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[ CAS No. 906673-45-8 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}

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2D 3D

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Chemical Structure| 906673-45-8

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Quality Control of [ 906673-45-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 906673-45-8 ]

Product Details of [ 906673-45-8 ]

CAS No. :	906673-45-8	MDL No. :	MFCD12165918
Formula :	C₁₄H₁₀BrNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	DAMOSKSUIVLOJT-UHFFFAOYSA-N
M.W :	304.14	Pubchem ID :	66738341
Synonyms :

Calculated chemistry of [ 906673-45-8 ]

Physicochemical Properties

Num. heavy atoms :	18
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.07
Num. rotatable bonds :	3
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	71.5
TPSA :	53.25 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-6.05 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.8
Log Po/w (XLOGP3) :	2.97
Log Po/w (WLOGP) :	3.45
Log Po/w (MLOGP) :	2.64
Log Po/w (SILICOS-IT) :	3.56
Consensus Log Po/w :	3.09

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.89
Solubility :	0.039 mg/ml ; 0.000128 mol/l
Class :	Soluble
Log S (Ali) :	-3.75
Solubility :	0.0539 mg/ml ; 0.000177 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-5.41
Solubility :	0.00118 mg/ml ; 0.00000389 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.22

Safety of [ 906673-45-8 ]

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

Application In Synthesis of [ 906673-45-8 ]

* 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 [ 906673-45-8 ]
Downstream synthetic route of [ 906673-45-8 ]

[ 906673-45-8 ] Synthesis Path-Upstream 1~3

1
[ 906673-54-9 ]
[ 906673-45-8 ]

Yield	Reaction Conditions	Operation in experiment
99%	at 10 - 30℃;	lOOg of 4-(4-bromo-3-fonnylphenoxy) benzonitrile (VI) was dissolved in 500mL of methanol at 25-30 °C and then cooled to 10-15 °C. 6.2 g of sodium borohydride was added to the reaction mass at 10-15 °C for 60-90 mm. The temperature of the reaction mass was raised to 15-20 °C. After completion of the reaction, 1000 mL of water was added to the reaction mass, stirred forlhr at 25-30 °C. The solid obtained was filtered under vacuum, washed with water and dried under vacuum below 55 °C to obtain 4-(4-bromo-3-(hydroxymethyl) phenoxy) benzonitrile (V).Yield percent: 99.0; Purity percent: 99.02
92%	at 25℃; for 4 h;	Will be 30.2g (0.1mol) 4-[(4-bromo-3-formyl)phenoxy)]benzonitrile (compound of formula I), 400 ml of methanol was added to the reaction kettle. 1.89 g (0.1 mol) of sodium borohydride was added in portions. After the addition, stirring was continued for 4 h at 25 ° C until the reaction of the starting material was complete. Recovering methanol, Add 1000ml of water to beat, filter, Drying to obtain a solid 27.8, yield 92percent;
80%	With sodium tetrahydroborate; water; sodium hydroxide In methanol at 0℃; for 1 h; Inert atmosphere	In a round bottom flask, under nitrogen atmosphere, a mixture of 4-(4-bromo-3- formylphenoxy)benzonitrile (compound A) (28.1 g, 93 mmol) and methanol (1 12 ml) was prepared and cooled to 0 °C. To the resulting suspension, a solution of sodium borohydride (1 .79 g, 46.5 mmol), water (5.9 ml) and 1 M NaOH (0.2 ml) was added dropwise for 15 minutes. The reaction mixture was stirred for 1 hour at 0 °C and 3M HCI was added until pH 4.5. Afterwards, water (1 12 ml) was added and the suspension was stirred for 1 hour at room temperature. The resulting solid was filtered and purified by recrystallization from a mixture of methanol to give 4-(4-bromo-3-(hydroxymethyl)phenoxy)benzonitrile (compound B). Yield: 80percent Purity by HPLC: >99.9percent ¹H-NMR (200 MHz, DMSO-d₆, δ ppm): 7.81-7.86 (2H, d, J=8); 7.60-7.64 (1 H, d, J=8 Hz); 7.21-7.22 (1 H, d, J=3 Hz), 7.10-7.14 (2H, d, J=8), 6.96-7.02 (1 H, dd, J=8, J=3), 5.51-5.56 (1 H, t, J=5), 4.46-4.48 (2H, d, J=5) ¹³C-NMR (50 MHz, DMSO-d₆, δ ppm): 161.04; 154.74; 144.08; 135.07; 134.08; 120.53; 1 19.73; 1 19.02; 1 18.82; 1 16.30; 106.02; 62.83 DSC: Endothermic peak at 94.2 °C.

