[ CAS No. 60702-69-4 ] {[proInfo.proName]}

Name: 60702-69-4|2-Chloro-4-fluorobenzonitrile|98%
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SKU: A180069
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Quality Control of [ 60702-69-4 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 60702-69-4 ]

Product Details of [ 60702-69-4 ]

CAS No. :	60702-69-4	MDL No. :	MFCD00042523
Formula :	C₇H₃ClFN	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	PGKPNNMOFHNZJX-UHFFFAOYSA-N
M.W :	155.56	Pubchem ID :	109000
Synonyms :

Calculated chemistry of [ 60702-69-4 ]

Physicochemical Properties

Num. heavy atoms :	10
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 :	36.13
TPSA :	23.79 Å²

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) :	-5.57 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.77
Log Po/w (XLOGP3) :	2.37
Log Po/w (WLOGP) :	2.77
Log Po/w (MLOGP) :	2.48
Log Po/w (SILICOS-IT) :	2.86
Consensus Log Po/w :	2.45

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.74
Solubility :	0.282 mg/ml ; 0.00181 mol/l
Class :	Soluble
Log S (Ali) :	-2.51
Solubility :	0.481 mg/ml ; 0.00309 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.36
Solubility :	0.0673 mg/ml ; 0.000433 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.77

Safety of [ 60702-69-4 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302+H312+H332-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 60702-69-4 ]

* 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 [ 60702-69-4 ]
Downstream synthetic route of [ 60702-69-4 ]

[ 60702-69-4 ] Synthesis Path-Upstream 1~6

1
[ 28163-00-0 ]
[ 3939-09-1 ]
[ 60702-69-4 ]

Reference： [1] Journal of Fluorine Chemistry, 1993, vol. 63, # 1-2, p. 25 - 30

2
[ 84194-36-5 ]
[ 60702-69-4 ]

Reference： [1] Biochemical Pharmacology, 2015, vol. 96, # 2, p. 93 - 106

3
[ 28163-00-0 ]
[ 60702-69-4 ]

Reference： [1] Tetrahedron Letters, 2010, vol. 51, # 14, p. 1906 - 1909

4
[ 625-98-9 ]
[ 60702-69-4 ]

Reference： [1] Journal of Medicinal Chemistry, 2009, vol. 52, # 22, p. 7186 - 7191

5
[ 28163-00-0 ]
[ 3939-09-1 ]
[ 60702-69-4 ]

Reference： [1] Journal of Fluorine Chemistry, 1993, vol. 63, # 1-2, p. 25 - 30

6
[ 60702-69-4 ]
[ 74-88-4 ]
[ 796600-15-2 ]

