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[ CAS No. 848192-96-1 ] {[proInfo.proName]}

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Chemical Structure| 848192-96-1
Chemical Structure| 848192-96-1
Structure of 848192-96-1 * Storage: {[proInfo.prStorage]}
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Product Details of [ 848192-96-1 ]

CAS No. :848192-96-1 MDL No. :MFCD13248564
Formula : C4H7ClF3NO Boiling Point : -
Linear Structure Formula :- InChI Key :BWGPIPWVIWINLD-UHFFFAOYSA-N
M.W : 177.55 Pubchem ID :46735152
Synonyms :

Calculated chemistry of [ 848192-96-1 ]

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 0
Fraction Csp3 : 1.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 5.0
Num. H-bond donors : 2.0
Molar Refractivity : 34.3
TPSA : 32.26 Ų

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) : -6.9 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.0
Log Po/w (XLOGP3) : 0.68
Log Po/w (WLOGP) : 1.56
Log Po/w (MLOGP) : 0.39
Log Po/w (SILICOS-IT) : 1.18
Consensus Log Po/w : 0.76

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.3
Solubility : 8.83 mg/ml ; 0.0497 mol/l
Class : Very soluble
Log S (Ali) : -0.93
Solubility : 20.7 mg/ml ; 0.116 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.04
Solubility : 16.3 mg/ml ; 0.092 mol/l
Class : Soluble

Medicinal Chemistry

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

Safety of [ 848192-96-1 ]

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 [ 848192-96-1 ]

* 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 [ 848192-96-1 ]

