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Chemical Structure| 22235-25-2 Chemical Structure| 22235-25-2

Structure of 22235-25-2

Chemical Structure| 22235-25-2

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Product Details of [ 22235-25-2 ]

CAS No. :22235-25-2
Formula : C9H8F3NO2
M.W : 219.16
SMILES Code : O=C(OC)C1=CC(C(F)(F)F)=CC(N)=C1
MDL No. :MFCD00625827
InChI Key :UOVPHHSFTNRQHJ-UHFFFAOYSA-N
Pubchem ID :4026781

Safety of [ 22235-25-2 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Computational Chemistry of [ 22235-25-2 ] Show Less

Physicochemical Properties

Num. heavy atoms 15
Num. arom. heavy atoms 6
Fraction Csp3 0.22
Num. rotatable bonds 3
Num. H-bond acceptors 5.0
Num. H-bond donors 1.0
Molar Refractivity 47.13
TPSA ?

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

52.32 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.87
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

1.98
Log Po/w (WLOGP)?

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

3.23
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.

2.36
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

2.05
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.3

Water Solubility

Log S (ESOL):?

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

-2.54
Solubility 0.626 mg/ml ; 0.00286 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.

-2.7
Solubility 0.433 mg/ml ; 0.00197 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

-3.01
Solubility 0.215 mg/ml ; 0.000979 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.

-6.23 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

0.0
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)

1.74

Application In Synthesis of [ 22235-25-2 ]

* 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 [ 22235-25-2 ]

[ 22235-25-2 ] Synthesis Path-Downstream   1~35

  • 3
  • [ 22227-63-0 ]
  • [ 22235-25-2 ]
YieldReaction ConditionsOperation in experiment
98% With tin(II) chloride dihdyrate; water; In methanol; at 70℃; for 2.0h; To a mixture of methyl 3-nitro-5- (trifluoromethyl)benzoate (350 mg, 1.40 mmol) and tin(II) chloride dihydrate (1.58 g, 7.02 mmol) in methanol (20 mL) was added water (1 mL) and the resulting mixture was stirred at 70 °C for 2 h. After cooling to room temperature, the reaction mixture was concentrated and was quenched by the addition of saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (3X). The combined organic portion was dried over magnesium sulfate, was filtered and was concentrated to give methyl 3-amino-5- (trifluoromethyl)benzoate (300 mg, 98percent yield) as a colorless solid. XH NMR (400 MHz,CDCI3): delta 7.65 (s, 1H), 7.48 (s, 1H), 7.05 (s, 1H), 3.99 (br s, 2H), 3.91 (s, 3H).
96% With hydrogen;palladium on activated charcoal; In methanol; at 20℃; for 3.0h; To a solution of methyl 3-nitro-5-(trifluoromethyl) benzoate (1.50 g, 6.02 mmol) in methanol (20 . mL) was added palladium carbon (50percent water-containing product,15 mg) , and the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hr. The reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure and dried to give the title compound(1.27 g, 96percent) as a white solid.1H-NMR (DMSO-d6, 300 MHz) delta 3.85 (3H, s) , 5.94 (2H, s) , 7.08 (IH, s), 7.26 (IH, s), 7.42 (IH, s) .