Yield	Reaction Conditions	Operation in experiment
76%	Stage #1: With lithium diisopropyl amide In tetrahydrofuran; hexanes at -78 - -65℃; for 6 h; Stage #2: at -65 - -5℃; for 14 h;	Cool a solution of diisopropylamine (80.6 niL, 0.575 mol) in THF (1 L) to about -5 ⁰C using an ice water/MeOH bath. Add /z-butyllithium (2.5 M in hexanes, 212 mL, 0.530 mol) dropwise over 1 h via a syringe pump (4 mL/min) while maintaining the reaction temperature between -5 to 0 ⁰C during the addition. Stir the lithium diisopropylamide (LDA) solution for 1 h at 0 °C and then transfer it via canula, over 1 h, to a -78 ⁰C solution of 2-chloro-4-fluoro-benzonitrile (68.7 g, 0.442 mol) in THF (1 L). Allow the temperature of the reaction mixture to warm to about -65 ⁰C during the initial addition of the LDA solution; however, keep the internal temperature below -70 ⁰C during the remainder of the LDA addition. Keep the temperature of the resulting dark red-orange reaction mixture below -70 ⁰C for 5 h and add iodomethane (251.2 g, 1.77 mol, ~3 mL/min) at such a rate that the reaction temperature is maintained below -65 ⁰C during the addition. Allow the reaction mixture to slowly warm overnight. After stirring for 14 h, the temperature of the reaction mixture is -5 ⁰C. Quench the reaction with saturated aqueous ammonium chloride (500 mL) and water (750 mL) and dilute with diethyl ether (about 2 L). Separate the layers and extract the aqueous layer with diethyl ether (about 1 L). Dry the combined organic layer (about 5.5 L) over MgSO₄, filter, and concentrate to afford the crude title compound as a red-brown oily solid (about 86.7 g). Subject the crude residue (dry loaded on silica gel using methylene chloride) to flash chromatography (silica gel (10 x 30 cm), gradient of 99: 1 to 93:7 hexane/EtOAc) to obtain the title compound (56.7 g, 76percent) as a white solid, m.p. 63 - 65 ⁰C; ¹H NMR (300 MHz, CDCl₃): δ 7.54 (dd, J= 8.6, 5.6 Hz, IH), 7.08 (dd, J = 8.6, 8.6 Hz , IH), 2.36 (d, / = 2.4 Hz, 3H).
74%	Stage #1: With n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; hexane at -70℃; Stage #2: at -70 - -5℃; for 19.5 h;	Preparation 12-Chloro-4-fluoro-3-methyl-benzonitrileTo a solution of diisopropylamine (474 mL, 3.35 mol) in anhydrous THF (5.8 L) at-5 °C under a nitrogen atmosphere is added dropwise 2.5 M n-butyllithium in hexanes (1.24 L, 3.10 mol) over 3 h and the resulting mixture is stirred at -5 °C for one additional hour. The LDA solution is added dropwise to a solution of 2-chloro-4-fluoro-benzonitrile (400 g, 2.58 mol) in anhydrous THF (5.8 L) at -70 °C over 6 h and then stirred at -70 °C overnight. lodomethane (643 mL, 10.32 mol) is added dropwise over 2.5 h and the temperature is raised to -5 °C for 17 h. Saturated aqueous ammonium chloride (3 L) is added. The solution is diluted with water (3.5 L) and extracted with diethyl ether (2 x 2 L). The organic phases are separated, combined, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a black solid. The solid is purified through a silica gel pad eluting withEtOAc/hexanes (1/40) to obtain the title compound (323 g, 74percent). 1H NMR (300 MHz, CDCls) δ 7.08 (dd, J= 8.6, 8.6 Hz, 1H), 7.54 (dd, J= 8.6, 5.6 Hz, 1H), 2.36 (d, J= 2.4 Hz, 3H).

Reference： [1] Patent: WO2006/124447, 2006, A2, . Location in patent: Page/Page column 45-46
[2] Patent: WO2013/55577, 2013, A1, . Location in patent: Page/Page column 24-25
[3] Journal of Medicinal Chemistry, 2016, vol. 59, # 2, p. 750 - 755
[4] Patent: WO2004/99144, 2004, A1, . Location in patent: Page 25

[ 60702-69-4 ] Synthesis Path-Downstream 1~88

1
[ 28163-00-0 ]
[ 3939-09-1 ]
[ 60702-69-4 ]

Reference： [1]Journal of Fluorine Chemistry,1993,vol. 63,p. 25 - 30

2
[ 401564-31-6 ]
[ 60702-69-4 ]
[ 401565-02-4 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one;	(1) The title compound (0.904 g) of Reference Example 10, diisopropylethylamine (1.57 mL) and <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> (0.467 g) were dissolved in N-methyl-2-pyrrolidone 9 mL), and the mixture was stirred at 80C for 8 hr.The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give 3-[(2S,4S)-1-tert-butoxycarbonyl-4-(3-chloro-4-cyanophenyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidine (0.630 g) as a colorless transparent oil.

