[ CAS No. 31181-84-7 ] {[proInfo.proName]}

Name: 31181-84-7|(5-(Trifluoromethyl)pyridin-2-yl)methanol|96%
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Quality Control of [ 31181-84-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 31181-84-7 ]

Product Details of [ 31181-84-7 ]

CAS No. :	31181-84-7	MDL No. :	MFCD04117762
Formula :	C₇H₆F₃NO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	GVAFEGOUIQFLQH-UHFFFAOYSA-N
M.W :	177.12	Pubchem ID :	3820787
Synonyms :

Calculated chemistry of [ 31181-84-7 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.29
Num. rotatable bonds :	2
Num. H-bond acceptors :	5.0
Num. H-bond donors :	1.0
Molar Refractivity :	35.37
TPSA :	33.12 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.75 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.5
Log Po/w (XLOGP3) :	0.89
Log Po/w (WLOGP) :	2.59
Log Po/w (MLOGP) :	0.98
Log Po/w (SILICOS-IT) :	2.19
Consensus Log Po/w :	1.63

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.74
Solubility :	3.25 mg/ml ; 0.0183 mol/l
Class :	Very soluble
Log S (Ali) :	-1.17
Solubility :	12.0 mg/ml ; 0.0676 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.74
Solubility :	0.324 mg/ml ; 0.00183 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.76

Safety of [ 31181-84-7 ]

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

Application In Synthesis of [ 31181-84-7 ]

* 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 [ 31181-84-7 ]
Downstream synthetic route of [ 31181-84-7 ]

[ 31181-84-7 ] Synthesis Path-Upstream 1~7

1
[ 31181-84-7 ]
[ 31224-82-5 ]

Yield	Reaction Conditions	Operation in experiment
74%	With Dess-Martin periodane In dichloromethane at 20℃; for 0.333333 h;	A solution of Example 34B (3.89 g, 22.0 mmol) in CH₂Cl₂ (10 mL) was added to a deoxygenated solution of Dess-Martin periodinane (1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one, 10.3 g, 24.2 mmol) in CH₂Cl₂ (73 mL) in one portion. The reaction was stirred under nitrogen at ambient temperature for about 20 minutes after which a solid formed. The reaction was diluted with 50 mL CH₂Cl₂ and carefully quenched with approximately 30 mL of saturated NaHCO₃ solution. The undissolved solid was filtered, and the filtrate was transferred to a separatory funnel. The aqueous phase was extracted with CH₂Cl₂, and the combined organic layer was washed with brine, dried over Na₂SO₄, filtered, and evaporated at reduced pressure to 50 mL. This solution was then loaded on silica gel (Analogix.(R). 40*150 column) and eluted with 25percent to 50percent EtOAc/hexanes. The result was 2.86 g (74percent) of the title compound as a clear oil, which solidified on standing. ¹H NMR (300 MHz, CDCl₃) δ 10.15 (s, 1H), 9.06 (m, 1H), 8.15 (m, 1H), 8.09 (d, J=8.1, 1H).

Reference： [1] Patent: US2009/124666, 2009, A1, . Location in patent: Page/Page column 26
[2] Patent: US2006/223837, 2006, A1, . Location in patent: Page/Page column 35
[3] Patent: US2015/232460, 2015, A1, . Location in patent: Paragraph 0478-0480

2
[ 124236-37-9 ]
[ 31181-84-7 ]

