[ CAS No. 50824-05-0 ] {[proInfo.proName]}

Name: 50824-05-0|1-(Bromomethyl)-4-(trifluoromethoxy)benzene|97%
Brand: Ambeed
SKU: A216393
Rating: 95 (35 reviews)

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Quality Control of [ 50824-05-0 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 50824-05-0 ]

CAS No. :	50824-05-0	MDL No. :	MFCD00061238
Formula :	C₈H₆BrF₃O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	JDNPUJCKXLOHOW-UHFFFAOYSA-N
M.W :	255.03	Pubchem ID :	142785
Synonyms :

Calculated chemistry of [ 50824-05-0 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.25
Num. rotatable bonds :	3
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	45.96
TPSA :	9.23 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.26 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.45
Log Po/w (XLOGP3) :	3.66
Log Po/w (WLOGP) :	4.59
Log Po/w (MLOGP) :	3.05
Log Po/w (SILICOS-IT) :	3.39
Consensus Log Po/w :	3.43

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.87
Solubility :	0.0344 mg/ml ; 0.000135 mol/l
Class :	Soluble
Log S (Ali) :	-3.54
Solubility :	0.073 mg/ml ; 0.000286 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.29
Solubility :	0.0132 mg/ml ; 0.0000519 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.66

Safety of [ 50824-05-0 ]

Signal Word:	Danger	Class:	8
Precautionary Statements:	P280-P305+P351+P338-P310	UN#:	3261
Hazard Statements:	H314	Packing Group:	Ⅱ
GHS Pictogram:

Application In Synthesis of [ 50824-05-0 ]

* 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 [ 50824-05-0 ]
Downstream synthetic route of [ 50824-05-0 ]

[ 50824-05-0 ] Synthesis Path-Upstream 1~8

1
[ 50824-05-0 ]
[ 330-12-1 ]

Reference： [1] Chemical Communications, 2016, vol. 52, # 5, p. 1013 - 1016

2
[ 1736-74-9 ]
[ 50824-05-0 ]

Yield	Reaction Conditions	Operation in experiment
66%	With phosphorus tribromide In dichloromethane at 0 - 20℃; for 3.5 h;	1-(Bromomethyl)-4-(trifluoromethoxy)benzene: To a solution of (4-(trifluoromethoxy)phenyl)methanol (3.6 g, 18.8 mmol) in CH₂Cl₂(60 mL) was added PBr₃(6 g, 22.2 mmol) dropwise with stirring, while cooling to a temperature of 0-10° C. over a time period of 30 min. The resulting mixture was stirred at room temperature for 3 h. Water (30 mL) was added and the mixture washed with aqueous NaHCO₃(2.x.30 mL) and brine (30 mL). The organic solution was dried (Na₂SO₄) and concentrated in vacuo to afford the title compound (3.5 g, 66percent) as a yellow oil.

Reference： [1] Patent: US2007/270434, 2007, A1, . Location in patent: Page/Page column 17
[2] J. Gen. Chem. USSR (Engl. Transl.), 1965, vol. 35, p. 1631 - 1637[3] Zhurnal Obshchei Khimii, 1965, vol. 35, p. 1628 - 1636
[4] Journal of Medicinal Chemistry, 2005, vol. 48, # 2, p. 556 - 568
[5] Organometallics, 2014, vol. 33, # 21, p. 5940 - 5943
[6] European Journal of Medicinal Chemistry, 2017, vol. 127, p. 100 - 114

3
[ 456-55-3 ]
[ 50824-05-0 ]

Yield	Reaction Conditions	Operation in experiment
60%	With sodium bromide; sulfuric acid; paraformaldehyde In tert-butyl methyl ether; water; acetic acid	Example 1 4-Bromomethyl-1-trifluoromethoxybenzene 300 g of trifluoromethoxybenzene, 111 g of paraformaldehyde, 456 g of sodium bromide, and 900 ml of glacial acetic acid were initially charged and heated at 90° C. To release hydrogen bromide, a mixture of 450 ml of glacial acetic acid and 678 g of concentrated sulfuric acid was then added dropwise. After the addition had ended, the reaction mixture was stirred at 90° C. for 20 hours. The reaction mixture was then poured onto 1,000 g of ice and extracted twice with in each case 300 ml of methyl tert-butyl ether. The combined organic extracts were washed with 100 ml of water and concentrated. The residue was distilled at 20 hPa in a spinning band column. This gave 324.3 g of 4-bromomethyl-1-trifluoromethoxybenzene as a colorless liquid (60percent of theory) of b.p. 82-83° C.

Reference： [1] Patent: US2002/82454, 2002, A1,

4
[ 659-28-9 ]
[ 50824-05-0 ]

Reference： [1] Journal of Medicinal Chemistry, 2005, vol. 48, # 2, p. 556 - 568
[2] European Journal of Medicinal Chemistry, 2017, vol. 127, p. 100 - 114

5
[ 587-18-8 ]
[ 50824-05-0 ]

Reference： [1] J. Gen. Chem. USSR (Engl. Transl.), 1965, vol. 35, p. 1631 - 1637[2] Zhurnal Obshchei Khimii, 1965, vol. 35, p. 1628 - 1636

6
[ 50824-05-0 ]
[ 4315-07-5 ]

Reference： [1] J. Gen. Chem. USSR (Engl. Transl.), 1965, vol. 35, p. 1631 - 1637[2] Zhurnal Obshchei Khimii, 1965, vol. 35, p. 1628 - 1636

7
[ 50824-05-0 ]
[ 287952-67-4 ]

Reference： [1] Patent: US2013/143864, 2013, A1,

8
[ 50824-05-0 ]
[ 872038-32-9 ]

Reference： [1] Organometallics, 2014, vol. 33, # 21, p. 5940 - 5943

[ 50824-05-0 ] Synthesis Path-Downstream 1~41

1
[ 1736-74-9 ]
[ 50824-05-0 ]

Yield	Reaction Conditions	Operation in experiment
66%	With phosphorus tribromide; In dichloromethane; at 0 - 20℃; for 3.5h;	1-(Bromomethyl)-4-(trifluoromethoxy)benzene: To a solution of <strong>[1736-74-9](4-(trifluoromethoxy)phenyl)methanol</strong> (3.6 g, 18.8 mmol) in CH2Cl2 (60 mL) was added PBr3 (6 g, 22.2 mmol) dropwise with stirring, while cooling to a temperature of 0-10 C. over a time period of 30 min. The resulting mixture was stirred at room temperature for 3 h. Water (30 mL) was added and the mixture washed with aqueous NaHCO3 (2×30 mL) and brine (30 mL). The organic solution was dried (Na2SO4) and concentrated in vacuo to afford the title compound (3.5 g, 66%) as a yellow oil.
	With phosphorus tribromide; In diethyl ether; at 0℃; for 0.5h;	General procedure: To a stirred solution of alcohol 2 (1 mmol) in dry ether (10 mL)was added phosphorus tribromide (0.5 mL) dropwise at 0 C and the reaction mixture was stirred for 0.5 h. After completion of thereaction (TLC monitoring), the reaction mixture was carefullypoured over ice, and the aqueous phase was extracted with ether.The combined organic layers werewashed with NaHCO3 and water,followed by brine. Drying over Na2SO4 and evaporation of thesolvents under reduced pressure affords the desired benzyl bromide3 which was used without further purification.

