page/Page column 83
[2] Journal of Fluorine Chemistry, 2017, vol. 203, p. 155 - 165
[3] Patent: EP1900735, 2008, A1, . Location in patent: Page/Page column 14-15
[4] Journal of the Chemical Society, 1908, vol. 93, p. 1379
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Reference: [1] Journal of Medicinal Chemistry, 2001, vol. 44, # 19, p. 3141 - 3149
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Reference: [1] Organic Process Research and Development, 2013, vol. 17, # 6, p. 940 - 945
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  • [ 56055-54-0 ]
Reference: [1] Organic Process Research and Development, 2013, vol. 17, # 6, p. 940 - 945
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Reference: [1] Patent: WO2012/122165, 2012, A2,
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YieldReaction ConditionsOperation in experiment
29% at 50℃; for 18 h; 6-Hydroxynicotinic acid 2 (25.0 g, 180 mmol) was dissolved in HNO3 fuming (1.52) (95 mL) and stirred at 50 oC for 18 h. After the solution was cooled to room temperature, the mixture was concentrated, and then co-evaporated with water, followed by the addition of MeOH to afford a brown precipitate. The precipitate was filtered and washed with 50 mL of cold MeOH twice. After drying under reduced pressure, a brown color product 3 was obtained; yield: 9.67 g (29percent); 1H NMR (300 MHz, CD3OD) 8.44 (d, J = 2.6 Hz, 1H), 8.85 (d, J = 2.6 Hz, 1H) ; HRMS (ES+): m/z 185.0194 (M+H+) (calcd for C6H5N2O5: 185.0198).
28% at 0℃; for 0.166667 h; Into a 2000-mL round-bottom flask, was placed sulfuric acid (150 mL). This was followed by the addition of 6-hydroxypyridine-3-carboxylic acid (50 g, 359.43 mmol, 1.00 equiv), in portions at 0oC in 5 min. To this was added HNO3 (34.7 mL, 2.00 equiv) at 0oC in 10 min. The resulting solution was stirred for 3 h at room temperature. The reaction was then quenched by the addition of 300 g of crush ice. The solids were collected by filtration. The solid was dried in an oven under reduced pressure. This resulted in 18.2 g (28percent) of 6-hydroxy- 5-nitropyridine-3-carboxylic acid as a gray solid
36% With conc. nitric acid In sulfuric acid a)
6-Hydroxy-5-nitro-nicotinic acid
To a solution of 30 g (0.217 mol) 6-hydroxy-nicotinic acid in 50 ml concentrated sulfuric acid was added 60 ml of a 1:1 mixture of conc. sulfuric acid and conc. nitric acid below 20° C. and stirred for 1 h at room temperature and afterwards heated to 80° C. for 4 h.
The mixture was poured onto ice and the formed precipitate was collected and dried to yield 14.2 g (36percent) of the title compound as a yellow amorphous solid.
MS m/e (percent): 184 (MH+, 100)
1H-NMR (300 MHz, DMSO-d6): δ=13.3 (s, br, 2H, COOH/OH), 8.65 (d, J=2.5 Hz, 1H, H-4), 8.38 (d, J=2.5 Hz, 1H, H-2).
9.77 g at 50℃; for 5 h; Compound 1 (25 g, 0.180 mol) was placed in a 500 mL recovery flask, and fuming nitric acid (1.52) (125 mL) was added. The flask was gradually heated using an oil bath while stirring, and stirring was conducted for 5 hours at 50° C. After stopping heating and allowing to cool to room temperature, the reaction solution was concentrated under reduced pressure. The residue obtained was cooled by an ice bath, and recrystallized using methanol as the solvent. Compound 2 (9.77 g, 0.053 mol) was obtained by drying the solid obtained by filtration, under reduced pressure. 1H NMR (300 MHz, CD3OD) 8.44 (d, J=2.6 Hz, 1H), 8.85 (d, J=2.6 Hz, 1H); HRMS (ES+): m/z 185.0194 (M+H)+ (calcd for C6H6N2O6: 185.0198).