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 8, p. 2129 - 2132
[2] Patent: WO2018/207216, 2018, A1, . Location in patent: Page/Page column 10
[3] Patent: CN108659024, 2018, A, . Location in patent: Paragraph 0038-0039
[4] Patent: WO2018/115362, 2018, A1, . Location in patent: Paragraph 0121
[5] Patent: US2007/293457, 2007, A1, . Location in patent: Page/Page column 39-40
[6] Patent: US2007/286822, 2007, A1, . Location in patent: Page/Page column 43

2
[ 2973-80-0 ]
[ 906673-45-8 ]

Reference： [1] Patent: WO2018/115362, 2018, A1,

3
[ 1194-02-1 ]
[ 906673-45-8 ]

Reference： [1] Patent: WO2018/115362, 2018, A1,

[ 906673-45-8 ] Synthesis Path-Downstream 1~23

1
[ 906673-54-9 ]
[ 906673-45-8 ]

Yield	Reaction Conditions	Operation in experiment
99%	With methanol; sodium tetrahydroborate; at 10 - 30℃;	lOOg of 4-(4-bromo-3-fonnylphenoxy) benzonitrile (VI) was dissolved in 500mL of methanol at 25-30 C and then cooled to 10-15 C. 6.2 g of sodium borohydride was added to the reaction mass at 10-15 C for 60-90 mm. The temperature of the reaction mass was raised to 15-20 C. After completion of the reaction, 1000 mL of water was added to the reaction mass, stirred forlhr at 25-30 C. The solid obtained was filtered under vacuum, washed with water and dried under vacuum below 55 C to obtain 4-(4-bromo-3-(hydroxymethyl) phenoxy) benzonitrile (V).Yield %: 99.0; Purity %: 99.02
92%	With methanol; sodium tetrahydroborate; at 25℃; for 4h;	Will be 30.2g (0.1mol) 4-[(4-bromo-3-formyl)phenoxy)]benzonitrile (compound of formula I), 400 ml of methanol was added to the reaction kettle. 1.89 g (0.1 mol) of sodium borohydride was added in portions. After the addition, stirring was continued for 4 h at 25 C until the reaction of the starting material was complete. Recovering methanol, Add 1000ml of water to beat, filter, Drying to obtain a solid 27.8, yield 92%;
92%	With methanol; sodium tetrahydroborate; at 25℃; for 2h;	302 g (1 mol) of 4-(4-bromo-3-(formyl)phenoxy)benzonitrile (a compound represented by Formula III),4000ml of methanol was added to the reaction kettle,Then 18.9 g (1 mol) of sodium borohydride was added to the reactor in batches,After the addition is complete, continue stirring at 25 C for 2h until the reaction of the raw materials is complete.Recover methanol, add 1000ml water to beat,Filtration and drying gave 281 g of solid with a yield of 92%;

