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[ CAS No. 875-35-4 ] {[proInfo.proName]}

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3d Animation Molecule Structure of 875-35-4
Chemical Structure| 875-35-4
Chemical Structure| 875-35-4
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Product Details of [ 875-35-4 ]

CAS No. :875-35-4 MDL No. :MFCD00052633
Formula : C7H4Cl2N2 Boiling Point : -
Linear Structure Formula :- InChI Key :LSPMHHJCDSFAAY-UHFFFAOYSA-N
M.W :187.03 Pubchem ID :70131
Synonyms :

Calculated chemistry of [ 875-35-4 ]

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.14
Num. rotatable bonds : 0
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 43.94
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) : -5.41 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.89
Log Po/w (XLOGP3) : 2.86
Log Po/w (WLOGP) : 2.57
Log Po/w (MLOGP) : 1.31
Log Po/w (SILICOS-IT) : 3.04
Consensus Log Po/w : 2.33

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.2
Solubility : 0.117 mg/ml ; 0.000624 mol/l
Class : Soluble
Log S (Ali) : -3.29
Solubility : 0.0961 mg/ml ; 0.000514 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.73
Solubility : 0.0347 mg/ml ; 0.000185 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.93

Safety of [ 875-35-4 ]

Signal Word:Danger Class:6.1
Precautionary Statements:P261-P264-P270-P271-P272-P280-P301+P310+P330-P302+P352+P312-P304+P340+P312-P305+P351+P338+P310-P333+P313-P403+P233-P405-P501 UN#:2811
Hazard Statements:H301-H312+H332-H315-H317-H318-H335 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 875-35-4 ]

* 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 [ 875-35-4 ]
  • Downstream synthetic route of [ 875-35-4 ]

