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Chemical Structure| 146137-78-2 Chemical Structure| 146137-78-2

Structure of 146137-78-2

Chemical Structure| 146137-78-2

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Product Details of [ 146137-78-2 ]

CAS No. :146137-78-2
Formula : C8H4F4O
M.W : 192.11
SMILES Code : O=CC1=CC(C(F)(F)F)=CC=C1F
MDL No. :MFCD00061311
Boiling Point : No data available

Safety of [ 146137-78-2 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Computational Chemistry of [ 146137-78-2 ] Show Less

Physicochemical Properties

Num. heavy atoms 13
Num. arom. heavy atoms 6
Fraction Csp3 0.12
Num. rotatable bonds 2
Num. H-bond acceptors 5.0
Num. H-bond donors 0.0
Molar Refractivity 36.79
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

17.07 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

1.69
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

2.37
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

4.23
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

2.94
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

3.43
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.93

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-2.73
Solubility 0.355 mg/ml ; 0.00185 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-2.37
Solubility 0.821 mg/ml ; 0.00428 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-3.51
Solubility 0.0588 mg/ml ; 0.000306 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble

Pharmacokinetics

GI absorption?

Gatrointestinal absorption: according to the white of the BOILED-Egg

High
BBB permeant?

BBB permeation: according to the yolk of the BOILED-Egg

Yes
P-gp substrate?

P-glycoprotein substrate: SVM model built on 1033 molecules (training set)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

Yes
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-5.79 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

2.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

1.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<1.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

1.47

Application In Synthesis of [ 146137-78-2 ]

* 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.

  • Downstream synthetic route of [ 146137-78-2 ]

[ 146137-78-2 ] Synthesis Path-Downstream   1~36

  • 1
  • [ 2365-48-2 ]
  • [ 146137-78-2 ]
  • [ 146137-92-0 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 2h; Production Example 1; A mixture of 5.0 g of 2-fluoro-5- ( trifluoromethyl ) benzaldehyde, 3.3 g of methyl thioglycolate , 4.0 g of potassium carbonate and 50 ml of DMF was stirred at 60C for 2 hours, and then the reaction mixture was cooled . to room temperature. To the reaction mixture was added water, and extracted with tert-butyl methyl ether 3 times. The combined organic layer was washed with water, followed by saturated aqueous sodium chloride solution. The mixture was dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was recrystallized from methanol to obtain 6.3 g of methyl 5- ( trifluoromethyl ) benzo[ b] thiophene-2- carboxylate (the present compound 1) .[ The present compound 1]1 H-N R ( CDCI3 ) δ: 8.16(s, ' 1H) , 8.13(s, 1H) , 7.99(d, J=8.7Hz, 1H) , 7.67(d, J=8.7Hz, 1H) , 3.98(s, 3H)
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 2h; Production Example 1; A mixture of 5.0 g of 2-fluoro-5- ( trifluoromethyl ) benzaldehyde, 3.3 g of methyl thioglycolate, 4.0 g of potassium carbonate and 50 ml of DMF was stirred at 60C for 2 hours, and then the reaction mixture was cooled to room temperature. To the reaction mixture was added water, and extracted with tert-butyl methyl ether 3 times. The combined organic layer was washed with water, followed by saturated aqueous sodium chloride solution. The mixture was dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was recrystallized from methanol to obtain 6.3 g of methyl 5- (trifluoromethyl ) benzo[ b] thiophene-2- carboxylate.
6.3 g With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 2h; Production Example 1 A mixture of 5.0 g of 2-fluoro-5-(trifluoromethyl)benzaldehyde, 3.3 g of methyl thioglycolate, 4.0 g of potassium carbonate and 50 ml of DMF was stirred at 60 C. for 2 hours. The reaction mixture was cooled down to room temperature. To the reaction mixture was added water, and the mixture was extracted with tert-butyl methyl ether three times. The combined organic layers were washed with water and saturated saline, and dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was recrystallized from methanol, to obtain 6.3 g of methyl 5-(trifluoromethyl)benzo[b]thiophene-2-carboxylate (present condensed ring compound 1). [Present Condensed Ring Compound 1] [0100] 1H-NMR (CDCl3) δ: 8.16 (s, 1H), 8.13 (s, 1H), 7.99 (d, J=8.7 Hz, 1H), 7.67 (d, J=8.7 Hz, 1H), 3.98 (s, 3H)
6.3 g With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 2h; A mixture of 5.0 g of 2-fluoro-5-(trifluoromethyl)benzaldehyde, 3.3 g of methyl thioglycolate, 4.0 g of potassium carbonate and 50 ml of DMF was stirred at 60 C. for 2 hours. The reaction mixture was cooled down to room temperature. To the reaction mixture was added water, and the mixture was extracted with tert-butyl methyl ether three times. The combined organic layers were washed with water and saturated saline, and dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was recrystallized from methanol, to obtain 6.3 g of methyl 5-(trifluoromethyl)benzo[b]thiophene-2-carboxylate (present condensed ring compound 1). [Present Condensed Ring Compound 1]. 1H-NMR (CDCl3) δ: 8.16 (s, 1H), 8.13 (s, 1H), 7.99 (d, J=8.7 Hz, 1H), 7.67 (d, J=8.7 Hz, 1H), 3.98 (s, 3H)
General procedure: To a solution of 15a-m in DMF, K2CO3 (25 mmol, 3.45 g) wasadded and the mixturewas stirred at room temperature for 30 min.Then 16 was added dropwise. The reactionwas allowed to warm to60 C and monitored by TLC. The reaction was poured into waterand the mixture was extracted with ethyl acetate three times. Thecombined extracts were dried, concentrated and purified to affordthe intermediate 17a-m. Intermediate AM4a-mwas prepared in a similar manner as thatfor intermediate AM1, using 17a-m instead of 9.