80%	With sodium tetrahydroborate; water; sodium hydroxide; In methanol; at 0℃; for 1h;Inert atmosphere;	In a round bottom flask, under nitrogen atmosphere, a mixture of 4-(4-bromo-3- formylphenoxy)benzonitrile (compound A) (28.1 g, 93 mmol) and methanol (1 12 ml) was prepared and cooled to 0 C. To the resulting suspension, a solution of sodium borohydride (1 .79 g, 46.5 mmol), water (5.9 ml) and 1 M NaOH (0.2 ml) was added dropwise for 15 minutes. The reaction mixture was stirred for 1 hour at 0 C and 3M HCI was added until pH 4.5. Afterwards, water (1 12 ml) was added and the suspension was stirred for 1 hour at room temperature. The resulting solid was filtered and purified by recrystallization from a mixture of methanol to give 4-(4-bromo-3-(hydroxymethyl)phenoxy)benzonitrile (compound B). Yield: 80% Purity by HPLC: >99.9% 1H-NMR (200 MHz, DMSO-d6, delta ppm): 7.81-7.86 (2H, d, J=8); 7.60-7.64 (1 H, d, J=8 Hz); 7.21-7.22 (1 H, d, J=3 Hz), 7.10-7.14 (2H, d, J=8), 6.96-7.02 (1 H, dd, J=8, J=3), 5.51-5.56 (1 H, t, J=5), 4.46-4.48 (2H, d, J=5) 13C-NMR (50 MHz, DMSO-d6, delta ppm): 161.04; 154.74; 144.08; 135.07; 134.08; 120.53; 1 19.73; 1 19.02; 1 18.82; 1 16.30; 106.02; 62.83 DSC: Endothermic peak at 94.2 C.
		To a solution of 2 (Z=H, 10.7 mmol) in methanol (30 mL) was added sodium borohydride (5.40 mol), and the mixture was stirred at room temperature for 1 h. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford 9.9 mmol of 3.
		To a solution of 2 (Z=H, 10.7 mmol) in methanol (30 mL) was added sodium borohydride (5.40 mol), and the mixture was stirred at room temperature for 1 h. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford 9.9 mmol of 3. 2.2.a 2-Bromo-5-(4-cyanophenoxy)benzyl Alcohol 1H-NMR (300 MHz, CDCl3) delta (ppm) 2.00 (br s, 1H), 4.75 (s, 2H), 6.88 (dd, J=8.5, 2.9 Hz, 1H), 7.02 (d, J=8.8 Hz, 1H), 7.26 (d, J=2.6 Hz, 1H), 7.56 (d, J=8.5 Hz, 1H), 7.62 (d, J=8.8 Hz, 2H).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 2129 - 2132
[2]Patent: WO2018/207216,2018,A1 .Location in patent: Page/Page column 10
[3]Patent: CN108659024,2018,A .Location in patent: Paragraph 0038-0039
[4]Patent: CN110357792,2019,A .Location in patent: Page/Page column 5-7
[5]Patent: WO2018/115362,2018,A1 .Location in patent: Paragraph 0121
[6]Patent: US2007/293457,2007,A1 .Location in patent: Page/Page column 39-40
[7]Patent: US2007/286822,2007,A1 .Location in patent: Page/Page column 43

3
[ 110-87-2 ]
[ 906673-45-8 ]
[ 943311-78-2 ]

Yield	Reaction Conditions	Operation in experiment
90%	With toluene-4-sulfonic acid; In dichloromethane; at 20℃;	Add intermediate III (30.4 g, 0.1 mol) to a three-necked flask.Dichloromethane (100 ml), 2,3-dihydropyran (9.24 g, 0.12 mol) and p-toluenesulfonic acid monohydrate (0.38 g, 0.002 mol) were stirred at room temperature overnight.To the system, 100 ml of 1% aqueous ammonia was added, and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to give a yellow oil, crystals of petroleum ether to give a white solid, intermediate IV, HPLC purity 96.5% The yield is 90%.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 2129 - 2132
[2]Patent: CN109517003,2019,A .Location in patent: Paragraph 0065; 0066; 0067; 0068; 0069; 0070; 0071-0073

4
[ 906673-45-8 ]
[ 121-43-7 ]
[ 906673-24-3 ]

Yield	Reaction Conditions	Operation in experiment
Ca. 17 g	With n-butyllithium; In tetrahydrofuran; at -78℃;	In a three-necked flask, Compound II (20 g) was added, tetrahydrofuran (600 mL), trimethyl borate (14 g) was cooled to -78C, and butyllithium (64 mL, 2.5 M concentration) was added dropwise.The reaction was completed for 30 minutes or more. After the reaction was completed, 1N hydrochloric acid (600 mL) was added to quench the reaction, stirred for 30 minutes or longer, and allowed to stand for stratification.The organic phase was concentrated to dryness under reduced pressure, methanol (200 mL) was added to the resulting oil, concentrated hydrochloric acid (5 mL), and the mixture was stirred overnight at room temperature. After completion of the reaction, the mixture was concentrated under reduced pressure to give about 17 g of the target compound I.

