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Chemical Structure| 66171-50-4
Chemical Structure| 66171-50-4
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Product Details of [ 66171-50-4 ]

CAS No. :66171-50-4 MDL No. :MFCD08436011
Formula : C7H7NO3 Boiling Point : -
Linear Structure Formula :- InChI Key :JTVVPKLHKMKWNN-UHFFFAOYSA-N
M.W :153.14 Pubchem ID :416343
Synonyms :

Calculated chemistry of [ 66171-50-4 ]

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.14
Num. rotatable bonds : 2
Num. H-bond acceptors : 4.0
Num. H-bond donors : 1.0
Molar Refractivity : 37.54
TPSA : 59.42 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) : -6.75 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.56
Log Po/w (XLOGP3) : 0.68
Log Po/w (WLOGP) : 0.57
Log Po/w (MLOGP) : 0.15
Log Po/w (SILICOS-IT) : 0.71
Consensus Log Po/w : 0.74

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.49
Solubility : 4.96 mg/ml ; 0.0324 mol/l
Class : Very soluble
Log S (Ali) : -1.5
Solubility : 4.79 mg/ml ; 0.0313 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.51
Solubility : 4.73 mg/ml ; 0.0309 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.58

Safety of [ 66171-50-4 ]

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 [ 66171-50-4 ]

* 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 [ 66171-50-4 ]
  • Downstream synthetic route of [ 66171-50-4 ]