Yield	Reaction Conditions	Operation in experiment
93%	at 0 - 20℃;	IV. (5-trifluoromethyl-2-pyridinyl)methanol To a solution of methyl 5-trifluoromethyl-pyridine-2-carboxylate (2 g, 9.75 mmol) in MeOH (30 mL) at 0°C was added NaB (738 mg, 19.5 mmol) portionwise. The mixture was stirred at room temperature for 2 h and concentrated. The residue was diluted with water (30 mL), acidified to pH~5 (IN HC1), extracted with EA (3 X 50 mL), dried, concentrated and purified by column chromatography on silica gel to give the title compound as a colorless oil (1.6 g, 93percent yield): 1H NMR (400 MHz, CDC1₃) δ ppm 8.82 (s, 1H), 7.90-7.92 (m, 1H), 7.40-7.42 (m, 1H), 4.82-4.83 (m, 2H), 3.44-3.46 (m, 1H); ES-LCMS m/z 178 ( +H)⁺.
82.2%	at 0 - 20℃; for 1 h;	Compound SM (1.0 g, 4.87 mmol) was dissolved in MeOH (15 mL). At 0 ° C, NaBH4 (368.9 mg, 9.75 mmol) was added portionwise with stirring. Reaction at room temperature for 1 hour. TLC showed the reaction was completed. The pH was adjusted to 5-6 with 1 M HCl solution and the EA extracted (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (710.0 mg, 82.2percent).
72%	Stage #1: With sodium tetrahydroborate In ethanolHeating / reflux Stage #2: With water; ammonium chloride In ethanol at 20℃;	NaBH₄ (0.369 g, 9.75 mmol) was added to Example 34A (1 g, 5 mmol) in EtOH (40 mL). The suspension was heated at reflux overnight. The reaction was cooled to ambient temperature and quenched with saturated NH₄Cl solution. The mixture was diluted with water and extracted with EtOAc. The separated organic layer was washed with water and brine, dried (Na₂SO₄), filtered, and concentrated in vacuo. The crude product was chromatographed on silica gel (Analogix.(R). 25*40 column, 30percent-50percent EtOAc/hexanes eluant) to afford 0.62 g (72percent) of the title compound as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 8.84 (s, 1H), 7.94 (dd, J=8.3, 2.1 1H), 7.43 (dd, J=8.2, 0.6 1H), 4.85 (d, J=5.2, 2H), 3.46 (t, J=5.3, 1H).

Reference： [1] Patent: WO2013/166621, 2013, A1, . Location in patent: Page/Page column 48
[2] Patent: CN106831840, 2017, A, . Location in patent: Paragraph 0102; 0103; 0104
[3] Patent: US2009/124666, 2009, A1, . Location in patent: Page/Page column 25-26

3
[ 67-56-1 ]
[ 100366-75-4 ]
[ 31181-84-7 ]

Reference： [1] Patent: US2015/232460, 2015, A1, . Location in patent: Paragraph 0663-0666

4
[ 541-41-3 ]
[ 80194-69-0 ]
[ 31181-84-7 ]

Yield	Reaction Conditions	Operation in experiment
0.12 g	Stage #1: With triethylamine In tetrahydrofuran at 0℃; for 0.166667 h; Stage #2: With sodium tetrahydroborate In tetrahydrofuran at 0℃; for 1 h;	A solution of 728 5-(trifluoromethyl)pyridine-2-carboxylic acid (0.19 g, 1.0 mmol) in 20tetrahydrofuran (10 mL) was cooled to 0° C., 14 triethylamine (0.18 mL, 1.3 mmol) and 126 ethylchloroformate (0.11 mL, 1.1 mmol) were added and the mixture was stirred for 10 min. The reaction mixturewas filtered, to the filtrate were added 49 sodium tetrahydroborate (49 mg, 1.3 mmol) and one piece of ice,and the mixture was stirred at 0° C. for 1 hr. To the reaction mixture was added aqueous sodium hydroxidesolution and the mixture was stirred for 30 min, and extracted with dichloromethane. The organic layer waswashed with water, dried over sodium sulfate, and the desiccant was filtered off. The solvent was evaporatedto give the 729 title compound as a crudely purified product (0.12 g) MS (ESI) m/z 178 (M+H)+

Reference： [1] Patent: US2016/332999, 2016, A1, . Location in patent: Paragraph 0890; 0891

5
[ 31224-82-5 ]
[ 31181-84-7 ]

Reference： [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 19, p. 6563 - 6585

6
[ 100366-75-4 ]
[ 31181-84-7 ]

Reference： [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 19, p. 6563 - 6585

7
[ 50488-42-1 ]
[ 31181-84-7 ]