Reference： [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 3662 - 3671
[2]Patent: EP1308439,2003,A1

3
[ 2935-44-6 ]
[ 60702-69-4 ]
[ 862582-56-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium n-butoxide; In tetrahydrofuran; at 20℃; for 72h;	EXAMPLE 28 2-Chloro-4-(4-hydroxy-1-methyl-pentyloxy)-benzonitrile To a solution of 2,5-hexanediol (28 mg, 0.240 mmol) in tetrahydrofuran was added an excess of potassium butoxide. The admixture was stirred, briefly, and <strong>[60702-69-4]2-chloro-4-fluoro-benzonitrile</strong> (37 mg, 0.240 mmol) was added. The admixture was stirred at room temperature for 72 hours. Purification by reverse phase high pressure chromatography eluding with a solvent gradient (15% of 0.1% formic acid/CH3CN in 0.1% formic acid/water to 100% of 0.1% formic acid/water) provided 28.4 mg of 2-chloro-4-(4-hydroxy-1-methyl-pentyloxy)-benzonitrile. 1H NMR (CDCl3) delta 7.50 (d, 1H), 6.95 (m, 1H), 6.79 (br d, 1H), 4.43 (m, 1H), 3.79 (m, 1H), 1.89-1.40 (m, 4H), 1.30 (d, 3H), 1.17 (d, 3H); MS m/z 253.

Reference： [1]Patent: US2005/182132,2005,A1 .Location in patent: Page/Page column 12

4
[ 60702-69-4 ]
[ 504-63-2 ]
[ 862582-57-8 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 29 2-Chloro-4-(3-hydroxy-propoxy)-benzonitrile To 1,3-propanediol (320 mg, 4.2 mmol) was added sodium (21 mg, 0.92 mmol). The mixture is stirred at room temperature for 10 minutes and <strong>[60702-69-4]2-chloro-4-fluoro-benzonitrile</strong> (156 mg, 1.0 mmol) was added. The reaction was heated to 105 C. for 24 hours. The reaction was cooled to room temperature, was diluted with water and was extracted with Et2O (3*). The organic solution was dried (MgSO4), filtered and concentrated. The residue was purified by reverse phase high pressure chromatography eluding with a solvent gradient (15% of 0.1% formic acid/CH3CN in 0.1% formic acid/water to 100% of 0.1% formic acid/water) to provide 107 mg of 2-chloro-4-(3-hydroxy-propoxy)-benzonitrile. 1H NMR (CDCl3) delta 7.54 (d, 1H), 7.00 (m, 1H), 6.85 (dd, 1H), 4.15 (t, 2H), 3.83 (t, 2H), 2.04 (m, 2H).

Reference： [1]Patent: US2005/182132,2005,A1 .Location in patent: Page/Page column 12

5
[ 504-01-8 ]
[ 60702-69-4 ]
[ 873097-12-2 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium fluoride on basic alumina; In acetonitrile; for 16h;Heating / reflux;	Example 26 2-Chloro-4-(3-hydroxy-cyclohexyloxy)-benzonitrile 1,3-Cyclohexanediol (116 mg, 1.0 mmole) was added to a flame dried round bottom flask under nitrogen. The flask was then charged with 5 mL of dry acetonitrile, 26 mg of potassium fluoride on alumina (0.1 mmol), and <strong>[60702-69-4]4-fluoro-2-chloro-benzonitrile</strong> (155 mg, 1.0 mmole) and heated at reflux for 16 h. Diethyl ether (15 ml) was added to the reaction mixture, which was then extracted with water (2*), dried (MgSO4) and concentrated. Purification using a chromatotron, eluding with 10% EtOAc/hex (ethylacetate and hexane) provided 22 mg of the title compound. GC/MS: 251 (M/Z for C13H14ClNO2).