Reference： [1]Patent: CN107759625,2018,A .Location in patent: Paragraph 0036-0039; 0040-0043; 0044-0047

5
[ 906673-45-8 ]
[ 5419-55-6 ]
[ 906673-24-3 ]

Yield	Reaction Conditions	Operation in experiment
Ca. 1.8 g	With n-butyllithium; In tetrahydrofuran; at -78℃;	In a three-necked flask, compound II (1.9 g), tetrahydrofuran (57 mL), triisopropyl borate (1.53 g) were added to cool down to -78C, and butyllithium (6.25 mL, 2.5 M concentration) was added dropwise.After completion of the reaction for 30 minutes or more, after completion of the reaction, 1N hydrochloric acid (57 mL) was added to quench the reaction, stirred for 30 minutes or more, and allowed to stand for stratification.The organic phase was concentrated under reduced pressure until no solvent was evaporated. Methanol (20 mL) was added to the obtained oil, concentrated hydrochloric acid (0.5 mL) was stirred at room temperature overnight, and after completion of the reaction, the mixture was concentrated under reduced pressure to obtain the target compound I (about 1.8 g).

Reference： [1]Patent: CN107759625,2018,A .Location in patent: Paragraph 0031-0035

6
[ 75-77-4 ]
[ 906673-45-8 ]
[5-(4-nitrylphenoxy)-2-bromophenyl-1-methoxy]trimethylsilane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With triethylamine; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere;	40.0 g (131 mmol) of 4-(4-bromo-3-hydroxymethyl-phenoxy)-benzonitrile of formula (II), prepared as described in Example 3, are added under nitrogen to 400 mL THF and 23.8 g (236 mmol) of triethylamine in a previously anhydrified flask. The solution is cooled down to 0 C. and 16.9 g (157 mmol) of trimethylsilyl chloride are added maintaining the temperature below 15 C. After completion of the addition, the mixture is allowed to reach room temperature. 50 mL of toluene and 100 mL of water are added and the phases are separated. The organic phase is washed with a saturated NaCl solution and evaporated to dryness under reduced pressure to obtain 49.4 g of 4-(4-bromo-3-trimethylsilanoxymethyl)-benzonitrile of formula (II) as a solid with a yield of 98%. The obtained product is used in the next step any without further purification. 1H-NMR (CDCl3, 300 MHz) delta (ppm): 7.63-7.60 (2H, m) 7.52 (1H, d, J=8.4 Hz), 7.22 (1H, m) 7.03-7.00 (2H), 6.85-6.80 (1H, m) 4.69 (2H, s), 0.17 (9H, s)
88%	With 1H-imidazole; In dichloromethane; at -15℃; for 16h;	Compound IV (3.00 g, 9.9 mmol, 1.0 eq) and Imidazole (1.34 g, 19.7 mmol, 2.0 eq) dissolved in dichloromethane (25mL) was added, cooled to -15C, trimethylchlorosilane (1.60 g, 14.7 mmol, 1.5 eq) was added and the reaction was stirred. After 16h, TLC showed that the basic reaction of the raw materials was completed, post-processing was carried out, the reaction mixture was quenched by adding 50 mL of water, extracted with 50 mL of dichloromethane, liquid separation was carried out, the organic phase was washed, dried, concentrated and the obtained crude product was purified by column chromatography to yield 3.26 g of yellow oil. That is, the target compound, the yield was 88%.
85%	With triethylamine; In dichloromethane; at 0 - 25℃; for 24h;	30.2 g (0.1 mol) of 4-[(4-bromo-3-hydroxymethyl)phenoxy)]benzonitrile, 300 ml of dichloromethane, and 30.3 g of triethylamine (0.3 mol) were added to the reaction kettle. The reaction was cooled to 0-10 C, 12.96 g of trimethylchlorosilane was added dropwise, the temperature was controlled to not exceed 10 C, stirred at 25 C for 24 h, quenched with water, extracted with dichloromethane, washed with water and dried over anhydrous magnesium sulfate, filtered, and the solvent was recovered to give an oil (31.8 g) , yield 85%;