[ 875-35-4 ] Synthesis Path-Upstream   1~11

  • 1
  • [ 875-35-4 ]
  • [ 5444-01-9 ]
YieldReaction ConditionsOperation in experiment
93% With hydrogen; sodium acetate; palladium dichloride In methanol at 23℃; for 14 h; Cyano-4-methylpyridine (112) [0145] (J. Org. Chem. 1960, 25, 560-564.) [0146] Palladium dichloride (50 mg, 0.3 mmol) was added to a degassed solution of 11 (5.0 g, 27 mmol) and sodium acetate (4.5 g, 55 mmol) in methanol (100 mL). The resulting mixture was stirred under hydrogen (1 atm) for 14 h at room temperature. The precipitate was filtered and washed with methanol (3×20 mL). The combined filtrates were evaporated under reduced pressure, and chloroform (50 mL) was added to the residue. The chloroform solution was filtered through a thin pad of silica gel, washing with additional portions of chloroform. The filtrate was evaporated to dryness to provide 112 (2.9 g, 93percent) as a yellow oil. 1H NMR (300 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.63 (s, J=6.0 Hz, 1H), 7.3 (d, J=6.0 Hz, 1H), 2.56 (s, 3H). 3-Cyano-4-methylpyridine (112) was used further without additional purification.
86% With hydrogen; sodium acetate In methanol at 20℃; for 16 h; Reference Example 5
4-methylnicotinonitrile (14)
Referring to JP-A-7-10841, 2,6-dichloro-4-methylnicotinonitrile (manufactured by Mabridge) (17.0 g, 90.9 mmol) was dissolved in methanol (450 ml), and 10percent Pd-C (1.7 g, 10 wt.percent) and sodium acetate (15.2 g, 186 mmol) were added.
The mixture was stirred at room temperature under hydrogen pressure for 16 hrs. and the catalyst and the like were filtered off.
The solvent was concentrated under reduced pressure, and the resulting mixture was partitioned between dichloromethane (300 ml) - 5percent aqueous sodium hydrogen carbonate (200 ml).
The organic layer was dried and the resulting mixture was concentrated under reduced pressure.
Recrystallization from a small amount of isopropyl ether gave the title compound (9.2 g, 86percent).
sublimability
1H-NMR (200Hz, CDCl3) δ: 2.58 (3H, s), 7.31 (1H, d, J =5.8 Hz), 8.66 (1H, d, J =5.8 Hz), 8.80 (1H, s).
81% With ammonium hydroxide; zinc In tetrahydrofuran at 70℃; for 4 h; Large scale 2,6-Dichloro-4-methylnicotinonitrile (2.5 kg, 13.3 mol)was added to the mixture of Zinc powder (4.3 kg, 66.1 mol)in THF (10 L). Then concentrated ammonia (25 L) wasdropped to the mixture. The solution was stirred under refluxfor 4 h. After being filtered at room temperature, the filtratewas extracted with ethyl acetate (25 L × 3). The combinedorganic phase was evaporated under reduced pressure(20 mmHg) to afford the crude product as brown oil. Thencompound 3 was obtained by vacuum distillation (70-72oC/2mmHg) as white solid (1.27 kg, 81percent). Mp 45-46oC (lit. 43-44oC [20]. IR (KBr): 2226 cm-1 (C≡N). 1H NMR (DMSO-d6,300 MHz): 8.91 (s, 1H), 8.71 (d, J = 5.1 Hz, 1H), 7.53 (dd, J= 5.1, 0.54 Hz 1H), 2.53 (s, 3H). 13C NMR (DMSO-d6, 75MHz): 152.5, 152.3, 150.6, 124.9, 115.9, 109.9, 19.4. MS(ESI): m/z 119.1 [M+H]+.
Reference: [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 4, p. 1682 - 1697
[2] Patent: US2014/18360, 2014, A1, . Location in patent: Paragraph 0146
[3] Patent: EP1348706, 2003, A1, . Location in patent: Page/Page column 36
[4] Letters in Organic Chemistry, 2016, vol. 13, # 6, p. 450 - 452
  • 2
  • [ 875-35-4 ]
  • [ 5444-01-9 ]
YieldReaction ConditionsOperation in experiment
85% With sodium acetate In methanol Step (3)
Preparation of 3-Cyano-4-methylpyridine
A mixture of 2,6-dichloro-3-cyano-4-methylpyridine (47 g, 0.25 mol), sodium acetate (41.2 g, 0.5 mol), and palladium (II) chloride (0.5 g) in 220 mL of methanol was hydrogenated on a Parr apparatus under 50 PSI (initial pressure).
When the uptake ceased the catalyst was filtered (solka floc) and the filtrate concentrated in vacuo.
