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[ CAS No. 22282-70-8 ] {[proInfo.proName]}

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Chemical Structure| 22282-70-8
Chemical Structure| 22282-70-8
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Product Details of [ 22282-70-8 ]

CAS No. :22282-70-8 MDL No. :MFCD03092926
Formula : C5H3FIN Boiling Point : -
Linear Structure Formula :- InChI Key :ADPRIAVYIGHFSO-UHFFFAOYSA-N
M.W :222.99 Pubchem ID :7023570
Synonyms :

Calculated chemistry of [ 22282-70-8 ]

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 : 0.0
Molar Refractivity : 36.91
TPSA : 12.89 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) : -6.28 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.72
Log Po/w (XLOGP3) : 1.94
Log Po/w (WLOGP) : 2.25
Log Po/w (MLOGP) : 1.85
Log Po/w (SILICOS-IT) : 2.83
Consensus Log Po/w : 2.12

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.0
Solubility : 0.223 mg/ml ; 0.001 mol/l
Class : Soluble
Log S (Ali) : -1.84
Solubility : 3.26 mg/ml ; 0.0146 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -3.26
Solubility : 0.122 mg/ml ; 0.000548 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.96

Safety of [ 22282-70-8 ]

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 [ 22282-70-8 ]

* 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 [ 22282-70-8 ]
  • Downstream synthetic route of [ 22282-70-8 ]