[ 66171-50-4 ] Synthesis Path-Upstream   1~16

  • 1
  • [ 67-56-1 ]
  • [ 5006-66-6 ]
  • [ 66171-50-4 ]
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
  • 2
  • [ 6018-41-3 ]
  • [ 66171-50-4 ]
YieldReaction ConditionsOperation in experiment
70% With 1,8-diazabicyclo[5.4.0]undec-7-ene; 1,1,1,3,3,3-hexamethyl-disilazane In acetonitrile at 20℃; for 48 h; Inert atmosphere; Schlenk technique To a solution of methyl coumalate (308mg, 2.0 mmol) in MeCN (1 mL) was added hexamethyldisilazane (387 mg, 2.4 mmol) and DBU(16 mL) and the mixture was stirred for 48 h at room temperature. After the solvent was removedunder vacuuo, the residue was chromatographed on silica gel (AcOEt/hexane = 4 : 1) to give1ad (213 mg, 70percent): 1H NMR (400MHz, CD3OD): δ 8.12 (s, 1H, Ar), 7.97 (d, 1H, J = 9.7 Hz,Ar), 6.50 (d, 1H, J = 9.7 Hz, Ar), 3.82 (s, 3H, Me); 13C NMR (100.5 MHz, CD3OD): δ 165.9,165.5, 141.8, 141.2, 120.3, 111.7, 52.4.
Reference: [1] Journal of Organometallic Chemistry, 2017, vol. 843, p. 14 - 19
  • 3
  • [ 5006-66-6 ]
  • [ 66171-50-4 ]
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,
  • 4
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  • [ 66171-50-4 ]
Reference: [1] Monatshefte fuer Chemie, 1901, vol. 22, p. 437
[2] Patent: US5512581, 1996, A,
[3] Patent: US5521173, 1996, A,
  • 5
  • [ 5006-66-6 ]
  • [ 18107-18-1 ]
  • [ 66171-50-4 ]
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
  • 6
  • [ 26218-80-4 ]
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Reference: [1] Heterocycles, 1993, vol. 36, # 2, p. 323 - 328
  • 7
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  • [ 79-37-8 ]
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Reference: [1] Patent: US2003/171377, 2003, A1,
  • 8
  • [ 66171-50-4 ]
  • [ 134531-63-8 ]
Reference: [1] Journal of Medicinal Chemistry, 2001, vol. 44, # 19, p. 3141 - 3149
  • 9
  • [ 66171-50-4 ]
  • [ 56055-54-0 ]
Reference: [1] Organic Process Research and Development, 2013, vol. 17, # 6, p. 940 - 945
  • 10
  • [ 66171-50-4 ]
  • [ 73781-91-6 ]
  • [ 56055-54-0 ]
Reference: [1] Organic Process Research and Development, 2013, vol. 17, # 6, p. 940 - 945
  • 11
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  • [ 77837-08-2 ]
Reference: [1] Patent: WO2012/122165, 2012, A2,
  • 12
  • [ 66171-50-4 ]
  • [ 98-80-6 ]
  • [ 77837-09-3 ]
YieldReaction ConditionsOperation in experiment
56% With pyridine; copper diacetate In dichloromethane at 20℃; for 12 h; Molecular sieve Methyl-6-oxo-1-phenyl-1,6-dihydropyridine-3-carboxylate Methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (6.0 g, 39.22 mmol), phenylboronic acid (5.74 g, 47.06 mmol), copper(II) acetate monohydrate (11.76 g, 58.82 mmol), pyridine (6.32 mL, 78.43 mmol) and molecular sieves (4 , 6.0 g) in dichloromethane (100 mL) was stirred at ambient temperature for 12 hours and filtered. Standard extractive work up provided a crude residue which was purified by silica gel column chromatography (100-200 mesh) (1-2percent methanol in chloroform) to give the title compound as a brown solid (5.0 g, 56percent). m.p. 100-105° C.; 1H NMR (400 MHz, CDCl3) δ 3.86 (s, 3H), 6.63 (d, J=9.5 Hz, 1H), 7.36-7.55 (m, 5H), 7.91 (dd, J=2.5, 9.9 Hz, 1H), 8.23 (d, J=2.5 Hz, 1H); IR (KBr) ν 3058, 2924, 2854, 1721, 1675, 1540, 1446, 1313, 1271, 1103 cm-1; MS 230 (M+1).
56% With pyridine; copper(II) acetate monohydrate In dichloromethane at 20℃; for 12 h; Molecular sieve Step 2; Methyl-6-oxo-l -phenyl- l,6-dihydropyridine-3-carboxylate; Methyl-6-oxo-l,6- dihydropyridine-3-carboxylate (6.0 g, 39.22 mmol), phenylboronic acid (5.74 g, 47.06 mmol), copper(II) acetate monohydrate (11.76 g, 58.82 mmol), pyridine (6.32 mL, 78.43 mmol) and molecular sieves (4 A, 6.0 g) in dichloromethane (100 mL) was stirred at ambient temperature for 12 hours and filtered. Standard extractive work up provided a crude residue which was purified by silica gel column chromatography (100-200 mesh) (1-2percent methanol in chloroform) to give the title compound as a brown solid (5.0 g, 56percent). m.p. 100-105 °C; *H NMR (400 MHz, CDC13) δ 3.86 (s, 3H), 6.63 (d, J = 9.5 Hz, 1H), 7.36-7.55 (m, 5H), 7.91 (dd, J = 2.5, 9.9 Hz, 1H), 8.23 (d, J = 2.5 Hz, 1H); IR (KBr) υ 3058, 2924, 2854, 1721, 1675, 1540, 1446, 1313, 1271, 1103 cm"1; MS 230 (M + 1).
Reference: [1] Patent: US2008/319026, 2008, A1, . Location in patent: Page/Page column 22
[2] Patent: WO2012/122165, 2012, A2, . Location in patent: Page/Page column 63
  • 13
  • [ 66171-50-4 ]
  • [ 77837-09-3 ]
  • [ 595576-44-6 ]
YieldReaction ConditionsOperation in experiment
40% With caesium carbonate In 1,2-dichloro-ethane at 120℃; General procedure: A 25 mL Teflon-sealed flask was charged with the corresponding 2-pyridone 1 (0.5 mmol), diaryliodonium salt 2 (0.75 mmol, 1.5 equiv),and Cs2CO3 (0.75 mmol, 1.5 equiv) under an air atmosphere. DCE (5mL) was added to the flask. Then, the reaction vessel was sealed witha Teflon cap. The reaction mixture was stirred at 120 °C until the2-pyridone 1 was consumed completely (monitored by TLC). At thistime, the solvent was removed in vacuo and the residue was purifiedby flash column chromatography (the crude residue was dry loadedon silica gel, 1:20 to 1:1, EtOAc/PE) to provide the desired products 3and 4 (Scheme 2, Tables 2, 3).1-Phenylpyridin-2(1H)-one (3aa)19Yield: 0.054 g (63percent); orange solid; mp 94–95 °C.1H NMR (500 MHz, CDCl3): δ = 7.50–7.47 (m, 2 H), 7.43–7.36 (m, 4 H),7.34 (d, J = 8.5 Hz, 1 H), 6.66 (d, J = 10.5 Hz, 1 H), 6.25 (t, J = 7.0 Hz, 1 H).13C NMR (125 MHz, CDCl3): δ = 162.3, 140.9, 139.8, 137.9, 129.2,128.4, 126.4, 121.8, 105.8.
Reference: [1] Synthesis (Germany), 2018, vol. 50, # 8, p. 1699 - 1710
  • 14
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  • [ 1360952-35-7 ]
  • [ 78686-77-8 ]
Reference: [1] Organic Process Research and Development, 2013, vol. 17, # 6, p. 940 - 945
  • 15
  • [ 66171-50-4 ]
  • [ 109205-68-7 ]
Reference: [1] Patent: WO2011/12622, 2011, A1, . Location in patent: Page/Page column 110
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  • [ 109205-68-7 ]
Reference: [1] Patent: US2002/49330, 2002, A1,
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