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Product Details of [ 4295-06-1 ]

CAS No. :4295-06-1 MDL No. :MFCD00006757
Formula : C10H8ClN Boiling Point : -
Linear Structure Formula :- InChI Key :HQAIROMRVBVWSK-UHFFFAOYSA-N
M.W : 177.63 Pubchem ID :77973
Synonyms :

Calculated chemistry of [ 4295-06-1 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 12
Num. arom. heavy atoms : 10
Fraction Csp3 : 0.1
Num. rotatable bonds : 0
Num. H-bond acceptors : 1.0
Num. H-bond donors : 0.0
Molar Refractivity : 51.72
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) : -4.92 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.32
Log Po/w (XLOGP3) : 3.47
Log Po/w (WLOGP) : 3.2
Log Po/w (MLOGP) : 2.71
Log Po/w (SILICOS-IT) : 3.56
Consensus Log Po/w : 3.05

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -3.74
Solubility : 0.032 mg/ml ; 0.00018 mol/l
Class : Soluble
Log S (Ali) : -3.42
Solubility : 0.0671 mg/ml ; 0.000378 mol/l
Class : Soluble
Log S (SILICOS-IT) : -4.7
Solubility : 0.00354 mg/ml ; 0.0000199 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.27

Safety of [ 4295-06-1 ]

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 [ 4295-06-1 ]

* 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 [ 4295-06-1 ]
  • Downstream synthetic route of [ 4295-06-1 ]

[ 4295-06-1 ] Synthesis Path-Upstream   1~21

  • 1
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YieldReaction ConditionsOperation in experiment
85% at 80℃; General procedure: Compounds 5a-c was added in POCl3, and the resulting mixture was refluxed for 12 h. The POCl3 was evaporated under reduced pressure, and the residue codisted once with CHCl3, and twice with toluene. The resulting solid was dissolved in CH2Cl2 and treated with triethylamine until aqueous washings of aliquots had pH >10. The solution was then filtered to yield the title compounds 6a-c.
84.14% at 0 - 80℃; for 4 h; Heating / reflux 1)
Synthesis of 4-chloro-2-methylquinoline
The commercially available 4-hydroxy-2-methylquinoline (6.522 g, 41 mmol) was added portionwise to POCl3 (35 mL) in a round flask at 0° C. with stirring.
The homogenous suspension was then immersed into a pre-heated at 80° C. oil bath and continuously refluxed for 4 h.
The reaction mixture was cooled to room temperature and the excess POCl3 was distilled out under reduces pressure.
The residue was treated carefully with ice (150 g) and then with saturated NaHCO3 aqueous solution (200 mL).
The mixture was extracted with CH2Cl2 (100*3 mL), dried over Na2SO4, and evaporated in vacuo to dryness to give known 4-chloro-2-methylquinoline,53 6.10 g (84.14percent) as oil, which was pure enough for using in next step. 1H NMR (DMSO) δ 2.61 (3H, s, Me), 7.66 (1H, s, ArH), 7.67-7.71 (1H, m, ArH), 7.82-7.85 (1H, s, ArH), 8.01 (1H, d, J=6.7 Hz, ArH), 8.12-8.14 (1H, s, ArH). Anal. Calcd. for (C10H8ClN): C, 67.62; H, 4.54; N, 7.89. Found: C, 67.62; H, 4.54; N, 7.89.
80% at 80℃; for 12 h; 4-Hydroxy-2-methylquinoline (5a, 1.59 g, 10 mmol) wasadded slowly to the pre-stirred POCl3 (7 mL) in a round bottomflask maintained at 0°C. The suspension was thenimmersed into a pre-heated oil bath at 80°C and refluxed for12 h. The reaction mixture was cooled down to room temperatureand the excess of POCl3 was distilled off under reduced pressure. The residue was treated carefully with ice.The crude mass was partitioned between saturated aq. Na-HCO3 and dichloromethane and 4-chloro-2-methylquinolinewas obtained in 80percent yield (6a, 1.42 g, 8 mmol) (Scheme 1).
69% at 120℃; for 2 h; Then, to a round necked bottom flask equipped with a reflux apparatus (Argon, stirrer) were added 2-methylquinolin-4-ol (2 g, 12.56 mmol, 1 eq.) and freshly distilled P0013 (7.4 mL). The mixture was heated at 12000 for 2 h. The reaction was monitored by TLC (DCM: 100percent). After completion of the reaction and cooling to room temperature the reaction mixture was poured into a saturated solution of sodium carbonate, and neutralized to pH = 7 with NaHCO3. Then, DCM was added, and the organic phase was separated. The aqueous phase was extracted with DCM twice. The combined organic phase was dried over MgSO4, filtered and concentrated under reduce pressure to afford the desired product 4-chloro-2- methylquinoline (3.157 g, 69percent) as a pale yellow oil. 1H NMR (300 MHz, 0D013): 6 [ppm] = 8.17 (d, 1H, J = 8.3 Hz), 8.03 (d, 1H, J = 8.5 Hz), 7.73 (t, 1 H, J = 8.3 Hz), 7.57 (t, 1 H, J = 8.3 Hz), 7.39 (5, 1 H), 2.72 (5, 3H).130 NMR (75 MHz, 0D013): 6 [ppm] = 159.0, 148.8, 142.7, 130.5, 129.1, 126.8,124.9, 124.1, 122.1, 25.3.
65% at 120℃; for 2 h; Will be 2.5g (88.9mmol) 2-methyl-4-hydroxy-quinoline and 125 ml phosphorus oxychloride (POCl3) underwaterly to 120 °C reaction 2h. Tilting the reaction mixture then is hydrolyzed in a water surplus POCl3, with hydrochloric acid to adjust the pH value to neutral grey solid, filtering collected gray solid.
64% at 120℃; for 2 h; A mixture of 1 (8.00 g, 88.9 mmol) and freshly distilled POCl3 (60 mL )was heated at 120 °C for 2 h. The reaction was monitored by using TLC. After completion of the reaction, excess of POCl3 was distilled off. The residue was stirred with ice water for 15 min, and then the pH value was adjusted to 7 with aqueous NaOH. The compound was collected by filtration and washed with water. The crude product was purified by using flash column chromatographywith CH2Cl2/petroleum ether (1: 1) elution to afford a white solid compound 2 in 64.0percent yield. m.p. 42.6-43.5 °C. 1H NMR (400 MHz, CDCl3): δ 8.16 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.72 (t, J = 8.0 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.37 (s, 1H), 2.71 (s, 3H). 13CNMR (101 MHz, DMSO-d6): δ 153.53, 143.27, 137.30, 125.10, 123.58,121.38, 119.41, 118.60, 116.63, 19.78. LC-MS m/z: 179.1 [M+H]+.These data are consistent with those reported previously [51].