The crude residue was distilled under vacuum through a Vigreaux column and the product collected at 68°-72° C./2 mm (25.3 g, 85percent, as a clear liquid).
NMR (400 MHz, CDCl3): δ 2.52 (s, 3H, ArCH3), 7.25 (d, 1H, J=5 Hz, ArH), 8.59 (d, 1H, J=5 Hz, ArH), 8.73 (s, 1H, ArH).
Reference: [1] Patent: US4859671, 1989, A,
  • 3
  • [ 875-35-4 ]
  • [ 65169-38-2 ]
Reference: [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 4, p. 1682 - 1697
  • 4
  • [ 5444-02-0 ]
  • [ 875-35-4 ]
YieldReaction ConditionsOperation in experiment
92% at 180℃; for 6 h; 3-ethynyl-4-methylpyridine-2,6-diol (28.0 g, 195.2 mmol) was dissolved in POCl3 (60.0 mL). The reaction mixture was sealed in a pressure tube and heated up to 180°C for 6h. After the reaction was cooled down to room temperature, the excessive POCl3 was removed under the vacuum. Slowly added crushed ice into the mixture, and the solid came out. Filtered the solid out and dried under the vacuum to get the final product 2,6-dichloro-4-methylpyridine-3-carbonitrile (yield -92percent) without further purity.
92% at 180℃; for 6 h; Sealed tube 3-ethynyl-4-methylpyridine-2,6-diol (28.0 g, 195.2 mmol) was dissolved in POCl3 (60.0 mL). The reaction mixture was sealed in a pressure tube and heated up to 180° C. for 6 h. After the reaction was cooled down to room temperature, the excessive POCl3 was removed under the vacuum. Slowly added crushed ice into the mixture, and the solid came out. Filtered the solid out and dried under the vacuum to get the final product 2,6-dichloro-4-methylpyridine-3-carbonitrile (yield ~92percent) without further purity.
92% at 180℃; for 6 h; Sealed tube 3-Ethynyl-4-methylpyridine-2,6-diol (28.0 g, 195.2 mmol) was dissolved in POCl 3 (60.0 mL). The reaction mixture was sealed in a pressure tube, And heated to 180 ° C. for 6 hours. After cooling the reaction to room temperature, excess POCl 3 Was removed under vacuum. Crushed ice was slowly added to the mixture to form a solid. The solid was filtered off and dried under vacuum to give the final product 2,6-dichloro-4-methylpyridine-3-carbonitrile (yield ~ 92percent) without further purification.
92% at 180℃; for 6 h; Sealed tube 3-Ethynyl-4-methylpyridine-2,6-diol (28.0 g, 195.2 mmol) was dissolved in POCl3 (60.0 mL).The reaction mixture was sealed in a pressure tube and heated to 180 ° C for 6h.After the reaction was cooled to room temperature, excess POCl3 was removed under vacuum. Slowly add crushed ice to the mixture, followed by the appearance of a solid.The solid was filtered and dried under vacuum to give the final product without further purification2,6-dichloro-4-methylpyridine-3-carbonitrile(Yield ~ 92percent).
89% at 120℃; 2, 6-dihydroxy-4-methyl-nicotinonitrile (6 g, 39.96 mmol) and benzyltriethyl ammonium chloride (18.20 g, 79.92 mmol) were added with phosphorous oxychloride (30.63 g, 199.8 mmol) and stirred overnight at 120 °C. The mixture was slowly added to cool water and the resulting solid was filtered to obtain 6.64 g (89percent) of 2, 6-dichloro-4-methyl-nicotinonitrile. 'H NMR (300 MHz, CDCl3) 8 7. 29 (s, 1H), 2.59 (s, 3H).
67% at 150 - 180℃; for 8 h; Sealed tube 3-Cyano-2,6-dichloro-4-methylpyridine (111) [0144] 3-Cyano-2,6-dihydroxy-4-methylpyridine (110, 10 g, 0.07 mol) and phosphorus oxychloride (25 mL, 0.27 mol) were sealed in a heavy-walled tube and the mixture was heated to 150-180° C. in an oil bath for 8 h. The resulting mixture was allowed to cool to room temperature and carefully quenched by pouring it into ice (200 g). The light brown precipitate was filtered, washed with water and dried to yield 111 (8.3 g, 67percent): mp 114-118° C. (lit. (J. Org. Chem. 1960, 25, 560-564.) mp 109-110° C.). 1H NMR (300 MHz, DMSO-d6) δ 6.77 (s, 1H), 1.49 (s, 3H).

