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[ CAS No. 17368-12-6 ] {[proInfo.proName]}

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Chemical Structure| 17368-12-6
Chemical Structure| 17368-12-6
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Product Details of [ 17368-12-6 ]

CAS No. :17368-12-6 MDL No. :MFCD01646108
Formula : C5H4ClNO Boiling Point : -
Linear Structure Formula :- InChI Key :VBEHFOMFHUQAOW-UHFFFAOYSA-N
M.W : 129.54 Pubchem ID :87010
Synonyms :
2-Chloro-4-pyridinol

Calculated chemistry of [ 17368-12-6 ]

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 31.27
TPSA : 33.12 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.05 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.2
Log Po/w (XLOGP3) : 1.46
Log Po/w (WLOGP) : 1.44
Log Po/w (MLOGP) : 0.4
Log Po/w (SILICOS-IT) : 1.61
Consensus Log Po/w : 1.22

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.12
Solubility : 0.987 mg/ml ; 0.00762 mol/l
Class : Soluble
Log S (Ali) : -1.76
Solubility : 2.24 mg/ml ; 0.0173 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.03
Solubility : 1.21 mg/ml ; 0.00938 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.49

Safety of [ 17368-12-6 ]

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 [ 17368-12-6 ]

* 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 [ 17368-12-6 ]
  • Downstream synthetic route of [ 17368-12-6 ]