  • 2
  • [ 146137-78-2 ]
  • [ 263266-18-8 ]
  • [ 548486-70-0 ]
  • 3
  • [ 23244-37-3 ]
  • [ 146137-78-2 ]
  • 2-(4-methyl-5-oxo-3-phenyl-5<i>H</i>-isoxazol-2-yl)-5-trifluoromethyl-benzaldehyde [ No CAS ]
  • 4
  • [ 72745-66-5 ]
  • [ 146137-78-2 ]
  • 2-(4-benzyl-3-methyl-5-oxo-5<i>H</i>-isoxazol-2-yl)-5-trifluoromethyl-benzaldehyde [ No CAS ]
  • 5
  • [ 29879-44-5 ]
  • [ 146137-78-2 ]
  • 2-(3-oxo-4,5,6,7-tetrahydro-3<i>H</i>-benzo[<i>c</i>]isoxazol-1-yl)-5-trifluoromethyl-benzaldehyde [ No CAS ]
  • 6
  • [ 80490-31-9 ]
  • [ 146137-78-2 ]
  • 2-(4-ethyl-5-oxo-3-phenyl-5<i>H</i>-isoxazol-2-yl)-5-trifluoromethyl-benzaldehyde [ No CAS ]
  • 7
  • [ 107598-58-3 ]
  • [ 146137-78-2 ]
  • 2-(4-benzyl-5-oxo-3-propyl-5<i>H</i>-isoxazol-2-yl)-5-trifluoromethyl-benzaldehyde [ No CAS ]
  • 8
  • [ 146137-78-2 ]
  • [ 641628-19-5 ]
  • 2-(3-oxo-6,7-dihydro-3<i>H</i>,4<i>H</i>-thiopyrano[4,3-<i>c</i>]isoxazol-1-yl)-5-trifluoromethyl-benzaldehyde [ No CAS ]
  • 9
  • [ 146137-78-2 ]
  • [ 25632-68-2 ]
  • 2-(3-methyl-5-oxo-4-phenyl-5<i>H</i>-isoxazol-2-yl)-5-trifluoromethyl-benzaldehyde [ No CAS ]
  • 10
  • 2-furan-2-yl-N5-pyrrolidin-2-ylmethyl-[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine [ No CAS ]
  • [ 146137-78-2 ]
  • <i>N</i>5-[1-(2-fluoro-5-trifluoromethyl-benzyl)-pyrrolidin-2-ylmethyl]-2-furan-2-yl-[1,2,4]triazolo[1,5-<i>a</i>][1,3,5]triazine-5,7-diamine [ No CAS ]
  • 11
  • [ 146137-78-2 ]
  • [ 57260-71-6 ]
  • [ 626219-95-2 ]
YieldReaction ConditionsOperation in experiment
92% With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 120℃; for 10h; To a solution of <strong>[146137-78-2]2-fluoro-5-trifluoromethylbenzaldehyde</strong> (10.0 mL, 68. 7 mmol) and 1-BOC-piperazine (15.4 g, 82.4 mmol) in 140 mL of DMF was added K2CO3 (47.4 g, 344 mmol). The reaction mixture was heated and stirred at 120 C for 10 hours. The reaction mixture was cooled to room temperature and diluted with 200 mL of EtOAc. The mixture was filtered, and the filter was washed well with EtOAc (3 x 50 mL). The filtrate was washed with 5% aqueous HCI (100 mL) and the aqueous layer was extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with H20 (2 x 40 mL) and brine (50 mL). After drying (MgSO4), and concentration in vacuo, the residue was triturated with hexanes (3 x 20 mL) to give a brown oil. The brown oil slowly solidified to give the compound la as a yellow solid (22.3 g, 92%).