Reference： [1]Patent: US2007/270434,2007,A1 .Location in patent: Page/Page column 17
[2]Journal of general chemistry of the USSR,1965,vol. 35,p. 1631 - 1637
Zhurnal Obshchei Khimii,1965,vol. 35,p. 1628 - 1636
[3]Journal of Medicinal Chemistry,2005,vol. 48,p. 556 - 568
[4]Organometallics,2014,vol. 33,p. 5940 - 5943
[5]European Journal of Medicinal Chemistry,2017,vol. 127,p. 100 - 114

2
[ 50824-05-0 ]
[ 151-50-8 ]
[ 49561-96-8 ]

Yield	Reaction Conditions	Operation in experiment
63%	In ethanol; water for 3h; Heating / reflux;	7.5 2-(4-(Trifluoromethoxy)phenyl)acetonitrile: To a solution of 1-(bromomethyl)-4-(trifluoromethoxy)benzene (3.5 g, 13.7 mmol) in EtOH (40 mL) was added a solution of KCN (1 g, 15.4 mmol) in water (10 mL). The resulting solution was heated at reflux for 3 h. The reaction mixture was cooled and volatiles were removed in vacuo. Water (50 mL) was added and the aqueous mixture was extracted from EtOAc (3×30 mL). The combined organic solution was dried (Na2SO4) and concentrated in vacuo to afford the title compound (2.0 g, 63%) as a yellow oil.
	In ethanol

Reference： [1]Current Patent Assignee: KALYPSYS, INC. - US2007/270434, 2007, A1 Location in patent: Page/Page column 17
[2]Orda,V.V. et al. [Journal of general chemistry of the USSR, 1965, vol. 35, p. 1631 - 1637][Zhurnal Obshchei Khimii, 1965, vol. 35, p. 1628 - 1636]

3
[ 453-71-4 ]
[ 21101-63-3 ]
[ 50824-05-0 ]
[ 107-95-9 ]
4-Oxo-5-(4-trifluoromethoxy-benzyl)-1-(4-trifluoromethylsulfanyl-benzyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carboxylic acid amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	solid-phase synthesis; Yield given. Multistep reaction;

Reference： [1]Schwarz, Matthias K.; Tumelty, David; Gallop, Mark A. [Tetrahedron Letters, 1998, vol. 39, # 46, p. 8397 - 8400]

4
[ 61204-01-1 ]
[ 50824-05-0 ]
1-(4-trifluoromethoxyphenyl)-2-[4-(trans-4-pentylcyclohexyl)phenyl]-ethane [ No CAS ]

Reference： [1]Molecular Crystals and Liquid Crystals,2004,vol. 411,p. 49/[1091]-56/[1098]

5
[ 50824-05-0 ]
[ 21642-98-8 ]
[ 950201-44-2 ]

Yield	Reaction Conditions	Operation in experiment
91%	With potassium carbonate; In acetonitrile; at 140℃; for 16.0h;	Commercially available 4-methoxy-2-oxo-l,2-dihydro-pyridine-3-carbonitrile (4.70 g, 31.29 mmol, 1 eq), 4-(trifluoromethoxy)benzylbromide (5.44 ml, 32.86 mmol, 1.05 eq) and K2CO3 (12.9 g, 93.8 mmol, 3 eq) were mixed in acetonitrile (200 ml). The mixture was heated at 140 0C for 16 hours into a sealed tube. The reaction was then cooled to room temperature and the solvents were evaporated in vacuum. The resulting residue was dissolved in DCM and filtered through a pad of celite. The filtrate was then concentrated in vacuo. Subsequently, the white solid thus obtained was triturated with di- ethylether to yield intermediate compound 10 as a white solid (9.20 g, 91 percent).

Reference： [1]Patent: WO2007/104783,2007,A2 .Location in patent: Page/Page column 43

6
[ 50824-05-0 ]
[ 4315-07-5 ]

Reference： [1]Journal of general chemistry of the USSR,1965,vol. 35,p. 1631 - 1637
Zhurnal Obshchei Khimii,1965,vol. 35,p. 1628 - 1636

7
[ 50824-05-0 ]
[ 112741-50-1 ]
C₂₉H₂₈F₃NO₅ [ No CAS ]

Reference： [1]Patent: US6350760,2002,B1 .Location in patent: Page column 38-39

8
[ 50824-05-0 ]
[ 49561-96-8 ]

Yield	Reaction Conditions	Operation in experiment
76.3%	In ethanol; water	3 (4-Trifluoromethoxyphenyl)acetonitrile Example 3 (4-Trifluoromethoxyphenyl)acetonitrile 150 g of ethanol, 28 ml of water, and 31.5 g of sodium cyanide were initially charged, and 127.5 g of 4-bromomethyl-1-trifluoromethoxybenzene were added. The reaction mixture was stirred at 90° C. for 3.5 hours and then poured into 250 ml of water and extracted twice with 50 ml portions of dichloromethane. The combined organic phases were concentrated and the residue was distilled at 18 hPa. This gave 81.5 g of (4-trifluoromethoxyphenyl)acetonitrile as a colorless liquid (76.3% of theory) of b.p. 110-112° C.
	In N,N-dimethyl-formamide	30 4-Trifluoromethoxybenzylcyanide 4-Trifluoromethoxybenzylcyanide To a solution containing 2.085 g (8.18 mmol) of 4-trifluoromethoxybenzyl bromide in 10 mL dry DMF was added 441 mg (8.99 mmol) of sodium cyanide. The reaction was stirred for 1 h at room temperature, poured into water and extracted with of ethyl acetate (2*40 mL). The combined organic extracts were dried (MgSO4) and evaporated. The crude product was used in the next reaction without further purification.