[ 22282-70-8 ] Synthesis Path-Upstream   1~18

  • 1
  • [ 22282-70-8 ]
  • [ 552331-00-7 ]
YieldReaction ConditionsOperation in experiment
90% With ammonium hydroxide In dimethyl sulfoxide at 100℃; for 40 h; A mixture of 2-fluoro-4-iodopyridine (10.00g, 43.50mmol), ammonium hydroxide (10mL) in DMSO (20mL) was stirred at 100 °C for 40 hours. H2O (100mL) was added to the reaction mixture and the precipitate was filtered to afford the compound 10a as a brown solid (8.62g, 90percent). MS: 221 (M+H) +.
60% With ammonia In water at 150℃; for 3 h; Sealed tube Reference Example 2; 4-iodopyridin-2-amine2-Fluoro-4-iodopyridine (11.2 g, 50 mmol) obtained in Reference Example 1 and 28percent aqueous ammonia solution (100 ml) were stirred at 150° C. for 3 hr in a sealed tube. The mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous sodium hydrogensulfate. The solvent was evaporated under reduced pressure. The obtained residue was crystallized from ethyl acetate to give the title compound (6.6 g, yield 60percent). melting point 167-168° C.1H-NMR (CDCl3) δ: 4.34 (2H, brs), 6.92 (1H, d, J=1.4 Hz), 6.99 (1H, dd, J=5.5, 1.4 Hz), 7.73 (1H, d, J=5.5 Hz).
37% With acetamide; potassium carbonate In ethyl acetate at 180℃; for 7 h; Example 75A
2-Amino-4-iodopyridine
A mixture of 2-floro-4-iodopyridine (3.0 g, 13.5 mmol), acetylamide (15.8 g, 269 mmol) and potassium carbonate (9.2 g, 67 mmol) was stirred at 180° C. for 7 hours, poured into ice (100 g), extracted with ethyl acetate, washed with brine, dried (MgSO4), filtered, and concentrated.
The concentrate was purified by flash column chromatography on silica gel with 50percent ethyl acetate/hexane to provide the title compound (1.1 g, 37percent). MS (DCI/NH3) m/e 221 (M+H).
Reference: [1] Patent: WO2017/211303, 2017, A1, . Location in patent: Page/Page column 43
[2] Patent: US2011/39893, 2011, A1, . Location in patent: Page/Page column 25
[3] Patent: US2003/199511, 2003, A1, . Location in patent: Page/Page column 33
  • 2
  • [ 60-35-5 ]
  • [ 22282-70-8 ]
  • [ 552331-00-7 ]
YieldReaction ConditionsOperation in experiment
37% With potassium carbonate In ethyl acetate Example 75A
2-Amino-4-iodopyridine
A mixture of 2-floro-4-iodopyridine (3.0 g, 13.5 mmol), acetylamide (15.8 g, 269 mmol) and potassium carbonate (9.2 g, 67 mmol) was stirred at 180° C. for 7 hours, poured into ice (100 g), extracted with ethyl acetate, washed with brine, dried (MgSO4), filtered, and concentrated.
The concentrate was purified by flash column chromatography on silica gel with 50percent ethyl acetate/hexane to provide the title compound (1.1 g, 37percent). MS (DCI/NH3) m/e 221 (M+H).
Reference: [1] Patent: US2003/187026, 2003, A1,
  • 3
  • [ 124-41-4 ]
  • [ 22282-70-8 ]
  • [ 98197-72-9 ]
YieldReaction ConditionsOperation in experiment
91% for 3 h; Heating / reflux (c) 59.4 g (253 mmol) of the crude product of 2-fluoro-4-iodopyridine obtained in step (b) was added to 500 mL of methanol, and 21.5 g (398 mmol) of sodium methoxide was added, followed by refluxing by heating for 3 hours. 300 mL of water was added to terminate the reaction, and methanol was distilled off under reduced pressure. Extraction with ethyl ether was carried out, then, the organic layer was dried over sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure to obtain 56.7 g (crude yield 91percent) of a crude product of 4-iodo-2-methoxypyridine.1H-NMR(CDCl3, 400 MHz) : δ (ppm) = 3.86(s,3H), 7.12-7.16(m,2H), 7.79(d,1H, J = 5.6 Hz)
Reference: [1] Patent: EP1559320, 2005, A1, . Location in patent: Page/Page column 6
  • 4
  • [ 67-56-1 ]
  • [ 22282-70-8 ]
  • [ 98197-72-9 ]
Reference: [1] Patent: WO2005/113494, 2005, A2, . Location in patent: Page/Page column 142
  • 5
  • [ 67-56-1 ]
  • [ 124-41-4 ]
  • [ 22282-70-8 ]
  • [ 98197-72-9 ]
YieldReaction ConditionsOperation in experiment
91% for 5 h; Heating / reflux (c); 500 ml of methanol was added to 59.4 g (253 mmol) of crude 2-fluoro-4-iodopyridine obtained in Step (b) so that it was dissolved in methanol, and 21.5 g (398 mmol) of sodium methoxide was added, followed by reflux with heating for 3 hours. 300 ml of water was added to terminate the reaction, and methanol was distilled off under reduced pressure. After extraction with ethyl ether, the organic layer was dried over sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure to obtain 56.7 g (crude yield: 91percent) of crude 4-iodo-2-methoxypyridine. 1H-NMR(CDCl3, 400 MHz) : δ (ppm) = 3.86(s,3H), 7.12-7.16(m,2H), 7.79(d,1H, J = 5.6 Hz)
Reference: [1] Patent: EP1679003, 2006, A1, . Location in patent: Page/Page column 13
  • 6
  • [ 372-48-5 ]
  • [ 113975-22-7 ]