Reference： [1] Patent: WO2013/166621, 2013, A1,

[ 31181-84-7 ] Synthesis Path-Downstream 1~39

2
[ 856245-58-4 ]
[ 31181-84-7 ]
7,8-bis(4-chlorophenyl)-2-((5-(trifluoromethyl)pyridin-2-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; toluene; at 20℃; for 0.5h;	To a solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (100 mg, 0.28 mmol), prepared as described in Example 1, Ph3P (220 mg, 0.84 mmol) and <strong>[31181-84-7](5-trifluoromethyl-pyridin-2-yl)methanol</strong> (50 mg, 0.28 mmol) in THF (2.0 mL) was added 40 wt % diethyl azodicarboxylate (DEAD) solution in toluene (0.33 mL, 0.84 mmol) at RT under argon. The reaction was stirred at RT for 30 min. Water (5.0 mL) was then added and the resulting mixture was extracted with EtOAc (3×5 mL). The combined organic layers were washed with water (2×5 mL) followed by saturated aqueous NaCl (2×5 mL). The combined organic layers were concentrated under reduced pressure to obtain the crude product. This crude product was purified using reverse phase preparative HPLC to give the title compound 7,8-bis(4-chlorophenyl)-2-((5-(trifluoromethyl)pyridin-2-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (69.2 mg, 48%) as a yellow solid. MS (M+H)=516; 1H NMR (CDCl3): delta 8.83 (1H, s), 8.20 (1H, s), 7.93 (1H, d, J=8.2 Hz), 7.40 (1H, d, J=10.0 Hz), 7.26-7.34 (6H, m), 7.11 (2H, d, J=10.0 Hz), 5.47 (2H, s).

Reference： [1]Patent: US2005/143381,2005,A1 .Location in patent: Page/Page column 16

3
[ 31181-84-7 ]
[ 31224-82-5 ]

Yield	Reaction Conditions	Operation in experiment
74%	With Dess-Martin periodane; In dichloromethane; at 20℃; for 0.333333h;	A solution of Example 34B (3.89 g, 22.0 mmol) in CH2Cl2 (10 mL) was added to a deoxygenated solution of Dess-Martin periodinane (1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one, 10.3 g, 24.2 mmol) in CH2Cl2 (73 mL) in one portion. The reaction was stirred under nitrogen at ambient temperature for about 20 minutes after which a solid formed. The reaction was diluted with 50 mL CH2Cl2 and carefully quenched with approximately 30 mL of saturated NaHCO3 solution. The undissolved solid was filtered, and the filtrate was transferred to a separatory funnel. The aqueous phase was extracted with CH2Cl2, and the combined organic layer was washed with brine, dried over Na2SO4, filtered, and evaporated at reduced pressure to 50 mL. This solution was then loaded on silica gel (Analogix 40*150 column) and eluted with 25% to 50% EtOAc/hexanes. The result was 2.86 g (74%) of the title compound as a clear oil, which solidified on standing. 1H NMR (300 MHz, CDCl3) delta 10.15 (s, 1H), 9.06 (m, 1H), 8.15 (m, 1H), 8.09 (d, J=8.1, 1H).
	With manganese(IV) oxide; In chloroform; at 20℃; for 15h;Heating / reflux;	EXAMPLE 18; trans-N-[4-(4,5-Dichloro-imidazol-1-yl)-3-trifluoromethyl-phenyl]-3-(5-trifluoromethyl-pyridin-2-yl)-acrylamide (Cpd 235) A. To a solution of compound 18a (3.84 g, 21.7 mmol), in 25 mL CHCl3 was added manganese dioxide (MnO2) (8.04 g). After stirring at ambient temperature for 15 hours the suspension was heated at reflux under a nitrogen atmosphere for an additional 23 hours. The reaction mixture was filtered over a pad of celite and the filter cake washed with additional CHCl3. The filtrate was evaporated in vacuo to yield the product, compound 18b as an orange oil. MS: M+H+=175.8, 1H NMR (CDCl3): delta 10.15 (s, 1H), 9.06 (s, 1H), 8.17-8.06 (m, 2H).
		Intermediate 13: 2-[5-(Trifluoromethyl)pyridin-2-yl]methyl}cyclopentan-1-amine Step (i): 5-(Trifluoromethyl)pyridine-2-carbaldehyde Dess-Martin periodinane (CAS number 87413-09-0; 13.17 g, 31.10 mmol) was added to a solution of <strong>[31181-84-7][5-(trifluoromethyl)pyridin-2-yl]methanol</strong> (CAS number 31181-84-7; 5.00 g, 28.2 mmol) in DCM (60 ml). The reaction was stirred at room temperature for 18 hours and then a saturated solution of sodium thiosulfate (aq, 100 ml) was added. The reaction was stirred for 45 min at room temperature and then phases separated. The aqueous phase was further extracted with DCM (60 ml) and the combined organics were washed with a saturated solution of sodium bicarbonate (aq, 60 ml), filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-20% ethyl acetate/petrol) to afford the title compound. MS ES+: 176