[ 848192-96-1 ] Synthesis Path-Downstream   1~19

  • 1
  • 1-benzhydryl-3-(trifluoromethyl)azetidin-3-ol trifluoroacetate [ No CAS ]
  • [ 848192-96-1 ]
YieldReaction ConditionsOperation in experiment
92% With hydrogenchloride; hydrogen;palladium dihydroxide; palladium on carbon; In methanol; water; under 2585.81 Torr; for 5h; 3-(trifluoromethyl)azetidin-3-ol. To a solution of 1-benzhydryl-3-(trifluoromethyl)lazetidin-3-ol (200 mg, 0.47 mmol) in MeOH (10 mL), Pd(OH)2 with 20% Pd on carbon (200 mg) and 1N HCl solution (0.47 mL, 0.47 mmol) were added. The reaction mixture was shaken under a hydrogenator at 50 psi for 5 hr. The catalyst was filtered through celite and washed with methanol. The filtrate was concentrated and dried under vacuum. The residue was then washed with hexanes. The organic layer was decanted and an orange solid was obtained as final product as hydrochloride salt. (77 mg, 92% yield). MS m/z 142(MH+). 1H NMR (500 MHz, MeOD) ? ppm 4.14 (d, J=13.12 Hz, 2 H) 4.42 (d, J=12.82 Hz, 2 H).
  • 2
  • [ 848192-96-1 ]
  • (-)-cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide, 8-cyclohexyl-N[(dimethylamino)sulfonyl]-1,1a,2,12b-tetrahydro-1a-[(3hydroxy-3-trfluoromethyl-1-azetidinyl)carbonyl]-11-methoxy [ No CAS ]
YieldReaction ConditionsOperation in experiment
86% EXAMPLE 6 (-) Cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide, 8-cyclohexyl-N-[(dimethylamino)sulfonyl]-1,1a,2,12b-tetrahydro-1a-[(3-hydroxy-3-trifluoromethyl-1-azetidinyl)carbonyl]-11-methoxy-. To a solution of (-)cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid, 8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxy- (50 mg, 0.091 mmol) in DMSO (2.0 mL), TBTU (43.8 mg, 0.137 mmol) and DIPEA (0.095 mL, 0.546 mmol) were added. The reaction mixture was stirred at rt for 15 min. Then <strong>[848192-96-1]3-(trifluoromethyl)azetidin-3-ol hydrochloride</strong> (19.3 mg, 0.109 mmol) was added and the reaction mixture was stirred at rt. overnight. It was then concentrated and the residue was purified by Prep. HPLC column to give an off-white solid as final productproduct. (53 mg, 86% yield). MS m/z 675(MH+), Retention time: 2.253 min. 1H NMR (500 MHz, MeOD) delta ppm 0.10 (m, 0.22 H) 1.11-1.63 (m, 5.78 H) 1.67-2.21 (m, 6 H) 2.43 (m, 0.22 H) 2.58-2.71 (m, 0.78 H) 2.72-3.04 (m, 7.78 H) 3.30-3.35 (m, 1.56 H) 3.44-3.64 (m, 1.22 H) 3.73-3.94 (m, 4.22 H) 4.14 (d, J=14.65 Hz, 0.22 H) 4.89 (d, J=14.65 Hz, 0.22 H) 5.09 (d, J=15.26 Hz, 0.78 H) 6.95-7.00 (m, 1 H) 7.13 (s, 0.22H) 7.17 (d, J=2.14 Hz, 0.78 H)7.25 (d, J=8.85 Hz, 0.78 H) 7.29 (d, J=8.55 Hz, 0.22 H) 7.54-7.61 (m, 1 H) 7.84-7.90 (m, 1 H) 7.96 (s, 0.78 H) 8.08 (s, 0.22 H).
  • 4
  • [ 848192-96-1 ]
  • [ 1352076-83-5 ]
  • [ 1352065-34-9 ]
YieldReaction ConditionsOperation in experiment
To a solution of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo- l-((S)-l-oxobutan-2-yl)piperidin-3-yl)acetic acid (70 mg, 0.151 mmol; Example 210, Step A) in DCE (3 mL) was added 53.8 mg (0.303 mmol) of <strong>[848192-96-1]3-(trifluoromethyl)azetidin-3-ol hydrochloride</strong> (U. S. patent application publication no 2007/0275930) and sodiumtriacetoxyborohydride (64.2 mg, 0.303 mmol). After stirring for 18 hours, the mixture was partitioned between water and DCM. The aqueous layer was washed with DCM. The combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous Na2S04, filtered and the filtrate was concentrated. The residue was purified by preparative thin layer chromatography on silica gel (eluent: 50% ethyl acetate/hexanes) to afford the title compound.1H NMR (400 MHz, MeOH) delta ppm 0.51 (t, J=7.43 Hz, 3 H) 1.36 (s, 3 H) 1.50 - 1.66 (m, 1 H) 1.71 - 1.86 (m, 1 H) 2.09 - 2.26 (m, 2 H) 2.38 (dd, J=12.52, 3.91 Hz, 1 H) 2.52 - 2.64 (m, 1 H) 2.75 (br. s., 1 H) 2.93 (d, J=14.87 Hz, 1 H) 3.11 - 3.27 (m, 2 H) 3.28 - 3.43 (m, 3 H) 3.66 - 3.79 (m, 2 H) 4.62 (d, J=10.56 Hz, 1 H) 6.86 - 6.98 (m, 1 H) 7.03 (s, 1 H) 7.09 - 7.22 (m, 4 H) 7.27 (d, J=7.24 Hz, 2 H). Mass Spectrum (ESI) m/z = 587.2 (M+l).
