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Chemical Structure| 10128-91-3
Chemical Structure| 10128-91-3
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Product Details of [ 10128-91-3 ]

CAS No. :10128-91-3 MDL No. :MFCD00661282
Formula : C7H7NO3 Boiling Point : -
Linear Structure Formula :- InChI Key :SILBTMNCGYLTOK-UHFFFAOYSA-N
M.W : 153.14 Pubchem ID :579028
Synonyms :

Calculated chemistry of [ 10128-91-3 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.14
Num. rotatable bonds : 2
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 38.34
TPSA : 59.16 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) : -7.04 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.4
Log Po/w (XLOGP3) : 0.27
Log Po/w (WLOGP) : 0.16
Log Po/w (MLOGP) : 0.2
Log Po/w (SILICOS-IT) : 1.34
Consensus Log Po/w : 0.67

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.23
Solubility : 8.99 mg/ml ; 0.0587 mol/l
Class : Very soluble
Log S (Ali) : -1.07
Solubility : 12.9 mg/ml ; 0.0844 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.99
Solubility : 1.56 mg/ml ; 0.0102 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.51

Safety of [ 10128-91-3 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 10128-91-3 ]

* 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 [ 10128-91-3 ]
  • Downstream synthetic route of [ 10128-91-3 ]

[ 10128-91-3 ] Synthesis Path-Upstream   1~10

  • 1
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YieldReaction ConditionsOperation in experiment
84% With sulfuric acid In toluene at 20℃; for 28 h; To a solution of 2-hydroxynicotinic acid (3-067-01) (50 g) in methanol (500 ml) were added conc. sulfuric acid (15 mL) and toluene (100 mL) at room temperature. After the reaction mixture was stirred for 28 h attached Dienstark reflux tube and neutralized with an aqueous potassium carbonate solution, the solvent was evaporated. To the residue were added aqueous saturated ammonium chloride solution and chloroform, and the organic layer was separated, and the aqueous layer was extracted with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give 2-hydroxynicotinic acid methyl ester (3-067-02) (46 g, 84percent) as a white solid.1H NMR (300 MHz, CDCl3): δ 3.92 (s, 3H), 6.45 (dd, J = 7.3, 6.4 Hz, 1H), 7.78 (dd, J = 6.4, 2.4 Hz, 1H), 8.29 (dd, J = 7.3, 2.4 Hz, 1H)
84%
Stage #1: With sulfuric acid In toluene at 20℃; for 28 h;
Stage #2: With potassium carbonate In water; toluene
To a solution of 2-hydroxynicotinic acid (3-067-01) (50 g) in methanol (500 ml) were added conc. sulfuric acid (15 ml) and toluene (100 mL) at room temperature. After the reaction mixture was stirred for 28 h attached Dienstark reflux tube and neutralized with an aqueous potassium carbonate solution, the solvent was evaporated. To the residue were added aqueous saturated ammonium chloride solution and chloroform, and the organic layer was separated, and the aqueous layer was extracted with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give 2-hydroxynicotinic acid methyl ester (3-067-02) (46 g, 84percent) as a white solid.<1>H NMR (300 MHz, CDCl3): delta 3.92 (s, 3H), 6.45 (dd, J = 7.3, 6.4 Hz, 1H), 7.78 (dd, J = 6.4, 2.4 Hz, 1H), 8.29 (dd, J = 7.3, 2.4 Hz, 1H).
83% at 90℃; for 1 h; Microwave irradiation A mixture of 1.00 g (7.20 mmol) of 2-hydroxypyridine-3-carboxylic acid and 7.20 mL of concentrated H2SO4 in 15.0 mL of CH3OH was heated in microwave at 90 °C for 60 min (power 200 W, pressure 100 psi, stirring off). After cooling the CH3OH was removed by evaporation under reduced pressure. The obtained mixture was treated with a solution of NaHCO3 (pH 7-8) and extracted with CH2Cl2. The organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated to dryness to give the desired compound as a white solid. (0.92 g, yield 83percent) mp: 152-154 °C; 1H NMR (DMSO) δ 12.09 (br, 1H, OH), 8.07 (dd, J = 7.1 and 2.2 Hz, 1H, Ar), 7.68 (dd, J = 6.4 and 2.2 Hz, 1H, Ar), 6.29 (m, 1H, Ar), 3.72 (s, 3H, CH3).
53%
Stage #1: With thionyl chloride In dichloromethane at 75℃; for 3 h;
Stage #2: at 20℃; for 2 h;
Example 117-2 Synthesis of methyl 2-hydroxy nicotinate [0404] After 1 g (7.19 mmol) of 2-hydroxynicotinic acid was dissolved in 20 mL of methylene chloride, 3.4 g (28.8 mmol) of thionyl chloride was added thereto. Afterward, the resulting reaction solution was stirred at about 75° C. for 3 hours. After termination of the reaction was determined by liquid chromatography, the solvent was removed in vacuo. This compound was dissolved in methanol and was then stirred at room temperature for about 2 hours. The compound was extracted three times with water and dichloromethane, and an organic solvent phase was purified using column chromatography (hexane:ethyl acetate=1:1) to obtain a target compound (Actual yield: 480 mg, Percent yield: 53percent).
26.8% With sulfuric acid In tolueneReflux; Dean-Stark 2-hydroxy-nicotinic acid (1.763 g, 12.7 mmol) was suspended in methanol (18 ml). Thereto concentrated sulfuric acid (0.54 ml), heated to reflux overnight using a Dienstark by addition of toluene (4 ml). After the reaction was quench with aqueous potassium carbonate solution. The solvent was distilled off. Chloroform and a saturated aqueous solution of sodium bicarbonate was added, and the mixture was extracted with chloroform. Dried over magnesium sulfate, the solvent was evaporated to give the title compound 522 mg, 26.8percent) as a white solid.