Reference： [1]Patent: US2006/9427,2006,A1 .Location in patent: Page/Page column 16-17

6
[ 3274-96-2 ]
[ 60702-69-4 ]
[ 873097-08-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In N,N-dimethyl-formamide; at 20℃; for 16h;Product distribution / selectivity;	Example 27 2-Chloro-4-(2-ethyl-cyclohexyloxy)-benzonitrile 4-Fluoro-2-chloro-benzonitrile (122 mg, 0.79 mmole) was added to a flame dried round bottom flask under nitrogen containing 2 mL of dry dimethylformamide ("DMF") and 63 mg of 60% sodium hydride as an oil dispersion (1.6 mmol). 2-Ethylcyclohexanol. (100 mg, 0.79 mmole) dissolved in 1 mL of dry DMF was then added to the reaction vessel via syringe in a dropwise manner. The reaction was stirred at room temperature for 16 h, after which time 5 mL of water was added dropwise. The mixture was extracted twice with diethyl ether, washed with water, dried (MgSO4) and concentrated. Purification using a chromatotron eluding with 5% EtOAc/hex followed by 5% EtOAc/hex gave 155 mg of the title compound. GC/MS: 263 (M/Z for C15H18ClNO).

Reference： [1]Patent: US2006/9427,2006,A1 .Location in patent: Page/Page column 17

7
[ 3057-74-7 ]
[ 60702-69-4 ]
[ 1006035-81-9 ]

Yield	Reaction Conditions	Operation in experiment
80%	With sodium hydrogencarbonate; In water; dimethyl sulfoxide; at 95℃; for 15h;	a) (2S)-2-[(3-Chloro-4-cyanophenyl)amino]-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoic acid<strong>[60702-69-4]2-Chloro-4-fluorobenzonitrile</strong> (2.13 g, 13.8 mmol), (2S)-2-amino-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoic acid (2.6 g, 13.8 mmol) and NaHCO3 (3.5 g, 41.4 mmol) in DMSO (70 mL) and H2O (10 mL) were stirred at 95 C. for 15 h. After cooling, the reaction mixture was diluted with H2O (100 mL) and washed with Et2O (100 mL). The H2O layer was acidified to Congo Red midpoint and extracted with Et2O (2×). The combined organic extracts were washed with H2O, dried over Na2SO4, filtered, and concentrated to give the titled product (3.59 g, 80%) as a foam. 1H-NMR (CDCl3) delta: 1.45 (9H, s), 2.89 (2H, m), 3.54 (1H, m), 4.42 (1H, m), 6.55 (1H, d, J=8.8 Hz), 6.70 (1H, s), 7.43 (1H, d, J=8.4 Hz). LC-MS (ES) m/e 325.4 (M+H)+.

Reference： [1]Patent: US2008/39517,2008,A1 .Location in patent: Page/Page column 8-9
[2]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 4664 - 4668

8
[ 770706-26-8 ]
[ 60702-69-4 ]
[ 1006035-79-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In water; dimethyl sulfoxide; at 75℃; for 18h;Product distribution / selectivity;	d) 2-Chloro-4-[(3S)-1-methyl-5-oxo-3-pyrrolidinyl]amino}benzonitrile1,1-Dimethylethyl [(3S)-1-methyl-5-oxo-3-pyrrolidinyl]carbamate (0.96 g, 4.5 mmol) was suspended in 4N HCl in dioxane (3 mL) and the mixture was stirred at room temperature for 12 h. Solvent was removed and the residue was dissolved in DMSO (27 mL) and H2O (3 mL). To this solution, <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> (0.77 g, 4.90 mmol) and NaHCO3 (1.89 g, 22.5 mmol) were added and the reaction mixture was stirred at 75 C. for 18 h. After cooling to room temperature, the reaction mixture was partitioned between H2O and EtOAc and the organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography with 0% MeOH in CH2Cl2 grading to 5% MeOH in CH2Cl2 to give the titled product (0.598 g, 53%) as a white solid. 1H-NMR (CDCl3) delta: 2.350 (1H, m), 2.914 (4H, m), 3.305 (1H, m), 3.825 (1H, m), 4.200 (1H, m), 4.835 (1H, d, J=6.8 Hz), 6.492 (1H, dd, J=8.4 Hz, 2.4 Hz), 6.626 (1H, d, J=2.4 Hz), 7.454 (1H, d, J=8.4 Hz). LC-MS (ES) m/e 250.0 (M+H)+.

