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[ CAS No. 68325-15-5 ] {[proInfo.proName]}

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Chemical Structure| 68325-15-5
Chemical Structure| 68325-15-5
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Product Details of [ 68325-15-5 ]

CAS No. :68325-15-5 MDL No. :MFCD05663706
Formula : C6H3ClN2 Boiling Point : -
Linear Structure Formula :- InChI Key :JLLJPPBGJVCFGG-UHFFFAOYSA-N
M.W : 138.55 Pubchem ID :10678306
Synonyms :

Calculated chemistry of [ 68325-15-5 ]

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 33.96
TPSA : 36.68 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.33 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.32
Log Po/w (XLOGP3) : 1.15
Log Po/w (WLOGP) : 1.61
Log Po/w (MLOGP) : 0.4
Log Po/w (SILICOS-IT) : 1.98
Consensus Log Po/w : 1.29

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.92
Solubility : 1.68 mg/ml ; 0.0121 mol/l
Class : Very soluble
Log S (Ali) : -1.51
Solubility : 4.23 mg/ml ; 0.0306 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.7
Solubility : 0.278 mg/ml ; 0.002 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.53

Safety of [ 68325-15-5 ]

Signal Word:Danger Class:6.1
Precautionary Statements:P261-P280-P305+P351+P338-P311 UN#:3439
Hazard Statements:H302+H312-H315-H319-H331-H335 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 68325-15-5 ]

* 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 [ 68325-15-5 ]
  • Downstream synthetic route of [ 68325-15-5 ]