Reference: [1] Patent: EP1477186, 2004, A1, . Location in patent: Page/Page column 41
[2] Patent: EP1357111, 2003, A1, . Location in patent: Page/Page column 59-60
[3] European Journal of Medicinal Chemistry, 2012, vol. 52, p. 284 - 294
[4] Patent: US2013/317059, 2013, A1, . Location in patent: Paragraph 0404
[5] Patent: JP2016/124812, 2016, A, . Location in patent: Paragraph 0331
[6] Journal of Medicinal Chemistry, 1993, vol. 36, # 18, p. 2676 - 2688
[7] Patent: EP2098517, 2009, A1, . Location in patent: Page/Page column 28
[8] Patent: WO2012/102580, 2012, A1, . Location in patent: Page/Page column 72-73
[9] Patent: WO2008/76425, 2008, A1, . Location in patent: Page/Page column 53-54
[10] Patent: WO2008/130600, 2008, A2, . Location in patent: Page/Page column 45
  • 2
  • [ 609-71-2 ]
  • [ 10128-91-3 ]
YieldReaction ConditionsOperation in experiment
22% With sulfuric acid In methanol; water; benzene EXAMPLE 208A
Methyl 2-hydroxynicotinate
2-Hydroxynicotinic acid (6.95 g, 50 mmol) was dissolved in 125 mL of methanol, 75 mL of benzene, and 0.75 mL of concentrated sulfuric acid under nitrogen and heated at reflux for 2.5 hours.
A Dean-Stark trap was added to the apparatus and heating was continued overnight.
The volatiles were removed under reduced pressure and the resulting solid was suspended in cold water (150 mL) and filtered to remove unreacted starting material.
The filtrate was extracted with methylene chloride and chloroform.
The combined organic extracts were concentrated in vacuo to afford 2.5 g.
Recrystallization from hot benzene afforded 1.7 g (22percent) of the title compound. 1 H NMR (CD3 OD, 300 MHz) δ 3.83 (s, 3H), 6.45 (t, 1H), 7.68 (dd, 1H), 8.29 (dd, 1H). MS (DCl/NH3) m/e 154 (M+H)+.
Reference: [1] European Journal of Medicinal Chemistry, 2013, vol. 61, p. 2 - 25
[2] Patent: US5250548, 1993, A,
  • 3
  • [ 67-56-1 ]
  • [ 609-71-2 ]
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Reference: [1] Chemical & Pharmaceutical Bulletin, 1987, vol. 35, # 10, p. 4068 - 4077
  • 4
  • [ 393-55-5 ]
  • [ 10128-91-3 ]
Reference: [1] Patent: US2013/317059, 2013, A1,
[2] Patent: WO2012/102580, 2012, A1,
  • 5
  • [ 67-56-1 ]
  • [ 28369-76-8 ]
  • [ 10128-91-3 ]
Reference: [1] European Journal of Medicinal Chemistry, 2013, vol. 61, p. 2 - 25
  • 6
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  • [ 78686-79-0 ]
Reference: [1] Journal of Organic Chemistry, 1989, vol. 54, # 15, p. 3618 - 3624
