[ CAS No. 123688-59-5 ]

Name: 123688-59-5|4-Bromo-3,5-difluorobenzonitrile|97%
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Quality Control of [ 123688-59-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 123688-59-5 ]

CAS No. :	123688-59-5	MDL No. :	MFCD11845964
Formula :	C₇H₂BrF₂N	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	LRMUGJVHRUVMHP-UHFFFAOYSA-N
M.W :	218.00	Pubchem ID :	14794290
Synonyms :

Calculated chemistry of [ 123688-59-5 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	38.77
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) :	-5.83 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.86
Log Po/w (XLOGP3) :	2.53
Log Po/w (WLOGP) :	3.44
Log Po/w (MLOGP) :	3.05
Log Po/w (SILICOS-IT) :	3.32
Consensus Log Po/w :	2.84

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.19
Solubility :	0.141 mg/ml ; 0.000647 mol/l
Class :	Soluble
Log S (Ali) :	-2.68
Solubility :	0.459 mg/ml ; 0.00211 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.9
Solubility :	0.0274 mg/ml ; 0.000126 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.72

Safety of [ 123688-59-5 ]

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

Application In Synthesis of [ 123688-59-5 ]

* 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 [ 123688-59-5 ]
Downstream synthetic route of [ 123688-59-5 ]

[ 123688-59-5 ] Synthesis Path-Upstream 1~7

1
[ 110301-23-0 ]
[ 123688-59-5 ]

Yield	Reaction Conditions	Operation in experiment
54%	Stage #1: at 20℃; for 1 h; Stage #2: With hydrogen bromide; copper(I) bromide In water at 20℃; for 13.5 h;	To concentrated sulfuric acid (25 mL) was added sodium nitrite (3.20 g) portionwise at 5 °C, and the mixture was stirred at room temperature for 0.5 h. The mixture was cooled down to 5 °C, and then acetic acid (40 mL) was added dropwise to the mixture. The mixture was stirred at 5 °C for 5 min. To the mixture was added 4-amino-3,5-difluorobenzonitrile (8, 6.50 g) portionwise, and then the mixture was stirred at room temperature for 1 h. The mixture was transferred into a dropping funnel, and was added dropwise to a solution of copper(I) bromide (9.07 g) in 47 wt percent hydrobromic acid (25 mL) over 0.5 h. The mixture was stirred at room temperature for 13 h. Water (300 mL) was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then dried. The desiccant was removed by filtration and the filtrate was evaporated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 9g (5.00 g, 54percent) as a white solid: ¹H NMR (DMSO-d₆) δ 7.98 (2H, d, J = 6.3 Hz); EI-MS m/z 217, 219 [(M)⁺].

Reference： [1] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 17, p. 5235 - 5246
[2] Patent: WO2018/75871, 2018, A1, . Location in patent: Page/Page column 68

2
[ 110301-23-0 ]
[ 123688-59-5 ]

Reference： [1] Patent: US5354502, 1994, A,

3
[ 110301-23-0 ]
[ 7787-70-4 ]
[ 123688-59-5 ]

Reference： [1] Patent: US5200110, 1993, A,
[2] Patent: US5030382, 1991, A,
[3] Patent: US4883609, 1989, A,

4
[ 7677-24-9 ]
[ 123688-59-5 ]

Yield	Reaction Conditions	Operation in experiment
5.6 g	at 80℃;	To a solution of intermediate 155 (10 g, 31 mmoles) in triethylamine (63 mL) there are added TMSCN (6.2 mL) and then Pd(PPh₃)₄(1.8 g). The reaction mixture is brought to 80° C., and 1.8 g of Pd(PPh₃)₄ are again added. The solution colours and a precipitate forms. After GC monitoring, the reaction mixture is returned to ambient temperature and then 50 mL of toluene are added. The mixture is filtered, and the filter is rinsed twice with 50 mL of toluene. The filtrate is treated with 300 mL of 1N HCl, and then with a saturated aqueous NaCl solution. Evaporation under reduced pressure yields 19 g of a solid. The residue is purified by chromatography on silica (solid deposit (100percent cyclohexane)). Intermediate 156 (5.6 g) is obtained in the form of a yellow solid. ¹H NMR (300 MHz, DMSO-d₆): δ 7.98 (m, 2H) IR (cm^-1): 2236, 1032; GC-EI (70 eV): 216.9

Reference： [1] Patent: US2017/137385, 2017, A1, . Location in patent: Paragraph 0243; 0250; 0251; 0252

5
[ 67567-26-4 ]
[ 123688-59-5 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 17, p. 5235 - 5246

6
[ 372-39-4 ]
[ 123688-59-5 ]