Reference: [1] European Journal of Medicinal Chemistry, 2017, vol. 138, p. 1114 - 1125
[2] Patent: US2008/171765, 2008, A1, . Location in patent: Page/Page column 19-20
[3] Australian Journal of Chemistry, 2003, vol. 56, # 1, p. 39 - 44
[4] Letters in Drug Design and Discovery, 2018, vol. 15, # 9, p. 937 - 944
[5] Patent: WO2018/178277, 2018, A1, . Location in patent: Paragraph 00114
[6] Patent: CN103204808, 2016, B, . Location in patent: Paragraph 0041; 0042; 0043; 0044
[7] European Journal of Medicinal Chemistry, 2014, vol. 89, p. 349 - 361
[8] Heterocyclic Communications, 2003, vol. 9, # 1, p. 83 - 88
[9] Chemistry of Heterocyclic Compounds, 2005, vol. 41, # 6, p. 778 - 781
[10] Tetrahedron, 2006, vol. 62, # 26, p. 6258 - 6263
[11] Medicinal Chemistry Research, 2012, vol. 21, # 10, p. 3073 - 3079,7
[12] Tetrahedron, 2013, vol. 69, # 24, p. 4922 - 4932
[13] Journal of Medicinal Chemistry, 2015, vol. 58, # 9, p. 3875 - 3891
[14] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 24, p. 5672 - 5676
[15] Tetrahedron Letters, 2016, vol. 57, # 46, p. 5042 - 5046
[16] Tetrahedron Letters, 2017, vol. 58, # 33, p. 3296 - 3300
[17] Dyes and Pigments, 2017, vol. 137, p. 191 - 199
[18] European Journal of Medicinal Chemistry, 2017, vol. 130, p. 139 - 153
[19] Dyes and Pigments, 2017, vol. 145, p. 1 - 6
[20] Molecules, 2018, vol. 23, # 12,
[21] Bioorganic Chemistry, 2019, vol. 85, p. 1 - 17
  • 2
  • [ 1076-28-4 ]
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YieldReaction ConditionsOperation in experiment
20% With trichlorophosphate In dichloromethane; N,N-dimethyl-formamide at 0 - 25℃; Inert atmosphere General procedure: To a stirred solution of the appropriate azine N-oxides in anhydrous CH2Cl2 (0.1M) at 0 °C is added POCl3 (1.2 equiv) followed by dropwise addition of DMF (0.5 equiv) under argon. The resulting reaction mixture was warmed to 25 °C and stirred for several hours until the reaction is complete as indicated by TLC. Saturated aqueous sodium carbonate solution is added to the reaction mixture slowly to adjust the pH to 7~8. The resulting mixture is separated and the aqueous phase is extracted with CH2Cl2 thoroughly. The organic phase is combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product, which is purified by flash column chromatography using PE/EA (80:1) as eluent.
Reference: [1] Tetrahedron Letters, 2014, vol. 55, # 51, p. 7130 - 7132
[2] Bollettino Scientifico della Facolta di Chimica Industriale di Bologna, 1941, vol. 2, p. 86
  • 3
  • [ 611-35-8 ]
  • [ 917-54-4 ]
  • [ 4295-06-1 ]
Reference: [1] Journal of Organic Chemistry, 2003, vol. 68, # 18, p. 7077 - 7084
  • 4
  • [ 4637-59-6 ]
  • [ 2065-66-9 ]
  • [ 4295-06-1 ]
Reference: [1] Angewandte Chemie - International Edition, 2018, vol. 57, # 39, p. 12737 - 12740[2] Angew. Chem., 2018, vol. 130, p. 12919 - 12922,4
  • 5
  • [ 607-67-0 ]
  • [ 68-12-2 ]
  • [ 34547-93-8 ]
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Reference: [1] Journal of the Indian Chemical Society, 2004, vol. 81, # 7, p. 598 - 601
[2] European Journal of Medicinal Chemistry, 2007, vol. 42, # 8, p. 1128 - 1136
