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[ CAS No. 3678-62-4 ] {[proInfo.proName]}

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Chemical Structure| 3678-62-4
Chemical Structure| 3678-62-4
Structure of 3678-62-4 * Storage: {[proInfo.prStorage]}
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Product Details of [ 3678-62-4 ]

CAS No. :3678-62-4 MDL No. :MFCD00023418
Formula : C6H6ClN Boiling Point : -
Linear Structure Formula :- InChI Key :MZVSTDHRRYQFGI-UHFFFAOYSA-N
M.W : 127.57 Pubchem ID :77248
Synonyms :
2-Chloro-4-picoline

Calculated chemistry of [ 3678-62-4 ]

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.17
Num. rotatable bonds : 0
Num. H-bond acceptors : 1.0
Num. H-bond donors : 0.0
Molar Refractivity : 34.21
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) : -5.75 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.82
Log Po/w (XLOGP3) : 1.87
Log Po/w (WLOGP) : 2.04
Log Po/w (MLOGP) : 1.41
Log Po/w (SILICOS-IT) : 2.5
Consensus Log Po/w : 1.93

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.36
Solubility : 0.552 mg/ml ; 0.00432 mol/l
Class : Soluble
Log S (Ali) : -1.76
Solubility : 2.2 mg/ml ; 0.0173 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.99
Solubility : 0.131 mg/ml ; 0.00103 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.34

Safety of [ 3678-62-4 ]

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 [ 3678-62-4 ]

* 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 [ 3678-62-4 ]
  • Downstream synthetic route of [ 3678-62-4 ]