[ 17368-12-6 ] Synthesis Path-Upstream   1~11

  • 1
  • [ 14432-12-3 ]
  • [ 17368-12-6 ]
YieldReaction ConditionsOperation in experiment
92%
Stage #1: With sulfuric acid; sodium nitrite In water at 0 - 20℃; for 24 h;
Stage #2: With sodium hydroxide In water
In a recovery flask, 4-amino-2-chloropyridine (3.0 g, 23.3 mmol) was dissolved in 40percent sulfuric acid (50 g) . While the solution was stirred at 00C, sodium nitrite (1.93 g, 28.0 mmol) was added. The mixture was stirred at room temperature for 24 hours. After the reaction completed, the reaction <n="39"/>liquid was neutralized by adding an aqueous sodium hydroxide solution and an aqueous sodium hydrogencarbonate solution. The organic phase was extracted with ethyl acetate. The organic phase was then dried over magnesium sulfate, filtered, distilled to remove the solvent, and dried under reduced pressure to give 2-chloro-4-hydroxypyridine (light brown solid). The solid weighed 2.78 g, and the yield was 92percent. [0088]1H-NMR (270 MHz, DMSO-d6) ppm: 11.20 (s, IH, -OH), 8.09 (d, IH, J = 5.4 Hz, ArH), 6.81 (s, IH, ArH), 6.77 (d, IH, J = 2.2 Hz, ArH)
Reference: [1] Patent: WO2009/11447, 2009, A2, . Location in patent: Page/Page column 37-38
  • 2
  • [ 23056-36-2 ]
  • [ 17368-12-6 ]
Reference: [1] Organic Letters, 2005, vol. 7, # 4, p. 577 - 579
  • 3
  • [ 458532-96-2 ]
  • [ 17368-12-6 ]
Reference: [1] Tetrahedron, 2005, vol. 61, # 6, p. 1417 - 1421
  • 4
  • [ 73583-37-6 ]
  • [ 17368-12-6 ]
Reference: [1] Angewandte Chemie - International Edition, 2018, vol. 57, # 7, p. 1968 - 1972[2] Angew. Chem., 2018, vol. 130, p. 1986 - 1990,5
  • 5
  • [ 458532-84-8 ]
  • [ 17368-12-6 ]
Reference: [1] Tetrahedron, 2005, vol. 61, # 6, p. 1417 - 1421
  • 6
  • [ 17228-67-0 ]
  • [ 17368-12-6 ]
Reference: [1] Journal of Organic Chemistry, 1980, vol. 45, # 8, p. 1347 - 1353
  • 7
  • [ 17368-12-6 ]
  • [ 74-88-4 ]
  • [ 17228-69-2 ]
Reference: [1] Patent: WO2016/95204, 2016, A1, . Location in patent: Page/Page column 57
  • 8
  • [ 17368-12-6 ]
  • [ 75-03-6 ]
  • [ 52311-50-9 ]
Reference: [1] Patent: WO2014/137883, 2014, A1, . Location in patent: Page/Page column 37
  • 9
  • [ 17368-12-6 ]
  • [ 394729-98-7 ]
Reference: [1] Patent: WO2016/95204, 2016, A1,
  • 10
  • [ 17368-12-6 ]
  • [ 2105-61-5 ]
  • [ 1225278-64-7 ]
YieldReaction ConditionsOperation in experiment
81%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 1 h; Inert atmosphere
Stage #2: at 90℃; for 3 h; Inert atmosphere
Sodium hydride (136 mg, 3.4 mmol, 60percent in mineral) was added to a O°C solution of 2-chloropyridin-4-ol (2 g, 15.4 mmol) in DMF (38 mL) under Ar. The mixture was stirred at 0 °C for 1 h. A solution of 1,2,4-trifluoro-5-nitrobenzene (626 mg, 3.1 mmol) in DMF (7.6 ml) was added and the reaction was stirred under Ar at 90 °C for 3 h. The mixture was cooled to RT and stirred overnight. The solvent was removed under reduced pressure and the crude product was partitioned between water (50 ml) and EtOAc (50 ml). The mixture was extracted with EtOAc (3 x 50 ml). The combined organic extracts were washed with brine, dried (Na2SO4), concentrated under reduced pressure and purified by silica gel column chromatography (hexanes/EtOAc) to yield 2-chloro-4-(2,5-difluoro-4-nitrophenoxy)pyridine (3.57 g, 81percent yield). 1H NMR (400 MHz, DMSO-d6): δ 8.43-8.33 (m, 2H), 7.85-7.79 (m, 1 H), 7.33 (d, 1H), 7.20-7.18 (m , 1H); MS (ESI) m/z: 287.0 (M+H+).
80%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil for 0.75 h; Cooling with ice; Inert atmosphere
Stage #2: at 20℃; for 18 h;
Example Al : Sodium hydride (60percent by weight in mineral oil) (3.08 g, 77 mmol) was placed in a 500 mL round bottom flask flushed with argon. DMF (140 mL) was added and the mixture was cooled in an ice bath. 2-Chloro-4-hydroxypyridine (7.68 g, 59.3 mmol) was then added slowly over 45 minutes. After addition of the hydroxypyridine was complete 2,4,5- trifluoronitrobenzene ( 10.5 g, 59.3 mmol) was added as a solution in DMF (29 mL). The mixture was warmed to room temperature and stirred for 18 hours. The reaction mixture was concentrated under reduced pressure to remove the majority of DMF in the mixture, and was then partitioned between ethyl acetate (300 mL) and 10percent aqueous lithium