95% With hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃; under 2068.65 Torr; for 1.0h; Reference Example 28Methyl 3-amino-5-(trifluoromethyl)benzoateA solution of methyl 3-nitro-5-(trifluoromethyl)benzoate (Reference Example 27, 24.6 g, 98.9 mmol) in ethanol (1500 mL) was sparged in a Parr bottle with nitrogen for 10 min.After this time, 10 wt percent Pd/C (5.0 g, 5.0 mmol) was added and the reaction mixture was subjected to 40 psi of hydrogen on Parr shaker at room temperature for 1 h.After this time, the reaction mixture was filtered through a pad of celite and concentrated under reduced pressure to provide Methyl 3-amino-5-(trifluoromethyl)benzoate (20.6 g, 95percent) as a light purple oil.1H NMR (500 MHz, CDCl3) delta ppm 3.92 (s, 3H), 4.02 (br s, 2H), 7.05 (s, 1H), 7.48 (s, 1H), 7.64 (s, 1H).
86% With hydrogen;palladium 10% on activated carbon; In methanol; Methyl 3-amino-5-(trifluoromethyl)benzoate. Methyl 3-nitro-5-(trifluoromethyl)benzoate (9.0 g, 36.1 mmol) in methanol (30 mL) was flushed with nitrogen, and treated with palladium (10percent on charcoal, 0.90 g). The flask was flushed with hydrogen and allowed to stir under an atmosphere of hydrogen overnight. The reaction was flushed with nitrogen, filtered through celite, and concentrated. Flash chromatography on silica gel (30percent ethyl acetate/hexanes) afforded 6.8 g (86percent). 1H-NMR (CDCl3, 500 MHz) delta 7.64 (s, H), 7.49 (s, 1H), 7.05 (s, 1H), 3.91 (s, 3H). Mass spec.: 220.05 (MH)+.
74% A solution of 3-nitro-5-trifluoromethyl-benzoic acid methyl ester (8.6 mmol, 2.15 g) and tin chloride dihydrate (25.8 mmol, 5.82 in ethanol (40 ml) is allowed to warm to 60 0C and stir for 4 hours. The mixture is cooled to room temperature, then concentrated under reduced pressure. The obtained residue is neutralized with saturated aq. NaHCO3. The mixture is filtered and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: hexane / EtOAc) to give 3-amino-5- trifluoromethyl-benzoic acid methyl ester (74percent, 1.4 g); ESI-MS m/z: 220 [M+1]\\ Retention time 1.81 min (condition A).
0.85 g With palladium on activated charcoal; hydrogen; In methanol; at 20℃; for 3.0h; (Reference Example 28) Synthesis of methyl 3-amino-5-(trifluoromethyl)benzoate: A solution of 3-nitro-5-(trifluoromethyl)benzoic acid (1.0 g, 4.2 mmol) and p-toluenesulfonic acid (0.05 g) in methanol was stirred while heating under reflux for eight hours. The obtained solution was returned to room temperature and then concentrated under vacuum. The obtained residue was dissolved in methanol, palladium (5.0percent by weight) on carbon (containing 50percent water by weight, 0.2 g) was added thereto, and the obtained solution was stirred at room temperature for three hours under hydrogen atmosphere. The reaction mixture was filtered through Celite® and the filtrate was concentrated under vacuum. The obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1, Rf = 0.47) to obtain the title compound (0.85 g, 91percent) (hereinafter referred to as the compound of Reference Example 28) as an oily substance. MS(ESI) [M + H]+: 220.