[ 3678-62-4 ] Synthesis Path-Upstream   1~25

  • 1
  • [ 695-34-1 ]
  • [ 3678-62-4 ]
YieldReaction ConditionsOperation in experiment
58% With sodium nitrite In hydrogenchloride a)
2-Chloro-4-methylpyridine
Sodium nitrite (13.88 g, 200 mmole) was added slowly at 0° C. to a solution of 2-amino-4-picoline (15.0 g, 139 mmole) in conc. HCl (200 mL).
The reaction mixture was allowed to warm to RT and was stirred for 16 hr, then was poured onto ice (500 g).
The pH was adjusted to 8.0 with conc. NH4OH, and the mixture was extracted with ether (3*300 mL).
The combined ether layers were washed sequentially with H2O (2*200 mL) and brine (200 mL).
Drying (MgSO4) and concentration gave the title compound (10.3 g, 58percent) as a faintly yellow oil: MS (ES) m/e 127.8 (M+H)+.
229.3 g With hydrogenchloride; sodium nitrite In water at 20℃; Industrial scale Firstly, 188 g of 2-amino-4-methylpyridine was fed into a round bottom flask, and then 250 g of sodium nitrite was added into a round bottom flask. Subsequently, 150 g of hydrogen chloride was continuously fed and the reaction temperature was controlled at 20 ° C.The reaction produces primiparous,The crude steamed isolated 229.3 g of 2-chloro-4-methylpyridine (content of 99percent).
Reference: [1] Patent: US2002/91264, 2002, A1,
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1988, p. 2791 - 2796
[3] Acta Chemica Scandinavica, 1992, vol. 46, # 2, p. 157 - 162
[4] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1988, p. 2791 - 2796
[5] Patent: CN107151229, 2017, A, . Location in patent: Paragraph 0023; 0027
  • 2
  • [ 13466-41-6 ]
  • [ 3678-62-4 ]
YieldReaction ConditionsOperation in experiment
98.7% With sodium carbonate In chloroform; water; trichlorophosphate (1)
Synthesis of 2-chloro-4-methylpyridine
2-Hydroxy-4-methylpyridine (20.3 g, 0.186 mol) was heated to 100° C. with stirring in 50 ml of phosphorus oxychloride for 4 hours.
The reaction solution was poured into iced water, followed by adding sodium carbonate so as to be weak alkalinity and extracting 2 times with 200 ml of chloroform.
After the extract solution was washed with saturated saline solution, it was dried with sodium sulfate and the solvent was distilled off in vacuum.
The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:10) to give a liquid.
Yield: 23 g, percent yield: 98.7percent IR NaCl liq.
Film cm-1: 1596, 1554, 1473, 1383, 1086, 870, 825. 1H-NMR (60 MHz, CDCl3, δ): 2.26 (3H, s, CH3), 6.8-7.1 (2H, m, pyridine ring H), 8.1 (1H, d, J=4 Hz, pyridine ring H).
Reference: [1] Patent: US6610853, 2003, B1,
[2] Patent: US6159901, 2000, A,
[3] Patent: US6200933, 2001, B1,
  • 3
  • [ 4021-08-3 ]
  • [ 3678-62-4 ]
YieldReaction ConditionsOperation in experiment
71% With tert-butylhypochlorite; sodium carbonate; sodium chloride In toluene at 80℃; for 20 h; Schlenk technique Weighing 4-methyl-2-picolinic acid (50.4 mg, 0.3 mmol),Sodium carbonate (64.0 mg, 0.6 mmol), NaCl (17.6 mg, 0.3 mmol), tert-butyl hypochlorite (32 μL, 0.3 mmol) into a 25 mL of Schlenk reaction bottle, Then add toluene (5 mL) and place in an 80 °C oil bath for 20 h. After completion of the reaction, the solvent was removed under reduced pressure and eluted with petroleum ether / ethyl acetate.The solvent was separated on a silica gel column, The yield of 4-methyl-2-chloropyridine was 71percent.
Reference: [1] Patent: CN108586334, 2018, A, . Location in patent: Paragraph 0064-0066
  • 4
  • [ 695-34-1 ]
  • [ 624-91-9 ]
  • [ 3678-62-4 ]
  • [ 100848-70-2 ]
YieldReaction ConditionsOperation in experiment
69.5%
Stage #1: With hydrogenchloride In methanol at 10 - 30℃; for 1.5 h;
Stage #2: at 20 - 30℃; for 13 h;
Stage #3: With sodium hydroxide In water at 30℃;
(a); Into a 2L four-necked flask equipped a stirrer, a thermometer and a gas introduction tube (inlet), 324 g (3.00 mol) of 2-amino-4-methylpyridine and 485 g of methanol were charged and mixed for dissolution, and while keeping the temperature in the system at from 10 to 30°C, 361.4 g (9.90 mol) of hydrogen chloride gas was introduced over a period of one and a half hours. Then, in a 2L four-necked flask equipped with a stirrer, a thermometer, a dropping funnel and an introduction tube (outlet) equipped with a bubble counter having a gas generation apparatus and a diazotization apparatus connected, 414 g (6.00 mol) of sodium nitrite, 211 g (6.60 mol) of methanol and 454 g of water were mixed, and 812.4 g (3.15 mol) of a 38percent sulfuric acid aqueous solution was dropwise added over a period of 5 hours while keeping the temperature in the system at from 20 to 30°C. In the methyl nitrite generation apparatus, simultaneously with dropwise