Reference： [1] Patent: US2017/137385, 2017, A1,

7
[ 203302-95-8 ]
[ 123688-59-5 ]

Reference： [1] Patent: US2017/137385, 2017, A1,

[ 123688-59-5 ] Synthesis Path-Downstream 1~22

1
[ 110301-23-0 ]
[ 7787-70-4 ]
[ 123688-59-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; sodium nitrite; In methanol; hydrogen bromide; acetic acid; acetone;	Step 9 While stirring 420 cm3 of concentrated sulfuric acid on an ice water bath, 54 g (0.78 mol) of finely pulverized NaNO2 was added at a rate which maintained the temperature below 40 C. The mixture was stirred on a warm water bath at 50 C. until the crystals were completely dissolved. The solution was stirred on an ice water bath and 700 cm3 of glacial acetic acid was added drop-wise. 108 g (0.70 mol) of 4-amino-3,5-difluorobenzonitrile was added at a rate which maintained the temperature at 20-25 C. and the mixture was stirred at that temperature until the crystals were completely dissolved to form the corresponding diazonium salt. An aqueous solution of the diazonium salt was added drop-wise for 2 hours to a solution of 143 g (1.0 mol) of copper (I) bromide dissolved in 420 cm3 of 47% hydrobromic acid while stirring on an ice water bath. The resulting solution was stirred for one hour on an ice water bath and allowed to sit overnight at room temperature. The product was filtered, washed with glacial acetic acid and recrystallized from a solvent mixture of acetone and methanol to yield 98 g (0.45 mol) of 4-bromo-3,5-difluorobenzonitrile.
	With hydrogen bromide; acetic acid; sodium nitrite; In methanol; water; acetone;	Step 3 24 g of sodium nitrite was added to 180 ml of concentrated sulfuric acid cooled to a temperature of at least 10 C. 38 ml of acetic acid was added to the mixture. 53 g of 4-cyano-2,6difluoroaniline was added gradually to keep the temperature of the solution between about 20and 25 C. The mixture was stirred at 20-25 C. for one hour. A solution was prepared by dissolving 60 g of copper (I) bromide in 180 ml of an aqueous 48% solution of hydrobromic acid. The mixture was added drop-wise to the solution and the solution was stirred at room temperature for 15 hours. Water was added to the solution, and the solution was extracted with chloroform and washed with water. The chloroform in the aqueous layer was distilled off and the residue was recrystallized from a solution mixture of methanol and acetone, to yield 25 g of 2-bromo-5-cyano-1,3-difluorobenzene.
	With sulfuric acid; acetic acid; In concentrated hydrobromic acid; water;	Step 4 4 g of sodium nitride was added to 30 ml of concentrated sulfuric acid and chilled to a temperature of 10 C. and 38 ml of acetic acid was added thereto. 8.9 ml of 4-cyano-2,6-difluoroaniline was added gradually to maintain the solution at a temperature of 20 to 25 C. The reaction mixture was added dropwise to a solution a 10 g of copper (I) bromide dissolved in 30 ml of concentrated hydrobromic acid. After the dropwise addition was completed, the reaction mixture was stirred for one and one half hours at room temperature. Water was added to the reaction mixture, the reaction mixture was extracted with chloroform and washed with water. The organic layer was removed by distillation, and the residue was recrystallized with a mixture of methanol and acetone to yield 6.6 g of 2-bromo-5-cyano-1,3-difluorobenzene.

Reference： [1]Patent: US5200110,1993,A
[2]Patent: US5030382,1991,A
[3]Patent: US4883609,1989,A

2
[ 110301-23-0 ]
concentrated H₂ SO₄ [ No CAS ]
[ 123688-59-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium nitrite;copper(I) bromide; In hydrogen bromide; acetic acid;	Step 2-3. While stirring 420 cm3 of concentrated H2 SO4 on an ice water bath, 54 g (0.78 mol) of pulverized NaNO2 was added at a rate that maintained a temperature under 40 C., and after the addition it was stirred in a hot water bath at 50 C. until the crystals dissolved completely. While stirring this solution on an ice water bath, 700 cm3 of glacial acetic acid was added dropwise, then 108 g (0.7 mol) of 4-amino-3,5-difluorobenzonitrile was added at a rate maintaining the temperature at 20-25 C., and after the addition was completed it was stirred at this temperature until the crystals were completely dissolved to prepare a diazonium salt solution. A solution with 143 g (1.0 mol) of CuBr dissolved in 420 cm3 of 47% HBr was stirred in an ice water bath while the previously prepared diazonium salt solution was added dropwise for 2 hours, and after the dropping was completed, it was stirred on an ice water bath for 1 hour and at room temperature overnight. The crystals formed were filtered, and after washing the crystals in glacial acetic acid, they were recrystallized from a mixture of acetone and methanol to obtain 98 g (0.44 mol) of 4-bromo-3,5-difluorobenzonitrile.