Reference： [1]Patent: US2008/39517,2008,A1 .Location in patent: Page/Page column 10-11

9
[ 111-49-9 ]
[ 60702-69-4 ]
[ 20925-52-4 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3651 - 3660

10
[ 6760-99-2 ]
[ 60702-69-4 ]
[ 735330-99-1 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide;	EXAMPLE 345B 4-(8-azabicyclo[3.2.1]oct-8-yl)-2-chlorobenzonitrile <strong>[60702-69-4]2-Chloro-4-fluorobenzonitrile</strong> (0.97 g, 6.2 mmol), 8-aza-bicyclo[3.2.1]octane hydrochloride (0.92 g, 6.2 mmol), and N,N-diisopropylethylamine (1.6 g, 12 mmol) were combined in DMSO (15 mL) and heated at 120 C. for 16 hours. The mixture was allowed to cool to ambient temperature and partitioned between diethyl ether and saturated NaHCO3 solution. The aqueous phase was separated and extracted with diethyl ether. The organic layers were combined, washed with water, brine, dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure to provide the title compound which was used in the next step without further purification.
	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide;	Example 345B 4-(8-azabicyclo[3.2.1]oct-8-yl)-2-chlorobenzonitrile <strong>[60702-69-4]2-Chloro-4-fluorobenzonitrile</strong> (0.97 g, 6.2 mmol), 8-aza-bicyclo[3.2.1]octane hydrochloride (0.92 g, 6.2 mmol), and N,N-diisopropylethylamine (1.6 g, 12 mmol) were combined in DMSO (15 mL) and heated at 120 C. for 16 hours. The mixture was allowed to cool to ambient temperature and partitioned between diethyl ether and saturated NaHCO3 solution. The aqueous phase was separated and extracted with diethyl ether. The organic layers were combined, washed with water, brine, dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure to provide the title compound which was used in the next step without further purification.

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3651 - 3660
[2]Patent: US6933311,2005,B2
[3]Patent: US2004/157849,2004,A1

11
[ 60702-69-4 ]
[ 946388-39-2 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3651 - 3660

12
[ 60702-69-4 ]
N-(2-chloro-4-azepan-1-ylbenzyl)-N'-1H-indazol-4-ylurea [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3651 - 3660

13
[ 60702-69-4 ]
4-(8-azabicyclo[3.2.1]oct-8-yl)-2-chlorobenzylamine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3651 - 3660
[2]Patent: US2004/157849,2004,A1

14
[ 60702-69-4 ]
[ 735330-98-0 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3651 - 3660
[2]Patent: US2004/157849,2004,A1

15
[ 60702-69-4 ]
1-(4-(8-azabicyclo[3.2.1]octan-8-yl)-2-chlorobenzyl)-3-(1H-indazol-4-yl)urea [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3651 - 3660
[2]Patent: US2004/157849,2004,A1

16
[ 60702-69-4 ]
[ 735330-87-7 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3651 - 3660

17
[ 60702-69-4 ]
C₂₃H₂₅ClN₄O [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3651 - 3660

18
[ 60702-69-4 ]
4-[3-(4-Cyano-benzyl)-3H-imidazol-4-ylmethoxy]-2-naphthalen-1-yl-benzonitrile [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5371 - 5376

19
[ 60702-69-4 ]
[ 172455-36-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 2019 - 2022
[2]Patent: WO2012/45196,2012,A1

20
[ 60702-69-4 ]
[ 497147-90-7 ]