  • 5
  • [ 848192-96-1 ]
  • [ 823-62-1 ]
  • 5-amino-6-chloro-3-N-(3-hydroxy-3-trifluoromethyl)azetidinyl-1,2,4-triazine [ No CAS ]
YieldReaction ConditionsOperation in experiment
100% With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 120℃; for 0.5h;Microwave irradiation; A vial was charged with 5-amino-3,6-dichloro-l ,2,4-triazine (290.27 mg, 1.759 mmol), diisopropylethylamine (1.5 mL, 8.61 mmol), 3-(trifluoromethyl)azetidin-3-ol HCl salt (371.5 mg, 2.093 mmol) in dioxane (3 mL). The mixture was heated at 120 C for 30 min using microwave. The mixture was concentrated to remove all of solvents. The residue was dissolved in dichloromethane, washed with aqueous sodium bicarbonate solution. Some brine was added. The organic solution was separated. The organic mixture was filtered and washed with dichloromethane to collect the white solid as product. The aqueous solution was saturated with sodium chloride, extracted with dichloromethane. The combined organic solution was concentrated to afford a residue. The residue was dissolved into a small of amount of warm dichloromethane, cooled. The solid was collected and washed with dichloromethane to afford second batch of product. The total yield was quantitative. NMR (500 MHz, Methanol-^) delta 4.30 (d, J = 10.0 Hz, 2H), 4.02 (d, J = 10.1 Hz, 2H). MS for C7H7C1F3N50: 270.0
  • 6
  • [ 848192-96-1 ]
  • [ 39919-65-8 ]
  • 1-(5-bromo-6-methyl-2-pyridyl)-3-(trifluoromethyl)azetidin-3-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
13.0% With N-ethyl-N,N-diisopropylamine; at 130℃; for 4h; 2,5 -dibromo-6-methylpyridine (1 .30 g, 5.18 mmo 1) and 3 -(trifluoromethyl)azetidin-3 -ol hydrochloride (1.00 g, 5.63 mmol) were added to a small RB flask with stirrer bar. N,Ndiisopropylethylamine (0.90 mL, 5.2 mmol) was added and the mixture heated to 130Cfor 4 hours. The mixture was cooled, diluted with dichloromethane (5OmL) and washed with sodium bicarbonate solution (5OmL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. Chromatography (silica, DCM gradient to 15% EtOAc in DCM) gave the title compound as a white solid (210 mg, 13.0% yield). 1H NMR (400 MHz, DMSO-d6) oe 7.70 (d, J= 8.7 Hz, 1H), 7.32 (s, 1H), 6.32 (dd, J= 8.7,0.7 Hz, 1H), 4.19 (dd, J 9.6, 1.0 Hz, 2H), 3.93 (dt, J= 9.4, 1.3 Hz, 2H), 2.42 (s, 3H). LC/MS Method 3: RT 2.02 minutes, mlz 313/315.
  • 7
  • [ 848192-96-1 ]
  • [ 1239358-93-0 ]
  • (S)-N-(cyclopropylcarboxylic)-1-{ 2-[ 1-(4-fluorophenyl)indolylethylamino]-6-(aminopyrazine-2-ylamino)pyrimidinecarboxylic-4-yl}azetidin-3-carboxamide hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
With tris(dibenzylideneacetone)dipalladium(0) chloroform complex; sodium t-butanolate; XPhos; In toluene; at 100℃; for 2h;Inert atmosphere; in deaerated toluene 6ml, (S) -4- {6- chloro-2- [1- (4-fluorophenyl) ethylamino] pyrimidin-4-yl} piperazin-2-one 196mg , 2-amino-pyrazine 55mg, 2- dicyclohexylphosphino-2 ', 4', successively added 6'-triisopropyl biphenyl 50mg, sodium t- butoxide 101mg and tris (dibenzylideneacetone) and (chloroform) dipalladium 27mg, under an argon atmosphere, the mixture was stirred for 2 hours at 100 . The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was distilled off, the resulting residue was purified by silica gel column chromatography to give the title compound 196mg as a pale brown powder.