  • 7
  • [ 10128-91-3 ]
  • [ 78686-83-6 ]
Reference: [1] Journal of Medicinal Chemistry, 1993, vol. 36, # 18, p. 2676 - 2688
[2] Patent: WO2008/76425, 2008, A1,
[3] Patent: WO2008/130600, 2008, A2,
  • 8
  • [ 10128-91-3 ]
  • [ 78686-83-6 ]
Reference: [1] Journal of Organic Chemistry, 1989, vol. 54, # 15, p. 3618 - 3624
  • 9
  • [ 10128-91-3 ]
  • [ 120034-05-1 ]
Reference: [1] Journal of Organic Chemistry, 1989, vol. 54, # 15, p. 3618 - 3624
  • 10
  • [ 10128-91-3 ]
  • [ 116387-40-7 ]
YieldReaction ConditionsOperation in experiment
81% With N-iodo-succinimide In dichloromethane at 20℃; for 16 h; Heating / reflux To a solution of 2-hydroxynicotinic acid methyl ester (3-067-02) (20 g) in methylene chloride (500 mL) was added N-iodosuccinimide (NIS, 38 g) at room temperature, and the reaction mixture was heated under reflux for 16 h, and evaporated. To the residue was added ethyl acetate (200 mL) and the reaction mixture was heated under reflux for 2 h. The insoluble solid was filtered to give 2-hydroxy-5-iodonicotinic acid methyl ester (3-067-03) (30 g, 81percent) as a white solid.1H NMR (300 MHz, CDCl3): δ 3.97 (s, 3H), 8.33 (brs, 1H), 8.43 (d, J = 2.4 Hz, 1H).
81% With N-iodo-succinimide In dichloromethane; ethyl acetate at 20℃; for 18 h; Heating / reflux To a solution of 2-hydroxynicotinic acid methyl ester (3-067-02) (20 g) in methylene chloride (500 mL) was added N-iodosuccinimide (NIS, 38 g) at room temperature, and the reaction mixture was heated under reflux for 16 h, and evaporated. To the residue was added ethyl acetate (200 mL) and the reaction mixture was heated under reflux for 2 h. The insoluble solid was filtered to give 2-hydroxy-5-iodonicotinic acid methyl ester (3-067-03) (30 g, 81percent) as a white solid.<1>H NMR (300 MHz, CDCl3): delta 3.97 (s, 3H), 8.33 (brs, 1H), 8.43 (d, J= 2.4 Hz, 1H).
Reference: [1] Journal of Medicinal Chemistry, 1993, vol. 36, # 18, p. 2676 - 2688
[2] Patent: EP1477186, 2004, A1, . Location in patent: Page/Page column 41
[3] Patent: EP1357111, 2003, A1, . Location in patent: Page/Page column 59-60
[4] Patent: US2005/203081, 2005, A1, . Location in patent: Page/Page column 13
[5] Patent: WO2008/76425, 2008, A1, . Location in patent: Page/Page column 54
[6] Patent: WO2008/130600, 2008, A2, . Location in patent: Page/Page column 46
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