92% With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 120℃; for 10h; EXAMPLE 3; 1- {4- 3- (2, 4-DICHLOROPHENYL) PROPIONYL]-1-PIPERAZINYL}-2- 1 S- (3- AMINOPROPIONYLAMIDO)-3-METHYLBUTYL]-4-TRIFLUOROMETHYLBENZENE 3-1; Step 3A. 2- [4''- (tert-Butoxvcarbonvl)-l-piperazinvl]-5-trifluoromethyl-benzaldehyde 3a :; To a solution of 2-fluoro-5-trifluoromethyl-benzaldehyde (10.0 mL, 68.7 mmol) and 1-BOC-piperazine (15.4 g, 82.4 mmol) in 140 mL of DMF was added K2CO3 (47.4 g, 344 mmol). The reaction mixture was heated and stirred at 120 C forlO hours. The reaction mixture was cooled to room temperature and diluted with 200 mL of EtOAc. The mixture was filtered, and the filter was washed well with EtOAc (3 x 50 mL). The filtrate was washed with 5% aqueous HC1 (100 mL) and the aqueous layer was extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with H20 (2 x 40 mL), brine (50 mL), dried (MgS04), and concentrated in vacuo. The residue was triturated with hexanes (3 x 20 mL) to form a brown oil which slowly solidified to give 3a as a yellow solid (22.3 g, 92%).
  • 12
  • [ 110-89-4 ]
  • [ 146137-78-2 ]
  • [ 34595-28-3 ]
  • 13
  • [ 146137-78-2 ]
  • [ 108-95-2 ]
  • [ 188725-94-2 ]
  • 14
  • [ 146137-78-2 ]
  • C20H13F3INO [ No CAS ]
  • 15
  • [ 146137-78-2 ]
  • C20H12F3NO [ No CAS ]
  • 16
  • [ 146137-78-2 ]
  • [ 1496-15-7 ]
  • 17
  • [ 146137-78-2 ]
  • 3-methyl-2-phenyl-6-trifluoromethyl-quinoline [ No CAS ]
  • 18
  • [ 146137-78-2 ]
  • 2-methyl-3-phenyl-6-trifluoromethyl-quinoline [ No CAS ]
  • 19
  • [ 146137-78-2 ]
  • 7-trifluoromethyl-1,2,3,4-tetrahydro-acridine [ No CAS ]
  • 20
  • [ 146137-78-2 ]
  • 3-ethyl-2-phenyl-6-trifluoromethyl-quinoline [ No CAS ]
  • 21
  • [ 146137-78-2 ]
  • (2S,3R)-3-Methyl-2-phenyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinoline [ No CAS ]
  • 22
  • [ 146137-78-2 ]
  • 3-benzyl-2-methyl-6-trifluoromethyl-quinoline [ No CAS ]
  • 23
  • [ 146137-78-2 ]
  • (4aS,9aS)-7-Trifluoromethyl-1,2,3,4,4a,9,9a,10-octahydro-acridine [ No CAS ]
  • 24
  • [ 146137-78-2 ]
  • [ 464191-94-4 ]
YieldReaction ConditionsOperation in experiment
38% EXAMPLE 60 5-Cyano-6-(2-fluoro-5-trifluoromethylphenyl)-4-methyl-2-oxo-3,6-dihydro-2H-pyrimidine-1-carboxylic acid ethyl ester Using <strong>[146137-78-2]2-fluoro-5-trifluoromethylbenzaldehyde</strong> and following the procedure of Example 25, intermediate XXIV was obtained in 41% yield and the title compound was obtained in 38% yield. 1H-NMR (CDCl3, 400 MHz): δ 8.27 (s, 1H), 7.65 (m, 1H), 7.58 (m, 1H), 7.25 (t, 1H, J=9.2 Hz), 6.03 (s, 1H), 4.28 (m, 2H), 2.20 (d, 3H, J=0.9 Hz), 1.29 (t, 3H, J=7.0 Hz). LC/MS (ES+) 372 (M+H)+, 394 (M+Na)+.
  • 25
  • [ 1826-67-1 ]
  • [ 146137-78-2 ]
  • [ 149946-78-1 ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; α-Ethenyl-2-fluoro-5-(trifluoromethyl)benzenemethanol 52.6 ml (0.0526 mol) of a 1M solution of vinylmagnesium bromide in THF are added dropwise at a temperature below 25 C. to a solution of 10.1 g (0.0526 mol) of 2-fluoro-5-(trifluoromethyl)benzaldehyde (prepared according to Example P) in 53 ml of anhydrous THF. The mixture is then stirred for 2 h 30 at room temperature. Hydrolysis is carried out with a saturated aqueous NH4 Cl solution while cooling between 10 and 20 C.; extraction is carried out with ether and the extract is washed with water, dried over Na2 SO4, filtered and evaporated under vacuum. The residue is used without subsequent purification in the following stage. Yd.: 11.6 g (quantitative) 1 H N.M.R. (CDCl3):2.3 (1H, broad s, exchangeable with D2 O), 4.7 to 6.5 (4H, m), 6.8 to 8.0 (3H, m).