  • 4
  • [ 1445-45-0 ]
  • [ 22235-25-2 ]
  • methyl 3-(5-methyl-1H-tetrazol-1-yl)-5-(trifluoromethyl)benzoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
58% Methyl 3-(5-methyl-1H-tetrazol-1-yl)-5-(trifluoromethyl)benzoate. Trimethylorthoacetate (0.41 mL, 3.4 mmol) in acetic acid (3 mL) was added dropwise to a solution of <strong>[22235-25-2]methyl 3-amino-5-(trifluoromethyl)benzoate</strong> (0.5 g, 2.28 mmol) in acetic acid (5 mL) at 75 C. After stirring for 45 min at 75 C., the reaction was treated with sodium azide (0.21 g, 3.4 mmol) carefully in portions over 15 min and stirring continued for 3 h. After cooling to room temperature, the reaction was concentrated and the residue dissolved in ethyl acetate. This was washed with water (2×), 1 N hydrochloric acid (2×), brine (2×), dried over sodium sulfate, and concentrated. Flash chromatography on silica gel (20% ethyl acetate/hexanes) gave 0.38 g (58%). LC/MS (HPLC method 3): tR=2.17 min, 287.12(MH)-.
  • 5
  • [ 22235-25-2 ]
  • [ 537039-44-4 ]
YieldReaction ConditionsOperation in experiment
100% To a suspension of lithium aluminum hydride (4 mmol, 152 mg) in THF (5 ml_) which is cooled to 0 0C is dropwise added a solution of <strong>[22235-25-2]3-amino-5-trifluoromethyl-benzoic acid methyl ester</strong> (2 mmol, 438 mg) in THF (1 mL) under nitrogen. The solution is allowed to warm to rt and stirred for 2 hours. To the solution is added diethyl ether (6 mL), then quenched with sodium sulfate decahydrate and brine. After decantation, the solution is dried over Na2SO4, filtrated, and concentrated under reduced pressure to give (3-amino-5- trifluoromethyl-phenyl)-methanol (quantitative yield), which is used in the next step without further purification); ESI-MS m/z: 192 [M+1]+, Retention time 1.30 min (condition A).
92% With lithium aluminium tetrahydride; In tetrahydrofuran; at 20℃; for 1h;Cooling with ice; (Reference Example 30) Synthesis of (3-amino-5-(trifluoromethyl)phenyl)methanol: To a solution of the compound of Reference Example 28 (0.4 g, 1.8 mmol) in tetrahydrofuran, lithium aluminium hydride (0.22 g, 5.7 mmol) was added portionwise under cooling on ice. The obtained reaction mixture was returned to room temperature and then stirred for one hour. After adding water to the reaction mixture to stop the reaction, the obtained solution was extracted with ethyl acetate and sequentially washed with a saturated aqueous solution of ammonium chloride and with saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated under vacuum, and the obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1, Rf = 0.32) to obtain the title compound (0.32 g, 92%) (hereinafter referred to as the compound of Reference Example 30) as a white solid. MS(ESI) [M + H]+: 192.
0.32 g With lithium aluminium tetrahydride; In tetrahydrofuran;Cooling with ice; To a solution of <strong>[22235-25-2]methyl 3-amino-5-(trifluoromethyl)benzoate</strong> (0.4 g, 1.825 mmol) in THF, lithium aluminium hydride (0.215 g, 5.66 mmol) was slowly added under cooling on ice. The ice bath was removed, and the obtained solution was stirred overnight. Water was slowly added to the reaction solution, and the obtained solution was extracted with ethyl acetate. The organic layer was sequentially washed with a saturated aqueous solution of ammonium chloride and with a saturated aqueous solution of sodium chloride. The obtained organic layer was dried over anhydrous sodium sulfate and then concentrated under vacuum, and the obtained crude product was purified by silica gel column chromatography (eluent; hexane:ethyl acetate = 90:10 ? 60:40) to obtain the title compound (0.32 g). MS(ESI) [M + H]+: 371.
  • 6
  • [ 22235-25-2 ]
  • 3-(2-carbamoyl-2-cyano-thioacetylamino)-5-trifluoromethyl-benzoic acid methyl ester [ No CAS ]
  • 7