  • 8
  • [ 848192-96-1 ]
  • 3-amino-5-(2-trifluoromethoxybenzenesulfonyl)pyridine-2-carboxylic acid [ No CAS ]
  • (3-amino-5-[2-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In 1-methyl-pyrrolidin-2-one; at 20℃; for 0.5h; Compound 85: (3-amino-5-[2-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)[3-hydroxy-3- (trifluoromethyl)azetidin-1-yl]methanone [00358] To a solution of 3-(trifluoromethyl)-azetidine-3-ol (HCl salt, CAS:848192-96-1, 23 mg, 0.13 mmol) in NMP (1 mL) and triethylamine (0.35 muL, 0.26 mmol), 3-amino-5-(2- trifluoromethoxy-benzenesulfonyl)-pyridine-2-carboxylic acid (Int 11, 45 mg, 0.13 mmol) and HATU (47 mg, 0.13 mmol) were added. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was added to water, sonicated and filtered. The solid was taken up again in water, sonicated and filtered, and washed with water and petroleum ether. Both the filtrate and solid were extracted with ethyl acetate. The combined organic fractions were washed with water and brine, dried over sodium sulfate, filtered and concentrated to dryness. The compound was purified by preparative chromatography to give the titled compound.
  • 9
  • [ 848192-96-1 ]
  • 3-amino-5-benzenesulfonylpyridine-2-carboxylic acid [ No CAS ]
  • [3-amino-5-(phenylsulfonyl)pyridin-2-yl][3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In 1-methyl-pyrrolidin-2-one; at 20℃; Compound 255: [3-amino-5-(phenylsulfonyl)pyridin-2-yl][3-hydroxy-3-(trifluoromethyl)azetidin- 1-yl]methanone [00369] 3-Amino-5-benzenesulfonyl-pyridine-2-carboxylic acid (Int 12, 200 mg, 0.72 mmol) was dissolved in NMP (4 mL) together with HATU (1-[bis(dimethylamino)methylene]-1H- 1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (301 mg, 0.79 mmol), triethylamine (221 muL, 1.58 mmol) and 3-(trifluoromethyl)azetidin-3-ol (HCl salt, CAS:848192- 96-1, 141 mg, 0.791 mmol). After overnight stirring at room temperature, the mixture was diluted with water to give a suspension. This suspension was filtered, and the obtained solid was purified using column chromatography (eluent gradient from 100% petroleum ether to 100% EtOAc) to give the titled compound.
  • 10
  • [ 848192-96-1 ]
  • 3-amino-5-(3-fluorobenzenesulfonyl)pyridine-2-carboxylic acid [ No CAS ]
  • {3-amino-5-[(3-fluorophenyl)sulfonyl]pyridin-2-yl}[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In 1-methyl-pyrrolidin-2-one; at 20℃; for 0.5h; Compound 256 : {3-amino-5-[(3-fluorophenyl)sulfonyl]pyridin-2-yl}[3-hydroxy-3- (trifluoromethyl)azetidin-1-yl]methanone [00370] To a solution of 3-(trifluoromethyl)-azetidine-3-ol (HCl salt, CAS:848192-96-1, 172 mg, 0.97 mmol) in NMP (6 mL) and triethylamine (0.25 mL, 1.76 mmol), 3-amino-5-(3-fluoro- benzenesulfonyl)-pyridine-2-carboxylic acid (Int 18, 260 mg, 0.88 mmol) and HATU (369 mg, 0.97 mmol) were added. The mixture was stirred at room temperature for 30 minutes. The mixture was added to water, and the precipitate was collected by filtration. The residue was 143 ABV12212USO1 triturated with water and diisopropyl ether. Water was added to obtain a suspension. The suspension was dried overnight on a freeze dryer to give the titled compound.
  • 11
  • [ 848192-96-1 ]
  • AN10248 [ No CAS ]