Reference： [1]Current Patent Assignee: LANXESS AG - US2002/82454, 2002, A1
[2]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - US6087358, 2000, A

9
[ 456-55-3 ]
[ 50824-05-0 ]

Yield	Reaction Conditions	Operation in experiment
60%	With sodium bromide; sulfuric acid; paraformaldehyde; In tert-butyl methyl ether; water; acetic acid;	Example 1 4-Bromomethyl-<strong>[456-55-3]1-trifluoromethoxybenzene</strong> 300 g of trifluoromethoxybenzene, 111 g of paraformaldehyde, 456 g of sodium bromide, and 900 ml of glacial acetic acid were initially charged and heated at 90 C. To release hydrogen bromide, a mixture of 450 ml of glacial acetic acid and 678 g of concentrated sulfuric acid was then added dropwise. After the addition had ended, the reaction mixture was stirred at 90 C. for 20 hours. The reaction mixture was then poured onto 1,000 g of ice and extracted twice with in each case 300 ml of methyl tert-butyl ether. The combined organic extracts were washed with 100 ml of water and concentrated. The residue was distilled at 20 hPa in a spinning band column. This gave 324.3 g of 4-bromomethyl-<strong>[456-55-3]1-trifluoromethoxybenzene</strong> as a colorless liquid (60% of theory) of b.p. 82-83 C.

Reference： [1]Patent: US2002/82454,2002,A1

10
[ 53937-02-3 ]
[ 50824-05-0 ]
[ 586372-98-7 ]

Yield	Reaction Conditions	Operation in experiment
96%	With potassium carbonate; In acetonitrile; for 24h;Heating / reflux;	l-Bromomethyl-4-trifluoromethoxybenzene (3.32 g, 13.04 mmol) and potassium carbonate (3.51 g, 25.46 mmol) were added to a mixture of 4-benzyloxy-i//-pyridin-2- one (2.5 g, 12.42 mmol) in acetonitrile (10 ml). The reaction mixture was heated at reflux temperature for 24 hours. After cooling to room temperature, it was filtered through diatomaceous earth, the solid residues were washed with methanol and the combined organic extracts were evaporated in vacuo. The crude residue thus obtained was precipitated with DIPE to yield intermediate D14 (4.5 g, 96%) as a white solid.

Reference： [1]Patent: WO2009/33704,2009,A1 .Location in patent: Page/Page column 30

11
[ 7745-92-8 ]
[ 50824-05-0 ]
[ 1100054-20-3 ]

Reference： [1]Journal of Organic Chemistry,2009,vol. 74,p. 1388 - 1390

12
[ 6279-86-3 ]
[ 50824-05-0 ]
[ 1094200-80-2 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;potassium iodide; In N,N-dimethyl-formamide; at 20℃; for 3h;	To a solution of triethyl methanetricarboxylate (4.55 g) in DMF (40 mL) were added 4-(trifluoromethoxy)benzyl bromide (5.00 g), potassium iodide in catalytic amount and potassium carbonate (4.07 g), and the mixture was stirred at room temperature for 3 hr. Ethyl acetate (200 mL) and water (100 mL) were added to extract the reaction mixture. The extract was washed sequentially with water and brine, and concentrated under reduced pressure to give the title compound (7.97 g) as an oil. 1H-NMR(300Mz, CDCl3)delta1.20(9H, t, J = 7.3Hz), 3.51(2H, s), 4.20(6H, q, J = 7.5Hz), 7.09(2H, d, J = 8.7Hz), 7.33(2H, d, J = 8.8H).

Reference： [1]Patent: EP2172450,2010,A1 .Location in patent: Page/Page column 53

13
[ 58481-11-1 ]
[ 50824-05-0 ]
[ 1251844-88-8 ]

Yield	Reaction Conditions	Operation in experiment
		In a dried flask was zinc powder (0.769 g, 11.76 mmol) suspended in anhydrous tetrahydrofuran (20 mL) under nitrogen. The resulting suspension was warmed to 60° C., then 1,2-dibromoethane (0.042 mL, 0.49 mmol) was added and stirred at that temperature for 15 min. It was cooled to room temperature, then chlorotrimethylsilane (0.050 mL, 0.39 mmol) was added and stirred at room temperature for 1 h. Then, 1-(bromomethyl)-4-(trifluoromethoxy)benzene (2.5 g, 9.80 mmol) in tetrahydrofuran (5 mL) was added over 2 min, then stirring continued at room temperature for 22 h. The stirring was switched off to let the solids settle. The supernatant was used in next transformation. To a solution of <strong>[58481-11-1]methyl 2-chloroisonicotinate</strong> (4.80 g, 28 mmol) and Pd(PPh3)4 (0.647 g, 0.56 mmol) in tetrahydrofuran (50 mL) under nitrogen in a dried flask was added a freshly prepared solution of (4-(trifluoromethoxy)benzyl)zinc(II) bromide (12.56 g, 39.20 mmol) in tetrahydrofuran (90 mL). The resulting bright yellow mixture was heated to 60° C. for 2 h 30 min, then cooled to room temperature. The reaction was quenched by the addition of 10percent aqueous NH4Cl. It was diluted with ethyl acetate. After phase separation, the organic layer was washed with brine, dried over MgSO4 and evaporated. The residue was suspended in 50 mL MTBE and sonicated, then the yellow insolubles were filtered off and washed with MTBE. The volume of the filtrate was increased to ca. 150 mL, then 5 mL MeOH was added, followed by hydrogen chloride (4 M in dioxane) (7.00 mL, 28.00 mmol). A colorless precipitate formed, which then dissolved again. The solvents were evaporated. The residue was dissolved in ca. 15 mL DCM and then MTBE and heptanes were added. An oil had formed that was triturated and after a few minutes a solid started to form. It was sonicated and then stirred at room temperature for 20 min. The formed solid was collected and washed with MTBE and dried. The solid was dissolved in DCM and washed with 10percent K2CO3. After phase separation, the aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO4 and evaporated. Methyl 2-(4-(trifluoromethoxy)benzyl)isonicotinate (8.04 g, 92percent) was isolated as a pale yellow oil. 1H NMR (400 MHz, cdcl3) delta 3.93 (s, 3H), 4.22 (s, 2H), 7.11-7.17 (m, 2H), 7.24-7.31 (m, 2H), 7.67-7.72 (m, 2H), 8.68-8.72 (m, 1H). MS m/z 312 (M+H)+