[3] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2007, vol. 46, # 6, p. 995 - 1000
  • 6
  • [ 607-67-0 ]
  • [ 497-19-8 ]
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Reference: [1] Patent: EP1308439, 2003, A1,
  • 7
  • [ 62-53-3 ]
  • [ 4295-06-1 ]
Reference: [1] Medicinal Chemistry Research, 2012, vol. 21, # 10, p. 3073 - 3079,7
[2] European Journal of Medicinal Chemistry, 2014, vol. 89, p. 349 - 361
[3] Journal of Medicinal Chemistry, 2015, vol. 58, # 9, p. 3875 - 3891
[4] Patent: CN103204808, 2016, B,
[5] European Journal of Medicinal Chemistry, 2017, vol. 130, p. 139 - 153
[6] Letters in Drug Design and Discovery, 2018, vol. 15, # 9, p. 937 - 944
[7] Patent: WO2018/178277, 2018, A1,
[8] Molecules, 2018, vol. 23, # 12,
[9] Bioorganic Chemistry, 2019, vol. 85, p. 1 - 17
  • 8
  • [ 607-67-0 ]
  • [ 68-12-2 ]
  • [ 34547-93-8 ]
  • [ 4295-06-1 ]
  • [ 503552-60-1 ]
Reference: [1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2003, vol. 42, # 9, p. 2069 - 2073
[2] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2004, vol. 43, # 4, p. 846 - 851
  • 9
  • [ 611-35-8 ]
  • [ 13061-96-6 ]
  • [ 4295-06-1 ]
Reference: [1] Chemical Science, 2016, vol. 7, # 10, p. 6407 - 6412
  • 10
  • [ 5781-53-3 ]
  • [ 1033931-93-9 ]
  • [ 1402597-29-8 ]
  • [ 4295-06-1 ]
Reference: [1] Angewandte Chemie - International Edition, 2015, vol. 54, # 24, p. 7144 - 7148[2] Angew. Chem., 2015, vol. 54, p. 7144 - 7148,5
[3] Angewandte Chemie - International Edition, 2015, vol. 54, # 24, p. 7144 - 7148[4] Angew. Chem., 2015, vol. 54, p. 7144 - 7148,5
  • 11
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  • [ 67-68-5 ]
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Reference: [1] Chemistry - A European Journal, 2018, vol. 24, # 40, p. 10064 - 10068
  • 12
  • [ 5660-24-2 ]
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Reference: [1] Chemische Berichte, 1887, vol. 20, p. 950[2] Chemische Berichte, 1888, vol. 21, p. 1971
[3] Journal fuer Praktische Chemie (Leipzig), 1925, vol. <2> 109, p. 67
  • 13
  • [ 6287-35-0 ]
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Reference: [1] Medicinal Chemistry Research, 2012, vol. 21, # 10, p. 3073 - 3079,7
  • 14
  • [ 17469-23-7 ]
  • [ 4295-06-1 ]
Reference: [1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2003, vol. 42, # 9, p. 2069 - 2073
  • 15
  • [ 587-95-1 ]
  • [ 4295-06-1 ]
Reference: [1] Letters in Drug Design and Discovery, 2018, vol. 15, # 9, p. 937 - 944
  • 16
  • [ 607-67-0 ]
  • [ 1402597-29-8 ]
  • [ 4295-06-1 ]
Reference: [1] Angewandte Chemie - International Edition, 2015, vol. 54, # 24, p. 7144 - 7148[2] Angew. Chem., 2015, vol. 54, p. 7144 - 7148,5
  • 17
  • [ 64965-49-7 ]
  • [ 1402597-29-8 ]
  • [ 4295-06-1 ]
Reference: [1] Angewandte Chemie - International Edition, 2015, vol. 54, # 24, p. 7144 - 7148[2] Angew. Chem., 2015, vol. 54, p. 7144 - 7148,5
  • 18
  • [ 1076-28-4 ]
  • [ 7791-25-5 ]
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Reference: [1] Bollettino Scientifico della Facolta di Chimica Industriale di Bologna, 1941, vol. 2, p. 86
  • 19
  • [ 1076-28-4 ]
  • [ 10026-13-8 ]