addition of the 38percent sulfuric acid aqueous solution, methyl nitrite gas in an equivalent amount was generated and introduced to the diazotization apparatus through the bubble counter. Further, for diazotization, the reaction apparatus was cooled with water so that the temperature in the system would be kept at from 20 to 30°C. After completion of the introduction of the methyl nitrite gas, stirring was carried out at the same temperature for 13 hours and the reaction was completed. After methanol was distilled off under reduced pressure, 648 g of water was charged, and 518 g of a 40percent sodium hydroxide aqueous solution was dropwise added at 30°C or below to adjust the pH in the system to 12. The formed oil was extracted with 910 g of diethyl ether, the aqueous layer was separated out, and the solvent was distilled off under reduced pressure to obtain 375.3 g of an oil. The oil (crude product) had a composition comprising 70.7percent (yield: 69.5percent) of 2-chloro-4-methylpyridine, 26.6percent (yield: 27.2percent) of 2-methoxy-4-methylpyridine and 2.6percent of 2-amino-4-methylpyridine.
Reference: [1] Patent: EP1679003, 2006, A1, . Location in patent: Page/Page column 20-21
  • 5
  • [ 26452-80-2 ]
  • [ 75-16-1 ]
  • [ 3678-62-4 ]
  • [ 3678-63-5 ]
Reference: [1] Organic Letters, 2013, vol. 15, # 14, p. 3698 - 3701
[2] Organic Letters, 2013, vol. 15, # 14, p. 3698 - 3701
  • 6
  • [ 108-89-4 ]
  • [ 3678-62-4 ]
Reference: [1] European Journal of Organic Chemistry, 2003, # 19, p. 3855 - 3860
[2] Chemische Berichte, 1924, vol. 57, p. 794
  • 7
  • [ 108-89-4 ]
  • [ 1984-23-2 ]
  • [ 3678-62-4 ]
Reference: [1] Tetrahedron Letters, 2005, vol. 46, # 13, p. 2279 - 2282
  • 8
  • [ 1003-67-4 ]
  • [ 3678-62-4 ]
Reference: [1] Tetrahedron Letters, 2001, vol. 42, # 4, p. 735 - 737
[2] European Journal of Organic Chemistry, 2004, # 16, p. 3477 - 3483
  • 9
  • [ 13466-41-6 ]
  • [ 3678-62-4 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1988, p. 2791 - 2796
  • 10
  • [ 153034-86-7 ]
  • [ 31729-70-1 ]
  • [ 3678-62-4 ]
Reference: [1] Synlett, 2015, vol. 26, # 17, p. 2395 - 2398
  • 11
  • [ 1003-67-4 ]
  • [ 3678-62-4 ]
  • [ 1822-51-1 ]
Reference: [1] Synthetic Communications, 2004, vol. 34, # 6, p. 1097 - 1103
  • 12
  • [ 108-89-4 ]
  • [ 78948-09-1 ]
  • [ 3678-62-4 ]
  • [ 108168-80-5 ]
Reference: [1] Journal of Organic Chemistry, 1991, vol. 56, # 22, p. 6298 - 6301
  • 13
  • [ 324028-95-7 ]
  • [ 3678-62-4 ]
Reference: [1] Journal of the Chemical Society, 1897, vol. 71, p. 653,655
  • 14
  • [ 13466-41-6 ]
  • [ 10026-13-8 ]
  • [ 3678-62-4 ]
Reference: [1] Chemische Berichte, 1924, vol. 57, p. 794
  • 15
  • [ 26452-80-2 ]
  • [ 75-16-1 ]
  • [ 3678-62-4 ]
  • [ 3678-63-5 ]
Reference: [1] Organic Letters, 2013, vol. 15, # 14, p. 3698 - 3701
[2] Organic Letters, 2013, vol. 15, # 14, p. 3698 - 3701
  • 16
  • [ 695-34-1 ]
  • [ 624-91-9 ]
  • [ 3678-62-4 ]
  • [ 100848-70-2 ]
YieldReaction ConditionsOperation in experiment
69.5%
Stage #1: With hydrogenchloride In methanol at 10 - 30℃; for 1.5 h;
Stage #2: at 20 - 30℃; for 13 h;
Stage #3: With sodium hydroxide In water at 30℃;
(a); Into a 2L four-necked flask equipped a stirrer, a thermometer and a gas introduction tube (inlet), 324 g (3.00 mol) of 2-amino-4-methylpyridine and 485 g of methanol were charged and mixed for dissolution, and while keeping the temperature in the system at from 10 to 30°C, 361.4 g (9.90 mol) of hydrogen chloride gas was introduced over a period of one and a half hours. Then, in a 2L four-necked flask equipped with a stirrer, a thermometer, a dropping funnel and an introduction tube (outlet) equipped with a bubble counter having a gas generation apparatus and a diazotization apparatus connected, 414 g (6.00 mol) of sodium nitrite, 211 g (6.60 mol) of methanol and 454 g of water were mixed, and 812.4 g (3.15 mol) of a 38percent sulfuric acid aqueous solution was dropwise added over a period of 5 hours while keeping the temperature in the system at from 20 to 30°C. In the methyl nitrite generation apparatus, simultaneously with dropwise addition of the 38percent sulfuric acid aqueous solution, methyl nitrite gas in an equivalent amount was generated and introduced to the diazotization apparatus through the bubble counter. Further, for diazotization, the reaction apparatus was cooled with water so that the temperature in the system would be kept at from 20 to 30°C. After completion of the introduction of the methyl nitrite gas, stirring was carried out at the same temperature for 13 hours and the reaction was completed. After methanol was distilled off under reduced pressure, 648 g of water was charged, and 518 g of a 40percent sodium hydroxide aqueous solution was dropwise added at 30°C or below to adjust the pH in the system to 12. The formed oil was extracted with 910 g of diethyl ether, the aqueous layer was separated out, and the solvent was distilled off under reduced pressure to obtain 375.3 g of an oil. The oil (crude product) had a composition comprising 70.7percent (yield: 69.5percent) of 2-chloro-4-methylpyridine, 26.6percent (yield: 27.2percent) of 2-methoxy-4-methylpyridine and 2.6percent of 2-amino-4-methylpyridine.