  • (3-hydroxy-3-(trifluoromethyl)azetidin-1-yl)(5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazin-2-yl)-methanone [ No CAS ]
  • 12
  • [ 848192-92-7 ]
  • [ 848192-96-1 ]
  • 13
  • [ 848192-96-1 ]
  • 4-chloro-5-(4-fluoro-3-methoxyphenyl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)imidazo[1,2-a]pyrazin-6-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one [ No CAS ]
  • 5-(4-fluoro-3-methoxyphenyl)-4-(3-hydroxy-3-(trifluoromethyl)azetidin-1-yl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)imidazo[1,2-a]pyrazin-6-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Into a flask were placed 3 -(trifluoromethyl)azetidin-3 -ol hydrochloride (154 mg, 0.87 mmol) in THF (3 mL) and Et3N (0.13 mL, 0.93 mmol) and the mixture was stirred at RT for 15 mm. The solid was filtered out and the filtrate was added into a 5-mL microwave vial, followed by the addition of the intermediate from Step B (165 mg, 0.29 mmol). The mixture was irradiated with microwave radiation at 150 C for 40 mm, then concentrated in vacuo. The residue was purified by column chromatography with EtOAc/petroleum ether (50-100%) and then by Prep-HPLC with water (10% ammoniumbicarbonate)/MeCN 0-50% to afford the racemic title compound. The racemic material was resolved using Prep-Chiral-HPLC Column (R,R)WHELK-01 5/100 Kromasil to afford isomers A (faster eluting) and B (slower eluting) of the title compound.
  • 14
  • [ 848192-96-1 ]
  • methyl 3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazole-5-carboxylate [ No CAS ]
  • 5-(4-chlorophenyl)-2-({5-[3-hydroxy-3-(trifluoromethyl)azetidine-1-carbonyl]-1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
91% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 65℃; for 2h;Microwave irradiation; A solution of methyl 3-( { 3-(4-chlorophenyl)-5-oxo-4- [(2S)-3,3,3-trifluoro-2-hydroxypropyl] -4,5- dihydro- 1H- 1,2,4-triazol- l-yl }methyl)- 1-[3-(trifluoromethyl)pyridin-2-yl]- 1H- 1 ,2,4-triazole-5-carboxylate (150 mg, 253 pmol) in DMF (1.0 ml) was treated with 3-(trifluoromethyl)azetidin-3-ol-hydrogen chloride (225 mg, 1.27 mmol) and N,N-diisopropylethylamine (260 p1, 1.5 mmol)and stirred 2 h at 65C under microwave irradiation. The reaction mixture was diluted with ethyl acetate and washed with an aqueous hydrochloric acid solution (iN). The aqueous phase was extracted 3 times with ethyl acetate and the combined organic layers were evaporated. The residue was purified by preparative HPLC (Method 11) and evaporated. Second purification bypreparative HPLC (Method 11) afforded 163 mg (91 % of th.) of the title compound.LC-MS (Method 2): R = 1.88 mm; MS (ESIpos): m/z = 701.1 [M+H]?H-NMR (400 MHz , DMSO-d6) oe [ppm]: 8.87 (d, 1H), 8.53 (dd, 1H), 7.92 (dd, 1H), 7.78-7.52 (m, 5H), 6.87 (d, 1H), 5.3 1-5.12 (m, 2H), 4.75 (br d, 1H), 4.55 (br d, 1H), 4.37-4.19 (m, 2H), 4.07-3.94 (m, 2H), 3.9 1-3.79 (m, 1H).
  • 15
  • [ 848192-96-1 ]
  • [ 1446507-68-1 ]
  • 3-trifluoromethyl-1-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-(2-(trifluoromethyl)pyridin-4-yl-1,3,5-triazin-2-yl))azetidin-3-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium carbonate; In tetrahydrofuran; for 16h;Reflux; 4-Chloro-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5- triazin-2-amine (420 mg, 1.00 mmol) prepared in step 4 of Example 1 was added to 10 mL of tetrahydrofuran, and <strong>[848192-96-1]3-trifluoromethyl azetidin-3-ol hydrochloride</strong> (143 mg, 1.22 mmol) and sodium carbonate (212 mg, 2.02 mmol) were added. The mixture was heated under reflux and reacted for 16 h, and then cooled. The resultant solution was filtered by suction, and silica gel was added to the filtrate to make a mixture for chromatography. The resultant mixture was purified by column chromatography to give the title compound. 1H NMR (300MHz, DMSO-d6): delta 10.89 (s, 1H), 8.66 (d, 2H), 8.58 (d, 1H), 8.33 (t, 1H), 8.12 (d, 1H), 7.99 (d, 1H), 7.60 (s, 1H), 4.50 (d, 2H), 4.27 (d, 2H). ES: m/z 526.1 [M+H]+.