[ 68325-15-5 ] Synthesis Path-Upstream   1~20

  • 1
  • [ 616-47-7 ]
  • [ 67-66-3 ]
  • [ 14508-49-7 ]
  • [ 17180-94-8 ]
  • [ 51269-82-0 ]
  • [ 68325-15-5 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1431 - 1435
  • 2
  • [ 626-60-8 ]
  • [ 7677-24-9 ]
  • [ 89809-64-3 ]
  • [ 38180-46-0 ]
  • [ 68325-15-5 ]
Reference: [1] Chemistry - A European Journal, 2017, vol. 23, # 59, p. 14733 - 14737
  • 3
  • [ 616-47-7 ]
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  • [ 14508-49-7 ]
  • [ 17180-94-8 ]
  • [ 51269-82-0 ]
  • [ 68325-15-5 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1431 - 1435
  • 4
  • [ 626-60-8 ]
  • [ 7677-24-9 ]
  • [ 89809-64-3 ]
  • [ 38180-46-0 ]
  • [ 68325-15-5 ]
Reference: [1] Chemistry - A European Journal, 2017, vol. 23, # 59, p. 14733 - 14737
  • 5
  • [ 100-48-1 ]
  • [ 68325-15-5 ]
YieldReaction ConditionsOperation in experiment
53%
Stage #1: With 2,2,6,6-tetramethyl-piperidine In tetrahydrofuran at -78 - 25℃; for 0.5 h;
Stage #2: With hexachloroethane In tetrahydrofuran at -78℃; for 0.5 h;
To a stirred solution of 2,2,6,6-tetramethyl piperidine (17.16 mL, 100.854 mmol) in THF (100 mL) was added n-BuLi (2.17 M, 44.26 mL, 96.052 mmol) at -30°C. After stirring the mixture for 15 mm at 25°C, it was cooled to -78°C and 4-cyanopyridine (5 g, 48.026 mmol) in THF (40 mL) was added dropwise. After stirring the reaction mixture for 30 mm at -78°C, hexachioroethane (23.87 g, 100.854 mmol) in THF (50 mL) was added at -78°C. The resulting mixture was stirred for 30 mm at -78°C and was quenched with saturated NH4C1 solution. Water (100 mL) was added to the reaction mixture and extracted with ethyl acetate (4 x 300 mL). The combined organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford the crude material which was purified by column chromatography using silica (100-200 mesh) and 5percent EtOAc-hexane as eluent to afford 3-chloropyridine-4-carbonitrile (3.5 g, 25.26 1 mmol, 53percent) as pale white solid. GCMS: 138 (mlz).
Reference: [1] Tetrahedron, 2006, vol. 62, # 25, p. 5862 - 5867
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 22, p. 10118 - 10129
[3] Patent: WO2014/186035, 2014, A1, . Location in patent: Page/Page column 182; 183
[4] Tetrahedron Letters, 2005, vol. 46, # 1, p. 135 - 137
[5] Journal of the American Chemical Society, 2013, vol. 135, # 24, p. 9213 - 9219
  • 6
  • [ 14906-59-3 ]
  • [ 68325-15-5 ]
YieldReaction ConditionsOperation in experiment
44.8% With hydrogenchloride; sodium hydroxide; phosphorus pentachloride; trichlorophosphate In n-heptane; water Preparation 71
3-Chloro-isonicotinonitrile
The title compound was prepared by a modified procedure based on the method of J.
Rokach and Y. Girard, J. Heterocycl. Chem. 1978, 15, 683-684. 4-Cyanopyridine-N-oxide (250 g, 2.08 mol) was added portionwise to a stirred suspension of PCl5 (599.94 g, 2.88 mol) and POCl3 (800 mL, 8.71 mol) at 20° C. under nitrogen, in a reactor fitted with a reflux condenser.
During the addition the temperature rose to 41° C.
The mixture was stirred at 100° C. for 3 h then cooled to 95° C. and transferred to a mixture of 6M HCl (200 mL) and a 6:4 mixture of ice and water (5994 g) at such a rate that the temperature stayed below 15° C. (about 35 min).
