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Chemical Structure| 17794-48-8

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2-(3-(Trifluoromethyl)benzamido)acetic acid

CAS No.: 17794-48-8

4.5 *For Research Use Only !

Cat. No.: A339960 Purity: 95%

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Product Details of [ 17794-48-8 ]

CAS No. :17794-48-8
Formula : C10H8F3NO3
M.W : 247.17
SMILES Code : O=C(O)CNC(C1=CC=CC(C(F)(F)F)=C1)=O
MDL No. :MFCD00029782
InChI Key :ZDGGJQMSELMHLK-UHFFFAOYSA-N
Pubchem ID :2777432

Safety of [ 17794-48-8 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H319
Precautionary Statements:P305+P351+P338

Calculated chemistry of [ 17794-48-8 ] Show Less

Physicochemical Properties

Num. heavy atoms 17
Num. arom. heavy atoms 6
Fraction Csp3 0.2
Num. rotatable bonds 5
Num. H-bond acceptors 6.0
Num. H-bond donors 2.0
Molar Refractivity 51.02
TPSA ?

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

66.4 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.23
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

2.11
Log Po/w (WLOGP)?

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

2.67
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.

1.84
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

1.78
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.93

Water Solubility

Log S (ESOL):?

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

-2.63
Solubility 0.576 mg/ml ; 0.00233 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.

-3.14
Solubility 0.181 mg/ml ; 0.000733 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

-3.07
Solubility 0.211 mg/ml ; 0.000853 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

No
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.

-6.31 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.

0.56

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

0.0 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)

1.52

Application In Synthesis [ 17794-48-8 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 17794-48-8 ]