Reference： [1]Patent: US2019/241585,2019,A1 .Location in patent: Paragraph 0152
[2]Patent: CN108047261,2018,A .Location in patent: Paragraph 0068; 0069
[3]Patent: CN108659024,2018,A .Location in patent: Paragraph 0040; 0041

7
[ 906673-45-8 ]
[ 104-15-4 ]
C₂₁H₁₆BrNO₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With 3,4-dihydro-2H-pyran; In dichloromethane; for 5h;	Compound IV (5.00 g, 16.4 mmol, 1.0 eq) and DHP (2.07 g, 24.6 mmol, 1.5 eq) was dissolved in dichloromethane (40 mL). p-Toluenesulfonic acid (0.28 g, 1.6 mmol, 0.1 eq) was added, and the reaction mixture was stirred. After 5h, TLC showed that the basic reaction of the raw materials was completed, post-processing was carried out, the reaction mixture was quenched by the addition of 50 mL of aqueous sodium hydrogencarbonate solution, extracted with 50 mL of dichloromethane, liquid separation was carried out, the organic phase was washed, dried, concentrated, and the obtained crude product was purified by column chromatography to yield 5.71 g of a yellow oil in a yield of 89%.

Reference： [1]Patent: CN108047261,2018,A .Location in patent: Paragraph 0070; 0071

8
[ 906673-45-8 ]
5-(4-cyanophenoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate [ No CAS ]

Reference： [1]Patent: CN108047261,2018,A
[2]Patent: WO2018/207216,2018,A1

9
[ 906673-45-8 ]
[ 906673-24-3 ]

Reference： [1]Patent: CN108047261,2018,A
[2]Patent: WO2018/207216,2018,A1
[3]Patent: WO2018/207216,2018,A1
[4]Patent: CN109517003,2019,A
[5]Patent: CN109517003,2019,A
[6]Patent: US2019/241585,2019,A1

10
[ 906673-45-8 ]
[ 108-24-7 ]
2-bromo-5-(4-cyanophenoxy)benzyl acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With pyridine; In dichloromethane; at 20℃;	To a solution of 40g (0.13 mole) of 4-(4-bromo-3-(hydroxymethyl) phenoxy) benzonitrile (V) and 20.21 g (0.198 mol) of acetic anhydride in dichloromethane, two drops of pyridine was added, and the mixture was stirred at room temperature. After completion of reaction, the reaction mixture was quenched with water and extracted with dichloromethane. The organiclayer was separated, washed with saturated sodium bicarbonate solution 0. iN hydrochloric acid and water and dried over sodium sulphate. On filtration, the filtrate was evaporated to remove the solvent completely and yield 2-bromo-5-(4-cyanophenoxy) benzyl acetate (IV).Yield %: 97.0; Purity %: 98.0
95%	With dmap; In tetrahydrofuran; at 20℃; for 1h;	Compound IV (30.00 g, 98.7 mmol, 1.0 eq), Acetic anhydride (12.08 g, 118.4 mmol, 1.2 eq), THF (150mL) and DMAP (15.65g, 128.3mmol, 1.3eq) were added to the reaction flask, and the reaction was stirred at room temperature. After 1h, TLC showed that the basic reaction of the raw materials was completed, post-processing was carried out, 200 mL of water and 200 mL of EA were added, liquid separation was carried out, the organic phase was washed, dried and concentrated to give a total of 32.36 g of white solid. That is, the compound of the formula III is 2-bromo-5-(4-cyanophenoxy)benzyl acetate in a yield of 95%.