chloride ( 1 50 mL). A precipitate formed which was removed via suction filtration and then the layers were separated. The organic layer was washed with additional 10percent aqueous lithium chloride (2 x 150 mL), saturated aqueous sodium bicarbonate (150 mL) and brine (150 mL). The organic layer was dried over magnesium sulfate and evaporated to yield a dark red solid which was purified by silica gel chromatography ( 10 to 30percent ethyl acetate/hexane) to give 2-chloro-4-(2,5-difluoro-4- nitrophenoxy)pyridine (13.56g, 80percent yield) as a yellow solid. NMR (400MHz, DMSO-t 6): δ 8.45 (dd, 1 H), 8.39 (d, 1 H), 7.87 (dd, 1 H), 7.39 (d, 1 H), 7.24 (dd, 1 H); MS (ESI) m/z: 287.0 (M+H+).
74.5%
Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 15 - 25℃; for 0.166667 h;
Stage #2: for 1.16667 h;
To a solution of 2-chloropyridin-4-ol (100 g, 772 mmol) in anhydrous DMF (2 L) was added K2CO3 (128 g, 926 mmol) in one portion at RT. The mixture was stirred for 10 min at RT, and was then treated with 1 ,2,4-trifluoro-5-nitrobenzene (88 mL, 772 mmol) slowly over 10 min. The internal temp of the reaction mixture was maintained below 24 °C during the addition. The reaction was stirred at RT for 1 h and then it was stopped by adding ice/water (10 L). The mixture was stirred for 2 h and then filtered to remove the solids. The solids were washed with water (5 L), hexanes (3 L) and then dried under vacuum at 50 °C to give 194.7 g of crude material. The solids were treated with MTBE (200 mL), stirred for 2 h, collected by filtration, washed with MTBE (50 mL) and dried under vacuum at 40 °C for 3 h to afford 2-chloro-4-(2,5-difluoro-4-nitrophenoxy)pyridine (164.6 g, 74.5percent yield). 1H NMR (400 MHz, DMSO-i¼): δ 8.48 (dd, J = 10.2, 7.0 Hz, 1 H), 8.41 (d, J = 5.6 Hz, 1 H), 7.90 (dd, J = 11.6, 6.7 Hz, 1 H), 7.41 (d, J = 2.1 Hz, 1 H), 7.26 (dd, J = 5.6, 2.4 Hz, 1 H); MS (ESI): m/z 287.0 (M+H+).
63%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.416667 h; Inert atmosphere; Cooling with ice
Stage #2: at 90℃; for 3 h;
Example Al: Anhydrous DMF (150 mL) was added to 60percent NaH in mineral oil (2.72 g, 67.9 mmol) under an Ar atmosphere, cooled in an ice bath, treated portion-wise with a solution of 2-chloropyridin-4-ol (8 g, 61.8 mmol) in DMF (30 mL) and stirred cold for 5 minutes. The cooling bath was removed and the mixture was warmed to RT and stirred for 20 minutes. 1 ,2,4-Trifluoro-5 -nitrobenzene (13.12 g, 74.1 mmol) was added and the reaction mixture heated at 90°C for 3 h. The reaction mixture was cooled to RT, concentrated to dryness, treated with EtOH (50 mL) and MeOH (20 mL), warmed gently, then cooled to RT. The yellow solid was collected by filtration, rinsed with EtOH (50 mL) and hexanes (20 mL) and dried under vacuum overnight to provide 2-chloro-4-(2,5-difluoro-4-nitrophenoxy)pyridine as a yellow solid (11.68 g, 63percent yield). ‘H NMR (400 MHz, DMSO-d6): 5 8.48 (dd, J = 10.2, 7.0 Hz, 1 H), 8.41 (d, J = 5.6 Hz, 1 H), 7.90 (dd, J = 11.6, 6.7 Hz, 1 H), 7.41 (d, J = 2.1 Hz, 1 H), 7.26 (dd, J = 5.6, 2.4 Hz, 1 H); MS (ESI): m/z 287.0 [M+H]
63%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.416667 h; Inert atmosphere; Cooling with ice
Stage #2: at 90℃; for 3 h; Inert atmosphere
Anhydrous DMF (150 mL) was added to 60percent NaH in mineral oil (2.72 g, 67.9 mmol) under an Ar atmosphere, cooled in an ice bath, treated portion-wise with a solution of 2-chloropyridin-4-ol (8 g, 61.8 mmol) in DMF (30 mL) and stirred cold for 5 minutes.
The cooling bath was removed and the mixture was warmed to RT and stirred for 20 minutes. 1,2,4-Trifluoro-5-nitrobenzene (13.12 g, 74.1 mmol) was added and the reaction mixture heated at 90° C. for 3 h.
The reaction mixture was cooled to RT, concentrated to dryness, treated with EtOH (50 mL) and MeOH (20 mL), warmed gently, then cooled to RT.
The yellow solid was collected by filtration, rinsed with EtOH (50 mL) and hexanes (20 mL) and dried under vacuum overnight to provide 2-chloro-4-(2,5-difluoro-4-nitrophenoxy)pyridine as a yellow solid (11.68 g, 63percent yield).
1H NMR (400 MHz, DMSO-d): δ 8.48 (dd, J=10.2, 7.0 Hz, 1H), 8.41 (d, J=5.6 Hz, 1H), 7.90 (dd, J=11.6, 6.7 Hz, 1H), 7.41 (d, J=2.1 Hz, 1H), 7.26 (dd, J=5.6, 2.4 Hz, 1H); MS (ESI): m/z 287.0 [M+H]