[ 17794-48-8 ] Synthesis Path-Downstream   1~24

  • 1
  • [ 17794-48-8 ]
  • [ 189700-10-5 ]
  • 4-[1-(2,3-Bis-benzyloxy-4-methoxy-phenyl)-meth-(Z)-ylidene]-2-(3-trifluoromethyl-phenyl)-4H-oxazol-5-one [ No CAS ]
  • 3
  • [ 2251-65-2 ]
  • [ 56-40-6 ]
  • [ 17794-48-8 ]
YieldReaction ConditionsOperation in experiment
95% A 12-L 4-neck round bottom flask equipped with a thermocouple controller, mechanical stirrer, heating mantle, condenser and a nitrogen in/outlet adapter was charged with gycine (1, Alfa Aesar) (318 g; 4.19 mol), acetonitrile (1.2 L), and a solution of sodium hydroxide (5.31 L; 10.62 mo) and the mixture was cooled to 4 C. with stirring. A solution of 3-(trifluoromethyl)benzoyl chloride (2, Alfa Aesar) (885.0 g; 4.12 mol) (640 mL) in acetonitrile (0.75 L) (total 1.39 L) was added dropwise over 2 h while the internal temperature was maintained between 4-6 C., and the slightly orange-pinkish solution was stirred at 4 C. for an additional 30 min. The reaction was acidified to pH=3 with conc. 37% HCl solution (400 mL added over 30 min) at 0-6 C., and stirred for 1 h at 0 C. (until a slightly yellowish suspension resulted). The solid was collected by filtration, washed with cold (0 C.) deionized ("D.I") H2O (300 mL*2), dried under air-suction for 2 h, and then placed in a drying oven at 60 C. under house vacuum (120 mmHg) for 20 h to afford pure 3 as an off-white solid. The filtrate was extracted with EtOAc (1 L*2), and the combined organic phases washed with brine (300 mL), and concentrated at 66 C. under house vacuum and then high vacuum (20 mmHg) to give crude product as an off-white waxy solid, which was triturated and sonicated with toluene (1 L) and stirred at 10 C. for 1 h. The resulting solid was collected by filtration, washed with hexanes (50 mL*2), dried in an vacuum oven at 50 C. under house vacuum to afford additional pure title compound, 3, as an off-white solid. The structure of 3 was confirmed with its 1H-NMR.
91% With hydrogenchloride; sodium hydroxide; In acetonitrile; at 0 - 3℃; for 1h;pH 2 - 3; Manufacturing example 1: (3-trifluoromethylbenzoylamino)-acetic acid [Show Image] Glycine 0.763 g (10.16 mmol) were suspended in acetonitrile 20 ml and 2 M NaOH aqueous solution 12.7 ml (25.40 mmol, 2.5 eq.) were also added. After chilling at 0-3C, 2.12 g (10.16 mmol, 1.0 eq.) of 3- (trifluoromethyl) -benzoyl chloride were diluted with 4 ml acetonitrile and added dropwise slowly to reaction mixture. After one hour agitation at the same temperature, pH was controlled to 2 to 3 with 3N hydrochloric acid aqueous solution. After keeping upright at room temperature, upper organic solution was separated, and lower aqueous solution was extracted with ethylacetate three times. Those organic solutions obtained as described above were brought all together, dried with anhydrous magnesium sulfate and concentrated, removing the solvent under decompression. Residues were solidified with toluene, filtered, washed with normal hexane and 2.28 g (91%) target compound as white solid were yielded. 1H NMR(400MHz,DMSO-d6) 3.94(2H,d), 7.74(1H,t), 7.93(1H,d), 8.16(1H,d), 8.20(1H,s), 9.12(1H,t)
91% With hydrogenchloride; sodium hydroxide; In water; acetonitrile; at 0 - 3℃; for 1h;pH 2 - 3; Manufacturing Example 1 (3-trifluoromethylbenzoylamino)-acetic acid Glycine 0.763 g (10.16 mmol) was suspended into acetonitrile 20 ml and 2M NaOH aqueous solution 12.7 ml (25.40 mmol, 2.5 eq.) was also added. After chilling at 0-3 C., 2.12 g (10.16 mmol, 1.0 eq.) of 3-(trifluoromethyl)-benzoyl chloride was diluted with 4 ml acetonitrile and was added dropwise slowly to reaction mixture. After one hour agitation at same temperature, pH was controlled to 2 to 3 with 3N hydrochloric acid aqueous solution. After keeping upright at room temperature, upper organic solution was separated, and lower aqueous solution was extracted with ethylacetate three times. Those organic solution obtained as above was brought all together, dried with anhydrous magnesium sulfate and concentrated removing its solvent under decompression. Residues was solidified with tolene, filtered, washed with normal hexane and 2.28 g (91%) target compound as white solid was yielded. 1H NMR (400 MHz, DMSO-d6) 3.94 (2H, d), 7.74 (1H, t), 7.93 (1H, d), 8.16 (1H, d), 8.20 (1H, s), 9.12 (1H, t)