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Reference: [1] Chemische Berichte, 1908, vol. 41, p. 2696
[2] Journal fuer Praktische Chemie (Leipzig), 1928, vol. <2> 118, p. 147
  • 20
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  • [ 7719-12-2 ]
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Reference: [1] Chemische Berichte, 1921, vol. 54, p. 1070
  • 21
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  • [ 6628-04-2 ]
YieldReaction ConditionsOperation in experiment
46% With ((+/-)-binap)Ni[P(OPh)3]2*2PhCH3; ammonia; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In 1,4-dioxane at 120℃; for 18 h; Inert atmosphere; Sealed tube General procedure: An oven-dried vial (35x12 mm) equipped with a PTFE-sealedxscrew cap was loaded with a magnetic stirrer bar, ((+/-)-binap)Ni[P(OPh)3]2*2PhCH3 (9) (39 mg, 25 mmol, 5mol-percent), (+/-)-binap (15 mg, 25 mmol, 5 mol-percent), and the corresponding aryl halide (0.50 mmol, 1.0 equiv.). The vial was then transferred into an argon-filled glovebox, where NaOtBu (216 mg, 2.20 mmol, 4.40 equiv.) and NH3 (0.5 M in 1,4-dioxane, 3.0 mL, 1.5 mmol, 3.0 equiv.) were added. The reaction vial was capped, removed from the glovebox, and placed into a preheated oil bath at 120 C to stir for 18 h. On cooling, the reaction mixture was diluted with Et2O (15 mL), and washed with 1 M NaOH (10 mL) and H2O (210 mL). The organic layer was fused onto silica and purified via flash column chromatography (EtOAc/hexanes or EtOAc/MeOH) to give the corresponding aniline. 2-Methylquinolin-4-amine (19g) Following the general procedure using 4-chloroquinaldine (100 mL, 0.500 mmol), the desired compound 19g was obtained after purification via flash column chromatography (EtOAc/MeOH 90 : 10) as an orange solid (36 mg, 0.23 mmol, 46 percent). The spectral data were in accordance with those reported in theliterature.[32] Rf 0.23 (EtOAc/MeOH 90 : 10). δH (CDCl3, 500 MHz) 8.06 (1H, d, J 8.4, Ar–H), 7.96 (1H, d, J 8.4, Ar–H), 7.72 (1H, ‘t’, J 7.7, Ar–H), 7.50 (1H, ‘t’, J 7.7, Ar–H), 7.08 (1H,s, Ar–H), 2.66 (3H, s, CH3), 2.07 (2H, br s, NH2). δC (CDCl3, 125 MHz) 159.6 (Ar–C), 149.2 (Ar–C), 145.8 (Ar–C), 130.1 (Ar–CH), 129.5 (Ar–C), 125.6 (Ar–CH), 120.5 (Ar–CH), 120.1(Ar–CH), 109.0 (Ar–CH), 25.7 (CH3).
Reference: [1] Chemistry - A European Journal, 2011, vol. 17, # 35, p. 9599 - 9604
[2] Angewandte Chemie - International Edition, 2015, vol. 54, # 12, p. 3773 - 3777[3] Angew. Chem., 2015, vol. 127, # 12, p. 3844 - 3848,5
[4] Australian Journal of Chemistry, 2015, vol. 68, # 12, p. 1842 - 1853
[5] Proceedings of the Royal Society of London, Series B: Biological Sciences, 1933, vol. 113, p. 293,298
[6] Yakugaku Zasshi, 1946, vol. 66, p. Ausg. B, S. 84[7] Chem.Abstr., 1951, p. 6647
[8] Gazzetta Chimica Italiana, 1940, vol. 70, p. 621,625
[9] Journal of the Chemical Society, 1942, p. 381
[10] Journal fuer Praktische Chemie (Leipzig), 1935, vol. <2> 143, p. 59,62
[11] Chemistry - A European Journal, 2009, vol. 15, # 18, p. 4528 - 4533
[12] Angewandte Chemie - International Edition, 2010, vol. 49, # 47, p. 8988 - 8992
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