Reference: [1] Patent: WO2010/51373, 2010, A1, . Location in patent: Page/Page column 73-74
[2] Patent: WO2011/137342, 2011, A1, . Location in patent: Page/Page column 31
[3] Patent: WO2013/78295, 2013, A2, . Location in patent: Paragraph 00171
[4] Patent: WO2014/145004, 2014, A1, . Location in patent: Paragraph 0100
[5] Patent: US2014/315917, 2014, A1, . Location in patent: Paragraph 0312
  • 11
  • [ 17368-12-6 ]
  • [ 4333-56-6 ]
  • [ 1209458-93-4 ]
YieldReaction ConditionsOperation in experiment
300 mg With caesium carbonate; sodium iodide In N,N-dimethyl acetamide at 170 - 180℃; for 0.833333 h; Microwave irradiation To a solution of 2-chloropyridin-4-ol (1 g, 7.75 mmol) in DMA (10 ml) was added bromocyclopropane (2.8 g, 23.2 mmol), Nal (1.16 g, 7.75 mmol) and CS2CO3 (5 g, 15.5 mmol). The mixture was stirred at MW 170 °C for 20 minutes, and then MW 180 °C for 30 minutes. The reaction mixture was extracted with EA. The organic layer was dried and concentrated. The residue was purified by flash column chromatography to give 300 mg of 2-chloro-4-cyclopropoxypyridine. 1H NMR (400MHz, CDC13) δ = 8.19 (d, J=5.8 Hz, IH), 7.02 (d, J=2.0 Hz, IH), 6.87 (dd, J=2.0, 5.8 Hz, IH), 3.80 (tt, J=3.0, 6.0 Hz, IH), 0.91 - 0.75 (m, 4H).
300 mg at 170℃; for 0.333333 h; Microwave irradiation (a)
2-chloro-4-cyclopropoxypyridine
To a solution of 2-chloropyridin-4-ol (1 g, 7.75 mmol) in DMA (10 ml) was added bromocyclopropane (2.8 g, 23.2 mmol), NaI (1.16 g, 7.75 mmol) and Cs2CO3 (5 g, 15.5 mmol).
The mixture was stirred at MW 170° C. for 20 minutes, and then MW 180° C. for 30 minutes.
The reaction mixture was extracted with EA.
The organic layer to was dried and concentrated.
The residue was purified by flash column chromatography to give 300 mg of 2-chloro-4-cyclopropoxypyridine.
1H NMR (400 MHz, CDCl3) δ=8.19 (d, J=5.8 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 6.87 (dd, J=2.0, 5.8 Hz, 1H), 3.80 (tt, J=3.0, 6.0 Hz, 1H), 0.91-0.75 (m, 4H),
300 mg With caesium carbonate; sodium iodide In N,N-dimethyl acetamide at 170 - 180℃; for 0.833333 h; To a solution of 2-chloropyridin-4-ol (1 g, 7.75 mmol) in DMA (10 ml) was added bromocyclopropane (2.8 g, 23.2 mmol), Nal (1.16 g, 7.75 mmol) and CS2CO3 (5 g, 15.5 mmol). The mixture was stirred at MW 170 °C for 20 minutes, and then MW 180 °C for 30 minutes. The reaction mixture was extracted with EA. The organic layer was dried and concentrated. The residue was purified by flash column chromatography to give 300 mg of 2-chloro-4-cyclopropoxypyridine. 1H NMR (400MHz, CDC13 ) δ = 8.19 (d, J=5.8 Hz, IH), 7.02 (d, J=2.0 Hz, IH), 6.87 (dd, J=2.0, 5.8 Hz, IH), 3.80 (tt, J=3.0, 6.0 Hz, IH), 0.91 - 0.75 (m, 4H)
Reference: [1] Patent: WO2014/114185, 2014, A1, . Location in patent: Page/Page column 162
[2] Patent: US2014/206681, 2014, A1, . Location in patent: Paragraph 0889; 0890
[3] Patent: WO2014/113932, 2014, A1, . Location in patent: Page/Page column 119
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