Reference： [1]Patent: US2010/261755,2010,A1 .Location in patent: Page/Page column 41-42

14
[ 773837-37-9 ]
[ 50824-05-0 ]
[ 49561-96-8 ]

Yield	Reaction Conditions	Operation in experiment
95%	In dimethyl sulfoxide at 90℃; for 1h;	51 Preparation of Intermediate 2-(4-(Trifluoromethoxy)phenyl)acetonitrile (I-51a) Preparation of Intermediate 2-(4-(Trifluoromethoxy)phenyl)acetonitrile (I-51a) Using analogous conditions and workup as described for the preparation of I-24a above, 1-(bromomethyl)-4-(trifluoromethoxy)benzene (5 g, 19.607 mmol) in DMSO (30 mL) was reacted with NaCN (1.44 g, 35.1864 mmol). The resulting mixture was stirred at 90° C. for 1 hour to afford 3.8 g of the product (95% yield). 1H NMR (300 MHz, CDCl3): 7.45-7.20 (m, 4H), 3.8 (s, 2H)
	In N,N-dimethyl-formamide at 20℃; for 1h;	To a solution of 4-trifluoromethoxybenzyl bromide (1.05 g, 4.09 mmol) in 5 mL dry DMF was added sodium cyanide (220 mg, 4.50 mmol). The reaction was stirred for 1 h at room temperature, poured into water and extracted with of ethyl acetate (2 x 20 mL). The combined layer was dried over anhydrous MgS04j filtered and concentrated in vacuo. The crude product HI was used in the next reaction without further purification.
	In N,N-dimethyl-formamide at 20℃; for 1h;	4 General Procedure for the Synthesis of H1 To a solution of 4-trifluoromethoxybenzyl bromide (1.05 g, 4.09 mmol) in 5 mL dry DMF was added sodium cyanide (220 mg, 4.50 mmol). The reaction was stirred for 1 h at room temperature, poured into water and extracted with ethyl acetate (2×20 mL). The combined layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product H1 was used in the next reaction without further purification.

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); DR REDDY'S LABORATORIES LIMITED; NOVARTIS AG - US2014/45872, 2014, A1 Location in patent: Paragraph 0847
[2]Current Patent Assignee: INSTITUT PASTEUR; NATIONAL INSTITUTE OF HEALTH AND MEDICAL RESEARCH - WO2011/113606, 2011, A1 Location in patent: Page/Page column 26
[3]Current Patent Assignee: INSTITUT PASTEUR; QURIENT CO LTD - US2014/155387, 2014, A1 Location in patent: Paragraph 0164; 0166

15
[ 53241-92-2 ]
[ 50824-05-0 ]
[ 1345869-51-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 6652 - 6656

16
[ 1004-40-6 ]
[ 50824-05-0 ]
[ 1039978-04-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In ethanol; water; at 20 - 50℃; for 17h;	General procedure: In 2-dram vials (round bottom, 15x75 mm) containing substituted alkyl or benzyl bromides (0.800 mmol) was added 0.5 mL of EtOH via a syringe. The stock solution containing 6-amino-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (0.500 mmol) and 3.45 M aqueous solution of NaOH (0.800 mmol) in EtOH was prepared as followed. In a 250 mL round-bottom flask was added 4.82 g of 6-amino-2-thioxo-2,3-dihydropyrimidin-4(1H)-one, 69.6 mL of EtOH, 20 mL of water, and 10.4 mL of 3.25 M aqueous solution of NaOH. This mixture was stirred at rt until a homogenous solution was formed. 2.50 mL of this stock solution was dispensed into each 2-dram vial.The vials were capped and heated to 50 C in a shaker. After 17 h, LCMSs were randomly taken from different reactions and all showed product formation cleanly. All vials were placed in a Genevac to remove the solvents and the product was purified by mass-directed high throughput purification.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 1055 - 1060

17
[ 50824-05-0 ]
[ 86542-94-1 ]
[ 1379615-52-7 ]

Yield	Reaction Conditions	Operation in experiment
50%	With potassium carbonate; In N,N-dimethyl-formamide; at 120℃;	Preparation ofl-(l-(4-( trifluoromethoxy )benzyl )piperidin-4-yl)propan-l -one 4v[00227] 4-Trifluoromethoxy benzyl bromide (1.52g, 5.94 mmol) was first added to a solution of l-(piperidin-4-yl)propan-l-one (0.7g, 4.95 mmol) in DMF (20mL) followed by K2C03 (1.4g, 9.9 mmol) and heated overnight at 120C. The DMF was removed under vacuum and the crude mixture was partitioned between water (10 mL) in EtOAc (30 mL). The organic layer was washed with brine and concentrated. Purification by flash column chromatography afforded the desired product. (Colorless oil, 50%); 1H NMR (400MHz, CDC13), deltaEta 7.33 (d, 2H, J = 8.3 Hz, Ar), 7.15 (d, 2H, J = 8.3 Hz, Ar), 3.48 (s, 2H, NCH2Ar), 2.88 (dd, 2H, J = 8.6 Hz, 3.1 Hz, CH2), 2.47 (q, 2H, J = 7.3 Hz, CH2CO), 2.32 (tt, 1H, J = 11.4 Hz, 3.9 Hz, CH), 2.09-1.96 (m, 2H, CH2), 1.80 (d, 2H, J = 11.3 Hz, CH2), 1.74-1.62 (m, 2H, CH2), 1.04 (t, 3H, J = 7.3 Hz, CH3); MS (ES+), [M + H] + (100), 316.2, HRMS calculated for 316.1524 Ci6H2iN02F3, found 316.1525.