Reference: [1] Patent: EP1679003, 2006, A1, . Location in patent: Page/Page column 20-21
  • 17
  • [ 3678-62-4 ]
  • [ 124-41-4 ]
  • [ 100848-70-2 ]
YieldReaction ConditionsOperation in experiment
46% at 100℃; for 4 h; Step 1
2-Methoxy-4-methylpyridine
Procedure:
A mixture of 2-chloro-4-methylpyridine (20 g, 0.156 mol) and NaOCH3 (9.3 g, 0.172 mol) in DMSO (200 mL) was stirred at 100° C. for 4 hours.
The solution was added to H2O and then extracted with ethyl acetate (50 mL*2).
The organic layer was washed with H2O (300 mL) brine (300 mL) and dried concentrated to give 2-methoxy-4-methylpyridine (9 g, 46percent). LC-MS: 124 [M+H]+, tR=1.21 min.
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1988, p. 2791 - 2796
[2] Patent: US2012/252777, 2012, A1, . Location in patent: Page/Page column 54
  • 18
  • [ 3678-62-4 ]
  • [ 67-56-1 ]
  • [ 124-41-4 ]
  • [ 100848-70-2 ]
Reference: [1] Patent: EP1679003, 2006, A1, . Location in patent: Page/Page column 21
  • 19
  • [ 3678-62-4 ]
  • [ 1620-76-4 ]
Reference: [1] Pharmaceutical Bulletin, 1957, vol. 5, p. 13
  • 20
  • [ 3678-62-4 ]
  • [ 39621-00-6 ]
Reference: [1] Patent: WO2015/26792, 2015, A1,
  • 21
  • [ 3678-62-4 ]
  • [ 4931-00-4 ]
YieldReaction ConditionsOperation in experiment
54% at 150℃; for 72 h; 2-Chloro-4- methylpyridine (3.43 mL, 39.19 mmol) and hydrazine hydrate (19.07 mL, 391.9 mmol) were suspended together in a flask and heated to 150 0C for 72 hours. The mixture was concentrated in vacuo to an oil. The oil was taken up in EtOAc and the resulting solid was removed by vacuum filtration. The organic filtrate was washed with 40percent aqueous NaOH (2 x 50 mL) and dried over Na2SO4, filtered and concentrated to provide the desired product (2.42 g, 54percent) as a white solid.
Reference: [1] Journal of the American Chemical Society, 2017, vol. 139, # 16, p. 5716 - 5719
[2] Patent: WO2010/22076, 2010, A1, . Location in patent: Page/Page column 111
[3] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 6, p. 1743 - 1747
  • 22
  • [ 3678-62-4 ]
  • [ 83004-15-3 ]
Reference: [1] Synthesis, 2008, # 18, p. 2996 - 3008
[2] European Journal of Organic Chemistry, 2015, vol. 2015, # 8, p. 1764 - 1770
  • 23
  • [ 1003-67-4 ]
  • [ 3678-62-4 ]
  • [ 1822-51-1 ]
Reference: [1] Synthetic Communications, 2004, vol. 34, # 6, p. 1097 - 1103
  • 24
  • [ 3678-62-4 ]
  • [ 157329-89-0 ]
Reference: [1] European Journal of Organic Chemistry, 2003, # 19, p. 3855 - 3860
  • 25
  • [ 3678-62-4 ]
  • [ 101990-73-2 ]
YieldReaction ConditionsOperation in experiment
79% With N-chloro-succinimide; 2,2'-azobis(isobutyronitrile) In acetonitrile for 2 h; Heating / reflux lOg of 1.-.2-Ghlar6-4-methylpyridine are ''dissolved in 50 ml.'of '-CH3CN.' and- heated to'.bul..bul. 85°C. Then a mixture of 32g -N-"Chlorosuccinimid and l,6g"AIBN is added over a period of 5 minutes. -The resulting- mixture is refluxed . for two.bul.hours,- -then the solvent is removed in vacuo, the residue treated .bul. with 100ml of CH2C12 .bul..bul. and washed with water 2.'times.''The organic phases 'are collected, dried over Na2S04 and the residue obtained after evaporation of the solvent-is- distilled (80°C, 100 mTorr) . Yield 79percent
79% With N-chloro-succinimide; 2,2'-azobis(isobutyronitrile) In acetonitrile at 85℃; for 2.08333 h; Heating / reflux 1Og of 2-chloro-4-methylpyridine are dissolved in 50 ml of CH3CN and heated to- 85°C. Then a mixture of 32g N-Chlorosuccinimid and l,6g AIBN is added over a period of 5 minutes. The. resulting, mixture is refluxed for two hours, then the solvent is removed in vacuo, the residue treated with 100ml of CH2Cl2 and washed with water 2 times. The organic phases are collected, dried over Na2S04 and the residue obtained after evaporation of the solvent is distilled (80°C, 100 mTorr). Yield 79percent
Reference: [1] Patent: WO2006/10642, 2006, A1, . Location in patent: Page/Page column 109
[2] Patent: WO2006/10643, 2006, A1, . Location in patent: Page/Page column 103
[3] Patent: US2004/248884, 2004, A1, . Location in patent: Page 53
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