The resulting brown solution was cooled to below 5° C. and taken to pH 4.15 by adding 33percent aqueous NaOH (about 4.5 L), keeping the temperature below 5° C.
The resulting beige precipitate was filtered and washed thoroughly with water (4*500 mL), sucking as dry as possible.
The residue was suspended in water (1.5 L) and n-heptane (7 L) and stirred at 30° C. for 1 h.
The aqueous phase was separated and extracted further with n-heptane (2*2 L), stirring for 30 min each time at 30° C.
The combined heptane layers were combined, dried (Na2SO4, 136 g), filtered and the resulting solution was concentrated under reduced pressure to a weight of 1.9 kg (about 3 L), at which point the product began to crystallise.
The mixture was cooled to 0° C., stirred for 1.5 h then the product was filtered, washed with cold n-heptane (2*125 mL) and dried at room temperature in a circulating air drier to give the product (129.08 g, 44.8percent) as a crystalline solid; m.p. 73.4° C.
39.9%
Stage #1: at 105℃;
Stage #2: at 0℃;
Step A: Preparation of 3-chloroisonicotinonitrile: In a 4 neck 3L round bottom flask equipped with mechanical stirrer and condenser, was added 4-cyanopyridine-n- oxide (50 g, 416 mmol), phosphoryl trichloride (153 ml, 1665 mmol), and phosphorous pentachloride(121 g, 583 mmol). The reaction was stirred at 105 0C overnight. The reaction mixture was cooled and then slowly added in portions to 2 kg ice. The pH was adjusted to about 8 by slow addition of 50percent NaOH. The mixture was extracted with ethyl acetate. The organic layer was dried and concentrated. The residue was purified by silica gel chromatography, eluting with 5-10percent ethyl acetate to give the desired product (23 g, 39.9percent yield) as light yellow solid.
39.9%
Stage #1: at 105℃;
Stage #2: With sodium hydroxide In water at 0℃;
Example 205 (Representative Example) 3-(2-chloropyridm-4-yloxy)isomcotinonitrile[00586] Step A: Preparation of 3-chloroisonicotinoiiitrile: In a 4 neck 3L round bottom flask equipped with mechanical stirrer and condenser, was added 4-cyanopyridine-n-oxide (50 g, 416 mmol), phosphoryl trichloride (153 ml, 1665 mmol). and phosphorous pentachloride(121 g5 583 mmol). The reaction was stirred at 105 0C overnight. The reaction mixture was cooled and then slowly added in portions to 2 kg ice. The pH was adjusted to about 8 by slow addition of 50percent NaOH. The mixture was extracted with ethyl acetate. The organic layer was dried and concentrated. The residue was purified by silica gel chromatography, eluting with 5-10percent ethyl acetate to give the desired product (23 g, 39.9percent yield) as light yellow solid.
21% With phosphorus pentachloride In trichlorophosphate at 120 - 130℃; for 2 h; Example 25.1 : 3-Chloro-isonicotinonitrile. A mixture of 1 -oxy-isonicotinonitrile (5.0 g, 0.042 mol), phosphorus pentachloride (12.0 g, 0.059 mol) and phosphorus oxychloridc (20 mL) was heated at 120-130° C for 2 hours. The reaction mixture was cooled, poured into ice and neutralized by the addition of solid sodium bicarbonate. The mixture was extracted with diethyl ether and the combined organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel to give 3-chloro-isonicotinonitrile (1.2 g, 21 percent). 1H NMR (300 MHz, CDCl3): δ(ppm) 8.65 (s, IH), 8.52 (d, IH), 7.40 (d, IH).