Reference： [1]Patent: WO2012/69856,2012,A1 .Location in patent: Page/Page column 69

18
[ 830-93-3 ]
[ 50824-05-0 ]
C₁₉H₁₉BrF₃N₂O⁽¹⁺⁾*Br^(1-) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane at 25℃;

Reference： [1]Todd, Robert; Huisman, Matthew; Uddin, Nazim; Oehm, Sarah; Hossain, M. Mahmun [Synlett, 2012, vol. 23, # 18, p. 2687 - 2691]

19
[ 78-40-0 ]
[ 50824-05-0 ]
(4-(trifluoromethoxy)phenyl)methyl diethylphosphate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	In tetrahydrofuran at 120℃; for 3h;	20.1 (1) (4-(trifluoromethoxy)phenyl)methyl diethylphosphate (1) (4-(trifluoromethoxy)phenyl)methyl diethylphosphate[0077] Triethyl phosphate (2.7 g, 15 mmol) was added to p-trifluoromethoxy benzyl bromide (2.56 g, 10 mmol), raised the temperature to 120 °C and stirred the reaction for 3 h. After the reaction was finished, column chromatography generated 2.2 g light yellow oily matter, yield: 72 %.MS (ESI/LR) : 313.1 [M+1]+
72%	at 120℃; for 3h;	20.1 (1) (4-(trifluoromethoxy)phenyl)methyl diethylphosphate (1) (4-(trifluoromethoxy)phenyl)methyl diethylphosphate Triethyl phosphate (2.7 g, 15 mmol) was added to p-trifluoromethoxy benzyl bromide (2.56 g, 10 mmol), raised the temperature to 120° C. and stirred the reaction for 3 h. After the reaction was finished, column chromatography generated 2.2 g light yellow oily matter, yield: 72%. MS (ESI/LR): 313.1 [M+1]+.

Reference： [1]Current Patent Assignee: NANJING CHANGAO PHARMACEUTICAL SCIENCE AND TEC - EP2573090, 2013, A1 Location in patent: Paragraph 0076-0077
[2]Current Patent Assignee: NANJING CHANGAO PHARMACEUTICAL SCIENCE AND TEC - US2013/143864, 2013, A1 Location in patent: Paragraph 0139; 0140

20
[ 50824-05-0 ]
[ 287952-67-4 ]

Reference： [1]Patent: US2013/143864,2013,A1

21
[ 6086-21-1 ]
[ 50824-05-0 ]
C₁₁H₁₁F₃N₃O⁽¹⁺⁾*Br^(1-) [ No CAS ]

Reference： [1]RSC Advances,2013,vol. 3,p. 3981 - 3989

22
[ 15297-33-3 ]
[ 50824-05-0 ]
(R)-N-methyl-1-(naphthalen-1-yl)-N-(4-(trifluoromethoxy)benzyl)ethanamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In acetonitrile; for 2h;Reflux; Inert atmosphere;	General procedure: N-Methyl-1-(naphthalen-1-yl)ethanamine (8) (0.37g, 2.00mmol), N,N-diisopropylethylamine (0.39g, 3.02mmol), 1-(bromomethyl)-4-tert-butylbenzene (0.50g, 2.20mmol) and acetonitrile (5mL) were mixed and stirred at reflux under an N2-atmosphere for 2h. The solvent was then removed at reduced pressure and CH2Cl2 (5mL) was added. The dichloromethane phase was washed with water (5mL) and the water phase was back extracted with CH2Cl2 (3×5mL). The combined organic fractions were dried over Na2SO4, and concentrated in vacuum. The crude product was purified by silica-gel column chromatography. Alternatively, the purification was done by filtration through a short silica-gel column (pentane:EtOAc, 9:1), followed by precipitation as it hydrochloride salt by addition of HCl saturated ether. The solid material was washed with cold pentane. Alternatively, using 8·HCl the reaction was run similarly, but employing a 3-fold excess of N,N-diisopropylethylamine.

Reference： [1]European Journal of Medicinal Chemistry,2013,vol. 68,p. 482 - 496

23
[ 1303587-99-6 ]
[ 50824-05-0 ]
2-chloro-8-(4-(trifluoromethoxy)benzyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃; for 1h;Inert atmosphere;	Synthesis of2-chloro-8-(4-(trifluoromethoxy) benzyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazine [0456] To a stirred solution of 2-chloro-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (150 mg, 0.87 mmol) in DMF (5 mL) under argon atmosphere were added sodium hydride (42 mg, 1.75 mmol) and l-(bromomethyl)-4-(trifluoromethoxy) benzene (268 mg, 1.05 mmol) at 0C. The reaction mixture was warmed to RT and stirred for 1 h. After consumption of the starting materials (monitored by TLC), the reaction was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography using 40% EtOAc:hexane to afford 2-chloro-8-(4- (trifluoromethoxy) benzyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (160 mg, 53%>) as an off-white solid. 1H-NMR (DMSO-<, 400 MHz): delta 7.71 (s, 1H), 7.42 (d, 2H), 7.34 (d, 2H), 4.80 (s, 2H), 4.21-4.19 (m, 2H), 3.52-3.50 (m, 2H); LCMS: 345.8 (M+); (column; X- Select CSH C-18 (50 3.0 mm, 3.5 mupiiota); RT 3.94 min 0.05% Aq TFA: ACN; 0.80 mL/min); TLC: 60% EtOAc/hexane (R 0.6).

Reference： [1]Patent: WO2015/66697,2015,A1 .Location in patent: Paragraph 0456

24
[ 22818-40-2 ]
[ 50824-05-0 ]
[4-(4-trifluoromethoxy)benzyloxy]-D-phenylglycine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 9354 - 9370

25
[ 50824-05-0 ]
[ 52980-28-6 ]
[ 1207748-62-6 ]

Yield	Reaction Conditions	Operation in experiment
87%	With potassium carbonate In N,N-dimethyl-formamide at 40 - 80℃; for 18h;	36 Compound 148Ethyl 4-oxo- 1 -(4-(trifluoromethoxy)benzyl)- 1 ,4-dihydroquinoline-3 -carboxylate To a suspension of ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (lg, 4.60 mmol)and K2C03 (1.20 g, 8.60 mmol) in DMF (7 mL) at 40 °C was added 4-trifluoromethoxybenzyl bromide (2.68 mL, 16.75 mmol) dropwise. The reactionmixture was stirred at 80 °C for 18 h. Solvent was removed under reduced pressureand the product purified by flash chromatography using a gradient of 0-20% MeOH in EtOAc to give the title product (1.56 g, 87%) as a white powder.HRIVIS m/z (El) 391.10268, calculated for C2oH,6NO4F3 391.10259.