  • [ 22235-25-2 ]
  • 3-(4-cyano-3-hydroxy-isothiazol-5-ylamino)-5-trifluoromethyl-benzoic acid methyl ester [ No CAS ]
  • 10
  • [ 22235-25-2 ]
  • [ 334792-88-0 ]
  • 11
  • [ 22235-25-2 ]
  • [ 334792-90-4 ]
  • 12
  • [ 22235-25-2 ]
  • [ 334792-89-1 ]
  • 15
  • [ 22235-25-2 ]
  • [ 334792-95-9 ]
  • 16
  • [ 22235-25-2 ]
  • [ 334792-94-8 ]
  • 18
  • [ 22235-25-2 ]
  • [ 75-03-6 ]
  • [ 677704-77-7 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 65℃; for 14h; A mixture of [3-AMINO-5-(TRIFLUOROMETHYL)-BENZOIC] acid methyl ester (J. Med. Chem. (1969) 12,299-303 ; 4.23 g, 19.3 [MMOL),] potassium carbonate (8.0 g, 57.9 [MMOL)] and iodoethane (3.12 mL, 38.6 [MMOL)] in 20 mL [N, N-DIMETHYLFORMAMIDE] is stirred at [65C] for 14 hours in a tightly closed vessel. After cooling, the reaction mixture is filtered and the filtrate evaporated to dryness under reduced pressure. The residue is treated with water and extracted three times with ethyl acetate. The combined extracts are dried [(NA2SO4)] and the solvent is evaporated off under reduced pressure. The resulting residue is purified by column chromatography on silica gel, eluent hexane/methylene chloride (1: 1). ['H-NMR] (400 MHz, [DMSO-D6,] 8) : 1.18 (t, 3H); 3.10 (m, 2H); 3.85 (s, 3H); 6.46 (t, 1H) ; 7.02 [(BR. 1 H) ; 7.29 (BR. S, 1 H) ; 7.37 (BR. , 1 H).]
  • 19
  • [ 632625-42-4 ]
  • [ 22235-25-2 ]
  • 3-{2-[5-chloro-2-(benzyloxy)phenyl]-5-methyl-pyrrol-1-yl}-5-trifluoromethylbenzoic acid methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
toluene-4-sulfonic acid; In 1-methyl-pyrrolidin-2-one; at 150℃; for 0.166667h;Microwave; [1- [5-CHLORO-2-BENZYLOXY)-PHENYL]-PENTANE-1,] 4-dione (104mg), 3-amino-5-trifluoromethyl- benzoic acid methyl ester (85mg) and [PTSA] (cat) were heated in NMP (1.5mL) at [150C] in a microwave for 10 minutes. The mixture was diluted with [ET20] and washed sequentially with 2M HCI and saturated [NAHCO3,] dried [(NA2SO4),] filtered and concentrated. The residue was purified on silica gel with iso-hexane containing EtOAc (5%) to give the title compound (70mg) LC/MS t=4.02 min, [MH+] 500,502.
  • 20
  • [ 632627-07-7 ]
  • [ 22235-25-2 ]
  • 3-{2-[5-bromo-2-(4-fluorobenzyloxy)phenyl]-5-methyl-pyrrol-1-yl}-5-trifluoromethylbenzoic acid methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
34% toluene-4-sulfonic acid; In 1-methyl-pyrrolidin-2-one; at 180℃; for 0.166667h;Microwave irradiation; [1- [5-BROMO-2- (4-FLUORO-BENZYLOXY)-PHENYL]-PENTANE-1,] 4-dione (0.10g, 0. [26MOL),] 3- amino-5-trifluoromethyl-benzoic acid methyl ester (0.055g, 0. [26MMOL)] and [P-TSA] (cat. ) in NMP (1 ml) were heated in a sealed vessel at [180C] for 10 minutes using a microwave. Upon cooling the reaction was diluted with EtOAc [(25MOI)] and washed with dil. NaHCO3, dil. [HCI] and brine, dried [(MGS04),] filtered and concentrated. The residue was purified by column chromatography using a Si SPE cartridge (5g) eluting in [1-20%] EtOAc/i-hex. to give the title compound (50mg, 34%). LC/MS t=4.39 min [[MH+]] 562/564.
  • 21
  • [ 632627-17-9 ]
  • [ 22235-25-2 ]
  • 3-{2-[5-fluoro-2-(4-fluorobenzyloxy)phenyl]-5-methyl-pyrrol-1-yl}-5-trifluoromethyl-benzoic acid methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
47% toluene-4-sulfonic acid; In acetonitrile; at 160℃; for 0.166667h;Microwave irradiation; [1- [5-FLUORO-2- (4-FLUORO-BENZYLOXY)-PHENYL]-PENTANE-1,] 4-dione (0.15g, 0. [47MMOL),] 3-amino- [5-TRIFLUOROMETHYL-BENZOIC] acid methyl ester (0.099g, 0. [47MMOL)] and [P-TSA] (cat. ) in CH3CN [(1ML)] were heated in a sealed vessel at [160C] for 10 minutes using a microwave. Upon cooling the reaction was diluted with [CH2CI2] (5ml) and shaken with dil. [HCI] [(1] ml). The organics were separated using a phase separator column with a NaS04 cartridge attached and concentrated. The residue was purified by column chromatography using [BIOTAGE 25M] cartridge, [WITH ISO-HEXANE/ETOAC] (5-50%) as eluant, to give the title compound [(110MG,] 47%). LC/MS t=4.16 min [MH+] 502.