  • [ 22282-70-8 ]
Reference: [1] Patent: US2005/20830, 2005, A1, . Location in patent: Page 24
  • 7
  • [ 113975-22-7 ]
  • [ 22282-70-8 ]
YieldReaction ConditionsOperation in experiment
96% With n-butyllithium; diethylamine In tetrahydrofuran at -78 - 0℃; for 2 h; A-40 oC solution of diethylamine (5. 51G, 55.5 mmol) in THF (80 mL) was treated dropwise with 2.5 M n-butyllithium in hexane (22.2 mL, 55.5 mmol), stirred at 0 C briefly, cooled TO-78 C, treated with a solution of Example 68A (9.9g, 44.4 mmol) in THF (80 mL), stirred at-78 oC for 2 hours, treated with water (3.6g, 200 mmol), stirred for 5 minutes, then poured into water (500 mL), and extracted with diethyl ether several times. The combined extracts were washed water and brine, dried (MGS04), filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel eluting with 25: 1 hexanes/ethyl acetate to provide 9.5g (96percent) of the desired product.
89% With n-butyllithium; diisopropylamine In tetrahydrofuran at -78℃; for 1 h; (b) 189 mL of n-butyllithium (1.57 mol/L hexane solution) was dropwise added at -20°C to a solution having 30.2 g (302 mmol) of diisopropylamine dissolved in 380 mL of tetrahydrofuran, followed by stirring for 1 hour. The solution was cooled to -78°C, a solution having 67.4 g (302 mmol) of the crude product of 2-fluoro-3-iodopyridine obtained in step (a) dissolved in 100 mL of tetrahydrofuran was added thereto, followed by stirring for 1 hour. 300 mL of water was added to the mixture to terminate the reaction, and tetrahydrofuran was distilled off under reduced pressure. Extraction with ethyl ether was carried out, the organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure, to obtain 59.3 g (crude yield 89percent) of a crude product of 2-fluoro-4-iodopyridine.1H-NMR(CDCl3, 400 MHz) : δ (ppm) = 7.33(d,1H, J = 2.8 Hz), 7.51(d,1H, J = 5.2 Hz), 7.88(dd,1H, J=5.2 Hz, 2.8 Hz)
87.5%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 4 h;
Stage #2: With water In tetrahydrofuran at -78 - 20℃;
[0189] To a solution of 2-fluoro-3-iodopyridine (4.0 g, 17.9 mmol) in dry THF (50 mL), was added LDA (8.96 mL of a 2M solution in THF, 17.9 mmol) dropwise at -78 °C. After stirring for 4 hours at -78 °C, H20 (0.5 mL) in THF (1 mL) was added. The mixture was slowly warmed to room temperature, followed by addition of brine (30 mL). The organic layer was separated, washed with brine, dried over anhydrous Na2S04 and then concentrated to give crude product, which was purified by column chromatography to give 2-fluoro-4- iodopyridine (3.5 g, yield : 87.5percent) as a white solid. LC/MS: m/z (M++H) = 224.
Reference: [1] Organic and Biomolecular Chemistry, 2006, vol. 4, # 10, p. 1927 - 1948
[2] Journal of Organic Chemistry, 1993, vol. 58, # 27, p. 7832 - 7838
[3] Patent: WO2004/76424, 2004, A1, . Location in patent: Page 85
[4] Patent: EP1559320, 2005, A1, . Location in patent: Page/Page column 6
[5] Patent: WO2013/6792, 2013, A1, . Location in patent: Paragraph 0189
[6] Tetrahedron, 2004, vol. 60, # 29, p. 6113 - 6120
[7] Organic Letters, 2010, vol. 12, # 9, p. 2136 - 2139
[8] Patent: WO2011/109254, 2011, A1, . Location in patent: Page/Page column 130
  • 8
  • [ 372-48-5 ]
  • [ 22282-70-8 ]
YieldReaction ConditionsOperation in experiment
28%
Stage #1: With n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; hexane at -78℃; for 5 h; Inert atmosphere
Stage #2: With iodine In tetrahydrofuran; hexane for 1 h; Inert atmosphere
Reference Example 1; 2-fluoro-4-iodopyridineA 1.6 M n-butyllithium-hexane solution (19 ml, 30.5 mmol) was added dropwise to a solution (95 ml) of diisopropylamine (9.84 ml, 70 mmol) in tetrahydrofuran at -78° C., and the mixture was stirred for 30 min under an argon atmosphere. 2-Fluoropyridine (6.8 g, 30.5 mmol) was added dropwise to the mixture, and the mixture was stirred for 4 hr at -78° C. A solution (60 ml) of iodine (8.9 g, 30.5 mmol) in tetrahydrofuran was added, and the mixture was stirred for 1 hr. Water was added to the mixture, and the mixture was extracted with diethyl ether. The extract was washed with water, and dried over anhydrous sodium hydrogensulfate. The solvent was evaporated under reduced pressure. A 1.6 M n-butyllithium-hexane solution (19 ml, 30.5 mmol) was added dropwise to a solution (95 ml) of diisopropylamine (9.84 ml, 70 mmol) in tetrahydrofuran at -78° C., and the mixture was stirred for 30 min under an argon atmosphere. A solution (15 ml) of the obtained residue in tetrahydrofuran was added dropwise to the mixture, and the mixture was stirred at -78° C. for 1 hr under an argon atmosphere. Water was added to the mixture, and the mixture was extracted with diethyl ether. The extract was washed with water, and dried over anhydrous sodium hydrogensulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give the title compound (3.4 g, yield 28percent) as a solid.1H-NMR (CDCl3) δ: 7.37 (1H, d, J=1.7 Hz), 7.54 (1H, d, J=5.2 Hz), 7.92 (1H, dd, J=5.2, 1.7 Hz).