Reference： [1]Patent: US5354502,1994,A

3
[ 123688-59-5 ]
4-bromo-3,5-difluorobenzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With stannous chloride; In diethyl ether; chloroform; water;	Step 2-4. 167 g (0.88 mol) of SnCl2 was added to 880 cm3 of diethyl ether, and dried HCl gas was absorbed to saturation at room temperature. 98 g (0.44 mol) of <strong>[123688-59-5]4-bromo-3,5-difluorobenzonitrile</strong> was added all at once to this mixture, and after stirring for i hour, it was let stand overnight. The reactant was poured into 1,000 cm3 of water, and ether was distilled on a hot water bath at 50 C. The residue was extracted by adding chloroform, and after washing in water the chloroform was removed. The residue was distilled under reduced pressure (b. p. 96 C./73 mmHg) to obtain 88 g (0.40 mol) of 4-bromo-3,5-difluorobenzaldehyde.

Reference： [1]Patent: US5354502,1994,A

4
[ 123688-59-5 ]
4-bromo-3,5-difluorobenzamidine hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With ammonia; In ethanol; benzene;	Step 5 2 g of <strong>[123688-59-5]2-bromo-5-cyano-1,3-difluorobenzene</strong> was dissolved in a solution of 4 ml of ethanol and 15 ml benzene and chilled to a temperature below 0 C. 16% ammonia absorption ethanol was added to the chilled solution which was then stirred for one hour. After the reaction was completed, the solvent of the solution was distilled off and the crystal residue was washed with ether to yield 2.1 g of 4-bromo-3,5-difluorobenzamidine hydrochloride.

Reference： [1]Patent: US4883609,1989,A

5
[ 123688-59-5 ]
[ 1370362-90-5 ]

Reference： [1]CrystEngComm,2012,vol. 14,p. 768 - 770

6
[ 110301-23-0 ]
[ 123688-59-5 ]

Yield	Reaction Conditions	Operation in experiment
54%		To concentrated sulfuric acid (25 mL) was added sodium nitrite (3.20 g) portionwise at 5 C, and the mixture was stirred at room temperature for 0.5 h. The mixture was cooled down to 5 C, and then acetic acid (40 mL) was added dropwise to the mixture. The mixture was stirred at 5 C for 5 min. To the mixture was added 4-amino-3,5-difluorobenzonitrile (8, 6.50 g) portionwise, and then the mixture was stirred at room temperature for 1 h. The mixture was transferred into a dropping funnel, and was added dropwise to a solution of copper(I) bromide (9.07 g) in 47 wt % hydrobromic acid (25 mL) over 0.5 h. The mixture was stirred at room temperature for 13 h. Water (300 mL) was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then dried. The desiccant was removed by filtration and the filtrate was evaporated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 9g (5.00 g, 54%) as a white solid: 1H NMR (DMSO-d6) delta 7.98 (2H, d, J = 6.3 Hz); EI-MS m/z 217, 219 [(M)+].
		NaN02 (1.60 g, 23.20 mmol) was added portion wise at 5C to a solution of H2SO4 (0309) (12.50 mL, 98 %), and the mixture was stirred at 15C for 0.5 hour. The mixture was cooled to 5C and AcOH (20.00 mL) was added dropwise. The mixture was stirred at 5C for 5 min. 3.25 g Compound BD6-1 (i.e., 4-amino-3,5-difluorobenzonitrile) was added portionwise and the mixture was stirred at 15C for 1 hour. The mixture was transferred into a dropping funnel and then added dropwise to a solution of CuBr (4.54 g, 31.64 mmol) in HBr (12.50 mL, 47 %) over 0.5 hour. The mixture was then stirred at 15C for 12 hour. TLC showed the reaction had completed. The reaction mixture was diluted by addition H20 (150 mL) and extracted with EtOAc (20 mL * 3). The combined extracted organic layers were washed with brine (20 mL * 3), dried over Na2SC>4, filtered and concentrated under reduced pressure to yield a residue. The residue was purified by column chromatography (S1O2, petroleum etherethyl acetate mixture in a ratio of 1:0 to 10: 1) to afford Compound BD6-2 (2.30 g, crude) as a white solid.

Reference： [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 5235 - 5246
[2]Patent: WO2018/75871,2018,A1 .Location in patent: Page/Page column 68

7
[ 123688-59-5 ]
[ 1395553-26-0 ]