Reference： [1]Patent: WO2018/207216,2018,A1 .Location in patent: Page/Page column 10; 11
[2]Patent: CN108047261,2018,A .Location in patent: Paragraph 0062; 0063

11
[ 906673-45-8 ]
[ 1133-49-9 ]
C₂₄H₂₂BrNO₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%		Compound IV (1.00 g, 3.3 mmol, 1.0 eq) was dissolved in DMF (15 mL), 60% sodium hydride (0.16 g, 4.0 mmol, 1.2 eq) was added, and stirred at room temperature for 30 min. 2,3,4-Trimethoxybenzyl chloride (1.00 g, 4.6 mmol, 1.4 eq) was added, and the reaction was stirred by heating to 85 C. After 6h, TLC showed that the basic reaction of the raw materials was completed, post-processing was carried out, and the reaction solution was cooled to room temperature. The reaction mixture was quenched by adding 20 mL of water, extracted with 50 mL EA, liquid separation was carried out, the organic phase was washed, dried, concentrated and the crude product was purified by column chromatography to give 1.46 g of yellow oil. That is, the target compound, the yield was 76%.

Reference： [1]Patent: CN108047261,2018,A .Location in patent: Paragraph 0066; 0067

12
[ 13675-18-8 ]
[ 906673-45-8 ]
[ 906673-24-3 ]

Yield	Reaction Conditions	Operation in experiment
80%	With (chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl)]palladium(II)); potassium acetate; ethylene glycol; XPhos; In methanol; at 64 - 66℃;Inert atmosphere; Sealed tube;	4-(4-bromo-3-(hydroxymethyl)phenoxy)benzonitrile (compound B) (10.0 g, 32.9 mmol), potassium acetate (9.7 g, 99.0 mmol), XPhos (0.078 g, 0.16 mmol), XPhos-Pd-G2 (0.068 g, 0.082 mmol) and tetrahydroxydiboron (4.4 g, 49.3 mmol) were added to an oven dried glass reactor with a positive N2 pressure. The vessel was sealed and then evacuated and backfilled with N2 (four times). MeOH (100 mL, degassed) was added via syringe, followed by the addition of ethylene glycol (5.5 mL, 99.0 mmol). The reaction was then heated to 64-66 C until the starting material was consumed (as monitored by TLC). The solvent was concentrated in vacuo and the crude reaction product was dissolved in EtOAc (50 mL) and then transferred to a separatory funnel. H20 was added (50 mL), the layers were separated and the aqueous layer was further extracted with more EtOAc (30 mL). The combined organic layers were washed once with 1 M HCI (30 mL) and once with H20 (30 mL), then dried over Na2S04 and concentrated in vacuo. The solid residue was purified twice by recrystallization in hot methanol, thus affording pure 4-[(1-hydroxy-1 ,3-dihydro- 2,1-benzoxaborol-5-yl)oxy]benzonitrile (crisaborole) (6.6 g, 26.3 mmol) as a white solid. Yield: 80% (calculated from 4-(4-bromo-3-(hydroxymethyl)phenoxy)benzonitrile) Purity by HPLC: > 99.9% 1H-NMR (200 MHz, DMSO-d6, delta ppm): 9.22 (1 H, s); 7.85-7.83 (2H, m, J= 8.9 Hz); 7.81 -7.79 (1 H, d, J= 8.1 Hz); 7.15-7.13 (3H, m); 7.10-7.08 (1 H, dd, J= 8.1 , 2.1 Hz); 4.97 (2H, s) 13C-NMR (50 MHz, DMSO-d6, ppm): 160.6; 157.1 ; 156.6; 134.7; 132.6; 1 18.9; 1 18.6; 1 12.7; 105.5; 69.7.] FT-IR: 2222.9, 1600.8, 1501.2, 1467.5, 1406.0, 1390.9, 1360.6, 1244.7, 1 167.3, 1 1 16.1 , 1010.7, 937.3, 892.5

Reference： [1]Patent: WO2018/115362,2018,A1 .Location in patent: Paragraph 0122; 0123

13
[ 2973-80-0 ]
[ 906673-45-8 ]

Reference： [1]Patent: WO2018/115362,2018,A1
[2]Patent: US2019/241585,2019,A1
[3]Patent: US2019/241585,2019,A1