90% (3-Trifluoromethyl-benzoylamino)acetic acid. To a rapid stirring solution of glycine (15.014 g, 0.20 mol) in MeCN (400 mL) and 2 M NaOH (250 mL) at 0 C. was slowly added a solution of 3-(trifluoromethyl)-benzoyl chloride (41.714 g, 0.20 mol) in 75 mL of MeCN over 30 min. The cloudy yellow solution was stirred at 0 C. for 30 min. The reaction mixture was acidified with 3 M HCl to pH=3, followed by removal of MeCN on rotary evaporator. The resulting mixture was then extracted with EtOAc (400 mL×3). The combined organic layers were dried, filtered and concentrated to give a light yellow solid (48.53 g), which was triturated with toluene (500 mL). After filtration, the solid product was washed with cold toluene until the filtrate was colorless. After dried under high vacuum over the weekend, a white powder product: 44.60 g (90%) was afforded. MS (M+H+)=248.1. 1H NMR (DMSO-d6) delta 12.70 (br s, 1 H), 9.17 (m, 1H), 8.20 (dd, 2H), 7.94 (dd, 1H), 7.78 (m, 1H), 3.97 (d, 2H).
90% Step A(3-Trifluoromethyl-benzoylamino)acetic acid. To a rapid stirring solution of glycine (15.014 g, 0.20 mol) in MeCN (400 mL) and 2 M NaOH (250 mL) at 0 C was slowly added a solution of 3-(trifluoromethyl)-benzoyl chloride (41.714 g, 0.20 mol) in 75 mL of MeCN over 30 min. The cloudy yellow solution was stirred at 0 C for 30 min. The reaction mixture was acidified with 3 M HCI to pH = 3, followed by removal of MeCN on rotary evaporator. The resulting mixture was then extracted with EtOAc (400 mL x 3). The combined organic layers were dried, filtered and concentrated to give a light yellow solid (48.53 g), which was triturated with toluene (500 mL). After filtration, the solid product was washed with cold toluene until the filtrate was colorless. After dried under high vacuum over the weekend, a white powder product: 44.60 g (90%) was afforded. MS (M+H+) = 248.1. 1H NMR (DMSO-d6) delta 12.70 (br s, 1 H), 9.17 (m, 1 H), 8.20 (dd, 2H), 7.94 (dd, 1 H), 7.78 (m, 1 H), 3.97 (d, 2H).
With sodium hydroxide; PREPARATION 1 Synthesis of N-(3-trifluoromethylbenzoyl)aminoacetic acid 5.5 of 3-trifluoromethylbenzoyl chloride were dropped slowly onto 15 ml of an aqueous solution containing 2.0 g of glycine and 2.1 g of sodium hydroxide, and then, after the dropwise addition was complete, the reaction solution was heated at 70 C. for 2 hours, with stirring. The mixture was allowed to stand to cool, and then the reaction solution was washed with ethyl acetate, the aqueous layer was neutralized with 8N hydrochloric acid, and the crystals which separated out were filtered to afford 4.6 g of the title compound, after drying.
With sodium hydroxide; at 20℃; for 4h; Add 10 mL of 10% NaOH solution to a 50 mL three-necked flask, add 0.75 g of glycine to dissolve, slowly add 2.14 g of m-trifluoromethylbenzoyl chloride, stir at room temperature for 4 h, adjust the pH to 1-2 with hydrochloric acid, and precipitate a white solid. The ethyl acetate was recrystallized and purified to carry out the next condensation reaction.Take compound VII 1.0mmol, prepared carboxylic acid 1.0mmol in 20mL CH2Cl2, temperatureControl about 0 C, add 1.2 mmol EDCI, 2.0 mmol DIPEA, 1.2 mmol HOBt, then stir at room temperature overnight. The reaction solution was washed with 10 mL 5% HCl solution, 10 mL 5% NaHCO3 solution, 10 mL saturated brine. After two times, it was dried over anhydrous Na 2 SO 4 and then dried. White solid, yield 63%;

  • 4
  • [ 17794-48-8 ]
  • [ 122-51-0 ]
  • 4-[1-Ethoxy-meth-(Z)-ylidene]-2-(3-trifluoromethyl-phenyl)-4H-oxazol-5-one [ No CAS ]
  • 5
  • [ 17794-48-8 ]
  • [ 61695-07-6 ]
  • <i>N</i>-[1-(4-chloro-benzyl)-pyrrolidin-3-ylcarbamoyl]-methyl}-3-trifluoromethyl-benzamide [ No CAS ]
  • 6
  • [ 17794-48-8 ]
  • [ 226249-01-0 ]
  • N-[2-[[(3R)-1-[(4-chlorophenyl)methyl]-3-pyrrolidinyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide [ No CAS ]
  • 7
  • [ 17794-48-8 ]
  • (3S)-1-(4-Chlorobenzyl)-3-pyrrolidinamine [ No CAS ]
  • (S)-1-(4-chlorobenzyl)-3-[N-{3-(trifluoromethyl)benzoyl}glycyl]aminopyrrolidine [ No CAS ]
  • 8
  • [ 17794-48-8 ]
  • [ 226249-34-9 ]
  • <i>N</i>-[1-(4-chloro-benzyl)-piperidin-3-ylcarbamoyl]-methyl}-3-trifluoromethyl-benzamide [ No CAS ]
  • 9
  • [ 17794-48-8 ]
  • (S)-2-(aminomethyl)-1-(4-chlorobenzyl)pyrrolidine [ No CAS ]
  • <i>N</i>-([1-(4-chloro-benzyl)-pyrrolidin-2-ylmethyl]-carbamoyl}-methyl)-3-trifluoromethyl-benzamide [ No CAS ]
  • 10
  • [ 17794-48-8 ]
  • <i>C</i>-[1-(4-chloro-benzyl)-pyrrolidin-2-yl]-methylamine [ No CAS ]
  • <i>N</i>-([1-(4-chloro-benzyl)-pyrrolidin-2-ylmethyl]-carbamoyl}-methyl)-3-trifluoromethyl-benzamide [ No CAS ]
  • 11
  • [ 17794-48-8 ]
  • [ 226249-40-7 ]
  • <i>N</i>-([1-(4-chloro-benzyl)-piperidin-4-ylmethyl]-carbamoyl}-methyl)-3-trifluoromethyl-benzamide [ No CAS ]
  • 12
  • [ 17794-48-8 ]
  • [ 60737-12-4 ]
  • <i>N</i>-([1-(4-chloro-benzyl)-pyrrolidin-2-ylmethyl]-carbamoyl}-methyl)-3-trifluoromethyl-benzamide [ No CAS ]
  • 13
  • [ 17794-48-8 ]
  • 5-Methyl-2-[5-oxo-2-(3-trifluoromethyl-phenyl)-oxazol-(4E)-ylidenemethyl]-amino}-benzoic acid [ No CAS ]
  • 14
  • [ 17794-48-8 ]
  • 5-Bromo-2-[5-oxo-2-(3-trifluoromethyl-phenyl)-oxazol-(4E)-ylidenemethyl]-amino}-benzoic acid [ No CAS ]
  • 15
  • [ 17794-48-8 ]
  • 5-Chloro-2-[5-oxo-2-(3-trifluoromethyl-phenyl)-oxazol-(4E)-ylidenemethyl]-amino}-benzoic acid [ No CAS ]
  • 16
  • [ 17794-48-8 ]
  • [ 50910-54-8 ]
  • [ 847956-35-8 ]
YieldReaction ConditionsOperation in experiment
Trans-4-aminocyclohexanol hydrochloride (500 mg) was dissolved DMF (11 mL) prior to the addition of <strong>[17794-48-8](3-trifluoromethyl-benzoylamino)-acetic acid</strong> (815.0 mg) and 4-methylmorpholine (1.0 mL). After 5 min, BOP reagent (1.4 g) was added and the reaction was stirred overnight. Ethyl acetate was added, and the solution was washed with brine, 1N HCl, and saturated NaHCO3. The desired (trans)-N-[(4-hydroxy-cyclohexylcarbamoyl)-methyl]-3-trifluoromethyl-benzamide (480.5 mg) was then collected as a solid. MS found: (M+H)+=345.1.
  • 17
  • [ 847956-57-4 ]
  • [ 17794-48-8 ]
  • [ 847956-58-5 ]
YieldReaction ConditionsOperation in experiment
With N,N-diethyl-N-isopropylamine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; In DMF (N,N-dimethyl-formamide); dichloromethane; at 20℃; for 12h; Step 3 A sample of [(1R,3R,4S)-4-amino-3-(3-methyl-butyl)-cyclohexyl]-carbamic acid tert-butyl ester (50 mg, 0.18 mmol) was dissolved in 1:1 CH2Cl2/DMF (2 mL). The resultant solution was charged successively with N,N-diethylisopropylamine (0.16 mL, 0.9 mmol), <strong>[17794-48-8](3-trifluoromethyl-benzoylamino)-acetic acid</strong> (47 mg, 0.19 mmol, prepared as described in WO PCT 0250019), and BOP (116 mg, 0.26 mmol). The reaction was stirred for 12 h at RT and then partitioned between EtOAc and sat. NaHCO3; the aqueous phase was back extracted with EtOAc (1*). The organic phases were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by silica gel chromatography afforded {(1R, 3R,4S)-3-(3-methyl-butyl)-4-[2-(3-trifluoromethyl-benzoylamino)-acetylamino]-cyclohexyl}-carbamic acid tert-butyl ester (33 mg). MS found: (M+H)+=514.3.
  • 18
  • [ 847956-84-7 ]
  • [ 17794-48-8 ]
  • tert-butyl (1R,3R,4S)-3-(methoxymethyl)-4-(2-(3-(trifluoromethyl)benzamido)acetamido)cyclohexylcarbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 2.75h; Step 3 A solution of tert-butyl (1R,3R,4S)-4-amino-3-(methoxymethyl)cyclohexylcarbamate (45 mg, assumed 0.163 mmol) in acetonitrile (1.5 mL) was treated sequentially with <strong>[17794-48-8]2-(3-(trifluoromethyl)benzamido)acetic acid</strong> (43 mg, 0.174 mmol, see PCT WO 0250019), diisopropylethylamine (61 muL, 0.348 mmol) and TBTU (62 mg, 0.192 mmol). The mixture was stirred at rt for 2.75 h, then was diluted with ethyl acetate, washed sequentially with 1.0 M aqueous HCl, saturated aqueous NaHCO3, water and brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluding with 1:3 v/v hexane-ethyl acetate, to provide tert-butyl (1R,3R,4S)-3-(methoxymethyl)-4-(2-(3-(trifluoromethyl)benzamido)acetamido)cyclohexylcarbamate as a white solid (48 mg). MS found: (M+H)+=488.3.
  • 19
  • [ 795307-81-2 ]
  • [ 17794-48-8 ]
  • [ 845797-02-6 ]
YieldReaction ConditionsOperation in experiment
With 4-methyl-morpholine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 0 - 20℃; (8a) (2S, 3S)-(2-Amino-3-hydroxy-hex-4-ynyl)-carbamic acid benzyl ester (2.53 g, prepared as in WO PCT 0250019) was dissolved in CH2Cl2 (50 ml) and 4-methylmorpholine (2.53 ml) and cooled to 0 C. prior to the addition of <strong>[17794-48-8](3-trifluoromethyl-benzoylamino)-acetic acid</strong> (1.49 g) and HATU (2.23 g). After the reaction was stirred overnight at room temperature, the CH2Cl2 was removed and EtOAc was added. The organic layer was washed with saturated NH4Cl solution (aq) brine, dried, filtered, and concentrated. Flashed chromatography of the resulting residue gave (2S, 3S)-{3-hydroxy-2-[2-(3-trifluoromethyl-benzoylamino)-acetylamino]-hex-4-ynyl}-carbamic acid benzyl ester (1.3 g). MS found: (M+H)+=492.3.
  • 20
  • [ 1379330-80-9 ]
  • [ 17794-48-8 ]
  • N-(2-(cis-4-((isopropyl(methyl)amino)methyl)cyclohexylamino)-2-oxoethyl)-3-(trifluoromethyl)benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine; In DMF (N,N-dimethyl-formamide); dichloromethane; A sample of (1s,4s)-4-(aminomethyl)-N,N-dibenzylcyclohexanamine (0.475 g) was taken through the procedure of Example 1h, Step 1 to give (1s,4s)-N,N-dibenzyl-4-((isopropyl(methyl)amino)methyl)cyclohexanamine (280 mg). This material was hydrogenated according to the procedure of Example 1h, Step 4 to give (1s,4s)-4-((isopropyl(methyl)amino)methyl)cyclohexanamine. The entirety of this sample (95 mg) was dissolved in methylene chloride (5 mL) and DMF (2 mL). The resultant solution was charged successively with <strong>[17794-48-8](3-trifluoromethyl-benzoylamino)-acetic acid</strong> (127 mg), PyBOP (268 mg), and triethylamine (0.14 mL). The mixture was stirred overnight and diluted with methylene chloride before being washed with water thrice. The organic phase was then washed with sat. sodium bicarbonate, dried (sodium sulfate), filtered, and concentrated in vacuo. The residue was purified by RP-HPLC to afford the title compound as an oil (5 mg). MS found: (M+H)+=414.
  • 21
  • [ 845797-28-6 ]
  • [ 17794-48-8 ]
  • [ 845797-02-6 ]
YieldReaction ConditionsOperation in experiment
With 4-methyl-morpholine; HATU; In dichloromethane; at 0 - 20℃; (8a) (2S, 3S)- (2-AMINO-3-HYDROXY-HEX-4-YNYL)-CARBAMIC acid benzyl ester (2.53 g, prepared as in WO PCT 0250019) was dissolved in CH2CL2 (50 ml) and 4-methylmorpholine (2.53 ml) and cooled to 0 C prior to the addition of (3- TRIFLUOROMETHYL-BENZOYLAMINO)-ACETIC acid (1.49 g) and HATU (2.23 g). After the reaction was stirred overnight at room temperature, the CH2CL2 WAS removed and EtOAc was added. The organic layer was washed with saturated NH4Cl solution (aq) brine, dried, filtered, and concentrated. Flashed chromatography of the resulting residue gave (2S, 3S)- {3-HYDROXY-2- [2- (3-TRIFLUOROMETHYL-BENZOYLAMINO)- ACETYLAMINO]-HEX-4-YNYL}-CARBAMIC acid benzyl ester (1.3 g). MS found : (M+H) + = 492. 3.
  • 22
  • [ 17794-48-8 ]
  • [ 122536-76-9 ]
  • [ 857650-89-6 ]
YieldReaction ConditionsOperation in experiment
96% With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; tert-Butyl [(3S)-1-([3-(Trifluoromethyl)benzoyl]amino}acetyl)pyrrolidin-3-yl]carbamate. To a solution of the carboxylic acid (2.7 g, 11 mmol) from step A and tert-butyl (3S)-pyrrolidin-3-ylcarbamate (2.0 g, 11 mmol) in DMF (30 mL) cooled in an ice bath was added BOP (5 g, 11 mmol) followed by triethylamine (3 mL, 22 mmol). The mixture was allowed to warm to temperature and stirred overnight. Ethyl acetate (150 mL) was added. The resulting solution was washed with NaHCO3 and brine each three times, dried over MgSO4 and concentrated. Chromatography on silica gel eluting with EtOAc provided 4.4 g (96%) of the desired product. MS (M-Boc+H)+ 316.
96% With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃;cooling with ice; Step BBocHN'tert-Butyl [(3S)-1 -([3-(Trifluoromethyl)benzoyl]amino}acetyl)pyrrolidin-3-yl]carbamate. To a solution of the carboxylic acid (2.7 g, 1 1 mmol) from step A and tert-butyl (3S)-pyrrolidin-3-ylcarbamate (2.0 g, 1 1 mmol) in DMF (30 mL) cooled in an ice bath was added BOP (5 g, 1 1 mmol) followed by triethylamine (3 mL, 22 mmol). The mixture was allowed to warm to temperature and stirred overnight. Ethyl acetate (150 mL) was added. The resulting solution was washed with NaHC03 and brine each three times, dried over MgS04 and concentrated. Chromatography on silica gel eluting with EtOAc provided 4.4 g (96%) of the desired product. MS (M-Boc+H)+ 316.
  • 23
  • [ 857651-11-7 ]
  • [ 17794-48-8 ]
  • [ 857651-12-8 ]
YieldReaction ConditionsOperation in experiment
81% With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 4h; (3R,5R)-5-Methylpyrrolidin-3-ol hydrochloride (1.80 g, 13 mmol) was dissolved in dichloromethane (50 mL) and diisopropylethylamine (2.1 mL, 12.0 mmol) under nitrogen. (3-Trifluoromethyl-benzoylamino)-acetic acid (2.93 g, 11.85 mmol) was added followed by EDC (3.41 g, 17.8 mmol) and the mixture was stirred at room temperature for four hours. The mixture was diluted with NH4Cl/H2O and extracted twice with ethyl acetate. The combined extracts were washed with NaHCO3/H2O and brine, dried over MgSO4, filtered and concentrated to give a dark orange oil. Chromatography on silica gel eluting with ethyl acetate to 5% methanol/ethyl acetate gave the coupled product as a pale orange solid, 3.19 g (81%, 2 steps). LC/MS (M+H)+ m/z=331.1. 1H NMR (CDCl3, major rotamer) delta 8.12 (s, 1H), 8.01 (d, 1H), 7.76 (d, 1H), 7.57 (t, 1H), 7.50 (m, 1H), 4.56 (m, 1H), 4.34 (m, 1H), 4.23 (m, 1H), 4.11 (m, 1H), 3.61 (dd, 1H), 3.51 (d, 1H), 2.71 (d, 1H), 2.17 (m, 1H), 1.81 (m, 1H), 1.32 (d, 3H).
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 4h;Inert atmosphere; Step GN-{2-[(2f?,4f?)-4-Hydroxy-2-methylpyrrolidin-1 -yl]-2-oxoethyl}-3-(trifluoro- methyl)benzamide. (3f?,5f?)-5-Methylpyrrolidin-3-ol hydrochloride (1.80 g) was dissolved in dichloromethane (50 mL) and diisopropylethylamine (2.1 mL, 12.0 mmol) under nitrogen. (3- Trifluoromethyl-benzoylamino)-acetic acid (2.93 g, 1 1.85 mmol) was added followed by EDC (3.41 g, 17.8 mmol) and the mixture was stirred at room temperature for four hours. The mixture was diluted with NH4CI/H20 and extracted twice with ethyl acetate. The combined extracts were washed with NaHC03/H20 and brine, dried over MgS04, filtered and concentrated to give a dark orange oil. Chromatography on silica gel eluting with ethyl acetate to 5% methanol/ethyl acetate gave the coupled product as a pale orange solid, 3.19 g (81 %, 2 steps). LC/MS (M+H)+ m/z = 331 .1. 1H NMR (CDCI3, major rotamer) delta 8.12 (s, 1 H), 8.01 (d, 1 H), 7.76 (d, 1 H), 7.57 (t, 1 H), 7.50 (m, 1 H), 4.56 (m, 1 H), 4.34 (m, 1 H), 4.23 (m, 1 H), 4.1 1 (m, 1 H), 3.61 (dd, 1 H), 3.51 (d, 1 H), 2.71 (d, 1 H), 2.17 (m, 1 H), 1.81 (m, 1 H), 1.32 (d, 3H).
  • 24
  • [ 857651-29-7 ]
  • [ 17794-48-8 ]
  • [ 857651-30-0 ]
YieldReaction ConditionsOperation in experiment
79% With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 4.5h;Heating / reflux; (2S,4R)-4-(Benzyloxy)-2-isopropylpyrrolidine (0.410 g, 1.90 mmol) was dissolved in dichloromethane (30 mL) under nitrogen. (3-Trifluoromethylbenzoylamino)-acetic acid (0.462 g; 1.90 mmol) was added followed by EDC (0.394 g, 2.06 mmol) and the mixture was stirred at room temperature-overnight. LC/MS revealed the reaction was not yet complete. More (3-Trifluoromethyl-benzoylamino)-acetic acid (0.12 g, 0.48 mmoles) and more EDC (0.30 g, 1.6 mmoles) were added and stirring continued for 3 hours at room temperature, then at reflux for 1.5 hours. The mixture was chromatographed on silica gel eluting with 30% ethyl acetate/hexane to provide 0.66 g (79%) of the coupled product as a colorless oil. LC/MS (M+H)+ m/z=449.2; 1H NMR (CDCl3) delta 8.03 (m, 1H), 7.76 (m, 1H), 7.58 (m, 2H), 7.34 (m, 5H), 4.52 (m, 2H), 4.03-4.34 (m, 4H), 3.65 (m, 1H), 3.48 (m, 1H), 2.54 (m, 1H), 2.12 (m, 1H), 1.92 (m, 1H), 0.92 (d, 3H), 0.77 (d, 3H).
79% With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;Inert atmosphere; Reflux; Step FN-{2-[(2S,4f?)-4-Benzyloxy-2-isopropylpyrrolidin-1-yl]-2-oxoethyl}-3- (trifluoromethyl)benzamide. (2S,4f?)-4-(Benzyloxy)-2-isopropylpyrrolidine (0.410 g, 1 .90 mmol) was dissolved in dichloromethane (30 mL) under nitrogen. (3-Trifluoromethyl- benzoylamino)-acetic acid (0.462 g, 1 .90 mmol) was added followed by EDC (0.394 g, 2.06 mmol) and the mixture was stirred at room temperature overnight. LC/MS revealed the reaction was not yet complete. More (3-Trifluoromethyl-benzoylamino)-acetic acid (0.12 g, 0.48 mmoles) and more EDC (0.30 g, 1 .6 mmoles) were added and stirring continued for 3 hours at room temperature, then at reflux for 1 .5 hours. The mixture was chromatographed on silica gel eluting with 30% ethyl acetate/hexane to provide 0.66 g (79%) of the coupled product as a colorless oil. LC/MS (M+H)+ m/z = 449.2; 1H NMR (CDCI3) delta 8.03 (m, 1 H), 7.76 (m, 1 H), 7.58 (m, 2H), 7.34 (m, 5H), 4.52 (m, 2H), 4.03-4.34 (m, 4H), 3.65 (m, 1 H), 3.48 (m, 1 H), 2.54 (m, 1 H), 2.12 (m, 1 H), 1 .92 (m, 1 H), 0.92 (d, 3H), 0.77 (d, 3H).
 

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