  • 22
  • [ 632627-48-6 ]
  • [ 22235-25-2 ]
  • 3-{2-[5-chloro-2-(4-bromo-2-fluorobenzyloxy)phenyl]-5-methyl-pyrrol-1-yl}-5-trifluoromethylbenzoic acid methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
36% With toluene-4-sulfonic acid; In acetonitrile; at 160℃; for 0.166667h;Microwave irradiation; [1- [5-CHLORO-2- (4-BROMO-2-FLUORO-BENZYLOXY)-PHENYL]-PENTANE-1,] 4-dione (150mg, 0. [363MMOL),] <strong>[22235-25-2]3-amino-5-trifluoromethylbenzoic acid methyl ester</strong> (80mg, 0. [363MOL)] and [PTSA] (5mg) were heated in [ACETONITRILE (2ML)] at [160C] for 10 minutes in the microwave. Upon cooling, the mixture was diluted with DCM and washed with 2M HCI, dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography, on silica, with cyclohexane containing a gradient of EtOAc (0-5%) to give the title compound (78mg, 36%). [1H] NMR [(400MHZ,] [CDCI3)] 2.18 (3H, s), 3.90 (3H, s), 4.70 (2H, s), 6.16 (1 H, d, J=3. 0Hz), 6.30 (1H, d, J=3.3Hz), 6.60 (1H, d, J=8.8Hz), 6.85-6. 91 (1H, m), 7.10-7. 15 (1H, m), 7.21 (1H, s), 7.23 (1H, s), 7.26-7. 29 (1H, m's excess), 7.39 (1H, s), 7.84 (1H, s), 8.15 (1H, s).
  • 23
  • [ 632627-55-5 ]
  • [ 22235-25-2 ]
  • 3-{2-[5-chloro-2-(2,6-difluorobenzyloxy)phenyl]-5-methyl-pyrrol-1-yl}-5-trifluoromethylbenzoic acid methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
32% With toluene-4-sulfonic acid; In acetonitrile; at 160℃; for 0.166667h;Microwave irradiation; [1- [5-CHLORO-2- (2, 6-DIFLUORO-BENZYLOXY)-PHENYL]-PENTANE-1,] 4-dione (150mg, 0. [43MMOL),] 3- [AMINO-5-TRIFLUOROMETHYLBENZOIC] acid methyl ester (93mg, 0. 43mmol) and [PTSA] (5mg) were heated in acetonitrile (2ml) at [160C] for 10 minutes in the microwave. Upon cooling, the mixture was diluted with DCM and washed with 2M HCI, dried [(NA2SO4),] filtered and concentrated. The residue was purified by chromatography, on silica, with cyclohexane containing a gradient of EtOAc (0-5%) to give the title compound (73mg, [32%).] 'H NMR [(400MHZ,] [CDCI3)] 2.15 (3H, s), 3.93 (3H, s), 4.78 (2H, s), 6.09 [(1H,] d, J=3.5Hz), 6.25 (1H, d, J=3.5Hz), 6. 81 (1H, d, J=8.5Hz), 6.83-6. 91 (2H, m), 7.12-7. 18 (2H, m), 7.26- 7.34 (1H, m's excess), 7.39 (1H, s), 7.86 (1H, s), 8.15 (1H, s).
  • 24
  • [ 632627-62-4 ]
  • [ 22235-25-2 ]
  • 3-{2-[5-chloro-2-(2,3-difluorobenzyloxy)phenyl]-5-methyl-pyrrol-1-yl}-5-trifluoromethylbenzoic acid methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
48% With toluene-4-sulfonic acid; In acetonitrile; at 160℃; for 0.166667h;Microwave irradiation; [1- [5-CHLORO-2- (2, 3-DIFLUORO-BENZYLOXY)-PHENYL]-PENTANE-1, 4-DIONE] (150mg, 0. [43MMOL),] 3- amino-5-trifluoromethylbenzoic acid methyl ester (93mg, 0. [43MMOL)] and [PTSA] (5mg) were heated in acetonitrile (2ml) at [160C] for 10 minutes in the microwave. Upon cooling, the mixture was diluted with DCM and washed with 2M HCI, dried [(NA2SO4),] filtered and concentrated. The residue was purified by chromatography, on silica, with cyclohexane containing a gradient of EtOAc (0-5%) to give the title compound [(107MG,] 48%). 'H NMR [(400MHZ,] CDCI3) 2.17 (3H, s), 3.90 (3H, s), 4.77 (2H, s), 6.16 [(1H,] d, J=3. 0Hz), 6.31 (1H, d, J=3.5Hz), 6.62 (1H, d, J=8.8Hz), 6.71-6. 77 (1H, m), 6.96-7. 03 (1H, m), 7.06- 7.16 (2H, m), 7.25-7. 31 (1H, m's excess), 7.39 (1H, s), 7.84 (1H, s), 8.15 (1H, s)
  • 25
  • [ 632627-76-0 ]
  • [ 22235-25-2 ]
  • 3-{2-[5-methyl-2-(4-fluorobenzyloxy)phenyl]-5-methyl-pyrrol-1-yl}-5-trifluoromethylbenzoic acid methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