14
[ 1194-02-1 ]
[ 906673-45-8 ]

Reference： [1]Patent: WO2018/115362,2018,A1
[2]Patent: CN110357792,2019,A
[3]Patent: CN110467544,2019,A

15
[ 906673-45-8 ]
4-(3-(hydroxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile [ No CAS ]

Reference： [1]Patent: WO2018/207216,2018,A1

16
[ 2737-20-4 ]
[ 1194-02-1 ]
[ 906673-45-8 ]

Yield	Reaction Conditions	Operation in experiment
96.2%	With potassium carbonate; In N,N-dimethyl-formamide; at 80 - 90℃;	2-bromo-5-hydroxybenzyl alcohol II (20.3 g, 0.1 mol) was sequentially added to a three-necked flask.N,N-dimethylformamide (50 mL), potassium carbonate (27.6 g, 0.2 mol)After the addition of p-fluorobenzonitrile (14.5 g, 0.12 mol), the reaction system was warmed to 80-90 C, and the reaction was completed by TLC. The mixture was slowly added to water (250 mL) and quenched.Filtration, drying to give a white solid, intermediate III, HPLC purity 93.5%, yield 96.2%.
54%	With potassium carbonate; In dimethyl sulfoxide; at 125℃; for 4h;Inert atmosphere;	27.2 g (197 mmol) of K2CO3, 11.9 g (98.5 mmol) of 4-fluorobenzonitrile of formula (IV), 20.0 g (98.5 mmol) of 2-bromo-5-hydroxy-benzyl alcohol of formula (III), obtained as described in Example 1, and 80 mL of DMSO are placed under nitrogen in a previously anhydrified flask. The mixture is heated to 125 C. and maintained at said temperature for 4 hours. 240 mL of H2O are added and the precipitate is filtered off and washed with H2O until reaching a neutral pH value. The solid is dried and analyzed by HPLC (yield of 70%). The mixture is then dissolved in 70 mL hot toluene and allowed to crystallize while cooling the solution down to room temperature obtaining 16.3 g of 4-(4-bromo-3-hydroxymethyl-phenoxy)-benzonitrile of formula (II) with a yield of 54%. 1H-NMR (DMSO-d6, 300 MHz) delta (ppm): 7.85-7.80 (2H, m) 7.62 (1H, d, J=8.4 Hz), 7.22 (1H, d, J=3.0 Hz), 7.13-7.11 (2H, m) 6.98 (1H, dd, J=3.0, J=8.4 Hz), 4.47 (2H, s).

Reference： [1]Patent: CN109517003,2019,A .Location in patent: Paragraph 0055; 0056; 0057; 0058; 0059; 0060; 0061-0063
[2]Patent: US2019/241585,2019,A1 .Location in patent: Paragraph 0151

17
[ 906673-45-8 ]
C₂₅H₃₀BNO₅ [ No CAS ]

Reference： [1]Patent: CN109517003,2019,A

18
[ 906673-45-8 ]
C₂₅H₃₂BNO₅ [ No CAS ]

Reference： [1]Patent: CN109517003,2019,A

19
[ 1194-02-1 ]
1-bromo-4-trimethylsilanoxy-2-trimethylsilanoxymethylbenzene [ No CAS ]
[ 906673-45-8 ]

Yield	Reaction Conditions	Operation in experiment
19.7 g	With potassium carbonate; In dimethyl sulfoxide; at 105℃; for 2h;Inert atmosphere;	27.1 g (197 mmol) of K2CO3, 12.13 g (100.3 mmol) of 4-fluorobenzonitrile of formula (IV), 34.2 g (98.3 mmol) of 1-bromo-4-trimethylsilanoxy-2-trimethylsilanoxymethyl benzene of formula (III), obtained as described in Example 2, and 60 mL of DMSO are placed under nitrogen in a previously anhydrified flask. The reaction mixture is heated to 105 C. and kept at the same temperature for 2 hours. Then, 120 mL of toluene and 240 mL of H2O are added, the phases are separated and the organic phase is washed with a solution of 10% K2CO3. The organic phase is allowed to cool down to room temperature and the product is allowed to crystallize providing 19.7 g 4-(4-bromo-3-hydroxymethyl-phenoxy)-benzonitrile of formula (II) with a yield of 66%. 1H-NMR (DMSO-d6, 300 MHz) delta (ppm): 7.85-7.80 (2H, m) 7.62 (1H, d, J=8.4 Hz), 7.22 (1H, d, J=3.0 Hz), 7.13-7.11 (2H, m) 6.98 (1H, dd, J=3.0, J=8.4 Hz), 4.47 (2H, s)