Reference： [1]Patent: US2009/124666,2009,A1 .Location in patent: Page/Page column 26
[2]Patent: US2006/223837,2006,A1 .Location in patent: Page/Page column 35
[3]Patent: US2015/232460,2015,A1 .Location in patent: Paragraph 0478-0480

4
[ 31181-84-7 ]
[ 1000773-62-5 ]

Yield	Reaction Conditions	Operation in experiment
86%	With phosphorus tribromide; In dichloromethane; at 0 - 20℃;	To an ice-cooled solution of (5-trifluoromethyl-pyridin-2-yl)-methanol (300 mg, 1.69 mmol) inDCM (10 mL) is added phosphoros tribromide (96 mul_, 1.02 mmol) and the reaction mixture is stirred for 2 h at room temperature. The reaction mixture is quenched with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer is dried over MgSO4 and evaporated under reduced pressure.Yield: 350 mg (86% of theory); ESI Mass spectrum: [M+H]+ = 239Retention time HPLC: 1.37 min (method J).
77%	With 1H-imidazole; bromine; triphenylphosphine; In dichloromethane; for 3h;	2-(bromomethyl)-5-(trifluoromethyl)pyridine<strong>[31181-84-7][5-(trifluoromethyl)pyridin-2-yl]methanol</strong> (2.Og, 11.29 mmol) was dissolved in DCM (20 ml_) at r.t. Imidazole (824 mg, 11.9 mmol) was added and allowed to dissolve. Triphenylphosphine (3.36 g, 12.4 mmol) was then added and dissolved. Bromine (0.58 ml_, 11.3 mmol) was added last and stirred for 3 hours. The reaction was quenched water and extracted with dichloromethane (2x 25 ml_). The organics were dried with magnesium sulfate and concentrated. The crude product was purified by flash chromatography (heptanes:ethyl acetate) to give the title compound as a clear liquid (2.1 g, 8.75 mmol, 77%).
		Reference Production Example 2. In 70 mL of tetrahydrofuran, 4.44 g of (5- trifluoromethylpyridin-2-yl) methanol was dissolved and 1.9 mL of methanesulfonyl chloride and 3.5 mL of triethylamine were added dropwise at 00C. After stirring at the same temperature for 0.5 hours, 10% hydrochloric acid was added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and then the resulting residue was dissolved in 30 mL of N, N-dimethylformamide. To the solution was added 4.4 g of lithium bromide at room temperature. The reaction mixture was heated to 90C and, after stirring for 10 minutes and returning to room temperature, 10% hydrochloric acid was added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and then the resulting residue was subjected to column chromatography to obtain 1.68 g of 2- bromomethyl-5-trifluoromethylpyridine.1H-NMR (CDCl3, TMS) : delta (ppm) 8.84 (IH, s), 7.94 (IH, dd) ,7.59 (IH, d) , 4,59 (2H, s).

	With phosphorus tribromide; In dichloromethane; at 0 - 20℃; for 3h;	Step (ii): 2-(Bromomethyl)-5-(trifluoromethyl)pyridine To a solution of <strong>[31181-84-7][5-(trifluoromethyl)pyridin-2-yl]methanol</strong> (5.0 g, 28.24 mmol) in DCM (50 ml) was added tribromophosphane (0.58 g, 3.50 mmol) at 0 C. The reaction was allowed to warm to room temperature and stirred for 3 hours. The reaction was then poured into water (50 ml) and the organics were extracted with DCM (2×50 ml), washed with brine, dried over sodium sulfate and concentrated in vacuo to afford the title compound which was used without further purification. MS ES+: 240, 242
	With phosphorus tribromide; In dichloromethane; at 20℃; for 3h;	Intermediate 1 (390.0 mg, 2.2 mmol) was dissolved in DCM (10 mL). 0 C, a solution of PBr3 (387.0 mg, 1.43 mmol) in DCM (2 mL) was added dropwise. The reaction was carried out for 3 hours at room temperature. TLC showed the reaction was completed. The pH was adjusted to 6-7 with saturated NaHCO3 solution, H2O (15 mL) added and DCM extracted (15 mLx3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (450.0 mg, 80.0% purity, 68.1% yield).