Reference: [1] Synthetic Communications, 1997, vol. 27, # 17, p. 2905 - 2916
[2] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 13, p. 4523 - 4536
[3] Patent: US2003/207857, 2003, A1,
[4] Patent: WO2008/91770, 2008, A1, . Location in patent: Page/Page column 32
[5] Patent: WO2007/89512, 2007, A1, . Location in patent: Page/Page column 194
[6] Patent: WO2008/112440, 2008, A1, . Location in patent: Page/Page column 43
[7] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 7, p. 1359 - 1362
  • 7
  • [ 620535-14-0 ]
  • [ 68325-15-5 ]
Reference: [1] Organic and Biomolecular Chemistry, 2013, vol. 11, # 15, p. 2466 - 2472
  • 8
  • [ 72990-37-5 ]
  • [ 68325-15-5 ]
Reference: [1] Organic and Biomolecular Chemistry, 2013, vol. 11, # 15, p. 2466 - 2472
  • 9
  • [ 626-60-8 ]
  • [ 7677-24-9 ]
  • [ 89809-64-3 ]
  • [ 38180-46-0 ]
  • [ 68325-15-5 ]
Reference: [1] Chemistry - A European Journal, 2017, vol. 23, # 59, p. 14733 - 14737
  • 10
  • [ 616-47-7 ]
  • [ 67-66-3 ]
  • [ 14508-49-7 ]
  • [ 17180-94-8 ]
  • [ 51269-82-0 ]
  • [ 68325-15-5 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1431 - 1435
  • 11
  • [ 68325-15-5 ]
  • [ 78790-79-1 ]
Reference: [1] Journal of Medicinal Chemistry, 2005, vol. 48, # 3, p. 664 - 670
[2] Journal of Organic Chemistry, 1981, vol. 46, # 21, p. 4179 - 4182
  • 12
  • [ 68325-15-5 ]
  • [ 2365-48-2 ]
  • [ 111042-91-2 ]
YieldReaction ConditionsOperation in experiment
80% With potassium carbonate In acetonitrile at 25℃; for 3 h; Reflux To a stirred solution of 3-chloropyridine-4-carbonitrile (6.2 g, 44.92 mmol) in MeCN (60 mL) was added mercapto-acetic acid methyl ester (4.26 mL, 47.173 mmol) and K2C03 (12.4 g, 89.855 mmol) at 25°C. The reaction mixture was refluxed for 3 hr and was concentrated under reduced pressure. The resulting residue was diluted with water (100 mL) and extracted with EtOAc (4 x 200 mL). The combined organic layer was dried over sodium sulfate and was concentrated under reduced pressure to afford the crude material which was purified by trituration with n-pentane to afford methyl 3-aminothieno[2,3-c]pyridine-2-carboxylate (7.5 g, 36.0 16 mmol, 80percent) as pale yellow solid. LCMS: 209 (M+H).
Reference: [1] Patent: WO2014/186035, 2014, A1, . Location in patent: Page/Page column 183
[2] Journal of Heterocyclic Chemistry, 1987, vol. 24, p. 85 - 89
  • 13
  • [ 68325-15-5 ]
  • [ 80935-77-9 ]
Reference: [1] Chemical & Pharmaceutical Bulletin, 1985, vol. 33, # 2, p. 626 - 633
  • 14
  • [ 68325-15-5 ]
  • [ 78790-88-2 ]
Reference: [1] Journal of Organic Chemistry, 1981, vol. 46, # 21, p. 4179 - 4182
  • 15
  • [ 68325-15-5 ]
  • [ 83431-02-1 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 17, p. 5352 - 5359
  • 16
  • [ 68325-15-5 ]
  • [ 114080-93-2 ]
Reference: [1] Zeitschrift fuer Chemie (Stuttgart, Germany), 1987, vol. 27, # 9, p. 337 - 338
  • 17
  • [ 546-88-3 ]
  • [ 68325-15-5 ]
  • [ 114080-94-3 ]
YieldReaction ConditionsOperation in experiment
41% With potassium carbonate In N,N-dimethyl-formamide at 20℃; Intermediate 1 : lsoxazolo[5,4-cipyridin-3-ylamine.; To a solution of 3-chloro-isonicotinitrile (1.13 g, 8.36 mmol) in DMF (6.0 mL) were added potassium carbonate (1.69 g, 12.2 mmol) and acetohydroxamic acid (0.91 g, 12.2 mmol). The reaction mixture was stirred at rt overnight, diluted with EtOAc (200 mL) and extracted with saturated aqueous NaHCO3 (200 mL) then saturated aqueous NaCI (100 mL). The aqueous layers were back extracted with EtOAc (200 mL) and the combined organic layers were dried (MgSO4) and concentrated. The crude residue was purified (FCC, 2 N NH3 in MeOH/DCM) to give isoxazolo[5,4-c]pyhdin-3-ylamine (0.447 g, 41 percent). MS (ESI+): calcd for C6H5N3O m/z 135.04, found 136.2 (M+H)+. 1H NMR (d6-DMSO): 8.93 (d, J = 0.8, 1 H), 8.45 (d, J = 5.2, 1 H), 7.88-7.86 (dd, J = 5.2, 1.2, 1 H), 6.72 (br s, 2H).
Reference: [1] Patent: WO2010/68452, 2010, A1, . Location in patent: Page/Page column 26
[2] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 24, p. 7357 - 7362
  • 18
  • [ 68325-15-5 ]
  • [ 114080-94-3 ]
YieldReaction ConditionsOperation in experiment
41% With acetylhydroxamic acid; potassium carbonate In N,N-dimethyl-formamide at 20℃; Inert atmosphere Intermediate 1 : lsoxazolo[5,4-c1pyridin-3-ylamine.; To a solution of 3-chloro-isonicotinitrile (1.13 g, 8.36 mmol) in DMF (6.0 mL) were added potassium carbonate (1.69 g, 12.2 mmol) and acetohydroxamic acid (0.91 g, 12.2 mmol). The reaction mixture was stirred at rt overnight, diluted with EtOAc (200 mL) and extracted with saturated aqueous NaHCO3 (200 mL) then saturated aqueous NaCI (100 mL). The aqueous layers were back extracted with EtOAc (200 mL) and the combined organic layers were dried (MgSO4) and concentrated. The crude residue was purified (FCC, 2 N NH3 in MeOH/DCM) to give isoxazolo[5,4-c]pyhdin-3-ylamine (0.447 g, 41 percent). MS (ESI+): calcd for C6H5N3O m/z 135.04, found 136.2 (M+H)+. 1H NMR (d6-DMSO): 8.93 (d, J = 0.8, 1 H), 8.45 (d, J = 5.2, 1 H), 7.88-7.86 (dd, J = 5.2, 1.2, 1 H), 6.72 (br s, 2H).
Reference: [1] Patent: WO2010/68453, 2010, A1, . Location in patent: Page/Page column 30
  • 19
  • [ 68325-15-5 ]
  • [ 87032-82-4 ]
Reference: [1] Patent: WO2007/89512, 2007, A1,
  • 20
  • [ 68325-15-5 ]
  • [ 654663-32-8 ]
Reference: [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 22, p. 10118 - 10129
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