Reference： [1]Current Patent Assignee: UNIVERSITY OF LONDON - WO2015/189560, 2015, A1 Location in patent: Page/Page column 106; 107

26
[ 50824-05-0 ]
[ 16093-82-6 ]
1-(4-(trifluoromethoxy)benzyl)-1H-imidazole-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;	General procedure: To a stirred solution of imidazole (1 eq) in anh. DMF (15 vol) was added K2CO3 (3 eq) followed by alkyl or benzyl halide (1.2 - 1.5 eq). Reactions were either stirred at rt, heated conventionally or heated in the microwave (80 - 120 C) until LCMS revealed consumption of the imidazole stating material. Additional portions of alkylating agent were added as necessary to drive the reaction to completion. Isolation by precipitation: the reaction was poured into water (200 vol) and the precipitate was filtered. The solid was washed with water and pet. spirits and dried under vacuum to obtain the crude product. Aqueous work up: the reaction was poured into water (200 vol) and isolated by extraction with EtOAc (3 x 100 vol). The combined organic layers were washed with brine, dried with anh. MgSO4 and filtered. Volatiles were removed in vacuo to obtain the crude product.

Reference： [1]European Journal of Medicinal Chemistry,2016,vol. 120,p. 353 - 362

27
[ 4518-10-9 ]
[ 50824-05-0 ]
methyl 3-(4-(trifluoromethoxy) benzylamino) benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With triethylamine In dichloromethane at 20℃; for 168h;	2.1.1.1. Methyl 3-(4-(trifluoromethoxy) benzylamino) Benzoate(5) Next, 3-aminobenzoic acid methyl ester 3 (2.0 g, 13.2mmol) was dissolved in (20 mL) dichloromethane (DCM),followed by the addition of 4-(trifluoromethoxy) benzylbromide4 (4.2 mL, 26.4 mmol), and triethylamine (9.2 mL, 66mmol). The mixture was stirred at room temperature for 7days. Evaporation of the mixture was done, and the intermediatemethyl 3-(4-(trifluoromethoxy) benzylamino) benzoate5 was purified by column chromatography using cyclohexane:ethyl acetate (8.5:1.5) as eluent. Off white powder was obtained (3.12 g). Yield. 63%,m.p. 85-86 °C, Rf= 0.46 (cyclohexane: ethyl acetate, 9:1), IRmax (KBr) cm-1: 3480, 3225, 2986, 1713, 1620, 1458, 1404,1303, 1250. 1HNMR (300MHZ, CDCl3): 3.84 (s, 2H, CH2);4.63 (s, 3H, OCH3); 6.83 (dd, J=6.0, 9.0HZ, 1H, ArH); 7.16(d, J=9.0HZ, 2H, ArH); 7.20-7.25 (m, 4H, ArH); 7.38 (d,J=9.0HZ, 1H, ArH); 7.44 ppm (s, 1H, NH). 13CNMR(300MHZ, CDCl3): 53.6, 59.6, 113.4, 117.1, 118.7, 121.4,128.1, 129.5, 130.5, 136.5, 150.0, 168.0 ppm.
44%	With triethylamine In dichloromethane at 20℃; for 120h;
44%	With triethylamine In dichloromethane at 20℃; for 120h;	2.2.1.1. Methyl 3-(4-(trifluoromethoxy) benzylamino) benzoate (5a) 1-(bromomethyl)-4-(trifluoromethoxy) benzene (4a, 4.2mL, 26.4 mmol), and triethylamine (9.2 mL, 66 mmol) were added to the solution of 3. The mixture was left under stirring at room temperature for 5 days then the mixture was evaporated. Column chromatography was carried out using cyclohexane: ethyl acetate (9:1) as eluent to afford 5a as off white powder (2.18 g, 44%); m.p. 85-86°C; R = 0.46 (cyclohexane:ethyl acetate, 9:1); 1H-NMR (300MHZ, CDCl3): δ3.84 (s, 2H, NHCH2), 4.63 (s, 3H, OCH3), 6.83 (dd, J=4, 15HZ, 1H, Ar-H), 7.20 (d, J=12 HZ, 2H, Ar-H), 7.22-7.25 (m,4H, Ar-H), 7.40 (d, J=12 HZ, 1H, Ar-H), 7.44 ppm (s, 1H,NHCH2); 13C-NMR (75MHZ, CDCl3): δ 53.6, 59.6, 113.4,117.1, 118.7, 121.4, 128.1, 129.5, 136.5, 150.0, 168.0 ppm; IR (KBr): 3480, 3225, 2986, 1713, 1620, 1458, 1404, 1303,1250 cm-1.

Reference： [1]Khalaf, Reema Abu; Al-Rawashdeh, Sarah; Sabbah, Dima; Sheikha, Ghassan Abu [Medicinal Chemistry, 2017, vol. 13, # 3, p. 239 - 253]
[2]Abu Khalaf, Reema; Sabbah, Dima; Al-Shalabi, Eveen; Bishtawi, Samar; Albadawi, Ghadeer; Abu Sheikha, Ghassan [Archiv der Pharmazie, 2017, vol. 350, # 12]
[3]Abu Khalaf, Reema; Abd El-Aziz, Hamada; Sabbah, Dima; Albadawi, Ghadeer; Abu Sheikha, Ghassan [Letters in drug design and discovery, 2017, vol. 14, # 12, p. 1391 - 1400]

28
[ 50824-05-0 ]
[ 460081-20-3 ]
ethyl 2-(4-(trifluoromethoxy)benzyl)oxazole-4-carboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 9769 - 9789

29
[ 617-05-0 ]
[ 50824-05-0 ]
ethyl 3-methoxy-4-((4-(trifluoromethoxy)benzyl)oxy)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2.26 g		In a round bottomed flask with nitrogen inlet and magnetic stir bar, potassium carbonate (1.86 g, 13.46 mmol), <strong>[617-05-0]ethyl 4-hydroxy-3-methoxybenzoate</strong> (1.2 g, 6.12 mmol) and acetonitrile (26 mL) were added. Mixture was stirred for 30 minutes before l-(bromomethyl)-4- (trifluoromethoxy)benzene (1.72 g, 6.74 mmol) was added. Reaction was heated to reflux overnight and then, cooled to room temperature. Water 100 mL was added and the aqueous mixture was extracted with ethyl acetate (3 chi 50 mL). The combined organic layers were evaporated and then dried to get 2.26 g of ethyl 3-methoxy-4-((4- (trifluoromethoxy)benzyl)oxy)benzoate. (0294) 1H NMR (400 MHz, Chloroform-d) delta 7.61 (ddd, J = 8.4, 2.0, 0.8 Hz, 1H), 7.56 (s, 1H), 7.45 (d, J = 8.9 Hz, 2H), 7.21 (d, J = 8.1 Hz, 2H), 6.86 (d, J = 8.4 Hz, 1H), 4.33 (q, J = 7.4 Hz, 1H), 3.92 (s, 7H), 1.36 (t, J = 7.1 Hz, 2H).