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[3] Patent: WO2016/138335, 2016, A1, . Location in patent: Paragraph 00372
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YieldReaction ConditionsOperation in experiment
89.03% at 75℃; for 14 h; A method for synthesizing 6-hydroxy-5-nitronicotinic acid comprises the following steps:(a) adding concentrated sulfuric acid and concentrated nitric acid sequentially into the reaction bottle, and stirring uniformly to obtain a reaction solution A, in which the molar ratio of concentrated sulfuric acid to concentrated nitric acid is 1: 5, the concentrated sulfuric acid used is 68percent The mass fraction of 86percent;(b) mixing the raw material 6-hydroxynicotinic acid and the catalyst ammonium bisulfate at a molar ratio of 60: 1 to obtain a reaction raw material B;(c) adding the reaction raw material B obtained in the step (b) to the reaction solution A obtained in the step (a) with stirring, and then carrying out the pre-nitration reaction by heating to 50 ° C. for 5 h, wherein the HNO 3 in the reaction solution A And 6-hydroxynicotinic acid in reaction raw material B is 1.0: 1;(d) The concentrated sulfuric acid and concentrated nitric acid (concentrated sulfuric acid used mass fraction of 68percent, concentrated nitric acid mass fraction of 86percent) at a molar ratio of 1: 5 mixed uniformly, and then added catalyst ammonium bisulfite Stir the reaction Solution C, wherein the molar ratio of concentrated nitric acid to the catalyst is 90: 1;(e) After the pre-nitrification reaction in the step (c) is completed, the reaction solution C obtained in the step (d) is added dropwise to the reaction flask in the step (c) under stirring and heated to 75 ° C for nitrification 14h, get nitrification reaction liquid;(f) The obtained nitration reaction liquid obtained in step (e) is crystallized at 4 DEG C for 26 hours, and the solid obtained by filtration under suction is crude product A. A method for separating and purifying the nitration reaction liquid of 6-hydroxy-5-nitronicotinic acid described above comprises the following steps:(1) rinsing the crude product A obtained in the above step (f) with cold methanol (2 ° C) and then vacuum drying to obtain a crude product B;(2) dissolving the crude product B obtained in the step (2) with an acidic aqueous solution having a pH value of 1 and then separating and purifying by a cooling crystallization method at a cooling rate of 1 ° C./min, a crystallization temperature of 4 ° C. and a crystallization time of 14 h Finally, the product 6-hydroxy-5-nitronicotinic acid was obtained.In this example, the yield of 6-hydroxy-5-nitronicotinic acid was 89.03percent and the conversion rate was 94.16percent. After isolation and purification in this Example, the product 6-hydroxy-5- The purity of nicotinic acid was 99.16percent.
Reference: [1] Patent: CN104370807, 2016, B, . Location in patent: Paragraph 0045-0064
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Reference: [1] Patent: WO2012/122165, 2012, A2,
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YieldReaction ConditionsOperation in experiment
1.18 g
Stage #1: at 60℃; for 16 h;
Stage #2: With phosphorus pentachloride; trichlorophosphate In methanol at 100℃; for 2 h;
Stage #3: at 10 - 35℃; for 2 h;
step A)
methyl 5-bromo-6-methoxynicotinate
Bromine (0.60 mL) was added to a solution of 6-hydroxynicotinic acid (1.02 g) in acetic acid (5 mL) and the mixture was stirred at 60°C for 16 hr.
The solvent was evaporated under reduced pressure and the residue was dissolved in phosphorus oxychloride (5 mL).
Phosphorus pentachloride (3.05 g) was added and the mixture was stirred at 100°C for 2 hr.
The solvent was evaporated under reduced pressure, and the residue was dissolved in methanol (5 mL), and the mixture was refluxed for 2 hr.
To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate.
The extract was washed with saturated brine, and dried over anhydrous sodium sulfate.
The solvent was evaporated under reduced pressure and the residue was dissolved in methanol (10 mL).
A methanol solution (28percent, 2.2 mL) of sodium methoxide was added and the mixture was stirred at room temperature for 2 hr.
To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate.
The extract was washed with saturated brine, and dried over anhydrous sodium sulfate.
The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.18 g) as white crystals.
1H NMR (400 MHz, CDCl3) δ3.92 (3H, s), 4.08 (3H, s), 8.40 (1H, d, J = 1.8 Hz), 8.75 (1H, d, J = 1.6 Hz).
Reference: [1] Patent: EP2816032, 2014, A1, . Location in patent: Paragraph 0549; 0550
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YieldReaction ConditionsOperation in experiment
72% at 100℃; for 12 h; Autoclave 0.13 mol of 6-hydroxynicotinic acid (18.2 g), 2.6 ml of anhydrous hydrofluoric acid (concentration of 95 wtpercent or more) (0.13 mol) and 42.1 g (0.39 mol) of sulfur tetrafluoride were charged into a stainless steel pressure canister And heated to 100 ° C and reacted at 0.15 MPa for 12 hours. The gaseous product was treated with an exhaust gas absorbing device. The remaining product was transferred to a polytetrafluoroethylene container and heated to 40 ° C to remove traces of hydrogen fluoride.The resulting product was added to 150 ml of water, adjusted to pH 6.8-7.2 with saturated sodium carbonate solution, extracted with chloroform, dried, filtered and dried to give 15.3 g (0.094 mol) of 2-hydroxy- 5-trifluoromethylpyridine, , Yield 72percent.
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