Reference: [1] Journal of Heterocyclic Chemistry, 1995, vol. 32, # 3, p. 979 - 984
[2] Patent: WO2014/165232, 2014, A1, . Location in patent: Paragraph 0174; 0175
[3] Patent: US2015/119387, 2015, A1, . Location in patent: Paragraph 0175; 0176
[4] Patent: JP2017/95498, 2017, A, . Location in patent: Paragraph 0079; 0080
[5] Patent: CN104530042, 2017, B, . Location in patent: Paragraph 0171; 0177; 0178; 0179
[6] Patent: WO2005/63768, 2005, A1, . Location in patent: Page/Page column 65
[7] Journal of Medicinal Chemistry, 2012, vol. 55, # 4, p. 1682 - 1697
[8] Patent: US2014/18360, 2014, A1, . Location in patent: Paragraph 0144
[9] Patent: US4859671, 1989, A,
[10] Patent: US4225716, 1980, A,
[11] Patent: US4225716, 1980, A,
[12] Patent: WO2012/97479, 2012, A1, . Location in patent: Page/Page column 136
[13] Patent: WO2012/97683, 2012, A1, . Location in patent: Page/Page column 71
[14] Patent: US2014/171429, 2014, A1, . Location in patent: Paragraph 0307; 0363
[15] Patent: WO2014/159733, 2014, A1, . Location in patent: Paragraph 0160-0161
[16] Patent: WO2016/191525, 2016, A1, . Location in patent: Paragraph 0229-0230
  • 5
  • [ 5444-02-0 ]
  • [ 141-43-5 ]
  • [ 875-35-4 ]
Reference: [1] Patent: US4325870, 1982, A,
  • 6
  • [ 5444-02-0 ]
  • [ 875-35-4 ]
Reference: [1] Chemistry of Heterocyclic Compounds, 2004, vol. 40, # 3, p. 308 - 314
  • 7
  • [ 39108-47-9 ]
  • [ 875-35-4 ]
  • [ 168697-58-3 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1995, vol. 32, # 3, p. 1007 - 1010
  • 8
  • [ 1026543-43-0 ]
  • [ 875-35-4 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1995, vol. 32, # 3, p. 1007 - 1010
  • 9
  • [ 875-35-4 ]
  • [ 62774-90-7 ]
YieldReaction ConditionsOperation in experiment
96% at 70 - 105℃; for 2 h; Method 2
Concentrated nitric acid (14 mL) was added to cooled (0° C.) concentrated sulfuric acid (43 mL) maintaining the internal temperature below 10° C.
After addition, the acid mixture was heated to 70° C. and commercially available (Avocado) 2,6-dichloro-4-methylnicotinonitrile (20.0 g, 107 mmol) was added.
The temperature was raised until the internal temperature of the reaction reached 105° C.
At this point the heating was stopped and after 2 h, TLC analysis revealed that the reaction was complete.
The reaction mixture was cooled to room temperature, and slowly added to ice (100 g) with strong agitation.
The solid was filtered and washed with cold water (10 mL).
The solid was dissolved in EtOAc (100 mL) and the solution was dried over Na2SO4 and concentrated to give 2,6-dichloro-4-methyl-nicotinic acid (21.0 g, 96percent) as a white solid: Rf=0.20 (1:1 EtOAc:Hex).
Reference: [1] Patent: US6677352, 2004, B1, . Location in patent: Page/Page column 46
[2] Chemistry of Heterocyclic Compounds, 2004, vol. 40, # 3, p. 308 - 314
[3] Journal of Organic Chemistry, 2000, vol. 65, # 10, p. 3111 - 3115
[4] Patent: WO2016/33009, 2016, A1, . Location in patent: Page/Page column 17
  • 10
  • [ 875-35-4 ]
  • [ 129432-25-3 ]
Reference: [1] Journal of Medicinal Chemistry, 1995, vol. 38, # 24, p. 4830 - 4838
  • 11
  • [ 875-35-4 ]
  • [ 950746-21-1 ]
Reference: [1] Patent: WO2012/97479, 2012, A1,
[2] Patent: WO2012/97683, 2012, A1,
[3] Patent: WO2013/185353, 2013, A1,
[4] Patent: WO2014/159733, 2014, A1,
[5] Patent: CN104530042, 2017, B,
[6] Patent: US2014/171429, 2014, A1,
[7] Patent: WO2014/165232, 2014, A1,
[8] Patent: WO2016/191525, 2016, A1,
[9] Patent: US2015/119387, 2015, A1,
[10] Patent: JP2017/95498, 2017, A,
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