Reference： [1]Patent: WO2018/144900,2018,A1 .Location in patent: Page/Page column 48

30
[ 50824-05-0 ]
[ 4522-35-4 ]
[ 1379615-65-2 ]

Reference： [1]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 1205 - 1210

31
[ 2403-88-5 ]
[ 50824-05-0 ]
N-p-trifluoromethoxybenzyl-2,2,6,6-tetramethylpiperidin-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	In toluene; at 130℃; for 40h;Autoclave;	General procedure: In a 30 mL PARR autoclave were introduced 2,2,6,6-tetramethylpiperidin-4-ol 1 ( 2.0 g, 1 equiv.) and the allyl or benzyl bromide 2 (0.5 equiv.) dissolved in dry toluene (13 mL). The autoclave was sealed and the mixture was heated to 130 C. After 40 hours stirring, the mixture was cooled down to room temperature then diluted in AcOEt and water. The aqueous layer was extracted 3 times with AcOEt (3x25 mL) and the combined organic phases were washed with water (20 mL), brine (20 mL) and dryed over Na2SO4. After filtration and concentration under vacuum, the residue was purified by flash chromatography on silicagel using a combination of petroleum ether and ethyl acetate for benzylic products and dichloromethane and methanol for allylic products to yield the pure desired products 3.

Reference： [1]Tetrahedron Letters,2019,vol. 60,p. 240 - 243

32
[ 868-77-9 ]
[ 50824-05-0 ]
C₁₅H₁₅F₃O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	Stage #1: 2-methyl-2-propenoic acid 2-hydroxyethyl ester With carbon dioxide; 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine In N,N-dimethyl-formamide at 40℃; for 3h; Autoclave; Stage #2: 4-trifluoromethoxybenzyl bromide With carbon dioxide In N,N-dimethyl-formamide at 40℃; for 72h; Autoclave;	3 Embodiment 3 To 50 ml high pressure reaction kettle adding N, N - dimethyl formamide (DMF, 20 ml), methyl methacrylate (50 mmol), 157 - three-folding nitrogen bicyclo (4.4.0) decyl -5 - ene (TBD, 50 mmol), carbon dioxide stability to 2 mpa, is 40 °C oil bath pot reaction 3 hours; from in-situ feeding tube by adding 4 - trifluro oxygen radical animal pen bromine (70 mmol), carbon dioxide stability to 4 mpa, is 40 °C oil bath pot reaction 72 hours, after the reaction remove salt by filtration, then dissolved by adding in water ethyl acetate extraction three times, combined organic phase dried with anhydrous sodium sulfate, after the petroleum ether/ethyl acetate=6 for: 1 as elution agent through the silica gel column chromatography to obtain the target product separation and purification, and the yield is 53%

Reference： [1]Current Patent Assignee: GUIZHOU UNIVERSITY - CN109928879, 2019, A Location in patent: Paragraph 0061-0063

33
[ 758684-29-6 ]
[ 50824-05-0 ]
N-hydroxy-4-(4-(trifluoromethoxy)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide [ No CAS ]

Reference： [1]Patent: WO2017/40963,2017,A1

34
[ 758684-29-6 ]
[ 50824-05-0 ]
C₁₈H₁₆F₃NO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl acetamide; at 50℃; for 16h;Sealed tube;	A half-dram vial was charged with methyl 3,4-dihydro-2H-benzo[b][l,4]oxazine-6- carboxylate (0.2 M in N,N-dimethylacetamide, 150 mu., 30 muiotaetaomicron) and potassium carbonate (20.7 mg, 150 muiotaetaomicron). Then a solution of l-(bromomethyl)-4-(trifluoromethoxy)benzene (0.2 M in N,N-di methyl acetamide, 400 mu., 80 muiotaetaomicron) was added. The system was sealed and shaken at 50 C for 16 h, and then the solvent was removed under a stream of nitrogen. The residue was diluted with ethyl acetate (0.6 mL) and brine (0.5 mL), and the mixture was shaken. The organic layer was separated, and the aqueous phase was extracted with ethyl acetate (0.6 mL). The combined organic layers were dried under a stream of nitrogen. THF/methanol (3 : 1, 200 mu.) was added to the residue. The vial was sealed and shaken at 50 C for 15 min to dissolve the residue, then cooled to room temperature. Hydroxylamine (150 mu., 50% v/v solution in water) was added, followed by 1 N aqueous sodium hydroxide solution (100 mu.). The mixture was sealed and then shaken at room temperature for 16 h. The reaction mixture was concentrated under a stream of nitrogen at room temperature, then dissolved in 500 mu^ of DMSO, and purified by mass triggered preparative HPLC (Column: Waters Sunfire CI 8, 5 mupiiota, 19x50 mm; Mobile Phase: water (0.1% formic acid) and acetonitrile (0.1% formic acid) (15% to 100% acetonitrile in 6 min; flow rate: 23 mL/min); Detector: UV 254/220 nm). The product-containing fractions were combined and concentrated in a Genevac to afford N-hydroxy-4-(4- (trifluoromethoxy)benzyl)-3,4-dihydro-2H-benzo[b][l,4]oxazine-6-carboxamide (6.7 mg, 60.6%). (ES, m/z) 369 [M+H]+, LC-MS Rt 1.35 min.