  • 16
  • [ 848192-96-1 ]
  • (5RS)-2-(4-methylbenzyl)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylic acid [ No CAS ]
  • (5RS)-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]carbonyl}-2-(4-methylbenzyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
68% With pyridine; HATU; In N,N-dimethyl-formamide; at 20℃; Example 131 (5RS)-[3-Hydroxy-3-(trifluoromethyl)azetidin-1-yl]carbonyl}-2-(4-methylbenzyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (Racemate) (5RS)-2-(4-Methylbenzyl)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylic Acid (Racemate) (150 mg, 522 mumol) was initially charged together with <strong>[848192-96-1]3-(trifluoromethyl)azetidin-3-ol hydrochloride</strong> (97.3 mg, 548 mumol) in pyridine/DMF (5/1) (3.0 ml) at room temperature. Subsequently, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (218 mg, 574 mumol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the residue was purified via preparative HPLC (Chromatorex C18, 10 mum, 125 mm*30 mm; eluent: acetonitrile/water gradient). The product-containing fractions were concentrated under reduced pressure, and 147 mg (68% of theory) of the title compound were obtained. LC-MS (Method 4): Rt=0.76 min; MS (ESIpos): m/z=411 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: -0.008 (0.49), 0.008 (0.45), 1.704 (1.35), 1.715 (1.20), 2.019 (0.55), 2.027 (0.58), 2.036 (0.57), 2.271 (16.00), 2.518 (0.75), 2.567 (1.09), 2.575 (1.21), 2.587 (1.01), 2.598 (0.45), 3.857 (0.57), 3.885 (0.67), 3.933 (0.61), 3.961 (0.86), 4.081 (1.14), 4.108 (0.81), 4.164 (0.94), 4.192 (1.19), 4.222 (0.65), 4.351 (0.56), 4.376 (0.89), 4.454 (1.17), 4.479 (0.74), 4.558 (0.60), 4.573 (0.90), 4.585 (0.67), 4.593 (0.61), 4.609 (0.77), 4.621 (1.19), 4.647 (0.77), 4.741 (2.29), 4.747 (2.82), 4.754 (4.40), 7.103 (0.62), 7.125 (13.60), 7.145 (0.56), 7.545 (1.60).
  • 17
  • [ 848192-96-1 ]
  • 6-[(pyrazin-2-yl)({5-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]thiophen-2-yl}methyl)amino]pyridazine-3-carboxylic acid [ No CAS ]
  • 1-{6-[(pyrazin-2-yl)({5-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]thiophen-2-yl}methyl)amino]pyridazine-3-carbonyl}-3-(trifluoromethyl)azetidin-3-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
63% With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 2h; To a solution of compound 1 (19.3 mg, 0.0429 mmol, 1.0 eq) in DMF (1 mL) was added A/,A/-diisopropylethylamine (30.0 pL, 0.172 mmol, 4.0 eq), HATU (24.5 mg, 0.0644 mmol, 1.5 eq) and 2-oxa-6-azaspiro[3.4]octane oxalate (2) (13.6 mg, 0.0859 mmol, 2.0 eq). The reaction was stirred at room temperature for 19 h then diluted with EtOAc (10 mL), washed with 1 M HCI (2 x 10 mL), H20 (10 mL), NaHC03 (2 x 10 mL), H20 again (10 mL) and brine (10 mL), dried over MgS04, filtered and concentrated in vacuo. Purification by silica gel chromatography using hexane/EtOAcMeOH (1 :0:0 - 0:1 :0 - 0:94:6) yielded compound FJ as an off-white solid (18.8 mg, 80%). (1281) LCMS (ES) 544.9 [M+Hf. (1282) 1H NMR (300MHz, DMSO-cf6), d: Two rotamers in 1 :1 ratio; 8.87 (dd, J=6.6, 1.3 Hz, 2 x 1 H), 8.43-8.49 (m, 2 x 1 H), 8.34-8.39 (m, 2 x 1 H), 7.78-7.91 (m, 2 x 2H), 7.75 (t, J=3.9 Hz, 2 x 1 H), 7.33 (dd, J=5.0, 3.9 Hz, 2 x 1 H), 5.77 (app. d, J=5.8 Hz, 2 x 2H), 4.63 (d, J=6.0 Hz, 2H), 4.43-4.56 (m, 2H + 4H), 4.04 (s, 1 H), 3.74- (1283) 3.84 (m, 4H), 3.56 (t, J=7.1 Hz, 2H), 2.19 (m, 2 x 2H). (1284) 19F NMR (282MHz, DMSO-cf6), d: Two rotamers in 1 : 1 ratio -64.79 (s, 3F), -64.79 (s, 3F).