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 6, p. 1679 - 1685
[2] Synlett, 2008, # 13, p. 2005 - 2010
[3] Patent: US2011/39893, 2011, A1, . Location in patent: Page/Page column 25
[4] Organic and Biomolecular Chemistry, 2006, vol. 4, # 10, p. 1927 - 1948
[5] Tetrahedron, 2004, vol. 60, # 29, p. 6113 - 6120
[6] Patent: WO2011/109254, 2011, A1,
[7] Patent: WO2013/6792, 2013, A1,
  • 9
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  • [ 113975-22-7 ]
  • [ 22282-70-8 ]
Reference: [1] Patent: US2005/20830, 2005, A1, . Location in patent: Page 24
  • 10
  • [ 168428-74-8 ]
  • [ 22282-70-8 ]
Reference: [1] Patent: EP1679003, 2006, A1, . Location in patent: Page/Page column 12-13
  • 11
  • [ 128071-98-7 ]
  • [ 22282-70-8 ]
Reference: [1] Journal of the American Chemical Society, 2015, vol. 137, # 33, p. 10480 - 10483
  • 12
  • [ 22282-70-8 ]
  • [ 74-88-4 ]
  • [ 153034-80-1 ]
YieldReaction ConditionsOperation in experiment
17.2 g
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 1 h; Inert atmosphere
Stage #2: at -78℃; for 2 h; Inert atmosphere
n-Butyl lithium (1.6M hexane solution, 53.8 mL) was added to a solution of diisopropylamine (8.71 g) in THF (200 mL) at -10 C.
After being stirred at the same temperature under nitrogen atmosphere for 1 hour, a solution of 2-fluoro-3-iodopyridine (18.3 g) in THF (70 mL) was added to the reaction mixture at -78 C.
The mixture was stirred at the same temperature under nitrogen atmosphere for 1 hour.
A solution of iodomethane (12.8 g) in THF (30 mL) was added to the reaction mixture at -78 C.
The mixture was stirred at the same temperature under nitrogen atmosphere for 2 hours.
The mixture was quenched with aqueous saturated ammonium chloride solution at 0 C and extracted with ethyl acetate.
The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo.
The residue was passed through NH-silica and concentrated in vacuo.
The residue was purified by a silica gel column chromatography (hexane/ethyl acetate) to give the title compound (17.2 g).
1H NMR (300 MHz, CDCl3) delta 2.39 (3H, d, J=1.5 Hz), 7.57-7.63 (1H, m), 7.65-7.70 (1H, m).
Reference: [1] Patent: US2015/119412, 2015, A1, . Location in patent: Paragraph 0495; 0496
  • 13
  • [ 124-41-4 ]
  • [ 22282-70-8 ]
  • [ 109-94-4 ]
  • [ 158669-26-2 ]
YieldReaction ConditionsOperation in experiment
94%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; n-heptane at -75 - -65℃; for 2 h;
Stage #2: at -75 - 20℃;
A mixture of DIP A (3.5 mL, 25 mmol) in THF (100 mL) was cooled to -20 °C and n- BuLi (2.7 M in heptane, 9.2 mL, 25 mmol) was added dropwise. After stirring 10 min, the r.m. was cooled to -75 °C and 2-fluoro-3-iodopyridine (5.55 g, 25 mmol) in THF (50 mL) was added dropwise. Stirring was continued for 2 h at -65 °C. The r.m. was cooled to -75 °C and ethyl formate (2.3 mL, 28 mmol) in THF (25 mL) was added dropwise. After 10 min sodium methoxide (5.8 mL, 0.95 g/mL, 25 mmol, 25percent purity) was added dropwise. The cooling bath was removed and the r.m. was allowed to come to r.t. and treated with brine (50 mL), Et20 (100 mL) and the layers were separated. The aq. layer was extracted with Et20 (100 mL) and the combined organic layers were treated with brine (50 mL), dried over MgSC^, filtered and concentrated in vacuo to afford intermediate 1 (6.15 g, 94percent), which was used as such in the next reaction step.
Reference: [1] Patent: WO2018/162445, 2018, A1, . Location in patent: Page/Page column 28; 29
  • 14
  • [ 5419-55-6 ]
  • [ 22282-70-8 ]
  • [ 401815-98-3 ]
Reference: [1] Patent: US2004/122237, 2004, A1, . Location in patent: Page 232-233; 387
  • 15
  • [ 688-74-4 ]
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  • [ 401815-98-3 ]
Reference: [1] Patent: US2004/53942, 2004, A1,
  • 16
  • [ 22282-70-8 ]
  • [ 100-51-6 ]
  • [ 896155-81-0 ]
Reference: [1] Organic and Biomolecular Chemistry, 2006, vol. 4, # 10, p. 1927 - 1948
[2] Patent: US2007/149513, 2007, A1, . Location in patent: Page/Page column 13
  • 17
  • [ 22282-70-8 ]
  • [ 858839-90-4 ]
Reference: [1] Patent: WO2011/73845, 2011, A1, . Location in patent: Page/Page column 31
  • 18
  • [ 22282-70-8 ]
  • [ 1453848-26-4 ]
Reference: [1] Patent: US2017/22183, 2017, A1,
[2] Patent: US2017/22183, 2017, A1,
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