Reference： [1]Patent: WO2009/103478,2009,A1 .Location in patent: Page/Page column 51
[2]Patent: WO2010/58318,2010,A1 .Location in patent: Page/Page column 78
[3]Patent: WO2009/25397,2009,A1 .Location in patent: Page/Page column 161-162
[4]Patent: US2015/232460,2015,A1 .Location in patent: Paragraph 0667-0668
[5]Patent: CN106831840,2017,A .Location in patent: Paragraph 0105; 0106; 0107

5
[ 124236-37-9 ]
[ 31181-84-7 ]

Yield	Reaction Conditions	Operation in experiment
93%	With methanol; sodium tetrahydroborate; at 0 - 20℃;	IV. (5-trifluoromethyl-2-pyridinyl)methanol To a solution of <strong>[124236-37-9]methyl 5-trifluoromethyl-pyridine-2-carboxylate</strong> (2 g, 9.75 mmol) in MeOH (30 mL) at 0C was added NaB (738 mg, 19.5 mmol) portionwise. The mixture was stirred at room temperature for 2 h and concentrated. The residue was diluted with water (30 mL), acidified to pH~5 (IN HC1), extracted with EA (3 X 50 mL), dried, concentrated and purified by column chromatography on silica gel to give the title compound as a colorless oil (1.6 g, 93% yield): 1H NMR (400 MHz, CDC13) delta ppm 8.82 (s, 1H), 7.90-7.92 (m, 1H), 7.40-7.42 (m, 1H), 4.82-4.83 (m, 2H), 3.44-3.46 (m, 1H); ES-LCMS m/z 178 ( +H)+.
82.2%	With methanol; sodium tetrahydroborate; at 0 - 20℃; for 1h;	Compound SM (1.0 g, 4.87 mmol) was dissolved in MeOH (15 mL). At 0 C, NaBH4 (368.9 mg, 9.75 mmol) was added portionwise with stirring. Reaction at room temperature for 1 hour. TLC showed the reaction was completed. The pH was adjusted to 5-6 with 1 M HCl solution and the EA extracted (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (710.0 mg, 82.2%).
72%		NaBH4 (0.369 g, 9.75 mmol) was added to Example 34A (1 g, 5 mmol) in EtOH (40 mL). The suspension was heated at reflux overnight. The reaction was cooled to ambient temperature and quenched with saturated NH4Cl solution. The mixture was diluted with water and extracted with EtOAc. The separated organic layer was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was chromatographed on silica gel (Analogix 25*40 column, 30%-50% EtOAc/hexanes eluant) to afford 0.62 g (72%) of the title compound as a colorless oil. 1H NMR (300 MHz, CDCl3) delta 8.84 (s, 1H), 7.94 (dd, J=8.3, 2.1 1H), 7.43 (dd, J=8.2, 0.6 1H), 4.85 (d, J=5.2, 2H), 3.46 (t, J=5.3, 1H).

Reference： [1]Patent: WO2013/166621,2013,A1 .Location in patent: Page/Page column 48
[2]Patent: CN106831840,2017,A .Location in patent: Paragraph 0102; 0103; 0104
[3]Patent: US2009/124666,2009,A1 .Location in patent: Page/Page column 25-26

6
[ 31181-84-7 ]
[ 1301167-65-6 ]
[ 1301168-19-3 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 5820 - 5835

7
[ 31224-82-5 ]
[ 31181-84-7 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 6563 - 6585

8
[ 31181-84-7 ]
[ 1333170-17-4 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 6563 - 6585

9
[ 31181-84-7 ]
[ 128790-14-7 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 6563 - 6585

10
[ 100366-75-4 ]
[ 31181-84-7 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 6563 - 6585

11
[ 50488-42-1 ]
[ 31181-84-7 ]