Reference： [1]Patent: WO2017/40963,2017,A1 .Location in patent: Paragraph 00266

35
[ 1076-22-8 ]
[ 50824-05-0 ]
C₁₄H₁₁F₃N₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;Sealed tube;	General procedure: Synthesis of VU0071063 analogs was carriedabout by alkylation of commercially available theophylline (1)with various benzyl bromides (2)(see Supplemental Table S1). Benzylbromides not commercially available were synthesized by reduction ofthe benzaldehyde to the alcohol then conversion to the bromide viaAppel reaction or by radical bromination of the methylbenzene.Generally, one equivalent of theophylline and benzyl bromide weredissolved in 1 ml of dimethylformamide (DMF) in a 2-dram screw capvial at room temperature. Two equivalents of potassium carbonatewere then added and the reactions were stirred overnight. The productwas precipitated by addition of 2 ml of water and an additional hour ofstirring, then isolated via vacuum filtration. Impure products werepurified by normal-phase column chromatography. Products wereisolated in 5%-85% yield. Guanine-based compounds were synthesizedfrom guanosine using the method above, except dimethylsulfoxide (DMSO) was used in place of DMF. After overnight stirring,the sugar was cleaved by addition of concentrated HCl and an hour ofstirring, then isolated via vacuum filtration. For VU0071063, theophylline(50 mg, 0.278 mmol) and 4-tert-butylbenzyl bromide (63.038 mg,0.278 mmol) were mixed in a 2-g vial. To this mixture was added DMF(1 ml, 0.278 M) and then potassium carbonate (77.831 mg, 0.555mmol). The reaction was stirred overnight, forming a white precipitate,to which 1 ml water was added to induce further precipitation.The white solid was collected via vacuum filtration, washed withwater, and dried under vacuum to yield VU0071063 (60 mg, 66%) asa white solid. Heteronuclear multiple bond coherence analysisconfirmed N7 alkylation. 1H NMR (400 MHz, CDCl3) d (ppm): 7.55(s, 1H), 7.38 (d, J 5 8.4 Hz, 2H), 7.26 (d, J 5 8.4 Hz, 2H), 5.47 (s, 2H),3.58 (s, 3H), 3.41 (s, 3H), 1.29 (s, 9H); 13C NMR (100.6 MHz, CDCl3)d (ppm): 155.4, 151.8, 151.7, 148.9, 140.9, 132.5, 127.9, 126.1, 107.1, 50.1,34.7, 31.3, 29.8, 28.1; high-resolution mass spectrometry (TOF, ES1):calculated for C18H22N4O2, 326.1743; found, 326.1746.

Reference： [1]Journal of Pharmacology and Experimental Therapeutics,2019,vol. 370,p. 350 - 359

36
[ 50824-05-0 ]
[ 374538-01-9 ]
(E)-3-(2-fluoro-5-(4-(trifluoromethoxy)benzyl)phenyl)-2-(methylsulfonyl)acrylonitrile [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 1148 - 1153

37
[ 50824-05-0 ]
[ 374538-01-9 ]
C₁₅H₁₀F₄O₂ [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 1148 - 1153

38
[ 755752-82-0 ]
[ 50824-05-0 ]
methyl 1-(4-(trifluoromethoxy)benzyl)-1H-indazole-7-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl-formamide; at 0 - 22℃; for 16h;	In a round-bottom flask equipped with a magnetic stir bar was suspended <strong>[755752-82-0]methyl 1H-indazole-7-carboxylate</strong> (1.0 equiv, Combi-Blocks, CAS 755752-82-0) and cesium carbonate (3 equiv) in DMF (0.71 M). This suspension was cooled to 0 C. and treated with neat 4-(trifluoromethoxy)benzyl bromide (1.2 equiv, Aldrich, CAS 50824-05-0) drop-wise over a period of 5 minutes. The resulting reaction mixture was allowed to 22 C. over 16 hours. The reaction was then carefully quenched with the addition of ice-water and extracted with tert-butyl methyl ether. The combined organic extracts were washed further with water and brine, dried over MgSO4, and filtered. Concentration of the filtrate thus obtained under vacuum furnished the crude reaction product as a golden yellow oil. Purification by column chromatography through silica gel on the Teledyne ISCO Rf eluting with 10% to 100% EtOAc in hexanes as a gradient afforded the title compound.

Reference： [1]Patent: US2019/315712,2019,A1 .Location in patent: Paragraph 1210; 1211

39
[ 313337-35-8 ]
[ 50824-05-0 ]
methyl 4-fluoro-1-(4-(trifluoromethoxy)benzyl)-1H-indole-7-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	Stage #1: methyl 4-fluoro-1H-indole-7-carboxylate With sodium tert-pentoxide In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: 4-trifluoromethoxybenzyl bromide In N,N-dimethyl-formamide at 0 - 22℃; for 1.25h;	H.1 Step 1: Preparation of methyl 4-fluoro-1-(4-(trifluoromethoxy)benzyl)-1H-indole-7-carboxylate To a solution of methyl 4-fluoro-1H-indole-7-carboxylate (1 equiv, PharmaBlock, CAS 313337-35-8) in DMF (0.1 M) cooled over an ice bath was added sodium tert-pentoxide (1.5 equiv) and the mixture was stirred at 0° C. for 30 minutes. After this time, 1-(bromomethyl)-4-(trifluoromethoxy)benzene (1.2 equiv, Aldrich, CAS 50824-05-0) was added drop-wise via syringe over 5 minutes, the ice bath was removed and the mixture was allowed to stir at 22° C. for 1.25 hours. LCMS analysis at this time revealed complete conversion to product. The mixture was quenched with sat. aqueous NH4Cl solution and extracted with Et2O (3×). The combined organic extracts were washed with brine (1×) and concentrated under reduced pressure. The resulting residue was loaded onto a silica gel pre-cartridge and then dried under vacuum. This pre-absorbed material was purified by column chromatography using a Teledyne ISCO silica cartridge eluting with 0% to 40% EtOAc in hexanes as a gradient. The fractions from the major peak which elutes at 15% EtOAc were combined and concentrated under vacuum to provide the title compound as a solid (75% yield).

Reference： [1]Current Patent Assignee: TEMPEST THERAPEUTICS INC - US2019/315712, 2019, A1 Location in patent: Paragraph 1008; 1009

40
[ 18718-79-1 ]
[ 50824-05-0 ]
5-methyl-3-phenyl-4-[[[4-(trifluoromethoxy)benzyl]oxy]methyl]isoxazole [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 8284 - 8310

41
[ 1416819-91-4 ]
[ 50824-05-0 ]
cobalt(II) bromide [ No CAS ]
C₂₁H₂₁Br₂CoF₆N₂O₂ [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2019,vol. 141,p. 18877 - 18889

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3-Methyl-5-(trifluoromethoxy)benzyl bromide

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1-(Bromomethyl)-3-(trifluoromethoxy)benzene

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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.
P283	Wear fire/flame resistant/retardant clothing.
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

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

[ CAS No. 50824-05-0 ] {[proInfo.proName]}

Quality Control of [ 50824-05-0 ]

Related Doc. of [ 50824-05-0 ]

Product Details of [ 50824-05-0 ]

Calculated chemistry of [ 50824-05-0 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 50824-05-0 ]

Application In Synthesis of [ 50824-05-0 ]

[ 50824-05-0 ] Synthesis Path-Upstream 1~8

[ 50824-05-0 ] Synthesis Path-Downstream 1~41

Related Functional Groups of [ 50824-05-0 ]

Fluorinated Building Blocks

Aryls

Bromides

Ethers

Benzyl Bromides

Trifluoromethyls

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 50824-05-0 ]