  • 26
  • [ 4088-84-0 ]
  • [ 146137-78-2 ]
YieldReaction ConditionsOperation in experiment
With formic acid;aluminum nickel; In water; 2-Fluoro-5-(trifluoromethyl)benzaldehyde A mixture of 18.7 g (0.0988 mol) of 2-fluoro-5-(trifluoromethyl)benzonitrile (prepared according to G. C. Finger et al., Chem. Comm., 1965, 430), 398 ml of 90% formic acid, 296 ml of water and 17.5 g of Raney nickel is heated for 5 hours at reflux and is then left standing overnight. The mixture is poured into 2.5 liters of water and extraction is carried out with methylene chloride (once 1 l and two times 500 ml). Filtration, washing with water, drying over Na2 SO4, filtration and distillation are carried out. Yd.: 10.1 g (53%) B.p.14 =70-72 C. IR: νc-o =1680 cm-1
  • 27
  • [ 75-16-1 ]
  • [ 146137-78-2 ]
  • [ 866615-76-1 ]
YieldReaction ConditionsOperation in experiment
3.0 M methylmagnesiumbromide (7.8 ml) was dropped, in a nitrogen atmosphere at 0 C, into the THF (30 ml) solution of 2-fluoro-5-trifluoromethyl benzaldehyde (3.0 g). After the mixture was warmed to room temperature, and was then stirred for 30 minutes, it was poured into a saturated ammonium chloride aqueous solution, and was then subjected to extraction with ethyl acetate. After its organic layer was washed with brine, and was then dried with anhydrous magnesium sulfate, it was filtered, and was then concentrated under reduced pressure to produce a crude chemical compound (58) (3.42 g).
  • 28
  • [ 107-21-1 ]
  • [ 146137-78-2 ]
  • [ 773102-32-2 ]
YieldReaction ConditionsOperation in experiment
With toluene-4-sulfonic acid; In benzene;Heating / reflux; The benzene (50 ml) solution of 2-fluoro-5-(trifluoromethyl)benzaldehyde (5.00 g), ethylene glycol (1.78 g), and p-toluene sulfonate monohydrate (0.49 g) were refluxed with heating over night. After the mixture was cooled to room temperature, it was poured into water, and was then subjected to extraction with ethyl acetate. After its organic layer was washed with brine, and was then dried with anhydrous magnesium sulfate, it was filtered, and its solvent was then evaporated to produce a crude chemical compound (39) (5.81 g).
  • 29
  • ([2S,3S]-2-phenylpiperidin-3-yl)amine dihydrochloride [ No CAS ]
  • [ 146137-78-2 ]
  • (2S,3S)-3-(2-Fluoro-5-(trifluoromethyl)benzyl)amino-2-phenylpiperidine [ No CAS ]
YieldReaction ConditionsOperation in experiment
With NaBH(OAc)3; In dichloromethane; (ii) (2S,3S)-3-(2-Fluoro-5-(trifluoromethyl)benzyl)amino-2-phenylpiperidine dihydrochloride (Compound 2) To a stirred suspension of Compound 1 (150 mg, 0.60 mmol) and 2-fluoro-5-(trifluoromethyl)benzaldehyde (116 mg, 0.60 mmol) in dry CH2Cl2 (6 ml) was added NaBH(OAc)3 (179 mg, 0.84 mmol) portionwise under nitrogen at room temperature. The reaction mixture was stirred at room temperature for 6.5 hr. This was basified with sat. NaHCO3 aq., extracted with CH2Cl2, dried with MgSO4, and concentrated to give crude (2S,3S)-3-(2-fluoro-5-(trifluoromethyl)benzyl)amino-2-phenylpiperidine as a colorless oil. This was purified with chromatography to give pure (2S,3S)-3-(2-fluoro-5-(trifluoromethyl)benzyl)amino-2-phenylpiperidine as a colorless oil (75 mg).
  • 30
  • [ 146137-78-2 ]
  • [ 146539-83-5 ]
YieldReaction ConditionsOperation in experiment
With sodium methylate; acetic acid; In water; (i) 2-Methoxy-5-(trifluoromethyl)benzaldehyde (Compound 4) To a stirred and ice-cooled solution of NaOMe (904 mg, 4.68 mmol) was added 2-fluoro-5-(trifluoromethyl)benzaldehyde (500 mg, 2.60 mmol) portionwise. The dropping funnel employed was washed with THF. The resultant suspension was stirred at room temperature for 5 hr. The reaction mixture was neutralizing for acetic acid (0.3 ml, 5.0 mmol), the solvent was removed. To the solid residue was added water and the mixture was extracted with CH2Cl2. The combined CH2Cl2 extracts were washed with sat. NaHCO3 aq., dried with MgSO4, and concentrated to give crude Compound 4 as a white solid. This was purified with preparative TLC to give pure Compound 4 as a white crystalline (363 mg, 68.4%). 1H-NMR(CDCl3) 10.47(s, 1H), 8.11(d, J=2.2 Hz, 1H), 7.80(dd, J=8.8, 2.2 Hz, 1H), 7.10(d, J=8.8 Hz, 1H), 4.01(s, 3H)
  • 31
  • C13H15F3N2O [ No CAS ]
  • [ 146137-78-2 ]
  • 3α-[5-(trifluoromethyl)-2-pyridyloxy]-8-(2-formyl-4-(trifluoromethyl)phenyl)-8-azabicyclo[3.2.1]octane [ No CAS ]
YieldReaction ConditionsOperation in experiment
2.77 g With potassium carbonate; In acetonitrile; for 3.5h;Reflux; 30 ml of acetonitrile suspension containing 2 g of the compound (H), 3.04 g of potassium carbonate, and 1.41 g of <strong>[146137-78-2]2-fluoro-5-trifluoromethylbenzaldehyde</strong> was refluxed for 3.5 hours. After being cooled to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saline and dried with anhydrous magnesium sulfate. 2.77 g of the target compound was obtained by evaporating the solvents under reduced pressure and purifying the residue with silica gel column chromatography (developing solution: mixed solvent of n-hexane and ethyl acetate). Melting temperature: 122-123C 1H-NMR(CDCl3, δppm):1.99-2.05(m, 2H), 2.12(s, 1H), 2.17(s, 1H), 2.21-2.28(m, 2H), 2.41(t, 1H), 2.45(t, 1H), 4.04(brs, 2H), 5.50(t, 1H), 6.79(d, 1H), 7.05(d, 1H), 7.61(d, 1H), 7.79(dd, 1H), 8.02(s, 1H), 8.44(s, 1H), 10.19(s, 1H)
  • 32
  • [ 146137-78-2 ]
  • [ 107-18-6 ]
  • [ 945227-08-7 ]
YieldReaction ConditionsOperation in experiment
60% With potassium carbonate; at 60℃; for 5h; Into a solution of 1 (3.00g, 15.6 mmol) in allyl alcohol was added K2CO3 (2.80g, 20.0 mmol). The mixture was heated to 60 C for 5 hours, cooled to room temperature, taken up in ethyl acetate, washed with water, then with brine and dried (Na2SO4), filtered and concentrated. The residue was purified on silica (eluted with a solution of ethyl acetate: hexane, 1 : 19) to give 2 (2.15g, 60% yield).1H NMR (300 MHz, CDCl3) δ 10.52 (s, IH), 8.12 (d, J= 1.5 Hz, IH), 7.76 (dd, J= 1.5, 8 Hz, IH), 7.07 (d, J= 8 Hz, IH), 6.18-5.84 (m, IH), 5.36-5.16 (m, 2H), 4.75 (d, J= 6 Hz, 2H).
60% With potassium carbonate; at 60℃; for 5h; Into a solution of 2-fluoro-5-(trifluoromethyl)benzaldehyde (3.0Og, 15.6 mmol) in allyl alcohol was added K2CO3 (2.8Og, 20.0 mmol). The mixture was heated to 60 C for 5 hours, cooled to room temperature, taken up in ethyl acetate, washed with water, then with brine and dried (Na2SO^, filtered and concentrated. The residue was purified on silica (eluted with a solution of ethyl acetate: hexane, 1 :19) to give 40a (2.15g, 60% yield).1H NMR (300 MHz, CDCI3) 5 10.52 (S, 1H), 8.12 (d, J = 1.5 Hz, 1 H), 7.76 (dd,J = 1.5, 8 Hz, 1H), 7.07 (d, J = 8 Hz, 1H), 6.18-5.84 (m, 1H), 5.36-5.16 (m, 2H),4.75 (d, J = 6 Hz, 2H).
  • 33
  • [ 506-59-2 ]
  • [ 146137-78-2 ]
  • [ 945847-58-5 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In toluene; at 120℃; To toluene (5ml) are added 2-fluoro-5-trifluoromethyl-benzaldehyde (650mg) and dimethylamine hydrochloride (2.76g), followd by addition of potassium carbonate (1.4g), and the mixture is stirred at 120C overnight. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and water, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 49: 1→4: 1) to give 2-dimethylamino-5-trifluoromethyl-benzaldehyde (529mg). MS (m/z): 218 [M+H]+.
  • 34
  • [ 95-77-2 ]
  • [ 146137-78-2 ]
  • [ 289717-76-6 ]
YieldReaction ConditionsOperation in experiment
In potassium carbonate; N,N-dimethyl-formamide; Preparation 1 2-(3,4-Dichlorophenoxy)-5-Trifluoromethylbenzaldehyde Under N2 in a 50 mL round-bottomed flask fitted with a reflux condenser and magnetic stirrer were placed 0.829 g (6.0 mmol) of K2CO3 and 0.342 g (2.1 mmol) of 3,4-dichlorophenol (Aldrich Chem. Co., Milwaukee, Wis.) in 10 mL of anhydrous N,N-dimethylformamide (DMF). After stirring the mixture for 5 min., 0.384 g (2.0 mmol) of <strong>[146137-78-2]2-fluoro-5-trifluoromethylbenzaldehyde</strong> (Aldrich) was added and the mixture was heated to 90-95 C. overnight. After allowing the reaction to cool to room temperature, the mixture was diluted with water and EtOAc, the aqueous layer was extracted with additional EtOAc and the organic layers were combined, washed with H2O and saturated NaCl and dried over MgSO4. Removal of the solvent in vacuo gave a light amber colored oil, 0680 g. 1H-NMR (CDCl3, 400 MHz): d 10.46 (s, 1H), 8.18 (s, 1H), 7.74 (m, 1H), 7.48 (m, 1H), 7.23 (m, 1H), 6.97 (m, 2H). Mass spectrum (GCMS, m/z): 334 (m+).