toluene-4-sulfonic acid; In 1-methyl-pyrrolidin-2-one; at 150℃; for 0.166667h;Microwave irradiation; 1- [5-Methyl-2- (4-fluoro-benzyloxy)-phenyl]-pentane-1, 4-dione [(110MG),] 3-amino-5- trifluoromethyl-benzoic acid methyl ester (96mg) and [PTSA] (cat) were heated in NMP at [150C] in a microwave for 10 minutes. The mixture was diluted with EtOAc and washed sequentially with 2M [HCI] and saturated NaHCO3, dried (Na2SO4), filtered and concentrated. The residue was purified on silica gel with iso-hexane containing EtOAc (3- 6%) to give the title compound. LC/MS t=4.28 min, [MH+] 498.
YieldReaction ConditionsOperation in experiment
100% Intermediate 47: Methyl 3-amino-5-(trifluoromethyl)benzoate Methanol (20 ml) was added to intermediate 46 (5.0 g, 20 mmol) to prepare a solution, and 3.0 g of 10% palladium-carbon was added to the solution. The mixturewas stirred in a hydrogen atmosphere at room temperature for 23.5 hr. The insolubles were filtered and were concentrated under the reduced pressure to give the title compound (4.3 g, 100%). Physicochemical properties of intermediate 47
  • 27
  • [ 326-90-9 ]
  • [ 22235-25-2 ]
  • [ 1202635-15-1 ]
  • 28
  • [ 22235-25-2 ]
  • [ 1214361-12-2 ]
YieldReaction ConditionsOperation in experiment
Reference Example 29 Methyl 3-chloro-5-(trifluoromethyl)benzoate To a stirred solution of <strong>[22235-25-2]methyl 3-amino-5-(trifluoromethyl)benzoate</strong> (Reference Example 28, 2.15 g, 9.81 mmol) in acetonitrile (50.0 mL) was added tert-butyl nitrite (3.04 g, 29.48 mmol) at room temperature. After 15 min copper(II) chloride (2.38 g, 17.70 mmol) was added and the reaction mixture was stirred overnight. After this time, the mixture was diluted with ethyl acetate, washed with water, saturated ammonium hydrochloride, and saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure to provide methyl 3-chloro-5-(trifluoromethyl)benzoate (2.20 g, 94%) as a brown oil, which was used without further purification or characterization.
  • 29
  • [ 22235-25-2 ]
  • [ 886496-87-3 ]
  • 30
  • [ 22235-25-2 ]
  • [ 477535-43-6 ]
  • 31
  • [ 22235-25-2 ]
  • [ 1252657-92-3 ]
  • 32
  • [ 24424-99-5 ]
  • [ 22235-25-2 ]
  • [ 1395416-25-7 ]
YieldReaction ConditionsOperation in experiment
76% With dmap; In dichloromethane; at 20℃; for 2h; To a solution of <strong>[22235-25-2]3-amino-5-trifluoromethyl-benzoic acid methyl ester</strong> (2 g, 9.13 mmol, CAS RN 22235-25-2) in CH2Cl2 (30 mL) was added di-tert-butyl dicarbonate (1.99 g, 9.13 mmol, CAS RN 24424-99-5) and DMAP (1.11 g, 9.13 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was treated with silica gel and concentrated under vacuum and purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 70:30). Colorless solid (76%). MS (GC_MS (EI)): 319.1 (M+).
76% With dmap; In dichloromethane; at 20℃; for 2h; To a solution of <strong>[22235-25-2]3-amino-5-trifluoromethyl-benzoic acid methyl ester</strong> (2 g, 9.13 mmol, CAS RN 22235-25-2) in CH2C12 (30 mL) was added di-ie/ -butyl dicarbonate (1.99 g, 9.13 mmol, CAS RN 24424-99-5) and DMAP (1.11 g, 9.13 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was treated with silica gel andconcentrated under vacuum and purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane : EtOAc (100 : 0 to 70 : 30). Colorless solid (76%). MS (GC_MS (EI)): 319.1 (M+).
  • 33
  • [ 22235-25-2 ]
  • (S)-methyl 2-(4-((2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)carbamoyl)phenylsulfonamido)-3-(3-(4-(pyrimidin-2-ylamino)piperidin-1-yl)-5-(trifluoromethyl)benzamido)propanoate [ No CAS ]
  • 34
  • [ 22235-25-2 ]
  • C36H45F3N10O9S [ No CAS ]
  • 35
  • [ 22235-25-2 ]
  • (S)-2-(4-((2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyI)carbamoyI)phenyIsulfonamido)-3-(3-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)-5-(trifIuoromethy1)benzamido)propanoic acid [ No CAS ]
 

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