  • 18
  • [ 848192-96-1 ]
  • 6-[(pyrazin-2-yl)({5-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]thiophen-2-yl}methyl)amino]pyridazine-4-carboxylic acid [ No CAS ]
  • 1-{6-[(pyrazin-2-yl)({5-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]thiophen-2-yl}methyl)amino]pyridazine-4-carbonyl}-3-(trifluoromethyl)azetidin-3-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
77% To a solution of acid 1 (50 mg, 0.1 1 mmol) in DMF (1 ml_) was added N- methylmorpholine (49 pL, 0.45 mmol) followed by PyBOP (87 mg, 0.17 mmol). The reaction mixture was stirred for 1 h at rt before addition of 3- (trifluoromethyl)azetidin-3-ol hydrochloride (40 mg, 0.22 mmol). After 26 h the reaction mixture was diluted with EtOAc (30 ml_), washed with HCI solution (5%, 3 x 10 ml_), water (10 ml_), sodium bicarbonate solution (5%, 3 x 5 ml_), and brine (10 ml_), before being dried over MgS04, filtered and concentrated in vacuo. Purification by flash column chromatography with hexanes/EtOAc (1 :0 to 0:1 ) afforded GD as light peach-coloured solids (49 mg, 77%). (1460) LCMS (ES): Found 572.8 [M+Hf. (1461) 1H NMR (300 MHZ, DMSO-cf6) d: 9.08 (d, J=1.7 Hz, 1 H), 8.84 (d, J=1.3 Hz, 1 H), 8.39 (dd, J=2.5, 1.4 Hz, 1 H), 8.33 (d, J=2.6 Hz, 1 H), 7.90 (d, J=1.7 Hz, 1 H), 7.74 (d, J=3.6 Hz, 1 H), 7.52 (s, 1 H), 7.31 (d, J=3.8 Hz, 1 H), 5.78 (s, 2H), 4.64 (d, J=10.2 Hz, 1 H), 4.26-4.40 (m, 2H), 4.07 (br d, J=1 1 .3 Hz, 1 H). (1462) 19F NMR (282 MHz, DMSO-cf6) d: -64.81 (s, 3F), -82.59 (s, 3F).
  • 19
  • [ 848192-96-1 ]
  • C17H10F3N7O3S [ No CAS ]
  • 1-{3-[(pyrazin-2-yl)({5-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]thiophen-2-yl}methyl)amino]pyrazine-2-carbonyl}-3-(trifluoromethyl)azetidin-3-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
19% (1574) To a stirred solution of 3-[(pyrazin-2-yl)({5-[5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl]thiophen-2-yl}methyl)amino]pyrazine-2-carboxylic acid (0.049 g, 0.1 mmol) in DMF (5 ml_) under an argon atmosphere at rt was added CDI (0.019 g, 0.12 mmol). The reaction mixture was stirred for 30 min and then 3- (1575) (trifluoromethyl)azetidin-3-ol hydrochloride (0.039 g, 0.22 mmol) was added, followed by N,N-diisopropylethylamine (0.028 g, 0.22 mmol) The reaction mixture was stirred overnight and then poured into saturated Na2C03 solution (10 ml_) and extracted with CH2CI2 (10 ml_) twice. The combined organic fractions were dried over MgS04, filtered and the solvent removed by evaporation in vacuo. Purification by silica gel column chromatography, EtOAc elution, yielded GQ (0.01 1 g, 19%). (1576) LCMS (ESI): Found 572.8 [M+Hf. (1577) 1H NMR (300 MHz, DMSO-cf6) d: 8.71 (s, 1 H), 8.68 (d, J=2.4 Hz, 1 H), 8.42 (d, J=2.4 Hz, 1 H), 8.23 (d, J=2.6 Hz, 1 H), 8.17 (s, 1 H), 7.75 (d, J=3.8 Hz, 1 H), 7.56 (s, 1 H), 7.42 (d, J=3.8 Hz, 1 H), 5.77 (d, J=16.8 Hz, 1 H), 5.65 (d, J=16.6 Hz, 1 H), (1578) 4.54 (d, J=10.5 Hz, 1 H), 4.28 (br d, J=10.4 Hz, 1 H), 3.97 (d, J=11.1 Hz, 1 H), (1579) 3.55 (br d, J=11.5 Hz, 1 H). (1580) 19F NMR (282 MHz, DMSO-cfe), d: -82.48 (s, 3F), -64.79 (s, 3F).
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