  • 35
  • N-ethyl-N-(3,5-ditrifluoromethylphenyl)methylamine [ No CAS ]
  • [ 146137-78-2 ]
  • 2-[(3,5-bis-trifluoromethyl-benzyl)-ethyl-amino]-5-trifluoromethyl-benzaldehyde [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 90℃; (3,5-Bis-trifluoromethyl-benzyl)-ethyl-amine (1.03g) is dissolved in N,N-dimethylformamide (10ml), and thereto are added 2-fTuoro-5- trifluoromethyl-benzaldehyde (1.45g) and potassium carbonate (1.48g), and the mixture is stirred under nitrogen atmosphere at 90C for 3 hours and at room temperature overnight. To reaction mixture is added a saturated brine and water, and the mixture is extracted five times with ethyl acetate and the organic layer is washed twice with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 10: 1) to give 2-[(3,5-bis-trifluoromethyl-benzyl)-ethyl- amino]-5-trifluoromethyl-benzaldehyde (282mg). MS (m/z): 444 [M+H]+.
  • 36
  • [ 26389-60-6 ]
  • [ 146137-78-2 ]
  • [ 945847-53-0 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In toluene; at 120℃; for 4h;Product distribution / selectivity; 2-Fluoro-5-trifluoromethyl-benzaldehyde (l-3g) and cyclopropylmethyl-propyl-amine (1.15g) are dissolved in toluene (13ml), and thereto is added potassium carbonate (2.8Ig) and the mixture is stirred at 120C overnight. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and water, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = l:0→97:3) to give 2- (cyclopropylmethyl-propyl-amino) - 5-trifluoromethyl-benzaldehyde ( 1.7g) . MS (m/z): 286 [M+H]+. Example 76(1) 2-Fluoro-5-trifluoromethyl-benzaldehyde (5g) and cyclopropylmethyl- propyl-amine (5.57ml) is dissolved in toluene (50ml), and thereto is added potassium carbonate (10.7g) and the mixture is stirred at 120C overnight. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and water, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 20: 1) to give 2- (cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzaldehyde (6.8g). MS (m/z): 286 [M+H]+. Example 85 (1) 2-Fluoro-5-trifluoromethyl-benzaldehyde (5.38g) and cyclopropylmethyl-propyl-amine (4.75g) is dissolved in toluene (50ml), and thereto are added potassium carbonate (11.6g) and the mixture is stirred at 120C for 4 hours. The reaction solution is cooled to room temperature, and thereto is added water and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1→4: 1) to give 2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzaldehyde (8.Og). MS (m/z): 286 [M+H]+.
 

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