Reference： [1]Patent: US2019/241585,2019,A1 .Location in patent: Paragraph 0150

20
[ 906673-45-8 ]
crisaborole isopropyl ester [ No CAS ]

Reference： [1]Patent: US2019/241585,2019,A1

21
[ 906673-45-8 ]
[ 76-83-5 ]
4-{4-bromo-3-[(trityloxymethyl)]phenoxy}benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 25 - 45℃; for 6h;	Trityl chloride (68.75 gm) was added to a stirred solution of methylene chloride (100 ml) at 25C - 30C. DIPEA (45.8 ml) was added to the reaction mixture and heated to 40C - 45C. The solution of <strong>[906673-45-8]2-bromo-5-(4-cyanophenoxy)benzyl alcohol</strong> (50 gm) in methylene chloride (400 ml) was added to the reaction mixture at 40C - 45 C over a 1 hour period and stirred for 5 hours at the same temperature. The reaction progress was monitored by thin layer chromatography (TLC). After completion of the reaction, reaction mixture was cooled to 25C - 30C and water (200 ml) was added slowly to the reaction mixture and stirred for 15 to 20 minutes. Organic layer was added with water and stirred for 15 to 20 minutes. The phases were separated and organic phase was distilled under vacuum at 40C - 45C. Methanol (250 ml) was added to the obtained reaction mass and heated up to the reflux temperature for 2 hour. The reaction mixture was cooled to 25C - 30C, stirred for 30 minutes and filtered. The solid was washed with methanol (25x2 ml) and dried at 50C in ATD for 2 hours and further dried at 25C - 30C under vacuum for 12 hrs to obtain crude 4-{4-halo-3- [(trityloxymethyl)]phenoxy} benzonitrile (85.5 gm); Purity = 88%. NMR (CDC13, 400MHz) 5 (ppm): 4.235 (s, 2H), 6.806-6.834 (dd, J=8.4, 2.8 Hz, 1H), 7.051-7.073 (dd, J=6.8, 2.0 Hz, 2H), 7.211-7.309 (m, 9H), 7.439-7.463 (m, 7H), 7.545-7.552 (d, J=2.8 Hz, 1H), 7.620-7.643 (dd, J=6.8, 2.0 Hz, 2H).

Reference： [1]Patent: WO2019/138422,2019,A1 .Location in patent: Page/Page column 16-17

22
[ 100-83-4 ]
[ 906673-45-8 ]

Reference： [1]Patent: CN110357792,2019,A
[2]Patent: CN110467544,2019,A

23
4-(3-(hydroxymethyl)phenoxy)benzonitrile [ No CAS ]
[ 906673-45-8 ]

Yield	Reaction Conditions	Operation in experiment
95%	With N-Bromosuccinimide; toluene-4-sulfonic acid; In acetonitrile; at 25℃; for 6h;Reflux;	225 g (1 mol) of 4- (3- (hydroxymethyl) phenoxy) benzonitrile (compound of formula III),1000ml of acetonitrile, 17.2g (0.1mol) of p-toluenesulfonic acid were added to the reaction kettle,196g (1.1mol) of NBS was added to the reactor in batches at 25 C. After the addition was completed, the mixture was refluxed for 6h.Recover acetonitrile, add water, filter, and dry to obtain 290 g of white solid with a yield of 95%;

Reference： [1]Patent: CN110467544,2019,A .Location in patent: Paragraph 0046; 0052; 0053; 0059-0060; 0061; 0067-0068

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Ghs Precautionary Statements

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
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P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Ghs Hazard Statements

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere